NO137444B - PROCEDURES FOR THE PREPARATION OF BENZODIAZEPIN-2-ON DERIVATIVES - Google Patents
PROCEDURES FOR THE PREPARATION OF BENZODIAZEPIN-2-ON DERIVATIVES Download PDFInfo
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- NO137444B NO137444B NO1796/73A NO179673A NO137444B NO 137444 B NO137444 B NO 137444B NO 1796/73 A NO1796/73 A NO 1796/73A NO 179673 A NO179673 A NO 179673A NO 137444 B NO137444 B NO 137444B
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- Prior art keywords
- benzodiazepine
- methyl
- dihydro
- phenyl
- solution
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title claims description 3
- 239000012286 potassium permanganate Substances 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- -1 hydroxy, methoxy, piperidino Chemical group 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229940117975 chromium trioxide Drugs 0.000 claims description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 2
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000002026 chloroform extract Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229940049706 benzodiazepine Drugs 0.000 description 3
- 150000001557 benzodiazepines Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004042 decolorization Methods 0.000 description 3
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 description 2
- ZCDOYSPFYFSLEW-UHFFFAOYSA-N chromate(2-) Chemical compound [O-][Cr]([O-])(=O)=O ZCDOYSPFYFSLEW-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JZEDNXCLZHTJOA-UHFFFAOYSA-N 1-methyl-5-[2-(trifluoromethyl)phenyl]-3h-1,4-benzodiazepin-2-one Chemical compound N=1CC(=O)N(C)C2=CC=CC=C2C=1C1=CC=CC=C1C(F)(F)F JZEDNXCLZHTJOA-UHFFFAOYSA-N 0.000 description 1
- ZNCTZFTUAXQUHQ-UHFFFAOYSA-N 7-chloro-1-methyl-5-phenyl-2-(piperidin-1-ylmethyl)-2,3-dihydro-1,4-benzodiazepine Chemical compound C1N=C(C=2C=CC=CC=2)C2=CC(Cl)=CC=C2N(C)C1CN1CCCCC1 ZNCTZFTUAXQUHQ-UHFFFAOYSA-N 0.000 description 1
- BMFGBFFDRUAKBF-UHFFFAOYSA-N 7-chloro-2-(chloromethyl)-1-methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepine;hydrochloride Chemical compound Cl.C12=CC(Cl)=CC=C2N(C)C(CCl)CN=C1C1=CC=CC=C1 BMFGBFFDRUAKBF-UHFFFAOYSA-N 0.000 description 1
- OTSKYYCWSQZLIY-UHFFFAOYSA-N 7-chloro-2-(methoxymethyl)-1-methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepine Chemical compound C12=CC(Cl)=CC=C2N(C)C(COC)CN=C1C1=CC=CC=C1 OTSKYYCWSQZLIY-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000004707 phenolate Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001003 psychopharmacologic effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- OOESZOOEEZGPST-UHFFFAOYSA-N tuclazepam Chemical compound C12=CC(Cl)=CC=C2N(C)C(CO)CN=C1C1=CC=CC=C1Cl OOESZOOEEZGPST-UHFFFAOYSA-N 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
- C07D243/26—Preparation from compounds already containing the benzodiazepine skeleton
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Foreliggende oppfinnelse angår en ny fremgangsmåte ved The present invention relates to a new method by
fremstilling av benzodiazepin-2-oner med den generelle formel: preparation of benzodiazepine-2-ones with the general formula:
hvor R^ er hydrogen eller lavere alkyl, R^ er halogen eller nitro, R^ er hydrogen, halogen eller trifluormethy1, og Rer hydrogen eller halogen, og syreaddisjonssalter derav. where R^ is hydrogen or lower alkyl, R^ is halogen or nitro, R^ is hydrogen, halogen or trifluoromethyl, and Rer is hydrogen or halogen, and acid addition salts thereof.
