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【结 构 式】 
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【药物名称】GW-7845 【化学名称】2(S)-[2-(Methoxycarbonyl)phenylamino]-3-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl]propionic acid 【CA登记号】196809-22-0 【 分 子 式 】C29H28N2O6 【 分 子 量 】500.55631 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Chemopreventive Agents, ONCOLYTIC DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, PPARgamma Agonists |
合成路线1
Oxazolylethanol (I) was coupled to N-Boc-L-tyrosine methyl ester (II) using Mitsunobu conditions in the presence of PPh3 and DEAD to give ether (III). Subsequent deprotection of the Boc group of (III) with trifluoroacetic acid afforded amine (IV), which was then condensed with methyl cyclohexanone-2-carboxylate (V) in boiling toluene to yield enamine (VI). Further heating of (VI) at 190 C in anisole in the presence of Pd/C resulted in aromatization of the cyclohexene ring to produce the anthranilate derivative (VII). Finally, selective hydrolysis of the aliphatic ester with LiOH under careful conditions provided the target monoester.
| 【1】 Cobb, J.E.; Blanchard, S.G.; Boswell, E.G.; Brown, K.K.; Charifson, P.S.; Cooper, J.P.; Collins, J.L.; Dezube, M.; Henke, B.R.; Hull-Ryde, E.A.; Lake, D.H.; Lenhard, J.M.; Oliver, W. Jr; Oplinger, J.; Pentti, M.; Parks, D.J.; Plunket, K.D.; Tong, W.Q.; N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent. J Med Chem 1998, 41, 25, 5055. |
| 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) | 19874 | 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-1-ethanol | C12H13NO2 | 详情 | 详情 | |
| (II) | 19875 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate | 4326-36-7 | C15H21NO5 | 详情 | 详情 |
| (III) | 19876 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propanoate | C27H32N2O6 | 详情 | 详情 | |
| (IV) | 19877 | methyl (2S)-2-amino-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propanoate | C22H24N2O4 | 详情 | 详情 | |
| (V) | 19878 | methyl 2-oxocyclohexanecarboxylate | 41302-34-5 | C8H12O3 | 详情 | 详情 |
| (VI) | 19879 | methyl 2-[((1S)-2-methoxy-1-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl]-2-oxoethyl)amino]-1-cyclohexene-1-carboxylate | C30H34N2O6 | 详情 | 详情 | |
| (VII) | 19880 | methyl 2-[((1S)-2-methoxy-1-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl]-2-oxoethyl)amino]benzoate | C30H30N2O6 | 详情 | 详情 |