WO2008152462A1

WO2008152462A1 - A process of sulfoxidation of biologically active compounds

Info

Publication number: WO2008152462A1
Application number: PCT/IB2008/001423
Authority: WO
Inventors: Milind Moreshwar Gharpure; Golakchandra Sudarshan Maikap; Rajendra Dagesing Mahale; Satish Ramanlal Mehta; Mukund Keshav Gurjar; Mahesh Ramsing Rajput; Prashant Sadashiv Gawari
Original assignee: Emcure Pharmaceuticals Limited
Priority date: 2007-06-15
Filing date: 2008-06-04
Publication date: 2008-12-18
Also published as: EA201070021A1; KR20100020035A; BRPI0813191B1; KR101432866B1; BRPI0813191A2; ZA200908887B; EA016297B1

Abstract

The present invention relates to a new process for the preparation of sulfoxides, preferably stereoselective preparation of substituted or unsubstituted chiral sulfinyl derivatives 2-(2- pyridylmethyl) sulfinyl-l H-benzimidazole by oxidation with oxaziridine in presence of suitable solvent and base.

Description

A PROCESS OF SULFOXIDATION OF BIOLOGICALLY ACTIVE

COMPOUNDS

Field of the Invention:

The present invention relates to an improved process for the preparation of sulfoxides and more particularly the invention provides stereoselective preparation of substituted or unsubstituted chiral sulfϊnyl derivates of general formula (I) by oxidation with oxaziridine 10 in presence of suitable solvent and base. o Il

25

Ri=H; R₂ & R₃=H, CH₃, -OCH₃, -OCH₂CF₃, -

OCH₂CH₂OCH₃, - O (CH₂)S-OCH₃

R₄= H, CH₃ and R₅=H, -OCH₃, -OCHF₂, R'₈= OH, NH₂, OR'₉,

NHR' 9, and R'₉= Cl-4 alkyl 3⁰ A= CH, N

Background of the Invention:

Sulfoxides having an asymmetric center in the sulphur atom and hence, exist as two optical isomers i.e. enantiomers. It is desirable to obtain compounds with improved 35 pharmacokinetic and metabolic properties, which will give an improved therapeutic profile such as a lower degree of interindividual variation.

Compounds of general formula (I) are usually prepared from corresponding sulfide intermediates by the oxidation of thioether group using different oxidizing agents. Such

40 prior art processes are generally accompanied by the formation of the corresponding sulfone derivatives as impurities. Furthermore, also the un-reacted sulfides may present as impurities in final product. The highly similar nature of physiochemical properties of the accompanying impurities complicates their separation, thus rendering the product of interest prone to contamination.

The sulfone impurity is formed during the sulfide to sulfoxide conversion due to over oxidation is alarming. The sulfone impurity is mainly due to over oxidation, which inturn is related to oxidizing agents. The oxidation thus needs to be controlled.

US 5,929,244 discloses a method for the preparation of esomeprazole by utilizing (3'S, 2R)-(-)-N-(phenylsulphonyl)-(3, 3-dichlorocamphoryl) oxaziridine in the presence of triethyl amine as a base and carbon tetrachloride as solvent. The optical purity is 94%, but however, the yield obtained is only 22%, thereby making the process unfeasible for commercial use. This is also compounded by the use of carbon tetrachloride as a solvent, which is banned on industrial scale.

US 5,948,789 describe an enantioselective synthesis of the single enantiomer of 2-(2- pyridinylmethylsulphinyI)-l H-benzimidazoles as well as of other structurally related sulphoxides. The process of oxidation is carried out in the presence of a base, oxidizing agent, chiral titanium complex and a solvent. However, this process suffers a major disadvantage of high content of sulfone impurity formed in the process. Moreover, these methods have obvious drawbacks which require titanium isopropoxide, which is not recoverable and is hazardous to environment. Further the reagent used for chiral induction is diethyl-tartarate which is difficult to recover due to epimerization and hydrolysis during workup. The reagent used for oxidation is cumene hydroperoxide, which is explosive and hazardous, apart from being costly.

US 6,919,459 make a passing reference to the utilization of N-sulfonyloxaziridines for the oxidation of sulfides to sulfoxides. However, the said patent does not suggest nor disclose any method for such an oxidation with any N-sulfonyloxaziridines.

Journal of the Chemical Society, Perkin Transactions 1, 1988, 1753-7 teaches a method for the preparation of chiral sulfoxides utilizing (+)-(3-oxocamphorsulfonyl) oxaziridine. Enantiomeric excess maximum of about 60% was observed, which is a limitation for industrial purpose.

