Technical field The above compound is commonly known as risperidone and is of the formula I : Formula I Risperidone elicits its action by antagonising serotonine.

Rispeiidone is a highly potent drug used in the treatment of schizophrenic states and also shows broader applications in other areas of psychosis.

Background Art Risperidone of the formula I is known to be prepared by the condensation of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido (1,2,-a]pyrimidin-4-one of the formula IIA: Formula IIA with 4- (2, 4-difluorobenzoyl) piperidine of the formula III: Formula III in organic solvent such as methylene dichloride, acetonitrile, N,N-dimethyl irmanide (duff) or N-methyl pyrrolidone in the presence of an inorganic base such as sodium hydroxide, carbonate or bicarbonate at 50-100°C, followed by oxidation and cyclisation (Spanish Patent No 2, 050, 069).

Inorganic bases used in the above reaction being sparingly soluble in organic solvent used as medium Ibr the reaction, they may not neutralise the acid by-product last with the result that the neutralisation may be sluggish. Due to the slow removal of the acid by-product from the reaction mixture, there are chances of decomposition of the condensation product, thereby reducing the yield and purity thereof. The yield of condensation product obtained by this condensation process is low of the order of 63. 1%.

This process is therefore inefficient and uneconomical. The medium for the condensation being organic, isolation of the condensation product is to be carried out by quenching the reaction mixture with water followed by extraction with organic solvent such as-methylene dichloride. Solvent extraction is cumbersome, lengthy and time-consuming and also engenders poor recovery of organic solvent used for the reaction. Also organic solvents such as DMF are reported to decompose in the presence of inorganic bases at elevated temperatures (Encyclopedia of Chemical Technology, 3rd edition, 11, 263) further complicating isolation. Besides, use of organic solvents as medium for the reaction makes the process further expensive and uneconomical. Moreover, solvents such as DMF are hazardous and pollute environment when used in large scale and also entail effluent disposal/treatment problems.

Risperidone of the formula I may also be prepared by the condensation of chlorotetrahydro pyridopyrimidine of the formula HA. with 6-fluoro-3- (4-piperidinyl)- 1, 2-benzisoxazole of the formula IV : Formula IV in an organic solvent such as DMF, 4-methyl-2-pentanone, benzene, ethanol, 1, 4-dioxane, tetrahydrofuran, nitrobenzene or I-methyl-2-pyrrolidinone in the presence of an organic base such as. N, N-dieEwJlethmnine, 4-ethyl morpholine or N- (I-methylethyl)-2-propanamine or an inorganic base such as sodium or potassium carbonate, sodium hydrogen carbonate or sodium methoxide, hydroxide or hydride, usually at 85-900C.- (US Patent No 4804663). The organic bases which may be used in the above condensation are expensive and their use makes the above reaction uneconomical.

Inorganic bases when used in organic solvent medium may result in decomposed condensation product as earlier discussed. The yield of the product obtained by this method is low of the order of 46% and renders the process inefficient and uneconomical. The reaction medium being organic, the isolation of the condensation product is to be carried out by quenching the reaction mixture with water followed by filktation of the resulting solid and recrystallisstion thereof from an organic solvent such as DMF. This isolation procedure besides being cumbersome, suffers from poor solvent recovery.

Also due to use of inorganic bases in organic solvent such as DMF, isolation becomes further complicated for reasons as explained earlier. Organic solvents used as reaction medium further makes the process expensive and uneconomical. Also this process is not free from the disadvantages due to use of solvents such as DMF as aforesaid.

The intermediate chloro tetrahydro pyddopyrimidine of the formula IIA in the synthesis of anti-psychotic rispendone of the formula I may be obtained by hydrogenation of 3-(2-chloroethyl)-2-methyl-4H- pyrido[1,2,-a]pyrimidin-4-one of the formula VA: Formula VA in acetic acid medium at 50 psi and at 25-30°C in the presence of Pd/C catalyst. (A Thesis entitled "Synthesis of Drugs & Drug Intermediates" submitted to "The University Of Mumbai" by Ms Evelyn D Lobo, p35, June 1996, for the degree of M M charm Sci.). This hydrogenation may produce predominantly decMonnated compounds as by-products, smce dechlorination may be accelerated in acetic acid medium. This may result in low yield and purity of the product. The yield of the product obtained by this method is low of the order of 77%, thus making this process inefficient and uneconomical.

The isolation of the product involves nitration of the catalyst followed by evaporation of acetic acid from the reaction mixture, dissolving the resulting residue in a solvent, deacidiiication and evaporation of solvent followed by recrystalhsation of the resulting solid from 2-propanol Such mutiple stçs for isolation are cumbersome, lengthy and time consuming. Acetic acid is a hazardous and ammable solvent and pollutes the environment when used in large scale. Also its use makes the process experisive and further uneconomicat.

The chloro tetrahydro pyddopydmidme reactant of the formula IIA may also be prepared by hydrogenation of the 3-(2-hyboxyethyl)-2- methyl-4H-pyrido[1,2,-a]pyrimidin-4-one of the formula VI : Formula VI using Pd/C catalyst m aqueous ethanol at 25-30°C followed by reacting the resulting hydroxyethyl tetrahydro pyridopyrimidine compound of the formula vil-- FormulaVII with thionyl chloride in methylene chloride at 25-30"C for 24 hours (Spanish Patent No 2,050, 069). This route involves two steps for the preparation of the compound of the formula IIA and is lengthy and time-consuming. Moreover, thionyl chloride is hazardous and when used in large scale, pollutes the environment. The overall yield of the product obtained by this method is low of the order of 44% due to two moderately yielding steps, thus making the process inefficient and uneconomical.

An object of the invention is to provide a process for the preparation of risperidone of the formula I, which is simple and less time consuming.

Another object of the invention is to provide a process for the preparation of risperidone of the formula I, which is inexpensive and economical.

Another object of the invention is to provide a process for the preparation of risperidone of the formula 1, which results in high yield and purity of lisperidone and is efficient.

Another of the invention is to provide a process for the preparation of risperidone of the formula I, which is safe and does not pollute the environment.

Another object of the invention is to provide a process for the preparation o weridone of the formula 1, which is commercially feasible.

Another object of the invention is to provide a process for the preparation of tetrahydro pyridopyrimidine of the formula Which lu simple and less time consuming.

Another object of the invention is to provide a process for the preparation of tetrahydro pyridopyrimidine of the formula IIB, which is inexpensive and economical.

Another object of the invention is to provide a process for the preparation of tetrahydro pyridopyrimidine of the formula IIB, which results in high yield and purity of tetrahydro pyridopyrimidine and is efficient.

Another object of the invention is to provide a process for the preparation of chlorotetrahydro pyiidopynmidine of the formulaIIB, which is safe and does not pollute the environment.

Another object of the invention is to provide a process for the preparation of chlorotetrahydro pyridopynmidine of the formula IIB, which is commercially feasible.

Disdosure of the invention According to the invention there is provided a process for the preparation of 3-substituted ethyl-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2,- ajpyrimidm-4-one of the formula IIB : Formula IIB where X may be halo, acyloxy, or sulfoyloxy such as tosyloxy or mesyloxy, comprising hydrogenation of 3-substit-uted ethyl-2-methyl-4H-py'ndo [1, 2,- alpyrimidin-4-one of the formula VB: Formula VB in aqueous inorganic acid medium at atmospheric to 60 psi at 0-lOQ°C m ie presence of a metal catalyst followed by isolation of the resulting product.

According to the invention there is also provided a process for the preparation of anti-psychotic 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- piperidinyl] ethyl3-6, 7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2,-a]pyrimidin-4- one, commonly known as lisperidone of the formula I : Formula I comprising condensation of 3-substituted ethyl-6, 7, 8,9-tetrahydro-2-methyl- 4H-pyrido[1,2,-a]pyrimidin-one of the formula IIB : Formula IIB where X may be halo, acyloxy or sulfonyl such as tosyloxy or mesyloxy, with 6-5uoio-3- (4-pipendmyl)-l, 2-ben2isoxazole of the formula IV : Formula IV in water in the presence of an inorganic base at 25-100°C followed by isolation of the resulting product.

The compound of the formula IIB is an intermediate in the synthesis of the anti-psychotic risperidone.

The term halo includes chloro, bromo or iodo. Preferably X may be chloro.

The pyndopyrimidine compound of the formula VB may be prepared in known manner. (A thesis entitled"Synthesis of Drugs and Drugs Intermediates"submitted to"The University of Mumbai"by Ms Evelyn D Lobo, p 30, June 1996, for the degree of M Pharm Sci.).

The inorganic acid in the aqueous medium for the hydrogenation may be sulfuric acid, hydrochloric acid or hydrobromic acid, preferably hydrochloric acid. The inorganic acid solubilises the pyndopyrimidine compound of the formula VB in aqueous medium by converting it to its water soluble salt, prior to hydrogenation.

The metal catalyst may be platinum, palladium, nickel, rhodium or ruthenium supported on solid support such as calcium carbonate, alumina, barium sulfate, silica or activated carbon. Preferably palladium supported on activated carbon may be used.

Preferably the reduction temperature may be 25-40°C.

Preferably the hydrogenaton is carried out at pressure of 25 psi.

The isolation of e ahydro pyIidopyrimidine of the formula IIB may be carried out bs filtration of the metal cmalyst followed by pH adjustment to 4 - 10 of the resulting mixture with a base such as an alkali metal hydroxide or carbonate. The resulting solid is then filtered at 0-50°C, preferably at 10-20°C. Alternatively the filtrate after removal of catalyst, may be directly subjected to insitu condensation with the compound of the formula IV to produce risperidone.

The benzisoxazole compound of the fonnula IV may be prepared in knownmanner (USPatent Nos 4,355,037 and 4,804,663).

The inorganic base used in the condensation may be an alkali metal carbonate such as sodium potassium or lithium carbonate or sodium bicarbonate or an alkaline earth metal carbonate such as calcium, barium or strontium carbonate or an alkali metal hydroxide such as sodium, potassium or lithium hydroxide or an alkaline earth metal hydroxide such as calcium, barium or strontium hydroxide. Preferably sodium carbonate may be used.

The condensation temperature may be preferably 60-90°C.

The isolation of lispeiidone from the reaction mixture is carried out by filtration at 25-40'C followed by purification, preferably by crystallisation using organic solvents such as DMF or N,N-dimethyl acetamide or C 3 aliphatic alkanol or ether such as diethyl ether or diisopropyl ether or tetrahydrofuran or ketone such as 2-propanone utanone or 4-methyl-2- pentanone, preferably DMF.

The process of the invention for the preparation of the tetrahydro pyridopyrimidme of the formula IIB is carried out in aqueous medium because of which it proceeds at a controlled rate. Therefore dechlorination of the compound of the formula IIB when X is chloro, is prevented. The process of the invention results in high yield (83%) and purity (99%) of the product of the formula IIB and is efficient and economical. The tetrahydro pyridopyrimidine compound of the formula IIB is obtained from a single step reaction and eliminates multiple steps for isolation as described in the prior art. The procedure to isolate the product of the formula IIB obtained by the process of the invention comprises filtration of the catalyst, pH adjustment and filtration of the resulting solid, and is therefore simple, less cumbersome, less tedious and less-time consuming when compared to the prior art methods. The compound of the formula IIB when subjected to insitu condensation makes the process for the preparation of rispeiidone furi. her less time-consuming md economical. The process also eliminates hazardous solvents and pollution of the environment caused thereby and is safe to carry out. The use of water instead of organic solvents as medium for the reaction makes the process further inexpensive and economical and also eliminates solvent recovery/disposal/treatment problems as in the prior art. Due to the above reasons, this process is also commercially feasible.

According to the invention the process for the preparation of risperidone is earned out in an aqueous medium in the presence of an inorganic base. The solubility of the inorganic base in the aqueous medium being high, the neutralisation of the acid by-product formed during the condensation is fast by the inorganic base in solution form. This prevents degradation of rispcridone by the acid by-product and also results in high yields (66-72%) and purity (-99%) thereof, thereby making the process efficient and economical. The process of the invention does not use organic bases and is inexpensive. The reaction medium being aqueous, quenching with water or extraction with organic solvents is unnecessary for isolation of risperidone. The isolation procedure involves a single step ie filtration and is therefore simple, less cumbersome and less time-consuming when compared to the prior art methods. The process eliminates use of hazardous solvents and pollution of the environment caused thereby and is safe. The use of water as medium instead of organic solvents is inexpensive and economical and eliminates solvent recovery/disposal/treatment problems as in the prior art. Due to the above reasons, the process of the invention is commercially feasible.

The following experimental examples are illustrative of the invention but not limitative of the scope thereof.

Example 1 Preparation of 3- (2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H- pyrido [1, 2,-a]pyrimidin-4-one of the formula II A :- To a 500 ml hydrogenation flask was charged 3- (2-chloroethyl)- 2-methyl-4H-pyrido[1,2,-a]pyrimidin-4-one (20.0 g 99% pure by HPLC analysis), water (50.0 ml), 30% HCl (10.0 ml) and 10% Pd/C (2.0 g). The contents of the flask were reduced with hydrogen gas at pressure 25 psi under agitation for 6 hours at 30°C The catalyst in the reaction mixture was filtered through Whatmann 1 filter paper. The filtrate free from catalyst was basified by addition of 45% caustic soda lye (6. 0 ml). The product was filtered and dried.

The product obtained was characterised by Nuclear Magnetic Resonance (NMR) Spectrosopy as follows : 1H NMR (60 MHz), CDCl3 : # 3.7 (m, 4H); # 2. 9 (t, J = 6Hz, 2H); # 2.3 (s, 3H); S 1. 8 (m, 6H).

Yield-16. 6 g (83%) Purity = 99% [when analysed by High Performance Liquid Chromatography (HPLC)] Example 2 Preparation of of [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 of the formula 1) :- To a 10. L flask was charged the tetrahydro pyridopyrimidine (666.0 g) of Example 1, water (3330.0 ml) and 6-fluoro-3-(4-piperidinyl)- 1, 2-benzisoxazol (639. 0 g) and sodium carbonate (1152. 0 g). The contents of the Bask were heated to 85-90'C and stirred for 4 hours. The reaction mixture was cooled to room temperature and filtered. The product was purified by crystallisation from DMF.

The product was characterised by NMR spectroscopic studies as follows : 'H NMR (60 lvfhz, CDCl3) : S 7. 5 - 7.9 (m, 1H) ; 6 6.8 - 7.45 (m, 2H); # 3.8 -4 (m, 2H); # 2.45 - 3. 5 (m, 11H) ; # 2. 35 (s, 3H); # 1.65 - 2. 25 (m, 8H).

Yield = 865 0 g (72%) Purity = 99% (when analysed by HPLC) Example 3 Preparation of 3- [2- [4- (6-fluoro-l, 2-benzisoxazol-3-yl)-l-piperidmyi] ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2,-a] pyrimidin-4-one (Risperidone of the formula 1) by one-pot reaction :- The BItrate free from catalyst of Example 1 was neutralised by addition of 45% caustic soda lye (5.5 ml) in a 250 ml flask. To it were charged 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (19.2 g) and sodium carbonate (34.6 g). The reaction mixture was heated to 85-90°C for 4 hours under stirring, cooled to room temperature and Stored. The cake was purified by crystallisation from DMF.

The product was was characterised by NMR spectroscopic studies as follows : IH NMR (60 MHz, CDCl3) : # 7.5-7. 9 (m, 1H); # 6.8 - 7.45 (m, 2H) ; # 3.8-4 (m, 2H); # 2.45-3.5 (m, 11H) ; 8 2.35 (s, 3H) ; 8 1.65-2.25 (m, 8H).

Yield = 30. 0 g (72%) Purity = 99% (when analysed by BPLC)