Patent ID: 6603000
Filing Date: 2003-08-05
Classification: C07D

Abstract:
A process of making a compound of the formula(I): wherein:the naphthyl ring is further optionally substituted by one or more R1 or R2; X is chosen from pyridinyl optionally independently substituted with one to three C1-4 alkyl, C1-4alkoxy, hydroxy, nitro, nitrile, amino, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen; Y is chosen from C1-4 unbranched carbon chain, C4 branched or unbranched carbon chain and C2-4 unsaturated carbon chain each optionally partially or fully halogenated; Z is chosen from morpholinyl optionally substituted with one to three nitrile, C1-6 alkyl, C1-6 alkoxy, hydroxy, amino, mono- or di-(C1-3 alkyl)amino-C1-3 alkyl, CONH2, phenylamino-C1-3 alkyl or C1-3 alkoxy-C1-3 alkyl; and halogen; R1 and R2 are independently chosen from: a C1-6 unbranched alkyl optionally partially or fully halogenated, C4-6 branched or unbranched alkyl optionally partially or fully halogenated, C1-4 unbranched alkoxy, C4 branched or unbranched alkoxy each being optionally partially or fully halogenated, halogen, C1-3 alkyl-S(O)m optionally partially or fully halogenated and phenylsulfonyl; m is 0, 1 or 2; said process comprising:i) reacting a Zâ€”Yâ€”Xâ€”COOâ€”Rx ester (II) with a di-ester (III), wherein Rx in both (II) and (III) is independently C1-5alkyl or aryl, in a suitable solvent and a suitable base and optionally in the presence of an additive at a temperature of about 0 to 200Â° C. for a reaction time of about 5 mm to 24 h, and isolating the compound intermediate (IV): ii) hydrolysing the product of step i) with acidic or basic hydrolysis, and decarboxylating under suitable acid conditions at a temperature of about 50 to 200Â° C. and for about 5 mm to 24 hours; followed by esterifying under appropriate conditions with a C1-5alcohol; subsequent phenyl nucleophilic addition wherein the phenyl is optionally independently substituted by R1 and R2; cleaving by reductive cleavage under appropriate conditions to form a carboxylic acid compound, and treating with a strong mineral acid optionally in a suitable solvent at RT to 200Â° C., to form a product intermediate of the formula(V), and isolating the product: iii) reacting the product from step ii) with HNRyRz or it's respective salt thereof, to form an enamine or imine compound of the formula(VI) under suitable conditions at about RT for about 1 to 24 h: wherein Ry is C1-5alkyl or hydrogen, Rz is C1-5alkyl, hydrogen or OH with the proviso that when formula (VI) is an enamine tautomer then Ry and Rz are both C1-5alkyl, or when formula (VI) is an imine tautomer then Rz is OH, C1-5alkyl or hydrogen and Ry is not present: iv) where the product of step iii) is an imine, in a one pot reaction acylating and reducing the product (VI); then treating the product of such reaction under oxidizing conditions capable of forming the naphthalene ring in the formula(I), followed by deprotecting under suitable conditions; or where the product of step iii) is an enamine, oxidizing the enamine under suitable oxidizing conditions to form the naphthalene ring, then deprotecting the amino nitrogen to form the formula (I):