Process for preparation of soluble guanylate cyclase stimulators
Inventors
Xue, Song • Karnati, Vishnu Vardhan Reddy • Livingston, Robert C.
Assignees
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Publication Number
US-11773089-B2
Publication Date
2023-10-03
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), 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 invention describes a process for preparing a compound of Formula II through a defined multi-step transformation sequence involving pyrimidine intermediates (7, 8B, 10) and chlorinating a derived alcohol. The process includes mono-hydroxylating a dichloropyrimidine (7) to afford hydroxypyrimidine (8B), then de-chlorinating the hydroxypyrimidine (8B) to provide fluorohydroxypyrimidine (10), and finally chlorinating the alcohol of fluorohydroxypyrimidine (10) using phosphoryl chloride.
The hydroxylation is performed with sodium hydroxide in a mixture of an aprotic and a protic solvent in the presence of a phase transfer catalyst. The de-chlorination step is performed with hydrogen gas or a transfer hydrogenation reagent, optionally with a metal catalyst and in the presence of a base.
The document also indicates a process for preparing a compound of Formula IV by the same sequence and defines substituent embodiments and constraints for R1, R2, R5, R6, R7, and R8, including heteroaryl substitution and fluoro/halogen choices at defined positions.
Claims Coverage
The provided material covers one independent claim directed to a process for preparing a compound of Formula II, with a Formula IV variant also described. The inventive features center on a three-step transformation sequence, with dependent refinements narrowing the substituent scope for R1, R2, and R5.
Three-step conversion of dichloropyrimidine to fluorohydroxypyrimidine and chlorinated product
A process comprising mono-hydroxylating a dichloropyrimidine (7) to afford hydroxypyrimidine (8B), de-chlorinating hydroxypyrimidine (8B) with hydrogen gas or a transfer hydrogenation reagent to provide fluorohydroxypyrimidine (10), and chlorinating the alcohol of fluorohydroxypyrimidine (10) with phosphoryl chloride to reach the compound of Formula II.
Restricted R1 heteroaryl scope for Formula II
R1 is unsubstituted phenyl or a 5 to 6-membered heteroaryl ring containing up to three ring heteroatoms independently selected from N, O or S, with further narrowing to five-membered heteroaryl containing up to three heteroatoms chosen from N, O, or S.
R1 specified as isoxazolyl
R1 is specified as isoxazolyl.
R2 phenyl substitution pattern limited with instance of R5
R2 is phenyl and is substituted with one instance of R5.
R5 limited to halogen
Each instance of R5 is independently selected from halogen.
Process applied to a stated Formula IV variant
The process is framed to prepare a compound of Formula IV by performing mono-hydroxylating of a dichloropyrimidine to form hydroxypyrimidine, de-chlorinating using hydrogen gas or a transfer hydrogenation reagent to provide fluorohydroxypyrimidine, and chlorinating the alcohol with phosphoryl chloride to reach the stated compound of Formula IV.
The inventive contribution is the specified three-step sequence on a dichloropyrimidine scaffold, with substituent-defined constraints for R1, R2, and R5 and a Formula IV variant that preserves the same sequence structure.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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