Title of Invention

A SIMPLE AND AN IMPROVED PROCESS FOR THE PREPERATION OF RISPERIDONE

Abstract The present invention relates to an improved process for the preparation of crystalline form of pure 3-[2-[ 4-(6-Fluoro-1, 2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6,7 ,8,9- tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, which is known as risperidone of Formula (1). The process for the preparation of pure risperidone of the present invention comprises the condensation of 3-(2-Chloroethyl)-6, 7 ,8,9-tetrahydro-2-methyl-4H-pyrido [1 ,2-a] pyrimidin-4-one and 6-Fluoro-3-( 4-piperidinyl)-1 ,2-benzisoxazole in presence a tertiary amine base like diisopropyl ethyl amine in lower alcohols like methanol. The process of the present invention is simple, cost-effective, eco-friendly non-hazardous and hence can be well suited for large-scale production.
Full Text

FIELD OF THE INVENTION
The present invention is the complete speciflcation form for our provisional application
No. 30/MAS/2003, dated 13/01/2003.
The present invention relates to an improved process for the preparation of crystalline form of pure 3-[2-[4-(6-Fluoro-l, 2-benzisoxazol-3-yl)-l-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, which is known as risperidone of Formula (1). It is marketed under brand name "risperidal". Risperidone of Formula (1) of the present invention is represented by the following structure.
rispenaone is usemi as aniipsycnoiic ageni m ine ireaimeni oi psycnouc aisoraers. BACKGROUND OF THE INVENTION
EF 196132 Bl disclosed certain l,2-benzisoxazol-3-yl derivatives having psychotic and anti-serotonin activity including 3-[2-[4-(6-Fluoro-l, 2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one (Risperidone), which is a mixed 5-HT2A/D2-receptor antagonist and is an example of typical neuroleptic drug. EP 196132 Bl exempUfied the process for the preparation of risperidone, which comprises the condensation of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l ,2-a] pyrimidin-4-one mono hydrochloride and 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole in N,N-dimethyl formamide in presence of sodium carbonate with catalytic amount of

potassium iodide. The crude risperidone product is crystallized from a mixture of DMF and isopropanol with an overall yield of 46%.
US 2002/0115672 and US 2002/0115673 also disclosed the process for the preparation of Risperidone including the processes for the preparation of polymorphs Form-A, Form-B and Form-E. The process for the preparation of risperidone comprises the condensation of 6-fluoro-3-(4-piperidin- yl)-l,2-benzisoxazole of the Formula (2)

and3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-oneofthe Formula (3)
in acetonitrile, isopropanol, iso-butanol, or methyl ethyl ketone, preferably acetonitrile as the solvent, and further recrystallised the crude risperidone from an alcohol such as, methanol, ethanol, isopropanol, propanol, butanol, sec-butanol and tert-butanol; a mixture of alcohols containing any combination of methanol, ethanol, isopropanol, propanol, butanol.

sec-butanol and tert-butanol; or a mixture of water and alcohol where the alcohol is one or more of the following alcohols, methanol, ethanol, isopropanol, propanol, butanol, sec-butanol and tert-butanol.
The process for the preparation of risperidone Form-A comprises of dissolving risperidone in an organic solvent selected from the group consisting of dimethylformamide, tetrahydrofuran, acetone, benzene, ethyl methyl ketone, n-butanol, methanol, isopropanol, absolute ethanol, acetonitrile, toluene, dimethyl sulfoxide, iso-butanol, and ethyl acetate or mixtures thereof, heating the solvent to reflux, cooling the solvent to facilitate precipitation to isolate the risperidone Form-A.
It also provides another process for preparing risperidone Form-A, which comprises of dissolving risperidone in dichloromethane followed by adding cyclohexane or hexane to facilitate precipitation to isolate risperidone Form-A.
It also provides another method for preparing risperidone Form-A, which comprises of heating risperidone Form-B (or a mixture of Form-A and Form-B) at a temperature of about 25-80 ^C for a time sufficient to induce to formation of risperidone Form-A, isolating risperidone Form-A. In another embodiment, the heating takes place under reduced pressure or at atmospheric pressure.
US 2002/0115672 also provides a process for preparing risperidone Form-B, which comprises of dissolving risperidone in chloroform followed by adding cyclohexane or hexane to facilitate precipitation to isolate risperidone Form-B.
US 2002/0115672 also provides a process for preparing risperidone Form-B, which comprises of dissolving risperidone in an aqueous solution of HCl followed by adding an aqueous solution of NaCOs to isolate risperidone Form-B.

