Description:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patent Rules 2003
COMPLETE SPECIFICATION
(see sections 10 & rule 13)
1. TITLE OF THE INVENTION
“AN ECONOMIC AND COMMERCIALLY VIABLE PROCESS FOR SYNTHESISING ATORVASTATIN AND/OR ITS PHARMACEUTICALLY ACCEPTABLE SALTS”

2. APPLICANT (S)
NAME NATIONALITY ADDRESS
Supriya Lifescience Limited INDIAN 207/208 Udyog Bhavan, Sonawala Road, Goregoan (East), Mumbai – 400063, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION

COMPLETE SPECIFICATION
The following specification particularly describes the invention and the manner in which it is to be performed
 
FIELD OF INVENTION
The present invention relates to an efficient process for synthesising Atorvastatin and/or its pharmaceutically acceptable salts (formula I) substantially free of impurity/impurities. The present invention utilizes mild catalysts, green solvents, and low temperatures, aligning with environmentally friendly green solvent, in-situ preparation of atorvastatin and its intermediates reduces dimer impurities, minimizing the number of purification steps and enhancing product purity.
BACKGROUND OF INVENTION
Atorvastatin Calcium, a medication used primarily to lower cholesterol and reduce the risk of heart disease, was approved by the U.S. Food and Drug Administration (FDA) on December 17, 1996. It is a statin (HMG-CoA reductase inhibitor) and works by reducing the production of cholesterol in the liver. The brand name for Atorvastatin is Lipitor, which was originally developed and marketed by Pfizer.
Atorvastatin calcium synthesis involves several complex chemical reactions. To make the process economically and commercially viable, it's essential to optimize the yield, minimize waste, and ensure high purity.
By considering all above the facts, synthesis of highly pure atorvastatin calcium requires a well-optimized process that balances economic viability, yield, and purity. By carefully considering factors such as starting materials, reaction conditions, purification techniques, and commercial considerations, it is possible to develop a profitable and sustainable process for the production of atorvastatin important pharmaceutical compound.
Following prior art describes the methods for preparation atorvastatin.
US20050239857A1 discloses preparation of [(4R,6R)-6-(2-Amino-ethyl) -2,2-dimethyl-[1,3]dioxan-4-yl]-acetic acid tert-butyl ester, wherein said preparation is carried out by reduction of ((4R,6R)-6-Cyanomethyl-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid tert-butyl ester using Raney Nickel (Ni), H2 source in presence of toluene, MeOH, NH3 under N2 atmosphere at 30oCto 40oC for 2 to 6 hrs.
WO2007049121A1 describes a preparation of [(4R,6R)-6-(2-Amino-ethyl) -2,2-dimethyl- [1,3]dioxan-4-yl]-acetic acid tert-butyl ester, wherein said preparation is carried out by reduction of ((4R,6R)-6-Cyanomethyl-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid tert-butyl ester using Raney Nickel (Ni), H2 source in presence of toluene, MeOH, and NH3 under N2 atmosphere at 30oC to 40oC for 2 to 6 hrs.
Woo et al. (“Atorvastatin, an HMG-COA reductase inhibitor and effective lipid-regulating agent. Part III. Syntheses of [2H5]-, [13C8], and [13C7,15N] atorvastatin and their application in metabolic and pharmacokinetic studies”; J. Labelled Cpd.Radiopharm,42, 135-145 (1999)) discloses preparation of compound 7c ([(4R,6R)-6-(2-Amino-ethyl) -2,2-dimethyl- [1,3]dioxan-4-yl]-acetic acid tert-butyl ester) by reduction of compound 18 ((4R,6R)-6-Cyanomethyl-2,2-dimethyl-[1,3] dioxan-4-yl)-acetic acid tert-butyl ester) by using H2 source, Raney Ni, MeOH & NH3.
CN109503542 A discloses preparation of 6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (yield: 97.5%), wherein said preparation is carried out by catalytic hydrogenation of (cyano compound) using H2, Raney Ni in presence of NH3 & MeOH at 30-40oC for 6hrs. Furthermore, it discloses 6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester is coupled with diketone compound (B-4) in presence of pivalic acid, tetrahydrofuran, n-heptane to obtain Atorvastatin intermediate which further hydrolysed with dil. HCl in MeOH for 4-5 hrs to give diol compound (ATR-II). The diol compound (ATR-II) is further hydrolysed with NaOH for 8hrs to obtain Na salt of Atorvastatin which is thereafter treated with Calcium acetate and acetic acid to obtain Ca salt of Atorvastatin.
EP2075246 A1 discloses describes preparation of atorvastatin hemi-calcium salt (formula I), wherein said preparation is carried out by hydrolysing compound of formula II (Atorvastatin tert-butyl ester) with dil. HCl in methanol for 6 to 9 hrs to an intermediate diol ester of formula V which further treated with 10% NaOH, MeOH, methyl-tert-butyl ether (MTBE) to obtain atorvastatin sodium salt of formula VI. Thereafter treatment with calcium acetate in demineralised water for 2 hrs to obtain atorvastatin hemi-calcium salt (formula I).
The formation of impurities (for example dimer, enantiomeric) in atorvastatin calcium synthesis can occur due to various factors, including reaction conditions, purification techniques, and the presence of impurities in starting materials. The U.S. Food and Drug Administration (FDA) and other regulatory bodies have strict guidelines for the purity and impurity levels of pharmaceuticals. Here are some of the key challenges: Atorvastatin has several chiral centres, making it difficult to control the stereochemistry during synthesis. The presence of multiple chiral centres can lead to the formation of diastereomers, which may be difficult to separate. Furthermore, the molecule contains various reactive functional groups, such as carboxylic acids, esters, and amides, which can interfere with each other during synthesis. Protecting groups may be required to selectively modify specific functional groups without affecting others, adding complexity to the synthetic route.
The synthesis of atorvastatin often involves multiple steps, each of which can introduce losses in yield. Side reactions or byproducts can reduce the overall yield of the desired product. The presence of impurities, such as isomers, dimers or byproducts, can make purification difficult and time-consuming. Chromatography techniques, such as column chromatography or HPLC, are often necessary for purification, which can be expensive and labour-intensive. Scaling up the synthesis of atorvastatin to commercial quantities can present unique challenges, such as maintaining consistency in reaction conditions and product quality.
While considering above mentioned challenges, there is a need for a more efficient and cost-effective process for the synthesis of highly pure atorvastatin calcium substantially free from enantiomeric and/or other impurity.
The present invention provides an efficient process for synthesising Atorvastatin and its pharmaceutically acceptable salts (Formula I) substantially free from impurities (enantiomeric and/or other impurity), wherein said process is carried out by In-Situ synthesis of an intermediate compound of Formula II through a reaction involving catalytic hydrogenation followed by coupling of a 1,4-diketone in presence of a cyclic amine. The intermediate compound of formula II is converted into Atorvastatin of Formula I by deprotection, hydrolysis and salt formation to get the pure atorvastatin with substantially free from impurities or with impurities within the limit.
OBJECTS OF THE INVENTION
Main object of the present invention is to provide synthesis of Atorvastatin and/or its pharmaceutically acceptable salts of formula I.
One of the objects of the present invention is to provide a process to prepare atorvastatin using an intermediate compound of formula II, wherein the process may be highly energy efficient, cheap, safe and easily scalable.
Another object of the present invention is to provide a process for preparing an intermediate compound of formula II, wherein said preparation is carried out in-situ to avoid dimer impurities which ultimately reduce the steps and minimise the said impurities.
Another embodiment of the present invention is to provide use of intermediate compound of formula II for the synthesis atorvastatin compound of formula I.
