DK166820B1 - METHOD FOR PREPARING 1- (2,6-DIMETHYLPHENOXY) -2-AMINOPROPAN OR ANY ACID ADDITION SALT FROM 2,6-DIMETHYLPHENOL - Google Patents
METHOD FOR PREPARING 1- (2,6-DIMETHYLPHENOXY) -2-AMINOPROPAN OR ANY ACID ADDITION SALT FROM 2,6-DIMETHYLPHENOL Download PDFInfo
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Description
DK 166820 B1DK 166820 B1
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af 1-(2,6-dimetylfenoxy)-2-aminopropan med formlen 5 /CH3 fX * \_/° ' CH2 - fH - C[i3 10 eller syreadditionssalte der ud fra 2,6-dimetylfenol.The present invention relates to a particular process for the preparation of 1- (2,6-dimethylphenoxy) -2-aminopropane of the formula 5 / CH3 fX * \ _ / ° 'CH2 - fH - C [i3] or acid addition salts therefrom 2, 6-dimetylfenol.
Forbindelsen med formlen la er kendt fra litteraturen og har værdifuld biologisk virkning.The compound of formula Ia is known from the literature and has valuable biological effect.
Således udviser 1-(2,6-dimetylfenoxy)-2-aminopro-pan og farmaceutisk acceptable syreadditionssalte 15 deraf gunstige virkninger på ventrikulære arrytmiske tilstande og forbindelsen kan med særlig fordel anvendes ved behandling af iskæmiske kardiale sygdomme, myokardial infarkt, ventrikulær fibrillation og takykardi (Brit. Heart J. 35, 558-559 (1973); Lancet 1973/11, 339-403, 404-407; Brit. J. Clin.Thus, 1- (2,6-dimethylphenoxy) -2-aminopropane and pharmaceutically acceptable acid addition salts thereof have beneficial effects on ventricular arrhythmic conditions and the compound can be particularly advantageously used in the treatment of ischemic cardiac disease, myocardial infarction, ventricular fibrillation and tachycardia. (Brit. Heart J. 35, 558-559 (1973); Lancet 1973/11, 339-403, 404-407; Brit. J. Clin.
20 Pharmacol. 1, 86-87, 229-232 (1974)). 1-(2,6-dimetylfenoxy)- 2-azidopropan har tilsvarende farmakologiske virkninger.Pharmacol. 1, 86-87, 229-232 (1974)). 1- (2,6-Dimethylphenoxy) -2-azidopropane has similar pharmacological effects.
I GB-PS nr. 1.205.958 er der beskrevet flere metoder til fremstilling af 1-(2,6-dimetylfenoxy)-2-aminopropan. Ifølge en af disse metoder fremstilles det ønskede produkt ved at 25 fjerne den eller de beskyttende grupper i en forbindelse med den almene formel /—/CH3 //\_ 11 30 \_/ ° " CH2 ' FH " CH3 DK 166820 B1 2 hvor B er en aminogruppe med en eller to beskyttelsesgrupper. Benzyl-, ftalyl-, toluensulfonyl- og formylgrupper nævnes som beskyttelsesgrupper i det citerede patentskrift, men udførelseseksemplerne omhandler kun fraspaltning af benzylgrup-5 pen.GB-PS No. 1,205,958 describes several methods for preparing 1- (2,6-dimethylphenoxy) -2-aminopropane. According to one of these methods, the desired product is prepared by removing the protecting group (s) in a compound of the general formula (CH2) FH CH3 DK 166820 B1 where B is an amino group having one or two protecting groups. Benzyl, phthalyl, toluene sulfonyl and formyl groups are mentioned as protecting groups in the cited patent, but the exemplary examples only deal with cleavage of the benzyl group.
Udgangsforbindelserne med den almene formel II kan i-følge det ovennævnte britiske patentskrift fremstilles ved at omsætte en forbindelse med den almene formel / ch3The starting compounds of the general formula II can, according to the aforementioned British patent, be prepared by reacting a compound of the general formula / ch 3
1° ,-J1 °, -J
(/ \— 0 - CH2 - CH - CH3 IH(/ \ - 0 - CH2 - CH - CH3 IH
\=^ Hal CH3 15 hvor Hal er et halogenatom, med en forbindelse med den almene formelHal = CH 3 where Hal is a halogen atom, with a compound of the general formula
B - Η IVB - Η IV
hvor B har den ovenfor angivne betydning.where B has the meaning given above.
20 Forbindelserne med den almene formel II kan også frem stilles ved at omsætte en keton med formlenThe compounds of the general formula II can also be prepared by reacting a ketone of the formula
/ch3 V/ ch3 V
(/ vv—0 - CH0 - C - CH, o ch3(/ vv - 0 - CH0 - C - CH, o ch3
med en forbindelse med den almene formel VIwith a compound of the general formula VI
H_N - Q VIH_N - Q VI
2 hvor Q er den beskyttelsesgruppe der er tilstede i substi-30 tuenten B, under reducerende betingelser (GB-PS nr. 1.205.958).2 where Q is the protecting group present in substituent B, under reducing conditions (GB-PS No. 1,205,958).
Den ovenfor nævnte fremgangsmåde har følgende ulemper: Hydrogenering af forbindelserne med den almene formel II, hvor beskyttelsesgruppen er benzyl, forløber kun ved 80°C under et tryk på mindst 5 atmosfære og den ønskede aminoforbin-35 delse vindes kim i et mellemstort udbytte (ca. 50 til 55%) .The above process has the following drawbacks: Hydrogenation of the compounds of the general formula II, wherein the protecting group is benzyl, proceeds only at 80 ° C under a pressure of at least 5 atmospheres and the desired amino compound is germinated in a medium yield (ca. 50 to 55%).
