GB1599622A - Processes for preparing thiophene derivatives - Google Patents

Description

PATENT SPECIFICATION ( 11) 1 599 622

C Kt ( 21) Application No 32164/79 ( 22) Filed 10 March 1978 ( 62) Divided out of No1599621 ( 9 ( 31) Convention Application No 52/026049 ( 32) Filed 11 March 1977 ( 9 ( 31) Convention Application No 52/026050 ( 32) Filed 11 March 1977 ( 31) Convention Application No 52/056426 ( 32) Filed 18 May 1977 ( 31) Convention Application No 52/056427 ( 32) Filed 18 May 1977 ( 31) Convention Application No 52/061059 ( 32) Filed 27 May 1977 ( 31) Convention Application No 52/146105 ( 32) Filed 7 Dec 1977 ( 31) Convention Application No 52/146106 ( 32) Filed 7 Dec 1977 in ( 33) Japan (JP) ( 44) Complete Specification published 7 Oct 1981 ( 51) INT CL 3 C 07 D 333/04 ( 52) Index at acceptance C 2 C 1510 200 215 220 22 Y 246 247 254 25 Y 30 Y 313 31 Y 337 339 360 362 364 366 367 368 36 Y 373 37 X 37 Y 43 X 462 464 465 47 X 490 491 500 509 50 Y 552 612 613 623 624 628 638 652 658 65 X 771 776 777 AB BL QT QU WL ZN ( 54) PROCESSES FOR PREPARING THIOPHENE DERIVATIVES ( 71) We, SAGAMI CHEMICAL RESEARCH CENTER, a Japanese Body Corporate of No 4-5, Marunouchi, 1-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: 5

The present invention relates to processes for preparing thiophene derivatives and in more detail, this invention relates to processes for preparing a series of thiophene derivatives, from which optionally substituted 2thiopheneacetic acid or esters thereof can easily be prepared, in high yields and selectivity by using substituted or unsubstituted thiophenes as the starting materials by easy 10 operations.

Prior to the invention, it was known that the compounds represented by the generic formula fi JCHCX 3 (I) OH (wherein R' and R 2 are independently selected from hydrogen or halogen atoms or 15 lower alkyl groups and X is chlorine or bromine) can be, for example, converted to useful insecticides structurally analogous to DDT by condensation with other aromatic compounds (e g, H D Hartough, "The Chemistry of Heterocyclic Compounds" Thiophene and its Derivatives, Interscience Publishers, Inc, New York, 1952, p 189), and the carboxylates of the compounds with the general 20 formula (I) themselves are reported to show insecticidal activities (R C Blinn et al., J Amer Chem Soc, 76, 37 ( 1954)).

The process for the preparation of a trihalomethyl 2 thiophenemethanols heretofore known to the art comprises the preparation of the Grignard reagent from a 2-bromothiophene and magnesium and then reacting the 25 said reagent with trichloroacetaldehyde to give an a trihalomethyl 2thiophenemethanol (J Amer Chem Soc, 71, 2859 ( 1949)) However, this process cannot be adopted commercially because of the difficulty in the selective synthesis of the starting material, i e 2-bromothiophene, and because the process disadvantageously requires anhydrous conditions and necessitates the use of 5 flammable ethers as the reaction medium when preparing the Grignard reagent.

Also, processes for the preparation of a-substituted 2-thiopheneacetic acid derivatives having the general formula RI Rj LHCOOH (II) R 3 (wherein R' and R 2 are independently selected from hydrogen or halogen atoms or 10 lower alkyl groups and R 3 is an alkoxyl group, hydroxyl group or amino group) heretofore known to the art are: (I) the condensation of a 2thiophenealdehyde 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 2 15 thiophenealdehyde 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 (I) necessitates the use of expensive bromoform and 2thiophenealdehyde as the raw materials and the yield of the product is low The 20 process ( 2) necessitates the use of expensive selenium dioxide and is difficult to adopt as a commercial process The process ( 3) requires 2thiophenealdehyde 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 25 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 30 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 35 Octrooiaanvrage 6506584), and 2-thiopheneacetic acids which are the compounds obtainable by replacing the substituent located in a-position of said asubstituted 2-thiopheneacetic acids with hydrogen are very usefyl as chemical modifiers of penicillin and cephalosporin (Cf J Amer Chem Soc, 84, 3401 ( 1962)) and various methods for the preparation of 2-thiopheneacetic acids have heretofore been 40 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 45 the experiment by the present inventors according to the literature procedure gave practically no 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 50 starting materials employed: 1) converting 2-chloromethylthiophene to 2cyanomethylthiophene first 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 at first and then conducting hydrolysis 55 thereof (Otto Dann, Ger P 832755 ( 1952)); 3) (a) reacting potassium cyanide and an ester of chloroformic acid with 2-thiophenealdehyde to form an aalkoxycarbonyloxy 2 thiopheneacetonitrile, and then conducting catalytic hydrogenation thereof to produce 2-cyanomethylthiophene, and further conducting hydrolysis thereof (Japanese Patent Disclosure No 46063/77); (b) 60 treating the condensation product of 2-thiophenealdehyde and methyl 1,599,622 3 1599,622 3 methylthiomethyl sulfoxide with hydrogen chloride in alcohol to form an ester of 2-thiopheneacetic 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 5 formed as by-product during the preparation of this compound The process 2) possesses its shortcomings in that it requires high-temperature and highpressure conditions 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 10 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 an acyloxy group at the a-position thereof are also known as useful chemical modifiers of penicillin and cephalosporin (Cf Japanese Patent 15 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 2-thiopheneglycolic 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 20 Accordingly, the object of this invention is to provide processes for preparing a series of thiophene derivatives, from which optionally substituted 2thiopheneacetic acid or esters thereof can easily be prepared, in a high yield by using substituted or unsubstituted thiophenes as the starting material by easy operations 25 To assist the understanding of this invention, the processes of the invention are given in a chemical scheme:

