DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF RISPERIDONE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO. 11, SURVEY NO. 9,
HITECH CITY, KONDAPUR,
HYDERABAD - 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which the same is to be performed.
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Risperidone by using phase transfer catalyst to avoid risperidone related compound-G.

BACKGROUND OF THE INVENTION
RISPERDAL® (risperidone) is an antipsychotic agent belonging to a new chemical class, the benzisoxazole derivatives. Risperidone chemically known as 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-?]pyrimidin-4-one and has the following structural formula I:

I

US 4,804,663, describes the synthesis of Risperidone. The synthesis involves condensation of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (Formula II) with 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-?]pyrimidin-4-one (Formula III) in presence of sodium carbonate (Na2CO3) or potassium carbonate (K2CO3) and potassium iodide (KI) in dimethylformamide (DMF) to provide Risperidone, which is crystallized from a mixture of DMF and isopropanol.

Further, WO 2001/085731 describes a process for preparation of Risperidone which involves condensation of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (Formula II) with 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-?]pyrimidin-4-one (Formula III) in presence of sodium bicarbonate in water.

However, the procedures provided in the prior art for Risperidone leads to formation impurities, for example, related compound G, which is difficult to remove from Risperidone by simple purifications.

Risperidone related compound-G

Therefore, there is need to provide an improved process for the preparation of Risperidone, which is simple, efficient and cost effective and convenience to operate on a commercial scale.

OBJECTIVE OF THE INVENTION
The objective of the present invention is to provide an improved process for the preparation of Risperidone, which avoids the formation of related compound G.

SUMMARY OF THE IVENTION
In an aspect of the present invention, there is provided an improved process for the preparation of Risperidone of Formula I, which comprises condensation of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole of formula II:

II

with 3-(2-chloroethy)-2-methyl-6,7,8,9-tetrahydo-4H-pyrido[1,2-?]pyrimidin-4-one of Formula III:
III
or salts thereof; in presence of a base and a phase transfer catalyst.

In another aspect of the present invention, there is provided a process for preparing risperidone, which comprises condensation of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride with 3-(2-chloroethy)-2-methyl-6,7,8,9-tetrahydo-4H-pyrido[1,2-?]pyrimidin-4-one hydrochloride in presence of base and tetrabutylammonium bromide.

DETAILED DESCRIPTION OF THE IVENTION

The term “pure”, unless specified otherwise, Risperidone having purity of greater than or equal to 99% or greater than or equal to 99.5% determined by HPLC.

In an aspect of the present invention, there is provided an improved process for preparation of Risperidone of Formula I, which comprises condensation of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole of formula II with 3-(2-chloroethy)-2-methyl-6,7,8,9-tetrahydo-4H-pyrido[1,2-?]pyrimidin-4-one of Formula III or salts thereof, in presence of base and phase transfer catalyst.

The salts of formula II and Formula III may be the same or different that may be selected from hydrochloride, hydrobromide, phosphate, sulfate, acetate, formate, triflouro acetate, 2,2-dichloroacetate, adipate, ascorbate and the like

The base comprises organic base or inorganic base. Inorganic base is selected from alkali hydroxide, alkali carbonate and bicarbonate, alkaline earth metal carbonate and bicarbonates, alkoxides and hydrides. The example of inorganic base includes but not limited to sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), sodium bicarbonate (NaHCO3), potassium bicarbonate (KHCO3), lithium bicarbonate (LiHCO3), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), lithium carbonate (Li2CO3), calcium carbonate (CaCO3), magnesium carbonate (MgCO3), sodium hydride, potassium tert-butoxide, sodium tert-butoxide and the like or mixtures thereof. The organic base is selected from pyridine piperidine, dimethyl amino pyridine, picolines, diisopropyl amine, diisopropyl ethyl amine, triethyl amine and the like or mixtures thereof preferably, NaHCO3.

The phase transfer catalyst comprises tetraalkylammonium halides, tetraarylammonium halides or tetra(alkyl)(aryl) ammonium halides. The alkyl is C1-6 alkyl, such as, methyl, ethyl, propyl, isopropyl, butyl and the like. The aryl is C6-10 aryl, such as phenyl. The halide is chloride, bromide or iodide. The phase transfer catalyst is preferably selected from the group consisting of tetrabutylammonium bromide or tetrabutylammonium iodide preferably, tetrabutylammonium bromide.

The condensation reaction may also be conducted in presence of other organic catalysts such as 1,8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), and N,N-dimethylaminopyridine (DMAP).

The reaction may be performed in presence or absence of solvent. The solvent may be selected from the group consisting of water, DMSO,, alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and 2-butanol; nitrile such as acetonitrile; amide such as dimethylacetamide and dimethylformamide; ketone such as acetone, methyl ethyl ketone, methyl iso-butyl ketone; hydrocarbon such as hexane, cyclohexane, heptane, benzene, toluene, xylene; ester such as ethyl acetate, methyl acetate and isobutyl acetate; ether such as tetrahydrofuran, isobutylmethyl ether, dibutyl ether and the like; or mixtures thereof. Preferably, the solvent is mixture of methyl iso-butyl ketone and water.

The reaction is performed at a temperature of about 0 to 100°C or at reflux based on the solvent used. In an embodiment, the temperature for the condensation is 70 to 90°C.

