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Preparation method and application of Syk and VEGFR2 double-target inhibitor

A compound and alkyl technology, applied in the field of preparation of dual target inhibitors of spleen tyrosine kinase and vascular endothelial growth factor 2

Active Publication Date: 2022-06-07
OCUMENSION THERAPEUTICS (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The purpose of the present invention is to overcome the existence of existing methods for preparing Syk and VEGFR2 dual-target inhibitors, which need to protect the pyrazole boronate as the reaction raw material to prevent complexation with the catalyst and require additional specific steps to remove The defect of the protecting group provides a method that does not need to protect the pyrazole boronic acid ester preferentially and can carry out the subsequent Suzuki reaction smoothly to prepare Syk and VEGFR2 dual-target inhibitors

Method used

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  • Preparation method and application of Syk and VEGFR2 double-target inhibitor
  • Preparation method and application of Syk and VEGFR2 double-target inhibitor
  • Preparation method and application of Syk and VEGFR2 double-target inhibitor

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Experimental program
Comparison scheme
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Embodiment

[0110] The synthetic route is as follows:

[0111]

[0112] 1) Preparation of compound 2-3

[0113] The raw materials and feeding amount of step 1 are shown in Table 1 below.

[0114] Table 1

[0115]

[0116] 11.0L of dimethyl sulfoxide was added to the 50L reaction kettle, the stirring was started, the rotating speed was 150rpm, and the temperature was shown as an internal temperature of 20°C. 833.0 g of compound 2-2, 1510.0 g of N,N-diisopropylethylamine and 1100.0 g of compound 2-1 were added in this order. The external temperature was set to 100°C, and the mixture was stirred at an internal temperature of 95 to 100°C for 24 hours.

[0117] The reaction solution was detected by HPLC, and HPLC showed that compound 2-1 remained less than 3%. The heating was turned off, and the reaction solution was cooled to 20-25°C. The reaction solution was slowly poured into 30.0 L of stirred water. The internal temperature was controlled to be 10 to 15° C., and the mixture was ...

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Abstract

The invention relates to a preparation method and application of a Syk and VEGFR2 double-target inhibitor. Specifically, the invention relates to a method for preparing a compound shown as a formula (I) or an isotope labeled compound thereof, or an optical isomer, a geometric isomer, a tautomer or an isomer mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, according to the method, the pyrazole boric acid ester does not need to be protected preferentially, and the subsequent Suzuki reaction can be smoothly carried out to prepare the Syk and VEGFR2 double-target inhibitor.

Description

technical field [0001] The application belongs to the field of pharmaceutical synthesis, and in particular, relates to a preparation method and use of a dual-target inhibitor of spleen tyrosine kinase (Syk) and vascular endothelial growth factor 2 (VEGFR2). Background technique [0002] Syk is a non-receptor tyrosine kinase that plays an important role in immune receptor-mediated and integrin-mediated signal transduction in a variety of cell types, including B cells, macrophages, Monocytes, mast cells, eosinophils, basophils, neutrophils, dendritic cells, T cells, natural killer cells, platelets and osteoclasts. The immunoreceptors described in this application include typical immunoreceptors and immunoreceptor-like molecules. Typical immune receptors include B-cell and T-cell antigen receptors and various immunoglobulin receptors (Fc receptors). Immunoreceptor-like molecules are structurally related to immune receptors or participate in similar signal transduction pathway...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/5377A61P29/00A61P37/02A61P43/00A61P27/02A61P35/00A61P3/10A61P11/06A61P11/00
CPCC07D487/04A61P29/00A61P37/02A61P43/00A61P27/02A61P35/00A61P3/10A61P11/06A61P11/00
Inventor 刘晔钱文远王宏健谭亮陈曙辉
Owner OCUMENSION THERAPEUTICS (SUZHOU) CO LTD