TITLE OF THE INVENTION
PROCESS FOR THE PRODUCTION OF ATORVASTATIN CALCIUM
FIELD OF THE INVENTION
/ The present Invention relates to a novel process for the
/
production of atorvastatln calcium. Particularly, the present invention relates to a novel process for the production of amorphous atorvastatin calcium from (6-{2-[2-(4-Fluoro-phenyl)-5- isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-l-yl]-ethyl}-2- phenyl- [1,3/2] dioxaborinan-4-yl)-acetic acid tert-butyi ester. BACKGROUND OF THE INVENTION:
Atorvastatin calcium is known by synonyms like [R- (R*, R*)]-2-(4-fluorophenyl)-aa, 6- dihydroxy-5- (l-methylethyl)-3- phenyl-4- [(phenylamino) carbonyy-lh-pyrrole-l-heptanoic acid hemicaldum salt; (pR,5R)- 2-(4-fluorophenyi)-p,§-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-, lH-Pyrrole-1- heptanoic acid hemicalcium salt; [R-(R*,R*)]-2-(4-fluorophenyl)- p,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-, lH-Pyrroie-l-heptanoic acid hemicalcium salt or (pR,6R)-2-(p-Fluorophenyl)-p,8-dihydroxy-5-isopropyl-3- phenyl-4-(phenylcarbamoyl)pyrrole-l-heptanoic acid hemicalcium salt.
Hemicalcium salt of [R-(R*,R*)]-2-(4-fluorophenyl)-p,5- / dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-, lH-Pyrrole-l-heptanoic acid, a synthetic HMG-CoA reductase inhibitor, is used for the treatment of hyperlipidemia and hypercholesterolemia, both of which are risk factors for arteriosclerosis and coronary heart disease. Open dihydroxy carboxylic acid, lactone and various salt forms of [R-fR*^*)]^^^ fluorophenyl)-p,5-dihydroxy-5-(l-methyiethyl)-3-phenyi-4- [(phenylamino)carbonyl]-, lH-Pyiirole-l-heptanoic acid have been synthesized.
US 5,273,995, describes that [R-(R*,R*)]-2-(4-fiuorophenvl)- P,5-dihydroxy-5-(l-methylethy!)-3-phenyl-4- [(phenylamino)carbonyl]-, lH-Pyrrole-l-heptanoic acid has surprising inhibition of the biosynthesis of cholesterol. Calcium salt of [R-(R*,R*)]-2-(4-fluorophenyl)-^8-dihydroxy-5-(l-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-, lH-Pyrrole-l-heptanoic acid (2:1) (formula I)
is more suited to formulations and has been recommended as a 'drug.
United states patents 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; ^216,174; 5,245,047; 5,248,793; 5,273,995; 5,280,126; 5,298,627; 5,342,952; 5,385,929; 5,397,792; European Patent 409^281; and WO 89/07598 describe various processes and key intermediates for preparing atorvastatin.
WO 97/03958 and WO 97/03959 disclose novel crystalline forms of atorvastatin calcium designated as Form I, Form II, Form III and Form IV and method for their preparation which provide more favorable filtration and drying characteristics.
WO 97/03960 and US Patent 6087511 describe the procedures for converting the crystalline form of atorvastatin calcium to the amorphous form. The process disclosed therein involve dissolving form I atorvastatin calcium in a non-hydroxy[ic solvent lite tetrahydrofuran or a mixture of tetrahydrofuran and toluene.
WO 00/7H16 describes the procedure for converting the crystalline form-I by dissolving it in a non-hydroxylic solvent Jike_ tetrahydrofuran and precipitating amorphous atorvastatin calcium by the addition of nonpolar hydrocarbon solvents like, n-hexane, cyclohexane or n-heptane.
It is the object of the present invention to provide a novel process for the preparation of atorvastatin calcium, which is unique
with respect to its simplicity, cost effectiveness and scalability.
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SUMMARY OF THE INVENTION
( The instant invention relates to a novel process of the preparation of atorvastatin calcium.
The novel process of instant invention comprises conversion of compound of formula II to atorvastatin calcium (formula I).

