(2S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid -Drug Synthesis Database

【结构式】

【分子编号】21154

【品名】(2S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid

【CA登记号】

【分子式】C₁₆H₁₆O₄

【分子量】272.30064

【元素组成】C 70.57% H 5.92% O 23.5%

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：(IX)

The condensation of benzophenone (I) with chloroacetic acid methyl ester (II) by means of sodium methoxide in THF gives the epoxide (III), which is treated with methanol/BF3.Et2O, yielding 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester (IV). The condensation of (IV) with 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine (V) by means of K2CO3 in DMF affords 2-(4,6-dimethoxypyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid methyl ester (VI), which is hydrolyzed with NaOH in hot dioxane/water to give the corresponding free acid (VII). Finally, this compound is submitted to optical resolution, affording LU-135252. Optical resolution of (VIII), the free acid derivative of (IV), with (R)-phenylethylamine, L-proline methyl ester, (S)-1-(4-nitrophenyl)ethylamine or (S)-1-(4--chlorophenyl)ethylamine leads to the enantiomerically pure (S)-enatiomer (IX), which by reaction with 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine (V) directly affords LU-135252.

参考文献中间体

合成目标

【1】 Jansen, R.; et al.; Structural similarity and its suprises: Endothelin receptor antagonists - Process research and development report. Org Process Res Dev 2001, 5, 1, 16.
【2】 Riechers, H.; Albrecht, H.-P.; Amberg, W.; et al.; Discovery and optimization of a novel class of orally active nonpeptidic endothelin-A receptor antagonists. J Med Chem 1996, 39, 11, 2123.
【3】 Silvestre, J.S.; Sorbera, L.A.; Castañer, J.; LU-135252. Drugs Fut 1999, 24, 2, 141.
【4】 Riechers, H.; Klinge, D.; Amberg, W.; Kling, A.; Müller, S.; Baumann, E.; Rheinheimer, J.; Vogelbacher, U.J.; Wernet, W.; Unger, L.; Raschack, M. (BASF AG); New carboxylic acid derivs., their preparation and their use. EP 0785926; JP 1998507190; WO 9611914 .

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)	18732	benzophenone	119-61-9	C₁₃H₁₀O	详情	详情
(III)	21148	methyl 3,3-diphenyl-2-oxiranecarboxylate		C₁₆H₁₄O₃	详情	详情
(IV)	21149	methyl 2-hydroxy-3-methoxy-3,3-diphenylpropanoate		C₁₇H₁₈O₄	详情	详情
(V)	21150	4,6-dimethoxy-2-(methylsulfonyl)pyrimidine; 4,6-dimethoxy-2-pyrimidinyl methyl sulfone		C₇H₁₀N₂O₄S	详情	详情
(VI)	21151	methyl 2-[(4,6-dimethoxy-2-pyrimidinyl)oxy]-3-methoxy-3,3-diphenylpropanoate		C₂₃H₂₄N₂O₆	详情	详情
(VII)	21152	2-[(4,6-dimethoxy-2-pyrimidinyl)oxy]-3-methoxy-3,3-diphenylpropionic acid		C₂₂H₂₂N₂O₆	详情	详情
(VIII)	21153	2-hydroxy-3-methoxy-3,3-diphenylpropionic acid		C₁₆H₁₆O₄	详情	详情
(IX)	21154	(2S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid		C₁₆H₁₆O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The esterification of 2(S)-hydroxy-3-methoxy-3,3-diphenylpropionic acid (I) with NaOMe and dimethyl sulfate gives the methyl ester (II), which is submitted to and acid (TsOH) catalyzed transetherification with 2-(3,4-dimethoxyphenyl)ethanol (III) to yield 3-[2-(3,4-dimethoxyphenyl)ethoxy-2(S)-hydroxy-3,3-diphenylpropionic acid methyl ester (IV). The hydrolysis of (IV) with KOH in methanol affords the corresponding free acid (V), which is finally condensed with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (VI) by means of lithium amide in DMF.

参考文献中间体

合成目标

【1】 Jansen, R.; Hillen, H.; Kettschau, G.; Unger, L.; Hergenröder, S.; Kling, A.; Raschack, M.; Klinge, D.; Riechers, H.; Amberg, W.; Discovery and synthesis of (S)-3-[2-(3,4-dimethoxyphenyl)ethoxy]-2-(4,6-dimethylpyrimidin-2-yloxy)-3,3-diphenylpropionic acid (LU 302872), a novel orally active mixed ETA/ETB receptor antagonist. J Med Chem 1999, 42, 16, 3026.

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)	21154	(2S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid		C₁₆H₁₆O₄	详情	详情
(II)	38710	methyl (2S)-2-hydroxy-3-methoxy-3,3-diphenylpropanoate		C₁₇H₁₈O₄	详情	详情
(III)	38711	2-(3,4-dimethoxyphenyl)-1-ethanol	7417-21-2	C₁₀H₁₄O₃	详情	详情
(IV)	38712	methyl (2S)-3-[(3,4-dimethoxyphenethyl)oxy]-2-hydroxy-3,3-diphenylpropanoate		C₂₆H₂₈O₆	详情	详情
(V)	38713	(2S)-3-[(3,4-dimethoxyphenethyl)oxy]-2-hydroxy-3,3-diphenylpropionic acid		C₂₅H₂₆O₆	详情	详情
(VI)	38714	4,6-dimethyl-2-(methylsulfonyl)pyrimidine; 4,6-dimethyl-2-pyrimidinyl methyl sulfone		C₇H₁₀N₂O₂S	详情	详情

Extended Information