Indian Patents. 208031:A PROCESS FOR THE PREPARATION OF 2-[{1-[1-[(4-FLUROPHENYL)METHYL]-1H-BENZIMIDAZOL-2-YL]-4-PIPERIDINYL}METHYLAMINO]-4-(3H)-PYRIMIDINONE(MIZOLASTINE)

Title of Invention	A PROCESS FOR THE PREPARATION OF 2-[{1-[1-[(4-FLUROPHENYL)METHYL]-1H-BENZIMIDAZOL-2-YL]-4-PIPERIDINYL}METHYLAMINO]-4-(3H)-PYRIMIDINONE(MIZOLASTINE)
Abstract	The present invention relates to an improved process for the preparation of Mizolastine, 2[{1-[-1-[(4-Fluorophenyl)methyl]-1-H-benzimidazol-2yl]-4-}piperidinyl}methylamino] 4(3H)-pyrimidinone, a second generation anti-histamine having the structural formula (1) given below.

Full Text	IMPROVED SYNTHETIC PROCESS FOR MIZOLASTINE Field of invention: The present invention relates to an improved process for the preparation of Mizolastine, 2-[ {1 - [-1 - [(4-Fluorophenyl)methyl] -1 -H-benzimidazol-2y 1] -4-} piperidinyl} methy lamino] 4(3H)-pyrimidinone, a second generation anti-histamine having the structural formula (1) given below. Background of invention; Histamine was first identified in 1910 and was recognized as major pathogenic mediator of allergic disorders such as rhinitis and urticaria. From 1940 to 1980 more than 40 histamine receptor antagonists reached the market. However first generation agents showed poor receptor specificity and CNS activity, which resulted in sedation and anticholinergic effects. Pharmaceutical industry embarked on the task of generating new antihistamines with improved selectivity and with less antichlonergic adverse effects, which resulted in second generation antihistamines like Cetirizine, Fexofenidine and Mizolastine, along with few others. Mizolastine was originally developed by Synthelabo, as described in their patent EP 217700B, 1944 (Priority Fr 13453, 1985, USP 4,820,710, 1989) for allergic rhinoconjuctivitis and urticaria and was launched in Europe in 2000. Mizolastine can be obtained in two related ways as shown in Scheme I. Condensation of 2-Chloro-l-(4-Fluorobenzyl)benzimidazole (2) with N-(4-Piperidinyl)carbamic acid ethyl ester (3) gives N-[l-{l-(4-Fluorobenzyl)benzimidazol-2-yl]piperidine-4-yl] carbamic acid ester (4) which was methylated with Mel in DMF using NaH as base. The decarboxylative hydrolysis of the compound 5 resulted in N~{l-[l-(4-Fluorobenzyl)-lH-benzimidazol-2-yl]piperidin-4-yl]-N-methylamine (6) which was finally condensed with 2-(methylsulfanyl)pyrimidine-4(3H)-one by heating at 170°C to give Mizolastine. The second route comprised of obtaining 6 by direct condensation of 2-Chloro-l-(4- Fluorobenzyl)-lH-benzimidazole (2) with 4-methylamine piperidine (7) by means of K2C03 in refluxing isoamyl alcohol. USP 4,820,710 also describes another process (Scheme II) apart from the one already discussed. According to this method compound 2 reacted with compound 8 in an alcoholic solvent at reflux temperature to give (1). Recognising the importance of new antihistamines, we continued the research to develop a more efficient, simple and commercially viable process for the preparation of the said compound (1). While developing the improved process we observed that the process for the preparation of Mizolastine (1) disclosed in EP 217700 suffered from the major draw-back for obtaining (6) is long and tedious which involves N-Protection and deprotection and were not able to get pure (6) in scale-up experiments. On the other hand, the processes described in EP21700 and USP 4,820,710 suffered major draw-back of using S-methylthiouracil which releases toxic mathanethiol in the final coupling reaction. Objectives of present invention : The main objective of the present invention is to provide a convergent synthesis of Mizolastine of the formula (1) without employing exotic, toxic and expensive chemicals thereby making the process commercially viable. Another objective of the present invention is to develop a simple and efficient process for the preparation of the compound of the formula (1) which would be friendly to manufacturing chemist with simple and safe operations even in commercial applications. Yet another objective of the present invention is to avoid column chromatography in all stages thereby making the process cost and time effecive. USP 4,820,710 also describes another process (Scheme II) apart from the one already discussed. According to this method compound 2 reacted with compound 8 in an alcoholic solvent at reflux temperature to give (1). Recognising the importance of new antihistamines, we continued the research to develop a more efficient, simple and commercially viable process for the preparation of the said compound (1). While developing the improved process we observed that the process for the preparation of Mizolastine (1) disclosed in EP 217700 suffered from the major draw-back for obtaining (6) is long and tedious which involves N-Protection and deprotection and were not able to get pure (6) in scale-up experiments. On the other hand, the processes described in EP21700 and USP 4,820,710 suffered major draw-back of using S-methylthiouracil which releases toxic mathanethiol in the final coupling reaction. Objectives of present invention ; The main objective of the present invention is to provide a convergent synthesis of Mizolastine of the formula (1) without employing exotic, toxic and expensive chemicals thereby making the process commercially viable. Another objective of the present invention is to develop a simple and efficient process for the preparation of the compound of the formula (1) which would be friendly to manufacturing chemist with simple and safe operations even in commercial applications. Yet another objective of the present invention is to avoid column chromatography in all stages thereby making the process cost and time effecive. SCHEME-III Approach I According to yet another embodiment of the present invention (Scheme III, Approach II) there is provided a process for the preparation of the compound of the formula (1) which comprises: 1. N-Arylation of the N-l -substituted 4-Methylamino piperidine of the formula (11) with 4-Alkoxy-2-Halopyrimidine of the general formula (6A) under basic conditions to give substituted pyrimidine of formula (12). 2. Deblocking of the substituted pyrimidine of the formula (12) under catalytic hydrogenation conditions in an appropriate solvent to give compound of the general formula (13). 3. N-l Alkylation of the substituted piperidine of the general formula (13) with 2-Chloro-l-(4-Fluorobenzyl)-lH-benzimidazole (2) under neat or basic conditions to give 2[{-l{(l-(4-Fluorophenyl)methyl)-lH-benzimidazol-2-yl}-4-piperidinyl] methylamino]-4-Alkoxypyrimidine (9). 4. Hydrolysis of the compound of formula (9) under acidic conditions to give Mizolastine Dihydrochloride of the formula (10). 5. Neutralisation of Mizolatine Dihydrochloride of general formula (10) to Mizolastine (1) under basic conditions by conventional methods. According to the second approach of the present invention for the preparation of the title compound Mizolastine of the formula (1) starts from l-N-Benzyl-4-methylaminopiperidine of the formula (11). N-Arylation of the compound of formula (11) with 4-Alkoxy-2-halo pyrimidine of the general formula (6A) in the presence of a base such as K2C03, Na2C03, NaH, NaOH and the like, in appropriate solvent such as DMF, DMA, sulfolane, IP A, Methanol, Butanol and the like at temperatures ranging from 60-180°C for 20-30 hrs. to give compound of formula (12). N-l-Position of the Piperidine ring in the compound of formula (12) was selectively deblocked under catalytic conditions using catalysts such as PD/C, Raney Nickel, Palladium Hydroxide, Pt/C and the like in an appropriate solvent such as Methanol, Ethanol, IPA and the like at pressures ranging from 4 Kg to 10 Kg/Sq. inch and heating at temperatures of 40-100°C for 20-30 hrs. to give compound of formula (13). Conversion of the compound of, the formula (13) to the compound of formula (9) was achieved by reacting the compound of the formula (13) with the compound of formula (2) under neat or basic conditions using bases such as K2C03, Na2C03, NaH, KOH, NaOH and the like in an appropriate solvent like DMA, DMF, IPA, Methanol, Ethanol, Isomylalcohol and the like at temperature ranging from 60-200°C, for 10-30 hrs. According to yet another embodiment of the present invention (Scheme III, Approach II) there is provided a process for the preparation of the compound of the formula (1) which comprises : 1. N-Arylation of the N-l-substituted 4-Methylamino piperidine of the formula (11) with 4-Alkoxy-2-Halopyrimidine of the general formula (6A) under basic conditions to give substituted pyrimidine of formula (12). 2. Deblocking of the substituted pyrimidine of the formula (12) under catalytic hydrogenation conditions in ah appropriate solvent to give compound of the general formula (13). 3. N-l Alkylation of the substituted piperidine of the general formula (13) with 2-Chloro-l-(4-Fluorobenzyl)-lH-benzimidazole (2) under neat or basic conditions to give 2[{-1 {(1 -(4-Fluorophenyl)methyl)-1 H-benzimidazol-2-yl} -4-piperidiny 1] methylamino]-4-Alkoxypyrimidine (9). 4. Hydrolysis of the compound of formula (9) under acidic conditions to give Mizolastine Dihydrochloride of the formula (10). 5. Neutralisation of Mizolatine Dihydrochloride of general formula (10) to Mizolastine (1) under basic conditions by conventional methods. According to the second approach of the present invention for the preparation of the title compound Mizolastine of the formula (1) starts from l-N-Benzyl-4-methylaminopiperidine of the formula (11). N-Arylation of the compound of formula (11) with 4-Alkoxy-2-halo pyrimidine of the general formula (6A) in the presence of a base such as K2C03, Na2C03, NaH, NaOH and the like, in appropriate solvent such as DMF, DMA, sulfolane, IP A, Methanol, Butanol and the like at temperatures ranging from 60-180°C for 20-30 hrs. to give compound of formula (12). N-l-Position of the Piperidine ring in the compound of formula (12) was selectively deblocked under catalytic conditions using catalysts such as PD/C, Raney Nickel, Palladium Hydroxide, Pt/C and the like in an appropriate solvent such as Methanol, Ethanol, IPA and the like at pressures ranging from 4 Kg to 10 Kg/Sq. inch and heating at temperatures of 40-100°C for 20-30 hrs. to give compound of formula (13). Conversion of the compound of the formula (13) to the compound of formula (9) was achieved by reacting the compound of the formula (13) with the compound of formula (2) under neat or basic conditions using, bases such as K2C03, Na2C03, NaH, KOH, NaOH and the like in an appropriate solvent like DMA, DMF, IPA, Methanol, Ethanol, Isomylalcohol and the like at temperature ranging from 60-200°C, for 10-30 hrs. Advantages of the present process This is a convergent new process for the synthesis of Mizolastine via its alkoxy derivative (9) without employing toxic and expensive chemicals. Use of column chromatography has been totally avoided in all stages thereby making the process cost & time effective. The examples which follow illustrate the invention. The analysis, IR and NMR spectra confirms the structures of the compounds. EXPERIMENTAL Approach I Example 1 Step - (i) l-{[l-[(4-Fluorophenyl)methyl]lH-benzimidazole-2-yl}-N-methyl-4-piperidinamin (6): 4-Mehylaminopiperidine (7) (60g) and 2-Chloro-l-[(4-Fluorophenyl)methyl]-lH-benzimidazol (2) (142 g) were heated in presence of solvents like isoamyl alcohol, isopropyl alcohol or in neat condition at temperatures ranging from 80-180°C for 10 hr. The solvents were evaporated arid the residue was diluted with water and basified with Aq.Sodium hydroxide to give solid (100 g) mp. 55°C. Step - (in 1 - {[ 1 -[(4-Fluorophenyl)methyl]-1 H-benzimidazol-2-yl} -N-(4-Methoxy-2-pyrimidinyl)-4-piperidinamine: (9). The Solid compound from step-(i) (100 g) was dissolved in mixture of Dimethyl formamide (700 ml) K2C03 (100 g> and 2-Chloro-4-methoxypyrimidine (100 g) and resulting mixture was refluxed for 4 hr. This was poured on to water and extracted with solvents like Ethyl Acetate or MDC. The organic layer was washed, dried and evaporated to give above compound as gum. This was separated by column chromatography to get pure compound 9 for analysis purpose and the crude compound is used as is for the next step. * f Step-(iii) The crude from step-(ii) (150 g) was dissolved in dilute Hydrochloric acid (500 ml) and refluxed for 6 hr. The white precipitate Mizolastine Dihydrochloride (10) was filtered and was washed with solvents like acetone, methanol or Isopropyl alcohol in cold condition to remove any impurities. Step-(iv) The white precipitate Mizolastine Dihydrochloride of the formula (10) (100 g) was dissolved in water (600 ml) and cooled to 0°C and is neutralized with Aq. Ammonia. The resulting precipitate is filtered and recrystalized from solvents like Methanol, Isopropyl alcohol to give Mizolastine (1) in quantitative yield. Approach II Example 2 Step - (i) 2-[(4-piperidinyl)methylamino]-4-methoxypyrimidine (12). N-Benzyl-4-methylaminopiperidine (11) (100 g) was treated with 2-Chloro-4-methoxy pyrimidine (6A) (100 g) in methanol (700 ml) in presence of Potassium Carbonate (75 g) for 12 hr. After the reaction is completed contents were poured on the crushed ice and the resulting organic material is extracted with methylene dichloride (500 ml). The organic layer is washed with water, dried and evaporated to give compound (12) as liquid. Step-(ii) The substituted pyrimidine (12) (80 g) from step-(i) was dissolved in methanol (800 ml) and Pd/C (8g) is added and the resulting suspension is hydrogenated at pressure ranging from 4 to 8 kg/Sq. in preferably at 5 kg and a temperature of 50°C. After completion of the reaction, the reaction mixture is filtered and solvent is distilled under reduced pressure to give compound of formula (13) as liquid in quantitative yield. Step-dip 1 - {[ 1 -[(4-Fluorophenyl)methyl]-1 H-benzimidazol-2-yl} -N-methyl-N-(4-Methoxy-2-pyrimidinyl)-4-piperidinamine (9). The substituted piperidine (13) (100 g) was treated with substituted 2-Chloro-l-(4-Fluorobenzyl)benzimidazole (2) at 100°C in neat condition. After completion of the reaction, the reaction mass is diluted with water and the resulting gum is extracted with ethyl acetate to give (9) as gum. Step-(iv) The crude (9) from step-(iii) (150 g) was dissolved in dilute Hydrochloric acid (500 ml) and refluxed for 6 hr. The white precipitate formed was filtered to get Mizolastine Dihydrochloride (10) which was washed with solvents like acetone, methanol or Isopropyl alcohol in cold condition to remove any impurities. Step-(v) The white precipitate Mizolastine Dihydrochloride of the formula (10) (100 g) was dissolved in water (600 ml) and cooled to 0°C and is neutralized with Aq. Ammonia. The resulting precipitate is filtered and recrystallized from solvents like methanol, Isopropyl alcohol to give Mizolastine (1) in quantitative yield. We claim : An improved process for preparation of Mizolastine represented by formula (1). Which comprises : 01. i) Reacting piperidine derivative (6) with substituted pyrimidine (6A) (2-Halo-4-alkoxypyrimidine) to yield alkoxy pyrimidine derivative (9). ii) Hydrolysing Alkoxy pyrimidine (9) by conventional methods to give Mizolastine Dihydrochloride (10). iii) Neutralisation (10) by conventional methods to Mizolastine (1). 02. i) Reacting N-substituted piperidine (11) with 2-Halo-4-alkoxypyrimidine (6A) to give (12). ii) Deprotection of (12) to substituted pyrimidine represented by structure (13) under hydrogenation conditions. iii) Reacting compound of formula (13) with substituted 2-Chloro benzimidazole (2) under alkaline or neat conditions to give alkoxy pyrimidine derivative (9). iv) Conversion of (9) to (10) by acid hydrolysis and conversion to (1). 3. An improved process in two different approaches. 4. The first approach involves steps i - iii of claim 1. 5. The second approach comprises of steps i - iv of claim 2. We claim • X ' 01. An improved process for the preparation of Mizolastine represented by the formula (1) which comprises : i. reacting piperidine derivative (6) with the substituted pyrimidine derivative (6A) (2-Halo-4-alkoxypyrimidine, Halo= chloro, bromo; Alkoxy = OR wherein R = Ci-4 straight chain alkyl, branched chain alkyl, cyclo alkyl, benzyl or substituted benzyl group) to yield alkoxy pyrimidine derivative (9). ii. hydrolysing alkoxy pyrimidine (9) by conventional methods to give Mizolastine. iii. neutralization 6f (10) by conventional methods to Mizolastine. 02. An alternative process for Mizolastine which involves; i. reacting N-substituted piperidine represented by the formula (11) with (6A) (2-Halo-4-alkoxypyrimidine, Halo= chloro, bromo; Alkoxy = OR wherein R= C1-4 straight chain alkyl, branched chain alkyl, cyclo alkyl, benzyl or substituted benzyl group) to yield 12. ii. deprotection of 12 to substituted pyrimidine represented by the structure (13) under hydrogenation conditions. iii. reacting compound of formula (13) with substituted 2-chlorobenzimidazoIe (2) to give alkoxy pyrimidine derivative (9). iv. conversion of (9) to (10) by acid hydrolysis and its conversion to Mizolastine (1) by neutralization. 3. According to claim-1 step-i: conversion of (6) to (9) was performed in presence of; bases like, potassium carbonate; sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like (preferably potassium carbonate) or organic bases like triethylamine, n-methylamine and the like, in organic solvents like dimethylformamide, dimethyl sulfoxide, dimethyl acetamide, sulfolane and the like (preferably dimethyl formamide) at temperatures ranging 140° - 200° C, (preferably at 140° C) for 20-25 hrs. 4. According to claim-1, step-ii, conversion of (9) to (10) was carried under acidic conditions by using inorganic acids like hydrochloric acid, sulfuric acid, phosphoric acid and the like, or a mixture of inorganic and organic acids; like acetic acid, propionic acid and the like at temperature ranging from 100° - 150°C for 10-15 hrs. to give Mizolastine dihydrochloride for the formula (10). 5. According to claim 1, step-iii, conversion of (10) to (1) was carried out by using potassium carbonate, sodium carbonate, sodium hydroxide, aquous ammonia and the like in cold conditions (0° - 10°C). 6. According to claim-2, step-i, N-substituted pyrimidine of formula (11) was reacted with (6A) (2-Halo-4-alkoxypyrimidine, Halo= chloro, bromo; Alkoxy = OR wherein R = C1-4 straight chain alkyl, branched chain alkyl, cyclo alkyl, benzyl or substituted benzyl group) in presence of a base such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and the like in an appropriate solvent like dimethyl formamide, dimethyl acetamide, sulfolane, isopropyl alcohol, methanol, butanol and the like a temperature ranging from 60° - 180°C for 20-30 hrs. to give compound of formula (12). 7. In step-ii of claim 2 deprotection of (12) was carried under hydrogenation conditions using palladium on carbon, rany nickel, platinum on carbon and the like in an appropriate solvent like methanol, ethanol, isopropyl alcohol and the like under pressures ranging from 4 to 10 kg and at temperatures ranging 40° - 100°C for 20-30 hrs. to give compound of formula (13). 8. In step-iii of claim-2 reaction between compound of formula (13) and compound of formula (2) under neat or basic conditions using bases such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and the like in an appropriate solvents like dimethyl acetamide, dimethyl formamide, isopropyl alcohol, methanol, ethanol, isopropyl alcohol and the like at temperature ranging from 60° -200°C for 10-30 hrs to give (9). 9. According to step-iv of claim 2 hydrolysis of the compound of formula (9) was carried out by using an inorganic acid like hydrochloric acid, sulphuric acid, phosphoric acid and the like (preferably hydrochloric acid) or a mixture of inorganic and organic acid like acetic acid, propionic and the like at temperatures from 60°-140°C for 20-30 hrs. to give Mizolastine dihydrochloride of the formula (10) which was neutralized under conditions mentioned in step iii of claim 1.

