DESC:FIELD OF THE INVENTION

The present invention relates to a process for the preparation of prochlorperazine having desired purity. Specifically, the invention relates to a process for preparing 2-chloro-10-[3-(4-methyl-1-piperazinyl)propyl]-10H-phenothiazine, (1) comprising reaction of 2-chloro-phenothiazine (2) with 1-(3-chloropropyl)-4-methylpiperazine (3) in presence of a mild base to give compound (1), conforming to regulatory specifications.

BACKGROUND OF THE INVENTION

Prochlorperazine of formula (1), chemically known as 2-chloro-10-[3-(4-methyl-1-piperazinyl)propyl]-10H-phenothiazine, has a prominent antiemetic and anti-vertiginous activity and is most often used for the short-term treatment of nausea, vomiting and vertigo. Prochlorperazine was originally approved by USFDA on October 23, 1956 and is presently being marketed as maleate and edisylate salts for the treatment of severe nausea, vomiting and also in the management of psychotic disorders.

prochlorperazine (1) Prochlorperazine edisylate (1a)

Prochlorperazine (1) was first disclosed in US 2,902,484 wherein the synthetic sequence comprised treatment of 3-chlorophenthiazine with sodamide in solvent toluene at 1200C and further reaction of resulting sodium derivative with 1-(3-chloropropyl)-4-methylpiperazine at the same temperature.
Use of an extremely hazardous reagent like sodium amide (sodamide) is the major drawback in the above synthetic method. Sodium amide reacts violently with water producing ammonia and sodium hydroxide. It also burns in air giving oxides of nitrogen and sodium. In addition to its hazardous nature, use of sodamide is restricted because of its poor solubility in various solvents, due to which excessive quantities of reagents and solvents are required during reaction, causing significant rise in associated impurities.
US2010/0099666 discloses a general synthetic method for prochlorperazine type compounds comprising reaction of 2-chlorophenothiazine derivatives with 1-(3-chloropropyl)-4-methylpiperazine in presence of a base such as sodium hydride.
Both the synthetic methods which employ hazardous bases like sodamide or sodium hydride pose serious safety related concerns for the reactions involved and render these processes inapplicable on industrial scale.
Further, it was experimentally observed that the above-mentioned reactions are accompanied by various impurities which are formed in significant proportions. This necessitates separation of these impurities, which is time consuming, energy-intensive, and yet inevitable in order to obtain the final compound having desired purity.
Thus, there still exists a need for an economical, industrially viable process for synthesis of prochlorperazine (1), which avoids use of hazardous and pyrophoric bases such as sodamide or sodium hydride, wherein the impurity formation is significantly controlled and prochlorperazine having desired purity is obtained in good yield.
The present inventors have developed a convenient process for synthesis of prochlorperazine (1) which is applicable on industrial scales. The process comprises reaction of 2-chloro phenothiazine (2) with 1-(3-chloropropyl)-4-methylpiperazine (3) in presence of bases such as alkali metal alkoxides to afford prochlorperazine (1) in high yield and conforming to regulatory specifications.

OBJECT OF THE INVENTION

An objective of the present invention is to provide prochlorperazine of formula (1) having desired purity by an industrially viable, convenient process which does not involve hazardous reagents or cumbersome separation procedures for removal of impurities.
Another object of the present invention is to provide an efficient process for preparation of prochlorperazine (1), wherein 2-chloro-phenothiazine (2) is reacted with 1-(3-chloropropyl)-4-methylpiperazine (3) in presence of alkali metal alkoxides to give prochlorperazine (1) conforming to regulatory specifications.
Yet another object of the present invention is to provide an efficient process for preparation of prochlorperazine edisylate (1a) having desired purity with a significant control on impurity formation.

SUMMARY OF THE INVENTION

The present invention relates to a novel method for synthesis of 2-chloro-10-[3-(4-methyl-1-piperazinyl)propyl]-10H-phenothiazine of formula (1) having desired purity.

An aspect of the invention relates to a process for preparation of prochlorperazine edisylate (1a) comprising the reaction of 2-chlorophenothiazine (2) with 1-(3-chloropropyl)-4-methylpiperazine (3) in presence of sodium tertiary butoxide and dimethyl sulfoxide as solvent followed by further treatment with 1,2-ethanedisulfonic acid to give prochlorperazine edisylate (1a) having desired purity.

The objectives of the present invention will become more apparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors, with the intent for developing a convenient and industrially applicable process for prochlorperazine aimed at a process which would afford the final compound having desired purity in good yield. The process would further avoid hazardous reagents like hydride or sodamide and also cumbersome separation procedures to get rid of the associated impurities generated during the synthetic sequence.

In the synthesis of prochlorperazine, the prior art methods resorted to use of strong bases like sodium hydride or sodamide to abstract the nitrogen- bound proton from phenothiazine derivative. The sodium salt, thus formed was further subjected to alkylation reaction with haloalkyl piperazine, However, it was observed that the extremely hazardous, potentially explosive nature of strong bases prevented their use for commercial scale operations. Bases like sodamide or sodium hydride react with moisture which generates gaseous products such as ammonia or hydrogen; thus imposing stringent requirements for anhydrous solvents and moisture-free reaction conditions. Further, poor solubility of sodamide or sodium hydride in various organic solvents necessitates either involvement of phase transfer catalysts or use of these reagents in excessive proportions, resulting in increase in side reactions and associated impurities, which had to be separated following cumbersome separation procedures. It was experimentally observed that the prior art processes provided prochlorperazine in poor yield due to the substantially high formation of impurities which had to be separated using time-consuming, tedious separation procedures.

It was also observed by the present inventors that some associated impurities were getting formed even with the use of mild bases. It was a challenge to get rid of these impurities, especially the dimeric impurities 4 and 5, which were not completely removed even after successive crystallizations.

While carrying out the extensive experimental work aimed at synthesis of prochlorperazine, the present inventors surprisingly found that when the alkylation reaction of chlorophenothiazine derivative using haloalkyl methyl piperazine was carried out in presence of a mild base, the reaction was facile enough to be carried out at temperatures significantly lower than those disclosed in prior art thus consequently reducing the formation of side products and impurities. Yet another related surprising observation by the inventors was that when the reactant, 1-(3-chloropropyl)-4-methylpiperazine (3) was used in less than stoichiometric proportions with respect to compound 2, there was significant reduction in impurities, especially the dimeric ones.

Thus, the present synthetic strategy effectively replaces the moisture sensitive, hazardous reagents such as sodamide or sodium hydride and provides an industrially feasible, convenient process for prochlorperazine, wherein the final product possesses purity conforming to specifications and is obtained in good yield.

Scheme 1: The method embodied in the present invention for preparation of
prochlorperazine edisylate (1a)

In an embodiment, 2-chlorophenothiazine of formula (2) was treated with 1-(3-chloropropyl)-4-methylpiperazine (3) in presence of a base and an organic solvent to give 2-chloro-10-[3-(4-methyl-1-piperazinyl)propyl]-10H-phenothiazine (1).

The base was selected from the group comprising alkali metal alkoxides such as methoxide, ethoxide, tertiary butoxide, isopropoxide etc. of sodium, potassium, lithium etc. or organic bases like triton B.

The organic solvent was selected from the group comprising polar aprotic solvents such as acetone, ethyl acetate, dimethyl sulfoxide, N,N dimethyl formamide, N,N dimethyl acetamide etc., and ethers like tetrahydrofuran.

The reaction was carried out in the temperature range of 20-500C. Molar equivalence ratio of compound 2 to compound 3 ranged from 1.0:0.4 to 0.4:1.0.

After completion of reaction as monitored by HPLC, the reaction mass was quenched with water, followed by addition of toluene, stirring and layer separation. The separated toluene layer was treated with aqueous hydrochloric acid. The acidic aqueous layer, after washing with organic solvents such as toluene, dichloromethane was neutralized with base, followed by extraction with toluene. Concentration of the toluene layer provided prochlorperazine (1).

