DK156898B - PROCEDURE FOR THE PREPARATION OF 2-ARYL PROPIONIC ACIDS USING DIRECT CLUTCH USING A MIXED MAGNESIUM HALOGENIDE COMPLEX - Google Patents
PROCEDURE FOR THE PREPARATION OF 2-ARYL PROPIONIC ACIDS USING DIRECT CLUTCH USING A MIXED MAGNESIUM HALOGENIDE COMPLEX Download PDFInfo
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- DK156898B DK156898B DK064578AA DK64578A DK156898B DK 156898 B DK156898 B DK 156898B DK 064578A A DK064578A A DK 064578AA DK 64578 A DK64578 A DK 64578A DK 156898 B DK156898 B DK 156898B
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- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
- C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
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- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
- C07C53/19—Acids containing three or more carbon atoms
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- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
- C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
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- C07C63/14—Monocyclic dicarboxylic acids
- C07C63/15—Monocyclic dicarboxylic acids all carboxyl groups bound to carbon atoms of the six-membered aromatic ring
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Description
DK 156898 BDK 156898 B
Den foreliggende opfindelse angâr en fremgangsmâde til frem-stilling af en 2-arylpropionsyre, hvori aryl er valgt fra den gpuppe, som bestâr af 6-methoxy-2-naphthy1, 4-alkylphenyl og 4 1 -f1uor-4-biphenyl, ved omsætning af en oplesning af et aryl-5 magnesiumbromid, hvori arylgruppen har den ovenfor angivne be-tydning, med en oplosning af en magnesiumforbindelse af a-brompropionsyre i et aprotisk, organisk opl0sningsmiddelmedium, som omfatter en ether, og surgering af det resulterende pro-dukt.The present invention relates to a process for the preparation of a 2-arylpropionic acid in which aryl is selected from the group consisting of 6-methoxy-2-naphthyl, 4-alkylphenyl and 4-1-fluoro-4-biphenyl. of a solution of an aryl-magnesium bromide, wherein the aryl group is as defined above, with a solution of a magnesium compound of α-bromopropionic acid in an aprotic organic solvent medium comprising an ether and acidification of the resulting product .
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En af de hyppigst anvendte syntetiske metoder til fremstilling af arylalkansyrer har været koblingen af et arylorganometal-reagens med et ha 1ogena1kansyrederivat sâsom en halogenalkan-syreester. Denne metode har vist sig at være af særlig betyd-15 ning ved fremsti11ingen af det værdifulde antiinflammatoriske middel 2-(6-methoxy-2-naphthyl)-propionsyre. Specielt til fremsti11ingen af denne forbindelse er der blevet anvendt kob-linger, som involverer en α-halogenpropionsyreester og 2-(6-methoxynaphthyl)kobber- (US patentskrift nr. 3.658.863), zink-20 (US patentskrift nr. 3.663.584) og cadmium- (US patentskift nr. 3.658.858 og nr. 3.694.476) reagenser. En ulempe ved disse metoder er, at det til koblingen anvendte organometalreagens skal fremstilles af det tilsvarende Grignard-reagens, sâledes at det er nedvendigt med en ekstra kemisk reaktion, yderligere 25 reagenser osv.One of the most frequently used synthetic methods for preparing arylalkanoic acids has been the coupling of an aryloro-organometal reagent with a halogenoalkanoic acid derivative such as a haloalkanoic acid ester. This method has been found to be of particular importance in the preparation of the valuable anti-inflammatory agent 2- (6-methoxy-2-naphthyl) propionic acid. Particularly for the preparation of this compound, couplings involving an α-halogenopropionic acid ester and 2- (6-methoxynaphthyl) copper (U.S. Patent No. 3,658,863), zinc-20 (U.S. Patent No. 3,663) have been used. 584) and cadmium (U.S. Patent No. 3,658,858 and No. 3,694,476) reagents. A disadvantage of these methods is that the organometallic reagent used for the coupling must be prepared from the corresponding Grignard reagent, so that an additional chemical reaction, an additional 25 reagents, etc. are required.
tysk offentliggerelsesskrift nr. 2145650 beskrives den di-rekte kobling af arylmagnesiumhalogenider med kalium-2-jodpro-pionat. Senere er det i det amerikanske patentskrift nr, 30 3.959.364 (~DK 153.138 B) blevet vist, at en forbedret direkte kobling kunne opnâs ved reaktion af et aryl-Grignard-reagens med lithium-, natrium-, magnésium- eller calciumsaltene af 2-brompropionsyre med formlen CH3CH(X)C0M, hvori X er brom, og M betegner OLi, ONa, 0(Mg)jg eller 0(Ca)^ (jf. tabel II i US 35 patentskrift nr. 3.959.364). Det har imidlertid vist sig, at fremsti11ingen af 2-ary1propionsyrer, specielt den værdifulde forbindelse 2-(6-methoxy-2-naphthyl)-propionsyre, ved denne metode lider af en række hermed forbundne mangler inklusiveGerman Publication No. 2145650 describes the direct coupling of arylmagnesium halides with potassium 2-iodine propionate. More recently, U.S. Patent No. 3,959,364 (~ DK 153,138 B) has shown that an improved direct coupling could be obtained by reacting an aryl-Grignard reagent with the lithium, sodium, magnesium or calcium salts of 2-bromopropionic acid of the formula CH3CH (X) COM wherein X is bromine and M represents OLi, ONa, 0 (Mg) jg or 0 (Ca) 2 (see Table II of U.S. Patent No. 3,959,364). However, it has been found that the preparation of 2-arylpropionic acids, especially the valuable compound 2- (6-methoxy-2-naphthyl) -propionic acid, suffers from this method from a number of associated deficiencies including
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2 fremsti11ingen af et halogenpropionatsalt i de aprotiske op-losningsmiddelmedier, som skal anvendes til koblingsreaktio-nen, hvilket forer til dàrlige resultâter, nâr der arbejdes i stor mâlestok.2, the preparation of a halogen propionate salt in the aprotic solvent media to be used for the coupling reaction, which results in poor results when used on a large scale.
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Det ville derfor være af meget stor værdi at hâve en koblings-proces, som ved at udnytte et aryl-Grignard-reagens og et eg-net halogenpropionsyrederivat giver de onskede 2-arylpropion-syrer let og i reproducerbart hojt udbytte og hoj renhed, og 10 som let kan anvendes til produktion i stor mâlestok.It would therefore be of great value to have a coupling process which, by utilizing an aryl-Grignard reagent and an appropriate halogenopropionic acid derivative, provides the desired 2-arylpropionic acids readily and in reproducibly high yield and high purity, and 10 which can easily be used for large scale production.
Den foreliggende opfindelse angâr sâledes en særlig fremgangs-mède til fremstilling af kendte værdifulde antiinf1ammatoriske midler, nemlig 2-arylpropionsyrer, sâsom 2-(6-methoxy-2-naph-15 thyl)-propionsyre, der er beskrevet i US patentskrift nr. 3.904.682, og fremgangsmâden er ejendommelig ved det i den kendetegnende de! af krav 1 angivne.The present invention thus relates to a particular method of preparing known valuable anti-inflammatory agents, namely 2-arylpropionic acids, such as 2- (6-methoxy-2-naphthyl) propionic acid disclosed in U.S. Patent No. 3,904 .682, and the method is peculiar to that of the distinguishing de! of claim 1.