us 2002/0115672 also provides a process for preparing risperidone Form-E, which
comprises of dissolving risperidone in isopropanol where the ratio of risperidone to
isopropanol is about 1:12, adding water to facilitate precipitation to isolate risperidone
Form-E.
The processes for the preparation of risperidone as disclosed in the above-mentioned patents
EP 196132 Bl and US 2002/0115672 is having some disadvantages as they include more
number of operations and stages, which turns the process into less cost-effective.
The process disclosed in EP 196132 consists the use of dimethylformamide-isopropanol
solvent mixture for recrystallisation, which makes the process less eco-friendly as the
recovery of dimethylformamide is cumbersome exercise.
Moreover during our laboratory experimentation as a part of process development an
impurity "3-[2-[4-(6-Fluoro-l, 2-benzisoxazol-3-yl)-l-piperidinylcarbonyloxy] ethyl]-
6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one", which is commonly
referred as carboxylate impurity. The said impurity is observed in the product while using
Na2CO3 as a base.
Hence, the object of the present invention is to provide an improved process for the
preparation of pure risperidone, which is simple, cost-effective, eco-friendly and
commercially suitable process by overcoming the problems encountered in the prior art
process.
The free flowing solids are in general preferred for pharmaceutical applications, present
inventive substance is in pure crystalline form, free from residual solvent and it can be used
for pharmaceutical applications without proceeding for fixrther purification.

Risperidone of the present invention is characterized by X-ray powder diffractogram and IR
spectrum.
SUMMERY OF THE INVENTION
An object of the present invention is to provide more efficient, simple and an improved process for making crystalUne form of pure 3-[2-[4-(6-Fluoro-l, 2-benzisoxazol-3-yl)-l-piperidinyl] ethyl]"6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one (Risperidone).
The process for the preparation of pure risperidone of the present invention comprises the condensation of 3-(2-Chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one and 6-Fluoro-3-(4-piperidinyl)-l,2-benzisoxazole in presence a tertiary amine base like diisopropyl ethylamine in lower alcohols like methanol.
Another aspect of the present invention is to minimize the impurities of "3-[2-[4-(6-fluoro-l, 2-benzisoxazol-3-yl)-l-piperidinyl] ethyl]-9-hydroxy-6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one" which is commonly referred as 9-hydroxy impurity and "3-[2-[4-(6-fluorO"l,2-benzisoxazol-3-yl)-l-piperidinylcarbonyloxy]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one", which is commonly referred as carboxylate impurity.
Crystalline form of pure risperidone obtained in the present invention is having substantially pure Form-I and thus it can be used as such without any further purification in the pharmaceutical formulations.
Thus the process of the present invention is simple, cost-effective, eco-firiendly non-hazardous and hence can be well suited for large-scale production.

BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS
Fig. 1 is a characteristic X-ray powder diffractogram of crystalline form pure risperidone of
the present inventive substance.
Fig. 2 is a characteristic Differential Scanning Colorimetric thermogram of crystalline form
pure risperidone of the present inventive substance.
Fig. 3 is a characteristic Infrared absorption spectrum of the crystalline form pure risperidone
of the present inventive substance.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to an improved process for the preparation of crystalline
form of pure risperidone. The crystalline nature of risperidone Form-I of the present
invention can be characterized by its X-ray powder diffractogram, Differential Scanning
Colorimetric thermogram and Infrared spectrum.
The X-ray powder diffraction pattern of crystalline form of pure risperidone was measured
on a Bruker Axs, D8 Advance Powder X-ray Diffractometer with Cu K alpha-1 Radiation
source.
The crystalline form of pure risperidone has X-ray powder diffraction pattern essentially as
shown in the Table-1. The X-ray powder diffraction pattern is expressed in terms of the
2-theta (degrees), and percentage of intensity (in %).
Table-1:


