WO2017060885A1

WO2017060885A1 - An improved process for preparation of atorvastatin or pharmaceutically acceptable salts thereof

Info

Publication number: WO2017060885A1
Application number: PCT/IB2016/056055
Authority: WO
Inventors: Ravindra Babu Bollu; Prasanta Kumar DALASINGH; Susmita DWARAMPUDI; Venkata Sunil Kumar Indukuri; Srihari Raju Kalidindi; Satyanarayana Chava
Original assignee: Laurus Labs Pvt Ltd
Current assignee: Laurus Labs Pvt Ltd
Priority date: 2015-10-09
Filing date: 2016-10-10
Publication date: 2017-04-13
Anticipated expiration: 2018-04-09

Abstract

The present invention provides an improved process for the preparation of Atorvastatin or pharmaceutically acceptable salts thereof in high yield and purity.

Description

"AN IMPROVED PROCESS FOR PREPARATION OF ATORVASTATIN OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF"

PRIORITY

This application claims the benefit under Indian Provisional Application No. 5404/CHE/2015 filed on 09 October 2015 and entitled "An improved process for preparation of atorvastatin or pharmaceutically acceptable salts thereof, the content of which is incorporated by reference herein. FIELD OF THE INVENTION

The present invention generally relates to an improved process for preparation of Atorvastatin and pharmaceutically acceptable salts thereof in high yield and purity. BACKGROUND OF THE INVENTION

Atorvastatin calcium is a drug compound that is used as a lipid-lowering agent, for treating hypercholesterolemia. The compound has the chemical name [R-(R*,R*)]-2-(4-fluorophenyl)- β, δ-dihydroxy- 5-(l-methylethyl)- 3-phenyl-4- [(phenylamino) carbonyl]-lH-pyrrole-l- heptanoic acid, calcium salt (2:1). Pharmaceutical products containing crystalline atorvastatin calcium trihydrate are sold using the trademark LIPITOR. Atorvastatin calcium has the following chemical structure:

Racemic trans-5-(4-fluorophenyl)-2-( 1 -methylethyl)-N,4-diphenyl- 1 - [2-tetrahydro-4-4- hydroxy- 6-oxo- 2H-pyran-2-yl) ethyl] -1H- pyrrole- carboxamide ("racemic atorvastatin lactone") or its hydroxy acid form or pharmaceutically acceptable salts thereof and methods for its preparation is reported in U.S. Pat. No. 4,681,893. U.S. Pat. No. 5,273,995 discloses atorvastatin, the pure [R(R*,R*)] enantiomer of 2-(4- fluorophenyl) - β, δ-dihydroxy- 5 - ( 1 -methylethyl) - 3 -phenyl-4- [(phenylamino) carbonyl] - 1 H- pyrrole-1 -heptanoic acid. Also disclosed are hemicalcium, hemimagnesium, hemizinc, monosodium, monopotassium, N-methylglucamine and l-deoxy-l-(methylamino)-D-glucitol salts of atorvastatin.

U.S. Pat. No. 5,969,156 discloses atorvastatin hemicalcium crystalline forms I, II and IV and their preparation process. There are several routes to atorvastatin disclosed in the art but the most prominent approach available till date is the pyrrole ring construction (Paal-Knorr pyrrole synthesis), which process involves reacting tert-butyl [(4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate ("amino ketal", compound III) with 4-(4-Fluorophenyl)-2-isobutyl-3-phenyl-4-oxo-N-phenyl butyramide ("1,4-diketone", compound II) to obtain diol protected atorvastatin ester of formula IV, followed by deprotection of the diol functionality and carboxylic acid functional group and then conversion in to atorvastatin, for example, in US 5,003,080, WO 2005/092852 and many other references.

The synthesis of Atorvastatin calcium by conventional Paal-Knorr pyrrole synthesis is sch

Like any synthetic compound, atorvastatin calcium can contain extraneous compounds or impurities that can come from many sources. Impurities in atorvastatin hemi-calcium salts or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.

These impurities include unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. In the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent. For example, the ICH Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.

Some of the impurities formed during the synthesis of atorvastatin calcium are:

Stach et al in Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 2, pp. 229-246 disclosed various impurities formed during the synthesis of atorvastatin and ways to prepare them; but is silent about the removal of these impurities from atorvastatin or its pharmaceutically acceptable salts.

Wade et al in Organic Process Research & Development 1997, 1, 320-324 disclosed a rework process for the preparation of high purity atorvastatin by converting atorvastatin sodium salt in to lactone form, crystallizing the lactone from toluene and converting the pure lactone to atorvastatin calcium. This process introduced additional steps of lactone crystallization and isolation to obtain the final product with high purity, which process increases the manufacturing cost. U.S. Publication No. 2009/081801 disclosed that during the Paal-Knorr pyrrole synthesis, an amide impurity of formula IVa, which is very difficult to remove, is formed when the compound of formula IV is further reacted with the unreacted compound of formula III, or impurity Ilia (a major contaminant in III) reacted with a compound II. To control this impurity in the preparations of compound IV, multiple crystallizations were required leading to significant product loss and increase in manufacturing cost. To minimize its content to not more than 0.16%, binary solvent systems that includes an alcohol solvent was used during the preparation of compound IV. The inventors of the present invention have found that the crude compound IV prepared by the above process contains approximately 0.4 to 0.5% of the amide impurity IVa which requires further purification from organic solvents to reduce the impurity IVa to 0.16%. Such crystallization processes though feasible in laboratory scale are not suitable for large-scale manufacturing processes as it increases the production cost.

IPCOM000225989D disclosed the synthesis of compound IV in the presence of catalytic amount of amidine base [e.g., l,8-diazabicycloundec-7-ene or l,5-diazabicyclo(4.3.0)non-5- ene] to achieve a purity of 99.5% having impurity IVa not more than 0.1%. Although, the process was reproducible, the impurity IVa was present in the level of about 0.2 to 0.4% and required additional purifications to minimize the impurity to not more than 0.1%. In view of the drawbacks of the reported processes, the inventors have developed an improved process for the preparation of Atorvastatin or pharmaceutically acceptable salts thereof and observed the following critical process parameters: During the preparation of compound IV, impurity of formula IVa is generated due to further reaction of compound IV with another molecule of compound III or by reaction of compound II with compound Ilia, which is impurity formed in previous steps during preparation of compound III. When compound of formula IV is contaminated with compound IVa, an impurity of Formula Va along with unreacted compound of formula IV is likely formed in the acid hydrolysis step for the preparation of atorvastatin ester V. Further, when compound V thus formed is hydrolyzed with strong alkaline condition, both compound V and impurity Va gets converted to the atorvastatin sodium salt of formula VI, while unreacted compound IV transforms to another impurity of formula IVb which is again difficult to remove once formed and is precipitated along with atorvastatin calcium.

During the ester hydrolysis of compound V using mild alkaline conditions atorvastatin sodium salt of formula VI is formed. However, when compound V contaminated with impurity Va along with unreacted compound IV is subjected to mild alkaline conditions, the compound Va gets converted in to compound Via while the unreacted compound IV remains unaltered (as the protection on C5-hydroxyl prevents the anchimeric assistance during the ester hydrolysis).

In view of the above observations, an improved process for the preparation of atorvastatin and pharmaceutically acceptable salts thereof is required which is free of above mentioned drawbacks.

The present invention takes the advantage of differences in the relative reaction rates of the intermediates and/or impurities and provides an improved process for preparation of atorvastatin or pharmaceutically acceptable salts thereof to circumvent yield loss for e.g. during the preparation of compound IV due to multiple crystallizations to reduce the impurity IVa.

Therefore, present invention fulfill the need in the art and provides an improved process for preparation of atorvastatin or pharmaceutically acceptable salts thereof by sequentially removing the impurities formed during the synthesis of atorvastatin or pharmaceutically acceptable salts thereof and circumvent disadvantages associated with prior art, proved to be advantageous from industrial point of view and also fulfill purity criteria's led by various regulatory authorities. Also provides a process for hydrolyzing the amide impurity in to atorvastatin sodium salt in a simple manner, which is economical and applicable on an industrial scale to obtain atorvastatin or pharmaceutically acceptable salts thereof with higher yield and greater purity.

SUMMARY OF THE INVENTION The present invention provides an improved process for the preparation of atorvastatin or pharmaceutically acceptable salts thereof.

In accordance with one embodiment, the present invention provides a process for the preparation of atorvastatin or ph thereof of formula I;

wherein M is H, Na⁺,K⁺,Mg⁺²,Ca⁺²; comprising:

a) treating a compound of formula IV with a suitable acid to obtain a compound of formula V;

b) hydrolyzing the compound of formula V with an alkaline base to obtain a compound of formula VI or a cation salt thereof;

c) treating the aqueous solution of compound of formula VI with a solvent immiscible or slightly miscible in water;

d) treating the compound of Formula VI or a cation thereof with a suitable base;

e) optionally washing the aqueous solution of step d) with a solvent immiscible or slightly miscible in water; and

f) converting the reaction mass of step e) into atorvastatin or pharmaceutically acceptable salts thereof.

In accordance with another embodiment, the present invention provides an improved process for the preparation of atorvastatin or pharmaceutically acceptable salts thereof, comprising: a) providing a solution of atorvastatin or a cation salt thereof;

b) concentrating the solution to obtain a residue;

c) combining the residue with water, and optional alcohol solvent to obtain an aqueous solution;

d) washing the aqueous solution with a solvent immiscible or slightly miscible in water; e) treating the aqueous solution of step d) with a suitable base; and

f) optionally washing the aqueous solution with a solvent immiscible or slightly miscible in water; and

g) converting the step f) solution to atorvastatin or pharmaceutically acceptable salts thereof.

In accordance with another embodiment, the present invention provides an improved process for the preparation of atorvastatin or pharmaceutically acceptable salts thereof having less than 0.1% by wt, as measured by HPLC of compound of Formula IV or compound of Formula IVb, comprising:

c) concentrating the alkaline solution of compound of Formula VI to obtain a residue; d) combining the residue with water, and optional alcohol solvent to obtain an aqueous solution;

e) washing the aqueous solution with a solvent immiscible or slightly miscible in water; and

f) converting the aqueous solution of step e) containing compound of Formula VI or a cation salt thereof having less than 0.1 % by wt, as measured by HPLC of compound of Formula IV or compound of Formula IVb to atorvastatin or pharmaceutically acceptable salts thereof.

In accordance with another embodiment, the present invention provides an improved process for the preparation of atorvastatin or pharmaceutically acceptable salts thereof; comprising: treating a mixture of compound of formula VI or a cation salt thereof and a compound of Formula Via with a suitable base to obtain atorvastatin or a cation salt thereof; and converting the co

In accordance with another embodiment, the present invention provides an improved process for the preparation of atorvastatin or pharmaceutically acceptable salts thereof; comprising: a) reacting a compound of formula II with a compound of formula III in presence of a base, an acid catalyst and a suitable solvent to obtain a compound of formula IV;

b) treating the compound of formula IV with a suitable acid to obtain a compound of formula V;

c) treating the compound of formula V with a suitable base to obtain a compound of formula VI; d) concentrating the step c) reaction solution to obtain a residue;

e) combining the residue with water, and optional alcohol solvent to obtain an aqueous solution;

f) washing the aqueous solution with solvent immiscible or slightly miscible in water; g) separating the organic solvent layer and aqueous layer;

h) treating the aqueous layer of step g) with a suitable base;

i) adjusting the pH of the reaction mass of step h) to lower than 9 with a suitable acid; j) washing the aqueous solution of step i) with a solvent immiscible or slightly miscible in water; and

converting the solution obtained in step j) into atorvastatin or pharmaceutically acceptable salts thereof;

wherein the atorvastatin or pharmaceutically acceptable salts thereof contains less than 0.1 % by wt, as measured by HPLC of each of compound of Formula IVa, compound of Formula IVb, compound of Formula Va and compound of Formula Via.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising therapeutically effective amount of atorvastatin or pharmaceutically acceptable salts thereof, preferably atorvastatin calcium salt prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.

DETAILED DESCRIPTION OF THE INVENTION:

As used herein the term "substantially pure atorvastatin or pharmaceutically acceptable salts thereof" refers to atorvastatin or pharmaceutically acceptable salts thereof containing any individual identified impurity less than 0.15% and unidentified impurity less than 0.10 %, as measured by HPLC.

In one embodiment, the present invention provides a process for the preparation of atorvastatin or pharmaceutically acceptable salts thereof of formula I;

wherein M is H, Na⁺,K⁺,Mg ,Ca⁺²; comprising:

b) hydrolyzing the compound of formula V with an alkaline base to obtain a compound of formula VI or a cation salt the

In a preferred embodiment, the present invention provides an improved process for the preparation of atorvastatin or pharmaceutically acceptable salts thereof; comprising:

a) reacting a compound of formula II with a compound of formula III in presence of a base, an acid catalyst and a suitable solvent to obtain a compound of formula IV;

c) treating the compound of formula V with a suitable base to obtain a compound of formula VI;

d) concentrating the step c) reaction solution to obtain a residue;

h) treating the aqueous layer of step g) with a suitable base;

k) converting the solution obtained in step j) into atorvastatin or pharmaceutically acceptable salts thereof. In another preferred embodiment, atorvastatin or pharmaceutically acceptable salts thereof prepared by the process of the present invention contains less than 0.1% by wt as measured by HPLC of each of compound of Formula IV a, compound of Formula IVb, compound of Formula Va and compound of Formula Via.

The starting compounds of Formula II and III are known in the art and can be prepared by any known methods, for example, starting compounds of Formula (II) may be synthesized according to US 5,124,482 or WO 03/004457 and compound of Formula III may be synthesized according to US 5,003,080 or US 6,001,615; which are incorporated herein by reference.

The step a) of the foregoing process may include reacting compound of formula II with a compound of formula III according to Paal-Knorr pyrrole synthesis in the presence of a base and an acid catalyst in a suitable solvent. The base used in step (a) is either inorganic or organic base. The inorganic base used herein is selected from the group comprising of alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide and the like; alkali metal hydride such as sodium hydride, potassium hydride and the like. The organic base used herein is selected from the group comprising of alkyl amines such as di-isopropyl ethyl amine, di-isopropyl amine, triethyl amine, triethanol amine, N-methyl morpholine and morpholine, piperidine and the like; heterocyclic amines such as pyridine and the like, amidine bases such as l,8-diazabicycloundec-7-ene (DBU) or l,5-diazabicyclo(4.3.0)non-5-ene (DBN) and the like. Preferably, the base is selected from di-isopropyl ethyl amine, triethyl amine, piperidine, triethanol amine, morpholine, N-methyl morpholine and DBU; more preferably triethyl amine, piperidine, triethanol amine, N-methyl morpholine and DBU.

The acid catalyst used is selected from any one or more of pivalic acid, formic acid, acetic acid, butyric acid, valeric acid, isovaleric acid, malic acid, succinic acid, malonic acid, citric acid, benzoic acid, oxalic acid, n-butyric acid and the like or mixtures thereof, preferably pivalic acid or acetic acid or mixtures thereof.

The order and manner of combining the reactants at any stage of the process are not critical and it may be varied. The reactants may be added to the reaction mixture as solids, or may be dissolved individually and combined as solutions. Further, any of the reactants may be dissolved together, or their solutions may be combined in any order.

Examples of suitable solvents used herein for step a) include but are not limited to aromatic hydrocarbons such as toluene, xylene and the like; aliphatic hydrocarbons such as heptanes, hexane, cyclohexane and the like; ethers such as methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether, di-methyl ether and the like; cyclic ethers such as tetrahydrofuran, 1 ,4-dioxane and the like; substituted cyclic ethers such as 2-methyl tetrahydrofuran and the like; nitriles such as acetonitrile, propionitrile and the like; halogenated hydrocarbons such as dichlorome thane, dichloroe thane, chloroform and the like; ketones such as acetone, methyl ethyl ketone and the like; dialkylformamides such as dimethyl formamide and the like, dialkylacetamides such as dimethyl acetamide and the like; dialkylsulfoxides such as dimethyl sulfoxide and the like or mixtures thereof. Preferably, the suitable organic solvent is cyclohexane.

The step a) reaction is carried out at a temperature of about 50° C to about 100° C; preferably at 70°C to 90°C, over a period of 6 hrs to 50 hrs.

After completion of the reaction, the resultant reaction mass may be washed with water, distilled out solvent, optionally co-distilled with organic solvents such as isopropanol, methanol and then the resultant compound of Formula IV can be isolated by known techniques, for example, by dissolving in organic solvents such as isopropanol, methanol, ethanol and the like and adding anti-solvent such as water to precipitate the compound of formula IV. After isolation of compound of formula IV, additional purification may be carried out using a suitable solvent selected from the group consisting of alcohols such as methanol, ethanol, isopropanol and the like and dried according to any of the methods known in the art such as a tray dryer, vacuum oven, air oven and the like.

Atorvastatin ester compound of Formula IV thus formed may contain substantial amounts of amide of Formula IVa as an impurity in the range of about 0.2-1.5%, which is not suitable for regulatory standards. It has been observed that purification procedures to control the impurity of Formula IVa at this stage of the process lead to substantial decline of product yield. The inventors of the present invention have found that instead of expensive purifications to remove the amide impurity at this stage, the ester compound of Formula IV along with amide impurity of Formula IVa obtained as such is further converted to atorvastatin according to the current process as described herein after, provided high purity atorvastatin or pharmaceutically acceptable salts thereof in good yields. The amide impurity of Formula IVa is advantageously converted in to a compound of Formula Va and/or Via in the subsequent stages of the process and finally the same were converted in to atorvastatin by additional base hydrolysis after ester hydrolysis step of the process of the invention.

Step b) of the aforementioned process involves deprotection of the hydroxy protecting groups by treatment with a suitable acid such as hydrochloric acid, acetic acid, sulfuric acid, oxalic acid, trifluoroacetic acid, phosphoric acid and formic acid in a suitable organic solvent. The organic solvent includes, but is not limited to halogenated solvents such as dichloromethane, chloroform and the like; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, t- butanol and the like; ether solvents such as tetrahydrofuran, diethyl ether and the like; ketone solvents such as methyl ethyl ketone, acetone and the like; ester solvents such as methyl acetate, ethyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; water and mixtures thereof. Preferably, the suitable acid is hydrochloric acid and the suitable solvent is selected from the group comprising methanol, isopropanol, t-butanol, acetonitrile or mixtures of any of these solvents with water. The deprotection reaction may be carried out at a temperature in the range of about 10°C to about 75°C, preferably about 15°C to about 65°C. The reaction mixture is maintained for lhr to about 8 hrs or until completion of the reaction, preferably 3-6 hrs. The resultant compound of Formula V can be processed directly in the same reaction medium to prepare the atorvastatin or a cation salt thereof, for example sodium salt of formula VI, which process involves hydrolysis of the compound of formula V with a suitable base like alkali metal hydroxide in a suitable solvent at a temperature from about 10°C to about 75°C, preferably about 25 °C to about 65 °C.

Suitable alkali metal hydroxides include but are not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; preferably sodium hydroxide. Selection of suitable organic solvents used for the step c) reaction can be same as solvents used for the step b) reaction. Preferably, suitable solvent is selected from the group comprising methanol, isopropanol, t-butanol, acetonitrile or mixtures of any of these solvents with water.

After completion of the ester hydrolysis of step c), the reaction mixture containing atorvastatin sodium of Formula VI may be treated with a suitable carbon followed by concentrating the resulting aqueous solution under reduced pressure to obtain atorvastatin sodium of Formula VI as residue.

Then, combining the resultant residue with water, and optional alcohol solvent to obtain an aqueous solution; preferably a mixture of water and an alcohol solvent and washing the aqueous solution with a solvent immiscible or slightly miscible in water. At this stage, the water immiscible solvent containing unreacted compound IV is separated from the aqueous layer containing compound VI and impurity Via.

The washing step using a solvent immiscible or slightly miscible in water with step e) aqueous solution may be carried out at a temperature of about 20°C to about 65°C, preferably at about 25°C to 35°C. The washing step may be repeated as long as the unwanted compound of Formula IV is minimized in the compound of Formula VI.

The alcohol solvent includes, but is not limited to methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol and the like, preferably the alcohol is methanol.

A solvent immiscible or slightly miscible in water for use in step f) can be selected from the group consisting of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate; diethyl ether, isopropyl ether, methyl tert-butyl ether, chloroform, dichlorome thane; cyclohexane, toluene or mixtures thereof; preferably cyclohexane, toluene or methyl tert-butyl ether.

It has been observed that during the deprotection of compound IV to compound V, small amount of unreacted compound IV remains along with the impurity Va. Upon ester hydrolysis, under mild alkaline condition, the compound V gets converted to atorvastatin sodium compound VI, impurity Va gets converted to Via whereas the unreacted compound IV remains unaltered. The unreacted compound IV can be removed effectively from the product containing atorvastatin sodium compound VI using solvent washings as described above thereby minimizing the additional solvent crystallizations to control the same.

In another embodiment, the present invention provides an improved process for the preparation of atorvastatin or pharmaceutically acceptable salts thereof having less than 0.1% by wt, as measured by HPLC of compound of Formula IV or compound of Formula IVb, comprising preparing the atorvastatin sodium compound VI by process described as above and converting the same in to atorvastatin or pharmaceutically acceptable salts thereof such as calcium salt.

It has been observed that, atorvastatin sodium compound VI obtained by the process described above still contain substantial amounts of compound of formula Via as impurity. The inventors of the present invention have found that the impurity Via can be minimized by further hydrolysis of atorvastatin sodium compound VI and impurity Via with a suitable base. The additional hydrolysis step minimizes the impurity Via by selectively hydrolyzing the impurity Via to atorvastatin sodium compound VI; thereby additional expensive purification techniques are not necessary for getting high pure atorvastatin or pharmaceutically acceptable salts thereof.

