FI80882C - Process for the preparation of 2-thiophenacetic acid derivatives - Google Patents

Description

1 80882

The present invention relates to a process for the preparation of 2-thiophene-5-acetic acid derivatives of the formula (I) 10 / -i n

N'S'X = CH-C09H

I Δ \ 1)

R

15 wherein R is an alkyl group having 1 to 4 carbon atoms.

These compounds are useful as intermediates in the preparation of drugs, especially anti-inflammatory agents.

The final products which can be prepared using the compounds obtained by this method as starting materials are described in particular in FR patent 2,068,425.

Several methods are now known for the preparation of compounds of formula (I).

In M. Bercot-Vatteroni et. Oh. Bull. Soc. Chim. France 1961, p. 1820, the following method is described: 2 80882

(1 (> c „2cN

C C ^ E12

J

5

Oh-co 2Η <_ϋΗζ> c „-cS“ opT ^ Or- r R R CO2Et R = alkyl 10 In F. Clemence et al. Eur. J. Med.

Chem. 1974 (9) 390 the following method is described: <r> 0 o \: 15 ^ CH3 Mgl fTT \ AC0H CH3 · ^ s) Uchco2h ^^ J_co2h '·' ch3 oh 20 In Sagami's FR patent publication no. 2,398,068 describes the following method: R _ halogenation q _ CH, 25 r - - - -, ä — 3ζ> ΤΗΗ ^

0 Rg q f ^ 2 OH

R 1 = H or a lower alkyl group Hal = halogen alkali-R 2 = H, a hydrocarbon or halogen group thallium hydroxide :: 30 / \> -C-CO 2 H ·

2 K

These methods have at least 4 steps when the starting materials are thiophene or substituted thiophene.

3 80882

A new process for the preparation of derivatives of formula (I) in three steps using thiophene as starting material is now presented. In addition, this method has proven to be advantageous to implement on an industrial scale.

This process is characterized in that the aldehyde of the formula R-CHO in the presence of a hydrohalic acid of the formula H-Hal or the compound of the formula. O-Alk 10 R-CH 2 Cl 2 wherein Alk is an alkyl group having 1 to 3 carbon atoms and Hal is a halogen atom is reacted with thiophene to give a compound of formula

A

Ns ^^ CH-Hal (III)

20 I

R

wherein Hal is a halogen atom, followed by reacting the obtained compound of formula (III) with a compound of formula A-CN 25, wherein A is an alkali metal atom, an alkaline earth metal equivalent or a hydrogen atom, to give a compound of formula 30 ^ NvCH-CN (iv)

R

And that the compound of formula (IV) is hydrolyzed to give the desired compound of formula 4 80882 (I).

Meanings of the substituent which may be mentioned are lower alkyl groups, namely methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, secondary butyl or tert-butyl.

The aldehyde representing R-CHO is the aldehyde corresponding to the desired R.

When R is a methyl group, par-aldehyde, which is a trimer of acetaldehyde, is preferably used. Among other aldehydes, propanal or butanal can be mentioned.

The hydrohalic acid preferably used is hydrochloric acid or hydrobromic acid. Hydrochloric acid is preferably used.

The reaction for converting a compound of formula (II) into a compound of formula (III), i.e. haloalkylation, preferably chloroalkylation and most preferably chloroethylation, can be carried out with or without an organic solvent. Among the solvents which may be used, a chlorinated solvent such as methylene chloride may be mentioned, but carbon tetrachloride or chloroform, an ether such as isopropyl ether, cyclohexane, ethanol or methanol may also be used. The further synthesis is carried out in a suitable manner using the compound of formula (III) as a starting material as a solution. Thus, the solvent 25 may be an extraction solvent similar or different from the reaction solvent. Preferably a reaction solvent is used. The best solvent is methylene chloride, which is also used for extraction.

In addition to the hydrohalic acid used directly in the reaction, the acidity of the reaction medium can be modified by adding another acid such as phosphoric acid or acetic acid. Lewis acid such as zinc or aluminum chlorides can also be used.

