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【结 构 式】

【分子编号】16640

【品名】Ethyl 2-bromoacetate; Ethyl bromoacetate

【CA登记号】105-36-2

【 分 子 式 】C4H7BrO2

【 分 子 量 】167.00238

【元素组成】C 28.77% H 4.22% Br 47.85% O 19.16%
与该中间体有关的原料药合成路线共 87 条
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合成路线1

该中间体在本合成路线中的序号：(II)

The reaction of 2-hydroxy-4-(3-methyl-2-butenyloxy)acetophenone (I) with ethyl bromoacetate (II) by means of KOH in acetone gives 2-ethoxycarbonylmethoxy-4-(3-methyl-2-butenyloxy)acetophenone (III), which is then condensed with 4-(3-methyl-2-butenyloxy)benzaldehyde (IV) by means of KOH in ethanol.

参考文献 中间体
合成目标
【1】 Grau, M.; Castaner, J.; Blancafort, P.; Serradell, M.N.; SU-88. Drugs Fut 1983, 8, 6, 513.
【2】 Kyogoku, K.; Hatayama, K.; Yokomori, S.; Sawada, J.; Tanaka, I. (Taisho Pharmaceutical Co., Ltd.); 2-(Carboxymethoxy)chalcones. DE 2705603; ES 455620; FR 2340924; GB 1523241; JP 52097950; US 4085135 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 16637 1-[2-hydroxy-4-[(3-methyl-2-butenyl)oxy]phenyl]-1-ethanone C13H16O3 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 36017 ethyl 2-[2-acetyl-5-[(3-methyl-2-butenyl)oxy]phenoxy]acetate C17H22O5 详情 详情
(IV) 19019 4-[(3-methyl-2-butenyl)oxy]benzaldehyde C12H14O2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(V)

The nitration of 1,2,3-trichlorobenzene (I) with concentrated HNO3 gives 2,3,4-trichloronitrobenzene (II), which by reaction with cuprous cyanide in hot pyridine is converted to 2,3-dichloro-6-nitrobenzonitrile (III). The reduction of (III) with borane in THF yields 2,3-dichloro-6-nitrobenzylamine (IV), which by reaction with ethyl bromoacetate (V) by means of triethylamine in refluxing dioxane affords ethyl N-(2,3-dichloro-6-nitrobenzyl)glycinate (VI). The reduction of (VI) with SnCl2 in concentrated HCl gives ethyl N-(6-amino-2,3-dichlorobenzyl)glycinate (VII), which is cyclized with cyanogen bromide (VIII) in toluene affording ethyl 5,6-dichloro-3,4-dihydro-2-(1H)-iminoquinazoline-3-acetate (IX). Finally, this compound is submitted to a new cyclization by means of triethylamine in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Jenks, T.A.; Beverung, W.N.Jr.; Partyka, R.A. (Bristol-Myers Squibb Co.); Preparation of 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one. CA 1137474 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 29082 1,2,3-trichlorobenzene 87-61-6 C6H3Cl3 详情 详情
(II) 29083 1,2,3-trichloro-4-nitrobenzene 17700-09-3 C6H2Cl3NO2 详情 详情
(III) 29084 2,3-dichloro-6-nitrobenzonitrile C7H2Cl2N2O2 详情 详情
(IV) 29085 (2,3-dichloro-6-nitrophenyl)methanamine 70380-49-3 C7H6Cl2N2O2 详情 详情
(V) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VI) 29086 ethyl 2-[(2,3-dichloro-6-nitrobenzyl)amino]acetate C11H12Cl2N2O4 详情 详情
(VII) 29087 ethyl 2-[(6-amino-2,3-dichlorobenzyl)amino]acetate C11H14Cl2N2O2 详情 详情
(VIII) 28017 cyanic bromide；cyanogen bromide 506-68-3 CBrN 详情 详情
(IX) 29088 ethyl 2-[5,6-dichloro-2-imino-1,4-dihydro-3(2H)-quinazolinyl]acetate C12H13Cl2N3O2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(G)

The condensation of 2,3-dichloroanisole (I) with isobutyryl chloride (D) by means of AlCl3 in CH2Cl2 gives 2',3'-dichloro-4'-methoxyisobutyrophenone (VII), which is brominated with Br2 in acetic acid yielding 2-bromo-2',3'-dichloro-4'-methoxyisobutyrophenone (VIII). The dehydrobromination of (VIII) with LiBr in DMF affords (IX), which is cyclized with H2SO4 giving 6,7-dichloro-2-methyl-5-methoxy-1-indanone (X). The phenylation of (X) with diphenyliodonium chloride (E) and potassium tert-butoxide in tert-butanol gives 6,7-dichloro-2-methyl-2-phenyl-5-methoxy-1-indanone (XI), which is demethylated with pyridine hydrochloride at 190 C yielding 6,7-dichloro-2-methyl-2-phenyl-5-hydroxy-1-indanone (XII). Finally, (XII) is treated first with ethyl bromoacetate (G) and K2CO3 in DMF, and then with KOH in hot water-methanol. The phenol (XII) can also be treated with chloroacetonitrile (H) and K2CO3 in acetone to give 6,7-dichloro-2-methyl-2-phenyl-1-oxo-5-indanyloxyacetonitrile (XIII), which is finally hydrolyzed with H2SO4 in acetic acid. The phenol (XII) can also be condensed with diethyl bromomalonate (F) by means of NaH in dimethoxyethane giving diethyl 6,7-dichloro-2-methyl-2-phenyl-1-oxo-5-indanyloxymalonate (XIV), which is hydrolyzed with Na2CO3 in refluxing ethanol yielding 6,7-dichloro-2-methyl-2-phenyl-1-oxo-5-indanyloxymalonic acid (XV). Finally, this acid is decarboxylated by heating at 150 C.

参考文献 中间体
合成目标
【1】 Cragoe, E.J. Jr.; Woltersdorf, O.W. Jr. (Merck & Co., Inc.); Substituted indanones. DE 2448454; ES 430900; FR 2247218; GB 1474459 .
【2】 Castaner, J.; Chatterjee, S.S.; MK 196. Drugs Fut 1977, 2, 3, 179.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(H) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(D) 14932 isobutyryl chloride; 2-methylpropanoyl chloride 79-30-1 C4H7ClO 详情 详情
(G) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(F) 35647 diethyl 2-bromomalonate 685-87-0 C7H11BrO4 详情 详情
(E) 40097 diphenyliodonium chloride 1483-72-3 C12H10ClI 详情 详情
(I) 40081 1,2-dichloro-3-methoxybenzene; 2,3-dichlorophenyl methyl ether 1984-59-4 C7H6Cl2O 详情 详情
(VII) 40088 1-(2,3-dichloro-4-methoxyphenyl)-2-methyl-1-propanone C11H12Cl2O2 详情 详情
(VIII) 40089 2-bromo-1-(2,3-dichloro-4-methoxyphenyl)-2-methyl-1-propanone C11H11BrCl2O2 详情 详情
(IX) 40090 1-(2,3-dichloro-4-methoxyphenyl)-2-methyl-2-propen-1-one C11H10Cl2O2 详情 详情
(X) 40091 6,7-dichloro-5-methoxy-2-methyl-1-indanone C11H10Cl2O2 详情 详情
(XI) 40092 6,7-dichloro-5-methoxy-2-methyl-2-phenyl-1-indanone C17H14Cl2O2 详情 详情
(XII) 40093 6,7-dichloro-5-hydroxy-2-methyl-2-phenyl-1-indanone C16H12Cl2O2 详情 详情
(XIII) 40094 2-[(6,7-dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]acetonitrile C18H13Cl2NO2 详情 详情
(XIV) 40095 diethyl 2-[(6,7-dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]malonate C23H22Cl2O6 详情 详情
(XV) 40096 2-[(6,7-dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]malonic acid C19H14Cl2O6 详情 详情

合成路线4

该中间体在本合成路线中的序号：(IV)

The reaction of 4-(1H-imidazol-1-yl)acetophenone (I) with dimethyl carbonate (III) by means of NaH in THF gives methyl 4-(1H-imidazol-1-yl)-beta-oxobenzenepropanoate (III), which by condensation with ethyl bromoacetate (IV) by means of NaH in THF is converted into ethyl 4-(1H-imidazol-1-yl-beta-(methoxycarbonyl)-gamma-oxobenzenebutanoate (V). Hydrolytic decarboxylation of (VI) in refluxing 6N HCl yields 4-(1H-imidazol-1-yl)-gamma-oxobenzenebutanoic acid (VI), which is finally cyclized with hydrazine in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Sircar, I.; Bristol, J.A.; Substituted 4,5-dihydro-6-(substituted)-phenyl-3(2H)-pyridazinones and 6-(substituted)phenyl-3(2H)-pyridazinones. CA 1190548; DD 208615; EP 0075436 .
【2】 Serradell, M.N.; Castaner, J.; CI-914. Drugs Fut 1984, 9, 4, 256.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 17772 4'-(Imidazol-1-yl)acetophenone; 1-[4-(1H-imidazol-1-yl)phenyl]-1-ethanone 10041-06-2 C11H10N2O 详情 详情
(II) 34197 dimethyl carbonate 616-38-6 C3H6O3 详情 详情
(III) 34198 methyl 3-[4-(1H-imidazol-1-yl)phenyl]-3-oxopropanoate C13H12N2O3 详情 详情
(IV) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(V) 34199 4-ethyl 1-methyl 2-[4-(1H-imidazol-1-yl)benzoyl]succinate C17H18N2O5 详情 详情
(VI) 34200 4-[4-(1H-imidazol-1-yl)phenyl]-4-oxobutyric acid C13H12N2O3 详情 详情

合成路线5

该中间体在本合成路线中的序号：(A)

The silylation of 3-hydroxy-4-aminobutyric acid (VII) with bistrimethylsilyl amine gives 3-(trimethylsilyloxy)-4-aminobutyric acid (VIII), which is cyclized to 4-(trimethylsilyloxy)-2-pyrrolidinone (IX) by heating. The treatment of (IX) with ethyl bromoacetate (A) affords ethyl 4-(trimethylsilyloxy)pyrrolidine-2-one-1-acetate (X), which by desilylation with HCl gives ethyl 4-hydroxypyrrolidine-2-one-1-acetate (VI). Finally, this compound is treated with ammonia in methanol.

参考文献 中间体
合成目标
【1】 Banfi, S.; et al. (ISF SpA); Preparation of pyrrolidine and pyrrolidin-2-one derivatives. DE 2758937; DE 2758939; ES 466856; FR 2380257; GB 1588075; JP 53101367; US 4173569 .
【2】 de Angelis, L.; Blancafort, P.; Serradell, M.N.; Castaner, J.; Oxiracetam. Drugs Fut 1980, 5, 8, 405.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VI) 32716 Ethyl 2-(4-hydroxy-2-oxo-1-pyrrolidinyl)acetate; Ethyl 4-hydroxypyrrolidine-2-one-1-acetate C8H13NO4 详情 详情
(VII) 32717 4-Amino-3-hydroxybutyric acid; 3-Hydroxy-4-aminobutyric acid 352-21-6 C4H9NO3 详情 详情
(VIII) 32718 4-Amino-3-[(trimethylsilyl)methyl]butyric acid; 3-(Trimethylsilyloxy)-4-aminobutyric acid C8H19NO2Si 详情 详情
(IX) 32719 4-(Trimethylsilyloxy)-2-pyrroIidinone C8H17NOSi 详情 详情
(X) 32720 Ethyl 2-[2-oxo-4-[(trimethylsilyl)methyl]-1-pyrrolidinyl]acetate; ethyl 4-(Trimethylsilyloxy)pyrrolidine-2-one-1-acetate C12H23NO3Si 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

The reaction of aniline (I) with ethyl bromoacetate (II) by means of triethylamine in benzene gives ethyl phenylaminoacetate (III), which is nitrosated with NaNO2 and HCl in water to yield ethyl N-nitrosophenylaminoacetate (IV). The reduction of (IV) with Zn in ethanol-water-acetic anhydride affords ethyl N1-phenylhydrazinoacetate (V), which is condensed with benzil (A) by means of HCl-sodium acetate in refluxing ethanol-water to yield ethyl alpha-benzoylbenzylidene-N1-phenylhydrazinoacetate (VI). The cyclization of (VI) by means of sodium ethoxide in refluxing ethanol gives 1,3,4-triphenylpyrazole-5-carboxylic acid (VII), which is reduced with LiAlH4 in ether-THF to produce 1,3,4-triphenyl-5-(hydroxymethyl)pyrazole (VIII). The reaction of (VIII) with SOCl2 in refluxing chloroform yields 1,3,4-triphenyl-5-(chloromethyl)pyrazole (IX), which by reaction with NaCN in hot DMSO is converted into 1,3,4-triphenylpyrazole-5-acetonitrile (X). Finally, this compound is hydrolyzed by means of NaOH in refluxing aqueous ethanol.

参考文献 中间体
合成目标
【1】 Gueremy, C.; Renault, C.; US 3984431 .
【2】 Castaner, J.; Arrigoni, Martelli, E.; Isofezolac. Drugs Fut 1980, 5, 1, 21.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 39056 Dibenzoyl; benzil 134-81-6 C14H10O2 详情 详情
(I) 12294 Aniline; Phenylamine 62-53-3 C6H7N 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 25701 ethyl 2-anilinoacetate 2216-92-4 C10H13NO2 详情 详情
(IV) 39055 　 C10H12N2O3 详情 详情
(V) 25702 ethyl 2-(1-phenylhydrazino)acetate C10H14N2O2 详情 详情
(VI) 39057 ethyl (Z)-4-oxo-3,4-diphenyl-2-(1-phenylhydrazino)-2-butenoate C24H22N2O3 详情 详情
(VII) 39058 1,3,4-triphenyl-1H-pyrazole-5-carboxylic acid C22H16N2O2 详情 详情
(VIII) 39059 (1,3,4-triphenyl-1H-pyrazol-5-yl)methanol C22H18N2O 详情 详情
(IX) 39060 5-(chloromethyl)-1,3,4-triphenyl-1H-pyrazole C22H17ClN2 详情 详情
(X) 39061 2-(1,3,4-triphenyl-1H-pyrazol-5-yl)acetonitrile C23H17N3 详情 详情

合成路线7

该中间体在本合成路线中的序号：(IX)

A new synthesis of CGS-14824A is given: The reaction of 3-bromo-1-phenylpropane (I) with KCN gives 4-phenylbutyronitrile (II), which is hydrolyzed to the corresponding butyric acid (III). The cyclization of (III) with polyphosphoric acid affords 1-tetralone (IV), which is brominated to 2-bromo-1-tetralone (V) and treated with hydroxylamine to give the oxime (VI). The Beckman rearrangement of (VI) yields 3-bromo-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is treated with sodium azide to afford the azide derivative (VIII). The N-alkylation of (VIII) with ethyl bromoacetate (IX) by means of KOH and tetrabutylammonium bromide in THF gives the N-alkylated azide (X), which is reduced by catalytic hydrogenation to the corresponding amine (XI). The hydrolysis of the ester group of (XI) with NaOH yields the free acetic acid derivative (XII), which is finally reductocondensed with ethyl 2-oxo-4-phenylbutyrate (XIII) by means of sodium cyanoborohydride.

参考文献 中间体
合成目标
【1】 Chaudhuri, N.K.; Patera, R.; Markus, B.; Sung, M.-S.; Synthesis of 14C-labeled 3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid hydrochloride ([14C]CGS 14824A). J Label Compd Radiopharm 1987, 24, 10, 1177-84.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 20884 1-(3-bromopropyl)benzene 637-59-2 C9H11Br 详情 详情
(II) 20885 4-phenylbutanenitrile 2046-18-6 C10H11N 详情 详情
(III) 20886 Benzenebutyric acid; 4-Phenylbutyric acid 1821-12-1 C10H12O2 详情 详情
(IV) 20720 3,4-dihydro-1(2H)-naphthalenone 529-34-0 C10H10O 详情 详情
(V) 20721 2-bromo-3,4-dihydro-1(2H)-naphthalenone C10H9BrO 详情 详情
(VI) 20722 2-bromo-3,4-dihydro-1(2H)-naphthalenone oxime C10H10BrNO 详情 详情
(VII) 20723 3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one C10H10BrNO 详情 详情
(VIII) 20891 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one C10H10N4O 详情 详情
(IX) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(X) 20893 ethyl 2-(3-azido-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate C14H16N4O3 详情 详情
(XI) 20894 ethyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate 109010-60-8 C14H18N2O3 详情 详情
(XII) 20895 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid C12H14N2O3 详情 详情
(XIII) 20896 Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester 64920-29-2 C12H14O3 详情 详情

合成路线8

该中间体在本合成路线中的序号：(II)

The reaction of 4-[2-(acetylamino)ethyl]phenol (I) with ethyl bromoacetate (II) by means of K2CO3 in refluxing butanone gives 4-[2-(acetylamino)ethyl]phenoxyacetic acid ethyl ester (III), which is hydrolyzed with refluxing aqueous HCl to 4-(2-aminoethyl)phenoxyacetic acid (IV). Finally, this compound is acylated with benzenesulfonyl chloride (V) by means of K2CO3 in hot water.

参考文献 中间体
合成目标
【1】 Witte, E.C.; Wolff, H.P.; Thiel, M.; Stegmeier, K.; Roesch, E.; Phenoxyalkylcarboxylic acid compounds and thrombocyte-aggregation inhibition. DE 2809377; EP 0004011; ES 478228; JP 54122250; US 4258058 .
【2】 Karup, G.L.; Preikschat, H.F. (GEA A/S Farmaceutisk Fabrik); Process for the preparation of 1,4-dihydropyridines and cpds. used in this process. WO 9925688 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 19989 N-(4-hydroxyphenethyl)acetamide C10H13NO2 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 34332 ethyl 2-[4-[2-(acetamido)ethyl]phenoxy]acetate C14H19NO4 详情 详情
(IV) 34333 2-[4-(2-aminoethyl)phenoxy]acetic acid C10H13NO3 详情 详情
(V) 14713 benzenesulfonyl chloride 98-09-9 C6H5ClO2S 详情 详情

合成路线9

该中间体在本合成路线中的序号：(A)

4,6-Dimethyl-7-acetylumbelliforone (4,6-dimethyl-7-acetoxycoumarin) (I) is submitted to the Fries' rearrangement, obtaining the 4,6-dimethyl-8-acetylumbelliferone (II); the latter (II) is condensed with ethylbromoacetate (A) and the resulting ethyl [(4,6-dimethyl-8-acetyl-7-coumarinyl)oxy]acetate (III) is hydrolyzed by refluxing with 5% KOH aqueous methanolic solution; from this solution, acidified with HCl, the [(4,6-dimethyl-8-acetyl-7-coumarinyl)oxy]acetic acid (IV) is extracted with EtOAc and purified by crystallization (EtOAc / n-hexane). Cyclization of (IV), carried out by refluxing in Ac2O in the presence of anhydrous natrium acetate, is accompanied by an almost complete decarboxylation of (V), yielding 4,6,4'-trimethylangelicin (TMA).

参考文献 中间体
合成目标
【1】 Guiotto, A.; et al.; 6-Methylangelicins: A new series of potential photochemotherapheutic agents for the treatment of psoriasis. J Med Chem 1984, 27, 8, 959.
【2】 Bordin, F.; Dall'Acqua, F.; Cristofolini, M.; Guiotto, A.; 4,6,4'-Trimethylangelicin. Drugs Fut 1985, 10, 4, 307.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(I) 29146 4,6-dimethyl-2-oxo-2H-chromen-7-yl acetate C13H12O4 详情 详情
(II) 29147 8-acetyl-7-hydroxy-4,6-dimethyl-2H-chromen-2-one C13H12O4 详情 详情
(III) 29148 ethyl 2-[(8-acetyl-4,6-dimethyl-2-oxo-2H-chromen-7-yl)oxy]acetate C17H18O6 详情 详情
(IV) 29149 2-[(8-acetyl-4,6-dimethyl-2-oxo-2H-chromen-7-yl)oxy]acetic acid C15H14O6 详情 详情
(V) 29150 4,6,9-trimethyl-2-oxo-2H-furo[2,3-h]chromene-8-carboxylic acid C15H12O5 详情 详情

合成路线10

该中间体在本合成路线中的序号：(IV)

The cyclization of alpha-bromo-4,4'-dimethoxidesoxybenzoin (I) with pyrrole-2-carbothioamide (II) in hot acetonitrile gives 4,5-bis(4-methoxyphenyl)-2-(pyrrol-2-yl)thiazole (III), which is then condensed with ethyl bromoacetate (IV) by means of NaOH and tetrabutylammonium bromide in refluxing dichloromethane - water.

参考文献 中间体
合成目标
【1】 Yoshino, K.; Seko, N.; Yokota, K.; Ito, K.; Tsukamoto, G. (Kanebo Pharmaceuticals, Ltd.); Novel 4,5-bis(4-methoxyphenyl)-2-(pyrrol-2-yl)thiazoles, process for the preparation thereof and pharmaceutical compsn. containing the same. EP 0159677; JP 1985222481; JP 1986033186; JP 1986200985; US 4659726 .
【2】 Prous, J.; Castaner, J.; KBT-3022. Drugs Fut 1991, 16, 2, 105.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 31235 2-bromo-1,2-bis(4-methoxyphenyl)-1-ethanone C16H15BrO3 详情 详情
(II) 31236 1H-pyrrole-2-carbothioamide C5H6N2S 详情 详情
(III) 31237 4,5-bis(4-methoxyphenyl)-2-(1H-pyrrol-2-yl)-1,3-thiazole; 4-[4-(4-methoxyphenyl)-2-(1H-pyrrol-2-yl)-1,3-thiazol-5-yl]phenyl methyl ether C21H18N2O2S 详情 详情
(IV) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情

合成路线11

该中间体在本合成路线中的序号：(II)

The reaction of phenol (I) with ethyl bromoacetate (II) by means of NaH in dimethoxyethane gives ethyl phenoxyacetate (III), which is condensed with dimethyl methylphosphonate (IV) by means of n-butyllithium in THF to afford dimethyl 2-oxo-3-phenoxypropylphosphonate (V). The Wittig condensation of (V) with (2'alpha-hydroxy-4'alpha-p-phenylbenzoyloxy-5'beta-ormylcyclopent-1'alpha-yl)acetic acid 1,2'-lactone (VI) by means of NaH in dimethoxyethane yields the ketonic lactone (VII), which is reduced with aluminum isopropoxide in refluxing toluene to give the hydroxy lactone (VIII). The hydrolysis of the protecting group of (VIII) with K2CO3 in methanol yields the dihydroxy lactone (IX), which is then protected with dihydropyran affording the bis(tetrahydropyranyloxy) compound (X). The reduction of the lactone group of (X) with diisobutylaluminum hydride in toluene yields the protected hemiacetal (XI), which is condensed with 4-pentinoic acid (XII) by means of LiCH3 in HMPT affording 6,9alpha-dihy-droxy-11alpha,15alpha-bistetrahydropyranyloxy-16-phenoxy-17,18,19,20-tetranorprost-4-yn-13-trans-enoic acid methyl ester (XIII) resulting from the methylation with CH2N2 of the acid intermediate.

参考文献 中间体
合成目标
【1】 Van Horn, A.R.; Garay, G.; Edwards, J.A. (Syntex (USA), Inc.); (dl)-16-Phenoxy- and 16-substituted phenoxy-9-keto prostatrienoic acid derivatives and processes for the production thereof. DE 2927715; EP 0008003; ES 482330; FR 2430939; GB 2025413; US 4178457 .
【2】 Muchowski, J.M.; Fried, J.H. (Syntex (USA), Inc.); 16-Phenoxy and 16-substituted phenoxy-prostatrienoic acid derivatives. DE 2627910; ES 449162; FR 2315263; US 3985791 .
【3】 Blancafort, P.; Castaner, J.; Serradell, M.N.; Hillier, K.; RS-84,135. Drugs Fut 1982, 7, 11, 812.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 23540 Phenol 108-95-2 C6H6O 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 32040 ethyl 2-phenoxyacetate 2555-49-9 C10H12O3 详情 详情
(IV) 13607 dimethyl methylphosphonate 756-79-6 C3H9O3P 详情 详情
(V) 32041 dimethyl 2-oxo-3-phenoxypropylphosphonate 40665-68-7 C11H15O5P 详情 详情
(VI) 32042 (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C21H18O5 详情 详情
(VII) 32043 (3aR,4R,5R,6aS)-2-oxo-4-[(E)-3-oxo-4-phenoxy-1-butenyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C30H26O6 详情 详情
(VIII) 32044 (3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C30H28O6 详情 详情
(IX) 32045 (3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]hexahydro-2H-cyclopenta[b]furan-2-one C17H20O5 详情 详情
(X) 32046 (3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-one C29H40O7 详情 详情
(XI) 32047 (3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ol C29H42O7 详情 详情
(XII) 32048 4-pentynoic acid 6089-09-4 C5H6O2 详情 详情
(XIII) 32049 methyl 6-hydroxy-7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4-heptynoate C35H50O9 详情 详情

合成路线12

该中间体在本合成路线中的序号：(VI)

1) The cyclization of 2-(benzyloxycarbonylamino)-4-chlorobenzoic acid (I) by means of PBr3 in refluxing ethyl ether gives 7-chloro-2H-3,1-benzoxazine-2,4(1H)-dione (II), which is condensed with 4-bromo-2-fluorobenzylamine (III) in refluxing THF yielding 2-amino-N-(4-bromo-2-fluorobenzyl)-4-chloro-benzamide (IV). The cyclization of (IV) with carbonyldiimidazole (CDI) in refluxing dioxane affords 3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione (V), which is alkylated with ethyl bromoacetate (VI) by means of NaH in DMF to give ethyl 3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-acetate (VII). Finally, this compound is hydrolyzed with NaOH in refluxing methanol.

参考文献 中间体
合成目标
【1】 Hashimoto, M.; Oku, T.; Ito, Y.; Namiki, T.; Sawada, K.; Kasahara, C.; Baba, Y. (Fujisawa Pharmaceutical Co., Ltd.); New quinazoline derivs., process for their production and pharmaceutical compsns. comprising them. EP 0218999; JP 1987096476; JP 1989125322; JP 1989131164; US 4734419; US 4883800 .
【2】 Prous, J.; Castaner, J.; FR-74366. Drugs Fut 1989, 14, 1, 26.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 19558 2-[[(benzyloxy)carbonyl]amino]-4-chlorobenzoic acid C15H12ClNO4 详情 详情
(II) 19559 4-Chloroisatoic anhydride; 7-chloro-2H-3,1-benzoxazine-2,4(1H)-dione C8H4ClNO3 详情 详情
(III) 19560 (4-bromo-2-fluorophenyl)methanamine; 4-bromo-2-fluorobenzylamine 112734-22-2 C7H7BrFN 详情 详情
(IV) 19561 2-amino-N-(4-bromo-2-fluorobenzyl)-4-chlorobenzamide C14H11BrClFN2O 详情 详情
(V) 19562 3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4(1H,3H)-quinazolinedione C15H9BrClFN2O2 详情 详情
(VI) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VII) 19564 ethyl 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-3,4-dihydro-1(2H)-quinazolinyl]acetate C19H15BrClFN2O4 详情 详情

合成路线13

该中间体在本合成路线中的序号：(VI)

2) The condensation of 4-chloro-2-nitrobenzoic acid (VIII) with benzylamine (III) by means of CDI in THF gives the corresponding amide (IX), which is reduced with Fe in acetic acid to the 2-aminobenzamide (IV). The cyclization of (IV) with carbonyldiimidazole (CDI) in refluxing dioxane affords 3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione (V), which is alkylated with ethyl bromoacetate (VI) by means of NaH in DMF to give ethyl 3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-acetate (VII). Finally, this compound is hydrolyzed with NaOH in refluxing methanol.

参考文献 中间体
合成目标
【1】 Hashimoto, M.; Oku, T.; Ito, Y.; Namiki, T.; Sawada, K.; Kasahara, C.; Baba, Y. (Fujisawa Pharmaceutical Co., Ltd.); New quinazoline derivs., process for their production and pharmaceutical compsns. comprising them. EP 0218999; JP 1987096476; JP 1989125322; JP 1989131164; US 4734419; US 4883800 .
【2】 Prous, J.; Castaner, J.; FR-74366. Drugs Fut 1989, 14, 1, 26.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 19560 (4-bromo-2-fluorophenyl)methanamine; 4-bromo-2-fluorobenzylamine 112734-22-2 C7H7BrFN 详情 详情
(IV) 19561 2-amino-N-(4-bromo-2-fluorobenzyl)-4-chlorobenzamide C14H11BrClFN2O 详情 详情
(V) 19562 3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4(1H,3H)-quinazolinedione C15H9BrClFN2O2 详情 详情
(VI) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VII) 19564 ethyl 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-3,4-dihydro-1(2H)-quinazolinyl]acetate C19H15BrClFN2O4 详情 详情
(VIII) 19565 4-chloro-2-nitrobenzoic acid 6280-88-2 C7H4ClNO4 详情 详情
(IX) 19566 N-(4-bromo-2-fluorobenzyl)-4-chloro-2-nitrobenzamide C14H9BrClFN2O3 详情 详情

合成路线14

该中间体在本合成路线中的序号：(VI)

3) The alkylation of 2-amino-4-chlorobenzamide (X) with ethyl bromoacetate (VI) by means of K2CO3 in hot DMF gives ethyl 2-(2-carbamoyl-4-chlorophenylamino)acetate (XI), which is cyclized with CDI at 150 C yielding ethyl 7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-acetate (XII). Finally, this compound is alkylated with 4-bromo-2-fluorobenzyl chloride (XIII) by means of NaH in DMF to afford quinazoline (VII) already obtained.

参考文献 中间体
合成目标
【1】 Hashimoto, M.; Oku, T.; Ito, Y.; Namiki, T.; Sawada, K.; Kasahara, C.; Baba, Y. (Fujisawa Pharmaceutical Co., Ltd.); New quinazoline derivs., process for their production and pharmaceutical compsns. comprising them. EP 0218999; JP 1987096476; JP 1989125322; JP 1989131164; US 4734419; US 4883800 .
【2】 Prous, J.; Castaner, J.; FR-74366. Drugs Fut 1989, 14, 1, 26.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VII) 19564 ethyl 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-3,4-dihydro-1(2H)-quinazolinyl]acetate C19H15BrClFN2O4 详情 详情
(X) 19567 2-amino-4-chlorobenzamide C7H7ClN2O 详情 详情
(XI) 19568 ethyl 2-[2-(aminocarbonyl)-5-chloroanilino]acetate C11H13ClN2O3 详情 详情
(XII) 19569 ethyl 2-[7-chloro-2,4-dioxo-3,4-dihydro-1(2H)-quinazolinyl]acetate C12H11ClN2O4 详情 详情
(XIII) 19570 4-bromo-1-(chloromethyl)-2-fluorobenzene C7H5BrClF 详情 详情

合成路线15

该中间体在本合成路线中的序号：(IV)

By condensation of 3-(4-acetamido-2-methoxyphenoxy)propyl p-toluenesulfonate with 1-(2-fluorophenyl)piperazine (II). The starting products are obtained as follows: a) The addition of 4-acetamido-2-methoxyphenol (III) to ethyl acrylate (IV) gives ethyl-3-(4-acetamido-2-methoxyphenoxy)propionate (V), which is reduced with LiAlH4 to the corresponding alcohol and tosylated with tosyl chloride to the starting compound (I). b) The condensation of benzylamine (VI) with ethyl bromoacetate (VII) by means of K2CO3 gives N,N-bis(ethoxycarbonyl methyl)benzylamine (VIII), which is reduced with LiAlH4 and treated with SOCl2 to afford N,N-bis(2-chloroethyl)benzylamine (IX). The cyclization of (IX) with 2-fluoroaniline (X) yields 1-benzyl-4-(2-fluorophenyl)piperazine (XI), which is finally debenzylated by hydrogenation with H2 over PdIC to give piperazine (II).

参考文献 中间体
合成目标
【1】 Fukuchi, I.; et al.; Neurochemical study of mafoprazine, a new phenylpiperazine derivative. Jpn Pharmacol 1988, 47, 9, 51.
【2】 Kanno, T.; Gaino, M.; Yamamura, M.; Ishida, R.; Shintomi, K. (Tanabe Seiyaku Co., Ltd.); N-Aryl-N-phenoxy-alkyl-piperazine compounds useful in decreasing intracranial presssure. EP 0034284; JP 156115769; US 4413006 .
【3】 Prous, J.; Castaner, J.; Mafoprazine mesylate. Drugs Fut 1988, 13, 10, 920.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 23114 3-[4-(acetamido)-2-methoxyphenoxy]propyl 4-methylbenzenesulfonate C19H23NO6S 详情 详情
(II) 23115 1-(2-fluorophenyl)piperazine 1011-15-0 C10H13FN2 详情 详情
(III) 23116 N-(4-hydroxy-3-methoxyphenyl)acetamide C9H11NO3 详情 详情
(IV) 10164 ethyl acrylate 140-88-5 C5H8O2 详情 详情
(IV) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(V) 23118 ethyl 3-[4-(acetamido)-2-methoxyphenoxy]propanoate C14H19NO5 详情 详情
(VI) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(VIII) 23121 ethyl 2-[benzyl(2-ethoxy-2-oxoethyl)amino]acetate C15H21NO4 详情 详情
(IX) 23122 N-benzyl-2-chloro-N-(2-chloroethyl)-1-ethanamine; N-Benzylbis(2-chloroethyl)amine 10429-82-0 C11H15Cl2N 详情 详情
(X) 22296 2-fluorophenylamine; 2-fluoroaniline 348-54-9 C6H6FN 详情 详情
(XI) 23124 1-benzyl-4-(2-fluorophenyl)piperazine C17H19FN2 详情 详情

合成路线16

该中间体在本合成路线中的序号：

Condensation of aminoguanidine carbonate (I) with formic acid gives 3-aminotriazole (II), which by treatment with concentrated nitric acid in a sodium nitrite solution gives 3-nitrotriazole (III). N-Alkylation of (III) with bromoacetic acid ethyl ester affords 2-(3-nitro-1,2,4-triazol-1-yl)acetic acid ethyl ester (IV). Reaction of (IV) with 2-methoxyethylamine in dioxane yields AK-2123.

参考文献 中间体
合成目标
【1】 Horning, E.C.; Organic Syntheses, Vol. 3, 1st Ed. University of Missouri 1995, 95.
【2】 Sugita, T.; Masuoka, M.; Nishikawa, Y.; Nishimoto, S.; Zhuo, L.; Sasai, K.; Kagiya, T.; Nitrotriazoles bearing sulfur-substituted side chains: Preparation and characterization as hypoxic cell radiosensitizers. Anti-Cancer Drug Des 1992, 7, 277-84.
【3】 Huan, L.C.; Rong, S.; AK-2123. Drugs Fut 1995, 20, 7, 659.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
34675 2-methoxyethylamine; 2-methoxy-1-ethanamine 109-85-3 C3H9NO 详情 详情
(I) 10015 1-Hydrazinecarboximidamide; Hydrazinecarboximidamide 79-17-4 CH6N4 详情 详情
(II) 12475 1H-1,2,4-Triazol-3-amine; 1H-1,2,4-Triazol-3-ylamine 61-82-5 C2H4N4 详情 详情
(III) 12476 3-Nitro-1H-1,2,4-triazole; 3-Nitro-1,2,4-triazole 24807-55-4 C2H2N4O2 详情 详情
(IV) 12477 ethyl 2-(3-nitro-1H-1,2,4-triazol-1-yl)acetate C6H8N4O4 详情 详情

合成路线17

该中间体在本合成路线中的序号：(VII)

The reaction of 7-methoxy-2-tetralone (I) with benzamide in refluxing toluene gives N-(7-methoxy-3,4-dihydronpahthalen-2-yl)benzamide (II), which is enantioselectively hydrogenated with H2 over a chiral Ru or Rh catalyst yielding the chiral benzamide (III). The hydrolysis of (III) with methanesulfonic acid in acetic acid at 160 C affords the chiral 7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-amine (IV) , which is treated with 48% HBr affording 7-hydroxy-1,2,3,4-tetrahydronaphthalen-2(S)-ylamine (V). The protection of the amino group of (V) with Boc2O and triethylamine gives the carbamate (VI), which is condensed with ethyl 2-bromoacetate (VII) by means of K2CO3 yielding 2-[7(S)-(tert-butoxycarbonylamino)-5,6,7,8-tetrahydronaphthalen-2-yloxy]acetic acid ethyl ester (VIII). The deprotection of (VIII) with TFA affords 2-(7(S)-amino-5,6,7,8-tetrahydronaphthalen-2-yloxy]acetic acid ethyl ester (IX), which is finally condensed with the chiral 2(R)-(3-chlorophenyl)oxirane (X) in hot DMS. The chiral intermediate 7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-amine (IV) can also by obtained by optical resolution of the racemic mixture (rac)-(IV) by means of (R)-(-)-mandelic acid.

参考文献 中间体
合成目标
【1】 Devocelle, M.; et al.; Alternative synthesis of the chiral atypical beta-adrenergic phenylethanolaminotetraline agonist SR58611A using enantioselective hydrogenation. Tetrahedron Lett 1999, 40, 24, 4551.
【2】 Cecchi, R.; et al.; Synthesis and beta-adrenergic activity of atypical beta-adrenergic phenylethanolaminotetralin stereoisomers. Eur J Med Chem 1994, 29, 4, 259.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
40592 Benzamide 55-21-0 C7H7NO 详情 详情
(rac)-(IV) 32818 7-methoxy-1,2,3,4-tetrahydro-2-naphthalenylamine; 7-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine C11H15NO 详情 详情
(I) 24999 7-methoxy-3,4-dihydro-2(1H)-naphthalenone 4133-34-0 C11H12O2 详情 详情
(II) 32816 N-(7-methoxy-3,4-dihydro-2-naphthalenyl)benzamide C18H17NO2 详情 详情
(III) 32817 N-[(2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]benzamide C18H19NO2 详情 详情
(IV) 32820 (2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenylamine; (2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine C11H15NO 详情 详情
(V) 32819 (7S)-7-amino-5,6,7,8-tetrahydro-2-naphthalenol C10H13NO 详情 详情
(VI) 32821 tert-butyl (2S)-7-hydroxy-1,2,3,4-tetrahydro-2-naphthalenylcarbamate C15H21NO3 详情 详情
(VII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VIII) 32822 ethyl 2-([(7S)-7-[(tert-butoxycarbonyl)amino]-5,6,7,8-tetrahydro-2-naphthalenyl]oxy)acetate C19H27NO5 详情 详情
(IX) 32823 ethyl 2-[[(7S)-7-amino-5,6,7,8-tetrahydro-2-naphthalenyl]oxy]acetate C14H19NO3 详情 详情
(X) 15271 (R)-(+)-3-Chlorostyrene oxide; (2R)-2-(3-Chlorophenyl)oxirane 62600-71-9 C8H7ClO 详情 详情

合成路线18

该中间体在本合成路线中的序号：(II)

Condensation of substituted aminothiophene (I) with ethyl bromoacetate (II) by means of K2CO3 in refluxing acetone furnishes the corresponding ethyl tetraester (III) (1), which can be converted into the desired strontium salt by treatment with NaOH in refluxing EtOH /H2O, followed by reaction with strontium hydroxide or strontium chloride in H2O. Alternatively, this transformation can also be achieved by direct treatment of (III) with strontium hydroxide in H2O/EtOH.

参考文献 中间体
合成目标
【1】 Wierzbicki, M.; et al.; Reactivity of 2-aminothiophenes. Application to the synthesis of some thieno[2,3-b]pyrroles. Bull Soc Chim France 1975, 7-8, Part 2, 1786.
【2】 Wierzbicki, M.; Bonnet, J.; Brisset, M.; Tsouderos, Y. (ADIR et Cie.); Bivalent metal salts of 2-N,N-di(carboxymethyl)amino, 3-cyano,4-carboxymethyl,5-carboxy-thiophene-acid, process for their preparation and pharmaceutical compsns. containing them. AU 9162033; EP 0415850; FR 2651497; JP 1991169876; US 5128367 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 50839 ethyl 5-amino-4-cyano-3-(2-ethoxy-2-oxoethyl)-2-thiophenecarboxylate C12H14N2O4S 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 50840 ethyl 5-[bis(2-ethoxy-2-oxoethyl)amino]-4-cyano-3-(2-ethoxy-2-oxoethyl)-2-thiophenecarboxylate C20H26N2O8S 详情 详情

合成路线19

该中间体在本合成路线中的序号：(IV)

Synthesis of the aminopyrazole intermediate (XIII): The reaction of butanal (I) with methylhydrazine (II) in dichloromethane in the presence of MgSO4 gives the corresponding hydrazide (III), which is alkylated with ethyl bromoacetate (IV) by means of the polymer-supported base 2-(tert-butylimino)-2-(diethylamino)-1,3-dimethylperhydro-1,3,2-diazaphosphorine (PS-BEMP) (V) and polymer-supported methylamine (VI) to yield the hydrazino ester (VII). Treatment of compound (VII) with an ion exchange tetramethylammonium cyanide resin (VIII) in refluxing ethanol containing a catalytic amount of HOAc affords the adduct (IX), which is dehydrogenated with Pd/C/cyclopentene or MnO2 and treated with a polymer-supported ethyl isocyanate resin (X) in order to eliminate the unreacted product, providing the hydrazone (XI). Cyclization of (XI) by means of PS-BEMP (V) in ethanol gives 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid ethyl ester (XII), which is finally treated with ammonia in methanol to afford the desired pyrazolecarboxamide intermediate (XIII).

参考文献 中间体
合成目标
【1】 Baxendale, I.R.; Ley, S.V.; Polymer-supported reagents for multi-step organic synthesis: Application to the synthesis of sildenafil. Bioorg Med Chem Lett 2000, 10, 17, 1983.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 23694 butyraldehyde 123-72-8 C4H8O 详情 详情
(II) 12091 1-Methylhydrazine; Monomethyl hydrazine 60-34-4 CH6N2 详情 详情
(III) 44339 butanal N-methylhydrazone C5H12N2 详情 详情
(IV) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(V) 44344 N-(tert-butyl)-N-[2-(diethylamino)-1,3-dimethyl-1,3,2lambda(5)-diazaphosphinan-2-ylidene]amine; 2-(tert-butylimino)-N,N-diethyl-1,3-dimethyl-1,3,2lambda(5)-diazaphosphinan-2-amine C13H31N4P 详情 详情
(VI) 11021 Methanamine; Methylamine 74-89-5 CH5N 详情 详情
(VII) 44340 ethyl 2-[2-[(E)butylidene]-1-methylhydrazino]acetate C9H18N2O2 详情 详情
(VIII) 44345 N,N,N-trimethylmethanaminium cyanide C5H12N2 详情 详情
(IX) 44341 ethyl 2-[2-(1-cyanobutyl)-1-methylhydrazino]acetate C10H19N3O2 详情 详情
(X) 11019 (Methylimino)(oxo)methane; methyl isocyanate C2H3NO 详情 详情
(XI) 44342 ethyl 2-[2-[(Z)-1-cyanobutylidene]-1-methylhydrazino]acetate C10H17N3O2 详情 详情
(XII) 44343 ethyl 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxylate C10H17N3O2 详情 详情
(XIII) 15627 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide; 4-amino-1-methyl-3-propyl-5-pyrazolecarboxamide 139756-02-8 C8H14N4O 详情 详情

合成路线20

该中间体在本合成路线中的序号：(VII)

The condensation of phthalic anhydride (I) with glycine (II) by heating at 160 C gives 2-phthalimidoacetic acid (III), which is treated with refluxing SOCl2 to yield the acetyl chloride (IV). The condensation of (IV) with Meldrum's acid (V) by means of pyridine in dichloromethane, followed by a treatment with refluxing ethanol, affords 4-phthalimidoaetoacetic acid ethyl ester (VI), which is condensed with 1-13C-labeled 2-bromoacetic acid ethyl ester (VII) by means of NaH in dimethoxyethane to provide labeled 2-(2-phthalimidoacetyl)succinic acid diethyl ester (VIII). Finally, this compound is treated with HCl in refluxing acetic acid to give the target labeled aminolevulinic acid.

参考文献 中间体
合成目标
【1】 Kurumaya, K.; Okazaki, T.; Seido, N.; Akasaka, Y.; Kawajiri, Y.; Kajiwara, M.; Kondo, M.; Facile synthesis of delta-aminolevulinic acid (ALA) regioselectively labeled with 13C and direct observation of enzymatic transformation from ALA to porphobilinogen (PBG). J Label Compd Radiopharm 1989, 27, 2, 217.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11900 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride 85-44-9 C8H4O3 详情 详情
(II) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(III) 10284 N-Phthaloylglycine; 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid 4702-13-0 C10H7NO4 详情 详情
(IV) 10278 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride 6780-38-7 C10H6ClNO3 详情 详情
(V) 14738 Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester 2033-24-1 C6H8O4 详情 详情
(VI) 61596 ethyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxobutanoate C14H13NO5 详情 详情
(VII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VII) 61597 ethyl 2-bromoacetate C4H7BrO2 详情 详情
(VIII) 61598 diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]succinate C18H19NO7 详情 详情
(VIII) 64690 diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]succinate C18H19NO7 详情 详情

合成路线21

该中间体在本合成路线中的序号：(VII)

The condensation of phthalic anhydride (I) with 1-13C-labeled glycine (II) by heating at 160 C gives 2-phthalimidoacetic acid (III), which is treated with refluxing SOCl2 to yield the acetyl chloride (IV). The condensation of (IV) with Meldrum's acid (V) by means of pyridine in dichloromethane, followed by a treatment with refluxing ethanol affords 4-phthalimidoaetoacetic acid ethyl ester (VI). This compound is condensed with 2-bromoacetic acid ethyl ester (VII) by means of NaH in dimethoxyethane to provide labeled 2-(2-phthalimidoacetyl)succinic acid diethyl ester (VIII). Finally, the compound is treated with HCl in refluxing acetic acid to give the target labeled aminolevulinic acid.

参考文献 中间体
合成目标
【1】 Kurumaya, K.; Okazaki, T.; Seido, N.; Akasaka, Y.; Kawajiri, Y.; Kajiwara, M.; Kondo, M.; Facile synthesis of delta-aminolevulinic acid (ALA) regioselectively labeled with 13C and direct observation of enzymatic transformation from ALA to porphobilinogen (PBG). J Label Compd Radiopharm 1989, 27, 2, 217.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11900 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride 85-44-9 C8H4O3 详情 详情
(II) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(II) 61599 glycine C2H5NO2 详情 详情
(III) 10284 N-Phthaloylglycine; 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid 4702-13-0 C10H7NO4 详情 详情
(III) 61600 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid C10H7NO4 详情 详情
(IV) 10278 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride 6780-38-7 C10H6ClNO3 详情 详情
(IV) 61627 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride C10H6ClNO3 详情 详情
(V) 14738 Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester 2033-24-1 C6H8O4 详情 详情
(VI) 61596 ethyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxobutanoate C14H13NO5 详情 详情
(VI) 61628 ethyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxobutanoate C14H13NO5 详情 详情
(VII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VIII) 61629 diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]succinate C18H19NO7 详情 详情
(VIII) 64690 diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]succinate C18H19NO7 详情 详情

合成路线22

该中间体在本合成路线中的序号：(VII)

The condensation of phthalic anhydride (I) with glycine (II) by heating at 160 C gives 2-phthalimidoacetic acid (III), which is treated with refluxing SOCl2 to yield the acetyl chloride (IV). The condensation of (IV) with Meldrum's acid (V) by means of pyridine in dichloromethane, followed by a treatment with refluxing ethanol affords 4-phthalimidoaetoacetic acid ethyl ester (VI). This compound is condensed with 2-13C-labeled 2-bromoacetic acid ethyl ester (VII) by means of NaH in dimethoxyethane to provide labeled 2-(2-phthalimidoacetyl)succinic acid diethyl ester (VIII). Finally, this compound is treated with HCl in refluxing acetic acid to give the target labeled aminolevulinic acid.

参考文献 中间体
合成目标
【1】 Kurumaya, K.; Okazaki, T.; Seido, N.; Akasaka, Y.; Kawajiri, Y.; Kajiwara, M.; Kondo, M.; Facile synthesis of delta-aminolevulinic acid (ALA) regioselectively labeled with 13C and direct observation of enzymatic transformation from ALA to porphobilinogen (PBG). J Label Compd Radiopharm 1989, 27, 2, 217.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11900 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride 85-44-9 C8H4O3 详情 详情
(II) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(III) 10284 N-Phthaloylglycine; 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid 4702-13-0 C10H7NO4 详情 详情
(IV) 10278 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride 6780-38-7 C10H6ClNO3 详情 详情
(V) 14738 Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester 2033-24-1 C6H8O4 详情 详情
(VI) 61596 ethyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxobutanoate C14H13NO5 详情 详情
(VII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VII) 61630 ethyl 2-bromoacetate C4H7BrO2 详情 详情
(VIII) 61631 diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]succinate C18H19NO7 详情 详情
(VIII) 64690 diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]succinate C18H19NO7 详情 详情

合成路线23

该中间体在本合成路线中的序号：(VII)

The condensation of phthalic anhydride (I) with glycine (II) by heating at 160 C gives 2-phthalimidoacetic acid (III), which is treated with refluxing SOCl2 to yield the acetyl chloride (IV). The condensation of (IV) with 2-13C-labeled Meldrum's acid (V) by means of pyridine in dichloromethane, followed by a treatment with refluxing ethanol affords 4-phthalimidoaetoacetic acid ethyl ester (VI). This compound is condensed with 2-bromoacetic acid ethyl ester (VII) by means of NaH in dimethoxyethane to provide labeled 2-(2-phthalimidoacetyl)succinic acid diethyl ester (VIII). Finally, the ester is treated with HCl in refluxing acetic acid to give the target labeled aminolevulinic acid.

参考文献 中间体
合成目标
【1】 Kurumaya, K.; Okazaki, T.; Seido, N.; Akasaka, Y.; Kawajiri, Y.; Kajiwara, M.; Kondo, M.; Facile synthesis of delta-aminolevulinic acid (ALA) regioselectively labeled with 13C and direct observation of enzymatic transformation from ALA to porphobilinogen (PBG). J Label Compd Radiopharm 1989, 27, 2, 217.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11900 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride 85-44-9 C8H4O3 详情 详情
(II) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(III) 10284 N-Phthaloylglycine; 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid 4702-13-0 C10H7NO4 详情 详情
(IV) 10278 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride 6780-38-7 C10H6ClNO3 详情 详情
(V) 14738 Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester 2033-24-1 C6H8O4 详情 详情
(V) 61632 2,2-dimethyl-1,3-dioxane-4,6-dione C6H8O4 详情 详情
(VI) 61596 ethyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxobutanoate C14H13NO5 详情 详情
(VI) 61633 ethyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxobutanoate C14H13NO5 详情 详情
(VII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VIII) 61634 diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]succinate C18H19NO7 详情 详情
(VIII) 64690 diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]succinate C18H19NO7 详情 详情

合成路线24

该中间体在本合成路线中的序号：(IV)

The condensation of 13C-labelled methyl phenyl sulfone (I) with 2-(tert-butyldimethylsilyloxy)acetic acid ethyl ester (II) by means of BuLi in THF gives the labelled propanone derivative (III), which is condensed with ethyl 2-bromoacetate (IV) by means of NaH in THF to yield the gamma-oxo ester (V). Desulfurization of (V) by means of Al/Hg in THF/water affords the silylated 5-hydroxy-4-oxopentanoic acid ethyl ester (VI), which is desilylated by means of AcOH in THF/water to provide the free hydroxyester (VII). The condensation of (VII) with phthalimide (VIII) by means of DEAD and PPh3 in toluene gives the phthalimido derivative (IX), which is finally treated with refluxing 6N HCl to provide the target labelled aminolevulinic acid.

