CLIAMS:We Claim:

1. A process for the preparation of 3-(hydroxymethyl)-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine of formula II:


Formula II
or its salt, which comprises:
a) reaction of [1-(2-phenylethyl)-1H-imidazol-2-yl](4-piperidinyl)methanone or its salt with formaldehyde in presence of acid at elevated temperature for a period of greater than 5 hours to provide (1-methyl-4-piperidinyl)[1-(2-phenylethyl)-1H-imidazol-2-yl]methanone of Formula III or its salt;

Formula III

b) reaction of (1-methyl-4-piperidinyl)[1-(2-phenylethyl)-1H-imidazol-2-yl]methanone or its salt with trifluoromethanesulfonic acid to provide 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine of Formula IV or its salt; and

Formula IV

c) reaction of 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine with formaldehyde in presence of acetic acid, sodium acetate and water to provide 3-(hydroxymethyl)-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine of formula II or its salt.

2. The process of claim 1, wherein the acid of step a) is acetic acid or formic acid.

3. The process of claim 1, wherein the elevated temperature is reflux temperature.

4. The process of claim 1, wherein the quantity of trifluoromethanesulfonic acid is about 5 to 20 molar equivalents per molar equivalent of compound of formula III or its salt.

5. The process of claim 1, wherein the reaction of step b) is carried out at a temperature of about 100 to 110 oC.

6. The process of claim 1, wherein the compound of formula IV or its may crystallized from acetonitrile.

7. The process of claim 1, wherein the formaldehyde of step c) is 37 to 40 % formaldehyde in water.

8. The process of claim 1, wherein the compound of formula II or its salt has the purity of greater than or equal to 98%.

9. A process for the preparation of 3-(hydroxymethyl)-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine of formula II:


Formula II

or its salt, which comprises reaction of 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine with formaldehyde in presence of acetic acid, sodium acetate and water.

10. The process of claim 9, wherein the reaction is performed at reflux temperature.
,TagSPECI:3. PREAMBLE TO THE DESCRIPTIONThe present invention provides an industrially advantageous process for the preparation of intermediate of alcaftadine, 3-(hydroxymethyl)-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine.
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, 3-(hydroxymethyl)-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine of formula II:


Formula II

Further, it relates to a process for preparation of alcaftadine 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 I, which is marketed under the trade name LASTACAFTTM.

Formula I

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, which involves hazardous reagents and expensive purification techniques like column chromatography.

Therefore, there is a need to provide an improved and industrially feasible process for the intermediate of Alcaftadine or its salt.

Summary of the Invention

The present invention provides a process for the preparation of intermediate of Alcaftadine, especially 3-(hydroxymethyl)-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine, or its salt and its conversion to Alcaftadine.

In an aspect, the present invention provides a process for the preparation of 3-(hydroxymethyl)-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine of formula II:


Formula II

or its salt, which comprises reaction of 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine or its salt with formaldehyde in presence of acetic acid, sodium acetate and water.

In another aspect, the present invention provides a process for the preparation of 3-(hydroxymethyl)-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine of formula II:


Formula II
or its salt, which comprises:
a) reaction of [1-(2-phenylethyl)-1H-imidazol-2-yl](4-piperidinyl)methanone or its salt with formaldehyde in presence of acid at elevated temperature for a period of greater than 5 hours to provide (1-methyl-4-piperidinyl)[1-(2-phenylethyl)-1H-imidazol-2-yl]methanone of Formula III or its salt;

Formula III

b) reaction of (1-methyl-4-piperidinyl)[1-(2-phenylethyl)-1H-imidazol-2-yl]methanone or its salt with trifluoromethanesulfonic acid to provide 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine of Formula IV or its salt; and

Formula IV

c) reaction of 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine or its salt with formaldehyde in presence of acetic acid, sodium acetate and water to provide 3-(hydroxymethyl)-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine of formula II or its salt.

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 III and IV and use of simple and cost effective reagents and solvents to provide 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 another aspect, the present invention provides a process for the preparation of 3-(hydroxymethyl)-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine of formula II:


Formula II
or its salt, which comprises:
a) reaction of [1-(2-phenylethyl)-1H-imidazol-2-yl](4-piperidinyl)methanone or its salt with formaldehyde in presence of acid at elevated temperature for a period of greater than 5 hours to provide (1-methyl-4-piperidinyl)[1-(2-phenylethyl)-1H-imidazol-2-yl]methanone of Formula III or its salt;

Formula III

b) reaction of (1-methyl-4-piperidinyl)[1-(2-phenylethyl)-1H-imidazol-2-yl]methanone or its salt with trifluoromethanesulfonic acid to provide 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine of Formula IV or its salt; and

Formula IV

c) reaction of 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine or its salt with formaldehyde in presence of acetic acid, sodium acetate and water to provide 3-(hydroxymethyl)-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine of formula II or its salt.

In an embodiment, the present invention provides a process for preparing (1-methyl-4-piperidinyl)-[1-(2-phenylethyl)-1H-imidazol-2-yl]methanone of Formula III:

Formula III
or its salt, which comprises reaction of [1-(2-phenylethyl)-1H-imidazol-2-yl](4-piperidinyl)methanone or its salt with formaldehyde in presence of acid at elevated temperature for a period of greater than 5 hours.

The acid used for the methylation reaction includes but are not limited to acetic acid and formic acid with or without combination of sodium acetate.

