HU195947B - Process for producing n-methyl-formanilide - Google Patents

Abstract

The present invention relates to a process for the preparation of N-methylformanilide by methylation of formanilide. According to the invention, the formanilide phase transfer in the presence of a catalyst and a base is methylated with dimethyl sulfate. The phase transfer catalyst is preferably an organic quaternary ammonium compound. 195947 -1-

Description

This invention relates to a novel process for the preparation of N-methyl formanilide by methylation of formanilide.

It is known to be. N-Melylformanilide is a valuable drug intermediate. It allows the introduction of a formyl group into activated aromatic compounds using the Vilsmeyer reaction. Examples of such a formyl-containing aromatic compound widely used in the pharmaceutical industry include veratrumaldehyde, 3,4,5-trimeLoxybenzaldehyde and the like.

N-methylformanilide is generally prepared from N-methylaniline with formic acid [Houben-Weyl, Methoden der Organischen Chemie, 11, p. 27]. This known process gives the product in good yield, but the starting material, N-methylaniline, can only be obtained by vaporizing the aniline at high temperature and high pressure. In addition to this type of methylation, not only the desired monomethylaniline is formed, but also dimethylaniline and unreacted aniline remains in the reaction mixture. The separation of these products requires a very large number of rectifying columns and considerable energy and time consumption.

N-methyl formanilide can be prepared from aniline in one step with methyl ortho-formic acid [J. Chem. Soc., 78, 4778 (1956)]. In this known process, twice the molar excess of ortho-formic acid methyl ester is required and the yield is only 61%.

It is an object of the present invention to provide an economical process for the preparation of N-methyl formanilide using readily available raw materials.

It has been found that the above object is achieved by methylation of formamylide from aniline and formic acid by simple boiling in dimethyl sulfate in the presence of a phase transfer catalyst and a base. This gives N-methyl formanilide in good yield.

This discovery was not expected based on e.digital knowledge in the literature. Κ. B. Wiberg et al., J. Med. Am. Chem. Soc., 79, 3160 (1957)] have already dealt with the methylation of formanilide and found that the silver salt of formanilide was reacted with methyl iodide in a yield of 56% in the form of the 0-methyl derivative, i.e., N-phenylformimide. methyl ester is formed.

The O-methyl compound isomerized at high temperature, with low yield, to the N-methyl compound only. In contrast, the process of the present invention provides pure N-methylformanilide, free of 0-methyl compound, in 80% yield.

In the process of the present invention, dimethyl sulfate is generally present in an amount of molar equivalent or at most 2 to 3 times that of formanilide.

As phase transfer catalysts, quaternary ammonium compounds such as tolraalkylammonium halide such as tetrabutylammonium bromide, benzyltrialkylammonium halide such as benzyltrimethylammonium bromide. or crown spaces, such as 1,4,7,10,13-pentaoxa-cyclopropyl decadecane, 1,4,7,10,13,36-hexaoxycyclo-ring, 2,3,11,12-dibenzo-1,4, 7,10,1 3,16-hexaoxa-e-cyclooctadeca-2,1-diene or 2,3,11,12-dicyclohexyl-1,4,7,10,13,16-hexaoxa-cyclooctadecane are used.

Suitable bases include alkali metal hydroxides, carbonates or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium hydroxide and the like. Dimethylsulfate alkylation may also be carried out in the presence of organic bases such as trimethylamine, triethylamine, pyridine, 1,4-dimethylpiperazine.

The process of the invention is conveniently carried out in the presence of a solvent inert to the reaction such that formarylide. dissolved in an organic solvent such as toluene, the required amount of dimethylsulfate is added and the base is added under cooling, preferably in concentrated water. The reaction mixture is quenched with aqueous dilution, the phases are separated and the product from the organic phase is recovered by distillation.

The process according to the invention may be prepared from a separate formanylide prepared and purified, the reaction may be carried out by reacting aniline and formic acid, evaporating the reaction mixture and methylating the remaining crude formanilide with diethyl sulfate.

The process of the present invention provides high purity N-methyl formanilide in 90% yield. The process requires readily available starting materials and is extremely easy to perform at atmospheric pressure and practically at ambient temperature and therefore has a low energy requirement.

The invention is illustrated in detail by the following examples:

Example 1

To 12.1 g (0.1 mol) of formanilide was added 50 ml of toluene, 17.36 g (0.14 mol) of dimethyl sulfate and 0.5 g of tetrabutylammonium bromide. A solution of 5.6 g of sodium hydroxide in 7 ml of water was added with cooling at 15-20 C for 2-3 hours. After stirring for two hours, the mixture was diluted with water (50 mL), the organic phase washed with water, dilute hydrochloric acid, water, and the toluene evaporated. 12.17 g (90%) of N-methyl formanilide are obtained, which is 99% pure by gas chromatography. Fp. 242-244 ° C.

Example 2

85.6% formic acid (100 mL) was added to IP.6.26 g (2 moles) aniline and refluxed in vacuo for 1.5 hours and finally at 100 ° C under vacuum for 2 hours. To the residue was added 1 liter of toluene, 277 g of dimethyl sulfate and 7 g of letrabutylammonium bronide. 88 g of sodium hydroxide dissolved in 140 ml of water 5 are added under stirring at 16-17 ° C over 3 hours. After stirring for 4 hours, the mixture was diluted with 650 ml of water, the upper organic layer was washed with water, hydrochloric acid and water, and the toluene was evaporated. 220 g (80%) of N-methylformanilide are obtained, which is 95% pure.

Fp. 241-243 ° C.

Claims (4)

A process for the preparation of N-methyl formanilide by methylation of formanilide, wherein the formanilide is methylated with dimethyl sulfate in the presence of a phase transfer catalyst and a base. The process according to claim 1, wherein the phase transfer catalyst is an organic quaternary ammonium compound, 3. The process of claim 2 wherein the organic quaternary ammonium compound is tetrabutylammonium bromide. 4. The 1st ' Process according to claim 1, characterized in that the base is an alkali metal hydroxide, preferably sodium hydroxide.