Full Text

IMPROVED SYNTHETIC PROCESS FOR MIZOLASTINE
Field of invention:
The present invention relates to an improved process for the preparation of Mizolastine, 2-[ {1 - [-1 - [(4-Fluorophenyl)methyl] -1 -H-benzimidazol-2y 1] -4-} piperidinyl} methy lamino] 4(3H)-pyrimidinone, a second generation anti-histamine having the structural formula (1) given below.
Background of invention;
Histamine was first identified in 1910 and was recognized as major pathogenic mediator of allergic disorders such as rhinitis and urticaria. From 1940 to 1980 more than 40 histamine receptor antagonists reached the market. However first generation agents showed poor receptor specificity and CNS activity, which resulted in sedation and anticholinergic effects. Pharmaceutical industry embarked on the task of generating new antihistamines with improved selectivity and with less antichlonergic adverse effects, which resulted in second generation antihistamines like Cetirizine, Fexofenidine and Mizolastine, along with few others.
Mizolastine was originally developed by Synthelabo, as described in their patent EP 217700B, 1944 (Priority Fr 13453, 1985, USP 4,820,710, 1989) for allergic rhinoconjuctivitis and urticaria and was launched in Europe in 2000.
Mizolastine can be obtained in two related ways as shown in Scheme I. Condensation of 2-Chloro-l-(4-Fluorobenzyl)benzimidazole (2) with N-(4-Piperidinyl)carbamic acid ethyl ester (3) gives N-[l-{l-(4-Fluorobenzyl)benzimidazol-2-yl]piperidine-4-yl] carbamic acid ester (4) which was methylated with Mel in DMF using NaH as base. The decarboxylative hydrolysis of the compound 5 resulted in N~{l-[l-(4-Fluorobenzyl)-lH-benzimidazol-2-yl]piperidin-4-yl]-N-methylamine (6) which was finally condensed with 2-(methylsulfanyl)pyrimidine-4(3H)-one by heating at 170°C to give Mizolastine. The second route comprised of obtaining 6 by direct condensation of 2-Chloro-l-(4-

Fluorobenzyl)-lH-benzimidazole (2) with 4-methylamine piperidine (7) by means of K2C03 in refluxing isoamyl alcohol.

USP 4,820,710 also describes another process (Scheme II) apart from the one already discussed.
According to this method compound 2 reacted with compound 8 in an alcoholic solvent at reflux temperature to give (1).

Recognising the importance of new antihistamines, we continued the research to develop a more efficient, simple and commercially viable process for the preparation of the said compound (1).
While developing the improved process we observed that the process for the preparation of Mizolastine (1) disclosed in EP 217700 suffered from the major draw-back for obtaining (6) is long and tedious which involves N-Protection and deprotection and were not able to get pure (6) in scale-up experiments.
On the other hand, the processes described in EP21700 and USP 4,820,710 suffered major draw-back of using S-methylthiouracil which releases toxic mathanethiol in the final coupling reaction.
Objectives of present invention :
The main objective of the present invention is to provide a convergent synthesis of Mizolastine of the formula (1) without employing exotic, toxic and expensive chemicals thereby making the process commercially viable.
Another objective of the present invention is to develop a simple and efficient process for the preparation of the compound of the formula (1) which would be friendly to manufacturing chemist with simple and safe operations even in commercial applications.
Yet another objective of the present invention is to avoid column chromatography in all stages thereby making the process cost and time effecive.

USP 4,820,710 also describes another process (Scheme II) apart from the one already discussed.
According to this method compound 2 reacted with compound 8 in an alcoholic solvent at reflux temperature to give (1).
Recognising the importance of new antihistamines, we continued the research to develop a more efficient, simple and commercially viable process for the preparation of the said compound (1).
While developing the improved process we observed that the process for the preparation of Mizolastine (1) disclosed in EP 217700 suffered from the major draw-back for obtaining (6) is long and tedious which involves N-Protection and deprotection and were not able to get pure (6) in scale-up experiments.
On the other hand, the processes described in EP21700 and USP 4,820,710 suffered major draw-back of using S-methylthiouracil which releases toxic mathanethiol in the final coupling reaction.
Objectives of present invention ;
The main objective of the present invention is to provide a convergent synthesis of Mizolastine of the formula (1) without employing exotic, toxic and expensive chemicals thereby making the process commercially viable.
Another objective of the present invention is to develop a simple and efficient process for the preparation of the compound of the formula (1) which would be friendly to manufacturing chemist with simple and safe operations even in commercial applications.
Yet another objective of the present invention is to avoid column chromatography in all stages thereby making the process cost and time effecive.

SCHEME-III Approach I

According to yet another embodiment of the present invention (Scheme III, Approach II) there is provided a process for the preparation of the compound of the formula (1) which comprises:
1. N-Arylation of the N-l -substituted 4-Methylamino piperidine of the formula (11) with 4-Alkoxy-2-Halopyrimidine of the general formula (6A) under basic conditions to give substituted pyrimidine of formula (12).
2. Deblocking of the substituted pyrimidine of the formula (12) under catalytic hydrogenation conditions in an appropriate solvent to give compound of the general formula (13).
3. N-l Alkylation of the substituted piperidine of the general formula (13) with 2-Chloro-l-(4-Fluorobenzyl)-lH-benzimidazole (2) under neat or basic conditions to give 2[{-l{(l-(4-Fluorophenyl)methyl)-lH-benzimidazol-2-yl}-4-piperidinyl] methylamino]-4-Alkoxypyrimidine (9).
4. Hydrolysis of the compound of formula (9) under acidic conditions to give Mizolastine Dihydrochloride of the formula (10).
5. Neutralisation of Mizolatine Dihydrochloride of general formula (10) to Mizolastine (1) under basic conditions by conventional methods.
According to the second approach of the present invention for the preparation of the title compound Mizolastine of the formula (1) starts from l-N-Benzyl-4-methylaminopiperidine of the formula (11). N-Arylation of the compound of formula (11) with 4-Alkoxy-2-halo pyrimidine of the general formula (6A) in the presence of a base such as K2C03, Na2C03, NaH, NaOH and the like, in appropriate solvent such as DMF, DMA, sulfolane, IP A, Methanol, Butanol and the like at temperatures ranging from 60-180°C for 20-30 hrs. to give compound of formula (12).
N-l-Position of the Piperidine ring in the compound of formula (12) was selectively deblocked under catalytic conditions using catalysts such as PD/C, Raney Nickel, Palladium Hydroxide, Pt/C and the like in an appropriate solvent such as Methanol, Ethanol, IPA and the like at pressures ranging from 4 Kg to 10 Kg/Sq. inch and heating at temperatures of 40-100°C for 20-30 hrs. to give compound of formula (13).
Conversion of the compound of, the formula (13) to the compound of formula (9) was achieved by reacting the compound of the formula (13) with the compound of formula (2) under neat or basic conditions using bases such as K2C03, Na2C03, NaH, KOH, NaOH and the like in an appropriate solvent like DMA, DMF, IPA, Methanol, Ethanol, Isomylalcohol and the like at temperature ranging from 60-200°C, for 10-30 hrs.

According to yet another embodiment of the present invention (Scheme III, Approach II) there is provided a process for the preparation of the compound of the formula (1) which comprises :
1. N-Arylation of the N-l-substituted 4-Methylamino piperidine of the formula (11) with 4-Alkoxy-2-Halopyrimidine of the general formula (6A) under basic conditions to give substituted pyrimidine of formula (12).
2. Deblocking of the substituted pyrimidine of the formula (12) under catalytic hydrogenation conditions in ah appropriate solvent to give compound of the general formula (13).
3. N-l Alkylation of the substituted piperidine of the general formula (13) with 2-Chloro-l-(4-Fluorobenzyl)-lH-benzimidazole (2) under neat or basic conditions to give 2[{-1 {(1 -(4-Fluorophenyl)methyl)-1 H-benzimidazol-2-yl} -4-piperidiny 1] methylamino]-4-Alkoxypyrimidine (9).
4. Hydrolysis of the compound of formula (9) under acidic conditions to give Mizolastine Dihydrochloride of the formula (10).
5. Neutralisation of Mizolatine Dihydrochloride of general formula (10) to Mizolastine (1) under basic conditions by conventional methods.
According to the second approach of the present invention for the preparation of the title compound Mizolastine of the formula (1) starts from l-N-Benzyl-4-methylaminopiperidine of the formula (11). N-Arylation of the compound of formula (11) with 4-Alkoxy-2-halo pyrimidine of the general formula (6A) in the presence of a base such as K2C03, Na2C03, NaH, NaOH and the like, in appropriate solvent such as DMF, DMA, sulfolane, IP A, Methanol, Butanol and the like at temperatures ranging from 60-180°C for 20-30 hrs. to give compound of formula (12).
N-l-Position of the Piperidine ring in the compound of formula (12) was selectively deblocked under catalytic conditions using catalysts such as PD/C, Raney Nickel, Palladium Hydroxide, Pt/C and the like in an appropriate solvent such as Methanol, Ethanol, IPA and the like at pressures ranging from 4 Kg to 10 Kg/Sq. inch and heating at temperatures of 40-100°C for 20-30 hrs. to give compound of formula (13).
Conversion of the compound of the formula (13) to the compound of formula (9) was achieved by reacting the compound of the formula (13) with the compound of formula (2) under neat or basic conditions using, bases such as K2C03, Na2C03, NaH, KOH, NaOH and the like in an appropriate solvent like DMA, DMF, IPA, Methanol, Ethanol, Isomylalcohol and the like at temperature ranging from 60-200°C, for 10-30 hrs.

