DE1906254C3 - Process for the preparation of 5-phenyl ^ -dihydro-1H-M-benzodiaze- - Google Patents
Process for the preparation of 5-phenyl ^ -dihydro-1H-M-benzodiaze-Info
- Publication number
- DE1906254C3 DE1906254C3 DE19691906254 DE1906254A DE1906254C3 DE 1906254 C3 DE1906254 C3 DE 1906254C3 DE 19691906254 DE19691906254 DE 19691906254 DE 1906254 A DE1906254 A DE 1906254A DE 1906254 C3 DE1906254 C3 DE 1906254C3
- Authority
- DE
- Germany
- Prior art keywords
- phenyl
- yield
- dihydro
- general formula
- dioxopiperazino
- 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.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- -1 methanol or ethanol Chemical compound 0.000 claims description 5
- MDPJHNGFYGSHME-UHFFFAOYSA-N 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine Chemical class C12=CC=CC=C2NCCN=C1C1=CC=CC=C1 MDPJHNGFYGSHME-UHFFFAOYSA-N 0.000 claims description 3
- JVVKRPCFYCPBNT-UHFFFAOYSA-N O=C1C(N(CCN1)C1=C(C(=O)C2=CC=CC=C2)C=CC=C1)=O Chemical compound O=C1C(N(CCN1)C1=C(C(=O)C2=CC=CC=C2)C=CC=C1)=O JVVKRPCFYCPBNT-UHFFFAOYSA-N 0.000 claims description 3
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- FBCZWQNVHNIQOD-UHFFFAOYSA-N 2-piperazin-1-yl-1H-indole Chemical compound C1CNCCN1C1=CC2=CC=CC=C2N1 FBCZWQNVHNIQOD-UHFFFAOYSA-N 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 229910000272 alkali metal oxide Inorganic materials 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- 150000001875 compounds Chemical class 0.000 claims 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L Calcium hydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims 1
- 229910001863 barium hydroxide Inorganic materials 0.000 claims 1
- 239000000920 calcium hydroxide Substances 0.000 claims 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminium hydride Substances [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 claims 1
- OCZDCIYGECBNKL-UHFFFAOYSA-N lithium;alumanuide Chemical compound [Li+].[AlH4-] OCZDCIYGECBNKL-UHFFFAOYSA-N 0.000 claims 1
- 239000001184 potassium carbonate Substances 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- ZUWXHHBROGLWNH-UHFFFAOYSA-N (2-amino-5-chlorophenyl)-phenylmethanone Chemical compound NC1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1 ZUWXHHBROGLWNH-UHFFFAOYSA-N 0.000 description 3
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-Chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 150000001557 benzodiazepines Chemical class 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 3
- JZWOKDTXYPEJEW-UHFFFAOYSA-N 7-chloro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine Chemical compound C12=CC(Cl)=CC=C2NCCN=C1C1=CC=CC=C1 JZWOKDTXYPEJEW-UHFFFAOYSA-N 0.000 description 2
- IWODVHYXSNXDAQ-UHFFFAOYSA-N O=C1N(CCNC1=O)C1=C(C(=O)C2=CC=CC=C2)C=C(C=C1)Cl Chemical compound O=C1N(CCNC1=O)C1=C(C(=O)C2=CC=CC=C2)C=C(C=C1)Cl IWODVHYXSNXDAQ-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 239000008079 hexane Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- NSGCECVNIHAAIE-UHFFFAOYSA-N 2,3-dihydro-1H-1,4-benzodiazepine Chemical compound N1CCN=CC2=CC=CC=C21 NSGCECVNIHAAIE-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- FEYRMXBCLPKSIJ-UHFFFAOYSA-N 3-phenyl-1H-indole-2-carboxylic acid Chemical class OC(=O)C=1NC2=CC=CC=C2C=1C1=CC=CC=C1 FEYRMXBCLPKSIJ-UHFFFAOYSA-N 0.000 description 1
- HJOHPCCUPCDFHG-UHFFFAOYSA-N 7-bromo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine Chemical compound C12=CC(Br)=CC=C2NCCN=C1C1=CC=CC=C1 HJOHPCCUPCDFHG-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N Benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- 229940035363 MUSCLE RELAXANTS Drugs 0.000 description 1
