DK157493B - PROCEDURE FOR PREPARING ALPHA-HYDROXY-2-THIOPHENIC ACETIC ACID COMPOUNDS - Google Patents
PROCEDURE FOR PREPARING ALPHA-HYDROXY-2-THIOPHENIC ACETIC ACID COMPOUNDS Download PDFInfo
- Publication number
- DK157493B DK157493B DK307583A DK307583A DK157493B DK 157493 B DK157493 B DK 157493B DK 307583 A DK307583 A DK 307583A DK 307583 A DK307583 A DK 307583A DK 157493 B DK157493 B DK 157493B
- Authority
- DK
- Denmark
- Prior art keywords
- compound
- formula
- alpha
- hydroxy
- methyl
- Prior art date
Links
Classifications
-
- 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
- C07D333/26—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
-
- 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
Description
- 1 -- 1 -
DK 157493 BDK 157493 B
Opfindelsen angår en særlig fremgangsmåde til fremstilling af kendte alpha-hydroxy-2-thiopheneddikesyreforbin-delser med den almene formel IThe invention relates to a particular process for the preparation of known alpha-hydroxy-2-thiophenacetic acid compounds of the general formula I
5 R2 R3 ytr (i)R2 R3 surface (i)
1 R1 R
10 hvor R betegner alkyl med 1-4 carbonatomer, og R^, R2 og R^, som kan være ens eller forskellige, hver betegner hydrogen eller alkyl med 1-4 carbonatomer.Wherein R represents alkyl of 1-4 carbon atoms and R 1, R 2 and R 2, which may be the same or different, each represent hydrogen or alkyl of 1-4 carbon atoms.
Disse forbindelser er mellemprodukter, som kan benyttes 15 til fremstillingen af farmaceutiske produkter, især betændelseshæmmende forbindelser.These compounds are intermediates which can be used in the preparation of pharmaceutical products, especially anti-inflammatory compounds.
Ud fra forbindelserne med formlen I kan man ifølge den fremgangsmåde, som er beskrevet af P. Clemence m.fl. i Eur. J. Med. Chem. 1974 (9) 390 eller i fransk patentskrift 20 nr. 2.167.334, fremstille forbindelser med formlen AFrom the compounds of formula I, according to the method described by P. Clemence et al. in Eur. J. Med. Chem. 1974 (9) 390 or in French Patent 20 No. 2,167,334, prepare compounds of formula A
R2 R5 yt &R2 R5 yt &
O B-€0oHO B- € 0oH
25 Rl λ 2 .25 Rl λ 2.
hvor R, R-^, R2 og R3 har samme betydning som ovenfor.wherein R, R 1, R 2 and R 3 have the same meaning as above.
Denne fremgangsmåde udmærker sig ved, at man benytter et 30 mildt metalreduktions middel såsom stannochlorid i saltsurt medium.This process is distinguished by the use of a mild metal reducing agent such as stannous chloride in hydrochloric acid medium.
Disse forbindelser med formlen A kan derpå omdannes til slutprodukter med farmakologiske egenskaber. En sådan omdannelse er f.eks. beskrevet i fransk patentskrift nr.These compounds of formula A can then be converted into end products with pharmacological properties. Such a transformation is e.g. disclosed in French patent no.
35 2.068.425 eller i ovennævnte franske patentskrift nr. 2.167.334.35,068,425 or in the aforementioned French Patent Specification No. 2,167,334.
- 2 -- 2 -
DK 157493 BDK 157493 B
I ovennævnte Eur. J. Med. Chem. 1974 (9) 390 har man beskrevet en metode til fremstilling af forbindelserne med formlen I. Denne fremgangsmåde er som følger: Q cicoco2Et ? (^_c-co2st cf_^ ζ>_ο-αο2Η o oIn the above Eur. J. Med. Chem. 1974 (9) 390 discloses a method for preparing the compounds of formula I. This process is as follows: Q cicoco2Et? (^ _c-co2st cf_ ^ ζ> _ο-αο2Η o o
i/ CHj Mg Ii / CH 2 Mg I
Af3 · xs^r-co,H (i)Af3 · xs ^ r-co, H (i)
Ah 2 15 Man har nu realiseret en hidtil ukendt fremgangsmåde til fremstilling af forbindelserne med formlen I ud fra magnesiumderivatet af et 2-halogenthiophen og en syre med formlen R-CO-COOH eller et alkalimetalsalt eller jord-alkalimetalsalt deraf.Ah 2 A novel process for preparing the compounds of formula I from the magnesium derivative of a 2-halogen thiophene and an acid of the formula R-CO-COOH or an alkali metal salt or alkaline earth metal salt thereof has now been realized.