(A) (B) (H) r T Acidic Condition R Am Reduction 2 1 Trihaclocetaldehyde2 1417 IL H Cl R S v R-v s SJCR X 3 RZ CH=%X OH In the presene of an alkali Under basic or alkaline earth metal hydroxide, condition.

R 3 H X R 40 H (C) (F) RI 4 Reduction RI -UC 2 OR R 2 4 IK) H-r-COOR 4 R 2: 2 COOR 4 \Acytation Rduction (G) In the scheme shown above, R' and R 2 represent independently, hydrogen, halogen, alkyl, aroyl or alkanoyl; R 3 represents alkoxy, hydroxyl, amino, alkylthio 30 or arylthio: R 4 represents hydrogen or alkyl; R 5 represents alkyl or aryl and X represents chlorine, bromine or iodine.

In the scheme shown above, compounds (C) are novel compounds when R 3 is an arylthio group and the compounds are useful as an intermediate of the synthesis of the final product (F) of the processes of this invention, i e 2thiopheneacetic 35 acid derivatives Compounds (H) are novel compounds, too, and are easily convertible to the final product (F) of the processes of this invention.

In this invention, the process to prepare compounds (C) via compounds (B) from compounds (A) is developed by the inventors through intensive studies toward establishing a process which overcomes the disadvantages found in the 40 prior art aforementioned and selectively affords only the desired compounds The desired compounds can be prepared in a good yield by treating under an acidic condition, a substituted or unsubstituted thiophene with a trihaloacetaldehyde both of which are easily obtainable as industrial raw materials.

Thus, the first object of this invention is to provide a process for preparing 2 45 thiopheneacetic acid derivatives (C) represented by the general formula I 1,599622 R 2,57 L OOR 4 (C) S 1 R 3 which comprises reacting a thiophene derivative (A) having the general formula R'< R 2 EJ (A) with a trihaloacetaldehyde represented by the general formula CX 3 CHO under acidic conditions to obtain an a trihalomethyl 2 thiophenemethanol (B) 5 having the general formula R' R 47 f) ch CX 3 (B) OH it being preferred to establish the acidic condition by the use of a Lewis acid, and then further reacting the reaction product thus obtained with a compound having the general formula R 3 H in the presence of an alkali or alkaline earth metal 10 hydroxide and if desired, the reaction product is further esterified in any suitable manner known in the art, such as reacting with an alcohol having the general formula R 40 H (wherein R', R 2, R 3, R 4 and X are as defined before) Hereinafter called Process (I).

The compounds (C) thus obtained by the Process (I) can easily be converted 15 to compounds (F), i e 2-thiopheneacetic acids which are final product of the processes 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 20 Thus, the 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).

The third object of this invention is to provide a process for preparing 25 compounds (F) which are the final products of the processes of this invention, via compounds (B) and novel compounds (H) from compounds (A), that is, a process for preparing compounds (F) having the general formula RI j CH COOR 4 (F) by reacting a substituting or unsubstituted thiophene (A) having the general 30 formula R' R 2: J (A) Is with a trihaloacetaldehyde represented by the general formula CX 3 CHO under acidic conditions to obtain an a trihalomethyl 2 thiophenemethanol (B) having the general formula 35 RZ 4 HCXX 3 (B) OH and then treating the reaction product thus obtained with a reducing agent to obtain 2 ( 2,2 dihalovinyl)thiophenes (H) represented by the general formula RI R _CH=GX (H) 1,599,622 and then, further reacting 2 ( 2,2 dihalovinyl)thiophenes thus prepared with a compound having the general formula R 40 H under basic conditions to effect hydrolysis or alcoholysis of compounds (H), and optionally further subjecting the reaction mixture to acidic conditions (wherein RI, R 2, R 4 and X are as defined before) This process, hereinafter called Process (II), differs from the 5 aforementioned Process (I), since in the route of this process, preparation of compounds (C) is not required Contrary to the above, in the aforementioned Process ( 1), preparation of compounds (C) is indispensable as an intermediate.

Compound (H) and its preparation by reduction of an a trihalomethyl 2 thiophenemethanol are described and claimed in our copending Patent 10 Application 8014644 (Serial No 1,599,623).

