The invention relates to a new process for the preparation of pure E isomer of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitro-phehyl)-acrylam ide of formula (1)

( D

in stable polymorphic form. The invention also relates to new intermediates formed in the process:

. ^" (E)-N, N-biethyl-2-cyano-3-(3,4-dihydroxy-5-nitrG-phenyl)-acrylamid e (further on: Ehtacapone) is a compound with catechol-O-methyl-transferase inhibiting effect, used in the treatment of Parkinson's disease. For therapeutic purposes the pure E isomer is used. Preparation of a mixture of the E and Z isomers and its use as an inhibitor of catechol-Ormethyl-transferase has been disclosed first in. US 4,963,590. According to the method disclosed therein a mixture of 5-nitro-vanilline, hydrogen bromide of 48 % strength and acetic acid is boiled for 20 hours, and the resulting 3,4-dihydroxy-5-nitro-benzaldehyde is reacted with N,N-diethyl-cyanoacetamide hydrochloride in the presence of piperidine acetate catalyst. Although it has not been mentioned in this paper, from a later patent of the same inventors (US 5,135,950) it

appears that the resulting product with a melting point of 153-156 ⁰ C is a mixture of the desired E isomer and of the undesired Z isomer, and comprises the undesired isomer in an amount of about 20-30 % by weight. It also appears from this latter US patent that, based on X-ray diffraction measurements, the pure E isomer exists in two polymorphic forms, termed therein as form "A" and form "B". The patent also indicates that both form "B" and the Z isomer are unstable. Upon standing, form "B" ^" slowly converts into the stable form "A" even at room temperature, whereas the Z isomer can be converted into the desired E isomer by heating or upon treatment with an acid. As the presence of geometric isomers and different forms is undesired in pharmaceutical products, according to the patent mentioned above the crude product, which also comprises the Z isomer and form "B" of the E isomer, is treated at 9O ⁰ C with formic acid or acetic acid also comprising hydrogen bromide or hydrogen chloride, the mixture is cooled then slowly to 2O ⁰ C, maintained at this temperature for 20 hours, thereafter it is cooled to 15 ⁰ C and maintained at this temperature for further 6 hours. The resulting product comprises up to 3 % by -weight ^■ of undesired ^" components (Z isomer and/or form -"B"); its melting point is 162-163 ⁰ C. -

According to the present invention Entacapone is prepared by a new process through intermediates which have not been disclosed before in the literature, achieving thereby that even the first intermediate is obtained practically solely in the form of the desired E geometric isomer. Thus the undesired Z isomer, which is in fact a ballast, does not appear in the further steps. The preferred forms of the process according to the invention enable one to use mild reaction conditions and short reaction times, thus the side reactions are suppressed and excellent yields can be obtained.

In the first step of the process according to the invention vanillin of formula (2)

( 2 )

is reacted with N.N-diethyl-cyanoacetamide in the presence of a weak organic acid and of an amine compound used as catalysts. As weak organic acid preferably an aliphatic carboxylic acid can be used, of which acetic acid is particularly preferred; whereas as amine compound suitably a secondary amine, preferably piperidine or diethyl amine, particularly preferably diethyl amine can be applied. The reaction can be performed in an aprotic solvent, preferably in acetonitrile or toluene, suitably at the boiling point of the solvent utilized. At the end of the reaction (E)-N, N-diethyl-2- cyano-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide of formula (3) •

( 3 ),

can be isolated from the reaction mixture in practically pure state. According to HPLC tests less than 1 % by weight of the Z geometric isomer can be detected in the product. Purification of the resulting compound of formula (3) is not necessary; it can be directly used in the next reaction.

In the next step the compound of formula (3) is nitrated to obtain (E)-N, N-di- ethyl-2-cyano-3-(3-methoxy-4-hydroxy-5-nitro-pheny!)-acrylam ide of formula (4).

( 4 )

Nitration can be performed by conventional methods under conventional conditions. According to a particularly preferred method nitric acid is used as nitrating agent and the reaction is performed in an organic acid or in an aqueous medium; under these conditions the reaction can also be performed at temperatures close to room temperature (at 15-3 ^' 5 ⁰ C, preferably a_t 25 ⁰ C). According to a.preferred- method nitric - acid with a strength of 55-63 % by weight, particularly of -58 % by weight, is used as reactant. Based on HPLC examinations, the resulting compound of formula (4) also comprises the Z geometric isomer in amounts of less than 1 % by weight; thus it does not require further purification and can be directly transferred to the next reaction. . ^{' " ■} To obtain Entacapone of formula (1) the compound of formula (4) is demethylated. Demethylation can be performed by conventional methods under conventional conditions: According to a particularly preferred method demethylation is performed in a dipolar aprotic solvent, in the presence of a Lewis acid and of an organic base. Under such conditions demethylation proceeds within a short period of

time (about 1 hour at a temperature of about 100 ⁰ C), whereas when other conven- . tional demethylating agents (such as hydrogen bromide) are used, longer - sometimes much longer - reaction times and/or temperatures exceeding 10O ⁰ C are required. As dipolar aprotic solvent e.g. ethyl acetate, dichloromethane or - preferably dimethyl formamide, dimethyl acetamide or N-methyl-pyrrolidone, as Lewis acid preferably aluminium chloride, whereas as organic base preferably pyridine can be used. Owing to the lower temperature and rather short reaction time the decomposition processes are strongly suppressed, and Entacapone can be obtained with excellent yield and purity.

If desired or necessary, the resulting end product can be purified further. According to a preferred method of purification the end product is recrystallized first from isopropanol and then from a mixture of acetone and acetic acid.

X-ray diffraction and HPLC test results have shown that by the method of the ^" invention Entacapone is obtained solely as the E isomer, and within this solely in the stable polymorphic form ' ¹ A"-. The melting point of the product is 164-165 ⁰ C.

The compounds of formulae (3) and (4), formed ^" as intermediates in the above process, are new. The invention also relates to these new compounds and to the preparation of the new compounds. .

Further details of the invention are illustrated by the following non-limiting Examples.

Example 1

Preparation of (E)-N, N-diethyl-Σ-cvano-S-O-methoxy^-hvdroxy-phenvD-acryl-

amide [compound of formula (3)1

15.2 g (0.1 moles) of vanillin, 14.0 g (0.1 moles) of N,N-diethyl-cyanoacet- amide, 300 ml of acetonitrile, 1.0 ml of piperidine and 0.8 ml of acetic acid are

weighed into a flask equipped with a stirrer and a thermometer. The reaction mixture is heated to boiling and is refluxed for 6 hours. After cooling the reaction mixture is evaporated, and the residue is crystallized from 200 ml of toluene. The product is filtered off and dried in air. 16.6 g of the title compound, comprising less than 1 % by weight of Z geometric isomer as determined by HPLC, are obtained; m.p.: 143- ,144 ⁰ C.

Example 2

Preparation of (E)-N. N-diethyl^-cyano-S-O-methoxy^-hydroxy-phenvD-acryl-

amide [compound of formula (3)1

15.2 g (0.1 moles) of vanillin, 14.0 g (0;1 moles) of N,N-diethyl-cyanoacet- ^" amide, 300 ml of toluene, 1.6 ml of diethyl amine and 0.8 ml of acetic acid are weighed into a flask equipped with a stirrer, a thermometer and a water separator. The reaction mixture is heated to boiling and _. refluxed for 3 hours under simultaneously removing the formed water in the water separator. After cooling the reaction mixture is washed with 15 ml of water. Crystallization of the product starts within a short time. The mixture is allowed to stand at ^" room temperature for the next day, and then the product is filtered off and dried in air. 17.8 g of the title compound, comprising less than 1 % by weight of Z geometric isomer as determined by HPLC, are obtained; m.p.: 143-145 ⁰ C.

Example 3

Preparation of (E)-N, N-diethyl-2-cyano-3-(3-methoxy-4-hvdroxy-5-nitro-

phenvD-acrylamide [compound of formula (4)1

28 g (0.1 moles) of (E)-N, N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-ρhenyl)- acrylamide and 250 ml of 96 % acetic acid are weighed into a flask equipped with a stirrer, a thermometer and a cooler. 90 ml of nitric acid with a strength of 58 % by

weight (0.11 moles) are added to the solution within about 1 hour under mild cooling. When addition of nitric acid is complete, cooling is terminated, and the reaction mixture is stirred at room temperature for additional 2 hours. Thereafter the mixture is diluted with 250 ml of water and stored in a refrigerator for 3 hours. The separated product is filtered off, washed acid-free with water and dried in air, 25.1 g of the title compound, comprising less than 1. % by weight of Z geometric isomer as determined by HPLC, are obtained; m.p.: 105-107 ⁰ C.

Example 4

Preparation of (E)-N, N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-5-nitro- phenvP-acrylamide [compound of formula (4)1

^' 28 g (0.1 moles) of (E)-N, N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy~phenyl)- acrylamide and 300 ml of water are weighed into a flask equipped with a stirrer, a thermometer and a reflux condenser. 90 ml of nitriG acid with a strength of 58 % by weight (0.11 moles) are added to the suspension within about 1 hour under mild . external cooling. When addition of nitric acid is complete, cooling is terminated, and the suspension is stirred at room temperature for additional 2 hours. The product is filtered off, washed acid-free with water and dried in air. 26.0 g of the title compound, comprising less than 1 % by weight of Z geometric isomer as determined by HPLC,- are obtained; m.p.: 106-108 ⁰ C.

Example 5

Preparation of (E)-N, N-diethyl-2-cvano-3-(3 ^' .4-dihydroxy-5-nitro-phenyl)-

acrylamide [compound of formula (1)1

31.9 g (0.1 moles) of (E)-N, N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-5-nitro- phenyl)-acrylamide and 250 ml of N-methyl-pyrrolidone are weighed into a flask equipped with a stirrer, a thermometer and a reflux condenser. 15.6 g (0.12 moles)

of aluminium chloride are added to the solution in portions under external cooling, and then still under cooling 24 ml of dry pyridine are dropped into the mixture. The reaction mixture is heated to 100 ⁰ C and stirred at this temperature for 1.5 hours. ■ After cooling to room temperature 56 ml of concentrated hydrochloric acid are added to the mixture under cooling, followed with 320 ml of water. After 2 hours of stirring the product is filtered off, washed with water, and dried at 5O ⁰ C under reduced pressure. 28.8 g of the title compound are obtained.

Example 6

Preparation of (E)-N, N-diethyl-2-cvano-3-(3,4-dihvdroxy-5-nitro-phenyl)-

acrylamide [compound of formula (1)1 - ^"

31 :9 g (0.1 moles) of (E)-N, N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-5-nitro- phenyl)-acrylamide and 200 ml of N,N-dimethyl formamide are weighed into a flask equipped with a stirrer, a thermometer and a reflux condenser. 15.6 g (0.12 moles) of aluminium chloride are added to the solution in portions under externa! cooling, and then still under cooling 24 ml of dry pyridine are dropped into the mixture. The -reaction mixture is heated to 100 ⁰ C and stirred at this temperature for 1 hour. After cooling to room temperature 56 ml of concentrated, hydrochloric acid are added to the mixture under cooling, followed with 320 ml of water. After 2 hours of stirring the product is filtered off, washed with water, and dried at 50 ⁰ C under reduced pressure. 29.8 g of the title compound are obtained.

Example 7

Purification of (E)-N, N-diethyl-2-cvano-3-(3,4-dihydroxy-5-nitro-phenyl)-

acrylamide [compound of formula (1)1

29.8 g of the title compound, prepared as described in Example 6, are dissolved in 450 ml of hot isopropanol, the hot solution is decolourized with 2 g of

activated carbon, and then carbon is removed by filtration. The solution is allowed to cool and then kept at 10-20 ⁰ C for 3 hours. The separated product is filtered off, washed with cold isopropanol and dried in air. The resulting 26.4 g of product are dissolved at 6O ⁰ C in a mixture of 100 ml of acetone and 8 ml of glacial acetic acid, the solution is decolourized with 2 g of activated carbon, the carbon is removed by filtration, and the filtrate is kept at 10-20 ⁰ C for 3 hours. The separated crystalline • product is filtered off, washed with cold acetone, and dried in air. 23 g of the title compound are obtained with a purity grade of 99.9 % as determined by HPLC; m.p.: 164-165 ⁰ C. X-ray diffraction pattern shows that this product consists solely of the stable polymorphic form. ^{' "} .