20 Disse to typer af forbindelser er let tilgængelige, og reaktionen kan udføres uden isolering af mellemprodukter. Fremgangsmåden udgør en bekvem kombination af trin og en yderligere adgangsvej til de omhandlede mellemprodukter.These two types of compounds are readily available and the reaction can be carried out without isolation of intermediates. The process provides a convenient combination of steps and a further access route to the intermediates in question.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved,The process according to the invention is characterized by
25 at man omsætter en forbindelse med formlen II25 to react a compound of formula II
X» . » 30X ». »30
hvor R^, R2f og R^ har samme betydning som ovenfor, og hvor X betegner et halogenatom, med en forbindelse med formlen IIIwherein R 2, R 2f and R 2 have the same meaning as above and where X represents a halogen atom, with a compound of formula III
R-C0-C00A (III) hvor R har samme betydning som ovenfor, og A betegner et hydrogenatom, et alkalimetalatom eller et ækvivalent af et 35 - 3 -R-C0-C00A (III) wherein R has the same meaning as above and A represents a hydrogen atom, an alkali metal atom or an equivalent of a 35 - 3 -
DK 157493 BDK 157493 B
jordalkalimetal, til opnåelse - efter hydrolyse - af den ønskede forbindelse med formlen I. Blandt de værdier, som substituenterne R, R-^, R2 og R^ kan betegne, kan man nævne methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl 5 eller tert.-butyl.alkaline earth metal to give - after hydrolysis - the desired compound of formula I. Among the values which the substituents R, R 1, R 2 and R 2 can denote are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.-butyl.
X kan betegne chlor, iod eller brom, fortrinsvis brom.X may represent chlorine, iodine or bromine, preferably bromine.
Foruden værdien hydrogen kan A især betegne natrium, kalium eller lithium. Man foretrækker hydrogen eller lithium, navnlig lithium. A kan ligeledes betegne et ækvivalent af 10 jordalkalimetal såsom magnesium, calcium eller barium.In addition to the value of hydrogen, A may in particular denote sodium, potassium or lithium. Hydrogen or lithium, especially lithium, is preferred. A can also denote an equivalent of 10 alkaline earth metals such as magnesium, calcium or barium.
Det magnesiumderivat med formlen II, som man omsætter med forbindelsen med formlen III, fremstilles fortrinsvis på stedet i et organisk opløsningsmiddel såsom tetrahydrofuran eller ethylether.The magnesium derivative of formula II which is reacted with the compound of formula III is preferably prepared on-site in an organic solvent such as tetrahydrofuran or ethyl ether.
15 Når man benytter et alkalimetalsalt, fortrinsvis lithiumsalt, som forbindelse med formlen III, kan dette salt ligeledes fremstilles på stedet i et organisk opløsningsmiddel såsom toluen eller tetrahydrofuran. Man kan ligeledes benytte benzen eller en ether såsom ethylether.When an alkali metal salt, preferably lithium salt, is used as a compound of formula III, this salt can also be prepared on-site in an organic solvent such as toluene or tetrahydrofuran. One can also use benzene or an ether such as ethyl ether.
20 Man kan foretage reaktionen i opløsningsmidlet til fremstilling af magnesiumderivatet eller den ovenfor angivne blanding af opløsningsmidler.The reaction can be carried out in the solvent to prepare the magnesium derivative or the above mixture of solvents.
Hydrolysen udføres i surt vandigt miljø, idet den benyttede syre er saltsyre, svovlsyre eller eddikesyre. Man 25 kan ligeledes arbejde i nærværelse af ammoniumchlorid.The hydrolysis is carried out in an acidic aqueous environment, the acid used being hydrochloric acid, sulfuric acid or acetic acid. Man 25 may also work in the presence of ammonium chloride.
