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NO752881L - - Google Patents

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Publication number
NO752881L
NO752881L NO752881A NO752881A NO752881L NO 752881 L NO752881 L NO 752881L NO 752881 A NO752881 A NO 752881A NO 752881 A NO752881 A NO 752881A NO 752881 L NO752881 L NO 752881L
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Norway
Prior art keywords
formula
carbon atoms
tert
compounds
group
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NO752881A
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Norwegian (no)
Inventor
F Troxler
E Wiskott
Original Assignee
Sandoz Ag
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Priority claimed from CH1169074A external-priority patent/CH597236A5/en
Priority claimed from CH443375A external-priority patent/CH611899A5/en
Application filed by Sandoz Ag filed Critical Sandoz Ag
Publication of NO752881L publication Critical patent/NO752881L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pyridine Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Fremgangsmåte for fremstilling av nye organiske forbindelser.Process for the preparation of new organic compounds.

Description

Foreliggende oppfinnelse vedrorer en fremgangsmåte for fremstilling av nye organiske forbindelser med formel I The present invention relates to a method for the production of new organic compounds with formula I

hvori in which

X står for et svovel- eller oksygenatom,X stands for a sulfur or oxygen atom,

R betyr alkyl med 3-7 karbonatomer eller cykloalkyl med 3-7 karbonatomer, med alkyl med 1-4 karbonatomer monosubstituert cykloalkyl med 3-7 karbonatomer, oc-dialkylpropynyl med 5-9 karbonatomer eller a-dialkylallyl med 5 - 9 karbonatomer, hydroksyalkyl med 2-7 karbonatomer eller fenoksyalkyl med 8 - R means alkyl with 3-7 carbon atoms or cycloalkyl with 3-7 carbon atoms, with alkyl with 1-4 carbon atoms monosubstituted cycloalkyl with 3-7 carbon atoms, oc-dialkylpropynyl with 5-9 carbon atoms or a-dialkylallyl with 5-9 carbon atoms, hydroxyalkyl with 2-7 carbon atoms or phenoxyalkyl with 8 -

.11 karbonatomer, idet i de to sistnevnte rester oksygenatomet.11 carbon atoms, with the oxygen atom remaining in the two latter

er adskilt fra det nitrogenatom hvortil R er bundet med minst to karbonatomer is separated from the nitrogen atom to which R is bonded by at least two carbon atoms

R^ står for hydrogen eller en i 2-, 3-, 6- eller 7-stillingen tilknyttet alkylrest med 1-4 karbonatomer, for i 2-, 3-,eller 7-stillingen tilknyttet klor eller brom, en i 2- eller 3-stillingen eller i 7-stillingen tilknyttet N02~eller NHA-rest, hvori A betyr formyl eller en alkanoylgruppe med 2 -j 4 karbonatomer, eller står for en i 2- eller 3-stillingen tilknyttet gruppe av rekken fluor, cyano eller GOOB, hvori B betyr alkyl med 1-4 karbonatomer, og 1*2 står for hydrogen eller en i 2-, 3-, 6- eller 7-stillingen tilknyttet alkylrest med 1-4 karbonatomer eller for en i 2-, ;3- eller 7-stillingen tilknyttet rest av rekken klor eller brom eller står for et i 2- eller 3-stillingen tilknyttet fluoratom, ;og deres syreaddisjonssalter.;X betyr foretrukket svovel.;R betyr spesielt den ovenfor definerte fenoksyalkyl-, cc-dialkylpropynyl- eller alkylgruppe; de to sistnevnte betydninger foretrekkes spesielt. ;Står R for den ovenfor definerte alkyl- eller hydroksyalkyl-rest;så er denne foretrukket forgrenet, spesielt i ct-stillingen til det nitrogenatom hvortil den er bundet. Spesielt foretrukkede alkylrester er isopropyl, tert.butyl, 3-pentyl og tert.pentyl. Foretrukkede hydroksyalkyl-rester er f.eks. a-dimetylhydroksyetyl-og a-dimetylhydroksypropylgruppen. ;Står R for den ovenfor definerte cykloalkylrest, betyr den;spesielt cyklopropyl, cyklopentyl eller cykloheksyl.;Står R for den ovenfor definerte med alkyl monosubstituerte cykloalkylgruppe, betyr dens alkylsubstituent spesielt metyl. ;En foretrukket alkylcykloalkylgruppe er 1-metylcykloheksyl.;Står R for det ovenfor definerte oc-dialkylpropylnyl eller a-dialkylallyl er de deri inneholdte alkylgrupper foretrukket identiske og betyr spesielt metyl. ;Står R for den ovenfor definerte fenoksyalkylrest betyr denne spesielt fenoksyetyl. ;R^står foretrukket for hydrogen, klor, brom, cyano og den;ovenfor definerte alkylgruppe; de to sistnevnte substituenter foretrekkes spesielt. ;1*2 står foretrukket for hydrogen eller den ovenfor definerte alkylgruppe. R^ stands for hydrogen or one in the 2-, 3-, 6- or 7-position associated alkyl residue with 1-4 carbon atoms, for in the 2-, 3-, or 7-position associated with chlorine or bromine, one in the 2- or The 3-position or in the 7-position associated with an N02~ or NHA residue, in which A means formyl or an alkanoyl group with 2-j 4 carbon atoms, or stands for a group in the 2- or 3-position associated with a group of the series fluorine, cyano or GOOB , in which B means alkyl with 1-4 carbon atoms, and 1*2 stands for hydrogen or one in the 2-, 3-, 6- or 7-position associated with an alkyl residue with 1-4 carbon atoms or for one in the 2-, ;3- or the 7-position attached to the rest of the chlorine or bromine series or represents a fluorine atom attached to the 2- or 3-position, ;and their acid addition salts.;X means preferably sulphur.;R means in particular the above-defined phenoxyalkyl-, cc-dialkylpropynyl- or alkyl group; the latter two meanings are particularly preferred. If R stands for the alkyl or hydroxyalkyl residue defined above, this is preferably branched, especially in the ct position of the nitrogen atom to which it is attached. Particularly preferred alkyl radicals are isopropyl, tert-butyl, 3-pentyl and tert-pentyl. Preferred hydroxyalkyl residues are e.g. the α-dimethylhydroxyethyl and α-dimethylhydroxypropyl group. ;If R stands for the above-defined cycloalkyl radical, it means;especially cyclopropyl, cyclopentyl or cyclohexyl.;If R stands for the above-defined alkyl monosubstituted cycloalkyl group, its alkyl substituent especially means methyl. ;A preferred alkylcycloalkyl group is 1-methylcyclohexyl.;If R stands for the above-defined α-dialkylpropylnyl or α-dialkylallyl, the alkyl groups contained therein are preferably identical and mean especially methyl. If R stands for the phenoxyalkyl residue defined above, this means in particular phenoxyethyl. R^ preferably stands for hydrogen, chlorine, bromine, cyano and the alkyl group defined above; the latter two substituents are particularly preferred. ;1*2 preferably stands for hydrogen or the alkyl group defined above.

