DE1545955A1 - Process for the preparation of benzodiazepine derivatives - Google Patents
Process for the preparation of benzodiazepine derivativesInfo
- Publication number
- DE1545955A1 DE1545955A1 DE19631545955 DE1545955A DE1545955A1 DE 1545955 A1 DE1545955 A1 DE 1545955A1 DE 19631545955 DE19631545955 DE 19631545955 DE 1545955 A DE1545955 A DE 1545955A DE 1545955 A1 DE1545955 A1 DE 1545955A1
- Authority
- DE
- Germany
- Prior art keywords
- acid
- hydrogen
- phenyl
- benzodiazepine
- halogen
- 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
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
- C07D243/20—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Inductance-Capacitance Distribution Constants And Capacitance-Resistance Oscillators (AREA)
Description
ι, Bftftl (Sohweia)ι, Bftftl (Sohweia)
Die Erfindung betrifft ein Verfahren zur Herstellung Ton Bensodiazepln-SeriTaten der allgemeinen formelThe invention relates to a method of manufacture Ton Bensodiazepln-SeriTaten of the general formula
(D(D
worin R, Wasserstoff, Alkanoyl oder Aralkanoyl, Rp Wasserstoff oder Alkyl, R, Wasserstoff, Halogen oder Trifluormethyl und R. Wasserstoff, Halogen, Trifluormethyl, Nitro, Alkylthio oder Alkyl bedeuten, where R, hydrogen, alkanoyl or aralkanoyl, R p is hydrogen or alkyl, R, hydrogen, halogen or trifluoromethyl and R. is hydrogen, halogen, trifluoromethyl, nitro, alkylthio or alkyl,
und deren Säureaddltioneealze.and their acid addition salts.
kettige und verzweigte niedere Alkyl^ruppen, wie Methyl, Aethyl, Propyl, Ieopropyl und dergleichen. Der Ausdruck Alkanoyl betrifft geradkettige und verwreigte niedere alipathieohe Oarboneäuregruppen, wie Acetyl, Pro-chain and branched lower alkyl groups, such as methyl, ethyl, propyl, ieopropyl and the like. The term alkanoyl refers to straight and twisted ones lower aliphatic acid groups, such as acetyl, pro
9ΛΠ ORIGINAL9ΛΠ ORIGINAL
pionyl,Bu.tyryl, Isovaleroyl und dergleichen.pionyl, Bu.tyryl, isovaleroyl and the like.
Das erfindungsgemässe Verfahren ist daduroh gekennzeichnet, dass man eine Verbindung der allgemeinen FormelThe method according to the invention is characterized by that you can get a compound of the general formula
(II)(II)
worin R1, R2, R, und R. die vorstehend angegebene Bedeutung haben und R- Alkanoyl, Aroyl oder Aral-wherein R 1 , R 2 , R, and R. have the meaning given above and R- alkanoyl, aroyl or aral
kanoyl bedeutet,
hydrolysiert,
und erwünschtenfalls die erhaltene Verbindung in ein Salzkanoyl means
hydrolyzed,
and if desired, the compound obtained into a salt
überführt.convicted.
Die Hydrolyse von Verbindungen der Formel II kann durch alkalische Hydrolyse oder durch saure Hydrolyse vorgenommenThe hydrolysis of compounds of the formula II can be carried out by alkaline hydrolysis or by acid hydrolysis
to werden. Die letztere wird vorzugsweise durch Behandlung des οto be. The latter is preferably done by treating the ο
*° Ausgangematerials mit einer wässrigen Lösung einer Mineral-* ° starting material with an aqueous solution of a mineral
^j säure, wie Chlorwasserstoffsäure, Bromwasserstoffsäure, Sohwe-^ j acid, such as hydrochloric acid, hydrobromic acid, Sohwe-
-* folsäure oder dergleichen, oder einer organischen Säure, wie . 2 Toluolsulfonsäure oder dergleichen vorgenommen. Die Säurebehandlung wird zweokmässigerweise bei Raumtemperatur durchgeführt, obwohl dies nioht kritisch ist und auch höhere oder- * folic acid or the like, or an organic acid, such as . 2 made toluenesulfonic acid or the like. The acid treatment is carried out in two ways at room temperature, although this is not critical and also higher or
BAD OR.'GiNALBAD OR.'GiNAL
tiefere Temperatur angewendet werden können. Bs ist selbstverständlich, dass die Temperatur nicht so hoch sein soll» dass eins Zersetzung des gewünschten Bndproduktes eintritt. Bs wurde festgestellt, dass die. saure Hydrolyse besonders vorteilhaft ist und stets hohe Ausbeuten liefert. Diese saure Hydrolyse wird zweckmässigerweiee in einem wässrigen Medium durchgeführt, das ein organisches Lösungsmittel, wie Dioxan, Tetrahydrofuran oder ähnliche mit Wasser mischbare Lösungsmittel enthält.lower temperature can be used. Bs is a matter of course, that the temperature should not be so high that the desired end product decomposes. Bs was found to be the. acid hydrolysis is particularly advantageous and always delivers high yields. This acid hydrolysis is expediently carried out in an aqueous medium, which contains an organic solvent such as dioxane, tetrahydrofuran or similar solvents miscible with water.
