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-11274096-B2
Publication Date
2022-03-15
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 simulators of soluble guanylate cyclase (sGC). Others are useful intermediates towards the preparation of said simulators. 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 for preparing compounds of Formula II by 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 an acid to form an intermediate of formula (3). The intermediate is then reacted at a pH>5, optionally in the presence of added N,O-dimethylhydroxylamine or a salt thereof, to form the compound of formula (4).
The compound of formula (4) is condensed with hydrazine of formula R2—CH2—NH—NH2 or a salt thereof, optionally in the presence of a base, to form the compound of Formula II. In a related process, the compound of formula (4) is condensed with hydrazine to form a compound of formula (24), and the intermediate of formula (24) is alkylated with an alkylating agent of formula (22) to provide the compound of Formula II.
The structural scope is defined by R1, R2, and R5. R1 is phenyl or a 5 to 6-membered heteroaryl ring optionally substituted with up to three instances independently selected from halogen or methyl, and containing up to 3 ring atoms selected from N, S or O. R2 is phenyl or a 6-membered heteroaryl ring optionally substituted with up to three instances of R5, where the ring contains up to 2 nitrogen ring atoms, and each R5 is independently methyl, methoxy or halogen.
Claims Coverage
The independent claims cover three related process routes centered on the same amide-to-pyrimidine coupling sequence. Across the claims, five inventive features are recited: coupling of amide (1) with pyrimidine (2), pH>5 conversion to compound (4) optionally with N,O-dimethylhydroxylamine, hydrazine condensation to Formula II, hydrazine condensation to intermediate (24) followed by alkylation, and structural limits on R1, R2, R5, and leaving group X.
Coupling amide with pyrimidine in aprotic organic 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 an acid to form an intermediate of formula (3).
Reaction at pH>5 optionally with added 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 II
Condensing the compound of formula (4) with a hydrazine of formula R2—CH2—NH—NH2 or a salt thereof, optionally in the presence of a base, to form the compound of Formula II.
Hydrazine condensation to intermediate (24) and alkylation with leaving group X
Condensing the compound of formula (4) with hydrazine to form the compound of formula (24), and alkylating intermediate of formula (24) with an alkylating agent of formula (22) to provide the compound of Formula II, wherein X is a leaving group selected from −Br, −I, −Cl, −F, and a sulfonate ester.
Structural definition of R1, R2, and R5
R1 is phenyl or a 5 to 6-membered heteroaryl ring optionally substituted with up to three instances independently selected from halogen or methyl, with the heteroaryl ring containing up to 3 ring atoms selected from N, S or O; R2 is phenyl or a 6-membered heteroaryl ring optionally substituted with up to three instances of R5, with up to 2 nitrogen ring atoms; each R5 is independently methyl, methoxy or halogen.
The claims are anchored by a shared coupling-to-intermediate sequence, pH>5 conversion to compound (4), and conversion to Formula II by hydrazine condensation, with one route adding alkylation through an intermediate (24). The claim set also explicitly limits R1, R2, R5, and the leaving group X.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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