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【结 构 式】

【分子编号】10315

【品名】2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone

【CA登记号】70-11-1

【 分 子 式 】C8H7BrO

【 分 子 量 】199.04698

【元素组成】C 48.27% H 3.54% Br 40.14% O 8.04%
与该中间体有关的原料药合成路线共 17 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17

合成路线1

该中间体在本合成路线中的序号：(II)

The bromination of labeled acetophenone (I) with Br2 and AlCl3 gives phenacyl bromide (II), which is condensed with N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylamine (III), yielding the 2-aminoacetophenone (IV). The reduction of (IV) with NaBH4 affords the secondary alcohol (V), which is finally cyclized by means of H2SO4 and trifluoroacetic acid to provide the target 3-benzazepine.

参考文献 中间体
合成目标
【1】 Hieble, J.P.; Wilson III, J.W.; Weinstock, J.; The chemistry and pharmacology of 3-benzazepines derivatives. Drugs Fut 1985, 10, 8, 645.
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) 10317 Acetophenone 98-86-2 C8H8O 详情 详情
(I) 44572 acetophenone C8H8O 详情 详情
(II) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(II) 44573 2-bromo-1-phenyl-1-ethanone C8H7BrO 详情 详情
(III) 18938 2-(3,4-dimethoxyphenyl)-N-methyl-1-ethanamine; N-(3,4-dimethoxyphenethyl)-N-methylamine 3490-06-0 C11H17NO2 详情 详情
(IV) 44047 2-[(3,4-dimethoxyphenethyl)(methyl)amino]-1-phenyl-1-ethanone C19H23NO3 详情 详情
(IV) 44574 2-[(3,4-dimethoxyphenethyl)(methyl)amino]-1-phenyl-1-ethanone C19H23NO3 详情 详情
(V) 44048 2-[(3,4-dimethoxyphenethyl)(methyl)amino]-1-phenyl-1-ethanol C19H25NO3 详情 详情
(V) 44575 2-[(3,4-dimethoxyphenethyl)(methyl)amino]-1-phenyl-1-ethanol C19H25NO3 详情 详情

合成路线2

该中间体在本合成路线中的序号：(B)

The reaction of beta-tetralone (I) with pyrrolidine (A) yields enamine (II), which is condensed with phenacyl bromide (B) in DMF to give the 1-phenacyl-2-tetralone (III). Finally, this diketone is cyclized with 5-aminosalycilic acid (C) in refluxing acetic acid.

参考文献 中间体
合成目标
【1】 Anderson, V.B.; et al.; Carboxyarylindoles as non steroidal anti-inflammatory agents. J Med Chem 1976, 1, 7, 320.
【2】 Castaner, J.; Arrigoni-Martelli, E.; Fendosal. Drugs Fut 1976, 1, 7, 320.
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) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(A) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(I) 39106 3,4-Dihydro-2(1H)-naphthalenone; beta-Tetralone 530-93-8 C10H10O 详情 详情
(II) 20382 1-(3,4-dihydro-2-naphthalenyl)pyrrolidine 21403-95-2 C14H17N 详情 详情
(III) 40460 1-(2-oxo-2-phenylethyl)-3,4-dihydro-2(1H)-naphthalenone C18H16O2 详情 详情
(C) 29932 5-amino-2-hydroxybenzoic acid 89-57-6 C7H7NO3 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

The bromination of labeled acetophenone (I) with Br2 and AlCl3 gives the phenacyl bromide (II), which is reduced with NaBH4, yielding 2-bromo-1-phenylethanol (III). The condensation of (III) with N-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]amine (IV) affords the tertiary amine (V), which is debenzylated by hydrogenolysis with H2 over Pd/C to provide the substituted ethanolamine (VI). Finally, this compound is cyclized and demethylated by treatment with 48% HBr to provide the target benzazepine.

参考文献 中间体
合成目标
【1】 Hieble, J.P.; Wilson III, J.W.; Weinstock, J.; The chemistry and pharmacology of 3-benzazepines derivatives. Drugs Fut 1985, 10, 8, 645.
【2】 Bass, L.S.; Dandridge, P.A.; Setler, P.E.; Sarau, H.M.; Garvey, E.; Clardy, J.; Hanhn, R.A.; Kaiser, C.; Absolute stereochemistry and dopaminergic activity of enantiomers of 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine. J Med Chem 1982, 25, 6, 697-703.
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) 10317 Acetophenone 98-86-2 C8H8O 详情 详情
(I) 44572 acetophenone C8H8O 详情 详情
(II) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(II) 44573 2-bromo-1-phenyl-1-ethanone C8H7BrO 详情 详情
(III) 44060 2-bromo-1-phenyl-1-ethanol C8H9BrO 详情 详情
(III) 44632 2-bromo-1-phenyl-1-ethanol C8H9BrO 详情 详情
(IV) 44061 N-benzyl-2-(3,4-dimethoxyphenyl)-1-ethanamine; N-benzyl-N-(3,4-dimethoxyphenethyl)amine C17H21NO2 详情 详情
(V) 44062 2-[benzyl(3,4-dimethoxyphenethyl)amino]-1-phenyl-1-ethanol C25H29NO3 详情 详情
(V) 44633 2-[benzyl(3,4-dimethoxyphenethyl)amino]-1-phenyl-1-ethanol C25H29NO3 详情 详情
(VI) 39206 2-[(3,4-dimethoxyphenethyl)amino]-1-phenyl-1-ethanol C18H23NO3 详情 详情
(VI) 44634 2-[(3,4-dimethoxyphenethyl)amino]-1-phenyl-1-ethanol C18H23NO3 详情 详情

合成路线4

该中间体在本合成路线中的序号：(VIII)

Two new syntheses of labeled azamianserin have been described: 1) [13C]-Labeled: The reaction of 2-chloropyridine-3-carbonitrile (I) with glycine ethyl ester (II) by means of Na2CO3 in DMSO gives N-(3-cyanopyridin-2-yl)glycine ethyl ester (III), which by reaction with methylamine in toluene is converted into the corresponding amide (IV). The treatment of (IV) with sodium hypophosphite and RaNi in water-acetic acid-pyridine affords N-(3-formylpyridin-2-yl)glycine methylamide (V), which is reduced with NaBH4 in methanol to the corresponding alcohol (VI). Further reduction of (VI) with LiAlH4 in refluxing dioxane gives 2-[2-(methylamino)ethylamino]-3-pyridinemethanol (VII), which is condensed with [13C]-labeled alpha-bromoacetophenone (VIII) [prepared from labeled benzene (IX) submitted to a Friedel-Crafts condensation with AlCl3 and acetic anhydride to acetophenone (X) and bromination with Br2 in ether] by means of triethylamine in dioxane to afford the substituted acetophenone (XI). The cyclization of (XI) by heating at 120 C yields the tricyclic compound (XII), which is reduced with LiAlH4 - AlCl3 in ethyl ether to give 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol (XIII). Finally, this compound is cyclized in hot H2SO4.

参考文献 中间体
合成目标
【1】 Wieringa, J.H.; Kaspersen, F.M.; van Rooij, F.A.M.; Sperling, E.G.M.; The synthesis of ORG 3770 labelled with 3H, 13C and 14C. J Label Compd Radiopharm 1989, 27, 9, 1055.
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) 10308 2-Chloronicotinonitrile; 2-Chloro-3-cyanopyridine 6602-54-6 C6H3ClN2 详情 详情
(II) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(III) 10310 ethyl 2-[(3-cyano-2-pyridinyl)amino]acetate C10H11N3O2 详情 详情
(IV) 10311 2-[(3-Cyano-2-pyridinyl)amino]-N-methylacetamide C9H10N4O 详情 详情
(V) 10312 2-[(3-Formyl-2-pyridinyl)amino]-N-methylacetamide C9H11N3O2 详情 详情
(VI) 10313 2-[[3-(Hydroxymethyl)-2-pyridinyl]amino]-N-methylacetamide C9H13N3O2 详情 详情
(VII) 10314 (2-[[2-(Methylamino)ethyl]amino]-3-pyridinyl)methanol C9H15N3O 详情 详情
(VIII) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(VIII) 44642 2-bromo-1-phenyl-1-ethanone C8H7BrO 详情 详情
(IX) 13364 Benzene 71-43-2 C6H6 详情 详情
(IX) 44640 benzene C6H6 详情 详情
(X) 10317 Acetophenone 98-86-2 C8H8O 详情 详情
(X) 44641 acetophenone C8H8O 详情 详情
(XI) 10318 2-[(2-[[3-(Hydroxymethyl)-2-pyridinyl]amino]ethyl)(methyl)amino]-1-phenyl-1-ethanone C17H21N3O2 详情 详情
(XI) 44643 2-[(2-[[3-(hydroxymethyl)-2-pyridinyl]amino]ethyl)(methyl)amino]-1-phenyl-1-ethanone C17H21N3O2 详情 详情
(XII) 10319 8-Methyl-6a-phenyl-7,8,9,10-tetrahydro-5H,6aH-pyrazino[2,1-b]pyrido[2,3-d][1,3]oxazine C17H19N3O 详情 详情
(XII) 44644 8-methyl-6a-phenyl-7,8,9,10-tetrahydro-5H,6aH-pyrazino[2,1-b]pyrido[2,3-d][1,3]oxazine C17H19N3O 详情 详情
(XIII) 10320 [2-(4-Methyl-2-phenylpiperazino)-3-pyridinyl]methanol 61337-89-1 C17H21N3O 详情 详情
(XIII) 44645 [2-(4-methyl-2-phenyl-1-piperazinyl)-3-pyridinyl]methanol C17H21N3O 详情 详情

合成路线5

该中间体在本合成路线中的序号：(X)

