DE1207938B - Process for the preparation of 7-halo-2-dimethylamino-5-phenyl-3H-1, 4-benzo-diazepine-4-oxides - Google Patents
Process for the preparation of 7-halo-2-dimethylamino-5-phenyl-3H-1, 4-benzo-diazepine-4-oxidesInfo
- Publication number
- DE1207938B DE1207938B DEW31289A DEW0031289A DE1207938B DE 1207938 B DE1207938 B DE 1207938B DE W31289 A DEW31289 A DE W31289A DE W0031289 A DEW0031289 A DE W0031289A DE 1207938 B DE1207938 B DE 1207938B
- Authority
- DE
- Germany
- Prior art keywords
- halo
- dimethylamino
- phenyl
- oxides
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 6
- 230000007935 neutral effect Effects 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000006049 ring expansion reaction Methods 0.000 description 3
- KFDNKXWSTFABQT-UHFFFAOYSA-N 6-chloro-2-(chloromethyl)-3-oxido-4-phenylquinazolin-3-ium Chemical compound [O-][N+]1=C(CCl)N=C2C=CC(Cl)=CC2=C1C1=CC=CC=C1 KFDNKXWSTFABQT-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- -1 diazepine compound Chemical class 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- ZCSCWVLTBTZMSU-UHFFFAOYSA-N 3-oxido-4-phenylquinazolin-3-ium Chemical compound [O-][N+]1=CN=C2C=CC=CC2=C1C1=CC=CC=C1 ZCSCWVLTBTZMSU-UHFFFAOYSA-N 0.000 description 1
- XPAZAEVQMWOYMA-UHFFFAOYSA-N 4-oxido-5h-1,4-benzodiazepin-4-ium Chemical class C1[N+]([O-])=CC=NC2=CC=CC=C21 XPAZAEVQMWOYMA-UHFFFAOYSA-N 0.000 description 1
- DQZUAVXXQQOPOW-UHFFFAOYSA-N 7-chloro-n,n-dimethyl-4-oxido-5-phenyl-3h-1,4-benzodiazepin-4-ium-2-amine Chemical compound [O-][N+]=1CC(N(C)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 DQZUAVXXQQOPOW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung von 7-Halogen-2-dimethylamino-5-phenyl-3H-1,4-benzodiazepin-4-oxyden Die Erfindung bezieht sich auf ein Verfahren zur Herstellung von 7-Halogen-2-dimethylamino-5-phenyl-3H-1,4-benzodiazepin-4-oxyden der allgemeinen Formel in der X ein Halogenatom, beispielsweise ein Fluor-, Chlor-, Brom- oder Iodatom, bedeutet, das dadurch gekennzeichnet ist, daß eine Lösung eines 6-Halogen-2-halogenmethyl-4-phenylchinazolin-3-oxyds der allgemeinen Formel in der X und Y Halogenatome, z. B. Fluor-, Chlor-, Brom- oder Iodatome bedeuten, in einem neutralen Lösungsmittel bei einer Temperatur zwischen -10 und -50°C mit Dimethylamin behandelt wird.Process for the preparation of 7-halo-2-dimethylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxides The invention relates to a process for the preparation of 7-halo-2-dimethylamino-5-phenyl-3H -1,4-benzodiazepine-4-oxides of the general formula in which X is a halogen atom, for example a fluorine, chlorine, bromine or iodine atom, which is characterized in that a solution of a 6-halo-2-halomethyl-4-phenylquinazoline-3-oxide of the general formula in which X and Y are halogen atoms, e.g. B. fluorine, chlorine, bromine or iodine atoms, is treated in a neutral solvent at a temperature between -10 and -50 ° C with dimethylamine.
