FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION
"AN IMPROVED PROCESS FOR THE PREPARATION OF PROMETHAZINE HYDROCHLORIDE"
Emcure Pharmaceuticals Limited.,
an Indian Company, registered under the Indian Company's Act 1957
and having its Registered Office at
Emcure House, T-184, M.I.D.C, Bhosari, Pune-411026, 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 process for the preparation of Promethazine hydrochloride. More particularly, the invention relates to a cost-effective process, which provides Promethazine hydrochloride having desired purity, free from its associated impurity.
BACKGROUND OF THE INVENTION
Promethazine hydrochloride of formula (I) is a phenothiazine derivative, chemically
known as (RS)-N,N-dimethyl-l-(10H-phenothiazin-10-yl)propan-2-amine
hydrochloride.

Promethazine is a first-generation H1 receptor antagonist of the phenothiazine chemical class used medically as an antihistamine. It has a strong sedative effect and in some countries is prescribed for insomnia when benzodiazepines are contraindicated. Promethazine exhibits its therapeutic activity by competitively and potently blocking histamine H1 receptors without blocking the secretion of histamine. It is also a moderate muscarinic acetylcholine antagonist and a very weak dopamine antagonist.
US 2,530,451 discloses preparation of phenothiazine derivatives which involves reaction of l-dimethylamino-2-chloropropane with either phenothiazine or its derivative having an alkyl or alkoxy substituent, in the presence of a halogen-acid binding agent, preferably sodamide and a aromatic hydrocarbon like xylene as solvent. The Promethazine compound thus obtained is converted to its hydrochloride salt by treating with hydrochloric acid in acetone and ethyl acetate. Hazardous reaction of sodamide

with water and use of high boiling solvent xylene makes this process unviable on an industrial scale.
US 2,607,773 and GB 680128 disclose the preparation of phenothiazine derivatives by reaction of a phenothiazine or a substituted phenothiazines with a Grignard reagent in a carcinogenic solvent such as benzene. Further this complex is reacted with the appropriate dialkylaminoalkyl halide to afford Promethazine. Grignard reagents are highly moisture sensitive and readily react with protic solvents such as water or with functional groups such as alcohols and amines leading to formation of high level of associated impurities and hence requires successive purification steps using a alcohol/ether solvent combination, which decreases the overall yield, thereby making the process less feasible for commercial scale.
US 2,687,414 relates to method for preparation of promethazine involving reaction of phenothiazine with p-dimethylaminoethyl chloride in absence of a solvent and in presence of an alkali like caustic soda as the condensation agent. The reaction mixture is extracted with ether, washed with water and concentrated and the residue is recrystallized from petroleum ether to remove the starting material. However the process is silent about purity of the final product.
A Indian patent 121/MUM/2006 discloses the preparation of pure promethazine hydrochloride which comprises reaction of phenothiazine with l-dimethylamino-2-chloropropane in the presence of an aqueous solution of a base like aqueous KOH and a suitable solvent like toluene. The biphasic mixture was stirred at room tempearature and after the reaction, the organic layer was washed with an aqueous solution of potassium carbonate to obtain the free base which was converted to its sulphate salt by treatment with sulphuric acid. The sulphate salt was then reconverted into the base by treating with an aqueous solution of potassium carbonate. The organic layer containing the free base was concentrated and converted to the pure hydrochloride salt by using isopropanol as solvent. Thus the method for obtaining pure Promethazine Hydrochloride is quite lengthy, cumbersome and diminishes the overall yield

considerably. Further, there is no mention about the final yield and purity of the pure product thus obtained.
All above prior art process are either silent about purity or are associated with drawbacks. Therefore, there is a need to develop an improved process which overcomes the drawbacks associated with the prior art processes as well as provide pure Promethazine Hydrochloride.
The present inventors found that promethazine hydrochloride could be obtained without the need for formation of the intermediate sulphate salts and the subsequent free base formation by a simple process in which the hydrochloride salt was formed directly in the aqueous layer. Subsequent extraction with an organic solvent like Dichloromethane was found to make the hydrochloride salt substantially free from polar impurities which were reducing the purity of the product. Promethazine hydrochloride thus obtained was optionally purified by recrystallization from acetone or isopropanol.
OBJECT OF THE INVENTION
It is therefore an object of the present invention to provide an improved process for the preparation of promethazine hydrochloride having the desired purity.
Another object of the present invention is to provide industrially viable method for the preparation of Promethazine hydrochloride.
SUMMARY OF THE INVENTION
According to one aspect of the present invention, it provides an improved process for the preparation of Promethazine Hydrochloride comprising:
i) condensing phenothiazine with l-dimethylamino-2-chloropropane or its salt
thereof in the presence of a base and catalytic amount of water in suitable
solvent to obtain promethazine free base,