After completion of the reaction, the reaction mixture may be cooled to less than room temperature or 0 to 35°C to affect the precipitation of solid, which may be purified by recrystallization or anti-solvent or any other known procedures in the art. In an embodiment, Risperidone is purified with the treatment of inorganic or organic base, particularly, with aqueous solution of sodium hydroxide.

In another aspect of the present invention, there is provided a process for the purification of Risperidone which comprises:
a) providing solution in a mixture of alcohol and amide solvent at elevated temperature;
b) optionally, treating the solution with charcoal at elevated temperature; and
c) cooling the solution of step (b) to obtain Risperidone having purity greater than or equal to 99.8% by HPLC.

The solution of step a) may be prepared by the dissolution of crude Risperidone having purity about 99.5% or less, preferably 99.2% or less, in a mixture of solvent or the solution may be obtained from the previous reaction step. The alcohol is selected from methanol, ethanol, isopropanol, n-butanol tert-butanol and the like; amide solvent such as dimethyl formamide and dimethyl acetamide. In an embodiment, the mixture of solvents is isopropanol and dimethyl formamide.

The elevated temperature is about 30 to about 100°C or reflux temperature of solvents used. In an embodiment, the elevated temperature is about 50 to about 90°C. The solution may be treated with charcoal or silica at 30 to 100°C and combined with seeding of Risperidone Form A and then cooled to below 50°C or below 30°C to initiate and enhance the precipitation of pure Risperidone.

The resultant of Risperidone has the purity greater than or equal to 99.8% by HPLC.

Having described the invention with reference to certain aspects embodiments, embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing the preparation of Risperidone and purification thereof. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

EXAMPLE 1: PREPARATION OF RISPERIDONE WITHOUT FORMATION OF RISPERIDONE RELATED COMPOUND-G.

6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (50 g, 0.195 moles) and 3-(2-Chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-?]pyrimidin-4-one hydrochloride (52.8 g, 0.20 moles) were charged into methyl isobutyl ketone (600 ml). Sodium bicarbonate (81.8 g, 0.97 moles) and DM Water (10 ml) and Tetra butyl ammonium bromide (10% w/w) were added to the reaction mixture and heated the contents to 82-87°C and maintained for 17 hrs. The reaction mixture was subjected for distillation of the solvent under reduced pressure at below 80°C to remove 250 ml of solvent. Thereafter, the mass was cooled to 10-14°C and stirred for 30 minutes. The mass was filtered, slurred the wet solid in aqueous sodium hydroxide solution (1.8 % w/w, 375 ml) at 40-45°C, filtered and dried to get Risperidone crude.

Yield: 62 g.

Purity: 99.29 % by HPLC;
Impurities: Risperidone isoxazole intermediate: 0.1%;
Risperidone Piperidopyrimidinone intermediate: 0.03%.
PURIFICATION OF RISPERIDONE:

Risperidone crude compound (60 g) dissolved in Isopropanol (525 ml) and N, N-Dimethylformamide (12.3 g) mixture at 80-85°C. Charcoal (6 g) treatment employed at the same temperature. Reheated the filtrate to dissolve the precipitated product at 72-76°C. Clear and hot reaction mixture seeded with Risperidone Crystalline form-A. Cooled to 22-25°C. Stir for 1 hr at this temperature. Filtered and washed with Isopropanol. Dried the compound to get pure Risperidone.

Yield: 47-52 g

Purity: 99.89;
Impurities: Risperidone isoxazole intermediate: 0.01%;
Risperidone Piperidopyrimidinone intermediate: 0.00% (ND). ,CLAIMS:WE CLAIM:

1. An improved process for the preparation of Risperidone of Formula I, which comprises condensation of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole of formula II:.

II

with 3-(2-chloroethy)-2-methyl-6,7,8,9-tetrahydo-4H-pyrido[1,2-?]pyrimidin-4-one of Formula III:

III

or salts thereof; in presence of a base and a phase transfer catalyst.

2. The process as claimed in claim 1, wherein the salt is selected from hydrochloride, hydrobromide, phosphate, sulfate, acetate, formate, triflouro acetate, 2,2-dichloroacetate, adipate and ascorbate hydrochloride.

3. The process as claimed in claim 1, wherein the base comprises organic base or inorganic base.

4. The process as claimed in claim 1, wherein the base is sodium bicarbonate.

5. The process as claimed in claim 1, wherein the phase transfer catalyst comprises tetraalkylammonium halides, tetraarylammonium halides or tetra(alkyl)(aryl) ammonium halides.

6. The process as claimed in claim 1, wherein the phase transfer catalyst is tetrabutylammonium bromide.

7. A process for the purification of Risperidone which comprises:
a) providing solution in a mixture of alcohol and amide solvent at elevated temperature;
b) optionally, treating the solution with charcoal at elevated temperature; and
c) cooling the solution of step (b) to obtain Risperidone having purity greater than or equal to 99.8% by HPLC.

8. The process as claimed in claim 7, wherein the alcohol is selected from methanol, ethanol, isopropanol, n-butanol and tert-butanol.

9. The process as claimed in claim 7, wherein the amide solvent is selected from dimethyl formamide and dimethyl acetamide.

10. The process as claimed in claim 7, wherein the mixture of alcohol and amide solvent is isopropanol and dimethyl formamide.