Merimepodib, VI-21497, VX-497
美泊地布Chemical Name: N-[3-[3-[3-Methoxy-4-(5-oxazolyl)phenyl]ureido]benzyl]carbamic acid tetrahydrofuran-3(S)-yl ester
CAS No. 198821-22-6, 243859-99-6 (deleted CAS), 198821-38-4 (undefined isomer)
项目整合开发状态: Phase II
项目研究机构: Vertex (Originator)
合成路线:The oxidation of 3-methoxy-4-methylnitrobenzene (I) with CrO3,H2SO4 and AC2O in acetic acid gives the gem-diacetate (II),which is hydrolyzed with HCl in refluxing dioxane to yield 2-methoxy-4-nitrobenzaldehyde (III).Cyclization of (III) with tosylmethyl isocyanide and K2CO3 in refluxing methanol affords 3-methoxy-4-(5-oxazolyl)nitrobenzene (IV),which is reduced with H2 over Pd/C in ethyl acetate to provide the corresponding aniline (V).The activation of (V) with carbonyldiimidazole (CDI) in THF gives the carboxamide (VI),which is condensed with 3-(tert-butoxycarbonylaminomethyl)aniline (VII),obtained by reaction of 3-aminobenzylamine with Boc2O,and DMAP in refluxing THF to yield the urea (IX).Deprotection of (IX) with TFA in dichloromethane affords the free benzylamine (X),which is finally condensed with the 3-furyl ester of the succinimidyl-activated carbonate (XI) by means of TEA in dichloromethane/DMF.
📌 参考资料/链接：
参考文献标题:Urea derivs.as inhibitors of IMPDH enzyme
文献作者:Armistead,D.M.; Badia,M.C.; Bemis,G.W.; Bethiel,R.S.; Frank,C.A.; Novak,P.M.; Ronkin,S.M.; Saunders,J.O.(Vertex Pharmaceuticals Inc.)
参考来源:EP 0902782; US 5807876; US 6054472; WO 9740028
📄 详细内容
合成路线:The oxidation of 3-methoxy-4-methylnitrobenzene (I) with CrO3,H2SO4 and AC2O in acetic acid gives the gem-diacetate (II),which is hydrolyzed with HCl in refluxing dioxane to yield 2-methoxy-4-nitrobenzaldehyde (III).Cyclization of (III) with tosylmethyl isocyanide and K2CO3 in refluxing methanol affords 3-methoxy-4-(5-oxazolyl)nitrobenzene (IV),which is reduced with H2 over Pd/C in ethyl acetate to provide the corresponding aniline (V).The activation of (V) with carbonyldiimidazole (CDI) in THF gives the carboxamide (VI),which is condensed with 3-(tert-butoxycarbonylaminomethyl)aniline (VII),obtained by reaction of 3-aminobenzylamine with Boc2O,and DMAP in refluxing THF to yield the urea (IX).Deprotection of (IX) with TFA in dichloromethane affords the free benzylamine (X),which is finally condensed with the 3-furyl ester of the succinimidyl-activated carbonate (XI) by means of TEA in dichloromethane/DMF.
参考文献标题:VX-497
文献作者:Mart韓,L.; Sorbera,L.A.; Castar,J.; Silvestre,J.S.
参考来源:Drugs Fut 2000,25(8),809
合成路线:The desired intermediate 5-(2-methoxy-4-nitrophenyl)oxazole (IV) has been obtained as follows.The carbonylation of 2-methoxy-4-nitrophenyldiazonium tetrafluoroborate (I) by means of carbon monoxide catalyzed by Pd(OAc)2 and Tes-H in ethyl ether/acetonitrile gives 2-methoxy-4-nitrobenzaldehyde (II),which is cyclized with tosylmethyl isocyanate (III) by means of K2CO3 in refluxing methanol to afford the target intermediate 5-(2-methoxy-4-nitrophenyl)oxazole (IV) (see scheme no.24362801a,intermediate (IV)).
参考文献标题:Preparation of 5-(2-methoxy-4-nitrophenyl)oxazole: A key intermediate for the construction of VX-497
文献作者:Wilson,J.D.; Meckler,H.; Herr,R.J.; Fairfax,D.J.
参考来源:Org Process Res Dev 2002,6(5),677
产品链接: CAS No. 198821-22-6›› 产品链接: CAS No.198821-38-4››