ii) extracting promethazine of step (i) in a suitable solvent
iii) treating suitable solvent solution having Promethazine of step (ii) with dilute
hydrochloric acid to obtain crude promethazine hydrochloride in aqueous
solvent, iv) extracting crude Promethazine Hydrochloride from aqueous solution of step
(iii) with a halogenated hydrocarbon v) evaporating organic layer of step (iv) to obtain crude Promethazine
Hydrochloride vi) optionally purifying crude Promethazine Hydrochloride of step (v)
DETAILED DESCIUPTION OF THE INVENTION
In an embodiment, the present invention provides a process for the preparation of promethazine hydrochloride having the desired purity comprising of condensing phenothiazine with l-dimethylamino-2-chloropropane in the presence of a base and catalytic amount of water in a suitable solvent to obtain promethazine base followed by treatment with hydrochloric acid, extracting the aqueous layer with a halogenated hydrocarbon and concentrating to obtain promethazine hydrochloride, which was then optionally purificed with a water-miscible solvent like a ketone or an alcohol..
Step (i) which involves condensation of phenothiazine with l-dimethylamino-2-chloropropane or its salt thereof was done at refluxing temperature of suitable solvent.
The term "base" used herein in step (i) includes but not limited to inorganic bases selected from the group consisting of alkali or alkaline metal hydroxide, carbonates, bicarbonates, alkoxide and the like and organic bases selected from the group consisting of amines such as alkyl amine etc. The preferred base is an alkoxide like sodium tertiary butoxide.
Suitable solvent used in step (i) and step (ii) which includes but not limited to water immiscible solvent selected from the group consisting of halogenated hydrocarbon, aliphatic or aromatic hydrocarbon, ester and the like. It was found that the reaction was

quite facile when catalytic amount of water was added to the reaction mixture. The water immiscible solvent used as suitable solvent which plays role of reaction solvent during reaction as well as extracting solvent during work up. The preferred suitable solvent is toluene.
Halogenated hydrocarbon used in step (iv) which includes but is not limited to chloroform, methylene chloride, ethylene chloride and the like. The preferred solvent is methylene chloride.
The solvent is added to the reacetion mixture and the organic layer was separated. Hydrochloric acid was added to the organic layer and the aqueous layer containing the active ingredient was separated and washed with a organic solvent like dichloromethane. The organic layer was separated and concentrated and a mixture of a water-miscible solvents like ketone or alcohol was added to the residue. The solid separating out was filtered and dried.
Purification of crude Promethazine Hydrochloride of step (vi) was carried out with organic solvents selected from group consisting of ketone such as acetone, methyl isobutyl ketone, diethyl ketone, isopropyl ketone as well as alcohol such as methanol, ethanol, isopropyl alcohol and the like. The preferred purification solvents are acetone and isopropyl alcohol.
The principles, preferred embodiments and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
Following are the advantages of the present invention,

i) The present invention was facile when catalytic amount of water was added to the reaction mixture. Hence, stringent anhydrous conditions usually required for reactions involving NaOtBu is not required.
ii) The purification method did not require preparation of salts other than hydrochloride followed by free base formation as disclosed in prior art for obtaining pure promethazine hydrochloride.
iii) The present invention proceeds by isolating the crude Hydrochloride salt directly without isolation of the intermediate free base and avoiding the subsequent Hydrochloride salt formation thereby increasing the yield and making the present invention cost effective.
The invention is further explained with the help of following illustrative examples, however, in no way these examples should be construed as limiting the scope of the invention.
EXAMPLES:
Toluene (800 mL), sodium-tert-butoxide (103 g) and Phenothiazine (100 g) were charged into a clean round bottom flask at 25 to 30 °C and stirred for 30 to 45 minutes. Dimethylaminoisopropyl chloride hydrochloride (81.5 g) and water (2.5 ml) was added to the reaction mixture and the contents were refluxed at 90 to 100°C with stirring for 3.0 hours. After completion of reaction, as monitored/confirmed by HPLC, the reaction mixture was cooled to 25-30°C and water (700 ml) was added. The reaction mixture was stirred for 15 minutes, the organic layer was separated and treated with dilute hydrochloric acid (600 ml). The organic layer was discarded and the aqueous layer containing the crude product was extracted back into dichloromethane (700 mL). The solvent was removed, the residue was stirred with a mixture of Acetone:Methanol (19:1) (400 mL) for 4 hours at room temperature and the solids were filtered.. The compound thus obtained was optionally purified utilizing Acetone:Methanol mixture. Yield: 60gms Purity: >99.8.

We claim:
1. A process for the preparation of Promethazine Hydrochloride comprising:
i) condensing phenothiazine with l-dimethylamino-2-chloropropane or its
salt thereof in the presence of base and catalytic amount of water in
suitable solvent to obtain Promethazine ii) extracting Promethazine of step (i) in suitable solvent iii) treating suitable solvent solution having Promethazine of step (ii) with
dilute Hydrochloride to obtain crude Promethazine Hydrochloride in
aqueous solvent iv) extracting crude Promethazine Hydrochloride from aqueous solution of
step (iii) in halogenated hydrocarbon v) evaporating halogenated hydrocarbon solution of step (iv) to obtain
crude Promethazine Hydrochloride vi) optionally purifying crude promethazine hydrochloride of step (v)
2. The process as claimed in claim 1, wherein the suitable solvent is selected from the group comprising of halogenated hydrocarbon, aliphatic or aromatic hydrocarbon, ester.
3. The process as claimed in claim 2, wherein the suitable solvent is toluene.
4. The process as claimed in claim 1, wherein the base is selected from the group consisting of alkali or alkaline metal hydroxide, carbonates, bicarbonates, alkoxide, alkyl amine is sodium tertiary butoxide.
5. The process as claimed in claim 4, wherein the base is sodium tertiary butoxide.
6. The process as claimed in claim 1, wherein the halogenated hydrocarbon solvent is selected from the group comprising of chloroform, methylene chloride, ethylene chloride.

7. The process as claimed in claim 6, wherein the halogenated hydrocarbon solvent is methylene chloride.