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Method for preparing novel Bc1-2 protein inhibitor derived from ABT-263

A technology of organic solvents and compounds, applied in the field of synthesis of novel Bcl-2 protein inhibitors

Inactive Publication Date: 2010-08-11
无锡好芳德药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There is no literature report on the structure of this compound

Method used

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  • Method for preparing novel Bc1-2 protein inhibitor derived from ABT-263
  • Method for preparing novel Bc1-2 protein inhibitor derived from ABT-263
  • Method for preparing novel Bc1-2 protein inhibitor derived from ABT-263

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Embodiment 1

[0049] Synthesis of Compound 2-1

[0050] In a 1L three-necked flask equipped with mechanical stirring, 37 g (149.6 mmol) of (R)-N-tert-butoxycarbonylaspartic acid-4-methyl ester was dissolved in 400 mL THF, and cooled to -10°C. 15.1g (149.6mmol) N-methylmorpholine was added dropwise with stirring, and after the dropwise addition, 16.2g (179.6mmol) ethyl chloroformate was slowly added, and the temperature was controlled at -10°C-5°C. React for 1 hour, add 17g (448mmol) sodium borohydride at one time, add 100mL methanol dropwise at 0°C, stir for 1 hour, add 400mL water, extract with ethyl acetate (4*200mL), combine organic phases, dry and concentrate , 31 g of the product was obtained after column chromatography, and the yield was 86%.

[0051] Synthesis of compound 2-2

[0052] In a three-necked flask equipped with magnetic stirring, 32.5 g (186.5 mmol) of diethyl azodicarboxylate and 48.9 g (186.5 mmol) of triphenylphosphine were dissolved in 500 mL of anhydrous dichloromet...

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Abstract

The invention discloses a method for preparing a novel Bc1-2 protein inhibitor compound 5 which is derived from ABT-263 and is a novel anti-tumor medicament. The method comprises the following steps of: reacting a compound 1 and a compound 2 under the action of alkali to obtain a compound 3; reacting the compound 3 and a compound 4 for 36 hours at room temperature under the condition of DMAP (Dimethylaminopyridine); and then carrying out column chromatographic separation after concentration and spin drying to obtain the compound 5. The compound 5 synthesized by the method has potential bioactivities, which is not reported in documents at home and abroad, and the preparation process is simple, is easily to control and can achieve high yield.

Description

technical field [0001] The present invention relates to the synthesis of a novel Bcl-2 protein inhibitor. Background technique [0002] ABT-263 is a small molecule Bcl-2 inhibitor that can induce apoptosis. Pharmacological studies have shown that the total effective rate of ABT-263 on small cell lung cancer (SCLC) and acute lymphoblastic leukemia (ALL) mice 100%; in mice inoculated with Bc1-2-dependent SCLC cell lines, the curative effect of this product is significantly higher than that of paclitaxel, vincristine and etoposide. At present, ABT-263 has entered clinical research, and its indications include lymphoma, chronic lymphocytic leukemia and some solid tumors. Compound 5 prepared by the present invention is a new compound, which is similar in structure to ABT-263, and its main difference lies in the position of the double bond of the mother nucleus, which is a new chemical entity with potential antitumor activity. There is no literature report about the structure of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/155A61P35/00
Inventor 沈立新李云峰刘福双徐兆付吴鹏程符龙波
Owner 无锡好芳德药业有限公司