Synthesis process of polyene taxol

A technology of docetaxel and its synthetic method, which is applied in the direction of organic chemistry, can solve the problems of reduced yield, high product cost, difficult separation, etc., and achieve the effect of less impurities, low cost and simple synthesis

Active Publication Date: 2007-03-21
SHANGHAI JINHE BIO TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its disadvantage is mainly that half of the racemic side chains are invalid isomers, which react with 10 deacetylbaccatin III to produce isomer impurities, and are difficult to separate, resulting in a decrease in yield and product higher cost

Method used

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  • Synthesis process of polyene taxol
  • Synthesis process of polyene taxol
  • Synthesis process of polyene taxol

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0034] Example 1, the protection of the 7-position and 10-position hydroxyl of 10-deacetyl baccatin III

[0035] Take 20 grams of 10-deacetylbaccadin III that has been dried in vacuum and add it to a four-necked reaction flask, vacuumize nitrogen or argon for three times, pass nitrogen or argon protection, add 360ml of anhydrous pyridine, stir, and control the reaction The system is at 0°C, and 17.4ml of (2,2,2-trichloro)ethyl chloroformate is extracted with a syringe, and slowly added dropwise to the reaction flask, and the temperature of the reaction system is controlled at 0±1°C. After the dropwise addition, spot the plate to judge the reaction end point (developing agent: ethyl acetate / n-hexane=4 / 6), and stop the reaction with an appropriate amount of deionized water after the reaction. Concentrate the reaction solution below 60°C to dryness, add an appropriate amount of dichloromethane to completely dissolve the concentrate, add 2mol / l hydrochloric acid to wash to acidic ...

example 2

[0036] Example 2, the protection of the 7-position and 10-position hydroxyl of 10-deacetyl baccatin III

[0037] Take 300 grams of 10-deacetylbaccatin III and add it to a 5-liter four-necked reaction flask, add pyridine, stir, control the reaction system at 10-15°C, and slowly add chloroformic acid-(2, 2,2-Trichloro)ethyl ester / dichloromethane (254ml / 280ml) solution, the dropwise addition time is about 10-20 minutes, and the temperature of the reaction system is controlled at 15±5°C. After the dropwise addition, continue to react for 10 minutes, point the plate to judge the end point of the reaction (developing agent: ethyl acetate / n-hexane=4 / 6), transfer to a 15-liter extraction bottle after the reaction, add 2L deionized water to terminate the reaction , extracted three times with 6L dichloromethane. Combine the extracts, add 4mol / l hydrochloric acid to wash to acidic (PH=4-5), add saturated sodium bicarbonate to wash to basic (PH=7-8), and then wash with deionized water to...

example 3

[0038] Example 3, Condensation Step of Intermediate 3 and Side Chain

[0039] Take 30.2 grams of 7,10-bis(trichloroethoxycarbonyl)-10-deacetylbaccatin III and add it to a 250ml four-necked reaction flask, vacuumize nitrogen or argon for three times, and pass nitrogen or argon Under gas protection, add 80ml of anhydrous tetrahydrofuran, stir, cool to -60°C, then slowly add 30% NaHMDS / THF 33ml dropwise, keep the reaction temperature not exceeding -60°C, after the addition is complete, continue the reaction at this temperature for about 30 minutes. Then 18.1 grams of side chains were added dropwise, keeping the reaction temperature not exceeding -60°C. After the addition was complete, the temperature was slowly raised to 0°C, and the reaction was completed in about 1 hour. Add 200 ml of saturated sodium bicarbonate to the reaction solution, extract three times with 400 ml of dichloromethane, combine the organic phases, wash with 300 ml of saturated brine, dry over anhydrous magne...

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Abstract

The present invention provides synthesis of polyene taxol, and the polyene taxol synthesizing path consists of three steps, including protection, condensation and hydrolysis, mainly. The material 10-deacetyl Baccatin III first has its 7th and 10th positions hydroxyl groups protected, then optical side chain introduced to its 13th position to obtain intermediate, and finally hydrolyzed to obtain the target product polyene taxol. The preparation process of the present invention has less steps, no isomer impurity, less side reactions, high utilization of material 10-deacetyl Baccatin III, high yield, low cost and other advantages. The product is for treating tumor clinically.

Description

technical field [0001] The present invention relates to the synthesis method of drug docetaxel for treating cancer. Background technique [0002] Paclitaxel is a natural product with a complex structure extracted from the bark of perennial yew, and Docetaxel is a semi-synthetic derivative of paclitaxel, which is a taxol derivative synthesized during the structural modification of natural paclitaxel. Anti-tumor drugs that promote microtubule polymerization in cancer cells are currently one of the most widely used and most important anti-tumor drugs in clinical practice. Docetaxel, also known as docetaxel, docetaxel (English name transliteration), chemical name: [2aR-[2aα, 4β, 4aβ, 6β, 9α, (αR * , βS * ), 11α, 12α, 12aα, 12bα]]-β-[[(1,1-dimethylethoxyl)carbonyl]amino]-α-hydroxybenzonepropanoic-acid (12b-acetyloxy-12-benzoyloxy)-2a, 3, 4, 4a , 5, 6, 9, 10, 12, 12a, 12b-dodecahydro-4, 6, 11-trihydroxy-4a, 8, 13, 13-tetramethyl-5-oxo-7, 11-methano-1H-cyclodcca[ 3,4]benz[1,2-b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/14
Inventor 张爱平张伟中赵宏武蔡志香高卅
Owner SHANGHAI JINHE BIO TECH
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