Benzodiazepin intermediate

NMR studies in a CDCl3 acetic acid solution clearly demonstrated an equilibrium between the dimers and the corresponding N-imines. Based on this observation, a mechanism for the formation of the 1,2-benzodiazepines via the diaziridines and o-quinonoid 2H-1,2-benzodiazepine intermediates is proposed. Considering their aromatic stability, the latter would be expected to undergo a photochemically allowed [l,7]-sigmatropic hydrogen shift to give the observed product (Eq. 42). 

Irradiation of quinoline JV-acetyl-239 and N-ethoxycarbonylimines215,240 in alcoholic solvents gives 2,3-dihydro-lH-l,2-benzodiazepines 114 and 115, respectively, as the major products. In these cases o-quinonoid 2H-l,2-benzodiazepine intermediates are stablized by incorporation of the solvent. Quinoline N-benzoylimine on irradiation in methanol yields exclusively 2-benzoylaminoquinoline (116).215,240... 

In the synthesis of Cholecystokinin-B receptor antagonists, a benzodiazepin intermediate bearing an isocyanato group plays a key role. It is prepared from the corresponding amine 423 by carbonylation with phosgene in 98% yield [292]. 

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. ... 

The anxiolytic agent buspirone (131) is notable for the fact that it does not interact with the receptor for the benzodiazepines. This difference in biochemical pharmacology is reflected in the fact that buspirone (131) seems to be devoid of some of the characteristic benzodiazepine side effects. The spiran function is apparently not required for anxiolytic activity. Alkylation of 3,3-dimethylglutarimide with dichlorobutane in the presence of strong base yields the intermedi-... 

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-... 

Diazocycloheptatriene (1), generated from the sodium salt of tropone tosylhydrazone, reacts with electron-deficient acetylenes to give H- 1,2-benzodiazepines 4 in moderate yield. It is suggested that the primary adducts 2 rearrange via the intermediates 3 to the products 4.114... 

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... 

Another 1,7-dipolar cyclization leading to 1,2-benzodiazepines, but with the difference that a C-C bond is formed, is the ring closure of the nitrile imines 15 to give 17 by a [1,5]-sigmatropic shift of hydrogen in the intermediates 16. The nitrile imines are generated from the (2-vinylphenyl)hydrazonoyl chlorides 14."8 120... 

Treatment of the benzodiazepine 3 with hydrogen chloride in methanol gives ethyl indole-1-carboxylate (6) via the isolable intermediates 4 and 5.164... 

DUiydroxy-2,3,4,5-tetrahydro-l//-benzodiazepine-2,4-dione (441) gave 2,3-(l//,47/)-quinoxalinedione (443) (xylene, reflux, 4 h 17% after purification) or 3-oxo-3,4-dihydro-2-quinoxalinecarboxylic acid (444) (2M HCl, reflux, 15 min 58%) both products appear to have come from the intermediate... 

Benzodiazepines and similar agents occupy a position of intermediate abuse potential, compared with most other sedative-hypnotics (Griffiths and Weerts 1997). Animal models of abuse habihty indicate that the reinforcing effects of benzodiazepines are less pronounced than are those of the barbiturates, opioids, and stimulants. Differences in abuse potential within the class have not been consistently demonstrated however, most chnicians agree that benzodiazepines with a rapid onset and short duration of action pose the greatest risk in susceptible individuals. 

Titanium(III) chloride (particularly in slightly alkaline medium) reduces the p-nitro groups of the thiophosphate insecticides to amino groups, which are then reacted with nitrite in acid mediiun in a second step to yield a diazonium compound as intermediate. This is then coupled to N-(l-naphthyl)-ethylenediamine dihydrochloride to yield an azo dye [3]. In the case of benzodiazepines the first reaction step includes an additional acid hydrolysis to the corresponding benzophenone derivative [2]. 

For testing sedative hypnotic drugs of the triazolam type the preparation was undertaken of 8-chloro-6-(o-chlorophenyl)-4ff-.y-triazolo[4,3-a][l,4]benzodiazepin-1 -valeric acid methyl ester as an intermediate, with subsequent cyclization and amida-... 

Gandolfo G., Scherschlicht R., Gottesmann C. (1994). Benzodiazepines promote the intermediate stage at the expense of paradoxical sleep in the rat. Pharmacol. Biochem. Behav. 49, 921 7. 

An intramolecular Pictet-Spengler type cyclisation in the intermediates 100, readily prepared in turn from 99, gave the new dihydropyrimido[4,5-fc][l,4]benzodiazepines 101. Yields were generally good to excellent (101, R1 = H, R2 = Pr, 65%) <06T2563>. 

