This application claims priority to the Indian patent application numbers 1341/CHE/2011 filed on April 19, 2011, and 3811/CHE/2011 filed on Nov 8, 2011 the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of amorphous Tolvaptan.

BACKGROUND OF THE INVENTION:

Tolvaptan chemically known as (±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl) carbonyl]-o tolu-m-toluidide (OPC-41061), is a selective, competitive arginine vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH), the trade name is Samsca, tolvaptan is structurally as shown below.

U.S patent 5258510 discloses a process for the benzazepines and its derivatives thereof, the diffculties arise in the preparation especially when a C5-substituent is required or if electron with -drawing groups are present in the aromatic ring. The preparation of tolvaptan required 11 liner steps, involves very critical conditions that limit the generality of this approach in Scheme -1;

Scheme 1

U.S application No 20090306369 discloses a process for the preparation of crystalline Tolvaptan by using methanol and water.

WO 2010026971 application disclosed an industrial method for the preparation of Tolvaptan by using spray drying technique. In this process, Tolvaptan and hydroxypropylcellulose were dissolved in dichloromethane and ethanol. The resulting mixture was treated by spray dryer and immediately dried by a vacuum dryer, thus obtaining amorphous Tolvaptan.

Amorphous Tolvaptan prepared in the prior art processes were contaminated with crystalline Tolvaptan. Therefore, there is a need to develop a process for preparation of amorphous Tolvaptan with out contamination of other polymorphic form. The inventors of the present invention found an efficient process for the preparation of amorphous Tolvaptan which is safe, cost effective and eco-friendly process.

OBJECTIVE OF THE INVENTION:

The main object of the present invention relates to novel process for the preparation of amorphous Tolvaptan.

SUMMARY OF THE INVENTION:

The main aspect of the present invention is to provide a novel process for the preparation of amorphous Tolvaptan comprising the steps of

a) dissolving Tolvaptan in an organic solvent or mixture thereof,
b) removing the solvent, and
c) Isolating pure amorphous Tolvaptan

Yet another aspect of the present invention is to provide process for the preparation of amorphous Tolvaptan comprising the steps of
a) dissolving Tolvaptan in an organic solvent or mixture thereof,
b) removing the solvent,
c) adding second solvent,
d) optionally drying the wet mass, and d) isolating amorphous tolvaptan

Another aspect of the present invention is to' provide amorphous Tolvaptan having melting range of 118-132 °C.

BRIEF DESCRIPTION OF THE DRAWINGS:

Fig. 1 is an X-ray powder diffraction (XRD) pattern of amorphous form of Tolvaptan.

Fig. 2 depicts the Differential Scanning Calorimetry (DSC) thermogram of amorphous Tolvaptan.

Fig. 3 depicts the TGA/DTA thermogram of amorphous Tolvaptan

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of an amorphous Tolvaptan.

In one embodiment, the present invention relates to an improved process for the preparation of an amorphous Tolvaptan comprising the steps of;

a) dissolving Tolvaptan in an organic solvent or mixture thereof,
b) removing the solvent, and
c) Isolating pure amorphous Tolvaptan

According to the present invention, dissolving tolvaptan in an organic solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n- butanol, tertiary-butyl alcohol, cyclohexanol; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and

cyclohexanone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether; nitriles such as acetonitrile, propionitrile; or polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide and dioxane or a mixture of thereof, optionally giving carbon treatment, removing the solvent using conventional techniques such as vacuum distillation, spray drying, agitated thin film drying and atmospheric evaporation to obtain amorphous Tolvaptan.

According to present invention, the solvent flow rate is about 8 to 4 ml/minute.
According to the present invention, the solvent(s) may be removed from the solution, suspension or dispersion optionally under reduced pressure of less than about 100 mbar and temperature less than about 80°C.

In another embodiment, the present invention relates to amorphous Tolvaptan having the X-ray powder diffraction pattern as shown in Fig 1.

