GB1599621A

GB1599621A - Process for preparing thiophene derivatives

Info

Publication number: GB1599621A
Application number: GB9497/78A
Authority: GB
Original assignee: SAGIMA CHEM RES CENTER
Current assignee: SAGIMA CHEM RES CENTER
Priority date: 1977-03-11
Filing date: 1978-03-10
Publication date: 1981-10-07
Also published as: FR2415109A1; FR2415109B3; GB1599623A; NL7802623A; DE2810262A1; GB1599622A

Description

(54) PROCESS FOR PREPARING THIOPHENE DERIVATIVES (71) We, SAGAMI CHEMICAL RESEARCH CENTER, a Japanese body corporate of No. 4-5, Marunouchi, l-chome, Chiyoda-ku, Tokyo, Japan do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates to a process for preparing thiophene derivatives and in more detail, this invention relates to a process for preparing a series of thiophene derivatives, from which 2-thiopheneacetic acid derivatives can easily be prepared, in high yields and selectivity by using substituted or unsubstftuted'2- acetylthiophenes, which are easily available from thiophenes, as the starting materials by easy operations.

The processes for the preparation of a-substituted 2-thiopheneacetic acid derivatives having the general formula

(wherein R' and R2 are independently selected from hydrogen, halogen atoms or lower alkyl groups and R3 is an alkoxy group, hydroxyl group or amino group) heretofore known to the art are: (1) the condensation of a 2-thiophenealdehyde with bromoform in the presence of a base (J. Amer. Chem. Soc., 83, 2755 (1961)), (2) the oxidation of a 2-acetylthiophene with selenium dioxide and then treating with an alkali (Arkiv Kemi., 11, 519 (1957)), (3) the preparation of 2thiophenealdehyde cyanohydrin and then conducting hydrolysis (Japanese Patent Disclosure 8775/73) and (4) the addition of glyoxalic acid on thiophene (Japanese Patent Disclosure 49954/74).

However, the process (1) necessitates the use of expensive bromoform and 2thiophenealdehyde as the raw materials and the yield of the product is low. The process (2) necessitates the use of expensive selenium dioxide and is difficult to adopt as a commercial process. The process (3) requires 2-thiophenealdehyde which is difficultly accessible, commercially and necessitates the use of highly poisonous hydrogen cyanide. Although the process (4) requires a shorter reaction step, yield of the product is low and is thus difficult to adopt as a commercial process.

Further, the process for the preparation of 2-thiopheneglycolic acid by the reduction of 2-thiopheneglyoxylic acid in an alcohol by the use of sodium amalgam was known prior to the invention (F. Ernst, Ber., 19, 3278 (1886)), however, commercial production by the process above is difficult, since none of the synthetic methods gives 2-thiopheneglyoxylic acid in high yield, which is required as the starting material.

It was known that the a-substituted 2-thiopheneacetic acid derivatives themselves can be converted to penicillin derivatives having antibiotic activities by reacting them with penicillanic acid derivatives (Cf. e.g. Netherlands Octrooiaanvrage 6506584), and 2-thiopheneacetic acids which are the compounds obtainable by replacing the substituents located in -position of said a-substituted 2-thiopheneacetic acids with hydrogen are very useful as chemical modifiers of penicillin and cephalosporin (Cf. J. Amer. Chem. Soc., 84, (1962)) and various methods for the preparation of 2-thiopheneacetic acids have heretofore been known (Senda, Yuki Gosei Kagaku Kyokai-shi (J. Synth. Org. Chem. Japan), 34, 779 (1976)). For the preparation of 2-thiopheneacetic acids by reduction of a 2thiopheneglycolic acid, the known process is a method of heating 2thiopheneglycolic acid with hydrogen iodide and phosphorus (F. Ernst, Ber., 19, 3278 (1886)). However, no yield is given in the above literature, and repetition of the experiment by the present inventors according to the literature procedure gave practically 2-thiopheneacetic acid, and therefore, this process can be difficultly adoptable as a commercial process.

The main processes for the preparation of 2-thiopheneacetic acid heretofore known may be classified into three processes described below, according to the starting materials employed: 1) converting 2-chloromethylthiophene to 2-cyanomethylthiophene by treating with an alkali cyanide, and then conducting hydrolysis thereof (M.J.

Soulal, M.C. Woodford, B.P. 1,122,658 (1968)); 2) converting by Willgerodt reaction of 2-acetylthiophene with ammonium polysulfide to 2-thiopheneacetamide and then conducting hydrolysis thereof (Otto Dann. Ger. P. 832755 (1952)); 3) (a) reacting potassium cyanide and an ester of chloroformic acid with 2thiophenealdehyde to form an a-alkoxycarbonyloxy - 2 - thiopheneacetonitrile, and then conducting catalytic hydrogenation thereof to produce 2cyanomethylthiophene, and further conducting hydrolysis thereof Japanese Patent Disclosure No. 46063/77; (b) treating the condensation product of 2-thiophenealdebyde and methyl methylthiomethyl sulfoxide with hydrogen chloride in alcohol to form an ester of 2thiopheneacetic acid and then conducting hydrolysis thereof (Japanese Patent Disclosure 46063/77). However, the process 1) includes difficulties in that 2chloromethylthiophene is difficult to handle because it is unstable, explosive, and is a lachrymatory substance, and also, highly poisonous bis(chloromethyl) ether is formed as by-product during the preparation of this compound. The process 2) possesses its shortcomings in that it requires a high-temperature and high-pressure condition in performing Willgerodt reaction, and requires severe conditions for the hydrolysis. Also, the process 3) (a) has its demerit in that it necessitates the use of highly poisonous cyanide compounds, and requires many reaction stages. The process 3) (b) is disadvantageous in that it needs attention in its handling, and sulfur compounds having strong unpleasant odors are produced.

Similar to the 2-thiopheneacetic acids stated above, 2-thiopheneacetic acid derivatives having acyloxy group at the -position thereof are also known as useful chemical modifiers of penicillin and cephalosporin (Cf. Japanese Patent Disclosure 10095/73). For the preparation of acyloxy derivatives of glycolic acids, acyl halides have been generally used advantageously, but the action of acyl halides on 2thiopheneglycolic acids resulted in the decomposition of the thiophene ring and therefore, said method could not be used as the method for the preparation of a acyloxy - 2 - thiopheneacetic acids.

Accordingly, the object of this invention is to provide processes for preparing a series of thiophene derivatives, from which 2-thiopheneacetic acid derivatives can easily be prepared, in a high yield by using substituted or unsubstituted 2acetylthiophenes, which are readily obtainable from thiophenes, as the starting material by easy operations.

To assist the understanding of this invention, the processes and products of the invention are given in a chemical scheme:

(D) (C) (F) R1 R1 Reduction R1 Rt;CH3 R2 LCH CooR4 R2 gLCH2COOR4 3 0/I I, 4cylatMx, R1(EJ * WAgentmn alkaline R earth 'i3\AcYta,tiĭRuction R}itCHX2 mealhydmxide R2+ ALCHCOOR4 0 In the scheme shown above, R1 and R2 represent independently, hydrogen, a halogen atom, an alkyl group, an aroyl group or an alkanoyl group; R3 represents a hydroxyl group, R4 represents hydrogen or an alkyl group; R5 represents an alkyl group or an aryl group and X represents chlorine, bromine or iodine.

In the scheme shown above, compounds (E) are useful not only as an intermediate of the synthesis of the final product (F) of the processes of this invention but also as an intermediate of the synthesis of thioprofenic acid which is known as an anti-inflammatory agent.

