FIELD OF INVENTION The invention relates to a process for the preparation of A lcaftadine. The invention also relates to a process for the preparation of crystal line form of Alcaftadine. .

BACKGROUND OF INVENTION

A lcaftadine is chem ical ly known as 6, 1 1 -dihydro- l ] -( l -methyl-4-piperidinyl idene)-5H- im idazo[2, 1 -b] [3] benzazepine-3-carboxaldehyde having the formula as represented below:

Alcaftadine is used for the treatment of histam ine H I receptor antagonist. The US Patent US5468743 first discloses the Alcaftadine and also the process for the preparation of Alcaftadine. The process in US'743 ' patent involves the steps of: reaction of piperidin-4-yl,6, 1 1 -dihydro-5H- im idazo[2, l -b][3]benzazepine with formaldehyde and form ic acid to obtain a compound methylpiperidin-4-yl,6, 1 l -dihydro-5H-im idazo[2, l -b][3]benzazepi ne; and reaction of the obtained compound with formaldehyde and acetic acid in presence of sodi um acetate to yield the compound methylpiperidin-4-y 1,6, 1 1 -dihydro-5 H-im idazo[2, l -b] [3]benzazepine methanol, followed by oxidation in the presence of manganese dioxide to obtain the Alcaftadine.

However, the disclosed process employs the column chromatography for isolation of intermediate as well as for Alcaftad ine. Practicing of column chromatography at commercial scale is cumbersoine.Therefore, there is a need to develop a process for preparing Alcaftadine, which is cost effective, commercially viable and does not employ any column chromatographic techinques.

OBJECTS OF THE INVENTION

The primary object of the invention is to provide an improved process for preparation of Alcaftadine or its pharmaceutical ly acceptable salts. Another object of the invention is to provide a process for preparation of novel crystal l ine form of

A lcaftadine.

A further object of the invention is to provide a process for purification of Alcaftadine or its pharmaceutical ly acceptable salts.

SUMMARY OF THE INVENTION

In one embodiment, the invention provides a process for preparation of Alcaftadine or its pharmaceutical ly acceptable salts comprising the steps of : i) cyclizing a compound of formula ΙΠΑ

Formula IMA

in presence of a triflurosu lfon ic acid (trifl ic acid) at a temperature of about 140° to I 45°C to obtain a compound of form u la VI,

Formula VI

ii) treating the compound of formula VI with formaldehyde and acetic acid in presence of potassium acetate in an amount of about 0. 1 to 0.5 mole ratio with respect to the compound of formula V I to obtain a compound of formula VI I

Formula VII iii) reacting the compound of formula VII with manganese dioxide to obtain Alcaftadine or its pharmaceutically acceptable salts.

Inanother embodiment, theinvention provides a process for preparation of Alcaftadine or its pharmaceutically acceptable salts comprising the steps of : i) cyclizing a compound of formula IV

Formula IV

in the presence of triflurosulfonic acid (triflic acid) at a temperature of about 140° to 145°C to obtain a compound of formula V,

Formula V

ii) methylating the compound of formula V in presence of methylating reagent to obtain a compound of formula VI,

Formula VI iii) treating the compound of formula VI with formaldehyde and acetic acid in the presence of potassium acetate in an amount of about 0. 1 to 0.5 mole ratio with respect to the compound of formula VI to obtain a compound of formula VI I

Formula VII

iv) reacting the compound of formula VII with manganese dioxide to obtain Alcaftadine or its pharmaceutically acceptable salts. In another embodiment, the invention provides a process for preparation of Alcaftadine or its pharmaceutical acceptable salts comprising the steps of : . i) treating the compound of formula VI

Formula VI with formaldehyde and acetic acid in presence of potassium acetate in an amount of about 0. 1 to 0.5 mole ratio with respect to the compound of formula VI to obtain the compound of formula VI I

Formula VII ii) reacting the compound of formula VII with manganese dioxide to obtain alcaftadine or its pharmaceutically acceptable salts.

In another embodiment, the invention provides a process for preparation of Alcaftadine or its pharmaceutically acceptable salts comprising the steps of : i) cyclizing the compound of formula 111 A

Formula IIIA

in presence of a triflurosulfonic acid (triflic acid) at a temperature of about 140° to I 45°C to obtain the compound of formula VI,

Formula VI

In another embodiment, the invention provides a process for preparation of Alcaftadine or its pharmaceutical acceptable salts comprising the steps of :

i) cyclizing the compound of formula IV

Formula IV

in presence of triflurosulfonic acid (triflic acid) at a temperature of about 140° to 145°C to obtain the compound of formula V,

Formula V In yet another embodiment, the the invention provides a process for preparation of Alcaftadine or its pharmaceutically acceptable salts comprising the steps of : i) reacting the compound of formula V

containing an impurity compound of formula VIII,

Formula VIII

with manganese dioxide till the substantially less amount of the compound having the formula VIII is detected;

(ii) washing the reaction mixture obtained in step (i) with acetonitrile;

(iii) reacting the washed reaction mass obtained in step (ii) with manganese dioxide to obtain Alcaftadine or its pharmaceutically acceptable salts.

In yet another embodiment, theinvention provides a process for purification of Alcaftadine or its pharmaceutically acceptable salts comprising the steps of:

(i) dissolving the Alcaftadine in a first organic solvent;

(ii) optionally, heating the solution obtained in step (i);

(iii) optionally, cooling the solution obtained in step (i) or step (ii);

(iv) adding a second organic solvent to the solution obtained in step (i) or (ii) or (iii);

(v) maintaining the contents obtained in step (iv) till the formation of solid;

(vi) filtering the solid Alcaftadine.

wherein, the first organic solvent is selected from the ester or mixtures containing the ester thereof: the second solvent is selected from the aliphatic hydrocarbons or mixtures containing the aliphatic hydrocarbons thereof. In yet another embodiment, the the invention provides a crystalline form of the compound 11-

(piperidin-4-ylidene)-6, 1 l-dihydro-5H-imidazo[2,l-/>][3]benzazepine as represented below:

Formula V In a further embodiment, the invention provides a process for preparing a Crystalline form of Alcaftadine comprising the steps of:

(i) dissolving Alcaftadine in ketone solvent;

(ii) optionally, cooling the solution obtained in step (i);

(iii) adding the aliphatic hydrocarbon solvent to the solution obtained in step (i) or (ii);

(iv) maintaining the mixture resulted in step (iii) till the formation of crystalline form.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 : Figure- 1 represents typical X-ray powder diffraction pattern of the crystalline form of the compound 1 l-(piperidin-4-ylidene)-6, 1 l-dihydro-5H-imidazo[2, l-&][3]benzazepine

Figure 2: Figure-2 represents DSC of the crystalline form of the compound 1 l-(piperidin-4- ylidene)-6,l l-dihydro-5H-imidazo[2, 1 -/>][3]benzazepine

Figure 3: Figure-3 represents TGA of the crystalline form of the compound 11 -(piperidin-4- ylidene)-6, 11 -dihydro-5H-imidazo[2, 1 -6][3]benzazepine

Figure 4: Figiire-4 represents typical X-ray powder diffraction pattern of crystalline Alcaftadine Figure 5: Figure-5 represents DSC of crystalline Alcaftadine form

Figure 6: Figure-6 represents TGA of crystalline Alcaftadine form DETAILED DESCRIPTION OF THE INVENTION

Detailed embodiments of the present invention are disclosed herein below. However, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which can be embodied in various forms. The scope of the invention is not limited to the disclosed embodiments and terms and phrases used herein are not intended to be limiting but rather to provide an understandable description of the invention. The invention is defined by claims appended hereto.

In an exemplary embodiment, the invention provides improved process for preparation of Alcaftadine or its pharmaceutically acceptable salts which are cost effective and commercially viable.

In one embodiment, the invention provides a novel process for preparation of Alcaftadine or its pharmaceutically acceptable salts comprising the steps of : i) treating a compound of formula I

Formula I

wherein, R is a leaving group;

with imidazole in presence of a base to obtain a compound of formula II

Formula II

ii) treating the compound of formula II with 1 -methylpiperidine-4-carbonyl chloride in presence of base to obtain a compound of formula III A

Formula IIIA

iii) cyclizing the compound of formula IIIA in presence of triflurosulfonic acid (triflic acid) at a temperature of about 140° to 145°C to obtain a compound of formula VI

Formula VI iv) treating the compound of formula VI with formaldehyde and acetic acid in presence of potassium acetate to obtain a compo

Formula VII

v) reacting the compound of formula VII with manganese dioxide to obtain Alcaftadine or its pharmaceutically acceptable salts.

The base empolyed in the step i) is selected form the group comprising of organic or inorganic bases, wherein the inorganic bases comprise alkali metal hydroxides like sodium hydroxide, potassium hydroxide, alkali metal carbonates like sodium carbonates, potassium carbonates, alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; organic bases comprise CI- C6 carbons containing amines such as alkyl amines like methyl amine, ethyl amine, aryl amines or substituted aryl amines like aniline, benzyl amine, or flouro aniline, flouro methyl phenyl amine and ammonia .

The base empolyed in the step ii) is selected form the group comprising of organic or inorganic bases, wherein the inorganic bases comprise alkali metal hydroxides like sodium hydroxide, potassium hydroxide, alkali metal carbonates like sodium carbonates, potassium carbonates, alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; organic bases comprise CI- C6 carbons containing amines such as alkyl amines like methyl amine, ethyl amine, aryl amines or substituted aryl amines like aniline, benzyl amine, or fluoro aniline, flouro methyl phenyl amine and ammonia . In second embodiment, the invention provided a process for preparation of Alcaftadine or its pharmaceutically acceptable salts, comprising the steps of : i) treating a compound of formula 1

Formula I

wherein, is leaving group ;

with imidazole in the presence of a base to obtain a compound of formula II

Formula II

ii) treating the compound of formula II with ethyl 4-chlorocarbonyl- l -piperidinecarbox.ylate in the presence of a base to obtain a compound of formula III

Formula III

iii) deesterificating the compound of formula 111 to obtain a compound of formula IV or its acid addition salts;

Formula IV iv) cyclizing the compound of formula IV in presence of triflurosulfonic acid (triflic acid) at a temperature of about 140° to 145°C to obtain . compound of formula V

H

Formula V

v) methylating the compound of formula V in the presence of methylating reagent to obta compound of formula VI

Formula VI

vi) treating the compound of formula VI with formaldehyde and acetic acid in presence of potassium acetate to obtain compound of formula VII

Formula VII

vii) reducing the compound of formula VII to obtain Alcaftadine or its pharmaceutically acceptable salts.

The base empolyed in the step i) is selected form the group comprising of organic or inorganic bases, wherein the inorganic bases comprise alkali metal hydroxides like sodium hydroxide, potassium hydroxide, alkali metal carbonates like sodium carbonates, potassium carbonates, alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; organic bases comprise Cl- C6 carbons containing amines such as alkyl amines like methyl amine, ethyl amine, aryl amines or substituted aryl amines like aniline, benzyl amine, or flouro aniline, flouro methyl phenyl amine and ammonia . The base empolyed in the step i i) is selected form the group comprising of organ ic or inorganic bases, wherein, the inorgan ic bases comprise alkal i metal hydroxides l ike sod ium hydroxide, potassium hydroxide, alkal i metal carbonates like sodium carbonates, potassium carbonates, alkal i metal bicarbonates like sodium bicarbonate and potassium bicarbonate; organic bases comprise C I - C6 carbons containing am ines such as alkyl amines like methyl am ine, ethyl am ine, aryl am ines or substituted aryl amines like ani line, benzyl am ine, or flouro anil ine, flouro methyl phenyl amine and ammonia .

The methylating reagent empolyed in the step v) is selected form the group comprising of methyl hal ides, dimethyl carbonate, dimethyl su lfate, phosgene or a m ixture of formaldehyde and form ic acid.

The patent US5468743 describes an alkylating reaction of the com pound with formaldehyde and acetic acid in the presence of sodium acetate to obtain an alkylated compound; This method involves column chromatography for the purification of the alkylated compound and is not efficient. Unexpectedly the inventors of the present invention found that the use of potassium acetate in an amount of about 0. 1 to 0.5 mole ratio with respect to the starting material increases the yield of the product and decreases the formation of impurities.

In third embodiment, the invention provides a process for preparation of A lcaftad ine or its pharmaceuticaly acceptable salts comprising the steps of : i) treating the compound of formu la V I

Formula VI with formaldehyde and acetic acid in the presence of potassium acetate in an amount of about 0. 1 to 0.5 mole ratio with respect to the com pound of formu la VI, to obtain compound of formula VI I

Formula VII i i) treating the compound of formu la VI I with manganese dioxide to obtain Alcaftadine or its pharmaceutically acceptable salts.

The patents US5393753 and US5468743 describe the cycl ization reaction in the presence of trifluoromethane su lfonic acid wh ich is done in the prior arts either at 60°C for 1 8 hours or at the temperature of 1 1 0°C for 72 hours. Both the methods involves column chromatographic separation technique for the purification of the compound wh ich affects yield of product. Surprisingly the inventors of the present invention found that the cycl ization reaction in the preparation of alcaftadine intermediates at a temperature of 1 40° to I 45°C does not require cumbersome column chromatographic purification.

In fourth embod iment, there is provided a process for preparation of Alcaftadine or its pharmaceutical ly acceptable salts comprising the steps of : i) cyclizing the compound of formula I I IA

Formula IIIA in the presence of a triflurosulfonic acid (triflic acid) at a temperature of about 1 40° to 1 45°C to obtain compound of formu la V I

Formula VI

In fifth embodiment, there is provided a process for preparation of Alcaftadine or its pharmaceutically acceptable salts comprising the steps of :

i) cyclizing the compound of formula IV

Formula IV

in the presence of triflurosulfon ic acid (triflic acid) at a temperature of about 140° to 145°C to obtain the compound of formula V

Formula V

The reaction of the compound having formu la VI I contain ing an impurity compound of formu la VI I I, with manganese dioxide resu lts in the formation of A lcaftad ine along with formation of impurities. The present inventors _. found that the purification of A lcaftad ine resulted in such processes involves cumbersome purification techniques. The inventors of the present invention developed a novel technique for the preparation, wherein the impurity having the formu la VI II in the compound having form ula VII is removed after the reaction with manganese d ioxide by washings with acetonitri le thereby separating the purified unreacted compound of formula V I I and l ittle amount of Alcaftadine. The separated A lcaftadine was then reacted with manganese dioxide to obtaine pure Alcaftadine. In sixth embodiment, there is provided a process for preparation of Alcaftadine or its pharmaceutically acceptable salts comprising the steps of : i) reacting the compound of formula VII

containing an impurity having the for

Formula VIII

with manganese dioxide till the substantially less amount of the compound having the formula Vlll is detected;

(ii) washing the reaction mixture obtained in step (i) with acetonitrile;

(iii) reacting the the washed reaction mass obtained in step (ii) with manganese dioxide to obtain Alcaftadine or its pharmaceutically acceptable salts.

The step (i) and (iii) may be carried out in any conventionally used suitable organic solvent.. Examples of such organic solvents include dichloromethane, chloroform, acetonitrile, toluene, and n-hexane.

In seventh embodiment, there is provided a process for purification of Alcaftadine or its pharmaceutically acceptable salts comprising the steps of:

(i) dissolving the Alcaftadine in a first organic solvent;

(ii) optionally, heating the solution obtained in step (i);

(iii) optionally, cooling the solution obtained in step (i) or step (ii);

(iv) adding a second organic solvent to the solution obtained in step (i) or (ii) or (iii); (v) maintaining the contents obtained in step (iv) till formation of the solid;

(vi) filtering the solid Alcaftadine. wherein, the first organic solvent is selected from the ester or mixtures containing the ester thereof; the second solvent is selected from the aliphatic hydrocarbons or mixtures containing the aliphatic hydrocarbons thereof.

The ester organic solvent used herein is selected from the group comprising of Butyl acetate Sec- Butyl acetate, Tert-butyl acetate, Ethyl acetoacetate, Ethyl butyrate, Ethyl acetate, Isopropyl acetate, Methyl acetate and the likes. The aliphatic hydrocarbon organic solvent used herein is selected from the group comprising of pentane, hexane, heptanes, octane, petroleum ether and the likes.

