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【结 构 式】

【分子编号】10146

【品名】Epichlorohydrin; 2-(Chloromethyl)oxirane

【CA登记号】106-89-8

【 分 子 式 】C3H5ClO

【 分 子 量 】92.5248

【元素组成】C 38.94% H 5.45% Cl 38.32% O 17.29%
与该中间体有关的原料药合成路线共 79 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)

By condensation of 4-hydroxycarbazole (I) with epichlorohydrin (II) by means of NaOH in aqueous dioxane at 40 C to yield 4-(2,3-epoxypropoxy)carbazole (III), followed by treatment with isopropylamine (IV) in refluxing ethanol

参考文献 中间体
合成目标
【1】 Weetman, D.F.; Castaner, J.; Carazolol. Drugs Fut 1977, 2, 11, 715.
【2】 Leinert, H.; et al. (Boehringer Ingelheim GmbH); Triyclic diphenylamines derivatives. CH 598216; DE 2240599; FR 2196165; GB 1369580; JP 49056973 .
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) 29480 4-Hydroxycarbazole; 9H-carbazol-4-ol 52602-39-8 C12H9NO 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 40171 9H-carbazol-4-yl 2-oxiranylmethyl ether; 4-(2-oxiranylmethoxy)-9H-carbazole 51997-51-4 C15H13NO2 详情 详情
(IV) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情

合成路线2

该中间体在本合成路线中的序号：(III)

The esterification of 3-(4-hydroxyphenyl)propionic acid (I) with methanol and H2SO4 gives the corresponding methyl ester (II), which by condensation with epichlorohydrin (III) by means of K2CO3 in refluxing acetone affords methyl 3-[4-(2,3-epoxypropoxy)phenyl]propionate (IV). Finally, the epoxide ring is opened by reaction with isopropylamine (V) in refluxing methanol, and a final treatment with ethereal HCl is performed.

参考文献 中间体
合成目标
【1】 Erhardt, P.W.; Woo, C.M.; Anderson, W.G.; Gorczynski, R.J.; Ultra-short-acting beta-adrenergic receptor blocking agents. 2. (Aryloxy)propanolamines containing esters on the aryl function. J Med Chem 1982, 25, 12, 1408.
【2】 Erhardt, P.W.; Bogman, R.J.; O'Donnell, J.P. (Baxter International Inc.); Method for treatment or prophylaxis of cardiac disorders. EP 0053435; EP 0065542; US 4387103; WO 8201869 .
【3】 Serradell, M.N.; Castaner, J.; Badia, A.; Esmolol Hydrochloride. Drugs Fut 1984, 9, 3, 183.
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) 25691 3-(4-hydroxyphenyl)propionic acid 501-97-3 C9H10O3 详情 详情
(II) 30341 methyl 3-(4-hydroxyphenyl)propanoate; 4-Hydroxyphenylpropionic acid methyl ester; 3-(4-Hydroxyphenyl)propionic acid methyl ester 5597-50-2 C10H12O3 详情 详情
(III) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(IV) 30342 methyl 3-[4-(2-oxiranylmethoxy)phenyl]propanoate 81147-94-6 C13H16O4 详情 详情
(V) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

For synthesizing alpha/beta-TGU a mixture of urazole (I), epichlorohydrin (II) and tetramethylammonium bromide or benzalcon A was heated to yield the corresponding chlorohydrin intermediate (III), which was converted to alpha/beta-TGU by addition of sodium hydroxide and purified by column chromatography or recrystallization.

参考文献 中间体
合成目标
【1】 Fischer, H.; et al. (Henkel KgA); N-Substituted polyglycidyl urazole compounds, processes for their production and pharmaceutical preparations. EP 0056962; JP 57142982; US 4801601 .
【2】 Castaner, J.; Serradell, M.N.; Triglycidylurazol. Drugs Fut 1984, 9, 3, 209.
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) 30371 1,2,4-triazolidine-3,5-dione 3232-84-6 C2H3N3O2 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 30372 1,2,4-tris(2-oxiranylmethyl)-1,2,4-triazolidine-3,5-dione C11H15N3O5 详情 详情

合成路线4

该中间体在本合成路线中的序号：(B)

The condensation of ethyl p-hydroxyphenylacetate (I) with benzyl chloride (II) by means of sodium ethoxide in refluxing ethanol gives ethyl p-(benzyloxy)phenylacetate (III), which is reduced with LiAlH4 in THF to 2-(p-benzyloxyphenyl)ethanol (IV). The etherification of (IV) with cyclopropyl bromide (A) by means of NaH in hot DMF affords 4-(cyclopropylmethoxyethyl)-1-benzyloxybenzene (V), which is debenzylated by hydrogenation with H2 and Pd/C in methanol giving rise to p-(cyclopropylmethoxyethyl)phenol (VI). The condensation of (VI) with epichlorohydrin (B) by means of NaOH in water yields 1-[p-(cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane (VII), which is treated with isopropylamine (C) and finally with HCl in ether.

参考文献 中间体
合成目标
【1】 Manoury, P.M.J.; et al. (Sanofi-Synthelabo ); Phenol ethers. DE 2649605; FR 2330383; GB 1515978; JP 52085146; US 4252984 .
【2】 Hillier, K.; Castaner, J.; Serradell, M.N.; Blancafort, P.; Betaxolol hydrochloride. Drugs Fut 1979, 4, 12, 867.
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(A) 22277 Cyclopropyl bromide; 1-(Bromomethyl)cyclopropane 7051-34-5 C4H7Br 详情 详情
(I) 24994 Ethyl 2-(4-hydroxyphenyl)acetate 17138-28-2 C10H12O3 详情 详情
(II) 19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(III) 28637 Ethyl 2-[4-(benzyloxy)phenyl]acetate; p-(Benzyloxy)phenylacetate C17H18O3 详情 详情
(IV) 33328 2-(p-Benzyloxyphenyl)ethanol; 2-[4-(Benzyloxy)phenyl]-1-ethanol C15H16O2 详情 详情
(V) 33329 4-(Cyclopropylmethoxyethyl)-1-benzyloxybenzene; 1-(Benzyloxy)-4-[2-(cyclopropylmethoxy)ethyl]benzene; Benzyl 4-[2-(cyclopropylmethoxy)ethyl]phenyl ether C19H22O2 详情 详情
(VI) 33330 4-[2-(Cyclopropylmethoxy)ethyl]phenol; p-(Cyclopropylmethoxyethyl)phenol C12H16O2 详情 详情
(VII) 33331 2-([4-[2-(Cyclopropylmethoxy)ethyl]phenoxy]methyl)oxirane; 1-[p-(Cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane; 4-[2-(Cyclopropylmethoxy)ethyl]phenyl 2-oxiranylmethyl ether C15H20O3 详情 详情
(C) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情

合成路线5

该中间体在本合成路线中的序号：(V)

The reaction of 3,4-dihydro-2H-1-benzopyran-3,8-diol (I) with ethyl chloroformate by means of triethylamine in THF gives 3,4-dihydro-8-lethoxy carbonyloxyl-2H-1-benzopyran-3-ol (II), which is treated with nitric acid and acetic anhydride in acetonitrile to yield 3,4-dihydro-8-(ethoxycarbonyloxy)-2H-1-benzopyran-3-ol-3-nitrate (III). The hydrolysis of (III) with NaOH in methanol affords 3,4-dihydro-8-hydroxy-2H-1-benzopyran-3-ol 3-nitrate (IV), which is condensed with epichlorohydrin (V) by means of NaOH in water giving 3,4-dihydro-8-(2,3-epoxypropoxy)-2H-1-benzopyran-3-ol 3-nitrate (VI). Finally, this compound is treated with isopropylamine in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Shiratsuohi, M.; Shimizu, N.; Shigyo, H.; Kyotani, Y.; Kunieda, H.; Kawamura, K.; Sato, S.; Akashi, T.; Nagakura, M. (Kowa Co., Ltd.); Dihydrobenzopyran compounds and pharmaceutical composition comprising said compounds. EP 0042299; JP 57007481; JP 82106619 .
【2】 Blancafort, P.; Thorpe, P.J.; Serradell, M.N.; Castaner, J.; K-351. Drugs Fut 1983, 8, 6, 497.
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) 30654 3,8-chromanediol C9H10O3 详情 详情
(II) 30655 ethyl 3-hydroxy-3,4-dihydro-2H-chromen-8-yl carbonate C12H14O5 详情 详情
(III) 30656 ethyl 3-(nitrooxy)-3,4-dihydro-2H-chromen-8-yl carbonate C12H13NO7 详情 详情
(IV) 30657 3-(nitrooxy)-8-chromanol C9H9NO5 详情 详情
(V) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(VI) 30658 3-(nitrooxy)-3,4-dihydro-2H-chromen-8-yl 2-oxiranylmethyl ether; 3-(nitrooxy)-8-(2-oxiranylmethoxy)chromane C12H13NO6 详情 详情
(VII) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情

合成路线6

该中间体在本合成路线中的序号：(VII)

By reaction of 3-(2-methyl-2-aminopropyl)indole (I) and 2-(2,3-epoxypropoxy)benzonitrile (II) by heating at 120-40 C followed by a treatment with HCl in ethanol. The starting products are obtained as follows: 1) The reaction of 3-(dimethylaminomethyl)indole (III) with 2-nitropropane (IV) by means of KOH gives 3-(2-methyl-2-nitropropyl)indole (V), which is then reduced with hydrazine and Raney-Ni in ethanol to yield (I). 2) The reaction of 2-hydroxybenzonitrile (VI) with epichlorohydrin (VII) by means of piperidine affords 2-(3-chloro-2-hydroxypropoxy)benzonitrile (VIII), which is epoxidized again to (II) by treatment with NaOH in hot THF-water.

参考文献 中间体
合成目标
【1】 Kreighbaum, W.E.; et al.; Antihypertensive indole derivatives of phenoxypropanolamines with beta-adrenergic receptor antagonist and vasodilating activity. J Med Chem 1980, 23, 3, 285-289.
【2】 Weetman, D.F.; Castaner, J.; Bucindolol Hydrochloride. Drugs Fut 1981, 6, 7, 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
10158 Piperidine 110-89-4 C5H11N 详情 详情
(I) 37566 2-(1H-indol-3-yl)-1,1-dimethylethylamine; 1-(1H-indol-3-yl)-2-methyl-2-propanamine C12H16N2 详情 详情
(II) 37567 2-(2-oxiranylmethoxy)benzonitrile C10H9NO2 详情 详情
(III) 37568 N,N-Dimethyl-1H-indole-3-methanamine;Gramine;N-(1H-indol-3-ylmethyl)-N,N-dimethylamine; 3-(dimethylaminomethyl)-indole[;]1H-indol-3-yl-N,N-dimethylmethanamine 87-52-5 C11H14N2 详情 详情
(IV) 21819 2-nitropropane 79-46-9 C3H7NO2 详情 详情
(V) 37569 3-(2-methyl-2-nitropropyl)-1H-indole C12H14N2O2 详情 详情
(VI) 21990 2-hydroxybenzonitrile 611-20-1 C7H5NO 详情 详情
(VII) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(VIII) 37570 2-(3-chloro-2-hydroxypropoxy)benzonitrile C10H10ClNO2 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

The condensation of 3-methylphenol (I) and epichlorohydrin (II) by means of NaOH gives 1,2-epoxy-3-(3-methylphenoxy)propane (III), which is then condensed with 3,4-dimethoxyphenylethylamine (V) by heating their mixture at 95-100 C.

参考文献 中间体
合成目标
【1】 Holmes, A.; Meyer, R.F.; New aminoalkanol compounds and methods for their production. FR 2163486; GB 1344976; JP 48067232 .
【2】 Milton, L.H.; et al.; Cardioselective beta-adrenergic blocking agents. 1. 1-[3,4-(dimethoxyphenethyl)amino]-3-aryloxy-2-propanols. J Med Chem 1975, 18, 2, 148-152.
【3】 Castaner, J.; Weetman, D.F.; Bevantol. Drugs Fut 1977, 2, 8, 500.
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) 17793 m-cresol; m-Methylphenol 108-39-4 C7H8O 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 33968 2-[(3-methylphenoxy)methyl]oxirane; 3-methylphenyl 2-oxiranylmethyl ether C10H12O2 详情 详情
(V) 10098 2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine 120-20-7 C10H15NO2 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 condensation of 3-methylphenol (I) with epichlorohydrin (II) by means of a catalytic amount of piperidine gives 1-(3-methylphenoxy)-3-chloro-2-propanol (IV), which is then condensed with 3,4-dimethoxyphenylethylamine (V) by heating their mixture at 95-100 C.

参考文献 中间体
合成目标
【1】 Holmes, A.; Meyer, R.F.; New aminoalkanol compounds and methods for their production. FR 2163486; GB 1344976; JP 48067232 .
【2】 Milton, L.H.; et al.; Cardioselective beta-adrenergic blocking agents. 1. 1-[3,4-(dimethoxyphenethyl)amino]-3-aryloxy-2-propanols. J Med Chem 1975, 18, 2, 148-152.
【3】 Castaner, J.; Weetman, D.F.; Bevantol. Drugs Fut 1977, 2, 8, 500.
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) 17793 m-cresol; m-Methylphenol 108-39-4 C7H8O 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(IV) 33967 1-chloro-3-(3-methylphenoxy)-2-propanol C10H13ClO2 详情 详情
(V) 10098 2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine 120-20-7 C10H15NO2 详情 详情

合成路线9

该中间体在本合成路线中的序号：(II)

[2H]-Labeled RSU-1069 is synthesized as follows: The condensation of 2-nitroimidazole (I) with 3-chloro-1,2-epoxypropane (II) gives 1-(3-chloro-2-hydroxypropyl)-2-nitroimidazole (III), which is oxidized with CrO3 - H2SO4 in acetone yielding 1-(3-chloro-2-oxopropyl)-2-nitroimidazole (IV). The reduction of (IV) with NaB[2H]4 in ethanol affords 1-(3-chloro-2-hydroxy-2(2H)-propyl)-2-nitroimidazole (V), which is cyclized with NaOH to the corresponding labeled epoxide (VI). Finally, this compound is condensed with aziridine (VII) by means of triethylamine in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Webb, P.; Threadgill, M.D.; Labelled compounds of interest as antitumour agents. Part II (1). Synthesis of 2H and 3H isotopomers of RSU 1069 and Ro 03-8799 (pimonidazole). J Label Compd Radiopharm 1990, 28, 3, 257.
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),(V) 10147 1-Chloro-3-(2-nitro-1H-imidazol-1-yl)-2-propanol C6H8ClN3O3 详情 详情
(I) 10145 2-Nitro-1H-imidazole; 2-Nitroimidazole 527-73-1 C3H3N3O2 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(IV) 10148 1-Chloro-3-(2-nitro-1H-imidazol-1-yl)acetone C6H6ClN3O3 详情 详情
(V) 44588 1-chloro-3-(2-nitro-1H-imidazol-1-yl)-2-propanol C6H8ClN3O3 详情 详情
(VI) 10150 2-Nitro-1-(2-oxiranylmethyl)-1H-imidazole C6H7N3O3 详情 详情
(VI) 44589 2-nitro-1-(2-oxiranylmethyl)-1H-imidazole C6H7N3O3 详情 详情
(VII) 10151 Ethyleneimine; Aziridine; Azirane 151-56-4 C2H5N 详情 详情

合成路线10

该中间体在本合成路线中的序号：(II)

[2H]-Labeled pimonidazole is synthesized as follows: The condensation of 2-nitroimidazole (I) with 3-chloro-1,2-epoxypropane (II) gives 1-(3-chloro-2-hydroxypropyl)-2-nitroimidazole (III), which is oxidized with CrO3 - H2SO4 in acetone yielding 1-(3-chloro-2-oxopropyl)-2-nitroimidazole (IV). The reduction of (IV) with NaB[2H]4 in ethanol affords 1-(3-chloro-2-hydroxy-2(2H)-propyl)-2-nitroimidazole (V), which is cyclized with NaOH to the corresponding labeled epoxide (VI). Finally, this compound is condensed with piperidine (VII) in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Webb, P.; Threadgill, M.D.; Labelled compounds of interest as antitumour agents. Part II (1). Synthesis of 2H and 3H isotopomers of RSU 1069 and Ro 03-8799 (pimonidazole). J Label Compd Radiopharm 1990, 28, 3, 257.
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),(V) 10147 1-Chloro-3-(2-nitro-1H-imidazol-1-yl)-2-propanol C6H8ClN3O3 详情 详情
(I) 10145 2-Nitro-1H-imidazole; 2-Nitroimidazole 527-73-1 C3H3N3O2 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(IV) 10148 1-Chloro-3-(2-nitro-1H-imidazol-1-yl)acetone C6H6ClN3O3 详情 详情
(V) 44588 1-chloro-3-(2-nitro-1H-imidazol-1-yl)-2-propanol C6H8ClN3O3 详情 详情
(VI) 10150 2-Nitro-1-(2-oxiranylmethyl)-1H-imidazole C6H7N3O3 详情 详情
(VI) 44589 2-nitro-1-(2-oxiranylmethyl)-1H-imidazole C6H7N3O3 详情 详情
(VII) 10158 Piperidine 110-89-4 C5H11N 详情 详情

合成路线11

该中间体在本合成路线中的序号：(I)

The condensation of epichlorohydrin (I) with 7-hydroxyflavone (II) by means of NaOH in ethanol - water gives 7-(2,3-epoxypropoxy)fIavone (III), which is then treated with propylamine (IV) in methanol, and neutralized with maleic acid.

参考文献 中间体
合成目标
【1】 Wu, E.S.-C. (Pennwalt Corp.); Antihypertensive agents. EP 0064165; US 4501755 .
【2】 Castaner, J.; Prous, J.; Flavodilol maleate. Drugs Fut 1986, 11, 10, 837.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
37495 Maleic acid; (Z)-2-Butenedioic acid 110-16-7 C4H4O4 详情 详情
(I) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(II) 23921 7-hydroxy-2-phenyl-4H-chromen-4-one 6665-86-7 C15H10O3 详情 详情
(III) 23922 7-(2-oxiranylmethoxy)-2-phenyl-4H-chromen-4-one C18H14O4 详情 详情
(IV) 23923 1-propanamine 107-10-8 C3H9N 详情 详情

合成路线12

该中间体在本合成路线中的序号：(II)

1) The reaction of phenol (I) with epichlorohydrin (II) gives 1,2-epoxy-3-phenoxypropane (III), which is treated with isopropylamine (IV) to afford 3-(isopropylamino)-1-phenoxy-2-propanol (V). Cyclization of (V) with diethyl carbonate (VI) yields 3-isopropyl-5-(phenoxymethyloxazolidin-2-one) (VII), which is chloromethylated with formaldehyde - HCl giving 3-isopropyl-5-(4-chloromethylphenoxymethyl)oxazolidin-2-one (VIII). Etherification of (VIII) with ethylene glycol monoisopropyl ether (IX) yields the corresponding ether (XI), which is finally deprotected by alkaline hydrolysis.

参考文献 中间体
合成目标
【1】 Harting, J.; et al.; Pharmacodynamic profile of the selective beta1-adrenoceptor antagonist bisoprolol. Arzneim-Forsch Drug Res 1986, 36, 2, 200.
【2】 Castaner, J.; Prous, J.; Bisoprolol fumarate. Drugs Fut 1986, 11, 10, 829.
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 23932 2-(phenoxymethyl)oxirane; oxiranylmethyl phenyl ether 122-60-1 C9H10O2 详情 详情
(IV) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情
(V) 23934 1-(isopropylamino)-3-phenoxy-2-propanol C12H19NO2 详情 详情
(VI) 17470 diethyl carbonate; diethylcarbonate 105-58-8 C5H10O3 详情 详情
(VII) 23936 3-isopropyl-5-(phenoxymethyl)-1,3-oxazolidin-2-one C13H17NO3 详情 详情
(VIII) 23937 5-[[4-(chloromethyl)phenoxy]methyl]-3-isopropyl-1,3-oxazolidin-2-one C14H18ClNO3 详情 详情
(IX) 23938 2-isopropoxy-1-ethanol 109-59-1 C5H12O2 详情 详情
(X) 23939 5-([4-[(2-isopropoxyethoxy)methyl]phenoxy]methyl)-3-isopropyl-1,3-oxazolidin-2-one C19H29NO5 详情 详情

合成路线13

该中间体在本合成路线中的序号：(IV)

The condensation of 4-hydroxybenzyl alcohol (I) with 2-isopropoxyethanol (II) by heating at 150 C gives the corresponding benzyl ether (III), which is condensed with epichlorohydrin (IV) to yield the adduct (V). Finally, this compound is treated with isopropylamine in ethanol.

参考文献 中间体
合成目标
【1】 Schliep, H.-J.; Enenkel, H.-J.; Minck, K.; Becker, K.-H.; Jonas, R. (Merck Patent GmbH); Phenoxy-amino-propanols. US 4258062 .
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) 23938 2-isopropoxy-1-ethanol 109-59-1 C5H12O2 详情 详情
(III) 40522 4-[(2-isopropoxyethoxy)methyl]phenol C12H18O3 详情 详情
(IV) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(V) 40523 4-[(2-isopropoxyethoxy)methyl]phenyl 2-oxiranylmethyl ether; 2-([4-[(2-isopropoxyethoxy)methyl]phenoxy]methyl)oxirane C15H22O4 详情 详情
(VI) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情

合成路线14

该中间体在本合成路线中的序号：(II)

The condensation of sodium 2-(2-exo-norbornyl)phenoxide [from 2-bicyclo[2.2.1]hept-2-ylphenol (I) and sodium] with epichlorohydrin (II) gives (III), which is then treated with isopropylamine (IV) and finally with isopropanolic HCl.

参考文献 中间体
合成目标
【1】 FR 75/09997; FR 76/24360 .
【2】 Michaud, R.; Bornaprolol hydrochloride. Drugs Fut 1982, 7, 2, 91.
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) 37059 2-bicyclo[2.2.1]hept-2-ylphenol C13H16O 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 37060 2-[(2-bicyclo[2.2.1]hept-2-ylphenoxy)methyl]oxirane; 2-bicyclo[2.2.1]hept-2-ylphenyl 2-oxiranylmethyl ether C16H20O2 详情 详情
(IV) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情

合成路线15

该中间体在本合成路线中的序号：(A)

The chlorohydrin (II) is obtained by the reaction of p-chlorobenzylmagnesium chloride (I) with epichlorohydrin (A) in ether. This is then converted to the crystalline alcohol (III) by reaction with sodium imidazole (B) in DMF. On treatment with thionyl chloride is converted to the corresponding chloro compound (IV). When (IV) is reacted with 2,6-dichloro thiophenol (C) in the presence of anhydrous potassium carbonate in acetone, the free base of butoconazole is formed. Neutralization of the free base (V) with nitric acid gives butoconazole.

参考文献 中间体
合成目标
【1】 Walker, K.A.M.; et al.; 1-[4-(4-chlorophenyl)-2-(2,6-dichlorophenylthio)n-butil]-1H-imidazole nitrate, a new patent antifungal agent. J Med Chem 1978, 21, 8, 840.
【2】 Arya, V.P.; Butoconazole nitrate. Drugs Fut 1979, 4, 2, 89.
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(B) 10255 Imidazole; 1H-Imidazole 288-32-4 C3H4N2 详情 详情
(I) 33290 Bromo(4-chlorobenzyl)magnesium; p-Chlorobenzylmagnesium chloride C7H6BrClMg 详情 详情
(II) 33291 1-chloro-4-(4-chlorophenyl)-2-butanol C10H12Cl2O 详情 详情
(III) 16486 4-(4-chlorophenyl)-1-(1H-imidazol-1-yl)-2-butanol C13H15ClN2O 详情 详情
(IV) 33292 1-[2-chloro-4-(4-chlorophenyl)butyl]-1H-imidazole C13H14Cl2N2 详情 详情
(V) 33294 1-[4-(4-chlorophenyl)-2-[(2,6-dichlorophenyl)sulfanyl]butyl]-1H-imidazole; 3-(4-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)propyl 2,6-dichlorophenyl sulfide C19H17Cl3N2S 详情 详情
(C) 33293 2,6-Dichloro thiophenol; 2,6-Dichlorobenzenethiol; 2,6-Dichlorophenylhydrosulfide 24966-39-0 C6H4Cl2S 详情 详情

合成路线16

该中间体在本合成路线中的序号：(I)

It can be prepared in two different ways: 1) The reaction of 1-chloro-2,3-propylene oxide (I) with tert-butylamine (II) in ether yields 1-chloro-3-tert-butylamino-2-propanol (III), which is condensed with 2,3-xylenol (IV) by means of KOH in ether-water. 2) By heating a mixture of 1-tert-butyl-3-azetidinol (V) and 2,3-xylenol (IV) at 155 C with KOH.

参考文献 中间体
合成目标
【1】 Suzuki, Y.; et al.; JP 45029294 .
【2】 Tsukamoto, K.; et al.; JP 46028534 .
【3】 Castaner, J.; Weetman, D.F.; D-32. Drugs Fut 1977, 2, 2, 91.
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(II) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
(III) 31720 1-(tert-butylamino)-3-chloro-2-propanol C7H16ClNO 详情 详情
(IV) 40074 2,3-dimethylphenol 526-75-0 C8H10O 详情 详情
(V) 40075 1-(tert-butyl)-3-azetidinol 13156-04-2 C7H15NO 详情 详情

合成路线17

该中间体在本合成路线中的序号：(IV)

This compound has been obtained in two related ways: 1. The reaction of 2-(2-bromoethoxy)anisole (I) with benzylamine (II) by heating at 80 C gives the secondary amine (III), which is condensed with epichlorohydrin (IV) by heating at 60 C to yield the isopropanol derivative (V). The condensation of (V) with 4-hydroxycarbazole (VI) by means of K2CO3 in refluxing dioxane affords the adduct (VII), which is finally debenzylated by hydrogenolysis with H2 over Pd/C in ethanol/water. 2. The condensation of the secondary amine (III) with 4-(2,3-epoxypropoxy)carbazole (VIII) in refluxing ethanol gives the already reported adduct (VII), which is debenzylated as indicated.

参考文献 中间体
合成目标
【1】 Seres, P.; Cselenyak, J.; Nagy, K.; Simig, G.; Gregor, T.; Nagy, P.K.; Greff, Z.; Balazs, L.; Barkoczy, J.; Vereczkey, G.D.; Nemeth, N.; Szabo, T.; Ratkai, Z.; Doman, I. (Egis Pharmaceuticals Ltd.); Process and intermediates for preparing 1-[9'H-carbazol-4'-yloxy]-3-[2''-(2'''-methoxy-phenoxy)ethyl]amino]-propan-2-ol (carvedilol). EP 0918055 .
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) 51402 2-(2-Bromoethoxy)methoxybenzene; 1-Bromo-2-(2-methoxyphenoxy)ethane 4463-59-6 C9H11BrO2 详情 详情
(II) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(III) 30528 N-benzyl-2-(2-methoxyphenoxy)-1-ethanamine; N-benzyl-N-[2-(2-methoxyphenoxy)ethyl]amine C16H19NO2 详情 详情
(IV) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(V) 51403 1-[benzyl[2-(2-methoxyphenoxy)ethyl]amino]-3-chloro-2-propanol C19H24ClNO3 详情 详情
(VI) 29480 4-Hydroxycarbazole; 9H-carbazol-4-ol 52602-39-8 C12H9NO 详情 详情
(VII) 51404 1-[benzyl[2-(2-methoxyphenoxy)ethyl]amino]-3-(9H-carbazol-4-yloxy)-2-propanol C31H32N2O4 详情 详情
(VIII) 40171 9H-carbazol-4-yl 2-oxiranylmethyl ether; 4-(2-oxiranylmethoxy)-9H-carbazole 51997-51-4 C15H13NO2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(IV)

The acylation of 8-hydroxy-1,2,3,4-tetrahydroquinoline (I) with nicotinoyl chloride (II) by means of triethylamine in benzene gives 8-hydroxy-1-nicotinoyl-1,2,3,4-tetrahydroquinoline (III), which is condensed with epichlorohydrin (IV) by means of potassium tert-butoxide in DMF to yield 1-nicotinoyl-8-(2,3-epoxy-1-propoxy)-1,2,3,4-tetrahydroquinoline (V). Finally, this compound is condensed with isopropylamine (VI) in ethanol.

参考文献 中间体
合成目标
【1】 Graewinger, O.; Raabe, T.; Beyerle, R.; Scholtholt, J.; Nitz, R.E.; 1-Acyl-8-(3-amino-2-hydroxypropoxy)-1,2,3,4-tetrahydroquinolines, compositions and use. DD 153368; DE 2934609; EP 0025864; JP 56034668; US 4335123 .
【2】 Castaner, J.; Serradell, M.N.; Hillier, K.; Nicainoprol. Drugs Fut 1984, 9, 10, 749.
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) 16022 1,2,3,4-tetrahydro-8-quinolinol C9H11NO 详情 详情
(II) 10753 Nicotinoyl chloride C6H4ClNO 详情 详情
(III) 34334 [8-hydroxy-3,4-dihydro-1(2H)-quinolinyl](3-pyridinyl)methanone C15H14N2O2 详情 详情
(IV) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(V) 34335 [8-(2-oxiranylmethoxy)-3,4-dihydro-1(2H)-quinolinyl](3-pyridinyl)methanone C18H18N2O3 详情 详情
(VI) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情

合成路线19

该中间体在本合成路线中的序号：(B)

This compound can be prepared in several ways from the lactone (I), which is obtained by treatment of benzyl cyanide (A) and epichlorhydrin (B) with sodium amide: 1) The opening of lactone (I) with SOBr2-ethanol gives a bromo ester, which is treated successively by ammonia and sodium hydroxide to yield the amino acid (II). The reaction of (II) with SOCl2 and diethylamine in ethanol gives the final product, which is converted to the hydrochloric salt by treatment with HCl ethanol. 2) Lactone (I), opened with 33% HBr-AcOH, gives the bromo acid (III), which is treated by SOCl2 and then diethylamine in ethanol. The bromoamide (IV) reacts with potassium phthalimide and is deprotected by hydrazine or methylamine to yield, after salification, title compound. 3) Lactone (I) is treated by potassium phthalimide and then SOCl2 and diethylamine in EtOH to give compound (V), treated as above. 4) Bromoamide (IV) can be treated by hexamethylenetetramine in butanol and hydrolyzed by refluxing with 15% HCl in ethanol.

参考文献 中间体
合成目标
【1】 Kasama, S.; et al.; Synthesis 1978, 4, 10, 304.
【2】 Patoiseau, J.-F.; Mouzin, G.; Bonnaud, B.; Cousse, H. (Pierre Fabre Medicament); Process for the preparation of (Z)-1-phenyl-1-diethylaminocarbonyl-2-aminomethyl-cyclopropane. EP 0200638; FR 2581059 .
【3】 Cousse, H.; Hascoet, P. (Pierre Fabre Medicament); Industrial process for the production of midalcipran. FR 2581060 .
【4】 Mouzin, G.; Cousse, H.; Bonnaud, B.; Morre, M.; Stenger, A. (Pierre Fabre Médicament); 1-Aryl-2-aminomethyl cyclopropane carboxyamide (Z) deivatives and their use as useful drugs in the treatment of disturbances of the central nervous system. EP 0068999; FR 2508035; JP 58004752; US 4478836 .
【5】 Briley, M.; Midalcipran Hydrochloride. Drugs Fut 1986, 11, 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
(B) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(A) 17046 Phenylacetonitrile; 2-phenylacetonitrile; Benzyl cyanide 140-29-4 C8H7N 详情 详情
(F) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(G) 28148 1-([2-[(diethylamino)carbonyl]-2-phenylcyclopropyl]methyl)-3,5,7-triaza-1-azoniatricyclo[3.3.1.1(3,7)]decane C21H32N5O 详情 详情
(E) 28150 2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-phenylcyclopropanecarboxylic acid C19H15NO4 详情 详情
(D) 28151 2-(hydroxymethyl)-1-phenylcyclopropanecarboxylic acid C11H12O3 详情 详情
(I) 28144 1-phenyl-3-oxabicyclo[3.1.0]hexan-2-one C11H10O2 详情 详情
(II) 28145 2-(aminomethyl)-1-phenylcyclopropanecarboxylic acid C11H13NO2 详情 详情
(III) 28146 2-(bromomethyl)-1-phenylcyclopropanecarboxylic acid C11H11BrO2 详情 详情
(IV) 28147 2-(bromomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide C15H20BrNO 详情 详情
(V) 28149 2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-N,N-diethyl-1-phenylcyclopropanecarboxamide C23H24N2O3 详情 详情
(C) 28143 2-(hydroxymethyl)-1-phenylcyclopropanecarboxylic acid C11H12O3 详情 详情

合成路线20

该中间体在本合成路线中的序号：(II)

The condensation of N-methyl-4-hydroxyisocarbostyril (I) with epichlorohydrin (II) by means of sodium methoxide in hot methanol gives 4-(2,3-epoxypropoxy)-N-methylisocarbostyril (III), which is then treated with tert-butylamine (IV) in methanol, and with HCl.

参考文献 中间体
合成目标
【1】 Fukushima, H.; Suzuki, Y. (Nisshin Flour Milling Co., Ltd.); Isocarbostyril derivatives. DE 2631080; GB 1501149; JP 52012178 .
【2】 Serradell, M.N.; Blancafort, P.; Thorpe, P.J.; Castaner, J.; N-696. Drugs Fut 1982, 7, 12, 889.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
(I) 32094 4-hydroxy-2-methyl-1(2H)-isoquinolinone C10H9NO2 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 32095 2-methyl-4-(2-oxiranylmethoxy)-1(2H)-isoquinolinone C13H13NO3 详情 详情

合成路线21

该中间体在本合成路线中的序号：(II)

By reaction of 1-(3-chloro-2-hydroxypropyl)-4-(2-methoxyphenyl)piperazine (III), obtained from 2-methoxyphenylpiperazine (I) and epichlorohydrine (II), with the sodium salt of 3,4,5-trimethoxyphenol (IV) in refluxing dioxane.

参考文献 中间体
合成目标
【1】 Kleemann, A.; DE 2814168 .
【2】 Engel, J.; Jakovlev, V.; Kleemann, A.; Enciprazine. Drugs Fut 1981, 6, 5, 278.
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) 11882 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine 35386-24-4 C11H16N2O 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 37161 1-chloro-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-propanol C14H21ClN2O2 详情 详情
(IV) 37162 sodium 3,4,5-trimethoxybenzenolate C9H11NaO4 详情 详情

合成路线22

该中间体在本合成路线中的序号：(II)

By reaction of 3,4,5-trimethoxyphenoxyglycidylether (VI) [obtained by reaction of 3,4,5-trimethoxyphenol (V) with epichlorohydrine (II)] with 1-(2-methoxyphenyl)piperazine (I) in refluxing isopropanol.

参考文献 中间体
合成目标
【1】 Kleemann, A.; DE 2814168 .
【2】 Engel, J.; Jakovlev, V.; Kleemann, A.; Enciprazine. Drugs Fut 1981, 6, 5, 278.
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) 11882 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine 35386-24-4 C11H16N2O 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(V) 37163 3,4,5-trimethoxyphenol C9H12O4 详情 详情
(VI) 37164 2,3-dimethoxy-5-(2-oxiranylmethoxy)phenyl methyl ether; 2-[(3,4,5-trimethoxyphenoxy)methyl]oxirane C12H16O5 详情 详情

合成路线23

该中间体在本合成路线中的序号：(A)

Compound can be prepared in several different ways: 1) The reaction of 2-acetyl-7-hydroxybenzofuran (I) with epichlorohydrin by means of piperidine hydrochloride (A) at 105 C gives 2-acetyl-7-(2,3-epoxypropoxy)benzofuran (II), which is then condensed with isopropylamine (B) in refluxing ethanol. 2) By reaction of (I) with 1-chloro-3-isopropylamino-2-propanol (C) by means of NaOH at 80 C in a sealed tube. 3) By reductocondensation of 2-[1,1-(ethylenedioxy)ethyl]-7-[2-oxo-3-(hydroxyimino)propoxy]benzofuran (III) with acetone by means of H2 and PtO2 in ethanol, followed by hydrolysis of the reduced product with HCl in ethanol. 4) The reaction of 2-[1,1-(ethylenedioxy)ethyl]-7-glyoxylmethoxybenz-furan (IV) with isopropylamine (B) in ethanol gives the corresponding Schiff base (V), which is then reduced with NaBH4 and hydrolyzed with HCl in ethanol. 5) By hydrolysis of 3-isopropyl-5-(2-acetyl-7-benzofuryloxymethyl)oxazolidinone (VI) with aqueous refluxing NaOH. 6) By reaction of 2-acetyl-7-(2-hydroxy-3-aminopropoxy)benzofuran (VII) with isopropyl bromide (D) in ethanol at 100 C.

参考文献 中间体
合成目标
【1】 Ito, K.; Ikemoto, M.; Kimura, K.; Uchida, K.; Nakanishi, T.; JP 7436664 .
【2】 Ito, K.; Ikemoto, M.; Kimura, K.; Uchida, K.; Nakanishi, T.; JP 7442664 .
【3】 Ito, K.; Ikemoto, M.; Kimura, K.; Uchida, K.; Nakanishi, T.; JP 7441358 .
【4】 Ito, K.; Ikemoto, M.; Kimura, K.; Nakanishi, T.; JP 7443960 .
【5】 Ito, K.; Ikemoto, M.; Kimura, K.; Uchida, K.; Nakanishi, T.; JP 7443961 .
【6】 Ito, K.; Ikemoto, M.; Kimura, K.; Nakanishi, T. (Kaken Pharmaceutical Co., Ltd.); 2-Substittuted-(2-hydroxy-3-lower alkalinopropoxy)benzofurans. DE 2223184; FR 2137901; JP 7242747; US 3853923 .
【7】 Castaner, J.; Blancafort, P.; Weetman, D.F.; Serradell, M.N.; Befunolol. Drugs Fut 1981, 6, 10, 601.
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(B) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情
(D) 32658 2-bromopropane 75-26-3 C3H7Br 详情 详情
(I) 32291 1-(7-hydroxy-1-benzofuran-2-yl)-1-ethanone 40020-87-9 C10H8O3 详情 详情
(II) 32292 1-[7-(2-oxiranylmethoxy)-1-benzofuran-2-yl]-1-ethanone C13H12O4 详情 详情
(III) 32293 3-[[2-(2-methyl-1,3-dioxolan-2-yl)-1-benzofuran-7-yl]oxy]-2-oxopropanal oxime C15H15NO6 详情 详情
(IV) 32294 3-[[2-(2-methyl-1,3-dioxolan-2-yl)-1-benzofuran-7-yl]oxy]-2-oxopropanal C15H14O6 详情 详情
(V) 32295 1-(isopropylimino)-3-[[2-(2-methyl-1,3-dioxolan-2-yl)-1-benzofuran-7-yl]oxy]acetone C18H21NO5 详情 详情
(VI) 32296 5-[[(2-acetyl-1-benzofuran-7-yl)oxy]methyl]-3-isopropyl-1,3-oxazolidin-2-one C17H19NO5 详情 详情
(VII) 32297 1-[7-(3-amino-2-hydroxypropoxy)-1-benzofuran-2-yl]-1-ethanone C13H15NO4 详情 详情
(C) 32298 1-chloro-3-(isopropylamino)-2-propanol C6H14ClNO 详情 详情

合成路线24

该中间体在本合成路线中的序号：(II)

1) By condensation of phenol (I) with 1-n-butoxy-2,3-epoxypropane (VII) in presence of potassium hydroxide. 2) By condensation of phenol (I) with 1-chloro-2,3-epoxypropane (II) followed either by addition of n-butanol (VI) in presence of a Lewis acid or in presence of a base (IV).

参考文献 中间体
合成目标
【1】 Hoffmann, H.; et al.; Procedimiento de fabricacion de sustancias medicinalmente activas y metodo de preparacion de medicamentos de accion coleretica. ES 402799; FR 2134389; GB 1393451; US 3839587 .
【2】 Janiak, P. St.; Febuprol. Drugs Fut 1978, 3, 3, 191.
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 33456 1-chloro-3-phenoxy-2-propanol C9H11ClO2 详情 详情
(IV) 33457 sodium 1-butanolate; Sodium butoxide; Sodium n-butoxide 2372-45-4 C4H9NaO 详情 详情
(V) 23932 2-(phenoxymethyl)oxirane; oxiranylmethyl phenyl ether 122-60-1 C9H10O2 详情 详情
(VI) 29766 butanol; n-butanol; 1-butanol 71-36-3 C4H10O 详情 详情
(VII) 33458 2-(butoxymethyl)oxirane; butyl 2-oxiranylmethyl ether 2426-08-6 C7H14O2 详情 详情

合成路线25

该中间体在本合成路线中的序号：(A)

4-Benzyloxy-indole-2-carboxylic acid (I) is converted into the corresponding dimethylamide (III), via the corresponding acid chloride (II); the dimethylamide (III) is reduced with LiAlH4 to give 4-benzyloxy-2-dimethylaminomethyl-indole (IV), which is hydrogenated to 4-hydroxy-2-methyl-indole (V). The reaction of (V) with epichlorohydrin (A) in aqueous NaOH gives the crude epoxide which without isolation is treated with isopropylamine (B) in refluxing dioxane.

参考文献 中间体
合成目标
【1】 Seemann, F.; et al.; Synthetic indoles. 10. Chemistry of 4-hydroxy-indoles. Helv Chim Acta 1971, 54, 8, 2411-19.
【2】 Troxler, F.; Hofmann, A.; Verfahren zur Herstellung neuer Indolderivate. AT 316542B; CH 502337 .
【3】 Troxler, F.; Hofmann, A.; Verfahren zur Herstellung neuer Indolderivate. CH 543505 .
【4】 Weetman, D.F.; Castaner, J.; Mepindolol. Drugs Fut 1978, 3, 5, 381.
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(B) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(I) 33536 4-(benzyloxy)-1H-indole-2-carboxylic acid C16H13NO3 详情 详情
(II) 33537 4-(benzyloxy)-1H-indole-2-carbonyl chloride C16H12ClNO2 详情 详情
(III) 33538 4-(benzyloxy)-N,N-dimethyl-1H-indole-2-carboxamide C18H18N2O2 详情 详情
(IV) 33539 N-[[4-(benzyloxy)-1H-indol-2-yl]methyl]-N,N-dimethylamine; [4-(benzyloxy)-1H-indol-2-yl]-N,N-dimethylmethanamine C18H20N2O 详情 详情
(V) 33540 4-Hydroxy-2-methylindole; 2-Methyl-1H-indol-4-ol 35320-67-3 C9H9NO 详情 详情

合成路线26

该中间体在本合成路线中的序号：(A)

The reaction of 4-hydroxy-2-methyl-indole (V) with 1-(N-benzylisopropylamino)-3-chloro-2-propanol (D) by means of NaOH in refluxing aqueous dioxane yields the corresponding benzylamine (X), which is debenzylated by catalytic hydrogenation. The reaction of 4-hydroxy-2-methyl-indole (V) with epichlorohydrin (A) and benzylamine (B) gives 4-(3-benzylamino-2-hydroxypropoxy)-2-methyl-indole (XI), which is debenzylated by hydrogenolysis to 4-(3-amino-2-hydroxypropoxy)-2-methyl-indole (XII). The condensation of (XII) with refluxing acetone (C) affords the corresponding N-isopropylidene derivative (XIII), which is finally hydrogenated with H2 over Pd/C in methanol.

参考文献 中间体
合成目标
【1】 Seemann, F.; et al.; Synthetic indoles. 10. Chemistry of 4-hydroxy-indoles. Helv Chim Acta 1971, 54, 8, 2411-19.
【2】 Troxler, F.; Verfahren zur Herstellung neuer Indolderivate. CH 472404; ES 337457 .
【3】 Troxler, F.; Verfahren zur Herstellung neuer Indolderivate. CH 469002; ES 337458 .
【4】 Troxler, F.; Verfahren zur Herstellung von neuem 4-(2-Hydroxy-3-isopropylaminopropoxy)-2-methylindol und seiner Saureadditionssalze Indolderivate. AT 317199 .
【5】 Weetman, D.F.; Castaner, J.; Mepindolol. Drugs Fut 1978, 3, 5, 381.
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(B) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(D) 33549 1-[benzyl(isopropyl)amino]-3-chloro-2-propanol C13H20ClNO 详情 详情
(V) 33540 4-Hydroxy-2-methylindole; 2-Methyl-1H-indol-4-ol 35320-67-3 C9H9NO 详情 详情
(X) 33548 1-[benzyl(isopropyl)amino]-3-[(2-methyl-1H-indol-4-yl)oxy]-2-propanol C22H28N2O2 详情 详情
(XI) 33545 1-(benzylamino)-3-[(2-methyl-1H-indol-4-yl)oxy]-2-propanol C19H22N2O2 详情 详情
(XII) 33546 1-amino-3-[(2-methyl-1H-indol-4-yl)oxy]-2-propanol C12H16N2O2 详情 详情
(XIII) 33547 1-[(1-methylethylidene)amino]-3-[(2-methyl-1H-indol-4-yl)oxy]-2-propanol C15H20N2O2 详情 详情
(C) 23199 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether 67-64-1 C3H6O 详情 详情

合成路线27

该中间体在本合成路线中的序号：(A)

The esterification of 5,8-dihydro-1-naphthol (I) with acetic anhydride gives the corresponding acetate (II), which is oxidized with silver acetate and I2 in acetic acid to yield 2,3-cis-1,2,3,4-tetrahydro-2,3,5-naphthalenetriol (III). The treatment of this product with sodium methylate and epichlorhydrin (A) in methanol gives 2,3-cis-1,2,3,4-tetrahydro-5-(2,3-epoxypropoxy)-2,3-naphthalenediol (IV), which is finally treated with tertbutylamine (B) in chloroform-methanol.

参考文献 中间体
合成目标
【1】 Hanck, F.P.; et al.; Tetrahydronaphthyloxyaminopropanols and related compounds. CA 979926; DE 2258995; GB 1358722 .
【2】 Weetman, D.F.; Castaner, J.; Nadolol. Drugs Fut 1976, 1, 9, 434.
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(B) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
(I) 40440 5,8-dihydro-1-naphthalenol 27673-48-9 C10H10O 详情 详情
(II) 40441 1-naphthyl acetate 830-81-9 C12H10O2 详情 详情
(III) 40442 (6R,7S)-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol C10H12O3 详情 详情
(IV) 40443 (2R,3S)-5-(2-oxiranylmethoxy)-1,2,3,4-tetrahydro-2,3-naphthalenediol C13H16O4 详情 详情

合成路线28

该中间体在本合成路线中的序号：(II)

The reaction of 2-cyclopentylphenol (I) with epichlorhydrin (II) in a basic medium yields 1,2-epoxy-3-(2'-cyclopentylphenoxy)propane (III), which is the condensed with tert-butylamine (IV) in hot ethanol.

参考文献 中间体
合成目标
【1】 Ruschig, H.; et al.; ZA 6807915 .
【2】 Castaner, J.; Weetman, D.F.; Penbutolol. Drugs Fut 1976, 1, 10, 494.
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) 40452 2-cyclopentylphenol C11H14O 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 40453 2-cyclopentylphenyl 2-oxiranylmethyl ether; 2-[(2-cyclopentylphenoxy)methyl]oxirane 28163-40-8 C14H18O2 详情 详情
(IV) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情

合成路线29

该中间体在本合成路线中的序号：(IV)

The condensation of 3-acetyl-4-hydroxyaniline (I) with N,N-diethylcarbamoyl chloride (II) in pyridine gives the urea (II), which is treated with epichlorohydrin (IV) and NaOH to yield N-[3-acetyl-4-(2,3-epoxypropoxy)phenyl]-N',N'-diethylurea (V). Finally, the epoxy ring of (V) is opened with tert-butylamine (VI).

参考文献 中间体
合成目标
【1】 Stormann-Menninger-Lerchenthal, H.; Pittner, H.; Zolss, G. (CL Pharma); 4-Ureido-2-acyl phenoxypropanolamine. DE 2458624; US 4034009 .
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) 33815 1-(5-amino-2-hydroxyphenyl)-1-ethanone C8H9NO2 详情 详情
(II) 33816 N,N'-Diethylcarbamoyl chloride; 1-[(chlorocarbonyl)(ethyl)amino]ethane 88-10-8 C5H10ClNO 详情 详情
(III) 33817 N'-(3-acetyl-4-hydroxyphenyl)-N,N-diethylurea C13H18N2O3 详情 详情
(IV) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(V) 33818 N'-[3-acetyl-4-(2-oxiranylmethoxy)phenyl]-N,N-diethylurea C16H22N2O4 详情 详情
(VI) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情

合成路线30

该中间体在本合成路线中的序号：(IV)

The reaction of 4-nitrophenol (I) with acetic anhydride in aqueous NaOH gives the corresponding acetate (II), which is submitted to a Fries migration with AlCl3 in nitrobenzene at 140 C to yield the acetophenone (III). The condensation of (III) with epichlorohydrin (IV) by means of K2CO3 affords the adduct (V), which is treated with tert-butylamine (VI) in water to obtain the aminoisopropanol derivative (VII). The reduction of the nitro group of (VII) with H2 over Pd/C in methanol gives the corresponding amino derivative (VIII), which is finally condensed with N,N-diethylcarbamoyl chloride (IX) by means of TEA in THF to yield the target urea.

参考文献 中间体
合成目标
【1】 Joshi, R.A.; et al.; A new and improved process for celiprolol hydrochloride. Org Process Res Dev 2001, 5, 2, 176.
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) 11236 4-Nitrophenol; p-Nitrophenol 100-02-7 C6H5NO3 详情 详情
(II) 50841 4-Nitrophenyl acetate; Acetic acid 4-nitrophenyl ester; p-Nitrophenyl acetate 830-03-5 C8H7NO4 详情 详情
(III) 50842 1-(2-hydroxy-5-nitrophenyl)-1-ethanone C8H7NO4 详情 详情
(IV) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(V) 50843 1-[5-nitro-2-(2-oxiranylmethoxy)phenyl]-1-ethanone C11H11NO5 详情 详情
(VI) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
(VII) 50844 1-[2-[3-(tert-butylamino)-2-hydroxypropoxy]-5-nitrophenyl]-1-ethanone C15H22N2O5 详情 详情
(VIII) 33819 1-[5-amino-2-[3-(tert-butylamino)-2-hydroxypropoxy]phenyl]-1-ethanone C15H24N2O3 详情 详情
(IX) 33816 N,N'-Diethylcarbamoyl chloride; 1-[(chlorocarbonyl)(ethyl)amino]ethane 88-10-8 C5H10ClNO 详情 详情

合成路线31

该中间体在本合成路线中的序号：(A)

The condensation of beta-phenyl-2-hydroxypropiophenone sodium salt (I) with 1-chloro-2,3-epoxypropane (A) at 100 C yields beta-phenyl-2-(2',3'-epoxypropoxy)propiophenone (II). which is then treated with n-propylamine (B) also at 100 C.

参考文献 中间体
合成目标
【1】 Beck, O.A.; et al.; Einfluß des antiarrhythmikus propafenon auf die intrakardiale erregungsleitung. Z Kardiol 1975, 64, 731-740.
【2】 Sauchse, R.; 2-Hydroxy-3-phenylpropiophenone derivatives. AT 308076B; BE 0785318; DE 2001431; FR 2144601; GB 1307455; NL 7208214 .
【3】 Prigge, E.; Hapke, H.J.; Zur Pharmakologie von 2'-[2-Hydroxy-3-(propylamino).propoxy]-3-phenylpropiophenon (Propafenon, SA79)-hydrochlorid. Arzneim-Forsch Drug Res 1976, 36, 10, 1849-57.
【4】 Castaner, J.; Bahring-Kuhmley, S.R.; Propafenone. Drugs Fut 1977, 2, 5, 325.
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(B) 23923 1-propanamine 107-10-8 C3H9N 详情 详情
(I) 33895 sodium 2-(3-phenylpropanoyl)benzenolate C15H13NaO2 详情 详情
(II) 24438 1-[2-(2-oxiranylmethoxy)phenyl]-3-phenyl-1-propanone C18H18O3 详情 详情

合成路线32

该中间体在本合成路线中的序号：(II)

The reaction of phenylpiperazine (I) with epichlorhydrin (II) leads to 1-chloro-3-(1-phenyl-4-piperazinyl)-2-propanol. This intermediate is dehydrohalogenated to 1-(1-phenyl-4-piperazinyl)-2,3-epoxypropane (III) using sodium hydroxide. The epoxide is converted without further purification into the corresponding 4,5-dihydro-5-[(4-phenyl-1-piperazinyl)methyl]-2-oxazolamine (COR3224) by condensation with monosodium cyanamide salt in methanol, which permits the solubilization of all compounds. The amidine group of the oxazoline ring induces a tautomeric amino-imino equilibrium. For COR3224 it has been shown by X-ray crystallography that the amino form is preponderant in the free base, whereas the imino form predominates in salts.

参考文献 中间体
合成目标
【1】 Creuzet, M.-H.; Feniou, C.; Jarry, C.; Prat, G.; Pontagnier, H. (Societé Cortial SA); Novel 2-amino-5-aminomethyl-2-oxazolines. EP 0106776; FR 2546167 .
【2】 D'Arnoux, C.; Panconi, E.; Descas, P.; Vaugien, B.; Lambrey, B.; Mosser, J.; Jarry, C.; Gomond, P.; Saudubray, F.; Roux, J.; COR3224. Drugs Fut 1991, 16, 10, 893.
【3】 Ouhabi, J.; Jarry, C.; Bosc, J.J.; Carpy, A.; Crystal and molecular structure of 5-(1-aryl-4-piperazino)-methyl-2-amino-2-oxazolines with antidepressant activity. Arch Pharm 1990, 323, 157-61.
【4】 Bosc, J.J.; Descas, P.; Carpy, A.; Panconi, E.; Jarry, C.; Synthesis and antidepressant activity of 5-(1-aryl-4-piperazino)methyl-2-amino-2-oxazolines. Eur J Med Chem 1992, 27, 5, 437.
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) 10756 N-Phenylpiperazine; 1-Phenylpiperazine; Phenyl piperazine 92-54-6 C10H14N2 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 10758 1-Chloro-3-(4-phenylpiperazino)-2-propanol C13H19ClN2O 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 reaction of 1-naphthol (I) with epichlorohydrin (II) in the presence of aqueous sodium hydroxide yields 1-(1-naphthyloxy)-2,3-epoxypropane (III). (III) is then reacted either in alcohol or without any solvent with 1-(2-methoxyphenyl)piperazine (IV).

参考文献 中间体
合成目标
【1】 Thiel, M.; Sponer, G.; Stach, K.; Witte, E.-C.; Roesch, E. (Roche Diagnostics GmbH); 1-[3-(Napht-1-yloxy)-2-hydroxypropyl]-piperazine c. GB 1445548; US 3997666 .
【2】 Prous, J.; Castaner, J.; Naftopidil. Drugs Fut 1987, 12, 1, 31.
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) 22935 alpha-naphthol; 1-naphthol 90-15-3 C10H8O 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 22937 2-[(1-naphthyloxy)methyl]oxirane; 1-naphthyl 2-oxiranylmethyl ether C13H12O2 详情 详情
(IV) 11882 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine 35386-24-4 C11H16N2O 详情 详情

合成路线34

该中间体在本合成路线中的序号：(III)

The reaction of 4-tert-butylbenzyl chloride (I) with Mg in ether gives the corresponding Grignard reagent (II), which is condensed with epichlorohydrin (III) yielding 4-(4-tert-butylphenyl)-1,2-epoxybutane (IV). The condensation of (IV) with methyl 4-hydroxybenzoate (V) by means of KOH in refluxing methanol affords 4-[4-(4-tert-butylphenyl)-2-hydroxybutoxy]benzoic acid methyl ester (VI), which is finally saponified with KOH in refluxing ethanol/water.

参考文献 中间体
合成目标
【1】 Rabasseda, X.; Castaner, J.; Mealy, N.; Lifibrol. Drugs Fut 1995, 20, 4, 325.
【2】 Grill, H.; Reiter, F.; Loser, R.; Schliack, M.; Seibel, K. (Klinge Pharma GmbH); p-Oxybenzoic acid derivs., as well as process for their preparation and their use as medicines. DE 3326164; EP 0133935; US 4582857 .
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) 10885 1-(tert-Butyl)-4-(chloromethyl)benzene; 1-Chloromethyl-4-tert-butyl benzene; 4-tert-Butylbenzyl chloride 19692-45-6 C11H15Cl 详情 详情
(II) 10886 [4-(tert-Butyl)benzyl](chloro)magnesium C11H15ClMg 详情 详情
(III) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(IV) 10888 2-[4-(tert-Butyl)phenethyl]oxirane C14H20O 详情 详情
(V) 10251 methyl 4-hydroxybenzoate; Methyl p-hydroxybenzoate 99-76-3 C8H8O3 详情 详情
(VI) 10890 methyl 4-[4-[4-(tert-butyl)phenyl]-2-hydroxybutoxy]benzoate C22H28O4 详情 详情

合成路线35

该中间体在本合成路线中的序号：(II)

The title compound is prepared by condensation of the acetamido isophthalamide (I) with epichlorohydrin (II) in 2-methoxyethanol.

参考文献 中间体
合成目标
【1】 Wille, K.; Hansen, P.-E.; Holtermann, H. (Amersham plc); X-ray contrast agents. EP 0108638; US 5349085 .
【2】 Cockbain, J.; Malthe-Soerenssen, D.; Schelver Hyni, A.C.; Aabye, A.; Bjoersvik, H.R.; Brekke, G.; Sjoegren, C.E. (Amersham plc); Process for the production of iodinated organic X-ray contrast agents. WO 9823296 .
【3】 Skailes, H.J.; Homestad, O.M. (Amersham plc); Preparation of iodixanol. WO 0047549 .
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) 59311 5-(acetylamino)-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide C16H20I3N3O7 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情

合成路线36

该中间体在本合成路线中的序号：(III)

In a different strategy, the acetamido isophthalamide (I) is treated with boric acid and KOH to form the cyclic diborate tripotassium salt (II). Subsequent condensation of (II) with epichlorohydrin (III) yields the dimeric adduct (IV). The borate groups of (IV) are finally removed upon quenching with diluted HCl.

参考文献 中间体
合成目标
【1】 Bjoersvik, H.-R.; et al.; A selective process for N-alkylation in competition with O-alkylation: Boric acid, borax, and metaborate as a cheap and effective protecting group applicable for industrial-scale synthetic processes. Org Process Res Dev 2001, 5, 5, 472.
【2】 Priebe, H. (Amersham plc); An N-alkylation. GB 2331098 .
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) 59311 5-(acetylamino)-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide C16H20I3N3O7 详情 详情
(II) 59314 　 C16H19B2I3K3N3O11 详情 详情
(III) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(IV) 59315 　 C35H44B4I6K4N6O23 详情 详情

合成路线37

该中间体在本合成路线中的序号：(I)

The reaction of epichlorohydrin (I) with benzyl alcohol (II) by means of NaOH in water gives 1,3-di-O-benzylglycerol (III), which is condensed with paraformaldehyde by means of HCl in methylene chloride to yield 1,3-di-O-benzyl-2-O-(chloromethyl)glycerol (IV). Acetylation of (IV) with potassium acetate in acetone affords 1,3-di-O-benzyl-2-O-(acetoxymethyl)glycerol (V), which is condensed with diacetylguanine (VI) by means of p-toluenesulfonic acid in sulfolane giving N2-acetyl-9-[[1,3-bis(benzyloxy)-2-propoxy]methyl]guanine (VII). Finally, this compound is deprotected by a treatment with palladium hydroxide in refluxing cyclohexane.

参考文献 中间体
合成目标
【1】 Dvorak, C.A.; Matthews, T.R.; Martin, J.C.; Verheyden, P.H.; Smee, D.F.; 9-[(1,3-Dihydroxy-2-propoxy)methyl]guanine: A new potent and selective antiherpes agent. J Med Chem 1983, 26, 5, 759-761.
【2】 Galloway, K.S.; Radatus, B.K.; Kennell, W.L.; Smith, K.O.; Ogilvie, K.K.; A new nucleoside analog, 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine, highly active in vitro aganist herpes simplex virus types 1 and 2. Antimicrob Agents Chemother 1982, 22, 1, 55-61.
【3】 Verheyden, J.P.; Martin, J.C. (Roche Bioscience); 9-(1,3-Dihydroxy-2-propoxymethyl)guanine as antiviral agent. EP 0066208; JP 4217983; JP 57203086; US 4355032 .
【4】 Pento, J.T.; Serradell, M.N.; Castaner, J.; BIOLF-62. Drugs Fut 1985, 10, 5, 365.
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(II) 18710 Benzyl alcohol; Phenylmethanol 100-51-6 C7H8O 详情 详情
(III) 29159 1,3-bis(benzyloxy)-2-propanol 6972-79-8 C17H20O3 详情 详情
(IV) 24432 1-[[3-(benzyloxy)-2-(chloromethoxy)propoxy]methyl]benzene C18H21ClO3 详情 详情
(V) 29160 [2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl acetate C20H24O5 详情 详情
(VI) 29161 N-(9-acetyl-6-oxo-6,9-dihydro-1H-purin-2-yl)acetamide; N2,9-Diacetylguanine 3056-33-5 C9H9N5O3 详情 详情
(VII) 29162 N-[9-([2-(benzyloxy)-1-[(benzyloxy)methyl]ethoxy]methyl)-6-oxo-6,9-dihydro-1H-purin-2-yl]acetamide C25H27N5O5 详情 详情

合成路线38

该中间体在本合成路线中的序号：(II)

The reaction of 5-hydroxy-7-tetralone (I) with epichlorohydrin (I) at reflux temperature gives 5-(3-chloro-2-hydroxypropoxy)-7-tetralone (III), which is then condensed with butylamine (IV) in refluxlng alcohol.

参考文献 中间体
合成目标
【1】 Shavel, J.Jr.; Farber, S. (Pfizer Inc.); 3,4-Dihydroxynaphtalenoneoxy-2-hydroxypropylamines. BE 0739195; DE 1948144; DE 1967162; FR 2018626; GB 1223527; JP 48043734B; US 3641152 .
【2】 Castaner, J.; Serradell, M.N.; Weetman, D.F.; Blancafort, P.; Levobunolol Hydrochloride. Drugs Fut 1983, 8, 9, 788.
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) 31099 5-hydroxy-3,4-dihydro-1(2H)-naphthalenone 28315-93-7 C10H10O2 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 31100 5-(3-chloro-2-hydroxypropoxy)-3,4-dihydro-1(2H)-naphthalenone C13H15ClO3 详情 详情
(IV) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情

合成路线39

该中间体在本合成路线中的序号：(A)

It can be obtained in two different ways both starting from the sodium salt of 5-hydroxy-3,4-dihydro-1(2H)-naphthalenone (I): 1) Its condensation with epichlorhydrine (A) in ethanol gives 5-(2,3-epoxypropoxy)-3,4-dihydro-1(2H)-naphthalenone (II), which is then condensed with tert-butylamine (B) in refluxing ethanol. 2) Its condensation with 3-chloro-1,2-propanediol (C) gives 5-(2,3-dihydroxy-propoxy)-3,4-dihydro-1(2H)-naphthalenone (III), which is esterified with tosyl chloride to the sulfonic ester (IV), and finally condensed with tert-butylamine.

参考文献 中间体
合成目标
【1】 Merrill, E.J.; Synthesis of 14C-labeled Bunolol. J Pharm Sci 1971, 60, 10, 1589-91.
【2】 Castaner, J.; Arrigoni-Martelli, E.; Bunolol. Drugs Fut 1976, 1, 9, 403.
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(B) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
(I) 40456 sodium 5-oxo-5,6,7,8-tetrahydro-1-naphthalenolate C10H9NaO2 详情 详情
(II) 40457 5-(2-oxiranylmethoxy)-3,4-dihydro-1(2H)-naphthalenone C13H14O3 详情 详情
(III) 40458 5-(2,3-dihydroxypropoxy)-3,4-dihydro-1(2H)-naphthalenone C13H16O4 详情 详情
(IV) 40459 2-hydroxy-3-[(5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)oxy]propyl 4-methylbenzenesulfonate C20H22O6S 详情 详情
(C) 12975 3-Chloro-1,2-propanediol; Glycerol alpha-monochlorohydrin 96-24-2 C3H7ClO2 详情 详情

合成路线40

该中间体在本合成路线中的序号：(A)

Compound can be prepared in three different ways: 1) Condensation of 2,5-dichlorophenol (I) with epichlorohydrin (A) by means of NaOH in water to give 1-(2,5-dichlorophenoxy)-2,3-epoxypropane (II), which is then condensed again with tert-butylamine in refluxing ethanol. Finally, HCl in ethanol is added. 2) Condensation of (I) with epichlorohydrin (A) by means of pyridine gives 1-(2,5-dichlorophenoxy)-3-chloro-2-propanol (III), which is then condensed with tert-butylamine as before. 3) Condensation of (I) with 1-(tertbutylamino)-2,3-epoxypropane (B) or with 1-(tertbutylamino)-3-chloro-2-propanol (C) by means of NaOH in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Hajos, A.; et al.; Aminopropanol derivative. DE 2213044; FR 2130284; GB 1337921; NL 7203323 .
【2】 Castaner, J.; Sumgurbey, K.; GYKI-41099. Drugs Fut 1978, 3, 4, 295.
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(B) 33503 N-(tert-butyl)-N-(2-oxiranylmethyl)amine; 2-methyl-N-(2-oxiranylmethyl)-2-propanamine C7H15NO 详情 详情
(I) 11953 2,5-Dichlorophenol 583-78-8 C6H4Cl2O 详情 详情
(II) 33501 2,5-dichlorophenyl 2-oxiranylmethyl ether; 2-[(2,5-dichlorophenoxy)methyl]oxirane C9H8Cl2O2 详情 详情
(III) 33502 1-chloro-3-(2,5-dichlorophenoxy)-2-propanol C9H9Cl3O2 详情 详情
(C) 31720 1-(tert-butylamino)-3-chloro-2-propanol C7H16ClNO 详情 详情

合成路线41

该中间体在本合成路线中的序号：(V)

By condensation of ethyl 8-propyl-7-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate (I) with 4-(2,3-epoxypropoxy)-3-propyl-2-hydroxyacetophenone (II) by means of benzyltrimethylammonium hydroxide in refluxing DMF, followed by hydrolysis with NaHCO3 in refluxing ethanol - water. The starting compounds (I) and (II) are prepared as follows: 1) The condensation of 3-propyl-2,4-dihydroxyacetophenone (III) with diethyl oxalate (IV) by means of sodium ethoxide in refluxing ethanol gives (I). 2) The condensation of acetophenone (III) with 1-chloro-2,3-epoxypropane (V) by means of KOH in refluxing ethanol - water gives (II).

参考文献 中间体
合成目标
【1】 Pratt, A.D.; Bantick, J..; Lee, T.B.; Chamberlain, T.R.; Hardern, D.N.; Appleton, R.A.; Antagonits of slow reacting substance od anaphylaxis. Synthesis of a series of chromone-2-carboxylic acids. J Med Chem 1979, 20, 3, 371.
【2】 Augstein, J.; Lee, T.B.; Carter, D. (AstraZeneca plc); Chromone derivs.. FR 2147287 .
【3】 Augstein, J.; Carter, D.; Lee, T.B. (AstraZeneca plc); Chrome cpds. having SRS-A properties. US 3882148 .
【4】 Blancafort, P.; Castaner, J.; Sneddon, J.M.; Serradell, M.N.; FPL-55,712. Drugs Fut 1982, 7, 7, 472.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
37126 　 C10H18NO 详情 详情
(I) 37124 ethyl 7-hydroxy-4-oxo-8-propyl-4H-chromene-2-carboxylate C15H16O5 详情 详情
(II) 37125 1-[2-hydroxy-4-(2-oxiranylmethoxy)-3-propylphenyl]-1-ethanone C14H18O4 详情 详情
(III) 13137 2',4'-Dihydroxy-3'-propylacetophenone; 1-(2,4-Dihydroxy-3-propylphenyl)-1-ethanone 40786-69-4 C11H14O3 详情 详情
(IV) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(V) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情

合成路线42

该中间体在本合成路线中的序号：(III)

The demethylation of 1-(4-methoxyphenyl)acetone (I) by means of AlCl3 gives the corresponding 4-hydroxy compound (III), which is condensed with epichlorohydrin (III), yielding the expected oxiranylmethyl ether (IV). The addition of 1-(2-methoxyphenyl)piperazine (V) to the epoxide ring of (IV) affords the isopropyl alcohol derivative (VI), which is condensed with dimethylformamide dimethylacetal (VII) to afford the dimethylaminobutenone (VIII). Finally, this compound is cyclized with 2-cyanoacetamide (IX) by means of sodium ethoxide, providing the target pyridone.

参考文献 中间体
合成目标
【1】 (Beiersdorf-Lilly GmbH); Phenylpiperazinylpropanol derivs.. DE 3424685; EP 0167121; ES 8608511; JP 1986030573; US 4631279; US 4631281 .
【2】 Armah, B.I.; Stenzel, W.; SATERINONE (BDF 8634): A DIFFERENT CONCEPT FOR PHARMACOTHERAPY OF CONGESTIVE HEART FAILURE. Drugs Fut 1989, 14, 5, 445.
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) 10038 4-Methoxyphenylacetone; 1-(4-Methoxyphenyl)acetone 122-84-9 C10H12O2 详情 详情
(II) 43654 1-(4-hydroxyphenyl)acetone C9H10O2 详情 详情
(III) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(IV) 43655 1-[4-(2-oxiranylmethoxy)phenyl]acetone C12H14O3 详情 详情
(V) 11882 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine 35386-24-4 C11H16N2O 详情 详情
(VI) 43656 1-(4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]propoxy]phenyl)acetone C23H30N2O4 详情 详情
(VII) 11984 N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal 4637-24-5 C5H13NO2 详情 详情
(VIII) 43657 (Z)-4-(dimethylamino)-3-(4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl]propoxy]phenyl)-3-buten-2-one C26H35N3O4 详情 详情
(IX) 12122 Cyanoacetamide; 2-Cyanoacetamide 107-91-5 C3H4N2O 详情 详情

合成路线43

该中间体在本合成路线中的序号：(II)

The condensation of 2'-hydroxy-3-phenylpropiophenone (I) with 1 chloro-2,3-epoxypropane (II) by means of K2CO3 gives 2'-(2,3-epoxypropoxy)-3-phenylpropiophenone (III), which is then treated with 2-methyl-2-aminobutane (IV) in refluxing methanol.

参考文献 中间体
合成目标
【1】 Petrik, G.; Sachse, R. (Helopharm KG); 2-[2'-Hydroxy-3'-(1,1-dimethylpropylamino)-propoxy]-beta-phenylpropiophenone, its physiologically acceptable acid addition salts, and pharmaceutical compsns.. DE 3133814; US 4460605 .
【2】 Prous, J.; Castaner, J.; Difrafenone. Drugs Fut 1986, 11, 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) 24436 1-(2-hydroxyphenyl)-3-phenyl-1-propanone 42772-82-7 C15H14O2 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 24438 1-[2-(2-oxiranylmethoxy)phenyl]-3-phenyl-1-propanone C18H18O3 详情 详情
(IV) 24439 2-methyl-2-butanamine 594-39-8 C5H13N 详情 详情

合成路线44

该中间体在本合成路线中的序号：(B)

The nitration of 8-hydroxy-3,4-dihydrocarbostyril (I) with HNO3 in acetic acid-acetic anhydride gives 5-nitro-8-hydroxy-3,4-dihydrocarbostyril (II), which is reduced with SnCl2 in concentrated HCl yielding 5-amino-8-hydroxy-3,4-dihydrocarbostyril (III). The oxidation of (III) with FeCl3 in aqueous HCl affords 5,8-dioxo-3,4,5,8-tetrahydrocarbostyril (IV), which by treatment with SO2 in water is converted into 5,8-dihydroxy-3,4-dihydrocarbostyril (V). The treatment of (V) with benzyl chloride (A) and potassium carbonate in acetone gives 5-hydroxy-8-benzyloxy-3,4-dihydrocarbostyril (VII), which by reaction with epichlorohydrin (B) by means of piperidine affords 8-benzyloxy-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril (VII). The opening of the epoxide ring of (VII) with tert-butylamine (C) in methanol yields 8-benzyloxy-5-(3-tert-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril (VIII) (1,2), which is finally hydrogenated with H2 over Pd/C.

参考文献 中间体
合成目标
【1】 Castaner, J.; Blancafort, P.; Serradell, M.N.; 8-Hydroxycarteolol. Drugs Fut 1980, 5, 2, 78.
【2】 Uchida, M.; et al.; Synthesis of 5-(3-tert-butylamino-2-hydroxypropxy)-8-3,4-dihydrocarbostyril hydochloride and its beta-adrenergic blocking agent. Yakugaku Zasshi 1976, 96, 5, 571-577.
【3】 Nakagawa, K.; et al.; US 4072683 .
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(A) 19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(I) 39062 8-hydroxy-3,4-dihydro-2(1H)-quinolinone 22246-18-0 C9H9NO2 详情 详情
(II) 39063 8-hydroxy-5-nitro-3,4-dihydro-2(1H)-quinolinone C9H8N2O4 详情 详情
(III) 39064 5-amino-8-hydroxy-3,4-dihydro-2(1H)-quinolinone C9H10N2O2 详情 详情
(IV) 39065 3,4,4a,8a-tetrahydro-2,5,8(1H)-quinolinetrione C9H9NO3 详情 详情
(V) 39066 5,8-dihydroxy-3,4-dihydro-2(1H)-quinolinone C9H9NO3 详情 详情
(VI) 39067 8-(benzyloxy)-5-hydroxy-3,4-dihydro-2(1H)-quinolinone C16H15NO3 详情 详情
(VII) 39068 8-(benzyloxy)-5-(2-oxiranylmethoxy)-3,4-dihydro-2(1H)-quinolinone C19H19NO4 详情 详情
(VIII) 39069 8-(benzyloxy)-5-[3-(tert-butylamino)-2-hydroxypropoxy]-3,4-dihydro-2(1H)-quinolinone C23H30N2O4 详情 详情
(C) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情

合成路线45

该中间体在本合成路线中的序号：(III)

A synthesis of (+)-(R)-flesinoxan has been described: The nitration of pyrocatechol (I) with nitric acid gives 3-nitrocatechol (II), which is cyclized with epichlorohydrin (III) and acylated with acetic anhydride, yielding 2-(acetoxymethyl)-5-nitro-1,4-benzodioxan (IV). The reduction of (IV) with H2 over Pd/C in ethanol affords the corresponding amine (V), which is cyclized with bis(2-chloroethyl)amine in refluxing chlorobenzene to afford the piperazine (VI). The reaction of (VI) with N-(4-fluorobenzoyl)aziridine (VII) by means of triethylamine in refluxing acetone gives racemic flesinoxan (VIII), which is then submitted to a carefully controlled enzymatic acetylation with Amano P-30 lipase, which acetylates the (R)-isomer selectively. After separation of the nonesterified compound, the acetate is hydrolyzed to give an enriched product, which is submitted to a new enzymatic esterification to improve the optical purity.

参考文献 中间体
合成目标
【1】 Ghazal, N.B.; Ennis, M.D.; The synthesis of (+)- and (-)-flesinoxan: Application of enzymatic resolution methodology. Tetrahedron Lett 1992, 33, 42, 6287.
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) 11599 o-Dihydroxybenzene; Catechol; Pyrocatechol 120-80-9 C6H6O2 详情 详情
(II) 11600 3-Nitro-1,2-benzenediol C6H5NO4 详情 详情
(III) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(IV) 11602 (5-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methyl acetate C11H11NO6 详情 详情
(V) 11603 (5-amino-2,3-dihydro-1,4-benzodioxin-2-yl)methyl acetate C11H13NO4 详情 详情
(VI) 11604 (5-piperazino-2,3-dihydro-1,4-benzodioxin-2-yl)methyl acetate C15H20N2O4 详情 详情
(VII) 11605 1-Aziranyl(4-fluorophenyl)methanone C9H8FNO 详情 详情
(VIII) 11606 4-fluoro-N-(2-[4-[2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperazino]ethyl)benzamide C22H26FN3O4 详情 详情

合成路线46

该中间体在本合成路线中的序号：(IX)

Flesinoxan hydrochloride is obtained in a multiple-step synthesis, including the resolution of one of the racemic intermediates (VIII), starting with the monobenzyl ether of catechol (I). Treatment of (I) with sulfuryl chloride in methylene chloride gives (II). This chloro compound is nitrated with nitric acid resulting in the mononitro derivative (III). In a one-pot procedure compound (III) is converted to the racemic benzodioxan structure (V) by condensation with epichlorohydrin, followed by treatment of the intermediate (IV) with hydrochloric acid and with potassium hydroxide, respectively. After conversion of the hydroxymethyl derivative to the benzoic ester (VI), compound (VII) can be obtained by catalytic hydrogenation of (VI). Treatment of (VII) with bischloroethylamine results in the racemic piperazine analogue (VIII). In this phase the resolution of the piperazine is carried out with (+)-camphorsulfonic acid. After several recrystallizations, the optically pure (+)-enantiomer is obtained. Reaction of this (+)-N-[2-(hydroxymethyl)-1,4-benzodioxan-5-yl]piperazine (VIII) with N-(4-fluorobenzoyl)aziridine, saponification of the benzoate ester and treatment with hydrochloric acid gives flesinoxan monohydrochloride.

参考文献 中间体
合成目标
【1】 Hartog, J.; Wouters, W.; FLESINOXAN HYDROCHLORIDE < Rec INN >. Drugs Fut 1988, 13, 1, 31.
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) 15209 Phenol, 2-(phenylmethoxy)-; 2-(benzyloxy)phenol 6272-38-4 C13H12O2 详情 详情
(II) 21575 2-(benzyloxy)-4-chlorophenol C13H11ClO2 详情 详情
(III) 21576 2-(benzyloxy)-4-chloro-6-nitrophenol C13H10ClNO4 详情 详情
(IV) 21577 2-[[2-(benzyloxy)-4-chloro-6-nitrophenoxy]methyl]oxirane; benzyl 5-chloro-3-nitro-2-(2-oxiranylmethoxy)phenyl ether C16H14ClNO5 详情 详情
(V) 21578 (7-chloro-5-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methanol C9H8ClNO5 详情 详情
(VI) 21579 (7-chloro-5-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methyl benzoate C16H12ClNO6 详情 详情
(VII) 21580 (5-amino-2,3-dihydro-1,4-benzodioxin-2-yl)methyl benzoate C16H15NO4 详情 详情
(VIII) 21581 [5-(1-piperazinyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl benzoate C20H22N2O4 详情 详情
(IX) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(X) 21583 2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine 821-48-7 C4H9Cl2N 详情 详情

合成路线47

该中间体在本合成路线中的序号：(V)

This compound has been obtained by two related ways: 1) The reaction of phenol (I) with formaldehyde gives 4-(hydroxymethyl)phenol (II), which is treated with NaCN in hot DMF to yield 2-(4-hydroxyphenyl)acetonitrile (III). The hydrolysis of (III) in refluxing ethanol/water, catalyzed by a Pt catalyst affords the corresponding acetamide (IV), which is condensed with an excess of hot epichlorohydrin (V) by means of piperidine gives 2-[4-(2-oxiranylmethoxy)phenyl]acetamide (VI). Finally, the oxirane ring of (VI) is opened with isopropylamine in methanol. 2)The condensation of acetonitrile (III) with epichlorohydrin (V) as before gives the 2-[4-(2-oxiranylmethoxy)phenyl]acetonitrile (VIII), which is treated with isopropylamine (VII) in methanol yielding 2-[4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]acetonitrile (IX). Finally, this compound is hydrolyzed with refluxing ethanol/water catalyzed by a Pt catalyst as before to afford the target acetamide.

参考文献 中间体
合成目标
【1】 Akisanya, J.; et al.; A synthesis of atenolol using a nitrile hydration catalyst. Org Process Res Dev 1998, 2, 4, 274.
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) 29474 4-(hydroxymethyl)phenol; 4-hydroxyphenylmethanol 4-hydroxybenzenemethanol; 4-Hydroxybenzyl alcohol 623-05-2 C7H8O2 详情 详情
(III) 32753 2-(4-hydroxyphenyl)acetonitrile; 4-Hydroxybenzyl cyanide 14191-95-8 C8H7NO 详情 详情
(IV) 32754 p-Hydroxyphenylacetamide; 2-(4-hydroxyphenyl)acetamide; 4-Hydroxybenzeneacetamide; 4-Hydroxyphenylacetamide 17194-82-0 C8H9NO2 详情 详情
(V) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(VI) 32755 2-[4-(2-oxiranylmethoxy)phenyl]acetamide C11H13NO3 详情 详情
(VII) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情
(VIII) 32756 2-[4-(2-oxiranylmethoxy)phenyl]acetonitrile C11H11NO2 详情 详情
(IX) 32757 2-[4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]acetonitrile C14H20N2O2 详情 详情

合成路线48

该中间体在本合成路线中的序号：(II)

Prepared in two steps by condensation of p-hydroxyphenylacetamide (I) and epichlorhydrine (II) with piperidine as catalyst, giving 1-(p-carbamoylmethylphenoxy)-2,3-epoxypropane (III), m.p. 158-60 C, followed by reaction of the epoxy ring with isopropylamine (IV).

参考文献 中间体
合成目标
【1】 Barret, A.; et al.; Alkanolaminderivate. CH 547257; CH 553747; DE 2007751; ES 376788; FR 2034561 .
【2】 Castaner, J.; Atenolol. Drugs Fut 1976, 1, 1, 7.
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) 32754 p-Hydroxyphenylacetamide; 2-(4-hydroxyphenyl)acetamide; 4-Hydroxybenzeneacetamide; 4-Hydroxyphenylacetamide 17194-82-0 C8H9NO2 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 32755 2-[4-(2-oxiranylmethoxy)phenyl]acetamide C11H13NO3 详情 详情
(IV) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情

合成路线49

该中间体在本合成路线中的序号：(IV)

The synthesis of the optical enantiomers of mosapride has been described: The reductocondensation of 4-fluorobenzaldehyde (I) with ethanolamine (II) by means of NaBH4 and NaHCO3 in refluxing methanol gives 2-(4-fluorobenzylamino)ethanol (III), which is condensed with epichlorohydrin (IV) to yield the diol (V). Compound (V), without isolation, is cyclized with conc. H2SO4 to afford 2-(chloromethyl)-4-(4-fluorobenzyl)morpholine (VI), which is treated with refluxing water-formamide to afford the corresponding methanol derivative (VII). Tosylation of (VII) with tosyl chloride and triethylamine/4-(dimethylamino)pyridine in dichloromethane gives the tosylate (VIII) as a racemic mixture. The optical resolution of (VIII) with N-(p-toluenesulfonyl)-L-glutamic acid in methanol affords the (S)-tosylate [(S)-IX] and the (R)-tosylate [(R)-IX]. The reaction of both [(S)-IX] and [(R)-IX] with sodium azide followed by reduction with bis(2-methoxyethoxy)aluminum hydride (vitride) gives the chiral amines [(S)-X] and [(R)-X], which are finally condensed with 4-amino-5-chloro-2-ethoxybenzoic acid (XI) by means of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC) in dichloromethane, yielding the (S)- and (R)-enantiomers of mosapride.

参考文献 中间体
合成目标
【1】 Morie, T.; Kato, S.; Harada, H.; Yoshida, N.; Matsumoto, J.; Synthesis and biological activities of the optical isomers of (±)-4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (mosapride). Chem Pharm Bull 1994, 42, 4, 877.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
((S)-IX) 12345 [(2S)-4-(4-fluorobenzyl)-1,4-oxazinan-2-yl]methyl phenylmethanesulfonate C19H22FNO4S 详情 详情
((R)-IX) 12346 [(2R)-4-(4-fluorobenzyl)-1,4-oxazinan-2-yl]methyl phenylmethanesulfonate C19H22FNO4S 详情 详情
((R)-X) 12347 [(2R)-4-(4-Fluorobenzyl)morpholinyl]methanamine; [(2R)-4-(4-Fluorobenzyl)morpholinyl]methylamine C12H17FN2O 详情 详情
((S)-X) 12348 [(2S)-4-(4-Fluorobenzyl)-1,4-oxazinan-2-yl]methylamine; [(2S)-4-(4-Fluorobenzyl)-1,4-oxazinan-2-yl]methanamine C12H17FN2O 详情 详情
(I) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(II) 10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情
(III) 12334 2-[(4-Fluorobenzyl)amino]-1-ethanol C9H12FNO 详情 详情
(IV) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(V) 12341 1-Chloro-3-[(4-fluorobenzyl)(2-hydroxyethyl)amino]-2-propanol C12H17ClFNO2 详情 详情
(VI) 12342 2-(Chloromethyl)-4-(4-fluorobenzyl)morpholine C12H15ClFNO 详情 详情
(VII) 12343 [4-(4-Fluorobenzyl)-2-morpholinyl]methanol C12H16FNO2 详情 详情
(VIII) 12344 [4-(4-fluorobenzyl)-2-morpholinyl]methyl 4-methylbenzenesulfonate C19H22FNO4S 详情 详情
(XI) 12333 4-Amino-5-chloro-2-ethoxybenzoic acid C9H10ClNO3 详情 详情

合成路线50

该中间体在本合成路线中的序号：(I)

This compound can be obtained in a simple way: Under nitrogen, borontrifluoride etherate solution is added to heated 2-methyl-1-propanol (II), and 1-chloro-2,3-epoxypropane (I) is added. When the reaction is completed, pyrrolidine (IV) is added to obtain alpha-[2-methyl-propoxymethyl]-1-pyrrolidine-ethanol (V). 1-[2-Chloro-3-(2-methylpropoxy)propyl]pyrrolidine (VI) is obtained by chlorination with thionyl chloride of the subsequent amino alcohol. The condensation of 1-propynyl-1-cyclohexanol (VII) with 1-[2-chloro-3-(2-methylpropoxy)propyl]pyrrolidine (VI) in toluene and sodium hydroxide in water affords dopropidil. Due to the pyrrolidine shift mechanism, the reaction yields the correct structure, confirmed by 1H and 13C NMR as well as by mass spectra and X-ray analysis. The pyrrolidine shift mechanism is explained by the assumption of an intermediate aziridinium ion (VIII), which is opened regiospecifically at the less hindered C-N bond by the nucleophile ion.

参考文献 中间体
合成目标
【1】 Carlier, P.; Montell, A.J.-C.; Simond, J.A.L. (Riom Laboratoires); Ethers of 1-(2-propynyloxy)-2-amino-3-propanol, their preparation and their application in therapeutic. EP 0031771; US 4430332 .
【2】 Dupont, L.; Dideberg, O.; Simond, J.; X-ray analysis of CERM 4205. Acta Cryst Sect C 1986, 42, 864.
【3】 Massingham, R.; Monteil, A.; DOPROPIDIL HYDROCHLORIDE. Drugs Fut 1990, 15, 5, 453.
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(II) 12982 2-Methyl-1-propanol 78-83-1 C4H10O 详情 详情
(III) 12983 2-(Isobutoxymethyl)oxirane; Isobutyl 2-oxiranylmethyl ether C7H14O2 详情 详情
(IV) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(V) 12985 1-Isobutoxy-3-(1-pyrrolidinyl)-2-propanol C11H23NO2 详情 详情
(VI) 12986 2-Chloro-3-(1-pyrrolidinyl)propyl isobutyl ether; 1-(2-Chloro-3-isobutoxypropyl)pyrrolidine C11H22ClNO 详情 详情
(VII) 12987 1-Propynyl-1-cyclohexanol; 1-(1-Propynyl)cyclohexanol 697-37-0 C9H14O 详情 详情
(VIII) 12988 1-(Isobutoxymethyl)-3-azoniaspiro[2.4]heptane C11H22NO 详情 详情

合成路线51

该中间体在本合成路线中的序号：(XXI)

Compound (XIX) reacts with 4-mercapto-N,N-bis(p-nitrobenzyloxycarbonyl)pyrazolidine (XX) in the presence of diisopropylethylamine to give p-nitrobenzyl (1R,5R,6S)-2-[[N,N-bis(p-nitrobenzyloxycarbonyl)pyrazolidin-4-yl]thio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (XXIII). Compound (XXIII) is reduced with H2 over Pd/C to give (1R,5R,6S)-2-[[N,N-bis(p-nitrobenzyloxycarbonyl)pyrazolidin-4-yl]thio]-6-[1(R)-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (XXIV), which is finally reacted with ethylformimidate hydrochloride (XXV). Compound (XX) is obtained from epichlorohydrin (XXI) by treatment with hydrazine monohydrate followed by reaction with p-nitrobenzyloxycarbonyl chloride to give 4-hydroxy-N,N-bis(p-nitrobenzyloxycarbonyl)pyrazolidine (XXII), which is subsequently treated with methanesulfonyl chloride and triethylamine in dichloromethane, potassium acetate in acetone and sodium methoxide in methanol-THF. Compound (XX) can also be obtained from hydrazine hydrate using a longer alternative procedure.

参考文献 中间体
合成目标
【1】 Kumagai, T.; Matsunaga, H.; Machida, Y.; Nagase, Y.; Hikida, M.; Nagao, Y. (Lederle (Japan), Ltd.); (1R,5S,6S)-2-(Substd. thio)-6-[(R)-1-hydroxy-ethyl]-1-methyl-carbapenem-3-carboxylic-acid derivatives. AU 8814428; EP 0289801; JP 1989025779; US 4925836 .
【2】 Abe, T.; Matsunaga, H.; Kumagai, T.; Nagase, Y. (Lederle (Japan), Ltd.); Method of preparation of carbapenem cpds. JP 1990088578 .
【3】 Hayashi, T.; Shimada, O.; Inoue, Y.; Nagao, Y.; Matsunaga, H.; Nagase, Y.; Kumagai, T.; Abe, T.; beta-Lactams. 3. Asymmetric total synthesis of new non-natural 1beta-methylcarbapenems exhibiting strong antimicrobial activities and stability against human renal dehydropeptidase-. J Org Chem 1992, 57, 15, 4243-9.
【4】 Rabasseda, X.; Prous, J.; Castaner, J.; Biapenem. Drugs Fut 1994, 19, 7, 631.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIX) 13224 4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate 90776-59-3 C29H27N2O10P 详情 详情
(XX) 13208 bis(4-nitrobenzyl) 4-sulfanyl-1,2-pyrazolidinedicarboxylate C19H18N4O8S 详情 详情
(XXI) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(XXII) 13210 bis(4-nitrobenzyl) 4-hydroxy-1,2-pyrazolidinedicarboxylate C19H18N4O9 详情 详情
(XXIII) 13211 bis(4-nitrobenzyl) 4-([(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-[2-(4-nitrophenyl)acetyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]sulfanyl)-1,2-pyrazolidinedicarboxylate C36H34N6O13S 详情 详情
(XXIV) 13212 (4R,5S,6S)-3-[(1,2-bis[[(4-Nitrobenzyl)oxy]carbonyl]-4-pyrazolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid C29H29N5O12S 详情 详情
(XXV) 13213 ethyl iminoformate C3H7NO 详情 详情

合成路线52

该中间体在本合成路线中的序号：(IV)

The formylation of 5-hydroxy-1,2,3,4-tetrahydroisoquinoline (I) with formamide (II) at 140 C gives N-formyl-5-hydroxy-1,2,3,4-tetrahydroisoquinoline (III), which is condensed with epichlorohydrin (IV) by means of NaOH in water yielding N-formyl-5-(2,3-epoxypropoxy)-1,2,3,4-tetrahydroisoquinoline (V). Finally, this compound is condensed with tert-butylamine (VI).

参考文献 中间体
合成目标
【1】 Knoll, A.-G. (Knoll AG); Isoquinoline derivatives. NL 7513301 .
【2】 Westermann, A.; Zimmermann, F.; Wuppermann, D.; Friedrich, L.; Raschack, M. (Knoll AG.); New isoquinoline derivatives. DE 2620179 .
【3】 Prous, J.; Castaner, J.; SOQUINOLOL MUCATE < Rec INNM >. Drugs Fut 1989, 14, 5, 439.
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) 20879 1,2,3,4-tetrahydro-5-isoquinolinol C9H11NO 详情 详情
(III) 20880 5-hydroxy-3,4-dihydro-2(1H)-isoquinolinecarbaldehyde C10H11NO2 详情 详情
(IV) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(V) 20882 5-(2-oxiranylmethoxy)-3,4-dihydro-2(1H)-isoquinolinecarbaldehyde C13H15NO3 详情 详情
(VI) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情

合成路线53

该中间体在本合成路线中的序号：(I)

The reaction of 2-hydroxy-3'-methoxybibenzyl (I) with epichlorohydrin (II) by means of NaH in DMF gives 2-(2,3-epoxypropoxy)-3'-methoxybibenzyl (III), which by reaction with dimethylamine in refluxing THF yields 2-[3-(dimethylamino)-2-hydroxypropoxy]-3'-methoxybibenzyl (IV). Finally, this compound is treated with succinic anhydride (V) in refluxing THF and with HCl in acetone.

参考文献 中间体
合成目标
【1】 Kikumoto, R.; Fukami, H.; Hara, H.; Ninomiya, K.; Sugano, M. (Mitsubishi Chemical Corp.); Pharmaceutically active (3-aminopropoxy)-bibenzyl derivs. EP 0072942 .
【2】 Prous, J.; Castaner, J.; Sarpogrelate Hydrochloride. Drugs Fut 1992, 17, 12, 1093.
【3】 Osakabe, M.; Fukami, H.; Sugano, M.; Kikumoto, R.; Ninomiya, K.; Tamao, Y.; Hara, H.; Syntheses and platelet aggregation inhibitory and antithrombotic properties of [2-[(omega-aminoalkoxy)phenyl]ethyl]benzenes. J Med Chem 1990, 33, 6, 1818.
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(II) 13604 2-(3-Methoxyphenethyl)phenol C15H16O2 详情 详情
(III) 13605 2-(3-Methoxyphenethyl)phenyl 2-oxiranylmethyl ether; 2-[[2-(3-Methoxyphenethyl)phenoxy]methyl]oxirane C18H20O3 详情 详情
(IV) 13606 1-(Dimethylamino)-3-[2-(3-methoxyphenethyl)phenoxy]-2-propanol C20H27NO3 详情 详情
(V) 11291 Dihydro-2,5-furandione; Succinic anhydride 108-30-5 C4H4O3 详情 详情

合成路线54

该中间体在本合成路线中的序号：

6-Hydroxy-2(1H)-quinolinone (I) is alkylated with epichlorohydrin in the presence of K2CO3 in MeOH to afford 6-(2,3-epoxypropoxy)-2(1H)-quinolinone (II). Ring opening of the epoxide (II) with 3,4-dimethoxybenzylamine gives OPC-18790. This compound is also obtained by the reductive alkylation of 6-(3-amino-2-hydroxypropoxy)-2(1H)-quinolinone (III) with 3,4-dimethoxybenzaldehyde.

参考文献 中间体
合成目标
【1】 Sumida, T.; Fujioka, T.; Teramoto, S.; Tominaga, M.; Yabuuchi, Y.; Mori, T.; Hosokawa, T.; Novel positive inotropic agents; synthesis and biological activities of 6-(3-amino-2-hydroxypropoxy)-2(1H)-quinolinone derivatives. J Med Chem 1992, 35, 20, 3607-12.
【2】 Fujioka, T.; OPC-18790. Drugs Fut 1993, 18, 12, 1114.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
13920 (3,4-Dimethoxyphenyl)methanamine; 3,4-Dimethoxybenzylamine; Veratrylamine 5763-61-1 C9H13NO2 详情 详情
18304 3,4-Dimethoxybenzaldehyde; Veratraldehyde 120-14-9 C9H10O3 详情 详情
(I) 13913 6-Hydroxy-2(1H)-quinolinone C9H7NO2 详情 详情
(II) 13914 6-(2-Oxiranylmethoxy)-2(1H)-quinolinone C12H11NO3 详情 详情
(III) 13915 6-(3-Amino-2-hydroxypropoxy)-2(1H)-quinolinone C12H14N2O3 详情 详情

合成路线55

该中间体在本合成路线中的序号：

2,4-Dihydroxyacetophenone (I) is formed by the Friedel-Crafts acetylation of resorcinol. This compound is condensed with diethyl oxalate in sodium ethoxide solution, affording (II). Disodium cromproxate (IV) is conveniently prepared from (II) by treatment with epichlorohydrine in aqueous ethanolic alkaline solution. It is recrystallized from hot water.

参考文献 中间体
合成目标
【1】 Ruyun, J.; Disodium Cromproxate. Drugs Fut 1991, 16, 5, 422.
【2】 Liang, X.; Qi, J.; Lu, Y.; A simplified synthesis of 1,3-bis-(2-carboxychromone-7-oxy)-2-hydroxypropane disodium salt (78012). Acta Pharm Sin 1982, 17, 2, 143-5.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
10361 1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol 108-46-3 C6H6O2 详情 详情
(I) 13961 Resacetophenone; 1-(2,4-Dihydroxyphenyl)-1-ethanone 89-84-9 C8H8O3 详情 详情
(II) 13962 ethyl 7-hydroxy-4-oxo-4H-chromene-2-carboxylate C12H10O5 详情 详情
(III) 13963 ethyl 7-(3-[[2-(ethoxycarbonyl)-4-oxo-4H-chromen-7-yl]oxy]-2-hydroxypropoxy)-4-oxo-4H-chromene-2-carboxylate C27H24O11 详情 详情

合成路线56

该中间体在本合成路线中的序号：(II)

The condensation of 4-[2-(cyclopropylmethoxy)ethyl]phenol (I) with epichlorohydrin (II) in pyridine gives the phenol ether (III), which is treated with HCl to open the epoxide ring and yield the racemic chloropropanol (IV). The optical resolution of (IV) by means of Lipase SP 435-L or AK and vinyl acetate (V) gives a mixture of (S)-acetate (S)-(VI) and unreacted (R)-alcohol (R)-(VI) that is easily separated. Finally, the chiral chloropropanol (R)-(VI) is treated with isopropylamine (VII) to afford the target betaxolol. The optical resolution of racemic betaxolol by means of the previously mentioned lipases has also been tried with poor results.

参考文献 中间体
合成目标
【1】 Di Bono, G.; Scilimati, A.; Synthesis 1995, 6, 688.
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) 33330 4-[2-(Cyclopropylmethoxy)ethyl]phenol; p-(Cyclopropylmethoxyethyl)phenol C12H16O2 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 33331 2-([4-[2-(Cyclopropylmethoxy)ethyl]phenoxy]methyl)oxirane; 1-[p-(Cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane; 4-[2-(Cyclopropylmethoxy)ethyl]phenyl 2-oxiranylmethyl ether C15H20O3 详情 详情
(IV) 55675 1-chloro-3-{4-[2-(cyclopropylmethoxy)ethyl]phenoxy}-2-propanol C15H21ClO3 详情 详情
(V) 24543 vinyl acetate 108-05-4 C4H6O2 详情 详情
(VI) 55676 (2R)-1-chloro-3-{4-[2-(cyclopropylmethoxy)ethyl]phenoxy}-2-propanol C15H21ClO3 详情 详情
(VII) 55676 (2R)-1-chloro-3-{4-[2-(cyclopropylmethoxy)ethyl]phenoxy}-2-propanol C15H21ClO3 详情 详情
(VIII) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情

合成路线57

该中间体在本合成路线中的序号：(II)

MCI-196 is synthesized by condensation of 2-methylimidazole (I) with epichlorohydrin (II) as follows: Equimolecular parts (0.5 M: 0.5 M) of (I) and (II) were allowed to condense in water (100 ml) at 90 C for 14 h; then 0.094 mol of (II) wa added and the reaction continued for 2 h at 45 C. The resulting resin was treated with 0.094 M of a 20% aqueous solution of NaOH and heated at 45 C for 2 h more. Finally, heat curing of the resin at 120 C for 5 h was performed. The resin was isolated by precipitation with water.

参考文献 中间体
合成目标
【1】 Toda, H. (Mitsubishi Chemical Corp.); Process for the preparation of granular basic ion exchange resins. JP 1985245626 .
【2】 Nomura, T.; Hamada, Y.; Kurihara, Y. (Mitsubishi Chemical Corp.); Oral hypocholesterolemic agents. JP 1992013627 .
【3】 Nomura, T.; Hamada, Y.; Kurihara, Y. (Mitsubishi Chemical Corp.); Oral hypocholesterolemic agents. JP 1990124819 .
【4】 Toda, H.; Kihara, K. (Bristol-Myers Squibb Co.); Novel quaternary salt of polymer. BE 0898807; CH 663415; DE 3403125; GB 2134119; NL 8400237 .
【5】 Toda, H.; Kihara, K. (Mitsubishi Chemical Corp.); Improved preparation process for anion exchange resins. JP 1984155421 .
【6】 Toda, H.; Mizogami, S.; Kihara, K.; Hashimoto, M.; Bile acid binding and hypocholesterolemic activity of a new anion exchange resin from 2-methylimidazol and epichlorohydrin. J Pharm Sci 1988, 77, 6, 531.
【7】 Castaner, J.; Prous, J.; MCI-196. Drugs Fut 1993, 18, 1, 15.
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) 15670 2-Methylimidazole; 2-Methyl-1H-imidazole 693-98-1 C4H6N2 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情

合成路线58

该中间体在本合成路线中的序号：(V)

N-(2,2-Diphenylacetyl)piperazine (IV) was prepared by acylation of N-formylpiperazine (II) with 2,2-diphenylacetyl chloride (I), followed by acid-promoted formyl deprotection of the resulting amide (III). Condensation of 5-hydroxyquinoline (VI) with epichlorohydrin (V) in the presence of potassium tert-butoxide in DMF at 90 C provided 5-(2,3-epoxypropoxy)quinoline (VII), which was subsequently coupled with acylpiperazine (IV) in boiling isopropanol to yield (VIII). This was finally treated with fumaric acid (IX) in MeOH to furnish the title sesquifumarate salt.

参考文献 中间体
合成目标
【1】 Suzuki, T.; et al.; Structure-activity relationship of newly synthesiz. J Med Chem 1997, 40, 13, 2047.
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) 23800 Diphenylacetyl chloride; 2,2-diphenylacetyl chloride 1871-76-7 C14H11ClO 详情 详情
(II) 23801 1-piperazinecarbaldehyde; N-Formylpiperazine 7755-92-2 C5H10N2O 详情 详情
(III) 23802 4-(2,2-diphenylacetyl)-1-piperazinecarbaldehyde C19H20N2O2 详情 详情
(IV) 23803 2,2-diphenyl-1-(1-piperazinyl)-1-ethanone C18H20N2O 详情 详情
(V) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(VI) 23805 5-quinolinol 578-67-6 C9H7NO 详情 详情
(VII) 23806 5-(2-oxiranylmethoxy)quinoline; 2-oxiranylmethyl 5-quinolinyl ether C12H11NO2 详情 详情
(VIII) 23807 1-[4-[2-hydroxy-3-(5-quinolinyloxy)propyl]-1-piperazinyl]-2,2-diphenyl-1-ethanone C30H31N3O3 详情 详情
(IX) 23808 Fumaric acid; (E)-2-butenedioic acid 110-17-8 C4H4O4 详情 详情

合成路线59

该中间体在本合成路线中的序号：

Proxodolol (V) was obtained as shown in Scheme 21696501a: Monoalkylation of pyrocatechol with chloroacetic acid gives 2-hydroxyphenoxyacetic acid (I), which is cyclized on heating into 1,4-benzodioxan-2-one (II). Condensation of (II) with acetamidoxime, giving 2-methyl-5-(2-hydroxyphenoxymethyl)-1,2,4-oxadiazole (III), followed by alkylation with epichlorohydrin yields the corresponding diether (IV), which smoothly reacts with tert-BuNH2, and the amine (V) is converted into its hydrochloride by reaction with HCl.

参考文献 中间体
合成目标
【1】 Mashkovski, M.D.; Sokolov, S.D.; Vinogradova, S.M.; Yuzhakov, S.D.; Yermakova, V.N.; Proxodolol. Drugs Fut 1997, 22, 5, 499.
【2】 Sokolov, S.D.; Vinogradova, S.M.; Azarevich, O.G.; Berg, M.V.; Mashkovski, M.D.; Yuzhakov, S.D.; Morozov, A.V. (Center for Chemistry of Drugs); The hydrochlorides of derivs. of 5-phenoxymethyl-1,2, 4-oxadiaxole, possessing beta- and alpha-adrenoblocking activities. SU 1132505 .
【3】 Sokolov, S.D.; Vinogradova, S.M.; Azarevich, O.G. (Center for Chemistry of Drugs); The method for producing of 5-(2-hydroxyphenoxymethyl)-1,2,4-oxadiazoles. SU 1139129 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
11599 o-Dihydroxybenzene; Catechol; Pyrocatechol 120-80-9 C6H6O2 详情 详情
11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
64134 N'-hydroxyethanimidamide C2H6N2O 详情 详情
(I) 16894 2-Hydroxyphenoxyacetic acid; o-Hydroxyphenoxyacetic acid; 2-(2-hydroxyphenoxy)acetic acid 6324-11-4 C8H8O4 详情 详情
(II) 16895 1,4-BENZODIOXAN-2-ONE; 1,4-benzodioxin-2(3H)-one 4385-48-2 C8H6O3 详情 详情
(III) 16896 2-[(3-methyl-1,2,4-oxadiazol-5-yl)methoxy]phenol C10H10N2O3 详情 详情
(IV) 16897 2-[(3-methyl-1,2,4-oxadiazol-5-yl)methoxy]phenyl 2-oxiranylmethyl ether; 3-methyl-5-[[2-(2-oxiranylmethoxy)phenoxy]methyl]-1,2,4-oxadiazole C13H14N2O4 详情 详情
(V) 16898 1-(tert-butylamino)-3-[2-[(3-methyl-1,2,4-oxadiazol-5-yl)methoxy]phenoxy]-2-propanol hydrochloride C17H26ClN3O4 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 reaction of 4-fluorophenol (I) with epichlorohydrin (II) by means of K2CO3 in refluxing acetone gives 2-(4-fluorophenoxymethyl)oxirane (III), which is submitted to an enantioselective ring opening with the Jacobsen (R,R)-catalyst yielding a mixture of the (R)-diol (IV) and unaltered epoxide (V), easily separated by column chromatography. The reaction of (IV) with tosyl chloride and pyridine in dichloromethane affords the primary monotosylate (VI), which is converted into the chiral epoxide (VII) by reaction with NaH in THF/DMF. The reaction of (VII) with allylmagnesium bromide (VIII) in ethyl ether gives the 2-hexenol derivative (IX), which is treated with benzenesulfonyl chloride and DMAP yielding the sulfonate (X). The ozonolysis of (X) with ozone in dichloromethane affords the aldehyde (XI), which is condensed with ethoxycarbonylmethylene(triphenyl)phosphorane (XII) yielding the 2-heptenoic ester (XIII). The reduction of (XIII) with diisobutylaluminum hydride (DIBAL) in toluene/dichloromethane provides the 2-hepten-1-ol (XIV), which is epoxidized with cumene hydroperoxide in the presence of diisopropyl (+)-tartrate and Ti(Oi-Pr)4 in dichloromethane to give the chiral epoxyalcohol (XV). The reaction of (XV) with triphenylphosphine/CCl4 in chloroform affords the corresponding chloride (XVI).

参考文献 中间体
合成目标
【1】 Adhikari, S.S.; Hymavathi, L.; Sadalapure, K.; Sharma, G.V.M.; Sreenivas, P.; Mhaskar, S.V.; Lalitha, S.V.S.; Chorghade, M.S.; Murugaiah, A.M.S.; Prasad, T.R.; Reddy, B.S.; Gurjar, M.K.; Reddy, V.G.; Krishna, P.R. (LeukoSite, Inc.); Substd. oxygen alicyclic cpds., including methods for synthesis thereof. WO 0001381 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
14713 benzenesulfonyl chloride 98-09-9 C6H5ClO2S 详情 详情
(I) 19639 4-fluorophenol 371-41-5 C6H5FO 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 22150 2-[(4-fluorophenoxy)methyl]oxirane; 4-fluorophenyl 2-oxiranylmethyl ether 18123-82-5 C9H9FO2 详情 详情
(IV) 32985 (2R)-3-(4-fluorophenoxy)-1,2-propanediol C9H11FO3 详情 详情
(V) 32986 4-fluorophenyl (2S)oxiranylmethyl ether; (2S)-2-[(4-fluorophenoxy)methyl]oxirane 108648-25-5 C9H9FO2 详情 详情
(VI) 32987 (2S)-3-(4-fluorophenoxy)-2-hydroxypropyl 4-methylbenzenesulfonate C16H17FO5S 详情 详情
(VII) 22150 2-[(4-fluorophenoxy)methyl]oxirane; 4-fluorophenyl 2-oxiranylmethyl ether 18123-82-5 C9H9FO2 详情 详情
(VIII) 10386 Allyl(bromo)magnesium 1730-25-2 C3H5BrMg 详情 详情
(IX) 32988 (2R)-1-(4-fluorophenoxy)-5-hexen-2-ol C12H15FO2 详情 详情
(X) 32989 (1R)-1-[(4-fluorophenoxy)methyl]-4-pentenyl benzenesulfonate C18H19FO4S 详情 详情
(XI) 32990 (1R)-1-[(4-fluorophenoxy)methyl]-4-oxobutyl benzenesulfonate C17H17FO5S 详情 详情
(XII) 14182 ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane 1099-45-2 C22H21O2P 详情 详情
(XIII) 32991 ethyl (E,6R)-7-(4-fluorophenoxy)-6-[(phenylsulfonyl)oxy]-2-heptenoate C21H23FO6S 详情 详情
(XIV) 32992 (1R,4E)-1-[(4-fluorophenoxy)methyl]-6-hydroxy-4-hexenyl benzenesulfonate C19H21FO5S 详情 详情
(XV) 32993 (1R)-1-[(4-fluorophenoxy)methyl]-3-[(2R,3S)-3-(hydroxymethyl)oxiranyl]propyl benzenesulfonate C19H21FO6S 详情 详情
(XVI) 32994 (1R)-3-[(2R,3R)-3-(chloromethyl)oxiranyl]-1-[(4-fluorophenoxy)methyl]propyl benzenesulfonate C19H20ClFO5S 详情 详情

合成路线61

该中间体在本合成路线中的序号：(II)

The enantiomerically pure benzodioxane derivative (VIII) was obtained in a straightforward route including five steps starting from pyrocatechin (I). Racemic (VI) was then resolved by means of crystallization with (-)-O,O'-dibenzoyl-L-tartaric acid.

参考文献 中间体
合成目标
【1】 Matyus, P.; GYKI-16084. Drugs Fut 1999, 24, 10, 1072.
【2】 3(2H)-Pyridazinone derivs. and pharmaceutical compsns. containing these cpds.. WO 9638441 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
18522 3-amino-1-propanol 156-87-6 C3H9NO 详情 详情
(I) 11599 o-Dihydroxybenzene; Catechol; Pyrocatechol 120-80-9 C6H6O2 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 28714 2,3-dihydro-1,4-benzodioxin-2-ylmethanol 3663-82-9 C9H10O3 详情 详情
(IV) 20959 2,3-dihydro-1,4-benzodioxin-2-ylmethyl 4-methylbenzenesulfonate C16H16O5S 详情 详情
(V) 20960 3-[(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)amino]-1-propanol C12H17NO3 详情 详情
(VI) 28715 3-chloro-N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-1-propanamine C12H16ClNO2 详情 详情
(VII) 16186 (2R,3R)-2,3-bis(benzoyloxy)butanedioic acid C18H14O8 详情 详情
(VIII) 28716 3-chloro-N-[(2R)-2,3-dihydro-1,4-benzodioxin-2-ylmethyl]-1-propanamine C12H16ClNO2 详情 详情

合成路线62

该中间体在本合成路线中的序号：(III)

Esterification of p-hydroxyphenylacetic acid (I) with NaHSO4 in refluxing butanol provides butyl acetate derivative (II), which is then subjected to reaction with epichlorohydrin (III) in pyridine to furnish a mixture of epoxypropane (IV) and chloro derivative (V). Treatment of the mixture (IV)/(V) with HCl affords derivative (VI), which is then selectively acylated by means of Lipase Amano PS (LAPS) and vinyl acetate or acetic anhydride/diisopropyl ether to yield compound (S)-(VII). Treatment of the mixture (IV)/(V) with acetyl chloride gives derivative (VIII), which is selectively deacylated using LAPS in butanol/diisopropyl ether to afford derivative (S)-(IX). Coupling of derivative (S)-(VII) with isopropylamine (X) in H2O, followed by removal of the acetyl group with NaOH furnishes derivative (XI) (alternatively, (XI) can also be synthesized by coupling of (S)-(IX) with amine (X)). Finally, conversion of (XI) into the desired product is achieved by treatment with ammonium hydroxide in MeOH.

参考文献 中间体
合成目标
【1】 Banerji, A.A.; Bevinakatti, H.S.; Lipase catalysis in organic solvents. Application to the synthesis of (R)- and (S)-atenolol. J Org Chem 1992, 57, 22, 6003.
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),(VI) 51078 butyl 2-[4-(3-chloro-2-hydroxypropoxy)phenyl]acetate C15H21ClO4 详情 详情
(S)-(VII) 51079 butyl 2-(4-[[(2R)-2-(acetoxy)-3-chloropropyl]oxy]phenyl)acetate C17H23ClO5 详情 详情
(S)-(IX) 51080 butyl 2-(4-[[(2R)-3-chloro-2-hydroxypropyl]oxy]phenyl)acetate C15H21ClO4 详情 详情
(I) 18430 2-(4-Hydroxyphenyl)acetic acid; 4-Hydroxyphenylacetic acid 156-38-7 C8H8O3 详情 详情
(II) 51075 butyl 2-(4-hydroxyphenyl)acetate C12H16O3 详情 详情
(III) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(IV) 51077 butyl 2-[4-(2-oxiranylmethoxy)phenyl]acetate C15H20O4 详情 详情
(VIII) 51082 butyl 2-[4-[2-(acetoxy)-3-chloropropoxy]phenyl]acetate C17H23ClO5 详情 详情
(X) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情
(XI) 51081 butyl 2-(4-[[(2S)-2-hydroxy-3-(isopropylamino)propyl]oxy]phenyl)acetate C18H29NO4 详情 详情

合成路线63

该中间体在本合成路线中的序号：(I)

Condensation of epichlorohydrin (I) with N-benzylethanolamine (II) in the presence of sulfuric acid afforded the (chloromethyl)morpholine (III). Halogen displacement in (III) by potassium phthalimide (IV) provided the substituted phthalimide (V). Further hydrazinolysis of (V) furnished racemic (aminomethyl)morpholine (VI) (1). The desired (S) enantiomer (VII) was obtained by crystallization of (VI) as the dibenzoyl-D-tartaric acid salt, followed by liberation of the base with NaOH. Eschweiler-Clarke reductive methylation of (VII) with formaldehyde and formic acid produced the dimethylamino derivative (VIII). The N-benzyl groupof (VIII) was then cleaved by transfer hydrogenation in the presence of hydrazine and Pd/C yielding chiral morpholine (IX). Finally, coupling of this morpholine (IX) with the difluoroqyuinolone boron chelate (X) provided the title morpholino quinolone.

参考文献 中间体
合成目标
【1】 Sakurai, N.; Sano, M.; Hirayama, F.; Kuroda, T.; Uemori, S.; Moriguchi, A.; Yamamoto, K.; Ikeda, Y.; Kawakita, T.; Synthesis and structure-activity relationships of 7-(2-aminoalkyl)morpholinoquinolones as anti-Helicobacter pylori agents. Bioorg Med Chem Lett 1998, 8, 16, 2185.
【2】 Uemori, S.; Hirayama, F.; Moriguchi, A.; Sano, M.; Yokoyama, Y.; Ikeda, Y.; Miyoshi, M.; Sakurai, N.; Yamamoto, K.; Kawakita, T.; Synthesis and anti-Helicobacter pylori activity of Y-34867, a new 7-morpholinoquinolone. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-85.
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(II) 25630 2-(benzylamino)-1-ethanol 104-63-2 C9H13NO 详情 详情
(III) 13396 4-Benzyl-2-(chloromethyl)morpholine C12H16ClNO 详情 详情
(IV) 10926 (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium C8H4KNO2 详情 详情
(V) 13398 2-[(4-Benzyl-2-morpholinyl)methyl]-1H-isoindole-1,3(2H)-dione C20H20N2O3 详情 详情
(VI) 13399 (4-Benzyl-2-morpholinyl)methylamine; (4-Benzyl-2-morpholinyl)methanamine C12H18N2O 详情 详情
(VII) 25362 1,4,8,11-Tetraazacyclotetradecane 295-37-4 C10H24N4 详情 详情
(VIII) 25633 N-[[(2S)-4-benzylmorpholinyl]methyl]-N,N-dimethylamine C14H22N2O 详情 详情
(IX) 25634 N,N-dimethyl-N-[(2R)morpholinylmethyl]amine C7H16N2O 详情 详情
(X) 25635 1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid diacetoxyboron complex C18H16BF2NO8 详情 详情

合成路线64

该中间体在本合成路线中的序号：(IX)

Condensation of isonicotinamide (I) with 1-chloro-2,4-dinitrobenzene (II) gave quaternary pyridinium salt (III). This was further converted into pyridinium salt (V) by treatment with 2-methoxyaniline (IV) in MeOH. Catalytic transfer hydrogenation of the pyridine ring of (V) provided piperidine (VI). The amide function of (VI) was then reduced to amine (VII) using either borane-dimethyl sulfide complex or LiAlH4. Condensation of 4-chlorocatechol (VIII) with epichlorohydrin (IX) in aqueous KOH produced a mixture of regioisomeric benzodioxans (X) and (XI), from which the major 7-chloro isomer (X) was isolated by flash chromatography after treatment with tosyl chloride and pyridine yielding tosylate (XII). This compound was finally coupled with amine (VII) in the presence of K2CO3 and KI in boiling acetonitrile.

参考文献 中间体
合成目标
【1】 Kerrigan, F.; Heal, D.J.; Martin, K.F. (The Boots Company plc); Bicyclic aromatic cpds. as therapeutic agents. EP 0717739; JP 1997502431; US 5767116; WO 9507274 .
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) 25191 isonicotinamide 1453-82-3 C6H6N2O 详情 详情
(II) 10378 1-Chloro-2,4-dinitrobenzene 97-00-7 C6H3ClN2O4 详情 详情
(III) 25192 4-(aminocarbonyl)-1-(2,4-dinitrophenyl)pyridinium chloride 475-25-2 C12H9ClN4O5 详情 详情
(IV) 25193 2-methoxyphenylamine; 2-methoxyaniline 517-28-2 C7H9NO 详情 详情
(V) 25194 4-(aminocarbonyl)-1-(2-methoxyphenyl)pyridinium chloride C13H13ClN2O2 详情 详情
(VI) 25195 1-(2-methoxyphenyl)-4-piperidinecarboxamide C13H18N2O2 详情 详情
(VII) 25196 [1-(2-methoxyphenyl)-4-piperidinyl]methylamine; [1-(2-methoxyphenyl)-4-piperidinyl]methanamine C13H20N2O 详情 详情
(VIII) 25197 4-chloro-1,2-benzenediol 2138-22-9 C6H5ClO2 详情 详情
(IX) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(X) 25199 (7-chloro-2,3-dihydro-1,4-benzodioxin-2-yl)methanol C9H9ClO3 详情 详情
(XI) 25198 (6-chloro-2,3-dihydro-1,4-benzodioxin-2-yl)methanol C9H9ClO3 详情 详情
(XII) 25200 (7-chloro-2,3-dihydro-1,4-benzodioxin-2-yl)methyl 4-methylbenzenesulfonate C16H15ClO5S 详情 详情

合成路线65

该中间体在本合成路线中的序号：(II)

Alkylation of 4-[2,3-dinitroxy)propoxymethyl]phenol (I) with epichlorhydrin (II) in the presence of NaOH provided the corresponding epoxypropoxy derivative (III). Then, epoxide opening with isopropylamine (IV) in refluxing MeOH furnished the desired amino alcohol.

参考文献 中间体
合成目标
【1】 Prat Quinones, M.; Pi Sallent, J.; Vedrilla Veit, D. (Almirall Prodesfarma, SA); 1-Aryloxy-3-alkylamino-2-propanol nitrate esters, the use thereof and corresponding pharmaceutical compsn.. EP 0637583; JP 1995089910 .
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) 36607 4-[[2,3-bis(nitrooxy)propoxy]methyl]phenol C10H12N2O8 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 36608 2-[(4-[[2,3-bis(nitrooxy)propoxy]methyl]phenoxy)methyl]oxirane; 4-[[2,3-bis(nitrooxy)propoxy]methyl]phenyl 2-oxiranylmethyl ether C13H16N2O9 详情 详情
(IV) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情

合成路线66

该中间体在本合成路线中的序号：(II)

N-(2,3-Epoxypropyl)piperidine (III), prepared from piperidine (I) and epichlorhydrin (II), was condensed with nicotinic acid amidoxime (IV) in the presence of basic catalysts, such as NaOH, t-BuOK, Al2O3 or SnO2, in hot DMF to provide the title compound, which was finally converted to the dihydrochloride salt.

参考文献 中间体
合成目标
【1】 Somfai, E,; Bertok, B.; Szekely, I.; Takacs, K.; Thurner, A.; Gajary, A.; Botar, S.; Nagy, L. (Chinoin Pharmaceutical and Chemical Works Co., Ltd.); Improved process for the preparation of amidoxime derivs.. WO 9008131 .
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) 10158 Piperidine 110-89-4 C5H11N 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 24452 1-(2-oxiranylmethyl)piperidine C8H15NO 详情 详情
(IV) 33684 N'-hydroxy-3-pyridinecarboximidamide C6H7N3O 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 acylation of 7-hydroxy-3,4-dihydro-2H-1,4-benzoxazine (I) with acetic anhydride gives the N-acetyl derivative (II), which is condensed with epichlorohydrin (III) by means of K2CO3 at 90-5 C yielding 4-acetyl-7-(2,3-epoxypropoxy)-3,4-dihydro-2H-1,4-benzoxazine (IV). Finally, the addition of 3,4-dimethoxybenzylamine (V) to the epoxy group of (IV) in hot isopropanol affords the target compound.

参考文献 中间体
合成目标
【1】 Iakovou, K.; et al.; Synthesis of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4-benzoxazine, beta-adrenergic affinity, inotropic, chronotropic and coronary vasodilating activities. Eur J Med Chem 1999, 34, 11, 903.
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) 38404 3,4-dihydro-2H-1,4-benzoxazin-7-ol C8H9NO2 详情 详情
(II) 38405 1-(7-hydroxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-1-ethanone C10H11NO3 详情 详情
(III) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(IV) 38406 1-[7-(2-oxiranylmethoxy)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]-1-ethanone C13H15NO4 详情 详情
(V) 13920 (3,4-Dimethoxyphenyl)methanamine; 3,4-Dimethoxybenzylamine; Veratrylamine 5763-61-1 C9H13NO2 详情 详情

合成路线68

该中间体在本合成路线中的序号：(II)

The condensation of vanillin (I) with epichlorohydrin (II) in ethanolic NaOH produced the glycidyl ether (III). Epoxide ring opening in (III) by means of tert-butylamine (IV) in EtOH furnished amino alcohol (V). The title dihydropyridine derivative was then obtained by reaction between aldehyde (V), methyl acetoacetate (VI), ammonia under Hantzsch condensation conditions, and was isolated after conversion to the hydrochloride salt.

参考文献 中间体
合成目标
【1】 Liang, J.-C.; Chen, I.-J.; Tsai, C.-H.; Liou, S.-F.; Wang, C.-S.; Yeh, J.-L.; The new generation dihydropyridine type calcium blockers, bearing 4-phenyl oxypropanolamine, display alpha-/beta-adrenoceptor antagonist and long-acting antihypertensive activities. Bioorg Med Chem 2002, 10, 3, 719.
【2】 Donovan, S. (Allergan, Inc.); Method for treating a neoplasm. WO 0209743 .
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 59599 3-methoxy-4-(2-oxiranylmethoxy)benzaldehyde C11H12O4 详情 详情
(IV) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
(V) 59600 4-[3-(tert-butylamino)-2-hydroxypropoxy]-3-methoxybenzaldehyde C15H23NO4 详情 详情
(VI) 11791 methyl 3-oxobutanoate; Methyl acetoacetate 105-45-3 C5H8O3 详情 详情

合成路线69

该中间体在本合成路线中的序号：(III)

The selective methylation of 5,6,7,8-tetrahydro-5,8-ethanonaphthalene-1,4-diol (I) with dimethylsulfate in a two phase system gives 4-methoxy-5,6,7,8-tetrahydro-5,8-ethano-1-naphthol (II), which is condensed with epichlorohydrin (III) by means of piperidine at 100 C yielding 1-methoxy-4-(2,3-epoxypropoxy)-5,6,7,8-tetrahydro-5,8-ethanonaphthalene (IV). The reaction of (IV) with tert-butylamine (V) at 100 C affords 1-methoxy-4-[3-(tert-butylamino)-2-hydroxypropoxy]-5,6,7,8-tetrahydro-5,8-ethanonaphthalene (VI), which is finally demethylated by treatment with pyridine hydrochloride at 160 C

参考文献 中间体
合成目标
【1】 Blancafort, P.; Serradell, M.N.; Castaner, J.; McGillion, F.B.; Nafetolol. Drugs Fut 1981, 6, 2, 92.
【2】 Momiyama, N.; Ichikawa, Y.; Hasegawa, S.; Ishikawa, T.; Matsuyama, R.; Miazaki, K.; Shimada, H.; Targeting MMP-7 via antisense oligonucleotide shows anti-metastatic effects in a colon cancer murine model. Eur J Med Chem 1974, 9, 5, 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
(I) 61070 tricyclo[6.2.2.0~2,7~]dodeca-2,4,6-triene-3,6-diol C12H14O2 详情 详情
(II) 61071 6-methoxytricyclo[6.2.2.0~2,7~]dodeca-2,4,6-trien-3-ol C13H16O2 详情 详情
(III) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(IV) 60172 4,5,6,7-tetrahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)-dione C17H12N2O2 详情 详情
(V) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
(VI) 60173 10-bromo-4,5,6,7-tetrahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)-dione C17H11BrN2O2 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 selective hydrolysis of 1,4-diacetoxy-5,6,7,8-tetrahydro-5,8-ethanonaphthalene (VII) with diethylamine in methanol gives 4-acetoxy-5,6,7,8-tetrahydro-5,8-ethano-1-naphthol (VIII), which is condensed with epichlorohydrin (III) by means of piperidine at 90 C to afford 1-acetoxy-4-(2,3-epoxypropoxy)-5,6,7,8-tetrahydro-5,8-ethanonaphthalene (VII). The reaction of (IX) with tert-butylamine (V) in refluxing toluene gives 1-acetoxy-4-[3-(tert-butylamino)-2-hydroxypropoxy]-5,6,7,8-tetrahydro-5,8-ethanonaphthalene (X), which is finally hydrolyzed with dry HCl in refluxing methanol

参考文献 中间体
合成目标
【1】 Lauria, F.; et al. (Carlo Erba, S.p.A.); BE 790188; CA 992983; CH 565741; DE 2251095; FR 2157897; GB 1351557; JP 7349750; NL 7214106; ZA 7207459 .
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; McGillion, F.B.; Nafetolol. Drugs Fut 1981, 6, 2, 92.
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(V) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
(VII) 61074 6-(acetyloxy)tricyclo[6.2.2.0~2,7~]dodeca-2,4,6-trien-3-yl acetate C16H18O4 详情 详情
(VIII) 61075 6-hydroxytricyclo[6.2.2.0~2,7~]dodeca-2,4,6-trien-3-yl acetate C14H16O3 详情 详情
(IX) 61076 6-(2-oxiranylmethoxy)tricyclo[6.2.2.0~2,7~]dodeca-2,4,6-trien-3-yl acetate C17H20O4 详情 详情
(X) 61077 6-[3-(tert-butylamino)-2-hydroxypropoxy]tricyclo[6.2.2.0~2,7~]dodeca-2,4,6-trien-3-yl acetate C21H31NO4 详情 详情

合成路线71

该中间体在本合成路线中的序号：(IV)

The acetylation of 4-acetamidophenol (I) with acetyl chloride in refluxing benzene gives 4-acetoxyacetanilide (II), which by a Fries reaction with AlCl3 at 170 C is converted into 2-hydroxy-5-acetamidoacetophenone (III). (1,2) The reaction of (III) with epichlorohydrin (IV) by means of sodium ethoxide in refluxing ethanol affords 1-(2-acetyl-4-acetamidophenoxy)-2,3-epoxypropane (V), which is finally treated with isopropylamine (VI) in refluxing ethanol. (1-3)

参考文献 中间体
合成目标
【1】 Woolbridge, K.R.H.; Basil, B (May & Baker, Ltd.); ZA 6808345 .
【2】 Basil, B.; et al.; New series of cardioselective adrenergic beta-receptor blocking compounds. 1-(2-Acyl-4-acylaminophenoxy)3-isopropylaminopropan-2-ols. J Med Chem 1976, 19, 3, 399.
【3】 Woolbridge, K.R.H.; Basil, B. (May & Baker, Ltd.); BE 715205; CA 834734; CH 485663; CH 489467; FR 1570087; FR M7616; GB 1231783; GB 681537; JP 7134414; NL 6806946; ZA 6803130 .
【4】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Weetman, D.F.; Diacetolol hydrochloride. Drugs Fut 1981, 6, 8, 467.
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) 21611 4'-Hydroxyacetanilide;4-Acetamidophenol;N-Acetyl-4-aminophenol;Paracetamol;Acetaminophen;p-Hydroxyacetanilide; Paracetamol; N-(4-hydroxyphenyl)acetamide 103-90-2 C8H9NO2 详情 详情
(II) 60980 4-(acetylamino)phenyl acetate C10H11NO3 详情 详情
(III) 21612 N-(3-acetyl-4-hydroxyphenyl)acetamide C10H11NO3 详情 详情
(IV) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(V) 60981 N-[3-acetyl-4-(2-oxiranylmethoxy)phenyl]acetamide C13H15NO4 详情 详情
(VI) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情

合成路线72

该中间体在本合成路线中的序号：(II)

The condensation of o-(methylthio)phenol (I) with epichlorohydrin (II) by means of sodium hydroxide in water gives 3-[o-(methylthio)phenoxy]-1,2-epoxypropane (III), which is then treated with isopropylamine (IV) in hot water and finally with ethanolic HCl

参考文献 中间体
合成目标
【1】 (N.V. Philips' Gloeilampenfabrieken); BE 679005; CA 832495; DE 1543790; FR 1552786; FR 6393; GB 1137764; JP 6902978; NL 6504268; US 3542874; US 3632780 .
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Weetman, D.F.; Tiprenolol hydrochloride. Drugs Fut 1979, 4, 11, 830.
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) 28075 2-(methylsulfanyl)phenol 1073-29-6 C7H8OS 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 60944 2-(methylsulfanyl)phenyl 2-oxiranylmethyl ether; 2-{[2-(methylsulfanyl)phenoxy]methyl}oxirane C10H12O2S 详情 详情
(IV) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情
(V) 60945 1-(isopropylamino)-3-[2-(methylsulfanyl)phenoxy]-2-propanol C13H21NO2S 详情 详情

合成路线73

该中间体在本合成路线中的序号：(VIII)

The condensation of vanillin (VII) with epichlorohydrin (VIII) in ethanolic NaOH produced the glycidyl ether (IX). Epoxide ring opening in (IX) by means of amine (VI) in EtOH furnished amino alcohol (X). The title dihydropyridine derivative was then obtained by reaction between aldehyde (X), methyl acetoacetate (XI), and ammonia under Hantzsch condensation conditions.

参考文献 中间体
合成目标
【1】 Liang, J.-C.; Chen, I.-J.; Tsai, C.-H.; Liou, S.-F.; Wang, C.-S.; Yeh, J.-L.; The new generation dihydropyridine type calcium blockers, bearing 4-phenyl oxypropanolamine, display alpha-/beta-adrenoceptor antagonist and long-acting antihypertensive activities. Bioorg Med Chem 2002, 10, 3, 719.
【2】 Lin, T.-H.; Chen, I.-J.; Guaiacoxypropanolamines with alpha/beta-adrenergic blocking activity. EP 1108710; WO 0005209 .
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) 31105 2-(2-methoxyphenoxy)ethylamine; 2-(2-methoxyphenoxy)-1-ethanamine 1836-62-0 C9H13NO2 详情 详情
(VII) 22701 4-hydroxy-3-methoxybenzaldehyde 121-33-5 C8H8O3 详情 详情
(VIII) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(IX) 59599 3-methoxy-4-(2-oxiranylmethoxy)benzaldehyde C11H12O4 详情 详情
(X) 59618 4-(2-hydroxy-3-{[2-(2-methoxyphenoxy)ethyl]amino}propoxy)-3-methoxybenzaldehyde C20H25NO6 详情 详情
(XI) 11791 methyl 3-oxobutanoate; Methyl acetoacetate 105-45-3 C5H8O3 详情 详情

合成路线74

该中间体在本合成路线中的序号：(IV)

Monoalkylation of hydroquinone (I) with decyl bromide (II) under basic conditions provided 4-(decyloxy)phenol (III), which was further condensed with epichlorohydrin (IV) in the presence of Cs2CO3 to yield the glycidyl ether (V). Ring opening of epoxide (V) with allyl 4-hydroxybenzoate (VI) furnished adduct (VII). Then, oxidation of the secondary alcohol (VII) using the Dess-Martin reagent afforded the keto ester (VIII), which upon deprotection with palladium tetrakis(triphenylphosphine) gave the target carboxylic acid.

参考文献 中间体
合成目标
【1】 Connolly, S.; Botterll, S.; Bennion, C.; et al.; Design and synthesis of a novel and potent series of inhibitors of cytosolic phospholipase A2 based on a 1,3-disubstituted propan-2-one skeleton. J Med Chem 2002, 45, 6, 1348.
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) 13163 p-Dihydrobenzene; Hydroquinone 123-31-9 C6H6O2 详情 详情
(II) 58570 1-Bromodecane; 1-Decyl bromide; Decyl bromide; n-decyl bromide 112-29-8 C10H21Br 详情 详情
(III) 58571 4-Decyloxyphenol C16H26O2 详情 详情
(IV) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(V) 58572 2-{[4-(decyloxy)phenoxy]methyl}oxirane; decyl 4-(2-oxiranylmethoxy)phenyl ether C19H30O3 详情 详情
(VI) 21022 allyl 4-hydroxybenzoate C10H10O3 详情 详情
(VII) 58573 allyl 4-{3-[4-(decyloxy)phenoxy]-2-hydroxypropoxy}benzoate C29H40O6 详情 详情
(VIII) 58574 allyl 4-{3-[4-(decyloxy)phenoxy]-2-oxopropoxy}benzoate C29H38O6 详情 详情

合成路线75

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】 Li SC, Huang HQ, Li ZJ. 2003. Synthesis of a novel antianginal agent Ranolazine. 中国药物化学杂志，13: 283～285
【2】 Lu WC, Li YQ, Zhao XG, et aL. 2004. Synthesis of ranolazine中国医药工业杂志，35: 641～642
【3】 Wang LS, Feng XY, Zhu HY. 2003. Synthesis of anti-angina drug ranolazine. 广西大学学报，自然科学版，28: 301～303
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) 13182 Guaiacol; 2-Methoxyphenol 90-05-1 C7H8O2 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 24103 2-[(2-methoxyphenoxy)methyl]oxirane C10H12O3 详情 详情
(IV) 17527 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine 87-62-7 C8H11N 详情 详情
(V) 24100 2-chloro-N-(2,6-dimethylphenyl)acetamide 2198-53-0 C10H12ClNO 详情 详情
(VI) 24102 N-(2,6-dimethylphenyl)-2-(1-piperazinyl)acetamide C14H21N3O 详情 详情

合成路线76

该中间体在本合成路线中的序号：(IV)

　

参考文献 中间体
合成目标
【1】 Yan J．2007. Synthesis of ranolazine.中国专利申请公开说明书．CN 1915982
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) 17527 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine 87-62-7 C8H11N 详情 详情
(II) 24100 2-chloro-N-(2,6-dimethylphenyl)acetamide 2198-53-0 C10H12ClNO 详情 详情
(III) 24102 N-(2,6-dimethylphenyl)-2-(1-piperazinyl)acetamide C14H21N3O 详情 详情
(IV) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(V) 13182 Guaiacol; 2-Methoxyphenol 90-05-1 C7H8O2 详情 详情
(VI) 24103 2-[(2-methoxyphenoxy)methyl]oxirane C10H12O3 详情 详情

合成路线77

该中间体在本合成路线中的序号：(I)

　

参考文献 中间体
合成目标
【1】 Moen AR, Karstad R.Antfiansen T. 2005. Chemo-enzymatic synthesis of both enantiomers of the anti-anginal drug ranolazine. Biocat Biotransfonn, 23: 45～51
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(II) 13182 Guaiacol; 2-Methoxyphenol 90-05-1 C7H8O2 详情 详情
(III) 24103 2-[(2-methoxyphenoxy)methyl]oxirane C10H12O3 详情 详情
(IV) 66620 1-chloro-3-(2-methoxyphenoxy)propan-2-ol 　 C10H13ClO3 详情 详情
(V) 66621 1-chloro-3-(2-methoxyphenoxy)propan-2-yl butyrate 　 C14H19ClO4 详情 详情
(VI) 66622 (R)-1-chloro-3-(2-methoxyphenoxy)propan-2-yl butyrate 　 C14H19ClO4 详情 详情
(VII) 66623 (R)-1-chloro-3-(2-methoxyphenoxy)propan-2-ol 　 C10H13ClO3 详情 详情
(VIII) 24102 N-(2,6-dimethylphenyl)-2-(1-piperazinyl)acetamide C14H21N3O 详情 详情

合成路线78

该中间体在本合成路线中的序号：(I)

　

参考文献 中间体
合成目标
【1】 Gutman A, Nisnevich G, Etinger M, et aL. 2005. Process for the preparation of prostaglandin derivatives. U S Pat Appl Publ. Cont-in-part of U S Ser N0478 849. US 2005209337(本专利属于Finetech Laboratories Ltd, Israel)
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) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 66881 1-chloro-3-(3-(trifluoromethyl)phenyl)propan-2-ol 6310-15-2 C10H10ClF3O 详情 详情
(IV) 66882 1-chloro-3-(3-(trifluoromethyl)phenyl)propan-2-one 　 C10H8ClF3O 详情 详情
(V) 66883 (Z)-2-(1-chloro-3-(3-(trifluoromethyl)phenyl)propan-2-ylidene)hydrazinecarboxamide 　 C11H11ClF3N3O 详情 详情
(VI) 66884 (Z)-dimethyl (2-(2-carbamoylhydrazono)-3-(3-(trifluoromethyl)phenyl)propyl)phosphonate 　 C13H17F3N3O4P 详情 详情
(VII) 60587 dimethyl 2-oxo-3-[3-(trifluoromethyl)phenyl]propylphosphonate C12H14F3O4P 详情 详情
(VIII) 43178 (3aR,4S,5R,6aS)-4-(hydroxymethyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate 31752-99-5 C21H20O5 详情 详情
(IX) 32122 (3aR,4R,5R,6aS)-2-oxo-4-[(E)-3-oxo-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C31H25F3O6 详情 详情
(X) 66885 　 　 C27H34O5Si 详情 详情
(XI) 66886 (3aR,4R,5R,6aS)-5-hydroxy tert-butyldimethylsilyl-4-[(E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]hexahydro-2H-cyclopenta[b]furan-2-one 　 C24H37F3O5Si 详情 详情
(XII) 66887 (Z)-7-((1S,3S,5R)-2-((E)-3-((tert-butyldimethylsilyl)oxy)-4-(3-(trifluoromethyl)phenoxy)but-1-en-1-yl)-3,5-dihydroxycyclopentyl)hept-5-enoic acid 　 C29H43F3O5Si 详情 详情
(XIII) 66888 (Z)-7-((1S,3S,5R)-3,5-dihydroxy-2-((E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-1-en-1-yl)cyclopentyl)hept-5-enoic acid 　 C23H29F3O6 详情 详情
33504 (II) 33504 3-(trifluoromethyl)phenol 98-17-9 C7H5F3O 详情 详情

合成路线79

该中间体在本合成路线中的序号：(XI)

Cyclization of 2-(chloromethyl)oxirane (XI) with benzhydrylamine (XII) in MeOH, followed by reaction of the resulting compound with Na2CO3 in CH2Cl2 yields 1-benzhydrylazetidin-3-ol (XIII). Catalytic hydrogenolysis of azetidine derivative (XIII) over Pd/C, followed by re-protection with Boc2O in THF, yields carbamate (XIV), which is oxidized to N-Boc-3-oxoazetidine (XV) by means of TEMPO in the presence of KBr in EtOAc . Wittig reaction of ketone (XV) with diethyl cyanomethylphosphonate (XVI) by means of t-BuOK or NaH in THF gives N-Boc-3-(cyanomethylene)azetidine (XVII) , which is deprotected with HCl in acetonitrile to produce azetidin-3-ylideneacetonitrile hydrochloride (XVIII). Finally, azetidine derivative (XVIII) is condensed with ethanesulfonyl chloride (XIX) using DIEA in acetonitrile .

参考文献 中间体
合成目标
【1】 Rodgers, J.D., Shepard, S., Li, Y.-L., Zhou, J., Liu, P., Meloni, D., Xia, M.(Incyte Corp.). Azetidine and cyclobutane derivatives as JAK inhibitors. CN 102026999, EP 2288610, JP 2011514909, KR 2010121657, KR 2012108042, US 2009233903, US 2012077798, US 8158616, US 8420629, US 2013225556, WO 2009114512.
【2】 Friedman, P.A., Fridman, J.S., Luchi, M.E., Williams, W.V. (Incyte Corp.). Janus kinase inhibitors for treatment of dry eye and other eye related dis-eases. EP 2349260, JP 2012504639, US 201011416, US 2012301464, WO 2010039939.
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) 68070 2-[1-(ethylsulfonyl)azetidin-3-ylidene]acetonitrile 　 C7H10N2O2S 详情 详情
(XI) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(XII) 15149 alpha-Aminodiphenylmethane; diphenylmethanamine; benzhydrylamine 91-00-9 C13H13N 详情 详情
(XIII) 12592 1-Benzhydryl-3-azetidinol; 1-Benzhydryl-3-hydroxyazetidine；1-benzhydrylazetidin-3-ol 18621-17-5 C16H17NO 详情 详情
(XIV) 68075 tert-butyl 3-hydroxyazetidine-1-carboxylate 141699-55-0 C8H15NO3 详情 详情
(XV) 68076 tert-butyl 3-oxoazetidine-1-carboxylate 398489-26-4 C8H13NO3 详情 详情
(XVI) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(XVII) 68077 N-Boc-3-(cyanomethylene)azetidine 　 C10H14N2O2 详情 详情
(XVIII) 68078 　 　 C5H6N2.HCl 详情 详情
(XIX) 54065 Ethanesulfonyl chloride; Ethylsulfonyl chloride 594-44-5 C2H5ClO2S 详情 详情
Extended Information