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【结 构 式】 
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【分子编号】20810 【品名】ethyl 2-bromo-4-phenylbutanoate 【CA登记号】 |
【 分 子 式 】C12H15BrO2 【 分 子 量 】271.1539 【元素组成】C 53.16% H 5.58% Br 29.47% O 11.8% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of tert-butylalanine (I) with ethyl 2-bromo-4-phenylbutanoate (II) by means of triethylamine in hot DMF gives N-[1-(ethoxycarbonyl)-3-phenylpropyl]alanine tert-butyl ester (III), which is hydrolyzed with trifluoroacetic acid to the corresponding N-substituted alanine (IV). The condensation of (IV) with benzyl 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline-3-carboxylate (V) by means of triethylamine, 1-hydroxybenzotriazole (HBT) and dicyclohexylcarbodiimide (DCC) in methylene chloride affords benzyl 2-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]alanyl]-1,2,3,4-tetrahydro-6,7-di-methoxyisoquinoline-3-carboxylate (VI), which is finally debenzylated by hydrogenation with H2 over Pd/C in THF.
| 【1】 Hoefle, M.L.; Klutchko, S. (Pfizer Inc.); Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids. DD 201787; EP 0049605; EP 0096157; US 4344949 . |
| 【2】 Prous, J.; Castaner, J.; CI-925. Drugs Fut 1986, 11, 4, 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 |
|---|---|---|---|---|---|---|
| (I) | 24040 | 5-amino-2,2-dimethyl-3,4-hexanedione | C8H15NO2 | 详情 | 详情 | |
| (II) | 20810 | ethyl 2-bromo-4-phenylbutanoate | C12H15BrO2 | 详情 | 详情 | |
| (III) | 24042 | ethyl 4-phenyl-2-[(1,4,4-trimethyl-2,3-dioxopentyl)amino]butanoate | C20H29NO4 | 详情 | 详情 | |
| (IV) | 24043 | N-[1-(ethoxycarbonyl)-3-phenylpropyl]alanine | C15H21NO4 | 详情 | 详情 | |
| (V) | 24044 | benzyl 6,7-dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate | C19H21NO4 | 详情 | 详情 | |
| (VI) | 24045 | benzyl 2-(2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate | C34H40N2O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The condensation of alanine tert-butyl ester (I) with ethyl 2-bromo-4-phenylbutanoate (II) by means of triethylamine in hot DMF gives ethyl 2-[[1-(tert-butoxycarbonyl)ethyl]amino]-4-phenylbutanoate (III), which is partially hydrolyzed with trifluoroacetic acid yielding ethyl 2-[[1-carboxyethyl]amino]-4-phenylbutanoate (IV). The condensation of (IV) with benzyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (V) [prepared from the corresponding acid (VI) and benzyl alcohol (A) by means of polyphosphoric acid] by means of triethylamine and 1-hydroxybenzotriazole affords benzyl 2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (VII), which is finally debenzylated by hydrogenolysis with H2 over Pd/C in THF.
| 【1】 Hoefle, M.L.; Klutchko, S. (Pfizer Inc.); Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids. DD 201787; EP 0049605; EP 0096157; US 4344949 . |
| 【2】 Castaner, J.; Serradell, M.N.; Blancafort, P.; CI-906. Drugs Fut 1983, 8, 12, 1014. |
| 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) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |
| (I) | 29385 | tert-butyl (2S)-2-aminopropanoate | C7H15NO2 | 详情 | 详情 | |
| (II) | 20810 | ethyl 2-bromo-4-phenylbutanoate | C12H15BrO2 | 详情 | 详情 | |
| (III) | 31121 | ethyl 2-[[(1S)-2-(tert-butoxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate | C19H29NO4 | 详情 | 详情 | |
| (IV) | 31124 | (2S)-2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid | C15H21NO4 | 详情 | 详情 | |
| (V) | 31122 | benzyl 1,2,3,4-tetrahydro-3-isoquinolinecarboxylate | C17H17NO2 | 详情 | 详情 | |
| (VI) | 13953 | (3S)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid; (S)-(-)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid | 74163-81-8 | C10H11NO2 | 详情 | 详情 |
| (VII) | 31123 | benzyl 2-((2S)-2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate | C32H36N2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The condensation of alanine tert-butyl ester (I) with ethyl 2-bromo-4-phenylbutanoate (II) by means of triethylamine in hot DMF gives ethyl 2-[[1-(tert-butoxycarbonyl)ethyl]amino]-4-phenylbutanoate (III), which is partially hydrolyzed with trifluoroacetic acid yielding ethyl 2-[[1-carboxyethyl]amino]-4-phenylbutanoate (IV). The condensation of (IV) with tert-butyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (VIII) [prepared from the corresponding acid (VI) and isobutylene (B) by means of H2SO4] as before gives tert-butyl-2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (IX), which is finally hydrolyzed partially by treatment with trifluoroacetic acid.
| 【1】 Hoefle, M.L.; Klutchko, S. (Pfizer Inc.); Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids. DD 201787; EP 0049605; EP 0096157; US 4344949 . |
| 【2】 Castaner, J.; Serradell, M.N.; Blancafort, P.; CI-906. Drugs Fut 1983, 8, 12, 1014. |
| 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) | 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 |
| (I) | 29385 | tert-butyl (2S)-2-aminopropanoate | C7H15NO2 | 详情 | 详情 | |
| (II) | 20810 | ethyl 2-bromo-4-phenylbutanoate | C12H15BrO2 | 详情 | 详情 | |
| (III) | 31121 | ethyl 2-[[(1S)-2-(tert-butoxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate | C19H29NO4 | 详情 | 详情 | |
| (IV) | 31124 | (2S)-2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid | C15H21NO4 | 详情 | 详情 | |
| (VI) | 13953 | (3S)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid; (S)-(-)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid | 74163-81-8 | C10H11NO2 | 详情 | 详情 |
| (VIII) | 31125 | tert-butyl 1,2,3,4-tetrahydro-3-isoquinolinecarboxylate | C14H19NO2 | 详情 | 详情 | |
| (IX) | 31126 | tert-butyl 2-((2S)-2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate | C29H38N2O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XII)1) The reduction of 2-thiophenecarboxaldehyde cyanohydrin (I) with LiAlH4 gives 2-amino-1-(2-thienyl)ethanol (II), which is N-protected with di-tert-butyl pyrocarbonate yielding 2-(tert-butoxycarbonylamino)-1-(2-thienyl)ethanol (III). The reaction of (III) with PCl5 in dichloromethane affords 2-(tert-butoxycarbonylamino)-1-chloro-1-(2-thienyl)ethane (IV), which is condensed with benzhydryl N-phthaloylcysteinate (V) by means of Na2CO3 in hot DMF giving the S-substituted cysteinate (VI). The deprotection of (VI) with trifluoroacetic acid in anisole yields S-[2-amino-1-(2-thienyl)ethyl]-N-phthaloylcysteine (VII), which is cyclized by means of diphenylphosphoryl azide (DPA) in DMF giving 6-phthalimido-2-(2-thienyl)perhydro-1,4-thiazepin-5-one (VIII). The condensation of (VIII) with tert-butyl bromoacetate (IX) by means of NaH in DMF affords tert-butyl 2-[6-phthalimido-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate (X), which is treated with methylhydrazine in methanol-dichloromethane yielding the 6-amino derivative (XI). The condensation of (XI) with ethyl 2-bromo-4-phenylbutyrate (XII) by means of Na2CO3 in hot DMF gives the tert-butyl ester of the desired product (XIII), which is finally deprotected with trifluoroacetic acid in anisole.
| 【1】 Yanagisawa, H.; Ishihara, S.; Ando, A.; Kanazaki, T.; Koike, H.; Tsujita, Y. (Sankyo Co., Ltd.); Perhydrothiazepine derivatives, their preparation and their therapeutical use. AU 8541058; EP 0161801; ES 8702388; ES 8801229; JP 85215678; JP 86267579 . |
| 【2】 Prous, J.; Castaner, J.; RS-5142. Drugs Fut 1989, 14, 4, 336. |
| 【3】 Ishihara, S.; Ando, A.; Miyamoto, S.; Kanazaki, T.; Hata, T.; Oizumi, K.; Matsushita, Y.; Koike, H.; Yanagisawa, H.; Iijima, Y.; Angiotensin-converting enzyme inhibitors: Perhydro-1,4-thiazepin-5-one derivatives. J Med Chem 1987, 30, 11, 1984. |
| 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) | 20799 | 2-hydroxy-2-(2-thienyl)acetonitrile | C6H5NOS | 详情 | 详情 | |
| (II) | 20800 | 2-amino-1-(2-thienyl)-1-ethanol | C6H9NOS | 详情 | 详情 | |
| (III) | 20801 | tert-butyl 2-hydroxy-2-(2-thienyl)ethylcarbamate | C11H17NO3S | 详情 | 详情 | |
| (IV) | 20802 | tert-butyl 2-chloro-2-(2-thienyl)ethylcarbamate | C11H16ClNO2S | 详情 | 详情 | |
| (V) | 20803 | benzhydryl 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-sulfanylpropanoate | C24H19NO4S | 详情 | 详情 | |
| (VI) | 20804 | benzhydryl 3-[[2-[(tert-butoxycarbonyl)amino]-1-(2-thienyl)ethyl]sulfanyl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoate | C35H34N2O6S2 | 详情 | 详情 | |
| (VII) | 20805 | 3-[[2-amino-1-(2-thienyl)ethyl]sulfanyl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propionic acid | C17H16N2O4S2 | 详情 | 详情 | |
| (VIII) | 20806 | 2-[5-oxo-2-(2-thienyl)-1,4-thiazepan-6-yl]-1H-isoindole-1,3(2H)-dione | C17H14N2O3S2 | 详情 | 详情 | |
| (IX) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (X) | 20808 | tert-butyl 2-[6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxo-2-(2-thienyl)-1,4-thiazepan-4-yl]acetate | C23H24N2O5S2 | 详情 | 详情 | |
| (XI) | 20809 | tert-butyl 2-[6-amino-5-oxo-2-(2-thienyl)-1,4-thiazepan-4-yl]acetate | 112968-38-4 | C15H22N2O3S2 | 详情 | 详情 |
| (XII) | 20810 | ethyl 2-bromo-4-phenylbutanoate | C12H15BrO2 | 详情 | 详情 | |
| (XIII) | 20811 | ethyl 2-[[4-[2-(tert-butoxy)-2-oxoethyl]-5-oxo-2-(2-thienyl)-1,4-thiazepan-6-yl]amino]-4-phenylbutanoate | C27H36N2O5S2 | 详情 | 详情 |