The esterification of N-(tert-butoxycarbonyl)-D-glutamic acid 5-O-benzyl ester (I) with phenol by means of DCC and pyridine in ethyl acetate gives the mixed ester (II), which is treated with H2 over Pd/C in methanol to yield the N-(tert-butoxycarbonyl)-D-glutamic acid 1-O-phenyl ester (III). The cyclization of (III) with O-benzylhydroxylamine (IV) by means of EDC, HOBT and TEA in dichloromethane affords N-[1-(benzyloxy)-2,6-dioxopiperidin-3(R)-yl]carbamic acid tert-butyl ester (V), which is treated with HCl gas in dichloromethane to provide 3(R)-amino-1-(benzyloxy)piperidine-2,6-dione (VI). The reaction of (VI) with phthalic anhydride (VII) by means of TEA in THF gives the phthalimido derivative (VIII), which is debenzylated with H2 over Pd/C in methanol to yield 1-hydroxy-3-(R)-(phthalimido)piperidine-2,6-dione (IX). Finally, the OH group of (IX) is eliminated by reaction with phenacyl bromide (X) and TEA in acetonitrile to afford the phenacyl ether (XI), which is submitted to a nucleophilic cleavage by means of DMAP as the base to obtain the target (R)-thalidomide.

参考文献 中间体
合成目标
【1】 Robin, S.; et al.; A convenient asymmetric synthesis of thalidomide. Tetrahedron Asymmetry 1995, 6, 6, 1249.
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) 57869 (2R)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid C17H23NO6 详情 详情
(II) 57862 5-benzyl 1-phenyl (2R)-2-[(tert-butoxycarbonyl)amino]pentanedioate C23H27NO6 详情 详情
(III) 57863 (4R)-4-[(tert-butoxycarbonyl)amino]-5-oxo-5-phenoxypentanoic acid C16H21NO6 详情 详情
(IV) 14640 O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene 622-33-3 C7H9NO 详情 详情
(V) 57864 tert-butyl (3R)-1-(benzyloxy)-2,6-dioxopiperidinylcarbamate C17H22N2O5 详情 详情
(VI) 57865 (3R)-3-amino-1-(benzyloxy)-2,6-piperidinedione C12H14N2O3 详情 详情
(VII) 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
(VIII) 57866 2-[(3R)-1-(benzyloxy)-2,6-dioxopiperidinyl]-1H-isoindole-1,3(2H)-dione C20H16N2O5 详情 详情
(IX) 57867 2-[(3R)-1-hydroxy-2,6-dioxopiperidinyl]-1H-isoindole-1,3(2H)-dione C13H10N2O5 详情 详情
(X) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(XI) 57868 2-[(3R)-2,6-dioxo-1-(2-oxo-2-phenylethoxy)piperidinyl]-1H-isoindole-1,3(2H)-dione C21H16N2O6 详情 详情

合成路线6

该中间体在本合成路线中的序号：(X)

The esterification of N-(tert-butoxycarbonyl)-L-glutamic acid 5-O-benzyl ester (I) with phenol by means of DCC and pyridine in ethyl acetate gives the mixed ester (II), which is treated with H2 over Pd/C in methanol to yield the N-(tert-butoxycarbonyl)-L-glutamic acid 1-O-phenyl ester (III). The cyclization of (III) with O-benzylhydroxylamine (IV) by means of EDC, HOBT and TEA in dichloromethane affords N-[1-(benzyloxy)-2,6-dioxopiperidin-3(S)-yl]carbamic acid tert-butyl ester (V), which is treated with HCl gas in dichloromethane to provide 3(S)-amino-1-(benzyloxy)piperidine-2,6-dione (VI). The reaction of (VI) with phthalic anhydride (VII) by means of TEA in THF gives the phthalimido derivative (VIII), which is debenzylated with H2 over Pd/C in methanol to yield 1-hydroxy-3-(S)-(phthalimido)piperidine-2,6-dione (IX). Finally the OH group of (IX) is eliminated by reaction with phenacyl bromide (X) and TEA in acetonitrile to afford the phenacyl ether (XI), which is submitted to a nucleophilic cleavage by means of DMAP as the base to obtain the target (S)-thalidomide. Alternatively, the phthalimido derivative (VIII) can also be obtained by reaction of 2(S)-(phthalimido)glutaric anhydride (XII) with O-benzylhydroxylamine (IV) by means of DCC and pyridine in dichloromethane.

参考文献 中间体
合成目标
【1】 Robin, S.; et al.; A convenient asymmetric synthesis of thalidomide. Tetrahedron Asymmetry 1995, 6, 6, 1249.
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) 25141 (2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid 13574-13-5 C17H23NO6 详情 详情
(II) 57870 5-benzyl 1-phenyl (2S)-2-[(tert-butoxycarbonyl)amino]pentanedioate C23H27NO6 详情 详情
(III) 57871 (4S)-4-[(tert-butoxycarbonyl)amino]-5-oxo-5-phenoxypentanoic acid C16H21NO6 详情 详情
(IV) 14640 O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene 622-33-3 C7H9NO 详情 详情
(V) 57872 tert-butyl (3S)-1-(benzyloxy)-2,6-dioxopiperidinylcarbamate C17H22N2O5 详情 详情
(VI) 57873 (3S)-3-amino-1-(benzyloxy)-2,6-piperidinedione C12H14N2O3 详情 详情
(VII) 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
(VIII) 57874 2-[(3S)-1-(benzyloxy)-2,6-dioxopiperidinyl]-1H-isoindole-1,3(2H)-dione C20H16N2O5 详情 详情
(IX) 57875 2-[(3S)-1-hydroxy-2,6-dioxopiperidinyl]-1H-isoindole-1,3(2H)-dione C13H10N2O5 详情 详情
(X) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(XI) 57876 2-[(3S)-2,6-dioxo-1-(2-oxo-2-phenylethoxy)piperidinyl]-1H-isoindole-1,3(2H)-dione C21H16N2O6 详情 详情
(XII) 57877 2-[(3S)-2,6-dioxotetrahydro-2H-pyran-3-yl]-1H-isoindole-1,3(2H)-dione C13H9NO5 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

2-Aminoacetophenone.HCl (IV) is prepared from acetophenone (I) via 2-bromoacetophenone (II) and the quaternary urotropine salt (III). Acetylation of (IV) with acetic anhydride in water in the presence of sodium hydrogen carbonate yields 2-acetamidoacetophenone (V), which is converted to 2-acetamido-3-hydroxypropiophenone.HCl (VI) with formaldehyde in water. After removing the acetyl group with hydrochloric acid in ethanol, 2-amino-3-hydroxypropiophenone.HCl (VII) is formed, which is reduced with hydrogen over Pd/C in methanol to rac-erythro-2-amino-1-phenyl-1,3-propanediol.HCl (VIII). Reductive condensation of the corresponding base (IX) with phenoxyacetone (X) and hydrogen over PtO2 affords a mixture of aminodiols epimeric at C-1' (XI). (XI) is finally converted to the corresponding hydrochloride salts, from which the salt of the less soluble [1R*,2S*(S*)]-stereoisomer, i.e., solpecainol is isolated by crystallization. Structure and purity of solpecainol have been confirmed by x-ray crystallography and HPLC-MS.

参考文献 中间体
合成目标
【1】 Central Res. Inst. Chem. Hung. Acad. Sci. Report (27.10.1983) 1983.
【2】 Levai, L.; Fazekas, G.; Petocz, L.; Grasser, K. (Egis Pharmaceuticals Ltd.); Novel N-alkyl derivs. of 1-phenyl-2-amino-1,3-propandiol and process for preparing same. DE 2810482; GB 1560470; JP 1978112827; US 4259257 .
【3】 Vida, L.; Szepesy, L.; Lakszner, K.; Comparison and evaluation of derivatization methods for gas chromatographic determination of various propanediols. Chromatographia 1984, 19, 304.
【4】 Berényi, E.; Petócz, L.; Blaskó, G.; Nógrádi, M.; Solpecainol Hydrochloride. Drugs Fut 1991, 16, 6, 514.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
34873 1,3,5,7-tetraazatricyclo[3.3.1.1(3,7)]decane 100-97-0 C6H12N4 详情 详情
(I) 10317 Acetophenone 98-86-2 C8H8O 详情 详情
(II) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(III) 14599 2-(1-bromo-1lambda(5),3,5,7-tetraazatricyclo[3.3.1.1(3,7)]dec-1-yl)-1-phenyl-1-ethanone C14H19BrN4O 详情 详情
(IV) 14600 2-(chloroamino)-1-phenylethanone C8H8ClNO 详情 详情
(V) 14601 N-(2-oxo-2-phenylethyl)acetamide C10H11NO2 详情 详情
(VI) 14602 N-[1-(hydroxymethyl)-2-oxo-2-phenylethyl]acetamide C11H13NO3 详情 详情
(VII) 14603 2-(Cloroamino)-3-hydroxy-1-phenyl-1-propanone C9H10ClNO2 详情 详情
(VIII) 14604 (1R,2S)-2-(Chloroamino)-1-phenylpropane-1,3-diol C9H12ClNO2 详情 详情
(IX) 14605 (1R,2S)-2-amino-1-phenyl-1,3-propanediol C9H13NO2 详情 详情
(X) 10875 1-Phenoxyacetone; 1-Phenoxy-2-propanone 621-87-4 C9H10O2 详情 详情
(XI) 14607 (1R,2S)-2-[(1-methyl-2-phenoxyethyl)amino]-1-phenyl-1,3-propanediol C18H23NO3 详情 详情

合成路线8

该中间体在本合成路线中的序号：

N-Boc-L-Threonine (LVI) was protected as the corresponding phenacyl ester (LVII) by treatment with 2-bromoacetophenone and Et3N. Esterification of (LVII) with the modified tyrosine building block (II) yielded the protected didepsipeptide (LVIII). Removal of the phenacyl ester group of (LVIII) under reductive conditions provided the carboxylic acid (VI). Coupling of acid (VI) with the depsipeptide segment (XXI), followed by deprotection by hydrogenolysis furnished the linear precursor (XXIII). Macrocyclization of (XXIII) using HATU and subsequent acidic Boc group cleavage led to the macrocyclic amine (XXV)