Står og/eller R2for alkyl med 1-4 karbonatomer inneholder disse rester spesielt 1 eller 2, foretrukket 1 karbonatom. If and/or R2 stands for alkyl with 1-4 carbon atoms, these residues contain especially 1 or 2, preferably 1 carbon atom.

A står foretrukket for formyl eller acetyl.A preferably stands for formyl or acetyl.

B står foretrukket for metyl, etyl eller tert.butyl.B preferably stands for methyl, ethyl or tert.butyl.

R^står foretrukket.i 2- eller 3-stillingen, spesielt i 2-stillingen. R2står foretrukket i 7-stillingen. R is preferably in the 2- or 3-position, especially in the 2-position. R2 is preferred in the 7 position.

Det særegne ved fremgangsmåten i henhold til oppfinnelsenThe peculiarity of the method according to the invention

for fremstilling av de nye forbindelser med formel I er atfor the production of the new compounds of formula I is that

a) i forbindelser med formel IIa) in compounds of formula II

hvori X, R, R^og R2har den ovennevnte betydning og wherein X, R, R^ and R 2 have the above meaning and

står for en hydrolytisk avspaltbar rest, hydrolyseres oksasolidingruppen, eller stands for a hydrolytically cleavable residue, the oxazolidine group is hydrolysed, or

b) forbindel-ser med formel IIIb) compounds of formula III

hvori X, og R2har den ovennevnte betydning og V betyr en anionisk utbyttbar gruppe, substitueres i 4-stillingen ved omsetning med forbindelser med formel V wherein X, and R2 has the above meaning and V means an anionic exchangeable group, is substituted in the 4-position by reaction with compounds of formula V

hvori R har den ovennevnte betydning. wherein R has the above meaning.

Fremgangsmåten i henhold til oppfinnelsen kan gjennomfores analogt med kjente metoder. The method according to the invention can be carried out analogously to known methods.

Fremgangsmåten a) er en hydrolyse av et oksasolidin. Oksasolidiner hydrolyseres lett (se Chemical Reviews 53/T9537 315-317). I forbindelsene med formel II kan derfor Z og Z1 stå for resten av et vilkårlig alifatisk eller aromatisk aldehyd eller keton Method a) is a hydrolysis of an oxazolidine. Oxazolidines are readily hydrolyzed (see Chemical Reviews 53/T9537 315-317). In the compounds of formula II, Z and Z1 can therefore stand for the residue of any aliphatic or aromatic aldehyde or ketone

f.eks. propionaldehyd, benzaldehyd, acetaldehyd eller e.g. propionaldehyde, benzaldehyde, acetaldehyde or

aceton. Hydrolysen av forbindelsene med formel II gjennomfores hensiktsmessig under sure betingelser: som egnet syre velges foretrukket fortynnet syre, spesielt mineralsyre, f.eks. 0,5N til 3N saltsyre eller lN svovelsyre. Man arbeider i nærvær av vann. Anvendelsen av et med vann blandbart, organisk losningsmiddel, f.eks. et lavere alkanol som etanol er mulig men anbefales ikke. Reaksjonstemperaturen kan variere, f.eks. mellom 0 og ca. 80°C, acetone. The hydrolysis of the compounds of formula II is suitably carried out under acidic conditions: dilute acid, especially mineral acid, e.g. 0.5N to 3N hydrochloric acid or 1N sulfuric acid. One works in the presence of water. The use of a water-miscible organic solvent, e.g. a lower alkanol such as ethanol is possible but not recommended. The reaction temperature can vary, e.g. between 0 and approx. 80°C,

men man arbeider hensiktsmessig ved forhbyet temperatur, f .eks.but it is appropriate to work at a high temperature, e.g.

ved 60 til 80°CCat 60 to 80°C

Fremgangsmåten b) utgjor en substitusjonsreaksjon på en aromatisk| nitrogenholdig heterosyklisk ring som på et karbonatom i nabostilling til nitrogenet bærer en anionisk utbyttbar gruppe. W betyr foretrukket klor, brom eller lavere alkyltiogruppe som metyltio. Method b) constitutes a substitution reaction on an aromatic| nitrogen-containing heterocyclic ring which carries an anionic exchangeable group on a carbon atom adjacent to the nitrogen. W preferably means chlorine, bromine or a lower alkylthio group such as methylthio.

W betyr spesielt klor. Substitusjonen skjer lett, f.eks. ved henstand av en ldsning av en forbindelse med formel III og en forbindelse med formel V. Den gjennomfores i et under reaksjons-betingelsene inert organisk losningsmiddel, f.eks. en lavere alkanol som tert.butanol. Man arbeider med fordel i nærvær av en base, f.eks. et alkalimetallalkoholat som kaliumtert.butylat. W specifically means chlorine. The substitution happens easily, e.g. in the presence of a solution of a compound of formula III and a compound of formula V. It is passed through in an organic solvent inert under the reaction conditions, e.g. a lower alkanol such as tert.butanol. One works with advantage in the presence of a base, e.g. an alkali metal alcoholate such as potassium tert-butylate.

