DK141725B - Analogous process for the preparation of 4- (o- (2 ', 3'-dihydroxypropyl-oxycarbonyl) -phenyl) -8-trifluoromethylaminoquinoline derivatives. - Google Patents
Analogous process for the preparation of 4- (o- (2 ', 3'-dihydroxypropyl-oxycarbonyl) -phenyl) -8-trifluoromethylaminoquinoline derivatives. Download PDFInfo
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- DK141725B DK141725B DK53475A DK53475A DK141725B DK 141725 B DK141725 B DK 141725B DK 53475 A DK53475 A DK 53475A DK 53475 A DK53475 A DK 53475A DK 141725 B DK141725 B DK 141725B
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01) FREMLÆGGELSESSKRIFT 141725 DANMARK m ,nLCI*3 c 07 D 405/12 §(21) Ansøgning nr. 534/75 (22) Indleveret dm 14. feb. 1975 (23) Lebedag 2% dec. 1968 (44) Ansøgningen fremlagt og * * frsmlæggelseeeltrjftet offentliggjort den ^ . I you01) PUBLICATION 141725 DENMARK m, nLCI * 3 c 07 D 405/12 § (21) Application No. 534/75 (22) Filed dm Feb 14 1975 (23) Living day 2% dec. 1968 (44) The application presented and * * the publication of the publication published on ^. I you
Dl REKTORATET FOR u . .Dl THE RECTORATE FOR u. .
PATENT-OG VAREMÆRKEVÆSENET (30) Prioritet begæret fra denPATENT AND TRADE MARKET (30) Priority requested from it
29. dec, 1967, 134404, FR 29. mar. 1968, 146326, FR29 Dec, 1967, 134404, FR 29 Mar. 1968, 146326, FR
(71) ROUSSEL-UCLAF S.A., 35, Boulevard des Invalides, Paris 7e, FR.(71) ROUSSEL-UCLAF S.A., 35, Boulevard des Invalides, Paris 7th, FR.
(72) Opfinder: Andre Allais, 65» rue du Garde-Chasse, Les Lilae (93).» FR:(72) Inventor: Andre Allais, 65 "rue du Garde-Chasse, Les Lilae (93)." FR:
Jean Meier, 24 rue des Fauvettes, Coeullly-Ghampigny (94), FR.Jean Meier, 24 rue des Fauvettes, Coeullly-Ghampigny (94), FR.
(74) Fuldmægtig under sagens behandling:(74) Plenipotentiary in the proceedings:
Patentagentfirmaet Magnus Jensens Eftf._ (54) Analogifremgangsmåde til fremstilling af 4-(o-'(2' ,3' -dihydroxypropyl= oxycarbonyl)-phenyl)-8-trifluormethylaminoquinolinderivater.The patent agent company Magnus Jensen's Eftf._ (54) Analogous process for the preparation of 4- (o - '(2', 3 '-dihydroxypropyl = oxycarbonyl) -phenyl) -8-trifluoromethylaminoquinoline derivatives.
Opfindelsen angår en analogifremgangsmåde til fremstilling af hidtil ukendte 4-(o-(2%3*-dihydroxypropyloxyoarbonyl)--phenyl)--8-trifluormethylaminoquinolinderivater ffié4 den i kravets indledning angivne almene formel 1°.The invention relates to an analogous process for the preparation of novel 4- (o- (2% 3 * -dihydroxypropyloxyoarbonyl) -phenyl) -8-trifluoromethylaminoquinoline derivatives according to the general formula 1 ° set out in the preamble of the claim.
De ved fremgangsmåden ifelge opfindelsen fremstillede hidtil ukendte forbindelser har interessante farmakologiske egenrtfcaber. De har især en betydelig betændelseshæmmende virkning og en kraftig smertestillende virkning.The novel compounds prepared by the process according to the invention have interesting pharmacological properties. In particular, they have a significant anti-inflammatory effect and a powerful analgesic effect.