In eighth embodiment, the invention provides a crystalline form of the compound 1 l-(piperidin-4- ylidene)-6, 1 l-dihydro-5H-imidazo[2, l-£][3]benzazepine as represented below:

Formula V

The process for preparing crystalline form of the compound 11 -(piperid in-4-y I idene)-6, 11- dihydro-5H-imidazo[2,l -6][3]benzazepine comprises the steps of:

1. suspending the compound 1 l-(piperidin-4-ylidene)-6, 1 l-dihydro-5H-imidazo[2, 1- b][3]benzazepine in acetone; and

2. stirring at a temperature of 25-30°C for 30 minutes.

In a further embodiment, the invention provides a process for preparing a Crystalline form of Alcaftadine comprising the steps of:

(i) dissolving Alcaftadine in ketone solvent;

(ii) optionally, cooling the solution obtained in step (i);

(iii) adding a aliphatic hydrocarbon solvent to the solution obtained in step (i) or (ii);

(iv) maintaining the mixture resulted in step (iii) till the formation of crystalline form. The ketone solvent used in step (i) is selected from the group comprising of acetone, methyl ketone and the likes. The aliphatic hydrocarbon organic solvent used in step (iii) is selected from the group comprising of pentane, hexane, heptanes, octane, petroleum ether and the likes.

The following examples are provided to enable one skilled in the art to practice the invention and merely illustrate the process of the invention. However, it is not intended in any way to limit the scope of the present invention.

EXAMPLES

Example 1 - Preparation of l-(Ethoxycarbonyl) piperidine-4-CarboxyIic Acid

To a solution of (154.8 gm) Sodium hydroxide in (750 ml) purified water, Isonipecotic acid (250gm) was added at 0-I0°C, followed by the slow addition of ethyl chloroformate (231 ml) at 5- 20°C. The reaction mixture was heated to 20-30°C and maintained for 3 hrs at the same temperature. After completion of the reaction, the reaction mass was acidified to a pH 1-2 by addition of hydrochloric acid. Then toluene (750 ml) was added to the reaction mass and stirred for 15 minutes at 25-30 °C. The organic layer was separated and concentrated under vacuum at below 70°C to obtain a residue. The res.idue_w_as_mj.xed. with cyclohexane (1250 ml) at 60-70°C, then cooled to 25-30°C and maintain for 1 hour at the same temperature. The resulted contents were filtered, and washed with cyclohexane (1250 ml) and dried at 50-55°C. Percentage Yield: 92%

Example 2 - Preparation of l-(2-phenylethyl)-lH-imidazole(KSM-II)

To a suspension of (100 gm) 2-phenyl ethyl alcohol in (1000 ml) of toluene, triethylamine (137.33 ml) and methane sulfonyl chloride (103.3 gm) was added at a temperature of 0-10°C and stirred for 1 hour at the same temperature. After the completion of the reaction, purified water (500.0 ml) was added and stirred for 30 minutes at 0-25 °C. The organic layer was separated and washed with purified water.

To the organic layer, Imidazole (67.0 gm), potassium carbonate (136.0 gm) and tetrabutyl ammonium bromide (16.0 gm) was added at 25-30°C, heated to 104-110 °C and stirred for 1 hr at the same temperature. After the completion of the reaction, water (500 ml) was added and stirred for 30 minutes. The organic layer separated and washed with water. Water (500ml) was added to the organic layer and the pH of the contents was adjusted to 2 or below with hydrochloric acid. The aqueous layer was separated and toluene was added to the aqueous layer. The biphasic medium was stirred for 15 minutes and adjusted to a pH of 10 to 14 with 10% aqueous sodium hydroxide solution. The temperature of the contents were raised to 25-30°C and stirred for 30 minutes at the same temperature. The organic layer was separated and disti lled off under vacuum at below 65°

Percentage Yield: 68.09%

Example-3 Preparation of [l-(2-phenylethyl)-lH-imidazole-2-yl](piperidin-4-yl)methano ne dihydrobromide

To (5 1.12 gm) of the compound obtained in example- 1 , toluene (25 ml) and D F ( 1 .53 ml) was added, followed by the slow addition of thionyl chloride (45.39 gm). The reaction mixture was then heated to 50-55 °C and maintained for 2 hours at the same temperature. After completion of the reaction, the excess of thionyl chloride and toluene from the reaction mixture was distilled under vacuum below 70°C. The residue obtained was cooled to 5- l 0°C under N2 atmosphere. To the cooled residue, a solution of compound obtained in example-2 (25gm) in acetonitrile ( 125ml) was slowly added at 0-20°C under N2 atmosphere followed by the slow addition of triethylamine (29.36gm) at 0-20°C for 2 hours and maintained for 3 hrs at the same temperature. The progress of the reaction was monitored by HPLC. After the completion of the reaction, ( 125ml) purified water and (75 ml) ethyl acetate was added to the reaction mixture and stirred for 10 minutes. The organic layer was separated, washed with water and concentrated the organic layer at mass temperature below 55°C under vacuum to get a residue. The residue was cooled to 25-30°C and (249.57gm) aqueous HBr was added to the residue. The contents were stirred for 10 min; then heated to 85- 90°C and maintained for 12 hrs at the same temperature. The reaction mass was cooled to 55-60°C and ( 167.5 ml). Isopropyl alcohol was added to the cooled reaction mass, then heated to 65-70°C and maintain for 1 hr at the same temperature. The reaction mass was filtered and dried the material in hot air oven at 60-65°C for 8 hrs.

Percentage Yield: 90% Example-4 Preparation of ll-piperidin-4-yIidene-6,ll-dihydro-5H-imidazo[2,l- £] [3]benzazepine

The suspension of ( 100.0 g) compound obtained example-3 and (300 ml) purified water was adjusted to the pH 9- 10 with 20% sodium hydroxide solution and dichloromethane (300 m l) was added. The contents were stirred for 30 minutes. The organic layer was separated and concentrated under vacuum at below 50°C to obtain a residue. The residue was cooled to 25-30°C and acetone ( 100 ml) was added to the residue and cooled to 0-5°C. The contents were stirred for 2 hours at 0- 5°C; filtered the solid; and washed with chilled acetone (25 ml) and dried under vacuum at 45-50°C for 4hr. The solid was then added to trifluorosulfonic acid (triflic acid) (3 volumes of dry solid) at 25 to 50°C; and heated to 140- 145°C. The reaction mixture was maintained for 1 0 hours at 140- 145°C. The progress of the reaction was monitored by HPLC. After the completion of the reaction mixture was cooled to 25-30°C and poured into the chilled water (150ml) maintaining the temperature less than 40°C. The pH of the reaction mass was adjusted to 8.5-9.5 with 20% sodium carbonate solution. Dichloromethane was added to the reaction mass and stirred for 15 minutes. The organic layer was separated, concentrated under vacuum at below 50°C to obtain a residue. The residue was mixed with acetone (50ml) at 25-30°C for 30 minutes. The contents were filtered, washed with acetone (25 ml) and dried at 50-55°C under vacuum. Yield: 25.5 g

Example-5 Preparation of ll-(l-methylpiperidin-4-ylidene)-6,ll-dihydro-5H-imidazo[2,l - b][3]benzazepine

To the compound obtained in example-4 (100 g), formic acid (60.75 g) and 37% formaldehyde solution (22.63 g) was added, heated to 75-80°C and stirred for 1.0 hr at the same temperature. The progress of the reaction was monitored by HPLC. After the completion of the reaction, the reaction mixture was cooled to 25-30 °C. The pH of the reaction mixture was adjusted to 12.0 -12.5 with 20% sodium hydroxide. Dichloromethane (300ml) was added to the reaction mixture and stirred for 30 minutes. The organic layer was separated and concentrated under vacuum at below 50°C to obtain a residue. The residue was cooled to 25-30 °C and added acetone (100 ml). The contents were stirred for 15 minutes; filtered the solid, washed with chilled acetone (50 ml) and dried at 50- 55°C under vacuum for 4 hrs.

The dried solid was suspended in tetrahydrofuran (3.0 volumes to above dry compound) and heated to reflux temperature to obtain a clear solution. The contents were cooled to 25-30°C, followed further cooling to 0-5°C and stirred for 1.0 hr at the same temperature. The contents were filtered and washed with chilled tetrahydrofuran (0.2 volumes) and dried the compound under vacuum at 50-55°C.

The dried solid was suspended in ethyl acetate (8.0 volumes to above dry compound) and heated to reflux temperature to obtain a clear solution. Activated carbon is added to the solution and stir for 15 minutes at reflux temperature. The carbon from the contents was filtered and filtrate was concentrated till 1.5 volumes of Ethyl acetate remains. The contents were then cooled to 0-5°C and stirred for 1 hours at the same temperature. The contents were filtered, washed with ethyl acetate and dried the compound under vacuum at 55-60°C. Yield: 26.8 g.

Example-6: Preparation of compound of formula VII

The compound obtained in example-5 (100 g) was mixed with acetic acid (50 ml), 37% aqueous formaldehyde (500 ml) and potassium acetate 12.29 g at 25-30 °C and heated the reaction mixture to 100°C. The reaction mixture was maintained for 10-13 hours at 100°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was cooled to 25-30 °C and dichioromethane (1000 ml) was added. The pH of the reaction mass was adjusted to 11-12 with 20% aqueous sodium hydroxide and stirred for 10-15 min. The organic layer was separated, washed brine solution and dehydrated by the addition of sodium sulphate (200 g) and filtered. The organic layer was concentrated below 60°C to obtain a residue. The residue was mixed with (200 ml) Chloroform and concentrated below 60°C to obtain a solid residue. Purity of the compound is not less than 65% and diol impurity is not more than 20%. Yield: 138 gin Example - 7: Preparation of Alcaftadine

Step-A: To a solution of the compound obtained in example-6 (110.8 g) in Chloroform 1000 ml, manganese dioxide (311.5 g) was added at 25 °C and heated to 55-65°C. The reaction mixture was maintained for 2 hours at the 55-65°C. The progress of the reaction was monitored by HPLC. The reaction was stopped if the HPLC shows diol impurity below 0.75%, the reaction mixture was cooled to 25-30°C, filtered through hyflow and washed with dichioromethane (500 ml). The washings of dichioromethane and the chloroform filtrate was combined and concentrated below 60°C to obtain a residue. The residue was mixed with acetonitrile (150 ml) and stirred for I hour at 25-30°C. The contents were filtered and washed. Step-B: To the solid obtained during filtration, chloroform (750 inL) and manganese dioxide (211 gm) was added at a temperature of 25-30°C. The reaction mixture was heated to 55-65°C and maintained at the same temperature for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 25-30°C; filtered through hyflow and washed with dichioromethane (500 ml). The washings of dichioromethane and the chloroform filtrate were combined; dehydratred with addition of sodium sulfate (250 gm); and concentrated to obtain a residue below 60°C. The residue was washed with acetonitrile; then mixed with acetonitrile (25 ml) and ethyl acetate (25 ml). The contents were heated to 70-80°C and maintained for 1 hour at the same temperature. The contents were then cooled to 10-15°C and maintained at the same temperature for 30 minutes. The solid obtained was filtered; and washed with chilled acetonitrile (1 .5 ml).

