Synthesis of bruton's tyrosine kinase inhibitors

A method of synthesizing a compound of Formula (I):

• wherein:
• R1 is selected from C5-10 aryl and C4-9 heteroaryl wherein the aryl or heteroaryl are optionally substituted with one or more groups independently selected from C1-6 alkyl;
• and
• R2 is selected from C1-6 alkyl and C2-6 alkenyl;
• comprising contacting the compound
• with an acid and a first solvent followed by contacting with the compound
• in the presence of one or more coupling reagents, an amine base, and a second solvent to obtain the compound of Formula (I).

A method of isolating the P atropisomer from a mixture of M and P isomers of compound of Formula (II), comprising the steps of:

• 1) Dissolving the compound of Formula (II) in one or more solvents in a vessel to form a solution;
• 2) Adding water to the solution and waiting for a time period of about 2 hours to 24 hours to form a suspension;
• 3) Filtering the suspension to obtain the crystals of compound of Formula P-(II);
• 4) Collecting the filtrate and heating the filtrate to a temperature of about 75° C. to about 150° C. for a time period of about about 5 minutes to about 1 hour;
• 5) Cooling the filtrate to a temperature of about 20° C. to about 30° C.;
• 6) Repeating steps 3-5 about 20-100 times until the M isomer is converted to the P isomer,
• 7) Collecting the precipitate, washing the precipitate, and drying the precipitate under humidified conditions to obtain the compound of Formula P-(II).