FORM2
THE PATENTS ACT, 1970
(39 of 1970) &
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - AN IMPROVED PROCESS FOR THE
PREPARATION OF CLONIDINE
HYDROCHLORIDE
2. Applicant(s)
(a) NAME : ALEMBIC LIMITED
(b) NATIONALITY An Indian Company.
(c) ADDRESS : Alembic Campus, Alembic Road, Vadodara - 390 003, Gujarat, India.
3. PREAMBLE TO THE DESCRIPTION
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 Clonidine hydrochloride.

Background of the invention:
The chemical name of Clonidine hydrochloride is 2-[(2, 6-dichlorophenyl)imino]-2-imidazoline hydrochloride and molecular formula is C9H9CI2N3.HCI and molecular weight is 266.55. The drug Clonidine hydrochloride is being sold by Boehringer under tradename CATAPRES® as a tablet.
Clonidine (Catapres) is an antihypertensive drug that is effective in the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). It has also been used to treat Tourette syndrome by reducing tics, improving hyperactivity and decreasing obsessive-compulsive symptoms. Clonidine is an alpha-adrenergic stimulating agent that acts on presynaptic neurons to inhibit norepinephrine activity.
U.S. Patent No. 3,202,660 describes a process for the preparation of 2-(2, 6-dichloroanilino)-l, 3-diazacyclopentene-(2) i.e. Clonidine or its salt, reacting N-(2, 6-dichlorophenyl) thiourea with methyl iodide to obtain N-(2, 6-dichlorophenyl)-S-methyl-isothiouronium hydroiodide which further reacted with ethylenediamine at 130-150°C followed by the treatment of dilute acetic acid and NaOH to obtain 2-(2, 6-dichloroanilino)-l, 3-diazacyclopentene-(2). The process is schematically depicted in the following Scheme-1:
2

Scheme-1

.

However, the above mentioned process provides the final product with unsatisfactory yield and involves high reaction temperature. Further, isolation and purification of 2-(2, 6-dichloroanilino)-l, 3-diazacyclopentene-(2) are also operationally difficult. These disadvantages make the overall process less suitable at an industrial scale.
U.S. Patent No. 3,468,887 discloses the preparation of 2-(2, 6-dichloroanilino)-l, 3-diazacyclopentene-(2) or its salts, in which 2, 6-dichloroaniline is refluxed with formic acid to obtain 2, 6-dichlorophenylformamide which is reacted with the mixture of sulfuryl chloride and thionyl chloride to obtain 2, 6-dichlorophenylisocyanide dichloride which is further reacted with ethylenediamine followed by the acidification with ethereal hydrochloride to obtain 2-(2,6-
3

dichlorophenylamino)-l,3-diazacyclopentene-(2) hydrochloride. The process is schematically depicted in the following Scheme-2:

Similar drawbacks are also associated with the above mentioned process and results in unsatisfactory yield and purity. Moreover, this process involves fractional distillation for isolation which makes this process difficult to handle at an industrial scale.
In summary, process disclosed in prior art for the preparation of Clonidine hydrochloride, are tedious, time consuming and operationally difficult at industrial scale. Therefore, there exists a need for improvement in the process which devoids the above mentioned drawbacks.
4

The present inventors have directed their research work toward developing an improved process which solves the above mentioned problems that is associated with the existing process.
Unexpectedly, the present inventors have found an improved process for preparing Clonidine hydrochloride, which is operationally simple, cost-effective, easy to handle and feasible at commercial scale.
Object of the invention:
It is therefore an object of the present invention to provide an improved process for the preparation of Clonidine hydrochloride.
Another object of the present invention is to provide a process for the preparation of Clonidine hydrochloride with improved yield and purity.
A further object of the present invention is to provide an improved process for preparing Clonidine hydrochloride, which is operationally simple, cost-effective, easy to handle and feasible at commercial scale.
Summary of the Invention:
Accordingly, the present invention provides an improved process for the preparation
of Clonidine hydrochloride comprising steps of:
(i) heating 2, 6-dichloroaniline with the mixture of acetic anhydride and formic
acid to obtain N-(2,6-dichlorophenyl) formamide (ii) carrying out an one-pot reaction without isolating the intermediates
comprising steps of a) reacting N-(2,6-dichlorophenyl) formamide with sulfuryl chloride in the
presence of thionyl chloride to obtain 2, 6-dichlorophenylisocyanide
dichloride
5

