C-2 hydroxyl protected-N-acyl (2R,3S)-3-phenylisoserine N-imido activated esters and method for production thereof

#This invention generally relates to the synthesis of paclitaxel from precursor compounds. More particularly, though, this invention concerns the semi-synthesis of paclitaxel using a protected baccatin III backbone which is esterified with suitably protected side chain activated esters to produce an intermediate that may be converted to paclitaxel.

#The chemical compound referred to in the literature as taxol, and more recently "paclitaxel", has received increasing attention in the scientific and medical community due to its demonstration of anti-tumor activity. Paclitaxel has been approved for the chemotherapeutic treatment of several different varieties of tumors, and the clinical trials indicate that paclitaxel promises a broad range of potent anti-leukemic and tumor-inhibiting activity. As is known, paclitaxel is a naturally occurring taxane diterpenoid having the formula and numbering system as follows: ##STR2##

#While the paclitaxel molecule is found in several species of yew (genus Taxus, family Taxaceae), the concentration of this compound is very low. Moreover, these evergreens are slow-growing. Thus, a danger exists that the increasing use of paclitaxel as an effective anti-cancer agent will deplete natural resources in the form of the yew trees. Indeed, while the bark of the yew trees typically exhibit the highest concentration of paclitaxel, the production of 1 kilogram of paclitaxel requires approximately 16,000 pounds of bark. Thus, the long term prospects for the availability of paclitaxel through isolation is discouraging.

#The present disclosure is broadly directed to a chemical process for the efficient production of paclitaxel, intermediates and precursors therefor. More specifically, the present invention concerns the semi- synthesis of paclitaxel by esterifying suitably protected 3-phenylisoserine activated esters having protecting groups at C-2 to the C-13 hydroxyl of 7O-protected baccatin III. More particularly, the present invention preferably utilizes CBZ protection at the C-7 site of the baccatin III. The general process described herein involves the production of C-7 CBZ baccatin III, the production of a suitably protected 3-phenylisoserine activated ester having a suitable protecting group at C-2, the condensation of the two compounds, and the subsequent deprotection, acylation, deprotection of the condensation product to form paclitaxel.

#A. Production of C7-CBZ Protected Baccatin III

#According to the present invention, two alternative routes are described which appear in copending Application Serial No. 08/922,684, to Sisti et al., for producing C7-CBZ protected baccatin III. On one hand, baccatin III can be protected at the C-7 site to yield C-7 CBZ baccatin III. On the other hand, 10-deacetylbaccatin III (10-DAB) can be directly converted to C-7 CBZ baccatin III without going through a baccatin III intermediate. Production from baccatin III is advantageous for its yield and simplicity. The method using 10-deacetylbaccatin III has an advantage since 10-deacetylbaccatin III is much more naturally abundant, and thus less expensive, than baccatin III; however, this alternative method has a reduced yield.