DK164550B - DERIVATIVE OF THIENYL-2-MALONIC ACID ESTABLES USED AS BASIC MATERIALS FOR PREPARING 2-THIOPHENIC ACETIC ACID COMPOUNDS - Google Patents
DERIVATIVE OF THIENYL-2-MALONIC ACID ESTABLES USED AS BASIC MATERIALS FOR PREPARING 2-THIOPHENIC ACETIC ACID COMPOUNDS Download PDFInfo
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- DK164550B DK164550B DK138490A DK138490A DK164550B DK 164550 B DK164550 B DK 164550B DK 138490 A DK138490 A DK 138490A DK 138490 A DK138490 A DK 138490A DK 164550 B DK164550 B DK 164550B
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- thienyl
- toluene
- alk
- malonic acid
- derivative
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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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
- i -- i -
DK 164550BDK 164550B
Opfindelsen angår hidtil ukendte derivater af thienyl-The invention relates to novel derivatives of thienyl
2-malonsyreester til brug som udgangsmateriale ved fremstilling af 2-thiopheneddikesyreforbindelser med den almene formel I2-Malonic Acid Ester for Use as a Starting Material in the Preparation of 2-Thiophenacetic Acid Compounds of General Formula I
5 R« R-z5 R «R-z
HH
R1/N5/^'CH-C02HR1 / N 5 / ^ 'CH-C02H
10 R10 R
hvor R betegner alkyl med 1-4 carbonatomer, og R^, R2 og R^, som kan være ens eller forskellige, hver for sig 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 2, which may be the same or different, each represent hydrogen, alkyl of 1-4 carbon atoms or halogen.
1515
Disse forbindelser er mellemprodukter, som finder anvendelse til fremstilling af lægemidler, især betændelseshæmmende forbindelser.These compounds are intermediates that are used in the manufacture of pharmaceuticals, especially anti-inflammatory compounds.
20 2-thiopheneddikesyreforbindelser med den almene formel I kendes bl.a. fra de franske patentskrifter nr. 2.068.425 og 2.398.068.2-thiophenacetic acid compounds of general formula I are known, inter alia, from French Patent Nos. 2,068,425 and 2,398,068.
Anvendelsen af derivaterne ifølge opfindelsen ved fremstil-25 lingen af forbindelserne I adskiller sig væsentligt fra den kendte teknik som f.eks. beskrevet i FR patentskrift nr. 2.260.575. Dette FR patentskrift omhandler nemlig 3-thie-nylforbindelser og ikke 2-thienylforbindelser som ved anvendelsen af derivaterne ifølge opfindelsen. Endvidere er i 30 FR 2.260.575 substituenten i alphastillingen i thienylker-nen en cyclohexylgruppe, hvor substituenten R ifølge opfindelsen betegner en ikke-cyklisk, lineær alkylgruppe.The use of the derivatives of the invention in the preparation of compounds I differs substantially from the prior art, e.g. disclosed in FR Patent Specification No. 2,260,575. Namely, this FR patent discloses 3-thienyl compounds and not 2-thienyl compounds as in the use of the derivatives of the invention. Furthermore, in FR 30,260,575, the substituent in the alpha position of the thienyl nucleus is a cyclohexyl group, wherein the substituent R of the invention represents a non-cyclic linear alkyl group.
De hidtil ukendte derivater af thienyl-2-malonsyreester 35 ifølge opfindelsen har den almene formel IV, hvor R, R^ og R^ betegner det samme som ovenfor, og Alk^ og Alk2 - 2 -The novel derivatives of thienyl-2-malonic acid ester of the invention have the general formula IV wherein R, R 2 and R 2 are the same as above, and Alk 2 and Alk 2 - 2 -
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betegner alkyl med 1-4 carbonatomer.represents alkyl of 1-4 carbon atoms.
