DK163817B - MAGNESIUM HALOGENIDE COMPLEX OF 2-BROMOPROPIONIC ACID AND PROCEDURES FOR PREPARING IT - Google Patents
MAGNESIUM HALOGENIDE COMPLEX OF 2-BROMOPROPIONIC ACID AND PROCEDURES FOR PREPARING IT Download PDFInfo
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Den foreliggende opfindelse angår et magnesiumhalogenidkom-pleks af 2-brompropionsyre til brug ved fremstilling af 2 —(6~ methoxy-2-naphthy 1)-, 2-(4-alkylphenyl)- eller 2-(41-f1uor-4-biphenyl)-propionsyre samt en fremgangsmåde til fremstilling 5 af magnesiumhalogenidkomplekset.The present invention relates to a magnesium halide complex of 2-bromopropionic acid for use in the preparation of 2- (6-methoxy-2-naphthy 1) -, 2- (4-alkylphenyl) - or 2- (41-fluoro-4-biphenyl) ) propionic acid and a process for the preparation of the magnesium halide complex.
En af de hyppigst anvendte syntetiske metoder til fremstilling af arylalkansyrer har været koblingen af et arylorganometalreagens med et halogenalkansyrederivat såsom en halogenalkansy-10 reester. Denne metode har vist sig at være af særlig betydning ved fremstillingen af det værdifulde antiinflammatoriske middel 2-(6-methoxy-2-naphthyl)-propionsyre. Specielt til fremstillingen af denne forbindelse er der blevet anvendt koblinger, som involverer en α-halogenpropionsyreester og 2-(6-meth-15 oxynaphthylJkobber (US patentskrift nr. 3.658.863), zink (US patentskrift nr. 3.663.584) og cadmium (US patentskrift 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, således 20 at det er nødvendigt med en ekstra kemisk reaktion, yderligere reagenser osv.One of the most frequently used synthetic methods for the preparation of arylalkanoic acids has been the coupling of an aryloro-organometal reagent with a haloalkanoic 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. In particular, for the preparation of this compound, couplings involving an α-halogenopropionic acid ester and 2- (6-methoxynaphthylcarbon) (U.S. Patent No. 3,658,863), zinc (U.S. Patent No. 3,663,584) and cadmium have been used. (U.S. Patent Nos. 3,658,858 and Nos. 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 is required. , additional reagents, etc.
tysk offentliggørelsesskrift nr. 2145650 beskrives den direkte kobling af arylmagnesiumhalogenider med kalium-2-jodpro-25 pionat. Senere er det i det amerikanske patentskrift nr.German Publication No. 2145650 discloses the direct coupling of arylmagnesium halides with potassium 2-iodine propionate. Later, in U.S. Pat.
3.959.364 blevet vist, at en forbedret direkte kobling kunne opnås ved reaktion af et aryl-Grignard-reagens med lithium-, natrium-, magnesium- eller calciumsaltene af 2-brompropionsy-re med formlen CH3CH(X)C0M, hvori X er brom, og M betegner 30 OLi, ONa, 0(Mg)i/2 eller 0(Ca)j/2 (jf. tabel II i US patentskrift nr. 3.959.364). Det har imidlertid vist sig, at fremstillingen af 2-arylpropionsyrer, specielt den værdifulde forbindelse 2-(6-methoxy-2-naphthyl)-propionsyre, ved denne metode lider af en række hermed forbundne mangler inklusive frem-35 stillingen af et halogenpropionatsalt i de aprotiske opløs ningsmiddelmedier, som skal anvendes til koblingsreaktionen, hvilket fører til dårlige resultater, når der arbejdes i stor målestok.3,959,364 has been 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 formula CH3CH (X) COM wherein X is bromine, and M represents 30 OLi, ONa, 0 (Mg) i / 2 or 0 (Ca) j / 2 (cf. 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, in this method suffers from a number of associated deficiencies including the preparation of a halopropionate salt in the aprotic solvent media to be used for the coupling reaction, leading to poor results when working on a large scale.
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Det ville derfor være af meget stor værdi at have en koblingsproces, som ved at udnytte et aryl-Grignard-reagens og et egnet halogenpropionsyrederivat giver de ønskede 2-arylpropion-syrer let og i reproducerbart højt udbytte og høj renhed, og 5 som let kan anvendes til produktion i stor målestok.Therefore, it would be of great value to have a coupling process which, by utilizing an aryl-Grignard reagent and a suitable halogenopropionic acid derivative, provides the desired 2-arylpropionic acids readily and in reproducibly high yield and high purity, and 5 which can readily used for large-scale production.
Den foreliggende opfindelse angår et mellemprodukt til anvendelse ved fremstillingen af kendte værdifulde antiinflammatoriske midler, specielt 2-arylpropionsyrer, såsom 2-{6-methoxy-10 2-naphthyl)-propionsyre, der er beskrevet i US patentskrift nr. 3.904.682.The present invention relates to an intermediate for use in the preparation of known valuable anti-inflammatory agents, especially 2-arylpropionic acids such as 2- (6-methoxy-10-2-naphthyl) -propionic acid disclosed in U.S. Patent No. 3,904,682.
Den omhandlede fremgangsmåde er en direkte koblingsproces, hvorved et ønsket arylmagnesiumbromid kobles med et blandet 15 magnesiumhalogenidkompleks af α-brompropionsyre i et højt udbytte til fremstilling af den tilsvarende 2-arylpropionsyre. Enhver henvisning til 2-arylpropionsyrer i beskrivelsen og patentkravene drejer sig om den racemiske form af disse foi— bindeiser.The present process is a direct coupling process whereby a desired aryl magnesium bromide is coupled with a mixed magnesium halide complex of α-bromopropionic acid in high yield to produce the corresponding 2-arylpropionic acid. Any reference to 2-aryl propionic acids in the specification and claims relates to the racemic form of these compounds.
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Eksempler på 2-arylpropionsyrerne, der kan fremstilles ved anvendelse af mellemproduktet ifølge den foreliggende opfindelse, er de, hvori aryldelen er 25 6-methoxy-2-naphthyl, dvs. 2-(6-methoxy-2-naphthyl)-propion syre, 4-alkylphenyl, hvor "alkyl" betegner ligekædede og forgrenede mættede hydrocarbongrupper med 1-4 carbonatomer, f.eks. 2-(4-30 methylphenyl)-propionsyre, 2-(4-isopropylphenyl)-propionsyre og 2-(4-isobutylphenyl)-propionsyre, og 4'-fluor-4-biphenyl, dvs. 2-(4'-fluor-4-biphenyl)-propionsyre.Examples of the 2-arylpropionic acids that can be prepared using the intermediate 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" means straight-chain and branched-chain saturated hydrocarbon groups of 1-4 carbon atoms, e.g. 2- (4-30 methylphenyl) propionic acid, 2- (4-isopropylphenyl) propionic acid and 2- (4-isobutylphenyl) propionic acid, and 4'-fluoro-4-biphenyl, i.e. 2- (4'-fluoro-4-biphenyl) propionic acid.
35 Som nævnt ovenfor beskrives i US patentskrift nr. 3.959.364 fremstillingen af ary1 alkansyrer ved den direkte kobling af et aryl-Grignard-reagens med Na- Li-, Cai/2- og Mgi/2-saltene af a-brompropionsyre.35 As mentioned above, U.S. Patent No. 3,959,364 describes the preparation of aryl alkanoic acids by the direct coupling of an aryl-Grignard reagent with Na-Li, Cai / 2 and Mgi / 2 salts of α-bromopropionic acid.
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Det har nu overraskende vist sig, at der fås en forbedret koblingsreaktion, hvis man i stedet for et af de førnævnte salte anvender et mellemprodukt i form af et blandet magnesiumhalo-genidkompleks af α-brompropionsyre, hvilket mellemprodukt er 5 ejendommeligt ved at det har formlen CH3CH(Br)C00MgX, hvori X er chlor eller brom eller er et etherat deraf.It has now surprisingly been found that an improved coupling reaction is obtained if, instead of one of the aforementioned salts, an intermediate in the form of a mixed magnesium halide complex of α-bromopropionic acid is used, which intermediate is characterized by having the formula CH3CH (Br) C00MgX, wherein X is chlorine or bromine or is an etherate thereof.
En direkte sammenligning mellem magnesiumsaltet af a-brompro-pionsyre (fremstillet ved begge de i US patentskrift nr.A direct comparison between the magnesium salt of α-bromopropionic acid (prepared by both of the U.S. Pat.
10 3.959.364 beskrevne metoder) og det hidtil ukendte magnesium- halogenidkompleks ifølge opfindelsen viser en bemærkelsesværdig forskel med hensyn til udbytte af opnåede slutprodukter (i det ene tilfælde et dobbelt så stort udbytte som i det andet tilfælde) og er angivet mere detaljeret i eksemplerne. Det er 15 en yderligere fordel ved den omhandlede koblingsproces, at de herved opnåede udbytter ikke påvirkes af fremstillingen af det blandede magnesiumhalogenidkompleks i den udstrækning, som udbytterne af koblingsprocessen ifølge US patentskrift nr. 3.959.364 påvirkes af fremgangsmåden til fremstilling af 20 2-brompropionatsaltet (jf. US patentskrift nr. 3.959.364, spalte 3, linie 10 og 11).10,959,364) and the novel magnesium halide complex of the invention show a remarkable difference in yield of end products obtained (in one case twice as much as in the other case) and are set forth 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 preparation of the mixed magnesium halide complex to the extent that the yields of the coupling process of U.S. Patent No. 3,959,364 are affected by the process for preparing the 20 2-bromopropionate salt. (cf. U.S. Patent No. 3,959,364, column 3, lines 10 and 11).
