PROCESS FOR PREPARING (CYCLOPENTYL[d]PYRIMIDIN-4-YL)PIPERAZINE COMPOUNDS

• US 20170247338A1
• Filed: 09/25/2015
• Published: 08/31/2017
• Est. Priority Date: 09/26/2014
• Status: Active Grant

• Current Assignee: F Hoffmann-La Roche AG (Roche Holding AG), Genentech, Inc. (Roche Holding AG)
• Original Assignee: F Hoffmann-La Roche AG (Roche Holding AG), Genentech, Inc. (Roche Holding AG)
• Inventors: Gosselin, Francis, Han, Chong, Iding, Hans, Reents, Reinhard, Savage, Scott, Wirz, Beat
• Granted Patent: US 10,457,648 B2
• Time in Patent Office: Days
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07B 57/00 Separation of optically-active compounds
• CPC Class Codes: C07C 253/30 by reactions not involving the formation of cyano groups
• CPC Class Codes: C07C 253/34 Separation; Purification
• CPC Class Codes: C07C 255/22 containing cyano groups and at least two carboxyl groups bound to the carbon skeleton
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 239/46 Two or more oxygen, sulphur or nitrogen atoms
• CPC Class Codes: C07D 239/54 as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
• CPC Class Codes: C07D 239/70 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C12N 9/78 acting on carbon to nitrogen bonds other than peptide bonds (3.5)
• CPC Class Codes: C12P 41/00 Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
• CPC Class Codes: C12Y 305/05001 Nitrilase (3.5.5.1)
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present disclosure relates to processes for preparing (cyclopentyl[d]pyrimidin-4-yl)piperazine compounds, and more particularly relates to processes for preparing (R)-4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d] pyrimidin-4-yl)piperazine and N-protected derivatives thereof, which may be used as an intermediate in the synthesis of Ipatasertib (i.e., (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)-propan-1-one). The present disclosure additionally relates to various compounds that are intermediates employed in these processes.

Claims

1. A process for preparing a compound of Formula

2. The process of claim 1, wherein the compound of Formula III, or a salt thereof, is prepared by contacting a compound of Formula IV:

3. The process of claim 2, wherein Y is bromo.

4. The process of claim 2 or claim 3, wherein Lv is selected from hydrogen and a halogen, and R¹ is selected from acetyl, trifluoroacetyl, phthalimidyl, benzyl, triphenylmethyl, benzylidenyl, p-toluenesulfonyl, p-methoxybenzyl, tertbutyloxycarbonyl, 9-fluorenylmethyloxycarbonyl and carbobenzyloxy.

5. The process of any one of claims 2-4, wherein the compound of Formula IV, or salt thereof, is contacted with from about 1 molar equivalent to about 1.5 molar equivalents of the piperazine compound.

6. The process of any one of claims 2-5, wherein the compound of Formula IV, or salt thereof, is contacted with the piperazine compound at room temperature.

7. The process of any one of claims 2-6, wherein the compound of Formula IV, or a salt thereof, is prepared by brominating a compound of Formula V:

8. The process of claim 7, wherein each X is chloro.

9. The process of claim 7, wherein each X is hydroxyl.

10. The process of any one of claims 7-9, wherein the brominating agent is selected from bromine, bromotrimethylsilane, phosphorus oxybromide, N-bromosuccinimide, and phosphorus tribromide.

11. The process of any one of claims 7-10, wherein the compound of Formula V, or salt thereof, is contacted with from about 2 molar equivalents to about 7 molar equivalents of the brominating agent.

12. The process of any one of claims 7-11, wherein the bromination reaction is carried out at a temperature of from about 70°

C. to about 75°

C.

13. The process of any one of claims 7-12, wherein the compound or salt of Formula IV is not isolated after the bromination of the compound or salt of Formula V and prior to reaction with the piperazine compound.

14. The process of any one of claims 7-13, wherein distillation is used to remove volatile byproducts during the bromination reaction.

15. The process of any one of claims 2-14, wherein the compound or salt of Formula IV is prepared by:

(i) chlorinating a compound of Formula V_b;

16. The process of claim 15, wherein the compound or salt of Formula V_c is not isolated after the chlorination of the compound or salt of V_b and prior to bromination.

17. The process of claim 15 or claim 16, wherein chlorinating agent is selected from phosphorus oxychloride and phosphorus trichloride.

18. The process of any one of claims 15-17, wherein the compound of Formula V_b, or salt thereof, is contacted with from about 1.5 molar equivalent to about 5 molar equivalents of the of the chlorinating agent.

19. The process of any one of claims 15-18, wherein the compound or salt of Formula V_b is prepared by cyclizing a compound of VI_b:

20. The process of claim 19, wherein the process comprises contacting the compound or salt of Formula VI_b with a formamidine salt to cyclize the compound of Formula VI_b, or salt thereof.

21. The process of claim 19 or claim 20, wherein the compound of Formula IV_b, or a salt thereof, is prepared by:

(i) contacting crotononitrile with malonate to form an isomeric mixture comprising a compound of Formula VI_a;

22. The process of claim 21, wherein separation is achieved by enzymatic resolution, and further wherein the enzymatic resolution is achieved by contacting the isomeric mixture comprising the compound of Formula IV_a and Formula VI_b, or salts thereof, with a nitrilase enzyme or a lipase enzyme.

23. The process of claim 22, wherein enzymatic resolution is achieved using a nitrilase enzyme.

24. The process of claim 22 or claim 23, wherein the isomeric mixture is not isolate from a reaction product mixture prior to enzymatic resolution.

25. The process of any one of claims 21-24, wherein the crotononitrile is contacted with from about 1 to about 1.5 molar equivalents of malonate.

26. The process of any one of claims 1-25, wherein R¹ is an amino protecting group.

27. The process of claim 26, wherein R¹ is selected from acetyl, trifluoroacetyl, phthalimidyl, benzyl, triphenylmethyl, benzylidenyl, p-toluenesulfonyl, p-methoxybenzyl, tertbutyloxycarbonyl, 9-fluorenylmethyloxycarbonyl and carbobenzyloxy.

28. The process of any one of claims 1-27, wherein metalating agent is an organometal compound.

29. The process of claim 28, wherein the organometal compound comprises magnesium or lithium.

30. The process of claim 29, wherein the organometal compound is selected from isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride, n-butyllithium, sec-butyllithium, t-butyllithium, lithium tri-n-butylmagnesiate, lithium triisopropylmagnesiate, and lithium (isopropyl)(di-n-butyl)magnesiate.

31. The process of any one of claims 1-30, wherein the compound of Formula III, or salt thereof, is contacted with from about 1 molar equivalent to about 1.5 molar equivalents of the of the metalating agent.

32. A compound of Formula I prepared by the process of any one of the preceding claims.

33. A process for preparing a compound of Formula IX:

34. A compound of Formula IX prepared by the process of claim 33.

35. The compound of Formula V_b:

36. The compound of Formula V_c:

37. The compound of Formula IV_b:

38. The compound of Formula IV_c:

39. The compound of Formula III: