DK150143B - ANALOGY PROCEDURE FOR THE PREPARATION OF INCIDENTAL DERIVATIVES - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF INCIDENTAL DERIVATIVES Download PDFInfo
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Description
150143150143
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte indolderivater (derivater af imidazo/I,2-a7indoler, pyrimido/I,2-a7indoler og diazepino/I,2-a/ indoler) med den almene formel 2 1501 A3 -w \ -r r5 r r1 l6 hvor R betyder hydroxyl, alkoxy med højst 6 carbonatomer, phenyl-alkoxy med højst 6 carbonatomer i alkoxygruppen, tetrahydropyra-nyloxy eller acyloxy med højst 6 carbonatomer, R^ betyder en phenyl- eller naphtylgruppe, der eventuelt er substitueret en eller to gange med halogen, alkyl med højst 6 carbonatomer, alkoxy med højst 6 carbonatomer eller trifluormethyl, eller R^ betyder thienyl, pyridyl, phenalkyl med højst 6 carbonatomer i alkylgrup-pen, alkyl med højst 6 carbonatomer, alkenyl med højst 6 carbonatomer, alkynyl med højst 6 carbonatomer eller aminoalkyl med højst 2 5 6 carbonatomer i alkylgruppen, R og R er ens eller forskellige og betyder hver for sig hydrogen, hydroxyl, alkyl med højst 6 carbonatomer, alkoxy med højst 6 carbonatomer, trifluormethyl, halogen, amino eller mono- eller dialkylamino, hvor alkylgruppen inde- 3 4 holder højst 6 carbonatomer, R og R er ens eller forskellige og betyder hver for sig hydrogen eller alkyl med højst 6 carbonatomer, 3 4 eller R betyder hydrogen, og R betyder hydroxy, n er 0, 1 eller 2, den punkterede linie repræsenterer en eventuel binding i den angivneThe present invention relates to an analogous process for the preparation of novel indole derivatives (derivatives of imidazo / I, 2-a-indoles, pyrimido / I, 2-a7 indoles and diazepino / I, 2-a / indoles) of the general formula 2 1501 A3-w where R is hydroxyl, alkoxy of not more than 6 carbon atoms, phenyl-alkoxy of not more than 6 carbon atoms in the alkoxy group, tetrahydropyryloxy or acyloxy of not more than 6 carbon atoms, R4 is a phenyl or naphthyl group optionally substituted once or twice by halogen, alkyl of not more than 6 carbon atoms, alkoxy of not more than 6 carbon atoms, or trifluoromethyl, or R 2 carbon atoms, alkynyl of not more than 6 carbon atoms or aminoalkyl of not more than 26 carbon atoms in the alkyl group, R and R are the same or different and each represents hydrogen, hydroxyl, alkyl of not more than 6 carbon atoms, alkoxy of not more than 6 carbon atoms r, trifluoromethyl, halogen, amino or mono- or dialkylamino, wherein the alkyl group contains at most 6 carbon atoms, R and R are the same or different and each independently means hydrogen or alkyl of not more than 6 carbon atoms, 3 4 or R means hydrogen and R is hydroxy, n is 0, 1 or 2, the dotted line represents a possible bond in the indicated
CC
stilling, og R , der kun er til stede, når den eventuelle binding repræsenteret ved den punkterede linie, ikke findes, betyder hydrogen eller phenalkyl med højst 6 carbonatomer i alkylgruppen, alkyl med højst 6 carbonatomer, alkenyl med højst 6 carbonatomer, alkynyl med højst 6 carbonatomer, aminoalkyl med højst 6 carbonatomer i alkylgruppen eller acyl med højst 6 carbonatomer, eller farmaceutisk acceptable syreadditionssalte ellerkvaternære ammoniumsalte deraf.position and R present only when the optional bond represented by the dotted line does not exist means hydrogen or phenalkyl of not more than 6 carbon atoms in the alkyl group, alkyl of not more than 6 carbon atoms, alkenyl of not more than 6 carbon atoms, alkynyl of not more than 6 carbon atoms, aminoalkyl of not more than 6 carbon atoms in the alkyl group or acyl of not more than 6 carbon atoms, or pharmaceutically acceptable acid addition salts or quaternary ammonium salts thereof.
3 43 4
Det er klart, at R og R kan være knyttet til samme eller forskellige carbonatomer, men det foretrækkes, at de er knyttet til samme carbonatom, f. eks. i 3-stillingen i pyrimido [1,2-a]indolerne eller i 2-stillingen (eller 3-stillingen) i imidazo [1,2-a]indolerne. Ved udtrykket amino-alkyl anvendt i forbindelse med gruppen R^ forstås usubstitueret aminoalkyl eller mono- eller disubstitueret aminoalkyl såsom alkylamino-alkyl, dialkylamino-alkyl eller heterocyclo-alkyl.Obviously, R and R may be attached to the same or different carbon atoms, but it is preferred that they be attached to the same carbon atom, for example at the 3-position of the pyrimido [1,2-a] indoles or in 2 position (or 3 position) in the imidazo [1,2-a] indoles. The term aminoalkyl used in conjunction with the group R ^ means unsubstituted aminoalkyl or mono- or disubstituted aminoalkyl such as alkylaminoalkyl, dialkylaminoalkyl or heterocycloalkyl.
150143 3150143 3
Da de her omhandlede forbindelser kan indeholde ét eller flere asymmetriske carbonatomer, er der mulighed for forekomst af optiske enantiomorfe former, og de her omhandlede forbindelser kan være de rene enantiomorfe former eller blandinger af sådanne enantiomorfe former, f.eks. racematerne.Since the compounds of the present invention may contain one or more asymmetric carbon atoms, there is the possibility of the occurrence of optical enantiomorphic forms, and the compounds of the invention may be the pure enantiomorphic forms or mixtures of such enantiomorphic forms, e.g. racemates.
Eksempler på R er hydroxyl, methoxy, ethoxy, n-propoxy, iso- -propoxy, n-butoxy, benzyloxy, phenethoxy, acetoxy, propionoxy og butyryloxy. Eksempler på R1 er eventuelt substitueret phenyl og naphthyl, thienyl og pyridyl. Egnede substituenter er halogen, f.eks. fluor, chlor eller brom, alkyl, f. eks. methyl, ethyl, propyl eller butyl, alkoxy, f. eks. methoxy, ethoxy, propoxy eller butoxy, og halogenalkyl, f. eks. trifluormethyl. Eksempler på phenalkylgrup- per R^· er benzyl og phenethyl, der hver især kan være substitueret med de ovenfor for arylgrupperne R1 anførte substituenter. Alkylgrup- per R1 kan være methyl, ethyl, propyl eller butyl, alkenylgrupperne kan være ligekædet eller forgrenede og er f. eks. allyl eller dime- thylallyl, alkynylgrupperne kan være ligekædede eller forgrenede og er f. eks. propargyl. Aminoalkylgrupper kan f. eks. være dimethylami- no-ethyl, dimethylaminopropyl, diethylaminopropyl, diethylaminoethyl, methylaminoethy1, methylaminopropyl, morfolinopropyl og piperdino- 2 5 propyl. Som eksempler på R og R kan nævnes alkyl, f. eks. methyl, ethyl, propyl og butyl, eller alkoxy, f. eks. methoxy, ethoxy, propoxy og butoxy. Halogenalkyl kan f. eks. være trifluormethyl, og halo- 3 gen kan f. eks. være chlor og brom. Eksempler på alkylgrupper R og 4 R er methyl, ethyl, propyl og butyl.Examples of R are hydroxyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, benzyloxy, phenethoxy, acetoxy, propionoxy and butyryloxy. Examples of R1 are optionally substituted phenyl and naphthyl, thienyl and pyridyl. Suitable substituents are halogen, e.g. fluorine, chlorine or bromine, alkyl, for example methyl, ethyl, propyl or butyl, alkoxy, for example methoxy, ethoxy, propoxy or butoxy, and haloalkyl, for example trifluoromethyl. Examples of phenalkyl groups R 2 are benzyl and phenethyl, each of which may be substituted by the substituents listed above for the aryl groups R 1. Alkyl groups R 1 can be methyl, ethyl, propyl or butyl, the alkenyl groups can be straight or branched and are, for example, allyl or dimethyl allyl, the alkynyl groups can be straight or branched and are, for example, propargyl. Aminoalkyl groups may be, for example, dimethylaminoethyl, dimethylaminopropyl, diethylaminopropyl, diethylaminoethyl, methylaminoethyl, methylaminopropyl, morpholinopropyl and piperidinopropyl. Examples of R and R include alkyl, for example, methyl, ethyl, propyl and butyl, or alkoxy, for example, methoxy, ethoxy, propoxy and butoxy. For example, haloalkyl may be trifluoromethyl, and halogen may be chlorine and bromine, for example. Examples of alkyl groups R and 4 R are methyl, ethyl, propyl and butyl.
Eksempler på phenalkylgrupper R° er benzyl og phenethyl, som hver for sig kan være substitueret med de ovenfor i forbindelse *L g med arylgrupperne R anførte substituenter. Alkylgrupper R kan være ligekædet eller forgrenet og indbefatter f.eks. methyl, ethyl, propyl og butyl, alkenylgrupperne kan være ligekædet eller forgrenede og kan f.eks. være alkyl eller dimethylallyl, alkynylgrupperne kan være ligekædet eller forgrenede og kan f.eks. være propargyl. Amino--alkylgrupper kan f.eks. være dimethylaminoethyl, dimethylaminopropyl, diethylaminopropyl, diethylaminoethyl, methylaminoethyl, methylaminopropyl, morpholinopropyl og piperidinopropyl. Acylgrupper R^ kan f.eks. være formyl, acetyl, propionyl.og butyryl.Examples of phenalkyl groups R ° are benzyl and phenethyl, each of which may be substituted by the substituents listed above in compound * L g with the aryl groups R. Alkyl groups R may be straight or branched and include e.g. methyl, ethyl, propyl and butyl, the alkenyl groups may be straight or branched and may e.g. be alkyl or dimethylallyl, the alkynyl groups may be straight or branched and may e.g. be propargyl. Amino-alkyl groups may e.g. be dimethylaminoethyl, dimethylaminopropyl, diethylaminopropyl, diethylaminoethyl, methylaminoethyl, methylaminopropyl, morpholinopropyl and piperidinopropyl. Acyl groups R be formyl, acetyl, propionyl and butyryl.
4 1501434 150143
De foretrukne forbindelser er sådanne med formlen (I), 2 3 4 5 hvori R , R , R og R betyder hydrogenatomer, R betyder hydroxyl, og R^" betyder en phenyl-, halogenphenyl- eller alkylphenylgruppe, og den punkterede linie repræsenterer en binding.The preferred compounds are those of formula (I), wherein R, R, R and R are hydrogen atoms, R is hydroxyl, and R R is a phenyl, halogenophenyl or alkylphenyl group and the dotted line represents a bond.
En foretrukken gruppe forbindelser med formlen (i) er tetra-hydropyrimido/ϊ,2-a7indolerne med den almene formel (la) R2 © © ® K3 φ -N^O><© © 1,4 (ia) R5 ® R R1 eller syreadditionssalte eller kvatemære ammoniumsalte deraf, i hvilken formel R og R1 har de ovenfor i forbindelse med formlen (i) angiv-A preferred group of compounds of formula (i) are the tetrahydropyrimido / ϊ, 2-α7indoles of the general formula (Ia) R2 © © ® K3 φ -N ^ O> <© © 1,4 (ia) R5 ® R R1 or acid addition salts or quaternary ammonium salts thereof, in which formulas R and R 1 have the above-mentioned compounds of formula (i)
2 R2 R
ne betydninger, R og Br kan være ens eller forskellige og betyder hydrogen, hydroxyl, lavere alkyl, lavere alkoxy, halogen-lavere-alkyl X 2l eller halogen, og Br og R , som kan være ens eller forskellige, betyder hydrogen eller lavere alkyl. Ringsystemet i pyrimido/1,2-a/indo-lerne nummereres som anvist i den almene formel (la).ne means R and Br may be the same or different and represent hydrogen, hydroxyl, lower alkyl, lower alkoxy, halo-lower alkyl X 2l or halogen, and Br and R, which may be the same or different, represent hydrogen or lower alkyl . The ring system in the pyrimido / 1,2-α / indoles is numbered as described in the general formula (Ia).
Særligt værdifulde forbindelser med formlen (la) er følgende: 2,3 ,4,10-Tetrahydro-lO-phenylpyrimido/1,2-a7indol-10-ol 10-m(-Chlorphenyl)-2,3,4,10-tetrahydropyrimido/l,2-a/indol-lO-ol 2.3.4.10- Tetrahydro-10- (p-chlorphenyl) pyrimido/l ,2-a/ indol-10-ol 2.3.4.10- Tetrahydro-10-(2-thienyl)pyrimido/ϊ,2-a/ indol-10-ol 10-(m-Pluorphenyl)-2,3,4,10-tetrahydropyrimIdq/I,2-a7indol-10-ol 10-(3,4-Dichlorphenyl)-2,3,4,10-tetrahydropyrimido^l,2-a7indol-10-ol 10-(m-Chlorphenyl)-2,3,4,10-tetrahydro-3,3-dimethylpyrimido/X,2-a7indol- -lO-ol 2 ,3,4,10-Tetrahydro-10-phenyl-3,3-dimethylpyrimido^I ,2-a7indol-10-ol (+)-2,3,4,10-Tetrahydro-10-(m-chlorphenyl)pyrimido/ΐ,2-a7indol-10-ol og (-)-2,3,4,10-Tetrahydro-10-(m-chlorphenyl)-pyrimido/I,2-a7indol-10-ol.Particularly valuable compounds of formula (Ia) are the following: 2,3, 4,10-Tetrahydro-10-phenylpyrimido / 1,2-a-indol-10-ol 10-m (-chlorophenyl) -2,3,4,10- tetrahydropyrimido / 1,2-a / indol-10-ol 2,3,4,10-Tetrahydro-10- (p-chlorophenyl) pyrimido / 1,2-a / indol-10-ol 2,3,4,10-Tetrahydro-10- (2- thienyl) pyrimido [2,2-a] indol-10-ol 10- (m-Fluorophenyl) -2,3,4,10-tetrahydropyrimidine [1,2-a] indol-10-ol 10- (3,4-dichlorophenyl) ) -2,3,4,10-Tetrahydropyrimido [1,2-a] indol-10-ol 10- (m-Chlorophenyl) -2,3,4,10-tetrahydro-3,3-dimethylpyrimido / X, 2-a7indole - -10-ol 2,3,4,10-Tetrahydro-10-phenyl-3,3-dimethylpyrimido [1,2-a] indol-10-ol (+) - 2,3,4,10-Tetrahydro-10 (m-chlorophenyl) pyrimido [1,2-a] indol-10-ol and (-) - 2,3,4,10-Tetrahydro-10- (m-chlorophenyl) -pyrimido [1,2-a] indol-10-ol .
Ved fremgangsmåden ifølge opfindelsen fremstilles andre tetra-hydropyrimido/I,2-a7indoler end sådanne med den almene formel (la).In the process of the invention, tetrahydropyrimido / 1,2-a-indoles other than those of the general formula (Ia) are prepared.
Der fremstilles eksempelvis forbindelser med den almene formel (Ib) r2 I X0H (Ib) r5 R R1 5 150143 eller syreadditionssalte eller kvaternære ammoniumsalte deraf, 12 5 i hvilken formel R, R , R og R har de ovenfor i forbindelse med formlen (I) angivne betydninger.For example, compounds of the general formula (Ib) r 2 I X H (Ib) r 5 R R1 5010143 or acid addition salts or quaternary ammonium salts thereof are prepared, in which formula R, R, R and R have the above compounds of formula (I) ) stated meanings.
En anden gruppe forbindelser, der falder inden for rammerne af formlen (i), er hexahydropyrimido/ϊ,2-a/indolerne, f.eks. forbindelser med den almene formel (le) r5 R h1 l6 og syreadditionssalte og kvaternære ammoniumsalte deraf, i hvilken formel R, R1 og R^ har de ovenfor i forbindelse med formel (I) angiv- 2 η 4 ^ ne betydninger, og R , Br, R og Br har de ovenfor i forbindelse med formel (la) angivne betydninger.Another group of compounds which fall within the scope of formula (i) are the hexahydropyrimido / ϊ, 2-α / indoles, e.g. compounds of the general formula (Ie) R5 R1 H16 and acid addition salts and quaternary ammonium salts thereof, in which Formula R, R1 and R4 have the meanings set forth above in connection with Formula (I), and 2, Br, R and Br have the meanings given above for formula (Ia).
En anden type forbindelser, som falder inden, for rammerne af den almene formel (I), er de forbindelser,· hvor n er 0 eller 2, dvs. imida-zo/I,2-a/indolerne og diazepino/I,2-a7indolerne. En særlig gruppe imidazo^/I,2-a7indoler er sådanne med den almene formel (Id) - R5 R R1 samt deres syreadditionssalte og kvaternære ammoniumsalte, i hvilken formel R og R1 har de ovenfor i forbindelse med formlen (I) angivne 2 3 4 5 betydninger, og R , R , R og R har de ovenfor i forbindelse med formlen (la) angivne betydninger.Another type of compounds falling within the scope of the general formula (I) are those compounds where n is 0 or 2, ie. the imida-zo / I, 2-a / indoles and the diazepino / I, 2-a7 indoles. A particular group of imidazo [1,2-a] indoles are those of the general formula (Id) - R 5 R 1, as well as their acid addition salts and quaternary ammonium salts, in which formulas R and R 1 have the above-mentioned compounds of formula (I) 45, and R, R, R and R have the meanings given above in connection with formula (Ia).
Indolderivater med den almene formel (I), fremstilles ved fremgangsmåden ifølge opfindelsen, som er ejendommelig ved, at en keton med den almene formelIndole derivatives of the general formula (I) are prepared by the process according to the invention, characterized in that a ketone of the general formula
(ID(ID
r5 IIr5 II
OISLAND
6 150143 2 3 4 5 hvor R , R , R , R ogn har de ovenfor angivne betydninger, omsættes med et Grignard-reagens med formlen R^MgY, hvor Y betyder halogen, og R1 har den ovenfor angivne betydning, eller med et 1' 1' aryllithium med den almene formel R Li, hvori R er phenyl eller naphthyl, eventuelt substitueret med en eller to af de ovenfor under R^ definerede substituenter, thienyl, eller pyridyl eller med natrium- eller kaliumacetylid, og eventuelt (a) alkyleres eller acyleres den dannede forbindelse med formlen I, hvori R betyder en hydroxylgruppe og den punkterede 1 2 3 4 5 linie en binding, ogR,R,R,R,R ogn har de ovenfor angivne betydninger, til dannelse af en tilsvarende forbindelse, hvori R betyder alkoxy, phenylalkoxy, tetrahydropyranyloxy eller acyl-oxy, som defineret i forbindelse med formel (I), og eventuelt (b) omdannes forbindelsen med den almene formel I, hvori 12 3 den punkterede linie repræsenterer en binding og R, R , R , R , 4 5 R , R og n har de ovenfor først angivne betydninger, til et syreadditionssalt eller et kvaternært ammoniumsalt deraf, og eventuelt (c) reduceres forbindelsen med formlen I, hvori den punkterede linie repræsentere en binding, og R, R1, R2, R3, R4, R5 og n har de ovenfor først angivne betydninger, eller et kvaternært ammoniumsalt deraf til dannelse af en forbindelse med formlen I, hvor bindingen repræsenteret ved den punkterede linie ikke er til stede, R, r\ R2, R3, R4 og R5 og n har de ovenfor først angivneWherein R, R, R, R and n have the above meanings, reacted with a Grignard reagent of the formula R 2 MgY, where Y means halogen and R 1 has the meaning given above, or with a 1 '1' aryllithium of the general formula R Li wherein R is phenyl or naphthyl optionally substituted with one or two of the substituents defined above under R 1, thienyl, or pyridyl or with sodium or potassium acetylide, and optionally (a) alkylated or the acylated compound of formula I is formed, wherein R is a hydroxyl group and the dotted line is a bond and R, R, R, R, R and n have the above meanings to form a corresponding compound wherein R is alkoxy, phenylalkoxy, tetrahydropyranyloxy or acyl-oxy, as defined in connection with formula (I), and optionally (b) is converted to the compound of general formula I wherein the dotted line represents a bond and R, R, R , R, 4,5, R, R and n have the above-mentioned bets (c) the compound of formula I wherein the dotted line represents a bond and R, R 1, R 2, R 3, R 4, R 5 and n have the meanings set forth above, are reduced to an acid addition salt or quaternary ammonium salt thereof. or a quaternary ammonium salt thereof to form a compound of formula I wherein the bond represented by the dotted line is not present, R, r \ R2, R3, R4 and R5 and n have the
CC
betydninger og R betyder hydrogen, og eventuelt (d) omdannes den dannede forbindelse med formlen I, hvori bindingen repræsenteret ved den punkterede linie ikke er til ste-1 2 3 4 5 de^ R,R,R,R,R,R ogn har de ovenfor først angivne betyd-6 ninger, og R betyder hydrogen, til et syreadditionssalt eller kvaternært ammoniumsalt deraf, og eventuelt .and R is hydrogen and optionally (d) the compound of formula I formed is converted in which the bond represented by the dotted line is not to denote R, R, R, R, R, R and n. have the meanings given above first, and R is hydrogen, to an acid addition salt or quaternary ammonium salt thereof, and optionally.
(e) alkyleres eller acyleres en forbindelse med formlen I, hvori bindingen repræsenteret ved den punkterede linie ikke er til 6 1 2 3 4 5 stede, R betyder hydrogen og R, R , R , R , R , R ogn har de ovenfor først angivne betydninger, til dannelse af en tilsvarende forbindelse, hvori R betyder phenalkyl, alkyl, alkenyl, alkynyl, aminoalkyl eller acyl som defineret i forbindelse med formel (I).(e) alkylating or acylating a compound of formula I wherein the bond represented by the dotted line is not present, R is hydrogen and R, R, R, R, R, R and means to form a corresponding compound wherein R is phenalkyl, alkyl, alkenyl, alkynyl, aminoalkyl or acyl as defined in formula (I).
150143 7150143 7
Ved ovennævnte metode vælges organometalforbindelsen fortrinsvis blandt (a) Grignardreagenser med formlen R^MgY, hvor Y betyder halogen, og R1 har den ovenfor anførte betydning, og (b) alkalimetalforbindelser såsom arylllthiumforbindelser med formlen R^Li, f. eks. phenyllithium, og natrium- og kaliumacetylid. Når n er O, er organometalforbindelsen fortrinsvis et aryllithium. Omsætningen med organometalforbindelsen gennemføres sædvanligvis i et indifferent organisk opløsningsmiddel, f.eks. ether eller tetrahydro-furan under anvendelse af kendte standardbetingelser for den pågældende reaktion.In the above method, the organometallic compound is preferably selected from (a) Grignard reagents of the formula R 1 MgY, where Y is halogen and R 1 has the meaning given above, and (b) alkali metal compounds such as arylllthium compounds of the formula R 1 Li, e.g. sodium and potassium acetylide. When n is 0, the organometallic compound is preferably an aryl lithium. The reaction with the organometal compound is usually carried out in an inert organic solvent, e.g. ether or tetrahydrofuran using known standard conditions for the reaction in question.
