Field of the Invention:

The present invention relates to an improved process for the preparation of 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methyhnethylsulfonami(lo) pyrimidin-5 -yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)-N,N-disubstitutedacetamides represented by the following structural formula-1.

Wherein R and R' is independently selected from hydrogen, alkyl, aryl or aralkyl. The present invention also relates to novel crystalline forms of formula-la (wherein R is n-butyl and R' is H).

The compounds of general formula-1 are important intermediates in the preparation of rosuvastatin, a member of drug class of statins (HMG-CoA reductase inhibitors), used to treat high cholesterol and related conditions, and to prevent cardiovascular disease.

Background of the Invention:

The compound of formula-1 and its use in the preparation of rosuvastatin was first disclosed in WO 2008/44243. The disclosed process involves the condensation of N-(4-(4-fluorophenyl)-6-isopropyl-5-((1-methyl-1H-benzo[d]imidazol-2-ylsiilfonyl) methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide with N-butyl-2-((4R,6S)-6-formyl -2,2-dimethyl-l,3-dioxan-4-yl)acetamide and the condensed intermediate was hydrolyzed followed by treatment with calcium ion source to provide the rosuvastatin calcium. The said process is having disadvantage of formation of high level unwanted Z isomer upto 5% along with required E isomer. Hence there is a need in the art for an improved process which able to control the formation of the unwanted isomer.
The main objective of the present invention is to provide an improved process for the preparation of compound of formula-1 which restricts the formation of unwanted isomer and also provides the novel crystalline forms of compound of formula-la and its use.
Brief Description of the invention:
The first aspect of the invention is to provide an improved process for the preparation of 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl methylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)-N,N-disubstitutedacetamide compounds of general formula-1 containing low levels of unwanted Z-isomer, which comprises of reacting the N-(4-(4-fluorophenyl)-6-isopropyl-5((1 -methyl-1 H-benzo[d]imidazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methyl methane sulfonamide compound of formula-2 with aldehyde compound of formula-3 in presence of suitable alkali metal alkoxide base in a suitable solvent to provide the compound of formula-1.

The second aspect of the present invention is to provide an improved process for the preparation of rosuvastatin calcium compound of formula-4, which comprises of the following steps

a)Treating the N-butyl-2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl) acetamide compound of formula-la with suitable organic acid in a suitable solvent to provide the dihydroxy compound of formula-5,

b) optionally purifying the compound of formula-5 using suitable solvent provides the highly pure compoimd of formula-S,

c) hydrolyzing the compound of formula-5 with suitable base in a suitable solvent provide the corresponding salt of rosuvastatin, which on in-situ treatment with a suitable calciimi source provides the rosuvastatin calcium compound of formula-4.

The third aspect of the present invention is to provide novel crystalline forms namely form I, form II & form III of N-butyl-2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetamide compound of formula-la, process for preparation and their use.

The fourth aspect of the present invention is to provide a novel crystalline form of (3R,5S,E)-N-butyl-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-yl)-3,5-dihydroxyhept-6-enamide compound of formula-5, process for its preparation and its use.
Detailed Description of the invention:
As used herein the present invention, the term "suitable solvent" refers to the solvent selected from "polar solvents" such as water; "polar aprotic solvents" such as dimethylsulfoxide, dimethylacetamide, dimethyl formamide and tetrahydrofuran; nitrile solvents such as acetonitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol and n-butanol and the like; "chloro solvents" such as methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform and the like; "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like; "esters solvents" such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; and their mixtures thereof.
As used herein the term "alkyl" refers to a straight or branched or cyclic C1 to C6 alkyl, including methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, cyclopentyl, n-hexyl, and isohexyl and the like. Further, the alkyl may be substituted by 1 to 3 substituents independently selected from the group consisting of halogen, amino, hydroxy and cyano. Halogen means fluorine chlorine, bromine and iodine.
As used herein the term "aryl" refers to C6-C12 aromatic group include phenyl, tolyl, xylyl, biphenyl, naphthyl and the like. The aryl may have 1 to 3 substituents independently selected from the group consisting of lower alkyl, halogen, amino, cyano, hydroxy.

