JPH0269473A - Production of thiopheneacetic acid derivative - Google Patents

Abstract

PURPOSE:To obtain the subject substance from an inexpensive raw material under mold condition in high purity and yield by reacting an (alkyl)thiophene with an acid halide and reacting the reaction product with orthoformates in the presence of an active iodine source. CONSTITUTION:The objective compound of formula IV can be produced by reacting a compound of formula I (R is H or alkyl) with a compound of formula II (R<1> is H or alkyl; X is halogen) at -5-+20 deg.C using AlCl3, etc., as a catalyst and reacting the reaction product of formula III with 1-14 times weight of an orthoformate in the presence of an active iodine source (e.g., iodine or methyl iodide) at 10-30 deg.C. The reaction rate of the above reaction can be increased by the addition of a protonic acid or Lewis acid. The active iodine source and the orthoformates can be recovered in high yield without using a precision apparatus. The compound of formula IV is useful as an intermediate for analgesic and anti-inflammatory agent.

Description

[Detailed description of the invention] Ryūto, Gosara-Satooka! The present invention relates to a method for producing thiophene acetic acid derivatives.

General formula (in the formula, R and R1 are the same as above) [In the formula, R, R' and R2 are the same or different and represent a hydrogen atom or an alkyl group. ] The thiophene acetic acid derivative represented by is characterized by its remarkable non-steroidal analgesic and anti-inflammatory effects, but its gastric mucosal stimulating effect is relatively weak compared to commonly used anti-inflammatory analgesics. [In the formula, R, R'- and R2
is the same as above. Ar) represents a cyclohexyl group, a cyclohexyl group, or a heterocyclic residue such as thienyl, furyl, tetrahydrofuryl, and pyridyl. The phenyl ring and cyclohexyl ring may be substituted with a halogen atom, an alkyl group, a trihalogenomethyl group, or an alkoxy group. ] It is an important compound as an intermediate for synthesizing the thiophene acetic acid derivative represented by

Conventionally, the thiophene acetic acid derivative represented by -maximum (1) above has been produced, for example, by the method shown below.

That is, first, (2-thienyl)acetonitrile obtained by the reaction of 2-(chloromethyl)thiophene and sodium cyanide is reacted with diethyl carbonate in the presence of metallic sodium to form ethyl α-cyano(2-thienyl)acetate. K. Pettersson.

Acta, Chem, 5cand,, 7.1311
(1953)), which was then methylated with methyl iodide in the presence of sodium ethoxide, followed by ethanol-
Hydrolyzed with potassium hydroxide, the resulting α-methyl-(2-thienyl)cyanoacetic acid is further decarboxylated to α-methyl-(2-thienyl)acetonitrile, and finally this is hydrolyzed to form α-methyl -2-thiopheneacetic acid is produced ()1. BerCOt-Vattero
ni, Bull, Soc, Chim, Fr,, 182
0 (1961)).

In the above method, 2-(
chloromethyl)thiophene is produced by chloromethylation of thiophene (F, F).

B! 1cke, J., Amer, Chem, Soc,, 6
1934 (1946)], but in this process, carcinogenic bis(chloromethyl)ether is unavoidably produced as a by-product, and the yield of 2-(chloromethyl)thiophene is approximately 47%. In addition, this 2-(chloromethyl)thiophene is explosive, so it has fatal drawbacks such as requiring extreme care when handling it. Therefore, 2-(chloromethyl)thiophene is not an easily available compound. cannot be said.

Furthermore, when converting this 2-(chloromethyl)thiophene into (2-thienyl)acetonitrile, it is essential to use highly toxic sodium cyanide.

As described above, the conventional method is unsuitable as an industrial method for producing the thiophene acetic acid derivative (1) above.

Means for Determining C1 The object of the present invention is to provide an industrially advantageous method for producing the above-mentioned thiophene acetic acid derivative (1).

That is, the present invention provides - maximum [wherein R is the same as above. ] A compound represented by the general formula %Formula % (4)C In the formula, X represents a halogen atom. R1 is the same as above. ) is then reacted with a compound represented by the following general formula [wherein R and R1 are the same as above]. [In the formula, R, R1 and R
2 is the same as above. The present invention relates to a method for producing a thiophene acetic acid derivative, which is characterized by obtaining a thiophene acetic acid derivative represented by the following.

