Processes and intermediates for the preparation of soluble guanylate cyclase stimulators
Inventors
Wallace, Debra Jane • Zhou, Fenger • Wang, Yuguang • Nakai, Takashi • Karnati, Vishnu Vardhan Reddy • Schairer, Wayne C. • Kissel, William • Xue, Song • Hashash, Ahmad
Assignees
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Publication Number
US-11708361-B2
Publication Date
2023-07-25
Expiration Date
Abstract
The present disclosure relates to novel processes for the preparation of compounds of Formula I. Some of these compounds are useful as stimulators of soluble guanylate cyclase (sGC). Others are useful intermediates towards the preparation of said stimulators. These processes are amenable to large scale preparation and produce stable 3-(2-pyrimidinyl)pyrazoles of Formula 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 relates to a process of preparing a compound of Formula IA through a multi-step sequence. The process couples an amide of formula (1′) with a pyrimidine compound of formula (2) in an aprotic organic solvent in the presence of a base, followed by quenching with an acid to form an intermediate of formula (3′). The intermediate of formula (3′) is then reacted at a pH>5, optionally in the presence of added N,O-dimethylhydroxylamine or a salt thereof, to form a compound of formula (4′).
The compound of formula (4′) is condensed with hydrazine, or a salt thereof, optionally in the presence of a base, to form Formula V, or in an alternative sequence a compound of formula (24′) is alkylated with an alkylating agent of formula (23A) to provide Formula V. Formula V is de-methylated to form an alcohol compound of formula (9′), which is chlorinated with phosphoryl chloride to form Formula VI. Finally, an amine of formula (17) reacts with Formula VI or Formula VIA, optionally in the presence of a base, to yield Formula IA.
The leaving-group variant defines X as a leaving group selected from —Br, —I, —Cl, —F, and a sulfonate ester. The documented route also includes preparation of soluble guanylate cyclase (sGC) stimulators and stable 3-(2-pyrimidinyl)pyrazoles represented by Formula I and related intermediates.
Claims Coverage
The consolidated claim coverage comprises two independent process claims and includes 7 inventive features in the common route, plus an alternative alkylation feature and a leaving-group definition for X.
Coupling amide with pyrimidine in aprotic solvent
Coupling an amide of formula (1′) with a pyrimidine compound of formula (2) in an aprotic organic solvent in the presence of a base, followed by quenching with acid to form an intermediate of formula (3′).
pH>5 conversion optionally with N,O-dimethylhydroxylamine
At a pH>5, optionally in the presence of added N,O-dimethylhydroxylamine or a salt thereof, allowing the mixture to react to form the compound of formula (4′).
Hydrazine condensation to form Formula V
Condensing the compound of formula (4′) with hydrazine, or a salt thereof, optionally in the presence of a base, to form Formula V.
Alkylation of intermediate (24′)
In an alternative sequence, forming a compound of formula (24′) and alkylating it with an alkylating agent of formula (23A) to provide Formula V.
De-methylation to alcohol compound (9′)
De-methylating Formula V to form an alcohol compound of formula (9′).
Phosphoryl chloride chlorination to Formula VI
Chlorinating the alcohol compound of formula (9′) with phosphoryl chloride to form Formula VI.
Final amine reaction to yield Formula IA
Reacting an amine of formula (17) with Formula VI or Formula VIA, optionally in the presence of a base, to yield Formula IA, wherein X is a leaving group selected from —Br, —I, —Cl, —F, and a sulfonate ester.
The claims define a sequential process centered on amide-pyrimidine coupling, pH>5 formation of intermediate (4′), hydrazine-based conversion to Formula V or an alkylation variant through (24′), de-methylation to alcohol (9′), chlorination with phosphoryl chloride to Formula VI, and final amine substitution to obtain Formula IA, with X limited to halides or a sulfonate ester in the leaving-group variant.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Preparation of soluble guanylate cyclase (sGC) stimulators.
Preparation of stable 3-(2-pyrimidinyl)pyrazoles represented by Formula I and related intermediates.
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