As used herein the term "aralkyl" refers to C1-C6 lower alkyl substituted by C6-C12 aromatic aryl group defined above. For example are benzyl, phenylethyl, phenylpropyl and the like each of which may have 1 to 3 substituents independently selected from the group consisting of alkyl, halogen, amino, cyano, hydroxy and the like

Accordingly the first aspect of the invention provides a process for the preparation of 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)-N,N-disubstitutedacetamide compounds of general formula-1 containing low levels of unwanted Z-isomer, wherein R and R' is independently selected from hydrogen, alkyl, aryl or aralkyl. which comprises of reacting the N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-IH-benzo[d]imidazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide compound of fonnula-2 with aldehyde compounds of general formula-3 wherein R and R' is independently selected from hydrogen, alkyl, aryl or aralkyl. in presence of suitable alkali metal alkoxide base selected from sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide, or mixtures thereof in a suitable solvent selected from polar aprotic solvents, alcohols, hydrocarbons, polar solvent or mixtures thereof to provide the compound of formula-1.

According to the present invention the alkali metal alkoxide base used in the ratio of 0.8 to 2.5 moles with respect to N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-IH-benzo[d]imidazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide compound of formula-2 and the condensation reaction is carried out at -30°C to 70°C, preferably at -20 to 25°C.

The compound of formula-1 prepared as per the process disclosed in WO 2007/125547 via Julia olefination provides the formula-1 with E/Z isomer content in the ratio of 95:5. Even though the process reduces the Z isomer content, still its content is considerably high as the condensation reaction takes place in presence of potassium carbonate at 70-75°C, it leads to the degradation of starting material and decrease in the yields and purity. The same has been avoided in the preparation of compound of formula-1, by replacing the potassium carbonate with alkali metal alkoxide and carrying out the reaction at lower temperature, which avoids the degradation of starting material and provides the final compound with high purity and low Z isomer content. It was possible to bring down the Z isomer content to less than 0.1 %.
The compound of formula-1 prepared as per the present invention is having the E/Z isomer content in the ratio 97:3, preferably 99:1; more preferably 99.9:0.1. When the same compound of formula-1 used in the preparation of rosuvastatin or its pharmaceutically acceptable salts, it provided product containing low levels of unwanted isomer i.e., E/Z isomer are in the ratio of 99:1 and preferably 99.9:0.1. Hence the process provides product with higher purity and greater yields.
In a preferred embodiment, the present invention provides a process for the preparation of N-butyl-2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyI)-6-isopropyl-2-(N-methyl
methylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetamide compound of formula-1 a, which comprise of reacting the N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-IH-benzo[d]imidazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide compound of fonnula-2 with N-butyl-2-((4R,6S)-6-formyl-2,2-dimethyl-l, 3-dioxan-4-yl) acetamide compound of formula-3a in presence of sodium or potassium tertiary butoxide, preferably sodium tertiary butoxide in a suitable polar aprotic solvent, preferably tetrahydrofuran to provide the compound of formula-la.

The second aspect of the present invention provides an improved process for the preparation of rosuvastatin calcium compound of formula-4
which comprises of the following steps;

a) Treating the N-butyl-2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-
methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)
acetamide compound of formula-la with suitable organic acid such as oxalic acid in a
suitable alcoholic solvent like methanol, ethanol, isopropanol, butanol or mixtures
thereof, preferably methanol to provide the dihydroxy compound of formula-5,

b) optionally purifying the compound of formula-5 using suitable solvent selected from aromatic hydrocarbon like toluene, heptane, hexane or cyclohexane; nitrile solvent like acetonitrile or mixtures thereof provides the high pure compound of formula-5,

c) hydrolyzing the compoimd of formula-S with suitable alkali metal hydroxide base like sodium hydroxide in a suitable alcoholic solvent like isopropyl alcohol provides the rosuvastatin sodium, which on in-situ treatment with aqueous calcium acetate solution provides the rosuvastatin calcium compound of formula-4.
The third aspect of the present invention provides novel crystalline forms of N-butyl-2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethyl sulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l ,3-dioxan-4-yl)acetamide compound of formula-la. The novel crystalline forms of formula-la of the present invention are herein designated as Form-I, Form-II and Form-Ill.