Advantages of the present process
This is a convergent new process for the synthesis of Mizolastine via its alkoxy derivative (9) without employing toxic and expensive chemicals.
Use of column chromatography has been totally avoided in all stages thereby making the process cost & time effective.
The examples which follow illustrate the invention. The analysis, IR and NMR spectra confirms the structures of the compounds.
EXPERIMENTAL
Approach I
Example 1
Step - (i)
l-{[l-[(4-Fluorophenyl)methyl]lH-benzimidazole-2-yl}-N-methyl-4-piperidinamin (6):
4-Mehylaminopiperidine (7) (60g) and 2-Chloro-l-[(4-Fluorophenyl)methyl]-lH-benzimidazol (2) (142 g) were heated in presence of solvents like isoamyl alcohol, isopropyl alcohol or in neat condition at temperatures ranging from 80-180°C for 10 hr. The solvents were evaporated arid the residue was diluted with water and basified with Aq.Sodium hydroxide to give solid (100 g) mp. 55°C.
Step - (in
1 - {[ 1 -[(4-Fluorophenyl)methyl]-1 H-benzimidazol-2-yl} -N-(4-Methoxy-2-pyrimidinyl)-4-piperidinamine: (9).
The Solid compound from step-(i) (100 g) was dissolved in mixture of Dimethyl formamide (700 ml) K2C03 (100 g> and 2-Chloro-4-methoxypyrimidine (100 g) and resulting mixture was refluxed for 4 hr. This was poured on to water and extracted with solvents like Ethyl Acetate or MDC. The organic layer was washed, dried and evaporated to give above compound as gum. This was separated by column chromatography to get pure compound 9 for analysis purpose and the crude compound is used as is for the next step.
* f

Step-(iii)
The crude from step-(ii) (150 g) was dissolved in dilute Hydrochloric acid (500 ml) and refluxed for 6 hr. The white precipitate Mizolastine Dihydrochloride (10) was filtered and was washed with solvents like acetone, methanol or Isopropyl alcohol in cold condition to remove any impurities.
Step-(iv)
The white precipitate Mizolastine Dihydrochloride of the formula (10) (100 g) was dissolved in water (600 ml) and cooled to 0°C and is neutralized with Aq. Ammonia. The resulting precipitate is filtered and recrystalized from solvents like Methanol, Isopropyl alcohol to give Mizolastine (1) in quantitative yield.
Approach II
Example 2
Step - (i)
2-[(4-piperidinyl)methylamino]-4-methoxypyrimidine (12).
N-Benzyl-4-methylaminopiperidine (11) (100 g) was treated with 2-Chloro-4-methoxy pyrimidine (6A) (100 g) in methanol (700 ml) in presence of Potassium Carbonate (75 g) for 12 hr. After the reaction is completed contents were poured on the crushed ice and the resulting organic material is extracted with methylene dichloride (500 ml). The organic layer is washed with water, dried and evaporated to give compound (12) as liquid.
Step-(ii)
The substituted pyrimidine (12) (80 g) from step-(i) was dissolved in methanol (800 ml) and Pd/C (8g) is added and the resulting suspension is hydrogenated at pressure ranging from 4 to 8 kg/Sq. in preferably at 5 kg and a temperature of 50°C. After completion of the reaction, the reaction mixture is filtered and solvent is distilled under reduced pressure to give compound of formula (13) as liquid in quantitative yield.
Step-dip
1 - {[ 1 -[(4-Fluorophenyl)methyl]-1 H-benzimidazol-2-yl} -N-methyl-N-(4-Methoxy-2-pyrimidinyl)-4-piperidinamine (9).
The substituted piperidine (13) (100 g) was treated with substituted 2-Chloro-l-(4-Fluorobenzyl)benzimidazole (2) at 100°C in neat condition. After completion of the reaction, the reaction mass is diluted with water and the resulting gum is extracted with ethyl acetate to give (9) as gum.

Step-(iv)
The crude (9) from step-(iii) (150 g) was dissolved in dilute Hydrochloric acid (500 ml) and refluxed for 6 hr. The white precipitate formed was filtered to get Mizolastine Dihydrochloride (10) which was washed with solvents like acetone, methanol or Isopropyl alcohol in cold condition to remove any impurities.
Step-(v)
The white precipitate Mizolastine Dihydrochloride of the formula (10) (100 g) was dissolved in water (600 ml) and cooled to 0°C and is neutralized with Aq. Ammonia. The resulting precipitate is filtered and recrystallized from solvents like methanol, Isopropyl alcohol to give Mizolastine (1) in quantitative yield.
We claim :
An improved process for preparation of Mizolastine represented by formula (1).

Which comprises :
01.
i) Reacting piperidine derivative (6) with substituted pyrimidine (6A) (2-Halo-4-alkoxypyrimidine) to yield alkoxy pyrimidine derivative (9).
ii) Hydrolysing Alkoxy pyrimidine (9) by conventional methods to give Mizolastine Dihydrochloride (10).
iii) Neutralisation (10) by conventional methods to Mizolastine (1).

02.
i) Reacting N-substituted piperidine (11) with 2-Halo-4-alkoxypyrimidine (6A) to give (12).
ii) Deprotection of (12) to substituted pyrimidine represented by structure (13) under hydrogenation conditions.
iii) Reacting compound of formula (13) with substituted 2-Chloro benzimidazole (2) under alkaline or neat conditions to give alkoxy pyrimidine derivative (9).
iv) Conversion of (9) to (10) by acid hydrolysis and conversion to (1).
3. An improved process in two different approaches.
4. The first approach involves steps i - iii of claim 1.
5. The second approach comprises of steps i - iv of claim 2.

We claim • X '
01. An improved process for the preparation of Mizolastine represented by the formula (1)
which comprises :
i. reacting piperidine derivative (6) with the substituted pyrimidine derivative (6A) (2-Halo-4-alkoxypyrimidine, Halo= chloro, bromo; Alkoxy = OR wherein R = Ci-4 straight chain alkyl, branched chain alkyl, cyclo alkyl, benzyl or substituted benzyl group) to yield alkoxy pyrimidine derivative (9).
ii. hydrolysing alkoxy pyrimidine (9) by conventional methods to give Mizolastine.
iii. neutralization 6f (10) by conventional methods to Mizolastine.
02. An alternative process for Mizolastine which involves;
i. reacting N-substituted piperidine represented by the formula (11) with (6A) (2-Halo-4-alkoxypyrimidine, Halo= chloro, bromo; Alkoxy = OR wherein R= C1-4 straight chain alkyl, branched chain alkyl, cyclo alkyl, benzyl or substituted benzyl group) to yield 12.
ii. deprotection of 12 to substituted pyrimidine represented by the structure (13) under hydrogenation conditions.
iii. reacting compound of formula (13) with substituted 2-chlorobenzimidazoIe (2) to give alkoxy pyrimidine derivative (9).
iv. conversion of (9) to (10) by acid hydrolysis and its conversion to Mizolastine (1) by neutralization.
3. According to claim-1 step-i: conversion of (6) to (9) was performed in presence of; bases like, potassium carbonate; sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like (preferably potassium carbonate) or organic bases like triethylamine, n-methylamine and the like, in organic solvents like dimethylformamide, dimethyl sulfoxide, dimethyl acetamide, sulfolane and the like (preferably dimethyl formamide) at temperatures ranging 140° - 200° C, (preferably at 140° C) for 20-25 hrs.
4. According to claim-1, step-ii, conversion of (9) to (10) was carried under acidic conditions by using inorganic acids like hydrochloric acid, sulfuric acid, phosphoric acid and the like, or a mixture of inorganic and organic acids; like acetic acid, propionic acid and the like at temperature ranging from 100° - 150°C for 10-15 hrs. to give Mizolastine dihydrochloride for the formula (10).
5. According to claim 1, step-iii, conversion of (10) to (1) was carried out by using potassium carbonate, sodium carbonate, sodium hydroxide, aquous ammonia and the like in cold conditions (0° - 10°C).

6. According to claim-2, step-i, N-substituted pyrimidine of formula (11) was reacted with (6A) (2-Halo-4-alkoxypyrimidine, Halo= chloro, bromo; Alkoxy = OR wherein R = C1-4 straight chain alkyl, branched chain alkyl, cyclo alkyl, benzyl or substituted benzyl group) in presence of a base such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and the like in an appropriate solvent like dimethyl formamide, dimethyl acetamide, sulfolane, isopropyl alcohol, methanol, butanol and the like a temperature ranging from 60° - 180°C for 20-30 hrs. to give compound of formula (12).
7. In step-ii of claim 2 deprotection of (12) was carried under hydrogenation conditions using palladium on carbon, rany nickel, platinum on carbon and the like in an appropriate solvent like methanol, ethanol, isopropyl alcohol and the like under pressures ranging from 4 to 10 kg and at temperatures ranging 40° - 100°C for 20-30 hrs. to give compound of formula (13).
8. In step-iii of claim-2 reaction between compound of formula (13) and compound of formula (2) under neat or basic conditions using bases such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and the like in an appropriate solvents like dimethyl acetamide, dimethyl formamide, isopropyl alcohol, methanol, ethanol, isopropyl alcohol and the like at temperature ranging from 60° -200°C for 10-30 hrs to give (9).
9. According to step-iv of claim 2 hydrolysis of the compound of formula (9) was carried out by using an inorganic acid like hydrochloric acid, sulphuric acid, phosphoric acid and the like (preferably hydrochloric acid) or a mixture of inorganic and organic acid like acetic acid, propionic and the like at temperatures from 60°-140°C for 20-30 hrs. to give Mizolastine dihydrochloride of the formula (10) which was neutralized under conditions mentioned in step iii of claim 1.

Documents:

350-mas-2002-abstract.pdf

350-mas-2002-claims duplicate.pdf

350-mas-2002-claims original.pdf

350-mas-2002-correspondence others.pdf

350-mas-2002-correspondence po.pdf

350-mas-2002-description complete duplicate.pdf

350-mas-2002-description complete original.pdf

350-mas-2002-description provisinol.pdf

350-mas-2002-form 1.pdf

350-mas-2002-form 3.pdf

350-mas-2002-form 5.pdf

350-mas-2002-other documents.pdf

« Previous Patent

Next Patent »

Patent Number

208031

Indian Patent Application Number

350/MAS/2002

PG Journal Number

31/2007

Publication Date

03-Aug-2007

Grant Date

06-Jul-2007

Date of Filing

10-May-2002

Name of Patentee

DR.REDDY'S HOLDINGS PVT LIMITED

Applicant Address

7-1-27;AMEERPET, HYDERABAD-500 016.

Inventors:

#	Inventor's Name	Inventor's Address
1	MALLELA SAMBU PRASAD SARMA	7-1-27;AMEERPET, HYDERABAD-500 016.

PCT International Classification Number

C07D239/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA