FORM 2
THE PATENT ACT 1970 (39 of 1970) & The Patents Rules,2003
COMPLETE SPECIFICATION
. (See section 10 and rule 13)
1. TITLE OF THE INVENTION:
A process for the preparation of Tolvaptan
2. APPLICANT (S)
(a) NAME: Enaltec Labs Pvt. Ltd.
(b) NATIONALITY:
An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS:
Enaltec Labs Pvt. Ltd., 17th Floor, Kesar Solitaire, Plot No. 5, Sector 19, Sanpada, Navi Mumbai- 400705, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field of the invention:
The present invention relates to a process for the preparation of Tolvaptan compound represented by structural formula (I) by using novel intermediate compound represented by structural formula (II). The present invention further relates to process for preparation of novel intermediate compound represented by structural formula
(II).
Background of the invention:
Tolvaptan is chemically known as (±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-lH-1-benzazepin-l-yl) carbonyl]-o-tolu-m-toluidide. It is selective vasopressin receptor antagonist, indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH). Tolvaptan is commercially sold under the brand name SAMSCA® and was first disclosed in U.S. patent number 5,258,510 and is represented by structural formula I.


U.S. Patent Number 5,258,510 discloses novel benzoheterocyclic compounds including tolvaptan and its derivatives, preparation of benzoheterocyclic compounds involves coupling of substituted benzoic acid activated as acid chloride, mixed anhydrides, or as an activated ester with a benzazepine derivative in presence of a base and a suitable solvent. Preparation of Tolvapatan is disclosed analogously. Same is represented in following reaction scheme.

Chinese Patent Application CN104418803 discloses synthesis of Tolvaptan compound represented by structural formula (I) wherein compound represented by structural formula III is reduced using sodium borohydride to provide 7-chloro-5-hydroxy-2,3,4,5-tetrahydro-lH-l-benzazepine compound represented by structural

formula (IV) which is further reacted with 2-methyl-4-(2-methylphenylamido)benzoyl chloride compound represented by structural formula (VI) to provide Tolvaptan compound represented by structural formula (I), but overall yield of Tolvaptan is less. Same is represented in following reaction scheme.

Chinese Patent Number CN102260213 provides process for preparation of Tolvaptan compound represented by structural formula (I) wherein compound represented by structural formula III is reduced using sodium borohydride to provide 7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-l-benzazepine compound represented by structural formula (IV) which is protected by silane group in the presence of strong base to provide compound represented by structural formula VIII which on coupling with anhydride of 2-methyl-4-(2-methylbenzamido) benzoic acid with pivaloyl chloride compound of formula XIII or trifluoroacetic acid followed by hydrolysis provides Tolvaptan compound represented by structural formula (I). The process involves use of harsh conditions like use of strong base which promotes impurity formation, use of corrosive reagents for preparation of anhydride like pivaloyl chloride and trifluoroacetic acid which are not recommended to use at commercial scale. Same is represented in following reaction scheme.


Chinese Patent Number CN102060769 describes a process for N-acylation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine compound represented by

structural formula (III) with 2-methyl-4- nitrobenzbyl chloride compound represented by structural formula (IX) in presence of. N-methyl morpholine as base to provide 7-chloro-l-(2-methyl-4-nitrobenzoyl)-3,4-dihydro-lH-benzo[b]azepin-5(2H)-one compound represented by structural formula (X) which is further reduced to amine compound represented by structural formula (XI) using SnCl2 which is condensed with 2-methylbenzoyl chloride compound represented by structural formula (XII) to provide compound represented by structural formula (XIII) and successive reduction using sodium borohydride provides Tolvaptan compound represented by structural formula (I). Disclosed process involves multiple steps and use of expensive reducing agents. Same is represented in following reaction scheme.

Bioorganic & Medicinal Chemistry (1999) 1743-1754, discloses preparation of Tolvaptan compound represented by structural formula (I). However, the method involves use of column chromatography for purification and provides yield of 30% after column chromatography which is not suitable for production of Tolvaptan on commercial scale.