Another object of the present invention is to provide In-Situ synthesis of diketone intermediate a catalytic hydrogenation followed by coupling of a 1,4-diketone compound in presence of a cyclic amine, and phase transfer catalyst to get the atorvastatin tert-butyl ester.
Yet another object of the present invention is to provide an efficient and cost-effective process for the synthesis of highly pure atorvastatin calcium.
Yet another embodiment of the present invention is to produce highly pure atorvastatin with substantially free from impurities or with impurities within the limit.
Another embodiment of the present invention is to provide mild reaction conditions such as mild catalyst, green solvent, low temperature for synthesising atorvastatin and/or its pharmaceutically accepted salt.
Another embodiment of the present invention is to provide a process for synthesising pure atorvastatin without purification steps.
Another embodiment of the present invention is to provide optimized reaction conditions to achieve the desired product yield and quality.
Another embodiment of the present invention is to provide minimum reaction steps in the synthesis of the calcium salt of atorvastatin which can be simplified and made more efficient.
SUMMARY OF THE INVENTION
Main aspect of the present invention provides a process for synthesising Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, the process comprising:
a) hydrogenating a compound of formula 1 in presence of 25% of hydrogenating agent at a temperature in the range of 25oC to 45°C with hydrogen pressure of 5 kg/cm2 for a period in the range of 10 hrs to 14 hrs in a solvent to obtain a compound of formula 2;
b) contacting a 1,4-diketone compound of formula 3 with the compound of formula 2 in the presence of a carboxylic acid, a phase transfer catalyst, cyclic amine and inorganic base at a temperature in the range 50oC to 100°C for a period in the range of 8hrs to 20hrs in a solvent to obtain an intermediate compound of Formula II; wherein step (a) and step (b) are carried out In-Situ;
c) hydrolysing the intermediate compound of Formula II with an inorganic acid at 45 min to 75 min at 40°C to 50°C in a solvent to obtain a diol compound of formula 4;
d) hydrolysing the diol compound of formula 4 with an alkali base at a temperature in the range of 25°C to 35°C for 1hrs to 3hrs in a solvent to obtain an alkali salt of compound of formula 5;
e) converting alkali salt of compound of formula 5 by using calcium carbonate monohydrate in presence of an acid at room temperature (RT) to obtain calcium salt of atorvastatin of Formula I with purity greater than 99.5% (by HPLC);
wherein step (c), step (d) and step (e) are carried out In-Situ (without isolating compound of formula 4, formula 5); and
wherein impurity comprises enantiomeric impurity and other impurity;
wherein enantiomeric impurity and other impurity content in the obtained calcium salt of atorvastatin of Formula I is not detected (ND), less than 0.08% (by HPLC) respectively.
DETAILED DESCRIPTION OF THE INVENTION
In the present invention different terms are used to describe the present invention. The definitions of the terms are provided below.
The term “substantially free” means that the desired obtained atorvastatin calcium is free of any traces impurities selected enantiomeric, other impurity, in process impurities, residual impurities and combinations thereof.
The term “substantially free of impurity/ impurities” used herein means a drug may be considered "substantially free of impurities" if the levels of contaminants are below a certain threshold set by regulatory agencies like the FDA, ensuring safety for consumption. Thus, it implies that its purity is high enough to perform its intended function without interference from contaminants. In the present invention the substantially free of impurity comprises enantiomeric and/or other impurity.
The term “enantiomeric impurity” used herein refers to the presence of the undesired enantiomer of atorvastatin in the final product. Since atorvastatin is a chiral molecule, it can exist in two enantiomeric forms, which are mirror images of each other. However, only one of these forms- specifically the (3R,5R)-enantiomer is therapeutically active. The other enantiomer, the (3S,5S)-enantiomer is considered an impurity and may impact the efficacy or safety of the drug if present in significant amounts.
The term “other impurities” used herein refers to organic impurities (for example Atorvastatin lactone, epoxy atorvastatin), inorganic impurities (for example Nickel, acids, bases), residual solvents (for example methanol, acetone, methylene chloride), degradation products (for example Atorvastatin lactone) formed during synthesis of atorvastatin calcium.
The term ‘solvent’ used herein refers to a substance that can dissolve another substance, or in which another substance is dissolved, forming a solution. The solvent used in the present invention can be polar or nonpolar solvent. The said solvent may be used in anhydrous form. The solvent includes such as but not limit to alcohols, ethers, ketones, acids, esters, acetonitrile (ACN), halogenated solvent(s) and/or deuterated form of alcohols, ethers, ketones, acids, esters, and/or deuterated halogenated solvent(s).
Another embodiment of the present invention provides an improved process for synthesizing atorvastatin and/or its pharmaceutically acceptable salt substantially free of impurity, wherein the hydrogenating the compound of formula I is carried out in presence of metal catalysts comprising heterogeneous metal catalysts and homogeneous metal catalysts. Solvent used to include such as but is not limited to aromatic hydrocarbons, alcohols, ethers, water, liquid ammonia, and basic substances like sodium hydroxide, and the like. However, the preferred solvents are alcohols, or alcohol-water, or alcohol-aromatic hydrocarbons. Hydrogen pressures and reaction temperatures are both relatively high and the use of ammonia is particularly recommended.
One of the embodiments of the present invention provides a process for synthesising Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, the process comprising:
a) hydrogenating a compound of formula 1 in presence of 25% of hydrogenating agent at a temperature in the range of 25oC to 45°C with hydrogen pressure of 5 kg/cm2 for a period in the range of 10 hrs to 14 hrs in a solvent to obtain a compound of formula 2;
b) contacting a 1,4-diketone compound of formula 3 with the compound of formula 2 in the presence of a carboxylic acid, a phase transfer catalyst, cyclic amine and inorganic base at a temperature in the range 50oC to 100°C for a period in the range of 8hrs to 20hrs in a solvent to obtain an intermediate compound of Formula II; wherein step (a) and step (b) are carried out In-Situ;
c) hydrolysing the intermediate compound of Formula II with an inorganic acid at 45 min to 75 min at 40°C to 50°C in a solvent to obtain a diol compound of formula 4;
d) hydrolysing the diol compound of formula 4 with an alkali base at a temperature in the range of 25°C to 35°C for 1hrs to 3hrs in a solvent to obtain an alkali salt of compound of formula 5;
e) converting alkali salt of compound of formula 5 by using calcium carbonate monohydrate in presence of an acid at room temperature (RT) to obtain calcium salt of atorvastatin of Formula I with purity greater than 99.5% (by HPLC);
wherein step (c), step (d) and step (e) are carried out In-Situ (without isolating compound of formula 4, formula 5); and
wherein impurity comprises enantiomeric impurity and other impurity.
Another embodiment of the present invention provides a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein enantiomeric impurity and other impurity in the obtained calcium salt of atorvastatin of Formula I is not detected (ND), less than 0.08% (by HPLC) respectively.
Another embodiment of the present invention provides a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein compound of formula 1 is tert-butyl 2-((4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl) acetate.
Another embodiment of the present invention provides a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein said process is represented as follows.
Reaction scheme:

Wherein a: Hydrogenating agent, H2 source, solvent; b: Acid, amine, PTC, solvent;
c: conc. acid; d: Alkali base, solvent; e: Calcium acetate, acid.
Another embodiment of the present invention provides a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein hydrogenation of compound of formula 1 is carried out in presence of a hydrogen source.
Another embodiment of the present invention provides a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein hydrogen source is molecular hydrogen (H₂ gas), formic acid or isopropanol; preferably molecular hydrogen (H₂ gas).
In another embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein hydrogenating agent is a metal catalyst selected from platinum, palladium, ruthenium, rhodium, Raney nickel and Raney cobalt and combinations thereof.
In another embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein hydrogenating agent is Raney Ni.
In another embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein the intermediate compound of Formula II is obtained by contacting 0.97mol eq. of 1,4-diketone compound of formula 3 with the compound of formula 2 in the presence of 1.0 mol eq. of carboxylic acid, 0.15 mol eq. of phase transfer catalyst, 0.8 mole eq. of amine and 0.25 mole eq. of inorganic base at a temperature in the range 70oC to 75°C for 10 hrs to 15 hrs. in a solvent.
In another embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein solvent is selected from water, methanol, ethanol, propyl alcohol, isopropanol, n-butanol, iso-butanol, the tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, ethylene glycol, propane diols, glycerine, N, N- dimethyl formamide (DMF), cyclohexane, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), toluene, acetonitrile, dioxane, 1-methyl-2-pyrrolidinone, dichloromethane, chloroform, ether, methyl tert-butyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether or glycol mono-ethyl ether and combinations thereof.
In another embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein compound of formula 2 is [(4R, cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate.
In another embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein 1,4-diketone compound of formula 3 is 2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxo-N-phenylpentanamide.
In another embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein carboxylic acid is selected from formic acid, acetic acid, benzoic acid, p-toluene sulphonic acid, methane sulphonic acid, phosphoric acid, pyrophosphoric acid, polyphosphoric acid and sulphuric acid, butyric acid, pivalic acid, benzoic acid, trichloroacetic acid, iso-butyric acid and combinations thereof.
In another embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein carboxylic acid is preferably pivalic acid.
In another embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein the phase transfer catalyst is selected from tetrabutylammonium hydrogen sulfate, tetramethyl ammonium hydrogen sulfate, tetraethylammonium hydrogen sulfate, tetrapropylammonium hydrogen sulfate and combinations thereof.
In most preferred embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein the phase transfer catalyst is tetrabutylammonium hydrogen sulfate.
In another embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein the cyclic amine is selected from morpholine, piperazine, piperidine and combinations thereof.
In another embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein inorganic base is selected from sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, cesium hydroxide, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, sodium sulfide, sodium hydride and combinations thereof.
In most preferred embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein inorganic base is sodium carbonate.
In another embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein an intermediate compound of Formula II is atorvastatin tert-butyl ester [tert-Butyl (4R,6R)-6-[2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1-pyrrolyl] ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate].
In another embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein diol compound of formula 4 is (3R,5R)-tert-butyl7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)- 1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate.
In another embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein the compound of formula 5 is sodium(3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate.
In another embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein the alkali base is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, Lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate and aqueous solution thereof and combinations thereof.
In another embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein inorganic base is selected from sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, cesium hydroxide, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, sodium sulfide, sodium hydride and combinations thereof.
In another embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein inorganic acid is selected from sulfuric acid, hydrochloric acid, hydrogen chloride gas, hydrobromic acid, hydroiodic acid, nitric acid and combinations thereof.
In another embodiment of the present invention there is provided a process for Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, wherein the acid is selected from formic acid, acetic acid, propionic acid, butanoic acid lactic acid, benzoic acid, oxalic acid, maleic acid, malonic acid, fumaric acid, malic acid, ascorbic acid, succinic acid, adipic acid, glutaric acid, tartaric acid, trichloroacetic acid, trifluoroacetic acid etc. and combinations thereof.
In an embodiment, in-situ preparation of compound of formula 2 (ATS -09) after reduction of compound of formula 1 (ATS -08) for preparation of compound of formula II (ATR-01), isolation of compound of formula 2 (ATS-09) due to avoid dimer impurity and further purification. Hence, the present invention provides higher purity (greater than 99.5% by HPLC) and yield (greater than 95%w/w).
Morpholine is used in combination of inorganic base like Sodium carbonate, Sodium Bicarbonate to controlled additional impurity therefore Yield is higher and purity is high. Purity more than 99.5%; Yield is 195gm form 150gm of DKT. Furthermore, workup in aqueous sodium carbonate solution above 60 deg. temp therefore impurity is purging out efficiently hence purity is higher. Due to higher purity material precipitated above 70 deg temp in aqueous IPA without seeding.
Advantages of the present invention:
1. Energy efficiency and cost-effectiveness: The process is highly energy-efficient, making it cheaper and scalable for large-scale production.
2. Impurity reduction: Conducting the preparation in-situ reduces enantiomeric impurities, dimer impurities, minimizing the number of purification steps and enhancing product purity.
3. High purity of product: The method ensures the production of highly pure atorvastatin calcium (greater than 99.5% by HPLC), either free from impurities or with impurities within acceptable limits.
4. Use of green chemistry: The process utilizes mild catalysts, green solvents (for example water), and low temperatures, aligning with environmentally friendly green chemistry principles.
5. Simplified and efficient synthesis: The synthesis involves fewer reaction steps (two steps), simplifying the process and increasing overall efficiency.
6. Optimized conditions for quality and yield: The reaction conditions are optimized to ensure both high yield and high-quality output.
7. Avoidance of additional purification: The process enables the synthesis of pure atorvastatin without the need for further purification, streamlining the manufacturing process.
8. Intermediate compound use: The method leverages the use of an intermediate compound for efficient atorvastatin synthesis.
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.
EXAMPLES
A. PREPARATION OF ATORVASTATIN CALCIUM:
1. Preparation of Tert-butyl 3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenyl carbamoyl) -5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxy heptanoater
Reaction scheme:

A solution of tert-butyl [6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl] acetate 66 g (0.241 mole, 1.0eq) in 264 ml cyclohexane and aqueous ammonia (20-24%) 66 ml was hydrogenated over Raney nickel 16.5 gm (25%) at 30-40°C with hydrogen pressure of 5 kg/cm2 for 12 hrs. and progress of the reaction was monitored by HPLC. After completion of the reaction was cooled to 25-30°C and the catalyst was removed by filtration under a Nitrogen blanket and added 5.94gm of sodium chloride in filtrate. The filtrate mass was stirred for 20min. The filtered mass was settled and separated into layers. The aqueous layer extracted with 66ml cyclohexane. Each organic layer was combined and filtered through hyflo bed.
The cyclohexane filtrate was degassed under vacuum at 20-25°C for 30min and then charged 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N- phenyl-butanamide 99.23.0gm (0.238 mole, 0.97mol eq) , pivalic acid 25.04 gm (0.245 mole, 1.0 mol eq) Morpholine 17.08 g, (0.196 mole, 0.8eq), tetra butyl ammonium hydrogen sulphate 12.48 gm, (0.035 mole, 0.15 mol eq) and Sodium carbonate 10 gm (0.094 mole, 0.25 mole eq.) The reaction mixture was heated at 70-75°C for 10-15 hrs. and the progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was gradually cooled to 60-65°C and washed with 200 ml 8% sodium carbonate solution and then washed with 100ml water. The cyclohexane layer was distilled out completely under vacuum and stripped out with 100 ml isopropyl alcohol to get a residue which was taken in 800 ml mixture of isopropyl alcohol and water (60:40) and the heterogeneous mixture was heated at 80-90°C for 60 min. The heterogeneous mixture was cooled to 10-15°C and stirred for 2 hrs. at the same temperature. The solid was filtered and washed with precooled 100 ml mixture of isopropyl alcohol and water (60:40) and suck dried.
The wet material was taken in 300 ml isopropyl alcohol and the heterogeneous mixture was heated to 80-90°C for 60 min. The mixture was then cooled to 10-15°C and stirred for 2 hrs. at the same temperature. The solid was filtered and washed with 100 ml chilled Isopropyl alcohol. The solid was dried under vacuum at 50-55°C for 12 hrs. to afford 142.89 gm, 89% yield of pure Tert-butyl 3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoater HPLC purity 99.9%.

2. Preparation of Atorvastatin Calcium:
Reaction scheme:

Dilute hydrochloric acid solution (1.6 g of 36.5% hydrochloric acid in 50 ml water) was added to a solution of 100 g (0. l52mole, 1.0 mole eq) pure Tert-butyl 3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoater in 1000 ml methanol at 25-30°C. The reaction mixture was stirred for 60min at 40-50 °C and approximately half of methanol was distilled off under vacuum at 40-50 °C. To the remaining solution 500 ml methanol and 30 ml water were added at 40-50 °C and the reaction mixture was stirred for 60 min at 45-50°C. The progress of the reaction was monitored by HPLC. After completion of the reaction to afford Tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-(phenyl)-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxy heptanoate (ART-II). The reaction mass was added to a solution of Sodium hydroxide (12.2 g in 500 ml water) and stirred for 2 hrs. at 25-35°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was distilled off under vacuum at 40-45°C to afford (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-(phenyl-d5)-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoic acid, sodium salt; (ATR-III) as a residue.
The residue was dissolved in a mixture containing 1000 ml water and 500ml Methyl tert-butyl ether. The solution was filtered through micron filter and pH of the mass was adjusted between 8.3 - 8.8 at about 40°C using dilute acetic acid. The solution was stirred and seeded with 7 gm Atorvastatin Calcium form-1 and then a solution of calcium acetate monohydrate in water was added (14.46 gm, 0.0916mol 0.6 mole eq) in 500 ml water at about 40°C. The slurry was agitated for 30 min at about 50°C. The mass was cooled to 45°C and stirred for 120 min at same temperature. The solid was filtered and washed with 50 ml water.
The wet cake was taken in a mixture of 500ml of ethyl acetate and 500ml cyclohexane at 20-30°C. The mass was heated to 60-65°C for 60 min and then cooled to 30-35°C. The mass was stirred for 60 min at 30-35°C. The solid was filtered at 30-35°C and washed with 200.0 ml mixture of ethyl acetate: cyclohexane (1:1).
The wet cake was taken in 1000ml DM water at 20-30°C in a 4 four neck RBF and then heated to 30-40°C. The mass was stirred for 60min at the same temperature. The solid was filtered at 30-40°C and washed with 200ml DM water. The product was dried under vacuum at 50-55 °C for 12-14 hrs. to afford 94 gm highly pure Atorvastatin calcium trihydrate. HPLC purity 99.95%, Any other impurity 0.05%, Enantiomeric impurity is ND.

