DK153404B - PROCEDURE FOR THE MANUFACTURE OF IMIDAZOBENZODIAZEPINES OR SALTS THEREOF - Google Patents

Description

Opfindelsen angår en hidtil ukendt fremgangsmåde til fremstilling af imidazobenzodiazepiner med den almene formel IThe invention relates to a novel process for the preparation of imidazobenzodiazepines of the general formula I

(I) hvor R^ betegner et hydrogenatom, et halogenatom, en nitrogruppe eller en trifluormethylgruppe, Rg betegner et hydrogen- eller halogenatom, og R^ og R^ sammen med det nitrogenatom, hvortil de er knyttet, betegner 4-alkylpiperazin-l-yl, 4-eycloalkylalkylpiperazin-l-yl, 4-phenylpiperazin-l-yl eller piperidino, eller deres additionssalte med uorganiske eller organiske syrer# I formlen I samt i det følgende gælder: - Mr R^ betegner et halogenatom, drejer det sig fortrinsvis om et fluor-, chlor- eller bromatom, især et chlor-atom, - Mr Rg betegner et halogenatom, drejer det sig fortrinsvis om et fluor-, chlor- eller bromatom, især et fluoreller chloratom. Mr Rg betegner et halogenatom er det desuden fortrinsvis i o-stillingen.(I) wherein R 2 represents a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group, R 8 represents a hydrogen or halogen atom, and R 2 and R 2 together with the nitrogen atom to which they are attached represent 4-alkylpiperazine-1 yl, 4-eycloalkylalkylpiperazin-1-yl, 4-phenylpiperazin-1-yl or piperidino, or their addition salts with inorganic or organic acids # In Formula I and in the following: - Mr R 2 represents a halogen atom, preferably if a fluorine, chlorine or bromine atom, especially a chlorine atom, Mr Rg represents a halogen atom, it is preferably a fluorine, chlorine or bromine atom, especially a fluorine or chlorine atom. Mr Rg represents a halogen atom, moreover, it is preferably in the o-position.

- Mr Rj og R^ sammen med det nitrogenatom, hvortil de er knyttet, betegner 4-alkylpiperazin-l-yl, drejer det sig fortrinsvis om 4-methylpiperazin-l-yl, 4-ethylpiperazin-l-yl eller 4-propylpiperazin-l-yl, især 4-methylpiperazin-l-yl.Mr R 1 and R 2 together with the nitrogen atom to which they are attached represent 4-alkylpiperazin-1-yl, preferably 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl or 4-propylpiperazine-1-yl. 1-yl, especially 4-methylpiperazin-1-yl.

- Mr R^ og R^ sammen med det nitrogenatom, hvortil de er knyttet, betegner 4-cycloalkylalkyl-piperazin-l-yl, drejer det sig fortrinsvis om cycloalkyl med 3-6 carbonatomer såsom cyclopropyl, cyclobutyl eller cyclopentyl# Blandt 4-cycloalkylalkylpiperazin-l-ylgrupperne skal især nævnes 4-cyclopropylmethylpiperazin-l-yl.Mr and R 5 together with the nitrogen atom to which they are attached represent 4-cycloalkylalkyl-piperazin-1-yl, preferably are cycloalkyl of 3-6 carbon atoms such as cyclopropyl, cyclobutyl or cyclopentyl # Among 4-cycloalkylalkylpiperazine The 1-yl groups should in particular be mentioned 4-cyclopropylmethylpiperazin-1-yl.

Additionssaltene med uorganiske eller organiske syrer kan f.eks# være de salte, som dannes med saltsyre, hy-drogenbromidsyre, hydrogeniodidsyre, salpetersyre, svovlsyre, phosphorsyre, propionsyre, eddikesyre, myresyre, benzoesyre, maleinsyre, fumarsyre, ravsyre, vinsyre, citronsyre, oxalsyre, glyoxylsyre, asparaginsyre og alkansulfonsyrer såsom methansulfonsyre og aryIsulfonsyrer såsom benzensulfonsyre.The addition salts with inorganic or organic acids may be, for example, the salts formed with hydrochloric acid, hydrobromic acid, hydrogen iodide acid, nitric acid, sulfuric acid, phosphoric acid, propionic acid, acetic acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid oxalic acid, glyoxylic acid, aspartic acid and alkanesulfonic acids such as methanesulfonic acid and arylsulfonic acids such as benzenesulfonic acid.

Forbindelserne med den almene formel I og deres salte samt en fremgangsmåde til fremstilling af disse er beskrevet i Qansk fremlæggelsesskrift nr. 141 250. So.n det fremgår af dette skrift, har forbindelserne med den almene formel I interessante sedative, hypnotiske, angstdæmpende, beroligende, krampedæmpende og muskelafslappende egenskaber.The compounds of general formula I and their salts as well as a process for their preparation are described in Qansk Publication No. 141 250. As can be seen from this specification, the compounds of general formula I have interesting sedative, hypnotic, anxiety-reducing, sedative antispasmodic and muscle relaxant properties.

Ben hidtil ukendte fremgangsmåde ifølge opfindelsen muliggør fremstillingen af forbindelserne med formlen I med gode udbytter i et mindre antal trin end i de fremgangsmåder, som er beskrevet i det nævnte danske fremlæggal sesskrift.Bone novel processes according to the invention enable the preparation of the compounds of formula I to be obtained in good yields in a smaller number of steps than in the methods described in said Danish disclosure.

Formålet med den foreliggende opfindelse er således at anvise en hidtil ukendt fremgangsmåde til fremstilling af forbindelserne med den almene formel I samt deres additionssalte med uorganiske eller organiske syrer, og denne fremgangsmåde er ejendommelig ved, at man omsætter en forbindelse med formlen IIThus, the object of the present invention is to provide a novel process for the preparation of the compounds of general formula I and their addition salts with inorganic or organic acids, and this process is characterized by reacting a compound of formula II

(II)(II)

hvor R^ °S ¾ kar sam®e betydning som ovenfor, med en amin med formlen IIIwherein R ^ ° S¾ has the same meaning as above, with an amine of formula III

%%

(Ill) hvor ale betegner en alkylgruppe med 1-3 carbonatomer, og og R^ har samme betydning som ovenfor, i et organisk opløsningsmiddel til opnåelse af den ønskede forbindelse med formlen I, som man om ønsket kan omdanne til salt.(III) wherein ale represents an alkyl group of 1-3 carbon atoms, and and R 1 has the same meaning as above, in an organic solvent to give the desired compound of formula I which can be converted into salt if desired.

Under foretrukne betingelser for udførelse af fremgangsmåden ifølge opfindelsen udføres omsætningen af forbindelsen med formlen II med forbindelsen med formlen III i et organisk opløsningsmiddel såsom methylenchlorid og i nærværelse af en amin såsom triethylamin.Under preferred conditions for carrying out the process of the invention, the reaction of the compound of formula II with the compound of formula III is carried out in an organic solvent such as methylene chloride and in the presence of an amine such as triethylamine.

Add i ti ons s alt ene- med- syre- af forbindelserne- med- formlen I kah fremstilles, idet man omsætter disse forbindelser med formlen I med en støkiometrisk mængde af en uorganisk eller organisk syre. Reaktionen udføres fortrinsvis i et organisk opløsningsmiddel eller en blanding af organiske opløsningsmidler såsom alkoholer, f.eks. methanol eller ethanol, eller alkylhalogenider som f.eks. methylenchlorid.In ten weeks, all of the one-acid acid of the compounds of formula I kah is prepared, reacting these compounds of formula I with a stoichiometric amount of an inorganic or organic acid. The reaction is preferably carried out in an organic solvent or a mixture of organic solvents such as alcohols, e.g. methanol or ethanol, or alkyl halides such as e.g. methylene chloride.

Som angivet i dansk fremlæggslsesskrift nr. 141.250 kan forbindelserne med formlen II fremstilles ud fra en forbindelse med formlen IVAs stated in Danish Patent Specification No. 141,250, the compounds of formula II can be prepared from a compound of formula IV

(IV)(IV)

hvor Rj og Rg har samme betydning som ovenfor, ved omsætning med glycin til opnåelse af en forbindelse med formlen Vwherein Rj and Rg have the same meaning as above, by reacting with glycine to give a compound of formula V

(v) hvor og Eg har samme betydning som ovenfor, som man de-hydratiserer til opnåelse af forbindelsen med formlen II.(v) where and Eg have the same meaning as above which is dehydrated to give the compound of formula II.

Dehydratiseringen kan med fordel udføres ved h^ælp af et carbodiimid såsom dicyclohexylcarbodiimid.The dehydration can advantageously be carried out by the aid of a carbodiimide such as dicyclohexylcarbodiimide.

Forbindelserne med formlen III kan, når de ikke er kendte, fremstilles ved omsætning af en forbindelse med formlen VIThe compounds of formula III, when not known, can be prepared by reacting a compound of formula VI

(VI) hvor E^ og E^ har samme betydning som ovenfor med en alkyl« ketal af dimethylformamid. It eksempel på en sådan præparation er anført nedenfor i den eksperimentelle del.(VI) wherein E ^ and E ^ have the same meaning as above with an alkyl «ketal of dimethylformamide. The example of such a preparation is given below in the experimental section.

Nedenstående eksempel illustrerer fremgangsmåden ifølge opfindelsen.The following example illustrates the method of the invention.

Eksempel.Example.

8-nitro-1.2-dihydro-2-(N-methylpiperazin-l-yl)-methylen-6--(o-ohlorphenyl)-lH.4H-imidazo/l«2-a7 /1.4/benzodiazepin-l-on. Trin A: 2-oarboxymethylamino-7-nitro-5-(o«chlorphenyl)-3H-/1,4 _7benzodiazepin.8-Nitro-1,2-dihydro-2- (N-methylpiperazin-1-yl) -methylene-6- (o-o-chlorophenyl) -1H.4H-imidazo [1,2-a7] 1,4-benzodiazepin-1-one . Step A: 2-oreboxymethylamino-7-nitro-5- (o-chlorophenyl) -3H- / 1,4-benzodiazepine.

I 3 liter afmineraliseret vand indfører man 1,360 kg glycin og derefter gradvis 1,450 kg natriumbiearbonat. Man omrører 30 minutter ved stuetemperatur og indfører 15 liter ethanol og derefter i løbet af ca. 5 minutter 3 kg 7-nitro--l,3-dihydro-5-(o-chlorphenyl)-2H-/i,4/benzodiazepin-2-thion.Into 3 liters of demineralized water are introduced 1,360 kg of glycine and then gradually 1,450 kg of sodium biorbonate. The mixture is stirred for 30 minutes at room temperature and 15 liters of ethanol are introduced, and then for approx. 5 minutes 3 kg of 7-nitro-1,3-dihydro-5- (o-chlorophenyl) -2H- [1,4] benzodiazepine-2-thione.

Man opvarmer til tilbagesvaling i 1 time 30 minutter, destillerer under formindsket tryk og tilsætter 15 liter af-mineraliseret vand ad to gange og derpå 7,5 liter methylen-chlorid, hvorpå man skiller faserne. Man genekstraherer den vandige fase med tre gange 6 liter methylenchlorid, vasker derpå methylenchloridfaserne med vand og forener alle vandige faser. Man tilsætter 18 liter methylenchlorid og ved 0-5°C 1,3 liter 22° Bé saltsyre. Man får en methylenchloridopløsning af 2-carboxymethylamino-7-nitro-5-(o-chlorphenyl)-3H--/Ij-^/benzodiazepin, som man umiddelbart benytter i det følgende trin.It is heated to reflux for 1 hour 30 minutes, distilled under reduced pressure, and 15 liters of de-mineralized water are added twice and then 7.5 liters of methylene chloride, after which the phases are separated. The aqueous phase is reextracted with three times 6 liters of methylene chloride, then the methylene chloride phases are washed with water and all aqueous phases are combined. 18 liters of methylene chloride and 1.3 liters of 22 ° B hydrochloric acid are added at 0-5 ° C. There is obtained a methylene chloride solution of 2-carboxymethylamino-7-nitro-5- (o-chlorophenyl) -3 H

Trin B: 8-nitro-1.2-dih.vdro-6-(o-ohlorphen.vl)-lH.4H-imidazo-/l,2-a//i,4/benzodiazepin-l-on.Step B: 8-Nitro-1,2-dihydro-6- (o-o-chlorophenyl) -1H.4H-imidazo- [1,2-a] [1,4] benzodiazepin-1-one.

Til den ovenfor fremstillede methylenchloridopløs-ning af 2-carboxymethylamino-7-nitro-5-(o~ehlorphenyl)-3H-/1,4/benzodiazepin sætter man ved 5°C i løbet af oa. 2 minutter en opløsning af 1,865 kg dicyclohexylcarbodiimid i 3 liter methylenchlorid, hvorpå man omrører i 30 minutter.To the above-prepared methylene chloride solution of 2-carboxymethylamino-7-nitro-5- (o-ehlorophenyl) -3H- / 1,4 / benzodiazepine is added at 5 ° C during, inter alia. For 2 minutes, a solution of 1.865 kg of dicyclohexylcarbodiimide in 3 liters of methylene chloride was stirred for 30 minutes.

Man lader henstå natten over, hvorpå man suger fra.You leave to stand overnight and then suck.

Man vasker to gange med 3 liter methylenchlorid og får methy-lenchloridopløsningen af 8-nitro-l,2-dihydro-6-(o-chlorphe-nyl)-lH,4H-imidazo/l,2-a//I,4/benzodiazepini-l-on, som man umiddelbart benytter i det næste trin.Wash twice with 3 liters of methylene chloride and give the methylene chloride solution of 8-nitro-1,2-dihydro-6- (o-chlorophenyl) -1H, 4H-imidazo / 1,2-a // I, 4 / benzodiazepini-l-on, which is used immediately in the next step.

Trin Qg. 8-nitro-l,2-dih.ydro-2-(H-methylpiperazin-l-yl)-meth.y°· len-6-(o-ohlorph eny1)-IH,4H-imid azo fl,2-a7/1,4/-benzodiazepin-l-on.Step Qg. 8-nitro-1,2-dihydro-2- (H-methylpiperazin-1-yl) -methylene-6- (o-chlorophenyl) -1H, 4H-imidazo [1,2-a] ? 7 / 1,4 / -benzodiazepine-l-one.

Til methylenchloridopløsningen af 8-nitro-l,2-dihydro--6-(o-chlorpheny1)-lH,4H-imid az o/l,2-a//l, 4/benzod iazepin--1-on fremstillet ovenfor sætter man i løbet af ca. 5 minutter og ved stuetemperatur 650 g triethylamin og derpå 2,4 kg af en opløsning af dimethylketal af N-formyl-H-methylpipera-zin, hvis fremstilling er angivet nedenfor.For the methylene chloride solution of 8-nitro-1,2-dihydro-6- (o-chlorophenyl) -1H, 4H-imidazole, 1,2-a // 1,4-benzodiazepine-1-one prepared above you put in about 5 minutes and at room temperature 650 g of triethylamine and then 2.4 kg of a solution of dimethyl ketal of N-formyl-H-methylpiperazine, the preparation of which is given below.

Man omrører 1 time 30 minutter, inddamper til tørhed under formindsket tryk og tilsætter 6 liter ethanol. Man de-stillerer, idet man holder niveauet konstant ved tilsætning af ethanol indtil opnåelsen af dampe ved 78°C, hvorpå man af= køler til 0-2°C, omrører i 2 timer og suger fra. Man vasker med ethanol og får 4,260 kg råprodukt, som man renser ved be= handling med aktivkul og derefter med ethanol. Der fås endelig 3,362 kg 8-nitro-l,2-dihydro-2-(IT-methylpiperazin-l-yl)« -me thy len-6 - (o-ch lo r ph eny 1) -IH, 4H-imi d az o/l, 2 -a//i, 4/benz o -diazepin-l-on.Stir for 1 hour 30 minutes, evaporate to dryness under reduced pressure and add 6 liters of ethanol. Distill, keeping the level constant by adding ethanol until the vapors are obtained at 78 ° C, then cooling to 0-2 ° C, stirring for 2 hours and suctioning. Wash with ethanol and give 4,260 kg of crude product, which is purified by treatment with activated charcoal and then with ethanol. Finally, 3,362 kg of 8-nitro-1,2-dihydro-2- (IT-methylpiperazin-1-yl) -methyl-6 - (o -chloro-phenyl-1) -IH, 4H-imi is obtained. d az o / l, 2 -a // i, 4 / benz o -diazepin-l-one.

