The present invention provides a process for the preparation of 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5//-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1.

Formula-1

The present invention also provides novel crystalline polymorph of compound of formula-1 and process for its preparation.

Background of the invention:

6,11 -dihydro-11 -(1 -methyl-4-piperidinylidene)-5//-imidazo[2,1 -b] [3] benzazepine-3-carboxaldehyde, commonly known as Alcaftadine is an ophthalmic histamine HI receptor antagonist.
Alcaftadine was discovered by Janssen Pharmaceuticals and marketed by Vistakon Pharmaceuticals, both subsidiaries of Johnson & Johnson. It was approved by the USFDA for the prevention of itching associated with allergic conjunctivitis.

Alcaftadine was believed to be first disclosed in US5468743. The disclosed process involves the usage of l-(2-phenylethyl)-lH-imidazole 4, which is now commercially available, otherwise it could be prepared by reacting imidazole III with 2-phenylethyl bromide II. Imidazole IV was reacted with acyl chloride V in presence of pyridine and triethylamine as base, to provide piperidinecarboxylate VI in 34% yield, followed by acid hydrolysis with 48% HBr aqueous solution to obtain piperidine dihydrobromide VII in 98% yield. The N-methylation of VII was achieved by Leuckart reaction with formaldehyde and formic acid to give 4-methylpiperidine VIII in 82% yield. Treatment of VIII with trifluoromethanesulfonic acid followed by subsequent basification triggered an intramolecular alkylation-dehydration reaction to generate benzazepine IX. Next, alcohol X was obtained by prolonged exposure (7 days) of IX to hydroxymethylation conditions using 40% aqueous formaldehyde. Oxidation of X with manganese (IV) oxide provided Alcaftadine. The yields of last three steps i.e., from compound IX to Alcaftadine were not provided in the patent.

One of the major disadvantages with the above process lies in that, Alcaftadine obtained by the above process is having very higher amounts of benzazepine impurity (formula-IX) i.e., around 4-6% which is found to be very difficult to wash out even after number of purifications which highly impacts the quality of the final product.

The above said process also involves longer reaction times and provides lesser yields which increase the cost of the final product. The present invention avoids the above said drawbacks and provides highly pure compound of formula-1 by developing an improved process for the preparation and purification of Alcaftadine.

Brief description of the invention:

The first aspect of the present invention is to provide a process for the preparation of 6,11 -dihydro-11 -(1 -methyl-4-piperidinylidene)-5H-imidazo[2,1 -b] [3] benzazepine-3-carboxaldehyde compound of formula-1.

The second aspect of the present invention is to provide a novel crystalline polymorph of 6,11 -dihydro-11 -(1 -methyl-4-piperidinylidene)-5H-imidazo[2,1 -b] [3 ] benzazepine-3 -carboxaldehyde compound of formula-1, herein after designated as crystalline form-M.

The third aspect of the present invention is to provide a process for the preparation of crystalline form-M of 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5H-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1.

The fourth aspect of the present invention is to provide hydrochloride salt of (1-methylpiperidin-4-yl) (l-phenethyl-lH-imidazol-2-yl)methanone compound of formula-6 and its crystalline polymorph (herein after designated as crystalline form-S).

The fifth aspect of the present invention is to provide maleate salt of 11-(1-methylpiperidin-4-ylidene)-6,l l-dihydro-5H-benzo[d]imidazo[l,2-a]azepine compound of formula-7 and its crystalline polymorph (herein after designated as crystalline form-N).

The sixth aspect of the present invention is to provide crystalline polymorph of 11-(1-methylpiperidin-4-ylidene)-6,11 -dihydro-5H-benzo[d]imidazo[ 1,2-a]azepine compound of formula-7 (herein after designated as crystalline form-L).

The seventh aspect of the present invention is to provide crystalline polymorph of (11-(1-mefhylpiperidin-4-ylidene)-6,11 -dihydro-5H-benzo[d]imidazo[ 1,2-a]azepin-3-yl)methanol compound of formula-8 (herein after designated as crystalline form-R).

The eighth aspect of the present invention is to provide a process for the purification of 6,11 -dihydro-11 -(1 -methyl -4-piperidinylidene)-5H-imidazo[2,1 -b] [3 ] benzazepine-3-carboxaldehyde compound of formula-1.

Brief description of the drawings:

Figure-1: Illustrates the PXRD pattern of crystalline form of 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5i/-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1.
Figure-2: Illustrates the DSC thermogram of crystalline form of 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5H-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1.
Figure-3: Illustrates the PXRD pattern of crystalline form-M of 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5H-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1.
Figure-4: Illustrates the DSC thermogram of crystalline form-M of 6,11-dihydro-11-(l-methyl-4 -piperidinylidene)-5H-imidazo[2, 1 -b] [3]benzazepine-3-carboxaldehyde compound of formula-1.
Figure-5: Illustrates the PXRD pattern of crystalline form-S of (l-methylpiperidin-4-yl)(l-phenethyl-lH-imidazol-2-yl)methanone hydrochloride compound of formula-6a.

Figure-6: Illustrates the PXRD pattern of crystalline form-N of 11-(l-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[d]imidazo[l,2-a]azepine maleate compound of formula-7a.

Figure-7: Illustrates the PXRD pattern of crystalline form-L of 11-(l-methylpiperidin-4- ylidene)-6,11 -dihydro-5H-benzo[d]imidazo[ 1,2-a]azepine compound of formula-7.
Figure-8: Illustrates the PXRD pattern of crystalline form-R of (ll-(l-methylpiperidin-4-ylidene)-6,11 -dihydro-5H-benzo[d]imidazo[ 1,2-a]azepin-3-yl)methanol compound of formula-8.

Detailed description of the invention:

As used herein the present invention the term "suitable solvent" refers to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methyl pyrrolidone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, t-butanol, n-pentanol and the like; "polar solvents" such as water; acetic acid or their mixtures.