The above compound (5) is produced by subjecting the compound (3) to a Friedel-Krach reaction with an acid halide of general formula (4) in the presence of a suitable catalyst. The compound of general formula (3) and the acid halide of -maximum (4) used as starting materials are both easily available and known compounds. - Maximum (4) acid halides include, for example, propionyl chloride, propionyl bromide, and the like. - The maximum amount of acid halide (4) to be used is usually about 0.7 to 1.2 times the molar amount, preferably about 0.8 to 1.1 times the molar amount of the maximum (3) compound. It is better to As the catalyst used in this reaction, a wide variety of conventional catalysts can be used, such as aluminum chloride, ferric chloride, antimony pentachloride, boron trifluoride, zinc chloride, tin tetrachloride, titanium chloride, boron fluoride, tetrafluoride, etc. Examples include titanium chloride. The amount of such catalyst used is -maximum (3)
The amount is usually about 0.5 to 2 times the molar amount, preferably about 0.7 to 1.5 times the molar amount of the compound. The above reaction is carried out without a solvent or in a suitable solvent. Examples of the solvent used include carbon disulfide, nitrobenzene, benzene, toluene, xylene, chloroform, carbon tetrachloride, methylene chloride, and dichloroethane. Such a solvent is usually about 1 to 30 times the weight of the compound (3) at most, preferably 1.5 to 25 times the weight of the compound (3).
It is best to use about twice the weight. The reaction is usually −10 to
The reaction proceeds suitably at about 30°C, preferably about -5 to 20°C, and generally completes in about 2 to 5 hours. In this way, a compound represented by general formula (5) is produced.

In the present invention, the compound of general formula (5) thus obtained may be isolated and then subjected to the next reaction, or the reaction mixture may be subjected to the next reaction.

In the present invention, the compound of general formula (5) is then reacted with an ortho-acid ester in the presence of an iodine active species. Examples of the iodine active species include iodine, methyl iodide, zinc iodide, copper iodide, and silver iodide. Such iodine active species are usually 0.1 for -maximum (5) compounds.
It is preferable to use about 1.5 to 1.5 times the molar amount, preferably about 0.2 to 1.4 times the molar amount. Alto 1 again! As the acid ester, a wide variety of conventionally known ones can be used, such as methyl orthoformate, ethyl orthoformate, and the like. Alt 1! The acid esters are usually used in an amount of about 0.8 to 15 times, preferably about 1 to 14 times, the weight of the -maximum (5) compound. The above reaction can be carried out either in the absence of a solvent or in a suitable solvent; however, when the reaction is carried out in a solvent, the amount of the orthoformates used can be significantly reduced. Examples of the solvent include halogenated methane and halogenated ethane. Furthermore, the reaction rate of the reaction can be increased by adding a protonic acid or a Lewis acid to the reaction system. Examples of the protonic acid include sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, trichloroacetic acid, trichlorosulfonic acid, etc., and examples of the Lewis acid include aluminum chloride, ferric chloride, antimony pentachloride, trifluorochloride, etc. Boron chloride, zinc chloride, titanium chloride, boron fluoride, tin tetrachloride,
Examples include titanium tetrachloride. The amount of these protonic acids and Lewis acids to be used is usually about 0.1 to 1.5 times the molar amount of the compound (5), preferably 0.2
It is preferable to set the amount to about 1.4 times the molar amount. The reaction normally proceeds suitably at about 0 to 40'C, preferably about 10 to 30'C, and is generally completed in about 10 to 30 hours. Thus, the object compound of the present invention, general formula (1)
A thiophene acetic acid derivative is produced.

The thiophene acetic acid derivative of general formula (1) obtained above is induced into the thiophene acetic acid derivative of -maximum (2) according to the method shown below.

That is, - the maximum (2) thiophene acetic acid derivative is produced by - subjecting the maximum (1) thiophene acetic acid derivative and an acid chloride to a Friedel-Krach reaction in the presence of a suitable catalyst. As the acid chloride, a wide variety of conventionally known ones can be used, such as benzoyl chloride, p-triated benzoyl chloride, hexahydrobenzoyl chloride,
Examples include α-thenoyl chloride, m-trifluoromethylbenzoyl chloride, and the like. The amount of such acid chloride is usually about 0.8 to 1.3 times, preferably about 0.9 to 1.1 times, the amount of the compound (1). As the catalyst used in the reaction, any catalyst used in the reaction between the compound of (3) above and the compound of general formula (4) can be used. The amount of such catalyst used is usually 0.5 to 1.5 per compound (1).
The amount should be about double the molar amount, preferably about 0.7 to 1.2 times the molar amount. The above reaction is carried out without a solvent or in a suitable solvent. As the solvent, any of the solvents used in the reaction between the compound of maximum (3) above and the compound of general formula (4) can be used.

The solvent is usually used in an amount of about 1 to 30 times, preferably about 1.5 to 25 times, the weight of the compound (1). The reaction normally proceeds suitably at a temperature of about 0 to 20°C, preferably about 5 to 10°C, and generally the reaction proceeds at a temperature of about 2 to 20°C.
It will be completed in about 5 hours.

Thus, the thiophene acetic acid derivative represented by the general formula (2) is obtained! ! ! will be built.

Effect of the invention The advantages of the method of the invention are as follows.

(1) The raw material compounds used in the method of the present invention are all extremely inexpensive and can be abundantly supplied on the market.