Det blandede magnesiumhalogenidkompleks af a-brompropionsyre kan fremstilles ved fremgangsmåden ifølge opfindelsen, der er 25 ejendommelig ved det i krav 4's kendtegnende del anførte.The mixed magnesium halide complex of α-bromopropionic acid can be prepared by the process according to the invention, which is characterized by the characterizing part of claim 4.
Selv om arten af hydrocarbondelen af Grignard-reagenset ikke er kritisk, foretrækkes det, at den ved reaktionen af a-brompropionsyre med Grignard-reagenset dannede fri hydrocarbon ik-30 ke indvirker på koblingstrinet eller oparbejdningen. Af denne grund er Grignard-reagenser, der er afledt af hydrocarboner, som er gasformige eller flydende ved reaktionstemperaturerne, særligt egnede, f.eks. alkylmagnesium-Grignard-reagenser med 1-12 carbonatomer eller arylmagnesium-Grignard-reagenser med 35 6-9 carbonatomer. Specifikke Grignard-reagenser, der kan an vendes til dette formål, er methylmagnesiumchlorid, methyl-magnesi umbromid, ethy1magnesi umchlorid, ethy1 magnes i umbromid,Although the nature of the hydrocarbon portion of the Grignard 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 work-up. 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 Grignard reagents that can be used for this purpose are methyl magnesium chloride, methyl magnesium umbromide, ethyl magnesium chloride, ethyl magnesium in umbromide,
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4 isopropylmagnesiumchlorid, phenylmagnesiumchlorid og o-, m-eller p-tolylmagnesiumchlorid og lignende. Methylmagnesium-chlorid og methylmagnesiumbromid foretrækkes specielt, for så vidt de er let tilgængelige, billige og fører til dannelsen 5 af methangas, som undslipper fra reaktionsblandingen og ikke indvirker under reaktionen eller oparbejdningen. Det har overraskende vist sig, at tilsætningen af et af de førnævnte Grignard-reagenser til a-brompropionsyre primært resulterer i dannelsen af det førnævnte kompleks. Addition af Grignard-re-10 agenset over carbonyldelen af carboxylsyren, en reaktion, som man normalt ville vente ville forløbe i større udstrækning, viser sig at være minimal, selv når der anvendes et molært overskud af Grignard-reagens.4 isopropylmagnesium chloride, phenylmagnesium chloride and o-, m- or p-tolylmagnesium chloride and the like. Methylmagnesium chloride and methylmagnesium bromide are especially preferred, inasmuch as they are readily available, inexpensive and lead to the formation of methane gas which escapes from the reaction mixture and does not interfere with the reaction or work-up. Surprisingly, it has been found that the addition of one of the aforementioned Grignard reagents to α-bromopropionic acid results primarily in the formation of the aforementioned complex. Addition of the Grignard re-agent 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.
15 Fremstillingen af det blandede magnesiumhalogenidkompleks gennemføres normalt i et aprotisk opløsningsmiddelmedium, som omfatter en ether, såsom diethylether, tetrahydrofuran, 1,2-dimethoxyethan, di-(n-butyl)-ether og lignende. Opløsningsmiddelmediet kan omfatte andre aprotiske opløsningsmidler så-20 som aromatiske hydrocarboner, f.eks. benzen eller toluen. Et foretrukket opløsningsmiddelmedium til kompleksfremsti 11 ing er tetrahydrofuran. Selv om rækkefølgen af tilsætningen af reagenser ikke er særlig kritisk, foretrækkes det normalt at tilsætte Grignard-reagenset til α-brompropionsyren. Grignard-25 reagenset i opløsning er fortrinsvis fra ca. 1 til 4 M, bedst fra ca. 2 til ca. 3 M. En kompleksopløsning til slut til anvendelse i det direkte koblingstrin på fra ca. 1 til ca. 2 M, fortrinsvis fra ca. 1,0 til 1,5 M, er ønskelig. Temperaturen ved kompleksdannelsestrinet holdes normalt mellem ca. -20°C 30 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 complex preparation is tetrahydrofuran. Although the order of reagent addition is not very critical, it is usually preferred to add the Grignard reagent to the α-bromopropionic acid. The Grignard 25 reagent in solution is preferably from ca. 1 to 4 M, 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 gennemføres hensigtsmæssigt ved at bringe en opløsning af det blandede magnesiumhalogenidkompleks af α-brompropionsyre i kontakt med arylmagnesiumbromi-35 det i et vandfrit aprotisk organisk opløsningsmiddelmedium. Egnede opløsningsmiddelmedier for reaktionen omfatter organiske ethere og blandinger af organiske ethere med aromatiskeThe 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
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5 hydrocarboner som nævnt ovenfor i forbindelse med kompleksdannelsestrinet. Et særligt foretrukket opløsningsmiddelmedium til koblingsreaktionen er tetrahydrofuran. Det foretrækkes, at arylmagnesiumbromidopløsningen er mellem 0,5 og 2 M, 5 fortrinsvis ca. 1,0 M.5 hydrocarbons as mentioned above in connection with the complex formation step. A particularly preferred solvent medium for the coupling reaction is tetrahydrofuran. It is preferred that the aryl magnesium bromide solution be between 0.5 and 2 M, preferably about 1.0 M.
