Synthesis of tipifarnib

Patent metadata

Field	Value
Publication number	US-11542244-B2
Application number	US-201917056745-A
Country	US
Kind code	B2
Filing date	May 17, 2019
Priority date	May 18, 2018
Publication date	Jan 3, 2023
Grant date	Jan 3, 2023

Abstract

Provided herein are methods of preparing a desired enantiomer 6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl) methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, otherwise known as tipifarnib.

First claim

The invention claimed is:

1. A method for preparing a desired enantiomer of tipifarnib comprising the steps of:
(i) obtaining a starting material comprising tipifarnib that is not enantiopure in the desired enantiomer;
(ii) transforming the starting material from step (i) to a racemic mixture of tipifarnib; and
(iii) recovering the desired enantiomer of tipifarnib from the racemic mixture of tipifarnib of step (ii);
wherein step (ii) comprises the steps of:
(ii)(a) reacting the starting material with sodium nitrite in a reaction solvent to give a product mixture;
(ii)(b) recovering a racemic alcohol of Formula (II) from the product mixture of step (ii)(a); and

(ii)(c) transforming the racemic alcohol of step (ii)(b) to the racemic mixture of tipifarnib.

2. The method of claim 1 , wherein the reaction solvent of step (ii)(a) is an organic solvent, water, or a mixture thereof.

3. The method of claim 2 , wherein the organic solvent is miscible with water.

4. The method of claim 1 , wherein step (ii)(a) takes place in the presence of an additive.

5. The method of claim 1 , wherein step (ii)(b) comprises:
adjusting the product mixture's pH with a base;
extracting the product mixture with an extraction solvent; and
crystallizing the racemic alcohol.

6. A method for preparing a desired enantiomer of tipifarnib comprising the steps of:
(i) obtaining a starting material comprising tipifarnib that is not enantiopure in the desired enantiomer;
(ii) transforming the starting material from step (i) to a racemic mixture of tipifarnib; and
(iii) recovering the desired enantiomer of tipifarnib from the racemic mixture of tipifarnib of step (ii),
wherein step (ii) comprises the steps of:
(ii)(a) heating the starting material in a reaction solvent to give a product mixture;
(ii)(b) recovering a racemic alcohol of Formula (II) from the product mixture of step (ii)(a); and

(ii)(c) transforming the racemic alcohol of step (ii)(b) to the racemic mixture of tipifarnib.

7. The method of claim 6 , wherein the reaction solvent of step (ii)(a) is an organic solvent, water, or a mixture thereof.

8. The method of claim 7 , wherein the organic solvent is miscible with water.

9. The method of claim 6 , wherein step (ii)(a) takes place in the presence of an additive.

10. The method of claim 6 , wherein step (ii)(b) comprises:
adjusting the product mixture's pH with a base;
extracting the product mixture with an extraction solvent; and
crystallizing the racemic alcohol.

11. The method of claim 1 , wherein step (iii) comprises:
(iii)(a) crystallizing the desired enantiomer of tipifarnib from the racemic mixture of tipifarnib in the presence of a chiral resolving agent; and
(iii)(b) separating crystals of the desired enantiomer of tipifarnib from a mother liquor.

12. The method of claim 11 , wherein the method further comprises:
(iv) recycling the mother liquor of step (iii)(b) to be used as the starting material in step (i).

13. The method of claim 12 , wherein the steps (i) to (iv) are run in multiple cycles.

14. The method of claim 1 , wherein the desired enantiomer of tipifarnib is (R)-(+)-tipifarnib.

15. The method of claim 1 , wherein the starting material of step (i) comprises an enantiomeric excess of an undesired enantiomer of tipifarnib.

16. The method of claim 6 , wherein the desired enantiomer of tipifarnib is (R)-(+)-tipifarnib.

17. The method of claim 6 , wherein the starting material of step (i) comprises an enantiomeric excess of an undesired enantiomer of tipifarnib.

18. The method of claim 7 , wherein reaction solvent of step (ii)(a) is a mixture of an organic solvent and water.

19. The method of claim 18 , wherein the organic solvent is acetonitrile, methylethylketone, acetone, DMF, or a mixture thereof.

20. The method of claim 18 , wherein the organic solvent is acetone.

21. The method of claim 7 , wherein step (ii)(a) takes place at a temperature ranging from about 60° C. to about 80° C.

22. The method of claim 9 , wherein the additive is an acid.

23. The method of claim 22 , wherein the acid is hydrochloric acid.

24. The method of claim 22 , wherein the acid is sulfuric acid.

25. The method of claim 10 , wherein the product mixture's pH is adjusted to about 8.

26. The method of claim 25 , wherein the base is sodium hydroxide.

27. The method of claim 25 , wherein the extraction solvent is isopropyl acetate.

28. The method of claim 25 , wherein the racemic alcohol is crystallized as a hydrochloride salt.

29. The method of claim 11 , wherein the chiral resolving agent of step (iii)(a) is (-)dibenzoyl-L-tartaric acid.

Assignees

• Kura Oncology Inc

Inventors

• Ren Pingda
• Deng Xiaohu
• Mai Wanping

Classifications

• C07B57/00

  Separation of optically-active compounds · CPC title

• C07B2200/07

  Optical isomers · CPC title

• C07B55/00 Primary

  Racemisation; Complete or partial inversion · CPC title

• C07D401/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title