DESC:FIELD OF THE INVENTION:
The present invention relates to an improved, efficient and industrially advantageous process for the preparation of Tolvaptan of Formula (I).
The present invention also relates to a process for the preparation of Tolvaptan intermediates namely 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine of Formula (V), 2-methyl-4-nitrobenzoyl chloride of Formula (IIa) and 2-methylbenzoyl chloride of Formula (IIb) and their use for the preparation of Tolvaptan.
BACKGROUND OF THE INVENTION:
Tolvaptan is chemically known as 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine, having the structure of Formula (I).

Formula (I)
Tolvaptan has been developed by Otsuka Pharmaceutical Co Ltd. and approved by US food and drug Administration (USFDA) on May 19th 2009 and approved by European Medicines Agency (EMA) on August 02nd 2009, under the proprietary name Samsca®. Tolvaptan is a selective vasopressin V2-receptor antagonist indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia including patients with heart failure and syndrome of inappropriate antidiuretic hormone.
The USA patent number US 5258510A first discloses Tolvaptan and its process.
The Chinese patent number CN 102060769B (herein after CN ‘769) discloses process for preparation of 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine comprising reacting 2-methyl-4-nitrobenzoic acid with thionyl chloride under reflux condition followed by distillation to obtain 2-methyl-4-nitrobenzoyl chloride having 97.27 % yield. Resulting 2-methyl-4-nitrobenzoyl chloride further reacted with 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine in presence of dichloromethane and N-methylmorpholine to obtain residue and recrystallized from anhydrous methanol to obtain 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine. Resulting 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine further treated with stannous chloride in presence of concentrated hydrochloric acid, ethanol to obtain residue and recrystallized from ethanol to obtain 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine having 68.7% yield.
The Indian patent application number IN 1303/CHE/2011 (herein after IN ‘1303) discloses in Example-2b process for preparation of 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine comprising reacting 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine with Raney nickel in presence of methanol followed by heating at 45° C to 50° C and to obtain crude. The resulting crude was recrystallized in isopropyl ether to obtain 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine having 76% yield.
The USA patent number US 9024015B2 (herein after US ‘015) discloses in Example 3 process for preparation of 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine comprising reacting 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine with tin chloride in presence of methanol. Further resulting reaction mixture was stirred for 16 hours at room temperature and then poured in to ice water followed by addition of sodium hydroxide at pH 8.0 to 9.0. Further solvent was distilled off from the reaction mixture to obtain 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine.
The Indian patent application number IN 1559/MUM/2012 (herein after IN ‘1559) discloses in Example-8 process for preparation of 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine comprising reacting 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine with stannous chloride dihydrate in presence of methanol and concentrated hydrochloric acid at 80° C to 85° C for 2 hours. Resulting reaction mixture was basified with sodium hydroxide solution at pH 12 to 14. Further reaction mixture was extracted with dichloromethane and the organic layer was washed with water to obtain 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine having 96.4 % yield.
The Indian patent number IN 304391 (herein after IN ‘391) discloses in Example 1 process for preparation 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine comprising reacting 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine with Iron powder in presence of methanol at 50° C to 60° C followed by addition of acetic acid. Further the reaction mixture was filtered to obtain 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine having 83.33% yield.
The Chinese patent number CN 113336773B (herein after CN ‘773) discloses process for preparation of 2-methyl-4-nitrobenzoyl chloride comprising reacting 2-methyl-4-nitrobenzoic acid with thionyl chloride in presence of N,N-dimethylformamide as catalyst at 80° C followed by evaporation of excess thionyl chloride to obtain 2-methyl-4-nitrobenzoyl chloride having 90 % yield.
Journal of Chemical Education Volume: 25 Pages: 481 Journal 1948 discloses process for preparation of 2-methylbenzoyl chloride comprising reacting o-toluic acid with thionyl chloride at 60° C to 65° C followed by recovering excess thionyl chloride by distillation to obtain 2-methylbenzoyl chloride having 91 % yield.
Journal of Chromatography, Biomedical Applications Volume 146 Issue 2 Pages 213-19 Journal 1978 discloses process for preparation of 2-methylbenzoyl chloride comprising reacting 2-methyl benzoic acid with thionyl chloride under reflux followed by removing excess thionyl chloride under vacuum distillation to obtain 2-methylbenzoyl chloride having 95 % yield.
The USA patent number US 4880576A (herein after US ‘576) discloses process for preparation of 2-methylbenzoyl chloride comprising reacting o-methylbenzoic acid with phosgene in presence of methylstearylformamide as catalyst at 100° C to obtain 2-methylbenzoyl chloride having 97 % yield.
The USA patent number US 3962326A (herein after US ‘326) discloses process for preparation of 2-methylbenzoyl chloride comprising reacting o-toluic acid with phosgene at temperature 0° C to 180° C in presence of trisubstituted phosphine oxide or phosphine sulfide as catalyst to obtain 2-methylbenzoyl chloride having 97.5% yield.
The above prior art references have several disadvantages such as tedious work up process, excess amount of catalyst, longer reaction time, lower yield and lower purity. Therefore, above prior-art processes are not good option for the large-scale industrial production of Tolvaptan and its intermediates. Therefore, there is an urgent need for an improved process for the preparation of Tolvaptan and its intermediate having high yield and purity which overcomes the drawbacks of the prior art processes.
The present inventors have developed an efficient process for the preparation of Tolvaptan and its intermediates which offer advantage over the prior art processes in terms of high yield, high purity and less effluents and simple scalable procedure suitable for large scale industrial production of Tolvaptan and its intermediates.
OBJECT OF THE INVENTION:
The main object of the present invention is to provide an efficient and industrially advantageous process for the preparation of Tolvaptan of Formula (I) having high yield and purity.
Another object of the present invention is to provide a process for the preparation of Tolvaptan intermediates namely 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine of Formula (V), 2-methyl-4-nitrobenzoyl chloride of Formula (IIa) and 2-methylbenzoyl chloride of Formula (IIb) having high yield and purity and their use for the preparation of Tolvaptan of Formula (I).
SUMMARY OF INVENTION:
First aspect of the present invention is to provide a process for preparation of compound of Formula (II),

Formula (II)
“wherein, R is hydrogen or nitro group”
comprising:
reacting compound of Formula (III),

Formula (III)
“wherein, R is hydrogen or nitro group”
with chlorinating agent in presence of triphenylphosphine as catalyst to obtain compound of Formula (II).
Second aspect of the present invention is to provide a process for preparation of compound of Formula (V),

Formula (V)
comprising:
reacting compound of Formula (IV),

Formula (IV)
with reducing agent in presence of base and solvent to obtain compound of Formula (V).
Third aspect of the present invention is to provide a process for preparation of crystalline Form of Tolvaptan of Formula (I),

Formula (I)
comprising the steps of:
a) treating Tolvaptan of Formula (I) in mixture of aliphatic halogenated and alcohol solvent at 35° C to reflux temperature;
b) adding activated carbon in the mixture of step (a);
c) filtering mixture of step (b) to obtain filtrate;
d) removing solvent of filtrate from the mixture of step (c);
e) adding alcohol solvent as anti-solvent in the step (d); and
f) isolating crystalline Form of Tolvaptan of Formula (I).

BRIEF DESCRIPTION OF DRAWINGS:
Figure 01: Illustrates the X-ray powder diffractogram (XRPD) of crystalline form of Tolvaptan of Formula (I).
DEFINITION:
All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25ºC and normal pressure unless otherwise designated.
All temperatures used herein are in degree Celsius unless specified otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements that may or may not be recited.
The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
The term "about", as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.
DETAILED DESCRIPTION OF INVENTION:
While the following specification concludes the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description and by studying the included examples.
The invention will now be described in detail in connection with certain preferred embodiments, so that various aspects thereof may be fully understood and appreciated.
The present invention provides an improved, efficient and industrially advantageous process for the preparation of Tolvaptan of Formula (I) and its intermediates.
According to first embodiment, the present invention provides a process for preparation of compound of Formula (II),

Formula (II)
“wherein, R is hydrogen or nitro group”
comprising reacting compound of Formula (III),

Formula (III)
“ wherein, R is hydrogen or nitro group”
with chlorinating agent in presence of triphenylphosphine as catalyst to obtain compound of Formula (II).
In the first embodiment, compound of Formula (III) can be prepared by process known in the prior-art.
In the first embodiment, chlorinating agent can be selected from the group consisting of phosphorus trichloride (PCl3), phosphorus pentachloride (PCl5), phosphorous oxychloride (POCl3) and thionyl chloride (SOCl2). Preferably chlorinating agent is thionyl chloride (SOCl2).
In the first embodiment, chlorination reaction can be carried out in presence solvent or in absence of solvent; wherein solvent can be selected from group consisting of chlorinated solvent such as dichloromethane, chloroform and ethylene dichloride or mixture (s) thereof; aromatic hydrocarbon solvent such as toluene, xylene, mesitylene or mixture(s) thereof. Preferably chlorinated solvent is dichloromethane.
In the first embodiment, chlorination reaction can be carried out in presence of triphenylphosphine as catalyst. The triphenylphosphine catalyst can be used in the molar equivalent of 0.005 mol equivalent to 0.006 mol equivalent with respect to the compound of Formula (III).
In the first embodiment, chlorination reaction can be carried out at temperatures 30° C to 50° C. Preferably chlorination can be carried out at temperature 35° C to 40° C.
In the first embodiment, chlorination reaction can be carried out for 1 hour to 7 hours. Preferably chlorination reaction is carried out time for 1 hour to 5 hours.
After completion of reaction, resulting reaction mixture can be heated at 38° C to 40° C for 1 hour to 4 hours and solvent can be removed from the reaction mixture by distillation at temperature 40° C to 100° C to obtain compound of Formula (II). The obtained compound of Formula (II) may have purity greater than 99 % by gas chromatography.
According to second embodiment, the present invention provides a process for preparation of compound of Formula (V),

Formula (V)
comprising reacting compound of Formula (IV),

Formula (IV)
with reducing agent in presence of base and solvent to obtain compound of Formula (V).
In the second embodiment, compound of Formula (IV) can be prepared by process known in the prior-art.
In the second embodiment, reducing agent can be selected from the group consisting of Stannous chloride (SnCl2), Iron powder, palladium on carbon, platinum on carbon, Raney nickel. Preferably reducing agent is Raney nickel.
In the second embodiment, reducing agent can be used in the presence of hydrogen gas.
In the second embodiment, the base can be selected from the group consisting of organic base or inorganic base.
Inorganic base can be selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate.
Organic base can be selected from group consisting of tertiary amines such as triethylamine, N,N-diisopropylethylamine (DIPEA), 4-dimethylaminopyridine, pyridine. Preferably base is organic base such as pyridine.
In the second embodiment, the base can be used in the molar equivalent of 0.03 to 0.04 with respect to compound of Formula (IV).
In the second embodiment, solvent can be selected from the group consisting of alcohol solvent such as methanol, ethanol, isopropyl alcohol, n-butanol, tertiary butyl alcohol or mixture(s) thereof; halogenated solvent such as ethylene dichloride, chloroform, dichloromethane or mixture(s) thereof. Preferably solvent is a mixture of dichloromethane and methanol.
In the second embodiment, reacting compound of Formula (IV) with reducing agent in presence of base and solvent can be carried out at temperature 20° C to 40° C. Preferably reaction is carried out at 20° C to 35° C.
In the second embodiment, reacting compound of Formula (IV) with reducing agent in presence of base and solvent can be carried out at 15 hours to 25 hours. Preferably reaction is carried out at 20 hours to 24 hours.
After completion of reaction, Raney nickel can be removed from the reaction mixture by filtration and washed the resulting reaction mixture with dichloromethane. The resulting product layer can be distilled out from the reaction mixture under reduced pressure and methanol can be added to the reaction mixture at reflux temperature. The resulting reaction mixture can be cooled and chilled at 0° C to 5° C. Resulting reaction mixture can be filtered and dried under vacuum at 50° C to 55° C to obtain compound of Formula (V).
The obtained compound of Formula (V) may have purity greater than 97 % by high performance liquid chromatography (HPLC).
According to third embodiment, the present invention provides a process for preparation of crystalline Form of Tolvaptan of Formula (I),

