FORM II

THE PATENTS ACT, 1970 (39 of 1970)
THE PATENTS RULES, 2010 COMPLETE SPECIFICATION
(See section 10; rule 13)
AN IMPROVED ONE-POT PROCESS FOR THE PREPARATION OF
CHLORHEXIDINE
CADILA PHARMACEUTICALS LIMITED
"Cadila Corporate Campus", Sarkhej - Dholka Road, Bhat, Ahmedabad - 382210,
Gujarat, India
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 one-pot process for the preparation of Chlorhexidine.
BACKGROUND OF THE INVENTION
Chlorhexidine is a bisbiguanide represented by structural formula I, chemically named as 1,6-di(4'chlorophenyldiguanido)hexane and used as an antiseptic or disinfectant. It is effective on both Gram-positive and Gram-negative bacteria. Chlorhexidine is water insoluble and used as dihydrochloride, diacetate, D-digluconate or other pharmaceutically acceptable salts.

The intermediate for preparation of Chlorhexidine is hexamethylene-bisdicyanodiamide (HMBDCA).
US2684924 discloses Chlorhexidine, its derivatives and their preparation wherein bisdicyandiamide derivatives are reacted with substituted p-chloroaniline hydrochloride using β-ethoxyethanol as a solvent at 130-150°C for 2 hours under reflux condition. The mixture is cooled and precipitated solid is filtered. The solid is washed with water and crystallized using 50% aqueous acetic acid to give Chlorhexidine dihydrochloride.
BR9300129 describes a process for the preparation of Chlorhexidine, wherein 1, 6-hexanediamine hydrochloride is reacted with sodium dicyanamide (SDC) in n-butanol to give HMBDCA, which is further reacted with p-chloroaniline hydrochloride in aqueous EtOH to give dihydrochloride salt of chlorhexidine and finally converted to chlorhexidine.
The present inventors have found that under such reaction conditions during the pH adjustment using aqueous hydrochloric acid the reaction of HMBDCA with p-

chloroaniline or its salt results in low yield of chlorhexidine due to formation of process impurities.
J. Chem. Soc, (1956) pp. 4422-4425 describes a preparation of HMBDCA by the reaction of sodium dicynamide with hexamethylene diamine dihydrochloride in stoichiometric proportions in n-butanol. The process suffers from disadvantages of low purity and yield with long reaction time.
WO/2008/031456 discloses a preparation of Chlorhexidine wherein HMBDCA is reacted with p-chloroaniline in presence of isopropyl alcohol using aqueous hydrochloric acid under the pressure of 2.4 to 2.8 bar. The process is resulting low yields.
US5041655 discloses a preparation of 1,6-di(N3-cyano-N1-guanidino) hexane, wherein 1,6-diaminohexane is converted to its hydrochloride salt by using aqueous hydrochloric acid and then reacted with sodium dicyanamide in presence of triethylamine using n-butanol, under reflux condition. This intermediate- HMBDCA is isolated by azeotropic distillation from the reaction mass. The resulting product is having yield & purity 86.3 % and 96.5% respectively.
There is an unmet need to modify the conditions disclosed in prior art processes to reduce the impurity levels and increase the yield and purity of chlorhexidine.
OBJECTS OF THE INVENTION
The main object of the invention is to provide an improved process for the preparation of chlorhexidine in high yield with reduced level of impurities.
Another object of the invention is to provide a one-pot process for the preparation of chlorhexidine using organic acid.
SUMMARY OF THE INVENTION
In accordance with the present invention, chlorhexidine is prepared by reacting hexamethylenediamine dihydrochloride with sodium dicyanamide in alcohol to give 1,1'-hexane-1,6-diylbis(3-cyanoguanidine) [HMBDCA] which is reacted with p-chloroaniline hydrochloride in the presence of organic acid to give Chlorhexidine

