CLIAMS:We Claim:

1. A process for the preparation of 4-[[1-(2-phenylethyl)-1H-imidazol-2-yl]carbonyl]-1-piperidinecarboxylate of Formula III:

Formula III

or salt which comprises:

a) condensation of (2-choloroethyl)benzene with imidazole using base in presence of N,N-dimethylformamide to provide 1-(2-Phenylethyl)-1H-imidazole or its salt; and

b) reaction of compound of step a) with N-ester-isonipecotic acid chloride using triethyl amine in presence of dimethyl formamide to provide 4-[[1-(2-phenylethyl)-1H-imidazol-2-yl]carbonyl]-1-piperidinecarboxylate or its salt.

2. The process of claim 1, wherein the base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
3. The process of claim 1, wherein the base is potassium carbonate.

4. The process of claim 1, wherein the condensation reaction of step a) conducted at a temperature of about 40 oC to about 90 oC.

5. The process of claim 1, wherein the process of step (b) comprises addition of mixture of 1-(2-Phenylethyl)-1H-imidazole or its salt, triethyl amine and dimethylformamide to N-ester-isonipecotic acid chloride at a temperature of about 0 to about 5 oC.

6. The process of claim 1, wherein said step b) is performed at a temperature of about 0 oC to about 35 oC.

7. A process for the preparation of 1-(2-Phenylethyl)-1H-imidazole of formula II:


Formula II

or its salt, which comprises condensation of (2-choloroethyl)benzene with imidazole using base in presence of N,N-dimethylformamide.

8. The process of claim 7, wherein the base is potassium carbonate.

9. A process for the preparation of 4-[[1-(2-phenylethyl)-1H-imidazol-2-yl]carbonyl]-1-piperidinecarboxylate of formula III:

Formula III

or its salt, which comprises reaction of formula II with N-ester-isonipecotic acid chloride using triethyl amine in presence of dimethyl formamide.
10. The process of claim 1, wherein the compound of 4-[[1-(2-phenylethyl)-1H-imidazol-2-yl]carbonyl]-1-piperidinecarboxylate is convert to alcaftadine.
,TagSPECI:3. PREAMBLE TO THE DESCRIPTIONThe present invention provides an industrially advantageous process for the preparation of intermediate of alcaftadine, 1-(2-Phenylethyl)-1H-imidazole from (2-chloroethyl)benzene.
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of Invention

The present invention relates to a process for the preparation of intermediate of alcaftadine, 1-(2-Phenylethyl)-1H-imidazole of formula II, or its salt from (2-chloroethyl)benzene to improve the purity and yield of the intermediate.

Formula II

Further, it relates to a process for preparation of 4-[[1-(2-phenylethyl)-1H-imidazol-2-yl]carbonyl]-1-piperidinecarboxylate from the compound of formula II.

Background of the invention

Alcaftadine, chemically known as 6,11-dihydro-11-(1methyl-4-piperidinylidene)-5H-imidazo[2,1b] [3] benzazepine-3-carboxaldehyde, having the structural formula 1, which is marketed under the trade name LASTACAFTTM.

Formula 1

LASTACAFTTM is a sterile, topically administered H1 receptor antagonist containing alcaftadine for ophthalmic use to prevent eye irritation brought on by allergic conjunctivitis.

U.S Pat. No. 5,468,743 discloses alcaftadine and salts thereof. The US ‘743 patent also discloses a process for the preparation of intermediate of Alcaftadine, 1-(2-Phenylethyl)-1H-imidazole, which involves condensation of (2-bromoethyl)benzene with imidazole using sodium methoxide in presence of methanol and N,N-dimethylformamide (DMF). This process requires fresh preparation of sodium methoxide, use of combination solvents and removal of solvents in number of times. Further, handling of bromointermediate is more difficult than other halo intermediates, for example, (2-chloroethyl)-benzene; hence, it is not suitable for large scale up.

Therefore, there is a need to prepare an improved and industrially feasible process for the intermediate of Alcaftadine or its salt, 1-(2-Phenylethyl)-1H-imidazole.

Summary of the Invention

The present invention provides a process for the preparation of intermediate of Alcaftadine, 1-(2-Phenylethyl)-1H-imidazole, or its salt and its conversion to another intermediate of alcaftadine of Formula III, which is key intermediate for the preparation of Alcaftadine in a single solvent, DMF.

In an aspect, the present invention is to provide a process for the preparation of 1-(2-Phenylethyl)-1H-imidazole of formula II:


Formula II

or its salt, which comprises condensation of (2-choloroethyl)benzene with imidazole using base in presence of N,N-dimethylformamide.

In another aspect, the present invention provides a process for the preparation of 4-[[1-(2-phenylethyl)-1H-imidazol-2-yl]carbonyl]-1-piperidinecarboxylate of formula III:

Formula III

or its salt, which comprises reaction of formula II with N-ester-isonipecotic acid chloride using triethyl amine in presence of dimethyl formamide.

Yet another aspect, the present invention provides a process for the preparation of 4-[[1-(2-phenylethyl)-1H-imidazol-2-yl]carbonyl]-1-piperidinecarboxylate of Formula III

Formula III

or salt which comprises:
a) condensation of (2-choloroethyl)benzene with imidazole using base in presence of N,N-dimethylformamide to provide 1-(2-Phenylethyl)-1H-imidazole; and

b) reaction of compound of step a) with N-ester-isonipecotic acid chloride using triethyl amine in presence of dimethyl formamide to provide 4-[[1-(2-phenylethyl)-1H-imidazol-2-yl]carbonyl]-1-piperidinecarboxylate.

Description of the Invention

The present invention provides a simple and industrially feasible process for the preparation of intermediates of alcaftadine and their conversion to alcaftadine or its salt.

The present invention may involve in-situ preparation of the compound of formula II, use of single solvent, simple and cost effective reagents and solvents, and provides positive effect with respect to yield and purity.

The intermediates and products of the present invention may be used or isolated as free base or salt thereof, for example, hydrochloride.

In an aspect of the present invention provides process for the preparation of 4-[[1-(2-phenylethyl)-1H-imidazol-2-yl]carbonyl]-1-piperidinecarboxylate of Formula III:

Formula III

or salt which comprises:

a) condensation of (2-choloroethyl)benzene with imidazole using base in presence of N,N-dimethylformamide to provide 1-(2-Phenylethyl)-1H-imidazole or its salt; and

b) reaction of compound of step a) with N-ester-isonipecotic acid chloride using triethyl amine in presence of dimethyl formamide to provide 4-[[1-(2-phenylethyl)-1H-imidazol-2-yl]carbonyl]-1-piperidinecarboxylate or its salt.

In an embodiment, the present invention provides a process for preparing 1-(2-Phenylethyl)-1H-imidazole or its salt which comprises condensation of (2-choloroethyl)benzene with imidazole using base in presence of N,N-dimethylformamide.

The base used for conducting reaction includes but are not limited to sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.

The quantity of the solvent used for the condensation reaction may range from 1 to 10 ml per gram of (2-choloroethyl)benzene.

The condensation reaction may be conducted at an elevated temperature, for example, at about 40 oC to about 90 oC or reflux temperatures. The reaction may be performed for a period of about 10 to 20 hours or more at elevated temperature.

After completion of the reaction, the reaction mixture may be filtered and then extracted the reaction mixture into dichloromethane. The resultant reaction mixture may be subjected for isolation of compound of formula II or it may be directly utilized for further reaction.

In another embodiment, the present invention provides a process for preparing 4-[[1-(2-phenylethyl)-1H-imidazol-2-yl]carbonyl]-1-piperidinecarboxylate of formula III or its salt comprises reaction of 1-(2-Phenylethyl)-1H-imidazole or its salt with N-ester-isonipecotic acid chloride using triethyl amine in presence of dimethyl formamide.

The quantity of solvent used for preparing the compound of Formula III may range from 1 to 10 ml per gram of 1-(2-Phenylethyl)-1H-imidazole.

The temperature for conducting the reaction of the present invention may about 0 to about 35 oC. The reaction may be stirred for about 1 to 5 hours or more at same temperature.

The process of present invention involves dropwise addition of mixture of 1-(2-Phenylethyl)-1H-imidazole or its salt, triethyl amine and dimethylformamide to N-ester-isonipecotic acid chloride at a temperature of about 0 to about 5 oC.

The reaction condition of the present invention affects the progress of the reaction and provides greater yield and purity in shorter time.

After completion of the reaction, the reaction mixture may transfer into water followed by extraction into dichloromethane. The resultant organic layer may be subjected for isolation of solid or it may be utilized for further reaction to provide alcaftadine.

The resultant intermediates of the present invention directly use for preparation of pure alcaftadine as per the process known in the art without subjecting any purification technique as known in the prior art.

The compound of Formula II and Formula III of the present invention may have purity greater than or equal to 98%.

The present invention may further be illustrated by the following examples which may be provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents may be apparent to those skilled in the art and may be intended within the scope of the present invention.

EXAMPLES
Example 1:
Preparation of 1-(2-Phenylethyl)-1H-imidazole

A mixture of (2-Chloroethyl)benzene (300 g, 2.13 mol), Imidazole (145 g, 2.13 mol), potassium carbonate (352.8 g, 2.56 mol), DMF (1.5 L) and a few crystals of potassium iodide was stirred at 70 – 80 oC for 20 h. The reaction mixture was cooled, filtered and washed cake with dichloromethane (1.0 L) and then poured into water (1.5 L). The organic layer was washed with water and recovered dichloromethane under vacuum to get 320 g of 1-(2-Phenylethyl)-1H-imidazole.

Example-2: Preparation of 4-[[1-(2-phenylethyl)-1H-imidazol-2-yl]carbonyl]-1-piperidinecarboxylate

N-ester-isonipecotic acid (110 g, 0.545 mol) was dissolved in toluene (500 mL) and then SOCl2 (250 mL) was added slowly. The reaction mixture was stirred at 50–55 oC for 1 h. Then the excess of SOCl2 and toluene was recovered under vacuum to get yellow color N-ester-isonipecotic acid chloride. This oil was used without further purification.

To a mixture of 1-(2-Phenylethyl)-1H-imidazole (94 g, 0.545 mol), triethylamine (122 g, 1.19 mol) and DMF (400 mL) at 5 – 10 oC was added, dropwise over 30 minutes, above crude N-ester-isonipecotic acid chloride. The solution was stirred for 5 h at ambient temperature. The reaction mixture was poured into water (1.5 L) and extracted with dichloromethane (500x2 mL). The combined organic layer was washed with water and recovered dichloromethane under vacuum to give oil 107 g of 4-[[1-(2-phenylethyl)-1H-imidazol-2-yl]carbonyl]-1-piperidinecarboxylate.

1H NMR, dppm (CDCl3-d): 1.22 – 1.26 (3H, t, CH3), 1.57 – 1.65 (2H, m, CH2), 1.84 – 1.87 (2H, m, CH2), 2.85 – 2.90 (2H, m, CH2), 2.98 – 3.02 (2H, t, CH2), 3.81 – 3.83 (1H, m, CH), 4.90 – 4.14 (2H, q, CH2), 4.55 – 4.59 (2H, t, CH2), 4.71 (2H, br s, CH2), 6.81 (1H, s, ArH), 7.05 – 7.07 (2H, m, ArH), 7.19 – 7.24 (3H, m, ArH), 7.50 – 7.52 (1H, m, ArH).

Mass Spectrometry: The protonated molecular ion at m/z 356.3 (M+) confirms the mass, which corresponds to molecular formula of C20H25N3O3.