SK8094A3 - Method for preparing 13-alpha-cinnamoyl baccatine iii or 10-deacetyl bacatine iii - Google Patents

Abstract

Process for the preparation of 13 alpha -cinnamoylbaccatin III or 13 alpha -cinnamoyl-10-deacetylbaccatin III of formula (I) by condensation of a mixed anhydride of general formula (II) with a derivative of baccatin III or of 10-deacetylbaccatin III of general formula (III). In the formulae (I) and (III), R1 represents an acetyl or 2,2,2-trichloroethoxycarbonyl radical. In the formula (II), R represents 1 to 5 substituents, which are identical or different (halogen, nitro, methyl or methoxy). <IMAGE>

Description

Process for the preparation of 13-alpha-cinamoyl-bacatin III or deacetylb a k a tin III

Technical field

The present invention relates to a novel process for the preparation of 13-alpha-

Of 10-deacetyl baccatin II

III or

(I) in which R ·.

represents an acetyl group or a 2,2,2-trichloroethoxycarbonyl group.

BACKGROUND OF THE INVENTION

In European patent E P-0 2 53

738 describes the preparation of a product of formula (I) by reacting cinnamic acid with de bivatate b and k a tine of III or deacetylbaccatin III of formula (II)

(II) in an aromatic hydrocarbon in the presence of a condensation of a rear reagent such as carbodiimide (dicyclohexylcarbodiimide) or reactive carbonate (2-dipyridyl carbonate), and activating dimethylaminopiperidine, in spinning the process is cinnamon selins per mole

Or only in these cases satisfactory results are obtained.

temperature between limit 6 and it is necessary to use baccatin III or an agent such as 90 ° C. for at least 4 moles of cyanobenzene deacety 1

SUMMARY OF THE INVENTION

The measure of the invention is that the product of formula (I) can be obtained by reacting mixed cinnamic anhydride and substituted benzoic acid with said baccatin III derivative in an alkaline medium and using one mole of said mixed anhydride per mole of said baccatin III derivative or 10 -deacetylbakatin III.

Said mixture of formula (III): wherein R is

substituents which halogen (chlorine atom, amethoxy group, cinnamon with acid chloride I and IV are different from bromine atoms), nitro, methyl group can be obtained by reaction of ny benzoic acid of the general formula atom (IV)

wherein R is as defined above, under the conditions described by J. Inag et al. in Bu 11. Chem.Soc.Japan, 52 (7) 1989-1993 (1979). Of particular interest is the use of 2,4,6-trichlorobenzoic acid chloride.

The mixed anhydride of formula III is usually obtained by reacting the acid chloride of formula IV with cinnamic acid in solution in a suitable organic solvent such as tetrahydrofuran in the presence of an organic base such as a tertiary amine such as triethylamine at a temperature between 0 and Deň: 29 ° C.

In order to avoid side reactions, it is preferred to carry out the reaction of the mixed anhydride of formula III with a baccatin III derivative or a 10-deacetyl 1-baccatin, a solution of the mixed anhydride in a suitable organic slow addition to a solution of the 10-deacetyl-baccatin III in a condensation agent, aminopyridine. Especially preferred

III by dissolving e

III, or in the presence of a pyrrolidinopyridine or dimethylamine, to carry out the reaction under an inert atmosphere, such as argon.

The solvent used is preferably an aromatic hydrocarbon selected from benzene, toluene and xylenes or an ether such as tetrahydrofuran.

It is particularly preferred to operate at a temperature of 40 to 100 ° C, in particular at 80 ° C.

The product of formula (I) obtained by the process of the invention may be converted into a product of formula (V)

C ₆ H ₅ -CH-NH-CO-R "COCgH" in which R represents a tert-butoxy or phenyl group and R't represents a hydrogen atom or an acetyl group, according to the procedures described in European patent applications EP-A-0 253 738 and EP-A-0 253 739.

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

DETAILED DESCRIPTION OF THE INVENTION

To 0.605 g of cinnamic acid (4 mmol) in solution in 10 cm @ ^{3 of} anhydrous tetrahydrofuran is added 0.580 ml of anhydrous triethylamine. 0.640 ml of 2,4,6-1-chlorobenzoyl chloride (4.1 mmol) in 10 cm ^{3 of} anhydrous tetrahydrofuran are then added under a nitrogen atmosphere. The reaction mixture is stirred for one hour at a temperature near 20 ° C. The triethylamine hydrochloride is separated by filtration on a glass frit. Tetrahydrofuran was removed by evaporation under reduced pressure. The mixed anhydride thus obtained is taken up in 50 cm @ ^{3 of} anhydrous toluene.

4.02 g of 7beta, 10beta - [(2,2,2-trichloroethoxy) carbonyloxy] -10-deacetyl baccatin III (4.48 mmol) and 1.16 g of pyrrolidinopyridine (7.83) are dissolved in a three-necked flask under argon. mmole) in 50 cm ^{3 of} anhydrous toluene while heating to 50 ° C. The reaction was monitored by thin layer chromatography. After 3 hours at a temperature of 80 ° C, the yeast has to be stored.

The toluene phase is washed with 1N hydrochloric acid and 2.5% aqueous sodium hydrogen carbonate solution and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue obtained is purified by chromatography on a column of silica gel (0.015-0.025 mm), eluting with a toluene / ether (95/5; v / v) mixture, yielding 13 .alpha.-cinamoyl- 1beta, 10betabis - [(2,2,2-trichloroethoxy) carbonyloxy] -10-deacetyl-baccatin III, the characteristics of which are identical to those described by F. Guerittevoegel et al. in Tetrahedron, Vol. 42, No 16, 4451-4460 (1986).

Yield: 2.5 g (61.9%).

Claims (5)

PATENT CLAIMS A process for the preparation of a taxane derivative of the formula wherein R 1 is an acetyl group or a 2,2,2-trifluoroethoxycarbonyl group, characterized in that the mixed anhydride of the formula wherein R is 1 to 5 substituents selected from halogen, n-nitro, methyl and methoxy, reacts with a baccatin III or 10-deacetyl-baccatin II derivative of the general formula wherein R 1 is acetyl or 2,2,2-trifluoroethoxycarbonyl group. 2. The process according to claim 1, wherein the reaction is carried out in an organic solvent selected from the group consisting of aromatic hydrocarbons and ethers. 2. The process of claim 1 wherein the reaction is carried out in the presence of an organic base. 4. The process according to claim 3, wherein the organic base is pyrrolidinopyridine or dimethylaminopyridine. A process according to any one of claims 1 to 4, characterized in that one mole of the mixed a nd class is used per mole of the derivative b and ketin of III or 10-deacetyl baccatin Σ11. A process according to any one of claims 1 to 5, wherein the reaction is carried out at a temperature of 40 to 110 ° C.