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【结 构 式】 
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【药物名称】Wy-44221 【化学名称】(S,S)-1-(2-Methyl-3-sulfanyl-1-oxopropyl)-2,3-dihydro-1H-indole-2-carboxylic acid 【CA登记号】78779-29-0 ((-)-enantiomer) 【 分 子 式 】C14H17NO3 【 分 子 量 】247.29649 |
【开发单位】Wyeth Pharmaceuticals (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Angiotensin-I Converting Enzyme (ACE) Inhibitors |
合成路线1
The esterification of indoline-2-carboxylic acid (I) with ethanol HCl gives the corresponding ethyl ester (II), which is acylated with 3-(benzoylthio)-2-methylpropionyl chloride (III) by means of K2CO3 in methylene chloride yielding ethyl N-[3-(benzoylthio)-2-methylpropionyl]indoline-2-carboxylate (IV). The deprotection of (IV) with hydrazine in the same solvent affords ethyl N-(3-mercapto-2-methylpropionyl)indoline-2-carboxylate (V), which is finally saponified with KOH in methanol water.
| 【1】 Stanton, J.L.; et al.; Angiotensin converting enzyme inhibitors: N-Substituted monocyclic and bibyvlic amino acid deivatives. J Med Chem 1983, 26, 9, 1267-77. |
| 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) | 34307 | (2S)-2,3-dihydro-1H-indole-2-carboxylic acid | C9H9NO2 | 详情 | 详情 | |
| (II) | 34308 | ethyl (2S)-2,3-dihydro-1H-indole-2-carboxylate | C11H13NO2 | 详情 | 详情 | |
| (III) | 34309 | S-[(2S)-3-chloro-2-methyl-3-oxopropyl] benzenecarbothioate | C11H11ClO2S | 详情 | 详情 | |
| (IV) | 34310 | ethyl (2S)-1-[(2R)-3-(benzoylsulfanyl)-2-methylpropanoyl]-2,3-dihydro-1H-indole-2-carboxylate | C22H23NO4S | 详情 | 详情 | |
| (V) | 34311 | ethyl (2S)-1-[(2R)-2-methyl-3-sulfanylpropanoyl]-2,3-dihydro-1H-indole-2-carboxylate | C15H19NO3S | 详情 | 详情 |
合成路线2
This compound can be obtained by several related ways: 1) The hydrolysis of ethyl indoline 2 carboxylate (I) with KOH in aqueous DMSO gives indoline 2-carboxylic acid (II), which is acylated with 3-(benzoylthio)-2-methylpropanoyl chloride (III) in methylene chloride yielding 1-[3-(benzoylthio)-2-methyl-1-oxopropyl]indoline-2-carboxylic acid (IV). Finally, this compound is debenzoylated by treatment with 2-methoxyethylamine (A). 2) The acylation of (I) with methacryloyl chloride (V) by means of triethylamine in ether yields ethyl 1-methacryloylindoline-2-carboxylate (VI), which is hydrolyzed with KOH in aqueous DMSO affording 1-methacryloylindoline-2-carboxylic acid (VII). Finally, this compound is treated with thiobenzoic acid (VIII) and 4-dimethylaminopyridine in acetone to give (IV), previously synthesized. 3) The acylation of acid (II) with (V) as before also gives (VII).
| 【1】 Kim, D.H.; et al.; Mercaptopropanoyl)indoline-2-carboxylic acids and related compounds as potent angiotensin converting enzyme inhibitors and antihypertensive agents. J Med Chem 1983, 26, 3, 394-403. |
| 【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; WY-44221. Drugs Fut 1983, 8, 11, 953. |
| 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) | 34675 | 2-methoxyethylamine; 2-methoxy-1-ethanamine | 109-85-3 | C3H9NO | 详情 | 详情 |
| (I) | 34308 | ethyl (2S)-2,3-dihydro-1H-indole-2-carboxylate | C11H13NO2 | 详情 | 详情 | |
| (II) | 34307 | (2S)-2,3-dihydro-1H-indole-2-carboxylic acid | C9H9NO2 | 详情 | 详情 | |
| (III) | 34309 | S-[(2S)-3-chloro-2-methyl-3-oxopropyl] benzenecarbothioate | C11H11ClO2S | 详情 | 详情 | |
| (IV) | 36214 | (2S)-1-[(2R)-3-(benzoylsulfanyl)-2-methylpropanoyl]-2,3-dihydro-1H-indole-2-carboxylic acid | C20H19NO4S | 详情 | 详情 | |
| (V) | 33553 | 2-methylacryloyl chloride | 920-46-7 | C4H5ClO | 详情 | 详情 |
| (VI) | 36211 | ethyl (2S)-1-methacryloyl-2,3-dihydro-1H-indole-2-carboxylate | C15H17NO3 | 详情 | 详情 | |
| (VII) | 36212 | (2S)-1-methacryloyl-2,3-dihydro-1H-indole-2-carboxylic acid | C13H13NO3 | 详情 | 详情 | |
| (VIII) | 36213 | benzenecarbothioic S-acid | 98-91-9 | C7H6OS | 详情 | 详情 |