FIELD OF THE INVENTION

The present invention relates to an improved process to prepare Chiral Diol sulfones of Formula I. wherein R| and R2 each independently represent group selected from CM alkyl, C1.4 alkenyl, C3.6 cycloalkyl, C6-10 aryl or C7.12 aralkyl, each of Ri 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 VIII 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 IX, X and XI.

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 Rosuvastatin, Fluvastatin and Pitavastatin. Rosuvastatin is being marketed under the proprietary name CRESTOR®, as an oral tablet; Fluvastatin is being marketed as its monosodium salt under the proprietary name LESCOL® as an oral tablet; and Pitavastatin is being marketed under the proprietary name Livalo®, as an oral tablet.

Rosuvastatin calcium:

Fluvastatin sodium:

Formula IV

In view of the importance of Lipid-lowering agents, several synthetic methods have been reported in the literature to prepare Statins. US RE37,314 E discloses a process for preparing Rosuvastatin, which is as shown below: The difficulty in the above process was 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. US 6,875,867 discloses a process for the preparation of statins, which is as summarized below: ' wherein R represents represents aryl, alkyl, arylalkyl or cycloalkyl and preferably phenyl; A represents hydrophobic anchor or residue of an HMG-CoA reductase inhibitor selected from the group comprising of formulae IX, X and XI. Formula IX Formula X Formula XI This process employs use of triflic anhydride 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.

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

OBJECTIVE

The objective of the present invention is to provide an improved process for preparing chiral diol sulfone compound of formula I with high yield and high purity. In yet another objective of the present invention is to provide an improved process for preparing statin 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 R1 and R2 each independently represent group selected from CM alkyl, CM alkenyl, C3.6 cycloalkyl, C6-10 aryl or C7.12 aralkyl, each of R| and R2 may be substituted and wherein R| 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, wherein R|, R2and R3 are same as defined above with nosyl chloride in the presence of a base in a solvent to give nosylate compound of Formula VI; wherein Ri, R2 and R3 are same as defined above b) condensing nosylate compound of Formula VI with 2-mercaptobenzothiazole in the presence of a base in the absence of solvent to give chiral diol sulfide compound of Formula VII; and wherein Ri, R2 and R3 are same as defined above c) oxidizing the chiral diol sulfide compound of Formula VII 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 VIII or pharmaceutically acceptable salts thereof from chiral diol sulfone compound of Formula I, wherein A represents hydrophobic anchor or residue of an HMG-CoA reductase inhibitor selected from the group of formulae IX, X or XI.

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 nosyl chloride in the presence of a base in a solvent to give nosylate compound of Formula VI;

b) condensing nosylate compound of Formula VI with 2-mercaptobenzothiazole in the presence of a base in the absence of solvent to give chiral diol sulfide compound of Formula VII; and

c) oxidizing the chiral diol sulfide compound of Formula VII using an oxidizing agent to give chiral diol sulfone compound of Formula I.

In one embodiment, the chiral diol alcohol of Formula V is reacted with nosyl chloride in presence of a base selected from a group comprising of triethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, piperidine and pyrrolidine; in a solvent selected from a group comprising of toluene, methylene chloride, methyl tert-butyl ether and mixtures thereof at a temperature ranging from -5 to 10°C, preferably at 0 to 5°C to give nosylate compound of Formula VI. In another embodiment, the nosylate compound of Formula VI is condensed with 2-mercaptobenzothiazole in the presence of a base selected from a group comprising of N-methylmorpholine, pyridine, piperidine and pyrrolidine to give chiral diol sulfide compound of Formula VII.. In yet another embodiment, the nosylate compound of Formula VI is condensed with 2-mercaptobenzothiazole in the absence of solvent at a temperature ranging from 60 to 100°C, preferably 80 to 90°C to give chiral diol sulfide compound of Formula VII.

In yet another embodiment, the chiral diol sulfide compound of Formula VII is oxidized using an oxidizing agent 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 in the presence or absence of a catalyst selected from a group comprising of salts or oxides of metals Vanadium (V), Cerium (Ce), Manganese (Mn), Nickel (Ni), Iron (Fe), Copper (Cu), Osmium (Os), Molybdenum (Mo), Tungsten (W), Rhenium (Re) and Ruthenium (Ru) at a temperature ranging from -20°C to 50°C. In yet another embodiment, the chiral diol sulfide compound of Formula VII is oxidized in a solvent selected from a group comprising of dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, 2-propanol, acetonitrile, acetic acid, toluene, water, NMP, DMSO, tetrahydrofuran, MTBE and mixtures thereof to give chiral diol sulfone of Formula I.

In yet another embodiment, the oxidation reaction is carried out in aqueous phase or in an organic phase in the presence of a phase transfer catalyst such as quaternary ammonium salts. In yet another aspect of the present invention, the compound of the Formula I prepared according to present invention is further converted to statin compound of formula VIII or pharmaceutical acceptable salt thereof by methods known in the art. The present inventors have found following advantages of the present invention:
> Isolation of nosylate compound as a stable intermediate.
> Control over quality of the intermediate.
> Replacement of nosyl group performed easily.
> High yields.
> Cheaper and economically viable.
> Solvent free reaction conditions.

The invention is illustrated with the following examples, which should not be construed to limit the scope of the invention in any manner whatsoever.

EXAMPLE-1

PREPARATION OF tert-BUTYL 2-[(4R,6S)-2,2-DIMETHYL-6-[(4-

NITROPHENYLSULFONYLOXY)METHYL-l,3-DIOXAN-4-YLlACETATE

[NOSYLATE COMPOUND]

To a solution of (ert-Buty\ 2-[(4/?,6S)-2,2-dimethyl-6-(hydroxymethyl)-l,3-dioxan-4-yl]acetate (50 g, 0.1923 mole) in toluene (300 ml) was added triethylamine (48.5 g, 0.48 mole) at 20-30°C. It was cooled to 0-5°C under nitrogen atmosphere and added a solution of nosyl chloride (51.1 g, 0.23 mole) dissolved in toluene (100 ml) slowly at 0-5°C. The resulting reaction mixture was stirred until TLC analysis indicated consumption of starting material (~3h). The reaction mixture was quenched by pouring into cold water (500 ml). The organic phase was washed with dilute acetic acid (30 ml diluted with DM water 400 ml) followed by washing with water (2 x 400 ml) at 20-30°C. The solvent was concentrated under reduced pressure at 40-50°C to obtain a solid mass. Hexanes (200 ml) was added and stirred for lh at 20-30°C. Product was isolated by filtration and dried under reduced pressure at 40-45°C to obtain title compound. Yield: 75 g Chromatographic Purity (by HPLC): 99%

EXAMPLE-2

PREPARATION OF tert-BUTYL 2-[(4/?,65')-6-[(BENZO[rf]THIAZOL-2- YLTHIO)METHYL]-2,2-DIMETHYL-1,3-DIOXAN-4-YL] ACE ATE [CHIRAL DIOL SULPHIDE] Nosylate compound (10 g, 0.022 mole), 2-mercaptobenzothiazole (3.75 g, 0.022 mole) and JV-Methylmorpholine (2.72 g, 0.027 mole) were mixed and heated at 80-90°C until HPLC analysis indicated consumption of the starting material (~3h). The reaction mixture was cooled to 20-30°C and methylene chloride (20 ml) was added to dissolve the reaction mass. It was washed with DM water (50 ml) and diluted with isopropyl alcohol (60 ml) and taken for next step.

EXAMPLE-3

PREPARATION OF tert-BUTYL 2-[(4JR,6S)-6-[(BENZO[rf]THIAZOL-2- YLSULFONYL)METHYL]-2,2-DIMETHYL-l,3-DIOXAN-4-YL]ACEATE [CHIRAL DIOL SULFONE] The solution of chiral diol sulphide was mixed with methylene chloride (20 ml) and isopropyl alcohol (60 ml) and cooled to 0-5°C. To the obtained solution 30% w/w solution of hydrogen peroxide (10.16 g) and ammonium molybdate tetrahydrate (1.4 g) were added slowly over a period of 30 min. The reaction mass was stirred at 20-30°C and stirred for 16 h and progress of the reaction was monitored by HPLC. Thereafter, water (100 ml) was added to the reaction mass and product was extracted with methylene chloride, washed with sodium metabisulphite and then with aqueous sodium chloride (100 ml). Solvents were evaporated under reduced pressure at 40-45°C to obtain the product as a thick oily mass which was further crystallized from IPA (35 ml) to obtain title product. Yield: 7 g Chromatographic Purity (by HPLC): 99.5%

EXAMPLE-4

PREPARATION OF tert-BUTYL 2-[(4/?,6S)-2,2-DIMETHYL-6-[(£)-2-[4-(4- FLUOROPHENYL)-6-ISOPROPYL-2-[A^-METHYL(7V-METHYLSULFONYL)- AMINO]PYRIMIDIN-5-YL]VINYL]-l,3-DIOXAN-4-YL]ACETATE [D1PROTECTED ROSUVASTATIN] A mixture of 4-(4-fluorophenyl)-6-isopropyl-2-(A/-methyl-iV-methylsulfonyl amino)pyrimidine-5-ylcarboxaldehyde (50 g, 0.142 mole) and chiral diol sulphone (62.82 g, 0.142 mole) was dissolved in tetrahydrofuran (750 ml) at 40-45°C. The above reaction mass was cooled to -75 to -80°C and thereafter potassium tert-butoxide (22.33 g, 0.199 mole) was dissolved in tetrahydrofuran (100 ml) slowly at -80°C to -75°C over a period of 45 min. Stirring was continued till pyrimidine carboxaldehyde was consumed (~1 h) and the progress of reaction was monitored by HPLC. After completion of the reaction, 20% aqueous ammonium chloride solution (500 ml) was added to the reaction mass at -75° to -80°C. Thereafter, temperature was raised to 20-30°C. The product was extracted with ethyl acetate (2 x 250 ml), washed with 10% w/w aqueous sodium chloride (500 ml) and solvent was evaporated under reduced pressure at 40-45°C. Thereafter, methanol (750 ml) was added to the concentrated mass and heated to 60-65°C to obtain a clear solution. It was cooled to 0-5°C and the title compound was isolated by filtration. Yield: 65 g Chromatographic Purity (by HPLC): 99%

EXAMPLES

PREPARATION OF (3R,5S,6E) 7-[4-(4-FLUOROPHENYL)-6-ISOPROPYL-2-[7V- METHYL(/V-METHYLSULFONYL)AMINO]PYRIMIDIN-5-YL]-3,5- DIHYDROXY-6-HEPTENOIC ACID, tert-BVTYL ESTER [ROSUVASTATIN tert- BUTYL ESTER] Diprotected /er/-butyl Rosuvastatin (30 g, 0.052 mole) was suspended in acetonitrile (210 ml) and water (70 ml) at 25-30°C. The pH of the reaction mass was adjusted to 2.5 with dilute hydrochloric acid (0.1 molar). Thereafter, the reaction mass was heated to 50-55°C and progress of the reaction was monitored by HPLC. After completion of reaction, pH of the reaction mass was adjusted to 8.5 with aqueous ammonia and stirred for 30 min. Product was filtered and dried at 40-45°C under reduced pressure to obtain title compound. Yield: 27 g Chromatographic Purity (by HPLC): 99.7%, Lactone diastereomer: 0.03%

EXAMPLE-6 PREPARATION OF (3R,5S,6E) 7-[4-(4-FLUOROPHENYL)-6-ISOPROPYL-2-[7V- METHYL(Af-METHYLSULFONYL)AMINO]PYRIMIDIN-5-YL]-3,5- DIHYDROXY-6-HEPTENOIC ACID, CALCIUM SALT [ROSUVASTATIN CALCIUM] Rosuvastatin ter/-butyl ester (20 g, 0.037 mole) was dissolved in a mixture of ethanol (100 ml) and tetrahydrofuran (20 ml) at 20-30°C. It was cooled to 0-5°C and added an aqueous solution of sodium hydroxide (1.53 g, Assay 97%, dissolved in 15 ml of water) slowly over a period of 30 min. Thereafter, temperature of the reaction mass was raised to 20-30°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, pH of the reaction mass was adjusted to 10 with dilute HC1 and solvents were evaporated under reduced pressure. Water (200 ml) was added to it and extracted with methyl /£r/-butyl ether (50). Traces of solvents were evaporated from the aqueous layer and aqueous calcium chloride was added at 20-25°C. The precipitated product was isolated by filtration and dried under reduced pressure at 30-40°C to obtain title compound. Yield: 18 g Chromatographic Purity (by HPLC): 99.9%. Anti-isomer: 0.09%

EXAMPLE-7 PREPARATION OF tert-BUTYL 2-[(4/f,65)-6-[(J?)-2-(2-CYCLOPROPYL-4-(4-FLUOROPHENYL)QUINOLIN-3-YL)VINYL]-2,2-DIMETHYL-l,3-DIOXAN-4-YLJACETATE [DIPROTECTED PRAVASTATIN] A mixture of 2-Cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxaldehyde (50 g, 0.171 mole) and chiral diol sulphone (75.77 g, 0.171 mole) was dissolved in tetrahydrofuran (750 ml) at 40-45°C. The above reaction mass was cooled to -75 to -80°C and thereafter potassium tert-butoxide (26.94g, 0.24 mole) was dissolved in tetrahydrofuran (100 ml) slowly at -80°C to -75°C over a period of 45 min. Stirring was continued till starting material was consumed (~1 h) and the progress of reaction was monitored by HPLC. After completion of the reaction, 20% aqueous ammonium chloride solution (500 ml) was added to the reaction mass at -75° to -80°C. Thereafter, temperature was raised to 20-30°C. The product was extracted with ethyl acetate (2 x 250 ml), washed with 10% w/w aqueous sodium chloride (500 ml) and solvent was evaporated under reduced pressure at 40-45°C. Thereafter, methanol (750 ml) was added to the concentrated mass and heated to 60-65°C to obtain a clear solution. It was cooled to 0-5°C and product was isolated by filtration to obtain title compound. Yield: 62 g Chromatographic Purity (by HPLC): 99.2%

EXAMPLE-8

PREPARATION OF ter/-BUTYL (3JR,55,6£)-7-[2-CYCLOPROPYL-4-(4- FLUOROPHENYL)QUINOLIN-3-YL]-3,5-DIHYDROXY-6-HEPTENOATE [tert- BUTYL PITAVASTATIN] Diprotected tert-butyl Pitavastatin (30 g, 0.058 mole) was suspended in acetonitrile (210 ml) and water (70 ml) at 25-30°C. The pH of the reaction mass was adjusted to 2.5 with dilute hydrochloric acid (0.1 molar). Thereafter, the reaction mass was heated to 50-55°C and progress of the reaction was monitored by HPLC. After completion of reaction, pH of the reaction mass was adjusted to 8.5 with aqueous ammonia and stirred for 30 min. Product was filtered and dried at 40-45°C under reduced pressure to obtain title compound. Yield: 27 g Chromatographic Purity (by HPLC): 99.6%, Lactone diastereomer: 0.09%

EXAMPLE-9

PREPARATION OF (S^SS^^-P-CYCLOPROPYL-^-FLUOROPHENYL)- QUINOLIN-3-YL]-3,5-DIHYDROXY-6-HEPTENOIC ACID CALCIUM SALT [PITAVASTATIN CALCIUM] Pitavastatin tert-butyl ester (20 g, 0.042 mole) was dissolved in a mixture of ethanol (100 ml) and tetrahydrofuran (20 ml) at 20-30°C. It was cooled to 0-5°C and added an aqueous solution of sodium hydroxide (1.72 g, Assay 97%, dissolved in 15 ml of water) slowly over a period of 30 min. Thereafter, temperature of the reaction mass was raised to 20-30°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, pH of the reaction mass was adjusted to 10 with dilute HC1 and solvents were evaporated under reduced pressure. Water (200 ml) was added to it and extracted with methyl tert-butyl ether (50). Traces of solvents were evaporated from the aqueous layer and aqueous calcium chloride was added at 20-25°C. The precipitated product was isolated by filtration and dried under reduced pressure at 30-40°C to obtain title compound. Yield: 15 g Chromatographic Purity (by HPLC): 99.8%. Anti-isomer: 0.09%

WE CLAIM:

1. A process for the preparation of chiral diol sulfone compound of formula I, wherein Ri and R2 each independently represent group selected from C^ alkyl, CM alkenyl, C3.6 cycloalkyl, C6-10 aryl or C7.12 aralkyl, each of Ri and R2 may be substituted and wherein R| 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, wherein Ri, R2and R3 are same as defined above with nosyl chloride in the presence of a base in a solvent to give nosylate compound of Formula VI; wherein Ri, R2 and R3 are same as defined above b) condensing nosylate compound of Formula VI with 2-mercaptobenzothiazole in the presence of a base in the absence of solvent to give chiral diol sulfide compound of Formula VII; and wherein R], R2 and R3 are same as defined above c) oxidizing the chiral diol sulfide compound of Formula VII using an oxidizing agent to give chiral diol sulfone compound of Formula I.

2. The process according to claim 1, wherein the base in step (a) is selected from a group comprising of triethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, piperidine and pyrrolidine.

3. The process according to claim 1, wherein the solvent in step (a) is selected from a group comprising of toluene, methylene chloride, methyl tert-butyl ether and mixtures thereof.

4. The process according to claim 1, wherein the base in step (b) is selected from a group comprising of N-methylmorpholine, pyridine, piperidine and pyrrolidine.

5. The process according to claim 1, wherein 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.

6. The process according to claim 1, wherein oxidation is carried out in a solvent selected from a group comprising of dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, 2-propanol, acetonitrile, acetic acid, toluene, water, NMP, DMSO, tetrahydrofuran, MTBE and mixtures thereof.

7. The process according to claim 1, wherein oxidation is carried out in presence of catalyst 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).

8. The process according to claim 1, wherein the compound of formula I is further converted into statin compound of formula VIII or pharmaceutically acceptable salt thereof, wherein A represents hydrophobic anchor or residue of an HMG-CoA reductase inhibitor selected from a group comprising of formulae IX, X and XI.

9. A process for the preparation of chiral diol sulfone of formula I substantially as described herein.