NO760240L

NO760240L -

Info

Publication number: NO760240L
Application number: NO760240A
Authority: NO
Inventors: K-H Weber; A Bauer; A Langbein
Original assignee: Boehringer Sohn Ingelheim
Priority date: 1975-01-27
Filing date: 1976-01-26
Publication date: 1976-07-28
Also published as: DK29276A; DE2503235A1; CA1058173A; ES444612A1; SE7600847L; JPS51100096A; FI753638A; LU74028A1

Description

Denne oppfinnelse angår en ny fremgangsmåte for fremstilling av 8-brom-tieno-triazolo-l,4-diazepiner med den generelle formel This invention relates to a new process for the production of 8-bromo-thieno-triazolo-1,4-diazepines with the general formula

hvor where

R betyr hydrogen, en lavere alkyl-, alkoksy-, hydroksymetyl-, R means hydrogen, a lower alkyl, alkoxy, hydroxymethyl,

alkylmerkapto- eller cykloalkylgruppe, et halogenatom eller en oksygen-, svovel- eller nitrogenholdig heterocyklisk ring , og alkyl mercapto or cycloalkyl group, a halogen atom or an oxygen, sulfur or nitrogen containing heterocyclic ring, and

R2betyr hydrogen, fluor, klor eller brom, en trifluormetyl-eller en nitrogruppe., R2 denotes hydrogen, fluorine, chlorine or bromine, a trifluoromethyl or a nitro group.,

Fremgangsmåten går ut fra forbindelser med den generelle formel The procedure is based on compounds with the general formula

hvor where

og R^har de ovenfor angitte betydninger, og Kt betyr et sølv-eller thallium-kation. Forbindelsene med den generelle formel II oppløses i inerte , aprotiske oppløsningsmidler, så som særlig karbontetraklorid, tetrakloretylen eller et halogenbenzen, og omsettes ved temperaturer fra 10°C til oppløsningsmidlets kokepunkt, fortrinnsvis i området fra 20 - 60°C , med elementært brom (B^) . and R^ have the meanings given above, and Kt means a silver or thallium cation. The compounds with the general formula II are dissolved in inert, aprotic solvents, such as in particular carbon tetrachloride, tetrachloroethylene or a halobenzene, and are reacted at temperatures from 10°C to the boiling point of the solvent, preferably in the range from 20 - 60°C, with elemental bromine (B ^) .

I henhold til en foretrukket utførelsesform av oppfin-nelsen innføres det godt tørrede sølvsalt med den generelle formel II i en karbontetraklorid-oppløsning som på forhånd er tilsatt brom, hvilket hensiktsmessig skjer porsjonsvis. According to a preferred embodiment of the invention, the well-dried silver salt of the general formula II is introduced into a carbon tetrachloride solution to which bromine has previously been added, which conveniently happens in portions.

Den nye fremgangsmåte representerer en bekvem og billig metode til fremstilling av forbindelsene med den generelle formel I som har verdifulle fysiologiske virkninger og kan anvendes som minor-beroligende middel. The new method represents a convenient and inexpensive method for the preparation of the compounds of the general formula I which have valuable physiological effects and can be used as minor sedatives.

De karboksylsyrer som ligger til grunn for saltene med den generelle formel II, og esterne derav, fra hvilke karboksylsyrene kan fremstilles ved forsepning, er nye. Også saltene med den generelle formel II og saltene av de karboksylsyrer som ligger til grunn for disse, med andre kationer, er tidligere ikke kjent. Disse forbindelser kan imidlertid fremstilles på i og for seg kjent måte efter følgende skjema, hvor R^og R_ har den ovenfor angitte betydning og R' betyr lavere alkyl: The carboxylic acids which form the basis of the salts of the general formula II, and the esters thereof, from which the carboxylic acids can be prepared by saponification, are new. Also the salts of the general formula II and the salts of the carboxylic acids which form the basis of these, with other cations, were not previously known. However, these compounds can be prepared in a manner known per se according to the following scheme, where R^ and R_ have the above-mentioned meaning and R' means lower alkyl:

Fremstilling av metallsaltene med den generelle formel II og andre salter av karboksylsyrene VII foretas likeledes på Preparation of the metal salts with the general formula II and other salts of the carboxylic acids VII is likewise carried out on

i og for seg kjent måte ved nøytralisering med alkali eller dobbelt omsetning med uorganiske salter. Utvinningen av sølvsaltene kan f.eks. skje ved omsetning av forbindelsene med den generelle formel VII med sølvnitrat, thalliumsaltene ved omsetning med thalliummetylat. in a manner known per se by neutralization with alkali or double reaction with inorganic salts. The extraction of the silver salts can e.g. take place by reaction of the compounds of the general formula VII with silver nitrate, the thallium salts by reaction with thallium methylate.

De forbindelser med den generelle formel III som i henhold til det foranstående skjema benyttes som utgangsmaterialer, kan på sin side , i den utstrekning det ikke er kjent, fremstilles i henhold til metoden beskrevet av 0. Hromatka et al. i Monats-hefte fur Chemie, bind 104, s. 973-978 (1973), hvor det for innfø-ring av resten R^istedenfor usubstituerte må anvendes tilsvarende substituerte cyanoacetofenoner. The compounds with the general formula III which according to the preceding scheme are used as starting materials can, on the other hand, to the extent that it is not known, be prepared according to the method described by 0. Hromatka et al. in Monats-hefte fur Chemie, volume 104, pp. 973-978 (1973), where, for the introduction of the residue R, correspondingly substituted cyanoacetophenones must be used instead of unsubstituted ones.

De følgende eksempler skal tjene til å illustrere, opp-finnelsen, ytterligere. The following examples shall serve to further illustrate the invention.

Eksempel 1 Example 1

8-brom-6-o-klorfenyl-l.-metyl-4H-s-triazolo-[3,4-c]-tieno-[2,3e]-1,4-diazepin 10 g (=0,03mol) 6-(o-klorfenyl)-l-metyl-4H-s-triazolo-[3,4c]-tieno-[2,3e]-1,4-diazepin-8-karboksylsyre, (smp. 302°C; etylester smp. 232°c) oppløses i en kalilut fremstilt av 1,85 g etskali og 85 ml vann, og tilsettes 4,8 g sølvnitrat i 50 ml vann. Det utskilte gråe sølvsalt avsuges efter en halv times henstand, vaskes godt og tørres i flere timer ved 100 - 110°C. Utbyttet er 10 - 11 g. 8-bromo-6-o-chlorophenyl-1.-methyl-4H-s-triazolo-[3,4-c]-thieno-[2,3e]-1,4-diazepine 10 g (=0.03 mol) 6-(o-chlorophenyl)-1-methyl-4H-s-triazolo-[3,4c]-thieno-[2,3e]-1,4-diazepine-8-carboxylic acid, (m.p. 302°C; ethyl ester m.p. 232°c) is dissolved in a potash prepared from 1.85 g of caustic soda and 85 ml of water, and 4.8 g of silver nitrate in 50 ml of water is added. The secreted gray silver salt is suctioned off after half an hour's rest, washed well and dried for several hours at 100 - 110°C. The yield is 10 - 11 g.

Inn i en oppløsning av 4 g brom i 300 ml karbontetraklorid innfører man ved 30°C i løpet av 1 time under kraftig omrøring det ovennevnte sølvsalt (finpulverisert) porsjonsvis og omrører derefter i 4 timer ved 70 - 75°C. Reaksjonsblandingen avsuges, Into a solution of 4 g of bromine in 300 ml of carbon tetrachloride, the above-mentioned silver salt (finely powdered) is introduced in portions at 30°C during 1 hour with vigorous stirring and then stirred for 4 hours at 70 - 75°C. The reaction mixture is suctioned off,

og residuet uttrekkes med metylenklorid. De organiske faser vaskes med 10 prosentig ammoniakk og derefter med vann. and the residue is extracted with methylene chloride. The organic phases are washed with 10 percent ammonia and then with water.

Efter kolonnekromatografi får man 500 - 700 mg av tittel-forbindelsen med smp. 209 - 210°C. After column chromatography, 500 - 700 mg of the title compound with m.p. 209 - 210°C.

I overensstemmelse med det foranstående eksempel ble ytterligere følgende forbindelser fremstilt: In accordance with the preceding example, the following further compounds were prepared:

Claims

1. Procedure for the preparation of compounds of the general formula

where R1 means hydrogen, a lower alkyl, alkoxy, hydroxymethyl, alkyl mercapto or cycloalkyl group, a halogen atom or an oxygen, sulfur or nitrogen containing heterocyclic ring, and R2 means hydrogen, fluorine, chlorine or bromine, a trifluoromethyl- or a nitro group, characterized in that compounds with the general formula

where R₁ and R₂ have the meanings given above and Kt means a silver or thallium cation, treated with elemental bromine.

2. Method as stated in claim 1, characterized in that the reaction is carried out in an inert, atropic solvent.

3. Method as stated in one of claims 1 and 2, characterized in that a starting compound with the general formula II is used where K t means silver.

4. Method as stated in one of the preceding claims, characterized in that the silver salt of the general formula II is added portionwise to a solution of bromine in carbon tetrachloride.

5. Compounds for use as starting material in the method according to claim 1, characterized in that they have the general formula

where R1 and R2 have the meanings given in claim 1 and Kt means a silver or thallium cation.

6. Procedure for the preparation of compounds with the general formula VIII

where R1 and R2 have the meanings given above and R' means lower alkyl, characterized in that compounds with the general formula

where R2 has the above meaning and R' means lower alkyl in treated with phosphorus pentasulphide, the compounds obtained with the formula

where R2 and R' have the meanings given above, a) is reacted either with hydrazine and the compounds thus obtained looks with formula VI

where R2 and R' have the meanings given above, are converted with compounds of the general formula

where R^ and R' have the meanings given above, to compounds of the general formula VIII

where R1# R2 and R<1> have the meanings given above, or. b) reacted with compounds of the general formula

where R± has the meaning given above, directly to compounds of the general formula VIII.

7. Process for the preparation of compounds of the general formula IX

where and R2 have the above meanings, and salts thereof, characterized in that compounds with the general formula VIII is saponified and possibly transferred to its salts by neutralization or double reaction.