Die im erfindungsgemässen Verfahren verwendeten Ausgangsmaterialien der Formel II können durch Umsetzung einer Verbindung der allgemeinen FormelThe starting materials used in the process according to the invention of the formula II can be obtained by reacting a compound of the general formula
(III)(III)
worin R1, R9, R, mid R. die vorstehende χχ.-cleutungwherein R 1 , R 9 , R, mid R. the above χχ.-definition
CO ^CO ^
° haben,° have
mit einem Säureanhydrid, Diaoylsulfid oder Säurehalogenid (die Chloride sind be-with an acid anhydride, diaoyl sulfide or acid halide (the chlorides are
ywerden, wobely
vorsugt) gewoimegfygine Abspaltung des Saueret off atoms in 4-ywerd en, wobely
preventive) gewoimegfygine splitting off of the Saueret off atom in 4-
Jjewirkt wird,
stoffatoHS in 3-Stellungi/T)ieee Reaktion wird sweckmässiger- Jjewirk t will
stoffatoHS in 3-positioni / T) the reaction is more gradual
weise in eines übliohen organischen Lösungsmittel, wie Dime-wise in a common organic solvent, such as dim-
thylformamid, Pyridln oder dergleichen, durchgeführt· Bei Verwendung eines Säureanhydride oder eine Diaoylsulfid ale Aoylierungsmittel gönnen diese Säureanhydride oder Diacylsulflde auoh direkt als Beaktionsmedium dienen. Die Umsetzung kann bei Baumtemperatur oder auoh oberhalb oder unterhalb derthylformamide, pyridine or the like Use of an acid anhydride or a diacyl sulfide as aoylating agent treat these acid anhydrides or diacyl sulfides also serve directly as a reaction medium. The implementation can be at tree temperature or auoh above or below the
Falls R, in Formel III Wasserstoff ist, erhält man Verbindungen der Formel Π, worin R, und R5 dieselben Acylgruppen sind. Anderseits kann man bei Venrendung eines Auegangsmaterials der Formel III, worin R, bereite eine Aoylgruppe bedeutet, Verbindungen erhalten, worin R1 unverändert ist und dementsprechend R. und P^ dieselben oder verschiedene Acylgruppen bedeuten. Is wurde ausserdem festgestellt, dass bei Verwendung von . Dimethylformamid als Reaktionsmedium Verbindungen der Formel III, worin R, Vaeserstoff ist, selektiv unter Bildung von Verbindungen der Formel I, worin R, Wasserstoff 1st, aoyliert werden können. Ie wurde ausserdem festgestellt, dass die Aroylierung selektiv an der 3-Steilung erfolgt und das Stickstoffatom in 2-Steilung nicht beeinflusst.If R 1 in formula III is hydrogen, compounds of the formula Π in which R 1 and R 5 are the same acyl groups are obtained. On the other hand, when using a starting material of the formula III in which R 1 is already an aoyl group, compounds in which R 1 is unchanged and accordingly R and P 1 are the same or different acyl groups can be obtained. Is has also been found to cause problems when using. Dimethylformamide as the reaction medium Compounds of the formula III in which R 1 is hydrogen can be aoylated selectively to form compounds of the formula I in which R 1 is hydrogen. It was also found that the aroylation takes place selectively at the 3-position and does not affect the nitrogen atom in the 2-position.
Verbindungen der Formel I bilden Säureadditionssalze mit sowohl anorganischen als auch organischen Säuren,Compounds of the formula I form acid addition salts with both inorganic and organic acids,
wie Salzsäure, Bromwasserstoffsäure, Salpetersäure, Schwe-such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric
"° feisäure, Phosphorsäure, Citronensäure, Ameisensäure, Bssig-"° Feic acid, phosphoric acid, citric acid, formic acid, acidic
**» luolsulfoneäure und dergleichen.** »luenesulfonic acid and the like.
Sie Verbindungen der Formeln I können als Sedative, Anticonvulsiva und Muskelrelaxantien verwendet werden. DieseThe compounds of the formula I can be used as sedatives, anticonvulsants and muscle relaxants. These
-S--S-
Verbindungen oder Ihre pharmazeutische verwendbaren Säureadditionssalze können als Hellmittel z.B. In Form pharmazeutischer Präparate Verwendung finden, welche sie oder Ihre Salze in Mischung mit einem für die enterale oder parenterale Applikation geeigneten pharamzeutisehen, organischen oder anorganischen inerten Trägermaterial« wie z.B. Wasser, Gelatine, Milchzukker, Stärke, Magnesiumstearat, Talk, pflanzliche OeIe, Gummi Polyalkylenglykole, Vaseline, usw. enthalten. Sie pharmazeutischen Präparate können in fester Form z.B. als Tabletten, Dragoes, SuppositorJen, Kapseln, oder in flüssiger Form,z.B. als Lösungen, Suspensionen oder Emulsionen, vorliegen. Gegebenenfalls sind sie sterilisiert und bzw. oder enthalten Hilfsstoffe, wie Konservierungs-, Stabilisierungs-« Netzoder Emulgiermittel, Salze ur Veränderung des osmotischen Druckes oder Puffer. Sie kennen auch noch andere therapeutisch wertvolle Stoffe enthalten.Compounds or their pharmaceutically acceptable acid addition salts can be used as a lightening agent, e.g. in the form of pharmaceutical preparations, which they or their salts in Mixture with a pharmaceutical, organic or inorganic, suitable for enteral or parenteral administration inert carrier material «such as water, gelatine, milk sugar, starch, magnesium stearate, talc, vegetable oils, gum Contains polyalkylene glycols, petroleum jelly, etc. You pharmaceutical Preparations can be in solid form, e.g. as tablets, dragoes, suppositories, capsules, or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contained Auxiliaries, such as preservatives, stabilizers, nets or Emulsifiers, salts for changing the osmotic pressure or buffers. You also know others therapeutically contain valuable substances.
Eine Lösung von 1,9 g 7-Chlor-2-(N-methyl-aoetamido)-3-acetoxy-5-phenyl-3H-l,4-benzodlazepin in 50 ml Dioxan wirdA solution of 1.9 g of 7-chloro-2- (N-methyl-aoetamido) -3-acetoxy-5-phenyl-3H-1,4-benzodlazepine in 50 ml of dioxane
co mit 10 ml 1 η Natronlauge versetzt. Die Mlaohung wird 20 Stun-co mixed with 10 ml 1 η sodium hydroxide solution. The Mlaohung will be 20 hours
<° den bei Raumtemperatur gerührt und hierauf in Vakuum eingeengt.<° the stirred at room temperature and then concentrated in vacuo.
^ Der Rückstand wird in Methylenchlorid gelöst und mit Wasser ge- -> waschen, und die organische Schicht abgetrennt, gttrocknet und im Vakuum eingeengt. Der Rückstand wird aus Methylenchlorid umkristallisiert und !liefert farblo·· Nadeln vom T-Chlor-a-methyl amino-S-phenyl-OH-l^-bensodiazepin^-ol. Fp. 191-192° (Zers.)j^ The residue is dissolved in methylene chloride and washed with water -> wash, and the organic layer separated, dried and concentrated in vacuo. The residue is recrystallized from methylene chloride and! supplies colorless needles of T-chloro-a-methyl amino-S-phenyl-OH-l ^ -bensodiazepine ^ -ol. Mp. 191-192 ° (dec.) J
Ausbeute 0,3g.Yield 0.3g.
