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
Inventors
Svenstrup, Niels • Zhang, Jun • Sun, Jikui • Chen, Yuyin • Kong, Jianshe • Ma, Rujian • Zhang, Junhua • Qin, Liang • XIAO, Huanming • SUN, Jinxu • Meng, Xiao • SUN, Fenglai • Zhu, Jingyang
Assignees
Cydan Development Inc • Changzhou Syntheall Pharmaceutical Co Ltd • Wuxi Apptec Hong Kong Ltd • Wuxi Apptec Tianjin Co Ltd • STA Pharmaceutical Hong Kong Ltd • Cardurion Pharmaceuticals Inc
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Publication Number
US-11370795-B2
Publication Date
2022-06-28
Expiration Date
Abstract
The present invention relates 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-a]pyrazin-8-one, comprising use of the chiral acid (+)-O,O-Dibenzoyl-D-tartaic acid.
Core Innovation
The invention relates to 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-a]pyrazin-8-one of formula P3.1. The process comprises reacting a compound of formula (S,S)-4 with a compound of formula 9 in the presence of potassium carbonate (K2CO3) followed by reaction with ammonium acetate (NH4OAc) to provide a compound of formula (S,S)-10. The compound of formula (S,S)-10 is then reacted with hydrogen gas in the presence of a Pd/C catalyst to provide a compound of formula (S,S)-11.
The compound of formula (S,S)-11 is then reacted with hydrochloric acid (HCl) to provide a compound of formula (S,S)-12. Finally, (S,S)-12 is reacted with a compound of a specified formula in the presence of N,N-diisopropylethylamine (DIPEA) to provide the compound of formula P3.1. The document further supports the disclosed enantiomeric form of Compound P3.1 by introducing a synthesis of Compound P3.1 (S,S enantiomer) involving chiral acid resolution using (+)-O,O-dibenzoyl-D-tartaric acid, and includes statements directed to stereochemical purity/impurity control and avoiding chiral chromatographic separation.
The document also provides an alternate precursor sequence to reach compound 9 using diisobutylaluminum hydride (DIBAL-H), aqueous ammonia, sodium methoxide (NaOMe), and N-bromosuccinimide (NBS). It further mentions an alternative asymmetric enzymatic hydrolysis (HLE) route using human leukocyte elastase, with reported enantiomeric excess (ee) and yield ranges from enzyme screening results. The synthesis to P3.1 includes quantitative quality targets, including yield and purity ranges reported for P3.1.
Claims Coverage
The consolidated claim coverage includes one independent claim directed to a sequential synthetic process to P3.1, plus dependent claims refining chiral preparation, precursor construction to reach intermediate 9, and quantitative constraints for chiral purity and yield. Across the claim set, the inventive features are organized around conversion to (S,S)-10, (S,S)-11, and (S,S)-12, hydrogenation and acid treatment, and final coupling, with additional refinements specifying upstream chiral resolution or creation and a single-reactor limitation.
Sequential conversion to (S,S)-10 via K2CO3 and NH4OAc
Reacting a compound of formula (S,S)-4 with a compound of formula 9 in the presence of potassium carbonate (K2CO3) followed by a reaction with ammonium acetate (NH4OAc), to provide a compound of formula (S,S)-10.
Hydrogenation to (S,S)-11 using H2 and Pd/C
Reacting the compound of formula (S,S)-10 with hydrogen gas in the presence of a Pd/C catalyst, to provide a compound of formula (S,S)-11.
HCl treatment to (S,S)-12
Reacting the compound of formula (S,S)-11 with hydrochloric acid (HCl), to provide a compound of formula (S,S)-12.
Final coupling to P3.1 in the presence of DIPEA
Reacting the compound of formula (S,S)-12 with a compound of the following formula in the presence of N,N-diisopropylethylamine (DIPEA), to provide 6-((3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one of the formula P3.1.
Chiral resolution and intermediate construction using named chiral and reagent steps
A process that forms an (S,S) intermediate by reacting a compound of formula 1 with a compound of Rac-2 in the presence of trifluoroacetic acid (TFA) to provide a compound of formula (S,S)-2, then reacting (S,S)-2 with (+)-O,O-dibenzoyl-D-tartaric acid to provide (S,S)-2, then reacting (S,S)-2 with di(tert-butyl) dicarbonate and hydrogen gas with a Pd/C catalyst to provide (S,S)-3, and reacting (S,S)-3 with a compound of the specified formula in the presence of triethylamine and tert-butyl magnesium chloride to provide (S,S)-4.
Chiral purity constraint for the (S,S) intermediate (S,S)-2
The process characterized in that the compound of formula (S,S)-2 has a chiral purity between 99.89% and 99.98%.
Alternate precursor sequence to reach compound 9 using DIBAL-H/ammonia/NaOMe/NBS
A process that reacts a compound of formula 5 with diisobutylaluminum hydride (DIBAL-H) to form formula 6, reacts formula 6 with a compound of the specified formula in the presence of aqueous ammonia to form formula 7, reacts formula 7 with sodium methoxide (NaOMe) to form formula 8, and reacts formula 8 with N-bromosuccinimide (NBS) to form compound 9.
Execution of step (a) in a single reactor
The process defined in that step (a) is carried out in a single reactor.
Yield range constraint for Compound of formula P3.1
The process further specifies that the yield 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 of formula P3.1 is within 50% to 80%.
The consolidated claim coverage centers on the defined sequential conversion steps using specified reagents and catalysts to reach formula P3.1, the use of chiral-resolution-related steps via (+)-O,O-dibenzoyl-D-tartaric acid to obtain (S,S) intermediates, and constraints on intermediate chiral purity and final yield, including performing step (a) in a single reactor and an alternate route to reach compound 9.
Stated Advantages
Low blood-brain barrier penetration.
PDE9 potency/selectivity.
Stated stereochemical purity/impurity control for the S,S enantiomer (via chiral acid resolution).
Documented Applications
Pharmaceutical composition and therapeutic use for sickle cell disease (SCD) and related conditions, and mention of related conditions including benign prostate hyperplasia (BPH), erectile dysfunction, type 2 diabetes, and beta thalassemia with fetal hemoglobin (HbF) in the context of the document.
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