WO2008007093A1

WO2008007093A1 - Process and product

Info

Publication number: WO2008007093A1
Application number: PCT/GB2007/002596
Authority: WO
Inventors: Andrzej Manikowski; Zofia Kolarska; Juraj Jerkovic
Original assignee: Pliva Hrvatska D.O.O.; Mcleish, Nicholas, Alistair, Maxwell
Priority date: 2006-07-12
Filing date: 2007-07-11
Publication date: 2008-01-17
Also published as: GB0613826D0; EP2046730A1

Abstract

The present invention relates to an improved process for isolation and purification of Entacapone, pharmaceutical compositions and therapeutic uses thereof. The process provides an improved yield and improved isomeric purity of produced Entacapone.

Description

PROCESS AND PRODUCT

The present invention relates to an improved process for the isolation and purification of Entacapone, Entacapone prepared in an improved yield and improved isomeric purity, and pharmaceutical compositions and therapeutic uses thereof.

Entacapone is the international non-proprietary name for (E)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N,N-diethyl-2-propenamide. Entacapone is the pharmaceutically active isomer of 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide. 2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide can, however, exist as a mixture of the two geometric isomers, (E) and (Z), formulae I and II respectively as follows.

Formula I Formula II

US 4963590 belongs to the NCE patent family first describing preparation of 2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide. Specifically, Example 100 describes preparation of 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide by condensation of 3,4-dihydroxy-5-nitrobenzaldehyde and N,N-diethylcyano acetamide according to the following reaction scheme.

2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide was obtained as a mixture of the above (E) and (Z) isomers.

US 4963590 describes that the compounds according to the invention are extremely effective catechol-O-methyltransferase (COMT) inhibitors. Catechol-O-methyltransferase (COMT) catalyzes the transfer of the methyl group from S-adenosyl-L-methionine to a number of compounds with catechol structures. This enzyme is important in the extraneuronal inactivation of catecholamines and drugs with catechol structures. COMT is one of the most important enzymes involved in the metabolism of catecholamines. It is present in most tissues, both in the periphery and the central nervous system. The highest activities are found in the liver, intestine and kidney.

In Parkinson's disease the dopaminergic neurones, primarily the nigrostriatal neurones, are damaged, causing dopamine deficiency in the cerebral basal ganglia. This deficiency can be compensated by levodopa, which is converted to dopamine in the central nervous system under the influence of dopa decarboxylase (DDC). In addition to DDC, COMT metabolizes levodopa, converting it to 3-O-methyldopa (3-OMD). 3-OMD readily penetrates the blood- brain barrier via an active transport system. Alone it is therapeutically ineffective and detrimental when competing with levodopa. 3-OMD is accumulated in tissues because of its long half-life (about 15 hours) compared to levodopa (about 1 hour). The high activity of COMT clearly correlates with the poor efficacy of levodopa, despite the often presence of a peripheral DDC inhibitor. COMT inhibitors, such as Entacapone, thus have been seen to have therapeutic utility in the treatment of Parkinson's disease.

WO 05/063693 also describes preparation of 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N- diethyl-2-propenamide as a mixture of the (E) and (Z) isomers according to the following reaction scheme

R = methyl or ethyl

US 5135950 describes crystallographically essentially pure and stable polymorphic form A of Entacapone, where crude 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2- propenamide (a mixture of isomers (E) and (Z)) is recrystallized from lower aliphatic carboxylic acid, such as formic or acetic acid, with a catalytic amount of hydrochloric or hydrobromic acid added.

WO 05/070881 also describes a process for the manufacture of crystallographically essentially pure and stable polymorphic form A of Entacapone, where crude 2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide is poured into aqueous ethyl acetate solution, followed by adjusting the pH to between 3.5 to 4.0 with acetic acid. Entacapone as form A is obtained from the ethyl acetate layer.

WO 05/063695 describes the preparation of polymorphic forms C and D of Entacapone. Polymorph C is obtained by crystallization of Entacapone from n-heptane and polymorph D is obtained by crystallization of Entacapone from solvents such as acetone/water, THF, 2- propanol/hexane and n-propanol/water.

There are a number of problems associated with the prior art processes of preparing Entacapone. In particular, there is a need to develop an improved process to Entacapone, which provides Entacapone in a substantially pure form (i.e. substantially uncontaminated by (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide) and also in high yield, thus providing an economical and industrially advantageous route to Entacapone.

According to the present invention, there is now provided, therefore, a process of preparing Entacapone, which process comprises converting (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N,N-diethyl-2-propenamide to Entacapone.

More specifically, the present invention provides a process of preparing Entacapone, which process comprises (i) preparing crude 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl- 2-propenamide comprising a mixture of Entacapone and (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N,N-diethyl-2-propenamide, (ii) isolating Entacapone therefrom so as to obtain a mother liquor enriched with (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2- propenamide, and characterised in (iii) further treating said mother liquor so as to convert (Z)- 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide present therein to further Entacapone and isolating said further Entacapone.

Isolation of Entacapone in a process according to the present invention, particularly in step (ii) above, is typically by way of solvent crystallization employing a suitable solvent, such as a C_1-4 alcohol, preferably methanol, to obtain substantially pure Entacapone. One or more, such as two or three, crystallizations, for example in step (ii) can be carried out, if required. In this way the purity of isolated Entacapone can thus be further increased if necessary until it is substantially pure, that is substantially only Entacapone is present.

The mother liquor obtained from step (ii), or the mother liquor from the or each crystallization step of step (ii), is enriched with (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2- propenamide. (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide present in one or more of these liquors, or the pooled liquors, may be converted into further Entacapone in step (iii).

Suitably, (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide, for example as present in one or more of these liquors, or the pooled liquors, is treated with an acid, suitably under reflux, in order to convert said (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N,N-diethyl-2-propenamide into said Entacapone. Typically, one or more of these mother liquors, or the pooled mother liquors, is initially concentrated under vacuum and treated with an organic solvent, such as toluene, followed by the above described addition of acid and reflux. Preferably the acid is hydrochloric acid, although other suitable acids may be employed. Subsequent to reflux, the reflux mixture is cooled, suitably to room temperature, followed by further addition of acid, again preferably hydrochloric acid. Isolation of Entacapone in step (iii) is again typically by way of solvent crystallization from a suitable solvent, such as a C_1-4 alcohol, preferably methanol, to obtain substantially pure further Entacapone.

Preparation of crude 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide comprising Entacapone and (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2- propenamide in step (i) is preferably by reaction of 3,4-dihydroxy-5-nitrobenzaldehyde and N,N-diethyl-2-cyanoacetamide, with reference to the preparation method in Example 100 of US 4963590. In a process according to the present invention, however, toluene instead of ethanol as used in US 4963590 is applied as a medium of reaction, with simultaneous azeotropic removal of water.

A process according to the present invention provides Entacapone as polymorph Form A, substantially free of (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2- propenamide and in improved yield compared to prior art process techniques. Polymorph Form A of Entacapone is characterised in US 5135950.

There is further provided by the present invention, therefore, Entacapone, preferably as polymorph Form A, having an isomeric purity of at least about 99%, more preferably at least about 99.5%, more preferably more than about 99.7% and even more preferably at least about 99.8%. In a particularly preferred embodiment, the present invention provides Entacapone having an isomeric purity of more than about 99.7%.

There is further provided by the present invention, therefore, a pharmaceutical reaction product comprising Entacapone, preferably as polymorph Form A, substantially free of (Z)-2- cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide, which Entacapone is present at a % yield of at least about 60%, more preferably at least about 63%, more preferably at least about 65%, more preferably at least about 68%, more preferably at least about 70% and more preferably at least about 75%. There is still further provided by the present invention a pharmaceutical reaction product of a process according to the present invention substantially as hereinbefore described, which reaction product comprises Entacapone, preferably as polymorph Form A, substantially free of (Z)-2-cyano-3-(3 ,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide, which Entacapone is present at a % yield of at least about 60%, more preferably at least about 63%, more preferably at least about 65%, more preferably at least about 68%, more preferably at least about 70% and more preferably at least about 75%.

Entacapone prepared by a process substantially as hereinbefore described, or present in a reaction product substantially as hereinbefore described, as provided by the present invention, has therapeutic utility in inhibition of catechol-O-methyltransferase and as such in the treatment of diseases prevented, ameliorated or eliminated by such enzyme inhibition, in particular Parkinson's disease.

The present invention further provides, therefore, a pharmaceutical composition comprising a therapeutically effective dose of Entacapone substantially as hereinbefore described, or present in or obtained from a reaction product substantially as hereinbefore described, together with a pharmaceutically acceptable carrier, diluent or excipient therefor. Excipients are chosen according to the pharmaceutical form and the desired mode of administration.

As used herein, the term "therapeutically effective amount" means an amount of Entacapone according to the invention, which is capable of inhibiting catechol-O-methyltransferase.

By "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient is compatible with Entacapone according to the invention, and not deleterious to a recipient thereof.

Pharmaceutical compositions according to the present invention may contain Entacapone substantially as hereinbefore described, or present in or obtained from a reaction product substantially as hereinbefore described, alone or combined with some other medicines. For the treatment of Parkinson's disease Entacapone as provided by the present invention is administered with levodopa, each as separate compositions or combined in one composition. Also peripheral dopa decarboxylase (DDC) inhibitors, such as carbidopa or benserazide may be present, even though they are not obligatory. However, current practice is that it is generally preferred that levodopa treatment for combination therapy according to the present invention is almost invariably supplemented with a peripheral DDC inhibitor to inhibit too early dopamine formation and thereby to increase the cerebral levodopa concentration and to decrease the peripheral side effects of dopamine.

There is further provided by the present invention, therefore, a pharmaceutical product containing (i) Entacapone substantially as hereinbefore described, or present in or obtained from a reaction product substantially as hereinbefore described, and (ii) levodopa, as a combined preparation for simultaneous, separate or sequential use in the treatment of disease states associated with dopamine deficiency, in particular Parkinson's disease.

There is further provided by the present invention, therefore, a pharmaceutical product containing (i) Entacapone substantially as hereinbefore described, or present in or obtained from a reaction product substantially as hereinbefore described, (ii) levodopa and (iii) a peripheral DDC inhibitor, as a combined preparation for simultaneous, separate or sequential use in the treatment of disease states associated with dopamine deficiency, in particular Parkinson's disease.

There is also provided by the present invention use of Entacapone substantially as hereinbefore described, or present in or obtained from a reaction product substantially as hereinbefore described, in the manufacture of a medicament for the treatment of disease states associated with dopamine deficiency in combination with levodopa.

There is also provided by the present invention use of Entacapone substantially as hereinbefore described, or present in or obtained from a reaction product substantially as hereinbefore described, in the manufacture of a medicament for the treatment of disease states associated with dopamine deficiency in combination with levodopa and a peripheral DDC inhibitor.

Entacapone as provided by the present invention may be administered in different dosage forms for any suitable enteral or parenteral way. The dosage forms such as tablets, pills, injection liquids and the like may be manufactured by known principles in the art. It is thus well within the skill of an addressee in the pharmaceutical field to employ pharmaceutically accepted additives, carrier, lubricants, fillers and the like to modify different properties of the dosage forms.

The present invention further provides Entacapone substantially as hereinbefore described, or present in or obtained from a reaction product substantially as hereinbefore described, for use in the manufacture of a medicament for inhibition of catechol-O-methyltransferase. More specifically, the present invention provides Entacapone substantially as hereinbefore described, or present in or obtained from a reaction product substantially as hereinbefore described, for use in the manufacture of a medicament for the treatment of Parkinson's disease and related conditions.