Reaksjonstemperaturen kan variere mellom omtrent 0 til 80°CThe reaction temperature can vary between about 0 to 80°C

men man arbeider hensiktsmessig ved romtemperatur. For påskyndelse av reaksjonen kan det foretas omrdring. but one works appropriately at room temperature. To speed up the reaction, reordering can be carried out.

Forbindelsene med formel I kan foreligge i fri form som baseThe compounds of formula I can be present in free form as a base

eller i form av addisjonssalter med syrer.or in the form of addition salts with acids.

Fra de fri baser lar seg på kjent måte fremstille syreaddisjonssalter, f.eks. hydrokloridet eller hydrogenmalonatet, og omvendt. From the free bases, acid addition salts can be prepared in a known manner, e.g. the hydrochloride or hydrogen malonate, and vice versa.

Karbonatomet i 2-stillingen av sidekjeden av forbindelsene med formel I er asymmetrisk og denne kan derfor opptre i form av de tilsvarende enantiomerer. The carbon atom in the 2-position of the side chain of the compounds of formula I is asymmetric and this can therefore appear in the form of the corresponding enantiomers.

Enantiomerene av forbindelsene med formel I kan erholdes på i og for seg kjent måte, f.eks. under utforelse av fremgangsmåten i henhold til oppfinnelsen under anvendelse av de tilsvarende enantiomerer av forbindelsene med formel II henhv. V, som kan erholdes ved å gå ut fra (R)-henhv. (S)-glyserolaldehyd. The enantiomers of the compounds of formula I can be obtained in a manner known per se, e.g. during execution of the method according to the invention using the corresponding enantiomers of the compounds of formula II or V, which can be obtained by proceeding from (R)-resp. (S)-glycerol aldehyde.

En del av forbindelsene med formel III er kjente (F. Eloy ogSome of the compounds with formula III are known (F. Eloy and

A. Deryckere, Heiv.Chim.Acta 53 /l9707£ 645-647; F. Eloy ogA. Deryckere, Heiv. Chim. Acta 53 /l9707£ 645-647; F. Eloy and

A. Deryckere,Bull.Soc.Chim.Belges 79 /I9707, 301-312 og 407-A. Deryckere, Bull.Soc.Chim.Belges 79 /I9707, 301-312 and 407-

414 og E.Bisagni et al. Bull.Soc.Chim. France /T9747, 515-518). 414 and E. Bisagni et al. Bull. Soc. Chim. France /T9747, 515-518).

Forbindelsene med formel IllaThe compounds with formula Illa

hvori X og R„ har den ovennevnte betydning, W<1>betyr klor eller brom og R1 står for hydrogen eller en i 2-, 3-, 6- eller 7-stillingen tilknyttet alkylgruppe med 1-4 karbonatomer, et i 2-,3- eller 7-stillingen tilknyttet klor7, eller bromatom, en i 7-stillingen tilknyttet nitrogruppe eller en i 2- eller 3-stillingen in which X and R„ have the above meaning, W<1>means chlorine or bromine and R1 stands for hydrogen or an alkyl group with 1-4 carbon atoms attached in the 2-, 3-, 6- or 7-position, an in 2- , the 3- or 7-position associated with chlorine7, or a bromine atom, one in the 7-position associated with a nitro group or one in the 2- or 3-position

tilknyttet gruppe av rekken fluor, cyano eller COOB, hvori B har den ovennevnte betydning, erholdes f.eks. ved behandling av forbindelsene med formel IV associated group of the series fluorine, cyano or COOB, in which B has the above-mentioned meaning, is obtained, e.g. when treating the compounds of formula IV

hvori X, og har den ovennevnte betydning, med fosforoksyklorid henhv. fosforoksybromid. in which X, and has the above meaning, with phosphorus oxychloride or phosphorus oxybromide.

Mononitrering av forbindelsene med formel Illa, hvori X, R9ogMononitration of the compounds of formula IIa, wherein X, R9 and

I I» I I»

W har den ovennevnte betydning og R^står for hydrogen, girW has the above meaning and R^ stands for hydrogen, giving

de tilsvarende 2- eller 3-nitroderivater. Stillingen av nitro-gruppen er ikke sikker men antas å være i 2-stillingen. the corresponding 2- or 3-nitro derivatives. The position of the nitro group is not certain but is believed to be in the 2-position.

En 2(3)- eller 7-nitrogruppe i forbindelsene med formel III kan omvandles i en NHA-gruppe, og en 4-klorsubstituent kan overfores i en alkyltiogruppe. A 2(3)- or 7-nitro group in the compounds of formula III can be converted into an NHA group, and a 4-chloro substituent can be transferred into an alkylthio group.

Forbindelsene med formelIVaThe compounds of formula IVa

hvori X har den ovennevnte betydning og R^1 og R^ betyr hydrogen, en i 2-, 3-, 6- eller 7-stillingen tilknyttet alkylgruppe med 1-4 karbonatomer eller eni:.2- eller 3-stillingen tilknyttet gruppe av rekken fluor, klor eller brom, kan erholdes ved kurtius-avbygning - over de in : situ dannede vinylisocyanater - av de in which X has the above-mentioned meaning and R^1 and R^ mean hydrogen, an alkyl group attached in the 2-, 3-, 6- or 7-position with 1-4 carbon atoms or in the 2- or 3-position attached group of series of fluorine, chlorine or bromine, can be obtained by Kurtius decomposition - over the in : situ formed vinyl isocyanates - of the

tilsvarende 2-tienyl henhv. 2-furylakrylsyreazider.corresponding to 2-thienyl or 2-Furyl acrylic acid azides.

Om bnsket kan deretter i forbindelsene med formelIVa ved klorering, bromering eller nitrering innfores en klor-, brom-eller nitro-substituent i 7-stillingen og/eller en i 2- eller 3-stillingen tilknyttet bromatom substitueres med en cyanogruppe og<idenne mulig forekommende cyanogruppe ytterligere ved alkoholyse omvandles i en COOB-gruppe, hvori B har den ovennevnte betydning. If desired, a chlorine, bromine or nitro substituent can then be introduced in the compounds of formula IVa by chlorination, bromination or nitration in the 7-position and/or a bromine atom associated in the 2- or 3-position can be substituted with a cyano group and this is possible occurring cyano group is further converted by alcoholysis into a COOB group, in which B has the above meaning.

Disse forholdsregler kan gjennomfores analogt med kjente metoder, de er beskrevet i litteraturen og delvis nærmere forklart i den eksperimentelle del. These precautions can be carried out analogously to known methods, they are described in the literature and partially explained in more detail in the experimental part.

I den utstrekning fremstillingen av utgangsproduktené ikke er beskrevet er disse kjente eller kan fremstilles analogt med kjente metoder henholdsvis analogt med de her beskrevede eller analogt med i og for seg kjente fremgangsmåter. To the extent that the production of the starting products is not described, these are known or can be produced analogously to known methods, respectively analogously to those described here or analogously to methods known in and of themselves.

Forbindelsene med formel I utmerker seg ved farmakologisk proving ved interessante virkninger og kan derfor anvendes som medisin. The compounds of formula I are characterized by interesting effects in pharmacological testing and can therefore be used as medicine.

Forbindelsene er kretslopregulerende, således fremviser de en blokkerende virkning på de adrenergiske (3-reseptorer. På grunn av denne virkning kan de nye forbindelser blant annet anvendes for profylakse og terapi av koronarsykdommer. The compounds are circulatory regulators, so they exhibit a blocking effect on the adrenergic (3) receptors. Due to this effect, the new compounds can be used, among other things, for the prophylaxis and therapy of coronary diseases.

Forbindelsene fremviser også en antiarrytmisk virkning. På grunn av denne virkning er forbindelsene også egnet for behandling av hjerterytmeforstyrrelser. The compounds also exhibit an antiarrhythmic effect. Because of this effect, the compounds are also suitable for the treatment of heart rhythm disorders.

Forbindelsene viser videre interessante stoffskiftevirkninger.The compounds also show interesting metabolic effects.

På grunn av disse metaboliske virkninger kan forbindelsene anvendes ved tilstander som forer til en ved cykisk stress ubnsket mobilisering av fri fettsyrer og glukose. Because of these metabolic effects, the compounds can be used in conditions which lead to an unwanted mobilization of free fatty acids and glucose due to cyclic stress.

For de ovennevnte anvendelser egner seg spesielt forbindelsene med formel iw hvori R<1>står for en i a-stillingen til det nitrogenatom hvortil R<1>er bundet, forgrenet alkylrest og R^betyr hydrogen eller en For the above-mentioned applications, the compounds of formula iw in which R<1> stands for a in the a-position of the nitrogen atom to which R<1> is bound, branched alkyl residue and R^ means hydrogen or a

i 2- eller 7-stillingen tilknyttet metylrest eller en i 2- eller 3-stillingen tilknyttet rest av rekken klor, brom eller cyano og R^ står for hydrogen eller en i 7-stillingen tilknyttet metylrest, og deres syreaddisjonssalter. in the 2- or 7-position associated with a methyl residue or one in the 2- or 3-position associated with a residue from the series chlorine, bromine or cyano and R^ stands for hydrogen or one in the 7-position associated with a methyl residue, and their acid addition salts.

(S)-enantiomeren av forbindelsene med formel I og deres syreaddisjonssalter er farmakologisk flere ganger så aktive som de tilsvarende (R)-enantiomerer. Dette gjelder spesielt for (S)-l-tert .butylamino-3- (2-metyltieno/3",2-c7pyridin-4-yloksy)-2-propanol og dens syreaddisjonssalter. The (S)-enantiomer of the compounds of formula I and their acid addition salts are pharmacologically several times as active as the corresponding (R)-enantiomers. This applies in particular to (S)-1-tert.butylamino-3-(2-methylthieno[3'',2-c7pyridin-4-yloxy)-2-propanol and its acid addition salts.

Forbindelsene med formel I kan anvendes i fri form eller i form av deres fysiologisk tålbare addisjonssalter med syrer. Disse medisiner, f.eks. i form av en lbsning eller tablett, kan fremstilles etter kjente metoder, under anvendelse av de vanlige hplpe- og bærerstoffer. The compounds of formula I can be used in free form or in the form of their physiologically tolerable addition salts with acids. These medicines, e.g. in the form of a solution or tablet, can be prepared according to known methods, using the usual hplpe and carrier substances.

I det etterfblgende eksempler er alle temperaturangivelser i °C og er ukorrigert. In the following examples, all temperature indications are in °C and are uncorrected.

Eksempel 1: 1-tert.butylamino-3- (2-metyl-4-tieno/3", 2-c7 Example 1: 1-tert.butylamino-3-(2-methyl-4-thieno/3", 2-c7

pyridinyloksy) - 2- propanol pyridinyloxy) - 2- propanol

(Fremgangsmåte a).(Procedure a).

2,0 g 4-(3-tert.butyl-2-fenyl-5-oksasolidinylmetbksy)-2-metyltieno /3,2-c7pyridin oppvarmes i 20 ml IN saltsyre i 1 time ved 70°C, 2.0 g of 4-(3-tert.butyl-2-phenyl-5-oxasolidinylmethyl)-2-methylthieno/3,2-c7pyridine is heated in 20 ml of 1N hydrochloric acid for 1 hour at 70°C,

ekstraheres med eter og den vandige fase innstilles alkalisk med fast kaliumkarbonat. Det ekstraheres med eter, eterlbsningen tbrres over magnesiumsulfat og inndampes. (Smeltepunkt av hydrogenmaleinatet 210 - 213°C). extracted with ether and the aqueous phase made alkaline with solid potassium carbonate. It is extracted with ether, the ether solution is passed over magnesium sulphate and evaporated. (Melting point of the hydrogen maleate 210 - 213°C).

Det som utgangsmaterial anvendte 4-(3-tert.butyl-2-fenyl-5-oksasolidinylmetoksy)-2-metyltieno/3/2-c7pyridin erholdes fra 2- formyl-5-metyltiofen på folgende måte: Den etter knoenenagei og doebner ved omsetning av 2-formyl-5-metyltiofen med malonsyre erholdte 3-(5-metyltieno-2-yl) akryl syre (smeltepunkt 163 til 165°C) overfores med tionylklorid i syre-kloridet og dette overfores ved omsetning med natriumazid i 3- (5-metyltieno-2-yl)akrylsyreazidet. Curtius-avbygning gir 4- hydroksy-2-metyltieno/3", 2-c7pyridin med smeltepunkt 214 til The 4-(3-tert.butyl-2-phenyl-5-oxasolidinylmethoxy)-2-methylthieno/3/2-c7pyridine used as starting material is obtained from 2-formyl-5-methylthiophene in the following way: reaction of 2-formyl-5-methylthiophene with malonic acid obtained 3-(5-methylthieno-2-yl) acrylic acid (melting point 163 to 165°C) is transferred with thionyl chloride into the acid chloride and this is transferred by reaction with sodium azide into 3- (5-methylthieno-2-yl)acrylic acid azide. Curtius decomposition gives 4-hydroxy-2-methylthieno/3", 2-c7pyridine with melting point 214 to

216°C (fra metylenklorid). Det sistnevnte gir ved omsetning med fosforoksyklorid 4-klor-2-metyltieno/3,2-c7pyridin med smeltepunkt 55 til 58°C. Etter omsetning av denne forbindelse med 3-tert.butyl-2-fenyl-5-hydroksymetyloksasolidin i nærvær av kalium-tert.butylat erholdes 4-(3-tert.butyl-2-fenyl-S^oksasolidinyl-metoksy)-2-metyltieno/3", 2-c7pyridin som en olje. 216°C (from methylene chloride). The latter yields on reaction with phosphorus oxychloride 4-chloro-2-methylthieno/3,2-c7pyridine with a melting point of 55 to 58°C. After reaction of this compound with 3-tert.butyl-2-phenyl-5-hydroxymethyloxazolidine in the presence of potassium tert.butylate, 4-(3-tert.butyl-2-phenyl-S^oxasolidinyl-methoxy)-2- methylthieno/3", 2-c7pyridine as an oil.

Eksempel 2: 1-tert.butylamino-3-(2-metyl-4-tieno/3,2-c7 Example 2: 1-tert.butylamino-3-(2-methyl-4-thieno/3,2-c7

pyridinyloksy) - 2- propanol ~ ~ pyridinyloxy) - 2- propanol ~ ~

(Fremgangsmåte b).(Procedure b).

0,49 g kalium loses i 60 ml varm tert.butanol. Etter avkjbling tilfbyes 1,5 g 1-tert.butyJ.amino-2, 3-dihydroksypropan og deretter 1,85 g 4-klor-2-metyltieno/3,2-c/pyridin. Etter 1 dags omrbring ved romtemperatur oppvarmes ytterligere i 1 dag ved 50°C. Reaksjonslbsningen inndampes under vakuum, resten opptas i lN saltsyre og eter, den vandige fase nbytraliseres med 2N soda-lbsning og ekstraheres med metylenklorid. Etter tbrting over magnesiumsulfat og inndamping erholdes den i overskriften nevnte forbindelse som en olje, som med maleinsyre i tetrahydrofuran gir hydrogenmaleinatet med smeltepunkt 210 til 213°C. 0.49 g of potassium is dissolved in 60 ml of hot tert.butanol. After cooling, 1.5 g of 1-tert.butylamino-2,3-dihydroxypropane and then 1.85 g of 4-chloro-2-methylthieno/3,2-c/pyridine are added. After 1 day's mixing at room temperature, it is further heated for 1 day at 50°C. The reaction solution is evaporated under vacuum, the residue is taken up in 1N hydrochloric acid and ether, the aqueous phase is neutralized with 2N soda solution and extracted with methylene chloride. After precipitation over magnesium sulfate and evaporation, the compound mentioned in the title is obtained as an oil, which with maleic acid in tetrahydrofuran gives the hydrogen maleate with a melting point of 210 to 213°C.

Analogt med eksemplene 1 og 2 under anvendelse av de tilsvarende Analogous to examples 1 and 2 using the corresponding

utgangsforbindelser med formel II, hvori starting compounds of formula II, wherein

står for (fremgangsmåten a)_7 eller formel III, hvori W står for klor /fremgangsmåten b)7 erholdes fblgende forbindelser med formel I: stands for (method a)_7 or formula III, in which W stands for chlorine /method b)7 the following compounds with formula I are obtained:

A) Det tilsvarende, som utgangsforbindelse med.formel IV A) The equivalent, as starting compound with formula IV

anvendte 4-hydroksy-2-karbonitril- henhv. 4-hydroksy-3-karbonitril-derivat kan fremstilles ved at 2-brom- henhv. '3-brom-4-hy drok sy-derivatet med formel IV oppvarmes med CuCN i dimetylformamid under tilbakelop, Ibsningen konsentreres under, vakuum, uthelles i en oppvarmet lbsning av kaliumcyanid in 1^0 og ekstraheres etter 1 time ved 50°C med metylenklorid. B) Den tilsvarende, som utgangsforbindelse med formel IV anvendte 4-hydroksy-2-karboksylsyreester henhv. 4-hydroksy-3-karboksylsyre-ester kan fremstilles ved koking av det tilsvarende 4-hydroksy-2-karbonitril henhv. 4-hydroksy-3-karbonitril-derivat med formel IV under tilbakelop i den tilsvarende alkanol og under innledning av HCl-gass. used 4-hydroxy-2-carbonitrile resp. 4-hydroxy-3-carbonitrile derivative can be prepared by 2-bromo- or The 3-bromo-4-hydroxy derivative of formula IV is heated with CuCN in dimethylformamide under reflux. methylene chloride. B) The corresponding 4-hydroxy-2-carboxylic acid ester used as starting compound with formula IV or 4-hydroxy-3-carboxylic acid ester can be prepared by boiling the corresponding 4-hydroxy-2-carbonitrile or 4-Hydroxy-3-carbonitrile derivative of formula IV under reflux in the corresponding alkanol and under introduction of HCl gas.

Eksempel 41: (S)-1-tert.butylamino-3-(2-metyl-tieno/3,2-c7 Example 41: (S)-1-tert-butylamino-3-(2-methyl-thieno/3,2-c7

pyridin- 4- yloksy)- 2- propanolpyridin-4-yloxy)-2-propanol

Det gås frem analogt med eksempel 1 ved å gå ut fra (S)-4-(3-tert. butyl-2-fenyl-5-oksasolidinylmétoksy)-2-metyltieno/3,2-c7pyridin (fremgangsmåte a) eller analogt med eksempel 2, ved å gå ut fra 4-klor-2-metyltieno/3,2-c7pyridin og KS)-1-tert.butyl-amino-2,3-dihydroksypropan (fremgangsmåte b) og den i overskriften nevnte forbindelse erholdes (smeltepunkt av hydrogenmaleinatet 166 - 167°c); / a/ ^<q>6=-12,2° (c = 1,94 i metanol). Proceed analogously to example 1 by starting from (S)-4-(3-tert.butyl-2-phenyl-5-oxasolidinylmethoxy)-2-methylthieno/3,2-c7pyridine (method a) or analogously to example 2, by starting from 4-chloro-2-methylthieno/3,2-c7pyridine and KS)-1-tert.butyl-amino-2,3-dihydroxypropane (method b) and the compound mentioned in the title is obtained ( melting point of the hydrogen maleate 166 - 167°c); / a/ ^<q>6=-12.2° (c = 1.94 in methanol).

Utgangsproduktene fremstilles på fblgende måte:The starting products are produced in the following way:

a) 30 g (R)-glyserolaldehyd, 36 ml tert.butylamin i 800 ml etanol hydrogeneres over 8 g 10% Pd/C i 4 timer med H^/ katalysatoren a) 30 g of (R)-glycerol aldehyde, 36 ml of tert.butylamine in 800 ml of ethanol are hydrogenated over 8 g of 10% Pd/C for 4 hours with the H^/ catalyst

frafiltreres og Ibsningen inndampes. Fra etylacetat/eter 2:1 erholdes (S)-1-tert.butylamino-2,3-dihydroksypropan i krystaller med smeltepunkt 76-8l°C./a? 2C»6 = -11/8<0>(c = 2/° 1 metanol). is filtered off and the Ibsningen is evaporated. From ethyl acetate/ether 2:1, (S)-1-tert.butylamino-2,3-dihydroxypropane is obtained in crystals with a melting point of 76-81°C./a? 2C»6 = -11/8<0>(c = 2/° 1 methanol).

b) 22 g (S)-1-tert.butylamino-2,3-dihydroksypropan, 20,7 g benzaldehyd og 46 ml benzen oppvarmes i 16 timer til tilbakelop b) 22 g (S)-1-tert.butylamino-2,3-dihydroxypropane, 20.7 g benzaldehyde and 46 ml benzene are heated for 16 hours to reflux

med vannutskiller. Benzen og benzaldehyd avdestilleres og resten destilleres under hbyvakuum. ;(S)-3-tert.butyl-5-hydroksymetyl-2-fenyloksasolidinet erholdes som en gulaktig olje (kokepunkt q01mm with water separator. Benzene and benzaldehyde are distilled off and the remainder is distilled under high vacuum. The (S)-3-tert.butyl-5-hydroxymethyl-2-phenyloxazolidine is obtained as a yellowish oil (boiling point q01mm

110-125°C); /|7 20 6 = -17,8° (c = 1,99 i kloroform). 110-125°C); /|7 20 6 = -17.8° (c = 1.99 in chloroform).

c) 3 g 4-klor-2-metyltieno/3,2-c7pyridin og 3,8 g (S)-3-tert.butyl-5-hydroksymetyl-2-fenyloksasolidin innfores i en losning av c) 3 g of 4-chloro-2-methylthieno/3,2-c7pyridine and 3.8 g of (S)-3-tert.butyl-5-hydroxymethyl-2-phenyloxazolidine are introduced into a solution of

0,64 g kalium i 100 ml tert.butylalkohol og oppvarmes under tilbakelop i 2 dogn. Lbsningen inndampes-på rotasjonsinndamper og det erholdte (S)-4-(3-tert.butyl-2-fenyl-5-oksasolidinylmetoksy-2-metyltieno/3,2-c7pyridin videreforarbeides direkte. 0.64 g potassium in 100 ml tert.butyl alcohol and heated under reflux for 2 days. The solvent is evaporated on a rotary evaporator and the obtained (S)-4-(3-tert.butyl-2-phenyl-5-oxasolidinylmethoxy-2-methylthieno/3,2-c7pyridine) is further processed directly.

Eksempel 42: (R) -1-tert .butylamino-3- (2r-metyltieno/3, 2-c7 Example 42: (R)-1-tert.butylamino-3-(2r-methylthieno[3,2-c7

pyridin- 4- yloksy)- 2- propanolpyridin-4-yloxy)-2-propanol

Det gås frem analogt med eksempel 1 ved å gå lit fra (R)-4-(3-tert.butyl-2-fenyl-5-oksasoli di nylmetoksy)-2-metyltieno/3,2-c7 pyridin (fremgangsmåte a) eller analogt med eksempel 2 ved å gå The procedure is analogous to example 1 by starting from (R)-4-(3-tert.butyl-2-phenyl-5-oxazoli di nylmethoxy)-2-methylthieno/3,2-c7 pyridine (method a) or analogously to example 2 by walking

ut fra 4-klor-2-metyltieno/3,2-c7pyridin og (R)-1-tert.butylamino-2,3-dihydroksypropan (fremgangsmåte b) og den i overskriften nevnte forbindelse erholdes (smeltepunkt av hydrogenmaleihatet 166-167°C); / aj \ qS +12,2° (c =2,09 i metanol). from 4-chloro-2-methylthieno/3,2-c7pyridine and (R)-1-tert.butylamino-2,3-dihydroxypropane (method b) and the compound mentioned in the title is obtained (melting point of the hydrogen maleate 166-167° C); / aj \ qS +12.2° (c =2.09 in methanol).

