WO2014108795A2

WO2014108795A2 - An improved process for the preparation of chiral diol sulfones and statins

Info

Publication number: WO2014108795A2
Application number: PCT/IB2014/000017
Authority: WO
Inventors: Sukumar Nandi; Vijay Kumar Handa; Balanarasimha Reddy Gona; Shanthan Kumar Reddy KANKANALA; Sivakumaran Meenakshisunderam
Original assignee: Aurobindo Pharma Limited
Priority date: 2013-01-10
Filing date: 2014-01-06
Publication date: 2014-07-17
Also published as: WO2014108795A3; WO2014108795A9; WO2014108795A8

Abstract

The present invention relates to an improved process to prepare chiral diol sulfones of formula (I), wherein R₁ and R₂ each independently represent group selected from C_1-4alkyl, C_1-4 alkenyl, C_3-6 cycloalkyl, C_6-10 aryl or C_7-12 aralkyl, each of R₁ and R₂ may be substituted and wherein R₁ and R₂ may form a ring together with the C-atom; R₃ represents group selected from C_1-5 alkyl, aryl or aralkyl.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF CHIRAL DIOL SULFONES AND STATINS

FIELD OF THE INVENTION

The present invention relates to an improved process to prepare chiral diol sulfones of Formula I.

Formula I wherein Ri and R₂ each independently represent group selected from C_1-4 alkyl, C_1-4 alkenyl, C_3-6 cycloalkyl, C_6-io aryl or C_7-12 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 Ci_-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,

Formula VIII

wherein 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 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:

Formula II

Formula III

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.

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: w

herein R represents , R4 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 or XI. ^j

Formula IX Formula X

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:

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 comprising of formulae IX, X and XI. The above process requires higher temperature for replacement of chloro group for the formation of sulfide intermediate. The chloro intermediate also decomposes with time at higher temperature and thereby results in poor yield of sulfide intermediate.

We have now found an improved process to prepare chiral diol sulfone compound of Formula I, which is useful in the preparation of statin compounds or pharmaceutically acceptable salts thereof. 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 com ound of Formula I,

Formula I

wherein Ri and R₂ each independently represent group selected from C_1-4 alkyl, Ci-4 alkenyl, C_3-6 cycloalkyl, C_6-10 aryl or C -i₂ 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 C_1-5 alkyl, aryl or aralkyl

which comprises:

a) activating chiral diol alcohol of Formula V,

Formula V

wherein R_\, R₂ and R₃ are same as defined above

with activating agent to give activated compound;

b) reacting the activated compound with 2-mercaptobenzothiazole to give chiral diol sulfide of Formula VII

Formula VII

wherein R_ls R₂ and R₃ are same as defined above

c) optionally, isolating chiral diol sulfide compound of formula VII; and d) oxidizing the chiral diol sulfide compound of Formula VII using an oxidizing agent to give chiral diol sulfone of Formula I.

In one aspect, the present invention relates to an improved process for preparing chiral diol sulfone compound of Formula I, which comprises:

a) activating chiral diol alcohol of Formula V with nosyl chloride as an activating agent to give activated compound;

b) reacting the activated compound with 2-mercaptobenzothiazole to give chiral diol sulfide of Formula VII;

In another aspect, the present invention relates to an improved process for preparing chiral diol sulfone compound of Formula I, which comprises:

a) activating chiral diol alcohol of Formula V with azodicarboxylate and phosphorous compound as an activating agents to give activated compound;

In yet 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,

Formula VIII

wherei 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

DETAILED DESCRIPTION OF THE INVENTION

Formula I

wherein R] and R₂ each independently represent group selected from C_1-4 alkyl, C_1-4 alkenyl, C_3-6 cycloalkyl, C_6-10 aryl or C_7-12 aralkyl, each of

and R₂ may be substituted and wherein Ri and R₂ may form a ring together with the C-atom; R₃ represents group selected from C_1-5 alkyl, aryl or aralkyl

which comprises: a) activating chiral diol alcohol of Formula V,

^Rl X- ^R2

(J O O „ ,

■ I II Formula V wherein Ri, R₂ and R₃ are same as defined above

with activating agent to give activated compound;

b) reacting the activated compound with 2-mercaptobenzothiazole to give chiral diol sulfide com ound of Formula VII; Formula VII

wherein R_l5 R₂ and R₃ are same as defined above; and

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

In one aspect, the present invention provides a process for preparing chiral diol sulfone compound of formula I, which comprises :

a) reacting chiral diol alcohol of Formula V with nosyl chloride in a solvent to give nosylate compound of Formula VI,

Formula VI

wherein R_\, R₂ and R₃ are same as defined above;

b) condensing the 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 of Formula I. In another aspect, the present invention provides a process for preparing chiral diol sulfone compound of formula I, which comprises:

a) reacting chiral diol alcohol of Formula V with 2-mercaptobenzothiazple in presence of azodicarboxylate and phosphorus compound in a solvent to obtain chiral diol sulfide compound of formula VII; and

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

In one embodiment, the chiral diol alcohol of Formula V is reacted with nosyl chloride in the presence of a base selected from a group comprising of triethylamine, pyridine, diisopropylethylamine, N-methylmorphoIine, 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 base selected from a group comprising of N-methylmorpholine, pyridine, piperidine and pyrrolidine 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 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 [DM AD], Ditert- butylazodicarboxylate [DTAD] and the like. The diarylazodicarboxylate is Di(4- chlorobenzyl)azodicarboxylate [DCAD] or the like. The diheterocyclicazodicarboxylate is l,l-(Azodicarbonyl)dipiperidine [ADDP] or the like. In yet another embodiment, 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, 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 system solvent is selected from the group comprising of toluene, methylene chloride, ethylacetate and mixtures thereof.

In yet another embodiment, the chiral diol sulfide compound of formula VII 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 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 solvent is selected from a group comprising of acetone, _N 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.

In yet another embodiment, the solvent system used for oxidation is selected from monophasic solvent system or biphasic solvent system. The oxidation is preferably 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 selected from a group comprising of quaternary ammonium salts such as 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, which comprises in situ activation of chiral diol compound of formula V to get chiral diol sulfide compound of formula VII and oxidizing the sulfide compound of formula VII to give chiral diol sulfone compound of formula I.

In one more aspect of the present invention, the chiral diol sulfone compound of the Formula I prepared according to present invention is further converted to statin compounds of formula VIII or pharmaceutical acceptable salts thereof by methods known in the art.

The present inventors have observed the following advantages of the present invention:

> Isolation of nosylate compound as a stable intermediate

Control over quality of the intermediates

> Replacement of nosyl group easily.

High yields

Cheaper and economically viable

Solvent free reaction conditions

> direct conversion of alcohol compound to the sulfide compound

> simpler work-up and isolation procedure.

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- NITROPHENYLSULFO YLOXY)METHYL-l,3-DIOXAN-4-YL]ACETATE

[NOSYLATE COMPOUND]

To a solution of tert-Butyl 2-[(4i?,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 ?,6.9)-6-[(BENZO[</lTHIAZOL-2- YLTHIO)METHYL]-2,2-DIMETHYL-l,3-DIOXAN-4-YL]ACEATE [CHIRAL DIOL SULFIDE]

Nosylate compound (10 g, 0.022 mole), 2-mercaptobenzothiazole (3.75 g, 0.022 mole) and N-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 isopropyt alcohol (60 ml) and taken for next step. EXAMPLE-3

PREPARATION OF tert-BUTYL 2-[(4Λ,65 6-[(ΒΕΝΖΟ[< )ΤΗΙΑΖΟί-2- YLSULFONYL)METHYL]-2,2-DIMETHYL-l,3-DIOXAN-4-YL]ACEATE

[CHIRAL DIOL SULFONE]

The solution of chiral diol sulfide 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 IP A (35 ml) to obtain title product.

