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【结 构 式】 
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【药物名称】KCL-1999000269 【化学名称】(+)-2(S)-[4-Methoxy-3-[N-[4-(trifluoromethyl)benzyl]carbamoyl]benzyl]butyric acid 【CA登记号】311769-66-1, 311769-49-0 (undefined isomer) 【 分 子 式 】C21H22F3NO4 【 分 子 量 】409.40899 |
【开发单位】Kyorin (Originator) 【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, PPARalpha Agonists |
合成路线1
The title enantiomer has been obtained by resolution of the racemic acid (I). Acid (I) is activated as the mixed anhydride (II) with pivalic acid and triethylamine. Subsequent coupling of anhydride (II) with the potassium anion of (S)-4-benzyl-2-oxazolidinone leads to a mixture of the diastereoisomeric imides (III) and (IV), which can be separated by column chromatography and recrystallization. Then, removal of the chiral auxiliary from the target isomer (III) by hydrolysis with lithium peroxide furnishes the desired (S)-enantiomer.
| 【1】 Miyachi, H.; Nomura, M.; Tanase, T.; Suzuki, M.; Murakami, K.; Awano, K.; Enantio-dependent binding and transactivation of optically active phenylpropanoic acid derivatives at human peroxisome proliferator-activated receptor alpha. Bioorg Med Chem Lett 2002, 12, 3, 333. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 | |
| (I) | 61870 | 2-[4-methoxy-3-({[4-(trifluoromethyl)benzyl]amino}carbonyl)benzyl]butanoic acid | C21H22F3NO4 | 详情 | 详情 | |
| (II) | 61871 | 1,1-dimethylpropanoic 1-[4-methoxy-3-({[4-(trifluoromethyl)benzyl]amino}carbonyl)benzyl]butanoic anhydride | C26H30F3NO5 | 详情 | 详情 | |
| (III) | 61872 | 5-((2S)-2-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}butyl)-2-methoxy-N-[4-(trifluoromethyl)benzyl]benzamide | C31H31F3N2O5 | 详情 | 详情 | |
| (IV) | 61873 | 5-((2R)-2-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}butyl)-2-methoxy-N-[4-(trifluoromethyl)benzyl]benzamide | C31H31F3N2O5 | 详情 | 详情 |
合成路线2
In an enantioselective synthesis of the (S)-enantiomer, asymmetric alkylation of the chiral N-butyryl oxazolidinone (I) with benzyl 5-bromomethyl-2-methoxybenzoate (II) in the presence of lithium hexamethyldisilazide leads to isomer (III) in high diastereomeric excess. Subsequent benzyl ester hydrogenolysis in (III) employing Pd/C affords carboxylic acid (IV), which is further converted to the mixed anhydride (V) with ethyl chloroformate and triethylamine. Coupling of anhydride (V) with 4-trifluoromethylbenzylamine (VI) furnishes the corresponding amide (VII). The chiral auxiliary is then removed from (VII) by hydrolysis with lithium peroxide to yield the target (S)-enantiomer.
| 【1】 Nomura, M.; Tanase, T.; Miyachi, H.; Efficient asymmetric synthesis of (S)-2-ethylphenylpropanoic acid derivative, a selective agonist for human peroxisome proliferator-activated receptor alpha. Bioorg Med Chem Lett 2002, 12, 16, 2101. |
| 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) | 10794 | (4S)-4-Benzyl-3-butyryl-1,3-oxazolan-2-one | C14H17NO3 | 详情 | 详情 | |
| (II) | 61874 | benzyl 5-(bromomethyl)-2-methoxybenzoate | C16H15BrO3 | 详情 | 详情 | |
| (III) | 61875 | benzyl 5-((2S)-2-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}butyl)-2-methoxybenzoate | C30H31NO6 | 详情 | 详情 | |
| (IV) | 61876 | 5-((2S)-2-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}butyl)-2-methoxybenzoic acid | C23H25NO6 | 详情 | 详情 | |
| (V) | 61877 | C26H29NO8 | 详情 | 详情 | ||
| (VI) | 21925 | [4-(trifluoromethyl)phenyl]methanamine; 4-(trifluoromethyl)benzylamine | 3300-51-4 | C8H8F3N | 详情 | 详情 |
| (VII) | 61873 | 5-((2R)-2-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}butyl)-2-methoxy-N-[4-(trifluoromethyl)benzyl]benzamide | C31H31F3N2O5 | 详情 | 详情 |