Process for preparing carboxamidine compounds

A process of making a compound of formula I:

• the process comprising:
• a) reducing a carbonyl compound of formula II under asymmetric reduction conditions, such as asymmetric hydrogenation or asymmetric transfer hydrogenation using, but not limited to, formic acid/triethylamine or potassium hydroxide/isopropyl alcohol, in the presence of a suitable catalyst, in a suitable solvent, to provide a compound of formula III:
• b) reacting the compound of formula III with a C1-5 dialkylcarbamoyl chloride, in a suitable solvent, in the presence of a suitable base, to provide a carbamate of formula IV, wherein R is C1-5 alkyl:
• c) reacting the compound of formula IV with a suitable borane, boronic acid or boronic acid ester, such as R2—B(YRa)(YRb), in a suitable solvent, in the presence of a suitable base, at a suitable temperature to provide an intermediate of formula V, wherein Y is a bond or oxygen, Ra and Rb are each independently hydrogen, C1-5 alkyl, C3-8 cycloalkyl, or Ra and Rb together with the atoms to which they are attached form a ring which is optionally substituted with 1-6 substituents selected from C1-3 alkyl, C3-6 cycloalkyl, and C1-3 alkoxyl:
• d) reacting the compound of formula V with a methylene equivalent such as, but not limited to, dichloromethane, in the presence of a suitable base such as metal-C1-5 dialkylamides or metal-C1-5 dialkyl bases wherein the metal is lithium, sodium, potassium, calcium or magnesium, in a suitable solvent, in the presence of an oxidizing agent such as, but not limited to, hydrogen peroxide, to provide a carboxaldehyde of formula VI:
• e) reacting the carboxaldehyde of formula VI with hydroxylamine, in a suitable solvent, to provide an oxime of formula VII:
• and
• f) reacting the oxime of formula VII with an acid, such as hydrogen chloride, followed by the reaction with reagents such as N-chlorosuccinimide and ammonium hydroxide, in a suitable solvent, to provide a carboxamidine of formula I:
• wherein:
• R1 and R2 are each independently hydrogen, C1-7 alkyl or C3-10carbocycle, with the proviso that both R1 and R2 are not simultaneously hydrogen;
• R4 is hydrogen, C1-3 alkyl, halogen or nitrile;
• and
• X is halogen.