Yield: 7 g

Chromatographic Purity (by HPLC): 99.5% EXAMPLE-4

PREPARATION OF tert-BUTYL 2-[(4R,6S)-6-[(BENZO[d]THIAZOL-2- YLSULFONYL)METHYL]-2,2-DIMETHYL-l,3-DIOXAN-4-YL]ACEATE

[CHIRAL DIOL SULFONE]

/ert-Butyl 2-[(4/?,6S)-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 % EXAMPLE-5

PREPARATION OF tert-BUTYL 2-[(4R,65)-6-[(BENZO[d]THIAZOL-2- YLSULFONYL)METHYL]-2,2-DIMETHYL-l,3-DIOXAN-4-YL]ACEATE

[CHIRAL DIOL SULFONE]

tert-B tyl 2-[(4i?,65)-2,2-dimethyl-6-(hydroxymethyl)-l,3-dioxan-4-yl]acetate (200 g) was dissolved in 1.0 L of tetrahydrofuran at 20-30°C. The reaction mass was cooled to 0-5 °C and 2-mercaptobenzothiazole (131.0 g), triphenyl phosphine (221.69 g) was added. Thereafter, diisopropylazodicarboxylate (170.9 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 1.0 L of acetic acid and 300 ml of water. It was cooled to 10-15°C and potassium permanganate (243.0 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 (2.0 L) was added to the reaction mass. The product was extracted with ethyl acetate (1.0 L x 2), washed with 1.0 L of -10% w/w aqueous sodium chloride solution and concentrated to obtain the crude chiral diol sulfone product. It was further crystallized from isopropyl alcohol and dried at 40-45°C under reduced pressure to obtain title compound.

Yield: 240g

Chromatographic Purity (by HPLC): 99.3% EXAMPLE-6

PREPARATION OF tert-BUTYL 2-((4Λ,65 -2,2-ΒΙΜΕΤΗΥ£-6-[(£)-2-[4-(4-

FLUOROPHENYL)-6-ISOPROPYL-2-[iV-METHYL( V-METHYLSULFONYL)-

AMINO]PYRIMIDIN-5-YL]VINYL]-l^-DIOXAN-4-YL]ACETATE

[DIPROTECTED ROSUVASTATIN]

A mixture of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-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% EXAMPLE-7

PREPARATION OF (3R,5S,6E) 7-[4-(4-FLUOROPHENYL)-6-ISOPROPYL-2-[JV- METHYL(N-METHYLSULFONYL)AMINO]PYRIMIDIN-5-YLI-3,5- DIHYDROXY-6-HEPTENOIC ACID, ferf-BUTYL ESTER [ROSUVASTATIN tert- BUTYL ESTER]

Diprotected tert-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 S

PREPARATION OF (3R,5S,6E) 7-[4-(4-FLUOROPHENYL)-6-ISOPROPYL-2-[ METHYL(N-METHYLSULFONYL)AMINO]PYRIMIDIN-5-YL]-3,5- DIHYDROXY-6-HEPTENOIC ACID, CALCIUM SALT [ROSUVASTATIN CALCIUM]

Rosuvastatin tert-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 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: 18 g

Chromatographic Purity (by HPLC): 99.9%. Anti-isomer: 0.09% EXAMPLE-9

PREPARATION OF tert-BUTYL 2-[(4J?,65)-6-[(£)-2-(2-CYCLOPROPYL-4-(4- FLUOROPHENYL)QUEVOLIN-3-YL)VINYL]-2,2-DlMETHYL-l,3-DIOXAN-4- YL]ACETATE [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-10

PREPARATION OF tert-BUTYL (3/,,5S,6£)-7-[2-CYCLOPROPYL-4-(4- FLUOROPHENYL)QUINOLIN-3-YL]-3,5-DIHYDROXY-6-HEPTENOATE [tert- BUTYL PRAVASTATIN]

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-11

PREPARATION OF (3_JR,55,6£)-7-[2-CYCLOPROPYL-4-(4-FLUOROPHENYL)- QUINOLIN-3-YL]-3,5-DIHYDROXY-6-HEPTENOiC ACID CALCIUM SALT [PRAVASTATIN 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%

Claims

21 WE CLAIM:

1. A process for the preparation of sulfone compound of formula I,

Formula I

wherein Ri and R₂ each independently represent group selected from C alkyl, Ci_-4 alkenyl, C_3-6 cycloalkyl, C6-i₀ ryl or C_7-12 aralkyl, each of Ri and R₂ may be substituted and wherein Ri and R₂ may form a ring together with the C-atom; R represents group selected from C_1-5 alkyl, aryl or aralkyl which comprises:

a) activatin chiral diol alcohol of Formula V,

Formula V

wherein Ri, R₂ and R₃ are same as defined above

using activating agent selected from nosyl chloride or azodicarboxylate and phosphorous compound to give activated compound;

Formula VII

wherein Ri, R₂ and R₃ are same as defined above

c) optionally, isolating chiral diol sulfide of formula VII; and

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

2. 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.

3. 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, N-methylpyrrolidone (NMP), Dimethylsulfoxide (DMSO), tetrahydrofuran, Methyl tert-butyl ether (MTBE) and mixtures thereof.

4. 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).

5. The process according to claim 1, wherein the process for the preparation of chiral diol sulfone compound of formula I 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 VII; and

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

6. The process according to claims 1 and 5, wherein azodicarboxylate is selected from a group comprising of dialkylazodicarboxylate, diarylazodicarboxylate and diheterocyclic azodicarboxylate.

7. The process according to claims 1 and 5, wherein the azodicarboxylate is selected from a group comprising of diisopropylazodicarboxylate [DIAD], diethylazodicarboxylate [DEAD], dimethylazodicarboxylate [DMAD], ditert- butylazodicarboxylate [DTAD], di(4-chlorobenzyl)azodicarboxylate [DCAD] and l,l-(Azodicarbonyl)dipiperidine [ADDP].

8. The process according to claims 1 and 5, wherein the phosphorus compound is triphenylphosphine [TPP] or phosphorane ylide.

9. The process according to claim 5, wherein the solvent in step (a) is selected from a group comprising of tetrahydrofuran, ethers or mixtures thereof.

10. The process according to claim 5, wherein the solvent in step (a) is biphasic solvent selected from a group comprising of toluene, methylene chloride, ethylacetate and mixtures thereof.

11. The process according to claim 1, wherein the process for the preparation of chiral diol sulfone compound of formula I comprises:

a) reacting chiral diol alcohol of Formula V with nosyl chloride in presence of a base in a solvent to give nosylate compound of Formula

VI;

Formula VI

wherein R_ls R₂ and R₃ are same as defined above;

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

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

12. The process according to claim 11, wherein the base in step (a) is selected from a group comprising of triethylamine, pyridine, diisopropylethylamine, N- methylmorpholine, piperidine and pyrrolidine.

13. The process according to claim 11, wherein the solvent in step (a) is selected from a group comprising of toluene, methylene chloride, methyl tert-butyl ether and mixtures thereof.

14. The process according to claim 11, wherein the base in step (b) is selected from a group comprising of N-methylmorpholine, pyridine, piperidine and pyrrolidine.

15. The process according to claim 1 , wherein the obtained chiral diol sulfone compound of formula I is further converted to statin compound of formula VIII or pharmaceutically acceptable salts thereof

Formula VIII

wherein A represents hydrophobic anchor or residue of an HMG-CoA reductase inhibitor selected from a group comprising of formulae IX, X and

XI.

Formula IX Formula X Formula XI