FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION "AN IMPROVED PROCESS FOR TOLVAPTAN"
Emcure Pharmaceuticals Limited.,
an Indian Company, registered under the Indian Company's Act 1957
and having its Registered Office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of tolvaptan and its intermediate of desired purity. Specifically, the invention relates to a process for removal of undesired associated impurities formed during the coupling of 7-chloro-l,2,3,4-tetrahydrobenzo[b]azepine-5-one with 2-methyl-4-nitrobenzoylchloride and its further conversion to tolvaptan.
BACKGROUND OF THE INVENTION
Tolvaptan chemically known as (±)-N-[4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-lH-l-benzazepin-l-ylcarbonyl)-3-methylphenyl]-2-methylbenzamide of formula (I), is a vasopressin antagonist, which blocks the binding of arginine vasopressin (AVP) V2 receptors and employed for the treatment of hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis and the syndrome of inappropriate antidiuretic hormone.

Formula (I)
The racemic form of tolvaptan was approved by USFDA on May 2009 and is marketed under the brand name 'Samsca' for oral administration, as immediate release tablet having 15 mg and 30 mg strength.
Various researchers have attempted to synthesize the active pharmaceutical ingredient tolvaptan of formula (I).

US 5,258,510 relating to novel benzoheterocyclic compounds including tolvaptan and its derivatives, describes a method for 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. However, the specification does not mention in details about the experimental condition for coupling reaction, purity and the yield of the product.
Bioorganic & Medicinal Chemistry 7 (1999) 1743-1754., describes the experimental condition for coupling of 7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine with 2-methyl-4-nitrobenzoic acid in presence of pyridine or triethylamine as base and dichloromethane as solvent. However, the method provides only a yield of 32% after column chromatography and is thus not suitable for production of tolvaptan on industrial scale. The method does not mention the formation of an impurity which could be obtained by the said process using a base.
CN 102060769 describes a process for N-acylation of 7-chioro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-methyl-4-nitrobenzoic acid in presence of. N-methyl morpholine as base. The process provides a yield of about 75% with purity of 97.9%; which implies that an associated impurity was formed during the reaction, necessitating for subsequent purification. However, additional purification step for obtaining a pure product conforming to regulatory specifications, further increases the number of steps and affects the overall yield which makes the process expensive for industrial applications.
The present inventors have observed that all the prior art methods are unable to provide the N-acylated product i.e. 7-chloro-l-(2-methyl-4-nitrobenzyl)-5-oxo-2,3,4,5-tetrahydro-lH-1-benzazepine of formula (II) without the associated impurity and having the desired quality on a commercial scale.
Since, the impurity formed during coupling reaction is not easily removed during purification by recrystallization; column chromatography is required, which is not

feasible on commercial scale. Regulatory authorities all over the world have very stringent norms for permissible limits of such impurities in either the active ingredient or in the final formulation.
Thus, there is a need to develop a process for N-acylation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-1-benzazepine with 2-methyl-4-nitrobenzoylchloride which obviates the formation of associated impurities and does not require column chromatography purification for getting the desired purity.
Considering the commercial importance of tolvaptan and to over come the prior art drawbacks, the present inventors have developed a method which provides desired quality product without utilizing chromatographic purification techniques.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide an improved and cost effective process for the preparation of a key tolvaptan intermediate with desired purity and without the utilization of column chromatography purification.
Another object of the present invention is to provide a process for elimination of undesired impurities formed during the coupling of 7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-1-benzazepine with 2-methyl-4-nitrobenzoylchloride and further converted to tolvaptan of desired purity in subsequent steps.
SUMMARY OF THE INVENTION
An aspect for present invention relates to a process for preparation of tolvaptan intermediate of formula (II) comprising reaction of N-acylation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1 -benzazepine with 2-methyl-4-nitrobenzoylchloride in an organic solvent and in absence of base.
Another aspect of the invention relates to a process for tolvaptan comprising N-acylation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine with 2-methyl-4-

nitrobenzoyl chloride in an organic solvent and in absence of a base, followed by reduction of the nitro group with a suitable reducing agent to give 7-chloro-l-(4-amino-2-methylbenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine, which on subsequent acylation with 2-methylbenzoylchloride and reduction with sodium borohydride provides Tolvaptan of desired purity.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for preparation of tolvaptan which includes coupling of 7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine with 2-methyl-4-nitrobenzoylchloride in an organic solvent and in absence of a base.
The present inventors have found that the coupling of 7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-1-benzazepine with 2-methyl-4-nitrobenzoylchloride in presence of a base and dichloromethane as solvent results in the formation of an impurity ranging between 2 and 4%. The inventors have separated and identified the impurity of formula
(III).

It was unexpectedly found after several experiments that the compound of formula (III) could be totally eliminated during the reaction, in absence of a base. Further, it was envisaged that in absence of a base which acts as an acid acceptor, there was likely to be formation of other impurities in the acidic environment. However, the inventors were amazed to note that not only the reaction was facile, but the absence of associated

impurities provided tolvaptan intermediate of formula (II) of desired purity with the associated impurities much below permissible regulatory limits. The inventors observed that the present invention provide a solution to the problem frequently encountered in the prior art.
One embodiment of the present invention relates to a process for coupling of 7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine with 2-methyl-4-nitrobenzoyl chloride in an organic solvent and in absence of base. The synthetic sequence for tolvaptan is represented in the following scheme I:
Scheme-I


Another embodiment of the invention relates to an improved process for preparation of tolvaptan comprising N-acylation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine with 2-methyl-4-nitrobenzoylchloride in an organic solvent, followed by reduction of the nitro group with suitable reducing agent to give 7-chloro-l-(4-amino-2-methylbenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine, which on acylation with 2-methylbenzoylchloride and reduction with sodium borohydride gave tolvaptan (I).
The organic solvent utilized for N-acylation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine is selected from nitriles, hydrocarbons or ethers.
The nitriles are selected from acetonitrile, propionitrile or butyronitrile, but preferably acetonitrile while the aromatic hydrocarbon is selected from the group comprising of toluene and xylene but preferably toluene and the ether solvent is selected from dioxane, but preferable 1,4-dioxane.
The volume of solvent employed is in the range of 4 to 10 volumes with respect to 7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine, preferably 5 to 8 volumes. The N-acylation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine with 2-methyl-4-nitrobenzoyl chloride is facile with acetonitrile or toluene or dioxane as solvent and in absence of a base without formation of any associated impurity of formula (III).
The process of N-acylation reaction is carried out at temperatures between 35°C to 90°C and preferably 75°C to 85°C.
After completion of the reaction, as monitored by HPLC, the reaction mixture was cooled and the product gradually separated out. The thick slurry was filtered and washed with organic solvent to obtain a molar yield of 85%, with more than 99.65% purity.

It should be noted that isolation of 7-chloro-l-(4-amino-2-methylbenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine (II) requires only cooling of the reaction mixture to obtain the tolvaptan intermediate and does not require any elaborate work up involving quenching of the reaction mixture, extraction, washing with water of either acidic or basic pH, followed by concentration of the organic layer and addition of an anti-solvent to give the desired product. It would suffice to mention that isolation of the product is quite convenient and does not require any purification thereby making the process quite suitable for commercial scale.
Another embodiment of the present invention, relates to preparation of tolvaptan by
utilizing 7-chloro-l-(4-amino-2-methylbenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l-
benzazepine (II) obtained from present invention. It was found that tolvaptan prepared by utilizing the said intermediate was found to have purity in the range of 99.50 to 99.90 (without column chromatography) and with over all yield in the range of 50 to 55% starting from preparation of the tolvaptan intermediate.
It should be noted that the present inventors have provided a method for preparation of 7-chloro-1 -(4-nitro-2-methylbenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1 -benzazepine of formula (II), wherein the associated impurities of formula (III) was found to be absent.
The present invention has the following advantages over prior art methods:
♦ Avoids the formation of impurity of formula (III),
♦ Avoids the use for column chromatography for purification,
♦ Over all increase in the yield from 32% to 85% of N-acylation reaction and
♦ Tolvaptan is obtained with an overall yield of=55%.
The present invention is described herein below with reference to examples, which are illustrative only and should not be construed to limit the scope of the present invention in any manner.

