Processes for the Preparation of Acalabrutinib and Intermediates Thereof

#The present invention relates to processes for the preparation of Acalabrutinib (1) and intermediates used in the preparation thereof.

#Acalabrutinib (1), or 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide, exhibits activity as a Bruton's tyrosine kinase (BTK) inhibitor and is undergoing evaluation in clinical trials in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in Europe and the United States. Acalabrutinib (1) has the following structural formula:

#Scheme 1 depicts a method of preparing Acalabrutinib (1) that is described in WO 2013/010868 A1. In this method, Acalabrutinib (1) is prepared from bromide (A) by Suzuki coupling with boronic acid (B), followed by deprotection of the pyrrolidine amine of intermediate (C) to provide intermediate (D), and a coupling with 2-butynoic acid (E) to yield Acalabrutinib (1).

#Development of the processes of the present invention followed from the discovery by the inventors that problems associated with the known processes for the preparation of Acalabrutinib (1) could be addressed through the use of novel activation and coupling conditions between a compound of Formula (5) and 2-butynoic acid (7). Additionally, when G1 is halide, a novel pathway to Acalabrutinib (1), proceeding through the compounds of Formulas (5-B) and (2) is provided. In both the direct and indirect pathways to Acalabrutinib (1), embodiments of the invention provide processes for the coupling of the compound of Formula (5) and 2-butynoic acid (7) in good yields.

#As used herein, the term “aliphatic”, alone or as part of another substituent, means, unless otherwise stated, a straight chain, branched chain or cyclic hydrocarbon radical, or a combination thereof, which may be fully saturated, or mono- or polyunsaturated, and can include di- and multivalent radicals, having the number of carbon atoms designated. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, hexanyl, 2-methyl-2-hexanyl, cyclohexyl, 1-methylcyclohexyl, cyclopropylmethyl, and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated hydrocarbon radical is one having one or more double bonds or triple bonds. Examples of unsaturated hydrocarbon radicals include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), norbornenyl, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, and the higher homologs and isomers.

#As used herein, the term “alkyl”, alone or as part of another substituent, means, unless otherwise stated, a straight or branched chain, saturated hydrocarbon radical having the number of carbon atoms designated (e.g., C1-C4 means one to four carbon atoms). When there is no indication of the number of carbon atoms in the alkyl, it is meant, unless otherwise indicated by context, that there are from 1 to 10 carbons. Examples of saturated hydrocarbon groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl and sec-butyl.