Fra dansk patentskrift 120.600 er det kjent å fremstille benzodiazepin-2-oner med formel I ved at man i tilsvarende benzodiazepinderivater oxyderer den usubstituerte methylengruppe i 2-stillingen til en 2-oxogruppe med oxydasjonsmidler hvis oxyda-sjonspotensial er høyere enn 0,74 V. Utbyttene ved denne frem- From Danish patent document 120,600 it is known to prepare benzodiazepine-2-ones of formula I by oxidizing the unsubstituted methylene group in the 2-position in corresponding benzodiazepine derivatives to a 2-oxo group with oxidizing agents whose oxidation potential is higher than 0.74 V. The dividends from this advance-
gangsmåte ligger i alminnelighet mellom 10 og 25% av det teoret- gait is generally between 10 and 25% of that theory-
iske. ice.
Foreliggende fremgangsmåte er karakterisert ved at en for- The present method is characterized by the fact that a pre-
bindelse med den generelle formel: bond with the general formula:
hvor R , R , R, og R- er som ovenfor angitt, og R er halogen, where R , R , R, and R- are as indicated above, and R is halogen,
1 J H J ^ hydroxy, methoxy, piperidino eller cyano, 1 J H J ^ hydroxy, methoxy, piperidino or cyano,
eller syreaddisjonssalter derav, oxyderes med kaliumpermanganat eller kromtrioxyd i nærvær; av et inert oppløsningsmiddel, og basen, hhv. syreaddisjonssaltet, isoleres. or acid addition salts thereof, are oxidized with potassium permanganate or chromium trioxide in the presence; of an inert solvent, and the base, respectively the acid addition salt, is isolated.
Fremgangsmåteproduktene er verdifulle legemidler som kan anvendes som psykofarmakologiske midler med overveiende sedativ og psykosedativ virkning. The process products are valuable drugs that can be used as psychopharmacological agents with predominantly sedative and psychosedative effects.
De som utgangsmaterialer ved foreliggende fremgangsmåte anvendte benzodiazepinderivater II, som selv har verdifulle farmasøytiske egenskaper, kan f.eks. fremstilles fra acyldiaminer med den generelle formel: The benzodiazepine derivatives II used as starting materials in the present method, which themselves have valuable pharmaceutical properties, can e.g. are prepared from acyldiamines with the general formula:
hvor R^, R^> R^ og R^ er som ovenfor-angitt, og R er en fri eller forestret hydroxylgruppe, ved behandling med ringslut-ningsreagenser.og eventuelt påfølgende omsetning med aminer, alkoholater, fenolater, cyanider, osv., eller med Lewis-syrer som f.eks. thionylklorid, i egnede oppløsningsmidler. where R^, R^> R^ and R^ are as indicated above, and R is a free or esterified hydroxyl group, by treatment with ring-closing reagents and possibly subsequent reaction with amines, alcoholates, phenolates, cyanides, etc., or with Lewis acids such as thionyl chloride, in suitable solvents.
Benzodiazepiner med formel 11 og fremgangsmåte for fremstilling av disse er beskrevet i norske patentansøkningér nr. 1797/73, 751349 og 7615SO. Benzodiazepines with formula 11 and methods for their production are described in Norwegian patent applications no. 1797/73, 751349 and 7615SO.
Foreliggende fremgangsmåte er i flere henseende over-raskende. Man måtte regne med at ved oxydasjon av f.eks. 7~ klor-2,3-dihydro-l-methyl-2-hydroxymethyl-5-fenyl-lH-1,4-benzodiazepin med kromsyre eller kaliumpermanganat 7-klor-2,3-dihydro-l-methyl-2-carboxy-5-fenyl-lH-l,4-benzodiazepin ville dannes. Dessuten kunne man ikke uten videre forutse at sub-stituenten på N1 av benzodiazepinet bare ville angripes oxydativt i meget liten underordnet. grad. Man kunne derfor slett ikke forutse at benzodiazepin-2-oner kunne erholdes i godt utbytte ved denne fremgangsmåte. The present method is in several respects surprising. One had to reckon that by oxidation of e.g. 7~ chloro-2,3-dihydro-1-methyl-2-hydroxymethyl-5-phenyl-1H-1,4-benzodiazepine with chromic acid or potassium permanganate 7-chloro-2,3-dihydro-1-methyl-2-carboxy -5-phenyl-1H-1,4-benzodiazepine would be formed. Moreover, one could not easily foresee that the substituent at N1 of the benzodiazepine would only be attacked oxidatively to a very small extent. degree. One could therefore not at all foresee that benzodiazepine-2-ones could be obtained in good yield by this method.
Oppfinnelsen vil bli ytterligere belyst ved følgende eks-empler . The invention will be further illustrated by the following examples.
Eksempel 1 Example 1
En oppløsning av 1 g 7-fluor-2,3-dihydro-l-methyl-2-klor-methyl-5-fenyl-lH-1,4-benzodiazepin-hydroklorid i 70 ml vann og 15 ml 32%-ig saltsyre ble omsatt ved værelsetemperatur med en opp-løsning av 280 mg kaliumpermanganat i 30 ml vann. Efter avfarvning av kaliumpermanganatet ble reaksjonsoppløsningen filtrert og filtratet ekstrahert med kloroform. De forenede kloroformekstrakter ble behandlet med fortynnet natronlut, skilt fra vannfasen, tørret og inndampet i vakuum. Residuet ble krystallisert fra ether. A solution of 1 g of 7-fluoro-2,3-dihydro-1-methyl-2-chloro-methyl-5-phenyl-1H-1,4-benzodiazepine hydrochloride in 70 ml of water and 15 ml of 32% hydrochloric acid was reacted at room temperature with a solution of 280 mg of potassium permanganate in 30 ml of water. After decolourisation of the potassium permanganate, the reaction solution was filtered and the filtrate extracted with chloroform. The combined chloroform extracts were treated with dilute caustic soda, separated from the aqueous phase, dried and evaporated in vacuo. The residue was crystallized from ether.
Man fikk 7-fluor-1-methyl-5-fenyl-1,3-difrydro-2H-l,4-benzodiazepin-2-on i form av blassgule krystaller med smeltepunkt 108 - 110°C. 7-fluoro-1-methyl-5-phenyl-1,3-diphydro-2H-1,4-benzodiazepine-2-one was obtained in the form of pale yellow crystals with a melting point of 108 - 110°C.
Eksempel 2 Example 2
En oppløsning av 5 g 7-klor-2,3-dihydro-l-methyl-2-klormethyl-5-fenyl-lH-1,4-benzodiazepin-hydroklorid, som inneholdt 1 mol isopropanol, i 200 ml vann og 25 ml 32%-ig saltsyre ble ved værelsetemperatur tilsatt en oppløsning av 2,5 g kaliumpermanganat i 50 ml vann. Oppløsningen ble derpå filtrert, filtratet ekstrahert med kloroform og de forenede kloroformekstrakter ble behandlet med fortynnet natronlut. Efter fraskilling av vannfasen og tørring ble kloroformen avdestillert i vakuum og residuet krystallisert fra isopropanol. Man fikk 2 g 7-klor-l-methyl-5-fenyl-1,3-dihydro-2H-1,4~benzodiazepin-2-on med smeltepunkt 130 - 131°C. A solution of 5 g of 7-chloro-2,3-dihydro-1-methyl-2-chloromethyl-5-phenyl-1H-1,4-benzodiazepine hydrochloride, containing 1 mol of isopropanol, in 200 ml of water and 25 ml At room temperature, 32% hydrochloric acid was added to a solution of 2.5 g of potassium permanganate in 50 ml of water. The solution was then filtered, the filtrate extracted with chloroform and the combined chloroform extracts treated with dilute caustic soda. After separation of the water phase and drying, the chloroform was distilled off in vacuum and the residue crystallized from isopropanol. 2 g of 7-chloro-1-methyl-5-phenyl-1,3-dihydro-2H-1,4~benzodiazepine-2-one with melting point 130 - 131°C were obtained.