EXAMPLE:
Example 1:
Preparation of 7-chloro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-
1-benzazepine (II):
2-Methyl-4-nirtobenzoic acid (200 gms) and thionyl chloride (219 gms) are suspended in toluene (800 ml) and heated to 60°C to 70°C till completion of reaction; excess thionyl chloride was distilled out by using toluene. Acetonitrile (1000 ml) and 7-chloro-1,2,3,4-tetrahydrobenzo[b]azepine-5-one (200 gms) was charged to the above residue at 25 to 30°C temperature and heated to reflux temperature for 2 to 6 hours. After completion, reaction mixture was cooled to 5°C to 10°C; product separating out was filtered and dried under reduced pressure to give a yield of 310 gms, Purity: > 99.5%.
Example 2:
Preparation of 7-chloro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-
1-benzazepine (II):
2-Methyl-4-nitrobenzoic acid (200gms) and thionyl chloride (219 gms) were suspended in toluene (800 ml) and heated to 60°C to 70°C till completion of reaction; excess thionyl chloride was distilled out by using toluene. Toluene (1000 ml) and 7-chloro-1,2,3, 4-tetrahydrobenzo[b]azepine-5-one (200 gms) were added to the above residue at 25 to 30°C temperature and heated to reflux temperature for 2 to 6 hours. After completion, reaction mixture was cooled to 5°C to 10°C; the product separating out was filtered and dried under reduced pressure to give a yield of 308 gms, Purity: > 99.6%.
Example 3:
Preparation of 7-chloro-l-(4-amino-2-methylbenzoyl)-5-oxo-2,3,4,5-tetrahydro-
lH-1-benzazepine:
7-chloro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (300 gms) and stannous chloride dihydrate (658 gms) are suspended in methanol (1500 ml) at 25°C to 30°C and heated to 65°C to 70°C for 2 to 6 hours. After reaction completion

methanol was distilled under reduced pressure below 70°C; to the residue water (6000 ml) and ethyl acetate (7500 ml) were added and pH adjusted to 7 to 8 with sodium carbonate (aqueous 20%). After layer separation organic layer was concentrated under reduce pressure and toluene (300 ml) charged and cooled to 5 to 10°C. Product filtered and washed with toluene and dried reduced pressure to give a yield of 205 gms, Purity: > 99.5%.
Example 4:
Preparation of 7-chloro-l-[2-methyl-4-[(2-methylbenzoyl) amino] benzoyl]-5-oxo-
2,3,4,5-tetrahydro-1H-1-benzazepine:
2-Methylbenzoic acid (100 gms) and thionyl chloride (131 gms) are suspended in toluene (800 ml) and heated to 60°C to 70°C till completion of reaction; excess thionyl chloride was distilled out by using toluene. 7-chloro-1-(4-amino-2-methylbenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepme (200 gms) and sodium carbonate (64.63 gms) were suspended in toluene (1600 ml) and was charged to the above residue in toluene at 25 to 30°C and heated to 65 to 75°C temperature for 8 to 12 hours. After completion, reaction mixture was cooled to 25°C to 30°C; filtered the solid and discard; toluene layer was distilled at below 70°C, to the residue dichloromethane (2000 ml) and methanol (200 ml) was added and stirred. The clear organic layer was used as such in the next step.
Example 5:
Preparation of Tolvaptan (I): To the organic layer (obtained form Example 4), sodium borohydride (10.4 gms) was added and stirred for 2 to 4 hours at 25 to 35°C. After completion of reaction, water (800 ml) charged to the reaction mixture and layer separated. Dichloromethane layer was distilled under reduced pressure and charged ethyl acetate (800 ml), aged for 2 hours. Product filtered and washed with ethyl acetate (200 ml). Crude product was further crystallized from methanol and dried under reduced pressure to give a yield of 180 gms, Purity: > 99.5%.

We claim,
1. A process for preparation of 7-chloro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine (II) of desired purity comprising, reaction of 7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine with 2-methyl-4-nitrobenzoyl chloride in an organic solvent and without a base at a temperature between 35°C and 90°C, cooling the mixture, filtering and drying.

2. The process as claimed in claim 1, wherein the organic solvent is selected from the group comprising of nitrile, aromatic hydrocarbon or ether.
3. The process as claimed in claim 2, wherein the nitrile is selected from acetonitrile, propionitrile and butyronitrile; aromatic hydrocarbon is selected from toluene, xylene but preferably toluene and the ether is dioxane.
4. The process as claimed in claim 1, wherein solvent employed is between 4 and 10 volumes per gram of 7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine but preferably between 5 and 8 volumes.
5. A process for preparation of tolvaptan (I) comprising,
i) reaction of 7-chloro-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine with 2-methyl-4-nitrobenzoyl chloride in an organic solvent and in absence of base at a temperature between 35°C and 90°C, cooling and isolating compound of formula (II),
ii) treating compound of formula (II) with stannous chloride to give 7-chloro-l-(4-amino-2-methylbenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine,

iii) acylating with 2-methylbenzoylchloride to obtain 7-chloro-l-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine and
iv) reducing with sodium borohydride to give tolvaptan (I) of desired purity.
6. The process as claimed in claim 5, wherein the organic solvent is selected from the group comprising of nitrile, aromatic hydrocarbon or ether.
7. The process as claimed in claim 6, wherein the nitrile is selected from acetonitrile, propionitrile and butyronitrile; aromatic hydrocarbon is selected from toluene, xylene but preferably toluene and ether is dioxane