| abstract |
A method for making a compound of formula I, R1 is -CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or -CF2H; X is YR2, halogen, nitro, NH2, or formyl amine; X2 is O or NR8; Y is O or S(O)m'; m' is 0, 1, or 2; R2 is independently selected from -CH3 or -CF2H; R3 is CN; R8 is hydrogen or C1-4alkyl optionally substituted by one to three fluorines; R' and R"" are independently hydrogen or -C(O)OX where X is hydrogen or metal or ammonium cation; which method comprises: (a) combining a group I(a) of group II(a) metal halide, with an aprotic dipolar amide-based solvent and water and a compound of formula II(a) or II(b), where R1, R3, X2 and X are the same as for formula (I); (b) heating the combination to a temperature of at least about 60 DEG for several hours, optionally under an inert atmosphere; (c) precipitating out a compound of formula (I) by adding a strong base to said combination; (d) removing the amide-based solvent and water from said precipitate, and optionally (1) purifying further the precipitate, or (2) acidifying the precipitate to obtain the free acid. |