In this invention, the process to prepare compounds (C) via compounds (E) from compounds (D) which can easily be prepared by well known acetylation process from compounds (A), is developed by the inventors through intensive studies to establish a process which overcomes the disadvantages found in the prior art aforementioned and selectively affords only the desired compounds, and it has been discovered that the desired compounds can be prepared in a good yield by using a 2-acetylthiophene derivatives as a starting material which is easily obtainable as an industrial raw material.

Thus, an object of this invention is to provide a process for preparing 2thiopheneglycolic acid derivatives (C) having the general formula

which comprises reacting 2-acetylthiophene derivatives (D) represented by the general formula

with a halogenating agent to obtain 2-dihaloacetylthiophene derivatives (E) having the general formula

and then treating the reaction product thus obtained with an alkali or alkaline earth metal hydroxide and if desired, the reaction product is further esterified in any suitable manner known in the art, e.g. reacting with an alcohol shown by the general formula R"OH (wherein Rr, R2, R4 and X are as aforedescribed).

The compounds (C) thus obtained can easily be converted to compounds (F), i.e. 2-thiopheneacetic acids which are final product of the process of this invention by reduction, and still further, the compounds (C) can be acylated, if desired. The acylated products (G) not only can be converted to compounds (F) by reduction as in the case shown above with a high conversion and selectivity but also can be used per se as chemical modifiers of cephalosporin.

That is, a second object of this invention is to provide a process for reducing the compounds (C) to provide compounds (F and also to provide a process for acylating the compounds (C) to provide compounds (G) and to provide a process to give compounds (F) by reduction of compounds (G).

It should be emphasized that the compounds (E) are useful not only as an intermediate of 2-thiopheneacetic acids but also as an intermediate for the preparation of thioprofenic acid known as an anti-inflammatory agent.

The process of this invention requires reacting a 2-acetylthiophene with a halogenating agent to obtain compounds (E) as an indispensable procedure in the first step.

As examples of the 2-acetylthiophenes represented by the general formula (D) which are used as the starting materials of this step, 2-acetylthiophene, 2acetylthiophenes having a lower alkyl group such as methyl group, ethyl group, npropyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group or tbutyl group, at the 3-, 4- or 5-position, 2-acetylthiophenes substituted by chlorine, bromine or iodine at the 4- or 5-position, 2-acetylthiophenes substituted by a halogen and a lower alkyl group at the 3- and 4-positions, 3- and 5-positions or 4and 5-positions, 5-aroyl-2-acetylthiophenes such as 5-benzoyl-2-acetylthiophene, may be cited. These 2-acetylthiophenes may be prepared readily and in high yield from the corresponding thiophenes by acetylation at the 2-position by the use of acetyl chloride or acetic anhydride in the presence of a Lewis acid or a proton acid.

If desired, they may be prepared by introducing various alkyl groups, halogen atoms and aroyl groups onto 2-acetylthiophene. Also, as examples of the halogenating agent which is the other starting material, chlorine, bromine, sulfuryl chloride, sulfuryl bromide, t-butyl hypochlorite, selenium oxychloride, Nchlorosuccinimide and N-bromosuccinimide, may be cited, but the use of chlorine and bromine is recommended as economical industrial starting materials.

In the practice of this process, use of a solvent is preferred, and many kinds of solvents, e.g. a halogenated hydrocarbon such as carbon tetrachloride, methylene chloride or chloroform, or a polar solvent such as an aliphatic carboxylic acid including acetic acid, propionic acid or butyric acid, may be used. The use of an aliphatic carboxylic acid is particularly preferred in order to minimize the formation of by-products such as the formation of products having a halogenated thiophene ring, monohaloacetylated product and trihaloacetylated product.

The reaction can be performed at a temperature range of from 0 C to the boiling point of the solvent used, but a temperature of from 0 C to 50"C is preferred to avoid the formation of the by-products such as those described above.

The desired 2-(dihaloacetyl)thiophene can be prepared in high yields by performing the present process under the conditions described above.

