IE55097B1 - Production of thiophene compounds - Google Patents

Production of thiophene compounds

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Publication number
IE55097B1
IE55097B1 IE1074/83A IE107483A IE55097B1 IE 55097 B1 IE55097 B1 IE 55097B1 IE 1074/83 A IE1074/83 A IE 1074/83A IE 107483 A IE107483 A IE 107483A IE 55097 B1 IE55097 B1 IE 55097B1
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IE
Ireland
Prior art keywords
formula
thiophene
acetic acid
process according
acid compound
Prior art date
Application number
IE1074/83A
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IE831074L (en
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Roussel Uclaf
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Publication date
Application filed by Roussel Uclaf filed Critical Roussel Uclaf
Publication of IE831074L publication Critical patent/IE831074L/en
Publication of IE55097B1 publication Critical patent/IE55097B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/12—Radicals substituted by halogen atoms or nitro or nitroso radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Catalysts (AREA)

Abstract

A 2-thiophene acetic acid compound of formula (I): <IMAGE> in which: R represents an alkyl radical of 1 to 4 carbon atoms; and R1, R2 and R3 are the same or different and each represents a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a halogen atom; is prepared by reacting a haloalkylthiophene of formula (III): <IMAGE> in which R, R1, R2 and R3 are as defined above and Hal represents a halogen atom, with a cyanide of formula A-CN in which A represents an alkali metal atom, an alkaline-earth metal equivalent or a hydrogen atom to produce a cyanoalkylthiophene of formula (IV): <IMAGE> in which R, R1, R2 and R3 are as defined above, and hydrolysing the cyanoalkylthiophene of formula (IV) to the 2-thiophene acetic acid compound of formula (I). The compound of formula (I) is an intermediate in the production of pharmaceuticals. [GB2132608A]

Description

55097 This invention relates tc· the production of 2-thicphene acetic acid compounds of formula (1): in which R represents an alkyl radical of 1 to A carbon 5 atoms and R^, Rj and R- are the same or different and each represents a hydrogen atom, an alkyl radical of 1 to a carbon atoms or a halogen atom.
These compounds are intermediates which can be used in the preparation of pharmaceutical products, in-10 particular anti-inflammatory products. End products which can be prepared from the compounds are described in particular in French Patent 2 068 425.
Several processes for the preparation of the compounds are already known. 16 The following process is described in M. BERCOT- -VATTEROWI et al., Bull. Soc, Chim. France 1961 p. 1820: 2 HCKO, CH2CN ί KOH ;k-cn · \:c23t The following process is described in F. CLEMENCE et al., Eur. J. Med. Chem. 1974 (9) 390: 5 C1C0C0, ^Of·00*"-25* O-S'C02s CKjMgl AcOH CH3 ^^-CHCOgH *-SriCl2^^_C-C02H CH, OH The following process is described in French Patent Application 2 398 068 in the name of SAGAMI: 3 C-CHHal2 Ο alkali metal hydroxide "3 C-CQpH — s or lover alkyl ‘ Hal — halogen j/ = h, hydrocarbon radical 2 or halogen 5 These processes involve at least 4 stages starting from thiophene or in the case of the last mentioned process an optionally substituted thiophene of formula A new process for the preparation of the compounds of formula (I) has now been discovered. Accordingly, the invention provides a process for the preparation 4 of a 2-thiophene acetic acid compound of formula (X): (X) R ch-co2h R in which R represents an alkyl radical of 1 to 4 carbon 5 atoms; and R1, Rg and Rg are the same or different and each represents a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a halogen atom; which process comprises reacting a haloalkylthiophene of 10 formula (III): CH-Hal R (III) in which R, R^, R2 and R^ are as defined above and Hal represents a halogen atom, with a cyanide of formula A-CN in which A represents an alkali metal atom, an alkaline-earth metal equivalent or a hydrogen atom to 5 produce a cyanoalkylthiophene of formula (IV): (IV) in which R, R^, R2 and R^ are as defined above, and hydrolysing the cyanoalkylthiophene of formula (IV) to the 2-thiophene acetic acid compound of formula (I).
The new process is better because it produces the 10 compounds more readily. If one starts from an optionally substituted thiophene of formula (II): 6 (II) the present process can produce the compounds in only 3 stages. Moreover, the present process has proved better on an industrial scale.
The haloalkylthiophene of formula (III) is 5 preferably prepared by haloalkylating a thio compound of formula (II), and thus the compound of formula (I) can be prepared from it in 3 stages.
The haloalkylation can be conducted by reacting the thio compound of formula (II) with an aldehyde of 10 formula RCHO in the presence of a hydrohalic acid of formula HHal. Alternatively, the haloalkylation can be conducted by reacting the thio compound of formula (II) with a derivative of the aldehyde of formula RCHO in the presence of a hydrohalic acid of formula HHal, the 15 derivative being reactive so as to enable the reaction to proceed.
R represents a lower alkyl radical, i.e. an alkyl radical of 1 to 4 carbon atoms, namely methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or 20 tert-butyl. R·^ R2 and R3 can independently represent one of these alkyl radicals or equally a halogen atom, namely fluorine, chlorine, bromine or iodine.
The aldehyde of formula RCHO is the aldehyde corresponding to the value of the desired R. When R 25 represents a methyl radical, paraldehyde which is the trimer of acetaldehyde is preferably used. Of the other 7 aldehydes, propanal and butanal may be mentioned.
Hal preferably represents an atom of chlorine or bromine, especially chlorine. Thus, the hydrohalic acid is preferably hydrochloric or hydrobromic acid, especially 5 hydrochloric acid.
The haloalkylation is preferably chloroalkylation, especially chloroethylation, and can be carried out with or without the addition of an organic solvent. The solvent is preferably a chlorinated solvent such as carbon 10 tetrachloride, chloroform or especially methylene chloride. Alternatively, the solvent can be an ether such as isopropyl ether, cyclohexane, ethanol or methanol. As a matter of convenience, the further stages in the synthesis can be carried out starting from ahaloalkylthiophene of 15 formula (III) in solution. The solvent can thus be an extraction solvent which is the same as or different from the reaction solvent. A reaction solvent is preferably used. The preferred solvent is methylene chloride which can equally be used for the extraction.
In addition to the hydrohalic acid which participates directly in the reaction, another acid such as phosphoric acid or acetic acid can be admixed to modify the acidity of the medium. It is likewise possible to use a Lewis acid such as zinc or aluminium chloride.
Obviously the different reagents : thio compound, aldehyde and acid can be introduced in different orders depending on the operational conditions used. The reaction 8 temperature likewise can vary. The preferred operating temperature is between -10°C and ambient temperature.
More particularly a temperature of about -5°C is used.
A particular example of such a reaction is described in Org. 5 Synth. Vol. 38 p. 86.
When a reactive derivative of the aldehyde of formula RCHO is employed, this reactive derivative is preferably of formula (V): in which Hal represents a halogen atom and Aik represents 10 an alkyl radical containing preferably 1 to 3 carbon atoms. This derivative of formula (V) can be prepared by reacting the aldehyde RCHO with the hydrohalic acid of formula HHal in an alcoholic solvent of formula AlkOH. Preferably the 15 reactive derivative is of formula 9 and is obtained by reacting acetaldehyde CH^CHO with hydrochloric acid in an alcohol of formula AlkOH, preferably methanol or ethanol.
The conversion of the haloalkylthiophene of. formula (III) to the cyanoalkylthiophene of formula (IV) is preferably carried out with an alkali metal or alkaline-earth cyanide such as sodium, potassium, lithium or calcium cyanide. Hydrocyanic acid could equally be used. Sodium cyanide is preferred. The operation can be 10 carried out with or without the presence of a base.
When operating in the presence of a base, sodium or potassium hydroxide is preferred, particularly sodium hydroxide. However it is preferred to operate without a base.
The conversion of the haloalkylthiophene of formula (III) to the cyanoalkylthiophene of formula (IV) is preferably carried out by aphase transfer reaction.
The operation is then carried out in the presence of a specific catalyst. This catalyst can be, for 20 instance, an ammonium, phosphonium or arsonium tetraalkyl or aralkyl salt, or a sulphonium salt. Of the catalysts of this type there may be mentioned, for example, triethyl benzylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium sulphate, 25 tetrabutylammonium hydroxide, tetra-n-butylammonium chloride, 10 tetramethylphosphonium iodide or tetra-n-butylphosphonium bromide. These salts can be fixed on ion exchange resin.
It is equally possible to employ a macrocyclic polyether, generally called an ether-ring. Such polyethers 5 are described for example in Tetrahedron Letters no. 18 (1972) p. 1793. Of the polyethers which can be employed there may be mentioned in particular 1, A, 7, 10, 13, 16-hexaoxacyclooctadecane. In short, it is possible to employ surface active agents formed by reacting a 10 higher alcohol or a fatty acid with for example ethylene oxide.
The catalyst is advantageously an ammonium halide, especially trialkyl benzylammonium or tetraalkylammonium bromide or chloride. The preferred catalyst is triethyl 15 benzylammonium chloride.
In a preferred mode of operation, as mentioned above, the haloalkylthiophene of formula (III) is used in an organic solution, preferably a methylene chloride solution, or in dichloroethane. It is equally possible 20 to use a polar solvent such as dimethyl formamide or dimethyl sulphoxide. Methylene chloride is used from preference.
The quantity of phase transfer catalyst can vary depending on the reactions used. For example it can vary 25 from 0.2 to 0.5 parts by weight relative to the haloalkylthiophene of formula (III).
The temperature can vary for example between 0°C Π and the reflux temperature of the solvent. It is preferred to operate at a low temperature of the order of 0 to +5°C.
The hydrolysis of the cyanoalkylthiophene of formula 5 (IV) to the acid compound of formula (I) can first convert the nitrile into a salt, preferably the sodium or potassium salt, of the desired acid, which salt is then acidified to the desired acid. When the nitrile has thus been converted into a salt of the desired acid, the 10 aqueous phase can be purified by an organic solvent. The aqueous phase can then be acidified and the desired compound extracted.
The first phase can be carried out in water or in a mixture of water and a water-miscible solvent. The 15 solvent preferably employed is a lower alcohol such as ethanol or isopropanol. The alkaline agent is preferably sodium or potassium hydroxide and the reaction preferably occurs at a temperature between 50°C and the reflux temperature. The operation is preferably carried out at 20 reflux in pure water. The reaction time is usually between 2 hours said 15 hours.
The organic solvent used to purify the aqueous solution of the salt obtained is preferably toluene, dichloroethane or methylene chloride, preferably methylene 25 chloride.
The final acidification is preferably carried out with concentrated hydrochloric acid. The reaction is 12 preferably conducted after the addition of a solvent chosen from the preceding group. The operation is usually conducted at a temperature between the ambient temperature and the reflux temperature of the solvent.
The hydrolysis of the cyanoalkylthiophene of formula (IV) to a compound of formula (I) can equally be carried out in an acid medium. The acid is preferably a mineral acid such as hydrochloric, sulphuric or phosphoric acid.
Rj_, R2 R3 preferably each represents a hydrogen atom, so that the acid compound is of formula (I'): In that event, the corresponding thio compound of formula (II) is thiophene.
R preferably represents a methyl radical.
In a preferred embodiment, oC-methyl 2-thiophene acetic acid is prepared as described above, starting from thiophene and acetaldehyde. 13 As mentioned above, the reaction of the cyanide of formula A-CN with the haioalkylthiophene of formula (III) is carried out preferably by a phase transfer reaction.
This reaction is preferably carried out in the presence as 5 catalyst of triethyl benzylammonium chloride, tetrapropyl-ammonium bromide, tetrabutylammonium bromide, tetrabutyl-ammonium sulphate or tetrabutylammonium hydroxide.
In a particularly advantageous way of carrying out this reaction, the haioalkylthiophene of formula (III) in 10 methylene chloride solution is poured into an aqueous solution of sodium cyanide and a phase transfer catalyst.
The phase transfer catalyst is as indicated previously preferably triethyl benzylammonium chloride.
Especially preferred is carrying out the present 15 process in the following way to produce ot-methyl 2-thiophene acetic acid: Hydrochloric acid arid paraldehyde are reacted with thiophene to produce 2-(1-chloroethyl)thiophene, which is reacted with sodium cyanide by phase transfer reaction in the presence of 20 triethyl benzylammonium chloride to produce otmethyl 2-thiophene acetonitrile, which is reacted with sodium hydroxide and then hydrochloric acid to obtain the desired compound.
The invention also provides a process for preparing 25 a pharmaceutical using as an intermediate a 2-thiophene acetic acid compound as defined above, in which process the compound is prepared in the present way. 14 The invention is illustrated by the following Examples.
EXAMPLE 1: OL-methyl 2-thiophene acetic acid Stage A: 2-(1-chloroethyl)thiophene 5 A mixture of 336 cc of methylene chloride and 75 cc of aqueous hydrochloric acid were cooled with stirring to -5°C and then on the one hand a mixture of 84 g of thiophene and 44 g of paraldehyde and on the other hand 36.5 g of gaseous hydrochloric acid were introduced at 10 this temperature over 5 hours. The mixture was stirred and 3.5 g of hydrochloric acid were added over thirty minutes. After three hours stirring at -5°C, the mixture was brought to 0°C and 50 g of ice were introduced. The resultant mixture was stirred at 0 to +5°C for 15 15 minutes, the organic phase was decanted, the aqueous phase was extracted at 0 to -t-5°C by 42 cc of methylene chloride and the two organic phases were combined.
Stage B: oc-methyl 2-thiophene acetonitrile 8.4 g of triethyl benzylammonium chloride were 20 added to a solution cooled to 0 to +5°C of 88.5 g of sodium cyanide in 168 cc of demineralised water. The methylene chloride solution of 2-(l-chloroethyl)thiophene obtained in Stage A was poured over one minute into the medium which was stirred constantly. Vigorous stirring 25 continued for 18 hours at 0 to +5°C, and then 252 cc of demineralised water were added. After stirring for 10 minutes, the organic phase was decanted and the aqueous 15 phase was extracted with 84 cc of methylene chloride and then with two batches of 42 cc of the same solvent. The organic phases were combined, and then washed by demineralised water, then by water containing 1% pure 5 hydrochloric acid and again by demineralised water.
The organic phase was concentrated under reduced pressure for 2 hours. 105 g of the expected product were obtained.
Stage C: «-methyl 2-thiophene acetic acid 10 A mixture of 105 g of the product obtained in Stage B, 500 cc of demineralised water and 63.2 g of sodium hydroxide were brought to reflux for two hours thirty minutes. It was cooled to 20°C and 168 cc of methylene chloride were added. After ten minutes stirring, 15 the methylene chloride phase was decanted. The same operation was repeated twice. 168 cc of toluene and then 168 cc of 22°Be hydrohloric acid were added to the aqueous phase. The mixture was brought to reflux for one hour, cooled to 20°C, and stirred for 15 minutes, 20 and then the aqueous phase was decanted and then washed four times, each time with 42 cc of demineralised water. The organic phase was concentrated under reduced pressure. 71 to 74 g of the expected product were obtained.
EXAMPLE 2: Stages A to C above can be modified in the following manner: Stage A’*': 2-(1-chloroethyl)thiophene 16 Gaseous hydrochloric acid was bubbled to saturation for 25 minutes into a mixture of 84 g of thiophene, 44 g of paraldehyde and 75 cc of 22°Be hydrochloric acid while maintaining the temperature at J0-i3°C.
The resultant mixture was poured into 75 cc of iced water, and after decanting, the aqueous phase was extracted with 168 cc of methylene chloride and the organic phase was washed three times with 50 cc of iced water.
Stage A2: Gaseous hydrochloric acid was introduced at +10°C to saturation into a mixture of 46 g of ethanol and 44 g of paraldehyde. This reagent was added over 10 minutes at +10°C with stirring to 84 g of thiophene. The procedure was then the same as described above for Stage A·*·.
Stage A3: A mixture of 84 g of thiophene, 44gof paraldehyde, 168 cc of methylene chloride and 75 cc of 22°Be hydrochloric acid acid was stirred at 10-13°C. This was saturated by 40 g of gaseous hydrochloric acid and then cooled to 0°C. 50 g of ice were added, and after decanting, the aqueous phase was extracted with 42 cc of methylene chloride and the combined organic phases were washed twice by 63 cc of iced water.
Stage B1: The triethyl benzylammonium chloride was replaced by each of the following reagents: - tetrapropylammonium bromide 17 - tetrabutyLammonium bromide - tetrabutylammonium sulphate - tetrabutylammonium hydroxide.
Stage C1: The methylene chloride was replaced by 5 dichloroethane as the extraction solvent. 18

Claims (15)

1. Process for the preparation of a 2-thiophene acetic acid compound of formula (I): R (I) 5 in which R represents an alkyl radical of 1 to 4 carbon atoms; and Rt, Rz and R, are the same or different and each represents a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a halogen atom; 10 which process comprises reacting a haloalkylthiophene of formula (HI): (HI) in which R, Rt, R2 and R3 are as defined above and Hal represents a halogen atom, with a cyanide of formula A-CN in which A represents an 19. alkali metal atom, an alkaline-earth metal equivalent or a hydrogen atom to produce a cyanoalkylthiophene of formula (IV): (IV) in which R, Rlt R2 and R3 are as defined above, and hydrolysing the 5 cyanoalkylthiophene of formula (IV) to the 2-thiophene acetic acid compound of formula (I).
2. Process according to claim 1 wherein the haloalkylthiophene of formula (III) is prepared by haloalkylating a thio compound of formula (II): in which R1( R2 and R3 are as defined in claim 1.
3. Process according to claim 2 wherein the haloalkylation is conducted by reacting the thio compound of formula (II) with an aldehyde of formula RCHO in which R is as defined in claim 1, in the presence of a hydrohalic 15 acid of formula HHal in which Hal is as defined in claim 1. 20.
4. Process according to claim 2 wherein the haloalkylation is conducted by reacting the thiophene of formula (II) with a reactive derivative of an aldehyde of formula RCHO in which R is as defined in claim 1, which derivative contains the halogen atom Hal as defined in claim 1.
5. Process according to any one of the preceding claims wherein R1( Rz and R2 each represents a hydrogen atom.
6. Process according to claim 5 wherein R represents a methyl radical.
7. Process according to claim 3 wherein R represents a methyl radical and the aldehyde RCHO is in the form of paraldehyde.
8. Process according to any one of the preceding claims wherein the reaction of the cyanide of formula A-CN with the haloalkylthiophene of formula (III) is carried out as a phase transfer reaction.
9. Process according to claim 8 wherein the phase transfer reaction is conducted in the presence as catalyst of triethyl benzylammonium 15 chloride, tetrapropylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium sulphate or tetrabutylammonium hydroxide.
10. Process according to claim 8 or 9 wherein in the phase transfer reaction the haloalkylthiophene of formula (III) in methylene chloride solution is poured into an aqueous solution of sodium cyanide and a phase 20 transfer catalyst.
11. Process for the preparation of α-methyl 2-thiophene acetic acid, which process comprises reacting hydrochloric acid and paraldehyde with thiophene to produce 2-(l-chloroethyl)thiophene, which is reacted with sodium cyanide in a phase transfer reaction in the presence of triethyl 25 benzylammonium chloride to produce a-methyl 2-thiophene acetonitrile, which is reacted with sodium hydroxide and then hydrochloric acid to produce the a-methyl 2-thiophene acetic acid. 21.
12. Process according to claim 1 performed substantially as described herein.
13. Process for preparing a 2-thiophene acetic acid compound of formula (I) as defined in claim 1, which process is performed substantially as 5 described herein in any one of the Examples.
14. A 2-thiophene acetic acid compound of formula (I) as defined in claim 1, when prepared by a process claimed in any one of the preceding claims.
15. Process for preparing a pharmaceutical using as an intermediate a 10 2-thiophene acetic acid compound of formula (I) as defined in claim 1, in which process the 2-thiophene acetic acid compound is as claimed in claim 14. Dated this 10th day of Hay 1983, TOMKINS & CO., Applicants1 Agents 5 Dartmouth Road DUBLIN 6. (signed) 22.
IE1074/83A 1982-12-03 1983-05-10 Production of thiophene compounds IE55097B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR8220272A FR2537138A1 (en) 1982-12-03 1982-12-03 PROCESS FOR THE PREPARATION OF ACETIC 2-THIOPHENE ACID DERIVATIVES

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IE831074L IE831074L (en) 1984-06-03
IE55097B1 true IE55097B1 (en) 1990-05-23

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AT (1) AT392785B (en)
AU (1) AU557065B2 (en)
BE (1) BE896440A (en)
CA (1) CA1201442A (en)
CH (1) CH653681A5 (en)
DE (1) DE3314028C2 (en)
DK (1) DK157492C (en)
ES (1) ES8401958A1 (en)
FI (1) FI80882C (en)
FR (1) FR2537138A1 (en)
GB (1) GB2132608B (en)
HU (1) HU191831B (en)
IE (1) IE55097B1 (en)
IT (1) IT1174758B (en)
LU (1) LU84749A1 (en)
NL (1) NL8301693A (en)
NZ (1) NZ204510A (en)
PT (1) PT76535B (en)
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IT1276738B1 (en) * 1995-06-16 1997-11-03 Erregierre Spa PROCESS FOR THE PREPARATION OF DERIVATIVES OF -METHYL-2- THIOPHENEACETIC ACID

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AU557065B2 (en) 1986-12-04
AT392785B (en) 1991-06-10
FR2537138A1 (en) 1984-06-08
FR2537138B1 (en) 1985-05-24
GB8312702D0 (en) 1983-06-15
KR840006987A (en) 1984-12-04
PT76535A (en) 1983-05-01
LU84749A1 (en) 1983-12-05
FI80882B (en) 1990-04-30
BE896440A (en) 1983-10-12
HU191831B (en) 1987-04-28
NZ204510A (en) 1986-02-21
PT76535B (en) 1986-03-12
DE3314028C2 (en) 1995-05-24
FI831116L (en) 1984-06-04
GB2132608A (en) 1984-07-11
DK157492C (en) 1990-06-11
AU1357383A (en) 1984-06-07
IE831074L (en) 1984-06-03
NL8301693A (en) 1984-07-02
DK140083A (en) 1984-06-04
CH653681A5 (en) 1986-01-15
ATA286783A (en) 1990-11-15
ES521231A0 (en) 1984-01-01
DE3314028A1 (en) 1984-06-07
JPS59106483A (en) 1984-06-20
ZA832697B (en) 1983-12-28
ES8401958A1 (en) 1984-01-01
IT1174758B (en) 1987-07-01
DK140083D0 (en) 1983-03-28
SE453918B (en) 1988-03-14
GB2132608B (en) 1986-06-04
CA1201442A (en) 1986-03-04
DK157492B (en) 1990-01-15
KR900003281B1 (en) 1990-05-12
FI831116A0 (en) 1983-03-31
SE8301786D0 (en) 1983-03-30
SE8301786L (en) 1984-06-04
FI80882C (en) 1990-08-10
JPH0439468B2 (en) 1992-06-29
IT8348216A0 (en) 1983-05-04

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