Utgangsproduktene erholdes som beskrevet i -eksempel 41 vedThe starting products are obtained as described in example 41 by

å ga ut fra (S)-glyserolaldehyd, idet folgende mellomprodukter isoleres: to start from (S)-glycerol aldehyde, the following intermediate products being isolated:

a) (R)-1-tert.butylamino-2,3-dihydroksypropan (smeltepunkt !76-81°C); / aj 20 6 = +14/°° (c = 2,02 i metanol). b) (R)-3-tertbutyl-5-hydroksymetyl-2-fenyloksasolidin (smeltepunkt 110-125°C);./ a7 20 6 = +17/°° (c = 2,0 i kloroform. c) (R) -4- (3-tert.butyl-2-fenyl-5-oksasolidinyl-metoksy)--2-metyltieno/3,2-c7pyridin (råprodukt). a) (R)-1-tert.butylamino-2,3-dihydroxypropane (melting point 176-81°C); / aj 20 6 = +14/°° (c = 2.02 in methanol). b) (R)-3-tertbutyl-5-hydroxymethyl-2-phenyloxasolidine (melting point 110-125°C);./ a7 20 6 = +17/°° (c = 2.0 in chloroform. c) (R ) -4-(3-tert.butyl-2-phenyl-5-oxasolidinyl-methoxy)-2-methylthieno/3,2-c7pyridine (crude product).

Claims (6)