Koblingsprocessen selv kan gennemføres inden for et temperaturområde fra ca. 0 til ca. 100°C, fortrinsvis mellem ca. 10°C og 60eC. Det foretrækkes specielt at lade temperaturen 10 stige gradvis under tilsætningen op til ca. 40-60°C og derpå falde igen til omgivelsernes temperatur, indtil den ønskede reaktionsgrad er blevet opnået.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 10 to rise gradually during the addition up to approx. 40-60 ° C and then fall back to ambient temperature until the desired reaction rate is achieved.
Selv om koblingsreaktionen kan gennemføres under anvendelse af 15 reagenserne i forskellige indbyrdes forhold, foretrækkes det, at der anvendes omtrent ækvimolære mængder af det blandede magnesiumhalogenidkompleks og aryl-Grignard-reagenset. Foretrukne 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. Preferred conditions are from approx. 0.9: 1.1 to 1.1: 0.9 complex: Grig-nard reagent.
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Reaktionen kan hensigtsmæssigt gennemføres ved at bringe de to reagenser i kontakt i opløsningsmiddelmediet på en vilkårlig af de i teknikken kendte områder. Det foretrækkes imidlertid specielt at sætte det blandede magnesiumhalogenidkom-25 pleks til Grignard-reagenset og holde disse reagenser inderligt blandede, indtil den ønskede reaktion er forløbet fuldstændig.The reaction may conveniently be carried out by contacting the two reagents in the solvent medium in any of the prior art areas. 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 gennemførelse af den ønskede reaktion nødvendige tid 30 vil naturligvis have sammenhæng med de specielt valgte reagenser, opløsningsmidler og den valgte reaktionstemperatur og vil på sædvanlig måde af fagmanden, som skal gennemføre reaktionen, blive justeret til opnåelse af den optimale produktion af det ønskede produkt. En sådan reaktionstid vil imid-35 lertid almindeligvis være af størrelsesordenen fra ca. 10 minutter til ca. 20 timer og er sædvanligvis i intervallet fra ca. 1 til ca. 5 timer.The time required for carrying 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 optimal production of the desired product. . However, such a reaction time will generally be of the order of from about. 10 minutes to approx. 20 hours and is usually in the range of about 1 to approx. 5 hours.
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Efter at koblingsreaktionen er forløbet i den ønskede udstrækning, afkøles reaktionsblandingen, som indeholder det koblede kompleks aryl CH(CH3)C00MgX, derpå hurtigt med en fortyndet syre, fortrinsvis en fortyndet vandig mineralsyre, 5 såsom saltsyre eller svovlsyre, på sædvanlig måde for Grig-nard-reaktioner. Det fri 2-arylpropionsyreprodukt kan derpå isoleres og renses fra den afkølede reaktionsblanding på sædvanlig måde såsom ekstraktion med vandig alkali (f.eks. vandig natrium- eller kaliumhydroxid), separering af den vandige 10 alkaliske fase fra den organiske fase og syrning af den vandige alkaliske fase til frigørelse af den ønskede syre, som eventuelt kan ekstraheres med et organisk opløsningsmiddel eller renses direkte på sædvanlig måde såsom ved vask og/eller krystal 1 isation.After the coupling reaction has proceeded to the desired extent, the reaction mixture containing the coupled complex aryl CH (CH3) C00MgX is then rapidly cooled with a dilute acid, preferably a dilute aqueous mineral acid, such as hydrochloric acid or sulfuric acid, in the usual manner for Grig. Bernard reactions. The free 2-arylpropionic acid product can then be isolated and purified from the cooled reaction mixture in the usual manner 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 purified directly in the usual manner such as by washing and / or crystal 1 isation.
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Det rå reaktionsprodukt kan om ønsket direkte omdannes til et farmaceutisk acceptabelt derivat af carboxylsyren såsom et salt, en ester eller et amid deraf eller spaltes i optiske i somere.The crude reaction product, if desired, can be directly converted to a pharmaceutically acceptable derivative of the carboxylic acid such as a salt, ester or amide thereof or cleaved in optical in the summers.
2020
Koblingsreaktionen gennemføres let og hensigtsmæssigt i stor målestok og giver udbytter af rensede produkter af størrelsesordenen 50-75%.The coupling reaction is carried out easily and conveniently on a large scale, yielding purified products on the order of 50-75%.
25 I det følgende belyses opfindelsen ved beskrivelse af fremstillingen af magnesiumhalogenidkomplekset ifølge opfindelsen i eksemplerne 1-4, mens anvendelsen af komplekserne belyses i fremstillingsmetoderne 1-6.In the following, the invention is illustrated by describing the preparation of the magnesium halide complex of the invention in Examples 1-4, while the use of the complexes is elucidated in Methods 1-6.
30 Eksempel 1Example 1
Fremstilling af 2-(6-methoxvnaphthvl)-maqnesiumbromid 2-brom-6-methoxynaphthalen (23,7 g, 0,1 mol) opløses i tolu-35 en (30 ml) og tetrahydrofuran (40 ml) under opvarmning. Denne opløsning tilsættes derpå i løbet af 10-15 minutter til et overskud af magnesiummetal (3 g, 0,12 mol), toluen (15 ml) og 7Preparation of 2- (6-methoxynaphthyl) magnesium bromide 2-bromo-6-methoxynaphthalene (23.7 g, 0.1 mole) 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 7
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tetrahydrofuran (15 ml) under en nitrogenatmosfære. Den resulterende blanding afkøles derpå og omrøres i yderligere 1 time ved 25-30°C. Reaktionsblandingen befries derpå for magnesiumoverskud og overføres til en ren tør beholder under ni-5 trogen og lagres ved 10°C til opnåelse af et 1,0 M Grignard-reagens.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 clean dry container under nitrogen and stored at 10 ° C to obtain a 1.0 M Grignard reagent.
Ved anvendelse af en tilsvarende fremgangsmåde kan Grignard-reagenset fremstilles under anvendelse af tetrahydrofuran som 10 det eneste opløsningsmiddel.Using a similar procedure, the Grignard reagent can be prepared using tetrahydrofuran as the sole solvent.
Ved at anvende en mindre opløsningsmiddelmængde kan der på lignende måde 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.
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Eksempel 2Example 2
Blandet magnesiumhalogenidkompleks af a-brompropionsyre 20 15,3 (0,1 mol) a-brompropionsyre og 40 ml toluen afkøles til 10eC, og en opløsning af 50 ml 2 M methylmagnesiumbromid i tetrahydrofuran/toluen (1:1) tilsættes derpå langsomt, idet temperaturen holdes på 10-20eC under tilsætningen, som varer 15-20 minutter. Reaktionsblandingen omrøres derpå ved 5eC i 25 yderligere 20 minutter af en 1,1 M opløsning af komplekset.Mixed magnesium halide complex of α-bromopropionic acid 20 15.3 (0.1 mole) of α-bromopropionic acid and 40 ml of toluene are cooled to 10 ° C and a solution of 50 ml of 2 M methylmagnesium bromide in tetrahydrofuran / toluene (1: 1) is then slowly added. the temperature is kept at 10-20 ° C during the addition, which lasts 15-20 minutes. The reaction mixture is then stirred at 5 ° C for a further 20 minutes by a 1.1 M solution of the complex.
Ved at gå frem på tilsvarende måde kan det blandede magnesi-umhalogenidkompleks fremstilles under anvendelse af tetrahy-drofuran som det eneste opløsningsmiddel.By proceeding in a similar manner, the mixed magnesium halide complex can be prepared using tetrahydrofuran as the sole solvent.
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Methylmagnesiumbromid kan ligeledes erstattes med andre Grig-nard-reagenser såsom methylmagnesiumchlorid, isopropylmagne-siumchlorid, phenylmagnesiumchlorid og lignende i koncentrationer varierende fra ca. 1 til ca. 4 M.Methylmagnesium bromide can also be replaced with other Grigard nard reagents such as methylmagnesium chloride, isopropylmagnesium chloride, phenylmagnesium chloride, and the like at concentrations ranging from ca. 1 to approx. 4 M.
Det blandede magnesiumchloridkompleks af a-brompropionsyre (fremsitllet som beskrevet ovenfor under anvendelse af 3 MThe mixed magnesium chloride complex of α-bromopropionic acid (prepared as described above using 3 M
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8 CH3MgCl i tetrahydrofuran) blev isoleret i krystallinsk form som dets tetrahydrofuranmonoetherat efter destillation af te-trahydrofuran fra en tetrahydrofuranopløsning og blev analyseret: smp. 147-155°C, infrarødt spektrum (KBr) 1625, 1450, 5 1420, 1372, 1291, 1200, 1070, 1030, 988 og 890 cm~l, kerne- magnetisk resonansspektrum (D2O) 6 1,8 (multiplet, 7) 3,7 (multiplet, 4) og 4,35 dele pr. million (kvartet, J=7). Elementæranal yse beregnet for C7H12BrClMg03Mg 8,57%, Cl 12,49%.(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, 5 1420, 1372, 1291, 1200, 1070, 1030, 988 and 890 cm -1, nuclear magnetic resonance spectrum (D2O) 6 1.8 (multiplet, 7 ) 3.7 (multiplet, 4) and 4.35 parts per million (quartet, J = 7). Elemental analysis calculated for C 7 H 12 BrClMgO 3 Mg 8.57%, Cl 12.49%.