Das Ausgangsmaterial kann wie folgt hergestellt werden:The starting material can be produced as follows:
Eine Lösung von 31 g^
3H-l,4-benzodiazepin-lK>xyd in einer Mischung von 36O ml Pyridin
und 180 ml Essigsäureanhydrid wird 20 Minuten auf 500 erhitzt und
hierauf während 4 Tagen bei Raumtemperatur stehen gelassen. Sodann wird die Lösung im Vakuum auf ein kleines Volumen eingeengt
und der Rückstand mit Aether und Petroläther behandelt, worauf sich Kristalle ausscheiden. Die erste Kristallfraktion
(19,1 g) besteht im wesentlichen aus reinem 7-Chlor-2-(N-methylacetamido)-5-phenyl-3H-l,4-benzodiazepin-4-oxyd.
Die zweite Fraktion (11,8 g) die man nach Zusatz von weiterem Petroläther erhält, schmilzt unter l40°. Nach dem Umkristallisieren dieser
Fraktion aus Aether oder, einer Mischung von Methylenchlorid,
Aether und Petroläther erhält man 7-Chlor-2-(N-methyl-acetamido)-3-acetoxy-5-phenyl-3H-l,4-benzodiazepin.
Das Produkt ist dimorph und bildet farblose Prismen vom Schmelzpunkt 145-146° bzw. 159-160°.
Ausbeute 27,8 g; 74,8 %. A solution of 31 g ^
3H-l, 4-benzodiazepin-lK> xyd in a mixture of 36O ml of pyridine and 180 ml acetic anhydride is heated for 20 minutes 50 0 and then allowed to stand for 4 days at room temperature. The solution is then concentrated to a small volume in vacuo and the residue is treated with ether and petroleum ether, whereupon crystals separate out. The first crystal fraction (19.1 g) consists essentially of pure 7-chloro-2- (N-methylacetamido) -5-phenyl-3H-1,4-benzodiazepine-4-oxide. The second fraction (11.8 g), which is obtained after adding more petroleum ether, melts below 140 °. After recrystallization of this fraction from ether or a mixture of methylene chloride, ether and petroleum ether, 7-chloro-2- (N-methyl-acetamido) -3-acetoxy-5-phenyl-3H-1,4-benzodiazepine is obtained. The product is dimorphic and forms colorless prisms with a melting point of 145-146 ° or 159-160 °. Yield 27.8 g; 74.8 %.
Beispiel 2
co Example 2
co
ω Eine Lösung von 3,8 g 7-Chlor-2-(N-methyl-acetamido)- ω A solution of 3.8 g of 7-chloro-2- (N-methyl-acetamido) -
** 3-acetoxy-5-phenyl-3H-l,4-benzodia»tpln in 50 ml Dioxan wird 2^ alt 10 Dl 1 η Natronlauge behandelt. Nach Stehen bei Rauratenperatür während 1 1/2 Stunden wird dl· Mischung im Vakuum auf ein kitin·! Volumen eingeengt und mit Wasser und Aether verdünnt.** 3-acetoxy-5-phenyl-3H-1,4-benzodia »tpln in 50 ml of dioxane 2 ^ old 10 Dl 1 η sodium hydroxide solution treated. After standing at rate peratur During 1 1/2 hours, the mixture is reduced to one in vacuo kitin ·! Volume reduced and diluted with water and ether.
▼olumtn eingeengt und die gebildeten Kristall· abfiltriert.The oil is concentrated and the crystals formed are filtered off.
Mach Umkristallisieren aus Aotton erhält man farblos« PrismenIf you recrystallize from Aotton, you get colorless prisms
von 7-ChloΓ-2-raethylamino-3-aoβtoxy-5-phβnyl··3H-l,4-beniBodiarepin. Fp. 202-203°. Ausbeute 1,3 Bi of 7-ChloΓ-2-raethylamino-3-aoβtoxy-5-phβnyl · · 3H-1,4-beniBodiarepin. 202-203 °. Yield 1.3 bi
Eine Lösung von 3#4 g T-phenyl-3H-l,4-benzodlazepln£n einer Mischung von 50 ml Dioxan und 10 al 1 η Natronlauge wird 4 Stunden bei Raumtemperatur gerührt und hierauf im Vakuum auf ein kleines Volumen eingeengt. Man setzt Wasser oiuldLactzahiert das Reaktionsprodukt mit Me thylenohlorid. Die organische Schicht wird getrocknet,im Vakuum eingeengt und das zurückbleibende OeI aus Aether kristallisiert. Naoh Umkristallisieren aus einer Mischung von Methylenchlorid und Petroläther erhält man farblose Nadeln von 7-Chlor-2-methylaeino-5-phenyl-3H-l,4-benzodiazepin-3-ol vom Schmelzpunkt 184-186°. Ausbeute 2,6 g; 87*.A solution of 3 # 4 g of T-phenyl-3H-1,4-benzodlazepln £ n a mixture of 50 ml of dioxane and 10 al 1 η sodium hydroxide solution is stirred for 4 hours at room temperature and then concentrated in vacuo to a small volume. Water is added and the reaction product is counted with methylene chloride. The organic layer is dried and concentrated in vacuo and the remaining oil is crystallized from ether. After recrystallization from a mixture of methylene chloride and petroleum ether, colorless needles of 7-chloro-2-methylaeino-5-phenyl-3H-1,4-benzodiazepin-3-ol are obtained from melting point 184-186 °. Yield 2.6 g; 87 *.