Formula (I)
comprising the steps of:
a) treating Tolvaptan of Formula (I) in mixture of aliphatic halogenated and alcohol solvent at 35° C to reflux temperature;
b) adding activated carbon in the mixture of step (a);
c) filtering mixture of step (b) to obtain filtrate;
d) removing solvent of filtrate from the mixture of step (c);
e) adding alcohol solvent as anti-solvent in the step (d); and
f) isolating crystalline Form of Tolvaptan of Formula (I).
In the third embodiment, of step a) aliphatic halogenated solvent can be selected from the group consisting of such as ethylene dichloride, chloroform, dichloromethane or mixture(s) thereof. Preferably halogenated solvent is dichloromethane.
In the third embodiment, of step a) alcohol solvent can be selected from the group consisting of such as methanol, ethanol, isopropyl alcohol, n-butanol, tert-butyl alcohol or mixture(s) thereof. Preferably alcohol solvent is methanol.
In the third embodiment, of step a) mixture of aliphatic halogenated solvent and alcohol can be prepared in 1:1 volume ratio.
In the third embodiment, of step a) treating Tolvaptan of Formula (I) with mixture of aliphatic halogenated and alcohol solvent at 35° C to reflux temperature.
In the third embodiment, of step b) activated carbon can be added to the mixture of step a). After completion of activated carbon addition, reaction mixture can be filtered and washed with solvent used.
In the third embodiment of step d), solvent can be removed from the mixture of step c) by distilling reaction mixture of step c) at 75° C under reduced pressure and stripping of alcohol can be done to remove traces of previously used solvent.
In the third embodiment of step e), alcohol solvent can be selected from the group consisting of such as methanol, ethanol, isopropyl alcohol, n-butanol, tert-butyl alcohol or mixture(s) thereof. Preferably alcohol solvent is isopropyl alcohol.
In the third embodiment of step e), alcohol as an anti-solvent can be added at 80° C to 85° C. After completion of step e), mixture can be cooled at 10° C to 20° C and mixture can be further chilled at -5° C to 5° C.
In the third embodiment of step f), Tolvaptan of Formula (I) can be isolated from the reaction mixture of step e) by filtration.
The obtained crystalline form of Tolvaptan of Formula (I) may have purity greater than 99 % by high performance liquid chromatography (HPLC).
The obtained crystalline form of Tolvaptan of Formula (I) characterized by x-ray powder diffractogram (XRPD) having peaks at 4.7, 15.4, 18.7, 21.7 and 23.5° ± 0.2° 2?.
While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES:
The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.
Example 01: Preparation of 2-methyl-4-nitrobenzoyl chloride of Formula (IIa)

Formula (IIa)
To a stirred solution of 2-methyl-4-nitrobenzoic acid (300 gm) in dichloromethane (300 mL) was added and heated at 35° C to 40° C. To the resulting reaction mixture triphenyl phosphine (3.0 gm) as catalyst and slowly thionyl chloride (240 gm) was added for 1 hour to 5 hours at 30° C to 40° C. Sulfur dioxide and hydrochloric acid gas was generated as reaction by product. The resulting reaction mixture was maintained at 38° C to 40° C for 4 hours. Further, slowly added thionyl chloride (45 gm) at 30° C to 40° C for 15 minutes to 30 minute and again reaction mixture was maintained at 38° C to 40 °C for 2 hours. After completion of reaction dichloromethane was removed from the reaction mixture at reduced pressure. Resulting crude product was distilled out at 80° C to 95° C by high vacuum distillation to obtain title compound of Formula (III).
Appearance: yellow clear liquid at above 40 °C.
Yield: 324.4 gm (98.14 %)
GC purity: 99.94 %
Example 02: Preparation of 2-methylbenzoyl chloride of Formula (IIb)

Formula (IIb)
To a stirred solution of 2-methylbenzoic acid (300 gm) in dichloromethane (300 mL) was added, and heated up to 35° C to 40° C. To the resulting reaction mixture triphenylphosphine (3.0 gm) as catalyst and slowly thionyl chloride (300 gm) was added at 25° C to 42°C for 1hour to 5 hours. Sulfur dioxide and hydrochloric acid gas was generated as reaction by product. The resulting reaction mixture was maintained at 38° C to 40° C for 4 hours. After completion of reaction dichloromethane was removed at reduced pressure. The resulting crude product was distilled out at 40° C to 90° C by high vacuum distillation to obtain title compound of Formula (IIb).
Appearance: colorless to yellow clear liquid.
Yield: 334.2 gm (98.15 %)
GC purity: 99.16 %
Example 03: Preparation of 7-Chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine of Formula (IV)

Formula (IV)
To a stirred solution of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (250 gm), dichloromethane (750 mL) and solution of 2-methyl-4-nitrobenzoyl chloride [2-methyl-4-nitrobenzoyl chloride (275 gm) in dichloromethane (750 mL)] was added and stirred at 25° C to 35° C. The resulting reaction mixture was maintained at 32° C to 37 °C for 60 minutes to 90 minutes and reaction mixture was cooled at 25° C to 30° C. To the resulting reaction mixture slowly pyridine (100 gm) was added at 25° C to 40 °C for 30 minutes to 60 minutes. The resulting reaction mixture again maintained at 38° C to 41° C for 4 hours. After completion of reaction, resulting reaction mixture was cooled and acidified with concentrated hydrochloric acid (312.5 gm) and mixture was allowed to separate organic and aqueous layers. The resulting organic layer washed with water to remove acidity. Further, 20 % sodium carbonate solution (250 gm) was added to remove 2-methyl-4-nitrobenzoic acid. further product layer was washed with water. Other side distillation set up was prepared and methanol (1500 mL) was added in flask and heated up to 55°C to 60° C. The resulting product layer was slowly added and methanol and dichloromethane was distilled out from the product layer. Further methanol was added to remove dichloromethane in the reaction mixture. The reaction mixture was cooled at 0° C to 5° C for 2 hours, reaction mixture was filtered and washed with methanol (125 mL x 2) to obtain crude. The resulting crude was purified in Toluene (750 mL) and crude was clear in toluene at 95°C to 110 °C. The resulting crude was recrystallized at 65° C to 75°C and reaction mixture was cooled at – 5° C to 5° C. Further resulting reaction mixture was maintained at – 5° C to 5 °C for 2 hours to 3 hours and filtered. The resulting reaction mixture was washed with Toluene (250 mL x 2) and dried under vacuum for 6 hours to 8 hours at 75° C to 80 ° C to obtain title compound of Formula (IV).
Yield: 421.9 gm ( 92.02 % )
HPLC purity: 99.96 %
Example 04: Preparation of 1-(4-Amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine of Formula (V)

