Process for preparing 2,5-dimethoxy benzaldehyde

Details Process for preparing 2,5-dimethoxy benzaldehyde Process for preparing 2,5-dimethoxy benzaldehyde

2002-04-18

2003-12-30

Keys, Rosalynd (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C568S438000, C568S426000

Reexamination Certificate

active

06670510

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to a process for preparing and isolating metal salts of 2-hydroxy-5-methoxy benzaldehyde from crude, or impure, 2-hydroxy-5-methoxy benzaldehyde and for preparing 2,5-dimethoxy benzaldehyde from those salts.
BACKGROUND OF THE INVENTION
2,5-dimethoxybenzaldehyde finds use as an intermediate for the preparation of developing agents for black-and-white and color photography (UK 853,482); as an intermediate for textile dyes (U.S. Pat. No. 3,691,210); and as an additive that can improve the performance of electroplating baths (U.S. Pat. No. 4,662,999). Numerous methods for its preparation have been reported, the two most common being direct formylation of 1,4-dimethoxybenzene (UK 1,069,409; Reaction 1, below), and alkylation of 2-hydroxy-5-methoxy benzaldehyde with dimethyl sulfate (U.S. Pat. No. 3,867,458; Reaction 2, below).
The first of these methods suffers from the need to use highly toxic hydrogen cyanide or zinc cyanide under acidic conditions, thus necessitating the use of expensive equipment to first contain and then destroy the toxic gases. The second of these methods overcomes the need to handle toxic gases, but the 2-hydroxy-5-methoxy benzaldehyde starting material must be purified before conversion to the title product. As such, an expensive and time consuming distillation step is necessary to achieve the appropriate purity (see, Comparative Examples 1(
a
) and 1(
b
)). Therefore, the need still exists for a process for preparing 2,5-dimethoxy benzaldehyde that avoids the use of highly toxic hydrogen cyanide or zinc cyanide while simultaneously eliminating the need for an expensive and time-consuming distillation step.
SUMMARY OF THE INVENTION
Among other aspects, the present invention is based on the discovery of a novel method for preparing and isolating a pure, or at least substantially pure, reactive sodium or potassium salt of 2-hydroxy-5-methoxy benzaldehyde. The ability to alkylate these sodium or potassium salts in turn provides an economically favorable method to obtain equally high or higher yields of 2,5-dimethoxy benzaldehyde by avoiding the need for costly distillation of the 2-hydroxy-5-methoxy benzaldehyde prior to a subsequent alkylation. Additionally, alkylating the potassium or sodium salt of 2-hydroxy-5-methoxy benzaldehyde proceeds at a lower temperature than the alkylation reaction of the pure aldehyde counterpart, which similarly results in a reduced overall cost for the alkylation step.
Accordingly, the present invention provides a process for preparing 2,5-dimethoxy benzaldehyde comprising the steps of: (a) reacting a crude 2-hydroxy-5-methoxy benzaldehyde with a metal hydroxide to produce a reaction mixture comprising a metal salt of 2-hydroxy-5-methoxy benzaldehyde; (b) separating the metal salt of 2-hydroxy-5-methoxy benzaldehyde from the reaction mixture of step (a) to obtain an at least substantially pure metal salt of 2-hydroxy-5-methoxy benzaldehyde; and (c) alkylating the metal salt of 2-hydroxy-5-methoxy benzaldehyde of step (b) with dimethylsulfate to produce 2,5-dimethoxy benzaldehyde.
Additional advantages and embodiments of the invention will be obvious from the description, or may be learned by practice of the invention. Further advantages of the invention will also be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. Thus, it is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory of certain embodiments of the invention and are not restrictive of the invention as claimed.
DETAILED DESCRIPTION OF THE INVENTION
The present invention may be understood more readily by reference to the following detailed description and the examples provided herein. It is also to be understood that this invention is not limited to the specific embodiments and methods described below, as specific components and/or conditions may, of course, vary. Furthermore, the terminology used herein is used only for the purpose of describing particular embodiments of the present invention and is not intended to be limiting in any way.
It must also be noted that, as used in the specification and the appended claims, the singular form “a”, “an”, and “the” comprise plural referents unless the context clearly indicates otherwise. For example, reference to a component in the singular is intended to comprise a plurality of components.
Ranges may be expressed herein as from “about” or “approximately” one particular value and/or to “about” or “approximately” another particular value. When such a range is expressed, another embodiment comprises from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about” or “approximately”, it will be understood that the particular value forms another embodiment.
The phrase “substantially pure” as applied to the metal salt of 2-hydroxy-5-methoxy benzaldehyde means a purity of at least about 70% on a weight % assay basis or, alternatively, at least about 95% based on HPLC area %. In more preferred embodiments, the purity is at least 80% or greater or, still more preferably, at least 90% on a weight % assay basis; when measured by HPLC area %, the purity is more preferably at least 98% or, still more preferably, at least 99%.
Throughout this application, where publications are referenced, the disclosures of these publications in their entireties are hereby incorporated by reference into this application in their entirety to more fully describe the state of the art to which this invention pertains.
As discussed above, the present invention provides a process for preparing 2,5-dimethoxy benzaldehyde comprising the steps of: (a) reacting a 2-hydroxy-5-methoxy benzaldehyde with a metal hydroxide to produce a reaction mixture comprising a metal salt of 2-hydroxy-5-methoxy benzaldehyde; (b) separating the metal salt of 2-hydroxy-5-methoxy benzaldehyde from the reaction mixture of step (a) to obtain an at least substantially pure metal salt of 2-hydroxy-5-methoxy benzaldehyde; and (c) alkylating the metal salt of 2-hydroxy-5-methoxy benzaldehyde of step (b) with dimethylsulfate to produce 2,5-dimethoxy benzaldehyde.
A common method for preparing the 2-hydroxy-5-methoxy benzaldehyde comprises reacting a magnesium salt of 4-methoxy phenol with formaldehyde or paraformaldehyde, which generates formaldehyde under the conditions of the reaction, followed by acidic quench and distillation or chromatography as disclosed in European Patent Application 92307354.8, and also disclosed in Acta Chemica Scandinavia, 53, 258, 1999, which references are hereby incorporated by reference in their entireties for all purposes. (See, Reaction (I) set forth below.) In the EP application referenced above, the source of Mg is magnesium methoxide; and in the Acta Chemica Scandinavia article, it is magnesium chloride.
Any inorganic acid strong enough to protonate the product phenoxide salt is suitable. Typically, a distillation or chromatography of the 2-hydroxy-5-methoxy benzaldehyde product has been necessary in order to achieve the desired level of purity prior to further processing to the title product. The Acta Chemica Scandinavia article professes a yield of 97% for the subject compound, which indicates few by-products. However, repetition of that disclosure (Example 1) indicates the presence of several impurities that lower the assay and the yield, which, when using the prior art process, necessitates a purification step prior to use in an alkylation reaction, (See, Comparative Examples 1
a
and 1
b
).
In accordance with the invention, Applicants have discovered that unpurified, or crude, reaction product obtained from the formation of the 2-hydroxy-5-methoxy benzaldehyde, for example, as set forth above can be treated in situ with a suitable metal hydroxide to generate pure, or at least substantially pure, metal salts of 2-hydroxy-5-methoxy benzaldehyde. (See Reaction (II), set

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