DESC:FIELD OF THE INVENTION
The present application provides an improved process for the preparation of chiral diol sulfones of formula (I) which are useful as potential intermediates for the preparation of Rosuvastatin in high yields and suitable for manufacturing in commercial scale.

Formula (I)
Where R1 is aryl;
R2 and R3 are each independently selected from C1 -4 alkyl, C1 -4 alkenyl, C3 -6 cycloalkyl, or R2 and R3 together with the carbon to which they are attached to form a cycloalkyl ring;
R4 is selected from C1 -4 alkyl, aryl, or aryl alkyl.

BACKGROUND OF THE INVENTION
Chiral diol sulfone compounds of formula (I) are the key intermediates for the preparation of Statin class of drugs which are useful as HMG CoA reductase inhibitors. Chiral diol sulfones are useful in the preparation of double bond containing statin drugs like Rosuvastatin, Pitavastatin and Fluvastatin.
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.

WO2002098854A1 discloses the below process to prepare Rosuvastatin as depicted below.

Wherein R1 is or R3 is alkyl, aryl, arylalkyl, cycloalkyl preferably Phenyl; R2 is residue of HMG CoA reductase inhibitor selected from Rosuvastatin, Pitavastatin, Fluvastatin etc…
The process uses more equivalents of triflic anhydride with respective to the starting material. Triflic anhydride is expensive reagent and extremely hazardous and not environment eco-friendly. Needs extra synthetic steps for sulfone formation like activation of alcohol with triflic anhydride.
IN 3028/MUM/2009 and WO2012098048A1 discloses the same process to process to prepare Rosuvastatin as shown below.

Wherein R1 is or R3 is alkyl, aryl, arylalkyl, cycloalkyl preferably Phenyl; R2 is residue of HMG CoA reductase inhibitor selected from Rosuvastatin, Pitavastatin, Fluvastatin etc…
The main disadvantage of the above process is higher temperature 100 0C to 130 0C is needed for the replacement of chloro group for the formation of sulphide intermediate. The chloro intermediate decomposes with time and higher temperature which gives less yield of sulphide intermediate. At most care should be taken in case a temperature at the higher end range is chosen to limit the degradation of the halo methyl substrate (starting material).
WO2014108975A1 discloses the below process to prepare Rosuvastatin intermediate which is depicted below.

Wherein R1 is and R2 is residue of HMG CoA reductase inhibitor selected from Rosuvastatin, Pitavastatin, Fluvastatin etc…
The process involves the usage of Mitsunobu kind reaction between hydroxy and thiol coupling by using reagents like triphenylphosphine, disiopropylazodicaboxylate and diethylazodicarboxylate. The alcohol used in the reaction need to be activated with azodicarboxylate and phosphorous compound to give activated compound and the activated compound is further reacts with 2- mercaptobenzothiazole gives chiral diol sulphide compounds.
The major disadvantage of the process is typically, diethyl azodicarboxylate (DEAD) and triphenylphosphine are employed as the oxidant and reducing agent in the Mitsunobu reaction, but production of a large amount of waste, i.e., diethyl hydrazine dicarboxylate and triphenylphosphine oxide, is unavoidable. These by-products often contaminate the desired product. In addition, DEAD is hazardous due to its toxicity and potential explosiveness. As a result, the use of the Mitsunobu reaction tends to be avoided in practical synthesis on plant scales.
Therefore, still there is a need for an improved process to prepare chiral diol sulfone compound of formula (I), which is useful in the preparation of statin drugs.

SUMMARY OF THE INVENTION
The present invention provides an improved process for the chiral diol sulfones compounds of formula (I)

Formula (I)
where R1 is aryl, heteroaryl, heterocyclic;
R2 and R3 are each independently selected from C1 -4 alkyl, C1 -4 alkenyl, C3 -6 cycloalkyl, or R2 and R3 together with the carbon to which they are attached to form a cycloalkyl ring;
R4 is selected from C1 -4 alkyl, aryl, or aryl alkyl
which comprises
a) reacting compound of formula (II)

formula (II)
with R1-SH compound of formula (III) in presence of suitable base, phase transfer catalyst and solvent give chiral diol sulphide compound of formula (IV); where in R1 is aryl; wherein R1 and R4 are same as defined above;

formula (IV)
b) optionally isolating chiral diol sulphide compound of formula (IV);
c) reacting chiral diol sulphide compound of formula (IV) with alcohol protecting group of compound of formula (V)

formula (V)
in presence of an acid catalyst and in suitable solvent gives protected chiral diol sulphide compound of formula (VI); wherein R1, R2, R3 and R4 are same as defined above;

formula (VI)
d) optionally isolating the protected chiral diol sulphide compound of formula (VI);
e) oxidising protected chiral sulphide compound of formula (VI) with an oxidising agent in suitable solvent gives chiral diol sulfone compound of formula (I); wherein R1, R2, R3 and R4 are same as defined above;

