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【结 构 式】 
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【分子编号】56817 【品名】(2S)-2-{[4-({[(6S)-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：(VI)The stereospecific synthesis for the title chiral compound was developed, based on the enzymatic reduction of dihydrofolate (V). Reduction of folic acid (IV) to dihydrofolate (V) was effected by means of either sodium dithionite or zinc dust and NaOH. Dihydrofolate reductase-catalyzed asymmetric reduction of (V) in the presence of several recycling enzymes for the reducing cofactor NADPH furnished (6S)-tetrahydrofolate (VI), which was subsequently isolated as the 5,10-methenyl derivative (III) upon treatment with formic acid and trifluoroacetic acid. Aqueous hydrolysis of (III) at a pH of 6.5-6.9 led to the title 5-formyl compound. The chiral (6S)-tetrahydrofolate (VI) has also been obtained by fractional crystallization of the sulfate and several sulfonate salts of the diastereomeric mixture of (6R,S)-tetrahydrofolates from a polar medium.
| 【1】 Stover, P.; Schirch, V.; Synthesis of (6S)-5-formyltetrahydropteroyl-polyglutamates and interconversion to other reduced pteroylpolyglutamate derivatives. Anal Biochem 1992, 202, 1, 82. |
| 【2】 Rees, L.; et al.; Asymmetric reduction of dihydrofolate using dihydrofolate reductase and chiral boron-containing compounds. Tetrahedron 1986, 42, 1, 117. |
| 【3】 Kuge, Y.; et al.; Large-scale chemoenzymatic synthesis of calcium (6S)-5-formyl-5,6,7,8-tetrahydrofolate [(-)-leucovorin] using the NADPH recycling method. J Chem Soc - Perkins Trans I 1994, 11, 1427. |
| 【4】 Uwajima, T.; et al.; Chemo-enzymatic synthesis of optically pure l-leucovorin, an augmentor of 5-fluorouracil cytotoxicity against cancer. Biochem Biophys Res Commun 1990, 171, 2, 684. |
| 【5】 Ulmann, M.; Conti, J.; Muller, H.R.; Murdel, G.; Process for the preparation of (6S)- and (6R)-tetrahydrofolic acid. EP 0495204 . |
| 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 | |
| (V) | 56816 | (2S)-2-[(4-{[(2-amino-4-oxo-1,4,7,8-tetrahydro-6-pteridinyl)methyl]amino}benzoyl)amino]pentanedioic acid | C19H21N7O6 | 详情 | 详情 | |
| (VI) | 56817 | (2S)-2-{[4-({[(6S)-2-amino-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}pentanedioic acid | C19H23N7O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Oxidation of the triamino pyrimidinone system (XX) by means of iodine produced the intermediate ortho-iminoquinone (XXI), which underwent hydrolysis to dione (XXII). Subsequent cyclization of (XXII) under controlled conditions led to the chiral tetrahydrofolic acid (VI). Finally, regioselective N5-formylation of (VI) was accomplished by treatment with formic acid and carbonyl diimidazole.
| 【1】 Bailey, S.W.; et al.; Synthesis of tetrahydropteridine C6-stereoisomers, including N5-formyl-(6S)-tetrahydrofolic acid. J Org Chem 1992, 57, 16, 4470. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 56817 | (2S)-2-{[4-({[(6S)-2-amino-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}pentanedioic acid | C19H23N7O6 | 详情 | 详情 | |
| (XX) | 56829 | (2S)-2-{[4-({(2S)-2-amino-3-[(2,5-diamino-6-oxo-3,6-dihydro-4-pyrimidinyl)amino]propyl}amino)benzoyl]amino}pentanedioic acid | C19H26N8O6 | 详情 | 详情 | |
| (XXI) | 56830 | (2S)-2-{[4-({(2S)-2-amino-3-[(2-amino-5-imino-6-oxo-5,6-dihydro-4-pyrimidinyl)amino]propyl}amino)benzoyl]amino}pentanedioic acid | C19H24N8O6 | 详情 | 详情 | |
| (XXII) | 56831 | (2S)-2-{[4-({(2S)-2-amino-3-[(2-amino-5,6-dioxo-5,6-dihydro-4-pyrimidinyl)amino]propyl}amino)benzoyl]amino}pentanedioic acid | C19H23N7O7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIIa)In an alternative enzymatic synthesis, exposure of the diastereoisomeric (6R,S)-tetrahydrofolates (VIIa-b), with a recombinant enzymatic domain as the source of 10-formyltetrahydrofolate synthetase activity, led to the diastereoselective formylation the (6S) tetrahydrofolate at the 10-N (XXIV), while leaving unchanged the unnatural (6R) isomer (XXIII). The chiral 10-formyl tetrahydrofolate (XXIV) was subsequently isomerized to (6S)-5-formyltetrahydrofolate either under acidic conditions, via formation of the intermediate 5,10-methenyl derivative (III) (22), or in the presence of a source of cyclohydrolase activity.
| 【1】 Pelletier, J.N.; McKenzie, R.E.; Methenyltetrahydrofolate cyclohydrolase catalyzes the synthesis of (6S)-5-formyltetrahydrofolate. Bioorg Chem 1996, 24, 3, 220. |
| 【2】 Schlingmann, G.; Rosenfeld, S.A. (Wyeth); Process for the preparation of optically pure diastereoisomers of tetrahydrofolate cpds.. EP 0432441 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIa) | 56817 | (2S)-2-{[4-({[(6S)-2-amino-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}pentanedioic acid | C19H23N7O6 | 详情 | 详情 | |
| (VIIb),(XXIII) | 56832 | (2S)-2-{[4-({[(6R)-2-amino-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}pentanedioic acid | C19H23N7O6 | 详情 | 详情 | |
| (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 | |
| (XXIV) | 56833 | (2S)-2-({4-[{[(6R)-2-amino-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}(formyl)amino]benzoyl}amino)pentanedioic acid | C20H23N7O7 | 详情 | 详情 |