In another embodiment, the present invention provides an improved process for the preparation of atorvastatin or pharmaceutically acceptable salts thereof; comprising: treating a mixture of compound of formula VI or a cation salt thereof and a compound of Formula Via with a suitable base to obtain atorvastatin or a cation salt thereof, and converting the compound VI to atorvast

The aqueous layer containing the atorvastatin sodium compound VI and impurity Via may be treated with a suitable base at a temperature from about 10°C to about 70°C. The suitable base include, but is not limited to alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; preferably sodium hydroxide.

After completion of the base hydrolysis, the reaction mixture of step h) can be treated with a suitable acid such as hydrochloric acid, acetic acid and the like to adjust the pH to less than 9 followed by washing the obtained aqueous solution with a solvent immiscible or slightly miscible in water. The solvent immiscible or slightly miscible in water can be selected from the group consisting of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate; diethyl ether, isopropyl ether, methyl tert-butyl ether, chloroform, dichlorome thane; toluene or mixtures thereof; preferably methyl tert-butyl ether. The washing step may be carried out at a temperature of about 20°C to about 65°C, preferably at about 25°C to 35°C.

Then, the product containing aqueous layer is separated and treated with a suitable salt source for the formation of atorvastatin or pharmaceutically acceptable salt thereof; preferably atorvastatin calcium. The calcium source may be selected from calcium hydroxide, calcium chloride or calcium acetate in a suitable solvent by a process well known in the art; for example, calcium acetate is used as calcium source. Atorvastatin calcium can be isolated by any method known in the art, such as filtration and drying.

It has been observed that purification of intermediate of formula IV to minimize the amount of amide impurity of formula IVa result in extensive loss of yield, which makes the process commercially unviable. Removal of such impurities from intermediate of formula IV requires additional purifications which is not amenable for the industrial synthesis. Therefore, the present invention avoids extensive purification at this stage and result in the development of a method for the hydrolysis of such impurity at final stage where adding a base to the aqueous phase containing atorvastatin sodium of formula VI and impurity of formula Via and maintaining the pH at about 13-14 allows the resulting high quality atorvastatin calcium to be obtained with good yield and purity.

According to the present invention, high purity atorvastatin calcium is obtained having a chemical purity of at least about 98%, as measured by HPLC, preferably at least about 99%, as measured by HPLC, and more preferably at least about 99.5%, as measured by HPLC. The present invention provides atorvastatin calcium, obtained by the process described herein, having a chiral purity of at least about 98% as measured by chiral HPLC, preferably at least about 99% as measured by chiral HPLC; more preferably at least about 99.5% as measured by chiral HPLC; impurity of Formula IVb is less than 0.1% as measured by HPLC and impurity of Formula Via is less than 0.1% as measured by HPLC.

Table- 1 : illustrates the different levels of impurities removed by the process of the present invention and after washing the aqueous layer containing atorvastatin sodium salt with water immiscible solvent:

Table-2: illustrates the effect of present invention without washing the aqueous layer containing atorvastatin sodium salt with water immiscible solvent: HI ³LC impurity profile (% area)

Product/sample

IV Via I/VI Va IVb V IVa

Input (IV) 99.5 — — — — — 0.28

Acid hydrolysis 0.69 ND 0.5 0.22 ND 96.3 0.02

Ester hydrolysis 0.02 0.05 98.5 ND 0.77 0.02 ND

Atorvastatin Calcium ND 0.02 98.7 ND 0.77 ND ND

In another embodiment, the present invention provides a pharmaceutical composition comprising therapeutically effective amount of atorvastatin or pharmaceutically acceptable salts thereof, preferably atorvastatin calcium salt prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. EXAMPLES:

The present invention is further illustrated by the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

Preparation of (4R-cis)-l,l-dimethyl ethyl-6-{2-[2-[(4-fluoro phenyl)-5-(l-methylethyl)-3- phenyl-4-[(phenylamino) carbonyl]-lH-pyrrol-l-yl]ethyl}-2,2-dimethyl- 1,3- dioxane-4- acetate (IV)

EXAMPLE 1:

A mixture of Diketone intermediate II (100 g), amino ketal intermediate III (68 g) and pivalic acid (9.1 g) in cyclohexane (450mL) was refluxed (80-84°C) in a Dean-Stalk apparatus, with azeotropic removal of water. A solution of DBU (13 g) in cyclohexane (50 mL) was added over a period of 60 min and the reaction mass maintained at mild reflux for 24h when HPLC analysis revealed completion of the reaction. The reaction mass was gradually cooled to 55- 65°C and washed with hot (55-65°C) water (500 mL), while maintain temperature above 55°C. Mild vacuum was applied and the solvent was completely distilled off, while maintaining temperature below 65°C. Isopropyl alcohol (100 mL) was added to the residue, stirred for 10- 30 min and the solvent again completely distilled off under vacuum while maintaining temperature below 65°C. Isopropyl alcohol (650 mL) was added to the residue and the temperature of the mixture was raised to 80-84°C and maintained at the same temperature till the material completely dissolved. Gradually cooled the reaction mixture to 40-46°C, seeded with ~1 g of compound IV and further cooled the reaction mixture to 25-35°C. The mixture was stirred for another 60-90 min and then DM water (500 mL) was added at 25-35°C, over a period of 60-90 min. The reaction mixture was slurred for lhr at 25-35°C, further cooled to 9- 15°C, stirred for another 3-4 h and filtered. The reaction vessel was rinsed with chilled (0-5°C) mixture of IPA (80 mL) & water (20 mL) and the wet cake washed with it. The material was dried for 15-60 min under suction. The above semi-dried material was dissolved in IPA (500 mL) at 80-84°C, gradually cooled to 25-35°C over a period of 2-3h. The reaction mass was slurred, at 25-35°C, for 30-60 min, further cooled to 0-6°C and maintained for 3-4 h at the same temperature. The precipitated material was washed with chilled (0-5°C) IPA (50 mL) and dried under vacuum at 54-60°C for 12 h to obtain compound of formula IV as off-white solid material (125g, 79% yield).

HPLC purity: 99.5%, Impurity IVa: 0.20%.

EXAMPLE 2:

A mixture of Diketone intermediate II (100 g), amino ketal intermediate III (68 g) and pivalic acid (16.4 g) in cyclohexane (500mL) was refluxed in a Dean-Stalk apparatus with azeotropic removal of water. Triethyl amine (16.2 g) was charged and reaction mass maintained at mild reflux for 36h when HPLC analysis revealed completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in hot IPA, cooled to ambient temperature, seeded and then water added. The precipitated material was filtered and then recrystallized from IPA to afford compound of formula IV as off-white solid material (120 g, 76% yield). HPLC purity: 99.28%, Impurity IVa: 0.45%.

EXAMPLE 3:

A mixture of Diketone intermediate II (100 g), amino ketal intermediate III (72 g) and pivalic acid (7.6 g) in cyclohexane (500 mL) was refluxed in a Dean-Stalk apparatus with azeotropic removal of water. Charged DBU (10.9 g) and the reaction mass maintained at mild reflux for 36h when HPLC analysis revealed completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in hot IPA, cooled to ambient temperature, seeded and then water added. The precipitated material was filtered and then recrystallized twice from methanol to afford compound of formula IV as off-white solid material (107 g, 68% yield). HPLC purity: 99.46%, Impurity IVa: 0.10%.

EXAMPLE 4:

A mixture of Diketone intermediate II (100 g), amino ketal intermediate III (59 g) and pivalic acid (16.4 g) in cyclohexane 450 mL) was refluxed in a Dean-Stalk apparatus with azeotropic removal of water. A solution of DBU (13 g) in cyclohexane (50 mL) was added over a period of 60 min and the reaction mass maintained at mild reflux for 36h when HPLC analysis revealed completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in hot IPA, cooled to ambient temperature, seeded, water added and then the precipitated material was filtered (content of Impurity IVa: 0.37%). The crude material was recrystallized from IPA to afford compound of formula IV as off-white solid material (110 g, 63% yield). HPLC purity: 99.02%, Impurity IVa: 0.21%.

EXAMPLE 5: A mixture of Diketone intermediate II (100 g), amino ketal intermediate III (72.4 g) and pivalic acid (16.4 g) in cyclohexane (450mL) was refluxed in a Dean-Stalk apparatus with azeotropic removal of water. A solution of DBU (13 g) in cyclohexane (50 mL) was added over a period of 60 min and the reaction mass maintained at mild reflux for 36h when HPLC analysis revealed completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in hot IPA, cooled to ambient temperature, seeded, water added and then the precipitated material was filtered (content of Impurity IVa: 0.44%). The crude material was recrystallized from IPA to afford compound of formula IV as off-white solid material (122 g, 77% yield). HPLC purity: 99.46%, Impurity IVa: 0.25%.

EXAMPLE 6:

A mixture of Diketone intermediate II (25 g), amino ketal intermediate III (17 g), pivalic acid (4.1 g), piperidine (1.75 mL) and acetic acid (1 mL) in cyclohexane (125mL) was refluxed in a Dean-Stalk apparatus with azeotropic removal of water. The reaction mass maintained at mild reflux for 30h when HPLC analysis revealed completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in hot IPA, cooled to ambient temperature, seeded, water added and then the precipitated material was filtered (content of Impurity IVa: 0.21%). The crude material was recrystallized from methanol to afford compound of formula IV as off-white solid material (23 g, 58% yield). HPLC purity: 98.49%, Impurity IVa: 0.13%.

EXAMPLE 7:

A mixture of Diketone intermediate II (10 g), amino ketal intermediate III (7.2 g), pivalic acid (0.73 g) and N-methyl morpholine (0.73 g) in cyclohexane (50 mL) was refluxed in a Dean- Stalk apparatus with azeotropic removal of water. The reaction mass maintained at mild reflux for 40h when HPLC analysis revealed completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in hot IPA, cooled to ambient temperature, seeded, water added and then the precipitated material was filtered (content of Impurity IVa: 0.43%). The crude material was recrystallized from methanol to afford compound of formula IV as off-white solid material (8.8 g, 56% yield). HPLC purity: 98.15%, Impurity IVa: 0.24%

EXAMPLE 8:

A mixture of Diketone intermediate II (25 g), amino ketal intermediate III (17 g), pivalic acid (4.1 g) and triethanolamine (5.9 g) in cyclohexane (125mL) was refluxed in a Dean-Stalk apparatus with azeotropic removal of water. The reaction mass maintained at mild reflux, for 30h when HPLC analysis revealed completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in hot IPA, cooled to ambient temperature, seeded, water added and then precipitated material was filtered (content of Impurity IVa: 0.58%). The crude material was recrystallized from IPA to afford compound of formula IV as off-white solid material (24.8 g, 63% yield). HPLC purity: 99.08%, Impurity IVa: 0.27%

Preparation of Atorvastatin (2:1) calcium (formula I): EXAMPLE 9:

A mixture of compound of formula IV (20 g; diamino-ester IVa content -0.28%) in a mixture of hydrochloric acid (3.6 mL), water (36 mL) and MeOH (420 mL) was stirred under inert atmosphere at 22+3 °C. After completion of the reaction, the pH of the mixture was made alkaline by addition of 6N aqueous sodium hydroxide (40 mL). The mixture was maintained for 16h at temperature 40+3 °C when HPLC analysis revealed completion of ester hydrolysis; HPLC analysis revealed the content of impurity-VIa to be 0.08%. After carbon treatment, the mass was concentrated under reduced pressure and the residue obtained was dissolved in a mixture of water (180 mL) and methanol (80 mL). The reaction mass was washed twice with MtBE. The aqueous layer was gradually added to a mixture of aqueous calcium acetate and seed material while maintaining temperature of 52+3 °C. After maintaining for 17h at the same temperature the mixture was cooled to ambient temperature and filtered to afford crystalline Atorvastatin (16.5 g, 89% yield). HPLC purity: 97.85%, Impurity Via: ND, Impurity IVb: 1.41%.

EXAMPLE 10:

A mixture of compound of formula IV (20 g; diamino-ester IVa content -0.28%) in a mixture of hydrochloric acid (3.6 mL), water (36 mL) and MeOH (420 mL) was stirred under inert atmosphere at 22+3 °C. After completion of the reaction, the pH of the mixture was made alkaline by addition of 6N aqueous lithium hydroxide (40 mL). The mixture was maintained at temperature 40+3 °C for 14h when HPLC analysis revealed completion of ester hydrolysis; HPLC analysis revealed the content of impurity-VIa to be 0.02%. After carbon treatment, the mass was concentrated under reduced pressure and the residue obtained was dissolved in a mixture of water (180 mL) and methanol (80 mL);The reaction mass was washed with MtBE and gradually added to a mixture of aqueous calcium acetate and seed material, while maintaining temperature of 52+3°C. After maintaining for 17h at the same temperature, the mixture was cooled to ambient temperature and filtered to afford crystalline Atorvastatin (17 g, 92% yield). HPLC purity: 98.06%, Impurity Via: 0.02%, Impurity IVb: 1.13%.

EXAMPLE 11:

A mixture of compound of formula IV (25 g; diamino-ester IVa content -0.28%) in a mixture of hydrochloric acid (4.5 mL), water (45 mL) and MeOH (525 mL) was stirred under inert atmosphere at 22+3°C. After completion of the reaction, the pH of the mixture was made alkaline by addition of 6N aqueous potassium hydroxide (50 mL). The mixture was maintained at temperature 40+3°C for 7-8h when HPLC analysis revealed completion of ester hydrolysis; HPLC analysis revealed the content of impurity-VIa to be 0.08%. After carbon treatment, the mass was concentrated under reduced pressure and the residue obtained was dissolved in a mixture of water (225 mL) and methanol (100 mL), the reaction mass was washed with MtBE and gradually added to a mixture of aqueous calcium acetate and seed material, while maintaining temperature of 52+3°C. After maintaining for 17h at the same temperature, the mixture was cooled to ambient temperature and filtered to afford crystalline Atorvastatin (21 g, 91% yield). HPLC purity: 98.79%, Impurity Via: 0.04%, Impurity IVb: 0.66%. EXAMPLE 12:

A mixture of compound of formula IV (50 g; diamino-ester IVa content -0.28%) in a mixture of hydrochloric acid (9.0 mL), water (90 mL) and MeOH (1050 mL) was stirred under inert atmosphere at 22+3 °C. After completion of the reaction, the pH of the mixture was made alkaline by addition of 4N aqueous sodium hydroxide (100 mL). The mixture was maintained for 4h at 60+3 °C when HPLC analysis revealed completion of ester hydrolysis; HPLC analysis revealed the content of impurity-VIa to be 0.08%. After carbon treatment, the mass was concentrated under reduced pressure and the residue obtained was dissolved in a mixture of water (450 mL) and methanol (200 mL). The reaction mixture was washed with MtBE (150 mL x 2) and gradually added to a mixture of aqueous calcium acetate and seed material while maintaining temperature of 52+3°C. After maintaining for 15h at the same temperature, the mixture was cooled to ambient temperature and filtered to afford crystalline Atorvastatin (40.5 g, 90% yield). HPLC purity: 99.07%, Impurity Via: ND, Impurity IVb: 0.51%. EXAMPLE 13:

A mixture of compound IV (100 g; diamino-ester IVa content -0.47%) in methanol (2100 mL) was stirred for 30 min, under inert atmosphere and IN dilute hydrochloric acid (198 mL) was added over a period of 30-60 min while maintaining temp below 25 °C. The mixture was stirred at 22+3 °C till HPLC complied (compound IV maximum 1.0%), the pH of the mixture was made alkaline by addition of 4N aqueous sodium hydroxide (120 mL). The mixture was maintained for 2h at 42+3 °C, when HPLC analysis revealed completion of ester hydrolysis. The reaction mass was gradually cooled to 25-35°C, activated charcoal (5 g) was charged, stirred the mixture for 20-30 min and filtered through a short bed of Hyflo. The filtrate was transferred to clean reaction flask with a provision for downward distillation. Mild vacuum was applied and the solvent completely distilled off while maintaining temperature below 35°C. Water (900 mL) and methanol (400 mL) were added to the residue, stirred till complete dissolution. HPLC analysis revealed content of starting material IV to be 0.81%. The mixture was repeatedly washed with MtBE (300 mL x 3) till the content of IV was maximum 0.10%. Aqueous sodium hydroxide solution (12.8 g NaOH dissolved in 80 mL water) was charged to the above separated aqueous layer over a period of 30-60 min. The temperature was gradually raised to 49-55°C and maintained at this temperature till the content of impurity Via was maximum 0.08%. The reaction mass was cooled to 25-35°C and the pH of the reaction mass was adjusted to 8-9 with drop wise addition of dilute hydrochloric acid (-10 mL HC1 dissolved in 90 mL water). The mixture was stirred for 20-30 min and washed the mixture with MTBE (300 mL x 2).

The separated aqueous layer was charged to a solution of Ca(OAc)2*H20 (15.0 g) dissolved in DM Water (1200 mL) and seeded with atorvastatin calcium form I (1 g) over a period of 90- 120 min at 49-55°C. The reaction mass was further maintained for 8-10 h at the same temperature, cooled the reaction mass temperature to 39-45°C and maintained for 30 min. Filtered the precipitated product, washed with water (100 mL) and dried the material in vacuum oven initially at room temperature for 2h and then at 47-53 °C to obtain crystalline atorvastatin calcium form I (84 g, yield 90%). HPLC purity: 99.83%, Impurity Via: ND, Impurity IVb: 0.02%.

EXAMPLE 14:

A mixture of compound of formula IV (25 g; diamino-ester IVa content -0.22%) in a mixture of hydrochloric acid (4.5 mL), water (45 mL) and IPA (525 mL) was stirred under inert atmosphere at 50+3°C. After completion of the reaction, the pH of the mixture was made alkaline by addition of 4N aqueous sodium hydroxide (50 mL). The mixture was maintained for 3h at temperature 52+3 °C when HPLC analysis revealed completion of ester hydrolysis; HPLC analysis revealed the content of impurity-VIa to be 0.08%. After carbon treatment, the mass was concentrated under reduced pressure and the residue obtained was dissolved in a mixture of water (225 mL) and methanol (100 mL). The reaction mass was washed with MtBE (75 mL x 2) and gradually added to a mixture of aqueous calcium acetate and seed material while maintaining temperature of 52+3°C. After maintaining for 15h at the same temperature, the mixture was cooled to 42+3°C and filtered to afford crystalline Atorvastatin (21 g, 91% yield). HPLC purity: 99.41%, Impurity Via: 0.07, Impurity IVb: 0.15%.

EXAMPLE 15:

A mixture of compound of formula IV (150 g; diamino-ester IVa content -0.27%) in a mixture of hydrochloric acid (27 mL), water (270 mL) and IPA (3000 mL) was stirred under inert atmosphere at 42+3 °C. After completion of the reaction, the pH of the mixture was made alkaline by addition of 4N aqueous sodium hydroxide (180 mL). The mixture was maintained for 3h at temperature 42+3°C when HPLC analysis revealed completion of ester hydrolysis. After carbon treatment, the mass was concentrated under reduced pressure and the residue obtained was dissolved in a mixture of water (1350 mL) and methanol (600 mL); HPLC analysis revealed the content of starting material IV to be -0.54%. The mixture repeatedly washed with MtBE (300 mL) till the content of IV was maximum 0.10%. A solution of sodium hydroxide (4N, 120 mL) was added and the mixture stirred at 52+3 °C till the content of impurity Via was maximum 0.08%. After HPLC complied, the mixture was cooled to ambient temperature and the pH adjusted to -9.0 with dilute HC1. The reaction mass was washed with MtBE (300 mL) and gradually added to a mixture of aqueous calcium acetate and seed material, while maintaining temperature of 52+3 °C. After maintaining for 8h at the same temperature the mixture was cooled to 42+3 °C and filtered to afford crystalline Atorvastatin (124.5 g, 90% yield). HPLC purity: 99.67%, Impurity Via: 0.07, Impurity IVb: 0.04%.

EXAMPLE 16:

A mixture of compound of formula IV (50 g; diamino-ester IVa content -0.27%) in a mixture of hydrochloric acid (9 mL), water (89 mL) and IPA (1000 mL) was stirred under inert atmosphere at 47+3 °C. After completion of the reaction, the pH of the mixture was made alkaline by addition of 4N aqueous sodium hydroxide (60 mL). The mixture was maintained for 8h at temperature 47+3°C when HPLC analysis revealed completion of ester hydrolysis. After carbon treatment, the mass was concentrated under reduced pressure and the residue obtained was dissolved in a mixture of water (450 mL) and methanol (200 mL); HPLC analysis revealed the content of starting material IV to be -0.32%. The mixture was washed repeatedly with MtBE till the content of IV was maximum 0.10%. A solution of sodium hydroxide (4N, 40 mL) was added and the mixture stirred at 52+3°C till the content of impurity-IV was maximum 0.08%. After HPLC complied, the mixture was cooled to ambient temperature and the pH adjusted to -9.0 with dilute HC1. The reaction mass was washed with MtBE and gradually added to a mixture of aqueous calcium acetate and seed material while maintaining temperature at 52+3 °C. After maintaining for 8h at the same temperature, the mixture was cooled to 42+3 °C and filtered to afford crystalline atorvastatin (40.3 g, 88% yield). HPLC purity: 99.56%, Impurity Via: 0.06, Impurity IVb: 0.04%.

EXAMPLE 17:

A mixture of compound of formula IV (50 g; diamino-ester IVa content -0.27%) in a mixture of hydrochloric acid (9 mL), water (89 mL) and IPA (1000 mL) was stirred under inert atmosphere at 32+3°C. After completion of the reaction, the pH of the mixture was made alkaline by addition of 4N aqueous sodium hydroxide (60 mL). The mixture was maintained for 8h at temperature 42+3°C when HPLC analysis revealed completion of ester hydrolysis. After carbon treatment, the mass was concentrated under reduced pressure and the residue obtained was dissolved in a mixture of water (450 mL) and methanol (200 mL); HPLC analysis revealed the content of starting material IV to be -0.71%. The mixture was washed repeatedly with MtBE till the content of IV was maximum 0.10%. A solution of sodium hydroxide (4N, 40 mL) was added and the mixture stirred at 52+3°C till the content of impurity-IV was maximum 0.08%. After HPLC complied, the mixture was cooled to ambient temperature and the pH adjusted to -9.0 with dilute HC1. The reaction mass was washed with MtBE and gradually added to a mixture of aqueous calcium acetate and seed material, while maintaining temperature of 52+3 °C. After maintaining for 8h at the same temperature, the mixture was cooled to 42+3 °C and filtered to afford crystalline atorvastatin (40.5 g, 88% yield). HPLC purity: 99.66%, Impurity Via: 0.04, Impurity IVb: 0.04%.

EXAMPLE 18:

A mixture of compound of formula IV (50 g; diamino-ester IVa content -0.27%) in a mixture of hydrochloric acid (9 mL), water (89 mL) and IPA (1000 mL) was stirred under inert atmosphere at 42+3°C. The reaction mass was terminated when -3% of the starting material remained unreacted in the reaction mass. The pH of the mixture was made alkaline by addition of 4N aqueous sodium hydroxide (60 mL). The mixture was maintained for 8h at 42+3 °C when HPLC analysis revealed completion of ester hydrolysis. After carbon treatment, the mass was concentrated under reduced pressure and the residue obtained was dissolved in mixture of water (450 mL) and methanol (200 mL); HPLC analysis revealed content of starting material IV to be -2.21%. The mixture was washed repeatedly with MtBE till the content of IV was maximum 0.10%. A solution of sodium hydroxide (4N, 40 mL) was added and the mixture stirred at 52+3°C till the content of impurity- IV was maximum 0.08%. After HPLC complied, the mixture was cooled to ambient temperature and the pH adjusted to -9.0 with dilute HC1. The reaction mass was washed with MtBE and gradually added to a mixture of aqueous calcium acetate and seed material while maintaining temperature of 52+3 °C. After maintaining for 8h at the same temperature the mixture was cooled to 42+3 °C and filtered to afford crystalline atorvastatin (41 g, 89% yield). HPLC purity: 99.59%, Impurity Via: 0.09, Impurity IVb: 0.05%. EXAMPLE 19:

A mixture of compound of formula IV (50 g; diamino-ester IVa content -0.27%) in a mixture of hydrochloric acid (9 mL), water (89 mL) and IP A (1000 mL) was stirred under inert atmosphere at 42+3 °C. After completion of the reaction, the pH of the mixture was made alkaline by addition of 4N aqueous sodium hydroxide (60 mL). The mixture was maintained for 8h at temperature 42+3 °C when HPLC analysis revealed completion of ester hydrolysis. After carbon treatment, the mass was concentrated under reduced pressure and the residue obtained was dissolved in a mixture of water (450 mL) and methanol (200 mL); HPLC analysis revealed the content of starting material IV to be -0.55%. The mixture was washed repeatedly with toluene till the content of IV was maximum 0.10%. A solution of sodium hydroxide (4N, 40 mL) was added and the mixture stirred at 52+3 °C till the content of impurity- IV was maximum 0.08%. After HPLC complied, the mixture was cooled to ambient temperature and the pH adjusted to -9.0 with dilute HC1. The reaction mass was washed with MtBE and gradually added to a mixture of aqueous calcium acetate and seed material, while maintaining temperature of 52+3°C. After maintaining for 8h at the same temperature, the mixture was cooled to 42+3 °C and filtered to afford crystalline atorvastatin (40 g, 87% yield). HPLC purity: 99.53%, Impurity Via: 0.04, Impurity IVb: 0.08%.

EXAMPLE 20:

A mixture of compound of formula IV (25 g; diamino-ester content -0.27%) in a mixture of hydrochloric acid (4.5 mL), water (44.5 mL) and acetonitrile (125 mL) was stirred under inert atmosphere at 25+3°C. After completion of the reaction, the pH of the mixture was made alkaline by addition of 4N aqueous sodium hydroxide (30 mL). The mixture was maintained for 2h at temperature 25+3°C when HPLC analysis revealed completion of ester hydrolysis. After carbon treatment, the mass was concentrated under reduced pressure and the residue obtained was dissolved in a mixture of water (225 mL) and methanol (100 mL); HPLC analysis revealed the content of starting material IV to be -0.98%. The mixture was repeatedly washed with MtBE till the content of IV was maximum 0.10%. A solution of sodium hydroxide (4N, 20 mL) was added and the mixture stirred at 52+3 °C till the content of impurity- IV was maximum 0.08%. After HPLC complied, the mixture was cooled to ambient temperature and the pH adjusted to -9.0 with dilute HC1. The reaction mass was washed with MtBE and gradually added to a mixture of aqueous calcium acetate and seed material while maintaining temperature of 52+3 °C. After maintaining for 7-8h at the same temperature, the mixture was cooled to 42+3°C and filtered to afford crystalline Atorvastatin (20.7 g, 90% yield). HPLC purity: 99.83%, Impurity Via: 0.04, Impurity IVb: 0.03%.

EXAMPLE 21:

A mixture of compound of formula IV (25 g; diamino-ester content -0.41%) in a mixture of hydrochloric acid (4.5 mL), water (45 mL) and t-butanol (525 mL) was stirred under inert atmosphere at 47+3°C. After completion of the reaction, the pH of the mixture was made alkaline by addition of 4N aqueous sodium hydroxide (50 mL). The mixture was maintained for 6h at temperature 47+5 °C when HPLC analysis revealed completion of ester hydrolysis; HPLC analysis revealed the content of impurity-VIa to be -0.10%. After carbon treatment, the mass was concentrated under reduced pressure and the residue obtained was dissolved in a mixture of water (225 mL) and methanol (100 mL). The reaction mass was washed with MtBE and gradually added to a mixture of aqueous calcium acetate and seed material while maintaining temperature at 52+3°C. After maintaining for 17h at the same temperature, the mixture was cooled to 42+3 °C and filtered to afford crystalline Atorvastatin (20.7 g, 91% yield). HPLC purity: 99.46%, Impurity Via: 0.06, Impurity IVb: 0.08%.

EXAMPLE 22:

A mixture of compound of formula IV (100 g) in mixture of methanol (1800 mL) and water (60 mL) was stirred at 37+3°C for 30-60 min. Cooled the mixture gradually to 22+3°C and dilute hydrochloric acid (44 mL) was added over a period of 30-60 min while maintaining below 25°C. The reaction mixture was stirred at 22+3°C till HPLC complies (compound IV NMT 2.0%). Distilled off -2-3 vols of the reaction solvent under vacuum while maintain temperature below 30°C. pH of the reaction mass was adjusted to alkaline with aqueous sodium hydroxide solution (18 g NaOH dissolved in 495 mL water) while maintaining temperature below 25 °C and stirred the reaction mixture at 22+3°C till HPLC revealed ester hydrolysis. The reaction mixture was washed with cyclohexane (300 mL x 3) till the content of IV was NMT 0.05%.

Aqueous sodium hydroxide solution (12.8 g NaOH dissolved in 80 mL water) was added over a period of 30-60 min. The temperature of the reaction mixture was gradually raised to 52+3 °C and maintained the reaction mixture at 52+3 °C till the content of impurity Via was NMT 0.10%. The reaction mass was cooled to 42+3°C and pH of the reaction mass was adjusted to 9.5-10.5 with drop wise addition of dilute hydrochloric acid (40 mL cone HC1 dissolved in 160 mL water). Activated charcoal (5 g) was added at 42+3°C, stirred the mixture for 20-30 min at 42+3°C and filtered the reaction mass through a short bed of Hyflo. The filtrate was transferred to the clean reaction flask with a provision for downward distillation. Vacuum was applied and solvent completely distilled off while maintaining temperature below 60 °C. Water (900 mL) and methanol (400 mL) were added to the residue followed by washing the mixture with MTBE (300 mL x 2).

A mixture of Ca(OAc)₂*H₂0 (13.0 g) in DM Water (1100 mL) was seeded with atorvastatin calcium form I (1 g). The above filtered reaction mass was added to this mixture at 52+3°C and stirred the reaction mass for 6-8h at 52+3 °C. Cooled the reaction mass gradually to 42+3 °C and stirred for 30-60 min at 42+3°C. Filtered the precipitated product, washed with hot water (500 mL) and dried the material in vacuum oven initially at room temperature for 2h and then at 47- 53°C to obtain crystalline atorvastatin calcium form I (75 g).

Claims

WE CLAIM

Claim 1 : A process for the preparation of atorvastatin or a pharmaceutically acceptable salts thereof of formula I;

wherein M is H, Na⁺,K⁺,Mg⁺²,Ca⁺²; comprising:

c) treating the aqueous solution of compound of formula VI with a solvent that is immiscible or slightly miscible in water;

e) optionally washing the aqueous solution of step d) with a solvent that is immiscible or slightly miscible in water; and

f) converting the compound of Formula VI of step e) into atorvastatin or pharmaceutically acceptable salts thereof.

Claim 2: The process of claim 1, wherein the suitable acid of step a) is selected from the group consisting of hydrochloric acid, acetic acid, sulfuric acid, oxalic acid, trifluoroacetic acid, phosphoric acid and formic acid. Claim 3: The process of claim 1 , wherein in step a) the suitable acid is hydrochloric acid.

Claim 4: The process of claim 1, wherein the suitable organic solvent of step a) is selected from the group consisting of dichloromethane, chloroform, methanol, ethanol, isopropanol, n-butanol, t-butanol, tetrahydrofuran, diethyl ether, methyl ethyl ketone, acetone, methyl acetate, ethyl acetate, acetonitrile, propionitrile, water and mixtures thereof.

Claim 5: The process of claim 4, wherein the suitable organic solvent is selected from methanol, isopropanol, t-butanol, acetonitrile or mixtures of any of these solvents with water.

Claim 6: The process of claim 1, wherein the step a) reaction is carried out at a temperature in the range of about 10°C to about 75 °C. Claim 7: The process of claim 1, wherein the alkaline base is selected from the group consisting of sodium hydroxide, potassium hydroxide and lithium hydroxide.

Claim 8: The process of claim 7, wherein the alkaline base is sodium hydroxide. Claim 9: The process of claim 1, wherein the step b) further comprises the steps of: a) concentrating the step b) reaction solution to obtain a residue; and

b) combining the residue with water and optionally an alcohol solvent to obtain an aqueous solution; wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, n-butanol and isobutanol.

Claim 10: The process of claim 1, wherein the solvent that is immiscible or slightly miscible in water is selected from the group consisting of methyl acetate, ethyl acetate, n- propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate; diethyl ether, isopropyl ether, methyl tert-butyl ether, chloroform, dichlorome thane, cyclohexane, toluene or mixtures thereof.

Claim 11 : The process of claim 1 , wherein the suitable base of step d) is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide. Claim 12: The process of claim 11, wherein the suitable base is sodium hydroxide.

Claim 13: The process of claim 1, wherein the suitable base of step d) is sodium hydroxide and the reaction is carried out at a temperature from about 25°C to about 70°C. Claim 14: The process of claim 1, wherein step f) further comprises the steps of:

a) adjusting the pH of the reaction mass to lower than 9 with a suitable acid selected from hydrochloric acid or acetic acid;

b) washing the aqueous solution with a solvent that is immiscible or slightly miscible in water; and

c) converting the solution obtained into atorvastatin or pharmaceutically acceptable salts thereof; wherein the solvent that is immiscible or slightly miscible in water is selected from the methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate; diethyl ether, isopropyl ether, methyl tert-butyl ether, chloroform, dichloromethane, cyclohexane, toluene or mixtures thereof. Claim 15: The process of claim 14, wherein the solvent that is immiscible or slightly miscible in water is methyl tert-butyl ether.

Claim 16: The process of claim 14, wherein the step c) process further comprises treating the obtained solution with a suitable calcium source.

Claim 17: The process of claim 16, wherein the calcium source is selected from calcium hydroxide, calcium chloride or calcium acetate.

Claim 18: An improved process for the preparation of atorvastatin or pharmaceutically acceptable salts thereof; comprising:

a) treating a mixture of compound of formula VI or a cation salt thereof and a compound of Formula Via with a suitable base at a temperature of about 25 °C to reflux to obtain pure compound of Formula VI, and

b) converting the compound of Formula VI to atorvastatin or pharmaceutically acceptable salts thereof.

Claim 19: The process of claim 18, wherein the suitable base is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide.

Claim 20: The process of claim 18, wherein the suitable base is sodium hydroxide and the reaction is carried out at a temperature from about 25 °C to about 70°C.

Claim 21: An improved process for the preparation of atorvastatin or pharmaceutically acceptable salts thereof; comprising:

a) reacting a compound of formula II with a compound of formula III in presence of a DBU, pivalic acid and cyclohexane to obtain a compound of formula IV;

b) treating the compound of formula IV with hydrochloric acid to obtain a compound of formula V;

c) treating the compound of formula V with sodium hydroxide to obtain a compound of formula VI;

d) concentrating the step c) reaction solution to obtain a residue;

e) combining the residue with water and methanol to obtain an aqueous solution;

f) washing the aqueous solution with methyl tert-butyl ether;

g) separating the organic solvent layer and aqueous layer;

h) treating the aqueous layer of step g) with a sodium hydroxide; i) adjusting the pH of the reaction mass of step h) to lower than 9 with hydrochloric acid; j) washing the aqueous solution of step i) with methyl tert-butyl ether; and

k) converting the solution obtained in step j) into atorvastatin or pharmaceutically acceptable salts thereof.

Claim 22: The process of claim 21, wherein the step k) process further comprises treating the obtained solution with calcium source such as calcium hydroxide, calcium chloride or calcium acetate.

Claim 23: A pharmaceutical composition comprising therapeutically effective amount of atorvastatin or pharmaceutically acceptable salts thereof, prepared according to claims 1 -22 and at least one pharmaceutically acceptable excipient.