Intermediates for the preparation of HMG-CoA reductase inhibitors
The present invention provides a process for preparing novel intermediates of Formula wherein, R 1 can be hydrogen, C 1 -C 4 alkyl, halogen, nitro, hydroxy, or C 1 -C 4 alkoxy; R x can be selected from hydrophobic residue of HMG-CoA reductase inhibitors; which can be effectively used for the preparation of HMG-CoA reductase inhibitors such as rosuvastatin and pharmaceutically acceptable salts thereof.
1. A process for the preparation of a compound of Formula IVa
wherein, R 1 is hydrogen, C 1 -C 4 alkyl, halogen, nitro, hydroxy, or C 1 -C 4 alkoxy; such process comprising the steps of:
(a) converting a compound of Formula Ia
to a compound of Formula IIa,
wherein, L is a leaving group; and
(b) reacting a compound of Formula IIa with a compound of Formula III
to give a compound of Formula IVa.
2. A process for the preparation of a compound of Formula Va
wherein R 1 is hydrogen, C 1 -C 4 alkyl, halogen, nitro, hydroxy or C 1 -C 4 alkoxy, such process comprising the steps of:
(a) converting a compound of Formula Ia
to a compound of Formula IIa,
wherein, L is a leaving group;
(b) reacting a compound of Formula Ha with a compound of Formula III
to give a compound of Formula IVa, and
c) oxidizing a compound of Formula IVa to a compound of Formula Va.
3. A compound of Formula IVa or a compound of Formula Va.
4. A process for the preparation of rosuvastatin calcium of formula
comprising the steps of:
(a) converting a compound of Formula Ia
to a compound of Formula IIa;
wherein ‘L’ is a leaving group
(b) reacting a compound of Formula IIa with a compound of Formula III
to give a compound of Formula IVa;
(c) oxidizing a compound of Formula IVa to a compound of Formula Va;
(d) condensing a compound of Formula Va with a compound of Formula VI,
wherein R 3 is alkyl, cycloalkyl, arylalkyl, aryl or carbonylbenzyloxy (cbz); P 1 and P 2 are hydrogen or a protecting group, wherein, P 1 and P 2 combines to form structure represented as
wherein, R 4 and R 5 is alkyl group, alkoxy group or can combine together to form a cyclic hydrocarbon chain or a carbonyl group, to give a compound of Formula VIIa;
(e) de-protecting or hydrolyzing a compound of Formula VIIa to give a compound of Formula VIIIa;
(f) converting a compound of Formula VIIIa to an amine salt; and
(g) converting an amine salt of a compound of Formula VIIIa to rosuvastatin calcium.
5. The process according to claim 4 , wherein ‘L’ is leaving group selected from a group consisting of alkyl sulphonyloxy, aryl suphonyloxy, phosphate or phosphite groups.
6. The process according to claim 5 , wherein ‘L’ is diphenyl phosphate.
7. The process according to claim 4 , wherein R 1 is C 1 -C 4 alkyl.
8. The process according to claim 4 , wherein the step (b) is reacted in the presence of a base selected from triethylamine, diisopropylethylamine, diisopropylamine, pyridine or dimethylaminopyridine.
9. The process according to claim 8 , wherein an organic base is diisopropylethylamine.
10. The process according to claim 4 , wherein the step (c) is performed using an oxidizing agent selected from a group consisting of permanganates, meta-chloro per benzoic acid, sodium hypochlorite, hydrogen peroxide, tert-butyl hydrogen peroxide, cumene hydroperoxide or oxone (2KHSO 5 .KHSO 4 .K 2 SO 4 ) in the presence of transition metal catalysts.
11. The process according to claim 10 , wherein oxidation is performed using hydrogen peroxide in the presence of ammonium molybdate.
12. The process according to claim 4 , wherein P 1 and P 2 are acetonide (isopropylidene) group.
13. The process according to claim 4 , wherein an amine salt is selected from a group consisting of methyl amine, ethyl amine, n-propyl amine, isopropyl amine, n-butyl amine or tert-butyl amine.
14. The process according to claim 13 , wherein an amine salt is tert-butyl amine salt.
15. The process according to claim 4 , wherein an amine salt is treated with a base and then converted to rosuvastatin calcium by treatment with calcium hydroxide.