Process for the preparation of an amino-pyrimidine and intermediates thereof

Patent metadata

Field	Value
Publication number	US-11142516-B2
Application number	US-201816958093-A
Country	US
Kind code	B2
Filing date	Dec 26, 2018
Priority date	Dec 26, 2017
Publication date	Oct 12, 2021
Grant date	Oct 12, 2021

Abstract

Provided herein is a novel process for the preparation of an amino-pyrimidine and salts thereof. Also provided herein are novel intermediates used in this process and their preparation.

First claim

The invention claimed is:

1. A method of preparing a compound of Formula (1):

or a salt thereof, comprising:
(i) reacting a compound of Formula (1A):

with 2-chloro-3-fluoropyridine to form a compound of Formula (1B):

(ii) reacting the compound of Formula (1B) with an aqueous acid to form a compound of Formula (1C):

and
(iii) converting the compound of Formula (1C) to the compound of Formula (1) or a salt thereof.

2. The method of claim 1 , further comprising obtaining the compound of Formula (1A) by reacting 1,3-dibromo-2,2-dimethoxypropane with tert-butyl 2-cyanoacetate to form the compound of Formula (1A).

3. The method of claim 2 , wherein the reaction of the 1,3-dibromo-2,2-dimethoxypropane with the tert-butyl 2-cyanoacetate is performed in the presence of a base.

4. The method of claim 3 , wherein the base is potassium tert-butoxide.

5. The method of claim 1 , further comprising obtaining the compound of Formula (1A) by converting a compound of Formula (1D):

to the compound of Formula (1A).

6. The method of claim 5 , further comprising obtaining the compound of Formula (1D) by converting a compound of Formula (1E):

to the compound of Formula (1D).

7. The method of claim 6 , further comprising obtaining the compound of Formula (1E) by converting a compound of Formula (1F):

to the compound of Formula (1E).

8. The method of claim 1 , wherein step (i) is performed in the presence of a base.

9. The method of claim 8 , wherein the base is sodium bis(trimethylsilyl)amide.

10. The method of claim 1 , wherein the aqueous acid of step (ii) is aqueous hydrochloric acid.

11. The method of claim 1 , wherein step (iii) comprises converting the compound of Formula (1C) to a compound of Formula (1G):

and converting the compound of Formula (1G) to the compound of Formula (1) or a salt thereof.

12. The method of claim 11 , wherein step (iii) further comprises converting the compound of Formula (1G) to a compound of Formula (1H):

and converting the compound of Formula (1H) to the compound of Formula (1) or a salt thereof.

13. The method of claim 12 , wherein step (iii) further comprises converting the compound of Formula (1H) to a compound of Formula (11)

and converting the compound of Formula (1I) to the compound of Formula (1) or a salt thereof.

14. The method of claim 13 , wherein step (iii) further comprises reacting the compound of Formula (1I) with

wherein X is chloro or fluoro, to form a compound of Formula (1J):

wherein Z is a protecting group or hydrogen,
and converting the compound of Formula (1J) to the compound of Formula (1) or a salt thereof.

15. The method of claim 14 , wherein step (iii) further comprises reacting the compound of Formula (1J) with

to form a compound of Formula (1K):

wherein Z is a protecting group or hydrogen,
and converting the compound of Formula (1K) to the compound of Formula (1) or a salt thereof.

16. The method of claim 15 , wherein step (iii) further comprises isolating the compound of Formula (1) or a salt thereof.

17. A compound of Formula (1B):

or a salt thereof.

18. A method of preparing a compound of Formula (1B):

or a salt thereof, comprising:
reacting a compound of Formula (1A):

with 2-chloro-3-fluoropyridine to form the compound of Formula (1B).

19. The method of claim 18 , further comprising obtaining the compound of Formula (1A) by reacting 1,3-dibromo-2,2-dimethoxypropane with tert-butyl 2-cyanoacetate to form the compound of Formula (1A).

20. The method of claim 19 , wherein the reaction of the 1,3-dibromo-2,2-dimethoxypropane with the tert-butyl 2-cyanoacetate is performed in the presence of a base.

21. The method of claim 20 , wherein the base is potassium tert-butoxide.

22. The method of claim 18 , further comprising obtaining the compound of Formula (1A) by converting a compound of Formula (1D):

to the compound of Formula (1A).

23. The method of claim 22 , further comprising obtaining the compound of Formula (1D) by converting a compound of Formula (1E):

to the compound of Formula (1D).

24. The method of claim 23 , further comprising obtaining the compound of Formula (1E) by converting a compound of Formula (1F):

to the compound of Formula (1E).

25. The method of claim 18 , wherein the reaction of the compound of Formula (1A) with the 2-chloro-3-fluoropyridine is performed in the presence of a base.

26. The method of claim 25 , wherein the base is sodium bis(trimethylsilyl)amide.

27. A compound of Formula (1D):

or a salt thereof.

28. A method of preparing a compound of Formula (1D):

or a salt thereof, comprising converting a compound of Formula (1E):

to the compound of Formula (1D) or a salt thereof.

29. The method of claim 28 , further comprising obtaining the compound of Formula (1E) by converting a compound of Formula (1F):

Assignees

• Cytokinetics Inc

Inventors

• Peterson Matthew
• Lu Kevin
• MORGAN Bradley
• Morgans David
• Fukuyama Tohru

Classifications

• C07C235/40

  having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton · CPC title

• C07C255/45

  having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings · CPC title

• C07C231/02

  from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines · CPC title

• C07D213/61

  Halogen atoms or nitro radicals · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title