The novel crystalline form I of formula-la of the present invention is characterized by its powder X-ray diffractogram having peaks at about 5.56, 7.47, 8.40, 9.78,14.75, 16.80, 17.46, 18.72,20.05,21.13,21.70,23.13,25.57, 31.68 & 45.35 ± 0.2 degrees 20.

The novel crystalline form II of formula-la of the present invention is characterized by its powder X-ray diffractogram peaks at about 3,74, 7.37, 8,17, 14.69,15.05, 17.25, 17.75, 18.42, 18.77, 19.20, 20.59, 22.42, 22.69, 23.67 & 28.01 ± 0.2 degrees 20.

The novel crystalline form III of formula-la of the present invention is characterized by its powder X-ray diffractogram having peaks at about 8.43, 9.58, 9.89, 14.65, 15.18, 16.76, 17.43, 18.75, 19.26, 19.90, 20.21, 21.11, 21.63, 22.30, 25.45 & 27.93 ± 0.2 degrees 29.

The novel crystalline form I, II and III of formula-la of the present invention are used to prepare highly pure rosuvastatin, its pharmaceutically acceptable salts and its intermediate such as formula-5.

Further the present invention provides a process for the preparation of crystalline form I of formula-la, which comprises of following steps;
a) dissolving the compound of formula-1 a in suitable hydrocarbon solvent,
b) concentrating the reaction mixture followed by co-distillation with cyclohexane,
c) adding suitable ether or alcohol solvent to the obtained residue,
d) stirring the reaction mixture,
e) filtering the solid and washing with suitable ether or alcohol solvent.
f) drying the solid to get the crystalline form I of formula-la.
In a preferred embodiment, a process for the preparation of crystalline form I of formula-la comprises of the following steps;
g) dissolving the compound of formula-1 a in toluene,
h) concentrating the reaction mixture followed by co-distillation with cyclohexane,
i) adding diisopropylether to the residue,
j) stirring the reaction mixture,
k) filtering the solid and washing with diisopropylether,
1) drying the solid to get the crystalline form I of formula-1 a.
The present invention also provides a process for the preparation of crystalline form II of formula-la, which comprises of the following steps,
a) dissolving the compound of formula-1 a in suitable hydrocarbon solvent.
b) concentrating the reaction mixture followed by co-distillation with cyclohexane,
c) adding cyclohexane to the residue,
d) stirring the reaction mixture,
e) filtering the solid and washing with cyclohexane,
f) drying the solid to get the crystalline form II of formula-la.
In a preferred embodiment, a process for the preparation of crystalline form II of formula-la comprises of the following steps,
g) dissolving the compound of formula-1 a in toluene,
h) concentrating the reaction mixture followed by co-distillation with cyclohexane,
i) adding cyclohexane to the residue,
j) stirring the reaction mixture,
k) filtering the solid and washing with cyclohexane,
1) drying the solid to get the crystalline form II of formula-1 a.
Further the present invention provides a process for the preparation of crystalline form III of formula-la, which comprises of the following steps;
a) dissolving the compound of formula-1 a in a suitable alcohol solvent,
b) adding water the above solution,
c) filtering the solid and washing with water,
d) drying the solid to get the crystalline form III of formula-la.
In a preferred embodiment, a process for the preparation of crystalline form III of formula-la comprises of the following steps;
a) dissolving the compound offormula-la in methanol,
b) adding water the above solution,
c) filtering the solid and washing with water,