5 Mk1 (IV) R^ | \ C°2 Alk25 Mk1 (IV) R ^ | 2 ° Alk 2
RR
Ved fremgangsmåden til fremstilling af forbindelserne med formlen I går man ud fra en ester af thienyl-2-eddikesyre, 10 eventuelt substitueret i thienylringen som angivet ovenfor. Thienyleddikesyre benyttes isar i syntesen af antibiotiske stoffer, navnlig cephalosporiner. Esterne, som afledes af thienyl-2-eddikesyre, er således tilgængelige i store mængder og til interessante priser.The process for preparing the compounds of formula I is based on an ester of thienyl-2-acetic acid, optionally substituted in the thienyl ring as indicated above. Thienyl acetic acid is used especially in the synthesis of antibiotics, in particular cephalosporins. Thus, the esters derived from thienyl-2-acetic acid are available in large quantities and at interesting prices.
1515
Disse udgangsforbindelser kan let fremstilles ud fra de tilsvarende syrer ved gængse esterificeringsmetoder.These starting compounds can be readily prepared from the corresponding acids by conventional esterification methods.
I nærværelse af en stærk base omsættes et alkylcarbonat med 20 formlen (Alk1)2C03In the presence of a strong base, an alkyl carbonate of formula (Alk1) 2CO3 is reacted
hvor Alk^ betegner det samme som ovenfor, med en ester med formlen IIwherein Alk 2 represents the same as above, with an ester of formula II
r2 R^r 2 R 2
KK
R/ ^ CK2-C02 Alk2 30R / CK2-CO2 Alk2 30
hvor R^, R2, R3 og Alk2 betegner det samme som ovenfor, til opnåelse af en forbindelse med formlen IIIwherein R 1, R 2, R 3 and Alk 2 represent the same as above to give a compound of formula III
3535
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- 3 - 8λΧ/^“ι (ni) 1 I ^COp Alkp- 3 - 8λΧ / ^ “ι (ni) 1 I ^ COp Alkp
HH
hvor R^, R2 og R^, Alk^ og Alk2 betegner det samme som ovenfor, som man i nærværelse af en stærk base omsætter med et alkyleringsmiddel med 1-4 carbonatomer i alkyldelen til 10 opnåelse af derivatet ifølge opfindelsen af thienyl-2-ma-lonsyreester med formlen IVwherein R 1, R 2 and R 2, Alk 2 and Alk 2 represent the same as above, which is reacted in the presence of a strong base with an alkylating agent having 1-4 carbon atoms in the alkyl part to give the derivative of the invention of thienyl-2 malonic acid ester of formula IV
R2 ^3 < |\C02Alk2R2 ^ 3 <| \ C02Alk2
RR
hvor R^, R2, R^, Alk^ og Alk^ betegner det samme som 20 ovenfor, som man underkaster en decarboxyleringsreaktion til opnåelse af den ønskede forbindelse med formlen I.wherein R 2, R 2, R 2, Alk 2 and Alk 2 represent the same as above, which is subjected to a decarboxylation reaction to give the desired compound of formula I.
Blandt de værdier, som substituenterne R, R^, R2 og R^ kan antage, skal nævnes methyl, ethyl, propyl, isopropyl, 25 butyl, isobutyl, sec.-butyl eller tert.-butyl. Substituenterne R^, R2 og R^ kan ligeledes betegne et hydrogenatom eller et halogenatom, nemlig 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, namely fluorine, chlorine, bromine or iodine.
30 Alk^ og Alk2 kan antage de for gruppen R angivne værdier.Alk 2 and Alk 2 can assume the values indicated for the group R.
Opfindelsen angår navnlig et hidtil ukendt thienyl-2-malon-syreesterderivat med den almene formel IVIn particular, the invention relates to a novel thienyl-2-malonic acid ester derivative of the general formula IV
35 - 4 -35 - 4 -
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On 5 | ^C0? Alk2On 5 | ^ C0? alk2
RR
hvor R, Alk^ og Alk^ har samme betydning som ovenfor. Dette derivat med formlen IV anvendes ved fremstilling af en 10 forbindelse med formlen 1' f\ CH-CCUH (!’) !wherein R, Alk ^ and Alk ^ have the same meaning as above. This derivative of formula IV is used in the preparation of a compound of formula 1 'f \ CH-CCUH (!')!