DETAILED DESCRIPTION OF THE INVENTION
In one aspect the present invention provides an improved process for the chiral diol sulfones compounds of formula (I)

Formula (I)
where R1 is aryl;
R2 and R3 are each independently selected from C1 -4 alkyl, C1 -4 alkenyl, C3 -6 cycloalkyl, or R2 and R3 together with the carbon to which they are attached to form a cycloalkyl ring;
R4 is selected from C1 -4 alkyl, aryl, or aryl alkyl
which comprises
a) reacting compound of formula (II)

formula (II)
with R1-SH compound of formula (III) in presence of suitable base, phase transfer catalyst and solvent give chiral diol sulphide compound of formula (IV); where in R1 is aryl; wherein R1 and R4 are same as defined above;

formula (IV)
b) optionally isolating chiral diol sulphide compound of formula (IV);
c) reacting chiral diol sulphide compound of formula (IV) with alcohol protecting group of compound of formula (V)

formula (V)
in presence of an acid catalyst and in suitable solvent gives protected chiral diol sulphide compound of formula (VI); wherein R1, R2, R3 and R4 are same as defined above;

formula (VI)
d) optionally isolating the protected chiral diol sulphide compound of formula (VI);
e) oxidising protected chiral sulphide compound of formula (VI) with an oxidising agent in suitable solvent gives chiral diol sulfone compound of formula (I); wherein R1, R2, R3 and R4 are same as defined above;
In another aspect the following scheme- 1 describe the process for the preparation of chiral diol sulfones compounds of formula (I)

Scheme-1
wherein R1, R2, R3 and R4 are as defined above.
In another aspect stage (a) of the present process involves reacting chloro diol compound of formula (II) with aryl thiol compound of formula (III) in presence of base a phase transfer catalyst in a suitable solvent gives chloro diol sulphide compound of formula (IV); wherein the base is selected from Na2CO3, K2CO3, NaHCO3 and CS2CO3, and phase transfer catalysts are selected from tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium hydrogen sulphate and the solvents are selected from DMF, DMSO, THF, Acetone, Acetonitrile, diglyme, monoglyme, poly ethylene glycol, methanol, ethanol, propanol, dichloromethane and chloroform.
In another aspect stage (b) of the present process involves protecting the chiral diol sulphide compound of formula (IV) with compound of formula (V) in presence of an acid gives protected chloro diol sulphide compound of formula (VI); where in the protecting reagent is selected from 2,2 dimethoxy propane, 2,2 dimethoxy butane, 3,3-dimethoxypentane, 1,1-dimethoxycyclohexane and the acid catalyst is methane sulfonic acid.
In another aspect stage (3) of the present process involves oxidising compound of formula (VI) with a suitable oxidising agent in presence of a catalyst at temperature ranging from -20 to 500C in a suitable solvent gives chiral diol sulfone compound of formula (I); wherein the oxidising agent is selected from hydrogen peroxide, peracetic acid, KMnO4, m-CPBA, oxones, borates, N-oxides, chromates, chlorates, perchlorates, periodates; wherein the catalyst is selected from the group Molybdenum, Manganese, Vanadium, Nickel, Iron, Copper; wherein the solvent is selected from dichloromethane, chloroform, acetone, methanol, ethanol, propanol, acetonitrile, NMP, DMF, DMSO, THF and MTBE.
According to the present process, an unprotected chiral diol halogen derivative can be used as starting compound. This is advantageous because the Kaneka alcohol generally is prepared from such a halogen derivative. Therefore, the present invention provides a process, in which additional steps in the prior art are made obsolete if the chiral diol sulfone is to be used in a Julia-Kocienski olefination.
The inventors of the present application observed that, unexpectedly the thio-ether compound of general formula (IV) could be prepared in this way, because as stated in WO2012098048 A1 nucleophic substitution conditions will lead to decomposition and/or to racemization (or epimerization, respectively) of the diol function in the case of compounds like shown in formula (II).
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 “alkenyl”, as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both “unsubstituted alkenyls” and “substituted alkenyls”, the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Examples of alkenyl groups are, but not limited to, ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl. The substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl or heteroaryl groups is contemplated.
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.
As used herein, the term “aryl alkyl” refers to an alkyl group substituted with an aryl group. Arylalkyl groups include benzyl and the like.
As used herein, the term “aryl” group is a residue sufficiently p-electron deficient to be suitable for the modified (or one-pot) Julia-Kocienski olefination. Preferably, the thiol-aryl compound contains as an aryl group an aromatic moiety having a hetero atom, more preferably nitrogen. More in particular, the aromatic residue contains an electrophilic imine-like moiety within the heterocycle. Preferred aryl groups include tetrazole, oxadiazole, substituted phenyl and benzimidazole type compounds. Specific examples of preferred aryl groups include, pyridine-2-yl, pyrimidin-2-yl, benzothiazol-2-yl, 1-phenyl-1H-tetrazole-5-thiol, 1-methyl-1H-tetrazole-5-thiol, 1-isopropyl-1H-tetrazole-5-thiol, 1-ethyl-1H-tetrazole-5-thiol 3,5-bis(trifluoromethyl)phenyl-1-yl, 5-methyl-1,3,4-thiadiazole-2-thiol, 5-phenyl-1,3,4-thiadiazole-2-thiol, 1-methylimidazol-2-yl, benzimidazol-2-yl, 4-methyl-1 ,2,4-triazol-3-yl and iso-quinolin-1-yl. Most preferred aryl groups are benzothiazol-2-yl, 1-phenyl-1H-tetrazole-5-thiol, 1-methyl-1H-tetrazole-5-thiol, 1-isopropyl-1H-tetrazole-5-thiol, 1-ethyl-1H-tetrazole-5-thiol 3,5-bis(trifluoromethyl)phenyl-1-yl, 5-methyl-1,3,4-thiadiazole-2-thiol, 5-phenyl-1,3,4-thiadiazole-2-thiol, 1-methylimidazol-2-yl and benzimidazol-2-yl.
In another embodiment the below are the abbreviations are used in the specification.
THF-Tetrahydrofuran, MTBE-Methyl tertiary butyl ether, g- Grams, LDA-Lithium diisopropyl amide, Sodium HMDS- Sodium heaxamethyl disilazane, mL-milliliters, °C- degrees centigrade, Eq-Equivalent, GC-Gas chromatography, HCl-Hydrochloric acid, Na2CO3- Sodium Carbonate, K2CO3Potassium carbonate, Sodium bi carbobate, Cesium carbonate, DMF- N-N-Dimethyl formamide, TBAB- tetrabutyl ammonium bromide, DMSO- Dimethyl Sulphoxide, THF- Tetrahydrofuran, KMnO4- Potassium permanganate, m-CPBA- metachloro per benzoic acid, NMP-N-methyl pyrrolidine, Na2SO4-Sodium Sulphate, DMSO-Dimethyl Sulphoxide, DMAc- Dimethyl acetamide, Mg2SO4-Magnesium Sulphate, TLC-Thin layer Chromatography, GC- Gas Chromatography, HPLC-High performance Liquid Chromatography, 1HNMR- Proton nuclear magnetic resonance spectroscopy, CDCl3-Deutirated Chloroform,
EXAMPLES
Example 1
Preparation of tert-butyl (3R,5S)-3,5-dihydroxy-6- ((5-methyl-1,3,4-thiadiazol-2 yl)thio)hexanoate
Method 1:

To a solution of 2-mercapto-5-methyl-1,3,4-thiadiazole (58.2 gm, 1.05eq) and 200 ml N,N-dimethylformamide was added Sodium carbonate (58 gm, 1.3 eq) at 25-30°C. To the reaction mass was added (3R,5S)-6-chloro-3,5-dihydroxyhexanoate (100 gm, 1.0 eq) and TBAB (1 gm, 0.1eq). The reaction mass was maintained at the same temperature until the starting material absent by HPLC. After completion of the reaction dichloromethane (600 mL) and water (400 mL) was added to the reaction mass. The organic layer was separated dried over Na2SO4 and concentrated under vacuum to get tert-butyl (3R,5S)-3,5-dihydroxy-6- ((5-methyl-1,3,4-thiadiazol-2 yl)thio)hexanoate (135.0gm, 97.0% yield). 1H NMR (CDCl3): 4.50 (s)1H, 4.289-4.229 (m) 2H, 4.13-4.078 (q) 1H, 3.9 (s) 1H, 3.526-3.482 (dd), 1H, 3.347-3.295 (q) 1H, 2.944-2867 (s) 1H, 2.711-2.703 (s) 3H, 1.75 (m) 2H, 1.44-1.42 (s) 9H and LCMS m/z: 334.9.
Method 2:

To a solution of 2-mercapto-5-methyl-1,3,4-thiadiazole (64.5 g, 1.0 eq) and 200 mL N,N-dimethylformamide was added Sodium carbonate (50 g, 1.1 eq) at 25-30°C. To the reaction mass was added (3R,5S)-6-chloro-3,5-dihydroxyhexanoate (100 gm, 1.0 eq) and TBAB (1 gm, 0.1eq). The reaction mass was maintained at the same temperature until the starting material absent by HPLC. After completion of the reaction dichloromethane (600 mL) and water (400 mL) was added to the reaction mass. The organic layer was separated dried over Na2SO4 and concentrated under vacuum to get tert-butyl (3R,5S)-3,5-dihydroxy-6- ((5-methyl-1,3,4-thiadiazol-2 yl)thio)hexanoate (133.0gm, 96.0% yield).
Example 2:
Preparation of tert-butyl 2-((4R,6S)-2,2-dimethyl-6-(((5-methyl-1,3,4-thiadiazol-2-yl)thio)methyl)-1,3-dioxan-4-yl)acetate

