Description:FIELD OF THE INVENTION
The present application provides impurity-controlled and cost-effective process for the preparation of Rosuvastatin intermediate in high yields which is suitable for manufacturing in commercial scale.

BACKGROUND OF THE INVENTION
Rosuvastatin calcium (7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic acid) is an HMG-CoA reductase inhibitor, used for the treatment of hypercholesterolemia, which reduces the LDL cholesterol levels by inhibiting activity of HMG-CoA reductase enzyme, which is involved in the synthesis of cholesterol in liver. Rosuvastatin calcium has the following chemical formula:

The general method for the preparation of Rosuvastatin was described below.

Even though Intermediate (I) and Intermediate (II) plays major role in the preparation of Rosuvastatin, the said intermediates nature is liquid and unstable. so, the intermediates (I) and (II) doesn’t have any commercial value. The compound of formula (I) having IUPAC name tert-Butyl (4R-cis)-6-[(acetyloxy)methyl]-2,2-dimethyl-1,3-dioxane-4-acetate (CAS NO: 154026-95-6) commercially known as D5 is a stable key intermediate for the preparation of Rosuvastatin. The intermediate has the following chemical formula:

Formula (I)
Preparation of compound of formula I is generally obtained by various methods of acetylation of tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (Formula (VI)) are discussed in detail here in after.

Formula (VI)
The conversion of chloro compound of formula VI to acetoxy compound of formula I was disclosed in patents WO 2002006266 A1, EP 1323717 A1, WO 2012017242 A1, WO 2014203045 A1, CN 104327039 A, WO 2003106447 A1, WO 2000008011 A1, CN 101624390 A, CN 111675689 A, CN 105968086 A and CN 105622566 A. The conversion was carried in presence of salts like potassium acetate, sodium acetate, ammonium acetate phase transfer catalyst like tetra butyl ammonium bromide and in presence of suitable solvents.
The inventors of the present application have repeated all the above disclosed procedures and observed the obtained yields are not matching with the yields disclosed in earlier patents. The inventors of the present application also observed that formation of hydroxy impurity (Intermediate (I)) is a major disadvantage with the earlier disclosed procedures. While working with the conversion the inventors observed that formed hydroxy impurity is miscible with water and unable to recover it from water and major yield loss was observed in tonnage level. So, the technologies disclosed earlier are not suitable for the commercial production of the Rosuvastatin key intermediate of formula I in tonnage levels. The hydroxy impurity has the following chemical formula:

“Hydroxy Impurity” Intermediate (I)
Therefore, still there is need for the development of commercially viable, cost-effective process for the preparation of Rosuvastatin intermediate of compound of formula (I).
In addition, several methods for the preparation of compound of formula (VI) are discussed here in below.
US 5278313 describes the below process for the preparation of compound of formula (I), which involves fermentation process for keto reduction gives 70% in low yields, and reagents like LiHMDS and LDA which are costly and not commercially viable. Moreover, the reagent methoxydiethylborane which is using for keto reduction is highly pyrophoric, not suitable for commercial scale production.
The overall yield for this process is low and required special equipment such as fermenters, etc and apart from that, this process is not cost effective due to use of costly reagent such as methoxydiethyl borane.

WO 2002/06266 A1 discloses the below mentioned process for the preparation of compound of formula (I), which involves the usage of excess bromine in the first step of synthesis and liberates CO2 which is not eco-friendly. The starting material 6-chloro-2,4,6-trideoxy-D-erythro-hexose is not commercially available and conversion efficiency of starting material at large scale towards (4R, 6S)-4-hydroxy-6-chIoromethyI-tetrahydropyran-2-one is less.

W02003/053950A1 discloses the below process for the preparation of compound of formula (I). The process involves usage of costly reagents like Grignard reagents and tetrabutyl ammonium acetate and involves isomer separations and column purification techniques, the overall yields are also low.

WO 2014/203045 discloses the below process for the preparation of compound of formula (I), which involves the usage of costly reagents like methoxy diethyl borane and tetrabutyl ammonium acetate and the yield is only 66% in conversion of Chloro to acetoxy. So, the process is not commercially suitable to produce Rosuvastatin intermediate.

