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1. A process for preparing a compound of Formula I:and pharmaceutically acceptable salts thereof,wherein said process comprises:
(A) (i) contacting the compound of Formula VI with bis(pinacoloato)diboron in the presence of an acetate or pivalate base, a transition metal catalyst, and optionally in the presence of a phosphorus ligand source, in a mixture of water and an organic solvent E, to provide an intermediate compound of Formula VII:then (ii) contacting the intermediate compound of formula VII with a compound of formula VIIbin the presence of a carbonate, acetate or pivalate base and a transition metal catalyst, and optionally in the presence of a phosphorus ligand source, in said mixture of water and organic solvent E, to provide a compound of formula VIII:wherein organic solvent E is selected from dimethylacetamide, toluene, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether, isopropanol, ethanol, ethyl acetate, isopropyl acetate and dimethoxyethane; and
(B) (i) contacting the di-p-nitrobenzoate salt of the compound of Formula VIII with an inorganic base, in an organic solvent F, for a time sufficient to remove the Boc protecting groups from the compound of Formula VIII, then (ii) contacting the deprotected compound in situ with HCl to provide a compound of Formula IX:wherein organic solvent F is selected from methanol, acetonitrile, tetrahydrofuran, 2-methyl tetrahydrofuran, ethanol, isopropanol and toluene; and
(C) contacting the compound of Formula IX with: (i) an additive selected from 2-hydroxypyridine-N-oxide, N-hydroxysuccinimide, HOBt and pyridine, and (ii) a non-nucleophilic base) in the presence of (i) a compound of formula Xa:and (ii) an amide coupling reagent in an organic solvent G to provide a compound of Formula I:wherein organic solvent G is selected from tetrahydrofuran, N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidinone and dimethylsulfoxide; andwherein
each occurrence of R1 is independently C1-C6 alkyl, C3-C7 cycloalkyl or C6-C10 aryl; each occurrence of R2 is independently C1-C6 alkyl, C3-C7 cycloalkyl, 3 to 7-membered monocyclic heterocycloalkyl or C6-C10 aryl; R3 is C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 5 or 6-membered monocyclic heteroaryl or 9 or 10-membered bicyclic heteroaryl, wherein said C3-C7 cycloalkyl group, said C6-C10 aryl group, said 5 or 6-membered monocyclic heteroaryl group or said 9 or 10-membered bicyclic heteroaryl group can be optionally substituted with up to three groups, each independently selected from C1-C6 alkyl and C3-C7 cycloalkyl; and Ra is Br, Cl or I. |
