Semi-synthetic taxanes with antitumor and antiangiogenetic activities
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example i
Preparation of C-seco-10-dehydro-10-deacetyl-7,9-bis-acetyl-baccatine III
[0040]A solution of 300 mg of 10-dehydro-10-deacetylbaccatine III in 5 ml of methanol is added with 1 equiv. of CeCl3.3H2O and the reaction mixture is stirred for 10 min. After complete dissolution, 80 mg of NaBH4 are added in small portions. After 10 min the solution is treated with an equal volume of a NH4Cl aqueous solution and extracted with CH2Cl2. The chlorinated solvent is removed, the residue is taken up in 1 ml of pyridine, cooled to 0° C. in 1 h, then added with 150 mg of acetic anhydride. The solution is left to stand for 2 h at 0° C., then diluted with 10 ml of water and back-extracted with CH2Cl2. The chlorinated solvent is distilled off under vacuum and the residue is chromatographed on silica gel eluting with a mixture of n-hexane / ethyl acetate to obtain 260 mg of C-seco-10-dehydro-10-deacetyl-7,9-bis-acetyl-baccatine III (m / z 630).
example ii
Preparation of 13-[(2R, 3S)-3-iso-butyl-2-hydroxy-3-tert-butoxycarbonylamino-propanoyl]-C-seco-10-dehydro-10-deacetyl-7,9-bis-acetyl-baccatine III
[0041]630 mg of C-sero-10-dehydro-10-deacetyl-7,9-bis-acetyl-baccatine III are dissolved in 5 ml of toluene and added with 335 mg of dicyclohexylcarbodiimide (DCC), 500 mg of (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4isobutyl-5-oxazolidine-carboxylic acid and 20 mg of 4-dimethylaminopyridine. The solution is heated at 60° C. for 24 h, then treated with ethyl acetate and a NaHCO3 saturated solution. The organic phase is dried and filtered through silica gel to remove urea. The solvent is evaporated to dryness under vacuum and the residue is taken up in methanol / hydrochloric acid, keeping a temperature of 0° C. for 1 h. The solution is neutralized to pH 5, then diluted with water and the desired compound is back-extracted with CH2Cl2. The solvent is evaporated off to obtain 700 mg of 13-[(2R, 3S)-3-iso-butyl-2-hydroxy-3-tert-butoxycarbonylamino...
example iii
Preparation of 13-[(2R, 3S)-3-phenyl-2-hydroxy-3-tert-butoxycarbonylamino-propanoyl]-C-seco-10-dehydro-10-deacetyl-7,9-bis-acetyl-baccatine III
[0042]630 mg of C-seco-10-dehydro-10-deacetyl-7,9-bis-acetyl-baccatine III are dissolved in 5 ml of toluene and added with 335 mg of DCC, 525 mg of (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)4-isobutyl-5-oxazolidine-carboxylic acid and 20 mg of 4dimethylaminopyridine. The solution is heated at 60° C. for 24 h, then treated with ethyl acetate and a NaHCO3 saturated solution. The organic phase is dried and filtered through silica gel to remove urea. The solvent is evaporated to dryness under vacuum and the residue is taken up in methanol / hydrochloric acid, keeping a temperature of 0° C. for 1 h. The solution is neutralized to pH 5, then diluted with water and the desired compound is back-extracted with CH2Cl2. The solvent is evaporated off to obtain 700 mg of 13-[(2R, 3S)-3-iso-butyl-2-hydroxy-3-tert-butoxycarbonylamino-propanoyl]-C-seco-10-dehydro-1...
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