Novel synthesis method of Selinexor active pharmaceutical ingredient

Abstract

The invention provides a novel synthesis method of a Selinexor active pharmaceutical ingredient. The method comprises the following steps: mixing a compound 6, dichloromethane and ethyl acetate, adding a compound 4, T3P and DIPEA (diisopropylethylamine) at low temperature, reacting, adding water and ethyl acetate, skimming, and drying up the organic phase by distillation to obtain a compound 7 crude product; mixing the compound 7, glacial acetic acid and sodium iodide, heating and reacting; after the reaction finishes, cooling, adding water and dichloromethane, standing to stratify, washing the organic phase, drying, and distilling to obtain a compound 8; mixing the compound 1, DBACO and DMF (N,N-dimethylformamide), dropwisely adding a compound 8 DMF solution, and reacting; and after the reaction finishes, adding water and ethyl acetate, drying up the organic phase by distillation, and recrystallizing to obtain the compound 5. The synthesis method solves the problem that the traditional synthesis technique can easily generate trans impurities, reduces the synthesis steps, enhances the yield, and provides a new technique for synthesizing the Selinexor active pharmaceutical ingredient.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a novel synthesis method of a Selinexor bulk drug. Background technique [0002] Selinexor is an oral biologically effective selective nuclear export protein inhibitor. It entered the clinic for the first time in 2012. So far, a total of 21 clinical trials have been carried out. The indications include chronic myeloid leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, Prostate cancer, melanoma, non-small cell lung cancer, glioma, neuroblastoma, gynecological tumor, diffuse large B-cell lymphoma, squamous cell carcinoma, rectal cancer, etc. In May 2014, the FDA granted Selinexor the orphan drug title for the treatment of acute myeloid leukemia and diffuse large B-cell lymphoma. In June 2014, EMA also awarded Selinexor the orphan drug title for the treatment of these two diseases. In January 2015, it was approved as an orphan drug by the FDA for the treatment of m...

AI Technical Summary

Problems solved by technology

[0007] However, in this method, the double bond from intermediate 1 to 2 is easy to reverse, and trans impurities are likely to be produced during synthesis and production, which are difficult to remove and affect the yield; when intermediate 3 and intermediate 4 synthesize raw material drug 5, it is necessary to Ultra-low temperature, and the product needs to be purified by column, the yield is only 20%

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