b) cyclizing unisolated 2, 6-dichlorophenylisocyanide dichloride obtained in step (ii) (a), with ethylenediamine in the presence of inert solvent to obtain 2-(2,6-dichlorophenylamino)-1,3-diazacyclopentene-(2)
c) treating unisolated 2-(2,6-dichlorophenylamino)-l,3-diazacyclopentene-(2) obtained in step (iii) (b), with alcoholic hydrochloride to obtain Clonidine hydrochloride
Detailed description of the invention:
Accordingly, the present invention provides an improved process for the preparation
of Clonidine hydrochloride comprising steps of:
(i) heating 2, 6-dichloroaniline with the mixture of acetic anhydride and formic
acid to obtain N-(2,6-dichlorophenyl) formamide (ii) carrying out an one-pot reaction without isolating the intermediates
comprising steps of
a) reacting N-(2,6-dichlorophenyl) formamide with sulfuryl chloride in the presence of thionyl chloride to obtain 2, 6-dichlorophenylisocyanide dichloride
b) cyclizing unisolated 2, 6-dichlorophenylisocyanide dichloride obtained in step (ii) (a), with ethylenediamine in the presence of inert solvent to obtain 2-(2,6-dichlorophenylamino)-l,3-diazacyclopentene-(2)
c) treating unisolated 2-(2,6-dichlorophenylamino)-l,3-diazacyclopentene-(2) obtained in step (iii) (b), with alcoholic hydrochloride to obtain Clonidine hydrochloride
The process in step (i) is carried out at a temperature in a range from about 30°C to about 80°C for 1-10 hrs. After completion of the reaction, water is added in the reaction mixture and solid material is filtered, washed with water and then with dichloromethane. The solid material was dried at 40-80°C to obtain N-(2, 6-dichlorophenyl) formamide.
6

The meaning of one-pot reaction as mentioned hereinabove is that reaction is carried out without isolating the intermediates. The subsequent reaction is taking place in the same pot.
The process in step (ii) (a), wherein sulfuryl chloride is added to a pre-cooled mixture of N-(2, 6-dichlorophenyl) formamide and thionyl chloride and reaction mixture is heated to 40-60°C for 4-15 hrs. After completion of the reaction, thionyl chloride is distilled out under reduced pressure and removed completely by adding toluene to obtain 2, 6-dichlorophenylisocyanide dichloride which is not isolated and proceeds for the process of step (b).
The process in step (ii) (b), wherein cyclization of 2, 6-dichlorophenylisocyanide dichloride which is not isolated in step (ii), with ethylenediamine in the presence of inert solvent to obtain 2-(2,6-dichlorophenylamino)-l,3-diazacyclopentene-(2) which is not isolated and proceeds for the process of step (c).
The suitable inert solvent like chlorinated hydrocarbon such as MDC, EDC, chloroform; ether such as diethyl ether; aromatic hydrocarbons such as toluene, benzene, xylene and the like. The preferable inert solvent is dichloromethane.
The process in step (ii) (c), wherein 2-(2, 6-dichlorophenylamino)-l, 3-diazacyclopentene-(2) which is not isolated, is treated with alcoholic hydrochloride and reaction mass is cooled, filtered, washed with dichloromethane and dried at 40-80°C to obtain Clonidine hydrochloride.
The suitable alcoholic hydrochloride is used in process of step (iv) (c) wherein alcohol are selected from methanol, ethanol, butanol, propanol, isopropanol and like or mixture thereof. The preferable alcohol is isopropanol.
Unexpectedly, the present inventors observed a significant improvement in yield and purity of the final products by the process of present invention.
7

Following is the comparison of the results of Clonidine hydrochloride as prepared by the present invention vis-a-vis Clonidine hydrochloride as prepared by the process as disclosed in prior art i.e. U.S. Patent No. 3,468,887.
Table-1

S.No. Process Overall Yield (%) Purity (%)
1 Clonidine hydrochloride as per prior art i.e. U.S. Patent No. 3,468,887 9.04 Not mentioned
2 Clonidine hydrochloride as per the present invention 63.46 99.9
Overall Yield (%) with respect to 2, 6-dichloroaniline (starting material) Following is the comparison of the results of yield of Clonidine hydrochloride and its intermediate as prepared by the process as disclosed in prior art i.e. U.S. Patent No. 3,468,887 with Clonidine hydrochloride as prepared by the present invention.
Table-2

Stage Prior art i.e. U.S. Patent No. 3,468,887- Yield (%) Present invention-Yield (%)
Step-1 64.6 95
Step-2 42 In-situ
Step-3 (Clonidine) 34 In-situ
Step-4 (Clonidine HC1) 98 (w.r. t. step-3) 71.56 (w.r.t. step-1)
Overall yield 9.04 63.4
Overall Yield (%) with respect to 2, 6-dichloroaniline (starting material)
8

