Methods And Intermediates for Preparing 2-[(4-{6-[(4-Cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, 1,3-Dihydroxy-2-(hydroxymethyl)propan-2-amine Salt

A process for preparing bis(4-methylbenzenesulfonate) salt of 3-fluoro-4-(((6-(piperidin-4-yl) pyridin-2-yl)oxy)methyl)benzonitrile,

• which process comprising:
• (a1) reacting tert-butyl 4-(6-chloropyridin-2-yl) piperidine-1-carboxylate with 3-fluoro-4-(hydroxymethyl)benzonitrile in the presence a palladium catalyst, a base, and a phosphorous ligand, in a solvent system, to form the tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl) piperidine-1-carboxylate, wherein the amount of the 3-fluoro-4-(hydroxymethyl)benzonitrile is about 1.0 to about 1.1 molar equivalents to the tert-butyl 4-(6-chloropyridin-2-yl) piperidine-1-carboxylate;
• (a2) upon reaction completion in Step (a1), adding water, ethyl acetate, and ethanol to the reaction mixture;
• (a3) separating the organic phase from Step (a2) from the aqueous phase;
• (b1) adding p-toluenesulfonic acid monohydrate to the separated organic phase from Step (a3), thereby reacting the tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl) piperidine-1-carboxylate with the p-toluenesulfonic acid monohydrate, to form bis(4-methylbenzenesulfonate) salt of 3-fluoro-4-(((6-(piperidin-4-yl) pyridin-2-yl)oxy)methyl)benzonitrile, wherein the amount of the p-toluenesulfonic acid monohydrate is about 2.0 to about 3.0 molar equivalents to the tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl) piperidine-1-carboxylate;
• and
• (b2) isolating the bis(4-methylbenzenesulfonate) salt of 3-fluoro-4-(((6-(piperidin-4-yl) pyridin-2-yl)oxy)methyl)benzonitrile from Step (b1).

A process for preparing bis(4-methylbenzenesulfonate) salt of 3-fluoro-4-(((6-(piperidin-4-yl) pyridin-2-yl)oxy)methyl)benzonitrile,

• which process comprising:
• (a1) reacting tert-butyl 4-(6-chloropyridin-2-yl) piperidine-1-carboxylate with 3-fluoro-4-(hydroxymethyl)benzonitrile in the presence of a copper catalyst, and a ligand, in a solvent system, to form tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl) piperidine-1-carboxylate, wherein the amount of the 3-fluoro-4-(hydroxymethyl)benzonitrile is about 1.1 to about 1.3 (e.g. 1.2) molar equivalents to the tert-butyl 4-(6-chloropyridin-2-yl) piperidine-1-carboxylate;
• (a2) filtering the reaction mixture from Step (a1), wherein the filtering further comprises washing with methyl tert-butyl ether (MTBE);
• (a3) concentrating the filtrate from Step (2) to obtain the tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl) piperidine-1-carboxylate;
• (b1) dissolving the tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl) piperidine-1-carboxylate from Step (a3) in a solvent system comprising 1,4-dioxane and MTBE to form a solution;
• and then adding p-toluenesulfonic acid monohydrate to the solution, thereby reacting the tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl) piperidine-1-carboxylate with the p-toluenesulfonic acid monohydrate, to form bis(4-methylbenzenesulfonate) salt of 3-fluoro-4-(((6-(piperidin-4-yl) pyridin-2-yl)oxy)methyl)benzonitrile, wherein the amount of the p-toluenesulfonic acid monohydrate is about 2.0 to about 2.5 molar equivalents to the tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl) piperidine-1-carboxylate;
• and
• (b2) isolating the bis(4-methylbenzenesulfonate) salt of 3-fluoro-4-(((6-(piperidin-4-yl) pyridin-2-yl)oxy)methyl)benzonitrile from Step (b1).