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Method for preparing paclitaxel

A technology of paclitaxel and hydroxyl, applied in the field of preparing paclitaxel, can solve the problems of impossible to achieve, optimization, various steps not specifically disclosed, etc.

Inactive Publication Date: 2008-02-20
SOC DETUD & DE RES & DEV & INGIE PHARMA SERIPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However the various steps, in particular the preceding steps for the preparation of protected 10-DAB or baccatin III are not specifically disclosed and are not optimized for efficient industrialization, which cannot possibly be achieved satisfactorily for larger scale industrial applications the result of

Method used

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  • Method for preparing paclitaxel

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] 7-o-triethylsilyl baccatin III

[0031]

[0032] 0.42 g (2.79 mmol) of triethylchlorosilane was added within 30 minutes to a stirred solution of 1 g (1.84 mmol) of 10-deacetylbaccatin in 2 ml of anhydrous pyridine at 5°C under an inert atmosphere. After reacting at 5°C for 24 hours, 0.37 g (3.62 mmol) of acetic anhydride was added within 30 minutes, and the reaction mixture was returned to room temperature. After 22 hours of reaction, 5 ml of a methanol / water (50 / 50) mixture were added within 30 minutes. The suspension was stirred for 30 minutes then filtered through a sintered glass.

[0033] After drying, 1.09 g of the above title compound was obtained in the form of a white solid (yield = 85%).

[0034] The resulting compound has the following characteristics:

[0035] 1 H NMR 400MHz (CDC1 3 ) (δppm): 8.11 (2H, d, J = 7.1Hz); 7.6 (III, t, J = 7.4Hz); 7.48 (2H, t, J = 7.7Hz); 6.46 (1H, s); 5.63 ( 1H, d, J = 7Hz); 4.96 (1H, d, J = 8.1Hz); 4.83 (1H, m); 4.49 ...

Embodiment 2

[0037] 13-o-[[(4S, 5R)-3-N-benzoyl-4-phenyloxazolidine-2RS-methoxy-5-yl]carbonyl Base]-7-o-triethylsilyl-baccatin III

[0038]

[0039] Under stirring in an inert atmosphere at room temperature, 1 g (1.43 mmol) of 7-o-triethylsilyl baccatin III was added to 0.58 g (1.77 mmol) of (4S,5R)-3-N-benzoyl -4-Phenyloxazolidine-2RS-methoxy-5-carboxylic acid in 6.5 ml of ethyl acetate. A solution of 0.73 g (3.54 mmol) of dicyclohexylcarbodiimide in 1 ml of ethyl acetate and 0.02 g (0.16 mmol) of 4-dimethylaminopyridine was added. After reacting for 1 hour, the insoluble matter was removed by filtration and the organic phase was concentrated under reduced pressure.

[0040] 1.36 g of the above title compound were obtained in the form of a pale yellow residue (yield = 95%).

[0041] The resulting compound has the following characteristics:

[0042] 1 H NMR 400MHz (CDCl 3 ) (δppm): 8.13 (2H, d, J = 7.3Hz); 7.75 (2H, d, J = 7.3Hz); 7.61 (1H, t, J = 7.4Hz); 7.50 (5H, m); 7.41 ( ...

Embodiment 3

[0044] paclitaxel

[0045]

[0046] Under an inert atmosphere, 2 mL (3 mmol) of 1.5 N aqueous HCl was added to 1 g (1 mmol) of 13-o-[[(4S,5R)-3-N-benzoyl -4-phenyloxazolidine-2RS-methoxy-5-yl]carbonyl]-7-o-triethylsilyl-baccatin III in a mixture of 8 ml ethyl acetate and 4 ml ethanol in solution. After 1 hour of reaction, 2 ml of water were added and the reaction mixture was stirred at 45° C. for another 3 hours. After adding 16 ml of ethyl acetate, the organic phase was washed with 11 ml of a saturated aqueous solution of sodium bicarbonate and then with 11 ml of a saturated aqueous solution of sodium chloride, and concentrated under reduced pressure.

[0047] The crude product was chromatographed on silica gel (10 μm) (eluent: cyclohexane / ethyl acetate, 5 / 5) and crystallized from a mixture of ethanol and water (25 / 75), whereby 0.65 g of Paclitaxel (Yield = 80%).

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Abstract

The invention concerns a method for preparing paclitaxel characterized in that it consists in starting with 10-deacetylbaccatine in accordance with a ''one-pot'' reaction including the following three steps: a) protecting the hydroxy radical in position 7 of 10-deacetylbaccatine with a silylated radical, then b) acetylating the hydroxy radical in position 10, c) optionally crystallizing the resulting baccatine III derivative, followed by condensation of (4S,5R)-3-N-benzoyl-2RS-methoxy-4-phenyl-l,3- oxazolidine-5-carboxylic acid, by esterifying in position 13 the acetylated 10-baccatine III derivative previously obtained, then opening the oxazolidine of the cyclic side chain and simultaneously releasing the hydroxy radical in position 7.

Description

technical field [0001] The invention relates to a method for preparing paclitaxel from 10-deacetylbaccatin (10DAB). Background technique [0002] Patent application WO 94 / 07878 discloses a process for the preparation of paclitaxel derivatives, especially paclitaxel, from protected 10-DAB or baccatin III, which involves intermediate production of baccatin III derivatives containing oxazolidine ring chains, followed by opening the chain. However the various steps, in particular the preceding steps for the preparation of protected 10-DAB or baccatin III are not specifically disclosed and are not optimized for efficient industrialization, which cannot possibly be achieved satisfactorily for larger scale industrial applications the result of. [0003] Patent application WO 2006 / 004708 discloses a process for the protection of taxanes of formula: [0004] [0005] where Z is -OH or protected -OH, and G 1 and G 2 The same or different and independently representing a hydrox...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/14
CPCC07D305/14A61P35/00
Inventor 安托万·保尔·加斯顿·莱泽
Owner SOC DETUD & DE RES & DEV & INGIE PHARMA SERIPHARM
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