FORM 2
THE PATENT ACT 1970
(39 of l970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10and rule 13)
1. TITLE OF THE INVENTION:
"The process for preparation of Clonazepam "
2. APPLICANT (S)
(a) NAME: Centaur Pharmaceuticals Pvt. ltd
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS:
Centaur Pharmaceuticals Pvt. ltd. Centaur House, shanti Nagar,Vakola, Santacruz (e) Mumbai 400055. Tel No. 022-66499144 Fax No. 022-66499108/112
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

The process for preparation of Clonazepam
Field of Invention:
This invention relates to an improved process for preparation of pharmaceutically active nitrobenzodiazepine derivative such as Clonazepam, is highly potent anticonvulsant, muscle relaxant, and anxiolytic properties having structural formula I:

Background of Invention:
Clonazepam (5-(2-chlorophenyl)-l,3-dihydro-7-nitrobenzo(l,4)-diazepin-2-one) is a nitrobenzodiazepine derivative with highly potent anticonvulsant, muscle relaxant, and anxiolytic properties. It is marketed by Roche under the trade-names Klonopin in the United States, and Ravotril in Chile. Other names like Rivotril or Rivatril are known throughout the large majority of the rest of the world. Clonazepam is a chlorinated derivative of nitrazepam and therefore a nitrobenzodiazepine. Clonazepam can be represented by above formula-I and was disclosed in US3121076 (hereinafter referred as '076' patent).

In US 3121076, disclosed the process for preparation of clonazepam in which, 5-nitro-(2-chlorophenyl)-3H-l,4-benzodiazepine-2-(lH)-one treated with cone, sulphuric acid and potassium nitrate and further neutralize by ammonia and finally crystallize by ethanol to yield a Clonazepam.
In CH 580,087 described the process for preparation of Nitrazepam in which, 2-chloroacetamido-5-nitrobenzopenone treated with urotropine in absolute ethanol and formic acid at reflux temperature to obtained crude nitrazepam which further by column chromatography in methylene dichloride is a solvent yield pure nitrazepam.
In Netherlands patent appl. 6, 405, 644,A 2-amino-2'-chloro-5-nitrobenzophenone in benzene is treated with bromoacetyl bromide, and a stream of dry air bubbling through the mixture, the reaction mixture is heated at 40°C for 2 h. Thereafter, the mixture is concentrated to dryness in vacuo, leaving about 143 g 2-(bromoacetamido)-2'-chloro-5-nitrobenzophenone.
The reported process for the preparation of Clonazepam in involves the usage of hazardous condition and or involves the tedious methodology of column chromatography
The present invention provides the novel process for preparation of nitrobenzodiazepine, derivatives which is commercially viable and allows the desired product to be obtained in improved yield without using any chromatographic technique. Also it avoids the usage of any environmentally hazardous chemicals, so this instant application having the industrial applicability which has became subject matter of the present invention.

Summary of Invention:
The principal object of present invention is to provide an improved process with
environment friendly and industrial reproducible without involving any chromatographic
technique as well as hazardous chemicals, thus minimize the operational problems.
The invention discloses the process for preparation of Clonazepam using the following
steps
a) reacting 2-(2-chloroacetamido)-5-2'-nitrobenzophenone with hexamine in mole ratio 1:2.5 in suitable aliphatic alcohol solvent at reflux temperature to obtained 2-(2-chloroacetamido)-5-2'-nitrobenzophenone-Hexamine complex (Scheme-I)
b) cyclizing 2-(2-chloroacetamido)-5-2,-nitrobenzophenone-Hexamine complex in suitable polar protic solvent in presence of aq. solution of inorganic salt at reflux temperature to obtain 5-(2-chlorophenyI)-l,3-dihydro-7-nitrobenzo(l?4)-diazepin-2-one (clonazepam)
c) further 5-(2-chlorophenyl)-l,3-dihydro-7-nitrobenzo(l,4)-diazepin-2-one (clonazepam) wash with hot water and crystallized from suitable aliphatic ester solvent to obtain pure clonazepam

Detail Description of invention
The description of present invention is given in details with certain preferred and optional embodiments, so that various aspect there of may be more fully understood and appreciated. The present invention provide an improved process for preparation of 5-(2-chIorophenyl)-1.3-dihydro-7-nitrobenzo(l,4)-diazepin-2-one (clonazepam) which has been depicted in below scheme-I.

