FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION:
A process for the preparation of benzazepine derivative.
APPLICANT:
(a) NAME: RPG LIFE SCIENCES LIMITED
(b) NATIONALITY: INDIAN COMPANY
(c) ADDRESS: RPG HOUSE, 463,
DR. ANNIE BESANT ROAD, WORLI, MUMBAI, MAHARASHTRA, INDIA. PIN CODE: 400 030. Phone:+91 22 2498 1650/1651, Fax:+91 22 2497 0127
PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field of invention
The present invention relates to a novel process for preparation of 7- chloro-5-hydroxy-l-[2-methyl-4-(2-rnethylbenzoylamino) benzoyl]-2, 3, 4, 5-tetrahydro-lH-1-benzazipine.
Background of the invention
It is known that Tolvaptan of formula 1, chemically known as 7- chloro-5-hydroxy-I-[2-methyl-4-(2-methylbenzoylamino) benzoyl]-2, 3, 4, 5-tetrahydro-lH-1-benzazipine also known as OPC-41061, is a selective, competitive 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). Tolvaptan is structurally represented as below.

Tolvaptan has been approved by the U.S. Food and Drug Administration (FDA)
on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name
Sam sea.
Indian patent application 1577/CHE/2011 gave schematic representation of the
process for synthesizing benzazepine and its derivatives which is earlier disclosed
in US5258510.
Scientific journal, Bioorganic & Medicinal Chemistry 7 (1999), pg. (1743-1754)
disclosed a process for synthesizing Tolvaptan (Formula-1) from 7- chloro-l-[2-

methyl-4-(2-methylbenzoylamino) benzoyl]- 5 oxo-2, 3, 4, 5-tetrahydro-lH-l-benzazipine (Formula 2) in 30% yield (scheme 1). Scheme 1:

The solvent used for this reaction is methanol. Sodium borohydride is used as hydrogenating agent in an amount of 1.5 moles per 1 mole of the formula 2. The isolated yield is only 30%. Purity data is not mentioned in the said journal [see the page no.1753, right column, 1st paragraph, compound 32]. In both the above processes along with low yield, the dehalogenated impurity which is chemically known as 5-hydroxy-l-[2-methyl-4-(2-methyIbenzoylamino) benzoyl]-2,3,4,5-tetrahydro-lH-l-benzazipine (Formula 3) is also generated at higher levels.

Also, preparation of Tolvaptan (Formula-1) from 7- chloro-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]- 5 oxo-2, 3, 4, 5-tetrahydro-lH-l-benzazipine (Formula 2) using hydrogenating agent is disclosed in US patent US8273735 ('735 patent) (Scheme-2). The hydrogenating agent is used in an amount of 0.25 to 1 moles and more preferably 0.25 to 0.5 moles per 1 mole of the formula 2.

This patent focuses on limiting the quantity of hydrogenating agent from 0.25 to lmole per 1 mole of formula 2 in order to minimize the generation of dehalogenated impurity (Formula 3) in the said preparation.

The processes involving hydrogenating agents as disclosed in example 2 of '735
patent are exothermic in nature. Such exothermic processes involving rise in
temperature are not safe from industrial prospective.
There is need to develop a novel process for making Tolvaptan which is safe and
high yielding.
The inventors of the present invention developed a novel, safe, industrially
feasible and efficient process for the preparation of Tolvaptan with high yield and
quality with dehalogenating impurity less than 0.1% by weight.
Summary of the invention:
Present invention relates to novel, safe , industrially feasible and efficient process for the preparation of Tolvaptan (Formula 1) from 7- chloro-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]- 5 oxo-2, 3, 4, 5-tetrahydro-lH-l-benzazipine (Formula 2). Schematically shown in following scheme 3:


