Processes and intermediates for the preparation of soluble guanylate cyclase stimulators
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.
1. A process of preparing a compound of Formula IA:
comprising the step of:
i) coupling an amide of formula (1′):
with a pyrimidine compound of formula (2):
in an aprotic organic solvent in the presence of a base, to form, after quenching with acid, an intermediate of formula (3′):
ii) 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′):
iii) condensing the compound of formula (4′) with a hydrazine of formula
or a salt thereof, optionally in the presence of a base, to form a compound of Formula V:
iv) de-methylating the compound of Formula V to form an alcohol compound of formula (9′):
v) chlorinating the alcohol compound of formula (9′) with phosphoryl chloride to form a compound of Formula VI:
vi) reacting an amine of formula (17):
with the compound of Formula VI, optionally in the presence of a base, to yield the compound of Formula IA.
2. A process of preparing a compound of Formula IA:
comprising the step of:
i) coupling an amide of formula (1′):
with a pyrimidine compound of formula (2):
in an aprotic organic solvent in the presence of a base, to form, after quenching with an acid, an intermediate of formula (3′):
and
ii) 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′):
iiia) condensing the compound of formula (4′) with hydrazine to form the compound of formula (24′):
iiib) alkylating intermediate of formula (24′) with an alkylating agent of formula (23A) to provide the compound of Formula V:
iv) de-methylating the compound of Formula V to form an alcohol compound of formula (9′):
v) chlorinating the alcohol compound of formula (9′) with phosphoryl chloride o form a compound of Formula VI:
and
vi) reacting an amine of formula (17):
with the compound of Formula VIA, optionally in the presence of a base, to yield the compound of Formula IA, wherein X is a leaving group selected from —Br, —I, —Cl, —F, and a sulfonate ester.
3. The process of claim 1 , wherein the process further comprises re-crystalization of the compound of Formula IA in a mixture of methanol and water.
4. The process of claim 3 , wherein the re-crystallization comprises the steps of: A′) dissolving the compound of Formula IA in methanol at a temperature between 30° C. and 65° C. to obtain a methanol solution of the compound of Formula IA; B′) filtering the methanol solution of the compound of Formula IA from step A′) to form a filtered methanol solution of the compound of Formula IA; C′) adding water to the filtered methanol solution of the compound of Formula IA at a temperature between 50° C. and 60° C. to yield a slurry; D′) cooling the slurry of step 3) to yield a recrystallized compound of Formula IA; and E′) filtering and drying the recrystallized compound of Formula IA.
5. The process of claim 1 , wherein the compound of formula (2) is prepared by a process comprising the steps of:
a) reacting dibromopyrimidine compound of formula (5):
with a base in methanol or a methoxide salt in an aprotic solvent to form a bromopyrimidine compound of formula (6):
b) coupling the bromopyrimidine compound of formula (6) with ethynyltrimethylsilane, in an aprotic organic solvent in the presence of a base and a Pd catalyst, optionally in the presence of a Cu(I) catalyst, to form a compound of formula (7):
and
c) de-silylating the compound of formula (7) to form the pyrimidine compound of (2).
6. The process of claim 1 , wherein the compound of formula (1′) is prepared by reacting a carboxylic acid of formula (8′)
with oxalyl chloride or an equivalent amide coupling reagent, followed by N,O-dimethylhydroxylamine or a salt thereof, in the presence of a base to form the amide of formula (1′).
7. The process of claim 1 , wherein the base in step i) is n-butyllithium.
8. The process of claim 1 , wherein the process comprises contacting the reaction product of the reaction between the amide of formula (1′) and the pyrimidine compound of formula (2) with a solution comprising N,O-dimethylhydroxylamine or a salt thereof and an acid to form the compound of formula (4′).
9. The process of claim 8 , wherein the solution comprises N,O-dimethylhydroxylamine hydrochloride.
10. The process of claim 8 , wherein the acid is an aqueous acid.
11. The process of claim 10 , wherein the acid is hydrochloric acid.
12. The process of claim 8 , wherein the acid is glacial acetic acid.
13. The process of claim 2 , wherein X is —Br.
14. The process of claim 2 , wherein said salt of N,O-dimethylhydroxylamine is HCl salt; said hydrazine is hydrazine hydrate; and said sulfonate ester is mesylate, tosylate or triflate.