Preparation method of cabazitaxel and intermediate thereof

A technology of cabazitaxel and compounds, which is applied in the field of drug synthesis, can solve the problems of low selectivity, low yield of cabazitaxel, and unsuitability for commercial production, and achieve the effect of high yield and low cost

Inactive Publication Date: 2013-04-03
BEIJING COLLAB PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the C-7, C-10 and C-13 hydroxyl groups of 10-deacetylbaccatin III (10-DAB) can all be methylated, the existing methods are not very selective in methylation , the yield of preparing cabazitaxel is low, the product is difficult to refine, and it is not suitable for commercial production

Method used

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  • Preparation method of cabazitaxel and intermediate thereof
  • Preparation method of cabazitaxel and intermediate thereof
  • Preparation method of cabazitaxel and intermediate thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0032] The preparation of the cabazitaxel intermediate shown in embodiment 1 formula I

[0033] Add 16.6g (30.5mmol) of the compound shown by formula II into a 2000ml three-necked flask, dissolve it in 1000ml of anhydrous tetrahydrofuran, add 10.5g (64.1mmol) of methyl triflate and cool it down to -60°C, slowly drop the concentration It is 50.8ml of 1.2M LiHMDS tetrahydrofuran solution (LiHMDS content is 61mmol). After the dropwise addition, close the freezing tank, and naturally raise the temperature to -30°C for 40min. After the reaction, add 50ml of saturated NaHCO to the reaction system 3 Aqueous solution quenched the reaction. Add a mixed solvent composed of 200ml dichloromethane and 800ml isopropyl ether to the reaction mixture, precipitate a white solid, filter, wash the solid with 30ml dichloromethane and 30ml isopropyl ether successively, and dry in vacuo to obtain a white powder which is formula I Shown compound, yield is 13.1g, and yield is 75.0%; Its spectral data...

Embodiment 2

[0035] The preparation of compound shown in embodiment 2 formula I

[0036] Add 16.6g (30.5mmol) of the compound shown by formula II into a 2000ml three-necked flask, dissolve it in 1000ml of anhydrous tetrahydrofuran, add 7.3g (64.1mmol) of methyl fluorosulfonate and cool it down to -60°C, slowly drop the concentration to 1.2 M LiHMDS tetrahydrofuran solution 50.8ml (LiHMDS content is 61mmol), after the dropwise addition, close the freezer, naturally warm to -30 ° C for 40min, after the reaction, add 50ml saturated NaHCO to the reaction system 3 Aqueous solution quenched the reaction. Add 200ml of dichloromethane and 800ml of isopropyl ether into the mixed solvent of the reaction mixture, a white solid precipitates, filters, washes the solid with 30ml of dichloromethane and 30ml of isopropyl ether, and vacuum-dries to obtain a white powder of formula Compound shown in I, output is 12.2g, and yield is 70.0%; Its spectral data are with embodiment 1.

Embodiment 3

[0037] The preparation of compound shown in embodiment 3 formula I

[0038] Add 16.6g (30.5mmol) of the compound shown by formula II into a 2000ml three-neck flask, dissolve it in 1000ml tetrahydrofuran, add 7.1g (64.1mmol) of methyl methanesulfonate and cool it down to -60°C, slowly dropwise add 1.0M NaHMDS tetrahydrofuran solution 61.0ml (NaHMDS content is 61.0mmol), after the dropwise addition, close the freezing tank, naturally warm up to -30°C for 40min, after the reaction, add 50ml saturated NaHCO 3 Aqueous solution quenched the reaction. Add a mixed solvent composed of 200ml dichloromethane and 800ml isopropyl ether to the reaction mixture, precipitate a white solid, filter, wash the solid with 30ml dichloromethane and 30ml isopropyl ether successively, and dry in vacuo to obtain a white powder which is formula I Shown compound, yield is 14.3g, and yield is 81.9%; Its spectral data are with embodiment 1.

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Abstract

The invention discloses a preparation method of a cabazitaxel intermediate 7,10-dimethoxy-10-baccatin III. In the presence of alkali, 10-deacetylbaccatin III and a specific methylation reagent are subjected to selective methylation reaction at low temperature to obtain the cabazitaxel intermediate 7,10-dimethoxy-10-baccatin III. In the preparation method, the methylation reaction has high selectivity for C-7 and C-10 hydroxy sites on the 10-deacetylbaccatin III, so the yield is high. The invention also discloses a preparation method of cabazitaxel, which comprises the following steps: preparing the cabazitaxel intermediate according to the preparation method above; condensing the cabazitaxel intermediate with one side chain of docetaxel; and hydrolyzing the obtained condensation product under acidic conditions to obtain the cabazitaxel. The preparation method of cabazitaxel has the advantage of high total yield and is suitable for commercialized production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of cabazitaxel and its intermediate. Background technique [0002] Cabazitaxel is a second-line drug for the treatment of prostate cancer developed by Sanofi-aventis, which was launched in the United States in June 2010. Cabazitaxel is a semi-synthetic taxane-like small molecule compound with the following structural formula: [0003] [0004] Cabazitaxel is a microtubule inhibitor indicated in combination with prednisone for the treatment of patients with metastatic hormone-refractory prostate cancer who have previously received a docetaxel-containing regimen. [0005] At present, there are two synthetic methods of cabazitaxel, one is to first synthesize docetaxel or its derivatives, and then hydroxymethylate the C-7 and C-10 positions (CN102311410, CN102060815, CN102675256). The other is to first hydroxymethylate the C-7 and C-10 positions of 10-deacetylb...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/14
Inventor 孙志国王宏志谈敦潮邹德超赵大龙王珂
Owner BEIJING COLLAB PHARMA
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