参考文献 中间体
合成目标
【1】 Kurumaya, K.; Okazaki, T.; Seido, N.; Akasaka, Y.; Kawajiri, Y.; Kajiwara, M.; Kondo, M.; Facile synthesis of delta-aminolevulinic acid (ALA) regioselectively labeled with 13C and direct observation of enzymatic transformation from ALA to porphobilinogen (PBG). J Label Compd Radiopharm 1989, 27, 2, 217.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 23622 methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane 3112-85-4 C7H8O2S 详情 详情
(I) 61635 methyl phenyl sulfone; methyl(dioxo)phenyl-lambda~6~-sulfane C7H8O2S 详情 详情
(II) 61636 ethyl 2-{[tert-butyl(dimethyl)silyl]oxy}acetate C10H22O3Si 详情 详情
(III) 61637 1-{[tert-butyl(dimethyl)silyl]oxy}-3-(phenylsulfonyl)acetone C15H24O4SSi 详情 详情
(III) 64694 1-{[tert-butyl(dimethyl)silyl]oxy}-3-(phenylsulfonyl)acetone C15H24O4SSi 详情 详情
(IV) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(V) 61639 ethyl 5-{[tert-butyl(dimethyl)silyl]oxy}-4-oxo-3-(phenylsulfonyl)pentanoate C19H30O6SSi 详情 详情
(V) 64691 ethyl 5-{[tert-butyl(dimethyl)silyl]oxy}-4-oxo-3-(phenylsulfonyl)pentanoate C19H30O6SSi 详情 详情
(VI) 61640 ethyl 5-{[tert-butyl(dimethyl)silyl]oxy}-4-oxopentanoate C13H26O4Si 详情 详情
(VI) 64692 ethyl 5-{[tert-butyl(dimethyl)silyl]oxy}-4-oxopentanoate C13H26O4Si 详情 详情
(VII) 61641 ethyl 5-hydroxy-4-oxopentanoate C7H12O4 详情 详情
(VII) 64693 ethyl 5-hydroxy-4-oxopentanoate C7H12O4 详情 详情
(VIII) 12376 Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione 85-41-6 C8H5NO2 详情 详情
(IX) 59167 ethyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoate C15H15NO5 详情 详情
(IX) 61642 ethyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoate C15H15NO5 详情 详情

合成路线25

该中间体在本合成路线中的序号：

Reformatskii reaction between 7-methoxy-1-tetralone (I) and the organozinc reagent generated from ethyl bromoacetate, followed by dehydration of the intermediate carbinol in the presence of P2O5 gives 2-(7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid ethyl ester (II). Aromatization of compound (II) by heating with sulfur at 215 C results in the corresponding naphthalene derivative (III), which is submited to basic hydrolysis of the ethyl ester group (III) to provide 2-(7-methoxy-1-naphthyl)acetic acid (IV). After activation of (IV) with SOCl2, the crude acid chloride is treated with ammonium hydroxide to produce amide (V), which by direct reduction with LiAlH4 furnishes amine (VI) in low yields. An alternative procedure consists of the dehydration of amide (V) with trifluoroacetic anhydride to afford nitrile (VII), which is then reduced to the desired amine (VI) by catalytic hydrogenation. Finally, agomelatine is obtained by reaction of amine (VI) with acetyl chloride in pyridine or in a biphasic medium (H2O­CHCl3) under Schotten-Baumann conditions.

参考文献 中间体
合成目标
【1】 Silvestre, J.S.; Bayes, M.; Chilman-Blair, K.; Castaner, J.; Agomelatine. Drugs Fut 2003, 28, 1, 7.
【2】 Andrieux, J.; Houssin, R.; Said, Y.; Guardiola-Lemaitre, B.; Lesieur, D. (ADIR et Cie.); Novel derivs. with a naphthalenic structure, their process of preparation and pharmaceutical compsns. containing them. EP 0447285; FR 2658819; JP 1995048331; US 5318994 .
【3】 Guardiola-Lemaitre, B.; Renard, P.; Pfeiffer, B.; Caignard, D.-H.; Andrieux, J.; Howell, H.-E.; Morgan, P.; Yous, S.; Lesieur, D.; Adam, G.; Novel naphthalenic ligands for the melatonin receptor. J Pharm Belg 1992, 47, 4, 374.
【4】 Morgan, P.J.; Howell, H.E.; Lesieur, D.; Guardiola-Lemaitre, B.; Pfeiffer, B.; Andrieux, J.; Renard, P.; Yous, S.; Novel naphthalenic ligands with high affinity for the melatonin receptor. J Med Chem 1992, 35, 8, 1484.
【5】 Depreux, P.; Lesieur, D.; Mansour, H.A.; et al.; Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. J Med Chem 1994, 37, 20, 3231.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
19273 acetyl chloride 75-36-5 C2H3ClO 详情 详情
(I) 21385 7-methoxy-3,4-dihydro-1(2H)-naphthalenone 6836-19-7 C11H12O2 详情 详情
(II) 58079 ethyl 2-[7-methoxy-3,4-dihydro-1(2H)-naphthalenylidene]acetate C15H18O3 详情 详情
(III) 58080 ethyl 2-(7-methoxy-1-naphthyl)acetate C15H16O3 详情 详情
(IV) 58081 2-(7-methoxy-1-naphthyl)acetic acid C13H12O3 详情 详情
(V) 58082 2-(7-methoxy-1-naphthyl)acetamide C13H13NO2 详情 详情
(VI) 58083 2-(7-methoxy-1-naphthyl)-1-ethanamine; 2-(7-methoxy-1-naphthyl)ethylamine C13H15NO 详情 详情
(VII) 36604 2-(7-methoxy-1-naphthyl)acetonitrile C13H11NO 详情 详情

合成路线26

该中间体在本合成路线中的序号：

The alkylation of ethyl 2-(benzyloxycarbonylamino)cyanoacetate (I) with ethyl bromoacetate and anhydrous potassium carbonate in acetone gives diethyl 2-(benzyloxycarbonylamino)-2-cyanosuccinate (II), which is hydrolyzed by means of hydrogen peroxide and sodium carbonate in acetone/water, yielding 3-(benzyloxycarbonylamino)-3-(ethoxycarbonyl)pyrrolidine-2,5-dione (III). Racemic (III) is then resolved by means of crystallization with cinchonidine in ethanol to give the (-)-enantiomer (IV) (>99.5% e.e.). Hydrogenolysis of (IV) over Pd/C in ethanol, followed by treatment with 2,5-dimethoxytetrahydrofuran in acetic acid, affords (-)-3-(ethoxycarbonyl)-3-(pyrrol-1-yl)pyrrolidine-2,5-dione (VI). Treatment of (VI) with trichloroacetyl chloride in ethyl acetate, followed by condensation with 4-bromo-2-fluorobenzylamine in the presence of triethylamine, gives AS-3201 (>99.4% e.e.).

参考文献 中间体
合成目标
【1】 Negoro, T.; Murata, M.; Ueda, S.; Fujitani, B.; Ono, Y.; Kuromiya, A.; Komiya, M.; Suzuki, M.; Matsumoto, J.; Novel, highly potent aldose reductase inhibitors: (R)-(-)-2-(4-Bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone (AS-3201) and its congeners. J Med Chem 1998, 41, 21, 4118-29.
【2】 Negoro, T.; Komiya, M.; Ono, Y.; AS-3201. Drugs Fut 2000, 25, 2, 131.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
19560 (4-bromo-2-fluorophenyl)methanamine; 4-bromo-2-fluorobenzylamine 112734-22-2 C7H7BrFN 详情 详情
(I) 32863 ethyl 2-[[(benzyloxy)carbonyl]amino]-2-cyanoacetate C13H14N2O4 详情 详情
(II) 32864 diethyl 2-[[(benzyloxy)carbonyl]amino]-2-cyanosuccinate C17H20N2O6 详情 详情
(III) 32865 ethyl 3-[[(benzyloxy)carbonyl]amino]-2,5-dioxo-3-pyrrolidinecarboxylate C15H16N2O6 详情 详情
(IV) 32866 ethyl (3R)-3-[[(benzyloxy)carbonyl]amino]-2,5-dioxo-3-pyrrolidinecarboxylate C15H16N2O6 详情 详情
(V) 32867 ethyl (3R)-3-amino-2,5-dioxo-3-pyrrolidinecarboxylate C7H10N2O4 详情 详情
(VI) 32868 ethyl (3R)-2,5-dioxo-3-(1H-pyrrol-1-yl)-3-pyrrolidinecarboxylate C11H12N2O4 详情 详情
(VII) 32869 ethyl (3R)-2,5-dioxo-3-[2-(2,2,2-trichloroacetyl)-1H-pyrrol-1-yl]-3-pyrrolidinecarboxylate C13H11Cl3N2O5 详情 详情

合成路线27

该中间体在本合成路线中的序号：(IV)

The synthesis of free compound is performed as follows: The condensation of 2-hydroxy-4-(3-methyl-2-butenyloxy)acetophenone (I) with 4-tert-butylbenzaldehyde (II) by means of KOH in hot ethanol gives 3-(4-tert-butylphenyl)-1-[4-hydroxy-4-(3-methyl-2-butenyloxy)phenyl]-2(E)-propen-1-one (III), which is condensed with ethyl bromoacetate (IV) by means of KOH in acetone to afford (E)-2-[2-(4-tert-butylcinnamoyl)-4-(3-methyl-2-butenyloxy)phenoxy] acetic acid ethyl ester (V). Finally, this compound is hydrolyzed with KOH in hot ethanol-water.

参考文献 中间体
合成目标
【1】 Yokomori, S.; Saijo, K.; Matsunaga, T.; Nakashima, Y.; Hatayama, K. (Taisho Pharmaceutical Co., Ltd.); Chalcone derivs. EP 0412803; JP 1991163042 .
【2】 Yokomori, S.; Saijo, K.; Hatayama, M. (Taisho Pharmaceutical Co., Ltd.); Antiulcerative agents. JP 1993058885 .
【3】 Rabasseda, X.; Castañer, J.; Mealy, N.; SU-840. Drugs Fut 1994, 19, 10, 923.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 16637 1-[2-hydroxy-4-[(3-methyl-2-butenyl)oxy]phenyl]-1-ethanone C13H16O3 详情 详情
(II) 16638 4-(tert-butyl)benzaldehyde; 4-tert-Butyl-benzaldehyde 939-97-9 C11H14O 详情 详情
(III) 16639 (E)-3-[4-(tert-butyl)phenyl]-1-[2-hydroxy-4-[(3-methyl-2-butenyl)oxy]phenyl]-2-propen-1-one C24H28O3 详情 详情
(IV) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(V) 16641 ethyl 2-[2-[(E)-3-[4-(tert-butyl)phenyl]-2-propenoyl]-5-[(3-methyl-2-butenyl)oxy]phenoxy]acetate C28H34O5 详情 详情

合成路线28

该中间体在本合成路线中的序号：

A general synthesis of this entire class of thrombin inhibitors has been published recently. An alternative synthesis for the preparation of napsagatran is outlined in Scheme 21319301a: L-Aspartic acid is sulfonated with naphthalenesulfochloride to give the sulfonamide (I). Reaction of (I) with formaldehyde leads to the oxazolinone (II), which is reacted with N-cyclopropylglycine ethyl ester (III) to afford the aspartate (IV). Condensation of (IV) with the guanidine (IX) and saponification of the ethyl ester group provides napsagatran. For the preparation of the guanidine (IX), picolylamine is hydrogenated to give the racemic 3-aminomethyl-piperidine, from which the desired enantiomer (V) is isolated as dibenzoyltartrate by crystallization. Reaction of piperidine (V) with acetoacetate affords the protected piperidine (VI), which is amidinated with amidinotriazole (VII) to give the protected guanidine (VIII). Deprotection of (VIII) with hydrochloric acid provides the enantiomerically pure guanidine (IX) as dihydrochloride.

参考文献 中间体
合成目标
【1】 Banner, D.W.; Hilpert, K.; Ackermann, J.; et al.; Design and synthesis of potent and highly selective thrombin inhibitors. J Med Chem 1994, 37, 23, 3889-901.
【2】 Gast, A.; Kirchhofer, D.; Soukup. M.; Roux, S.; Ackermann, J.; Hilpert, K.; Tschopp, T.B.; Schmid, G.; Napsagatran. Drugs Fut 1995, 20, 5, 476.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
13070 L-Aspartic acid; (2S)-2-Aminobutanedioic acid 56-84-8 C4H7NO4 详情 详情
16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
18731 3-pyridinylmethanamine; 3-pyridinylmethylamine 3731-52-0 C6H8N2 详情 详情
(I) 16803 (2S)-2-[(2-naphthylsulfonyl)amino]butanedioic acid C14H13NO6S 详情 详情
(II) 16804 2-[(4S)-3-(2-naphthylsulfonyl)-5-oxo-1,3-oxazolan-4-yl]acetic acid C15H13NO6S 详情 详情
(III) 16805 ethyl 2-(cyclopropylamino)acetate C7H13NO2 详情 详情
(IV) 16806 (3S)-4-[cyclopropyl(2-ethoxy-2-oxoethyl)amino]-3-[(2-naphthylsulfonyl)amino]-4-oxobutyric acid C21H24N2O7S 详情 详情
(V) 16807 (3S)hexahydro-3-pyridinylmethylamine; (3S)hexahydro-3-pyridinylmethanamine C6H14N2 详情 详情
(VI) 16808 methyl (Z)-3-[[(3R)hexahydro-3-pyridinylmethyl]amino]-2-butenoate C11H20N2O2 详情 详情
(VII) 16809 1H-1,2,4-triazole-1-carboximidamide hydrochloride C3H6ClN5 详情 详情
(VIII) 16810 methyl (Z)-3-[([(3S)-1-[amino(imino)methyl]piperidinyl]methyl)amino]-2-butenoate hydrochloride C12H23ClN4O2 详情 详情
(IX) 16811 (3S)-3-(aminomethyl)-1-piperidinecarboximidamide C7H16N4 详情 详情

合成路线29

该中间体在本合成路线中的序号：

Condensation of benzodiazepinone (IV) with 4-nitrobenzoyl chloride (V) afforded amide (VI), which was alkylated with ethyl bromoacetate in the presence of NaH to give (VII). The nitro group of (VII) was reduced to aniline (VIII) using Fe and AcOH. Subsequent coupling of (VIII) with the acid chloride generated from biphenyl carboxylic acid (III) and oxalyl chloride produced the corresponding amide (IX). The ester group of (IX) was then hydrolyzed with NaOH, and the resulting carboxylic acid (X) was finally condensed with N-methylpiperazine (XI) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole as the coupling reagents.

参考文献 中间体
合成目标
【1】 Hosogai, N.; Tanaka, H.; Tomita, M.; Ohkawa, T.; Hemmi, K.; Setoi, H.; Zenkoh, O.; Synthesis and characterization of orally active nonpeptide vasopressin V2 receptor antagonists. Chem Pharm Bull 1999, 47, 4, 501.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 16915 4'-methyl[1,1'-biphenyl]-2-carboxylic acid 7148-03-0 C14H12O2 详情 详情
(IV) 18498 1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one C9H10N2O 详情 详情
(V) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(VI) 27975 5-(4-nitrobenzoyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one C16H13N3O4 详情 详情
(VII) 27976 ethyl 2-[5-(4-nitrobenzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetate C20H19N3O6 详情 详情
(VIII) 27977 ethyl 2-[5-(4-aminobenzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetate C20H21N3O4 详情 详情
(IX) 27978 ethyl 2-[5-(4-[[(4'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]benzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetate C34H31N3O5 详情 详情
(X) 27979 2-[5-(4-[[(4'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]benzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetic acid C32H27N3O5 详情 详情
(XI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线30

该中间体在本合成路线中的序号：(II)

The synthesis of rofecoxib can be performed by several different ways: 1) The condensation of phenylacetic acid (I) with ethyl bromoacetate (II) by means of triethylamine in THF yields 2-(phenylacetoxy)acetic acid ethyl ester (III), which is cyclized to the hydroxyfuranone (IV) by means of potassium tert-butoxide in tert-butanol. The reaction of (IV) with triflic anhydride and diisopropylethylamine in dichloro-methane affords the corresponding triflate (V), which by reaction with LiBr in hot acetone yields the bromofuranone (VI). The condensation of (VI) with 4-(methylsulfanyl)phenylboronic acid (VII) by means of Na2CO3 and Pd(Ph3P)4 in hot toluene gives 4-[4-(methylsulfanyl)-phenyl]-3-phenylfuran-2(5H)-one (VIII), which is finally oxidized with 2KHSO5.KHSO4.K2SO4 (oxone). 2) The intermediate (VIII) can also be obtained by condensation of triflate (V) with boronic acid (VII) by means of Na2CO3 and Pd(Ph3P)4 in hot toluene. 3) The intermediate (VIII) can also be synthesized by the reaction of triflate (V) with tetramethylammonium chloride, giving the chlorofuranone (IX), which is then condensed with boronic acid (VII) as before.

参考文献 中间体
合成目标
【1】 Sorbera, L.A.; Rabasseda, X.; Castañer, J.; Rofecoxib. Drugs Fut 1998, 23, 12, 1287.
【2】 Tillyer, R.; Desmond, R.; Dolling, U.; Marcune, B.; Tschaen, D. (Merck & Co., Inc.); Process for making phenyl heterocycles useful as COX-2 inhibitors. WO 9608482 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 16148 Benzeneacetic acid; 2-Phenylacetic acid; Phenyl Acetic Acid 103-82-2 C8H8O2 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 19255 2-ethoxy-2-oxoethyl 2-phenylacetate C12H14O4 详情 详情
(IV) 19256 4-hydroxy-3-phenyl-2(5H)-furanone 23782-85-6 C10H8O3 详情 详情
(V) 19257 5-oxo-4-phenyl-2,5-dihydro-3-furanyl trifluoromethyl sulfate C11H7F3O6S 详情 详情
(VI) 19258 4-bromo-3-phenyl-2(5H)-furanone C10H7BrO2 详情 详情
(VII) 18561 4-(methylsulfanyl)phenylboronic acid 98546-51-1 C7H9BO2S 详情 详情
(VIII) 19260 4-[4-(methylsulfanyl)phenyl]-3-phenyl-2(5H)-furanone C17H14O2S 详情 详情
(IX) 19261 4-chloro-3-phenyl-2(5H)-furanone C10H7ClO2 详情 详情

合成路线31

该中间体在本合成路线中的序号：(V)

The reaction of isovanillin with hydroxylamine sulfate and NaOH in refluxing ethanol/water gives the corresponding oxime (II), which is reduced with Raney-Ni and NaOH in the same solvent yielding the benzylamine (III). The protection of the amino group of (III) with benzyloxycarbonyl chloride affords the carbamate (IV), which is condensed with ethyl bromoacetate (IV) by means of K2CO3 in refluxing 2-butanone to give the ester (VI). The hydrolysis of (VI) with NaOH in hot methanol/water yields the corresponding acid (VII), which is condensed with 1-benzylpiperazine (VIII) by means of ethyl chloroformate in THF to afford the piperazide (IX). The deprotection of the amino group of (IX) with H2 over Pd/C in hot ethanol gives the benzylamine (X), which is finally condensed with 4,5-dichloropyridazin-3(2H)-one (XI) by means of triethylamine in refluxing ethanol/water.

参考文献 中间体
合成目标
【1】 Tanikawa, K.; Saito, A.; Hirotsuka, M.; Shikada, K. (Nissan Chemical Industry, Ltd.); Pyridazinone derivs. with pharmaceutical activity. EP 0706517; JP 1996041033; US 5728702; US 5929074; WO 9501343 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 18455 3-hydroxy-4-methoxybenzaldehyde; Isovanillin 621-59-0 C8H8O3 详情 详情
(II) 30957 2-methoxy-5-[(methylimino)methyl]phenol C9H11NO2 详情 详情
(III) 30958 5-(aminomethyl)-2-methoxyphenol C8H11NO2 详情 详情
(IV) 30959 benzyl 3-hydroxy-4-methoxybenzylcarbamate C16H17NO4 详情 详情
(V) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VI) 30960 ethyl 2-[5-([[(benzyloxy)carbonyl]amino]methyl)-2-methoxyphenoxy]acetate C20H23NO6 详情 详情
(VII) 30961 2-[5-([[(benzyloxy)carbonyl]amino]methyl)-2-methoxyphenoxy]acetic acid C18H19NO6 详情 详情
(VIII) 28542 N-Benzylpiperazine; 1-Benzylpiperazine 2759-28-6 C11H16N2 详情 详情
(IX) 30962 benzyl 3-[2-(4-benzyl-1-piperazinyl)-2-oxoethoxy]-4-methoxybenzylcarbamate C29H33N3O5 详情 详情
(X) 30963 2-[5-(aminomethyl)-2-methoxyphenoxy]-1-(4-benzyl-1-piperazinyl)-1-ethanone C21H27N3O3 详情 详情
(XI) 24750 Bis(isopropylamine)dichloro platinum complex C6H18Cl2N2Pt 详情 详情

合成路线32

该中间体在本合成路线中的序号：(XIII)

Dehydroxylation of compound (I) by hydrogenation over Pd/C in MeOH provides tetralinecarboxylic acid methyl ester (II), which is then reduced by means of LiAlH4 in THF to afford tetralinemethanol as a mixture of enantiomers (III). Separation of isomers in (III) is then achieved by first acylation of the alcohol with (-)-menthyl chloroformate (IV) in pyridine, followed by the separation of the two resulting diastereomers by recrystallization to give (-)-menthyl carbonate (V) and its subsequent hydrolysis with NaOH in THF/H2O to furnish compound (VI).

参考文献 中间体
合成目标
【1】 Tsubaki, K.; Hattori, K.; Tabuchi, S.; Okitsu, O.; Sakane, K.; Tanaka, H.; Taniguchi, K.; A novel pyridazinone derivative as a nonprostanoid PGI2 agonist. Bioorg Med Chem Lett 2000, 10, 24, 2787.
【2】 Taniguchi, K.; Nagano, M.; Hattori, K.; Tsubaki, K.; Okitsu, O.; Tabuchi, S. (Fujisawa Pharmaceutical Co., Ltd.); Naphthalene derivs. as prostaglandin I2 agonists. EP 0749424; JP 1997509958; US 5763489; WO 9524393 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 46774 methyl (1R,2S)-1-hydroxy-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenecarboxylate C13H16O4 详情 详情
(II) 46775 methyl (2S)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenecarboxylate C13H16O3 详情 详情
(III) 46776 (5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)methanol C12H16O2 详情 详情
(IV) 46777 (1S,2R,4R)-2-[(chlorocarbonyl)oxy]-1-isopropyl-4-methylcyclohexane 14602-86-9 C11H19ClO2 详情 详情
(V) 46778 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl [(2S)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]methyl carbonate C23H34O4 详情 详情
(VI) 46779 [(2S)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]methanol C12H16O2 详情 详情
(VII) 46780 1,1-diphenylacetone 781-35-1 C15H14O 详情 详情
(VIII) 15618 2-Oxoacetic acid; Glyoxylic Acid 298-12-4 C2H2O3 详情 详情
(IX) 46781 2-hydroxy-4-oxo-5,5-diphenylpentanoic acid C17H16O4 详情 详情
(X) 46782 6-benzhydryl-1,6-dihydro-3(2H)-pyridazinone C17H16N2O 详情 详情
(XI) 46783 6-benzhydryl-2-[[(2S)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]methyl]-1,6-dihydro-3(2H)-pyridazinone C29H30N2O2 详情 详情
(XII) 46784 6-benzhydryl-2-[[(2S)-5-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl]methyl]-1,6-dihydro-3(2H)-pyridazinone C28H28N2O2 详情 详情
(XIII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(XIV) 46785 ethyl 2-[((6S)-6-[[3-benzhydryl-6-oxo-3,6-dihydro-1(2H)-pyridazinyl]methyl]-5,6,7,8-tetrahydro-1-naphthalenyl)oxy]acetate C32H34N2O4 详情 详情

合成路线33

该中间体在本合成路线中的序号：(II)

The alkylation of 4,4'-dihydroxybiphenyl (I) with ethyl bromoacetate (II) in the presence of sodium methoxide afforded the (biphenylyloxy)acetate (III). Heating of ester (III) with benzylamine (IV) at 85 C produced amide (V), which was subsequently reduced to amine (VI) by means of borane, generated in situ from NaBH4 and BF3. Finally, condensation of the secondary amine (VI) with methyl isocyanate gave rise to the title urea derivative.

参考文献 中间体
合成目标
【1】 Fex, T.; Asp, B.; Stamvik, A.; Carlsson, J.-I.; Billstrom, A. (Pharmacia AB); Novel antitumour cpds. with antimitotic activity. WO 9529155 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 55986 4,4'-Biphenol; 4,4'-Dihydroxybiphenyl; 4,4'-Dihydroxydiphenyl; 4,4'-Diphenol 92-88-6 C12H10O2 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 55987 ethyl 2-[(4'-hydroxy[1,1'-biphenyl]-4-yl)oxy]acetate C16H16O4 详情 详情
(IV) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(V) 55988 N-benzyl-2-[(4'-hydroxy[1,1'-biphenyl]-4-yl)oxy]acetamide C21H19NO3 详情 详情
(VI) 55989 4'-[2-(benzylamino)ethoxy][1,1'-biphenyl]-4-ol C21H21NO2 详情 详情

合成路线34

该中间体在本合成路线中的序号：(II)

The alkylation of 4,4'-dihydroxybiphenyl (I) with ethyl bromoacetate (II) in the presence of sodium methoxide afforded the (biphenylyloxy)acetate (III). Heating of ester (III) with m-fluorobenzylamine (IV) at 85 C produced amide (V), which was subsequently reduced to amine (VI) by means of borane, generated in situ from NaBH4 and BF3. Finally, condensation of the secondary amine (VI) with methyl isocyanate gave rise to the title urea derivative.

参考文献 中间体
合成目标
【1】 Fex, T.; Asp, B.; Stamvik, A.; Carlsson, J.-I.; Billstrom, A. (Pharmacia AB); Novel antitumour cpds. with antimitotic activity. WO 9529155 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 55986 4,4'-Biphenol; 4,4'-Dihydroxybiphenyl; 4,4'-Dihydroxydiphenyl; 4,4'-Diphenol 92-88-6 C12H10O2 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 55987 ethyl 2-[(4'-hydroxy[1,1'-biphenyl]-4-yl)oxy]acetate C16H16O4 详情 详情
(IV) 48834 3-Fluorobenzylamine 100-82-3 C7H8FN 详情 详情
(V) 55990 N-(3-fluorobenzyl)-2-[(4'-hydroxy[1,1'-biphenyl]-4-yl)oxy]acetamide C21H18FNO3 详情 详情
(VI) 55991 4'-{2-[(3-fluorobenzyl)amino]ethoxy}[1,1'-biphenyl]-4-ol C21H20FNO2 详情 详情

合成路线35

该中间体在本合成路线中的序号：(XV)

The reaction of L-phenylalanine (I) with benzyl bromide and K2CO3 in hot ethanol/water gives N,N,O-tribenzyl derivative (II), which is condensed with acetonitrile (III) by means of NaNH2 in THF yielding the pentanenitrile (IV). The reaction of nitrile (IV) with benzylmagnesium chloride (V) in THF affords the diphenylhexenone (VI), which is reduced with NaBH4 in THF to give the diphenylhexanol (VII). The protection of the amino group of (VII) with Boc2O and K2CO3 in methyl tert-butyl ether yields the carbamate (VIII), which is debenzylated with ammonium formate over Pd/C in methanol affording the amino compound (IX). The condensation of (IX) with 2-(2,6-dimethylphenoxy)acetic acid (X) by means of EDAC in DMF provides the corresponding amide (XI), which is deprotected at the carbamate group with TFA in dichloromethane to give (XII) with a free amino group. Finally, this compound is condensed with 3-methyl 2(S)-(2-oxoperhydropyrimidin-1-yl)butyric acid (XIII) by means of EDAC in DMF or SOCl2 and imidazole to furnish the target compound. The intermediate 2-(2,6-dimethylphenoxy)acetic acid (X) has been obtained by condensation of 2,6-dimethylphenol (XIV) with ethyl 2-bromoacetate (XV) by means of Cs2CO3 in refluxing dioxane to give the acetate ester (XVI), which is hydrolyzed with LiOH ethanol/water to afford the target intermediate (X).

参考文献 中间体
合成目标
【1】 Stoner, E.J.; et al.; Synthesis of ABT-378, an HIV protease inhibitor candidate: Avoiding the use of carbodiimides in a difficult peptide coupling. Org Process Res Dev 1999, 3, 2, 145.
【2】 Sham, H.L.; Stewart, K.D.; Kempf, D.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds.. EP 0876353; JP 2000502997; WO 9721683 .
【3】 Retroviral protease inhibiting cpds.. EP 0882024; JP 2000502085; US 5914332; WO 9721685 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(I) 13952 (S)-(-)-Phenylalanine; L-Phenylalanine 63-91-2 C9H11NO2 详情 详情
(II) 37670 benzyl (2S)-2-(dibenzylamino)-3-phenylpropanoate C30H29NO2 详情 详情
(III) 37210 acetonitrile 75-05-8 C2H3N 详情 详情
(IV) 38263 (4S)-4-(dibenzylamino)-3-oxo-5-phenylpentanenitrile C25H24N2O 详情 详情
(V) 18327 benzyl(chloro)magnesium 6921-34-2 C7H7ClMg 详情 详情
(VI) 37671 (2S,4E)-5-amino-2-(dibenzylamino)-1,6-diphenyl-4-hexen-3-one C32H32N2O 详情 详情
(VII) 37672 (2S,3S,5S)-5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol C32H36N2O 详情 详情
(VIII) 38542 tert-butyl (1S,3S,4S)-1-benzyl-4-(dibenzylamino)-3-hydroxy-5-phenylpentylcarbamate C37H44N2O3 详情 详情
(IX) 38543 tert-butyl (1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentylcarbamate C23H32N2O3 详情 详情
(X) 38270 2-(2,6-dimethylphenoxy)acetic acid C10H12O3 详情 详情
(XI) 38545 tert-butyl (1S,3S,4S)-1-benzyl-4-[[2-(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenylpentylcarbamate C33H42N2O5 详情 详情
(XII) 38546 N-[(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentyl]-2-(2,6-dimethylphenoxy)acetamide C28H34N2O3 详情 详情
(XIII) 38264 (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butyric acid C9H16N2O3 详情 详情
(XIV) 38388 4-[(5-formyl-1H-imidazol-1-yl)methyl]benzonitrile C12H9N3O 详情 详情
(XV) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(XVI) 38544 ethyl 2-(2,6-dimethylphenoxy)acetate C12H16O3 详情 详情

合成路线36

该中间体在本合成路线中的序号：(XII)

The condensation of 2-methylaniline (I) with 2-fluorobenzonitrile (II) by means of BCl3 and AlCl3 gives 2-amino-2'-fluoro-3-methylbenzophenone (III), which is acylated at the amino group with bromoacetyl bromide (IV) in pyridine yielding the bromoacetamide (V). The cyclization of (V) with hydroxylamine and NaOH affords the benzodiazepinone-N-oxide (VI), which is treated with acetic anhydride to provide 3-acetoxy-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (VII). The reaction of (VII) with potassium phthalimide (VIII) and NaI gives the phthalimido derivative (IX), which by cleavage with hydrazine yields 3-amino-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (X). The protection of the amino group of (X) with Boc2O and TEA affords the carbamate (XI), which is alkylated with ethyl bromoacetate (XII) by means of NaH giving the ethoxycarbonylmethyl derivative (XIII). The hydrolysis of (XIII) with NaOH affords the corresponding carboxymethyl derivative (XIV), which is condensed with 3-azabicyclo[3,2,2]nonane (XV) by means of HOBT, WSCD and TEA to give the expected amide (XVI). The cleavage of the tert-butoxycarbonyl group of (XVI) with HCl yields the amine (XVII), which is finally condensed with the activated carbamate (XVIII) to furnish the title compound.

参考文献 中间体
合成目标
【1】 Toyoda, T.; Adachi, M.; Sugasawa, T.; et al.; Aminohaloborane in organic synthesis. I. Specific ortho substitution reaction of anilines. J Am Chem Soc 1978, 100, 4842.
【2】 Satoh, Y.; Tabuchi, S.; Mitsui, H.; Design of dual CCK-A and CCK-B receptor antagonists. Drugs Fut 1997, 22, 10, 1117.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 15511 o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine 95-53-4 C7H9N 详情 详情
(II) 41199 2-fluorobenzonitrile 394-47-8 C7H4FN 详情 详情
(III) 41200 (2-amino-3-methylphenyl)(2-fluorophenyl)methanone C14H12FNO 详情 详情
(IV) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(V) 41201 2-bromo-N-[2-(2-fluorobenzoyl)-6-methylphenyl]acetamide C16H13BrFNO2 详情 详情
(VI) 41202 5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-4-ium-4-olate C16H13FN2O2 详情 详情
(VII) 41203 5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl acetate C18H15FN2O3 详情 详情
(VIII) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(IX) 41204 2-[5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-1H-isoindole-1,3(2H)-dione C24H16FN3O3 详情 详情
(X) 41205 3-amino-5-(2-fluorophenyl)-9-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one C16H14FN3O 详情 详情
(XI) 41206 tert-butyl 5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-ylcarbamate C21H22FN3O3 详情 详情
(XII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(XIII) 41207 ethyl 2-[3-[(tert-butoxycarbonyl)amino]-5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-1-yl]acetate C25H28FN3O5 详情 详情
(XIV) 41208 2-[3-[(tert-butoxycarbonyl)amino]-5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-1-yl]acetic acid C23H24FN3O5 详情 详情
(XV) 41209 3-azabicyclo[3.2.2]nonane C8H15N 详情 详情
(XVI) 41210 tert-butyl 1-[2-(3-azabicyclo[3.2.2]non-3-yl)-2-oxoethyl]-5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-ylcarbamate C31H37FN4O4 详情 详情
(XVII) 41211 3-amino-1-[2-(3-azabicyclo[3.2.2]non-3-yl)-2-oxoethyl]-5-(2-fluorophenyl)-9-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one C26H29FN4O2 详情 详情
(XVIII) 41212 4-nitrophenyl 3-(1H-1,2,3,4-tetraazol-5-yl)phenylcarbamate C14H10N6O4 详情 详情

合成路线37

该中间体在本合成路线中的序号：(VIII)

The protection of the NH2 group of L-serine (I) gives N-(benzyloxycarbonyl)-L-serine (II), which is converted into the N-methylamide (III). The reduction of the amide group of (III) affords the diaminopropanol (IV), which is N-protected to provide the Boc-protected compound (V). The mesylation of the OH group of (V) gives the mesylate (VI), which is treated with ethylamine to yield the triaminopropane (VII). The condensation of (VII) with ethyl bromoacetate (VIII) affords the aminoacetate (IX), which is selectively deprotected with HCl to provide the intermediate (X). The cyclization of (X) by means of NaOEt gives the perhydro-1,4-diazepin-2-one (XI), which is reduced with BH3/THF to yield the perhydro-1,4-diazepine (XII). Cbz deprotection in (XII) by hydrogenation with H2 over Pd/C gives the 1-ethyl-4-methylperhydro-1,4-diazepin-6(R)-amine (XIII), which is condensed with 5-bromo-2-methoxy-6-(methylamino)pyridine-3-carboxylic acid (XIV) by means of ethyl chloroformate and TEA to yield the target amide (XV). Finally, this compound is treated with fumaric acid (XVI) in ethanol to afford the desired fumarate salt.

参考文献 中间体
合成目标
【1】 Hirokawa, Y.; et al.; Process development of the synthetic route to (R)-6-amino-1-ethyl-4-methylhexahydro-1,4-diazepine. Org Process Res Dev 2002, 6, 1, 28.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 20915 methyl (2S)-2-amino-3-hydroxypropanoate 5680-80-8 C4H9NO3 详情 详情
(II) 51660 methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoate C12H15NO5 详情 详情
(III) 53991 benzyl (1S)-1-(hydroxymethyl)-2-(methylamino)-2-oxoethylcarbamate n/a C12H16N2O4 详情 详情
(IV) 53992 benzyl (1R)-2-hydroxy-1-[(methylamino)methyl]ethylcarbamate n/a C12H18N2O3 详情 详情
(V) 53993 benzyl (1R)-2-[(tert-butoxycarbonyl)(methyl)amino]-1-(hydroxymethyl)ethylcarbamate n/a C17H26N2O5 详情 详情
(VI) 53994 (2R)-2-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)(methyl)amino]propyl methanesulfonate n/a C18H28N2O7S 详情 详情
(VII) 53995 benzyl (1S)-2-[(tert-butoxycarbonyl)(methyl)amino]-1-[(ethylamino)methyl]ethylcarbamate n/a C19H31N3O4 详情 详情
(VIII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(IX) 53999 ethyl 2-[{(2S)-2-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)(methyl)amino]propyl}(ethyl)amino]acetate n/a C23H37N3O6 详情 详情
(X) 54000 ethyl 2-[[(2R)-2-{[(benzyloxy)carbonyl]amino}-3-(methylamino)propyl](ethyl)amino]acetate n/a C18H29N3O4 详情 详情
(XI) 54001 benzyl (6S)-4-ethyl-1-methyl-2-oxo-1,4-diazepan-6-ylcarbamate n/a C16H23N3O3 详情 详情
(XII) 53997 benzyl (6S)-1-ethyl-4-methyl-1,4-diazepan-6-ylcarbamate n/a C16H25N3O2 详情 详情
(XIII) 17802 (6S)-1-ethyl-4-methyl-1,4-diazepan-6-ylamine; (6S)-1-ethyl-4-methyl-1,4-diazepan-6-amine C8H19N3 详情 详情
(XIV) 17801 5-bromo-2-methoxy-6-(methylamino)nicotinic acid C8H9BrN2O3 详情 详情
(XV) 53998 5-bromo-N-[(6S)-1-ethyl-4-methyl-1,4-diazepan-6-yl]-2-methoxy-6-(methylamino)nicotinamide n/a C16H26BrN5O2 详情 详情
(XVI) 23808 Fumaric acid; (E)-2-butenedioic acid 110-17-8 C4H4O4 详情 详情

合成路线38

该中间体在本合成路线中的序号：(VII)

The quinolinecarboxylic acid (III) was obtained by the Pfitzinger reaction of isatin (I) with 2-methoxyacetophenone (II) in ethanolic KOH at 80 C. Subsequent methyl ether cleavage in (III) using concentrated HI provided 3-hydroxy-2-phenylquinoline-4-carboxylic acid (IV). Coupling of acid (IV) with (S)-1-phenylpropylamine (V) by means of DCC and HOBt gave amide (VI). Ester (VIII) was then obtained by alkylation of the 3-hydroxy quinoline (VI) with ethyl bromoacetate (VII) in the presence of K2CO3 and KI. Finally, hydrolysis of the ethyl ester (VIII) with refluxing HCl afforded the corresponding carboxylic acid.

参考文献 中间体
合成目标
【1】 Giardina, G.A.M.; et al.; Discovery of a novel class of selective non-peptid. J Med Chem 1999, 42, 6, 1053.
【2】 Giardina, G.A.M.; Grugni, M.; Raveglia, L.F.; Farino, C. (GlaxoSmithKline plc); Quinoline derivs.. EP 0876347; JP 2000501104; US 6277862; WO 9721680 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 14098 2,3-Indolinedione; 1H-Indole-2,3-dione; Isatin 91-56-5 C8H5NO2 详情 详情
(II) 23641 2-methoxy-1-phenyl-1-ethanone 4079-52-1 C9H10O2 详情 详情
(III) 23642 3-methoxy-2-phenyl-4-quinolinecarboxylic acid C17H13NO3 详情 详情
(IV) 23643 3-hydroxy-2-phenyl-4-quinolinecarboxylic acid 485-89-2 C16H11NO3 详情 详情
(V) 23644 (1S)-1-phenylpropylamine; (1S)-1-phenyl-1-propanamine 3789-59-1 C9H13N 详情 详情
(VI) 58526 3-hydroxy-2-phenyl-N-[(1S)-1-phenylpropyl]-4-quinolinecarboxamide C25H22N2O2 详情 详情
(VII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VIII) 58527 ethyl 2-{[2-phenyl-4-({[(1S)-1-phenylpropyl]amino}carbonyl)-3-quinolinyl]oxy}acetate C29H28N2O4 详情 详情

合成路线39

该中间体在本合成路线中的序号：(B)

The precursor amino alcohol (XXVIII) was prepared by the following synthetic routes. Claisen orthoester rearrangement of (-)-myrtenol (XXIII) with triethyl orthoacetate at 165-195 C afforded the gamma,delta-unsaturated ester (XXIV). Subsequent ozonolysis of the exocyclic double bond gave rise to keto ester (XXV). Alternatively, keto ester (XXV) was obtained as the major diastereoisomer by alkylation of the lithium enolate of (R)-(+)-nopinone (XXVI) with ethyl bromoacetate in the presence of 1,3-dimethyl-2-imidazolidinone (DMI). Ketone (XXV) was either converted to oxime (XXVI) or to O-methyl oxime (XXVII) by treatment with hydroxylamine or O-methyl hydroxylamine, respectively. Reduction of the hydroxyimino and ester groups of (XXVI) to the key amino alcohol intermediate (XXVIII) was performed by using the combination LiAlH4/AlCl3 or with NaBH4 in the presence of several Lewis acids. The O-methyl oxime (XXVII) was directly reduced to amino alcohol (XXVIII) employing NaBH4 in the presence of boron trifluoride etherate or AlCl3 or, alternatively, with sodium metal in n-propanol. Optionally, the oxime ester (XXVII) was converted to (XXVIII) in a two step procedure, by first reduction of the ester group to alcohol (XXIX) with sodium bis(2-methoxyethoxy)aluminium hydride, and then reduction of the O-methyl oxime with sodium in n-propanol.

参考文献 中间体
合成目标
【1】 Arimura, A.; Honma, T.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Benzothiophenecarboxamide derivs. and PGD2 antagonists comprising them. EP 0944614; JP 2000514824; US 6083974; WO 9825919 .
【2】 Hiramatsu, Y.; Honma, T.; Mitsumori, S. (Shionogi & Co. Ltd.); Novel process for producing bicyclic amino alcohol. EP 1193243; WO 0102334 .
【3】 Okada, T.; Honma, T.; Kakinuma, M.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Process for producing benzothiophenecarboxylic acid amide derivs.. EP 1069123; WO 9950261 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(A) 60678 (1R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-one C9H14O 详情 详情
(XXIII) 51423 [(1R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methanol C10H16O 详情 详情
(XXIV) 52246 ethyl 2-(6,6-dimethyl-2-methylidenebicyclo[3.1.1]hept-3-yl)acetate C14H22O2 详情 详情
(XXV) 52247 ethyl 2-(6,6-dimethyl-2-oxobicyclo[3.1.1]hept-3-yl)acetate C13H20O3 详情 详情
(XXVI) 52251 ethyl 2-[2-(hydroxyimino)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]acetate C13H21NO3 详情 详情
(XXVII) 52246 ethyl 2-(6,6-dimethyl-2-methylidenebicyclo[3.1.1]hept-3-yl)acetate C14H22O2 详情 详情
(XXVIII) 52250 2-(2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)-1-ethanol C11H21NO 详情 详情
(XXIX) 60679 (1R,3R,5R)-3-(2-hydroxyethyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-one O-methyloxime C12H21NO2 详情 详情

合成路线40

该中间体在本合成路线中的序号：(XI)

The reaction of 4-hydroxybenzyl alcohol (V) with ethyl 2-bromoacetate (XI) by means of K2CO3 gives the phenoxyacetate (XII), which is then treated with SOCl2 in THF to obtain the benzyl chloride (XIII). Reaction of (XIII) with the indole derivative (VII) by means of NaH in DMF yields the adduct (XIV), whose ester group is reduced with LiAlH4 in THF to afford the 2-hydroxyethoxy compound (XV). Treatment of (XV) with CBr4 and PPh3 in THF provides the 2-bromoethoxy compound (XVI), which is converted into compound (XVIIII) by reaction with hexamethyleneimine (homopiperidine) (XVII) in THF. Finally, compound (XVIII) is debenzylated by hydrogenation with either H2 over Pd/C in ethanol/THF or with cyclohexadiene and Pd/C in THF/EtOH.

参考文献 中间体
合成目标
【1】 Miller, C.P.; Collini, M.D.; Tran, B.D.; et al.; Design, synthesis, and preclinical characterization of novel, highly selective indole estrogens. J Med Chem 2001, 44, 11, 1654.
【2】 Harris, H.A.; Miller, C.P.; Komm, B.S.; Bazedoxifene Acetate. Drugs Fut 2002, 27, 2, 117.
【3】 Miller, C.P.; Tran, B.D.; Collini, M.D. (American Home Products Corp.); Estrogenic agents. EP 0802183; JP 1998036346; US 5998402 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 29474 4-(hydroxymethyl)phenol; 4-hydroxyphenylmethanol 4-hydroxybenzenemethanol; 4-Hydroxybenzyl alcohol 623-05-2 C7H8O2 详情 详情
(VII) 38490 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indole; benzyl 4-[5-(benzyloxy)-3-methyl-1H-indol-2-yl]phenyl ether C29H25NO2 详情 详情
(XI) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(XII) 51988 ethyl 2-[4-(hydroxymethyl)phenoxy]acetate C11H14O4 详情 详情
(XIII) 38491 ethyl 2-[4-(chloromethyl)phenoxy]acetate C11H13ClO3 详情 详情
(XIV) 38492 ethyl 2-[4-([5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indol-1-yl]methyl)phenoxy]acetate C40H37NO5 详情 详情
(XV) 38493 2-[4-([5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indol-1-yl]methyl)phenoxy]-1-ethanol C38H35NO4 详情 详情
(XVI) 38494 benzyl 4-[5-(benzyloxy)-1-[4-(2-bromoethoxy)benzyl]-3-methyl-1H-indol-2-yl]phenyl ether; 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-1-[4-(2-bromoethoxy)benzyl]-3-methyl-1H-indole C38H34BrNO3 详情 详情
(XVII) 18672 azepane 111-49-9 C6H13N 详情 详情
(XVIII) 38495 1-[4-[2-(1-azepanyl)ethoxy]benzyl]-5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indole; 4-[1-[4-[2-(1-azepanyl)ethoxy]benzyl]-5-(benzyloxy)-3-methyl-1H-indol-2-yl]phenyl benzyl ether C44H46N2O3 详情 详情

合成路线41

该中间体在本合成路线中的序号：(XIII)

The reaction of (S)-2-amino-6-hydroxyhexanoic acid (I) with N-(ethoxycarbonyl)phthalimide (II) by means of Na2CO3 in water gives 6-hydroxy-2(S)-(phthalimido)hexanoic acid (III), which is esterified with benzyl bromide and Cs2CO3 in DMF yielding the benzyl ester (IV). The oxidation of the terminal OH group of (IV) with (COCl)2 in dichloromethane affords the aldehyde (V), which is methylated with AlMe3 in dichloromethane giving 6-hydroxy-2(S)-(phthalimido)heptanoic acid (VI). The oxidation of (VI) with oxalyl chloride as before yields the ketone (VII), which is methylated with TiCl4 and methylmagnesium chloride to provide the carbinol (VIII). The reaction of (VIII) with trimethylsilyl azide in dichloromethane gives the azido derivative (IX), which is cyclized by reduction with H2 over Pd/C in DMF yielding the perhydroazepinone (X). Elimination of phthalimido protecting group of (X) with hydrazine in methanol/dichloromethane affords 3(S)-amino-7,7-dimethylperhydroazepin-2-one (XI), which is protected with trityl chloride and TEA in dichloromethane to give the tritylamino compound (XII). The condensation of (XII) with ethyl 2-bromoacetate (XIII) by means of LHMDS, followed by deprotection with TFA affords the adduct (XIV) with a free amino group, which is acylated with 2(R)-benzyl-3-(benzyloxyamino)propionic acid (XV) by means of HOBT and EDAD in dichloromethane providing the amide (XVI). The formylation of (XVI) with formic acid and acetic anhydride gives the formamide (XVII), which is deprotected with H2 over Pd/C in ethanol yielding intermediate (XVIII). Finally, this compound is hydrolyzed with NaOH in methanol.

参考文献 中间体
合成目标
【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257.
【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(I) 22502 (2S)-2-amino-6-hydroxyhexanoic acid 6033-32-5 C6H13NO3 详情 详情
(II) 10283 ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide 22509-74-6 C11H9NO4 详情 详情
(III) 22512 (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoic acid C14H15NO5 详情 详情
(IV) 26841 benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyhexanoate C21H21NO5 详情 详情
(V) 26842 benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxohexanoate C21H19NO5 详情 详情
(VI) 26843 benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxyheptanoate C22H23NO5 详情 详情
(VII) 26844 benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxoheptanoate C22H21NO5 详情 详情
(VIII) 26845 benzyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-hydroxy-6-methylheptanoate C23H25NO5 详情 详情
(IX) 26846 benzyl (2S)-6-azido-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-methylheptanoate C23H24N4O4 详情 详情
(X) 26847 2-[(3S)-7,7-dimethyl-2-oxoazepanyl]-1H-isoindole-1,3(2H)-dione C16H18N2O3 详情 详情
(XI) 26848 (3S)-3-amino-7,7-dimethyl-2-azepanone C8H16N2O 详情 详情
(XII) 37281 (3S)-7,7-dimethyl-3-(tritylamino)-2-azepanone C27H30N2O 详情 详情
(XIII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(XIV) 37282 ethyl 2-[(6S)-6-amino-2,2-dimethyl-7-oxoazepanyl]acetate C12H22N2O3 详情 详情
(XV) 37283 (2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid C17H19NO3 详情 详情
(XVI) 37284 ethyl 2-[(6S)-6-([(2R)-2-benzyl-3-[(benzyloxy)amino]propanoyl]amino)-2,2-dimethyl-7-oxoazepanyl]acetate C29H39N3O5 详情 详情
(XVII) 37285 ethyl 2-[(6S)-6-([(2R)-2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-2,2-dimethyl-7-oxoazepanyl]acetate C30H39N3O6 详情 详情
(XVIII) 37286 ethyl 2-[(6S)-6-([(2R)-2-benzyl-3-[formyl(hydroxy)amino]propanoyl]amino)-2,2-dimethyl-7-oxoazepanyl]acetate C23H33N3O6 详情 详情

合成路线42

该中间体在本合成路线中的序号：(VII)

Sodium azide (I) is treated with sulfuric acid to give hydrazoic acid (II), which is condensed with 1-tetralone (III) in hot aqueous sulfuric acid yielding 2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (IV). The bromination of (IV) with Br2 in chloroform affords the 3-bromo derivative (V), which is treated with sodium azide in DMSO to give the corresponding azido derivative (VI). The condensation of (VI) with ethyl 2-bromoacetate (VII) by means of KOH and tetrabutylammonium bromide in THF yields the adduct (VIII). The azido group of (VIII) is reduced with H2 over Pd/C in ethanol the amine (IX) as a racemic mixture, which is submitted to optical resolution with L-tartaric acid affording the desired (S)-enantiomer (X). The condensation of intermediate (X) with 2(R)-benzyl-3-benzyloxyamino)propionic acid (XI) by means of HOBT and EDAC in dichloromethane provides the amide (XII), which is formylated with formic acid and acetic anhydride yielding the formamide (XIII). The debenzylation of (XIII) with H2 over Pd/C in methanol affords the intermediate (XIV), which is finally hydrolyzed with NaOH in methanol.