A Ar-B is( benzotri azoly I methy Famines 638 derived from benzyl or phenethylamines undergo cyclocondensation with allylsilanes catalyzed by S11CI4 to give 4-chloropiperidines 640 (Scheme 99) <1999JOC3328>. This [3+3] cyclocondensation is assumed to proceed in two steps via intermediate 639. [3+4] cyclocondensation of derivatives 638, originating from various aromatic and aliphatic amines, with dilithiated benzamides leads to 2,4-benzodiazepin-1-ones 641 <2002JOC8237>. 

Cyclative cleavage strategies release the final compound into solution following intramolecular attack of a nucleophile or electrophile upon the linkage site. Synthesis byproducts and intermediates do not incorporate the necessary nucleophile or electrophile therefore only the desired products are released into solution to yield high purity materials. Seminal examples of this approach are the library syntheses of benzodiazepines and hydantoins (Scheme 3). 

Hydrolytic cleavage of a seven-membered ring occurs in the metabolism of chlordiazepoxide (5.82, Fig. 5.22,a) and other benzodiazepines (see also Sect. 11.9). The lactam ring opened metabolite 5.83 was detected in humans and dogs and is believed to be generated by hydrolysis of the intermediate lactam [181][182], However, the diazepine ring can be split by other mech-... 

Benzodiazepines are preferred by many for the management of agitation in nonpsychotic bipolar patients, though antipsychotics are effective as well. The most widely used benzodiazepines for this purpose are lorazepam and clonazepam. Lorazepam is perhaps the most versatile of the benzodiazepines. It has an intermediate duration of action, does not tend to accumulate and thereby cause confusion or excessive drowsiness, and can be administered by mouth, intramuscular injection, or intravenous injection. Lorazepam should be administered on an as-needed basis several times daily at 0.5-2mg per dose. The calming effects of lorazepam are usually evident within 20-30 minutes and will last for several hours. 

It does bear special mention that many mental health practitioners consider lorazepam (Ativan) to be the most versatile of the benzodiazepines. Lorazepam has an intermediate onset and duration of action. Because it is easily metabolized, lorazepam is preferred when a benzodiazepine must be used to treat medically compromised or elderly patients. Most importantly, lorazepam is the only benzodiazepine that can be administered via oral, intramuscular, and intravenous routes. As a result, the transition between inpatient and outpatient care is rendered much easier with lorazepam than other benzodiazepines. 

Benzodiazepines. Like the barbiturates, benzodiazepines bind to the GABA receptor and are therefore cross-tolerant with alcohol. As a result, they also make suitable replacement medications for alcohol and are widely used for alcohol detoxification. Theoretically, any benzodiazepine can be used to treat alcohol withdrawal. However, short-acting benzodiazepines such as alprazolam (Xanax) are often avoided because breakthrough withdrawal may occur between doses. Intermediate to long-acting benzodiazepines including chlordiazepoxide (Librium), diazepam (Valium), oxazepam (Serax), lorazepam (Ativan), and clonazepam (Klonopin) are more commonly utilized. 

Like the barbiturates, the benzodiazepines make it easier to fall asleep and to stay asleep through the night. However, they also suppress REM sleep, which can lead to REM rebound when they are discontinued. Tolerance to their sleep-promoting effects often develops after chronic use. Some long-acting benzodiazepines, such as flurazepam (Dalmane), are associated with pronounced hangover effects in the morning and are therefore problematic as sedative-hypnotics. Others, with a short-to-intermediate dnration of action, are more desirable as hypnotics. 

Reductive ring closure of l-(2-nitrobenzyl)-2-pyrrole carbaldehyde 200 results in pyrrolo[2,l-c][l,4]benzodiazepine 201 (Scheme 42 (1999BMCL1737)). On the other hand, oxo derivative 203 can be synthesized starting from aldehyde 200 through a nitrile formation/cyclizations multistep sequence. The alternate synthetic strategy included reduction of the intermediate acid (R = H) or ester (R = Et) 205 followed by CDI or thermal cyclization (1992JHC1005). 

Thieno benzodiazepine 253 is available in two steps starting from o-nitro halobenzenes and a thieno amino nitrile through intermediate 252 (Scheme 53 (1997BMCL25)). 

As with pyrrolo-benzodiazepine (1992JHC1005), 0x0 derivative of pyrrolo-benzothiadiazepine 203 (X = SO2) can be synthesized by the thermal cyclization of intermediate 205 (Scheme 42, Section 3.1.1.2 (1992SC1433)). 

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