Enhver henvisning til 2-arylpropionsyrer i beskrivelsen og i 20 patentkravene drejer sig om den racemiske form af disse for-fa i ndelser.Any reference to 2-arylpropionic acids in the specification and in the patent claims relates to the racemic form of these compounds.
Eksempler pâ 2-arylpropionsyrerne, hvis fremstilling omfattes af den foreliggende opfindelse, er de, hvori aryldelen er 25 6-methoxy-2-naphthyl, dvs. 2-(6-methoxy-2-naphthy1)-propionsyre, 4-alkylphenyl, hvori "alkyl" betegner ligekædede og forgrenede 30 mættede hydrocarbongrupper med 1-4 carbonatomer, f.eks. 2-(4-methylphenyl)-propionsyre, 2-(4-isopropylphenyl)-propionsyre og 2-(4-isobutylphenyl)-propionsyre, og 41-fluor-4-biphenyl, dvs. 21 -(4'-fluor-4-biphenyl)-propionsy-35 re.Examples of the 2-aryl propionic acids whose preparation is within the scope of the present invention are those wherein the aryl portion is 6-methoxy-2-naphthyl, i.e. 2- (6-methoxy-2-naphthyl) propionic acid, 4-alkylphenyl, wherein "alkyl" represents straight and branched chain saturated hydrocarbon groups of 1-4 carbon atoms, e.g. 2- (4-methylphenyl) propionic acid, 2- (4-isopropylphenyl) propionic acid and 2- (4-isobutylphenyl) propionic acid, and 41-fluoro-4-biphenyl, i.e. 21 - (4'-Fluoro-4-biphenyl) -propionic acid.
Som nævnt ovenfor beskrives i US patentskrift nr. 3.959.364 fremsti11ingen af arylalkansyrer ved den direkte kobling af 3As mentioned above, U.S. Patent No. 3,959,364 describes the preparation of arylalkanoic acids by the direct coupling of 3
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et aryl-Grignard-reagens med Na-, Li-, Ca^- og Mgj^-saltene af α-brompropi onsyre.an aryl-Grignard reagent with the Na, Li, Ca 2 and Mg 2 salts of α-bromopropionic acid.
Det har nu overraskende vist sig, at der fâs en forbedret kob-5 1ingsreaktion, hvis man i stedet for et af de fernævnte salte anvender et blandet magnesiumhalogenidkompleks af a-brompro-pionsyre, dvs. en form med formlen CH3CH(Br)CQOMgX, hvori X er chlor eller brom. En direkte sammen 1 igning mellem magnesium-saltet af α-brompropionsyre (fremsti "Met ved begge de i US pa-10 tentskrift nr. 3.959.364 beskrevne metoder) og det heri om-handlede hidtil ukendte kompleks viser en bemærkelsesværdig forskel med hensyn til udbytte af opnàede siutprodukter (i det ene tilfælde et dobbelt sà stort udbytte som i det andet til— fælde) og er angivet mere detaljeret i eksemplerne. Det er en 15 yderligere fordel ved den foreliggende koblingsproces, at de herved opnàede udbytter ikke pâvirkes af fremsti11ingen af det blandede magnesiumhalogenidkompleks i den udstrækning, som udbytterne af kob1ingsprocessen ifolge US patentskrift nr. 3.959.364 pâvirkes af fremgangsmâden til fremstilling af 2-20 brompropionatsaltet (jf. US patentskrift nr. 3.959.364, spalte 3, 1i nie 10 og 11).It has now surprisingly been found that an improved coupling reaction is obtained if, instead of one of the aforementioned salts, a mixed magnesium halide complex of α-bromo propionic acid is used, i.e. a form of the formula CH3CH (Br) CQOMgX wherein X is chlorine or bromine. A direct correlation between the magnesium salt of α-bromopropionic acid (prepared by both methods described in U.S. Patent No. 3,959,364) and the novel complex herein disclosed shows a remarkable difference in yield of obtained salts (in one case twice the yield as in the other case) and is set out in more detail in the Examples. It is a further advantage of the present coupling process that the yields thus obtained are not affected by the manufacture. of the mixed magnesium halide complex to the extent that the yields of the coupling process according to U.S. Patent No. 3,959,364 are affected by the process for preparing the 2-20 bromopropionate salt (cf. U.S. Patent No. 3,959,364, column 3, 1i ni 10 and 11). .
Det blandede magnesiumhalogenidkompleks af a-brompropîonsyre kan fremstilles ved behandling af den fri syre med et egnet 25 Grignard-reagens. Selv om arten af hydrocarbondelen af 6 r i g -nard-reagenset ikke er kritisk, foretrækkes det, at den ved reaktionen af α-brompropionsyre med Grignard-reagenset dannede fri hydrocarbon ikke indvirker pâ koblingstrinet eller opar-bejdningen. Af denne grund er Grignard-reagenser, der er af-30 ledt af hydrocarboner, som er gasformige eller flydende ved reaktionstemperaturerne, særligt egnede, f.eks. alkylmagne-sium-Grignard-reagenser med 1-12 carbonatomer eller arylmagne-sium-Grignard-reagenser med 6-9 carbonatomer. Specifikke Grig-nard-reagenser, der kan anvendes til dette formâl, er methyl-35 magnesiumchlorid, methylmagnesiumbromid, ethylmagnesiumchlo-rid, ethylmagnesiumbromid, isopropylmagnesiumchlorid, phenyl-magnesiumchlorid og o-, m- eller p-tolylmagnesiumchlorid og lignende. Methylmagnesiumchlorid og methylmagnesiumbromidThe mixed magnesium halide complex of α-bromopropionic acid can be prepared by treating the free acid with a suitable 25 Grignard reagent. Although the nature of the hydrocarbon portion of 6 r in the g -nard reagent is not critical, it is preferred that the free hydrocarbon formed during the reaction of α-bromopropionic acid with the Grignard reagent does not interfere with the coupling step or preparation. For this reason, Grignard reagents derived from hydrocarbons which are gaseous or liquid at the reaction temperatures are particularly suitable, e.g. alkylmagnesium-Grignard reagents having 1-12 carbon atoms or arylmagnesium-Grignard reagents having 6-9 carbon atoms. Specific Grigard reagents that can be used for this purpose are methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride, ethyl magnesium bromide, isopropyl magnesium chloride, phenyl magnesium chloride and o-, m- or p-tolyl magnesium chloride and the like. Methylmagnesium chloride and methylmagnesium bromide
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4 foretrækkes specielt, for sâ vidt de er let tiIgængelige, bi1 -Tige og forer til dannelsen af methangas, som undslipper fra reaktionsblandingen og ikke indvirker under reaktionen elTer oparbejdningen. Det har overraskende vist sig, at tiTsætningen 5 af et af de fornævnte Grignard-reagenser til a-brompropionsyre primært resulterer i dannelsen af fornævnte kompTeks. Addition af Grignard-reagenset over carbonyldelen af carboxylsyren, en reaktion, som man normalt ville vente ville forlobe i storre udstrækning, viser sig at være minimal, selv nâr der anvendes 10 et molært overskud af Grignard-reagens.4 is particularly preferred, inasmuch as they are readily available, readily and lead to the formation of methane gas which escapes from the reaction mixture and does not interfere with the reaction or the work-up. Surprisingly, it has been found that the addition 5 of one of the aforementioned Grignard reagents to α-bromopropionic acid primarily results in the formation of the aforementioned complex. Addition of the Grignard reagent over the carbonyl portion of the carboxylic acid, a reaction that would normally be expected to proceed to a greater extent, is found to be minimal even when a molar excess of Grignard reagent is used.
Fremsti11ingen af det blandede magnesiumhalogenidkompleks gen-nemfores normalt i et aprotisk oplosningsmiddelmedium, som om-fatter en ether, sàsom diethylether, tetrahydrofuran, 1,2-di-15 methoxyethan, di-(n-butyl)ether og lignende. Oplosningsmiddel-mediet kan omfatte andre aprotiske oplosningsmidler sâsom aro-matiske hydrocarboner, f.eks. benzen eller toluen. Et fore-trukket oplosningsmiddelmedium til kompleksfremsti11ing er tetrahydrof uran. Selv om rækkefolgen af tilsætningen af reagen-20 ser ikke er særlig kritisk, foretrækkes det normalt at tilsæt-te Grignard-reagenset til α-brompropionsyren. Grignard-reagenset i oplosning er fortrinsvis fra ca. 1 til 4M, bedst fra ca. 2 til ca. 3 M. En kompleksoplosning til slut til anvendel-se i det direkte koblingstrin pà fra ca. 1 til ca. 2 M, for-25 trinsvis fra ca. 1,0 til 1,5 M, er onskelig. Temperaturen ved kompleksdannelsestrinet holdes normalt mellem ca. -20°C og +30°C, fortrinsvis mellem ca. -10°C og +20°C.The preparation of the mixed magnesium halide complex is usually carried out in an aprotic solvent medium comprising an ether such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, di- (n-butyl) ether and the like. The solvent medium may comprise other aprotic solvents such as aromatic hydrocarbons, e.g. benzene or toluene. A preferred solvent for complexing is tetrahydro uranium. Although the order of addition of reagents is not very critical, it is usually preferred to add the Grignard reagent to the α-bromopropionic acid. The Grignard reagent in solution is preferably from ca. 1 to 4M, best from approx. 2 to approx. 3 M. An end-to-end complex solution for use in the direct coupling step of approx. 1 to approx. 2 M, preferably from ca. 1.0 to 1.5 M, is desirable. The temperature of the complex formation step is usually maintained between about -20 ° C and + 30 ° C, preferably between ca. -10 ° C and + 20 ° C.
Selve koblingsreaktionen gennemfores hensigtsmæssigt ved at 30 bringe en oplosning af det blandede magnesiumhalogenidkompleks af α-brompropionsyre i kontakt med arylmagnesiumbromidet i et vandfrit aprotisk organisk oplosningsmiddelmedium. Egnede op-losningsmiddelmedier for reaktionen omfatter organiske ethere og blandinger af organiske ethere med aromatiske hydrocarboner 35 som nævnt ovenfor i forbindelse med kompleksdannelsestrinet.The coupling reaction itself is conveniently carried out by contacting a solution of the mixed magnesium halide complex of α-bromopropionic acid with the arylmagnesium bromide in an anhydrous aprotic organic solvent medium. Suitable solvent media for the reaction include organic ethers and mixtures of organic ethers with aromatic hydrocarbons 35 mentioned above in connection with the complex formation step.
Et særligt foretrukket oplosningsmiddelmedium til koblings-reaktionen er tetrahydrofuran. Det foretrækkes, at arylmagne-siumbromidoplosningen er mellem 0,5 og 2 M, fortrinsvis ca.A particularly preferred solvent medium for the coupling reaction is tetrahydrofuran. It is preferred that the arylmagnesium bromide solution is between 0.5 and 2M, preferably about 0.5m.
1,0 M.1.0 M.
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Koblingsprocessen selv kan gennemfores inden for et tempera-turomrâde fra ca. 0 til ca. 100°C, fortrinsvis mellem ca. 10°C og 60°C. Det foretrækkes specielt at lade temperaturen stige gradvis under ti1sætningen op til ca. 40-60°C og derpâ falde 5 igen til omgivelsernes temperatur, indtil den enskede reak-tionsgrad er blevet opnâet.The coupling process itself can be carried out within a temperature range of approx. 0 to approx. 100 ° C, preferably between ca. 10 ° C and 60 ° C. It is especially preferred to allow the temperature to rise gradually during the addition up to approx. 40-60 ° C and then drop 5 again to ambient temperature until the individual reaction rate has been achieved.
Selv om koblingsreaktionen kan gennemfores under anvendelse af reagenserne i forskellige indbyrdes forhold, foretrækkes det, 10 at der anvendes omirent ækvimolære mængder af det blandede magnesiumhalogenidkompleks og aryl-Grignard-reagenset. Fore-trukne forhold er fra ca. 0,9:1,1 til 1,1:0,9 kompleks: Grig-nard-reagens.Although the coupling reaction can be carried out using the reagents in different proportions, it is preferred that approximately equimolar amounts of the mixed magnesium halide complex and the aryl-Grignard reagent be used. Pre-drawn conditions are from approx. 0.9: 1.1 to 1.1: 0.9 complex: Grig-nard reagent.
15 Reaktionen kan hensigtsmæssigt gennemferes ved at bringe de to reagenser i kontakt i oplosningsmiddelmediet pâ en vilkârlig af de i teknikken kendte mâder. Det foretrækkes imidlertid specielt at sætte det blandede magnèsiumhalogenidkompleks til Grignard-reagenset og holde disse reagenser inderligt blande-20 de, indtil den onskede reaktion er forlebet fuldstændig.The reaction may conveniently be carried out by contacting the two reagents in the solvent medium in any of the methods known in the art. However, it is especially preferred to add the mixed magnesium halide complex to the Grignard reagent and keep these reagents intimately mixed until the desired reaction is complete.
Den til gennemforelse af den «nskede reaktion nsdvendige tid vil naturligvis hâve sammenhæng med de specielt valgte reagenser, oplosningsmidler og den valgte reaktionstemperatur og vil 25 pâ sædvanlig mâde af fagmanden, som skal gennemfere reaktionen, blive justeret til opnâelse af den optimale produktion af det enskede produkt. En sàdan reaktionstid vil imidlertid al -mindeligvis være af storrelsesordenen fra ca. 10 minutter til ca. 20 timer og er sædvanligvis i interval let fra ca. 1 til 30 ca. 5 timer.The time required to carry out the desired reaction will, of course, be related to the specially selected reagents, solvents and the selected reaction temperature and will be adjusted in the usual manner by the person skilled in the reaction to achieve the optimum production of the individual. product. However, such a reaction time will, of course, be of the order of ca. 10 minutes to approx. 20 hours and is usually in the interval easily from approx. 1 to 30 approx. 5 hours.
