Patent ID: 6452022
Filing Date: 2002-09-17
Classification: C07C,C07D

Abstract:
An improved process for preparing a compound of formula (I) R1 is â€”(CR4R5)rR6 wherein the alkyl moieties may be optionally substituted with one or more halogens; r is 0 to 6; R4 and R5 are independently selected from hydrogen or a C1-2 alkyl; R6 is 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; 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)OX where X is hydrogen or Li; which method comprises: a) combining a Group I(a) or Group II(a) metal halide, with an aprotic dipolar amide-based solvent and water and a compound of formula II(a) or II(b), â€ƒwhere R1, R3, X2 and X are the same as for formula (I) b) heating the combination to a temperature of at least about 60Â° for several hours, optionally under an inert atmosphere; wherein the improvement comprises: c) precipitating out a compound of formula (I) by adding sufficient LiOH to said combination to form a compound of formula (I) where the X in â€”C(O)OX is Li; d) removing the amide-based solvent and water from said precipitate, and optionally: i) purifying further the Li salt; or ii) acidifying the Li salt to obtain the free acid.