Blandt forbindelserne med den almene formel 1° skal fremhæves 4-(0-(2f ,3 •-dihydroxyprcpyloxyearbønyl )-phenyl)-amino-8-tri-fluormethylguinolin-aoetonid, smp, 108°C,Among the compounds of the general formula 1 ° are highlighted 4- (0- (2f, 3β-dihydroxyprypyloxyearbonyl) -phenyl) -amino-8-trifluoromethylguinoline aetonetonide, m.p., 108 ° C,
Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i kravets kendetegnende del anførte.The process according to the invention is characterized by the characterizing part of the claim.
2 I4tr252 I4tr25
Alkylgruppen i de substituerede 4-pbenylaminoquinoliner II0 vælges blandt lavmolekylære alkylgrupper, og man benytter især 4-(o--methoxycarbonylamino)-8-trifluormethylquinoliner.The alkyl group of the substituted 4-pbenylaminoquinolines II0 is selected from the low molecular weight alkyl groups and 4- (o-methoxycarbonylamino) -8-trifluoromethylquinolines in particular are used.
Det 2,2-P-Q-4-hydroxymethy1-1,3-d ioxolan, som man kondenserer med quinolinderivatet, er især 2,2-dimetby1-4-hydroxymethyl-1,3--dioxolan.In particular, the 2,2-P-Q-4-hydroxymethyl-1,3-dioxolane condensed with the quinoline derivative is 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane.
Omsætningen af 2,2-P-Q-4-byd roxymethy1-1,3-d ioxolan III med 4-(o-alkoxycarbonylphenylamino)-8-trifluormethyIquinolin II0, udføres med fordel i nærværelse af et basisk middel såsom et alkalime-talhydrid eller -amid eller et alkalimetal, idet man eliminerer den dannede alkanol fra reaktionsblandingen.The reaction of 2,2-PQ-4-butoxymethyl-1, 3-dioxolane III with 4- (o-alkoxycarbonylphenylamino) -8-trifluoromethylquinoline IIO is advantageously carried out in the presence of a basic agent such as an alkali metal hydride or - amide or an alkali metal, eliminating the formed alkanol from the reaction mixture.
Fjernelsen af den dannede alkanol kan især opnås ved opvarmning af reaktionsblandingen over alkanolens kogepunkt, eller idet man afdestillerer den under formindsket tryk.The removal of the formed alkanol can be achieved in particular by heating the reaction mixture above the boiling point of the alkanol or distilling it under reduced pressure.
4-( o-alkoxycarbonylphenylamino)-8-trifluormethylquinoliner- ne II0 kan især fremstilles ved kondensation af et passende substitueret 4-chlorquinolin og et alkylanthranilat.In particular, 4- (o-alkoxycarbonylphenylamino) -8-trifluoromethylquinolines IIO may be prepared by condensation of an appropriately substituted 4-chloroquinoline and an alkyl anthranilate.
Man har sammenlignet de ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser med α-glyceridet af 4-(2’-carboxy-phenylamino)-7-chlorquinolin, som er beskrevet i dansk patentskrift 102.625. Det drejer sig om .et produkt, som går i handelen under navnet "Glafenin" (ikke indregistreret dansk varemærke).Compounds prepared by the process according to the invention have been compared with the α-glyceride of 4- (2'-carboxy-phenylamino) -7-chloroquinoline, which is described in Danish patent 102,625. This is a product that trades under the name "Glafenin" (not registered Danish trademark).
..... I et forsøg for betændelseshæmmende virkning (forsøg med ødem frembragt af naphtoylheparamin) er den 40$ aktive dosis for "Glafenin" (DA^q) 55 mg/kg, og i forsøget for smertestillende virkning (forsøg med eddikesyre) er den 50$ aktive dosis af "Glafenin" (DA5t)J 50 mg/kg...... In a test for anti-inflammatory action (trial of edema caused by naphtoyl heparamine), the $ 40 active dose for "Glafenin" (DA ^ q) is 55 mg / kg, and in the trial for analgesic (acetic acid test) is the $ 50 active dose of "Glafenin" (DA5t) J 50 mg / kg.
For den i eksemplet nedenfor beskrevne forbindelse er den smertestillende virkning 2 gange så stor som virkningen af "Glafenin", og den betændelseshæmmende virkning er ca. halvt så stor som for "Glafenin".For the compound described in the example below, the analgesic effect is 2 times the effect of "Glafenin" and the anti-inflammatory effect is approx. half the size of "Glafenin".