dihydrochloride and further converted to chlorhexidine. The purity of the product is >99.50%.
DETAILED DESCRIPTION OF INVENTION
Accordingly, the present invention provides a one pot synthesis of chlorhexidine comprising steps:
(a) reacting hexamethylene diamine with hydrochloric acid in organic solvent to form hexamethylenediamine dihydrochloride;
(b) reacting hexamethylene diamine dihydrochloride with sodium dicynamide at pH 9.2 to 9.4 using an organic base;
(c) removing water and maintaining reaction mass at reflux;
(d) adding p-chloroaniline or its salt to the reaction mass;
(e) adjusting pH of the reaction mass between 2-4 using organic acid;
(f) basifying the reaction mass using alkali; and
(g) removing the solvent and isolating chlorhexidine using lower alcohol followed by drying to give solid.
The organic solvent used in step-a is selected from C3 to C5 alcohols, preferably butanol; or alkoxy alcohols, preferably ethyl cellosolve..
The base used step-b is selected from an organic base such as trialkyl amine having from 1 to 6 carbon atoms.
The organic acid used in step-e is selected from C1 to C3 acid. The preferable organic acid is formic acid or acetic acid.
In step-e, alkali is added to basify chlorhexidine dihydrochloride and alcohol layer containing chlorhexidine is separated and washed with water, if required. The alcohol is partly distilled and methanol is added to concentrated mass. The volume of alcohol in the reaction mass is so selected that at temperature >50°C there is no precipitation of solid material. The alcoholic solution containing chlorhexidine is cooled, solid is precipitated which is again warmed to get clear solution, which on cooling gives solid mass.

The alkali used in step-f is Potassium hydroxide or Sodium hydroxide to bring pH between 10 to 14
In step-g, the solid mass so obtained is separated, washed with alcoholic solvent and dried. Preferably the alcoholic solvent is methanol.
The present invention includes HMBDCA preparation from hexamethylenediamine and sodium dicynamide then in-situ condensation with p-chloroaniline hydrochloride to give chlorhexidine.
Following impurities/degradation products are formed when aqueous hydrochloric acid is used for adjusting pH during the preparation of HMBDCA and chlorhexidine at higher temperature above 50°C; especially when reaction is performed at 50°C to 150°C.

1-(4,-Chlorophenyldiguanido)-6-(urido)hexane (Impurity E)
Due to degradation of HMBDCA, the other reactant i.e. p-chloroaniline remains in excess which further reacts with generated HMBDCA impurities having the same functional groups. These condensed impurities with chlorhexidine having similar physical characteristics, are difficult to remove from final product. The formation of impurities/byproducts not only creates contamination but also lowers the yield of chlorhexidine.

Surprisingly, substituting aqueous hydrochloric acid with organic acid for controlling pH, reduces the degradation of HMBDCA and Chlorhexidine. The use of organic acid for adjusting pH which improves yield of chlorhexidine up to 10-12% with respect to the prior art process wherein aqueous hydrochloric acid is used for adjusting pH. According to present invention the organic acid is selected from acetic acid, formic acid. The present invention reduces/prevents the degradation of HMBDCA and allows it to react with p-chloroaniline hydrochloride to give chlorhexidine in improved yield. The process of present invention also results in increasing the purity over 99.50%.
The invention is further illustrated by following non-limiting examples.
Example-1
Hexamethylenediamine [100 gm] was added to butanol [1900 ml] at 25-30°C, the reaction mass was cooled to 10-15°C. Concentrated hydrochloric acid [-175-180 ml] was added with stirring till pH between 4.2 to 6.2 was achieved. Sodium dicynamide [152.48 gm] was added to reaction at ambient temperature. Triethylamine was added to maintain pH 9.2 to 9.4.The heating was started with stirring, separating a mixture of triethylamine, water and butanol till temperature of 115 to 117°C was obtained and maintained for 4 hours. The reaction mass was cooled to 40-45eC, p-chloroaniline HCl [304 gm] was added and the reaction mass was stirred at 95-100'C. Addition of formic acid [85 %; 60 ml] was started over about 30 minutes, the reaction was maintained for about 1.5 hours, pH was maintained to 2.0 to 3.5 using formic acid. Water was added [480 ml]. Caustic solution [120 gm NaOH in 360 ml water] was added and stirred at 70-80°C for about 15 minutes. pH of the reaction mass was maintained to alkaline. The stirring was stopped and the reaction mass was settled and lower aqueous layer was separated. Hot water [480 ml] was added to organic phase and stirred at 15 minutes at 70-80°C, the stirrer was stopped, the reaction mass was settled and the lower aqueous layer was separated. The organic layer was filtered through hyflo bed and washed with hot butanol [100 ml]. Butanol [1275-1300 ml] was distilled out under vacuum at 75-100°C. The reaction mass was cooled to 68-70°C. Methanol [1900 ml] was added to the reaction mass and stirred for 30-45 minutes. The reaction mass was cooled to 30-35°C, filtered, washed with methanol. The wet cake was again stirred with methanol, the

reaction mass was stirred at reflux temperature for 2 hours, cooled, filtered, washed with methanol and dried.
Wt = 260-270 gm.
Example-2
Aqueous hydrochloric acid 200 ml (CP, 32.0 - 33.0 %) was added to cooled solution of hexamethylenediamine [100 gm] in butanol [800 ml] till pH of 4 to 6 was achieved. Sodium dicynamide [152.48 gm] was added to reaction mass at 20-30°C and triethylamine was added to reaction mass at ambient temperature, maintaining pH 9.2 to 9.4.
The reaction mixture was heated to obtain temperature of 115 to 117°C and maintained for 4 hours with stirring. The reaction mass was cooled to 40-45°C, followed by addition of p-chloroaniline HCI [312 gm] and again heated with stirring to about 95-100°C. Slowly, formic acid [85%; 60 ml] was added to reaction mixture to obtain pH of 2-3.5 and stirred for 1.5 hours.
Caustic solution was added to above reaction mixture and stirred at 70-80°C for about 15 minutes. The stirring was stopped and the reaction mass was allowed to settle and organic layer was separated. Hot water was added to organic phase and stirred at 70-80°C for 15 minutes. The organic layer was filtered through hiflo bed and washed with butanol. Organic layer was distilled under vacuum at 75-100°C. The reaction mass was cooled to 68-70cC and methanol was added to the reaction mass and the reaction mass was cooled to 40-45°C. The reaction mass was again heated to 68-72°C and stirred at same temperature for 30-45 minutes. The reaction mass was cooled to 30-35°C, filtered and dried to obtain chlorhexidine. Wt. = 259.2 gm. (Yields 61.88 %, Purity by HPLC = 99.86 %)

We claim:
1. An improved one pot process for the preparation of chlorhexidine, comprising
the steps of:
a. reacting hexamethylene diamine with hydrochloric acid in organic
solvent to form hexamethylenediamine dihydrochloride;
b. reacting hexamethylene diamine dihydrochloride with sodium
dicynamide using an organic base;
c. removing water and maintaining reaction mass at reflux;
d. adding p-chloroaniline or its salt to the reaction mass;
e. adjusting pH of the reaction mass between 2-4 using organic acid
f. basifying the reaction mass using alkali; and
g. removing the solvent and isolating chlorhexidine using lower alcohol
followed by drying to give solid
2. The process as claimed in claim 1, wherein organic solvent used in step (a) is selected from C3 to C5 alcohols or alkoxy alcohols.
3. The process as claimed in claim 2, wherein the preferred alcohol is butanol.
4. The process as claimed in claim 2, wherein the alkoxy alcohol is ethyl cellosolve.
5. The process as claimed in claim 1, wherein the organic base used in step (b) is trialkyl amine having from 1 to 6 carbon atoms,
6. The process as claimed in claim 5, wherein the base is triethyl amine.
7. The process as claimed in claim 1, wherein the organic acid used in step (e) is selected from acetic acid or formic acid.
8. The process as claimed in claim 1, wherein the alkali used in step-f is Potassium hydroxide or Sodium hydroxide to bring pH between 10 to 14.

9. The process as claimed in claim 1, wherein the lower alcohol used in step (g) is methanol.