Eksempel 3 Example 3
En oppløsning av 1 g 7_klor-2,3-dihydro-1-methyl-2-hydroxy-methyl-5-fenyl-lH-1,4-benzodiazepin i.15 ml eddiksyre ble dråpevis tilsatt 3 ml kromat reagens (Djerassi et al. J. Org. Chem. 2_1, 1547 A solution of 1 g of 7-chloro-2,3-dihydro-1-methyl-2-hydroxy-methyl-5-phenyl-1H-1,4-benzodiazepine in 15 ml of acetic acid was added dropwise to 3 ml of chromate reagent (Djerassi et al . J. Org. Chem. 2_1, 1547
(1946)). Efter 30 minutter ble reaksjonsblandingen helt på is, gjort alkalisk med ammoniakk og ekstrahert med kloroform. Av det i vakuum inndampede kloroformekstrakt fikk man ved krystallisasjon f ra isopropanol 7-klor-l-methyl-5-fenyl-1,3-dihydro-2H-1,4-benzo-diazepin -2 -on med smeltepunkt 130 - 131°C. (1946)). After 30 minutes, the reaction mixture was poured onto ice, made alkaline with ammonia and extracted with chloroform. From the vacuum evaporated chloroform extract, 7-chloro-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzo-diazepin-2-one with melting point 130 - 131° was obtained by crystallization from isopropanol C.
Eksempel 4 Example 4
En oppløsning av 100 mg 7~klor-2,3-dihydro-l-methyl-2-methoxymethyl-5-fenyl-lH-1,4-benzodiazepin i 12 ml vann og 0,8 ml 32%-ig saltsyre ble dråpevis tilsatt 21 ml 0,1 N kaliumpermanganat-oppløsning. Efter avfarvning analogt med eksempel 2 fikk man 7-klor-1 -methyl-5-fenyl-1,3-dihydro-2H-1,4-;benzodiazepin-2-on med smeltepunkt 128 - 130°C. A solution of 100 mg of 7-chloro-2,3-dihydro-1-methyl-2-methoxymethyl-5-phenyl-1H-1,4-benzodiazepine in 12 ml of water and 0.8 ml of 32% hydrochloric acid was added dropwise added 21 ml of 0.1 N potassium permanganate solution. After decolorization analogously to example 2, 7-chloro-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one with melting point 128 - 130°C was obtained.
Eksempel 5 Example 5
En oppløsning av 500 mg 7-klor-l-methyl-2-piperidinomethyl-5-fenyl-2,3-dihydro-lH-l,4-benzodiazepin i 6o ml vann og 4 ml konsentrert saltsyre ble tilsatt 237 mg kaliumpermanganat i 15 ml vann. Efter opparbeidelse analogt med eksempel 2 fikk man 7-klor-l-methyl-5-fenyl-1,3-dihydro-2H-l,4-benzodiazepin-2-on, som var identisk med produktet erholdt i eksempel 2. A solution of 500 mg of 7-chloro-1-methyl-2-piperidinomethyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine in 60 ml of water and 4 ml of concentrated hydrochloric acid was added to 237 mg of potassium permanganate in 15 ml of water. After working up analogously to example 2, 7-chloro-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one was obtained, which was identical to the product obtained in example 2.