As examples of the starting materials of the present invention represented by the general formula R 2 X 3 (A) (wherein R' and R 2 are as defined before), thiophene, 2-chlorothiophene, 2 15 bromothiophene, 2,3-dichlorothiophene, 2-methylthiophene, 2ethylthiophene, 2methyl-3-chlorothiophene and 2-chloro-3-methylthiophene may be cited As examples of the other starting compound represented by the general formula CX 3 CHO (wherein X is as aforementioned), trichloroacetaldehyde and tribromoacetaldehyde may be cited 20 Process (I) of the present invention requires treatment of the two starting materials described above under acidic conditions, and the acidic conditions can, preferably, be established by the presence of an inorganic acid such as sulfuric acid and phosphoric acid, an ion-exchange resin in which such acid is supported on a polymer substance, or a Lewis acid such as titanium tetrachloride, stannic 25 tetrachloride, boron trifluoride, iron chloride and aluminium chloride The use of a Lewis acid is particularly preferred It is usually sufficient to use an equimolar amount of such acidic substance, but in the reaction of this kind in general, the reaction may proceed beyond the desired stage in some cases to afford 1,1dithienylethanes as by-products It is preferable to conduct the reaction in the 30 presence also of titanium tetrachloride and/or a titanium alkoxide in order to reduce the formation of such by-products to a minimum, and usual solvents for Friedel-Crafts reactions, namely an aliphatic hydrocarbon such as hexane and heptane, a halogenated hydrocarbon such as methylene chloride and trichloroethane, and carbon disulfide, and, if desired, ethers may be used as the 35 solvent without disadvantage Usually, the reaction proceeds at room temperature, but if desired, the reaction may be accelerated by heating.

As described above, 1,1-dithienylethanes may be formed as by-products in some cases, and to avoid the formation of such by-products, reaction solvents may be used, or the formation of the by-products may be reduced by adopting a 40 procedure which allows only the starting materials to recycle and come into contact with the catalyst by utilizing the boiling point difference between the starting materials and the products.

Under such conditions as described above, a trihalomethyl 2 thiophenemethanols (B) above can be formed in high yields The compounds, after 45 isolation or without isolation, can be used for the treatment of the next step.

The second step comprises the reaction of an a trihalomethyl 2 thiophenemethanol (B) above with a compound represented by the general formula R 3 H As examples of compounds R 3 H, water, an alcohol such as methanol, ethanol, isopropanol, and butanol, a thiol such as methyl mercaptan, 50 ethyl mercaptan, isopropyl mercaptan, thiophenol, and tolyl mercaptan, and an amine such as ammonia, methylamine, ethylamine, isopropylamine, dimethylamine and diethylamine may be cited.

The second step requires as the indispensable condition, the use of an alkali or an alkaline earth metal hydroxide as the condensation reagent, and the use of 55 sodium hydroxide or potassium hydroxide is preferred from an economical view It is preferable to use at least 3 molar equivalents of these bases to compounds (B), and the desired compounds (C) can generally be prepared selectively by the use of 3 to 4 molar equivalent amounts of a base It is preferable to use solvents in conducting the reaction, and when the compound represented by the general 60 formula R 3 H is an alcohol, for example, an excess alcohol may be used as the 1,599,622 solvent When a thiol or an amine is used as the compound represented by R 3 H, an alcohol may be used as the solvent, and in this case, thiol or amine react preferentially because of the difference in the reaction rates As in the case of the first step, the reaction of this step proceeds even at room temperature, but it is preferred to operate the reaction at the reflux temperature of the solvent used in 5 order to accelerate the reaction and to selectively obtain only the desired compounds.

Further, the a substituted 2-thiopheneacetic acid derivatives (C) prepared in accordance with Process (I) described above can be readily converted to 2thiopheneacetic acid derivatives (F) by reductive treatment 10 With regard to the reductive treatment, it is preferable to perform the reduction by the following methods depending upon the kind of the R 3 substituent of the general formula (C) Thus, when R 3 is an alkoxyl group, a nickeltype catalyst such as Raney-nickel, a palladium-type catalyst such as palladiumcharcoal, or a platinum catalyst may be used These catalysts are commonly used 15 for catalytic hydrogenation reactions of benzyl ethers Water, acetone, a hydrocarbon solvent or an ether solvent may be exemplified as the solvent The reaction can be performed at room temperature and under atmospheric pressure.

In order to improve the selectivity of the reaction, a mineral acid such as hydrochloric acid and sulfuric acid, or a mineral or an organic base such as sodium 20 or potassium hydroxide, sodium or potassium acetate, triethylamine or pyridine may be added Besides the catalytic hydrogenation described above, the reduction treatment by the use of hydrogen halide, and particularly hydrogen iodide, red phosphorus and hydrogen iodide (or iodine), or red phosphorus and hydrochloric acid may be used as the general reductive procedure The reaction is performed, 25 preferably, in a water-acetic acid system, but any other solvents such as acetone, hydrocarbon solvents and ether solvents which do not directly affect the reaction may be used additionally, and the reaction is generally completed by heating under reflux.

When R 3 is a hydroxyl group, the reduction method by the use of stannous 30 chloride and hydrochloric acid, and the catalytic hydrogenation method by the use of copper-chromium oxide or molybdenium sulfide may be exemplified as the general reduction method, in addition to the catalytic hydrogenation method and the reduction method by the use of a hydrogen halide as exemplified above in the case of the alkoxyl group derivatives 35 In the above, the use of platinum group metal catalysts or red phosphorusiodine is particularly preferred as shown in detail hereinafter.

When R 3 is an alkylthio group or an arylthio group, usual methods of reductive desulfurization of a-thiocarboxylic acids can be used Namely, the method using a combination of zinc and an acid such as acetic acid, hydrochloric 40 acid, or sulfuric acid, or using aluminium amalgam or zinc amalgam or using a nickel-type catalyst such as Raney-nickel, can be utilized.

When R 3 is an amino group, the method employing a nickel-type catalyst such as Raney-nickel or a palladium-type catalyst such as palladium-charcoal may be exemplified 45 In the following, some of the typical examples of the aforementioned reduction processes are described in more detailed and material fashion.

One of the preferred reduction process is catalytically hydrogenating an asubstituted 2-thiopheneacetic acid represented by the general formula RI< 77 O? 11 4 (C') 50 (wherein R', R 2 and R 4 are as defined before and R 3 ' is hydroxyl group, an alkoxyl group, an alkanoyloxy group, or an aroyloxy group) 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, 55 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 60 -6 1,599,622 7 1,599,6227 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 2thiopheneacetic acid per se or to its solution Alcohols such as methanol and ethanol can be used as 5 the solvent This reaction may be performed at a temperature ranging from room temperature to 150 'C, but a temperature between 50 and 80 MC is preferable 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 1-10 % by weight of a 10 palladium catalyst with respect to the acids, but use of 1-3 % 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 15 acids (C') without decomposing the thiophene ring, by reducing asubstituted 2thiopheneacetic acids by the use of red phosphorus and iodine.

In the practice of this process, it is preferable to dissolve an asubstituted 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 20 organic acid, which dissolve the a-substituted 2-thiopheneacetic acid 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 25 such as phosphoric acid and sulfuric acid to the reaction system In this reaction, the amount of phosphorous used is from 0 1 molar equivalent to a slight excess based on the a-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 150 'C, but it is desirable to perform the reaction by 30 heating in view of the reaction rate.

Incidentally, to obtain compounds (G), 2-thiopheneglycolic acids obtained by aforementioned Process (I) 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 2 35 thiopheneglycolic 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 40 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 directly affect 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 45 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 modifiers of cephalosporin.

The other process which can afford 2-thiopheneacetic acid derivatives 50 (Process (II)) is branched from the route of Process (I) from intermediate compounds (B), i e a trihalomethyl 2 thiophenemethanol derivatives In this process, novel compounds (H) can be prepared in the course of the reactions.

This process requires treating an a trihalomethyl 2 thiophenemethanol derivative represented by the general formula: 55 R 7-C Hcx 3 (B' OH (wherein RI, R 2 and X are as defined before) with a reducing agent The compounds of the general formula (B') above, used as starting materials, can be readily prepared by the condensation of a trihaloacetaldehyde such as chloral with thiophene 60 1,599,622 8 1,599,622 8 As examples of the reducing agents employed in the present process, zinc or a zinc-copper alloy and acetic acid, hydrochloric acid, or acetic acidhydrochloric acid, a metal such as sodium, magnesium or aluminum, or an amalgam thereof, a metal salt in its lower oxidation stage such as chromium (II) salt, and zinc (II) chloride-phosphorous oxychloride-pyridine system, an alkali metal salt such as 5 sodium iodide or potassium iodide, and an organometallic compound such as butyllithium and phenyllithium, which are common reducing reagents for the preparation of olefins from halohydrin derivatives, may be cited, and the use of zinc-acetic acid is preferred for a ready and smooth operation.

In the practice of the reaction, the use of a solvent is not always required, 10 but, if desired, an ether such as ether or tetrahydrofuran, a hydrocarbon such as benzene, toluene or hexane, or an alcohol such as methanol or ethanol, or acetic acid which is used as one of the reduction agent, may be used as the solvent too without disadvantage The reaction proceeds smoothly at a temperature from room temperature to the refluxing temperature of the solvent used 15 To prepare 2-thiopheneacetic acids (F) by this process, it is necessary to conduct hydrolysis or alcoholysis of a 2 ( 2,2 dihalovinyl)thiophene (H) under basic conditions The establishment of basic conditions may be realized, by allowing an alkali metal salt such as sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide, or an alkali metal alkoxide such as 20 sodium methoxide, sodium ethoxide or potassium methoxide, to co-exist in water or alcohol The reaction proceeds smoothly at a temperature range of from room temperature to the boiling point of water or an alcohol At this stage, a compound represented by the general formula:

4 j O Rctc and/or R,2 T OR' 25 S OR' S = OO R (wherein R' is a hydrogen atom or an alcohol residue, and RW, R' and X are asdefined before) is formed, in which at least one of the halogen atoms of the dihalovinyl group underwent hydrolysis or alcoholysis It is preferred to subject this reaction mixture to acidic conditions This step can be accelerated by direct addition of an acidic substance to the reaction system As examples of the acidic 30 substance employed, an inorganic acid such as hydrochloric acid, sulfuric acid or ammonium chloride, and an organic acid such as acetic acid, benzoic acid or ptoluenesulfonic acid, may be cited This step also proceeds smoothly from at room temperature to by heating, and results in the formation of the desired compounds (F) 35 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 40 abbreviations are used in the conventional manner As the internal standard used in the NMR measurement, tetramethylsilan was used in every cases and the values were shown by 8, in ppm.

Example I

Thiophene ( 4 2 g, 50 mmol) and trichloroacetaldehyde ( 7 35 g, 50 mmol) were 45 dissolved in n-heptane ( 25 ml) The solution was heated under reflux for 3 5 hr.

under a Soxleht apparatus in which Amberlyst 15 ( 4 2 g) had been placed.

