FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of Propiomazine maleate. More particularly, the invention relates to a cost-effective process, which provides Propiomazine maleate of formula-I with high purity, which is free from isomeric impurity, specifically isopropiomazine.
BACKGROUND OF THE INVENTION:
Propiomazine maleate of formula-I is a phenothiazine derivative, chemically known as 1-[ 10-(2-dimethylaminopropyI)-10H-phenothiazin-2-yl]propan-1 -one maleate.Propiomazine is an antihistamine drug, which acts by blocking HI receptors. It is used to treat insomnia, and to produce sleepiness or drowsiness and to relieve anxiety before or during surgery or other procedures and in combination with analgesics also during labor. Propiomazine is a derivative of Phenothiazine.

The process for preparation of Propiomazine has been discussed in "Kathleen B. Crombie and Leo F. Cullen. Analytical profiles of drug substances., pp 439-466 (1973)" which reported two synthetic routes for the preparation of Propiomazine hydrochloride.
According to the above review article,.one of the two synthetic routes is illustrated in Scheme-1 discloses the preparation of Propiomazine base by reacting 2-dimethylaminopropyl chloride with 2-prapionylphenothiazine in the presence of sodium amide as die condensing agent, and subsequently converting the base form to the hydrochloride.
The other synthesis route is illustrated in Scheme-2, which was developed by Establissements Clin-RylaB for the preparation of Propiomazine hydrochloride is based on the decarboxylation by heating of the aminoalkyl ester of the N-carboxyphenothiazine. Specifically 2-propionylphenothiazine is converted in to its N-carbonyl chloride derivative by reacting with phosgene. Reaction of the chloride with 2-dimethylamino-l-propanol yields die ester hydrochloride, which is decarboxylated by heating to obtain Propiomazine hydrochloride.

The above mentioned routes for Propiomazine hydrochloride have considerable disadvantages, which involve multiple steps for the synthesis and use of expensive starting materials.
Synthesis of Propiomazine maleate has not been disclosed in any literature which is available in the public domain.
The present inventors have now found a simple, cost-effective process, which provides propiomazine maleate with high purity and free from isopropiomazine impurity.
OBJECT OF TIIE INVENTION:
The main object of the present invention is to provide simple, cost-effective and industrially viable method for the preparation of Propiomazine maleate of formula-I on commercial scale.
SUMMARY OF THE INVENTION:
The main aspect of the present invention is to provide an improved process for the preparation of Propiomazine maleate of formula-I.

The first aspect of the present invention is to provide an improved process for the preparation of l-[lO-(2-dimethylaminopropyl)-10H-phenothiazin-2-yl]propan-l-one of formula-II comprises the steps of reacting hydrochloride salt of 2-dimethylaminoisopropyl chloride with 2-propionyl phenothiazine in presence of a base and suitable solvent.
The second aspect of the present invention is process for preparation of Propiomazine maleate with high purity which is free from isomeric impurity of formula-Ill. The isomeric impurity produced during the preparation of Propiomazine base of formula II is controlled during the preparation of Propiomazine maleate. The Propiomazine base of formula II is dissolved in alcoholic media to get a clear solution. Addition of maleic acid to the above clear solution produces Propiomazine maleate of formula-I which is free from isomeric impurity.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to an improved process for the preparation of Propiomazine maleate of formula-I and its purification from the undesired isomeric impurity, i.e., isopropiomazine of formula-Ill.
The first embodiment of the present invention is an improved process for the preparation of U[10-(2-dimethylaminopropyl)-10H-phenothiazin-2-yl]propan-l-one of formula-II, which comprises condensing 2-propionyl phenothiazine of formula -IV
with hydrochloride salt of 2-dimefhylaminoisopropyl chloride of formula-V
in presence of a base and suitable solvent to obtain the compound of Propiomazine base
of formula-II.
The process is schematically represented as below:

Further embodiment of the present invention relates to process for preparation of Propiomazine maleate with high purity and free from isopropiomazine impurity of formula-Ill. The isomeric impurity is controlled during the preparation of Propiomazine maleate. The crude Propiomazine base obtained in the above condensation step contains isomeric impurity of 20-25%. The Propiomazine base of formula II is dissolved in alcoholic media to get a clear solution. Addition of maleic acid to the above clear solution produces Propiomazine maleate of formula-I which is free from isomeric impurity.
The process is schematically represented as below:
According to one embodiment of the present invention the base used in condensation step is selected from potassium hydroxide, sodium hydroxide, potassium tertiary butoxide, preferably potassium hydroxide.
According to another embodiment of the present invention solvent used in condensation step is selected from the group comprising of toluene, xylene, preferably toluene.
According to yet another embodiment of the present invention alcoholic media used in purification step is selected from methanol, ethanol, isopropyl alcohol, preferably methanol.
The present invention can be illustrated in the following non- limiting example.

EXAMPLE:
Preparation of Propiomazine maleate: To a stirred solution of 2-dimethylaminoisopropyl chloride hydrochloride (67.5 gm, 0,427 mole) in water (50 ml) and Toluene (250 ml) mixture was basified with aqueous sodium hydroxide solution at below 10°C and separate the organic layer. To obtained base toluene layer was added 2-propionyl phenothiazine (50 gm, 0.171 mole) and potassium hydroxide flakes (19 gm, 0.342 mole) at below 10°C. Reaction mixture temperature was slowly heated to reflux and maintained for 5-6 hrs under azeotropic condition. Progress of the reaction was monitored/ confirmed by HPLC. After completion of reaction, the reaction mixture was cooled to 25-30°C and water (200 ml) was added and stirred for 10-15 minutes. The organic layer was separated and concentrated to get Propiomazine crude compound. Crude compound was dissolved in methanol (200 ml) and stirred for 10-15 minutes at 25-30°C to get clear solution, Maleic acid (20 gm) was added to the above clear solution and stirring was continued for another 4-5 hrs at 25-30°C and the precipitated solid was Filtered and dried to get Propiomazine maleate in pure form. Yield: 34 gms. Purity: greater than 99.5% and isopropiomazine content below 0.10% by HPLC.