WO2013149566A1

WO2013149566A1 - Process for the preparation of entacapone and its intermediate thereof

Info

Publication number: WO2013149566A1
Application number: PCT/CN2013/073429
Authority: WO
Inventors: Dongsheng Zhou; Liu Liu; Bin MAO; Yun Liu
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Sunshine Lake Pharma Co Ltd
Priority date: 2012-04-01
Filing date: 2013-03-29
Publication date: 2013-10-10
Anticipated expiration: 2014-10-01

Description

PROCESS FOR THE PREPARATION OF ENTACAPONE AND ITS INTERMEDIATE THEREOF

FIELD OF THE INVENTION

[001] The present invention relates to the field of pharmaceutical chemistry. More particularly, the invention relates to methods of preparing entacapone, a catechol-O-methyl transferase (COMT) inhibitor, and intermediates of entacapone.

BACKGROUND OF THE INVENTION

[002] Entacapone, also known as (E)-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N,N-diethyl acrylamide, has Formula (I):

[003] Entacapone, a specific catechol-O-methyl transferase (COMT) inhibitor, has been approved by FDA on October 1999 for the adjuvant treatment of Parkinson's disease (PD).

[004] WO 2006/064296 has disclosed a novel method for preparing entacapone by condensing vanillin with N,N-diethyl-cyanoacetamide in the presence of a weak organic acid and an amine compound as catalysts to produce (E)- N,N- diethyl-2-cyano-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide of formula (IV) , followed by the nitration reaction to obtain an intermediate compound (E)-N, N- diethyl-2-cyano-3 -(3 -methoxy-4-hydroxy-5-nitro-phenyl) -acrylamide, i. e., Formula (V):

[005] The compound of Formula (V) obtained can be demethylated to produce entacapone of Formula (I). The nitration reaction involves the use of concentrated nitric acid in polar solvents with high boiling point such as water and acetic acid. The mixing of concentrated nitric acid with the polar solvents is generally extremely exothermic and may accompany with serious side reactions. Furthermore, it is difficult to remove the high boiling point solvents, e.g., acetic acid. When water is used as the solvent, a compound of Formula (IV):

shows a poor solubility in water even after the addition of concentrated nitric acid. In this case, the heterogeneity of the immiscible reaction system results in unreacted starting materials and poor reaction yield, which makes it impractical for industrial application. Moreover, other disadvantages of the demethylation step is carried out athigh reaction temperatures. Therefore, the demethylation reaction is high energy consumption. The overall yield is only about 37% even the process is optimized.

SUMMARY OF THE INVENTION

[006] In one aspect, provided herein are processes for preparing a compound of Formula (V):

comprising nitrating a compound of Formula (IV):

with a nitrating agent in the presence of a catalyst.

[007] In some embodiments, the catalyst is a metal nitrite. In further embodiments, the metal nitrite is an alkali metal nitrite. In still further embodiments, the metal nitrite is sodium nitrite, potassium nitrite, lithium nitrite or a combination thereof.

[008] In certain embodiments, the nitrating agent is a dilute nitric acid. In further embodiments, the concentration of the dilute nitric acid is less than about 68 wt.%, from about 5 wt.% to about 50 wt.%, or from about 10 wt.% to about 20 wt.%, based on the total weight of the dilute nitric acid.

[009] In some embodiments, the nitration reaction is carried out in a low- boiling point solvent. In further embodiments, the boiling point of the low-boiling point solvent is less than about 90 °C, less than about 80 °C, or less than about 70 °C. In further embodiments, the low-boiling point solvent is a halogenated solvent. In still further embodiments, the low-boiling point solvent is dichloromethane, 1,2- dichloro ethane, tetrachloromethane or a combination thereof.

[0010] In certain embodiments, the mass ratio of the catalyst to the compound of Formula (IV) is from about 0.01% to about 5%, from about 0.1% to about 3%, or from about 1.5% to about 2.5%.

[0011] In another aspect, provided herein are processes for preparing a compound of Formula (IV):

comprising the steps of: a) condensing a compound of Formula (II):

with a compound of Formula (III):

to produce a reaction mixture; and b) adding the compound of Formula (IV) as a seed to the reaction mixture.

[0012] In another aspect, provided herein are processes for preparing entacapone of Formula (I):

comprising demethylating a compound of Formula (V):

in the presence of an organic base or acid at an elevated reaction temperature.

[0013] In some embodiments, the low boiling point solvent is an

etherealsolvent. In further embodiments, the low boiling point solvent is

tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a combination thereof.

DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS AND GENERAL TERMINOLOGY

[0014] The term "nitrating agent" as used herein refers to the reagent that can add a nitro (N0₂) substituent to aromatic compounds. Exemplary nitrating agents include, but not limiting to, nitric acid and nitrate salts, such as alkali metal nitrate salts, e.g., KN0₃.

[0015] The term "catalyst" as used herein refers to a substance that can reduce the activation energy of a chemical reaction or change the rate of a chemical reaction, such as nitration reaction. [0016] As used herein, the term "room temperature" refers to a temperature from about 18 °C to about 35 °C or a temperature from about 20 °C to about 24 °C or a temperature at about 22 °C.

[0017] In the following description, all numbers disclosed herein are approximate values, regardless whether the word "about" is used in connection therewith. The value of each number may differ by 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20%. Therefore, whenever a number having a value N is disclosed, any number having the value N+/-l%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8%, N+/-10%, N+/-1 % or 20 N+/-20% is specifically disclosed, wherein "+/-" refers to plus or minus. Whenever a numerical range with a lower limit, L, and an upper limit, Ry, is disclosed, any number falling within the range is specifically disclosed. In particular, the following numbers within the range are specifically disclosed: R=R_L ⁺k*(Ru-R_L)= wherein k is a variable ranging from 1% to 100% with a 1% increment, i.e., k is 1%, 2%, 3%, 4%, 5%,..., 50%, 1%, 52%,..., 95%, 96%, 97%, 98%, 99%, or 100%.

Moreover, any numerical range defined by two R numbers as defined above is also specifically disclosed.

[0018] In one aspect, the present invention provides a process for preparing a compound of Formula (V), i.e., (E)-N, N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy- 5 -nitro-phenyl)-acrylamide :

under simple and mild reaction conditions suitable for industrial use. In some embodiments, the compound of Formula (V) is prepared by nitrating the compound of Formula (IV), i.e., (E)-N,N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-phenyl)- acrylamide:

with a nitrating agent in the presence of a catalyst.

[0019] Any nitrating agent that can undergo an electrophilic substitution reaction with an aromatic compound, such as the compound of Formula (IV), to form the corresponding nitro compound, such as the compound of Formula (V), can be used herein. In certain embodiments, the nitrating agent is nitric acid, sulfuric acid, one or more metal nitrates, a non-nitrous oxide, acetic acid or a combination thereof. In certain embodiments, the nitrating agent is nitric acid. In some embodiments, the nitrating agent is a mixture of nitric acid and sulfuric acid. In certain embodiments, the nitrating agent is a mixture of one of more metal nitrates and sulfuric acid. In some embodiments, the nitrating agent is a mixture of a non-nitrous oxide, nitric acid and acetic acid. In certain embodiments, the nitrating agent is nitric acid. In further embodiments, the nitrating agent is diluted nitric acid. In some embodiments, the concentration of the diluted nitric acid is less than about 68 wt.%, from about 5 wt.% to about 50 wt.%, or from about 10 wt.% to about 20 wt.%, based on the total weight of the dilute nitric acid. In some embodiments, the molar ratio of the compound of Formula (IV) to the nitrating agent is from about 1 :1 to about 1 :3. In certain embodiments, the molar ratio is from about 1 :1.1 to about 1 :1.5. [0020] In some embodiments, the catalyst comprises a metal nitrite, such as an alkali metal nitrite. In certain embodiments, the alkali metal nitrite is sodium nitrite, potassium nitrite, lithium nitrite or a combination thereof. In certain embodiments, the mass ratio of the catalyst to the compound of Formula (IV) is from about 0.01% to about 5%, from about 0.1% to about 3%, or from about 1.5% to about 2.5%

[0021] In some embodiments, the nitration reaction disclosed herein is carried out in a low-boiling point solvent. The boiling point of the low-boiling point solvent is less than about 90 °C; or less than about 80 °C; or less than about 70 °C. In certain embodiments, the low-boiling point solvent is a halogenated solvent. The

halogenated solvent is dichloromethane, chloroform, 1,2-dichloroethane,

tetrachloromethane or a combination thereof. In some embodiments, the low-boiling point solvent is an ethereal solvent. In further embodiments, the ethereal solvent is diethylether, diisopropyl ether, tetrahydrofuran, diethylene glycol dimethyl ether, methyl /er/-butyl ether or a combination thereof. In certain embodiments, the low- boiling point solvent is a ketone solvent. In further embodiments, the ketone solvent is acetone, methyl ethyl ketone, diethyl ketone or a combination thereof. In some embodiments, the low-boiling point solvent is an ester solvent. In further

embodiments, the ester solvent is ethyl acetate, isopropyl acetate, butyl acetate or a combination thereof. In certain embodiments, the low-boiling point solvent is a nitrile solvent. In further embodiments, the nitrile solvent is acetonitrile, propionitrile or a combination thereof. In some embodiments, the low-boiling point solvent is one or more halogenated solvents, one or more ether solvents, or combinations thereof. In other embodiments, the low-boiling point solvent is dichloromethane or tetrahydrofuran.

[0022] In another aspect, provided herein are processes for preparing entacapone of Formula (I):

comprising demethylating the compound of Formula (V):

in the presence of an organic base and a suitable acid at an elevated reaction temperature.

[0023] In some embodiments, the demethylation reation occurs in ethyl acetate, dichloromethane , tetrahydrofuran, dioxane, methyl tert-butyl ether, dimethoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, dimethyl formamide, dimethyl acetamide or N-methyl-pyrrolidone or a combinations thereof.

[0024] In certain embodiments, the elevated reaction temperature is below about 100 °C, below about 90 °C, below about 80 °C, below about 70 °C, below about 60 °C, or below about 50 °C, or ranging from 30 °C to 80 °C or from 50 °C to 70 °C.

[0025] In some embodiments, the acid is a protonic acid, a Lewis acid or a combination thereof. In some embodiments, the protonic acid is hydrogen chloride, hydrogen bromide or a combination thereof. In certain embodiments, the Lewis acid is aluminum chloride, zinc chloride, lithium bromide, zinc bromide or a combination thereof. In some embodiments, the molar ratio of the compound of Formula (V) to the Lewis acid is from about 1 :1 to about 1 :3; or from about 1 :1.1 to about 1 :1.5.

[0026] In certain embodiments, the organic base is pyridine, triethylamine, diethylamine, diisopropylamine, 4-dimethylaminopyridine (DMAP) or a combination thereof. In some embodiments, the organic base is triethylamine. In certain embodiments, the organic base is pyridine. In some embodiments, the molar ratio of the compound of Formula (V) to the organic base is from about 1 :1 to about 1 :5; or from about 1 :2 to about 1 :4.

[0027] In another aspect, provided herein are processes for preparing the compound of Formula (IV), i.e., (E)-N,N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy- pheny 1) -aery lamide :

comprising the step of condensing a compound of Formula (II), i.e., vanillin:

with a compound of Formula (III), i.e., N, N-diethyl-cyano-acetamide:

in the presence of a weak organic acid and a suitable base in a certain temperature. In some embodiments, a small amount of the compound of Formula (IV) is added after the condensation reaction is completed.

[0028] As shown in scheme 1 below, after the condensation reaction is completed, the Z-isomer of N,N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-phenyl)- acrylamide having Formula (IVa) and E-isomer of N,N-diethyl-2-cyano-3-(3- methoxy-4-hydroxy-phenyl)-acrylamide, i.e., the compound of Formula (IV), are in equilibrium in the reaction mixture. A seed crystal of the E-isomer, i.e., the compound of Formula (IV), can be added to the reaction mixture to promote the crystallization process of the E-isomer and thus the conversion of Z-isomer to E-isomer so as to eliminate or reduce the amount of the Z-isomer to less than 1 mole %, less than 0.8 mole %, less than 0.6 mole %, less than 0.4 mole %, less than 0.2 mole %, or less than 0.1 mole %.

SCHEME 1

[0029] In some embodiments, the condensation reaction can be carry out in a hydrocarbon solvent, an alcohol solvent, an ester solvent or a combination thereof. In certain embodiments, the hydrocarbon solvent is n-hexane, n-heptane, cycloalkane (e.g., cyclohexane), an aromatic solvent (e.g., benzene, toluene and xylene) or a combination thereof. In some embodiments, the alcohol solvent is Ci-C₆ aliphatic alcohols such as methanol, ethanol, isopropanol, butanol or a combination thereof. In certain embodiments, the ester solvent is ethyl acetate, butyl acetate or a combination thereof.

[0030] In some embodiments, the weak organic acid is an aliphatic carboxylic acid. In certain embodiments, the weak organic acid is a Q-Ce carboxylic acid such as acetic acid. In some embodiments, the molar ratio of the compound of Formula (II) to the weak organic acid is from about 1 :0.1 to about 1 :1 ; or from about 1 :0.2 to about 1 :0.5.

[0031] In certain embodiments, the base is a secondary or tertiary amine. In certain embodiments, the base is diethylamine, piperidine, diazabicycloundecene (DBU), D AP, diisopropylamine, pyridine or a combination thereof. In some embodiments, the base is diethylamine. In certain embodiments, the base is piperidine. In some embodiments, the molar ratio of the compound of Formula (II) to the base is from about 1 :0.1 to about 1 :1. In some embodiments, the molar ratio is from about 1 :0.2 to about 1 :0.5.

[0032] In some embodiments, the reaction temperature of the condensation reaction is the reflux temperature of the solvent. In certain embodiments, the reaction temperature ranges from 60 °C to 150 °C. In some embodiments, the reaction temperature ranges from 90 °C to 120 °C.

[0033] The processes for preparing Entacapone may comprise up to three steps: condensation, nitration and demethylation. Each of these three steps involves non-hazardous conditions, environment friendly and easy to handle reagents, and reduced reaction times, and thus is suitable for industrial scale. Each of these three steps is optimized to produce high yield (> 90%) and purity (>99.5% of the E-isomer). For example, the nitration step can be carried out under mild condition by adding a catalyst; the demethylation step involving a low reaction temperature is low energy consumption and environment friendly; and the condensation step comprising adding a seed to the reaction mixture after the reaction is completely, which produce a product practically soley in the form of the desired E-isomer.

DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 depicts the HPLC spectrum of (E)-N,N-diethyl-2-cyano-3-(3- methoxy-4-hydroxyphenyl) acrylamide (Formula IV) obtained from Example 1.

[0035] Figure 2 depicts the HPLC spectrum of (E)-N, N-diethyl-2-cyano-3 -(3- methoxy-4-hydroxy-5-nitrophenyl) acrylamide (Formula V) obtained from Example 4.

[0036] Figure 3 depicts the HPLC spectrum of entacapone obtained from Example 5.

[0037] Figure 4 depicts the HPLC spectrum of entacapone obtained from Example 7. EXAMPLES

[0038] The present invention discloses a method for preparing entacapone and its intermediates. The skilled in the art can learn from the present invention and improve the process parameters appropriately. It should be noted that it can be readily apparent to those of ordinary skill in the art that certain modifications may be made thereto within the scope of the invention. Some embodiments of the invention are disclosed herein, obviously, a skilled artisan can make any alterations, changes or combinations thereof appropriately to implement and apply the present invention without departing from the content, spirit and scope of the present invention.

Example 1 - Preparation of (E)-N,N-diethyl-2-cyano-3-(3-methoxy-4-hydroxyphenyl) acrylamide (Formula IV)

[0039] Toluene (1360 mL), vanillin (73 g), N,N-diethyl-cyano-acetamide (70.6 g), glacial acetic acid (5.88 g) and diethylamine (7.72 g) were added to a 2L flask equipped with a water separator at room temperature to form a reaction mixture. The reaction mixture was then heated under reflux and stirred for 6 to 8 hours. The water formed was removed by means of the water separator. After the reaction mixture was cooled, a small amount of (E)-N,N-diethyl-2-cyano-3-(3-methoxy-4- hydroxyphenyl) acrylamide was added to the reaction mixture. The reaction mixture was then cooled to 30 °C and filtered to obtain a solid. The solid was subsequently washed with toluene and dried to obtain 118.5 g of (E)-N,N-diethyl-2-cyano-3- (3- methoxy-4-hydroxyphenyl) acrylamide. The yield was 90%. The HPLC purity of the E-isomer was 99.84%.

Example 2 - Preparation of (E)-N,N-diethyl-2-cyano-3-(3-methoxy-4-hydroxyphenyl) acrylamide (Formula IV)

[0040] Cyclohexane (650 mL), vanillin (36 g), N,N-diethyl-cyanoacetamide (35.3 g), glacial acetic acid (2.90 g) and diethylamine (3.9 g) were added to a 1 L flask equipped with a water separator and stirred at room temperature to form a reaction mixture. The reaction mixture was heated under reflux for 6 to 8 hours. The water formed was removed by means of the water separator. After the reaction mixture was cooled, a small amount of (E)-N, N-diethyl-2-cyano-3-(3-methoxy-4- hydroxyphenyl) acrylamide was then added to the reaction mixture. The reaction mixture was then cooled to 25 °C and filtered to obtain a solid. The solid was subsequently washed with toluene and then dried to obtain 58.0 g of (E)-N,N- diethyl-2-cyano-3-(3-methoxy-4-hydroxyphenyl) acrylamide. The yield was 92%. The HPLC purity of the E-isomer was 99.4%.

Example 3 - Preparation of (E)-N,N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-5- nitrophenyl) -acrylamide (Formula V)

[0041] (E)-N,N-diethyl-2-cyano-3-(3-methoxy-4-hydroxyphenyl)acrylamide (20 g), dichloromethane (250 mL) and sodium nitrite (0.3 g) were added to a 500 mL flask and stirred at room temperature for 10 minutes until the complete dissolution of (E)-N,N-diethyl-2-cyano-3-(3-methoxy-4-hydroxyphenyl) acrylamide to form a solution. After the solution was cooled and kept at 20 °C, 30 mL of nitric acid (20%) was added dropwise to the solution. The temperature of the solution was kept at 20 °C for an hour. After the water phase was removed, the organic phase was extracted for three times with water followed by evaporating to dryness to obtain 20.9 g of (E)-N, N-diethyl-2-cyano-3 -(3 -methoxy-4-hydroxy-5 -nitrophenyl)-acrylamide. The yield was 90.3%. The HPLC purity of the E-isomer was 99.79%.

Example 4 - Preparation of (E)-N, N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-5- nitrophenyl) aery I amide (Formula V)

[0042] (E)-N,N-diethyl-2-cyano-3-(3-methoxy-4-hydroxyphenyl) acrylamide (20 g), dichloromethane (250 mL) and sodium nitrite (0.48 g) were added to a 500 mL flask and stirred at room temperature for 10 minutes until the complete dissolution of (E)-N,N-diethyl-2-cyano-3-(3-methoxy-4-hydroxyphenyl) to form a solution . After the solution was cooled and kept at 20 °C, 30 mL of nitric acid (15%) was added dropwise to the solution. The temperature of the solution was further kept at 20 °C for

2 hours. After the water phase was removed, the organic phase of the solution was extracted for three times with water. The organic phase was evaporated to dryness, refined with ethanol, centrifuged and then dried to obtain 21.8 g of (E)-N, N-diethyl- 2-cyano-3-(3-methoxy-4-hydroxy-5-nitrophenyl)-acrylamide. The yield was 94%. The HPLC purity of the E-isomer was 99.90%.

Example 5 - Preparation of (E)-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide (entacapone)

[0043] (E)-N,N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy-5- nitrophenyl)acrylamide (32 g) and tetrahydrofuran (250 mL) were added to a 500 mL flask at room temperature to form a reaction mixture. The mixture was cooled toO °C.

After anhydrous aluminum chloride (16.0 g) was added to the reaction mixture, triethylamine (41.6 mL) was added dropwise to the reaction mixture. The reaction mixture was heated under reflux and then cooled. The cooled mixture was dropwise added to dilute hydrochloric acid (10%) followed by adding 314 mL of water. It was allowed to maintain at the same temperature for 6 hours for crystallization and was centrifuged and dried to obtain 28.0 g of (E)-N, N-diethyl-2-cyano-3-(3,4-dihydroxy- 5-nitrophenyl) acrylamide (entacapone). The yield was 92%. The HPLC purity of the E-isomer was 99.92%.

Example 6 Preparation of (E)-N, N-diethyl-2 - cyano-3 - (3,4 - dihydroxy-5 - nitrophenyl) acrylamide (Entacapone)

[0044] (E)-N,N-diethyl-2-cyano-3-(3-methoxy-4-hydroxy~5- nitrophenyl)acrylamide (32 g), DMF (200 ml) were added to a flask, after the mixture was cooled to 0 °C , anhydrous aluminum chloride (16.0 g) and triethylamine (13.8 ml) were added, then the mixture was heated to 65 ^°C, after stirred for about lhour, the reaction mixture was cooling and was added to a dilute hydrochloric acid, followed with 314 ml of water, after stirring for 6 hours, the product is filtered off and dried to obtained (E)-N, N-diethyl-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl) acrylamide (Entacapone) 28.0 g, yield 92 %,

Example 7 - Preparation of (E)-N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide (entacapone)

[0045] Methanol (180 mL) was added to entacapone (180 g) prepared by the method illustrated in Example 5 in a 250 mL flask. The entacapone was dissolved to form a solution by heating under reflux and then was slowly cooled to 55 °C. A small amount of (E)-N,N-diemyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide was added to the solution. The temperature of the solution was maintained for an hour in a crystallization process. The solution was then cooled and stirred for 8 hours to 5 °C.

The solution was centrifuged and dried to obtain 167.4 g of entacapone. The yield was 93%. The HPLC purity of the E-isomer was 99.98%.

Example 8

Chromatographic conditions for measuring the purity of entacapone by a reversed- phase HPLC with UV photodiode array detector were as follows: column, Waters XTerra Phenyl, 4.6 x 250 mm, 5 μηι; detection wavelength, 300 nm; column temperature, 25 °C; mobile phase, a 54:44:2 (v/v/v) mixture of buffer: methanol :THF; flow rate, 1 mL/min; injection volume, 10 μΐ. The buffer is a phosphate buffer solution with 2.34 g/L of sodium dihydrogen phosphate dehydrate. pH value of the buffer was adjusted by phosphoric acid to 2.1.

Example 9

[0046] Chromatographic conditions for measuring the purity of intermediates Formulae (IV) and (V) by a reversed-phase HPLC with UV photo diode array detector were as follows: column, Agilent SB-C18, 4.6 x 150 mm, 5 μηι; detection wavelength,

310 nm; column temperature, 30 °C; mobile phase, 0.1% aqueous phosphoric acid and acetonitrile.

[0047] Those illustrative embodiments herein are used to help understand the methods and core ideas about this present invention. It should be noted that many adaptations and modifications may be made thereto without departing from the the scope of the appended claims in accordance with the common general knowledge of those of ordinary skill in the art.

Claims

WHAT IS CLAIMED IS:

1. A process for preparing a compound of Formula (V):

comprising nitrating a compound of Formula (IV):

with a nitrating agent in the presence of a catalyst.

2. The process of claim 1, wherein the catalyst is a metal nitrite.

3. The process of claim 2, wherein the metal nitrite is an alkali metal nitrite, or the metal nitrite is sodium nitrite, potassium nitrite, lithium nitrite or a combination thereof.

4. The process of any one of claims 1-3, wherein the nitrating agent is a dilute nitric acid.

5. The process of claim 4, wherein the concentration of the dilute nitric acid is less than about 68 wt.%, from about 5 wt.% to about 50 wt.%, or from about 10 wt.% to about 20 wt.%, based on the total weight of the dilute nitric acid.

6. The process of any one of claims 1-5, wherein the nitration reaction is carried out in a low-boiling point solvent.

7. The process of claim 6, wherein the boiling point of the low-boiling point solvent is less than about 90 °C, less than about 80 °C, or less than about 70 °C.

8. The process of claim 6, wherein the low-boiling point solvent is a halogenated solvent, or the low-boiling point solvent is dichloromethane, chloroform, 1,2-dichloroethane, tetrachloromethane or a combination thereof.

9. The process of any one of claims 1 -8, wherein the mass ratio of the catalyst to the compound of Formula (IV) is from about 0.01% to about 5%, from about 0.1% to about 3%, or from about 1.5% to about 2.5%.

10. A process for preparing a compound of Formula (IV):

comprising the steps of: a) condensing a compound of Formula (II):

with a compound of Formula (III):

to produce a reaction mixture; and adding the compound of Formula (IV) as a seed to the reaction mixture.

11. A process for preparing entacapone of Formula (I):

comprising demethylating a compound of Formula (V):

in the presence of an organic base and a suitable acid at a temperature below 100 °C .

12. The process of claim 11, wherein the demethylation reation occurs in ethyl acetate, dichloromethane , tetrahydrofuran, dioxane, methyl ert-butyl ether, dimethoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, dimethyl formamide, dimethyl acetamide or N-methyl-pyrrolidone or a combinations thereof.