As used herein the present invention the term "suitable base" refers to "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide and the like; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or their mixtures.

The first aspect of the present invention provides a process for the preparation of 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5//-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1, comprising of;

a) Reacting piperidine-4-carboxylic acid compound of formula-2

Formula-2 with formaldehyde solution in a suitable solvent followed by reducing the obtained compound with a suitable reducing agent to provide 1-methylpiperidine-4-carboxylic acid compound of formula-3,

Formula-3

b) converting the compound of formula-3 into its hydrochloride salt compound of formula-3 a by treating it with a suitable HC1 source in a suitable solvent,

Formula-3 a

c) treating the compound of formula-3 a with a suitable chlorinating agent in a suitable solvent to provide 1-methyl piperidine-4-carbonyl chloride hydrochloride compound of formula-4a,

Formula-4a

d) reacting the compound of formula-4a with 1-phenethyl-lH-imidazole compound of formula-5 in presence of a suitable base or mixture of bases in a suitable solvent to provide (1-methylpiperidin-4-yl) (l-phenethyl-lH-imidazol-2-yl)methanone compound of formula-6,


Formula-6

e) converting the compound of formula-6 into its hydrochloride salt compound of formula-6a Formula-6a by treating it with a suitable HC1 source in a suitable solvent,

f) neutralizing the compound of formula-6a by treating it with a suitable base in a suitable solvent to provide free base compound of formula-6, which on in-situ treatment with a suitable cyclization agent at a suitable temperature provides ll-(l-methylpiperidin-4-ylidene)-6,11 -dihydro-5H-benzo[d]imidazo[ 1,2-a]azepine compound of formula-7,

g) reacting the compound of formula-7 with maleic acid in a suitable solvent to provide 11-(1-methylpiperidin-4-ylidene)-6,11 -dihydro-5H-benzo[d]imidazo[ 1,2-a]azepine maleate compound of formula-7a,

h) neutralizing the compound of formula-7a by treating it with a suitable base in a suitable solvent to provide free base compound of formula-7, which on in-situ reaction with formaldehyde in presence of acetic acid and sodium acetate provides (ll-(l-methylpiperidin-4-ylidene)-6,l l-dihydro-5H-benzo[d]imidazo[l,2-a]azepin-3-yl)methanol compound of formula-8,

i) oxidizing the compound of formula-8 with a suitable oxidizing agent in a suitable solvent to provide 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5H-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1, j) purifying the compound of formula-1 from a suitable solvent or mixture of solvents to provide pure compound of formula-1.

Wherein, in step-a) the suitable solvent is selected from alcohol solvents, polar solvents, polar aprotic solvents, ether solvents, ester solvents or their mixtures; the suitable reducing agent is selected from Pd/C, Pt/C, Rh/C, NaBH4, NaBH3CN, sodium triacetoxyborohydride (NaBH(OAc)3), Raney Ni, LiAlH4 and the like;

In step b) & step e) the suitable HC1 source is selected from dry HC1 gas, aq. HC1, ethyl acetate-HCl, ethanol-HCl, isopropyl alcohol-HCl, ethereal HC1, acetyl chloride, tri(Ci-C6 alkyl)silyl chloride, NH4CI and the like, wherein acetyl chloride and tri(C1-C6 alkyl)silyl chloride are used preferably in combination with alcohol solvents; the suitable solvent is selected from alcohol solvents, ester solvents, ether solvents, ketone solvents, nitrile solvents or their mixtures;

In step c) the suitable chlorinating agent is selected from phosphorous oxychloride, thionyl chloride, phosphorous trichloride, phosphorous pentachloride, oxalyl chloride and the like; the suitable solvent is selected from hydrocarbon solvents, alcohol solvents, ether solvents, ester solvents, ketone solvents, chloro solvents, polar solvents, polar-aprotic solvents, nitrile solvents or their mixtures;

In step d) the suitable base is selected from organic bases; preferably mixture of pyridine and triethylamine and the suitable solvent is selected from hydrocarbon solvents, alcohol solvents, ether solvents, ester solvents, ketone solvents, chloro solvents, polar solvents, polar-aprotic solvents, nitrile solvents or their mixtures;

In step f) the suitable base used is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates; the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents, polar solvents, polar-aprotic solvents, nitrile solvents or mixtures thereof; and the suitable cyclizing agent is selected from polyphosphoric acid, trifluoroacetic acid, trifluoromethane sulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid or their mixtures; the suitable temperature is 160-220°C, preferably 180-210°C, more preferably 190-200°C;

In step g) the suitable solvent is selected from hydrocarbon solvents, alcohol solvents, ether solvents, ester solvents, ketone solvents, chloro solvents, polar solvents, polar-aprotic solvents, nitrile solvents or their mixtures;

In step h) the suitable base and the suitable solvent are same as defined in above step f);

In step i) the suitable oxidizing agent is selected from sodium hypochlorite (NaOCl), l,l,l-triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one (Dess-Martin periodinane or DMP), oxalyl chloride/dimethylsulfoxide (Swern oxidation), trichloroisocyanuric acid (TCICA), potassium permanganate, pyridinium chlorochromate (PCC), potassium dichromate, manganese dioxide, oxone, chromium trioxide, bis(acetoxy)iodobenzene (BAIB), N-chlorosuccinimide in combination with dimethylsulfide and the like; the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, polar-aprotic solvents, nitrile solvents, ketone solvents or their mixtures;

In step j) the suitable solvent is selected from hydrocarbon solvents, alcohol solvents, ether solvents, ester solvents, ketone solvents, chloro solvents, polar solvents, polar-aprotic solvents, nitrile solvents or their mixtures.

