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Synthetic method of cabazitaxel

A cabazitaxel and synthetic method technology, which is applied in the production of bulk chemicals, organic chemistry and other directions, can solve the problems of the general Raney nickel reduction yield, the high cost of cabazitaxel, and the waste of materials, and achieves low price and high yield. The effect of improving the efficiency and reducing the production cost

Active Publication Date: 2014-08-06
BRIGHTGENE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method introduces a chiral oxazolidine carboxylic acid side chain from the beginning, resulting in waste of expensive materials, and the Pummerer rearrangement reaction and Raney nickel reduction yield are average.
[0009] In the reported methods, the disadvantages of complex route, many by-products, low yield and high cost lead to high cost of cabazitaxel

Method used

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  • Synthetic method of cabazitaxel
  • Synthetic method of cabazitaxel
  • Synthetic method of cabazitaxel

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] route 1

[0055] (1) formula II-1 Compound Synthesis:

[0056] In a 250ml three-neck flask, under nitrogen protection, dissolve 10.81g of 10-deacetylbaccatin III in 100ml of anhydrous pyridine, cool down to 0°C and stir for 10 minutes, dissolve 8ml of trichloroethyl chloroformate in 50ml of anhydrous In dichloromethane, slowly drop into the reaction solution, keep stirring at 0°C for 30 minutes, rise to room temperature and stir for 30 minutes, slowly add a small amount of water dropwise to terminate the reaction, concentrate the reaction solution to oil, add 100ml of dichloromethane to dissolve, Wash with 2M hydrochloric acid until the water layer is acidic, then wash with saturated sodium bicarbonate solution (50ml×2), water (50ml×2), saturated sodium chloride solution (50ml×2), stir, and wash with anhydrous Dry over magnesium sulfate for 2 hours, filter, and spin dry. Add 20ml of diethyl ether / petroleum ether (volume ratio 1 / 1) mixed solution, stir at room tem...

Embodiment 2

[0075] route 2

[0076] (1) Synthesis of formula II-2 compound 7,10-bis(trichloroethoxycarbonyl)-10-deacetylbaccatin III:

[0077] Referring to the method described in Example 1, the compound of formula II-2 was obtained with a yield of 91.2%.

[0078] (2) Synthesis of the compound of formula III-2:

[0079] Dissolve 3.44g of 7,10-bis(trichloroethoxycarbonyl)-10-deacetylbaccatin III in 50ml of pyridine, then slowly drop into 0.62g of TESCl (triethylchlorosilane) and heat to 120 ℃, stirred for 4 hours, added 100ml of water to the reaction solution, then extracted the aqueous layer with ethyl acetate (100ml×3), combined the organic layers, washed with water (50ml×2), washed with saturated brine (50ml×2), added Dry over magnesium sulfate, and use petroleum ether / dichloromethane (volume ratio 2 / 1) silica gel column chromatography to obtain 2.92g of 7,10-bis(trichloroethoxycarbonyl)-13-triethylchlorosilane- 10-Deacetylbaccatin III, yield 90.0%.

[0080] 1 H-NMR (400 MHz, CD...

Embodiment 3

[0094] route 3

[0095] (1) Synthesis of the compound of formula II-3:

[0096] In a 250ml three-neck flask, under nitrogen protection, dissolve 10.81g of 10-deacetylbaccatin III in 100ml of anhydrous pyridine, cool down to 0°C and stir for 10 minutes, dissolve 8ml of methoxyethoxymethane in 50ml of anhydrous di In methyl chloride, slowly add the reaction solution dropwise, keep stirring at 0°C for 30 minutes, rise to room temperature and stir for 40 minutes, slowly add a small amount of water dropwise to terminate the reaction, concentrate the reaction solution to an oily state, add 100ml of dichloromethane to dissolve, and use Wash with 2M hydrochloric acid until the water layer is acidic, then wash with saturated sodium bicarbonate solution (50ml×2), wash with water (50ml×2), and saturated sodium chloride solution (50ml×2). Magnesium was dried for 2 hours, filtered and spin-dried. Add 20ml of diethyl ether / petroleum ether (volume ratio 1 / 1) mixed solution, stir at room...

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Abstract

The invention relates to a synthetic method of Cabazitaxel, which uses compound 10-desacetylbaccatin III as a starting material to react with a protecting agent to selectively protect the 7- and 10-position hydroxyl groups, and then selectively protect the 13-position hydroxyl groups of the compound Carry out selective protection, remove the protecting group at position 7 and 10 and carry out methylation reaction, remove the protecting group at position 13 and perform condensation reaction with the side chain of oxazolidine carboxylic acid, and deprotect the condensation product to obtain cabazitaxel . The present invention selects a suitable protecting group and deprotection method, and finally connects the oxazolidine carboxylic acid side chain, which has the characteristics of low production cost, high yield, mild reaction conditions and simple operation, and is especially suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a synthesis method of Cabazitaxel. Background technique [0002] Prostate cancer is a common malignancy in men, often affecting older men, and is the second most common cancer in men in the United States after skin cancer. According to statistics from the Centers for Disease Control and Prevention, approximately 203,415 men suffered from prostate cancer in 2006, and 28,372 of them died. [0003] Cabazitaxel is a second-line drug for prostate cancer developed by Sanofi, and its trade name is Jevtana. Cabazitaxel is a semi-synthetic taxane-like small molecular compound, the key raw material of which is mainly extracted from the needles of Taxus chinensis. The anti-cancer mechanism and characteristics of Cabazitaxel are similar to those of docetaxel, and it belongs to anti-microtubule drugs. Cabazitaxel binds to tubulin, promotes its assembly into microtubules, prevents the dis...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D305/14
CPCY02P20/55
Inventor 刘平袁建栋
Owner BRIGHTGENE PHARMA