Synthesis of compound ABT-263

A technology of ABT-263 and synthetic method, which is applied in the field of synthesis of Bcl-2 and Bcl-xl inhibitor compound ABT-263, can solve problems such as difficult to prepare large quantities of compounds, shorten reaction steps, and environmental pollution, and achieve synthetic method The effect of simplicity, shortening the route, and avoiding environmental pollution

Active Publication Date: 2008-07-16
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The structure of this compound is currently only involved in the US patent application US2007027135 (Benzoylaminoarylsulfonamide as apoptosis promoters and their preparation, pharmaceuticalai compositions and use in the treatment of cancers). From the structural point of view, the compound mainly involves the synthesis of three fragments, and fragment 1 has been U.S. patent application US2005272744 (Preparation of N-sulfonylcarboximidamides for use as apoptosis promoters.) reports that we use different starting materials and synthetic

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  • Synthesis of compound ABT-263
  • Synthesis of compound ABT-263
  • Synthesis of compound ABT-263

Examples

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Embodiment 1

[0042] Synthesis of compound 1

[0043]In a 500mL three-neck flask, add 200mL tetrahydrofuran, add 20mL N-methylmorphine and (R)-N-tert-butoxycarbonylaspartic acid-4-benzyl ester (32.3g, 0.1mol) at -10°C, Add tert-butyl chloroformate (16.2g, 0.12mol) dropwise under stirring, react for 30 minutes, add sodium borohydride (7.6g, 0.2mol), add methanol 150ml dropwise, stir for 2 hours; spin the organic solvent to dry, Add 150ml of water, extract with ethyl acetate (3×100mL), combine, dry, concentrate, and pass through the column to obtain compound 119.7g with a yield of 64%.

[0044] Synthesis of Compound 2

[0045] Diethyl azodicarboxylate (13g, 75mmol) and triphenylphosphine (19.6g, 75mmol) were dissolved in 150mL of dichloromethane, compound 1 (15.5g, 50mmol) was added dropwise, followed by thiophenol (8.25 g, 75 mmol), stirred at room temperature for 24 hours, spin-dried the organic solvent, and separated by column chromatography to obtain compound 2 (11.2 g, yield 56%).

[...

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Abstract

The invention discloses a synthetic method for a compound ABT-263, which essentially comprises the following steps: a compound 5 reacts with a compound 9 under a basic condition to derive a compound 13; the compound 13 and a compound 12 are dissolved in dichloromethane to react by adding EDCI and DMAP for 24 hours at a room temperature; the compound ABT-263 is derived via spin drying, watering, acetic ether extraction, drying, condensing, and column chromatographic separation. The invention adopts different starting materials, different synthetic courses, easier available raw materials and methods, and improves the oxidation method of 2-fluoro sulfide phenyl trifluoromethyl; thereby avoiding the pollution of large amount of heavy metal to the environment, as catalytic amount of chromic anhydride is adopted, the yield is improved from 17 percent to 90 percent; in additional, as the adoption of Mannich reaction shortens the reaction steps, the yield is improved.

Description

technical field [0001] The invention relates to a synthesis method of Bcl-2 and Bcl-xl inhibitor compound ABT-263. technical background [0002] The compound ABT-263 (shown in the following structural formula) is a Bcl-2 family protein antagonist, which can effectively induce tumor cell apoptosis. The bc1-2 family proteins are highly expressed in many tumor cells, can inhibit tumor cell apoptosis, and play an important role in the formation, development and drug resistance of tumors. Preclinical studies have shown that ABT-263 can kill certain tumor cells, such as non-small cell lung cancer cells, and enhance the sensitivity of tumor cells to chemotherapy and radiotherapy. ABT-263 has entered phase I clinical research, and its indications include lymphoma, chronic lymphocytic leukemia and some solid tumors. [0003] The structure of this compound is currently only involved in the US patent application US2007027135 (Benzoylaminoarylsulfonamide as apoptosis promoters and the...

Claims

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Application Information

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IPC IPC(8): C07D295/14C07D295/125A61P35/00
Inventor 丁克王广军张虎山周净
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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