DESC:FIELD OF THE INVENTION
The present invention relates to a process for the preparation of statin advanced intermediates by using Julia-Kocienski reaction between an aldehyde and a sulfone derivative in the presence of combination of solvents and a metal hydroxy base. The resulting derivatives are advanced intermediates for statin type compounds such as, Fluvastatin, Pitavastatin and Rosuvastatin. The present application also provides a cost effective and improved process for the preparation of advanced intermediates of statin related drugs in high yields and suitable for manufacturing in commercial scale.

BACKGROUND OF THE INVENTION
Rosuvastatin, Pitavastatin and Fluvastatin are HMG-CoA reductase inhibitors, 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 is sold in the market under brand name CRESTOR; Pitavastatin is sold in the market under the brand name LIVALO and Fluvastatin is sold in the market under the brand name LESCOL.
Rosuvastatin Calcium

Pitavastatin Calcium

Fluvastatin Sodium

There are several synthetic methods have been reported in the literature to prepare lipid lowering statin drugs.
WO2000049014A1 discloses the below process to prepare Rosuvastatin which contains several steps. The process uses Witting Horner reaction which contains reaction between phosphonate ester and aldehydes in presence of strong base and costly reagents like NaHMDS in turn gives double bond containing products. The main disadvantage with the process is percentage of required isomer is (E/Z) low i.e., only 70:30. The synthesis of aldehyde side chain requires eight steps.

WO2005054207A1 discloses the below process to prepare Rosuvastatin. The main disadvantages of the below process are usage of toxic reagents like PBr3 and triphenyl phosphine which are not eco-friendly. The condensation of triphenyl phosphine bromide salt aldehyde part of the side chain provides very low yields, and the required product E/Z ratio was not defined. The preparation of side chain aldehyde part involves many steps and stability of the aldehyde is less and at higher temperatures like 700C to 800C the aldehyde will decompose.

In first generation synthesis the main disadvantage in coupling aliphatic aldehyde part and aromatic phophonium salts using Witting technology is the ratio of E/Z. The formation of required E isomer is 70% and the unwanted Z isomer is 30%. So, to product Statin related drugs using this technology is not commercially viable and not cost effective.

In second generation synthesis of Statin related drugs, it requires an aldehyde and sulphones intermediates which undergoes Julia-Kocienski Olefination to give olefin intermediate. The main advantage of the reaction is formation of desired E isomers in high yields.

WO2001096347A1 discloses the below process to prepare statin related drugs in the following manner. It involves the usage of costly reagents like LiHMDS. So, using this technology is not commercially viable and not cost effective.

The major drawback of the bases like LiHMDS, NaHMDS, KHMDS which are using in Julia-Kocienski Olefination are, they can easily form unwanted side products like de protonation of the methyl group alpha to the sulphone intermediate.
WO2007125547A2 discloses the below process to prepare Rosuvastatin. The preparation of side chain aldehyde part involves many steps and stability of the aldehyde is less and at higher temperatures like 700C to 800C the aldehyde will decompose.

WO2012098049A1 discloses the below process to prepare Rosuvastatin intermediate. The process uses the metal alkoxy bases which are having a pKa of 16 to 21. But the disadvantage of the process is the isolated yields are very less like 48% (Example 3 step (a)). The process uses the molar solutions of the metal alkoxy bases which are very costly. So, using this technology is not commercially viable and not cost-effective.

It is, therefore, desirable to provide an efficient process for the preparation of statins which improves the economics by employing less expensive reagents and is more productive compared to the known processes.
Disadvantages of the prior art processes:
• Usage of costly reagents like NaHMDS and LiHMDS which leads to the formation of unwanted side products.
• Usage of strong base like LDA / n-BuLi followed by usage of Na/Hg in Julia classical olefmation reactions, which are highly pyrophoric in nature, hence those are not recommended for commercial scale up.
• Stability of side chain aldehyde part at higher temperatures.
• Less control over unwanted Z isomer.
• Using molar solutions of potassium or sodium tertiary butoxide is not cost effective and not commercially viable.

SUMMARY OF THE INVENTION
The present invention provides a cost-effective and improved process for the preparation of advanced statin drugs intermediates of formula R1-C=C-R2;
wherein
R1 is selected from
;
R2 is
, wherein R3 and R4 are independently selected from C1-C5 alkyl or R3 and R4 to gather with the carbon atom to which they are attached to form a C3-C8 cycloalkyl ring; and R5 is C1-C5 alkyl.