Zu einer Lösung von 6,9 g 3-Acetoxy-2-methylamino-5-phenyl· 7-trifluormethyl-3H-lJ4-benzodiazepin-hydrochlorid in 150 ml Aβthanöl setzt man bei 30° 25 ml 2 η Natronlauge zu und rührt die Reaktionsmischung hierauf 20 Minuten bei 40-50°. Nach Abkühlen und Verdünnen mit 150 ml Wasser werden 16,7 »1 1 η Salzsäure zugesetzt. Die Lösung wird sodann mit Chloroform extrahiert, die Chloroformschicht mit Wasser gewaschen, über Natriumsulfat getrocknet, filtriert und im Vakuum zur Trockene gebracht. Nach Erwärmen des Rückstandes mit Hexan kristallisiert 2-Methylandno-5-phenyl-7-trifluormethyl-3H-l,4-benzodiazepin-3-ol-To a solution of 6.9 g of 3-acetoxy-2-methylamino-5-phenyl.7-trifluoromethyl-3H-1 J 4-benzodiazepine hydrochloride in 150 ml of ethanol is added at 30 ° 25 ml of 2 η sodium hydroxide solution and stirred the reaction mixture then 20 minutes at 40-50 °. After cooling and dilution with 150 ml of water, 16.7 »1 1 η hydrochloric acid are added. The solution is then extracted with chloroform, the chloroform layer washed with water, dried over sodium sulfate, filtered and brought to dryness in vacuo. After heating the residue with hexane, 2-Methylandno-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepin-3-ol-
g09847/1183 BAD originalg09847 / 1183 BAD original
sieren aus einer Mischung von Benzol und Hexan liefert Büschel von farblosen Stäbchen mit unverändertem Schmelzpunkt. Ausbeute 3,15 g; 57#.Sizing from a mixture of benzene and hexane produces tufts of colorless rods with an unchanged melting point. Yield 3.15g; 57 #.
Zu einer Lösung von 10 mMol 2-Methylamino-5-phenyl-7-triohlormethyl-3H-l,4-benzodiazepin-4-oxyd in 20 ml Dimethylformamid setzt man unter Rühren 15 mMol Acetylchlorid zu. Man lässt die Lösung 1 Stunde bei Raumtemperatur stehen und destilliert hierauf das Lösungsmittel im Vakuum unterhalb 35° Ab. Der Rückstand wird mit Aceton zum Rückfluss erhitzt, abgekühlt und filtriert, worauf man 3-Acetoxy-2-methylamino-5-phenyl-7-trifluormethyl-3H-l,4-benzodiazepin-hydrochlorld erhält, das nach zweimaligem Umkristallisieren aus Acetonitril farblose Nadeln vom Schmelzpunkt 206-207° liefert.To a solution of 10 mmol of 2-methylamino-5-phenyl-7-triohlomethyl-3H-1,4-benzodiazepine-4-oxide 15 mmol of acetyl chloride are added to 20 ml of dimethylformamide with stirring. The solution is left to stand at room temperature for 1 hour and The solvent is then distilled off in vacuo below 35 °. The residue is refluxed with acetone and cooled and filtered, whereupon 3-acetoxy-2-methylamino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine hydrochloride obtained which, after recrystallizing twice from acetonitrile, gives colorless needles with a melting point of 206-207 °.