A preferred embodiment of the present invention provides a process for the preparation of 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-57/-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1, comprising of;

a) Reacting piperidine-4-carboxylic acid compound of formula-2 with formaldehyde solution in water followed by reducing with 5% Pd/C to provide l-methylpiperidine-4-carboxylic acid compound of formula-3,

b) converting the compound of formula-3 into its hydrochloride salt compound of formula-3 a by treating it with isopropyl alcohol-HCl in isopropyl alcohol,

c) treating the compound of formula-3 a with thionyl chloride in chloroform to provide 1-methyl piperidine-4-carbonyl chloride hydrochloride compound of formula-4a,

d) reacting the compound of formula-4a with 1-phenethyl-lH-imidazole compound of formula-5 in presence of pyridine and triethylamine in acetonitrile to provide (1 -methylpiperidin-4-yl)( 1 -phenethyl-1 H-imidazol-2-yl)methanone compound of formula-6,

e) converting the compound of formula-6 into its hydrochloride salt compound of formula-6a by treating it with ethyl acetate-HCl in a mixture of ethyl acetate and isopropyl alcohol,

f) neutralizing the compound of formula-6a by treating it with aqueous sodium carbonate solution in a mixture of dichloromethane and water to provide free base compound of formula-6, which on in-situ treatment with polyphosphoric acid provides ll-(l-methylpiperi din-4-ylidene)-6,11 -dihydro-5H-benzo[d]imidazo[ 1,2-a]azepine compound of formula-7,

g) reacting the compound of formula-7 with maleic acid in acetone to provide 11-(1-methylpiperidin-4-ylidene)-6,11 -dihydro-5H-benzo[d]imidazo[ 1,2-a]azepine maleate compound of formula-7a,

h) neutralizing the compound of formula-7a with aqueous sodium carbonate solution in a mixture of dichloromethane and water to provide free base compound of formula-7, which on in-situ reaction with formaldehyde in presence of acetic acid and sodium acetate provides (ll-(l-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[d]imidazo[l,2-a]azepin-3-yl) methanol compound of formula-8, i) oxidizing the compound of formula-8 with manganese dioxide in chloroform to provide 6,11dihydro-11-(l-methyl-4-piperidinylidene)-5H-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1,

j) purifying the compound of formula-1 from a mixture of isopropyl alcohol and water to provide pure compound of formula-1.

The second aspect of the present invention provides a novel crystalline polymorph of 6,11 -dihydro-11 -(1 -methyl -4-piperidinylidene)-5H-imidazo[2,1 -b] [3] benzazepine-3-carboxaldehyde compound of formula-1, which is herein after designated as crystalline form-M. The said crystalline form-M is characterized by its powder X-Ray diffraction pattern having peaks at 10.1, 11.5, 12.0, 15.5, 16.3, 18.4, 19.7, 20.3, 20.6, 23.1, 23.6 and 29.3 ± 0.2° of 29. The crystalline form-M of the present invention is further characterized by its PXRD pattern having peaks at 22.1, 24.7, 25.5, 25.9, 28.8, 29.3, 30.3, 31.4, 33.7, 37.1, 39.4 and 41.2 ± 0.2° of 20. The novel crystalline form-M of compound of formula-1 is further characterized by its PXRD pattern as illustrated in figure-3 and its differential scanning calorimetric (DSC) thermogram as illustrated in figure-4.

The novel crystalline form-M of compound of formula-1 of the present invention is having moisture content of 0.09%, which confirms the anhydrous nature of the compound.

The crystalline form-M of compound of formula-1 of the present invention is highly stable and non-hygroscopic in nature. The non-hygroscopic nature of the compound is determined by the method described in European pharmacopeia.

The non-hygroscopic nature of crystalline form-M obtained by the process of the present invention is confirmed by the fact that there is no substantial change in the water content even after the compound is placed in a desiccator containing saturated ammonium chloride solution for a period of 24 hours at 80±2% relative humidity (RH). The water content of crystalline form-M produced according to the present invention is increased by 0.06% in 24 hours, which confirms the non-hygroscopic nature of the compound. The said characteristic nature is always an advantageous property for the formulation of active pharmaceutical ingredients.

The crystalline form-M of 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5//-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1 of the present invention can be further utilized in the preparation of pharmaceutical compositions useful for the treatment of overactive bladder syndrome.

The third aspect of the present invention provides a process for the preparation of crystalline form-M of 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5#-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1. The said process comprising of,

a) Dissolving the 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5//-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1 in a suitable solvent or mixture of solvents at a suitable temperature,

b) optionally treating the reaction mixture with carbon,

c) optionally adding water to the reaction mixture at a suitable temperature,

d) cooling the reaction mixture to a suitable temperature,

e) filtering the precipitated solid to provide crystalline form-M of 6,11 -dihydro-11 -(1 -methyl-4-piperidinylidene)-5Z7-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1.

Wherein, in step-a) the suitable solvent is selected from alcohol solvents, polar solvents or their mixtures and the suitable temperature is ranging from 30°C to 100°C, preferably 50°C-90°C, more preferably 60°C-80°C;

In step-c) the suitable temperature is ranging from room temperature to 100°C, preferably 50°C-90°C, more preferably 60°C-80°C;

In step-d) the suitable temperature is ranging from 30°C to -10°C, preferably 0-5°C.

The fourth aspect of the present invention provides hydrochloride salt of (1-methylpiperidin-4-yl) (l-phenethyl-lH-imidazol-2-yl)methanone compound of formula-6 (herein after referred as compound of formula-6a) and its crystalline polymorph. The said crystalline polymorph of compound of formula-6a is herein after designated as crystalline form-S and it is characterized by its powder X-Ray diffraction pattern having peaks at 6.5, 10.8, 15.6, 17.6, 21.8, 22.3, 27.7, 32.1, 34.6 and 40.1 ± 0.2° of 20. The crystalline form-S of compound of formula-6a is further characterized by its PXRD pattern as illustrated in figure-5.

The fifth aspect of the present invention provides maleate salt of ll-(l-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[d]imidazo[l,2-a]azepine compound of formula-7 (herein after referred as compound of formula-7a) and its crystalline polymorph. The said crystalline polymorph of compound of formula-7a is herein after designated as crystalline form-N and it is characterized by its powder X-Ray diffraction pattern having peaks at 8.5, 9.7, 10.3, 13.8, 15.1,15.4, 16.5, 17.0, 17.6, 18.2, 19.6, 20.8, 21.2, 22.5, 23.9, 24.3, 24.6, 25.2, 25.6, 26.5, 26.8, 27.4, 27.8, 28.1, 29.3, 34.0, 34.3, 38.9 ± 0.2° of 29. The crystalline form-N of compound of formula-7a is further characterized by its PXRD pattern as illustrated in figure-6.

The hydrochloride salt compound of formula-6a and the maleate salt compound of formula-7a of the present invention are very useful intermediates in the synthesis of corresponding highly pure compound of formula-6 & formula-7 as well as in the preparation of highly pure 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5//-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1.

The compound of formula-6a and the compound of formula-7a of the present invention are obtained as highly pure crystalline solids. These high pure compounds when utilized in the synthesis of compound of formula-1 in-turn increases the purity of compound of formula-1, which is highly advantageous to the formulators.

The sixth aspect of the present invention provides crystalline polymorph of 11-(1-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[d]imidazo[l,2-a]azepine compound of formula-7, which is herein after designated as crystalline form-L. The said crystalline form-L is characterized by its powder X-Ray diffraction pattern having characteristic peaks at 7.4, 9.8, 12.3, 13.8, 14.9, 16.1, 16.6, 17.3, 17.9, 18.6, 19.3, 19.7, 20.1, 22.0, 22.4, 24.6, 26.1, 30.1 and 33.7 ± 0.2° of 29. The crystalline form-L of the present invention is further characterized by its PXRD pattern as illustrated in figure-7.

The seventh aspect of the present invention provides crystalline polymorph of (11-(1-methylpiperidin-4-ylidene)-6,11 -dihydro-5H-benzo[d]imidazo[ 1,2-a]azepin-3-yl)methanol compound of formula-8, which is herein after designated as crystalline form-R. The said crystalline form-R is characterized by its powder X-Ray diffraction pattern having characteristic peaks at 7.9, 10.9, 12.7, 14.8, 15.5, 16.7, 17.0, 18.6, 20.1, 20.5, 21.6, 22.0, 22.4, 25.0, 25.5, 27.6, 30.5, 32.9, 35.5, 38.4, 44.8 and 48.7 ± 0.2° of 29. The crystalline form-R of the present invention is further characterized by its PXRD pattern as illustrated in figure-8.

The eighth aspect of the present invention provides a process for the purification of 6,11-dihydro-1 l-(l-methyl-4-piperidinylidene)-5ii/-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1, comprising dissolving the compound of formula-1 in a first solvent or mixture of solvents at a suitable temperature followed by crystallizing the compound by optionally adding a second solvent at a suitable temperature.

Wherein, the first solvent is selected from alcohol solvents, ketone solvents, nitrile solvents, polar-aprotic solvents, ether solvents, polar solvents or their mixtures; and the second solvent is selected from polar solvents, alcohol solvents, polar-aprotic solvents or their mixtures.

A preferred embodiment of the present invention provides a process for the purification of 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5H-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1, comprising of;

a) Dissolving the 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5H-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1 in a mixture of isopropyl alcohol and water at 70-75°C,

b) treating the reaction mixture with carbon,

c) filtering the reaction mixture,

d) adding water to the filtrate at 70-75 °C,

e) cooling the reaction mixture to 0-5°C,

f) filtering the precipitated solid to provide pure compound of formula-1.

By developing the above purification process the present inventors succeeded in controlling the levels of benzazepine impurity to minimum levels.

The PXRD analysis of the crystalline compounds of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using CuKa radiation of wavelength 1.5406 A° and at a continuous scan speed of 0.03°/min.

Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10°C/min.

The 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5/7-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde of the present invention was analyzed by HPLC under following conditions; Apparatus: A liquid chromatographic system equipped with variable wavelength PDA detector; Column: Xterra RP8 150x4.6, 3.5 um; Flow rate: 1.0 mL/min; Wavelength: 215 nm; Column temperature: 40°C; Injection volume: 10 uL; Run time: 52 min; Elution: gradient; Diluent: water: acetonitrile (70:30 v/v); Sample concentration: 1.0 mg/ml; Mobile phase-A: Buffer; Mobile phase-B: Acetonitrile: buffer (80:20, v/v); Buffer: Weigh accurately about 5 mM of diammonium hydrogen phosphate in 1000 ml of milli-Q water, filter through 0.45 um nylon membrane paper.

6,11 -dihydro-11 -(1 -methyl-4-piperidinylidene)-5//-imidazo [2,1 -b] [3 ] benzazepine-3 -carboxaldehyde compound of formula-1 produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The present invention is schematically represented as follows.

formula-l

The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provides as illustration only and hence should not be construed as limitation of the scope of the invention. Examples: Example-1: Preparation of 1-phenethyl-lH-imidazole (Formula-5)

A mixture of (2-bromoethyl)benzene (500 gm), imidazole (560 gm), potassium carbonate (560 gm) and toluene (2500 ml) was heated to 110-115°C and stirred for 3 hrs at the same temperature. Cooled the reaction mixture to 65-70°C and distilled off the solvent completely from the reaction mixture under reduced pressure. Water and dichloromethane were added to the obtained compound at 25-30° and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with water. Distilled off the solvent completely from the organic layer to get title compound; Yield: 379.0 gm. Example-2: Preparation of l-methylpiperidine-4-carboxylic acid hydrochloride

(Formula-3a)

Process-1: Piperidine-4-carboxylic acid compound of formula-2 (300 gm), water (900 ml) and formic acid (375 ml) were charged into an autoclave vessel at 25-30°C and 5% Pd/C (30 gm) was added to it under nitrogen atmosphere. 4.0-5.0 Kg/cm2 hydrogen gas pressure was applied to the reaction mixture. Heated the reaction mixture to 65-70°C and stirred for 4 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and filtered it through hyflow bed. Distilled off water completely from the filtrate under reduced pressure. Toluene (1200 ml) was added to the obtained compound and heated the reaction mixture azeotropically to reflux temperature and stirred for 6 hrs at the same temperature. Distilled off the solvent completely under reduced pressure and co-distilled with isopropyl alcohol. 75 ml of isopropyl alcohol was added to the obtained compound at 25-30°C. Isopropyl alcohol-HCl (425 ml) was added to the reaction mixture, heated to 70-75 °C and stirred for 60 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Further cooled the reaction mixture to 0-5°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid and dried to get the title compound; Yield: 290.0 gm.

Process-2: A mixture of piperidine-4-carboxylic acid compound of formula-2 (25 gm), formic acid (125 ml) and formaldehyde (31.5 ml) was heated to 85-90°C and stirred for 6 hrs at the same temperature. Distilled off the reaction mixture completely and co-distilled with toluene followed by with isopropyl alcohol. To the obtained compound, isopropyl alcohol (25 ml) and isopropyl alcohol-HCl (26 ml) were added at 25-30°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid and dried to get the title compound; Yield: 23.0 gm. Example-3: Preparation of (l-methylpiperidin-4-yl)(l-phenethyl-lH-imidazol-2-yl) methanone hydrochloride (Formula-6a)

a) Preparation of 1-methyl piperidine-4-carbonyl chloride hydrochloride (Formula-4a):

A mixture l-methylpiperidine-4-carboxylic acid compound of formula-3 (167 gm) and chloroform (1200 ml) was heated to 50-55°C. Thionyl chloride (226 gm) was slowly added to the reaction mixture at 50-55°C and stirred for 3 hrs at the same temperature. Distilled off the solvent completely under reduced pressure and co-distilled with chloroform and followed by acetonitrile to get the title compound.

b) Preparation of (l-methylpiperidine-4-yl)(l-phenethyl-lH-imidazole-2-yl)methanone hydrochloride (Formula-6a):

Acetonitrile (700 ml) was added to the compound obtained in step-a) and cooled the reaction mixture to 0-5°C. A solution of 1-phenethyl-lH-imidazole compound of formula-5 (100 gm) dissolved in acetonitrile (100 ml) was slowly added to the reaction mixture at 0-5°C. A mixture of pyridine (50 ml) and triethylamine (407 ml) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 60 min at the same temperature. Heated the reaction mixture to 80-85°C and stirred for 4 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Water and toluene were added to the obtained compound at 25-30°C and cooled the reaction mixture to 10-15°C. Basified the reaction mixture using aqueous sodium carbonate solution and raised the temperature of the reaction mixture to 25-30°C. Both the organic ad aqueous layers were separated and the organic layer was washed with 10% sodium chloride solution. Distilled off the solvent completely from the organic layer and finally expelled with nitrogen for 1 hr. Isopropyl alcohol (50 ml) and ethyl acetate (50 ml) were added to the obtained compound at 25-3 0°C and cooled the reaction mixture to 5-10°C. Ethyl acetate-HCl (470 ml) was added to the reaction mixture at 5-10°C and stirred for 2 hrs at the same temperature. Distilled off the solvent completely under reduced pressure. Isopropyl alcohol (150 ml) and ethyl acetate (150 ml) were added to the obtained compound, heated the reaction mixture to 45-50°C and stirred for 60 min at the same temperature. Cooled the reaction mixture to 5-10°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid and washed with mixture of isopropyl alcohol and ethyl acetate. To the obtained wet material, isopropyl alcohol (200 ml) and ethyl acetate (200 ml) were added and heated the reaction mixture to 80-85°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 5-10°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with a mixture of isopropyl alcohol and ethyl acetate and dried to get the titled compound; Yield: 105.0 gm; MR: 201-206°C.
Example-4: Preparation of ll-(l-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[d]imidazo[l,2-a|azepine maleate (Formula-7a)

A mixture of (l-methylpiperidin-4-yl)(l-phenethyl-lH-imidazol-2-yl)methanone hydrochloride compound of formula-6a (200 gm), dichloromethane (600 ml) and water (200 ml) was cooled to 15-20°C. Basified the reaction mixture using 20% aqueous sodium carbonate solution. Both the organic and aqueous layers were separated and the organic layer was washed with 5% aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer. Polyphosphoric acid (500 gm) was added to the obtained compound, heated the reaction mixture to 195-200°C and stirred for 24 hrs at the same temperature. Cooled the reaction mixture to 155-160°C and polyphosphoric acid (200 gm) was added to it. Heated the reaction mixture to 195-200°C and stirred for 12 hrs at the same temperature. Cooled the reaction mixture to 100°C and water was added to it. Basified the reaction mixture using aqueous sodium hydroxide solution (1200 gm in 1200 ml of water) at 25-30°C. Toluene was added to the reaction mixture, heated to 55-60°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with water followed by with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with acetone. 100 ml of acetone was added to the obtained compound at 25-30°C and stirred for 15 min at the same temperature. Maleic acid (83.5 gm) was added to the reaction mixture at 25-30°C and stirred for 2 hrs at the same temperature. Cooled the reaction mixture to 5-10°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid and acetone (400 ml) was added to it. Heated the reaction mixture to 80-85°C and stirred for 60 min at the same temperature. Cooled the reaction mixture to 5-10°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with acetone and dried to get the title compound; Yield: 120.0 gm; MR: 175-180°C.