The present invention of crystalline form of pure risperidone was characterized by its X-ray powder diffraction substantially as depicted in Figure (1).
The present invention provides the Differential Scanning Calorimetry thermogram of crystalline form of pure risperidone. The Differential Scanning Calorimetry thermogram exhibits a significant endotherm peak at 173.27^C and substantially as depicted in Figure (2). The present invention provides the Infrared data for crystalline form of pure risperidone, which was measured by KBr-transmission method with significant peaks about 3015.08, 2942.16, 2757.32, 1650.83, 1535.45, 1130.48, 958.59, 842.40, 817.45, 711.91, 611.14 and 533.16 cm"'.

The present invention provides the Infra-red spectrum of crystalUne form of pure risperidone substantially as depicted in Figure (3).
Accordingly an improved process for the preparation of crystalline form of pure 3-[2-[4-(6-fluoro-l, 2-benzisoxazol-3-yl)-l-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one (pure risperidone), which comprises;
a) heating the reaction mixture of 3-(2-chloroethyl)-6J,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one and 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole in presence a tertiary amine base like triethyl amine, tributyl amine, diisopropyl ethylamine, preferably diisopropyl ethylamine, lower alcohols like methanol, ethanol, isopropanol, butanol, iso-butanol, preferably methanol to a temperature of35-60^C, preferably 45-50 ^C;
b) maintaining the reaction mixture of step (a) at the same temperature for 25-125 hours, preferably 50-100 hours;
c) cooling the reaction mixture of step (b) to room temperature;
d) isolating the compound obtained in step (c) by conventional methods;
e) drying the isolated solid obtained in step (d) at a temperature of 55 to SO^^C to afford the desired pure form of risperidone.
Crystalline form of the risperidone of the present invention is free flowing solid. Thus the process of the present invention is simple, cost-effective, eco-friendly non-hazardous and hence can be well suited for large-scale production. The present invention is illustrated by the following examples, which are not intended to limit the effective scope of the claims.

EXAMPLE-1
6-Fluoro-3- (4-piperidinyl)-l,2-benzisoxazole (20.0 grams), 3-(2-chloroethyl)-6,7,8,9-
tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one( 22.6 grams), diisopropyl ethylamine
(14.1 grams) and methanol (90.0 ml) were maintained at 45-50oC for about 70 hours . The
reaction mass was then cooled to 25-35*^0 filtered the separated product and washed with
methanol (20.0 ml) followed by water (120.0 ml). The wet cake was dried at 70-80^C.
(Yield: 29.0 g; 77.8%; % purity by HPLC is 99.93%)
DETAILED DESCRIPTION OF ACCOMPANYING DRAWINGS
Fig: 1 is characteristic X-ray powder diffraction pattem of the crystalline form of pure
risperidone
Vertical axis: hitensity (CPS); Horizontal axis: 2 Theta (degrees).
The significant 2 theta values (in degrees) obtained are 6.918, 10.534, 11.330, 14.111,
14.726, 15.375, 16.317, 18.372, 18.821, 19.686, 21.194, 22.034, 22.363, 23.067, 23.365,
24.272, 25.161, 27.428, 28.373, 28.915, 32.972, 38.419.
Fig: 2 is characteristic Differential Scanning Calorimetric thermogram of crystalline form of
pure risperidone. The Differential Scanning Calorimetric thermogram exhibits a significant
endotherm peak at 173.27oC.
Vertical axis: Temperature (in oC); Horizontal axis: Signal (in mV).
Fig: 3 is characteristic Infra-red spectrum of crystalline form of pure risperidone with
identified significant peaks at about 3015.08, 2942.16, 2757.32, 1650.83, 1535.45, 1130.48,
958.59, 842.40, 817.45, 711.91, 611.14 and 533.16 cm-
Vertical axis: Wave length (in Cm-1); Horizontal axis: Transmission (in %).



