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Synthesis method of eribulin intermediate

A synthetic method and a suitable technology are applied in the field of synthesis of eribulin intermediates, which can solve the problems of difficult post-processing and purification, unfavorable industrial production, troublesome quality control, etc., and achieve simple and easy post-processing operations, improved yield and purity. , The effect of simple operation and easy handling

Active Publication Date: 2018-05-01
WUYAN PHARM TECH (SHANGHAI) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] WO2005118565A1 discloses a method for preparing the compound shown in formula 4. The process route is to protect the hydroxyl group first and then add the leaving group. This process has cumbersome operation steps, and impurities are easily generated during the reaction process, and the subsequent Purification is difficult, resulting in low product purity and yield of the entire reaction system, poor quality of key intermediates, etc., which brings great troubles to the quality control of the raw material drug synthesis process, and is not conducive to industrial production

Method used

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  • Synthesis method of eribulin intermediate
  • Synthesis method of eribulin intermediate
  • Synthesis method of eribulin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Step 1) Nitrogen protection in the reactor, add 14ml of toluene solution at room temperature, 4.54g (0.01mol) of the compound shown in formula 1, 22ml of acetonitrile solution, and then add a catalytic amount of 100mg (0.0007mol) tert-butyldimethyl Chlorosilane TBSCl, stirred for 30 minutes, then added N-iodosuccinimide NIS 6.92g (0.03mol) at 25°C, continued to stir for 2 hours, TLC detected that the reaction was complete, and added 8.4g of sodium bicarbonate to neutralize the reaction, Extracted with 100ml of ethyl acetate, washed with 100ml of brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 5.07g of the compound represented by formula 6 as an oily product with a yield of 97%, which was directly put into the next reaction.

[0050] Step 2) Nitrogen protection in the reactor, add 25ml of acetic acid and 25ml of water at room temperature, 5.23g (0.01mol) of the compound shown in formula 6, then heat to 95 ° C, stir for 4 hours, TLC detectio...

Embodiment 2

[0053] Step 1) Nitrogen protection in the reactor, add 14ml of toluene solution at room temperature, 4.54g (0.01mol) of the compound shown in formula 1, 22ml of acetonitrile solution, and then add a catalytic amount of 14.3mg (0.0001mol) tert-butyl dimethyl Chlorosilane TBSCl, stirred for 30 minutes, then added 4.61g (0.02mol) of N-iodosuccinimide NIS at 20°C, continued to stir for 4 hours, TLC detected that the reaction was complete, and added 8.4g of sodium bicarbonate to neutralize the reaction , extracted with 100ml ethyl acetate, washed with 100ml brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 5.06g of the compound shown in formula 6 as an oily product with a yield of 96.8%, which was directly put into the next reaction.

[0054] Step 2) Nitrogen protection in the reactor, add 25ml of acetic acid and 25ml of water at room temperature, 5.23g (0.01mol) of the compound shown in formula 6, then heat to 90 ° C, stir for 2 hours, TLC detection re...

Embodiment 3

[0057] Step 1) Nitrogen protection in the reactor, add 14ml of toluene solution at room temperature, 4.54g (0.01mol) of the compound shown in formula 1, 22ml of acetonitrile solution, and then add a catalytic amount of 14.3mg (0.0001mol) tert-butyl dimethyl Chlorosilane TBSCl, stirred for 30 minutes, then added N-iodosuccinimide NIS 4.61g (0.02mol) at 30°C, continued to stir for 3 hours, TLC detected that the reaction was complete, and added 8.4g of sodium bicarbonate to neutralize the reaction , extracted with 100ml ethyl acetate, washed with 100ml brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 5.1g of the compound shown in formula 6 as an oily product with a yield of 97.5%, which was directly put into the next reaction.

[0058] Step 2) Nitrogen protection in the reactor, add 30ml of acetic acid and 30ml of water at room temperature, 5.23g (0.01mol) of the compound shown in formula 6, then heat to 100 ° C, stir for 6 hours, TLC detects that th...

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Abstract

The invention discloses a synthesis method of an eribulin intermediate. The synthesis method mainly comprises the following steps: taking a compound shown as a formula 1 as a raw material to react with N-iodosuccinimide and then carrying out hydroxyl protection reaction to obtain a target product, namely a compound shown as a formula 4. The synthesis method provided by the technical scheme has theadvantages of simple and convenient operation steps, moderate reaction conditions and a few of byproducts in a reaction process; compared with the prior art, the productivity and the yield of the target product are remarkably improved and the synthesis method is very suitable for industrial production.

Description

[technical field] [0001] The invention relates to a synthetic method of an eribulin intermediate. [Background technique] [0002] Eribulin (eribulin) is a derivative of macrolide compound halichondrinB extracted from the marine sponge Halichondriaokadai, and it is a chemically active substance. Its medicinal action mechanism is to inhibit mitosis by directly binding to tubulin, inhibit the growth of microtubules, and inhibit the growth of cancer cells to exert therapeutic effects. The clinical medicinal ingredient of the drug is Eribulin mesylate, the trade name is Halaven, developed by Eisai Corporation of Japan, and it was first listed in the United States on November 15, 2010. The U.S. Food and Drug Administration (FDA) approved Halaven (A Eribulin sulfonate) is used for the treatment of patients with metastatic breast cancer who have received at least two chemotherapy treatments for advanced disease. The drug was subsequently launched in Singapore, the European Union, S...

Claims

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Application Information

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IPC IPC(8): C07D493/04C07F7/18
CPCC07D493/04C07F7/188Y02P20/55
Inventor 郭松坡邱东成
Owner WUYAN PHARM TECH (SHANGHAI) CO LTD
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