Desuden er udgangsforbindelserne i sig selv vanskelige at fremstille. Når forbindelserne med den almene formel II fremstilles ved omsætning af en forbindelse med den almene for- 3 DK 166820 B1 mel III med en forbindelse med den almene formel IV sker der også dobbelt alkylering på grund af benzylamins høje reaktionsdygtighed, hvilket resulterer i dannelsen af et bis-derivat med formlen 5 /CH3 V \— O - CH2 - CH - CH3In addition, the starting compounds are inherently difficult to manufacture. When the compounds of the general formula II are prepared by reacting a compound of the general formula III with a compound of the general formula IV, double alkylation also occurs due to the high reactivity of benzylamine, which results in the formation of a bis derivative of the formula 5 / CH3 V \ - O - CH2 - CH - CH3
N=< I VIIN = <I VII
cH3 ' jt\ 10 /“<CH3 I Xt==j/ V Λ— 0 - CH2 - CH - CH3 CH3 15 som biprodukt. Desuden indebærer reaktionen, der forløber med et overskud af aminen, eliminering af hydrohalogenid, hvilket fører til dannelsen af yderligere biprodukter. Selve produkterne er vanskelige at rense, hvilket fører til yderligere formindskelse af udbyttet.cH3 'jt \ 10 / “<CH3 I Xt == j / V Λ— 0 - CH2 - CH - CH3 CH3 15 as a by-product. In addition, the reaction which proceeds with an excess of the amine involves the elimination of hydrohalide, which leads to the formation of additional by-products. The products themselves are difficult to clean, leading to further diminishing the yield.
20 Forbindelserne med den almene formel II kan også frem stilles ved at omsætte en keton med den almene formel V med en passende beskyttet amin med den almene formel VI under reducerende betingelser. Denne metode er imidlertid ikke eksemplificeret i det ovennævnte patentskrift.The compounds of general formula II may also be prepared by reacting a ketone of general formula V with a suitably protected amine of general formula VI under reducing conditions. However, this method is not exemplified in the above patent.
25 Der opstår yderligere vanskeligheder ved fremstillin gen af selve ketonen med formel V, da denne forbindelse syntetiseres ved at omsætte et salt af 2,6-dimetylfenol med kloracetone eller bromacetone, som er yderst giftige forbindelser (N.I. Sax: Handbook of Dangerous Materials, Reinhold Publ. Corp., 30 New York, 1951, side 94).Further difficulties arise in the preparation of the ketone of formula V, as this compound is synthesized by reacting a salt of 2,6-dimethylphenol with chloroacetone or bromoacetone, which are highly toxic compounds (NI Sax: Handbook of Dangerous Materials, Reinhold Publ. Corp., New York, 1951, page 94).
GB-PS nr. 1.205.958 nævner også anvendelsen af ftalyl-, toluensulfonyl- og formylbeskyttelsesgrupper, men disse metoder er ikke illustreret ved eksempler.GB-PS No. 1,205,958 also mentions the use of phthalyl, toluene sulfonyl and formyl protecting groups, but these methods are not illustrated by examples.
Ifølge en yderligere fremgangsmåde beskrevet i GB-PSAccording to a further method described in GB-PS
35 nr. 1.205.958 behandles ketonen med formel V først med ammoniak, hydroxylamin eller hydrazin og den resulterende forbindelse med den almene formel 4 DK 166820 B1 /CH3No. 1,205,958, the ketone of formula V is first treated with ammonia, hydroxylamine or hydrazine and the resultant compound of general formula 4 B1 / CH3
/ \-O - CH2 - C - CH3 VIII/ \ -O - CH2 - C - CH3 VIII
NN
ch3 ^ hvor Y er hydrogen, hydroxy eller amino, reduceres enten ved katalytisk hydrogenering eller med et passende komplekst me-talhydrid til dannelse af 1-(2,6-dimetylfenoxy)-2-aminoprcpan.wherein Y is hydrogen, hydroxy or amino is reduced either by catalytic hydrogenation or by a suitable complex metal hydride to form 1- (2,6-dimethylphenoxy) -2-aminoprcpan.
Også denne metode har flere ulemper. Hydrogeneringen 5 kan kun udføres med moderate udbytter (51,5% for oximen og 44,3% for iminen; der er ikke givet noget eksempel på reduktion af hydrazonen), desuden er som nævnt ovenfor den som udgangsforbindelse anvendte keton med formel V vanskelig at fremstille.This method also has several disadvantages. Hydrogenation 5 can only be carried out with moderate yields (51.5% for the oxime and 44.3% for the imine; no example of the reduction of the hydrazone is given), in addition, as mentioned above, the ketone of formula V is difficult to manufacture.
10 Ifølge en yderligere fremgangsmåde der er beskrevet . i det ovennævnte britiske patentskrift kan 1-(2,6-dimetyl-fenoxy)-2-aminopropan fremstilles direkte ud fra 2,6-dimetyl-fenol ved at omsætte det med 1-metylaziridin. Der gives imidlertid ingen eksempler på denne metode i det nævnte patentskrift. 15 Ulempen ved denne metode ligger i anvendelsen af 1- metylaziridin. Denne forbindelse er ligesom ætylenimin yderst giftig (se N.I. Sax: Handbook of Dangerous Materials, Reinhold Publ. Corp., New York, 1951, side 328), og desuden er den i høj grad tilbøjelig til at polymerisere. Polymerisationen sætter 20 ind selv ved opvarmning af blandingen eller ved indvirkning af spormængder af syrer (såsom fenol).10 According to a further method described. In the above-mentioned British patent, 1- (2,6-dimethyl-phenoxy) -2-aminopropane can be prepared directly from 2,6-dimethyl-phenol by reacting it with 1-methyllaziridine. However, no examples of this method are given in said patent. The disadvantage of this method lies in the use of 1- methyllaziridine. Like ethyleneimine, this compound is extremely toxic (see N.I. Sax: Handbook of Dangerous Materials, Reinhold Publ. Corp., New York, 1951, p. 328), and, moreover, it is highly prone to polymerization. The polymerization sets in even by heating the mixture or by the action of trace amounts of acids (such as phenol).
Ved en yderligere metode, der er beskrevet i GB-PS nr. 1.205.958, anvendes et salt af 2,6-dimetylfenol som udgangsforbindelse. Saltet omsættes med en forbindelse med den almene for-25 mel Z - CH2 - CH - CH3 ix nh2 hvor Z er en reaktionsdygtig gruppe, såsom halogen. Denne metode er heller ikke eksemplificeret.In a further method described in GB-PS No. 1,205,958, a salt of 2,6-dimethylphenol is used as the starting compound. The salt is reacted with a compound of the general formula Z - CH2 - CH - CH3 ix nh2 where Z is a reactive group such as halogen. This method is also not exemplified.
