Process for preparing 7-trialkylsilyl baccatin III

Details Process for preparing 7-trialkylsilyl baccatin III Process for preparing 7-trialkylsilyl baccatin III

1996-10-03

1997-09-23

Shaver, Paul F.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D30514

Patent

active

056706588

DESCRIPTION:

BRIEF SUMMARY
It is known, in particular according to J-N. Denis and A. E. Greene, J. Amer. Chem. Soc., 110, 5917-5919 (1998), to prepare a product of general formula (I) from 10-deacetylbaccatin III of formula (II) by first carrying out the selective silylation at position -7 of the taxane ring system in order to obtain 7-trialkylsilyl-10-deacetylbaccatin III, and then by selectively acetylating at position -10 the 7-trialkylsilyl-10-deacetylbaccatin III thus obtained.
According to the known process, the silylation reaction is carried out by treating 10-deacetylbaccatin III with excess trialkylsilyl halide of general formula: in a basic organic solvent such as pyridine, at a temperature in the region of 20.degree. C. Generally, 7-trialkylsilyl-10-deacetylbaccatine III is obtained with a yield in the region of 85%.
According to the known process, the acetylation is carried out by treating 7-triethylsilyl-10-deacetylbaccatin III with excess acetyl chloride, working in a basic organic solvent such as pyridine, at a temperature in the region of 0.degree. C. Generally, 7-trialkylsilyloxybaccatin III of formula (I) is obtained with a yield of 85% from 7-triethylsilylbaccatin III.
Thus, according to the known process, a 7-trialkylsilylbaccatin III is obtained with a yield in the region of 72%.
It has now been found, and this forms the subject of the present invention, that the product of general formula (I) may be obtained with better yields by carrying out the silylation and the acetylation without isolation of the intermediate 7-trialkylsilyl-10-deacetylbaccatin III.
According to the invention, 10-deacetylbaccatin III, dissolved in a basic organic solvent chosen from pyridine and pyridines substituted with one or more alkyl radicals containing 1 to 4 carbon atoms, is treated with a silylating agent of general formula (III) at a temperature between 0.degree. and 15.degree. C., and then with acetic anhydride at a temperature in the region of 20.degree. C.
The use of the process according to the invention requires the use of a much smaller excess of silylating agent than in the known process. Generally, from 1.5 to 2.5 mol of silylating agent are used per mole of 10-deacetylbaccatin III used.
Generally, 5 to 7 mol of acetic anhydride are used per mole of 10-deacetylbaccatin III used.
The 7-trialkylsilylbaccatin III may be isolated after precipitation in water and crystallization, from its solution in an aliphatic ester such as ethyl acetate, using an ether such as isopropyl ether. Generally, the yield is in the region of 80% from the 10-deacetylbaccatin III used.
The 7-trialkylsilylbaccatin III, obtained according to the process of the present invention, may be used, after isolation or dissolved in an aliphatic ester such as ethyl acetate, in order to prepare paclitaxel or derivatives thereof according to known processes as described, for example, in European Patent EP-0,336,840 or in International Application WO 92/09589.
The example which follows illustrates the use of the process according to the invention.


EXAMPLE

To a solution of 293.9 g of 10-deacetylbaccatin III in 2.7 liters of pyridine are added, over 1 hour 20 minutes, 182 g of triethylsilyl chloride. The solution obtained is stirred for 40 hours at 5.degree. C. 360 g of acetic anhydride are then added while maintaining the temperature at 5.degree. C. The suspension obtained is stirred for 48 hours at 20.degree. C. and is then poured onto 40 liters of ice-cold water. The precipitate obtained is separated by filtration and then washed with 8 times 2 liters of water and finally dissolved in 3 liters of ethyl acetate. The organic phase is dried over magnesium sulphate. After filtration and concentration under reduced pressure, the product obtained is crystallized from isopropyl ether. 7-triethylsilylbaccatin III is thus obtained with a yield of 77%, the characteristics of which product are as follows: ppm):0.58 (mt, 6H:CH.sub.2 ethyl); 0.92 (t, J=7.5 Hz, 9H:CH.sub.3 ethyl); 1.02 (s, 3H:CH.sub.3); 1.18 (s, 3H:CH.sub.3); 1.68 (s, 3H:CH.sub.3); 1.75 (broad s, 1H:OH at 1

REFERENCES:
patent: 5405972 (1995-04-01), Holton et al.
patent: 5449790 (1995-09-01), Zheng et al.
patent: 5597931 (1997-01-01), Danishefsky et al.
patent: 5599820 (1997-02-01), Ojima et al.
Denis et al., J. Am. Chem. Soc., vol. 110 (17), pp. 5917-5919, Jun. 1988.

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