Chemical Sciences (1990), 45(12), 1689-94 discloses a method for oxidation of sulfides to sulfoxides with a camphorlactone-sulfonyloxaziridine, 3-endo-bromocamphorsulfonyl oxaziridine etc. A carcinogenic solvent like carbon tetrachloride was the preferred solvent as it gave the highest enantiomeric excess (upto 85%). Another limitation of "standard concentration" requires higher dilution for the preferred solvent disclosed in the lone example.

3-camphorlactonesulfonyloxaziridine 3-endo-bromocamphorylsulfonyl oxaziridine (IIA) (HB)

However, carbon tetrachloride is not utilized in pharmaceutical industry due to the carcinogenic and its highly toxic nature. Such mediocre enantiomeric excess is possible for the substrates having vast difference in both the sides of the sulfide group. For substrates such as benzyl phenyl sulfide the enantiomeric excess is drastically poor (36%).

The limitation is compounded by the utilization of carbon tetrachloride. Hence, the use of oxaziridine teaches away from substrates such as benzyl phenyl sulfide. Time required for the optional reaction can be even 160 hours. With lower reaction time, the enantiomeric excess is quite poor, which is way below the industrially acceptable limits.

Journal of Organic Chemistry 1992, 57(26), 7274-7285 discloses a method for the preparation of [(8, 8-dihalocamphoryl) sulfonyl] oxaziridines and a process for the oxidation of sulfides to sulfoxides using deuterated chloroform. On industrial scale, the use of deuterated solvents is prohibitively expensive. Also, this reference teaches the use of carbon tetrachloride as solvent, which is not industrially permissible as referred earlier. Furthermore, the enantiomeric excess of the desired isomer obtained is in the range of 1 - 75%, which is very low for the preparation of any optically pure pharmaceutical compound. An effort to obtain such enantiomeric excess also requires stringent and prohibitive reaction temperature of -78⁰C for routine solvent.

Another method to carry out the enantioselective synthesis is by the use of chiral oxaziridines (III) (Journal of American Chemical Society 1992, 1 14, 1428-1437). Using chiral oxaziridines, the e.e is acceptable for the prochiral sulfides for example when prochiral sulfide has one very bulky substituent as 9-anthryl and the other one as methyl. The reaction is also solvent dependant and gives more e.e. in CCU₁ which is not at all environment friendly. The chiral oxirane used for the oxidation are

(III)

The e.e. is better, when X is halogen over hydrogen. Thus, use of chiral oxiranes to produce enantiomerically pure PPIs is not known in the art and at the same time it is limited due to: a) size of groups on prochiral sulfide, b) substitution on chiral oxaziridines, c) solvent etc.

Tetrahedron Asymmetry 1995, 6(12), 291 1-2914 discloses a method for the oxidation of sulfides to sulfoxides utilizing [(3,3-dimethoxycamphoryl) sulfonyl]oxaziridine (IV) in the presence of hydrogen peroxide. Utilization of this oxaziridine gives sulfoxides from non- aryl sulfides with good enantioselectivity.

[(3,3-dimethoxycamphoryl)sulfonyl]imine (IV) The disadvantage of this method lies in the fact that when aryl sulfides are oxidized the enantiomeric excess of the desired isomer is only around 61%, hence this method is not industrially feasible for oxidation of active pharmaceutical ingredients having an aryl substituents.

Indian Journal of Chemistry 2001, 4OB, 1 132-1133 teaches (Scheme-II) that alkyl alkylthiomethyl sulfides and aryl arylthiomethyl sulfides can be oxidized to the respective sulfoxides by 10-camphorsulfonyl oxaziridine with 70-80% yield and 90-95% enantioselectivity. In order to get such kind of product the purification necessitated is by using preparative thin layer chromatography. However, on an industrial scale such purification is not possible.

The method relates to oxidation of a sulfide group, which is flanked by either an aryl or alkyl group on one side or an alkyl group on the other side. There is no example of an oxidation wherein the sulfide group is flanked by a bulky group on either side, because a bulky group tends to alter the enantiomeric selectivity and there is a likelihood that a low enantiomeric selectivity would be obtained.

Tetrahedron Asymmetry 2003, 14, 407-410 teaches a method for the preparation of (R)- lansoprazole by utilizing a heterogenous catalytic system Of WO₃, 30% H₂O₂ and cinchona alkaloids. Industrial use of such a system is quite restricted due to the use of costly reagents like WO₃ and cinchona alkaloids. Further restriction is also due to hazards of H₂O₂.

Ternois James et. al. (Tetrahedron Asymmetry 18, 2007, 2959-2964) disclose a method for the enantioselective oxidation of the sulfide group to sulfoxide using an oxaziridine of formula (V) for preparation of certain pharmaceutical compounds.

However, there are several disadvantages associated with this method as referred herein. The method either utilizes carbon tetrachloride, ionic liquids and the reaction time is about 48 hours reducing the efficiency of the process.

Use of carbon tetrachloride has several adverse health effects, like carbon tetrachloride is a carcinogenic solvent, ozone depleting agent. Chronic exposure of carbon tetrachloride can affect the central nervous system, cause liver and kidney damage and could result in cancer. Further the use of ionic liquid like l-butyl-3-methylimidazolium hexafluorophosphate, which are known to be non-volatile, pose grave problems during drying of active pharmaceutical ingredients. Utilizing such ionic liquids can be used as solvent for their preparation, due to their non-volatility; also, these ionic liquids require the use of an ultrasonic device to degrade solutions of imidazolium-based ionic liquids with hydrogen peroxide and acetic acid to relatively innocuous compounds. Furthermore, the enantiomeric excess obtained by using oxaziridine reagent is upto 78%, which is insufficient.

Organic Letters 2007, 9(12), 2265-2268 discloses a method for the preparation of (R)- lansoprazole from the corresponding sulfide intermediate involving oxidation with an oxaziridine of formula (VI) obtained from an azacholesterol derivative.

The method requires low temperature of around -7O⁰C and provides only 60% conversion of the sulfide intermediate to the desired product. Due to the stringent temperature conditions and low product conversion, apart from the drawbacks of the oxidizing agents, this method is not suitable for industrial purpose.

Thus, there are number of problems like low yields and enantiomeric purity, recovery of chiral reagent used in the process, multiple extractions, increased hazards on the manufacturing site with respect to higher quantities of peroxides, use of expensive catalysts in the process are associated with the prior art process.

Hence, there is unmet need to develop a simple, cost effective, environment friendly process for the stereoselective preparation of chiral sulfinyl derivates, which is convenient to perform on a commercial scale, operationally safe and provide the product in high enantiomeric purity.

Objects of the Invention: An object of the present invention is to provide an improved, simple, cost effective and environment friendly process for the stereoselective preparation of substituted or unsubstituted chiral sulfinyl derivates of general formula (I) with good yield and high enantiomeric purity.

Summary of the Invention:

The present invention relates to an improved, simple, cost effective and environment friendly process for the stereoselective preparation of substituted or unsubstituted chiral sulfinyl derivates with less sulfone impurity and high enantiomeric purity by oxidation with oxaziridine in presence of suitable solvent and base.

Detailed Description of the Invention:

Accordingly, the present invention provides a process for preparing the compound of formula (I) comprising the steps of reacting the compound of formula (Ia) with an oxaziridine of formula (VII) in presence of a solvent and a base and isolating a compound of formula (I) as required for pharmaceutical substances.

(Ia) base / solvent (I)

Ri=H; R₂ & R₃=H, CH₃, -OCH₃, -OCH₂CF₃, - OCH₂(CH₂)OCH₃, - O (CH₂)S-OCH₃ R₄= H, CH₃ and R₅=H, -OCH₃, -OCHF₂, R'₈= OH, NH₂, OR' 9, NHR'g, and R'₉= Cl-4 alkyl A=CH,N R₉=Rio=H,X_/ -0-Cl-4 alkyl, -O-(CH₂)_n-O- where n=2 or 3 and

The process as discussed above causes asymmetric oxidation of a prochiral sulfide in order to obtain the enantiomerically enriched form of the corresponding sulfoxide, The sulphur atom from sulfide does not have asymmetry, whereas upon stereoselective oxidation the sulfoxide formed is present as chiral compound.

By such stereoselective oxidation, one of the enantiomers may be obtained in enantiomeric excess over the other.

For purposes of this invention, if

Wherein R₁=H; R₂ & R₃=H, CH₃₅-OCH₃₅-OCH₂CF₃, -OCH₂CH₂OCH₃, - O (CH₂)_3-OCH₃ R4=H, CH₃ and R5=H,-OCH₃,-OCHF₂, A=CH₅N then compound of formula (I) may be selected from the group comprising optically active prazoles such as pantoprazole, lansoprazole, rabeprazole, tenatoprazole, pariprazole and omeprazole or the compound as disclosed in US 5,776,765.

For purposes of this invention, if

Wherein R'₈=0H, NH₂, 0R'₉, NHR'₉, and R'₉= Cl-4 alky I then compound of formula (I) may be armodafinil as disclosed in US 4,927,855.

Modafinil has a stereogenic center at the sulphur atom and thus exists as two optical isomers i.e. enantiomers. Modafinil chemically known as 2-[(diphenylmethyl) sulfinyl] acetamide i.e. 2(benzhydrylsulfinyl) acetamide (B) and which can be prepared from respective sulfide (A), is a eugeroic drug generally prescribed to treat narcolepsy.

The R enantiomer of modafϊnil which is the preferential enantiomers is known as armodafinil and has chemical name 2-[(R)-(diphenylmethyl) sulfinyl] acetamide.thus, the process of the invention may be used for the preparation of any racemic sulfoxide, examples of which have been disclosed above.

For obtaining the racemic sulfoxides, the racemic oxaziridines may be used. The oxidizing agent used is compound of formula (VIII)

(VIII)

wherein one or more Of R₆, R₇ and Rg are chiral moieties having chiral center. Preferably it forms cyclic system. Preferably the oxidizing agent used in the present invention is dextrorotatory or levorotatory isomers of the (2R, 8aS)-10-(Camphoryl sulfonyl) oxaziridine as depicted in formula (VII). The (+) enantiomer i.e. (+)-(2R,8aS)-10- (camphorsulfonyl) oxaziridine is used to get the respective enantiomer of sulfoxide. The (- ) isomer of the same compound can also be used for obtaining the enantiomerically enriched compound.

i) R₉ = R₁₀ = H,

Ii) R₉ = R₁₀ = X = Cl₁ Br, I iii) R_s = Rio = -O- C, .₄ alky I , iv) R₉ = R₁₀ = -O-CH₂)_n-O- where n = 2,3. v) R₉ = R₁₀ = ketone, The chiral oxidizing agent used according to the process is chiral oxaziridine, which can be obtained without use of metal complexes such as titanium tetra isopropoxide. Titanium tetraisopropoxide is the enormous load on effluent treatment plant and hence it is not environment friendly.

The reaction of the present invention is carried in the presence of organic or inorganic base. The inorganic base is selected from the group comprising of hydroxides, alkoxides, and bicarbonates, carbonates of alkali or alkaline earth metals and preferred inorganic base is sodium hydroxide or potassium hydroxide. However, the preferred base is an organic base..

The organic base used is selected from the group comprising of 1,8-diazabicyclo [5.4.0] undec-7-ene, diisopropyl ethyl amine, hexamethylene tetra amine, triethyl amine and alike.

The preferred base utilized for the oxidation is 1,8-diazabicyclo [5.4.0] undec-7-ene.

The solvent used for the present invention is selected from the group of organic solvents comprising of alcohols, ethers, esters, amides, nitriles, aromatic hydrocarbons, water etc. or combinations thereof. The preferred solvents are selected from the group comprising of methanol, ethanol, isopropanol, butanol, diisopropyl ether, toluene, water, tetrahydrofuran, acetonitrile, dimethylformamide, diethylformamide, dimethoxyethane or combinations thereof etc. The solvent does not cover ionic solvents.

The reaction of the formation of the sulfoxide is carried out at room temperature.

The invention is illustrated by the following examples which are only meant to illustrate the invention and not act as limitations. AU embodiments apparent to a process their in the art are deemed to fall within the scope of the present invention. Examples

Example 1: In 250 ml. flask, 10 gm of Rabeprazole sulfide was suspended in 70 ml isopropylalcohol. To it 4.4 gm 1 ,8-Diazabicyclo [5.4.0] undec-7-ene was added and cooled to 10 to 15⁰C. Further, 6.6 gm (+)-(2R, 8aS)-10-(Camphoryl sulfonyl) oxaziridine was added and stirred till the sulfide is reacted (for about 20 hrs) at 25 to 30⁰C. The reaction mixture was filtered and solid was washed with isopropyl alcohol to get 5.1 gm (-)-(Camphorsulfonyl) imine (Recovery 78%).

To the filtrate, 1.1 gm sodium hydroxide was added and the reaction mass was concentrated under vacuum to get viscous oil. Water (50 ml) was added to get clear solution. Ethyl acetate (50 ml) was added in aqueous layer and pH was further adjusted to 10 using dil. acetic acid. Organic layer was separated and washed with water 25 ml. Organic layer was concentrated to get viscous oil. Toluene (100 ml) was added to get clear solution. Solution of 1.2 gm sodium hydroxide in water 2 ml was added and stirred for 15 min. The solid was filtered and washed with Toluene 25 ml. to get off white solid.

Result:

Yield: 8 gm

Chemical Purity covering R and S isomer: 97.67% R-Isomer: 89.35%. S-Isomer: 10.65%. ^■

Enantiomeric purity of any single isomer for example R-isomer can be further enriched by converting R-Rabeprazole into R-Rabeprazole sodium and / or by dissolving R- Rabeprazole sodium in water and adjusting the pH with acetic acid.

Purification of R-isomer:

8 gm R-Rabeprazole sodium obtained above was dissolved in 20 ml water and pH 9.5 was adjusted using acetic acid at 10 to 15⁰C. Solid was filtered & washed with 10 ml water. Result:

R-isomer: 95.09%.

S-isomer: 4.91% Chemical Purity covering R and S isomer: 99.22%

Example 2 (Armodafinil)

In 250 ml. flask, 10 gm of benzhydryl thioacetic acid was added in 100 ml toluene. The reaction mass was cooled to 0-5⁰C. To it 5.9 gm 1,8-diazabicyclo [5.4.0] undec-7-ene was added and cooled at 0-5 ⁰C. The reaction mass was stirred for 30 minutes. Further, 8.8 gm

(+)-(2R, 8aS)-10-(Camphorylsulfonyl) oxaziridine was added and stirred till at 25 to 30⁰C till the reaction goes to completion. The reaction mixture was filtered and solid was washed with water to get chirally pure 8 gm Armodafinic acid.

Yield: 75.25% Optical purity: R isomer : 82.17 %

S isomer : 17.83 %

Example 3

Rabeprazole sulfide (lgm, 0.0029 moles) was^'added to Isopropyl alcohol (7ml) in a 100ml flask. The flask was cooled to 15 to 2O⁰C, 1,8-Diazabicyclo [5.4.0] undec-7-ene (0.44gms, 0.0029moles) was added and stirred for 10 min. Reaction mass was further cooled to 10 to 15⁰C and diisopropyl ether (3ml) was charged along with (+)-(2R,8aS)-10- (Camphorylsulfonyl) oxaziridine (0.66gms, 0.0029moles) at 10 to 15⁰C. Reaction mass was stirred for 10 to 15 minutes and stirred further at 25 to 3O⁰C. The reaction was monitored by HPLC, till completion of reaction. Chemical Purity: 96.20 % R-Isomer: 91.34%. S-Isomer: 8.66%.

Example 4

Rabeprazole sulfide (l gm, 0.0029 mole) was added to water (7ml) in a flask and cooled to 15 to 2O⁰C. 1 ,8-Diazabicyclo [5.4.0] undec-7-ene (0.44gms, 0.0029moles) was added and stirred for 5 minutes. Reaction mass was further cooled to 10 to 15⁰C and (+)-(2R,8aS)- 10-(Camphorylsulfonyl) oxaziridine (0.66gms, 0.0029moles) was added. Reaction mass was stirred for 30min and stirred further at 25 to 3O⁰C, till completion of reaction as monitored by HPLC. Chemical Purity: 62.54% R-Isomer: 70.45%. S-Isomer: 29.54%.

Example 5

Rabeprazole sulfide (lgm, 0.0029 mole) was added to dimethyl formamide (7ml) in a flask and cooled to 15 to 2O⁰C. 1,8-Diazabicyclo [5.4.0] undec-7-ene (0.44gms,

0.0029moles) was added and stirred for 5min. Reaction mass was further cooled to 10 to

15⁰C and (+)-(2R,8aS)-10-(Camphorylsulfonyl) oxaziridine (0.66gms, 0.0029moles) was charged at 1 O⁰C. Reaction mass was agitated for 30 minutes at 10 to 15⁰C and stirred at 25 to 3O⁰C, till the completion of reaction as monitored by HPLC, Chemical Purity: 91.92%.

R-Isomer: 83.04%.

S-Isomer: 16.96%.

Example 6 Pantoprazole sulfide (lgm, 0.0027 moles) was added to dichloromethane (7ml) into a flask and cooled to 15 to 2O⁰C. 1,8-Diazabicyclo [5.4.0] undec-7-ene (0.41gms, 0.0027moles) was added and stirred for 10 minutes. Reaction mixture was further cooled to 10 to 15⁰C and (+)-(2R,8aS)-10-(Camphorylsulfonyl) oxaziridine (0.63gms, 0.0027moles) was added.

The reaction mixture was stirred for 30 minutes at 10 to 15⁰C and then stirred further at 25 to 3O⁰C. The reaction mixture was monitored by HPLC, till completion of reaction and then quenched with aqueous sodium hydroxide and extracted with MDC. The organic layer was separated and concentrated to get the product.

Chemical Purity: 83.75%.

R-lsomer: 80.30%. S-Isomer: 19.70%. Example 7 (S-Pantoprazole: diisopropylethylamine as base and methanol as solvent) Pantoprazole sulfide (l gms, 0.0027 moles) was added to methanol (7ml) in a 100ml flask and cooled to 15 to 2O⁰C. Diisopropyl ethyl amine (0.35gms, 0.0027moles) was added and stirred for 10 minutes. The reaction mixture was further cooled to 10 to 15⁰C and (+)- (2R,8aS)-10-(Camphoryl sulfonyl) oxaziridine (0.63gms, 0.0027moles) was added. Reaction mixture was agitated at 25 to 3O⁰C, till the completion of reaction by TLC. The reaction mixture was quenched with dilute sodium hydroxide and extracted with dichloromethane. The organic layer was separated and concentrated. Chemical Purity: 98.24% R-Isomer: 74.67%. S-Isomer: 25.33%.

Example 8 (Pantoprazole using an inorganic base in an organic solvent)

Pantoprazole sulfide (lgm; 0.0027 moles) was added to methanol (4ml) in a 100ml flask. Flask was cooled to 15 to 2O⁰C, and sodium hydroxide solution (0.108gms, 0.0027moles) was added and stirred at 10 to 15⁰C and (+)-(2R,8aS)-10-Camphorylsulfonyl oxaziridine (0.63gms,0.0027moles) (0.63gms, 0.0027moles) was charged. Reaction mixture was stirred at 25 to 3O⁰C, till the completion of reaction on TLC and HPLC, Dichloromethane (5ml) was added to the reaction mixture and the organic layer separated, which was then concentrated to obtain the product. Chemical Purity: 98.36%, R-Isomer: 69.58%. S-Isomer: 30.42%.

Example 9 (different molar equivalent of (+)-(2R, 8aS)-10-(camphoryl sulphonyl oxaziridine)

Rabeprazole sulfide (40gms, 0.116 moles) was added to isopropyl alcohol (7ml) in a 100ml flask and cooled to 15 to 2O⁰C. 1,8-Diazabicyclo [5.4.0] undec-7-ene (17.9gms, O.l lόmoles) was added and stirred at 10 to 15⁰C. (+)-(2R, 8aS)-10-camphoryl sulphonyl oxaziridine (25.3gms, 0.1 lOmoles) was charged. Reaction mass was stirred at 25 to 3O⁰C, till the completion of reaction. The reaction mass was filtered and the filtrate was concentrated under reduced pressure. Water (200ml) was added to residue and the solid separating out was filtered. The filtrate was treated with aqueous solution of sodium hydroxide (12 gms in 15ml of water) with stirring. The pH was then adjusted with acetic acid (25%) to pH 1 1 at 15 to 2O⁰C. Ethyl acetate was added to the mixture and the pH adjusted to 9.5 by using acetic acid (25%). The organic layer was separated and partially concentrated under reduced pressure and the residue diluted with toluene (120ml). The resulting mixture was stirred with sodium hydroxide solution (4.65gm in 5ml water) at 10 to 15⁰C and the solid separating out was filtered redissolved in water (200ml), and washed with dichloromethane (160ml). Combined organic layer was extracted with a solution of Sodium hydroxide (2.5gms in 80ml water). Aqueous layer was stirred under vacuum and pH was adjusted to 9.5 with acetic acid. Ethyl acetate was added and solution was stirred for 30min. Solid obtained was filtered and washed twice with water (40ml each).

Wet solid was taken in 500ml flask along with 200ml of water and flask was cooled to 10 to 15⁰C. Further sodium hydroxide solution (4.65gms in 5ml of water) was charged to the stirring mass at 10 to 15⁰C. PH was adjusted to 9.5 with acetic acid. Reaction mass was aged for 30min at 10 to 15⁰C, solid obtained during aging. Solid was filtered and washed twice with water (200ml each). Off white product was obtained after drying and chiral purity was recorded as R isomer 98.9% ee. Chemical Purity: 99.60 %. R-Isomer: 99.00%. S-Isomer: 1.0%.

Example 10 (Reaction for any prazole in any solvent without an inorganic or organic base in any solvent)

Rabeprazole sulfide (lgm, 0.0029 moles) was added to Isopropyl alcohol (7ml) in a 100 ml flask and cooled to 10 to 15⁰C. (+)-(2R,8aS)-10-camphoryl sulphonyl oxaziridine (0.66gms, 0.0029moles) was added and the reaction mixture stirred at 25 to 3O⁰C, till the completion of reaction as monitored by TLC and HPLC,. Sodium hydroxide solution was added to the reaction mixture followed by dichloromethane (5ml). The organic layer was separated and concentrated to obtain the product.

Chemical Purity: 28.47% R-Isomer: 56.14%.

S-Isomer: 43.86%. Example 11 (Tenatoprazole)

Tenatoprazole sulfide (415gms; 1.25 moles) was added to isopropyl alcohol (4980ml) in a flask. 1 , 8-Diazabicyclo [5.4.0] undec-7-ene (191.3gms, 1.25 moles) was added to the flask and cooled to 10 to 15⁰C. l(R)-(-)-(Camphorylsulphonyl)oxaziridine (3O3gms, 1.31 moles) was added to the flask^'and stirred at 25 to 3O⁰C, till the completion of reaction based on TLC and HPLC, The reaction mass was filtered and the filtrate concentrated under reduced pressure. Water (2075ml) was added to the residue and the solid separating out was filtered.

