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 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.
1. A process for preparing a compound of formula (4):
comprising the steps 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), wherein:
R 1 is phenyl, or a 5 to 6-membered heteroaryl ring; optionally substituted with up to three instances independently selected from the group consisting of halogen or methyl; wherein said 5 or 6-membered heteroaryl ring contains up to 3 ring atoms selected from the group consisting of N, S or O.
2. A process for preparing a compound of Formula II:
comprising the steps 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):
and
iii) condensing the compound of formula (4) with a hydrazine of formula R 2 —CH 2 —NH—NH 2 or a salt thereof, optionally in the presence of a base, to form the compound of Formula II, wherein:
R 1 is phenyl, or a 5 to 6-membered heteroaryl ring; optionally substituted with up to three instances independently selected from the group consisting of halogen or methyl; wherein said 5 or 6-membered heteroaryl ring contains up to 3 ring atoms selected from the group consisting of N, S or O; and
R 2 is phenyl or a 6-membered heteroaryl, optionally substituted with up to three instances of R 5 ; wherein said 6-membered heteroaryl ring contains up to 2 nitrogen ring atoms; and
each R 5 is independently methyl, methoxy or halogen.
3. A process of preparing a compound of Formula II:
comprising the steps 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):
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):
and
iiib) alkylating intermediate of formula (24) with an alkylating agent of formula (22) to provide the compound of Formula II
R 2 —CH 2 —X (22);
wherein:
R 1 is phenyl, or a 5 to 6-membered heteroaryl ring; optionally substituted with up to three instances independently selected from the group consisting of halogen or methyl; wherein said 5 or 6-membered heteroaryl ring contains up to 3 ring atoms selected from the group consisting of N, S or O; and
R 2 is phenyl or a 6-membered heteroaryl, optionally substituted with up to three instances of R 5 ; wherein said 6-membered heteroaryl ring contains up to 2 nitrogen ring atoms;
each R 5 is independently methyl, methoxy or halogen;
X is a leaving group selected from —Br, —I, —Cl, —F, and a sulfonate ester.
4. The process of claim 2 , further comprising step iv) de-methylating the compound of Formula II to form an alcohol Compound (9):
5. The process of claim 4 , further comprising step v) chlorinating the alcohol compound of formula (9) with phosphoryl chloride, to form the compound of Formula III:
6. 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, and 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 formula (2).
7. 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).
8. The process of claim 1 , wherein R 1 is a 5-membered heteroaryl ring.
9. The process of claim 8 , wherein R 1 is an unsubstituted 5-membered heteroaryl ring containing up to 2 ring heteroatoms selected from the group consisting of N and O.
10. The process of claim 2 , wherein R 2 is phenyl optionally substituted with up to two instances of R 5 ; or R 2 is phenyl optionally substituted with one instance of R 5 .
11. The process of claim 10 , wherein R 2 is represented by formula
12. The process of claim 10 , wherein R 2 is a 6-membered heteroaryl, optionally substituted with up to two instances of R 5 ; and wherein said 6-membered heteroaryl ring contains up to 2 nitrogen ring atoms.
13. The process of claim 2 , wherein each R 5 is independently methyl or halogen.
14. The process of claim 13 , wherein each R 5 is fluoro.
15. The process of claim 1 , wherein the process is for preparing a compound of formula (4′):
and the process comprises the steps 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′):
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′).
16. The process of claim 2 , wherein the process is for preparing a compound of Formula V:
and wherein the process comprises the steps 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′):
and
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 the compound of Formula V.
17. The process of claim 3 , wherein the process is for preparing a compound of Formula V:
and wherein the process comprises the steps 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′):
iiia) condensing the compound of formula (4′) with hydrazine to form the compound of formula (24′):
and
iiib) alkylating intermediate of formula (24′) with an alkylating agent of formula (23A) to provide the compound of Formula V:
wherein X is a leaving group selected from —Br, —I, —Cl, —F, and a sulfonate ester.
18. The process of claim 16 , further comprising step iv) de-methylating the compound of Formula V to form an alcohol Compound (9′):
19. The process of claim 18 , further comprising step v) chlorinating the alcohol compound of formula (9′) with phosphoryl chloride to form the compound of Formula VI:
20. The process of claim 3 , wherein X is —Br.
21. The process of claim 3 , wherein said salt of the N,O-dimethyldhydroxylamine is HCl salt; said hydrazine is hydrazine hydrate; and said sulfonate ester is mesylate, tosylate or triflate.
22. The process of claim 17 , wherein said salt of the N,O-dimethyldhydroxylamine is HCl salt; said hydrazine is hydrazine hydrate; and said sulfonate ester is mesylate, tosylate or triflate.