The present invention discloses an improved and simple process for the preparation of veratraldehyde.
Background of the Invention
Veratraldehyde (3,4-dimethoxybenzaldehyde), represented as Formula I, is present in small amounts in Cymbopogon javanensis essential oil. It is used in relatively few perfume compounds, odorants, and food aromatizers, and also as intermediate in synthesis of certain pharmaceutical drugs like donepezil, galanthamine, etc.
CHO
x
Y^OCH3 OCH3
Formula I
A widely known process for the preparation of veratraldehyde is O-methylation of vanillin by various methylating agents.
Organic Syntheses, 1933, 13, 102 discloses O-methylation of vanillin by dimethyl sulphate in presence sodium hydroxide. The disclosed process suffered a major disadvantage that mixing of strong base i.e. sodium hydroxide with vanillin is to be done at high temperature so as to avoid precipitation of sodium salt of vanillin, as once precipitated it hindered the mechanical working of reactor/apparatus. Further, the process also involved the addition of dimethyl sulfate in a number of lots, which itself is not feasible to work upon at industrial scale where high temperature reactions are involved. Thus, the disclosed process suffered the working incompatibility with respect to ease of implementation at large scale.
Tetrahedron, 1979, 35, (18) discloses the preparation of veratraldehyde using methyl iodide. Methyl iodide is a known allergen and exposure to methyl iodide by inhalation may depress the central nervous system (CNS), irritate the lungs and skin. Thus, a

process involving use of methyl iodide is highly unsafe to be applicable on industrial scale.
US 4453004 discloses process for the preparation of veratraldehyde from vanillin wherein the reaction is carried out in liquid melt phase by heating the reaction mixture at least to the melting point of the vanillin and in the absence of a solvent with an alkylating agent. Such processes being carried out in hot-melt phase are very difficult to handle to be applicable on industrial scale in the absence of any solvent medium.
Journal of Organic Chemistry, 2001, 66(7), 2246 discloses preparation of veratraldehyde using diazomethane, which is highly explosive and toxic in nature. Thus, handling of such reagents at large scale is difficult, which makes process unsafe and infeasible to be used for industrial application.
CN 105622377 discloses a process for the preparation of veratraldehyde from vanillin using dimethyl carbonate in the presence of base and phase transfer catalyst, wherein the process involves very long reaction time in the range of 30-50 hours. The processes involving very long reaction times consume large amount of energy and thus are not economical for application on industrial scale, thus the disclosed process is not suitable for large scale production.
ChemSusChem, 2016, 9(17), 2312 disclosed a process for the preparation of veratraldehyde using l,3-dimethylimidazolium-2-carboxylate catalyst in about 3 hours at 160 °C. Use of homogeneous catalyst l,3-dimethylimidazolium-2-carboxylate gave good yield but there are several problems associated with use of such catalysts as they have to be neutralized and cannot be recycled, thereby making the process polluting and inefficient in terms of being economical on industrial scale. Further, such higher temperature is avoided on industrial scale.
Thus, considering the importance and application of veratraldehyde and the above mentioned drawbacks of prior arts involving additional chemical operations, increased energy input, difficult operating conditions at commercial scale and use of hazardous reagents, there is a need to develop a process for the preparation of veratraldehyde, which

not only overcomes the disadvantages of prior art but also provides a simple, green and efficient process to be applicable on large scale.
The present invention provides a simple, convenient, commercially viable and energy efficient improved process for synthesis of veratraldehyde.
Object of the Invention
The principal object of the present invention is to provide an improved process for the preparation of veratraldehyde, which alleviates one or more of the drawbacks of prior art processes.
It is yet another object of the present invention to provide a simple process for the synthesis of veratraldehyde.
In an embodiment, the present invention provides a process for the preparation of veratraldehyde, comprising,
(a) methylating vanillin of Formula II with methylating agent in presence of 1.2 to 1.5 mole equivalents of base and hydrocarbon solvent;
CHO


OCH3 OH
Formula II

(b) isolating veratraldehyde of Formula I.
CHO


OCH3 OCH3
Formula I
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Description of the Invention
The routes for the preparation of veratraldehyde well known in literature and that followed in the present invention involve use of reaction conditions that are very much prone to the formation of impurities and are difficult to handle. The formation of impurities or the control on formation of impurities is dependent upon the reagents, solvents and safer conditions used for carrying out various reactions, therefore it is a challenge for the present inventors to reach at such reaction conditions that they provide veratraldehyde with required purity standards wherein the process should not involve working difficulties/higher utilities, involve high costs, expensive techniques/reagents, rather the process should be simple, convenient, easy to operate, environment friendly and economical.
In view of above requirements, the present invention is directed to a process of preparing veratraldehyde that is simple, convenient, environment friendly and economical for industrial application. The method utilizes a careful selection of reagents and reaction conditions that avoids the additional requirements of purification at various stages and accordingly reduces the use of solvents and reagents which results in decrease in costs attributed to a more efficient use of reagents and solvents along with easy handling. The inventors have invented the conditions, wherein only 1.2 to 1.5 mole equivalents of base is needed to carry out the methylation reaction as compared to more than 3 mole equivalent base requirement in known prior art, which not only saves reagents and become more economical, but also reduces the chances of formation of any by-products like ethanol derivatives, thereby reducing multiple purification requirements. Further, the process involves use of hydrocarbon solvent which diminishes the chances of precipitation of salt of vanillin as is observed in prior art, which makes process operationally feasible. Also, such solvents are recoverable and recyclable.
In an embodiment, the present invention provides a process for the preparation of veratraldehyde, comprising,
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(a) methylating vanillin of formula II with a methylating agent in presence of 1.2 to
1.5 mole equivalents of base in hydrocarbon solvent;
CHO
X
Y^OCH3 OH
Formula II
(b) isolating veratraldehyde of Formula I.

CHO
OCH3 OCH3
Formula I
According to the present invention, the process of step (a) involves methylation of vanillin of formula II with methylating agent in hydrocarbon solvent in the presence of 1.2 to 1.5 mole equivalents of base, wherein the methylating agent used is selected from the group comprising of dimethyl sulphate, trimethyl phosphate and the like. The hydrocarbon solvent used is selected from the group comprising of toluene, xylene, chlorobenzene and the like. The base used is selected from the group comprising of organic and inorganic. The organic base is selected from the group comprising of methylamine, dimethylamine, diisopropyl ethylamine and the like. The inorganic base is selected from the group comprising of ammonia, alkali and alkaline earth metal carbonate, bicarbonate and the like, wherein the alkali and alkaline earth metal is selected from the group comprising of sodium, potassium, calcium, magnesium and the like. The reaction is carried out at reflux temperature and the reaction is complete in about 4 hours.
According to the present invention, the veratraldehyde is isolated in step (b) using techniques selected from crystallization, extraction and the like. The solvent used for crystallization and extraction is selected from the group comprising of hydrocarbons,
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ethers, ketones, water and mixtures thereof; particularly toluene, cyclohexane, dichloromethane, methyl tertiary butyl ether, acetone, methyl ethyl ketone, water and mixtures thereof.
The veratraldehyde obtained is optionally crystallized from suitable solvent to get pure veratraldehyde. The suitable solvent is selected from the group comprising of ketones, hydrocarbons, water or mixtures thereof; particularly acetone, methyl ethyl ketone, dichloromethane, water or mixtures thereof
According to the present invention, the veratraldehyde obtained is having purity not less than 99%.
The process of present invention has following advantages:
(a) The reaction conditions are very simple and does not contain operationally difficult process steps.
(b) The process involve use of base in minimum stoichiometric amounts, thus avoiding the formation of by-products.
(c) The process involves very simple work-up.
(d) The filtrate from crystallization step are recycled in the subsequent batches which further reduces the effluent load.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of veratraldehyde. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
Examples:
Example 1: Preparation of veratraldehyde from vanillin
To a solution of vanillin (50.0 g) in toluene (250 ml), added sodium carbonate (43.54 g) at room temperature. The temperature of reaction mixture was raised to 50-55 deg C
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under nitrogen and slowly added dimethyl sulphate (51.81 g). After completion of addition, the temperature of reaction mixture was further raised to reflux and reaction mixture was stirred at reflux temperature for 3-4 hours. The progress of reaction was monitored using HPLC. On completion of reaction, the reaction mixture was cooled to room temperature and water was added. The organic layer was separated, washed with water and the solvent was removed under vacuum to obtain an oily mass. To the oily mass added water (200 ml) at room temperature, seeded with crystals of veratraldehyde and stirred for about 8 hours to precipitate veratraldehyde. The solid was filtered, washed with water and dried under suction to obtain solid veratraldehyde (50 g).
Yield: 92%
HPLC purity: 99.5%

Claims

1.A process for the preparation of veratraldehyde comprising,
(a) methylating vanillin of formula II with a methylating agent in presence of 1.2 to 1.5 mole equivalents of base in hydrocarbon solvent;
CHO


*OCH3
OH
Formula II

(b) isolating veratraldehyde of Formula I.
CHO


OCH3 OCH3
Formula I
The process according to claim 1, wherein methylating agent used in. step (a) is selected from dimethyl sulphate and trimethyl phosphate.
The process according to claim 1, wherein base used in step (a) is selected from organic and inorganic.
The process according to claim 3, wherein the organic base is selected from the group comprising of methylamine, dimethylamine and diisopropyl ethylamine.
The process according to claim 3, wherein the inorganic base is selected from the group comprising of ammonia, alkali and alkaline earth metal carbonate and bicarbonate, wherein alkali and alkaline earth metal is selected from the group comprising of sodium, potassium, calcium and magnesium.

The process according to claim 1, wherein the hydrocarbon solvent used is selected from the group comprising of toluene, xylene and chlorobenzene.
The process according to claim 1, wherein isolation of veratraldehyde in step (b).