Present invention in first aspect provides a process for producing?- chloro-5-hydroxy-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]-2, 3, 4, 5-tetrahydro-lH-1-benzazipine (Formula-1), which comprises reducing a 7- chloro-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]- 5 oxo-2, 3, 4, 5-tetrahydro-lH-l-benzazipine of the formula 2

using hydrogenating agent selected from the group consisting of lithium
borohydride, sodium borohydride, zinc borohydride and potassium borohydride in
a solvent mixture containing alcohol and water.
The alcohol and water in process are taken in proportion such that the percentage
of water in the solvent mixture containing alcohol and water is in the range of 5%
to 30% both inclusive.
The process of this invention gives more than 80% yield. The dehalogenated
impurity generation in the process is less than 0.1%.
Another aspect of the invention is to provide a process for producing 7- chloro-5-
hydroxy-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]-2, 3, 4, 5-tetrahydro-

lH-1-benzazipine (Formula-1), which comprises reducing a 7- chloro-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]- 5 oxo-2, 3, 4, 5-tetrahydro-lH-l-benzazipine of the Formula 2

using hydrogenating agent sodium borohydride in a solvent mixture containing alcohol and water.
The alcohol in solvent mixture is one or more selected from the group consisting of methanol, ethanol, n-propanol, isopropanol and t-butanol. The alcohol and water in process are taken in proportion such that the percentage of water in the solvent mixture containing alcohol and water is in the range of 5% to 30% both inclusive. Sodium borohydride is added in amount of about 0.5 to about 1.5 moles, more preferably about 1.2 to about 1.4 per 1 mole of Formula 2. This process gives more than 80% yield. The dehalogenated impurity generation in the process is less than 0.1%.
Yet another advantage of the present invention is obtaining pure Tolvaptan (Formula 1) with dehalogenated impurity (Formula 3) less than 0.1% by weight. Dehalogenated impurity limit in pharmaceutical product is crucial and once formed, this impurity cannot be easily removed from the product. Thus, the process of current invention is advantageous in limiting this impurity.
Detailed Description of the invention:
Present invention provides a novel, safe , industrially feasible and efficient process for the preparation of 7- chloro-5-hydroxy-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]-2, 3, 4, 5-tetrahydro-lH-l-benzazipine (Formula

1). The yield obtained in this process is high. The product has high purity. The dehalogenated impurity (Formula 3) generation in this process is less than 0.1% by weight.
In Tolvaptan, the dehalogenated imurity once formed more than 0.1% by weight is very difficult to remove by any conventional method of purification. Several purifications to reduce this impurity lead to yield loss and add up extra cost. Present invention provides a process for producing 7- chloro-5-hydroxy-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]-2, 3, 4, 5-tetrahydro-lH-l-benzazipine (Formula-1), which comprises reducing a 7- chloro-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]- 5 oxo-2, 3, 4, 5-tetrahydro-lH-l-benzazipine of the formula 2

using hydrogenating agent selected from the group consisting of lithium borohydride, sodium borohydride, zinc borohydride and potassium borohydride in a solvent mixture containing alcohol and water.
The starting material that is 7- chloro-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]- 5 oxo-2, 3, 4, 5-tetrahydro-lH-l-benzazipine (Formula 2) used for preparation of Tolvaptan is obtainable by any conventional methods disclosed in the prior arts mentioned in background part of this specification. This starting material is dissolved in solvent mixture of alcohol and water. The alcohol and water in process are taken in proportion such that the percentage of water in the solvent mixture containing alcohol and water is in the range of 5% to 30% both inclusive. More preferably, it is in the range of 10% to 20% both inclusive. The examples of alcohol solvents include methanol, ethanol, n-

propanol, isopropanol and t-butanol or mixture thereof. Hydrogenating agent for
use in this process include lithium borohydride, sodium borohydride, zinc
borohydride and potassium borohydride. Preferably, sodium borohydride can be
employed in this process. Sodium borohydride is added in an amount of about 0.5
to about 1.5 moles, more preferably 1.2 to 1.4 moles per 1 mole of formula 2.
After completion of reaction if required acid may be added to reaction mixture to
neutralize excess of alkalinity or un-consumed hydrogenating agent. Hydrochloric
acid and sulfuric acid or any other suitable mineral acid can be used for this
purpose.
The solid obtained is isolated by conventional technique for example by cooling
the reaction mixture, filtering, concentrating and extracting the product etc.
This process gives more than 80% yield.
The process of current invention limits the dehalogentaed impurity below 0.1%.
Example 2 of US '735 patent disclosed the conversion of formula 2 to formula 1
in methanol using hydrogenating agent in most preferable range of 0.25 to 0.5
moles per 1 mole of compound of formula 2. This process is exothermic in nature
and if reaction is carried out at lower temperature to curtail exotherm, reaction
rate is slow leading to incomplete reaction or formation of side product.
The process of current invetion does not generate exotherm making it safe and
industrially scalable. It can be carried out at room temperature. Further it is not
required to restrict the amount of hydrogenating agent to any particular amount
range.
Accordingly, the invention provides a process for producing 7- chloro-5-
hydroxy-l-[2-methyl-4-(2-methyIbenzoyIamino) benzoyI]-2, 3, 4, 5-tetrahydro-
lH-1-benzazipine (Formula-1), which comprises reducing 7- chloro-l-[2-methyl-
4-(2-methy lbenzoy lam ino) benzoyl]- 5 oxo-2, 3, 4, 5 -tetrahydro-1H-1 -
benzazipine of the formula 2


using a hydrogenating agent, sodium borohydride in a solvent mixture containing
alcohol and water.
The alcohol and water in process are taken in proportion such that the percentage
of water in the solvent mixture containing alcohol and water is in the range of 5%
to 30% both inclusive. More preferably, it is in the range of 10% to 20% both
inclusive. The examples of alcohol solvents include methanol, ethanol, n-
propanol, isopropanol and t-butanol or mixture thereof. More preferably alcohol
in the solvent mixture is methanol.
Sodium borohydride is added in an amount of about 0.5 to about 1.5 moles, more
preferably 1.2 to 1.4 moles per 1 mole of formula 2.
If required after completion of reaction acid may be added to reaction mixture to
neutralize excess alkalinity or unconsumed hydrogenating agent. Hydrochloric
acid and sulfuric acid or any other suitable mineral acid can be used for this
purpose.
The solid obtained is isolated by conventional technique for example by cooling
the reaction mixture, filtering, concentrating and extracting the product.
This process gives more than 80% yield.
The dehalogenated impurity generation in process of current invention is less than
0.1%.
The present invention is illustrated in more detail by the following Examples but
should not be construed to be limited thereof.
EXAMPLES:

EXAMPLE-1:
7- chloro-l-[2-methyl-4-(2-methylbenzoyiamino) benzoyl]- 5 oxo-2, 3, 4, 5-tetrahydro-lH-1-benzazipine (6.5 gm.) was dissolved in methanol (104 ml) & water (10.4 ml) and then added sodium borohydride (0.385 gm.) at 30°C and the reaction mixture was stirred for lhr. To the reaction mixture was added hydrochloric acid (39 ml). Then the reaction mixture was stirred for 2 hours. The solid obtained was collected by filtration and dried to give 7- chloro-5-hydroxy-l-[2-methyl-4-(2-methylbenzoyl amino) benzoyl]-2, 3, 4, 5-tetrahydro-lH-l-benzazipine (5.8 gm.) Yield-89.23% Purity by HPLC-99.85% Dehalogenated Impurity-0.07%
EXAMPLE-2:
7- chloro-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]- 5 oxo-2, 3, 4, 5-tetrahydro-lH-1-benzazipine (25 gm.) was dissolved in methanol (600 ml) & water (180 ml) and then added sodium borohydride (2.95 gm.) at 25°C and the reaction mixture was stirred for lhr. To the reaction mixture was added hydrochloric acid (150 ml). Then the reaction mixture was stirred for 2 hours. The solid obtained was collected by filtration and dried to give 7- chloro-5-hydroxy-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]-2, 3, 4, 5-tetrahydro-lH-l-benzazipine (22.8 gm.) Yield-91.2% Purity by HPLC- 98.92% Dehalogenated Impurity-0.01%
EXAMPLE-3:
7- chloro-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]- 5 oxo-2, 3, 4, 5-tetrahydro-lH-1-benzazipine (2 gm.) was dissolved in n-propanol (80 ml) & water (12 ml) and then added sodium borohydride (0.253 gm.) at 35°C and the reaction mixture was stirred for lhr. To the reaction mixture was added hydrochloric acid

(12 ml). Then the reaction mixture was stirred for 1 hour. The solid obtained was
collected by filtration and dried to give 7- chloro-5-hydroxy-l-[2-methyI-4-(2-
methylbenzoylamino) benzoyl]-2, 3,4, 5-tetrahydro-lH-I-benzazipine (1.65 gm.)
Yield-82.5%
Purity by HPLC-99.73%
Dehalogenated Impurity- 0.01%
EXAMPLE -4:
7- chloro-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]- 5 oxo-2, 3, 4, 5-
tetrahydro-lH-1-benzazipine (2 gm) was dissolved in methanol (48 ml) & water
(12 ml) and then added sodium borohydride (0.236 gm.) at 25°C and the reaction
mixture was stirred for lhr. To the reaction mixture was added water (12 ml) and
stirred for 2 hours at 25-30°C. The solid obtained was collected by filtration and
dried to give 7- chloro-5-hydroxy-l-[2-methyl-4-(2-methylbenzoylamino)
benzoyl]-2, 3, 4, 5-tetrahydro-lH-l-benzazipine (1.70 gm.)
Yield-85%
Purity by HPLC-99.65%
Dehalogenated Impurity- below detection level
EXAMPLE -5:
7- chioro-l-[2-methyl-4-(2-methyIbenzoyIamino) benzoyl]- 5 oxo-2, 3, 4, 5-tetrahydro-lH-1-benzazipine (5 gm.) was dissolved in methanol(40 ml) & water (6 ml) and then added sodium borohydride (0.21 lgm.) at 30°C and the reaction mixture was stirred for lhr. To the reaction mixture was added hydrochloric acid (30 ml). Then the reaction mixture was stirred for 2 hours. The solid obtained was collected by filtration and dried to give 7- chloro-5-hydroxy-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]-2, 3, 4, 5-tetrahydro-lH-l-benzazipine (4.55 gm.)
Yield-91.0%
Purity by HPLC-99.08%

Dehalogenated Impurity- 0.03%

We Claims:
1. A process for producing 7- chloro-5-hydroxy-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]-2, 3, 4, 5-tetrahydro-lH-l-benzazipine, which comprises reducing a 7- chloro-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]- 5 oxo-2, 3, 4, 5-tetrahydro-lH-l-benzazipine of the formula 2

using a hydrogenating agent selected from the group consisting of lithium borohydride, sodium borohydride, zinc borohydride and potassium borohydride in a solvent mixture containing alcohol and water.
2. The process claimed in claim 1 wherein, the alcohol in the solvent mixture is one or more selected from the group consisting of methanol, ethanol, n-propanol, isopropanol and t-butanol.
3. The process claimed in claim 1 and 2 wherein, the alcohol is methanol.
4. The process claimed in claim 1 wherein, the percentage of water in the solvent mixture containing alcohol and water is in the range of 5% to 30% both inclusive.
5. The process claimed in claim 1 and 4 wherein, the percentage of water in the solvent mixture containing alcohol and water is in the range of 10% to 20% both inclusive.

6. The process claimed in claim 1 wherein, hydrogenating agent is sodium borohydride.
7. The process claimed in claim 1 and 6 wherein, hydrogenating agent is sodium borohydride in an amount from about 0.5 to about 1.5 moles per 1 mole of formula 2.
8. The process claimed in claim 1 and 7 wherein, hydrogenating agent is sodium borohydride in an amount from about 1.2 to about 1.4 moles per 1 mole of formula 2.
9. A process for producing 7- chloro-5-hydroxy-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]-2, 3, 4, 5-tetrahydro-lH-l-benzazipine, which comprises reducing a 7- chloro-l-[2-methyl-4-(2-methylbenzoylamino) benzoyl]- 5 oxo-2, 3, 4, 5-tetrahydro-lH-l-benzazipine of the formula 2

using a hydrogenating agent sodium borohydride in a solvent mixture containing alcohol and water.
10. The process claimed in claim 9 wherein, the alcohol in the solvent mixture is one or more selected from the group consisting of methanol, ethanol, n-propanol, isopropanol and t-butanol.

11. The process claimed in claim 9 and 10 wherein, the alcohol is methanol.
12. The process claimed in claim 9 wherein, the percentage of water in the solvent mixture containing alcohol and water is in the range of 5% to 30% both inclusive.
13. The process claimed in claim 9 and 12 wherein, the percentage of water in the solvent mixture containing alcohol and water is in the range of 10% to 20% both inclusive.
14. The process claimed in claim 9 wherein, sodium borohydride is in an amount from about 0.5 to about 1.5 moles per 1 mole of formula 2.
15. The process claimed in claim 14 wherein, sodium borohydride is in the amount of about 1.2 to about 1.4 moles per 1 mole of formula 2.