METHOD OF PREPARING DOCETAXEL AND INTERMEDIATES USED THEREIN
The present invention relates to a novel method for preparing docetaxel having anti-tumor and anti-leukemia activity, and intermediates useful for preparing docetaxel.
1 - 12 . (canceled)
13 . A method of preparing docetaxel of formula (I), which comprises the steps of:
(i) bringing 10-deacetylbaccatin III of formula (II) to react with benzoyl halide of formula (III) in the presence of a base to obtain a compound of formula (IV) having protected 7- and 10-hydroxy groups;
(ii) subjecting the compound of formula (IV) to a coupling reaction with an oxazolidine derivative of formula (V) or a salt thereof in the presence of a condensation agent to obtain a taxane of formula (VI) having an oxazolidine side chain;
(iii) subjecting the side chain of the compound of formula (VI) to a ring opening reaction in an organic solvent in the presence of an acid to obtain the docetaxel of formula (VII) having protected 7- and 10-hydroxy groups; and
(iv) removing the protecting groups at the positions 7 and 10 of the compound of formula (VII) using a base in a solvent:
wherein,
Ph is phenyl;
Ac is acetyl;
Bz is benzoyl;
Boc is t-butoxycarbonyl;
R is 4-methoxyphenyl, isopropyl or t-butyl;
B is
R′ and R″ are each independently hydrogen or nitro; and
X is halogen.
14 . The method of claim 13 , wherein the benzoyl halide of formula (III) used in step (i) is 4-nitrobenzoyl chloride, 3,5-dinitrobenzoyl chloride or 1,4-dinitrobenzoyl chloride.
15 . The method of claim 13 , wherein the amount of the benzoyl halide of formula (III) used in step (i) is 2 to 5 equivalents based on 10-deacetylbaccatin III.
16 . The method of claim 13 , wherein the base used in step (i) is pyridine or triethylamine.
17 . The method of claim 13 , wherein the condensation agent used in step (ii) is dicyclohexylcarbodiimide.
18 . The method of claim 13 , wherein 4-dimethylaminopyridine or pyridine is further added during step (ii) as an activating agent.
19 . The method of claim 13 , wherein the acid used in step (iii) is hydrochloric acid, sulfuric acid, formic acid, or p-toluenesulfonic acid.
20 . The method of claim 19 , wherein the amount of the acid used in step (iii) is 1 to 100 equivalents based on the compound of formula (VI).
21 . The method of claim 13 , wherein the base used in step (iv) is morpholine, diethylamine, ammonia, methylamine, or t-butyl amine.
22 . A compound of formula (IV):
wherein,
Ac is acetyl;
Bz is benzoyl; and
B is 4-nitrobenzoyl, 3,5-dinitrobenzoyl, or 2,4-dinitrobenzoyl.