FIELD OF THE INVENTION:

The present invention relates to a novel process for the preparation of Tolcapone or its pharmaceutically acceptable salts thereof of Formula -I.

BACKGROUND OF THE INVENTION:

Tolcapone is chemically known as (3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl) methanone, which is represented by a structural formula I Tolcapone is an inhibitor of catechol-O-methyl transferase (COMT), marketed by Valeant Pharmaceuticals under the trade name TASMAR®. Tasmar is used to treat patients with Parkinson's disease. Parkinson's disease is a progressive brain disorder that causes shaking, slow movement and muscle stiffness. The commercially available tablet contains Tolcapone 100 Mg and 200 Mg along with inert compression excipients. Tolcapone was first disclosed in US 5,236,952, which is assigned to Hoffmann La Roche Inc. • This patent discloses Tolcapone and its analogues, which are well known catechol-O-methyl-transferase (COMT) inhibitors and are especially suitable for the therapy of Parkinson's disease and for the treatment of depression and similar disease states. The synthesis of Tolcapone, as reported in this patent is as depicted below: The other analogous catechol-O-methyltransferase inhibitors are described by Borgulya et al. (Helvetica Chimica Acta (1989) 72, 952-968), using a similar process, which is schematically represented as above, which have an unsubstituted phenyl ring. Further, US patent US 5,236,952 also discloses another route for synthesizing Tolcapone, which is as depicted below:

SCHEME – II Synthesis of 4-benzyloxy-3-methoxy-4-methyl benzhydrol is achieved by reacting 4-benzyloxy-3-methoxy bromo benzene with 4-methyl benzaldehyde in the presence of n-butyl lithium. Further conversion of this intermediate is similar to the process used in the scheme I US 5,476,875 B2 assigned to Hoffmann La Roche Inc., this patent discloses a method of use of Tolcapone for treating Parkinsonism. US 6,962,717 Bl assigned to Disphar Internat B V., discloses Pharmaceutical Composition for preparation of oral tablet of Tolcapone. Another method of synthesis is reported in Synthetic Communications 38 (5) pp 810-815 (2008) which is schematically represented as below:

SCHEME – III According to this process, 4-benzyloxy-3-methoxy benzaldehyde is reacted with 4-methyl phenyl magnesium bromide to give 4-benzyloxy-3-methoxy-4'-methyl benzhydrol, which on oxidation, gives the corresponding benzophenone derivative. Debenzylation of 4-benzyloxy- 3-methoxy-4'-methyl benzophenone using ammonium formate in the presence of Pd/C gives 4-hydroxy-3-methoxy-4'-methyl benzophenone, which on nitration, yields 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzophenone. Demethylation of 4-hydroxy-3-methoxy-4'-methyl-5-nitro benzophenone gives Tolcapone. US patent 5,877,353 discloses a different from process and the route of synthesis is represented as below:

SCHEME – IV According to the process, Veratrol is reacted with p-methylbenzoyl chloride in the presence of aluminium chloride using Freidel-Craft acylation to form 4-hydroxy-3-methoxy-4'-methylbenzophenone, which is treated with nitric acid to obtain 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzophenone, which is further demethylated to produce Tolcapone. The above mentioned routes for related benzophenones, has considerable disadvantages, which are primarily associated with the high number of steps of the synthesis and the time/apparatus expenditure associated therewith. Moreover, relatively expensive starting materials and also the industrially disadvantageous steps. The present inventors have now found a much simpler, cost effective process when compared to other prior art process.

OBJECTIVE OF THE INVENTION:

The main object of the present invention is to provide a novel, simple, cost effective and industrially advantageous process for the preparation of Tolcapone and its pharmaceutically acceptable salts thereof on commercial scale.

SUMMARY OF THE INVENTION:

The main objective of the present invention is to provide a novel process for the preparation of Tolcapone and its pharmaceutically acceptable salts of formula –I The first aspect of the present invention is to provide a novel process for the preparation of formula VI: wherein, Ri and R2 represents Hydrogen, Ci to C4 alkyl, benzyl, substituted benzyl, reacting the compound of Formula-IV with chlorinating agent to yield compound of formula V; which, is reacted with toluene to obtain the compound of formula VI, which is optionally subjected to purification and crystallization. The second aspect of the present invention is to provide a novel process for the preparation of Tolcapone. chlorinating the 3,4-dihydroxy-5-nitrobenzoic acid, to obtain 3,4-dihydroxy-5-nitro- benzoyl chloride in presence of a chlorinating agent and a solvent; which, is reacted with toluene to obtain the compound of Tolcapone, which is optionally subjected to purification and crystallization. Another main objective of the present invention is to disclose a novel Intermediate formula II

BRIEF DESCRIPTION OF THE DRAWINGS;

The present invention, Tolcapone obtained after crystallization is crystalline in nature and is designated as polymorph R Figure 1 illustrates the XRPD pattern of Form R Tolcapone Figure 2 illustrates the DSC pattern of Form R of Tolcapone DETAILED DESCRIPTION OF THE INVENTION: The present invention related to a novel process for the preparation of Tolcapone by reacting 3,4-dihydroxy-5-nitrobenzoic acid with the chlorinating agent to obtain 3,4-dihydroxy-5-nitrobenzoyl chloride, which is further reacted with the Toluene using Friedel-Crafts acylation to obtain Tolcapone. The process is schematically represented as shown in scheme V:

SCHEME – V The present invention also relates to a novel process for the preparation of Benzophenone derivatives or its related compounds schematically represented as shown in scheme VI; wherein, Riand R2 represents Hydrogen, Cito C4 alkyl, benzyl, Substituted benzyl, According to one embodiment of the present invention chlorinating agent is selected from thionyl chloride, phosphorous chloride, phosphorus oxy chloride, phosphorous tri chloride, oxalyl chloride preferably thionyl chloride and oxalyl chloride and more preferably thionyl chloride. The mole ratio of substrate and chlorinating reagent is 1:4, preferably 1:3 and more preferably 1:2.5. According to one more embodiment, the chlorination is carried out in a solvent selected from the group consisting of cyclohexane, toluene, dichloromethane, dichloroethane and chloroform at a temperature of 40°C to 80°C, preferably cyclohexane and toluene, at 55 to 70°C, more preferably in toluene at 65 to 67°C for 15-20 hr. Chlorination reaction is preferably carried out in an inert atmosphere.

According to another embodiment of the present invention Friedel crafts reaction using a suitable reagent selected from the group consisting of anhydrous AICI3, anhydrous FeCU stannic chloride and titanium chloride preferably anhydrous AICI3. Addition of anhydrous AICI3, is preferably carried out in installments, maintaining mass temperature of-5°C to 8°C under nitrogen blanket, more preferably anhydrous AICI3 is added maintaining the mass temperature of 0-5°C under nitrogen atmosphere. After the addition, the reaction mass is preferably stirred at 0-5°C for 15 to 20hrs and 25-30°C for 3-6hr, more preferably stirred at 0-5°C for 15-17hours and at 25-30°C for 4-5hrs. On completion of the reaction (monitor by HPLC), it is processed by adding to cold dilute hydrochloric acid maintaining the temperature less than 10°C. After the addition and stirring for an hour, the aqueous suspension is preferably filtered to remove any suspended matter and organic layer is separated. 3, 4-dihydroxy-4'-methyl-5-nitrobenzophenone (Tolcapone) present in the organic layer is preferably separated by stirring with aqueous ammonia solution. The organic extract is stirred with aqueous ammonia solution and the precipitated compound, which is orange in color, is separated by filtration. The precipitate obtained is stirred with water and acidified with dilute hydrochloric acid to a pH of 1.0. A bright yellow precipitate, which is formed, is stirred for an hour, filtered, washed to neutral pH and separated. The crude Tolcapone is about 80-90% pure.

In yet another embodiment of this invention, crude Tolcapone is purified by crystallization in a suitable solvent selected from the group consisting of cyclohexane, toluene, dichloromethane, dichloroethane, chloroform, ethyl acetate, acetone and acetonitrile, preferably dichloromethane, dichloroethane or chloroform, more preferably in dichloromethane to achieve a purity off 99.5 to 99.9%. In still another embodiment of the present invention, crystallized Tolcapone is further purified by stirring with an aqueous aprotic or protic polar solvent, selected from the group consisting of aqueous acetone, aqueous isopropanol, preferably aqueous ethanol, aqueous isopropanol, preferably ethanol, and more preferably aqueous ethanol. The purification method yields Tolcapone of about 99.8% to 99.9% HPLC purity in a yield of about 70 to 80%. As used herein "Tolcapone" is any Tolcapone moiety containing substance that exhibits pharmaceutical activity and specifically includes Tolcapone free base or its pharmaceutically acceptable salts thereof and mixtures or combinations of two or more of any such Tolcapone substances like polymorphs, salts, derivatives, hydrates. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES:

EXAMPLE -1; Preparation of crude Tolcapone In a four necked R&B flask, fitted with a mechanical stirrer, condenser and addition funnel with provision for maintaining nitrogen atmosphere, was charged toluene (500.0ml), 3,4- to » dihydroxy-5-nitrobenzoic acid (50.0g) and catalytic amount of N,N-Dimethyl formamide (5.0ml). To the stirred reaction mixture at 25-30°C, thionyl chloride (60.0g) was added dropwise maintaining the reaction temperature 25-30°C. After completion of addition, the reaction mass was slowly heated to 63-68°C under nitrogen atmosphere and maintained for about 20hrs. On completion (monitor by HPLC), the reaction mixture was cooled to about 0-5°C, and anhydrous AICI3 (80.0g) was added in installments maintaining the reaction mass temperature 0-5°C. After complete addition, the reaction mass was stirred at 0-5°C under nitrogen atmosphere for 15hrs and then slowly allowed to reach 25-30°C. The reaction mass was further stirred at 25-30°C for 4-5hrs. Subsequently, the reaction mixture was cooled to 0-5°C and cold aqueous hydrochloric acid solution (550ml) was added dropwise maintaining the mass temperature below 20°C, stirred for another hour and filtered. Toluene layer was separated from the filtrate. The aqueous layer was extracted with toluene (100ml x 2) and all the toluene extracts were mixed. The combined toluene extract was basified with ammonia to a pH of 9.5 to 10.5, stirred for further one-half hour and filtered to isolate a solid. The wet cake was separated, suspended in water (300ml) and acidified to a pH of about 1.0, under stirring using dilute hydrochloric acid. The slurry, formed was stirred for about one and half hour, filtered and the precipitate are washed to neutral pH. This solid was dried to obtain crude Tolcapone (50-55 g) with HPLC purity of- 88.0%. The crude product was suspended in dichloromethane about 12-15 volumes of the solid weight, stirred at reflux, treated with carbon and filtered. On cooling the filtrate under stirring to about 5-10°C, bright yellowish red crystals precipitated out. Crystalline Tolcapone was filtered, washed with dichloromethane (2x25ml), separated and dried to give Tolcapone of greater than 99% HPLC purity and yield 25.8g.

EXAMPLE -2; Preparation of 3,4-hydroxy-5-nitobenzoylchloride This reaction was repeated as per the procedure given in example-1 using the same quantities of 3,4-dihydroxy-5-nitrobenzoic acid, thionylchloride and toluene. After formation of 3,4-dihydroxy-5-nitrobenzoylchloride, this was filtered under nitrogen blanket, washed with toluene and sucked dry. The semi-dry 3,4-hydroxy-5-nitrobenzoylchloride was suspended in toluene and subjected to Friedel-craft reaction as given in example 1. The crude product was isolated and in the manner given in examplel to give 22 g of 99.75% HPLC purity.

EXAMPLE -3; Preparation of crude Tolcapone This experiment was carried as per the procedure given in example-1 using the same quantities of reactants. After formation of 3,4-dihydroxy-5-nitrobenzoylchloride the slurry was added slowly to a cooled (0-5°C) suspension of anhydrous A1C13 (80.0g) in toluene (250ml) maintaining reaction mass temperature at 0-5°C. After completion of the addition, the remaining part of this reaction was carried out as given in example-1. Isolation of the crude product and purification was carried out as given in example -1 to give 21.5g of Tolcapone with purity 99.85% by HPLC.

EXAMPLE -4; Preparation of Tolcapone using methylenedichloride as solvent In a four necked RB flask fitted with a mechanical stirrer, addition funnel, a condenser and provision for maintaining nitrogen atmosphere was added 3,4-dihydroxy-5-nitro benzoic acid (50.0g), methylenedichloride (150ml) and N,N-dimethylformamide, (5.0ml) were charged and thionylchloride (60.0g) was added from the dropping funnel maintaining the reaction mass temperature 25-30°C. After addition, the reaction mass was stirred at reflux (~40°C) for about 20hrs. On completion (HPLC analysis), reaction was cooled to 25to30°C, diluted with toluene (350ml) and cooled further to 0-5°C. All operations were carried out under nitrogen atmosphere. Anhydrous AICI3 (80g) was added in installments maintaining reaction temperature at 0-5°C. After completion of addition, the reaction mass was stirred at 0-5°C for about 14-16 hr. Progress of the reaction was monitored by HPLC. Then it was allowed to warm up to 25°Cto 30°C, stirred about 4hrs and again cooled to 0-5°C. Later cold dilute aqueous hydrochloric acid (ml) was added to the reaction mass maintaining it at 0-5°C. Stirred for about lhr and filtered organic layer washed with toluene (50 * 2ml), all the toluene extracts were mixed, washed once with water (100ml) and separated. Separated organic extract was treated with aqueous ammonia (~18%), under stirring, to a pH of about 9.5 to 10.5 stirred for about one-half hour and solid formed was filtered. The wet solid was separated, water (250ml) added and pH was adjusted to about 1.0 using dilute hydrochloric acid. The precipitated solid was filtered, washed with water dried and purified by a similar method given in example 1. About 21.2g of purified crystalline Tolcapone, with HPLC purity of 99.82% was obtained.

EXAMPLE -5: Preparation of 3,4-dihydroxy-5-nitro benzoyl chloride using reagent oxallyl chloride followed by preparation of tolcapone Experiment was carried out as per the details given example-1, except using oxallyl chloride (64.0g) instead of thionylchloride. About 35g of crude Tolcapone was obtained, which on purification from methylenedichloride and aqueous ethanol, yielded about 20.0g of pure Tolcapone with 99.8% purity.

EXAMPLE -6: Preparation of Tolcapone This experiment was carried using same quantities of 3,4-dihydroxy-5-nitrobenzoic acid and anhydrous AICI3 . The variation adopted was oxalylchloride (64.0g) for chlorination with methylenedichloride as solvent and a mixture of methylenedichloride and toluene for the Friedel craft reaction. Under these conditions about 20.8g of 99.8% Tolcapone was isolated.

EXAMPLE -7: Re-crystallization of Tolcapone Crude Tolcapone (50.0g) was stirred in aqueous methanol (140 ml) at 45-60°C for 3hrs, cooled, filtered, washed with aqueous methanol and dried to give pure Tolcapone (>99.85%).

EXAMPLE -8: Re-crystallization of Tolcapone This experiment was conducted as given in example-7 by using aqueous ethanol 150ml for 50.0g of crude product instead of aqueous methanol to give pure Tolcapone (-99.95%)

EXAMPLE-9: Preparation of 4-Hydroxy-3-methoxy 5-nitro-4' methyl benzophenone. In a four necked R&B flask, fitted with a mechanical stirrer, condenser and addition funnel with provision for maintaining nitrogen atmosphere, was charged toluene (500.0ml), 4-hydroxy-3-methoxy-5-nitrobenzoic acid (50.0g) and catalytic amount of N,N-Dimethyl formamide (5.0ml). To the stirred reaction mixture at 25-30°C, thionyl chloride (60.0g) was added dropwise maintaining the reaction temperature 25-30°C. After completion of addition, the reaction mass was slowly heated to 63-68°C under nitrogen atmosphere and maintained for about 20hrs. On completion (monitor by HPLC), the reaction mixture was cooled to about 0-5°C, and anhydrous AICI3 (80.0g) was added in installments maintaining the reaction mass temperature 0-5°C. After complete addition, the reaction mass was stirred at 0-5°C under nitrogen atmosphere for 15hrs and then slowly allowed to reach 25-30°C. The reaction mass was further stirred at 25-30°C for 4-5hrs.

Subsequently, the reaction mixture was cooled to 0-5°C and cold aqueous hydrochloric acid solution (550ml) was added dropwise maintaining the mass temperature below 20°C, stirred for another hour and filtered. Toluene layer was separated from the filtrate. The aqueous layer was extracted with toluene (100ml x 2) and all the toluene extracts were mixed. The combined toluene extract was basified with ammonia to a pH of 9.5 to 10.5, stirred for further one-half hour and filtered to isolate a solid. The wet cake was separated, suspended in water (300ml) and acidified to a pH of about 1.0, under stirring using dilute hydrochloric acid. The slurry, formed was stirred for about one and half hour, filtered and the precipitate are washed to neutral pH. This solid was dried to obtain crude 3-methoxy-4-hydroxy-5-nitro-4'methyl benzophenone (methoxy tolcapone) 55-60 g with HPLC purity of- 88.0%.

Example 10: Preparation of Tolcapone from methoxy tolcapone derivative. 50.0g of crude 3-methoxy-4-hydroxy-5-nitro-4'methyl benzophenone was treated with 75ml of 48% Hydrobromic acid at temperature 90-110°C for a period of 8-10hrs undergoes dealkylation and gave tolcapone. The reaction mass was cooled to 25-30°C, diluted with water, filtered, washed with water and dried. Yield 40-43g. The obtained product was re-crystallized in methylenedichloride and followed by aqueous alcohol gave pure tolcapone.

EXAMPLE-11: Preparation of tolcapone from 4-Hydroxy-3-methoxy- 5-nitro- benzoic acid In a four necked R&B flask, fitted with a mechanical stirrer, condenser and addition funnel with provision for maintaining nitrogen atmosphere, was charged toluene (250.0ml), 4-hydroxy-3-methoxy-5-nitrobenzoic acid (50.0g) and catalytic amount of N,N-Dimethyl formamide (5.0ml). To the stirred reaction mixture at 25-30°C, thionyl chloride (55.0g) was added dropwise maintaining the reaction temperature at 25-30°C. After completion of addition, the reaction mass was slowly heated to 60-62°C under nitrogen atmosphere and maintained for about 20hrs. On completion (monitor by HPLC), the reaction mixture was cooled to about 0-5°C, and anhydrous A1C13 (90.0g) was added in installments maintaining the reaction mass temperature 0-5°C. After complete addition, the reaction mass was stirred at 0-5°C under nitrogen atmosphere for 15hrs and then slowly allowed to reach 25-30°C. The reaction mass was further stirred at 25-30°C for 4-5hrs. Then 50g of triethylamine was slowly introduced and maintained at 50-55°C for a period of 4-8hrs to undergo demethylation Subsequently, the reaction mixture was cooled to 0-5°C and cold aqueous hydrochloric acid solution (750ml) was added dropwise maintaining the mass temperature below 20°C, stirred for another hour and filtered. Toluene layer was separated from the filtrate. The aqueous layer was extracted with toluene (150ml x 3) and all the toluene extracts were mixed. The combined toluene extract was basified with ammonia to a pH of 9.5 to 10.5, stirred for further one-half hour and filtered to isolate a solid. The wet cake was separated, suspended in water (300ml) and acidified to a pH of about 1.0, under stirring using dilute hydrochloric acid. The slurry, formed was stirred for about one and half hour, filtered and the precipitate were washed to neutral pH. This solid was dried to obtain crude 3,4-dihydroxy-5-nitro-4'methyl benzophenone (tolcapone) 45-50 g.

WE CLAIM:

1) A novel process for the preparation of compound of formula VI: wherein, Rjand R2 represents Hydrogen, Cito C4 alkyl, benzyl, Substituted benzyl, reacting the compound of Formula-IV with chlorinating agent to yield compound of formula V; which is further reacted with toluene to obtain the compound of formula VI, which is optionally subjected to purification and crystallization.

2) A novel process for the preparation of Tolcapone, comprising the following steps:

a) chlorinating the 3,4-dihydroxy-5-nitrobenzoic acid, to obtain 3,4-dihydroxy-5-nitro- benzoyl chloride in presence of a chlorinating agent and a solvent;

b) condensing the 3,4-dihydroxy-5-nitro-benzoyl chloride, with toluene using a Friedal-craft's acylation to obtain Tolcapone;

c) optionally purifying and crystallizing the obtained Tolcapone.

3) An intermediate useful in the preparation of Tolcapone of Formula II

4) According to claim 2, the reaction is carried out in one pot.

5) According to claim 1 and 2, wherein chlorination of 3,4-dihydroxy-5-nitrobenzoic acid, using a chlorinating reagent selected from a group consisting of thionylchloride, sulfuryl chloride, phosphorous tri chloride, phosphorous oxy tri chloride phosphorous pentachloride and oxalylchloride and more preferably thionyl chloride.

6) According to claim 1 and 2, wherein an organic solvent for chlorination is selected from the group consisting of cyclohexane, toluene, chloroform, dichloromethane and dichloroethane and more and preferably toluene.

7) According to claim 1 and 2, wherein solvent used for condensation step is selected from the group consisting of cyclohexane, toluene, methylenedichloride and ethylene dichloride preferably toluene.

8) According to claim 1 and 2, wherein Freidel-craft acylation is carried out in the presence of a Lewis acid catalyst selected from the group consisting of anhydrous -AICI3, anhydrous AlBr3, anhydrous FeCl3 anhydrous SnCU and TiCU and preferably anhydrous A1C13.

9) A process as claimed in claims 2, wherein Tolcapone is crystallized in an organic solvent, selected from the group consisting of toluene, dichloromethane, dichloroethane, chloroform and ethyl acetate, preferably in dichloromethane to give crystalline polymorph R of Tolcapone.

10) A novel process for the preparation of Tolcapone, comprising the following steps:

a) chlorinating the 4-Hydroxy-3-methoxy-5-nitrobenzoic acid, to obtain 3,4-dihydroxy-5-nitro-benzoyl chloride in presence of a chlorinating agent and a solvent;

b) condensing the 4-hydroxy-3-methoxy-5-nitro-benzoyl chloride, with toluene using a Friedal-craft's acylation to obtain Tolcapone;

11) According to claim 9, the Form-R of Tolcapone has a XPRD 29 values as depicted in figure 1 and DSC having an endotherm 146°C, wherein depicted in figure 2.