METHOD FOR THE ENANTIOSELECTIVE SYNTHESIS OF 2(S)-AMINO-6-BORONOHEXANOIC ACID (ABH) AND PURIFICATION THEREOF

摘要

The invention relates to a method for the enantioselective synthesis and purification of 2(S)-amino-6-boronohexanoic acid (ABH) and the preparation of the corresponding synthetic intermediates. The method comprises the preparation of ABH from BPB-Ni-Gly, which is treated with a strong base in a suitable solvent, and is made to react with 2-(4-lower bromoalkyl)benzo[d] [1,3,2]dioxaborol, where the lower alkyl is an alkyl with between 1 and 6 carbon atoms, preferably 2-(4- bromo-butyl)benzo[d][1,3,2]dioxaborol, while stirring, in a nitrogen atmosphere and with a cryogenic bath at a low temperature (-50°C), in order to then permit same to reach ambient temperature, removing the cryogenic bath, before neutralising in aqueous medium with a weak organic acid, and extracting with dichloromethane, drying the resulting organic extract which is subsequently filtered and vacuum evaporated. The resulting alkylated complex is dissolved in a C1-C5 alcohol, adding a hydrochloric acid, refluxing in a nitrogen atmosphere, and is subsequently cooled to ambient temperature, and concentrated in order to achieve the precipitation of (S)-2-[N-(N'- benzylprolyl) amino]benzophenone (BPB), as the hydrochloride salt, filtering and extracting with dichloromethane, and after dissolving the aqueous phase of the filtrate in water, it is treated with ammonia concentrated to pH 9, and once again extracted with dichloromethane, the ammoniacal aqueous phase being vacuum evaporated until dry, in order to produce crude ABH, as the ammonium salt, which is subsequently purified by means of ion-exchange chromatography. The invention also relates to a method for preparing the Gly-Ni-BPB complex, 2-(4- bromo-butyl)benzo[d][1,3,2]dioxaborol, which is used as an alkylating agent in the form of a borate side chain, and (S)-N- benzylproline (BP).