Process for the synthesis of intermediates useful for the synthesis of tubulin inhibitors

1. A process for the preparation of an aldehyde of the formula:

wherein:

R 1 and R 2 are independently selected from H, straight chain alkyl of 1 to 4 carbon atoms, halogen and alkoxy of 1 to 4 carbon atoms;

R 3 is straight chain alkyl of 1 to 4 carbon atoms;

by reacting a substituted oxirane of the formula:

with tris(pentafluorophenyl) borane to afford an aldehyde of the formula

2. A process for the preparation of an aldehyde of the formula:

wherein:

R 1 and R 2 are independently selected from H, straight chain alkyl of 1 to 4 carbon atoms, halogen and alkoxy of 1 to 4 carbon atoms;

R 3 is straight chain alkyl of 1 to 4 carbon atoms;

R 4 is straight chain alkyl of 1 to 4 carbon atoms and branched chain alkyl of 3 to 4 carbon atoms;

R 5 is straight chain alkyl of 1 to 4 carbon atoms;

comprising

a) alkylating benzylnitrile of the formula:

with an alkylating agent R 3 LG, in the presence of a strong base, to obtain a nitrile of the formula:

and

b) reducing a nitrile of step a with a reducing agent to give an aldehyde of the formula:

3. A process according to claim 2 wherein the strong base according to claim step a is potassium tert-butoxide ( t BuOK), sodium tert-butoxide ( t BuONa), lithium tert-butoxide ( t BuOLi), sodium hydride, potassium hydride, sodium hydroxide, or lithium diisopropylamide.

4. A process according to claim 3 wherein the strong base is potassium tert-butoxide ( t BuOK).

5. A process according to claim 2 step a wherein the alkylating agent R 3 LG is methyl iodide or methyl bromide or optionally methyl bromide in the presence of sodium iodide or tetrabutyl ammonium iodide.

6. A process according to claim 2 step b wherein the reducing agent is tin chloride/hydrochloric acid, lithium aluminum hydride or diisobutylaluminum hydride (DIBAL-H).

7. A process according to claim 6 wherein the reducing agent is diisobutylaluminum hydride (DIBAL-H).