SUMMARY OF THE INVENTION
The present invention provides a cost effective and commercially viable process for the preparation of Rosuvastatin intermediate compound of formula (I)

Formula (I)
In an aspect the present application provides a process for preparation of compound of formula (I)

formula (I)
which comprises
a) reacting (S)-4-chloro-3-hydroxybutanenitrile a compound of formula (II)

formula (II)
with trimethyl silyl chloride and hexamethyldisilazane in a suitable solvent to form (S)-4-chloro-3-((trimethylsilyl)oxy)butanenitrile of formula (III)

formula (III)
b) reacting compound of formula (III) with tert-butyl bromo acetate in presence of Zinc and methane sulfonic acid in a suitable solvent to form compound of formula (IV)

formula (IV)
c) compound of formula (IV) undergoes keto reduction in presence of a keto reductase enzyme in a suitable solvent to give chloro dihydroxy compound of formula (V)

formula (V)
d) reacting chloro dihydroxy compound of formula (V) with 2,2 dimethoxy propane in presence of methane sulfonic acid or perchloric acid absorbed silica in a suitable solvent to form compound of formula (VI)

formula (VI)
e) reacting compound of formula (VI) with acetate salts in presence of acetic anhydride and a phase transfer catalyst in a suitable solvent to give compound of formula (I)
f) optionally purifying the compound of formula (I) a suitable solvent.

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment the present invention particularly describes process for the preparation of Rosuvastatin intermediate compound of formula (I)

Formula (I)
In another embodiment the following scheme- 1 describe the process for the preparation of Rosuvastatin intermediate compound of formula (I).
Scheme-1
In another embodiment step (a) of the present process involves reacting compound of formula (II) with Hexamethyl disilazane and trimethyl silyl chloride in suitable solvent to form silyl protected compound of formula (III); wherein the suitable solvent is dichlromethane, chloroform, THF or mixtures thereof.
In another embodiment step (b) of the present process involves, reacting silyl protected compound of formula (III) with tert-butyl bromoacetate in presence of Zinc powder and methanesulfonic acid in suitable solvent to form compound of formula (IV); wherein the suitable solvent is THF or Toluene or mixtures thereof.
In another embodiment step (c) of the process involves compound of formula (IV) undergoes keto reduction with keto reductase enzyme, D-glucose and in presence of a phosphate buffer, in suitable solvent to form chloro dihydroxy compound of formula (V); wherein the suitable solvent is water, and the buffer is sodium dihydrogen phosphate dehydrate with a pH of 7.0±1.0.
In another embodiment step (d) of the present process involves reacting chloro di hydroxy compound of formula (V) with 2,2 dimethoxy propane in presence of acid catalyst and in suitable solvent to form 2,2 DMP protected compound of formula (VI); where in the acid catalyst is methane sulfonic acid or silica absorbed perchloric acid and the suitable solvent is hexane or heptane or mixtures thereof.
In another embodiment step (e) of the present process involves conversion of 2,2 DMP protected compound of formula (VI) to acetoxy compound of formula (I) in presence of acetate salts, a phase transfer catalyst and acetic anhydride in a suitable solvent; wherein the acetate salts are sodium acetate or potassium acetate, and the phase transfer catalyst is tetrabutyl ammonium bromide or tetrabutyl ammonium chloride and the solvent is DMF.
In another embodiment step (e) of the process involves the avoiding the formation of hydroxy impurity intermediate (I) by adding acetic anhydride in the reaction in the formation of compound of formula (I) in high yields.
In another embodiment the below are the abbreviations are used in the specification.
THF-Tetrahydrofuran, MTBE-Methyl tertiary butyl ether, g- Grams, mL-milliliters, °C- degrees centigrade, Eq-Equivalent, GC-Gas chromatography, HCl-Hydrochloric acid, LDA- Lithium diisopropyl amide, LiHMDS-Lithium bis(trimethylsilyl)amide, NaBH4- Sodium boro hydride, TBA acetate- tetrabutyl ammonium acetate, NMP- N-methyl pyrrolidine, Na2CO3- Sodium Carbonate, PTSA- Para toluene sulfonic acid, NaOH- Sodium hydroxide, DMF- N, N Dimethyl formamide, K2CO3-Potassium Carbonate, TMSCl- Trimethyl Silyl Chloride, THF- Tetrahydrofuran, TEA- Triethyl amine, CH3SO3H-Methane sulfonic acid (MSA), HMDS- Bis(trimethylsilyl)amine or hexamethyldisilazane, TBAB- Tetrabutyl ammonium bromide, 2,2 DMP-2,2 dimethoxy propane, DCM- Dichloromethane, Na2SO4-Sodium Sulphate, DMSO-Dimethyl Sulphoxide, Mg2SO4-Magnesium Sulphate, TLC-Thin layer Chromatography, HPLC-High performance Liquid Chromatography, PXRD- Powder X-ray Diffraction,

EXAMPLES
Example 1:
Preparation of (S)-4-chloro-3-((trimethylsilyl)oxy)butanenitrile

Method 1:
To the pre-cooled solution of (S) 4-chloro-3-hydroxybutyronitrile (50 gm 1.0 eq) in DCM (200 mL) at -20C, Hexamethyldisilazane (80 gm, 1.2 eq), was added by controlling the temperature at 0-5℃, and trimethylchlorosilane (1.0 gm, 0.02 eq) was added dropwise to the reaction mass. After the addition was completed, the reaction was maintained at 25±2°C for 5 hrs. After the complete consumption of starting material in TLC, the reaction mass was transferred to the saturated sodium carbonate aqueous solution and stirred for 30 minutes. To the reaction mass 10% ammonium chloride aqueous solution was added and stirred for 30 minutes. The organic layer was separated dried over Na2SO4 and concentrated under reduced pressure at 50-55℃ to obtain the desired product 78.0 gm. (Yield: 97.5% and 99.0% purity by GC).
Example 2:
Preparation of (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate

Method 1:
Under nitrogen atmosphere in tetrahydrofuran (600 mL), Zn Powder (68.0 gm, 2.0 eq) and methane sulfonic acid (6.0 gm, 0.2 eq) was added. The reaction mass was refluxed at 65 to 70 0C for 1 hr. At the same temperature tert-butyl bromoacetate (10.2 gm, 0.1eq) was added and maintained at same temperature for a period of 1 hr. Then slowly (S)-4-chloro-3-(trimethylsilyl)oxy)butanenitrile (100 gm, 1.0 eq) and tert-butyl bromoacetate (112.0gm,1.1eq)
was added at the same temperature simultaneously for a period of 1-2 hrs. The reaction mass was maintained at the same temperature until the completion of starting material in TLC. The reaction mass was cooled to 5-10℃ then dilute hydrochloric acid (250.0 gm) was added dropwise into reaction by controlling the control pH at 2.5-4.5. After the addition was completed, stir for 30 minutes at 20-25°C for 1 hour. Ethyl acetate (500 mL) was added, and the pH of the aqueous layer was adjusted to 6.5 to 8.5 by saturated sodium carbonate solution.
The organic layer was separated dried over Na2SO4 and concentrated under reduced pressure to obtain desired compound as oily liquid (115.0 gm, 93% yield) having 98.8% purity by HPLC.

Method 2:
Under nitrogen atmosphere in tetrahydrofuran (50 mL) and toluene (500 mL) Zn Powder (85.4 gm, 2.5 eq) and Methane sulfonic acid (6.0 gm 0.2 eq) added. The reaction mass was refluxed at 65 to 70 0C for 1 hr. At the same temperature tert-butyl bromoacetate (10.2 gm, 0.1eq) was added and maintained at same temperature for a period of 1 hr. Then slowly (S)-4-chloro-3-(trimethylsilyl)oxy)butanenitrile (100 gm, 1.0 eq) and tert-butyl bromoacetate (112.0gm,1.1eq)
was added at the same temperature simultaneously for a period of 1-2 hrs. The reaction mass was maintained at the same temperature until the completion of starting material in TLC. The reaction mass was cooled to 5-10℃ then dilute hydrochloric acid (250.0 gm) was added dropwise into reaction by controlling the control pH at 2.5-4.5. After the addition was completed, stir for 30 minutes at 20-25°C for 1 hour. Ethyl acetate (500 mL) was added, and the pH of the aqueous layer was adjusted to 6.5 to 8.5 by saturated sodium carbonate solution.
The organic layer was separated dried over Na2SO4 and concentrated under reduced pressure to obtain desired compound as oily liquid (110 gm, 90% yield) having the 98.5% purity by HPLC.
Example 3:
Preparation of (3R,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate

 
Method 1:
Phosphate buffer solution was prepared by mixing disodium hydrogen phosphate (5.0 gm 0.5 eq) and sodium dihydrogen phosphate dihydrate (1.0 gm, 0.1eq) in water at 300C. To the buffer solution (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate (100 gm, 1.0 eq) and glucose (100 gm, 2.0 eq) was added at the same temperature. The pH of the reaction mass was adjusted to 7.0 - 8.0 with 15% sodium hydroxide aqueous solution. Keto reductive enzyme was added to the reaction mass (5.0 gm 5% loading). The pH of the reaction mass was controlled at 7.0±1.0 by adding 15% sodium hydroxide aqueous solution, and the reaction was maintained for 8-10 hours. After the completion of the starting material in TLC ethyl acetate (500 mL) was added to the reaction mass and the organic layer was separated and dried over Na2SO4 and concentrated under reduced pressure to obtain the desired product as oily liquid (100 gm, 98% yield) and 98.0% purity by HPLC.

Method 2:
Phosphate buffer solution was prepared by mixing disodium hydrogen phosphate (5.0 gm 0.5 eq) and sodium dihydrogen phosphate dihydrate (1.0 gm 0.1 eq) in water at 300C. To the buffer solution (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate (100 gm,1.0 eq) and glucose (100 gm, 2.0 eq) was added at the same temperature. The pH of the reaction mass was adjusted to 7.0 - 8.0 with 15% sodium hydroxide aqueous solution. Keto reductive enzyme was added to the reaction mass (10.0 gm 10% loading). The pH of the reaction mass was controlled at 7.0±1.0 by adding 15% sodium hydroxide aqueous solution, and the reaction was maintained for 8-10 hours. After the completion of the starting material in TLC ethyl acetate (500 mL) was added to the reaction mass and the organic layer was separated and dried over Na2SO4 and concentrated under reduced pressure to obtain the desired product as oily liquid (98 gm, 97% yield) and 98.2% purity by HPLC.

Example 4:
Preparation of tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate
Method 1:

To the compound 2, 2-Dimethoxypropane (50.0 gm, 1.1 eq) in Hexane (700 ml), was added (3R,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate (100 gm, 1.0 eq). The reaction mass was cooled to 5-15°C and the pH was adjusted to 2.0-3.0 with per chloric acid absorbed on silica gel (10 gm). The temperature of the reaction mass was raised to 10-15°C and maintained for 2 hours. After the completion of the reaction in TLC, the reaction mass was filtered and the pH was adjusted to 7.0-8.0 using saturated sodium carbonate, then the organic layer was separated dried over Na2SO4 concentrated under reduced pressure at 45-50℃ to get desired product as semi solid material (111.0 gm Yield: 95% and 99.2% purity by GC)

Method 2:
To the compound 2, 2-Dimethoxypropane (50.0 gm, 1.1eq) in Hexane (700 ml), was added (3R,5S)-tert-butyl 6-chloro-3,5-dihydroxyhexanoate (100 gm, 1.0 eq). The reaction mass was cooled to 5-15°C and the pH was adjusted to 2.0-3.0 methanesulfonic acid (2 gm). The temperature of the reaction mass was raised to 10-15°C and maintained for 2 hours. After the completion of the reaction in TLC, the reaction mass was filtered and the pH was adjusted to 7.0-8.0 using saturated sodium carbonate, then the organic layer was separated dried over Na2SO4 concentrated under reduced pressure at 45-50℃ to get desired product as semi solid material (110.0 gm, Yield: 93% and 99.0% purity by GC)

Example 5:
Preparation of (4R-Cis)-6-[(Acetyloxy)methyl]-2,2-dimethyl-1,3-dioxane-4-aceticacid,1,1-dimethylethyl ester

Method 1: (Without acetic anhydride)
In DMF (200 mL), TBAB (50 gm, 0.5 eq), and potassium acetate (105 gm, 3 eq) were added sequentially. The reaction mass temperature was raised to 70-75°C and maintained for 1hr. To the reaction mass tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (100 gm) was added .The reaction mass temperature was raised to 125-135℃ and maintained at same temperature for 22 hours. The reaction was monitored by GC showing 8.5% of Hydroxy Impurity content and 0.1% staring material content. The temperature of the reaction mass was reduced to 35-40 ℃. To the reaction mass water and hexane were added, the organic layer was separated and dried over Na2SO4 and concentrated under reduced pressure. The obtained crude material was triturated with hexane to obtain a light brown colour Solid 82.0gm and 99.50% purity by HPLC, Hydroxy impurity: 0.05%.

