JPS59106483A - Manufacture of 2-thiopheneacetic acid derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The subject of the present invention is a compound of the following formula (I) in which R represents an alkyl group having 1 to 4 carbon atoms, and R,, IL, and R3 are the same or different. 2-thiopheneacetic acid derivatives, each of which may represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a herogen atom.

These compounds are intermediate compounds that can be used in the preparation of pharmaceutical compounds, especially anti-inflammatory compounds.

The final products that can be prepared starting from the compounds obtained by the process of the invention are particularly described in French Patent No. 2
No. 068425.

Several methods for producing compounds of formula (1) are already known.

For example, the following method is M, 13ercot-vatte
Bull, 5oc, Chim, by roni et al.
France 1961, p.

1820.

RRR C'02Et R=alkyl The following method is also described by F. Clemence et al. in Ear, J. Med, Chem, 1974 (9
It is described on p. 590.

The following methods are also described in French Patent No. 2,398,068. These methods involve at least four steps starting from a thiophene or substituted thiophene.

Here, starting from substituted thiophene or thiophene, 3
A new manufacturing method for conductors based on formula (1) was completed at this stage. Furthermore, this method offers many advantages for implementation on an industrial scale.

In this method, an aldehyde of the formula R-CHO is added to a compound of the following formula (I[) (wherein R1, R, and R3 have the meanings given above) in the presence of hydroheric acid of the formula H-Ha1. Alternatively, derivatives of aldehydes of the formula R-CHO may be reacted to obtain compounds of the following formula l (wherein Hal represents a herogen atom), and compounds of formula (4) may be reacted with the following formula A-CN (wherein Representing 4 atoms of alkali gold JiI and an equivalent amount of alkaline earth metal or hydrogen atom), a compound of the following formula aV) is obtained, and the compound of 2) is reacted with a hydrolyzing agent to obtain the desired compound of formula (1). It is characterized by obtaining a compound.

Substituents R, R1, , Rz and R3 can be represented by lower alkyl groups, i.e. methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, 5ec
-butyl or t-butyl. In addition, substituent R
1, R2 and R3 are /z”gll non-children, i.e.
It can represent chlorine, bromine and iodine.

As the aldehyde represented by the formula R-CHO, when OR, which is an aldehyde corresponding to the desired meaning of R, represents a methyl group, valaldehyde, which is a hair acetaldehyde trimer, is preferably used. Among other aldehydes, mention may be made of propanal and butanal.

The hydrogel/hydrogen acid used is preferably hydrochloric acid or hydrobromic acid. Hydrochloric acid is most often used.

The reaction for converting the compound of formula (II) into the compound of formula (2) includes heroalkylation, preferably chloroalkylation,
In particular, chloroethylation can be carried out with or without the addition of organic solvents. Solvents that can be used include preferably chlorinated solvents such as methylene chloride, but carbon tetrachloride or chloroform, ethers such as isopropyl ether, cyclohexane, ethanol or methanol can also be used. Preferably, the synthesis sequence is carried out starting from the compound of formula (7) in solution. The solution may thus be an extraction solvent that is the same as or different from the reaction solvent.

A reaction solvent is preferably used. A preferred solvent is methylene chloride, which can also be used for extraction.

Besides the hydrohalic acid directly involved in the reaction, the acidity of the medium can be varied by adding other acids such as phosphoric acid or acetic acid. Additionally, Lewis acids such as zinc or aluminum chloride can be used.

Obviously, the various reactants, namely thiophene, aldehyde and acid, can be introduced in various orders depending on the operating conditions used.

Reaction temperatures also range over a wide range. Preferred operating temperatures may be between -10°C and ambient temperature. In particular, a temperature around -5°C is used. A particular example of such a reaction is Org, 5
ynth, VOI, 58.9.86.

When a reactive derivative of an aldehyde of the formula R-CHO is used, this reactive derivative preferably has the formula It is a compound representing a group). The above compound of the formula is prepared by reacting an aldehyde of the formula R-CHO with a hydroheric acid of the formula H-Ha I in an alcoholic solvent of -OH to A1.

As is clear, the preferred reactive derivative used in this case is acetaldehyde CHs-C in an alcohol, preferably methanol or ethanol, of Takehito Ik-OH.
It is a compound of the following formula obtained by reacting HO and hydrochloric acid.

The conversion of compounds of formula (4) to compounds of formula (1) is preferably carried out with alkali metal or alkaline earth metal cyanides, such as sodium, potassium, lithium or calcium cyanide. Hydrocyanic acid could also be used. Sodium cyanide is preferred. The operation may be carried out in the presence of a base or without it. when carried out in the presence of a base, sodium or potassium hydroxide;
Particularly preferred is sodium hydroxide. However, it is preferred to work without a base. Preferably, the reaction of the compound of formula (7) to the compound of formula (IV) is carried out by a so-called phase transfer reaction. The operation is then carried out in the presence of specific catalysts. The catalyst may be, for example, a tetraalkyl or aralkylammonium, phosphonium or arsonium salt, or a sulfonium salt. Catalysts of this type include, for example, triethylbenzylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium sulfate, tetrabutylammonium hydroxide, tetra-n-phthylammonium chloride, iodide. Examples include tetramethylphosphonium and tetra-n-butylphosphonium bromide. These salts may be immobilized on an ion exchange resin. Furthermore, a giant cyclic polyether generally called an ether ring can also be used.

Such compounds include, for example, Tetrahedron
Letters Al s (i 972), p-1793
It is described in. A compound that can be used is 1,4°7.10,13.16-hexaoxacyclooctadecane. In short, surfactants formed by reacting higher alcohols or fatty acids with, for example, ethylene oxide can be used.

The catalyst used is preferably an ammonium halide, preferably a trialkylbenzyl bromide or chloride or a trialkylammonium chloride. Preferred compounds are
Triethylbenzylammonium salt.

As mentioned above, in a preferred method of implementation, formula (5)
The compound is used in organic solution, preferably in methylene chloride or dichloroethane. It is also possible to use polar solvents such as dimethylformamide or dimethylsulfoxide. Preferably methylene chloride is used. The amount of phase transfer catalyst can vary depending on the reaction used. For example, it is 0 for the compound of formula (1)
．． It will be 2 to 0.5 parts.

The temperature is from 0° C. to the reflux temperature of the solvent.

It is preferable to carry out at a low temperature of about 0 to +5°C.

Hydrolysis of compounds of formula (I) to compounds of formula (I) first involves converting the nitrile into the salt of the desired acid, preferably the sodium or potassium salt. At this stage the aqueous phase can be purified with organic solvents. Finally, the aqueous phase is aged and the desired product is extracted.

The first step is carried out in water or in a mixture of water and a water-miscible solvent. The solvent used is preferably a lower alcohol such as ethanol or isopropanol. An alkaline agent, preferably sodium or potassium hydroxide, is reacted preferably at a temperature between 50°C and reflux temperature.

The operation is preferably carried out in pure water at reflux.

The reaction time may be 2 hours to 15 hours.

The organic solvent used to purify the aqueous solution of the salt obtained is:
It is selected from the group consisting of toluene, dichloroethane or methylene chloride, preferably methylene chloride.

The final acidification is preferably carried out with concentrated hydrochloric acid. The reaction is preferably carried out after adding a solvent selected from the above group. The operation is carried out at a temperature which may be between ambient temperature and the reflux temperature of the solvent.

The hydrolysis of the compound of formula (1) to the compound of formula (1) can also be carried out in a commercial medium, preferably in the presence of an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid.

In particular, the present invention relates to a production process, which is carried out as described above from thiophene to obtain a compound of the following formula (I') (wherein R has the meaning given above).

The compound of formula (I') corresponds to the compound of formula (1) in which R1, R2 and R3 each represent a hydrogen atom.

More particularly, the invention relates to a process for the production of α-methyl-2-thiopheneacetic acid, characterized in that it is carried out as described above starting from thiophene and acetaldehyde.

A preferred embodiment of the method that is the subject of the invention includes:
A method is used, characterized in that the action of the compound of formula A-CN on the compound of formula (1) is carried out by a phase transfer reaction. This method preferably comprises triethylbenzylammonium chloride, tetrapropylammonium bromide,
It is carried out in the presence of a catalyst selected from the group consisting of tetracyptyl ammonium bromide, tetrabutylammonium sulfate and tetrabutylammonium hydroxide.

In a particularly preferred method of practicing Kempo, a methylene chloride solution of the compound of formula (4) is injected into an aqueous solution of sodium cyanide and a phase transfer catalyst. The phase transfer catalyst is preferably triethylbenzylammonium chloride as described above.

Finally, the method for producing α-methyl-2-thiophene acetic acid, which is the subject of the present invention, is carried out under the following preferred conditions.

By reacting hydrochloric acid and paraldehyde with thiophene, 2-(
1-chloroethyl)thiophene was obtained, and this was treated with sodium cyanide in the presence of triethylbenzylammonium chloride through a phase transfer reaction to obtain α-methyl-2-thio7-acetonitone, which was first subjected to hydroxylation. The desired compound is obtained by reacting with sodium and then with hydrochloric acid in 1. The following examples illustrate the present invention and do not limit it in any way.

Engineering iA: 2-(1-chloroethyl)thiophene 3M
A mixture of 6 CC of methylene chloride and 75 CC of aqueous hydrochloric acid was cooled to -5°C with stirring, and then 8
4. A mixture of F thiophene and 44N paraldehyde was introduced on the other hand, and an aqueous solution of 3&5y hydrochloric acid was introduced over a period of 5 hours at the above temperature. The mixture was stirred and 55g of hydrochloric acid was added over 30 minutes. After stirring at -5℃ for 6 hours,
Bring the mixture to 0°C, 50! I added ice cubes. 0 for the whole
Stir for 15 minutes at ~+5°C, decant the organic phase, extract the aqueous phase with 42 cc of methylene chloride at 0-+5°C, and combine the two organic phases.

Step B: α-Methyl-2-thio7ene acetonitrile 8.4 g of triethylbenzylammonium chloride was added to a solution of 88, 59 sodium cyanide dissolved in 168 cc of demineralized water and cooled to 0 to +5°C. To this medium, stirred constantly, was added the 2-(1-chloroethyl) obtained above.
A solution of thiophene in methylene chloride was poured in for 1 minute. 0～
Continue stirring vigorously for 18 hours at 5°C, then at 252 C.C.
of demineralized water was added. After stirring for 10 minutes, the organic phase was decanted and the aqueous phase was extracted with 84 CC of methylene chloride and then twice with 42 CC of the same solvent.

The organic phases were combined and then washed with demineralized water, then with water containing 1% pure hydrochloric acid, and then with demineralized water.

The organic phase was concentrated under reduced pressure for 2 hours to obtain 105 g of the expected product.

Step C A mixture of 105 g of the product obtained above, 500 CC of demineralized water and 63.2 g of sodium hydroxide was refluxed for 2 hours and 30 minutes.

This was cooled to 20° C. and 168 CC of methylene chloride was added. After stirring for 10 minutes, the methylene chloride phase was decanted. The same operation was repeated twice. 168CC
Ene and then 168°B6 hydrochloric acid were added to the aqueous phase. This was refluxed for 1 hour, cooled to 20°C, stirred for 15 minutes, then the aqueous phase was decanted and 42CC
Washed four times with demineralized water. The organic phase was concentrated under reduced pressure. 71-74 g of the expected compound were obtained.

Example 2 Steps A-C of Example 1 were modified in the following manner.

Step A”: 2-(1-chloroethyl)thiophene 8
4, j9 thiophene, 4411 paraldehyde and 75CC 22°B6 hydrochloric acid at a temperature of 10-1
While maintaining the temperature at 3°C, gaseous hydrochloric acid was blown in for 25 minutes until saturation.

After pouring the whole into 75 CC of ice-cold water and decanting, the organic phase was extracted with 168 CC of methylene chloride and the organic phase was washed three times with 50 CC of cold water.

Process A! Gaseous hydrochloric acid was introduced into a mixture of 46 g of ethanol and 441i paraldehyde at +10° C. until saturation.

This reactant was added to 84.9 thiophene at +10° C. for 10 minutes with stirring. The procedure was then carried out as shown in AI.

Step A1 84, li+ thiophene, 44g paraldehyde,
168 CC methylene chloride and 75 CC17) 22
'The mixture of EA hydrochloric acid was stirred at 10-13°C. This was saturated with 40 p of gaseous hydrochloric acid and then cooled to 0"C. After adding 5011 g of ice and decanting, the aqueous phase was extracted with 42 cc of methylene chloride and the entire organic phase was extracted with 63 cc of cold water. Washed twice.

Step B1 The following reactant was used in place of triethylbenzylammonium chloride.

Tetrapropylammonium bromide Tetrabutylammonium bromide Tetrabutylammonium sulfate Tetrabutylammonium hydroxide Step C! Dichloroethane was used as an extraction solvent instead of methylene chloride.

Procedural amendment (formality) Indication of the case of Mr. Kazuo Wakasugi, Commissioner of the Japan Patent Office, February 5, 1980 Patent application No. 87856, 1988 Title of the invention Relationship with the case of a person amending the manufacturing method of a derivative of 2-thiophene acetic acid Name of patent applicant Title Contents of the amendment subject to the Lesseloille-Craft amendment Amendment of the specification as attached (no change in content)

Claims (1)

[Claims] (1) Formula (I) - (wherein R represents an alkyl group having 1 to 4 carbon atoms, and R1, R, and R3 may be the same or different, In preparing derivatives of 2-thiophene acetic acid of the following formula (II) (representing a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a halogen atom, respectively), R1, R2 and R3 have the meanings defined above. A compound having the following formula 1 (where Hal
represents a halogen atom), and the compound of formula (3) is reacted with a compound of the following formula -CN (where A represents an alkali metal atom, an equivalent alkaline earth metal or a hydrogen atom) to obtain a compound of the following formula 2- characterized in that the compound of formula (g) is obtained, and the compound of formula (g) is reacted with a hydrolyzing agent to obtain the desired compound of formula (I).
Method for producing thiophene acetic acid derivatives. (2) Starting from thiophene, a compound of the following formula (1') (wherein R has the meaning given in claim 1) is produced: Claim 1 Manufacturing method described. (3) The production method according to claim 2, characterized in that α-methyl-2-thiophene acetic acid is produced starting from thiophene and acetaldehyde. (4) The production method according to any one of claims 1 to 3, wherein the action of the Takejin-CN compound on the compound of formula (2) is carried out by a phase transfer reaction. (5) The action of the compound of Bujin-〇N on the compound of formula (6) consists of triethylbenzylammonium chloride, tetrarubuvir ammonium bromide, tetrabutylammonium bromide, tetrabutylammonium sulfate, and tetonoptylammonium hydroxide. 5. The method according to claim 1, wherein the method is carried out by a phase transfer reaction in the presence of a catalyst selected from the group consisting of: (6) Claims 1 to 5, characterized in that during the phase transfer reaction, a methylene chloride solution of the compound of formula (2) is injected into an aqueous solution of sodium cyanide and a phase transfer catalyst.
The manufacturing method described in any of paragraphs. (7) Reaction of hydrochloric acid and paraldehyde to thiophene tC
2-(1-chloroethyl)thiophene was obtained, which was reacted with sodium cyanide in the presence of triethylbenzylammonium chloride through a phase transfer reaction to form α-methyl-2
-obtained thiopheneacetonitrile and first reacted with sodium hydroxide and then with hydrochloric acid to produce α-methyl-2-thiopheneacetic acid. Manufacturing method.