FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
PROVISIONAL SPECIFICATION
(SECTION 10 and Rule 13)
“A PROCESS OF SULFOXIDATION OF BIOLOGICALLY ACTIVE COMPOUNDS”
Emcure Pharmaceuticals Limited.,
an Indian company, registered under the Indian company's Act 1957
and having its registered office at
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE
INVENTION
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FIELD OF THE INVENTION
This invention relates to a new process for the stereoselective preparation of substituted or unsubstituted 2-(2-pyridylmethyl) sulfinyl-lH-benzimidazole compounds such as lansoprazole, rabeprazole, pantoprazole, tenatoprazole, pariprazole, leminoprazole and omeprazole and salts thereof. The invention provides a process for preparing 2-(2-pyridylmethyl-sulfinyl) benzimidazole compounds by subjecting 2-(2-pyridylmethyl-thio) benzimidazole compounds to oxidation with oxaziridines in the presence of a suitable solvent. Preferably, using chiral oxaziridines, enantiomerically enriched compound is obtained.
BACKGROUND OF THE INVENTION

R1=H; R2=H, CH3; R3= H, -OCH3, -OCH2CF3, -OCH2CH2OCH3, -0-(CH2)3-OCH3; R4=H, CH3> -OCH3 and R5=H, -OCH3, -OCHF2
A= CH, N
Pyridine-2-yl-methylsulfinyl-lH-benzimidazole derivatives, represented by formula (I), such as rabeprazole, pantoprazole, omeprazole, lansoprazole, tenatoprazole, leminoprazole and pariprazole are H+/K+ ATPase inhibitors used for the treatment of diseases caused due to increased gastric acid secretion. The treatment of the conditions caused by acid is done by these
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inhibitors. All of such drugs fall in the class of proton pump inhibitors (PPIs), which work by blocking the production of acid in the stomach. The treatment of acid-caused conditions such as stomach, and duodenal ulcers, gastroesophageal reflux disease is treated with PPIs. Rabeprazole like the other PPIs, blocks the enzyme in the wall of the stomach which is responsible for the secretion of the acid in the stomach. By blocking the enzyme, the acid secretion in the stomach is decreased which further allows the ulcers in the stomach and esophagus to heal. Ref: http.7/www.medicinenet.com/rabeprazole/article.htm
These compounds being sulphoxides have an asymmetric center in the sulphur atom and hence, exists as two optical isomers i.e. enantiomers. It is desirable to obtain compounds with improved pharmacokinetic and metabolic properties, which will give an improved therapeutic profile such as a lower degree of interindividual variation ref: US 5,776,765.
Substituted 2-(2-pyridylmethyl)sulfinyl-lH-benzimidazole compounds of formula (I) are usually prepared from corresponding sulfide intermediates by the oxidation of thioether group using different oxidizing agents. Such prior art processes for the preparation of the benzimidazoles of the present invention is generally accompanied by the formation of the corresponding sulfone derivatives as impurities. Furthermore, also the unreacted sulfides are present as impurities in final product. The said impurities are very difficult to remove due to their very similar physico-chemical properties.
The sulfone impurity formed during the sulfide to sulfoxide conversion due to over oxidation is alarming. This is evident from WO 2005/077936 Al.
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The sulfone impurity is mainly due to over oxidation, which inturn is related to oxidizing agents listed in WO '936. The oxidation needs to be controlled.
WO 2007/017244 describes the process of the oxidation of the thiobenzimidazole to the compounds of the present invention by making use of sodium hypochlorite. As per this PCT application a suspension of cold mixture of compounds of the thio benzimidazoles in a suitable organic solvent in the basic medium. The suitable organic solvents used are dichloromethane, dichloroethane, chloroform, carbon tetrachloride etc. Suitable catalyst like triethylbenzyl ammonium chloride is used. However, the sulphone impurity associated with the sulphoxide is around 0.5% thus making the process industrially less favorable.
Use of several other oxidizing agents have been reported in different patents for oxidation of sulphide to sulphoxides such as tertiary butyl hydroperoxide or oxone which has been reported in US 2003036554. The oxidizing agent sodium perborate in the presence of molybdenum salt as a catalyst is reported in WO 2001068504. But all these reagents have either disadvantages of high cost or impurities such as sulphone analogue formation, during the oxidation. Further the catalysts used in the process also make the process costly.
US 4,758,579 describes the process for the preparation of Pantoprazole Sodium by condensation of 2-chloro-3,4-dimethoxypyridinium hydrochloride with 5-difluoromethoxy-2-mercaptobenzimidazole to get the sulfide intermediate, which is oxidized with metachloroperoxybenzoic acid in dichloromethane yielding Pantoprazole. However, the formation of
