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Synthetic method of cabazitaxel

A technique for the synthesis of cabazitaxel, which is applied in the production of bulk chemicals and organic chemistry, can solve the problems of general Raney nickel reduction yield, high cost of cabazitaxel, and many by-products, and achieve low price, Yield improvement and usage reduction effect

Active Publication Date: 2012-09-12
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.
[0010] 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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Route 1

[0058] (1) Synthesis of the type II-1 compound:

[0059] In dichloromethane, add the reaction solution slowly, keep it at 0 ° C for 30 minutes, rise to room temperature for another 30 minutes, slowly dripping a small amount of water to terminate the reaction, the concentrated reaction solution is oily, add 100ml dichloromethane to dissolve, and dissolve it.Wash 2m hydrochloride until the water layer is acidic, and then wash with saturated sodium bicarbonate solution (50ml × 2), washed (50ml × 2), washed with saturated sodium chloride solution (50ml × 2).Dry magnesium sulfate for 2 hours, filter, and dry.Add a mixed solution of 20ml ether / petroleum ether (volume ratio 1 / 1), stir at room temperature for 2 hours, filtrate, 40 ° C vacuum dry 7,10-dual (trichloroaceteoxyl) -10-de-acetylkbaka Pavilion PavilionIII 16.12g, revenue: 90.6%.

[0060] 1 H-NMR (400 MHz, CDCL 3 ) δ = 1.12 (s, 3H), 1.15 (s, 3H), 1.84 (s, 3H), 2.05 (m, 1H), 2.14 (m, 1H), 2.17 (S, 3H), 2.31 (m, ...

Embodiment 2

[0079] Route 2

[0080] (1) Format II-2 compound 7,10-dual (trichlorolyxyxyl) -10-synthesis of de-acetyl Kiba Kataki Pavilion III:

[0081] With reference to the method of Example 1, the type II-2 compound is obtained, and the yield is 91.2%.

[0082] (2) Synthesis of the type III-2 compound:

[0083] Solk the 3.44g 7,10-dual (trichlorolyxyxyl) -10-de-acetylkaba Kataki III in 50ml pyridine, and then slowly drip into TESCL (triathyl chloride) 0.62g, heated to 120℃, stir 4 hours, add 100ml water to the reaction solution, and then use acetate (100ml × 3) to extract the water layer, combine the organic layer, wash (50ml × 2), wash the saturated salt water (50ml × 2), add no additionDry water and sulfate, and use petroleum ether / dichloromethane (volume ratio 2 / 1) silicone column layer, that is, to obtain 2.92g of 7,10-dual (trichlorine steroxyl) -13-trTeechlor chothrose-10-de-acetyl Kuba Kaitting III, the earnings of 90.0%.

[0084] 1 H-NMR (400 MHz, CDCL 3 ) δ = 0.55 (m, 6H), 0.93 (...

Embodiment 3

[0099] Route 3

[0100] (1) Synthesis of the type II-3 compound:

[0101] Among the 250ml triangular bottle, nitrogen protection, 10.81g of 10-de-acetyl Kabata Pavilion III III at 100ml water pyridine, stir to 0 ° C for 10 minutes, dissolve 8ml methane methaneIn chloride, add the reaction solution slowly, keep it at 0 ° C for 30 minutes, rose to room temperature for another 40 minutes, slowly dripping a small amount of water to terminate the reaction, the concentrated reaction solution is oily, add 100ml dichloromethane dissolved, use2M hydrochloride was washed to the water layer as acidic, and then washed with saturated sodium bicarbonate solution (50ml × 2), washed (50ml × 2), washed with saturated sodium chloride solution (50ml × 2), stirred, and water -free sulfuric acidMagnesium dried for 2 hours, filtered, and dried.Add a mixed solution of 20ml ether / petroleum ether (volume ratio 1 / 1), stir at room temperature for 2.5 hours, filter, 40 ° C vacuum drying 7,10-double (metham...

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Abstract

The invention relates to a synthetic method of cabazitaxel, which comprises the following steps: taking a compound 10-deacetylbaccatin III as a starting raw material and reacting with a protective agent to carry out selective protection on 7 and 10 hydroxyls; then carrying out selective protection on 13 hydroxyls of the compound, removing 7 and 10 protection radicals and carrying out methylation reaction; removing 13 protection radicals and carrying out condensation reaction with an oxazolidine carboxylic acid side chain; and removing and protecting a condensation product to obtain the cabazitaxel. The synthetic method has the beneficial effects that the proper protection radicals and a removal and protection method are selected, the oxazolidine carboxylic acid side chain is finally connected, and the synthetic method has the characteristics of low production cost, high yield, mild reaction conditions and simplicity in operation and is particularly suitable for industrial production.

Description

[0001] Technical field [0002] The invention involves the field of pharmaceutical chemistry, especially the synthesis method of a Cabazitaxel. Background technique [0003] Prostate cancer is a common malignant tumor of men and often develops in elderly men. In the United States, it is the second largest common male cancer other than skin cancer.According to statistics from the Center for Disease Prevention and Control, about 20,3415 men suffered from prostate cancer in 2006, of which 28,372 died. [0004] Cabazitaxel is a second -line drug for prostate cancer developed by Sanofi. Its product is called Jevtana.Cabazitaxel is a chemical semi -synthesis of pacane small molecular compounds. The key raw materials are mainly extracted from the red bean needle lobe.Cabazitaxel's anti -cancer mechanism and characteristics are similar to Dorcy, which belongs to anti -microtuba drugs.By combined with microtubuin protein to promote its assembly into a microtubal, at the same time, the mic...

Claims

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Application Information

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