3. Preparation of Tert-butyl 3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenyl carbamoyl) -5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoater
Reaction scheme:

A solution of tert-butyl [6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl] acetate 66 g (0.241 mole, 1.0eq) in 264 ml cyclohexane and aqueous ammonia (20-24%) 66 ml was hydrogenated over Raney nickel 16.5 gm (25%) at 30-40°C with hydrogen pressure of 5 kg/cm2 for 12 hrs. and progress of the reaction was monitored by HPLC. After completion of the reaction was cooled to 25-30°C and the catalyst was removed by filtration under a Nitrogen blanket and added 5.94gm of sodium chloride in filtrate. The filtrate mass was stirred for 20min. The filtered mass was settled and separated into layers. The aqueous layer extracted with 66ml cyclohexane. Each organic layer was combined and filtered through hyflo bed.
The cyclohexane filtrate was degassed under vacuum at 20-25°C for 30min and then charged 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N- phenyl-butanamide 99.23.0gm (0.238 mole, 0.97mol eq), pivalic acid 25.04 gm (0.245 mole, 1.0 mol eq) Morpholine 17.08 g, (0.196 mole, 0.8eq), and tetra butyl ammonium hydrogen sulphate 12.48 gm, (0.035 mole, 0.15 mol eq). The reaction mixture was heated at 70-75°C for 10-15 hrs. and the progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was gradually cooled to 60-65°C and washed with 200 ml 8% sodium carbonate solution and then washed with 100ml water. The cyclohexane layer was distilled out completely under vacuum and stripped out with 100 ml isopropyl alcohol to get a residue which was taken in 800 ml mixture of isopropyl alcohol and water (60:40) and the heterogeneous mixture was heated at 80-90°C for 60 min. The heterogeneous mixture was cooled to 10-15°C and stirred for 2 hrs. at the same temperature. The solid was filtered and washed with precooled 100 ml mixture of isopropyl alcohol and water (60:40) and suck dried. The wet material was taken in 300 ml isopropyl alcohol and the heterogeneous mixture was heated to 80-90°C for 60 min. The mixture was then cooled to 10-15°C and stirred for 2 hrs. at the same temperature. The solid was filtered and washed with 100 ml chilled Isopropyl alcohol. The solid was dried under vacuum at 50-55°C for 12 hrs. to afford 130 gm, 81% yield of pure Tert-butyl 3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoater HPLC purity 99.6%.
4. Preparation of Atorvastatin Calcium:
Reaction scheme:

Dilute hydrochloric acid solution (1.6 g of 36.5% hydrochloric acid in 50 ml water) was added to a solution of 100 g (0. l52mole, 1.0 mole eq) pure Tert-butyl 3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoater in 1000 ml methanol at 25-30°C. The reaction mixture was stirred for 60min at 40-50 °C and approximately half of methanol was distilled off under vacuum at 40-50 °C. To the remaining solution 500 ml methanol and 30 ml water were added at 40-50 °C and the reaction mixture was stirred for 60 min at 45-50°C. The progress of the reaction was monitored by HPLC. After completion of the reaction to afford Tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-(phenyl)-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxy heptanoate (ART-II). The reaction mass was added to a solution of Sodium hydroxide (12.2 g in 500 ml water) and stirred for 2 hrs. at 25-35°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was distilled off under vacuum at 40-45°C to afford (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-(phenyl-d5)-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoic acid, sodium salt; (ATR-III) as a residue.
The residue was dissolved in a mixture containing 1000 ml water and 500ml Methyl tert-butyl ether. The solution was filtered through micron filter and pH of the mass was adjusted between 8.3 - 8.8 at about 40°C using dilute acetic acid. The solution was stirred and seeded with 7 gm Atorvastatin Calcium form-1 and then a solution of calcium acetate monohydrate in water was added (14.46 gm, 0.0916mol 0.6 mole eq) in 500 ml water at about 40°C. The slurry was agitated for 30 min at about 50°C. The mass was cooled to 45°C and stirred for 120 min at same temperature. The solid was filtered and washed with 50 ml water.
The wet cake was taken in a mixture of 500ml of ethyl acetate and 500ml cyclohexane at 20-30°C. The mass was heated to 60-65°C for 60 min and then cooled to 30-35°C. The mass was stirred for 60 min at 30-35°C. The solid was filtered at 30-35°C and washed with 200.0 ml mixture of ethyl acetate: cyclohexane (1:1).
The wet cake was taken in 1000ml DM water at 20-30°C in a 4 four neck RBF and then heated to 30-40°C. The mass was stirred for 60min at the same temperature. The solid was filtered at 30-40°C and washed with 200ml DM water. The product was dried under vacuum at 50-55 °C for 12-14 hrs. to afford 92 gm highly pure Atorvastatin calcium trihydrate. HPLC purity 99.97%, Any other impurity 0.05%, Enantiomeric impurity is ND.
5. Preparation of Tert-butyl 3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenyl carbamoyl) -5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoater
Reaction scheme:

A solution of tert-butyl [6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl] acetate 66 g (0.241 mole, 1.0eq) in 264 ml cyclohexane and aqueous ammonia (20-24%) 66 ml was hydrogenated over Raney nickel 16.5 gm (25%) at 30-40°C with hydrogen pressure of 5 kg/cm2 for 12 hrs. and progress of the reaction was monitored by HPLC. After completion of the reaction was cooled to 25-30°C and the catalyst was removed by filtration under a Nitrogen blanket and added 5.94gm of sodium chloride in filtrate. The filtrate was stirred for 20min. Then it was settled and separated into layers. The aqueous layer extracted with 66ml cyclohexane. Each organic layer was combined and filtered through a hyflo bed.
The cyclohexane filtrate was degassed under vacuum at 20-25°C for 30min and then charged 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N- phenyl-butanamide 99.23.0gm (0.238 mole, 0.97mol eq), pivalic acid 25.04 gm (0.245 mole, 1.0 mol eq) Piperidine 16.69 g, (0.196 mole, 0.8 mol eq) and tetra butyl ammonium hydrogen sulphate 12.48 gm, (0.035 mole, 0.15 mol eq). The reaction mixture was heated at 70-75°C for 10-15 hrs. and the progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was gradually cooled to 60-65°C and washed with 200 ml 8% sodium carbonate solution and then washed with 100ml water. The cyclohexane layer was distilled out completely under vacuum and stripped out with 100 ml isopropyl alcohol to get a residue which was taken in 800 ml mixture of isopropyl alcohol and water (60:40) and the heterogeneous mixture was heated at 80-90°C for 60 min. The heterogeneous mixture was cooled to 10-15°C and stirred for 2 hrs. at the same temperature. The solid was filtered and washed with precooled 100 ml mixture of isopropyl alcohol and water (60:40) and suck dried. The wet material was taken in 300 ml isopropyl alcohol and the heterogeneous mixture was heated to 80-90°C for 60 min. The mixture was then cooled to 10-15°C and stirred for 2 hrs. at the same temperature. The solid was filtered and washed with 100 ml chilled Isopropyl alcohol. The solid was dried under vacuum at 50-55°C for 12 hrs. to afford 125 gm, 77.90 % yield of pure Tert-butyl 3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoater HPLC purity 99.8%.
6. Preparation of Atorvastatin Calcium:
Reaction scheme:

Dilute hydrochloric acid solution (1.6 g of 36.5% hydrochloric acid in 50 ml water) was added to a solution of 100 g (0. l52mole, 1.0 mole eq) pure Tert-butyl 3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoater in 1000 ml methanol at 25-30°C. The reaction mixture was stirred for 60min at 40-50 °C and approximately half of methanol was distilled off under vacuum at 40-50 °C. To the remaining solution 500 ml methanol and 30 ml water were added at 40-50 °C and the reaction mixture was stirred for 60 min at 45-50°C. The progress of the reaction was monitored by HPLC. After completion of the reaction to afford Tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-(phenyl)-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate (ART-II). The reaction mass was added to a solution of Sodium hydroxide (12.2 gm in 500 ml water) and stirred for 2 hrs. at 25-35°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was distilled off under vacuum at 40-45°C to afford (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-(phenyl-d5)-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoic acid, sodium salt; (ATR-III) as a residue.
The residue was dissolved in a mixture containing 1000 ml water and 500ml Methyl tert-butyl ether. The solution was filtered through micron filter and pH of the mass was adjusted between 8.3 - 8.8 at about 40°C using dilute acetic acid. The solution was stirred and seeded with 7 gm Atorvastatin Calcium form-1 and then a solution of calcium acetate monohydrate in water was added (14.46 gm, 0.0916mol 0.6 mole eq) in 500 ml water at about 40°C. The slurry was agitated for 30 min at about 50°C. The mass was cooled to 45°C and stirred for 120 min at same temperature. The solid was filtered and washed with 50 ml water.
The wet cake was taken in a mixture of 500ml of ethyl acetate and 500ml cyclohexane at 20-30°C. The mass was heated to 60-65°C for 60 min and then cooled to 30-35°C. The mass was stirred for 60 min at 30-35°C. The solid was filtered at 30-35°C and washed with 200.0 ml mixture of ethyl acetate: cyclohexane (1:1).
The wet cake was taken in 1000ml DM water at 20-30°C in a 4 four neck RBF and then heated to 30-40°C. The mass was stirred for 60min at the same temperature. The solid was filtered at 30-40°C and washed with 200ml DM water. The product was dried under vacuum at 50-55 °C for 12-14 hrs. to afford 92.9 gm highly pure Atorvastatin calcium trihydrate. HPLC purity 99.93%, Any other impurity 0.07%, Enantiomeric impurity is ND.

7. Preparation of Tert-butyl 3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenyl carbamoyl) -5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoater
Reaction scheme:

A solution of tert-butyl [6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl] acetate 66 g (0.241 mole, 1.0eq) in 264 ml cyclohexane and aqueous ammonia (20-24%) 66 ml was hydrogenated over Raney nickel 16.5 gm (25%) at 30-40°C with hydrogen pressure of 5 kg/cm2 for 12 hrs. and progress of the reaction was monitored by HPLC. After completion of the reaction was cooled to 25-30°C and the catalyst was removed by filtration under a Nitrogen blanket and added 5.94gm of sodium chloride in filtrate. The filtrate mass was stirred for 20min. The filtered mass was settled and separated into layers. The aqueous layer extracted with 66ml cyclohexane. Each organic layer was combined and filtered through a hyflo bed.
The cyclohexane filtrate was degassed under vacuum at 20-25°C for 30min and then charged 4-(4-fluorophenyl)-2-isobutyryl-3-phenyl-4-oxo-N- phenyl-butanamide 99.23.0gm (0.238 mole, 0.97mol eq) , pivalic acid 25.04 gm (0.245 mole, 1.0 mol eq) Piperazine 16.89 g, (0.196 mole, 0.8eq) and tetra butyl ammonium hydrogen sulphate 12.48 gm, (0.035 mole, 0.15 mol eq) . The reaction mixture was heated at 70-75°C for 10-15 hrs. and the progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was gradually cooled to 60-65°C and washed with 200 ml 8% sodium carbonate solution and then washed with 100ml water. The cyclohexane layer was distilled out completely under vacuum and stripped out with 100 ml isopropyl alcohol to get a residue which was taken in 800 ml mixture of isopropyl alcohol and water (60:40) and the heterogeneous mixture was heated at 80-90°C for 60 min. The heterogeneous mixture was cooled to 10-15°C and stirred for 2 hrs. at the same temperature. The solid was filtered and washed with precooled 100 ml mixture of isopropyl alcohol and water (60:40) and suck dried. The wet material was taken in 300 ml isopropyl alcohol and the heterogeneous mixture was heated to 80-90°C for 60 min. The mixture was then cooled to 10-15°C and stirred for 2 hrs. at same temperature. The solid was filtered and washed with 100 ml chilled Isopropyl alcohol. The solid was dried under vacuum at 50-55°C for 12 hrs. to afford 122 gm, 76% yield of pure Tert-butyl 3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoater, HPLC purity 99.7%.
8. Preparation of Atorvastatin Calcium
Reaction scheme:

Dilute hydrochloric acid solution (1.6 g of 36.5% hydrochloric acid in 50 ml water) was added to a solution of 100 g (0. l52mole, 1.0 mole eq) pure Tert-butyl 3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoater in 1000 ml methanol at 25-30°C. The reaction mixture was stirred for 60min at 40-50 °C and approximately half of methanol was distilled off under vacuum at 40-50 °C. To the remaining solution 500 ml methanol and 30 ml water were added at 40-50 °C and the reaction mixture was stirred for 60 min at 45-50°C. The progress of the reaction was monitored by HPLC. After completion of the reaction to afford Tert-butyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-(phenyl)-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxy heptanoate (ART-II). The reaction mass was added to a solution of Sodium hydroxide (12.2 g in 500 ml water) and stirred for 2 hrs. at 25-35°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was distilled off under vacuum at 40-45°C to afford (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-(phenyl-d5)-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoic acid, sodium salt; (ATR-III) as a residue.
The residue was dissolved in a mixture containing 1000 ml water and 500ml Methyl tert-butyl ether. The solution was filtered through micron filter and pH of the mass was adjusted between 8.3 - 8.8 at about 40°C using dilute acetic acid. The solution was stirred and seeded with 7 gm Atorvastatin Calcium form-1 and then a solution of calcium acetate monohydrate in water was added (14.46 gm, 0.0916mol 0.6 mole eq) in 500 ml water at about 40°C. The slurry was agitated for 30 min at about 50°C. The mass was cooled to 45°C and stirred for 120 min at same temperature. The solid was filtered and washed with 50 ml water.
The Wet cake was taken in a mixture of 500ml of ethyl acetate and 500ml cyclohexane at 20-30°C. The mass was heated to 60-65°C for 60 min and then cooled to 30-35°C. The mass was stirred for 60 min at 30-35°C. The solid was filtered at 30-35°C and washed with 200.0 ml mixture of ethyl acetate: cyclohexane (1:1).
The wet cake was taken in 1000ml DM water at 20-30°C in a 4 four neck RBF and then heated to 30-40°C. The mass was stirred for 60min at the same temperature. The solid was filtered at 30-40°C and washed with 200ml DM water. The product was dried under vacuum at 50-55 °C for 12-14 hrs. to afford 90.86 gm highly pure Atorvastatin calcium trihydrate. HPLC purity 99.92%, Any other impurity 0.08%, Enantiomeric impurity is ND.
 