d) drying the solid to get the crystalline form III offormula-la.
According to the present invention the term ether solvent refers to the solvent selected fi-om di-tert-butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether and tetrahydrofuran or mixtures thereof; the term
"hydrocarbon solvent" refers to the solvent selected from toluene, xylene, hexane, heptane and cyclohexane or mixtures thereof; the term "alcohol solvent" refers to the solvent selected form methanol, ethanol, isopropanol, butanol or mixtures thereof; the term "nitrile solvent" refers to acetonitrile,
The third aspect of the present invention provides a novel crystalline form of (3R,5S,E)-N-butyl-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-yl)-3,5-dihydroxyhept-6-enamide compound of formula-5
The novel crystalline form of formula-5 of the present invention is characterized by its powder X-ray diffractograra peaks at about 3.88,7.49,7.75,9.27,10.58,14.58, 15.58,18.54,19.02,19.38,19.88,22.24,24.06 & 28.12 ± 0.2 degrees 20.
The novel crystalline form of formula-5 of the present invention is used to prepare highly pure rosuvastatin and its pharmaceutically acceptable salts.
The present invention further provides a process for the preparation of novel crystalline form of formula-5 of the present invention, which comprises of the following steps,
a) dissolving the compound of formula-5 in a suitable hydrocarbon solvent by heating to reflux temperature,
b) cooling the reaction mixture to 0-5°C and stirring the reaction mixture,
c) filtering the solid and washing with suitable hydrocarbon solvent,
d) dissolving the obtained solid in a suitable solvent selected from hydrocarbon solvent, nitrile solvent or mixture thereof at reflux temperature,
e) cooling the reaction mixture and stirring,
f) filtering the solid and washing with hydrocarbon solvent,
g) drying the solid to get the crystalline form of fonnula-5.
In a preferred embodiment, process for the preparation of novel crystalline form of formula-5 comprises of the following steps,
a) dissolving the compound of formula-5 in toluene by heating to reflux temperature,
b) cooling the reaction mixture to 0-5°C and stirring the reaction mixture,
c) filtering the solid and washing with toluene,
d) dissolving the obtained solid in a mixture of toluene and acetonitrile at reflux temperature,
e) cooling the reaction mixture and stirring,
f) filtering the solid and washing with toluene,
g) drying the solid to get the crystalline form of formula-5.
As used herein the term "highly pure" refers to the compound with purity greater than 99.00 % by HPLC, preferably greater than 99.50 % by HPLC and more preferably greater than 99.90% by HPLC.
Related substances and E and Z isomer content of compound of formula-1 and la was analyzed by High Performance Liquid Chromatography using the following conditions:
Apparatus: A liquid chromatography is equipped with variable wavelength integrator and detector; Column: Lichrosphere; 250X4.0mm, 5jim or equivalent; Flow rate: 1.0 ml/min; Wavelength: 242 nm; Temperature: ambient; Load: 20 |il and using mixture of acetonitrile and water in ratio of 80:20 as a diluent. Mixture of aqueous dihydrogen ortho phosphate buffer and acetonitrile as a mobile phase.
The present invention is schematically represented by the following scheme.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples:
Example-1: Preparation of N-butyI-2-((4R,6S)-6-((E)-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)~2,2-dimethyM3-dioxan-4-yl) acetamide of formula-la:

Sodium tertiarybutoxide (3 grams) was added to a mixture of N-(4-(4-fluorophenyl)-6-isopropyl-5-(l-methyl-lH-benzo[£flimidazol-2-ylsulfonyl)pyrimidin-2-yl)-N-methylmethane sulfonamide (15.5 grams) in tetrahydrofuran (40 ml) at -20 to -15°C and this mixture was added to a solution of N-butyl-2-(4R,6R)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetamide in tetrahydrofuran (10 gm) at -20 to -15°C and stirred. After the completion of reaction, quenched it will sodium bicarbonate solution and stirred for 10 minutes at 5-10°C. The reaction mixture temperature was raised to 25-35°C and stirred for 4 hours. The solid obtained was filtered, washed with water and then dried to get the title compound. Yield: 15 grams
Example-2: Preparation of N-butyl-2-((4R,6S)-6-((E)-(4-(4-fluorophenyl)-6-
isopropyl-2-(N-methylmethyIsulfonamido)pyrimidin-5-yl)yinyl)-2^-dimethyl-13-dioxan-4-yl) acetamide of formula-la:

Sodium tertiarybutoxide (4.28 grams) was added to a mixture of N-(4-(4-fluorophenyl)-6-isopropyl-5-(l-methyl-lH-benzo[d]limidazol-2-ylsulfonyl)pyrimidin-2-yl)-N-methylmethane sulfonamide (15.5 grams) in tetrahydrofuran (40 ml) at -20 to -15°C and this mixture was added to a solution of N-butyl-2-(4R,6R)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetamide in tetrahydrofuran (10 gm) at -20 to -15°C and stirred. After the completion of reaction, quenched it will sodium bicarbonate solution and stirred for 10 minutes at 5-10°C. The reaction mixture temperature was raised to RT and stirred for 30 minutes. Sodium chloride solution (50 ml) was added to it and extracted the reaction mixture into toluene (80 ml) and stirred for 45 minutes at 0-5°C. The reaction mixture was filtered and washed with toluene. The filtrate was slurried with

silicagel and filtered. Distilled off the filtrate completely followed by co-distillation with
cyclohexane. Diisopropylether (20 ml) was added to the obtained residue and stirred for
30 minutes at 25-30°C. The solid was filtered, washed with diisopropylther and dried to
get the title compound.
Yield: 10 grams
Purity by HPLC: 99.24%; 0.2% (Z isomer)
ExampIe-3: Preparation of N-butyl-2-((4R,6S)-6-((E)-(4-(4-fluorophenyl)-6-
i$opropyl-2-(N-methylmethylsiilfonamido)pyrimidin-5-yl)yinyl)-2,2-diniethyl-13-dioxaii-4-yl) acetamide of formula-la:

Sodium tertiarybutoxide (4.28 grams) was added to a mixture of N-(4-(4-fluorophenyl)-6-isopropyl-5-(l-methyl-lH-benzo[d]imidazol-2-ylsulfonyl)pyrimidin-2-yl)-N-methylmethane sulfonamide (15.5 grams) in tetrahydrofuran (40 ml) at -20 to -15°C and this mixture was added to a solution of N-butyl-2-(4R,6R)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yI)acetamide in tetrahydrofiiran (10 gm) at -20 to -15°C and stirred. After the completion of reaction, quenched it will chilled water and stirred for 10 minutes at 5-10''C. The reaction mixture temperature was raised to 25-35°C and stirred for 30 minutes. Sodium chloride solution (50 ml) was added to it and extracted the reaction mixture into toluene (80 ml) and stirred for 45 minutes at 0-5°C. The reaction mixture was filtered and washed with toluene. The filtrate was slurried with silicagel and filtered. Distilled off the filtrate completely followed by codistiUation with cyclohexane. Diisopropylether (20 ml) was added to the obtained residue and stirred for 30 minutes at 25-30°C. The solid was filtered, washed with diisopropylther and dried to get the title compound. Yield: 10 grams
ExampIe-4: Preparation of N-butyl-2-((4R,6S)-6-((E)-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonaniido)pyrimidin-5-yI)vinyl)-2,2-dimethyl-13-dioxan-4-yl) acetamide of formula-la:
The title compoimd is prepared in a similar maimer to example-2 except that the final compound is isolated from methanol instead of diisopropylether. Yield: 9.5 grams

Exmaple-5: Preparation of (3R,5S,E)-N-butyl-7-(4-(4-fluorophenyl)-6-isopropyI-2-(N-methylinethylsulfonamido)pyrimidiii-5-yl)-3,5-dihydroxyhept-6-enamide compound of formula-5:

Oxalic acid (42.0 grams in 420 ml of water) was added to N-butyl-2-((4R,6S)-6-
((E)-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-
yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl) acetamide (175 grams) in methanol (890 ml) at 45-50°C and stirred at 45-50''C. After completion of the reaction the reaction mixture was cooled to 5-10°C and quenched with aqueous ammonia solution. The reaction mixture temperature was adjusted to 25-30°C and water was added to it and stirred for 3 hour. The solid obtained was filtered, washed with water and dried to get the title compound. Yield: 155 grams
£xmaple-6: Purification of (3R,5S,E)-N-butyl-7-(4-(4-!luorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyriniidin-5-yl)-3,5-dlhydroxyhept-6-eiiamide compound of formula-5:
Compound of formula-5 (140 grams) obtained in example-2 was dissolved toluene (980 ml) at 70-75°'C. The reaction mixture was slowly cooled to 0-5°C and stirred for 3 hours. The solid obtained was filtered and washed with toluene. The obtained wet solid was dissolved in a mixture of toluene (880 ml) and acetonitrile (22 ml) at 70-75°C. The reaction mixture was slowly cooled to 0-5°C and stirred for 3 hours. The obtained solid was filtered, washed with toluene and then dried to get the title compound. The PXRD of obtained solid was shown in Figure-4. Yield: 126 grams
Example-7: Preparation of rosuvastatin calcium:
A mixture of (3R,5S,E)-N-butyl-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl methylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enamide of formula-5 (25 grams), isopropyl alcohol (125 ml), aqueous sodium hydroxide (7.5 grams in 75 ml of water) was heated to reflux temperature and stirred at reflux upto completion of the reaction. After completion, the reaction mixture was cooled to 25-30''C and both organic and aqueous layer was separated. Organic layer was subjected to carbon treatment then

filtered through hyflow and washed with isopropylalcohol. The organic layer was distilled off completely under reduced pressure and the obtained residue was cooled to 25-30°C and water (125 ml) was added to it. The reaction mixture was washed with tertiary butyl acetate. The pH of the reaction mixture was adjusted to 9.2 to with aqueous hydrochloric acid and expel the reaction mixture. The reaction mixture was filtered through filter paper and calcium acetate solution (4.62 grams in 100 ml of water) at 35-40°C and stirred for 30 minutes. The reaction mixture was cooled to 30-35°C and stirred for 45 minutes. The solid was filtered, washed with water and then dried at 35-40°C to get the title compound. Yield: 20 grams
Example-8: Preparation of rosuvastatin calcium:

A mixture of (3R,5S,E)-N-butyl-7-(4-(4-fluorophenyl)-6-isopropyI-2-(N-methyl methylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enamide of formula-S (25 grams), isopropyl alcohol (125 ml), aqueous sodium hydroxide (7.5 grams in 75 ml of water) was heated to reflux temperature and stirred at reflux upto completion of the reaction. After completion, the reaction mixture was cooled to 25-30°C and both organic and aqueous layer was separated. Organic layer was subjected to carbon treatment then filtered through hyflow and washed with isopropylalcohol. The organic layer was distilled off completely under reduced pressure and the obtained residue was cooled to 25-30°C and water (125 ml) was added to it. The reaction mixture was washed with tertiary butyl acetate. The pH of the reaction mixture was adjusted to 9.1 to with aqueous hydrochloric acid and expel the reaction mixture. The reaction mixture was filtered through filter paper and calcium acetate solution (4.1 grams in 100 ml of water) at 25-29°C and stirred for 60 minutes. The solid was filtered, washed with water and then dried at 35-40°C to get the title compound. Yield: 19.5 grams
Example-9: Preparation of crystalline form I of formuki-la:
Sodium tertiarybutoxide (3 grams) was added to a mixture of N-(4-(4-fluorophenyl)-6-isopropyl-5-(l-methyl-lH-benzo[d]|imidazol-2-ylsulfonyl)pyrimidin-2-yl)-N-methylmethane sulfonamide (15.5 grams) in tetrahydrofuran (40 ml) at -20 to

-15°C and this mixture was added to a solution of N-butyl-2-(4R,6R)-6-formyl-2,2-dimethyl-l,3-dioxaii-4-yl)acetamide (lOgm) in tetrahydrofuran at -20 to -15°C and stirred. After the completion of reaction, quenched it will sodium bicarbonate solution and stirred for 10 minutes at 5-10°C. The reaction mixture temperature was raised to RT and stirred for 4 hours. The solid obtained was filtered and washed with water. The wet solid was dissolved in toluene (30 ml) and distilled off under reduced pressure. Cyclohexane was added and co-distilled the solvent completely under reduced pressure. Diisopropyl ether (50ml) was added to the obtained residue and stirred for an hour 25-35°C. The solid obtained was filtered, washed with diisopropylether and then dried to get the crystalline compoimd of formula-la. Yield: 12.5 grams
Example-10: Preparation of crystalline form II of formula-la:
The compound of formula-la (10 gm) obtained as per example-1 was dissolved in toluene (50ml). The solvent from the reaction mixture was distilled off under reduced pressure followed by co-distillation with cyclohexane. Cyclohexane (75ml) was added to the obtained residue and stirred for an hour at 25-30°C. The solid obtained was filtered, washed with cyclohexane and dried to get the crystalline form II of formula-la. Yield: 8.5 grams
ExampIe-11: Preparation of crystalline form III of formula-la:
The crystalline form I of formula-la (lOgm) was dissolved in methanol (50ml) and stirred for 10 minutes. Water (50 ml) was added to reaction mixture. The obtained solid was filtered at 25-30°C, washed with water and then dried to get the crystalline form III of formula-la. Yield: 8 grams
Example-12: Preparation of N-butyl-2-((4R,6S)-6-((E)-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l^-dioxan-4-yl) acetamide of formula-la:
Sodium tertiarybutoxide (4.28 grams) was added to a mixture of N-(4-(4-fluorophenyl)-6-isopropyl-5-(l-methyl-lH-benzo[d]imidazol-2-ylsulfonyl)pyrimidin-2-

yl)-N-methylmethane sulfonamide (15.5 grams) in tetrahydrofuran (40 ml) at -20 to -15°C and this mixture was added to a solution of N-butyl-2-(4R,6R)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetamide in tetrahydrofuran (10 gm) at -20 to -15°C and stirred. After the completion of reaction, reaction mixture was added to chilled water and stirred for 10 minutes at 5-10°C. Toluene (50 ml) was added to the reaction mixture temperature and organic layer was separated. The organic layer containing product was washed with sodium chloride solution and then distilled off the solvent from the organic layer under reduced pressure. Toluene (50 ml) was added to the residue, stirred and then filtered. The filtrate was slurried with silicagel and filtered. Distilled off the filtrate completely followed by co-distillation with cyclohexane. Diisopropylether (50 ml) was added to the obtained residue and stirred for 2 hours at 25-30°C. The solid was filtered, washed with diisopropylther and dried to get the title compound. Yield: 9 grams Purity by HPLC: 99.27%; 0.15% (Z isomer)

We claim:

1. A process for the preparation of 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl) -N,N-disubstitutedacetamide compounds of general formula-1 containing low level of unwanted Z-isomer,wherein R and R' is independently selected from hydrogen, alkyl, aryl or aralkyl which comprises of reacting the N-(4-(4-fluorophenyl) -6-isopropyl-5((l-methyl-IH-benzo[d]imidazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-2
with aldehyde compounds of general formula-3
wherein R and R' is independently selected from hydrogen, alkyl, aryl or aralkyl. in presence of suitable alkali metal alkoxide base selected from sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide, or mixtures thereof in a suitable solvent selected from polar aprotic solvents, alcohols, hydrocarbons, polar solvent to provide the compound of formula-l, characterized in that the alkoxide base is used in the ratio of 0.8 to 2.5 moles with respect to N-(4-(4-fluorophenyl)-6-isopropyl-5(( 1 -methyl-1 H-benzo[d]imida2ol-2-ylsulfonyl)methyl) pyrimidin-2-yl)-N-methylmethane sulfonamide compound of fonnula-2 and the reaction is carried out at a temperature ranges from -20°C to 40°C.

2. A process for the preparation of N-butyl-2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetaraide compound of formula-la, having E/Z content in the ratio of 98:2, preferably 99:1 and more preferably 99.9:0.1, which comprise of reacting the N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-lH-benzo[d]imidazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-2 with N-butyl-2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetamide compound of formula-3a in presence of soammor potassium ternary ouioxiae n a suitable polar aprotic solvent to provide the compound of formula-la, characterized in that the alkoxide base is used in the ratio of 0.8 to 2.5 moles with respect N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-lH-benzo[d]imidazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methyl methane sulfonamide compound of formula-2 and the reaction is carried out at a temperature ranges from -20°C to 40°C.

