DESC:FORM 2
THE PATENT ACT, 1970
[39 OF 1970]
&
PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

PROCESS FOR THE PREPARATION OF
ROSUVASTATIN VIA NOVEL INTERMEDIATES

IND-SWIFT LABORATORIES LIMITED
S.C.O. NO. 850, SHIVALIK ENCLAVE,
NAC, MANIMAJRA,
CHANDIGARH-160101

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to an industrially advantageous and cost-effective process for preparation of rosuvastatin of formula I or pharmaceutically acceptable salts thereof,

Formula I

via novel intermediates of formulae II and III.

Formula II

whereinR is selected from , R1 is selected from hydrogen, straight or branched chain alkyl group preferably C1-C4;

Formula III

The present invention also provides novel and efficient processes for the preparation of compounds of formulae II and III, and converting these to rosuvastatin of formula I or pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
Rosuvastatin, represented by formula I is a 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor from the class of statin drugs.
Rosuvastatin was marketed under trade name as Crestor having rosuvastatin calcium of formula Ia as active ingredient which is chemically known as bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt.

Formula Ia

Rosuvastatin is first disclosed in US patent RE 37,314 (reissue of US5,260,440). The said patent also discloses a process for the synthesis of rosuvastatin calcium as shown below:

The major drawback of process is that it involves application of four distinct chemical steps, wherein generation of the basic rosuvastatin skeleton requires condensation of the phosphorane side chain with the substituted benzaldehyde under Wittig reaction conditions, which leads to formation of excess amounts of undesired ‘Z’ isomer, whose removal requires multiple purification which makes the process uneconomical.
A modified Wittig reaction, also known as Horner-Emmons reaction has been applied in US patent 6,844,437, wherein rosuvastatin intermediate containing tert-butyl ester group is prepared by condensation of diphenyl [4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidine-5-yl-methyl] phosphine oxide with tert-butyl-2-[4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in presence of a strong base at -20 to -90ºC.
Following an alternative approach, Wittig reaction has also been used in US patent 7,312,329 wherein condensation of triphenyl [4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-yl-methyl]phosphonium bromide with tert-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl] acetate in presence of potassium carbonate in dimethyl sulfoxide gives tert-butyl (E)-(6-[2-[4-(4-fluoro-phenyl)-6-isopropyl-2[methyl(methylsulfonyl)amino]pyri midine-5-yl](4R,6S)-2,2-dimethyl[1,3]dioxane acetate, as shown in scheme below, which is further converted into free acid and then into calcium salt.
Several other publications WO2004/103977; WO2005/092867; WO2006/091771; WO2006/106526; WO2008/044243 disclose processes for the preparation of rosuvastatin via Wittig reaction by making use of differently substituted intermediates.
PCT publication WO2007/125547 discloses a different methodology by following modified Julia-olefination reaction by condensing pyrimidine ring substituted heterocyclic sulfone compound with carboxyaldehyde or carboxyamide aldehyde compound, wherein the reaction takes place in presence of an alkali and alkaline earth metal bases in a polar aprotic solvent. The resulting dihydroxy protected derivative shows the E/Z isomer content in the ratio of 95:5. Moreover, the condensation reaction is performed at higher temperature which may be leading to the degradation of starting material resulting in decreased yield and purity. The reaction scheme is shown as below:

wherein Het. represents compound selected from aryl, substituted aryl, tetrazole, benzimidazole, benzoxazole, benzthiazole, indole etc.
Similarly several publications WO2008/044243; WO2010/023678; WO2011/ 083495; WO2011/132172 and WO2012/098050 involve use of modified Julia olefination reaction by using differently substituted sulfonyl intermediates.
Various other strategies to prepare rosuvastatin are disclosed in several patent applications such as US2005/0222415, US2008/0207903, US2008/0255170, US2008/0300406, US2010/048899, US2010/0228028, WO2006/106526, WO2008/093205, WO2009/024323 and WO 2009/143776 etc.
In addition to this, many different strategies to prepare statin compounds are reported in literature, for example US6,777,552, US7,371,865 and the like. US patent US7,371,865 discloses a process to prepare statins using amide intermediates but specifically describes the synthesis of only fluvastatin and pitavastatin. Each intermediate has its own characteristic properties and it is not possible to employ the same strategy for synthesis of all the statin molecules. As nature of other functional group in the substrates has great impact on progress of the reaction as well product formation. So it is possible to get different results for different statins as they have only common feature related to side chain but the main moiety is different. In most of the references, olefinic bond in rosuvastatin has been generated using Wittig or Julia olefination reaction by employing different strategies and using different reagents.
Further, there are several publications such as US patents 6,838,566; 6,841,554; 7,777,034; US patent applications 2007/0105882; 2009/0036680; 2009/0111839; 2010/0069635 and PCT publication WO2008/038132 which disclose purification of rosuvastatin through formation of its amine salt.
As mentioned above, though there are currently many methods reported in literature for the preparation of statins, specifically rosuvastatin and its salts, which have their own advantages and disadvantages, still there is a continuing need to develop alternative processes for the same by employing novel intermediates which can address the problems being encountered during scale up for achieving purity and meeting cost concerns. Therefore, the present invention intends to provide an easy to scale up and cost effective process which is found to be more convenient to use, provides product in a better yield, reduces the number of steps involved, and make use of intermediates which are novel, when compared to previously known processes.
OBJECTIVES OF THE INVENTION
It is the foremost objective of the present invention to provide an industrially advantageous and cost efficient process for the preparation of pure rosuvastatin or pharmaceutically acceptable salts thereof.
Another objective of the present invention is to provide a process for the preparation of pure rosuvastatin or pharmaceutically acceptable salts thereof using novel substituted pyrimidine and amide intermediates.
Another objective of the present invention is to provide a process for the preparation of pure rosuvastatin or pharmaceutically acceptable salts thereof using novel sulfonyl intermediate.
Another objective of the present invention is to provide a process for the preparation of pure rosuvastatin or pharmaceutically acceptable salts thereof using novel amide intermediate.
Another objective of the present invention is to provide a novel sulfone intermediate and a process for its preparation.
Another objective of the present invention is to provide a novel amide intermediate and a process for its preparation.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an industrially advantageous and cost efficient process for the preparation of pure rosuvastatin of formula I or pharmaceutically acceptable salts thereof,

Formula I

which involves condensation of substituted pyrimidine intermediate of compound of formula II,

Formula II

whereinR is selected from , , and R1 is selected from hydrogen, straight or branched chain alkyl group preferably C1-C4. X is selected from halogen,
and amide intermediate of formula III.

Formula III

According to one embodiment, the present invention provides a process for preparation of pure rosuvastatin of formula I or pharmaceutically acceptable salts thereof, comprising the steps of;
a). condensing substituted pyrimidine intermediate of compound of formula II;

Formula II

wherein R is as defined above
with amide intermediate of formula III,

Formula III
in the presence of a suitable base in a suitable organic solvent to obtain an acetonide protected amide compound of formula IV;

Formula IV
b). converting acetonide protected amide compound of formula IV to rosuvastatin of formula I or pharmaceutically acceptable salts thereof.

Formula I

According to another embodiment, the present invention provides a process for preparation of pure rosuvastatin of formula I or pharmaceutically acceptable salts thereof comprising the steps of:
a). condensing the substituted pyrimidine intermediate of compound of formula II with amide intermediate of formula III in the presence of a suitable base in a suitable organic solvent to obtain a acetonide protected amide compound of formula IV;

Formula IV
b). deprotecting the acetonide protected amide compound of formula IV using a suitable reagent;
c). treating the resulting compound with naphthylethylamine to obtain the rosuvastatin naphthylethylamine salt of formula V;

Formula V
d). neutralizing rosuvastatin naphthylethylamine salt of compound of formula V to rosuvastatin of formula I, in the presence of suitable acid and solvent and;
e). converting it to its pharmaceutically acceptable salts.
According to one other embodiment, the present invention provides a process for preparation of triazolyl sulfonylmethyl pyrimidine intermediate of formula IIa,

Formula IIa

wherein R1 is selected from hydrogen, straight or branched chain alkyl group preferably C1-C4.
comprising the steps of:
a). condensing halo methyl pyrimidine compound of formula VI

Formula VI
wherein X refers to halogen; selected from chlorine, bromine, fluorine, iodine; or any other leaving group.
with triazolyl thiol compound of formula VII,

Formula VII
wherein R1 is selected from hydrogen, straight or branched chain alkyl group preferably C1-C4
in the presence of a suitable base in a suitable solvent to obtain triazolyl sulfanylmethyl pyrimidine compound of formula VIII;

Formula VIII
wherein R1 is as defined above
b). oxidizing the resulting triazolyl sulfanylmethyl pyrimidine compound of formula VIII in presence of a suitable oxidizing agent to obtain triazolyl sulfonylmethyl pyrimidine compound of formula IIa.

Formula IIa
wherein R1 is as defined above.
According to one other embodiment, the present invention provides a process for preparation of novel amide intermediate of formula III comprising the steps of:
a.) hydrolyzing hydroxy ester compound of formula IX using a suitable hydrolyzing agent in a solvent;

Formula IX
to obtain the hydroxy acid compound of formula X or salts thereof;

Formula X
b.) condensing the hydroxy compound of formula X with a-methyl benzyl amine in presence of a suitable reagent to obtain hydroxy amide compound of formula XI;

Formula XI
c.) oxidizing the hydroxy amide compound of formula XI in presence of a suitable oxidizing agent to obtain an amide intermediate of formula III;

Formula III
According to another embodiment, the present invention provides a process for preparation of pure rosuvastatin of formula I or pharmaceutically acceptable salts thereof comprising the steps of:
a). condensing halo methyl pyrimidine compound of formula VI with triazolyl thiol compound of formula VII in presence of a suitable base in a suitable solvent to obtain a triazolyl sulfanylmethyl pyrimidine compound of formula VIII;
b). oxidizing the resulting triazolyl sulfanylmethyl pyrimidine compound of formula VIII in presence of a suitable oxidizing agent to obtain the triazolyl sulfonylmethyl pyrimidine compound of formula IIa;
c). condensing triazolyl sulfonylmethyl pyrimidine compound of formula IIa with amide compound of formula III in the presence of a suitable base in a organic solvent to obtain an acetonide protected amide compound of formula IV;
d). deprotecting the resulting acetonide protected amide compound of formula IV with suitable reagent;
e). optionally treating the resulting compound with naphthylethylamine to obtain the rosuvastatin naphthylethylamine salt of formula V;
f). optionally converting rosuvastatin naphthylethylamine salt of compound of formula V to rosuvastatin of formula I or pharmaceutically acceptable salts thereof in the presence of suitable reagent and a solvent.
According to another embodiment, the present invention provides a novel triazolyl sulfonylmethyl pyrimidine compound of formula IIa and process for its preparation.
According to still another embodiment, the present invention provides a novel amide intermediate of compound of formula III and process for its preparation.
According to another embodiment, the present invention provides a novel triazolyl sulfanylmethyl pyrimidine compound of formula VIII and process for its preparation.
According to another embodiment, the present invention provides a novel hydroxy amide compound of formula XI and process for its preparation.

BRIEF DESCRIPTION OF DRAWINGS
Figure-1: represents powder X-ray diffractogram of acetonide protected amide compound of formula IV
Figure-2: represents DSC thermogram of acetonide protected amide compound of formula IV

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides an industrially advantageous and cost efficient process for the preparation of pure rosuvastatin of formula I or pharmaceutically acceptable salts thereof.
According to one embodiment, the present invention provides a process for preparation of rosuvastatin or its pharmaceutically acceptable salts via condensation of substituted pyrimidine compound of formula II

Formula II

wherein R is selected from , , and R1 is selected from hydrogen, straight or branched chain alkyl group preferably C1-C4. X is selected from halogen.
and novel amide compound of formula III.

Formula III
In the substituted pyrimidine compound of formula II, when R is , then substituted pyrimidine compound of general formula II is represented by formula IIa as provided earlier.
when R is , then substituted pyrimidine compound of general formula II is represented by formula IIb

Formula IIb

wherein X is selected from halogen.
when R is , then substituted pyrimidine compound of general formula II is represented by formula IIc

Formula IIc

The process comprises condensation of triazolyl sulfonylmethyl pyrimidine compound of formula IIa with novel amide intermediate of formula III via Julia- olefinic condensation. Alternatively, condensation of substituted pyrimidine compound of formulae IIb and IIc with novel amide intermediate of formula III is achieved through Wittig reaction. Therefore condensation of substituted pyrimidine compound of general formula II with novel amide intermediate of formula III forms an inventive part of invention.
Accordingly, the process of condensation of triazolyl sulfonylmethyl pyrimidine compound of formula IIa with novel amide intermediate of formula III is carried out in the presence of a suitable base in an organic solvent at a suitable temperature to afford acetonide protected amide compound of formula IV. The suitable base used in condensation reaction can be selected from alkali metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, or the like; alkali metal bicarbonates such as potassium bicarbonate, sodium bicarbonate, lithium bicarbonate, cesium bicarbonate, or the like; alkali metal alkoxide such as sodium methoxide, sodium ethoxide, sodium propoxide, sodium tertiary butoxide, potassium methoxide, potassium ethoxide, potassium tertiary butoxide, magnesium tertiary butoxide, or the like; amines such as lithium diisopropylamine, lithium hexamethylpyrimidine or the like; metal disilazides such as sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl) amide, lithium bis(trimethylsilyl)amide, or the like, or mixtures thereof. Organic solvent used for condensation reaction includes but is not limited to polar aprotic solvents, such as acetonitrile, dimethyl sulfoxide, dimethyl acetamide, dimethylformamide or the like; aliphatic ether solvent such as C3-C8 ethers, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,2-dimethylether, 1,2-diethyl ether, hydrocarbons such as benzene, toluene and xylene, or the like, or mixtures thereof.
Generally, the process involves condensation reaction at a temperature of -30 ºC to 90ºC for few minutes to several hours, preferably at -20 ºC to 50ºC, more preferably from -10 ºC to 10ºC for 3-4 hours or till the completion of the reaction. The completion of reaction can be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), fast liquid chromatography (FLC), and the like. After completion of reaction, the reaction mass is quenched with water and the resulting compound can be isolated from the reaction mixture by using suitable techniques known in the art. For the purpose of present invention, the resulting acetonide protected amide compound of formula IV can be isolated from the reaction mixture by generation of biphasic system in reaction mixture. After layer separation, the organic layer can be washed with aqueous solution of acid, base or pure water. The solvent at this stage can be selected from water immiscible solvents such as halogenated solvents, aliphatic esters, aliphatic ethers or hydrocarbons or mixtures thereof. Optionally, solvent can be distilled off under reduced pressure. The resulting solid, thus obtained, can optionally be purified using suitable solvent.
In an alternate embodiment, the substituted pyrimidine compound of formulae IIb and IIc can be condensed with amide compound of formula III in presence of a suitable base and solvent at a suitable temperature. The suitable base for use herein include, but are not limited to, alkali metal carbonates, such as sodium carbonate, potassium carbonate, magnesium carbonate and the like; alkali metal hydroxides such as sodium hydroxides, potassium hydroxides, lithium hydroxides and the like and mixtures thereof. Generally, the base may be present in the range of greater than 2 mole equivalents per molar equivalent of Wittig reagent and preferably about 2.2 to about 4.5 molar equivalents per equivalent of Wittig reagent. The solvent for the condensation reaction can be selected from an aprotic solvent which includes, but are not limited to, dimethylsulfoxide, dimethylformamide, dimethylacetamide and the like and mixtures thereof. The condensation reaction can be carried out at temperatures in the range of 50-90ºC and preferably between 70-85ºC. After completion of reaction, acetonide protected amide compound of formula IV can be isolated from the reaction mixture, by quenching the reaction mass with water or acid followed by extraction of desired compound using water immiscible solvent, which includes but are not limited to halogenated solvents, aliphatic esters, aliphatic ethers or hydrocarbons or mixtures thereof. Particularly, after completion of reaction, the reaction mass can be cooled and filtered to remove unreacted base, present in reaction, followed by pH adjustment using acid solution followed by extraction of desired compound in organic layer, then organic solvent can be distilled off under reduced pressure. The resulting compound can optionally be purified using suitable solvent such as alcohols, water or mixtures thereof.
In general state of art, the amide compound of formula III can be condensed with the substituted pyrimidine compound of formula II, but it is not the limitation of the present invention. Further amide intermediate of formula III can be condensed with any substituted pyrimidine intermediate having facile leaving group.
According to present invention, the acetonide protected amide compound of formula IV can be in any form, solid or oil or solvated form or mixtures thereof. Preferably, the acetonide protected amide compound of formula IV is crystalline in nature and is characterized by PXRD and differential scanning thermogram. The X-ray diffraction patterns, as obtained for the acetonide protected amide compound of formula IV, is represented in Figure 1 and differential scanning thermogram is represented in Figure 2.
The X-ray diffraction patterns were measured on PAN analytical, X'pert PRO powder diffractrometer equipped with goniometer of ?/? configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2? range of 2.0°-40.0°. One with ordinary skills in the art understands that experimental differences may arise due to differences in the instrument, sample preparation and other factors.
The DSC measurements were carried out on TA Q1000 of TA instrument. The experiments were performed at a heating rate of 5 or 10.0°C/min over a temperature range of 50°C to 250°C purging with nitrogen at a flow rate of 50ml/min.
Generally, the condensation product, acetonide protected amide compound of formula IV can be hydrolyzed insitu and converted to rosuvastatin or pharmaceutically acceptable salts thereof such as formula Ia. In one another aspect of present invention, rosuvastatin acid can be converted into any salt of rosuvastatin i.e., to its lithium, sodium, potassium or calcium or amine salt, by simple adding respective source in a solvent to rosuvastatin acid.
The acetonide protected amide compound of formula IV can be deprotected and/or hydrolyzed to give a dihydroxy amide compound of formula IVa

Formula IVa

by methods known in the art such as acidic or basic hydrolytic conditions. Particularly, the acidic hydrolysis can be carried out using an inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, or like; organic acid such as methane or ethane sulphonic acid, formic acid, acetic acid, trifluoroacetic acid or like; and/or basic hydrolysis can be carried out using inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, or like. Hydrolysis can be carried out in a suitable solvent for providing the reaction media and can be selected from water or water miscible solvents such as alcohols like methanol, ethanol, isopropyl alcohol, n-butanol, acetonitrile, tetrahydrofuran and the like or mixtures thereof. Usually hydrolysis can be carried out at a temperature of 0ºC to 80ºC for a period of 30 minutes to 10 hours. In general course of reaction, after the completion of hydrolysis reaction, the resulting dihydroxy amide compound of formula IVa, can be converted to rosuvastatin of formula I or its salts under the basic hydrolysis conditions, which can be optionally isolated. The hydrolysis of dihydroxy amide compound can be carried out using a suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, tetraalkylammonium hydroxides including tetrabutylammonium hydroxide, or like and/or mixtures thereof. In a preferred embodiment, the hydrolysis of dihydroxy amide compound of formula IVa can be carried out using potassium hydroxide along with tetrabutylammonium hydroxide. The suitable solvent for hydrolysis of dihydroxy amide compound can be selected from water, alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol, acetonitrile, tetrahydrofuran and the like or mixtures thereof. Usually, hydrolysis can be carried out at a temperature of 0ºC to 80ºC for a period of 2 hour to 30 hours.
It has been observed that alongwith the formation of rosuvastatin of formula I or its salts, its lactone derivative of formula XII can also be formed. Therefore, a mixture of rosuvastain or its salts and its lactone of formula XII can be isolated from the reaction mixture by generation of biphasic system or can be used in situ for the salt formation.

Formula XII
The resulting compound alone or as a mixture with lactone of formula XII is converted to pharmaceutically acceptable salts, preferably calcium salt using calcium chloride, calcium hydroxides or calcium acetate or the like.
In a preferred embodiment of present invention, compound of formula I can be converted into an amine salt by reacting it with an corresponding organic amine in a solvent. The amine for formation of amine salts is selected from primary amines, secondary amines or tertiary amines or cyclic amines or the like. Preferably, the primary amine employed for salt formation in the present invention can be a specific isomer of 1-(1-naphthyl)ethyl amine or mixture of isomers such as (±)-1-(1-naphthyl)ethylamine, (R)-(+)-1-(1-naphthyl)ethylamine, (S)-(-)-1-(1-naphthyl)ethylamine or a mixture thereof. Suitable solvent employed during salt formation can be selected from aliphatic esters such as methyl acetate, ethyl acetate, isopropyl acetate; aliphatic nitriles such as acetonitrile, propionitrile; aliphatic or aromatic hydrocarbons such as toluene, 1,2-xylene, 1,4-xylene, n-hexane, n-heptane, cyclohexane; aliphatic ethers such as diethyl ethers, methyl tertiary butyl ethers, tetrahydrofuran, 2-methyl tetrahydrofuran,1,2-dimethyl ether, 1,2-diethyl ether and the like or mixtures thereof. The amine salt of rosuvastatin can be isolated from reaction mixture or can be in situ converted to rosuvastatin or pharmaceutically acceptable salts thereof of formula Ia by methods known in the prior art. 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 the desired compound. The suitable antisolvent 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. Rosuvastatin l-(l-naphthyl)ethylamine salt of formula V, thus prepared, can be optionally purified to enhance the purity and remove impurities so that final product of high purity can be obtained. The suitable solvent for purification 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.
Rosuvastatin 1-(1-naphthyl)ethylamine salts thus prepared can be further converted in to pure rosuvastatin or pharmaceutically acceptable salts thereof by
neutralization using a suitable acid at a temperature of 0ºC to 80ºC for 10 minutes to 10 hours, preferably till the completion of the reaction. Suitable acid employed for neutralization include 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. Neutralization can be carried out in a suitable solvent for providing the reaction medium. Suitable solvents includes water or water immiscible organic solvents which can be selected from but are 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 solvents 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, neutralization reaction can be carried out at a temperature of 10ºC to 15ºC for 10 minutes to 3 hours. After completion of neutralization, pure rosuvastatin can be isolated from the reaction mixture or can be in situ proceeded for the conversion to rosuvastatin or pharmaceutically acceptable salts thereof. Specifically, after the 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 the further conversion to pharmaceutically acceptable salts of rosuvastatin.
In a preferred embodiment of present invention, rosuvastatin of formula I or pharmaceutically acceptable salts of formula Ia, as obtained by above process has purity of more than 99.76% when analyzed by HPLC with ‘Z’ isomer at a level of less than 0.15%.
The starting materials i.e., substituted pyrimidine compound of formula II, and amide compound of formula III are also prepared in an inventive manner. Among these, substituted pyrimidine compound of formula IIa is a novel compound and is prepared using the process of present invention, whereas the compound of formula IIb and IIc, used as Wittig reagents in the present reaction, can be prepared by methods known in the prior art or can be procured from available commercial source or can be prepared as described herein.
In another embodiment of present invention, the novel triazolyl sulfonylmethyl pyrimidine compound of formula IIa is prepared by starting from halo methyl pyrimidin methyl-methansulfonamide of compound of formula VI. The halo methyl pyrimidin methyl-methansulfonamide of compound of formula VI can be prepared by methods known in the art or can be procured from available commercial source. Preferably, halo methyl pyrimidin methyl-methansulfonamide of compound of formula VI can be prepared from hydroxylmethyl pyrimidin methyl-methansulfonamide compounds. Particularly, halomethyl pyrimidin methyl-methansulfonamide of compound of formula VI is prepared by halogenating the hydroxylmethyl pyrimidin methyl-methansulfonamide compounds namely N-[4-(4-fluoro-phenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl]-N-methyl-methane sulfonamide with respective halogenating agent in a suitable solvent. For example, the N-[5-chloromethyl-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidine-2-yl]-N-methyl-methanesulfonamide can be prepared by chlorinating the N-[4-(4-fluoro-phenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide with methanesulfonyl chloride in presence of a suitable base and solvent. Similarly, N-[5-bromo methyl-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidine-2-yl]-N-methyl-methane sulfonamide can be prepared by brominating N-[4-(4-fluoro-phenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl]-N-methyl-methane sulfonamide with phosphorous tribromide in presence of a suitable solvent. Preferably the reaction can be carried out in halogenated solvents such as chloroform, carbon tetrachloride; aliphatic nitrile such as acetonitrile or hydrocarbon solvent.
In another embodiment of present invention, halo methyl pyrimidin methyl-methansulfonamide of compound of formula VI can be condensed with triazolyl thiol compound of formula VII in the presence of a base to obtain triazolyl sulfanylmethyl pyrimidine compound of formula VIII. The triazolyl thiol compound of formula VII can be prepared by methods known in the prior art or can be procured from available commercial source.
The suitable base used in condensation reaction is preferably selected from organic or inorganic bases. The organic base can be selected from trimethylamine, triethylamine, tributylamine, isopropylethylamine, pyridine, 8-diazabicyclo [5.4.0]undec-7-ene, 4-N,N-dimethylaminopyridine, or the like; inorganic base is selected from metal hydroxides such as sodium hydroxide, potassium hydroxide; metal carbonates such as lithium carbonate, cesium carbonate, sodium carbonate, potassium carbonate; metal bicarbonates such as sodium bicarbonate, potassium bicarbonate or the like or mixtures thereof. The solvent used for the condensation can be selected from halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, or the like; aliphatic ketones such as acetone, 2-butanone, methyl isobutyl ketone, methyl ethyl ketone, or the like; aliphatic esters such as ethyl acetate, methyl acetate, tertiary butyl acetate, or the like; aliphatic nitriles such as acetonitrile, propionitrile or the like; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2-dimethoxy ether, 1,2-diethoxy ether, 1,4-dioxane, diethyl ether, isopropyl ether, methyl tertiary butyl ether or the like; aprotic polar organic solvents such as dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, or the like or mixtures thereof.
The suitable reaction temperature for condensation reaction can be selected from 0 to 50ºC and maintained at this temperature for 30 minutes to 6 hours preferably the reaction mixture can be stirred over a period of 2 to 4 hours, more preferably till completion of the reaction. The completion of reaction can be monitored by any one of chromatographic techniques such TLC, HPLC, FLC, and the like. The compound of formula VIII can be isolated from the reaction mixture using any conventional method known in the art. For the purpose of present invention, the obtained triazolyl sulfanylmethyl pyrimidine compound of formula VIII can be isolated from the reaction mixture by generation of biphasic system in reaction mixture. After layer separation, the organic layer can be washed with water or sodium chloride solution. Optionally, the solvent is distilled off under reduced pressure. The solvent at this stage can be selected from any water immiscible solvent, such as those described for the preparation of compound of formula II. Accordingly, the triazolyl sulfanylmethyl pyrimidine compound of formula VIII is considered as a novel compound of present invention and can be in any form such as crystalline or amorphous or mixtures thereof.
The compound of formula VIII, as obtained, can be purified further before being used in the next step or used as such to prepare compound of formula IIa. In a preferred embodiment, triazolyl sulfanylmethyl pyrimidine compound of formula VIII is oxidized using an oxidizing agent under suitable reaction conditions. The oxidizing agent can be selected from permanganates such as potassium permanganates or the like; meta-chloroperbenzoic acid; peracetic acid; sodium hypochlorite; hydrogen peroxide; tertiary butyl hydrogen peroxide; cumene hydro peroxide; or oxone in presence of an appropriate catalyst such as ammonium molybdate, ammonium hepta molybdate tetra hydrate, alkali metal tungstate or like or without catalyst in a suitable solvent selected from halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, or the like; aliphatic ketones such as acetone, 2-butanone, methyl isobutyl ketone, methyl ethyl ketone, or the like; aliphatic esters such as ethyl acetate, methyl acetate, tertiary butyl acetate, or the like; alcoholic solvents such as methanol, ethanol, 1-propanol or 2-propanol or mixtures thereof. Optionally, the oxidation reaction can be facilitated in the presence of phase transfer catalysts selected from alkyl ammonium halides such as tetrabutyl ammonium bromide, tetraethyl ammonium chloride, or the like.
The suitable reaction temperature for oxidation reaction can be selected from 0 to 40ºC and maintained at this temperature for 30 minutes to 15 hours. Preferably the reaction mixture can be stirred over a period of 4 to 12 hours, more preferably till completion of the reaction. The completion of reaction can be monitored by any one of chromatographic techniques as described above. The compound of formula IIa can be isolated from the reaction mixture by using any conventional method known in the art. For the purpose of present invention, the obtained triazolyl sulfonylmethyl pyrimidine compound of formula IIa can be isolated from the reaction mixture by generation of biphasic system in reaction mixture. After layer separation, the organic layer can be washed with water or saturated sodium chloride solution. Optionally, solvent is distilled off under reduced pressure. The solvent at this stage can be selected from halogenated solvent or hydrocarbons or mixtures thereof. The resulting solid material can optionally be purified using solvent selected from the group comprising alcohols, aliphatic esters; aliphatic ketones; aliphatic ethers; halogenated solvents; hydrocarbons; protic or aprotic solvents and mixtures thereof. Purification, can be carried out by any method known in the art, such as crystallization, acid base treatment, dissolution and distillation of solvent, dissolution and precipitation by adding anti solvent etc. Preferably, according to present invention the crude product is dissolved in solvent at 30 to 50ºC and crystallized or precipitated using the antisolvent, preferably, hydrocarbon such as n-hexane or n-heptane. The solvent for crystallization is selected from aliphatic esters such as ethyl acetate. The compound can be further purified using hydrocarbon solvent as described above.
In one other embodiment of present invention, if in triazolyl substitued pyrimidine compound of the formula IIa, R1 is hydrogen, then the reaction with a suitable alkylating agent is carried out to prepare triazolyl substitued pyrimidine compound of the formula IIa, wherein R1 is alkyl. Particularly, alkylation is carried out using any alkylating agent such as dimethyl sulfate or methyl iodide or the like in presence of a suitable base selected from alkali metal hydroxides, in a suitable solvent selected from halogenated solvents to provide an alkylated triazolyl pyrimidine compound of formula IIa.
Accordingly, the triazolyl substituted pyrimidine compound of the formula IIa should be considered as novel compound of present invention and can be isolated in any form such as crystalline or amorphous or mixtures thereof.
In one other embodiment of invention, substituited pyrimidine compound of formula IIb, can be prepared by halogenating the corresponding hydroxymethyl sulfonylmethyl pyrimidine compound using a suitable halogenating agent in a suitable solvent at suitable temperature. The suitable halogenating agent can be selected from halogen acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid; and inorganic acid halides such as thionyl chloride, sulfur tetrafluoride, phosphorous trichloride, phosphorous pentachloride, phosphorous tribromide, phosphoryl chloride. The suitable solvent can be selected from chloroform, dichloromethane, chlorobenzene, dichlorobenzene or like. Particularly for the purpose of present invention hydroxymethyl sulfonylmethyl pyrimidine compound can be brominated using phosphorous tribromide at a temperature -2 to 25°C for 10-60 minutes in dichloromethane. After completion of reaction, bromomethyl sulfonylmethyl pyrimidine compound can be isolated from the reaction mixture or can be converted insitu to substituited pyrimidine compound of formula IIb. The isolation of bromomethyl sulfonylmethyl pyrimidine compound can be affected by generation of biphasic system in reaction mixture. After layer separation, the organic layer can be washed with acid, base or brine solution. The solvent at this stage can be selected from water immiscible solvent such as halogenated solvent, aliphatic ester or aliphatic ether or hydrocarbon or mixtures thereof. Optionally, solvent can be distilled off under reduced pressure and the resulting solid, thus obtained, can optionally be purified using suitable solvent. The bromomethyl sulfonylmethyl pyrimidine compounds further converted to substituited pyrimidine compound of formula IIb by reacting the bromomethyl sulfonylmethyl pyrimidine compound with a suitable phosphorous derivative, preferably triphenylphosphine in a suitable solvent at suitable temperature. The suitable solvent can be selected from hydrocarbons such as toluene; aliphatic ketones such as acetone, diethyl ketone, ethyl methyl ketone or halogenated solvent such as dichloromethane, chloroform. The reaction with phosphorous derivative can be generally carried out at a temperature 20-100°C in time ranging from 10 minutes to 2 hours. After completion of reaction, the reaction product is filtered and washed with a suitable hydrocarbon solvent.
In one other embodiment of invention, the amide compound of formula III can be prepared by first hydrolyzing the compound of formula IX in a suitable solvent to obtain the hydroxy compound of formula X or salt thereof, preferably the hydroxy compound of formula X is prepared in its salt form. The hydrolysis can be carried out in presence of alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate preferably sodium hydroxide. The solvent for the hydrolysis reaction can be selected from alcohols such as C1-C3 alcohols; alkyl nitriles such as acetonitrile, propionitrile, ethers such as tetrahydrofuran, 2-methyl hydrocarbon, 1,2-dimethoxyether, 1,2-diethyl ether; aliphatic ketones such as acetone, diethyl ketone, ethyl methyl ketone or the like or mixtures thereof.
The hydroxy compound of formula X or salt thereof can be condensed with a-methyl benzyl amine in presence of suitable coupling reagent and solvent at 0-40ºC for 1-5 hours preferably till completion of reaction to give the hydroxy amide compound of formula XI. The suitable coupling agent conventionally used for amide synthesis are selected from N,N'-dicyclo hexylcarbodiimide, N,N'-diisopropylcarbodiimide, N,N'-carbonyldiimidazole and carbonyl-di-(1,2,4-triazole). Generally, along with above agent, a catalytic auxiliary nucleophiles such as l-hydroxybenzotriazole, 1-hydroxy-7-aza-benzotriazole, ethyl 2-cyano-2-(hydroxyimino)acetate,(benzotriazol-1-yl-oxytripyrrolidinophosphonium hexa fluorophosphate, benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexa fluorophosphate, N-hydroxysuccinimide and N-hydroxy-5-norbene-endo-2,3-dicarboxamide and a like can also be used.
The reaction can be carried out in suitable solvent selected from class of alcohols; halogenated solvents; ethers; aliphatic ketones; alkyl nitriles and the like or mixtures thereof. Amide formation is carried out using a-methyl benzylamine, however another isomer or mixture of two can be used for the reaction, particularly R-(+)-a-methyl benzylamine is used. For the purpose of present invention the hydroxy amide compound of formula XI forms a novel part of invention. After complete formation of amide, the product can be isolated from the reaction mixture by employing any suitable techniques known in the art or used as such for further oxidation reaction. Preferably, intermediate of formula XI can be isolated from the reaction mixture by adding water to the reaction mixture followed by extraction with a suitable solvent. Suitable solvent used for the extraction can be any water immiscible solvent selected from esters; halogenated solvents; aliphatic or aromatic hydrocarbons, and the like or mixture thereof. The resulting solution can be optionally washed with an aqueous solution of acid/base/water and/or brine. Hydroxy amide compound of formula XI can be recovered from the resulting solution by removal of solvent using suitable techniques, preferably by evaporation, or distillation. The hydroxy amide compound of formula XI can be optionally purified prior to oxidation reaction to enhance the purity of compound and/or remove impurities present in the product. Preferably the hydroxy amide compound of formula XI can be purified using a suitable solvent such as isopropyl ether to get the purity greater than 98.50%. Any suitable purification method can be employed for purification, as described above for purification.
The resulting hydroxy amide compound of formula XI is then converted to amide compound of formula III, via oxidation. Generally, the hydroxy amide compound of formula XI is oxidized in a suitable solvent with sodium hypochlorite in the presence of sodium bicarbonate, sodium bromide or potassium bromide and a catalytic amount of (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO) for a suitable period of time and temperature. Optionally, any oxidizing reagent, described in literature, can be used to convert the alcohol group to aldehyde group.
The hydroxy ester compound of formula IX can be prepared by methods known in the prior art or procured from commercial source.
Thus, isolated final product of formula I as well as its intermediates described herein, in the present invention may be optionally purified to enhance the purity of the product. Any suitable purification procedure such as, for example, crystallization, derivatization, slurry wash, salt preparation, various chromatographic techniques, solvent-anti-solvent system or combination of these procedures, may be employed to get the purified material. However, other equivalent procedures such as acid-base treatment could, also be used, to purify the intermediates as well as final product. The solvents used for the purification of final compound and intermediates of the present invention may be selected depending upon the nature of the compound to be purified, however the solvent can be chosen amongst water, C1-6 alcohols, aliphatic C3-6 ketones, aliphatic or aromatic hydrocarbons, C2-10 esters, C3-6 ethers, C1-3 alkyl nitrile, halogenated solvents, polar aprotic solvents such as N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methyl pyrrolidinone, sulfolane and the like or mixtures thereof in suitable proportion.
As used herein, the term “conventional methods for the isolation of intermediates as well as final product” may be varied depending upon the nature of the reactions, nature of product of the reaction, medium of the reaction and the like. The suitable conventional methods can be selected amongst but not limited to distillation of the solvent, addition of water to the reaction mixture followed by extraction with water immiscible solvents, removal of the insoluble particles from the reaction mixture, if present, by filtration or centrifugation or by decantation, addition of water immiscible organic solvent, addition of a solvent to the reaction mixture which precipitate the product, neutralizing the reaction mixture with a suitable acid or base whichever is applicable.
The main advantage of the present invention is that it provide an industrially advantageous and cost efficient process for preparation of rosuvastatin or pharmaceutically acceptable salts thereof and provides product with high trans regioisomer contents through use of novel compounds of formulae II and III. The process of present invention is cost effective, reproducible as well as industrially advantageous and employs very mild reaction conditions.
EXAMPLES:
Example 1: Preparation of 2-(6-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl)-N-(1-phenyl-ethyl)-acetamide
Method A: (6-Hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid tertiary-butyl ester (100g) was hydrolyzed with sodium hydroxide (38.5g) in methanol (1000ml) at 25-30°C for 10-12 hours. After completion of reaction, the solvent was distilled off to obtain a residue which was dissolved in dichloromethane (1000ml) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (110.8g), 4-hydroxybenzotrizole (52g) were added successively. To the resulting reaction mass, methylbenzyl amine (47.4g) was slowly added and stirred for 3 hours at 25-30°C. After completion of reaction, water was added and layers were separated. Organic layer was washed sequentially with 5% aqueous hydrochloric acid (400ml), 5% sodium bicarbonate solution (400ml), water (400ml), and brine (400ml). The solvent was distilled off to obtain the title compound which was characterized by 1H-NMR and mass spectra.
1H-NMR, (400 MHz, CDCl3, ppm):1.15 (m,11H), 2.2(m,2H), 2.82(b,1H), 3.35 (m,2H), 3.86(m,1H), 4.10(m,1H),4.96 (m,1H) 6.74(dd,1H), 7.1(m,1H), 7.2(m,4 H);
Mass (M+1)=308 amu
Method B: 6-Hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid tert-butyl ester (420g) was hydrolyzed with sodium hydroxide (160g) in methanol (2.44L) at 20-25°C for 10-12 hours. After completion of reaction, the solvent was distilled off completely to obtain a residue which was dissolved in dichloromethane (3.28L) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (462g) and 4-hydroxybenzotrizole (262g) were added successively. To the resulting reaction mass, R (+) alpha methylbenzyl amine (240g) was added slowly and stirred for 3 hours at 28-32°C. After completion of reaction, water (1.68L) was added, stirred and layers were separated. Organic layer was washed sequentially with dilute HCl solution, aqueous NaHCO3 solution and then with water. Solvent was distilled out completely under vacuum and the product was isolated using n-hexane and then purified from isopropyl ether to get the title product (315g).Purity by HPLC 96.38%.
The above obtained product (10g) was again purified using isopropyl ether to obtain the title product having purity 98.70% as measured by HPLC.
Mass (M+1)=308 amu
Example 2: Preparation of 2-(6-formyl-2,2-dimethyl-[1,3]dioxan-4-yl)-N-(1-phenyl-ethyl)-acetamide
Method A: To a solution of 2-(6-Hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl)-N-(1-phenyl-ethyl)-acetamide (1g) in dichloromethane (20ml) at 0-5°C, (2,2,6,6-tetramethyl piperidin-1-yl)oxy (10mg), sodium bromide (0.03g) and sodium bicarbonate (0.45g) were successively added. Thereafter, sodium hypochlorite solution (8-10%, 4.65ml) was added slowly at 0-5°C and the reaction mixture was stirred for 2.0 hours. After completion of reaction, 5% aqueous sodium thiosulfate solution (10ml) was added and layers were separated. Organic layer was washed with brine solution and concentrated under vacuum to give (7g) of title compound.
Mass (M+1)=306 amu
Method B: 2-(6-Hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl)-N-(1-phenyl-ethyl)-acetamide (300.0g) was dissolved in dichloromethane (4.5L) and cooled to -10°C, 2,2,6,6-tetramethylpiperidin-1-yl)oxy (7.80g) and potassium bromide (87g) were added followed by addition of sodium bicarbonate (123g). Thereafter, sodium hypochlorite (8-10%, 972ml) was added slowly at -10°C. After completion of reaction, 10% aqueous sodium thiosulfate solution (3L) was added to the reaction mass and layers were separated. Organic layer was washed with brine (1.5L) and concentrated under vacuum. The product was isolated from n-hexane (225g). Purity by HPLC 96.79 %.
The above obtained product (10g) was purified using isopropyl ether to obtain the title product having purity 98.42% as measured by HPLC.
1H-NMR, (400 MHz, CDCl3, ppm): 1.37 (m, 11H), 2.33 (m, 2H), 4.24 (m, 2H), 5.06(m, 1H), 6.47 (d, 1H), 7.23(m, 5H), 9.55 (s, 1H);
Mass (M+1)=306 amu
Example 3: Preparation of N-[4-(4-fluoro-phenyl)-6-isopropyl-5-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)pyrimidin-2-yl]-N-methyl-methane- sulfonamide
Method A: To a solution of 4-methyl-4H-[1,2,4]triazole-3-thiol (7.62g) in ethyl acetate (250ml), potassium carbonate (20g) was added and the reaction mixture was stirred for 30 minutes at 25 to 30ºC. N-[5-Bromomethyl-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methyl-methane sulfonamide (25g) was added and temperature was raised to 30 to 35ºC and stirred for 4 hours. After completion of reaction, the reaction mass was quenched with water (200ml). The organic layer was separated and aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried on anhydrous sodium sulphate and concentrated. Isopropyl ether (50ml) was added to the residue and stirred for 30 minutes at 25-30ºC and the resulting solid was filtered, washed with diisopropyl ether and dried to give (27g) of title compound which is characterized by 1H-NMR and mass spectra.
1H-NMR, (400 MHz, CDCl3, ppm): 1.34 (d, 6H), 3.50 (s, 4H), 3.53 (s, 6H), 4.50 (s, 2H), 7.12 (dd, 2H), 7.65 (dd, 2H), 8.19 (s, 1H);
Mass (M+1)=451 amu
Method B: To a mixture of 4-methyl-4H-[1,2,4]triazole-3-thiol (1.52g) in ethyl acetate (50ml), potassium carbonate (8g) was added and stirred for 60 minutes at 25 to 30ºC. N-[5-Chloromethyl-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methyl-methane sulfonamide (5g) was added and temperature was raised to 30 to 35oC and stirred for 12 hours. After completion of reaction, the reaction mass was quenched with chilled water (50ml). The organic layer was separated and aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried on anhydrous sodium sulphate and concentrated. To the resulting residue, diisopropyl ether (10ml) was added and stirred for 30 min at 25 to 30ºC and the solid thus prepared, was filtered, washed with diisopropyl ether and dried to obtain 5g of title compound.
Example 4: Preparation of N-[4-(4-fluoro-phenyl)-6-isopropyl-5-(4-methyl-4H-[1,2,4]triazole-3-sulfonylmethyl)pyrimidin-2-yl]-N-methyl-methane sulfonamide
To a solution of N-[4-(4-fluorophenyl)-6-isopropyl-5-(4-methyl-4H-[1,2,4] triazol-3-ylsulfanylmethyl) pyrimidin-2-yl]-N-methyl-methanesulfonamide (6.0g) in dichloromethane (60ml) at 0 to 5ºC, m-chloroperbenzoic acid (9.6g) was added and stirred for 12 hours at 28 to 32ºC. After completion of reaction, the mass was filtered and the filtrate was successively washed with solution of sodium sulphite and sodium bicarbonate, and concentrated. Ethyl acetate (18ml) was added to the resulting residue at 50ºC and then cooled slowly to 35ºC followed by addition of hexane. The reaction mass was further stirred for 30 minutes and then filtered, washed with n-hexane and dried at 50ºC for 12 hours to give (5.6g) title compound which is characterized by 1H-NMR.
1H-NMR, (400 MHz, CDCl3, ppm): 1.33 (d, 6H), 3.49 (s, 4H), 3.54 (s, 3H), 3.72 (s, 3H), 5.17 (s, 2H), 7.10 (dd, 2H), 7.44 (dd, 2H), 8.19 (s, 1H);
Example 5: Preparation of 2-(6-{2-[4-(4-fluoro-phenyl)-6-isopropyl-2-(metha- nesulfonyl-methylamino)pyrimidin-5-yl]vinyl}-2,2-dimethyl-[1,3]dioxan-4-yl) -N-(1-phenyl-ethyl)-acetamide
To a solution of N-[4-(4-fluorophenyl)-6-isopropyl-5-(4-methyl-4H-[1,2,4] triazole-3-sulfonylmethyl)-pyrimidin-2-yl]-N-methyl-methanesulfonamide (514mg) in tetrahydrofuran (5ml), sodium methoxide (54g) was added at 0 to -5 ºC, and stirred. A solution of 2-(6-formyl-2,2-dimethyl-[1,3]dioxan-4-yl)-N-(1-phenyl-ethyl)-acetamide (500mg) in tetrahydrofuran (2ml) was added slowly at 0 to -5ºC and stirred for 3 hours. After completion of the reaction, reaction mass was quenched with water, the product was extracted in dichloromethane and the solvent distilled off completely to get the (0.8g) title compound.
Mass (M+1)=625 amu
Example 6: Preparation of 2-(6-{2-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methylamino)pyrimidin-5-yl]vinyl}-2,2-dimethyl-[1,3] dioxan-4-yl) -N-(1-phenyl-ethyl)-acetamide
Method A: [[4-(4-Fluorophenyl)-6-(1-methylethyl)-2-[N-methyl-N-methyl sulfonyl)amino]-5-pyrimidinyl]methyl]triphenylphosphonium bromide (1.62g) was dissolved in dimethyl sulfoxide (5ml) and potassium carbonate (1.3g) was added. Reaction mass was heated to 80-85°C and a solution of 2-(6-formyl-2,2-dimethyl-[1,3]dioxan-4-yl)-N-(1-phenyl-ethyl)-acetamide (0.5g) in dimethyl sulfoxide (2ml) was added, slowly, and stirred for 2 hours. After completion of the reaction, the mass was cooled to 20-30°C and quenched with water. The product, thus formed, was extracted with ethyl acetate and successively washed with water and sodium chloride solution. The organic layer was distilled off completely to get the (0.8g) title compound.
Mass (M+1)=625 amu
Method B: [[4-(4-Fluorophenyl)-6-(1-methylethyl)-2-[N-methyl-N-methyl sulfonyl)amino]-5-pyrimidinyl] methyl]triphenylphosphonium bromide (512.4g) and 2-(6-formyl-2,2-dimethyl-[1,3]dioxan-4-yl)-N-(1-phenyl-ethyl)-acetamide (210g) were dissolved in dimethyl sulfoxide (2.1L) and potassium carbonate (237.3g) was added. Reaction mass was heated to 80-85°C and stirred for 1 hour. After completion of the reaction, reaction mass was cooled to room temperature, filtered and pH of the reaction mass was adjusted to 4-5 with concentrated hydrochloric acid. Water (2.1L) was added and the product was extracted with toluene (2.31L). Organic layer was washed with 5.0% aqueous sodium bicarbonate solution (1.05L) and brine (1.05L). Solvent was distilled off completely under vacuum and the product was isolated from aqueous ethanol (2.94L) and then purified from ethanol (1.44L) to obtain 262.5g of title compound having purity 99.71% by HPLC.
1H-NMR, (400 MHz, CDCl3, ppm): 1.18 (m, 17H), 2.34 (m, 2H), 3.35 (m, 1H), 3.51(s, 3H), 3.56(s, 3H), 4.23(m, 1H), 4.39 (m, 1H), 5.09(m, 1H), 5.43(dd, 1H), 6.49(m, 2H), 7.06 (m, 9H);
Mass (M+1)=625 amu
Example 7: Preparation of 1-naphthalen-1-yl-ethylamine salt of rosuvastatin
Method A: To a cooled solution of 2-(6-{2-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methane sulfonyl -methylamino)pyrimidin-5-yl]vinyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-N-(1-phenyl-ethyl)-acetamide (1g) in tetrahydrofuran and methanol, aqueous hydrochloric acid (1N) was added slowly and stirred for 6 hours at 25-30°C. After reaction completion, aqueous sodium hydroxide solution (10%) was added to adjust pH to12.0-12.5 and stirred for 1 hour. The reaction mass was filtered and concentrated under vacuum. Methyl-tertiary butyl ether and water were added to the resulting residue and layers were separated. Dilute hydrochloric was added to aqueous layer and desired product was extracted in ethyl acetate. Organic layer was washed with brine solution. To the resulting organic layer, 1-(1-naphthyl) ethylamine was added and stirred for 10-12 hours. The solid was filtered, washed with ethyl acetate and dried to get the title compound.
Method B: 2-(6-{2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl methyl amino) pyrimidin-5-yl] vinyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-N-(1-phenyl-ethyl)-acetamide (250g) was taken in a mixture of isopropanol (2.5L) and water (250ml). Hydrochloric acid (125ml) was added slowly to the reaction mass and stirred for 30 minutes at 35-40°C. After completion of reaction potassium hydroxide (125g) and tetrabutylammonium hydroxide (750ml) were added in reaction mass and stirred for 24 hour at 80-85°C. Isopropanol was distilled out under vacuum and the reaction mass was filtered at 25-30°C and washed with methyl-tertiary butyl ether. pH of the reaction mass was adjusted to 1-2 from hydrochloric acid and product was extracted in methyl-tertiary butyl ether. Organic layer was washed with brine (1.25L) and 1-(1-naphthyl)ethylamine (75.0g) was added and the solvent was distilled out completely. Ethyl acetate was added to the residue and again 1-(1-naphthyl)ethylamine (70.0g) was added. Reaction mass was stirred at room temperature for 6 hours, thereafter, n-heptane was added. The resulting solid was filtered and purified from acetonitrile to get 177g of the title compound having purity 99.81% by HPLC, antiisomer 0.13%.
1H-NMR, (400 MHz, CDCl3, ppm): 0.85(m, 2H), 1.16(d, 6H), 1.56(m, 5H), 3.24(m, 1H), 3.43(s, 3H), 3.49(s, 3H), 3.51(m, 1H), 4.06(m, 1H), 4.99(m, 1H), 5.23(dd, 1H), 6.44(d, 1H), 6.64(br., 4H), 6.96(m, 11H)
Example 8: Preparation of rosuvastatin calcium salt
Method A: 1-Naphthalen-1-yl-ethylamine salt of N-[5-(3,5-dihydroxy-7-oxo-oct-1-enyl)-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methane sulfonamide (170g) as obtained above, was taken in ethyl acetate(1.19L) and the reaction mass was cooled to 10-15°C. Water was added and the pH was adjusted to 1-2 with dilute hydrochloric acid, layers were separated and extracted with ethyl acetate. Organic layer was washed successively with 1N hydrochloric acid and water at 40-45°C. Organic layer was concentrated and compound was dissolved in methyl-tertiary butyl ether(1.19L) and cooled to 10-15°C. Water (1.19L) was added and pH of reaction mass was adjusted to 9.0-11.0 with 10% sodium hydroxide solution, stirred and layers were separated. Organic layer was concentrated and aqueous solution of calcium acetate (42.5g in 340ml) was added to the reaction mass and stirred for 1 hour at 25-30°C. Product was filtered, washed with water and dried to obtain 108g of rosuvastatin calcium as amorphous white to offwhite powder having purity 99.74%, antiisomer 0.14% by HPLC.
Method B: 2-(6-{2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methylamino)pyrimidin-5-yl]vinyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-N-(1-phenyl-ethyl)-acetamide (1g) was stirred in a mixture of tetrahydrofuran and methanol to get clear solution and cooled to 15°C. Dilute hydrochloric acid (1N) was added slowly and stirred for 6 hours at 25-30°C. Completion of reaction was monitored by TLC and pH was adjusted to12.0-12.5 by aqueous sodium hydroxide solution (10%).The reaction mass was filtered and concentrated under vacuum. Layers were separated using water and methyl-tertiary butyl ether. Aqueous solution of calcium acetate was added in reaction mass and stirred for 1 hour, filtered, washed with water and dried under vacuum to give amorphous rosuvastatin calcium as a white to off-white powder.

WE CLAIM,
1. A process for the preparation of rosuvastatin of formula I or pharmaceutically acceptable salts thereof,

Formula I

comprises the steps of;
a.) condensing a substituted pyrimidine intermediate of formula II;

Formula II

wherein R is selected from , , and R1 is selected from hydrogen, straight or branched chain alkyl group preferably C1-C4. X is selected from halogen.
with amide intermediate of formula III,

Formula III
in the presence of a suitable base in a suitable organic solvent to obtain an acetonide protected amide compound of formula IV;

Formula IV
b.) converting acetonide protected amide compound of formula IV to rosuvastatin of formula I or pharmaceutically acceptable salts thereof.
2. The process as claimed in claim 1, wherein in step a) a suitable base is selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal alkoxide, amines, or mixtures thereof; in step a) a suitable organic solvent is selected from polar aprotic solvents, such as acetonitrile, dimethyl sulfoxide, dimethyl acetamide, dimethylformamide; aliphatic ethers such as C3-C8 ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,2-dimethylether, 1,2-diethylether; hydrocarbons such as benzene, toluene and xylene, or mixtures thereof.
3. The process as claimed in claim 1, wherein in step b) conversion of acetonide protected amide compound of formula IV to rosuvastatin of formula I or pharmaceutically acceptable salts thereof is carried out by comprising the steps of:
a.) deprotecting the acetonide protected amide compound of formula IV using a suitable acidic reagent to prepare dihydroxy amide intermediate of formula IVa;

Formula IVa

b.) hydrolyzing dihydroxy amide intermediate of formula IVa, to rosuvastatin of formula I or pharmaceutically acceptable salts thereof in presence of a suitable base in a suitable solvent.
4. The process as claimed in claim 1, wherein in step b) conversion of acetonide protected amide compound of formula IV to rosuvastatin of formula I or pharmaceutically acceptable salts thereof is carried out by comprising the steps of:
a.) deprotecting the acetonide protected amide compound of formula IV using a suitable acidic reagent to prepare dihydroxy amide intermediate of formula IVa;
b.) hydrolyzing dihydroxy amide intermediate of formula IVa, to rosuvastatin of formula I or pharmaceutically acceptable salts thereof in presence of a suitable base in a suitable solvent;
c.) treating the resulting compound with naphthylethylamine to obtain the rosuvastatin naphthylethylamine salt of formula V;

Formula V
d.) neutralizing rosuvastatin naphthylethylamine salt of formula V to rosuvastatin of formula I in presence of a suitable acid in a suitable solvent, and;
e.) converting it to its pharmaceutically acceptable salts.
5. The process as claimed in claims 3 and 4, wherein in step a) a suitable deprotecting reagent is selected from inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid; organic acid such as methane or ethane sulphonic acid, formic acid, acetic acid, trifluoroacetic acid.
6. The process as claimed in claims 3 and 4, wherein in step b) a suitable base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, tetraalkylammonium hydroxide such as tetrabutylammonium hydroxide, or mixtures thereof.
7. The process as claimed in claim 4, wherein in step d) a suitable acids is formic acid, acetic acid, propionic acid, butyric acid, hydrochloric acid, hydrobromic acid, phosphoric acid; in step d) a suitable solvent is selected from water or water immiscible organic solvents such as aliphatic esters; aliphatic ethers; hydrocarbons; halogenated solvents or mixtures thereof.
8. A process for the preparation of rosuvastatin of formula I or pharmaceutically acceptable salts thereof

Formula I

comprises the steps of:
a.) hydrolyzing hydroxy ester compound of formula IX using a suitable hydrolyzing agent in a solvent,

Formula IX
to obtain the hydroxy acid compound of formula X or salts thereof;

Formula X
b.) condensing the hydroxy compound of formula X with a-methyl benzyl amine in presence of a suitable reagent to obtain hydroxy amide compound of formula XI;

Formula XI
c.) oxidizing the hydroxy amide compound of formula XI in presence of a suitable oxidizing agent to obtain an amide intermediate of formula III;

Formula III
d.) converting an amide intermediate of formula III to rosuvastatin of
formula I or pharmaceutically acceptable salts thereof.
9. The process as claimed in claim 8, wherein in step a) the suitable hydrolyzing agent includes alkali or alkaline earth metal hydroxides; in step a) the solvent is selected from alcohol; alkyl nitriles; ethers; ketones or the like or mixtures thereof; in step b)suitable reagent is selected from N,N'-dicyclo hexylcarbodiimide, N,N'-diisopropylcarbodiimide, N,N'-carbonyl diimidazole, carbonyl-di-(1,2,4-triazole), l-hydroxybenzo triazole, 1-hydroxy-7-aza-benzotriazole, ethyl 2-cyano-2-(hydroxyimino) acetate, (benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluoro phosphate,benzotriazole-1-yl-oxy-tris-(dimethylamino) phosphoniumhexafluoro phosphate, N-hydroxysuccinimide and N-hydroxy-5-norbene-endo-2,3-dicarboxamide; in step c) the suitable oxidizing reagent is selected from sodium hypochlorite in the presence of potassium bromide, sodium bicarbonate and a catalytic amount of (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO).
10. A process for the preparation of rosuvastatin of formula I or pharmaceutically acceptable salts thereof

Formula I

comprises the steps of;
a.) condensing halo methyl pyrimidine compound of formula VI

Formula VI
wherein X refers to halogen; or any other leaving group,
with triazolyl thiol compound of formula VII,

Formula VII
wherein R1 is selected from hydrogen, straight or branched chain alkyl group,
in the presence of a suitable base in a suitable solvent to obtain triazolyl sulfanylmethyl pyrimidine compound of formula VIII;

Formula VIII
wherein R1 is as defined above
b.) oxidizing the resulting triazolyl sulfanylmethyl pyrimidine compound of formula VIII in presence of a suitable oxidizing agent to obtain triazolyl sulfonylmethyl pyrimidine compound of formula IIa.

Formula IIa
wherein R1 is as defined above.
c.)converting the resulting triazolyl sulfonylmethyl pyrimidine compound of formula IIa to rosuvastatin of formula I or pharmaceutically acceptable salts thereof.

,CLAIMS:WE CLAIM,
1. A process for the preparation of rosuvastatin of formula I or pharmaceutically acceptable salts thereof,

Formula I

comprises the steps of;
a.) condensing a substituted pyrimidine intermediate of formula II;

Formula II

wherein R is selected from , , and R1 is selected from hydrogen, straight or branched chain alkyl group preferably C1-C4. X is selected from halogen.
with amide intermediate of formula III,

Formula III
in the presence of a suitable base in a suitable organic solvent to obtain an acetonide protected amide compound of formula IV;

Formula IV
b.) converting acetonide protected amide compound of formula IV to rosuvastatin of formula I or pharmaceutically acceptable salts thereof.
2. The process as claimed in claim 1, wherein in step a) a suitable base is selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal alkoxide, amines, or mixtures thereof; in step a) a suitable organic solvent is selected from polar aprotic solvents, such as acetonitrile, dimethyl sulfoxide, dimethyl acetamide, dimethylformamide; aliphatic ethers such as C3-C8 ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,2-dimethylether, 1,2-diethylether; hydrocarbons such as benzene, toluene and xylene, or mixtures thereof.
3. The process as claimed in claim 1, wherein in step b) conversion of acetonide protected amide compound of formula IV to rosuvastatin of formula I or pharmaceutically acceptable salts thereof is carried out by comprising the steps of:
a.) deprotecting the acetonide protected amide compound of formula IV using a suitable acidic reagent to prepare dihydroxy amide intermediate of formula IVa;

Formula IVa

b.) hydrolyzing dihydroxy amide intermediate of formula IVa, to rosuvastatin of formula I or pharmaceutically acceptable salts thereof in presence of a suitable base in a suitable solvent.
4. The process as claimed in claim 1, wherein in step b) conversion of acetonide protected amide compound of formula IV to rosuvastatin of formula I or pharmaceutically acceptable salts thereof is carried out by comprising the steps of:
a.) deprotecting the acetonide protected amide compound of formula IV using a suitable acidic reagent to prepare dihydroxy amide intermediate of formula IVa;
b.) hydrolyzing dihydroxy amide intermediate of formula IVa, to rosuvastatin of formula I or pharmaceutically acceptable salts thereof in presence of a suitable base in a suitable solvent;
c.) treating the resulting compound with naphthylethylamine to obtain the rosuvastatin naphthylethylamine salt of formula V;

Formula V
d.) neutralizing rosuvastatin naphthylethylamine salt of formula V to rosuvastatin of formula I in presence of a suitable acid in a suitable solvent, and;
e.) converting it to its pharmaceutically acceptable salts.
5. The process as claimed in claims 3 and 4, wherein in step a) a suitable deprotecting reagent is selected from inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid; organic acid such as methane or ethane sulphonic acid, formic acid, acetic acid, trifluoroacetic acid.
6. The process as claimed in claims 3 and 4, wherein in step b) a suitable base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, tetraalkylammonium hydroxide such as tetrabutylammonium hydroxide, or mixtures thereof.
7. The process as claimed in claim 4, wherein in step d) a suitable acids is formic acid, acetic acid, propionic acid, butyric acid, hydrochloric acid, hydrobromic acid, phosphoric acid; in step d) a suitable solvent is selected from water or water immiscible organic solvents such as aliphatic esters; aliphatic ethers; hydrocarbons; halogenated solvents or mixtures thereof.
8. A process for the preparation of rosuvastatin of formula I or pharmaceutically acceptable salts thereof

Formula I

comprises the steps of:
a.) hydrolyzing hydroxy ester compound of formula IX using a suitable hydrolyzing agent in a solvent,

Formula IX
to obtain the hydroxy acid compound of formula X or salts thereof;

Formula X
b.) condensing the hydroxy compound of formula X with a-methyl benzyl amine in presence of a suitable reagent to obtain hydroxy amide compound of formula XI;

Formula XI
c.) oxidizing the hydroxy amide compound of formula XI in presence of a suitable oxidizing agent to obtain an amide intermediate of formula III;

Formula III
d.) converting an amide intermediate of formula III to rosuvastatin of
formula I or pharmaceutically acceptable salts thereof.
9. The process as claimed in claim 8, wherein in step a) the suitable hydrolyzing agent includes alkali or alkaline earth metal hydroxides; in step a) the solvent is selected from alcohol; alkyl nitriles; ethers; ketones or the like or mixtures thereof; in step b)suitable reagent is selected from N,N'-dicyclo hexylcarbodiimide, N,N'-diisopropylcarbodiimide, N,N'-carbonyl diimidazole, carbonyl-di-(1,2,4-triazole), l-hydroxybenzo triazole, 1-hydroxy-7-aza-benzotriazole, ethyl 2-cyano-2-(hydroxyimino) acetate, (benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluoro phosphate,benzotriazole-1-yl-oxy-tris-(dimethylamino) phosphoniumhexafluoro phosphate, N-hydroxysuccinimide and N-hydroxy-5-norbene-endo-2,3-dicarboxamide; in step c) the suitable oxidizing reagent is selected from sodium hypochlorite in the presence of potassium bromide, sodium bicarbonate and a catalytic amount of (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO).
10. A process for the preparation of rosuvastatin of formula I or pharmaceutically acceptable salts thereof

Formula I

comprises the steps of;
a.) condensing halo methyl pyrimidine compound of formula VI

Formula VI
wherein X refers to halogen; or any other leaving group,
with triazolyl thiol compound of formula VII,

Formula VII
wherein R1 is selected from hydrogen, straight or branched chain alkyl group,
in the presence of a suitable base in a suitable solvent to obtain triazolyl sulfanylmethyl pyrimidine compound of formula VIII;

Formula VIII
wherein R1 is as defined above
b.) oxidizing the resulting triazolyl sulfanylmethyl pyrimidine compound of formula VIII in presence of a suitable oxidizing agent to obtain triazolyl sulfonylmethyl pyrimidine compound of formula IIa.

Formula IIa
wherein R1 is as defined above.
c.)converting the resulting triazolyl sulfonylmethyl pyrimidine compound of formula IIa to rosuvastatin of formula I or pharmaceutically acceptable salts thereof.
Dated this 14th day of September, 2013
Dr. Asha Aggarwal,
Head-IPM Department,
Ind-Swift Laboratories Limited,
E-5,Phase-II, Industrial Area,
Mohali-160055,
Punjab, India