Process for the synthesis of 6-((3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-3-(tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one

A process for the synthesis of 6-((3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-3-(tetrahydropyran-4-yl-7H-imidazo[1,5-α]pyrazin-8-one (Compound P3.1) of the following formula:

• wherein the process comprises the following steps:
• (a1) reacting a compound of formula 1:
• with a compound of the following formula:
• in the presence of trifluoroacetic acid (TFA), to provide a compound of formula Rac-2:
• (a2) reacting the compound of formula Rac-2 above with (+)-O,O-dibenzoyl-D-tartaric acid, to provide a compound of formula (S,S)-2:
• (a3) reacting the compound of formula (S,S)-2 above with di(tert-butyl) dicarbonate, followed by reacting with hydrogen gas in the presence of a Pd/C catalyst, to provide a compound of formula (S,S)-3:
• and
• (a4) reacting the compound of formula (S,S)-3 above with a compound of the following formula:
• in the presence of triethylamine and tert-butylmagnesium chloride, to provide a compound of formula (S,S)-4:
• (a5) reacting a compound of formula 5:
• with diisobutylaluminum hydride (DIBAL-H), to provide a compound of formula 6:
• (a6) reacting the compound of formula 6 above with a compound of the following formula:
• in the presence of aqueous ammonia, to provide a compound of formula 7:
• (a7) reacting the compound of formula 7 above with sodium methoxide (NaOMe), to provide a compound of formula 8:
• and
• (a8) reacting the compound of formula 8 above with N-bromosuccinimide (NBS), to provide a compound of formula 9:
• (a) reacting the compound of formula (S,S)-4:
• with the compound of formula 9:
• in the presence of potassium carbonate (K2CO3), followed by reacting with ammonium acetate (NH4OAc), to provide a compound of formula (S,S)-10:
• (b) reacting the compound of formula (S,S)-10 above with hydrogen gas in the presence of a Pd/C catalyst, to provide a compound of formula (S,S)-11:
• (c) reacting the compound of formula (S,S)-11 above with hydrochloric acid (HCl), to provide a compound of formula (S,S)-12:
• and
• (d) reacting the compound of formula (S,S)-12 above with a compound of the following formula:
• in the presence of N,N-diisopropylethylamine (DIEA), to provide 6-((3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-3-(tetrahydropyran-4-yl-7H-imidazo[1,5-α]pyrazin-8-one (Compound P3.1) above;
• wherein the process does not comprise chromatographic chiral resolution of the enantiomeric forms of any intermediates;
• and
• wherein the process does not comprise chromatographic chiral resolution of the enantiomeric forms of 6-((3S,4S)-4-methyl- 1 -(pyrimidin-2-ylmethyl)pyrrolidin-3 -yl)-3 -(tetrahydropyran-4-yl-7H-imidazo[1,5-α]pyrazin-8-one (Compound P3.1).