The reaction is performed at elevated temperature, for example, at about 35 to about 80 oC or at reflux temperature. The reaction may be performed for a period of greater than 5 or 10 hours or more at same temperature to improve the conversion of the reactants to provide greater yield without effecting the formation of impurities.

After completion of the reaction, the reaction mixture may be diluted with water and then basified with base, for example, sodium hydroxide. The resultant the reaction may be extracted into organic solvent, for example, dichloromethane.

The resultant organic layer may be subjected for isolation of solid or directly used for further steps to obtain alcaftadine or its salt. The isolation of solid may be performed using crystallization or anti-solvent technique using hydrochloric acid in presence of chlorinated solvent such as dichloromethane, chloroform, and the like.

The yield of the compound of Formula III or its salt obtained from the present invention is greater than or equal to 80 %.

In another embodiment, the present invention provides a process for preparing dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine of Formula IV

Formula IV

or its salt, which comprises reaction of (1-methyl-4-piperidinyl)[1-(2-phenylethyl)-1H-imidazol-2-yl]methanone or its salt with trifluoromethanesulfonic acid.

The quantity of the trifluoromethanesulfonic acid for performing the reaction may range from about 5 to about 10 molar equivalents per the equivalent of the compound of Formula III or its salt.

The temperature for the conducting the reaction may be greater than 40 to 120 oC or at reflux temperature. The period of time for completing the reaction may range from about 10 to about 20 hours or more at the same temperature.

After completion of the reaction, the reaction mixture may be basified by using suitable base, which is selected from the group of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, and the like. The resultant reaction mixture may be extracted into organic solvent, for example, dichoromethane.

The resultant organic layer may be subjected for isolation of solid by using suitable technique such as evaporation of solvent, crystallization using acetonitrile solvent or both, or it may be used directly for further reactions to afford alcaftadine. The present invention utilizes inexpensive crystallization technique than expensive column chromatography technique to isolate the purified compound of formula IV or its salt.

The purity of the resultant compound of formula IV or its salt is greater than or equal to 98%.

In another embodiment, the present invention provides a process for the preparation of 3-(hydroxymethyl)-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine of formula II:


Formula II

or its salt, which comprises reaction of 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine or its salt with formaldehyde in presence of acetic acid, sodium acetate and water.

The formaldehyde used for the reaction may be prepared as 37 to 40 % of formaldehyde in water and added drop-wise to the reaction.

The sodium acetate in acetic acid may be added dropwise to the reaction mixture at a ambient temperature or below to regulate the formation of process impurities.

The reaction may be performed at a temperature of about 35 to about 100 oC or at a reflux temperature for a period of 1 to 3 days or more.

After completion of the reaction, the reaction mixture may be basified by using suitable base, for example, sodium hydroxide, and then extracted the reaction mixture into organic solvent, for example, dichloromethane. The resultant organic layer may be concentrated or subjected for isolation using recrystallization technique in presence of chlorinated solvent or nitrile solvent and acid, for example, hydrochloric acid.

The resultant compound of formula II or its salt of the present invention has the purity greater than or equal to 98%.

The resultant intermediates of the present invention directly use for preparation of pure alcaftadine as per the process known in the art, for example, US 5,468,743, without subjecting any purification technique.

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-methyl-4-piperidinyl)[1-(2-phenylethyl)-1H-imidazol-2-yl]methanone


A mixture of [1-(2-phenylethyl)-1H-imidazol-2-yl](4-piperidinyl)methanone dihydrobromide (70 g, 0.15 mol), formaldehyde (120 mL) and formic acid (120 mL) was stirred at reflux for 10 hours. The reaction mixture was cooled, diluted with water and basified with NaOH solution. The product was extracted into dichloromethane (300x2 mL) and then the obtained organic layer was washed with water. The organic layer was evaporated under vacuum to afford (1-methyl-4-piperidinyl)[1-(2-phenylethyl)-1H-imidazol-2-yl]methanone.

The solid was isolated by converting the resultant residue to its salt by using especially hydrochloric acid.

Yield: 82%

Example-2:
Preparation of 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine

To a mixture of (1-methyl-4-piperidinyl)[1-(2-phenylethyl)-1H-imidazol-2-yl]methanone (32 g, 0.107 mol) and trifluoromethanesulfonic acid (160 mL) was stirred for 24 hours at 100 – 110 oC. After cooling, the reaction mixture was poured into ice-water and basified with NaOH solution. The product was extracted with dichloromethane (100x2 mL) and then organic layer was washed with water. The organic layer was evaporated under reduce presser to give crude product. The crude product was crystallized from acetonitrile to afford 28 g of 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine.

Purity: 98%

Example-3:
Preparation of 3-(hydroxymethyl)-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine

A mixture of 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine (3.5 g, 0.012 mol), 37 % formaldehyde in water (40 mL), and sodium acetate (8 g) in acetic acid (10 mL) was stirred at reflux for 3 days. After completion of the reaction, the mixture was cooled, poured into ice-water and basified with NaOH solution. The product was extracted with dichloromethane (50x2 mL) and organic layer was washed with water. The organic layer was evaporated under reduce presser to afford 1.7 g of 3-(hydroxymethyl)-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine.
Mass Spectrometry: The protonated molecular ion at m/z 310.2 (M+) confirms the mass, which corresponds to molecular formula of C19H23N3O.

Purity: 98%