5 DK 166820 B15 DK 166820 B1
Ulempen ved denne metode ligger i anvendelsen af reaktanterne med formel IX, da disse er vanskelige at fremstille og temmelig let dimeriserer under dannelse af piperazin-derivater.The disadvantage of this method lies in the use of the reactants of formula IX, as these are difficult to prepare and fairly easily dimerize to form piperazine derivatives.
5 1-(2,6-Dimetylfenoxy)-2-hydroxypropan er nævnt i US-PS1- (2,6-Dimethylphenoxy) -2-hydroxypropane is mentioned in US-PS
nr. 3.979.460 som et uønsket biprodukt, der dannes i et udbytte på 12% under syntesen af 4,4 ’ -hydroxy-3,3'-tetrametyldifenyl-sulfid. Dette patentskrift angiver ikke hydroxyforbindelsens fysiske konstanter.No. 3,979,460 as an undesirable by-product formed in a 12% yield during the synthesis of 4,4'-hydroxy-3,3'-tetramethyldiphenyl sulfide. This patent does not specify the physical constants of the hydroxy compound.
10 Det har nu vist sig, at 1-(2,6-dimetylfenoxy)-2- aminopropan kan fremstilles på let måde og i høje udbytter ved anvendelse af fremgangsmåden ifølge opfindelsen, der er ejendommelig ved, at man omsætter: 2,6-Dimetylfenol med propylenoxid i et alkalisk 15 medium, hvorpå man acylerer den resulterende forbindelse med den i krav 1 viste almene formel I, hvor A er hydroxy, hvorpå man omsætter den resulterende forbindelse med den almene formel I, hvor A er en acyloxygruppe, alkyl-sulfonyloxygruppe eller arylsulfonyloxygruppe, med et al-20 kalimetalazid i nærværelse af vand og et vandopløseligt organisk opløsningsmiddel, hvorpå man reducerer den vundne forbindelse med den almene formel I, hvor A er azido, og om ønsket omdanner den opnåede 1-(2,6-dimetylfenoxy)-2-aminopropan til syreadditionssalte deraf.It has now been found that 1- (2,6-dimethylphenoxy) -2-aminopropane can be readily prepared and in high yields using the process of the invention which is characterized by reacting: 2.6- Dimethylphenol with propylene oxide in an alkaline medium to acylate the resultant compound of the general formula I as claimed in claim 1, wherein A is hydroxy and then react the resulting compound of the general formula I where A is an acyloxy group, alkyl sulfonyloxy group or arylsulfonyloxy group, with an alkali metal azide in the presence of water and a water-soluble organic solvent, reducing the obtained compound of the general formula I where A is azido and, if desired, converting the obtained 1- (2.6- dimethylphenoxy) -2-aminopropane to its acid addition salts.
25 Forbindelserne hvor A er en acyloxygruppe, alkyl- sulfonyloxygruppe, arylsulfonyloxygruppe eller en azido-gruppe er hidtil ukendte forbindelser, mens forbindelsen hvor A er en hydroxygruppe er kendt fra litteraturen.The compounds where A is an acyloxy group, alkylsulfonyloxy group, arylsulfonyloxy group or an azido group are novel compounds, while the compound where A is a hydroxy group is known from the literature.
Det er ved forsøg vist at 1-(2,6-dimetylfenoxy)-2-30 hydroxypropan kan fremstilles på let måde og med et godt udbytte ved at sætte en overskydende mængde af propylenoxyd og et vandopløseligt organisk opløsningsmiddel til en vandig alkalisk opløsning af 2,6-dimetylfenol og omrøring af den resulterende blanding under opvarmning. Det foretrækkes at anvende 35 natriumhydroxyd eller kaliumhydroxyd som det alkaliske middel, da disse danner opløselige fenolater med udgangsforbindelsen. Der anvendes almindeligvis 1,05 til 10 mol, fortrinsvis 1,2 mol, af alkali til et mol 2,6-dimetylfenol. Som vandopløseligt organisk opløsningsmiddel kan der anvendes et lavere al- 6 DK 166820 B1 kohol eller keton, acetonitril, tetrahydrofuran eller dioxan, fortrinsvis ætanol eller acetone. Reaktionen kan gennemføres ved temperaturer fra 20°C til reaktionsblandingens kogepunkt, fortrinsvis ved 50 til 60°C. Om ønsket kan den rå l-(2,6-di-5 metylfenoxy)-2-hydroxypropan, der vindes efter behandling af reaktionsblandingen, anvendes direkte til fremstilling af de forbindelser med den almene formel I, hvor A er en acyloxy-gruppe, alkylsulfonyloxygruppe eller arylsulfonyloxygruppe.It has been shown by experiment that 1- (2,6-dimethylphenoxy) -2-30 hydroxypropane can be readily prepared and in good yield by adding an excess amount of propylene oxide and a water-soluble organic solvent to an aqueous alkaline solution of 2 , 6-dimethylphenol and stirring the resulting mixture with heating. It is preferred to use 35 sodium hydroxide or potassium hydroxide as the alkaline agent as these form soluble phenolates with the starting compound. Generally, 1.05 to 10 moles, preferably 1.2 moles, of alkali to a mole of 2,6-dimethylphenol are used. As a water-soluble organic solvent, a lower alcohol or ketone, acetonitrile, tetrahydrofuran or dioxane, preferably ethanol or acetone, may be used. The reaction can be carried out at temperatures from 20 ° C to the boiling point of the reaction mixture, preferably at 50 to 60 ° C. If desired, the crude 1- (2,6-dimethylphenoxy) -2-hydroxypropane obtained after treatment of the reaction mixture can be used directly to prepare the compounds of general formula I wherein A is an acyloxy group, alkylsulfonyloxy group or arylsulfonyloxy group.
