DK150850B - PROCEDURE FOR MANUFACTURING TRICYCLIC COMPOUNDS - Google Patents
PROCEDURE FOR MANUFACTURING TRICYCLIC COMPOUNDS Download PDFInfo
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- DK150850B DK150850B DK165273AA DK165273A DK150850B DK 150850 B DK150850 B DK 150850B DK 165273A A DK165273A A DK 165273AA DK 165273 A DK165273 A DK 165273A DK 150850 B DK150850 B DK 150850B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/32—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
150850 i150850 i
Fra J. Org. Chem. 34, Nr. 4, 1969, s. 1143-1145 er det kendt at amidere cycliske amider i nærværelse af complexer af titan (IV) med ammoniak, primære eller sekundære aminer. Ved denne metode fører nærværelse af titantetrachlorid hovedsagelig til en spaltning af lactambindingen, hvorved der indtræder omamidering, hvorfor der kun fås ringe udbytter af ami-diner. Det har nu vist sig, at cycliske amider kan amideres ved hjælp af titan IV- eller zirconium-IV-piperazincomplexer med godt udbytte.From J. Org. Chem. 34, no. 4, 1969, pp. 1143-1145, it is known to amide cyclic amides in the presence of complexes of titanium (IV) with ammonia, primary or secondary amines. In this method, the presence of titanium tetrachloride mainly leads to a cleavage of the lactam bond, which results in re-amidation, so that only poor yields of amine dinar are obtained. It has now been found that cyclic amides can be amidated by titanium IV or zirconium IV piperazine complexes in good yield.
Den foreliggende opfindelse angår derfor en særlig fremgangsmåde til fremstilling af tricycliske forbindelser med den almene formel IThe present invention therefore relates to a particular process for the preparation of tricyclic compounds of general formula I
R1 t u -ΤΎ"°Ύ· i hvor R betegner hydrogen, alkoxyalkyl med i alt højst 6 carbonatomer, alkyl eller hydroxyalkyl med hver højst 4 carbonatomer, idet hydroxy- alkylgruppen eventuelt yderligere kan være acyleret med en acylgruppe, 4 der indeholder højst 18 carbonatomer, R betegner hydrogen, alkyl, alkoxy eller alkylthio, hvor alkylgrupperne hver indeholder 1-4 carbonatomer, halogen eller trifluormethyl, og A betegner grupperne eller Z2 r2 ' 'fi πWherein R represents hydrogen, alkoxyalkyl of not more than 6 carbon atoms, alkyl or hydroxyalkyl of not more than 4 carbon atoms, the hydroxyalkyl group being optionally further acylated with an acyl group 4 containing at most 18 carbon atoms R represents hydrogen, alkyl, alkoxy or alkylthio, wherein the alkyl groups each contain 1-4 carbon atoms, halogen or trifluoromethyl, and A represents the groups or Z2 r2
Cl 3 eller II \\ Z1 Z2 150850 2 hvor a) såfremt A er Z^, X betegner -O-, -S-, -NH eller -N-alkyl, 2 hvor alkylgruppen indeholder 1-3 carbonatomer, R betegner hydrogen, alkyl, dialkylaminosulfonyl, alkylsulfonyl, hvor hver alkylgruppe indeholder 1-4 carbonatomer, alkoxy eller alkylthio med hver 1-4 carbonatomer, halogen, nitro, trifluormethylsulfonyl, trifluormethoxy, trifluormeth- 3 ylthio, acetyl, cyano eller trifluormethyl, og R betegner hydrogen, halogen eller alkyl med 1-4 carbonatomer, eller b) såfremt A er Z2, X betegner eller -S-,Cl 3 or II \ Z1 Z2 Z2 where a) if A is Z 1, X represents -O-, -S-, -NH or -N-alkyl, 2 wherein the alkyl group contains 1-3 carbon atoms, R represents hydrogen, alkyl, dialkylaminosulfonyl, alkylsulfonyl, each alkyl group containing 1-4 carbon atoms, alkoxy or alkylthio with each 1-4 carbon atoms, halogen, nitro, trifluoromethylsulfonyl, trifluoromethoxy, trifluoromethylthio, acetyl, cyano or trifluoromethyl, and R represents hydrogen, and R or alkyl of 1-4 carbon atoms, or b) if A is Z2, X represents or -S-,
eller syreadditionssalte deraf, hvilken fremgangsmåde er ejendommelig ved, at forbindelser med den almene formel IIor acid addition salts thereof, characterized in that compounds of the general formula II
0 il 40 il 4
hvor X, A og R har den ovenfor anførte betydning, omsættes med et metal-amin-complex bestående af titan eller zirconium og en forbindelse med den almene formel IIIwherein X, A and R are as defined above, reacted with a metal-amine complex consisting of titanium or zirconium and a compound of the general formula III
-7 ^ 1 HF F-R-1- 111 v_/ hvor R har den ovenfor anførte betydning, og resulterende forbindelser med formlen I, hvor R er en acyleret hydr-oxyalkylgruppe, eventuelt hydrolyseres, eller vundne forbindelser med 3 150850 ' i formlen I, hvor R er en hydroxyalkylgruppe, eventuelt forestres, og/eller vundjie forbindelser eventuelt omdannes til deres syreadditionssalte.Wherein R is as defined above and resulting compounds of Formula I wherein R is an acylated hydroxyalkyl group, optionally hydrolyzed, or obtained compounds of Formula I, wherein R is a hydroxyalkyl group optionally esterified and / or desired compounds optionally converted to their acid addition salts.
En foretrukken udførelsesform af fremgangsmåden ifølge opfindelsen består i, at forbindelser med formlen II omsættes med metal-amin-complexet i nærværelse af et syrebindende middel. Som syrebindende middel kan anvendes en tertiær amin, f.eks. triethylamin, pyridin, dimethylanilin eller et overskud af en forbindelse med formlen III. Andelen af den syrebindende aminoforbindelse beregnet på (1 mol) metal-amin-complex skal være mindst 1 mol (ækvivalent mængde), dog fortrinsvis 2 mol (dobbelt ækvivalent mængde).A preferred embodiment of the process of the invention consists in reacting compounds of formula II with the metal-amine complex in the presence of an acid-binding agent. As an acid binding agent a tertiary amine, e.g. triethylamine, pyridine, dimethylaniline or an excess of a compound of formula III. The proportion of the acid-binding amino compound calculated on (1 mole) metal-amine complex must be at least 1 mole (equivalent amount), but preferably 2 mole (double equivalent amount).
Omsætningen udføres hensigtsmæssigt i et organisk opløsningsmiddel, f.eks. et aromatisk opløsningsmiddel såsom toluen, et halogeneret aromatisk opløsningsmiddel såsom chlorbenzen, et halogeneret aliphatisk opløsningsmiddel såsom dichlorethan eller en ether såsom anisol. Reaktionstemperaturen skal her ligge mellem stuetemperatur og 150°C, fortrinsvis mellem 50 og 120°C.The reaction is conveniently carried out in an organic solvent, e.g. an aromatic solvent such as toluene, a halogenated aromatic solvent such as chlorobenzene, a halogenated aliphatic solvent such as dichloroethane or an ether such as anisole. Here, the reaction temperature should be between room temperature and 150 ° C, preferably between 50 and 120 ° C.
2 3 4 I substituenterne R , R og R er halogen fortrinsvis chlor eller brom, især chlor. Såfremt hydroxyalkylgruppen R er acyleret, indeholder acylgruppen højst 18 carbonatomer, fortrinsvis højst 10 carbonatomer. Acylgruppen er fortrinsvis aliphatisk og kan være mættet eller umættet.In the substituents R, R and R, halogen is preferably chlorine or bromine, especially chlorine. If the hydroxyalkyl group R is acylated, the acyl group contains at most 18 carbon atoms, preferably at most 10 carbon atoms. The acyl group is preferably aliphatic and may be saturated or unsaturated.
Det til den omhandlede omsætning anvendte metal-amin-complex fås ved omsætning af et halogenid, fortrinsvis tetrachloridet eller tetrabromidet af titan eller zirconium med en forbindelse med formlen III, hensigtsmæssigt i et molforhold på 1:4. Omsætningen foretages hensigtsmæssigt i det senere til hoved reaktionen anvendte opløsningsmiddel. Hertil anvendes metalhalogenidet i form af dets opløselige (mono- eller di-) etherat, fortrinsvis anisol-dietheratet.The metal-amine complex used for the present reaction is obtained by reacting a halide, preferably the tetrachloride or tetrabromide of titanium or zirconium with a compound of formula III, suitably in a molar ratio of 1: 4. The reaction is conveniently carried out in the solvent used for the main reaction. To this end, the metal halide is used in the form of its soluble (mono or di) etherate, preferably the anisole dietherate.
4 1508504 150850
Efter endt omsætning omdannes de i reaktionsblandingen værende, i vid udstrækning uopløselige metalforbindelser ved tilsætning af en alkohol,f.eks. isopropanol, til en opløselig form og udfæl= des derefter ved tilsætning af vandig ammoniak. Af den således for metalforbindelser befriede reaktionsblanding isoleres de ifølge opfindelsen fremstillede forbindelser med formlen I på i og for sig kendt måde efter inddampning af reaktionsblandingen ved ud= krystallisation og renses derefter på i og for sig kendt måde, f.eks. ved omkrystallisation af isopropanol.Upon completion of the reaction, the largely insoluble metal compounds in the reaction mixture are converted by the addition of an alcohol, e.g. isopropanol, to a soluble form and then precipitated by the addition of aqueous ammonia. From the reaction mixture thus liberated for metal compounds, the compounds of the formula I according to the invention are isolated in a manner known per se after evaporation of the reaction mixture by crystallization and then purified in a manner known per se, e.g. by recrystallization from isopropanol.
Ted fremstillingen af forbindelserne med formlen I, hvor R1 er en hydroxy-alkylgruppe, kan reaktionsproduktet udfældes geléagtigt, da hydroxyalkylgruppen ligeledes reagerer med metalhalogenidet under esterdannelse. For at forhindre dannelsen af en for stærk gelé, som kan forstyrre reaktionsforløbet, er det hensigtsmæssigt at arbejde i nærværelse af større mængder opløsningsmidler, f.eks. chlorbenzen eller anisol, under- tilsætning af et overskud (10 -20 ganges molært overskud) af en tertiær amin, f.eks. triethylamin.For the preparation of the compounds of formula I wherein R 1 is a hydroxyalkyl group, the reaction product can be precipitated gelled as the hydroxyalkyl group also reacts with the metal halide during ester formation. In order to prevent the formation of an overly strong jelly which may interfere with the course of the reaction, it is advisable to work in the presence of larger quantities of solvents, e.g. chlorobenzene or anisole, adding an excess (10-20 times the molar excess) of a tertiary amine, e.g. triethylamine.
Forbindelser med formlen I, hvor R er en hydroxyalkylgruppe, kan ligeledes fremstilles ved alkalisk hydrolyse af forbindelser med formlen I, hvor R1 er en acyleret hydroxyalkylgruppe, f.eks. ved hjælp af en fortyndet natriumhydroxidopløsning.Compounds of formula I wherein R is a hydroxyalkyl group may also be prepared by alkaline hydrolysis of compounds of formula I wherein R 1 is an acylated hydroxyalkyl group, e.g. using a dilute sodium hydroxide solution.
Forestringen af forbindelser med formlen I, hvor R1 er en hydroxy= alkylgruppe, kan foretages på i og for sig kendt måde, f.eks. ved hjælp af et reaktivt syrederivat, f.eks. et halogenid af en relevant syre, i et opløsningsmiddel såsom chloroform, hensigtsmæssigt i nærværelse af et syrebindende middel, f.eks. triethylamin, ved stuetemperatur.The esterification of compounds of formula I wherein R 1 is a hydroxy = alkyl group may be carried out in a manner known per se, e.g. by means of a reactive acid derivative, e.g. a halide of a relevant acid, in a solvent such as chloroform, conveniently in the presence of an acid binding agent, e.g. triethylamine, at room temperature.
De resulterende forbindelser med formlen I kan omdannes til syre= additionssalte deraf og omvendt. Egnede salte er f.eks. hydro= chlorider, hydrobromidet, sulfater, fumarater, maleinater og p-toluensulfonater.The resulting compounds of formula I can be converted into acid addition salts thereof and vice versa. Suitable salts are e.g. hydro = chlorides, the hydrobromide, sulfates, fumarates, maleinates and p-toluenesulfonates.
s 150850s 150850
De til den omhandlede fremgangsmåde anvendte udgangsforbindelser med formlen li er for den største dels vedkommende kendte, eller de kan fremstilles ud fra kendte udgangsforbindelser på i og for sig kendt måde. Fremstillingen af endnu ikke kendte forbindelser med formlen II beskrives i eksemplerne eller kan foretages ana= logt med disse eksempler. Forbindelserne med formlen III er i almindelighed også kendte eller kan fremstilles ud fra kendte udgangsforbindelser på i og for sig kendt måde. Forbindelser med formlen III, hvor R^” er en aeyleret hydroxyalkylgruppe, kan f.eks. fremstilles ved omsætning af E-benzylpiperazin med en halogenal= kohol, hydroxygruppen kan forestres ved hjælp af et reaktivt syre= derivat, f.eks. halogenidet, især chloridet, af en relevant syre, hvorefter benzylgruppen fjernes hydrogenolytisk.The starting compounds of formula I used for the process according to the present invention are for the most part known or can be prepared from known starting compounds in a manner known per se. The preparation of compounds of formula II as yet unknown is described in the Examples or may be analogous to these Examples. The compounds of formula III are generally also known or can be prepared from known starting compounds in a manner known per se. Compounds of formula III wherein R 2 is an aeylated hydroxyalkyl group can be, for example, is prepared by reaction of E-benzylpiperazine with a haloalcohol, the hydroxy group can be esterified by a reactive acid = derivative, e.g. the halide, especially the chloride, of a relevant acid, after which the benzyl group is removed hydrogenolytically.
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser med formlen I er for den største dels vedkommende allerede kendte og kan anvendes i terapien på for disse forbindelser kendte måder.The compounds of formula I according to the invention are, for the most part, already known and can be used in the therapy in ways known to these compounds.
F.eks. er forbindelsen 2-chlor-ll-(4-methyl-l^piperazinyl)dibenz= [b,f][l,4]thiazepin kendt som et yderst virksomt antipsychotikum under navnet Clothiapin (intumin). De hidtil ukendte forbindelser med formlen I, især 10H-thieno[3,2-c][l]benzazepiner kan anvendes som an tip sy cho tika, sedativa, sovemidler og muskelrelaxanter.Eg. For example, the compound is 2-chloro-11- (4-methyl-1β-piperazinyl) dibenz = [b, f] [1,4] thiazepine known as a highly effective antipsychotic under the name Clothiapine (intumin). The novel compounds of formula I, in particular 10H-thieno [3,2-c] [1] benzazepines, can be used as therapeutic agents, sedatives, sleeping agents and muscle relaxants.
2 I den almene formel I sidder substituenten R , såfremt A er Z-,, 3 x fortrinsvis i 2- eller 3-stillingen, substituenten R fortrinsvis i 4-stillingen, og substituenten fortrinsvis i 7- eller 8-stil-1ingen.2 In the general formula I, substituent R is substituted if A is Z-, 3x preferably in the 2 or 3 position, substituent R preferably in the 4-position, and the substituent preferably in the 7- or 8-position.
Fremgangsmåden ifølge opfindelsen·belyses nærmere i nedenstående eksempler, hvor "stuetemperatur" angiver en temperatur mellem 20 og 30°C, såfremt intet andet er anført: 6 150850The process according to the invention is further elucidated in the examples below, where "room temperature" indicates a temperature between 20 and 30 ° C, unless otherwise stated: 6 150850
Eksempel 1.Example 1.
8-Ohlor-ll- (4-methyl-l-pip~ razinyl) - 5H-dibenzo [b, e ] [1,4] diazepin.8-Ohlor-11- (4-methyl-1-piperazinyl) - 5H-dibenzo [b, e] [1,4] diazepine.
I en med tildrypningstragt, tilbagesvalingskøler og termometer forsynet 21/2 liters sulfideringskolbe anbringes 840 ml toluen, 90 ml anisol og 79,2 g titantetrachlorid ved stuetemperatur, h.vor= ved der dannes en mørkebrun klar opløsning. Under ydre køling med vand tilsættes en blanding af 167 g U-methylpiperazin og 100 ml toluen, hvorved temperaturen stiger til 50 - 55°0, og amincomplexet danner i findelt form en beige til mørkebrun farvet suspension. Derefter tilsættes 102 g 8-chlor-10,ll-dihydro-ll-oxo-5H-dibenzo= [b,e][l,4]diazepin og 83 g U-methylpiperazin, og reaktionsblandin= gen opvarmes til kogning (110 - 112°C) i 3 timer under omrøring. Derpå afkøles blandingen til 60 - 70°C og tilsættes 125 ml isopro= panol, hvorved de under reaktionen dannede uopløselige titanfor= bindeiser atter går i opløsning. Yed tilsætning af 8 g kiselgur-og derpå 115 ml koncentreret ammoniak (ca. 27$*s) afkøles der un= der omrøring til ca. 30°C, og det dannede bundfald frafiltreres. Eilterremanensen vaskes med 2-3 portioner på hver 330 ml toluen. Derpå rystes filtratet med vand, og den organiske fase ekstraheres med ca. 10$* s fortyndet saltsyre. Basen udfældes ved, at den salt= sure ekstrakt dryppes til et overskud af fortyndet ammoniak. Derpå optages basen i ether, og etheropløsningen vaskes med vand og tør= res over natriumsulfat. Efter afdampning af etheret og omkrystal= lisation af isopropanol fås 8-ohlor-ll-(4-methyl-l-piperazinyl)= -5H-dibenzo[b,e][l,4]diazepin med smeltepunkt 184 - 185°C i et udbytte på 90$ af det teoretiske, beregnet på anvendt lactam.In a droplet funnel, reflux condenser and thermometer fitted with a 21/2 liter sulfidation flask, place 840 ml of toluene, 90 ml of anisole and 79.2 g of titanium tetrachloride at room temperature, respectively = where a dark brown clear solution is formed. Under external cooling with water, a mixture of 167 g of U-methylpiperazine and 100 ml of toluene is added, raising the temperature to 50-55 ° and the amine complex forms a beige to dark brown colored suspension. Then, 102 g of 8-chloro-10,11-dihydro-11-oxo-5H-dibenzo = [b, e] [1,4] diazepine and 83 g of U-methylpiperazine are added and the reaction mixture is heated to boiling (110 - 112 ° C) for 3 hours with stirring. The mixture is then cooled to 60-70 ° C and 125 ml of isopropanol is added, whereby the insoluble titanium precursor titrates formed during the reaction again dissolve. After the addition of 8 g of diatomaceous earth and then 115 ml of concentrated ammonia (about 27 $ * s), cool with stirring to ca. 30 ° C and the resulting precipitate is filtered off. The Eilter residue is washed with 2-3 portions on each 330 ml of toluene. The filtrate is then shaken with water and the organic phase is extracted with ca. 10 $ * diluted hydrochloric acid. The base is precipitated by dripping the salt-acidic extract to an excess of dilute ammonia. The base is then taken up in ether and the ether solution is washed with water and dried over sodium sulfate. After evaporation of the ether and recrystallization of isopropanol, 8-ohloro-11- (4-methyl-1-piperazinyl) = -5H-dibenzo [b, e] [1,4] diazepine is obtained, mp 184 - 185 ° C. a yield of $ 90 of theoretical lactam.
Eksempel 2.Example 2.
6-(4-tert.Butyl-1-piperazinyl)morphantridin.6- (4-tert-Butyl-1-piperazinyl) morphantridin.
I en med tildrypningstragt, tilbagesvalingskøler og termometer 7 150850" forsynet 2 1/2 liters sulfideringskolbe anbringes 840 ml toluen, 90 ml anisol og 93,5 g zirconiumtetrachlorid ved stuetemperatur, hvorved der dannes en mørkebrun klar opløsning. Hertil sættes under ydre afkøling med vand en blanding af 248 g H-tert.butyl= piperazin og 100 ml toluen, hvorved temperaturen stiger til 50 -55°C, og amincomplexet danner i findelt form en mørkebrun far= vet suspension. Derpå tilsættes 87 g morphantridin-6-on og 123,5 g ΪΓ-tert.butylpiperazin, og reaktionsblandingen opvarmes til kogning (110 - 112°C) i 3 timer under omrøring. Derpå afkøles blandingen til 60 - 70°C og tilsættes 125 ml isopropanol, hvorved de under reaktionen dannede uopløselige zirconiumforbindelser igen går i opløsning. Efter tilsætning af 8 g kiselgur og derefter 115 ml koncentreret ammoniakvand (ca. 27^’s) afkøles blandingen under om røring til ca. 30°C, og det dannede bundfald frafiltreres. Eil= terremanensen vaskes med 2-3 portioner på hver 330 ml toluen.In a drip funnel, reflux condenser and thermometer 7 150850 "2 1/2 liter sulfidation flask place 840 ml of toluene, 90 ml of anisole and 93.5 g of zirconium tetrachloride at room temperature to form a dark brown clear solution. Add to this under external cooling with water a mixture of 248 g of H-tert.butyl = piperazine and 100 ml of toluene, increasing the temperature to 50 -55 ° C and the amine complex forming a dark brown colored suspension, then adding 87 g of morphantridine-6-one and 123.5 g of ΪΓ-tert.butylpiperazine and the reaction mixture is heated to boiling (110 - 112 ° C) for 3 hours with stirring, then cooled to 60 - 70 ° C and added 125 ml of isopropanol to form the insoluble zirconium compounds during the reaction. After adding 8 g of diatomaceous earth and then 115 ml of concentrated ammonia water (about 27 ° C), the mixture is cooled while stirring to about 30 ° C and the precipitate formed is filtered off. d 2-3 portions of each 330 ml of toluene.
Derpå rystes filtratet med vand, og den organiske fase ekstraheres med ca. 10$'s saltsyre. Basen udfældes ved at dryppe den saltsure ekstrakt i et overskud af fortyndet ammoniakvand. Derefter optages basen i ether, og etheropløsningen vaskes med vand og tørres over natriumsulfat. Efter afdampning af etheret opløses remanensen i acetone, og til opløsningen sættes 38 g maleinsyre. Derpå ind= dampes blandingen og tilsættes ethylacetat og noget ether, og det dannede bundfald frafiltreres. Efter omkrystallisation af acetone/ ethylacetat/ether smelter det resulterende 6-(4-tert.butyl-l-pipe= razinyl)morphantridinmaleinat ved 138 - 141°C.The filtrate is then shaken with water and the organic phase is extracted with ca. 10 $ hydrochloric acid. The base is precipitated by dripping the hydrochloric acid extract into an excess of dilute ammonia water. The base is then taken up in ether and the ether solution is washed with water and dried over sodium sulfate. After evaporation of the ether, the residue is dissolved in acetone and 38 g of maleic acid are added to the solution. The mixture is then evaporated and ethyl acetate and some ether are added and the resulting precipitate is filtered off. After recrystallization from acetone / ethyl acetate / ether, the resulting 6- (4-tert-butyl-1-pipe = razinyl) morphantridine malinate melts at 138-141 ° C.
