Processes for the preparation of pyrimidinylcyclopentane compounds

• US 9,862,689 B2
• Filed: 11/13/2014
• Issued: 01/09/2018
• Est. Priority Date: 11/15/2013
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Iding, Hans, Reents, Reinhard, Scalone, Michelangelo, Gosselin, Francis
• Primary Examiner(s): Murray, Jeffrey H
• Application Number:
  US15/036,741
• Publication Number:
  US 20160297773A1
• Time in Patent Office: 1,153 Days
• Field of Search: None
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 269/06 by reactions not involving the formation of carbamate groups
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07D 239/70 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C12P 17/165 Heterorings having nitrogen atoms as the only ring heteroatoms
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to a process for the preparation of a compound of formula (I), wherein R¹ is as defined herein, which is useful as an intermediate in the preparation of active pharmaceutical compounds.

Claims

1. A process for the preparation of a compound of formula (I)

2. The process according to claim 1, wherein R¹ is tert-butoxycarbonyl (BOC).

3. The process according to claim 1, wherein R² is tert-butoxycarbonyl (BOC).

4. The process according to claim 1, wherein M is Na⁺.

5. The process according to claim 1, comprising the following reaction steps:

a) Deprotection of the compound of formula (III) in a solvent under acidic conditions;

b) Adjustment to an alkaline pH using a base;

c) Addition of a solution comprising the compound of formula (II) in a solvent;

d) Addition of a solution comprising a coupling agent in a solvent.

6. The process according to claim 5, wherein the deprotection in step a) is performed using hydrochloric acid.

7. The process according to claim 5, wherein the solvent used for the deprotection in step a) is selected from n-propanol and isopropanol.

8. The process according to claim 5, wherein the base in step b) is selected from N-ethyl morpholine (NEM), triethylamine (TEA), tri(n-propyl)amine (TPA), diisopropylethylamine (DIPEA), pyridine and lutidine.

9. The process according to claim 5, wherein the solvent in step c) is selected from n-propanol and isopropanol.

10. The process according to claim 5, wherein the coupling agent used in step d) is propylphosphonic anhydride (T3P).

11. The process according to claim 5, wherein the solvent used in step d) is a mixture of n-propanol and toluene.

12. The process according to claim 1, further comprising preparing the compound of formula (II)

13. The process according to claim 1, further comprising deprotecting the compound of formula I or a salt thereof to provide a compound of formula (VI)

14. The process according to claim 13, comprising the following reaction steps:

i) Deprotection of the compound of formula (I) in a solvent under acidic conditions;

ii) Adjustment of the pH using a base in a solvent;

iii) Optionally crystallizing the compound of formula (VI).

15. The process according to claim 14, wherein the deprotection in step i) is performed using hydrochloric acid, sulfuric acid, trifluoro acetic acid or hydrobromic acid.

16. The process according to claim 14, wherein the solvent used for the deprotection in step i) is selected from n-propanol and isopropanol.

17. The process according to claim 14, wherein the base in step ii) is ammonia.

18. The process according to claim 14, wherein the solvent in step ii) is selected from n-propanol and isopropanol.

19. The process according to claim 14, wherein the crystallization in step iii) is performed by a solvent switch to a crystallization solvent selected from toluene, heptane, tetrahydrofuran, 2-propanone, 2-butanone, ethylene glycol dimethyl ether, ethyl acetate, butyl acetate, isopropyl acetate and mixtures thereof.

20. A mixture comprising a compound of formula (VI) or a pharmaceutically acceptable salt thereof as described in claim 13 and between 1 ppb and 100 ppm of a compound of formula (I) or a salt thereof.

22. A mixture comprising a compound of formula (I) or a salt thereof as described in claim 1 and between 1 ppb and 100 ppm of a compound of formula (II).

23. A mixture comprising a compound of formula (I) or a salt thereof as described in claim 1 and between 1 ppb and 1 ppm of a compound of formula (II).

24. A mixture comprising a compound of formula (I) or a salt thereof as described in claim 1 and between 1 ppb and 100 ppm of a compound of formula (III).

25. A mixture comprising a compound of formula (I) or a salt thereof as described in claim 1 and between 1 ppb and 1 ppm of a compound of formula (III).

26. A mixture comprising a compound of formula (I) or a salt thereof as described in claim 1 and between 1 ppb and 100 ppm of a compound of formula (II) and between 1 ppb and 100 ppm of a compound of formula (III).

27. A mixture comprising a compound of formula (I) or a salt thereof as described in claim 1 and between 1 ppb and 1 ppm of a compound of formula (II) and between 1 ppb and 1 ppm of a compound of formula (III).

21. A mixture comprising a compound of formula (VI) or a pharmaceutically acceptable salt thereof as described in 13 and between 1 ppb and 1 ppm of a compound of formula (I) or a salt thereof.