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sulfone analogue in this process is difficult to remove. Further, the use of metachloroperoxybenzoic acid, which is a costly reagent and gives metachloro benzoic acid as byproduct thus increasing the impurity level. WO 2003/008406 describes a process for the preparation of the proton pump inhibitors of the benzimidazole-type such as rabeprazole, omeprazole, pantoprazole, lansoprazole etc. comprising oxidation of the corresponding sulfide compound followed by the extraction of the reaction mixture with an aqueous alkaline solution with a pH ranging from 9.50 to 12.00 and removing the water layer. Further, the extraction of the organic layer is carried out with an aqueous alkaline solution having a pH of 13.0 or higher and removing the organic layer and then isolating the desired compound from the water layer. However, this process has several disadvantages. Multiple operations are used in this process. The process also makes use of multiple extractions thus limiting its use on the commercial scale.
In an effort to develop a method for the selective oxidation of sulphides to sulfoxides, Chouodary et al. J.Mol. Catalysts, 75LL7-L12 (1992) describe the use of TBHP in the presence of vanadium pillared clay. However, the use of vanadium in the process makes the process costly.
US 20060089386 describes the process, wherein a diastereomeric mixture is synthesized from the racemate. The diastereomers are then separated by fractional crystallization and one of the diastereomer is converted to optically pure sulfoxide in the hydrolytic step. The above method suffers from fundamental disadvantages like racemic intermediate has to undergo couple of reaction steps, resolution processes described involve complicated
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separation step and there is large wastage of highly refined material in the form of opposite distereomer.
Though the chiral sulfoxides acting as the PPIs are very useful compounds, there is not much study known in literature.
US 5,948,789 describes an enantioselective synthesis of the single enantiomer of 2-(2-pyridinylmethylsulphinyl)-lH-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 di-ethyl-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 reagent.
DE 4035455 discloses the procedure to obtain the single enantiomers by forming the derivative of the prochiral sulfide by forming the derivative of the prochiral compound using the chiral moiety wherein the distereomers are formed. Further, laborious chromatographic separation of the desired distereomer followed by the cleaving of the chiral moiety, used for forming derivative leads to the chiral enantiomers. This process is very tedious and involves various chemical steps giving poor yield. Also, the process is limited due to the large waste of unwanted enantiomers obtained during the
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process. Hence, chiral resolution process is not encouraged over stereoselective oxidation.
Further, there are also reports of enantioselective synthesis of single enantiomers (ref: Pitchen P, Dunach E, Kagan H.B. Journal of American Chemical Society 106, (1984), 8188). The chiral sulfoxides have e.e. of about 30%, which demands several crystallizations. More interestingly, the said process as noted by Astra, is not the general process (US 5,948,789), due to lack of repeatability of the experiment.
As reported by Kagan et al the enantioselectivity is dependant on both the substituents of prochiral sulfide. If the two substituents on either side have the similar size (bulk) then the e.e. is desirable for example incase of aryl methyl sulfoxide the e.e. is more than 50%, whereas in case of benzyl p-toluyl sulfide having the groups of similar size only 7% ee is observed.
The further literature provides the higher enantiomeric excess, but it is handicapped by the synthetic route having several steps and use of strong and very hazardous reagent, lithium diisopropyl amide. Thus the process of Pitchen et al (Tetrahedron Letters (1994), 35,485) is not industry friendly.
Astra (US 7,776,765) has disclosed the process for the preparation of enantiomerically pure sulfoxide by use of microbial organism or microbial enzyme system. Such reactions have the limitations of having dedicated facility only for such enzymatic reactions. They are substrate selective and very much dependant on pH and temperature, which makes them industry non-friendly compared to other synthetic reactions.
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Another method to carry out the enantioselective synthesis is by the use of chiral oxaziridines. (Davis. Et al. Journal of American Chemical Society 1992, 114, 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 CCU, which is not at all industrial friendly. The chiral oxirane used for the oxidation are

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.
The other oxaziridine such as
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Ph


though known Bohe et al. Tetrahedron 55, (1999) 155-166, apart from the above referred limitations, gives poor e.e.
Thus, there has been a long felt need for efficient controlled and safe methods for the selective oxidation of the sulphide to sulfoxide. The task is challenging in light of the number of problems from literature processes for the oxidation of the sulphide to the sulphoxide.
1) Content of high sulfone impurity in the oxidized product.
2) Recovery of the chiral reagents used.
3) Multiple extractions.
4) Cost effective processes.
5) Increased hazards on the manufacturing site w.r.t. the higher quantities of peroxides.
6) Use of expensive catalysts in the process.
7) Requirement of excessive crystallizations to achieve the desired pharmaceutical grade purity.
8) The increased time cycle for the manufacturing batch due to unavoidable purifications.
9) Increased utilities, manpower and cost due to above factors.
In view of the above shortcomings, it was necessary to develop an alternate oxidizing agent, which would give the substituted 2-(2-pyridylmethyl)sulfinyl-lH-benzimidazole compounds such as lansoprazole, rabeprazole, tenatoprazole, omeprazole, leminoprazole, pantoprazole and pariprazole i.e. compound of formula (I), by a process, which is industrially feasible and viable.
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The present invention discloses the use of oxaziridines for preparation of chiral sulfoxide using prochiral sulfides.
SUMMARY OF THE INVENTION
The present inventors have developed a process for the oxidation of the sulphide by making use of an oxaziridine.
The present inventors have developed an oxidizing process, which provides the chiral sulphide with less sulfone impurity.
The present inventors have developed a simple, safe, eco-friendly and cost effective process for the oxidation of sulphides to sulphoxides.
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OBJECT OF THE INVENTION
First object of the present invention is to provide a novel and improved process for the preparation of the 2-(2-pyridylmethyl-sulfinyl) benzimidazole (PPIs) by making use of an industrially feasible oxidation process.
Second object of the invention is to provide the oxidation process using oxiranes in which the oxidizing agent can be easily recovered.
Third object of the invention is to provide 2-(2-pyridylmethyl-sulfinyl) benzimidazole in pharmaceutically acceptable purity.
Fourth object of the invention is to provide 2-(2-pyridylmethyl-sulfinyl) benzimidazole by a process which is simple, economical, safe and eco-friendly.
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DETAILED DESCRD7TION OF THE INVENTION
The process under discussion is an 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, where as upon stereoselective oxidation the sulfoxide formed is chiral compound.
According to the present invention stereoselective oxidation refers to the oxidation, wherein there is enrichment of one of the enantiomers over the other.
R1

R1=H; R2=H, CH3; R3= H, -OCH3> -OCH2CF3, -OCH2CH2OCH3, -0-(CH2)3-OCH3; R4=H, CH3, -OCH3 and R5=H, -OCH3, -OCHF2
A= CH, N
Pyridine-2-yl-methylsulfinyl-lH-benzimidazole derivatives, represented by formula (I), such as rabeprazole, pantoprazole, lansoprazole, omeprazole, tenatoprazole, pariprazole and luminoprazole can be synthesized by making use of oxaziridines as an oxidizing agent.
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The present invention provides a process for preparing a sulphoxide compound of formula (I), comprising reacting a thioether compound of formula (II)

wherein R1 to R5 and A are as formula (I), with an oxidizing agent to produce selective oxidation of the thioether compound of formula (II) to form the thioester compound of formula (I).
Preferably the sulphoxides prepared by the novel process are sulfoxides of formula (I) either as a single enantiomers or in an enantiomerically enriched form.
Thioether of compound of formula (II) is suspended in a suitable solvent and the appropriate quantity of the oxidizing agent i.e. chiral oxaziridine is added. The reaction mass is stirred for the required period of time. The reaction mass is then filtered and the obtained solid is washed with suitable solvent to recover the chiral moiety to obtain the desired salt such as sodium, potassium etc.
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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.
For obtaining the racemic sulfoxides, the racemic oxaziridines can be used. The oxidizing agent used is compound of formula (III)

