Synthesis of BTK inhibitor and intermediates thereof

A process for preparing Compound 3′

• wherein HX is a pharmaceutically acceptable acid, comprising the steps of:
• a) combining a transaminase enzyme with a buffer solution or water, and a solid support, followed by incubation to prepare an immobilized transaminase enzyme;
• b) washing the immobilized transaminase enzyme with a buffer solution or water;
• c) washing with a transamination solvent;
• d) combining Compound 2 with isopropylamine and transamination solvent to provide a reaction stream;
• e) combining the reaction stream with the immobilized transaminase enzyme to produce a slurry comprising Compound 3;
• f) separating the slurry comprising Compound 3 from the immobilized transaminase enzyme to produce a solution comprising Compound 3;
• g) combining the solution comprising Compound 3 with a solution of an acid in a transamination solvent to produce a slurry comprising Compound 3′;
• and
• h) filtering the slurry to obtain Compound 3′ as a solid.

A process for preparing Compound 4′

• wherein HX is a pharmaceutically acceptable acid, comprising the steps of:
• a) adding Compound 3′ to a weakly coordinating solvent;
• b) adding a silane reductant or a borane reductant, and a Lewis acid and heating to about 30 to about 70° C. to produce a resulting solution;
• c) adding an alcohol to produce a solution comprising Compound 4′;
• d) cooling the solution to produce a slurry comprising Compound 4′;
• and
• e) filtering the slurry to obtain Compound 4′ as a solid.

A process for preparing Compound 4b comprising the steps of:

• a) adding Compound 3′ to an organic solvent;
• b) adding an organic base to produce a reaction mixture;
• c) adding a silane reductant and trimethylsilyl trifluoromethanesulfonate to the reaction mixture to produce a resulting solution;
• d) adding water to the resulting solution to create a two-layer mixture comprising Compound 4b, said two-layer mixture having a top layer and a bottom layer, and separating the bottom from the two-layer mixture comprising Compound 4b;
• e) cooling the bottom phase to produce a resulting slurry;
• and
• f) filtering the slurry to obtain Compound 4b as a solid.