参考文献 中间体
合成目标
【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257.
【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 37288 1H-triazirine HN3 详情 详情
(III) 20720 3,4-dihydro-1(2H)-naphthalenone 529-34-0 C10H10O 详情 详情
(IV) 30511 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one C10H11NO 详情 详情
(V) 20723 3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one C10H10BrNO 详情 详情
(VI) 20891 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one C10H10N4O 详情 详情
(VII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VIII) 20893 ethyl 2-(3-azido-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate C14H16N4O3 详情 详情
(IX) 37292 ethyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate C14H18N2O3 详情 详情
(X) 20894 ethyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate 109010-60-8 C14H18N2O3 详情 详情
(XI) 37283 (2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid C17H19NO3 详情 详情
(XII) 37289 ethyl 2-[(3S)-3-([(2R)-2-benzyl-3-[(benzyloxy)amino]propanoyl]amino)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate C31H35N3O5 详情 详情
(XIII) 37290 ethyl 2-[(3S)-3-([(2R)-2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate C32H35N3O6 详情 详情
(XIV) 37291 ethyl 2-[(3S)-3-([(2R)-2-benzyl-3-[formyl(hydroxy)amino]propanoyl]amino)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate C25H29N3O6 详情 详情

合成路线43

该中间体在本合成路线中的序号：

Alkylation of methyl 4-oxo-3-piperidinecarboxylate (I) with ethyl bromoacetate provided piperidineacetate (II). Subsequent decarbomethoxylation of (II) using LiCl in boiling DMF produced piperidone (III). On the other hand, coupling between 4-aminobenzonitrile (IV) and N-Boc-glycine (V) via activation with carbonyldiimidazole gave amide (V). The Boc group of (V) was then deprotected with HCl in EtOAc to yield 2-amino-N-(4-cyanophenyl)acetamide (VI). Reductive condensation of amine (VI) with piperidone (III) employing NaBH(OAc)3 furnished adduct (VII), which was further reductocondensed with chloroacetaldehyde to give chloroethyl amine (VIII). Cyclization of (VIII) in the presence of NaH generated piperazinone (IX). Finally, addition of hydroxylamine to the cyano group of (IX) provided the corresponding hydroxyamidine.

参考文献 中间体
合成目标
【1】 Suzuki, K.; Tsukamoto, S.; Yanagisawa, I.; Matsumoto, Y.; Ichihara, M.; Akamatsu, S.; Kaku, S.; Kawasaki, T.; Novel orally active GPIIb/IIIa antagonists: Synthesis and structure-activity relationship studies of oxopiperazine derivatives. Symp Med Chem 1999, Abst 1P-02.
【2】 Matsumoto, Y.; Akamatsu, S.; Ichihara, M.; Kawasaki, T.; Kaku, S.; Yanagisawa, I. (Merck Patent GmbH; Yamanouchi Pharmaceutical Co., Ltd.); Substd. amidinobenzene derivs. and medicinal compsns. thereof. EP 0905129; US 6057324; WO 9745413 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(I) 28106 methyl 4-oxo-3-piperidinecarboxylate 56026-52-9 C7H11NO3 详情 详情
(II) 37983 methyl 1-(2-ethoxy-2-oxoethyl)-4-oxo-3-piperidinecarboxylate C11H17NO5 详情 详情
(III) 37984 ethyl 2-(4-oxo-1-piperidinyl)acetate C9H15NO3 详情 详情
(IV) 15361 4-Aminobenzonitrile 873-74-5 C7H6N2 详情 详情
(V) 37985 tert-butyl 2-(4-cyanoanilino)-2-oxoethylcarbamate C14H17N3O3 详情 详情
(VI) 37986 2-amino-N-(4-cyanophenyl)acetamide C9H9N3O 详情 详情
(VII) 37988 ethyl 2-(4-[[2-(4-cyanoanilino)-2-oxoethyl]amino]-1-piperidinyl)acetate C18H24N4O3 详情 详情
(VIII) 37987 ethyl 2-(4-[(2-chloroethyl)[2-(4-cyanoanilino)-2-oxoethyl]amino]-1-piperidinyl)acetate C20H27ClN4O3 详情 详情
(IX) 37989 ethyl 2-[4-[4-(4-cyanophenyl)-3-oxo-1-piperazinyl]-1-piperidinyl]acetate C20H26N4O3 详情 详情

合成路线44

该中间体在本合成路线中的序号：(II)

Ethyl 2-(3-formylphenoxy)acetate (III) was prepared by alkylation of 3-hydroxybenzaldehyde (I) with ethyl bromoacetate (II) in the presence of K2CO3 and KI. Reduction of aldehyde (III) with NaBH4 provided the benzyl alcohol (IV), which was further protected as the silyl ether (V) by treatment with tert-butyldimethylsilyl chloride and imidazole. Addition of methylmagnesium bromide to the ester function of (V) yielded the tertiary alcohol (VI). Condensation of the sodium alkoxide of (VI) with 3-(bromomethyl)thiophene (VII) furnished ether (VIII). After desilylation of (VIII) employing tetrabutylammonium fluoride, the resultant benzyl alcohol (IX) was treated with methanesulfonyl chloride and triethylamine to afford mesylate (X). Alkylation of amine (XI) with mesylate (X) furnished the target tertiary amine, which was finally treated with HCl in EtOAc to afford the corresponding hydrochloride salt.

参考文献 中间体
合成目标
【1】 Okumura, H.; Washizuka, K.; Fujii, N.; Takasugi, H. (Fujisawa Pharmaceutical Co., Ltd.); Substd. amine derivs.. JP 2000517314; WO 9808838 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 28537 3-hydroxybenzaldehyde 100-83-4 C7H6O2 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 56003 ethyl 2-(3-formylphenoxy)acetate C11H12O4 详情 详情
(IV) 56004 ethyl 2-[3-(hydroxymethyl)phenoxy]acetate C11H14O4 详情 详情
(V) 56005 ethyl 2-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenoxy]acetate C17H28O4Si 详情 详情
(VI) 56006 1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenoxy]-2-methyl-2-propanol C17H30O3Si 详情 详情
(VII) 56007 3-(bromomethyl)thiophene 34846-44-1 C5H5BrS 详情 详情
(VIII) 56008 tert-butyl(dimethyl)silyl 3-[2-methyl-2-(3-thienylmethoxy)propoxy]benzyl ether; tert-butyl(dimethyl)({3-[2-methyl-2-(3-thienylmethoxy)propoxy]benzyl}oxy)silane C22H34O3SSi 详情 详情
(IX) 56009 {3-[2-methyl-2-(3-thienylmethoxy)propoxy]phenyl}methanol C16H20O3S 详情 详情
(X) 56010 3-[2-methyl-2-(3-thienylmethoxy)propoxy]benzyl methanesulfonate C17H22O5S2 详情 详情
(XI) 56011 (E)-N-ethyl-6,6-dimethyl-2-hepten-4-yn-1-amine; N-[(E)-6,6-dimethyl-2-hepten-4-ynyl]-N-ethylamine C11H19N 详情 详情

合成路线45

该中间体在本合成路线中的序号：(IV)

3',4'-Dihydroxyacetophenone (I) was selectively alkylated at position 4' with alpha-bromo-2,6-difluorotoluene (II) in the presence of Li2CO3 in DMF. The resulting ether (III) was further alkylated with ethyl bromoacetate (IV) to give (V). Subsequent Horner-Emmons condensation of (V) with the phosphonoacetamide (VI) provided cinnamide (VII). The target carboxylic acid was then obtained by saponification of the ethyl ester of (VII) with NaOH.

参考文献 中间体
合成目标
【1】 Greenspan, P.D.; Fujimoto, R.A.; Marshall, P.J.; Raychaudhuri, A.; Lipson, K.E.; Zhou, H.; Doti, R.A.; Coppa, D.E.; Zhu, L.; Pelletier, R.; Uziel-Fusi, S.; Jackson, R.H.; Chin, M.H.; Kotyuk, B.L.; Fitt, J.J.; Carboxy-substituted cinnamides: A novel series of potent, orally active LTB4 receptor antagonists. J Med Chem 1999, 42, 1, 164.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 22315 1-(3,4-dihydroxyphenyl)-1-ethanone 1197-09-7 C8H8O3 详情 详情
(II) 22316 2-(bromomethyl)-1,3-difluorobenzene 85118-00-9 C7H5BrF2 详情 详情
(III) 22317 1-[4-[(2,6-difluorobenzyl)oxy]-3-hydroxyphenyl]-1-ethanone C15H12F2O3 详情 详情
(IV) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(V) 22319 ethyl 2-[5-acetyl-2-[(2,6-difluorobenzyl)oxy]phenoxy]acetate C19H18F2O5 详情 详情
(VI) 22320 diethyl 2-(diethylamino)-2-oxoethylphosphonate C10H22NO4P 详情 详情
(VII) 22321 ethyl 2-[5-[(E)-3-(diethylamino)-1-methyl-3-oxo-1-propenyl]-2-[(2,6-difluorobenzyl)oxy]phenoxy]acetate C25H29F2NO5 详情 详情

合成路线46

该中间体在本合成路线中的序号：(V)

The condensation of 4-amino-5-chloro-2-methoxybenzoic acid (I) with 4-amino-1-(triphenylmethyl)piperidine (II) by means of ethyl chloroformate and triethylamine in THF gives the corresponding amide (III), which is deprotected with HCl in actone yielding 4-amino-5-chloro-2-methoxy-N-(4-piperidyl)benzamide (IV). The condensation of (IV) with ethyl bromoacetate (V) by means of K2CO3 in DMF affords the substituted acetate (VI), which is finally saponified with NaOH in methanol.

参考文献 中间体
合成目标
【1】 Ito, Y.; Kato, H.; Yasuda, S.; Iwasaki, N.; Nishino, H.; Takeshita, M. (Hokuriku Seiyaku Co., Ltd.); Benzamide deriv.. EP 0640601; US 5395832; US 5500422; WO 9214705 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 12419 4-Amino-5-chloro-2-methoxybenzoic acid 7206-70-4 C8H8ClNO3 详情 详情
(II) 19955 1-trityl-4-piperidinylamine; 1-trityl-4-piperidinamine C24H26N2 详情 详情
(III) 19956 4-amino-5-chloro-2-methoxy-N-(1-trityl-4-piperidinyl)benzamide C32H32ClN3O2 详情 详情
(IV) 19957 4-amino-5-chloro-2-methoxy-N-(4-piperidinyl)benzamide C13H18ClN3O2 详情 详情
(V) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VI) 19959 ethyl 2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidinyl]acetate C17H24ClN3O4 详情 详情

合成路线47

该中间体在本合成路线中的序号：(XV)

The intermediate amine (X) has been obtained as follows: The reaction of ethyl 2-bromoacetate (XV) with cyclohexylmethylamine (XVI) by means of Et3N in THF gives the N-(cyclohexylmethyl)glycine ethyl ester (XVII), which is protected with (Boc)2O in dichloromethane yielding (XVIII). The hydrolysis of (XVIII) with NaOH in water gives the corresponding free acid (XIX), which is condensed with 2-[2-(methylamino)ethyl]pyridine (XX) by means of BOP-PF6 and DIEA in DMF to provide the amide (XXI). Finally, this compound is deprotected with HCl in dioxane/water to obtain the ddesired intermediate (X).

参考文献 中间体
合成目标
【1】 Simoneau, B.; Lavallee, P.; Anderson, P.C.; et al.; Discovery of non-peptidic P2-P3 butanediamide renin inhibitors with high oral efficacy. Bioorg Med Chem 1999, 7, 3, 489.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 29540 2-[(cyclohexylmethyl)amino]-N-methyl-N-[2-(2-pyridinyl)ethyl]acetamide C17H27N3O 详情 详情
(XV) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(XVI) 29545 cyclohexylmethanamine; cyclohexylmethylamine 3218-02-8 C7H15N 详情 详情
(XVII) 29546 ethyl 2-[(cyclohexylmethyl)amino]acetate C11H21NO2 详情 详情
(XVIII) 29547 ethyl 2-[(tert-butoxycarbonyl)(cyclohexylmethyl)amino]acetate C16H29NO4 详情 详情
(XIX) 29548 2-[(tert-butoxycarbonyl)(cyclohexylmethyl)amino]acetic acid C14H25NO4 详情 详情
(XX) 29549 N-methyl-2-(2-pyridinyl)-1-ethanamine; N-methyl-N-[2-(2-pyridinyl)ethyl]amine 5579-84-0 C8H12N2 详情 详情
(XXI) 29550 tert-butyl cyclohexylmethyl(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)carbamate C22H35N3O3 详情 详情

合成路线48

该中间体在本合成路线中的序号：

Alkylation of N-acetyl-D-cysteine (I) with 1-fluoro-5-methyl-2-nitrobenzene (II) gave adduct (III). After hydrolysis of the acetamido group of (III) with aqueous sulfuric acid, the resulting amine (IV) was protected as the benzyl carbamate (V). Reduction of the nitro group of (V) provided amino acid (VI), which was cyclized to the benzothiazepinone (VII) using EDC. Subsequent alkylation of (VII) with ethyl bromoacetate under phase-transfer conditions yielded (VIII) (1). Cleavage of both N-Cbz group and ethyl ester by HBr in AcOH, followed by introduction of the N-Boc group afforded intermediate (X) (2). Optionally, hydrogenolysis of the N-Cbz group of (VIII) provided amino lactam (XI). This was coupled with N-Boc-O-benzylserine (XII) to give amide (XIII). Then, basic hydrolysis of the ethyl ester produced carboxylic acid (XIV).

参考文献 中间体
合成目标
【1】 Dodey, P.; Luccarini, J.-M.; Martinez, J.; Amblard, M.; Daffix, I. (Fournier Industrie et Santé); Peptides agonists of bradykinine B2 receptor. FR 2756566; WO 9824809 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(I) 39365 (2S)-2-(acetamido)-3-sulfanylpropionic acid 616-91-1 C5H9NO3S 详情 详情
(II) 39366 2-fluoro-4-methyl-1-nitrobenzene 446-34-4 C7H6FNO2 详情 详情
(III) 39367 (2S)-2-(acetamido)-3-[(5-methyl-2-nitrophenyl)sulfanyl]propionic acid C12H14N2O5S 详情 详情
(IV) 39368 (2S)-2-amino-3-[(5-methyl-2-nitrophenyl)sulfanyl]propionic acid C10H12N2O4S 详情 详情
(V) 39369 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(5-methyl-2-nitrophenyl)sulfanyl]propionic acid C18H18N2O6S 详情 详情
(VI) 39370 (2S)-3-[(2-amino-5-methylphenyl)sulfanyl]-2-[[(benzyloxy)carbonyl]amino]propionic acid C18H20N2O4S 详情 详情
(VII) 39371 benzyl (3S)-8-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-ylcarbamate C18H18N2O3S 详情 详情
(VIII) 39372 ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate C22H24N2O5S 详情 详情
(IX) 39376 2-[(3S)-3-amino-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid C12H14N2O3S 详情 详情
(X) 39377 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid C17H22N2O5S 详情 详情
(XI) 39373 ethyl 2-[(3S)-3-amino-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate C14H18N2O3S 详情 详情
(XII) 16886 (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine 23680-31-1 C15H21NO5 详情 详情
(XIII) 39374 ethyl 2-[(3S)-3-([(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate C29H37N3O7S 详情 详情
(XIV) 39375 2-[(3S)-3-([(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid C27H33N3O7S 详情 详情

合成路线49

该中间体在本合成路线中的序号：(VIII)

The alkylation of dimethyl L-glutamate (I) with 2-bromoacetonitrile (II) by means of LiHMDS in THF gives stereoselectively the cyanomethyl derivative (III), which is reduced with H2 over PtO2 in methanol/CHCl3 to yield the corresponding 2-aminoethyl derivative (IV). The cyclization of (IV) by means of Na2CO3 in the same solvent affords the pyrrolidinone (V), whose ester group is reduced with NaBH4 in methanol/THF to provide the propanol derivative (VI). The oxidation of (VI) with SO3/pyridine and DIEA in DMSO/dichloromethane gives the aldehyde (VII), which is finally condensed with ethyl 2-bromoacetate (VIII) by means of Et3P in dichloromethane to yield the chiral 4-(tert-butoxycarbonyl)-5-(2-oxopyrrolidin-3-yl)-2-pentanoic acid ethyl ester (IX), the desired target key intermediate.

参考文献 中间体
合成目标
【1】 Tian, Q.; et al.; An efficient synthesis of a key intermediate for the preparation of the rhinovirus protease inhibitor AG7088 via asymmetric dianionic cyanomethylation of N-Boc-L-(+)-glutamic acid dimethyl ester. Tetrahedron Lett 2001, 42, 39, 6807.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 55035 dimethyl (2S)-2-[(tert-butoxycarbonyl)amino]pentanedioate C12H21NO6 详情 详情
(II) 31883 2-bromoacetonitrile 590-17-0 C2H2BrN 详情 详情
(III) 55036 dimethyl (2S,4R)-2-[(tert-butoxycarbonyl)amino]-4-(cyanomethyl)pentanedioate C14H22N2O6 详情 详情
(IV) 55037 dimethyl (2S,4S)-2-(2-aminoethyl)-4-[(tert-butoxycarbonyl)amino]pentanedioate C14H26N2O6 详情 详情
(V) 55038 methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[(3S)-2-oxopyrrolidinyl]propanoate C13H22N2O5 详情 详情
(VI) 55039 tert-butyl (1S)-2-hydroxy-1-{[(3S)-2-oxopyrrolidinyl]methyl}ethylcarbamate C12H22N2O4 详情 详情
(VII) 55040 tert-butyl (1S)-1-formyl-2-[(3S)-2-oxopyrrolidinyl]ethylcarbamate C12H20N2O4 详情 详情
(VIII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(IX) 55041 ethyl (E,4S)-4-[(tert-butoxycarbonyl)amino]-5-[(3S)-2-oxopyrrolidinyl]-2-pentenoate C16H26N2O5 详情 详情

合成路线50

该中间体在本合成路线中的序号：(II)

The intermediate 1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (VIII) has been obtained by three different ways: 1) The cyclization of 2-hdroxybenzaldehyde (I) with ethyl 2-bromoacetate (II) by means of K2CO3 in DMF gives ethyl benzofuran-2-carboxylate (III), which is reduced with LiAlH4 in refluxing THF to the carbinol (IV). The reaction of (IV) with acetone cyanohydrin (V), PPh3 and DEAD yields the acetonitrile (VI), which is reduced with H2 over Raney-Ni to afford the ethylamine (VII). Finally, this compound is cyclized with formaldehyde in refluxing water to provide the desired intermediate (VIII). 2) The intermediate ethyl benzofuran-2-carboxylate (III), is hydrolyzed with NaOH to the corresponding free acid (IX), which is decarboxylated with Cu at 240 C in quinoline to yield benzofuran (X). The reaction of (X) with oxirane (XI) by means of n-BuLi in ethyl ether affords 2-(2-benzofuryl)ethanol (XII), which is treated first with MsCl and TEA, and then with NaI in refluxing acetone to provide the 2-(2-iodoethyl)benzofuran (XIII). The reaction of (XIII) with hexamethylenetetramine (HMT) gives the adduct (XIV), which is finally cyclized to the target intermediate (VIII) by means of HCl in refluxing ethanol. 3) The target intermediate (VIII) can also be obtained by cyclization of O-phenylhydroxylamine (XV) with 4-piperidone (XVI) in refluxing isopropanol. Finally, intermediate (VIII) is condensed with 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidine (XVII) by means of Na2CO3 and KI in a refluxing organic solvent such as 4-methyl-2-pentanone.

参考文献 中间体
合成目标
【1】 Bischoff, F.P.; Kennis, L.E.J.; Mertens, C.J.; et al.; New 2-substituted 1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine having highly active and potent central alpha2-antagonistic activity as potential antidepressants. Bioorg Med Chem Lett 2000, 10, 1, 71.
【2】 Bischoff, F.P.; Kennis, L.E.J.; Love, C.J. (Janssen Pharmaceutica NV); 1,2,3,4-Tetrahydro-benzofuro[3,2-c]pyridine derivs.. EP 1019408; JP 2000505115; WO 9845297 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 21351 2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde 90-02-8 C7H6O2 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 38334 ethyl 1-benzofuran-2-carboxylate C11H10O3 详情 详情
(IV) 38335 1-benzofuran-2-ylmethanol C9H8O2 详情 详情
(V) 18029 Acetone cyanohydrin; 2-Hydroxy-2-methylpropanenitrile; 2-Hydroxy-2-methylpropionitrile; 2-Hydroxyisobutyronitrile; 2-Methyllactonitrile; alpha-Hydroxyisobutyronitrile 75-86-5 C4H7NO 详情 详情
(VI) 38336 2-(1-benzofuran-2-yl)acetonitrile C10H7NO 详情 详情
(VII) 38337 2-(1-benzofuran-2-yl)-1-ethanamine; 2-(1-benzofuran-2-yl)ethylamine C10H11NO 详情 详情
(VIII) 38338 1,2,3,4-tetrahydro[1]benzofuro[3,2-c]pyridine C11H11NO 详情 详情
(IX) 38339 Benzofuran-2-carboxylic acid; 1-benzofuran-2-carboxylic acid 496-41-3 C9H6O3 详情 详情
(X) 38340 1-benzofuran 271-89-6 C8H6O 详情 详情
(XI) 10393 Oxirane; Ethylene oxide 75-21-8 C2H4O 详情 详情
(XII) 38341 2-(1-benzofuran-2-yl)-1-ethanol C10H10O2 详情 详情
(XIII) 38342 2-(2-iodoethyl)-1-benzofuran C10H9IO 详情 详情
(XIV) 38343 1-[2-(1-benzofuran-2-yl)ethyl]-3,5-diaza-1-azoniatricyclo[3.3.1.1(3,7)]decane iodide C17H22IN3O 详情 详情
(XV) 25770 1-(aminooxy)benzene; O-phenylhydroxylamine C6H7NO 详情 详情
(XVI) 27115 4-piperidinone 40064-34-4 C5H9NO 详情 详情
(XVII) 38344 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one C11H11ClN2O 详情 详情

合成路线51

该中间体在本合成路线中的序号：(I)

Condensation of ethyl bromoacetate (I) with dimethyl sulfide gave the sulfonium salt (II). Addition of the sulfur ylide resulting from (II) and DBU to cyclopentenone (III) produced the bicyclic compound (IV). This was converted into the silyl enolate (V), which was subsequently oxidized to the unsaturated ketone (VI) by means of palladium diacetate. Alternatively, (IV) was directly oxidized to (VI) using allyl methyl carbonate and palladium diacetate. Treatment of enone (VI) with tert-butyl hydroperoxide and DBU produced epoxide (VII), which was further converted into hydroxy ketone (VIII) by reaction with diphenyl diselenide in the presence of N-acetyl-cysteine and sodium borate. Bucherer-Bergs reaction of ketone (VIII) with potassium cyanide and ammonium carbamate produced a mixture of diastereomeric hydantoins (IX). After N-alkylation of the hydantoin ring of (IX) with benzyl bromide, the desired isomer (X) was isolated by preparative HPLC. Finally, alcohol oxidation, with concomitant hydantoin hydrolysis, by treatment with Jones reagent furnished the title compound.

参考文献 中间体
合成目标
【1】 Massey, S.M.; Monn, J.A.; Valli, M.J. (Eli Lilly and Company); Excitatory amino acid receptor modulators. EP 0878463; US 5958960 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IXa) 44097 　 C11H14N2O5 详情 详情
(IXb) 44098 　 C11H14N2O5 详情 详情
(I) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(II) 11947 (2-Ethoxy-2-oxoethyl)(dimethyl)sulfonium bromide 5187-82-6 C6H13BrO2S 详情 详情
(III) 25950 2-cyclopenten-1-one 930-30-3 C5H6O 详情 详情
(IV) 44092 ethyl (1S,5R,6S)-2-oxobicyclo[3.1.0]hexane-6-carboxylate C9H12O3 详情 详情
(V) 44093 ethyl (1S,5R,6S)-2-[(trimethylsilyl)oxy]bicyclo[3.1.0]hex-2-ene-6-carboxylate C12H20O3Si 详情 详情
(VI) 44094 ethyl (1R,5S,6S)-4-oxobicyclo[3.1.0]hex-2-ene-6-carboxylate C9H10O3 详情 详情
(VII) 44095 ethyl (1R,2R,4R,6S,7S)-5-oxo-3-oxatricyclo[4.1.0.0(2,4)]heptane-7-carboxylate C9H10O4 详情 详情
(VIII) 44096 ethyl (1R,2S,5S,6S)-2-hydroxy-4-oxobicyclo[3.1.0]hexane-6-carboxylate C9H12O4 详情 详情
(X) 44099 　 C18H20N2O5 详情 详情

合成路线52

该中间体在本合成路线中的序号：(II)

The reaction of di-tert-butyl malonate (I) with ethyl 2-bromoacetate (II) by means of NaH in THF gives di-tert-butyl 2-(ethoxycarbonylmethyl)malonate (III), which is condensed with trans-4-methylcyclohexylcarbonyl chloride (IV) by means of NaH in THF, and without isolation is treated with p-toluenesulfonic acid in refluxing toluene to afford trans-4-(4-methylcyclohexyl)-4-oxobutyric acid ethyl ester (V). Finally, this compound is hydrolyzed with aqueous NaOH.

