Process for preparing 4-alkyl- or 4-aryl-oxycarbonyl paclitaxel analogs and novel intermediates
AssigneeBristol-Myers Squibb Company
InventorsFrank S. Gibson, Joydeep Kant, Rajendra P. Deshpande, Karen L. TenHuisen, Jing Liang, Jun Li, Susan D. Boettger, Edward J. Gublo, Ulhas P. Dhokte
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Abstract
A process is provided for preparing 4-alkyl- or 4-aryl-oxycarbonyl paclitaxel analogs which includes the steps of converting paclitaxel into a C-7 acylprotected paclitaxel employing an electrophilic protecting group, such as benzoyloxycarbonyl, and converting the C-7 protected analog into the 4-alkyloxycarbonyl or 4-aryloxycarbonyl paclitaxel analog. Novel intermediates produced in the process are also provided.
Claims16
A compound having the structure
- wherein
- Q1 is tri C 1–C4 alkylsilyl;
- Q2 is an electrophilic protecting group selected from the group consisting of benzoyloxycarbonyl (Cbz), t-butoxycarbonyl (BOC), and those provided by an electrophilic protecting agent of the general formula
- wherein Rx is alkyl, aryl, R′O—, R′2N—, or R′S, and X is halogen, imidazoyl, benzotriazole, N-(benzyloxycarboxyloxy) succinimide, OR′, or—OOCOR′ and wherein R′ is alkyl or alkenyl having 1–6 carbons atoms, benzyl, phenyl, trichloroethyl, trifluoroethyl, 2-trimethylsilylethyl or triisopropylsilyl;
- and
- R is C1–C7 alkyl or aryl, and all stereoisomers thereof.
A process for preparing a taxane having the structure
- wherein R is C1–C7 alkyl or aryl, which comprises:
- (a) subjecting paclitaxel having the structure
- to silyl protection by treating paclitaxel with a tri-C1–C4-alkylsilychloride in the presence of a base and organic solvent to form the protected compound (7) of the structure
- wherein Q1 is a tri C1–C4 alkylsilyl group;
- (b) treating compound (7) with an electrophilic protecting agent to provide a Q2 electrophilic protecting group selected from the group consisting of benzoyloxycarbonyl (Cbz), t-butoxycarbonyl (BOC), and those of the general formula
- wherein Rx is alkyl, aryl, R′O—, R′2N—, or R′S, wherein R′ is alkyl or alkenyl having 1–6 carbons atoms, benzyl, phenyl, trichloroethyl, trifluoroethyl, 2-trimethylsilylethyl or triisopropylsilyl;
- which is in the presence of a base and an organic solvent to form the 7-protected compound (8) of the structure
- (c) deprotecting compound (8) by treating compound (8) with an ammonium compound of the structure
- (Rx)4N+X
- wherein Rx is C1–C7 alkyl or aryl, and X is OCH3 or a halogen, in the presence of dichioromethane to form compound (9);
- (d) treating compound (9) with a benzoyl (Bz) protecting agent in the presence of a base and an organic solvent to form the Bz protected compound (10),
- (e) subjecting compound (10) to carbonate formation by treating compound (10) with a haloformate of the structure ROOCX wherein X is Cl, Br, F or I, (ROOC)2O, or R-pyrocarbonate, in the presence of an organic solvent, a base and a catalyst to form R-oxycarbonyl substituted compound (11) of the structure
- and
- (f) subjecting compound (11) to catalytic transfer-hydrogenation by treating compound (11) with a deprotecting agent in the presence of an organic acid, organic solvent, catalyst and formate compound or hydrogen, to form the compound (2).
Dependencies are inferred from the claim text.