Step-C: The wet solid obtained in step-B was mixed with acetonitrile (150 ml) and refluxed at 75-

85°C. Acetonitrile was slowly added to the contents till formation of a clear solution. Activated charcoal (0.5 gm) was added to the solution and refluxed for 30 minutes at 75-80°C. The contents were filtered through hyflow at 75-80°C and wash the bed with hot acetonitrile (25 ml). The filtrate and washings were combined and heated to 75-80°C and maintained for 30 minutes at the temperature. The contents were then cooled to 10-15°C and maintained for 1 hour at the same temperature. The obtained solid was filtered and washed with chilled acetonitirile (12.5 ml). Step-D: The wet solid obtained in step-C was mixed with acetonitrile (150 ml) and refluxed at 75- 85°C. Acetonitrile was slowly added to the contents till formation of a clear solution. The contents were then cooled to I0-15°C and maintained for 1 hour at the same temperature. The obtained solid was filtered and washed with chilled acetonitirile (12.5 ml). Step-E: (Purification of the Alcaftadine) The wet solid obtained in step-D was refluxed with ethyl acetate (25 ml) at 75-80°C for 1 hour. The contents were then cooled to 0-5°C. Then n-heptane (75 ml) was added and stirred for 1 hours at 0-5°C. The obtained solid was filtered; washed with chilled n-heptane (25 ml); and dried in vacuum at 55-60°C for 10-12 hours. Percentage Yield: 20% ExampIe-8 : Preparation of Alcaftadine

Step-A: To a solution of the compound obtained in example-6 (110.8 g) in Chloroform 1000 ml, manganese dioxide (311.5 g) was added at 25 °C and heated to 55-65°C. The reaction mixture was maintained for 2 hours at the 55-65°C. The progress of the reaction was monitored by HPLC. The reaction was stopped if the HPLC shows diol impurity below 0.75%, the reaction mixture was cooled to 25-30°C, filtered through hyflow and washed with dichloromethane (500 ml). The washings of dichloromethane and the chloroform filtrate was combined and concentrated below 60°C to obtain a residue. The residue was mixed with dichloromethane (750 ml) and refluxed at 35- 40°C for 15 minutes and cooled to 25 to 30°C. The cooled solution filtered through hyflow and the bed hyflow was washed with dichloromethane (250 ml). The filtrate and washings were combined to obtain a residue. The residue was acetonitrile (300 ml) and stirred for 1 hour at 25-30°C. The contents were filtered and washed with acetonitrile (50 ml). The wet solid was mixed with acetonitrile (100 ml) and refluxed to 65-75°C for 1 hour. The contents were the cooled to 25 to 30°C and maintained at the same temperature. The resulted was filtered and washed with acetonitrile (25 ml).

Step-B: To the solid obtained during filtration, chloroform (750 niL) and manganese dioxide (211 gm) was added at a temperature of 25-30°C. The reaction mixture was heated to 55-65°C and maintained at the same temperature for 2 hours. The progress of the reaction was monitored by

TLC. After completion of the reaction, the reaction mixture was cooled to 25-30°C; filtered through hyflow and washed with dichloromethane (500 ml). The washings of dichloromethane and the chloroform filtrate was combined; and concentrated to obtain a residue below 60°C. The residue was mixed with acetonitirile (100 ml) and co-distilled below 60°C to obtain a residue. The residue was charged with acetonitrile (50 ml) and stirred for I hour at a temperature of 25-30°C. The resulted solid was filtered and washed with acetonitrile (25 ml).

Step-C: The wet solid obtained in step-B was mixed with acetonitrile (105 ml) and refluxed at 75- 85°C. Purified water (15 ml) was added to the contents till formation of a clear solution and refluxed at 75-80°C. The contents were filtered through hyflow at 75-80°C and wash the hyflow bed with hot acetonitrile (10 ml). The filtrate and washings were combined and refluxed at 75-80°C for 30 minutes. The refluxed contents were then cooled to 10-15°C and maintained for 1 hour at the same temperature. The resulted solid was filtered and washed with acetonitrile (10 ml).

Step-E: (Preparation of crystalline Alcaftadine form) The wet solid obtained in step-D was suspended in acetone (375 ml) and heated to a temperature of 50-55°C. The contents were maintained and stirred at the temperature of 50-55°C till a clear solution was formed. Activated charcoal (0.5 gm) was added to the solution and refluxed for 30 minutes at a temperature of 50- 55°C. The contents were filtered through hyflow and washed the hyflow bed with hot acetone (50 ml). The filtrate and the washings were combined at concentrated to obtain a residue. The residue was mixed with acetone (25 ml) at 25-30°C and cooled to 0-5°C. The n-heptane (150 ml) was added to the contents at 0-5°C and maintained at the same temperature for 1 hour at the same temperature. The crystalline solid obtained was then filtered, washed with chilled n-heptane (10 ml) and dried in vacuum at 55-60°C for 6- 12 h. Yield: 18.5%.

