DK143898B - PROCEDURE FOR MANUFACTURING INDOLES - Google Patents

Description

(19) DANMARK ,¾(19) DENMARK, ¾

da» FREMLÆGGELSESSKRIFT od U3898Ben »PUBLICATION MANUAL OR U3898B

DIREKTORATET FOR PATENT- OG VAREMÆRKEVÆSENETDIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Ansøgning nr. 5964/70 (51) |nt.CI.3 C 07 D 209/04 (22) Indleveringsdag 24. nov. 1970 C07D491/056 (24) Løbedag 24. nov. 1970 (41) Aim. tilgængelig 25· maj 1971 (44) Fremlagt 26. okt. 1981 (86) International ansøgning nr.(21) Application No. 5964/70 (51) | nt.CI.3 C 07 D 209/04 (22) Filing date 24 Nov. 1970 C07D491 / 056 (24) Race day 24 Nov. 1970 (41) Aim. available May 25, 1971 (44) Posted Oct 26 1981 (86) International application no.

(86) International indleveringsdag (85) Videreførelsesdag -(62) Stamansøgning nr. -(86) International filing day (85) Continuation day - (62) Master application no. -

(30) Prioritet 24. nov. 1969, 879619, US(30) Priority 24 Nov. 1969, 879619, US

(71) Ansøger F. HOFFMANN-LA ROCHE & CC. AKTIENGESELLSCHAFT, CH-4002 Ba= s el, CH.(71) Applicant F. HOFFMANN-LA ROCHE & CC. SHARE COMPANY, CH-4002 Ba = s el, CH.

(72) Opfinder Andrew David Batcho, US: Willy Leimgruber, US.(72) Inventor Andrew David Batcho, US: Willy Leimgruber, US.

(74) Fuldmægtig Plougmann & Vlngtoft Patent bureau.(74) Plougmann & Vlngtoft's Patent Office.

(54) Fremgangsmåde til fremstilling af indoler.(54) Process for the preparation of indoles.

Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af indoler med den almene formel IThe present invention relates to a particular process for the preparation of indoles of general formula I

R1 ifnR1 ifn

Γ5 τ,Ζ HΓ5 τ, Ζ H

o Ro R

OISLAND

j- 12 _ hvor R og R hver for sig betegner hydrogen, C^_^-alkyl, aryl, hy= ^ droxy, Cj__7-alkoxy, aryl-C1_7-alkoxy, aryloxy, acyloxy, formyl, 3 2 143898 aroyl, hydroxymethyl, aryl-hydroxymethyl, carboxy, C^_^-alkoxy= carbonyl, carbamoyl, halogen, amino, mono-C^_^-alkylamino, di-C^_^- alkylamino, C^_ ^-alkoxycarbonylamino, aryl-C^_ ^-alkoxycarbonylamino, acylamino, N-C, 7-alkylacylamino, di-C, -.-alkylformamidino eller di-l ^ 2 ' C^_^-alkoxymethyl, eller R og R tilsammen betegner C2_^-alkylendioxy.j-12 wherein R and R are each independently hydrogen, C 1-6 alkyl, aryl, hydroxy, C 1-7 alkoxy, aryl C 1-7 alkoxy, aryloxy, acyloxy, formyl, aroyl, hydroxymethyl , aryl-hydroxymethyl, carboxy, C ^ _ ^ alkoxy = carbonyl, carbamoyl, halogen, amino, mono-C ^ _ ^ alkylamino, di-C ^ _ ^ alkylamino, C ^ _ ^alkoxycarbonylamino, aryl-C C 1-6 alkoxycarbonylamino, acylamino, NC, 7-alkylacylamino, di-C 1-6 alkylformamidino or di-1,2 C 1-6 alkoxymethyl, or R and R taken together represent C 2-6 alkylenedioxy.

Fremgangsmåden ifølge opfindelsen til fremstilling af indolerne den almene formel I er ejendommelig ved, at man kondenserer en o-nitro=The process according to the invention for the preparation of the indoles of general formula I is characterized by condensing an o-nitro =

toluen med den almene formel IIItoluene of the general formula III

111 R2 X *°2 1 2111 R2 X * ° 2 1 2

hvor R og R har de ovenfor anførte betydninger, med en formamid= acetal med den almene formel IVwherein R and R have the above meanings, with a formamide = acetal of the general formula IV

R50 R3R50 R3

^CH - R ^ IV^ CH - R ^ IV

E6(/ VE6 (/ V

3 4 hvor R oq R hver for sig betegner lavere alkyl eller tilsammen 5 63 4 where R and R each independently represent lower alkyl or together 5 6

lavere alkylen, og R og R hver for sig betegner lavere alkyl, aral= kyl eller cycloalkyl eller tilsammen lavere alkylen, og behandler den dannede o-nitro-Ø-aminostyren med den almene formel IIlower alkylene, and R and R each represent lower alkyl, aralkyl or cycloalkyl or together lower alkylene, and treat the o-nitro-O-amino-amino group formed of the general formula II

E1 /r5 h2'^5/X'H02 JL 2 3 4 hvor R , R , Γί og R har de ovenfor anførte betydninger, med et reduktionsmiddel.E1 / r5 h2 '^ 5 / X'H02 JL 2 3 4 wherein R, R, Γί and R have the above meanings, with a reducing agent.

3 143898 0- Nitro-P-aminostyrener med den almene formel II, hvori mindst én 'Z λ af substituenterne R og R er forskellig fra methyl, såfremt ét 1 2 af symbolerne R og R betyder hydrogen og det andet hydrogen eller methyl i 3-stilling, er hidtil ukendte forbindelser.O-Nitro-β-amino styrenes of the general formula II, wherein at least one 'Z λ of the substituents R and R is different from methyl if one of the symbols R and R represents hydrogen and the other hydrogen or methyl in 3 position, are novel compounds.

Udtrykkene "lavere alkyl" eller "C^-alkyl" skal her - for sig og i kombinationer - betegne ligekædede eller forgrenede carbonhydridgrupper med 1- 7 carbonatomer, f.eks. methyl, ethyl, propyl, isopropyl, butyl, tert.butyl, neopentyl, pentyl og heptyl. Udtrykket "C-^-alkoxy" skal her - for sig eller i kombinationer - betegne C1_7~alkyl= ethergrupper, hvor alkylgruppen har den ovenfor anførte betydning, og som eksempler på sådanne grupper kan nævnes methoxy, ethoxy, pro= poxy og pentoxy. Udtrykket "halogen" skal her omfatte alle fire halogener, dvs. brom, chlor, fluor og iod. Udtrykket "aryl" skal her betegne phenyl, som kan være usubstitueret eller substitueret én eller flere gange med halogen, trifluormethyl, c^-alkyl, C^_7~alkoxy, nitro, amino, C^__,-alkylamino eller di-C1_y-alkyl= amino. Udtrykket "aryloxy" skal her betegne arylethergrupper, i hvilke arylgruppen har den ovenfor anførte betydning, f.eks. phenoxy. Udtrykket "acyl" skal her betegne en alkanoylrest af en aliphatisk carboxylsyre med 1-7 carbonatomer, f.eks. formyl, acetyl eller propionyl, og en aroylrest af en aromatisk carboxyl= syre, f.eks. benzoyl. Udtrykket "acyloxy" betegner her en alkanoyloxyrest af en aliphatisk carboxylsyre med 1-7 carbonatomer, f.eks. formyloxy, acetoxy eller propionyloxy, og en aroyloxyrest af en aromatisk carboxylsyre, f.eks. benzoyloxy. Udtrykket "C2_5-alkylendioxy" betegner her en alkylendlether med 1-7 carbonatomer, f.eks. ethylendioxy eller propylendioxy. Udtrykket "lavere alkylen" betegner her en carbonhydrIdgruppe med 2-5 carbon= atomer, fortrinsvis 2-3 carbonatomer, f.eks. ethylen, propylen, butylen og pentylen. Udtrykket "aralkyl" betegner her en lavere al= kylgruppe, hvor ét eller flere hydrogenatomer er udskiftet med en arylgruppe, og som eksempel på en sådan gruppe kan nævnes benzyl. Udtrykket "cycloalkyl" betegner her en cyclisk carbonhydridgruppe med 3-6 carbonatomer.The terms " lower alkyl " or " C ' -alkyl " here refer - individually and in combinations - to straight or branched hydrocarbon groups of 1-7 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, neopentyl, pentyl and heptyl. The term "C 1-6 alkoxy" is intended herein to mean, individually or in combination, C 1-7 alkyl = ether groups, the alkyl group having the meaning given above, and examples of such groups being methoxy, ethoxy, propoxy and pentoxy. The term "halogen" here means all four halogens, ie. bromine, chlorine, fluorine and iodine. The term "aryl" as used herein refers to phenyl which may be unsubstituted or substituted one or more times by halogen, trifluoromethyl, C 1-4 alkyl, C 1-7 alkoxy, nitro, amino, C 1-6 alkylamino or di-C 1- alkyl = amino. The term "aryloxy" as used herein refers to aryl ether groups in which the aryl group has the meaning given above, e.g. phenoxy. The term "acyl" as used herein refers to an alkanoyl residue of an aliphatic carboxylic acid having 1-7 carbon atoms, e.g. formyl, acetyl or propionyl, and an aroyl residue of an aromatic carboxylic acid, e.g. benzoyl. The term "acyloxy" here refers to an alkanoyloxy residue of an aliphatic carboxylic acid having 1-7 carbon atoms, e.g. formyloxy, acetoxy or propionyloxy, and an aroyloxy residue of an aromatic carboxylic acid, e.g. benzoyloxy. The term "C2-5 alkylenedioxy" here refers to an alkylene ethers having 1-7 carbon atoms, e.g. ethylenedioxy or propylenedioxy. The term "lower alkylene" here refers to a hydrocarbon group having 2-5 carbon atoms, preferably 2-3 carbon atoms, e.g. ethylene, propylene, butylene and pentylene. The term "aralkyl" here refers to a lower alkyl group in which one or more hydrogen atoms are replaced by an aryl group, and as an example of such a group may be mentioned benzyl. The term "cycloalkyl" here refers to a cyclic hydrocarbon group of 3-6 carbon atoms.

Det skal bemærkes, at o-nitro-Ø-aminostyrenerne med den almene for= mel II foreligger i trans-konfiguration.It should be noted that the o-nitro-β amino styrenes of the general formula II are in trans configuration.

4 1438984 143898

Eksempler på aryl-0-^_η-alkoxygrupper er benzyloxy, 1-phenylethoxy, og 2-chlorbenzyloxy. Eksempler på aryl-hydroxymethylgrupper er phen= ylhydroxymetliyl og p-chlorphenylhydroxymethyl; eksempler på C.j_7-alkoxycarbonylgrupper er methoxycarbonyl og ethoxycarbonyl. Eksemp= ler på mono-C-j_7-alky laminogrupper er methylamino, ethylamino, propylamino, Isopropylamlno, butylamino og pentylamino. Eksempler på di-C^^-alky lamino grupper er dime thy lamino, diethylamino, ethyl= metb.ylami.no og dipropylamino; eksempler på c^_7~alkoxycarbony1= aminogrupper er methoxycarbonylamino og ethoxycarbonylamino. Eksemp= ler på aryl-C^_7~alkoxycarbonylaminogrupper er benzyloxycarbonyl= amino og p-cblorbenzyloxycarbonylamino; eksempler på acylaminogrup= per er formyl ami.no, acetylamino, propionylamino og benzoylamino. Eksempler på N-C^_7~alkylacylaminogrupper er N-methylacetylamino, F-methylformylamino og F-etby1acetylamino; eksempler på di-C1_7-a.1 kyl formamidinogrupper er dimethylformamidino og diethylformamidino.Examples of aryl-O- η-alkoxy groups are benzyloxy, 1-phenylethoxy, and 2-chlorobenzyloxy. Examples of aryl hydroxymethyl groups are phenylhydroxymethyl and p-chlorophenyl hydroxymethyl; Examples of C 1-7 alkoxycarbonyl groups are methoxycarbonyl and ethoxycarbonyl. Examples of mono-C 1-7 alkylamino groups are methylamino, ethylamino, propylamino, isopropylamino, butylamino and pentylamino. Examples of di-C 1-4 alkylamino groups are dime thy lamino, diethylamino, ethylmethylmethylamino and dipropylamino; Examples of C 1-7 alkoxycarbonyl = amino groups are methoxycarbonylamino and ethoxycarbonylamino. Examples of aryl-C 1-7 alkoxycarbonylamino groups are benzyloxycarbonyl = amino and p-cblorobenzyloxycarbonylamino; Examples of acylamino groups are formyl ami.no, acetylamino, propionylamino and benzoylamino. Examples of N-C 1-7 alkylacylamino groups are N-methylacetylamino, F-methylformylamino and F-etbylacetylamino; Examples of di-C 1-7 -alkyl formamidino groups are dimethylformamidino and diethylformamidino.

1 21 2

Fortrinsvis betyder R og E hver for sig hydrogen, c1_7-alkyl, hydroxy, C-^_7-alkoxy, aryl-C^_7~alkoxy, acyloxy, formyl, aroyl, halogen, amino eller acylamino eller tilsammen C_ ,--alkylendioxy, og fortrinsvis betyder R , R , E? og R° hver for sig C, 7-alkyl eller R5 og R^ eller Έ? og R° tilsammen lavere alkylen.Preferably, R and E each represent hydrogen, C 1-7 alkyl, hydroxy, C 1-7 alkoxy, aryl C 1-7 alkoxy, acyloxy, formyl, aroyl, halogen, amino or acylamino or together C 1-6 alkylenedioxy, and preferably R, R, E mean? and R ° are each C, 7-alkyl or R5 and R ^ or Έ? and R ° together lower alkylene.

Ifølge en særlig foretrukken udnyttelse af den foreliggende opfin= delse kondenseres o-nitrotoluen med F,F-dimethyIformamid-dime thy1= acetal under dannelse af 3-dimethylamino-2-nitrostyren, som ved re= duktion omdannes til den tilsvarende indol.According to a particularly preferred use of the present invention, o-nitrotoluene is condensed with F, F-dimethylformamide-dime thyl = acetal to give 3-dimethylamino-2-nitrostyrene, which is reduced by reduction to the corresponding indole.

Eet her omhandlede særlige fremgangsmådetrin består helt alment i, at methylgruppen i en o-nitrotoluen kondenseres med en formylgruppe i en formamidacetal, hvorved der dannes et nitrobenzenderivat, som har en F,F-disubstitueret aminovinylgruppe i o-stilling i forhold til nitrogruppen. Yed reduktion af denne nitrogruppe fås en aminogruppe, som under cyclisering fortrænger den F,F-disubstituerede aminogruppe til dannelse af et indolskelet.The particular process step in question here generally consists in condensing the methyl group in an o-nitrotoluene with a formyl group in a formamide acetal to form a nitrobenzene derivative having an F, F disubstituted aminovinyl group at the o-position relative to the nitro group. To reduce this nitro group, an amino group is obtained which, during cyclization, displaces the F, F-disubstituted amino group to form an indole skeleton.

Fra Liebigs Annalen der Chemie, bind 641 (1961), side 7, er det ganske vist kendt, at formamidoacetaler kan omsættes med 2,4-dinitrotoluen.It is known from Liebigs Annalen der Chemie, volume 641 (1961), page 7, that formamido acetals can be reacted with 2,4-dinitrotoluene.

Det var imidlertid fra Helv. Chim. Acta, 22, (1939), side 1471/72 kendt, at o-nitrotoluen er en yderst reaktionstræg forbindelse, og medens reaktionen med p-nitrotoluen som udgangsmateriale giver en styren, 5 143898 angives det her, at den analoge reaktion med o-nitrotoluen ikke er mulig. Som grund hertil angives, at der mangler den aktiverende nitro= gruppe i p-stilling i forhold til methylgruppen. Det var derfor fuld= stændig overraskende, at der ved det første trin i fremgangsmåden i= følge opfindelsen fås praktisk taget kvantitative udbytter.However, it was from Helv. Chim. Acta, 22, (1939), page 1471/72, is known to indicate that o-nitrotoluene is an extremely slow reaction compound, and while the reaction with p-nitrotoluene as a starting material gives a styrene, it is stated here that the analogous reaction with o nitrotoluene is not possible. For this reason, it is stated that the activating nitro = group is missing at the β position relative to the methyl group. It was therefore quite surprising that in the first step of the process according to the invention practically quantitative yields are obtained.

Endvidere er det fra Chem. Berichte, 101 (1968), side 4080 - 4051 kendt at omsætte o-nitrotoluen med aminalestere, idet det her angives, at aminalesteres reaktivitet over for methylenaktive forbindelser skulle være større end reaktiviteten af amidacetaler. Ved omsætningen af o-nitrotoluen med de i dette litteratursted anbefalede aminalestere op= nås kun ca. det halve udbytte som ved fremgangsmåden ifølge opfindelsen. Denne udbyttestigning kunne imidlertid ikke forudses.Furthermore, it is from Chem. Berichte, 101 (1968), pages 4080-4051, is known to react o -nitrotoluene with amine esters, stating here that the reactivity of amine esters to methylene active compounds should be greater than the reactivity of amide acetals. By reacting the o-nitrotoluene with the amine esters recommended in this literature, only approx. half the yield as in the process of the invention. However, this yield increase could not be predicted.

Tilsammen fører de to trin i fremgangsmåden ifølge opfindelsen således i kombination på overraskende måde til de ønskede indolderivater i højt udbytte.Together, the two steps of the process of the invention thus, in combination, surprisingly lead to the desired high yield indole derivatives.

Fremgangsmåden ifølge opfindelsen, som gør talrige forbindelser af kommerciel betydning tilgængelige, kompletterer teknikken med en fordelagtig fremstillingsmetode, der er særlig betydningsfuld af den grund, at den gør de pågældende forbindelser tilgængelige på en mere fordel= agtig måde, end det hidtil var muligt.The process of the invention, which makes numerous compounds of commercial importance available, complements the technique with an advantageous method of preparation which is particularly significant in that it makes the compounds in question more accessible in a more advantageous way than previously possible.

o-Nitrotoluenerne med den almene formel III er kendte forbindelser eller kan fremstilles efter i og for sig kendte metoder. Eksempler på sådanne forbindelser er 3-methyl-4-nitrobiphenyl, 2-methyl-3-ni= trobenzylalkohol, 4-methyl-3-nitrobenzoesyreamid, 4-methyl-3-nitro= benzophenon, 4-methyl-3-nitrobenzoesyremethylester, N,N-dimethyl-3= -nitro-p-toluidin, 4-methyl-3-nitrobenzoesyre, 4-methyl-3-nitroben= zophenon,. N-methyl-3-nitro-p-toluidin og 3-nitro-p-toluidin.The o-nitrotoluenes of general formula III are known compounds or can be prepared by methods known per se. Examples of such compounds are 3-methyl-4-nitrobiphenyl, 2-methyl-3-ni = trobenzyl alcohol, 4-methyl-3-nitrobenzoic acid amide, 4-methyl-3-nitro = benzophenone, 4-methyl-3-nitrobenzoic acid methyl ester, N , N-dimethyl-3 = -nitro-p-toluidine, 4-methyl-3-nitrobenzoic acid, 4-methyl-3-nitrobenz = zophenone,. N-methyl-3-nitro-p-toluidine and 3-nitro-p-toluidine.

Formamidacetalerne med den almene formel IV er ligeledes kendte for= bindeiser eller kan fremstilles efter i og for sig kendte metoder. Foretrukne eksempler på sådanne forbindelser er N,N-dimethylformamid= -diethylacetal, Ν,Ν-dimethylformamid-dimethylacetal, N-formylpyrroli= din-dimethylacetal, 2-dimethylamino-l,3-dioxolan, N-formyl-piperi= din-dimethylacetal, Ν,Ν-dimethylformamid-dibenzylacetal, N,N-dimethyl= formamid-dicyclohexylacetal, N,N-dimethylformamid-dineopentylaeetal, Ν,Ν-dimethylformamid-diisopropylacetal og N,N-dimethylformamid-di-n= -heptylacetal.The formamide acetals of the general formula IV are also known as binding compounds or can be prepared by methods known per se. Preferred examples of such compounds are N, N-dimethylformamide = -diethylacetal, Ν, Ν-dimethylformamide-dimethylacetal, N-formylpyrrolidine-dimethylacetal, 2-dimethylamino-1,3-dioxolane, N-formylpiperidine-dimethylacetal , Ν, Ν-dimethylformamide-dibenzyl acetal, N, N-dimethyl = formamide-dicyclohexyl acetal, N, N-dimethylformamide-dinopentylate metal, Ν, Ν-dimethylformamide-diisopropylacetal and N, N-dimethylformamide-di-n = -heptylacetal.

6 1438986 143898

Kondensationen af en o-nitrotoluen med den almene formel III med en formamidacetal med den almene formel IV kan udføres i nærværelse el= ler fraværelse af et inert organisk opløsningsmiddel. Det foretrækkes imidlertid at udføre kondensationen i nærværelse af et polært aprot opløsningsmiddel, f.eks. Ν,Κ-dimethylformamid (DM]?), diethylengly= col-dimethylether (diglyme) eller hexamethylphosphorsyretriamid (HMPT). Reaktionsbetingelserne for kondensationen kan variere inden for relativt vide grænser. Således kan kondensationen udføres ved en temperatur mellem stuetemperatur og reaktionsblandingens tilbage= svalingstemperatur. Reaktionen udføres fortrinsvis i et temperatur= område på 100 - 160°C, helst ved reaktionsblandingens tilbagesvalings= temperatur. Kondensationen kan udføres ved atmosfæretryk eller over= tryk, men udføres fortrinsvis ved atmosfæretryk.The condensation of an o-nitrotoluene of the general formula III with a formamide acetal of the general formula IV can be carried out in the presence or absence of an inert organic solvent. However, it is preferred to carry out the condensation in the presence of a polar aprotic solvent, e.g. Ν, Κ-dimethylformamide (DM]?), Diethylene glycol = dimethyl ether (diglyme) or hexamethylphosphoric triamide (HMPT). The reaction conditions for the condensation may vary within relatively wide limits. Thus, the condensation can be carried out at a temperature between room temperature and the reflux temperature of the reaction mixture. The reaction is preferably carried out at a temperature = range of 100 - 160 ° C, preferably at the reflux temperature of the reaction mixture. The condensation can be carried out at atmospheric or overpressure, but preferably is carried out at atmospheric pressure.

o-SFitro-P-aminostyrenerne med den almene formel II reduceres kemisk eller katalytisk under dannelse af de tilsvarende indoler med den almene formel I. Den katalytiske reduktion kan udføres på alle sæd= vanlige måder, men den udføres fortrinsvis ved en temperatur om= kring stuetemperatur og ved et hydrogentryk på fra ca. 1 til ca. 10 atmosfærer. Der kan anvendes en hvilken som helst sædvanlig hydro= generingskatalysator, f.eks. metallerne chrom, molybden, wolfram, platin, palladium, rhodium, cobalt, nikkel eller ruthenium, deres oxider og kombinationer deraf, f.eks. en blanding af oxiderne af cobalt og molybden, herunder cobaltmolybdat. Foretrukne hydrogene= ringskatalysatorer er palladium, Raney-nikkel eller andre metaller af platingruppen. Katalysatoren er hensigtsmæssigt anbragt på kul eller et lignende bæremateriale.The o-SFitro-β amino styrenes of general formula II are chemically or catalytically reduced to form the corresponding indoles of general formula I. The catalytic reduction can be carried out in any usual manner, but it is preferably carried out at a temperature about room temperature and at a hydrogen pressure of from approx. 1 to approx. 10 atmospheres. Any conventional hydrogenation catalyst, e.g. the metals chromium, molybdenum, tungsten, platinum, palladium, rhodium, cobalt, nickel or ruthenium, their oxides and combinations thereof, e.g. a mixture of the oxides of cobalt and molybdenum, including cobalt molybdate. Preferred hydrogenation catalysts are palladium, Raney nickel or other metals of the plate group. The catalyst is suitably placed on charcoal or a similar support material.

Det er fordelagtigt at anvende katalysatoren i nærværelse af et inert opløsningsmiddel. Eksempler på sådanne opløsningsmidler er alkano= ler såsom methanol og ethanol, carbonhydrider såsom benzen og toluen, ethylacetat og E,K-dimethylformamid. Det mest foretrukne opløsnings^ . middel er benzen.It is advantageous to use the catalyst in the presence of an inert solvent. Examples of such solvents are alkanols such as methanol and ethanol, hydrocarbons such as benzene and toluene, ethyl acetate and E, K-dimethylformamide. The most preferred solution. benzene.

Den kemiske reduktion kan udføres efter sædvanlige metoder, f.eks. med et metal såsom jern, zink eller tin, i en organisk eller uorganisk syre såsom eddikesyre eller saltsyre,med tin(II)-chlorid i saltsyre, jern(II)-sulfat, natriumdithionit eller natrium- eller ammoniumsulfid eller -hydrogensulfid. Reaktionsbetingelserne for den kemiske reduk= tion er ikke kritisk. Fortrinsvis udføres reduktionen i et tempera= turområde mellem stuetemperatur og reaktionsblandingens tilbagesva= 7 143898 lingstemperatur og i nærværelse af et med vand blandbart opløsnings= middel eller 1 nærværelse af vand. Eksempler på med vand blandbare opløsningsmidler er alkanoler, f.eks. methanol og ethanol, og tetra= hydrofuran.The chemical reduction can be carried out by conventional methods, e.g. with a metal such as iron, zinc or tin, in an organic or inorganic acid such as acetic or hydrochloric acid, with tin (II) chloride in hydrochloric acid, iron (II) sulfate, sodium dithionite or sodium or ammonium sulfide or hydrogen sulfide. The reaction conditions for the chemical reduction are not critical. Preferably, the reduction is carried out in a temperature range between room temperature and the reaction temperature of the reaction mixture and in the presence of a water-miscible solvent or in the presence of water. Examples of water-miscible solvents are alkanols, e.g. methanol and ethanol, and tetra = hydrofuran.

1 21 2

Selv om substltuenterne R og R almindeligvis selv ikke indgår i no= gen reaktion under kondensationen og den efterfølgende reduktion, kan dette dog ske i visse tilfælde. Således kan f.eks. under konden= sationen en carboxylgruppe omdannes til en estergruppe og en pheno= lisk hydroxylgruppe omdannes til en phenolisk ethergruppe. Også en dialkoxymethylgruppe kan alt efter reaktionsbetingelserne enten be= vares eller hydrolyseres. I nærværelse af en syre spaltes den, og såfremt der ikke er nogen syre til stede, bevares den.However, although substituents R and R are themselves not involved in any reaction during the condensation and subsequent reduction, however, this may occur in some cases. Thus, e.g. during the condensation, a carboxyl group is converted to an ester group and a phenolic hydroxyl group is converted to a phenolic ether group. Also, a dialkoxymethyl group may either be retained or hydrolyzed depending on the reaction conditions. In the presence of an acid, it is cleaved and, if no acid is present, it is preserved.

Når reaktionen er tilendebragt, kan slutprodukterne om ønsket isole= res efter kendte metoder, f.eks. ved krystallisation, destillation eller dampdestillation. De ved fremgangsmåden ifølge opfindelsen til= gængelige produkter, nemlig forbindelser med den almene formel X, er beskrevet i litteraturen og kan anvendes til forskellige formål, f.eks. som mellemprodukter til fremstilling af aminosyrer, alkaloider eller tryptaminer. Således kan f.eks. indol, 6-methoxyindol og 5-benzyloxyindol anvendes som mellemprodukter til fremstilling af tryptophan, reserpin eller serotonin.When the reaction is complete, the final products can be isolated if desired by known methods, e.g. by crystallization, distillation or steam distillation. The products available in the process according to the invention, namely compounds of the general formula X, are described in the literature and can be used for various purposes, e.g. as intermediates for the preparation of amino acids, alkaloids or tryptamines. Thus, e.g. indole, 6-methoxyindole and 5-benzyloxyindole are used as intermediates for the preparation of tryptophan, reserpine or serotonin.

Fremgangsmåden ifølge opfindelsen belyses nærmere ved følgende eksemp= ler, idet dog eksemplerne 23 - 30 omhandler fremstillingen af mellemprodukter af formlen II.The process of the invention is further illustrated by the following examples, but Examples 23-30 deal with the preparation of intermediates of formula II.

Eksempel 1.Example 1.

En blanding af 137 g o-ni tro toluen, 191 g Ν,Ν-dimethylf ormamiddiethyl= acetal og 235 ml Ν,Ν-dimethylformamid opvarmes under nitrogenatmos= fære i 24 timer til en indvendig temperatur på 145 - 150°C, idet det dannede ethanol afdestilleres kontinuerligt over en kolonne. Derefter afdestilleres de flygtige bestanddele ved reduceret tryk under nitrogenatmosfære. Ved destillation af den som remanens vundne mørkerøde væske fås 186 g (97# af det teoretiske) trans-P-dimethyl= amino-2-nitrostyren i form af en mørkerød væske med kogepunkt 125°C/0,03 mm Hg.A mixture of 137 g of o-ni tro toluene, 191 g of Ν, Ν-dimethylformamide diethyl = acetal and 235 ml of Ν, Ν-dimethylformamide is heated under nitrogen atmosphere for 24 hours to an internal temperature of 145-150 ° C. formed ethanol is continuously distilled off over a column. Then the volatiles are distilled off at reduced pressure under a nitrogen atmosphere. By distillation of the dark red liquid obtained as the residue, 186 g (97 # of theory) of trans-P-dimethyl = amino-2-nitrostyrene is obtained in the form of a dark red liquid with a boiling point of 125 ° C / 0.03 mm Hg.