Som allerede nævnte kan forbindelsen, hvori R betyder en-hydroxylgruppe, og den punkterede linie betyder en binding i den angivne stilling, eventuelt alkyleres eller aeyleres til indføring af en lavere alkoxy-, aryl-lavere-alkoxy-, tetrahydropyranyloxy- eller acyl-oxyrest R. Sådanne alkylerings- eller aeyleringsreaktioner gennemføres ved hjælp af kendte standardmetoder. Hydroxyforbindelsen kan f.eks. " omdannes til dens alkalimetalderivat, især natriumderivatet, og derpå behandles med det egnede alkylerings- eller aeyleringsmiddel. Eksempler på alkyleringsmidler er lavere alkyl- eller aryl-lavere-alkylhalogeni-der såsom chlorideme, bromideme eller iodideme, medens eksempler på acyleringsmidler er syrehalogenider, specielt chlorideme, eller syreanhydrider af de aliphatiske carboxylsyrer.As already mentioned, the compound wherein R represents a hydroxyl group and the dotted line represents a bond at the indicated position may be optionally alkylated or aeylated to introduce a lower alkoxy, aryl lower alkoxy, tetrahydropyranyloxy or acyl oxy residue R. Such alkylation or aeylation reactions are carried out by known standard methods. The hydroxy compound may e.g. "is converted to its alkali metal derivative, especially the sodium derivative, and then treated with the appropriate alkylating or aeylating agent. Examples of alkylating agents are lower alkyl or aryl lower alkyl halides such as the chlorides, bromides or iodides, while examples of acylating agents are acid halides, the chlorides, or acid anhydrides of the aliphatic carboxylic acids.
Forbindelserne med den almene formel (I), hvori bindingen repræsenteret ved den punkterede linie ikke er til stede, har den almene ” formel (VI) H UH2 V B? R4 (VI) R5 R R1 |β hvor R, R1, R^, R^, R4, R^, R^ og n har de ovenfor i forbindelse med formlen (I) angivne betydninger, kan fremstilles ved at reducere, f. éks. raed et hydridoverføringsmiddel såsom et kompleksmetalhydrid, en forbindelse med den almene formel (VII) 8 150143 RLix_ L/ I JL 4—(vn) r5 it^r1 eller et kvatemært ammoniumsalt deraf, hvor kationen har formlen (VIII) 5CH2]n r3 L \ 1 3 4 (VIII) r5 R-^R1 l6, 1 p -5 11 k • hvor R, R , R , Rr, R , Rv og n har de umiddelbart ovenfor angivne betydninger, og R^ betyder aryl-lavere-alkyl, lavere alkyl, lavere alkenyl, lavere alkynyl eller aminolavere-alkyl, og eventuelt omdannes én gruppe R og/eller R^ og/eller R2 og/eller R^ og/eller R^ til en anden gruppe R og/eller R1 og/eller R2 og/eller R^ og/eller R^ med de ovenfor anførte betydninger for R, r\ R2, R^ og R^, eller eventuelt omdannes en fri base til et syreadditionssalt eller et kvatemært ammoniumsalt deraf.The compounds of general formula (I) in which the bond represented by the dotted line is not present, has the general "formula (VI) H UH2 V B? R4 (VI) R5 R R1 | β where R, R1, R ^, R ^, R4, R ^, R ^ and n have the meanings given above in connection with formula (I) can be prepared by reducing, f. Ex. a hydride transfer agent such as a complex metal hydride, a compound of the general formula (VII) 8, or a quaternary ammonium salt thereof, wherein the cation has the formula (VIII) 5CH2] n r3 L \ 1 3 4 (VIII) r5 R- ^ R1 16, 1 p -5 11 k • where R, R, R, Rr, R, Rv and n have the meanings immediately above, and R alkyl, lower alkyl, lower alkenyl, lower alkynyl or amino-lower alkyl, and optionally one group R and / or R 2 and / or R 2 and / or R 2 and / or R 2 is converted to another group R and / or R and / or R 2 and / or R 2 and / or R 2 having the above meanings for R, R 1, R 2 and R 2, or optionally a free base is converted to an acid addition salt or a quaternary ammonium salt thereof.
Når der f.eks. ønskes fremstillet en forbindelse med den almene formel (le), hvori R, R1, R2, , R^ og R^ har de ovenfor i forbindel se med formlen (VI) angivne betydninger, og R^ betyder hydrogen, kan 1 2 "5 4 en forbindelse med den almene formel (la),i hvilken R,R,R,R,R og R^ har de ovenfor i forbindelse med formlen (VI) angivne betydninger, reduceres på kendt måde. Fortrinsvis gennemføres reduktionen ved hjælp af et hydridoverføringsmiddel, især et komplekst metalhydrid såsom natriumborhydrid eller lithiumaluminiumborhydrid. Omsætningen gennemføres under anvendelse af kendte standardbetingelser for det specifikt anvendte reduktionsmiddel.For example, when it is desirable to prepare a compound of the general formula (Ie) wherein R, R 1, R 2, R 2 and R 2 have the meanings given above in compound of formula (VI) and R 2 is hydrogen, 4, a compound of the general formula (Ia) in which R, R, R, R, R and R 2 have the meanings given above in connection with formula (VI) is reduced in known manner. Hydride transfer agent, especially a complex metal hydride such as sodium borohydride or lithium aluminum borohydride The reaction is carried out using known standard conditions for the specifically used reducing agent.
Når det ønskes at fremstille en forbindelse med den almene formel (le), hvori R, r\ R2, , R^ og R^ har de ovenfor i forbindelse med formlen (VI) angivne betydninger, og R^ betyder aryl-lavere-alkyl, lavere alkyl, alkenyl, alkynyl eller aminolavere-alkyl, reduceres en kvatemær forbindelse, hvor kationen har den almene formel 9 150143 R\ r5 16 hvori R, R1, R2, Tp, R^, Jp og R^ har de umiddelbart ovenfor anførte betydninger, som beskrevet ovenfor.When it is desired to prepare a compound of the general formula (Ie) wherein R 1, R 1, R 2, R 2 and R 2 have the meanings given above in connection with Formula (VI) and R 1 is aryl-lower-alkyl , lower alkyl, alkenyl, alkynyl or amino-lower alkyl, a quaternary compound is reduced, where the cation has the general formula 9 wherein R, R1, R2, Tp, R meanings, as described above.
Når først der er fremstillet en forbindelse med den almene 1 o * ii. c g formel (I), hvor R, R , R , R , R , R·^ og R har de ovenfor i forbindelse med formlen (I) angivne betydninger, kan én gruppe R og/eller R^ og/eller R2 og/eller R? og/eller R^ og/eller R^ og/eller R^, såfremt de er til stede, eventuelt omdannes til en anden gruppe R og/eller R^ 2 3 4 c g og/eller R og/eller Jr og/eller R og/eller Rp og/eller R , som hver 12 3 4 5 især har de ovenfor angivne betydninger for R, R , R , R-', R , R·^ og 6 2 *5 R . Når R og/eller Jr betyder et hydrogenatom, kan dette f.eks. omdannes til et halogenatom eller en nitrogruppe på kendt måde, især i 8-stillingen i pyrimido/I,2-a7indolerne. Når chlorforbindelsen ønskes fremstillet, kan dette ske ved at foretage behandling med N-chlorsuccin-imid. Når endvidere R og/eller R^ er en lavere alkoxygruppe, især en methoxygruppe, kan denne deetherificeres på kendt måde til dannelse 2 af den tilsvarende hydroxylgruppe R og/eller R , eller omvendt kan 2 5 en hydroxylgruppe R og/eller R^ alkyleres på kendt måde til dannelse af en lavere alkoxygruppe R og/eller R . Når R er en alkynylgruppe, kan denne reduceres til en alkenylgruppe R^. En dimethylaminoalkylgrup-pe R^- kan monodeme thylere s til dannelse af den tilsvarende methylamino-alkylgruppe. Eventuelt kan en hydroxylfunktion R alkyleres eller acyle-res på de tidligere beskrevne metoder til dannelse af en lavere alkoxy-, aryl-lavere-alkoxy- eller acylgruppe R.Once a compound has been prepared with the general one. and formula (I) wherein R, R, R, R, R, R · and R have the meanings given above in connection with formula (I), one group R and / or R 2 and / or R 2 and / or R? and / or R 2 and / or R 2 and / or R 2, if present, optionally converted to another group R and / or R 2 2 4 4 cg and / or R and / or Jr and / or R and / or R p and / or R, each having in particular the meanings set forth above for R, R, R, R ', R, R ·, and 6 2 * 5 R. When R and / or Jr means a hydrogen atom, this may e.g. is converted into a halogen atom or a nitro group in known manner, especially in the 8-position of the pyrimido / 1,2-a-indoles. When the chlorine compound is desired to be prepared, this can be done by treating with N-chlorosuccinimide. Furthermore, when R and / or R 2 is a lower alkoxy group, especially a methoxy group, it can be deetherified in known manner to form 2 of the corresponding hydroxyl group R and / or R, or conversely, a hydroxyl group R and / or R in a known manner to form a lower alkoxy group R and / or R. When R is an alkynyl group, it can be reduced to an alkenyl group R A dimethylaminoalkyl group R 1 - can monodeme thyler s to form the corresponding methylamino alkyl group. Optionally, a hydroxyl function R can be alkylated or acylated by the previously described methods to form a lower alkoxy, aryl lower alkoxy or acyl group R.
Når R^ betyder et hydrogenatom, kan forbindelsen alkyleres eller acyleres på kendt måde til indføring af en gruppe R^, som er forskellig fra hydrogen. Om nødvendigt kan en vilkårlig reaktiv gruppe i en forbindelse beskyttes på kendt måde, inden der gennemføres nogen af de ovenfor beskrevne reaktioner, hvorpå beskyttelsesgruppen kan fjernes på kendt måde efter reaktionen.When R 1 represents a hydrogen atom, the compound may be alkylated or acylated in known manner to introduce a group R 2 other than hydrogen. If necessary, any reactive group of a compound may be protected in known manner before carrying out any of the above-described reactions, after which the protecting group may be removed in known manner after the reaction.
Ketonudgangsmaterialeme med den almene formel (il) kan fremstilles ved cyclisering af en keton med den almene formel (III) 150143 ίο IT (III)The ketone starting materials of the general formula (II) can be prepared by cyclizing a ketone of the general formula (III) 150143 or IT (III)
c II Nc II N
Ir 0 2 3 4 ^ * » hvor R , R , R , Hr og n har de ovenfor i forbindelse med formel (II) angivne betydninger, og X betyder halogen, og eventuelt kan én gruppe og/eller R·^ omdannes til en anden gruppe R og/eller R på kendt måde.Wherein R, R, R, Hr and n have the meanings given above for formula (II) and X is halogen and optionally one group and / or R second group R and / or R in known manner.
Ketonen med den almene formel (ill) kan cycliseres ved en modificeret Ullmann-reaktion. Ketonen kan f.eks. behandles med et metallisk middel, f.eks..kobber eller et salt deraf, især cuprioxid eller cuprochlorid. Omsætningen gennemføres sædvanligvis i nærværelse af en base såsom et alkalimetalearbonat, f.eks. kaliumcarbonat, triethyl-amin eller N-ethylmorpholin og fortrinsvis i et opløsningsmiddel, f.eks. dimethylacetamid, pyridin, 'hexamethylphosphorsyretriamid eller fortrinsvis dimethylformamid.The ketone of the general formula (III) can be cyclized by a modified Ullmann reaction. The ketone can e.g. is treated with a metallic agent, for example, copper or a salt thereof, especially cuprioxide or cuprous chloride. The reaction is usually carried out in the presence of a base such as an alkali metal carbonate, e.g. potassium carbonate, triethylamine or N-ethylmorpholine and preferably in a solvent, e.g. dimethylacetamide, pyridine, hexamethylphosphoric triamide or preferably dimethylformamide.
Gruppen X betyder fortrinsvis brom, og i ketonen med den almene 2 5 formel (IV) er R og R1 fortrinsvis hydrogen eller elektrontiltrækkende grupper såsom halogen.The group X preferably represents bromine and in the ketone of the general formula (IV), R and R 1 are preferably hydrogen or electron-attracting groups such as halogen.
Ketonerne med den almene formel (III) kan fremstilles ved oxidation af de tilsvarende hydroxyforbindelser med den almene formel (IX) p2 -7 \ X H(CHp)The ketones of general formula (III) can be prepared by oxidation of the corresponding hydroxy compounds of general formula (IX) p2 -7 \ X H (CHp)
x' 2>" Kx '2> "K
Γ Jf ϊ (ix)Γ Jf ϊ (ix)
/ H X0H/ H X0H
2 3 4 5 hvor R , R , R , R, n og X har de ovenfor angivne betydninger. Fortrinsvis gennemføres oxidationen med et mildt oxidationsmiddel såsom mangandioxid (f.eks. i opløsningsmidler såsom dichlormethan, chloroform, benzen, acetone eller vandig acetone) eller blytetraacetat (f.eks.2 3 4 5 wherein R, R, R, R, n and X have the above meanings. Preferably, the oxidation is carried out with a mild oxidizing agent such as manganese dioxide (e.g., in solvents such as dichloromethane, chloroform, benzene, acetone or aqueous acetone) or lead tetraacetate (e.g.
i pyridin). Forbindelsen med formlen (IX), hvori RJ betyder hydrogen, 4 og R er hydroxy, kan oxideres selektivt til forbindelsen med den al- 4 mene formel (III), hvori R-' og R har de samme betydninger, ved anvendelse af egnede milde oxidationsmidler såsom fældet mangandioxid.in pyridine). The compound of formula (IX) wherein R 1 is hydrogen, 4 and R is hydroxy can be selectively oxidized to the compound of general formula (III) wherein R 1 and R have the same meanings, using suitable mild oxidizing agents such as precipitated manganese dioxide.
Forbindelserne med den almene formel (IX) er beskrevet i litteraturen eller kan fremstilles ud fra kendte forbindelser på kendt måde. De kan f.eks. fremstilles ved den af Neilscn et al. i J.Chem.The compounds of the general formula (IX) are described in the literature or may be prepared from known compounds in known manner. For example, they can prepared by that of Neilscn et al. in J. Chem.
Soc. (C), 1968, 1855, beskrevne metode.Soc. (C), 1968, 1855, method described.
150143 11110143 11
Ketonudgangsmaterialerne med den almene formel (II)/ hvor n er 1, kan fremstilles ved en alternativ metode, der omfatter hydrolyse af den tilsvarende forbindelse med den almene formel (X) R5 ||The ketone starting materials of general formula (II) / where n is 1 may be prepared by an alternative method comprising hydrolysis of the corresponding compound of general formula (X) R5 ||
ZZ
hvori Z betyder en alkylenketalrest eller di-alkoxyrest.wherein Z represents an alkylene ketal residue or a di-alkoxy residue.
Hydrolysen kan gennemføres på i og for sig kendt måde, f.eks. ved opvarmning med syre, f.eks. fortyndet mineralsyre, såsom saltsyre. Udbyttet af ketonen (II), der ved denne metode sædvanligvis isoleres som mineralsyresaltet, er kun af størrelsesordenen 50$· Ved en fore-trukken hydrolysemetode behandles forbindelsen med koncentreret svovlsyre ved stuetemperatur. Ved denne metode isoleres ketonen (II) sædvanligvis som den fri base i udbytter af størrelsesordenen 90$.The hydrolysis can be carried out in a manner known per se, e.g. by heating with acid, e.g. dilute mineral acid such as hydrochloric acid. The yield of the ketone (II), which in this method is usually isolated as the mineral acid salt, is only of the order of $ 50. In a preferred hydrolysis method, the compound is treated with concentrated sulfuric acid at room temperature. In this method, the ketone (II) is usually isolated as the free base in yields of the order of $ 90.
Ved en foretrukken metode til fremstilling af forbindelserne med formlen X, hydrogeneres et substitueret isatin med den almene formel (IV) R2 lpIn a preferred method of preparing the compounds of formula X, a substituted isatin of the general formula (IV) R
-N - 0Ho - C - CN-N - 0Ho - C - CN
[ I ί R* (IV) r5 z 2 hvor Z har den umiddelbart ovenfor angivne betydning, og R , R·^, R^ og R^ har de i forbindelse med formlen (i) angivne betydninger. Hydrogene ringen gennemføres sædvanligvis i nærværelse af en nikkel-, palladium- eller platinkatalysator ved forhøjet temperatur og tryk.[I ί R * (IV) r5 z 2 wherein Z has the meaning given immediately above and R, R · ^, R ^ and R ^ have the meanings specified in formula (i). The hydrogen ring is usually conducted in the presence of a nickel, palladium or platinum catalyst at elevated temperature and pressure.
Ved anvendelse af temperaturer i området ved 100°C giver sædvanligvis direkte den tricycliske forbindelse. I nogle tilfælde og tillige når der anvendet noget lavere temperaturer, består det isolerede produkt 12 150143 -l af en blanding af den ønskede tricycliske forbindelse og en intermediær amin med formlen (V) _N - CH, - 0 - CftjKHoWhen using temperatures in the range of 100 ° C, the tricyclic compound usually gives directly. In some cases and even when somewhat lower temperatures are used, the isolated product 12 consists of a mixture of the desired tricyclic compound and an intermediate amine of formula (V) - N - CH
Cn 1 (v) R3^V"° zCn 1 (v) R3 ^ V "° z
Aminen kan dehydratiseres til dannelse af den ønskede tri-eycliske forbindelse ved at vinderkaste blandingen azeotrop destillation med et opløsningsmiddel såsom benzen, xylen eller toluen. Forbindelserne med formlen IV og V er kendt eller kan fremstilles på kendt måde.The amine can be dehydrated to form the desired tri-cyclic compound by winding the mixture azeotropic distillation with a solvent such as benzene, xylene or toluene. The compounds of formulas IV and V are known or can be prepared in known manner.
Forbindelserne med formlen (I) kan danne syreadditionssalte med syrer, især farmaceutisk acceptable syrer, og ved fremgangsmåden ifølge opfindelsen fremstilles også sådanne salte. Saltene kan isoleres direkte ved den ovenfor beskrevne metode eller kan fremstilles ved at opløse den specifikke forbindelse med formlen (I) i baseform i et egnet organisk opløsningsmiddel og behandle med en opløsning af den valgte syre i overensstemmelse med' kendt teknik ved fremstilling af syreadditionssalte ud fra baseforbindelser. Som eksempler på syrer kan nævnes saltsyre, hydrogenbromidsyre, vinsyre, phosphorsyre, maleinsyre, citronsyre, eddikesyre og benzoesyre.The compounds of formula (I) can form acid addition salts with acids, especially pharmaceutically acceptable acids, and in the process of the invention such salts are also prepared. The salts can be isolated directly by the method described above or can be prepared by dissolving the specific compound of formula (I) in base form in a suitable organic solvent and treating with a solution of the selected acid in accordance with the prior art in the preparation of acid addition salts. from base compounds. Examples of acids include hydrochloric, hydrobromic, tartaric, phosphoric, maleic, citric, acetic and benzoic.
Forbindelserne med den almene formel (i) kan også danne kva-temære ammoniumsalte, og sådanne salte fremstilles også ved fremgangsmåden ifølge opfindelsen. De kvaternære salte kan fremstilles ved at behandle forbindelsen i baseform i nærværelse eller fraværelse af et opløsningsmiddel med et aryl-lavere-alkylhalogenid, et lavere-alkylha-logenid, et alkenylhalogenid, et alkynylhalogenid eller et amino-lave-re-alkylhalogenid. Eksempler på sådanne halogenider er methyliodid og benzylchlorid samt benzylbromid.The compounds of general formula (i) may also form quaternary ammonium salts, and such salts are also prepared by the process of the invention. The quaternary salts can be prepared by treating the compound in base form in the presence or absence of a solvent with an aryl-lower-alkyl halide, a lower-alkyl halide, an alkenyl halide, an alkynyl halide or an amino-lower-lower alkyl halide. Examples of such halides are methyl iodide and benzyl chloride as well as benzyl bromide.
De optisk isomere af forbindelserne med formlen (I) kan fremstilles ved forskellige metoder. Fortrinsvis resolveres en racemisk blanding af en forbindelse med den almene formel (i) ved kendte standardmetoder. Racematet kan fremstilles ved en vilkårlig af de ovenfor skitserede metoder. Det er klart, at resolveringen kan gennemføres på den racemiske blanding af det ønskede slutprodukt eller på et racemat 1501 A3 13 af én af forbindelserne med den almene formel (I), hvorefter de optisk isomere kan underkastes efterbehandlinger såsom alkylering, acylering, hydrolyse, hydrogenolyse og reduktion til dannelse af det ønskede produkt med formlen (i).The optical isomers of the compounds of formula (I) can be prepared by various methods. Preferably, a racemic mixture of a compound of the general formula (i) is resolved by known standard methods. The racemate can be prepared by any of the methods outlined above. It is to be understood that the resolution may be carried out on the racemic mixture of the desired final product or on a racemate 1501 A3 13 of one of the compounds of general formula (I), after which the optical isomers may be subjected to post-treatments such as alkylation, acylation, hydrolysis, hydrogenolysis and reduction to form the desired product of formula (i).
Eventuelt kan en optisk aktiv isomer af en forbindelse med den almene formel (I) fremstilles ved en vilkårlig åf de ovenfor beskrevne metoder under anvendelse af et optisk aktivt udgangsmateriale, eller der kan foretages resolvering på et vilkårligt trin inden dannelsen af forbindelsen med den almene formel (I). Eventuelt kan den således fremstillede optisk aktive isomere underkastes reaktioner såsom alkylering, acylering, hydrolyse, hydrogenolyse eller reduktion til dannelse af det ønskede produkt.Optionally, an optically active isomer of a compound of the general formula (I) can be prepared by any of the methods described above using an optically active starting material, or resolution can be made at any stage before forming the compound of the general formula (IN). Optionally, the optically active isomer thus prepared can be subjected to reactions such as alkylation, acylation, hydrolysis, hydrogenolysis or reduction to form the desired product.
En resolvering gennemføres fortrinsvis på en raeemisk blanding af en basisk forbindelse med den almene formel (i) på kendt måde, f.eks. ved anvendelse af en optisk aktiv syre. En opløsning af racema-tet i et egnet opløsningsmiddel såsom en alkohol behandles eksempelvis med en opløsning af en optisk aktiv syre til frembringelse af krystallisation af saltet af én speciel enantiomorf. Den anden enantiomorfe kan ofte udvindes fra moderluden eller om nødvendigt ved behandling med en base og derpå med den anden optiske isomere af den optisk aktive syre, eller eventuelt kan en frisk opløsning af racematet behandles med en opløsning af den anden enantiomorfe af den optisk aktive syre. Det aktuelle opløsningsmiddel og den aktuelle optisk aktive syre, som skal anvendes i hvert enkelt tilfælde, kan bestemmes ved rutineforsøg. Den bedste kombination er en sådan, der tillader den letteste isolering af saltet i høj' renhed, dvs. uden indhold af den anden enantiomere, og i krystallinsk form.A resolution is preferably carried out on a novel mixture of a basic compound of the general formula (i) in a known manner, e.g. using an optically active acid. For example, a solution of the racemate in a suitable solvent such as an alcohol is treated with a solution of an optically active acid to produce crystallization of the salt of one particular enantiomorph. The second enantiomorph can often be recovered from the mother liquor or, if necessary, by treatment with a base and then with the second optical isomer of the optically active acid, or optionally a fresh solution of the racemate can be treated with a solution of the second enantiomorph of the optically active acid. . The current solvent and the current optically active acid to be used in each case can be determined by routine experimentation. The best combination is one which allows the lightest isolation of the salt in high purity, ie. without content of the second enantiomer, and in crystalline form.
Det har vist sig, at D(-) og L(+)-vinsyre er særlig velegnede til resolvering af nogle af forbindelserne med formlen (I).It has been found that D (-) and L (+) - tartaric acid are particularly suitable for resolving some of the compounds of formula (I).
Forbindelserne med den almene formel (I) udviser farmakologisk virkning. Især er mange af forbindelserne i besiddelse af én eller flere af de nedenfor anførte virkninger, hvilket er påvist ved standardforsøg med varmblodede dyr. Disse virkninger er antide-pressiv virkning, antiinflammatorisk virkning, antihistaminvirkning, cardiocaskulær virkning, diætetisk virkning og hypoglycaemisk virkning. Mange af forbindelserne med den almene formel (I), i hvilke n er 1, dvs. pyrimido/I,2-a/indolerne, er særligt vigtige som antidepressive midler, bedømt ved f.eks. deres antireserpinvirk-ninger in vivo i overensstemmelse med den af Beryl M. Askew i Life 150143 14The compounds of general formula (I) exhibit pharmacological action. In particular, many of the compounds possess one or more of the effects listed below, as demonstrated by standard experiments with warm-blooded animals. These effects are antidepressant, anti-inflammatory, antihistamine, cardiocascular, dietary and hypoglycaemic. Many of the compounds of general formula (I) in which n is 1, i. The pyrimido / I, 2-a / indoles, are particularly important as antidepressants, evaluated by e.g. their antireserpine effects in vivo according to that of Beryl M. Askew in Life 150143 14
Sciences, 1, 725-730 (1963) beskrevne metode, jfr. de i nedenstående tabel anførte resultater af netop denne prøve udført på de ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser (dvs. en række repræsentative forbindelser fremstillet ifølge de angivne eksempler nedenfor). Nogle forbindelser, f. eks. 10-- (m-chlorphenyl)-2,3,4,10-tetrahydropyrimido [1,2-a]indol-10-ol udviser mange af de konventionelle tricycliske antidepressive forbindelsers antidepressive egenskaber, men udviser mindre anti-cholinergbivirkninger ved farmakologisk afprøvning. Derfor er det hensigtsmæssigt ifølge opfindelsen, at 10-(m-chlorphenyl)-2,3,4, 10-tetrahydropyrimido [l,2-a]-indol-10-ol fremstilles. Nogle af pyrimido [1,2-a]-indolerne har vist sig at have antihistaminegenskaber ved afprøvning af den af H.O. Schild i Brit. J. Pharmacol., 2, 189-206 (1947) beskrevne metode.Sciences, 1, 725-730 (1963), cf. the results of this particular test set out in the table below are carried out on the compounds prepared by the process of the invention (i.e., a number of representative compounds prepared according to the examples given below). Some compounds, e.g., 10 - (m-chlorophenyl) -2,3,4,10-tetrahydropyrimido [1,2-a] indol-10-ol exhibit many of the antidepressant properties of conventional tricyclic antidepressants, but exhibit minor anti-cholinergic side effects in pharmacological testing. Therefore, it is appropriate according to the invention that 10- (m-chlorophenyl) -2,3,4,10-tetrahydropyrimido [1,2-a] indol-10-ol be prepared. Some of the pyrimido [1,2-a] indoles have been shown to have antihistamine properties when tested by H.O. Shield in Brit. J. Pharmacol., 2, 189-206 (1947).
1501 A3 151501 A3 15
Antidepressiv aktivitet målt ved temperaturændring efter reser-pin-fremkaldt hypothermi ifølge Beryl M. Askew, Life Sciences, 1963, 1, 725-730Antidepressant Activity Measured by Temperature Change after Reser-Pin-Induced Hypothermia According to Beryl M. Askew, Life Sciences, 1963, 1, 725-730
Forbindelse Temperaturstigning Dosis fremstillet (°C) (mg/kg pr. os) ifølge eks. nr.Compound Temperature rise Dose prepared (° C) (mg / kg per ounce) according to Example no.
4,5,6 5,3 8 7.3 16 9.6 32 7 4,4 4 2,9 8 6,2 16 7,8 32 9 2,9 5 4.7 10 4.0 20 12 4,4 3 8.5 9 9.6 27 16 7,5 29 9.3 40 17 6,3 20 6.4 40 10,2 50 18 4,0 5 4,2 50 19 5,1 10 6.0 20 8.4 40 20 7,6 10 7.5 20 9,0 40 10,9 50 150143 164,5,6 5.3 8 7.3 16 9.6 32 7 4.4 4 2.9 8 6.2 16 7.8 32 9 2.9 5 4.7 10 4.0 20 12 4.4 3 8.5 9 9.6 27 16 7 , 5 29 9.3 40 17 6.3 20 6.4 40 10.2 50 18 4.0 5 4.2 50 19 5.1 10 6.0 20 8.4 40 20 7.6 10 7.5 20 9.0 40 10.9 50 150143 16
Forbindelse Temperaturstigning Dosis fremstillet °C (mg/kg pr. os) ifølge eks. nr._ 21 7,4 10 10,5 15 9,0 20 24 6 20 25 5,5 5 6,9 10 9.8 20 26 4,6 5 7.5 10 9.8 20 28 5,2 5 8.5 10 9.5 20 30 4,9 5 7,2 10 10,9 20 31 2,8 5 4.9 10 9.4 20 36 4,3 10 3.4 20 39 7,9 16 6.5 32 4Q 6,2 8 5.6 10 6.6 15 41 8,8 8 9.9 10 12,0 15 150143 17Compound Temperature increase Dose prepared ° C (mg / kg per ounce) according to Example No. 21 7.4 10 10.5 15 9.0 20 24 6 20 25 5.5 5 6.9 10 9.8 20 26 4, 6 5 7.5 10 9.8 20 28 5.2 5 8.5 10 9.5 20 30 4.9 5 7.2 10 10.9 20 31 2.8 5 4.9 10 9.4 20 36 4.3 10 3.4 20 39 7.9 16 6.5 32 4Q 6.2 8 5.6 10 6.6 15 41 8.8 8 9.9 10 12.0 15 150143 17
Forbindelse Temperaturstigning Dosis fremstillet °C (mg)kg pr. os) ifølge eks. nr.Compound Temperature increase Dose prepared ° C (mg) kg per US) according to Ex.
50 4,9 40 52 7,0 3 8,7 9 10,2 20 12,5 80 53 4,4 2.5 8,9 5 9,3 10 11,7 20 150143 1850 4.9 40 52 7.0 3 8.7 9 10.2 20 12.5 80 53 4.4 2.5 8.9 5 9.3 10 11.7 20 150143 18
Fremgangsmåden ifølge opfindelsen illustreres nærmere i de følgende eksempler.The process of the invention is further illustrated in the following examples.
Eksempel 1 5 * ^-Dihydrospiro/I,5-dioxolan-2,10'(2H,10H)pyrimido/I,2-a7indol7.Example 1 5 * -Dihydrospiro / 1,5-dioxolane-2,10 '(2H, 10H) pyrimido / 1,2-a-indole7.
57 g 21 -Oxospiro/Ϊ ,5-dioxolan-2 ,51 -indolin7-11 -propionitril 2 reduceres ved et begyndelsestryk på 84,4 kg pr., cm og en sluttempera-tur på 100°C i 200 ml ethanol, der er halvt mættet med ammoniak,! nærværelse af 6 g Raneynikkel i 5 timer. Efter afkøling frafiltreres katalysatoren, og opløsningsmidlet fjernes under formindsket tryk, hvorved fås en viskos olie. Olien opløses i 200 ml xylen og opvarmes under tilbagesvaling under omrøring i 26 timer i et apparat forsynet med en vandudskiller. Xylenet fjernes under formindsket tryk. Den mørke olie opløses i varm ethylacetat og behandles med affarvningskul. Der fås 29,5 g farveløse nåle med smp. ll4-115°C.57 g of 21-oxospiro / Ϊ, 5-dioxolane-2, 51 -indolin7-11 -propionitrile 2 are reduced at an initial pressure of 84.4 kg / cm and a final temperature of 100 ° C in 200 ml of ethanol which is half saturated with ammonia,! presence of 6 g of Raneynickel for 5 hours. After cooling, the catalyst is filtered off and the solvent removed under reduced pressure to give a viscous oil. The oil is dissolved in 200 ml of xylene and heated under reflux with stirring for 26 hours in an apparatus fitted with a water separator. The xylene is removed under reduced pressure. The dark oil is dissolved in hot ethyl acetate and treated with decolorizing coal. 29.5 g of colorless needles are obtained with m.p. ll4-115 ° C.
Analyse for ci^hi2j.N202 :Analysis for c12 H20 N2 O2:
Cfo E% W°Cfo E% W °
Beregnet 67,8 6,1 12,2Calculated 67.8 6.1 12.2
Fundet 68,0 5,9 12,2Found 68.0 5.9 12.2
Eksempel 2 5,4-Dihydropyrimido/I,2-a7indol-10/2H7-on 12,2 g y ^’-dihydrospiro^/I^-dioxolan^jlO' (2H,10H)pyrimido-(l,2-a)indol7 suspenderes i 50 ml vand, og der tilsættes 50 ml koncentreret saltsyre under omrøring. Blandingen opvarmes til 85°C i 5 timer. Blandingen inddampes til en rød olie under formindsket tryk, opløses i 100 ml absolut ethanol og inddampes til 50 ml. Ved afkøling fås 1,9 g højrødt nåleformet produkt med smp. 215-225°C (sønderdeling).Example 2 5,4-Dihydropyrimido / 1,2-a-indole-10 / 2H7-one 12.2 gy 2 '- dihydrospiro' / 1 '-dioxolanyl' 10 '(2H, 10H) pyrimido- (1,2-a) indol7 is suspended in 50 ml of water and 50 ml of concentrated hydrochloric acid is added with stirring. The mixture is heated to 85 ° C for 5 hours. The mixture is evaporated to a red oil under reduced pressure, dissolved in 100 ml of absolute ethanol and evaporated to 50 ml. On cooling, 1.9 g of high-red needle-shaped product with m.p. 215-225 ° C (dec.).
Analyse for C11H10N20: Q/fo UfoAnalysis for C11H10N2O: Q / fo Ufo
Beregnet 59.5 5,0 12,6Calculated 59.5 5.0 12.6
Fundet 59,0 5,0 12,5· 150143 19Found 59.0 5.0 12.5 · 150143 19
Eksempel 3 5 Λ-Dihydropyrimido/I,2-a7indol-10/2H7-on 10 g finpulveriseret 3,,4'-dihydrospiro//I,3-dioxolan-2,10'-(2H,10H)pyrimido-(l,2-a)-indol7 sættes portionsvis til 50 ml omrørt koncentreret svovlsyre, som holdes ved 25°C ved afkøling med et isbad. Efter endt tilsætning omrøres blandingen ved stuetemperatur natten over, hældes i is og neutraliseres med vandig koncentreret ammoniak, idet temperaturen holdes under 30UC. Blandingen ekstraheres med chloroform og tørres over vandfri magnesiumsulfat. Efter inddampning krystalliseres produktet af en blanding af benzen og let petroleum (koge-interval 60-80°C), hvorved fås 7*3 g stærkt røde krystalnåle med smp. 121-122°C.Example 3 5 Λ-Dihydropyrimido [1,2-a] indol-10 / 2H7-one 10 g of finely powdered 3,4,4'-dihydrospiro // 1,3-dioxolane-2,10 '- (2H, 10H) pyrimido- (1 2-a) -indole 7 is added portionwise to 50 ml of stirred concentrated sulfuric acid which is maintained at 25 ° C by cooling with an ice bath. After the addition is complete, the mixture is stirred at room temperature overnight, poured into ice and neutralized with aqueous concentrated ammonia, keeping the temperature below 30UC. The mixture is extracted with chloroform and dried over anhydrous magnesium sulfate. After evaporation, the product is crystallized by a mixture of benzene and light petroleum (boiling range 60-80 ° C) to give 7 * 3 g of strong red crystal needles with m.p. 121-122 ° C.
Analyse for O-qH^q^O: C% H% W°Analysis for O-qH ^ q ^ O: C% H% W °
Beregnet 70,95 5 *4 15>05Calculated 70.95 5 * 4 15> 05
Fundet 71#0 5Λ 14,7Found 71 # 0 5Λ 14.7
Eksempel 4 2,5 Λ,10-Tetrahydro-10-phenylpyrimido/i,2-a7indol-10-ol 5,82 g finpul veriseret 3 ^-dihydropyrimido/l ,2-a7 indol-10/2I|7--on-hydrochlorid sættes portionsvis til phenylmagnesiumbromid fremstillet ud fra 12,9 g magnesium og 8,2 g brombenzen i 100 ml ether. Efter endt tilsætning opvarmes reaktionsblandingen under tilbagesvaling nat- . ten over, afkøles og hældes i en blanding af is og 10 g ammoniumchlo-rid. Det udskilte gule faste stof frafiltreres og vaskes med vand og ether, hvorved fås 3*67 g næsten hvidt pulver med smp. 246-247°C.Example 4 2.5 Λ, 10-Tetrahydro-10-phenylpyrimido [1,2-a] indol-10-ol 5.82 g of finely pulverized 3β-dihydropyrimido / 1,2-a7 indole-10 / 2I | 7-one Hydrochloride is added portionwise to phenylmagnesium bromide prepared from 12.9 g of magnesium and 8.2 g of bromobenzene in 100 ml of ether. Upon completion of the addition, the reaction mixture is heated under reflux overnight. over, cool and pour into a mixture of ice and 10 g of ammonium chloride. The separated yellow solid is filtered off and washed with water and ether to give 3 * 67 g of almost white powder with m.p. 246-247 ° C.
Basen omkrystalliseres af ethanol i form af farveløse rhomber med smp. 247-248°C.The base is recrystallized from ethanol in the form of colorless rhombus with m.p. 247-248 ° C.
Analyse for 0ι7Ηι6Ν20: G% E% WoAnalysis for 0ι7Ηι6Ν20: G% E% Wo
Beregnet 77*5 6,1 10,6Calculated 77 * 5 6.1 10.6
Fundet 77*6 6,2 10,5Found 77 * 6.2 6.2 10.5
Hydrochloridet af basen fremstilles ved opløsning i varm absolut ethanol og tilsætning af en opløsning af hydrogenchloridgas i tør ether. Der fås et produkt i form af farveløse nåle med smp. 264-270°C (sønderdeling).The hydrochloride of the base is prepared by dissolving in hot absolute ethanol and adding a solution of hydrogen chloride gas in dry ether. A product in the form of colorless needles with m.p. 264-270 ° C (dec.).
Analyse for Ci7Hi6N20:Analysis for C17 H16 N2 O:
Efo N foEfo N fo
Beregnet .67,85 5*7 9*5Calculated .67.85 5 * 7 9 * 5
Fundet 68,2 5*7 9*2 20.Found 68.2 5 * 7 9 * 2 20.
150143150143
Eksempel 5 2.3.4.10- Tetrahydro-10-phenylpyrimldo/l,2-a7indol-10-ol 0,05 mol phenyllithium i ether sættes dråbevis til en omrørt suspension af 2,2 g af pyrimido/I,2-a7indol-10/5H7-on-hydrochloridet fra eksempel 2 i 1 liter tør ether under en nitrogenstrøm. Den dannede farveløse opløsning henstilles ved stuetemperatur natten over og sønderdeles ved tilsætning af 35 ml vand og 15 ml 2 N saltsyre. Det dannede faste stof frafiltreres, vaskes med vand og tørres, hvorved fås 1,59 S af den tilsigtede forbindelse med smp. 220-225°C. Efter omkrystallisation af ethanol stiger smeltepunktet til 246-247°C.Example 5 2.3.4.10- Tetrahydro-10-phenylpyrimido / 1,2-a7indol-10-ol 0.05 mole of phenyllithium in ether is added dropwise to a stirred suspension of 2.2 g of pyrimido / I, 2-a7indole-10 / The 5H7-on hydrochloride of Example 2 in 1 liter of dry ether under a stream of nitrogen. The colorless solution formed is left at room temperature overnight and decomposed by the addition of 35 ml of water and 15 ml of 2N hydrochloric acid. The solid formed is filtered off, washed with water and dried to give 1.59 S of the intended compound, m.p. 220-225 ° C. After recrystallization from ethanol, the melting point rises to 246-247 ° C.
Eksempel 6 2.3.4.10- Tetrahydro-lO-phenylpyrimido/I,2-a7indol-10-ol 5,58 g 3,4-dihydropyrimido/I,2-a7indol-10-on i tør tetrahydro-furan sættes dråbevis under omrøring til 0,05 mol phenylmagnesiumbromid i 200 ml tør ether. Reaktionsblandingen opvarmes under tilbagesvaling under omrøring i 3 timer. Reaktionsblandingen spaltes ved udhældning i en blanding af is og ammoniumchlorid, hvorved fås 6,38 g lyserødt pulver med smp. 230-235°C (sønderdeling). Efter omkrystallisation af ethanol stiger smeltepunktet til 246-248°C (sønderdeling).Example 6 2.3.4.10- Tetrahydro-10-phenylpyrimido / 1,2-a7indol-10-ol 5.58 g of 3,4-dihydropyrimido / 1,2-a7indol-10-one in dry tetrahydrofuran is added dropwise with stirring to 0.05 mole of phenylmagnesium bromide in 200 ml of dry ether. The reaction mixture is heated under reflux with stirring for 3 hours. The reaction mixture is cleaved by pouring into a mixture of ice and ammonium chloride to give 6.38 g of pink powder with m.p. 230-235 ° C (dec.). After recrystallization of ethanol, the melting point rises to 246-248 ° C (dec.).
Eksempel 7 2.3.4.10- Tetrahydro-10-(p-ehlorphenyl)-pyrimido/I,2-a7indol-10-ol 6,5 g, 0,03 mol, finpulveriseret 3,4-dihydropyrimido/I,2-a/in-dol-10/2g7-on-hydrochlorid omsættes med 0,2 mol p-chlorphenylmagnesiumbromid i 700 ml tør ether på den i eksempel 4 beskrevne måde. Oparbejdning med is og ammoniumchlorid giver basen med smp. 185-191°C (sønderdeling) .Example 7 2.3.4.10- Tetrahydro-10- (p-ehlorophenyl) pyrimido [1,2-a] indol-10-ol 6.5 g, 0.03 mol, finely powdered 3,4-dihydropyrimido / I, 2-a indole-10 / 2g7-one hydrochloride is reacted with 0.2 mole of p-chlorophenylmagnesium bromide in 700 ml of dry ether in the manner described in Example 4. Processing with ice and ammonium chloride gives the base with m.p. 185-191 ° C (dec.).
Analyse for C^H^NgClO: C% Ef E% Cl foAnalysis for C ^H ^NgClO: C% Ef E% Cl fo
Beregnet 60,4 5,35 7,8 10,1Calculated 60.4 5.35 7.8 10.1
Fundet 60,3 5,3 7,6 9,9 .Found 60.3 5.3 7.6 9.9.
Der fås i alt 2,6 g af hydrochloridet med opløsning i ethanol og opvarmning med en opløsning af hydrogenchlorid i tør ether, smp. 275-279°C (sønderdeling).A total of 2.6 g of the hydrochloride with solution in ethanol is obtained and heating with a solution of hydrogen chloride in dry ether, m.p. 275-279 ° C (dec.).
Analyse for C^H, NpC10.HCl.l/2 C „IL OH: C % E% N fo Cl foAnalysis for C ^H, NpCl10.HCl.l / 2 C „IL OH: C% E% N for Cl
Beregnet 60,4 5,35 7,8 10,1Calculated 60.4 5.35 7.8 10.1
Fundet 60,3 5,3 7,6 9,9 150143 21Found 60.3 5.3 7.6 9.9 150143 21
Eksempel 8 2,3»il-,10-Tefcrahydro-10-(o-tol.yl)pyrimldo/Ii2-a7lncLol-10-ol 6,66 g, 0,03 mol, 3,4-Dihydropyrimido/l,2-87^^1-10^/2117-011-hydrochlorid omsættes med 0,1 mol o-tolylmagnesiumbromid i 1 liter ether på den i eksempel 4 beskrevne måde. Ved oparbejdning fås 4,1 g af basen med smp. 205-207°C (sønderdeling).EXAMPLE 8 2,3 µl, 10-Tefcrahydro-10- (o-tolyl) pyrimido [1,2-a] nyl] Chol-10-ol 6.66 g, 0.03 mol, 3,4-Dihydropyrimido / 1,2 Hydrochloride is reacted with 0.1 mole of o-tolylmagnesium bromide in 1 liter of ether in the manner described in Example 4. When working up, 4.1 g of the base are obtained with m.p. 205-207 ° C (dec.).
Analyse for C^gH^gN^O: G% E% NfoAnalysis for C ^ gHH gNNO: G% E% Nf0
Beregnet 77*7 6,5 10,1Calculated 77 * 7 6.5 10.1
Pundet 77*5 6,7 9*9Pound 77 * 5 6.7 9 * 9
Ved behandling af basen i isopropanol med tør hydrogenchlorid 1 ether fås hydrochloridet i form af farveløse fine nåle i en mængde på 4,4 g, smp. 30O-302°C (sønderdeling).When treating the base in isopropanol with dry hydrogen chloride 1 ether, the hydrochloride is obtained in the form of colorless fine needles in an amount of 4.4 g, m.p. 30O-302 ° C (dec.).
Analyse for C-^gH-^gNgO.HCl: C% E% N$Analysis for C- gHH ^GNgO.HCl: C% E% N $
Beregnet 68,7 6,1 8,9Calcd 68.7 6.1 8.9
Fundet 68,7 6,25 8*8Found 68.7 6.25 8 * 8
Eksempel 9 2,5,4,10-Tetrahydro-10-(p-tolyl)pyrimido/I,2-a7indol-10-olExample 9 2,5,4,10-Tetrahydro-10- (p-tolyl) pyrimido [1,2-a] indol-10-ol
Analogt med den i eksempel 4 beskrevne fremgangsmåde omsættes 6,6 g 5*4-dihydropyrimido/I,2-a7indol-10/2H7-on-hydroehlorid og 0,15 nil p-tolylmagnesiumbromid i 1500 ml tør ether, hvorved fås 1,28 g af hy-droohloridet af ovenstående forbindelse i form af farveløse nåle, smp. 265-267°C (sønderdeling).Analogous to the procedure described in Example 4, 6.6 g of 5 * 4-dihydropyrimido / 1,2-a-indole-10 / 2H7-one hydrochloride and 0.15 nil of p-tolylmagnesium bromide are reacted in 1500 ml of dry ether to give 1, 28 g of the hydrochloride of the above compound in the form of colorless needles, m.p. 265-267 ° C (dec.).
Analyse for C-^gH^gNgO.HCl:Analysis for C- gHH gNNO.HCl:
Cfo E% N foCfo E% N fo
Beregnet 68,7 6,1 8,9Calcd 68.7 6.1 8.9
Fundet 68,9 6,5 8,9Found 68.9 6.5 8.9
Eksempel 10 2 ,3,4,10-Tetrahydro-lO-methylpyrimido/I,2-a7indol-10-olExample 10 2, 3,4,10-Tetrahydro-10-methylpyrimido [1,2-a] indol-10-ol
Analogt med den i eksempel 6 beskrevne fremgangsmåde omsættes 5*72 g 3>^-dihydropyrimido/I,2-a7indol-10-/2H7-on og 0,06 mol methyl-magnesiumiodid i 500 ml ether. Efter opvarmning under tilbagesvaling i 4 timer og henstand natten over hældes reaktionsblandingen i is og ammoniumohlorid, etherlaget isoleres, og det vandige lag ekstraheres med chloroform. Chloroformekstrakterne tørres over vandfri magnesiumsulfat og inddampes til et fast stof, der omkrystalliseres af isopropa- 22 tSO143 nol, hvorved fås 2,1 g lysebrune rhomber med smp. l89-191°C.Analogous to the procedure described in Example 6, 5 * 72 g of 3β-dihydropyrimido / 1,2-a-indole-10- / 2H7-one and 0.06 mol of methyl magnesium iodide are reacted in 500 ml of ether. After refluxing for 4 hours and standing overnight, the reaction mixture is poured into ice and ammonium chloride, the ether layer is isolated and the aqueous layer is extracted with chloroform. The chloroform extracts are dried over anhydrous magnesium sulfate and evaporated to a solid which is recrystallized from isopropa 22 TSO143 nol to give 2.1 g of light brown rhombs with m.p. l89-191 ° C.
Analyse for c 12^14¾0: C <fo Hfo W°Analysis for c 12 ^ 14¾0: C <fo Hfo W °
Beregnet 71,5 7,0 15,85Calculated 71.5 7.0 15.85
Fundet 71,6 7,1 15.9Found 71.6 7.1 15.9
Ved opløsning af dette faste stof i isopropanol og behandling med vandfri hydrogenehiorid i ether fås 2,0 g af hydrochloridet med smp. 210-212°C.By dissolving this solid in isopropanol and treating with anhydrous hydrogen peroxide in ether, 2.0 g of the hydrochloride is obtained with m.p. 210-212 ° C.
Analyse for C-, ρΗΊ 2,Np0:HCl: C% H% N %Analysis for C, ρΗΊ 2, Np0: HCl: C% H% N%
Beregnet 60,4 6,5 11,7Calculated 60.4 6.5 11.7
Fundet 60,8 6,5 11,7Found 60.8 6.5 11.7
Eksempel 11 lO-Benzyl-2,5 Λ,10-tetrahydropyrlmido/1,2-a7indol-10-olExample 11 10-Benzyl-2,5Λ, 10-tetrahydropyrimido / 1,2-a-indol-10-ol
Analogt med den i eksempel 6 beskrevne fremgangsmåde sættes 5,72 5,72 g 5,4-dihydropyrimidoi/I,2-a7indol-10/2I^7-on dråbevis til en omrørt opløsning af 0,04 mol benzylmagnesiumehlorid i 50Q ml tør ether. Reaktionsblandingen opvarmes under tilbagesvaling i 4 timer, henstilles natten over og spaltes ved udhældning på is og ammoniumchlorid, hvorved fås 4,5 g af den ønskede base med smp. 225-250°C (sønderdeling).Analogous to the procedure described in Example 6, 5.72 g of 5.72 g of 5,4-dihydropyrimidoi / 1,2-a-indole-10 / 2I ^ 7-one is added dropwise to a stirred solution of 0.04 mole of benzylmagnesium chloride in 50 ether. The reaction mixture is heated at reflux for 4 hours, left overnight and cleaved by pouring on ice and ammonium chloride to give 4.5 g of the desired base, m.p. 225-250 ° C (dec.).
Ved behandling med en isopropanolopløsning med hydrogenchlorid i tør ether fås hydrochloridet i form af farveløse fine nåle med smp.When treated with an isopropanol solution with hydrogen chloride in dry ether, the hydrochloride is obtained in the form of colorless fine needles with m.p.
241-245°C (sønderdeling).241-245 ° C (dec.).
Analyse for C^gH^gNgO.HCl: C% Hfo N <foAnalysis for C ^ gH ^ gNNO.HCl: C% H₂O N fo fo
Beregnet 68,7 6,1 8,9Calcd 68.7 6.1 8.9
Fundet 68,9 6,2 9,1Found 68.9 6.2 9.1
Eksempel 12 10-(m-Chlorphenyl)-2,5,4,10-tetrahydropyr3mido/I,2-a7indol-10-olExample 12 10- (m-Chlorophenyl) -2,5,4,10-tetrahydropyrimido [1,2-a] indol-10-ol
Analogt med den i eksempel 6 beskrevne fremgangsmåde omsættes 3,72 g 5,4-dihydropyrimido/i,2-a7indol-10/2H7-on med 0,04 mol m-chlor-phenylmagnesiumbromid i 500 ml tør ether. Reaktionsblandingen opvarmes under tilbagesvalihg i 6 timer og henstilles derpå natten over. Blandingen hældes ud i is og ammoniumchlorid, og det frafiltrerede produkt giver 4,1 g hvidt pulver med smp. 195-195°C (sønderdeling). Efter omdannelse til hydrochloridet fås 4,79 g fine nåle med smp. 275-280°C (sønderdeling).Analogous to the procedure described in Example 6, 3.72 g of 5,4-dihydropyrimido [1,2-a] indol-10 / 2H7-one is reacted with 0.04 mole of m-chlorophenylmagnesium bromide in 500 ml of dry ether. The reaction mixture is heated under reflux for 6 hours and then left overnight. The mixture is poured into ice and ammonium chloride and the filtered product gives 4.1 g of white powder with m.p. 195-195 ° C (dec.). After conversion to the hydrochloride, 4.79 g of fine needles are obtained, m.p. 275-280 ° C (dec.).
Analyse for 0.HC1: 2 Cfo Efo NfoAnalysis for 0.HC1: 2 Cfo Efo Nfo
Beregnet 60,9 4,7 8,4Calculated 60.9 4.7 8.4
Fundet 6l,0 4,9 8,5 150143 23Found 6L, 0 4.9 8.5
Eksempel 13 8 '-Chlor-31 ,4 ,-dlhydrospiro//I,^-dioxolan-2,10' (2H,10H)pyrimido(l,2-a)- _indol7_ 2,3 g3',4,-dihydrospiro//l,3“dioxolan-2,10,(2H,10H)pyrimido--(l,2-a)-indol7 opvarmes under tilbagesvaling og omrøring i 50 ml car-bontetrachlorid med 1,43 g N-chlorsuccinimid i 16 timer. Efter afkøling vaskes carbontetrachloridet med 2 N natriumhydrogencarbonatopløsning. Derpå vaskes det organiske lag med 2 N saltsyre. Syreekstrakteme gøres basisk med koncentreret vandig ammoniakvand, og det hvide faste stof ekstraheres med ether. Efter tørring med vandfri magnesiumsulfat fjernes opløsningsmidlet, hvorved fås en olie, der krystalliserer fra let petroleum (kogeinterval 100-120°C) indeholdende nogle få dråber benzen. Der fås 0,73 g produkt i form af farveløse nåle med smp. 112-114°C. Analyse for C-^H^ClNgOg: C fo Efo N foExample 13 8 '-Chloro-31,4-dihydrospiro // 1,3 -dioxolane-2.10' (2H, 10H) pyrimido (1,2-a) -indole7,3,3 g3 ', 4, -dihydrospiro // 1,3 'dioxolane-2.10, (2H, 10H) pyrimido - (1,2-a) -indole7 is heated under reflux and stirring in 50 ml of carbon tetrachloride with 1.43 g of N-chlorosuccinimide for 16 hours. hours. After cooling, the carbon tetrachloride is washed with 2 N sodium hydrogen carbonate solution. The organic layer is then washed with 2N hydrochloric acid. The acid extracts are made basic with concentrated aqueous ammonia water and the white solid is extracted with ether. After drying with anhydrous magnesium sulfate, the solvent is removed to give an oil crystallizing from light petroleum (boiling range 100-120 ° C) containing a few drops of benzene. 0.73 g of product is obtained in the form of colorless needles with m.p. 112-114 ° C. Analysis for C- HH ^ClNgOg: Cf Efo N fo
Beregnet 59,0 4,95 10,6Calculated 59.0 4.95 10.6
Pundet 58,95 5,0 10,3Pound 58.95 5.0 10.3
Eksempel 14 31,4'-Dihydrospiro/ΐ ,3-dioxolan-3’,3'-dimethyl-2,101(2H,10H)pyrimido- _(l,2-a)indol7_ (a) 7,35 g isatin, 11,2 ml ethylenglycol og 2 g toluen-p-sul-fonsyre i 300 ml benzen opvarmes under tilbagesvaling i et apparatur forsynet med en vandudskiller i 5 timer, hvorunder der opsamles 2,1 ml vand i vandudskilleren, og reakt i ons bl andingen bliver farveløs. Reaktionsblandingen afkøles, vaskes med natriumhydrogencarbonatopløsning og vand. Efter tørring over magnesiumsulfat fjernes benzenet under formindsket tryk, og remanensen krystalliseres af methanol, hvorved fås 9,9 g 2'-oxospiro/l,3-dioxolan-2,3'-indolin/ i form af svagt lyserøde nåle med smp. 131-132°C.Example 14 31,4'-Dihydrospiro [3,3-dioxolane-3 ', 3'-dimethyl-2,101 (2H, 10H) pyrimido- (1,2-a) indole7 (a) 7.35 g isatin, 11 , 2 ml of ethylene glycol and 2 g of toluene-p-sulphonic acid in 300 ml of benzene are heated under reflux in an apparatus equipped with a water separator for 5 hours, during which 2.1 ml of water is collected in the water separator and the reaction is stirred in the mixture colorless. The reaction mixture is cooled, washed with sodium bicarbonate solution and water. After drying over magnesium sulfate, benzene is removed under reduced pressure and the residue is crystallized by methanol to give 9.9 g of 2'-oxospiro / 1,3-dioxolane-2,3'-indoline / in the form of pale pink needles, m.p. 131-132 ° C.
Analyse for C10H9N303:Analysis for C10H9N3O3:
Cfo H# - H#Cfo H # - H #
Beregnet . 62,8 4,8 7,2 ' Pundet 62,72 4,8 7,2 (b) 42,0 g t-butylcyanid opvarmes ved 60°C under omrøring i en blanding af 26 ml brom og 1 liter carbontetraehlorid i 7 dage, idet der samtidig bestråles med en ultraviolet lampe med moderat tryk. Carbontetrachloridet fjernes under formindsket tryk, og remanensolien opløses i dichlormethan og vaskes med natriumhydrogencarbonatopløsning og derpå med vand. Efter tørring over vandfri magnesiumsulfat fjernes opløsningsmidlet, og ved destillation fås 26 g produkt bestående af 3-hrom--2,2-dimethylpropionitril i form af en farveløs med kp. 77-82°C/12 itrni Hg.Calculated. 62.8 4.8 7.2 'Pound 62.72 4.8 7.2 (b) 42.0 g of t-butyl cyanide is heated at 60 ° C with stirring in a mixture of 26 ml of bromine and 1 liter of carbon tetrachloride for 7 hours. days, while simultaneously irradiating with an ultraviolet lamp at moderate pressure. The carbon tetrachloride is removed under reduced pressure and the residual oil is dissolved in dichloromethane and washed with sodium hydrogen carbonate solution and then with water. After drying over anhydrous magnesium sulfate, the solvent is removed and by distillation 26 g of product consisting of 3-hromo-2,2-dimethylpropionitrile in the form of a colorless with kp are obtained. 77-82 ° C / 12 it Hg.
24 15014324 150143
Analyse for C^HgBrN: 0% Uf> NtfAnalysis for C ^ HHgBrN: 0% Uf> Ntf
Beregnet 37,1 5,0 8,65Calculated 37.1 5.0 8.65
Pundet 38,1 4,8 7 >3 (c) 3,8 g 2,-oxospiro/lJ3-dioxolan-2,3'-indolln7 sættes portionsvis til en omrørt suspension af 0,84 g natriumamid i 30 ml tør hexamethylphosphorsyretriamid under en nitrogenstrøm. Reaktionsblan-dingen opvarmes til 40°C i 2 timer, afkøles til 10°C, og der tilsættes på én gang 3,24 g 3-brom-2,2-dimethylpropionitril. Reaktionsblandingen omrøres ved stuetemperatur i 2 dage. Reaktionsblandingen hældes i vand og ekstraheres med benzen. Benzenekstrakteme vaskes med fortyndet saltsyre, tørres over vandfri magnesiumsulfat og inddampes til en mørk olie. Krystallisation fra absolut ethanol giver 3,05 g 2'-oxo-spiro/1,3-dioxolan-2,3' -indolin7-l1 -[%. ,2-dimethylpropionitril/ i form af farveløse rhomber med smp. 112-113°C.Pound 38.1 4.8 7> 3 (c) 3.8 g of 2, -oxospiro / 1J3-dioxolane-2,3'-indole is added portionwise to a stirred suspension of 0.84 g of sodium amide in 30 ml of dry hexamethylphosphoric triamide under reduced pressure. a stream of nitrogen. The reaction mixture is heated to 40 ° C for 2 hours, cooled to 10 ° C and 3.24 g of 3-bromo-2,2-dimethylpropionitrile are added at once. The reaction mixture is stirred at room temperature for 2 days. The reaction mixture is poured into water and extracted with benzene. The benzene extracts are washed with dilute hydrochloric acid, dried over anhydrous magnesium sulfate and evaporated to a dark oil. Crystallization from absolute ethanol gives 3.05 g of 2'-oxo-spiro / 1,3-dioxolane-2,3'-indolin7-l1 - [%. 2-dimethylpropionitrile / in the form of colorless rhombs with m.p. 112-113 ° C.
Analyse for C^H^gNgO-^: C fo Uf> UfoAnalysis for C ^H ^ gN₂O-: C fo UfOf> Ufo
Beregnet 66,2 5,9 10,3Calculated 66.2 5.9 10.3
Fundet 66,5 6,2 10,3 (d) 2,7 g af det ovenfor under (c) fremstillede produkt reduceres i ethanolisk ammoniak i nærværelse af Raneynikkel på den i eksempel 1 beskrevne måde. Efter oparbejdning opvarmes produktet under tilbagesvaling med toluen i 24 timer. Fjernelse af toluenet og omkrystallisation af benzen giver 1,23 g af den tilsigtede forbindelse i form af farveløse rhomber med smp. 109-110°C.Found 66.5 6.2 10.3 (d) 2.7 g of the product prepared under (c) is reduced in ethanolic ammonia in the presence of Raneynickel in the manner described in Example 1. After working up, the product is refluxed with toluene for 24 hours. Removal of the toluene and recrystallization of benzene give 1.23 g of the intended compound in the form of colorless rhombus with m.p. 109-110 ° C.
Analyse for C-^H^gN^O:Analysis for C- HH ^ gNNO:
Cfo Ufo Nf>Cfo Ufo Nf>
Beregnet 69,7 7,0 10,85Calculated 69.7 7.0 10.85
Fundet 70,0 7,2 11,1Found 70.0 7.2 11.1
Eksempel 15 8-Chlor-2,3,4,10-tetrahydropyrimido/I,2-a7indol-10/2H7-on 8,0 g 8’-chlor-3’,4,-dihydro-spiro/I,3-dioxolan-2,10’(2H,10H)-pyrimido(l,2-a)indol7 finpulveriseres og sættes til 50 ml koncentreret svovlsyre på den i eksempel 3 beskrevne måde. Analogt med fremgangsmåden i eksempel 3 foretages oparbejdning og omkrystallisation af benzen, hvorved fås 5,8 g røde pladeformede krystaller med smp. l63-l65°C (sønderdeling).Example 15 8-Chloro-2,3,4,10-tetrahydropyrimido [1,2-a] indol-10 / 2H7-one 8.0 g of 8'-chloro-3 ', 4,4-dihydro-spiro / I, 3- dioxolane-2.10 '(2H, 10H) -pyrimido (1,2-a) indole7 is finely powdered and added to 50 ml of concentrated sulfuric acid in the manner described in Example 3. Analogously to the procedure of Example 3, the benzene is worked up and recrystallized to give 5.8 g of red plate crystals with m.p. 163-165 ° C (dec.).
Analyse for C-^H^CIN^O:Analysis for C- HH ^CIN₂O:
Cfo Ufo UfoCfo Ufo Ufo
Beregnet 59,9 4,1 12,7Calculated 59.9 4.1 12.7
Fundet 60,2 3,9 12,8 25 1501 A3Found 60.2 3.9 12.8 25 1501 A3
Eksempel 16 8-Chlor-2 ,3 ,4,10-tetrahydro-10-phenylpyrimido/I ^-aJindol-lO-olExample 16 8-Chloro-2,3,4,10-tetrahydro-10-phenylpyrimido [1 H] -indole-10-ol
Analogt med den 1 eksempel 6 beskrevne fremgangsmåde sættes 8-chlor-2,5^jl0-tetrahydropyrimido^i,2-a7indol-10-on i 60 ml tetra-hydrofuran til en opløsning af 0,026 mol phenylmagnesiumbromid i 50 ml ether. Blandingen opvarmes under tilbagesvaling og omrøring i 5 timer, og efter henstand natten over hældes blandingen i en blanding af is og ammoniumchlorid. Det dannede faste stof frafiltreres og vaskes med vand og ether, hvorved fås 2,74 g lysebrunt pulver med snip. 240-250°C (sønderdeling).Analogous to the procedure described in Example 6, 8-chloro-2,5 µl-tetrahydropyrimido [1,2-a] indol-10-one in 60 ml of tetrahydrofuran is added to a solution of 0.026 mol of phenylmagnesium bromide in 50 ml of ether. The mixture is heated under reflux and stirring for 5 hours and after standing overnight, the mixture is poured into a mixture of ice and ammonium chloride. The solid formed is filtered off and washed with water and ether to give 2.74 g of light brown powder with snip. 240-250 ° C (dec.).
Analyse for C^H^ClNgO: C f H fo NfAnalysis for C ^H ^ClNgO: C fH fo NNf
Beregnet 68,9 5,6 9,4Calculated 68.9 5.6 9.4
Fundet 67,6 5,3 8,9Found 67.6 5.3 8.9
Pulveret suspenderes i varm absolut ethanol og behandles med en opløsning af tør hydrogenchloridgas i tør ether, hvorved fås 1,89 g fine nåle med smp. 279-282°C (sønderdeling).The powder is suspended in warm absolute ethanol and treated with a solution of dry hydrogen chloride gas in dry ether to give 1.89 g of fine needles, m.p. 279-282 ° C (dec.).
Analyse for C-^H-j^ClNgO.HCl:Analysis for C- HH-jClNgO.HCl:
Cf Hf NfCf Hf Nf
Beregnet 60,9 4,8 8,1Calculated 60.9 4.8 8.1
Fundet 61,25 4,8 8,5Found 61.25 4.8 8.5
Eksempel 17 8-Chlor-2,3 ,4,10-tetrahydro-10-(m-chlorphenyl)-pyrimido/1,2-a7indol-10-ol Analogt med den i eksempel 6 beskrevne fremgangsmåde sættes 2,8 g 8-chlor-2,5,4,10-tetrahydropyrimido/(I,2-a7indol-10-on i 60 ml tør tetrahydrofuran til 0,03 mol m-chlorphenylmagnesiumbromid i 60 ml ether. Reakt ionsblandingen opvarmes under tilbagesvaling i 4 timer.Example 17 8-Chloro-2,3,4,10-tetrahydro-10- (m-chlorophenyl) -pyrimido / 1,2-a-indol-10-ol Analogously to the procedure described in Example 6, 2.8 g of 8- chloro-2,5,4,10-tetrahydropyrimido / (1,2-a-indol-10-one in 60 ml of dry tetrahydrofuran to 0.03 mole of m-chlorophenylmagnesium bromide in 60 ml of ether. The reaction mixture is refluxed for 4 hours.
Efter henstand natten over hældes reaktionsblandingen i is og ammonium-chlorid. Det organiske lag isoleres, og det vandige lag ekstraheres med methylendichlorid. Det organiske lag ekstraheres med 2 N saltsyre, det sure lag gøres basisk, ekstraheres med methylendichlorid, og efter tørring over magnesiumsulfat fjernes opløsningsmidlet, og remanensen opløses i absolut ethanol og behandles med en opløsning af hydrogen-chlorid i tør ether. Der fås l,6l g lyserøde rhomber med smp. 279°C (sønderdeling).After standing overnight, the reaction mixture is poured into ice and ammonium chloride. The organic layer is isolated and the aqueous layer is extracted with methylene dichloride. The organic layer is extracted with 2N hydrochloric acid, the acidic layer is made basic, extracted with methylene dichloride, and after drying over magnesium sulfate, the solvent is removed and the residue is dissolved in absolute ethanol and treated with a solution of hydrogen chloride in dry ether. 1, 6l g of pink rhombs are obtained with m.p. 279 ° C (dec.).
Analyse for C^yH^ClgNgO.HCl:Analysis for C ^ yHHClgNgO.HCl:
Cf Hf NfCf Hf Nf
Beregnet 55,2 4,1 7,6Calculated 55.2 4.1 7.6
Fundet 54,8 4,15 7,3 26 150143Found 54.8 4.15 7.3 26.150143
Eksempel 18 10- (m-Anlsyl) -2,5,4,10-tetrahydropyrmido/I,2-a7indol-10-olExample 18 10- (m-Anlsyl) -2,5,4,10-tetrahydropyrmido [1,2-a] indol-10-ol
Analogt med den i eksempel 6 beskrevne fremgangsmåde sættes 3,72 g 2i3,4i10-tetrahydropyrimido//l,2-a7indol-10-on i 50 ml tør tetrahydrofuran til 0,04 mol m-anisylmagnesiumbromid 1 50 ml ether. Der opvarmes under tilbagesvaling og omrøring i 5 timer, hvorefter der henstilles natten over og udhældes på is og ammoniumchlorid. Efter syre--base-ekstraktion fås 2,16 g base med smp. 255°C (sønderdeling). Det faste stof omdannes til hydrochloridet ved opløsning i ethanol og tilsætning af hydrogenehlorid i tør kether, hvorved fås 2,2 g farveløse rhomber med smp. 260-262°C (sønderdeling).Analogous to the procedure described in Example 6, 3.72 g of 2,3,4i10-tetrahydropyrimido [1,2-a] indol-10-one in 50 ml of dry tetrahydrofuran is added to 0.04 mole of m-anisylmagnesium bromide in 50 ml of ether. Reflux and stir for 5 hours, then leave overnight and pour on ice and ammonium chloride. After acid-base extraction, 2.16 g of base are obtained with m.p. 255 ° C (dec.). The solid is converted to the hydrochloride by dissolving in ethanol and adding hydrogen chloride in dry kether to give 2.2 g of colorless rhombus with m.p. 260-262 ° C (dec.).
Analyse for C^gH^gNgO^-HCl: <# E% N$Analysis for C ^ gHH gNNO ^-HCl: <# E% N $
Beregnet 65,5 5*8 8,5Calculated 65.5 5 * 8 8.5
Fundet 65,5 6,0 8,5Found 65.5 6.0 8.5
Eksempel 19 2.5.4.10- Tetrahydro-10-(m-tolyl)pyrimido/I,2-a7indol-10-ol Analogt med den i eksempel 6 beskrevne fremgangsmåde sættes 2.5.4.10- tetrahydropyrimido/l,2-a/7indol-10-on i 50 ml tetrahydrofuran til 0,05 mol m-1olylmagnesiumbromid i 200 ml ether. Efter endt tilsætning opvarmes blandingen under tilbagesvaling i 5 timer. Efter henstand natten over hældes reaktionsblandingen ud i en blanding af is og ammo-niumehlorid. Det organiske lag isoleres, og det vandige lag ekstraheres med chloroform. Efter tørring fjernes chloroformet, hvorved fås en rød olie. Ved triturering med ether fås et hvidt fast stof. Det faste stof omkrystalliseres af en blanding af benzen og ether, hvorved fås 1,36 g lysegule rhomber med smp. 179-l80°C.Example 19 2.5.4.10- Tetrahydro-10- (m-tolyl) pyrimido / 1,2-a-indol-10-ol Analogous to the procedure described in Example 6, 2.5.4.10-tetrahydropyrimido / 1,2-a / 7indole-10 is added. -one in 50 ml of tetrahydrofuran to 0.05 mole of m-1olylmagnesium bromide in 200 ml of ether. After the addition is complete, the mixture is heated under reflux for 5 hours. After standing overnight, the reaction mixture is poured into a mixture of ice and ammonium chloride. The organic layer is isolated and the aqueous layer is extracted with chloroform. After drying, chloroform is removed to give a red oil. Trituration with ether gives a white solid. The solid is recrystallized from a mixture of benzene and ether to give 1.36 g of pale yellow rhombus with m.p. 179-L80 ° C.
Analyse for C^gH^gNgO: Q.% Efo EfoAnalysis for C ^ gH ^ gNGO: Q.% Efo Efo
Beregnet 77,7 6,5 10,1Calculated 77.7 6.5 10.1
Fundet 77,4 6,7 9,8Found 77.4 6.7 9.8
Eksempel 20 2,5,4, 10-Tetrahydro-10(2-thienyl)pyrimido/l,2-a7indol-10-ol 3,72 g 2,3,4,10-tetrahydropyrimido^/l,2-a/indol-10-on i 150 ml tør tetrahydrofuran sættes til 0,05 mol 2-thienylmagnesiumbromid på den i eksempel 19 beskrevne måde. Efter endt tilsætning omrøres reaktionsblandingen under tilbagesvaling i 4 timer. Reaktionsblandingen hældes på is og ammoniumchlorid og filtreres, hvorved fås 4,38 g gråt pulver. Pulveret suspenderes i absolut ethanol og behandles med en opløsning af hydrogenehlorid i tør ether, blandingen koges og behandles 150143 27 derpå med trækul og filtreres. Ved fortynding med ether fås 3*68 g af den tilsigtede forbindelse i form af farveløse nåle med smp. 226-228°C (sønderdeling).Example 20 2,5,4,10-Tetrahydro-10 (2-thienyl) pyrimido [1,2-a] indol-10-ol 3.72 g of 2,3,4,10-tetrahydropyrimido [1,2-a] indol-10-one in 150 ml of dry tetrahydrofuran is added to 0.05 mole of 2-thienylmagnesium bromide in the manner described in Example 19. After the addition is complete, the reaction mixture is stirred under reflux for 4 hours. The reaction mixture is poured onto ice and ammonium chloride and filtered to give 4.38 g of gray powder. The powder is suspended in absolute ethanol and treated with a solution of hydrogen ether in dry ether, the mixture is boiled and then treated with charcoal and filtered. By dilution with ether, 3 * 68 g of the intended compound is obtained in the form of colorless needles with m.p. 226-228 ° C (dec.).
Analyse for C^^H-^^NgOS.HCl: C% E% N$Analysis for C ^^ HH - ^^ NNgOS.HCl: C% E% N $
Beregnet 58*7 4,9 9*1Calculated 58 * 7 4.9 9 * 1
Bundet 58,6 5*0 9*9Tied 58.6 5 * 0 9 * 9
Eksempel 21 10-(m-Fluorphenyl)-2,5.4 *10-tetrahydropyrmido/1,2-a7indol-10-ol 5*72 g 3*^_dihydropyrimido/I*2-a7indol-10//2H7 i 100 ml tør te-trahydrofuran sættes dråbevis til en omrørt opløsning af 0*05 mol m-fluorphenylmagnesiumbromid i tør ether. Reaktionsblandingen opvarmes vinder tilbage svaling i 4 timer, afkøles og sønderdeles ved udhældning på en blanding af is og ammoniumchlorid. Det organiske lag isoleres, og det vandige lag ekstraheres med chloroform. De kombinerede organiske ekstrakter vaskes med vand og tørres over vandfri magnesiumsulfat.Example 21 10- (m-Fluorophenyl) -2,5,4 * 10-tetrahydropyrmido / 1,2-a-indindol-10-ol 5 * 72 g 3 * - dihydropyrimido / l * 2-a7indole-10 // 2 H7 in 100 ml dry tetrahydrofuran is added dropwise to a stirred solution of 0 * 05 mol of m-fluorophenylmagnesium bromide in dry ether. The reaction mixture is heated to reflux for 4 hours, cooled and decomposed by pouring on a mixture of ice and ammonium chloride. The organic layer is isolated and the aqueous layer is extracted with chloroform. The combined organic extracts are washed with water and dried over anhydrous magnesium sulfate.
Efter fjernelse af opløsningsmidlet tritureres remanensen med ether, hvorved fås 5*5 g lysebrunt fast stof. Det faste stof suspenderes i kogende absolut ethanol, der tilsættes en opløsning af hydrogenchlorid-gas i tør ether* og den fremkomne opløsning behandles med trækul og filtreres. Efter afkøling af filtratet krystalliserer den ønskede forbindelse i form af hydrochloridet, og der fås 3*5 g nåleformet produkt med smp. 280-290°C (sønderdeling).After removal of the solvent, the residue is triturated with ether to give 5 * 5 g of light brown solid. The solid is suspended in boiling absolute ethanol, a solution of hydrogen chloride gas in dry ether * is added, and the resulting solution is treated with charcoal and filtered. After cooling the filtrate, the desired compound crystallizes in the form of the hydrochloride and gives 3 * 5 g of needle-shaped product with m.p. 280-290 ° C (dec.).
Analyse for C^yH^FNgO.HCls C fo E% Ef°Analysis for C
Beregnet 64,05 5*1 8,9Calculated 64.05 5 * 1 8.9
Fundet 64*0 5*1 8*9Found 64 * 0 5 * 1 8 * 9
Eksempel 22 10-(1-Naphthyl)-2,3,4,10-tetrahydropyrimido/I,2-a7indol-10-olExample 22 10- (1-Naphthyl) -2,3,4,10-tetrahydropyrimido [1,2-a] indol-10-ol
Analogt med den i eksempel 21 beskrevne fremgangsmåde sættes 2*86 g 3*4-dihydropyrimido/l,2-a7indol-10(2H)-on i 100 ml tør tetrahy-drofuran til 0,05 mol 1-naphthylmagnesiumbromid. Efter oparbejdning og fjernelse af opløsningsmidlet fås basen i form af en olie, som omdannes til hydrochloridet på sædvanlig måde. Der fås 5*8 g produkt med smp. 270-274°C (sønderdeling).Analogous to the procedure described in Example 21, 2 * 86 g of 3 * 4-dihydropyrimido [1,2-a] indol-10 (2H) -one in 100 ml of dry tetrahydrofuran is added to 0.05 mole of 1-naphthylmagnesium bromide. After working up and removing the solvent, the base is obtained in the form of an oil which is converted into the hydrochloride in the usual manner. 5 * 8 g of product with m.p. 270-274 ° C (dec.).
Analyse for C2]Hl8N20.HCl.l/4H20: C ^ Η % NfoAnalysis for C2] H18 N2 O.HCl.1 / 4H2 O: C ^Η% N₂O
Beregnet 71*25 5*5 7*9Calculated 71 * 25 5 * 5 7 * 9
Fundet 71*0 5*5 7*7 28 150143Found 71 * 0 5 * 5 7 * 7 28 150143
Eksempel 25 10-(o-Chlorphenyl)-2,3 ,4 i10-tetrahydropyrimido/I,2-a7indol-10-olExample 25 10- (o-Chlorophenyl) -2,3,4'10-tetrahydropyrimido [1,2-a] indol-10-ol
Analogt med den i eksempel 21 beskrevne fremgangsmåde sættes 2,8 g 5,4-dihydropyrimido/I,2-^indol-10/227-on..fcil en opløsning af 0,05 mol o-chlorphenylmagnesiumbromid i 100 ml tør tetrahydrofuran.Analogous to the procedure described in Example 21, 2.8 g of 5,4-dihydropyrimido [1,2-indole-10/227-one] sulfur is added to a solution of 0.05 mole of o-chlorophenylmagnesium bromide in 100 ml of dry tetrahydrofuran.
Efter udhældning af reaktionsblandingen på is og ammoniumchloridopløs-ning frafiltreres det dannede faste stof og vaskes med vand og ether, Hydrochloridet fremstilles på sædvanlig måde i form af farveløse rhomber, og der fås 5,47 g produkt med smp. 287-290°C (sønderdeling).After pouring the reaction mixture on ice and ammonium chloride solution, the solid formed is filtered off and washed with water and ether. The hydrochloride is prepared in the usual manner in colorless rhombus and 5.47 g of product are obtained, m.p. 287-290 ° C (dec.).
Analyse for C^^ClNgO.HCl.l^ CgH^OH:Analysis for C ^^ ClClNgO.HCl.llCgH ^OH:
Gfo W° N#Gfo W ° N #
Beregnet 60,55 5,9 7,7Calculated 60.55 5.9 7.7
Fundet 60,1 5,8 7,7Found 60.1 5.8 7.7
Eksempel 24 2,3,4,10-Tetrahydro-10-(m-trifluormethylphenyl)pyrimido/I,2-a7indol-10-ol Analogt med den i eksempel 21 beskrevne fremgangsmåde sættesExample 24 2,3,4,10-Tetrahydro-10- (m-trifluoromethylphenyl) pyrimido [1,2-a] indol-10-ol Analogous to the procedure described in Example 21 is added.
2.7 g 3A-dihydropyrimido(/I,2-a7indol-10/5H7-on til en opløsning af 0,05 mol m-trifluormethylphenylmagnesiumbromid. Efter udhældning på is og ammoniumchloridopløsning fjernes den udfældede base, og det organiske lag oparbejdes og fordampes, hvorved fås en yderligere mængde base. Basen omdannes til hydrochloridet på sædvanlig måde, hvorved fås 5,95 g af den ønskede forbindelse i form af hydrochloridet med smp. 291-292°CTo a solution of 0.05 mole of m-trifluoromethylphenylmagnesium bromide. After pouring on ice and ammonium chloride solution, the precipitate is removed and the organic layer is worked up and evaporated An additional amount of base is obtained The base is converted to the hydrochloride in the usual manner to give 5.95 g of the desired compound in the form of the hydrochloride, mp 291-292 ° C
(sønderdeling).(Decomposition).
Analyse for C^gH^F^NgO.HCl: C% Hfo W°Analysis for C ^ gH ^F ^NgO.HCl: C% H
Beregnet 58,6 4,4 7,6Calculated 58.6 4.4 7.6
Fundet 58,6 5,5 7,5Found 58.6 5.5 7.5
Eksempel 25 10-(5,4-Diohlorphenyl)-2,5,4,10-tetrahydropyrimido/I,2-a7indol-10-olExample 25 10- (5,4-Diohlorophenyl) -2,5,4,10-tetrahydropyrimido [1,2-a] indol-10-ol
Analogt med den i eksempel 21 beskrevne fremgangsmåde omsættes 2.7 g 5,4-dihydropyrimido/I,2-a/indol-10/2H7-on med 0,05 mol 5,^-di-chlorphenylmagnesiumbromid. Efter oparbejdning isoleres det organiske lag, og det vandige lag ekstraheres med chloroform. De kombinerede organiske ekstrakter behandles med 2 N saltsyre, og det udfældede hydrochlo-rid frafiltreres og tørres. Ved omkrystallisation af en blanding af methanol og ether fås 5,4 g farveløse nåle med smp. 287-290°C (sønderdeling).Analogous to the procedure described in Example 21, 2.7 g of 5,4-dihydropyrimido / 1,2-a / indol-10 / 2H7-one is reacted with 0.05 mole of 5β-dichlorophenylmagnesium bromide. After working up, the organic layer is isolated and the aqueous layer is extracted with chloroform. The combined organic extracts are treated with 2N hydrochloric acid and the precipitated hydrochloride is filtered off and dried. Recrystallization of a mixture of methanol and ether gives 5.4 g of colorless needles with m.p. 287-290 ° C (dec.).
Analyse for 0η„H,lClpW„0.HC1: C fo H fo WoAnalysis for 0η "H, lClpW" 0.HCl: C for H for Wo
Beregnet 55,2 4,1 7,6Calculated 55.2 4.1 7.6
Fundet 54,9 4,1 7,5 150143 29Found 54.9 4.1 7.5 29
Eksempel 26 10-( p-Fluorphenyl)-2,3 ,4 .10-tetrahydropyrimido/I,2-a7indol-10-olExample 26 10- (p-Fluorophenyl) -2,3,4,10-tetrahydropyrimido [1,2-a] indol-10-ol
Analogt med den 1 eksempel 21 beskrevne fremgangsmåde omsættes 2,5 g 3,4-dihydropyrimido/l,2-a7indol-10/2H7-on med 0,05 mol p-fluor-phenylmagnesiumbromid. Hydrochloridet fremstilles på sædvanlig måde, og der fås 2,4 g cremefarvede nåle med smp. 270-272°C.Analogous to the procedure described in Example 21, 2.5 g of 3,4-dihydropyrimido / 1,2-a-indol-10 / 2H7-one is reacted with 0.05 mole of p-fluoro-phenylmagnesium bromide. The hydrochloride is prepared in the usual manner and 2.4 g of cream colored needles are obtained with m.p. 270-272 ° C.
Analyse for C-^H^ENgO.HCl:Analysis for C-H H ENN₂O.HCl:
Qfo EfoQfo Efo
Beregnet 64,0 5,1 8,8Calculated 64.0 5.1 8.8
Fundet 63,9 4,9 8,6Found 63.9 4.9 8.6
Eksempel 27 2,3,4,10-Tetrahydro-10-(o-trifluorphenyl)pyrimido/l,2-a7indol-10-ol Analogt med den i eksempel 21 beskrevne fremgangsmåde omsættes 2,79 g 3,4-dihydropyrimido(/I,2-ai7indol-10/2g7-on med 0,05 mol o-trifluormethylphenylroagnesiumbromid. Hydrochloridet fås i en mængde på 3,72 g og i form af fine nåle med smp. 255-257°C (sønderdeling).Example 27 2,3,4,10-Tetrahydro-10- (o-trifluorophenyl) pyrimido [1,2-a] indol-10-ol According to the procedure described in Example 21, 2.79 g of 3,4-dihydropyrimido (/ I, 2-aiindole-10 / 2g7-one with 0.05 mole of o-trifluoromethylphenylroagnesium bromide The hydrochloride is obtained in an amount of 3.72 g and in the form of fine needles, mp 255-257 ° C (decomposition).
Analyse for C-^gH^F-^NgO.HCl.l/^ GgH^OH: C% EfoAnalysis for C- gHH FF- ^NgO.HCl.1 / GGgH ^ OH: C% Efo
Beregnet 58,2 4,9 7,15Calculated 58.2 4.9 7.15
Fundet 58,4 4,9 7,3Found 58.4 4.9 7.3
Eksempel 28 10-(2,5-Dichlorphenyl)-2,3,4,10-tetrahydropyrlmido/I,2-a7indol-10-olExample 28 10- (2,5-Dichlorophenyl) -2,3,4,10-tetrahydropyrimido [1,2-a] indol-10-ol
Analogt med den i eksempel 21 beskrevne fremgangsmåde omsættes 1,86 g 3,4-dihydropyrimido(/I,2-a7indol-10/2H7-on med 0,025 mol 2,3-di-chlorphenylmagnesiumbromid. Efter oparbejdning fås basen i form af en olie, der giver 1,95 g af hydrochloridet med smp. 292-294°C (sønderdeling) .Analogous to the procedure described in Example 21, 1.86 g of 3,4-dihydropyrimido ([1,2-a] indol-10 / 2H7-one is reacted with 0.025 moles of 2,3-dichlorophenylmagnesium bromide. After working up the base is obtained in the form of oil giving 1.95 g of the hydrochloride, mp 292-294 ° C (dec.).
Analyse for C-^^H^ClgNgO.HCl.HgO:Analysis for C - HH HClgNgO.HCl.HgO:
Cfo Hfo 0Cfo Hfo 0
Beregnet 52,7 4,4 7,2Calculated 52.7 4.4 7.2
Fundet 52,7 4,1 7,5Found 52.7 4.1 7.5
Eksempel 29 3,4-Dihydro-5,5-dimethylpyrimido/I,2-a7indol-10/2H7-on 8,5. g 3,,i^,-dihydrospiro^I,3-dioxolan-3,,5,-diπletbyl-2,10,-(2H,10H)pyrimido/l,2-a7indol sættes portionsvis til 100 ml koncentreret svovlsyre, idet temperaturen holdes under 30°C, og tilsætningshastigheden reguleres således, at al ketalen er opløst, inden den næste portion tilsættes. Der henstilles natten over ved stuetemperatur og -under omrøring, hvorefter blandingen udhældes på is og neutraliseres med koncentreret vandig ammoniak, idet temperaturen holdes under 30 1501A3 30°C. Den røde olie ekstraheres med methylendiehlorid, tørres over vandfri magnesiumsulfat, fordampes til et rødt skum, som giver 5i98 g røde rhomber med smp. 125-126°C efter krystallisation i en blanding af benzen og let petroleum (kogeinterval 40-60°C).Example 29 3,4-Dihydro-5,5-dimethylpyrimido / 1,2-a-indol-10 / 2H7-one 8.5. g of 3, 1, - dihydrospiro, 1,3-dioxolane-3,5,5-dimethylbyl-2,10, - (2H, 10H) pyrimido [1,2-a] indole is added portionwise to 100 ml of concentrated sulfuric acid, the temperature is kept below 30 ° C and the rate of addition is adjusted so that all the ketal is dissolved before the next batch is added. Stir overnight at room temperature and stirring, then pour the mixture on ice and neutralize with concentrated aqueous ammonia, keeping the temperature below 30 ° C 30 ° C. The red oil is extracted with methylene dihydrochloride, dried over anhydrous magnesium sulfate, evaporated to a red foam which gives 598 g red rhombs with m.p. 125-126 ° C after crystallization in a mixture of benzene and light petroleum (boiling range 40-60 ° C).
Analyse for C15Hl4N20: C% Hfo Ef>Analysis for C 15 H 14 N 2 O: C% H
Beregnet 72,9 6,6 13,1Calculated 72.9 6.6 13.1
Pundet 73,3 6,7 13,0Pound 73.3 6.7 13.0
Eksempel 30 10-(m-Chlorphenyl)-2,3,4,10-tetrahydro-3,3-dimethylpyrimido/I,2-a/indol-__-IQ-ol_Example 30 10- (m-Chlorophenyl) -2,3,4,10-tetrahydro-3,3-dimethylpyrimido [1,2-a] indole -__-IQ-ol
Analogt med den i eksempel 21 beskrevne fremgangsmåde sættes 2,4 g 3,4-dihydropyrimido-3,3-dimethyl/I,2-a/indol-10/SH7-on til en opløsning af 0,05 mol m-chlorphenylmagnesiumbromid. Efter oparbejdning fra filtreres basen og omdannes til hydrochloridet på den sædvanlige måde, hvorved fås 2,0 g af det ønskede hydrochlorid med smp. 271-273°C (sønderdeling).Analogous to the procedure described in Example 21, 2.4 g of 3,4-dihydropyrimido-3,3-dimethyl / 1,2-a / indole-10 / SH7-one is added to a solution of 0.05 mole of m-chlorophenylmagnesium bromide. After working up, the base is filtered and converted to the hydrochloride in the usual manner to give 2.0 g of the desired hydrochloride with m.p. 271-273 ° C (dec.).
Analyse for C-^H^CIN^O · HC1:Analysis for C- HH ^CIN ^O · HCl:
Cfo Efo EfoCfo Efo Efo
Beregnet 62,8 5,55 7,7Calculated 62.8 5.55 7.7
Pundet 62,8 5,5 7,6Pound 62.8 5.5 7.6
Eksempel 31 ; 2,3,4,10-Tetrahydro-10-phenyl-3,5-dimethylpyrimido/I.2-a7indol-10-olExample 31; 2,3,4,10-Tetrahydro-10-phenyl-3,5-dimethylpyrimido / I.2-a7indol-10-ol
Analogt med den i eksempel 21 beskrevne fremgangsmåde omsættes 3 g 3,4-dihydro-3,3-dimethylpyrimido/I,2-a7indol-10/5g7-on med 0,05 mol phenylmagnesiumbromid. Efter oparbejdning fås 2,4 g af hydrochloridet med smp. 260-261°C (sønderdeling).Analogous to the procedure described in Example 21, 3 g of 3,4-dihydro-3,3-dimethylpyrimido [1,2-a] indol-10 / 5g7-one is reacted with 0.05 mole of phenylmagnesium bromide. After working up, 2.4 g of the hydrochloride is obtained with m.p. 260-261 ° C (dec.).
Analyse for C^Hg^igO^Cl:Analysis for C ^ HHg ^ igOOCl:
Cfa Efo EfoCfa Efo Efo
Beregnet 69,4 6,4 8,5Calculated 69.4 6.4 8.5
Pundet 69,0 6,75 8,3Pound 69.0 6.75 8.3
Eksempel 32 3,4-Dihydro-8-methoxypyrimido/I,2-a7indol-10(2H)-on.Example 32 3,4-Dihydro-8-methoxypyrimido [1,2-a] indole-10 (2H) -one.
a) 5-Methoxy-2,3-dioxoindolin-l-propionitril 20,28 g 5-methoxyisatin og 5 ml 4o$'s vandig benzyltrimethylammo-niumhydroxidopløsning opvarmes til tilbagesvaling i 500 ml absolut ethanol, og der tilsættes dråbevis 19 ml acrylonitril. Blandingen opvarmes under tilbagesvaling i 30 minutter, afkøles, og de purpurrøde krystaller frafiltreres, hvorved fås 17,39 g af den ønskede forbindelse. Pro- 3i 150143 duktet omkrystalliseres af vandig dimethylformamid med henblik på karakterisering, smp. 182-185°C.a) 5-Methoxy-2,3-dioxoindoline-1-propionitrile 20.28 g of 5-methoxyisatin and 5 ml of 4 O $ aqueous benzyltrimethylammonium hydroxide solution are heated to reflux in 500 ml of absolute ethanol and 19 ml of acrylonitrile are added dropwise. The mixture is heated at reflux for 30 minutes, cooled and the purple red crystals are filtered off to give 17.39 g of the desired compound. The product is recrystallized from aqueous dimethylformamide for characterization, m.p. 182-185 ° C.
Analyse for ci2H10N2°3: C% E% WoAnalysis for c12 H10 N2 ° 3: C% E% Wo
Beregnet 62,5 4,4 12,2Calculated 62.5 4.4 12.2
Fundet 62,5 4,5 12,2 b) 2 *-Oxospiro/1,2-dioxolan-2,5 *-/5-methoxyindolin77-l'-propionitril 12 ml ethan-l,2-diol, 16,4 g 5-roethoxy-2,3-dioxoindolin-l--propionitril, 500 ml benzen og 0,5 g toluen-p-sulfonsyre opvarmes sammen under tilbagesvaling i et apparatur forsynet med en vandudskiller. Efter 12 timers forløb er den teoretiske mængde vand udskilt. Blandingen vaskes med vand og derefter med natriumhydrogencarbonatopløsning, og den organiske fase tørres over vandfri magnesiumsulfat. Efter fjernelse af opløsningsmidlet og omkrystallisation af propan-2-ol fås 13,6 g produkt med smp. 110-111°C.Found 62.5 4.5 12.2 b) 2 * -Oxospiro / 1,2-dioxolane-2,5 * - / 5-methoxyindolin77-1'-propionitrile 12 ml Ethane-1,2-diol, 16.4 g of 5-Roethoxy-2,3-dioxoindoline-1-propionitrile, 500 ml of benzene and 0.5 g of toluene-p-sulfonic acid are heated together under reflux in an apparatus equipped with a water separator. After 12 hours, the theoretical amount of water is separated. The mixture is washed with water and then with sodium bicarbonate solution and the organic phase is dried over anhydrous magnesium sulfate. After removal of the solvent and recrystallization of propan-2-ol, 13.6 g of product are obtained with m.p. 110-111 ° C.
Analyse forAnalysis for
C% E% WC% E% W
Beregnet 61,2 5,1 10,2Calculated 61.2 5.1 10.2
Fundet 61,5 5 A 10*2 c) 3',4,-Dihydrospiro/l,3-dioxolan-2,10'(2H,10H)-8,-methoxypyrimido- _/1,2-a7indol7_ 13 g af det ovenfor under (b) fremstillede produkt reduceres o ved et begyndelseshydrogentryk på 77,4 kg/em og en temperatur på 40°C i 400 ml absolut ethanol, der er halvt mættet med ammoniak, i nærværelse af 2,0 g W7 Raneynikkel i et tidsrum på 4 timer. Reaktion's-blandingen afkøles, katalysatoren frafiltreres, og ethanolet fjernes under formindsket tryk. Produktet opløses i toluen og opvarmes under tilbagesvaling med 10 dråber phosphoroxychlorid i 12 timer. Det uopløselige materiale frafiltreres, og toluenet fjernes under formindsket tryk, hvorved fås en olie, der spontant krystalliserer. Olien omdannes til hydrochloridet og omkrystalliseres af propan-2-ol, hvorved fås 5,65 g produkt, der sønderdeles ved 300-360°C.Found 61.5 A 10 * 2 c) 3 ', 4, -Dihydrospiro / 1,3-dioxolane-2.10' (2H, 10H) -8, -methoxypyrimido-1,2-a-indole7 13 g of the product prepared under (b) is reduced o at an initial hydrogen pressure of 77.4 kg / cm and a temperature of 40 ° C in 400 ml of absolute ethanol, which is semi-saturated with ammonia, in the presence of 2.0 g of W7 Raney nickel in a period of 4 hours. The reaction's mixture is cooled, the catalyst is filtered off and the ethanol is removed under reduced pressure. The product is dissolved in toluene and heated under reflux with 10 drops of phosphorus oxychloride for 12 hours. The insoluble material is filtered off and the toluene is removed under reduced pressure to give an oil which spontaneously crystallizes. The oil is converted to the hydrochloride and recrystallized from propan-2-ol to give 5.65 g of product, decomposed at 300-360 ° C.
Analyse for C^H^gNgO-^.HCl: C fo E% WoAnalysis for C ^H ^ ^NNOO - HCl: C C E E% Wo
Beregnet 56,65 5,8 9,4Calculated 56.65 5.8 9.4
Fundet 56,53 5,7 9,15 32 150143 d) 4,6 g af det ovenfor under c) fremstillede produkt sættes under omrøring til 50 ml koncentreret svovlsyre, idet temperaturen holdes under 20°C. Blandingen omrøres i 30 minutter og hældes derpå på is. Efter neutralisation med ammoniak ekstraheres det purpurfarvede produkt med chloroform, tørres over magnesiumsulfat og omkrystalliseres efter fjernelse af opløsningsmidlet fra benzen, hvorved fås 2,7 g purpurfarvede rhomber med smp. 150-151°C.Found 56.53 5.7 9.15 32 154343 d) 4.6 g of the product prepared above under (c) is added with stirring to 50 ml of concentrated sulfuric acid, keeping the temperature below 20 ° C. The mixture is stirred for 30 minutes and then poured on ice. After neutralization with ammonia, the purple product is extracted with chloroform, dried over magnesium sulfate and recrystallized after removal of the solvent from benzene to give 2.7 g of purple rhombus with m.p. 150-151 ° C.
Analyse for ci2H12N2°2:Analysis for c12 H12 N2 ° 2:
Cfo Efo E%Cfo Efo E%
Beregnet 66,7 5*6 13,0Calculated 66.7 5 * 6 13.0
Pundet 66,9 5*7 12,7Pound 66.9 5 * 7 12.7
Eksempel 33 10-(m-Chlorphenyl)-2,3,4,10-tetrahydropyrimido/I,2-a7indol-10-olExample 33 10- (m-Chlorophenyl) -2,3,4,10-tetrahydropyrimido [1,2-a] indol-10-ol
Analogt med den i eksempel 21 beskrevne fremgangsmåde omsættes 1,45 g 3i^-dihydro-8-methoxypyrimido/I,2-a7indol-10(2H)-on og 0,025 mol m-chlorphenylmagnesiumbromid. Ved oparbejdning fås 1,36 g af hydrochloridet med smp. 282-283°C (sønderdeling).Analogous to the procedure described in Example 21, 1.45 g of 3β-dihydro-8-methoxypyrimido / 1, 2-a-indole-10 (2H) -one and 0.025 mole of m-chlorophenylmagnesium bromide are reacted. On working up, 1.36 g of the hydrochloride is obtained with m.p. 282-283 ° C (dec.).
Analyse for C-^H^ClNgOg. HC1: C# Hfo N#Analysis for C- HH ^ClNgOg. HC1: C # Hfo N #
Beregnet 59,1 5,0 7,6Calculated 59.1 5.0 7.6
Pundet 39#2 5A 7>6Pound 39 # 2 5A 7> 6
Eksempel 34 2.3.4.10- Tetrahydro-8-methoxy-10-phenylpyrimido/I,2-a7indol-10-ol Analogt med den i eksempel 21 beskrevne fremgangsmåde omsættes 1,45 g 3,4-dihydro-8-methoxypyrimidq/I,2-a7indol-10(2H)-on med 0,025 mol phenylmagnesiumbromid.' Ved oparbejdning fås 1,29 S af hydrochloridet med smp. 285-288°C (sønderdeling).Example 34 2.3.4.10- Tetrahydro-8-methoxy-10-phenylpyrimido [1,2-a] indol-10-ol Analogous to the process described in Example 21, 1.45 g of 3,4-dihydro-8-methoxypyrimidine / I are reacted, 2-a-indole-10 (2H) -one with 0.025 mole of phenylmagnesium bromide. At work-up, 1.29 S of the hydrochloride are obtained with m.p. 285-288 ° C (dec.).
Analyse for C^gH-^gNgOg.HCl: C fo . Efo Ef>Analysis for C ^ gH- ^GNgOg.HCl: C fo.. Efo Ef>
Beregnet 65,25 5,8 8,45Calculated 65.25 5.8 8.45
Pundet 64,1 5*8 8,4Pound 64.1 5 * 8 8.4
Eksempel 35 2.3.4.10- Tetrahydro-8-nitropyrimido/I,2-a7indol-10(2H)-on 6,92 g finpulveriseret 3',4'-dihydrospiro/I,3-dioxolan-2,10'-(2H,10H)-pyrimido-(l,2-a)indol7sættes til 30 ml koncentreret svovlsyre. Efter endt tilsætning omrøres blandingen ved stuetemperatur i 2 timer, afkøles til -10°C, og der tildryppes 2 ml rygende salpetersyre. Reaktionsblandingen får lov til at antage stuetemperatur, hvorefter der omrøres i 30 minutter. Blandingen hældes på is og neutraliseres med 33 150143 koncentreret ammoniakvand ved en temperatur under 3°Ο0. Bundfaldet fra-filtreres og ekstraheres med varm benzen. Den gule remanens vejer vejer 5,95 S og sønderdeles uden smeltning mellem 300 og 360°C.Example 35 2.3.4.10- Tetrahydro-8-nitropyrimido / 1,2-a-indole-10 (2H) -one 6.92 g of finely powdered 3 ', 4'-dihydrospiro / 1,3-dioxolane-2.10' - (2H 10 H) -pyrimido (1,2-a) indole is added to 30 ml of concentrated sulfuric acid. When the addition is complete, the mixture is stirred at room temperature for 2 hours, cooled to -10 ° C and 2 ml of nitric acid are added dropwise. The reaction mixture is allowed to reach room temperature, then stirred for 30 minutes. The mixture is poured onto ice and neutralized with concentrated ammonia water at a temperature below 3 ° Ο0. The precipitate is filtered off and extracted with hot benzene. The yellow residue weighs 5.95 S and decomposes without melting between 300 and 360 ° C.
Analyse for C^H^N^O-^: C fo E?o 0Analysis for C ^ HH ^N OO-: C CF E? 0
Beregnet 57,1 5,9 18,2Calculated 57.1 5.9 18.2
Pundet 57,2 4,05 18,3Pound 57.2 4.05 18.3
Eksempel 36 10-(o-Fluorphenyl)-2,3,4,10-tetrahydropyrimido/l,2-a7indol-10-ol 1.86 g 3*4-dihydropyrimido/I,2-a7indol-10(2H)-on i 80 ml tør tetrahydrofuran sættes til en opløsning af 0,02 mol o-fluorphenyl-lithium i 50 ml ether ved -60°C. Efter endt tilsætning omrøres den farveløse reaktionsblanding ved -60°C i 2 timer, hvorpå den bældes på is og ammoniumchloridopløsning. Når blandingen har antaget stuetemperatur frafiltreres basen. Hydrochloridet fremstilles på sædvanlig måde, hvorved fås 2,8 g produkt med smp. 269-270°C (sønderdeling^Example 36 10- (o-Fluorophenyl) -2,3,4,10-tetrahydropyrimido [1,2-a] indol-10-ol 1.86 g of 3 * 4-dihydropyrimido [1,2-a] indole-10 (2H) -one in 80 ml of dry tetrahydrofuran is added to a solution of 0.02 mole of o-fluorophenyl lithium in 50 ml of ether at -60 ° C. After the addition is complete, the colorless reaction mixture is stirred at -60 ° C for 2 hours, then bubbled on ice and ammonium chloride solution. When the mixture has reached room temperature, the base is filtered off. The hydrochloride is prepared in the usual manner to give 2.8 g of product with m.p. 269-270 ° C (dec.)
Analyse for C^H-^FNgO.HCl: 0% Efo 0Analysis for C ^H- ^FNgO.HCl: 0% Efo0
Beregnet 64,05 5,1 8,6Calculated 64.05 5.1 8.6
Fundet 63,6 5*0 8,6Found 63.6 5 * 0 8.6
Eksempel 37 2,3,4,10-Tetrahydro-10-(2,6-dimethylphenyl)pyrimido/1,2-a7indol-10-ol 1.86 g 3,4-dihydropyrimido1/I,2-a7indol-10(2H)-on i tetrahydrofuran sættes til 0,02 mol 2,6-dimethylphenylmagnesiumbromid fremstillet ved den såkaldte indblandingsmetode. Reaktionsblandingen oparbejdes som beskrevet i eksempel 1, og der fås 1,35 g af hydrochloridet i form af farveløse nåle med smp. 274-27β°0 (sønderdeling).Example 37 2,3,4,10-Tetrahydro-10- (2,6-dimethylphenyl) pyrimido [1,2-a] indol-10-ol 1.86 g of 3,4-dihydropyrimido [1,2-a] indole-10 (2H) -one in tetrahydrofuran is added to 0.02 moles of 2,6-dimethylphenylmagnesium bromide prepared by the so-called admixture method. The reaction mixture is worked up as described in Example 1 and 1.35 g of the hydrochloride is obtained in the form of colorless needles, m.p. 274-27β ° 0 (decomposition).
Analyse for C^^HgQNgO.HCl: C fo H fo 00Analysis for C ^^ HHgQNgO.HCl: C fo HH foO 00
Beregnet 69,0 6,4 8,5Calculated 69.0 6.4 8.5
Fundet 69,5 6,55 8*4Found 69.5 6.55 8 * 4
Eksempel 38 10-Ethynyl-2,3 *4,10-tetrahydropyrimido/1,2-a7indol-10-ol 7,4 g 3*4-dihydropyrimido/l,2-a7indol-10-(2H)-on i tetrahydrofuran omsættes med 0,15 mol ethynylmagnesiumbromid analogt med den i eksempel 21 beskrevne fremgangsmåde. Ved oparbejdning fås 5*8 g af basen med smp. 224-226°C (sønderdeling). Hydrochloridet har smp. 210-215°C (sønderdeling).Example 38 10-Ethynyl-2,3 * 4,10-tetrahydropyrimido / 1,2-a-indol-10-ol 7.4 g of 3 * 4-dihydropyrimido / 1,2-a-indindol-10- (2H) -one in tetrahydrofuran react with 0.15 moles of ethynylmagnesium bromide by analogy to the procedure described in Example 21. When working up, 5 * 8 g of the base are obtained with m.p. 224-226 ° C (dec.). The hydrochloride has m.p. 210-215 ° C (dec.).
150143 34150143 34
Analyse for C^iinnNpOfHCl; 0 0 0Analysis for C ^inninnNpOfHCl; 0 0 0
Beregnet 62,8 5*3 11*3Calculated 62.8 5 * 3 11 * 3
Fundet 62,5 5 λ H*0Found 62.5 λ H * 0
Eksempel 39 2,5 ,4,10-Tetrahydro-lO-(m-chlorphenyl)pyrimido/l,2-a7indol-10-ol-acetat 3 g 2,3,4,10-tetrahydro-10-(m-chlorphenyl)pyrimidoi/I,2-É£7indol--ΙΟ-ol opløses i 100 ml eddikesyreanhydrid og henstilles ved stuetemperatur 1 48 timer. Eddikesyreanhydridet fjernes under formindsket tryk, og remanensen geninddampes med 50 ml toluen. Remanensen opløses i mindst mulig ethanol og behandles med en opløsning af hydrogenchlorid i tør ether. Der fås 5,24 g af hydrochloridet i form af farveløse rhomber med smp. 213-2l6°C (sønderdeling).Example 39 2,5, 4,10-Tetrahydro-10- (m-chlorophenyl) pyrimido [1,2-a] indol-10-ol-acetate 3 g 2,3,4,10-tetrahydro-10- (m-chlorophenyl) ) pyrimidoi / l, 2-É £ 7indol - ΙΟ-ol is dissolved in 100 ml of acetic anhydride and left at room temperature for 48 hours. The acetic anhydride is removed under reduced pressure and the residue is re-evaporated with 50 ml of toluene. The residue is dissolved in as little ethanol as possible and treated with a solution of hydrogen chloride in dry ether. 5.24 g of the hydrochloride is obtained in the form of colorless rhombus with m.p. 213-216 ° C (dec.).
Analyse for σΐ9%γΝ2^2 *5 Øo Øo ØoAnalysis for σΐ9% γΝ2 ^ 2 * 5 Øo Øo Øo
Beregnet 60,5 4,8 7,4Calculated 60.5 4.8 7.4
Fundet 60,4 4,8 7,3Found 60.4 4.8 7.3
Eksempel 40 (+)-2,5,4,10-Tetrahydro-10-(m-chlorphenyl)pyrimido/l,2-a7indol-10-ol 6,6 g 2,3,4,10-tetrahydro-10-(m-chlorphenyl)pyrimido/I,2-a/in-dol-10-ol opløses i varm absolut ethanol, og der tilsættes 3*3 g L(+) (natural) vinsyre. Blandingen opvarmes til fuldstændig opløsning.Example 40 (+) - 2,5,4,10-Tetrahydro-10- (m-chlorophenyl) pyrimido [1,2-a] indol-10-ol 6.6 g 2,3,4,10-tetrahydro-10 (m-chlorophenyl) pyrimido / 1,2-a-indole-10-ol is dissolved in warm absolute ethanol and 3 * 3 g of L (+) (natural) tartaric acid is added. The mixture is heated to complete dissolution.
Ved krystallisation fås 2,23 g af L(+) tartratsaltet. Ved omkrystallisation tre gange og inddampning af moderluden fås i alt 2,1 g produkt med Zs7|4 + 70,9° (c = 1 i methanol), smp. ll8°C (sønderdeling).Crystallization gives 2.23 g of the L (+) tartrate salt. By recrystallization three times and evaporation of the mother liquor, a total of 2.1 g of product is obtained with Zs7 | 4 + 70.9 ° (c = 1 in methanol), m.p. 18 ° C (dec.).
Analyse for C^H^ClNgO. (CH0H.C00H)2: C fo Øo N$Analysis for C ^H ^ClNNO. (CHOH.C00H) 2: C fo Ø N $
Beregnet 56,2 4,7 6,2Calculated 56.2 4.7 6.2
Fundet 55*7 5*0 6,2Found 55 * 7 5 * 0 6.2
Eksempel 4l (-)-2,5,4,10-Tetrahydro-10-(m-ohlorphenyl)pyrimido/l,2-a7indol-10-olExample 4L (-) - 2,5,4,10-Tetrahydro-10- (m-chlorophenyl) pyrimido [1,2-a] indol-10-ol
Moderluden fra eksempel 40 indeholdende den (-)isomere inddampes til tørhed og omdannes til 3*84 g af basen. Basen opløses i varm ethanol og behandles med D(-) (ikke-natural) vinsyre. Efter oparbejdning som i eksempel 40 fås 2,0 g af levobasen som D(-) tartratsal tet. Ia7^ -71*4° (c = 1 i methanol), smp. ll8°C (sønderdeling).The mother liquor of Example 40 containing the (-) isomer is evaporated to dryness and converted to 3 * 84 g of the base. The base is dissolved in hot ethanol and treated with D (-) (non-natural) tartaric acid. After working up as in Example 40, 2.0 g of the levobase is obtained as the D (-) tartrate salt. 177 -71 ° 4 ° (c = 1 in methanol), m.p. 18 ° C (dec.).
150143 35150143 35
Eksempel 42 2,3 ,4,10-Tetrah.ydro-lQ- (2-pyridyl) pyrimido/I,2-a7indol-10-ol 4,0 g 3,4-dihydropyrimido//l,2-a7indol-10-(2H)-on i 10 ml tør tetrahydrofuran sættes til en opløsning af 0,04 mol 2-pyridyllithium ved -40°C. Reaktionsblandingen får lov til at antage stuetemperatur i løbet af 2 timer, hvorefter den spaltes ved tilsætning til is og ammo-niumchlorid. Det organiske lag isoleres, og det vandige lag ekstrahe-res med chloroform. Efter tørring over vandfri magnesiumsulfat fjernes opløsningsmidlet, og der fås 2,73 g base i form af et lysebrunt pulver. Hydrochloridet dannes på sædvanlig måde, og der fås 3,0 g med smp. 268-270°C.Example 42 2,3,4,10-Tetrahydro-1Q- (2-pyridyl) pyrimido [1,2-a] indol-10-ol 4.0 g of 3,4-dihydropyrimido [1,2-a] indole-10 - (2H) -one in 10 ml of dry tetrahydrofuran is added to a solution of 0.04 mol of 2-pyridyllithium at -40 ° C. The reaction mixture is allowed to reach room temperature over 2 hours, after which it is cleaved by the addition of ice and ammonium chloride. The organic layer is isolated and the aqueous layer is extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent is removed and 2.73 g of base is obtained in the form of a light brown powder. The hydrochloride is formed in the usual way and 3.0 g with m.p. 268-270 ° C.
Analyse for ci6Hi5N3°*2HC1.1/4 H20: C % H% N$Analysis for c16 H15 N3 ° * 2HCl1 / 4H2O: C% H% N $
Beregnet 56,1 5,0 12,3Calculated 56.1 5.0 12.3
Fundet 56,0 5,2 12,4Found 56.0 5.2 12.4
Eksempel 43 10-(m-Chlorphenyl)-2,3,4,10-tetrahydro-10-hydroxy-l-methylpyrimido-_/1,2-a7indoliniumiodid_ 2,94 g 10-(m-chlorphenyl)-2,3,4,10-tetrahydropyrimido/I,2-a7in-dol-10-ol opløses i 50 ml varm propanol, og der tilsættes 2 ml methyliodid. Der opvarmes under tilbagesvaling i 30 minutter. Efter afkøling udskilles indoliniumiodidet, og der fås 4,03 g produkt, som sønderdeles uden smeltning ved 250-254°C.Example 43 10- (m-Chlorophenyl) -2,3,4,10-tetrahydro-10-hydroxy-1-methylpyrimido-β-1,2-aindolinium iodide 2.94 g of 10- (m-chlorophenyl) -2,3 , 4,10-Tetrahydropyrimido / 1,2-a-7in-dol-10-ol is dissolved in 50 ml of hot propanol and 2 ml of methyl iodide is added. Reflux for 30 minutes. After cooling, the indolinium iodide is separated and 4.03 g of product are obtained which decompose without melting at 250-254 ° C.
Analyse for C^H^gClINgO: C% N$Analysis for C ^ HH g gClNgO: C% N $
Beregnet 49,1 4,1 6,35Calculated 49.1 4.1 6.35
Fundet 49,3 4,3 6,6Found 49.3 4.3 6.6
Eksempel 44 ' 10- (m-Chlorphenyl) -1,2,3,4 ilOjlOa-hexahydro-l-methylpyrimido^/1,2-a/ in-__dol-10-ol_ 2,5 g af det ovenfor i eksempel 43 fremstillede kvatemære salt sættes portionsvis til en omrørt suspension af 1,8 g lithium-aluminiumhydrid i 100 ml tør tetrahydrofuran. Reaktionsblandingen omrøres -under tilbagesvaling i 5 timer, afkøles og sønderdeles ved tilsætning af 5 ml vand. Det udfældede organiske materiale frafiltreres, filtratet tørres over vandfri magnesiumsulfat og fordampes, hvorved der fås en olie, der krystalliserer af en blanding af benzen og let petroleum (kogeinterval 60-80°C), hvorved fås 9^1 mg produkt med smp. 135-137°C.EXAMPLE 44 '10- (m-Chlorophenyl) -1,2,3,4'10 O10-hexahydro-1-methylpyrimido [1,2-a] in-dole-10-ol 2.5 g of the above in Example 43 prepared quaternary salt is added portionwise to a stirred suspension of 1.8 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran. The reaction mixture is stirred at reflux for 5 hours, cooled and decomposed by the addition of 5 ml of water. The precipitated organic material is filtered off, the filtrate is dried over anhydrous magnesium sulfate and evaporated to give an oil which crystallizes from a mixture of benzene and light petroleum (boiling range 60-80 ° C) to give 9 µm of product with m.p. 135-137 ° C.
36 15QU336 15QU3
Analyse for C^H^^ClNgO: 0 0 0Analysis for C ^ HH₂ Cl ClNgO: 0 0 0
Beregnet 68,7 6,1 7*8Calculated 68.7 6.1 7 * 8
Pundet 68,2 6,8 7*8Pound 68.2 6.8 7 * 8
Eksempel 45 1,2,3,4,10,1Oa-Hexahydro-l0-phenylpyrimi do/ϊ,2-a7indol-10-ol 1,9 g 1,2,3 ,4-tetrahydro-10-phenylpyrimidoZI,2-a/indol-10-ol sættes i form af en opslæmning i tør tetrahydrofuran til en suspension af 0,6 g lithiumaluminiumhydrid i 20 ml tør tetrahydrofuran. Reaktionsblandingen omrøres under tilbagesvaling i 3 timer, afkøles og spaltes med vand. Efter adskillelse af det organiske materiale og fjernelse af opløsningsmidlet fås en gul olie, der størkner ved triturering med ether, hvorved fås 1,0 g produkt med smp. l47°C.Example 45 1,2,3,4,10,1Oa-Hexahydro-10-phenylpyrimido [2,2-a] indol-10-ol 1.9 g 1,2,3,4-tetrahydro-10-phenylpyrimidoZI, 2- α / indol-10-ol is added in the form of a slurry in dry tetrahydrofuran to a suspension of 0.6 g of lithium aluminum hydride in 20 ml of dry tetrahydrofuran. The reaction mixture is stirred under reflux for 3 hours, cooled and digested with water. After separating the organic material and removing the solvent, a yellow oil is obtained which solidifies by trituration with ether to give 1.0 g of product with m.p. L47 ° C.
Analyse for 017ΗηοΝρ0: C % H% ØoAnalysis for 017ΗηοΝρ0: C% H% Øo
Beregnet 76,7 6,8 10,5Calculated 76.7 6.8 10.5
Pundet 76,25 7,0 10,4Pound 76.25 7.0 10.4
Fumaratet fremstilles ud fra 2-propanol, smp. 157°·The fumarate is prepared from 2-propanol, m.p. 157 ° ·
Analyse for Z^i7Hi8N2£72,C4H4°4: C fo H fo 00Analysis for Z 2 H 7 N 2 O 2 72, C 4 H 4 ° 4: C
Beregnet 70,35 6,2 8,6Calculated 70.35 6.2 8.6
Fundet 70,3 6,2 8,4Found 70.3 6.2 8.4
Eksempel 46 1,2,3,4,10,lOa-HexahydrospiroZl,3-dioxolan-2,10'Z3*,3-dimethyl7 pyri-mido/l,2-a7indol7_ 17 i5 g 2’-oxospiroZl,3-dioxolan-2,31-indolin/-1'-/2,2-dimethyl-Example 46 1,2,3,4,10,10a-HexahydrospiroZl, 3-dioxolane-2,10'Z3 *, 3-dimethyl-7-pyrimido [1,2-a7indole] 17 g of 2'-oxospiroZl, 3-dioxolane -2.31-indoline / -1 '- / 2,2-dimethyl-
OISLAND
propionitril7 reduceres ved et begyndelsestryk på 105,5 kg/cm og ved 100°C i 5 timer i 200 ml ethanol halvmættet med ammoniak i nærværelse af 8 g Raneynikkel W7· Katalysatoren fjernes, og ethanolet fjernes under formindsket tryk. Remanensolien krystalliseres af benzen, hvorved fås .12,09 g produkt med smp. 93-96°C.propionitrile7 is reduced at an initial pressure of 105.5 kg / cm and at 100 ° C for 5 hours in 200 ml of ethanol semi-saturated with ammonia in the presence of 8 g of Raneynickel W7 · The catalyst is removed and the ethanol is removed under reduced pressure. The residual oil is crystallized by benzene to give .12.09 g of product, m.p. 93-96 ° C.
Analyse for C15H20N2°2:Analysis for C 15 H 20 N 2 ° 2:
Cfo 0 0Cfo 0 0
Beregnet 69,2 7,7 10,8Calculated 69.2 7.7 10.8
Fundet 69,7 7,7 10,8Found 69.7 7.7 10.8
Eksempel 47 3,4-Dihydropyrimido/I,2-a7indol-10/2H7-on A__o-Bromphenyl (1,4,5,6-tetrahydro-2-pyrimldyl) -keton (a) En opløsning af 20 g a-o-bromphenyl-(1,4,5,6-tetrahydro-2--pyrimidyl)methanol i 1000 ml diehlormethan omrøres med 150 g fældet mangandioxid ved stuetemperatur i 48 timer. Efter filtrering omrøres 150143 37 mangandioxidet med 400 ml frisk dichlormethan i yderligere 1 time, hvorefter der filtreres, og det kombinerede filtrat tørres over magnesiumsulfat. Fjernelse af opløsningsmidlet under formindsket tryk og krystallisation af remanensen fra let petroleum (kogeinterval 60-80°C) giver 12,1 g produkt i form af farveløse nåle med smp. 100-101°C.Example 47 3,4-Dihydropyrimido [1,2-a] indol-10 / 2H7-one A 10 -Bromophenyl (1,4,5,6-tetrahydro-2-pyrimidyl) ketone (a) A solution of 20 g of ao-bromophenyl - (1,4,5,6-tetrahydro-2-pyrimidyl) methanol in 1000 ml of Diehlormethane is stirred with 150 g of precipitated manganese dioxide at room temperature for 48 hours. After filtration, the manganese dioxide is stirred with 400 ml of fresh dichloromethane for an additional 1 hour, then filtered and the combined filtrate is dried over magnesium sulfate. Removal of the solvent under reduced pressure and crystallization of the residue from light petroleum (boiling range 60-80 ° C) yields 12.1 g of product in the form of colorless needles, m.p. 100-101 ° C.
Analyse for cnHiiBrN2®: C % H% N#Analysis for cnHiiBrN2®: C% H% N #
Beregnet 49,45 4,15 10,5Calculated 49.45 4.15 10.5
Fundet 49,45 4,15 10,45 (b) En opløsning af 2,69 g, 0,01 mol, a-o-brompheny1-(1,4,5,6--tetrahydro-2-pyrimidyl)methanol og 5>35 g, 0,012 mol blytetraacetat i 40 ml tør pyridin omrøres ved stuetemperatur i 60 timer. Efter fjernelse af pyridinet under formindsket tryk, fortyndes remanensen med vand og ekstraheres med chloroform. De kombinerede ekstrakter vaskes med vand, tørres over MgSO^ og opløsningsmidlet fjernes til dannelse af en brun remanens. Ved krystallisation af petroleumsether (kp. 60-80°C), efter behandling med trækul, fører til produktet.Found 49.45 4.15 10.45 (b) A solution of 2.69 g, 0.01 mol, ao-bromophenyl- (1,4,5,6-tetrahydro-2-pyrimidyl) methanol and 5 35 g, 0.012 mole of lead tetraacetate in 40 ml of dry pyridine is stirred at room temperature for 60 hours. After removing the pyridine under reduced pressure, the residue is diluted with water and extracted with chloroform. The combined extracts are washed with water, dried over MgSO 4 and the solvent removed to give a brown residue. Crystallization of petroleum ether (bp 60-80 ° C), after treatment with charcoal, leads to the product.
B_5,4-Dihydropyrimido/l,2-a7indol-10/2H7-onB_5,4-dihydropyrimido / l, 2-a7indol-10 / 2H7-one
En blanding af 0,67 g, 0,0025 mol, o-bromphenyl-(1,4,5,6-tetra-hydro-2-pyrimidyl)-keton, 0,345 g, 0,0025 mol, kaliumcarbonat og 0,025 g cuprioxid i 5 ml tør dimethylformamid omrøres under nitrogen ved 90°C i 2 timer. Blandingen fortyndes med 100 ml benzen, filtreres, filtratet vaskes med 4 x 50 ml og tørres over MgSO^. Ved fjernelse af opløsningsmidlet og krystallisation af remanensen fra benzeneyclohexan, efter behandling med trækul, giver 0,088 g produkt i form af orangefarvede nåle med smp. ll8-121°C.A mixture of 0.67 g, 0.0025 mol, o-bromophenyl (1,4,5,6-tetrahydro-2-pyrimidyl) ketone, 0.345 g, 0.0025 mol, potassium carbonate and 0.025 g of cuprioxide in 5 ml of dry dimethylformamide is stirred under nitrogen at 90 ° C for 2 hours. The mixture is diluted with 100 ml of benzene, filtered, the filtrate washed with 4 x 50 ml and dried over MgSO 4. Upon removal of the solvent and crystallization of the residue from benzeneyclohexane, after treatment with charcoal, 0.088 g of product in the form of orange needles with m.p. ll8-121 ° C.
Eksempel 48 2,3-Dihydro-2,2 (eller 5,3)-dimethylimidazo/I,2-a7-indol-/9H7-9-on (a) En opløsning af 29,4 g, 0,1 mol, ethyl-o-brommandelimidat-hy-drochlorid og 8,8 g, 0,1 mol, l,2-diamino-2-methylpropan i 150 ml absolut ethanol opvarmes under tilbagesvaling i 5 timer. Ved fjernelse af opløsningsmidlet og krystallisation af remanensen fra en blanding af isopropanol og ether fås 23,4 g råt hydroehlorid. En vandig opløsning af det rå hydroehlorid gøres basisk med NaOH under samtidig kradsning på kolben, hvorved fås 16,2 g krystallinsk a-(o-brompheny1)-4,4 (eller 5,5)-dimethyl-2-imidazolinmethanol i form af den fri base med smp. 128-130°C.Example 48 2,3-Dihydro-2,2 (or 5,3) -dimethylimidazo [1,2-a7-indole- / 9H7-9-one (a) A solution of 29.4 g, 0.1 mole, Ethyl o-bromandelimidate hydrochloride and 8.8 g, 0.1 mol, 1,2-diamino-2-methylpropane in 150 ml of absolute ethanol are heated under reflux for 5 hours. By removing the solvent and crystallizing the residue from a mixture of isopropanol and ether, 23.4 g of crude hydrochloride are obtained. An aqueous solution of the crude hydrochloride is made basic with NaOH while simultaneously scrubbing on the flask to give 16.2 g of crystalline α- (o-bromophenyl) -4,4 (or 5.5) -dimethyl-2-imidazoline methanol in the form of the free base with m.p. 128-130 ° C.
Eventuelt kan den fri base ekstraheres med chloroform, ekstrakterne tørres over MgSO^ og remanensen tritureres med letpetroleum (kogeinterval 60-80°C) efter fjernelse af opløsningsmidlet.Optionally, the free base can be extracted with chloroform, the extracts dried over MgSO4 and the residue triturated with light petroleum (boiling range 60-80 ° C) after removal of the solvent.
150143 38150143 38
Der fremstilles en analytisk prøve af hydrochloridet ved syrning af en opløsning af den fri base i isopropanol med etherisk saltsyre, smp. 213-217°C.An analytical sample of the hydrochloride is prepared by acidifying a solution of the free base in isopropanol with ethereal hydrochloric acid, m.p. 213-217 ° C.
Analyse for ci2Ii15BrN2°* HC1: C % H% N$Analysis for c12 H15 N2 BrN2 ° * HCl: C% H% N $
Beregnet 45,1 5,05 8,75Calculated 45.1 5.05 8.75
Pundet 45,35 5,05 8,6 (b) En opløsning af 15,8 g a-(o-bromphenyl)-4,4 (eller 5,5)-dime-thyl-2-imidazolinmethanol i 750 ml dichlormethan omrøres med 150 g fældet mangandioxid ved stuetemperatur i 40 timer. Mangandioxidet frafil-treres og omrøres med yderligere 400 ml dichlormethan i 1 time. Efter filtrering tørres de kombinerede filtrater over MgSO^, opløsningsmidlet fjernes, og remanensen omkrystalliseres af petroleum (kogeinterval 60-80°C), hvorved fås 11,01 g o-bromphenyl-4,4 (eller 5,5)-dimethyl-2- , -imidazolinylketon med smp. 107-108°C.Pound 45.35 5.05 8.6 (b) A solution of 15.8 g of α- (o-bromophenyl) -4,4 (or 5.5) dimethyl-2-imidazoline methanol in 750 ml of dichloromethane is stirred. with 150 g of precipitated manganese dioxide at room temperature for 40 hours. The manganese dioxide is filtered off and stirred with an additional 400 ml of dichloromethane for 1 hour. After filtration, the combined filtrates are dried over MgSO 4, the solvent removed and the residue recrystallized from petroleum (boiling range 60-80 ° C) to give 11.01 g of o-bromophenyl-4.4 (or 5.5) -dimethyl-2 -, -imidazolinyl ketone, m.p. 107-108 ° C.
Analyse for C^H-^BrNgO: C% H% N %Analysis for C ^H- ^ BrNgO: C% H% N%
Beregnet 51,25 4,65 9,95Calculated 51.25 4.65 9.95
Pundet 51,25 4,85 10,05.Pound 51.25 4.85 10.05.
(c) En opløsning af 0,7 g, 0,0025 mol, o-bromphenyl-4,4 (eller 5,5)--dimethyl-2-imidazolinylketon i 5 ml tør dimethylformamid omrøres med 0,545 g, 0,0025 mol, vandfri kaliumearbonat og 0,030 g euprioxid under tør nitrogen ved 125°C i 1 1/2 time. Reaktionsblandingen fortyndes med 100 ml benzen, filtreres, filtratet vaskes med 4 x 50 ml vand og tørres over MgSO^. Fjernelse af opløsningsmidlet under formindsket tryk og krystallisation af remanensen fra cyclohexan giver 0,244 g af den ønskede forbindelse i form af stærkt røde nåle med smp. 136-138°C.(c) A solution of 0.7 g, 0.0025 mol, o-bromophenyl-4.4 (or 5.5) -dimethyl-2-imidazolinyl ketone in 5 ml dry dimethylformamide is stirred with 0.545 g, 0.0025 mol , anhydrous potassium carbonate and 0.030 g of euprioxide under dry nitrogen at 125 ° C for 1 1/2 hours. The reaction mixture is diluted with 100 ml of benzene, filtered, the filtrate washed with 4 x 50 ml of water and dried over MgSO 4. Removal of the solvent under reduced pressure and crystallization of the residue from cyclohexane gives 0.244 g of the desired compound in the form of bright red needles, m.p. 136-138 ° C.
Analyse for C,pH,?NpO: C% H% N$Analysis for C, pH, NpO: C% H% N $
Beregnet 72,0 6,05 14,0Calculated 72.0 6.05 14.0
Fundet 71,7 6,1 13,9Found 71.7 6.1 13.9
Hydrochloridet krystalliser som orange prismer af en blanding af ethanol og etherisk saltsyre og sønderdeles ved en temperatur over ca. 230°C Analyse for Ο-,ρΗ-,ρΝρΟ.ΗΟΙ: Η% N %The hydrochloride crystallizes as orange prisms from a mixture of ethanol and ethereal hydrochloric acid and decomposes at a temperature above ca. 230 ° C Analysis for Ο-, ρΗ-, ρΝρΟ.ΗΟΙ: Η% N%
Beregnet 56,6 5,95 11,0Calculated 56.6 5.95 11.0
Fundet 56,8 6,2 10,95 39 .150143Found 56.8 6.2 10.95 39 .150143
Eksempel 49 2,3-Dihydro-2,2 (eller 3,3)-dimethylimidazo/I,2-a7-indol-/9H7-9-on 0,59 g, 0,0025 mol o-chlorphenyl-4,4 (eller 5,5)-dimethyl-2--imidazolinylketon, fremstillet som beskrevet i eksempel 48 (a) og (b) for den tilsvarende o-bromphenylforbindelse, i 5 ml tør dimethyl-formamid omrøres med 0,345 g, 0,0025 mol, vandfri kaliumcarbonat og 0,030 g cuprochlorid' under tør nitrogen ved 125°C i 3 timer. Reaktionsblandingen oparbejdes som beskrevet i eksempel 48 (c), hvorved fås 0,255 g produkt med smp. 136-138°C.Example 49 2,3-Dihydro-2,2 (or 3,3) -dimethylimidazo [1,2-a7-indole-9H7-9-one 0.59 g, 0.0025 mol of o-chlorophenyl-4.4 (or 5.5) -dimethyl-2-imidazolinyl ketone, prepared as described in Example 48 (a) and (b) for the corresponding o-bromophenyl compound, in 5 ml of dry dimethylformamide is stirred with 0.345 g, 0.0025 mol , anhydrous potassium carbonate and 0.030 g of cuprous chloride under dry nitrogen at 125 ° C for 3 hours. The reaction mixture is worked up as described in Example 48 (c) to give 0.255 g of product with m.p. 136-138 ° C.
Eksempel 50 9-(m-Chlorphenyl)-2,3-dihydro-2,2 (eller 3,3)-dimethylimidazo/I,2-a7in-dol-9/57-9-01_Example 50 9- (m-Chlorophenyl) -2,3-dihydro-2,2 (or 3,3) -dimethylimidazo [1,2-a] nine-dol-9 / 57-9-01
Til en omrørt opløsning af m-chlorphenyllithium, som er fremstillet ud fra 9,6 g, 0,05 mol, m-bromchlorbenzen og'27 ml, 0,045 mol, af en 1,67 M opløsning af n-butyllithium i pentan, i 25 ml tør ether under nitrogen ved 0°C sættes 3,0 g, 0,015 mol, 2,3-dihydro-2,2 (eller 3,3)-dimethylimidazo/I,2-a7indol-/927-9-on i 50 ml tør tetrahydrofuran i løbet af 5 minutter. Den mørkegrønne opløsning omrøres i 30 minutter ved 0°C, hældes i en blanding af is og ammoniumchloridopløsning og ekstraheres med chloroform. De kombinerede ekstrakter vaskes med vand, tørres over MgSO^, opløsningsmidlet fjernes, og remanensen tritureres med petroleum (kogeinterval 60-80°C), hvorved fås 4,01 g hvidt krystallinsk produkt.To a stirred solution of m-chlorophenyllithium prepared from 9.6 g, 0.05 mole, m-bromochlorobenzene and 27 ml, 0.045 mole, of a 1.67 M solution of n-butyllithium in pentane, 25 ml of dry ether under nitrogen at 0 ° C are added 3.0 g, 0.015 mole, 2,3-dihydro-2,2 (or 3,3) -dimethylimidazo [1,2-a] indol-927-9-one 50 ml of dry tetrahydrofuran over 5 minutes. The dark green solution is stirred for 30 minutes at 0 ° C, poured into a mixture of ice and ammonium chloride solution and extracted with chloroform. The combined extracts are washed with water, dried over MgSO 4, the solvent removed and the residue triturated with petroleum (boiling range 60-80 ° C) to give 4.01 g of white crystalline product.
3,5 g af den rå base opløses i en lille mængde ethanol, syr-nes med etherisk saltsyre, fortyndes med et stort volumen ether, og hy-drochloridet får lov til at krystallisere, udbytte 3,72 g, sønderdeling ved en temperatur over ca. 205°C.3.5 g of the crude base are dissolved in a small amount of ethanol, acidified with ethereal hydrochloric acid, diluted with a large volume of ether and the hydrochloride is allowed to crystallize, yield 3.72 g, decomposing at a temperature above ca. 205 ° C.
Analyse for C-^H-^ClNgO.HCl: C % H fo N$Analysis for C- HH- ^ClNgO.HCl: C% H for N $
Beregnet 61,9 5,2 8,0Calculated 61.9 5.2 8.0
Pundet 61,9 5,3 8,0Pound 61.9 5.3 8.0
Ved omsætning af henholdsvis p-chlorphenyllithium og phenyl-lithium med 2,3-dihydro-2,2 (eller 3,3)-dimethylimidazo^I,2-a7indol--Z927-9 -on fremstilles på analog måde henholdsvis 9“(p~chlorphenyl)--2,3-dihydro-2,2 (eller 3,3)-dimethylimidazo-/!,2-a/indol-9/H7-9-0I, der sønderdeles ved en temperatur over ca. 215°C-, og 2,3-dihydro-2,2 (eller 3,3-dimethyl-9-phenylimidazo/I,2-a7indol-9/^S7“9-ol, der sønderdeles ved en temperatur over ca. 240°C.By reaction of p-chlorophenyl lithium and phenyl-lithium with 2,3-dihydro-2,2 (or 3,3) -dimethylimidazo [1,2-a] indole - Z927-9 -one, respectively, are prepared in an analogous manner to 9 "( p-chlorophenyl) -2,3-dihydro-2,2 (or 3,3) -dimethylimidazolo [2,2-a] indole-9 / H7-9-0I, which decomposes at a temperature above ca. 215 ° C and 2,3-dihydro-2,2 (or 3,3-dimethyl-9-phenylimidazo [1,2-a] indole-9β-S7 “9-ol) which decompose at a temperature above ca. 240 ° C.
40 1501A340 1501A3
Eksempel 51 2,5-Dihydroimidazo/I,2-a7indol-/9H7-9-on (a) En opløsning af 16,0 g a-(o-bromphenyl)-2-imidazollnmethanol i 160 ml acetone omrøres i 2 timer med 100 g fældet mangandioxid, der forinden er deaktiveret ved omrøring med vand. Efter filtrering og vask-ning af mangandioxidet med acetone inddampes opløsningen til et lille rumfang under formindsket tryk, fortyndes med vand og ekstraheres med chloroform. De kombinerede ekstrakter tørres over MgSO^* opløsningsmidlet fjernes, og remanensen får lov til at krystallisere af et lille rumfang ether, hvorved fås 11,5 g råt o-bromphenyl-2-imidazolinylketon. En prøve omkrystalliseret af en blanding af benzen og petroleum (kogeinterval 60-80°C) har smp. l49-151°C.Example 51 2,5-Dihydroimidazo / 1,2-a7indole- / 9H7-9-one (a) A solution of 16.0 g of α- (o-bromophenyl) -2-imidazoline methanol in 160 ml of acetone is stirred for 2 hours with 100 g of precipitated manganese dioxide, previously deactivated by stirring with water. After filtration and washing of the manganese dioxide with acetone, the solution is evaporated to a small volume under reduced pressure, diluted with water and extracted with chloroform. The combined extracts are dried over the MgSO 4 solvent, and the residue is allowed to crystallize from a small volume of ether to give 11.5 g of crude o-bromophenyl-2-imidazolinyl ketone. A sample recrystallized from a mixture of benzene and petroleum (boiling range 60-80 ° C) has m.p. l49-151 ° C.
Analyse for C]_oH9N2Br0: C$ H% N$Analysis for C ]oH9N₂BrO: C $ H% N $
Beregnet 4-7*5 5,6 11*1Calculated 4-7 * 5 5.6 11 * 1
Pundet 47*9 5,7 11,1 (b) En opløsning af 0,65 g* 0,0025 mol* o-bromphenyl-2-imidazo-linylketon i 5 ml tør dimethylformamid omrøres med 0*55 g* 0,0025 mol, kaliumcarbonat og 0,050 g cuprioxid under tør nitrogen ved 140 C i 1/2 time. Blandingen fortyndes med 100 ml benzen, filtreres, og filtratet vaskes med 4 x 50 ml vand. Fjernelse af opløsningsmidlet og krystallisation af remanensen fra cyclohexan giver 0,151 g produkt i form af røde nåle* der sønderdeles ved en temperatur over ca. 100 C.Pound 47 * 9 5.7 11.1 (b) A solution of 0.65 g * 0.0025 mol * o-bromophenyl-2-imidazolinyl ketone in 5 ml dry dimethylformamide is stirred with 0 * 55 g * 0.0025 mole, potassium carbonate and 0.050 g of cuprioxide under dry nitrogen at 140 C for 1/2 hour. The mixture is diluted with 100 ml of benzene, filtered and the filtrate washed with 4 x 50 ml of water. Removal of the solvent and crystallization of the residue from cyclohexane yields 0.151 g of product in the form of red needles * which decompose at a temperature above ca. 100 C.
Analyse for C10HgN20: G% Έ.% N %Analysis for C10HgN2O: G% Έ.% N%
Beregnet 69,8 4*7 16,5Calculated 69.8 4 * 7 16.5
Fundet 70*2 4,7 16*45Found 70 * 2 4.7 16 * 45
Eksempel 52 11-(m-Chlorphenyl)-2,4,5,11-tetrahydro-3H-l,3-diazepino[1,2-a]-_indol-ll-ol_____ (a) o-Bromphenyl-4,5,6,7-tetrahydro-lH-l,3-diazepino--2-methanol-hydrochlorid.Example 52 11- (m-Chlorophenyl) -2,4,5,11-tetrahydro-3H-1,3-diazepino [1,2-a] -indol-11-ol-ol (a) o-Bromophenyl-4,5 , 6,7-tetrahydro-lH-l, 3-diazepino - 2-methanol hydrochloride.
8,8 g 1,4-diaminobutan i 10 ml absolut ethanol sættes dråbevis til en omrørt isafkølet opløsning af 29,5 g ethyl-o--brommandelimidat-hydrochlorid i 200 ml absolut ethanol. Efter endt tilsætning omrøres blandingen i yderligere 1 time under afkøling med et isbad, hvorpå blandingen opvarmes under tilbagesvaling i 20 timer. Efter afkøling koncentreres opløsnin- 150143 41 gen under formindsket tryk, og der tilsættes ether, hvorved der udskilles 24,15 g hvidt krystallinsk produkt med smp.8.8 g of 1,4-diaminobutane in 10 ml of absolute ethanol are added dropwise to a stirred ice-cooled solution of 29.5 g of ethyl-o-bromandelimidate hydrochloride in 200 ml of absolute ethanol. After the addition is complete, the mixture is stirred for an additional 1 hour with cooling with an ice bath, and the mixture is heated under reflux for 20 hours. After cooling, the solution is concentrated under reduced pressure and ether is added to give 24.15 g of white crystalline product with m.p.
213-216°C (sønderdeling). Ved omkrystallisation fra en blanding af ethanol og ether fås en analytisk prøve med smp. 213-216°C (sønderdeling).213-216 ° C (dec.). Recrystallization from a mixture of ethanol and ether gives an analytical sample with m.p. 213-216 ° C (dec.).
Analyse for C^H^Br^O.HCl: C% H% N«Analysis for C ^H ^Br ^O.HCl: C% H% N «
Beregnet 45,1 5,05 8,75Calculated 45.1 5.05 8.75
Fundet 45,2 5,2 9,0.Found 45.2 5.2 9.0.
(b) o-Bromphenyl-4,5,6,7-tetrahydro-lH-l,3-diazepino--2-yl-keton.(b) o-Bromophenyl-4,5,6,7-tetrahydro-1H-1,3-diazepino-2-yl-ketone.
En suspension af 6,0 g o-bromphenyl-4,5,6,7-tetrahydro--lH-l,3-diazepino-2-methanol-hydrochlorid i 300 ml tør benzen omrøres med 50 g aktivt mangandioxid ved stuetemperatur i 60 timer. Efter filtrering gennem kiselgur fjernes opløsningsmidlet, og der fås 2,274 g remanens med smp. 57-60°C, som krystalliseres fra en let jordoliefraktion med kogeinterval 60-80°C efter behandling med trækul. Ved omkrystallisation fra den lette jordoliefraktion fås en analytisk prøve med smp. 62-63°C.A suspension of 6.0 g of o-bromophenyl-4,5,6,7-tetrahydro-1H-1,3-diazepino-2-methanol hydrochloride in 300 ml of dry benzene is stirred with 50 g of active manganese dioxide at room temperature for 60 minutes. hours. After filtration through diatomaceous earth, the solvent is removed and 2.227 g of residue are obtained with m.p. 57-60 ° C which crystallized from a light petroleum fraction at a boiling range of 60-80 ° C after treatment with charcoal. Recrystallization from the light petroleum fraction gives an analytical sample with m.p. 62-63 ° C.
Analyse for C12Hi3BrN20: C% H% N%Analysis for C12 H13 BrN2 O: C% H% N%
Beregnet 51,25 4,65 9,95Calculated 51.25 4.65 9.95
Fundet 51,55 4,8 10,0 (c) 2,3,4,5-Tetrahydro-l,3-diazepino[1,2-a]indol-ll-on En opløsning af 0,7 g o-bromphenyl-4,5,6,7-tetrahydro- -lH-l,3-diazepin-2-yl-keton i 5 ml tør dimethylformamid omrøres med 0,35 g kaliumcarbonat og 0,030 g cuprioxid ved 90°C i 2 timer under nitrogen. Blandingen fortyndes med 100 ml benzen, filtreres, vaskes med 3 x 50 ml vand og tørres over magnesiumsulfat. Efter fjernelse af opløsningsmidlet under formindsket tryk ekstrahe-res remanensen med ca. 150 ml varm cyclohexan. Fra ekstrakterne sker der en langsom udkrystallisation af 0,179 g 2,3,4,5-tetra-hydro-1,3-diazepino[1,2-a]indol-ll-on i form af rødligbrune nåle med smp. 137-139°C (sønderdeling). En analytisk prøve omkrystalliseres fra toluen, smp. 140-141°C (sønderdeling).Found 51.55 4.8 10.0 (c) 2,3,4,5-Tetrahydro-1,3-diazepino [1,2-a] indol-11-one A solution of 0.7 g of o-bromophenyl -4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl ketone in 5 ml of dry dimethylformamide is stirred with 0.35 g of potassium carbonate and 0.030 g of cuprioxide at 90 ° C for 2 hours under nitrogen . The mixture is diluted with 100 ml of benzene, filtered, washed with 3 x 50 ml of water and dried over magnesium sulfate. After removing the solvent under reduced pressure, the residue is extracted with ca. 150 ml of warm cyclohexane. From the extracts, a slow crystallization of 0.179 g of 2,3,4,5-tetrahydro-1,3-diazepino [1,2-a] indol-11-one is obtained in the form of reddish-brown needles, m.p. 137-139 ° C (dec.). An analytical sample is recrystallized from toluene, m.p. 140-141 ° C (dec.).
Analyse for C^H-^^O: C% H% N%Analysis for C ^H - ^^O: C% H% N%
Beregnet 72,0 6,05 14,0Calculated 72.0 6.05 14.0
Fundet 72,0 6,2 13,75.Found 72.0 6.2 13.75.
180143 42 (d) 2,4,5,11-Tetrahydro-11-phenyl-3H-1,3-diazepino-[1,2-a]indol-ll-ol.(D) 2,4,5,11-Tetrahydro-11-phenyl-3H-1,3-diazepino- [1,2-a] indol-11-ol.
Ved omsætning af 2,3,4,5-tetrahydro-l,3-diazepino-[l/2-a]indol-ll-on med phenylmagnesiumbrqmid analogt med den i eksempel 6 beskrevne fremgangsmåde fås hydrochloridet af den i overskriften anførte forbindelse, smp. 266-270°C (sønderdeling).By reacting 2,3,4,5-tetrahydro-1,3-diazepino- [1,2-a] indol-11-one with phenylmagnesium bromide analogous to the procedure described in Example 6, the hydrochloride of the title compound is obtained. mp. 266-270 ° C (dec.).
Eksempel 53Example 53
Spiro[1,3-dioxolan-2,31]-7-methylindolin-2-onSpiro [1,3-dioxolane-2.31] -7-methylindolin-2-one
En blanding af 53,6 g 7-methylisatin, 40 ml ethylen-glycol og 0,5 g toluen-p-sulfonsyre opvarmes under tilbagesvaling med omrøring i 1,5 liter chloroform i et apparat forsynet med en vandudskiller. Efter 24 timer er der opsamlet 7,5 ml vand (teoretisk mængde 6 ml). Reaktionsblandingen afkøles, vaskes med vand og tørres over magnesiumsulfat. Opløsningsmidlet fjernes, hvorved fås et lysorangefarvet fast stof, som omkrystalliseres fra isopropanol, hvorved fås 64,3 g krystallinsk produkt med smp. 184-185°C.A mixture of 53.6 g of 7-methylisatin, 40 ml of ethylene glycol and 0.5 g of toluene-p-sulfonic acid is heated under reflux with stirring in 1.5 liters of chloroform in an apparatus fitted with a water separator. After 24 hours 7.5 ml of water (theoretical amount of 6 ml) have been collected. The reaction mixture is cooled, washed with water and dried over magnesium sulfate. The solvent is removed to give a light orange solid which is recrystallized from isopropanol to give 64.3 g of crystalline product, m.p. 184-185 ° C.
Analyse for C11HHN03: C% H% N%Analysis for C11 HHNO3: C% H% N%
Beregnet 64,4 5,14 6,8Calculated 64.4 5.14 6.8
Eundet 64,7 5,4 6,9.Found 64.7 5.4 6.9.
7'-Me thyl-2'-oxospiro[1,3-dioxolan-2,3'-indolin]-11-propionitril 60 g spiro[l,3-dioxolan-2,3r]-7-methylindolin-2-on opløses i kogende isopropanol, og til den tilbagesvalende opløsning, som holdes omrørt, sættes dråbevis en 40%'s vandig opløsning af 7,5 ml "Triton B" L ® (tetramethylammoniumhydroxid) og 3,5 ml acry-lonitril. Reaktionsblandingen opvarmes i 1 time under tilbagesvaling, hvorefter der afkøles. Det krystallinske produkt frafiltres og vaskes med isopropanol, hvorved der fås 37 g produkt med smp. 122-123°C.7'-Methyl-2'-oxospiro [1,3-dioxolan-2,3'-indoline] -11-propionitrile 60 g of spiro [1,3-dioxolan-2,3r] -7-methylindolin-2-one dissolve in boiling isopropanol, and to the refluxing solution which is kept stirring is added dropwise a 40% aqueous solution of 7.5 ml of Triton B "L® (tetramethylammonium hydroxide) and 3.5 ml of acrylonitrile. The reaction mixture is heated at reflux for 1 hour and then cooled. The crystalline product is filtered off and washed with isopropanol to give 37 g of product, m.p. 122-123 ° C.
Analyse for c14H24N2°3i C% H% N%Analysis for c14H24N2 ° 3i C% H% N%
Beregnet 65,1 5,5 10,9Calculated 65.1 5.5 10.9
Fundet 65,1 5,5 10,9 31 4'-Dihydro-e-methylspiro[1,3-dioxolen-2,10' (2Ή)pyrimido(1,2-a) indol] 10 g 7'-methy1-2'-oxospiro[l,3-dioxolan-2,3'-indolin]-1'--propionitril reduceres ved 105,5 atm i ethanol, som er halvt mættet med 150 ml ammoniak i nærværelse af Raney-nikkel (W7) i 4 timer ved 100°C. Efter afkøling fjernes katalysatoren, opløsningsmidlet fjernes under formindsket tryk, og produktet omkrystalliseres fra ethylacetat, hvorved fås 5,2 g med smp. 166-167°C.Found 65.1 5.5 10.9 31 4'-Dihydro-e-methylspiro [1,3-dioxolen-2.10 '(2Ή) pyrimido (1,2-a) indole] 10 g of 7'-methyl 2'-oxospiro [1,3-dioxolane-2,3'-indoline] -1 '- propionitrile is reduced by 105.5 atm in ethanol, which is half saturated with 150 ml of ammonia in the presence of Raney nickel (W7) for 4 hours at 100 ° C. After cooling, the catalyst is removed, the solvent is removed under reduced pressure and the product is recrystallized from ethyl acetate to give 5.2 g of m.p. 166-167 ° C.
150143 43150143 43
Analyse for ci4HigN202! C% H% N%Analysis for ci4HigN2O2! C% H% N%
Beregnet 68,8 6,6 11,5Calcd 68.8 6.6 11.5
Fundet 69,3 6,7 11,5.Found 69.3 6.7 11.5.
2.3.4.10- Tetrahydro-6-methylpyrimido[1,2-a]indol-10-on 2 g 3,,4,-dihydro-6-methylspiro[l,3-dioxolan-2,10'(2,H)-pyrimido[1,2-a]indo1] sættes langsomt til 15 ml omrørt koncentreret svovlsyre, idet temperaturen holdes under 30°C ved afkøling.2.3.4.10- Tetrahydro-6-methylpyrimido [1,2-a] indol-10-one 2 g 3,4,4-dihydro-6-methylspiro [1,3-dioxolane-2,10 '(2, H) -Pyrimido [1,2-a] indole] is slowly added to 15 ml of stirred concentrated sulfuric acid, keeping the temperature below 30 ° C on cooling.
Efter omrøring i 1 time hældes reaktionsblandingen i is og neutraliseres ved en temperatur under 30°C med koncentreret ammoniakvand. Ved ekstraktion med dichlormethan fås ketonen, som omkry-stalliseres fra benzen, hvorved fås et rødt fast stof med smp. 142-144°C.After stirring for 1 hour, the reaction mixture is poured into ice and neutralized at a temperature below 30 ° C with concentrated ammonia water. By extraction with dichloromethane the ketone is obtained which is recrystallized from benzene to give a red solid with m.p. 142-144 ° C.
2.3.4.10- Tetrahydro-6-methylpyrimido[1,2-a]indol-10-ol 1,75 g rå 2,3,4,lO-tetrahydro-6-methylpyrimido[1,2-a]-indol-10-on i 17 ml tør tetrahydrofuran sættes til en omrørt opløsning af 0,022 mol phenylmagnesiumbromid i 35 ml tør tetrahydrofuran. Reaktionsblandingen opvarmes under tilbagesvaling i 2 timer, hvorefter den omrøres natten over ved stuetemperatur. Komplekset sønderdeles med is og ammoniumchlorid og ekstraheres med chloroform. Efter tørring over magnesiumsulfat fjernes opløsningsmidlet, hvorved fås en rød olie, som ved triturering med ether giver 1,86 g lyserødt fast stof. Det faste stof opløses i ethanol og behandles med en opløsning af hydrogenchlo-rid i tør ether, hvorved fås den ønskede forbindelse i form af hydrochloridet i en mængde på 1,68 g med smp. 258-259°C (sønderdeling) .2.3.4.10- Tetrahydro-6-methylpyrimido [1,2-a] indol-10-ol 1.75 g crude 2,3,4,10-tetrahydro-6-methylpyrimido [1,2-a] indole-10 -one in 17 ml of dry tetrahydrofuran is added to a stirred solution of 0.022 mol of phenylmagnesium bromide in 35 ml of dry tetrahydrofuran. The reaction mixture is heated at reflux for 2 hours, then stirred overnight at room temperature. The complex is decomposed with ice and ammonium chloride and extracted with chloroform. After drying over magnesium sulfate, the solvent is removed to give a red oil which, upon trituration with ether, gives 1.86 g of pink solid. The solid is dissolved in ethanol and treated with a solution of hydrogen chloride in dry ether to give the desired compound in the form of the hydrochloride in an amount of 1.68 g, m.p. 258-259 ° C (dec.).
Analyse for C18H18N2°*HC1: C% H% N%Analysis for C 18 H 18 N 2 ° HCl: C% H% N%
Beregnet 68,7 6,1 8,9Calcd 68.7 6.1 8.9
Fundet 68,7 6,2 8,8.Found 68.7 6.2 8.8.
Claims (2)
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB125071*[A GB1366133A (en) | 1971-01-11 | 1971-01-11 | Fused ring indole derivatives |
GB125071 | 1971-01-11 | ||
GB4095971 | 1971-09-02 | ||
GB4095971 | 1971-09-02 | ||
GB5646771 | 1971-12-06 | ||
GB5646771 | 1971-12-06 |
Publications (2)
Publication Number | Publication Date |
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DK150143B true DK150143B (en) | 1986-12-15 |
DK150143C DK150143C (en) | 1987-06-01 |
Family
ID=27253859
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK11672A DK150143C (en) | 1971-01-11 | 1972-01-10 | ANALOGY PROCEDURE FOR THE PREPARATION OF INCIDENTAL DERIVATIVES |
Country Status (20)
Country | Link |
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JP (1) | JPS5531156B2 (en) |
AR (1) | AR192734A1 (en) |
AT (1) | AT312595B (en) |
AU (1) | AU464388B2 (en) |
BE (1) | BE777911A (en) |
CA (1) | CA1012150A (en) |
CH (1) | CH573938A5 (en) |
CY (1) | CY926A (en) |
DK (1) | DK150143C (en) |
EG (1) | EG10888A (en) |
ES (2) | ES398678A1 (en) |
FI (1) | FI54120C (en) |
FR (1) | FR2121699B1 (en) |
GB (1) | GB1366133A (en) |
HK (1) | HK52877A (en) |
IE (1) | IE35956B1 (en) |
KE (1) | KE2777A (en) |
MY (1) | MY7800048A (en) |
NL (1) | NL174251C (en) |
SE (1) | SE398645B (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1520611A (en) * | 1976-06-11 | 1978-08-09 | Wyeth John & Brother Ltd | Fused ring indole derivatives |
JPS5845741B2 (en) * | 1977-06-06 | 1983-10-12 | 株式会社日立製作所 | information retrieval device |
ZA824382B (en) * | 1981-07-07 | 1984-02-29 | Wyeth John & Brother Ltd | Anti-obesity agents |
JPS60204057A (en) * | 1984-03-28 | 1985-10-15 | Casio Comput Co Ltd | Small-sized electronic apparatus with data storage function |
GB8606253D0 (en) * | 1986-03-13 | 1986-04-16 | Wyeth John & Brother Ltd | Pyrimidoindoles |
GB8606254D0 (en) * | 1986-03-13 | 1986-04-16 | Wyeth John & Brother Ltd | Substituted pyrimidoindoles |
GB8614246D0 (en) * | 1986-06-11 | 1986-07-16 | Wyeth John & Brother Ltd | Substituted pyrimidoindoles |
WO2010090680A1 (en) * | 2008-12-15 | 2010-08-12 | Wyeth Llc | Substituted oxindole cb2 agonists |
Family Cites Families (2)
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US3888846A (en) * | 1967-03-30 | 1975-06-10 | Hoffmann La Roche | Process for 2(2-(1,3-diazacycloalk-2-enyl))benzophenone derivatives and 1,3-diazacycloalkenyl(2,1-a)isoindole derivatives |
US3586693A (en) * | 1969-07-07 | 1971-06-22 | American Home Prod | Imidazo(1,2-a)indolin-9-ols |
-
1971
- 1971-01-11 GB GB125071*[A patent/GB1366133A/en not_active Expired
- 1971-12-14 CY CY926A patent/CY926A/en unknown
-
1972
- 1972-01-04 AU AU37558/72A patent/AU464388B2/en not_active Expired
- 1972-01-05 AT AT7772A patent/AT312595B/en not_active IP Right Cessation
- 1972-01-08 ES ES398678A patent/ES398678A1/en not_active Expired
- 1972-01-08 IE IE14/72A patent/IE35956B1/en unknown
- 1972-01-09 EG EG12/72A patent/EG10888A/en active
- 1972-01-10 FR FR7200619A patent/FR2121699B1/fr not_active Expired
- 1972-01-10 DK DK11672A patent/DK150143C/en not_active IP Right Cessation
- 1972-01-10 AR AR240009A patent/AR192734A1/en active
- 1972-01-10 FI FI45/72A patent/FI54120C/en active
- 1972-01-11 JP JP725481A patent/JPS5531156B2/ja not_active Expired
- 1972-01-11 SE SE7200278A patent/SE398645B/en unknown
- 1972-01-11 NL NLAANVRAGE7200415,A patent/NL174251C/en not_active IP Right Cessation
- 1972-01-11 BE BE777911A patent/BE777911A/en not_active IP Right Cessation
- 1972-01-11 CH CH36472A patent/CH573938A5/xx not_active IP Right Cessation
- 1972-10-26 KE KE2777A patent/KE2777A/en unknown
- 1972-11-23 CA CA157,326A patent/CA1012150A/en not_active Expired
- 1972-12-05 ES ES409296A patent/ES409296A1/en not_active Expired
-
1977
- 1977-10-13 HK HK528/77A patent/HK52877A/en unknown
-
1978
- 1978-12-31 MY MY197848A patent/MY7800048A/en unknown
Also Published As
Publication number | Publication date |
---|---|
NL174251B (en) | 1983-12-16 |
CY926A (en) | 1977-12-23 |
NL7200415A (en) | 1972-07-13 |
ES409296A1 (en) | 1976-03-16 |
MY7800048A (en) | 1978-12-31 |
IE35956B1 (en) | 1976-07-07 |
JPS4839500A (en) | 1973-06-09 |
AU3755872A (en) | 1973-07-05 |
KE2777A (en) | 1977-10-21 |
AR192734A1 (en) | 1973-03-14 |
FI54120C (en) | 1978-10-10 |
CA1012150A (en) | 1977-06-14 |
NL174251C (en) | 1984-05-16 |
ES398678A1 (en) | 1975-05-16 |
AU464388B2 (en) | 1975-08-28 |
JPS5531156B2 (en) | 1980-08-15 |
HK52877A (en) | 1977-10-20 |
EG10888A (en) | 1978-06-30 |
DK150143C (en) | 1987-06-01 |
GB1366133A (en) | 1974-09-11 |
AT312595B (en) | 1974-01-10 |
IE35956L (en) | 1972-07-11 |
FR2121699B1 (en) | 1975-08-01 |
SE398645B (en) | 1978-01-09 |
BE777911A (en) | 1972-07-11 |
FR2121699A1 (en) | 1972-08-25 |
CH573938A5 (en) | 1976-03-31 |
FI54120B (en) | 1978-06-30 |
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