10 Fundet: Mg 8,63%, Cl 12,97%.Found: Mg 8.63%, Cl 12.97%.
Eksempel 3Example 3
Fremstilling af arvlmagnesiumbromider 15 0,025 mol arylbromid opløses i tetrahydrofuran (18 ml). Denne opløsning sættes til et overskud af magnesiummetal (3 g, 0,02 mol) og tetrahydrofuran (7 ml) under en nitrogenatmosfære. Temperaturen holdes på 50-60eC med afkøling i tiIsætningspe-20 ri oden på 10-15 minutter. Reaktionsblandingen befries derpå for magnesiumoverskud og overføres til en ren tør beholder under nitrogen og lagres ved 10°C til opnåelse af et 1,0 M Grignard-reagens . På denne måde blev følgende Grignard-rea-genser fremstillet: 25 2-(6-methoxynaphthyl)-magnesiumbromid 4.(41-fluorbi phenyl)-magnesiumbromid l-(4.-i sopropy 1 phenyl) -mag nes i umbromid 1-(4-i sobuty1 phenyl)-magnesi umbromid 30 l-(4-methylphenyl)-magnesiumbromid.Preparation of aryl magnesium bromide 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 in the addition period of 10-15 minutes. The reaction mixture is then freed from magnesium excess and transferred to a clean dry container under nitrogen and stored at 10 ° C to obtain a 1.0 M Grignard reagent. In this way, the following Grignard reagents were prepared: 2- (6-methoxynaphthyl) magnesium bromide 4. (41-fluorobi phenyl) magnesium bromide 1- (4.-sopropylphenyl) phenyl) in umbromide 1- (4-isobutyl phenyl) magnesium bromide 1- (4-methylphenyl) magnesium bromide.
3535
DK 163817 BDK 163817 B
99
Eksempel 4 A. Fremstilling af det blandede magnesiumhalogenidkompleks af g-brompropionsyre 5 a-brompropionsyre (3,8 g, 0,025 mol) opløses i tetrahydrofu-ran (8 ml), og opløsningen afkøles til -10eC. Til denne opløsning sættes 3 M methylmagnesiumchlorid i tetrahydrofuran (8 ml) i løbet af en 15 minutters periode, medens temperatu-10 ren holdes mellem -10°C og 0eC. Dette giver en 1,1 molær opløsning af komplekset, som lagres ved 0°C eller herunder, indtil det anvendes.Example 4 A. Preparation of the mixed magnesium halide complex of g-bromopropionic acid 5? -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 is added 3 M methylmagnesium chloride in tetrahydrofuran (8 ml) over a 15 minute period while maintaining the temperature between -10 ° C and 0 ° C. This gives a 1.1 molar solution of the complex which is stored at 0 ° C or below until used.
Ved at erstatte 3 M methylmagnesiumchlorid med 1 M methylmag-15 nesiumbromid kan på lignende måde fremstilles det tilsvarende magnes i umbrom idkompleks.Similarly, by replacing 3 M methylmagnesium chloride with 1 M methylmagnesium bromide, the corresponding magnesium can be prepared in the umbromide complex.
B. Fremstilling af magnesiumsaltet af a-brompropionsyre 20 a-brompropionsyre (3,8 g, 0,025 mol) opløses i methanol (6 ml) og opløsningen afkøles til -10eC. Hertil sættes et 0,5 M mag-nesiummethoxid i methanol opløsning (25 ml) i løbet af en 10 minutters periode, medens temperaturen holdes med -10°C og 0°C. Methanol fjernes derpå under reduceret tryk til opnåelse 25 af det faste salt, som tørres i vakuum ved 50°C i 12 timer til fremstilling af det tørre magnesiumsalt (4,1 g, 0,0125 mol, 97,2% rent). Dette salt opløses i 19 ml tetrahydrofuran til kobl ingsreaktionen.B. Preparation of the magnesium salt of α-bromopropionic acid 20 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 magnesium methoxide in methanol solution (25 ml) over a 10 minute period while maintaining the temperature at -10 ° C and 0 ° C. Methanol is then removed under reduced pressure to give the solid salt which is dried in vacuo at 50 ° C for 12 hours to prepare the dry magnesium salt (4.1 g, 0.0125 mol, 97.2% pure). This salt is dissolved in 19 ml of tetrahydrofuran for the coupling reaction.
