Abstract:
A process for the preparation of 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 (I). Risperidone of Formula (I) is represented by the following structure.

Description:
FIELD OF THE INVENTION  
       [0001]     The present invention relates to an improved process for the preparation 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 (I). It is marketed under brand name “risperidal”. Risperidone of Formula (I) of the present invention is represented by the following structure.  
                         
 
         [0002]     Risperidone is useful as antipsychotic agent in the treatment of psychotic disorders.  
       BACKGROUND OF THE INVENTION  
       [0003]     EP 196132 B1 describes certain 1,2-benzisoxazol-3-yl derivatives having psychotic and anti-serotonin activity including 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 (Risperidone), which is a mixed 5-HT 2 A/D2-receptor antagonist and is an example of typical neuroleptic drug.  
         [0004]     EP 196132 B1 exemplified the process for the preparation of Risperidone, which includes the condensation between 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one mono hydrochloride and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole in the presence of N,N-dimethyl formamide, sodium carbonate and catalytic amount of potassium iodide. The crude risperidone product was crystallized from a mixture of DMF and isopropanol to yield of 46% of Risperidone.  
         [0005]     U.S. 2002/0115672 and U.S. 2002/0115673 describes the process for the preparation of Risperidone, which also includes the processes for the preparation of crystalline Form-A, Form-B and Form-E. The process for the preparation of Risperidone comprises the condensation of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole of the Formula (II)  
                         
 
 and 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one of the Formula (III)  
                         
 
 in acetonitrile, further, the resulting crude mass was recrystallised from alcohols to get Risperidone. 
 
         [0006]     EP 196132 B1 and U.S. 2002/0115672 were suffering with many disadvantages like involving multiple operation, recovery stages and poor quality. Moreover, the product obtained from described process suffering with non-controllable impurity like “3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinylcarbonyloxy]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one”, which is commonly referred as carboxylate impurity.  
         [0007]     Hence, the object of the present invention is to provide an improved process for the preparation of substantially pure Risperidone, which is simple, cost-effective, eco-friendly and commercially suitable process by overcoming the problems encountered in the above prior art process.  
         [0008]     The free flowing solids are in general preferred for pharmaceutical applications. Apparently, the present inventive substance was pure crystalline in nature, free from residual solvents and it can be readily used for pharmaceutical applications without proceeding for further purification.  
       SUMMERY OF THE INVENTION  
       [0009]     The present invention comprises, 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 N ethyl diisopropyl amine in lower alcohols like methanol.  
         [0010]     Another objective of the present invention is to minimize the level of impurities like “3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-9-hydroxy-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one and “3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinylcarbonyloxy]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one”) in desired final product by recrystallization in aqueous alcohols  
         [0011]     Thus the process of the present invention is simple, reproducible, cost-effective, eco-friendly non-hazardous and hence can be well suited for large-scale production. 
     
    
     DESCRIPTION OF FIGURES  
       [0012]      FIG. 1  is an X-ray powder diffractogram of a Risperidone crystalline form prepared by according to the present invention.  
         [0013]      FIG. 2  is a differential scanning calorimetric thermogram of a Risperidone crystalline form prepared by according to the present invention.  
         [0014]      FIG. 3  is an infrared absorption spectrum of a Risperidone crystalline form prepared by according to the present invention 
     
    
     DESCRIPTION OF THE INVENTION  
       [0015]     The present invention related to process for the preparation of 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 comprises; 
        a) dissolving 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 lower alcohols like methanol, ethanol, propanol;     b) adding an organic base like N ethyl diisopropyl amine to the above step (a) solution;     c) heating the resulting solution of step (b) upto 45 to 50° C.;     d) maintaining the reaction mass of step (c) for about 55 to 80 hours;     e) cooling the above solution of step (d) upto 25 to 35° C.;     f) separated solids from step (e) were filtered and washed with methanol;     g) slurring the wet filtered solids of step (f) with water for about 30 to 60 minutes at 25 to 35° C.;     h) filtering the solids of step (g), followed by washing with water and then spin dried for 30 to 60 minutes;     i) wet compound further dried at 70 to 75° C. for 4 hours under reduced pressure;     j) loading the resulting compound in 5-15% aqueous ethanol;     k) heating the resulted mass upto 40 to 45° C. for complete dissolution;     l) maintaining the above solution for about 20 minutes at the same temperature and filtered out under nitrogen atmosphere;     m) cooling the solution to 0 to 5° C. and then maintained for about 30 to 60 minutes;     n) centrifuging the solid of step of (m);     o) washing the separated solids of step (n) with chilled 5% aqueous ethanol and spin dried for 30 to 60 minutes to get 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.        
 
         [0031]     Crystalline form of the Risperidone of the present invention is free flowing solid.  
         [0032]     The present invention is illustrated by the following examples, which are not intended to limit the effective scope of the invention.  
       Process for the Preparation of 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  
     EXAMPLE 1  
       [0033]     6-Fluoro-3-(4-piperidinyl)-1,2-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) and diisopropyl ethylamine (14.1 grams) were dissolved in methanol (90.0 ml). The resulting reaction mixture was maintained at 45-50° C. for about 70-100 hours. The reaction mass was then cooled to 25-35° C. and then separate solid product. The solid mass was filtered and washed with methanol (20.0 ml) followed by water (120.0 ml). The wet product was dried at 70-80° C. to get 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. (Yield: 29.0 g; 77.8%; purity by HPLC is 99.93%)  
       EXAMPLE 2  
       [0034]     6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10 Kg), 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (11.3 Kg) and diisopropyl ethylamine (7 Kg) were dissolved in methanol (45 Lt). The resulting reaction mixture was maintained at 45-50° C. for about 70 to 100 hours. The reaction mass was then cooled to 25-35° C. and then separate solid product. The solid mass was filtered and washed with methanol (10 Lt) followed by water (60 Lt). The wet product was dried at 70-80° C. to get 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. (Yield: 18 Kg, purity by HPLC is 99.93%).  
       Purification of 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  
     EXAMPLE 3  
       [0035]     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 (15 Kg) was charged into 5% aqueous ethanol (180 Lt). The resulting mixture was heated up to 40 to 45° C. and maintained at the temperature upto 20 minutes. The solution was filtered through a cartridge filter at the same temperature. The clear solution was cooled to 0 to 5° C. and maintained for 30 to 60 minutes. The resulting crystalline material was centrifuged and washed with chilled 5% aqueous ethanol (7.5 Lt). The wet material was dried in a vacuum cone drier at 70 to 75° C. for about 7 hours. The hot material was cooled to room temperature.