700 mg 3-Aoetoxy-2-mβthylamino-5-phβnyl-7-trifluormβthyl-3H-l,4-benzodiazepin-hydroohlorid wird zwieohen Chloroform und verdünnter Natriumcarbonatlösung verteilt. Die organische Schicht wird mit Wasser gewaschen, über Natriumsulfat getrocknet, filtriert und im Vakuum zur Trockene gebracht. Der Rückstand wird co700 mg 3-Aoetoxy-2-methylamino-5-phβnyl-7-trifluoromβthyl-3H-1,4-benzodiazepine hydrochloride is distributed between chloroform and dilute sodium carbonate solution. The organic layer is washed with water, dried over sodium sulfate, filtered and brought to dryness in a vacuum. The residue is co
<o aus einer Mischung von Benzol und Hexan kristallisiert und lie-<o crystallized from a mixture of benzene and hexane and
*- fert j-Acetoxy^-methyleiiilno-S-phenyl-T-trifluoniietliyl-JH-l,^·?· Il benzodiazepin, das in grossen farblosen Prismen vom Schmelzpunkt oa 211-212° kristallisiert. Weiteres Umkristallisieren ändert den* - fert j-Acetoxy ^ -methyleiiilno-S-phenyl-T-trifluoniietliyl-JH-l, ^ ·? · Il benzodiazepine, which in large colorless prisms from the melting point oa 211-212 ° crystallized. Further recrystallization changes that
Claims (4)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17855162A | 1962-03-09 | 1962-03-09 | |
US240750A US3340253A (en) | 1962-11-28 | 1962-11-28 | Preparation of certain benzodiazepine compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
DE1545955A1 true DE1545955A1 (en) | 1969-11-20 |
Family
ID=26874429
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE19631445873 Pending DE1445873A1 (en) | 1962-03-09 | 1963-02-23 | Process for the preparation of benzodiazepine derivatives |
DE19631545955 Pending DE1545955A1 (en) | 1962-03-09 | 1963-02-23 | Process for the preparation of benzodiazepine derivatives |
DE19631545957 Pending DE1545957A1 (en) | 1962-03-09 | 1963-02-23 | Process for the preparation of benzodiazepine derivatives |
DE19631545956 Pending DE1545956A1 (en) | 1962-03-09 | 1963-02-23 | Process for the preparation of benzodiazepine derivatives |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE19631445873 Pending DE1445873A1 (en) | 1962-03-09 | 1963-02-23 | Process for the preparation of benzodiazepine derivatives |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE19631545957 Pending DE1545957A1 (en) | 1962-03-09 | 1963-02-23 | Process for the preparation of benzodiazepine derivatives |
DE19631545956 Pending DE1545956A1 (en) | 1962-03-09 | 1963-02-23 | Process for the preparation of benzodiazepine derivatives |
Country Status (9)
Country | Link |
---|---|
BE (1) | BE629227A (en) |
CA (1) | CA976547A (en) |
CH (2) | CH442326A (en) |
DE (4) | DE1445873A1 (en) |
DK (1) | DK127507B (en) |
ES (1) | ES285854A1 (en) |
GB (2) | GB1013900A (en) |
NL (3) | NL7010711A (en) |
SE (2) | SE328583B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES405260A1 (en) * | 1972-07-28 | 1975-07-01 | Stabilimenti Chim Farmac Riuni | Benzodiazepine compounds for therepeutical use |
NL173269C (en) * | 1974-04-30 | 1984-01-02 | Ferrer Int | METHOD FOR PREPARING A MEDICINAL PRODUCT WITH THE ACTIVE SUBSTANCE OF A 1,4-BENZODIAZEPINE DERIVATIVE AND METHOD FOR THE PREPARATION OF THE 1,4-BENZODIAZEPINE DERIVATIVE |
DE3413592C2 (en) * | 1984-04-11 | 1986-06-05 | Dolorgiet GmbH & Co KG, 5205 St Augustin | Medicaments containing 5- (2-fluorophenyl) -1,3-dihydro-3-hydroxy-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-one |
DK287185A (en) * | 1984-06-26 | 1986-02-24 | Merck & Co Inc | BENZODIAZEPINE DERIVATIVE AND PHARMACEUTICAL PREPARATION CONTAINING A SEED ANTI-DERIVATIVE |
-
0
- NL NL289735D patent/NL289735A/xx unknown
-
1963
- 1963-02-21 CH CH222063A patent/CH442326A/en unknown
- 1963-02-21 CH CH1765866A patent/CH457464A/en unknown
- 1963-02-23 DE DE19631445873 patent/DE1445873A1/en active Pending
