WO2012176218A1

WO2012176218A1 - Process for preparing rosuvastatin calcium through novel amine salt

Info

Publication number: WO2012176218A1
Application number: PCT/IN2012/000442
Authority: WO
Inventors: Shekhar Bhaskar Bhirud; Anshul Kumar Jain; Vinay Kumar SAINI; Alok Sharma
Original assignee: Ind-Swift Laboratories Limited
Priority date: 2011-06-24
Filing date: 2012-06-21
Publication date: 2012-12-27
Also published as: WO2012176218A8

Abstract

The present invention provides a process for preparing pure rosuvastatin of formula I, or pharmaceutically acceptable salts thereof through rosuvastatin l-(l-naphthyl)ethyl salt of formula II wherein wavy line (>~w) represent (R), (S) stereochemistry or racemate thereof.

Description

"PROCESS FOR PREPARING ROSUVASTATIN CALCIUM

THROUGH NOVEL AMINE SALT"

FIELD OF THE INVENTION

The present invention relates to a process for preparing pure rosuvastatin of formula I or pharmaceutically acceptable salts thereof.

Formula I

through rosuvastatin l-(l-naphthyl)ethylamine salt of formula II,

Formula II

wherein wavy line (_^wv) represent (R), (S) stereochemistry or racemate thereof

The present invention also provides rosuvastatin l-(t-naphthyl)ethylamine salt of formula I and process for preparation thereof.

BACKGROUND OF THE INVENTION

Rosuvastatin of formula I, chemically known as (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- methyl(methyl sulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxy hept-6-enoic acid,

Formula I

is a synthetic lipid lowering agent and inhibitor of HMG-CoA (3-hydroxy-3-methylglutaryl- coenzyme A) reductase. It can lower LDL-cholesterol and triglycerides more effectively than first generation drugs. It is marketed as Crestor having rosuvastatin calcium of formula la as active ingredient.

Ca2+ Formula la

Rosuvastatin was first disclosed in US patent RE 37,314 (reissue of US 5,260,440) as a useful hypocholesterolemic agent for treatment of hypercholesterolemia, and atherosclerosis. Rosuvastatin is prepared by process as shown below:

HF

Acetonitrile

I) Saponification

II) CaCl₂

Rosuvastatin

Process involves isolation of most of intermediates using silica gel chromatography which is considered as cumbersome and time consuming process and thus not suitable for industrial synthesis. Patent discloses an amorphous form of the calcium salt of rosuvastatin and the sodium salt is obtained therein as powdery crystals. Further, this patent describes preparation of calcium salt of rosuvastatin by dissolving corresponding sodium salt in water and adding calcium chloride and collecting the resultant precipitate by filtration. It is found to be very difficult to obtain pure rosuvastatin calcium using the above process as it is not possible to purify intermediate, rosuvastatin sodium.

US patent 6,838,566 describes novel salts of HMG-CoA reductase inhibitors (including rosuvastatin) with organic amines which include (±)-l,2-dimethylpropylamine, 3-(2- aminoethylamino)- propylamine, n-butylamine, secondary butylamine, tertiary butylamine (TBA), dibutylamine, tertiary amylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, dicyclohexylamine (DCHA), N-methylcyclohexylamine, Ν,Ν'- diisopropylethylenediamine (DIPEDA), Ν,Ν'-diethylenediamine, N-niethyl-1,3- propanediamine, N-methylethylenediamine, N,N,N',N'-tetramethyl-l,2- diaminoethane, Ν,Ν,Ν',Ν'-tetramethyl- 1 ,4-diaminobutane, Ν,Ν,Ν',Ν'-tetramethyl- 1 ,6- diaminohexane, 1 ,2- dipiperidinethane, dipiperidinemethane, 2-amino-3, 3- dimethylbutane, N,N- dimethylcyclohexylamine, neopentylarhine, adamantylamine, N,N-diethylcyclohexylamine, N-isopropylcyclohexylamine, N-methylcyclohexylamine, cyclobutylamine and norborylamine.

US patent 6,841,554 describes preparation of several crystalline salts of rosuvastatin, namely, ammonium, methylammonium, ethylammonium, diethanolammonium, tri(hydroxyrnethyl)- methylammonium, benzylammonium, 4-methoxybenzyl ammonium, lithium and magnesium salts to overcome problem associated with amorphous nature of calcium and sodium salt of rosuvastatin.

US patent 7,777,034 discloses crystalline rosuvastatin cyclohexyl ammonium and isopropyl ammonium salt as intermediates to get purified amorphous rosuvastatin calcium. Patent discloses preparation of said rosuvastatin amine salt by neutralization of rosuvastatin calcium with an acid followed by reaction of amine to form rosuvastatin amine salt and further conversion to rosuvastatin calcium.

US patent application 2007/0105882 discloses crystalline as well as amorphous form of tri(hydroxymethyl)methyl ammonium salt of rosuvastatin.

US patent application 2009/0036680 discloses various amine salts of rosuvastatin comprising cyclohexyl ammonium salt, diisopropyl ammonium salt, isopropyl ammonium salt, dicyclohexyl ammonium salt and (S) (+)-methylbenzyl ammonium salt.

US patent application 2009/01 1 1839 discloses isopropyl ammonium, N-methylcyclohexyl ammonium, Ν,Ν,Ν,Ν-tetramethylguanidine, dicyclohexyl ammmonium, pyrrolidinium, piperidinium, morpholinium, 1-adamantyl ammonium, tert-octylammonium salt of rosuvastatin.

US patent application 2010/0069635 discloses preparation of rosuvastatin calcium by using dehydroabeitylamine salt of rosuvastatin. Rosuvastatin dehydroabietyl amine salt is prepared starting from diketo intermediate by its reduction, hydrolysis and then reaction with dehydroabietyl amine to give corresponding amine salt in 96.7 % purity. But to achieve purity of 99.29 % said amine is purified using three re-crystallisations and two washings with acetonitrile and isopropyl alcohol, which makes the process unattractive from commercial point of view.

International Patent Publication WO 2008/038132 discloses preparation of rosuvastatin calcium using rosuvastatin N,N-dibenzylethylenediamine salt which is larger organic group. It is evident from the available prior art processes that purification through amine salt seems to be mandatory for most of active pharmaceutical ingredients like rosuvastatin or intermediates to get required purity. Those skilled in pharmaceutical arts understand that purification of an intermediate or final compound through crystallization offers best method for attaining important qualities like chemical quality, particle size, and polymorphic content. With advent of worldwide pharmaceutical regulation, and increased emphasis on drug product quality, it is very important for pharmaceutical companies to produce drug substance having higher purity and lower impurity.

Purity of an active pharmaceutical ingredient is necessary criterion in commercial manufacturing process. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. The ICH guidelines for Active Pharmaceutical Ingredient manufacturers requires that process impurities to 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. Hence it is important to have a purification method in the manufacturing process of any API to remove the impurities which are formed in the chemical reactions as well as by unused reagents and raw materials etc. The purification can be done in any steps of the manufacturing process for example at an intermediate stage or at the final stage.

The prior art teaches number of ways for purification of rosuvastatin, in which purification through formation of amine salt of an intermediate compound or final stage compound proves to be beneficial in providing pure form of rosuvastatin.

Even though numbers of amine salts are known in the art for purification of rosuvastatin, it will be appreciable to have a new amine salt to perform purification and thereby increasing the purity and yield of pharmaceutically useful compound. This provides a new opportunity to improve performance characteristics of a pharmaceutical product like rosuvastatin. Thus there is need in the art for a process for preparing other possible amine salts of active pharmaceutical ingredient in higher purity and higher yields in commercial scale. Therefore, present invention provides new amine salt of rosuvastatin that proved to be beneficial and efficient to yield rosuvastatin or pharmaceutically acceptable salt with high purity.

OBJECTIVES OF THE INVENTION

It is the foremost objective of the present invention to provide an industrially advantageous and efficient process for the preparation of pure rosuvastatin of formula I and calcium salt thereof through rosuvastatin l-(l-naphthyl)ethylamine salt of formula II. Another objective of the present invention is to provide novel rosuvastatin 1-(1- naphthyl)ethylamine salt of formula II.

Yet another object of the present invention is to provide a process for the preparation of rosuvastatin l-(l-naphthyl)ethylamine salt of formula II.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides an industrially advantageous and efficient process for the preparation of pure rosuvastatin of formula I or pharmaceutical acceptable salt thereof,

Formula I

using rosuvastatin l-(l-naphthyl)ethylamine salt of formula II,

Formula II

wherein wavy line (_^) represent (R), (S) stereochemistry or racemate thereof

including dissolved forms, solvent free form or hydrate, anhydrate or a solvate, non-solvate form, both in crystalline and amorphous form thereof.

According to one embodiment, the present invention provides a process for preparation of pure rosuvastatin or pharmaceutically acceptable salts thereof, comprising the steps of:

a) , providing a compound of formula I in a suitable solvent;

b) . reacting with l-(l-naphthyl)ethylamine or isomers thereof for a sufficient period of time till formation of rosuvastatin l-(l-naphthyl)ethylamine salt of formula II;

c) . isolating rosuvastatin l-(l-naphthyl)ethylamine salt of formula II;

d) . purifying rosuvastatin l-(l-naphthyl)ethylamine salt of formula II;

e) . treating rosuvastatin l-(l-naphthyl)ethylamine salt of formula II with an acid;

f) . optionally, isolating rosuvastatin or a lactone or mixture thereof;

g) . optionally treating the same with a suitable base to obtain salt of rosuvastatin;

h) . treating the resulting salt of rosuvastatin with a calcium ion source; and

i) . isolating rosuvastatin calcium there from. According to one another embodiment, the present invention provides a process for preparation of pure rosuvastatin calcium, comprising the steps of:

a) , providing a compound of formula III in a suitable solvent;

Formula III

wherein R; is selected from alkyl, aryl, aralkyl and the like; or when Rj is hydrogen, it can be a free acid or lactone thereof

b) . hydrolyzing compound of formula III with a suitable hydrolyzing agent to prepare rosuvastatin of formula I;

c) . reacting rosuvastatin of formula I with l -(l-naphthyl)ethylamine or isomers thereof for a sufficient period of time till formation of rosuvastatin l -(l-naphthyl)ethylamine salt of formula II;

d) . isolating rosuvastatin l-(l -naphthyl)ethylamine salt of formula II;

e) . purifying rosuvastatin l-(l -naphthyl)ethylamine salt of formula II; and

f) . converting rosuvastatin l-(l-naphthyl)ethylamine salt of formula II in to pure rosuvastatin of formula I or pharmaceutically acceptable salts thereof.

According to another embodiment, present invention provides rosuvastatin 1 -(1 - naphthyl)ethylamine salt of formula II including dissolved forms, solvent free form or hydrate, anhydrate or a solvate, non-solvate form, both in crystalline and amorphous form thereof.

According to still another embodiment, the present invention provides a process for preparation of rosuvastatin l -(l-naphthyl)ethylamine salt of formula II, comprising the steps of:

a) , providing compound of formula III in a suitable solvent;

b) . hydrolyzing compound of formula III with a suitable hydrolyzing agent to obtain crude rosuvastatin of formula I;

c). reacting rosuvastatin of formula I with l-(l-naphthyl)ethylamine or isomers thereof for a sufficient period of time till formation of rosuvastatin l-(l -naphthyl)ethylamine salt of formula II;

d). isolating rosuvastatin l-(l -naphthyl)ethylamine salt of formula II.

According to yet another embodiment, present invention provides a process for preparation of pure rosuvastatin or pharmaceutically acceptable salts thereof, comprising the steps of: a), condensing an intermediate of formula IV,

Formula IV

wherein R_/ is as defined above; R₂, R3, and R₄ are same or different and can be independently selected from alkyl or aryl, alkoxy and the like; or any one of R₂, R3 and R4 can be an oxo group; Pi is hydroxyl protecting group

with pyrimidine aldehyde intermediate of formula V,

Formula V

to give an intermediate of formula VI,

Formula VI

wherein Pi and R_/ are as defined above

b). deprotecting keto protected hydroxyl intermediate of formula VI using a suitable

to form keto hydroxy intermediate of formula VII,

Formula VII

c). reducing keto hydroxy intermediate of formula VII using a suitable reducing reagent to form compound of formula III,

Formula III

d) . hydrolyzing compound of formula III with a suitable hydrolyzing agent to obtain crude rosuvastatin of formula I;

e) . reacting rosuvastatin of formula I with l-(l-naphthyl)ethylamine or isomers thereof for a sufficient period of time till formation of rosuvastatin l-(l-naphthyl)ethylamine salt of formula II; f) . treating rosuvastatin l-(l-naphthyl)ethylamine salt of formula II with an acid;

g) . optionally, isolating rosuvastatin or a lactone or mixture thereof;

h) . optionally treating the same with a suitable base to obtain salt of rosuvastatin;

i) . treating the resulting salt of rosuvastatin with a calcium ion source; and

j). isolating rosuvastatin calcium there from.

DETAILED DESCRIPTION OF THE INVENTION

As used herein all the "rosuvastatin l-(l-naphthyl)ethyl amine salt" or "rosuvastatin amine salt" includes their specific isomer like (R), (S) or racemates (±), dissolved forms, solvent free form or hydrate, anhydrate or a solvate, non-solvate form, both in crystalline and amorphous form thereof.

The present invention provides an industrially advantageous and efficient process for the preparation of pure rosuvastatin or pharmaceutically acceptable salts thereof, preferably rosuvastatin calcium.

According to one embodiment, present invention provides a process for preparation of rosuvastatin or pharmaceutically acceptable salts thereof through novel rosuvastatin 1-(1- naphthyl)ethyl amine salt formation.

Generally, process involves treatment of crude rosuvastatin of formula I with 1-(1- naphthyl)ethyl amine in a suitable solvent. Salt formation can be achieved at a temperature of -10°C to 40°C and it may take about 30 minutes to 20 hours for complete salt formation. Amine employed for salt formation can be a specific isomer of l-(l-naphthyl)ethyl amine or mixture of isomers such as (±)-l-(l-naphthyl) ethylamine, (R)-(+)-l-(l-naphthyl)ethylamine, (S)-(-)-l-(l-naphthyl)ethylamine or mixture thereof. Suitable solvent employed during salt formation includes but not limited to esters such as ethyl acetate; nitriles such as acetonitrile; aliphatic or aromatic hydrocarbons such as toluene, hexane, heptane, cyclohexane and the like or mixture thereof. Preferably salt formation completes in 30 minutes to 6 hours. In general, salt formation does not require heating and/or cooling of reaction solution to facilitate precipitation, but such an arrangement is not excluded from the scope of invention. After completion of salt formation, rosuvastatin l-(l-naphthyl)ethylamine salt of formula II can be isolated from reaction mixture or can be in situ converted to rosuvastatin or pharmaceutically acceptable salts thereof.

Preferably, after completion of the salt formation, rosuvastatin amine salt can be isolated from reaction mixture by lowering reaction temperature or by adding an antisolvent to precipitate desired compound. Choice for use of antisolvent depends on solvent used for salt preparation and can be selected from aliphatic or aromatic hydrocarbon such as n- heptane, n- hexane, cyclohexane, toluene and the like or mixture thereof. Resulting product can be isolated by suitable techniques such as filtration, centrifugation and the like.

Crude rosuvastatin can exist as rosuvastatin free acid or a lactone or mixture thereof. Reaction mixture containing rosuvastatin or a lactone or mixture thereof can be used for further conversion to rosuvastatin l-(l-naphthyl)ethylamine salt formation. Crude rosuvastatin, solvent and l-(l-naphthyl)ethylamine can be added in any order to reaction vessel as order of adding reactants does not have any impact on salt formation.

In one way, rosuvastatin can be combined with a solution of l-(l-naphthyl)ethylamine in a solvent to form rosuvastatin 1 -( 1 -naphthyl)ethylamine salt.

In an alternate way, solution of rosuvastatin as well as solution of l-(l-naphthyl)ethylamine can be prepared separately before contacting with each other.

Preferably, a solution of crude rosuvastatin in a suitable solvent can be prepared by adding a suitable solvent at ambient temperature prior to reaction with a l-(l-naphthyl)ethylamine. Solvent employed are same as defined above for the salt formation. The solution of crude rosuvastatin in a solvent can optionally be heated to a temperature of 35°C to 40 °C for 10 minutes to 3 hours for complete dissolution. After cooling, the resulting organic solution can be optionally charcoalised and/or dried over suitable drying agent such as sodium sulfate, magnesium chloride and the like. Resulting solution is then reacted with 1-(1- naphthyl)ethylamine to give corresponding rosuvastatin amine salt.

In another way, rosuvastatin-(l-naphthyl)ethylamine salt can be prepared starting from a compound of formula III (where Rj is selected from alkyl, aryl or aralkyl group) i.e. rosuvastatin ester by hydrolysis of ester intermediate using a suitable hydrolyzing agent to prepare crude rosuvastatin followed by treatment with l-(l-naphthyl)ethylamine.

Generally, process involves hydrolysis of ester intermediate of formula III (where R_/ is selected from alkyl, aryl or aralkyl group) using a suitable hydrolyzing agent at a temperature 5°C to 80 °C for 1 to 5 hours, preferably at a temperature suitable for hydrolysis reaction till completion of reaction. Hydrolyzing agent can be an acid or a base. Acid can be selected from organic acid such as formic acid, acetic acid and the like; inorganic acid such as hydrochloric acid, sulphuric acid and the like. Base can be selected from inorganic bases such as alkali or alkaline metal hydroxide, carbonates, bicarbonates, alkoxide thereof. Preferably bases can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide monohydrate and the like. Hydrolysis reaction can be carried out in a suitable solvent for providing the reaction media and can be selected from water, alcohol such as methanol, ethanol, isopropyl alcohol, butanol; nitriles such as acetonitrile, ether such as tetrahydrofuran and the like or mixture thereof. Usually, hydrolysis reaction can be carried out at a temperature of 10°C to 75°C for 1 to 5 hours. After the completion of hydrolysis reaction, rosuvastatin or a lactone or mixture thereof can be isolated from the reaction mixture or can be used in situ for the salt formation.

Preferably, whenever hydrolysis is carried out under basic condition, rosuvastatin or salt thereof can be recovered from the reaction mixture by removal of solvent from the reaction mixture followed by treatment with a suitable acid. Solvent can be removed from the reaction mixture using suitable techniques such as distillation, evaporation, concentration and the like. Resulting reaction mass can be optionally charcoalised after dilution with water or can be optionally washed with a suitable water immiscible solvent can be selected from ester such as ethyl acetate; halogenated solvent such as dichloromethane, chloroform; ether such as methyl tert-butyl ether; ketone such as methyl isobutyl ketone, methyl ethyl ketone and the like or mixture thereof. Thereafter, reaction mixture can be treated with a suitable acid followed by addition of water immiscible solvent to extract the desired product. Suitable acid can be organic acid selected from formic acid, acetic acid and the like; or inorganic acid selected from hydrochloric acid, sulphuric acid and the like. Water immiscible solvent can be selected from ester such as ethyl acetate; halogenated solvent such as dichloromethane, chloroform; ether such as methyl tert-butyl ether; ketone such as methyl isobutyl ketone, methyl ethyl ketone and the like or mixture thereof. It is advantageous to maintain the pH of reaction mixture towards basic conditions by the addition of suitable base to minimize the chances of impurities in the final product. It is found on our hand that heating in acidic condition results in formation of some impurities, therefore addition of a suitable base to the reaction mixture proved to be beneficial in generating the pure compound. Suitable base can be selected from primary, secondary or tertiary amine such as phenyl glycinol or naphthylethylamine and the like; or inorganic base such as alkali or alkaline metal carbonates and bicarbonates and the like. Desired product can be isolated from the resulting reaction mixture by solvent removal or can be used as such for the salt formation with l-(l-naphthyl)ethylamine salt under the conditions as specified above.

Rosuvastatin l-(l-naphthyl)ethylamine salt includes various forms of salt including dissolved forms, solvent free form or it may be isolated as a hydrate, anhydrate or a solvate, non- solvate form, both in crystalline and amorphous form, which forms the novel feature of the invention. Rosuvastatin amine salt thus prepared can exist in amorphous as well as crystalline forms. Rosuvastatin l-(l-naphthyl)ethylamine salt of formula II, thus prepared can be optionally purified to enhance the purity and remove impurities so that final product of high purity can be obtained. Any suitable purification method can be employed such as spray wash, slurry wash, crystallization using a suitable solvent and the like.

Specifically, rosuvastatin l-(l-naphthyl)ethylamine salt in a suitable solvent can be purified at a temperature of -10°C to 80 °C for 30 minutes to 6 hours, preferably mixture can be maintained at a temperature of 10°C to 35°C for 1 to 2 hours. Suitable solvent can be selected from ester such as ethyl acetate, methyl acetate; nitriles such as acetonitrile; aromatic solvent such as toluene; aliphatic hydrocarbon such as heptane and the like or mixture thereof. Resulting solution or suspension can be optionally stirred for 1 to 2 hours. Thereafter, purified rosuvastatin 1 -(1 -naphthyl)ethylamine salt can be isolated from reaction mixture by a suitable techniques such as reducing the temperature of the mixture or by the addition of anti solvent selected from aliphatic hydrocarbons such as hexane, pentane, heptane, n-hexane, n- heptane, n-pentane; and the like or mixture thereof. The reaction mixture can be optionally seeded to obtain desired polymorphic form of rosuvastatin l-(l-naphthyl)ethylamine salt. Rosuvastatin l-(l-naphthyl)ethylamine salt can be isolated by suitable techniques known in the art such as filtration, centrifugation and the like. Rosuvastatin l-(l-naphthyl)ethylamine salt can be slurried in a suitable solvent to provide purified rosuvastatin amine salt. Solvent used for the different purification method can be selected depending upon the nature of purification process employed.

Rosuvastatin l-(l-naphthyl)ethylamine salt of the present invention have high purity, preferably rosuvastatin l-(l-naphthyl)ethylamine salt have purity more than 98 % and preferably more than 99%, more preferably more than 99.5 % by HPLC. Rosuvastatin 1-(1- naphthyl)ethylamine thus prepared by the present invention is highly advantageous to be used as an intermediate for purification of rosuvastatin acid or pharmaceutically acceptable salts thereof as it results in increased purity of final product i.e. rosuvastatin calcium.

Rosuvastatin l-(l-naphthyl)ethylamine salt of the present invention is easy to isolate. Rosuvastatin amine salt of present invention may be precipitated quite easily in various solvents. The readily isolable rosuvastatin l-(l-naphthyl)ethylamine salt is highly advantageous as it provide a simple and efficient method for purification of rosuvastatin and circumvents need of tedious chromatographic purification. Although number of rosuvastatin amine salts are reported in prior art, rosuvastatin amine salt of present invention afford high purity and gives best results in terms of yield and purity due to their solubility characteristics. Purification process involving rosuvastatin amine salts of present invention provides rosuvastatin of formula I or pharmaceutically acceptable salts thereof having purity more than 98 % by HPLC, preferably more than 99 %; or more preferably 99J % by HPLC.

Rosuvastatin l-(l-naphthyl)ethylamine salt as described by the present invention can be in solid or dissolved state and can be characterized by suitable techniques known in the art. Preferably, rosuvastatin l-(l-naphthyl)ethylamine salt of the present invention can be characterized by various spectroscopic techniques like ^lH and ¹³C Nuclear magnetic resonance (NMR), Mass spectrometry (MS), Infrared spectroscopy (IR) and X-ray diffraction chromatogram (XRD). Rosuvastatin amine salt can also be characterized by differential scanning calorimetry (DSC) .

According to one embodiment, present invention provides rosuvastatin 1-(1- naphthyl)ethylamine salt including (R)-isomer or (S)- isomer or racemate thereof.

Specifically, the present invention relates to rosuvastatin (±)-l-(l-naphthyl)ethylamine salt in a solid or dissolved state. Solid rosuvastatin (±)-l-(l-naphthyl)ethylamine salt can be in an amorphous or crystalline state and crystalline state can have many polymorphs.

Rosuvastatin (±)- l-(l-naphthyl)ethylamine salt is characterized by:

Infra-red spectrum (IR): shows the peak at 3413.2, 2970.6, 16.1.0, 1546.6, 1 149.8, 3672.7cm^"1.

Ή-NMR (CDC1₃): 0.92-1.20(m,2H,-CH₂),1.22-1.24(s,6H,-CH₃), 1.62-1.76(m,5H,-CH₃ and - CH₂), 3.30-3.37(m,lH,-CH), 3.49(s,3H,-CH₃), 3.55(s,3H,CH₃), 3.59-3.63 (m,lH-CH), 4.13- 4.14(t,lH,-CH), 5.06-5.1 l(m,lH,-CH), 5.30-5.35(dd,lH,-CH), 6.50-6.55(d,lH,-CH), 6.62- 6.73(br,4H,-NH₂ and -OH), 7.02-7.88(m, 1 Ι Η,ΑΓ.Η)

Melting point: 116°C-123°C

According to another embodiment, present invention also provides crystalline rosuvastatin (±)- 1 -( 1 -naphthyl)ethylamine, which can be characterized by X-ray diffraction chromatogram (XRD) or differential scanning calorimetry (DSC) .

Crystalline rosuvastatin (±)-l-(l-naphthyl)ethylamine salt is characterised by an XRD pattern having characteristics peaks at 4.3; 7.2; 7.5; 10.2; 10.813.9; 15.0;15.2;15.6; 16.6; 17.8; 18.0; 18.4; 19.3; 23.7 and ±0 °0.

Crystalline rosuvastatin l-(l-naphthyl)ethylamine salt display endothermic peak in range of 135°C-145°C in DSC thermogram and melting point is in the range of 128-134 °C.

Rosuvastatin (R)-l-(l-naphthyl)ethylamine salt is characterized by:

Infra-red spectrum (IR): shows the peak at 3413.2, 2964.1, 16.4.9, 1546.6, 1 149.8,

3649.8cm-'_.

Ή-NMR (CDC ): Melting point: 100°C-109°C

Rosuvastatin 1 -(1 -naphthyl)ethylamine salts thus prepared can be further converted in to pure rosuvastatin or pharmaceutically acceptable salts thereof.

Generally, process involves treatment of rosuvastatin l-(l-naphthyl)ethylamine salt with a suitable acid in a suitable solvent at a temperature of 0°C to 80°C for 10 minutes to 10 hours, preferably till the completion of the reaction. Suitable acid employed for reaction includes organic acids such as formic acid, acetic acid, propionic acid, butyric acid and the like; and inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and the like. Suitable solvent includes water or water immiscible organic solvents which can be selected from but not limited to aliphatic esters such as methyl acetate, ethyl acetate, propyl acetate; aliphatic ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether; hydrocarbon solvent such as toluene, 1,2- or 1,4-xylene; halogenated solvents such as dichloromethane, chloroform, 1 ,2-dichloroethane and the like or mixture thereof. Usually, reaction can be carried out at a temperature of 10 °C to 15°C for 10 minutes to 3 hours. After completion of reaction, pure rosuvastatin can be isolated from the reaction mixture or can be in situ proceeded for the conversion to rosuvastatin pharmaceutically acceptable salts thereof. Specifically, after completion of neutralization reaction, biphasic reaction mixture can be separated and organic layer can be optionally charcoalised, washed with water and/or dried over suitable drying agent such as sodium sulfate. Rosuvastatin can be isolated from the resulting organic layer by suitable techniques or organic layer can be used as such for further conversion to rosuvastatin pharmaceutically acceptable salts.

Rosuvastatin or lactone thereof can be converted to rosuvastatin calcium using a suitable base and calcium ion source.

Specifically, process involves the reaction of rosuvastatin or lactone thereof with a suitable base and then resulting rosuvastatin salt is contacted with calcium ion source in a suitable solvent at a temperature of 0 to 80 °C for 10 minutes to 10 hours preferably till the completion of the salt formation. Salt formation can be carried out in water using suitable base, which can be selected from alkali or alkaline metal hydroxide, carbonate, bicarbonate thereof, preferably can be selected amongst sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate or potassium bicarbonate and the like. Calcium ion source can be selected from calcium chloride, calcium hydroxide, calcium carbonate, calcium acetate, calcium sulfate, calcium borate, calcium tartrate, calcium bromide or any other compound capable of generating calcium ions. Source of calcium ion employed can be used as such or in mixture with a suitable solvent selected from water and the like or mixture thereof.

Preferably, prior to addition of calcium ion source, Suitable base can be added to rosuvastatin or lactone thereof in biphasic system, which is generated by addition of water and water immiscible solvent followed by layer separation. Thereafter, calcium ion source is added to the aqueous layer containing compound to give rosuvastatin calcium. Water immiscible solvent can be selected from esters such as ethyl acetate, ethers such as methyl tert-butyl ether, hydrocarbons such as toluene and the like.

After completion of reaction, reaction mass can be optionally charcoalised. Resulting product can be isolated from the resulting solution by the removal of solvent with suitable techniques such as filtration, centrifugation, decantation and the like. Product thus obtained can be optionally purified by stirring the resulting product in a suitable solvent which include water, aliphatic ester such as methyl acetate, ethyl acetate, aliphatic or aromatic hydrocarbon such as n-pentane, n-hexane, n-heptane; aliphatic ethers such as diethyl ether, isopropyl ether, methyl tert-butyl ether and the like or mixture thereof.

Alternatively, rosuvastatin l-(l-naphthyl)ethyl amine salt is treated with a suitable base and calcium ion source to form directly rosuvastatin calcium without in situ formation of rosuvastatin or lactone thereof.

Rosuvastatin calcium obtained by the process of present invention is highly pure in nature; it may have purity more than 99 %, preferably more than 99.5 %. More preferably it may have purity 99.8 % by HPLC. Rosuvastatin calcium is found to have identified and/or unidentified impurity in an amount less than 0.15 %, preferably less than 0.10 %, or more preferably free from the impurities.

Compound of formula HI used for the process of present invention can be procured from the commercial source or can be prepared by any method known in the art specifically by process as given herein for reference.

Intermediate of formula IV can be condensed with pyrimidine aldehyde intermediate of formula V to form intermediate of formula VI.

Generally, process involves condensation of intermediate of formula IV with pyrimidine aldehyde intermediate of formula V in a suitable solvent at a temperature of 0 °C to reflux temperature of solvent for few minutes to several hours. Suitable solvent employed for the reaction includes hydrocarbons such as toluene, benzene, xylene, cyclohexane, hexane; nitriles such as acetonitrile; aprotic solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide; ether such as diethyl ether, tetrahydrofuran, isopropyl ether, methyl tert- butyl ether and the like or mixture thereof. Usually reaction can be carried out at 60 to 100 °C for 10 to 15 hours. After completion of reaction, intermediate of formula VI can be isolated from reaction mixture using a suitable method such as solvent removal using distillation, evaporation and the like or can be used as such for further reaction.

