Processes for preparation of soluble guanylate cyclase stimulators
Inventors
Xue, Song • Karnati, Vishnu Vardhan Reddy • Livingston, Robert C. • Barden, Timothy Claude • Schairer, Wayne C.
Assignees
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Publication Number
US-12247025-B2
Publication Date
2025-03-11
Expiration Date
Abstract
The present disclosure relates to novel processes for the preparation of compounds useful as stimulators of soluble guanylate cyclase (sGC). These processes are amenable to large scale preparation and produce stable 3-(2-pyrimidinyl)pyrazoles of Formula (I), including Compound (I), Compound (IA) and Compound (IB), in high purity and yields. The present invention has the additional advantage of facile reaction conditions, amenable to scale up for large scale manufacturing. The disclosure also provides novel intermediates useful in the preparation of said compounds.
Core Innovation
The disclosure provides processes for preparing soluble guanylate cyclase (sGC) stimulators comprising 3-(2-pyrimidinyl)pyrazoles of Formula I, including related compounds such as Compound I, Compound IA, and Compound IB, and compounds represented by Formula II, Formula III, Formula IV, Formula XA, and Formula XB. The preparation is directed to producing stable Formula I compounds in high purity and yields, with pharmaceutically acceptable salts also contemplated in the disclosed context.
A key aspect is the disclosure of novel intermediates and key synthetic transformations en route to the successive structural stages associated with Formula II and further to Formula III and Formula IV. The document explicitly outlines multi-step intermediate sequences that involve formation and conversion of intermediates such as an amide, a β-enaminoketoester, a pyrazole ester intermediate, amidine formation, and subsequent transformations to a diol and dichloropyrimidine, followed by methoxylation and further de-chlorination/hydrogenation and de-methylation and final chlorination.
The document further discloses alternative routes for preparing the intermediates toward the target 3-(2-pyrimidinyl)pyrazoles, including phase-transfer hydroxylation, alternative de-chlorination approaches, and coupling an amine to a chloropyrimidine. Alternative synthetic routes also include conversion of a bromo intermediate to aminated intermediates using cyanide substitution reagents, followed by ammonia to form amine, and one-step coupling with chloropyrimidines of Formula IV to furnish Compound I.
An extended route is described that uses malic acid salt formation with (D)-malic acid or (L)-malic acid to control chirality, yielding chiral intermediates (18A) and (18B). The disclosed pathways are stated to support scale-up amenability and facile reaction conditions, while also providing high yield/purity, avoiding a genotoxic epoxide intermediate referenced from prior art, and higher purity versus earlier schemes involving regioisomer mixtures.
Claims Coverage
The provided claim content identifies 2 inventive features, both directed to structural-selection refinements represented by Formula XA and Formula XB.
Compound represented by Formula XA
A compound is defined as represented by Formula XA, with associated structural elements including Cl, F, H2N, O, CF3, OH, (R), and N.
Compound represented by Formula XB
A compound is defined as represented by Formula XB, with associated structural elements including Cl, F, H2N, O, CF3, OH, H2S, and S.
Claim coverage is limited to compounds represented by Formula XA and Formula XB, while the process and intermediate disclosures are not explicitly reflected in the claim text shown.
Stated Advantages
Provides high purity and high yield formation of a symmetrical intermediate (6)/(6′) using a symmetrical reagent (27).
Reduces impurities in the preparation of Formula II/IV compounds.
Enables multiple high-yield conversion routes to Formula II/IV from steps vi)–x) and also includes a one-step conversion route to the final product.
Supports scalable preparation, including large-scale manufacture, for the disclosed scalable process (Scheme 5).
Provides high overall yields and purities for access to Formula III, V, VI, and Compound I via intermediate (7)/(7′).
Avoids chromatography by using simple precipitations and crystallizations to obtain isolated high-purity intermediates.
Enables preparation of enantiomerically pure Compound IA/IB.
Avoids a genotoxic epoxide impurity.
Stable Formula I compounds are produced in high purity and yields.
The processes are stated to be amenable to scale-up.
Facile reaction conditions are stated to be provided.
Higher purity versus earlier schemes involving regioisomer mixtures.
Documented Applications
Use of Scheme 4 to prepare Formula II/IV compounds from amidine intermediates or salts (5A/5A′, 5B/5B′), including preparation of a final Formula IV product.
Use of Scheme 5 to access Formula III, V, VI, and Compound I via intermediate (7)/(7′) derived from intermediate (6)/(6′).
Use of Scheme 6/7 to obtain enantiomerically pure Compound IA/IB, including separation of enantiomers before coupling to expensive intermediates such as Formula IV or 7′ and avoiding a genotoxic epoxide impurity.
sGC stimulators comprising 3-(2-pyrimidinyl)pyrazoles, characterized in the context of soluble guanylate cyclase (sGC) stimulation and cyclic guanosine monophosphate (cGMP) related framework.
The disclosed compounds are described as sGC stimulators for NO related disorders.
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