FIELD OF THE INVENTION
The invention relates to an improved, cost effective and industrially scalable process for the synthesis of Tolcapone.
BACKGROUND OF THE INVENTION
Tolcapone is a known catechol-O-methyl-transferase (COMT) inhibitor which is used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa medication, and is also helpful in treatment of depressions and similar disease states. Chemically, Tolcapone is (3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone represented by the following Formula I.
The following procedures are reported for the synthesis of Tolcapone.
US5236952 describes the synthesis of Tolcapone involving use of butyl lithium and also involving separation of regioisomers of the nitration compounds. The process described uses butyl lithium which is difficult to handle on a large scale.
Synthetic communications 38 (5):810-815; describes synthesis of Tolcapone which involves several reactions including a Grignard reaction, an oxidation reaction and catalytic hydrogenation in presence of Palladium. These reactions make it a commercially unviable process.
Another method reported in US 5877353 involves a Friedel-Crafts acylation of Veratrol with p-methyl benzoyl chloride in presence of Aluminium chloride followed by the demethylation which yields two isomeric hydroxyl methoxybenzophenones. These two isomers are converted in to potassium salts in aqueous solution and later selectively crystallized the desired isomer as sodium salt or lithium salt by addition of saturated

aqueous solution of NaCl or LiCl. However, the selective crystallization of desired isomer of the sodium or lithium salt of 4-hydroxy-3-methoxy-4'-methyl benzophenone from a mixture of isomers is practically complicated to perform on a large scale.
Therefore, there exists a need to develop a process which can offer a simple and efficient method for the separation of the undesired intermediates formed during the demethylation of the Friedel-craft product and thereby developing a process for the industrial scale production of Tolcapone.
OBJECTS OF THE INVENTION
The primary object of the invention is to provide an improved process for the preparation of Tolcapone of Formula-I.
Another object of the invention is to provide an improved, cost effective and industrially scalable process for the synthesis of Tolcapone.
SUMMARY OF THE INVENTION
Accordingly, the invention provides process for the preparation of Tolcapone comprising:
a) reacting jO-Toluoyl chloride (formula II) with Veratrole (formula III) in presence of a Lewis acid in an organic solvent to give a mixture of isomers of 4-hydroxy-3-methoxy-4'-methylbenzophenone (VA) and 3-hydroxy-4-methoxy-4'-methylbenzophenone (VB);
b) removal of the undesired isomer 3-hydroxy-4-methoxy-4'-methylbenzophenone (VB) by crystallizing it in an organic acid solvent; filtration of the crystallised solid VB and addition of a nitrating agent to the filtrate containing 4-hydroxy-3-methoxy-4'-methylbenzophenone (VA) to generate 4-hydroxy-3-methoxy-4'methyl-5-nitrobenzophenone (VIA);
or step b alternatively follows the process of:

converting a mixture of 3-hydroxy-4-methoxy-4'-methylbenzophenone (VB) and 4-hydroxy-3-methoxy-4'-methylbenzophenone (VA) to nitro derivatives by treating with Nitric acid /acetic acid mixture and quenching the reaction mixture with water to yield only the required isomer of the nitro derivative VIA;
c) demethylation of 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzophenone (VIA) using demethylating agent in presence of organic base and organic solvent to give Tolcapone of formula I;
d) purification of the crude Tolcapone using acetone and water.
The Lewis acid employed in step (a) is selected from AICI3, TiCb, BF3Et20, FeCb, ZnCb, MOCI5, SnCU, BCI3, and preferably aluminium trichloride.
The organic solvent used in step (a) is selected from dichloromethane, cyclohexane, methyl cyclohexane, Nitro methane, Nitro benzene, dichlorobenzene, trichloromethane, and carbon tetrachloride, preferably dichloromethane.
The organic acid used in step (b) is selected from acetic acid, formic acid, ethanoic acid and propanoic acid, preferably acetic acid
The demethylating agent employed in step (c) is selected from AICI3, TiCb, BF3Et20, FeCl3, ZnCl2, MOCl5, SnCl4 and BC13, preferably aluminium trichloride (A1C13).
The organic base employed in step (c) is selected from triethylamine, diethylamine, dimethylaminopyridine and Pyridine, preferably pyridine. The organic solvent used in step (c) is selected from dichloromethane, cyclohexane, methyl cyclohexane, Nitro methane, Nitro benzene, dichlorobenzene, trichloromethane and carbon tetrachloride, preferably dichloromethane.

DETAILED DESCRIPTION OF THE INVENTION
One aspect of the invention is to obtain a suitable method for purifying the intermediate VA from the undesired isomer VB. Inventors have found a novel method of purifying intermediate VA by crystallizing the undesired isomer VB from a mixture of VA and VB using organic acid such as acetic acid, formic acid and the like and preferably acetic acid.
In another aspect of the invention, the inventors surprisingly found that the nitration reaction when carried out on a mixture of VA and VB, the desired intermediate VIA from the undesired isomer VIB was removed by directly quenching the reaction mixture in water after the nitration and isolation.
Finally, Tolcapone was purified by recrystallizing from a mixture of water and acetone.
The applicant has now developed a reproducible large scale industrial synthetic process without involving laborious purifications and provides the required (3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone (Tolcapone) in high yield with high purity.
The present invention is further elaborated below:
The improved process according to present invention for the preparation of Tolcapone (Formula-I)comprises the steps of:
(a) reacting jc-Toluoyl chloride (formula II) with Veratrole (formula III) in presence of a Lewis acid in an organic solvent to give a mixture of isomers of 4-hydroxy-3-methoxy-4'-methylbenzophenone (formula VA) and 3-hydroxy-4-methoxy-4'-methylbenzophenone (formula VB);
(b) removal of the undesired isomer 3-hydroxy-4-methoxy-4'-methylbenzophenone (formula VB) by crystallizing it in an organic acid solvent. Filtration of the crystallised solid VB and addition of a nitrating agent to the filtrate containing4-hydroxy-3-methoxy-4'-methylbenzophenone (VA) to generate 4-hydroxy-3-methoxy-4'methyl-5-nitrobenzophenone (formula VIA);

(c) demethylation of 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzophenone (formula VIA) using demethylating agent in the presence of organic base and organic solvent to give Tolcapone of formula I;
(d) purification of the crude Tolcapone using acetone and water.
Surprisingly, it has been found that the undesired isomer of formula VB is easily crystallisable in an organic acid, preferably acetic acid, where as desired isomer of formula VA stays in acetic acid. Other organic acids that may be employed for the crystallization of VB are formic acid, ethanoic acid and propanoic acid.
Coupling of formula II and formula III can be carried out in the presence of suitable Lewis acids AlCb, TiCb, BF3Et20, FeCl3, ZnCl2, MOCl5, SnCl4, BC13, and preferably in the presence of aluminium trichloride. The reaction can be carried out in the presence of organic solvent dichloromethane, cyclohexane, methyl cyclohexane, nitro methane, nitro benzene, dichlorobenzene, trichloromethane, carbon tetrachloride and preferably dichloromethane.
According to one aspect of the invention removal of undesired isomer of formula VB by crystallization can be carried in an organic acid solvents such as acetic acid, formic acid,

ethanoic acid, propanoic acid, and preferably in acetic acid. The nitration of the desired isomer VA can be carried in the presence of nitric acid.
A further aspect of the invention demethylation of formula VIA can be carried out in presence of Lewis acids such as AlCb, T1CI3, BF3Et20, FeCh, ZnCb, MOCI5, SnCU, BCI3, and preferably in aluminium trichloride (A1CI3). The reaction can be carried out in suitable base selected from triethylamine, diethylamine, dimethylaminopyridine, Pyridine and, preferably pyridine. The reaction is carried out in the presence of organic solvent selected from the group comprising dichloromethane, cyclohexane, methyl cyclohexane, nitro methane, nitro benzene, dichlorobenzene, trichloromethane, carbon tetrachloride or combinations thereof, preferably in dichloromethane.
As shown in scheme-2, alternatively the mixture of isomers of formula VA and formula VB can also be directly converted into their nitro derivatives of formula VIA and formula VIB, in which the required isomer of formula VIA is directly precipitated in pure form from the reaction mixture without any further purification (Scheme 2).It has also been found that even if nitration reaction proceeded with the mixture of isomers of formula VA and formula VB, the desired nitro compound of formula VIA is isolated in pure form directly from reaction mixture after quenching with water.

Examples:
The process of the invention is illustrated by the following examples to obtain Tolcapone.
Example 1
Preparation of (4-hydroxy-3-methoxyphenyl)(/?-tolyl)methanone (formula VA) &
(3-hydroxy-4-methoxyphenyl)(p-tolyI)methanone (formula VB)
To a solution of compound of formula 11(117.3 g, 0.759 mol) in dichloromethane (1000 mL) was added Aluminium chloride (101.2 g, 0.758 mol) at 0 °C. To this 1,2-dimethoxybenzene (formula 111) (100 g, 0.723 mol) was added slowly over a period of 60 min at 0-5 °C and stirred for 3 h. Then the reaction mixture was allowed to warm to room temperature, and then Aluminium chloride was added in 3 lots (139.4 g, 1.04 mol) in intervals of 4 h at room temperature. Stirring was continued for another 4h, after completion of the starting material, the reaction mixture was poured in to a mixture of hydrochloric acid (1000 mL) and ice cold water (50 mL). After stirring for 30 min, the combined organic layer was washed with NaHCCb followed by brine solution (500 mL), solvent is removed at reduced pressure to afford a mixture of formula VA and formula VB isomers (65:35 to 70:30 ratio) (145 g, 83%).
Example 2:
Preparation of (4-hydroxy-3-methoxy-5-nitrophenyl)(p-tolyl)methanone (formula
VIA)

Acetic acid (350 mL) was added to a mixture of isomers of compound of formula VA & formula VB (100 g, 0.412 moI),and stirred at room temperature for 30 min. The solid was filtered off, the obtained filtrate was diluted with acetic acid (150 mL), cooled to 10-20 °C, then added a mixture of nitric acid (29 g) in acetic acid (5 mL) slowly for a period of 30 min. After completion of the reaction the mass was poured into ice cold water and stirring was continued for another 1 h at 10-20 °C. The obtained solid was filtered, washed with water and dried under vacuum at 40 "C to afford the intermediate VIA (68 g, 57%).

Example 3:
Preparation of (3, 4-dihydroxy-5-nitrophenyl) (/>-tolyl) methanone (Tolcapone)
A solution of Aluminium chloride (185.6 g, 1.392 mol) in pyridine and dichloromethane (500 mL) was dosed in to the dichloromethane (500 mL) solution of compound of formula VIA (100 g, 0.348 mol) at 0-5°C.Subsequently the reaction temperature was raised to reflux and stirred for6 h. After completion, reaction mixture was poured into IN ice cold hydrochloric acid (500 mL), organic layer was separated, washed with water followed by sodium chloride solution, dried over Na2SC>4 and solvent was removed under reduced pressure to give crude Tolcapone (83.6 g, 88%). The crude Tolcapone was purified using acetone and water and obtained as pale yellow solid (71 g) which meets EP specifications.
Example 4:
Preparation of (4-hydroxy-3-methoxy-5-nitrophenyI)(/Molyl)methanone (formula
VIA)
A mixture of 70% Nitric acid (42 g) in acetic acid (10 mL) was slowly added to the solution of a mixture of isomers of compound of formula VA&VB (100 g, 0.412 mol) in acetic acid (1200 mL) at 10-20 °C for a period of 30 minutes. After stirring for 30 minutes at same temperature, reaction mass was poured in to ice cold water and stirred for further 1 h at 10-20 °C. The obtained solid was filtered, washed with water and dried under vacuum at 40°C yielded the required intermediate VIA in pure form (70 g, 59%).

We Claim:
1. A process for the preparation of Tolcapone comprising:
a), reacting /?-Toluoyl chloride (formula II) with Veratrole (formula III) in presence of a Lewis acid in an organic solvent to give a mixture of isomers of 4-hydroxy-3-methoxy-4'-methylbenzophenone (VA) and 3-hydroxy-4-methoxy-4'-methylbenzophenone (VB);
b). removal of the undesired isomer 3-hydroxy-4-methoxy-4'-methylbenzophenone (VB) by crystallizing it in an organic acid solvent, filtration of the crystallised solid VB and addition of a nitrating agent to the filtrate containing 4-hydroxy-3-methoxy-4'-methylbenzophenone (VA) to generate 4-hydroxy-3-methoxy-4'methyl-5-nitrobenzophenone (VIA);
or step b alternatively follows the process of:
converting a mixture of 3-hydroxy-4-methoxy-4'-methylbenzophenone (VB) and 4-hydroxy-3-methoxy-4'-methylbenzophenone (VA) to nitro derivatives by treating with Nitric acid /acetic acid mixture and quenching the reaction mixture with water to yield only the required isomer of the nitro derivative VIA;
c). demethylation of 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzophenone (VIA) using demethylating agent in presence of organic base and organic solvent to give Tolcapone of formula I;
d). purification of the crude Tolcapone using acetone and water.
2. The process as claimed in claim 1, wherein in step (a) the Lewis acid is selected from A1C13, TiCl3, BF3Et20, FeCl3, ZnCl2, MOCl5, SnCl4 and BC13, preferably aluminium trichloride.
3. The process as claimed in claim 1, wherein in step (a) the organic solvent is selected from dichloromethane, cyclohexane, methyl cyclohexane, Nitro methane, Nitro

4. The process as claimed in claim 1, wherein in step (b) the organic acid is selected from acetic acid, formic acid, ethanoic acid and propanoic acid, preferably acetic acid.
5. The process as claimed in claim 1, wherein in step (c) the demethylating agent is selected from A1C13, TiCl3, BF3Et20, FeCl3, ZnCl2, MOCl5, SnCl4 and BC13, preferably aluminium trichloride (AICI3).
6. The process as claimed in claim I, wherein in step (c) the organic base is selected from triethylamine, diethylamine, dimethylaminopyridine and Pyridine, preferably pyridine.
7. The process as claimed in claim 1, wherein in step (c), and the organic solvent is selected from dichloromethane, cyclohexane, methyl cyclohexane, Nitro methane, Nitro benzene, dichlorobenzene, trichloromethane and carbon tetrachloride, preferably dichloromethane.
8. A process for preparation of 4-hydroxy-3-methoxy-4'methyl-5-nitrobenzophenone (VIA) which comprises: removal of the undesired isomer 3-hydroxy-4-methoxy-4'-methylbenzophenone (VB) by crystallizing it in an organic acid solvent; filtration of the crystallised solid VB and addition of a nitrating agent to the filtrate containing 4-hydroxy-3-methoxy-4'-methy]benzophenone (VA) to generate 4-hydroxy-3-methoxy-4'methyl-5-nitrobenzophenone (VIA).
9. The process as claimed in claim 8, wherein the organic acid is selected from acetic acid, formic acid, ethanoic acid and propanoic acid, preferably acetic acid and the nitrating agent is Nitric acid.
10. The process as claimed in claim 8 which comprises an additional step of converting
VIA into Tolcapone.

t
11. A process for the preparation of 4-hydroxy-3-methoxy-4'methyl-5-nitrobenzophenone (VIA) which comprises converting a mixture of 3-hydroxy-4-methoxy-4'-methylbenzophenone (VB) and 4-hydroxy-3-methoxy-4'-methylbenzophenone (VA) to nitro derivatives by treating with Nitric acid /acetic acid mixture and quenching the reaction mixture with water to yield only the required isomer of the nitro derivative VIA.
12. The process as claimed in claim 11, which comprises additional step of converting VIA into Tolcapone.