Synthetic method of paclitaxel side chain

A technology of paclitaxel side chain and synthesis method, applied in the field of chemical synthesis, can solve the problems of a large number of impurities and isomers, difficult purification, harsh production conditions, etc., and achieves less harsh production and preparation conditions, simple and easy operation, and production cycle. short effect

Pending Publication Date: 2020-10-13
YUNNAN HANDE BIO TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the existing paclitaxel side chain synthesis patents, there are many ways to prepare by splitting, but the disadvantages are low extraction efficiency, low yield, harsh production conditions, and high investment in cost, resulting in excessive product prices. High, not conducive to the reduction of disease treatment expenditure
There are also some synthetic methods that are prepared by ring-opening epoxy compounds with ammonia and azide compounds, but the ring-opening regioselectivity of these compounds is low, and a large amount of impurities and isomers are produced, which makes the subsequent purification difficult. The low yield of the product is caused, and at the same time, due to the dangerous nature of the azide compound, there is a huge safety hazard in the production operation, and it is not suitable for large-scale production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1: The synthetic method of this paclitaxel side chain, concrete operation is as follows:

[0035] 1. Take 100g of (2R,3S)-3-phenylisoserine hydrochloride as raw material, dissolve it in 2000mL of anhydrous methanol, add 50mL of thionyl chloride under ice bath conditions, then leave the ice bath at room temperature After 3.67 hours of reaction, the reaction ended. At this time, the pH value of the reaction solution was 2, and it was inactivated with 1700mL saturated sodium bicarbonate solution; Add water to dilute at the ratio of water=1L:0.2L, extract the concentrated solution with 400mL n-butanol twice, collect and combine the n-butanol extract, and dry it through anhydrous sodium sulfate (according to n-butanol extract: no (2R, 3S)-phenylisoserine methyl Crude ester 106g (oil);

[0036] 2. Dissolve the crude (2R,3S)-phenylisoserine methyl ester obtained above in 3000mL of anhydrous dichloromethane under ice bath conditions, then add 63.6mL of benzoyl chlo...

Embodiment 2

[0039] Embodiment 2: The synthetic method of this paclitaxel side chain, concrete operation is as follows:

[0040] 1. Take 200g of (2R,3S)-3-phenylisoserine hydrochloride as raw material, dissolve it in 4800mL of anhydrous methanol, add 150mL of thionyl chloride under ice bath conditions, then leave the ice bath at room temperature After reacting for 5.67 hours, the reaction ended. At this time, the pH value of the reaction solution was 2~3, and inactivated with 3500mL saturated sodium bicarbonate solution; Solution: water = 1L: 0.3L by adding water to dilute, the concentrated solution after dilution was extracted 3 times with 800mL n-butanol, collected and combined n-butanol extract, dried by anhydrous sodium sulfate (according to n-butanol extract : Anhydrous sodium sulfate = 1L: 120g (add anhydrous sodium sulfate) at a temperature of 60-65°C and a vacuum of 0-0.08MPa under reduced pressure and rotary evaporation to obtain (2R, 3S)-phenylisoserine Crude methyl ester 213g (...

Embodiment 3

[0044] Embodiment 3: The synthetic method of this paclitaxel side chain, concrete operation is as follows:

[0045] 1. Take 300g of (2R,3S)-3-phenylisoserine hydrochloride as raw material, dissolve it in 7500mL of methanol, add 240mL of thionyl chloride under ice bath conditions, then leave the ice bath and react at room temperature for 6h After the end of the reaction, the pH value of the reaction solution was 2 to 3, and it was deactivated with a saturated sodium bicarbonate solution; the reaction solution was concentrated and removed under the conditions of 65° C. of temperature and a vacuum of 0 to -0.08 MPa to remove methanol, according to the concentrated solution: water = Add water to dilute at a ratio of 1L:0.2L, extract the diluted concentrated solution with 1220mL n-butanol for 3 times, collect and combine the n-butanol extract, and dry it through anhydrous sodium sulfate (according to n-butanol extract: anhydrous sulfuric acid Sodium=1L:150g (adding anhydrous sodium...

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PUM

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Abstract

The invention discloses a synthetic method of a paclitaxel side chain. The method comprises the steps of taking (2R, 3S)-3-phenyl isoserine hydrochloride as a raw material; carrying out esterificationreaction under the participation of methanol and thionyl chloride to obtain (2R, 3S)-phenyl isoserine methyl ester; then preparing (2R, 3S)-N-benzoyl-phenyl isoserine methyl ester through a benzoylation reaction; preparing (4S, 5R)-5-methoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-3-benzoyl-1,3-oxazolidine through a cyclization protection reaction; finally, obtaining a paclitaxel side chain crude product through hydrolysis, and further purifying the paclitaxel side chain crude product through recrystallization to obtain a paclitaxel side chain finished product. The method is simple and easy to operate, short in production period, low in cost, high in purification efficiency and suitable for industrial application and market popularization.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a method for synthesizing paclitaxel side chains. Background technique [0002] Since paclitaxel was approved by the US Food and Drug Administration (FDA) in 1992, it has been favored by the international anti-tumor drug research field due to its unique mechanism of action, exact curative effect and less side effects. The number one drug in malignancies such as breast cancer, non-small cell lung cancer and Kaposi'S sarcoma. In the past, the main source of paclitaxel was the bark of the natural yew, but the content was very small, the extraction cost was high, and the natural resources were severely damaged. In recent years, with the rise of yew planting, extracting paclitaxel from yew branches and leaves has become a mainstream method to obtain natural paclitaxel, which not only protects natural plant resources, but also expands the production of natural paclitaxel. However, n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/04
CPCC07D263/04
Inventor 杨青春滕院赵晓怡赵泽熙胡倩马秋丽
Owner YUNNAN HANDE BIO TECH
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