NO133714B - - Google Patents
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- NO133714B NO133714B NO4214/71A NO421471A NO133714B NO 133714 B NO133714 B NO 133714B NO 4214/71 A NO4214/71 A NO 4214/71A NO 421471 A NO421471 A NO 421471A NO 133714 B NO133714 B NO 133714B
- Authority
- NO
- Norway
- Prior art keywords
- benzodiazepine
- chloro
- diethylaminoethyl
- fluorophenyl
- dihydro
- Prior art date
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- SAADBVWGJQAEFS-UHFFFAOYSA-N flurazepam Chemical compound N=1CC(=O)N(CCN(CC)CC)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1F SAADBVWGJQAEFS-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 150000001557 benzodiazepines Chemical class 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 229920002261 Corn starch Polymers 0.000 description 4
- ZIIJJOPLRSCQNX-UHFFFAOYSA-N Flurazepam hydrochloride Chemical compound Cl.Cl.N=1CC(=O)N(CCN(CC)CC)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1F ZIIJJOPLRSCQNX-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 235000019759 Maize starch Nutrition 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 239000003929 acidic solution Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 208000019116 sleep disease Diseases 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- PUGVROXLRUQCAF-UHFFFAOYSA-N Flurazepam monohydrochloride Chemical compound Cl.N=1CC(=O)N(CCN(CC)CC)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1F PUGVROXLRUQCAF-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 210000004913 chyme Anatomy 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 208000022925 sleep disturbance Diseases 0.000 description 1
- 230000008454 sleep-wake cycle Effects 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000012485 toluene extract Substances 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Forbindelsen 7-klor-l-(2-dietylaminoetyl)-5- (2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on har ifolge sine fremragende terapeutiske egenskaper oppnådd en ledende posisjon ved be-handling av alle slags søvnforstyrrelser, og da spesielt slike som innebærer forstyrrelser ved innsovning, hyppig oppvåkning om natten eller for tidlig oppvåkning om morgenen. Dessuten egner forbindelsen seg for regulering av den forstyrrede sove-oppvåknings-rytmen, og for fjerning av sovn-forstyrrelser, hvilke oppkommer som folge av kroniske sykdommer. The compound 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one has achieved a leading position in be - action of all kinds of sleep disorders, and especially those that involve disturbances when falling asleep, frequent awakenings at night or waking too early in the morning. Furthermore, the compound is suitable for regulating the disturbed sleep-wake rhythm, and for removing sleep disturbances, which arise as a result of chronic diseases.
Forbindelsen ble tidligere anvendt som dihydroklorid til tross The compound was previously used as the dihydrochloride despite
for at dette dihydroklorid ved bearbeidelse til tilfredsstillende. so that this dihydrochloride by processing to satisfactory.
og stabile legemidler har bydd på store vanskeligheter. Således er dihydrokloridet f.eks. meget sterkt fuktighetsomtålig og gir sterke sure losninger. Det er derfor bare egnet for fremstilling av kapsler, og selv i denne farmasøytiske anven-delsesform kan en tilfredsstillende stabilitet bare oppnås under iakttagelse av visse arbeidstekniske grenser, såsom vannfri granulering i lokaler med mindre enn 20% relativ luft-fuktighet, anvendelse av bare meget vanskelig tilgjengelig, vannfri laktose, lagring av kapsler over silikagel o.l. and stable drugs have presented great difficulties. Thus, the dihydrochloride is e.g. very highly resistant to moisture and produces strong acidic solutions. It is therefore only suitable for the production of capsules, and even in this pharmaceutical form of use, a satisfactory stability can only be achieved by observing certain work-technical limits, such as anhydrous granulation in premises with less than 20% relative humidity, the use of only very difficult to access, anhydrous lactose, storage of capsules over silica gel, etc.
Til tross for de her beskrevne ulemper blir, som innledningsvis nevnt, utelukkende dihydrokloridet anvendt. Man var tidligere åpenbart av den oppfatning at dette dihydrokloridet var det eneste praktisk brukbare saltet av det nevnte benzodiazepinet. Despite the disadvantages described here, as mentioned at the outset, only the dihydrochloride is used. It was previously evidently of the opinion that this dihydrochloride was the only practically usable salt of the aforementioned benzodiazepine.
Innen rammen av nærværende oppfinnelse ble det nå overraskende funnet at det tilsvarende monohydrokloridet lett lar seg fremstille, og at de terapeutiske egenskapene til monohydrokloridet overensstemmer med egenskapene til dihydrokloridet. Det ble videre overraskende fastslått at monohydrokloridet ikke oppviser de ovennevnte ulempene til dihydrokloridet. Således kan monohydrokloridet bearbeides uten at man må ta spesielle forholdsregler, og det er uinnskrenket stabilt også Within the scope of the present invention, it was now surprisingly found that the corresponding monohydrochloride can be easily prepared, and that the therapeutic properties of the monohydrochloride correspond to the properties of the dihydrochloride. It was further surprisingly established that the monohydrochloride does not exhibit the above-mentioned disadvantages of the dihydrochloride. Thus, the monohydrochloride can be processed without having to take special precautions, and it is also infinitely stable
i tablettform og i torre ampuller. Monohydrokloridet har dessuten i tillegg den fordel at det gir betydelig mindre sure losninger enn det tilsvarende dihydrokloridet. in tablet form and in dry ampoules. The monohydrochloride also has the additional advantage that it produces significantly less acidic solutions than the corresponding dihydrochloride.
Nærværende oppfinnelse vedrorer således monohydrokloridet av 7-klor-l-(2-dietylaminoetyl)-5- (2-fluorfenyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-on, dvs. en forbindelse med formel, såvel som en fremgangsmåte for dets fremstilling. The present invention thus relates to the monohydrochloride of 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one, i.e. a compound of formula , as well as a method for its production.
Fremgangsmåten ifolge oppfinnelsen er karakterisert ved at man bringer 7-klor-l-(2-dietylaminoetyl)-5- (2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on til reaksjon med ikke mer enn den ekvimolare mengden klorhydrogensyre, eller at man omsetter det tilsvarende dihydrokloridet med den ekvimolare mengde base eller vann, og at man isolerer det dannede 7-klor-l-(2-dietylaminoetyl)-5- (2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiaze-pi n - 2 - on-monohy dr oki or i d. The method according to the invention is characterized by bringing 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one into reaction with more than the equimolar amount of hydrochloric acid, or that one reacts the corresponding dihydrochloride with the equimolar amount of base or water, and that one isolates the formed 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1, 3-dihydro-2H-l,4-benzodiaze-pi n - 2 - on-monohy dr oki or i d.
Omsetningen av 7-klor-l-(2-dietylaminoetyl)-5-(2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on med ikke mer enn den ekvimolare mengde klorhydrogensyre, foretas hensiktsmessig i et organisk losningsmiddel, såsom metanol, etanol, isopropanol, aceton o.l. Fortrinnsvis foretas omsetningen med alkoholholdig saltsyre, f.eks. etanolholdig saltsyre, hvorved monohydrokloridet kan utfelles ved tilsetning av eter. Ved fremstilling av storre mengder kan monohydrokloridet også fremstilles ved at man i en losning av 7-klor-l-(2-dietylaminoetyl)-5-(2-fluor-fenyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-on innleder en ekvi-molar mengde klorhydrogengass. The reaction of 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one with no more than the equimolar amount of hydrochloric acid is conveniently carried out in an organic solvent, such as methanol, ethanol, isopropanol, acetone, etc. Preferably, the reaction is carried out with alcoholic hydrochloric acid, e.g. ethanolic hydrochloric acid, whereby the monohydrochloride can be precipitated by the addition of ether. When producing large quantities, the monohydrochloride can also be prepared by adding, in a solution of 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluoro-phenyl)-1,3-dihydro-2H-1,4- benzodiazepine-2-one introduces an equimolar amount of hydrogen chloride gas.
EKSEMPEL 2 EXAMPLE 2
I et rorekar tilsettes til en blanding av 56,20 kg vann, 10,60 In a stirring vessel, add to a mixture of 56.20 kg of water, 10.60
kg 28%'ig natronlut og 60,50 kg toluen ved 25° under god omror-ing 15,54 kg (33,72 mol) 7-klor-l-(2-dietylaminoetyl)-5-(2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on-dihydroklorid i små porsjoner. Etter endt tilsetning rores reaksjonsblandingen ytterligere 30 minutter, hvorefter man overforer reaksjonsblandingen til en spiss kjele. Rorekjelen vaskes derefter med 36,5 kg toluen. Denne toluenlosningen forenes med reaksjonsblandingen. Derefter avskilles den vandige fasen, hvorefter den bringes over i den spiss-formede kjelen og hvor man ekstraherer med 48,5 kg toluen. Derefter blir begge toluen-ekstraktene vasket med to ganger 40 kg og en gang med 25 kg vann, hvorefter de forenes og overfores til en destillasjonskjele. Til slutt blir losningsmidlet avdestillert under redusert trykk ved 35 - 45°. Efter opplosning av den oljeaktige resten i 31,0 kg abs. etanol, lar man i lopet av 30 minutter 5,620 liter av en 6,O-n etanolholdig saltsyre stromme til, hvorved tem-peraturen holdes mellom 25 og 30° ved kjoling. Efter endt tilsetning omrores ytterligere 5 minutter. Derefter blir losningsmidlet avdestillert under redusert trykk ved 30 - 35°. Resten opploses ved 25° i 7,5 kg abs. etanol, tilsettes 31,5 kg eter og tilsatt krystallisasjonskimer. Efter sugefiltrering blir det krystallinske produktet vasket to ganger med hver gang 5,5 liter av en til 0° forkjolt eter/alkohol-blanding (5,3:1), kg 28% caustic soda and 60.50 kg toluene at 25° under good stirring 15.54 kg (33.72 mol) 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)- 1,3-dihydro-2H-1,4-benzodiazepine-2-one dihydrochloride in small portions. After the addition is complete, the reaction mixture is stirred for a further 30 minutes, after which the reaction mixture is transferred to a pointed kettle. The stirrer is then washed with 36.5 kg of toluene. This toluene solution is combined with the reaction mixture. The aqueous phase is then separated, after which it is transferred to the tip-shaped boiler and extracted with 48.5 kg of toluene. Both toluene extracts are then washed twice with 40 kg and once with 25 kg of water, after which they are combined and transferred to a still. Finally, the solvent is distilled off under reduced pressure at 35 - 45°. After dissolving the oily residue in 31.0 kg abs. ethanol, 5.620 liters of a 6.0-n ethanol-containing hydrochloric acid is allowed to flow over the course of 30 minutes, whereby the temperature is kept between 25 and 30° during cooling. After the addition is complete, stir for a further 5 minutes. The solvent is then distilled off under reduced pressure at 30 - 35°. The residue is dissolved at 25° in 7.5 kg abs. ethanol, 31.5 kg of ether are added and added crystallization chemical. After suction filtration, the crystalline product is washed twice with each time 5.5 liters of an ether/alcohol mixture precooled to 0° (5.3:1),
og derefter torket ved 60° under redusert trykk. Herved får man 7-klor-l-(2-dietylamirioétyl)-5-(2-fluorfenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-on-monohydroklorid, smp. 203,5°. and then dried at 60° under reduced pressure. This gives 7-chloro-1-(2-diethylamirioethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one monohydrochloride, m.p. 203.5°.
EKSEMPEL 3 EXAMPLE 3
2,3 g (5,0 mol) 7-klor-l-(2-dietylaminoetyl)-5-(2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on-dihydroklorid og 2,1 g 2.3 g (5.0 mol) 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one dihydrochloride and 2.1 g
(5,4 mmol) 7-klor-l-(2-dietylaminoetyl)-5-(2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on opploses sammen i 5 ml etanol og tilsettes 15 ml eter; Efter tilsetning av krystallkimer og henstand over natten får man 7-klor-l-(2-dietylaminoetyl)-5-(2-fluorfenyl)-1,3-dihydrb-2H-l,4-benzodiazepin-2-on-mono-hydroklorid med smp. 203°. (5.4 mmol) 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one are dissolved together in 5 ml of ethanol and 15 ml of ether are added; After addition of crystal seeds and standing overnight, 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydrob-2H-1,4-benzodiazepine-2-one-mono- hydrochloride with m.p. 203°.
EKSEMPEL 4 EXAMPLE 4
2,3 g (5,0 mmol) 7-klor-l-(2-dietylaminoetyl)-5-(2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on-dihydroklorid suspenderes i 2,5 ml etanol, tilsatt en opplosning av 0,33 g (5 mmol) kaliumhydroksyd i 2,5 ml etanol, og omrystet 30 minutter på en rystemaskin, derefter avfiltreres det utfelte kaliumkloridet, 2.3 g (5.0 mmol) of 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one dihydrochloride are suspended in 2.5 ml of ethanol, added a solution of 0.33 g (5 mmol) of potassium hydroxide in 2.5 ml of ethanol, and shaken for 30 minutes on a shaking machine, then the precipitated potassium chloride is filtered off,
og filtratet inndampes under redusert trykk til 3 ml. Efter tilsetning av 3 ml eter blir den svakt grumsete losningen fil- and the filtrate is evaporated under reduced pressure to 3 ml. After adding 3 ml of ether, the slightly cloudy solution is filtered
trert, tilsatt ytterligere 3 ml eter og derefter tilsatt krystallkimer. Man får 7-klor-l- (2-dietylaminoetyl)-5- (2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on-monohydro- triturated, added another 3 ml of ether and then added crystal chyme. 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one-monohydro-
klorid med smp. 202 - 203°. chloride with m.p. 202 - 203°.
EKSEMPEL 5 EXAMPLE 5
1 g (2,17 mmol) 7-klor-l-(2-dietylaminoetyl)-5-(2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on-dihydroklorid opploses i 20 ml vann og ekstraheres tre ganger med hver gang 25 ml metyl-enklorid. Metylenkloridekstraktene blir torket med natriumsul-fat og inndampet under redusert trykk til torrhet. Krystal- 1 g (2.17 mmol) of 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one dihydrochloride is dissolved in 20 ml of water and extracted three times with 25 ml of methylene chloride each time. The methylene chloride extracts are dried with sodium sulfate and evaporated under reduced pressure to dryness. crystal
lisasjon av resten i etanol/eter gir 7-klor-l-(2-dietylaminoetyl)-5- (2-fluorfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on-mono-hydroklorid med smp. 202 - 203°. lysis of the residue in ethanol/ether gives 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one-mono-hydrochloride with m.p. 202 - 203°.
EKSEMPEL 6 EXAMPLE 6
Man fremstiller tabletter med folgende sammensetning: Tablets are produced with the following composition:
Pr. tablett 7-klor-l-(2-dietylaminoetyl)-5-(2-fluorfenyl)-1,3-dihydro-2H-1,4-benzodi azepin-2-on-mono- Per tablet 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one-mono-
Aktivsubstansen, mannitten og en del av maisstivelsen blandes godt i et egnet blandingskar, hvorefter dette fuktes med en polyvinylpyrrolidon-losning i etanol eller et klorert hydrokarbon, granulert og torket. Derefter tilsettes talkum, magnesiumstearat og resten av maisstivelsen. Blandingen blandes og presses. The active substance, the mannitol and part of the maize starch are mixed well in a suitable mixing vessel, after which this is moistened with a polyvinylpyrrolidone solution in ethanol or a chlorinated hydrocarbon, granulated and dried. Talc, magnesium stearate and the rest of the cornstarch are then added. The mixture is mixed and pressed.
EKSEMPEL 7 EXAMPLE 7
Man fremstiller tabletter med folgende sammensetning: Tablets are produced with the following composition:
Aktivsubstansen, mannitten og en del av maisstivelsen blandes godt i et egnet blandingskar, hvorefter dette fuktes med en polyvinylpyrrolidon-losning i etanol eller et klorert hydrokarbon, granulert og torket. Derefter tilsettes talkum, magnesiumstearat og resten av maisstivelsen. Blandingen blandes og presses. The active substance, the mannitol and part of the maize starch are mixed well in a suitable mixing vessel, after which this is moistened with a polyvinylpyrrolidone solution in ethanol or a chlorinated hydrocarbon, granulated and dried. Talc, magnesium stearate and the rest of the cornstarch are then added. The mixture is mixed and pressed.
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH832571A CH553792A (en) | 1971-06-08 | 1971-06-08 | PROCESS FOR THE PREPARATION OF 7-CHLORO-1- (2-DIAETHYL-AMINOAETHYL) -5- (2-FLUOROPHENYL) -1,3-DIHYDRO-2H-1,4-BENZODIAZEPINE-2-ON-MONOHYDROCHLORIDE. |
Publications (2)
Publication Number | Publication Date |
---|---|
NO133714B true NO133714B (en) | 1976-03-08 |
NO133714C NO133714C (en) | 1976-06-16 |
Family
ID=4338591
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO4214/71A NO133714C (en) | 1971-06-08 | 1971-11-15 |
Country Status (31)
Country | Link |
---|---|
JP (1) | JPS5230568B1 (en) |
AT (1) | AT313281B (en) |
BE (1) | BE777897A (en) |
BG (1) | BG19173A3 (en) |
BR (1) | BR7108123D0 (en) |
CA (1) | CA945989A (en) |
CH (1) | CH553792A (en) |
CS (2) | CS155106B2 (en) |
CY (1) | CY868A (en) |
DD (1) | DD98679A5 (en) |
DE (1) | DE2157112C3 (en) |
DK (1) | DK127506B (en) |
ES (1) | ES397552A1 (en) |
FI (1) | FI51352C (en) |
FR (1) | FR2140371B1 (en) |
GB (1) | GB1331823A (en) |
HU (1) | HU170152B (en) |
IE (1) | IE35846B1 (en) |
IL (1) | IL38252A (en) |
KE (1) | KE2652A (en) |
LU (1) | LU65469A1 (en) |
MX (1) | MX149567A (en) |
MY (1) | MY7400115A (en) |
NL (1) | NL7116376A (en) |
NO (1) | NO133714C (en) |
PH (1) | PH13530A (en) |
PL (1) | PL81437B1 (en) |
RO (2) | RO59000A (en) |
SE (2) | SE388856B (en) |
SU (1) | SU475776A3 (en) |
ZA (1) | ZA717880B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1199304A1 (en) * | 1997-03-05 | 2002-04-24 | Takeda Chemical Industries, Ltd. | Bicyclic compounds and pharmaceutical composition containing tricyclic compound for treating or preventing sleep disorders |
-
1971
- 1971-02-01 ES ES397552A patent/ES397552A1/en not_active Expired
- 1971-06-08 CH CH832571A patent/CH553792A/en not_active IP Right Cessation
- 1971-11-15 NO NO4214/71A patent/NO133714C/no unknown
- 1971-11-15 FI FI713268A patent/FI51352C/en active
- 1971-11-16 DK DK561771AA patent/DK127506B/en not_active IP Right Cessation
- 1971-11-16 SE SE7114654A patent/SE388856B/en unknown
- 1971-11-17 DE DE2157112A patent/DE2157112C3/en not_active Expired
- 1971-11-17 HU HUHO1433A patent/HU170152B/hu unknown
- 1971-11-18 AT AT996671A patent/AT313281B/en not_active IP Right Cessation
- 1971-11-22 PL PL1971151697A patent/PL81437B1/pl unknown
- 1971-11-23 ZA ZA717880A patent/ZA717880B/en unknown
- 1971-11-23 GB GB5436871A patent/GB1331823A/en not_active Expired
- 1971-11-23 CY CY868A patent/CY868A/en unknown
- 1971-11-23 CA CA128,336A patent/CA945989A/en not_active Expired
- 1971-11-24 IE IE1489/71A patent/IE35846B1/en unknown
- 1971-11-25 BG BG019094A patent/BG19173A3/en unknown
- 1971-11-29 NL NL7116376A patent/NL7116376A/xx unknown
- 1971-11-29 IL IL38252A patent/IL38252A/en unknown
- 1971-11-29 SU SU1959119A patent/SU475776A3/en active
- 1971-12-02 JP JP46096838A patent/JPS5230568B1/ja active Pending
- 1971-12-02 RO RO68930A patent/RO59000A/ro unknown
- 1971-12-02 RO RO75458A patent/RO58965A/ro unknown
- 1971-12-04 MX MX131834A patent/MX149567A/en unknown
- 1971-12-08 BR BR8123/71A patent/BR7108123D0/en unknown
- 1971-12-09 PH PH13088A patent/PH13530A/en unknown
- 1971-12-29 DD DD159994A patent/DD98679A5/xx unknown
- 1971-12-30 CS CS752472A patent/CS155106B2/cs unknown
- 1971-12-30 CS CS913171A patent/CS155105B2/cs unknown
-
1972
- 1972-01-11 BE BE777897A patent/BE777897A/en not_active IP Right Cessation
- 1972-01-11 FR FR7200802A patent/FR2140371B1/fr not_active Expired
- 1972-06-06 LU LU65469A patent/LU65469A1/xx unknown
-
1974
- 1974-12-30 MY MY115/74A patent/MY7400115A/en unknown
-
1975
- 1975-11-20 SE SE7513088A patent/SE7513088L/en unknown
-
1976
- 1976-07-21 KE KE2652*UA patent/KE2652A/en unknown
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