FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(see section 10 and rule 13)
A PROCESS FOR DEMETHYLATION OF 5-NITROVANILLIN
PIRAMAL ENTERPRISES LIMITED, a company incorporated under the Companies Act 1956, of Piramal Tower, Ganpatrao Kadam Marg, Lower Parel, Mumbai - 400013, States of Maharashtra, India
The following specification particularly describes the invention and the manner in which it is to be performed

Field of the invention
The present invention relates to a process for the preparation of 3,4-dihydroxy-5-nitrobenzaldehyde, a key intermediate used in the synthesis of entacapone. More particularly, the present invention relates to a process for preparation of 3,4-dihydroxy-5-nitrobenzaldehyde by demethylation of 5-nitrovanillin.
Background of the invention
Entacapone is also known as N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide or (E)-2-cyano-3-(3, 4-dihydroxy-5-nitrophenyl)-N, N-diethyl-2-propenamide. Entacapone is structurally represented by following formula I
Entacapone has been approved by USFDA on October 1999 for the use an adjunct to levodopa / carbidopa to treat patients with idiopathic Parkinson's Diseases. Entacapone is a potent and specific peripheral catechol-O-methyl transferase (COMT) inhibitor. It enhances the effect of levedopa/carbidopa by improving muscle control. Entacapone is marketed by Orion Corporation under tradename Comtan and is available in the market as a 200 mg tablet.
US Patent No. 5,446,194 discloses entacapone and its process for preparation involving 3,4-dihydroxy-5-nitrobenzaldehyde of formula II as an intermediate. The process for preparation of compound of formula II disclosed in said patent involves demethylation of 5-nitrovanillin of formula III using hydrobromic acid in acetic acid in the presence of charcoal. The acetic acid used in the process is of 118°C boiling point and therefore, removal of such high boiling point solvent is difficult.

US Patent Application No. 20080076825 discloses a process for demethylation of 5-nitrovanillin of formula III comprising aluminium chloride and pyridine in the presence of chlorobenzene as a solvent at a temperature of 70 °C to 80 °C to yield 3,4-dihydroxy-5-nitrobenzaldehyde of formula II.
US Patent Application No. 20100234632 describes a process for demethylation of 5-nitrovanillin of formula III comprising use of anhydrous aluminium chloride and pyridine at a temperature of 50 °C to 55°C and followed by treatment with hydrochloric acid to yield 3,4-dihydroxy-5-nitrobenzaldehyde of formula II.
CN Patent Application No. CN103130681 discloses a process for preparation of 3,4-dihydroxy-5-nitrobenzaldehyde of formula II from 5-nitrovanillin of formula III comprising reaction with aluminium chloride and pyridine in the presence of acetonitrile at a temperature of 50°C for 10 hours to yield 3,4-dihydroxy-5-nitrobenzaldehyde.
PCT Application Publication No. WO2013149566 (hereinafter referred to as WO'566 appln.) discloses a process for demethylation of compound of formula A to yield entacapone in the presence of an organic base and a suitable acid.
According to the WO'566 appln. the said acid is a protonic acid or a Lewis acid and the said organic base is selected from pyridine, triethylamine, diethylamine, diisopropylamine or 4-dimethylaminopyridine (DMAP).
The journal reference, Synthetic Communications, 38(15), 2507-2520, 2008 describes a process for the preparation of 3,4-dihydroxy-5-nitrobenzaldehyde of formula II from 5-nitrovanillin of formula III comprising reacting with boron tribromide in the presence of

dichloromethane and in absence of a base at a reflux temperature for 6 hours to yield compound of formula II.
The process for demethylation of 5-nitrovanillin of formula III to yield 3,4-dihydroxy-5-nitrobenzaldehyde of formula II disclosed in the prior art references mainly involves use of a base such as pyridine, triethylamine, diethylamine, diisopropylamine, 4-dimethylaminopyridine and in the presence of reagents such as aluminium chloride, boron trifluoride, boron tribromide and the like. However, these organic bases are genotoxic and hazardous in nature and therefore these organic bases should be controlled below threshold of toxicological concern (TTC) limits in any of the downstream synthetic steps for the preparation of final product and the final product as well.
Also, the journal reference, Synthetic Communications, 38(15), 2507-2520, 2008 teaches the process for preparation of 3,4-dihydroxy-5-nitrobenzaldehyde of formula II by demethylation of 5-nitro vanillin of formula III in the absence of a base. However, the inventors of the present invention carried out the process as disclosed in the said journal reference and observed that the process does not reach to completion even after 50 hours.
Thus, there is a need to develop a process for the preparation of 3,4-dihydroxy-5-nitrobenzaldehyde of formula II by demethylation of 5-nitro vanillin of formula III avoiding use of genotoxic and hazardous organic bases and at the same time, the reaction should be proceed towards completion with maximum conversion of 5-nitrovanillin of formula III to 3,4-dihydroxy-5-nitrobenzaldehyde of formula II.
Objects of the invention
An object of the present invention is to provide a process for the preparation of 3,4-dihydroxy-5-nitrobenzaldehyde of formula II from 5-nitrovanillin of formula III.

An object of the present invention is provide a process for the preparation of 3,4-dihydroxy-5-nitrobenzaldehyde of formula II by demethylation of 5-nitrovanillin of formula III avoiding use of a base.
Another object of the present invention is to provide a process for the preparation of 3,4-dihydroxy-5-nitrobenzaldehyde of formula II which is simple, cost-effective, efficient and industrially applicable.
Summary of the invention
In accordance with an object of the present invention, there is provided a process for the preparation of 3,4-dihydroxy-5-nitrobenzaldehyde of formula II, a key intermediate used in the synthesis of entacapone of formula I comprising reaction of 5-nitrovanillin of formula III with aluminium chloride and dimethylformamide in the presence of a solvent to yield compound of formula II.
The process of the present invention is schematically depicted herein:
The compound of formula II obtained according to a process of the present invention may be subjected to treatment with water to remove the inorganic impurities present in compound of formula II.
In accordance with another aspect of the present invention, the process of the present invention overcomes the disadvantages associated with the processes described in the prior art, which is mainly concerned with the use of a base, such as pyridine, triethylamine, diethylamine, diisopropylamine, 4-dimethylaminopyridine and the like;

which are genotoxic and hazardous. The process of the present invention avoids use of a base, thereby making the instant process simple, cost-effective, efficient and industrially applicable.
Detailed description of the invention
The present invention relates to a process for the preparation of 3,4-dihydroxy-5-nitrobenzaldehyde of formula II
comprising reaction of 5-nitrovanillin of formula III
with aluminium chloride (AlCl3) and dimethylformamide in the presence of a solvent to yield formula II.
In an embodiment of the present invention the compound of formula III reacted with aluminium chloride and dimethylformamide, in the absence of a base and in the presence of a solvent to yield compound of formula II.
In accordance with an embodiment of the present invention, the said solvent is selected from halogenated solvents, aromatic solvents, aprotic non-polar solvents or aprotic polar solvents or a mixture thereof.

In accordance with an embodiment of the present invention, the said halogenated solvent is selected from dichloromethane, 1,2-dichloroethene, chloroform or 1,1,2-trichloroethene.
In accordance with an embodiment of the present invention, the said aromatic solvent is selected from chlorobenzene or nitrobenzene.
In accordance with an embodiment of the present invention, the said aprotic non-polar solvent is selected from hexane, cyclohexane, heptane or methyl tert-butyl ether.
In accordance with an embodiment of the present invention, the said aprotic polar solvent is selected from ethyl acetate, acetonitrile, tetrahydrofuran, dioxane or N-methylpyrrolidone.
In accordance with an embodiment of the present invention, the reaction is carried out using 3 to 15 volumes of solvent based on the quantities of compound of formula III.
In accordance with an embodiment of the present invention, the said reaction is carried out using 1 to 6 molar equivalents of aluminium chloride based on the quantities of compound of formula III.
In accordance with an embodiment of the present invention, the said reaction is carried out using 2 to 10 molar equivalents of dimethylformamide based on the quantities of compound of formula III.
In accordance with an embodiment of the present invention, the reaction is carried out at a temperature range of 30 °C to 60 °C.
In accordance with an embodiment of the present invention, the reaction is carried out at a temperature range of 30 °C to 60 °C for 15 h to 30 h.

In accordance with an embodiment of the present invention, the process further comprises treatment of compound of formula II with water at a temperature range of 60 °C to l00°C.
The compound of formula II obtained according to the process of the present invention may contain some traces of inorganic impurities, such as aluminium chloride, aluminium hydroxide and the like. These impurities can be removed by treatment of compound of formula II with water at a temperature range of 60 °C to 100 °C. The resulting reaction mixture filtered and dried to yield compound of formula II. The treatment of compound of formula II with water may also be referred to as a process for purification of compound II.
The compound of formula III, 5-nitrovanillin is a known compound and can be prepared by a person skilled in the art by following the processes known in the art. For example, the compound of formula III can be prepared by following the process disclosed in the Journal of organic chemistry, 1951, vol. 16, page no. 216-220. The process involves reaction of vanillin with fuming nitric acid in the presence of glacial acetic acid to yield compound of formula III.
The compound of formula II, 3,4-dihydroxy-5-nitrobenzaldehyde obtained according to process of the present invention is further converted to entacapone of formula I according to processes known in the art. For example, entacapone of formula I can be prepared from compound of formula III by following the process disclosed in the US Patent No. 5,446,194, which is incorporated herein by reference. The process involves reaction of 3,4-dihydroxy-5-nitrobenzaldehyde with N,N-diethylcyanoacetamide in the presence of catalytic amount of piperidine acetate in ethanol at reflux temperature for overnight to yield entacapone.
The following examples which fully illustrate the practice of the preferred embodiments of the present invention are intended to be for illustrative purpose only and should not be considered in anyway to limit the scope of the present invention.

Examples
Reference Example:
To a reaction flask, was charged dichloromethane (75 mL) and AICI3 (20.3 g), to which compound of formula III (15 g) was then added to the reaction mixture and the resulting reaction mixture was refluxed at a temperature of 35 - 45 °C for 5-50 hours. The resulting reaction mixture was then cooled and charged with aqueous hydrochloric acid (52.5 mL). Dichloromethane was evaporated from the reaction mixture and the resulting mixture was filtered to yield compound of formula II.
Table-l: The progress of reaction carried out in absence of base

Reaction Time Reaction temperature maintained Results
8h 35 - 45 °C Only compound of formula III present in the reaction mixture
24 h 35 - 45 °C 75 % of unreacted compound of formula III present in the reaction mixture
50 h 35 - 45 °C 60 % of unreacted compound of formula III present in the reaction mixture
Example 1: Preparation of compound of formula II in absence of base
To a reaction flask, was charged dichloromethane (600 mL) and AICI3 (202.50 g) and the reaction mixture was cooled to 2 °C to 6 °C. Then to the reaction mixture dimethylformamide (333.5 g) was added and maintained the reaction mixture at a temperature of 10 °C to 15 °C for 30 - 40 min. The compound of formula III (150 g) was then added to the reaction mixture and the resulting reaction mixture was refluxed at a temperature of 35°C to 45 °C for 15 h to 28 h. The resulting reaction mixture was then cooled and charged with aqueous hydrochloric acid (1050 mL). Dichloromethane was evaporated from the reaction mixture and resulting mixture was filtered to yield compound of formula II. Yield 90-95%.

Example 2: Process for purification of compound II
In a reaction flask was charged water (800 mL) and compound of formula II (450 g). The reaction mixture was heated at a temperature of 75 °C to 90 °C for 1 h. The reaction mixture was then cooled to 25 °C to 30 °C and filtered. The product obtained was dried to yield pure compound of formula II. Yield 80-86 %.

We claim
1. A process for the preparation of 3,4-dihydroxy-5-nitrobenzaldehyde of formula II
comprising reaction of 5-nitrovanillin of formula III
with aluminium chloride and dimethylformamide in the presence of a solvent to yield formula II.
2. The process according to claim 1, further comprising treatment of compound of formula II with water to yield pure compound of formula II.
3. The process according to claim 1, wherein the reaction is carried out using 1 to 6 molar equivalents of aluminium chloride based on the quantities of compound of formula III.
4. The process according to claim 1, wherein the reaction is carried out using 2 to 10 molar equivalents of dimethylformamide based on the quantities of compound of formula III.

5. The process according to claim 1, wherein the solvent is selected from halogenated solvents, aromatic solvents, aprotic non-polar solvents or aprotic polar solvents or a mixture thereof
6. The process according to claim 1, wherein the reaction is carried out using 3 to 15 volumes of solvent based on the quantities of compound of formula III.
7. The process according to claim 1, wherein the reaction is carried out at a temperature range of 30 °C to 60 °C.
8. The process according to claim 1, wherein the reaction is carried out at a temperature range of 30 °C to 60 °C for 15 h to 30 h.
9. The process according to claim 2, wherein the reaction is carried out at a temperature range of 60 °C to 100 °C.