NO127349B - - Google Patents
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- NO127349B NO127349B NO03021/71A NO302171A NO127349B NO 127349 B NO127349 B NO 127349B NO 03021/71 A NO03021/71 A NO 03021/71A NO 302171 A NO302171 A NO 302171A NO 127349 B NO127349 B NO 127349B
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- 150000001875 compounds Chemical class 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 239000000543 intermediate Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical class N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- -1 lithium aluminum hydride Chemical compound 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- UVGLQEHMAHOVRY-UHFFFAOYSA-N 7-chloro-4-hydroxy-1-methyl-5-phenyl-3,5-dihydro-2H-1,4-benzodiazepine Chemical compound ClC=1C=CC2=C(C(N(CCN2C)O)C2=CC=CC=C2)C1 UVGLQEHMAHOVRY-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 239000012022 methylating agents Substances 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D497/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Forbindelser for anvendelse som mellomprodukter ved fremstillingen av terapeutisk virksomme 1,4-benzodiazepiner. Compounds for use as intermediates in the preparation of therapeutically active 1,4-benzodiazepines.
Nærværende oppfinnelse vedrorer nye forbindelser med den generelle formel The present invention relates to new compounds of the general formula
hvor betyr halogen, where does halogen mean,
R2 hydrogen aller metyl, og R2 hydrogen all methyl, and
X lavere alkoksy eller lavere acyloksy. X lower alkoxy or lower acyloxy.
De nya forbindelser kan anvandas som mellomprodukter. F.eks. får man terapeutisk verdifulle forbindelser med den generelle formel The new compounds can be used as intermediates. E.g. one obtains therapeutically valuable compounds with the general formula
hvor R, og R2 har de foran angitte betydninger, R4 betyr hydroksy og where R, and R2 have the previously stated meanings, R4 means hydroxy and
R^ hydrogen eller R^ hydrogen or
R 4 og R^ betyr sammen en ytterligere C-N-binding, R 4 and R^ together mean an additional C-N bond,
idet man behandler en forbindelse med den generelle formel II med et komplekst metallhydrid som litiumaluminiumhydrid eller diisobutylaluminiumhydrid og, hvis onsket, dehydratiserer en oppnådd forbindelse. treating a compound of general formula II with a complex metal hydride such as lithium aluminum hydride or diisobutylaluminum hydride and, if desired, dehydrating a compound obtained.
Forbindelser med formel II lar seg fremstille ved ringåpning av en aziridinoforbindelse med den generelle formel Compounds of formula II can be prepared by ring opening of an aziridino compound of the general formula
hvor R^ har den under formel II angitte where R^ has the one indicated under formula II
betydning, importance,
idet man som middel for åpning av ringen anvender en forbindelse med den generelle formel using a compound with the general formula as an agent for opening the ring
hvor B betyr hydrogen eller et alkalimetallatom, where B means hydrogen or an alkali metal atom,
f.eks. natrium og e.g. sodium and
X har foran angitte betydning. X has the meaning stated above.
Forbindelser som omfattes av den generelle formel BX. er enten syrer som eddiksyre, hvor B betyr hydrogen og X en acetoksy-gruppe, eller propionyloksy eller andre lavara alkanoyloksy-grupper, hvor B tilsvarende betyr hydrogen og X en propionyloksy- eller en tilsvarende lavere alkanoyloksygruppe, eller en base,, hvor B f. eks. betyr natrium og X f .eks. etoksy. Compounds covered by the general formula BX. are either acids such as acetic acid, where B means hydrogen and X an acetoxy group, or propionyloxy or other low alkanoyloxy groups, where B correspondingly means hydrogen and X a propionyloxy or a corresponding lower alkanoyloxy group, or a base, where B f e.g. means sodium and X e.g. ethoxy.
Denne reaksjon gjennomfores hensiktsmessig i nærvær av et opplosningsmiddel som f.eks. en lavere alkanol som etanol eller en eter som etyleter eller andre inerte opplosningsmidler som hydrokarboner eller halogenerte hydrokarboner som benzen eller kloroform. Temperaturen er intet kritisk-aspekt ved gjennom-føringen av denne reaksjon, dog er det generelt å tilstrebe og arbeide i et temperaturområde mellom ca. -70 og 80°C, særlig foretrukket mellom 10 og 30°C. This reaction is conveniently carried out in the presence of a solvent such as e.g. a lower alkanol such as ethanol or an ether such as ethyl ether or other inert solvents such as hydrocarbons or halogenated hydrocarbons such as benzene or chloroform. The temperature is not a critical aspect in carrying out this reaction, however it is generally to strive and work in a temperature range between approx. -70 and 80°C, particularly preferably between 10 and 30°C.
Forbindelser med formel II, hvor X betyr en alkoksygruppe, lar seg fremstille etter en annen fremgangsmåte. Ved denne fremgangsmåte omsettes en forbindelse med den generelle formel Compounds of formula II, where X means an alkoxy group, can be prepared by another method. In this method, a compound with the general formula is reacted
hvor R-^ har den under formel II angitte where R-^ has the one indicated under formula II
betydning, importance,
med en sterk base, f.eks. natriumalkoksyd, fortrinnsvis natrium-etylat i nærvær av en lavere alkanol, f.eks. etanol, og man får de foran beskrevne forbindelser med formel II. Denne reaksjon gjennomfores i et inert opplosningsmiddel som en eter, f.eks. tetrahydrofuran, i et temperaturområde mellom omtrent -70 og 80°C, særlig foretrukket ved romtemperatur. with a strong base, e.g. sodium alkoxide, preferably sodium ethylate in the presence of a lower alkanol, e.g. ethanol, and the above-described compounds of formula II are obtained. This reaction is carried out in an inert solvent such as an ether, e.g. tetrahydrofuran, in a temperature range between approximately -70 and 80°C, particularly preferably at room temperature.
For det tilfelle at i en forbindelse med den generelle formel For the case that in a connection with the general formula
II Rp skal bety en metylgruppe, kan en tilsvarende forbindelse med formel II, hvor betyr hydrogen, underkastes en metylering, idet man overforer denne forbindelse med formel II enten i nærvær av at inert organisk opplosningsmiddel med et alkaliamid (f.eks. litiumamid), et alkalihydrid (f.eks. natriumhydrid) eller et alkalialkoholat (f.eks. natriummatylat) i 1-stilling til et alkalisalt, hvorved toluen, dimetylformamid osv. kan finne anvendelse som inert opplosningsmiddel, og deretter behandles datte alkalimetallderivat med et metylerings-middel. Egnede matyleringsmidlar er f.eks. dimetylsulfat eller matylhalogenider som metyljodid. II Rp shall mean a methyl group, a corresponding compound of formula II, where means hydrogen, can be subjected to a methylation, transferring this compound of formula II either in the presence of that inert organic solvent with an alkali amide (e.g. lithium amide), an alkali hydride (e.g. sodium hydride) or an alkali alcoholate (e.g. sodium methylate) in the 1-position to an alkali salt, whereby toluene, dimethylformamide etc. can be used as an inert solvent, and then this alkali metal derivative is treated with a methylating agent . Suitable methylating agents are e.g. dimethyl sulfate or methyl halides such as methyl iodide.
Uttrykket "lavere alkoksy" omfatter rettkjedede og forgrenda hydrokarbongrupper med 1-7, fortrinnsvis 1-4 karbonatomar, som inneholder an oksygenfunksjon slik som metoksy, etoksy osv. Uttrykket "halogen" omfatter alle 4 halogenatomer dvs. klor, brom, fluor og jod, når intet annet uttrykkelig er angitt, idet klor er et foretrukket halogenatom. Uttrykket "lavere acyloksy" omfatter grupper som The term "lower alkoxy" includes straight-chain and branched hydrocarbon groups with 1-7, preferably 1-4 carbon atoms, which contain an oxygen function such as methoxy, ethoxy, etc. The term "halogen" includes all 4 halogen atoms, i.e. chlorine, bromine, fluorine and iodine, when nothing else is expressly stated, chlorine being a preferred halogen atom. The term "lower acyloxy" includes groups which
En foretrukken lavere acyloksygruppa er A preferred lower acyloxy group is
acetoksygruppan. acetoxy group.
De folgenda eksempler illustrerer oppfinnelsen. Alle tempera-turer er angitt i Celsiusgrader. The following examples illustrate the invention. All temperatures are given in degrees Celsius.
EKSEMPEL 1 EXAMPLE 1
Under omroring tilsettes til en suspensjon av 13,4 g (49,6 mmol) 7-klor-l,3-dihydro-5-fenyl-2H-azirino[l,2-a]kinazolin-4- oksyd i 300 ml eter 3 ml (50 mmol) eddiksyre. Blandingen omrores ytterligere 3 timer og deretter filtreres det gule bunnfall fra. Man får 3-acetoksy-7-klor-2,3-dihydro-5-fenyl-1H-1,4-benzodiazepin-4-oksyd som smelter ved 99 - 100° under spailtning. Omkrystallisering fra metylenklorid/heksan gir gule nåler med et smeltepunkt på 98 - 100° (spaltning). While stirring, 13.4 g (49.6 mmol) of 7-chloro-1,3-dihydro-5-phenyl-2H-azirino[1,2-a]quinazoline-4-oxide in 300 ml of ether are added to a suspension 3 ml (50 mmol) acetic acid. The mixture is stirred for a further 3 hours and then the yellow precipitate is filtered off. 3-acetoxy-7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-4-oxide is obtained which melts at 99 - 100° during distillation. Recrystallization from methylene chloride/hexane gives yellow needles with a melting point of 98 - 100° (decomposition).
EKSEMPEL 2 EXAMPLE 2
En opplosning av 2,16 g (8 mmol) 7-klor-l,3-dihydro-5-fenyl-2H-azirino[l,2-aJkinazolin-4-oksyd i 200 ml etanol og 8 ml l-n natriumhydroksydopplosning oppvarmes 2 timer under til-bakelop. Reaksjonsblandingen avkjoles, noytraliseres med l-n saltsyre, helles i 800 ml vann og ekstraheres tre ganger med metylenklorid. Metylenkloridekstraktene vaskes tre ganger med vann og deretter med saltopplosning og torkes over natriumsulfat. Metylenkloridet trekkes av i vakuum, og resten omkrystalliseres fra benzen/heksan. Man får 7-klor-3-etoksy-2,3-dihydro-5- fenyl-lH-l,4-benzodiazepin-4-oksyd, som etter omkrystallisering fra etanol faller ut i form av gule nåler som smelter ved 196 - 199° under spaltning. A solution of 2.16 g (8 mmol) of 7-chloro-1,3-dihydro-5-phenyl-2H-azirino[1,2-aJquinazoline-4-oxide in 200 ml of ethanol and 8 ml of 1-n sodium hydroxide solution is heated for 2 hours under to-back. The reaction mixture is cooled, neutralized with 1-1 hydrochloric acid, poured into 800 ml of water and extracted three times with methylene chloride. The methylene chloride extracts are washed three times with water and then with saline and dried over sodium sulphate. The methylene chloride is drawn off in vacuo, and the residue is recrystallized from benzene/hexane. 7-chloro-3-ethoxy-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-4-oxide is obtained, which after recrystallization from ethanol precipitates in the form of yellow needles melting at 196 - 199 ° during cleavage.