Prochlorperazine thus obtained was treated with 1,2-ethanedisulfonic acid dihydrate in presence of alcohols like isopropyl alcohol, ethanol etc. in the temperature range of 50-800C. Further treatment of the resulting product with cyclohexane yielded prochlorperazine edisylate (1a).
Compound 2 and compound 3 were prepared by following procedures known in the art.

The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.

EXAMPLES

Example 1: Preparation of prochlorperazine (1)

1-(3-chloropropyl)-4-methylpiperazine (3, 42.6 g) was gradually added to the mixture of 2-chlorophenothiazine (2, 75.0 g), sodium tertiary butoxide (37.05 g) and dimethyl sulfoxide (260 ml), stirred at 10-200C. The reaction mixture was heated to 30-500C and stirred at the same temperature till completion of the reaction as monitored by HPLC.
After completion, the reaction mixture was quenched by addition of water and extracted with toluene. The organic layer was separated and washed with dilute hydrochloric acid. The aqueous layer so obtained was washed with toluene, dichloromethane and basified using aqueous sodium hydroxide. Extraction with toluene, followed by separation and concentration of the organic layer gave prochlorperazine.
Yield: 75.3 gms
% Yield: 61.9%.

Example 2: Preparation of prochlorperazine (1)

1-(3-Chloropropyl)-4-methylpiperazine (3, 56.7gms) was gradually added to a mixture of 2-chlorophenothiazine (2, 100.2 g), sodium tertiary butoxide (50.4gms) and dimethyl sulfoxide (350 ml), stirred at 10-200C. The reaction mixture was heated to 30-500C and stirred at the same temperature till completion of the reaction as monitored by HPLC. After completion, the reaction mixture was quenched by addition of water and extracted with toluene. The organic layer was separated and washed with dilute hydrochloric acid. The aqueous layer so obtained was washed with toluene, dichloromethane and basified using aqueous sodium hydroxide. Extraction with toluene, followed by separation and concentration of the organic layer gave prochlorperazine.
Yield: 100.2gms.
% Yield: 62.1%.

Example 3: Preparation of prochlorperazine edisylate (Ia)
A solution of 1,2-ethanedisulfonic acid (108.8 g) in ethanol (950 ml) was gradually added to a mixture of prochlorperazine (199.4 g) and ethanol (800 ml) and the stirred mass was heated to 60-700C till completion of the reaction as monitored by HPLC. After completion, the reaction mixture was cooled to 20-300, stirred, filtered and washed with cyclohexane to give prochlorperazine edisylate.
Yield: 239.3 g,
% Yield: 80.2%
Purity: 99.88 % (HPLC).
,CLAIMS:1. A process for preparation of prochlorperazine edisylate (1a) comprising reaction of 2-chlorophenothiazine of formula (2) with 1-(3-chloropropyl)-4-methylpiperazine of formula (3) in presence of a base, in an organic solvent to give prochlorperazine of formula (1), followed by further treatment with 1,2-ethanedisulfonic acid to give prochlorperazine edisylate (1a).

2. A process as claimed in claim 1, wherein the base is selected from sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tertiary butoxide, potassium tertiary butoxide, sodium isopropoxide, potassium isopropoxide and combinations thereof.

3. A process as claimed in claim 1, wherein the molar ratio of compound 3 with respect to compound 2 is between 0.4 to 0.9.

4. A process as claimed in claim 1, wherein the organic solvent is selected from a group of polar aprotic solvents.

5. A process as claimed in claim 4, wherein the polar aprotic solvent is selected from a group comprising tetrahydrofuran, polar aprotic solvents such as acetone, ethyl acetate, dimethyl sulfoxide, N,N dimethylformamide, N,N dimethylacetamide and mixtures thereof.

6. A process as claimed in claim 1, wherein the reaction with 1-(3-chloropropyl)-4-methylpiperazine is carried out in the temperature range of 20°C to 50°C.

7. A process as claimed in claim 1, wherein the reaction with 1,2-ethanedisulfonic acid is carried out in the temperature range of 50°C to 80°C.