The 2-(dihaloacetyl)thiophene represented by the general formula (E) thus obtained is then treated with an alkali or an alkaline earth metal hydroxide. As to the hydroxide, the use of sodium hydroxide or potassium hydroxide is preferred from an economical as well as an industrial view-point. It is preferable to use 4 molar equivalents of these hydroxides to compound (E), and generally, the desired compounds can be prepared selectively by the use of 3 to 6 molar equivalents of the hydroxides. In practice, heating is required to initiate the reaction, but heating at around 50"C is sufficient, and the reaction proceeds with evolution of heat. The desired compounds (C) can be prepared in high yields and in a practically pure form by performing this step under the conditions described above.

Further, the a-substituted 2-thiopheneacetic acid derivatives (C) prepared in accordance with the process described above can be readily converted to 2thiopheneacetic acid derivatives (F) by reductive treatment.

One preferred reduction process is catalytically hydrogenating an asubstituted 2-thiopheneacetic acid represented by the general formula

(wherein, R', R2 and-R4 are as defined before and R3 is a hydrogen atom) in the presence of a platinum group metal or a supported platinum group metal catalyst.

It is known that the double bond and the carbon-sulfur bond of a thiophene ring are generally susceptible to reduction, and it gives rise to various products, and that thiophenes poison catalysts. Accordingly, processes for hydrogenation by the use of catalysts which would overcome such difficulties were investigated by the inventors, and it was found that catalysts containing a platinum group metal and a platinum group metal which is supported on a carrier can give good results, and that palladium black and supported palladium are highly active and their use is preferred. As examples of carriers, carbon, calcium carbonate, barium sulfate, barium carbonate and asbestos, may be cited.

In the practice of this process, it is preferred to perform the reaction under a hydrogen atmosphere, by adding a catalyst to the a-substituted 2-thiopheneacetic acid per se or to its solution. Alcohols such as methanol and ethanol can be used as the solvent. This reaction may be performed at a temperature ranging from room temperature to 1500C, but a temperature between 50 and 80"C is preferably in view of the reaction rate and selectivity. The reaction can be conducted under a high pressure, but an atmospheric pressure is desirable to avoid the leakage of hydrogen from the reaction vessel. It is sufficient to use 0.110% by weight of a palladium catalyst with respect to the acids, but use of 13% by weight is preferred.

Aside from the catalytic reduction process described above, after the extensive studies, the inventors have found a process which allows a selective cleavage of only the oxygen-carbon linkage of a-position of a-substituted 2thiopheneacetic acids (C') without decomposing the thiophene ring, by reducing asubstituted 2-thiopheneacetic acids by the use of red phosphorus and iodine.

In the practice of this process, it is preferable to dissolve an -substituted 2thiopheneacetic acid in a solvent and to treat it with a mixture of red phosphorus and iodine which had been previously mixed in a solvent. Acetone, methanol or an organic acid, which dissolve the a-substituted 2-thiopheneacetic acid of the starting material and do not participate directly with the reduction reaction may be used as the solvent, but the use of an organic acid is preferred in view of the solubility, reaction rate and yield, and the use of acetic acid is advantageous because of its ready availability. The reaction may be performed by addition of a strong acid such as phosphoric acid and sulfuric acid to the reaction system. In this reaction, the amount of phosphorus used is from 0.1 molar equivalent to a slight excess based on the cr-substituted 2-thiopheneacetic acid, and the iodine is used only in a catalytic amount. The present reaction may be performed at a temperature range of from room temperature to 1500C, but it is desirable to perform the reaction by heating in view of the reaction rate.

Incidentally, to obtain compounds (G), 2-thiopheneglycolic acids obtained by aforementioned process are acylated with the use of a carboxylic acid anhydride which is readily available.

In the practice of the acylation process, it is sufficient to merely mix a 2thiopheneglycolic acid with a carboxylic acid anhydride, and when the carboxylic acid anhydride is a liquid, a solvent is not required, and an excess amount of the anhydride per se may be used to act also as the solvent. When the carboxylic acid anhydride is a solid, it is preferable to use a solvent, and a saturated hydrocarbon such as hexane, or pentane, an aromatic hydrocarbon such as benzene or toluene, a halogenated hydrocarbon such as carbon tetrachloride, chloroform or methylene chloride, a cyclic or acyclic ether such as tetrahydrofuran or ethyl ether, as well as other aprotic solvents which do not affect directly in the reaction, can be used as the solvent. The present reaction can be performed at a temperature within the range of from room temperature to 150"C, but the reaction under heating is desirable to accelerate the reaction.

The acylated compounds can readily be converted to compounds (F) by reducing them in a manner described before, and the acylated compounds per se are also useful as chemical modifier of cephalosporin.

In the following, the invention will be explained in more detailed and material fashion by illustration of Examples, however, please note that these Examples are given only for the purpose of illustration and are not to be construed as limiting this invention thereto. Incidentally, in this specification, the abbreviations of "sh" and "br" are used to show "shoulder" and "broad", respectively, and the other abbreviations are used in the conventional manner. As the internal standard used in NMR measurement, tetramethylsilan was used in every cases and the values were shown by , in ppm.

Example 1 2-Acetylthiophene (6.31 g, 50.0 mmol) was dissolved in glacial acetic acid (25 ml) and chlorine gas was introduced to the reaction system under water cooling.

The cooling water was so adjusted that the temperature of the reaction system was kept below 28"C. After passing chlorine for ca. 2 hr., the reaction was completed and the reaction solution showed a pale yellow coloration. At this point, the introduction of chlorine was stopped, the reaction solution was poured onto 150 ml of crushed ice, and was extracted with diethylether. The ether layer was washed with cold water and dried with sodium sulfate. Removal of the ether under a reduced pressure gave 9.8 g of 2-(dichloroacetyl)thiophene as an oily substance.

The value 9.8 g is the quantitative yield.

bp: 79--82"C/0.15 mmHg NMR (CCl4): 6.24 (s, 1H), 7.13 (dd, J=5.2 Hz, J=3.9 Hz, 1H), 7.73 (dd, J=5.2 Hz, J=1.0 Hz, 1H) and 7.97 (dd, J=3.9 Hz, J=1.0 Hz, 1H).

IR (liquid film, KBrplate): 3090, 1692, 1682 (sh), 1675 (sh), 1515, 1413, 805,727 and 716 (cam~').

MS (70 eV) (m/e): 196 (below 1%), 194 (below 1%), 111 (100%) and 83 (10?).

Example 2 The reaction was performed in the same manner as in Example 1 except that the reaction was carried out at room temperature by the use of carbon tetrachloride as the solvent instead of acetic acid, giving 3.7 g of 2 (dichloroacetyl)thiophene (yield: 39%).

Example 3 The reaction was conducted in the same manner as in Example 1 except that the reaction was carried out at 470C using carbon tetrachloride as the solvent instead of acetic acid, giving 4.0 g of 2-(dichloroacetyl)thiophene (yield: 41No)* Example 4 To an aqueous solution of 10.0 g (250 mmol) of sodium hydroxide kept at 50"C; 9.8 g (50 mmol) of 2-(dichloroacetyl)thiophene was added dropwise with vigorous stirring. The temperature of the reaction mixture rose to 550C by the heat of the reaction, and the rate of the addition was so adjusted that the temperature did not rise above the temperature. The addition of 2-(dichloroacetyl)thiophene described above required ca. 2 hr., and after the addition, stirring was continued for another 1 hr. at the same temperature. The reaction mixture was cooled to room temperature, washed with diethylether to remove neutral substances, and then made acidic (pH ca. 1) by addition of 12N hydrochloric acid to the aqueous solution under ice cooling. The aqueous solution was extracted three times with diethylether (100 ml), and the ether layer was washed with a saturated aqueous solution of sodium chloride, and then dried with sodium sulfate. Removal of the extraction solvent under a reduced pressure gave 7.9 g of 2-thiopheneglycolic acid.

The value 7.9 g is the quantitative yield.

mp: 750C (recrystallization from benzene) NMR (CDCl3): 5.42 (s, 1H), 6.7-7.4 (m, 3H) and 8.17 (br. s, 2H).

IR (KBr disc): 3380, 3500-2500 (broad), 1725, 1528, 1430, 1278, 1050 and 703 (cm-').

MS (70 eV) (m/e): 158 (4.1%) (M+), 156(4.6%), 113 (37.3%), 111 (100 o) and 97 (77.9%).

Example 5 The reaction was performed in the same manner as in Example 4 except that a solution of 8.0 g (200 mmol) of sodium hydroxide in 90 ml of water was used and 14.2 g (50 mmol) of 2-(dibromoacetyl)thiophene was used, gave 5.6 g of 2thiopheneglycolic acid (yield: 770d).

Example 6 Chlorine was bubbled through a solution of 6.31 g (50 mmol) of 2acetylthiophene in glacial acetic acid (25 ml). The reaction solution which evolved heat was cooled with water and kept below 28"C. The reaction was discontinued at the stage when the reaction solution turned slight yellow by the excess chlorine, and then acetic acid was distilled off at room temperature under a reduced pressure to give crude 2-(dichloroacetyl)thiophene. This crude product was added in dropwise with vigorous stirring to a solution of 10.0 g (250 mmol) of sodium hydroxide in water (90 ml) which was kept at 500 C. The temperature of the reaction solution rose to ca. 550C. The addition was completed after ca. 2 hr., and the mixture was stirred for another 1 hr. at the same temperature. After cooling to room temperature, the reaction mixture was washed with diethylether, then acidified (pH 1) by addition of 12N hydrochloric acid under ice cooling. The acidic material which separated out was extracted with diethylether, and the ether layer was washed with a saturated aqueous solution of sodium chloride, and after drying with sodium sulfate, the solvent was distilled off to give 2-thiopheneglycolic acid in quantitative yield (7.9 g).

Example 7 To a solution of 6.30 g (50 mmol) of 2-acetylthiophene in carbon disulfide (40 ml), 16.0 g (100 mmol) of bromine was added in dropwise under ice cooling. Carbon disulfide was then distilled off under a reduced pressure at room temperature to give crude 2-(di-bromoacetyl)thiophene. This crude product was treated with an aqueous alkaline solution in the same manner as in Example 6 to give 2thiopheneglycolic acid in 63% yield (5.0 g).

Example 8 A mixture of 421 mg of 2-thiopheneglycolic acid and 40 mg of 30% palladiumasbestos catalyst in 2.7 ml of methanol was heated under reflux with stirring under a hydrogen atmosphere at a normal pressure. After 15 hr., the catalyst was filtered off and methanol was then distilled off under a reduced pressure to give 127 mg of 2-thiopheneacetic acid and 283 mg of unreacted 2-thiopheneglycolic acid. The conversion of 2-thiopheneglycolic acid was 33% and the selectivity to 2thiopheneacetic acid was 100%.

NMR (CDCl3): 3.91 (s, 2H), 7.30 (d, J=3 Hz, 2H), 7.31 (t, J=3 Hz, 1H), and 11.12 (s, lH).

Example 9 2-Thiopheneglycolic acid (2.06 g, 13 mmol) was dissolved in 2.65 g (26 mmol) of acetic anhydride, and the solution was heated at 500C for 15 hr. Acetic anhydride and acetic acid were removed by distillation in vacuo, and from the residue, 2.27 g of a - acetoxy - 2 - thiopheneacetic acid was obtained (yield: 87%).

NMR (CDCl3): 2.17 (s, 3H), 6.22 (s, 1H), 7.03 (t, J=4 Hz, 1H), 7.23 (d, J=4 Hz, 1H), 7.37 (d, J=4 Hz, iH) and 11.68 (s, 1H).

Example 10 A mixture of 1.51 g of a - acetoxy - 2 - thiopheneacetic acid and 0.40 g of 30% palladium-asbestos catalyst in 8.0 ml of methanol was stirred and heated under reflux under a hydrogen atmosphere at a normal pressure. After 75 hr., the catalyst was filtered off and methanol was then distilled off under a reduced pressure to give 1.165 g of 2-thiopheneacetic acid, conversion: 66%, selectivity: 83%.

Example 11 Red phosphorus (372 mg) and 141 mg of iodine were added to 5.0 ml of acetic acid and the mixture was stirred for 20 min. at room temperature. A solution of 2thiopheneglycolic acid (1565 mg) in 1.0 ml of acetic acid was then added to the mixture and the resulting mixture was heated under reflux for 2 hr. After cooling to room temperature, the insoluble precipitate was filtered off, and acetic acid was then distilled off under a reduced pressure. The residue was dissolved in diethylether and the ether layer was washed with saturated aqueous solution of sodium chloride, and dried with anhydrous magnesium sulfate. The ether was distilled off to give 1258 mg of 2-thiopheneacetic acid (yield: 890o).

Example 12 Red phosphorus (100 mg) and 40 mg of iodine were added to 1.5 ml of acetic acid and the mixture was stirred for 20 min. at room temperature. A solution of 564 mg of a - acetoxy - 2 - thiopheneacetic acid in 1.5 ml of acetic acid was then added to the mixture, and the resulting mixture was heated under reflux for 2 hr.

After cooling to room temperature, the insoluble precipitate was filtered off and acetic acid was then distilled off under a reduced pressure. The residue was dissolved in diethylether, and the ether layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate, and the ether was then distilled off to give 400 mg of 2-thiopheneacetic acid.

Yield: 100% Comparative Example 1 Red phosphorus (186 mg) and 632 mg of 2-thiopheneglycolic acid were added to 4.0 ml of hydroiodic acid (sp. gr., 1.7) and the resulting mixture was heated under reflux for 2 hr. After cooling to room temperature. insoluble material was separated by filtration. The insoluble material was washed with diethylether and the ether washings were combined to the aqueous filtrate, and the mixture was extracted by further addition of diethylether. The ether layer was washed successively with a saturated aqueous solution of sodium chloride in which a small amount of sodium thiosulfate had been added, and with a saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate, and then the ether was distilled off to leave 283 mg of oily material. The NMR spectrum of this material showed strong absorption between 1--3 ppm and showed practically no absorption assigned to a thiophene ring.

WHAT WE CLAIM IS: 1. A process for the preparation of 2-thiopheneglycolic acids represented by the general formula:

which comprises reacting a 2-acetylthiophene represented by the general formula:

with a halogenating agent to obtain a 2-(dihaloacetyl)thiophene represented by the general formula:

and then treating a 2-(dihaloacetyl)thiophene thus obtained with an alkali or an alkaline earth met

Claims

**WARNING** start of CLMS field may overlap end of DESC **. diethylether and the ether layer was washed with saturated aqueous solution of sodium chloride, and dried with anhydrous magnesium sulfate. The ether was distilled off to give 1258 mg of 2-thiopheneacetic acid (yield: 890o). Example 12 Red phosphorus (100 mg) and 40 mg of iodine were added to 1.5 ml of acetic acid and the mixture was stirred for 20 min. at room temperature. A solution of 564 mg of a - acetoxy - 2 - thiopheneacetic acid in 1.5 ml of acetic acid was then added to the mixture, and the resulting mixture was heated under reflux for 2 hr. After cooling to room temperature, the insoluble precipitate was filtered off and acetic acid was then distilled off under a reduced pressure. The residue was dissolved in diethylether, and the ether layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate, and the ether was then distilled off to give 400 mg of 2-thiopheneacetic acid. Yield: 100% Comparative Example 1 Red phosphorus (186 mg) and 632 mg of 2-thiopheneglycolic acid were added to 4.0 ml of hydroiodic acid (sp. gr., 1.7) and the resulting mixture was heated under reflux for 2 hr. After cooling to room temperature. insoluble material was separated by filtration. The insoluble material was washed with diethylether and the ether washings were combined to the aqueous filtrate, and the mixture was extracted by further addition of diethylether. The ether layer was washed successively with a saturated aqueous solution of sodium chloride in which a small amount of sodium thiosulfate had been added, and with a saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate, and then the ether was distilled off to leave 283 mg of oily material. The NMR spectrum of this material showed strong absorption between 1--3 ppm and showed practically no absorption assigned to a thiophene ring. WHAT WE CLAIM IS:

1. A process for the preparation of 2-thiopheneglycolic acids represented by the general formula:

and then treating a 2-(dihaloacetyl)thiophene thus obtained with an alkali or an alkaline earth metal hydroxide, and if desired, the product is further esterified by reacting with an aliphatic alcohol (wherein R1 and R2 represent, independently, hydrogen, halogen, an alkyl group, an aroyl group or an alkanoyl group; R4 represents hydrogen or an alkyl group; and X represents chlorine, bromine or iodine).

2. A process as claimed in claim 1 in which an aliphatic carboxylic acid is used

as the solvent in the halogenation step.

3. A process for the preparation of or - acyloxy - 2 - thiopheneacetic acids represented by the general formula:

which comprises reacting a 2-thiopheneglycolic acid prepared by the process of claim 1 or 2 represented by the general formula:

with a carboxylic acid anhydride represented by the general formula: (R5CO)2O (wherein R' and R2 represents, independently, hydrogen, halogen, an alkyl group, an aroyl group or an alkanoyl group; R4 represents hydrogen or an alkyl group; and R5 represents an alkyl group or an aryl group).

4. A process for the preparation of 2-thiopheneacetic acids represented by the general formula:

which comprises hydrogenating an < z-substituted 2-thiopheneacetic acid prepared by the process of anyone of Claims 1, 2 and 3 represented by the general formula:

in which hydrogenation is conducted catalytically in the presence of a platinum group metal catalyst having or not having a carrier (wherein R' and R2 represent, independently, hydrogen, a halogen, an alkyl group, an aroyl group or an alkanoyl group: R3' represents a hydroxyl group, an alkanoyloxy group or an aroyloxy group; and R4 represents hydrogen or an alkyl group).

5. A process as claimed in Claim 4 in which the catalyst is palladium black having or not having a carrier.

6. A process for the preparation of 2-thiopheneacetic acids represented by the general formula:

which comprises hydrogenating an a-substituted 2-thiopheneacetic acid prepared by the process of anyone of Claims 1, 2 and 3 represented by the general formula:

in which hydrogenation is conducted by the use of red phosphorus and iodine (wherein R' and R2 represent, independently, hydrogen, a halogen, an alkyl group.

an aroyl group or an alkanoyl group; R3 represents a hydroxyl group, an alkanoyloxy group or an aroyloxy group: and R4 represents hydrogen or an alkyl group).

7. Processes as claimed in any one of claims 1, 3 4 or 6 and substantially as hereinbefore described with reference to the Examples.

8 A process as claimed in claim I in which R4 is hydrogen and R1 and R2 represent, independently, hydrogen, halogen, an alkyl group or an aroyl group.

9. A process as claimed in claim 3 in which R' is hydrogen, halogen or lower alkyl and R2 is hydrogen, alkyl or alkanoyl.