15 R15 R
hvor R har samme betydning som ovenfor, ud fra en ester af thienyleddikesyre med formlen II' 20 (Λ CH2-C02 Alk2 hvor Alk2 betegner det samme som ovenfor.wherein R has the same meaning as above, from an ester of thienyl acetic acid of formula II '20 (Λ CH 2 -CO 2 Alk 2 where Alk 2 represents the same as above.
2525
Nedenstående eksempler illustrerer nærmere opfindelsen.The following examples further illustrate the invention.
Eksempel 1; Anvendelse af thienyl-2-methylmalonsyreethyl-ester til fremstilling af alpha-methyl-2-thiopheneddikesyre 30Example 1; Use of thienyl-2-methylmalonic acid ethyl ester to prepare alpha-methyl-2-thiophenacetic acid 30
Præparation af udgangsmaterialerPreparation of starting materials
Trin A: Thienyl-2-malonsyreethylester 35 Man blander under nitrogenatmosfære 225 ml absolut ethanol og 16,5 g natrium. Man holder ethanolet under tilbage- - 5 -Step A: Thienyl-2-malonic acid ethyl ester 225 ml of absolute ethanol and 16.5 g of sodium are mixed under a nitrogen atmosphere. The ethanol is retained under - 5 -
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svaling indtil opløsning og inddamper derefter til tørhed under formindsket tryk til eliminering af ethanolet. Til natriumethylatet ved 100°C indfører man under opretholdelse af temperaturen mellem 90 og 95°C 150 ml ethyl- carbonat og derpå i løbet af 10 minutter 100 g thi-5 enyl-2-eddikesyreethylester og 100 ml toluen. Man opvarmer til 105°C og afdestillerer i løbet af ca. 2 timer 120 ml blanding af toluen, ethanol og ethylcarbonat. Man holder ved 105°C i yderligere 2 timer, hvorpå man afkøler til 20°C og hælder i 600 ml iskoldt vand indeholdende 10 80 ml ren 22° Bé saltsyre.cooling to solution and then evaporating to dryness under reduced pressure to eliminate the ethanol. To the sodium ethylate at 100 ° C, 150 ml of ethyl carbonate are added while maintaining the temperature between 90 and 95 ° C and then within 10 minutes 100 g of thi-5-ethyl-2-acetic acid ethyl ester and 100 ml of toluene. Heat to 105 ° C and distillate over approx. 2 hours 120 ml mixture of toluene, ethanol and ethyl carbonate. Keep at 105 ° C for an additional 2 hours, then cool to 20 ° C and pour into 600 ml of ice-cold water containing 10 80 ml of pure 22 ° B hydrochloric acid.
Man dekanterer, genekstraherer den vandige fase med toluen og vasker de forenede toluenfaser med vand. Man inddamper toluenopløsningen under formindsket tryk. Man får det 15 forventede råprodukt, som man destillerer under et tryk på 2 mm Hg. Der fås 134,4 g af den forventede forbindelse. Kp. ved 2 mm Hg 118-120°C.Decant, re-extract the aqueous phase with toluene and wash the combined toluene phases with water. The toluene solution is evaporated under reduced pressure. The 15 expected crude product is obtained, which is distilled under a pressure of 2 mm Hg. 134.4 g of the expected compound are obtained. Kp. at 2 mm Hg 118-120 ° C.
Trin B: Thienyl-2-methylmalonsyreethylester 20Step B: Thienyl-2-methylmalonic acid ethyl ester 20
Man indfører under nitrogenatmosfære 10,45 g natrium i 160 ml absolut ethanol. Man opretholder tilbagesvalingen i 45 minutter og afdestillerer 60 ml ethanol. Man tilsætter 300 ml toluen, opvarmer til tilbagesvaling under stadig 25 omrøring og afdestillerer ethanolet under konstant rumfang ved tilsætning af toluen. Man tilsætter således 250 ml toluen og opsamler ca. 250 ml blanding af ethanol og toluen.10.45 g of sodium in 160 ml of absolute ethanol is introduced under nitrogen atmosphere. The reflux is maintained for 45 minutes and 60 ml of ethanol is distilled off. 300 ml of toluene are added, heated to reflux while still stirring, and the ethanol is distilled off under constant volume by the addition of toluene. Thus, 250 ml of toluene are added and approx. 250 ml mixture of ethanol and toluene.
30 Man afkøler til 20°C og tilsætter 100 g thienyl-2-malon-syreethylester og 200 ml toluen. Man omrører 20 minutter, afdestillerer 150 ml blanding af toluen og ethanol under formindsket tryk og indfører derpå under nitrogenstmosfære 100 ml toluen. Man opvarmer til 70°C og tilsætter i løbet •35 af ca. 30 minutter 60 g dimethylsulfat. Man holder ved 80°C i 45 minutter, afkøler til 20-25°C og tilsætter 200 ml - 6 -It is cooled to 20 ° C and 100 g of thienyl-2-malonic acid ethyl ester and 200 ml of toluene are added. Stir for 20 minutes, distill off 150 ml of toluene and ethanol mixture under reduced pressure and then introduce 100 ml of toluene under nitrogen atmosphere. Heat to 70 ° C and add • 35 of approx. 30 minutes 60 g of dimethyl sulfate. Keep at 80 ° C for 45 minutes, cool to 20-25 ° C and add 200 ml - 6 -
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afxnineraliseret vand. Man omrører 15 minutter, dekanterer, vasker toluenfasen med 100 ml vand tilsat 5% 22° Bé salt syre og derefter fire gange med 100 ml afmineraliseret 5 vand. Man afdestillerer 450 ml toluen under formindsket tryk og lader koncentratet henstå ved 70°C under et tryk på 15-20 mm Hg i 1 time og får 105 g af det forventede stof.demineralized water. Stir for 15 minutes, decant, wash the toluene phase with 100 ml of water added with 5% 22 ° B of hydrochloric acid and then four times with 100 ml of demineralized 5 water. 450 ml of toluene is distilled off under reduced pressure and the concentrate is left at 70 ° C under a pressure of 15-20 mm Hg for 1 hour to obtain 105 g of the expected substance.
Fremstilling af alpha-methyl-2-thiopheneddikesyre 10Preparation of alpha-methyl-2-thiophenacetic acid 10
Man sætter 100 g thienyl-2-methylmalonsyreethylester og 200 ml ethanol til en opløsning af 62,6 g natriumhydroxid i 400 ml afmineraliseret vand. Man opvarmer til 50°C i 4 timer og afdestillerer derpå 300 ml blanding af ethanol 15 og vand under formindsket tryk, idet man holder temperaturen under 50°C. Man anbringer under nitrogenatmosfære og tilsætter i rækkefølge 200 ml toluen og 140 ml 22° Bé saltsyre. Man opvarmer 1 time og 30 minutter til tilbagesvaling og afkøler derpå til 20°C, dekanterer, vasker 20 toluenfasen flere gange med 50 ml vand og inddamper under formindsket tryk under afdestillation af 180 ml toluen. Koncentratet desolvatiseres ved 70°C i 1 time ved et tryk på 15-20 mm Hg. Der fås 58,8 g af den forventede forbindelse, kp. ved 1,5 mm Hg = 117-118°C, kp. ved 0,5 mm Hg 25 = 110°C.100 g of thienyl-2-methylmalonic acid ethyl ester and 200 ml of ethanol are added to a solution of 62.6 g of sodium hydroxide in 400 ml of demineralized water. It is heated to 50 ° C for 4 hours and then distilled 300 ml mixture of ethanol 15 and water under reduced pressure, keeping the temperature below 50 ° C. It is placed under a nitrogen atmosphere and 200 ml of toluene and 140 ml of 22 ° B hydrochloric acid are added successively. The mixture is heated to reflux for 1 hour and 30 minutes and then cooled to 20 ° C, decanted, washed with the toluene phase several times with 50 ml of water and evaporated under reduced pressure under distillation of 180 ml of toluene. The concentrate is desolvated at 70 ° C for 1 hour at a pressure of 15-20 mm Hg. 58.8 g of the expected compound are obtained, b.p. at 1.5 mm Hg = 117-118 ° C, bp. at 0.5 mm Hg 25 = 110 ° C.
