(1S,2R,4R)-2-[(chlorocarbonyl)oxy]-1-isopropyl-4-methylcyclohexane -Drug Synthesis Database

【结构式】

【分子编号】46777

【品名】(1S,2R,4R)-2-[(chlorocarbonyl)oxy]-1-isopropyl-4-methylcyclohexane

【CA登记号】14602-86-9

【分子式】C₁₁H₁₉ClO₂

【分子量】218.72336

【元素组成】C 60.41% H 8.76% Cl 16.21% O 14.63%

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：(VIII)

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

合成路线2

该中间体在本合成路线中的序号：(IV)

Dehydroxylation of compound (I) by hydrogenation over Pd/C in MeOH provides tetralinecarboxylic acid methyl ester (II), which is then reduced by means of LiAlH4 in THF to afford tetralinemethanol as a mixture of enantiomers (III). Separation of isomers in (III) is then achieved by first acylation of the alcohol with (-)-menthyl chloroformate (IV) in pyridine, followed by the separation of the two resulting diastereomers by recrystallization to give (-)-menthyl carbonate (V) and its subsequent hydrolysis with NaOH in THF/H2O to furnish compound (VI).

参考文献中间体

合成目标

【1】 Tsubaki, K.; Hattori, K.; Tabuchi, S.; Okitsu, O.; Sakane, K.; Tanaka, H.; Taniguchi, K.; A novel pyridazinone derivative as a nonprostanoid PGI2 agonist. Bioorg Med Chem Lett 2000, 10, 24, 2787.
【2】 Taniguchi, K.; Nagano, M.; Hattori, K.; Tsubaki, K.; Okitsu, O.; Tabuchi, S. (Fujisawa Pharmaceutical Co., Ltd.); Naphthalene derivs. as prostaglandin I2 agonists. EP 0749424; JP 1997509958; US 5763489; WO 9524393 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	46774	methyl (1R,2S)-1-hydroxy-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenecarboxylate		C₁₃H₁₆O₄	详情	详情
(II)	46775	methyl (2S)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenecarboxylate		C₁₃H₁₆O₃	详情	详情
(III)	46776	(5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)methanol		C₁₂H₁₆O₂	详情	详情
(IV)	46777	(1S,2R,4R)-2-[(chlorocarbonyl)oxy]-1-isopropyl-4-methylcyclohexane	14602-86-9	C₁₁H₁₉ClO₂	详情	详情
(V)	46778	(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl [(2S)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]methyl carbonate		C₂₃H₃₄O₄	详情	详情
(VI)	46779	[(2S)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]methanol		C₁₂H₁₆O₂	详情	详情
(VII)	46780	1,1-diphenylacetone	781-35-1	C₁₅H₁₄O	详情	详情
(VIII)	15618	2-Oxoacetic acid; Glyoxylic Acid	298-12-4	C₂H₂O₃	详情	详情
(IX)	46781	2-hydroxy-4-oxo-5,5-diphenylpentanoic acid		C₁₇H₁₆O₄	详情	详情
(X)	46782	6-benzhydryl-1,6-dihydro-3(2H)-pyridazinone		C₁₇H₁₆N₂O	详情	详情
(XI)	46783	6-benzhydryl-2-[[(2S)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]methyl]-1,6-dihydro-3(2H)-pyridazinone		C₂₉H₃₀N₂O₂	详情	详情
(XII)	46784	6-benzhydryl-2-[[(2S)-5-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl]methyl]-1,6-dihydro-3(2H)-pyridazinone		C₂₈H₂₈N₂O₂	详情	详情
(XIII)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(XIV)	46785	ethyl 2-[((6S)-6-[[3-benzhydryl-6-oxo-3,6-dihydro-1(2H)-pyridazinyl]methyl]-5,6,7,8-tetrahydro-1-naphthalenyl)oxy]acetate		C₃₂H₃₄N₂O₄	详情	详情

Extended Information