Example-5: Preparation of (ll-(l-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[d] imidazo [1,2-a] azepin-3-yl)methanol (Formula-8)

A mixture of ll-(l-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[d]imidazo[l,2-ajazepine maleate compound of formula-7a (130 gm), dichloromethane (650 ml) and water (130 ml) was cooled to 5-10°C. Basified the reaction mixture using aqueous sodium carbonate solution (140 gm in 600 ml of water) at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C. Both the organic and aqueous layers were separated and the washed the organic layer with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure.

Transferred the obtained compound into an autoclave vessel and 37% formalin solution (454 ml) was added at 25-30°C. Acetic acid (65 ml) and sodium acetate (26.3 gm) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 100-105°C and stirred for 12 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and transferred the reaction mixture into round bottom flask. Dichloromethane was added to the reaction mixture and cooled to 10-15°C. Basified the reaction mixture using aqueous sodium hydroxide solution (66 gm of NaOH in 220 ml of water). Filtered the reaction mixture through hyflow bed. Both the organic and aqueous layers were separated and washed the organic layer with 10% aqueous sodium metabisulfate solution. Distilled off the solvent completely from the organic layer and co-distilled with acetone. 130 ml of acetone was added to the obtained compound at 25-3 0°C and stirred for 2 hrs at the same temperature.
Cooled the reaction mixture to 0-5°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with acetone and dried to get the title compound; Yield: 22.5 gm; MR: 212-216°C.

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

Process-a): A mixture of (ll-(l-methylpiperidin-4-ylidene)-6,11-dihydro-5H-benzo[d] imidazo[l,2-a]azepin-3-yl)methanol compound of formula-8 (50 gm), chloroform (500 ml) and carbon (5 gm) was heated to 65-70°C and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed. Manganese dioxide (281 gm) was added to the filtrate, heated the reaction mixture to 65-70°C and stirred for 3 hrs at the same temperature. Filtered the reaction mixture and washed with chloroform. Distilled off the solvent completely from the filtrate and co-distilled with diethyl ether. 50 ml of diethyl ether was added to the obtained compound at 25-3 0°C and stirred the reaction mixture for 2 hrs at the same temperature.

Cooled the reaction mixture to 0-5°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with diethyl ether and dried to get title compound; Yield: 32.0 gm; Purity by HPLC: 94.48%; Benzazepine impurity (formula-7): 4.5%. PXRD pattern of the obtained compound is shown in figure-1 and DSC is shown in figure-2. Process-b): Prepared by the process same as described in process A). Instead of diethyl ether, pet ether is used for isolation of the compound; Yield: 38.0 gm. Process-c): Prepared by the process same as described in process A). Instead of diethyl ether, methyl tert. butyl ether is used for isolation of the compound; Yield: 39.0 gm.

Example-7: Purification of 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5H-imidazo [2,1-b] [3] benzazepine-3-carboxaldehyde (Formula-1)

Water (350 ml) was added to compound of formula-1 (70 gm) at 25-30°C and heated the reaction mixture to 70-75°C. Isopropyl alcohol (140 ml) was added to the reaction mixture at 70-75°C. Carbon (7 gm) was added to the reaction mixture at 70-75°C and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with aqueous isopropyl alcohol. Heated the filtrate to 70-75°C and water (315 ml) was added to it at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hrs at the same temperature. Further cooled the reaction mixture to 5-10°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with aqueous isopropyl alcohol and dried the material to get pure title compound; The above purification process is repeated to get high pure compound. Yield: 40.0 gm; M.R: 170-172°C; Purity by HPLC: 99.83%; Benzazepine impurity (formula-7): 0.04%; PXRD of the obtained compound is shown in figure-3 & DSC is shown in figure-4.

Example-8: Preparation of crystalline form-M of 6,11-dihydro-11-(l-niethyl-4-piperidinylidene)-5H-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde

Process-a): from methanol/ dichloromethane mixture

Compound of formula-1 (5 gm) was dissolved in 1:1 mixture of methanol and dichloromethane (80 ml) at 25-30°C. Distilled off the solvent completely from the reaction mixture to get the title compound. Yield: 2.5 gm. Process-b): from dimethylformamide Dimethylformamide (12.5 ml) was added to compound of formula-1 (5 gm) at 25-30°C. Heated the reaction mixture to 75-80°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid and dried to get the title compound; Yield: 1.0 gm. Process-c): from acetonitrile

Acetonitrile (50 ml) was added to compound of formula-1 (5 gm) at 25-30°C. Heated the reaction mixture to 75-80°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid and dried to get the title compound; Yield: 4.0 gm. Process-d): from a mixture of dichloromethane and heptane

Dichloromethane (15 ml) was added to compound of formula-1 (5 gm) at 25-30°C and stirred for 30 min at the same temperature. Filtered the reaction mixture, heptane (50 ml) was added to the filtrate and stirred the reaction mixture for 1 hr. Filtered the precipitated solid and washed with heptane to get the title compound. Yield: 2.7 gm. Process-e) from mixture of methanol and water

Methanol (25 ml) and water (75 ml) were added to compound of formula-1 (5 gm) at 25-30°C. Filtered the reaction mixture and washed with methanol. Freeze-dried the obtained filtrate at -85°C to -90°C and stirred for 10 hrs at the same temperature. Filtered the precipitated solid to get the title compound; Yield: 3.6 gm. Process-e) from mixture of methanol and water

Methanol (25 ml) was added to compound of formula-1 (5 gm) at 25-30°C and stirred for 15 min at the same temperature. Water (150 ml) was added to the reaction mixture at 25-30°C. 75 ml of methanol was added to the reaction mixture at 25-30°C and stirred for 4 hrs at the same temperature. Filtered the precipitated solid and washed with water to get title compound. Yield: 2.3 gm.

We Claim:

1. Anhydrous crystalline 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5H-imidazo[2,l-b] [3] benzazepine-3 -carboxaldehyde.

2. Crystalline form of 6, 11-dihydro-11-(l -methyl-4-piperidinylidene)-5H-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde, characterized by its PXRD pattern having characteristic peaks at 10.1, 11.5, 12.0, 15.5, 16.3, 18.4, 19.7, 20.3, 20.6, 23.1, 23.6 and 29.3 ± 0.2° of 26.

3. Crystalline form of 6,ll-dihydro-ll-(l-methyl-4-piperidinylidene)-5H-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde according to claims 1& 2, which is further characterized by;

a) Its PXRD pattern having peaks at 22.1, 24.7, 25.5, 25.9, 28.8, 29.3, 30.3, 31.4, 33.7, 37.1, 39.4 and 41.2 ±0.2° of 26,

b) its PXRD pattern substantially as illustrated in figure-3,

c) its DSC thermogram substantially in accordance with figure-4.

4. Salt of (l-methylpiperidin-4-yl) (l-phenethyl-lH-imidazol-2-yl)methanone with hydrochloric acid.

5. Salt of ll-(l-methylpiperidin-4-ylidene)-6,ll-dihydro-5H-benzo[d]imidazo[l,2-a]azepine with maleic acid.

6. Crystalline polymorphs of intermediates of 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde, wherein;

a) crystalline form-S of (1 -methylpiperidin-4-yl) (1 -phenethyl-1 H-imidazol-2-yl)methanone hydrochloride salt compound of formula-6a is characterized by its PXRD pattern having peaks at 6.5, 10.8, 15.6, 17.6, 21.8, 22.3, 27.7, 32.1, 34.6 and 40.1 ± 0.2° of 26,

b) crystalline form-N of ll-(l-methylpiperidin-4-ylidene)-6,ll-dihydro-5H-benzo[d] imidazo[l,2-a]azepine maleate salt compound of formula-7a is characterized by its PXRD pattern having peaks at 8.5, 9.7, 10.3, 13.8, 15.1, 15.4, 16.5,17.0, 17.6, 18.2, 19.6, 20.8, 21.2, 22.5, 23.9, 24.3, 24.6, 25.2, 25.6, 26.5, 26.8, 27.4, 27.8, 28.1, 29.3, 34.0, 34.3, 38.9 ±0.2° of 26,

c) crystalline form-L of 11 -(1 -methylpiperidin-4-ylidene)-6,11 -dihydro-5H-benzo[d]imidazo [l,2-a]azepine compound of formula-7 is characterized by its PXRD pattern having peaks at 7.4, 9.8, 12.3, 13.8, 14.9, 16.1, 16.6, 17.3, 17.9, 18.6, 19.3, 19.7, 20.1, 22.0, 22.4, 24.6, 26.1, 30.1 and 33.7 ± 0.2° of 26,

d) crystalline form-R of (ll-(l-methylpiperidin-4-ylidene)-6,ll-dihydro-5H-benzo[d] imidazo[l,2-a]azepin-3-yl)methanol compound of formula-8 is characterized by its PXRD pattern having peaks at 7.9, 10.9, 12.7, 14.8, 15.5, 16.7, 17.0, 18.6, 20.1, 20.5, 21.6, 22.0, 22.4, 25.0, 25.5, 27.6, 30.5, 32.9, 35.5, 38.4, 44.8 and 48.7 ± 0.2° of 20.

7. Process for the preparation of 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5//-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1, comprising of;

a) Reacting piperidine-4-carboxylic acid compound of formula-2
Formula-2 with formaldehyde solution in a suitable solvent followed by reducing the obtained compound with a suitable reducing agent to provide 1-methylpiperidine-4-carboxylic acid compound of formula-3,

b) converting the compound of formula-3 into its hydrochloride salt compound of formula-3 a by treating it with a suitable HC1 source in a suitable solvent,

c) treating the compound of formula-3a with a suitable chlorinating agent in a suitable solvent to provide 1-methyl piperidine-4-carbonyl chloride hydrochloride of formula-4a,

d) reacting the compound of formula-4a with 1 -phenethyl-1 H-imidazole of formula-5 in presence of a suitable base or mixture of bases in a suitable solvent to provide (1 -methylpiperidin-4-yl) (1 -phenethyl-1 H-imidazol-2-yl)methanone of formula-6,

e) converting the compound of formula-6 into its hydrochloride salt of formula-6a by treating it with a suitable HC1 source in a suitable solvent,

f) neutralizing the compound of formula-6a by treating it with a suitable base in a suitable solvent to provide free base compound of formula-6, which on in-situ treatment with a suitable cyclization agent at a suitable temperature provides ll-(l-methylpiperidin-4-ylidene)-6,11 -dihydro-5H-benzo[d]imidazo[ 1,2-a]azepine compound of formula-7,

g) reacting the compound of formula-7 with maleic acid in a suitable solvent to provide 11-(1 -methylpiperidin-4-ylidene)-6,11 -dihydro-5H-benzo[d]imidazo[ 1,2-a]azepine maleate compound of formula-7a,

h) neutralizing the compound of formula-7a by treating it with a suitable base in a suitable solvent to provide free base compound of formula-7, which on in-situ reaction with formaldehyde in presence of acetic acid and sodium acetate provides (11-(1-methylpiperidin-4-ylidene)-6,11 -dihydro-5H-benzo[d]imidazo[ 1,2-a]azepin-3-yl) methanol compound of formula-8,

Formula-8

i) oxidizing the compound of formula-8 with a suitable oxidizing agent in a suitable solvent to provide 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5//-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1,

j) purifying the compound of formula-1 from a suitable solvent or mixture of solvents to provide pure compound of formula-1.

8. A process according to claim 7, wherein, in step-a) the suitable solvent is selected from alcohol solvents, polar solvents, polar aprotic solvents, ether solvents, ester solvents or their mixtures; the suitable reducing agent 10 is selected from Pd/C, Pt/C, Rh/C, NaBH4, NaBH3CN, sodium triacetoxyborohydride (NaBH(OAc)3), Raney Ni, LiAlH4; in step b) & step e) the suitable hydrochloride source is selected from dry HC1 gas, aq.HCl, ethyl acetate-HCl, ethanol-HCl, isopropyl alcohol-HCl, ethereal HC1, acetyl chloride, tri(Ci-C6 alkyl)silyl chloride, NH4CI, wherein acetyl chloride and tri(Ci-C6 alkyl)silyl chloride are used preferably in combination with alcohol solvents; the suitable solvent is selected from alcohol solvents, ester solvents, ether solvents, ketone solvents, nitrile solvents or their mixtures; In step c) the suitable chlorinating agent is selected from phosphorous oxychloride, thionyl chloride, phosphorous trichloride, phosphorous pentachloride, oxalyl chloride; the suitable solvent is selected from hydrocarbon solvents, alcohol solvents, ether solvents, ester solvents, ketone solvents, chloro solvents, polar solvents, polar-aprotic solvents,nitrile solvents or their mixtures;
In step d) the suitable base is selected from organic bases; preferably mixture of pyridine and triethylamine and the suitable solvent is selected from hydrocarbon solvents, alcohol solvents, ether solvents, ester solvents, ketone solvents, chloro solvents, polar solvents, polar-aprotic solvents, nitrile solvents or their mixtures; In step f) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates; the suitable solvent is selected from chlorosolvents, hydrocarbon solvents, ether solvents, ester solvents, polar solvents, polar-aproticsolvents, nitrile solvents or their mixtures; and the suitable cyclizing agent is selected frompolyphosphoric acid, trifluoroacetic acid, trifluoromethane sulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid and hydro iodic acid or their mixtures; the suitable temperature is 160-220°C, preferably 180-210°C, more preferably 190-200°C;

In step g) the suitable solvent is selected from hydrocarbon solvents, alcohol solvents, ether solvents, ester solvents, ketone solvents, chloro solvents, polar solvents, polar-aprotic solvents, nitrile solvents or their mixtures;

In step h) the suitable base and the suitable solvent are same as defined above in step f);

In step i) the suitable oxidizing agent is selected from sodium hypochlorite, 1,1,1-triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one (Dess-Martin periodinane or DMP), oxalyl chloride/dimethylsulfoxide (Swern oxidation), trichloroisocyanuric acid (TCICA), potassium permanganate, pyridinium chlorochromate (PCC), potassium dichromate, manganese dioxide, oxone, chromium trioxide, bis(acetoxy)iodobenzene (BAIB), N-chlorosuccinimide in combination with dimethylsulfide and the like; the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, polar-aprotic solvents, nitrile solvents, ketone solvents or their mixtures;

In step j) the suitable solvent is selected from hydrocarbon solvents, alcohol solvents, ether solvents, ester solvents, ketone solvents, chloro solvents, polar solvents, polar-aprotic solvents, nitrile solvents or their mixtures.

9. Process for the preparation of 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5i/-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1, comprising of;

a) Reacting piperidine-4-carboxylic acid compound of formula-2 with formaldehyde solution in water followed by reducing with 5% Pd/C to provide 1 -methylpiperidine-4-carboxylic acid compound of formula-3,

b) converting the compound of formula-3 into its hydrochloride salt compound of formula-3 a by treating it with isopropyl alcohol-HCl in isopropyl alcohol,

c) treating the compound of formula-3a with thionyl chloride in chloroform to provide 1-methyl piperidine-4-carbonyl chloride hydrochloride compound of formula-4a,

d) reacting the compound of formula-4a with 1-phenethyl-lH-imidazole compound of formula-5 in presence of pyridine and triethylamine in acetonitrile to provide (1 -methylpiperidin-4-yl)( 1 -phenethyl-1 H-imidazol-2-yl)methanone of formula-6,

e) converting the compound of formula-6 into its hydrochloride salt compound of formula-6a by treating it with ethylacetate-HCl in a mixture of ethyl acetate and isopropyl alcohol,

f) neutralizing the compound of formula-6a by treating it with aqueous sodium carbonate

solution in a mixture of dichloromethane and water to provide free base compound of formula-6, which on in-situ treatment with polyphosphoric acid at 195-200°C provides 11 -(1 -methyl piperidin-4-ylidene)-6,11 -dihydro-5H-benzo[d]imidazo[ 1,2-a]azepine of formula-7,

g) reacting the compound of formula-7 with maleic acid in acetone to provide 11-(1-methylpiperidin-4-ylidene)-6,11 -dihydro-5H-benzo[d]imidazo[ 1,2-a]azepine maleate compound of formula-7a,

h) neutralizing the compound of formula-7a with aqueous sodium carbonate solution in a mixture of dichloromethane and water to provide free base compound of formula-7, which on in-situ reaction with formaldehyde in presence of acetic acid and sodium acetate provides (11 -(1 -methylpiperidin-4-ylidene)-6,11 -dihydro-5H-benzo[d]imidazo [l,2-a]azepin-3-yl) methanol compound of formula-8,

i) oxidizing the compound of formula-8 with manganese dioxide in chloroform to provide compound of formula-1,

j) purifying the compound of formula-1 from a mixture of isopropyl alcohol and water to provide pure compound of formula-1.

10. A process for the purification of 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5H-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1, comprising of,

a) Dissolving the 6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5^-imidazo[2,l-b] [3] benzazepine-3-carboxaldehyde compound of formula-1 in a mixture of isopropyl alcohol and water at a suitable temperature,

b) optionally treating the reaction mixture with carbon,

c) filtering the reaction mixture,

d) optionally adding water to the filtrate,

e) cooling the reaction mixture to a suitable temperature,

f) filtering the precipitated solid and drying to provide highly pure compound of formula-1.