Processes 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-11319308-B2
Publication Date
2022-05-03
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 disclosure provides a process for preparing a compound of Formula II and related formulas by a defined sequence of chemical transformations. The sequence includes amidating a starting material to an amide, alkylating the amide to form a β-enaminoketoester, and condensing the β-enaminoketoester with a hydrazine of formula R2—CH2—NH—NH2 or its HCl salt to form a pyrazole ester intermediate. The process further converts the pyrazole ester intermediate to an amidine or amidine salt.
The core sequence then forms a diol by condensing the amidine or amidine salt with fluoromalonate, followed by chlorination to afford dichloropyrimidine. Dichloropyrimidine is then mono-methoxylated to form methoxypyrimidine. The process includes de-chlorinating methoxypyrimidine to provide fluoromethoxypyrimidine, demethylating fluoromethoxypyrimidine to form an alcohol intermediate, and final chlorination to obtain a chlorinated product of Formula II.
The process constrains the chemical space by defining R1 as unsubstituted phenyl or a 5 to 6-membered heteroaryl ring containing up to three ring heteroatoms independently selected from N, O or S, and defining R2 and R5 by ring-type and substitution limits. The disclosure also includes stable, high-purity 3-(2-pyrimidinyl)pyrazoles and related intermediate preparation for sGC stimulator compounds, including Compound I.
Claims Coverage
Two independent claim themes are explicitly reflected across the inputs, and their coverage centers on a constrained multi-step synthesis to reach Formula II. The inventive features combine defined substituent selections for R1, R2, and R5 with a sequence of intermediate transformations from amidation through terminal chlorination, as well as the related preparation of stable, high-purity 3-(2-pyrimidinyl)pyrazoles.
Multi-step process to prepare a compound of Formula II via amidation to chlorination
A process for preparing a compound of Formula II comprising amidating starting material (1) to afford amide (2), alkylating amide (2) to form β-enaminoketoester (3), condensing β-enaminoketoester (3) with a hydrazine of formula R2—CH2—NH—NH2 or its HCl salt to afford pyrazole ester intermediate (4), converting intermediate (4) to amidine (5A) or amidine salt (5B), condensing amidine (5A)/(5B) with fluoromalonate to afford diol (6), chlorinating diol (6) to afford dichloropyrimidine (7), mono-methoxylating dichloropyrimidine (7) to afford methoxypyrimidine (8), de-chlorinating methoxypyrimidine (8) to provide fluoromethoxypyrimidine (9), de-methylating fluoromethoxypyrimidine (9) to afford alcohol (10), and chlorinating alcohol (10) to afford Formula II.
Substituent constraints defining R1, R2, and R5 in Formula II
R1 is defined as unsubstituted phenyl or a 5 to 6-membered heteroaryl ring containing up to three ring heteroatoms independently selected from N, O or S; R2 is defined as phenyl or a 6-membered heteroaryl optionally substituted with up to three instances of R5, wherein the 6-membered heteroaryl ring contains up to 2 nitrogen ring atoms; and each R5 is independently selected from C1-6 alkyl, C1-6 alkoxy or halogen.
Overall, the claim coverage centers on a fixed sequence of transformations that generate amidine and then build a substituted pyrimidine framework through fluoromalonate condensation, chlorination, methoxylation, de-chlorination, demethylation, and final chlorination, with substituent definitions constraining R1, R2, and R5.
Stated Advantages
Stable, high-purity 3-(2-pyrimidinyl)pyrazoles.
Improved scalability versus earlier schemes.
High yield/purity and reduced impurities, including crystallization-related and chromatography-avoidance advantages.
Scale-up and facile conditions.
Documented Applications
Production of sGC stimulator compounds, including Compound I, via described synthetic routes and intermediate preparation.
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