Example - 9: Process for the preparation of l-(2-phenylethyl-lH-imidazole)

The 2-phenyl ethyl sulfonate (150 gm) was dissolved in THF at 25-30°C, followed by the imidazole (100.5 gm) was at same temperature. The potassium carbonate (0.9 mol) was added at 25-30°C. The temperature of the reaction mixture was raised to 70-75°C and stirred for 18-20 hours in the same temperature. The reaction mixture was cooled to 25-30°C. The contents were filtered and wash with the ethyl acetate (1000 ml). The filtrate was distilled under vacuum and the residue was dissolved in (1500 ml) ethyl acetate at 25-30°C. The hydrochloride solution was added to the reaction mixture. Aqueous layer was separated. The pH of the aqueous layer was adjusted to 8-9 by using 20% sodium carbonate and extracted with dichloromethane (750 ml). The organic layers were separated and distilled to obtain the compound. Yield: 65% Example - 10: Process for the preparation of Ethyl 4-{[l-(2-phenylethyl)-lH-imidazole-2-yl] carbonyl}-l-piperidinecarboxylate

The compound of example-9 (88 gm) was dissolved in (300 ml) acetonitrile followed by (143 ml) triethylamine was added at 25-30°C. The reaction mixture was cooled to 0-5°C and stirred for 30 minutes at the same temperature. The mixture of ethyl 4-(chlorocarbonyl) piperidine-l-carboxylate (0.7 mol) and (140 ml) acetonitrile was added to the above reaction mixture at 0-5°C and stirred at the same temperature. The progress of the reaction was monitored by TLC. After the completion of the reaction, ethyl acetate (440 ml) was added and stirred for 10 minutes. The organic layers was separated. The organic layer was distilled to obtain the residue. Yield: 98%

Example - 11: Preparation of |l-(2-phenyIethyI)-lH-imidazole-2-yl](4-piperidinyl)methanon e dihydrobromide

The compound of example- 10 (178 gms) was dissolved in 534 ml aqueous hydro bromide at 25- 30°C and stirred for 10 min.at same temperature. The temperature of the reaction mixture was raised to 70-75°C for azeotropic distillation. The reaction mixture was then cooled at 25-30°C and isopropyl alcohol (712 ml) was added at same temperature. The contents were filtered and the resultant solid was washed with isopropyl alcohol (534 ml) and dried the compound. Yield: 70%

Example -12 : Preparation of [l-(2-phenylethyl)-lH-imidazole-2-yl](4-piperidinyl)methanon e The compound of example-11 was dissolved in (900ml) 20% sodium carbonate solution and the pH of the reaction mixture was adjusted to 8-9, followed by the addition of (804 ml) methylene dichloride. The organic layer was separated and distilled to obtain the compound. Yield: 98%

Example-13: Preparation of ll-piperidin-4-ylidene-6, ll-dihydro-5H-imidazo[2,l- ][3)benzazepine

The compound of example- 12 (82 gm) was dissolved in (50 ml) methylene chloride at 25-30°C and heated to 40-45°C. Distilled the methylene chloride to get a concentrated mixure and cooled to 25- 30°C. The triflic acid (64 ml) was added to the reaction mixture and the reaction mixture was heated to I35-I40°C. The progress of the reaction was monitored by TLC. After the completion of the reaction mixture, the reaction mass cooled to 25-30°C and the pH of the reaction mixture was adjusted to 8-9 with 20% aq. Sodium carbonate solution (-800 ml). The methylene dichloride (410 ml) was added to the reaction mixture and stirred for 10 minutes. The organic layer was separated and was distilled at 40-45°C to obtain the compound. Yield: 88% Example -14: Preparation of l l-(l-methylpiperidin-4-ylidene)-6, ll-dihydro-5H-imidazo[2,l-

6] [3]benzazepine

The compound of example- 13 ( 34.4gm ) was added to (206 ml ) 37% formaldehyde solution at 25-30°C followed by 98% formic acid (69 ml ) was added to the reaction mixture at 25-30°C. The temperature of the reaction mixture was raised to 1 1 0°C. After the completion of the reaction, the reaction mixture was cooled to 25-30°C and the pH was adjusted to 8-9 with aq. Sodium carbonate solution. Methylene chloride (480 ml) was added to the reaction mixture and stirred for 10 minutes. The organic layer was separated and disti lled to obtain the compound. Yield: 82% Example -15: Preparation of [ll-(l-methylpiperidin-4-ylidene)-6,ll-dihydro-5H-imidazo[2, l- b\ [3] benzazepin-3-y I] methanol

The compound of example- 14 was dissolved in (60 ml) 37% formaldehyde solution at 25-30°C and the temperature of the reaction was raised to l l 0°C. The reaction mixture was stirred at 1 10°C- 1 15°C till completion of reaction. The progress of the reaction was monitored by TLC. The reaction m ixture was cooled to 25-30°C and the pH of the reaction was adjusted to 8-9 with (50 ml) aq. Sodium carbonate solution. The reaction mixture was extracted with (70 ml) of methylene chloride. The organic layer was separated, washed with (50 ml) brine solution, dried over magnesium sulphate and concentrated the total organic layer on rota vapour at 40-45°C to get semi solid compound.

Example -16: Preparation of l l-(l-methylpiperidin-4-ylidene)-6,ll-dihydro-5H-imidazo[2,l- b] [3] benzazepine-3-carbaldehyde

The compound of example- 1 5 was dissolved in (60 m l) chloroform at 25-30°C, fol lowed by the addition of (20gm) manganese dioxide at same temperature. The temperature of the reaction mass was raised up to reflux. The progress of the reaction was monitored by TLC. After completion of reaction, reaction mass was cooled to 25-30°C and filtered through cel ite bed. The filtrate was washed with ( 15 ml) chloroform and distilled to obtain the compound.