Formula (V)
To a stirred solution of 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine of Formula (IV) (350 gm) a mixture of dichloromethane (1750 mL) and Methanol (1750 mL) was added at 20° C to 35° C. To the resulting reaction mixture pyridine (3.5 gm) and Raney nickel (17.5 gm) in a mixture of dichloromethane (17.5 mL) and methanol (17.5 mL) was added at 20° C to 35 °C then hydrogen gas pressure 12 to 15 kg/cm2 was applied for 20 hours to 24 hours. From the resulting reaction mixture Raney nickel was removed by high flow filtration method, washed with dichloromethane (700 mL) and separated each layer. The resulting product layer was distilled out under reduced pressure at 70° C to 75° C, followed by methanol (525 mL) stripping. In resulting reaction mixture methanol (350 mL) was added at reflux temperature for 1 hour to 2 hours, further reaction mixture was cooled at 0° C to 5° C and maintained for 3 hours at same temperature. Resulting reaction mixture was filtered, washed with methanol (87.5 mL x 3) and dried under vacuum for 6 hours to 8 hours at 50° C to 55° C to obtain title compound of Formula (V).
Yield : 310.8 gm (96.90 % )
HPLC purity: 97.00 %

Example 05: Preparation of Tolvaptan of Formula (I)

Formula (I)
To a stirred solution of 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetra-hydro-1H-1-benzazepine of Formula (V) (280 gm) a dichloromethane (1400 mL) was added at 25° C to 35° C. To the resulting reaction mixture 2-methylbenzoyl chloride (140 gm) and dichloromethane (140 mL) was added at 25° C to 40° C and reaction mixture was stirred at 35° to 42° C for 3 hours. To the resulting reaction mixture slowly pyridine (154 gm) and dichloromethane (140 mL) was added at same temperature at 37° C to 42° C for 4 hours. After completion of reaction the reaction mixture was cooled and purified water (280 mL) was added, stirred and each layer was separated. To the aqueous layer and organic layer dichloromethane (28 mL) was added, further all the organic layer was combined and water (280 mL) and hydrochloric acid (140 gm) was added and stirred for 40 minutes to 60 minutes at 25° C to 35° C. Further each layer was separated and organic layer was washed with water (280 mL) and 2 to 10 % aqueous sodium carbonate solution at 25° to 35° C and stirred for 1 hour to remove 2-chlorobenzoic acid from the reaction mixture. Further both the aqueous and organic layer was separated and organic layer containing product and aqueous layer was washed with dichloromethane (28 mL) and combined with organic layer containing product 7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one of Formula (VII). The resulting organic layer was filtered through hyflow and washed with dichloromethane (840 mL), to the resulting filtrate methanol (1960 mL) was added at 25° C to 30° C and reaction mixture was chilled at 0° C to 10° C. To the resulting reaction mixture slowly sodium borohydride (50.4 gm) was added at same temperature for 4 hours to 6 hours, further reaction mixture was maintained for 1hour to 2 hours at same temperature. After completion of reaction the reaction mixture, solvent was distilled out at 75° C. To the resulting reaction mixture water (1260 mL) was added and cooled at 30° C to 40° C, further reaction mixture was quenched with concentrated hydrochloric acid (140 gm) and water ( 140 mL) to adjust the pH of reaction mixture at 2.0. Resulting reaction mixture was filtered and washed with water (40 mL x 3), further water (840 mL) was added to the reaction mixture and filtered and washed with water (140 mL x 3). To the reaction mixture dichloromethane (560 mL) was added at 25° C to 35 ° C for 1 hour to 2 hours, further reaction mixture was filtered and washed with dichloromethane (140 mL x 2) and dried at 70° C to 80° C in air trey dryer for 4 hours to 5 hours to obtain title compound of Formula (I)
Yield : 363.2 gm (95.38 %)
HPLC purity : 99.90 %

Example 06: Preparation of Crystalline Form of Tolvaptan of Formula (I)