We claim:
1. A process for synthesising Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, the process comprising:
a) hydrogenating a compound of formula 1 in presence of 25% of hydrogenating agent at a temperature in the range of 25oC to 45°C with hydrogen pressure of 5 kg/cm2 for 10 hrs to 14 hrs in a solvent to obtain a compound of formula 2;
b) contacting a 1,4-diketone compound of formula 3 with the compound of formula 2 in the presence of a carboxylic acid, a phase transfer catalyst, an amine and inorganic base at a temperature in the range 50oC to 100°C for 8 hrs to 20 hrs. in a solvent to obtain an intermediate compound of Formula II; wherein step (a) and step (b) are carried out In-Situ;
c) removing the protecting group acetonide from the intermediate compound of Formula II with an inorganic acid at 45 min to 75 min at 40°C to 50°C in a solvent to obtain a diol compound of formula 4;
d) hydrolysing the diol compound of formula 4 with an alkali base at 25°C to 35°C for 1hrs to 3hrs in a solvent to obtain alkali salt of compound of formula 5;
e) converting alkali salt of compound of formula 5 by using calcium carbonate monohydrate in presence of an acid at room temperature (RT) to obtain calcium salt of atorvastatin of Formula I with purity greater than 99.5% (by HPLC);
wherein step (c), step (d) and step (e) are carried out In-Situ (without isolating compound of formula 4, formula 5); and
wherein impurity comprises enantiomeric impurity and other impurity; and
wherein enantiomeric impurity and other impurity in the obtained calcium salt of atorvastatin of Formula I is not detected (ND), less than 0.08% (by HPLC) respectively.
2. The process as claimed in claim 1, wherein compound of formula 1 is tert-butyl 2-((4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl) acetate.
3. The process as claimed in claim 1, wherein hydrogenation of compound of formula 1 is carried out in presence of a hydrogen source selected from hydrogen (H₂ gas), formic acid or isopropanol; preferably molecular hydrogen (H₂ gas); and wherein hydrogenating agent is selected from metal catalyst selected from platinum, palladium, ruthenium, rhodium, Raney nickel and Raney cobalt and combinations thereof; preferably Raney Ni.
4. The process as claimed in claim 1, wherein the intermediate compound of Formula II is obtained by contacting 0.97mol eq. of 1,4-diketone compound of formula 3 with the compound of formula 2 in the presence of 1.0 mol eq. of carboxylic acid, 0.15 mol eq. of phase transfer catalyst, 0.8 mole eq. of amine and 0.25 mole eq. of inorganic base at a temperature in the range 70oC to 75°C for 10 hrs to 15 hrs. in a solvent.
5. The process as claimed in claim 1, wherein solvent is selected from water, methanol, ethanol, propyl alcohol, isopropanol, n-butanol, iso-butanol, tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, ethylene glycol, propane diols, glycerine, N, N- dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), Methyl tert-butyl ether (MTBE), cyclohexane, toluene, acetonitrile, dioxane, 1-methyl-2-pyrrolidinone, dichloromethane, chloroform, ether, glycol dimethyl ether, diethylene glycol dimethyl ether or glycol mono-ethyl ether and combinations thereof.
6. The process as claimed in claim 1, wherein compound of formula 2 is [(4R, cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate; and 1,4-diketone compound of formula 3 is 2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxo-N-phenylpentanamide.
7. The process as claimed in claim 1, wherein carboxylic acid is selected from formic acid, acetic acid, benzoic acid, p-toluene sulphonic acid, methane sulphonic acid, phosphoric acid, pyrophosphoric acid, polyphosphoric acid and sulphuric acid, butyric acid, pivalic acid, benzoic acid, trichloroacetic acid, iso-butyric acid and combinations thereof; preferably Pivalic acid.
8. The process as claimed in claim 1, wherein the phase transfer catalyst is selected from tetrabutylammonium hydrogen sulfate, tetramethyl ammonium hydrogen sulfate, tetraethylammonium hydrogen sulfate, tetrapropylammonium hydrogen sulfate and combinations thereof; tetrabutylammonium hydrogen sulfate.
9. The process as claimed in claim 1, wherein amine is selected from morpholine, piperazine, piperidine and combinations thereof.
10. The process as claimed in claim 1, wherein inorganic base is selected from sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, cesium hydroxide, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, sodium sulfide, sodium hydride and combinations thereof; preferably sodium carbonate.
11. The process as claimed in claim 1, wherein an intermediate compound of Formula II is [tert-Butyl (4R,6R)-6-[2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1-pyrrolyl] ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate].
12. The process as claimed in claim 1, wherein diol compound of formula 4 is 3R,5R)-tert-butyl7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)- 1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate; and the compound of formula 5 is sodium(3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate.
13. The process as claimed in claim 1, wherein an alkali base is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, Lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate and aqueous solution thereof and combinations thereof.
14. The process as claimed in claim, wherein inorganic base is selected from sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, cesium hydroxide, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, sodium sulfide, sodium hydride and combinations thereof.
15. The process as claimed in claim 1, wherein inorganic acid is selected from sulfuric acid, hydrochloric acid, hydrogen chloride gas, hydrobromic acid, hydroiodic acid, nitric acid and combinations thereof.
16. The process as claimed in claim 1, wherein the acid is selected from formic acid, acetic acid, propionic acid, butanoic acid lactic acid, benzoic acid, oxalic acid, maleic acid, malonic acid, fumaric acid, malic acid, ascorbic acid, succinic acid, adipic acid, glutaric acid, tartaric acid, trichloroacetic acid, trifluoroacetic acid etc. and combinations thereof.

