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 7-Chloro-5-oxo-l-(2-methyl-4-aminobenzoyl)-2,3,4,5 -tetrahydro-1H-1 -benzazepine.
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
Present invention provides a novel process for the preparation of 7-Chloro-5-oxo-1 -(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro- 1H-l -benzazepine.
Background of the invention
7-Chloro-5-oxo-l-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-lH-l-benzazepine of Formula- I is a key intermediate used in the preparation of Tolvaptan (Formula- II).

Tolvaptan 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).
US patent 5753677 ('677 patent) discloses process for preparation of 7-Chloro-5-
oxo-1 -(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-l H-1 -benzazepine. The
process is depicted in Scheme-1.


Scheme-1
As per this Scheme-1, 7 -Chloro-5-oxo-l-(2-methyI-4- nitro benzoyl) -2,3,4,5-
tetrahydro-lH-1-benzazepine (Nitro amide) obtained by condensation of 7-
Chloro-5-oxo-2,3,4,5-tetrahydro-lH-I-benzazepine with 2-methyl-4-nitro benzoyl
chloride is reduced to 7-Chloro-5-oxo-l-(2-methyl-4-amino benzoyl)-2,3,4,5-
tetrahydro-lH-1-benzazepine (Formula-1) using Pd/C [Palladium on carbon] as
catalyst following process of reference example 2.
Journal article "Bioorganic & Medicinal Chemistry 7(1999) 1743-1754" utilizes
Stannous Chloride as a reducing agent. It also mentions use of Platinum oxide for
reduction of Nitro amide to 7-Chloro-5-oxo-l-(2-methyl-4-amino benzoyl)-
2,3,4,5-tetrahydro-IH-l-benzazepine (Formula-1).
All the prior arts processes described above suffer from draw backs.
Processes of patent '677 and above referred Journal article make use of noble
metal catalysts like Palladium and Platinum respectively. These catalysts are very
expensive. They require special equipments suitable for carrying out high pressure

reactions. Their use involves fire hazards. These short comings make them
industrially unfeasible.
The yield of stannous chloride reduction reaction as reported in above said Journal
article is very low (39%). Further stannous chloride reductions leads to formation
of high level of inorganic side products making them environmentally not
acceptable.
Most importantly use of Pd/C [Palladium on carbon] in reduction leads to
formation of dehalogenated side product (impurity) represented below by
formula- III:

Present invention provides a novel process for preparation of 7-Chloro-5-oxo-l-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-lH-l-benzazepine (formula- I) with high yield and purity. Further the process does not make use of expensive, hazardous reagents and special equipments making it industrially feasible.
Summary of the invention:
Present invention provides a novel, simple, cost effective , industrially feasible
and safe process for the preparation of 7-Chloro-5-oxo-l-(2-methyl-4-
aminobenzoyl)-2,3,4,5-tetrahydro-lH-l-benzazepine (Formula-1).
Accordingly the process of present invention for producing 7-Chloro-5-oxo-l-(2-
methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-lH-l-benzazepine, comprises
reducing a 7-Chloro-5-oxo-l-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-lH-l-enzazepine (Nitro amide) of following formula,


with iron and with an acid or an iron salt of an acid in solvent.
Suitable solvent is one or more selected from the group consisting of ethanol,
methanol, n-propanol, isopropanol, t-butanol and water.
Detailed Description of the invention:
A process for producing 7-Chloro-5-oxo-l-(2-methyI-4-aminobenzoyl)-2,3,4,5-tetrahydro-lH-1-benzazepine, comprises reducing a 7 -Chloro-5-oxo-l-(2-methyl-4- nitrobenzoyl) -2,3,4,5-tetrahydro-lH-l-benzazepine (Nitro amide) of following formula,

with iron and with an acid or an iron salt of an acid in solvent. Below is the schematic representation of present invention.


Starting material, Nitro Amide is obtainable by any conventional methods
disclosed in the prior arts mentioned in background part of this specification.
Iron for use in the process of present invention is preferably in the form of iron
powder.
An acid for use in process of present invention is one or more selected from the
group consisting of C1 to C3 organic acids and mineral acids.
A mineral acid is any inorganic acid. All mineral acids form hydrogen ions and
the conjugate base ions when dissolved in water. Most commonly used mineral
acids are hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid etc.
Examples of acid that can be employed in process of present invention include but
not limited to formic acid, acetic acid, propionic acid, hydrochloric acid, nitric
acid, sulfuric acid, phosphoric acid etc.
An iron salt of an acid preferably includes iron salt with mineral acid. Examples
of iron salt of mineral acid include ferrous sulphate, ferric chloride etc.

While any suitable solvent can be employed in this process, alcohol and water are
more preferable. These can be used either alone or in mixtures. Alcohols include
straight chain as well as branched alcohols. Alcohols like ethanol, methanol, n-
propanol, isopropanol, t-butanol etc. are the preferable alcohols for this process.
Any alcohol either alone or a combination of two or more alcohols with or
without water can be used as solvent. Methanol is more preferable alcohol for the
process of this invention.
Preferably the reaction is carried out a temperature in the range of 40°C to 120°C.
The product obtained can be isolated from reaction mass using conventional
techniques. These isolation techniques include but not limited to filtration;
evaporation of solvent, adding another solvent followed by filtration; isolation of
product from filtrate by adding anti-solvent etc.
The HPLC purity of compound of Formula- I obtained by the process of this
invention is more than 97.5%. The yield of compound of Formula-1 obtained by
the process of present invention is more than 80%.
The process of the present invention does not make use any hazardous, expensive
or toxic chemicals. Further it is simple and without any requirement of special
equipment and special flameproof facility.
The present invention is illustrated in more detail by the following Examples but
should not be construed to be limited thereof.
EXAMPLES:
Example 1: Preparation of 7-Chloro-5-oxo-l-(2-methyI-4-aminobenzoyl)-
2,3,4,5-tetrahydro-lH-l-benzazepine
7 -Chloro-5-oxo-l-(2-methyl-4- nitrobenzoyl) -2,3,4,5-tetrahydro-lH-l-benzazepine (120 gm.) was dissolved in methanol (1800 ml) and heated to 50-60°C. Iron powder (198 gm.) was added to it. Stirred for 10-15 minutes and then added acetic acid (1260 ml). This reaction mixture was stirred for 2 hours at 60-65°C. Reaction mixture was filtered and filtrate was collected and poured into ice water. The solid obtained was collected by filtration and dried to give 7-Chloro-5-

oxo-1 -(2-methyl-4-aminobenzoy l)-2,3,4,5-tetrahydro-1H-1 -benzazepine (100
gm).
Yield-83.33%
HPLC purity- 97.64 %

We Claim:
1) A process for producing 7-Chloro-5-oxo-l-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-lH-l-benzazepine, which comprises reducing a 7 -Chloro-5-oxo-l-(2-methy]-4- nitrobenzoyl) -2,3,4,5-tetrahydro-lH-l-benzazepine (Nitro amide) of following formula,

with iron and with an acid or an iron salt of an acid in solvent.
2) The process of claim 1, wherein the solvent is selected from alcohol, water and mixture thereof.
3) The process of claim 1, wherein the solvent is one or more selected from group consisting of ethanol, methanol, n-propanol, isopropanol, t-butanol, and water.
4) The process of claim 2 and 3, wherein the solvent is methanol.
5) The process of claim 2 and 3, wherein the solvent is water.
6) The process of claim 1, wherein iron is added in the form of powder.
7) The process of claim 1, wherein acid is one or more selected from the group consisting of C1 to C3 organic acids and mineral acids.

8) The process of claim 1 and 7 wherein, acid is acetic acid.
9) The process of claim 1 wherein, iron salt of an acid is iron salt with mineral acid.
10) The process of claim 9 wherein, the iron salt of mineral acid is ferrous sulphate.
11) The process of claim 1 wherein, the reduction is carried out at temperature in the range of 40°C to l20°C.