Betegnelserne "acyloxy", "alkylsulfonyloxy" og "aryl-10 sulfonyloxy" anvendes i nærværende beskrivelse og i kravene i den bredeste betydning, dvs. de omfatter alle grupper afledt ved at substrahere hydrogen fra en karboxylsyre, alkylsulfon-syre og arylsulfonsyre. Kulbrintedelene i disse grupper kan være substitueret med en eller flere grupper, såsom halogen-15 atomer, alkylgrupper osv.The terms "acyloxy", "alkylsulfonyloxy" and "aryl-sulfonyloxy" are used herein and in the broadest sense, i.e. they include all groups derived by subtracting hydrogen from a carboxylic acid, alkylsulfonic acid and arylsulfonic acid. The hydrocarbon moieties in these groups may be substituted by one or more groups such as halogen atoms, alkyl groups, etc.
1-(2,6-Dimetylfenoxy)-2-hydroxypropan kan omdannes til de respektive acyloxy-, alkylsulfonyloxy- eller arylsulfon-yloxyderivater ved konventionelle acyleringsmetoder (se Houben-Weyl: Methoden der organischen Chemie, Georg Thieme Verlag, 201952, bind 8, side 543).1- (2,6-Dimethylphenoxy) -2-hydroxypropane can be converted to the respective acyloxy, alkylsulfonyloxy or arylsulfonylloxy derivatives by conventional acylation methods (see Houben-Weyl: The Method of Organic Chemistry, Georg Thieme Verlag, 201952, vol. 8, page 543).
Acylering gennemføres fortrinsvis i pyridin eller i en blanding af diklorætan og triætylamin ved en temperatur under 10°C. De acylerede forbindelser dannes i en meget ren tilstand med fremragende udbytter (over 98%). Om ønsket kan acyl-25 derivaterne anvendes direkte til· fremstillingen af 1-(2,6-dimetylfenoxy)-2-azidopropan (formel I, A = azido).Acylation is preferably carried out in pyridine or in a mixture of dichloroethane and triethylamine at a temperature below 10 ° C. The acylated compounds are formed in a very pure state with excellent yields (over 98%). If desired, the acyl derivatives can be used directly for the preparation of 1- (2,6-dimethylphenoxy) -2-azidopropane (Formula I, A = azido).
Azidoforbindelsen fremstilles ved at omsætte en forbindelse med den almene formel I, hvor A er en acyloxygruppe, alkylsulfonyloxygruppe eller arylsulf onyloxygruppe, med et alkalime-30talazid, fortrinsvis natriumazid, i nærværelse af vand og et vandopløseligt organisk opløsningsmiddel, fortrinsvis ætylen-glykolmonometylæter eller ætylenglykolmonoætylæter. Det resulterende 1-(2,6-dimetylfenoxy)-2-azidopropan er overraskende stabilt (det kan destilleres og sønderdeler ikke selv ved op-35 varmning til 200°C) og dannes med gode udbytter (83 til 89%).The azido compound is prepared by reacting a compound of the general formula I wherein A is an acyloxy group, alkylsulfonyloxy group or arylsulfon onyloxy group, with an alkali metal azide, preferably sodium azide, in the presence of water and a water-soluble etheryl ethanol ethanol etheric acid, ethyl acid ethanol, ethylene ethanol etheryl ether, preferably The resulting 1- (2,6-dimethylphenoxy) -2-azidopropane is surprisingly stable (it can be distilled and does not decompose even when heated to 200 ° C) and is formed in good yields (83 to 89%).
Om ønsket kan denne forbindelse anvendes direkte uden yderligere rensning til fremstilling af det respektive aminoderivat.If desired, this compound can be used directly without further purification to prepare the respective amino derivative.
DK 166820 B1 7DK 166820 B1 7
Aminoforbindelsen, dvs. 1-(2,6-dimetylfenoxy)-2-amino-propan, fremstilles ved at reducere det respektive azidederi-vat på i og for sig kendt måde (se Houben-Weyl:Methoden der organischen Chemie, Georg Thieme Verlag, 1957, bind 11/1, side 5 262, 539 og 1002). Reduktion gennemføres fortrinsvis ved katalytisk hydrogenering.The amino compound, i.e. 1- (2,6-Dimethylphenoxy) -2-amino-propane is prepared by reducing the respective azide derivative in a manner known per se (see Houben-Weyl: The Method of Organic Chemistry, Georg Thieme Verlag, 1957, Vol. 11/1, pages 5,262, 539 and 1002). Reduction is preferably carried out by catalytic hydrogenation.
Ved den sidstnævnte reaktion vindes 1-(2,6-dimetylfenoxy) -2-aminopropan-base som det eneste produkt fri for biprodukter i et næsten kvantitativt udbytte. Reaktionen kan o-10 vervåges på let måde ved tyndtlagskromatografi. Reaktionen er let at gennemføre og kræver ikke noget specifikt udstyr.In the latter reaction, 1- (2,6-dimethylphenoxy) -2-aminopropane base is recovered as the only by-product free in an almost quantitative yield. The reaction can be easily monitored by thin layer chromatography. The reaction is easy to carry out and requires no specific equipment.
Den særlige fremgangsmåde ifølge opfindelsen giver følgende hovedfordele: 1) Alle udgangsforbindelserne er lette at fremstille og 15 håndtere og er ikke skadelige for helbredet.The particular process of the invention provides the following main advantages: 1) All the starting compounds are easy to prepare and handle and are not harmful to health.
2) Reaktionerne kan udføres på let måde uden anvendelse af specifikt udstyr og de forløber med fremragende udbytter.2) The reactions can be carried out easily without the use of specific equipment and they proceed with excellent yields.
3) Alle forbindelserne med den almene formel I er stabile forbindelser som er lette at håndtere og selv i rå tilstand 20 er de tilstrækkeligt rene til at underkaste dem yderligere omdannelser.3) All the compounds of general formula I are stable compounds which are easy to handle and even in the crude state 20 are sufficiently pure to subject them to further conversions.
