Patent ID: 8497374
Filing Date: 2013-07-30
Classification: C07F,Y02P

Abstract:
1. A process of synthesizing bortezomib in its anhydride form of the following formula comprising the steps of: i) coupling a compound of formula I wherein: HX is a mineral acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, perchloric acid, and periodic acid; or an organic acid selected from the group consisting of acetic acid, chloroacetic acid, dichloroacetic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, benzoic acid, 4-phenylbenzoic acid, 4-chlorobenzoic acid, 4-bromobenzoic acid, tartaric acid, citric acid, malic acid, oxalic acid, malonic acid, 4-methylbenzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, and a natural amino acid; and the moiety is selected from the group consisting of with an N-protected enantio-enriched L-phenylalanine of the following formula to provide a mixture comprising compounds of formula IV and formula V wherein PO is an N-protecting group selected from the group consisting of tert-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), benzyloxy-carbonyl (Cbz), 9H-fluoren-9-ylmethoxycarbonyl (Fmoc), triphenylmethyl (Trityl), and dimethoxy)triphenylmethyl (DMTr); ii) deprotecting the compounds of formula IV and formula V, which are present in the mixture obtained in step i) in the presence of an acid to provide a mixture of a compound of formula II and a compound of formula III wherein HY is a mineral acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, perchloric acid, and periodic acid; or an organic acid selected from the group consisting of acetic acid, chloroacetic acid, dichloroacetic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, benzoic acid, 4-phenylbenzoic acid, 4-chlorobenzoic acid, 4-bromobenzoic acid, tartaric acid, citric acid, malic acid, oxalic acid, malonic acid, 4-methylbenzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, and a natural amino acid; and iii) resolving the compounds of formula II and formula III, which are present in the mixture obtained in step ii), to provide an enriched compound of formula II, iv) reacting the compound of formula II with 2-pyrazinecarboxylic acid in the presence of a base to provide a compound of formula VI v) converting the compound of formula VI obtained in step iv), in the presence of an acid followed by extraction into dichloromethane (DCM) and concentration and precipitation from EtOAc and n-heptane, to provide bortezomib in its anhydride form.