参考文献 中间体
合成目标
【1】 Shinkai, H.; Ozeki, H.; Motomura, T.; Ohta, T.; Furukawa, N.; Uchida, I.; 4-(trans-4-Methylcyclohexyl)-4-oxobutyric acid (JTT-608). A new class of antidiabetic agent. J Med Chem 1998, 41, 27, 5420.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 14346 di(tert-butyl) malonate; Di-tert-butyl malonate 541-16-2 C11H20O4 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 24798 1,1-di(tert-butyl) 2-ethyl 1,1,2-ethanetricarboxylate C15H26O6 详情 详情
(IV) 24799 4-methylcyclohexanecarbonyl chloride C8H13ClO 详情 详情
(V) 24800 ethyl 4-(4-methylcyclohexyl)-4-oxobutanoate C13H22O3 详情 详情

合成路线53

该中间体在本合成路线中的序号：(II)

The intermediate 2-[4-(chloromethyl)phenoxy]acetic acid ethyl ester (IV) has been obtained as follows: The reaction of 4-hydroxybenzyl alcohol (I) with ethyl 2-bromoacetate (II) by means of K2CO3 gives the phenoxyacetate (III), which is then treated with SOCl2 in THF to obtain the desired intermediate (IV). The cyclization of 4-(benzyloxy)aniline (V) with 2-bromo-1-[4-(benzyloxy)phenyl]-1-propanone (VI) by means of TEA in DMF gives 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indole (VII), which is alkylated with the intermediate (IV) by means of NaH in DMF to yield the adduct (VIII). The reduction of the ester group of (VIII) with LiAlH4 in THF affords the 2-hydroxyethoxy compound (IX), which is treated with CBr4 and PPh3 in THF to provide the 2-bromoethoxy compound (X). The reaction of (X) with piperidine in THF gives the piperidinoethoxy compound (XI), which is finally debenzylated by hydrogenation with H2 over Pd/C in ethanol/THF to afford the target indole derivative.

参考文献 中间体
合成目标
【1】 Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Pipendoxifene. Drugs Fut 2002, 27, 10, 942.
【2】 Miller, C.P.; Collini, M.D.; Tran, B.D.; et al.; Design, synthesis, and preclinical characterization of novel, highly selective indole estrogens. J Med Chem 2001, 44, 11, 1654.
【3】 Miller, C.P.; Tran, B.D.; Collini, M.D. (American Home Products Corp.); Estrogenic agents. EP 0802183; JP 1998036346; US 5998402 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 29474 4-(hydroxymethyl)phenol; 4-hydroxyphenylmethanol 4-hydroxybenzenemethanol; 4-Hydroxybenzyl alcohol 623-05-2 C7H8O2 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 51988 ethyl 2-[4-(hydroxymethyl)phenoxy]acetate C11H14O4 详情 详情
(IV) 38491 ethyl 2-[4-(chloromethyl)phenoxy]acetate C11H13ClO3 详情 详情
(V) 22460 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine C13H13NO 详情 详情
(VI) 38489 4-Benzyloxy-alpha-bromopropiophenone; 1-[4-(benzyloxy)phenyl]-2-bromo-1-propanone; alpha-Bromo-4-benzyloxy propiophenone 54081-45-9 C16H15BrO2 详情 详情
(VII) 38490 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indole; benzyl 4-[5-(benzyloxy)-3-methyl-1H-indol-2-yl]phenyl ether C29H25NO2 详情 详情
(VIII) 38492 ethyl 2-[4-([5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indol-1-yl]methyl)phenoxy]acetate C40H37NO5 详情 详情
(IX) 38493 2-[4-([5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indol-1-yl]methyl)phenoxy]-1-ethanol C38H35NO4 详情 详情
(X) 38494 benzyl 4-[5-(benzyloxy)-1-[4-(2-bromoethoxy)benzyl]-3-methyl-1H-indol-2-yl]phenyl ether; 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-1-[4-(2-bromoethoxy)benzyl]-3-methyl-1H-indole C38H34BrNO3 详情 详情
(XI) 46523 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1-[4-[2-(1-piperidinyl)ethoxy]benzyl]-1H-indole; benzyl 4-(5-(benzyloxy)-3-methyl-1-[4-[2-(1-piperidinyl)ethoxy]benzyl]-1H-indol-2-yl)phenyl ether C43H44N2O3 详情 详情

合成路线54

该中间体在本合成路线中的序号：(II)

The condensation of 4-(2-bromoethyl)phenol (I) with ethyl bromoacetate (II) in the presence of K2CO3 produced the phenoxyacetate (III). This was then condensed with (1R,2S)-2-amino-1-(4-hydroxyphenyl)-propan-1-ol (IV) to give adduct (V). the ethyl ester group of (V) was finally hydrolyzed with NaOH to yield the title carboxylic acid.

参考文献 中间体
合成目标
【1】 Tamai, T.; Akahane, M.; Mukaiyama, H.; Muranaka, H.; Tanaka, N.; Sato, M.; Hirabayashi, A. (Kissei Pharmaceutical Co., Ltd.); Aminoethylphenoxyacetic acid derivs. and drugs for pain remission and calculi removal promotion in urinary lithiasis. EP 1002791; WO 9905090 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 46834 4-(2-bromoethyl)phenol C8H9BrO 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 46835 ethyl 2-[4-(2-bromoethyl)phenoxy]acetate C12H15BrO3 详情 详情
(IV) 46836 4-[(1R,2S)-2-amino-1-hydroxypropyl]phenol C9H13NO2 详情 详情
(V) 46837 ethyl 2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl)phenoxy]acetate C21H27NO5 详情 详情

合成路线55

该中间体在本合成路线中的序号：(II)

Alkylation of the benzamido piperidine (I) with ethyl chloroacetate (II) provided the piperidine acetate ethyl ester (III), which was further hydrolyzed with NaOH to the corresponding carboxylic acid (IV). The title butyl ester was prepared by reaction of acid (IV) with n-butyl bromide in the presence of K2CO3.

参考文献 中间体
合成目标
【1】 Sakaguchi, J.; et al.; Synthesis and gastrointestinal prokinetic activity of novel benzamide derivatives with amphoteric side chains. Chem Pharm Bull 2001, 49, 4, 424.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 19957 4-amino-5-chloro-2-methoxy-N-(4-piperidinyl)benzamide C13H18ClN3O2 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 19959 ethyl 2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidinyl]acetate C17H24ClN3O4 详情 详情
(IV) 56564 2-{4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidinyl}acetic acid C15H20ClN3O4 详情 详情

合成路线56

该中间体在本合成路线中的序号：(IV)

Synthesis of [18F]FEtNTI: The intermediate 2-(N1-phenylhydrazino)acetic acid ethyl ester (II) has been obtained by two different ways: 1.- By nitrosation of N-phenylglycine ethyl ester (I) with NaNO2 followed by readuction with Zn/acetic acid (low yields). 2.- By condensation of phenylhydrazine (III) with ethyl bromoacetate (IV) by means of an excess of triethylamine. The cyclization of intermediate (II) with naltrexone (V) by mans of HCl in methanol gives the indolomorphinanylacetic ester (VI), which is benzyl protected at the OH group by means of benzyl bromide and K2CO3 in DMF yielding the benzyl ether (VII). The reduction of the ester group of (VII) with LiAlH4 in THF/toluene afords the indolomorphinanylethanol (VIII), which is treated with tosyl chloride and potassium trimethylsilanolate in toluene to provide the corresponding tosylate (IX). The reaction of (IX) with potassium [18F]fluoride, K2CO3 and Kryptpfix [2.2.2] in hot DMF gives the 18F labeled intermediate (X), which is finally debenzylated by hydrogenation with H2 over Pd/C in DMF/triethylamine.

参考文献 中间体
合成目标
【1】 Mathews, W.B.; et al.; Synthesis of N1´-([F-18]fluoroethyl)naltrindole ([F-18]FEtNTI): A radioligand for positron emission tomographic studies of delta opioid receptors. J Label Compd Radiopharm 1999, 42, 1, 43.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 25701 ethyl 2-anilinoacetate 2216-92-4 C10H13NO2 详情 详情
(II) 25702 ethyl 2-(1-phenylhydrazino)acetate C10H14N2O2 详情 详情
(III) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(IV) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(V) 25079 (1S,5R,13R,17S)-4-(cyclopropylmethyl)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one; Naltrexone 16590-41-3 C20H23NO4 详情 详情
(VI) 25704 ethyl 2-[(1S,2S,13S,21R)-22-(cyclopropylmethyl)-2,16-dihydroxy-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-11-yl]acetate C31H33NO5 详情 详情
(VII) 25705 ethyl 2-[(1S,2S,13S,21R)-16-(benzyloxy)-22-(cyclopropylmethyl)-2-hydroxy-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-11-yl]acetate C38H39NO5 详情 详情
(VIII) 25706 (1S,2S,13S,21R)-16-(benzyloxy)-22-(cyclopropylmethyl)-11-(2-hydroxyethyl)-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-2-ol C36H37NO4 详情 详情
(IX) 25707 2-[(1S,2S,13S,21R)-16-(benzyloxy)-22-(cyclopropylmethyl)-2-hydroxy-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-11-yl]ethyl 4-methylbenzenesulfonate C43H43NO6S 详情 详情
(X) 25708 (1S,2S,13S,21R)-16-(benzyloxy)-22-(cyclopropylmethyl)-11-(2-fluoroethyl)-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-2-ol C36H36FNO3 详情 详情
(X) 45358 (1S,2S,13S,21R)-16-(benzyloxy)-22-(cyclopropylmethyl)-11-(2-fluoroethyl)-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-2-ol C36H36FNO3 详情 详情

合成路线57

该中间体在本合成路线中的序号：(A)

The condensation of 5-(4-chlorophenyl)-2-furaldehyde (I) with ethyl bromoacetate (A) by means of Zn in benzene gives ethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropanoate (II), which is then hydrolyzed with NaOH in refluxing aqueous ethanol.

参考文献 中间体
合成目标
【1】 Castañer, J.; Blancafort, P.; Orpanoxin. Drugs Fut 1978, 3, 12, 888.
【2】 Pelosi, S.S. Jr. (Norwich Eaton); 3-(5-aryl-2-furyl)-3-hydroxypropionic acids and ethyl esters. DE 2637596; ES 448530; FR 2321286; GB 1479264; US 3962284 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(I) 16147 5-(4-Chloro-phenyl)-furan-2-carbaldehyde; 5-(4-Chlorophenyl)-2-furaldehyde 34035-03-5 C11H7ClO2 详情 详情
(II) 39927 ethyl 3-[5-(4-chlorophenyl)-2-furyl]-3-hydroxypropanoate C15H15ClO4 详情 详情

合成路线58

该中间体在本合成路线中的序号：(IV)

The condensation of 4-hydroxy-3-methoxybenzaldehyde (I) with ethyl cyanoacetate (II) by means of NaOH in ethanol gives the 2-cyanopropenoate (III), which is then alkylated at the OH group with ethyl 2-bromoacetate (IV) by means of K2CO3 and tetrabutylammonium bromide in THF.

参考文献 中间体
合成目标
【1】 Tiwari, S.; et al.; Synthesis and antileishmanial activity of alpha-cyano ethyl propenoates - A new class of antileishmanials. Arzneim-Forsch Drug Res 1999, 49, 2, 144.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 22701 4-hydroxy-3-methoxybenzaldehyde 121-33-5 C8H8O3 详情 详情
(II) 11877 Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate 105-56-6 C5H7NO2 详情 详情
(III) 30896 ethyl (Z)-2-cyano-3-(4-hydroxy-3-methoxyphenyl)-2-propenoate C13H13NO4 详情 详情
(IV) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情

合成路线59

该中间体在本合成路线中的序号：(II)

The alkylation of 2-iodo-5-(trifluoromethyl)phenol (I) with ethyl 2-bromoacetate (II) and K2CO3 in acetone gives the phenyl ether (III), which is condensed with the phosphonate (IV) by means of BuLi in THF to yield the ketophosphonate (V). The condensation of the Corey aldehyde (VI) with phosphonate (V) by means of ClLi and TEA in THF affords the ketonic intermediate (VII), which is reduced with (-)-chlorodiisopinocampheylborane [(-)-DIPCl] in THF to produce C-15 hydroxy epimer predominantly with the desired stereochemistry (VIII).The hydrolysis of the benzoate group of (VIII) with K2CO3 in methanol gives the dihydroxylactone (IX), which is protected with DHP and Ts-OH in dichloromethane to yield the bis-tetrahydropyranyl ether (X). The lactone group of (X) is reduced with DIBAL in THF to yield the lactol (XI), which is submitted to a Wittig condensation with 4-carboxybutyltriphenylphosphonium bromide (XII) by means of tBu-OK in THF to afford the carboxylic acid (XIII). The esterification of (XIII) with isopropyl iodide and DBU in acetone affords the isopropyl ester (XIV), which is deprotected (elimination of the THP protecting groups) with HCl in methanol/water and purified by chromatography (elimination of the unwanted C15-epimer) to afford the precursor (XV). Finally the iodine atom of (XV) is eliminated by hydrogenation with hydrogen over Pd/C in ethyl acetate.

参考文献 中间体
合成目标
【1】 Selliah, R.; et al.; Synthesis of [phenyl-2-H-3]-travoprost: Isopropyl ester prodrug of a selective prostaglandin FP receptor agonist. J Label Compd Radiopharm 2001, 44, 3, 173.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 52922 2-iodo-5-(trifluoromethyl)phenol C7H4F3IO 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 52923 ethyl 2-[2-iodo-5-(trifluoromethyl)phenoxy]acetate n/a C11H10F3IO3 详情 详情
(IV) 13607 dimethyl methylphosphonate 756-79-6 C3H9O3P 详情 详情
(V) 52924 dimethyl 3-[2-iodo-5-(trifluoromethyl)phenoxy]-2-oxopropylphosphonate C12H13F3IO5P 详情 详情
(VI) 33585 (8R,9S,10R,13S,14S)-13-ethyl-11-methylene-3-(1-pyrrolidinyl)-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one C24H33NO 详情 详情
(VII) 52925 (3aR,4R,5R,6aS)-4-{(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-oxo-1-butenyl}-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C25H20F3IO6 详情 详情
(VIII) 52926 (3aR,4R,5R,6aS)-4-{(E)-3-hydroxy-4-[2-iodo-5-(trifluoromethyl)phenoxy]-1-butenyl}-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C25H22F3IO6 详情 详情
(IX) 52927 (3aR,4R,5R,6aS)-5-hydroxy-4-{(E)-3-hydroxy-4-[2-iodo-5-(trifluoromethyl)phenoxy]-1-butenyl}hexahydro-2H-cyclopenta[b]furan-2-one C18H18F3IO5 详情 详情
(X) 52928 (3aR,4R,5R,6aS)-4-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one C28H34F3IO7 详情 详情
(XI) 52929 (3aR,4R,5R,6aS)-4-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-ol C28H36F3IO7 详情 详情
(XII) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(XIII) 52930 (Z)-7-[(1R,2R,3R,5S)-5-hydroxy-2-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoic acid C33H44F3IO8 详情 详情
(XIV) 52931 isopropyl (Z)-7-[(1R,2R,3R,5S)-5-hydroxy-2-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate C36H50F3IO8 详情 详情
(XV) 52932 isopropyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-{(E,3R)-3-hydroxy-4-[2-iodo-5-(trifluoromethyl)phenoxy]-1-butenyl}cyclopentyl)-5-heptenoate C26H34F3IO6 详情 详情

合成路线60

该中间体在本合成路线中的序号：(II)

The alkylation of 2-iodo-5-(trifluoromethyl)phenol (I) with ethyl 2-bromoacetate (II) and K2CO3 in acetone gives the phenyl ether (III), which is condensed with the phosphonate (IV) by means of BuLi in THF to yield the ketophosphonate (V). The condensation of the Corey aldehyde (VI) with phosphonate (V) by means of ClLi and TEA in THF affords the ketonic intermediate (VII), which is reduced with (-)-chlorodiisopinocampheylborane [(-)-DIPCl] in THF to produce C-15 hydroxy epimer (VIII) predominantly with the desired stereochemistry. The hydrolysis of the benzoate group of (VIII) with K2CO3 in methanol gives the dihydroxylactone (IX), which is protected with DHP and Ts-OH in dichloromethane to yield the bis-tetrahydropyranyl ether (X). The lactone group of (X) is reduced with DIBAL in THF to yield the lactol (XI), which is submitted to a Wittig condensation with 4-carboxybutyltriphenylphosphonium bromide (XII) by means of tBu-OK in THF to afford the carboxylic acid (XIII). The esterification of (XIII) with isopropyl iodide and DBU in acetone affords the isopropyl ester (XIV), which is deprotected (elimination of the THP protecting groups) with HCl in methanol/water and purified by chromatography (elimination of the unwanted C15-epimer) to afford the precursor (XV). Finally the iodine atom of (XV) is substituted with tritium by hydrogenation with tritium gas over Pd/C in ethyl acetate.

参考文献 中间体
合成目标
【1】 Selliah, R.; et al.; Synthesis of [phenyl-2-H-3]-travoprost: Isopropyl ester prodrug of a selective prostaglandin FP receptor agonist. J Label Compd Radiopharm 2001, 44, 3, 173.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 52922 2-iodo-5-(trifluoromethyl)phenol C7H4F3IO 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 52923 ethyl 2-[2-iodo-5-(trifluoromethyl)phenoxy]acetate n/a C11H10F3IO3 详情 详情
(IV) 13607 dimethyl methylphosphonate 756-79-6 C3H9O3P 详情 详情
(V) 52924 dimethyl 3-[2-iodo-5-(trifluoromethyl)phenoxy]-2-oxopropylphosphonate C12H13F3IO5P 详情 详情
(VI) 33585 (8R,9S,10R,13S,14S)-13-ethyl-11-methylene-3-(1-pyrrolidinyl)-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one C24H33NO 详情 详情
(VII) 52925 (3aR,4R,5R,6aS)-4-{(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-oxo-1-butenyl}-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C25H20F3IO6 详情 详情
(VIII) 52926 (3aR,4R,5R,6aS)-4-{(E)-3-hydroxy-4-[2-iodo-5-(trifluoromethyl)phenoxy]-1-butenyl}-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C25H22F3IO6 详情 详情
(IX) 52927 (3aR,4R,5R,6aS)-5-hydroxy-4-{(E)-3-hydroxy-4-[2-iodo-5-(trifluoromethyl)phenoxy]-1-butenyl}hexahydro-2H-cyclopenta[b]furan-2-one C18H18F3IO5 详情 详情
(X) 52928 (3aR,4R,5R,6aS)-4-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one C28H34F3IO7 详情 详情
(XI) 52929 (3aR,4R,5R,6aS)-4-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-ol C28H36F3IO7 详情 详情
(XII) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(XIII) 52930 (Z)-7-[(1R,2R,3R,5S)-5-hydroxy-2-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoic acid C33H44F3IO8 详情 详情
(XIV) 52931 isopropyl (Z)-7-[(1R,2R,3R,5S)-5-hydroxy-2-[(E)-4-[2-iodo-5-(trifluoromethyl)phenoxy]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-5-heptenoate C36H50F3IO8 详情 详情
(XV) 52932 isopropyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-{(E,3R)-3-hydroxy-4-[2-iodo-5-(trifluoromethyl)phenoxy]-1-butenyl}cyclopentyl)-5-heptenoate C26H34F3IO6 详情 详情

合成路线61

该中间体在本合成路线中的序号：

The synthesis of the tricyclic precursors has been reported by two alternative routes. Alkylation of 3-(3-methoxyphenyl)indene (XVI) with ethyl bromoacetate using lithium hexamethyldisilazide provided indeneacetate (XVII). Subsequent oxidative cleavage of (XVII) gave rise to the arylsuccinic derivative (XVIII). The benzoyl group of (XVIII) was then reduced to the benzyl analogue (XIX) by catalytic hydrogenation in the presence of Pd/C in AcOH. After conversion of (XIX) to the corresponding acid chloride (XX), Friedel-Crafts cyclization produced the tricyclic ketoester (XXI). Then reduction of the ketone group of (XXI) by hydrogenation over Pd/C furnished intermediate (IX).

参考文献 中间体
合成目标
【1】 Miller, W.H.; Samanen, J.M.; Heerding, D.; Bondinell, W.E. (SmithKline Beecham Corp.); Vitronectin receptor antagonists. EP 1025090; WO 9915508 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(IX) 34522 ethyl 2-(3-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)acetate C20H22O3 详情 详情
(XVI) 34528 3-(3-methoxyphenyl)-1H-indene; 3-(1H-inden-3-yl)phenyl methyl ether C16H14O 详情 详情
(XVII) 34529 ethyl 2-[3-(3-methoxyphenyl)-1H-inden-1-yl]acetate C20H20O3 详情 详情
(XVIII) 34530 4-ethoxy-2-[2-(3-methoxybenzoyl)phenyl]-4-oxobutyric acid C20H20O6 详情 详情
(XIX) 34531 4-ethoxy-2-[2-(3-methoxybenzyl)phenyl]-4-oxobutyric acid C20H22O5 详情 详情
(XX) 34532 ethyl 4-chloro-3-[2-(3-methoxybenzyl)phenyl]-4-oxobutanoate C20H21ClO4 详情 详情
(XXI) 34533 ethyl 2-(3-methoxy-11-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)acetate C20H20O4 详情 详情

合成路线62

该中间体在本合成路线中的序号：(X)

This compound has been obtained by several related ways: 1.- The Sam and Thompson cyclization of 3-(2-thienyl)acrylic acid (I) gives the thienocyclopentanone (II), which is condensed with oxoacetic acid (III) yielding 2-(4-oxo-5,6-dihydro-4H-cyclopenteno[b]furan-5-ylidene)acetic acid (IV). The reduction of (IV) with Zn and acetic acid affords the corresponding saturated compound (V), which is condensed with 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (VI) by means of DCC and HOBt in dichloromethane to give the corresponding piperidide (VII). The protection of the ketonic group of (VII) with ethylene glycol and TsOH yields the ethylene ketal (VIII), which is reduced at the piperidide group with LiAlH4 in ethyl ether yielding the final intermediate (IX). Finally, this compound is treated with HCl to eliminate the ethylene ketal protecting group. 2.- The condensation of the thienocyclopentanone (II) with ethyl bromoacetate (X) by means of LDA gives the acetate (XI), which is hydrolyzed with KOH in ethanol affording the previously reported saturated acetic acid derivative (V). 3.- The condensation of acetate (XI) with piperidine (VI) by means of Me3Al gives also the previously reported piperidide (VII).

参考文献 中间体
合成目标
【1】 Negreira, J.; Cid, J.; Raviña, E.; et al.; Conformationally constrained butyrophenones with mixed dopaminergic (D(2)) and serotoninergic (5-HT(2A), 5-HT(2C)) affinities: Synthesis, pharmacology, 3D-QSAR, and molecular modeling of (aminoalkyl)benzo- and -thienocycloalkanones as putative atypical an. J Med Chem 1999, 42, 15, 2774.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(I) 31893 (Z)-3-(2-thienyl)-2-propenoic acid 15690-25-2 C7H6O2S 详情 详情
(II) 31894 5,6-dihydro-4H-cyclopenta[b]thiophen-4-one C7H6OS 详情 详情
(III) 15618 2-Oxoacetic acid; Glyoxylic Acid 298-12-4 C2H2O3 详情 详情
(IV) 31895 2-(4-oxo-4,6-dihydro-5H-cyclopenta[b]thiophen-5-ylidene)acetic acid C9H6O3S 详情 详情
(V) 31896 2-(4-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)acetic acid C9H8O3S 详情 详情
(VI) 17910 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole C12H13FN2O 详情 详情
(VII) 31897 5-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-oxoethyl]-5,6-dihydro-4H-cyclopenta[b]thiophen-4-one C21H19FN2O3S 详情 详情
(VIII) 31898 3-[4,4-(Ethylenedioxy)-5,6-dihydro-4H-cyclopeta[b]thiophen-5-yl]-1-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)-1-propanone C23H23FN2O4S 详情 详情
(IX) 31899 1-[2-[4,4-(Ethylenedioxy)-5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl]ethyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine C23H25FN2O3S 详情 详情
(X) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(XI) 31900 ethyl 2-(4-oxo-5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl)acetate C11H12O3S 详情 详情

合成路线63

该中间体在本合成路线中的序号：(VII)

Friedel-Crafts acylation of 2-methylbenzofuran (I) with p-anisoyl chloride (II) in the presence of SnCl4 afforded the benzoyl benzofuran derivative (III). Ketone (III) reduction to the corresponding benzyl benzofuran (IV) was accomplished employing either LiAlH4 or NaBH4 and ZnI2. The methyl ether group of (IV) was then cleaved with melted pyridine hydrochloride to give phenol (V). Aromatic iodination of (V) with either I2/KI or with ICl in morpholine led to the diiodo phenol (VI). This was then alkylated with ethyl bromoacetate (VII) to furnish ester (VIII), which was finally hydrolyzed with NaOH to the target carboxylic acid.