In summary, the results clearly depicts that the present invention significantly improves the purity and yield of Clonidine hydrochloride.
Moreover, the process of the present invention has following advantages:
• It provides a process which is economical, operational and industrially applicable.
• The process is simple and easy to handle and does not require special handling care or critical temperature conditions.
• It reduces the time period of the reaction.
The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.
Example-1:
Process for Clonidine Hydrochloride
Stage-I: Preparation ofN-(2, 6-dichlorophenyl) formamide
2, 6-Dichloroaniline (100 g) in a mixture of acetic anhydride (175 ml) and formic acid (52 ml) was heated at 30-80°C for 1-10 hrs. Water (600 ml) was added to reaction mixture and the solid material was filtered, washed with water (400 ml) and then with dichloromethane (200 ml). The material was dried at 40-80°C to obtain 1 l0g of N-(2, 6-dichlorophenyl) formamide.
HPLC purity: -99.8%
Stage-II: Preparation of Clonidine Hydrochloride
Sulfuryl chloride (51 ml) was added to a pre-cooled mixture of N-(2, 6-dichlorophenyl) formamide (100 g) in thionyl chloride (500 ml). The reaction mixture was heated to 40-60°C for 4-15 hrs. Thionyl chloride was distilled out under reduced
9

pressure and removed completely by adding toluene (100 ml) to the remaining mass and distilling out. Dichloromethane (400 ml) was added to the residual mass and the mixture was cooled. Ethylenediamine (70 ml) was added to the reaction mixture and stirred for 2-24 hrs. The reaction mixture was filtered and to the filtrate was added IPA.HC1 (133 ml). The reaction mixture was then cooled to obtain Clonidine hydrochloride. The solid product was filtered, washed with dichloromethane (100 ml X 2) and was finally dried at 40-80°C to obtain l00g of the product.
HPLC purity: -99.9%
10

We claim:
1. A process for the preparation of Clonidine hydrochloride comprising steps of:
(i) heating 2, 6-dichloroaniline with the mixture of acetic anhydride and
formic acid to obtain N-(2,6-dichlorophenyl) formamide (ii) carrying out an one-pot reaction without isolating the intermediates comprising steps of
a) reacting N-(2,6-dichlorophenyl) formamide with sulfuryl chloride in the presence of thionyl chloride to obtain 2, 6-dichlorophenylisocyanide dichloride
b) cyclizing unisolated 2, 6-dichlorophenylisocyanide dichloride obtained in step (ii) (a), with ethylenediamine in the presence of inert solvent to obtain 2-(2,6-dichlorophenylamino)-1,3-diazacyclopentene-(2)
c) treating unisolated 2-(2,6-dichlorophenylamino)-l,3-diazacyclopentene-(2) obtained in step (iii) (b), with alcoholic hydrochloride to obtain Clonidine hydrochloride.

2. The process of claim 1, wherein the reaction in step (i) is carried out at a temperature 30°C to 80°C for 1-10 hrs.
3. The process of claim 1, wherein the reaction in step (ii) (a) is carried out at temperature 40°C to 60°C for 4-15 hrs.
4. The process of claim 1, wherein the inert solvent in step (ii) (b) is selected from methylenedichloride (MDC), ethylenedichloride (EDC), chloroform, diethyl ether, toluene, benzene, xylene or mixture thereof.
5. The process of claim 1, wherein the alcoholic hydrochloride in step (ii) (c), wherein alcohol is selected from methanol, ethanol, butanol, propanol, isopropanol or mixture thereof.
Dated this 4th day of April 2006


11

Ashwini Sandu
Of S .Majumdar & Co. Applicant's Agent

Abstract
The present invention relates to provide an improved process for the preparation of Clonidine hydrochloride comprising steps of:
(i) heating 2, 6-dichloroaniline with the mixture of acetic anhydride and
formic acid to obtain N-(2,6-dichlorophenyl) formamide
(ii) carrying out an one-pot reaction without isolating the intermediates comprising steps of
a) reacting N-(2,6-dichlorophenyl) formamide with sulfuryl chloride in the presence of thionyl chloride to obtain 2, 6-dichlorophenylisocyanide dichloride
b) cyclizing unisolated 2, 6-dichlorophenylisocyanide dichloride obtained in step (ii) (a), with ethylenediamine in the presence of inert solvent to obtain 2-(2,6-dichlorophenylamino)-1,3-diazacyclopentene-(2)
c) treating unisolated 2-(2,6-dichlorophenylamino)-l,3-diazacyclopentene-(2) obtained in step (iii) (b), with alcoholic hydrochloride to obtain Clonidine hydrochloride.
12