Eksempel 2: Anvendelse af thienyl-2-ethylmalonsyreethyl-ester til fremstilling af thienyl-2-smørsyre 30 Præparation af udgangsmaterialerExample 2: Use of thienyl-2-ethylmalonic acid ethyl ester to produce thienyl-2-butyric acid Preparation of starting materials
Thienyl-2-ethylmalonsyreethylester 35 Man indfører under nitrogenatmosfære 12,54 g natrium i 192 ml absolut ethanol. Man holder under tilbagesvaling i 45 minutter og afdestillerer derpå 72 ml ethanol. Man tilsætter 360 ml toluen og opvarmer til tilbagesvaling til afdestillation af ethanol ved konstant rumfang gennem - 7 -Thienyl-2-ethylmalonic acid ethyl ester 12.54 g of sodium are added under nitrogen atmosphere in 192 ml of absolute ethanol. It is refluxed for 45 minutes and then 72 ml of ethanol is distilled off. 360 ml of toluene are added and heated to reflux to distill off ethanol at constant volume through - 7 -
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tilsætning af toluen. Man tilsætter således 300 ml toluen og optager samme rumfang blanding af toluen og ethanol. Man 5 afkøler til 20°C og tilsætter 120 g thienyl-2-malonsyre-ethylester og 240 ml toluen. Man omrører 20 minutter og afdestillerer derpå under formindsket tryk 180 ml blanding af toluen og ethanol og indfører derpå under nitrogenatmosfære 120 ml toluen. Man opvarmer til 75°C og tilsætter 10 derpå i løbet af 30 minutter 99,3 g diethylsulfat. Man opvarmer til tilbagesvaling i 1 time, afkøler til 20-25°C, tilsætter 240 ml afmineraliseret vand, omrører 15 minutter, dekanterer og vasker toluenfasen med 120 ml afmineraliseret vand tilsat 5% 22° Bé saltsyre og derefter 4 gange med 15 120 ml vand. Man inddamper toluenfasen under formindsket tryk efter tørring over natriumsulfat. Man desolvatiserer koncentratet under et tryk på 15-20 mm Hg ved 70°C i 1 time og får 145,6 g af den forventede forbindelse.addition of toluene. Thus, 300 ml of toluene is added and the same volume of mixture of toluene and ethanol is taken up. It is cooled to 20 ° C and 120 g of thienyl-2-malonic acid ethyl ester and 240 ml of toluene are added. The mixture is stirred for 20 minutes and then 180 ml of toluene / ethanol mixture is distilled off under reduced pressure and 120 ml of toluene is added under a nitrogen atmosphere. It is heated to 75 ° C and 10.3 g of diethyl sulfate is then added over 30 minutes. Reflux for 1 hour, cool to 20-25 ° C, add 240 ml of demineralized water, stir 15 minutes, decant and wash the toluene phase with 120 ml of demineralised water with 5% 22 ° B hydrochloric acid and then 4 times with 15 120 ml water. The toluene phase is evaporated under reduced pressure after drying over sodium sulfate. The concentrate is desolvated under a pressure of 15-20 mm Hg at 70 ° C for 1 hour to give 145.6 g of the expected compound.
20 Denne forbindelse renses ved destillation ved et tryk på 0,5 mm Hg. Der fås 113 g forbindelse, som destillerer ved en temperatur på 95-120°C.This compound is purified by distillation at a pressure of 0.5 mm Hg. 113 g of compound are obtained, which distils at a temperature of 95-120 ° C.
Fremstilling af thienyl-2-smørsyre 25Preparation of thienyl-2-butyric acid 25
Man omrører under nitrogenatmosfære indtil fuldstændig opløsning en blanding af 62,6 g natriumhydroxid i 400 ml afmineraliseret vand og tilsætter derpå 105,4 g thienyl-2-ethylmalonsyreethylester og derefter 200 ml 30 ethanol. Man opvarmer til 50°C i 4 timer og afdestillerer derpå under et tryk på 20 mm Hg ved en temperatur på 50°C ca. 300 ml blanding af ethanol og vand. Derpå tilsætter man under nitrogenatmosfære 200 ml toluen og derefter 140 ml 22° Bé saltsyre. Man opvarmer til tilbagesvaling i 35 1 time 30 minutter, afkøler til 20°C, dekanterer, ekstra- herer den vandige fase med 50 ml toluen og vasker flere gange toluenfasen med 50 ml vand. Man tørrer toluenfasen over natriumsulfat og inddamper til tørhed ved et tryk på 15-20 mm Hg ved 70°C. Man holder under disse betingelseri - 8 -A mixture of 62.6 g of sodium hydroxide in 400 ml of demineralized water is stirred under nitrogen atmosphere until complete solution and then 105.4 g of thienyl-2-ethylmalonic acid ethyl ester and then 200 ml of ethanol are added. It is heated to 50 ° C for 4 hours and then distilled off under a pressure of 20 mm Hg at a temperature of 50 ° C approx. 300 ml mixture of ethanol and water. Then, under nitrogen atmosphere, 200 ml of toluene and then 140 ml of 22 ° B hydrochloric acid are added. Reflux for 35 hours for 30 minutes, cool to 20 ° C, decant, extract the aqueous phase with 50 ml of toluene and wash the toluene phase with 50 ml of water several times. The toluene phase is dried over sodium sulfate and evaporated to dryness at a pressure of 15-20 mm Hg at 70 ° C. These conditions are maintained - 8 -
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yderligere 1 time og får 66,3 g af den forventede forbindelse.an additional 1 hour and received 66.3 g of the expected compound.
5 10 155 10 15
Claims (3)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8220271A FR2537137B1 (en) | 1982-12-03 | 1982-12-03 | PROCESS FOR THE PREPARATION OF ACETIC 2-THIOPHENE ACID DERIVATIVES AND INTERMEDIATE PRODUCTS NECESSARY FOR THEIR PREPARATION |
| FR8220271 | 1982-12-03 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK138490A DK138490A (en) | 1990-06-06 |
| DK138490D0 DK138490D0 (en) | 1990-06-06 |
| DK164550B true DK164550B (en) | 1992-07-13 |
| DK164550C DK164550C (en) | 1992-11-30 |
Family
ID=9279757
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK139983A DK160427C (en) | 1982-12-03 | 1983-03-28 | PROCEDURE FOR THE PREPARATION OF 2-THIOPHENIC ACETIC ACID COMPOUNDS |
| DK138490A DK164550C (en) | 1982-12-03 | 1990-06-06 | DERIVATIVE OF THIENYL-2-MALONIC ACID ESTABLES USED AS BASIC MATERIALS FOR PREPARING 2-THIOPHENIC ACETIC ACID COMPOUNDS |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK139983A DK160427C (en) | 1982-12-03 | 1983-03-28 | PROCEDURE FOR THE PREPARATION OF 2-THIOPHENIC ACETIC ACID COMPOUNDS |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS59106482A (en) |
| KR (1) | KR900005681B1 (en) |
| AT (1) | AT392784B (en) |
| AU (1) | AU556803B2 (en) |
| BE (1) | BE896439A (en) |
| CA (1) | CA1201441A (en) |
| CH (2) | CH655722A5 (en) |
| DE (1) | DE3314029A1 (en) |
| DK (2) | DK160427C (en) |
| ES (1) | ES8401957A1 (en) |
| FI (1) | FI83646C (en) |
| FR (1) | FR2537137B1 (en) |
| GB (1) | GB2132607B (en) |
| HU (1) | HU192136B (en) |
| IE (1) | IE55075B1 (en) |
| IT (1) | IT1174757B (en) |
| LU (1) | LU84748A1 (en) |
| NL (1) | NL8301692A (en) |
| NZ (1) | NZ204509A (en) |
| PT (1) | PT76534B (en) |
| SE (2) | SE453992B (en) |
| ZA (1) | ZA832698B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE132865T1 (en) * | 1988-04-22 | 1996-01-15 | Byk Gulden Lomberg Chem Fab | 3-ANILINO-2-HYDROXYCARBONYL-4-THIOPHENACETIC ACID N |
| IT1276738B1 (en) * | 1995-06-16 | 1997-11-03 | Erregierre Spa | PROCESS FOR THE PREPARATION OF DERIVATIVES OF -METHYL-2- THIOPHENEACETIC ACID |
| DE102004008807A1 (en) | 2004-02-20 | 2005-09-08 | Bayer Cropscience Ag | pyrazolopyrimidine |
| CN113896709B (en) * | 2021-11-22 | 2023-02-28 | 南京一苇医药科技有限公司 | Synthetic method of benzothiophene-3-acetic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB683337A (en) * | 1949-10-01 | 1952-11-26 | Warner Hudnut Inc | Improvements in or relating to the preparation of antispasmodic compounds |
| IE33054B1 (en) * | 1968-04-16 | 1974-03-06 | Ici Ltd | Heterocyclic compounds |
| FR2260575A1 (en) * | 1974-02-11 | 1975-09-05 | Innothera Lab Sa | Cyclohexyl 3-thienyl acetic acid prodn - from methyl 3-thienylacetate through diethyl cyclohexyl 3-thienyl malonate as starting material for basic esters as drugs |
| GB2003570B (en) * | 1977-06-08 | 1982-01-20 | Imi Opella Ltd | Stop valve |
| FR2421897A1 (en) * | 1978-04-04 | 1979-11-02 | Labaz | Alpha substd. 3-thienyl:acetamide derivs. - useful as hypnotic, anticonvulsant and tranquillising agents |
-
1982
- 1982-12-03 FR FR8220271A patent/FR2537137B1/en not_active Expired
-
1983
- 1983-03-28 DK DK139983A patent/DK160427C/en not_active IP Right Cessation
- 1983-03-30 SE SE8301785A patent/SE453992B/en not_active IP Right Cessation
- 1983-03-31 FI FI831115A patent/FI83646C/en not_active IP Right Cessation
- 1983-04-05 ES ES521230A patent/ES8401957A1/en not_active Expired
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- 1983-04-12 CH CH1967/83A patent/CH655722A5/en not_active IP Right Cessation
- 1983-04-12 BE BE0/210536A patent/BE896439A/en unknown
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- 1983-04-14 LU LU84748A patent/LU84748A1/en unknown
- 1983-04-15 AU AU13574/83A patent/AU556803B2/en not_active Ceased
- 1983-04-18 DE DE19833314029 patent/DE3314029A1/en active Granted
- 1983-04-18 ZA ZA832698A patent/ZA832698B/en unknown
- 1983-04-23 KR KR1019830001729A patent/KR900005681B1/en not_active IP Right Cessation
- 1983-05-04 IT IT48215/83A patent/IT1174757B/en active
- 1983-05-09 GB GB08312701A patent/GB2132607B/en not_active Expired
- 1983-05-10 IE IE1075/83A patent/IE55075B1/en not_active IP Right Cessation
- 1983-05-11 NL NL8301692A patent/NL8301692A/en active Search and Examination
- 1983-05-20 JP JP58087835A patent/JPS59106482A/en active Granted
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1987
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1990
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