143898 δ I en 500 ml’s trehalset kolbe, som er udstyret med termometer og røre= værk, anbringes 19,2 g (0,10 mol) trans-P-dimethylamino-2-nitrosty= ren, 100 ml ethanol og 100 ml iseddike, og i løbet af 5 minutter til= sættes 41,9 g (0,75 mol) pulveriseret jernpulver. Når tilsætningen er tilendebragt, omrøres suspensionen i yderligere 2 timer, idet tempe= raturen i løbet af dette tidsrum stiger til 45°0 (temperaturen regu= leres med et vandbad). Derpå tilsættes der 30 ml IN saltsyre, hvor= ved den røde farve forsvinder, og temperaturen stiger til ca, 45°C. Efter 18 timers henstand hældes reaktionsblandingen ud i 1 liter is= vand og tilsættes 250 ml benzen. Derpå filtreres faserne gennem dia= tomejord, og benzenfasen skilles fra den vandige fase. De organiske ekstrakter vaskes med 2 x 200 ml 0,5N svovlsyre og 100 ml 10$'s ka= liumcarbonatopløsning. Derpå tørres benzenfasen med natriumsulfat, hvorefter den filtreres og inddampes til tørhed. Den brune remanens (4,2 g) opløses i den mindst mulige mængde benzen og chromatograferes på 50 g aluminiumoxid. De eluerede fraktioner (petroleumsether/ben= zen 9:1), der indeholder indol, forenes i overensstemmelse med tyndt= lagschromatogrammet. Ted afdampning af opløsningsmidlet og sublima= tion af remanensen (40 - 50°C/0,03 mm Hg) fås 2,02 g (17$ af det teo= retiske) indol i form af hvide krystalsmåblade med smeltepunkt 51,5 -52,5° C.In a 500 ml three-neck flask equipped with a thermometer and stirrer, place 19.2 g (0.10 mol) of trans-P-dimethylamino-2-nitrosty, 100 ml of ethanol and 100 ml of glacial acetic acid. and in 5 minutes = 41.9 g (0.75 mole) of powdered iron powder is added. When the addition is complete, the suspension is stirred for another 2 hours as the temperature rises to 45 ° during this time (the temperature is controlled by a water bath). Then 30 ml of 1N hydrochloric acid is added, where = with the red color disappears and the temperature rises to about, 45 ° C. After standing for 18 hours, pour the reaction mixture into 1 liter of ice = water and add 250 ml of benzene. The phases are then filtered through diatomaceous earth and the benzene phase is separated from the aqueous phase. The organic extracts are washed with 2 x 200 ml of 0.5N sulfuric acid and 100 ml of 10 $ potassium carbonate solution. The benzene phase is then dried with sodium sulfate and then filtered and evaporated to dryness. The brown residue (4.2 g) is dissolved in the least amount of benzene and chromatographed on 50 g of alumina. The eluted fractions (petroleum ether / bone = zen 9: 1) containing indole are combined according to the thin = layer chromatogram. To evaporate the solvent and sublimate the residue (40 - 50 ° C / 0.03 mm Hg), 2.02 g (17 $ of the theoretic) indole is obtained in the form of white crystal blades, mp 51.5-52 , 5 ° C.

Eksempel 2.Example 2.

En blanding af 137,1 g o-nitrotoluen, 121,6 g 98$'s N,N-dimethyl= formamid-dimethylacetal og 200,0 g dimethylformamid opvarmes i 24 timer til tilbagesvaling under nitrogenatmosfære. Derefter afdestil= leres det dannede methanol ved en indvendig temperatur på 135 - 155°C over en kolonne, hvorved der kan opfanges 56,0 g destillat.A mixture of 137.1 g of o-nitrotoluene, 121.6 g of 98 $ N, N-dimethyl = formamide-dimethyl acetal and 200.0 g of dimethylformamide is heated for 24 hours to reflux under a nitrogen atmosphere. Thereafter, the methanol formed is distilled off at an internal temperature of 135 - 155 ° C over a column, whereby 56.0 g of distillate can be captured.

Ted forsigtig destillation i vakuum kan der fra reaktionsblandingen fjernes 206,3 g DMF (kogepunkt 51 - 55°C/20 mm Hg) og 13,0 g (10$ af det teoretiske) o-nitrotoluen (kogepunkt 109°C/23 mm Hg). Ted destillation af den som remanens vundne mørke væske fås 167,0 g (87$ af det teoretiske) trans^-dimethylamino-2-ni trostyren i form af en mørkerød væske med kogepunkt 128°C/0,05 mm Hg.By gentle vacuum distillation, 206.3 g of DMF (boiling point 51 - 55 ° C / 20 mm Hg) and 13.0 g (10 $ of theory) o-nitrotoluene (boiling point 109 ° C / 23 mm) can be removed from the reaction mixture Hg). Ted distillation of the dark liquid obtained as the residue is obtained 167.0 g (87 $ of theory) of trans ^ -dimethylamino-2-ni faith styrene in the form of a dark red liquid of boiling point 128 ° C / 0.05 mm Hg.

9 1438989 143898

En godt omrørt opløsning af 19»2 g (0,10 mol) trans-6-dimethylamino= -2-nitrostyren i 500 ml vand og 200 ml methanol tilsættes portions= vis i løbet af 5 minutter en blanding af 55,0 g (0,315 mol) natrium= dithionit og 28,0 g (0,20 mol) kaliumcarbonat, idet temperatur med et vandbad holdes på 60 - 65°G. Den på denne måde dannede suspension tilsættes 300 ml methanol og omrøres videre i 45 minutter. Reaktions= blandingen tilsættes 20 ml 30#1 s ammoniumhydroxidopløsning, og me= thanolet fjernes på rotationsfordamper. Derefter tilsættes yderligere 60 ml 30#'s ammoniumhydroxidopløsning, og der ekstraheres med 3 x 400 ml benzen. De organiske faser tørres med natriumsulfat, filtreres og inddampes til tørhed. Den mørkebrune remanens (3,5 g) opløses i den mindst mulige mængde benzen og chromatograferes på 60 g aluminiumoxid. De eluerede fraktioner (petroleumsether), der indeholder indol, for= enes i overensstemmelse med tyndtlagschromatogrammet. Ved fjernelse af opløsningsmidlerne og sublimation af remanensen fås 2,14 g (18# af det teoretiske) indol, smeltepunkt 50 - 52°C.A well-stirred solution of 19 »2 g (0.10 mol) of trans-6-dimethylamino = -2-nitrostyrene in 500 ml of water and 200 ml of methanol is added portionwise over a 5 minute mixture of 55.0 g 0.315 mole) of sodium = dithionite and 28.0 g (0.20 mole) of potassium carbonate, maintaining a water bath temperature of 60-65 ° G. The suspension thus formed is added to 300 ml of methanol and further stirred for 45 minutes. The reaction = mixture is added to 20 ml of 30 # 1 s ammonium hydroxide solution and the methanol removed on rotary evaporator. Then add an additional 60 ml of 30 # ammonium hydroxide solution and extract with 3 x 400 ml of benzene. The organic phases are dried over sodium sulfate, filtered and evaporated to dryness. The dark brown residue (3.5 g) is dissolved in the least amount of benzene and chromatographed on 60 g of alumina. The eluted fractions (petroleum ether) containing indole are combined according to the thin layer chromatogram. Removal of the solvents and sublimation of the residue afforded 2.14 g (18 # of theory) of indole, mp 50-52 ° C.

Eksempel 3· 15.6 g 95#'s dimethylformamid-diethylacetal og 13,7 g o-nitrotoluen opvarmes i 24 timer i autoklav til 155°C under et nitrogentryk på 35 atmosfærer. Ved destillation af reaktionsproduktet fås 13,4 g (70# af det teoretiske) trans-p-dimethylamino-2-nitrostyren i form af en rød væske med kogepunkt 134 - 136°C/0,25 mm Hg.Example 3 · 15.6 g of 95 # dimethylformamide diethyl acetal and 13.7 g of o-nitrotoluene are heated for 24 hours in autoclave to 155 ° C under a nitrogen atmosphere of 35 atmospheres. Distillation of the reaction product gives 13.4 g (70 # of theory) of trans-p-dimethylamino-2-nitrostyrene in the form of a red liquid of boiling point 134 - 136 ° C / 0.25 mm Hg.

nærværelse af 2,0 g 10#’s palladium/kul-katalysator og under etpresence of 2.0 g of 10 # palladium / carbon catalyst and together

Eksempel 4.Example 4

10 14389810 143898

En blanding af 24,32 g 5-benzyloxy-2-nitrotoluen, 23,0 g F,F-dimethyl= formamid-diethylacetal og 25 ml dimethylformamid opvarmes under ni= trogenatmosfære i 40 timer ved en indvendig temperatur på 140°C, idet det dannede ethanol afdestilleres kontinuerligt over en kolonne. De flygtige bestanddele fjernes derefter under formindsket tryk på rotationsfordamper. Ved krystallisation af råproduktet af 300 ml ether og 25 ml benzen fås 23,3 g (78$ af det teoretiske) trans-5= -b enzyloxy-β-dime thylamino-2-nitro styren i form af røde krystalnåle med smeltepunkt 97,5 - 99°C.A mixture of 24.32 g of 5-benzyloxy-2-nitrotoluene, 23.0 g of F, F-dimethyl = formamide diethyl acetal and 25 ml of dimethylformamide is heated under nitrogen atmosphere for 40 hours at an internal temperature of 140 ° C. the ethanol formed is continuously distilled off over a column. The volatiles are then removed under reduced pressure on the rotary evaporator. Crystallization of the crude product of 300 ml of ether and 25 ml of benzene gives 23.3 g (78 $ of theory) of trans-5 = -b enzyloxy-β-dime thylamino-2-nitro styrene in the form of red crystal needles, m.p. 5 - 99 ° C.

Udgangsmaterialet kan fremstilles på følgende måde: lil en godt omrørt opløsning af 15,3 g 3-methyl-4-nitrophenol i 200 ml absolut ethanol sættes under nitrogenatmosfære 5,40 g natriumme= thylat i løbet af 15 minutter, hvorefter reaktionsblandingen opvar= mes til tilbagesvaling under omrøring i 1 1/2 time. Derefter tilsæt= tes der dråbevis 12,66 g benzylchlorid, og reaktionsblandingen op= varmes i 20 timer til tilbagesvaling. Derpå afdampes alkoholen, og remanensen fordeles mellem 200 ml ether og 100 ml 1F natriumhydro= xidopløsning. Etheropløsningen vaskes derefter med 100 ml 1F natri= umhydroxidopløsning og med 100 ml vand. De vandige faser syrnes med phosphorsyre og ekstraheres derefter med methylenchlorid (3 x 200 ml). De forenede methylenchloridekstrakter tørres med natriumsulfat og inddampes til tørhed, hvorved der kan tilbagevindes 2,8 g (18$ af det teoretiske) 3-methyl-4-nitrophenol (udgangsmateriale). Etherekstrak= terne tørres med natriumsulfat og inddampes til tørhed. Ved krystalli= sation af remanensen af 75 ml methanol fås 15,1 g (62$ af det teore= tiske) 5-benzyloxy-2-nitrotoluen i form af hvide krystalnåle med smeltepunkt 70,5 - 71,5°C.The starting material can be prepared as follows: To a well stirred solution of 15.3 g of 3-methyl-4-nitrophenol in 200 ml of absolute ethanol is added under nitrogen atmosphere to 5.40 g of sodium methylate over 15 minutes and then the reaction mixture is heated. to reflux with stirring for 1 1/2 hours. Then 12.66 g of benzyl chloride is added dropwise and the reaction mixture is heated to reflux for 20 hours. The alcohol is then evaporated and the residue is partitioned between 200 ml of ether and 100 ml of 1F sodium hydroxide solution. The ether solution is then washed with 100 ml of 1F sodium hydroxide solution and with 100 ml of water. The aqueous phases are acidified with phosphoric acid and then extracted with methylene chloride (3 x 200 ml). The combined methylene chloride extracts are dried over sodium sulfate and evaporated to dryness to give 2.8 g (18 $ of theory) of 3-methyl-4-nitrophenol (starting material). The ether extracts are dried over sodium sulfate and evaporated to dryness. Crystallization of the residue of 75 ml of methanol gives 15.1 g (62 $ of the theoretical) of 5-benzyloxy-2-nitrotoluene in the form of white crystal needles, mp 70.5 - 71.5 ° C.

En opløsning af 15,0 g trans-5-benzyloxy-P-dimethylamino-2-nitro= styren i 250 ml 80$'s ethanol/dimethylformamid rystes i nærværelse af en teskefuld Raney-nikkel i et Parr-apparat under hydrogentryk, indtil hydrogenoptagelsen er gået i stå. Katalysatoren frafiltreres, og filtratet inddampes under formindsket tryk. Remanensen sublime= res og omkrystalliseres derefter af ether/petroleumsether, hvorved der fås 5,1 g (45$ af det teoretiske) 5-benzyloxyindol i form af hvide krystalnåle med smeltepunkt 103 - 105°C.A solution of 15.0 g of trans-5-benzyloxy-β-dimethylamino-2-nitro = styrene in 250 ml of 80 $ ethanol / dimethylformamide is shaken in the presence of a teaspoon of Raney nickel in a Parr apparatus under hydrogen pressure until hydrogen uptake has stalled. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue is sublime and then recrystallized from ether / petroleum ether to give 5.1 g (45 $ of theory) of 5-benzyloxyindole in the form of white crystal needles, mp 103 - 105 ° C.

143898 u143898 u

Eksempel 5.Example 5

En blanding af 18,1 g 3-methy]r~4-nitrobenzoesyre, 57,6 g Ν,ΒΓ-dimethyls formamid-dimethylacetal og 25 ml F,H-dimethylformamid henstår under nitrogenatmosfære i 4 1/2 time i et oliebad med temperatur 100°C, Her= ' efter afdestilleres det dannede ethanol kontinuerligt over en kolonne ved en indvendig temperatur på 155°C. Derpå afdestilleres de flygtige andele i vakuum. Efter rivning med petroleumsether krystalliserer remanensen, hvorved der fås 18,5 g (70$ af det teoretiske) trans-3= -(P-dimethylaminovinyl)-4-nitrobenzoesyre-ethylester i form af røde krystaller med smeltepunkt 55 - 56,5®C,A mixture of 18.1 g of 3-methyl-4-nitrobenzoic acid, 57.6 g of Ν, ΒΓ-dimethyls formamide-dimethyl acetal and 25 ml of F, H-dimethylformamide is left under nitrogen atmosphere for 4 1/2 hours in an oil bath with temperature 100 ° C, whereupon the ethanol formed is continuously distilled off over a column at an internal temperature of 155 ° C. The volatiles are then distilled off in vacuo. After tearing with petroleum ether, the residue crystallizes to give 18.5 g (70 $ of theory) of trans-3 = - (P-dimethylaminovinyl) -4-nitrobenzoic acid ethyl ester in the form of red crystals, mp 55-56.5® C,

En opløsning af 7,5 g trans-3-(P-dimethylaminovinyl)-4-nitrobenzoe-syre-ethylester i 250 ml absolut ethanol rystes i et Parr-apparat i nærværelse af 715 mg 10$’s palladlum/kul-katalysator ved et begyn= delseshydrogentryk på 3,5 atmosfærer, indtil hydrogenoptagelsen er gået i stå. Katalysatoren frafiltreres, og filtratet tørres og ind- ; dampes. Råproduktet chromatograferes på 1QQ g magnesiumoxid-silicagel. Efter eluering med benzen og efterfølgende krystallisation af ether/» petroleumsether fås 2,1 g (39$ af det teoretiske) 5-indolcarbosyl^ syreethylester i form af hvide krystaller med smeltepunkt 95 - 96°C.A solution of 7.5 g of trans-3- (β-dimethylaminovinyl) -4-nitrobenzoic acid ethyl ester in 250 ml of absolute ethanol is shaken in a Parr apparatus in the presence of 715 mg of 10 $ palladium / carbon catalyst at an initial hydrogen pressure of 3.5 atmospheres until hydrogen uptake is stopped. The catalyst is filtered off and the filtrate is dried and evaporated; steamed. The crude product is chromatographed on 1 g of g magnesium silica gel. After eluting with benzene and subsequent crystallization of ether / petroleum ether, 2.1 g (39 $ of theory) of 5-indole carboxylic acid ethyl ester are obtained in the form of white crystals, mp 95-96 ° C.

Eksempel 6.Example 6

En blanding af 17,16 g 2-chlor-6-nitrotoluen, 24 g FjN-dimethylfornte amid-diethylacetal og 100 ml Ν,Ν-dimethylformamid opvarmes under nitrogenatmosfære i 6 timer ved en indvendig temperatur på 140®0, idet det dannede ethanol afdestilleres kontinuerligt over en kolonne.A mixture of 17.16 g of 2-chloro-6-nitrotoluene, 24 g of FjN-dimethylformed amide-diethyl acetal and 100 ml of Ν, Ν-dimethylformamide is heated under nitrogen atmosphere for 6 hours at an internal temperature of 140 ° O, forming the ethanol. is continuously distilled over a column.

De flygtige bestanddele afdestilleres i vakuum ved 25°C/3 mm Hg.The volatiles are distilled off in vacuo at 25 ° C / 3 mm Hg.

Ved destillation af råproduktet fås 20,2 g (89$ af det teoretiske) trans-6-chlor-P-dimethylamino-2-nitrostyren i form af en mørkerød væske med kogepunkt 111^0/0,03 mm Hg.Distillation of the crude product gives 20.2 g (89 $ of theory) of trans-6-chloro-P-dimethylamino-2-nitrostyrene in the form of a dark red liquid with boiling point 111 ^0 / 0.03 mm Hg.

12 143898 10,4 g trans-P-dimethylamino-6-chlor-2-nitrostyren opløses i 250 ml benzen og hydrogeneres i nærværelse af en halv teskefuld Raney-nikkel ved et begyndelsestryk på 5,5 atmosfærer, Mr hydrogenoptagelsen er gået i stå, frafiltreres katalysatoren, og denne vaskes nogle gange med,benzen. Benzenfasen ekstraheres derefter med 3 x 75 ml 1M svovl= syre og 100 ml vand. De forenede benzenfaser tørres med kaliumcarbo= nat, filtreres og inddampes til tørhed, hvorved der fås 5,4 g af en mørkegrøn olie, Ved destillation af råproduktet fås 4,5 g af en gul væske med kogepunkt 116°0/2 mm Hg. Efter en yderligere destillation fås 4,41 g (63$ af det teoretiske) 4-chlorindol i form af en svagt gul væske, kogepunkt 90°C/0,04 mm Hg.12.43898 10.4 g of trans-P-dimethylamino-6-chloro-2-nitrostyrene are dissolved in 250 ml of benzene and hydrogenated in the presence of half a teaspoon of Raney nickel at an initial pressure of 5.5 atmospheres, Mr hydrogen uptake is stopped , the catalyst is filtered off and this is sometimes washed with benzene. The benzene phase is then extracted with 3 x 75 ml of 1M sulfuric acid and 100 ml of water. The combined benzene phases are dried over potassium carbonate, filtered and evaporated to dryness to give 5.4 g of a dark green oil. On distillation of the crude product, 4.5 g of a yellow liquid is obtained at boiling point 116 ° / 2 mm Hg. After further distillation, 4.41 g ($ 63 of theory) of 4-chloroindole is obtained in the form of a pale yellow liquid, boiling point 90 ° C / 0.04 mm Hg.

Eksempel 7.Example 7

En blanding af 34,3 g 5-chlor-2-nitrotoluen, 55,0 g 85$'s H,H-di= methylformamid-diethylacetal og 200 ml Η,Η-dimethylformamid opvarmes i 7 timer under nitrogenatmosfære ved en indvendig temperatur på 146°C, idet det dannede ethanol afdestilleres kontinuerligt over en kolonne. De flygtige bestanddele afdestilleres derefter i vakuum (oliebad= temperatur 70°C/0,5 mm Hg). Ved krystallisation af den mørkerøde remanens af 275 ml af en blanding af ether og petroleumsether fås 33,2 g røde krystaller med smeltepunkt 81,5 - 82,5°C. Af moderluden kan der isoleres yderligere 6,6 g krystaller med smeltepunkt 78 - 81°C. Det samlede udbytte af trans-5-chlo r-β-dime thylamino-2-nitr o s tyren er'· 39,8 g (88$ af det teoretiske).A mixture of 34.3 g of 5-chloro-2-nitrotoluene, 55.0 g of 85 $ H, H-di = methylformamide diethyl acetal and 200 ml of Η, Η-dimethylformamide is heated for 7 hours under an atmosphere of nitrogen at an internal temperature. at 146 ° C, the ethanol formed being continuously distilled off over a column. The volatiles are then distilled off in vacuo (oil bath = temperature 70 ° C / 0.5 mm Hg). Crystallization of the dark red residue of 275 ml of a mixture of ether and petroleum ether gives 33.2 g of red crystals, mp 81.5 - 82.5 ° C. From the mother liquor an additional 6.6 g of crystals can be isolated, mp 78-81 ° C. The total yield of trans-5-chloro-β-dime thylamino-2-nitr o s bull is' 39.8 g (88 $ of theory).

En opløsning af 11,6 g trans-5-chlor-p-dimethylamino-2-nitrostyren i 250 ml benzen rystes i et Parr-apparat i nærværelse af en halv teskefuld Raney-nikkel og ved et begyndelseshydrogentryk på 3,5 atmosfærer, indtil hydrogenoptagelsen er gået i stå. Derpå frafil= treres katalysatoren, og denne vaskes nogle gange efter med benzen. Eiltratet vaskes derefter med 2 x 100 ml IH svovlsyre, 2 x 100 ml vand og 100 ml 10$!s natriumbicarbonatopløsning.A solution of 11.6 g of trans-5-chloro-p-dimethylamino-2-nitrostyrene in 250 ml of benzene is shaken in a Parr apparatus in the presence of half a teaspoon of Raney nickel and at an initial hydrogen pressure of 3.5 atmospheres until hydrogen uptake has stalled. The catalyst is then filtered off and this is sometimes washed with benzene. The filtrate is then washed with 2 x 100 ml of 1 H sulfuric acid, 2 x 100 ml of water and 100 ml of 10% sodium bicarbonate solution.

13 14389813 143898

De forenede benzenfaser tørrer over natriumsulfat, filtreres og ind= dampes til tørhed. Ved destillation af råproduktet fås 6,26 g af et hvidt fast stof, som opløses i ether og filtreres gennem ca. 1 g aluminiumoxid. Filtratet inddampes, og råproduktet krystalliseres af 30 ml petroleumsether, hvorved der fås 6,0 g (78$ af det teore= tiske) 5-ehlorindol i form af hvide krystalsmåblade med smeltepunkt 71 - 72°C.The combined benzene phases dry over sodium sulfate, filter and evaporate to dryness. Distillation of the crude product gives 6.26 g of a white solid which is dissolved in ether and filtered through ca. 1 g of alumina. The filtrate is evaporated and the crude product is crystallized from 30 ml of petroleum ether to give 6.0 g (78 $ of theory) of 5-ehlorindole in the form of white crystal blades, mp 71-72 ° C.

Eksempel 8.Example 8.

En blanding af 17,15 g 4-chlor-2-nitrotoluen og 18,0 g N,N-dimethyl= formamid-diethylacetal henstår i 58 timer under nitrogenatmosfære i et oliebad med temperatur 145°C, og efter 24 timers forløb tilsættes yderligere 3 g af acetalen. De flygtige bestanddele afdestilleres derefter ved formindsket tryk under nitrogenatmosfære, indtil tempe= raturen begynder at stige til 158°0/0,09 mm Hg. Ved destillation fås 12,0 g (57$ af det teoretiske) trans-4-ehlor-P-dimethylamino-2= -nitrostyren i form af en rød væske, kogepunkt 158°C/0,09 mm Hg.A mixture of 17.15 g of 4-chloro-2-nitrotoluene and 18.0 g of N, N-dimethyl = formamide diethyl acetal is left for 58 hours under an atmosphere of nitrogen in an oil bath at a temperature of 145 ° C, and after a further 24 hours is added. 3 g of acetal. The volatiles are then distilled off at reduced pressure under a nitrogen atmosphere until the temperature begins to rise to 158 ° 0 / 0.09 mm Hg. Distillation gives 12.0 g (57 $ of theory) of trans-4-ehloro-P-dimethylamino-2 = nitrostyrene in the form of a red liquid, boiling point 158 ° C / 0.09 mm Hg.

4,50 g trans-4-chlor-P-dimethylamino-2-nitrostyren opløses i 250 ml absolut ethanol og hydrogeneres i nærværelse af 1 teskefuld Haney= -nikkel. Når hydrogenoptagelsen er gået i stå, frafiltreres kataly= satoren, og filtratet inddampes til tørhed, Remanensen chromatogram feres på 25 g magnesiumoxid-silicagel. Efter eluering med 5$*s ben= zen/hexan og krystallisation af benzen/hexan fås 1,59 g (52$ af det teoretiske) 6-chlorindol i form af hvide krystaller, smeltepunkt 89 - 89,5°C.4.50 g of trans-4-chloro-P-dimethylamino-2-nitrostyrene are dissolved in 250 ml of absolute ethanol and hydrogenated in the presence of 1 teaspoon of Haney = nickel. When the hydrogen uptake is stopped, the catalyst is filtered off and the filtrate is evaporated to dryness, the residue chromatogram is passed on 25 g of magnesium oxide-silica gel. After elution with 5 $ * benzene / hexane and crystallization of benzene / hexane, 1.59 g (52 $ of theory) of 6-chloroindole are obtained in the form of white crystals, mp 89-89.5 ° C.

Eksempel 9.Example 9

En blanding af 33,0 g 5-nitropseudocumen, 48,3 g N,N-dimethylform= amid-diethylacetal og 200 ml Ν,Ν-dimethylformamid opvarmes under nL= trogenatmosfære i 30 timer ved en indvendig temperatur på ca. 140°C, idet det dannede ethanol afdestilleres kontinuerligt over en kolonne.A mixture of 33.0 g of 5-nitropseudocumen, 48.3 g of N, N-dimethylform = amide-diethyl acetal and 200 ml of Ν, dim-dimethylformamide is heated under nL = trogen atmosphere for 30 hours at an internal temperature of approx. 140 ° C, the ethanol formed being continuously distilled off over a column.

14 14389814 143898

De flygtige bestanddele fjernes i vakuum ved destillation ved 25°C/0,5 mm Hg, og remanensen rives med methanol. Ved krystallisa= tion af de uopløselige bestanddele af 600 ml methanol fås 25,5 g (58$ af det teoretiske) trans-P-dimethylamino-2,5-dimethyl-4-nitro= styren i form af mørkerøde krystalnåle med smeltepunkt 130 - 131°C.The volatiles are removed in vacuo by distillation at 25 ° C / 0.5 mm Hg and the residue is triturated with methanol. Crystallization of the insoluble constituents of 600 ml of methanol gives 25.5 g (58 $ of theory) of trans-P-dimethylamino-2,5-dimethyl-4-nitro = styrene in the form of dark red crystal needles, m.p. 131 ° C.

Ben ved den ovennævnte behandling med methanol vundne opløsning ind= dampes, og remanensen digereres med petroleumsether (20 x 100 ml). Petroleumsetherekstrakterne giver 14,5 g af et rødt, fast stof, som opløses i 50 ml ethanol. Benne opløsning sættes til en opløsning af 140 g jern(ll)-sulfat-heptahydrat, 500 ml vand og 85 ml koncentre= ret ammoniak. Reaktionsblandingen opvarmes derefter i 15 minutter til tilbagesvaling, og det herved dannede bundfald frafiltreres. Pil= tratet inddampes på rotationsfordamper og ekstraheres med 3 x 200 ml carbontetrachlorid. Be forenede organiske faser tørres med natrium= sulfat, filtreres og inddampes til tørhed. Berpå filtreres remanen= sen gennem aluminiumoxid med en 5$'s benzen/hexan-blanding. Piltratet inddampes til tørhed, hvorved der fås 450 mg af et hvidt fast stof. Ved krystallisation af 8 ml petroleumsether fås 277 mg 5,6-dimethyl= indol i form af hvide krystalnåle med smeltepunkt 64,5 - 65,5°C.Bones in the above solution with methanol obtained are evaporated and the residue is digested with petroleum ether (20 x 100 ml). The petroleum ether extracts give 14.5 g of a red solid which is dissolved in 50 ml of ethanol. Bone solution is added to a solution of 140 g of iron (II) sulfate heptahydrate, 500 ml of water and 85 ml of concentrated ammonia. The reaction mixture is then heated to reflux for 15 minutes, and the resulting precipitate is filtered off. The arrow = funnel is evaporated on a rotary evaporator and extracted with 3 x 200 ml of carbon tetrachloride. The combined organic phases are dried with sodium sulfate, filtered and evaporated to dryness. On the residue, the residue is filtered through alumina with a 5 $ benzene / hexane mixture. The filtrate is evaporated to dryness to give 450 mg of a white solid. Crystallization of 8 ml of petroleum ether gives 277 mg of 5,6-dimethyl = indole in the form of white crystal needles, mp 64.5 - 65.5 ° C.

Eksempel 10.Example 10.

En blanding af 20,00 g 5-fluor-2-nitrotoluen, 56,0 g 85$’s F,H-di= methylformamid-diethylacetal og 100 ml ΪΓ,R-dimethylformamid opvar= mes under nitrogenatmosfære i 3 1/2 time ved en indvendig tempera= tur på 140°C, idet det dannede ethanol afdestilleres kontinuerligt over en kolonne. Be flygtige andele afdestilleres i vakuum ved 25°C/0,5 mm Hg, og den mørkerøde remanens krystalliseres af 70 ml ether/petroleumsether, hvorved der fås 20,55 g røde krystalnåle med smeltepunkt 52 - 55°C. Af moderluden kan der ved destillation vindes yderligere 4,24 g af et rødt fast stof med smeltepunkt 56 -58°C. Bet samlede udbytte er 24,79 g (92$ af det teoretiske). Ved en yderligere krystallisation af en prøve fås trans-P-dimethylamino-5= -fluor-2-nitrostyren i form af røde krystaller med smeltepunkt 56 -58° C.A mixture of 20.00 g of 5-fluoro-2-nitrotoluene, 56.0 g of 85 $ F, H-di = methylformamide diethyl acetal and 100 ml of ΪΓ, R-dimethylformamide are heated under a nitrogen atmosphere for 3 1/2 hour at an internal temperature of 140 ° C, the ethanol formed being continuously distilled off over a column. The volatiles are distilled off in vacuo at 25 ° C / 0.5 mm Hg, and the dark red residue is crystallized by 70 ml of ether / petroleum ether to give 20.55 g of red crystal needles, mp 52-55 ° C. An additional 4.24 g of a red solid, m.p. 56-58 ° C, can be obtained from the mother liquor. Bet total yield is 24.79 g ($ 92 of theory). Upon further crystallization of a sample, trans-β-dimethylamino-5 = -fluoro-2-nitrostyrene is obtained in the form of red crystals, mp 56-58 ° C.

15 143898143898

En opløsning af 10,51 g trans-6-dimethylamino-5--fluor-2-nitrostyren i 250 ml benzen rystes ved et begyndelseshydrogentryk på 3,5 atmos= færer i nærværelse af en halv teskefuld Raney-nikkel, indtil hydro= genoptagelsen er gået i stå. Derpå frafiltreres katalysatoren, som vaskes efter nogle gange med benzen. Derefter ekstraheres benzen= filtratet med 2 x 100 ml 1M svovlsyre, 2 x 150 ml vand og 150 ml 10%'3 natriumbicarbonatopløsning. Den organiske fase tørres med na= triumsulfat, filtreres og inddampes til tørhed, hvorved der fås 5,23 g af et brunt fast stof. Ved destillation (kogepunkt 85°C/0,5 mm Hg)og efterfølgende krystallisation af pentan fås 2,36 g 5-fluor= indol i form af hvide krystalsmåblade med smeltepunkt 46,5 - 47°C. Moderluden filtreres med ether gennem 10 g aluminiumoxid. Ved sub= limation af dette materiale fås yderligere 1,07 g af det ønskede slutprodukt med smeltepunkt 46 - 47°C. Det samlede udbytte er såle= des 3,44 g (51% af det teoretiske).A solution of 10.51 g of trans-6-dimethylamino-5-fluoro-2-nitrostyrene in 250 ml of benzene is shaken at an initial hydrogen pressure of 3.5 atmospheres in the presence of half a teaspoon of Raney nickel until the hydrochloric reaction have stopped. The catalyst is then filtered off, which is washed after some time with benzene. The benzene = filtrate is then extracted with 2 x 100 ml of 1M sulfuric acid, 2 x 150 ml of water and 150 ml of 10% sodium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness to give 5.23 g of a brown solid. Distillation (boiling point 85 ° C / 0.5 mm Hg) and subsequent crystallization of pentane yields 2.36 g of 5-fluoro = indole in the form of white crystal blades, mp 46.5 - 47 ° C. The mother liquor is filtered with ether through 10 g of alumina. Sublimation of this material gives an additional 1.07 g of the desired final product, mp 46-47 ° C. The total yield is thus = 3.44 g (51% of theory).

Eksempel 11.Example 11.

En blanding af 11,18 g 4-methyl-3-nitrobenzaldehyddimethylacetal, 11,8 g Ν,Ν-dimethylformamid-diethylacetal og 50 ml N,N-dimethylform= amid opvarmes under nitrogenatmosfære i 8 timer ved en temperatur på 140°C, idet det dannede ethanol afdestilleres kontinuerligt over en kolonne. De flygtige bestanddele afdestilleres i vakuum ved 25°0/0,5 mm Hg, og den mørkerøde remanens rives med koldt methanol.A mixture of 11.18 g of 4-methyl-3-nitrobenzaldehyde dimethyl acetal, 11.8 g of Ν, Ν-dimethylformamide diethyl acetal and 50 ml of N, N-dimethylformamide is heated under a nitrogen atmosphere for 8 hours at a temperature of 140 ° C. the ethanol formed being continuously distilled off over a column. The volatiles are distilled off in vacuo at 25 ° / 0.5 mm Hg and the dark red residue is triturated with cold methanol.

Det som remanens vundne faste stof omkrystalliseres af 30 ml ether/pen= tan, hvorved dér'fås 7,22 g trans-4-(P-dimethylaminovinyl)-3-ni= trobenzaldehyd-dimethylacetal, smeltepunkt 67 - 68,5°C. Moderluden inddampes til tørhed, og remanensen krystalliseres af 5 ml ether/pen= tan, hvorved der fås yderligere 0,57 g af det ønskede slutprodukt, smeltepunkt 66,5 - 68°C. Det samlede udbytte er 7,79 g (55# af det teoretiske).The solid obtained as the residue is recrystallized from 30 ml of ether / pentane, to give 7.22 g of trans-4- (P-dimethylaminovinyl) -3-ni = trobenzaldehyde dimethyl acetal, m.p. 67 - 68.5 ° C . The mother liquor is evaporated to dryness and the residue is crystallized by 5 ml of ether / penetan to give an additional 0.57 g of the desired final product, mp 66.5 - 68 ° C. The total yield is 7.79 g (55 # of theory).

En opløsning af 5,31 g trans-4-(p-dimethylaminovinyl)-3-nitrobenzaldehyd-dimethylacetal i 250 ml benzen rystes ved et begyndelseshydrogen= 16 143898 tryk på 3,5 atmosfærer i nærværelse af en halv teskefuld Raney-nikkel, indtil hydrogenabsorptionen er tilendebragt. Katalysatoren frafil= treres og eftervaskes nogle gange med benzen. Filtratet inddampes til tørhed, og remanensen chromatograferes på 150 g aluminiumoxid, idet der elueres først med 20$ benzen/hexan-blanding og derefter med ether. De forenede fraktioner chromatograferes endnu en gang på 300 g aluminiumoxid. Efter eluering med ether fås 1,35 g af et råprodukt, der krystalliseres af ether/pentan, hvorved der fås 0,76 g (26$ af det teoretiske) 6-formylindol, smeltepunkt 127 - 128,5°C.A solution of 5.31 g of trans-4- (p-dimethylaminovinyl) -3-nitrobenzaldehyde dimethyl acetal in 250 ml of benzene is shaken at an initial hydrogen = 16 pressure at 3.5 atmospheres in the presence of half a teaspoon of Raney nickel until the hydrogen absorption is completed. The catalyst is filtered off and sometimes washed with benzene. The filtrate is evaporated to dryness and the residue is chromatographed on 150 g of alumina, eluting first with 20 $ benzene / hexane mixture and then with ether. The combined fractions are again chromatographed on 300 g of alumina. After elution with ether, 1.35 g of a crude product crystallized by ether / pentane is obtained to give 0.76 g (26 $ of theory) of 6-formylindole, mp 127 - 128.5 ° C.

Eksempel 12.Example 12.

En blanding af 11,18 g 4-methyl-3-nitrobenzaldehyddimethylacetal, 11,8 g Ν,Ν-dimethylf ormamid-diethylacetal og 50 ml F, IT- dime thy 1 f o rm= amid opvarmes under nitrogenatmosfære i 8 timer ved en temperatur på 140°0, idet det dannede ethanol afdestilleres kontinuerligt over en kolonne. De flygtige bestanddele afdestilleres i vakuum ved 25°C/0,5 mm Hg, og den mørkerøde remanens rives med koldt methanol.A mixture of 11.18 g of 4-methyl-3-nitrobenzaldehyde dimethyl acetal, 11.8 g of Ν, Ν-dimethylformamide-diethyl acetal and 50 ml of F, IT-dime thi fo rm = amide is heated under a nitrogen atmosphere for 8 hours. at 140 ° 0, the ethanol formed being continuously distilled off over a column. The volatiles are distilled off in vacuo at 25 ° C / 0.5 mm Hg and the dark red residue is triturated with cold methanol.

Det som remanens vundne faste stof omkrystalliseres af 30 ml ether/pen= tan, hvorved dér"fås 7,22 g trans-4-(β-dimethylaminovinyl)-3-ni= trobenzaldehyd-dimethylacetal, smeltepunkt 67 - 68,5°C. Moderluden inddampes til tørhed, og remanensen krystalliseres af 5 ml ether/pen= tan, hvorved der fås yderligere 0,57 g af det ønskede slutprodukt, smeltepunkt 66,5 - 68°C. Det samlede udbytte er 7,79 g (55$ af det teoretiske).The solid obtained as the residue is recrystallized from 30 ml of ether / pentan to give 7.22 g of trans-4- (β-dimethylaminovinyl) -3-ni = trobenzaldehyde dimethyl acetal, m.p. 67 - 68.5 ° C The mother liquor is evaporated to dryness and the residue is crystallized from 5 ml of ether / penetan to give an additional 0.57 g of the desired final product, mp 66.5 - 68 ° C. The total yield is 7.79 g (55 $ of the theoretical).

En opløsning af 6,65 g trans-4-(β-dimethylaminovinyl)-3-nitrobenz= aldehyd-dimethylacetal i 125 ml benzen tilsættes 1,0 g kaliumcarbo= nat og 0,352 g 10$’s palladium/kul-katalysator og omrøres derefter under en hydrogenatmosfære. Hår hydrogenoptagelsen er gået i stå, frafiltreres katalysatoren, som vaskes nogle gange med benzen. Fil= tratet inddampes til tørhed, og remanensen (4,95 g) destilleres, hvorved der fås 1,74 g af en purpurfarvet olie, som størkner ved afkøling. Ved krystallisation af 10 ml ether/petroleumsether fås 1,18 g af et hvidt fast stof med smeltepunkt 62 - 63,5°C. Moderluden chromatograferes på 10 g aluminiumoxid, hvorved der efter eluering med en blanding af ether og petroleumsether i forholdet 1:1 fås yder= ligere 0,52 g produkt. Yed en yderligere krystallisation af ether/pes= troleumsether fås 1,34 g (51$ af det teoretiske) 6-formylindol= -dimethylacetal, smeltepunkt 62 - 63,5°C.A solution of 6.65 g of trans-4- (β-dimethylaminovinyl) -3-nitrobenz = aldehyde dimethyl acetal in 125 ml of benzene is added 1.0 g of potassium carbonate and 0.352 g of 10 $ palladium / carbon catalyst and stirred. then under a hydrogen atmosphere. Once the hydrogen uptake has stopped, the catalyst, which is sometimes washed with benzene, is filtered off. The filtrate is evaporated to dryness and the residue (4.95 g) is distilled to give 1.74 g of a purple oil which solidifies upon cooling. Crystallization of 10 ml of ether / petroleum ether gives 1.18 g of a white solid, mp 62 - 63.5 ° C. The mother liquor is chromatographed on 10 g of alumina to give, after elution with a mixture of ether and petroleum ether in a ratio of 1: 1, an additional = 0.52 g of product. Further crystallization of ether / pes = troleum ether gives 1.34 g (51 $ of theory) of 6-formylindole = -dimethylacetal, mp 62 - 63.5 ° C.

17 14389817 143898

Eksempel 13.Example 13

En blanding af 17,9 g 2-nitro-p-cumen, 17,9 g H,H-dimethylformamid= -dimethylacetal og 25 ml Η,Η-dimethylformamid opvarmes under nitro= genatmosfære 1 42 timer ved en oliebadtemperatur på 150° C t idet me=* thanolet (8 ml) afdestilleres kontinuerligt over en kolonne. Efter fjernelse af de flygtige bestanddele i vakuum (indtil 13Q°C/0,06 mm Hg) destilleres råproduktet, Hvorved der fås 19,61 g (84$ af det teoretiske) trans-P-dimethylamino-4'-isopropyl-2-ni trostyren i form af en rød væske (kogepunkt 138 - 140°C/0,06 mm Hg).A mixture of 17.9 g of 2-nitro-β-cumene, 17.9 g of H, H-dimethylformamide = dimethyl acetal and 25 ml of Η, Η-dimethylformamide is heated under nitro = atmosphere for 42 hours at an oil bath temperature of 150 ° C. as the me = * thanolet (8 ml) is continuously distilled over a column. After removal of the volatiles in vacuo (up to 13 ° C / 0.06 mm Hg), the crude product is distilled to give 19.61 g (84 $ of theory) of trans-β-dimethylamino-4'-isopropyl-2- nine faith styrene in the form of a red liquid (boiling point 138 - 140 ° C / 0.06 mm Hg).

En opløsning af 11,71 g trans-p-dimethylamino-4-isopropyl-2-nitro= styren i 125 ml benzen omrøres under hydrogenatmosfære i nærværelse af 0,234 g 10$'s palladium/kul-katalysator, Hår hydrogenoptagelsen er gået i stå, frafiltreres katalysatoren, som eftervaskes nogle gange med benzen. Filtratet ekstraheres derefter med 2 X 50 ml IH svovlsyre, 100 ml vand og 50 ml 10$’s natriumfcicarbonatopløsning.A solution of 11.71 g of trans-p-dimethylamino-4-isopropyl-2-nitro = styrene in 125 ml of benzene is stirred under a hydrogen atmosphere in the presence of 0.234 g of 10 $ palladium / carbon catalyst. , the catalyst is filtered off, which is sometimes washed with benzene. The filtrate is then extracted with 2 x 50 ml of 1 H sulfuric acid, 100 ml of water and 50 ml of 10 $ sodium bicarbonate solution.

Een organiske fase tørres med natriumsulfat, filtreres og inddampes til tørhed. Remanensen (7,47 g) rives med 3 x 20 ml ether, hvorved der fås 6,8 g af en etheropløselig, grøn væske. Ved destillation (kogepunkt 79 37°C/0,05 mm Hg) og efterfølgende krystallisation af pentan fås 4,04 g (51$ af det teoretiske) 6-isopropylindol, smeltepunkt 40 - 41°0.An organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The residue (7.47 g) is triturated with 3 x 20 ml ether to give 6.8 g of an ether-soluble green liquid. Distillation (boiling point 79 37 ° C / 0.05 mm Hg) and subsequent crystallization of pentane give 4.04 g (51 $ of theory) of 6-isopropylindole, mp 40 - 41 ° 0.

Eksempel 14.Example 14.

En blanding af 25,1 g 4-methy1-4-nitroanisol, 42,0 g 88$’s H,H-di= methylformamid-diethylaeetal 150 ml Η,Ν-dimethylformamid opvarm mes i 70 timer under nitrogenatmosfære ved en indvendig temperatur på 140°C, idet det dannede ethanol afdestilleres kontinuerligt over en kolonne. Ee flygtige andele fjernes derefter under nitrogenatmos= fære ved formindsket tryk (indtil 95°C/0,05 mm Hg). Ved destilla= tion af remanensen fås 21,2 g (64$ af det teoretiske) trans-P-dime-thylamino-4-methoxy-2-nitrostyren i form af en mørkerød væske, koge?: punkt 152°C/0,06 mm Hg.A mixture of 25.1 g of 4-methyl-4-nitroanisole, 42.0 g of 88 $ H, H-di = methylformamide diethyl ether 150 ml of Η, Ν-dimethylformamide is heated for 70 hours under an atmosphere of nitrogen at an internal temperature. at 140 ° C, the ethanol formed being continuously distilled off over a column. One volatile fraction is then removed under nitrogen atmosphere at reduced pressure (up to 95 ° C / 0.05 mm Hg). Distillation of the residue gives 21.2 g (64 $ of theory) of trans-P-dime-thylamino-4-methoxy-2-nitrostyrene in the form of a dark red liquid, boiling point 152 ° C / 0. 06 mm Hg.

18 14389818 143898

En opløsning af 13,478 g trans-P-dimethylamino-4-methoxy-2-nitrostyren i 250 ml benzen rystes i et Parr-apparat ved et begyndelseshydrogen= tryk på 3,5 atmosfærer og i nærværelse af en halv teskefuld Raney= -nikkel, indtil hydrogenoptagelsen er gået i stå. Katalysatoren frafiltreres og vaskes nogle gange med benzen. Benzenopløsningen ekstraheres derefter med 2 x 100 ml 1M svovlsyre, 2 x 100 ml vand og 100 ml 10$’s natriumbiearbonatopløsning. Den organiske fase tør= res med natriumsulfat og inddampes til tørhed. Ved destillation af remanensen (6,7 g) fås 5,64 g (63$ af det teoretiske) 6-methoxyindol i form af et praktisk taget hvidt fast stof med smeltepunkt 88 - 90°C.A solution of 13,478 g of trans-P-dimethylamino-4-methoxy-2-nitrostyrene in 250 ml of benzene is shaken in a Parr apparatus at an initial hydrogen = pressure of 3.5 atmospheres and in the presence of half a teaspoon of Raney = nickel, until the hydrogen uptake is stopped. The catalyst is filtered off and sometimes washed with benzene. The benzene solution is then extracted with 2 x 100 ml of 1M sulfuric acid, 2 x 100 ml of water and 100 ml of 10 $ sodium biorbonate solution. The organic phase is dried over sodium sulfate and evaporated to dryness. Distillation of the residue (6.7 g) gives 5.64 g ($ 63 of theory) of 6-methoxyindole in the form of a practically white solid, mp 88-90 ° C.

Eksempel 15.Example 15

En blanding af 16,7 g 5-methoxy-2-nitrotoluen, 32,3 g N,N-dimethyl= formamid-diethylacetal og 100 ml ΪΓ,H-dimethylf ormamid opvarmes under nitrogenatmosfære i 22 timer ved en indvendig temperatur på 140°C, idet det dannede ethanol afdestilleres kontinuerligt over en kolonne. De flygtige andele fjernes i vakuum ved 25°C/0,5 mm Hg, og den mørke= røde.remanens krystalliseres af 100 ml ether og 75 ml petroleumsether, . hvorved der fås 17,0 g trans-8-dimethylamino-5-metho:xy-2-nitrostyren i form af røde krystaller med smeltepunkt 67,5 - 69,5°C. Moderluden inddampes til tørhed, og remanensen rives med 10 ml iskoldt methanol. Yed krystallisation af det på denne måde vundne faste stof (2,8 g) af 10 ml methanol fås yderligere 2,7 g af det ønskede slutprodukt med smeltepunkt 68 - 69°C. Det samlede udbytte er 19,7 g (89$ af det teoretiske).A mixture of 16.7 g of 5-methoxy-2-nitrotoluene, 32.3 g of N, N-dimethyl = formamide diethyl acetal and 100 ml of ΪΓH-dimethylformamide is heated under nitrogen atmosphere for 22 hours at an internal temperature of 140 ° C, the ethanol formed being continuously distilled off over a column. The volatiles are removed in vacuo at 25 ° C / 0.5 mm Hg and the dark red residue is crystallized by 100 ml ether and 75 ml petroleum ether. to give 17.0 g of trans-8-dimethylamino-5-metho: xy-2-nitrostyrene in the form of red crystals, mp 67.5 - 69.5 ° C. The mother liquor is evaporated to dryness and the residue is peeled with 10 ml of ice-cold methanol. After crystallization of the thus obtained solid (2.8 g) of 10 ml of methanol, an additional 2.7 g of the desired final product is obtained, mp 68-69 ° C. The total yield is 19.7 g ($ 89 of theory).

En opløsning af 11,11 g trans-β-dime thylamino-5-me thoxy-2-nitro sty= ren i 250 ml benzen rystes i et Parr-apparat ved et begyndelseshy= drogentryk på 3,5 atmosfærer i nærværelse af 230 mg 10$Ts palladi= um/kul-katalysator, indtil hydrogenoptagelsen er gået i stå. Katalysa= toren frafiltreres og vaskes nogle gange med benzen. Eiltratet ek= straheres derefter med 2 x 100 ml 1M svovlsyre, 2 x 100 ml vand og 100 ml 10$'s natriumbiearbonatopløsning. De forenede benzenfaser tørres med natriumsulfat og inddampes til tørhed. Yed destillation af remanensen (5,45 g) fås 5,26 g (72$ af det teorebiske) 5-methoxy= indol i form af en svagt gul væske med kogepunkt 108°C/0,3 mm Hg.A solution of 11.11 g of trans-β-dime thylamino-5-me thoxy-2-nitro styrene in 250 ml of benzene is shaken in a Parr apparatus at an initial hypertension of 3.5 atmospheres in the presence of 230 mg. 10 $ Ts palladi = um / coal catalyst until hydrogen uptake is stopped. The catalyst is filtered off and sometimes washed with benzene. The filtrate is then extracted with 2 x 100 ml of 1M sulfuric acid, 2 x 100 ml of water and 100 ml of 10 $ sodium biorbonate solution. The combined benzene phases are dried over sodium sulfate and evaporated to dryness. To distill off the residue (5.45 g), 5.26 g ($ 72 of the theory) of 5-methoxy = indole is obtained in the form of a pale yellow liquid, boiling at 108 ° C / 0.3 mm Hg.

Ved afkøling størkner væsken til en hvid masse med smeltepunkt 56 -57°C.On cooling, the liquid solidifies to a white mass, mp 56 -57 ° C.

Eksempel 16.Example 16.

19 14399819 143998

En blanding af 18,1 g 4,5-methylendioxy-2-nitrotoluen, 20 g N,N-di= methylformamid-diethylacetal og 100 ml υ,Ν-dimethylformamid opvarmes under nitrogenatmosfære i 17,5 timer ved en indvendig temperatur på 140°C, idet det dannede ethanol afdestilleres kontinuerligt over en kolonne. De flygtige bestanddele afdestilleres i vakuum ved en tempe= ratur på 25°C/0,05 mm Hg. Ved krystallisation af remanensen af 300 ml ethanol fås 17,0 g (72$ af det teoretiske) trans-0-dimethylamino= -4,5-methylendioxy-2-nitrostyren i form af rødbrune krystaller med smeltepunkt 114 - 116°C.A mixture of 18.1 g of 4,5-methylenedioxy-2-nitrotoluene, 20 g of N, N-di = methylformamide diethyl acetal and 100 ml of υ, Ν-dimethylformamide is heated under nitrogen atmosphere for 17.5 hours at an internal temperature of 140 ° C as the ethanol formed is continuously distilled off over a column. The volatiles are distilled off in vacuo at a temperature of 25 ° C / 0.05 mm Hg. Crystallization of the residue of 300 ml of ethanol gives 17.0 g (72 $ of theory) of trans-O-dimethylamino = -4,5-methylenedioxy-2-nitrostyrene in the form of reddish brown crystals, mp 114 - 116 ° C.

Udgangsmaterialet kan fremstilles på følgende måde:The starting material can be prepared as follows:

En opløsning af 75,0 g piperonal, 200 ml iseddike og 1 ml koncentre= ret saltsyre omrystes i en autoklav ved et begyndelseshydrogentryk på 35 atmosfærer i nærværelse af 4 g 10$'s palladium/kul-katalysator, indtil hydrogenoptagelsen er gået i stå. Katalysatoren frafiltreres, og til filtratet sættes under omrøring i løbet af 1 time en opløs= ning af 80 ml koncentreret salpetersyre i 200 ml iseddike, idet re= aktionstemperaturen ved afkøling med is/acetone holdes under 10°0.A solution of 75.0 g of piperonal, 200 ml of glacial acetic acid and 1 ml of concentrated hydrochloric acid is shaken in an autoclave at an initial hydrogen pressure of 35 atmospheres in the presence of 4 g of 10 $ palladium / carbon catalyst until hydrogen uptake is stopped . The catalyst is filtered off and to the filtrate is added a stirring solution of 80 ml of concentrated nitric acid in 200 ml of glacial acetic acid, keeping the reaction temperature by cooling with ice / acetone below 10 ° 0.

Når tilsætningen er tilendebragt, opvarmes reaktionsblandingen til stuetemperatur og hældes til en blanding af natriumhydroxid og is.When the addition is complete, the reaction mixture is warmed to room temperature and poured into a mixture of sodium hydroxide and ice.

Den på denne måde vundne suspension ekstraheres med 4 x 1000 ml me= thylenchlorid, og de forenede organiske faser tørres med natriumsul= fat, filtreres og inddampes til tørhed. Ved krystallisation af rema= nensen af 300 ml ethanol fås 76,5 g (84$ af det teoretiske) 4,5-me= thylendioxy-2-nitrotoluen i form af gule krystalnåle med smeltepunkt 85 - 86,5°C.The suspension thus obtained is extracted with 4 x 1000 ml methylene chloride and the combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness. Crystallizing the residue from 300 ml of ethanol gives 76.5 g (84 $ of theory) of 4,5-methylenedioxy-2-nitrotoluene in the form of yellow crystal needles, mp 85-86.5 ° C.

En opløsning af 11,83 g trans-p-dimethylamino-4,5-methylendioxy-2= -nitrostyren i 250 ml benzen rystes ved et begyndelseshydrog?ntryk på 3,5 atmosfærer og i nærværelse af en teskefuld Raney-nifckel, ind= til hydrogenoptagelsen er gået i stå. Katalysatoren frafiltreres og vaskes nogle gange med benzen, filtratet vaskes med 2 x 100 ml 1M svovlsyre, 100 ml vand og 100 ml 10$'s natriumbicarbonatopløsning.A solution of 11.83 g of trans-p-dimethylamino-4,5-methylenedioxy-2 = nitrostyrene in 250 ml of benzene is shaken at an initial hydrogen pressure of 3.5 atmospheres and in the presence of a teaspoon of Raney Nifckel, until the hydrogen uptake has stopped. The catalyst is filtered off and sometimes washed with benzene, the filtrate is washed with 2 x 100 ml of 1M sulfuric acid, 100 ml of water and 100 ml of 10 $ sodium bicarbonate solution.

De forenede organiske faser tørres med natriumsulfat, filtreres og inddampes til tørhed. Den brune remanens (5,52 g) opløses i benzen , og filtreres gennem aluminiumoxid. filtratet inddampes til tørhed, 20 143898 og remanensen sublimeres ved 110°C/0,2 mm Hg, hvorved der fås 5,2 g af et hvidt fast stof. Ved krystallisation af sublimatet af methy= lenchlorid/hexan fås 4*50 g (50$ af det teoretiske) 5,6-methylendioxy= indol i form af hvide krystalnåle med smeltepunkt 109,5 - 110,5°C.The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness. The brown residue (5.52 g) is dissolved in benzene and filtered through alumina. the filtrate is evaporated to dryness, and the residue is sublimated at 110 ° C / 0.2 mm Hg to give 5.2 g of a white solid. Crystallization of the sublimate of methylene chloride / hexane gives 4 * 50 g (50 $ of theory) of 5,6-methylenedioxy = indole in the form of white crystal needles, mp 109.5-110.5 ° C.

Eksempel 17.Example 17

En blanding af 15,22 g 3-nitro-o-xylen, 20 g Ν,Η-dimethylformamid= -diethylacetal og 100 ml H,F-dimethylformamid opvarmes under nitro= genatmosfære i 24 timer ved en indvendig temperatur på 140°0, idet det dannede ethanol kontinuerligt afdestilleres via en kolonne. Efter fjernelse af de flygtige andele i vakuum (indtil en temperatur på 90°C/0,1 mm Hg) destilleres remanensen, hvorved der fås 14,54 g (70$ af det teoretiske) trans-p-dimethylamino-6-methyl-2-nitrostyren i ferm af en mørkerød væske, kogepunkt 108°C/0,05 mm Hg.A mixture of 15.22 g of 3-nitro-o-xylene, 20 g of Ν, Η-dimethylformamide = diethyl acetal and 100 ml of H, F-dimethylformamide is heated under a nitrogen atmosphere for 24 hours at an internal temperature of 140 ° the ethanol formed being continuously distilled off through a column. After removing the volatiles in vacuo (up to a temperature of 90 ° C / 0.1 mm Hg), the residue is distilled to give 14.54 g (70 $ of theory) of trans-p-dimethylamino-6-methyl 2-nitrostyrene in the firm of a dark red liquid, boiling point 108 ° C / 0.05 mm Hg.

En opløsning af 9,327 g trans-β-dimethylamino-6-methyl-2-nitrostyren i 250 ml benzen rystes i et Parr-apparat ved et begyndelseshydrogen= tryk på 3,5 atmosfærer og i nærværelse af en halv teskefuld Raney= -nikkel, indtil hydrogenoptagelsen er gået i stå. Katalysatoren fra= filtreres og vaskes nogle gange med benzen. Piltratet ekstraheres derefter med 2 x 100 ml 1M svovlsyre, 2 x 100 ml vand og 100 ml 10$’s natriumbiearbonatopløsning, tørres med natriumsulfat og ind= dampes til tørhed, hvorved der fås 3,89 g af en brun olie. Ved to destillationer af råproduktet fås 3,37 g (57$ af det teoretiske) 4-methylindol i form af en gul væske med kogepunkt 82°C/0,4 mm Hg.A solution of 9,327 g of trans-β-dimethylamino-6-methyl-2-nitrostyrene in 250 ml of benzene is shaken in a Parr apparatus at an initial hydrogen = pressure of 3.5 atmospheres and in the presence of half a teaspoon of Raney = nickel, until the hydrogen uptake is stopped. The catalyst is filtered off and sometimes washed with benzene. The filtrate is then extracted with 2 x 100 ml of 1M sulfuric acid, 2 x 100 ml of water and 100 ml of 10% sodium biorbonate solution, dried over sodium sulfate and evaporated to dryness to give 3.89 g of a brown oil. Two distillations of the crude product give 3.37 g (57 $ of theory) of 4-methylindole in the form of a yellow liquid, boiling point 82 ° C / 0.4 mm Hg.

Eksempel 18.Example 18.

En blanding af 30,23 g 2-nitro-m-xylen, 64,77 g H,H-dimethylformamid= -diethylacetal og 200 ml H,F-dimethylformamid opvarmes under nitro= genatmosfære i 46 timer ved en indvendig temperatur på 140°C, idet det dannede ethanol afdestilleres kontinuerligt over en kolonne. De flygtige bestanddele afdestilleres i vakuum ved 25°C/0,5 mm Hg.A mixture of 30.23 g of 2-nitro-m-xylene, 64.77 g of H, H-dimethylformamide-diethyl acetal and 200 ml of H, F-dimethylformamide is heated under a nitrogen atmosphere for 46 hours at an internal temperature of 140 °. C, the ethanol formed being continuously distilled off over a column. The volatiles are distilled off in vacuo at 25 ° C / 0.5 mm Hg.

21 14389821 143898

Den som remanens rundne mørkerøde væske destilleres 1 vakuum, hvor= ved der fås 16,60 g (40# af det teoretiske) trans-3-dimethylamino= -3-methyl-2-nitrostyren i form af en rød væske (kogepunkt 116 -117°C/0,04 mm Hg), som ved afkøling størkner og derefter har smel= tepunkt 75 - 77°C. Forløbet (15,32 g, kogepunkt 93 - 99°C/0,02 mm Hg) består af en blanding af trans-p-dimethylamino-3-methyl-2-nitro= styren og 2-nitro-m-sylen i forholdet 3:5.The dark red liquid of the residue is distilled in 1 vacuum to give 16.60 g (40 # of theory) of trans-3-dimethylamino = -3-methyl-2-nitrostyrene as a red liquid (boiling point 116 - 117 ° C / 0.04 mm Hg) which, upon cooling, solidifies and then has a melting point of 75 - 77 ° C. The process (15.32 g, boiling point 93 - 99 ° C / 0.02 mm Hg) consists of a mixture of trans-p-dimethylamino-3-methyl-2-nitro = styrene and 2-nitro-m-sylene ratio 3: 5th

En opløsning af 10,31 g trans-P-dimethylamino-3-methyl-2-nitrostyren i 250 ml benzen rystes ved et begyndelseshydrogentryk på 3,5 atmosfæ= rer og i nærværelse af 103 mg 10#'s palladium/kul-katalysator, indtil hydrogenoptagelsen er gået i stå. Katalysatoren frafiltreres og vaskes nogle gange med benzen. Benzenfiltratet ekstraheres derefter med 2 x 100 ml 1M svovlsyre, 100 ml vand og 100 ml 10#’s natriumbi= carbonatopløsning, tørres med natriumsulfat, filtreres og inddampes til tørhed. Ved destillation af remanensen i vakuum fås 4,203 g (kogepunkt 109°C/0,9 mm Hg) af et svagt gulbrunt fast stof, som-f11= treres gennem 50 g aluminiumoxid. Ved krystallisation af filtratet af 30 ml ether/petroleumsether fås 3,15 g (48# af det teoretiske) 7-methylindol i form af hvide krystaller med smeltepunkt 83 - 84°C.A solution of 10.31 g of trans-β-dimethylamino-3-methyl-2-nitrostyrene in 250 ml of benzene is shaken at an initial hydrogen pressure of 3.5 atmospheres and in the presence of 103 mg of 10 # palladium / carbon catalyst until hydrogen uptake is stopped. The catalyst is filtered off and sometimes washed with benzene. The benzene filtrate is then extracted with 2 x 100 ml of 1M sulfuric acid, 100 ml of water and 100 ml of 10 # sodium bicarbonate solution, dried with sodium sulfate, filtered and evaporated to dryness. By distillation of the residue in vacuo, 4.203 g (boiling point 109 ° C / 0.9 mm Hg) of a pale yellow-brown solid is obtained, which is f11 = triturated through 50 g of alumina. Crystallization of the filtrate of 30 ml of ether / petroleum ether gives 3.15 g (48 # of theory) of 7-methylindole in the form of white crystals, mp 83-84 ° C.

Eksempel 19.Example 19.

En blanding af 98,6 g 4,5-dimethoxy-2-nitrotoluen, 500 ml H,N-dime= thylformamid og '120 g N, Ν'-dime thylformamiddimethylacetal opvarmes under nitrogenatmosfære i 42 timer ved en indvendig temperatur på 140°C. De flygtige andele fjernes i vakuum ved 25°C/0,1 mm Hg. Den faste remanens består af råt trans-P-dimethylamino-4,5-dimethoxy-2= -nitrostyren. Yed krystallisation af en prøve af methanol fås trans= -P-dimethylamino-4,5-dimethoxy-2^nitrostyren med smeltepunkt 125 -126° C.A mixture of 98.6 g of 4,5-dimethoxy-2-nitrotoluene, 500 ml of H, N-dime = thylformamide and '120 g of N, Ν'-dime thylformamide dimethyl acetal is heated under nitrogen for 42 hours at an internal temperature of 140 ° C. The volatiles are removed in vacuo at 25 ° C / 0.1 mm Hg. The solid residue consists of crude trans-β-dimethylamino-4,5-dimethoxy-2 = -nitrostyrene. After crystallization of a sample of methanol, trans = -P-dimethylamino-4,5-dimethoxy-2 ^ nitrostyrene is obtained, m.p. 125 -126 ° C.

En opløsning af det rå trans-P-dimethylamino-4,5-dimethoxy-2-nitro= styren, fremstillet som beskrevet ovenfor, i 2 liter benzen omrystes i 22 143898 nærværelse af 10 g 10$'s palladium/kul-katalysator ved et begyndel= seshydrogentryk på 7 atmosfærer. Mr hydrogenoptagelsen er gået i stå (3 molækvi'valenter)ffrafiltreres katalysatoren, som vaskes med 2 liter benzen. Filtraterne inddampes i vakuum til et rumfang på 2 liter og ekstraheres med 3 x 300 ml IH svovlsyre, 200 ml IH natrium= hydroxidopløsning og 200 ml vand. Den organiske fase tørres med na= triumsulfat og filtreres gennem 2S0 g silicagel. Filtratet inddampes til tørhed, og remanensen rives med ether. Yed krystallisation af det som remanens vundne hvide faste stof af 700 ml benzen fås 24,5 g (28$ af det teoretiske) 5,6-dimethoxyindol i form af hvide krystaller, smeltepunkt 154 - 155°C.A solution of the crude trans-β-dimethylamino-4,5-dimethoxy-2-nitro = styrene, prepared as described above, in 2 liters of benzene is shaken in the presence of 10 g of 10 $ palladium / carbon catalyst at a beginning = sesh hydrogen pressure of 7 atmospheres. After hydrogen uptake is stopped (3 molar equivalents), the catalyst is filtered off, which is washed with 2 liters of benzene. The filtrates are evaporated in vacuo to a volume of 2 liters and extracted with 3 x 300 ml IH sulfuric acid, 200 ml IH sodium = hydroxide solution and 200 ml water. The organic phase is dried over sodium sulfate and filtered through 2S0 g of silica gel. The filtrate is evaporated to dryness and the residue is triturated with ether. To crystallize the white solid obtained as the residue from 700 ml of benzene, there is obtained 24.5 g (28 $ of theory) of 5,6-dimethoxyindole in the form of white crystals, mp 154 - 155 ° C.

Eksempel 20.Example 20

En blanding af 87,3 g 4,5-dibenzyloxy-2-nitrotoluen, 38,0 g H,H-di= methylformamid-dimethylacetal og 250 ml Η,Η-dimethylformamid opvarmes under nitrogenatmosfære i 48- timer ved en indvendig temperatur på 140°0, idet det dannede methanol afdestilleres kontinuerligt over en kolonne. De flygtige bestanddele afdestilleres i vakuum (badtem= peratur 65°C/0,1 mm Hg). Yed krystallisation af remanensen af metha= nol (2,5 liter) fås 86,8 g af et rødt fast stof, smeltepunkt 99 -100°C. En analytisk prøve fra et forudgående forsøg kan identifice= res som trans-4,5-dibenzyloxy-^-dimethylamino-2-nitrostyren, smelte= punkt 99,5 - 101°C.A mixture of 87.3 g of 4,5-dibenzyloxy-2-nitrotoluene, 38.0 g of H, H-di = methylformamide-dimethylacetal and 250 ml of Η, Η-dimethylformamide is heated under a nitrogen atmosphere for 48 hours at an internal temperature of 140 ° 0, the methanol formed being continuously distilled off over a column. The volatiles are distilled off in vacuo (bath temperature = 65 ° C / 0.1 mm Hg). To crystallize the residue of methanol (2.5 liters) 86.8 g of a red solid, m.p. 99-100 ° C are obtained. An analytical sample from a previous experiment can be identified as trans-4,5-dibenzyloxy-β-dimethylamino-2-nitrostyrene, melting = 99.5-101 ° C.

En opløsning af 10,11 g trans-4,5-dibenzyloxy-3-dimethylamino-2-ni= trostyren i 250 ml benzen rystes i et Parr-apparat ved et begyndel= seshydrogentryk på 3,5 atmosfærer og i nærværelse af en teskefuld Raney-nikkel, indtil hydrogenoptagelsen er gået i stå. Filtratet ekstraheres derefter med 3 x 100 ml IH svovlsyre, 250 ml vand, 3 x 100 ml IH natriumhydroxidopløsning og til slut 250 ml vand. De for= enede organiske faser tørres med natriumsulfat, filtreres og inddam= pes til tørhed. Remanensen (7,67 g) opløses i en ringe mængde benzen og.chromatograferes på 40 g silicagel. De eluerede fraktioner (ben= 23 143898 zen/hexan 1:1) forenes i overensstemmelse med tyndtlagschromatogram= met. Efter fjernelse af opløsningsmidlerne krystalliseres remanensep (5,8 g) af benzen/hexan, hvorved der fås 4>34 g (54$ af det teore= tiske) 5,6-dibenzyloxyindol i form af hvide krystalnåle med smelte= punkt 112 - 113°C.A solution of 10.11 g of trans-4,5-dibenzyloxy-3-dimethylamino-2-ni = trostyrene in 250 ml of benzene is shaken in a Parr apparatus at an initial hydrogen pressure of 3.5 atmospheres and in the presence of a teaspoon Raney nickel until hydrogen uptake is stopped. The filtrate is then extracted with 3 x 100 ml 1 H sulfuric acid, 250 ml water, 3 x 100 ml 1 H sodium hydroxide solution and finally 250 ml water. The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness. The residue (7.67 g) is dissolved in a small amount of benzene and chromatographed on 40 g of silica gel. The eluted fractions (leg = 23 zen / hexane 1: 1) are combined according to the thin layer chromatogram. After removal of the solvents, residue residue (5.8 g) of benzene / hexane is crystallized to give 4> 34 g ($ 54 of the theoretical) 5,6-dibenzyloxyindole in the form of white crystal needles with melt = pp. 112 - 113 ° C.

Eksempel 21.Example 21.

En blanding af 13,7 g (0,10 mol) o-nitrotoluen, 16,0 g (0,11 mol) N-formylpyrrolidin-dimethylacetal og 50 ml Ν,Ν-dimethylformamid op= varmes under nitrogenatmosfære i 1,5 time ved en indvendig tempera= tur på 130 - 150°C, idet det dannede methanol afdestilleres konti= nuerligt over en kolonne. Efter fjernelse af de flygtige andele ved vakuumdestillation (badtemperatur 50°C/l mm Hg) fås som remanens råt trans-2-nitro-P-pyrrolidinostyren i form af en rød væske. Det rå produkt renses i 100 ml benzen og rystes ved et begyndelseshydrogéh» tryk på 3,5 atmosfærer og i nærværelse af 440 mg 10$’s palladium/kul= -katalysator, indtil hydrogenoptagelsen er tilendebragt (3 mol= ækvivalenter). Katalysatoren frafiltreres under anvendelse af diato=# méjord og vaskes tre gange med 50 ml benzen. Filtratet ekstraheres derefter med 2 x 200 ml 1M svovlsyre, 2 x 200 ml vand og 100 ml 1M ' natriumcarbonatopløsning i den angivne rækkefølge. Den organiske fase tørres med natriumsulfat, filtreres og inddampes til tørhed på rota= tionsfordamper. Yed destillation af remanensen (11,0 g) fås 9,61 g (82$ af det teoretiske) indol, kogepunkt 78°C/0,3 mm Hg, smeltepunkt 50 - 51,5°C.A mixture of 13.7 g (0.10 mol) of o-nitrotoluene, 16.0 g (0.11 mol) of N-formylpyrrolidine-dimethyl acetal and 50 ml of Ν, Ν-dimethylformamide is heated under a nitrogen atmosphere for 1.5 hours. at an internal temperature of 130 - 150 ° C, the methanol formed being continuously distilled off over a column. After removal of the volatiles by vacuum distillation (bath temperature 50 ° C / 1 mm Hg), the crude trans-2-nitro-P-pyrrolidino styrene residue is obtained as a red liquid. The crude product is purified in 100 ml of benzene and shaken at an initial hydrogen pressure of 3.5 atmospheres and in the presence of 440 mg of 10 $ palladium / carbon = catalyst until hydrogen uptake is complete (3 mol = equivalents). The catalyst is filtered off using diatomaceous earth and washed three times with 50 ml of benzene. The filtrate is then extracted with 2 x 200 ml of 1M sulfuric acid, 2 x 200 ml of water and 100 ml of 1M sodium carbonate solution in the order given. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness on a rotary evaporator. To distill the residue (11.0 g), 9.61 g ($ 82 of theory) of indole is obtained, boiling point 78 ° C / 0.3 mm Hg, mp 50-51.5 ° C.

Eksempel 22.Example 22.

En blanding af 13,40 g (0,10 mol) o-nitrotoluen, 13,40 g (0,10 mol) N-formylpiperidin-dimethylacetal og 25 ml Ν,Ν-dimethylformamid opvarm mes under nitrogenatmosfære i 3 timer ved en indvendig temperatur på 130 - 150°C, idet det dannede methanol afdestilleres kontinuer= ligt over en kolonne. Efter fjernelse af de flygtige bestanddele i vakuum (vandbad 60°C/0,5 mm Hg) fås som remanens råt trans-2-nitro= -β-piperidinostyren i form af en rød væske. Det rå produkt opløses i 250 ml benzen og rystes ved et hydrogenbegyndelsestryk på 3,5 atmosfærer i nærværelse af 0,460 g 5$*s palladium/kul, indtil hydro= 24 143898 genoptagelsen er gået i stå (3 molækvivalenter). Katalysatoren fra= filtreres og vaskes nogle gange med benzen. Filtratet ekstråheres derefter med 3 x 100 ml 1M svovlsyre, 100 ml vand, 2 x 100 ml IN natriumhydroxidopløsning og 100 ml vand. De organiske faser tørres med natriumsulfat, filtreres og inddampes til tørhed. Ved destilla= tion af den brune remanens (9,06 g) fås 7,66 g (70$ af det teoretiske) indol, kogepunkt 60 - 65°C/0,06 mm Hg, smeltepunkt 44 - 49°C.A mixture of 13.40 g (0.10 mole) of o-nitrotoluene, 13.40 g (0.10 mole) of N-formylpiperidine-dimethyl acetal and 25 ml of Ν, Ν-dimethylformamide is heated under an atmosphere of nitrogen for 3 hours. temperature of 130 - 150 ° C, the methanol formed being continuously distilled off over a column. After removal of the volatiles in vacuo (water bath 60 ° C / 0.5 mm Hg), as the crude residue of the residue, trans-2-nitro = -β-piperidinostyrene is obtained in the form of a red liquid. The crude product is dissolved in 250 ml of benzene and shaken at a hydrogen initial pressure of 3.5 atmospheres in the presence of 0.460 g of 5 $ * palladium / coal until hydro = 24 resumption is stopped (3 molar equivalents). The catalyst is filtered off and sometimes washed with benzene. The filtrate is then extracted with 3 x 100 ml of 1M sulfuric acid, 100 ml of water, 2 x 100 ml of 1N sodium hydroxide solution and 100 ml of water. The organic phases are dried over sodium sulfate, filtered and evaporated to dryness. Distillation of the brown residue (9.06 g) gives 7.66 g (70 $ of theory) of indole, boiling point 60 - 65 ° C / 0.06 mm Hg, mp 44 - 49 ° C.

Eksempel 23.Example 23

En.blanding af 8,25 g 4-methyl-3-nitrobenzaldehyd, 11,1 g N,N-di= methylformamid-diethylacetal og 50 ml Ν,ΪΓ-dimethylformamid opvarmes i.45 minutter i et oliebad ved 145°C under nitrogenatmosfære. De flygtige andele fjernes i vakuum ved 25°C/0,5 mm Hg, og den mørkerøde remanens rives tre gange med 10 ml petroleumsether. Den faste rema= nens krystalliseres af methanol, hvorved der fås 5,47 g af et råt produkt. Ved omkrystallisation af 100 ml methylenchlorid/ether fås 4,61 g trans-4-(β-dimethylaminovinyl)-3-nitrobenzaldehyd i form af røde krystaller, smeltepunkt 134 - 136°C. Moderluden inddampes til tørhed, og remanensen krystalliseres af 12 ml ethylacetat, hvorved der fås yderligere 2,21 g af det ønskede slutprodukt, smeltepunkt 134 - 136°-C. Det samlede udbytte er 6,81 g (62$ af det teoretiske).A mixture of 8.25 g of 4-methyl-3-nitrobenzaldehyde, 11.1 g of N, N-di = methylformamide-diethyl acetal and 50 ml of Ν, ΪΓ-dimethylformamide is heated for 45 minutes in an oil bath at 145 ° C. nitrogen atmosphere. The volatiles are removed in vacuo at 25 ° C / 0.5 mm Hg and the dark red residue is triturated three times with 10 ml of petroleum ether. The solid residue is crystallized by methanol to give 5.47 g of a crude product. Recrystallization of 100 ml of methylene chloride / ether gives 4.61 g of trans-4- (β-dimethylaminovinyl) -3-nitrobenzaldehyde in the form of red crystals, m.p. 134 - 136 ° C. The mother liquor is evaporated to dryness and the residue is crystallized by 12 ml of ethyl acetate to give an additional 2.21 g of the desired final product, mp 134 - 136 ° C. The total yield is 6.81 g ($ 62 of theory).

Eksempel 24.Example 24.

En blanding af 6,85 g (0,05 mol) o-nitrotoluen, 7,25 g (0,05 mol) N-formylpyrrolidin-dimethylacetal og 25 ml N,N-dimethylformamid op= varmes i 1 time under nitrogenatmosfære i et oliebad ved 160°C, idet det dannede methanol afdestilleres kontinuerligt over en kolonne (2,8 ml). Efter fjernelse af de flygtige bestanddele ved vakuumdestil= lation destilleres en del af remanensen under delvis spaltning i et kortvejs-destillationsapparat (badtemperatur 150°C/0,1 mm Hg). De= stillatet underkastes derefter 2 gange molekyldestillation (badtem= peratur 110°C/0,04 mm Hg), idet der hver gang kasseres et lille for= løb. På denne måde fås 560 mg analyserent trans-2-nitro-p-pyrrolidi= no-styren i form af en rød væske.A mixture of 6.85 g (0.05 mole) of o-nitrotoluene, 7.25 g (0.05 mole) of N-formylpyrrolidine-dimethyl acetal and 25 ml of N, N-dimethylformamide is heated for 1 hour under an atmosphere of nitrogen. oil bath at 160 ° C, the methanol formed being continuously distilled off over a column (2.8 ml). After removal of the volatiles by vacuum distillation, part of the residue is distilled under partial decomposition in a short-distance distillation apparatus (bath temperature 150 ° C / 0.1 mm Hg). The = scaffold is then subjected to 2 times molecular distillation (bath temperature = 110 ° C / 0.04 mm Hg), discarding a small feed each time. In this way, 560 mg of analytically pure trans-2-nitro-p-pyrrolidine-no styrene is obtained in the form of a red liquid.

Eksempel 25.Example 25

25 14389825 143898

En blanding af 6,85 g o-nitrotoluen, 8,76 g N-formylpiperidin-dimeth;y\L= acetal og 25 ml Ν,Ν-dimethylformamid opvarmes under nitrogenatmosfære i 7 timer i et oliebad ved 150°G, idet det dannede methanol afdestil= leres kontinuerligt over en kolonne (4 ml). Efter fjernelse af de flygtige bestanddele destilleres remanensen i vakuum, hvorved der kan opfanges tre fraktioner: 2,86 g (kogepunkt 144 - 145°C/0,06 mm Hg) 0,73 g (kogepunkt 145 - 146°0/0,06 mm Hg) og 5,35 g (kogepunkt 146 -147°0/0,07 mm Hg). Een sidste fraktion består af analyserent trans« -5-nitro-P-piperidinostyren.A mixture of 6.85 g of o-nitrotoluene, 8.76 g of N-formylpiperidine-dimethyl γ = L acetal and 25 ml of Ν, dim-dimethylformamide is heated under a nitrogen atmosphere for 7 hours in an oil bath at 150 ° G. formed methanol is distilled off continuously over a column (4 ml). After removal of the volatiles, the residue is distilled in vacuo to give three fractions: 2.86 g (boiling point 144 - 145 ° C / 0.06 mm Hg) 0.73 g (boiling point 145 - 146 ° 0/0), 06 mm Hg) and 5.35 g (boiling point 146 -147 ° 0 / 0.07 mm Hg). One final fraction consists of assay trans? -5-nitro-β-piperidino styrene.

Eksempel 26.Example 26

En blanding af 8,35 g (50 millimol) 3-methyl-4-nitroanisol, 8,0 g (55 millimol) N-formylpyrrolidin-dimethylacetal og 25 ml N,N-dime« thylformamid opvarmes under nitrogenatmosfære i 2 timer ved en ind=? vendig temperatur på 135°C, idet det dannede methanol afdestilleres kontinuerligt over en kolonne. Ee flygtige bestanddele afdestilleres i vakuum (badtemperatur 40°C/1 mm Hg), og den røde remanens krystal« liseres af 75 ml methanol, idet der fås 2 fraktioner røde krystalnåle på i alt 11,7 g (94$ af det teoretiske), smeltepunkt 71 - 72°C.A mixture of 8.35 g (50 millimoles) of 3-methyl-4-nitroanisole, 8.0 g (55 millimoles) of N-formylpyrrolidine-dimethyl acetal and 25 ml of N, N-dimethylformamide is heated under a nitrogen atmosphere for 2 hours. in =? operating temperature of 135 ° C, the methanol formed being continuously distilled off over a column. One volatiles are distilled off in vacuo (bath temperature 40 ° C / 1 mm Hg) and the crystal of the red residue is lysed by 75 ml of methanol to give 2 fractions of red crystal needles totaling 11.7 g ($ 94 of theory) , mp 71-72 ° C.

Yed omkrystallisation af en prøve af den første fraktion af methanol fås analyserent trans-5-metho:xy-2-nitro-p-pyrrolidinostyren, smelte* punkt 71 - 72°C.To recrystallize a sample of the first fraction of methanol, analytical trans-5-metho: xy-2-nitro-p-pyrrolidino styrene is obtained, m.p. 71 - 72 ° C.

Eksempel 27.Example 27

En blanding af 8,55 g (0,050 mol) 5-methyl-4-nitroanisol, 14,58 g (0,062 mol) Ν,Ν-dimethylformamid-dineppentylacetal og 50 ml N,N-di= methylformamid opvarmes under nitrogenatmosfære i 41 timer til til=. bagesvaling. Efter fjernelse af de flygtige bestanddele destilleres remanensen i vakuum, hvorved der fås 4,75 g af en rød væske (153°C/0,04 mm Hg), som efter gnidning krystalliserer, smeltepunkt 61 - 65°C.A mixture of 8.55 g (0.050 mol) of 5-methyl-4-nitroanisole, 14.58 g (0.062 mol) of Ν, Ν-dimethylformamide dinepentyl acetal and 50 ml of N, N-di = methylformamide is heated under nitrogen atmosphere for 41 hours. to to =. refluxing. After removal of the volatiles, the residue is distilled in vacuo to give 4.75 g of a red liquid (153 ° C / 0.04 mm Hg) which crystallizes after rubbing, mp 61-65 ° C.

Efter omkrystallisation af 70 ml ether/petroleumsether fås 3,70 g (33$ af det teoretiske) trans-p-dimethylamino-5-methoxy-2-nitrosty= ren, smeltepunkt 68,5 - 69,5°0.After recrystallization from 70 ml of ether / petroleum ether, 3.70 g (33 $ of theory) of trans-p-dimethylamino-5-methoxy-2-nitrostysteine, m.p. 68.5-69.5 ° are obtained.

U3898 26U3898 26

Eksempel 28.Example 28.

En blanding af 3,0 g (0,018 mol) 3-methyl-4-nitroanisol, 5,1 g (0,020 mol) H,H-dimethylformamid-dicyclohexylacetal og 25 ml H,H-dimethyl= formamid opvarmes under nitrogenatmosfære i 40 timer til tilbagesva= ling. Efter fjernelse af de flygtige bestanddele destilleres remanen= sen i vakuum, hvorved der fås 1,89 g af en rød væske, kogepunkt 158°C/0,04 mm Hg, som krystalliserer efter gnidning, smeltepunkt 61 - 64°C. Ved omkrystallisation af 10 ml ether og 7 ml petroleums= ether fås 1,46 g (36$ af det teoretiske) trans^-dimethylamino-5= -methoxy-2-nitrostyren, smeltepunkt 67,5 - 69°C.A mixture of 3.0 g (0.018 mol) of 3-methyl-4-nitroanisole, 5.1 g (0.020 mol) of H, H-dimethylformamide dicyclohexyl acetal and 25 ml of H, H-dimethyl = formamide is heated under a nitrogen atmosphere for 40 hours. for reversal. After removing the volatiles, the residue is distilled in vacuo to give 1.89 g of a red liquid, boiling point 158 ° C / 0.04 mm Hg, which crystallizes after rubbing, mp 61-64 ° C. Recrystallization of 10 ml of ether and 7 ml of petroleum = ether gives 1.46 g (36 $ of theory) of trans -dimethylamino-5 = -methoxy-2-nitrostyrene, m.p. 67.5-69 ° C.

Eksempél29.Example 29.

En blanding af 16,71 g (0,10 mol) 3-methyl-4-nitroanisol, 30,00 g (0,11 mol) Η,Η-dimethylformamid-dibenzylacetal og 50 ml E,E-dime= thylformamid opvarmes under nitrogenatmosfære i 17 timer til tilbage= svaling. Efter fjernelse af de flygtige bestanddele destilleres re= manensen i vakuum, hvorved der fås 9,42 g af en rød væske (koge= punkt 158°C/0,10 mm Hg), som efter gnidning giver et klæbrigt fast stof.' Ved krystallisation af 150 ml ether/petroleumsether fås to fraktioner på i alt 7,15 g (32$ af det teoretiske) trans-P-dimethyl= amino-5-methoxy-2-nitrostyren, smeltepunkt 68,0 - 69,5°C.A mixture of 16.71 g (0.10 mol) of 3-methyl-4-nitroanisole, 30.00 g (0.11 mol) of Η, Η-dimethylformamide-dibenzyl acetal and 50 ml of E, E-dimethylformamide is heated under nitrogen atmosphere for 17 hours for back = cooling. After removal of the volatiles, the residue is distilled in vacuo to give 9.42 g of a red liquid (boiling = point 158 ° C / 0.10 mm Hg) which after rubbing gives a sticky solid. Crystallization of 150 ml of ether / petroleum ether gives two fractions totaling 7.15 g (32 $ of theory) of trans-β-dimethyl = amino-5-methoxy-2-nitrostyrene, m.p. 68.0 - 69.5 ° C.

Eksempel 30.Example 30.

En blanding af 8,35 g (50 millimol) 3-methyl-4-nitroanisol, 8,76 g (75 millimol) ΪΓ,ΕΓ-dime thylformamid-ethylenacetal (2-dimethylamino= -1,3-dioxolan) og 25 ml ΙΓ,ΕΓ-dime thylf ormamid opvarmes under nitrogen^ atmosfære i 53 timer ved 150°G. Ved fjernelse af de flygtige bestand= dele destilleres remanensen i vakuum, hvorved der fås 4,00 g af en rød væske (kogepunkt 149°C/0,07 mm Hg), som efter gnidning giver et gummiagtigt fast stof. Ved krystallisation af 15 ml methanol fåsA mixture of 8.35 g (50 millimoles) of 3-methyl-4-nitroanisole, 8.76 g (75 millimoles) of ΪΓ, ΕΓ-dime thylformamide-ethylene acetal (2-dimethylamino = -1,3-dioxolane) and 25 ml ΙΓ, ΕΓ-dime thylph ormamide is heated under nitrogen ^ atmosphere for 53 hours at 150 ° G. Upon removal of the volatiles, the residue is distilled in vacuo to give 4.00 g of a red liquid (boiling point 149 ° C / 0.07 mm Hg) which after rubbing gives a gummy solid. Crystallization of 15 ml of methanol is obtained

Claims (2)

143898 27 1,57 g (14$ af det teoretiske) trans-P-dimethylamino-5-metho:xy-2= -nitrostyren, smeltepunkt 68 - 69°C. Patentkrav.1.57 g (14 $ of theory) of trans-β-dimethylamino-5-metho: xy-2 = -nitrostyrene, m.p. 68-69 ° C. Claims. 1. Fremgangsmåde til fremstilling af indoler med den almene formel I El|K_ xJL nJJ 1 R2^ B 1 2 hvor R og R hver for sig betegner hydrogen, C^_7-alkyl, aryl, hydroxy, C^_7~alkoxy, aryl-C^_7-alkoxy, aryloxy, acyloxy, formyl, aroyl, hydroxymethyl, aryl-hydroxymethyl, carboxy, C1_7-alkoxy= carbonyl, carbamoyl, halogen, amino, mono~C^_7-alkylamino, di= -C1_7~alkylamino, C1_7~alkoxycarbonylamino, aryl-C^_7-alkoxycar= bonylamino, acylamino, N-C. 7-alkylacylamino, di-C. 7-alkylform= i-/ ^ 2±-/ amidino eller di-C^_7~alkoxymethyl, eller R og R tilsammen be= tegner C2_g-alkylendioxy, kendetegnet ved, at man kondenserer en o-nitrotoluen med den almene formel III R1 i^V'0®3 V i 111 hvor R1 og R2 har de ovenfor anførte betydninger, med en formamid= acetal med den almene formel IV R50 R5 \ 4 Rb0 R4 IVA process for the preparation of indoles of the general formula I El | K_ xJL nJJ 1 R2 ^ B 1 2 wherein R and R are each independently hydrogen, C1-7 alkyl, aryl, hydroxy, C1-7 alkoxy, aryl -C 1-7 alkoxy, aryloxy, acyloxy, formyl, aroyl, hydroxymethyl, aryl hydroxymethyl, carboxy, C 1-7 alkoxy = carbonyl, carbamoyl, halogen, amino, mono-C 1-7 alkylamino, di = -C 1-7 alkylamino, C1-7 alkoxycarbonylamino, aryl C1-7 alkoxycar = bonylamino, acylamino, NC. 7-alkylacylamino, di-C. 7-alkyl form = 1 - 2 ± - / amidino or di-C 1-7 alkoxymethyl, or R and R together represent C 2 wherein R 1 and R 2 have the meanings given above, with a formamide = acetal of the general formula IV R 50 R 5 \ 4 R b0 R 4 IV