|
【结 构 式】 
|
【分子编号】12323 【品名】isopropyl (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutanoate 【CA登记号】 |
【 分 子 式 】C13H25NO3 【 分 子 量 】243.34644 【元素组成】C 64.16% H 10.35% N 5.76% O 19.72% |
合成路线1
该中间体在本合成路线中的序号：(II)2) Synthesis of (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester (II): Phenylalanine methyl ester (XIII) is protected with isopropyl chloroformate and triethylamine in THF to give N-(isopropoxycarbonyl)phenylalanine methyl ester (XIV), which is reduced with NaBH4 - LiCl in THF - ethanol, yielding N-(isopropoxycarbonyl)phenylalaninol (XV). The hydrogenation of (XV) with H2 over Rh/Al2O3 in methanol affords N-(isopropoxycarbonyl)cyclohexylalaninol (XVI), which is oxidized with pyridine - SO3 in DMSO to the corresponding aldehyde (XVII). The reaction of (XVII) with NaCN - HCl in CHCl3 - water affords (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid (XVIII), which is finally esterified with isopropanol - HCl to give (II). 3) Synthesis of KRY-1314: By condensation of N(tau)-tert-butoxycarbonyl-N(alpha)-[2(R)-(morpholinocarbonylmethyl)-3-(1-naphthyl)propionyl]histidine (I) with (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester (II) by means of dicyclohexylcarbodiimide (DCC) and N-hydroxy-5-norbornene-2,3-dicarboximide (HONB) in acetonitrile - triethylamine.
| 【1】 Harada, H.; Iyobe, A.; Tsubaki, A.; Yamaguchi, T.; Kamijo, T.; Kiso, Y.; Iizuka, K.; Hirata, K.; A practical synthesis of an orally potent renin inhibitor, isopropyl (2R,3S)-4-cyclohexyl-2-hydroxy-3-[N-[(2R)-2-morpholinocarbonylmethyl-3-(1-naaphthyl)propionyl]-L-histidyl]aminobutyrate. J Chem Soc - Perkins Trans I 1990, 9, 2497-500. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 26492 | 2-[(chlorocarbonyl)oxy]propane | 108-23-6 | C4H7ClO2 | 详情 | 详情 | |
| (I) | 12312 | (2S)-3-[1-(tert-Butoxycarbonyl)-1H-imidazol-5-yl]-2-[[(2R)-4-(4-morpholinyl)-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propionic acid | C30H36N4O7 | 详情 | 详情 | |
| (II) | 12323 | isopropyl (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutanoate | C13H25NO3 | 详情 | 详情 | |
| (XIII) | 12324 | methyl (2R)-2-amino-3-phenylpropanoate | 21685-51-8 | C10H13NO2 | 详情 | 详情 |
| (XIV) | 12325 | methyl (2S)-2-[(isopropoxycarbonyl)amino]-3-phenylpropanoate | C14H19NO4 | 详情 | 详情 | |
| (XV) | 12326 | isopropyl N-[(1S)-1-benzyl-2-hydroxyethyl]carbamate | C13H19NO3 | 详情 | 详情 | |
| (XVI) | 12327 | isopropyl N-[(1S)-2-cyclohexyl-1-(hydroxymethyl)ethyl]carbamate | C13H25NO3 | 详情 | 详情 | |
| (XVII) | 12328 | isopropyl N-[(1S)-2-cyclohexyl-1-formylethyl]carbamate | C13H23NO3 | 详情 | 详情 | |
| (XVIII) | 12329 | (2R,3S)-3-Amino-4-cyclohexyl-2-hydroxybutyric acid | C10H19NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)By condensation of N-[3-(morpholinocarbonyl)-2(R)-(1-naphthylmethyl)propionyl-L-histidine methyl ester (I) with isopropyl 3(S)-amino-4-cyclohexyl-2(R)-hydroxybutyrate (II) by means of diphenyl phosphoryl azide (DPA) in DMF. The starting products are prepared as follows: The condensation of 3-(morpholinocarbonyl)-2(R)-(1-naphthylmethyl)propionic acid (III) and histidine methyl ester (IV) by means of DPA in DMF gives the substituted histidine ester (I). The hydrogenation of N-(tert-butoxycarbonyl)-L-phenylalanine (V) with H2 over Rh/Al2O3 gives N-(tert-butoxycarbonyl)-L-cyclohexylalanine (VI), which is reduced with borane to the corresponding alaninol (VII). Controlled oxidation of (VII) with SO3-pyridine in benzene-DMSO affords N-(tert-butoxycarbonyl)-L-cyclohexylalaninal (VIII), which by treatment with KCN followed by hydrolysis with concentrated HCl yields 3-amino-4-cyclohexyl-2-hydroxybutyric acid (IX). Finally, this compound is esterified with isopropanol and hydrochloric acid to the starting ester (II).
| 【1】 108th Annu Meet Pharm Soc Jpn (April 4-7, Hiroshima) 1988, Abst 5e06 11-3. |
| 【2】 Khandewal, Y.; Rajgopalan, R.; Dohadwalla, A.N.; Rupp, R.H.; De Souza, N.J. (Aventis SA); 7-Acyloxy-6-aminoacyloxypolyoxylabdanes, process for their preparation and their use. DE 3623300; EP 0252482; JP 1988023878 . |
| 【3】 Castaner, J.; Prous, J.; KRI-1314. Drugs Fut 1988, 13, 12, 1042. |
| 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) | 23045 | methyl (2S)-3-(1H-imidazol-4-yl)-2-[[(2R)-4-(4-morpholinyl)-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propanoate | C26H30N4O5 | 详情 | 详情 | |
| (II) | 12323 | isopropyl (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutanoate | C13H25NO3 | 详情 | 详情 | |
| (III) | 12864 | (2R)-4-(4-Morpholinyl)-2-(1-naphthylmethyl)-4-oxobutyric acid | C19H21NO4 | 详情 | 详情 | |
| (IV) | 23048 | methyl (2S)-2-amino-3-(1H-imidazol-4-yl)propanoate | C7H11N3O2 | 详情 | 详情 | |
| (V) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (VI) | 23050 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropionic acid | C14H25NO4 | 详情 | 详情 | |
| (VII) | 23051 | tert-butyl (1S)-2-cyclohexyl-1-(hydroxymethyl)ethylcarbamate | C14H27NO3 | 详情 | 详情 | |
| (VIII) | 15853 | tert-butyl N-[(1S)-2-cyclohexyl-1-formylethyl]carbamate | C14H25NO3 | 详情 | 详情 | |
| (IX) | 12329 | (2R,3S)-3-Amino-4-cyclohexyl-2-hydroxybutyric acid | C10H19NO3 | 详情 | 详情 |