LY-465608
Chemical Name: 2-[4-[2-[2-(Biphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy]phenoxy]-2-methylpropionic acid
CAS No. 328918-26-9
项目整合开发状态: Preclinical
项目研究机构: Ligand (Originator), Lilly (Originator)
合成路线: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.
📌 参考资料/链接：
参考文献标题:Biaryl-oxa(thia)zole derivs.and their use as PPARs modulators
文献作者: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.)
参考来源:EP 1206457; US 6417212; WO 0116120
📄 详细内容
合成路线: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.
参考文献标题: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
文献作者:Brooks,D.A.; Etgen,G.J.; Rito,C.J.; Shuker,A.J.; Dominianni,S.J.; Warshawsky,A.M.; Ardecky,R.J.; Paterniti,J.R.; Tyhonas,J.S.; Karanewsky,D.S.; Kauffman,R.F.; Broderick,C.L.; Oldham,B.A.; Montrose-Rafizadeh,C.; Winneroski,L.L.; et al.
参考来源:J Med Chem 2001,44(13),2061
产品链接: CAS No. 328918-26-9››