|
【结 构 式】 
|
【分子编号】12329 【品名】(2R,3S)-3-Amino-4-cyclohexyl-2-hydroxybutyric acid 【CA登记号】 |
【 分 子 式 】C10H19NO3 【 分 子 量 】201.2658 【元素组成】C 59.68% H 9.52% N 6.96% O 23.85% |
合成路线1
该中间体在本合成路线中的序号：(XVIII)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：(IX)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 |
合成路线3
该中间体在本合成路线中的序号：(XIX)Cyclohexylalanine (XIV) was protected as the Boc derivative (XV) and then coupled with N,O-dimethylhydroxylamine to produce the Weinreb amide (XVI). Reduction of (XVI) with LiAlH4 at -78 C gave aldehyde (XVII) and subsequent addition of tert-butyl isonitrile furnished hydroxy amide (XVIII). After acid hydrolysis of (XVIII), amino acid (XIX) was protected as the N-Boc derivative (XX). This was coupled with benzodioxolylmethyl amine (XXI) yielding amide (XXII). Acid deprotection of the Boc group of (XXII) gave (XXIII), which was further coupled with dipeptide (VII) to generate tripeptide amide (XXIV). Following hydrogenolytic deprotection of the N-nitro group of (XXIV), Swern oxidation of the alcohol group gave rise to the title compound.
| 【1】 Semple, J.E.; et al.; Novel, potent, and selective factor Xa inhibitors featuring a hydrophobic P1-ketoamide moiety. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 193. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIII | 39362 | (3S)-3-amino-N-(1,3-benzodioxol-5-ylmethyl)-4-cyclohexyl-2-hydroxybutanamide | C18H26N2O4 | 详情 | 详情 | |
| (VII) | 39350 | C16H24N6O7S | 详情 | 详情 | ||
| (XIV) | 39357 | (2S)-2-amino-3-cyclohexylpropionic acid; L-Cyclohexylalanine | 27527-05-5 | C9H17NO2 | 详情 | 详情 |
| (XV) | 23050 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropionic acid | C14H25NO4 | 详情 | 详情 | |
| (XVI) | 39358 | tert-butyl (1S)-1-(cyclohexylmethyl)-2-[methoxy(methyl)amino]-2-oxoethylcarbamate | C16H30N2O4 | 详情 | 详情 | |
| (XVII) | 15853 | tert-butyl N-[(1S)-2-cyclohexyl-1-formylethyl]carbamate | C14H25NO3 | 详情 | 详情 | |
| (XVIII) | 39359 | tert-butyl (1S)-3-(tert-butylamino)-1-(cyclohexylmethyl)-2-hydroxy-3-oxopropylcarbamate | C19H36N2O4 | 详情 | 详情 | |
| (XIX) | 12329 | (2R,3S)-3-Amino-4-cyclohexyl-2-hydroxybutyric acid | C10H19NO3 | 详情 | 详情 | |
| (XX) | 39360 | (3S)-3-[(tert-butoxycarbonyl)amino]-4-cyclohexyl-2-hydroxybutyric acid | C15H27NO5 | 详情 | 详情 | |
| (XXI) | 33669 | 1,3-benzodioxol-5-ylmethylamine; 1,3-benzodioxol-5-ylmethanamine; 3,4-Methylendioxybenzylamine | 2620-50-0 | C8H9NO2 | 详情 | 详情 |
| (XXII) | 39361 | tert-butyl (1S)-3-[(1,3-benzodioxol-5-ylmethyl)amino]-1-(cyclohexylmethyl)-2-hydroxy-3-oxopropylcarbamate | C23H34N2O6 | 详情 | 详情 | |
| (XXIV) | 39363 | C34H48N8O10S | 详情 | 详情 |