JPH06166655A - Production of tetramethoxymethylbenzaldehyde - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as an intermediate for therapeutic agent for hepatic diseases in high yield at a low cost by reacting 2,3,4,5- tetramethoxytoluene with a formamide derivative in the presence of phosphorus oxychloride. CONSTITUTION:The objective compound of formula III is produced by reacting the compound of formula I with a compound of formula II (R is H, methyl or ethyl) in the presence of phosphorus oxychloride at 20-110 deg.C) and hydrolyzing the reaction product. The amounts of phosphorus oxychloride and the compound of formula II are 2-5mol and 1-3mol based on 1mol of the compound of formula I, respectively. N-phenyl-N-methylformamide is an example of the formamide derivative of formula II.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel process for producing 2,3,4,5-tetramethoxy-6-methylbenzaldehyde.

[0002]

2. Description of the Related Art 2,3,4,5-Tetramethoxy-6-methylbenzaldehyde is a useful substance as a synthetic intermediate for drugs such as drugs for treating liver diseases.

Conventionally, as a method for producing this compound, it has been known to perform formylation with dichloromethyl methyl ether in titanium tetrachloride. However, in this method, the raw material dichloromethyl methyl ether has a high unit price and there is a risk of carcinogenicity, and since titanium oxide is mixed in the waste liquid, there is a problem in environmental hygiene such as pollution, so industrially Is hard to adopt. In addition, as another method, the present inventor may react D with trifluoroacetic acid and hexamethylenetetramine.
The uff reaction was tried, but the yield was low at about 60%, and trifluoroacetic acid was a high unit price and used in a large amount, which was not an economical method. Furthermore, a Vilsmeier reaction with dimethylformamide and phosphorus oxychloride was tried, but the reaction hardly proceeded. It is known that there is no great difference in the yield when N-phenyl-N-methylformamide is used instead of dimethylformamide in this Vilsmeier reaction (published by Maruzen Co., Ltd., New Experimental Chemistry Course 14, Organic Compounds). Synthesis and reaction, page 688),
Vil with N-phenyl-N-methylformamide
In the Smeier reaction, 2,3,4,5-tetramethoxy-
It was expected that little 6-methylbenzaldehyde would be obtained.

[0004]

[Problems to be Solved by the Invention] Under these circumstances,
Elucidation of a method for producing 2,3,4,5-tetramethoxy-6-methylbenzaldehyde in a high yield and economically is required.

[0005]

As a result of various studies to solve these problems, the present inventors have found that the target compound can be obtained in a high yield and by a method suitable for industrial production. The invention was completed.

That is, the present invention provides the formula (I)

[Chemical 4] 2,3,4,5-tetramethoxytoluene represented by the formula (II) in the presence of phosphorus oxychloride.

[Chemical 5] (Wherein R is hydrogen, methyl or ethyl) and then hydrolyzed to formamide (II)
I)

[Chemical 6] It is characterized in that 2,3,4,5-tetramethoxy-6-methylbenzaldehyde represented by

The amount of phosphorus oxychloride used in the present invention is preferably 1 time mol or more, and particularly preferably 2 to 5 times mol, based on 2,3,4,5-tetramethoxytoluene of the formula (I).

The formamide derivatives used in the present invention include N-phenylformamide, N-phenyl-N-methylformamide and N-phenyl-N-ethylformamide. It is preferable to use the formamide derivative in an amount of 1 fold or more, and particularly 1 to 3 fold, based on 2,3,4,5-tetramethoxytoluene of the formula (I).

The reaction temperature is 20 to 110 ° C., especially 70 to 9
0 ° C is preferred. The reaction time is generally about 1-10 hours. After the reaction is completed, the reaction mixture is subjected to a hydrolysis process. The hydrolysis is carried out in the presence of an excessive amount of water at the same reaction temperature and reaction time as in the above reaction. After completion of the hydrolysis, the desired product can be taken out by any purification means.

Next, examples will be given to explain the present invention more specifically, but the present invention is not limited to these examples.

Example 1 To 55 g of 2,3,4,5-tetramethoxytoluene was added 61 ml of N-phenyl-N-methylformamide and 93 ml of phosphorus oxychloride, and the mixture was allowed to stand at room temperature for 1 hour, then at 4 ° C at 75 ° C.
Stir for hours. Pour this mixture into ice water and cool with ice.
Stir for 0 minutes. Then, this solution is heated to 70 ° C. and stirred for 1 hour, then cooled, ethyl acetate is added thereto for extraction, and the ethyl acetate layer is washed with a dilute aqueous sodium hydroxide solution and then with water. The obtained solution was dried over magnesium sulfate and concentrated, and the residue was purified by a silica gel column to obtain 59.1 g of 2,3,4,5-tetramethoxy-6-methylbenzaldehyde (yield 95%).

Example 2 To 55 g of 2,3,4,5-tetramethoxytoluene was added 55 ml of N-phenyl-N-methylformamide and 81 ml of phosphorus oxychloride, and the mixture was allowed to stand at room temperature for 30 minutes and then at 85 ° C. for 3 hours and a half. Stir. The mixture is poured into ice water, stirred for 30 minutes and then at 60 ° C. for 1 hour. After cooling, ethyl acetate is added to this solution for extraction, and the ethyl acetate layer is washed with a dilute aqueous sodium hydroxide solution and then with water. The obtained solution is dried over magnesium sulfate and then concentrated, and 600 ml of a saturated aqueous solution of sodium hydrogen sulfite is added to the residue and stirred for 3 hours. The precipitated crystals are filtered and washed, and then the crystals are decomposed with a dilute aqueous sodium hydroxide solution. Ethyl acetate was added to this for extraction, the ethyl acetate layer was washed, dried over magnesium sulfate and concentrated to give 2,3,4,5-tetramethoxy-
52.9 g of 6-methylbenzaldehyde was obtained (yield 85%).

[0013]

According to the present invention, 2,3,4,5-tetramethoxy-6-methylbenzaldehyde can be produced economically in a very high yield.

Claims (1)

[Claims] 1. Formula (I): In the presence of phosphorus oxychloride, 2,3,4,5-tetramethoxytoluene represented by the formula (II) (Wherein R is hydrogen, methyl or ethyl) and then hydrolyzed to formamide (II)
I) [Chemical 3] A method for producing 2,3,4,5-tetramethoxy-6-methylbenzaldehyde represented by: