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【结 构 式】 
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【药物名称】LR-90 【化学名称】2,5,5-Tris(4-chlorophenyl)-1,3-dioxane-2-carboxylic acid 【CA登记号】 【 分 子 式 】C23H17Cl3O4 【 分 子 量 】463.74854 |
【开发单位】Lipha (Originator) 【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Type 2 Diabetes Mellitus, Agents for, PPARalpha Agonists, PPARgamma Agonists |
合成路线1
Darzen’s condensation of 4,4'-dichlorobenzophenone (I) with ethyl chloroacetate (II) produced the glycidic ester (III), which was subsequently converted to aldehyde (IV) upon treatment with KOH. Diol (V) was then obtained by Tollens’ reaction of aldehyde (IV) with formaldehyde. Ethyl 4-chlorophenylglyoxylate (VII) was prepared by addition of the Grignard reagent prepared from 1-bromo-4-chlorobenzene (VI) to diethyl oxalate. The condensation between diol (V) and keto ester (VII) in the presence of boron trifluoride furnished the cyclic ketal (VIII). Finally, saponification of the ethyl ester group gave rise to the target carboxylic acid.
| 【1】 Al Hazaa, A.; et al.; ZD1839 (Iressa(TM)), an EGFR-TKI, and cisplatin have an additive effect on programmed cell death in human head and neck squamous carcinoma cells in vitro. Clin Cancer Res 2000, 6, Suppl., Poster Nº 308. |
| 【2】 Zeiller, J.-J.; Raspé, E.; Guerrier, D.; Berthelon, J.-J. (Merck Patent GmbH); Cyclic cpds. useful in the treatment of dyslipidaemia, atherosclerosis and diabetes, pharmaceutical compsns. and preparation process. EP 1098893; FR 2781222; WO 0004011 . |
| 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) | 47449 | bis(4-chlorophenyl)methanone | 90-98-2 | C13H8Cl2O | 详情 | 详情 |
| (II) | 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 |
| (III) | 47450 | ethyl 3,3-bis(4-chlorophenyl)-2-oxiranecarboxylate | C17H14Cl2O3 | 详情 | 详情 | |
| (IV) | 47451 | 2,2-bis(4-chlorophenyl)acetaldehyde | C14H10Cl2O | 详情 | 详情 | |
| (V) | 47452 | 2,2-bis(4-chlorophenyl)-1,3-propanediol | C15H14Cl2O2 | 详情 | 详情 | |
| (VI) | 14733 | 4-Bromochlorobenzene; 1-bromo-4-chlorobenzene | 106-39-8 | C6H4BrCl | 详情 | 详情 |
| (VII) | 47453 | ethyl 2-(4-chlorophenyl)-2-oxoacetate | C10H9ClO3 | 详情 | 详情 | |
| (VIII) | 47454 | ethyl 2,5,5-tris(4-chlorophenyl)-1,3-dioxane-2-carboxylate | C25H21Cl3O4 | 详情 | 详情 |