Diazepam synthesis

Applications to Diazepam Synthesis. The Sumitomo process for diazepam is depicted below (11). According to some reports, this is a major route by which diazepam (Valium), a widely-prescribed anti-anxiety drug, is prepared on an industrial scale. I have highlighted three reactions in the Sumitomo synthesis. These reactions involve toxic or corrosive reagents which would best be avoided if pollution control is an objective. It is worth noting that almost all of the other publish pathways for the synthesis of diazepam involve Friedel Crafts reactions in the key carbon-carbon bond forming step. 

Diaza-l,6,6aA -trithiapentalene synthesis, 6, 591 Diazatrithiapentalenes synthesis, 6, 914 Diazecine synthesis, 7, 730 Diazepam... 

Chlorine and iodine can be introduced into aromatic rings by electrophilic substitution reactions, but fluorine is too reactive and only poor yields of monofluoro-aromatic products are obtained by direct fluorinafion. Aromatic rings react with CI2 in the presence of FeCl3 catalyst to yield chlorobenzenes, just as they react with Bi 2 and FeBr3. This kind of reaction is used in the synthesis of numerous pharmaceutical agents, including the antianxiety agent diazepam, marketed as Valium. 

Finally, the presence in human post-mortem brain tissue of the active metabolite of diazepam, desmethyldiazepam, raised some curiosity and frank alarm (Sangameswaran et al. 1986). At the time of its discovery in the brain it was thought that there was no enzyme system capable of producing such halogenated compounds and that its presence in the brain reflected dietary intake from an environment contaminated by overuse of its parent compound. However, its discovery in stored brain tissue which had been obtained before the synthesis of the benzodiazepines allayed these fears. It is now thought possible that some benzodiazepines, including desmethyldiazepam, occur naturally and that they are taken in as part of a normal diet (Table 19.5). 

Dexivacaine, 95 DBxnorgBstrel acetime, 152 Diabetes, 116 Diamocaine, 336 Diapamide, 93 Diaveridine, 302 Diazepam, 452 Diazoxide, 395 Dibenzepin, 424, 471 DichloroisopTTOterenol, 106 Diclofenac, 70 Dicyanamide, 21 Dieckmann cyclization, 72 Difenoximide, 331 Difenoxin, 331 Diflucortolone, 192 Diflumidone, 98 Diflunisal, 85, 86 Difluoromethylene groups, from ketones, 196 Difluprednate, 191 Dihydrocodeinone, 318 Dihydropyridine synthesis, 283... 

Diazepam is used for the control of anxiety and tension, the relief of muscle spasms, and the management of acute agitation during alcohol withdrawal, but it itself may be habit-forming. Chlordiazepoxide has similar uses and its synthesis is somewhat analogous to diazepam. Flurazepam is a hypnotic, useful for insomnia treatment. It is reported to provide 7-8 hr of restful sleep. 

The synthesis of these compounds will be described in Section 3.1, Opioid analgesics. Besides opioids, benzodiazepines (diazepam, lorazepam, and midazolam), which have anxiolytic, sedative, and anticonvulsant effects, that cause amnesia and muscle relaxation, are frequently used to relieve patients anxiety during anesthesia. 

Diazepam From a chemical point of view, diazepam, 7-chloro-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one (5.1.2), is the most simple of all of the examined derivatives of l,4-benzodiazepin-2-ones. Various ways for the synthesis of diazepam from 2-amino-5-chlorobenzophenone have been proposed. The first two ways consist of the direct cyclocondensation of 2-amino-5-chlorobenzophenone or 2-methylamino-5-chlorobenzophenone with the ethyl ester of glycine hydrochloride. The amide nitrogen atom of the obtained 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one (5.1.1), is methylated by dimethylsulfate, which leads to the formation of diazepam (5.1.2). 

The third way for the synthesis emanates from 2-methylamino-5-chlorobenzophenone (5.1.5), which is acylated by chloracetic acid chloride, forming 2-chloracetylmethylamido-5-chlorbenzophenone (5.1.6). Reaction of this product with hexamethylenetetramine replaces the chlorine atom in the chloracetyl part of the molecule, giving a hexamethyl-enetetramino derivative of 2-aminoacetyhnethylamido-5-chlorbenzophenone, which upon hydrolysis in an hydrochloric acid ethanol solution undergoes cyclocondensation and gives diazepam (5.1.2) [6,7]. 

The second way of making medazepam consists of the initial reduction of the carbonyl group by lithium aluminum hydride into 7-chloro-5-phenyl-2,3-dihydro-17f-l,4-benzodi-azepin-2-one (5.1.1)—the first intermediate product in the synthesis of diazepam—which is synthesized by the cyclocondensation of 2-amino-5-chlorobenzophenone with glycine ethyl ester into 7-chloro-2,3-dihydro-5-phenyl-17/-l,4-benzodiazepine (5.1.41), and the subsequent methylation of the secondary amine nitrogen atom of the resulting product by methyliodide, using sodium hydride as a base [41,42]. 

Benzodiazepines are primarily used in medicine as tranquilizers. However, they also have been snccessfully used for epilepsy in controlling long-lasting convnlsions. The most widely nsed is diazepam (5.1.2) and chlordiazepoxide (5.1.22). The synthesis of these was described in Chapter 5. 

Figure 3.5 The synthesis of diazepam is initiated by the double acylation of an aromatic amine with an aromatic acid chloride. A second equivalent of the p-chloroaniline leads to a six-membered ring with two nitrogens. This is hydrolytically opened to expose a free amino group which reacts with an aminoester to yield a seven-member ring. The amide nitrogen is then methylated.

Pd(OAc)2] in the presence of PPh3 was used as catalyst. The use of vinyl bromides in lactam formation has also been reported.498 Imides were obtained from aryl bromides. The method has further been applied to the synthesis of diazepam and 1,4-benzodiazepines499 and to a-methylene lactams and lactones.S00 501 In connection with the synthesis of natural products, the reaction has been employed in the preparation of hexadehydrohimbane,502 anthramycin503 and berbine derivatives.504 The catalyst was prepared in situ from [Pd(OAc)2] (106) and PPh3 in all cases. The mechanism of lactam formation is analogous to that for amides (Scheme 42). 

The synthesis of the title compound [3H]TCIB, 227, has been accomplished317 starting from 5-chloroisatoic anhydride 228 (equation 152) via the precursor 229 and free tritium gas318. The product 227 is a high affinity ligand for the diazepam insensitive (DI) subtype319 of the benzodiazepine receptor (BZR). The tritiated TCIB has been synthesized to study the structure, function and pharmacological role of DI receptors. 

Synthesis of 2/-[125l]iodo-desmethyl diazepam (2 -[125l]IDMDZ)... 

In obese women, the AAG concentrations are doubled, and the unbound plasma fraction of propranolol is 30 /o lower than that in women with normal body weight.f In the obese, the albumin concentrations, and phenytoin binding are normal, whereas diazepam binding is slightly reduced. In undernourished or hospitalized patients, the AAG concentrations are 30 0% higher than those in unhospitalized patients, and the propranolol free fraction is reduced by approximately, 30%. A marked decrease in albumin concentration has been reported in malnutrition, and it seems associated with a reduction in protein synthesis. ... 

---