Process disclosed in prior art provides Tolvaptan compound represented by structural formula (I) in lower yield, involves multiple steps and requires purification by column chromatography hence reduces productivity and increases cost of production. Accordingly there is a need in the art to develop a process of preparing Tolvaptan compound represented by structural formula (I), which is simple, economic, safe and industrially viable providing substantially pure Tolvaptan with high yield.
Object of the invention:
i) The primary object of the present invention is to provide a simple, economic, safe and industrially viable process for preparation of Tolvaptan compound represented by structural formula I.
ii) Another object of present invention is to provide a process for preparation of Tolvaptan compound represented by structural formula I by using novel intermediate compound represented by structural formula (II).
iii) Yet another object of present invention is to provide a novel intermediate compound represented by structural formula (II) and process for preparation thereof.
Summary of the invention:
First aspect of the present invention is to provide a simple, economic, safe and industrially viable process for preparation of Tolvaptan compound represented by structural formula I by using novel intermediate compound of structural formula (II).
Second aspect of the present invention is to provide a process for preparation of Tolvaptan compound represented by structural formula I


comprises,
a) reacting the compound represented by structural formula (IV) with silylating
agent in presence of a base in an organic solvent to obtain a compound
represented by structural formula (II);

b) reacting a compound represented by structural formula (V) with thionyl chloride
or oxalyl chloride to obtain the compound represented by structural formula
(VI);

c) reacting the compound represented by structural formula (VI) with the
compound represented by structural formula (II) obtained in step-a) in presence
of a base to obtain a compound represented by structural formula (VII); and


d) hydrolyzing the compound represented by structural formula (VII) to obtain a Tolvaptan compound represented by structural formula (I).

Third aspect of the present invention is to provide a process for preparation of Tolvaptan compound represented by structural formula I

comprises,
a) reacting the compound represented by structural formula (IV) with silylating
agent selected from halotrimethylsilane or hexamethyldisilazane in presence of
a base in an organic solvent to obtain a compound represented by structural
formula (II);

b) reacting a compound represented by structural formula (V) with thionyl chloride
or oxalyl chloride in a solvent to obtain the compound represented by structural
formula (VI);


c) reacting the compound represented by structural formula (VI) with the
compound represented by structural formula (II) obtained in step-a) in a solvent
and in presence of a base to obtain a compound represented by structural
formula (VII); and

d) hydrolyzing the compound represented by structural formula (VII) to obtain a
Tolvaptan compound represented by structural formula (I).

Fourth aspect of the present invention is to provide a novel intermediate compound represented by structural formula (II) for preparation of Tolvaptan.


Fifth aspect of the present invention is to provide a process for preparation of novel intermediate compound represented by structural formula (II)

comprises,
reacting the compound represented by structural formula (IV) with silylating agent selected from halotrimethylsilane or hexamethyldisilazane in presence of a base in an organic solvent to obtain a compound represented by structural formula (II).

Detail description of the invention:
In accordance with an aspect of the present invention is to provide a process for preparation of Tolvaptan compound represented by structural formula I.

comprises,

a) reacting the compound represented by structural formula (IV) with silylating
agent in presence of a base and in an organic solvent to obtain a compound
represented by structural formula (II);

b) reacting a compound represented by structural formula (V) with thionyl chloride
or oxalyl chloride in a solvent to obtain the compound represented by structural
formula (VI);

c) reacting the compound represented by structural formula (VI) with the
compound represented by structural formula (II) obtained in step-a) in a solvent
and in presence of a base to obtain a compound represented by structural
formula (VII); and

d) hydrolyzing the compound represented by structural formula (VII) to obtain a
Tolvaptan; compound represented by structural formula (I).


The compound represented by structural formula (IV) can be obtained by process disclosed in U.S. Patent Number 5,258,510, Chinese Patent Application CN104418803 and Chinese Patent Number CN102260213 which are incorporated herein by reference only.
Reaction of the compound represented by structural formula (IV) with silylating agent is carried out in a solvent and in presence of a base to obtain the compound represented by structural formula (II).
Silylating agent can be selected from halotrimethylsilane or hexamethyldisilazane. Halotrimethylsilane can be selected from chlorotrimethylsilane or bromotrimethylsilane.
The solvent can be selected from group consisting of halogenated hydrocarbons and polar aprotic solvents.
Halogenated solvents can be selected from the group consisting of dichloromethane, dichloroethane, chloroform and carbon tetrachloride.
Polar aprotic solvents can be selected from the group consisting of dimethylformamide, dimethylsulfoxide, THF, ethyl acetate and acetonitrile.