EKSEMPEL 3 EXAMPLE 3
Til en opplosning av 3,55 g (11,6 mmol) 6-klor-2-klor-metyl-1,2-dihydro-4-fenylkinazolin-3-oksyd i 100 ml tetrahydrofuran tilsettes 0,55 g av en 50 %'ig dispersjon av natriumhydrid i mineralolje og 5 ml etanol, og blandingen står til henstand 2 dager ved romtemperatur. Deretter nøytraliseres med eddiksyre, fortynnes med vann og tetrahydrofuranet destilleres av i vakuum. Den vandige fase dekanteres, og resten omkrystalliseres fra eter. Ytterligere omkrystallisasjon fra etylacetat gir 7-klor-3-etoksy-2,3-dihydro-5-fenyl-1H-1,4-benzodiazepin-4-oksyd som smelter ved 185 - 190° under spaltning. Ytterligere omkrystallisering fra etylacetat gir et preparat som smelter ved 196 - 199°. Infrarodspektret av denne forbindelse er identisk med det av forbindelsen som fremstilles ifolge 0.55 g of a 50% ig dispersion of sodium hydride in mineral oil and 5 ml of ethanol, and the mixture is allowed to stand for 2 days at room temperature. It is then neutralized with acetic acid, diluted with water and the tetrahydrofuran is distilled off in a vacuum. The aqueous phase is decanted, and the residue is recrystallized from ether. Further recrystallization from ethyl acetate gives 7-chloro-3-ethoxy-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-4-oxide which melts at 185-190° with cleavage. Further recrystallization from ethyl acetate gives a preparation which melts at 196 - 199°. The infrared spectrum of this compound is identical to that of the compound prepared accordingly
eksempel 2. example 2.
EKSEMPEL 4 EXAMPLE 4
Til en opplosning av 3,16 g (10 mmol) 7-klor-3-etoksy-2,3-dihydro-5-fenyl-lH-l,4-benzodiazepin-4-oksyd i 100 ml tort dimetylformamid tilsettes 0,58 g (12 mmol) av en 50 %'ig dispersjon av natriumhydrid i mineralolje, og blandingen rores deretter om 10 minutter ved romtemperatur. Deretter tilsettes 2 g (14 mmol) metyljodid og omrores videre 3 timer. Reaksjonsblandingen fortynnes med 500 ml vann og ekstraheres så med metylenklorid. Metylenkloridekstraktene vaskes med vann, torkes over natriumsulfat og dampes inn i vakuum. Det blir tilbake en gul olje. To a solution of 3.16 g (10 mmol) of 7-chloro-3-ethoxy-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-4-oxide in 100 ml of dry dimethylformamide is added 0.58 g (12 mmol) of a 50% dispersion of sodium hydride in mineral oil, and the mixture is then stirred for 10 minutes at room temperature. 2 g (14 mmol) of methyl iodide are then added and stirred for a further 3 hours. The reaction mixture is diluted with 500 ml of water and then extracted with methylene chloride. The methylene chloride extracts are washed with water, dried over sodium sulphate and evaporated in vacuo. A yellow oil remains.
Til en opplosning av 2,4 g av den ifolge forskriften i foran nevnte avsnitt oppnådde gule olje i 125 ml tort tetrahydrofuran tilsettes 0,3 g litiumaluminiumhydrid, og blandingen omrores 1 time ved romtemperatur. Det overskytende litiumaluminiumhydrid odelegges ved tilsetning av etylacetat og mettet bikarbonatopplosning. De utfelte uorganiske salter filtreres fra og vaskes ut med tetrahydrofuran. Det organiske skikt av filtratet skilles fra, torkes over natriumsulfat og dampes inn i vakuum. Resten krystalliseres fra vandig metanol, og kry-stallisatet omkrystalliseres fra cykloheksan. Man får 7-klor-2,3,4,5-tetrahydro-4-hydroksy-l-metyl-5-fenyl-lH-1,4-benzo-diazepin med et smeltepunkt på 137 - 140°. Identifiseringen finner sted ved blandingssmeltepunkt og sammenligning av de. infrarodspektrene med et autentiskt preparat. 0.3 g of lithium aluminum hydride is added to a solution of 2.4 g of the yellow oil obtained according to the instructions in the above-mentioned section in 125 ml of dry tetrahydrofuran, and the mixture is stirred for 1 hour at room temperature. The excess lithium aluminum hydride is decomposed by the addition of ethyl acetate and saturated bicarbonate solution. The precipitated inorganic salts are filtered off and washed out with tetrahydrofuran. The organic layer of the filtrate is separated, dried over sodium sulphate and evaporated in vacuo. The residue is crystallized from aqueous methanol, and the crystallisate is recrystallized from cyclohexane. 7-chloro-2,3,4,5-tetrahydro-4-hydroxy-1-methyl-5-phenyl-1H-1,4-benzo-diazepine is obtained with a melting point of 137 - 140°. The identification takes place by mixing melting points and comparing them. the infrared spectra with an authentic preparation.
