FORM 2
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:
(b) NATIONALITY
(c) ADDRESS :

ALEMBIC LIMITED
An Indian Company
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:
Scheme-1


NH ^NH
^ .HI
MeOH; refluxed 2.5 hrs; solvent evaporated
CH3l

-CH,
isothiouronium hydroiodide (MP. 170°C)

NH2
H2N
heated 130-150X
dil acetic acid, NaOH, ♦ vacuum filtration



acidify in the presence of organic solvent and HCI
.HCI -*-

Clonidine hydrochloride (MP. 305°C)

Clonidine (MP. 130°C)

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



CI
Sulfuryl chloride, thionyl NH. chloride, 55-60°C CHO
NH2
formic acid, reflux, 100°C
recrystalization from benzene-ethanol
2,6-dichlorophenylformamide MP. 176-176.5°C
ci

,N^ ^Cl CI
2,6-dichlorophenyl-isocyanide-dichloride M.P. 65-68°C



benzene, ethylenediamine
ethereal HCI
<
recrystallization
from Methanol

MP. 316-318°C

MP. 136-138°C

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.
Furthermore, in prior art process forms acetyl impurity i.e. N-{2,6-dichlorophenyl)acetamide having structural formula given below during preparation of 2, 6-dichlorophenylformamide.



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.
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 with improved yield and purity.
Another 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.
Yet another object of the present invention is to provide a process for the preparation of N-(2,6-dichlorophenyl) formamide with improved yield and purity.


Further object of the present invention is to provide a novel process for the preparation of pivalic formic anhydride which is utilized as a formylation reagent for the preparation of N-(2,6-dichlorophenyl) formamide.
Summary of the Invention:
Accordingly, the present invention provides an improved process for the preparation
of Clonidine hydrochloride comprising steps of:
(i) reacting 2, 6-dichloroaniline with pivalic formic anhydride in the presence of
solvent 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
Another aspect of the present invention provides a process for the preparation of N-(2, 6-dichlorophenyl) formamide comprising a step of reacting 2, 6-dichloroaniline with pivalic formic anhydride in the presence of solvent to obtain N-(2, 6-dichlorophenyl) formamide.


Yet another aspect of the present invention provides a novel process for the preparation pivalic formic anhydride comprising a step of treating formic acid with pivaloyl chloride in the presence of base and solvent to obtain pivalic formic anhydride.
Detailed description of the invention:
Accordingly, the present invention provides an improved process for the preparation
of Clonidine hydrochloride comprising steps of:
(i) reacting 2, 6-dichloroaniline with pivalic formic anhydride in the presence of
solvent 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
The process in step (i) is carried out at a temperature in a range from about 0° to -10°C for 1-3 hrs. After completion of the reaction, water is added in the reaction mixture at 0° to 20°C followed by stirring at same temperature for 1 hr. The solid material is filtered and washed with water. The solid material is dried under vacuum at 25°-35°C to obtain N-(2, 6-dichlorophenyl) formamide.


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 methylene dichloride, ethylene dichloride, 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.


Another embodiment of the present invention provides a process for the preparation N-(2, 6-dichlorophenyl) formamide comprising a step of reacting 2, 6-dichloroaniline with pivalic formic anhydride in the presence of solvent to obtain N-(2, 6-dichlorophenyl) formamide.
The examples of the solvent mentioned hereinabove include but not limited to chlorinated hydrocarbon such as methylene dichloride, ethylene dichloride, chloroform; ether such as diethyl ether; aromatic hydrocarbons such as toluene, benzene, xylene and the like. The preferable inert solvent is dichloromethane.
Yet another embodiment of the present invention provides a novel process for the preparation pivalic formic anhydride comprising a step of treating formic acid with pivaloyl chloride in the presence of base and solvent to obtain pivalic formic anhydride which is used as formylating reagent for formylation of 2, 6-dichloro aniline.
The examples of the base mentioned hereinabove include but not limited to organic base such as triethyl amine, diethyl amine, methylamine, t-butylamine, pyrrolidine, di-N-propylamine, morpholine, n-butylamine, isopropylamine, piperidine, pyridine, picolines, luridines, collidines, NMM, NMP, 1,8 diazabicyclo [5,4,0] undec 7-ene (DBU), Tetramethyl guanidine (TMG), 1,4 diazabicyclo [2,2,2] octane (DABCO), 1,5-diazabicyclo [4,3,0] non-5-ene (DBN), dicyclo hexyl amine (DCHA) or inorganic base such as NH3, Mg(OH)2, CaCO3, MgCO3, Na2CO3, K2CO3, Li2CO3, CaCO3, MgCO3, NaHCO3, KHCO3, LiHCO3, NaOH, KOH, LiOH and the like or mixture thereof.
The examples of the solvent mentioned hereinabove include but not limited to ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and the like or


mixture thereof; aromatic hydrocarbons such as toluene, xylene and the like or mixture thereof; lower alcohols such as methanol, ethanol, isopropanol and the like or mixture thereof; polar solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dimethylacetamide and the like or mixture thereof.
Unexpectedly, the present inventors observed a significant improvement in yield and purity of the final products by the process of present invention.
Following is the comparison of the results of yield of N-(2,6-dichlorophenyl) formamide prepared by the process as disclosed in prior art with N-(2,6-dichlorophenyl) formamide as prepared by the present invention.
Table-1

Process Yield (%) Purity(%) Acetyl impurity (%)
Preparation of N-(2,6-dichlorophenyl) formamide using formic acid (Prior art) 64.6 Not mentioned Not formed
Preparation of N-(2,6-dichlorophenyl) formamide using acetic formic anhydride (Prior art) 87 99.40 0.40
Preparation of N-(2,6-dichlorophenyl) formamide using pivalic formic anhydride 98.12 99.92 Not detected
Overall Yield (%) with respect to 2, 6-dichloroaniline (starting material) In summary, the results clearly depicts that the present invention significantly improves the purity and yield of N-(2,6-dichlorophenyl) formamide as well as 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 the preparation of pivalic formic anhydride
The mixture of mixture of DCM (50 ml) and formic acid (14.11 g) was stirred and followed by addition of triethyl amine (17.25 g) and pivaloyl chloride (18.68 g) respectively at 0 to -10°C under nitrogen atmosphere. The resultant mixture was stirred for 1-3 hrs at 0 to -10°C. The resulting reaction mixture was used for formylation of 2, 6-dichloro aniline.
Example-2:
Process for the preparation of Clonidine Hydrochloride
Stage-I: Preparation of N-(2, 6-dichlorophenyl) formamide
2, 6-dichloroaniline (10 g) was added portion wise to the stirred pivalic formic anhydride solution in dichloromethane at 0 to -10°C. The reaction mixture was stirred at 0 to -10°C for further 60 to 180 min. After completion of reaction, D I water (50


ml) was added at 0 to 20°C. The content was stirred at same temperature for 60 min,
filtered and washed with D I water (4 x 20 ml). The resultant wet material was dried
under vacuum 25 to 35°C up to moisture not more than 1.0% (w/w)
Yield: 11.5 g
Purity: 99.92 %
Acetyl impurity: Not detected
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 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%


WE CLAIM;
1. A process for the preparation of Clonidine hydrochloride comprising steps of:
(i) reacting 2, 6-dichloroaniline with pivalic formic anhydride in the presence
of solvent 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 solvent in step (i) is selected from group comprising of the chlorinated hydrocarbon, ether, aromatic hydrocarbon or mixture thereof.
3. The process of claim 2, wherein the solvent is selected from group comprising of methylene dichloride, ethylene dichloride, chloroform, diethyl ether, toluene, benzene, xylene or mixture thereof.
4. The process of claim 1, wherein the reaction in step (i) is carried out at a temperature 0°C to -10°C for 1-3 hrs.


5. 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.
6. 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.
7. 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.
8. A process for the preparation of N-(2, 6-dichlorophenyl) formamide comprising a step of reacting 2, 6-dichloroaniline with pivalic formic anhydride in the presence of solvent to obtain N-(2,6-dichlorophenyl) formamide.
9. The process of claim 8, wherein the solvent is selected from group comprising of the chlorinated hydrocarbon, ether, aromatic hydrocarbon or mixture thereof.
10. The process of claim 9, wherein the solvent is selected from group comprising of methylene dichloride, ethylene dichloride, chloroform, diethyl ether, toluene, benzene, xylene or mixture thereof.
11. A process for the preparation pivalic formic anhydride comprising a step of treating formic acid with pivaloyl chloride in the presence of base and solvent to obtain pivalic formic anhydride.


12. A process of claim 11, wherein base is selected from group comprising of organic base such as triethyl amine, diethyl amine, methylamine, t-butylamine, pyrrolidine, di-N-propylamine, morpholine, n-butylamine, isopropylamine, piperidine, pyridine, picolines, luridines, collidines, NMM, NMP, 1,8 diazabicyclo [5,4,0] undec 7-ene (DBU), Tetramethyl guanidine (TMG), 1,4 diazabicyclo [2,2,2] octane (DABCO), 1,5-diazabicyclo [4,3,0] non-5-ene (DBN), dicyclo hexyl amine (DCHA) or inorganic base such as NH3, Mg(OH)2, CaCO3, MgCO3, Na2CO3, K2CO3, Li2CO3, CaCO3, MgCO3, NaHC03, KHCO3, LiHCO3, NaOH, KOH, LiOH or mixture thereof.
13. A process of claim 11, wherein solvent is selected from the group comprising of ethers, aromatic hydrocarbons, lower alcohols, polar solvents or mixture thereof.
14. A process of claim 13, wherein solvent is selected from the group comprising of dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, toluene, xylene, methanol, ethanol, isopropanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dimethylacetamide or mixture thereof.
15. Clonidine hydrochloride having acetyl impurity less than 0.05%.
Dated this 13th day of December 2007

ABSTRACT
The present invention relates to provide an improved process for the preparation of Clonidine hydrochloride comprising steps of:
(i) reacting 2, 6-dichloroaniline with pivalic formic anhydride in the presence
of solvent 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