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【结 构 式】 
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【分子编号】21148 【品名】methyl 3,3-diphenyl-2-oxiranecarboxylate 【CA登记号】 |
【 分 子 式 】C16H14O3 【 分 子 量 】254.28536 【元素组成】C 75.57% H 5.55% O 18.88% |
合成路线1
该中间体在本合成路线中的序号：(III)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.
| 【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：(X)A pilot plant process was further developed for the (S)-enantiomer. Darzens condensation of benzophenone (VIII) with methyl chloroacetate gave the glycidic ester (X). Epoxide opening in (X) with trimethylaluminum furnished methyl 2-hydroxy-3,3-diphenylbutyrate (XI), which was hydrolyzed to the corresponding acid (VI) by using KOH in isopropanol. Treatment of the racemic acid (VI) with (S)-1-(4-chlorophenyl)ethylamine (XII) provided the desired (S)-acid salt (XIII). This was finally condensed with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (XIV) in the presence of lithium amide to yield the title compound.
| 【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. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 48526 | 2-hydroxy-3,3-diphenylbutyric acid | C16H16O3 | 详情 | 详情 | |
| (VIII) | 18732 | benzophenone | 119-61-9 | C13H10O | 详情 | 详情 |
| (IX) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (X) | 21148 | methyl 3,3-diphenyl-2-oxiranecarboxylate | C16H14O3 | 详情 | 详情 | |
| (XI) | 48528 | methyl 2-hydroxy-3,3-diphenylbutanoate | C17H18O3 | 详情 | 详情 | |
| (XII) | 48529 | (S)-4-Chloro-alpha-methylbenzylamine; 1-(4-Chlorophenyl)ethylamine | 4187-56-8 | C8H10ClN | 详情 | 详情 |
| (XIII) | 48530 | (1S)-1-(4-chlorophenyl)-1-ethanaminium (2S)-2-hydroxy-3,3-diphenylbutanoate | C24H26ClNO3 | 详情 | 详情 | |
| (XIV) | 38714 | 4,6-dimethyl-2-(methylsulfonyl)pyrimidine; 4,6-dimethyl-2-pyrimidinyl methyl sulfone | C7H10N2O2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The condensation of benzophenone (I) with methyl 2-chloroacetate (II) by means of NaOMe in THF gives 3,3-diphenyloxirane-2-carboxylic acid methyl ester (III), which by treatment with BF3/Et2O and methanol, followed by optical resolution, yielded the pure enantiomer 2(S)-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester (IV). The condensation of (IV) with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (V) by means of K2CO3 in DMF affords 2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid methyl ester (VI), which is finally hydrolyzed with KOH in hot dioxane to afford the target propionic acid as a racemic mixture.
| 【1】 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. |
| 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 |
| (II) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (III) | 21148 | methyl 3,3-diphenyl-2-oxiranecarboxylate | C16H14O3 | 详情 | 详情 | |
| (IV) | 38710 | methyl (2S)-2-hydroxy-3-methoxy-3,3-diphenylpropanoate | C17H18O4 | 详情 | 详情 | |
| (V) | 38714 | 4,6-dimethyl-2-(methylsulfonyl)pyrimidine; 4,6-dimethyl-2-pyrimidinyl methyl sulfone | C7H10N2O2S | 详情 | 详情 | |
| (VI) | 56710 | methyl (2S)-2-[(4,6-dimethyl-2-pyrimidinyl)oxy]-3-methoxy-3,3-diphenylpropanoate | C23H24N2O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)
| 【1】 Jansen R, Knopp M, Amberg W, et al. 2001. Structural similarity and its surprises: endothelin receptor antagonists-process research and development report. Org Proc Res Dev, 5(1):16～22. |
| 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 |
| (II) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 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) | 21153 | 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid | C16H16O4 | 详情 | 详情 | |
| (VI) | 67028 | (S)-1-(p-tolyl)ethanamine | 27298-98-2 | C9H13N | 详情 | 详情 |
| (VII) | 67029 | C16H16O4.C9H13N | 详情 | 详情 | ||
| (VIII) | 21150 | 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine; 4,6-dimethoxy-2-pyrimidinyl methyl sulfone | C7H10N2O4S | 详情 | 详情 |