METHOD OF PREPARING TAXANE DERIVATIVES AND INTERMEDIATES USED THEREIN

1 . A method for preparing a taxane derivative of formula (I), which comprises the steps of:

(i-a) reacting the compound of formula (II) with 1-dimethoxymethyl naphthalene in an organic solvent in the presence of an acid catalyst to obtain the oxazolidine methyl ester derivative of formula (III), and then (i-b) subjecting the obtained compound of formula (III) to hydrolysis under a basic condition to obtain the oxazolidic acid derivative of formula (IV) or a salt thereof;

(ii) subjecting the compound of formula (IV) or the salt thereof to a coupling reaction with a protected 10-deacetylbaccatin III of formula (V) in the presence of a condensation agent to obtain a taxane of formula (VI) having an oxazolidine side chain;

(iii) subjecting the compound of formula (VI) to a ring opening reaction in an organic solvent in the presence of an acid, followed by an optional step of replacing the t-butoxycarbonyl group of the resulting compound with a benzoyl group, to obtain a compound of formula (VII); and

(iv) removing at least one of protecting groups on the positions 7 and 10 of the compound of formula (VII):

wherein,

Ph is phenyl;

Ac is acetyl;

Bz is benzoyl;

Boc is t-butoxycarbonyl;

R 1 is t-butoxycarbonyl or benzoyl;

R 2 is acetyl or hydrogen;

R 3 is a hydroxy protecting group which is 3,5-dinitrobenzoyl, trichloroacetyl, dichloroacetyl or 2,2,2-trichloroethoxycarbonyl; and

R 4 is R 3 or acetyl.

2 . The method of claim 1 , wherein 1-dimethoxymethylnaphthalene in step (i-a) is used in an amount ranging from 1 to 3 equivalents based on the compound of formula (II).

3 . The method of claim 1 , wherein the acid catalyst used in step (i-a) is selected from the group consisting of pyridinium p-toluenesulfonate, pyridinium 3-nitrobenzenesulfonate, pyridinium benzenesulfonate, and a mixture thereof.

4 . The method of claim 1 , wherein the base used in hydrolysis in step (i-b) is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, and a mixture thereof.

5 . The method of claim 1 , wherein the oxazolidic acid derivative of formula (IV) used in step (ii) is used in an amount ranging from 1 to 5 equivalents based on the protected deacetylbaccatin III of formula (V).

6 . The method of claim 1 , wherein the condensation agent used in step (ii) is dicyclohexylcarbodiimide.

7 . The method of claim 1 , wherein 4-dimethylaminopyridine or pyridine is further added during step (ii) as an activating agent.

8 . The method of claim 1 , wherein the acid used in step (iii) is selected from the group consisting of hydrochloric acid, sulfuric acid, formic acid, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, and a mixture thereof.

9 . The method of claim 1 , wherein the acid in step (iii) is used in an amount ranging from 1 to 30 equivalents based on the compound of formula (VI).

10 . The method of claim 1 , wherein C 1-3 alcohol is further added to the ring opening of step (iii).

11 . A compound of formula (IV):

wherein,

Boc and Ph have same meanings as defined in claim 1 .

12 . A compound of formula (VI):

wherein,

Ph, Ac, Bz, Boc, R 3 and R 4 have same meanings as defined in claim 1 .