Reaction benzodiazepine

Keywords acetone, o-phcnylcndiaminc, cyclization, cascade reaction, gas-solid reaction, benzodiazepine, benzothiazolidine... 

In psychosomatic reactions, benzodiazepines can exert an uncoupling effect. They Luellmann, Color Atlas of Pharmacology All rights reserved. Usage subject to terms... 

Fig. 2. Synthesis of uma2enil (18). The isonitrosoacetanihde is synthesized from 4-f1iioroani1ine. Cyclization using sulfuric acid is followed by oxidization using peracetic acid to the isatoic anhydride. Reaction of sarcosine in DMF and acetic acid leads to the benzodiazepine-2,5-dione. Deprotonation, phosphorylation, and subsequent reaction with diethyl malonate leads to the diester. After selective hydrolysis and decarboxylation the resulting monoester is nitrosated and catalyticaHy hydrogenated to the aminoester. Introduction of the final carbon atom is accompHshed by reaction of triethyl orthoformate to...

The benzodiazepine fused azetes (353 R = Et, Pr) have been claimed as useful tranquilizers and sedatives (76BRP1448895). However, their stability and formation from benzodiazepines (352) by reaction with an aldehyde and base is hard to reconcile with the proposed structure. 

H-2,3-Benzodiazepine, 3,4-dihydro-synthesis, 7, 596, 599 5H-2,3-Benzodiazepine, 4-phenyI-acylation, 7, 602 photochemical reactions, 7, 600 5 H-2,3 - Benzodiazepine, 1,2,3,4-tetrahydro-synthesis, 7, 596... 

Benzodiazepines as antianxiety agents, 1, 170 as anticonvulsants, 1, 166 organometallic complexes, 7, 604 as sedatives, 1, 166 IH- 1,2-Benzodiazepines conversion to 3H-1,2-benzodiazepines, 7, 604 synthesis, 7, 597, 598, 604 3H-1,2-Benzodiazepines acid-catalyzed reactions, 7, 601 nucleophilic reactions, 7, 604 oxidation, 7, 603 synthesis, 7, 596 thermal reactions, 7, 600 5H-1,2-Benzodiazepines photochemical reactions, 7, 599 synthesis, 7, 603... 

Pyrrolo[2,1 -c][l, 4]benzodiazepines synthesis, 7, 614 Pyrrolo[l, 6]benzodiazocines synthesis, 7, 515 Pyrrolo[3,4-c]benzopyrazoles reactions, 6, 1034 Pyrrolobenzothiazoles synthesis, 4, 785 Pyrrolo[l, 2-c]benzotriazines synthesis, 4, 240 Pyrrolo[3,4-c]cinnolines synthesis, 4, 240... 

A particularly interesting example of this method of synthesis is the cy-clrzation of the 4-amino-3-(2-aminophyenyl)-l,2,4-triazoloes 73 with cyanogen bromide. Primarily, this reaction was applied to synthesize the 6-amino-l,2,4-triazolo[4,3-d]benzodiazepine hydrobromides 74 the obtained products, however, were found to be the l,5-diamino-l,2,4-triazolo-[l,5-c]quinazolin-ium bromides 77. Structure elucidation of 77 was accomplished by direct... 

Thus, ynaminoketones with 1,2-diaminobenzene form benzodiazepines with retention of the dialkylamino group. The reaction occurs as a nucleophilic addition in the absence of catalysts. With Q, /3-acetylenic ketones 1,2-diaminobenzene reacts in the same manner, but under proton-catalyzed conditions (72LA24). At the same time, ynamines and enynamines furnish with 1,2-diaminobenzene substituted benzimidazoles as aresultof double attack at the acetylene bond(83ZOR926 84ZOR1648). 

The reaction of methyl anthranilate and 3-amino-2-chloropyridine in 1,2,4-trichlorobenzene in the presence of KOt-Bu at 50 °C gave 5,1 l-dihydro-6//-pyrido[2,3-Z)]benzodiazepin-6-one and 6-amino-ll//-pyr-ido[2,l-Z)]quinazolin-l 1-one as a by-product (99BMCL3031). 

Fusion of an additional heterocyclic ring onto that already present in the benzodiazepines has led to some medicinal agents with considerable activity. Treatment of an intermediate like 15 with phosphorus pentasulfide affords the corresponding thio-amide (37). Condensation of this intermediate with acetyl hydra-zide affords triazolam )37). The same agent can be prepared by reaction of the amidine, 38, ° with acetylhydrazide. ... 

Fusion of an additional heterocyclic ring onto a benzodiazepine is well known to considerably increase potency. This increase in potency is apparently maintained when the benzene ring is replaced by thiophene. Thiophene aminoketone 161 is converted to the benzodiazepine analogue 164 via chloroacetamide 162 and then glycine derivative 163 by the same sequence as that used in the benzene series. Treatment of the product 164 with phosphorus pentasulfide gives the thio-amide 165 reaction of that intermediate with hydrazine leads to the amino amidine 166. Conden-... 

A suspension of 45 g 3-phenoxycarbonyloxy-1 -methyl-7-chloro-5-pheny -1,3-dihydro-2H-1,4-benzodiazepin-2-one in 450 ml methanol is treated with stirring, with 43 ml of a solution of dimethylamine in methanol (containlng31 gdimethylamine in 100 ml). Stirring ismaintained at 20°C to 25°C during 5 hours. The reaction mixture is filtered, and the filtrate is diluted with 450 ml water. The precipitate thus formed, is 3-(N,N-dimethylcarbamoyloxy)-1-methy -7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, which is collected on a filter, dried and recrystallized from ethyl acetate, and has a melting point of 173°C to 174°C. 

Ninety-eight grams of 6-chloro-2-chloromethyl-4-phenylquinazoline 3-oxide hydrochloride were introduced into 600 cc of ice cold 25% methanolic methylamine. The mixture was initially cooled to about 30°C and then stirred at room temperature. After 15 hours the reaction product which precipitated was filtered off. The mother liquor was concentrated in vacuo to dryness. The residue was dissolved in methylene chloride, washed with water and dried with sodium sulfate. The methylene chloride solution was concentrated in vacuo and the crystalline residue was boiled with a small amount of acetone to dissolve the more soluble impurities. The mixture was then cooled at 5°C for 10 hours and filtered. The crystalline product, 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4-oxide, was recrystallized from ethanol forming light yellow plates, MP 236° to 236.5°C. 

To a stirred suspension of 10 grams (35 mmol) of 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2(1H) one 4-oxide in approximately 150 ml of methanol was added in portions an excess of a solution of diazomethane in ether. After about one hour, almost complete solution had occurred and the reaction mixture was filtered. The filtrate was concentrated in vacuo to a small volume and diluted with ether and petroleum ether. The reaction product, 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1 H)-one 4-oxide, crystallized in colorless prisms. The product was filtered off and recrystallized from acetone, MP 188°-189°C. 

A mixture of 3 grams (0.01 mol) of 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1 H)-one 4-oxide, 30 ml of chloroform and 1 ml of phosphorus trichloride was refluxed for one hour. The reaction mixture was then poured on ice and stirred with an excess of 40% sodium hydroxide solution. The chloroform was then separated, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in methylene chloride and crystallized by the addition of petroleum ether. The product, 7-chloro-Tmethyl-5-phenyl-3H-1,4-benzodiazepin-2(1 H)-one, was recrystallized from a mixture of acetone and petroleum ether forming colorless plates melting at 125°-126°C. 

A solution of 60 g of chromic anhydride in 40 ml of water was added dropwise to a suspension of 60 g of 2-aminomethyl-1 -methyl-5-chloro-3-(o-fluorophenyl)-indole hydrochloride in 600 ml of acetic acid. The mixture was stirred at room temperature overnight. To the reaction mixture was added 1.1 liters of ether and 1 liter of water and then 800 ml of 28% ammonium hydroxide, in small portions. The ethereal layer separated, washed with water, dried, and concentrated under reduced pressure. The residue (51.8 g) was dissolved in 100 ml of ethanol, and 100 ml of 20% ethanollc hydrogen chloride was added to the solution and the mixture was cooled. The precipitate was collected by filtration to yield 46.5 g of 1 -methyl-7-chloro-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one hydrochloride, melt-... 

A mixture of 16.8 g of 2-aminobenzophenone, 11.9 g of glycine ethyl ester hydrochloride and 200 cc of pyridine was heated to reflux. After one hour, 20 cc of pyridine was distilled off. The solution was refluxed for 15 hours, then 11.9 g of glycine ethyl ester hydrochloride was added and the refluxing was continued for an additional 4 hours. The reaction mixture was continued for an additional 4 hours. The reaction mixture was concentrated in vacuo, then diluted with ether and water. The reaction product, 5-phenyl-3H-1,4-benzodiazepin-2(1 H)-one, crystallized out, was filtered off, and then recrystallized from acetone in the form of colorless rhombic prisms, MP 182°Cto 183°C. 

A mixture of 38.6 g (0.1 mol) of 3,4,3, 4 -tetramethoxy-6-(a-acetopropyl)-benzophenone, 5.5 g (0.11 mol) of 100% hydrazine hydrate or 3.52 g (0.11 mol) of hydrazine, and 500 ml of absolute ethanol is boiled for 5 hours. After adding 100 ml of benzene, 400 ml of solvent mixture Is distilled off from the reaction mixture by slow boiling for 3 hours. After cooling for 8 hours, 19 g of 5H-2,3-benzodiazepine derivative are separated from the residue as small, white crystals. The melting point is 133°C to 1 36°C (after recrystallizing from absolute ethanol, 136°C). 

In the case of sodium 2-(diarylmethylene)cyclopentanone tosylhydrazones 3, however, thermolysis gives the 3//-1,2-benzodiazepines 6 in good yield selected examples are shown. It is suggested that steric constraints in the diazo compounds 4 favor the [1,7] ring closure. The reaction proceeds by way of the intermediates 5, which rearrange to the products by a [1,5] shift of hydrogen.115... 

Reactions of 3//-1,2-Benzodiazepine 2-Oxides 11 with Nucleophiles Under Basic Conditions. Preparation of 3-Methoxy-lW-l,2-bcnzodiazepine (12c) Typical Procedure 124... 

The 2,3-benzodiazepin-l-one 5c is transformed into the corresponding thione 18 by reaction with diphosphorus peniasuifide. 32... 

The 3-[2-(acylamino)phenyl]-2-azidoprop-2-enoates 1 undergo a Staudinger reaction on treatment with triphenylphosphane at 20 C to give the stable imino-/.5-phosphanes 2 in nearly quantitative yields. The latter cyclize to 3/7-1,3-benzodiazepines 3 (40-50%) when heated in refluxing xylene for 15 hours. No further details were reported.19... 

Similarly, reaction of the bis(imino-/.5-phosphane) 4 with aroyl chlorides gives 1,3-benzodiazepines, which, however, were assigned the 1//-structures 5. < 3a-b... 

The hydroxy lactams 1 are converted into the 2//-2,4-benzodiazepin-l(3//)-ones 3 in refluxing benzene in the presence of p-toluenesulfonic acid. The reaction proceeds by ring opening to the oxo amides 2, followed by dehydration.16,166... 

Aminobenzylamine (1, R1 = H) reacts with benzil in refluxing acetic acid for 24 hours to give the yellow 2,3-diphenyl-5//-l,4-benzodiazepine (2) in 47% yield, but the reaction is not general. However, 2-chloro-2//-azirines function as diketone equivalents, yielding the benzodiazepines 3, when treated with equivalent amounts of the diamines 1 in pyridine at 20 C. Further details were not reported.192... 

Alkoxy-3//-l,4-benzodiazepin-5(4//)-ones by Intramolecular Aza-Wittig Reactions... 

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