Efter at koblingsreaktionen er forlebet i den enskede udstræk-ning, afkeles reaktionsblandingen, som indeholder det koblede kompleks aryl-CH(CH3)C00MgX, derpâ hurtigt med en fortyndet 35 syre, fortrinsvis en fortyndet vandig mineralsyre, sâsom salt-syre eller svovlsyre, pâ sædvanlig mâde for Grignard-reaktio-ner. Det fri 2-arylpropionsyreprodukt kan derpâ isoleres og renses fra den afkelede reaktionsblanding pâ sædvanlig mâdeAfter the coupling reaction is preceded to the individual extent, the reaction mixture containing the coupled complex aryl-CH (CH3) C00MgX is precipitated rapidly with a dilute acid, preferably a dilute aqueous mineral acid, such as hydrochloric acid or sulfuric acid. usual way for Grignard reactions. The free 2-arylpropionic acid product can then be isolated and purified from the cooled reaction mixture in the usual manner
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6 sâsom ekstraktion med vandig alkali (f.eks. vandigt natrium-eller kaliumhydroxid), separering af den vandige alkaliske fase fra den organiske fase og syrning af den vandige alkaliske fase til frigorelse af den onskede syre, som eventuelt 5 kan ekstraheres med et organisk oplosningsmiddel eller renses direkte pâ sædvanlig mâde sâsom ved vaskning og/eller krystal-1isation.6 such as extraction with aqueous alkali (e.g. aqueous sodium or potassium hydroxide), separation of the aqueous alkaline phase from the organic phase and acidification of the aqueous alkaline phase to release the desired acid, which may optionally be extracted with an organic solvent or directly purified in the usual manner such as by washing and / or crystalization.
Det râ reaktionsprodukt kan om onsket direkte omdannes til et 10 farmaceutisk acceptabelt dérivât af carboxylsyren sâsom et sait, en ester eller et amid deraf eller spaltes i optiske i somerer.The crude reaction product, if desired, can be directly converted to a pharmaceutically acceptable derivative of the carboxylic acid such as a site, an ester or an amide thereof or cleaved into optical in the summers.
Fremgangsmâden if0lge opfindelsen gennemfores let og hensigts-15 mæssigt i stor mâlestok og giver udbytter af rensede produkter af storrelsesordenen 50-75%.The process according to the invention is easily and conveniently carried out on a large scale and yields purified products on the order of 50-75%.
De folgende eksempler belyser fremgangsmâden ifolge den fore-liggende opfindelse.The following examples illustrate the process of the present invention.
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Fremsti11ingsmetode 1Preparation Method 1
Fremstilling af 2-(6-methoxvnaphthyl)magnesiumbromid 25 2-brom-6-methoxynaphthalen (23,7 g, 0,1 mol) oploses i toluen (30 ml) og tetrahydrofuran (40 ml) under opvarmning. Denne oplesning tilsættes derpâ i l0bet af 10-15 minutter til et overskud af magnesiummetal (3 g, 0,12 mol), toluen (15 ml) og tetrahydrofuran (15 ml) under en nitrogenatmosfære. Den resul-30 terende blanding afkoles derpâ og omrores i yderligere 1 time ved 25-30°C. Reaktionsblandingen befries derpâ for magnesium-overskud og overfores til en ren ter beholder under nitrogen og lagres ved 10°C til opnàelse af et 1,0 M Grignard-reagens.Preparation of 2- (6-methoxynaphthyl) magnesium bromide 2-Bromo-6-methoxynaphthalene (23.7 g, 0.1 mol) is dissolved in toluene (30 ml) and tetrahydrofuran (40 ml) under heating. This solution is then added over 10-15 minutes to an excess of magnesium metal (3 g, 0.12 mol), toluene (15 ml) and tetrahydrofuran (15 ml) under a nitrogen atmosphere. The resulting mixture is then cooled and stirred for an additional 1 hour at 25-30 ° C. The reaction mixture is then freed of magnesium excess and transferred to a pure ter container under nitrogen and stored at 10 ° C to obtain a 1.0 M Grignard reagent.
35 Ved anvendelse af en tilsvarende fremgangsmâde kan Grignard-reagenset fremstilles under anvendelse af tetrahydrofuran som det eneste oplosningsmiddel.35 Using a similar procedure, the Grignard reagent can be prepared using tetrahydrofuran as the sole solvent.
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Ved at anvende en mindre oplosningsmiddelmængde kan der pâ lignende mâde fremstilles et mere koncentreret Grignard-rea-gens, f.eks. et 1,5 M reagens.By using a smaller amount of solvent, a more concentrated Grignard reagent, e.g. a 1.5 M reagent.
5 Fremsti11ingsmetode 2Preparation Method 2
Blandet magnesiurnhalogenidkompleks af a-brompropionsyre 15,3 g (0,1 mol) α-brompropionsyre og 40 ml toluen afkoles til 10 10°C, og en oplosning af 50 ml 2 M methylmagnesiumbromid i te- trahydrofuran/toluen (1:1) tilsættes derpâ langsomt, idet tem-peraturen holdes pâ 10-20eC under tiIsætningen, som varer 15-20 minutter. Reaktionsblandingen omrores derpâ ved 5°C i yderligere 20 minutter til fremstilling af en 1,1 M oplæsning 15 af komplekset.Mixed magnesium halide complex of α-bromopropionic acid 15.3 g (0.1 mole) of α-bromopropionic acid and 40 ml of toluene are cooled to 10 10 ° C and a solution of 50 ml of 2 M methylmagnesium bromide in tetrahydrofuran / toluene (1: 1). is then added slowly, keeping the temperature at 10-20 ° C during the addition, which lasts 15-20 minutes. The reaction mixture is then stirred at 5 ° C for an additional 20 minutes to prepare a 1.1 M solution 15 of the complex.
Ved at gâ frem pâ tilsvarende mâde kan det blandede magnesium-halogenidkompleks fremstilles under anvendelse af tetrahydro-furan som det eneste oplesningsmiddel.By proceeding in a similar manner, the mixed magnesium-halide complex can be prepared using tetrahydrofuran as the sole solvent.
2020
Methylmagnesiumbromid kan ligeledes erstattes med andre G r i g-nard-reagenser sâsom methylmagnesiumchlorid, ispropylmagne-siumchlorid, phenylmagnesiumchlorid og lignende i koncentra-tioner varierende fra ca. 1 til ca. 4 M.Methylmagnesium bromide can also be substituted with other G r in g nard reagents such as methylmagnesium chloride, ispropylmagnesium chloride, phenylmagnesium chloride and the like at concentrations varying from approx. 1 to approx. 4 M.
2525
Det blandede magnesiumchloridkompleks af α-brompropionsyre (fremstillet som beskrevet ovenfor under anvendelse af 3 M CH3MgCl i tetrahydrofuran) blev isoleret i krystallinsk form som dets tetrahydrofuranmonoetherat efter destination af te-30 trahydrofuran fra en tetrahydrofuranoplesning og blev analyse- ret: smp. 147-155°C, infrarodt spektrum (KBr) 1625, 1450, 1420, 1372, 1291, 1200, 1070, 1030, 988 og 890 cm"l, kernemag-netisk resonansspektrum (D20) delta 1,8 (multiplet, 7) 3,7 (multiplet, 4) og 4,35 dele pr. million (kvartet, J=7). Ele-35 mentæranalyse beregnet for C7H12BrClMg03: Mg 8,57%, Cl 12,49%.The mixed magnesium chloride complex of α-bromopropionic acid (prepared as described above using 3 M CH 3 MgCl in tetrahydrofuran) was isolated in crystalline form as its tetrahydrofuran monoetherate after distillation of tetrahydrofuran from a tetrahydrofuran solution and analyzed: m.p. 147-155 ° C, infrared spectrum (KBr) 1625, 1450, 1420, 1372, 1291, 1200, 1070, 1030, 988 and 890 cm -1, nuclear magnetic resonance spectrum (D20) delta 1.8 (multiplet, 7) 3.7 (multiplied, 4) and 4.35 parts per million (quartet, J = 7). Elemental analysis calculated for C7H12BrClMg03: Mg 8.57%, Cl 12.49%.
Fundet: Mg 8,63%, Cl 12,97%.Found: Mg 8.63%, Cl 12.97%.
DK 156898 BDK 156898 B
88
Frerosti11ingsmetode 3Method of freezing 3
Fremstilling af arylmagnesiumbromider 5 0,025 mol arylbromid opleses i tetrahydrofuran (18 ml). Oenne oplesning sættes til et overskud af magnesiummetal (3 g, 0,02 mol) og tetrahydrofuran (7 ml) under en nitrogenatmosfære. Temperaturen holdes pâ 50-60°C med afkeling i tilsætningsperi-oden pâ 10-15 minutter. Reaktionsblandingen befries derpâ for 10 magnesiumoverskud og overferes til en ren ter beholder under nitrogen og lagres ved 10eC til opnâelse af et 1,0 M Grignard-reagens. Pâ denne mâde blev felgende Grignard-reagenser frem-st i11 et : 15 2-(6-methoxynaphthy1)magnesiumbromid 4-(4'-fluorbiphenyl)magnesiumbromid l-(4-isopropylphenyl)magnesiumbromid l-(4-isobutylphenyl)magnesi umbromid l-(4-methylphenyl)magnesi umbromid.Preparation of aryl magnesium bromides 0.025 mol of aryl bromide is dissolved in tetrahydrofuran (18 ml). This solution is added to an excess of magnesium metal (3 g, 0.02 mol) and tetrahydrofuran (7 ml) under a nitrogen atmosphere. The temperature is kept at 50-60 ° C with cooling during the addition period of 10-15 minutes. The reaction mixture is then freed of 10 magnesium excess and transferred to a pure container under nitrogen and stored at 10 ° C to obtain a 1.0 M Grignard reagent. Grignard reagents prepared in this way were prepared in 2- (6-methoxynaphthyl) magnesium bromide 4- (4'-fluorobiphenyl) magnesium bromide 1- (4-isopropylphenyl) magnesium bromide 1- (4-isobutylphenyl) magnesium bromide 1 - (4-methylphenyl) magnesium umbromide.
2020
Fremsti11ingsmetode 4 A. Fremstilling af det blandede magnesiumhaloqenidkompleks af g-brompropionsyre 25 a-brompropionsyre (3,8 g, 0,025 mol) opleses i tetrahydrofuran (8 ml), og oplesningen afkeles til -10°C. Til denne oplesning sættes 3 M methylmagnesiumchlorid i tetrahydrofuran (8 ml) i lobet af en 15 minutters période, medens temperaturen holdes 30 mellem -10°C og 0°C. Dette giver en 1,1 molær oplesning af komplekset, som lagres ved 0°C eller herunder, indtil det an-vendes.Preparation Method 4 A. Preparation of the mixed magnesium halogenide complex of g-bromopropionic acid 25 α-bromopropionic acid (3.8 g, 0.025 mol) is dissolved in tetrahydrofuran (8 ml) and the solution is cooled to -10 ° C. To this solution, 3 M methylmagnesium chloride in tetrahydrofuran (8 ml) is added over a 15 minute period while maintaining the temperature between -10 ° C and 0 ° C. This gives a 1.1 molar readout of the complex which is stored at 0 ° C or below until used.
Ved at erstatte 3 M methylmagnesiumchlorid med 1 M methylmag-35 nesiumbromid kan pâ lignende mâde fremstilles det tilsvarende magnesi umbromidkompleks.By replacing 3 M methylmagnesium chloride with 1 M methylmagnesium bromide, the corresponding magnesium bromide complex can similarly be prepared.
DK 156898 BDK 156898 B
9 B· Fremstillinq af magnesiumsa1tet af α-brompropionsyre a-brompropionsyre (3,8 g, 0,025 mol) opleses i methanol (6 ml), og oplesningen afkeles til -10°C. Hertil sættes et 0,5 M 5 magnesiummethoxid i methanoloplesning (25 ml) i lebet af en 10 minutters période, medens temperaturen holdes me 11em -10®C og 0®C. Methanol fjernes derpâ under reduceret tryk til opnâelse af det faste sait, sont terres i vakuum ved 50°C i 12 timer til fremstilling af det terre magnesiumsalt (4,1 g, 0,0125 mol, 10 97,2¾ rent). Dette sait opleses i 18 ml tetrahydrofuran til koblingsreaktionen.9 B · Preparation of the magnesium salt of α-bromopropionic acid α-bromopropionic acid (3.8 g, 0.025 mol) is dissolved in methanol (6 ml) and the solution is cooled to -10 ° C. To this is added a 0.5 M 5 magnesium methoxide in methanol solution (25 ml) over a 10 minute period while keeping the temperature at 11 ° C -10 ° C and 0 ° C. Methanol is then removed under reduced pressure to give the solid site, sonicated in vacuo at 50 ° C for 12 hours to prepare the terre magnesium salt (4.1 g, 0.0125 mol, 97.2¾ pure). This site is read into 18 ml of tetrahydrofuran for the coupling reaction.