4) Reduktionen af 1-(2,6-dimetylfenoxy)-2-azidopropan til den respektive amin kan gennemføres ved stuetemperatur under atmosfærisk tryk med et næsten kvantitativt udbytte og 25 der fremstilles en ren forbindelse.4) The reduction of 1- (2,6-dimethylphenoxy) -2-azidopropane to the respective amine can be carried out at room temperature under atmospheric pressure with an almost quantitative yield and a pure compound is prepared.
5) 1-(2,6-Dimetylfenoxy)-2-aminopropan kan på yderst let måde adskilles fra reaktionsblandingen.5) 1- (2,6-Dimethylphenoxy) -2-aminopropane can be readily separated from the reaction mixture.
Opfindelsen belyses nærmere ved hjælp af de følgende eksempler.The invention is further illustrated by the following examples.
3030
Eksempel 1 1-(2,6-Dimetylfenoxy)-2-hydroxypropan 12,2 g (0,1 mol) 2,6-dimetylfenol opløses i en opløs-35 ning af 4,2 g (0,105 mol) natriumhydroxyd i 20 ml vand. 25 ml ætanol og 8,7 g (0,15 mol) propylenoxyd sættes til opløsningen og blandingen omrøres ved 60°C i 12 timer. Blandingen køles, der tilsættes 200 ml benzen og 200 ml vand og den organi- 8 DK 166820 B1 ske fase skilles fra. Den vandige fase ekstraheres med 200 ml benzen. Benzenopløsningerne forenes, vaskes med 200 ml vand, tørres over natriumsulfat og inddampes til tørhed under vakuum (40 mm Hg) på et dampbad. Der vindes 14,6 g (81%) af :et 5 olieagtigt stof. Dette rå produkt kan anvendes direkte i acy-leringsreaktionerne der beskrives i eksemplerne 2 til 5. Den rå 1-(2,6-dimetylfenoxy)-2-hydroxypropan kan renses ved destillation, k.p.: 84°C/ Rf = 0,6 (kromatografi på "Merck" ^ sili- kagellag med en tykkelse på 0,1 til 0,3 mm i en blanding af ^ benzen og pyridin i forholdet 6:1, fremkaldelse med o-tolui-din efter klorering, se også Z. Anal. Chem. 148, 181 (1955)) Beregnet for “ 180,24): C 73,30 H 8,95Example 1 1- (2,6-Dimethylphenoxy) -2-hydroxypropane 12.2 g (0.1 mole) of 2,6-dimethylphenol are dissolved in a solution of 4.2 g (0.105 mole) of sodium hydroxide in 20 ml water. 25 ml of ethanol and 8.7 g (0.15 mol) of propylene oxide are added to the solution and the mixture is stirred at 60 ° C for 12 hours. Cool the mixture, add 200 ml of benzene and 200 ml of water and separate the organic phase. The aqueous phase is extracted with 200 ml of benzene. The benzene solutions are combined, washed with 200 ml of water, dried over sodium sulfate and evaporated to dryness under vacuum (40 mm Hg) on a steam bath. 14.6 g (81%) is obtained from: a 5 oily substance. This crude product can be used directly in the acylation reactions described in Examples 2 to 5. The crude 1- (2,6-dimethylphenoxy) -2-hydroxypropane can be purified by distillation, bp: 84 ° C / Rf = 0.6 ( chromatography on "Merck" silica gel layer 0.1 to 0.3 mm thick in a 6: 1 benzene-pyridine mixture, developing with o-toluidine after chlorination, see also Z. Anal Chem. 148, 181 (1955) Calculated for "180.24": C 73.30 H 8.95
Fundet: C 73,60 H 9,07%.Found: C, 73.60; H, 9.07%.
^ Eksempel 2 1-(2,6-Dimetylfenoxy)-2-(4-metylfenylsulfonyloxy)-propan 9,0 g (0,05 mol) rå 1-(2,6-dimetylfenoxy)-2-hydroxy-propan, vundet som beskrevet i eksempel 1, opløses i 50 ml 20 tør pyridin og der sættes 19,0 g (0,1 mol) tosylklorid til opløsningen i små portioner under køling med is. Under tilsætningen skal blandingens temperatur holdes under 10°C. Når tilsætningen er tilendebragt fjernes kølebadet og blandingen får lov til at varme til 20-25°C og omrøres i 1 time ved denne 25 temperatur. Ved reaktionens slutning udhældes blandingen i 100 g knust is og produktet ekstraheres med 200 ml benzen. Benzenopløsningen vaskes med vand, tørres over natriumsulfat, og inddampes til tørhed under vakuum. Den vundne krystallinske remanens omkrystalliseres fra 20 ml isopropanol hvorved der 30 vindes 16,5 g (98,7%) 1-(2,6-dimetylfenoxy)-2-(4-metylfenyl-sulf ony loxy)-propan med smp. 63-64°C. Det rå produkt, der smelter ved 59-61°C, kan anvendes direkte i den reaktion der er beskrevet i eksempel 6.Example 2 1- (2,6-Dimethylphenoxy) -2- (4-methylphenylsulfonyloxy) propane 9.0 g (0.05 mol) of crude 1- (2,6-dimethylphenoxy) -2-hydroxy-propane, obtained as described in Example 1, dissolve in 50 ml of dry pyridine and add 19.0 g (0.1 mole) of tosyl chloride to the solution in small portions while cooling with ice. During the addition, the temperature of the mixture must be kept below 10 ° C. When the addition is complete, the cooling bath is removed and the mixture is allowed to warm to 20-25 ° C and stirred for 1 hour at this temperature. At the end of the reaction, the mixture is poured into 100 g of crushed ice and the product is extracted with 200 ml of benzene. The benzene solution is washed with water, dried over sodium sulfate and evaporated to dryness under vacuum. The crystalline residue obtained is recrystallized from 20 ml of isopropanol to give 16.5 g (98.7%) of 1- (2,6-dimethylphenoxy) -2- (4-methylphenylsulfonyloxy) -propane with m.p. 63-64 ° C. The crude product melting at 59-61 ° C can be used directly in the reaction described in Example 6.
Rf = 0,8 (kromatografi på "Merck" ® silikagellag med 35 en tykkelse på 0,1-0,3 mm i en blanding af benzen og pyridin i forholdet 6:1, fremkaldelse med o-toluidin efter klorering). Beregnet for ci8H22S04 = 334,42): C 64,64 H 6,63 S 9,59 Fundet: C 64,84 H 6,86 S 9,86%.Rf = 0.8 (chromatography on "Merck" ® silica gel layer having a thickness of 0.1-0.3 mm in a mixture of benzene and pyridine in 6: 1 ratio, developing with o-toluidine after chlorination). Calc'd for C18 H22 SO4 = 334.42): C 64.64 H 6.63 S 9.59 Found: C 64.84 H 6.86 S 9.86%.
DK 166820 Bl 9DK 166820 Pg 9
Eksempel 3 1-(2,6-Dimetylfenoxy)-2-metansulfonyloxypropanExample 3 1- (2,6-Dimethylphenoxy) -2-methanesulfonyloxypropane
Man går frem på samme måde som beskrevet i eksempel 2 med den forskel at der dryppes 11,4 g (0,1 mol) mesylklorid ind 5 i pyridinopløsningen af l-(2,6-dimetylfenoxy)-2-hydroxypropan. Reaktionsblandingen behandles på samme måde som beskrevet i eksempel 2 hvorved der vindes 12,8 g (99,1%) 1-(2,6-dimetyl-fenoxy)-2-metansulfonyloxypropan som et honninglignende viskost stof. Dette rå produkt kan anvendes direkte i den reak-tion der er beskrevet i eksempel 7.Proceed in the same manner as described in Example 2 with the difference that 11.4 g (0.1 mole) of mesyl chloride is dropped into the pyridine solution of 1- (2,6-dimethylphenoxy) -2-hydroxypropane. The reaction mixture is treated in the same manner as described in Example 2 to give 12.8 g (99.1%) of 1- (2,6-dimethyl-phenoxy) -2-methanesulfonyloxypropane as a honey-like viscous substance. This crude product can be used directly in the reaction described in Example 7.
Rf = 0,8 (kromatografi på "Merck" ® silikagellag med en tykkelse på 0,1-0,3 mm i en blanding af benzen og pyridin i forholdet 6:1, fremkaldelse med o-toluidin efter klorering).Rf = 0.8 (chromatography on "Merck" ® silica gel layer having a thickness of 0.1-0.3 mm in a mixture of benzene and pyridine in a 6: 1 ratio, developing with o-toluidine after chlorination).
Beregnet for ci2Hl8°4S = 258,33): 15 C 55,78 H 7,02 S 12,41 Fundet: C 56,20 H 7,52 S 12,14%.Calcd for C 21 H 18 ° 4 S = 258.33): 15 C 55.78 H 7.02 S 12.41 Found: C 56.20 H 7.52 S 12.14%.
Eksempel 4 20 1-(2,6-Dimetylfenoxy)-2-trikloracetyloxypropanExample 4 1- (2,6-Dimethylphenoxy) -2-trichloroacetyloxypropane
Man går frem som beskrevet i eksempel 2 med den forskel at der dryppes 18,1 g (0,1 mol) trikloracetylklorid i pyridinopløsningen af 1-(2,6-dimetylfenoxy)-2-hydroxypropan. Reaktionsblandingen behandles som beskrevet i eksempel 2 25 hvorved der vindes 16,1 g (98,9%) af den rå, olieagtige 1-(2,6-dimetylfenoxy)-2-trikloracetyloxypropan, der kan anvendes uden rensning i den fremgangsmåde der er beskrevet i eksempel 8. Produktet kan renses ved destillation, k.p. 146°C/ 0,4 mm Hg.Proceed as described in Example 2 except that 18.1 g (0.1 mole) of trichloroacetyl chloride is dropped into the pyridine solution of 1- (2,6-dimethylphenoxy) -2-hydroxypropane. The reaction mixture is treated as described in Example 2 to give 16.1 g (98.9%) of the crude oily 1- (2,6-dimethylphenoxy) -2-trichloroacetyloxypropane which can be used without purification in the process which is described in Example 8. The product can be purified by distillation, b.p. 146 ° C / 0.4 mm Hg.
50 Rf = 0,85 (kromatografi på "Merck" ® silikagellag med en tykkelse på 0,1-0,3 mm i en blanding af benzen og pyridin i forholdet 6:1, fremkaldelse méd o-toluidin efter klorering).50 Rf = 0.85 (chromatography on "Merck" ® silica gel layer, 0.1-0.3 mm thick in a mixture of benzene and pyridine in 6: 1 ratio, developing with o-toluidine after chlorination).
Beregnet for ci3Hi5C13°3 (molvægt = 325,62): 35 C 47,95 H 4,64 Cl 32,67Calcd for C ciH55Cl13 ° 3 (mol weight = 325.62): 35 C 47.95 H 4.64 Cl 32.67
Fundet: C 48,12 H 4,92 Cl 32,48%.Found: C 48.12 H 4.92 Cl 32.48%.
10 DK 166820 B110 DK 166820 B1
Eksentpel 5 1-(2,6-Dimetylfenoxy)-2-(4-metylfenylsulfonyloxy)-propan 11,1 g (0,11 mol) triætylamin sættes til en opløsning af 9,0 g (0,05 mol) rå 1-(2,6-dimetylfenyloxy)-2-hydroxy-5 propan, vundet som beskrevet i eksempel 1, i 100 ml tør diklor-ætan. Opløsningen omrøres under isafkøling og en opløsning af 19,0 g (0,1 mol) tosylklorid i 50 ml tør diklorætan tilsættes dråbevis. Når tilsætningen er tilendebragt fjernes kølebadet og reaktionsblandingen får lov til at varme op til 20-25°C 10 og omrøres i 1 time ved denne temperatur. Ved reaktionens slutning sønderdeles blandingen med 100 g knust is og faserne adskilles fra hinanden. Diklorætanlaget vaskes med vand, tørres over natriumsulfat og inddampes til tørhed under vakuum.Example 5 1- (2,6-Dimethylphenoxy) -2- (4-methylphenylsulfonyloxy) propane 11.1 g (0.11 mole) of triethylamine is added to a solution of 9.0 g (0.05 mole) of crude 1- (2,6-Dimethylphenyloxy) -2-hydroxy-propane, obtained as described in Example 1, in 100 ml of dry dichloroethane. The solution is stirred under ice-cooling and a solution of 19.0 g (0.1 mole) of tosyl chloride in 50 ml of dry dichloroethane is added dropwise. When the addition is complete, the cooling bath is removed and the reaction mixture is allowed to warm to 20-25 ° C and stirred for 1 hour at this temperature. At the end of the reaction, the mixture is decomposed with 100 g of crushed ice and the phases are separated. The dichloromethane layer is washed with water, dried over sodium sulfate and evaporated to dryness under vacuum.
Den krystallinske remanens omkrystalliseres som beskrevet i 15 eksempel 2 hvorved der vindes 16,55 g (98,9%) l-(2,6-dimetyl-fenoxy)-2-(4-metylfenylsulfonyloxy)-propan med smp. 58-61°C. Denne forbindelse er identisk med det produkt der vandtes ifølge eksempel 2 og den kan anvendes direkte i den reaktion der er beskrevet i eksempel 6.The crystalline residue is recrystallized as described in Example 2 to give 16.55 g (98.9%) of 1- (2,6-dimethyl-phenoxy) -2- (4-methylphenylsulfonyloxy) -propane with m.p. 58-61 ° C. This compound is identical to the product watered according to Example 2 and it can be used directly in the reaction described in Example 6.
2020
Eksempel 6 1-(2,6-Dimetylfenoxy)-2-azidopropan 8,36 g (0,025 mol) rå 1-(2,6-dimetylfenoxy)-2-(4-metylfenylsulfonyloxy ) -propan, fremstillet som beskrevet i eksempel 25 2 eller 5, opløses i 50 ml ætylenglykolmonometylæter. En opløsning af 3,25 g (0,05 mol) natriumazid i 15 ml vand tilsættes i en enkelt portion og den resulterende blanding koges under tilbagesvaling i 5 timer. Blandingen får lov til at køle, blandes med 100 ml vand og 100 ml kloroform og den organiske 30 fase skilles fra. Kloroformopløsningen vaskes med 200 ml vand, tørres over natriumsulfat og inddampes til tørhed under vakuum (40-60 mm Hg) over et dampbad. Der vindes 4,6 g (89,6%) rå l-(2,6-dimetylfenoxy)-2-azidopropan som kan anvendes direkte i den reaktion der er beskrevet i eksempel 9. Produktet kan 35 renses ved destillation, kp.: 106°C/0,7 mm Hg.Example 6 1- (2,6-Dimethylphenoxy) -2-azidopropane 8.36 g (0.025 mol) of crude 1- (2,6-dimethylphenoxy) -2- (4-methylphenylsulfonyloxy) propane, prepared as described in Example 25 2 or 5, dissolve in 50 ml of ethylene glycol monomethyl ether. A solution of 3.25 g (0.05 mole) of sodium azide in 15 ml of water is added in a single portion and the resulting mixture is refluxed for 5 hours. The mixture is allowed to cool, mixed with 100 ml of water and 100 ml of chloroform and the organic phase is separated. The chloroform solution is washed with 200 ml of water, dried over sodium sulfate and evaporated to dryness under vacuum (40-60 mm Hg) over a steam bath. 4.6 g (89.6%) of crude 1- (2,6-dimethylphenoxy) -2-azidopropane are obtained which can be used directly in the reaction described in Example 9. The product can be purified by distillation, bp: 106 ° C / 0.7 mm Hg.
= 0,75 (kromatografi på "Merck" ® silikagellag med en tykkelse på 0,1-0,3 mm i en blanding af benzen og pyridin 11 DK 166820 B1 i forholdet 6:1, fremkaldelse med o-toluidin efter klorering). Beregnet for cnHi5^3° (molvægt = 205,25): C 64,37 H 7,37 N 20,47 Fundet:C 64,65 H 7,48 N 20,30%.= 0.75 (chromatography on "Merck" ® silica gel layer with a thickness of 0.1-0.3 mm in a mixture of benzene and pyridine 6: 1 ratio: developing with o-toluidine after chlorination). Calcd for cnHi5 + 3 ° (mol weight = 205.25): C 64.37 H 7.37 N 20.47 Found: C 64.65 H 7.48 N 20.30%.
55
Eksempel 7 1-(2,6-Dimetylfenoxy)-2-azidopropanExample 7 1- (2,6-Dimethylphenoxy) -2-azidopropane
Man går frem som beskrevet i eksempel 6 med den forskel at 6,46 g (0,025 mol) rå 1-(2,6-dimetylfenoxy)-2-metansulfonyl-10 oxypropan, vundet som beskrevet i eksempel 3, anvendes som udgangsforbindelse i stedet for 1-(2,6-dimetylfenoxy)-2-(4-metylfenylsulfonyloxy)-propan. Reaktionsblandingen behandles som beskrevet i eksempel 6 hvorved der vindes 4, 3 g (83,8%) rå 1-(2,6-dimetylfenoxy)-2-azidopropan, der er identisk med 15 det produkt der vandtes ifølge eksempel 6.Proceed as described in Example 6 with the difference that 6.46 g (0.025 mol) of crude 1- (2,6-dimethylphenoxy) -2-methanesulfonyl-oxypropane, obtained as described in Example 3, is used as the starting compound instead. for 1- (2,6-dimethylphenoxy) -2- (4-methylphenylsulfonyloxy) propane. The reaction mixture is treated as described in Example 6 to give 4,3 g (83,8%) of crude 1- (2,6-dimethylphenoxy) -2-azidopropane identical to the product obtained in Example 6.