30 Fremstillingsmetode 1 A. Opløsningen af kompleks fra eksempel 2 sættes langsomt til Grignard-opløsningen fra eksempel 1, idet temperaturen holdes på 15-20°C under tilsætningen, som varer fra 10 til 15 minut-35 ter. Reaktionsblandingen får lov til at antage stuetemperatur og omrøres derpå i 2 timer. Reaktionsblandingen afkøles derpå i et isbad, og en opløsning af 20 ml kold N saltsyre ogPreparation Method 1 A. The solution of complex of Example 2 is slowly added to the Grignard solution of Example 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 then 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
DK 163817 BDK 163817 B
10 150 ml vand tilsættes. Efter omrøring i 5 minutter filtreres tofasessystemet, og filterkagen vaskes med 55 ml toluen og 50 ml vand. Den organiske fase ekstraheres med 10% kaliumhydroxidopløsning (2 x 150 ml), og de forenede basiske ekstrak-5 ter vaskes med toluen (30 ml) og neutraliseres med 12 N saltsyre til pH-værdi 1. Den hvide faste 2-(6-methoxy-2-naph-thyl)-propionsyre filtreres under vakuum og tørres ved 55°C i vakuum, hvilket giver 15,2 g (66%), smeltepunkt 149,5-153,50 C, 10 B. Efter filtrering kan den organiske fase alternativt ekstraheres med 10% kaliumhydroxidopløsning (2 x 150 ml), som vaskes med toluen (30 ml) og filtreres. 15 ml methanol og 12 ml toluen tilsættes, derpå tilsættes tilstrækkeligt 12 N saltsyre til 15 at indstille pH-værdien på mellem 4 og 5. Den resulterende opslæmning opvarmes derpå til tilbagesvaling i 1 time, afkøles og filtreres. Bundfaldet vaskes med vand (20 ml), toluen (2 x 3 ml) og hexan (2 x 3 ml) og tørres ved 55°C i vakuum til fremstilling af 15,0 g (65,1%) produkt med smeltepunkt 154,5-20 155°C.Add 150 ml of water. 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 10% potassium hydroxide solution (2 x 150 ml) and the combined basic extracts are washed with toluene (30 ml) and neutralized with 12 N hydrochloric acid to pH 1. The white solid 2- (6- methoxy-2-naphthyl) propionic acid is filtered under vacuum and dried at 55 ° C in vacuo to give 15.2 g (66%), mp 149.5-153.50 C, 10 B. After filtration, alternatively, organic phase is extracted with 10% potassium hydroxide solution (2 x 150 ml) which is 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 dried at 55 ° C in vacuo to give 15.0 g (65.1%) of product, m.p. 154, 5-20 155 ° C.
Fremstillingsmetode 2 67 ml af en 1,5 M opløsning af det blandede magnesiumchlorid-25 kompleks af α-brompropionsyre i tetrahydrofuran (fremstillet under anvendelse af 3 M methylmagnesiumchlorid) sættes langsomt til en afkølet (10°C) opløsning af 1,5 M 2-(6-methoxy-naphthyl)-magnesiumbromid i tetrahydrofuran (67 ml) med en sådan hastighed, at temperaturen holdes på 55°C eller herunder.Preparation Method 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 cooled (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 maintained at 55 ° C or below.
30 Den resulterende opslæmning omrøres ved 50eC i 1 time og opvarmes derpå til tilbagesvaling, idet 30-40% af tetrahydrofu-ranen får lov til at afdesti1lere. Reaktionsblandingen afkøles til 50°C, 30 ml toluen tilsættes, og reaktionsblandingen afkøles hurtigt med vandig saltsyre og oparbejdes som beskrevet i 35 fremstillingsmetode IB til fremstilling af 2-{6-methoxy-2-naphthyl)-propionsyre, smeltepunkt 156-157*0, i et udbytte på 73%.The resulting slurry is stirred at 50 ° C for 1 hour and then heated to reflux, allowing 30-40% of the tetrahydrofuran to distribute. 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 Preparation Method IB to prepare 2- (6-methoxy-2-naphthyl) -propionic acid, mp 156-157 ° , in a yield of 73%.
DK 163817 BDK 163817 B
1111
Fremstillingsmetode 3 A. Magnesiumsaltet af α-brompropionsyre, dvs.Preparation Method 3 A. The magnesium salt of α-bromopropionic acid, i.e.
[CH3CH(Br)C00]2Mg blev fremstillet ved at omsætte syren med 5 1/2 molærækvivalent magnesiumcarbonat efterfulgt af tørring af saltet ved 60eC i vakuum. Erstatning af det blandede magnesi-umchloridkompleks, der blev anvendt i fremstillingsmetode 2, med dette salt resulterede i et produktudbytte på 34,7%.[CH3CH (Br) C00] 2Mg was prepared by reacting the acid with 5 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 Preparation Method 2 with this salt resulted in a yield of 34.7%.
