FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Entacapone of formula (I).

BACKGROUND OF THE INVENTION:

Entacapone is chemically known as (E)-N, N-diethyl-2-cyano-3-(3, 4-dihydroxy-5-Nitrophenyl) acrylamide, which is represented by a structural formula I

Entacapone is a potent and specific catechol-o-methyltransferase (COMT) inhibitor, marketed in USA as COMT AN®, in Europe COMTESS® and under trademark STALEVO® in a fixed combination (Levodopa: Carbidopa: Entacapone: 50 mg: 12.5 mg: 200 mg, 100 mg:25 mg:200 mg and 150 mg:37.5 mg:200 mg) to treat Parkinson's disease. Parkinson's disease is a progressive brain disorder that causes shaking, slow movement and muscle stiffness.

There are number of methods disclosed in several patents, for the preparation of Entacapone. A few of the relevant methods pertaining to the present invention are given below:

Entacapone was first disclosed in US 4,963,590, which describes a process for the preparation of Entacapone of formula (I) by the condensation of 3,4-dihydroxy-5-nitro benzaldehyde of formula (II) with N,N-diethyl cyanoacetamide of formula (III) in absolute ethanol, containing piperidine acetate. This process yields Entacapone in about 70-75% and the product is a mixture of (E) & (Z) geometrical isomers. Additionally, the process is lengthy, making it uneconomical.

US 5,135,950 discloses a process for the preparation of a stable and crystallographically essentially pure polymorphic form A, having a melting point of 162-163°C. In the patent 5,135,950 crystallization is carried out from an aliphatic carboxylic acid, containing catalytic amount of hydrochloric acid or hydrobromic acid giving an yield of 70-80% of crystalline polymorphic form A.

US 5,446,194 discloses a method for the preparation of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-
nitrophenyl)acrylamide by refluxing a solution containing 3,4-dihydroxy-5-nitrobenzaldehyde,
N,N-di ethyl-2-cyanoacetamide and a catalytic amount of piperidine acetate in dry ethanol. The
yield of said method is 73%. The product is a crude mixture of the E and Z isomers of N,N-diethyl-
2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide having a melting point of 153-156° C.

The condensation reaction used in US Pat. No. 5,446,194 is called a Knoevenagel condensation.

WO2005/070881 discloses a process for the manufacturing of crystallographie polymorphic form A by the condensation of 3,4-dihydroxy-5-nitrobenzaldehyde of formula (II) with N,N-diethyl cyanoacetamide of formula (III) in an alcoholic solvent selected from the group consisting of methanol, ethanol, isopropanol, isobutanol ,n-butanol, preferably isopropanol and in the presence of suitable organic base selected from the group consistent of piperidine, N-methyl morpholine, pyridine, piperazine, preferably piperidine as base at reflux temperature. After completion of the reaction, it is poured into a mixture of chilled water and ethyl acetate mixture. The pH of the solution is adjusted to about 3.5 to 4.0, ethyl acetate layer is separated and concentrated to obtain polymorphic Form-A. A serious draw- back of the method is that the total yield of the process is low. In the process pure (E) isomer is isolated, leaving about 30% of (Z)-isomer in solution.

In WO2005/063696, a process for the preparation of Entacapone of formula (I) is achieved by the condensation of 3,4-dihydroxy-5-nitrobenzaldehyde of formula (II) with N,N-diethyl cyano acetamide of formula (III) in toluene, containing acetic acid and diethyl amine and by removal of water, formed during the reaction azeotropically.

US 2010/0234632A1 has disclosed the synthesis of Entacapone of formula (I) by the condensation of 3,4-dihydroxy-5-nitrobenzaldehyde of formula (II) with N,N-diethyl cyano acetamide of formula (III) in a mixed solvent system, containing a base and in the presence of a PTC. The solvent system is selected from the group comprising of toluene and cyclohexane, toluene and acetonitrile and toluene and ethyl acetate. The base is selected from the group comprising of pyridine acetate, piperidine acetate, pyridinium paratoluene sulfonate etc and the PTC is selected from the group comprising tetrabutyl ammonium bromide, tetrabutyl ammonium hydrogensulfate, tricapryl methyl ammonium chloride, dodecyl sulfate sodium salt etc.

US 7,932,415 disclosed a process for the preparation of Entacapone of formula (I) by the condensation of 3, 4-dihydroxy-5-nitrobenzaldehyde of formula (II) with N, N-di ethyl cyanoacetamide of formula (II) in n-butanol, containing catalytic amount of methyl amine.HCl and piperidine at 70° to 108 °C at a reduced pressure (80KPa). In this process a mixture of (E) and (Z) mixture of geometrical isomer is enriched to more of (E) isomer and is isolated by seeding with crystals of (E)-geometrical isomer.

The aforementioned patent processes described, has one or other drawbacks and some of them are:

a) longer reaction time

b) lower yields

c) formation of mixture of (E) and (Z) geometrical isomers

d) formation of trans amination produced, For example in the condensation of 3,4-dihydroxy-5-nitrobenzaldehyde of formula (II) with N,N-diethyl cyanoacetamide (III) in toluene containing catalytic amount of piperidine acetate, the following trans aminated product of formula (IV) is formed.

If this trans aminated product is. more than 2 to 4% in Entacapone, several crystallizations are needed to get pure product.

Considering the short comings in the prior art methods, it is imperative to develop an improved method for the preparation of Entacapone of formula (I), wherein maximum extent of (E)-isomer is isolated to reduce the content of the impurity of formula (IV), which is controlled within the limits.

The present inventors have now disclosed a much simpler, cost effective process when compared to other prior art methods.

OBJECTIVE OF THE INVENTION:

The main object of the present invention is to provide simple, cost effective, high yielding and industrially advantageous process for the preparation of Entacapone to achieve maximum yield of the (E)-isomer and limiting the formation of impurity of formula (IV).

SUMMARY OF THE INVENTION:

The main object of the present invention is to provide an improved process for the preparation of Entacapone of formula (I).

The process for the preparation of (E)-N, N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide comprises the steps of reacting 3,4-dihydroxy-5-nitrobenzaldehyde of formula-II with N, N-diethyl cyanoacetamide of formula (III) in a non-polar solvent, containing a polar component (0,5%-5.0%) and a catalyst (1% to 5%) at reflux temperature (90-95°C) for 12 to 18hr;

b). distilling solvent slowly till the mass temperature reaches to 100-110 °C;

c). cooling the reaction mass to about 60-70 °C, adding catalytic amount of the polar component
and continuing reflux at 90-95°C for 12-18hr;

d). distilling solvent slowly till the mass temperature reaches 100°C to 110 °C;

e). cooling the reaction mass to 60-70°C and distilling solvent completely under vacuum till the
mass temperature reaches to about 80 °C;

f). cooling the reaction mass to 50-55 °C, dissolving in methanol and distilling it almost
completely up to mass temperature of -70 °C;

g). cooling the mass, dissolving in ethyl acetate, giving carbon treatment, filtering and
concentrating;

h). cooling (30 °C) and dissolving in ethyl acetate treating with ethyl acetate containing
hydrogen chloride (-15%), stirring at 25 to 35 °C for 10-15hr, cooling to 0-10°C and filtering the
technical material;

i). treating the technical material in ethyl acetate containing hydrogen chloride (5-15%), stirring
at 25-35 °C, later cooling to 0-5 °C, filtering and isolating pure Entacapone of 99.5% to 99.9%
containing total impurities 0.1 to 0.5% and trans aminated product of below 0.05%

The other object of the present invention is to provide a process for purification of Entacapone comprises:

a), treating crude enatacapone with methanol and distilling methanol almost completely at 70 °C;

b). treating with ethyl acetate and distilling ethyl acetate completely at 80 °C;

c). treating with ethyl acetate and ethyl acetate-hydrogen chloride at 25-30 °C for 14hr, cooling
the reaction mass.and filtering to give the pure product.

The detailed description of the invention will explain the critical parameters, which help in achieving the objective of the invention namely, developing an economical industrial manufacturing process of Entacapone.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention is related to an improved process for the preparation of Entacapone of. formula (I). by Knoevenagel condensation of 3,4-dihydroxy-5-Nitro benzaldehyde of formula (II). with N,N-diethyl cyanoacetamide of formula (III)

The Knoevenagel condensation is a nucleophilic condensation reaction between aldehyde or ketone and an active methylene compound in the presence of ammonia or another amine as a catalyst, followed by dehydration reaction to afford a, p-unsaturated compounds.

The first aspect of the invention is to achieve higher yields of (E)- isomer, which contains negligible extent of (Z)- isomer.

Further aspect of the present invention is to manufacture Entacapone, containing all impurities well within limits particularly the trans amination product, for example, when the Knoevengel condensation of 3, 4-dihydroxy -5-nitro benzaldehyde of formula with N, N-diethyl cyanoacetamide of formula (III) in toluene containing piperidine-acetic acid as a catalyst, the product of formula (IV) is formed as the trans aminated impurity. The scheme given below clearly explains this.

The current process for the preparation of Entacapone, disclosed by the applicant, is described vividly below:

The preparation N, N-diethyl-2-cyano-3-(3, 4-dihydroxy-5-Nitrophenyl) acrylamide (Entacapone) of formula I comprises:

a) knoevenagel condensation of 3, 4-dihydroxy -5-nitro benzaldehyde of formula II; with N, N-diethyl cyanoacetamide of formula (III) in a non-polar solvent, containing a polar component (0.5% to 3.0%) and a catalyst (1 to 5%) at reflux temperature (90-95°C) for 12 to 18hr;

b) distillation of solvent slowly till the reaction mass temperature reaches 100 to 110°C;

c) cooling the reaction mass to 60-70 °C, adding catalytic amount of the polar component (0.5%
to 5.0%) and continuing the reflux for 12 to 18hr;

d) distilling the solvent slowly till mass temperature reaches 100 to 110°C;

e) cooling the reaction mass to 60-70 °C and distilling the solvent completely under vacuum, till the mass temperature reaches to about 80°C;

f) cooling the mass, dissolving in methanol and distilling it almost completely;

g) cooling the mass, dissolving in ethyl acetate, giving carbon treatment, filtering and
concentrating;

h) cooling and dissolving the mass in ethyl acetate, treating with ethyl acetate containing
hydrogen chloride, stirring at 25-35 °C for 10-15hr, cooling to 0-5 °C and filtering technical
material;

i) taking the technical material in ethyl acetate and diluting with ethyl acetate containing
hydrogen chloride (5 to 15%) stirring at 25 to 35°C, filtering and isolating pure Entacapone of
99.5% to 99.9%, containing total impurities 0.1% to 0.5% and the trans aminated product less
than 0.05%.

According to the first embodiment of the present invention, the reaction is conducted in a non-polar solvent selected from the group comprising of benzene, toluene, xylene, fluoro benzene, or mixture thereof, preferably toluene.

According to the second embodiment of the present invention, polar component in toluene is selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, 2-methoxy ethanol, 2-ethoxy ethanol, and acetonitrile, preferably methanol, ethanol, n-propanol and isopropanol and most preferably methanol. The polar component is used to the extent of 0.5% to 5.0% and preferably 1% to 3.0%.

The catalyst used for Knoevenagel condensation is selected piperidine-acetic acid. The catalyst is used preferably in 1% to 5% and more preferably in 1 to 3%.

The reaction is conducted for duration of 10 to 15hr, preferably at 12-14hr at reflux temperature. After maintenance, distillation is carried out till the mass temperature reaches 100-110 °C and preferably 103 to 105 °C.

According to the third embodiment of the present invention, mineral acid used for the crystallization is selected from either dilute hydrochloric acid or hydrobromic acid, preferably hydrochloric acid in ethyl acetate in5% to 15% concentration and preferably 9 to 12% concentration.

The process disclosed herein gives pure Entacapone in 80-85% yield and it is 99.5% to 99.9%, ■ purity preferably 99.8% to 99.9%. The total impurities are below 0.5% and preferably 0.1% to 0.2% and the critical impurity is less than 0.1% and preferably below 0.05%.

Hence the process disclosed has the following advantages.

a) Entacapone is obtained in very good yield and excellent purity.

b) The process is simple, and comfortably scaled up and hence industrially applicable.

c) The polar component, methanol is very important in controlling the critical impurity of formula IV.
The process of the present invention is described by the following examples, which are illustrative and should not be construed so as to limit the scope of the invention.

EXAMPLES:

REFERENCE EXAMPLE:

In a three necked RB flask, fitted with a mechanical stirrer, condenser and stopper, toluene (500ml), 3, 4-dihydroxy-5-nitrobenzaldehyde (lOOg) and N, N- diethyl cyanoacetamide (95g) were charged. The reactants were stirred and then acetic acid (15ml) and piperidine (7.5ml) were also charged. During the addition of acetic acid, followed by piperidine, the reaction mass temperature should be controlled below 30°C. After completing the addition, the reaction mass was heated to reflux (100-112 °C) and maintained for 8-l4hr with simultaneous collection of water azeotropically. Progress of the reaction was monitored by HPLC. When reaction was completed (% of 3,4-dihydroxy -5-nitrobenzaldehyde below 2.0%), the reaction mass was cooled to 70-80°C and toluene was distilled under vacuum, keeping the mass temperature less than 80°C. The mass was degassed, cooled to 50-55°C, dissolved in methanol (100ml) and then cooled to about 25-30°C. Then slowly 35ml concentrated hydrochloric acid and 100ml of water was added to the reaction during 90-120 min, keeping the temperature below 35°C. The pH of the reaction mass was checked and it should be below 0.5 ad the reaction mass was stirred at 25-

30 °C for 4-5hr. Subsequently the mass was cooled to about 18-22 °C, solid formed was filtered washed with water and dried initially at 25-30°C and later at 70-75 °C.

The technical product, obtained as given above, was purified by crystallization from ethyl acetate (given carbon treatment). In a three necked RB flask fitted with mechanical stirrer, condenser and stopper were charged ethyl acetate (1400ml) and technical Entacapone. The mass was heated to reflux, given carbon treatment, filtered through hyflo bed. The filtrate was concentrated completely (vacuum was applied towards the end). Then the residue was dissolved in ethyl acetate (100ml) and ethyl acetate- hydrogen chloride (150ml). The mass was stirred at 25-28 °C for 12-14hr, then cooled to about 0-5°C for 3-4hr and the solid was filtered, washed with chilled ethyl acetate.

The process of treating with ethyl acetate and concentrated hydrochloric acid was repeated two more times in order to get pure Entacapone, with trans aminated product with more than.

permissible limits.

The working example will provide a solution to the process referred in the reference example.

WORKING EXAMPLE:

In a 4 necked round bottom flask, fitted with a mechanical stirrer, condenser and a thermometer socket, toluene (500.0 ml), 3, 4-dihydroxy-5-nitrobezaldehyde (100-Og) and N, N-diethyl cyanoacetamide (92.0 g) were charged. The reactants were stirred at 25-30°C for 10-15min and slowly acetic acid (15.0g), piperidine (7.5g) and methanol (13.0 ml) were also added. During the addition of acetic acid and piperidine the reaction temperature was maintained at 27-29°C.The reactants were stirred and slowly heated to reflux temperature (~90-95°C)- The reactants were stirred at reflux for about 15hr and later solvent was distilled until the temperature of the mass attained about 103 to 105 °C. Subsequently, the contents were cooled to about 50-55°C, a second portion of methanol (13ml) was added and the reaction mass was heated to reflux temperature (90-95 °C) slowly and maintained for about 15hr. Later the solvent was distilled till the temperature of the mass reached about 103-105°C. The progress of the reaction was monitored by HPLC and if it was complete, the reaction mass was cooled to about 60-80 °C. Then toluene was distilled almost completely under vacuum, maintaining the mass temperature up to 80 °C. The reaction mass was cooled to about 50 °C, dissolved in methanol (20ml) and methanol was distilled off almost completely up to temperature of ~80°C under vacuum. The mass was then cooled to about 50 °C, treated with ethyl acetate (1400ml), stirred at reflux for about an hour and filtered through a bed of Hyflo and washed with 20.0ml of ethyl acetate. The clear filtrate was subjected to distillation, and towards the end vacuum was used to strip-off solvent completely.

