Merimepodib, VI-21497, VX-497, -Drug Synthesis Database

【结构式】

【药物名称】Merimepodib, VI-21497, VX-497

【化学名称】N-[3-[3-[3-Methoxy-4-(5-oxazolyl)phenyl]ureido]benzyl]carbamic acid tetrahydrofuran-3(S)-yl ester

【CA登记号】198821-22-6, 243859-99-6 (deleted CAS), 198821-38-4 (undefined isomer)

【分子式】C₂₃H₂₄N₄O₆

【分子量】452.47093

【开发单位】Vertex (Originator)

【药理作用】Anti-Hepatitis C Virus Drugs, Anti-Hepatitis Virus Drugs, ANTIINFECTIVE THERAPY, Antiviral Drugs, Inosine 5'-Monophosphate Dehydrogenase (IMPDH) Inhibitors

合成路线1 合成路线2

合成路线1

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.

参考文献中间体

【1】 Martín, L.; Sorbera, L.A.; Castañer, J.; Silvestre, J.S.; VX-497. Drugs Fut 2000, 25, 8, 809.
【2】 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.); Urea derivs. as inhibitors of IMPDH enzyme. EP 0902782; US 5807876; US 6054472; WO 9740028 .

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)	39654	methyl 2-methyl-5-nitrophenyl ether; 2-methoxy-1-methyl-4-nitrobenzene	13120-77-9	C₈H₉NO₃	详情	详情
(II)	39655	(acetoxy)(2-methoxy-4-nitrophenyl)methyl acetate		C₁₂H₁₃NO₇	详情	详情
(III)	39656	2-methoxy-4-nitrobenzaldehyde		C₈H₇NO₄	详情	详情
(IV)	39657	methyl 5-nitro-2-(1,3-oxazol-5-yl)phenyl ether; 5-(2-methoxy-4-nitrophenyl)-1,3-oxazole		C₁₀H₈N₂O₄	详情	详情
(V)	39658			C₁₀H₁₀N₂O₂	详情	详情
(VI)	39659	N-[3-methoxy-4-(1,3-oxazol-5-yl)phenyl]-1H-imidazole-1-carboxamide		C₁₄H₁₂N₄O₃	详情	详情
(VII)	39660	tert-butyl 3-aminobenzylcarbamate		C₁₂H₁₈N₂O₂	详情	详情
(VIII)	39661	3-(aminomethyl)aniline; 3-aminobenzylamine	4403-70-7	C₇H₁₀N₂	详情	详情
(IX)	39662	tert-butyl 3-([[3-methoxy-4-(1,3-oxazol-5-yl)anilino]carbonyl]amino)benzylcarbamate		C₂₃H₂₆N₄O₅	详情	详情
(X)	39663	N-[3-(aminomethyl)phenyl]-N'-[3-methoxy-4-(1,3-oxazol-5-yl)phenyl]urea		C₁₈H₁₈N₄O₃	详情	详情
(XI)	39664	1-([[(3S)tetrahydro-3-furanyloxy]carbonyl]oxy)-2,5-pyrrolidinedione		C₉H₁₁NO₆	详情	详情

合成路线2

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)).

参考文献中间体

【1】 Wilson, J.D.; Meckler, H.; Herr, R.J.; Fairfax, D.J.; Preparation of 5-(2-methoxy-4-nitrophenyl)oxazole: A key intermediate for the construction of VX-497. Org Process Res Dev 2002, 6, 5, 677.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	56908		C₇H₆BF₄N₃O₃	详情	详情
(II)	39656	2-methoxy-4-nitrobenzaldehyde	C₈H₇NO₄	详情	详情
(III)	56909	isocyanatomethyl 4-methylphenyl sulfone; (isocyanatomethyl)(4-methylphenyl)dioxo-lambda~6~-sulfane	C₉H₉NO₃S	详情	详情
(IV)	39657	methyl 5-nitro-2-(1,3-oxazol-5-yl)phenyl ether; 5-(2-methoxy-4-nitrophenyl)-1,3-oxazole	C₁₀H₈N₂O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)