Semi-synthesis of taxane derivatives using metal alkoxides and oxazinones

Claim 2

A process for the preparation of a taxane derivative comprising: providing a metal alkoxide having the tetracyclic taxane nucleus, the metal being a Group IA, IIA, IIIA, IVA, VA, VIA or transition metal and is attached to the oxygen at the C-13 position of the nucleus, reacting the metal alkoxide with an oxazinone to form an intermediate, wherein the oxazinone has the formula: ##STR25## wherein R 1 is --OR 6 ; R 2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R 3 and R 4 are not both acyl; R 5 is alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy or heteroaryloxy; and R 6 is a hydroxy protecting group; and converting said intermediate to the taxane derivative by removing the hydroxy protecting group.

Claim 3

The process of claim 1 wherein R 2 and R 4 are hydrogen or lower alkyl, R 3 is aryl, and R 6 is a hydroxy protecting group.

Claim 4

The process of claim 2 wherein R 3 is phenyl and R 6 is 1-ethoxyethyl or 2,2,2-trichloroethoxymethyl.

Claim 5

The process of claim 1 wherein the metal alkoxide is a meal alkoxide of 7-protected baccatin III.

Claim 6

The process of claim 4 wherein the metallic oxide substituent is selected from the group of metal substituents consisting of LiO--, MgO NaO--, KO--, and TiO--.

Claim 7

The process of claim 1 wherein the metal alkoxide is derived from an alcohol having the formula: ##STR26## wherein T 1 is a hydroxy protecting group, Z is --OT 2 , and T 2 is acetyl or hydroxy protecting group.

Claim 8

The process of claim 1 wherein the metal alkoxide has the following formula: ##STR27## wherein: R 15 and R 16 are independently hydrogen, hydroxy, lower alkanoyloxy, alkenoyloxy, alkynoyloxy, aryloyloxy or R 15 and R 16 together form an oxo; R 17 and R 18 are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or R 17 and R 18 together form an oxo; R 19 and R 20 are independently hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; R 21 and R 22 are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or R 21 and R 22 together form an oxo; R 24 is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; or R 23 and R 22 together form an oxetane ring; R 25 is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or R 26 is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; or R 26 and R 25 taken together form an oxo; and R 27 is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy.

Claim 9

The process of claim 7 wherein R 16 is hydrogen, R 15 is --OT 2 or --OCOCH 3 , T 2 is a hydroxy protecting group and M is selected from the group comprising Li, Mg, Na, K and Ti.

Claim 10

The process of claim 7 wherein R 2 and R 4 are hydrogen or lower alkyl, R 3 is aryl, and R 6 is a hydroxy protecting group.

Claim 11

A process for the preparation of a taxane derivative comprising: providing a metal alkoxide having the tetracyclic taxane nucleus, the metal being a Group IA, IIA, IIIA, IVA, VA, VIA or transition metal and is attached to the oxygen at the C-13 position of the nucleus, reacting the metal alkoxide with the oxazinone to form an intermediate, wherein the oxazinone has the formula: ##STR28## wherein R 1 is --OR 6 ; R 2 is hydrogen; R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R 3 and R 4 are not both acyl; R 5 is alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy or heteroaryloxy; and R 6 is a hydroxy protecting group; and converting said intermediate to the taxane derivative by removing the hydroxy protecting group.

Claim 12

A process for the preparation of a taxane derivative comprising: providing a metal alkoxide having the tetracyclic taxane nucleus, the metal being a Group IA, IIA, IIIA, IVA, VA, VIA or transition metal and is attached to the oxygen at the C-13 position of the nucleus, reacting the metal alkoxide with the oxazinone to form an intermediate, wherein the oxazinone has the formula: ##STR28## wherein R 1 is --OR 6 ; R 2 is hydrogen; R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R 3 and R 4 are not both acyl; R 5 is alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy or heteroaryloxy; and R 6 is a hydroxy protecting group; and converting said intermediate to the taxane derivative by removing the hydroxy protecting group.

Claim 13

The process of claim 10 wherein R 6 is 1-ethoxyethyl or 2,2,2-trichloroethoxymethyl.

Claim 14

The process of claim 10 wherein the metal alkoxide is derived from an alcohol having the formula: ##STR29## wherein T 1 is a hydroxy protecting group, Z is --OT 2 , and T 2 is acetyl or hydroxy protecting group.

Claim 15

The process of claim 10 wherein R 16 is hydrogen, R 15 is --OT 2 or --OCOCH 3 , T 2 is a hydroxy protecting group and M is selected from the group comprising Li, Mg, Na, K and Ti.