Process for the preparation of tubulin inhibitors

A process for the preparation of a 6-[(substituted)phenyl]-triazolopyrimidine dicarboxylic acid salt and as a hydrated salt having the structural formula (I)

• wherein:
• R1 is CF3 or C2F5;
• R2is H or C1-C3 alkyl;
• n is an integer of 2, 3, or 4;
• X is Cl or Br;
• R3 and R4 are each independently H or C1-C3 alkyl;
• or
• R3 and R4 when optionally taken together with the nitrogen atom to which each is attached form a 4 to 6 membered saturated heterocyclic ring having 1-2 nitrogen atoms and 0-1 oxygen atoms or 0-1 sulfur atoms, and optionally substituted with R5;
• R5 is C1-C3 alkyl;
• wherein the dotted line is an optional bond,
• which process comprises:
• a. reacting a malonic acid ester of the formula
• where R6 and R7 are independently C1-C3 alkyl with 3-amino-1,2,4-triazole, in the presence of trialkyl amine base and heating at about 130-170° C., for about 1 to 6 h, cooling to about 130° C., diluting with toluene, cooling to about 20° C. to about 30° C., and adding at least two equivalents of aqueous alkali metal hydroxide (MOH) and isolating the dimetal salt of the formula
• b. halogenating the dimetal salt with a halogenating reagent POX3 where X is Br or Cl to obtain the halogenated product of the formula
• c. reacting the halogenated product with an amine
• in an aprotic solvent at about 20° C. to about 30° C. to obtain the amine product of the formula
• d. reacting an alkali metal hydride with an aminoalcohol HO—(CH2)n—NR3R4 for about 30 minutes in tetrahydrofuran at about 10 to 40° C., adding the amine product and heating to about 55-60° C. for about 12 to 20 h, to obtain the 6-[(substituted)phenyl]-triazolopyrimidine product
• e. reacting the 6-[(substituted)phenyl]-triazolopyrimidine product in water with a dicarboxylic acid of the formula
• wherein the dashed line is an optional bond and adding a solvent selected from t-butylmethyl ether, ethyl acetate and toluene to obtain the 6-[(substituted)phenyl]-triazolopyrimidine dicarboxylic acid salt as a solid
• f. crystallizing the 6-[(substituted)phenyl]-triazolopyrimidine dicarboxylic acid salt from water and collecting the 6-[(substituted)phenyl]-triazolopyrimidine dicarboxylic acid salt;
• g. forming the anhydrous 6-[(substituted)phenyl]-triazolopyrimidine dicarboxylic acid salt by drying the 6-[(substituted)phenyl]-triazolopyrimidine dicarboxylic acid salt;
• and
• h. treating the anhydrous 6-[(substituted)phenyl]-triazolopyrimidine dicarboxylic acid salt with water to obtain a 6-[(substituted)phenyl]-triazolopyrimidine dicarboxylic acid salt of formula (I) as a hydrated salt