The Study On Synthesis Process Of Bendamustine Hydrochloride And Preparation Process Of Bendamustine Hydrochloride For Injection

The incidence of CLL in our country is low, only 10% of chronic leukemia, the incidence in Europe and America is very high, is 50% or higher.Usually, the patients were old people, 90% is over 50 years old, the ratio of male to female was 2: 1. Bendamustine is a cytotoxic medicine with both alkylating and anti-metabolic effects, in many kinds of hematological malignancies and solid tumors shows good curative effect, unique heterocyclic structure gives the unique anti-tumor activity. Bendamustine has been developed for many years, and been used in the clinical for many years. The first Bendamustine for injection in the United States listed for sale is Cephalon’s TREANDA, and its curative effect is very good, recognized in the clinical use, and included as the reference preparation by the FDA in the Orange Book.Bendamustine hydrochloride was synthesized by German scientists in the last century 80’s. There are two main synthetic routes of bendamustine hydrochloride, fist, taking Nmethyl-4- nitro o phenylenediamine as starting material, react With glutaric anhydride, then the synthesis of benzimidazole ring derivatives,The nitro is then reduced to amino by hydrogenation,The hydrogen of amino is replaced by ethylene oxide, then chloro substitution, and salification in concentrated hydrochloric acid; Second, taking 2, 4-dinitrochlorobenzene as the starting material, by ammonia methylation, acylation and cyclization, hydrogenation, reductive amination, salification finally. Afterwards, the new routes was developed based upon the first classic route, but the main part was not changed. The synthetic route in this article is also developed on the basis of the first classic route, is suitable for industrial production line, the number of reaction steps in line with the requirements of drug registration regulations. It is beneficial to improve the yield and avoid the dangerous operation in the first few steps. By controlling the quality of the starting material and intermediate, ensure that the product is in accordance with the expected acceptable standard. Through the structure elucidation method of MS, IR, and NMR, the structure of Bendamustine Hydrochloride is confirmed. It further approved that the synthetic route is reasonable and the process parameter is scientific and reasonable.According to the referance drug “Treanda”, the strength, dosage form and excipient of the Bendamustine for Injection was determined. On the basis of the above experiments,the solvent type and volume, the inert gas, the pH regulator and so on is chosen. Then the formula of the product was determined. In the process study of production, study the preparation temperature, the holding temperature and time, and the freezing and drying process. According to the quality of the finished, comparison of the results, select the process with the best quality as the process of Bendamustine for Injection. The process is validated in the sorkshop and the result is acceptable. It is proved that the process is scientific, reasonable, controllable and reliable.Bendamustine is neither a new drug nor a new biological targeted drugs, but have unique curative effect to lymphoproliferative disorders, with other alkylating agent used in combination showed better response rate. At present, there is no bendamustine and drug formulations in China. Successful development of this product will bring cheaper drug formulations to the domestic patients, improve the treatment level, reduce the medical expenses of patients. So, it is very important to develope Bendamustine and Bendamustine drug product.