DK157492B - PROCEDURE FOR THE PREPARATION OF 2-THIOPHENIC ACETIC ACID COMPOUNDS - Google Patents
PROCEDURE FOR THE PREPARATION OF 2-THIOPHENIC ACETIC ACID COMPOUNDS Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- 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
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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
- C07D333/24—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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Description
- 1 -- 1 -
DK 157492 BDK 157492 B
Opfindelsen angår en særlig fremgangsmåde til fremstilling af kendte 2-thiopheneddikesyreforbindelser med den almene formel IThe invention relates to a particular process for the preparation of known 2-thiophenacetic acid compounds of general formula I
R? R* kkR? R * kk
«1 ^ XCH-CO,H«1 ^ XCH-CO, H
I 2I 2
RR
10 hvor R betegner alkyl med 1-4 carbonatomer, og R-^, R2 og R^f som kan være ens eller forskellige, hver betegner hydrogen, alkyl med 1-4 carbonatomer eller halogen.Wherein R represents alkyl of 1-4 carbon atoms and R 1, R 2 and R f may be the same or different, each representing hydrogen, alkyl of 1-4 carbon atoms or halogen.
15 Disse forbindelser er mellemprodukter, som kan anvendes til fremstilling af lægemidler, især betændelseshæmmende forbindelser.These compounds are intermediates which can be used in the manufacture of pharmaceuticals, especially anti-inflammatory compounds.
Slutforbindelser, som kan fremstilles ud fra de ved frem-20 gangsmåden ifølge opfindelsen fremstillede forbindelser, er navnlig beskrevet i fransk patentskrift nr. 2.068.425.Final compounds which can be prepared from the compounds of the process according to the invention are described in particular in French Patent Specification No. 2,068,425.
Man kender allerede flere fremgangsmåder til fremstilling af forbindelserne med formlen I.Several methods for preparing the compounds of formula I. are already known.
2525
Bercot-Vatteroni m.fl. beskriver i Bull. Soc. Chim. France 1961 side 1820 følgende fremgangsmåde: 30 35Bercot-Vatteroni et al. describes in Bull. Soc. Chim. France 1961 page 1820 the following procedure: 30 35
DK 157492 BDK 157492 B
- 2 - OHCH0, HCX [J~\ NaCN [j~\ -» L^z1 2-> ^^-ch2cn -1 CO-^Eto 5 3 2 i/ O- ™ 04“ ^Qf-a- 2 - OHCH0, HCX [J ~ \ NaCN [j ~ \ - »L ^ z1 2-> ^^ - ch2cn -1 CO- ^ Eto 5 3 2 i / O- ™ 04“ ^ Qf-a
^ i 3 i R R * alkyl V^ i 3 i R R * alkyl V
F. Clemence m.fl. beskriver i Eur. J. Med. Chem. 1974 (9) 15 390 følgende fremgangsmåde:F. Clemence et al. describes in Eur. J. Med. Chem. 1974 (9) 15,390 the following procedure:
O Ci^^C^'c°2Et 0~if"c°2HO Ci ^^ C ^ 'c ° 2Et 0 ~ if "c ° 2H
20 -0 0 CH, MgI \/ ? ACOH CH^ chco2h ^^2///^^0^-00^20 -0 0 CH, MgI \ /? ACOH CH ^ chco2h ^^ 2 /// ^^ 0 ^ -00 ^
25 CH^ OHCH 2 OH
35 fransk patentskrift nr. 2.398.068 er følgende fremgangs- 2 2q måde beskrevet:French Patent No. 2,398,068 describes the following procedure 2q:
DK 157492 BDK 157492 B
- 3 - n . R 9H3- 3 - n. R 9H3
R1 —p halogenering η—n ^JT~W IR1 - p halogenation η - n ^ JT ~ W I
^1~F~Vc-CH Hal, —v\ JM1-™ Hal2 ,.R^^» 3 ‘»Λ i« b alkalimetal- R1=H eller lavmol. alkyl Hal = halogén hydroxid .^ 1 ~ F ~ Vc-CH Hal, —v \ JM1- ™ Hal2, .R ^^ »3 '» Λ i «b alkali metal- R1 = H or low mol. alkyl Hal = halogen hydroxide.
Rp=Hf carbonhydridgruppe el- ler halogen _ „„R p = Hf hydrocarbon group or halogen
• · ' 2 H• · '2 H
15 Disse fremgangsmåder omfatter mindst 3 trin ud fra thiophen eller et substitueret thiophen.These methods comprise at least 3 steps based on thiophene or a substituted thiophene.
Man har nu realiseret en hidtil ukendt fremgangsmåde til fremstilling af forbindelserne med formlen I i tre trin ud 20 fra et substitueret thiophen eller thiophen. Desuden er denne fremgangsmåde industrielt mere fordelagtig at gennemføre.A novel process for the preparation of the compounds of formula I in three steps out of 20 from a substituted thiophene or thiophene has now been realized. In addition, this approach is industrially more advantageous to implement.
Denne fremgangsmåde er ejendommelig ved, at man omsætter 25 enten et aldehyd med formlen R-CHO, hvor R betegner en al-kylgruppe med 1-4 carbonatomer, i nærværelse af en hydro-genhalogenidsyre eller et reaktionsdygtigt derivat af aldehydet med formlen R-CHO, hvilket derivat fortrinsvis er en forbindelse med formlen R-CH-OAlk, hvor Hal betegner 30 Hal et halogenatom, og Alk betegner en alkylgruppe med fortrinsvis 1-3 carbonatomer, med en forbindelse med formlenThis process is characterized by reacting either an aldehyde of formula R-CHO, wherein R represents an alkyl group of 1-4 carbon atoms, in the presence of a hydrogen halide acid or a reactive derivative of the aldehyde of formula R-CHO which derivative is preferably a compound of formula R-CH-OAlk, wherein Hal represents 30 Hal a halogen atom and Alk represents an alkyl group of preferably 1-3 carbon atoms, with a compound of formula
IIII
3535
DK 157492 BDK 157492 B
- 4 - R« R-r 'b 5 R1- 4 - R «R-r 'b 5 R1
hvor R^, R2 og R^ har samme betydning som ovenfor, til opnåelse af en forbindelse med formlen IIIwherein R 1, R 2 and R 2 have the same meaning as above, to give a compound of formula III
10 Ro R3 ΛΧ R- OH-Hal 1 I ·10 Ro R3 ΛΧ R- OH-Hal 1 I ·
15 . . R15. . R
hvor R, R^, R2^ R3 og Hal betegner det samme som ovenfor, hvilken forbindelse med formlen III man omsætter med en forbindelse med formlen A-CN, hvor A betegner et alkalimetalatom, et ækvivalent jordalkalimetal eller et hydrogen-20 atom, til opnåelse af en forbindelse med formlen IVwherein R, R 2, R 2, R 3 and Hal represent the same as above, which compound of formula III is reacted with a compound of formula A-CN wherein A represents an alkali metal atom, an equivalent alkaline earth metal or a hydrogen atom, to obtaining a compound of formula IV
R« R* K ....R «R * K ....
25 /^S^CH-CN25 S-CH-CN
R1 IR1 I
R · hvor R, R^, R2 og R^ betegner det samme som ovenfor, hvilken forbindelse IV man behandler med et hydrolysemiddel til 30 opnåelse af en tilsvarende forbindelse med formlen I.R 1, wherein R, R 2, R 2 and R 2 represent the same as above, which compound IV is treated with a hydrolyzing agent to give a corresponding compound of formula I.
Blandt de værdier, som substituenterne R, R^, R2 og R^ kan antage, skal nævnes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl eller tert.-butyl. Substituen-35 terne R^, R2 og R^ kan ligeledes betegne et hydrogenatom eller et halogenatom, altså fluor, chlor, brom eller iod.Among the values that the substituents R, R 2, R 2 and R 2 can be assumed are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert-butyl. The substituents R 1, R 2 and R 2 may also represent a hydrogen atom or a halogen atom, i.e. fluorine, chlorine, bromine or iodine.
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- 5 -- 5 -
Det aldehyd, som R-CHO repræsenterer, er det aldehyd, som svarer til den ønskede værdi af R.The aldehyde represented by R-CHO is the aldehyde corresponding to the desired value of R.
Når R betegner methyl, benytter man fortrinsvis paraldehyd, 5 som er trimeren af acetaldehyd. Blandt andre aldehyder kan nævnes propanal og butanal.When R represents methyl, paraldehyde, which is the trimester of acetaldehyde, is preferably used. Other aldehydes include propanal and butanal.
Den hydrogenhalogenidsyre, som man benytter, er fortrinsvis saltsyre eller hydrogenbromidsyre. Navnlig foretrækkes 10 saltsyre.The hydrogen halide acid used is preferably hydrochloric or hydrobromic acid. In particular, 10 hydrochloric acid is preferred.
Den reaktion, som gør det muligt at omdanne forbindelsen med formlen II til forbindelsen med formlen III, altså ha-logenalkyleringen, fortrinsvis chloralkyleringen og ganske 15 særlig chlorethyleringen, kan udføres med eller uden tilsætning af organisk opløsningsmiddel. Blandt de opløsningsmidler, som man kan benytte, skal især nævnes et chlo-reret opløsningsmiddel såsom fortrinsvis methylenchlorid, men man kan også benytte carbontetrachlorid eller chloro-20 form, en ether såsom isopropylether, cyclohexan, ethanol eller methanol. Syntesens fortsættelse udføres bekvemt ud fra en forbindelse III i opløsning. Opløsningsmidlet kan da være et ekstraktionsopløsningsmiddel, som er identisk med eller forskelligt fra reaktionsopløsningsmidlet. Man 25 benytter fortrinsvis et reaktionsopløsningsmiddel. Opløsningsmidlet er fortrinsvis methylenchlorid, som ligeledes benyttes til den afsluttende ekstraktion.The reaction which allows the compound of formula II to be converted to the compound of formula III, i.e., the halogen alkylation, preferably the chloroalkylation and in particular the chloroethylation, can be carried out with or without the addition of organic solvent. Among the solvents which can be used, in particular, mention is made of a chlorinated solvent such as preferably methylene chloride, but one may also use carbon tetrachloride or chloroform, an ether such as isopropyl ether, cyclohexane, ethanol or methanol. The continuation of the synthesis is conveniently carried out from a compound III in solution. The solvent may then be an extraction solvent identical to or different from the reaction solvent. Preferably, a reaction solvent is used. The solvent is preferably methylene chloride, which is also used for the final extraction.
Foruden hydrogenhalogenidsyren, som direkte indgår i reak-30 tionen, kan mediets surhed modificeres ved tilsætning af en anden syre såsom phosphorsyre eller eddikesyre. Man kan ligeledes benytte en Lewis-syre såsom zink- eller alumini-umchlorid.In addition to the hydrogen halide acid which is directly involved in the reaction, the acidity of the medium can be modified by the addition of another acid such as phosphoric acid or acetic acid. A Lewis acid such as zinc or aluminum chloride can also be used.
35 Naturligvis kan de forskellige reaktionsdeltagere i form af thiophen, aldehyd og syre indføres i forskellig rækkefølge alt efter de benyttede operationsbetingelser.Of course, the various reaction participants in the form of thiophene, aldehyde and acid can be introduced in different order according to the operating conditions used.
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- 6 -- 6 -
Reaktionstemperaturen kan ligeledes variere. Man arbejder fortrinsvis ved en temperatur mellem -10°C og stuetemperatur, navnlig ved ca. -5°C.The reaction temperature may also vary. It is preferable to operate at a temperature between -10 ° C and room temperature, especially at approx. -5 ° C.
55
Et særligt eksempel på en sådan reaktion er beskrevet i Org. Synth. Bd. 38 side 86.A particular example of such a reaction is described in Org. Synth. Bd. 38 page 86.
10 Når man benytter et reaktionsdygtigt derivat af aldehydet med formlen R-CHO, er dette reaktionsdygtige derivat fortrinsvis en forbindelse med formlen R-CH-OAlk 15When using a reactive derivative of the aldehyde of formula R-CHO, this reactive derivative is preferably a compound of formula R-CH-OAlk 15
Hal hvor Hal betegner et halogenatom, og Alk betegner en alkyl-gruppe med fortrinsvis 1-3 carbonatomer. Denne forbindelse med formlen R-CH-OAlkHal represents a halogen atom and Alk represents an alkyl group having preferably 1-3 carbon atoms. This compound of formula R-CH-OAlk
U IU I
Hal fremstilles ved indvirkning af aldehydet R-CHO på hydrogen-halogenidsyren med formlen H-Hal i et alkoholisk opløsningsmiddel med formlen Alk-OH. Naturligvis er det reak-25 tionsdygtigt derivat, som man fortrinsvis benytter i dette tilfælde, forbindelsen med formlen CH^-CH-OAlk iHal is prepared by the action of the aldehyde R-CHO on the hydrogen halide acid of formula H-Hal in an alcoholic solvent of formula Alk-OH. Of course, the reactive derivative which is preferably used in this case is the compound of the formula CH 2 -CH-OAlk
Cl 30 som fås ved omsætning af acetaldehyd CH^-CHO med saltsyre i en alkohol med formlen Alk-OH, fortrinsvis methanol eller ethanol.Cl 30 obtained by reaction of acetaldehyde CH 2 -CHO with hydrochloric acid in an alcohol of the formula Alk-OH, preferably methanol or ethanol.
Overgangen af forbindelserne med formlen III til forbindel-35 serne med formlen IV udføres fortrinsvis med et alkalimetal- eller jordalkalimetalcyanid såsom natrium-, kalium-, lithium- eller calciumcyanid. Man kan ligeledes benytte hydrogencyanidsyre. Man foretrækker natriumcyanid. ManThe transition of the compounds of formula III to the compounds of formula IV is preferably carried out with an alkali metal or alkaline earth metal cyanide such as sodium, potassium, lithium or calcium cyanide. Hydrogen cyanic acid can also be used. Sodium cyanide is preferred. You
DK 157492BDK 157492B
- 7 - arbejder med eller uden tilstedeværelsen af en base. Når man arbejder i nærværelse af en base, foretrækker man natrium- eller kaliumhydroxid, især natriumhydroxid. Man arbejder imidlertid fortrinsvis uden base.- 7 - works with or without the presence of a base. When working in the presence of a base, sodium or potassium hydroxide is preferred, especially sodium hydroxide. However, one prefers to work without a base.
55
Det er ganske særlig fordelagtigt, at omsætningen til omdannelse af forbindelserne med formlen III til forbindelserne med formlen IV udføres ved en såkaldt faseoverføringsreaktion. Man arbejder da i nærværelse af en specifik 10 katalysator. Denne katalysator kan fx være et tetraalkyl-eller aralkylammonium-, -phosphonium- eller -arsoniumsalt eller et sulfoniumsalt. Blandt katalysatorerne af denne type kan fx nævnes triethylbenzylammoniumchlorid, tetrapro-pyl- og tetrabutylammoniumbromid, tetrabutylammoniumsulfat, 15 tetrabutylammoniumhydroxid, tetra-n-butylammoniumchlorid, tetramethylphosphoniumiodid og tetra-n-butylphosphoniumbro-mid. Disse salte kan være fikseret på ionbytterharpikser.It is particularly advantageous that the reaction to convert the compounds of formula III to the compounds of formula IV is carried out by a so-called phase transfer reaction. One then works in the presence of a specific catalyst. This catalyst may be, for example, a tetraalkyl or aralkylammonium, phosphonium or arsonium salt or a sulfonium salt. Among the catalysts of this type are, for example, triethylbenzylammonium chloride, tetra-propyl and tetrabutylammonium bromide, tetrabutylammonium sulfate, tetrabutylammonium hydroxide, tetra-n-butylammonium chloride, tetramethylphosphonium iodide and tetra-phosphonium iodide and tetra These salts may be fixed on ion exchange resins.
Man kan ligeledes benytte en makrocyklisk polyether, som 20 normalt betegnes en crown-ether. Sådanne forbindelser er fx beskrevet i Tetrahedron Letters nr. 18 (1972) side 1973.A macrocyclic polyether, usually referred to as a crown ether, can also be used. Such compounds are described, for example, in Tetrahedron Letters No. 18 (1972) page 1973.
Blandt anvendelige forbindelser kan nævnes 1,4,7,10,13,16-hexaoxacyclooctadecan. Man kan endelig benytte de overfla-25 deaktive midler, som dannes ved omsætning af en højmolekylær alkohol eller en fed syre med fx ethylenoxid.Useful compounds include 1,4,7,10,13,16-hexaoxacyclooctadecane. Finally, the surfactants which are formed by reaction of a high molecular weight alcohol or a fatty acid with, for example, ethylene oxide can be used.
Som katalysator benytter man fortrinsvis et ammoniumhaloge-nid, især trialkylbenzyl- eller tetraalkylammoniumchlorid 30 eller -bromid.As an catalyst, an ammonium halide, preferably trialkylbenzyl or tetraalkylammonium chloride or bromide, is preferably used.
Den foretrukne forbindelse er triethylbenzylammoniumchlorid.The preferred compound is triethylbenzylammonium chloride.
35 Ved en foretrukket udførelsesmåde som angivet ovenfor benyttes forbindelsen med formlen III i organisk opløsning, fortrinsvis i methylenchlorid eller dichlorethan. Man kanIn a preferred embodiment as indicated above, the compound of formula III is used in organic solution, preferably in methylene chloride or dichloroethane. You can
DK 157492 BDK 157492 B
- 8 - ligeledes benytte et polært opløsningsmiddel såsom dimethyl formamid eller dimethylsulfoxid. Man benytter navnlig methylenchlorid.- 8 - also use a polar solvent such as dimethyl formamide or dimethyl sulfoxide. Methylene chloride in particular is used.
5 Mængden af faseoverføringskatalysator kan variere efter de benyttede reaktioner. Den kan fx variere fra 0,2 til 0,5 dele i forhold til forbindelsen med formlen III.The amount of phase transfer catalyst may vary according to the reactions used. For example, it may range from 0.2 to 0.5 parts relative to the compound of formula III.
Temperaturen kan variere mellem 0°C og tilbagesvalingstem-10 peraturen for opløsningsmidlet. Man arbejder fortrinsvis ved en lav temperatur af størrelsesordenen 0-5°C.The temperature may vary between 0 ° C and the reflux temperature of the solvent. It is preferred to operate at a low temperature of the order of 0-5 ° C.
Hydrolysen af forbindelsen med formlen IV til forbindelsen med formlen I kan ske ved at omdanne nitrilen til først et 15 salt, fortrinsvis natrium- eller kaliumsalt af den ønskede syre.The hydrolysis of the compound of formula IV to the compound of formula I can be effected by converting the nitrile to first a salt, preferably sodium or potassium salt of the desired acid.
På dette stadium kan man rense den vandige fase med et organisk opløsningsmiddel. Endelig syrner man den vandige 20 fase og ekstraherer den ønskede forbindelse.At this stage, the aqueous phase can be purified with an organic solvent. Finally, the aqueous phase is acidified and the desired compound is extracted.
Den første fase udføres enten i vand eller i en blanding af vand og et med vand blandbart opløsningsmiddel. Som opløsningsmiddel benytter man da fortrinsvis en lavmolekylær al-25 kohol såsom ethanol eller isopropanol. Det alkaliske middel, fortrinsvis natrium- eller kaliumhydroxid, omsættes fortrinsvis ved en temperatur mellem 50°C og tilbagesvalingstemperaturen. Man arbejder fortrinsvis under tilbagesvaling i rent vand. Varigheden af reaktionen kan være 30 mellem 2 timer og 15 timer. Det organiske opløsningsmiddel, hvormed man kan rense den opnåede vandige saltopløsning, vælges fortrinsvis blandt toluen, dichlorethan og me-thylenchlorid, fortrinsvis methylenchlorid.The first phase is carried out either in water or in a mixture of water and a water-miscible solvent. A low molecular alcohol such as ethanol or isopropanol is then preferably used as a solvent. The alkaline agent, preferably sodium or potassium hydroxide, is preferably reacted at a temperature between 50 ° C and the reflux temperature. Preference is given to refluxing in pure water. The duration of the reaction can be 30 between 2 hours and 15 hours. The organic solvent to purify the aqueous saline solution obtained is preferably selected from toluene, dichloroethane and methylene chloride, preferably methylene chloride.
35 Den endelige syrning udføres fortrinsvis med koncentreret saltsyre. Reaktionen udføres med fordel efter tilsætning af et opløsningsmiddel, som vælges blandt de netop nævnte.The final acidification is preferably carried out with concentrated hydrochloric acid. The reaction is advantageously carried out after the addition of a solvent selected from those just mentioned.
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Man arbejder ved en temperatur, som kan variere mellem stuetemperatur og opløsningsmidlets tilbagesvalingstemperatur.You operate at a temperature which can vary between room temperature and the reflux temperature of the solvent.
5 Hydrolysen af forbindelsen med formlen IV til forbindelsen med formlen I kan ligeledes udføres i surt miljø, fortrinsvis i nærværelse af en uorganisk syre såsom saltsyre, svovlsyre eller phosphorsyre.The hydrolysis of the compound of formula IV to the compound of formula I can also be carried out in an acidic environment, preferably in the presence of an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid.
10 Opfindelsen angår navnlig en fremgangsmåde til fremstilling af en forbindelse med formlen 1' O-In particular, the invention relates to a process for preparing a compound of formula I
CH—C09 HCH-CO9 H
15 i ^15 i ^
RR
hvor R har samme betydning som ovenfor, og denne fremgangsmåde er ejendommelig ved, at man anvender den ovenfor an-20 givne fremgangsmåde, idet man går ud fra thiophen.wherein R has the same meaning as above, and this process is peculiar to using the above method, starting from the thiophene.
Forbindelserne med formlen 1' svarer til forbindelserne med formlen I, hvor , R£ og R^ hver betegner et hydrogenatom.The compounds of formula 1 'correspond to the compounds of formula I, wherein, R og and R et each represent a hydrogen atom.
25 Specielt angår den foreliggende opfindelse en fremgangsmåde til fremstilling af alpha-methyl-2-thiopheneddikesyre, som er ejendommelig ved, at man benytter den ovenfor beskrevne fremgangsmåde, idet man går ud fra thiophen og acetaldehyd.In particular, the present invention relates to a process for the preparation of alpha-methyl-2-thiophenacetic acid which is characterized by using the process described above, starting from thiophene and acetaldehyde.
30 Blandt de foretrukne udførelsesformer for fremgangsmåden ifølge opfindelsen er en fremgangsmåde, som er ejendommelig ved, at indvirkningen af forbindelsen med formlen A-CN på forbindelsen med formlen III udføres ved en faseoverføringsreaktion .Among the preferred embodiments of the process of the invention is a process which is characterized in that the effect of the compound of formula A-CN on the compound of formula III is effected by a phase transfer reaction.
Denne fremgangsmåde udføres fortrinsvis i nærværelse af en katalysator, som vælges blandt triethylbenzylammoniumchlo- 35This process is preferably carried out in the presence of a catalyst selected from triethylbenzylammonium chloride.
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- 10 - rid, tetrapropylammoniumbromid, tetrabutylammoniumbromid, tetrabutylammoniumsulfat og tetrabutylammoniumhydroxid.- 10 - riding, tetrapropylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium sulfate and tetrabutylammonium hydroxide.
Ved en særlig fordelagtig udførelsesform for fremgangsmåden 5 hælder man forbindelsen med formlen III opløst i methylen-chlorid i en vandig opløsning af natriumcyanid og en faseoverføringskatalysator. Paseoverføringskatalysatoren er som angivet ovenfor fortrinsvis triethylbenzylammoniumchlo-rid.In a particularly advantageous embodiment of process 5, the compound of formula III dissolved in methylene chloride is poured into an aqueous solution of sodium cyanide and a phase transfer catalyst. The phase transfer catalyst, as indicated above, is preferably triethylbenzylammonium chloride.
1010
Endelig iværksætter man den omhandlede fremgangsmåde under følgende foretrukne betingelser til fremstilling af alpha-methyl-2-thiopheneddikesyre: Man lader saltsyre og paral dehyd indvirke på thiophen til opnåelse af 2-(l-chlor-15 ethyl)-thiophen, som man i en faseoverføringsreaktion underkaster indvirkning af natriumcyanid i nærværelse af tri-ethylbenzylammoniumchlorid til opnåelse af alpha-methyl-2-thiophenacetonitril, som man først underkaster indvirkning af natriumhydroxid og derpå indvirkning af saltsyre til op-20 nåelse af den ønskede forbindelse.Finally, the subject process is carried out under the following preferred conditions for the preparation of alpha-methyl-2-thiophenacetic acid: Hydrochloric acid and paral dehyde are allowed to act on thiophene to give 2- (1-chloro-ethyl) -thiophene which phase transfer reaction undergoes the action of sodium cyanide in the presence of triethylbenzylammonium chloride to give alpha-methyl-2-thiophenacetonitrile, which is first subjected to the action of sodium hydroxide and then the effect of hydrochloric acid to give the desired compound.
Nedenstående eksempler illustrerer fremgangsmåden ifølge opfindelsen.The following examples illustrate the method of the invention.
25 Eksempel 1 alpha-methyl-2-thiopheneddikesyre Trin Å: 2-(1-chlorethyl)-thiophenExample 1 alpha-methyl-2-thiophenacetic acid Step A: 2- (1-chloroethyl) -thiophene
Man afkøler under omrøring til -5°C en blanding af 336 ml methylenchlorid og 75 ml saltsyre, og derpå indfører man 30 ved denne temperatur i løbet af 5 timer dels en blanding af 84 g thiophen og 44 g paraldehyd, dels 36,5 g gasformigt hydrogenchlorid. Man omrører og tilsætter i løbet af 30 minutter 3,5 g saltsyre. Man omrører 3 timer ved -5°C, bringer på 0°C og indfører 50 g is. Man omrører ved 0-5°C 35 i 15 minutter, dekanterer den organiske fase, ekstraherer den vandige fase ved 0-5°C med 42 ml methylenchlorid og forener de to organiske faser.A mixture of 336 ml of methylene chloride and 75 ml of hydrochloric acid is cooled under stirring to -5 ° C, then a mixture of 84 g of thiophene and 44 g of paraldehyde is added over a period of 5 hours and 36.5 g of gaseous hydrogen chloride. 3.5 g of hydrochloric acid are stirred and added over 30 minutes. Stir for 3 hours at -5 ° C, bring to 0 ° C and introduce 50 g of ice. Stir at 0-5 ° C for 15 minutes, decant the organic phase, extract the aqueous phase at 0-5 ° C with 42 ml of methylene chloride and combine the two organic phases.
DK 157492 BDK 157492 B
- n -- n -
Trin B: alpha-methyl-2—thiophenacetonitrilStep B: alpha-methyl-2-thiophenacetonitrile
Man sætter 8,4 g triethylbenzylammoniumchlorid til en til 0-5°C afkølet opløsning af 88,5 g natriumcyanid i 168 ml afmineraliseret vand. Den ovennævnte methylenchloridopløs-5 ning af 2-(1-chlorethyl)-thiophen hældes i løbet af 1 minut i mediet, som holdes under omrøring. Man holder under voldsom omrøring i 18 timer ved 0-5°C og tilsætter derpå 252 ml afmineraliseret vand. Man omrører 10 minutter, afdekanterer den organiske fase og ekstraherer den vandige fase med 10 84 ml methylenchlorid og derefter med 2 gange 42 ml af sam me opløsningsmiddel. Man forener de organiske faser og vasker dem med afmineraliseret vand, med vand tilsat 1% saltsyre samt atter med afmineraliseret vand.8.4 g of triethylbenzylammonium chloride are added to a solution cooled to 0-5 ° C of 88.5 g of sodium cyanide in 168 ml of demineralized water. The above methylene chloride solution of 2- (1-chloroethyl) thiophene is poured over 1 minute into the medium which is kept under stirring. Vigorously stir for 18 hours at 0-5 ° C and then 252 ml of demineralized water is added. Stir for 10 minutes, decant the organic phase and extract the aqueous phase with 10 84 ml of methylene chloride and then with 2 times 42 ml of the same solvent. The organic phases are combined and washed with demineralized water, with water added with 1% hydrochloric acid and again with demineralized water.
15 Den organiske fase inddampes under formindsket tryk i 2 timer. Der fås 105 g af den forventede forbindelse.The organic phase is evaporated under reduced pressure for 2 hours. 105 g of the expected compound are obtained.
Trin C: alpha-methyl-2-thiopheneddikesyreStep C: alpha-methyl-2-thiophenacetic acid
Man tilbagesvaler i 2 timer 30 minutter en blanding af 20 105 g af den ovenfor opnåede forbindelse, 500 uni afminera liseret vand og 63,2 g natriumhydroxid. Man afkøler til 20°C og tilsætter 1'68 ml methylenchlorid. Man omrører 10 minutter og afdekanterer methylenchloridfasen. Man foretager samme operation yderligere 2 gange. Til den 25 vandige fase sætter man 168 ml toluen og derpå 168 ml 22° Bé saltsyre. Man opvarmer 1 time til tflbagesvaling, afkøler til 20°C, omrører 15 minutter, dekanterer den vandige fase og vasker 4 gange med 42 ml afmineraliseret vand hver gang. Man inddamper den organiske fase under 30 formindsket tryk. Der fås 71-74 g af den forventede forbindelse, kp. ved 1,5 mm Hg = 117-118°C, kp. ved 0,5 mm Hg = 110°C.A mixture of 20 105 g of the above-obtained compound, 500 µl of demineralized water and 63.2 g of sodium hydroxide is refluxed for 2 hours for 30 minutes. Cool to 20 ° C and add 1'68 ml of methylene chloride. Stir for 10 minutes and decant the methylene chloride phase. The same operation is performed two more times. To the aqueous phase, 168 ml of toluene and 168 ml of 22 ° B hydrochloric acid are added. Heat for 1 hour to reflux, cool to 20 ° C, stir for 15 minutes, decant the aqueous phase and wash 4 times with 42 ml of demineralized water each time. The organic phase is evaporated under reduced pressure. 71-74 g of the expected compound are obtained, b.p. at 1.5 mm Hg = 117-118 ° C, bp. at 0.5 mm Hg = 110 ° C.
Eksempel 2 35 Trin A-C ovenfor kan modificeres som følger:Example 2 Step A-C above can be modified as follows:
DK 157492 BDK 157492 B
- 12 -- 12 -
Trin A^~: 2- (1-chlorethyl) -thiophenStep A2: 2- (1-Chloroethyl) -thiophene
Man lader i 25 minutter gasformigt hydrogenchlorid indtil mætning boble gennem en blanding af 84 g thiophen, 44 g paraldehyd og 75 ml 22° Bé saltsyre, idet man holder tempe-5 raturen på 10-13°C.Gaseous hydrogen chloride is allowed to bubble for 25 minutes until saturation is bubbled through a mixture of 84 g of thiophene, 44 g of paraldehyde and 75 ml of 22 ° Bé hydrochloric acid, maintaining the temperature at 10-13 ° C.
Man hælder i 75 ml iskoldt vand, dekanterer, ekstraherer den vandige fase med 168 ml methylenchlorid og vasker den organiske fase 3 gange med 50 ml iskoldt vand.Pour into 75 ml of ice-cold water, decant, extract the aqueous phase with 168 ml of methylene chloride and wash the organic phase 3 times with 50 ml of ice-cold water.
10 210 2
Trin A :Step A:
Man indfører ved 10°C gasformigt hydrogenchlorid indtil mætning i en blanding af 46 g ethanol og 44 g paraldehyd.Gaseous hydrogen chloride is introduced at 10 ° C until saturation in a mixture of 46 g ethanol and 44 g paraldehyde.
Dette reagens sættes i løbet af 10 minutter ved 10°C under 15 omrøring til 84 g thiophen. Man fortsætter derpå som angivet under A^, 2. afsnit.This reagent is added over 10 minutes at 10 ° C with stirring to 84 g of thiophene. Then proceed as indicated under A ^, 2nd paragraph.
33
Trin A :Step A:
Man omrører ved 10-13°C en blanding af 84 g thiophen, 44 g 20 paraldehyd, 168 ml methylenchlorid og 75 ml 22° Bé saltsyre. Man mætter med 40 g gasformigt hydrogenchlorid og afkøler derpå til 0°C. Man tilsætter 50 g is, dekanterer, ekstraherer den vandige fase med 42 ml methylenchlorid og vasker de forenede organiske faser med 2 gange 63 ml is-25 koldt vand.A mixture of 84 g of thiophene, 44 g of paraldehyde, 168 ml of methylene chloride and 75 ml of 22 ° B hydrochloric acid is stirred at 10-13 ° C. Saturate with 40 g of gaseous hydrogen chloride and then cool to 0 ° C. 50 g of ice are added, decanted, the aqueous phase is extracted with 42 ml of methylene chloride and the combined organic phases are washed with 2 times 63 ml of ice-25 cold water.
Trin B^:Step B
Triethylbenzylammoniumchloridet erstattes med følgende reagenser: 30 - tetrapropylammoniumbromid, - tetrabutylammoniumbromid, tetrabutylammoniumsulfat, tetrabutylammoniumhydroxid.The triethylbenzylammonium chloride is replaced with the following reagents: - tetrapropylammonium bromide, - tetrabutylammonium bromide, tetrabutylammonium sulfate, tetrabutylammonium hydroxide.
35 Trin C1:Step C1:
Man benytter dichlorethan i stedet for methylenchlorid som ekstraktionsopløsningsmiddel.Dichloroethane is used instead of methylene chloride as the extraction solvent.
Claims (6)
Applications Claiming Priority (2)
| 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 |
| FR8220272 | 1982-12-03 |
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| Publication Number | Publication Date |
|---|---|
| DK140083D0 DK140083D0 (en) | 1983-03-28 |
| DK140083A DK140083A (en) | 1984-06-04 |
| DK157492B true DK157492B (en) | 1990-01-15 |
| DK157492C DK157492C (en) | 1990-06-11 |
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| JP (1) | JPS59106483A (en) |
| KR (1) | KR900003281B1 (en) |
| AT (1) | AT392785B (en) |
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| 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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| ZA (1) | ZA832697B (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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| IE33054B1 (en) * | 1968-04-16 | 1974-03-06 | Ici Ltd | Heterocyclic compounds |
| GB2003570B (en) * | 1977-06-08 | 1982-01-20 | Imi Opella Ltd | Stop valve |
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1982
- 1982-12-03 FR FR8220272A patent/FR2537138A1/en active Granted
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1983
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- 1983-03-31 FI FI831116A patent/FI80882C/en not_active IP Right Cessation
- 1983-04-05 ES ES521231A patent/ES8401958A1/en not_active Expired
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- 1983-04-23 KR KR1019830001730A patent/KR900003281B1/en not_active IP Right Cessation
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