SK50832005A3 - Method for preparation of 7-trialkylsilylbaccatine III - Google Patents

Abstract

It is described a process for preparing 7-trialkylsilylbaccatine III of the general formula (I), in which the general symbols R, which are the same or different, represent alkyl groups containing 1 to 4 carbon atoms and being optionally substituted with a phenyl group, from 10-deacetylbaccatine III.

Description

Technical field

The present invention relates to a novel effective process for the preparation of 7-trialkylsilylbaccatin III of the general formula (T).

in which the same R or the same or different denotes alkyl groups having 1 to 4 carbon atoms and optionally substituted by a phenyl group, from 10-deacetylbaccatin III.

BACKGROUND OF THE INVENTION

The preparation of a compound of formula (I) is described by J-N. Denis and A. E. Green in J. Am. Chem. Soc., 1988, 110, 5917-5919, starting from 10-deacetylbaccatin III of the formula

the selective hydroxyl group at the 7-position is first protected by an excess of the trialkylsilyl chloride of formula III)

C1-Si (R) ₃ (III), wherein R, which are the same or different, denote alkyl groups containing 1 to 4 carbon atoms and optionally substituted by a phenyl group, in pyridine to form 7-trialkylsilyl-10-deacetylbaccatin III, which is isolated and subsequently acetylated with excess acetyl chloride in pyridine to give 7-trialkylsilylbaccatin III. The overall yield is 72%.

Another innovative method for preparing 7-trialkylsilylbaccatin III has been described by J-P. Bastart and J-P. Leconte in WO 95 26967 (Slovak equivalent SK 280448), when silylation and acetylation were carried out without isolation of the intermediate 7-trialkylsilyl-10-deacetylbaccatin III, with a total yield of 77%.

SUMMARY OF THE INVENTION

It has now been found, and this finding is the essence of the invention, that the compound of formula T can be obtained more efficiently and in a much higher yield than reported in the literature.

In the context of the invention, 10-deacetylbaccatin III is reacted with a trialkylsilyl chloride of the general formula ΊΙΓ, and then first with acetic acid and then with acetyl chloride or acetyl bromide without isolation of the intermediates. Preferably, the reaction is carried out in a pyridine solution. Generally, a 1.5 to 2.5 molar excess of the silylating agent is used. Acetic acid is then added to the reaction mixture, followed by acetyl chloride or acetyl bromide at room temperature over time. Preferably a 5 to 10 molar excess of acetic acid is used, preferably a 6 molar excess, and it is preferred that a 5 to 10 molar excess of acetyl chloride or acetyl bromide is subsequently used. Preferably, there is a time difference, preferably 30 to 60 minutes, between the addition of acetic acid and the addition of acetyl chloride or acetyl bromide. The reaction is preferably carried out at temperatures of -10 to 25 ° C.

Surprisingly we have found that by successively adding acetic acid first followed by acetyl chloride, the yield is significantly increased to about 95% of the isolated product.

Since it is generally known that the reaction of acetic acid with acetyl chloride (or acetyl bromide) produces acetic anhydride, under the conditions described by the invention, the existence of acetic anhydride is ruled out, since the yield is significantly increased compared to using only pure acetic anhydride by about 15%. Most likely, the acetic acid-pyridine complex together with the acetyl chloride-pyridine complex participate in acetylation.

In the following, the invention will be explained in more detail by way of a specific exemplary embodiment, which is illustrative only, and is not intended to limit the scope of the invention as defined by the claims.

DETAILED DESCRIPTION OF THE INVENTION

Preparation of 7-triethylsilylbaccatin III:

To a solution of 10-deacetylbaccatin III (30 g) in dried pyridine (600 ml) was added dropwise triethylsilyl chloride (21 ml) at room temperature. The mixture was allowed to stir for 22 hours. Then the reaction mixture was cooled to 0 ° C and acetic acid (18 mL) was added to the reaction mixture and allowed to stir at room temperature for 1 hour, then the reaction mixture was recooled to 0 ° C and acetyl chloride (21 mL) was added. the mixture is again allowed to stir at room temperature for 20 hours. The reaction mixture was poured into distilled water (2000 mL) and extracted with ethyl acetate (5 x 500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness on a rotary evaporator. The residue was purified by column chromatography (silica gel, eluent dichloromethane-methanol = 20: 1). Fractions containing product were combined and concentrated on a rotary evaporator. Yield 36.6 g, 95%.

PF TOg 3-<<

Modified assets

Claims (6)

PATENT CLAIMS A process for the preparation of a 7-trialkylsilylbaccatin III of the formula I wherein R, which are the same or different, represent alkyl groups containing 1 to 4 carbon atoms and optionally substituted by a phenyl group, characterized in that 10-deacetylbaccatin is of the formula is reacted with a silylating agent of formula ΙΙΓ Cl-Si (R) ₃ (III), wherein R is as defined above, and then first with acetic acid and then with acetyl chloride or acetyl bromide without isolation of the intermediates. Process according to claim 1, characterized in that the solvent used is pyridine. Method according to claims 1 and 2, characterized in that a 5 to 10 molar excess of acetic acid, preferably a 6 molar excess, is used. Process according to claims 1 to 3, characterized in that a 5 to 10 molar excess of acetyl chloride or acetyl bromide is subsequently used. Method according to claims 1 to 4, characterized in that there is a time difference, preferably 30 to 60 minutes, between the addition of acetic acid and the addition of acetyl chloride or acetyl bromide. Process according to claims 1 to 5, characterized in that the reaction is carried out at temperatures of -10 to 25 ° C.