(2) The reactions in each step of the present invention proceed easily, and produce very few by-products, so that the desired product can be produced in high yield and purity.

(3) After the reaction, the iodine active species and orthoformates used in the method of the present invention can be recovered in high yield without requiring any precision equipment, and can be reused in the next reaction. can.

Therefore, the target compound of the present invention can be easily produced without almost any replenishment of active iodine species or orthoformates.

(4) The method of the present invention does not require high temperature or high pressure;
It can be carried out extremely safely at room temperature and under normal pressure.
Furthermore, since no complicated and expensive equipment is required, the operation is simple and economical.

Example Examples are given below to further clarify the present invention.

Example 1 Synthesis of propionylthiophene Thiophene '1OOCI and propionyl chloride 11
0 () into the reactor, and without stirring tin tetrachloride 30
0 g was added dropwise over several hours while maintaining the reaction temperature at -5 to 20°C. After further stirring at the same temperature for 4 hours, the mixture was hydrolyzed and extracted with chloroform. After chloroform was distilled off, a 73°C/7mmHg fraction was collected by vacuum distillation to obtain 159.5q of propionylthiophene. This corresponds to 95.9% of the theoretical amount.

IR spectrum): 1670.1420,800,712cm-1M5 spectrum (m/e): 140.248NMR spectrum
δppm near, 1-7.7 (m, 3H), 2.8 (Q, 2H), 1.3 (t, 3H) Example 2 Synthesis of methyl α-methyl-2-thiophene acid Propionylthiophene 21 (7 , 46q1 iodine, 64 mf2 ortho-methyl formate, and 200 m12 dichloroethane were charged into a reactor, and stirring was continued for 20 hours while maintaining the reaction temperature at 20-30'C.Then, dichloroethane, iodine, and ortho-1!methyl were collected, and the residue was Vacuum distilled to 85
When the °C/7 mmHg fraction is collected, α-methyl-
24.1 CI of methyl 2-thiophene acetate was obtained. This corresponds to 94.5% of the theoretical amount.

IR spectrum: 1740.1435.700 cm' MS spectrum (m/e): 170.038 NMR spectrum δppm: 6.9-7.2 (m, 3H), 4, 0 (q, 1H), 3.
7 (s, 3H), 1.6 (d, 3H
) Example 3 A of methyl α-methyl-2-thiophene acid 21 g of propionylthiophene, 46Q of iodine, 2 of methyl orthoformate
10mf2. p-Toluenesulfone M3c+ and aluminum chloride 2q were charged into a reaction apparatus, and the reaction temperature was set at 20
Stirring was continued for 15 hours while maintaining the temperature at ~30°C. Thereafter, treatment was carried out in the same manner as in Example 2 to obtain 23.50 methyl α-methyl-2-thiophene acetate. This is the theoretical quantity of 92.
This corresponds to 2%.

Example 3 Synthesis of α-methyl-2-thiophene methyl acetate Propionylthiophene 21C], iodine 46C1 and methyl orthoformate 210mf2 were charged into a reactor, and the reaction temperature was 20~
Stirring was continued for 23 hours while maintaining the temperature at 30°C. Thereafter, it was treated in the same manner as in Example 2 to obtain 24.90 methyl α-methyl-2-thiophene acetate. This is the theoretical quantity of 97.6
Corresponds to %.

Reference Example 5 - Synthesis of benzoyl-α-methyl-2-thiopheneacetic acid 20.5 g of methyl α-methyl-2-thiophene acetate and 25.0 CI of benzoyl chloride were charged into a reaction apparatus.
After dissolving in 150 ml of chloroform, 17.2 G of anhydrous aluminum chloride was added over a period of 1 hour while maintaining the reaction temperature at 10 to 30°C. After further stirring at the same temperature for 45 minutes, the mixture was hydrolyzed, extracted with ether, and concentrated. This was poured into an alkaline aqueous solution, stirred at 50 to 60°C for several hours, and then acidified using 1N hydrochloric acid to precipitate crystals. When the precipitated crystals are recrystallized with carbon tetrachloride, 5-benzoyl-α-methyl-2-thiophene vinegar is obtained! 2
9.9Cl was obtained. This corresponds to 95.6% of the theoretical amount.

Melting point: 94.2-95.8℃ (that's all)

Claims (1)

[Claims] (1) General formula ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ [In the formula, R represents a hydrogen atom or an alkyl group. ] and the general formula R^1CH_2COX [wherein R^1 represents a hydrogen atom or an alkyl group]. X represents a halogen atom. [In the formula, R and R^1 are the same as above. ] The compound represented by is reacted with orthoformic acid esters in the presence of an iodine active species to form the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^2 represents a hydrogen atom or an alkyl group. R and R^1 are the same as above. ] A method for producing a thiophene acetic acid derivative, the method comprising obtaining a thiophene acetic acid derivative represented by: