DK147973B - ANALOGY PROCEDURE FOR PREPARING 1,4-DIPHENYL-3-PYRAZOLYL ACETIC ACIDS - Google Patents
ANALOGY PROCEDURE FOR PREPARING 1,4-DIPHENYL-3-PYRAZOLYL ACETIC ACIDS Download PDFInfo
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- DK147973B DK147973B DK356676AA DK356676A DK147973B DK 147973 B DK147973 B DK 147973B DK 356676A A DK356676A A DK 356676AA DK 356676 A DK356676 A DK 356676A DK 147973 B DK147973 B DK 147973B
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- C07C251/72—Hydrazones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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Description
1.First
147973147973
Opfindelsen angår en analogifremgangsmåde til fremstilling af hidtil ukendte 1,4-diphenyl-3-pyrazolyl=ddikesyrer med den almene formel IThis invention relates to an analogous process for the preparation of novel 1,4-diphenyl-3-pyrazolyl acetic acids of the general formula I
2 147973 1 2 3 hvori R betyder fluor, chlor eller brom, R og R er ortho-, meta- eller parastillede substituenter og betyder hydrogen, methyl, fluor eller chlor, og X betyder en alkoxycarbonylgruppe med 1-6 carbonatomer eller en carboxylgruppe, eller fysiologisk acceptable salte deraf.Wherein R is fluorine, chlorine or bromine, R and R are ortho-, meta- or para-substituted substituents and means hydrogen, methyl, fluorine or chlorine, and X is an alkoxycarbonyl group having 1-6 carbon atoms or a carboxyl group, or physiologically acceptable salts thereof.
Med fysiologisk acceptable salte skal eksempelvis forstås alkalieller jordalkalimetalsalte, såsom f. eks. natriumsalte, lithiumsalte, kalciumsalte eller magnesiumsalte, kobbersalte eller aminsalte, såsom f. eks. N-methylglucaminsalte, Ν,Ν-dimethylglucaminsalte, ethanol= aminsalte, diethanolaminsalte og morpholinsalte.By physiologically acceptable salts is meant, for example, alkali or alkaline earth metal salts such as, for example, sodium salts, lithium salts, calcium salts or magnesium salts, copper salts or amine salts, such as, for example, N-methylglucamine salts, Ν, Ν-dimethylglucamine salts, ethanol = amine salts, diethanol salts.
Fremgangsmåden ifølge opfindelsen er kendetegnet ved, at man omsætter et pyrazolderivat med den almene formel IIThe process according to the invention is characterized by reacting a pyrazole derivative of the general formula II
"O" i ! ”” 12 3 hvori R ,R og R har den ovenfor anførte betydning, og Y betegner et halogenatom, med et alkalimetalcyanid og hydrolyserer " de opnåede cyanider og om ønsket omdanner de dannede carboxylsyrer til deres salte eller forestrer dem med en lavere alkanol."O" i! Wherein R, R and R are as defined above and Y represents a halogen atom, with an alkali metal cyanide and hydrolyzes the cyanides obtained and, if desired, convert the carboxylic acids formed to their salts or esterify them with a lower alkanol.
Fremgangsmåden ifølge opfindelsen kan gennemføres under betingelser, som man sædvanligvis anvender til udskiftning af halogenatomer med en cyanogruppe.The process of the invention may be carried out under conditions usually used to replace halogen atoms with a cyano group.
Hertil anvender man som udgangsforbindelser med den almene formel II fortrinsvis sådanne forbindelser, der som substituenter Y bærer et chlor-, brom- eller jodatom.For this purpose, starting compounds of general formula II are preferably used as compounds which, as substituents Y, carry a chlorine, bromine or iodine atom.
3 1479733 147973
Reaktionen gennemføres fortrinsvis i et dipolært, aprotisk opløsningsmiddel (såsom dimethylformamid, N-methylacetamid, N-methylpyrrolidon, acetonitril, dimethylsulfoxid eller hexamethylphosphorsyretriamid).The reaction is preferably carried out in a dipolar aprotic solvent (such as dimethylformamide, N-methylacetamide, N-methylpyrrolidone, acetonitrile, dimethylsulfoxide or hexamethylphosphoric triamide).
Som alkalimetalcyanid anvender man fortrinsvis natriumcyanid eller kaliumcyanid.As the alkali metal cyanide, sodium cyanide or potassium cyanide is preferably used.
Ved denne omsætning kan man accelerere reaktionshastigheden betydeligt, når man gennemfører omsætningen i nærværelse af en kronether.With this reaction, the reaction rate can be significantly accelerated when conducting the reaction in the presence of a crown ether.
Den eventuelt påfølgende forestring af de frie syrer foregår ifølge i og for sig kendte arbejdsmetoder. Man kan således eksempelvis omsætte syrerne med diazomethan eller diazoethan og opnår de tilsvarende methyl- eller ethylestere. En generelt anvendelig metode er omsætningen af syrerne med alkanoler i nærværelse af carbonyldiimid= azol eller dicyklohexylcarbodiimid.The possible subsequent esterification of the free acids takes place according to working methods known per se. Thus, for example, the acids can be reacted with diazomethane or diazoethane to obtain the corresponding methyl or ethyl esters. A generally applicable method is the reaction of the acids with alkanols in the presence of carbonyl diimide = azole or dicyclohexylcarbodiimide.
Endvidere er det eksempelvis muligt at omsætte syrerne med alkylhalo= genider i nærværelse af kobber(I)-oxid eller sølvoxid.Furthermore, it is possible, for example, to react the acids with alkyl halides in the presence of copper (I) oxide or silver oxide.
En yderligere metode består i, at man omdanner de frie syrer til de tilsvarende syrealkylestere med de tilsvarende dimethylformamidalkylacet= aler. Endvidere kan man i nærværelse af stærkt sure katalysatorer, såsom saltsyre, svovlsyre, perchlorsyre, trifluormethylsulfonsyre eller p-toluensulfonsyre, omsætte syrerne med alkoholerne eller med de lavere alkancarboxylsyreestere af alkoholerne.A further method consists in converting the free acids to the corresponding acid alkyl esters with the corresponding dimethylformamide alkyl acetals. Furthermore, in the presence of highly acidic catalysts such as hydrochloric acid, sulfuric acid, perchloric acid, trifluoromethylsulfonic acid or p-toluenesulfonic acid, the acids can be reacted with the alcohols or with the lower alkanecarboxylic acid esters of the alcohols.
Det er imidlertid også muligt at omdanne carboxylsyrerne til syrechlo= riderne eller blandede syreanhydrider og at omsætte disse med alkoho= lerne i nærværelse af basiske katalysatorer, såsom pyridin, collidin, lutidin eller 4-dimethylaminopyridin.However, it is also possible to convert the carboxylic acids to the acid chlorides or mixed acid anhydrides and to react with the alcohols in the presence of basic catalysts such as pyridine, collidine, lutidine or 4-dimethylaminopyridine.
Saltene af carboxylsyrerne dannes eksempelvis ved hydrolysering af es= trene ved hjælp af basiske katalysatorer eller ved neutralisation af syrerne med fysiologisk acceptable baser.The salts of the carboxylic acids are formed, for example, by hydrolyzing the esters by basic catalysts or by neutralizing the acids with physiologically acceptable bases.
De omhandlede pyrazolderivater med den almene formel I er farmakologisk virksomme stoffer, der navnlig udmærker sig ved, at de har en udpræget antiinflammatorisk virkning samt en god maveforligelighed og kun udviser en relativt ringe toksicitet. Derudover udmærker forbindelserne sig ofte ved en hurtig virkningsindtræden, en høj virkningsintensitet 4 147973 og en lang virkningsvarighed, og de har en god resorberbarhed og en relativt god stabilitet i galeniske præparater.The present pyrazole derivatives of the general formula I are pharmacologically active substances which are particularly distinguished by their pronounced anti-inflammatory effect and good gastric compatibility and exhibit only a relatively low toxicity. In addition, the compounds are often characterized by a rapid onset of action, a high intensity of action and a long duration of action, and they have good resorbability and relatively good stability in galenic preparations.
FORSØGSRAPPORTTEST REPORT
1. Carragenin-poteødem-forsøg (se Proc. Soc. Exptl. Biol. Med. 111, 1962, 544.) I rottepoten frembringes en akut exsudativ betændelse ved indsprøjtning af en carrageninopløsning. Denne betændelse kan hammes ved hjælp af antiphlogistika. Ødemet måles volumetrisk.1. Carragenin paw edema trial (see Proc. Soc. Expt. Biol. Med. 111, 1962, 544.) In the rat paw, an acute exudative inflammation is produced by injection of a carrageenin solution. This inflammation can be inhibited by antiphlogistics. The edema is measured volumetrically.
Der anvendes hanlige (SPF) Wistar-rotter i et vægtområde fra 120-140 g. 16 timer før den orale indgivelse af stofferne sættes dyrene fra foderet, men tilbydes vand ad libitum.Male (SPF) Wistar rats are used in a weight range of 120-140 g. 16 hours before oral administration of the substances, the animals are released from the feed, but water is offered ad libitum.
Carragenin benyttes som pirringsmiddel. 10 mg/ml carragenin optages i en 0,9% kogsaltopløsning, og 0,1 ml deraf indsprøjtes i rottepoten.Carragenin is used as a stimulant. 10 mg / ml carragenin is taken up in a 0.9% saline solution and 0.1 ml thereof injected into the rat paw.
Den enkelte dosis af det til afprøvning bestemte stof bliver for hvert forsøgsdyr først indgivet en time før ødemfremkaldelsen i 0,5 ml af bæreren pr. 100 g legemsvægt. Som bærer tjener fysiologisk kogsaltopløsning. I tilfælde af vanduopløselige stoffer fremstilles en mikro-suspension i fysiologisk natriumchloridopløsning med "Myrj" 53 (85 mg/ 100 ml).For each test animal, the individual dose of the substance to be tested is first administered one hour before the edema induction in 0.5 ml of the carrier per ml. 100 g body weight. As a carrier, physiological saline solution serves. In the case of water-insoluble substances, a micro-suspension in physiological sodium chloride solution is prepared with "Myrj" 53 (85 mg / 100 ml).
Forsøgets udførelse.Test execution.
Til hver dosisgruppe benyttes 5 dyr. Efter plethysmografisk volumenmåling af den højre bagpote indgives stofferne oralt. En time senere frembringes betændelsen ved hjælp af indsprøjtning af 0,1 ml pirringsmiddel i fodsålen. Efter yderligere 3 timer måles potevolumenerne på-ny, og betændelseshæmningen beregnes.For each dose group, 5 animals are used. After plethysmographic volume measurement of the right hind paw, the substances are administered orally. One hour later, the inflammation is produced by injecting 0.1 ml of irritant into the foot sole. After another 3 hours, the paw volumes are re-measured and the inflammation inhibition calculated.
Y · looY · loo
Bedømmelse: % hæmning = 100--g- .Rating:% inhibition = 100 - g-.
Y = gennemsnitlig forskel mellem potevolumener i behandlingsgruppen.Y = mean difference between paw volumes in the treatment group.
Z = gennemsnitlig forskel mellem potevolumener i kontrolgruppen.Z = mean difference between paw volumes in the control group.
147973 5 2. Adjuvans-arthritis-forsøg (se Brit. J. Pharmacol., 21, 1963, 127)2. Adjuvant Arthritis Trials (see Brit. J. Pharmacol., 21, 1963, 127)
Efter indsprøjtning af Freunds adjuvans (M. butyricum) udvikles hos rotter i løbet af ca. 2 uger en polyarthritis, som kan hæmmes ved hjælp af antiphlogistika.Following injection of Freund's adjuvant (M. butyricum), rats develop over ca. 2 weeks a polyarthritis, which can be inhibited by antiphlogistics.
Der anvendes hunlige og hanlige rotter af Lewis-stammen (LEW) i vægtområdet 110-190 g. Dyrene tilbydes drikkevand og "Altromin"-pressefoder ad libitum.Male and male rats of the Lewis strain (LEW) are used in the weight range of 110-190 g. The animals are offered drinking water and "Altromin" press feed ad libitum.