Of course, different reaction components: thiophene, al-35 dehyde and acid can be added in a different order depending on the procedures used.

5 80882

The reaction temperature can also be varied. Preferably a temperature between -10 ° C and room temperature is used. Most preferably, the temperature is about -5 ° C.

A specific example of such a reaction is described in Org. Synth. Vol 38 p. 86.

When a reactive derivative of an aldehyde of the formula R-CHO is used, this reactive derivative is an OAlk 10 compound of the formula R-CH wherein Hal is halo.

The halogen atom and Alk is an alkyl group having 1 to 3 carbon atoms. This compound of formula R-CH is prepared by reacting the aldehyde R-CHO with a hydrohalic acid of formula H-Hal in an alcohol solvent of formula Alk-OH. Of course, the reactive derivative which is preferably used in this case is a compound of formula CH3-CH which

Cl is obtained by reacting acetaldehyde CH3-CHO with hydrochloric acid in an alcohol of formula Alk-OH, preferably methanol or ethanol.

The conversion of compounds of formula (III) to compounds of formula (IV) is preferably carried out with an alkali metal or alkaline earth metal cyanide such as sodium, potassium, lithium, calcium cyanide. Hydrocyanic acid can also be used. The best is sodium cyanide. The reaction is carried out either without or in the presence of a base.

When operating in the presence of a base, NaOH or KOH are best, especially NaOH. However, it is preferred to operate without a base.

The conversion of compounds of formula (III) into compounds of formula (IV) is very preferably carried out by the phase change reaction mentioned. The operation is then carried out in the presence of a specific catalyst. This catalyst can be, for example, a tetraalkyl or aralkylammonium, phosphonium or arsonium salt or a sulfonium salt.

Catalysts of this type include, for example, triethylbenzylammonium chloride, tetra-propyl and tetrabutylammonium bromides, tetrabutylammonium sulfate, tetrabutylammonium hydroxide, tetra-n-butylammonium chloride-n-butodium n-butodium phosphonium, tetramethylphosphine, tetramethylphosphide. These salts can be bound to ion exchange resins.

It is also possible to use a macrocyclic polyether, commonly referred to as an ether crown. Such compounds are described, for example, in Tetrahedron Letters No. 15 18 (1972) p. 1793.

Among the useful compounds, 1,4,7,10,13,16-hexaoxacyclooctadecane can be mentioned. Finally, surfactants formed when a long chain alcohol or fatty acid reacts with, for example, ethylene oxide can be used.

The catalyst used is preferably ammonium halide, preferably trialkylbenzyl or tetraalkyl ammonium chloride or bromide.

The best compound is triethylbenzylammonium chloride. In a preferred embodiment, as indicated above, the compound of formula (111) is used in an organic solution, preferably chloromethylene solution or dichloroethane. Polar solvents such as dimethylformamide or dimethylsulfoxide can also be used. Methylene chloride is preferably used.

The amount of phase transfer catalyst may vary depending on the reactions used. It may range, for example, from 0.2 to 0.5 parts relative to the compound of formula (lii).

35 The temperature can range from 0 ° C to the boiling point of the solvent. Preferably operated at low temperatures at about 0 + 5 ° C.

When a compound of formula (IV) is hydrolysed to a compound of formula (I), the intention is first to convert the nitrile to a salt, preferably the sodium or potassium salt of the desired acid.

At this point, the aqueous phase can be purified as an organic solvent. Finally, the aqueous phase is acidified and the desired compound is extracted.

10 The first step is performed either in water or in a mixture of water-water soluble solvent. Thus, a low molecular weight alcohol such as ethanol or isopropanol is preferably used as the solvent. A base, preferably NaOH or KOH, is added to the reaction preferably at a temperature of 50 ° C to 15 ° C. Preferably operated at the boiling temperature of clean water. The reaction time is from two hours to 15 hours.

The organic solvent for purifying the aqueous solution of the salt obtained is preferably selected from toluene, dichloroethane or methylene chloride, preferably methylene chloride.

The final acidification is preferably performed with concentrated hydrochloric acid. The reaction is preferably carried out after the addition of a solvent selected from the previous group. Operate at a temperature that can range from room temperature to the boiling point of the solvent.

The hydrolysis of a compound of formula (IV) to a compound of formula (I) may be carried out in an acidic environment, 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 process for the preparation of α-methyl-2-thiopheneacetic acid, which process is characterized in that it is carried out as described above using thiophene and acetal-dehyde as starting materials.

8 80882

Among the best embodiments of the invention, a method is used which is characterized in that the reaction of a compound of formula A-CN with a compound of formula (II) is carried out as a phase transfer reaction.

This process is preferably carried out in the presence of a catalyst selected from the group consisting of triethylbenzylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium bromide, tetrabutyl-ammonium sulfate and tetrabutylammonium hydroxide.

In a particularly preferred embodiment of this process, the compound of formula (III) in chloromethylene solution is poured into an aqueous solution of sodium cyanide with a phase transfer catalyst. The phase-15 transfer catalyst is, as indicated above, preferably triethylbenzylammonium chloride.

Finally, the process of the present invention is preferably carried out under the following conditions for the preparation of α-methyl-2-thiopheneacetic acid: hydrochloric acid and paraldehyde are reacted with thiophene to give 2- (1-chloroethyl) thiophene which undergoes a phase transfer reaction with sodium cl to give α-methyl-2-thiopheneacetonitrile, which reacts first with NaOH, then with hydrochloric acid to give the desired compound.

The following examples illustrate the invention.

Example 1: α-Methyl-2-thiopheneacetic acid Step A: 2- (1-chloroethyl) thiophene.

Cool, with stirring, to 5 ° C a mixture of 336 cm3 of methylene chloride and 75 cm3 of aqueous hydrochloric acid, then at this temperature over a period of five hours a mixture of 84 g of thiophene and 44 g of paraldehyde and 36.5 g of gaseous hydrogen chloride is added. -35 acids. Stir for three hours at -5 ° C, bring to 80 ° C and add 50 g of ice. Stir at 0.5 ° C for 15 minutes, decant the organic phase, extract the aqueous phase at 0.5 ° C with 42 cm 3 of methylene chloride and combine the two organic phases.

5 Step B: α-Methyl-2-thiopheneacetonitrile.

8.4 g of triethylbenzylammonium chloride are added to a solution cooled to 0 + + ° C and containing 88.5 g of sodium cyanide in 168 m3 of deionized water. The chloromethylene-10 solution of 2- (1-chloroethyl) thiophene obtained above is poured into the stirred mixture in one minute. Keep under vigorous stirring for 18 hours at 0 + 5 oC, then add 252 cm3 of deionized water. Stir for ten minutes, decant the organic phase and extract the aqueous phase with 84 cm3 of methylene chloride, then twice with 42 cm3 of the same solvent. The organic phases are combined, washed with deionized water and then with water containing 1% hydrochloric acid, then again with deionized water.

The organic phase is concentrated under reduced pressure for 2 hours. 105 g of the expected compound are obtained. Step C: α-Methyl-2-thiopheneacetic acid.

A mixture of 105 g of the compound obtained above, 500 cm3 of deionized water 25 and 63.2 g of NaOH is kept under reflux for two hours and thirty minutes. Cool to 20 ° C and add 168 cm3 of methylene chloride. Stir for ten minutes and decant the chloromethylene phase. The same delivery is repeated twice. 168 cm3 of toluene are added to the aqueous phase, then 168 cm3 of 22% hydrochloric acid. Heat under 30 condensers for one hour, cool to 20 ° C, stir for 15 minutes, decant the aqueous phase and wash four times with 42 cm3 of deionized water. The organic phase is concentrated under reduced pressure. 71-74 g of the desired compound are obtained.

35 10 80882

Example 2: Steps A-C can be modified as follows:

Step A1: 2- (1-chloroethyl) thiophene.

Gaseous hydrochloric acid is bubbled for 25 minutes to saturation into a mixture of 84 g of thiophene, 44 g of oaraldehyde and 75 cm3 of 22% hydrochloric acid and maintaining the temperature at 10-13 ° C.

The mixture is poured into 75 cm3 of ice water, decanted, the aqueous phase is extracted with 168 cm3 of methylene chloride and the organic phase is washed three times with 50 cm3 of ice water.

Lie A2: Add gaseous hydrochloric acid at + 10 ° C until a solution of 46 g of ethanol and 44 g of paraldehyde is saturated. This reactant is added over 10 minutes at + 10 [deg.] C. with stirring to 84 cm <3> of thiophene.

15 Then proceed as in A1.

Step A3: Stir at 10-13 ° C a mixture of 84 g of thiophene, 44 g of paraldehyde, 168 cm3 of methylene chloride and 75 cm3 of 22% hydrochloric acid. The solution is saturated with 40 g of gaseous hydrochloric acid, then cooled to 20 ° C. 50 ml of ice are added, the mixture is decanted, the aqueous phase is extracted with 42 cm3 of methylene chloride and the combined organic phases are washed twice with 63 cm3 of ice-cold water. False B1: Triethylbenzylammonium chloride is replaced by the following reagents: - tetrapropylammonium bromide, - tetrabutylammonium bromide, - tetrabutylammonium sulphate, - tetrabutylammonium hydroxide

Step C1: Dichloroethane is replaced with methylene chloride as the extraction solvent.

Claims (6)

11 80882 A process for the preparation of 2-thiopheneacetic acid derivatives of the formula 5 A NS '/ ^ CH-CO9H (I) I z R wherein R is an alkyl group having 1 to 4 carbon atoms, characterized in that the aldehyde of the formula R-CHO in the presence of a hydrohalic acid of the formula H-Hal or a compound of the formula O-Alk R-CH 2 Hal 2 in which Alk is An alkyl group having 1 to 3 carbon atoms and Hal is a halogen atom is reacted with thiophene to give a compound of formula 25-N-CH-Hal (I11 »R 30 wherein Hal is a halogen atom, followed by reaction with a compound of formula (III) with a compound of formula A-CN, wherein A is an alkali metal atom, an alkaline earth metal equivalent or a hydrogen atom, to give a compound of formula 35 12 80882 (CH 2 CN-CH (CN) R 5 and that of formula (IV) The compound of formula (I) is hydrolyzed to give the desired compound of formula (I). Process for the preparation of α-methyl-2-thiopheneacetic acid according to Claim 1, characterized in that thiophene and acetaldehyde are used as starting materials. Process according to Claim 1 or 2, characterized in that the reaction of the compound of the formula A-CN with the compound of the formula (III) is carried out as a phase transfer reaction. Process according to one of Claims 1 to 3, characterized in that the reaction of a compound of formula A-CN with a compound of formula (III) is carried out as a phase transfer reaction in the presence of a catalyst selected from triethylbenzylammonium chloride, tetropropylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium bromide tetrabutyyliammoniumhydrok-dioxide. Process according to one of Claims 1 to 4, characterized in that, in order to carry out the phase transfer reaction, the compound of the formula (III) dissolved in chloromethylene is poured into an aqueous solution of sodium cyanide and a phase transfer catalyst. Process for the preparation of o-methyl-2-thiopheneacetic acid according to one of Claims 1 to 5, characterized in that hydrochloric acid and paraldehyde are reacted with thiophene to obtain 2- (1-chloroethyl) thiophene, which is subjected to a phase transfer reaction. -thio with sodium cyanide in the presence of triethylbenzylammonium chloride 35 to give 1'a-methyl-2-thiopheneaceto- 14 80882