Title of Invention

ONE POT PROCESS FOR PREPARATION OF MECLIZINE HYDROCHLORIDE

Abstract

Disclosed herein is one pot synthesis for preparation of meclizine hydrochloride which comprises sequential bromination of m-xylene to obtain 3-methyl benzyl bromide followed by in situ condensation of bromocompound with 4-chloro benzhydryl piperazine in the presence of acid acceptor to give meclizine base of formula I, which on treatment with hydrochloric acid to obtain meclizine hydrochloride salt. The invention further discloses the effective purification of meclizine base with citric acid to obtain meclizine hydrochloride substantially free from dimeric impurity in the next step.

Full Text

FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION: "One pot process for preparation of Meclizine Hydrochloride" 2. APPLICANT (S) (a) NAME: FDC Ltd. (b)NATIONALITY: Indian company incorporated under the Companies Act 1956 (c) ADDRESS: 142-48, S.V. Road, Jogeshwari (W), Mumbai - 400 102, Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed. Field of the Invention: The present invention relates to an improved one-pot process for manufacture of Meclizine Hydrochloride {l-[(4-chlorophenyl)phenyl-methyl]-4-[(3-methylphenyl) methyl] piperazine Hydrochloride^' Formula-I, comprising in situ condensation of brominated compound, 3-methyl benzyl bromide with 4-chloro benzhydryl piperazine ( N-alkylation) to obtain Meclizine free base followed by purification and converting to Hydrochloride salt. Background of the invention: Meclizine Hydrochloride is used in the treatment of nausea, vomiting, marine syndrome, motion-sickness, sea-sickness, vertigo, and chronic labyrinthitis. The compound is widely used in anti-emetic therapy. GB705979, the sole patent on Meclizine Hydrochloride describes 1, 4-aralkylpiperazine derivatives as shown below: These compounds may be prepared by causing a l-aralkypiperazine to react on a halogen derivative of another aralkyl, i.e. a compound of the form R-N(C4H8)NH. Further, in GB705979 patent, method of manufacture of 1, 4-aralkylpiperazine derivatives comprising Catalytic debenzylation of I-para-halo or I-p-methyl-benzhydryl-4-benzyl-piperazine followed by condensation with aralkyi halide is disclosed. The process involves hydrogenation operation, involving use of hydrogenation and pyrophoric Raney Nickel catalyst and tedious high vacuum distillation. The prior art process employs as described in GB705979 traditional method and prepares Meclizine Hydrochloride {i-|(4-chlorophcnyl) phenyl-methyl]-4-[(3-methylphenyl) methyl] piperazine Hydrochloride! in a step-wise procedure involving scheme I: Scheme I 4-Chlorobenzhydryl piperazine (IV) 3-Methylbenzaldehyde H2 (Ni) | Maclizine base (I) 1. NaNH2 2. Workup & vacuum distillation HjC^ ♦ IJ Salt formation 4-Chlorobenzhydryl piperazine (IV) Meclizine Hydrochloride The manufacturing process involves hydrogenation operation, involving use of hydrogenation and pyrophoric Raney Nickel catalyst and tedious high vacuum distillation. Also, the manufacturing process uses Sodamide as a base which is hygroscopic, pyrophoric, in nature. These facts warrant for suitable substitution in the existing lengthy manufacturing process. The prior art process is thus difficult to carry out, using chemicals hazardous to health, forming a huge amount of industrial waste. The said patent also does not describe any details pertaining to yield, quality and process details The new process discloses the bromination of m-xylene using NBS, results in formation of mono-bromo along with minor formation of di-bromo compound, followed by reacting with 4-chlorobenzhydrylpiperazine to give Meclizine Base and Impurity I ( 1,3 -bis (( 4-(( 4- Chlorophenyl)(phenyl)methyl)piperazine - l-yl)methyl)benzene. Purification of Meclizine Base crude and salt formation yields Meclizine Hydrochloride pure Impurity I Thus, there is a need in the art for preparation of Meclizine Hydrochloride {I-[(4-chlorophenyl) phenyl-inethyl]-4-((3-methylphenyl) methyl] piperazine Hydrochloride}, which is efficient, economical, environment friendly and gives high yield and substantially free of any dimeric Impurity 1. Object of the Invention: An objective of the present invention is to provide cost-effective, efficient green process for preparation of Meclizine Hydrochloride {l-f(4-chlorophenyl) phenyl-methyl]-4-[(3-methylphenyl) methyl] piperazine Hydrochloride, which eliminates formation of hazardous waste and gives high yield. Another object of the invention is to provide a process for preparation of Meclizine Hydrochloride (l-[(4-chlorophenyl) phenyl-methyl]-4-f(3-methylphenyl) methyl] piperazine Hydrochloride}, which employs less number of reaction steps and is less time consuming, easy and convenient to carry out. Summary of the Invention: The present invention disclosed a process for preparation of Meclizine Hydrochloride {1- [(4-chlorophenyl) phenyl-methyl]-4-[(3-melhylphenyl) methyl] piperazine Hydrochloride}, comprising of the following steps: i) brominating m-xylene to obtain bromo compound of formula II; ii) condensing bromo compound II in situ with 4-chloro benzhydryl piperazine of formula IV in the presence of acid acceptor to give Meclizine base of formula I ; iii) purifying the Meclizine base 1; and iv) converting Meclizine base to the corresponding Hydrochloride salt All the four steps are carried out without isolating product from each reaction stage and opting for in-situ processing in next step. Detailed Description of Invention: The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. Making Active Pharmaceutical Ingredient (API) requirements a long chain of chemical reactions, and a large quantity of solvent, in order to achieve overall process efficiency. It is mandatory to involve reactions which are more efficient, and environment friendly. Pharmaceutical companies product huge amounts of hazardous waste, per year. Green manufacturing programmes are an indication that many industries are centered around, efficient waste management and making the entire process green, from the start. According to the present invention, a process for the manufacture of Meclizine Hydrochloride {l-[(4-chlorophenyl) phenyl-methyl]-4-[(3-methylphenyl) methyl] piperazine Hydrochloride} of Formula-I, comprises sequential Bromination followed by in situ Condensation (N-Alkylation), followed by Purification and Hydrochloride Formation. The reaction sequence of the present invention is shown in Scheme II Scheme II HjC-,. H3C^ NRS m-Xylene Dibromo comnound (Tin Bromo compound (II) Cl Meclizine Base (I) ,-v xx /^ /Chi, I ! '? T T 1 ! - -'X y X yX r x Purification & salt formation 4-Chlorobenzhydryl piperazine (IV) "v_v" Impurity -I . 2 HC1 . ITO Meclizine Hydrochloride (IA) The reaction sequence in the manufacturing process of the present invention involves bromination, condensation, purification and hydrochloride formation, wherein the entire process is carried out without isolating the intermediates in the stages 1, 2 and 3 thus making overall process facile and operated in One-pot. This invention also, narrates the method to eliminate dimeric impurity 1 which gets inevitably formed in the manufacture of Meclizine hydrochloride by chemical treatment. The formation of said impurity has been further confirmed by its synthesis and subsequent HPLC analysis, wherein this impurity matches with the one present in Crude API. Thus, the invention has aimed to eliminate the dimeric impurity formation by preparing the 3-methyl benzyl bromide substantially free from dibromo compound of formula HI. Accordingly. Meclizine Hydrochloride {l-[(4-chlorophenyl) phenyl-methyl]-4-[(3-methylphenyl) methyl] piperazine Hydrochloride} is prepared by bromination of m-xylene using brominating agent and a radical initiator, which gives in situ bromo compound of formula II, which on condensation with 4-chloro benzhydryl piperazine in presence of acid acceptor in m-xylene as solvent yields Meclizine Base. Meclizine base thus formed is treated with aqueous citric acid to eliminate dimeric impurity along with unreacted starting materials. Meclizine base is further reacted with Hydrochloric Acid gives Meclizine Hydrochloride J l-[(4-chIorophenyl) phenyl-methyl]-4-[(3-methylphenyl) methyl] piperazine Hydrochloride]. The bromination is carried out at temperature of 50° to I00°C, preferably between 50° to 70°C and the brominating agent is N-Bromo succinimide. The radical initiator used is selected from AIBN, Benzoyl Peroxide, 2.2'-azobis(2-aminopropane)dichloride (Vazo 50), 2, 2'-azobis{2-methyl-N-! 1,1- bis (hydroxymethyl)-2-hydroxyethyl] propionamide (Vazo 80), more preferably AIBN. The bromination is carried out in aromatic hydrocarbon solvents, selected from Toluene, Benzene, Xylene or combination thereof but, more preferably m-Xylene. The step of in situ N-alkylation of 4-chloro benzhydryl piperazine is carried out at 0° to 50°C, more preferably at 30° to 40°C in the presence of acid acceptor. The acid acceptor is selected from alkali metal salts such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate. The N-alkylation is carried out in aromatic hydrocarbon solvents. CI to C4 alcohols, Ketones, Ethers, or combination thereof, more preferably m-Xylene. Hydrochloride formation is carried out after the Meclizine Base formed, is purified by repeated washing with aqueous citric acid. After washing with aqueous citric acid, the organic layer is washed with water, before proceeding to salt formation. It is necessary to introduce purification process to take care of carryover impurities like side product and starting materials in desired product. Introduction of aqueous citric acid washing in purification of base in present invention is to restrict impurities like starting materials and dimer impurity. The dimeric salt seems to be preferential citric acid salt forming ability as compare to parent Meclizine. This adduct forms a solid mass which can be removed by simple filtration. This chemical operation does the job of purification of Meclizine making it substantially lower with dimeric impurity. The Hydrochloride formation is carried out using aqueous Hydrochloric acid or mixture of IPA and Hydrochloric acid having different strength or by passing HCI gas. Advantages associated with the current process for preparation of Meclizine Hydrochloride | l-[(4-chlorophenyl) phenyl-inethyl]-4-|(3-methylphenyl) methyl] piperazine Hydrochloride}, which employs less number of reaction steps and is less time consuming, easy and convenient to carry out. The process involves use of cheaper and easily available raw materials thereby making the reaction more economic and industrially applicable. The solvents employed in the reaction process are recycled and reused. The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention. Example 1: Preparation of bromo compound (3-methyl benzyl bromide): In a 100 lit RB flask. 10.0 lit m-xylene and N-Bromo succinimide 3.6 kg and AIBN catalyst 0.166 kg were charged. The reaction mass was heated up to 50°C by maintaining the temperature for two hours. Then, the temperature was raised slowly up to 60° - 65°C, to initiate the reaction and the reaction mass was stirred till the brown colour of reaction mass disappears. The reaction mass was cooled up to 30°C and was washed with 5.5 lit water, followed by washing with 6% sodium bicarbonate three times, and then again washed with 5.5 lit water. Then, organic layer was washed over sodium sulphate and the reaction mass was consumed directly to the next step. Yield: 11.46 kg Purity : 81.2% ( By HPLC) Example 2: Preparation of Meclizine Hydrochloride {l-[(4-chlorophenyl) phenyl-methyl]-4-[(3-methylphenyl) methyl] piperazine Hydrochloride}: In 100 lit RB flask (28.0 lit) m-xylene, (3.98 kg) 4-chlorobenzhydryl piperazine and (2.3 kg) potassium carbonate were charged. The addition of Bromo compound (prepared in Examplel), was added slowly, by taking advantage of exotherm. The reaction mass was stirred for two to three hours for completion of reaction. The conversion of 4-chloro benzhydryl piperazine was checked by TLC. After completion of the reaction, the reaction mass was filtered on hyllo bed to salvage potassium carbonate. The organic layer was washed with aqueous citric acid (1.5 kg in 18 lit water) four times. After washing with aqueous citric acid, the organic layer was washed with 10.0 lit water. The organic layer was taken in 100 lit. clean RB flask and IPA in HC1 (9.6 lit), or aqueous HC1 (3.2 lit) was charged. The product was filtered on Buchner funnel and was washed by m-Xylene (3.0 lit), followed by sucking to dry and dried in oven at 70°C. Dry weight of Meclizine = 3.8 kg Purity: 99.24 %( By HPLC ) Example 3: Preparation of Impurity-1 [ ( 1,3 -bis (( 4-(( 4- Chlorophenyl)(phenyl)methyl)piperazine - I -yl)methyl)benzene ] In 250 ml RBF Isopropyl Alcohol (100 ml), 4-chloro benzhydryl piperazine (11.5 g) and (10 g )Sodium Carbonate were charged. The reaction mass was stirred for 10 minutes and 5.26 g of dibromo compound (from example 1) was charged and the reaction mass was maintained for 30° to 40°C for 2 hours. The TLC for conversion of 4-chloro benzhydryl piperazine was checked. The product was filtered and was added in clear reaction mass of 20 ml of Hydrochloric Acid. The white precipitated product was filtered on Buchner funnel and the cake was washed with chilled Isopropyl Alcohol. The product was dried in oven till constant weight. Dry weight = 8 g of white solid product. Purity : 99.6% ( By HPLC) M.P. : 200 - 205 °C It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. We claim: 1. One-pot process for preparation of Meclizine Hydrochloride {l-[(4-chlorophenyl) phenyl- methyl]-4-[(3-methylphenyl) methyl] piperazine Hydrochloride} of Formula-I, comprising the following steps: i) brominating m-xylene to obtain broino compound of formula II; ii) condensing bromo compound II in situ with 4-chloro benzhydryl piperazine of formula IV in the presence of acid acceptor to give Meclizine base of formula 1 iii) purifying the Meclizine base of formula I ; and iv) converting Meclizine base to the corresponding Hydrochloride salt IA; 2. The process as claimed in claim 1. wherein the bromination is carried out in aromatic hydrocarbon solvents, selected from Toluene. Benzene, Xylene or combination thereof, preferably in m-Xylene 3 The process as claimed in claim I. wherein the radical initiator used in bromination is selected from AIBN, Benzoyl Peroxide. 2.2'-azobis(2-aminopropane)dichloride (Vazo 50), 2, 2'-azobis{2-methyl-N-{ 1,1- bis (hydroxymethyl)-2-hydroxyethyl] propionamide (Vazo 80), more preferably AIBN. 4. The process as claimed in claim I. wherein the bromination is carried out at temperature 50° to I00°C. preferably between 50° to 7()°C. 5 The process as claimed in claim I. wherein the condensation (N-alkylation) is carried out in solvents selected from aromatic hydrocarbon solvents. C1-C4 alcohols, Ketones, Ethers, or combination thereof, more preferably m-Xylene. 6. The process as claimed in claim 1. wherein the acid acceptor is selected from alkali metal salts such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate. 7. Hie process as claimed in claim I. wherein the reaction steps i) to iv) are carried out in one pot. using m-Xylene as solvent. 8. The process as claimed in claim I, wherein Meclizine Base is purified by flushing with citric acid. 9. The process as claimed in claim 1, wherein the condensation is carried out at 0° to 50°C, more preferably at 30° to 40°C. 10. The process as claimed in claim I, wherein Hydrochloride formation is carried out with or without isolation of Meclizine Base. 11. The process as claimed in claim 1. wherein the Hydrochloride formation is carried out using aqueous Hydrochloric acid or mixture of IPA and Hydrochloric acid having different strength or by passing 11CI gas. 12. One-pot process for preparation of Meclizine Hydrochloride {l-[(4-chlorophenyl) phenyl- methyl]-4-[(3-methylphenyl) methyl] piperazine Hydrochloride} of Formula-I, as substantially described herein with reference to forgoing examples I to 3. Abstract: Disclosed herein is one pot synthesis for preparation of Meclizine hydrochloride which comprises sequential bromination of m-xylene to obtain 3-methyl benzyl bromide followed by in situ condensation orbromocompound with 4-chloro benzhydryl piperazine in the presence of acid acceptor to give Meclizine base of formula I, which on treatment with hydrochloric acid to obtain meclizine hydrochloride salt. The invention further discloses the effective purification of meclizine base with citric acid to obtain meclizine hydrochloride substantially free from dimeric impurity in the next step.

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387-mum-2008-abstract.doc

387-mum-2008-abstract.pdf

387-MUM-2008-CLAIMS(AMENDED)-(24-4-2012).pdf

387-MUM-2008-CLAIMS(MARKED COPY)-(24-4-2012).pdf

387-mum-2008-claims.doc

387-mum-2008-claims.pdf

387-MUM-2008-CORRESPONDENCE(23-10-2009).pdf

387-mum-2008-correspondence-received.pdf

387-mum-2008-description (complete).pdf

387-mum-2008-digram.doc

387-MUM-2008-FORM 1(7-3-2008).pdf

387-MUM-2008-FORM 18(23-10-2009).pdf

387-MUM-2008-FORM 2(TITLE PAGE)-(25-2-2008).pdf

387-MUM-2008-FORM 26(25-2-2008).pdf

387-mum-2008-form-1.pdf

387-mum-2008-form-2.doc

387-mum-2008-form-2.pdf

387-mum-2008-form-3.pdf

387-mum-2008-form-5.pdf

387-MUM-2008-REPLY TO EXAMINATION REPORT(22-1-2013).pdf

387-MUM-2008-REPLY TO EXAMINATION REPORT(24-4-2012).pdf