(2S)-2-[(4-{[(2-amino-4-oxo-1,4-dihydro-6-pteridinyl)methyl]amino}benzoyl)amino]pentanedioic acid -Drug Synthesis Database

【结构式】

【分子编号】56815

【品名】(2S)-2-[(4-{[(2-amino-4-oxo-1,4-dihydro-6-pteridinyl)methyl]amino}benzoyl)amino]pentanedioic acid

【CA登记号】

【分子式】C₁₉H₁₉N₇O₆

【分子量】441.40344

【元素组成】C 51.7% H 4.34% N 22.21% O 21.75%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

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.

参考文献中间体

合成目标

【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	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：(IV)

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.

参考文献中间体

合成目标

【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

Extended Information