A mixture of tert-butyl (3R,5S)-3,5-dihydroxy-6-((5-methyl-1,3,4-thiadiazol-2-yl)thio)hexanoate (100.0gm,1.0eq) and 2,2-Dimethoxypropane(68.5g,2.2eq) is cool to 10-15°C and the add methane sulfonic acid(1.0gm,0.1w)into the flask. Maintain the reaction for 1-2hrs.Progess of the reaction monitor by TLC. After completion of TLC charge MDC (300.0ml) and 5% sodium carbonate solution (300.0ml) in the flask. Stir the reaction for 15mins and layer separation. The separated organic distil under vacuum to yielded as the titled compound (106.0gm, 94.7%).
Example 3:
Preparation of 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

To a solution of tert-butyl 2-((4R,6S)-2,2-dimethyl-6-(((5-methyl-1,3,4-thiadiazol-2-yl)thio)methyl)-1,3-dioxan-4-yl)acetate (100 g, 1 eq), in DCM (500 mL) was added ammonium molybdate (5 gm, 0.05 eq), TBAB (1 g, 0.1 eq). The temperature of the reaction mass was raised to 35 to 40 0C, then slowly 30 % hydrogen peroxide (350 mL, 3.4 vol) was added to the reaction mass. The reaction was maintained at the same temperature for a period of 10-15 hrs. The progress of the reaction was monitored by TLC. After completion of the reaction 20% sodium carbonate solution was added to the reaction mass. The organic layer was separated dried over sodium sulphate and concentrated under vacuum. The obtained crude was triturated with isopropyl alcohol to obtain the desired product (101 g, yield 93%).
,CLAIMS:1. An improved process for the chiral diol sulfones compounds of formula (I)

formula (I)
wherein R1 is aryl, hetero aryl, heterocyclyl; wherein heterocyclyl is ;
R2 and R3 are each independently selected from C1 -4 alkyl, C1 -4 alkenyl, C3 -6 cycloalkyl, or R2 and R3 together with the carbon to which they are attached to form a cycloalkyl ring;
R4 is selected from C1 -4 alkyl, aryl, or aryl alkyl;
which comprises
a) reacting compound of formula (II)

formula (II)
with R1-SH compound of formula (III) in presence of suitable base, phase transfer catalyst and solvent give chiral diol sulphide compound of formula (IV); where in R1 is hetero aryl, heterocycle, aryl; wherein R1 and R4 are same as defined above;

formula (IV)
b) optionally isolating chiral diol sulphide compound of formula (IV);
c) reacting chiral diol sulphide compound of formula (IV) with alcohol protecting group of compound of formula (V);

formula (V)
in presence of an acid catalyst and in suitable solvent gives protected chiral diol sulphide compound of formula (VI); wherein R1, R2, R3 and R4 are same as defined above;

formula (VI)
d) optionally isolating the protected chiral diol sulphide compound of formula (VI);
e) oxidising protected chiral sulphide compound of formula (VI) with an oxidising agent in suitable solvent gives chiral diol sulfone compound of formula (I); wherein R1, R2, R3 and R4 are same as defined above.

2. A process for the preparation of compound of formula (IV)
which comprises
a) reacting compound of formula (II)

formula (II)
with R1-SH compound of formula (III) in presence of suitable base, phase transfer catalyst and solvent give chiral diol sulphide compound of formula (IV); where in R1 hetero aryl, heterocycle, aryl;
R4 is selected from C1 -4 alkyl, aryl, or aryl alkyl;

formula (IV)
b) optionally isolating chiral diol sulphide compound of formula (IV).

3. The process as claimed in claim 1 and 2, wherein the base is selected from sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, calcium carbonate, barium carbonate or mixture thereof.

4. The process as claimed in claim 1 and 2, wherein the base is sodium carbonate, potassium carbonate or mixture thereof.

5. The process as claimed in claim 1 and 2, wherein the oxidising agent is selected from hydrogen peroxide, MCPBA, peracetic acid, KMnO4 or mixture thereof.

6. The process as claimed in claim 1 and 2, wherein the catalysts are selected from tetrabutylammonium bromide, benzyl triethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, hexadecyltributylphosphonium bromide or mixture thereof.

7. The process as claimed in claim 1 and 2, wherein the catalyst is selected from tetrabutylammonium bromide.

8. The process as claimed in claim 1 and 2, wherein the solvents are selected from dimethyl formamide, dichloromethane, diglyme, monoglyme, acetonitrile, THF, 2-methyl THF and dimethylacetamide or mixture thereof.