Formula (I)
To a stirred solution of Tolvaptan (320 gm) obtained in Example 05 a mixture of dichloromethane (1280 mL) and methanol (1280 mL) was added at 25°C to 35° C and reaction mixture was heated at 36° C to 40° C till the clear reaction mixture was observed. To the resulting reaction mixture activated carbon (16.0 gm) was added and stirred for 1 hour, further reaction mixture was filtered through hyflow filtration and washed with a mixture of dichloromethane and methanol (1:1 V/V). Resulting filtrate was distilled out at 75° C under reduced pressure to remove solvent and isopropyl alcohol (320 mL x 2) was added to remove mixture of dichloromethane and methanol. To the resulting reaction mixture isopropyl alcohol (640 mL)was added at 80° C to 85° C for 2 hours, further reaction mixture was cooled at 10° C to 20° C and maintained for 1 hour and reaction mixture was chilled at -5°C to 5° C for 2 hours. Resulting reaction mixture was filtered and washed with isopropyl alcohol (160 mL x 2). To the resulting reaction mixture water (960 mL) was added and stirred for 2 hours, reaction mixture was filtered and washed with water(160 mL x 2). Resulting material was dried under vacuum at 70° C to 80° C for 10 hours to 12 hours to obtain title compound of Formula (I).
Yield : 301 gm (94.06 %)
HPLC purity : 99.85 %

,CLAIMS:I / We claim:
1. A process for preparation of compound of Formula (II),

Formula (II)
“wherein, R is hydrogen or nitro group”
comprising:
reacting compound of Formula (III),

Formula (III)
“wherein, R is hydrogen or nitro group”
with chlorinating agent in presence of triphenylphosphine as a catalyst to obtain compound of Formula (II).
2. The process as claimed in claim 01; wherein, chlorinating agent is selected from the group consisting of phosphorus trichloride (PCl3), phosphorus pentachloride (PCl5), phosphorous oxychloride (POCl3) and thionyl chloride (SOCl2).
3. The process as claimed in claim 01; wherein, chlorination reaction is carried out with or without solvent at temperatures of 30°C to 50°C; and solvent is selected from group consisting of chlorinated solvent such as dichloromethane, chloroform, ethylene dichloride, aromatic hydrocarbon solvent such as toluene, xylene, mesitylene or mixture(s) thereof.
4. A process for preparation of compound of Formula (V),

Formula (V)
comprising:
reacting compound of Formula (IV),

Formula (IV)
with reducing agent in presence of base and solvent to obtain compound of Formula (V).
5. The process as claimed in claim 04; wherein, reducing agent is selected from the group consisting of stannous chloride (SnCl2), iron powder, palladium on carbon, platinum on carbon, Raney nickel; and base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, tertiary amines such as triethylamine, N,N-diisopropylethylamine (DIPEA), 4-dimethylaminopyridine, and pyridine.
6. The process as claimed in claim 04; wherein, molar equivalent of base with respect to compound of Formula (IV) is 0.03 to 0.04.
7. The process as claimed in claim 04; wherein, solvent is selected from the group consisting of alcohol solvent such as methanol, ethanol, isopropyl alcohol, n-butanol, tertiary butyl alcohol, halogenated solvent such as ethylene dichloride, chloroform, dichloromethane or mixture(s) thereof.
8. The process as claimed in claim 04; wherein, reaction of compound of Formula (IV) with reducing agent in presence of base and solvent is carried out at temperature 20°C to 40°C.
9. A process for preparation of crystalline form of Tolvaptan of Formula (I),

Formula (I)
comprising the steps of:
a) treating Tolvaptan of Formula (I) in mixture of aliphatic halogenated and alcohol solvent at 35° C to reflux temperature;
b) adding activated carbon to the mixture obtained in step (a);
c) filtering mixture obtained in step (b) to obtain filtrate;
d) removing solvent of filtrate from the mixture obtained in step (c);
e) adding alcohol solvent as anti-solvent to the step (d); and
f) isolating crystalline Form of Tolvaptan of Formula (I).

10. The process as claimed in claim 09; wherein, aliphatic halogenated solvent is selected from the group consisting of such as ethylene dichloride, chloroform, dichloromethane or mixture(s) thereof; and alcohol solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-butanol, tert-butyl alcohol or mixture(s) thereof.

Dated this 30th day of March 2024

Mr. Raju Sharma
Sr. Manager- IPR,
Ami Lifesciences Pvt. Ltd.