(Amberlyst is a Registered Trade Mark) After cooling, the n-heptane solution was concentration, and the residue was purified by distillation to give 2 32 g of ac trichloromethyl 2 thiophenemethanol boiling at 98-100 C/I 0 mm Hg 50 Example 2

To a solution of titanium tetrachloride in methylene chloride ( 1 molar concentration: 30 ml, 30 mmol), titanium tetraisopropoxide ( 4 26 g, 15 mmol) was added under an argon atmosphere with stirring and under water cooling After 10 min, thiophene ( 2 52 g, 30 mmol) was added and then trichloroacetaldehyde ( 8 82 55 g, 60 mmol) was added dropwise during 10 min with stirring and under icewater cooling After the addition was completed, stirring was continued for further 10 min, and then water and methylene chloride were added successively, and the organic layer was separated The organic layer was washed with water and dried over anhydrous magnesium sulfate The solution was filtered and, after removal of the solvent by distillation under a reduced pressure with an aspirator, the residue was distilled to afford chloral isopropyl alcoholate initially and then 5 0 g of a trichloromethyl 2 thiophenemethanol.

Yield: 72 ?/ (based on thiophene) 5 bp: 95-97 C/0 7 mm Hg (Literature value: 140-142 C/10 mm Hg).

IR (cm-'): 3425, 1065, 1044, 822 and 710.

NMR (CDCI,): 3 48 (d, J= 5 Hz, IH), 5 40 (d, J= 5 Hz, 1 H) and 6 88-7 50 (m, 3 H).

Example 3 10

Titanium tetraisopropoxide ( 2 13 g, 7 5 mmol) was dissolved in methylene chloride ( 10 ml) To the solution, titanium tetrachloride solution in methylene chloride (I molar solution, 30 ml, 30 mmol) was added The mixture was cooled to -70 C and then, trichloroacetaldehyde ( 8 8 g, 59 7 mmol) was added thereto.

Further, 2-chlorothiophene ( 3 56 g, 30 mmol) solution in methylene chloride ( 10 15 ml) was added into the mixture The mixture was kept at the same temperature under agitation for 1 hr and then, the temperature was raised slowly to 10 C.

The reaction mixture was poured into ice-water and the organic layer was separated The organic layer was washed with sodium chloride solution in water and dried with magnesium sulfate After removal of solvent, vacuum distillation 20 was conducted Thereby, 2,2,2 trichloro 1 ( 5 chlorothiophene 2) ethanol ( 3 52 g, 44/0) was obtained.

bp: 94-100 C/0 15 mm Hg.

NMR (CC 14): 3 20 (d, J= 4 Hz, 1 H), 5 20 (d, J= 4 Hz, 1 H), 6 72 (d, J= 4 Hz, 1 H) and 6 97 (d, J= 4 Hz, 1 H 11) 25 Example 4

Under an argon atmosphere, potassium hydroxide ( 1 12 g, 20 mmol) was dissolved in methanol ( 10 ml) A solution of a trichloromethyl 2thiophenemethanol ( 1 16 g, 5 mmol) in methanol ( 3 ml) was added with stirring and under water cooling After 10 min, the mixture was heated up gradually and 30 heated under reflux for 1 hr with vigorous stirring It was cooled to room temperature, most of the solvent was removed by distillation under a reduced pressure, diethylether was then added and the mixture was decomposed with dilute hydrochloric acid The ether layer was separated and the water layer was extracted with ethyl acetate The organic layers thus obtained were combined to one layer 35 and was washed with an aqueous solution of sodium chloride and dried with anhydrous sodium sulfate After filtration, the filtrate was concentrated under a reduced pressure to give 620 mg of a methoxy 2 thiopheneacetic acid.

Yield: 73.

IR (cm-'): 3100, 2925, 1730, 1180, 1100, 880, 845 and 707 40 NMR (CDCI 3): 3 38 (s, 3 H), 5 00 (s, 1 H), 6 81-7 40 (m, 3 H), and 10 58 (s, 1 H).

Example 5

Under an argon atmosphere, potassium hydroxide ( 1 12 g, 20 mmol) was dissolved in methanol ( 10 ml) Thiophenol ( 0 6 g, 5 45 mmol) was added to this solution with stirring and under water cooling After 10 min, a solution of a 45 trichloromethyl 2 thiophenemethanol ( 1 16 g, 5 mmol) in methanol ( 3 ml) was added After 10 min, the mixture was gradually heated up and was heated under reflux for 2 hr with vigorous stirring After cooling to room temperature and after removal of most of the solvent by distillation under a reduced pressure, diethylether was added and the mixture was decomposed with dilute hydrochloric 50 acid The ether layer was separated, washed with water, and dried with anhydrous magnesium sulfate After filtration, the filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane= 1:4) to give 940 mg of a phenylthio 2 thiopheneacetic acid as a viscous oil 55 Yield: 76 o,.

IR (cm-'): 3060, 1715, 1587, 1485, 1440, 1416, 1253, 750, 705 and 694.

NMR (CDCI 3): 5 03 (s, l H), 6 62-7 60 (m, 8 H) and 11 47 (s, 1 H).

Example 6

Into 20 ml of ethanol, atrichloromethyl 2 thiophenemethanol ( 2 32 g, 10 60 mmol) was dissolved and an aqueous solution of sodium methyl mercaptide ( 20 %, g, 29 mmol) was further added thereto Into the solution, potassium hydroxide 1,599,622 ( 2.4 g, 36 mmol) solution in ethanol ( 20 ml) was added in drop-wise After the addition was completed, the reaction mixture was agitated for 30 min at room temperature Thereafter, the temperature was raised to 50 C and agitation was further conducted for 5 hr at the temperature, then, the solvent was distilled off under vacuum The residue thus obtained was dissolved in water and was washed 5 with methylene chloride After acidied with hydrochloric acid, extraction was conducted with methylene chloride After drying of the organic layer with magnesium sulfate, the organic layer was concentrated Thereby, crude a methylthio 2 thiopheneacetic acid ( 1 75 g, 93 %) was obtained After purification with silica gel chromatography, 1 66 g ( 88 %) of pure product was 10 obtained.

