Preparation of 3-memory-4,5-methylenedioxybenzaldehyde

3-Methoxy-4,5-methylenedioxybenzaldehyde is facilely and improvedly prepared by reacting 4,5-dihydroxy-3-methoxybenzaldehyde with a dihalomethane in a two-phase reaction medium and at a pH of from 7 to 12.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to a simplified and improved process for the 
preparation of 3-methoxy-4,5-methylenedioxybenzaldehyde and, more 
especially, to such simplified/improved process employing a 
4,5-dihydroxy-3methoxybenzaldehyde (or hydroxyvanillin) starting material. 
2. Description of the Prior Art 
3-Methoxy-4,5-methylenedioxybenzaldehyde is known to this art as a very 
important compound which is a useful intermediate for the synthesis of 
many alkaloids, pharmaceutical precursors and pharmaceuticals, per se. 
Various techniques for the synthesis of 
3-methoxy-4,5-methylenedioxybenzaldehyde have been proposed to the art. 
Among the most recent, the following methods of preparation are 
representative: 
An article in the Bulletin of Chemical Society Japan (Matsumoto, 1985, 58 
(1), pages 346 to 351) describes a process which firstly consists in 
preparing methyl 4,5-methylenedioxy-3-methoxybenzoate by reacting 
dibromomethane with methyl 4,5-dihydroxy-3-methoxybenzoate and then in 
reducing the ester group into a CH.sub.2 OH group with lithium aluminum 
hydride and, finally, in oxidizing this primary alcohol group thus created 
into an aldehyde group. According to the article, the overall yield of 
this three-stage synthesis is 57%. This process is far too complicated and 
the productivity thereof is too low for it to be employed industrially. 
In an article in Chemische Zeitung (Dallacker 1984, 108, (5) pages 
186-187), another preparative method is described. It consists in starting 
with 4,5-methylenedioxy-3-methoxyaniline in order to form 
5-bromo-1,2-methylenedioxy-3-methoxybenzene; the bromine is then replaced 
by an aldehyde group. The overall yield of this synthesis is approximately 
37%. Like the above process, this process is complicated and the 
productivity thereof is too low for it to be employed on an industrial 
scale. 
Another article in Journal of Chemical Society Perkin Trans. (1, 1984 (4) 
pages 709-712 by McKiftrick and R. Stevenson) describes a procedure which 
forms a methylenedioxy bridge on hydroxyvanillin. The reaction between 
hydroxyvanillin and dibromomethane in the presence of potassium carbonate 
is carried out in dimethyl sulfoxide. As the recovery of the final product 
requires a treatment with water, this makes the recycling of the very 
expensive solvent difficult. No yield is specified. 
The processes of the prior art typically entail the formation of the 
aldehyde group in the final stage; the process mentioned immediately 
above, which consists in forming a methylenedioxy bridge on a compound 
already bearing an aldehyde substituent, employs a solvent which is 
expensive and difficult to recycle. 
SUMMARY OF THE INVENTION 
Accordingly, a major object of the present invention is the provision of an 
improved process for the synthesis of 
3-methoxy-4,5-methylenedioxybenzaldehyde, which is simple and which can 
readily be carried out on an industrial scale. 
Briefly, the present invention features the preparation of 
3-methoxy-4,5-methylenedioxybenzaldehyde by reacting 
4,5-dihydroxy-3-methoxybenzaldehyde and dihalomethane, and wherein the 
reaction is carried out (a) in a two-phase medium of water and a liquid 
organic compound, and (b) at a pH of from 7 to 12. 
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION 
More particularly according to the present invention, it will be 
appreciated that 4,5-dihydroxy-3-methoxybenzaldehyde is a compound which 
can readily be prepared, notably from vanillin, a common industrial 
material. 
The halogenation, especially bromination, selective for vanillin, in the 
ortho position relative to the hydroxyl group, is carried out 
industrially. The hydrolysis of the halovanillin thus formed is also an 
industrial reaction for the production of 
4,5-dihydroxy-3-methoxybenzaldehyde (or hydroxyvanillin). 
The dihalomethane which serves as both the reagent and the organic phase in 
the process is more particularly selected from among symmetrical or mixed 
chlorinated and brominated derivatives. Thus, dichloromethane, 
dibromomethane, chlorobromomethane, or mixtures thereof, are 
advantageously employed. 
In practice, dichloromethane, which is the most common and the least 
expensive compound, will preferably be used. 
