JPS608288A - Production of monohaloacetylthiophenecarboxylic acid and its ester - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate of pharmaceuticals, agricultural chemicals, and rubber chemicals, economically in an industrial scale, by reacting an acetylthiophenecarboxylic acid with elemental halogen using an alcohol as the solvent. CONSTITUTION:The objective compound of formula II (R is H or 1-8C hydrocarbon group) is produced by reacting the acetylthiophenecarboxylic acid of formula I (preferably 5-acetyl-2-thiophenecarboxylic acid) with elemental halogen (preferably Br) in an alcoholic solvent of formula ROH (R is 1-8C saturated aliphatic hydrocarbon group or alicyclic hydrocarbon group) (preferably methanol) preferably at 30-50 deg.C. EFFECT:The refining process can be simplified. The objective compound can be separated in high yield and purity.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing monohaloacetylthiophenecarboxylic acids and esters thereof.

More specifically, the present invention relates to a method for producing monohaloacetylthiophenecarboxylic acid by reacting acetylthiophenecarboxylic acid with a halogen element in an alcohol solvent.

Monohaloacetylthiophenecarboxylic acid is a medicine.

It is a compound useful as an intermediate in the production of agricultural chemicals and rubber drugs.

Conventionally, there is no known method for producing monohaloacetylthiophenecarboxylic acid by directly halogenating acetylthiophenecarboxylic acid, nor is it described in the literature.

V Org, Syn, Co11. Iol 1t4so
(194B) has an analogy Io! A method for producing monobromoacetylbenzene in a yield of 64-66% is described by brominating two acetophenols as a compound and brominating them using diethyl ether as a solvent.

-I-921 (1936) & J, A in carbon disulfide
Chem, Soc 4] 77 (1919) describes a method of bromination in acetic acid at °C, but in both cases the yield is low, at most 75%.

Among these, the reaction in monoacetic acid is excellent, but it is not an industrially advantageous method because the solubility of the raw material is low and the volumetric efficiency is low.

The present inventors carried out bromination of acetylthiophenecarboxylic acid in acetic acid according to the example of Acetophenono in Uij, and the reaction was carried out at a production rate of 80%.
There is a drawback that 0% formation occurs, and crystallization Q
When W was used, the yield decreased to 70-75%.

In view of this situation, the present inventors have made extensive studies on the production of industrially advantageous monohaloacetylthiophenecarboxylic acids and their esters, and have found that halogenation can be carried out efficiently by using alcohol as a solvent. We discovered what we could do and came up with the present invention.

That is, an object of the present invention is to provide an industrially advantageous method for producing 7-tubular acetylthiophenecarboxylic acid. ffi
d411 d Indicates an aliphatic hydrocarbon or alicyclic hydrocarbon group. ) or the C+-, -Cs hydrocarbon group, which is characterized by being reacted with a halogen element in an alcohol solvent represented by
indicates a halogen atom. ) is a method for producing monohaloacetylthiophenecarboxylic acid and its ester.

The solubility M of acetylthiophenecarboxylic acid in alcohol is relatively large, and the volumetric efficiency is improved.

The concentration of the alcohol solution of acetylthiophenecarboxylic acid is 80% by weight or more, preferably in the range of 5 to 15% by weight.If it is less than this, the volumetric efficiency is poor;
Since the reaction will not proceed smoothly beyond this point, the above range is economically desirable.

Solvent alcohols include methanol, ethanol, aliphatic alcohols from methanol to heptatool and octatool, and cyclohexanol.

Although alicyclic alcohol solutions such as cycloheptatool can be used, methanol is often used due to economic efficiency and ease of handling, and good results can be obtained using it.

As the halogen element, chlorine, bromine, and iodine can all be used, but bromine is often used, which is often more convenient for the subsequent reaction. The halogen element may be used in an amount equimolar to the amount of acetylthiophenecarboxylic acid Q, but better results are usually obtained when an excess of N is used.

To add a halogen element to an alcoholic solution of acetylthiophenecarboxylic acid, it can be added in gaseous or liquid form, or in the same alcoholic solution. At this time, it is preferable to add the necessary stones in portions rather than all at once, such as by blowing into the solution if it is gaseous or dropping it dropwise if it is liquid.

The temperature of the halogenation reaction can be as low as θ°C or as high as above the boiling point of the solvent, but for industrial purposes it is convenient to carry out the reaction at normal pressure, so it is preferably 30°C above room temperature and 70°C. It is advantageous to maintain the reaction temperature in the range ˜50°C.

The method of the present invention can be carried out on compounds in which the acetyl group and the carboxyl group are located at any position on the thiophene.
For the production of promoacetylthiophene-2-carboxylic acid and its methyl ester, 31&sup.

A disadvantage of the process according to the invention is that the monohalides are obtained as mixtures of free carboxylic acids and their esters, which, as in the case of 5-bromoacetylthiophene-2-carboxylic acid, are Next process 4°4 or other methods) +7- carboxylic acid and its ester
I! It will never be the 11th of the month.

According to the method of the present invention, the reaction proceeds almost quantitatively, which simplifies the purification process. Its industrial value is great, as it can be made 311°.

Hereinafter, the present invention will be explained in more detail with reference to Example 4 l511 and comparative examples.

Example 1 79113 g of 5-acetylthiophene-2-carvone
(0-605 mol) was dissolved in 1050 g of methanol and heated to 35°C.
5 mol) was added dropwise over 2 hours. During that time, the temperature of the reaction solution was maintained at 87-41°C. After dropping, keep at the same temperature for 30 minutes.
Aged for a minute. When the reaction solution was analyzed by high-performance liquid chromatography, the yield of 5-bromoacetylthiophene-2-carboxylic acid and its methyl ester was 96.5%, with unreacted raw materials being 2.2% and 5-dibromoacetylthiophene-2-carboxylic acid. 2-carboxylic acid and its methyl ester are 1.
3% detected.

Methanol was distilled off from the reaction solution, water was added to crystallize the product, and the crystals were filtered and dried to obtain 160.8 g of crystals. Analysis of this crystal by high performance liquid chromatography revealed that 35.4 g (0.54·4 mol) of 5-bromoacetylthiophene-2-carvone 1'1' and 21.3 g (o, ost mol) of its methyl ester.
It turned out to be a mixture of.

The content of free acid and its ester in the obtained crystals was 97.5%, and the yield was 94.0%.

Example 2 The same procedure as in Example 1 was carried out except that the reaction temperature was changed to 60°C.
．． 4%, and there was almost no unreacted raw material, but 9.2% of 5-dibromoacetylthiophene-2-carboxylic acid and its methyl ester were produced, and some tar-like substances were also produced.

The Ia content of the product taken out as crystals was 96.2%, and the yield was 84.0%.

Example 3 Use isopropanol 135 instead of methanol as solvent
The procedure was carried out in the same manner as in Example 1 except that the amount was changed to 0 g, and crystal 14
6.4 g was obtained. Free carboxylic acid is 137.6
g (0,553 mol), whose isopropyl ester is 3.4. Contains g (0,012 mol). The content is 9
(i, 3%, yield was 8560%.

Example 4 □ The same procedure as Example 1 was carried out except that ethanol was used instead of °C methanol as the solvent, and 152.6 g of crystals were obtained.
I got it.

It was a mixture of 134.8 g (0,589 mol) of free carvone jI and 7 g (0,049 mol) of xa, the content was 97.0% and the yield was 88.4%.

Example 5 Example 1 except that chlorine was blown in instead of bromine.
5-chloroacetylthiophene-2-
Contains a mixture of carboxylic acids and their methyl esters containing 9
4.5%, yield 82.5%.

Example 6 The same procedure as Example 4 was carried out except that 15% ethanol solution of iodine was used instead of bromine, and 5-iodoacetylthiophene-2-carboxylic acid and its ethyl ester mixture were impregnated with 97.8% %, with a yield of 90.6%.

Example 7 Instead of 5-acetylthiophene-2-carboxylic acid,
Example 1 was carried out with the exception that 4-acetylthiophene-2-carboxylic acid was used, and a mixture of 41-7'' lomoacetylthiophene-2-carboxylic acid and its methyl ester was used at a content of 95-7X.

Obtained with a yield of 89.5%.

Run 1 Row 8 Instead of 5-acetylthiophene-2-carboxylic acid,
Same as in Example 1 except that 2-acetylthiopheno-4-carboxylic acid was used.Real f12L Contains a mixture of 2-bromoacetylthiophene-4-carboxylic acid and its methyl ester at 1196.0%.

The yield was 87.6%.

Comparative Example 5-Acetylthiophene-2-carboxylic acid 50g (0
, 294 mol] was dissolved in 1] 9750 g of vinegar by raising the temperature to 260°C. At the same temperature, 4.7 g (0,294 mol) of bromine was added dropwise over 1 hour, and then at the same temperature. de1
Time aged. When this reaction solution was analyzed by high performance liquid chromatography, it was found that the unreacted raw material and 5-dibromoacetylthiophene-2-carboxylic acid were each 10%, and 5-bromoacetylthiophene-2-carboxylic acid was 10%.
The production L1: was 80%.

The first acid was distilled off from this reaction mixture, water was added to crystallize the product, filtered, and then recrystallized from an acetic acid-water system at °C with a purity of 95.0%. 53.9 g (0,206 mol) of thiophene-2-carboxylic acid were obtained. The yield was 70%.

Applicant: Steel Chemical Industry Co., Ltd. Representative Hiroshi Sasaki

Claims (1)

[Claims] (1) Formula (I) Formula (1) in an alcoholic solvent represented by ROH (where R represents a C1 to C8 saturated aliphatic hydrocarbon or alicyclic hydrocarbon group) It has a special +1 to react with halogen elements. 2 represents a C1 to C8 hydrocarbon group, and X represents a halogen atom. ) A method for producing monohaloacetylthiophenecarboxylic acid and its ester. (2) Claims that allow the reaction to occur at room temperature to 70°C (
1) Method (8) Claim (1) wherein the acetylthiophenecarboxylic acid is 5-acetyl-2-thiophenecarboxylic acid.
) method described. (4) Claim (1) in which the solvent is methanol
Method 6 (5) Claim (1) in which the halogen element is bromine
) method described.