Yet another embodiment, the present invention relates to amorphous Tolvaptan characterized by DSC thermogram as shown in Figure 2.

According to the present invention, the amorphous Tolvaptan prepared according to the present invention have the melting range of 118 -132 °C.

In yet another embodiment, the present invention relates to amorphous Tolvaptan characterized by TGA thermogram as shown in Figure 3.

In another embodiment, the present invention relates to process for the preparation of an amorphous Tolvaptan comprising the steps of;

a) dissolving Tolvaptan in an organic solvent or mixture thereof,
b) removing the solvent,
c) adding second solvent,
d) optionally drying the wet mass, and d) isolating amorphous tolvaptan

According to the present invention, dissolving tolvaptan in an organic solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n- butanol, tertiary-butyl alcohol, cyclohexanol; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and cyclohexanone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride, esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether; nitriles such as acetonitrile, propionitrile; or polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide and dioxane or a mixture of thereof, optionally the solution is given carbon treatment and filtered. The solvent is removed using conventional techniques such as filtration, distillation, vacuum-distillation to obtain a residue. Adding second solvent selected from toluene, xylene, n-hexane, n-heptane or cyclohexane. The solution is maintained and filtered. The wet mass was dried to obtain amorphous tolvaptan.

According to present invention, amorphous Tolvaptan further characterized as having weight loss of between 0.5 % and about 2.0% as measured by using thermo gravimetric analysis over the range in between about 25°C to 300°C.

According to the present invention, the amorphous Tolvaptan prepared according to the present invention has a mean particle size less than 24.17 urn in diameter.

According to the present invention, amorphous Tolvaptan is packed by using HMLDPE bag under vacuumised nitrogen sealing at below 60 % RH. The HMLDPE bag is further inserted in a triple laminated bag under vacuumised nitrogen sealing with two silica gel sachets and one molecular sieve sachet. Again it is inserted in a triple laminated aluminum bag under vacuumised nitrogen sealing with two silica gel sachets and one molecular sieve sachet. Such "bags are further packed in HOPE containers.

The examples given below illustrate few aspects of the invention and should not be construed to limit the scope of the present invention

EXAMPLES

Example 1: Process for the preparation of Amorphous Tolvaptan.

N-[4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-benzo[b]azepin-1-carbonyl)-3-methyl-phenyl]-2-methyl-benzamide (10 g Tolvaptan ) and methanol (400 ml) was stirred to get clear solution. Added activated carbon (0.05 g) and continued the stirring for 60 minutes at room temperature. The activated carbon was removed by filtration. The clear solution obtained was concentrated under vacuum to remove methanol for 3 hours to give 9.5 g amorphous tolvaptan.

Example 2: Process for the preparation of Amorphous Tolvaptan.
N-[4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-benzo[b]azepin-1-carbonyl)-3-methyl-phenyl]-2-methyl-benzamide (5 g Tolvaptan ) and methanol (200 ml) was stirred to get clear solution.

Added activated carbon (0.05 g) and continued the stirring for 60 minutes at room temperature. The activated carbon was removed by filtration. The clear solution obtained was concentrated under vacuum to remove methanol to give amorphous tolvaptan as residue. To this residue added heptane (25ml) and stirred for 1 hr at room temperature, filtered. The wet mass was dried at 40-90°C in vacuum oven between 0- 50 mbar. Cool the system below 40°C and unloaded under nitrogen, controlled humidity, RH less than 60 % and thus isolating wet powdered form of amorphous Tolvaptan.

Packing mode: The material shall be packed in HMLDPE bag under vacuumised nitrogen sealing at below 60 % RH. It is then inserted in triple laminated aluminum bag under vacuumised nitrogen sealing with two silica gel sachets and one molecular sieve sachet. Again it is inserted in a triple laminated aluminum bag under vacuumised nitrogen sealing with two silica gel sachets and one molecular sieve sachet. Such bags are further packed in HDPE containers.

Example 3: Process for the preparation of Amorphous Tolvaptan.

Tolvaptan (10 g) was dissolved in methanol (50 ml) and Dichloromethane (50 ml) at room temperature and the solution was filtered to remove any undissolved particle if any. The clear solution was concentrated under vacuum in Rota evaporator at about 40° C to 50° C completely and degas for 4-6 hours under vacuum. The amorphous material was isolated in n-heptane and dried under vacuum 60-70° C with out affecting amorphous nature. (Yield-92 %) The PXRD pattern of amorphous form of Tolvaptan

Example 4: Process for the preparation of Amorphous Tolvaptan.

Tolvaptan (10 g) was dissolved in methanol (50 ml) and Dichloromethane (50 ml) at room temperature and the solution was filtered to remove any undissolved particle if any. The clear solution was concentrated under vacuum in Rota evaporator at about 50° C to 60° C completely and degas for 4-6 hours under vacuum. The amorphous material was isolated in n-heptane and dried under vacuum 60-70° C with out affecting amorphous nature. (Yield-93 %) The PXRD pattern of amorphous form of Tolvaptan.

Example 5: Process for the preparation of Amorphous Tolvaptan.

Tolvaptan (10 g) was dissolved in methanol (50 ml) and Dichloromethane (50 ml) at room temperature and the solution was filtered to remove any undissolved particle if any. The clear solution was concentrated under vacuum in Rota evaporator at about 60° C to 70° C completely and degas for 4-6 hours under vacuum. The amorphous material was isolated in n-heptane and dried under vacuum 60-70° C with out affecting amorphous nature. (Yield-91 %) The PXRD pattern of amorphous form of Tolvaptan

Example 6: Process for the preparation of Amorphous Tolvaptan.

Tolvaptan (10 g) was dissolved in methanol (50 ml) and Dichloromethane (50 ml) at room temperature and the solution was filtered to remove any undissolved particle if any. The clear solution was concentrated under vacuum at about 40° C to 50° C completely and degas for 4-6 hours under vacuum. The amorphous material was isolated in n-heptane and dried under vacuum 60-70° C with out affecting amorphous nature. (Yield-92 %) The PXRD pattern of amorphous form of Tolvaptan

Example 7: Process for the preparation of Amorphous Tolvaptan.

Tolvaptan (10 g) was dissolved in ethanol (50 ml) and Dichloromethane (50 ml) at room temperature and the solution was filtered to remove any undissolved particle if any. The clear solution was concentrated under vacuum at about 40° C to 50° C completely and degas for 4-6 hours under vacuum. The amorphous material was isolated in n-heptane and dried under vacuum 60-70° C with out affecting amorphous nature. (Yield-91 %) The PXRD pattern of amorphous form of Tolvaptan

Example 8: Process for the preparation of Amorphous Tolvaptan.

Tolvaptan (10 g) was dissolved in methanol (40 ml) and Dichloromethane (60 ml) at room temperature and the solution was filtered to remove any undissolved particle if any. The clear solution was concentrated under vacuum in Rota evaporator at about 40° C to 50° C completely and degas for 4-6 hours under vacuum. The amorphous material was isolated in n-heptane and dried under vacuum 60-70° C with out affecting amorphous nature. (Yield-92 %) The PXRD pattern of amorphous form of Tolvaptan.

Example 9: Process for the preparation of Amorphous Tolvaptan.

Tolvaptan (10 g) was dissolved in methanol (60 ml) and Dichloromethane (40 ml) at room temperature and the solution was filtered to remove any undissolved particle if any. The clear solution was concentrated under vacuum in Rota evaporator at about 40° C to 50° C completely and degas for 4-6 hours under vacuum. The amorphous material was isolated in n-heptane and dried under vacuum 60-70° C with out affecting amorphous nature. (Yield-89 %) The PXRD pattern of amorphous form of Tolvaptan.

Example 10: Process for the preparation of Amorphous Tolvaptan.

Tolvaptan (10 g) was dissolved in Dichloromethane (50 ml) and acetone (50 ml) at room temperature and the solution was filtered to remove any undissolved particle if any. The clear solution was concentrated under vacuum in Rota evaporator at about 40° C to 50° C completely and degas for 4-6 hours under vacuum. The amorphous material was isolated in n-heptane and dried under vacuum 60-70° C with out affecting amorphous nature.
(Yield-94 %). The PXRD pattern of amorphous form of Tolvaptan.

Example 11: Process for the preparation of Amorphous Tolvaptan.

Tolvaptan (10.0 g) was dissolved in methanol (400 ml) at room temperature and the solution was filtered to remove any undissolved particle if any. The clear solution was spray dried at about 70° C, 2.0-kg/cm2 nitrogen pressure, aspirator at 100% and at a rate of about 6.0 ml per minute. A spray dryer was operated under closed loop nitrogen circulation with nitrogen as the drying and spraying medium. The material was recovered from receiver and further dried under vacuum at 60-70° C. Yield: 7.0 g.

Example 12: Process for the preparation of Amorphous Tolvaptan.

Tolvaptan (10.0 g) was dissolved in methanol (100 ml) and Dichloromethane (100 ml) at room temperature and the solution was filtered to remove any undissolved particle if any. The clear solution was spray dried at about 60° C, 2.0-kg/cm2 nitrogen pressure, aspirator at 100% and at a rate of about 5.0 ml per minute. A spray dryer was operated under closed loop nitrogen circulation with nitrogen as the drying and spraying medium. The material was recovered from receiver and further dried under vacuum at 60-70° C. Yield: 4.5 g.

Example 13: Process for the preparation of Amorphous Tolvaptan.

Tolvaptan (10.0 g) was dissolved in methanol (50 ml) and Dichloromethane (50 ml) at room temperature and the solution was filtered to remove any undissolved particle if any. The clear solution was spray dried at about 40° C, 2.0-kg/cm2 nitrogen pressure, aspirator at 100% and at a rate of about 5.0 ml per minute. A spray dryer was operated under closed loop nitrogen circulation with nitrogen as the drying and spraying medium. The material was recovered from receiver. Yield: 3.1 g.

Example 14: Process for the preparation of Amorphous Tolvaptan.

Tolvaptan (10.0 g) was dissolved in methanol (50 ml) and Dichloromethane (50 ml) at room temperature and the solution was filtered to remove any undissolved particle if any. The clear solution was spray dried at about 50° C, 2.0-kg/cm2 nitrogen pressure, aspirated to 100% and at a rate of about 5.0 ml per minute. A spray dryer was operated under closed loop nitrogen circulation with nitrogen as the drying and spraying medium. The material was recovered from receiver and further dried under vacuum at 60-70° C. Yield: 2.85 g.

Example 15: Process for the preparation of Amorphous Tolvaptan.

Tolvaptan (10.0 g) was dissolved in methanol (50 ml) and Dichloromethane (50 ml) at room temperature and the solution was filtered to remove any undissolved particle if any. The clear solution was spray dried at about 55° C, 2.0-kg/cm2 nitrogen pressure, aspirator at 100% and at a rate of about 5.0 ml per minute. A spray dryer was operated under closed loop nitrogen circulation with nitrogen as the drying and spraying medium. The material was recovered from receiver and further dried under vacuum at 60-70° C. Yield: 4.26 g.

Example 16: Process for the preparation of Amorphous Tolvaptan.

Tolvaptan (10.0 g) was dissolved in methanol (50 ml) and Dichloromethane (50 ml) at room temperature and the solution was filtered to remove any undissolved particle if any. The clear solution was spray dried at about 80° C, 2.0-kg/cm2 nitrogen pressure, aspirator at 100% and at a rate of about 5.0 ml per minute. A spray dryer was operated under closed loop nitrogen circulation with nitrogen as the drying and spraying medium. The material was recovered from receiver and further dried under vacuum at 60-70° C. Yield: 5.93 g.

Example 17: Process for the preparation of Amorphous Tolvaptan.

Tolvaptan (10.0 g) was dissolved in ethanol (100 ml) and Dichloromethane (100 ml) at room temperature and the solution was filtered to remove any undissolved particle if any. The clear solution was spray dried at about 80° C, 2.0-kg/cm2 nitrogen pressure, aspirator at 100% and at a rate of about 5.0 ml per minute. A spray dryer was operated under closed loop nitrogen circulation with nitrogen as the drying and spraying medium. The material was recovered from receiver and further dried under vacuum at 60-70° C. Yield: 5.2 g

Example 18: Process for the preparation of Amorphous Tolvaptan.

Tolvaptan (5.0 g) was dissolved in methanol (30 ml) and Dichloromethane (20 ml) at room temperature and the solution was filtered to remove any undissolved particle if any. The clear solution was spray dried at about 70° C, 2.0-kg/cm2 nitrogen pressure, aspirator at 100% and at a rate of about 5.0 ml per minute. A spray dryer was operated under closed loop nitrogen circulation with nitrogen as the drying and spraying medium. The material was recovered from receiver and further dried under vacuum at 60-70° C. Yield: 3.8 g.

Example 19: Process for the preparation of Amorphous Tolvaptan.

Tolvaptan (5.0 g) was dissolved in Acetone (50 ml) and Dichloromethane (50 ml) at room temperature and the solution was filtered to remove any undissolved particle if any. The clear solution was spray dried at about 70° C, 2.0-kg/cm2 nitrogen pressure, aspirator at 100% and at a rate of about 5.0 ml per minute. A spray dryer was operated under closed loop nitrogen circulation with nitrogen as the drying and spraying medium. The material was recovered from receiver and further dried under vacuum at 60-70° C. Yield: 3.1 g.

We claim:

1. Process for the preparation of an amorphous Tolvaptan comprising the steps of;
a) dissolving Tolvaptan in an organic solvent or mixture thereof,
b) removing the solvent, and
c) Isolating pure amorphous Tolvaptan

2. Process for the preparation of an amorphous Tolvaptan comprising the steps of;
a) dissolving Tolvaptan in an organic solvent or mixture thereof,
b) removing the solvent,
c) adding second solvent,
d) optionally drying the wet mass, and
e) isolating amorphous tolvaptan.

3. The process according to claim land 2, wherein organic solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n- butanol, tertiary-butyl alcohol, cyclohexanol; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and cyclohexanone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether; nitriles such as acetonitrile, propionitrile; or polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide and dioxane or a mixture of thereof.

4. The process according to claim 3, wherein the organic solvent is selected from methanol, ethanol, acetone, dichloromethane or their mixtures thereof.

5. The process according to claim 2, where in second solvent is selected from hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane or water, or its mixture thereof.

6. The process according to claim land 2, wherein the solvent is removed by using conventional techniques such as filtration, distillation, vacuum-distillation, evaporation at atmospheric temperature, vacuum evaporation, agitated thin film evaporator, tray drying, spray drying, vacuum drying or freeze-drying.

7. The process according to claim 6, wherein solvent is removed by spray drying.

8. Amorphous Tolvaptan having at least one of the characteristics selected from the group consisting of:

i) Loss on drying less than 2.0%
ii) Particle size distribution less than 24.17 |jm
iii) Amorphous tolvaptan having melting range of 118 -132 °C

9. A method for packing an amorphous Tolvaptan comprising the steps of;

a) placing amorphous Tolvaptan in HMLDPE bag under inert atmosphere at 55±5% RH,
b) placing HMLDPE bag in a triple laminated aluminum bag under inert atmosphere with two silica gel sachets and one molecular sieve sachet,
c) placing the contents of step b in a triple laminated aluminum bag under inert atmosphere with two silica gel sachets and one molecular sieve sachet; and
d) packing the contents of step c in a closed high density polyethylene ("HDPE") container.