The reaction mass, thus obtained, was cooled to about 45 °C, treated with ethyl acetate (100ml) and ethyl acetate containing -15% hydrogen chloride (150ml) and stirred at 25-28°C for about 12 to 14hr. Later the reaction mixture was cooled to about 5-10 °C, stirred for 3-4hr, solid formed was centrifuged and washed with chilled ethyl acetate (100ml).

The solid, obtained after filtration, was treated with ethyl acetate (600ml), .concentrated hydrochloric acid (10ml), water (180ml) and stirred under reflux for about 30minutes. The reaction mass was then cooled to about 5-10 °C, maintained for about 3hrs, filtered and washed with ethyl acetate (100ml). Once again the treatment with ethyl acetate (250ml) concentrated hydrochloric acid and water was repeated. Finally Entacapone was separated and dried to get pure product purity by HPLC 99.95%, Z-isomer 0.02%. trans aminated derivative less than 0.05 (formula-IV)

WE CLAIM:

1. An improved process for manufacturing E-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitro phenyl) acryl amide (Entacapone), comprising: a) condensing 3,4-dihydroxy-5-nitrobenzaldehyde of formula (II);
with N,N-diethyl cyanoacetamide of formula (III), in a non-polar solvent, containing catalytic amount of a polar component and a catalyst, at a temperature of 90-95°C for 12-18hr;

b) distilling solvent slowly until the reaction mass temperature reaches about 100-110°C;

c) cooling the reaction mass to about 60-70 °C, adding catalytic amount of the polar component and continuing reflux at 90-95°C for 12-18hr;

d) distilling solvent slowly till the mass temperature reaches 100-110°C;

e) cooling the reaction mass to about 60-70°C, distilling solvent completely under vacuum till the mass temperature reaches about 80 °C;

f) cooling the mass to 50-55°C dissolving in methanol and distilling under vacuum it almost completely up to mass temperature of about 70°C;

g) cooling the mass, dissolving in ethyl acetate, giving carbon treatment filtering and concentrating;

h) cooling the mass to about 30°C, dissolving in ethyl acetate treating with ethyl acetate -hydrogen chloride (15%), stirring at 25-35°C for 10-15hr, cooling and separating the technical product;
i) purifying the technical product to give pure Entacapone.

2. According to claim 1, the non-polar solvent is selected from the group comprising of benzene, toluene, xylene, fluorobenzene or a mixture thereof, preferably toluene, xylene, most preferably toluene.

3. According to claim 1, the polar component is selected from the group comprising of methanol, ethanol, n-propanol, isoproanol, 2-methoxy ethanol, 2-ethoxy ethanol, or acetonitrile, preferably methanol, ethanol, n-propanol and isopropanol and most preferably methanol.

4. According to claim 1, the catalyst selected is piperidine - acetic acid in 1 to 5.0%.

5. According to claim 1 & 4, a catalyst is used preferably in 1% to 5% and more preferably in 1 to 3%.

6. According to claims 1 and 3, the polar component, methanol is used in 1 to 10 %, preferably 1 to 3 %.

7. According to claim 1, wherein reaction maintenance temperature is at 90-95°C for about 14-15hr and distillation of solvent is up to 103-105°G.

8. The process for purification of Entacapone comprising:

a) treating crude Entacapone with methanol and distilling methanol almost completely up to 80 °C.

b) treating with ethyl acetate and distilling ethyl acetate completely up to 80 °C.

c) treating with ethyl acetate and ethyl acetate-hydrogen chloride at 25-28 °C for 14hr, cooling the
reaction mass and filtering to give the pure Entacapone.

9. According to claim 1, wherein purification of (E)-N,N-diethyl-2-cyano-3-(3,4-dihydroxy -5-nittrophenyl)acrylamide (Entacapone) is carried out by stirring with ethyl acetate and concentrated hydrochloric acid initially at 25-28 °C for 12-14hr and later at 0-5 °C for 3-4hr to give pure Entacapone with purity (HPLC) of 99.8-99.9% with Z-isomer less than 0.1%, say less than 0.05% and trans aminated product of formula IV less than 0.05%, say 0.02%.