NMR (CC 14): 1 98 (s, 3 H), 4 67 (s, 1 H), 6 75 6 97 (m, IH), 7 00-7 28 (m, 2 H) and 11 95 (s, IH).

Example 7

Into 2 4 ml of water, potassium hydroxide ( 0 67 g, 12 minmol) and lithium 15 chloride ( 0 254 g, 6 mmol) were dissolved then, into the solution above, a trichloromethyl 2 thiophenemethanol ( 0 693 g, 3 mmol) solution in dioxane ( 2.4 ml) was added and agitation was conducted for 12 hr at room temperature and for 3 hr at 80 C Thereafter, water ( 20 ml) was added thereto and diethylether was further added into the reaction mixture The ether soluble part was separated The 20 water layer was acidified with hydrochloric acid and then, extracted with diethylether The organic layer was dried with anhydrous magnesium sulfate and was treated with activated carbon and filtered Thereafter, the filtrate was concentrated and gave 0 246 g of 2-thiopheneglycolic acid as crystals.

Crude yield: 52 % 25 NMR (CDCI 3): 5 47 (s, 1 H), 6 80-7 35 (m, 3 H) and 8 52 (br s, 2 H).

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 30 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 (CDCI 3): 3 91 (s, 2 H), 7 30 (d, J= 3 Hz, 2 H), 7 31 (t, J= 3 Hz, l H), and 35 11.12 (s, 1 H).

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 50 C for 15 hr Acetic unhydride and acetic acid were removed by distillation in vacuo, and from the 40 residue, 2 27 g of a acetoxy 2 thiopheneacetic acid was obtained (yield: 87).

NMR (CDC 13): 2 17 (s, 3 H), 6 22 (s, 1 H), 7 03 (t, J= 4 Hz, IH), 7 23 (d, J= 4 Hz, l H), 7 37 (d, J= 4 Hz, 1 H) and 11 68 (s, l H).

Example 10

A mixture of 1 51 g of a acetoxy 2 thiopheneacetic acid and 0 40 g of 45 430 % palladium-asbestos catalyst in 8 0 m l 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 % 50 Example 11

Red phosphorus ( 372 m g) and 141 m g 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 m g) in 1 0 m l of acetic acid was then added to the mixture and the resulting mixture was heated under reflux for 2 hr After cooling to 55 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: 89 o%) 60 1,599,622 Example 12

Red phosphorus ( 180 mg) and iodine ( 60 mg) were added to acetic acid ( 2 85 ml), and the mixture was stirred for 30 min A solution of water ( 60 mg) and a methoxy 2 thiopheneacetic acid ( 860 mg, 5 mmol) in acetic acid ( 1 5 ml) was added to this mixture and the resulting mixture was heated under reflux for 2 hr 5 with vigorous stirring After cooling to room temperature, water and ethyl acetate were added thereto After filtering off the precipitate by the use of Celite (Registered Trade Mark), the organic layer was separated It was washed with saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate After filtration, the solution was concentrated under a reduced 10 pressure, and the crystals which remained were recrystallized from ethyl acetate:

n-hexane to give 2-thiopheneacetic acid ( 610 mg) melting at 620 C (Literature value: 62-650 C).

Yield: 86 %.

Example 13 15

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 20 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 %/ 25 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 30 the ether washings were combined with 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 to 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 35 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.

Example 14 a Phenylthio 2 thiopheneacetic acid ( 890 mg, 3 56 mmol) was dissolved 40 in acetic acid ( 6 ml), then zinc dust ( 350 mg, 5 4 mmol) was added and the mixture was heated under reflux with vigorous stirring After 30 min, zinc dust ( 350 mg, 5 4 mmol) was added again, and the mixture was heated under reflux for another 4 hr.

with stirring, then cooled to room temperature, and most of the solvent was removed by distillation Water and ethyl acetate were added and the precipitate 45 was filtered off by the use of Celite (Registered Trade Mark), and the layers of the filtrate were separated The organic layer was washed with an aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate After filtration, the solution was concentrated under a reduced pressure and the crystals thus obtained were further recrystallized from ethyl acetate: n-hexane to give 2thiopheneacetic 50 acid ( 430 mg) melting at 62 C (Literature value: 62-65 C).

Yield: 85 %'.

Example 15

A mixture of a trichloromethyl 2 thiophenemethanol ( 15 5 g, 67 1 mmol) and acetyl chloride ( 15 5 ml) was heated under reflux with stirring for 15 hr in 55 accordance with the literature procedure (V W Floutz, J Amer Chem Soc, 71, 2859 ( 1949)) Acetyl chloride was distilled off under a reduced pressure and the residue was extracted with diethylether The organic layer was washed with an aqueous solution of sodium bicarbonate and then with water, and dried with anhydrous magnesium sulfate After filtration, the solvent was distilled off to give 60 2,2,2 trichloro 1 ( 2 thiophene) ethyl acetate ( 18 0 g, Yield: 978 %) as white crystals.

1,599,622 1 1 1 1 12 1,599,622 12 1 Example 16

2,2,2 Trichloro 1 ( 2 thiophene) ethyl acetate ( 18 g) was dissolved in acetic acid ( 108 ml), then zinc dust ( 3 g) was added to this solution, and the mixture was heated under reflux with vigorous stirring Other portions of zinc dust ( 3 g) were added twice with one hour's interval, and after 5 hr, the mixture was cooled 5 to room temperature Acetic acid was distilled off under a reduced pressure and the residue was extracted with diethylether The ether extract was washed with a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate After treating with activated carbon, the crude crystals ( 10 8 g, yield 91 5 %) which remained after distilling off of the solvent, was distilled under a 10 reduced pressure to give 2 ( 2,2 dichlorovinyl)thiophene ( 9 23 g), boiling at 103-108 C/20 mm Hg This crystallized on standing.

Yield: 78 2/.

mp: 38-39 C.

IR (Nujol): 1605, 1510, 1420, 1350, 1310, 1282, 1245, 1215, 1120, 1075, 1050 15 and 910 (cm-').

(Nujol is a Registered Trade Mark).

NMR (CDCI,): 6 88-7 30 (min, 3 H, ring H) and 6 93 (s, 1 H, CH=CCI).

Calculated for C 6 H C 12 S: C, 40 25; H, 225 % Found: C, 40 38; H, 2 41 % 20 Example 17 a Trichloromethyl 2 thiophenemethanol ( 300 mg, 1 3 mmol) was dissolved in acetic acid ( 3 m l), then zinc dust ( 170 m g, 2 6 mmol) was added and the mixture was heated under reflux for 3 hr with vigorous stirring After cooling, water and ethyl acetate were added and the organic layer was separated The 25 organic layer was washed successively with water, an aqueous solution of sodium bicarbonate, and then water, and dried with anhydrous magnesium sulfate The solution was filtered and concentrated to give 200 mg of an oily material Analysis by gas chromatography ( 2 % EGA, 1 m, 120 C) showed the formation of 2 ( 2,2 dichlorovinyl)thiophene in 77 % yield 30 Example 18

To a solution of a trichloromethyl 2 thiophenemethanol ( 300 mg, 1 3 mmol) in acetic acid ( 3 ml), zinc dust ( 170 mg, 2 6 mmol) and sodium acetate ( 11 mg, 0 13 mmol) were added and the mixture was heated under reflux with vigorous stirring After 4 hr, zinc dust ( 100 mg, 1 5 mmol) was added and the mixture was 35 further heated under reflux for another 3 hr After cooling, the mixture was treated in the same manner as in Example 17, and analyzed by gas chromatography, which showed that 2 ( 2,2 dichlorovinyl)thiophene was formed in 68 % yield.

Example 19

To a solution of a trichloromethyl 2 thiophenemethanol ( 300 mg, 1 3 40 mmol) in pyridine ( 500 mg), acetic anhydride ( 400 mg) was added with stirring and cooling with ice-water The temperature of the mixture was allowed to rise gradually to room temperature, and after 2 hr, acetic acid ( 3 ml) and zinc dust ( 170 mg, 2 6 mmol) were added, and the reaction mixture was heated under reflux with vigorous stirring After 2 hr, zinc dust ( 80 mg) was added, and after 30 min, a 45 further portion of zinc dust ( 80 mg, 1 2 mmol) was added After heating under reflux for a total of 3 hr, the mixture was cooled The mixture was then treated in the same manner as in Example 17, and analyzed by gas chromatography, showing the formation of 2 ( 2,2 dichlorovinyl)thiophene in 74 %o overall yield.

Example 20 50

A solution of sodium methoxide was prepared by addition of sodium ( 1 53 g) in methanol ( 85 ml) To this solution, 2 ( 2,2 dichlorovinyl)thiophene ( 3 0 g, 16 8 mmol) was added and the resulting mixture was heated overnight under reflux.

After confirming the disappearance of the starting material by thin-layer chromatography, the reaction solution was acidified by bubbling through it 55 hydrogen chloride gas under cooling with ice-water, and the mixture was heated overnight under reflux Methanol was distilled off under a reduced pressure, and the residue was extracted with diethylether The ether layer was washed with water, and dried with anhydrous magnesium sulfate After filtration, the solution 1,599,622 was concentrated and the residue was distilled under a reduced pressure to give methyl 2 thiopheneacetate ( 2 10 g) boiling at 109-111 C/23 mm Hg.

Yield: 80 2 %.

NMR (CCI 4): 3 65 (s, 3 H), 3 70 (s, 2 H) and 6 75-7 20 (m, 3 H 1).

Claims (1)

1. WHAT WE CLAIM IS:-

   1 A process for the preparation of a trihalomethyl 2 5 thiophenemethanols represented by the general formula:

   FR 77 CHCX 3 ell% OH which comprises reacting a thiophene derivative represented by the general formula: 10 R 2 g with a trihaloacetaldehyde represented by the general formula CX 3 CHO under acidic conditions (wherein R' and R 2 represent, independently, hydrogen, a halogen, an alkyl group, an aroyl group or an alkanoyl group; and X represents chlorine, bromine or iodine) 15 2 A process as claimed in Claim 1 in which the acidic conditions are established by the use of a Lewis acid.

   3 A process as claimed in Claim 1 or 2 in which the reaction is conducted in the presence of titanium tetrachloride and/or a titanium alkoxide.

   4 A process for the preparation of a-substituted 2-thiopheneacetic acids 20 represented by the general formula:

   R' 2 iv 77 i LCHH-q R 4 which comprises reacting an a trihalomethyl 2 thiophenemethanol prepared by the process of any one of Claims I to 3, represented by the general formula:

   R, R 2 < CHCX 3 25 S 01OH with a compound represented by the general formula R 3 H in the presence of an alkali or an alkaline earth metal hydroxide, and if desired, the product is further esterified by reacting with an aliphatic alcohol (wherein R' and R 2 represent, independently, hydrogen, a halogen, an alkyl group, an aroyl group or an alkanoyl group: R 3 represents an alkoxy group, hydroxyl group, an amino group, an 30 alkylthio group or an arylthio group; R 4 represents hydrogen or an alkyl group; and X represents chlorine, bromine or iodine).

   A process for the preparation of a acyloxy 2 thiopheneacetic acids represented by the general formula:

   RI R 35 which comprises reacting a 2-thiopheneglycolic acid prepared by the process of Claim 4 represented by the general formula:

   rid OH R< 2 l'H Cr R 4 with a carboxylic acid anhydride represented by the general formula:

   1,599,622 (R 5 CO)20 (wherein R' and R 2 represent, independently, hydrogen, a halogen, an alkyl group, an aroyl group or an alkanoyl group; R 4 represents hydrogen or an alkyl group:

   and R 5 represents an alkyl group or an aryl group).

   6 A process for the preparation of 2-thiopheneacetic acids represented by the general formula: 5 R' R 2 S C 2 t CO O R which comprises hydrogenating an a-substituted 2-thiopheneacetic acid prepared by the process of Claims 4 or 5 represented by the general formula:

   RI R 31 Rt R 12 1 LCHCO R 4 S 2 in which hydrogenation is conducted by the use of (a) a platinum group metal 10 catalyst having or not having a carrier, (b) red phosphorus and iodine or (c) zinc and an acid (wherein RI and RZ represent, independently, hydrogen, halogen, an alkyl group, an aroyl group or an alkanoyl group; R 3 ' represents an alkoxy group, hydroxyl group, an alkanoyloxy group, an aroyloxy group, an amino group, an alkylthio group or an arylthio group; and R 4 represents hydrogen or an alkyl 15 group).

   7 A process as claimed in Claim 6 in which R 3 ' is any one of a hydroxyl group, an alkoxy group, an alkanoyloxy group and an aroyloxy group and hydrogenation is conducted catalytically in the presence of a platinum group metal catalyst having or not having a carrier 20 8 A process as claimed in Claim 7 in which the catalyst is palladium black having or not having a carrier.

   9 A process as claimed in Claim 6 in which R 3 is any one of a hydroxyl group, an alkoxy group, an alkanoyloxy group and an aroyloxy group and hydrogenation is conducted by the use of red phosphorus and iodine 25 A process as claimed in Claim 6 in which R 3 ' is an alkylthio group or an arylthio group and the hydrogenation is conducted by the use of zinc and an acid.

   11 A process for the preparation of 2 ( 2,2 dihalovinyl)thiophenes represented by the general formula:

   R 7 C X 30 which comprises treating an a trihalomethyl 2 thiophenemethanol prepared by the process of any one of Claims 1 to 3 represented by the general formula:

   f)T 3 CHCX 3 OH with a reducing agent (wherein RI and R 2 represent, independently, hydrogen, halogen, an alkyl group, an aroyl group or an alkanoyl group; and X represents 35 chlorine, bromine or iodine).

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

   RI R 2:2 J-%CG Oe R which comprises conducting hydrolysis or alcoholysis of a 2 ( 2,2 40 dihalovinyl)thiophene prepared by the process of Claim 11 represented by the general formula:

   # R,2 Y LCH=GX 2 under basic conditions and optionally, thereafter subjecting the reaction mixture to acidic conditions (wherein RI and R 2 represent, independently, hydrogen, a 45 1,599,622 halogen, an alkyl group, an aroyl group or an alkanoyl group; R 4 represents hydrogen or an alkyl group; and X represents chlorine, bromine or iodine).

   13 Processes as claimed in any one of Claims 1, 4, 5, 6, 11 and 12 and substantially as hereinbefore described with reference to the Examples.

   14 A process as claimed in Claim I in which R' and R 2 represent, 5 independently, hydrogen, a halogen or an alkyl group, and X represents chlorine or bromine.

   A process as claimed in Claim 4 in which R 4 is hydrogen, R' and R 2 represent, independently, hydrogen, a halogen or an alkyl group, and X represents chlorine or bromine 10 16 A process as claimed in Claim 5 in which R' represents hydrogen, a halogen or an alkyl group and R 2 represents hydrogen, an alkyl group or an alkanoyl group.

   17 A process as claimed in Claim 11 in which each of R' and R 2 is hydrogen.

   18 A process as claimed in Claim 12 in which each of R' and R 2 is hydrogen 15 W P THOMPSON & CO, Coopers Building, Church Street, Liverpool, Ll 3 AB, Chartered Patent Agents.

   Printed for Her Majesty's Stationery Office, by the Courier Press, Leamington Spa, 1981 Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A IAY, from which copies may be obtained.

   1,599,622