DETAILED DESCRIPTION OF THE INVENTION
In one aspect the present invention provides a cost-effective and improved process for the preparation of advanced statin drugs intermediates of formula R1-CH=CH-R2;
wherein
R1 is selected from
;
R2 is
, wherein R3 and R4 are independently selected from C1-C5 alkyl or R3 and R4 to gather with the carbon atom to which they are attached to form a C3-C8 cycloalkyl ring; and
R5 is C1-C5 alkyl;
which comprises
a) reacting compound of formula R1-CHO with a compound of formula R6-SO2-CH2-R2 in presence of metal hydroxy bases and a solvent;
wherein R2 is as defined above;
R6 is ; wherein X-Y is N=N, R7C=CR8, N=CR8 or X-Y taken together with the carbon atoms to which they are attached to form aryl ring;
R7 and R8 are independently selected from hydrogen or alkyl; and
Z is S or N-R9; wherein R9 is C1-C5 alkyl or phenyl.
In another aspect of the present invention, the sulfone of general formula R2 reacts with an aldehyde of general formula R1-CHO in which is chosen so as to obtain suitable precursors to obtain useful statin-type compounds including Pitavastatin, Rosuvastatin and Fluvastatin.
The preferred examples of the aldehydes are mentioned below.

The preferred examples of the sulfone intermediates are mentioned below.
, , , , , , and .

The Julia-Kocienski olefination between the intermediates like R1-CHO and R6-SO2-CH2-R2 is carried out in presence of a bases like NaHMDS, KHMDS, Sodium hydride, Lithiumm hydride, Potassium hydride, Sodium hydroxide, Potassium hydroxide and metal alkoxy bases like Sodium methoxide, sodium ethoxide, sodium isopropoxide, Sodium tert butoxide, Lithium methoxide, Lithium ethoxide, Lithium isopropoxide, Lithium tert butoxide, Potassium methoxide, Potassium ethoxide, Potassium isopropoxide and Potassium tert butoxide. The disadvantages with Silicon based reagents is it contains more toxic waste streams and formation of unwanted side products like de protonation of the methyl group alpha to the sulphone intermediate. The other disadvantage of the Silicon based reagents is, the E/Z ratio in the final products. Normally E/Z ratio was varying in between 60:40 and 80:20. The E/Z ratio in the final product depends upon various parameters like type of base, type of sulfone intermediate and solvents.

In WO2012098049A1 it was observed that, using bases like NaOtBu or KOtBu which are having pKa 15-22 particularly 16-21 will be having an advantage like, very low percent formation of unwanted side products (1-2%). But the major disadvantage in this technology is the isolated yields are very less i.e., only 48%. Usage of molar solutions of metal alkoxy bases such as Sodium tert butoxide and potassium tert butoxide will not be commercially viable.

Surprisingly the inventors of the present application have found that using metal hydroxy bases such as sodium hydroxide, potassium hydroxide in presence of combination of polar and chlorinated solvents like methanol, ethanol, isopropanol, tertiary butanol, acetonitrile, DMSO, DMF dichloromethane and chloroform for Julia Kocienski olefination results very less formation of unwanted side products, more percentage of required isomer i.e., E/Z ratio is 99/1 to 99.9/non detectable levels. The method also gives us a minimum of 90% isolated yields which is very viable to produce the statin related advanced intermediates in commercial scales.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning and the meaning of such terms is independent at each occurrence thereof and is as commonly understood by one of skill in art to which the subject matter herein belongs. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name and an ambiguity exists between the structure and the name, the structure predominates. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated.
As used herein, the term “alkyl” refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, and which is attached to the rest of the molecule by a single bond. The alkane radical may be straight or branched. For example, the term “C1-C6 alkyl” refers to a monovalent, straight, or branched aliphatic group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, 1-propyl, n-butyl, 1-butyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neo-pentyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl, and the like).
As used herein, the term “cycloalkyl” refers to C3-C10 saturated cyclic hydrocarbon ring. A cycloalkyl may be a single ring, which typically contains from 3 to 7 carbon ring atoms. Examples of single ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. A cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused, and spirocyclic carbocyclyls.
The below are the abbreviations are used in the specification.

Sodium HMDS- Sodium heaxamethyl disilazane, KHMDS- Potassium hexamethyl disilazane, NaOH- Sodium hydroxide, KOH- Potassium hydroxide, mL-milliliters, °C- degrees centigrade, Eq-Equivalent, HCl-Hydrochloric acid, K2CO3-Potassium carbonate, DMF- N-N-Dimethyl formamide, DMSO- Dimethyl Sulphoxide, Na2SO4-Sodium Sulphate, DMSO-Dimethyl Sulphoxide, TLC-Thin layer Chromatography, GC- Gas Chromatography, HPLC-High performance Liquid Chromatography, ND-non detectable.

EXAMPLES
Example 1:
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-1,3-dioxan-4-yl)acetate
Method 1: (Using Tertiary butanol, DCM, and KOH)

To dichloromethane (1000 mL) solvent at -60 0C was added N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (200 gm, 1 eq), tert-butyl 2-((4R,6S)-2,2-dimethyl-6-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl)-1,3-dioxan-4-yl)acetate (230 gm, 1.1 eq). In another flask tertiary butanol (50 mL) was taken and cooled to -5 to -10 0C, to this potassium hydroxide (70.2 gm, 2.2 eq) was added by maintaining the temperature at -5 to -10 0C. This potassium hydroxide and tertiary butanol solution was added to the above solution at -60 0C. The reaction was maintained at -50 0C about 3 to 4 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction the temperature of the reaction mass was raised to 10 to 15 0C. To the reaction mass 30% potassium carbonate solution was added, the organic layer was separated dried over Na2SO4 and concentrated under vacuum to obtain the desired product as crude. To the obtained crude methanol (400 mL) was added and the temperature was raised to 60- 65 0C, wait until it forms the clear solution, methanol was cooled to 5- 10 0C to solidify the desired compound. (289.0gm. 90.0% yield) Purity:99.5% and Z-isomer-ND.
Method 2: (Using isopropanol, DCM, and KOH)
To dichloromethane (1000 mL) solvent at -60 0C was added N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (200 gm, 1 eq), tert-butyl 2-((4R,6S)-2,2-dimethyl-6-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl)-1,3-dioxan-4-yl)acetate (230 gm, 1.1 eq). In another flask isopropyl alcohol (75 mL) was taken and cooled to -5 to -10 0C, to this potassium hydroxide (70.2 gm, 2.2 eq) was added by maintaining the temperature at -5 to -10 0C. This potassium hydroxide and tertiary butanol solution was added to the above solution at -60 0C. The reaction was maintained at -50 0C about 3 to 4 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction the temperature of the reaction mass was raised to 10 to 15 0C. To the reaction mass 30% potassium carbonate solution was added, the organic layer was separated dried over Na2SO4 and concentrated under vacuum to obtain the desired product as crude. To the obtained crude methanol (400 mL) was added and the temperature was raised to 60- 65 0C, wait until it forms the clear solution, methanol was cooled to 5- 10 0C to solidify the desired compound. (291.0gm. 90.6% yield) Purity:99.45% and Z-isomer-ND.
Method 3: (Using Acetonitrile /DCM with KOH
To dichloromethane (900 mL) solvent at -60 0C was added N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (200 gm, 1 eq), tert-butyl 2-((4R,6S)-2,2-dimethyl-6-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl)-1,3-dioxan-4-yl)acetate (230 gm, 1.1 eq). In another flask Acetonitrile (192 mL) was taken and cooled to -5 to -10 0C, to this potassium hydroxide (115 gm, 3.6 eq) was added by maintaining the temperature at -5 to -10 0C. This potassium hydroxide and tertiary butanol solution was added to the above solution at -60 0C. The reaction was maintained at -50 0C about 3 to 4 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction the temperature of the reaction mass was raised to 10 to 15 0C. To the reaction mass 30% potassium carbonate solution was added, the organic layer was separated dried over Na2SO4 and concentrated under vacuum to obtain the desired product as crude. To the obtained crude methanol (400 mL) was added and the temperature was raised to 60- 65 0C, wait until it forms the clear solution, methanol was cooled to 5- 10 0C to solidify the desired compound. (288 gm. 90.0% yield) Purity:99.8% and Z-isomer-ND%