参考文献 中间体
合成目标
【1】 Edge, A. (Diacrin, Inc.); Method for improving graft acceptance in a recipient by administration of a cytokine profile altering agent. WO 0051630 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(II) 50747 (2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid C19H21NO5 详情 详情
(VI) 52709 (2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoic acid C28H36N2O9 详情 详情
(XXI) 62536 benzyl (2S)-1-{(2S)-2-[((4S)-4-{[(3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoyl]oxy}-2,5-dimethyl-3-oxohexanoyl)amino]-4-methylpentanoyl}-2-pyrrolidinecarboxylate C34H53N3O8 详情 详情
(XXIII) 62538 (2S)-1-{(2S,7S,11S,12R,15S,16R,19S)-15-[(tert-butoxycarbonyl)amino]-11-hydroxy-2-isobutyl-7-isopropyl-19-(4-methoxybenzyl)-5,16-dimethyl-12-[(1S)-1-methylpropyl]-4,6,9,14,18-pentaoxo-8,17-dioxa-3,13,20-triazahenicos-1-anoyl}-2-pyrrolidinecarboxylic C47H75N5O14 详情 详情
(XXV) 50768 (3S,6R,7S,10R,11S,15S,17S,20S,25aS)-7-amino-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]tetradecahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosine-1,4,8,13,16,18,21(17H)-heptone C42H65N5O11 详情 详情
(LVI) 50745 N-BOC-L-threonine; Boc-Threonine; N-tert-Butoxycarbonyl-L-threonine; N-(tert-Butoxycarbonyl)-L-threonine; BOC-L-Threonine 2592-18-9 C9H17NO5 详情 详情
(LVII) 62565 2-oxo-2-phenylethyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutanoate C17H23NO6 详情 详情
(LVIII) 62566 2-oxo-2-phenylethyl (2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoate C36H42N2O10 详情 详情

合成路线9

该中间体在本合成路线中的序号：(II)

6-Hydroxyquinolin-2-one (I) was O-alkylated with 2-bromoacetophenone (II) by means of K2CO3 to give the phenacyl ether (III). Then, a Reformatsky-type condensation of (III) with ethyl 2-(bromomethyl)acrylate (IV) and Zn, with concomitant cyclization, yielded the target methylenebutyrolactone.

参考文献 中间体
合成目标
【1】 Wang, T.-C.; et al.; alpha-Methylidene-gamma-butyrolactones: Synthesis and evaluation of quinolin-2(1H)-one derivatives. Helv Chim Acta 1998, 81, 6, 1038.
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) 13913 6-Hydroxy-2(1H)-quinolinone C9H7NO2 详情 详情
(II) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(III) 21429 6-(2-oxo-2-phenylethoxy)-2(1H)-quinolinone C17H13NO3 详情 详情
(IV) 11328 ethyl 2-(bromomethyl)acrylate 17435-72-2 C6H9BrO2 详情 详情

合成路线10

该中间体在本合成路线中的序号：(A)

The reduction of diethyl 2-phenylmalonate (I) with LiAlH4 in ethyl ether gives the expected diol (II), which is tosylated with tosyl chloride and pyridine yielding the ditosylate (III). The cyclization of (III) with diethyl malonate (IV) by means of NaH in dioxane affords the diethyl 3-phenylcyclobutane-1,1-dicarboxylate (V), which is saponified with KOH to the diacid (VI). The partial decarboxylation of (VI) by heating at 200 C provides 3-phenylcyclobutane-1-carboxylic acid (VII), which is esterified with phenacyl bromide to the corresponding phenacyl ester (VIII). The oxidation of (VIII) with ruthenium chloride and periodic acid gives cyclobutane-1,3-dicarboxylic acid monophenacyl ester (IX) as a 1:1 mixture of the cis and trans isomers. The condensation of (IX) with malonic acid monoethyl ester (X) by means of oxalyl chloride and BuLi in THF yields tyhe intermediate diester (XI), which is condensed with thioxanthen (XII) in acetic acid to provide the thioxanthenyl acetic ester (XIII). The decarboxylative hydrolysis of (XIII) with NaOH in ethanol gives the ketoacid (XIV), which is cyclized with KCN and ammonium carbonate in ethanol/water yielding the imidazolidinedione (XV). The hydrolysis of (XV) with NaOH affords the 3-[1-amino-1-carboxy-2-(9-thioxanthenyl)ethyl]cyclobutane-1-carboxylic acid (XVI) as a 2:1 mixture of the cis and trans racemates. Finally, this mixture is treated with L-lysine and crystallized to afford the pure target compound.

参考文献 中间体
合成目标
【1】 Clark, B.P.; et al.; alpha-Substituted-cyclobutylglycine LY393675 potently antagonises group 1 metabotropic glutamate receptors. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.125.
【2】 Clark, B.P.; Harris, J.R. (Eli Lilly and Company); Pharmaceutical acidic cpds.. EP 0837061; JP 1998120635; US 6054448 .
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) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(I) 26952 diethyl 2-phenylmalonate 83-13-6 C13H16O4 详情 详情
(II) 24198 2-phenyl-1,3-propanediol C9H12O2 详情 详情
(III) 26953 3-[[(4-methylphenyl)sulfonyl]oxy]-2-phenylpropyl 4-methylbenzenesulfonate C23H24O6S2 详情 详情
(IV) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(V) 26954 diethyl 3-phenyl-1,1-cyclobutanedicarboxylate C16H20O4 详情 详情
(VI) 26955 3-phenyl-1,1-cyclobutanedicarboxylic acid C12H12O4 详情 详情
(VII) 26956 3-phenylcyclobutanecarboxylic acid C11H12O2 详情 详情
(VIII) 26957 2-oxo-2-phenylethyl 3-phenylcyclobutanecarboxylate C19H18O3 详情 详情
(IX) 26958 3-[(2-oxo-2-phenylethoxy)carbonyl]cyclobutanecarboxylic acid C14H14O5 详情 详情
(X) 15086 3-ethoxy-3-oxopropionic acid 1071-46-1 C5H8O4 详情 详情
(XI) 26959 2-oxo-2-phenylethyl 3-(3-ethoxy-3-oxopropanoyl)cyclobutanecarboxylate C18H20O6 详情 详情
(XII) 26071 9H-thioxanthen-9-ol C13H10OS 详情 详情
(XIII) 26960 2-oxo-2-phenylethyl 3-[3-ethoxy-3-oxo-2-(9H-thioxanthen-9-yl)propanoyl]cyclobutanecarboxylate C31H28O6S 详情 详情
(XIV) 26961 3-[2-(9H-thioxanthen-9-yl)acetyl]cyclobutanecarboxylic acid C20H18O3S 详情 详情
(XV) 26962 3-[2,5-dioxo-4-(9H-thioxanthen-9-ylmethyl)-4-imidazolidinyl]cyclobutanecarboxylic acid C22H20N2O4S 详情 详情
(XVI) 26963 3-[1-amino-1-carboxy-2-(9H-thioxanthen-9-yl)ethyl]cyclobutanecarboxylic acid C21H21NO4S 详情 详情

合成路线11

该中间体在本合成路线中的序号：(VII)

The reaction of phenacyl bromide (VII) with 2-aminothiazoline (VIII) in MeCN at 100 C gives 2-imino-3-phenacylthiazolidine (IX), which is reduced to the corresponding alcohol (X) with NaBH4 in methanol. Finally, this compound is cyclized with SOCl2 and refluxing acetic anhydride giving the racemic levamisole which is resolved resolved in its optical isomers through the d-10-camphorsulfonate, N-benzene (or p-toluene)sulfonyl-L-(+)-glutamic salt. Compound (X) can be acetylated under milder conditions than before giving the N-acetyl compound (XI), which is cyclized SOCl2 and refluxing acetic anhydride.

参考文献 中间体
合成目标
【1】 Janssen Pharm. N.V.; US 3274209 .
【2】 US 3579530 .
【3】 Castañer, J.; Hopkins, S.J.; Blancafort, P.; Serradell, M.N.; Levamisole hydrochloride. Drugs Fut 1979, 4, 6, 420.
【4】 Bullock, M.W.; DE 1645975 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(rac)-(XII) 39503 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole C11H12N2S 详情 详情
(VII) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(VIII) 39504 4,5-dihydro-1,3-thiazol-2-ylamine; 4,5-dihydro-1,3-thiazol-2-amine 1779-81-3 C3H6N2S 详情 详情
(IX) 39505 2-(2-imino-1,3-thiazolidin-3-yl)-1-phenyl-1-ethanone C11H12N2OS 详情 详情
(X) 39506 2-(2-imino-1,3-thiazolidin-3-yl)-1-phenyl-1-ethanol C11H14N2OS 详情 详情
(XI) 39507 N-[3-(2-hydroxy-2-phenylethyl)-1,3-thiazolidin-2-yl]acetamide C13H18N2O2S 详情 详情

合成路线12

该中间体在本合成路线中的序号：(X)

The intermediate sulfonyl chloride (VIII) has been obtained as follows: The reaction of phenacyl bromide (X) with sodium azide in hot DMF gives the azide (XI), which is condensed with 3-cyclopentylpropionyl chloride (XII) by means of LDA yielding the enol ester (XIII). The cyclization of (XIII) by means of triethyl phosphite in refluxing hexane affords 2-(2-cyclopentylethyl)-5-phenyloxazole (XIV), which is finally sulfonated with chlorosulfonic acid to afford the target sulfonyl chloride (VIII).