参考文献 中间体
合成目标
【1】 Singh, B.N.; Malm, J.; Mellin, C.; Li, Y.-L.; Nilsson, S.; Temciuc, M.; Carlsson, B.; Synthesis and preliminary characterization of a novel antiarrhythmic compound (KB130015) with an improved toxicity profile compared with amiodarone. J Med Chem 2002, 45, 3, 623.
【2】 Norinder, U.; Bajorath, J.; Stearns, J.F. (Karo Bio AB); Receptor ligands. WO 9220331 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 56239 2-Methylbenzofuran C9H8O 详情 详情
(II) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(III) 56240 (4-methoxyphenyl)(2-methyl-1-benzofuran-3-yl)methanone C17H14O3 详情 详情
(IV) 56241 3-(4-methoxybenzyl)-2-methyl-1-benzofuran; methyl 4-[(2-methyl-1-benzofuran-3-yl)methyl]phenyl ether C17H16O2 详情 详情
(V) 56242 4-[(2-methyl-1-benzofuran-3-yl)methyl]phenol C16H14O2 详情 详情
(VI) 56243 2,6-diiodo-4-[(2-methyl-1-benzofuran-3-yl)methyl]phenol C16H12I2O2 详情 详情
(VII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VIII) 56244 ethyl 2-{2,6-diiodo-4-[(2-methyl-1-benzofuran-3-yl)methyl]phenoxy}acetate C20H18I2O4 详情 详情

合成路线64

该中间体在本合成路线中的序号：(V)

Treatment of 2,4-difluorophenylacetic acid (I) with NaOH in dimethylimidazolinone at 135 C afforded 4-fluorosalicylic acid (II). After activation of (II) with SOCl2, coupling with 3-nitrobenzylamine (III) gave amide (IV). Subsequent O-alkylation of (IV) by means of ethyl bromoacetate (A) and K2CO3 yielded ether (V). Conversion of the amide function of (V) to the corresponding thioamide (VI) was accomplished using phosphorus pentasulfide (P4S10) in pyridine. Finally, the ester group of (VI) was hydrolyzed with NaOH to the title carboxylic acid.

参考文献 中间体
合成目标
【1】 Van Zandt, M.C.; Sibley, E.O.; Combs, K.J.; et al.; Design and synthesis of novel inhibitors of aldose reductase for the treatment of diabetic complications. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 137.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 35123 2,4-difluorobenzoic acid 1583-58-0 C7H4F2O2 详情 详情
(II) 35124 4-fluoro-2-hydroxybenzoic acid 345-29-9 C7H5FO3 详情 详情
(III) 35125 (3-nitrophenyl)methanamine; 3-nitrobenzylamine C7H8N2O2 详情 详情
(IV) 35126 4-fluoro-2-hydroxy-N-(3-nitrobenzyl)benzamide C14H11FN2O4 详情 详情
(V) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(VI) 35127 ethyl 2-(5-fluoro-2-[[(3-nitrobenzyl)amino]carbonyl]phenoxy)acetate C18H17FN2O6 详情 详情
(VII) 35128 ethyl 2-(5-fluoro-2-[[(3-nitrobenzyl)amino]carbothioyl]phenoxy)acetate C18H17FN2O5S 详情 详情

合成路线65

该中间体在本合成路线中的序号：(XIII)

Alkylation of 4-nitroimidazole (XII) by means of ethyl bromoacetate (XIII) gave ethyl 2-(4-nitro-1-imidazolyl)acetate (XIV). Reduction of (XIV) to the corresponding amine (XV) was effected by catalytic hydrogenation over Pd/C. Coupling of (XV) with dipeptide (XI) gave (XVI), which was hydrolyzed to carboxylic acid (XVII) using LiOH. This was finally coupled with proline amide (XIX), (obtained by treatment of L-proline (XVIII) with benzylamine and CDI), to furnish the title compound.

参考文献 中间体
合成目标
【1】 Growth hormone secretagogues. EP 0933365; WO 9908699 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(XI) 18473 (2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoic acid C20H30N2O5 详情 详情
(XII) 35764 4-nitro-1H-imidazole 3034-38-6 C3H3N3O2 详情 详情
(XIII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(XIV) 38800 ethyl 2-(4-nitro-1H-imidazol-1-yl)acetate C7H9N3O4 详情 详情
(XV) 38801 ethyl 2-(4-amino-1H-imidazol-1-yl)acetate C7H11N3O2 详情 详情
(XVI) 38802 ethyl 2-(4-[[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoyl]amino]-1H-imidazol-1-yl)acetate C27H39N5O6 详情 详情
(XVII) 38803 2-(4-[[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-5-phenylpentanoyl]amino]-1H-imidazol-1-yl)acetic acid C25H35N5O6 详情 详情
(XVIII) 16731 L-proline 147-85-3 C5H9NO2 详情 详情
(XIX) 38804 (2S)-N-benzyl-2-pyrrolidinecarboxamide C12H16N2O 详情 详情

合成路线66

该中间体在本合成路线中的序号：(II)

By condensation of cycloheximide (I) with ethyl 2-bromoacetate (II) by means of K2CO3 and 18-crown-6 in acetone.

参考文献 中间体
合成目标
【1】 Grabley, S.; Wyrwa, R.; Schummann, D.; Marsch, S.; Christner, C.; Küllertz, G.; Fischer, G.; Thiericke, R.; Synthesis and cytotoxic evaluation of cycloheximide derivatives as potential inhibitors of FKBP12 with neuroregenerative properties. J Med Chem 1999, 42, 18, 3615.
【2】 Thiericke, R.; Fischer, G.; Küllertz, G.; Christner, C.; Grabley, S.; Wyrwa, R. (Hans Knöll Institute for Natural Product Research; Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. ); Cyclohexamide derivs. which influence the regeneration of neural tissue. WO 0026188 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 38236 4-[(2R)-2-[(1S,3S,5R)-3,5-dimethyl-2-oxocyclohexyl]-2-hydroxyethyl]-2,6-piperidinedione 66-81-9 C15H23NO4 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情

合成路线67

该中间体在本合成路线中的序号：(III)

The alcoholysis of 1-benzyl-2-pyrrolidinone (I) with HCl in ethanol gives 4-(benzylamino)butyric acid ethyl ester (II), which is condensed with ethyl 2-bromoacetate (III) to yield the tertiary amine (IV). The cyclization of (IV) by means of NaOEt affords 1-benzyl-3-hydroxy-1,2,5,6-tetrahydropyridine-4-carboxylic acid ethyl ester (V), which by hydrogenolytic debenzylation, followed by reaction with methyl chloroformate (VI), affords the 1,4-dicarboxylate (VII). The reduction of (VII) with H2 over Ni gives the cis-3-hydroxy-1,4-dicarboxylate (VIII), which is hydrolyzed and selectively decarboxylated with HCl, yielding cis-3-hydroxypiperidine-4-carboxylic acid (IX). Finally, this compound is dehydrated by means of HBr and TEA.

参考文献 中间体
合成目标
【1】 Christensen, V.; Krogsgaard-Larsen, P.; Falch, E.; Chemistry and pharmacology of the GABA agonists THIP (Gabodaxol) and isoguvacine. Drugs Fut 1984, 9, 8, 597.
【2】 Johnston, G.A.R.; Krogsgaard-Larsen, P.; Structure-activity studies on the inhibition of GABA binding to rat brain membranes by muscinol and related compounds. J Neurochem 1978, 30, 1377-1382.
【3】 Krogsgaard-Larsen, P.; Christensen, T.R.; GABA agonists. Synthesis and structure-activity studies on analogues of isoguvacine and THIP. Eur J Med Chem 1979, 14, 157-164.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 43664 1-benzyl-2-pyrrolidinone 5291-77-0 C11H13NO 详情 详情
(II) 43665 ethyl 4-(benzylamino)butanoate C13H19NO2 详情 详情
(III) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(IV) 43666 ethyl 4-[benzyl(2-ethoxy-2-oxoethyl)amino]butanoate C17H25NO4 详情 详情
(V) 43667 ethyl 1-benzyl-5-hydroxy-1,2,3,6-tetrahydro-4-pyridinecarboxylate C15H19NO3 详情 详情
(VI) 16993 methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate 79-22-1 C2H3ClO2 详情 详情
(VII) 43668 4-ethyl 1-methyl 5-hydroxy-3,6-dihydro-1,4(2H)-pyridinedicarboxylate C10H15NO5 详情 详情
(VIII) 43669 4-ethyl 1-methyl (3S,4S)-3-hydroxy-1,4-piperidinedicarboxylate C10H17NO5 详情 详情
(IX) 43670 (3S,4S)-3-hydroxy-4-piperidinecarboxylic acid C6H11NO3 详情 详情

合成路线68

该中间体在本合成路线中的序号：(III)

Benzoxazinone (IV) was prepared by condensation of 2-amino-5-nitrophenol (I) with either chloroacetyl chloride (II) in the presence of NaHCO3 or ethyl bromoacetate (III) in the presence of KF. Subsequent N-alkylation of (IV) with iodomethane provided (V). After reduction of the nitro group of (V) to amine (VI) by hydrogenation over Pd/C, condensation with benzyl chloroformate afforded carbamate (VII). The chiral oxazolidinone (IX) was obtained by reaction of (VII) with (-)-(R)-glycidyl butyrate (VIII) in the presence of butyllithium in THF at low temperature. Conversion of (IX) to mesylate, followed by displacement with NaN3 gave azide (X). Amine (XI) was then obtained by either hydrogenation of (X) over Pd/C or by reduction with trimethyl phosphite. Finally, reaction of (XI) with acetyl chloride and triethylamine provided the title acetamide.

参考文献 中间体
合成目标
【1】 Haebich, D.; Haerter, M.; Bartel, S.; Riedl, B.; Stolle, A.; Raddatz, S.; Kroll, H.P.; Guarnieri, W.; Endermann, R.; Wild, H.; Rosentreter, U.; Ruppelt, M.; Synthesis and antibacterial activity of novel heteroaryl oxazolidinones: II. Benzoxazinone- and benzthiazinone-oxazolidinones. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F566.
【2】 Shridhar, D.R.; et al.; A facile synthesis of 2-alkyl(aryl)-6- and -7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazines. Synthesis 1982, 986.
【3】 Endermann, R.; Habich, D.; Ruppelt, M.; Raddatz, S.; Rosentreter, U.; Riedl, B.; Bartel, S.; Wild, H.; Stolle, A.; Guarnieri, W.; Kroll, H.-P. (Bayer AG); Novel bicyclene-substd. oxazolidinones. DE 19802239; WO 9937641 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 33067 2-amino-5-nitrophenol 121-88-0 C6H6N2O3 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(IV) 33068 7-nitro-2H-1,4-benzoxazin-3(4H)-one C8H6N2O4 详情 详情
(V) 33069 4-methyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one C9H8N2O4 详情 详情
(VI) 33070 7-amino-4-methyl-2H-1,4-benzoxazin-3(4H)-one C9H10N2O2 详情 详情
(VII) 33071 benzyl 4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-ylcarbamate C17H16N2O4 详情 详情
(VIII) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(IX) 33072 7-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]-4-methyl-2H-1,4-benzoxazin-3(4H)-one C13H14N2O5 详情 详情
(X) 33073 7-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-4-methyl-2H-1,4-benzoxazin-3(4H)-one C13H13N5O4 详情 详情
(XI) 33074 7-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-4-methyl-2H-1,4-benzoxazin-3(4H)-one C13H15N3O4 详情 详情

合成路线69

该中间体在本合成路线中的序号：(II)

Condensation of 1,2,3-benzotriazin-4(3H)-one (I) with ethyl bromoacetate (II) in refluxing butanone afforded the 3-(ethoxycarbonylmethyl) derivative (III). The ethyl ester group of (III) was then converted into the target amide by reaction with N,N-diethylethylenediamine (IV) in hot MeOH

参考文献 中间体
合成目标
【1】 Caliendo, G.; De Nucci, G.; Meli, R.; Mattace Raso, G.; Fiorino, F.; Perissutti, E.; Zanesco, A.; Grieco, P.; Santagada, V.; Preparation and local anaesthetic activity of benzotriazinone and benzoyltriazole derivatives. Eur J Med Chem 1999, 34, 12, 1043.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 36890 1,2,3-benzotriazin-4(3H)-one C7H5N3O 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 36891 ethyl 2-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]acetate C11H11N3O3 详情 详情
(IV) 12420 N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine 100-36-7 C6H16N2 详情 详情

合成路线70

该中间体在本合成路线中的序号：(III)

The ethanolysis of 1-benzylpyrrolidin-2-one (I) with HCl in ethanol gives 4-(benzylamino)butyric acid ethyl ester (II), which is alkylated with ethyl bromoacetate (III), yielding the tertiary amine (IV). The cyclization of (IV) by means of sodium ethoxide affords 1-benzyl-3-hydroxy-1,2,5,6-tetrahydropyridine-4-carboxylic acid ethyl ester (V), which by hydrogenolytic debenzylation, followed by reaction with methyl chloroformate (VI), affords the 1,4-dicarboxylate (VII). The reaction of (VII) with ethyleneglycol (VIII) and TsOH gives the cyclic ketal (IX), which is treated with hydroxylamine and NaOMe to yield the carbohydroxamic acid (X). The cyclization of (X) by means of H2SO4 affords 3-hydroxy-4,5,6,7-tetrahydropyrido[4,3-d]oxazole-6-carboxylic acid methyl ester (XI), which is finally decarboxylated by means of HBr and TEA.

参考文献 中间体
合成目标
【1】 Krogsgaard-Larsen, P.; Muscimol analogues. II. Synthesis of some bicylic 3-isoxazol zwitterions. Acta Chem Scand 1977, B31, 584-588.
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Paton, D.M.; THIP. Drugs Fut 1980, 5, 5, 257.
【3】 Christensen, V.; Krogsgaard-Larsen, P.; Falch, E.; Chemistry and pharmacology of the GABA agonists THIP (Gabodaxol) and isoguvacine. Drugs Fut 1984, 9, 8, 597.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 43664 1-benzyl-2-pyrrolidinone 5291-77-0 C11H13NO 详情 详情
(II) 43665 ethyl 4-(benzylamino)butanoate C13H19NO2 详情 详情
(III) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(IV) 43666 ethyl 4-[benzyl(2-ethoxy-2-oxoethyl)amino]butanoate C17H25NO4 详情 详情
(V) 43667 ethyl 1-benzyl-5-hydroxy-1,2,3,6-tetrahydro-4-pyridinecarboxylate C15H19NO3 详情 详情
(VI) 16993 methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate 79-22-1 C2H3ClO2 详情 详情
(VII) 43668 4-ethyl 1-methyl 5-hydroxy-3,6-dihydro-1,4(2H)-pyridinedicarboxylate C10H15NO5 详情 详情
(VIII) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(IX) 43675 10-ethyl 7-methyl 1,4-dioxa-7-azaspiro[4.5]decane-7,10-dicarboxylate C12H19NO6 详情 详情
(X) 43676 methyl 10-[(hydroxyamino)carbonyl]-1,4-dioxa-7-azaspiro[4.5]decane-7-carboxylate C10H16N2O6 详情 详情
(XI) 43677 methyl 3-hydroxy-4,7-dihydroisoxazolo[5,4-c]pyridine-6(5H)-carboxylate C8H10N2O4 详情 详情

合成路线71

该中间体在本合成路线中的序号：(II)

The alkylation of 2-isopropyl-6-methoxyphenol (I) with ethyl bromoacetate (II) under phase-transfer conditions in the presence of NaOH provided (aryloxy)acetic acid (III) which, upon treatment with SOCl2, was converted into acid chloride (IV). Coupling of (IV) with 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (V) then furnished the target amide. The title compound was finally isolated as the hydrochloride salt.

参考文献 中间体
合成目标
【1】 Leonardi, A.; Motta, G.; Boi, C.; Testa, R. (Recordati Industria Chimica e Farmaceutica SpA); Quinazolinyl-amino derivs. having alpha-antagonist activity. EP 0750614; JP 1997511238; US 5798362; WO 9525726 .
【2】 Leonardi, A.; Motta, G.; Boi, C.; Testa, R.; Poggesi, E.; De Benedetti, P.G.; Menziani, M.C.; Synthesis, pharmacological evaluation, and structure-activity relationship and quantitative structure-activity relationship studies on novel derivatives of 2,4-diamino-6,7-dimethoxyquinazoline alpha1-adrenoceptor antagonists. J Med Chem 2000, 42, 3, 427.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 40765 2-isopropyl-6-methoxyphenol C10H14O2 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 40766 2-(2-isopropyl-6-methoxyphenoxy)acetic acid C12H16O4 详情 详情
(IV) 40767 2-(2-isopropyl-6-methoxyphenoxy)acetyl chloride C12H15ClO3 详情 详情
(V) 12050 6,7-Dimethoxy-2-piperazino-4-quinazolinylamine; 6,7-Dimethoxy-2-piperazino-4-quinazolinamine C14H19N5O2 详情 详情

合成路线72

该中间体在本合成路线中的序号：(VIII)

o-Fluoronitrobenzene (I) is converted into (III) by an aromatic nucleophilic substitution with N-Ac-Cysteine (II) in EtOH in the presence of NaHCO3. Derivative (III) is then deacetylated by means of H2SO4 and NH4OH and reprotected as its Z-form by reaction with (IV) in the presence of NaOH to provide (V). Reduction of the nitro moiety of (V) with Zn in MeOH and in the presence of NH4Cl affords amine (VI), which is then converted into lactam (VII) using 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide (DEC) hydrochloride in DMF. The next step is alkylation of (VII) with ethyl bromoacetate (VIII) in THF in the presence of KOH and n-Bu4NBr to give (IX) (Scheme 28946801a).

参考文献 中间体
合成目标
【1】 Slade, J.; Mazzegna, G.C.; Ben-David, D.; Stanton, J.L.; Angiotensin Converting Enzyme Inhibitors: 1,5-Benzothiazepine Derivatives. J Med Chem 1985, 28, 1517-1521.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13463 o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene 1493-27-2 C6H4FNO2 详情 详情
(II) 39365 (2S)-2-(acetamido)-3-sulfanylpropionic acid 616-91-1 C5H9NO3S 详情 详情
(III) 43244 (2S)-2-(acetamido)-3-[(2-nitrophenyl)sulfanyl]propionic acid C11H12N2O5S 详情 详情
(IV) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(V) 43245 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(2-nitrophenyl)sulfanyl]propionic acid C17H16N2O6S 详情 详情
(VI) 43246 (2S)-3-[(2-aminophenyl)sulfanyl]-2-[[(benzyloxy)carbonyl]amino]propionic acid C17H18N2O4S 详情 详情
(VII) 43247 benzyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-ylcarbamate C17H16N2O3S 详情 详情
(VIII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(IX) 43248 ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate C21H22N2O5S 详情 详情

合成路线73

该中间体在本合成路线中的序号：(VIII)

Aromatic nucleophilic substitution of o-fluoronitrobenzene (I) with N-Ac-cysteine (II) in EtOH in the presence of NaHCO3 yields (III). Derivative (III) is then deacetylated by means of H2SO4 and NH4OH and reprotected as its Z-form by reaction with (IV) in the presence of NaOH to provide (V). Reduction of the nitro moiety of (V) with Zn in MeOH and the presence of NH4Cl affords amine (VI), which is then converted into lactam (VII) using 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide (DEC) hydrochloride in DMF. The next step is alkylation of (VII) with ethyl bromoacetate (VIII) in THF in the presence of KOH and n-Bu4NBr to give (IX) (1) (Scheme 28947001a). Cleavage of both the Z protecting group and ethyl ester of derivative (IX) with HBr in AcOH, followed by introduction of a Boc group by treatment with Boc2O in dioxane in the presence of NaOH, affords (X), which is then anchored to the resin via its Cs salt to yield (XI). Deprotection of the amine moiety of (XI) with TFA in the presence of EDT as a scavenger, followed by coupling with Boc-Ser(Bzl)-OH in the presence of BOP and DIEA, affords (XII). The peptidic chain is then elongated by successive deprotection with TFA/EDT and coupling of protected amino acids (Boc-Igl-OH, Boc-Gly-OH, Boc-Hyp-OH, Boc-Pro-OH, Boc Arg(Tos)-OH, Boc-Lys(COOCH2Ph)-OH (x2)) with BOP/DIEA, providing derivative (XIV), which is finally deprotected and cleaved by a first treatment with TFA/EDT followed by HF in the presence of anisole (2,3) (Scheme 28947001[b-d]).

参考文献 中间体
合成目标
【1】 Slade, J.; Mazzegna, G.C.; Ben-David, D.; Stanton, J.L.; Angiotensin Converting Enzyme Inhibitors: 1,5-Benzothiazepine Derivatives. J Med Chem 1985, 28, 1517-1521.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13463 o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene 1493-27-2 C6H4FNO2 详情 详情
(II) 39365 (2S)-2-(acetamido)-3-sulfanylpropionic acid 616-91-1 C5H9NO3S 详情 详情
(III) 43244 (2S)-2-(acetamido)-3-[(2-nitrophenyl)sulfanyl]propionic acid C11H12N2O5S 详情 详情
(IV) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(V) 43245 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(2-nitrophenyl)sulfanyl]propionic acid C17H16N2O6S 详情 详情
(VI) 43246 (2S)-3-[(2-aminophenyl)sulfanyl]-2-[[(benzyloxy)carbonyl]amino]propionic acid C17H18N2O4S 详情 详情
(VII) 43247 benzyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-ylcarbamate C17H16N2O3S 详情 详情
(VIII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(IX) 43248 ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate C21H22N2O5S 详情 详情

合成路线74

该中间体在本合成路线中的序号：(A)

Synthesis of intermediate (XIV): Protection of 4-piperidone (I) with (Boc)2O in presence of DMAP and Et3N yields (II), which is converted into hydantoin (III) by means of NaCN in presence of (NH4)2CO3. Hydantoin (III) is then fully protected to provide (IV) by treatment with (Boc)2O and DMAP in THF. Alternatively (IV) can be obtained by treatment of 4-piperidone (I) with KCN in presence of (NH4)2CO3 to yield hydantoin (V), which is then protected with (Boc)2O and DMAP in DME. Hydrolysis of (IV) with NaOH affords aminoacid (VI) whose free amine is protected to provide carboxylic acid (VII). Treatment of (VII) with isobutyl chloroformate (IBCF) in DME in presence of NMM, followed by aqueous ammonia, yields amide (VIII), which is converted to (IX) by hydrogenation with H2 over Pd/C. Reductive amination of (IX) with aldehyde (X) affords amino amide (XI), which is treated with triethyl orthoformate to provide spirocycle (XII). Reduction of (XII) with NaBH4 in EtOH gives (XIII), which is alkylated with ethyl bromoacetate (A) followed by hydrolysis with NaOH to yield intermediate (XIV).

参考文献 中间体
合成目标
【1】 Wysong, C.L.; et al.; 4-Aminopiperidine-4-carboxamylic acid: A cyclic alpha,alpha-disubstituted amino acid for preparation of water-soluble highly helical peptides. J Org Chem 1996, 61, 22, 7650-51.
【2】 Amblard, M.; Subra, G.; Bedos, P.; et al.; A rational approach to the design and synthesis of a new bradykinin B1 receptor antagonist. J Med Chem 2000, 43, 12, 2387.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(I) 18178 4,4-piperidinediol 73390-11-1 C5H11NO2 详情 详情
(II) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(III) 41678 tert-butyl 2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate C12H19N3O4 详情 详情
(IV) 41679 tri(tert-butyl) 2,4-dioxo-1,3,8-triazaspiro[4.5]decane-1,3,8-tricarboxylate C22H35N3O8 详情 详情
(V) 41680 1,3,8-triazaspiro[4.5]decane-2,4-dione 13625-39-3 C7H11N3O2 详情 详情
(VI) 41681 4-amino-1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid 183673-71-4 C11H20N2O4 详情 详情
(VII) 41682 1-(tert-butoxycarbonyl)-4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-piperidinecarboxylic acid C26H30N2O6 详情 详情
(VIII) 41683 tert-butyl 4-(aminocarbonyl)-4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-1-piperidinecarboxylate C26H31N3O5 详情 详情
(IX) 41684 tert-butyl 4-amino-4-(aminocarbonyl)-1-piperidinecarboxylate C11H21N3O3 详情 详情
(X) 18456 2-phenylacetaldehyde 122-78-1 C8H8O 详情 详情
(XI) 41685 tert-butyl 4-(aminocarbonyl)-4-(phenethylamino)-1-piperidinecarboxylate C19H29N3O3 详情 详情
(XII) 41686 tert-butyl 4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]dec-2-ene-8-carboxylate C20H27N3O3 详情 详情
(XIII) 41687 tert-butyl 4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate C20H29N3O3 详情 详情
(XIV) 41688 2-[8-(tert-butoxycarbonyl)-4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]dec-3-yl]acetic acid C22H31N3O5 详情 详情

合成路线75

该中间体在本合成路线中的序号：(II)

The condensation of 2-(4-aminophenyl)ethanol (I) with ethyl 2-bromoacetate (II) by means of K2CO3 in DMF gives 2-[4-(2-hydroxyethyl)phenylamino]acetic acid ethyl ester (III), which is chlorinated with t-butyl hypochlorite in dichloromethane to yield the 2,6-dichlorophenyl derivative (IV). The bromination of (IV) by means of PPh3 and CBr4 in dichloromethane affords the 2-bromoethyl derivative (V), which is condensed with (1R,2S)-2-amino-1-(4-hydroxyphenyl)-1-propanol (VI) by means of DIEA in hot DMF to provide the ethyl ester precursor (VII). Finally, this compound is hydrolyzed with aq. 1N NaOH to give the target N-phenylglycine derivative.

