Process for preparing the calcium salt of rosuvastatin

• US 20060116391A1
• Filed: 08/07/2003
• Published: 06/01/2006
• Est. Priority Date: 08/13/2002
• Status: Active Grant

• Current Assignee: Astrazeneca AB (Astrazeneca PLC), Astrazeneca UK Limited (Astrazeneca PLC)
• Original Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Inventors: Horbury, John, Taylor, Nigel Philip
• Granted Patent: US 7,511,140 B2
• Time in Patent Office: Days
• US Class Current: 514/275
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30

Abstract

An improved process for manufacture of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl)(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt, which is useful for the production of a pharmaceutical useful in the treatment of, inter alia, hypercholesterolemia, hyperlipoproteinemia and atherosclerosis, is described.

Claims

1. A process for the manufacture of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt, which process comprises mixing of a solution of calcium chloride with a solution of a water-soluble salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, wherein the process parameters are selected to give a product which demonstrates improved efficiency of filtration.

2. A process according to claim 1 comprising mixing of a solution of calcium chloride with a solution of a water-soluble salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid such that the addition temperature is selected to give a product which demonstrates improved efficiency of filtration.

3. A process according to any preceding claim wherein the addition temperature is 30-45°

C.

4. A process according to any preceding claim comprising mixing of a solution of calcium chloride with a solution of a water-soluble salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid such that the addition time is selected to give a product which demonstrates improved efficiency of filtration.

5. A process according to any preceding claim wherein the addition time is 5 to 60 minutes.

6. A process according to any preceding claim comprising mixing of a solution of calcium chloride with a solution of a water-soluble salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid such that the hold time is selected to give a product which demonstrates improved efficiency of filtration.

7. A process according to any preceding claim wherein the hold time is at least 10 minutes.

9. A process according to any preceding claim wherein the addition temperature is adjusted to give a product with a specific surface area less than or equal to 1 m²/g (measured by Fisher technique).

10. A process according to any preceding claim wherein the addition temperature, addition time and hold time are adjusted to give a product with a specific surface area less than or equal to 1 m²/g (measured by Fisher technique).

11. A process according to any preceding claim wherein the addition temperature, addition time and hold time are adjusted to give a product with a specific surface area less than or equal to 0.5 m²/g (measured by Fisher technique).

12. A process according to any preceding claim wherein the product has a paste strength of more than about 45% w/w.

13. A process according to any preceding claim in which the product paste strength after a maximum of 15 minutes filtration on a laboratory scale is at least 50% w/w.

14. A process according to any one of claims 1 to 11 wherein the product is obtained with a paste strength of more than about 70% w/w.

15. A process according to any preceding claim wherein the water soluble salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid is an alkali metal salt.

16. A process according to any preceding claim wherein the water soluble salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid is the sodium salt.

17. A process according to any one of claims 1 to 14 wherein the water soluble salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6enoic acid is an ammonium salt, a methylamine salt or a TRIS salt.

18. A process according to any one of claims 1 to 14 wherein the water soluble salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid is generated from the ammonium salt.

19. A process according to any one of claims 1 to 14 wherein the solution of the water soluble salt is generated from (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid or a salt thereof.

20. A process according to claim 19 wherein the water soluble salt is the sodium salt.

21. A process according to claim 20 wherein the sodium salt is generated by treatment of an amine salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid with a sodium base.

22. A process according to claim 21 where sodium base is sodium hydroxide.

23. A product obtainable by a process as claimed in any preceding claim.

24. A product obtained by a process as claimed in any preceding claim.

8. A process according to any claim which comprises addition of a solution of calcium chloride to a solution of a water-soluble salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid over 5 to 60 minutes at a temperature of 30 to 45°

C., holding the mixture at a temperature of 30 to 45°

C. for at least 10 minutes, filtering, optionally washing, and drying of the resultant product.