FIELD OF THE INVENTION
The present invention relates to an improved process to prepare chiral diol sulfones of formula I.

wherein Ri and R2 each independently represent group selected from C1.4 alkyl, C1.4 alkenyl, C3-6 cycloalkyl, C6-10 aryl or C7.12 aralkyl, each of R] and R2 may be substituted and wherein Ri and R2 may form a ring together with the C-atom; R3 represents group selected from C1.5 alkyl, aryl or aralkyl.
In another embodiment, the present invention relates to an improved process to prepare statin compounds of formula VII or salt thereof from chiral diol sulfones of Formula I,
wherein A represents hydrophobic anchor or residue of an HMG-CoA reductase inhibitor selected from the group comprising of formulae VIII, IX and X.

BACKGROUND OF THE INVENTION
Chiral diol sulfones of formula I, are the key intermediate for the preparation of statins, a class of compounds useful as HMG CoA reductase inhibitors. Especially chiral diol sulfones of formula I are used in the preparation of unsaturated statin derivatives in which carbon-carbon double bond is formed such as anti-lipemic drugs such as Rosuvastatin, Fluvastatin and Pitavastatin.
Rosuvastatin is being marketed under the proprietary name CRESTOR^1, as an oral tablet; Fluvastatin is being marketed as its monosodium salt under the proprietary name LESCOL t as an oral tablet; and Pitavastatin is being marketed under the proprietary name Livalo!, as an oral tablet.
Rosuvastatin calcium:

2
[3]

Fluvastatin sodium:

In view of the importance of Lipid-lowering agents, several synthetic methods
have been reported in the literature to prepare Statins.

S02CH3 CH3
US RE37,314 E discloses a process for preparing Rosuvastatin, which is as shown below:

The difficulties in the above process were that the phosphorane intermediate may not be obtained in pure form readily. The purification of phosphorane intermediate is tedious and overall yield is extremely low. If phosphorane intermediate was obtained in pure form, its condensation with aldehyde intermediate does not result in right quality of Rosuvastatin which contains unacceptable quantity of impurities. Further, the intermediates are obtained as liquid, which makes it difficult to purify.
WO 2000/049014 discloses a process for the preparation of Rosuvastatin, which is as summarized below:

This process employs the use of phosphorane side chain, the preparation of side chain requires eight synthetic steps and involves expensive reagents. The process is uneconomical and time consuming; and hence, may not be appropriate for commercial scale operation.
Therefore, alternative approaches have been developed for preparation of statins wherein statin side chains are appropriately derivatized.
US 6,875,867 discloses a process for the preparation of Statin, which is as summarized below:
[5]

H3C CH3
cr^o o
CH3
wherein R represents , R4 represents aryl, alkyl,
aryialkyl or cycloalkyl and preferably phenyl; A represents hydrophobic anchor or residue of an HMG-CoA reductase inhibitor selected from a group comprising of formulae VIII, IX and X.

F
S02CH3 CH3
Formula VIII
Formula IX
H3C^
This process employs use of triflic anhydride to activate the alcohol functional group, in a mole ratio about 1.5:1 to about 2:1 with respect to alcohol. Triflic anhydride is an extremely hazardous and expensive component, which causes costly work-up procedures due to environmentally problematic waste streams.
[6]

IN 3028/MUM/2009 A discloses a process to prepare Rosuvastatin, which is as summarized below:

wherein R represents

R5 represents aryl such as

phenyl; A represents hydrophobic anchor or residue of an HMG-CoA reductase inhibitor selected from a group of formulae VIII, IX and X. The above process requires higher temperature for replacement of chloro group for the formation of sulphide intermediate. The chloro intermediate also decomposes with time at higher temperature and thereby results in poor yield of sulphide intermediate.
We have now found an improved process to prepare chiral diol sulfone compound of formula I without isolating sulfide compound, which is useful in the preparation of statin compounds or pharmaceutically acceptable salts thereof.
[7]

OBJECTIVE
The objective of the present invention is to provide an improved process for preparing chiral diol sulfone compound of formula I, which is cost effective and commercially feasible.
Another objective of the present invention is to provide an improved process to prepare chiral diol sulfone compound of formula I, wherein chiral diol alcohol of formula V is activated in situ and chiral diol sulfide of formula VII is optionally isolated.
Yet another objective of the present invention is to provide an improved process for preparing statin compounds by using chiral diol sulfone compound of formula I, which is simple, industrially applicable and economically viable.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for preparing chiral diol sulfone compound of formula I,
wherein Ri and R2 each independently represent group selected from C1.4 alkyl, CM alkenyl, C3.6 cycloalkyl, C6-10 aryl or C7.12 aralkyl, each of R| and R2 may be substituted and wherein Ri and R2 may form a ring together with the C-atom; R3 represents group selected from C1.5 alkyl, aryl or aralkyl which comprises:
a) reacting chiral diol alcohol of formula V,
[8]

v
wherein Ri, R2 and R3 are same as defined above
with 2-mercaptobenzothiazole in presence of azodicarboxylate and phosphorus compound in a solvent to obtain sulfide compound of formula VI; and

wherein Ri, R2 and R3 are same as defined above b) oxidizing the chiral diol sulfide compound of formula VI using an oxidizing agent to give chiral diol sulfone compound of formula I.
In another aspect, the present invention relates to a process for the preparation of statin compound of formula VII or pharmaceutically acceptable salts thereof from sulfone compound of formula I,
OH OH O
^. III Formula VII
A--^^\^\^\ 0H
wherein A represents hydrophobic anchor or residue of an HMG-CoA reductase inhibitor selected from a group comprising of formulae VIII, IX and X.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for preparing chiral diol sulfone compound of formula I, which comprises:
a) reacting chiral diol alcohol of formula V with 2-mercaptobenzothiazole in presence of azodicarboxylate and phosphorus compound in a solvent to obtain sulfide compound of formula VI; and
b) oxidizing the chiral diol sulfide compound of formula VI using an oxidizing agent to give chiral diol sulfone compound of formula I.
[9]

In one embodiment of the present invention, the azodicarboxylate is selected from
a group comprising of dialkylazodicarboxylate, diarylazodicarboxylate and
diheterocyclicazodicarboxylate. The dialkylazodicarboxylate is selected from a
group comprising of Diisopropylazodicarboxylate [DIAD],
Diethylazodicarboxylate [DEAD], Dimethylazodicarboxylate [DMAD], Ditert-
butylazodicarboxylate [DTAD] and the like. The diarylazodicarboxylate is Di(4-
chlorobenzyl)azodicarboxylate [DCAD] or the like. The
diheterocyclicazodicarboxylate is 1,1 -(Azodicarbonyl)dipiperidine [ADDP] or the like.
In yet another embodiment of the present invention, the phosphorus compound is
selected from triphenylphosphine [TPP] or phosphorane ylides. The phosphorane
ylides are selected from a group comprising of
(Cyanomethylene)triphenylphosphorane, (Cyanomethylene)tributylphosphorane and the like.
In yet another embodiment of the present invention, the reaction of chiral diol alcohol of formula V with 2-mercaptobenzothiazole is carried out in monophasic solvent system or biphasic solvent system. The monophasic solvent is selected from a group comprising of tetrahydrofuran, ethers and mixtures thereof. The biphasic solvent is selected from a group comprising of toluene, methylene chloride, ethylacetate and mixtures thereof.
In yet another embodiment of the present invention, the chiral diol sulfide compound of formula VI is oxidized using an oxidizing agent in the presence or absence of a catalyst at a temperature ranging from -20°C to +50°C in a solvent. The oxidizing agent is selected from a group comprising of hydrogen peroxide, 3-chloroperoxybenzoic acid, peroxyacetic acid, monoperoxyphthalic acid, perborates, N-oxides, permanganates, chromates, chlorates, bromates, perchlorates, periodates, tert-butylhydroperoxides, oxones and air/oxygen. The
[10]