Forbindelsen er identisk med den, som er beskrevet i eksempel 28 i ovennævnte danske fremlæggelsesskrift, udbytte 79,8%.The compound is identical to that described in Example 28 of the above Danish presentation, yield 79.8%.

Opløsningen af dimethylketal af H-formyl-N-methyl-piperazin kan fremstilles som følger: I 2 kg dimethylketal af dimethylfomnamid indfører man 3,3 kg N-methylpiperazin, og man opvarmer til tilbagesva-ling i 15 timer. Man afdestillerer uomsat U-methylpiperazin under formindsket tryk, omrører 1 time under formindsket tryk ved 115-120°C og afkøler derpå til 20°C. Der fås 3,920 kg af en brun opløsning af dimethylketal af U-formyl-U-methylpipe-razin.The solution of dimethylketal of H-formyl-N-methyl-piperazine can be prepared as follows: In 2 kg of dimethylketal of dimethyl fomnamide 3.3 kg of N-methylpiperazine is introduced and heated to reflux for 15 hours. Unreacted U-methylpiperazine is distilled off under reduced pressure, stirred for 1 hour under reduced pressure at 115-120 ° C and then cooled to 20 ° C. 3,920 kg of a brown solution of U-formyl-U-methylpiperazine dimethyl ketal is obtained.

Claims (2)

1, Fremgangsmåde til fremstilling af imidazobenzo-diazepiner med den almene formel I1, A process for the preparation of imidazobenzo-diazepines of the general formula I (I) hvor R^ betegner hydrogen, halogen, nitro eller trifluorme-thyl, R2 betegner hydrogen eller halogen, og R^ og R^ sammen med det nitrogenatom, hvortil de er knyttet, betegner 4-al~ kylpiperazin-l-yl, 4-cycloalkylalkylpiperazin-l-yl, 4-phenyI-piperazin-l-yl eller piperidino, eller deres additionssalte med uorganiske eller organiske syrer, kendetegnet ved, at man omsætter en forbindelse med formlen II(I) wherein R 2 represents hydrogen, halogen, nitro or trifluoromethyl, R 2 represents hydrogen or halogen, and R 2 and R 2 together with the nitrogen atom to which they are attached represent 4-alkylpiperazin-1-yl, 4-cycloalkylalkylpiperazin-1-yl, 4-phenyl-piperazin-1-yl or piperidino, or their addition salts with inorganic or organic acids, characterized by reacting a compound of formula II (II) hvor R^ og Rg har samme betydning som ovenfor, med en amin med formlen(II) wherein R 1 and R 9 have the same meaning as above, with an amine of the formula hvor alc betegner en alkylgruppe med 1-3 carbonatomer, og R^ og R^ har samme betydning som ovenfor, i et organisk (III) opløsningsmiddel til opnåelse af den ønskede forbindelse med formlen I, som man om ønsket kan omdanne til salt.wherein alc represents an alkyl group of 1-3 carbon atoms and R 1 and R 2 have the same meaning as above, in an organic (III) solvent to give the desired compound of formula I, which can be converted into salt if desired. 2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at omsætningen af forbindelsen med formlen II med forbindelsen med formlen III udføres i methylenchlorid og i nærværelse af en amin såsom triethylamin.Process according to claim 1, characterized in that the reaction of the compound of formula II with the compound of formula III is carried out in methylene chloride and in the presence of an amine such as triethylamine.