Det til denne fremgangsmåde som udgangsforbindelse anvendte l-tert.= butylpiperazin kan fremstilles på følgende måde: 1) 1-Benzyl-4-1ert.butylpip era zin.The 1-tert. = Butylpiperazine used for this process as a starting compound can be prepared as follows: 1) 1-Benzyl-4-1ert.butylpiperazine.
En opløsning af bis-(2-chlorethyl)tert.butylamin i 500 ml ethanol og en opløsning af 1095 g benzylamin i 750 ml ethanol dryppes sam= tidigt til 1000 ml kogende ethanol. Efter endt tilsætning opvar= mes reaktionsblandingen til kogetemperatur i yderligere 1 time.A solution of bis- (2-chloroethyl) tert-butylamine in 500 ml of ethanol and a solution of 1095 g of benzylamine in 750 ml of ethanol are dropped simultaneously to 1000 ml of boiling ethanol. After the addition is complete, the reaction mixture is heated to boiling temperature for an additional 1 hour.
Derpå inddampes blandingen i vakuum, og remanensen opløses i for= tyndet saltsyre. Den sure opløsning vaskes med ether og indstilles derefter på alkalisk reaktion ved tilsætning af koncentreret van= dig natriumhydroxidopløsning. Den herved frigjorte base udrystes s 150850 med ether, og etherremanensen destilleres. l-Benzyl-4-tert.butyl= piperazin koger ved 160 - 162°C/12 mm Hg.The mixture is then evaporated in vacuo and the residue is dissolved in dilute hydrochloric acid. The acidic solution is washed with ether and then adjusted to alkaline reaction by the addition of concentrated aqueous sodium hydroxide solution. The thus released base is shaken with ether and the ether residue is distilled. 1-Benzyl-4-tert-butyl = piperazine boils at 160 - 162 ° C / 12 mm Hg.
2) l-tert.Butylpiperazin.2) l-tert.Butylpiperazine.
348,5 g l-benzyl-4-tert.butylpiperazin opløses i 1200 ml 99$*s ethanol, og til den resulterende opløsning sættes 10 g 5fols palla= dium-kul-katalysator. Derpå rystes opløsningen i et hydrogenerings= apparatur i hydrogenatmosfære (l atmosfære) ved stuetemperatur til endt hydrogenoptagelse. Derpå filtreres blandingen, filtratet inddampes i vakuum, og remanensen destilleres i vakuum. l-tert.Bu= tylpiperazin fås herved i form af en farveløs olie, som koger ved 66 - 70°C/12 mm Hg og udkrystalliserer ved henstand. Krystallerne smelter ved 35 - 40°C.348.5 g of 1-benzyl-4-tert.butylpiperazine are dissolved in 1200 ml of 99% ethanol and to the resulting solution is added 10 g of 5-fold palladium-carbon catalyst. Then, the solution is shaken in a hydrogenation apparatus in hydrogen atmosphere (1 atmosphere) at room temperature to complete hydrogen uptake. The mixture is then filtered, the filtrate is evaporated in vacuo and the residue is distilled in vacuo. 1-tert.Bu = tylpiperazine is hereby obtained in the form of a colorless oil which boils at 66 - 70 ° C / 12 mm Hg and crystallizes on standing. The crystals melt at 35 - 40 ° C.
Under anvendelse af de i eksemplerne 1 og 2 beskrevne fremgangs= måder samt ved anvendelse af relevante udgangsforbindelser fås på analog måde følgende forbindelser: 5- Me thyl-11-(4-methyl-l-piperazinyl)dibenz[b,e][1,4]diazepin, som efter omkrystallisation af ether/petroleumsether smelter ved 122 -124°0; 2-chlor-11-(4-methyl-1-piperaziny1)dibenz[b,f][l,4]thiazepin, som efter omkrystallisation af ether/petroleumsether smelter ved 116 -120°C; 6- (4-methyl-l-piperazinyl)morphantridin, som efter omkrystallisa= tion af acetone/petroleumsether smelter ved 138 - 139°C; 2-methyl-ll-(4-methyl-l-piperazinyl)dibenz[b,f][1,4]thiazepin, som efter omkrystallisation af petroleumsether smelter ved 99 - 107°C; 2-chlor-ll-(4-methyl-l-piperazinyl)dibenz[b,f][l,4]oxazepin, som efter omkrystallisation af petroleumsether smelter ved 104 - 110°C; 2-brom-ll-(4-methyl-l-piperazinyl)dibenz[b,f][l,4]thiazepin, som efter omkrystallisation af acetone/petroleumsether smelter ved 138 - 139° C; 9 150850 2-nitro-ll- (4-methyl-l-piperazinyl)dibenz[b, f ] [ 1,4] oxazepin, som efter omkrystallisation af chloroform/acetone/petroleumsether smelter ved 192 - 193°C; 2-dimethylaminosulfonyl-11-(4-methyl-l-piperazinyl)dibenz[b,f][l,4]= thiazepin, som efter omkrystallisation af acetone/petroleums= ether smelter ved 192 - 193° C; 2-dimethylamino sulf onyl-11- (4-methyl-l-piperazinyl) dibenz [b,f][l,4]= oxazepin, som efter omkrystallisation af ether/petroleumsether smelter ved 149 - 150°C.Using the procedures described in Examples 1 and 2, and using relevant starting compounds, the following compounds are obtained in an analogous manner: 5- Me thyl-11- (4-methyl-1-piperazinyl) dibenz [b, e] [1 , 4] diazepine, which after recrystallization from ether / petroleum ether melts at 122 -124 ° 0; 2-chloro-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] thiazepine, which after recrystallization from ether / petroleum ether melts at 116-120 ° C; 6- (4-methyl-1-piperazinyl) morphantridine, which after recrystallization from acetone / petroleum ether melts at 138 - 139 ° C; 2-methyl-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] thiazepine, which after recrystallization from petroleum ether melts at 99 - 107 ° C; 2-chloro-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] oxazepine, which after recrystallization from petroleum ether melts at 104 - 110 ° C; 2-bromo-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] thiazepine, which after recrystallization from acetone / petroleum ether melts at 138-139 ° C; 2-nitro-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] oxazepine, which after recrystallization from chloroform / acetone / petroleum ether melts at 192 - 193 ° C; 2-dimethylaminosulfonyl-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] = thiazepine, which after recrystallization from acetone / petroleum = ether melts at 192 - 193 ° C; 2-Dimethylamino sulfonyl-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] = oxazepine, which after recrystallization from ether / petroleum ether melts at 149-150 ° C.
2-methylsulfonyl-11-(4-methyl-l-piperazinyl)dibenz[b,f][1,4]oxaze= pin, som efter omkrystallisation af acetone/ether/petroleumsether smelter ved 178 - 179°G; 2-trifluormetboxy-11-(4-methyl-l-piperazinyl)dibenz[b,f][1,4]oxa= zepin-dibydrociilorid-monohydrat, som efter omkrystallisation af alkohol/ether smelter ved 200 - 210°C; 7-chlor-4-(4-methyl-l-piperazinyl) th.ieno[ 2,3-b][l, 5 jbenzothiazep in, som efter omkrystallisation af ethylacetat/ethylester smelter ved 162 - 164°C; 2-trifluormethylsulfonyl-11-(4-methyl-l-piperazinyl)dibenz[b,f][l,4]= thiazepin, som efter omkrystallisation af ether/petroleumsether smelter ved 168 - 170°C; 2-ace tyl-11-(4-me thyl-l-p ip era zinyl)dib enz[b,f][l,4]oxazepin, som efter omkrystallisation af acetone/petroleumsether smelter ved 116 - 118°0; 2-trifluormethyl-11-(4-methyl-l-piperazinyl)dibenz[b,f][1,4]oxaze= pin, hvis fumarat efter omkrystallisation af acetone/petroleums= ether smelter ved 214 - 216°C; 2-trifluormethylsulfonyl-11-(4-methyl-l-piperazinyl)dibenz[b,f]= [1,4]oxazepin, som efter omkrystallisation af ether/petroleumsether smelter ved 120 - 122°C; 10 150850 2-methylsulfonyl-11-(4-e thyl-l-p ip erazinyl)dibenz[b,f][l,4]oxaze= pin, som efter omkrystallisation af acetone/petroleumsether smelter ved 190 - 191°C; 4-(4-methyl-l-piperazinyl)thieno[2,3-b][1,5]benzothiazepin, som efter omkrystallisation af absolut ethanol smelter ved 112 - 114°C; 4_(4_methyl-l-piperazinyl)-10H-thieno[3,2-c][l]benzazepin, som efter omkrystallisation af ether/petroleumsether smelter ved 145 - 147° C; 8-chlor-4-(l-piperazinyl)-10H-thieno[5j2-c][l]benzazepin, som efter omkrystallisation af acetone/vand i nærværelse af kul smelter ved 80 - 100°C; 8-chlor-4-(4-(2-acetoxyethyl)-l-piperazinyl)-10H-thieno[3,2-c]benz= azepin, som efter omkrystallisation af ether/petroleumsether smel= ter ved 185 - 189°C; 8-chlor-4-(4-methyl-l-piperazinyl)-10H-thieno[3,2-c][l]benzazepin, som efter omkrystallisation af acetone/petroleumsether smelter ved 195 - 195°C; 2-methylthio-ll-(4-methyl-l-piperazinyl)dibenz[b,f][1,4]oxazepin, som efter omkrystallisation af maleinatet smelter ved 198 - 201°C; 4-(4-tert.butyl-l-piperazinyl)-10H-thieno[ 3,2- c ] [ 1]benzazepin, som efter omkrystallisation af maleinatet smelter ved 147 - 176°C; 7-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[3,2-c][l]benzaze= pin, som efter omkrystallisation af acetone/petroleumsether smelter ved 180 - 181°C; 7-chlor-4-(4-me thyl-l-piperazinyl)-10H-thieno[3,2-c][1]benzazepin, som efter omkrystallisation af acetone smelter ved 184 - 185°C; 7-ehlor-4-(4-P-hydroxyethyl-l-piperazinyl)-10H-thieno[3j2-o][l]= benzazepin, som efter omkrystallisation af ethylacetat smelter ved 192 - 194°C; 11 150850 8-chio r-4-(4-β-hy drοxy ethyl-1-p ip era zinyl)-1OH-thi eno[3,2-c][1] = benzazepin, som efter omkrystallisation af ethylacetat smelter ved 202 - 203°C; 2-trif luormethylsulf onyl-11- [4- ( β-pentanoyloxyethyl )-l-piperazinyl]= dibenz[b,f][l,4]oxazepin, hvis oxalat smelter ved 213 - 216°C; 2-trifluormethylsulfonyl-11-(4^-hydroxyethyl-l-piperazinyl)dibenz= [b,f][l,4]oxazepin, som efter omkrystallisation af ether/petro= leumsether smelter ved 121 - 123° C; 2-trifluormethylsulfonyl-11-(1-piperazinyl)dibenz[b,f][1,4]oxazepin, som efter omkrystallisation af ether smelter ved 183 - 186°C; 2-trifluormethylsulfonyl-11-(4^-hydroxypropyl-l-piperazinyl)dibenz= [b,f][l,4]oxazepin, som efter omkrystallisation af ether/petroleums= ether smelter ved 132 - 134°C; 2-trifluormethylthio-ll-(4-^-hydroxyethyl-1-piperazinyl)dibenz= [b,f][1,4]oxazepin, som efter omkrystallisation af petroleums= ether smelter ved 121 - 123°0; 2-trifluormethylsulfonyl-11-(4^-oleyloxyethyl-l-piperazinyl)dibenz= [b,f][1,4]oxazepin (olie med E^-værdi = 0,88 under anvendelse af chloroform/cyclohexan/diethylamin (5:4:1) som løbemiddel og Dragen= dorff’s reagens til påvisning); 1.4- dimethyl-11-(4-methyl-l-piperazinyl)dibenz[b,f][1,4]oxazepin, som efter omkrystallisation af ether/petroleumsether smelter ved 143 - 144°C; 3.4- dime thyl-11-(4-methyl-l-piperazinyl)dibenz[b,f][1,4]oxazepin, som efter omkrystallisation af acetone/petroleumsether smelter ved 167 - 169°C; 2,8-dichlor-ll-(4-methyl-1-piperazinyl)dibenz[b,f][1,4]oxazepin, som efter omkrystallisation af acetone/petroleumsether smelter ved 130 - 131°Cj i2 150850 4,8-dichlor-ll-(4-methyl-l-piperazinyl)dibenz[b, f ] [l, 4] oxazepin, som efter omkrystallisation af acetone/petroleumsether smelter yed 134 - 135°C; 4-methyl-8-chlor-ll- (4-methyl-l-piperazinyl)dibenz[b ,f ] [l, 4]oxa= zepin, som efter omkrystallisation af ether/petroleumsether smelter ved 150 - 151°C; 4-methyl-7-chlor-ll-(4-methyl--l-piperazinyl)dibenz[b,f ] [l,4]oxa= zepin, som efter omkrystallisation af acetone/petroleumsether smel= ter ved 167 - 168°C; 2.4- dichlor-ll-(4-methyl-l-piperazinyl)dibenz[b,f] [1,4]oxazepin, som efter omkrystallisation af acetone/petroleumsetlier smelter ved 135 - 138°0; 2-chlor-ll-(l-piperazinyl)dibenz[b,f][1,4]oxazepin, som efter om= krystallisation af acetone/petroleumsether smelter ved 178 - 180°C.2-methylsulfonyl-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] oxaze = pin, which after recrystallization from acetone / ether / petroleum ether melts at 178 - 179 ° G; 2-trifluoromethboxy-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] oxa = zepine dibydrociiloride monohydrate, which after recrystallization from alcohol / ether melts at 200 - 210 ° C; 7-chloro-4- (4-methyl-1-piperazinyl) thieno [2,3-b] [1,5] benzothiazepine, which after recrystallization from ethyl acetate / ethyl ester melts at 162 - 164 ° C; 2-trifluoromethylsulfonyl-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] = thiazepine, which after recrystallization from ether / petroleum ether melts at 168 - 170 ° C; 2-acetyl-11- (4-methyl-1-p ip era zinyl) dib enz [b, f] [1,4] oxazepine, which after recrystallization from acetone / petroleum ether melts at 116 - 118 ° 0; 2-trifluoromethyl-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] oxaze = pin whose fumarate after recrystallization from acetone / petroleum = ether melts at 214 - 216 ° C; 2-trifluoromethylsulfonyl-11- (4-methyl-1-piperazinyl) dibenz [b, f] = [1,4] oxazepine, which after recrystallization from ether / petroleum ether melts at 120 - 122 ° C; 2-methylsulfonyl-11- (4-thyl-1-p ip erazinyl) dibenz [b, f] [1,4] oxaze = pin, which after recrystallization from acetone / petroleum ether melts at 190 - 191 ° C; 4- (4-methyl-1-piperazinyl) thieno [2,3-b] [1,5] benzothiazepine which after recrystallization from absolute ethanol melts at 112 - 114 ° C; 4_ (4-methyl-1-piperazinyl) -10H-thieno [3,2-c] [1] benzazepine, which after recrystallization from ether / petroleum ether melts at 145 - 147 ° C; 8-chloro-4- (1-piperazinyl) -10H-thieno [5,2-c] [1] benzazepine, which after recrystallization from acetone / water in the presence of coal melts at 80-100 ° C; 8-Chloro-4- (4- (2-acetoxyethyl) -1-piperazinyl) -10H-thieno [3,2-c] benz = azepine, which after recrystallization from ether / petroleum ether melts at 185 - 189 ° C ; 8-chloro-4- (4-methyl-1-piperazinyl) -10H-thieno [3,2-c] [1] benzazepine, which after recrystallization from acetone / petroleum ether melts at 195 - 195 ° C; 2-methylthio-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] oxazepine, which upon recrystallization of the maleinate melts at 198 - 201 ° C; 4- (4-tert-butyl-1-piperazinyl) -10H-thieno [3,2-c] [1] benzazepine, which upon recrystallization of the maleinate melts at 147 - 176 ° C; 7-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [3,2-c] [1] benzaze = pin, which after recrystallization from acetone / petroleum ether melts at 180 - 181 ° C; 7-chloro-4- (4-methyl-1-piperazinyl) -10H-thieno [3,2-c] [1] benzazepine, which after recrystallization from acetone melts at 184 - 185 ° C; 7-ehloro-4- (4-P-hydroxyethyl-1-piperazinyl) -10H-thieno [3,2-a] [1] = benzazepine, which after recrystallization from ethyl acetate melts at 192 - 194 ° C; 11-Chio r-4- (4-β-hydroxyethyl-1-piperazinyl) -1OH-thieno [3,2-c] [1] = benzazepine, which after recrystallization from ethyl acetate melts at 202 - 203 ° C; 2-trifluoromethylsulfonyl-11- [4- (β-pentanoyloxyethyl) -1-piperazinyl] = dibenz [b, f] [1,4] oxazepine, whose oxalate melts at 213 - 216 ° C; 2-trifluoromethylsulfonyl-11- (4'-hydroxyethyl-1-piperazinyl) dibenz = [b, f] [1,4] oxazepine, which after recrystallization from ether / petro = leum ether melts at 121 - 123 ° C; 2-trifluoromethylsulfonyl-11- (1-piperazinyl) dibenz [b, f] [1,4] oxazepine, which after recrystallization from ether melts at 183 - 186 ° C; 2-trifluoromethylsulfonyl-11- (4β-hydroxypropyl-1-piperazinyl) dibenz = [b, f] [1,4] oxazepine, which after recrystallization from ether / petroleum = ether melts at 132 - 134 ° C; 2-trifluoromethylthio-11- (4-hydroxyethyl-1-piperazinyl) dibenz = [b, f] [1,4] oxazepine, which after recrystallization from petroleum ether melts at 121 - 123 ° 0; 2-Trifluoromethylsulfonyl-11- (4β-oleyloxyethyl-1-piperazinyl) dibenz = [b, f] [1,4] oxazepine (oil with E ^ value = 0.88 using chloroform / cyclohexane / diethylamine (5 : 4: 1) as a solvent and the dragon = dorff's reagent for detection); 1,4-dimethyl-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] oxazepine, which after recrystallization from ether / petroleum ether melts at 143 - 144 ° C; 3,4-dime thyl-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] oxazepine, which after recrystallization from acetone / petroleum ether melts at 167 - 169 ° C; 2,8-dichloro-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] oxazepine, which upon recrystallization from acetone / petroleum ether melts at 130-131 ° C. dichloro-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] oxazepine, which upon recrystallization from acetone / petroleum ether melts at 134 - 135 ° C; 4-methyl-8-chloro-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] oxa = zepine, which after recrystallization from ether / petroleum ether melts at 150 - 151 ° C; 4-methyl-7-chloro-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] oxa = zepine, which after recrystallization from acetone / petroleum ether melts at 167 - 168 ° C; 2,4-dichloro-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] oxazepine, which after recrystallization from acetone / petroleum ether melts at 135 - 138 ° 0; 2-Chloro-11- (1-piperazinyl) dibenz [b, f] [1,4] oxazepine, which after crystallization of acetone / petroleum ether melts at 178 - 180 ° C.
Udgangsforbindelserne til fremstilling af 10H-thieno[3,2-c][l]= benzazepiner kan fremstilles på følgende måde: 4.5- Dihydro-lOH-thieno [ 3,2-e] [l]benzazepin-4-on.The starting compounds for the preparation of 10H-thieno [3,2-c] [1] = benzazepines can be prepared as follows: 4.5-Dihydro-10H-thieno [3,2-e] [1] benzazepin-4-one.
14,8 g 2-(2-aminoplienyl)tliienon, 23,8 g fast kaliumhydroxid og 19,6 g hydrazinhydrat opvarmes til kogning under tilbagesvaling i 180 ml diethylenglycol i 3 timer. Efter fortynding af reaktions= blandingen med isvand ekstraheres den med ether. Etherfasen vaskes tre gange med vand, tørres med natriumsulfat og inddampes. Der fås 2-(2-aminobenzyl)thiophen i form af en lysegul olie med kogepunkt 128 - 130°C/0,1 mm Hg.14.8 g of 2- (2-aminoplienyl) thienone, 23.8 g of solid potassium hydroxide and 19.6 g of hydrazine hydrate are heated to reflux in 180 ml of diethylene glycol for 3 hours. After diluting the reaction mixture with ice water, it is extracted with ether. The ether phase is washed three times with water, dried with sodium sulfate and evaporated. 2- (2-aminobenzyl) thiophene is obtained in the form of a light yellow oil, boiling point 128 - 130 ° C / 0.1 mm Hg.
lil en opløsning af 9,8 g af dette produkt i 60 ml toluen dryppes ved --30C under omrøring 46 ml 20$*s opløsning af phosgen i toluen. Derpå lades reaktionsblandingen opvarme til stuetemperatur under tilledning af en phosgenstrøm, og den opvarmes derefter i yderligere 1/2 time til kogning under tilbagesvaling. Efter afdrivning af den overskydende mængde phosgen ved hjælp af en nitrogenstrøm ind= dampes reaktionsblandingen i vakuum, og remanensen destilleres.To a solution of 9.8 g of this product in 60 ml of toluene, drop at -30 ° C with stirring 46 ml of 20 $ * solution of phosgene in toluene. Then, the reaction mixture is allowed to warm to room temperature with the addition of a phosgene stream, and then heated for an additional 1/2 hour to reflux. After evaporating the excess amount of phosgene by means of a nitrogen stream, the reaction mixture is evaporated in vacuo and the residue distilled.
w 150850w 150850
Der fås 10,8 g 2-(2-isocyanatobenzyl)thiophen med kogepunkt 108°C/0,05 mm Hg.10.8 g of 2- (2-isocyanatobenzyl) thiophene is obtained at a boiling point of 108 ° C / 0.05 mm Hg.
10,5 g 2-(2-isocyanatobenzyl)thiophen (kogepunkt 108°0/0,05 mm Hg) opvarmes til 110° C med 105 g polyphosphorsyre i 1 time under om= røring. Derefter indstilles blandingen på alkalisk reaktion ved Hjælp af koncentreret ammoniakopløsning under indre og ydre is= afkøling, og det udfældede bundfald frafiltreres. Dette vaskes med vand og krystalliseres efter tørring af acetone under behandling med kul. Der fås 4,5-dihydro-10H-thieno[3,2-c][l]benzazepin-4-on i form af korn med smeltepunkt 225 - 236°C (mellem 150 og 200°0, omdannelse til lyse nåle).10.5 g of 2- (2-isocyanatobenzyl) thiophene (boiling point 108 ° 0 / 0.05 mm Hg) are heated to 110 ° C with 105 g of polyphosphoric acid for 1 hour with stirring. Then, the mixture is adjusted to alkaline reaction by means of concentrated ammonia solution under internal and external ice cooling and the precipitated precipitate is filtered off. This is washed with water and crystallized after drying acetone under coal treatment. 4,5-dihydro-10H-thieno [3,2-c] [1] benzazepin-4-one is obtained in the form of grains having a melting point of 225 DEG-236 DEG C. (between 150 DEG and 200 DEG C., conversion to light needles) .
8-Chlor- eller 7-chlor-4,5-dihydro-10H-thieno[3,2-c][l]benzazepin= -4-on.8-Chloro- or 7-chloro-4,5-dihydro-10H-thieno [3,2-c] [1] benzazepin = -4-one.
6 g F-p--toluensulfonyl-5-chlor-( eller 4-chlor)anthranilsyre opvar= mes til kogning under tilbagesvaling med 10 ml thionylchlorid i 1 1/2 time. Efter inddampning i vakuum til tørhed omkrystalliseres remanensen af methylenchlorid/petroleumsether. Det resulterende H-p-toluensulfonyl-5-chlor-anthranilsyrechlorid smelter ved 134 -136°C, H-p-toluensulfonyl-4-chlor-anthranilsyrechlorid smelter ved 135 - 140°C.6 g of F-p - toluenesulfonyl-5-chloro (or 4-chloro) anthranilic acid are heated to reflux with 10 ml of thionyl chloride for 1 1/2 hours. After evaporation in vacuo to dryness, the residue is recrystallized from methylene chloride / petroleum ether. The resulting H-p-toluenesulfonyl-5-chloro-anthranilic acid chloride melts at 134 -136 ° C, H-p-toluenesulfonyl-4-chloro-anthranilic acid chloride melts at 135 - 140 ° C.
Til en blanding af 7 g fint pulveriseret E-p-toluensulfonyl-5-chlor (eller 4-chlor)anthranilsyrechlorid og 3,4 g th.iopb.en i 25 ml carbondisulfid dryppes langsomt en opløsning af 6 g stannichlorid i 10 ml carbondisulfid. Efter endt tilsætning omrøres blandingen i yderligere 2 timer ved stuetemperatur. Derpå fjernes opløsnings= midlet i vakuum, remanensen behandles med isvand og saltsyre og udrystes med ethylacetat. Ethylacetatekstrakten vaskes med 2H saltsyre, vand og mættet vandig kaliumhydrogencarbonatopløsning, tørres med natriumsulfat og inddampes. Inddampningsremanensen for= deles mellem ether og IH vandig natriumhydroxidopløsning. Den van= dig-alkaliske opløsning syrnes med koncentreret saltsyre, og det dannede bundfald frasuges. Sugefiltreringsremanensen vaskes med vand og omkrystalliseres af ethylacetat/petroleumsether. 2-(2-p= -Ioluensulfonamido-5-chlorphenyl)thienonen smelter ved 164 - 167°0, 2-(2-p-toluensulfonamido-4-chlorphenyl)thienonen ved 140 - 141°C.To a mixture of 7 g of finely powdered E-p-toluenesulfonyl-5-chloro (or 4-chloro) anthranilic acid chloride and 3.4 g of thiobbene in 25 ml of carbon disulfide, a solution of 6 g of stannous chloride in 10 ml of carbon disulfide is slowly dripped. After the addition is complete, the mixture is stirred for an additional 2 hours at room temperature. The solvent is then removed in vacuo, the residue treated with ice water and hydrochloric acid and shaken with ethyl acetate. The ethyl acetate extract is washed with 2H hydrochloric acid, water and saturated aqueous potassium hydrogen carbonate solution, dried over sodium sulfate and evaporated. The evaporation residue is partitioned between ether and 1H aqueous sodium hydroxide solution. The aqueous alkaline solution is acidified with concentrated hydrochloric acid and the resulting precipitate is suctioned off. The suction filtration residue is washed with water and recrystallized from ethyl acetate / petroleum ether. 2- (2-p = -oluenesulfonamido-5-chlorophenyl) thienone melts at 164 - 167 ° 0, 2- (2-p-toluenesulfonamido-4-chlorophenyl) thienone at 140-141 ° C.
** 150850 8,4 g 2-(2-p-toluensulfonamido-5-chlor (eller 4-chlor)phenyl)thienon røres med 100 ml koncentreret svovlsyre ved stuetemperatur i 4 timer. Derpå hældes reaktionsproduktet ud på is, og den resulterende blan= ding indstilles på alkalisk reaktion under afkøling med koncentre= ret vandig natriumhydroxidopløsning. Herved dannes et bundfald, som optages i ether. Etheropløsningen vaskes med vand, tørres med na= triumsulfonat og inddampes, hvorved der fås en remanens. Efter om= krystallisation af ether/petroleumsether i nærværelse af kul og aluminiumoxid smelter 2-(2-amino-5-chlorphenyl)thienon ved 97 -98°O og 2-(2-amino-4-chlorphenyl)thienon ved 66 - 72°C.** 8.4 g of 2- (2-p-toluenesulfonamido-5-chloro (or 4-chloro) phenyl) thienone are stirred with 100 ml of concentrated sulfuric acid at room temperature for 4 hours. Then, the reaction product is poured onto ice and the resulting mixture is adjusted to alkaline reaction with cooling with concentrated aqueous sodium hydroxide solution. Thereby a precipitate is formed which is absorbed in ether. The ether solution is washed with water, dried with sodium sulfonate and evaporated to give a residue. After recrystallization of ether / petroleum ether in the presence of carbon and alumina, 2- (2-amino-5-chlorophenyl) thienone melts at 97 -98 ° O and 2- (2-amino-4-chlorophenyl) thienone at 66-72 ° C.
15,5 g 2-(2-amino-5-chlor (eller 4-chlor)phenyl)thienon, 23,8 g fast kaliumhydroxid og 19,6 g hydrazinhydrat opvarmes til kogning under tilbagesvaling i 180 ml diethylenglycol i 2 timer. Efter for= tynding af reaktionsblandingen med isvand ekstraheres den med ether. Etherfasen vaskes tre gange med vand, tørres med natriumsulfat og inddampes. I form af en olie fås 2-(2-amino-5-chlorbenzyl)thie= non med kogepunkt 150 - 157°C/0,1 mm Hg og 2-(2-amino-4-chlorben= zyl)thienon med kogepunkt 137 - 140°C/0,05 mm Hg.15.5 g of 2- (2-amino-5-chloro (or 4-chloro) phenyl) thienone, 23.8 g of solid potassium hydroxide and 19.6 g of hydrazine hydrate are heated to reflux in 180 ml of diethylene glycol for 2 hours. After diluting the reaction mixture with ice water, it is extracted with ether. The ether phase is washed three times with water, dried with sodium sulfate and evaporated. In the form of an oil, 2- (2-amino-5-chlorobenzyl) thienone with boiling point 150-175 ° C / 0.1 mm Hg and 2- (2-amino-4-chlorobenzyl) thienone with boiling point are obtained. 137-140 ° C / 0.05 mm Hg.
Til en opløsning af 11 g 2-(2-amino-5-chlor (eller 4-chlor)benzyl)= thiophen i 60 ml toluen dryppes ved -3°C under omrøring 46 ml 20^’s opløsning af phosgen i toluen. Derpå lades reaktionsblan= dingen opvarme til stuetemperatur under tilledning af en phosgen= strøm, og den opvarmes derefter i yderligere 1/2 time til kogning under tilbagesvaling. Efter afdrivning af den overskydende mængde phosgen ved hjælp af en nitrogenstrøm inddampes reaktionsblandin= gen i vakuum, og remanensen destilleres. Der fås 2-(2-isocyano= -5-ehlorbenzyl)thiophen med kogepunkt 137 - 139°C/0,1 mm Hg og 2-(2-isocyanato-4-chlorbenzyl)thiophen med kogepunkt 124 - 125°0/ 0,05 mm Hg.To a solution of 11 g of 2- (2-amino-5-chloro (or 4-chloro) benzyl) = thiophene in 60 ml of toluene, drop at -3 ° C while stirring 46 ml of 20 µl of phosgene in toluene. Then, the reaction mixture is allowed to warm to room temperature with the addition of a phosgene stream, and it is then heated for an additional 1/2 hour to reflux. After evaporating the excess amount of phosgene by means of a nitrogen stream, the reaction mixture is evaporated in vacuo and the residue distilled. 2- (2-Isocyano = -5-ehlorobenzyl) thiophene with boiling point 137 - 139 ° C / 0.1 mm Hg and 2- (2-isocyanato-4-chlorobenzyl) thiophene with boiling point 124 - 125 ° 0/0 are obtained. , 05 mm Hg.
Ved ringslutning af 2-(2-isocyanato-5-chlor (eller 4-chlor)benzyl)= thiophen under anvendelse af den i forbindelse med eksempel 2 be= skrevne fremgangsmåde fås 8-chlor-4,5-dihydro-10H-thieno[3,2-c][l]= benzazepin-4-on med smeltepunkt 280 - 281°C (efter omkrystallisa= tion af dioxan/acetone) og 7-chlor-4,5-dihydro-10H-thieno[3,2-e]= [l]benzazepin-4-on med smeltepunkt 264 - 266°C (efter omkrystalli= sation af acetone).By cyclizing 2- (2-isocyanato-5-chloro (or 4-chloro) benzyl) = thiophene using the process described in Example 2, 8-chloro-4,5-dihydro-10H-thieno is obtained. [3,2-c] [1] = benzazepin-4-one, m.p. 280-281 ° C (after recrystallization from dioxane / acetone) and 7-chloro-4,5-dihydro-10H-thieno [3, 2-e] = [1] benzazepin-4-one, mp 264-26 ° C (after recrystallization from acetone).
Claims (1)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH490172 | 1972-04-04 | ||
| CH490172A CH569731A5 (en) | 1972-04-04 | 1972-04-04 | |
| CH489872 | 1972-04-04 | ||
| CH489872A CH569730A5 (en) | 1972-04-04 | 1972-04-04 |
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| Publication Number | Publication Date |
|---|---|
| DK150850B true DK150850B (en) | 1987-07-06 |
| DK150850C DK150850C (en) | 1987-11-30 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK165273A DK150850C (en) | 1972-04-04 | 1973-03-26 | PROCEDURE FOR MANUFACTURING TRICYCLIC COMPOUNDS |
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| Country | Link |
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| JP (2) | JPS4913189A (en) |
| AR (1) | AR195913A1 (en) |
| AT (1) | AT340428B (en) |
| BE (1) | BE797671A (en) |
| BG (1) | BG21221A3 (en) |
| CA (1) | CA1029372A (en) |
| CH (2) | CH569730A5 (en) |
| CS (1) | CS178125B2 (en) |
| CY (1) | CY990A (en) |
| DD (1) | DD105614A5 (en) |
| DK (1) | DK150850C (en) |
| ES (1) | ES413252A1 (en) |
| FI (1) | FI61029C (en) |
| FR (1) | FR2179071B1 (en) |
| GB (1) | GB1418363A (en) |
| HK (1) | HK11079A (en) |
| HU (1) | HU166524B (en) |
| IL (1) | IL41936A (en) |
| LU (1) | LU67351A1 (en) |
| MY (1) | MY7900116A (en) |
| NL (1) | NL175621C (en) |
| NO (1) | NO138210C (en) |
| PH (1) | PH11180A (en) |
| PL (1) | PL89178B1 (en) |
| RO (1) | RO72458A (en) |
| SE (1) | SE399890B (en) |
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| YU (1) | YU39906B (en) |
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| NL7403657A (en) * | 1973-03-23 | 1974-09-25 | ||
| JPS51135089A (en) * | 1975-05-19 | 1976-11-22 | Hitachi Zosen Corp | Under-water operation assistant ship |
| IT1207417B (en) * | 1982-03-15 | 1989-05-17 | Menarini Sas | AZEPINA-6-ONE WITH ACTIVITIES TRICYCLIC COMPOUNDS DERIVED FROM PHARMACOLOGICAL, AND PROCEDURES OF 5,6-DIHYDRO-11H-DIBENZO (B, E) RELATED MANUFACTURE |
| GB8607684D0 (en) * | 1986-03-27 | 1986-04-30 | Ici America Inc | Thiazepine compounds |
| CN101962369A (en) | 2003-12-22 | 2011-02-02 | 阿卡蒂亚药品公司 | Amino diaryl [a, d] the suberene analogue that replaces is as the purposes of muscarinic agonist and the methods of treatment of neuropsychiatric disease |
| PE20110029A1 (en) | 2008-06-20 | 2011-02-11 | Astrazeneca Ab | DIBENZOTHIAZEPINE DERIVATIVES |
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1972
- 1972-04-04 CH CH489872A patent/CH569730A5/xx not_active IP Right Cessation
- 1972-04-04 CH CH490172A patent/CH569731A5/xx not_active IP Right Cessation
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1973
- 1973-01-29 JP JP48011246A patent/JPS4913189A/ja active Pending
- 1973-03-26 DK DK165273A patent/DK150850C/en not_active IP Right Cessation
- 1973-03-27 NO NO1257/73A patent/NO138210C/en unknown
- 1973-03-27 FI FI943/73A patent/FI61029C/en active
- 1973-03-28 SE SE7304365A patent/SE399890B/en unknown
- 1973-03-29 SU SU1900401A patent/SU457220A3/en active
- 1973-03-30 NL NLAANVRAGE7304441,A patent/NL175621C/en active Search and Examination
- 1973-03-30 PH PH14474A patent/PH11180A/en unknown
- 1973-04-02 GB GB1566773A patent/GB1418363A/en not_active Expired
- 1973-04-02 CS CS2346A patent/CS178125B2/cs unknown
- 1973-04-02 ES ES413252A patent/ES413252A1/en not_active Expired
- 1973-04-02 YU YU881/73A patent/YU39906B/en unknown
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- 1973-04-02 CY CY990A patent/CY990A/en unknown
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- 1973-04-02 CA CA167,668A patent/CA1029372A/en not_active Expired
- 1973-04-03 LU LU67351A patent/LU67351A1/xx unknown
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- 1973-04-03 AT AT291173A patent/AT340428B/en not_active IP Right Cessation
- 1973-04-03 JP JP48037479A patent/JPS5142118B2/ja not_active Expired
- 1973-04-03 AR AR247360A patent/AR195913A1/en active
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- 1973-04-03 HU HUWA277A patent/HU166524B/hu unknown
- 1973-04-04 FR FR7312056A patent/FR2179071B1/fr not_active Expired
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