CH491937A - Process for the preparation of benzodiazepine derivatives - Google Patents
Process for the preparation of benzodiazepine derivativesInfo
- Publication number
- CH491937A CH491937A CH1122867A CH1122867A CH491937A CH 491937 A CH491937 A CH 491937A CH 1122867 A CH1122867 A CH 1122867A CH 1122867 A CH1122867 A CH 1122867A CH 491937 A CH491937 A CH 491937A
- Authority
- CH
- Switzerland
- Prior art keywords
- methyl
- chloroethyl
- general formula
- phenyl
- aniline
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 16
- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 title claims description 4
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 title claims 2
- 238000002360 preparation method Methods 0.000 title description 5
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 9
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 6
- 239000002841 Lewis acid Substances 0.000 claims description 5
- 150000007517 lewis acids Chemical class 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- NHWQMJMIYICNBP-UHFFFAOYSA-N 2-chlorobenzonitrile Chemical compound ClC1=CC=CC=C1C#N NHWQMJMIYICNBP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- YLCXGBZIZBEVPZ-UHFFFAOYSA-N Medazepam Chemical compound C12=CC(Cl)=CC=C2N(C)CCN=C1C1=CC=CC=C1 YLCXGBZIZBEVPZ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 150000001557 benzodiazepines Chemical class 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- -1 (p-chloroethyl) -p-chloroaniline Chemical compound 0.000 description 1
- GNGNAATWQOUAPF-UHFFFAOYSA-N 1-methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepine Chemical compound C12=CC=CC=C2N(C)CCN=C1C1=CC=CC=C1 GNGNAATWQOUAPF-UHFFFAOYSA-N 0.000 description 1
- INGWZEYBHANKIQ-UHFFFAOYSA-N 4-chloro-n-(2-chloroethyl)aniline Chemical compound ClCCNC1=CC=C(Cl)C=C1 INGWZEYBHANKIQ-UHFFFAOYSA-N 0.000 description 1
- XCEYKKJMLOFDSS-UHFFFAOYSA-N 4-chloro-n-methylaniline Chemical compound CNC1=CC=C(Cl)C=C1 XCEYKKJMLOFDSS-UHFFFAOYSA-N 0.000 description 1
- SCHCMVHTSBEPGC-UHFFFAOYSA-N 7-chloro-5-(2-chlorophenyl)-1-methyl-2,3-dihydro-1,4-benzodiazepine Chemical compound C12=CC(Cl)=CC=C2N(C)CCN=C1C1=CC=CC=C1Cl SCHCMVHTSBEPGC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Verfahren zur Herstellung von Benzodiazepin-Derivaten Die Erfindung betrifft ein Verfahren zur Herstellung von Benzodiazepinderivaten der allgemeinen Formel
EMI0001.0004
worin R, Wasserstoff, Halogen, Trifluormethyl, R_ Cy- cloalkyl- Cycloalkenyl, Phenyl oder Phenyl, substituiert mit Halogen, und R3 niederes Alkyl, vorzugsweise Me- thyl bedeuten,
und Säureadditionssalzen dieser Verbin- duneen.
Das erfindungsgemässe Verfahren ist dadurch ge kennzeichnet, dass man eine Verbindung der allgemeinen Formel
EMI0001.0020
worin R, und R3 obige Bedeutung haben und X eine aus tretende Gruppe bedeutet, mit einem Nitril der allgemei nen Formel R_-C=N worin R, die obige Bedeutung hat, in Gegenwart einer Lewissäure umsetzt. Eine erhaltene Verbindung kann er wünschtenfalls in ein Säureadditionssalz überführt wer den.
Eine besondere Ausführungsform des erfindungsge mässen Verfahrens betrifft die Herstellung von Verbin dungen der allgemeinen Formel I, worin R3 Methyl, R1 Chlor und R_ Phenyl bedeuten, d.h. 7-Chlor-2,3-dihydro- -1-methyl-5-phenyl-lH-1,4-benzodiazepin. Wenn R_ eine substituierte Phenylgruppe ist, befindet sich der Substi- tuent vorzugsweise in o-Stellung des Phenylringes.
Der in dieser Beschreibung verwendete Ausdruck uAlkyl umfasst geradkettige und verzweigte Kohlenwas serstoffradikale mit 1-7, vorzugsweise 1-4 Kohlenstoff atomen. Der Ausdruck uHalogen umfasst alle vier Glie der dieser Familie, d.h. Chlor, Brom, Jod und Fluor.
Die Reaktion einer Verbindung der allgemeinen For mel 1I mit einem Nitril der allgemeinen Formel<B>111</B> in Ge genwart einer Lewissäure, kann in Anwesenheit eines inerten organischen Lösungsmittels wie Nitrobenzol oder in der Schmelze vorgenommen werden. Die Reaktion wird zweckmässigerweise bei Temperaturen von 50-200 , vorzugsweise bei 100-150 C durchgeführt. Der Druck ist kein kritischer Aspekt: es kann daher z.B. bei Ver wendung eines tiefsiedenden organischen Lösungsmittels auch bei erhöhtem Druck gearbeitet werden.
Für die Durchführung des erfindungsgemässen Ver fahrens geeignete Lewissäuren sind z.B. Zinntetrachlorid, Aluminiumchlorid, Titantetrachlorid, Eisen(3)chlorid, Bortrifluorid, besonders bevorzugt sind jedoch Alumi- niumtrichlorid und Zinntetrachlorid.
Die Ausgangsmaterialien für das erfindungsgemässe Verfahren, d.h. Verbindungen der allgemeinen Formel 1I sind zum Teil neu. Sie können durch Umsetzung eines Anilins der allgemeinen Formel
EMI0002.0001
worin R, und R3 die vorstehend angegebene Bedeutung haben, mit einer Verbindung der allgemeinen Formel X-CH.,-CHz-Y (V) worin X und Y je eine austretende Gruppe, vorzugs weise Halogen bedeuten, hergestellt werden.
Geeisnete austretende Gruppen sind z.B. Halogen, eine Arylsulfonylgruppe, oder eine Alkylsulfonylgruppe. Die mit X bezeichnete austretende Gruppe kann auch eine Hydroxygruppe sein. In einer besonders vorteilhaf ten Ausführungsform werden Brom oder Chlor als aus tretende Gruppe verwendet.
Die folgenden Beispiele veranschaulichen das erfin- dungsgemässe Verfahren. Alle Temperaturen sind in C angegeben.
<I>Beispiel I</I> Eine Mischung von 141g p-Chlor-N-methyl-anilin, 140 g 1-Brom-2-chlor-äthan und 200 ml Toluol wird während 24 Stunden unter Rückfluss gekocht. Das Re aktionsgemisch wird nach dem Erkalten mit 10 /oiger Sodalösung und Wasser gewaschen, über Natriumsulfat getrocknet und im Vakuum vom Lösungsmittel befreit. Fraktionierung des erhaltenen Öls im Hochvakuum über eine Vigreuxkolonne ergibt N-Methyl-N(2-chlor-äthyl)- -p-chloranilin vom Siedepunkt 93-100 bei 0,07 bis 0,1 Torr. n28 ,>: 1,587.
Das Analysenpräparat wird zur weiteren Reinigung an Kieselgel chromatographiert und im Kugelrohr destil liert. n-e D: 1,5866.
<I>Beispiel 2</I> Zu einer Mischung von 6,8g N-Methyl-N-(ss-chlor- äthyl)anilin und 4,12 g Benzonitril werden 4,6 ml Zinn tetrachlorid zugetropft. Die teilweise erstarrende Reak tionsmischung wird während 2 Stunden auf 110-120 er wärmt. Das entstehende, rotgefärbte Produkt wird mit 50 ml Äther und 100 ml 2n Natronlauge hydrolysiert. Die Ätherphase wird abgetrennt, mit Wasser gewaschen, über Natriumsulfat getrocknet und eingedampft.
Der Rückstand wird an 150 g Kieselgel mit Äthylacetat chromatographiert. Nach Umkristallisation aus Äther/ Petroläther erhält man 2,3-Dihydro-l-methyl-5-phenyl- -1H-1,4-benzodiazepin vom Schmelzpunkt 113-115 .
<I>Beispiel 3</I> Zu 65 g o-Chlor-benzonitril und 62 g N-Methyl-N- ((p-chloräthyl)-p-chloranilin werden unter Rühren 55 ml Zinntetrachlorid zugetropft. Diese Mischung wird 16 Stunden auf 110-l20 erhitzt. Nach dem Abkühlen wird die erstarrte Masse mit 30%iger Natronlauge und Äther bis zur Homogenität hydrolysiert. Die Ätherphase wird mit Wasser gewaschen, über Natriumsulfat getrocknet und eingedampft.
Das erhaltene Öl wird an 1 kg Kiesel- gel mit dem Lösungsmittelsystem Benzol/Äthylacetat (4: 1) chromatographiert. Nach Umkristallisation aus Äther/Hexan erhält man 7-Chlor-2,3-dihydro-l-methyl- -5-(o-chlorphenyl)-1H-1,4-benzodiazepin vom Schmelz punkt 93-95 .
<I>Beispiel 4</I> 4,2 g Benzonitril, 8,2 g N-Methyl-N(@-chloräthyl)-p- -chloranilin und 4,6 ml Zinntetrachlorid werden während 3 Stunden auf 110-l20 erwärmt. Nach dem Erkalten wird die rotbraune, erstarrte Masse mit 40 ml 307oiger Natronlauge und 50 ml Äther hydrolysiert. Die Äther phase wird mit Wasser gewaschen, über Natriumsulfat getrocknet und eingedampft.
Das erhaltene Öl wird an Kieselgel mit dem Lösungsmittelsystem Benzol/Äthyl- acetat (2: 1) chromatographiert und ergibt 7-Chlor-2,3- -dihydro-l-methyl-5-phenyl-1H- 1,4-benzodiazepin vom Schmelzpunkt 95-97 C.
Process for the preparation of benzodiazepine derivatives The invention relates to a process for the preparation of benzodiazepine derivatives of the general formula
EMI0001.0004
where R, hydrogen, halogen, trifluoromethyl, R_ cycloalkyl-cycloalkenyl, phenyl or phenyl, substituted by halogen, and R3 are lower alkyl, preferably methyl,
and acid addition salts of these compounds.
The inventive method is characterized in that a compound of the general formula
EMI0001.0020
where R and R3 have the above meaning and X is a leaving group with a nitrile of the general formula R_-C = N where R, which has the above meaning, is reacted in the presence of a Lewis acid. If desired, a compound obtained can be converted into an acid addition salt.
A particular embodiment of the process according to the invention relates to the preparation of compounds of the general formula I in which R3 is methyl, R1 is chlorine and R_ is phenyl, i.e. 7-chloro-2,3-dihydro- -1-methyl-5-phenyl-1H-1,4-benzodiazepine. If R_ is a substituted phenyl group, the substituent is preferably in the o-position of the phenyl ring.
The term u-alkyl used in this description includes straight-chain and branched hydrocarbon radicals with 1-7, preferably 1-4 carbon atoms. The term uHalogen includes all four members of this family, i.e. Chlorine, bromine, iodine and fluorine.
The reaction of a compound of the general formula 1I with a nitrile of the general formula 111 in the presence of a Lewis acid can be carried out in the presence of an inert organic solvent such as nitrobenzene or in the melt. The reaction is conveniently carried out at temperatures of 50-200, preferably 100-150.degree. The pressure is not a critical aspect: it can therefore e.g. when using a low-boiling organic solvent, work can also be carried out at elevated pressure.
Lewis acids suitable for carrying out the process according to the invention are e.g. Tin tetrachloride, aluminum chloride, titanium tetrachloride, iron (3) chloride, boron trifluoride, but aluminum trichloride and tin tetrachloride are particularly preferred.
The starting materials for the process according to the invention, i. Some of the compounds of the general formula 1I are new. You can by implementing an aniline of the general formula
EMI0002.0001
in which R 1 and R 3 have the meaning given above, with a compound of the general formula X-CH., - CH 2 -Y (V) in which X and Y each represent a leaving group, preferably halogen.
Iced outgoing groups are e.g. Halogen, an arylsulfonyl group, or an alkylsulfonyl group. The leaving group labeled X can also be a hydroxy group. In a particularly advantageous embodiment, bromine or chlorine are used as the leaving group.
The following examples illustrate the method according to the invention. All temperatures are given in C.
<I> Example I </I> A mixture of 141 g of p-chloro-N-methyl-aniline, 140 g of 1-bromo-2-chloroethane and 200 ml of toluene is refluxed for 24 hours. After cooling, the reaction mixture is washed with 10% sodium carbonate solution and water, dried over sodium sulfate and freed from the solvent in vacuo. Fractionation of the oil obtained in a high vacuum over a Vigreux column gives N-methyl-N (2-chloro-ethyl) - -p-chloroaniline with a boiling point of 93-100 at 0.07 to 0.1 Torr. n28,>: 1.587.
The analysis preparation is chromatographed on silica gel for further purification and distilled in a bulb tube. n-e D: 1.5866.
<I> Example 2 </I> 4.6 ml of tin tetrachloride are added dropwise to a mixture of 6.8 g of N-methyl-N- (ss-chloroethyl) aniline and 4.12 g of benzonitrile. The partially solidifying reaction mixture is heated to 110-120 for 2 hours. The resulting, red-colored product is hydrolyzed with 50 ml of ether and 100 ml of 2N sodium hydroxide solution. The ether phase is separated off, washed with water, dried over sodium sulfate and evaporated.
The residue is chromatographed on 150 g of silica gel with ethyl acetate. After recrystallization from ether / petroleum ether, 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine with a melting point of 113-115 is obtained.
<I> Example 3 </I> 55 ml of tin tetrachloride are added dropwise with stirring to 65 g of o-chlorobenzonitrile and 62 g of N-methyl-N- ((p-chloroethyl) -p-chloroaniline, and this mixture is left for 16 hours 110-120. After cooling, the solidified mass is hydrolyzed to homogeneity with 30% sodium hydroxide solution and ether. The ether phase is washed with water, dried over sodium sulfate and evaporated.
The oil obtained is chromatographed on 1 kg of silica gel using the benzene / ethyl acetate (4: 1) solvent system. After recrystallization from ether / hexane, 7-chloro-2,3-dihydro-1-methyl--5- (o-chlorophenyl) -1H-1,4-benzodiazepine with a melting point of 93-95 is obtained.
<I> Example 4 </I> 4.2 g of benzonitrile, 8.2 g of N-methyl-N (@ - chloroethyl) -p- -chloroaniline and 4.6 ml of tin tetrachloride are heated to 110-120 for 3 hours. After cooling, the red-brown, solidified mass is hydrolyzed with 40 ml of 307% sodium hydroxide solution and 50 ml of ether. The ether phase is washed with water, dried over sodium sulfate and evaporated.
The oil obtained is chromatographed on silica gel with the solvent system benzene / ethyl acetate (2: 1) and gives 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine with a melting point 95-97 C.
Claims (1)
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1122867A CH491937A (en) | 1967-08-09 | 1967-08-09 | Process for the preparation of benzodiazepine derivatives |
| YU174668A YU34130B (en) | 1967-08-09 | 1968-07-23 | Process for preparing benzodiazepine derivatives |
| ES356713A ES356713A1 (en) | 1967-08-09 | 1968-07-31 | Procedure for obtaining benzodiazepine derivatives. (Machine-translation by Google Translate, not legally binding) |
| AT760168A AT281039B (en) | 1967-08-09 | 1968-08-05 | Process for the preparation of benzodiazepine derivatives and acid addition salts of these compounds |
| DK381568A DK135311B (en) | 1967-08-09 | 1968-08-07 | Process for the preparation of 1,4-benzodiazepine derivatives or acid addition salts thereof. |
| FI223668A FI48352C (en) | 1967-08-09 | 1968-08-07 | Process for the preparation of 1-alkyl-2,3-dihydro-1H-1,4-benzodiazepines. |
| NL6811365A NL6811365A (en) | 1967-08-09 | 1968-08-09 | |
| SE1076868A SE338322B (en) | 1967-08-09 | 1968-08-09 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1122867A CH491937A (en) | 1967-08-09 | 1967-08-09 | Process for the preparation of benzodiazepine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH491937A true CH491937A (en) | 1970-06-15 |
Family
ID=4371367
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1122867A CH491937A (en) | 1967-08-09 | 1967-08-09 | Process for the preparation of benzodiazepine derivatives |
Country Status (8)
| Country | Link |
|---|---|
| AT (1) | AT281039B (en) |
| CH (1) | CH491937A (en) |
| DK (1) | DK135311B (en) |
| ES (1) | ES356713A1 (en) |
| FI (1) | FI48352C (en) |
| NL (1) | NL6811365A (en) |
| SE (1) | SE338322B (en) |
| YU (1) | YU34130B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6104802A (en) | 1997-02-10 | 2000-08-15 | Genesys Telecommunications Laboratories, Inc. | In-band signaling for routing |
| US6985943B2 (en) | 1998-09-11 | 2006-01-10 | Genesys Telecommunications Laboratories, Inc. | Method and apparatus for extended management of state and interaction of a remote knowledge worker from a contact center |
| US6332154B2 (en) | 1998-09-11 | 2001-12-18 | Genesys Telecommunications Laboratories, Inc. | Method and apparatus for providing media-independent self-help modules within a multimedia communication-center customer interface |
-
1967
- 1967-08-09 CH CH1122867A patent/CH491937A/en not_active IP Right Cessation
-
1968
- 1968-07-23 YU YU174668A patent/YU34130B/en unknown
- 1968-07-31 ES ES356713A patent/ES356713A1/en not_active Expired
- 1968-08-05 AT AT760168A patent/AT281039B/en not_active IP Right Cessation
- 1968-08-07 FI FI223668A patent/FI48352C/en active
- 1968-08-07 DK DK381568A patent/DK135311B/en not_active IP Right Cessation
- 1968-08-09 NL NL6811365A patent/NL6811365A/xx unknown
- 1968-08-09 SE SE1076868A patent/SE338322B/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK135311C (en) | 1977-09-19 |
| YU34130B (en) | 1978-12-31 |
| NL6811365A (en) | 1969-02-11 |
| SE338322B (en) | 1971-09-06 |
| FI48352B (en) | 1974-05-31 |
| DK135311B (en) | 1977-04-04 |
| FI48352C (en) | 1974-09-10 |
| YU174668A (en) | 1978-05-15 |
| ES356713A1 (en) | 1970-02-01 |
| AT281039B (en) | 1970-05-11 |
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