|
【结 构 式】 
|
【药物名称】LY-465608 【化学名称】2-[4-[2-[2-(Biphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy]- phenoxy]-2-methylpropionic acid 【CA登记号】328918-26-9 【 分 子 式 】C28H27NO5 【 分 子 量 】457.53109 |
【开发单位】Ligand (Originator), Lilly (Originator) 【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Type 2 Diabetes Mellitus, Agents for, Fibrates, PPARalpha Agonists, PPARgamma Agonists |
合成路线1
The cyclization of 4-bromobenzaldehyde (I) with butanedione monooxime (II) by means of HCl in acetic acid gives 2-(4-bromophenyl)-4,5-dimethyloxazole N-oxide (III), which is chlorinated with POCl3 in refluxing chloroform to yield the chloromethyl derivative (IV). The reaction of (IV) with KCN and KI in hot DMF affords the cyanomethyl compound (V), which is hydrolyzed with KOH in water/2-methoxyethanol to provide the acetic acid derivative (VI). The reduction of (VI) with BH3/THF in THF gives the ethanol intermediate (VII), which is condensed with phenylboronic acid (VIII) by means of PPh3 and Pd(OAc)2 in propanol to yield the biphenyl derivative (IX). The reaction of the OH group of (IX) with tosyl anhydride in dichloromethane affords the tosylate (X), which is condensed with 2-(4-hydroxyphenoxy)-2-methylpropionic aid ethyl ester (XI) by means of Cs2CO3 in hot DMF to provide the ethyl ester precursor (XII). Finally, this compound is hydrolyzed with NaOH in methanol/water to obtain the target propionic acid.
| 【1】 Brooks, D.A.; et al.; Design and synthesis of 2-methyl-2-{4-[2-(5-methyl-2-aryloxazol-4-yl)ethoxy]phenoxy}propionic acids: A new class of dual PPARalpha/gamma agonists. J Med Chem 2001, 44, 13, 2061. |
| 【2】 Matthews, D.P.; Hay, D.A.; Ardecky, R.J.; Warshawsky, A.M.; Gossett, L.S.; Dominianni, S.J.; Rito, C.J.; Shuker, A.J.; Brooks, D.A.; Michellys, P.-Y.; Tyhonas, J.S. (Eli Lilly and Company; Ligand Pharmaceuticals, Inc.); Biaryl-oxa(thia)zole derivs. and their use as PPARs modulators. EP 1206457; US 6417212; WO 0116120 . |
| 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) | 22231 | 4-Bromobenzaldehyde | 1122-91-4 | C7H5BrO | 详情 | 详情 |
| (II) | 55397 | 2,3-Butanedione 2-oxime; 2,3-Butanedione monoxime; 2,3-Butanedione oxime; 2,3-Butanedione-2-monoxime; Diacetyl monoxime | 57-71-6 | C4H7NO2 | 详情 | 详情 |
| (III) | 55398 | 2-(4-bromophenyl)-4,5-dimethyl-1,3-oxazol-3-ium-3-olate | C11H10BrNO2 | 详情 | 详情 | |
| (IV) | 55399 | 2-(4-bromophenyl)-4-(chloromethyl)-5-methyl-1,3-oxazole | C11H9BrClNO | 详情 | 详情 | |
| (V) | 55400 | 2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]acetonitrile | C12H9BrN2O | 详情 | 详情 | |
| (VI) | 55401 | 2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]acetic acid | C12H10BrNO3 | 详情 | 详情 | |
| (VII) | 55402 | 2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]-1-ethanol | C12H12BrNO2 | 详情 | 详情 | |
| (VIII) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (IX) | 55403 | 2-(2-[1,1'-biphenyl]-4-yl-5-methyl-1,3-oxazol-4-yl)-1-ethanol | C18H17NO2 | 详情 | 详情 | |
| (X) | 55404 | 2-(2-[1,1'-biphenyl]-4-yl-5-methyl-1,3-oxazol-4-yl)ethyl 4-methylbenzenesulfonate | C25H23NO4S | 详情 | 详情 | |
| (XI) | 55405 | ethyl 2-(4-hydroxyphenoxy)-2-methylpropanoate | C12H16O4 | 详情 | 详情 | |
| (XII) | 55406 | ethyl 2-{4-[2-(2-[1,1'-biphenyl]-4-yl-5-methyl-1,3-oxazol-4-yl)ethoxy]phenoxy}-2-methylpropanoate | C30H31NO5 | 详情 | 详情 |