The present invention also provides a method of treating a disease state prevented, ameliorated or eliminated by the administration of an inhibitor of catechol-O- methyltransferase in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of Entacapone substantially as hereinbefore described, or present in or obtained from a reaction product substantially as hereinbefore described. More specifically, the present invention provides a method of treating Parkinson's disease and related conditions, in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of Entacapone substantially as hereinbefore described, or present in or obtained from a reaction product substantially as hereinbefore described.

The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention. It will thus be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be falling within the scope of the invention.

Example 1 - Preparation of (Ε)-2-cvano-3-(3,4-dihvdroxy-5-nitrophenyl)-N,N-diethyl-2- propenamide, Entacapone A solution containing 10.0Og of 3,4-dihydroxy-5-nitrobenzaldehyde, 8.42g of N,N-diethyl-2- cyanoacetamide and 0.84g of piperidine acetate in 150ml of toluene was refluxed for 3.5 hours with water removal by azeotropic distillation. The content of the reactor was cooled to room temperature and 10ml of methanol was added. 100ml 4.5% HCl was added dropwise to obtain a yellow-green solid and the mixture was stirred at 7-10⁰C for 1 hour. Crude 2-cyano- 3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide being a mixture of (E) and (Z) isomers was filtered off, washed with 2x15ml toluene and dried to a constant mass. Yield: 15.7g (94 %). The product was purified by crystallization from methanol to obtain 8.2g (49%) of pure Entacapone as polymorph form A.

Mother liquors, containing mainly isomer (Z), were concentrated under vacuum, treated with 100ml of toluene and a catalytic amount of hydrochloric acid (2ml), and stirred under reflux for 4 hours, with the aim of conversion of isomer (Z) ((Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N,N-diethyl-2-propenamide) into isomer (E) (Entacapone). After cooling down to room temperature, 50ml 4.5% HCl was added dropwise and the obtained suspension was stirred at 7-10⁰C for 1 hour. A second batch of crude 2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N,N-diethyl-2-propenamide (a mixture of (E) and (Z) isomers) was filtered off, washed with 2x10ml toluene and dried at 40⁰C. Crystallization from methanol gave 2.4g (14%) of pure Entacapone as polymorph form A.

Both the first and second crop of crystallized Entacapone are in pure (E) form and have a chromatographic purity of at least 99 %.

Example 2 - Purity Analysis

The purity of Entacapone as prepared by the present invention was measured employing the following apparatus and operating conditions.

Equipment and working conditions:

HPLC operating conditions (Agilent 1100):

1. Flow rate: about 2ml/min

2. Injection volume: about 50 μl 3. Column and pre-column: Octylsilane chemically bonded to totally porous silica particles (USP L7 packing) 4.6 mm x 150 mm columns that contain packing USP L3 (Phenomenex Gemini C 18, 5μm, 4.6 mm x 150 mm)

4. Column temperature: thermostated at 35°C

5. Detector: UV - wavelength 213 nm (BW 4nm, ref. 700nm, BW 100 run)

6. Mobile phase (typical): A - phosphate buffer solution pH 3.0 (Ph. Eur.)

B - methanol

7. Gradient (typical):

8. Analytical run: 25 minutes (and 5 minutes of equilibration (or time needed for stable baseline)

Degas prepared mobile phases for about 10 minutes.

Reagents:

Methanol gradient grade for chromatography potassium dihydrogen phosphate p.a. phosphoric acid p.a. water SG

Preparation of solutions:

Amber glassware was used to protect analyte.

1. Phosphate buffer solution pH 3.0: 3.40 g of potassium dihydrogen phosphate was dissolved in 900ml of water. The pH was adjusted to 3.0 with phosphoric acid and diluted to 1000.0 ml with water.

2. Diluent: Methanol: phosphate buffer solution pH 3.0 (1 : 1 v/v) was thoroughly mixed and equilibrated to room temperature to provide sufficient diluent to prepare all the solutions. 3. Test solution: A known concentration of sample solution was prepared, about 0.6 mg/ml (30.0 mg of Entacapone as prepared by the present invention was dissolved in diluent and diluted to 50.0 ml with diluent). The test solution was prepared in duplicate.

4. Reference solution (a): A known concentration of Entacapone WS solution, about 0.6 mg/ml was prepared. (30.0 mg of Entacapone WS in diluent was prepared and diluted to 50.0 ml with diluent.) This was prepared in duplicate.

5. Reference solution (b): A diluted solution of Entacapone having known concentration, about 0.6 μg/ml, was prepared. (1.0 ml of reference solution (a) was diluted to 10.0 ml with diluent and 1.0 ml of this solution was further diluted to 100.0 ml with diluent.) A duplicate reference solution (b) was prepared from duplicate reference solution (a).

6. Reference solution (c): A solution of Entacapone WS of about 0.6 mg/ml was prepared and impurity A (Z-isomer) AS of about 0.2 mg/ml (about 30.0 mg of Entacapone WS and about 10.0 mg of impurity A AS were dissolved in diluent and diluted to 50.0 ml with diluent).

7. Reference solution (d): A diluted solution of Entacapone having known concentration of about 0.3 μg/ml was prepared (5.0 ml of reference solution (b) was diluted to 10.0 ml with diluent; a single reference solution (b) which having lowest amount of analyte was used).

The prepared solutions were stable for 24 h at 5°C protected from light.

Procedure:

The column was equilibrated with the initial eluent composition until stable baseline was obtained. The gradient profile by starting method without injection (blank run) was recorded.

a) System suitability - selectivity:

Reference solution (c) was chromatographed. System suitability parameters for selectivity are given in the following table:

The test was not valid until all requirements were met.

b) System suitability - sensitivity (^"precision at LOQ)

The relative standard deviation for replicate injections (at least 5) of the reference solution (d) was not more than 15.0%.

c) System suitability - precision

The relative standard deviation for replicate injections (at least 6) of the reference solution (a) was not more than 2.0%

The relative standard deviation for replicate injections (at least 6) of the reference solution (b) was not more than 5.0%

d) Injection scheme

Blank solution (diluent) - Ref. sol. (d) (5x) - Ref. sol. (c) - Ref. sol. (a) (2x) - blank solution - Ref. sol. (b) (2x) - Test solution - Ref. sol (a) (2x) - Ref. sol (b) (2x) - Test solution - Ref. sol. (a) (2x) - Ref. sol. (b) (2x)

e) Calculations - impurity content

Individual detector response factors (RF) for Entacapone was calculated from all reference solution (b) preparation injections using the following equation:

RF= A / C

C = concentration of Entacapone in reference solution (b) (in mg/ml) A = peak area of the Entacapone from calibration chromatogram

The average detector response factors <RF> were calculated from all calibration injections. The test solution chromatograms were compared with chromatograms obtained from reference solution (c) and blank solution. Any peak originating from the blank solution was disregarded.

Impurities content was calculated using the following equation:

Si (%) = 100 * Ai / (<RF> *Cs)

Si = impurity content (in %)

Ai = peak area of the impurity from test solution chromatogram

Cs = concentration of Entacapone in test solution (in mg/ml)

f) Calculations - assay

Individual detector response factors (RF) for Entacapone were calculated from all reference solution (a) preparation injections using the following equation:

RF= A / C

C = concentration of Entacapone in reference solution (a) (in mg/ml) A = peak area of the Entacapone from calibration chromatogram

Average detector response factors <RF> were calculated from all calibration injections.

The assay was calculated using the following equation:

Assay (%) = 100 * A / (<RF> * Cs)

Assay = assay (in %)

A = peak area of the Entacapone in test solution chromatogram

Cs = concentration of the Entacapone in test solution (in mg/ml) The accompanying Figures are examples of typical chromatograms obtained by the above analysis.