Ausgangsmaterialien dieser vorstehenden Formel sind in der USA: Patentschrift 2 893 992 beschrieben. Es ist bereits bekannt, daß bei Umsetzung von 6-Chlor-2-chlormethyl-4-phenylchinazolin-3-oxyd mit Ammoniak oder bestimmten primären Aminen in einem zwischen Raumtemperatur und 30°C liegenden Temperaturbereich Ringerweiterung unter Bildung der Diazepinverbindung eintritt. Bei Umsetzung unter den gleichen Reaktionsbedingungen, jedoch mit dem entsprechenden sekundären Amin, wie es auch bei den vorliegenden Verfahren verwendet wird, tritt dagegen lediglich eine Substitution des 2-Chlormethylsubstituenten des 4-Phenylchinazolin-3-oxyds ein, ohne daß Ringerweiterung erfolgt. Beim Arbeiten unter den erfindungsgemäßen Bedingungen tritt jedoch überraschenderweise hier die Ringerweiterung ein. Die Umsetzung dauert 1 bis 10 Tage. Als neutrale Lösungsmittel werden niedermolekulare, aliphatische Alkohole, wie Methanol und Äthanol, bevorzugt. Erfindungsgemäß wurde festgestellt, daß die Reaktionstemperatur wesentlich ist und zwischen -10 und -50°C, vorzugsweise zwischen -25 und -40°C, gehalten werden sollte. Bei Temperaturen oberhalb -10°C wird die Ausbeute an gewünschtem Produkt durch Nebenreaktionen auf einen unbedeutenden Wert herabgesetzt, während bei Temperaturen unter -50°C andererseits keine Spur von Umsetzung vorhanden ist.Starting materials of this formula above are in the USA: Patent 2,893,992. It is already known that when 6-chloro-2-chloromethyl-4-phenylquinazoline-3-oxide is reacted with ammonia or certain primary amines in a room between room temperature and 30 ° C temperature range ring expansion with formation of the diazepine compound entry. When implemented under the same reaction conditions, but with the corresponding secondary amine, as also used in the present processes is, on the other hand, only a substitution of the 2-chloromethyl substituent occurs 4-phenylquinazoline-3-oxide without ring expansion occurring. At work under the conditions according to the invention, however, surprisingly occurs here Ring expansion a. Implementation takes 1 to 10 days. As a neutral solvent low molecular weight aliphatic alcohols such as methanol and ethanol are preferred. According to the invention it was found that the reaction temperature is essential and should be kept between -10 and -50 ° C, preferably between -25 and -40 ° C. At temperatures above -10 ° C, the yield of the desired product is reduced by side reactions reduced to an insignificant value, while at temperatures below -50 ° C on the other hand, there is no trace of implementation.
Die Verfahrensprodukte besitzen eine bedeutsame pharmakologische Aktivität und sind einerseits als Sedativa, aber auch als wertvolle Zwischenprodukte bei der Gewinnung anderer 1,4-Benzodiazepin-4-oxydderivate verwendbar.The products of the process have significant pharmacological activity and are on the one hand as sedatives, but also as valuable intermediates in the Obtaining other 1,4-benzodiazepine-4-oxide derivatives can be used.
Das nachstehende Beispiel soll die Erfindung weiterhin erläutern: B 3,0 g 6-Chlor-2-chlormethyl-4-phenylchinazolin-3-oxyd werden bei -33°C einer Lösung von 6,5 g Dimethylamin in 200 ccm' Methanol zugesetzt. Die Mischung wird 6 Tage lang auf dieser Temperatur von -33°C gehalten, indem das Reaktionsgefäß in ein Bad aus flüssigem Ammoniak eingetaucht wird. Der nach Filtrieren der Mischung verbleibend2 Feststoff (2.5 g) wird bei Raumtemperatur im Vakuum getrocknet. Umkristallisieren aus Acetonitril gibt 0,65 g reines 7-Chlor-2-dimethylamino-5-phenyl-3H-1,4-benzodiazepin-4-oxyd vom F. 206 bis 210°C. Analyse: Berechnet .. . C 65,07, H 5,14, N 13,39, Cl 11,30; gefunden ... C 65,22, H 5,36, N 13,35, Cl 11,30.The following example is intended to explain the invention further: B 3.0 g of 6-chloro-2-chloromethyl-4-phenylquinazoline-3-oxide are added at -33 ° C. to a solution of 6.5 g of dimethylamine in 200 cc of methanol. The mixture is kept at this temperature of -33 ° C. for 6 days by immersing the reaction vessel in a bath of liquid ammonia. The solid (2.5 g) remaining after filtering the mixture is dried in vacuo at room temperature. Recrystallization from acetonitrile gives 0.65 g of pure 7-chloro-2-dimethylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide with a melting point of 206 ° to 210 ° C. Analysis: Calculated ... C 65.07, H 5.14, N 13.39, Cl 11.30; Found ... C 65.22, H 5.36, N 13.35, Cl 11.30.
Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1207938XA | 1961-05-29 | 1961-05-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1207938B true DE1207938B (en) | 1965-12-30 |
Family
ID=22392594
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEW31289A Pending DE1207938B (en) | 1961-05-29 | 1961-12-14 | Process for the preparation of 7-halo-2-dimethylamino-5-phenyl-3H-1, 4-benzo-diazepine-4-oxides |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1207938B (en) |
-
1961
- 1961-12-14 DE DEW31289A patent/DE1207938B/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| None * |
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