According to embodiment 2-(2-chIoroacetamido)-5-2'-nitrobenzophenone react with hexamine in 1:2.5 mole ratio in suitable aliphatic alcohols such as methanol,

ethanol, propanol,iso-propanol,butanol or mixture thereof at reflux temperature for 5-10 hours to obtain 2-(2-chloroacetamido)-5-2,-nitrobenzophenone-Hexamine complex.
This step is cost effective and easy to carry out on industrial scale as reaction goes to completion to form 2-(2-chloroacetamido)-5-2'-Nitrobenzophenone-Hexamine complex in good yield ( %) ,herein reaction completion at low temperature due to solvent selectivity. The product obtained by above said method washed by the same said reaction solvent and followed by water.
The 2-(2-chloroacetamido)-5-2'-nitrobenzophenone-Hexamine complex cyclize in presence of aqu. solution of suitable inorganic salt such as magnesium chloride,calcium chloride,ammonium chloride,zinc chloride or mixture thereof in polar protic solvent such as water,methanol,ethanol,propanol,isopropanol or mixture thereof at reflux temprature for 10-12 hours to obtain 5-(2-chlorophenyl)-l,3-dihydro-7-nitrobenzo(l,4)-diazepin-2-one (clonazepam). This is key step of this process in which mild acidic solution of inorganic salt in a polar protic solvent exert easy cyclization without formation of side product.
The clonazepam which obtained from above said process further taken in 5 volume of hot water and filter which finally crystallize in suitable aliphatic ester solvent such as methyl aceate,ethyl acetate,propyl acetate, ethyl acetoacetate,isoamyl acetate or mixture therof to obtain pure clonezepam .

Example:
Charged 1.0 mole of 2-(2-chloroacetamido)-5-2'-nitrobenzophenone with 2.5 moles of hexamine in isopropanol at reflux temperature for 5 - 10 hrs. The product may then be isolated by filtration. The isolated product then washed with isopropanol followed by water. The wet solid product is taken in 15 volumes of methanol and was added 17 moles of ammonium chloride along with 1.5 volume of water. The reaction mixture was refluxed for 12 hrs. The reaction mixture was cooled and filtered. The solid was taken in 5 volumes of hot water and again filtered. The dried product was crystallized from ethyl acetate. Dry Weight: 51-53%
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative example and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

We claim:
1) A process for preparation of 5-(2-chlorophenyl)-13-dihydro-7-nitrobenzo(l,4)-diazepin-2-one (clonazepam) comprising the steps of:
a) reacting 2-(2-chloroacetamido)-5-2'-nitrobenzophenone with hexamine in mole ratio 1:2.5 in aliphatic alcohol at reflux temperature to obtained 2-(2-chloroacetamido)-5 -2' -nitrobenzophenone-Hexamine complex;
b) cyclizing 2-(2-chloroacetamido)-5-2'-nitrobenzophenone-Hexamine complex in polar protic solvent in presence of aq. solution of inorganic salt at reflux temperature to obtain 5-(2-chlorophenyl)-l,3-dihydro-7-nitrobenzo(l,4)-diazepin-2-one (clonazepam);
c) 5-(2-chlorophenyl)-l ,3_dihydro-7-nitrobenzo(l ,4)-diazepin-2-one (clonazepam) wash with hot water and concomitant to crystallized from aliphatic ester solvent to obtain pure clonazepam;
2) A process for preparing Clonazepam according to claim 1 wherein, aliphatic alcohols
used for formation of complex such as methanol, ethanol, propanoicso-propanol,butanol or
mixture thereof.
3) A process for preparing Clonazepam according to claim 1 wherein, aliphatic alcohol is
iso-prapanol.

4) A process for preparing Clonazepam according to claim 1 wherein, polar protic solvent used for cyclization are water.methanol,ethanol,propanolsisopropanol or mixture thereof.
5) A process for preparing Clonazepam according to claim 1 wherein, polar protic solvent is methanol.
6) A process for preparing Clonazepam according to claim 1 wherein, cyclization carried out in presence of aqueous solution of inorganic salt such as magnesium chloride,calcium chloride,ammonium chloride,zinc chloride or mixture thereof.
7) A process for preparing Clonazepam according to claim 1 wherein, inorganic salt is ammonium chloride.
8) A process for preparing Clonazepam according to claim 1 wherein, crystallization are carried out by using aliphatic ester solvent such as methyl aceate,ethyl acetate,propyl acetate, ethyl acetoacetate,isoamyl acetate or mixture therof.
9) A process for preparing Clonazepam according to claim 1 wherein, crystallization is carried out by using ethyl acetate.