Synthesis And Study Of Anticancer Drug Lonidamine

Indazole and indole is a pair of bioisosteres. They both have extensive biological activities and increasingly attracted the attention of the researchers of drug designments. Lonidamine is an oral absorption anticancer drug which was listed by Italy Angelini company in1976. Lonidamine was originally used as a antispermatogenic agent. As a kind of antineoplastic different from traditional antineoplastic and thermallly sensitive drug, it is a variety of cancer inhibition, such as head and neck cancer, lung cancer, breast cancer, prostate cancer and chronic lymphocytic leukemia, etc. Therefore, the synthesis of lonidamine has great significance.Based on a large amount of literatures, this paper selected phenylhydrazine and2,4-dichlorotoluene as the starting materials to synthesize antitumor drug lonidamine which were analysed and characterized. Lonidamine was synthesized using phenylhydrazine and2,4-dichlorobenzyl bromide as the raw materials, Phenylhydrazine was acetylated, and then reacted with hydroxylamine hydrochloride, chloral hydrate and sodium sulphate to form N-acetyla-minoisonitrosoacetanilide, which was continuously hydrolyzed to obtain1H-indazole-3-carboxylic acid after Beckmann rearrangement and ring rearrangement reaction;2,4-dichlorobenzyl bromide was prepared from2,4-dichlorotoluene and NBS with AIBN as catalyst, and then reacted further with1H-indazole-3-carboxylic-acid to give the product lonidamine. Structure of product was characterized by IR,1H NMR and MS. This synthetic route has a lower cost, a higher yield, and is easy to deal with "three industrial wastes" and suitable for industrial production.N-acetylhydrazine was synthesized by using phenylhydrazine as starting material, which reacted with glacial acetic acid and water, the yield was86.0%. The process conditions were optimized and the optimal reaction conditions were as follows: n(phenylhydrazine):n(glacial acetic acid): n(water)=1:4.5:13.2, reaction time is4h.N-acetyla-minoisonitrosoacetanilide was synthesized by N-acetylhydrazine, hydroxylamine hydrochloride, chloral hydrate and sodium sulfate with glacial acetic acid as the catalyst, the yield was86.9%. The optimal reaction conditions were as follows: n(N-acetylhydrazine):n(chloral hydrate):n(hydroxylamine hydrochloride)=1:1.3:3, reacted at90℃by13min.1H-indazole-3-carboxylic acid was obtained by Beckmann rearrangement and ring rearrangement reaction with concentrated sulphuric acid as the catalyst. The process conditions were optimized, the yield was80.0%. The optimum reaction conditions listed as follow:reactants including concentrated sulfuric acid was dropped into ice water slowly to make temperature less than or equal to15℃. The reaction time of hydrolysis is4h.1H-indazole-3-carboxylic acid is the key drug intermediates, the papers on the purification process have been studied in detail.2,4-dichlorobenzyl bromide was synthesized from2,4-dichlorotoluene and NBS by using AIBN as catalyst, the yield was82.1%. The synthese conditions were optimized and the optimal reaction conditions listed as follows:n(2,4-dichlorotoluene):n(NBS)=1:1, reacted at80℃by8h.Lonidamine was synthesized with1H-indazole-3-carboxylic acid and2,4-dichlo-robenzyl bromide in aqueous solution of sodium hydroxide. Replace2,4-dichloroben-zylchloride with2,4-dichlorobenzyl bromide, the reaction rate is accelerated to shorten the reaction time from4h to2h, the yield was improved89.0%. The reaction conditions were optimized and the mole rate of1H-indazole-3-carboxylic acid and2,4-dichlorobenzyl bromide was1:1.