3. Novel crystalline form-I of N-butyl-2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-
isopropyl -2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetamide compound of fonnula-la characterized by its powder X-ray dif&actogram having peaks at about 5.56,7.47. 8.40. 9.78,14.75,16.80,17.46, 18.72, 20.05,21.13, 21.70,23.13,25.57,31.68 & 45.35 ± 0.2 degrees 29.

4. Novel crystalline form-II of N-butyl-2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetamide compound of formula-la characterized by its powder X-ray diffractogram having peaks at about 3.74, 7.37, 8.17, 14.69, 15.05, 17.25, 17.75, 18.42,18.77,19.20,20.59,22.42,22.69,23.67 & 28.01 ± 0.2 degrees 29.

5. A process for preparation of crystalline forms of formula-la claimed according to claim 3 & 4 prepared by any of the following processes,

a) dissolving the compound of formula-1 a in toluene,

b) concentrating the reaction mixture followed by co-distillation with cyclohexane,

c) adding diisopropylether to the residue,

d) stirring the reaction mixture,

e) filtering the solid and washing with diisopropylether,

f) drying the solid to get the crystalline form of formula-1 a.

(or)

a) dissolving the compound of formula-1 a in toluene,

b) concentrating the reaction mixture followed by co-distillation with cyclohexane,

c) adding cyclohexane to the residue,

d) stirring the reaction mixture,

e) filtering the solid and washing with cyclohexane,

f) drying the solid to get the crystalline form of formula-1 a.

6. Novel crystalline form-Ill of N-butyl-2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-
isopropyl -2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetamide compound of formula-la characterized by its powder X-ray diffractogram having peaks at about 5.56, 8.43, 9.58,9.89,14.65, 15.18, 16.76, 17.43, 18.75,19.26,19.90,20.21, 21.11, 21.63,22.30,25.45 & 27.93 ± 0.2 degrees 29.

7. A process for preparation of crystalline form of formula-la claimed according to claim-6, which comprises of the following steps,

a) dissolving the compound of formula-la in a suitable alcohol solvent like methanol, ethanol, isopropanol and butanol or mixtures thereof,

b) adding water the above solution,

c) filtering the solid and washing with water,

d) drying the solid to get the crystalline form III of formula-la.

8. Novel crystalline form of (3R,5S,E)-N-butyl-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-yl)-3,5-dihydroxyhept-6-enamide compound of formula-5 characterized by its powder X-ray dif&actogram peaks at about 3.88, 7.49, 7.75, 9.27, 10.58, 14.58, 15.58, 18.54, 19.02, 19.38, 19.88, 22.24, 24.06 & 28.12 ±0.2 degrees 29.

9. A process for the preparation of novel crystalline form of formula-5 claimed according to claim 7, which comprises of the following steps,

a) dissolving the compound of formula-5 in a suitable hydrocarbon solvent by heating to reflux temperature,

b) cooling the reaction mixture to 0-5°C and stirring the reaction mixture,

c) filtering the solid and washing with suitable hydrocarbon solvent,

d) dissolving the obtained solid in a suitable solvent selected from hydrocarbon solvent, nitrile solvent or mixture thereof at reflux temperature,

e) cooling the reaction mixture and stirring,

f) filtering the solid and washing with hydrocarbon solvent,

g) drying the solid to get the crystalline form of formula-5.

10. An improved process for the preparation of rosuvastatin calcium compound of formula-4

which comprises of the following steps

a) Treating the N-butyl-2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl methylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-(iimethyl-l,3-dioxan-4-yl) acetamide compound of formula-la with suitable organic acid such as oxalic acid in a suitable alcoholic solvent like methanol, ethanol, isopropanol, butanol or mixtures thereof to provide the dihydroxy compound of formula-S,

b) optionally purifying the compound of formula-5 using suitable solvent selected from aromatic hydrocarbon like toluene, heptane, hexane or cyclohexane; nitrile solvent like acetonitrile and mixtures thereof provides the highly pure compound of formula-5,

c) hydrolyzing the compound of formula-5 with suitable alkali metal hydroxide base like sodium hydroxide in a suitable alcoholic solvent like isopropyl alcohol provides the rosuvastatin sodium, which on in-situ treatment vsith aqueous calcium acetate solution provides the rosuvastatin calcium compound of formula-4.