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Method for purifying docetaxel

A docetaxel and purification method technology, applied in the field of drug synthesis, can solve problems such as difficult purification, cumbersome operation, complex structure, etc., achieve high yield and improve product purity

Active Publication Date: 2019-06-04
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] ICH has a limit of 0.10% for non-specified impurities, and docetaxel is clinically used as an injection preparation, which has stricter control over the content of impurities, but Its structure is complex, its molecular weight is 807.88, it is easy to mix with impurities, it is difficult to purify, and it is difficult to remove most of the impurities at one time by recrystallization
The method commonly used in the prior art that can better remove impurities in the crude product of docetaxel is first purified by column chromatography, followed by further recrystallization, the operation is cumbersome, and it is not suitable for industrial production

Method used

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  • Method for purifying docetaxel
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  • Method for purifying docetaxel

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

[0038] Reference Example 1: Intermediate 2

[0039]

[0040] Add 900 g of 10-deacetylbaccatin III (compound 1) and 4.5 kg of dried pyridine into the reaction flask under stirring, and control the temperature of the feed liquid at 0-10°C, slowly add trichloroethyl chloroformate dropwise into the feed liquid 980.1 g of ester, after dropping, keep the feed liquid temperature at 0-10° C. for 2 hours, monitor by TLC, stop the reaction after the reaction is complete.

[0041] Add 7.2L of dichloromethane, control the temperature of the feed liquid at 10-25°C, slowly add 6mol / L hydrochloric acid dropwise, adjust the pH of the feed liquid to 2-3, let stand and separate the layers, back-extract the water phase with 3.6L of dichloromethane, and combine The organic phase was washed with purified water, collected, dried over anhydrous sodium sulfate, and suction filtered. The filtrate was collected and concentrated under reduced pressure to about 1 / 3 of the volume of the raw material s...

reference example 2

[0042] Reference Example 2: Intermediate 3

[0043]

[0044] Add 15.1L of dichloromethane, 1370g of intermediate 2, (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyloxazolidine-5-acid in sequence into a 30L glass reaction tank 589.8g and 97.3g of 4-dimethylaminopyridine were cooled to 5-15°C under the protection of nitrogen. Control the feed liquid temperature at 15-25°C, and add 787.8 g of N,N'-dicyclohexylcarbodiimide in batches. After the injection was completed, after stirring and reacting at 15-25°C for 1 hour, the reaction progress was tracked by TLC, and the reaction was stopped when the intermediate 2 basically reacted completely. Suction filtration, dichloromethane 2.7L wash filter cake. The filtrate was concentrated under reduced pressure at 20-30°C to nearly dryness. Add 7.1 L of anhydrous methanol, and concentrate under reduced pressure at 10-20°C until there is basically no dichloromethane in the feed solution. Stir and crystallize at -5 to 5°C for 1 hour...

reference example 3

[0045] Reference Example 3: Intermediate 4

[0046]

[0047] Add 1456g of crushed intermediate 3 and 14.6L of formic acid into a 30L glass reaction tank, and stir and react at 25-35°C. After reacting for 1 hour, TLC followed the reaction process, and stopped the reaction when the raw materials basically reacted completely. Add 26.2kg of ethyl acetate and saturated sodium chloride solution, then slowly add 5.5% sodium carbonate aqueous solution, after the addition, let it stand for stratification, extract the aqueous phase with 8.6kg of ethyl acetate in two equal parts, combine the organic layers, add 7.6 % sodium carbonate aqueous solution, adjust the pH to 7-8, wash the organic phase once with saturated sodium chloride solution, collect the organic phase, and dry over anhydrous sodium sulfate. Suction filtration, the filtrate was collected, and the filtrate was concentrated to about 14.6 L under reduced pressure at 45-50°C to obtain an ethyl acetate solution of intermedia...

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Abstract

The invention discloses a method for purifying docetaxel. A docetaxel solid precipitates from a dichloromethane and toluene mixed solution. The purifying method has the advantages of great reduction of the single content of every impurity in docetaxel, introduction of few impurities, improvement of the purity of the product, and high yield, and is very suitable for industrial large-scale production, and the obtained product meets preparation demands, and can be directly used to prepare a docetaxel injection.

Description

technical field [0001] The application relates to the field of drug synthesis, in particular to a purification method of docetaxel. Background technique [0002] Docetaxel is a paclitaxel antitumor drug that inhibits the mitosis and proliferation of cancer cells by promoting tubulin aggregation and preventing microtubule depolymerization. At present, the method of industrially synthesizing docetaxel is mainly prepared by the route of scheme 1, that is, compound 1 (10-deacetylbaccatin III) is used as the starting material, and finally prepared by removing the protecting group Troc through the reaction of Zn and acetic acid The crude product of docetaxel is obtained, and then further refined and purified to obtain docetaxel that meets the pharmaceutical specifications. [0003] Process 1: [0004] [0005] ICH has a limit of 0.10% for non-specified impurities. Docetaxel is clinically used as an injection preparation, which has stricter control over the content of impuriti...

Claims

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Application Information

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IPC IPC(8): C07D305/14
CPCY02P20/55
Inventor 陆银胡明通
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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