catalyst is selected from a group comprising of salts or oxides of Vanadium (V), Cerium (Ce), Manganese (Mn), Nickel (Ni), Iron (Fe), Copper (Cu), Osmium (Os), Molybdenum (Mo), Tungsten (W), Rhenium (Re) and Ruthenium (Ru). The oxidation reaction is carried out in a solvent selected from a group comprising of acetone, dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, 2-propanol, acetonitrile, acetic acid, toluene, water, N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), tetrahydrofuran, methyl tert-butyl ether (MTBE) and mixtures thereof. The solvent system used for oxidation is selected from monophasic solvent system or biphasic solvent system.
In yet another embodiment, the oxidation is carried out in biphasic solvent system
comprising of an aqueous phase and an organic phase in the presence of a phase
transfer catalyst to give chiral diol sulfone of formula I. The phase transfer
catalyst is quaternary ammonium salts selected from a group comprising of tetra-
n-butyl ammonium bromide, tetramethylammonium chloride,
tetramethylammonium hydroxide, tetraethylammonium bromide,
tetraethylammonium chloride, tetraphenylammonium bromide and tetraphenylammonium borate.
In yet another aspect, the present invention provides a process for the preparation of sulfone compound of formula-I, by preparing sulfide compound of formula VI in situ and oxidizing to give sulfone compound of formula I.
In yet another aspect of the present invention, the chiral diol sulfone compound of the Formula I, is further converted to statin compound of formula VII or pharmaceutical acceptable salt thereof by methods known in the art.
The present inventors have observed following advantages of the present invention:
> Direct conversion of alcohol compound to the sulfide compound
> Simpler work-up and isolation procedure
[11]

> Cost effective process
> High yield.
The invention is illustrated with the following examples, which should not be construed to limit scope of the invention in manner whatsoever.
EXAMPLE-1
PREPARATION OF tert-BUTYL 2-[(4/?,65)-6-[(BENZO[d]THIAZOL-2-
YLSULFONYL)METHYL]-2,2-DIMETHYL-l,3DIOXAN-4-YL]ACEATE
[CH1RAL DIOL SULFONE]
tert-Butyl 2-[(47?,65)-2,2-dimethyl-6-(hydroxymethyl)-l,3-dioxan-4-yl]acetate (85 g) was dissolved in 500 ml of tetrahydrofuran at 20-30°C. The reaction mass was cooled to 0-5°C and 2-mercaptobenzothiazole (56.5 g), triphenyl phosphine (95.5 g) was added. Thereafter, diisopropylazodicarboxylate (73.57 g) was slowly added to the above reaction mass in -30 min at 0-5°C. Reaction was continued at 0-5°C and progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was concentrated at 30-40°C under reduced pressure and obtained sulfide compound was taken as such for oxidation.
The above obtained sulfide compound was dissolved in 500 ml of acetic acid and 150 ml of water. It was cooled to 10-15°C and potassium permanganate (62.78 g) was added to it. The reaction was continued stirring at 10-15°C till completion of reaction which was monitored by HPLC. Thereafter, -10% aqueous sodium metabisulfite solution (1.0 L) was added to the reaction mass. The product was extracted with ethyl acetate (500ml x 2), washed with 500 ml of -10% w/w aqueous sodium chloride solution and concentrated to obtain the crude chiral diol sulfone product. The crude product was further crystallized from isopropyl alcohol and dried at 40-45°C under reduced pressure to obtain title compound. Yield: 100 g Chromatographic Purity (By HPLC): 99 %
[12]

EXAMPLE-2
PREPARATION OF tert-BUTYL 2-[(4y?,6S)-6-[(BENZO[d]THIAZOL-2-
YLSULFONYL)METETYL]-2,2-DIMETHYL-1,3-DIOXAN-4- YLJ ACEATE
[CH1RAL DIOL SULFONE]
/