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10-deacetylbaccatin iii and method for methoxylation of its derivative

A deacetylation bacca, methoxylation technology, applied in organic chemistry, silicon organic compounds, etc., can solve the problem that the reaction cannot be carried out smoothly and quickly.

Active Publication Date: 2012-06-27
无锡紫杉药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It will cause the reaction to be unable to proceed smoothly and quickly.

Method used

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  • 10-deacetylbaccatin iii and method for methoxylation of its derivative
  • 10-deacetylbaccatin iii and method for methoxylation of its derivative
  • 10-deacetylbaccatin iii and method for methoxylation of its derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0031] In a 5L reaction flask, 100.0g (0.15mol) of 13-triethylsilyl-10-DAB was dissolved in 2.5L of anhydrous ether, and 1g (0.003mol) of tetrabutyl bromide was added under mechanical stirring Ammonium chloride, cryogenically cooled to -40 degrees Celsius. Then, a solution of dimethyl sulfate (1 mol, 126 g) in 200 mL of anhydrous ether was added dropwise into the reaction flask. Then add 60% NaH 134.7g (3.3mol) powder in batches from the feeding tube. The addition is completed in about 1 hour, and the addition rate is controlled so that the temperature of the reaction solution in the reaction bottle is below -15 degrees Celsius. After stirring for another hour, the ice-salt bath was removed; according to the detection of TLC, after the reaction of the starting materials was completed, 1000 mL of 0.5 mol / L hydrochloric acid was added dropwise with the ice bath turned on, and then the lower layer of water was separated, and then 1000 mL was added. .5mol / L hydrochloric acid sol...

Embodiment 2

[0033] Suspend 100.0 g (0.18 mol) of 10-DAB in 2.5 L of anhydrous ether in a 5 L reaction flask, add 1 g of tetrabutylammonium bromide with mechanical stirring, and bathe in ice-salt water to 0 °C. Then, a solution of dimethyl sulfate (1 mol, 126 g) in 200 mL of anhydrous ether was added dropwise into the reaction flask. Then add 60% NaH 134.7g (3.3mol) powder in batches from the feeding tube. The addition was completed in about 1 hour, and the addition rate was controlled so that the temperature of the reaction solution in the reaction bottle was below 5 degrees Celsius. After stirring for another hour, the ice-salt bath was removed; after the reaction of the starting materials was completed according to TLC detection, 1000 mL of 0.5 mol / L hydrochloric acid was added dropwise with the ice bath turned on, and the lower aqueous phase was separated, and then 1000 mL of After the 0.5mol / L hydrochloric acid solution was stirred, the lower aqueous phase was separated. Then, after...

Embodiment 3

[0035]Suspend 100.0 g (0.18 mol) of 10-DAB in 2.5 L of anhydrous toluene in a 10 L reaction flask, add 1 g of tetrabutylammonium bromide with mechanical stirring, and bathe in ice-salt water to 0 degrees Celsius. Then a solution of dimethyl sulfate (0.5 mol, 63 g) in 1000 mL of anhydrous toluene was added dropwise into the reaction flask. Then add 6.58 g (0.24 mol) of 90% NaH solid powder in batches from the feeding tube. The addition was completed in about 1 hour, and the addition rate was controlled so that the temperature of the reaction solution in the reaction bottle was below 5 degrees Celsius. After stirring for another 1 hour, the ice-salt bath was removed; after the reaction of the starting materials was completed according to TLC detection, 1000 mL of 0.5 mol / L hydrochloric acid was added dropwise with the ice bath turned on, and the lower aqueous phase was separated, and then 1000 mL of After the 0.5mol / L hydrochloric acid solution was stirred, the lower aqueous ph...

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Abstract

The invention relates to 10-deacetylbaccatin III and a method for methoxylation of its derivative, which belongs to the medicine synthesis technical field. The invention is characterized in that the under the condition that 10-DAB, the 7 position and the 10 position of its derivative are hydroxy or one of them is hydroxyl, a phase transfer catalyst quaternary ammonium salt N<+>R4X<-> is added under the existence of a methylating agent, and dissolved according to a weight ratio of 1:10-100 of solute to organic solvent, and reacted with low temperature, a lower layer water phase is separated after finishing the reaction, an organic phase is washed by a saturated salt solution, and the organic phase is concentrated by concentrated acid, a petroleum ether is added for completely deposing, filtered, deposed and dried to obtain the product. The invention provides a simple and easy method for preparing the 10-DAB and a methoxy compound of the 7 position and the 10 position hydroxy of its derivative. The method for large scale intermediate preparation enables possibility of preparation of docetaxel with large dosage, and is a key step for preparing cabazitaxel.

Description

technical field [0001] The invention relates to a method for methoxylation of 10-deacetylbaccatin III and its derivatives, belonging to the technical field of drug synthesis. Background technique [0002] In June 2010, the United States approved the anti-prostate cancer drug cabazitaxel (JEVTANA), namely 7,10-dimethylated docetaxel (CAS number: 183133-96-2; molecular formula: C 45 h 57 NO 14 ), its structural formula is as follows: [0003] [0004] The difference between cabazitaxel and docetaxel is only the difference between the 7th and 10th positions. As shown in the above structural formula, the 7th and 10th positions of docetaxel are hydroxyl groups, while the 7th and 10th positions of cabazitaxel are hydroxyl groups. The number position is methoxy. Since the synthetic process of docetaxel was listed in 1994, there have been many mature synthetic process routes suitable for large quantities (kilogram level). The synthesis of cabazitaxel can be carried out by us...

Claims

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Application Information

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IPC IPC(8): C07F7/08C07D305/14
Inventor 蔡强冉秀琼王旭阳徐信保王琼
Owner 无锡紫杉药业股份有限公司
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