参考文献 中间体
合成目标
【1】 Ok, H.O.; Candelore, M.R.; Reigle, L.B.; et al.; Substituted oxazole benzenesulfonamides as potent human beta3 adrenergic receptor agonists. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 114.
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) 26718 4-[2-(2-cyclopentylethyl)-1,3-oxazol-5-yl]benzenesulfonyl chloride C16H18ClNO3S 详情 详情
(X) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(XI) 26720 2-azido-1-phenyl-1-ethanone C8H7N3O 详情 详情
(XII) 26721 3-cyclopentylpropanoyl chloride 104-97-2 C8H13ClO 详情 详情
(XIII) 26722 (Z)-2-azido-1-phenylethenyl 3-cyclopentylpropanoate C16H19N3O2 详情 详情
(XIV) 26723 2-(2-cyclopentylethyl)-5-phenyl-1,3-oxazole C16H19NO 详情 详情

合成路线13

该中间体在本合成路线中的序号：(I)

The cyclization of phenacyl bromide (I) with acetamide (II) by heating at 130 C gives 2-methyl-5-phenyloxazole (III), which is brominated with NBS in CCl4 to yield the dibromo derivative (IV). The condensation of (IV) with cyclopentylmethylmagnesium bromide (V) by means of Li2CuCl4 affords 4-bromo-2-(2-cyclopentylethyl)-5-phenyloxazole (VI), which is debrominated by hydrogenation with H2 over Pd(OH)2 in methanol, providing 2-(2-cyclopentylethyl)-5-phenyloxazole (VII). The sulfonation of the phenyl ring of (VII) with chlorosulfonic acid gives the sulfonyl chloride (VIII), which is condensed with the aniline derivative (IX) by means of pyridine in dichloromethane to yield the sulfonamide (X). Finally, elimination of the Boc protecting group of (X) by means of HCl in methanol affords the target compound.

参考文献 中间体
合成目标
【1】 Candelore, M.R.; Ok, H.O.; Reigle, L.B.; et al.; Substituted oxazole benzenesulfonamides as potent human beta3-adrenergic receptor agonist. Bioorg Med Chem Lett 2000, 10, 14, 1531.
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) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(II) 50352 Acetamide; Acetic acid amide; Ethanamide 60-35-5 C2H5NO 详情 详情
(III) 50348 2-methyl-5-phenyl-1,3-oxazole C10H9NO 详情 详情
(IV) 50349 4-bromo-2-(bromomethyl)-5-phenyl-1,3-oxazole C10H7Br2NO 详情 详情
(V) 50350 bromo(cyclopentylmethyl)magnesium C6H11BrMg 详情 详情
(VI) 50351 4-bromo-2-(2-cyclopentylethyl)-5-phenyl-1,3-oxazole C16H18BrNO 详情 详情
(VII) 26723 2-(2-cyclopentylethyl)-5-phenyl-1,3-oxazole C16H19NO 详情 详情
(VIII) 26718 4-[2-(2-cyclopentylethyl)-1,3-oxazol-5-yl]benzenesulfonyl chloride C16H18ClNO3S 详情 详情
(IX) 26553 tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate C20H27N3O3 详情 详情
(X) 26718 4-[2-(2-cyclopentylethyl)-1,3-oxazol-5-yl]benzenesulfonyl chloride C16H18ClNO3S 详情 详情

合成路线14

该中间体在本合成路线中的序号：(II)

Condensation of salicylaldehyde (I) with 2-bromoacetophenone (II) produced benzofuranyl phenyl ketone (III), which was reduced to 2-benzyl benzofuran (IV) under Wolff-Kishner conditions. Subsequent Friedel-Crafts acylation of (IV) with anisoyl chloride (V) employing SnCl4 afforded ketone (VI). Methyl ether cleavage in (VI) with concomitant intramolecular cyclization, followed by dehydration by means of BBr3 gave rise to benzo naphthofuran (VII). This was brominated in AcOH to yield tribromo derivative (VIII). Mitsunobu coupling of (VIII) with (S)-methyl-2-hydroxy-3-phenylpropionate (IX) furnished ether (X). Finally, the methyl ester group of (X) was hydrolyzed with KOH.

参考文献 中间体
合成目标
【1】 Dietrich, A.; Katz, A.; Sullivan, D.; Wrobel, J.; Sawicki, D.R.; Tio, C.; Li, Z.; Seestaller, L.; Wu, L.; Zhang, Z.-Y.; Sredy, J.; Moxham, C.; PTP1B inhibition and antihyperglycemic activity in the ob/ob mouse model of novel 11-arylbenzo[b]naphto[2,3-d]furans and 11-arylbenzo[b]naphtho[2,3-d]thiophenes. J Med Chem 1999, 42, 17, 3199-3202.
【2】 Dietrich, A.J.; Wrobel, J.E.; Li, Z. (American Home Products Corp.); 11-Aryl-benzo[b]naphtho[2,3-d]furans and 11-aryl-benzo[b]naphtho[2,3-d]thiophenes useful in the treatment of insulin resistance and hyperglycemia. WO 9958521 .
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) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(III) 33663 1-benzofuran-2-yl(phenyl)methanone C15H10O2 详情 详情
(IV) 33664 2-benzyl-1-benzofuran C15H12O 详情 详情
(V) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(VI) 33665 (2-benzyl-1-benzofuran-3-yl)(4-methoxyphenyl)methanone C23H18O3 详情 详情
(VII) 33666 4-naphtho[2,3-b][1]benzofuran-11-ylphenol C22H14O2 详情 详情
(VIII) 33667 2,6-dibromo-4-(6-bromonaphtho[2,3-b][1]benzofuran-11-yl)phenol C22H11Br3O2 详情 详情
(IX) 13878 methyl (2R)-2-hydroxy-3-phenylpropanoate C10H12O3 详情 详情
(X) 33668 methyl (2R)-2-[2,6-dibromo-4-(6-bromonaphtho[2,3-b][1]benzofuran-11-yl)phenoxy]-3-phenylpropanoate C32H21Br3O4 详情 详情

合成路线15

该中间体在本合成路线中的序号：(A)

By condensation of 2-nitrobenzylmethylamine (I) with alpha-bromoacetophenone (A) in ethanol to give omega-[N-(2-nitrobenzyl)methylamino]acetophenone (II) (HCl salt, m.p. 165-7 C), which is then reduced first with H2 over Pd/C, or Ni-diatomaceous earth and afterwards with NaBH4 in CH2Cl2 to give N-(2-aminobenzyl)-1-phenyl-2-methylaminoethanol (III), m.p. 67-9 C. This product is finally cyclized with sulfuric acid.

参考文献 中间体
合成目标
【1】 Chatterjee, S.S.; Castañer, J.; Nomifensin. Drugs Fut 1976, 1, 2, 72.
【2】 Hoffmann, I.; Gustav, E.; Schmitt, K.; 8-Amino-4-phenyl-1,2,3,4-tetrahydroisoquinolines, a new group of anti-depressive psycholeptic drugs. Arzneim-Forsch Drug Res 1971, 21, 7, 1045.
【3】 Hoffmann, I.; Gustav, E.; Heinrich, O.; Schmitt, K. (Aventis Pharma AG); 4-Phenyl-8-amino tetrahydroisoquinolines. DE 1670694; DE 1670848; FR 1524487; FR 6496M; FR 6646M; GB 1164192; US 3577424 .
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) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(I) 15242 N-methyl(2-nitrophenyl)methanamine; N-methyl-N-(2-nitrobenzyl)amine C8H10N2O2 详情 详情
(II) 40345 2-[methyl(2-nitrobenzyl)amino]-1-phenyl-1-ethanone C16H16N2O3 详情 详情
(III) 40346 2-[(2-aminobenzyl)(methyl)amino]-1-phenyl-1-ethanol C16H20N2O 详情 详情

合成路线16

该中间体在本合成路线中的序号：(III)

The alkaline hydrolysis of 5-methoxyisatin (I) provides the ortho-(aminophenyl)glyoxylic acid salt (II), which is then alkylated by 2-bromoacetophenone (III) to furnish the N-phenacylisatin (IV). Rearrangement of (IV) in the presence of NaOH gives rise to a 40:60 mixture of the indolecarboxylic acid (V) and the target decarboxylated compound.

参考文献 中间体
合成目标
【1】 Black, D.S.C.; Wong, L.C.H.; A simple synthesis of 2-acyl indoles from isatins. J Chem Soc Chem Commun 1980, 4, 200.
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) 11892 5-Methoxy-1H-indole-2,3-dione 39755-95-8 C9H7NO3 详情 详情
(II) 57931 sodium 2-(2-amino-5-methoxyphenyl)-2-oxoacetate C9H8NNaO4 详情 详情
(III) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(IV) 57932 5-methoxy-1-(2-oxo-2-phenylethyl)-1H-indole-2,3-dione C17H13NO4 详情 详情
(V) 57933 2-benzoyl-5-methoxy-1H-indole-3-carboxylic acid C17H13NO4 详情 详情

合成路线17

该中间体在本合成路线中的序号：(II)

Phenacyl ester (III) was prepared by treatment of the cesium salt of N-Boc-tryptophan (I) with 2-bromoacetophenone (II) in DMF. Cyclization of keto ester (III) with ammonium acetate in refluxing xylene yielded the target imidazole (IV). Acidic Boc group deprotection of (IV) then gave amine (V). Finally, Pictet-Spengler cyclization of (V) with 6-undecanone (VI) provided the desired tetrahydrocarboline.

参考文献 中间体
合成目标
【1】 Poitout, L.; et al.; Identification of potent non-peptide somatostatin antagonists with sst3 selectivity. J Med Chem 2001, 44, 18, 2990.
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) 16114 N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid 13139-14-5 C16H20N2O4 详情 详情
(II) 10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(III) 50501 2-oxo-2-phenylethyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoate C24H26N2O5 详情 详情
(IV) 50502 tert-butyl (1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethylcarbamate C24H26N4O2 详情 详情
(V) 50503 (1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)-1-ethanamine; (1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)ethylamine C19H18N4 详情 详情
(VI) 50504 6-Hendecanone; 6-Undecanone; Di-n-amyl ketone; Diamyl ketone 927-49-1 C11H22O 详情 详情
Extended Information