Example - 17: Preparation of l-methylpiperidine-4-carboxylic acid hydrochloride

The Piperidine-4-carboxylic acid (25 gm) was added to the formic acid (52 ml) at 25-30°C, followed by addition of a solution of 37 % formaldehyde (33.75 ml) arid the temperature of the reaction mixture was raised up to reflux and stirred the reaction mixture at same temperature till completion of the reaction. The progress of the reaction was monitored by TLC. The reaction mass was distilled to get a thick mass. The residue was dissolved in cone. HCl ( 12.5 ml) and stirred to obtain the semisolid. To the above contents, acetone (75 ml) was added and stirred at 25-30°C for minutes. The contents were filtered and the resulting solid was washed with acetone. Yield

85.75%

Example - 18: Preparation of l-methylpiperidine-4-carbonyl chloride hydrochloride.

The compound of example-6a (30 gm) was dissolved in toluene (90 ml) at 25-30°C, followed by addition of DMF (3.0 ml). The thionyl chloride (15.4 ml) was added to the reaction mixture and the temperature of the reaction mixture was raised up to 70-75°C. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was distilled to get a residue. Yield: 93%

Example - 19: preparation of (l-methylpiperidine-4-yl)[l-(2-Phenylethyl)-lH-imidazol-2- yl]methanone Hydrobromide

The compound of I-(2-phenylethyl-lH-imidazole) (10.7 gm) was dissolved in acetonitrile (57 ml) at 25 - 30°C, followed by the addition of triethyl amine (25.95 ml), then the reaction mixture was slowly cooled to 0-5°C and stirred for 30 mints at same temperature. The mixture of 1- methylpiperidine-4-carbonyl chloride hydrochloride (20.93 gm) and acetonitrile (50 ml) was added to the above reaction mixture at 0-5°C. The temperature of reaction mixture was raised up to 25- 30°C and; water (53.5 ml), ethyl acetate (53.5 ml ) was added and stirred for 10 minutes. The organic layer was separated and washed with water. The organic layer was distilled and the resulting residue was dissolved in aqueous HBr (21.4 ml). The temperature of the contents was raised to 80-85°C. The progress of the reaction was monitored by TLC. After the completion of the reaction, distilled the reaction mixture at 70-75°C, then cooled the reaction mixture to 25-30°C and mixed with isopropyl alcohol (21.4 ml). The contents were filtered, the resulted compound was dried. Yield: 42%

Example- 20: Preparation of ll-(l-methyIpiperidin-4-ylidene)-6,ll-dihydro-5H-imidazo[2,l - A][3]benzazepine

The compound of (l-methylpiperidine-4-yl)[l-(2-PhenylethyI)-lH-imidazol-2-yl ]methanone hydrobromide (12 gm) was dissolved in water (50 ml) at 25-30°C and the pH of the solution was adjusted to 9 -10 with aqueous sodium hydroxide (-50 ml) at 25-30°C. Then methylene chloride

(36 ml ) was added to the above reaction mixture at same temperature and stirred. The organic layer was separated and distilled to get the concentrated liquid. The triflic acid (14 ml) was added to the concentrated liquid at 25- 30°C and temperature of the reaction mixture was raised up to 140-

145°C, stirred for 1 hour, then cooled to to 25 -30°C. The pH of the reaction mass was adjusted to 9-10 with aqueous sodium hydroxide. The reaction mixture was extracted with methylene dichloride (37 ml). The methylene chloride layer was distilled. The residue was recrystallized in acetone.

Example - 21: purification of ll-(l-methylpiperidin-4-ylidene)-6,ll-dihydro-5H-imidazo[2,l - Z>][3]benzazepine-3-carbaldehyde

The crude 1 l-(l-methylpiperidin-4-ylidene)-6, 1 l-dihydro-5H-imidazo[2,l-Z>][3]benzazepine-3- carbaldehyde (3 gm) was dissolved in (15 ml) acetonitrile at 25-30°C. The temperature of the reaction mixture was raised up to reflux and was filtered in hot condition through celite bed. The reaction mixture was slowly cooled to 25-30°C, then cooled to 0-5°C and stirred for 1 hour at same temperature. The contents were filtered under the vacuum. The resulting solid was washed with (3 ml) acetonitrile and dried. Yield : 90%; Melting point: I67.37°C (DSC endothermic peak)

Example-22: Preparation of [ll-(l-methylpiperidin-4-yIidene)-6,ll-dihydro-5H-imidazo[2, l- Z>][3]benzazepin-3-yl] methanol

To a mixture of compound of example-6 (39 gm) and acetic acid (195 ml), 37% aqueous formaldehyde (195 ml) was added at 25 °C and heated the reaction mixture at 100 °C for 4.5 hours. After completion of the reaction, the reaction mixture was cooled to 25 °C and 20 % sodium hydroxide was slowly added at the same temperature till the pH is 11 to 12. The obtained compound was repeatedly extracted with dichloromethane and the combined extracts were evaporated to get a residue.

Example-23: Preparation of ll-(l-met ylpiperidin-4-yIidene)-6,ll-dihydro-5H-imidazo[2,l- 0][3]benzazepine-3-carbaldehyde

To the compound obtained in example-11 (21.0 gms) suspended in chloroform (300 ml), manganese dioxide (130 gm) was added at 25 °C and refluxed for 4 hours at 60°C. After the completion of the reaction, the reaction mixture was cooled to 25 °C and filtered the resultant solid. The filtrate was mixed with activated charcoal (1 gm) and stirred for 30 minutes at 25°C. The reaction mass was filtered and filtrate was evaporated below 40°C to obtained a residue. The residue was mixed with cyclohexane (52 ml) for 15 minutes at 25°C. The resultant solid was filtered, dissolved in acetonitrile (147 ml) by refluxing to get a clear solution and the contents were maintained for 30 minutes. Then the contents were cooled to 0°C in 2 hours. The resultant solid was isolated, washed with precooled acetonitrile (21 ml) and dried at 40°C.