Preparation method of drug-connector MC-MMAF for antibody drug conjugate and intermediate thereof

Abstract

The invention provides a preparation method of drug-connector MC-MMAF for antibody drug conjugate and an intermediate thereof. By the preparation method, reaction activity of N terminal is improved, so that racemization is controlled effectively; toxin MMAF is not used directly, and fragment peptide with low toxicity is adopted, so that operation difficulty during mass production is lowered; reverse phase preparation is not needed, and operation is simple and convenient.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a method for preparing drug-linker MC-MMAF used in antibody-drug conjugates and an intermediate thereof. Background technique [0002] Antibody drug conjugate (ADC) is a new type of anti-tumor drug. Its principle is to link cytotoxins to antibodies, recognize specific antigens on the surface of cancer cells through antibodies, and enter cancer cells through endocytosis. Cells, so as to transport cytotoxins to the target, to achieve the purpose of targeted treatment of malignant tumors. Compared with traditional small-molecule anti-tumor drugs, ADC is more specific and effective because it can rely on the target recognition of antibodies and the high activity of toxins. [0003] ADCs consist of three distinct components, namely antibodies, linkers and cytotoxins. The antibody achieves targeting, and the linker ensures the stability of the ADC during blood transport, and after re...

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Problems solved by technology

[0010] There is a methyl group on the N of the N-terminal valine of this route MMAF, and the steric hindrance is relatively large. In this case, the reaction speed of connecting 1-maleimido n-hexanoic acid to MMAF will be slower. Racemization of the chiral carbon attached to the phenylpropanamide group of MMAF even with different amide condensing agents

This route is used for the synthesis of MC-MMAF less than 1g. Finally, high-pressure reverse phase preparation should be used to remove isomer impurities, and the yield is less than 50%.

[0011] This reaction route shows certain defects when enlarging production, such as: 1. This method causes 30-50% racemization because the condensing agent can activate the carboxyl group on MMAF simultaneously, forms the isomer impurity that is difficult to remove, affects Productivity; 2. Due to the aforementioned steric hindrance, the reaction time is long and there are many impurities, which cause difficulties in post-processing and purification of the reaction; 3. The final product needs high-pressure reverse-phase preparation to remove isomers, which increases operating costs; 4. Directly The toxin MMAF is used as a raw material, and a large number of synthetic operations need to be well protected, and the selection of protective equipment will bring obstacles to production operations

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