Process for the preparation of rosuvastatin
The present invention relates to a process for the preparation of rosuvastatin calcium, a promising new HMG-CoA reductase inhibitor.
1. A process for producing rosuvastatin of structural formula I,
comprising:
a. condensing 1-cyano (2S)-2-[(tert-butyldimethylsilyl)oxy]-5-oxo-6-triphenylphosphanylidene hexanenitrile of structural formula II
with 4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)-5-pyrimidinecarbaldehyde of structural formula III
to give a condensed product of structural formula IV
b. deprotecting of the tert-butyldimethylsilyl group of the condensed product to afford a cyanoketo alcohol of structural formula V,
c. reducing the cyanoketo alcohol to cyanodiol of structural formula VI,
d. hydrolyzing the cyanodiol of structural formula VI.
2. The process of claim 1 wherein step (a) is carried out in an organic solvent.
3. The process of claim 2 wherein the organic solvent is selected form the group consisting of toluene, benzene, cyclohexanes, heptanes and mixture(s) thereof.
4. The process of claim 3 wherein the organic solvent is toluene.
5. The process of claim 1 wherein step (b) is performed in an organic solvent.
6. The process of claim 5 wherein the organic solvent is selected from the group consisting of sulfolane, dioxane, dimethyl sulfoxide, dimethyl acetamide, N-methyl pyrrolidone, acetonitrile, diethyl ether, tetrahydrofuran, dimethylformamide, methanol, ethanol, propanol, and mixtures thereof.
7. The process of the claim 6 wherein the organic solvent is methanol.
8. The process of clam 1 wherein the deprotection at step (b) is performed by treating with acids or tetrabutylammonium fluoride.
9. The process of claim 8 wherein the acid is selected from the group consisting of methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, trifluroacetic acid, and acetic acid.
10. The process of claim 9 wherein the acid is methanesulfonic acid.
11. The process of claim 1 wherein the reduction at step c is carried out in the presence of diethylmethoxyborane and sodium borohydride.
12. The process of claim 11 wherein the reduction is performed in an organic solvent mixture comprising an alcohol and a non-alcoholic solvents.
13. The process of claim 12 wherein the alcohol is selected from the group consisting of methanol, ethanol, propanol and butanol.
14. The process of claim 13 wherein the alcohol is methanol.
15. The process of claim 12 wherein the non-alcoholic organic solvent is selected from the group consisting of acetonitrile, diethyl ether, tetrahydrofuran and dimethylformamide.
16. The process of claim 15 wherein the non-alcoholic organic solvent is tetrahydrofuran.
17. The process of claim 1 wherein the hydrolysis at step (d) is performed after the reaction at step c is completed.