【结 构 式】 |
【药物名称】Delapril hydrochloride, REV-6000A, CV-3317, Delaket, Cupressin, Adecut 【化学名称】(S)-N-(2,3-Dihydro-1H-inden-2-yl)-N-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]glycine monohydrochloride 【CA登记号】83435-67-0, 83435-66-9 (free base), 83435-62-5 (monoHBr) 【 分 子 式 】C26H33ClN2O5 【 分 子 量 】489.01631 |
【开发单位】Takeda (Originator), Chiesi (Licensee) 【药理作用】Angina pectoris, Treatment of, CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Angiotensin-I Converting Enzyme (ACE) Inhibitors |
合成路线1
The reductocondensation of ethyl glycinate (I) with 2-indanone (II) by means of sodium cyanoborohydride in methanol gives ethyl N-(2-indanyl)glycinate (III), which is condensed with N-benzyloxycarbonyl-L-alanine (IV) by means of isobutyl chlorocarbonate and triethylamine in THF yielding N-(N-benzyloxycarbonyl-L-alanyl)-N-(2-indanyl)glycine ethyl ester (V). The partial hydrolysis of (V) with NaOH in methanol affords N-(N-benzyloxycarbonyl-L-alanyl)-N-(2-indanyl)glycine (VI), which is deprotected by hydrogenolysis with H2 over Pd/C in ethanol giving N-(L-alanyl)-N-(2-indanyl)glycine (VII). Finally, this compound is reductocondensed with ethyl 2-oxo-4-phenylbutanoate (VIII) by means of sodium cyanoborohydride in ethanol.
【1】 Oka, Y.; Nishikawa, K.; Miyake, A. (Takeda Chemical Industries, Ltd.); Bicyclic compounds, their production and use. EP 0051391; GB 2086393; JP 82179141; JP 8277651; US 4385051 . |
【2】 Serradell, M.N.; Castaner, J.; CV-3317. Drugs Fut 1984, 9, 5, 324. |
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) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
(II) | 30550 | 1,3-dihydro-2H-inden-2-one | 615-13-4 | C9H8O | 详情 | 详情 |
(III) | 30551 | ethyl 2-(2,3-dihydro-1H-inden-2-ylamino)acetate | C13H17NO2 | 详情 | 详情 | |
(IV) | 61209 | CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine | C11H13NO4 | 详情 | 详情 | |
(V) | 30552 | ethyl 2-[((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)(2,3-dihydro-1H-inden-2-yl)amino]acetate | C24H28N2O5 | 详情 | 详情 | |
(VI) | 30553 | 2-[((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)(2,3-dihydro-1H-inden-2-yl)amino]acetic acid | C22H24N2O5 | 详情 | 详情 | |
(VII) | 30554 | 2-[[(2S)-2-aminopropanoyl](2,3-dihydro-1H-inden-2-yl)amino]acetic acid | C14H18N2O3 | 详情 | 详情 | |
(VIII) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
合成路线2
The reductocondensation of (II) with tert-butyl glycinate (IX) by means of sodium cyanoborohydride in ethanol gives tert-butyl-N-(2-indanyl)glycinate (X), which is condensed with (IV) by means of isobutyl chlorocarbonate as before yielding tert-butyl-N-[N-(tert-butoxycarbonyl)-L-alanyl]-N-(2-indanyl)glycinate (XI). Deprotection of (XI) by hydrogenolysis with H2 over Pd/C in methanol affords tert-butyl N-(L-alanyl)-N-(2-indanyl)glycinate (XII), which is reductocondensed with (VIII) using H2 and Raney-Ni in ethanol to afford tert-butyl N-[N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-N-(2-indanyl)glycinate (XIII). Finally, this compound is saponified with HBr in acetic acid.
【1】 Oka, Y.; Nishikawa, K.; Miyake, A. (Takeda Chemical Industries, Ltd.); Bicyclic compounds, their production and use. EP 0051391; GB 2086393; JP 82179141; JP 8277651; US 4385051 . |
【2】 Serradell, M.N.; Castaner, J.; CV-3317. Drugs Fut 1984, 9, 5, 324. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(II) | 30550 | 1,3-dihydro-2H-inden-2-one | 615-13-4 | C9H8O | 详情 | 详情 |
(IV) | 61209 | CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine | C11H13NO4 | 详情 | 详情 | |
(VIII) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
(IX) | 27841 | tert-butyl 2-aminoacetate;tert-butyl glycinate;Glycine tert-butyl ester | 6456-74-2 | C6H13NO2 | 详情 | 详情 |
(X) | 30555 | tert-butyl 2-(2,3-dihydro-1H-inden-2-ylamino)acetate | C15H21NO2 | 详情 | 详情 | |
(XI) | 30556 | tert-butyl 2-[((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)(2,3-dihydro-1H-inden-2-yl)amino]acetate | C26H32N2O5 | 详情 | 详情 | |
(XII) | 30557 | tert-butyl 2-[[(2S)-2-aminopropanoyl](2,3-dihydro-1H-inden-2-yl)amino]acetate | C18H26N2O3 | 详情 | 详情 | |
(XIII) | 30558 | ethyl (2S)-2-([(1S)-2-[[2-(tert-butoxy)-2-oxoethyl](2,3-dihydro-1H-inden-2-yl)amino]-1-methyl-2-oxoethyl]amino)-4-phenylbutanoate | C30H40N2O5 | 详情 | 详情 |