Method 4: (Using DMF/DCM with KOH)
To dichloromethane (900 mL) solvent at -60 0C was added N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (200 gm, 1 eq), tert-butyl 2-((4R,6S)-2,2-dimethyl-6-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl)-1,3-dioxan-4-yl)acetate (230 gm, 1.1 eq). In another flask N,N-dimethyl formamide (100 mL) was taken and cooled to -5 to -10 0C, to this potassium hydroxide (115 gm, 3.6 eq) was added by maintaining the temperature at -5 to -10 0C. This potassium hydroxide and tertiary butanol solution was added to the above solution at -60 0C. The reaction was maintained at -50 0C about 3 to 4 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction the temperature of the reaction mass was raised to 10 to 15 0C. To the reaction mass 30% potassium carbonate solution was added, the organic layer was separated dried over Na2SO4 and concentrated under vacuum to obtain the desired product as crude. To the obtained crude methanol (400 mL) was added and the temperature was raised to 60- 65 0C, wait until it forms the clear solution, methanol was cooled to 5- 10 0C to solidify the desired compound. (251gm. 78% yield) Purity:99.8% and Z-isomer-ND%.
Method 5: (Using DMSO/DCM with KOH)
To dichloromethane (800 mL) solvent at -60 0C was added N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (200 gm, 1 eq), tert-butyl 2-((4R,6S)-2,2-dimethyl-6-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl)-1,3-dioxan-4-yl)acetate (230 gm, 1.1 eq). In another flask Dimethyl sulphoxide (98 mL) was taken and cooled to -5 to -10 0C, to this potassium hydroxide (79.8 gm, 2.5 eq) was added by maintaining the temperature at -5 to -10 0C. This potassium hydroxide and tertiary butanol solution was added to the above solution at -60 0C. The reaction was maintained at -50 0C about 3 to 4 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction the temperature of the reaction mass was raised to 10 to 15 0C. To the reaction mass 30% potassium carbonate solution was added, the organic layer was separated dried over Na2SO4 and concentrated under vacuum to obtain the desired product as crude. To the obtained crude methanol (400 mL) was added and the temperature was raised to 60- 65 0C, wait until it forms the clear solution, methanol was cooled to 5- 10 0C to solidify the desired compound. (240 gm. 75% yield) Purity:99.3% and Z-isomer-ND.

ADVANTAGES OF THE PRESENT PROCESS
Less formation of undesired impurities.
High yielding process, suitable for commercial scale production.
Low-cost raw materials like NaOH, KOH, alcoholic solvents, acetonitrile, DMF and DMSO.
High selectivity towards required E isomer in the advanced intermediate, almost undesired Z isomer is in non-detectable levels.
,CLAIMS:1. A process for the preparation of advanced statin drugs intermediates of formula R1-CH=CH-R2;
wherein
R1 is selected from
;
R2 is
, wherein R3 and R4 are independently selected from C1-C5 alkyl or R3 and R4 to gather with the carbon atom to which they are attached to form a C3-C8 cycloalkyl ring; and
R5 is C1-C5 alkyl;
which comprises
a) reacting compound of formula R1-CHO with a compound of formula R6-SO2-CH2-R2 in presence of metal hydroxy bases and solvents;
wherein R2 is as defined above;
R6 is ; wherein X-Y is N=N, R7C=CR8, N=CR8 or X-Y taken together with the carbon atoms to which they are attached to form aryl ring;
R7 and R8 are independently selected from hydrogen or alkyl; and
Z is S or N-R9; wherein R9 is C1-C5 alkyl or phenyl.

2. The process as claimed in claim 1, wherein the metal hydroxy bases are selected from LiOH, NaOH, KOH, CsOH or mixture thereof.

3. The process as claimed in claim in 1, wherein the solvents are selected from polar solvents and chlorinated solvents or combination thereof.

4. The process as claimed in claim 1, R1-CHO is selected from

5. The process as claimed in claim 1, wherein R2 is selected from , , , , , , and .

6. The process as claimed in claim 3, wherein the solvents are selected from methanol, ethanol, isopropanol, tertiary butanol, DMF, DMSO, dichloromethane and chloroform or a combination thereof.

7. The process as claimed in claim 1 to 8, wherein the preferable combination of metal hydroxy bases and solvents are selected from, potassium hydroxide: isopropyl alcohol: Dichloromethane, potassium hydroxide: tertiary butyl alcohol: Dichloromethane, potassium hydroxide: acetonitrile: DCM, potassium hydroxide: DMSO: Dichloromethane, potassium hydroxide: DMF: Dichloromethane or mixture thereof.

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

Formula (I)
which comprises reacting compound of formula R1-CHO

with a compound of formula R6-SO2-CH2-R2

in presence of combination of metal hydroxy bases and solvents at a temperature of -50 to -60 0C; wherein the preferable combination is selected from potassium hydroxide: isopropyl alcohol: Dichloromethane or potassium hydroxide: tertiary butyl alcohol: Dichloromethane or potassium hydroxide: acetonitrile: Dichloromethane.

9. The process as claimed in claim 1 to 8, wherein the preferable combination of metal hydroxy bases and solvents are selected from, potassium hydroxide: isopropyl alcohol: Dichloromethane, potassium hydroxide: tertiary butyl alcohol: Dichloromethane or mixture thereof.
10. The process as claimed in claim 1 to 8, wherein the preferable combination of metal hydroxy bases and solvents are selected from, potassium hydroxide: acetonitrile: Dichloromethane, potassium hydroxide: DMSO: Dichloromethane, potassium hydroxide: DMF: Dichloromethane or mixture thereof.