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Method for preparing Chk protein kinase antagonist AZD-7762

A technology of AZD-7762, protein kinase, applied in organic chemistry and other directions, to achieve the effect of good reproducibility, convenient operation and improved reproducibility

Inactive Publication Date: 2011-02-09
SYNTHESIS MED SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, there is no report of using the reaction route to synthesize AZD-7762

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  • Method for preparing Chk protein kinase antagonist AZD-7762

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Experimental program
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Embodiment 1

[0041] a. Preparation of trichloroacetamide-thiophene-2-carboxylic acid methyl ester (A-2)

[0042] 320mmol (50g) of 3-amino-thiophene-2-carboxylic acid methyl ester and 320mmol (32.3g) of triethylamine were dissolved in 400ml of tetrahydrofuran, and then at a temperature of 5°C, 320mmol (58.4g) of trichloroacetyl chloride was slowly Add dropwise to the reaction solution, after the dropwise addition, continue to stir for 30 minutes, quench with 500ml of distilled water, extract with 250ml*4 ethyl acetate, dry with anhydrous sodium sulfate, reduce pressure at 40°C and 0.1MPa pressure The solvent was removed to obtain 94.8 g of the product as 3-trichloroacetamide-thiophene-2-carboxylic acid methyl ester (A-2), and the yield was 98%. The NMR structure analysis of the A-2 compound was carried out, and the test data were as follows:

[0043] 1 H NMR (400MHZ, DMSO), δppm: 8.07-8.05(d,1H), 7.89-7.88(d,1H), 3.89(s,3H)

[0044] LC / MS: [M+1] + : 303

[0045] b. Preparation of 5-brom...

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Abstract

The invention discloses a method for preparing a Chk protein kinase antagonist AZD-7762. The method is characterized by comprising the following steps: performing Suzuki coupling reaction between 3-amino-5-bromine-thiophene-2-methyl formate and 3-fluorophenylboronic acid; performing hydrolysis and amide coupling reaction on the obtained methyl formate; protecting the amino on the site 3 of the thiophene methyl formate; introducing chiral aminopiperidine segments and m-fluorotoluene segments to the thiophene matrix ring one by one; and then introducing a urea functional group to obtain the product AZD-7762. The invention has the advantages of effectively reducing the dosage of expensive raw material reagent chiral aminopiperidine and reducing the production cost, has simple process, convenient operation, high reproducibility and high reaction yield, and is a synthesis method with broad application prospect and high practical value and particularly suitable for industrial production.

Description

[0001] technical field [0002] The invention relates to the fields of medicinal chemistry and organic synthetic chemistry, in particular to a preparation method of Chk protein kinase antagonist AZD-7762. Background technique [0003] AZD-7762 is a fully synthetic small molecule. As a selective antagonist of Chk protein kinase, it can be used as a drug for the treatment of solid cancers. This small molecule can enhance chemotherapy and radiation when used in combination with other drugs that disrupt DNA replication. The effect of the treatment. AZD-7762 is currently being used together with another anticancer drug, Gemcitabine, as a combined drug for the treatment of solid cancers. It is in the first phase of clinical research. AZD-7762 is expected to be approved by the US FDA within three years and become a chemical drug for the treatment of solid cancers . [0004] The current method for preparing AZD-7762 is mainly based on the synthetic route adopted in the patent publ...

Claims

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Application Information

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IPC IPC(8): C07D409/12
Inventor 部先永
Owner SYNTHESIS MED SHANGHAI