参考文献 中间体
合成目标
【1】 Tanaka, N.; Mukaiyama, H.; Akahane, M.; Miyata, H.; Akahane, S.; Muranaka, H.; Hirabayashi, A.; Tamai, T.; Discovery of novel N-phenylglycine derivatives as potent and selective beta3-adrenoceptor agonists for the treatment of frequent urination and urinary incontinence. J Med Chem 2001, 44, 9, 1436.
【2】 Sato, M.; Tanaka, N.; Akahane, M.; Tamai, T.; Muranaka, H.; Mukaiyama, H.; Hirabayashi, A. (Kissei Pharmaceutical Co., Ltd.); Phenylaminoalkylcarboxylic acid derivs. and medicinal compsns. containing the same. EP 1043308; WO 9931045 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 14019 p-Aminophenylethanol; 2-(4-Aminophenyl)-1-ethanol 104-10-9 C8H11NO 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 55795 ethyl 2-[4-(2-hydroxyethyl)anilino]acetate C12H17NO3 详情 详情
(IV) 55796 ethyl 2-[2,6-dichloro-4-(2-hydroxyethyl)anilino]acetate C12H15Cl2NO3 详情 详情
(V) 55797 ethyl 2-[4-(2-bromoethyl)-2,6-dichloroanilino]acetate C12H14BrCl2NO2 详情 详情
(VI) 46836 4-[(1R,2S)-2-amino-1-hydroxypropyl]phenol C9H13NO2 详情 详情
(VII) 55798 ethyl 2-[2,6-dichloro-4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)anilino]acetate C21H26Cl2N2O4 详情 详情

合成路线76

该中间体在本合成路线中的序号：(IV)

Lithiation of 1,3-bis(O-methoxymethyl)resorcinol (I) by means of n-butyllithium, followed by acylation with acetyl chloride, gave the protected acetophenone (II). Subsequent acid hydrolysis of the methoxymethyl protecting groups furnished diol (III). The 4-hydroxybenzofuran derivative (VI) was prepared by monoalkylation of (III) with ethyl bromoacetate (IV), followed by base-catalyzed cyclization of the resulting keto ester (V). Alkylation of the hydroxybenzofuran (VI) with 1,3-dibromopropane (VII) gave the bromopropyl ether (VIII). This was finally condensed with 3-picolylamine (IX) to produce the title compound.

参考文献 中间体
合成目标
【1】 Masubuchi, M.; et al.; Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 1. Bioorg Med Chem Lett 2001, 11, 14, 1833.
【2】 Fujii, T.; Tsujii, S.; Liu, P.; Ohtsuka, T.; Ebiike, H.; Masubuchi, M.; Aoki, Y.; Kawasaki, K. (F. Hoffmann-La Roche AG); Novel bicyclic cpds.. US 6376491; WO 0037464 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 52123 [3-(methoxymethoxy)phenoxy]methyl methyl ether; 1,3-bis(methoxymethoxy)benzene C10H14O4 详情 详情
(II) 52124 1-[2,6-bis(methoxymethoxy)phenyl]-1-ethanone C12H16O5 详情 详情
(III) 27511 1-(2,6-dihydroxyphenyl)-1-ethanone 699-83-2 C8H8O3 详情 详情
(IV) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(V) 52125 ethyl 2-(2-acetyl-3-hydroxyphenoxy)acetate C12H14O5 详情 详情
(VI) 52126 ethyl 4-hydroxy-3-methyl-1-benzofuran-2-carboxylate C12H12O4 详情 详情
(VII) 12581 1,3-Dibromopropane 109-64-8 C3H6Br2 详情 详情
(VIII) 52127 ethyl 4-(3-bromopropoxy)-3-methyl-1-benzofuran-2-carboxylate C15H17BrO4 详情 详情
(IX) 18731 3-pyridinylmethanamine; 3-pyridinylmethylamine 3731-52-0 C6H8N2 详情 详情

合成路线77

该中间体在本合成路线中的序号：(II)

The condensation of 4-bromophenyl-3-pyridyl ketone (I) with ethyl bromoacetate (II) by means of Zn in refluxing benzene gives ethyl 3-hydroxy-3-(3-pyridyl)-3-(4-bromophenyl)propionate (III), which is reduced with LiAlH4 in refluxing ethyl ether yielding 1-(3-pyridyl)-1-(4-bromophenyl)propane-1,3-diol (IV). Finally this compound is treated first with PBr3 and HBr in refluxing acetone, and then with methylamine (V) at 110 C in a pressure vessel

参考文献 中间体
合成目标
【1】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Sweetman, A.J.; Nomelidine. Drugs Fut 1979, 4, 12, 885.
【2】 Carlsson, P.A.E.; et al. (Astra Lakemedel AB); BE 835802; DD 122528; DE 2550005; FR 2291751; JP 7676278; NL 7513648; ZA 7506893 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 60939 (4-bromophenyl)(3-pyridinyl)methanone C12H8BrNO 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 60940 ethyl 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridinyl)propanoate C16H16BrNO3 详情 详情
(IV) 60941 1-(4-bromophenyl)-1-(3-pyridinyl)-1,3-propanediol C14H14BrNO2 详情 详情
(V) 11021 Methanamine; Methylamine 74-89-5 CH5N 详情 详情

合成路线78

该中间体在本合成路线中的序号：(II)

The condensation of 4-bromophenyl-3-pyridyl ketone (I) with ethyl bromoacetate (II) by means of Zn in refluxing benzene gives ethyl 3-hydroxy-3-(3-pyridyl)-3-(4-bromophenyl)propionate (III), which is converted into the corresponding methylamide (VI) by treatment with methylamine (V) in ethanol. This compound is reduced with NaBH4 in THF yielding 3-(3-pyridyl)-3-(4-bromophenyl)-3-hydroxy-N-methylpropylamine (VII), which is finally dehydrated by treatment with 50% H2SO4 at 110 C

参考文献 中间体
合成目标
【1】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Sweetman, A.J.; Nomelidine. Drugs Fut 1979, 4, 12, 885.
【2】 Carlsson, P.A.E.; et al. (Astra Lakemedel AB); BE 835802; DD 122528; DE 2550005; FR 2291751; JP 7676278; NL 7513648; ZA 7506893 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 60939 (4-bromophenyl)(3-pyridinyl)methanone C12H8BrNO 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 60940 ethyl 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridinyl)propanoate C16H16BrNO3 详情 详情
(V) 11021 Methanamine; Methylamine 74-89-5 CH5N 详情 详情
(VI) 60942 3-(4-bromophenyl)-3-hydroxy-N-methyl-3-(3-pyridinyl)propanamide C15H15BrN2O2 详情 详情
(VII) 60943 1-(4-bromophenyl)-3-(methylamino)-1-(3-pyridinyl)-1-propanol C15H17BrN2O 详情 详情

合成路线79

该中间体在本合成路线中的序号：(I)

Alkylation of N,N-dimethyl-1,3-propanediamine (II) with ethyl bromoacetate (I) afforded the diamino ester (III). Basic hydrolysis of (III) and subsequent nitrosation of the resulting diamino acid (IV) yielded the nitrosamine (V). Cyclization of (V) in hot acetic anhydride as the dehydrating agent gave rise to sydnone (VI). Lithiation of (VI), followed by condensation with aldehyde (VII), produced adduct (VIII) as an inseparable mixture of diastereomers. The hydroxyl group of (VIII) was then protected as the methyl ether (IX) by alkylation with iodomethane and NaH. The azomethyne intermediate, generated by ejection of CO2 from (IX) upon heating in xylene, underwent an intramolecular 1,3-dipolar cycloaddition with the olefin double bond to furnish the indazole derivative (X). Finally, the target compound was obtained by aromatization of (X) under acidic conditions in the presence of platinum catalyst.

参考文献 中间体
合成目标
【1】 Yeu, J.P.; et al.; An expedient synthesis of 1-[3-(dimethylamino)propyl]-5-methyl-3-phenyl-1H-indazole (FS-32) - An antidepressant. Synthesis 2001, 12, 1775.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(II) 25248 N-(3-aminopropyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,3-propanediamine 109-55-7 C5H14N2 详情 详情
(III) 50245 ethyl 2-[[3-(dimethylamino)propyl]amino]acetate C9H20N2O2 详情 详情
(IV) 50246 2-[[3-(dimethylamino)propyl]amino]acetic acid C7H16N2O2 详情 详情
(V) 50247 　 C7H15N3O3 详情 详情
(VI) 50248 3-[3-(dimethylamino)propyl]-1,2,3-oxadiazol-3-ium-5-olate C7H13N3O2 详情 详情
(VII) 50249 (E)-3-methyl-6-phenyl-5-hexenal C13H16O 详情 详情
(VIII) 50250 3-[3-(dimethylamino)propyl]-4-[(E)-1-hydroxy-3-methyl-6-phenyl-5-hexenyl]-1,2,3-oxadiazol-3-ium-5-olate C20H29N3O3 详情 详情
(IX) 50251 3-[3-(dimethylamino)propyl]-4-[(E)-1-methoxy-3-methyl-6-phenyl-5-hexenyl]-1,2,3-oxadiazol-3-ium-5-olate C21H31N3O3 详情 详情
(X) 50252 3-(7-methoxy-5-methyl-3-phenyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N,N-dimethyl-1-propanamine; N-[3-(7-methoxy-5-methyl-3-phenyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)propyl]-N,N-dimethylamine C20H29N3O 详情 详情

合成路线80

该中间体在本合成路线中的序号：(II)

The reaction of 2-thiobarbituric acid (I) with ethyl bromoacetate (II) by means of NaHCO3 in ethanol - water gives ethyl-(4,6-dihydroxy-2-pyrimidinylthio)acetate (III), which by halogenation with POCl3 and N,N-diethylaniline yields ethyl (4,6-dichloro-2-pyrimidinylthio)acetate (IV). The condensation of (IV) with 2,3-dimethylaniline (V) by means of Na2CO3 in refluxing ethanol affords ethyl [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetate (VI), which is finally hydrolyzed with Na2CO3 in refluxing ethanol. Description.- Crystals, m.p. 146-51 C; Na salt, m.p. 183 C (decomp.).

参考文献 中间体
合成目标
【1】 Castaner, J.; Paton, D.M.; Wy - 14643. Drugs Fut 1978, 3, 5, 404.
【2】 Santilli, A.A.; et al.; Natural product resveratrol: Novel sensitizer of tumor cells for TRAIL- or cytotoxic drug-induced apoptosis by cell cycle-mediated survivin depletion. Experientia 1974, 30, 10, 1110.
【3】 Santilli, A.A.; et al.; US 3940394 .
【4】 Santilli, A.A.; et al. (American Home Products Corp.); US 3910910 .
【5】 Santilli, A.A.; et al. (American Home Products Corp.); CA 967571; DE 2314160; FR 2182917; GB 1413892; US 3814761; US 3876789; US 3896129; ZA 7301526 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 25623 2-Thiobarbituric acid; 4,5-Dihydroxy-2-mercaptopyrimidine; 2-sulfanyl-4,6-pyrimidinediol 504-17-6 C4H4N2O2S 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 61116 ethyl 2-[(4,6-dihydroxy-2-pyrimidinyl)sulfanyl]acetate C8H10N2O4S 详情 详情
(IV) 61117 ethyl 2-[(4,6-dichloro-2-pyrimidinyl)sulfanyl]acetate C8H8Cl2N2O2S 详情 详情
(V) 23025 2,3-Dimethylphenylamine; 2,3-Dimethylaniline; 2,3-Xylidine 87-59-2 C8H11N 详情 详情
(VI) 61118 ethyl 2-{[4-chloro-6-(2,3-dimethylanilino)-2-pyrimidinyl]sulfanyl}acetate C16H18ClN3O2S 详情 详情

合成路线81

该中间体在本合成路线中的序号：(II)

The reaction of perhydroazepinone (I) with ethyl 2-bromoacetate (II) by means of LiHMDS in THF, followed by hydrolysis with KOH in methanol/water, gives the perhydroazepinylacetic acid (III), which is condensed with the pyrrolidine derivative (IV) by means of HOBt, WSCl and DIEA in dichloromethane to yield the adduct (V). The cleavage of the carbamate group of (V) with TFA in dichloromethane affords the 3-aminoperhydroazepinone (VI), which is condensed with ethyl 4-bromobutyrate (VII) by means of DIEA in acetonitrile to provide the 4-aminobutyrate derivative (VIII). The reaction of the cyano group of (VIII) with HCl in ethanol, followed by amonolysis with NH3 in the same solvent, gives the carboxamidine derivative (IX), which is hydrolyzed with KOH in ethanol/water to yield the target butyric acid derivative.

参考文献 中间体
合成目标
【1】 Park, C.-H.; Koo, B.-A.; Nam, W.-H. (C & C Research Laboratories); Substd. aromatic amidine deriv. and medicinal compsn. comprising the same. WO 0055156 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 54736 2,2-dimethyl-N-[(3R)-2-oxoazepanyl]propanamide C11H20N2O2 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 54737 2-{(3R)-3-[(2,2-dimethylpropanoyl)amino]-2-oxoazepanyl}acetic acid C13H22N2O4 详情 详情
(IV) 50438 1-ethyl-2-[2-[(2S)pyrrolidinyl]ethyl]-1H-indole-6-carbonitrile C17H21N3 详情 详情
(V) 54738 N-[(3R)-1-(2-{(2R)-2-[2-(6-cyano-1-ethyl-1H-indol-2-yl)ethyl]pyrrolidinyl}-2-oxoethyl)-2-oxoazepanyl]-2,2-dimethylpropanamide C30H41N5O3 详情 详情
(VI) 54739 2-[2-((2R)-1-{2-[(3R)-3-amino-2-oxoazepanyl]acetyl}pyrrolidinyl)ethyl]-1-ethyl-1H-indole-6-carbonitrile C25H33N5O2 详情 详情
(VII) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(VIII) 54740 ethyl 4-{[(3R)-1-(2-{(2R)-2-[2-(6-cyano-1-ethyl-1H-indol-2-yl)ethyl]pyrrolidinyl}-2-oxoethyl)-2-oxoazepanyl]amino}butanoate C31H43N5O4 详情 详情
(IX) 54741 ethyl 4-[((3R)-1-{2-[(2R)-2-(2-{6-[amino(imino)methyl]-1-ethyl-1H-indol-2-yl}ethyl)pyrrolidinyl]-2-oxoethyl}-2-oxoazepanyl)amino]butanoate C31H46N6O4 详情 详情

合成路线82

该中间体在本合成路线中的序号：(IX)

The Boc-protected amino alcohol (VIII) is condensed with ethyl bromoacetate (IX) in the presence of potassium tert-butoxide to afford ether (X). After alkaline hydrolysis of the ethyl ester group of (X), the resultant carboxylic acid (XI) is activated as the thioimide (XIII) upon treatment with thiazolidine-2-thione (XII) and EDC. Coupling of the acyl thiazolidinone (XIII) with cytosine arabinoside (XIV) leads to the N-acyl cytosine derivative (XV). The Boc protecting group of (XV) is then removed under acidic conditions to furnish amine (XVI).

参考文献 中间体
合成目标
【1】 Choe, Y.H.; et al.; Anticancer drug delivery systems: multi-loaded N-4-acyl poly(ethylene glycol) prodrugs of ara-C. II. Efficacy in ascites and solid tumors. J Control Release 2002, 79, 1-3, 55.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 57574 tert-butyl 2-(2-hydroxyethoxy)ethylcarbamate C9H19NO4 详情 详情
(IX) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(X) 57575 ethyl 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-oate C13H25NO6 详情 详情
(XI) 57576 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-oic acid C11H21NO6 详情 详情
(XII) 54751 Thiazolidine-2-thione C3H5NS2 详情 详情
(XIII) 57577 tert-butyl 2-{2-[2-oxo-2-(2-thioxo-1,3-thiazolidin-3-yl)ethoxy]ethoxy}ethylcarbamate C14H24N2O5S2 详情 详情
(XIV) 32709 Cytarabine; Cytosine Beta-D-Arabinofuranoside; 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone 147-94-4 C9H13N3O5 详情 详情
(XV) 57578 tert-butyl 2-{2-[2-({1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl}amino)-2-oxoethoxy]ethoxy}ethylcarbamate C20H32N4O10 详情 详情
(XVI) 57579 2-[2-(2-aminoethoxy)ethoxy]-N-{1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl}acetamide C15H24N4O8 详情 详情

合成路线83

该中间体在本合成路线中的序号：(II)

The intermediate dimesylate (VI) can be obtained as follows: The condensation of 2,3-dihydro-1,4-benzodioxin-5-amine (I) with ethyl bromoacetate (II) by means of Hunig's base and NaI in refluxing toluene gives the tertiary amine (III), which is reduced by means of LiAlH4 in THF to yield the diethanolamine (IV). Finally, this compound is esterified by means of mesyl chloride (V) to provide the desired dimesylate intermediate (VI). Alternatively, the diethanolamine (IV) can be obtained by direct condensation of 2,3-dihydro-1,4-benzodioxin-5-amine (I) with 2-chloroethanol (VII) by means of Hunig's base.

参考文献 中间体
合成目标
【1】 Jirkovsky, I.; Zeldis, J.; Chan, A.W.-Y.; Fiegelson, G.B. (Wyeth); Preparation of N1-(2'-pyridyl)-1,2-propanediamine sulfamic acid and its use in the synthesis of biologically active piperazines. WO 0378396 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 22000 2,3-dihydro-1,4-benzodioxin-5-amine; 2,3-dihydro-1,4-benzodioxin-5-ylamine; 5-Amino-1,4-benzodioxane 16081-46-2 C8H9NO2 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 64784 ethyl 2-[2,3-dihydro-1,4-benzodioxin-5-yl(2-ethoxy-2-oxoethyl)amino]acetate C16H21NO6 详情 详情
(IV) 64785 2-[2,3-dihydro-1,4-benzodioxin-5-yl(2-hydroxyethyl)amino]-1-ethanol C12H17NO4 详情 详情
(V) 13467 Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride 124-63-0 CH3ClO2S 详情 详情
(VI) 64786 2-(2,3-dihydro-1,4-benzodioxin-5-yl{2-[(methylsulfonyl)oxy]ethyl}amino)ethyl methanesulfonate C14H21NO8S2 详情 详情
(VII) 10384 2-Chloro-1-ethanol; Ethylene chlorohydrin 107-07-3 C2H5ClO 详情 详情

合成路线84

该中间体在本合成路线中的序号：(IV)

Friedel-Crafts acylation of 3-(p-methoxybenzoyl)pyrrole (I) with p-methoxybenzoyl chloride (II) gives rise to diketone (III). Subsequent alkylation of pyrrole (III) with ethyl bromoacetate (IV) in the presence of NaH and tris[(2-methoxyethoxy)ethyl]amine (TDA) furnishes the pyrrolylacetate (V). Finally, saponification of the ethyl ester group of (V) affords the target carboxylic acid.

参考文献 中间体
合成目标
【1】 Nicolaou, I.; Demopoulos, V.J.; Substituted pyrrol-1-ylacetic acids that combine aldose reductase enzyme inhibitory activity and ability to prevent the nonenzymatic irreversible modification of proteins from monosaccharides. J Med Chem 2003, 46, 3, 417.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 64031 [4-(methyloxy)phenyl](1H-pyrrol-3-yl)methanone C12H11NO2 详情 详情
(II) 22071 2-[1,2-bis[[(E)-(2,6-dichloro-4-methoxyphenyl)methylidene]amino]-2-(2-hydroxyphenyl)ethyl]phenol C30H24Cl4N2O4 详情 详情
(III) 64032 [5-(4-methoxybenzoyl)-1H-pyrrol-3-yl](4-methoxyphenyl)methanone C20H17NO4 详情 详情
(IV) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(V) 64033 ethyl 2-(2,4-bis{[4-(methyloxy)phenyl]carbonyl}-1H-pyrrol-1-yl)acetate C24H23NO6 详情 详情

合成路线85

该中间体在本合成路线中的序号：(III)

4-Hydroxy-6-methyl-3-nitropyridone (I) is chlorinated to (II) by treatment with POCl3 in the presence of benzyltriethylammonium chloride. Alkylation of pyridone (II) with ethyl bromoacetate (III) and NaH leads to the pyridoneacetate (IV) (1). Displacement of the chloride group of (IV) with 2-mercaptobenzothiazole (V) affords the thioether (VI). After reduction of the nitro group of (VI) by catalytic hydrogenation, the resultant amine (VII) is protected as the di-Boc derivative (VIII) with di-tert-butyl dicarbonate and DMAP. Oxidation of the thioether (VIII) with KmnO4 gives the sulfone (IX), which is submitted to reductive cleavage with Zn/AcOH. Finally chlorination of the intermediate zinc sulfinate with NCS furnishes the sulfonyl chloride (X) (1,2).

参考文献 中间体
合成目标
【1】 Sanderson, P.E.J.; Cutrona, K.J.; Savage, K.L.; Naylor-Olsen, A.M.; Bickel, D.J.; Bohn, D.L.; Clayton, F.C.; Krueger, J.A.; Lewis, S.D.; Lucas, B.J.; Lyle, E.A.; Wallace, A.A.; Welsh, D.C.; Yan, Y.; 3-Amino-4-sulfonylpyridinone acetamide and related pyridothiadiazine thrombin inhibitors. Bioorg Med Chem Lett 2003, 13, 8, 1441.
【2】 Sanderson, P.E.; Cutrona, K. (Merck & Co., Inc.); Thrombin inhibitors. EP 1117660; JP 2002525370; US 6117888; WO 0018762 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 23337 4-hydroxy-6-methyl-3-nitro-2(1H)-pyridinone 4966-90-9 C6H6N2O4 详情 详情
(II) 23339 4-chloro-6-methyl-3-nitro-2(1H)-pyridinone C6H5ClN2O3 详情 详情
(III) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(IV) 64710 ethyl 2-[4-chloro-6-methyl-3-nitro-2-oxo-1(2H)-pyridinyl]acetate C10H11ClN2O5 详情 详情
(V) 24677 1,3-benzothiazol-2-ylhydrosulfide 149-30-4 C7H5NS2 详情 详情
(VI) 64711 ethyl 2-[4-(1,3-benzothiazol-2-ylsulfanyl)-6-methyl-3-nitro-2-oxo-1(2H)-pyridinyl]acetate C17H15N3O5S2 详情 详情
(VII) 64712 ethyl 2-[3-amino-4-(1,3-benzothiazol-2-ylsulfanyl)-6-methyl-2-oxo-1(2H)-pyridinyl]acetate C17H17N3O3S2 详情 详情
(VIII) 64713 ethyl 2-[4-(1,3-benzothiazol-2-ylsulfanyl)-3-[bis(tert-butoxycarbonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetate C27H33N3O7S2 详情 详情
(IX) 64714 ethyl 2-[4-(1,3-benzothiazol-2-ylsulfonyl)-3-[bis(tert-butoxycarbonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetate C27H33N3O9S2 详情 详情
(X) 64715 ethyl 2-[3-[bis(tert-butoxycarbonyl)amino]-4-(chlorosulfonyl)-6-methyl-2-oxo-1(2H)-pyridinyl]acetate C20H29ClN2O9S 详情 详情

合成路线86

该中间体在本合成路线中的序号：(II)

　

参考文献 中间体
合成目标
【1】 Wilken J. Nerenz F, Kanschik-Conndsen A. 2004. A process for the synthesis of 3-hydroxy3-(2-phenylethyl) hexanoic acid，useful as an intermediate for antiviral. US 2004110957(本专利属于Honey-well International, Inc.，USA)
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 21159 (3R)-3-hydroxy-3-phenethylhexanoic acid C14H20O3 详情 详情
(VII) 66860 (S)-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one 　 C16H20O3 详情 详情
(I) 17233 1-phenyl-3-hexanone C12H16O 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 21156 ethyl 3-hydroxy-3-phenethylhexanoate C16H24O3 详情 详情
(IV) 13355 2-Amino-1-phenyl-1-propanol; (1S,2R)-(+)-Norephedrine 37577-28-9 C9H13NO 详情 详情
(VI) 66856 (S)-ethyl 5-hydroxy-3-oxo-5-phenethyloctanoate 　 C18H26O4 详情 详情
(IX) 17236 (6R)-3-[(1R)-1-(3-aminophenyl)propyl]-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one C25H31NO3 详情 详情

合成路线87

该中间体在本合成路线中的序号：(II)

Condensation of the 1,5-benzothiazepin-8-ol derivative (I) with ethyl bromoacetate (II) in the presence of Bu4NBr and Na2CO3 in refluxing acetonitrile yields ethyl ester (III), which is then hydrolyzed with NaOH in EtOH to give the corresponding acid (IV). Subsequent coupling of carboxylic acid (IV) with (R)-2-phenylglycine methyl ester hydrochloride (V) using TBTU and DIEA in CH2Cl2 followed by hydrolysis of the resultant methyl ester (VI) with NaOH in MeOH produces the N-acyl amino acid (VII). After coupling of acid (VII) with tert-butyl glycinate (VIII), using the same procedure as above, the resulting tert-butyl ester (IX) is finally cleaved using TFA in CH2Cl2 .

参考文献 中间体
合成目标
【1】 Starke, I., Blomberg, D., Dahlstrom, M. (AstraZeneca AB; AstraZeneca plc). Chemical compounds. EP 1345918, JP 2004196815, JP 2004516285, US 2004067933, US 7192945, WO 2002050051.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 68515 3,3-dibutyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide 　 C24H33NO3S2 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 68516 ethyl 2-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acetate 　 C28H39NO5S2 详情 详情
(IV) 68517 2-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acetic acid 　 C26H35NO5S2 详情 详情
(V) 68518 (R)-2-phenylglycine methyl ester hydrochloride 　 C9H11NO2.HCl 详情 详情
(VI) 68519 (R)-methyl 2-(2-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acetamido)-2-phenylacetate 　 C35H44N2O6S2 详情 详情
(VII) 68520 (R)-2-(2-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acetamido)-2-phenylacetic acid 　 C34H42N2O6S2 详情 详情
(VIII) 27841 tert-butyl 2-aminoacetate;tert-butyl glycinate;Glycine tert-butyl ester 6456-74-2 C6H13NO2 详情 详情
(IX) 68521 (R)-tert-butyl 2-(2-(2-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acetamido)-2-phenylacetamido)acetate 　 C40H53N3O7S2 详情 详情
Extended Information