Field of the Invention:
The present invention relates to an improved process for the preparation of dihydroxy protected derivatives represented by the following structural formula-1.

Wherein R is selected from alkyl or aryl.
Dihydroxy protected 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 (wherein R is (CH3)3) and its use in the preparation of rosuvastatin was first disclosed in US 6784171. The disclosed process involves the condensation of diphenyl [4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methyl sulfonyl) amino]pyrimidin-5-ylmethyl]phosphine with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl]acetate in presence of sodiumbis(trimethylsilyl)amide to provide tert-butyl (E)-(6- {2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl) amino]pyrimidin-5-yl}(4R,6S)-2,2-dimethyl[l,3]dioxan-4-yl)acetate. The condensed protected compound is deprotected with acid and hydrolyzed with base followed by treatment with calcium ion source to provide the rosuvastatin calcium.
International publication WO 2005/054207 disclosed a process for the preparation of compound of formula-1 (wherein R is (CH3)3), which involves the condensation of triphenyl[4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl) amino] pyrimidin-5-ylmethyljphosphonium bromide with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dixan-4-yl}acetate in presence of potassium carbonate in dimethyl sulfoxide to give

tert-butyI(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl}(4R,6S)-2,2-dimethyl[l,3]dioxin-4-yl) acetate which is fimher converted into free acid then to calcium salt by contacting with calcium source.
In general, the disclosed process for the preparation of rosuvastatin and its pharmaceutically acceptable salts proceeds through the compound of formula-1 and involves the usage of different bases like alkalimetal hydroxide, alkali metal carbonates and amides. The above process is having a disadvantage of formation of high level unwanted Z isomer along with required E isomer. Hence there is a need in the art for an improved process which controls the formation of unwanted Z isomer.
When the present inventor were working on to solve this problem by varying the process parameters and regents it was surprisingly foimd that the usage of alkali metal alkoxide for the preparation of condensed compound of formula-1, provided the product with less amount of unwianted Z isomer. Hence when the same has been used to produce the rosuvastatin it led to formation of highly pure rosuvastatin and its pharmaceutically acceptable salts.
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 which is obtained in the prior art.
Brief Description of the invention:
The first aspect of the present invention is to provide an improved process for the preparation of dihydroxy protected derivative compound of formula-1 with low levels of unwanted Z-isomer, which comprises of reacting the 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 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 one-pot process for the preparation of N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-lH-benzo[d]imidazol-2-yl

sulfonyl)methyl)pyrimidin-2-yl)-N-methyl methane sulfonamide compound of fonnula-2, which comprises of oxidizing the sulfide compound of fomula-6 with a suitable oxidizing agent in presence of a catalyst in a suitable solvent to provide the sulfone compound of formula-?, which on in-situ reaction with a suitable methylating agent provides the compound of fonnula-2.
The third aspect of the present invention is to provide one-pot process for the preparation of compound of fonnula-6, which comprises of reacting N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-4 with suitable brominating agent in a suitable solvent to provide the N-(5-(bromomethyl)-4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-5, which on in-situ reaction with lH-benzo[d]imidazole-2-thiol in presence of a base and a solvent to provide the compound of formula-6.
Detailed Description of the invention:
As used herein the presented invention, the term "suitable solvent" refers to the solvents 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
Accordingly the first aspect of the invention provides a process for the preparation of dihydroxy protected derivative compounds of general formula-1


Wherein R is selected from alkyl or aryl;
with low level of unwanted Z-isomer, which comprises of reacting the N-(4-(4-
fluorophenyl)-6-isopropyl-5((l-methyl-lH-benzo[d]imidazol-2-ylsulfonyl)me%l)
pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-2

Wherein R is selected from alkyl or aryl;
in presence of suitable alkali metal alkoxide base selected fix)m 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 with low level of Z isomer.
According to the present invention the alkoxide base used in the ratio of 0.8 to 2.3 moles with respect to N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-IH-

benzo[d]imidazol-2-ylsulfonyl)me%l)pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-2 and the condensation reaction is carried out at -SCC to 70°C, preferably at -20 to 5°C.
Even though number of process reported for the preparation of compounds of formula-1, the E/Z isomers ratio is not satisfactory. In general, the compound of formula-1 prepared as per the prior art have the E and Z isomers ratio of 70:30. For example when compound of formula-1 (wherein R is alkyl) prepared as per the process disclosed in WO 2005/054207 is having E/Z isomers in the ratio of 75:25.
The compound of formula-1 prepared as per the process disclosed in WO 2007/125547 via Julia ole&iation 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 the Z isomer content is high and more over the condensation reaction take place in presence of potassium carbonate at 70-75''C, led to the degradation of starting material and decrease the yields and purity. The same has been avoided by the present inventors in the preparation of compound of formula-1, by replacing the potassium carbonate with alkali metal alkoxide and carrying out the reaction at low temperature, which avoids the degradation of starting material and provides the final compound with high purity and low Z isomer content. Hence the process provides the product with higher purity and greater yields. It was possible to bring down the Z isomer content to less than 0.1% by using alkali metal alkoxide bases.
The compound of formula-1 prepared as per the present invention having the E/Z isomer content in the ratio of 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 will leads to the rosuvastatm or its salt with low levels of unwanted isomer i.e., E/Z isomer in the ratio of 99:1 and preferably 99.9:0.1.
In a preferred embodiment, the present invention provides a process for the preparation of tert-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)acetate compound of formula-1 a.


which comprise of reacting the compound of formula-2 with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yI]acetate compound of fonnula-3a

in presence of sodium or potassixim tertiary butoxide, more preferably sodium tertiary butoxide in a suitable polar aprotic solvent, more preferably tetrahydrofuran to provide the compound of formula-la.
Further the present invention provides the use of alkali metal alkoxide bases to improve the E/Z isomer ratio in the condensation reaction between the N-(4-(4-fluorophenyl)-6-isopropyl-5(( 1 -methyl-1 H-benzo[d]imidazol-2-ylsulfonyl)methyl) pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-2 and aldehyde compounds of general formula-3.
The second aspect of the present invention provides a one pot process for the preparation of N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-lH-benzo[d]imida2ol-2-yl sulfonyl)methyl)pyrimidin-2-yl)-N-methyl methane sulfonamide compound of formula-2.



with a suitable oxidizing agent like metachloro perbenzoicacid, sodium hypochlorite, hydrogen peroxide, tertiary butyl hydrogen peroxide, cumene hydro peroxide, in the presence of an appropriate catalyst like ammonium hepta molybdate tetrahydrate in a suitable solvent selected ftom alcoholic solvents like chloro solvents or mixture thereof, to provide the sulfone compound of formula-7,

which on in-situ reaction with a suitable methylating agent like dimethyl sulfate in presence of a suitable base selected from alkali metal hydroxides in a suitable solvent selected from chloro solvents to provide the compound of formula-2.
In a preferred embodiment, one pot process for the preparation of N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-lH-benzo[d]miidazol-2-ylsulfonyl)raethyl) pyrimidin-2-yl)-N-methyl methane sulfonamide compound of formula-2, which comprises of oxidizing the sulfide compound of fomula-6 with hydrogen peroxide in presence of anunonium hepta molybdate tetrahydrate in methylene chloride to provide the sulfone compound of formula-7, which on in-situ reaction with a dimethyl sulfate in presence of a suitable base selected from alkali metal hydroxides in a suitable solvent selected from chloro solvents to provide the compound of formula-2.

The third aspect of the present invention provides a one-pot process for the preparation of N-(5-((lH-benzo[d]imidazol-2-ylthio)methyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methyhnethanesulfonamide compound of fonnula-6,

which comprises of reacting N-(4-(4-flurophenyl)-5-(hydroxymethyl)-6-isopropyl pyrimidin-2-yl)-N-methyhnethane sulfonamide compound of formula-4

with suitable brominating agent selected from phosphorus tribromide in a suitable solvent selected from chloro solvent to provide the N-(5-(bromomethyl)-4-(4-fluorophneyl)-6-isopropyl pyrimidin-2-yl)-N-methyUnethane sulfonamide compound of formula-5,

which on in-situ reaction with lH-benzo[d]imidazole-2-thiol in presence of a suitable base selected from alkali metal hydroxide like sodium hydroxide and a solvent selected

from ketone, chloro solvent, polar aprotic solvent preferably keto solvent to provide the compound of formula-6.
In a preferred embodiment, one pot process for the preparation of compound of formula-6, which comprises of reacting N-(4-(4-flurophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methyhnethane sulfonamide compound of fonnula-4 with phosphorus tribromide in methylene chloride to provide the N-(5-(bromomethyl)-4-(4-fluorophneyl)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formuIa-5, which on in-situ reaction with lH-benzo[d]imidazole-2-thiol in presence of sodiimi hydroxide in acetone to provide the compoimd of formula-6.
As used herein the present invention "alkali metal alkoxide base" refers to the bases selected from sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide and the like or mixtures thereof
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; 250X4.0nun, Sjmi 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 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 tert-butyl-2-(4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethane suIfonamide)pyrimidui-5-yI)vinyl-2-dimethyI-13-dioxan-4-yl)acetate of formula-la:
Sodium tertiary butoxide (36.8 grams) was added to a mixture of N-(4-(4-f[uorophenyl)-6-isopropyl-5-( 1 -methyl-1 H-benzo[fl(]imidazol-2-ylsulfonyl)pyriraidin-2-yl)-N-methyhnethane sulfonamide (185 grams) in tetrahydrofuran (400 ml) and this mixture was added to tert-butyl 2-((4R,6R)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate (100 grams) in tetrahydrofuran (200 ml) at -20 to -ISC and stirred. After the completion of reaction, quenched it with sodium bicarbonate solution. The reaction mixture was stirred for 4 hours at 25-30°C. The solid was filtered and washed with water. The wet solid was recrystallized fi*om methanol to get the title compound. Yield: 165 grams Purity by HPLC: 99.62%; 0.03% (Z isomer)
Example-2: Preparation of N-(4-(4-fluorophenyl)-6-isopropyl-5-((l-methyl-lH-benzo[d]imidazol-2-yIsulfonyl)methyl)pyrimidin'2-yl)-N-methylmethane sulfonamide of formula-2:
A solution of hydrogen peroxide (70 ml) with anamonium heptamolybdate tetrahydrate (2 grams) was added to a mixture of N-(5-((lH-benzo[d]imidazol-2-ylthio)methyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide (100 grams), tertiary butylammonium bromide (2 grams) and methylene chloride (200 ml) at 10-20*'C and stirred. After completion of the reaction, quenched it with sodium sulphite solution and stirred. Sodium bicarbonate solution followed by aqueous sodium hydroxide was added and stirred for 30 minutes at RT. Dimethyl sulfate (23.5 grams) was added to the reaction mixture and stirred for 2 hours at RT. The organic and aqueous layers were separated and organic layer washed with water. The solvent from the organic layer was distilled off completely under reduced pressure at below

40°C. Methanol was added to the obtained residue and heated to reflux temperature then stirred for 30 minutes. The reaction mixture was cooled to -5 to 0°C and stirred for an hour. The solid obtained was filtered and washed with methanol. The wet solid was dissolved in methylene chloride and the solvent was distilled off under reduced pressure at below 40''C. Water was added to the obtained residue and stirred for 60 minutes. The solid obtained was filtered, washed with water and dried to get the title compound. Yield: 92 grams Purity by HPLC: 98.12%
Example-3: Preparation of N-(5-(lH-benzo[d]iiiiidazol-2-ylthio)methyl)-4-(4-fluorophenyI)-6-isopropyIpyrimidiii-2-yI)-N-methylmethanesulfon8mide compound offormula-6:
Phosphorous tribromide (14 ml) was added to a solution of N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide (100 grams) in methylene chloride (500 ml) and stirred at 25-30°C. After completion of the reaction, quenched it with sodium bicarbonate solution at 10-15°C and the organic and aqueous layers were separated. The organic layer was washed with sodium thiosulphate solution followed by water. The solvent from the organic layer was distilled off completely under reduced pressure at below 40°C. The obtained residue was dissolved in methanol (400 ml) and this solution was added to mixture of aqueous sodium hydroxide (11.3 grams in 30 ml of water) and lH-benzo[d]imida2ole-2-thiol (42.5 grams) at 25-30°C and stirred for 90 minutes. The solvent was distilled off completely under reduced pressure, water was added to the obtained residue and stirred for 30 minutes at 25-30''C. The solid formed was filtered, washed with water and dried to get the title compound. Yield: 132 grams

We claim:
1. A process for the preparation of dihydroxy protected derivative compounds of general formula-1,

wherein R is selected from alkyl or aryl,
with low levels of unwanted Z-isomer, which comprises of reacting the N-(4-(4-
f[uorophenyl)-6-isopropyl-5((l-methyl-lH-benzo[d]imidazol-2-ylsulfonyl)
methyl)pyrimidin-2-yl)-N-methyhnethane sulfonamide compound of formula-2

wherein R is selected from alkyl or aryl.
in presence of suitable alkali metal alkoxide bases 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-1.

2. A process for the preparation of tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-
isopropyl-2-(N-methylinethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l
dioxan-4-yl)acetate compound of formula-la,

which comprise of reacting the N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-IH-ben2o[d]imidazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methyhnethane sulfonamide compound of formula-2 with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl]acetate compound of formula-3a

in presence of sodium or potassium tertiary butoxide in a suitable polar aprotic solvent to provide the compound of formula-la.
3. The process according to any of the preceding claims wherein the alkoxide base is used in the ratio of 0.8 to 2.3 moles with respect to tert-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)acetate compoimd of formula-2 and the reaction is carried out at a temperature ranges from -20°C to 40*'C.
4. The process according to any of the preceding claims, wherein the compound of formula-l or la having E/Z content in the ratio of 98:2, preferably 99:1 and more preferably 99.9:0.1.

5. A process for the preparation of tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonainido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate compound of formula-la with Z isomer content less than 1%, which comprises of reacting the compound of formula-2 with tert-butyl 2-[(4R,6S)-6-fonnyl-2,2-dimethyl-l,3-dioxan-4-yl]acetate compound of fonnula-3a in presence of sodium tertiary butoxide in tetrahydrofuran to provide the compound of formula-la., characterized in that the sodium tertiarybutoxide used in the mole ratio of 0.8 to 2.5 mole with respect to the compound of formula-2 at a temperature ranges from -20 to 50°C.
6. Usage of alkali metal alkoxide bases to improve the E/Z isomer ratio in the condensation reaction between the N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-lH-benzo[d]imida2ol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formuIa-2

and aldehyde compounds of general formula-3

wherein R is selected from alkyl or aryl.
7. One pot process for the preparation of 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,


which comprises of oxidizing the sulfide compound of fomula-6

with a suitable oxidizing agent like metachloroperbenzoic acid, sodium hypochlorite, hydrogen peroxide, tertiary butyl hydrogen peroxide, cumene hydro peroxide, in the presence of an appropriate catalyst like ammonium hepta molybdate tetrahydrate in a suitable solvent selected from alcoholic solvents like chloro solvents or mixture thereof, to provide the sulfone compound of formula-7,

which on in-situ reaction with a suitable methylating agent like dimethyl sulfate in presence of a suitable base selected from alkali metal hydroxides in a suitable solvent selected from chloro solvents to provide the compound of formula-2.

8. One pot process for the preparation of N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyHH-benzo[d]iniidazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methyl methane sulfonamide compound of fonnula-2, which comprises of oxidizing the sulfide compound of fomula-6 with hydrogen peroxide in the presence of ammonium hepta molybdate tetrahydrate in methylene chloride to provide the sulfone compound of formula-7, which on in-situ reaction with dimethyl sulfate in presence of a suitable base selected from alkali metal hydroxides in a suitable solvent selected from chloro solvents to provide the compound of formula-2.
9. One-pot process for the preparation of compound of formula-6,

which comprises of reacting N-(4-(4-flurophenyl)-5-(hydroxymethyl)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-4

with suitable brominating agent selected from phosphorus tribromide in a suitable solvent selected from chloro solvent to provide the N-(5-(bromomethyl)-4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropyl pyrimidin-2-yl)-N-methyhnethane sulfonamide compound of formula-5.


which on in-situ reaction with lH-benzo[d]imidazole-2-thiol in presence of a suitable base selected from alkali metal hydroxide like sodium hydroxide and a solvent selected from ketone, chloro solvent, polar aprotic solvent or mixtures thereof to provide the compoimd of fonnula-6.
10. One pot process for the preparation of N-(5-((lH-benzo[d]imidazol-2-ylthio)methyl)-4-(4-fluorophenyl)-6-isopropylpyrinudin-2-yl)-N-methylmethanesulfonamide compoimd of formula-6, which comprises of reacting N-(4-(4-flurophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide compound of formula-4 with phosphorus tribromide in methylene chloride to provide the N-(5-(bromomethyl)-4-(4-fluorophneyI)-5-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-S, which on in-situ reaction with lH-benzo[d]imidazole-2-thiol in presence of sodium hydroxide in acetone to provide the compound of formula-6.