wherein one or more of R6, R7 and R8 are chiral moieties having chiral center. Preferably it forms cyclic system. Preferably the oxidizing agent used in the present invention is (+)-(2R, 8aS)-10-(Camphoryl sulfonyl) oxaziridine as depicted in formula (IV). The (-) isomer of the same compound can also be used for obtaining the enantiomerically enriched compound.


(IV)

The solvent used for the present invention is selected from the group of organic solvents comprising of alcohols, ethers, esters, amides, nitriles,
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water etc. or combinations thereof. The preferred solvents are selected from the group comprising of methanol, ethanol, isopropanol, butanol, diisopropyl ether, toluene, water, THF, acetonitrile, DMF, DME or combinations thereof etc.
The reaction of the present invention is carried in the presence or absence of organic or inorganic base. The inorganic base is selected from the group comprising of alkali or alkaline earth metals. The organic base used is 1,8-diazabicyclo [5.4.0] undec-7-ene, diisopropyl ethyl amine, Hexamethylene tetra amine, triethyl amine and alike.
The reaction of the formation of the sulfoxide is carried out at room temperature.
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.
Thus, the current embodiment, while taking care of the several disadvantages, makes use of a process, which is advantageous in achieving the following aspects:
a) Cost effective and industrially feasible process.
b) Makes use of an oxidizing agent which can be easily recovered.
c) Pharmaceutically acceptable purity.
d) Use of less steps for the purification thus increasing the overall yields of the final product.
e) The process is safe.
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f) Eco-friendly process.
The invention is described in detail here below with respect to the following examples, which are provided merely for illustration and are not intended to restrict the scope of the invention in any manner. Any embodiments that may be apparent to a person skilled in the art are deemed to fall within the scope of the present invention.
EXPERIMENTAL
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 15°C. 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 30°C. The reaction mixture was filtered and solid was washed with isopropyl alcohol to get 5.1 gm (-)-(Camphorsulfonyl) imine (Recovery 78%).
To the filterate, 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.
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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 15°C. 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%
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EXPERIMENTS WITH PANTOPRAZOLE SULFIDE
According to the procedure from Example 1, pantoprazole sulfide was used as starting material and the following results were obtained:

Ex No Condition Sulfoxide% Sulfone% R-isomer% S-isomer%
Solvent Base Time
2 Methanol DIPEA 24Hrs 98.24 0.06 74.67 25.33
3 MDC DBU 16Hrs 83.75 0.00 80.30 19.70
4 Methanol DBU 16Hrs 73.40 0.05 80.29 19.71
5 IPA DBU 16Hrs 69.02 0.09 86.16 13.84
If the other enantiomer of chiral oxaziridine is used, (S) enantiomer can be obtained in enriched form.
EXPERIMENTS WITH RABEPRAZOLE SULFIDE

Ex No Condition Sulfoxide% R-isomer% S-isomer%
Solvent Base Time
6 IPA DBU 16Hrs 85.25 87.76 12.24
7 IPA DBU 24Hrs 92.41 86.24 13.76
8 IPA + DIPE DBU 20Hrs 96.20 91.34 8.66
9 IPA + DIPE DBU 18Hrs 93.52 89.13 10.83
10 Water DBU 18Hrs 62.54 70.45 29.54
11 DMF DBU 18Hrs 91.92 83.04 16.96
12 IPA DBU 24Hrs 91.86 89.16 10.94
13 IPA DBU 24Hrs 93.20 90.94 10.16

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ABSTRACT
The present invention relates to a process for the oxidation of the sulphide by making use of an oxaziridine. The invention relates to the oxidation process, which provides the chiral sulphide with less sulfone impurity. Invention further discloses a simple, safe, eco-friendly and cost effective process for the oxidation of sulphides to sulphoxides.