Method 2: (Addition of acetic anhydride in the reaction)
In DMF (200 mL), TBAB (50 gm, 0.5 eq), and potassium acetate (105 gm, 3 eq) were added sequentially. The reaction mass temperature was raised to 70-75°C and maintained for 1hr. To the reaction mass tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (100 gm) was added .The reaction mass temperature was raised to 125-135℃ and maintained at same temperature for 22 hours. The reaction was monitored by GC showing 8.21 % of Hydroxy Impurity content and 0.02 % staring material content. The temperature of the reaction mass was reduced to 35-40℃ and acetic anhydride (12 gm) was added, and the reaction was maintained at same temperature for 5 hrs. GC analysis shows that hydroxy impurity content of 0.3 %. To the reaction mass water (600 mL) and hexane were added, the organic layer was separated and dried over Na2SO4 and concentrated under reduced pressure. The obtained crude material was triturated with hexane to obtain a light brown colour Solid 91.0gm and 99.70% purity, Hydroxy impurity: 0.03%.

 
Method 3: (Addition of excess acetic anhydride in the reaction)
In DMF (200 mL), TBAB (50 gm, 0.5 eq), and potassium acetate (105 gm, 3 eq) were added sequentially. The reaction mass temperature was raised to 70-75°C and maintained for 1hr. To the reaction mass tert-butyl 2-((4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (100 gm) was added .The reaction mass temperature was raised to 125-135℃ and maintained at same temperature for 22 hours. The reaction was monitored by GC showing 8.0 % of Hydroxy Impurity content and 0.05 % staring material content. The temperature of the reaction mass was reduced to 35-40℃, and acetic anhydride (20 gm) was added, and the reaction was maintained at same temperature for 5 hrs. GC analysis shows that hydroxy impurity content of 0.2 %. To the reaction mass water and hexane were added, the organic layer was separated and dried over Na2SO4 and concentrated under reduced pressure. The obtained crude material was triturated with hexane to obtain a light brown colour Solid. (Yield 91.0 gm and 99.70% purity, Hydroxy impurity: 0.03%).
, Claims:1. A process for the preparation of compound of formula (I)

formula (I)
which comprises
a) reacting (S)-4-chloro-3-hydroxybutanenitrile a compound of formula (II)

formula (II)
with trimethyl silyl chloride and hexamethyldisilazane in a suitable solvent to form (S)-4-chloro-3-((trimethylsilyl)oxy)butanenitrile of formula (III)

formula (III)
b) reacting compound of formula (III) with tert-butyl bromo acetate in presence of Zinc and methane sulfonic acid in a suitable solvent to form compound of formula (IV)

formula (IV)
c) compound of formula (IV) undergoes keto reduction in presence of a keto reductase enzyme in a suitable solvent to give compound of formula (V)

formula (V)
d) reacting chloro dihydroxy compound of formula (V) with 2,2 dimethoxy propane in presence of methane sulfonic acid or perchloric acid absorbed silica in a suitable solvent to form compound of formula (VI)

formula (VI)
e) reacting compound of formula (VI) with acetate salts in presence of acetic anhydride and a phase transfer catalyst in a suitable solvent to give compound of formula (I)
f) optionally purifying the compound of formula (I) a suitable solvent.

2. The process as claimed in claim 1 for the preparation of compound of formula (I)

formula (I)
which comprises
a) reacting (S)-4-chloro-3-hydroxybutanenitrile a compound of formula (II)

formula (II)
with trimethyl silyl chloride and hexamethyldisilazane in dichloromethane, chloroform or THF solvent to form (S)-4-chloro-3-((trimethylsilyl)oxy)butanenitrile of formula (III)

formula (III)
b) reacting compound of formula (III) with tert-butyl bromo acetate in presence of Zinc and methane sulfonic acid in THF, toluene or mixture of solvent to form compound of formula (IV)

formula (IV)
c) compound of formula (IV) undergoes keto reduction in presence of a keto reductase enzyme in water as solvent to give compound of formula (V)

formula (V)
d) reacting chloro dihydroxy compound of formula (V) with 2,2 dimethoxy propane in presence of methane sulfonic acid or perchloric acid absorbed silica in hexane or heptane as solvent to form compound of formula (VI)

formula (VI)
e) reacting compound of formula (VI) with acetate salts in presence of acetic anhydride and a phase transfer catalyst in DMF as solvent to give compound of formula (I)
f) purifying the compound of formula (I) in hexane as solvent.

3. The process as claimed in claim 1-2, step (e) wherein the acetate salts are potassium acetate, sodium acetate, and the phase transfer catalysts are tetrabutyl ammonium bromide or tetrabutyl ammonium chloride and the suitable solvent is DMF.

4. A process for the preparation of compound of formula (I)

formula (I)
which comprises reacting compound of formula (VI)

formula (VI)
with potassium acetate, acetic anhydride in presence of a phase transfer catalyst tetrabutyl ammonium bromide in DMF as solvent to form compound of formula (I).