Opfindelsen angår navnlig en fremgangsmåde til fremstilling af en forbindelse med formlen I'.In particular, the invention relates to a process for preparing a compound of formula I '.
30 €M-co2H (i'):30 € M-co 2 H (i '):
I 2 RI 2 R
hvor R har samme betydning som ovenfor, og denne fremgangsmåde er ejendommelig ved,at man benytter den ovenfor 35 beskrevne fremgangsmåde ud fra et 2-thienylmagnesiumhalo-genid.wherein R has the same meaning as above, and this process is peculiar to using the method described above from a 2-thienylmagnesium halide.
Fremgangsmåden ifølge opfindelsen angår specielt frem-The process according to the invention relates in particular to
DK 157493 BDK 157493 B
- 4 - stillingen af en forbindelse med formlen I', hvor R betegner methyl eller ethyl, og denne fremgangsmåde er ejendommelig ved, at man benytter den ovenfor beskrevne fremgangsmåde med en forbindelse med formlen III, hvor R betegner methyl eller 5 ethyl.The position of a compound of formula I 'wherein R represents methyl or ethyl and this process is characterized by using the above-described process with a compound of formula III wherein R represents methyl or ethyl.
Navnlig angår fremgangsmåden ifølge opfindelsen fremstillingen af alpha-methyl-alpha-hydroxy-2-thiopheneddike-syre, hvor man i den ovenfor beskrevne fremgangsmåde benytter en forbindelse med formlen II, hvor R-jyR2 °9 R3 hver især 10 betegner et hydrogenatom, og en forbindelse med formlen III, hvor R betegner methyl.In particular, the process of the invention relates to the preparation of alpha-methyl-alpha-hydroxy-2-thiophene acetic acid, using the compound of formula II described above, wherein R-yyR 2 ° 9 R 3 each represents a hydrogen atom, and a compound of formula III wherein R is methyl.
Som udgangsprodukt ved den omhandlede fremgangsmåde benytter man fortrinsvis en forbindelse med formlen II, hvor X betegner et bromatom, og en forbindelse med formlen III, 15 hvor Ά betegner hydrogen eller lithium.As a starting product of the present process, a compound of formula II is preferably used, where X represents a bromine atom and a compound of formula III, 15 wherein Ά represents hydrogen or lithium.
Hydrolysen udføres især i vandigt surt miljø.Hydrolysis is performed especially in aqueous acidic environment.
Endelig angår opfindelsen specielt en fremgangsmåde til fremstilling af alpha-methyl-alpha-hydroxy-2-thiopheneddike-syre, og denne fremgangsmåde er ejendommelig ved, at man 20 lader 2-thienylmagnesiumbromid indvirke på lithiumpyruvat og hydrolyserer den fremkomne forbindelse ved hjælp af saltsyre.Finally, the invention relates in particular to a process for the preparation of alpha-methyl-alpha-hydroxy-2-thiophenacetic acid, and this process is characterized in that 2-thienylmagnesium bromide is allowed to act on lithium pyruvate and hydrolyzes the resulting compound by hydrochloric acid.
Nedenstående eksempler illustrerer fremgangsmåden ifølge opfindelsen.The following examples illustrate the method of the invention.
25 30 35 - 5 -25 30 35 - 5 -
DK 157493 BDK 157493 B
Eksempel 1 alpha-methyl-alpha-hydroxy-2-thiopheneddikesyre a) Fremstilling af lithiumpyruvatExample 1 alpha-methyl-alpha-hydroxy-2-thiophenacetic acid a) Preparation of lithium pyruvate
Man opvarmer til kogning en suspension af 7,96 kg 5 lithiumcarbonat i 210 liter toluen og indfører i løbet af 2-3 timer under omrøring og under opretholdelse af en indvendig temperatur på 105-108°C, og idet man afdekanterer det dannede vand, 24,6 kg pyrodruesyre. Man opretholder tilbagesvalingen 1 time 30 minutter, idet man afdekanterer 10 4 liter af en blanding af dannet vand og pyrodruesyre.To boil, a suspension of 7.96 kg of lithium carbonate in 210 liters of toluene is heated and stirred for 2-3 hours while maintaining an internal temperature of 105-108 ° C and decanting the water formed. 24.6 kg of pyruvic acid. The reflux is maintained for 1 hour 30 minutes, decanting 10 4 liters of a mixture of formed water and pyruvic acid.
Man destilierer ved atmosfæretryk i løbet af ca. 30 minutter til eliminering af de sidste spor af vand og syre.Distillate at atmospheric pressure over approx. 30 minutes to eliminate the last traces of water and acid.
Der fås således 35 liter af en blanding af toluen, syre og vand.Thus, 35 liters of a mixture of toluene, acid and water are obtained.
15 b) Fremstilling af thienylmagnesiumbromidB) Preparation of thienylmagnesium bromide
Man indfører under argonatmosfære 5,74 kg magnesiumdrejespåner i 81,5 liter tetrahydrofuran og derefter ca. 2,5 g sublimeret iod. Man omrører i 10 minutter ved 2-25°C og indfører ca. 5 liter af en 20 opløsning af 35 kg 2-brom-thiophen i 60 liter tetrahydrofuran. Efter indledning af en reaktion lader man temperaturen stige til 35°C, og når den er stabiliseret, indfører man på regelmæssig måde i løbet af 1 time 30 minutter og under opretholdelse af temperaturen 25 resten af den ovenfor fremstillede opløsning af 2-brom- thiophen. Efter afsluttet tilsætning omrører man i 2 timer under argonatmosfære, idet man holder temperaturen på 30-35°C.Under argon atmosphere, 5.74 kg of magnesium turnips are introduced into 81.5 liters of tetrahydrofuran and then approx. 2.5 g of sublimated iodine. Stir for 10 minutes at 2-25 ° C and introduce approx. 5 liters of a 20 solution of 35 kg of 2-bromothiophene in 60 liters of tetrahydrofuran. After initiating a reaction, the temperature is allowed to rise to 35 ° C and, when stabilized, is introduced on a regular basis over 1 hour 30 minutes and maintaining the temperature of the remainder of the 2-bromothiophene solution prepared above. . After completion of the addition, stir for 2 hours under an argon atmosphere, maintaining the temperature of 30-35 ° C.
c) Kondensation 30 Man afkøler under omrøring til -15°C den ovenfor under a) fremstillede suspension af lithiumpyruvat og indfører på regelmæssig måde i løbet af ca. 5 minutter og under overføring ved hjælp af nitrogentryk den ovenfor under b) fremstillede opløsning af magnesiumderivat, idet man 35 samtidig afkøler suspensionen ved hjælp af en udvendig cirkulation af saltvand ved en temperatur på mellem -15 og - 6 -c) Condensation 30 The mixture of lithium pyruvate prepared above under a) is cooled with stirring to -15 ° C and introduced in a regular manner over approx. 5 minutes and under transfer by means of nitrogen pressure the solution of magnesium derivative prepared above under b) while simultaneously cooling the suspension by means of an external circulation of saline at a temperature between -15 and -6 -
DK 157493 BDK 157493 B
-20°C. Temperaturen stiger til ca. 45°C. Under tilsætningen dispergeres magnesiumderivatopløsningen ved hurtig omrøring. Man skyller ved hjælp af 35 liter tetrahydrofuran, og derpå sænker man på regelmæssig måde i løbet af ca. 35 5 minutter den indvendige temperatur til 20-25°C, og man omrører i ca. 16 timer under nitrogenatmosfære ved denne temperatur .-20. The temperature rises to approx. 45 ° C. During the addition, the magnesium derivative solution is dispersed by rapid stirring. Rinse with 35 liters of tetrahydrofuran and then lower regularly in approx. The internal temperature is maintained at 20-25 ° C for 5 minutes and stirred for approx. 16 hours under nitrogen atmosphere at this temperature.
I løbet af ca. 15 minutter hælder man suspensionen i en blanding af 140 kg knust is og 47 liter saltsyre. Man 10 holder den indvendige temperatur på 25°C ved tilsætning af is efter behov. Man skyller apparatet med 50 liter vand og indstiller pH-værdien på 1 ved hjælp af saltsyre. Man omrører ved 20-25°C indtil fuldstændig opløsning, fraskiller den organiske fase og ekstraherer den vandige fase 3 gange 15 med 20 liter toluen hver gang. Man forener de organiske faser og tilsætter 12 liter vand. Derpå indfører man langsomt indtil en pH-værdi på 4 ca. 1,5 liter ammoniak. Man dekanterer og foretager en anden vaskning med 12 liter af-mineraliseret vand og tilsætter derpå lidt ammoniak indtil 20 en pH-værdi på 4. Man fraskiller den organiske fase og inddamper den under formindsket tryk indtil et rumfang på 122 liter, idet man holder den indvendige temperatur under 40°C. Der fås således ca. 175 liter toluen indeholdende tetrahydrofuran, vand og den ønskede forbindelse. Man fo-25 retager 3 på hinanden følgende destillationer med hver gang 70 liter toluen. Man afkøler til 0°C og omrører i 2 timer ved denne temperatur. Man frasuger den fremkomne forbindelse og vasker 2 gange med 35 liter toluen ved 0°C, tørrer i tørreskab og får 27,35 kg af den forventede forbindelse 30 med smp. 115°C .Over approx. For 15 minutes, pour the suspension into a mixture of 140 kg of crushed ice and 47 liters of hydrochloric acid. The internal temperature of 25 ° C is maintained by the addition of ice as needed. Rinse the apparatus with 50 liters of water and adjust the pH to 1 with hydrochloric acid. Stir at 20-25 ° C until complete dissolution, separate the organic phase and extract the aqueous phase 3 times 15 with 20 liters of toluene each time. The organic phases are combined and 12 liters of water are added. Then slowly enter until a pH of 4 approx. 1.5 liters of ammonia. Decant and wash another with 12 liters of de-mineralized water and then add a little ammonia up to 20 to a pH of 4. The organic phase is separated and evaporated under reduced pressure to a volume of 122 liters, holding it. internal temperature below 40 ° C. Thus, approx. 175 liters of toluene containing tetrahydrofuran, water and the desired compound. Three consecutive distillations are made with 70 liters of toluene each time. Cool to 0 ° C and stir for 2 hours at this temperature. The resulting compound is aspirated and washed twice with 35 liters of toluene at 0 ° C, dried in a drying cabinet and 27.35 kg of the expected compound are obtained with m.p. 115 ° C.
Anvende1seseksempe1 alpha-methy1-2-thiopheneddikesyreUse example alpha-methyl-2-thiophenetic acetic acid
Man opvarmer til 40°C under nitrogenatmosfære en blanding af 75 liter 22° Bé saltsyre og 75 kg stannochlo-35 rid, hvortil der på én gang er sat 125 liter iseddike.A mixture of 75 liters of 22 ° B hydrochloric acid and 75 kg of stannous chloride was added to 40 ° C under a nitrogen atmosphere to which 125 liters of glacial acetic acid were added at one time.
Efter opløsning indfører man på regelmæssig måde under omrøring og gennembobling af nitrogen i 30 minutter - 7 -After dissolving, stirring and bubbling nitrogen regularly for 30 minutes - 7 -
DK 157493 BDK 157493 B
50 kg alpha-methyl-alpha-hydroxy-2-thiopheneddikesyre.50 kg of alpha-methyl-alpha-hydroxy-2-thiophenacetic acid.
Man holder temperaturen på 40°C, idet man omrører i 1 time 30 minutter under ni trogengennembob1ing. Derpå afkøler man til 20-25°C og hælder i løbet af 15 minutter i en 5 blanding af 150 liter afmineraliseret vand og 100 kg knust is. Man omrører yderligere 15 minutter efter tilsætningen og ekstraherer den vandige fase 6 gange med 50 liter dichlorethan ved 20°C - 2°C. Man vasker dichlorethan-ekstrakterne 4 gange med 8,5 liter 22° Bé' saltsyre i 10 22,5 liter vand og derpå 3 gange med 50 liter vand.The temperature is maintained at 40 ° C, stirring for 1 hour 30 minutes during nine bursting. It is then cooled to 20-25 ° C and poured over 15 minutes into a mixture of 150 liters of demineralized water and 100 kg of crushed ice. Stir another 15 minutes after the addition and extract the aqueous phase 6 times with 50 liters of dichloroethane at 20 ° C - 2 ° C. The dichloroethane extracts were washed 4 times with 8.5 liters of 22 ° B hydrochloric acid in 22.5 liters of water and then 3 times with 50 liters of water.
Man inddamper dichlorethanopløsningen under formindsket tryk uden at passere 40°C. Man får 45,3 kg af den forventede syre i rå tilstand.The dichloroethane solution is evaporated under reduced pressure without passing 40 ° C. You get 45.3 kg of the expected acid in the raw state.
Denne forbindelse destilleres under et tryk på 0,7 15 torr uden at passere 120°C. Der fås 39,45 kg af den forventede forbindelse. Smp. 110-112°C.This compound is distilled under a pressure of 0.7 15 torr without passing 120 ° C. 39.45 kg of the expected compound is available. Mp. 110-112 ° C.
Eksempel 2 alpha-methyl-alpha-hydroxy-2-thiopheneddikesyre 20 Man indfører 50 ml opløsning af 375 g 2-bromthio- phen i 500 ml tetrahydrofuran i en blanding af 59,3 g magnesiumdrej espåner i 750 ml tetrahydrofuran. Man tilsætter en iodkrystal. Efter indledning af reaktionen indføres resten af opløsningen af bromthiophen under omrøring ved 35°C 25 i løbet af 1 time. Man fortsætter omrøringen i yderligere 2 timer efter afsluttet tilsætning, idet man lader temperaturen falde til 25°C.Example 2 alpha-methyl-alpha-hydroxy-2-thiophenacetic acid 20 50 ml of solution of 375 g of 2-bromothiophene in 500 ml of tetrahydrofuran are introduced into a mixture of 59.3 g of magnesium turning in 750 ml of tetrahydrofuran. An iodine crystal is added. After initiating the reaction, the remainder of the bromothiophene solution is introduced with stirring at 35 ° C over 1 hour. Stirring is continued for another 2 hours after completion of addition, lowering the temperature to 25 ° C.
Derpå tilsætter man ved 25°C i løbet af 45 minutter en opløsning af 102 g pyrodruesyre i 500 ml tetrahydrofu-30 ran. Man omrører 18 timer ved 25°C og hælder derpå i 2,6 liter af en blanding af vand og is indeholdende 130 ml 66° Bé svovlsyre. Man omrører 10 minutter, dekanterer den organiske fase og genekstraherer med 4 gange 260 ml ethylace-tat. De organiske faser vaskes med 2 gange 260 ml afmine-35 raliseret vand og genekstraheres derpå med 520 ml og derpå 3 gange 260 ml"iskold 2 N vandig natriumhydroxidopløsning. Natriumhydroxidopløsningerne vaskes med 4 gange 260 ml - 8 -Then, at 25 ° C, a solution of 102 g of pyruvic acid in 500 ml of tetrahydrofuran is added over 45 minutes. The mixture is stirred at 25 ° C for 18 hours and then poured into 2.6 liters of a mixture of water and ice containing 130 ml of 66 ° B sulfuric acid. Stir for 10 minutes, decant the organic phase and re-extract with 4x 260 ml of ethyl acetate. The organic phases are washed with 2x260 ml of demineralized water and then re-extracted with 520 ml and then 3x260 ml of ice cold 2N aqueous sodium hydroxide solution. The sodium hydroxide solutions are washed with 4x260 ml - 8
DK 157493 BDK 157493 B
ethylacetat og syrnes til en pH-værdi på 1 ved tilsætning, i nærværelse af is og under omrøring, af 120 ml 22° Bé saltsyre. Man ekstraherer med 520 ml og 4 gange 260 ml ethylacetat. De organiske faser vaskes med 2 gange 260 ml afmineraliseret vand og tørres over natriumsulfat, og der 5 tilsættes ca. 10 g aktivkul. Efter frasugning afdampes opløsningsmidlerne til tørhed under formindsket tryk. Der fås 145,5 g af den forventede forbindelse. Smp. 115°C.ethyl acetate and acidified to a pH of 1 by the addition, in the presence of ice and with stirring, of 120 ml of 22 ° B hydrochloric acid. Extract with 520 ml and 260 times ethyl acetate 4 times. The organic phases are washed with 2x260 ml of demineralized water and dried over sodium sulfate, and 5 are added. 10 g of activated carbon. After suctioning, the solvents are evaporated to dryness under reduced pressure. 145.5 g of the expected compound are obtained. Mp. 115 ° C.
10 15 20 25 30 3510 15 20 25 30 35
Claims (7)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8307021A FR2545085B1 (en) | 1983-04-28 | 1983-04-28 | NOVEL PROCESS FOR THE PREPARATION OF A-HYDROXY 2-THIOPHENE ACETIC ACID DERIVATIVES |
| FR8307021 | 1983-04-28 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK307583D0 DK307583D0 (en) | 1983-07-04 |
| DK307583A DK307583A (en) | 1984-10-29 |
| DK157493B true DK157493B (en) | 1990-01-15 |
| DK157493C DK157493C (en) | 1990-06-11 |
Family
ID=9288331
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK307583A DK157493C (en) | 1983-04-28 | 1983-07-04 | PROCEDURE FOR PREPARING ALPHA-HYDROXY-2-THIOPHENIC ACETIC ACID COMPOUNDS |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS59204185A (en) |
| KR (1) | KR900006558B1 (en) |
| AT (1) | AT392786B (en) |
| AU (1) | AU559749B2 (en) |
| BE (1) | BE897362A (en) |
| CA (1) | CA1201443A (en) |
| CH (1) | CH655316A5 (en) |
| DE (1) | DE3325456A1 (en) |
| DK (1) | DK157493C (en) |
| ES (1) | ES524648A0 (en) |
| FI (1) | FI832473L (en) |
| FR (1) | FR2545085B1 (en) |
| GB (1) | GB2139215B (en) |
| HU (1) | HU194206B (en) |
| IE (1) | IE55905B1 (en) |
| IT (1) | IT1171855B (en) |
| LU (1) | LU84931A1 (en) |
| NL (1) | NL8302564A (en) |
| NZ (1) | NZ205514A (en) |
| PT (1) | PT77010B (en) |
| SE (1) | SE451018B (en) |
| ZA (1) | ZA835613B (en) |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1067828A (en) * | 1951-01-19 | 1954-06-18 | Sterling Drug Inc | Improvements relating to a process for preparing organic chemicals |
| GB806710A (en) * | 1955-07-05 | 1958-12-31 | Metal & Thermit Corp | Reactions of organomagnesium chloride complexes |
| GB820083A (en) * | 1955-07-05 | 1959-09-16 | Metal & Thermit Corp | Reactions of organomagnesium chloride reagents |
| FR2068425B1 (en) * | 1969-11-12 | 1973-01-12 | Roussel Uclaf | |
| FR2167334A1 (en) * | 1972-01-13 | 1973-08-24 | Roussel Uclaf | 4-aroyl-5-alkylthiophene-2-acetic acids - with analgesic and antiinflammatory activity |
| GB1584120A (en) * | 1977-07-21 | 1981-02-04 | Sagami Chem Res | Process for the preparation of thiophene derivatives and thiophene derivatives obtained therethrough |
| GB2030131B (en) * | 1978-09-12 | 1982-12-22 | Taiyo Pharma Ind | Process for producing 2-(4-(2-thienyl-carbonyl) phenyl) propionic acid |
| JPS5835145A (en) * | 1981-08-26 | 1983-03-01 | Taisho Pharmaceut Co Ltd | Preparation of alpha-arylalkanoic acid ester |
-
1983
- 1983-04-28 FR FR8307021A patent/FR2545085B1/en not_active Expired
- 1983-07-04 DK DK307583A patent/DK157493C/en not_active IP Right Cessation
- 1983-07-05 FI FI832473A patent/FI832473L/en not_active Application Discontinuation
- 1983-07-06 HU HU832431A patent/HU194206B/en unknown
- 1983-07-07 SE SE8303887A patent/SE451018B/en not_active IP Right Cessation
- 1983-07-11 PT PT77010A patent/PT77010B/en not_active IP Right Cessation
- 1983-07-14 DE DE19833325456 patent/DE3325456A1/en active Granted
- 1983-07-18 NL NL8302564A patent/NL8302564A/en active Search and Examination
- 1983-07-22 CH CH4036/83A patent/CH655316A5/en not_active IP Right Cessation
- 1983-07-25 BE BE0/211226A patent/BE897362A/en unknown
- 1983-07-26 AU AU17309/83A patent/AU559749B2/en not_active Ceased
- 1983-07-27 LU LU84931A patent/LU84931A1/en unknown
- 1983-07-27 KR KR1019830003476A patent/KR900006558B1/en not_active IP Right Cessation
- 1983-07-28 JP JP58136930A patent/JPS59204185A/en active Granted
- 1983-08-01 ES ES524648A patent/ES524648A0/en active Granted
- 1983-08-01 ZA ZA835613A patent/ZA835613B/en unknown
- 1983-08-08 IT IT48823/83A patent/IT1171855B/en active
- 1983-08-08 AT AT2868/83A patent/AT392786B/en not_active IP Right Cessation
- 1983-08-22 CA CA000435081A patent/CA1201443A/en not_active Expired
- 1983-09-01 GB GB08323492A patent/GB2139215B/en not_active Expired
- 1983-09-02 IE IE2074/83A patent/IE55905B1/en not_active IP Right Cessation
- 1983-09-07 NZ NZ205514A patent/NZ205514A/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK170335B1 (en) | Process for the preparation of 5-cyano-10-nitro-5H-dibenz (b, f) azepine | |
| SU578870A3 (en) | Method of preparing n-(methoxymethyl)furilmethyl-6,7-benzomorphanes or morhinanes or their salts | |
| SU421187A3 (en) | METHOD OF OBTAINING 2- (FURILMETHIL) -6,7- BENZOMORPHANES | |
| DK149230B (en) | METHOD OF ANALOGUE FOR THE PREPARATION OF 5-BENZOYL-6-HYDROXY-INDANE-1-CARBOXYLIC ACID DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF | |
| US3979379A (en) | Process for producing 1,3,5,7-tetraalkanoyl-1,3,5,7-octahydrotetrazocines | |
| DK157493B (en) | PROCEDURE FOR PREPARING ALPHA-HYDROXY-2-THIOPHENIC ACETIC ACID COMPOUNDS | |
| US3978085A (en) | Process for benz[f]-2,5-oxazocines | |
| JPS6160634A (en) | 2,4-dichloro-3-alkyl-6-nitrophenol and synthesis | |
| Kiang et al. | 268. The action of acyl cyanides on 2-and 1: 2-substituted indoles. Part II. Derivatives of 2-o-aminophenylindole | |
| Angier et al. | Pteridine Chemistry. IV. Structure of the Reaction Products Obtained from Acrylonitrile and 2-Amino-4-hydroxypteridines | |
| JPS6157302B2 (en) | ||
| NO149353B (en) | PROCEDURE FOR PREPARING 6-CHLORO-ALFA-METHYL CARBZOL-2-ACETIC ACID | |
| SU534183A3 (en) | Method for preparing benzocycloheptaoxazolone derivatives | |
| DK164550B (en) | DERIVATIVE OF THIENYL-2-MALONIC ACID ESTABLES USED AS BASIC MATERIALS FOR PREPARING 2-THIOPHENIC ACETIC ACID COMPOUNDS | |
| NO153134B (en) | PROCEDURE FOR THE PREPARATION OF A CARBZOLD DERIVATIVE | |
| US3314974A (en) | Thienyl-1-naphthalene acetic acids and related compounds | |
| JPH05500797A (en) | Improved methods for the preparation of ketone compounds | |
| US2648689A (en) | Preparation of p' (benzoylsulfamyl) phthalanilic acid | |
| JPH06135883A (en) | Production of aromatic acyl compound | |
| JPH0136469B2 (en) | ||
| JPS645024B2 (en) | ||
| NO132836B (en) | ||
| Stephen et al. | XXXII.—αδ-Derivatives of adipic and β-methyladipic acids, and the preparation of muconic and β-methylmuconic acids | |
| JPH03197482A (en) | Production of apovincaminic acid ester | |
| JPS63255259A (en) | Production of asymmetric sulfone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUP | Patent expired |