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 Tianjin Co Ltd • Wuxi Apptec Hong Kong Ltd • STA Pharmaceutical Hong Kong Ltd • Cardurion Pharmaceuticals Inc
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Publication Number
US-11999741-B2
Publication Date
2024-06-04
Expiration Date
Abstract
The present disclosure relates to processes for preparing 64(3s,4s)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-3-(tetrahydropyran-4-yl-7h-imidazo[1,5-a]pyrazin-8-one.
Core Innovation
The disclosed subject matter 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-α]pyrazin-8-one (Compound P3.1). The process comprises sequential reactions of defined formula intermediates, including (S,S)-4 and compound of formula 9, followed by potassium carbonate, ammonium acetate, hydrogen gas with Pd/C, hydrochloric acid, and N,N-diisopropylethylamine, culminating in Compound P3.1 according to the defined formula.
A key aspect is that the process does not comprise chromatographic chiral resolution of the enantiomeric forms of any intermediates or of Compound P3.1. Instead, stereochemical outcomes are obtained within the synthesis sequence, including conversion routes that involve racemic-to-(S,S) formation using reagents described in the process, such as (+)-O,O-dibenzoyl-D-tartaric acid and related chiral acids in the claim set.
The synthesis description further includes example preparation of Compound P3.1 and key intermediates, with conversion steps through (S,S)-2, (S,S)-3, (S,S)-4, intermediate 9, (S,S)-10, (S,S)-11, and (S,S)-12, followed by final deprotections to P3.1. The document also reports formulation and stability studies for P3.1, including packaging in capsules and solution stability under ambient and refrigerated conditions.
Claims Coverage
The partial content provides two independent claims. Across these independent claims, there are multiple inventive features centered on a defined multi-step synthetic sequence to Compound P3.1 and an explicit exclusion of chromatographic chiral resolution, with one claim additionally covering an extended pre-sequence using specific stereochemical handling reagents.
Multi-step synthesis to Compound P3.1 using defined intermediates
A process for the synthesis of Compound P3.1 in which defined steps react (S,S)-4 with compound of formula 9 in the presence of K2CO3 and then ammonium acetate, use hydrogen gas with Pd/C to provide (S,S)-11, reaction with HCl to provide (S,S)-12, and reaction with a compound of the following formula in the presence of DIEA to provide Compound P3.1.
No chromatographic chiral resolution of intermediates or Compound P3.1
The process does not comprise chromatographic chiral resolution of the enantiomeric forms of any intermediates, and does not comprise chromatographic chiral resolution of the enantiomeric forms of Compound P3.1.
Extended pre-sequence with specified reagents prior to (S,S)-4
A process comprising steps in which a compound of formula 1 reacts with TFA to provide Rac-2; Rac-2 reacts with (+)-O,O-dibenzoyl-D-tartaric acid to provide (S,S)-2; (S,S)-2 reacts with di(tert-butyl) dicarbonate followed by hydrogen gas with Pd/C to provide (S,S)-3; (S,S)-3 reacts with a compound of the following formula in the presence of triethylamine and tert-butylmagnesium chloride to provide (S,S)-4; and further steps transform formula 5 through formula 9 using DIBAL-H, aqueous ammonia, NaOMe, and NBS.
Both independent claims require a multi-step synthetic process to Compound P3.1 using specified intermediate transformations and explicitly exclude chromatographic chiral resolution for intermediates and for Compound P3.1. One independent claim additionally specifies an extended pre-sequence that produces (S,S)-4 from Rac-2 via (+)-O,O-dibenzoyl-D-tartaric acid and includes further reagent-defined transformations to reach the (S,S)-4 stage.
Stated Advantages
Avoids chromatographic chiral resolution of the enantiomeric forms of any intermediates.
Avoids chromatographic chiral resolution of the enantiomeric forms of Compound P3.1.
Documented Applications
Treatment context for sickle cell disease, including increasing cGMP and HbF and reducing sickle RBC percentage, bilirubin, and leucocytes.
Formulation and stability studies for Compound P3.1, including packaging in capsules and stability of P3.1 in solution at ambient and refrigerated conditions.
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