A kind of preparation method of ederaris

Abstract

The invention belongs to the field of medicine synthesis and provides a novel idelalisib preparation method. The novel idelalisib preparation method includes steps: in an appropriate solvent, subjecting a compound A to nucleophilic substitution reaction with B in existence of an acid-binding agent to obtain an intermediate C; hydrolyzing the compound C into an intermediate D under appropriate alkali action; subjecting the intermediate D and a compound E to condensation to obtain an intermediate F; in an appropriate solvent, subjecting the intermediate F to ring closing reaction under a catalytic system of HMDS (hexamethyl disilazane) / lewis acid to obtain a final product namely idelalisib.

Description

technical field [0001] The invention relates to a novel method for preparing idelaris, which belongs to the field of drug synthesis. Background technique [0002] Phosphatidylinositol 3-kinase / protein kinase B (PI3K / Akt) signaling pathway plays an important role in the occurrence, development, treatment and metastasis of malignant tumors. Phosphoinositide 3-kinase (PI3K ) as a bridge molecule connecting extracellular signals and cell response effects, under the influence of a series of upstream or bypass signal molecules, it acts on downstream signal molecules and plays a very important role in regulating cell apoptosis. The anti-apoptosis of PI3K and Akt has been confirmed in many studies, the expression level of Akt is increased and promotes the growth of cancer cells by protecting cells from apoptosis. Studies have found that PI3K is related to the products of oncogenes such as viral oncogene expression protein v-Src and cellular proto-oncogene expression protein c-Src, ...

AI Technical Summary

Problems solved by technology

[0009] 1) The step of preparing compound 5 from compound 3 involves the preparation of key intermediate 4. Intermediate 4 is extremely unstable and will be hydrolyzed when it meets water. Therefore, the reaction needs to be strictly controlled under anhydrous and oxygen-free conditions. There are defects that the raw materials are difficult to react completely, the entire reaction system has many impurities, and it is not easy to purify, resulting in extremely low yield and cumbersome operation in this step, which is not suitable for industrial production;

[0010] 2) Zn / AcOH reagent was used during the preparation of compound 6, the by-product zinc acetate obtained after the reaction was completed was difficult to handle, the product was difficult to extract, a large amount of acetic acid was difficult to recycle, and the waste was serious, while the use of zinc powder easily caused the metal residue of the drug, Caused Idelalisib to be ineligible;

[0011] 3) Expensive 6-bromopurine is used in the step of preparing Idelaris from compound 7, and its substitution reaction will produce bromine-containing wastewater, which will pollute the environment;

[0012] 4) This route uses compound 1 as the starting material, and obtains Idelaris through 7 steps of reaction, the total yield is only 20%, and the synthesis efficiency is not high

Compared with the method described in WO2005113554, this method has made some improvements, shortened the reaction steps, and the reaction conditions are milder, but the product yield is only about 60%

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