Methods of regioselective synthesis of 2,4-disubstituted pyrimidines

• US 10,005,737 B2
• Filed: 11/22/2016
• Issued: 06/26/2018
• Est. Priority Date: 10/07/2013
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Charrier, Jean-Damien, O'Donnell, Michael Edward
• Primary Examiner(s): Rao, Deepak R
• Application Number:
  US15/358,634
• Publication Number:
  US 20170073315A1
• Time in Patent Office: 581 Days
• Field of Search: 544122, 544323, 544324
• CPC Class Codes: C07D 239/34 One oxygen atom
• CPC Class Codes: C07D 239/47 One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings

Abstract

The present invention relates to the novel regioselective syntheses of 2,4-disubstituted pyrimidines through sequential nucleophilic aromatic substitutions.

Claims

1. A method of preparing a compound of Formula I:

2. The method of claim 1, wherein

R¹ is optionally substituted aryl, optionally substituted alkenyl or optionally substituted heteroaryl;

the R¹-reagent is (R⁶O)₂B—

R¹, wherein each R⁶ is independently —

H, C_1-6 alkyl, or both (R⁶O) groups taken together with the boron atom to which they are attached form a 5- or 6-membered heterocyclic ring optionally substituted with 1-4 C_1-3 alkyl groups; and

the reaction of step ii) is performed in the presence of a transition metal catalyst.

3. The method of claim 2, wherein the transition metal catalyst of step ii) comprises palladium.

4. The method of claim 3, wherein the transition metal catalyst of step ii) is a palladium (0) catalyst.

5. The method of claim 3, wherein the transition metal catalyst of step ii) comprises tetrakis(triphenylphosphine) palladium (0).

6. The method of claim 2, wherein R¹ is optionally substituted aryl.

7. The method of claim 6, wherein R¹ is optionally substituted phenyl.

8. The method of claim 1, wherein

R¹ is optionally substituted C_3-8 cycloalkyl, alkenyl, aryl, allyl, or optionally substituted fully saturated or partially unsaturated 5-10 membered heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S;

the R¹-reagent is X—

Zn—

R¹, wherein X is —

Cl, —

Br, or —

I; and

the reaction of step ii) is performed in the presence of a transition metal catalyst.

9. The method of claim 8, wherein the transition metal catalyst of step ii) comprises nickel or palladium.

10. The method of claim 9, wherein the transition metal catalyst of step ii) further comprises a triaryl phosphine.

11. The method of claim 1, wherein

R¹ is

12. The method of claim 11, wherein the transition metal catalyst of step ii) comprises copper or palladium.

13. A method of preparing a compound of Formula II:

14. The method of claim 13, wherein the reaction of step iia) is performed in the presence of an acid;

R⁴ is —

H or C_1-4 alkyl; and

R⁵ is a mono- or bicyclic aryl, or a 6-10 membered mono- or bicyclic heteroaryl, wherein the aryl or heteroaryl group is optionally substituted.

15. The method of claim 14, wherein HNR⁴R⁵ is selected from

16. The method of claim 14, wherein the acid of step iia) is pivalic acid.

17. The method of claim 13, wherein the reaction of step iia) is performed in the presence of a base;

and

R⁴ is —

H or C_1-4 alkyl;

R⁵ is C_1-6 alkyl, C_3-8 cycloalkyl, or a 3-8 membered heterocycle having 1-3 heteroatoms independently selected from N, O, or S, any of which are optionally substituted with 1-2 groups independently selected from aryl or a 6-10 membered mono- or bicyclic heteroaryl, or

R⁴ and R⁵ taken together with the nitrogen atom to which they are attached form an optionally substituted 5-8 membered partially saturated or fully saturated heterocyclic ring having up to 1 additional heteroatom selected from N, O, or S.

18. The method of claim 13, wherein HNR⁴R⁵ is selected from

19. The method of claim 13, wherein the base of step iia) is an amine base.

20. The method of claim 19, wherein the amine base comprises a trialkyl amine, an optionally substituted 5-6 membered fully saturated heterocyclic ring having 1-2 nitrogen atoms, or any combination thereof.

21. The method of claim 20, wherein the amine base comprises triethylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, 1,4-diazabicyclo[2.2.2]octane, or any combination thereof.

22. The method of claim 13, wherein the reaction of step iiia) is performed in the presence of an acid;

R⁸ is —

H or C_1-4 alkyl; and

R⁹ is a mono- or bicyclic aryl, or a 6-10 membered mono- or bicyclic heteroaryl, wherein the aryl or heteroaryl group is optionally substituted.

23. The method of claim 22, wherein HNR⁸R⁹ is selected from

24. The method of claim 22, wherein the acid of step iiia) is a strong acid.

25. The method of claim 24, wherein the acid of step iiia) is HCl.

26. The method of claim 13, wherein the reaction of step iiia) is performed in the presence of a base;

R⁸ is —

H or C_1-4 alkyl; and

R⁹ is C_1-6 alkyl, C_3-8 cycloalkyl or a 3-8 membered heterocycle having 1-3 heteroatoms independently selected from N, O, or S, any of which are optionally substituted with 1-2 groups independently selected from aryl or a 6-10 membered mono- or bicyclic heteroaryl, or

R^8b and R^9b taken together with the nitrogen atom to which they are attached form an optionally substituted 5-8 membered partially saturated or fully saturated heterocyclic ring having up to 1 additional heteroatom selected from N, O, or S.

27. The method of claim 26, wherein HNR⁸R⁹ is selected from

28. The method of claim 26, wherein the base of step iiia) is an amine base.

29. The method of claim 28, wherein the amine base comprises a trialkyl amine, an optionally substituted 5-6 membered fully saturated heterocyclic ring having 1-2 nitrogen atoms, or any combination thereof.

30. The method of claim 29, wherein the amine base comprises triethylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, 1,4-diazabicyclo[2.2.2]octane, or any combination thereof.

31. The method of claim 13, further comprising

i) reacting a compound of Formula A with a compound of Formula B to generate the compound of Formula C;

32. The method of claim 31, wherein n is 3 or 5.

33. The method of claim 31, wherein the compound of Formula C is selected from

34. The method of claim 31, wherein the base of step i) is an amine base.

35. The method of claim 34, wherein the amine base comprises a trialkyl amine, an optionally substituted 5-6 membered fully saturated heterocyclic ring having 1-2 nitrogen atoms, or any combination thereof.

36. The method of claim 35, wherein the amine base comprises triethylamine, N,N-diisopropylethylamine, N-methylpyrrolidine or 1,4-diaza[2.2.2]octane, or any combination thereof.