Triazole-benzodiazepine 4 - Acetic Acid And Quinazoline Derivatives Synthesis

Benzodiazepines are a kind of important compounds with high biological activity and wide medicinal value. Now a lot of drugs on market which are used as therapy of mental diseases are benzodiazepines. These compounds are rare in nature and most of them are synthesized. However few studies are reported about the derivatives of the 3-position benzodiazepine and 4-position triazole benzodiazepine. Enantiomers of the same drug always give a different effect to the object according to the modern drug design theory. The discovering of optically pure enantiomer leads the trend of chiral drug. In this work, we try to find a new, short-step and economic method to synthesize a couple of enantiomers of the 4-position triazole benzodiazepine derivatives.In chapter 2, We chose a low price 5-Methoxy-2-nitro-benzoic acid as the starting material, after hydrogen reduction with Pd/C as a catalyst, amino protection, coupling, substitution with grinard reagent and de-protection to afford the key intermediate (2-Amino-5-methoxy-phenyl)-(4-chloro-phenyl) methanone. From this key intermediate, we introduced a pair of chiral amino-acid, to give two different configuration intermediates, after de-protection, cyclization to get the core of 3-position-1,4-benzodiazepine with defined structure configuration. The carbonyl group in 2-postion of the benzodiazepine core was converted to thiocarbonyl group by treated with lawesson reagent, the intermediate obtained was substituted by anhydrous hydrazine, coupling with acetyl chloride and then cyclization to introduce the triazole ring. Target compounds (R)-Triazole-benzodiazepine-4-acetic acid derivative and (S)-Triazole-benzodiazepine-4-acetic acid derivative were finally obtained after the tert-butyl ester is hydrolyzed.Compared with the traditional method, this route is a less reaction steps and economic method. The overall yield of two compounds is 17.6% and 20.2%. The chiral-HPLC result shows no racemization observed, ee>95%.In chapter 3, we synthesized a quinazoline derivative, from low price and readily available 2-amino-benzamide,2-position group was introduced after coupling with acid or acid chloride, after cyclization to afford the quinazolone. Quinazolone was chlorinated by thionyl chloride, substituted by amine to introduce the 4-position group.