Eksempel 8 1-(2,6-Dimetylfenoxy)-2-azidopropanExample 8 1- (2,6-Dimethylphenoxy) -2-azidopropane
Man går frem som beskrevet i eksempel 6 med den for-20 skel at 8,14 g (0,025 mol) rå 1- (2,6-dimetylf enoxy )-2-triklor-acetyloxypropan, vundet som beskrevet i eksempel 4, anvendes som udgangsforbindelse i stedet for l-(2,6-dimetylfenoxy)-2-(4-metylfenylsulfonyloxy)-propan. Reaktionsblandingen behandles som beskrevet i eksempel 6 hvorved der vindes 4,5 g (87,7%) 25 rå 1-(2,6-dimetylfenoxy)-2-azidopropan, der er identisk med det produkt der vandtes ifølge eksempel 6.The procedure is as described in Example 6 with the difference that 8.14 g (0.025 mol) of crude 1- (2,6-dimethylphenoxy) -2-trichloroacetyloxypropane, obtained as described in Example 4, is used as starting compound instead of 1- (2,6-dimethylphenoxy) -2- (4-methylphenylsulfonyloxy) propane. The reaction mixture is treated as described in Example 6 to give 4.5 g (87.7%) of crude 1- (2,6-dimethylphenoxy) -2-azidopropane identical to the product obtained in Example 6.
Eksempel 9 1-(2,6-Dimetylfenoxy)-2-aminopropan-hydroklorid 30 1 g palladium-på-trækul-katalysator sættes til en opløs ning af 4,1 g (0,02 mol) rå 1-(2,6-dimetylfenoxy)-2-azidopropan, fremstillet ifølge et hvilket som helst af eksemplerne 6-8, i 100 ml ætanol. Hydrogen bobles langsomt og kontinuerligt gennem kolben og blandingen hydrogeneres under rystning 35 ved 20-25°C i 5 timer. Reaktionens fremadskriden overvåges ved kromatografering på "Merck" ®silikagellag med en tykkelseExample 9 1- (2,6-Dimethylphenoxy) -2-aminopropane hydrochloride 1 g of palladium-on-charcoal catalyst is added to a solution of 4.1 g (0.02 mol) of crude 1- (2.6 -dimethylphenoxy) -2-azidopropane, prepared according to any of Examples 6-8, in 100 ml of ethanol. Hydrogen is bubbled slowly and continuously through the flask and the mixture is hydrogenated under shaking 35 at 20-25 ° C for 5 hours. The progress of the reaction is monitored by chromatography on "Merck" ® silica gel layers with a thickness
Claims (5)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUGO001401 | 1978-04-28 | ||
| HU78GO1401A HU176102B (en) | 1978-04-28 | 1978-04-28 | Process for preparing phenylethers |
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| Publication Number | Publication Date |
|---|---|
| DK172679A DK172679A (en) | 1979-10-29 |
| DK166820B1 true DK166820B1 (en) | 1993-07-19 |
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| DK172679A DK166820B1 (en) | 1978-04-28 | 1979-04-26 | METHOD FOR PREPARING 1- (2,6-DIMETHYLPHENOXY) -2-AMINOPROPAN OR ANY ACID ADDITION SALT FROM 2,6-DIMETHYLPHENOL |
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| JP (1) | JPS5547641A (en) |
| AT (1) | AT365169B (en) |
| CA (1) | CA1132598A (en) |
| CS (1) | CS208498B2 (en) |
| DD (1) | DD143249A1 (en) |
| DE (1) | DE2917178A1 (en) |
| DK (1) | DK166820B1 (en) |
| ES (1) | ES479867A1 (en) |
| FI (1) | FI791340A (en) |
| HU (1) | HU176102B (en) |
| IL (1) | IL57080A (en) |
| IN (1) | IN150039B (en) |
| NO (1) | NO148450C (en) |
| PL (3) | PL215181A1 (en) |
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| JPS5932685A (en) * | 1982-08-16 | 1984-02-22 | Hitachi Constr Mach Co Ltd | Capacity controller for variable capacity pump |
| JPS60146713U (en) * | 1984-03-09 | 1985-09-28 | 株式会社 名機製作所 | Injection molding machine with hydraulic oil heating circuit |
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| DE1643240A1 (en) * | 1966-09-16 | 1971-06-24 | Boehringer Sohn Ingelheim | Process for the preparation of new racemic or optically active 1-phenoxy-2-aminoalkanes |
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1978
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1979
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- 1979-04-16 IN IN368/CAL/79A patent/IN150039B/en unknown
- 1979-04-24 ES ES479867A patent/ES479867A1/en not_active Expired
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- 1979-04-25 YU YU996/79A patent/YU41861B/en unknown
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- 1979-04-26 DK DK172679A patent/DK166820B1/en active IP Right Grant
- 1979-04-26 PL PL1979225751A patent/PL126968B1/en unknown
- 1979-04-26 SU SU792760454A patent/SU980614A3/en active
- 1979-04-26 AT AT0312379A patent/AT365169B/en not_active IP Right Cessation
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1980
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| IL57080A0 (en) | 1979-07-25 |
| SU978724A3 (en) | 1982-11-30 |
| NO148450C (en) | 1983-10-12 |
| HU176102B (en) | 1980-12-28 |
| NO148450B (en) | 1983-07-04 |
| CS208498B2 (en) | 1981-09-15 |
| IN150039B (en) | 1982-07-03 |
| CA1132598A (en) | 1982-09-28 |
| SU980616A3 (en) | 1982-12-07 |
| PL125109B1 (en) | 1983-03-31 |
| DE2917178A1 (en) | 1979-11-08 |
| SU980614A3 (en) | 1982-12-07 |
| YU41861B (en) | 1988-02-29 |
| JPS5547641A (en) | 1980-04-04 |
| IL57080A (en) | 1983-05-15 |
| FI791340A (en) | 1979-10-29 |
| ATA312379A (en) | 1981-05-15 |
| PL215181A1 (en) | 1980-01-28 |
| NO791412L (en) | 1979-10-30 |
| AT365169B (en) | 1981-12-28 |
| DD143249A1 (en) | 1980-08-13 |
| JPS6338979B2 (en) | 1988-08-03 |
| DE2917178C2 (en) | 1989-01-12 |
| YU99679A (en) | 1982-10-31 |
| DK172679A (en) | 1979-10-29 |
| ES479867A1 (en) | 1980-08-16 |
| PL126968B1 (en) | 1983-09-30 |
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