Ek sempel 6 Oak sample 6
En oppløsning av 55 g 7-brom-l-methyl-2-klormethyl-5-(2',6'-difluorfenyl)-2,3-dihydro-lH-l,4-benzodiazepin i 250 ml saltsyre, 1970 ml vann og 420 ml kloroform tilsettes ved værelsetemperatur under omrøring dråpevis en oppløsning av 24,7 g kaliumpermanganat i 485 ml vann. Efter avfarvning av kaliumpermanganatet filtreres reaksjonsoppløsningen, og filtratet ekstraheres med kloroform. De forenede kloroformekstrakter behandles med fortynnet natronlut, tørres efter fraskillelse av vannfasen, og inndampes i vakuum. Residuet krystalliseres fra aceton. Man får 16,9 g (34% av det teoretiske) 7-brom-1-methyl - 5-(2 * ,6'-difluorfenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-on med smeltepunkt 179 - 181°C A solution of 55 g of 7-bromo-1-methyl-2-chloromethyl-5-(2',6'-difluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine in 250 ml of hydrochloric acid, 1970 ml of water and 420 ml of chloroform is added dropwise at room temperature with stirring to a solution of 24.7 g of potassium permanganate in 485 ml of water. After decolorizing the potassium permanganate, the reaction solution is filtered, and the filtrate is extracted with chloroform. The combined chloroform extracts are treated with dilute caustic soda, dried after separation of the water phase, and evaporated in a vacuum. The residue is crystallized from acetone. 16.9 g (34% of the theoretical) of 7-bromo-1-methyl-5-(2*,6'-difluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one are obtained with melting point 179 - 181°C
Eksempel 7 Example 7
En oppløsning av 4,5 g 7-nitro-2-klormethyl-5-fenyl-2,3~ dihydro-lH-1,4-benzodiazepin i 45 ml iseddik tilsettes under av-kjøling 13,5 ml kromatreagens (se eksempel 3). Efter 2 timer fortynnes med vann, og råproduktet felles med konsentrert ammoniakk ved pH 8- Bunnfallet avsuges, oppløses i aceton og tilsettes en oppløsning av 1,72 g p-toluensulfonsyre i aceton. Det erholdte salt avsuges og omkrystalliseres fra ethanol. Man får 2,93 9 (46% av det teoretiske) 7-nitro-5-fenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-on som p-toluensulfonsyresaltet med smeltepunkt 240 - 244°C. A solution of 4.5 g of 7-nitro-2-chloromethyl-5-phenyl-2,3~ dihydro-1H-1,4-benzodiazepine in 45 ml of glacial acetic acid is added while cooling to 13.5 ml of chromate reagent (see example 3 ). After 2 hours, dilute with water, and the crude product is combined with concentrated ammonia at pH 8. The precipitate is suctioned off, dissolved in acetone and a solution of 1.72 g of p-toluenesulfonic acid in acetone is added. The salt obtained is suctioned off and recrystallized from ethanol. 2.93 9 (46% of the theoretical) of 7-nitro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one is obtained as the p-toluenesulfonic acid salt with melting point 240 - 244°C.
Saltet lar seg på vanlig vis kvantitativt overføre til basen med smeltepunkt 224 - 226°C. The salt can normally be quantitatively transferred to the base with a melting point of 224 - 226°C.
Eksempel 8 Example 8
Ved den i eksempel 2 beskrevne fremgangsmåte får man fra l-methyl-2-klormethyl-5-(2 *-trifluormethylfenyl)-2,3-dihydro-1H-1,4-benzodiazepin i 42,5% utbytte 1-methyl-5-(2'-trifluor-methylfenyl)-1,3-dihydro-2H-l,4-benzodiazepin-2-on med smeltepunkt 135 - 137°C. By the method described in example 2, 1-methyl-2-chloromethyl-5-(2*-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepine is obtained in 42.5% yield of 1-methyl- 5-(2'-trifluoromethylphenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one with melting point 135 - 137°C.
Eksempel 9 Example 9
En oppløsning av 20 g 7-klor-l-methyl-2-hydroxymethyl-5-(2'-klorfenyl)-2,3-dihydro-lH-l,4-benzodiazepin i 500 ml vann og 6o ml konsentrert saltsyre tilsettes ved værelsetemperatur dråpevis en oppløsning av 10 g kaliumpermanganat i 300 ml vann. A solution of 20 g of 7-chloro-1-methyl-2-hydroxymethyl-5-(2'-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine in 500 ml of water and 60 ml of concentrated hydrochloric acid is added at room temperature dropwise a solution of 10 g of potassium permanganate in 300 ml of water.
Efter avfarvningen av permanganatet filtreres reaksjonsoppløs- After the decolorization of the permanganate, the reaction solution is filtered
ningen, og filtratet ekstraheres med kloroform. De forenede kloroformekstrakter behandles med fortynnet natronlut, skilles fra vannfasen og tørres, og inndampes i vakuum. Råproduktet filtreres med toluen over 100 g Al 0 . Man får 4 9 (21% av det teoretiske) 7-klor-l-methyl-5-(2 *-klorfenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-on med smeltepunkt 134 - 135°C (isopropanol). ning, and the filtrate is extracted with chloroform. The combined chloroform extracts are treated with dilute caustic soda, separated from the aqueous phase and dried, and evaporated in vacuo. The crude product is filtered with toluene over 100 g Al 0 . One obtains 4 9 (21% of the theoretical) 7-chloro-1-methyl-5-(2*-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one with melting point 134 - 135 °C (isopropanol).
Eksempel 10 Example 10
Ved den i eksempel 2 beskrevne fremgangsmåte får man fra 7-klor-l-methyl-2-cyanomethyl-5-fenyl-2,3-dihydro-1H-1,4- The method described in example 2 gives from 7-chloro-1-methyl-2-cyanomethyl-5-phenyl-2,3-dihydro-1H-1,4-
benzodiazepin i et utbytte på ca. 15% 7_klor-l-methyl-5-fenyl-1,3~dihydro-2H-l,4~benzodiazepin-2-on med smeltepunkt 130 - 131°C. benzodiazepine in a yield of approx. 15% 7_chloro-1-methyl-5-phenyl-1,3~dihydro-2H-1,4~benzodiazepine-2-one with melting point 130 - 131°C.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19722221536 DE2221536A1 (en) | 1972-05-03 | 1972-05-03 | Benzodiazepin-2-ones prepn - by oxidn of 5-phenyl -2,3-dihydro-2-(substd methyl)-1,4-benzodiazepines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO137444B true NO137444B (en) | 1977-11-21 |
| NO137444C NO137444C (en) | 1978-03-01 |
Family
ID=5843890
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO1796/73A NO137444C (en) | 1972-05-03 | 1973-05-02 | PROCEDURES FOR THE PREPARATION OF BENZODIAZEPIN-2-ON DERIVATIVES |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS5341159B2 (en) |
| KR (1) | KR780000053B1 (en) |
| AT (1) | AT332875B (en) |
| CH (1) | CH574943A5 (en) |
| DD (1) | DD105221A5 (en) |
| DE (1) | DE2221536A1 (en) |
| DK (1) | DK137184C (en) |
| ES (1) | ES414231A1 (en) |
| NO (1) | NO137444C (en) |
| SE (1) | SE409710B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2754112A1 (en) * | 1977-12-05 | 1979-06-13 | Kali Chemie Pharma Gmbh | 1,4-BENZODIAZEPINE DERIVATIVES, THEIR SALTS AND MEDICINAL PREPARATIONS CONTAINING THESE COMPOUNDS |
-
1972
- 1972-05-03 DE DE19722221536 patent/DE2221536A1/en not_active Ceased
-
1973
- 1973-03-28 CH CH448973A patent/CH574943A5/xx not_active IP Right Cessation
- 1973-04-09 DD DD170141A patent/DD105221A5/xx unknown
- 1973-04-30 ES ES414231A patent/ES414231A1/en not_active Expired
- 1973-05-01 JP JP4900473A patent/JPS5341159B2/ja not_active Expired
- 1973-05-02 DK DK238473A patent/DK137184C/en active
- 1973-05-02 NO NO1796/73A patent/NO137444C/en unknown
- 1973-05-02 SE SE7306127A patent/SE409710B/en unknown
- 1973-05-03 KR KR7300715A patent/KR780000053B1/en active
- 1973-05-03 AT AT389773A patent/AT332875B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5341159B2 (en) | 1978-10-31 |
| NO137444C (en) | 1978-03-01 |
| DD105221A5 (en) | 1974-04-12 |
| DE2221536A1 (en) | 1973-11-22 |
| JPS4941390A (en) | 1974-04-18 |
| KR780000053B1 (en) | 1978-03-16 |
| CH574943A5 (en) | 1976-04-30 |
| ATA389773A (en) | 1976-02-15 |
| DK137184C (en) | 1978-07-03 |
| DK137184B (en) | 1978-01-30 |
| AT332875B (en) | 1976-10-25 |
| SE409710B (en) | 1979-09-03 |
| ES414231A1 (en) | 1976-01-16 |
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