- 229940083876 Muscle relaxants FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 1
- GCAVNCINXJNLED-UHFFFAOYSA-N N-[(2-amino-5-chlorophenyl)-phenylmethylidene]hydroxylamine Chemical compound NC1=CC=C(Cl)C=C1C(=NO)C1=CC=CC=C1 GCAVNCINXJNLED-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000002921 anti-spasmodic Effects 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- FSLOLRKVZPTMHC-UHFFFAOYSA-N ethyl 5-chloro-3-phenyl-1H-indole-2-carboxylate Chemical compound CCOC(=O)C=1NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 FSLOLRKVZPTMHC-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000000147 hypnotic Effects 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002936 tranquilizing Effects 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
Description
(II)(II)
.15.15
4040
H2C NHH 2 C NH
CH,CH,
(III)(III)
in der X und Y die vorstehende Bedeutung haben, in einem Lösungsmittel in Gegenwart eines Alkalimetall- oder Erdalkalimetallhydroxids, Alkalimetallcarbonats oder von Ammoniumhydroxid erhitzt.in which X and Y have the above meaning, in a solvent in the presence of an alkali metal or alkaline earth metal hydroxide, alkali metal carbonate or heated by ammonium hydroxide.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man die Umsetzung in Gegenwart von Natriumhydroxid ausführt.2. The method according to claim 1, characterized in that the reaction is carried out in the presence of Sodium hydroxide executes.
in der X und Y die vorstehende Bedeutung haben, mit einem Oxidationsmittel hergestellt werden.
Die Piperazinoindole der allgemeinen Formel III können ihrerseits durch Reduktion von 1-Cyanmethyl-3-phenylindol-2-carbonsäureestern
der allgemeinen Formel IVin which X and Y are as defined above, are prepared with an oxidizing agent.
The piperazinoindoles of the general formula III can in turn by reducing 1-cyanomethyl-3-phenylindole-2-carboxylic acid esters of the general formula IV
Die Erfindung betrifft den in den Ansprüchen gekennzeichneten Gegenstand.The invention relates to the subject matter characterized in the claims.
Die Benzodiazepine der allgemeinen Formel I sind Tranquilizer, Hypnotika, Muskelrelaxantien und Spasmolytika. Sie sind auch wertvolle Zwischenprodukte zur Herstellung anderer Benzodiazepine mit ähnlichen pharmakologischen Eigenschaften.The benzodiazepines of the general formula I are tranquilizers, hypnotics, muscle relaxants and antispasmodics. They are also valuable intermediates in the manufacture of other benzodiazepines with similar ones pharmacological properties.
Es sind verschiedene Verfahren zur Herstellung der Benzodiazepine der allgemeinen Formel I bekannt. So kann z.B. S-Phenyl-Z-chlor^-dihydro-i H-l,4-benzodiazepin ausgehend von 2-Amino-5-chIorbenzophenon über das 2-Amino-5-chiorbenzophenonoxim (Ausbeute X-Various processes for the preparation of the benzodiazepines of the general formula I are known. So e.g. S-phenyl-Z-chloro ^ -dihydro-i H-1,4-benzodiazepine starting from 2-amino-5-chlorobenzophenone via the 2-amino-5-chlorobenzophenone oxime (yield X-
(IV)(IV)
COORCOOR
in der X und Y die vorstehende Bedeutung haben und R ein Wasserstoffatom oder ein Alkylrest mit 1 bis 4 C-Atomen ist, hergestellt werden.in which X and Y have the above meanings and R is a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms is produced.
Die 1 -Cyanmethyl-S-phenylindol^-carbonsäureester der allgemeinen!The 1 -Cyanmethyl-S-phenylindole ^ -carboxylic acid esters the general!
eines 3-Pher.ylindol-2-carbonsäureesters der allgemeinen Formel Vof a 3-Pher.ylindole-2-carboxylic acid ester of the general Formula V
(V)(V)
COORCOOR
4040
in der X, Y und R die vorstehende Bedeutung haben, mit einem reaktionsfähigen Ester des Cyanmethylalkohols in Gegenwart eines basischen Kondensationsmittels hergestelltin which X, Y and R have the above meaning with a reactive ester of cyanomethyl alcohol produced in the presence of a basic condensing agent
Die 3-Phenylindol-2-carbonsäureester der allgemeinen Formel V werden nach J. Proc Roy. Soc New South Wales, Bd. 71 (1938), S. 475, aus den entsprechenden Anilinen über die Diazoniumsalze und a-Benzylacetessigsäureester hergestelltThe 3-phenylindole-2-carboxylic acid esters of the general Formula V according to J. Proc Roy. Soc New South Wales, Vol. 71 (1938), p. 475, from the corresponding Anilines via the diazonium salts and a-benzyl acetic acid ester manufactured
Sämtliche vorgenannten Verfahren verlaufen glatt und ergeben die entsprechenden Verbindungen in hoher Ausbeute. So beträgt die Gesamtausbeute bei der Herstellung von 5-Phenyl-7-chlor-2,3-dihydro-l H-1,4-benzodiazepin, ausgehend von p-Chloranilin, etwa 31% d. Th. Im bekannten Verfahren beträgt die Gesamtausbeute, ausgehend von 2-Amino-5-chIorbenzophenon, etwa 37,6% d. Th. Das 2-Amino-5-chlorbenzophenon wird seinerseits aus p-Chloranilin und Benzoylchlorid mit einer Ausbeute von 45,5% d. Th. hergestellt Somit beträgt die Gesamtausbeute im bekannten Verfahren, ausgehend von p-Chloranilin, etwa 17% d. Th.All of the above processes run smoothly and result in the corresponding connections in high Yield. The total yield in the production of 5-phenyl-7-chloro-2,3-dihydro-l H-1,4-benzodiazepine is, starting from p-chloroaniline, about 31% d. Th. In the known process, the total yield is starting from 2-amino-5-chlorobenzophenone, about 37.6% of theory Th. The 2-amino-5-chlorobenzophenone is in turn from p-chloroaniline and benzoyl chloride with a yield of 45.5% d. Th. Manufactured Thus the total yield in the known process, starting from p-chloroaniline, is about 17% of theory. Th.
Beispiel 1
5-Phenyl-7-chlor-2,3-dihydro-1 H-1,4-benzodiazepinexample 1
5-phenyl-7-chloro-2,3-dihydro-1 H-1,4-benzodiazepine
Eine Lösung von 2 g Natriumhydroxid in 5 ml Wasser und 50 ml Äthanol wird mit 3,3 g 2-(2,3-Dioxopiperazino)-5-chlorbenzophenon versetzt. Das Gemisch wird 3 Stunden unter Rückfluß gekocht, danach mit 50 ml Wasser versetzt und weitere 17 Stunden unter Rückfluß erhitzt Anschließend wird der größte Teil des Äthanols abdestilliert. Der Rückstand wird mit 200 ml Wasser versetzt und auf 8O0C erhitzt. Die Kristalle werden werden abfiltriert. Ausbeute 2 g (78% d. Th.) 5-Phenyl-7-chlor-2,3-dihydro-l H-1,4-benzodiazepin. Nach Umkristallisation aus Äthanol schmelzen die gelben Kristalle bei 1730C.3.3 g of 2- (2,3-dioxopiperazino) -5-chlorobenzophenone are added to a solution of 2 g of sodium hydroxide in 5 ml of water and 50 ml of ethanol. The mixture is refluxed for 3 hours, then 50 ml of water are added and the mixture is refluxed for a further 17 hours. Most of the ethanol is then distilled off. The residue is mixed with 200 ml of water and heated to 8O 0 C. The crystals are filtered off. Yield 2 g (78% of theory) of 5-phenyl-7-chloro-2,3-dihydro-1 H-1,4-benzodiazepine. After recrystallization from ethanol, the yellow crystals melt at 173 ° C.
Die Ausgangsverbindung wird folgendermaßen hergestellt: The output connection is established as follows:
A) l-Cyanmethyl^-äthoxycarbonyl-S-phenyl-5-chlorindol A) l-Cyanmethyl ^ ethoxycarbonyl-S-phenyl-5-chloroindole
Ein Gemisch aus 1,1 g 50prozentigem Natriumhydrid und 10 ml Dimethylformamid wird mit einer Lösung von 6 g 3-Phenyl-5-chlorindol-2-carbonsäureäthylester in (.0 30 ml Dimethylformamid bei 30 bis 350C versetzt. Nach 15minütigem Rühren bei 30"C wird bei 30 bis 350C eine Lösung von 1,7 g Chloracetonitril in 10 ml Dimethylformamid eingetropft. Das Gemisch wird anschließend eine Stunde bei 25 bis 3O0C gerührt, hierauf mit Wasser ι··, versetzt und mit Äther extrahiert. Die Ätherlösung wird mit Wasser gewaschen, über Natriumsulfat getrocknet und eingedampft. Es hintcrbicibcn 7 g eines Feststoffs, der mit 100 ml Hexan versetzt wird. Das Gemisch wird filtriert Es werden 5,5 g (81,2% d. Th.) l-Cyanmethyl-3-phenyl-S-chlorindol^-carbonsäureäthylester erhalten. Nach Umkristallisation aus einer Mischung von Benzol und Hexan werden gelbliche Nadeln vom F. 1263 bis 127°C erhalten.A mixture of 1.1 g 50prozentigem sodium hydride and 10 ml of dimethylformamide is treated with a solution of 6 g of 3-phenyl-5-chloroindole-2-carboxylic acid ethyl ester in (.0 30 ml of dimethylformamide at 30 to 35 0 C. After 15 minutes of stirring at 30 "C is at 30 to 35 0 C is added dropwise a solution of 1.7 g of chloroacetonitrile in 10 ml of dimethylformamide. The mixture is then stirred for one hour at 25 to 3O 0 C, then with water ι ··, and extracted with ether The ether solution is washed with water, dried over sodium sulfate and evaporated. 7 g of a solid are left behind, to which 100 ml of hexane are added. The mixture is filtered -Cyanmethyl-3-phenyl-S-chloroindole ^ -carboxylic acid ethyl ester After recrystallization from a mixture of benzene and hexane, yellowish needles with a melting point of 1263 to 127 ° C. are obtained.
B) 7-Chlor-9-phenyl-10-oxopiperazino-(l,2-a)-indol B) 7-chloro-9-phenyl-10-oxopiperazino- (1,2-a) indole
Eine Lösung von 10 g l-Cyanmethyl^-carbäthoxy-S-phenyl-5-chlorindol in 100 ml Tetrahydrofuran wird mit einem Katalysator versetzt der durch 1 stündige Behandlung einer 50prozentigen Raney-Nickellegierung mit Natronlauge bei 100° C erhalten wurde. Danach wird das Gemisch bei Normaldruck und 18° C mit Wasserstoff hydriert Nach 12 Stunden sind 2 Mol Wasserstoff aufgenommen, und die Hydrierung ist beendet Der Katalysator wird abfiltriert, das Tetrahydrofuran unter vermindertem Druck abdestilliert und der Rückstand in heißem Äthanol aufgenommen. Die Lösung wird 15 Stunden im Kühlschrank stehengelassen. Die abgeschiedenen Kristalle werden abfiltriert und aus einer Mischung von Äthanol und wenig Benzol umkristallisiert Ausbeute 3,6 g hellgelbe Nadeln des Produktes vom F. 244,5 bis 245°C Die Mutterlauge wird unter vermindertem Druck eingedampft der Rückstand mit 50 ml Tetrachlorkohlenstoff aufgekocht bis alles in Lösung gegangen ist und die Lösung auf Raumtemperatur abgekühlt.A solution of 10 g of l-cyanomethyl ^ -carbethoxy-S-phenyl-5-chloroindole in 100 ml of tetrahydrofuran, a catalyst is added which lasts for 1 hour Treatment of a 50 percent Raney nickel alloy was obtained with sodium hydroxide solution at 100 ° C. The mixture is then at normal pressure and 18 ° C hydrogenated with hydrogen After 12 hours, 2 mol of hydrogen have been taken up and the hydrogenation is complete The catalyst is filtered off, the tetrahydrofuran is distilled off under reduced pressure and the residue taken up in hot ethanol. The solution is left to stand in the refrigerator for 15 hours. The deposited crystals are filtered off and made from a mixture of ethanol and a little benzene recrystallized Yield 3.6 g of light yellow needles of the product with a melting point of 244.5 to 245 ° C. The mother liquor is evaporated under reduced pressure, the residue boiled with 50 ml of carbon tetrachloride until everything was in Solution has gone and the solution cooled to room temperature.
Die abgeschiedenen Kristalle werden abfiltriert, mit Tetrachlorkohlenstoff gewaschen und getrocknet. Es werden weitere 3,4 g Produkt vom F. 244,5 bis 245° erhalten. Gesamtausbeute 80% d. Th.The deposited crystals are filtered off, washed with carbon tetrachloride and dried. It a further 3.4 g of product with a melting point of 244.5 ° to 245 ° are obtained. Total yield 80% of theory Th.
Ein Gemisch aus 1,6 g 7-Chlor-9-phenyl-10-oxopiperazino-(l,2-a)-indol und 35 ml Essigsäure wird mit einer Lösung von 1,6 g Chromsäureanhydrid in 2 ml Wasser bei 10° C versetzt.A mixture of 1.6 g of 7-chloro-9-phenyl-10-oxopiperazino- (1,2-a) indole and 35 ml of acetic acid is mixed with a solution of 1.6 g of chromic anhydride in 2 ml of water added at 10 ° C.
Nach 16stündigem Rühren bei 200C wird das Gemisch in 500 ml Wasser eingegossen. Der pH-Wert wird mit wäßriger Ammoniaklösung auf 7 bis 8 eingestellt und das Reaktionsgemisch mit Chloroform extrahiert. Die Chloroformlösung wird mit Wasser gewaschen, über Natriumsulfat getrocknet und eingedampft. Es hinterbleiben 1,5 g (84,7% d.Th.) hellgelbe Kristalle. Nach Umkristallisation aus wäßrigem Äthanol fällt das Produkt in Form farbloser Kristalle vom F. 198° C an.After stirring for 16 hours at 20 0 C, the mixture in 500 ml of water is poured. The pH is adjusted to 7 to 8 with aqueous ammonia solution and the reaction mixture is extracted with chloroform. The chloroform solution is washed with water, dried over sodium sulfate and evaporated. 1.5 g (84.7% of theory) of light yellow crystals remain behind. After recrystallization from aqueous ethanol, the product is obtained in the form of colorless crystals with a melting point of 198 ° C.
Beispiel 2
5-Phenyl-2,3-dihydro-lH-l,4-benzodiazepinExample 2
5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine
Gemäß Beispiel 1 wird 5-Phenyl-2,3-dihydro-1H-1,4-benzodiazepin vom F. 144 bis 146° C aus 2-(2,3-Dioxopiperazino)-benzophenon hergestellt. Das Produkt wird aus Petroläther umkristallisiert. Ausbeute 70% d. Th.According to Example 1 there is 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine from a melting point of 144 to 146 ° C from 2- (2,3-dioxopiperazino) benzophenone manufactured. The product is recrystallized from petroleum ether. Yield 70% of theory Th.
Beispiel 3
5-Phenyl-7-brom-2,3-dihydro-IH-1,4-benzodiazepinExample 3
5-phenyl-7-bromo-2,3-dihydro-IH-1,4-benzodiazepine
Gemäß Beispiel 1 wird 5-Phenyl-7-brom-2,3-dihydro IH-1,4-benzodiazepin vom F. 173 bis 175°C aus 2-(2,3- Dioxopiperazino)-5-brombenzophenon hergestellt. Ausbeute 77% d. Th.According to Example 1, 5-phenyl-7-bromo-2,3-dihydro IH-1,4-benzodiazepine has a melting point of 173 to 175 ° C 2- (2,3-Dioxopiperazino) -5-bromobenzophenone prepared. Yield 77% of theory Th.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19691906254 DE1906254C3 (en) | 1968-05-10 | 1969-02-07 | Process for the preparation of 5-phenyl ^ -dihydro-1H-M-benzodiaze- |
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP895168 | 1968-02-13 | ||
| JP2188768 | 1968-04-02 | ||
| JP2253068 | 1968-04-04 | ||
| JP3146668 | 1968-05-10 | ||
| JP3146668 | 1968-05-10 | ||
| JP3326068A JPS4826752B1 (en) | 1968-05-17 | 1968-05-17 | |
| JP3624968 | 1968-05-27 | ||
| JP4110668 | 1968-06-13 | ||
| DE19691906254 DE1906254C3 (en) | 1968-05-10 | 1969-02-07 | Process for the preparation of 5-phenyl ^ -dihydro-1H-M-benzodiaze- |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE1906254A1 DE1906254A1 (en) | 1969-09-18 |
| DE1906254B2 DE1906254B2 (en) | 1977-05-18 |
| DE1906254C3 true DE1906254C3 (en) | 1978-01-19 |
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