For hver dosis gruppe anvendes 10 rotter.For each dose group, 10 rats are used.
Mycobacterium butyricum fra firmaet Difko, Detroit, anvendes som pirringsmiddel. En suspension af 0,5 mg M. butyricum i 0,1 ml tyndtflydende paraffin (DAB 7) indsprøjtes under fodsålen i den højre bagpote.Mycobacterium butyricum from Difko, Detroit, is used as a stimulant. A suspension of 0.5 mg M. butyricum in 0.1 ml thin-liquid paraffin (DAB 7) is injected under the sole of the foot into the right hind paw.
Forsøgsforbindelserne indgives oralt dagligt i 4 dage fra den 11. forsøgsdag. Forbindelserne administreres som en klar vandig opløsning eller som en krystalsuspension under tilsætning af "Myrj" 53 (85 mg %) i isotonisk natriumchloridopløsning.The test compounds are administered orally daily for 4 days from the 11th test day. The compounds are administered as a clear aqueous solution or as a crystal suspension with the addition of "Myrj" 53 (85 mg%) in isotonic sodium chloride solution.
Forsøgets udførelse.Test execution.
Rotterne bliver i henseende til deres legemsvægt inddelt så ensartet som muligt i forskellige grupper. Efter plethysmografisk volumenmåling af den højre og venstre bagpote indsprøjtes 0,1 ml adjuvans i den højre bagpote under fodsålen. De højre bagpcter måles fra den 14. forsøgsdag og indtil afslutning af forsøget. Ligeledes foretages målingen af de u-pirrede venstre bagpoter fra den 14. forsøgsdag. Forsøgets varighed andrager 3 uger.For their body weight, the rats are divided as uniformly as possible into different groups. After plethysmographic volume measurement of the right and left hind paw, 0.1 ml of adjuvant is injected into the right hind paw under the sole of the foot. The right hindquarters are measured from the 14th trial day until the end of the trial. Likewise, the unpirated left hind legs are measured from the 14th trial day. The duration of the trial is 3 weeks.
Bedømmelse: % hæmning = 100 - ^ z y = gennemsnitlig forskel mellem potevolumener i behandlingsgruppen, z = gennemsnitlig forskel mellem potevolumener i kontrolgruppen.Assessment:% inhibition = 100 - ^ z y = mean difference between paw volumes in the treatment group, z = average difference between paw volumes in the control group.
3. Sår-forsøg (se Arch. Int. Pharmacodys. 192, 1971, 370 ff.) 147973 63. Wound Testing (see Arch. Int. Pharmacodys. 192, 1971, 370 et seq.) 147973 6
Fremkomsten af mavesår er en hyppig komplikation ved behandlingen med ikke-steroidale betændelseshæmmere. Denne bivirkning kan påvises ved dyreforsøg.The appearance of peptic ulcer is a frequent complication of treatment with non-steroidal inflammatory inhibitors. This side effect can be detected by animal testing.
Der anvendes hanlige Wistar-rotter (SPF). Dyrene ligger i et vægtcmråde fra 130-10 g. 16 timer før forsøgets begyndelse sættes dyrene fra foderet, men tilbydes vand ad libitum.Male Wistar rats (SPF) are used. The animals are in a weight range of 130-10 g. 16 hours before the start of the experiment, the animals are put off the feed, but water is offered ad libitum.
Der anvendes 5 dyr pr. dosis. Forbindelserne administreres én gang oralt, opløst i natriumchloridopløsning eller som krystalsuspension under tilsætning af 85 mg% "Myrj" 53.5 animals are used per day. dosage. The compounds are administered once orally, dissolved in sodium chloride solution or as a crystal suspension with the addition of 85 mg% "Myrj" 53.
3 timer efter administrationen af forbindelsen indsprøjter man 1 ml af en 3% opløsning af farvestoffet Diphenylblåt intravenøst og dræber dyret. Maven resekteres og undersøges mikroskopisk for antal og størrelse af epi-thellæsioner og sår, som fremtræder som følge af farvestofkoncentration.3 hours after administration of the compound, 1 ml of a 3% solution of the dye Diphenyl blue is injected intravenously and the animal is killed. The abdomen is microscopically resected and examined for the number and size of epithelial lesions and ulcers that appear as a result of dye concentration.
Resultaterne opnået ved de ovennævnte forsøg fremgår af den efterfølgende tabel.The results obtained in the above experiments are shown in the following table.
g g 7 g j, 147973g g 7 g j, 147973
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Pyrazolderivaterne med den almene formel I metaboliseres i legemet på anden måde end de kendte antiinflammatorisk virksomme forbindelser.The pyrazole derivatives of the general formula I are metabolized in the body by other means than the known anti-inflammatory active compounds.
De omhandlede forbindelser egner sig i kombination med de i den gale= ni ske farmaci sædvanlige bæremidler til behandling af eksempelvis a) lokalt: Kontaktdermatitis, eksemer af forskellig art, neurodermitis, erythrodermi, 1. grads forbrændinger, Pruritus vulvae et ani, Rosacea, Erythematodes curaneus, Psoriasis, Lichen ruber pla= nus et verrucosus.The compounds of the present invention are suitable in combination with the usual carriers in the pharmaceutical industry for the treatment of, for example: curaneus, Psoriasis, Lichen ruber pla = nus et verrucosus.
b) oralt: akut og kronisk Polyarthritis, Neurodermitis, Asthma bron= chiale, høfeber o.a.b) Oral: acute and chronic Polyarthritis, Neurodermitis, Asthma bronchial = chial, hay fever etc.
Fremstillingen af lægemiddelspecialiteterne foregår på sædvanlig måde, idet man med egnede tilsætninger, bærestoffer og smagskorrigenter o-verfører de aktive stoffer til de ønskede administrationsf omer, tabletter, dragéer, kapsler, opløsninger, salver, inhalationsmidler osv.The preparation of the drug specialties is carried out in the usual way, with the appropriate additives, carriers and flavoring agents transferring the active substances to the desired administration forms, tablets, dragees, capsules, solutions, ointments, inhalants, etc.
Til den orale anvendelse egner sig navnlig tabletter, dragéer og kapsler, der eksempelvis indeholder 1-250 mg aktivt stof og 50 mg - 2 g af en farmakologisk uvirksom bærer, såsom eksempelvis lactose, amylose, talkum, gelatine, magnesiumstearat og lignende samt de sædvanlige tilsætninger. Til den topiske anvendelser egner sig puddere, salver, ae= rosoler og lignende præparater, som fortrinsvis indeholder 0,01 til 2% af det aktive stof.For oral use, in particular, tablets, dragees and capsules containing, for example, 1-250 mg of active substance and 50 mg - 2 g of a pharmacologically inactive carrier such as, for example, lactose, amylose, talc, gelatin, magnesium stearate and the like, as well as the usual, are suitable. additives. Suitable for topical applications are powders, ointments, ae = rosols and similar preparations which preferably contain 0.01 to 2% of the active substance.
De hidtil ukendte udgangsforbindelser med den almene formel II kan fremstilles ud fra de tilsvarende carboxylsyreestere, idet man reducerer disse med eksempelvis lithiumaluminiumhydrid til dannelse af de tilsvarende carbinoler og udskifter disses hydroxygruppe med halo= gen.The novel starting compounds of the general formula II can be prepared from the corresponding carboxylic acid esters, reducing these with, for example, lithium aluminum hydride to form the corresponding carbinols and replacing their hydroxy group with halogen.
De efterfølgende eksempler tjener til belysning af fremgangsmåden ifølge opfindelsen.The following examples serve to illustrate the process of the invention.
Eksempel 1 a) En opløsning af 19,2 g 2—chlor-2-phenylhydrazono-eddikesyreethyl= ester i 100 ml chloroform bliver ved tildrypning sat til en opløsning af 22,7 g a-dimethylamino-4-nitrostyren i 100 ml chloroform og 10,5 g triethylamin. Man lader reaktionsblandingen henstå i en time ved 9 147973 50°C og i 16 timer ved 20°Cr vasker den med 2N saltsyre, og derefter med mættet natriumhydrogencarbonatopløsning. Derpå inddamper man chloroformopløsningen i vakuum, behandler resten med petroleumsether og opnår 24,6 g 3-dimethylaminoethylen-3-(4-nitrophenyl)-2-phenyl= hydrazono-propionsyreethylester med smeltepunkt 139°C.Example 1 a) A solution of 19.2 g of 2-chloro-2-phenylhydrazonoacetic acid ethyl ester in 100 ml of chloroform is added, by drip, to a solution of 22.7 g of α-dimethylamino-4-nitrostyrene in 100 ml of chloroform and 10.5 g of triethylamine. The reaction mixture is allowed to stand at 50 ° C for one hour and washed with 2N hydrochloric acid for 16 hours at 20 ° C and then with saturated sodium hydrogen carbonate solution. The chloroform solution is then evaporated in vacuo, the residue treated with petroleum ether to give 24.6 g of 3-dimethylaminoethylene-3- (4-nitrophenyl) -2-phenyl = hydrazono-propionic acid ethyl ester, mp 139 ° C.
b) 20,5 g 3-dimethylaminomethylen-3-(4-nitrophenyl)-2-phenylhydrazono-propionsyreethylester tilsættes 200 ml dioxan og 70 ml 2N saltsyre og opvarmes i 45 min. under tilbagesvaling. Man lader reaktionsblandingen køle, inddamper den i vakuum og optager resten i chloroform. Chloroformfasen vaskes med vand, inddampes i vakuum, og resten behandles med petroleumsether, hvorefter man opnår 12,0 g 4-(4-nitrophenyl)-l-phenyl-3-pyrazolcarboxylsyreethylester med smeltepunkt 143°C.b) 20.5 g of 3-dimethylaminomethylene-3- (4-nitrophenyl) -2-phenylhydrazonopropionic acid ethyl ester are added to 200 ml of dioxane and 70 ml of 2N hydrochloric acid and heated for 45 minutes. under reflux. The reaction mixture is allowed to cool, evaporated in vacuo and the residue taken up in chloroform. The chloroform phase is washed with water, evaporated in vacuo and the residue treated with petroleum ether to give 12.0 g of 4- (4-nitrophenyl) -1-phenyl-3-pyrazole carboxylic acid ethyl ester, m.p. 143 ° C.
c) 24 g af den ifølge eksempel lb) opnåede forbindelse opløses i 500 ml ethanol, tilsættes 5 g Raney-nikkel og hydrogeneres ved stuetemperatur under normalt tryk. Derefter frafiltrerer man katalysatoren, inddamper filtratet i vakuum, krystalliserer resten fra me= thanol og opnår 20 g 4-(4-aminophenyl)-l-phenyl-3-pyrazolylcarbozyl= syreethylester med smeltepunkt 142°C.c) Dissolve 24 g of the compound of Example 1b in 500 ml of ethanol, add 5 g of Raney nickel and hydrogenate at room temperature under normal pressure. The catalyst is then filtered off, the filtrate is evaporated in vacuo, the residue is crystallized from methanol to give 20 g of 4- (4-aminophenyl) -1-phenyl-3-pyrazolylcarbozyl = acid ethyl ester, m.p. 142 ° C.
d) 3,1 g 4-(4-aminophenyl)-l-phenyl-3-pyrazolvlcarboxylsyreethyl= ester bliver i 13 ml 15% saltsyre ved -5°C tilsat en opløsning af 760 mg natriumnitrit i 1,5 ml vand. Derpå sættes yderligere 25 ml 3% saltsyre til blandingen, og den -5°C kolde blanding bliver ved tildrypning sat til en 60°C varm opløsning af 1,5 g kobber (II) chlo-rid i 30 ml 12% saltsyre. Man lader yderligere henstå i 10 min. ved 60°C, køler, ekstraherer med eddikeester, inddamper ekstrakten, optager resten i toluen, filtrerer gennem en klselgelsøjle, inddamper opløsningen og opnår 2,47 g 4-(4-chlorphenyl)-l-phenyl-3-pyra= zolcarboxylsyreethylester med smeltepunkt 96°C.d) 3.1 g of 4- (4-aminophenyl) -1-phenyl-3-pyrazolylcarboxylic acid ethyl ester is added in 13 ml of 15% hydrochloric acid at -5 ° C to a solution of 760 mg of sodium nitrite in 1.5 ml of water. Then an additional 25 ml of 3% hydrochloric acid is added to the mixture and the -5 ° C cold mixture is added, by dripping, to a 60 ° C hot solution of 1.5 g of copper (II) chloride in 30 ml of 12% hydrochloric acid. Allow to stand for 10 min. at 60 ° C, cool, extract with acetic ester, evaporate the extract, take up the residue in toluene, filter through a silica gel column, evaporate the solution and obtain 2.47 g of 4- (4-chlorophenyl) -1-phenyl-3-pyra = zolcarboxylic acid ethyl ester with mp 96 ° C.
e) En opløsning af 2,40 g 4-(4-chlorphenyl)-l-phenyl-3-pyrazolcarbo= xylsyreethylester i 20 ml tetrahydrofuran bliver ved tildrypning sat til en til 0°C kølet suspension, af 0,6 g lithiumaluminiumhydrid i 20 ml tetrahydrofuran. Man omrører blandingen i yderligere 1 time, sætter 3,6 ml mættet natriumchloridopløsning dertil og tilsætter derefter 13 ml 20% saltsyre. Derefter ekstraherer man reaktionsblandingen med ether, inddamper etherfasen i vakuum, behandler resten med petroleumsether og opnår 1,3 g 4-(4-chlorphenyl)-l-phenyl-3-pyrazolmethanol med smeltepunkt 145°C.e) A solution of 2.40 g of 4- (4-chlorophenyl) -1-phenyl-3-pyrazolecarboxylic acid ethyl ester in 20 ml of tetrahydrofuran is added dropwise to a suspension cooled to 0 ° C, of 0.6 g of lithium aluminum hydride. 20 ml of tetrahydrofuran. The mixture is stirred for an additional hour, 3.6 ml of saturated sodium chloride solution is added thereto, and then 13 ml of 20% hydrochloric acid is added. The reaction mixture is then extracted with ether, the ether phase is evaporated in vacuo, the residue is treated with petroleum ether to give 1.3 g of 4- (4-chlorophenyl) -1-phenyl-3-pyrazole methanol, m.p. 145 ° C.
Claims (1)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2536003 | 1975-08-08 | ||
| DE2536003A DE2536003C2 (en) | 1975-08-08 | 1975-08-08 | Pyrazole derivatives, their preparation and pharmaceutical derivatives containing them |
| DE19762633992 DE2633992A1 (en) | 1975-08-08 | 1976-07-26 | Antiinflammatory (1,4)-diphenyl-(3)-alkyl-carboxy-pyrazole - prepd. by treating corresp. (3)-halide with a cyanide, and opt. hydrolysing or reducing |
| DE2633992 | 1976-07-26 | ||
| AU22014/77A AU514889B2 (en) | 1975-08-08 | 1977-02-07 | Pyrazole derivatives |
| AU2201477 | 1977-02-07 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK356676A DK356676A (en) | 1977-02-09 |
| DK147973B true DK147973B (en) | 1985-01-21 |
| DK147973C DK147973C (en) | 1985-07-08 |
Family
ID=40520846
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK356676A DK147973C (en) | 1975-08-08 | 1976-08-06 | ANALOGY PROCEDURE FOR PREPARING 1,4-DIPHENYL-3-PYRAZOLYL ACETIC ACIDS |
Country Status (11)
| Country | Link |
|---|---|
| AU (1) | AU514889B2 (en) |
| BE (1) | BE844972A (en) |
| CS (3) | CS216205B2 (en) |
| DD (1) | DD128130A5 (en) |
| DE (1) | DE2633992A1 (en) |
| DK (1) | DK147973C (en) |
| GB (1) | GB1562943A (en) |
| HU (1) | HU175423B (en) |
| IE (1) | IE43659B1 (en) |
| LU (1) | LU75548A1 (en) |
| NL (1) | NL188696C (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3203307A1 (en) * | 1982-01-27 | 1983-07-28 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Phosphonates, and pharmaceutical compounds containing them |
| US4826868A (en) * | 1986-05-29 | 1989-05-02 | Ortho Pharmaceutical Corporation | 1,5-Diaryl-3-substituted pyrazoles pharmaceutical compositions and use |
| AU611437B2 (en) * | 1987-05-29 | 1991-06-13 | Ortho Pharmaceutical Corporation | Pharmacologically active 2- and 3-substituted (1',5'-diaryl-3-pyrazolyl)-n-hydroxypropanamides and method for synthesizing the same |
| IT1226387B (en) * | 1988-07-08 | 1991-01-15 | Seuref Ag | PROCESS FOR THE PREPARATION OF 1,4-DIARYL-3-PYRAZOL-ACETIC ACIDS |
| BRPI0918430A2 (en) * | 2008-08-14 | 2015-11-24 | Bayer Cropscience Ag | 4-phenyl-1h-pyrazols insecticides. |
| EP2757886A1 (en) * | 2011-09-23 | 2014-07-30 | Bayer Intellectual Property GmbH | Use of 4-substituted 1-phenyl-pyrazole-3-carboxylic-acid derivatives as agents against abiotic plant stress |
| WO2015054283A1 (en) * | 2013-10-08 | 2015-04-16 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE755924A (en) * | 1969-09-12 | 1971-02-15 | Byk Gulden Lomberg Chem Fab | PYRAZOLE-4-ACETIC ACID DERIVATIVES, THEIR PROCESS OF PREPARATION AND MEDICINAL PRODUCTS CONTAINING |
| DE2347015C2 (en) * | 1973-09-14 | 1985-12-12 | Schering AG, 1000 Berlin und 4709 Bergkamen | New pyrazolyloxyacetic acid derivatives, processes for their preparation and compositions containing them |
-
1976
- 1976-07-26 DE DE19762633992 patent/DE2633992A1/en active Granted
- 1976-08-06 LU LU75548A patent/LU75548A1/xx unknown
- 1976-08-06 NL NLAANVRAGE7608810,A patent/NL188696C/en not_active IP Right Cessation
- 1976-08-06 DK DK356676A patent/DK147973C/en not_active IP Right Cessation
- 1976-08-06 BE BE169630A patent/BE844972A/en not_active IP Right Cessation
- 1976-08-09 GB GB33042/76A patent/GB1562943A/en not_active Expired
- 1976-08-09 IE IE1758/76A patent/IE43659B1/en not_active IP Right Cessation
-
1977
- 1977-01-12 DD DD7700196901A patent/DD128130A5/en not_active IP Right Cessation
- 1977-01-14 HU HU77SCHE592A patent/HU175423B/en not_active IP Right Cessation
- 1977-02-07 CS CS77787A patent/CS216205B2/en unknown
- 1977-02-07 CS CS773720A patent/CS216206B2/en unknown
- 1977-02-07 AU AU22014/77A patent/AU514889B2/en not_active Expired
-
1979
- 1979-05-30 CS CS793721A patent/CS216207B2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NL188696C (en) | 1992-09-01 |
| CS216206B2 (en) | 1982-10-29 |
| DK147973C (en) | 1985-07-08 |
| AU514889B2 (en) | 1981-03-05 |
| DK356676A (en) | 1977-02-09 |
| IE43659L (en) | 1977-02-08 |
| DE2633992A1 (en) | 1978-02-09 |
| DE2633992C2 (en) | 1988-04-28 |
| NL7608810A (en) | 1977-02-10 |
| BE844972A (en) | 1977-02-07 |
| CS216205B2 (en) | 1982-10-29 |
| AU2201477A (en) | 1978-08-17 |
| GB1562943A (en) | 1980-03-19 |
| DD128130A5 (en) | 1977-11-02 |
| CS216207B2 (en) | 1982-10-29 |
| HU175423B (en) | 1980-07-28 |
| NL188696B (en) | 1992-04-01 |
| IE43659B1 (en) | 1981-04-22 |
| LU75548A1 (en) | 1977-03-25 |
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