【结 构 式】 |
【分子编号】56819 【品名】(2S)-2-[(4-{[(2-amino-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl)methyl]amino}benzoyl)amino]pentanedioic acid 【CA登记号】 |
【 分 子 式 】C19H23N7O6 【 分 子 量 】445.4352 【元素组成】C 51.23% H 5.2% N 22.01% O 21.55% |
合成路线1
该中间体在本合成路线中的序号:(VII)Alternatively, folic acid (IV) was chemically reduced to the (6R,S)-epimeric mixture of tetrahydrofolates (VII) with sodium borohydride in aqueous NaOH. After derivatization of (VII) with (-)-menthyl chloroformate (VIII), the desired (6S) carbamate (IX) was isolated in high diastereoisomeric purity, taking advantage of the different solubility of the diastereoisomers in n-butanol. The menthyloxycarbonyl derivative (IX) was converted to the 5,10-methenyltetrahydrofolate (III) using a mixture of formic acid and acetic acid, saturated with HBr. The cyclic formamidinium salt (III) was then hydrolyzed to the 5-formyl compound, which was finally converted to the corresponding calcium salt. In a closely related method, folic acid (IV) was hydrogenated in the presence of rhodium (I) catalysts supported on an optically active phosphane to provide a diastereomeric mixture of tetrahydrofolate epimers (VII) with moderate diastereomeric excess of the desired (6S) isomer. After derivatization with menthyl chloroformate, the resultant mixture of epimeric mono- and bis-menthyl carbamates was separated using preparative HPLC. The target carbamate (IX) was then converted into the title compound as outlined above.
【1】 Brunner, H.; Rosenboem, S.; Enantioselective catalyses CXXXV [1]. Stereoselective hydrogenation of folic acid and 2-methylquinoxaline with optically active rhodium(I)-phosphane complexes. Monatsh Chem 2000, 131, 12, 1371. |
【2】 Owens, J.; et al.; The preparation of the (6R)- and (6S)-diastereoisomers of 5-formyltetrahydrofolate (leucovorin). J Chem Soc - Perkins Trans I 1993, 7, 871. |
【3】 Brunner, H.; Huber, C.; Asymmetric Catalysis, 67. Diastereoselective hydrogenation of folic acid with optically active rhodium(I)-diphosphane complexes. Chem Ber 1992, 125, 9, 2085. |
【4】 Brunner, H.; et al.; Asymmetric catalysis, 105. Stereoselective hydrogenation of folic acid with immobilized optically active rhodium(I)/diphosphane catalysts. Chem Ber 1997, 130, 1, 55. |
【5】 Rees, L.; et al.; A simple and effective method for preparation of the 6(R)- and 6(S)-diastereoisomers of 5-formyltetrahydrofolate (leucovorin). J Chem Soc Chem Commun 1987, 6, 470. |
【6】 Wood, H.C.S.; Rees, L.; Suckling, C.J. (University of Strathclyde); Optically active pteridine derivs.. EP 0266042; EP 1275393; US 2002198212; US 6500829 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(III) | 56814 | (6aR)-3-amino-8-[4-({[(1S)-1,3-dicarboxypropyl]amino}carbonyl)phenyl]-1-oxo-1H,4H,5H,6H,6aH,7H,8H-imidazo[1,5-f]pteridin-10-ium | C20H22N7O6 | 详情 | 详情 | |
(IV) | 56815 | (2S)-2-[(4-{[(2-amino-4-oxo-1,4-dihydro-6-pteridinyl)methyl]amino}benzoyl)amino]pentanedioic acid | C19H19N7O6 | 详情 | 详情 | |
(VII) | 56819 | (2S)-2-[(4-{[(2-amino-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl)methyl]amino}benzoyl)amino]pentanedioic acid | C19H23N7O6 | 详情 | 详情 | |
(VIII) | 46777 | (1S,2R,4R)-2-[(chlorocarbonyl)oxy]-1-isopropyl-4-methylcyclohexane | 14602-86-9 | C11H19ClO2 | 详情 | 详情 |
(IX) | 56818 | (2S)-2-{[4-({[(6S)-2-amino-5-({[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy}carbonyl)-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}pentanedioic acid | C30H41N7O8 | 详情 | 详情 |