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US77677568A | 1968-11-18 | 1968-11-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO127349B true NO127349B (en) | 1973-06-12 |
Family
ID=25108328
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO04554/69A NO126625B (en) | 1968-11-18 | 1969-11-17 | |
NO03021/71A NO127349B (en) | 1968-11-18 | 1971-08-12 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO04554/69A NO126625B (en) | 1968-11-18 | 1969-11-17 |
Country Status (14)
Country | Link |
---|---|
AT (1) | AT294839B (en) |
BE (1) | BE741765A (en) |
BR (1) | BR6914223D0 (en) |
CH (1) | CH526557A (en) |
DE (1) | DE1957961A1 (en) |
ES (1) | ES373596A1 (en) |
FI (1) | FI50626C (en) |
FR (1) | FR2023553A1 (en) |
GB (1) | GB1233828A (en) |
IL (1) | IL33251A0 (en) |
NL (1) | NL6916954A (en) |
NO (2) | NO126625B (en) |
SE (2) | SE367198B (en) |
YU (1) | YU34206B (en) |
-
1969
- 1969-10-27 IL IL33251A patent/IL33251A0/en unknown
- 1969-10-27 CH CH1597469A patent/CH526557A/en not_active IP Right Cessation
- 1969-11-07 FI FI693223A patent/FI50626C/en active
- 1969-11-11 NL NL6916954A patent/NL6916954A/xx not_active Application Discontinuation
- 1969-11-11 GB GB1233828D patent/GB1233828A/en not_active Expired
- 1969-11-17 YU YU2878/69A patent/YU34206B/en unknown
- 1969-11-17 ES ES373596A patent/ES373596A1/en not_active Expired
- 1969-11-17 BR BR214223/69A patent/BR6914223D0/en unknown
- 1969-11-17 NO NO04554/69A patent/NO126625B/no unknown
- 1969-11-17 BE BE741765D patent/BE741765A/xx unknown
- 1969-11-17 AT AT1071469A patent/AT294839B/en not_active IP Right Cessation
- 1969-11-18 DE DE19691957961 patent/DE1957961A1/en active Pending
- 1969-11-18 FR FR6939572A patent/FR2023553A1/fr not_active Withdrawn
- 1969-11-18 SE SE15821/69A patent/SE367198B/xx unknown
-
1971
- 1971-08-12 NO NO03021/71A patent/NO127349B/no unknown
-
1972
- 1972-09-18 SE SE7212032A patent/SE398748B/en unknown
Also Published As
Publication number | Publication date |
---|---|
FI50626B (en) | 1976-02-02 |
FR2023553A1 (en) | 1970-08-21 |
IL33251A0 (en) | 1969-12-31 |
BR6914223D0 (en) | 1973-02-08 |
SE398748B (en) | 1978-01-16 |
FI50626C (en) | 1976-05-10 |
AT294839B (en) | 1971-12-10 |
BE741765A (en) | 1970-05-19 |
GB1233828A (en) | 1971-06-03 |
YU287869A (en) | 1978-06-30 |
NL6916954A (en) | 1970-05-20 |
ES373596A1 (en) | 1973-04-16 |
YU34206B (en) | 1979-02-28 |
SE367198B (en) | 1974-05-20 |
CH526557A (en) | 1972-08-15 |
NO126625B (en) | 1973-03-05 |
DE1957961A1 (en) | 1970-06-18 |
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