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Method for semi-synthesis of paclitaxel on industrialized basis

A paclitaxel and semi-synthetic technology, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of many by-products and long reaction time, and achieve the effects of less by-products, short reaction time, and reduced operation links.

Active Publication Date: 2012-01-11
上海卓鼎生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the above-mentioned method of semi-synthesizing paclitaxel, the ring-opening deprotection all uses solvents such as ethyl acetate, methanol or ethanol, the reaction time is long, and there are many by-products

Method used

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  • Method for semi-synthesis of paclitaxel on industrialized basis
  • Method for semi-synthesis of paclitaxel on industrialized basis
  • Method for semi-synthesis of paclitaxel on industrialized basis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] a, the synthesis of baccatin III:

[0034] Add 1 g of 10-DAB to a dry round-bottomed flask, dissolve in 20 ml of THF, stir magnetically to dissolve, then add 80 mg of CeCl 3 .6H 2 O, add 3ml of acetic anhydride again, stir and react at room temperature for 1.5 hours, TLC detects that the reaction is complete, the reaction solution is poured into ice water and left to stand, white particles crystallize out, and filtered with a glass sand funnel.

[0035] After drying, 1.04 g of bacatin III solid was obtained with a yield of 95%.

[0036] b. Preparation of baccatin III in which trichloroethyl chloroformate protects the 7-hydroxyl group:

[0037] Dissolve 1 g of baccatin III in 20 ml of anhydrous dichloromethane, stir to dissolve, add 0.62 ml of anhydrous pyridine, 0.5 ml of trichloroethyl chloroformate, and react at 10°C for 1.5 hours. TLC detects that the reaction is complete. Add ice water to the bottle to stop the reaction. The organic phase was washed three times wi...

Embodiment 2

[0043] a, the synthesis of baccatin III:

[0044] Add 1 g of 10-DAB to a dry round-bottomed flask, dissolve it in 15 ml of tetrahydrofuran, and stir to dissolve it, then add 50 mg of anhydrous CeCl 3 , then add 5ml of acetic anhydride, stir and react at room temperature for 2 hours, TLC detects that the reaction is complete. After drying, 0.95 g of bacatin III solid was obtained with a yield of 88%.

[0045] b. Preparation of baccatin III in which trichloroethyl chloroformate protects the 7-hydroxyl group:

[0046] Dissolve 1 g of baccatin III in 15 ml of anhydrous dichloromethane, stir to dissolve, add 0.7 ml of anhydrous pyridine, 0.7 ml of trichloroethyl chloroformate, and react at 20 ° C for 1 hour. TLC detects that the reaction is complete. Add ice water to the bottle to stop the reaction. The organic phase was washed three times with 5% hydrochloric acid, then washed with saturated sodium carbonate, and finally washed with saturated brine, the organic phase was dried ...

Embodiment 3

[0051] a, the synthesis of baccatin III:

[0052] Add 1 g of 10-DAB to a dry round-bottomed flask, dissolve in 25 ml of THF, stir magnetically to dissolve and add 150 mg of CeCl 3 .7H 2 O, add 4ml of acetic anhydride again, stir and react at room temperature for 3 hours, TLC detects that the reaction is complete, the reaction solution is poured into ice water and left to stand, white particles are crystallized, and filtered with a glass sand funnel.

[0053] After drying, 0.93 g of bacatin III solid was obtained with a yield of 86%.

[0054] b. Preparation of baccatin III in which trichloroethyl chloroformate protects the 7-hydroxyl group:

[0055] Dissolve 1g of baccatin III in 25ml of anhydrous dichloromethane, stir to dissolve, add 0.55ml of anhydrous pyridine, 0.8ml of trichloroethyl chloroformate, and react at 5°C for 2 hours. TLC detects that the reaction is complete. Add ice water to the bottle to stop the reaction. The organic phase was washed three times with 5% h...

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Abstract

The invention provides a method for the semi-synthesis of paclitaxel on an industrialized basis. The method comprises the following steps: a) acetylating the 10-hydroxyl in the presence of CeCl3.6H2O as a high-efficiency specific catalyst to obtain baccatin III through the reaction; b) protecting the C-7-hydroxyl in the presence of trichloroethyl chloroformate to obtain baccatin III, wherein the C-7 position of baccatin III is protected; c) conducting the esterification reaction between the baccatin III obtained in the reaction of step b) and (4S, 5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-5-oxazolinyl carboxylate to obtain the following derivatives; and d), opening the oxazole ring on the ring-shaped lateral chain of (4S, 5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-5-oxazolinyl baccatin III, and synchronously removing the 7-protective group to obtain paclitaxel. The method of the invention breaks with the conventional method which sequentially comprising the steps of protecting the 7-position hydroxyl and acetylating the 10-position hydroxyl, so that the method has the advantages of shorter reaction time and less by-products; the yield of single-step reaction reaches 90%; and eachstep of reaction is conducted at normal pressure in the absence of protective inert gases. Therefore, the method is suitable for industrialized production.

Description

technical field [0001] The invention relates to an industrial production method for preparing paclitaxel from 10-deacetylbaccatin III as a raw material. Background technique [0002] Paclitaxel is a diterpenoid compound extracted from the yew plant, which has a unique anti-cancer mechanism of inhibiting mitosis, and is internationally recognized as the drug with the best anti-cancer effect. According to the report of the World Health Organization, the incidence of cancer in the world has shown an obvious increasing trend in recent decades. From 1991 to 2000, the incidence and death of cancer worldwide increased by 22%. In 2000, the number of new cancers in the world exceeded 10 million, and the number of deaths caused by cancer was about 6.3 million people in the world every year, accounting for the total number of deaths. nearly 12 percent. The World Health Organization predicts that by 2020, the annual number of new cancer patients will reach 15 million, and cancer will ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D305/14
CPCY02P20/55
Inventor 付翠花马回民
Owner 上海卓鼎生物技术有限公司
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