- 1963-02-23 DE DE19631545955 patent/DE1545955A1/en active Pending
- 1963-02-23 DE DE19631545957 patent/DE1545957A1/en active Pending
- 1963-02-23 DE DE19631545956 patent/DE1545956A1/en active Pending
- 1963-02-27 CA CA869,700A patent/CA976547A/en not_active Expired
- 1963-03-06 BE BE629227A patent/BE629227A/en unknown
- 1963-03-07 GB GB4791264A patent/GB1013900A/en not_active Expired
- 1963-03-07 GB GB909463A patent/GB1013229A/en not_active Expired
- 1963-03-08 SE SE02566/63A patent/SE328583B/xx unknown
- 1963-03-08 ES ES285854A patent/ES285854A1/en not_active Expired
-
1970
- 1970-07-20 NL NL7010711A patent/NL7010711A/xx unknown
- 1970-07-20 NL NL7010712A patent/NL7010712A/xx unknown
- 1970-09-11 SE SE12424/70A patent/SE361174B/xx unknown
-
1972
- 1972-01-18 DK DK25372A patent/DK127507B/en unknown
Also Published As
Publication number | Publication date |
---|---|
NL7010711A (en) | 1970-10-26 |
DE1545957A1 (en) | 1969-12-11 |
CH457464A (en) | 1968-06-15 |
GB1013900A (en) | 1965-12-22 |
NL7010712A (en) | 1970-10-26 |
NL289735A (en) | |
SE328583B (en) | 1970-09-21 |
DE1545956A1 (en) | 1969-11-20 |
DK127507B (en) | 1973-11-19 |
GB1013229A (en) | 1965-12-15 |
CA976547A (en) | 1975-10-21 |
CH442326A (en) | 1967-08-31 |
BE629227A (en) | 1963-10-21 |
ES285854A1 (en) | 1963-08-16 |
DE1445873A1 (en) | 1969-04-10 |
SE361174B (en) | 1973-10-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
DE1545936A1 (en) | Process for the preparation of benzodiazepine derivatives | |
DE1445878A1 (en) | Process for the preparation of benzodiazepine derivatives | |
EP0021338B1 (en) | Quinazoline derivatives and pharmaceutical preparations | |
DE1545955A1 (en) | Process for the preparation of benzodiazepine derivatives | |
DE1288609B (en) | 2-Oxo-1, 2-dihydro-3H-1, 4-benzodiazepines | |
AT242705B (en) | Process for the preparation of new benzodiazepine derivatives | |
DE3538063A1 (en) | 6-PHENETHYLAMINOALKYL-FURO- (3,4-C) -PYRIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THESE THERAPEUTIC COMPOSITIONS | |
AT242706B (en) | Process for the preparation of new benzodiazepine derivatives | |
DE2010884A1 (en) | New benzodiazepine derivatives and processes for their preparation | |
DE1445913A1 (en) | Process for the preparation of benzodiazepine derivatives | |
DE1695769C3 (en) | 4-Phenyl-2 (1H) -quinazolinones substituted in the 1-position, process for their preparation and pharmaceuticals containing them | |
DE2043536A1 (en) | New 4 amino 2 methyl pyrimidines | |
AT256829B (en) | Process for the preparation of new 2-nitro-imidazole derivatives and their acid addition salts | |
DE1695129A1 (en) | Process for the preparation of benzodiazepine derivatives | |
CH560201A5 (en) | 1 4-benzodiazepin derivs anti-convulsive, - muscle relaxant, tranquillising | |
AT257590B (en) | Process for the preparation of new 2-nitroimidazole derivatives and their acid addition salts | |
DE1695163A1 (en) | Process for the preparation of heterocyclic compounds | |
DE1445073C (en) | 3H-1,4-Benzodiazepine-4-oxides | |
DE634198C (en) | Process for the preparation of cyclohexenyl alkyl hydantoins | |
AT296316B (en) | Process for the preparation of new benzodiazepine derivatives and their N-4-oxides | |
AT239794B (en) | Process for the preparation of new benzoxazepine derivatives | |
DE1443647A1 (en) | Process for the production of new methylandrostanes | |
AT309453B (en) | Process for the preparation of new benzodiazepine derivatives and their acid addition salts | |
AT252924B (en) | Process for the preparation of new benzodiazepine derivatives | |
AT344179B (en) | PROCESS FOR THE PREPARATION OF NEW BENZODIAZEPINE DERIVATIVES |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
SH | Request for examination between 03.10.1968 and 22.04.1971 |