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Title:
IMPROVED PROCESS FOR THE MANUFACTURE OF BEPOTASTINE AND ITS BESILATE SALT
Document Type and Number:
WIPO Patent Application WO/2019/073486
Kind Code:
A1
Abstract:
The present invention discloses a process for preparation of Bepotastine and its Besilate salt of formula I with good yield and purity. The invention also describes a process for recycle and reuse of the Ethyl-4-hydroxy piperidine-1-carboxylate from the aqueous medium after isolating the 2-[(S)-(4-Chlorophenyl)(piperidin-4- yloxy)methyl]pyridine, for subsequent batches in the production of Ethyl 4-[(4- Chlorophenyl)(pyridin-2-yl)methoxy]piperidine-1-carboxylate. The invention further discloses novel intermediates, viz., 2-[Chloro(4- chlorophenyl)methyl]pyridine hydrochloride and bis{2-[(S)-(4- Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine} Dibenzoyl tartrate, useful in the preparation of Bepotastine and its Besilate salt.

Inventors:
NANDEPU VENKATESWARA RAO (IN)
BATINA SATYANARAYANA (IN)
Application Number:
IN2018/050652
Publication Date:
April 18, 2019
Filing Date:
October 12, 2018
Export Citation:
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Assignee:
METROCHEM API PVT LTD (IN)
International Classes:
C07D401/12
Foreign References:
US20140046068A12014-02-13
CN105669652A2016-06-15
CN104031029A2014-09-10
Attorney, Agent or Firm:
NAIR, Gopakumar G. (IN)
Download PDF:
Claims:
We claim,

1. A process for preparation of Bepotastine besilate comprising;

a) Reacting 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride with Ethyl 4-Hydroxypiperidine -1 -carboxylate in presence of a base to obtain Ethyl 4-[(4-Chlorophenyl)(pyridin-2-yl)methoxy]piperidine-l- carboxylate followed by hydrolysis with alkali metal hydroxide to obtain 2-[(4-Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine;

b) Chirally resolving the 2-[(4-Chlorophenyl)(piperidin-4- yloxy)methyl]pyridine with L-(+)-Tartaric acid or Dibenzoyl D-(-)- tartaric acid in organic solvent to afford 2-[(S)-(4- Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine tartrate or bis{2-[(S)- (4-Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine} Dibenzoyl tartrate respectively;

c) Reacting the tartrate or Dibenzoyl tartrate salt of (S)(-)-4- [(4Chlorophenyl)(2-pyridyl) methoxy)piperidine with Ethyl 4-bromo butyrate to give Ethyl (S)-4-[4-(4-chlorophenyl)(2- pyridyl)methoxy]piperidino butanoate;

d) Hydrolysing the Ethyl(S)-4-[4-(4-chlorophenyl)(2- pyridyl)methoxy]piperidino butanoate in presence of alkali to obtain Bepotastine; and optionally

e) Treating the Bepotastine with Benzenesulfonic acid to obtain Bepotastine besilate.

2. The process as claimed in claim 1, wherein, the 2[Chloro(4- chlorophenyl)methyl]pyridine hydrochloride is prepared by a process which comprises;

a) Subjecting Pyridine-2-carboxaldehyde to Grignard reaction with 1- Bromo-4-chlorobenzene to obtain (4-Chlorophenyl)(pyridin-2- yl)methanol; and b) Reacting (4-Chlorophenyl)(pyridin-2-yl)methanol with Thionyl chloride and Toluene to give 2-[Chloro(4- chlorophenyl)methyl]pyridine hydrochloride; and

c) isolating the 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride.

3. The process as claimed in step (b) of claim 1, wherein, the solvent is selected from the group consisting of hydrocarbon, lower alcohol and combinations thereof.

4. The process as claimed in step (c) of claim 1, wherein, the reaction is conducted in presence of a base and optionally use a phase transfer catalyst in aqueous medium.

5. The process as claimed in claim 4, wherein, the base may be selected from carbonates and hydroxides of alkali and alkaline earth metals.

6. The process as claimed in claim 4, wherein, the phase transfer catalyst is a quarternary ammonium salt selected from the group consisting of Tetrabutylammonium bromide, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, methyltricapryl ammonium chloride, methyltributyl ammonium chloride, and methyltrioctyl ammonium chloride.

7. bis{2-[(S)-(4-Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine}

dibenzoyl-D-tartrate as claimed in claim 1(c).

8. The process as claimed in step a) of claim 1, wherein, the Ethyl 4- Hydroxypiperidine-l-carboxylate is recovered from the aqueous medium after the hydrolysis of Ethyl 4-[(4-Chlorophenyl)(pyridin-2- yl)methoxy]piperidine-l-carboxylate by extracting the aqueous layer with a chlorinated hydrocarbon solvent.

9. The process for preparation of Bepotastine besilate by any one of the preceding claims comprising the steps of;

a) Subjecting Pyridine-2-carboxaldehyde to Grignard reaction with 1- Bromo-4-chlorobenzene to obtain (4-Chlorophenyl)(pyridin-2- yl)methanol;

b) Reacting (4-Chlorophenyl)(pyridin-2-yl)methanol with Thionyl chloride and Toluene to give 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride;

c) optionally isolating the 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride;

d) Reacting the 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride with Ethyl 4-Hydroxypiperidine -1-carboxylate in presence of a base to obtain Ethyl 4-[(4-Chlorophenyl)(pyridin-2-yl)methoxy]piperidine-l- carboxylate followed by hydrolysis with sodium hydroxide to obtain 2- [(4-Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine;

e) Chirally resolving the 2-[(4-Chlorophenyl)(piperidin-4- yloxy)methyl]pyridine with L-(+)-Tartaric acid or Dibenzoyl D-(-)- tartaric acid in organic solvent to afford 2-[(S)-(4- Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine tartrate or bis{2-[(S)- (4-Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine} Dibenzoyl tartrate respectively;

f) Reacting the tartrate or Dibenzoyl tartrate salt of (S)(-)-4- [(4Chlorophenyl)(2-pyridyl) methoxy)piperidine with Ethyl 4-bromo butyrate to give Ethyl (S)-4-[4-(4-chlorophenyl)(2- pyridyl)methoxy]piperidino butanoate; g) Hydrolysing the Ethyl(S)-4-[4-(4-chlorophenyl)(2- pyridyl)methoxy]piperidino butanoate in presence of alkali to obtain Bepotastine and optionally

h) Treating the Bepotastine with Benzenesulfonic acid to obtain Bepotastine besilate.

10. 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride of the following formula, as claimed in claim 2(c).

2[Chloro(4-chlorophenyl)

methyl]pyridine hydrochloride

Description:
"IMPROVED PROCESS FOR THE MANUFACTURE OF BEPOTASTINE

AND ITS BESILATE SALT"

Field of Invention:

The present invention relates to process for preparation of Bepotastine and its Besilate salt with good yield and purity. The invention further relates to a process for recycle and reuse of the Ethyl-4-hydroxy piperidine-l-carboxylate from the aqueous medium after isolating the 2-[(S)-(4-Chlorophenyl) (piperidin-4-yloxy) methyl] pyridine, for subsequent batches in the production of Ethyl 4-[(4- Chlorophenyl) (pyridin-2-yl) methoxy] piperidine-l-carboxylate. The invention further relates to novel intermediates, viz., 2-[Chloro(4- chlorophenyl)methyl]pyridine hydrochloride and bis{2-[(S)-(4- Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine} Dibenzoyl tartrate, useful in the preparation of Bepotastine and its Besilate salt.

Background and prior art:

Bepotastine, chemically known as (+)-(S)-4-{4-[(4-Chlorophenyl) (2-pyridyl) methoxy] piperidino} butyric acid, was first reported in JP 19880069711. Bepotastine is useful as a therapeutic agent in the treatment of Skin allergies like Eczema, Dermatitis and Nettle rash. It is also useful in the treatment of allergic rhinitis and bronchial asthma.

It has been reported that (S)-Bepotastine exhibits better antihistaminic activity and anti-allergic activity compared to (R)-Bepotastine and therefore it is important to provide a process for preparation of Bepotastine besilate in the form of (S)-Isomer with higher purity.

Bepotastine besilate of formula I is an organic salt of Bepotastine and Benzene sulfonic acid, as depicted below. H

(Formula I)

The steps involved in the production of Racemic ethyl 4-[(4-chlorophenyl)(pyridin- 2-yl)methoxy]piperidine-l-carboxylate are described in KCS 34(2), 549-552. The S-isomer of 4-[(4-Chlorophenyl)(2-pyridyl)methoxy]piperidine is reported in US7282589, wherein the racemic mixture of 4-[(4-Chlorophenyl)(2- pyridyl)methoxy]piperidine is resolved using L (+)-Tartaric acid.

US6780877 discloses optical resolution of (RS)-4-[(4-Chlorophenyl)(2- pyridyl)methoxy] piped dine using (2R,3R)-2-Hydroxy-3-(4-methoxyphenyl)-3-(2- nitro-5-chlorophenylthio) propionic acid to obtain the desired (S)-isomer of Bepotastine.

According to US2010/0168433, N-benzyloxycarbonyl L-aspartic acid is used in the optical resolution of (RS)-Bepotastine L-methyl ester derived from (RS)-4-[(4- Chlorophenyl)(2-pyridyl) methoxy]piperidine to obtain the (S)-Bepotastine for synthesis of a desired final compound.

The asymmetric acids used in the above prior arts viz., (2R,3R)-2-Hydroxy-3-(4- methoxyphenyl)-3-(2-nitro-5-chlorophenylthio) propionic acid (US6780877) and N-benzyloxycarbonyl L-aspartic acid (US2010/0168433) are not readily available and hence has to be synthesized prior to its use, which escalates cost of the overall process.

US20140046068 discloses use of L-a-Hydroxy acid for chiral resolution to form an L-a-Hydroxy acid salt, so as to synthesize Bepotastine or its Benzenesulfonic acid salt. 2-(Chloro-4-chlorophenyl) methyl pyridine is an important starting material in the synthesis of Bepotastine or its Benzenesulfonic acid salt. The handling of 2- (Chloro-4-chlorophenyl) methyl pyridine during commercial production is extremely difficult due to its lachrymatory property. Also, the yields and purities are not optimal requiring several purifications leading to a loss of yield and longer reactor occupancy. Also, prior art methods require use of expensive toxic solvents like acetonitrile for the isolation of the final product, Bepotastine besilate. Moreover, the prior arts fail to make any effort to recover and re-use of Ethyl-4- hydroxy piperidine-l-carboxylate, an expensive and important reagent in the production of Bepotastine besilate. Also, prior art fails to identify a robust solvent system for the isolation of tartrate or Dibenzoyl tartrate salt of (S)(-)-4-[(4- Chlorophenyl)(2-pyridyl) methoxy)piperidine with good purity.

Therefore, there remains a need in the art to provide an efficient and cost-effective process for the preparation of Bepotastine besilate.

In line with the above, the present invention aims to address some of the problems of prior art, by providing a robust process for the production of Bepotastine besilate that can streamline the process by employing 2[Chloro(4- chlorophenyl)methyl]pyridine hydrochloride; avoids the use of toxic solvents; provides a robust solvent system for the preparation of Tartrate or Dibenzoyl tartrate salt of (S)(-)-4-[(4-Chlorophenyl)(2-pyridyl) methoxy)piperidine and further provides an efficient process for the recovery and recycle of the reagent, viz., Ethyl-4-hydroxy piperidine-l-carboxylate.

Summary of the invention:

In line with the above objective, the invention provides a process for preparation of Bepotastine besilate which comprises;

a) Reacting 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride with Ethyl 4-hydroxypiperidine-l-carboxylate to obtain Ethyl 4-[(4- Chlorophenyl)(pyridin-2-yl)methoxy] piperidine-l-carboxylate followed by hydrolysis with an alkali to obtain 2-[(4-Chloro phenyl)(piperidin-4- yloxy)methyl]pyridine;

b) Chirally resolving the 2-[(4-Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine with L-(+)-Tartaric acid or Dibenzoyl D-(-)-tartaric acid to afford 2-[(S)-(4- Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine L-(+)-tartrate or bis{2-[(S)- (4-Chlorophenyl)(piperidin-4-yloxy)m ethyl] pyridine} Dibenzoyl -D-tartrate respectively;

c) Reacting the Tartrate or Dibenzoyl-D-tartrate salt of (S)(-)-4- [(4Chlorophenyl)(2-pyridyl) methoxy)piperidine with Ethyl 4-bromo butyrate to give Ethyl (S)-4-[4-(4-chlorophenyl)(2-pyridyl) methoxy]piperidino butanoate;

d) Hydrolysing the Ethyl (S)-4-[4-(4-Chlorophenyl)(2- pyridyl)methoxy]piperidino butanoate in presence of alkali to obtain Bepotastine and optionally

e) Treating the Bepotastine with Benzenesulfonic acid to obtain Bepotastine besilate.

In another aspect, the present invention provides a process for preparation of 2[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride, which process comprises;

a) Subjecting Pyridine-2-carboxaldehyde to Grignard reaction with 1-Bromo- 4-chlorobenzene to obtain (4-Chlorophenyl)(pyridin-2-yl)methanol; and b) Reacting (4-Chlorophenyl)(pyridin-2-yl)methanol with Thionyl chloride in presence of Toluene to obtain 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride; and

c) Isolating the 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride.

In yet another aspect, the invention provides novel salt of 2-[Chloro(4- chlorophenyl)methyl]pyridine i.e., Hydrochloride salt of -[Chloro(4- chl oropheny l)m ethyl ] py ri dine . In yet another aspect, the invention provides a process for recovery of Ethyl-4- hydroxy piperidine-l-carboxylate from the aqueous medium after isolating the 2- [(S)-(4-Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine, that can be used in the subsequent batches in the production of Ethyl 4-[(4-Chlorophenyl)(pyridin-2- yl)methoxy]piperidine- 1 -carboxylate.

In yet another aspect, the invention provides novel salt of 2-[(S)-(4-Chlorophenyl) (piperidin-4-yloxy)methyl] pyridine, i.e., dibenzoyl-D-tartrate of bis{2-[(S)-(4- Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine.

Detailed description of the invention:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be fully understood and appreciated.

Accordingly, in an embodiment, the invention provides a process for preparation of Bepotastine besilate which process comprises;

a) Reacting 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride with Ethyl 4-hydroxypiperidine -1 -carboxylate to obtain Ethyl 4-[(4- Chlorophenyl)(pyridin-2-yl)methoxy]piperidine-l -carboxylate followed by hydrolysis with an alkali to obtain 2-[(4-Chlorophenyl)(piperidin-4- yloxy)methyl]pyridine;

b) Chirally resolving the 2-[(4-Chlorophenyl)(piperidin-4- yloxy)methyl]pyridine with L-(+)-Tartaric acid or Dibenzoyl D-(-)-tartaric acid to afford 2-[(S)-(4-Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine tartrate or bis{2-[(S)-(4-Chlorophenyl)(piperidin-4-yloxy)methyl] pyridine} Dibenzoyl -D-tartrate respectively;

c) Reacting the Tartrate or Dibenzoyl-D-tartrate salt of (S)(-)-4- [(4Chlorophenyl)(2-pyridyl) methoxy)piperidine with Ethyl 4-bromo butyrate to give Ethyl (S)-4-[4-(4-chlorophenyl)(2- pyridyl)methoxy]piperidino butanoate; d) Hydrolysing the Ethyl(S)-4-[4-(4-chlorophenyl)(2- pyridyl)methoxy]piperidino butanoate to obtain Bepotastine and optionally e) Treating the Bepotastine with Benzenesulfonic acid to obtain Bepotastine besilate.

In another embodiment, the invention provides a process for preparation of 2[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride, which process comprises;

a) Subjecting Pyridine-2-carboxaldehyde to Grignard reaction with l-Bromo-4- chlorobenzene to obtain (4-Chlorophenyl)(pyridin-2-yl)methanol; and b) Reacting (4-Chlorophenyl)(pyridin-2-yl)methanol with thionyl chloride in presence of toluene to give 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride and

c) Isolating the 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride.

In yet another embodiment, the invention provides a process for preparation of Bepotastine besilate which comprises the steps of;

a) Subjecting Pyridine-2-carboxaldehyde to Grignard reaction with l-Bromo-4- chlorobenzene to obtain (4-Chlorophenyl)(pyridin-2-yl)methanol;

b) Reacting (4-Chlorophenyl)(pyridin-2-yl)methanol with Thionyl chloride and Toluene to give 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride; c) optionally isolating the 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride;

d) Reacting the 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride with Ethyl 4-Hydroxypiperidine -1-carboxylate in presence of a base to obtain Ethyl 4-[(4-Chlorophenyl)(pyridin-2-yl)methoxy]piperidine- 1 -carboxylate followed by hydrolysis with sodium hydroxide to obtain 2-[(4-Chlorophenyl)(piperidin- 4-yloxy)methyl]pyridine;

e) Chirally resolving the 2-[(4-Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine with L-(+)-Tartaric acid or Dibenzoyl D-(-)-tartaric acid in organic solvent to afford 2-[(S)-(4-Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine L-(+)- tartrate or bis{2-[(S)-(4-Chlorophenyl)(piperidin-4-yloxy)methyl]pyridin e Dibenzoyl D-(-)-tartrate respectively;

f) Reacting the tartrate or Dibenzoyl tartrate salt of (S)(-)-4-[(4Chlorophenyl)(2- pyridyl) methoxy)piperidine with Ethyl 4-bromo butyrate to give Ethyl (S)-4-[4- (4-chlorophenyl)(2-pyridyl)methoxy]piperidino butanoate;

g) Hydrolysing the Ethyl(S)-4-[4-(4-chlorophenyl)(2-pyridyl)methoxy]piperidine butanoate in presence of alkali to obtain Bepotastine and optionally

h) Treating the Bepotastine with Benzenesulfonic acid to obtain Bepotastine besilate.

The process of the present invention is depicted in scheme 1 below:

Scheme 1:

methoxy]piperidino butanoate

As described above, the processes reported in the literature suffer from several draw backs. The starting material, 2-(Chloro-4-chlorophenyl) methyl pyridine is extremely lachrymatory and difficult to handle during commercial production. The yields and purities are also not optimal requiring several purifications leading to a loss in yield and longer Reactor occupancy.

Thus the process of the present invention eliminates the drawbacks of the prior arts by providing an efficient and robust process for commercial manufacture of Bepotastine besilate and its intermediates.

Accordingly, in an embodiment, the invention provides 2[Chloro(4- chlorophenyl)methyl]pyridine hydrochloride salt and process for preparation thereof. Being a solid intermediate, the hydrochloride salt of 2[Chloro(4- chlorophenyl)methyl]pyridine, having the following formula

2[Chloro(4-chlorophenyl)

methyl]pyridine hydrochloride

eliminates the problem associated with lachrymatory property of this compound and improves the ease in handling the compound during the synthesis of Bepotastine besilate.

In another embodiment, the invention provides a cost effective and seamless process for the resolution of 2-[(4-Chlorophenyl)(piperidin-4- yloxy)methyl]pyridine by using cheaper and commercially available optical acids viz., L-(+)-Tartaric acid and Dibenzoyl D-(-)-tartaric acids in a combination of hydrocarbon solvent and lower alcohol to obtain respective salts of 2[S(-)(4- Chlorophenyl)piperidine-4-yloxy)methyl]pyridine.

The hydrocarbon solvents are selected from Benzene, Toluene, n-Hexane and n- Heptane and the alcoholic solvents are selected from Methanol, Ethanol, Isopropanol and ter. Butanol. In one preferred embodiment, the combination includes Toluene and Isopropanol. Further the L-(+)-Tartaric acid and Dibenzoyl D-(-)-tartaric acid salts of 2[S(-)(4-Chlorophenyl)piperidine-4- yloxy)methyl]pyridine are purified from a solvent selected from the group consisting of hydrocarbon, alcohol or combinations thereof.

In additional embodiment, the expensive reagent, Ethyl-4-hydroxy piperidine-1 - carboxylate is recovered from the aqueous medium for reuse after the isolation of 4-[(4-Chlorophenyl)(2-pyridyl)methoxy]-piperidine. According to this embodiment, the invention provides a process wherein, the recovery of excess Ethyl-4-hydroxy piperidine-1 -carboxylate, from the aqueous medium after isolating the 2-[(S)-(4-Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine, is carried out by simply extracting the product from aqueous layer using a chlorinated hydrocarbon solvent such as dichloromethane followed by distillation of the same to obtain Ethyl-4-hydroxy piperidine-1 -carboxylate. Ethyl-4-hydroxy piperidine-1 - carboxylate thus obtained can be reused in the subsequent batches for the production of 2-[(S)-(4-Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine.

In yet another embodiment, the invention provides novel salt of 2-[(S)-(4- Chlorophenyl) (piperidin-4-yloxy)methyl]pyridine, i.e., dibenzoyl-D-tartrate of 2- [(S)-(4-Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine, having the following formula.

bis{2-[(S)-(4-Chlorophenyl)piperidin-4-yloxy)methyl] pyridine}

dibenzoyl-D-tartaric acid

In a further embodiment, the invention provides a process for preparation of Ethyl (S)-4-[4-(4-chlorophenyl)(2-pyridyl)methoxy]piperidino butanoate which comprises, the direct reaction of the Tartrate or Dibenzoyl-D-tartrate salt of (S)(-)- 4-[(4Chlorophenyl)(2-pyridyl) methoxy)piperidine with Ethyl 4-bromo butyrate in presence of a base and optionally using a phase transfer catalyst in aqueous medium. The base may be selected from carbonates and hydroxides of alkali and alkaline earth metals. The phase transfer catalyst is a quarternary ammonium salt selected from the group consisting of Tetrabutylammonium bromide, Benzyltrimethylammonium chloride, Benzyltri ethyl ammonium chloride, Methyltricaprylammonium chloride, Methyltributylammonium chloride, and Methyltrioctylammonium chloride.

In view of the above features, the process of the present invention for the preparation of Bepotastine besilate is robust and cost-effective.

Other features and embodiments of the invention will become apparent by the following examples which are given for illustration of the invention rather than limiting its intended scope. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art.

Example-1:

Process for Preparation of H-chlorophenyl)(pyridin-2-yl)methanol:

Into a 3 lit RB Flask, 22.28 gm of Magnesium turnings was added. 200 ml of Tetrahydrofuran and 400 ml of Toluene were added which was then heated to 65°C and reaction was initiated and added 214.4 gm of 4-Bromochlorobenzene solution in 440 ml of Toluene. After careful addition and maintenance of reaction at 75-90°C for 1 hr 30 min, cooled the contents of the reaction to 45°C. A solution of 100 gm of Pyridine-2-carbaldehyde dissolved in 200 ml Toluene was added at 48-52°C and maintained the reaction mass for 1 hr at 45-55°C, the reaction was decomposed by the addition of above reaction mass to 1 lit of 33% Ammonium chloride solution, followed by extraction with Toluene. The Toluene layer was distilled under vacuum and the product was isolated by Hexane.

Yield: 160-170 gm

Example-2:

Process for Preparation of 2- [Chloro(4-chlorophenyl)methyll pyridine hydrochloride: Into a 1 lit RB Flask, 320 ml of Toluene and 80 gm of (4-Chlorophenyl)(pyridin-2- yl)methanol were added and then heated to 50°C, stirred to dissolve the contents and clarified with Carbon, cooled the contents to 20-25°C followed by the addition of 80 gm of Thionyl chloride slowly and maintained the reaction mass at 30-35°C for 3-4 hrs. Excess Thionyl chloride was distilled under vacuum completely for 5- 6 hrs followed by the addition of 160 ml of Toluene and filtered the product under Nitrogen media.

Yield: 90 gm

IR Spectrum of Compound 2-[Chloro(4-chiorophen l)methyl]pyridine hydrochloride: Sample has characteristic peaks at 3087 cm '1 , 2938 cm '1 , 1612 cm " 1591 cm- 1 , 1409 cm -1 , 1268 cm "1 , 630 cm "1 .

1H NMR (CDC13) of Compound 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride: δ 12.79 (bs, 1H), δ 8.72-8.70 (t, 1H), δ 8.46-8.42 (m, IH), δ 8.13- 8.11 (d, IH), δ 7.89-7.86 (t, IH), δ 7.64-7.62 (dd, i l l). 5 7.32-7.30 (dd, 1H), δ 7.09 (s, IH).

Mass Spectrum of Compound 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride: Sample has a Positive peak at 238.

Example-3:

Process for preparation of 2-[(S)-(4-Chlorophenyl)(piperidin-4- yloxy)methyll pyridine L-tartrate:

Into a 5 lit RB Flask, 500 ml of Toluene and 312.5 gm of Sodium carbonate were added and stirred for 10 min. 250 gm of 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride was added in Lot Wise. 337.5 gm of Ethyl-4-hydroxypiperidine-l- carboxylate was added. Then the temperature was raised to 140°C and maintained for 3 hrs at the same temperature. The reaction mass was cooled to Room temperature and 1000 ml of Water was added along with 750 ml of Toluene and stirred for 15 min. Toluene layer and aqueous layer were separated and aqueous layer was extracted with Toluene. Toluene layer was washed with Water, dried with Sodium sulphate and distilled under vacuum. The crude was added in 1150 ml of Methanol in 5 lit RB Flask and 250 gm of Sodium hydroxide in 250 ml of Water, which was then heated to vigorous reflux and maintained for 22-24 hrs. Methanol was distilled under vacuum at 60°C. 1440 ml of Water and 1080 ml of Toluene were added, stirred for 30 min and then settled for 1 hr. Toluene layer was separated and washed with Brine solution. 720 ml of Water was added and pH was adjusted to 4.0-4.5 with Nitric acid. Toluene layer and aqueous layer were separated and to the aqueous layer 260 ml of Toluene was added and pH was adjusted to 12.0-12.5 with Sodium hydroxide solution and extracted with Toluene. The Toluene was distilled under vacuum. The resultant crude was added in to the 2 lit RB flask along with 720 ml of Toluene, stirred for 10 min, and clarified with Carbon. 72 gm of L-(+)- Tartaric Acid dissolved in 720 ml of Isopropyl alcohol at 60°C and was added slowly into the above Toluene mass for 30 min. Contents were heated to 70-75°C, slowly cooled to Room temperature, maintained for 2 hrs, filtered and washed with the Toluene and Isopropyl alcohol mixture. The wet product was purified by addition of 540 ml of Toluene and 180 ml of Methanol at 30-35°C, stirred for 12 hrs and filtered. This step was repeated for 3 times to get pure 2-[(S)-(4- chlorophenyl)(piperidin-4-yloxy)methyl]pyridine tartaric acid.

Yield: 55-60 gm

Example-4:

Process for preparation of bis{2-liS)-(4-Chlorophenyl)(piperidin-4- yloxy)methyll pyridine} dibenzoyl-D-tartrate:

Into a 5 lit RB Flask, 500 ml of Toluene and 312.5 gm of Sodium carbonate were added and stirred for 10 min. 250 gm of 2-[Chloro(4-chlorophenyl)methyl]pyridine hydrochloride was added in Lot Wise. 337.5 gm of Ethyl-4-hydroxypiperidine-l- carboxylate was added. Then the temperature was raised to 140°C and maintained for 3 hrs at the same temperature. The reaction mass was cooled to Room temperature and 1000 ml of Water was added along with 750 ml of Toluene and stirred for 15 min. Toluene layer and aqueous layer were separated and Toluene extractions are given to aqueous layer. Toluene layer was washed with Water, dried with Sodium sulphate and distilled under vacuum. The crude was added in 1150 ml of Methanol in 5 lit RB Flask and 250 gm of Sodium hydroxide in 250 ml of Water, which was then heated to vigorous reflux and maintained for 22-24 hrs. TLC was checked and Methanol was distilled under vacuum at 60°C. 1440 ml of Water and 1080 ml of Toluene were added, stirred for 30 min and then settled for 1 hr. Toluene layer was separated and washed with Brine solution. 720 ml of Water was added and pH was adjusted to 4.0-4.5 with Nitric acid. Toluene layer and aqueous layer were separated and to the aqueous layer 260 ml of Toluene were added and pH was adjusted to 12.0-12.5 with Sodium hydroxide solution and extracted Toluene layer was distilled under vacuum. The resultant crude was added in to the 2 lit RB Flask along with 360 ml of Methanol, stirred for 10 min, and clarified with Carbon. 72 gm of Dibenzoyl-D-tartaric acid dissolved in 720 ml of Isopropyl alcohol at 60°C, was added slowly into the above Methanol mass for 30 min. Contents were heated to 70-75°C, slowly cooled to Room temperature, maintained for 12 hrs, filtered and washed with Methanol and Isopropyl alcohol mixture. The resultant product was dissolved in 330 ml of Methanol and later 660 ml of Water was added at 60°C. The resultant reaction mixture was maintained at room temperature for 2 hrs and filtered.

Yield: 73 gm

IR Spectrum of Compound bis{2-[(S)-(4-Chlorophenyl)(piperidin-4- yloxy)methyl] pyridine} dibenzoyl-D-tartrate: Sample has characteristic peaks at 3421 cm "1 , 2966 cm "1 , 2740 cm "1 , 2510 cm "1 , 1716 cm "1 , 1636 cm "1 , 11089 cm "1 , 1071 cm "1 , 719 cm "1 , 647 cm "1 , 519 cm "1 .

1H NMR (CDC13) of Compound bis{2-[(S)-(4-Chlorophenyl)(piperidin-4- yloxy)methyl] pyridine} dibenzoyl-D-tartrate: δ 8 492-8 481 (d, 2H), δ 7.955- 7.935 (d, 4H), δ 7.662-7.620 (m, 2H), δ 7.406-7.351 (m, 4H), δ 7.259 (s, 8H), δ 7.217-7.133 (m, 6H), δ 5.676 (s, 2H), δ 5.343-5.340 (d, 2H), δ 4.734 (bs, 2H), δ 3.253 (s, 21 1 ). δ 3.035-3.013 (d, 4H), δ 2,836 (s, 4H), δ 1 ,697-1.567 (t, 8H).

Example-5:

Process for preparation of 2-[(S)-(4-Chlorophenyl)(piperidin-4- yloxy)methyll pyridine L-tartrate: Into a 3 lit RB Flask, 11.14 gm of Magnesium turnings was added. 200 ml of Tetrahydrofuran and 200 ml of Toluene were added which was then heated to 65°C when reaction was initiated add 107.2 gm of 4-Bromochlorobenzene solution in 220 ml of Toluene was added. After careful addition and maintenance at 75-90°C for 1 hr 30 min, cooled the contents of the reaction to 45°C. A solution of 50 gm of Pyridine-2-carbaldehyde dissolved in 100 ml Toluene was added at 48-52°C and maintained the reaction mass for 1 hr at 45-55°C, then the reaction mass was decomposed by the addition of 500 ml of 33% Ammonium chloride solution followed by extraction with Toluene. To the Toluene layer, 90 gm of Thionyl chloride was added at 20-25°C for 3-4 hrs and maintained for 3-5 hrs. Thionyl chloride was distilled under vacuum at 30-35°C for 5-6 hrs. 300 ml of Chilled Water was added. Aqueous layer and Toluene layer were separated and to the Toluene layer, water was added and pH was adjusted to 7.0-7.5 with Sodium carbonate solution. Toluene layer and aqueous layer were again separated and Water washing was given to Toluene layer. 90 gm of Sodium carbonate and 140 gm of and Ethyl- 4-hydroxy piperidine-l-carboxylate were added to the Toluene layer at Room temperature, and temperature was raised to 140°C and maintained for 3 hrs at same temperature. 270 ml of Toluene and 500 ml Water were added and pH was adjusted to 7.0-7.5 and washed with Water. The Toluene mass was distilled under vacuum. The resultant reaction mass was added into the Flask along with 416 ml of Methanol and solution of 188.5 gm of Sodium hydroxide in 188.5 ml of Water. Temperature was raised to vigorous reflux and maintained for 22-24 hrs. Methanol was distilled under vacuum at 60°C. To the resultant mixture, 520 ml of Water and 390 ml of Toluene were added, stirred for 30 min and settled for 1 hr. Toluene layer was separated and washed with Brine solution. Water was added and pH was adjusted to 4.0-4.5 with Nitric acid. Toluene layer and aqueous layer were separated and the aqueous layer was basified and extracted with 260 ml of Toluene and added to the toluene mass. The combined toluene mass was distilled under vacuum. To the resultant crude, 280 ml of Toluene was added, stirred to dissolve the contents and heated to temperature 50-55°C. Solution of 28 gm of L-(+)-Tartaric acid in 280 ml of Isopropyl alcohol was added and stirred for 30 min, maintained at 70-75°C for 2 hrs, cooled to Room temperature and again maintained for 2 hrs and filtered. The resultant reaction mass was added to the flask along with 210 ml of Toluene and 70 ml of Methanol and maintained for 12 hrs, filtered the product and washed with Toluene and Methanol mixture. This entire process of purification, maintenance, filtering and washing was repeated at least for 3 times.

Yield: 27gm

Example-6:

Process for the recovery of Ethyl-4-hydroxy piperidine-l-carboxylate:

Aqueous layer from Example-3 was taken and 600 ml of Dichloromethane extractions have given. Extracted Dichloromethane layer was distilled to give the title compound.

Yield: 140-145 gm

Example-7:

Process for preparation of 2-[(S)-(4-Chlorophenyl)(piperidin-4- yloxy)methyll pyridine L-tartrate:

200 ml of Toluene and 125 gm of Sodium carbonate were added into 1 lit RB Flask at Room temperature and stirred for 10 min. 100 gm of 2-[Chloro(4- chlorophenyl)methyl]pyridine Hydrochloride was added in lots. 135 gm of recovered Ethyl-4-hydroxypiperidine-l-carboxylate from the above Example-6 was added. Then the temperature was raised to 150°C and maintained for 3 hrs at same temperature. The reaction mass was cooled to Room temperature and 400 ml of Water was added along with 300 ml of Toluene and stirred for 15 min. Toluene layer and aqueous layer were separated and Toluene extractions were given to aqueous layer. Toluene layer was washed with Water, dried with Sodium sulphate and distilled under vacuum. The resultant crude was added into the Flask along with 416 ml of Methanol and solution of 188.5 gm of Sodium hydroxide in 188.5 ml of Water. Temperature was raised to vigorous reflux and maintained for 22-24 hrs. Then Methanol was distilled under vacuum at 60°C. To the resultant reaction mixture, 520 ml of Water and 390 ml of Toluene were added, stirred for 30 min and settled for 1 hr. Toluene layer was separated and washed with Brine solution. Water was added and pH was adjusted to 4.0-4.5 with Nitric acid. Toluene layer and aqueous layer were separated and the aqueous layer was basified and extracted with 260 ml of Toluene. Toluene layer was distilled under vacuum. To the resultant crude 280 ml of Toluene was added and stirred to dissolve and heated to temperature 50-55°C. Solution of 28 gm of L-(+)-Tartaric acid in 280 ml of Isopropyl alcohol was added and stirred for 30 min, maintained at 70-75°C for 2 hrs, cooled to Room temperature and again maintained for 2 hrs and filtered. The resultant product was added to the Flask along with the 210 ml of Toluene and 70 ml of Methanol and maintained for 12 hrs, and then filtered and washed with Toluene and Methanol mixture. This entire process of purification was repeated for 3 more times to get pure compound.

Yield: 20 gm

Example-8:

Process for preparation of Bepotastine besilate

Into a 2 lit RB Flask, 600 ml of Water and 100 gm of 2-[(S)-(4- Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine L-tartrate were added to the Flask along with 120 gm of Potassium carbonate, stirred for 15 min and 2 gm of Tetrabutylammonium bromide and 51 gm of Ethyl 4-bromobutanoate were added and heated to temperature 50-55°C and maintained for 13 hrs at same temperature and cooled to Room temperature. Extracted with Toluene and distilled the toluene under vacuum. The resultant crude was added into the Flask along with 500 ml of Water at Room temperature. Solution of 32 gm of Sodium hydroxide in 100 ml of Water was added and maintained for 3-4 hrs at 20-25°C. pH was lowered to 10.7 with Hydrochloric acid. Resultant mass was washed with 200 ml of Dichloromethane for 3 times. 600 ml of Dichloromethane was added and again pH was adjusted to 4.0-4.5 with Hydrochloric acid and extracted the product into Dichloromethane. 45 gm of Benzene sulfonic acid was added to 175 ml of Water and stirred to dissolve the contents followed by the addition of the same into Dichloromethane mass. Dichloromethane layer was separated. To the aqueous layer, 600 ml of Dichloromethane was added and pH was adjusted to 3.7-3.9 with Sodium hydroxide solution. Dichloromethane extractions have given. Extracted Dichloromethane was treated with Carbon and distilled under vacuum. 200 ml of Acetone was added and stirred at 45°C for 30 min. The reaction mixture was then maintained at 0-5°C for 2-3 hrs. The product was filtered and dried.

Yield: 83 gm; Purity: 99.82%; ee: 0.77

Example-9:

Process for preparation of Bepotastine besilate

Into a 2 lit RB Flask, 600 ml of Water and 100 gm of 2-[(S)-(4- Chlorophenyl)(piperidin-4-yloxy)methyl]pyridine dibenzoyl-D-tartrate were added to the Flask along with 120 gm of Potassium carbonate, stirred for 15 min and 2 gm of Tetrabutylammonium bromide and 45 gm of Ethyl 4-bromobutanoate were added and heated to temperature at 50-55°C and maintained for 13 hrs at same temperature and cooled to Room temperature. Toluene was added and distilled under vacuum. The resultant crude was added into the Flask along with 500 ml of Water at Room temperature. Solution of 32 gm of Sodium hydroxide in 100 ml of Water was added at 10-15°C and maintained for 3-4 hrs at 20-25°C. pH was lowered to 10.7 with Hydrochloric acid. Resultant mass was washed with 200 ml of Dichloromethane for 3 times. 600 ml of Dichloromethane was added and again pH was adjusted to 4.0-4.5 with Hydrochloric acid and extracted into Dichloromethane. Solution of 45 gm of Benzene sulfonic acid in 175 ml of Water was prepared under stirring to dissolve the contents followed by the addition of Dichloromethane mass. Dichloromethane layer was separated. To the aqueous layer, 600 ml of Dichloromethane added and pH was adjusted to 3.7-3.9 with Hydrochloric acid. Dichloromethane extractions have given. Extracted Dichloromethane was treated with Carbon and distilled under vacuum. 200 ml of Acetone was added and stirred at 45°C for 30 min. Then the reaction mixture was maintained at 0-5°C for 2-3 hrs. The product was filtered and Dried.

Yield: 65 gm; Purity: 99.81%; ee: 0.65 Example-10:

Process for preparation of Bepotastine besilate:

125 ml of Water and 25 gm of 2-[(S)-(4-Chlorophenyl)(piperidin-4- yloxy)methyl]pyridine dibenzoyl-D-tartrate were added into 1 lit RB Flask at Room temperature along with 30 gm of Potassium carbonate, stirred for 15 min and 10 gm of Ethyl 4-bromobutanoate was added and heated to 50-55°C and maintained for 24 hrs at same temperature and cooled to Room temperature. 150 ml of Toluene was added and stirred for 15 min. Aqueous layer and Toluene layers were separated and 25 ml of Water washings were given for 2 times. Aqueous layer and Toluene layers were separated and then Toluene layer was dried using Sodium sulphate and distilled under vacuum at 60°C. To the resultant crude 125 ml of Water and Sodium hydroxide solution were added at room temperature and maintain for 3-4 hrs. 11.25 gm of Benzene sulfonic acid was added and pH was adjusted to 3.7-3.9 with dilute Hydrochloric acid followed by the addition of 125 ml of Dichlorom ethane. Aqueous layer and Dichloromethane layer were separated and 25 ml of Dichloromethane extractions were given for 3 times, treated with Carbon, filtered through the Hyflow bed, dried with Sodium sulphate and then distilled under vacuum. To the resultant crude, 50 ml of Acetone was added and stirred for freeness at room temperature. Reaction mass was then heated to 50-55°C and maintained for 30 min, cooled to room temperature and maintained for 2 hrs. Finally filtered and washed with Acetone to get the title product.

Out Put: 16.9 gm; Purity: 99.56%; ee: 0.20

Example-11:

Process for preparation of Bepotastine besilate:

1500 ml of Water, 250 gm of 2-[(S)-(4-Chlorophenyl)(piperidin-4- yloxy)methyl]pyridine L-tartrate and 300 gm of Potassium carbonate added into 3 lit RB Flask at Room temperature, stirred for 15 min, 127.5 gm of Ethyl 4- bromobutanoate added and heated to temperature 50-55°C and maintained for 13 hrs at same temperature and cooled to Room temperature. Toluene was added and distilled under vacuum. The resultant reaction mass was added into the Flask along with 1500 ml of Water at Room temperature. Solution of 80 gm of Sodium hydroxide in 500 ml of Water was added at 10-15°C, heated to 20-25°C and maintained for 3-4 hrs and 112.5 gm of Benzene sulfonic acid was added. 1500 ml of Dichloromethane was added and pH was adjusted to 3.7-3.9 with Sodium hydroxide solution. Dichloromethane extractions have given. Extracted Dichloromethane was treated with Carbon and distilled under vacuum. 500 ml of Acetone was added and stirred at 45°C for 30 min. The reaction mixture was then maintained at 0-5°C for 2-3 hrs, filtered the product and Dried.

Yield: 200 gm; Purity: 99.52%; ee: 0.80