Process for preparing R-gossypol L-phenylalaninol dienamine
This invention relates to a process for preparing R-gossypol L-phenylalaninol dienamine using non-chromatographic purification methods. In particular, the invention is directed to resolution of R- and S-gossypol L-phenylalaninol dienamine by crystallization. R-gossypol L-phenylalaninol dienamine is a useful intermediate for the preparation of R-(−)-gossypol and R-(−)-gossypol acetic acid co-crystal. R-(−)-Gossypol acetic acid and its co-crystal is useful for inducing apoptosis in cells and for sensitizing cells to the induction of apoptotic cell death.
1. A process for preparing R-gossypol L-phenylalaninol dienamine from a mixture of R- and S-gossypol L-phenylalaninol dienamine comprising crystallizing said mixture from a solvent system comprising acetonitrile and water and isolating crystalline R-gossypol L-phenylalaninol dienamine substantially free from said S-gossypol L-phenylalaninol dienamine.
2. The process of claim 1 wherein said crystalline R-gossypol L-phenylalaninol dienamine is isolated by filtration.
3. The process of claim 1 wherein the acetonitrile:water ratio is about 5:1.
4. The process of claim 3 wherein the acetonitrile:water ratio is 5:1.
5. The process of claim 1 further comprising:
a) washing said crystalline R-gossypol L-phenylalaninol dienamine with a solvent system comprising acetonitrile and water; and
b) drying said crystalline R-gossypol L-phenylalaninol dienamine in vacuo.
6. A process for preparing R-gossypol L-phenylalaninol dienamine comprising:
a) condensing gossypol with L-phenylalaninol in acetonitrile to provide a mixture of R- and S-gossypol L-phenylalaninol dienamine;
b) adding water to the reaction mixture at the completion of a) to obtain crystallized R-gossypol L-phenylalaninol dienamine; and
c) isolating said crystalline R-gossypol L-phenylalaninol dienamine substantially free from said S-gossypol L-phenylalaninol dienamine.
7. The process of claim 6 wherein said crystalline R-gossypol L-phenylalaninol dienamine is isolated by filtration.
8. The process of claim 6 wherein the acetonitrile:water ratio in b) is about 5:1.
9. The process of claim 8 wherein the acetonitrile:water ratio is 5:1.
10. The process of claim 6 further comprising:
a) washing said crystalline R-gossypol L-phenylalaninol dienamine with a solvent system comprising acetonitrile and water; and
b) drying said crystalline R-gossypol L-phenylalaninol dienamine in vacuo.
11. The process of claim 1 or 6 wherein said crystallization is induced by seeding with crystalline R-gossypol L-phenylalaninol dienamine.
12. The process of claim 1 or 6 wherein said crystalline R-gossypol L-phenylalaninol dienamine has a purity of about 90% or more.
13. The process of claim 12 wherein said purity is about 95% or more.
14. The process of claim 13 wherein said purity is about 98% or more.
15. The process of claim 12 wherein said purity is about 99% or more.
16. In a process for preparing R-(−)-gossypol acetic acid co-crystals, the improvement comprising crystallizing a mixture of R- and S-gossypol L-phenylalaninol dienamine from a solvent system comprising acetonitrile and water and isolating crystalline R-gossypol L-phenylalaninol dienamine substantially free from said S-gossypol L-phenylalaninol dienamine; and preparing the R-(−)-gossypol acetic acid co-crystals.
17. The process of claim 16 , further comprising isolating said crystalline R-gossypol L-phenylalaninol dienamine by filtration.
18. The process of claim 16 , wherein the acetonitrile:water ratio is about 5:1.
19. The process of claim 18 , wherein the acetonitrile:water ratio is 5:1.
20. The process of claim 16 , further comprising:
a) washing said crystalline R-gossypol L-phenylalaninol dienamine with a solvent system comprising acetonitrile and water; and
b) drying said crystalline R-gossypol L-phenylalaninol dienamine in vacuo.
21. In a process for preparing R-(−)-gossypol acetic acid co-crystals, the improvement comprising:
a) condensing gossypol with L-phenylalaninol in acetonitrile to provide a mixture of R- and S-gossypol L-phenylalaninol dienamine;
b) adding water to the reaction mixture at the completion of a) to obtain crystallized R-gossypol L-phenylalaninol dienamine; and
c) isolating said crystalline R-gossypol L-phenylalaninol dienamine substantially free from said S-gossypol L-phenylalaninol dienamine; and
preparing the R-(−)-gossypol acetic acid co-crystals.
22. The process of claim 21 , further comprising isolating said crystalline R-gossypol L-phenylalaninol dienamine by filtration.
23. The process of claim 21 , wherein the acetonitrile:water ratio is about 5:1.
24. The process of claim 23 , wherein the acetonitrile:water ratio is 5:1.
25. The process of claim 21 , further comprising:
a) washing said crystalline R-gossypol L-phenylalaninol dienamine with a solvent system comprising acetonitrile and water; and
b) drying said crystalline R-gossypol L-phenylalaninol dienamine in vacuo.