10 B. Saltet fra afsnit A blev også fremstillet under anvendelse af 1/2 molærækvivalent magnesiummethoxid, idet methanol fjernes som en azeotrop. Anvendelse af saltet ved fremgangsmåden fra fremgangsmåde 2 gav et produktudbytte på 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 method 2 gave a product yield of 43.0%.
15 Fremstillingsmetode 4Preparation Method 4
Fremstillingsmetode 3A blev gentaget, bortset fra at 1/2 molærækvivalent vandfrit magnesiumchlorid blev sat til magnesiumsaltet før koblingsreaktionen. Der blev opnået et produktud-20 bytte på 5,1%.Preparation Method 3A was repeated except that 1/2 molar equivalent of anhydrous magnesium chloride was added to the magnesium salt prior to the coupling reaction. A product yield of 5.1% was obtained.
Fremstillingsmetode 5Preparation Method 5
Fremgangsmåden fra fremstillingsmetode 3B blev gentaget, bort-25 set fra at der blev anvendt ækvimolære mængder af a-brompro-pionsyre og magnesiummethoxid. Produktudbyttet var 35,1%.The method of Preparation Method 3B was repeated except that equimolar amounts of α-bromopropionic acid and magnesium methoxide were used. The product yield was 35.1%.
Fremstillingsmetode 6 30 Sammenlignende koblingsreaktioner under anvendelse af blandede magnesiumhalogenidkomplekser og Mgi/2salte Følgende koblingsreaktioner (efter den nedenfor anførte skala) blev gennemført under anvendelse af såvel det blandede magne-35 siumchloridkompleks af α-brompropionsyre (fremstillet ifølge eksempel 4A) eller magnesiumsaltet af o-brompropionsyre (fremstillet ifølge eksempel 4B) med det tilsvarende Grignard-rea-Preparation Method 6 Comparative Coupling Reactions Using Mixed Magnesium Halide Complexes and MgI / 2 Salts The following coupling reactions (according to the scale below) were performed using either the mixed magnesium-chloride complex of α-bromopropionic acid (prepared according to Example 4A) or the magnesium salt of bromopropionic acid (prepared according to Example 4B) with the corresponding Grignard reaction.
DK 163817 BDK 163817 B
12 gens (fremstillet ifølge eksempel 3). Fremgangsmåden (illustreret for en 0,025 mol skala) var som følger: 1,0 M opløsningen af arylmagnesiumbromid afkøles til 10°C, og 5 opløsningen af enten magnesiumsaltet eller magnesiumchlorid-komplekset i tetrahydrofuran tilsættes i løbet af en 5 minutters periode, medens temperaturen holdes mellem 10eC og 55°C. Reaktionsblandingen omrøres derpå ved 25-30eC i 2 timer. Reaktionsblandingen afkøles derpå til 10eC, og en opløsning af 12 10 N saltsyre (10 ml) og vand (50 ml) tilsættes. Toluen (50 ml) tilsættes derpå, og den vandige fase skilles fra og kasseres. Den organiske fase ekstraheres to gange med 10% kaliumhydroxid (50 ml). De basiske ekstrakter forenes og neutraliseres med saltsyre til fremstilling af et bundfald, der filtreres og 15 tørres ved 50°C. Resultaterne er anført i den efterfølgende tabel.12 gens (prepared according to Example 3). The procedure (illustrated for 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 maintaining 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 10 N hydrochloric acid (10 ml) and water (50 ml) is added. Toluene (50 ml) is then added and the aqueous phase is separated and discarded. The organic phase is extracted twice with 10% potassium hydroxide (50 ml). The basic extracts are combined and neutralized with hydrochloric acid to produce a precipitate which is filtered and dried at 50 ° C. The results are given in the following table.
: 20 25 30 35: 20 25 30 35
13 DK 163817 B13 DK 163817 B
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P H CD Φ M Ί |5.HP H CD Φ M Ί | 5.H
Claims (4)
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Application Number | Priority Date | Filing Date | Title |
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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 | ||
DK64578 | 1978-02-13 | ||
DK064578A DK156898C (en) | 1977-02-16 | 1978-02-13 | PROCEDURE FOR THE PREPARATION OF 2-ARYL PROPIONIC ACIDS USING DIRECT CLUTCH USING A MIXED MAGNESIUM HALOGENIDE COMPLEX |
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DK163817C DK163817C (en) | 1992-08-31 |
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DK005084A DK163817C (en) | 1977-02-16 | 1984-01-05 | MAGNESIUM HALOGENIDE COMPLEX OF 2-BROMOPROPIONIC ACID AND PROCEDURES FOR PREPARING IT |
DK5184A DK163234C (en) | 1977-02-16 | 1984-01-05 | MAGNESIUM HALOGENIDE COMPLEX OF A 2-ARYLPROPIONIC ACID AND PROCEDURES FOR PREPARING IT |
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