Method for docetaxel synthesis
AssigneesNaPro BioTherapeutics, Inc., Bryn Mawr College
InventorsNicholas J. Sisti, Charles S. Swindell
Life of this patent
Estimating the term…
Abstract
A method of producing docetaxel comprises the esterification of C7, C10 di-CBZ 10-deacetyl baccatin III and an N-CBZ C2'-protected 3-phenyl isoserine side chain wherein C2' is protected by a hydrogenatable benyl-type protecting group. The C7, C10 carbobenzyloxy groups are then replaced with hydrogen and the carbobenzyloxy group at the C3' nitrogen site is replaced with t-butoxycarbonyl. Finally, the resulting compound is deprotected at C2' by replacing the benzyl-type protecting group with hydrogen to produce docetaxel. The esterification preferably employs an excess, such as six equivalents, of the side chain for each equivalent of the C7, C10 di-CBZ 10-deacetyl baccatin III. Benzyloxymethyl is the preferred protecting group at C2'.
Claims24
A method of producing docetaxel, comprising the steps of:
- (a) esterifying C7, C10 di-CBZ 10-deacetyl baccatin III of the formula ##STR17## with an N--CBZ C2'-protected 3-phenyl isoserine side chain of the formula ##STR18## to form a first intermediate compound of the formula ##STR19## wherein P.sub.1 is a hydrogenatable benzyl-type protecting group;
- (b) substituting hydrogen for the C7, C10 carbobenzyloxy groups and substituting t-butoxycarbonyl for the carbobenzyloxy group at the C3' nitrogen site to form a second intermediate compound of the formula:
- ##STR20## wherein P.sub.1 is a hydrogenatable benzyl-type protecting group;
- and (c) deprotecting the second intermediate compound by substituting hydrogen for P.sub.1 to produce docetaxel.
A method of producing docetaxel, comprising the steps of:
- (a) esterifying C7, C10 di-CBZ 10-deacetyl baccatin III of the formula:
- ##STR21## with an excess of N--CBZ C2'-protected 3-phenylisoserine side chain of the formula:
- ##STR22## in solution with toluene and a dialkylcarbodiimide to produce a first intermediate compound of the formula:
- ##STR23## wherein P.sub.1 is a hydrogenatable benzyl-type protecting group;
- (b) substituting hydrogen for the C7, C10 and the C3' nitrogen carbobenzyloxy groups in the first intermediate compound by dissolving the first intermediate compound in isopropanol/ethyl acetate in a presence of Pearlman's catalyst to form a first mixture that is then hydrogenated to produce an amine;
- (c) acylating at the C3' nitrogen site with t-BOC by taking the amine up in tetrahydrofuran and a tertiary amine base, followed by the addition of di-tert-butyldicarbonate to form C2'-OP.sub.1 docetaxel;
- and
- (d) deprotecting the C2'-OP.sub.1 docetaxel by substituting hydrogen for P.sub.1 to produce docetaxel.
Dependencies are inferred from the claim text.