FORMULA II
In particular the novel process of instant invention comprises treating compound of formula n with calcium oxide.
■■ ~
The process of instant invention is novel, simple, one step, economic and industrially scalable.
The novel process of instant invention has following advantages:
1. De-protection of boronate ester and cleavage of tert-butyl ester and formation of calcium salt is done in one step employing a single reagent.
2. Simple procedure involving inexpensive CaO.
3. Calcium salt is obtained directly without need for making sodium salt or any other intermediates and thereby reducing number of
r
steps.
DETAILED DESCRIPTION OF THE INVENTION
As mentioned earlier, the novel process of the instant invention related to preparation of [R-(R*,R*)]-2-(4-fluorophenyl)- (3,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-, lH-Pyrrole-l-heptanoic acid hemicalcium salt.
. The novel process of instant invention comprises conversion of (6-{2-[2-(4-Fluorp-phenyl)-5-isopropyl-3-phenyl-4- phenylcarbamoyl-pyrrolidin-l-yl]-ethyl>-2-phenyl- [1,3,2] dioxaborinan-4-yl)-acetic acid tert-butyl ester to [R-(R*,R*)]-2-(4- fluorophenyl)-p,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-, lH-Pyrrole-l-heptanoic acid hemicalcium, its stereoisomers or polymorphic forms, which is simple, one step, economic and industrially scalable.
In particular, the novel process of instant invention comprises treating (6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4- phenylcarbamoyl-pyrrolidin-l-yl]-ethyl}-2-phenyl- [1,3,2] dioxaborinan-4-yl)-acetic acid tert-butyl ester with calcium oxide in a suitable solvent.
The suitable solvent of the instant invention can be selected from water, water miscible or water immiscible solvent.
The solvent system used can be single or mixture of two or more solvents.
The water miscible solvent can be selected from one or more among methanol, ethanol, isopropanol, acetone, THF or acetooitrile.
The reaction of the instant invention can be carried out at suitable reaction conditions required for satisfactory conversion of the starting material (formula n) to atorvastatin calcium.
The reaction of the instant invention can be carried out at a temperature between 25 to 100Q C. Preferably, the reaction of the
instant invention is carried out at a temperature between 40 to 70°
-
c.
The reaction of the instant invention can be carried out for a time period between 1 to 24 hours. Preferably, the reaction is carried out for a time period between 5 to 15 hours.
After satisfactory conversion, the product can be isolated with or without further purification.
The present invention will now be illustrated by the following examples, which are not intended to limit the effective scope of the claims. Consequently, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as claimed. The present invention has been described in terms of its specific embodiments and various modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of present invention. EXAMPLES Example 1
A mixture of (6-{2-[2-(4-Huoro-phenyl>5-isopropyl-3-
phenyl-4-phenylcarbamoyl-pyijQlidi^ £1,3,2]
dioxaborinan-4-yl)-acetic acid tert-butyl ester (5 g, 0.007 mol), water (200 ml), methanol (200 ml) and calcium oxide (5.0 g, 0.09
mol) was stirred at 50-60° C for 10 hours. After filtering the
/■r
* reaction mixture, dear filtrate was concentrated to about 150ml and washed with methyl tert-butyl ether (50 ml). The aqueous layer was evaporated and solid obtained was dissolved in THF (50 ml). The solution was filtered and concentrated to yield [R- (R*/R*)]-2-(4-fluorophenyl)-p,8-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-, lH-Pyrrole-l-heptanoic acid hemicalcium salt. Example 2
A mixture of (6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3- phenyl-4-phenylcarbamoyl-pyrrolidin-l-yl]-ethyl}-2-phenyl- [1,3,2] dioxaborinan-4-yl)-acetic acid tert-butyl ester (50 g, 0.07 mol), . water (2 L), THF (2 L) and calcium oxide (50 g, 0.9 mol) was stirred at 50-60° C for 8 hours. After filtering the reaction mixture, clear filtrate was concentrated to about 1.5 L and washed with methyl tert-butyl ether (500 ml). The aqueous layer was evaporated and solid obtained was dissolved in THF (500 ml). The solution was filtered and concentrated to yield atorvastatin calcium. Example 3
A mixture of (6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3- phenyl-4-phenylcarbamoyl-pyrrolidjn-l-yl]-ethyi}-2-phenyl- [1,3,2] dioxaborinan-4-yl)-acetic acid tert-butyl ester (100 g, 0.14 mol), water (3.0 L), acetonitrile (3.0 L) and calcium oxide (75 g, 1.35 mol) was stirred at 50-60° C for 12 hours. After filtering the reaction mixture, clear filtrate was concentrated to about 3.0 L and washed with methyl tert-butyl ether (1.0 L). The aqueous layer was evaporated and solid obtained was dissolved in acetonitrile (1.0 L).
The solution was filtered and concentrated to yield [R-(R*,R*)]-2-(4- fluorophenyl)-p,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-, lH-Pyrrole-l-heptanoic acid hemicalcium salt.
Example 4: A mixture of (6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3- phenyl-4-phenylcarbamoyl-pyrrolidin-l-yl]-ethyl}-2-phenyl- [1, 3, 2] dioxaborinan-4-yl)-acetic acid ter-butyl ester (50 g, 0.07 mol), water (2 L), THF (2 L) and calcium hydroxide (66.6 g, 0.9 mol) was stirred at 50- 60° C for 8 hours. After filtering the reaction mixture, clear filtrate was concentrated to about 1.5 L and washed with methyl ter-butyl ether (500 ml). The aqueous layer was evaporated and solid obtained was dissolved in THF (500 ml). The solution was filtered and concentrated to yield atorvastatin calcium.

We claim:
1. A process for the preparation of compound of formula I characterized by treating compound of formula II with CaO or Ca(OH)2


FORMULA I FORMULA II
in the presence of solvent.
2. The process as claimed in claim 1, wherein the solvent is selected from water, water miscible solvent or water immiscible solvent.
3. The process as claimed in claim 2, wherein the solvent is selected from water and water miscible solvents.
4. The process as claimed in claim 3, wherein the water miscible solvent is selected from dielectric polar solvent.
5. The process as claimed in claim 4, wherein the solvent is selected from methanol, ethanol, isopropanol, acetone, acetonitrile or THF.
6. The process as claimed in claim 1, wherein the reaction is carried out at a temperature between 25 to 100°C.
7. The process as claimed in claim 6, wherein the reaction is carried out at a temperature between 40 to 70°C.
8. The process as claimed in claim 1, wherein the reaction is carried out for a time period between 1 to 24 hour.
9. The process as claimed in claim 8, wherein the reaction is carried out for a time period between 1 to 10 hour.
10. The process as claimed in claim 1, wherein the compound of formula I is afforded by precipitation or crystallization.
11. The process as claimed in claim 1, resulting in amorphous state of compound of formula I.
12. A process as in claim 1, wherein the compound of formula I is [R- (R*,R*)]-2-(4-fluorophenyl)-(3,8-dihydroxy-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-, lH-Pyrrole-l-heptanoic acid hemicalcium salt.