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【结 构 式】 
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【分子编号】56813 【品名】(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 【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：(IIa)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：(IIa)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 |