Process for preparing btk inhibitors

A method of reducing byproduct formation in a Suzuki coupling reaction, the method comprising:

• (a) forming a reaction mixture comprising compound 170, compound 181, a palladium catalyst, a solvent system, and a base, wherein the equivalent ratio of the palladium catalyst to compound 170 is from about 0.001:1 to less than 0.005:1;
• and
• (b) reacting the reaction mixture to form a reaction product mixture comprising compound 190, or salt thereof, according to the following scheme:
• wherein the palladium catalyst comprises a palladium(II) species containing a phosphine ligand and at least one palladium-carbon bond,
• wherein:
• (i) the fragment giving rise to the palladium-carbon bond is an allyl derivative of the formula
• wherein each of R6 to R10 is independently selected from the group consisting of H, optionally substituted C1-6 alkyl, optionally substituted C6 aryl, and optionally substituted heteroaryl;
• and R6 and R10 may optionally come together to form a fused bicycle comprising an aromatic ring;
• wherein:
• (a) the content of a dimer impurity is less than 0.1 area % based on compound 190, or salt thereof, wherein the dimer impurity is of the structure
• and
• (b) the combined content of an alcohol and a ketone impurity is less than 0.25 area % based on compound 190, or salt thereof, wherein the alcohol and ketone impurities are of the structures

A method of preparing compound 141, or a salt thereof, the method comprising:

• (a) forming a first reaction mixture comprising compound 140, a catalyst, a solvent, and hydrogen;
• (b) reacting the first reaction mixture to form a first reaction product mixture comprising compound 141 according to the following scheme
• wherein the first reaction mixture catalyst is selected from the group consisting of Ra—Ni, Ra—Co, Pt/V@C, Co@Chitin, Ni-phen@SiO2, and Ni-phen@TiO2;
• and
• wherein the yield of compound 141 based on compound 140 is at least 95%.

A composition, comprising at least 98.5 w/w % compound 190, or salt thereof,

• and wherein
• (a) the content of a dimer impurity is less than 0.15 area % based on compound 190, wherein the dimer impurity is of the structure
• and
• (b) the combined content of an alcohol and a ketone impurity is less than 0.35 area % based on compound 190, wherein the alcohol and ketone impurities are of the structures