The pH of the medium is maintained at a value of from 7 to 12 throughout 
the reaction period. Therefore, the hydrogen halide which is formed must 
be neutralized. An aqueous alkaline solution may, for example, be added 
continuously. In general, an aqueous solution of an alkali metal hydroxide 
or carbonate, most typically an aqueous solution of sodium hydroxide, will 
be employed. 
In order to achieve an adequate reaction rate, while preventing any side 
reactions to the greatest possible extent, the reaction is preferably 
carried out at a pH of from 8 to 10. 
Although the use of dihalomethane as the organic phase in the process 
according to the invention is preferred, its role as the bridging agent 
between the two hydroxyl groups of 4,5-dihydroxy-3-methoxybenzaldehyde is 
distinct from that as the organic solvent. 
In this case, at least a stoichiometric amount of dihalomethane relative to 
4,5-dihydroxy-3-methoxybenzaldehyde is employed and a water-immiscible 
organic solvent is used. This organic solvent may be any organic solvent 
that is inert towards the reagents. 
This may especially be an aromatic hydrocarbon such as, for example, 
benzene, toluene, chlorobenzenes and xylenes; an arylaliphatic ether such 
as, for example, anisole; an aliphatic or alicyclic hydrocarbon such as, 
for example, hexane or cyclohexane; an aliphatic ether such as, for 
example, dibutyl ether. 
The ratio of aqueous phase:organic phase is such that phase separation 
occurs on standing. 
The concentration of 4,5-dihydroxy-3-methoxybenzaldehyde in the aqueous 
phase is not critical. Most often, it depends on the previous stage for 
the preparation of the said 4,5-dihydroxy-3-methoxybenzaldehyde. 
However, it is obvious that it is not economically advantageous to use too 
low a concentration as to provide an inadequate productivity of the 
equipment/apparatus. 
The initial concentration of 4,5-dihydroxy-3-methoxybenzaldehyde in the 
aqueous phase typically ranges from 5% to 50% by weight. 
The reaction is advantageously catalyzed by a conventional phase transfer 
catalyst. Compare, in this respect, the text Phase Transfer Catalysis by 
E. V. Dehmlov (Monograph in Modern Chemistry, Vol. 11, Verlag Chemie). 
A quaternary ammonium compound (especially a halide) which is a 
conventionally known catalyst for this type of reaction is generally 
employed. This catalyst is preferably recycled. 
Nor is the reaction temperature a critical feature of the process. 
The reaction is generally carried out at a temperature of from 30.degree. 
C. to 150.degree. C. This temperature will preferably range from 
50.degree. C. to 120.degree. C. 
As mentioned above, the 4,5-dihydroxy-3-methoxybenzaldehyde may be prepared 
by hydrolyzing 5-halo-4-hydroxy-3-methoxybenzaldehyde. In this case, it is 
not necessary to isolate the 4,5-dihydroxy-3-methoxybenzaldehyde before 
reacting it, according to the process of the invention, with the 
dihalomethane. 
The aqueous solution obtained in the preceding stage may be used directly.

In order to further illustrate the present invention and the advantages 
thereof, the following specific examples are given, it being understood 
that same are intended only as illustrative and in nowise limitative. 
EXAMPLE 1 
600 g (approximately 500 cm.sup.3) of an aqueous solution having a pH of 9, 
containing the following materials in the form of sodium derivatives, were 
charged into a 1.5 liter stainless steel reactor equipped with an anchor 
stirrer, a heating system and a liquid injection system: 
(i) 0.844 mole of 4,5-dihydroxy-3-methoxybenzaldehyde; and 
(ii) 0.200 mole of vanillin (impurity originating from the previous stages 
for the preparation of 4,5-dihydroxy-3-methoxybenzaldehyde). 
670 g (approximately 500 cm.sup.3) of dichloromethane and 80 g of 
tetrabutylammonium bromide were then added thereto. 
The reactor was closed, swept with nitrogen and heated at 100.degree. C., 
under stirring. 
The pH of the reaction medium was maintained at a value of 9.+-.0.5 by 
injecting therein an aqueous sodium hydroxide solution having a 
concentration of 30% by weight. 
After 5 hr, 30 min, of reaction, the reaction mixture was cooled to ambient 
temperature and it was withdrawn. The mixture settled; the lower organic 
phase was separated and the aqueous phase was extracted with 2.times.250 
cm.sup.3 of dichloromethane. 
The organic phase and the extracts obtained were combined. 
The dichloromethane was distilled in order to recycle it into a subsequent 
operation. 
The crude product obtained was washed with 250 cm.sup.3 of water in order 
to extract the tetrabutylammonium bromide which will also be recycled into 
a subsequent experiment. 
The crude product was then distilled under reduced pressure (approximately 
65 pascals). 
127.5 g of a fraction distilling at 110.degree.-115.degree. C. at the 
pressure mentioned above were obtained. 
The NMR and the mass spectra were in agreement with the structure of 
4,5-methylenedioxy-3-methoxybenzaldehyde. 
The melting point of the product obtained was 134.degree. C., which 
corresponds to the melting point of the reference product. 
The yield of 4,5-methylenedioxy-3-methoxybenzaldehyde based on the 
4,5-dihydroxy-3-methoxybenzaldehyde employed was 83%. 
EXAMPLE 2 
This example illustrates the combination of the reactions for the 
preparation of 4,5-dihydroxy-3-methoxybenzaldehyde starting with 
5-bromo-4-hydroxy-3-methoxybenzaldehyde (bromovanillin) and the reaction 
of the 4,5-dihydroxy-3-methoxybenzaldehyde thus produced with 
dichloromethane. 
The following materials were charged into the reaction employed in Example 
1: 
(i) 800 cm.sup.3 of water; 
(ii) 68.8 g of sodium hydroxide pellets; 
(iii) 101 g of 5-bromo-4-hydroxy-3-methoxybenzaldehyde; 
(iv) 1.6 g of copper powder. 
The mixture was heated for 4 hours at 135.degree. C., under stirring, in 
order to effect hydrolysis and produce 
4,5-dihydroxy-3-methoxybenzaldehyde. 
The mixture was then cooled to 100.degree. C. and the pH was adjusted to a 
value of 8 by adding 50 cm.sup.3 of 50% sulfuric acid. 
The following materials were then charged: 
265 g (approximately 200 cm.sup.3) of dichloromethane; 
14 g of tetrabutylammonium bromide. 
The temperature was maintained at 100.degree. C. 
The pH was maintained at 8.+-.0.1 by injecting an aqueous 30% by weight 
sodium hydroxide solution. 
On completion of the reaction and after the treatments described in Example 
1, an aqueous phase and an organic phase were separated. 
The two phases were analyzed by high pressure liquid chromatography (HPLC). 
The following results were obtained: rate of conversion of 
5-bromo-4-hydroxy-3-methoxybenzaldehyde: 100%; 
yield of 4,5-methylenedioxy-3-methoxybenzaldehyde: 41%; 
yield of vanillin (determined in the aqueous phase): 9%; and 
yield of 4,5-dihydroxy-3-methoxybenzaldehyde (determined in the aqueous 
phase): 34%. 
No product of reaction between the OH groups of the two compounds and the 
dichloromethane was observed. 
EXAMPLE 3 
The following materials were charged into a three necked round-bottomed 
flask made of glass, equipped with a magnetic stirrer, a condenser, an 
electrode for determining the pH of the reaction medium, a liquid 
introduction system and a thermometer: 
(i) 250 g (100 cm.sup.3) of dibromomethane; 
(ii) 3.2 g of tetrabutylammonium bromide; 
(iii) 17.7 g of 4,5-dihydroxy-3-methoxybenzaldehyde dissolved in 250 g of 
water. 
The aqueous solution of 4,5-dihydroxy-3-methoxybenzaldehyde originated from 
a known synthesis, carried out in sequence, in several stages: 
conversion of 2-methoxyphenol into 2,4-di(hydroxymethyl)-5-methoxyphenol; 
oxidation of 2,4-di(hydroxymethyl)-5-methoxyphenol into 
2,4-diformyl-5-methoxyphenol; and 
Dakin reaction on the aldehyde group located in the ortho position relative 
to OH in order to form the 4,5-dihydroxy-3-methoxybenzaldehyde. 
The mixture was heated, under stirring, for 2 hr, 30 min, at 80.degree. C., 
while maintaining the pH at approximately 9 by adding an aqueous sodium 
hydroxide solution. 
After cooling and the usual treatment, the following results were obtained 
after analysis of the organic phase by HPLC: 
rate of conversion of 4,5-dihydroxy-3-methoxybenzaldehyde: 100%; and 
yield of 4,5-methylenedioxy-3-methoxybenzaldehyde: 100%. 
While the invention has been described in terms of various preferred 
embodiments, the skilled artisan will appreciate that various 
modifications, substitutions, omissions, and changes may be made without 
departing from the spirit thereof. Accordingly, it is intended that the 
scope of the present invention be limited solely by the scope of the 
following claims, including equivalents thereof.