| 主权项 |
1. A process of making a compound of formula I: the process comprising: a) reducing a carbonyl compound of formula II under asymmetric reduction conditions selected from the group consisting of asymmetric hydrogenation and asymmetric transfer hydrogenation using, 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 of the following formula R2—B(YRa)(YRb), in a suitable solvent, in the presence of a suitable metal-C1-5dialkylamide or metal-disilylC1-5alkylamide base wherein the metal is lithium, sodium, potassium, calcium or magnesium, 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 unsubstituted or substituted with 1-6 substituents selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, and C1-3 alkoxyl: d) reacting the compound of formula V with a methylene equivalent in the presence of a suitable metal-C1-5dialkylamide or metal-disilylC1-5alkylamide base wherein the metal is lithium, sodium, potassium, calcium or magnesium, in a suitable solvent, in the presence of an oxidizing agent, 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, followed by the reaction with 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 C3-10 carbocycle, with the proviso that both R1 and R2 are not simultaneously hydrogen; R4 is hydrogen, C1-3 alkyl, halogen or nitrile; and X is bromo or iodo. |
