Process for making substituted thiazolyl-amino pyridines

A process for preparing 4-[2-(5-cyano-thiazol-2-ylamino)-pyridin-4-ylmethyl]-piperazine-1-carboxylic acid methylamide which comprises the steps of:

• a) preparing a slurry of 2-chloro-4-formylpyridine, 2-aminothiazole and K3PO4 in toluene;
• b) adding Pd2(dba)3 and Xantphos to the slurry to produce a coupling product;
• c) adding N-methylaminocarbonylpiperazine in DMAc to the coupling product;
• and
• d) completing a reductive amination by adding Et3N, acetic acid and NaBH(OAc)3 to produce 4-[2-(5-cyano-thiazol-2-ylamino)-pyridin-4-ylmethyl]-piperazine-1-carboxylic acid methylamide.

A process for preparing a compound of Formula I

• 48
• or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
• R is H, unsubstituted or substituted C1-C10 alkyl or unsubstituted or substituted aryl;
• R1 is —C(═O)NR3H;
• R2 is
• 1) H,
• 2) OH,
• 3) OC1-C6 alkyl,
• 4) C1-C6 alkyl, or
• 5) halo;
• and
• R3 is C1-C6 alkyl;
• which comprises the steps of:
• a) preparing a slurry of a compound of Formula II
• 49
• (where R is defined above), a compound of Formula III
• 50
• (where Z is CN or CO2H;
• X is a halo and R2 is defined above) and a base in a solvent;
• b) adding a palladium catalyst and a bisphosphine ligand to the slurry to produce a coupling product of Formula IV
• 51
• c) reducing the coupling product of Formula IV;
• d) adding a piperazine-urea of Formula V
• 52
• to the coupling product of Formula IV;
• and
• e) completing a reductive amination to produce the compound of Formula I.

A process for preparing a compound of Formula I

• 53
• or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
• R is H, unsubstituted or substituted C1-C10 alkyl or unsubstituted or substituted aryl;
• R1 is —C(═O)NR3H;
• R2 is
• 1) H,
• 2) OH,
• 3) OC1-C6 alkyl,
• 4) C1-C6 alkyl, or
• 5) halo;
• and
• R3 is C1-C6 alkyl;
• which comprises the steps of:
• a) preparing a slurry of a compound of Formula II
• 54
• (where R is defined above), a compound of Formula III
• 55
• (where X is a halo and R2 is defined above) and a base in a solvent;
• b) adding a palladium catalyst and a bisphosphine ligand to the slurry to produce a coupling product of Formula IV
• 56
• c) halogenating the coupling product of Formula IV;
• d) adding a piperazine-urea of Formula V
• 57
• to the coupling product of Formula IV;
• and
• e) completing a reductive amination to produce the compound of Formula I.

A process for preparing a compound of Formula I

• 58
• or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
• R is H, unsubstituted or substituted C1-C10 alkyl or unsubstituted or substituted aryl;
• R1 is —C(═O)NR3H;
• R2 is
• 1) H,
• 2) OH,
• 3) OC1-C6 alkyl,
• 4) C1-C6 alkyl, or
• 5) halo;
• and
• R3 is C1-C6 alkyl;
• which comprises the steps of:
• a) preparing a slurry of a compound of Formula II
• 59
• (where R is defined above), a compound of Formula III
• 60
• (where X is a halo and, R and R2 are defined above) and a base in a solvent;
• b) adding a palladium catalyst and a bisphosphine ligand to the slurry to produce a coupling product of Formula IV
• 61
• c) adding a piperazine-urea of Formula V
• 62
• to the coupling product of Formula IV;
• and
• d) completing a reductive amination to produce the compound of Formula I.

A process for preparing Xantphos comprising the steps of:

• a) adding MTBE, 9,9-dimethylxanthene and TMEDA to produce a solution;
• b) adding s-BuLi to the solution to produce a mixture;
• c) slowly adding Ph2PCl to produce a resulting mixture;
• d) aging the resulting mixture and adding more Ph2PCl;
• and
• e) filtering to isolate Xantphos.