Base can be selected from group consisting of triethylamine, monomethyl amine, diisopropyl amine, pyridine and morpholine.
Reaction of the compound represented by structural formula (IV) with silylating agent is carried out at a temperature in the range of 0°C to 20°C for the period of 1 hour to 3 hours to obtain the compound represented by structural formula (II).
The compound represented by structural formula (II) can be used for next reaction without isolation.
A sample of compound represented by structural formula (II) is isolated and
characterized by following data:
Mass spectra: m/z 270 [M+H]+
1H NMR(DMSO-d6), δ 7.45(s, 1H), 7.01(d, 1H), δ 6.64(d,1H), δ 4.70-4-67(dd, 1H),
8 3.74-3.70(dd, 1H), δ 3.26-3.25(t, 1H), δ 2.69-2.68(t, 1H), δ 2.65-2.63(m, 1H), δ
1.99-1.98(m, 2H), δ 1.59-1.57(m, 1H)
The compound represented by structural formula (V) can be reacted with thionyl chloride or oxalyl chloride in a solvent to obtain the compound represented by structural formula (VI).
The solvent can be halogenated hydrocarbon selected from the group consisting of dichloromethane, dichloroethane, chloroform and carbon tetrachloride with catalytic amount of dimethylformamide.
The compound represented by structural formula (V) is reacted with thionyl chloride or oxalyl chloride in a solvent at a temperature in the range of 30°C to 50°C for a period of 1 hour to 4 hours to obtain the compound represented by structural formula (VI).

The reaction of the compound represented by structural formula (VI) with the compound represented by structural formula (II) obtained in step-a) is carried out in a solvent and in presence of a base to obtain a compound represented by structural formula (VII).
The solvent can be halogenated hydrocarbon selected from the group consisting of dichloromethane, dichloroethane, chloroform and carbon tetrachloride.
Base can be selected from group consisting of triethylamine, monomethyl amine, diisopropyl amine, pyridine and morpholine.
The reaction of the compound represented by structural formula (VI) with the compound represented by structural formula (II) can be carried out at a temperature in the range of 0°C to 30°C for a period of 1 hour to 5 hours to obtain compound represented by structural formula (VII).
Hydrolysis of the compound represented by structural formula (VII) can be carried out in a solvent in presence of an acid to obtain Tolvaptan compound represented by structural formula (I).
The solvent can be an alcohol solvent selected from group consisting of methanol, ethanol, propanol and butanol.
An acid can be selected from hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulphuric acid, acetic acid, trifluoroacetic acid and formic acid.
Hydrolysis of the compound represented by structural formula (VII) is carried out at a temperature in the range of 25°C to 75°C for a period of 1 hour to 6 hours.

Tolvaptan compound represented by structural formula (I) can be isolated by combination of one or more steps selected from filtration, centrifugation, washing, recrystallization and drying.
Tolvaptan compound represented by structural formula (I) can be recrystallized from an alcohol solvent selected from group consisting of methanol, ethanol, propanol and butanol.
Examples:
The present invention is described in the examples given below; further these are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention.
Example-1: Synthesis of Compound represented by structural formula VII (N-
(4-(7-chloro-5-((trimethylsilyl)oxy)-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-
carbonyI)-3-methyIphenyl)-2-methyIbenzamide):
Step-A:

To a solution of 7-chloro-2,3,4,5-tetrahydro-lH-benzo[b]azepin-5-ol (IV) (100 g) in dichloromethane (800) ml was added triethyl amine (154 g) at 25°C to 30°C. The reaction mass was cooled to 10°C to15°C and chlorotrimethylsilane (110 g) was added to reaction mass. The reaction mass was stirred for 1 hour. Water (500 ml) was added to the reaction mass and layers were separated. Organic layer was washed with

10% sodium bicarbonate solution (500ml) followed by 10% sodium chloride solution (500 ml). The organic layer contains compound represented by structural formula (II) i.e. 7-chloro-5-((trimethylsilyl)oxy)-2,3,4,5-tetrahydro-lH-benzo[b]azepine and is used for Step-C without isolation. A sample was isolated and compound is characterized by following data. m/z 270 [M+H]+
1H NMR(DMSO-d6), δ 7.45(s, 1H), 7.0l(d, 1H), 5 6.64(d,lH), 8 4.70-4-67(dd, 1H), 8 3.74-3.70(dd, 1H), 8 3.26-3.25(t, 1H), 8 2.69-2.68(t, 1H), 8 2.65-2.63(m, 1H), 8 1.99-1.98(m, 2H), 8 1.59-1.57(m, 1H)
Step-B:

To a solution of 2-methyl-4-(2-methylbenzamido) benzoic acid (V) (180 g) in dichloromethane (1800 ml) was added dimethylformamide 2 ml and thionyl chloride (111.3 g) at 25°C to 30°C and stirred at 35-40°C for 2 to 3 hours. Dichloromethane was completely distilled out and crude mass was degassed well, resulting residue was dissolved in dichloromethane 1800 ml and the solution was used for Step-C without isolation.
Step-C:


A solution of Step-B was added to the mixture of step-A organic layer and triethyl amine (154 g) at a temperature in the range of 0°C to 10°C. The reaction mass was stirred for 2 to 3 hours at a temperature in the range of 10°C to 20°C. Water (500 ml) was added and layers were separated. Organic layer was washed with 10% sodium bicarbonate solution (500 ml) followed by 10% sodium chloride solution (500 ml). The obtained organic layer was distilled completely under vacuum to get N-(4-(7-chloro-5-((trimethylsilyl)oxy)-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methylphenyl)-2-methylbenzamide (VII) 250.0 g. Yield: 95%, Purity: 99.30%
Example-2: Preparation of Tolvaptan compound represented by structural formula (I):

To a solution of N-(4-(7-chloro-5-((trimethylsilyl)oxy)-2,3,4,5-tetrahydro-lH-benzo[b]azepine-l-carbonyl)-3-methylphenyl)-2-methylbenzamide (VII) (100 g) in methanol (500ml) was added concentrated hydrochloric acid (100ml). Reaction mixture was stirred at 50°C to 55°C for 2 to 3 hours. Reaction mixture was cooled to 25°C to 30°C and stirred for 1 hour. The obtained solid was filtered and washed with 100 ml water and suck well. The resulting crude was recrystallized in methanol to give 82 g of pure Tolvaptan (I). Yield: 95%, Purity: 99.9%

We claim:
1. A process for preparation of Tolvaptan compound represented by structural formula I.

Comprises,
a. reacting the compound represented by structural formula (IV) with silylating
agent in presence of a base in an organic solvent to obtain a compound
represented by structural formula (II);

b. reacting a compound represented by structural formula (V) with thionyl
chloride or oxalyl chloride to obtain the compound represented by structural
formula (VI);

c. reacting the compound represented by structural formula (VI) with the
compound represented by structural formula (II) obtained in step-a) in
presence of a base to obtain a compound represented by structural formula
(VII); and


d. hydrolyzing the compound represented by structural formula (VII) in a solvent to obtain a Tolvaptan compound represented by structural formula
(i).
2. The process as claimed in claim 1, step a) wherein solvent is halogenated hydrocarbons selected from the group consisting of dichloromethane, dichloroethane, chloroform and carbon tetrachloride; Polar aprotic solvents selected from the group consisting of dimethylformamide, dimethylsulfoxide, THF, ethyl acetate and acetonitrile or mixture (s) thereof.
3. The process as claimed in claim 1, step a) wherein silylating agent is selected from halotrimethylsilane selected from chlorotrimethylsilane and bromotrimethylsilane or hexamethyldisilazane.
4. The process as claimed in claim 1, step a) wherein base is selected from group consisting of triethylamine, monomethyl amine, diisopropyl amine, pyridine and morpholine.
5. The process as claimed in claim 1, step a) wherein reaction of the compound represented by structural formula (IV) with silylating agent is carried out at a

temperature in the range of 0°C to 20°C for the period of 1 hour to 3 hours to obtain the compound represented by structural formula (II).
6. The process as claimed in claim 1, step c) wherein base is selected from group consisting of triethylamine, monomethyl amine, diisopropyl amine, pyridine and morpholine.
7. The process as claimed in claim 1, step d) wherein solvent is an alcohol solvent selected from group consisting of methanol, ethanol, propanol and butanol.
8. The process as claimed in claim 1, step d) wherein hydrolysis of the compound represented by structural formula (VII) is carried out by using acid selected from hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulphuric acid, acetic acid, trifluoroacetic acid and formic acid at a temperature in the range of 25°C to 75°C for a period of 1 hour to 6 hours.
9. An intermediate compound represented by structural formula (II)

10. A process for preparation of an intermediate compound represented by structural
formula (II).

comprises,
reacting the compound represented by structural formula (IV) with silylating agent selected from halotrimethylsilane or hexamethyldisilazane in presence of a base in an organic solvent to obtain a compound represented by structural formula (II).