Dated this: Sep 27, 2024

Vijaykumar Shivpuje
IN/PA-1096
Agent for the Applicant
To
The Controller of Patents
The Patent Office, Mumbai
 
ABSTRACT

“AN ECONOMIC AND COMMERCIALLY VIABLE PROCESS FOR SYNTHESISING ATORVASTATIN AND/OR ITS PHARMACEUTICALLY ACCEPTABLE SALTS”

The present invention relates to an efficient process for synthesising Atorvastatin (Formula I) and its pharmaceutically acceptable salts substantially free of impurity and/impurities. The process involves the synthesis of an intermediate compound of Formula II through a reaction involving In-Situ catalytic hydrogenation followed by coupling of a 1,4-diketone compound in presence of a cyclic amine and inorganic base. The intermediate compound of formula II is converted into Atorvastatin of Formula I by deprotection, hydrolysis and salt formation.

, Claims:We claim:
1. A process for synthesising Atorvastatin and/or its pharmaceutically acceptable salt of formula I substantially free of impurity, the process comprising:
a) hydrogenating a compound of formula 1 in presence of 25% of hydrogenating agent at a temperature in the range of 25oC to 45°C with hydrogen pressure of 5 kg/cm2 for 10 hrs to 14 hrs in a solvent to obtain a compound of formula 2;
b) contacting a 1,4-diketone compound of formula 3 with the compound of formula 2 in the presence of a carboxylic acid, a phase transfer catalyst, an amine and inorganic base at a temperature in the range 50oC to 100°C for 8 hrs to 20 hrs. in a solvent to obtain an intermediate compound of Formula II; wherein step (a) and step (b) are carried out In-Situ;
c) removing the protecting group acetonide from the intermediate compound of Formula II with an inorganic acid at 45 min to 75 min at 40°C to 50°C in a solvent to obtain a diol compound of formula 4;
d) hydrolysing the diol compound of formula 4 with an alkali base at 25°C to 35°C for 1hrs to 3hrs in a solvent to obtain alkali salt of compound of formula 5;
e) converting alkali salt of compound of formula 5 by using calcium carbonate monohydrate in presence of an acid at room temperature (RT) to obtain calcium salt of atorvastatin of Formula I with purity greater than 99.5% (by HPLC);
wherein step (c), step (d) and step (e) are carried out In-Situ (without isolating compound of formula 4, formula 5); and
wherein impurity comprises enantiomeric impurity and other impurity; and
wherein enantiomeric impurity and other impurity in the obtained calcium salt of atorvastatin of Formula I is not detected (ND), less than 0.08% (by HPLC) respectively.
2. The process as claimed in claim 1, wherein compound of formula 1 is tert-butyl 2-((4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl) acetate.
3. The process as claimed in claim 1, wherein hydrogenation of compound of formula 1 is carried out in presence of a hydrogen source selected from hydrogen (H₂ gas), formic acid or isopropanol; preferably molecular hydrogen (H₂ gas); and wherein hydrogenating agent is selected from metal catalyst selected from platinum, palladium, ruthenium, rhodium, Raney nickel and Raney cobalt and combinations thereof; preferably Raney Ni.
4. The process as claimed in claim 1, wherein the intermediate compound of Formula II is obtained by contacting 0.97mol eq. of 1,4-diketone compound of formula 3 with the compound of formula 2 in the presence of 1.0 mol eq. of carboxylic acid, 0.15 mol eq. of phase transfer catalyst, 0.8 mole eq. of amine and 0.25 mole eq. of inorganic base at a temperature in the range 70oC to 75°C for 10 hrs to 15 hrs. in a solvent.
5. The process as claimed in claim 1, wherein solvent is selected from water, methanol, ethanol, propyl alcohol, isopropanol, n-butanol, iso-butanol, tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, ethylene glycol, propane diols, glycerine, N, N- dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), Methyl tert-butyl ether (MTBE), cyclohexane, toluene, acetonitrile, dioxane, 1-methyl-2-pyrrolidinone, dichloromethane, chloroform, ether, glycol dimethyl ether, diethylene glycol dimethyl ether or glycol mono-ethyl ether and combinations thereof.
6. The process as claimed in claim 1, wherein compound of formula 2 is [(4R, cis)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate; and 1,4-diketone compound of formula 3 is 2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxo-N-phenylpentanamide.
7. The process as claimed in claim 1, wherein carboxylic acid is selected from formic acid, acetic acid, benzoic acid, p-toluene sulphonic acid, methane sulphonic acid, phosphoric acid, pyrophosphoric acid, polyphosphoric acid and sulphuric acid, butyric acid, pivalic acid, benzoic acid, trichloroacetic acid, iso-butyric acid and combinations thereof; preferably Pivalic acid.
8. The process as claimed in claim 1, wherein the phase transfer catalyst is selected from tetrabutylammonium hydrogen sulfate, tetramethyl ammonium hydrogen sulfate, tetraethylammonium hydrogen sulfate, tetrapropylammonium hydrogen sulfate and combinations thereof; tetrabutylammonium hydrogen sulfate.
9. The process as claimed in claim 1, wherein amine is selected from morpholine, piperazine, piperidine and combinations thereof.
10. The process as claimed in claim 1, wherein inorganic base is selected from sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, cesium hydroxide, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, sodium sulfide, sodium hydride and combinations thereof; preferably sodium carbonate.
11. The process as claimed in claim 1, wherein an intermediate compound of Formula II is [tert-Butyl (4R,6R)-6-[2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1-pyrrolyl] ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate].
12. The process as claimed in claim 1, wherein diol compound of formula 4 is 3R,5R)-tert-butyl7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)- 1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate; and the compound of formula 5 is sodium(3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate.
13. The process as claimed in claim 1, wherein an alkali base is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, Lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate and aqueous solution thereof and combinations thereof.
14. The process as claimed in claim, wherein inorganic base is selected from sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, cesium hydroxide, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, sodium sulfide, sodium hydride and combinations thereof.
15. The process as claimed in claim 1, wherein inorganic acid is selected from sulfuric acid, hydrochloric acid, hydrogen chloride gas, hydrobromic acid, hydroiodic acid, nitric acid and combinations thereof.
16. The process as claimed in claim 1, wherein the acid is selected from formic acid, acetic acid, propionic acid, butanoic acid lactic acid, benzoic acid, oxalic acid, maleic acid, malonic acid, fumaric acid, malic acid, ascorbic acid, succinic acid, adipic acid, glutaric acid, tartaric acid, trichloroacetic acid, trifluoroacetic acid etc. and combinations thereof.