The filtrate was cooled to 15 to 2O⁰C and the pH adjusted with acetic acid around pH 7.5. The reaction mass, was stirred for 2 hours at 15 to 2O⁰C and the solid separating out was filtered. The wet cake was suspended in water (3735ml). Sodium hydroxide solution (55.2gms in 415ml of water) was added to the flask and stirred for 30 minutes. The solid obtained was filtered; the filtrate was extracted with dichloromethane (830ml). The aqueous layer was separated and the pH adjusted to 7.45 with 50% acetic acid solution. The aqueous layer was separated and extracted with dichloromethane (830ml). The organic layer was separated, partially concentrated and diluted with ethyl acetate (2905ml). The mixture was partially concentrated under reduced pressure and cooled to 25 to 3O⁰C. The solid separating out was filtered, washed with ethyl acetate (1660ml) and dried.

Yield: 81.15% Chemical Purity: 99.38% S-Isomer: 88.81%.

Example 12 A. (Reaction for Preparation of Esomeprazole)

Omeprazole sulfide (50gms; 0.152 moles) was added to isopropyl alcohol (350ml). 1,8- Diazabicyclo [5.4.0] undec-7-ene (23.1 gms; 0.152 moles) was added to the mixture at 10- 15⁰C. l(R)-(-)-(Camphorylsulfonyl)oxaziridine (34.8gms; 0.151moles) was added to the mixture and allowed to stir for 20 hours till completion of reaction as monitored on TLC. The reaction was filtered and the filtrate concentrated at reduced pressure. Water (250ml) was added to the residue and the pH adjusted around 8.5 with acetic acid. Ethyl acetate was added and the organic layer separated, which was then concentrated under vacuum. Acetone (150 ml) was added to the mixture and filtered. The resultant mixture was concentrated and the residue diluted with toluene (8ml) and methanol (75ml). Sodium methoxide (8.2 gms) was added to the mixture and stirred for 14 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. Diisopropyl ether (150ml) was added to the residue and the reaction mixture filtered to obtain Esomeprazole sodium. Yield: 23.4gms. %Yield: 46.8%. Chiral Purity of (S)-Esomeprazole sodium salt: 99.64%.

Example 12B: Preparation of Esomeprazole Magnesium

Esomeprazole sodium (5.0gms; 0.1636moles) was dissolved in water (30ml) and added dropwise to a solution of magnesium chloride (0.54gms; 0.0068moles) in water (30ml) at room temperature. The resultant mixture was stirred for 1 hour and filtered. The wet cake was washed with water (30ml) and dried. Yield: 4.87 gms.

%Yield: 96%.

(S)-Omeprazole: 99.64%

(R)-Omeprazole: 0.36%.

Example 13 (Lansoprazole: DBU as base)

Lansoprazole sulfide (l .Ogm; 0.0028moles) was added to isopropyl alcohol (7ml) at 25- 3O⁰C with stirring. 1,8-Diazabicyclo [5.4.0] undec-7-ene (0.43gms; 0.0028moles) was then added to the mixture and stirred at 10-15⁰C. (-) Dichlorooxaziridine [(-)-(8,8- dichlorocamphorylsulfonyl)oxaziridine (0.8gms; 0.0027moles) was then added and the reaction stirred at 25-3O⁰C, till completion of reaction. The reaction was quenched with dilute sodium hydroxide solution and extracted with dichloromethane. The organic layer was concentrated to obtain the product. Chemical Purity: 92.43% (S) isomer: 90.29% (R) isomer: 9.71% Example 14 (Dichlorooxaziridine without base)

Lansoprazole sulfide (l .Ogm; 0.0028moles) was added to isopropyl alcohol (7ml) at 25- 30⁰C with stirring and cooled to 10-15⁰C. [(-)-(8,8-dichlorocamphorylsυlfonyl)oxaziridine (0.8gms; 0.0027moles) was then added and the reaction stirred at 25-30⁰C, for 15 hours. The reaction was quenched with dilute sodium hydroxide solution and extracted with dichloromethane. The organic layer was concentrated to obtain the product. Chemical Purity: 6.85% (S) isomer: 68.29% (R) isomer: 31.71%

Example 15 (S-Pantoprazole sulfide)

Pantoprazole sulfide (400gms; 1.089moles) was added to isopropyl alcohol (3600ml). 1,8- Diazabicyclo [5.4.0] undec-7-ene (164gms) was added to the mixture and cooled to 10- 15°C. (R)-(-)-Camphorylsulphonyl)oxaziridine (259.70gms; 1.133moles) was added and the temperature raised to 25-3O⁰C and stirred till completion of reaction by HPLC. The reaction mixture was filtered and the filtrate partially concentrated under reduced pressure. Water (2000ml) was added to the residue and filtered. The pH of the filtrate was adjusted to 9.5 with acetic acid and diluted with ethyl acetate (2000ml). The pH was further adjusted around 7.5 with acetic acid and separated the organic layer, which was then concentrated partially and diluted with cyclohexane. The mixture was cooled to 10-15⁰C and the product separating out was filtered. The wet cake was added to ethyl acetate (2800ml), warmed to 7O⁰C and partially concentrated under reduced pressure. The residue was diluted with cyclohexane (400ml) and the product separating out was filtered at 10- 15⁰C. Yield: 243gms % Yield: 60%. Chemical Purity: 99.95%. Optical Purity: 98.62%.

Advantages:

The advantages of the present invention are as under: A. Cost effective and industrially feasible process. B. Makes use of an oxidizing agent which can easily recover.

C. Product obtained at the end of the reaction having pharmaceutically acceptable purity.

D. Use of fewer steps for the purification thus increasing the overall yields of the final product.

E. Eco-fπendly, safe, and simple process for the stereoselective preparation of substituted or unsubstituted chiral sulfinyl derivates with less sulfone impurity and high enantiomeric purity.

F. Recovery of chiral reagent can be achieved.

G. Avoiding of multiple recrystallization steps.

H. Avoiding use of peroxides/enzymes.

Claims

WE CLAIM:

1. A process for preparing the compound of formula (I) comprising the steps of reacting the compound of formula (Ia) with an oxaziridine of formula (XVII) in presence of solvent and base and finally isolating a compound of formula (I).

(Ia) base •^•' solvent (I)

Ri=H; R₂ & R₃=H, CH₃, -OCH₃, -OCH₂CF₃, - OCH₂(CH₂)OCH₃, - O (CH₂)S-OCH₃ R₄= H, CH₃ and R₅=H, -OCH₃, -OCHF₂, R'₈= OH, NH_2/

OR' ₉, NHR' ₉, and R'₉= Cl-4 alkyl A=CH, N

Rg=RiO=H, X, -O-Cl-4 alkyl, -O-(CH₂)_n-O- where n=2 or 3 and ketone,

and wherein the solvent is other than an ionic solvent.

2. A process as claimed in claim 1, wherein

Ri=H; R₂ & R₃=H, CH₃, -OCH₃, -OCH₂CF₃, - OCH₂(CH₂)OCH₃, - O (CH₂)S-OCH₃ R₄= H, CH₃ and R₅=H, -OCH₃, -OCHF₂, A=CH,N

3. A process as claimed in claim 2, wherein the compound of formula (I) is selected from the group comprising of optically- active pantoprazole, lansoprazole, rabeprazole, tenatoprazole, pariprazole and omeprazole.

4. A process as claimed in claim 1, wherein

Ph O

^h -^ R'8

R'₈=0H, NH₂; 0R'₉, NHR'₉, and R^{^} ₉= C M aIRyI.

5. A process as claimed in claim 4, wherein the compound of formula (I) is armodafinil.

6. A process as claimed in claim 1, wherein (2R,8aS)-camphorylsulfonyl oxaziridine of formula (XVII) is either the dextrorotatory or the levorotatory isomer.

7. A process as claimed in claim 1, wherein the base is either an organic or an inorganic base.

8. A process as claimed in claim 7, wherein the base is preferably an organic base.

9. A process as claimed in claims 8, wherein the organic base is selected from the group comprising of l,8-diazabicyclo[5.4.0]undec-7-ene, diisopropyl ethyl amine, hexamethylene tetramine and triethyl amine.

10. A process as claimed in claim 9, wherein the organic base is preferably 1,8- diazabicyclo[5.4.0]undec-7-ene.

11. A process as claimed in claim 7, wherein the inorganic base is preferably an hydroxide of an alkali metal.

12. A process as claimed in claim 1 1, wherein the inorganic base is preferably sodium hydroxide or potassium hydroxide.

13. A process as claimed in claim 1, wherein the solvent is selected from the group comprising of alcohol, aromatic hydrocarbon, ether, ester, amide, nitrile, water or mixtures thereof.

14. A process according to claim 13, wherein the solvent is preferably alcohol or an aromatic hydrocarbon

15. A process as claimed in claim 13, wherein the solvent is preferably selected from the group comprising of methanol, ethanol, isopropanol, butanol, diisopropyl ether, toluene, water, tetrahydrofuran, acetonitrile, dimethylformamide, diethylformamide, dimethoxyethane or combinations thereof.

16. A process according to claim 14, wherein the solvent is preferably isopropanol or toluene.