Minalrestat, WAY-ARI-509, WAY-121509, ARI-509

合成路线:ARI-509 can be obtained by four related synthetic routes (a-d),scheme 16434601a: A key advanced intermediate (VI) was used for the preparation of ARI-509.This intermediate (VI) was prepared by two synthetic routes a and b:In route a,commercially available homophthalic acid diester (I) or homophthalic anhydride (II) was reacted with 4-bromo-2-fluorobenzyl amine to give homophthalimide (IV).Treatment of (IV) with Mander's reagent yielded the key intermediate (VI).In route b,2-chloro-4-fluorobenzoic acid (III) was converted to diester (V) by the Hurtley reaction.Treatment of (V) with thionyl chloride and further reaction of the generated acid chloride with 4-bromo-2-fluorobenzyl amine gave the key intermediate (VI).Conversion of (VI) to the final product was accomplished by routes c and d:In route c,alkylation of (VI) with tert-butyl bromoacetate,followed by acidic hydrolysis gave acid (VII).Generation of the acid chloride of (VII) with thionyl chloride and treatment with ammonia yielded amide (VIII).In route d,amide (VIII) was obtained in a more direct way,by formation of nitrile (IX) from (VI) with bromoacetonitrile and subsequent acidic hydrolysis.Amide (VIII) was cyclized to the final product (ARI-509),upon treatment with a variety of bases including sodium hydride,sodium methoxide or lithium bis(trimethylsilyl)amide.

参考文献标题:Regioselective synthesis of beta-ketoesters from lithium enolates and methyl cyanoformate
文献作者:Sethi,P.; Mander,L.N.
参考来源:Tetrahedron Lett 1983,245425


合成路线:ARI-509 can be obtained by four related synthetic routes (a-d),scheme 16434601a: A key advanced intermediate (VI) was used for the preparation of ARI-509.This intermediate (VI) was prepared by two synthetic routes a and b:In route a,commercially available homophthalic acid diester (I) or homophthalic anhydride (II) was reacted with 4-bromo-2-fluorobenzyl amine to give homophthalimide (IV).Treatment of (IV) with Mander's reagent yielded the key intermediate (VI).In route b,2-chloro-4-fluorobenzoic acid (III) was converted to diester (V) by the Hurtley reaction.Treatment of (V) with thionyl chloride and further reaction of the generated acid chloride with 4-bromo-2-fluorobenzyl amine gave the key intermediate (VI).Conversion of (VI) to the final product was accomplished by routes c and d:In route c,alkylation of (VI) with tert-butyl bromoacetate,followed by acidic hydrolysis gave acid (VII).Generation of the acid chloride of (VII) with thionyl chloride and treatment with ammonia yielded amide (VIII).In route d,amide (VIII) was obtained in a more direct way,by formation of nitrile (IX) from (VI) with bromoacetonitrile and subsequent acidic hydrolysis.Amide (VIII) was cyclized to the final product (ARI-509),upon treatment with a variety of bases including sodium hydride,sodium methoxide or lithium bis(trimethylsilyl)amide.
参考文献标题:A study of the copper-catalyzed direct arylation of beta-dicarbonyl compounds with 2-bromobenzoic acid
文献作者:Bruggin,K.A.; McKillop,A.
参考来源:Tetrahedron 1975,312607-19


产品链接: CAS No. 129688-50-2››