NO118747B - - Google Patents

Description

Fremgangsmåte for fremstilling av benzodiazepin-derivater. Process for the production of benzodiazepine derivatives.

Nærværende oppfinnelse vedrorer en fremgangsmåte for fremstilling av 7-klor-l-(3-dimetylamino-propyl)-5-(2-fluor-fenyl )-l,3-dihydro-2H-l,4-benzodiazepin-2-on og dets syreaddisjonssalter. Denne forbindelse og dens medisinske anvendelige syreaddisjonssalter har antikonvulsive, analgetiske, sedative, muskelrelakserende, hypotensive og antidepressive egenskaper. The present invention relates to a process for the production of 7-chloro-1-(3-dimethylamino-propyl)-5-(2-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one and its acid addition salts. This compound and its medically useful acid addition salts have anticonvulsant, analgesic, sedative, muscle relaxant, hypotensive and antidepressant properties.

Fremgangsmåten ifolge oppfinnelsen består i at man omsetter 7-klor-5-(2-fluor-fenyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-on med et 3-dimetylamino-propyl-halogenid og at man, hvis onsket, overforer det erholdte produkt til et syreaddisjonssalt. The method according to the invention consists in reacting 7-chloro-5-(2-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one with a 3-dimethylamino-propyl halide and if desired, the product obtained is converted to an acid addition salt.

Blant halogenene i reaksjonskomponenten er brom, klor og jod foretrukket. Among the halogens in the reaction component, bromine, chlorine and iodine are preferred.

Substitusjonen i 1-stilling i benzodiazepin-utgangsmaterialet fremkalles fortrinnsvis over dets 1-natrium-derivat. Om-vandlingen til dette 1-natrium-derivat kan f.eks. finne sted ved hjelp av natriummetoksyd, natriumhydrid og lignende. The substitution in the 1-position in the benzodiazepine starting material is preferentially induced over its 1-sodium derivative. The conversion to this 1-sodium derivative can e.g. take place using sodium methoxide, sodium hydride and the like.

Reaksjonen mellom benzodiazepinutgangsmaterialet og reagenset som innforer det onskede radikal i 1-stilling, som også med dimetylamin kan gjennomføres i et inert organisk opplbs-ningsmiddel under anvendelse av en eller flere opplos-ningsmiddelkomponenter, som aceton, metyl-etyl-keton, metanol, etanol, dimetylformamid, benzen, N-metyl-pyrrolidon eller lignende. Temperaturene og trykkene er ikke kritiske; reaksjonen kan utfores såvel ved værelsetemperatur og atmosfæretrykk som også ved forhbyede temperaturer og/ eller forhoyede trykk. ' The reaction between the benzodiazepine starting material and the reagent which introduces the desired radical in the 1-position, which can also be carried out with dimethylamine in an inert organic solvent using one or more solvent components, such as acetone, methyl ethyl ketone, methanol, ethanol , dimethylformamide, benzene, N-methyl-pyrrolidone or the like. The temperatures and pressures are not critical; the reaction can be carried out both at room temperature and atmospheric pressure as well as at elevated temperatures and/or elevated pressures. '

Sluttproduktet ved fremgangsmåten ifolge oppfinnelsen danner syreaddisjonssalter med uorganiske og organiske syrer, The final product of the method according to the invention forms acid addition salts with inorganic and organic acids,

som klorhydrogensyre, bromhydrogensyre, svovelsyre, fosfor-syre, salpetersyre, vinsyre, salicylsyre, toluensulfon-syre, askorbinsyre, maleinsyre, ravsyre, maursyre, eddiksyre og lignende.. such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, tartaric acid, salicylic acid, toluenesulfonic acid, ascorbic acid, maleic acid, succinic acid, formic acid, acetic acid and the like.

Fremgangsmåteproduktet kan finne anvendelse som legemiddel f.eks. i form av farmasbytiske preparater, hvilke inneholder de eller deres salter i blanding med et for den enterale, perkutane eller parenterale administrasjon egnet farmasøytisk organisk eller uorganisk inert bærematerial, som f.eks. vann, gelatin, gummi arabicum, melkesukker, stivelse, magnesium-stearat, talkum, vegetabilske oljer, polyalkylenglykoler, vaselin osv. De farmasbytiske preparatene kan foreligge i fast form, f.eks. som tabletter, dragéer, suppo!sitorier, kapsler; i halvfast form, f.eks. som salver; eller i flytende form, f.eks. som oppløsninger, suspensjoner eller emulsjoner. Eventuelt er de sterilisert og/eller inneholder hjelpestoffer, som konserverings-, stabiliserings-, fuk-tnings- eller emulgermiddel, salter til forandring av det osmotiske trykk eller puffer. De kari^også inneholde ennå andre terapeutisk verdifulle stoffer. The method product can find use as a medicine, e.g. in the form of pharmaceutical preparations, which contain them or their salts in mixture with a pharmaceutical organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral administration, such as e.g. water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragees, suppositories, capsules; in semi-solid form, e.g. which salves; or in liquid form, e.g. as solutions, suspensions or emulsions. They are optionally sterilized and/or contain auxiliary substances, such as preservatives, stabilisers, wetting or emulsifying agents, salts to change the osmotic pressure or buffers. They may also contain other therapeutically valuable substances.

EKSEMPEL EXAMPLE

En oppløsning av natriummetoksyd i metanol (101,5 ml av en oppløsning inneholdende 0,00407 mol/ml; 0,410 mol NaOCH3) tilsettes til en rbrt opplosning av 100 g (0,346 mol) 7-klor-5-(2-fluor-fenyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-on i 200 ml N,N-dimetylformamid. Man rorer reaksjonsblandingen i 30 minutter ved 10°C og tilsetter så i lbpet av 10 minutter en opplosning av 105 g (0,865 mol) y-dimetylamino-propyl-klorid i 200 ml toluen. A solution of sodium methoxide in methanol (101.5 ml of a solution containing 0.00407 mol/ml; 0.410 mol NaOCH3) is added to a rbrt solution of 100 g (0.346 mol) 7-chloro-5-(2-fluoro-phenyl) )-1,3-dihydro-2H-1,4-benzodiazepine-2-one in 200 ml of N,N-dimethylformamide. The reaction mixture is stirred for 30 minutes at 10°C and then a solution of 105 g (0.865 mol) of γ-dimethylaminopropyl chloride in 200 ml of toluene is added over the course of 10 minutes.

Reaksjonsblandingen rbres og oppvarmes til 70°C og holdes The reaction mixture is stirred and heated to 70°C and held

3 1/2 time ved 70 - 75°C. Man fjerner så opplbsnings-midlet under forminsket trykk og fordeler resten mellom 400 ml eter og 400 ml vann. Skiktene skilles og det vandige skikt ekstraheres med 200 ml eter. De forente eterskikt settes til 400 ml vann. Under rystning tilsetter man 3-n saltsyre inntil pH-verdien er nådd 5. Deretter skilles skiktene og det vandige skikt vaskes to ganger, hver gang med 100 ml eter. De forente eterskikt vaskes med fortynnet ammoniakk og vann, torkes over natriumsulfat, filtreres og konsentreres. 3 1/2 hours at 70 - 75°C. The solvent is then removed under reduced pressure and the residue distributed between 400 ml of ether and 400 ml of water. The layers are separated and the aqueous layer is extracted with 200 ml of ether. The combined ether layers are added to 400 ml of water. While shaking, 3-n hydrochloric acid is added until the pH value is reached 5. The layers are then separated and the aqueous layer is washed twice, each time with 100 ml of ether. The combined ether layers are washed with dilute ammonia and water, dried over sodium sulfate, filtered and concentrated.

Det sure vandige skikt innstilles basisk med en 20%'ig natriumkarbonatopplbsning og ekstraheres to ganger, hver gang med 200 ml eter. De forente eterskikt vaskes med vann og mettet koksaltopplbsning og torkes over vannfritt natriumsulfat. Man sf Utrerer og konsentrerer til en olje. Denne oppløses i 150 ml etanol. Man leder i lbpet av ca. 15 minutter klorhydrogen gjennom oppløsningen og krystalliserer deretter reaksjonsproduktet ved tilsetning av 500 ml eter bg 1 times avkjøling. Man filtrerer og omkrystalliserer ved The acidic aqueous layer is made basic with a 20% sodium carbonate solution and extracted twice, each time with 200 ml of ether. The combined ether layers are washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. Man sf Extracts and concentrates into an oil. This is dissolved in 150 ml of ethanol. One leads in the pound of approx. 15 minutes hydrogen chloride through the solution and then crystallizes the reaction product by adding 500 ml of ether bg 1 hour of cooling. You filter and recrystallize wood

Claims (1)

Fremgangsmåte ifolge norsk patent nr. 109.984 for fremstilling av 7-klor-l-(3-dimetylamino-propyl)-5-(2-fluor-fenyl)-1,3- dihydro-2H-l,4-benzodiazepin-2-on og dets syreaddisjonssalter,karakterisert ved at man omsetter 7-klor-5-(2-fluor-fenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on med et dimetylamino-propyl-halogenid og, hvis bnsket, overforer en erholdt forbindelse til et syreaddisjonssalt. opplosning i 100 ml metanol, tilsetning av 500 ml eter og avkjdling. Etter tre omkrystallisasjoner danner 7-klor-l-(3-dimetylamino-propyl)-5-(2-fluor-fenyl)-l,3-dihydro-2H-1,4-benzodiazepin-2-on-dihydrokloridet svakt gulfargede prismer, som smelter i lukket ror under spaltning ved 200 - 213°C.Method according to Norwegian patent no. 109,984 for the production of 7-chloro-1-(3-dimethylamino-propyl)-5-(2-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2- one and its acid addition salts, characterized by reacting 7-chloro-5-(2-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one with a dimethylamino-propyl halide and, if desired, transfer a compound obtained to an acid addition salt. dissolution in 100 ml of methanol, addition of 500 ml of ether and cooling. After three recrystallizations, the 7-chloro-1-(3-dimethylamino-propyl)-5-(2-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one dihydrochloride forms slightly yellow prisms , which melts in a closed vessel during cleavage at 200 - 213°C.