Intermediate of formula VI, thus prepared can be optionally purified to enhance purity and/or to minimize amounts of impurities using any suitable purification method such as crystallization, slurry wash, acid base treatment, salt formation, addition of silica gel etc. to provide pure intermediate of formula VI. Preferably, intermediate of formula VI can be optionally dissolved in a suitable solvent in which impurities have less solubility or no solubility so that impurities can be removed by filtration or wash by a suitable aqueous solvent in which impurities are soluble. Suitable solvent for dissolving the desired compound can be selected from ether such as isopropyl ether, methyl tertiary butyl ether, hexane, cyclohexane and the like suitable solvent for washing can be selected from aqueous alcohols. Purified intermediate of formula VI can be recovered from the resulting solution by suitable techniques such as evaporation distillation and the like.

Alternatively, intermediate of formula VI can be purified using silica gel which adsorb impurities on it and results in intermediate of formula VI in high purity. Intermediate of formula VI in a suitable solvent is stirred with silica gel for 30 minutes to 4 hours. Suitable solvent employed can be selected from ester such as ethyl acetate; hydrocarbon solvent such as cyclohexane, hexane and the like or mixture thereof. Purified intermediate of formula VI can be recovered from the resulting solution by suitable techniques such as evaporation distillation and the like.

Purification processes can be optionally repeated or combined with one another to achieve purified intermediate of formula VI having reduced level of by products such as triphenyl phosphine oxide or free from by products.

Hydroxy group of intermediate of formula VI can be deprotected using a suitable deprotecting reagent to form keto hydroxyl intermediate of formula VII.

Generally, process involves reaction of intermediate of formula VI with a suitable deprotecting reagent at a temperature of 0 °C to reflux temperature of the solvent for few minutes to several hours, preferably at 15 to 60 °C till the completion of the reaction. Deprotecting reagent can be selected from any reagent known in the art that effectively serves purpose of deprotection of hydroxyl group. Specifically, deprotecting reagent can be selected from but not limited to acid such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, sulfonic acid such as methanesulfonic acid; fluoride salts such as tetrabutylammonium fluoride, hydrogen fluoride and the like. Deprotection reaction can be carried out in suitable solvent selected from nitrile such as acetonitrile; alcohol such as methanol; ether such as dioxane and the like or mixture thereof. Usually, deprotection reaction completes in 5 to 15 hours at a temperature of 25 to 50 °C. After the completion of the reaction, intermediate of formula VII can be isolated from the reaction or can be used as such for the further reduction reaction. Intermediate of formula VII can be isolated from the reaction mixture by using suitable techniques, preferably intermediate of formula VII can be isolated from the reaction mixture by addition of a suitable base and metal salt to the reaction mixture followed by layer separation. Suitable base can be organic or inorganic base. Organic base includes methylamine, triethylamine, diisopropylethylamine, and the like. Inorganic base includes alkali or alkaline metal hydroxide, carbonates, bicarbonate, hydride, alkoxide thereof such as sodium carbonate, sodium bicarbonate, sodium methoxide and the like. Metal salt include sodium chloride, potassium chloride and the like to ensure the layer separation. Resulting organic layer can be optionally further treated with a saturated brine solution. Intermediate of formula VII can be isolated from the resulting organic layer by using suitable techniques such as evaporation, distillation and the like.

Intermediate of formula VII can be optionally purified to enhance the purity of product and/or to remove presence of impurities in the product. Preferably, intermediate of formula VII can be purified with a suitable solvent selected from alcohol such as ethanol; aliphatic hydrocarbon such as hexane, heptane, cyclohexane and the like or mixture thereof.

Intermediate of formula VII can be reduced stereo selectively using a suitable reducing agent to form compound of formula III.

Generally, process involves the reaction of intermediate of formula VII with a suitable reducing agent in presence of a suitable chelating agent at a temperature of -110°C to 0 °C for few minutes to several hours, preferably till completion of reduction reaction. Reduction can be carried out using catalytic hydrogenation in the presence of hydrogenation catalyst such as ruthenium catalyst such as (Ru(cod)(nu-3-(2-methylally))₂; hydrides which includes borohydride, aluminoborohydride such as diisobutyl aluminium borohydride, lithium aluminium hydride; alkali or alkaline metal hydride such as sodium borohydride, lithium borohydride; alkali metal cyanoborohydride such as sodium cyanoborohydride; diborane; diisopinocampheyl chloroborane; CBS-oxazaborolidines and the like. Chelating agent used for the reaction includes but not limited to trialkyl borane or boronates selected from dialkyl alkoxy borane such as diethyl-methoxy-borane, diethyl ethoxy borane, dimethyl methoxy borane, borane tetrahydrofuran, bromodimethylsulfonium bromide and the like. Reduction can be carried out using an inert solvent which includes ether such as tetrahydrofuran; nitrile such as acetonitrile; halogenated solvent such as dichloromethane, chloroform; protic solvent such as alcohol (methanol, isopropyl alcohol) and the like or mixture thereof. Further reduction can be effectively accomplished at a temperature of -80°C to -1 10 °C for 1 to 3 hours, preferably till completion of reaction. After completion of reaction, reaction mixture can be optionally quenched with a suitable quenching agent. Suitable quenching agent includes acid such as acetic acid, citric acid, hydrogen peroxide and the like or mixture thereof. After completion of reaction, compound of formula III can be isolated from reaction mixture^* using suitable techniques or can be used as such for further reaction. Preferably, Compound of formula III can be isolated from reaction mixture by removal of solvent using evaporation or distillation and the like.

It is optional to add a suitable solvent such as alcohol selected from methanol, ethanol and the like to resulting residue followed by removal of solvent to remove the traces of previous solvent. Compound of formula III can be recovered from the resulting residue by adding water and water immiscible solvent followed by layer separation. Water immiscible solvent includes but not limited to ester such as ethyl acetate; halogenated solvent such as dichloromethane; ethers and the like or mixture thereof. Resulting organic layer can be optionally washed with a solution of suitable base and/or brine. Suitable base can be selected from alkali or alkaline metal hydroxide, carbonates, bicarbonate thereof such as sodium bicarbonate, sodium carbonate, potassium carbonate, potassium biocarbonate, sodium hydroxide or potassium hydroxide and the like. Product can be isolated from resulting organic layer using suitable techniques such as evaporation, distillation and the like.

The order and manner of combining the reactants at any stage of the process are not critical and 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 as sub-groups, and those solutions may be combined in any order. The ' time required for the completion of the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvents employed. Wherever required, progress of the reaction may be monitored by suitable chromatographic techniques such as High performance liquid chromatography (HPLC), ultra pressure liquid chromatography (UPLC) or thin layer chromatography (TLC).

Main advantage of the present invention is to provide an industrially advantageous and efficient process for preparation of highly pure rosuvastatin or pharmaceutically acceptable salts thereof in high yield through novel amine salts of rosuvastatin i.e. l-(l-naphthyl)ethyl amine salt due to easily isolable nature of l-(l-naphthyl)ethyl amine salt of rosuvastain.

Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.

EXAMPLES

Example 1: Preparation of 3-(tert-butyI-dimethyl-silanyloxy)-7-[4-(4-fluoro-phenyl)-6- isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-5-oxo-hept-6-enoic acid methyl ester Method A: N-[4-(4-Fluoro-phenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-N-methyl- methane- sulfonamide (100 g) and methyl (3R)-(tert-butyl-dimethyl-silanyloxy)-5-oxo-6- (triphenylphosphoranylidene)-hexanoate (228 g) was taken in acetonitrile (200 ml) and refluxed for 15 hours. After completion of reaction (monitored by TLC), solvent was distilled off completely. Isopropyl ether (400 ml) was added to resulting residue to crystallize by- product triphenylphosphine oxide (TPPO). The reaction mixture was filtered to remove triphenylphosphine oxide (TPPO) and insoluble particulate. Resulting filtrate was concentrated under vacuum to get 225 g of title compound.

A portion of resulting product was purified by column chromatography to give title compound having purity 96.6 %; triphenylphosphine oxide 0.12% by HPLC.

Method B: N-[4-(4-Fluoro-phenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-N-methyl- methane- sulfonamide (50 g) and methyl (3R)-(tert-butyl-dimethyl-silanyloxy)-5-oxo-6- (triphenylphosphoranylidene)-hexanoate (80 g) was taken in acetonitrile (200 ml) and heated to 80-85 °C for 15 hours. After completion of reaction, solvent was distilled off completely and then co-distilled with cyclohexane (50 ml). Thereafter cyclohexane (850 ml) was added to reaction mass and refluxed for 1 hour. Reaction mixtire was cooled to 10-15 °C, stirred for 1 hours and filtered. Resulting filtrate was partially concentrated (approximately half) under vacuum to give title product having triphenylphosphine oxide 20.08% by HPLC. Silica gel (50 g) was added to resulting reaction mass and stirred for 30 minutes. Reaction mixture was filtered and washed with cyclohexane. Solvent is distilled off from the resulting filtrate to give title compound having purity 78.26 %; triphenylphosphine oxide 14.50 % by HPLC. A portion of resulting product was again filtered through silica gel using 10 % ethyl acetate in hexane to give title compound having purity 93.10 %; triphenylphosphine oxide 4.66 % by HPLC.

Method C: N-[4-(4-Fluoro-phenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-N-methyl- methane- sulfonamide (50 g) and methyl (3R)-(tert-butyl-dimethyl-silanyloxy)-5-oxo-6- (triphenylphosphoranylidene)-hexanoate (77.5 g) was taken in cyclohexane (50 ml) and heated to 80-85 °C for 24 hours. After completion of reaction, cyclohexane (200 ml) was added to reaction mass and stirred at ambient temperature for 4 hours. Reaction mass was further cooled tol0-15°C, stirred for 2.0 hr, filtered to remove the by-product triphenylphosphine oxide (TPPO) and washed with cyclohexane. To the resulting combined filtrate, methyl- tertiary butyl ether (200 ml), denatured spirit (400 ml), and DM water (200 ml) were added and stirred. Layers were separated and organic layer was washed again with aqueous ethanol (800ml). Organic layer was distilled out completely to obtain title compound having purity 94.97% and triphenylphosphine oxide 1.80% by HPLC. Example 2: Preparation of 7-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl- methyl-amino)-pyrimidin-5-yl]-3-hydroxy-5-oxo-hept-6-enoic acid methyl ester

To a mixture 3-(tert-butyl-dimethyl-silanyloxy)-7-[4-(4-fluoro-phenyl)-6-isopropyl-2- (methane sulfonyl-methyl-amino)-pyrimidin-5-yl]-5-oxo-hept-6-enoic acid methyl ester (171 g) in acetonitrile (855 ml), a solution of methanesulfonic acid (35 g in 171 ml of water) was added and stirred for 15 hours at 20-30 °C. After completion of reaction (monitored by TLC), 10% sodium bicarbonate solution (600 ml) and sodium chloride (75 g) was added to the reaction mixture and layers were separated. Organic layer was treated with saturated sodium chloride solution (300 ml). The organic layer was concentrated under vacuum to give 152 g of title compound having purity 94.2% by HPLC.

Similarly, 3-(tert-butyl-dimethyl-silanyloxy)-7-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methane sulfonyl-methyl-amino)-pyrimidin-5-yl]-5-oxo-hept-6-enoic acid methyl ester (215g) yields oily product which was isolated from n-heptane to give 148 g of title compound. Example 3: Preparation of 7-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methane- sulfonyl- methyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoic acid methyl ester

Method A: 7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]-3-hydroxy-5-oxo-hept-6-enoic acid methyl ester (152 g) was dissolved in tetrahydrofuran (1824 ml) and methanol (456 ml). Reaction mass was cooled to -78 °C under nitrogen atmosphere followed by addition of diethylmethoxyborane (346.56 ml, 1M in tetrahydrofuran) and stirred for 30 minutes. Thereafter, sodium borohydride (24 g) was added to the reaction mixture at -78 °C and stirred for 3 hours. After completion of reaction, temperature of the reaction mass was raised to -15 °C and acetic acid (117 ml) was added to the reaction mass. Solvents were distilled off completely under vacuum from the reaction mixture. Methanol (150 ml) was added to resulting residue and distilled out. Water (760 ml) was added to resulting residue followed by extraction of product with ethyl acetate (760 ml). Organic layer was concentrated under vacuum to give 150 g of title compound having purity 93 % by HPLC.

Method B: 7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]-3-hydroxy-5-oxo-hept-6-enoic acid methyl ester (50 g) was dissolved in tetrahydrofuran (1200 ml) and methanol (4300 ml). Reaction mass was cooled to -90 °C under nitrogen atmosphere followed by addition of diethylmethoxyborane (1 14 ml, 1M in tetrahydrofuran) and stirred for 60 minutes. Thereafter, sodium borohydride (8 g) was added to the reaction mixture at -105 to -95 °C and stirred for 2 hours. After completion of reaction, acetic acid (39 ml) was added to the reaction mass and temperature of reaction mass was raised to 20-25 °C. Solvents were distilled off completely under vacuum from the reaction mixture. Methanol (2 x 100 ml) was added to resulting residue and distilled out. Water (250 ml) was added to resulting residue followed by extraction of product with ethyl acetate (250 ml). Organic layer was washed with saturated solution of sodium bicarbonate and then with staturated sodium chloride solution. Resulting organic layer was concentrated under vacuum to give 52 g of title compound having purity 91.18^'%; and anti-isomer- 0.86 % by HPLC. Method C: Sodium borohydride (3.2g) was added to a cold solution of tetrahydrofuran (130 ml) and methanol (30 ml) at -105°C to -95°C, followed by addition of diethylmethoxyborane (28ml, 1M in THF). Thereafter, a solution of 7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl- methyl-amino)-pyrimidin-5-yl]-3-hydroxy-5-oxo-hept-6-enoic acid methyl ester (20 g) in tetrahydrofuran (30 ml) and methanol (10 ml) was added to above reaction mass at -105°C to -95°C. After completion of reaction, acetic acid (15.4 ml) was added to the reaction mass and temperature of reaction mass was raised to 20-25 °C. Solvents were distilled off completely under vacuum from the reaction mixture. Methanol (40 ml) was added to resulting residue and distilled out. Water (100 ml) was added to resulting residue followed by extraction of product with ethyl acetate (100 ml). Organic layer was washed with saturated solution of sodium bicarbonate and then with saturated sodium chloride solution. Resulting organic layer was concentrated under vacuum to give 22 g of title compound having purity 94.93 %; and anti-isomer- 0.96 % by HPLC. Example 4: Preparation of rosuvastatin (±)-l-(l-naphthyl)ethylamine salt

Method A: 7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoic acid methyl ester (75 g) was dissolved in methanol (375 ml) at temperature 25°C to 30°C and cooled the mixture to 10-15 °C followed by addition of 225 ml demineralised water. Aqueous sodium hydroxide (10 %, 75 ml) was added to resulting mixture at ambient temperature and stirred for 2 hour. After completion of reaction, reaction mass was concentrated. Demineralized water (300 ml) and activated carbon (7.5 g) was added to resulting residue and stirred for 15 minutes. Reaction mixture was filtered through hyflow bed and wash bed with water. Resulting filtrate was washed with methyl tert-butyl ether (3 x 150ml). Ethyl acetate (300 ml) was added to resulting mixture followed by addition of concentrated hydrochloric acid to adjust pH of reaction mixture 1 to 3 at 10-15 °C and stirred for 30 minutes. Layers were separated and organic layer was washed with brine solution. Resulting organic layer was concentrated under vacuum. Ethyl acetate (240 ml) was added to resulting residue and cooled the reaction mass at 0°C, add diluted (±)-l-(l-naphthyl)ethylamine (25.6 g) with ethyl acetate (60 ml) at 0 °C. Reaction mass was stirred for 30 minutes at 0 °C and then at ambient temperature for 6 hours, n- Heptane (240 ml) was added to resulting mixture and cooled the mixture at -10 °C. Resulting reaction mixture was stirred for 1 hour at -10 ⁰ C, filtered, washed with n-heptane and ethyl acetate mixture and dried to give 60g of title compound having purity 99.1 % by HPLC.

Similarly, 7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin- 5-yl]-3,5-dihydroxy-hept-6-enoic acid methyl ester (50 g) was dissolved in acetonitrile in place of methanol and hydro lyzed followed reaction with (+)-l-(l-naphthyl)ethylamine to give title compound which was purified with acetonitrile in place of ethyl acetate and n- heptane to give 33 g of title compound having purity 99.72 %; anti-isomer: 0.2 %; lactone: not detected; 5-keto acid: not detected by HPLC. Method B : 7- [4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-n ethyl-amino)- pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoic acid methyl ester (500 g) was treated with aqueous sodium hydroxide ( 60 g sodium hydroxide in 2.5 L water ) and stirred the reaction mass at 25-35 °C for 1-2 hours. After completion of reaction, reaction mass was cooled to ambient temperature and activated carbon (25 g) was added and stirred for 30 minutes. Reaction mixture was filtered through hyflow bed and wash bed with water. Resulting filtrate was washed with methyl tert-butyl ether (4 x 1.5 L). Ethyl acetate (2.5 L) was added to resulting mixture followed by addition of concentrated hydrochloric acid to adjust pH of reaction mixture 1 to 2 at 10-15 °C and stirred. Layers were separated and aqueous layer was re-extracted with ethyl acetate (1 L). Combined organic layer was washed with brine solution. (+)-l-(l-naphthyl)ethylamine (175 g) diluted with ethyl acetate (250 ml) was added to the resulting organic layer to adjust the pH of reaction mixture to 7- 8. Solvent was distilled off completely from the reaction mixture. Ethyl acetate (2.5 L) was added to resulting residue followed by addition of (+)-l-(l-naphthyl)ethylamine (170 g) diluted with ethyl acetate (250 ml) and stirred for 6-8 hours at ambient temperature. n-Heptane (1.5 L ml) was added to resulting mixture and cooled the mixture at -5 °C. Resulting reaction mixture was stirred for 1 hour, filtered, washed with n-heptane. Resulting wet product was slurried in acetonitrile (2.5 L), filtered, washed with acetonitrile (250 ml) and dried to give 310 g of title compound having purity 99.74 %; anti-isomer: 0.2 %; lactone: not detected; 5-keto acid impurity: not detected by HPLC.

Example 5: Preparation of rosuvastatin (±)-l-(l-naphthyl)ethylamine salt

A mixture of rosuvastatin (60 g) in ethyl acetate (300 ml) was cooled to 0°C and a solution of (+)-l-(l-naphthyl)ethylamine (21 g) in ethyl acetate (60 ml) was added. Reaction mixture was stirred for 30 minutes at same temperature. Thereafter; temperature of reaction mixture was raised to ambient temperature and stirred for further 10 hours. n-Heptane (240 ml) was added to the reaction mixture to induce precipitation. Reaction mixture was cooled to -10 °C and stirred for 1 hour at same temperature. Product, thus formed, was filtered, washed with n-heptane and ethyl acetate mixture and dried to give 60 g of title compound having purity 96.5 % by HPLC.

Example 6: Preparation of rosuvastatin (R)-l-(l-naphthyl)ethylamine salt 7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-3,5- dihydroxy-hept-6-enoic acid methyl ester (1 1.0 g) was dissolved in methanol (1 10 ml) at room temperature and mixture was cooled at 10 - 15°C. Aqueous sodium hydroxide solution (10 %, 1 1 ml) was added to the reaction mixture at 10-15 °C and stirred for 2 hour at ambient temperature. After completion of reaction, reaction mass was concentrated followed by addition of demineralized water (55 ml) and activated carbon (1.1 g). Reaction mixture was stirred for 15 minutes, filtered through hyflow bed and bed was washed with water. Resulting filtrate was washed with methyl tert-butyl ether (3 x 50ml). Ethyl acetate (1 10 ml) was added to the resulting reaction aqueous layer and pH was adjusted to 1 - 2 by addition of concentrated hydrochloric acid at 10-15 °C. Reaction mixture was stirred for 30 minutes followed by layer separation. Organic layer was washed with brine solution and then concentrated under vacuum. Ethyl acetate (55 ml) was added to resulting residue and cooled reaction to 0 °C. R(+)-l-(l-Naphthyl)ethylamine (3.80 g) in ethyl acetate (1 1 ml) was added to mixture at 0 °C and stirred for 30 minutes at 0 °C. Reaction mixture was stirred at ambient temperature for 12 hours, n- Heptane (44 ml) was added to resulting mixture and cooled reaction mixture at -10 °C. Reaction mixture was stirred for 1 hour at same temperature, filtered, washed with n-heptane and ethyl acetate mixture and dried to give 7.0 g of title compound having purity 98.82 % by HPLC. Example 7: Purification of rosuvastatin l-(l-naphthyl)ethylamine salt

Method A: A mixture of rosuvastatin l-(l-naphthyl)ethylamine salt (10 g, having purity 96.5%) in ethyl acetate (50 ml) was stirred for 30 minutes at 20-25 °C. n-Heptane (20 ml) was added to mixture and stirred for 1 hours. Resulting product was filtered, washed with n- heptane (100 ml) and dried to give 8.3 g of title having purity 98.12 % by HPLC.

Method B: A mixture of rosuvastatin l-(l-naphthyl)ethylamine salt (10 g, having purity 96.5%) in ethyl acetate (50 ml) was stirred for 60 minutes at 20-25 °C. Resulting product was filtered, washed with cold ethyl acetate (20 ml) and dried to give 7.58 g of title having purity 99.76 % by HPLC.

Method C: A mixture of rosuvastatin l-(l-naphthyl)ethylamine salt (10 g, having purity 96.5%) in acetonitrile (70 ml) was stirred for 60 minutes at 20-25 °C. Resulting product was filtered, washed with acetonitrile (20 ml) and dried to give 4.0 g of title compound.

Method D: A mixture of rosuvastatin l-(l-naphthyl)ethylamine salt (10 g, having purity 96.5%) in acetonitrile (70 ml) was stirred for 60 minutes at 20-25 °C. Mixture was cooled to 0-5 °C and stirred for 1 hour. Resulting product was filtered, washed with cold acetonitrile (20 ml) and dried to give 5.6 g of title compound.

Similarly, rosuvastatin (R)l-(l-naphthyl)ethylamine salt and rosuvastatin (S)l-(l- naphthyl)ethylamine salt were purified to give respective pure compounds.

Example 8: Preparation of rosuvastatin calcium

To a mixture of rosuvastatin (±)-l-(l-napthyl)ethylamine salt (10 g) in ethyl acetate (100 ml) and demineralized water (100 ml), aqueous hydrochloric acid (10 %) was added at 5-10 °C till pH of mixture reached 1 to 2 and thereafter reaction mixture was stirred for 30 minutes. Layers were separated and organic layer was washed with water (2 x 50 ml). Organic layer was concentrated under vacuum. Resulting residue was dissolved in methyl tert-butyl ether (100 ml) and demineralized water (100 ml) followed by addition of 10 % sodium hydroxide at 5-10 °C till pH of reaction mixture was adjusted to 9.0 to 1 1.0. Reaction mixture was stirred for 30 minutes followed by layer separation. Aqueous layer was washed with methyl tert-butyl ether (50 x 2 ml) to remove the traces of (±)-l-(l-naphthyl)ethylamine. Aqueous calcium chloride dihydrate (1.57 g in 10 ml water) was added slowly to the reaction mass at 25 °C and stirred for 2 hours. Resulting product was filtered, washed with demineralized water and dried to give 6.2 g of title compound having purity 99.8 % by HPLC.

Similarly, rosuvastatin (±)-l-(l-napthyl)ethylamine salt (340 g) was converted to 221 g of title compound having purity 99.8 %; anti-isomer: 0.1 %, lactone: 0.05 %, 5-keto impurity: 0.02 % by HPLC.

Example 9: Preparation of rosuvastatin calcium

To a mixture of rosuvastatin l-(l-napthyl)ethylamine salt (10 g) in methyl tert-butyl ether (150 ml) and demineralized water (100 ml), aqueous hydrochloric acid (10 %) was added at 5-10 °C till pH of mixture reached 1 to 2 and thereafter reaction mixture was stirred for 30 minutes. Layers were separated and organic layer was washed with water (2 x 50 ml). Demineralized water (100 ml) was added to reaction mixture and cooled to 10-15 °C. 10 % Sodium hydroxide was added to reaction mixture to adjust pH of reaction mixture to 9.0 to 1 1.0. Reaction mixture was stirred for 30 minutes followed by layer separation. Aqueous layer was washed with methyl tert-butyl ether (2 x 50 ml) to remove the traces of 1 -(1 - naphthyl)ethylamine.. Aqueous calcium chloride dihydrate (1.57 g in l0 ml water) was added slowly to the reaction mass at 25 °C and stirred for 2 hours. Resulting product was filtered, washed with demineralized water and dried to give 6.1 g of title compound having purity 99.57 % by HPLC. Example 10: Preparation of rosuvastatin calcium

To a mixture of rosuvastatin (±)-l-(l -napthyl)ethylamine salt (50 g) in ethyl acetate (350 ml) and demineralized water (350 ml) and cooled to 10-15 °C. Aqueous hydrochloric acid (10 %) was added to the reaction mixture till pH of mixture reached 1 to 2. Layers were separated and extracted with ethyl acetate (100 ml). Combined organic layer was washed with 1 N hydrochloric acid solution (250 ml) followed by water (2 x 250 ml) at 40-45 °C. Organic layer was concentrated under vacuum. Resulting residue was dissolved in methyl tert-butyl ether (350 ml) and demineralized water (350 ml) and cooled to 10-15 °C. 10 % Sodium hydroxide was added to reaction mass till pH of reaction mixture was adjusted to 9.0 to 1 1.0. Reaction mixture was stirred followed by layer separation. Aqueous solution of calcium acetate (12.50 g in 75 ml water) was added to the reaction mass at ambient temperature and stirred for 2 hours. Resulting product was filtered, washed with demineralized water and dried to give 28.5 g of title compound having purity: 99.91 %; anti-isomer: 0.07 %, lactone: 0.02 %, 5-keto impurity: not detected by HPLC.

Example 11: Preparation of rosuvastatin calcium

To a mixture of rosuvastatin (±)-l -(l-napthyl)ethylamine salt (500 g) in ethyl acetate (3.5 L) and demineralized water (3.5 L) and cooled to 10-15 °C. Aqueous hydrochloric acid (10 %) was added to the reaction mixture till pH of mixture reached 1 to 2. Layers were separated and extracted with ethyl acetate (1.0 L). Combined organic layer was washed with 1 N hydrochloric acid solution (2.5 L) followed by water (2 x 2.5 L) at 40-45 °C. Organic layer was concentrated under vacuum. Resulting residue was dissolved in methyl tert-butyl ether (3.5 L) and demineralized water (3.5 L) and cooled to 10-15 °C. 10 % Sodium hydroxide was added to reaction mass till pH of reaction mixture was adjusted to 9.0 to 1 1.0. Reaction mixture was stirred followed by layer separation. The resulting aqueous solution was charcolized and filtered through high flow. Aqueous solution of calcium acetate (145 g in 750 ml water) was added to the resulting reaction mass at ambient temperature and stirred for 2 hours. Resulting product was filtered, washed with demineralized water and dried to give 325 g of title compound having purity: 99.92 %; anti-isomer: 0.06 %, lactone: 0.03 %, 5-keto impurity: not detected by HPLC.

Claims

WE CLAIM:

1. A process for preparation of pure rosuvastatin of formula I,

Formula I

or pharmaceutically acceptable salts thereof, comprising the steps of:

a) , providing a rosuvastatin of formula I in a suitable solvent;

Formula II

wherein wavy line ( ) represent (R), (S) stereochemistry or racemate thereof including dissolved forms, solvent free form or hydrate, anhydrate or a solvate, non- solvate form, both in crystalline and amorphous form thereof

c) . isolating rosuvastatin l-(l-naphthyl)ethylamine salt of formula II;

d) . purifying rosuvastatin l-(l-naphthyl)ethylamine salt of formula II;

f) . optionally, isolating rosuvastatin or a lactone or mixture thereof;

h) . treating the resulting salt of rosuvastatin with a calcium ion source; and

i) . isolating rosuvastatin calcium there from.

2. The process according to claim 1, wherein in step a) suitable solvent is selected from esters such as ethyl acetate; nitriles such as acetonitrile; aliphatic or aromatic hydrocarbons such as toluene, hexane, heptane, cyclohexane and the like or mixture thereof; and in step e) acid is selected from organic acids such as formic acid, acetic acid, propionic acid, butyric acid and the like; and inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and the like.

3. The process according to claim 1 , wherein in step g) suitable base is selected from alkali or alkaline metal hydroxide, carbonate, bicarbonate thereof such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate or potassium bicarbonate and the like; and in step h) calcium ion source is selected from calcium chloride, calcium hydroxide, calcium carbonate, calcium acetate, calcium sulfate, calcium borate, calcium tartrate, calcium bromide and the like.

A process for preparation of pure rosuvastatin calcium, comprising the steps of:

a), providing a compound of formula III in a suitable solvent;

Formula III

wherein Ri is selected from alkyl, aryl, aralkyl and the like; or when Rj is hydrogen, it can be a free acid or lactone thereof

c) . reacting rosuvastatin of formula I with l-(l-naphthyl)ethylamine or isomers thereof for a sufficient period of time till formation of rosuvastatin l-(l-naphthyl)ethylamine salt of formula II;

d) . isolating rosuvastatin l-(l-naphthyl)ethylamine salt of formula II;

e) . purifying rosuvastatin l-(l-naphthyl)ethylamine salt of formula II; and

The process according to claim 4, wherein in step a) suitable solvent is selected from water, alcohol such as methanol, ethanol, isopropyl alcohol, butanol; nitriles such as acetonitrile, ether such as tetrahydrofuran and the like or mixture thereof.

The process according to claim 4, wherein in step b) suitable hydrolyzing is selected from acid selected from acid or base.

The process according to claim 6, wherein in acid is selected from organic acid such as formic acid, acetic acid and the like; inorganic acid such as hydrochloric acid, sulphuric acid and the like; and base is inorganic base which is selected from alkali or alkaline metal hydroxide, carbonates, bicarbonates, alkoxide thereof such as sodium hydroxide, potassium hydroxide, lithium hydroxide monohydrate and the like.

Rosuvastatin 1 -( 1 -naphthyl)ethylamine salt of formula II, Formula II

wherein wavy line ( ~) represent (R), (S) stereochemistry or racemate thereof

including dissolved forms, solvent free form or hydrate, anhydrate or a solvate, non- solvate form, both in crystalline and amorphous form thereof.

A process for preparation of rosuvastatin l-(l -naphthyl)ethylamine salt of formula II, comprising the steps of:

a) , providing compound of formula III in a suitable solvent;

d) . isolating rosuvastatin l-(l-naphthyl)ethylamine salt of formula II.

The process according to claim 9, wherein in step a) suitable solvent is selected from water, alcohol such as methanol, ethanol, isopropyl alcohol, butanol; nitriles such as acetonitrile, ether such as tetrahydrofuran and the like or mixture thereof; and in step b) suitable hydrolyzing is acid selected from organic acid such as formic acid, acetic acid and the like; inorganic acid such as hydrochloric acid, sulphuric acid and the like; or inorganic base selected from alkali or alkaline metal hydroxide, carbonates, bicarbonates, alkoxide thereof such as sodium hydroxide, potassium hydroxide, lithium hydroxide monohydrate and the like.