Figure 1 is a representative chromatogram obtained as above for a blank solution. Figure 2 is a representative chromatogram obtained as above for reference solution (c). Figure 3 is a representative chromatogram obtained as above for reference solution (a). Figure 4 is a representative chromatogram obtained as above for reference solution (b). Figure 5 is a representative chromatogram obtained as above for reference solution (d). Figure 6 is a representative chromatogram obtained as above for a test solution.

Claims

1. A process of preparing Entacapone, which process comprises converting (Z)-2-cyano- 3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide to Entacapone.

2. A process according to claim 1, wherein (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N,N-diethyl-2-propenamide is treated with an acid under reflux for conversion to Entacapone.

3. A process according to claim 2, wherein said acid is hydrochloric acid.

4. A process according to any of claims 1 to 3, wherein Entacapone is isolated by solvent crystallization employing a CM alcohol.

5. A process according to claim 4, wherein said Ci_-4 alcohol is methanol.

6. A process of preparing Entacapone, which process comprises (i) preparing crude 2- cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide comprising a mixture of Entacapone and (Z)-2-cyano-3 -(3 ,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide, (ii) isolating Entacapone therefrom so as to obtain a mother liquor enriched with (Z)-2-cyano- 3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide, and characterised in (iii) further treating said mother liquor so as to convert (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)- N,N-diethyl-2-propenamide present therein to further Entacapone and isolating said further Entacapone.

7. A process according to claim 6, wherein isolation of Entacapone in step (ii) is by solvent crystallization employing a Ci_-4 alcohol.

8. A process according to claim 7, wherein said Ci_-4 alcohol is methanol.

9. A process according to any of claims 6 to 8, wherein (Z)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N,N-diethyl-2-propenamide present in said mother liquor is treated with an acid under reflux for conversion to Entacapone.

10. A process according to claim 9, wherein said acid is hydrochloric acid.

11. A process according to any of claims 6 to 10, wherein isolation of Entacapone in step (iii) is by way of solvent crystallization from a Cj_-4 alcohol.

12. A process according to claim 11, wherein said Ci_-4 alcohol is methanol.

13. A process according to any of claims 6 to 12, wherein preparation of crude 2-cyano-3- (3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide comprising Entacapone and (Z)-2- cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide in step (i) is by reaction of 3,4-dihydroxy-5-nitrobenzaldehyde and N,N-diethyl-2-cyanoacetamide.

14. A process according to claim 13, wherein piperidine acetate is present as a catalyst in toluene as a solvent and the reaction mixture is refluxed with concomitant removal of water by azeotropic distillation.

15. A process according to any of claims 1 to 14, which prepares Entacapone having an isomeric purity of at least about 99%.

16. A process according to claim 15, which prepares Entacapone having an isomeric purity of at least about 99.5%.

17. A process according to claim 16, which prepares Entacapone having an isomeric purity of more than about 99.7%.

18. A process according to claim 17, which prepares Entacapone having an isomeric purity of at least about 99.8%.

19. A process according to any of claims 1 to 18, which prepares Entacapone as polymorph Form A.

20. A process according to any of claims 1 to 19, which prepares Entacapone, substantially free of (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2- propenamide and at a % yield of at least about 60%.

21. A process according to claim 20, which prepares Entacapone at a % yield of at least about 63%.

22. A process according to claim 21, which prepares Entacapone at a % yield of at least about 65%.

23. A process according to claim 22, which prepares Entacapone at a % yield of at least about 68%.

24. A process according to claim 23, which prepares Entacapone at a % yield of at least about 70%.

25. A process according to claim 24, which prepares Entacapone at a % yield of at least about 75%.

26. Entacapone having an isomeric purity of at least about 99%.

27. Entacapone according to claim 26, having an isomeric purity of at least about 99.5%.

28. Entacapone according to claim 27, having an isomeric purity of more than about 99.7%.

29. Entacapone according to claim 28, having an isomeric purity of at least about 99.8%.

30. Entacapone according to any of claims 26 to 29, which is polymorph Form A.

31. A pharmaceutical reaction product comprising Entacapone, substantially free of (Z)-2- cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide, wherein said Entacapone is present at a % yield of at least about 60 %.

32. A pharmaceutical reaction product of a process according to any of claims 1 to 25, which reaction product comprises Entacapone, substantially free of (Z)-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide, wherein said Entacapone is present at a % yield of at least about 60 %.

33. A pharmaceutical reaction product according to claim 31 or 32, wherein said Entacapone is present at a % yield of at least about 63%.

34. A pharmaceutical reaction product according to claim 33, wherein said Entacapone is present at a % yield of at least about 65%.

35. A pharmaceutical reaction product according to claim 34, wherein said Entacapone is present at a % yield of at least about 68%.

36. A pharmaceutical reaction product according to claim 35, wherein said Entacapone is present at a % yield of at least about 70%.

37. A pharmaceutical reaction product according to claim 36, wherein said Entacapone is present at a % yield of at least about 75%.

38. A pharmaceutical reaction product according to any of claims 31 to 37, wherein Entacapone is present as polymorph Form A.

39. A pharmaceutical composition comprising a therapeutically effective dose of (i) Entacapone prepared by a process according to any of claims 1 to 25, or (ii) Entacapone according to any of claim 26 to 30, or (iii) Entacapone present in or obtained from a reaction product according to any of claims 31 to 38, together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

40. A pharmaceutical product containing (i) Entacapone prepared by a process according to any of claims 1 to 25, or Entacapone according to any of claim 26 to 30, or Entacapone present in or obtained from a reaction product according to any of claims 31 to 38, and (ii) levodopa, as a combined preparation for simultaneous, separate or sequential use in the treatment of disease states associated with dopamine deficiency.

41. A pharmaceutical product containing (i) Entacapone prepared by a process according to any of claims 1 to 25, or Entacapone according to any of claim 26 to 30, or Entacapone present in or obtained from a reaction product according to any of claims 31 to 38, (ii) levodopa and (iii) a peripheral DDC inhibitor, as a combined preparation for simultaneous, separate or sequential use in the treatment of disease states associated with dopamine deficiency.

42. A pharmaceutical product according to claim 40 or 41, for use in the treatment of Parkinson's disease

43. Use of (i) Entacapone prepared by a process according to any of claims 1 to 25, or (ii) Entacapone according to any of claim 26 to 30, or (iii) Entacapone present in or obtained from a reaction product according to any of claims 31 to 38, in the manufacture of a medicament for the treatment of disease states associated with dopamine deficiency in combination with levodopa.

44. Use of (i) Entacapone prepared by a process according to any of claims 1 to 25, or (ii) Entacapone according to any of claim 26 to 30, or (iii) Entacapone present in or obtained from a reaction product according to any of claims 31 to 38, in the manufacture of a medicament for the treatment of disease states associated with dopamine deficiency in combination with levodopa and a peripheral DDC inhibitor.

45. Entacapone prepared by a process according to any of claims 1 to 25, or Entacapone according to any of claim 26 to 30, or Entacapone present in or obtained from a reaction product according to any of claims 31 to 38, for use in the manufacture of a medicament for inhibition of catechol-O-methyltransferase.

46. Entacapone prepared by a process according to any of claims 1 to 25, or Entacapone according to any of claim 26 to 30, or Entacapone present in or obtained from a reaction product according to any of claims 31 to 38, for use in the manufacture of a medicament for the treatment of Parkinson's disease and related conditions.

47. A method of treating a disease state prevented, ameliorated or eliminated by the administration of an inhibitor of catechol-O-methyltransferase in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of (i) Entacapone prepared by a process according to any of claims 1 to 25, or (ii) Entacapone according to any of claim 26 to 30, or (iii) Entacapone present in or obtained from a reaction product according to any of claims 31 to 38.

48. A method of treating Parkinson's disease and related conditions, in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of (i) Entacapone prepared by a process according to any of claims 1 to 25, or (ii) Entacapone according to any of claim 26 to 30, or (iii) Entacapone present in or obtained from a reaction product according to any of claims 31 to 38.