Patent ID: 6337408
Filing Date: 2002-01-08
Classification: A61P,C07C,C07D

Abstract:
A method for making a compound of formula I R1 is â€”(CR4R5)nC(O)O(CR4R5)mR6, â€”(CR4R5)nC(O)NR4(CR4R5)mR6, â€”(CR4R5)nO(CR4R5)mR6, or â€”(CR4R5)rR6 wherein the alkyl moieties may be optionally substituted with one or more halogens; m is 0 to 2; n is 1 to 4; r is 0 to 6; R4 and R5 are independently selected from hydrogen or a C1-2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC1-3 alkyl, halo substituted aryloxyC1-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group; provided that: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then R6 is other than H in â€”(CR4R5)nO(CR4R5)mR6; X is YR2, halogen, nitro, NH2, or formyl amine; X2 is O or NR8; Y is O or S(O)mâ€²; mâ€² is 0, 1, or 2; R2 is independently selected from â€”CH3 or â€”CH2CH3 optionally substituted by 1 or more halogens; R3 is hydrogen, halogen, C1-4 alkyl, CH2NHC(O)C(O)NH2, halo-substituted C1-4 alkyl, â€”CH&boxH;CR8â€²R8â€², cyclopropyl optionally substituted by R8â€², CN, OR8, CH2OR8, NR8R10, CH2NR8R10, C(Zâ€²)H, C(O)OR8, C(O)NR8R10, or Câ‰¡CR8â€²R8 is hydrogen or C1-4 alkyl optionally substituted by one to three fluorines; R8â€² is R8 or fluorine; R10 is OR8 or R11; R11 is hydrogen, or C1-4 alkyl optionally substituted by one to three fluorines; Zâ€² is O, NR9, NOR8, NCN, C(â€”CN)2, CR8CN, CR8NO2, CR8C(O)OR8, CR8C(O)NR8R8, C(â€”CN)NO2, C(â€”CN)C(O)OR9, or C(â€”CN)C(O)NR8R8; Râ€² and Râ€³ are independently hydrogen or â€”C(O)OH; which method comprises treating a compound of formula II â€ƒwhere R1, R3, X2 and X are the same as for formula (I), with a Lewis acid in a an aqueous solution at a temperature between about 60Â° and 100Â° C., optionally under an inert atmosphere for a time sufficient for the reaction to go to completion.