Process for preparing substituted imidazo[1,5-α]pyrazines

A process for preparing a compound of formula IX:

• or a stereoisomer thereof,
• wherein:
• R7 is C1-6 alkyl, CmH2m—C(O)OR, CmH2m—C3-7 cycloalkyl-C(O)OR, C3-7 cycloalkyl, or phenyl-C(O)OR;
• R is H or C1-6 alkyl;
• m is 1, 2, 3, 4, 5, or 6;
• and
• is or
• wherein the process comprises the following steps:
• (a) reacting a compound of formula II:
• with hydrogen in the presence of a solvent and a palladium catalyst or a platinum catalyst, to form a compound of formula III:
• (b) reacting the compound of formula III formed in step (a) above with a hydrolase selected from the group consisting of an amidase and a peptidase, or a mixture thereof, to form a compound of formula I:
• or a salt or stereoisomer thereof,
• wherein:
• is or
• (c) protecting the compound of formula I formed in step (b) above, or a salt or stereoisomer thereof, with an amino protecting group (PG) selected from the group consisting of di-tert-butyl dicarbonate (Boc2O) and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile, to form a compound of formula IV:
• or a salt or stereoisomer thereof,
• wherein:
• is or
• (d) reacting the compound of formula IV formed in step (c) above, or a salt or stereoisomer thereof, with a compound of the following formula:
• R7—NH2,
• wherein:
• R7 is C1-6 alkyl, CmH2m—C(O)OR, CmH2m—C3-7 cycloalkyl-C(O)OR, C3-7 cycloalkyl, or phenyl-C(O)OR;
• R is H or C1-6 alkyl;
• and
• m is 1, 2, 3, 4, 5, or 6;
• in the presence of a base and the coupling agent, carbonyldiimidazole (CDI), to form a compound of formula V:
• or a salt or stereoisomer thereof,
• wherein:
• PG is C(O)OC(CH3)2;
• R7 is C1-6 alkyl, CmH2m—C(O)OR, CmH2m—C3-7 cycloalkyl-C(O)OR, C3-7 cycloalkyl, or phenyl-C(O)OR;
• R is H or C1-6 alkyl;
• m is 1, 2, 3, 4, 5, or 6;
• and
• is or
• (e) reacting the compound of formula V formed in step (d) above, or a salt or stereoisomer thereof, with oxalyl chloride, to form a compound of formula VI:
• or a stereoisomer thereof,
• wherein:
• PG is C(O)OC(CH3)2;
• R7 is C1-6 alkyl, CH2m—C(O)OR, CmH2m—C3-7 cycloalkyl-C(O)OR, C3-7 cycloalkyl, or phenyl-C(O)OR;
• R is H or C1-6 alkyl;
• m is 1, 2, 3, 4, 5, or 6;
• and
• is or
• (f) reacting the compound of formula VI formed in step (e) above, or a stereoisomer thereof, with a reducing agent selected from the group consisting of BH3·THF and NaBH4, to form a compound of formula VII:
• or a stereoisomer thereof,
• wherein:
• PG is C(O)OC(CH3)2;
• R7 is C1-6 alkyl, CmH2m—C(O)OR, CmH2m—C3-7 cycloalkyl-C(O)OR, C3-7 cycloalkyl, or phenyl-C(O)OR;
• R is H or C1-6 alkyl;
• m is 1, 2, 3, 4, 5, or 6;
• and
• is or and
• (g) deprotecting the compound of formula VII formed in step (f) above, or a stereoisomer thereof, with concentrated HCl in methyl isobutyl ketone (MIBK), to form a compound of formula IX:
• or a stereoisomer thereof,
• wherein:
• R7 is C1-6 alkyl, CmH2m—C(O)OH, CmH2m—C3-7 cycloalkyl-C(O)OH, C3-7 cycloalkyl, or phenyl-C(O)OH;
• m is 1, 2, 3, 4, 5, or 6;
• and
• is or .