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【结 构 式】 
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【分子编号】56814 【品名】(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 【CA登记号】 |
【 分 子 式 】C20H22N7O6 【 分 子 量 】456.43826 【元素组成】C 52.63% H 4.86% N 21.48% O 21.03% |
合成路线1
该中间体在本合成路线中的序号：(IIb),(III)The title compound was isolated by fractional crystallization of the diastereoisomeric mixture of calcium (6R,S)-folinate (Ia-b). This separation has been further improved with the addition of sodium EDTA. The separation of (6R,S) folinic acid has also been described by fractional crystallization of several diamine or polyamine salts of the diastereomeric mixture or by preparative chromatography. Alternatively, the fractional crystallization of 5,10-methenyl-(6R,S)-tetrahydrofolic acid (IIa-b) furnished isomer (III), which was subsequently hydrolyzed to the title compound at a pH of 5.5 to 6.5 in the presence of calcium chloride.
| 【1】 Felder, E.; Ripa, G.; Distaso, C. (Bracco SpA; Dibra SpA); A process for the preparation and separation of diastereomeric salts of folinic acid. US 5710271; WO 9533749 . |
| 【2】 Ambrosini, L.; Sala, B.; Method for the industrial preparation of (6S) folic acid derivs. by chromatographic separation. EP 0627435 . |
| 【3】 Ulmann, M.; Conti, J.; Muller, H.R.; Murdel, G.; Process for the separation of folinic acid. EP 0367902; US 5010194 . |
| 【4】 Felder, E.; Ripa, G.; Piva, R. (Bracco SpA); Process for separating stereoisomers of folinic acid. WO 9317022 . |
| 【5】 Vecchi, G.; A process for the separation of folinic acids. WO 9315076 . |
| 【6】 Vecchi, G.; A process for the preparation of substd. tetrahydrofolic derivs. in the 6(R,S)(-) forms and of their active 6(S)(-) N5 diastereoisomers in form of alkali and earth alkali metal salts. EP 0537842 . |
| 【7】 Mueller, H.R.; Ulmann, M.; Conti, J.; Muerdel, G.; Process for separation of folinic acids. WO 8808844 . |
| 【8】 Ulmann, M.; Conti, J.; Muller, H.R.; Murdel, G.; Process for the preparation of tetrahydrofolates. EP 0348641; US 5006655 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Ia) | 56811 | calcium (2S)-2-{[4-({[(6S)-2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}pentanedioate | C20H21CaN7O7 | 详情 | 详情 | |
| (Ib) | 56812 | calcium (2S)-2-{[4-({[(6R)-2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}pentanedioate | C20H21CaN7O7 | 详情 | 详情 | |
| (IIa) | 56813 | (6aS)-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 | |
| (IIb),(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 |
合成路线2
该中间体在本合成路线中的序号：(III)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3
该中间体在本合成路线中的序号：(III)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 |
合成路线4
该中间体在本合成路线中的序号：(III)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 |
合成路线5
该中间体在本合成路线中的序号：(IIb)The cyclic orthoamide (XXVa-b) was prepared from either the diastereomeric mixture of 5,10-methenyl-(6R,S)-tetrahydrofolic acids (IIa-b) or from calcium (6R,S)-folinate (Ia-b) in a formic acid/ammonium formate buffer at a pH of 2.3. After isolation of the pure (6S) diastereoisomer (XXV) by repeated recrystallization from aqueous formic acid, the orthoamide function was hydrolyzed employing a buffered solution of tris(hydroxymethyl)aminomethane at a pH of 7.3 to furnish the title compound.
| 【1】 Marazza, F.; Melera, A.; Viterbo, R.; Diastereoisomeric cpds. derived from tetrahydrofolic acid, process for their preparation and use in the synthesis of diastereoisomers 6S and 6R of reduced folates. FR 2659330; US 5239074; WO 9113890 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Ia) | 56811 | calcium (2S)-2-{[4-({[(6S)-2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}pentanedioate | C20H21CaN7O7 | 详情 | 详情 | |
| (Ib) | 56812 | calcium (2S)-2-{[4-({[(6R)-2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl]methyl}amino)benzoyl]amino}pentanedioate | C20H21CaN7O7 | 详情 | 详情 | |
| (IIa) | 56813 | (6aS)-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 | |
| (IIb) | 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 | |
| (XXVa) | 56834 | (2S)-2-({4-[(8aR)-5-amino-1,7,8,8a-tetrahydro-3-oxa-2,4,6,7,8b-pentaazacyclopenta[bc]acenaphthylen-2(2aH)-yl]benzoyl}amino)pentanedioic acid | C20H21N7O6 | 详情 | 详情 | |
| (XXVb) | 56835 | (2S)-2-({4-[(8aS)-5-amino-1,7,8,8a-tetrahydro-3-oxa-2,4,6,7,8b-pentaazacyclopenta[bc]acenaphthylen-2(2aH)-yl]benzoyl}amino)pentanedioic acid | C20H21N7O6 | 详情 | 详情 |