1. Fremgangsmåte for fremstilling av nye organiske forbindelser med formel I1. Process for the production of new organic compounds of formula I hvori X står for et svovel- eller oksygenatom, R betyr alkyl med 3-7 karbonatomer eller cykloalkyl med 3-7 karbonatomer, med alkyl med 1-4 karbonatomer monosubstituert cykloalkyl med 3-7 karbonatomer, a-dialkylpropynyl med 5-9 karbonatomer eller a-dialkylallyl med 5-9 karbonatomer, hydroksyalkyl med 2-7 karbonatomer eller fenoksyalkyl med 8-11 karbonatomer, idet i de to sistnevnte rester oksygenatomet er skilt fra det nitrogenatom, hvortil R er bundet, med minst to karbonatomer, R1 står for hydrogen eller en i 2-,f 3-, 6- eller 7-stillingen tilknyttet alkylrest med 1-4 karbonatomer, for i 2-, 3- eller 7-stillingen tilknyttet klor eller brom, en i 2- eller 3-stillingen eller i 7-stillingen. tilknyttet N02 eller NHA-rest, hvori A betyr formyl eller en alkanoylgruppe med 2-4 karbonatomer, eller står for en i 2- eller 3-stillingen tilknyttet gruppe av rekken fluor, cyano eller COOB, hvori B betyr alkyl med 1-4 karbonatomer, og R2 står for hydrogen eller en i 2-, 3-, 6 eller 7-stillingen tilknyttet alkylrest med 1-4 karbonatomer eller står for en i 2-, 3- eller 7-stillingen tilknyttet rest av rekken klor eller brom eller står for et i 2- eller 3-stillingen tilknyttet fluoratom, og deres syreaddisjonssalter, karakterisert ved at a) i forbindelser med formel II in which X stands for a sulfur or oxygen atom, R means alkyl with 3-7 carbon atoms or cycloalkyl with 3-7 carbon atoms, with alkyl with 1-4 carbon atoms monosubstituted cycloalkyl with 3-7 carbon atoms, α-dialkylpropynyl with 5-9 carbon atoms or α-dialkylallyl with 5-9 carbon atoms, hydroxyalkyl with 2-7 carbon atoms or phenoxyalkyl with 8-11 carbon atoms, in that in the two latter residues the oxygen atom is separated from the nitrogen atom to which R is bound by at least two carbon atoms, R1 stands for hydrogen or an alkyl residue with 1-4 carbon atoms attached to the 2-, 3-, 3-, 6- or 7-position, for chlorine or bromine attached to the 2-, 3- or 7-position, an in the 2- or 3 - position or in the 7 position. attached to N02 or NHA residue, in which A means formyl or an alkanoyl group with 2-4 carbon atoms, or stands for a group in the 2- or 3-position attached to the series fluorine, cyano or COOB, in which B means alkyl with 1-4 carbon atoms , and R2 stands for hydrogen or an alkyl residue with 1-4 carbon atoms attached to the 2-, 3-, 6- or 7-position or stands for a residue from the series chlorine or bromine attached to the 2-, 3- or 7-position or stands for a in the 2- or 3-position associated with a fluorine atom, and their acid addition salts, characterized by that a) in compounds of formula II hvori X, R, R^ og R£ har den ovennevnte betydning og wherein X, R, R^ and R£ have the above meaning and står for en hydrolytisk avspaltbar rest, hydrolyseres oksasolidingruppen ellerb) forbindelser med formel III stands for a hydrolytically cleavable residue, the oxazolidine group is hydrolysed orb) compounds of formula III hvori X, R^ og R2 har den ovennevnte betydning og W betyr en anionisk utbyttbar gruppe, substitueres i 4-stillingen ved omsetning med forbindelser med formel V in which X, R 1 and R 2 have the above meaning and W means an anionically exchangeable group, is substituted in the 4-position by reaction with compounds of formula V hvori R har den ovennevnte betydning, og de således erholdte forbindelser med formel I utvinnes som base eller som syreaddisjonssalter. wherein R has the above meaning, and the thus obtained compounds of formula I are recovered as a base or as acid addition salts. 2. Fremgangsmåte som angitt i krav 1, for fremstilling av en tert. butylamino-3-(2-metyl-4-tieno/3,2-c7pyridinyloksy)-2-propanol, karakterisert ved ata) i en forbindelse med formel II, hvori X betyr svovel, R- betyr 2-metyl, R 2 betyr hydrogen, R betyr tert.butyl og 2. Method as stated in claim 1, for the production of a tart. butylamino-3-(2-methyl-4-thieno/3,2-c7pyridinyloxy)-2-propanol, characterized by ata) in a compound of formula II, in which X means sulphur, R- means 2-methyl, R 2 means hydrogen, R means tert-butyl and betyr en hydrolytisk avspaltbar rest, hydrolyseres oksasolidingruppen eller b) en forbindelse med formel III, hvori X betyr svovel, R^ betyr 2-metyl, R^ betyr hydrogen og W betyr en anionisk utbyttbar gruppe, substitueres i 4-stillingen ved omsetning med 1-tert.butyl-amino-2,3-dihydroksypropan. means a hydrolytically cleavable residue, the oxazolidine group is hydrolyzed or b) a compound of formula III, in which X means sulphur, R^ means 2-methyl, R^ means hydrogen and W means an anionically exchangeable group, is substituted in the 4-position by reaction with 1-tert-butyl-amino-2, 3-Dihydroxypropane. 3. Fremgangsmåtexisom angitt i krav 1, for fremstilling av 1-tert.butylamino-3- (2-cyano-4-tieno/3, 2-c7pyridinyloksy)-2-propanol, karakterisert ved at a) i en forbindelse med formel II, hvori X betyr svovel, R^ betyr 2-cyano, R 2 betyr hydrogen, R betyr tert.butyl og 3. Process as stated in claim 1, for the production of 1-tert.butylamino-3-(2-cyano-4-thieno/3,2-c7pyridinyloxy)-2-propanol, characterized in that a) in a compound of formula II, in which X means sulphur, R^ means 2-cyano, R 2 means hydrogen, R means tert-butyl and betyr en hydrolytisk avspaltbar rest, hydrolyseres oksasolidingruppen eller b) en forbindelse med formel III, hvori X betyr svovel, R^ betyr 2-cyano, R2 betyr hydrogen og W betyr en anionisk utbyttbar gruppe, substitueres i 4-stillingen ved omsetning med 1-tert.butyl-amino-2,3-dihydroksypropan. means a hydrolytically cleavable residue, the oxazolidine group is hydrolyzed or b) a compound of formula III, in which X means sulphur, R^ means 2-cyano, R 2 means hydrogen and W means an anionic exchangeable group, is substituted in the 4-position by reaction with 1-tert-butyl-amino-2,3 -dihydroxypropane. 4. Fremgangsmåte som angitt i krav 1, for fremstilling av 1-tert.butylamino-3- (2-brom-4-tieno</3, 2-c7pyridinyloksy) -2-propanol, karakterisert ved at a) i en forbindelse med formel II, hvori X betyr svovel, R. betyr 2-brom, R2 betyr hydrogen, R betyr tert.butyl og 4. Method as stated in claim 1, for the production of 1-tert.butylamino-3-(2-bromo-4-thieno</3,2-c7pyridinyloxy)-2-propanol, characterized in that a) in a compound of formula II, in which X represents sulfur, R. represents 2-bromo, R2 means hydrogen, R means tert.butyl and betyr en hydrolytisk avspaltbar rest, hydrolyseres oksasolidingruppen, eller b) en forbindelse med formel III, hvori X betyr svovel, R^ betyr 2-brom, betyr hydrogen og W betyr en anionisk utbyttbar gruppe, substitueres i 4-stillingen ved omsetning med 1 -tert-i-butylamino-2,3-dihydroksypropan, means a hydrolytically cleavable residue, the oxazolidine group is hydrolyzed, or b) a compound of formula III, in which X means sulphur, R^ means 2-bromo, means hydrogen and W means an anionically exchangeable group, is substituted in the 4-position by reaction with 1-tert-i-butylamino-2,3- dihydroxypropane, 5. Fremgangsmåte som angitt i krav 1, for fremstilling av (S)-enantiomerer av forbindelsene med formel I, hvori X, R, R^ og R2 har den i krav 1 angitte betydning, karakterisert ved at a) i (S)-enantiomerene av forbindelsene med formel II, hvori X, R, Rx,. R2 og 5. Process as stated in claim 1, for the production of (S)-enantiomers of the compounds of formula I, in which X, R, R^ and R2 have the meaning stated in claim 1, characterized in that a) in the (S)-enantiomers of the compounds of formula II, in which X, R, Rx, . R2 and har den i krav 1 angitte betydning, hydrolyseres oksasolidingruppen, eller b) forbindelser med formel III, hvori X, R^ , R2 og W har den i krav 1 angitte betydning, substitueres i 4-stillingen ved omsetning med (S)-enantiomerene av forbindelsene med formel V, hvori R har den i krav 1 angitte betydning. has the meaning stated in claim 1, the oxazolidine group is hydrolysed, or b) compounds of formula III, in which X, R , R 2 and W have the meaning stated in claim 1, are substituted in the 4-position by reaction with the (S)-enantiomers of the compounds of formula V, in which R has the meaning in claim 1 stated meaning. 6. Fremgangsmåte som angitt i krav 5, for fremstilling av (S)-1-tert.butylamino-3-(2-metyltieno/3,2-c7pyridin-4-yloksy)-2-propanol, karakterisert ved at a) i eh (S)-forbindelse med formel II, hvori X, R-, R?, R og 6. Process as stated in claim 5, for the production of (S)-1-tert.butylamino-3-(2-methylthieno/3,2-c7pyridin-4-yloxy)-2-propanol, characterized in that a) in eh (S) compound of formula II, in which X, R-, R?, R and har den i krav 2 angitte betydning, hydrolyseres oksasolidingruppen eller b) en forbindelse med formel III, hvori X, R^ , R2 og W har den i krav 2 angitte betydning, substitueres i 4-stillingen ved omsetning med .'{S) -1-tert. butyl amino-2, 3-dihydroksypropan.has the meaning stated in claim 2, the oxazolidine group is hydrolysed or b) a compound of formula III, in which X, R 1 , R 2 and W have the meaning specified in claim 2, is substituted in the 4-position by reaction with .'{S) -1-tert. butyl amino-2, 3-dihydroxypropane.
NO752881A 1974-08-27 1975-08-19 NO752881L (en)

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CH1169074A CH597236A5 (en) 1974-08-27 1974-08-27 1-Amino-3-(thieno (3,2-c)pyridine-4-yl-oxy)-2-propanols
CH443375A CH611899A5 (en) 1975-04-08 1975-04-08 Process for the preparation of novel thieno[3,2-c]pyridine derivatives

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