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【结 构 式】 
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【药物名称】Etomoxir, B-8910-02(Na salt), B-877-44, B-80754(racemate), B-82733(racemate, Na salt), B-83721(racemate, free acid) 【化学名称】(+)-(R)-2-[6-(4-Chlorophenoxy)hexyl]oxirane-2-carboxylic acid ethyl ester 【CA登记号】124083-20-1, 82258-36-4 (racemate) 【 分 子 式 】C17H23ClO4 【 分 子 量 】326.82346 |
【开发单位】Altana Pharma (Originator), MediGene (Licensee) 【药理作用】Antidiabetic Drugs, CARDIOVASCULAR DRUGS, ENDOCRINE DRUGS, Heart Failure Therapy, Carnitine O-Palmitoyltransferase 1 (CPT-1) Inhibitors, Fatty Acid Oxidation Inhibitors |
合成路线1
1) Alkylation of diethyl malonate (II) with 1 6-dibromohexane (I) results in diethyl 6-bromohexylmaionate (III). Compound (II) is hydrolyzed to the monoester (IV), followed by condensation with paraformaldehyde in ethanol/piperidine/2-methylquinoline to yield ethyl 8-bromo-2-methyleneoctanoate (V), which is oxidized with permaleic acid to (VI). Subsequent reaction with 4-chlorophenolate produces etomoxir.
| 【1】 Eistetter, K.; Ludwig, G.; Rapp, E.; Wolf, H. (Byk Gulden Lomberg Chemische Fabrik GmbH); Phenoxyalkoxyalkyl- and phenoxyalkyl-substd. oxiranecarboxylic acids, their use and medicaments containing them. EP 0046590; US 4337267 . |
| 【2】 Eistetter, K.; Wolf, H.P.O.; ETOMOXIR. Drugs Fut 1986, 11, 12, 1034. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 62997 | 4-chlorobenzenolate | C6H4ClO | 详情 | 详情 | ||
| (I) | 24786 | 1,6-dibromohexane | 629-03-8 | C6H12Br2 | 详情 | 详情 |
| (II) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (III) | 24864 | diethyl 2-(6-bromohexyl)malonate | C13H23BrO4 | 详情 | 详情 | |
| (IV) | 24865 | 8-bromo-2-(ethoxycarbonyl)octanoic acid | C11H19BrO4 | 详情 | 详情 | |
| (V) | 24866 | ethyl 2-(6-bromohexyl)acrylate | C11H19BrO2 | 详情 | 详情 | |
| (VI) | 24867 | ethyl 2-(6-bromohexyl)-2-oxiranecarboxylate | C11H19BrO3 | 详情 | 详情 |
合成路线2
2) Alternatively, etomoxir can be prepared as follows: Alkylation of 4-chlorophenol with 1,6-dibromohexane (I) yields 1 bromo-6-(4-chlorophenoxy)hexane (VII). Diethyl malonate (II) is alkylated by (VII), yielding (VIII), followed by hydrolysis to the monoester (IX), which is condensed with para formaldehyde/pyridine/piperidine to give ethyl 8-(4-chlorophenoxy)-2-methyleneoctanoate (IX). Oxidation with m-chloroperbenzoic acid produces etomoxir.
| 【1】 Eistetter, K.; Ludwig, G.; Rapp, E.; Wolf, H. (Byk Gulden Lomberg Chemische Fabrik GmbH); Phenoxyalkoxyalkyl- and phenoxyalkyl-substd. oxiranecarboxylic acids, their use and medicaments containing them. EP 0046590; US 4337267 . |
| 【2】 Eistetter, K.; Wolf, H.P.O.; ETOMOXIR. Drugs Fut 1986, 11, 12, 1034. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 35543 | 4-chlorophenol | 106-48-9 | C6H5ClO | 详情 | 详情 | |
| (I) | 24786 | 1,6-dibromohexane | 629-03-8 | C6H12Br2 | 详情 | 详情 |
| (II) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (VII) | 24870 | 6-bromohexyl 4-chlorophenyl ether | C12H16BrClO | 详情 | 详情 | |
| (VIII) | 24871 | diethyl 2-[6-(4-chlorophenoxy)hexyl]malonate | C19H27ClO5 | 详情 | 详情 | |
| (IX) | 24872 | 8-(4-chlorophenoxy)-2-(ethoxycarbonyl)octanoic acid | C17H23ClO5 | 详情 | 详情 | |
| (X) | 24873 | ethyl 2-[6-(4-chlorophenoxy)hexyl]acrylate | C17H23ClO3 | 详情 | 详情 |