We claim:
1. An improved process for the preparation of crystalline form of pure 3-[2-[4-(6-
Fluoro-1, 2-benzisoxazol-3-yl)-l-piperidinyl] ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-
pyrido [1,2-a] pyrimidin-4-one (pure risperidone) of Formula (1) comprises of:
a) heating the reaction mixture of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one and 6-Fluoro-3-(4-piperidinyl)-l,2-benzisoxazole in presence a tertiary amine base like triethyl amine, tributyl amine, diisopropyl ethylamine, preferably diisopropyl ethylamine, lower alcohols like methanol, ethanol, isopropanol, butanol, isobutanol, preferably methanol to a temperature of 35-60^C, preferably 45-50*^0;
b) maintaining the reaction mixture of step (a) at the same temperature for 25-125 hours, preferably 50-100 hours;
c) cooling the reaction mixture of step (b) to room temperature;
d) isolating the compound obtained in step (c) by conventional methods;
e) drying the isolated solid obtained in step (d) at a temperature of 55 to 80oC to afford the desired pure form of risperidone.

2. The process according to claim 1 of step (a), where in the solvent used is selected from C1-4 straight or breached chain alkanol.
3. The process according to claim 2, where in the alkanol solvent used is methanol.
4. The process according to claim 1 of step (a), where in the base used is tertiary amine base.
5. The process according to claim 4, where in the tertiary amine base used is diisopropyl ethylamine.

6. The process according to claim 1 of step (a), where in the temperature is ranging from
45-50oC.
7. The process according to claim 1, where in the final product of the present inventive
substance has purity of more than 99.9% by chromatography.
8. The process according to claim 7, where in the final product of the present inventive
substance has singe maximum impurity less than 0.1 % by chromatography.
9. The process according to claim 8, where in the final product of the present inventive
substance has 3-[2-[4-(6-Fluoro-l, 2-benzisoxazol-3-yl)-l-piperidinyl]-ethyl]-9-
hydroxy-6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one (9-hydrxy
impurity) less than 0.0025 % by chromatography.
10. The product obtained as per the claim lis free from the residual solvent methanol.
11. A process according to claim 1, wherein the final product of the present inventive
substance is having less than 1% of Form-II.
12. A process according to claim 1, wherein the final product of the present inventive
substance is having moisture less than 0.2%
13. The process for the preparation of crystalline form of pure risperidone substantially as
herein exemplified.


Documents:

030-che-2003-abstract.pdf

030-che-2003-claims.pdf

030-che-2003-correspondnece-others.pdf

030-che-2003-correspondnece-po.pdf

030-che-2003-description(complete).pdf

030-che-2003-description(provisional).pdf

030-che-2003-drawings.pdf

030-che-2003-form 1.pdf

30-CHE-2003 AMANDED PAGES OF SPECIFICATION 15-12-2009.pdf

30-CHE-2003 EXAMINATION REPORT REPLY RECEIVED15-12-2009.pdf

abs-30-che-2003.jpg

abs-30.jpg


Patent Number 239409
Indian Patent Application Number 30/CHE/2003
PG Journal Number 13/2010
Publication Date 26-Mar-2010
Grant Date 18-Mar-2010
Date of Filing 13-Jan-2003
Name of Patentee DR.REDDYS LABORATORIES LIMITED
Applicant Address DR.REDDYS LABARATORIES, 7-1-27,AMEERPET, HYDERABAD
Inventors:
# Inventor's Name Inventor's Address
1 DHRI. REGURI BUCHI REDDY DR.REDDYS LABARATORIES, 7-1-27,AMEERPET, HYDERABAD
2 SUNKARI SUDHAKAR DR.REDDYS LABARATORIES, 7-1-27,AMEERPET, HYDERABAD
3 CHAKKA RAMESH DR.REDDYS LABARATORIES, 7-1-27,AMEERPET, HYDERABAD
4 TAMMA RANGA REDDY DR.REDDYS LABARATORIES, 7-1-27,AMEERPET, HYDERABAD
PCT International Classification Number C07D239/70
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA