US 11,999,741 B2
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
Niels Svenstrup, Charlottenlund (DK); Jun Zhang, Tianjin (CN); Jikui Sun, Tianjin (CN); Yuyin Chen, Beijing (CN); Jianshe Kong, Franklin Park, NJ (US); Rujian Ma, Shanghai (CN); Junhua Zhang, Chang Zhou (CN); Liang Qin, Chang Zhou (CN); Huanming Xiao, Beijing (CN); Jinxu Sun, Beijing (CN); Xiao Meng, Shanghai (CN); Fenglai Sun, Shanghai (CN); and Jingyang Zhu, Monmouth Junction, NJ (US)
Assigned to Cardurion Pharmaceuticals, Inc., Burlington, MA (US)
Filed by Cardurion Pharmaceuticals, Inc., Burlington, MA (US)
Filed on Apr. 19, 2022, as Appl. No. 17/723,669.
Application 17/723,669 is a continuation of application No. 16/615,347, granted, now 11,370,795, previously published as PCT/US2018/034566, filed on May 25, 2018.
Claims priority of provisional application 62/511,367, filed on May 26, 2017.
Prior Publication US 2023/0183244 A1, Jun. 15, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 487/04 (2006.01)
CPC C07D 487/04 (2013.01) 11 Claims
 
1. 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:

OG Complex Work Unit Chemistry
wherein the process comprises the following steps:
(a) reacting a compound of formula (S,S)-4:

OG Complex Work Unit Chemistry
with a compound of formula 9:

OG Complex Work Unit Chemistry
in the presence of potassium carbonate (K2CO3), followed by reacting with ammonium acetate (NH4OAc), to provide a compound of formula (S,S)-10:

OG Complex Work Unit Chemistry
(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:

OG Complex Work Unit Chemistry
(c) reacting the compound of formula (S,S)-11 above with hydrochloric acid (HCl), to provide a compound of formula (S,S)-12:

OG Complex Work Unit Chemistry
and
(d) reacting the compound of formula (S,S)-12 above with a compound of the following formula:

OG Complex Work Unit Chemistry
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-ylmethyppyrrolidin-3-yl)-3-(tetrahydropyran-4-yl-7H-imidazo [1,5-α]pyrazin-8-one (Compound P3.1).