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser er forbindelserne ifølge fransk medicinalskrift 4775 M overlegne, jvf. nedenfor.The compounds prepared by the process according to the invention are the compounds according to French medicinal product 4775 M superior, cf. below.
Nedenstående eksempel illustrerer fremgangsmåden ifølge opfindelsen.The following example illustrates the method of the invention.
3 1417253 141725
Eksempel,Example,
Acctonid af 4-(o-(2* ^-dihydroxypropyloxycarbonylj-pheny^-amino--8-trifluormethylquinolin.Acctonide of 4- (o- (2 *) -dihydroxypropyloxycarbonylj-phenyl) -amino-8-trifluoromethylquinoline.
Til 80 ml 2,2-dimethyl-4-hydroxymethyl-l,3-dioxolan sættes 100 ml toluen, hvorpå toluenet afdestilleres under formindsket tryk, så at tilstedeværende vand fjernes. Til det således opnåede vandfrie 2,2-dimethyl-4-rhydroxymethyl-lf3-dioxolan sættes under indiffe«^ rent atmosfære 0,25 g 50$fs oliesuspension af natriumhydrld og dernæst 21,5 g 4-(o-methoxyoarbonylphenylamino)-8-trifluormethylquino-lin. Der omrøres i 5 timer ved 85°C ved et vakuum på 50-100 mm Hg*To 80 ml of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane is added 100 ml of toluene and the toluene is distilled off under reduced pressure to remove the water present. To the thus obtained anhydrous 2,2-dimethyl-4-rhydroxymethyl-lf3-dioxolane is added under an indifferent atmosphere 0.25 g of 50 $ fs sodium suspension of sodium hydride and then 21.5 g of 4- (o-methoxyoarbonylphenylamino) -8 -trifluormethylquino-lin. Stir for 5 hours at 85 ° C under a vacuum of 50-100 mm Hg *
Han afkøler, tilsætter en vandig natriumekloridopløsning, øerører, ekstraherer den vandige fase med methylenehlorid, vasker methylen-ehloridekstrakterne med vand, tørrer dem og inddamper dem til tørhed ved destillation under formindsket tryk, vasker inddampningaresten med petroleumsether (kp. 65-75°C), tørrer des, krystalliserer den af isopropylether og får 23,8 g aeetonid af 4-(o-(2',3,-dihydroxypro-pyloxycarbonyl)-phenyl)-amino-8-trifluormethylquinolin med smp* 108°C.He cools, adds an aqueous sodium chloride solution, ear tubes, extracts the aqueous phase with methylene chloride, washes the methylene-ehloride extracts with water, dries them and evaporates them to dryness under reduced pressure, washing the residue with petroleum ether (bp 65-75 ° C) , then dried, crystallized from isopropyl ether to obtain 23.8 g of aeetonide of 4- (o- (2 ', 3, -dihydroxypropyloxycarbonyl) -phenyl) -amino-8-trifluoromethylquinoline, mp * 108 ° C.
Produktet fås i fora af farveløs· krystaller, som er opløselige i ethanol, chloroform, acetone og methylenehlorid, lidet oplø** eelige i isopropylether og uopløselige i vand.The product is available in forums of colorless crystals which are soluble in ethanol, chloroform, acetone and methylene chloride, slightly soluble in isopropyl ether and insoluble in water.
Analyse: ^3^21^3¾^ = 4*6,42 heregnet: C$ 61,88 H$ 4,74 H 12,77 6,28 fundet: 61,9 4,8 12,9 6,4 ·Analysis: ^ 3 ^ 21 ^ 3¾ ^ = 4 * 6.42 Found: C $ 61.88 H $ 4.74 H 12.77 6.28 Found: 61.9 4.8 12.9 6.4 ·
Denne forbindelse menes ikke at være beekrevet i littera- ' turen.This connection is not believed to be required in literature.
Udgangsproduktet, 4-(o-methoxyoarbonylphenylamino)-8-tri-fluormethylquinolin, fremstilles eom angivet i det følgende:The starting product, 4- (o-methoxyoarbonylphenylamino) -8-trifluoromethylquinoline, is prepared as set forth below:
Trin A: o-trifluormethylanllinomethylenmalonsyreethylester.Step A: o-Trifluoromethylanilinomethylene malonic acid ethyl ester.
En blanding af 54,8 g o-trifluormethylanilin og 73,5 g ethoxymethylenmalonsyreethylester opvarmes til 120°C under indifferent atmosfære. Man holder reaktionsblandingen på denne temperatur i 1 time, idet man ved destillation fjerner det dannede ethanol.A mixture of 54.8 g of o-trifluoromethylaniline and 73.5 g of ethoxymethylene malonic acid ethyl ester is heated to 120 ° C under inert atmosphere. The reaction mixture is kept at this temperature for 1 hour, removing by distillation the ethanol formed.
Man afkøler, afslutter elimineringen af ethanol ved destillation under formindsket tryk, afkøler og får 115 g o-trifluørmetfcylani-linomethylenmalonsyreethylester, som umiddelbart benyttes i det næste trin.It is cooled, eliminated by the removal of ethanol by distillation under reduced pressure, cooled and obtained 115 g of o-trifluoromethyl-methylanomethylene malonic acid ethyl ester, which is used immediately in the next step.
En prøve af dette produkt omkryetallieeres af petrøleums-ether (kp. 65-75°C). Smp. 94°C.A sample of this product is recrystallized from petroleum ether (bp 65-75 ° C). Mp. 94 ° C.
141725 4141725 4
Analyse: σΐ5%6^3^4 = 531,288 beregnet: C i» 54,38 Hfo 4,87 17,21 W° 4,23 fundet: 54,5 4,7 16,8 4,5Analysis: σΐ5% 6 ^ 3 ^ 4 = 531.288 calculated: C in »54.38 Hfo 4.87 17.21 W ° 4.23 found: 54.5 4.7 16.8 4.5
Denne forbindelse menes ikke at være beskrevet i litteraturen.This connection is not believed to be described in the literature.
grin B: 5-carbethoxy-4-bydroxy-8-trif luorme thylquino lin.lane B: 5-carbethoxy-4-hydroxy-8-trifluoromethyl thylquino lin.
En blanding af 115 g o-trifluormethylanilinomethylenmalon-syreethylester i rå tilstand som opnået i trin A og 115 ml phenyl-oxid opvarmes hurtigt under indifferent atmosfære. Ted 195°C begynder det dannede ethanol at afdestilleres. Efter ca. 30 minutters forløb er den indvendige temperatur 250°C, og reaktionsblandingen tilbagesvales, lilbagesvalingen opretholdes 1 time, hvorpå man afkøler, tilsætter 25 ml acetone, lader krystallisere og ved frasugning isolerer de dannede krystaller, som man vasker og tørrer* Der fås 71,5 g 3-carbethoxy-4-hydroxy-8-trifluormethylquinolin med smp* 210-214°C, som umiddelbart benyttes i det næste trin.A mixture of 115 g of o-trifluoromethylanilinomethylene malonic acid ethyl ester in the crude state as obtained in step A and 115 ml of phenyl oxide is rapidly heated under inert atmosphere. At 195 ° C, the ethanol formed begins to distill off. After approx. Within 30 minutes, the internal temperature is 250 ° C and the reaction mixture is refluxed, the lilac reflux is maintained for 1 hour, then it is cooled, 25 ml of acetone is added, crystallized and, by suctioning, the crystals formed which are washed and dried are isolated. g of 3-carbethoxy-4-hydroxy-8-trifluoromethylquinoline, mp * 210-214 ° C, which is used immediately in the next step.
En prøve af dette produkt krystalliseres af ethanol. Smp.A sample of this product is crystallized by ethanol. Mp.
216°C.216 ° C.
Analyse: = 285,218 beregnet: cJé 54,74 H% 3,53 Ή 19,98 4,91 fundet: 54,5 3,8 19,6 4,9Analysis: = 285.218 Calcd: ce 54.74 H% 3.53 Ή 19.98 4.91 Found: 54.5 3.8 19.6 4.9
Denne forbindelse menes ikke at være beskrevet i litteraturen.This connection is not believed to be described in the literature.
grin C: 5-carbo%y-4-hydroxy-8-trifluormethyltluinolin.Grin C: 5-carboxy-4-hydroxy-8-trifluoromethyltluinoline.
I en blanding af 300 ml vand og 100 ml 10 E vandig natriumhydroxidopløsning indfører man under indifferent atmosfære 70 g 3-carbethoxy-4-hydroxy-8-trifluormethylquinolin i rå tilstand som opnået i trin B, Man tilbagesvaler reaktionsblandingen i 2 timer 45- minutter. Den fremkomne opløsning hældes i en blanding af vand, is og 100 ml 11,8 E vandig saltsyre. Man isolerer den dannede udfældning ved frasugning, vasker den med vand og indfører den i en opløsning af 20 g natriumbicarbonat i 2 liter vand. Man opvarmer blandingen til 90°0, isolerer ved filtrering en smule uopløseligt materiale og syrher filtratet med eddikesyre, så at pH-værdien bliver 3,5. Den dannede udfældning isoleres ved frasugning, vaskes .og tørres, og man får 58 g 3-carboxy-4-hydroxy-8-trifluormethylguinolin med smp. 290-292°C, som umiddelbart benyttes i det næste trin.In a mixture of 300 ml of water and 100 ml of 10 U aqueous sodium hydroxide solution, 70 g of 3-carbethoxy-4-hydroxy-8-trifluoromethylquinoline in crude state is obtained under inert atmosphere as the reaction mixture is refluxed for 2 hours 45 minutes. . The resulting solution is poured into a mixture of water, ice and 100 ml of 11.8 U aqueous hydrochloric acid. The formed precipitate is isolated by suction, washed with water and introduced into a solution of 20 g of sodium bicarbonate in 2 liters of water. The mixture is heated to 90 ° 0, by filtration, slightly insoluble material is isolated and the filtrate is acidified with acetic acid so that the pH is 3.5. The precipitate formed is isolated by suction, washed and dried to give 58 g of 3-carboxy-4-hydroxy-8-trifluoromethylguinoline, m.p. 290-292 ° C, which is used immediately in the next step.
- U1725 o- U1725 o
En prøve af dette produkt omkrystalliseres i varmen og i kulden af acetone under behandling med dyrekul· Der fås således rent 3-carboxy-4-hydroxy-8-trifluormethylquinolin med smp. 292°C.A sample of this product is recrystallized in the heat and cold of acetone during treatment with animal charcoal. Thus, pure 3-carboxy-4-hydroxy-8-trifluoromethylquinoline is obtained, m.p. 292 ° C.
Analyse: C^HgP^ITO^ = 257*16 6 beregnet: 05É 51,37 H# 2,35 22,16 5,45 fundet: 51,6 2,6 21,8 5,3 * . ·. a-Analysis: C ^Hg₂P ^ ITO = = 257 * 16 6 calculated: 05É 51.37 H # 2.35 22.16 5.45 found: 51.6 2.6 21.8 5.3 *. ·. a-
Denne forbindelse menes ikke at være beskrevet i litteraturen.This connection is not believed to be described in the literature.
Trin D: 4-byd roxy-8-trifluormetb ylquinolin.Step D: 4-by-roxy-8-trifluoromethylquinoline.
I 110 ml phenyloxid indfører man under indifferent atmosfære 56.5 g råt 3-carboxy-4-hydroxy-8-1rifluormethy1quinolin som fremstillet i trin C. Man opvarmer hurtigt reaktionsblandingen til tilbage svaling og fortsætter tilbagesvalingen i 1 time 15 minutter.In 110 ml of phenyloxide, 56.5 g of crude 3-carboxy-4-hydroxy-8-trifluoromethylquinoline as prepared in step C. are added under inert atmosphere. The reaction mixture is rapidly heated to reflux and the reflux is continued for 1 hour 15 minutes.
Reaktionsblandingen afkøles til 50°0, og ©an tilsætter 20 ml isopro-pylether, afkøler til 20°C og lader krystallisere. Man isolerer den, dannede udfældning ved frasugning, vasker den, tørrer den og får 45,8 g 4-hydroxy-8-trifluormethylq.uinolin med smp. 180°C.The reaction mixture is cooled to 50 ° 0 and added 20 ml of isopropyl ether, cooled to 20 ° C and allowed to crystallize. The resulting precipitate is isolated by suction, washed, dried and 45.8 g of 4-hydroxy-8-trifluoromethylquinoline with m.p. 180 ° C.
En prøve af dette produkt krystalliseres af acetone under behandling med dyrekul. Der fås således rent 4-hydroxy-8-trifluorme-thylquinolin med smp. 180°C.A sample of this product is crystallized by acetone during animal charcoal treatment. Thus pure 4-hydroxy-8-trifluoromethylquinoline is obtained with m.p. 180 ° C.
Analyse:' C^øHgP^NO = 213,156 beregnet: 0# 56,34 2,84 Ff° 26,74 N$ 6,57 fundet: 56,8 3,1 26,5 6,5 ·Analysis: C 21 H 20 P 2 NO = 213.15 calculated: 0 # 56.34 2.84 Ff ° 26.74 N $ 6.57 found: 56.8 3.1 26.5 6.5 ·
Denne forbindelse menes ikke at være beskrevet i litteraturen.This connection is not believed to be described in the literature.
Trin E: 4-chlor-8-trifluormethyIquinolln.Step E: 4-Chloro-8-trifluoromethylquinoline.
I 130 ml phosphoroxychlorid indfører man i småportioner 44.5 g råt 4-hydroxy-8-trifluormethylquinolin som fremstillet i trin D, lader henstå 15 minutter ved stuetemperatur, hvorpå man opvarmer til tilbagesvaling og opretholder tilbagesvalingen i 1 time. Man afkøler og eliminerer overskudet af phosphoroxychlorid ved destillation under formindsket tryk. Den fremkomne harpiks tilsættes vand og is og dernæst 80 ml 22° Bé vandig ammoniakopløsning. Man omrører, ekstraherer den vandige fase med ether, vasker etherekstrak-terne med en fortyndet vandig ammoniakopløsning og dernæst med vand. Efter tørring, behandling med dyrekul og inddampning til tørhed fås 45,4 g 4-chlor-8-trifluormethylquinolin med smp. 78°C, som man umiddelbart benytter til fremstilling af 4-(o-methoxycarbonylphenylami- c 141725 6 no) -8-trif luormethylquinolin.In small batches of phosphorus oxychloride, 44.5 g of crude 4-hydroxy-8-trifluoromethylquinoline as prepared in step D is introduced, allowed to stand for 15 minutes at room temperature, then heated to reflux and maintained at reflux for 1 hour. The excess phosphorus oxychloride is cooled and eliminated by distillation under reduced pressure. The resulting resin is added to water and ice and then 80 ml of 22 ° B aqueous ammonia solution. Stir, extract the aqueous phase with ether, wash the ether extracts with a dilute aqueous ammonia solution and then with water. After drying, treatment with animal charcoal and evaporation to dryness, 45.4 g of 4-chloro-8-trifluoromethylquinoline are obtained with m.p. 78 ° C, which is used immediately to prepare 4- (o-methoxycarbonylphenylamycin) -8-trifluoromethylquinoline.
En prøve af råt 4-chlor-8-trifluormethylquinolin krystalliseres af petroleumsether (kp. 65-75°C). Smp. 78°C.A sample of crude 4-chloro-8-trifluoromethylquinoline is crystallized by petroleum ether (bp 65-75 ° C). Mp. 78 ° C.
Analyse: = 231,605Analysis: = 231.605
Beregnet: Cfi 51,86 Hfo 2,18 rø 24,61 Clfo 15,3 3$ 6,05 fundet: 52,2 2,3 24,9 15,5 5,8Calculated: Cfi 51.86 Hfo 2.18 red 24.61 Clfo 15.3 3 $ 6.05 found: 52.2 2.3 24.9 15.5 5.8
Denne forbindelse menes ikke at være beskrevet i litteraturen.This connection is not believed to be described in the literature.
Trin ff: 4-(o-metboxycarbonylphenylamino)-8-trifluorme thvlcmino lin.Step ff: 4- (o-Metboxycarbonylphenylamino) -8-trifluoromethylamine amino.
I 100 ml 2 ΙΓ saltsyre indføres 23,15 g råt 4-chlor-8-tri-fluormethylquinolin som fremstillet i trin E og dernæst 15,85 g me-thylanthranilat. Man opvarmer reaktionsblandingen til tilbagesvaling og opretholder tilbagesvalingen i 50 minutter. Derpå afkøler man og lader krystallisationen udvikle sig, hvorefter man isolerer den dannede udfældning ved frasugning og indfører udfældningen i 300 ml vandig mættet natriumbicarbonatopløsning. Der omrøres, og man tilsætter methylenchlorid og omrører igen, fjerner noget uopløseligt materiale ved filtrering og fraskiller den organiske fase ved dekantering, hvorpå man vasker ‘den med vand og inddamper den til tørhed.Into 100 ml of 2 ΙΓ hydrochloric acid are introduced 23.15 g of crude 4-chloro-8-trifluoromethylquinoline as prepared in step E and then 15.85 g of methyl anthranilate. The reaction mixture is heated to reflux and the reflux is maintained for 50 minutes. The crystallization is then cooled and allowed to develop, after which the formed precipitate is isolated by suction and the precipitate is introduced into 300 ml of aqueous saturated sodium bicarbonate solution. Stir and methylene chloride is added and stirred again, removing any insoluble material by filtration and separating the organic phase by decantation, washing it with water and evaporating it to dryness.
Inddampningsresten krystalliseres af methanol, og man får 21,3 g 4 -(o-methoxycarbonylphenylamino) -8-trifluormethylquinolin med smp. 176°C.The residue is crystallized by methanol to give 21.3 g of 4- (o-methoxycarbonylphenylamino) -8-trifluoromethylquinoline, m.p. 176 ° C.
Analyse: ^8^13^3¾^½ = 546,30 beregnet: Gfi 62,43 H$ 3,78 E# 16,46 tø 8,09 fundet: 62,2 4,0 16,3 8,0 I-.R. spektrum (chloroform):Analysis: ^ 8 ^ 13 ^ 3¾ ^ ½ = 546.30 calculated: Gfi 62.43 H $ 3.78 E # 16.46 th 8.09 found: 62.2 4.0 16.3 8.0 I-. R. spectrum (chloroform):
Absorption ved 3297 og 3264 cm“^ svarende til gruppen -Ε-Ξ absorption ved 1691 cm-1 svarende til en carbonylgruppe absorption ved 1142 og 1147 cm*“^ svarende til gruppen CP^.Absorption at 3297 and 3264 cm “^ corresponding to the -Ε-Ξ absorption group at 1691 cm-1 corresponding to a carbonyl group absorption at 1142 and 1147 cm *“ corresponding to the group CP ^.
Denne forbindelse menes ikke at være beskrevet i litteraturen.This connection is not believed to be described in the literature.
7 U17257 U1725
Fysiologiak undersøgelse.Physiology examination.
Ben smertestillende virkning af forbindelsen ifølge eksemplet (forbindelse A) og forbindelserne ifølge eksempel 1 og 2 i fransk medieinalpatentskrift 4775 M, nemlig acetonidet af 4-(2,-oarbo-a--glyceryloxyphenylamino)-8-chlorquinolin og acetonidet af 4-(2’--carbo-a-glyceryloxyphenylamino-7-chlorq.uinolin, i det følgende betegnet produkt B og produkt C, er blevet undersøgt som følger:Leg analgesic effect of the compound of Example (Compound A) and the compounds of Examples 1 and 2 of French Patent Specification 4775 M, namely the acetonide of 4- (2, -oarbo-a - glyceryloxyphenylamino) -8-chloroquinoline and the acetonide of 4- ( 2 '- Carbo-α-glyceryloxyphenylamino-7-chloroquinoline, hereinafter referred to as product B and product C, has been investigated as follows:
Ben benyttede prøve er baseret på den iagttagelse ifølge R. Koster m.fl. (Fed. Proc., 159, 18 412), at intraperitoneal indsprøjtning af eddikesyre på mus fremkalder gentagne karakteristiske strække- og vridningsbevægelser, som kan vare ved i mere end 6 timer. Be smertestillende stoffer forebygger eller eliminerer dette syndrom, der følgelig kan betragtes som eksterioriseringen af en diffus abdominal smerte.Legs used are based on the observation according to R. Koster et al. (Fed. Proc. 159, 18412) that intraperitoneal injection of acetic acid into mice induces repeated characteristic stretching and twisting movements that can last for more than 6 hours. Asking painkillers prevents or eliminates this syndrome, which can therefore be considered the exteriorization of a diffuse abdominal pain.
Man anvender en 6^fs eddikesyreopløening i vand, tilsat 19$ gummi arabicum. Ben dosis, som udløser syndromet tinder disse betingelser, er på 0,01 ml pr. g eller 60 mg/ϊφ eddikesyre. Forbindelserne indgives ad oral vej 30 minutter før den intraperitoneale indsprøjtning af eddikesyre, idet dyrene er fastende fra dagen før forsøget. For hver dosis og for kontroldyrene, som hvert forsøg obligatorisk omfatter, benytter man en gruppe på 5 dyr. Strækkebevægelser-ne iagttagee, noteres og tælles for hver mus, hvorpå de lægges sammen for hver gruppe på 5 i en observationsperiode på 15 minutter, som begynder straks efter indsprøjtningen af eddikesyre.A 6 µs acetic acid solution is used in water, added with $ 19 gum arabic. The bone dose that triggers the syndrome alleviates these conditions is 0.01 ml per day. g or 60 mg / ϊφ acetic acid. The compounds are administered orally 30 minutes before the intraperitoneal injection of acetic acid, the animals fasting from the day before the test. A group of 5 animals is used for each dose and for the control animals, which are mandatory for each experiment. The stretch movements are observed, noted and counted for each mouse, and then added to each group of 5 for a 15 minute observation period beginning immediately after the injection of acetic acid.
Resultaterne udtrykt i BA^0 fremgår af følgende tabel: Μ50The results expressed in BA ^ 0 are shown in the following table: Μ50
Produkt A 15 mg AgProduct A 15 mg Ag
Produkt B 50 mg AgProduct B 50 mg Ag
Produkt C 30 mg AgProduct C 30 mg Ag
Konklusion:conclusion:
Produkt A har en smertestillende virkning, som er to gange større end virkningen af forbindelse C og mere end 3 gange større end virkningen af forbindelse B.Product A has an analgesic effect that is twice greater than the effect of compound C and more than 3 times greater than the effect of compound B.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK53475A DK141725B (en) | 1967-12-29 | 1975-02-14 | Analogous process for the preparation of 4- (o- (2 ', 3'-dihydroxypropyl-oxycarbonyl) -phenyl) -8-trifluoromethylaminoquinoline derivatives. |
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR134404A FR6935M (en) | 1967-12-29 | 1967-12-29 | |
| FR134404 | 1967-12-29 | ||
| FR146326 | 1968-03-29 | ||
| FR146326 | 1968-03-29 | ||
| DK635468 | 1968-12-27 | ||
| DK635468AA DK134672B (en) | 1967-12-29 | 1968-12-27 | Analogous process for the preparation of 4- (o- (2 ', 3'-dihydroxypropyloxycarbonyl) -phenyl) -aminoquinoline derivatives or salts thereof. |
| DK53475A DK141725B (en) | 1967-12-29 | 1975-02-14 | Analogous process for the preparation of 4- (o- (2 ', 3'-dihydroxypropyl-oxycarbonyl) -phenyl) -8-trifluoromethylaminoquinoline derivatives. |
| DK53475 | 1975-02-14 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK53475A DK53475A (en) | 1975-08-04 |
| DK141725B true DK141725B (en) | 1980-06-02 |
| DK141725C DK141725C (en) | 1980-10-20 |
Family
ID=27439338
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK53475A DK141725B (en) | 1967-12-29 | 1975-02-14 | Analogous process for the preparation of 4- (o- (2 ', 3'-dihydroxypropyl-oxycarbonyl) -phenyl) -8-trifluoromethylaminoquinoline derivatives. |
Country Status (1)
| Country | Link |
|---|---|
| DK (1) | DK141725B (en) |
-
1975
- 1975-02-14 DK DK53475A patent/DK141725B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK141725C (en) | 1980-10-20 |
| DK53475A (en) | 1975-08-04 |
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| Date | Code | Title | Description |
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| PBP | Patent lapsed |