Eksempel 1 15 A. Oplesningen af kompleks fra fremsti11ingsmetode 2 sættes langsomt til Grignard-oplesningen fra fremst i11ingsmetode 1, idet temperaturen holdes pâ 15-20°C under tiIsætningen, som varer fra 10 til 15 minutter. Reaktionsblandingen fâr lov til at antage stuetemperatur og omreres derpâ i 2 timer. Reak-20 tionsblandingen afkeles derpâ i et isbad, og en oplesning af 20 ml kold N saltsyre og 150 ml vand tilsættes. Efter omrering i 5 minutter filtreres tofasesystemet, og filterkagen vaskes med 55 ml toluen og 50 ml vand. Den organiske fase ekstraheres med 10¾ kaliumhydroxidoplesning (2 x 150 ml), og de forenede 25 basiske ekstrakter vaskes med toluen (30 ml) og neutraliseres med 12 N saltsyre til pH-værdi 1. Den hvide faste 2-(6-meth-oxy-2-naphthy1)propionsyre filtreres under vakuum og terres ved 55eC i vakuum, hvilket giver 15,2 g (66%), smeltepunkt 149,5-153,5°C.Example 1 15 A. The solution of complex from Preparation Method 2 is slowly added to the Grignard solution from Preparation Method 1, keeping the temperature at 15-20 ° C during the addition, which lasts from 10 to 15 minutes. The reaction mixture is allowed to reach room temperature and stirred for 2 hours. The reaction mixture is then cooled in an ice bath and a solution of 20 ml of cold N hydrochloric acid and 150 ml of water is added. After stirring for 5 minutes, the two-phase system is filtered and the filter cake is washed with 55 ml of toluene and 50 ml of water. The organic phase is extracted with 10¾ potassium hydroxide solution (2 x 150ml) and the combined 25 basic extracts are washed with toluene (30ml) and neutralized with 12N hydrochloric acid to pH 1. The white solid 2- (6-methoxy) The 2-naphthylpropionic acid is filtered in vacuo and terred at 55 ° C in vacuo to give 15.2 g (66%), mp 149.5-153.5 ° C.
30 B. Efter filtrering kan den organiske fase alternativt ekstraheres med 10% kal iumhydroxidoplesni ng (2 x 150 ml), som vaskes med toluen (30 ml) og filtreres. 15 ml methanol og 12 ml toluen tilsættes, derpâ tilsættes tilstrækkeligt 12 N salt-35 syre til at indstille pH-værdien pâ mellem 4 og 5. Den resul-terende opslæmning opvarmes derpâ til tiIbagesvaling i 1 time, afkeles og filtreres. Bundfaldet vaskes med vand (20 ml), toluen (2 x 3 ml) og hexan (2 x 3 ml) og terres ved 55°C iB. After filtration, the organic phase may alternatively be extracted with 10% potassium hydroxide solution (2 x 150 ml), washed with toluene (30 ml) and filtered. 15 ml of methanol and 12 ml of toluene are added, then sufficient 12N hydrochloric acid is added to adjust the pH to between 4 and 5. The resulting slurry is then heated to reflux for 1 hour, cooled and filtered. The precipitate is washed with water (20 ml), toluene (2 x 3 ml) and hexane (2 x 3 ml) and terred at 55 ° C
. DK 156898B. DK 156898B
10 vakuum til fremstilling af 15,0 g (65,1%) produkt med smelte-punkt 154,5155°C.In vacuo to produce 15.0 g (65.1%) of product, mp 154.5155 ° C.
Eksempel 2 5 67 ml af en 1,5 M oplosning af det blandede magnesiumchlorid-kompleks af α-brompropionsyre i tetrahydrofuran {fremstillet under anvendelse af 3 M methylmagnesiumchlorid) sættes lang-somt til en sfkelet (10eC) oplesning af 1,5 M 2-(6-methoxy-10 naphthyl)magnesiumbromid i tetrahydrofuran (67 ml) med en sâdan hastighed, at temperaturen holdes pà 55°C eller herun-der. Den resulterende opslæmning omreres ved 50°C i 1 time og opvarmes derpâ til ti1bagesva1ing, idet 30-40% af tetrahydro-furanen fâr lov til at afdestillere. Reaktionsblandingen afke-15 les til 50°C, 30 ml toluen tilsættes, og reaktionsblandingen afkoles hurtigt med vandig saltsyre og oparbejdes som beskre-vet i eksempel 18 til fremstilling af 2-(6-methoxy-2~ naphthyl)propionsyre, smeltepunkt 156-157°C, i et udbytte pâ 73%.Example 2 67 ml of a 1.5 M solution of the mixed magnesium chloride complex of α-bromopropionic acid in tetrahydrofuran (prepared using 3 M methylmagnesium chloride) is slowly added to a spiked (10 ° C) solution of 1.5 M 2 - (6-methoxy-naphthyl) magnesium bromide in tetrahydrofuran (67 ml) at a rate such that the temperature is kept at 55 ° C or below. The resulting slurry is stirred at 50 ° C for 1 hour and then heated to reflux, with 30-40% of the tetrahydrofuran being allowed to distill off. The reaction mixture is cooled to 50 ° C, 30 ml of toluene is added and the reaction mixture is rapidly cooled with aqueous hydrochloric acid and worked up as described in Example 18 to prepare 2- (6-methoxy-2-naphthyl) propionic acid, m.p. 157 ° C, in a yield of 73%.
2020
Eksempel 3 A. Magnesiumsaltet af α-brompropionsyre, dvs.Example 3 A. The magnesium salt of α-bromopropionic acid, i.e.
[CH3CH(Br)C00]2Mg blev fremstillet ved at omsætte syren med 25 1/2 molærækvivalent magnesiumcarbonat efterfulgt af terring af saltet ved 60°C i vakuum. Erstatning af det blandede magne-siumchloridkompleks, der blev anvendt i eksempel 2, med dette sait resulterede i et produktudbytte pâ 34,7%.[CH3CH (Br) C00] 2Mg was prepared by reacting the acid with 25 1/2 molar equivalent of magnesium carbonate followed by drying the salt at 60 ° C in vacuo. Replacement of the mixed magnesium chloride complex used in Example 2 with this site resulted in a yield of 34.7%.
30 B. Saltet fra afsnit A blev ogsâ fremstillet under anvendelse af 1/2. molærækvivalent magnesiummethoxid, idet methanol fjer-nes som en azeotrop. Anvendelse af saltet ved fremgangsmâden fra eksempel 2 gav et produktudbytte pâ 43,0%.B. The salt from Section A was also prepared using 1/2. molar equivalent of magnesium methoxide, removing methanol as an azeotrope. Use of the salt in the method of Example 2 gave a product yield of 43.0%.
3535
DK 156898 BDK 156898 B
1111
Eksempel 4Example 4
Eksempel 3A blev gentaget, bortset fra at 1/2 molærækvivalent vandfrit magnesiumchlorid blev sat til magnesiumsaltet fer 5 koblingsreaktionen. Der blev opnâet et produktudbytte pâ 5,1¾.Example 3A was repeated except that 1/2 molar equivalent of anhydrous magnesium chloride was added to the magnesium salt during the coupling reaction. A product yield of 5.1¾ was obtained.
Eksempel 5Example 5
Fremgangsmâden fra eksempel 3B blev gentaget, bortset fra at 10 der blev anvendt ækvimolære mængder af α-brompropionsyre og magnesiummethoxid. Produktudbyttet var 35,1¾.The procedure of Example 3B was repeated except that equimolar amounts of α-bromopropionic acid and magnesium methoxide were used. The product yield was 35.1¾.
Eksempel 6 15 Sammenliqnende koblinqsreaktioner under anvendelse af blandede magnesiumhalogenidkomplekser og Mg^salteExample 6 Comparative Coupling Reactions Using Mixed Magnesium Halide Complexes and Mg
Felgende koblingsreaktioner (efter den nedenfor anferte skala) blev gennemfert under anvendelse af sâvel det blandede magne-20 siumchloridkompleks af a-brompropionsyre (fremstillet ifelge fremstillingsmetode 4A) eller magnesiumsaltet af a-brompropionsyre (fremstillet ifelge fremstillingsmetode 4B) med det tilsvarende Grignard-reagens (fremstillet ifelge fremstillingsmetode 3). Fremgangsmâden (illustreret for en 0,025 mol 25 skala) var som felger: 1,0 M oplesningen af arylmagnesiumbromid afkeles til 10°C, og oplesningen af enten magnesiumsaltet eller magnesiumchlorid-komplekset i tetrahydrofuran tilsættes i lebet af en 5 minut-30 ters période, medens temperaturen holdes mellem 10°C og 55°C. Reaktionsblandingen omreres derpâ ved 25-30°C i 2 timer. Reak-tionsblandingen afkeles derpâ til 10eC, og en oplesning af 12 N saltsyre (10 ml) og vand (50 ml) tilsættes. Toluen (50 ml) tilsættes derpâ, og den vandige fase skilles fra og kasseres.Scaling coupling reactions (according to the scale given below) were carried out using both the mixed magnesium chloride complex of α-bromopropionic acid (prepared according to Preparation Method 4A) or the magnesium salt of α-Bromopropionic acid (prepared according to Preparation Method 4B) with the corresponding Grignard reagent ( manufactured according to method of manufacture 3). The procedure (illustrated on a 0.025 mol scale) was as follows: The 1.0 M solution of arylmagnesium bromide is cooled to 10 ° C and the solution of either the magnesium salt or the magnesium chloride complex in tetrahydrofuran is added over a 5 minute period, while keeping the temperature between 10 ° C and 55 ° C. The reaction mixture is then stirred at 25-30 ° C for 2 hours. The reaction mixture is then cooled to 10 ° C and a solution of 12 N hydrochloric acid (10 ml) and water (50 ml) is added. Toluene (50 ml) is added thereto and the aqueous phase is separated and discarded.
35 Den organiske fase ekstraheres to garge med 10¾ kaliumhydroxid (50 ml). De basiske ekstrakter forenes og neutraliseres med saltsyre til fremstilling af et bundfald, der filtreres og terres ved 50°C. Resultaterne er anfort i den efterfelgende tabel:35 The organic phase is extracted two yarns with 10¾ potassium hydroxide (50 ml). The basic extracts are combined and neutralized with hydrochloric acid to produce a precipitate, which is filtered and tarred at 50 ° C. The results are given in the following table:
12 DK 156898 B12 DK 156898 B
X O) m JJ o\° o\o o\° o\° o\°X O) m JJ o \ ° o \ o o \ ° o \ ° o \ °
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4J ^ o\° · CO CM LD CN4J ^ o \ ° · CO CM LD CN
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000 eu a s ® cd o *, · fi CO 04 Î-J -fi , CO CD fi CO CD -0 1000 eu a s ® cd o *, · fi CO 04 Î-J -fi, CO CD fi CO CD -0 1
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X (U fi (U o fi g fi II II fi r, ^ TJ 10 S1 gX {U fi (U o fi g fi II II fi r, ^ TJ 10 S1 g
lui 0U'§1 °« J"ü g IIlai 0U'§1 ° «J" ü g II
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1 -¾ -g ati - H bp10 18.S1 -¾ -g ati - H bp10 18.S
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g g X X , . Jj Λ V. $ & ^ •i ê? &g g X X ,. Jj Λ V. $ & ^ • i ê? &
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H g -Η (0 -H CÇrH CÇrH rjHIH ^ SH g -Η (0 -H CÇrH CÇrH rjHIH ^ S
tM SL @ &o!qo rOu o! 8 S 8 Y R* s £*δ Ή fi Ή fi O fi py h ^ΊεΊβΊ Blal &§tM SL @ & o! qo rOu o! 8 S 8 Y R * s £ * δ Ή fi Ή fi O fi py h ^ ΊεΊβΊ Blal & §
a (U -fi (U H îfi H HH CO -fi CD Ha (U -fi (U H îfi H HH CO -fi CD H
f 8 f 8 -8 8 ΐ 8 V 8 sa γ& f& γ& y| y| <N g *4 g 4* |j H g H g alf 8 f 8 -8 8 ΐ 8 V 8 so γ & f & γ & y | y | <N g * 4 g 4 * | j H g H g al
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S CD eu Sn fi nj (d Θ (U tn (U fi g H eu fi , , Ύ d , (U ^4 I HH O Q H d H § "fi ^ ^ ^ m inS CD eu Sn fi nj {d Θ {U tn {U fi g H eu fi,, Ύ d, (U ^ 4 I HH O Q H d H § "fi ^ ^ ^ m in
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DK 156898 BDK 156898 B
1313
Af det ovennævnte fremgâr det, at der i hvert tilfælde blev opnâet et hejere udbytte (ca. dobbelt sâ stort) af et mere rent produkt af det blandede magnesiumchloridkompleks.From the above, it appears that in each case a higher yield (about twice as large) of a more pure product of the mixed magnesium chloride complex was obtained.
5 Sammenlignelige resultater kan pâ tilsvarende mâde opnâs med fremstt11ingen af felgende 2-arylpropionsyrer: 2-(4-isobutylphenyl)propionsyre, 2-(4-methylpheny1Jproplonsyre.Comparable results can similarly be obtained with the preparation of the following 2-aryl propionic acids: 2- (4-isobutylphenyl) propionic acid, 2- (4-methylphenyl) propanoic acid.
1010
Hvis den ovennævnte fremgangsmâde afbrydes fer hurtig afkeling med vandig syre, og oplosningsmidlet fjernes i vakuum, kan ds koblede magnesiumhalogenidkomplekser, ArylCH(CH3C00MgX eller etherater deraf, isoleres.If the above process is interrupted, rapid aqueous acid cooling and the solvent removed in vacuo, the coupled magnesium halide complexes, ArylCH (CH 3 CO 100 MgX or etherates thereof) can be isolated.
1515
Det blandede magnesiumchloridkompleks af 2-(6-methoxy-2-naphthyl)propionsyre og dets tetrahydrofuranmonoetherat (98,1% renhed) giver felgende egenskaber: 20 Smeltepunkt 113°C (dekomponering), infraredt spektrum (KBr-Skive) 1600, 1450, 1410, 1260, 1210, 1155, 1025, 923, 885, 850, 805 og 750 cm~l, kernemagnetisk resonansspektrum (DMSO-dg) delta (TMS) 1,4 (dublet, 2H), 1,9 (multiplet, 4H), 3,6 (multiplet, 5H), 3,9 (singlet, 3H), 7,5 (multiplet, 6H) 25 dele per million.The mixed magnesium chloride complex of 2- (6-methoxy-2-naphthyl) propionic acid and its tetrahydrofuran mono etherate (98.1% purity) gives the following properties: Melting point 113 ° C (decomposition), infrared spectrum (KBr disk) 1600, 1450, 1410, 1260, 1210, 1155, 1025, 923, 885, 850, 805 and 750 cm -1, Nuclear Magnetic Resonance Spectrum (DMSO-dg) delta (TMS) 1.4 (doublet, 2H), 1.9 (multiplet, 4H ), 3.6 (multiplet, 5H), 3.9 (singlet, 3H), 7.5 (multiplet, 6H) 25 parts per million.
Tilsvarende er de blandede magnesiumchloridkomplekser (tetrahydrof uranmonoetherater ) af de felgende 2-arylpropionsyrer med felgende fysiske konstanter blevet isoleret: 30 2-aryl-propionsyre fysiske konstanter_ 2-(4-methylphenyl)- smp.: 70-79°C (dek.); ir (KBr- propionsyre skive): 3400, 1630, 1585, 1512, 1458, 1420, 1365, 1285, 1070, 35 815, 790, 730 cm"!, NMR (DMSO-dg) Ô (TMS): 1,3 (dublet, 3H), 1,8 (multiplet, 4H) , 2,3 (singlet, 3H), 3,6Similarly, the mixed magnesium chloride complexes (tetrahydro uranium monoetherates) of the precipitating 2-aryl propionic acids with precipitating physical constants have been isolated: 2-aryl-propionic acid physical constants 2- (4-methylphenyl) - mp: 70-79 ° C (dec) ; ir (KBr propionic acid disk): 3400, 1630, 1585, 1512, 1458, 1420, 1365, 1285, 1070, 35 815, 790, 730 cm -1 NMR (DMSO-dg) Ô (TMS): 1.3 (doublet, 3H), 1.8 (multiplet, 4H), 2.3 (singlet, 3H), 3.6
Claims (10)
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DK5184A DK163234C (en) | 1977-02-16 | 1984-01-05 | MAGNESIUM HALOGENIDE COMPLEX OF A 2-ARYLPROPIONIC ACID AND PROCEDURES FOR PREPARING IT |
DK005084A DK163817C (en) | 1977-02-16 | 1984-01-05 | MAGNESIUM HALOGENIDE COMPLEX OF 2-BROMOPROPIONIC ACID AND PROCEDURES FOR PREPARING IT |
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US76907077A | 1977-02-16 | 1977-02-16 | |
US76907077 | 1977-02-16 | ||
US05/863,290 US4144397A (en) | 1977-02-16 | 1977-12-19 | Preparation of 2-aryl-propionic acids by direct coupling utilizing a mixed magnesium halide complex |
US86329077 | 1977-12-19 |
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DK64578A DK64578A (en) | 1978-08-17 |
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CH (3) | CH640499A5 (en) |
DD (3) | DD137099A5 (en) |
DK (1) | DK156898C (en) |
ES (1) | ES467037A1 (en) |
FI (1) | FI64571C (en) |
HK (2) | HK25483A (en) |
HU (2) | HU179309B (en) |
IE (1) | IE46614B1 (en) |
IL (1) | IL54019A (en) |
IT (1) | IT1107880B (en) |
MY (2) | MY8400040A (en) |
NO (1) | NO145435C (en) |
NZ (1) | NZ186472A (en) |
PL (1) | PL108144B1 (en) |
PT (1) | PT67654B (en) |
SE (3) | SE430155B (en) |
SU (2) | SU1003749A3 (en) |
YU (3) | YU41427B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8915531D0 (en) * | 1989-07-06 | 1989-08-23 | Ass Octel | Alkaline earth,transition and lanthanide metal inorganic salt complexes |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK153138B (en) * | 1973-05-24 | 1988-06-20 | Boots Co Plc | PROCEDURE FOR THE PREPARATION OF 2-ARYL PROPIONIC ACIDS |
-
1978
- 1978-02-09 HU HU78SI1618A patent/HU179309B/en unknown
- 1978-02-09 HU HU802271A patent/HU183210B/en unknown
- 1978-02-09 FI FI780417A patent/FI64571C/en not_active IP Right Cessation
- 1978-02-10 IT IT67279/78A patent/IT1107880B/en active
- 1978-02-10 IL IL54019A patent/IL54019A/en unknown
- 1978-02-13 DK DK064578A patent/DK156898C/en not_active IP Right Cessation
- 1978-02-13 YU YU329/78A patent/YU41427B/en unknown
- 1978-02-13 SE SE7801648A patent/SE430155B/en not_active IP Right Cessation
- 1978-02-14 PT PT67654A patent/PT67654B/en unknown
- 1978-02-14 NZ NZ186472A patent/NZ186472A/en unknown
- 1978-02-14 IE IE320/78A patent/IE46614B1/en not_active IP Right Cessation
- 1978-02-15 DD DD78203717A patent/DD137099A5/en not_active IP Right Cessation
- 1978-02-15 DD DD78214578A patent/DD148212A5/en not_active IP Right Cessation
- 1978-02-15 CH CH167578A patent/CH640499A5/en not_active IP Right Cessation
- 1978-02-15 DD DD78214577A patent/DD145107A5/en not_active IP Right Cessation
- 1978-02-15 SU SU782580499A patent/SU1003749A3/en active
- 1978-02-15 NO NO780524A patent/NO145435C/en unknown
- 1978-02-16 ES ES467037A patent/ES467037A1/en not_active Expired
- 1978-02-16 PL PL1978204667A patent/PL108144B1/en unknown
- 1978-10-11 SU SU782672198A patent/SU963462A3/en active
-
1982
- 1982-03-09 SE SE8201458A patent/SE453093B/en not_active IP Right Cessation
- 1982-03-09 SE SE8201459A patent/SE453094B/en not_active IP Right Cessation
- 1982-09-07 CH CH531782A patent/CH640498A5/en not_active IP Right Cessation
- 1982-09-07 CH CH531882A patent/CH640500A5/en not_active IP Right Cessation
-
1983
- 1983-03-10 YU YU587/83A patent/YU43302B/en unknown
- 1983-03-10 YU YU588/83A patent/YU42843B/en unknown
- 1983-08-04 HK HK254/83A patent/HK25483A/en not_active IP Right Cessation
- 1983-08-04 HK HK253/83A patent/HK25383A/en not_active IP Right Cessation
-
1984
- 1984-12-30 MY MY40/84A patent/MY8400040A/en unknown
- 1984-12-30 MY MY39/84A patent/MY8400039A/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK153138B (en) * | 1973-05-24 | 1988-06-20 | Boots Co Plc | PROCEDURE FOR THE PREPARATION OF 2-ARYL PROPIONIC ACIDS |
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