Methods of preparing amino acid taxane derivatives and polymer conjugates containing the same

A method of preparing a 2′-substituted taxane, comprising:

• a) reacting a taxane of the formula (I)
• wherein:
• R1 is selected from the group consisting of phenyl, t-butoxy, isopropyloxy, propyloxy, —C(CH3)═CH—CH3, 2-naphthyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-fluorophenyl, 2-methyl-1-propenyl, cyclopropyl, 3-furanyl, 3-thioethyl and 2-propenyl;
• R2 is selected from the group consisting of acetyl, —CH3, —CH2CH3 and —CHO;
• R3 is selected from the group consisting of acetyl, H and C1-6 alkyl;
• R4 is selected from among H, F, C1-6 alkyl, —C(O)—CH2CH2CH2CH2CH3, —CH2SCH3, —SiEt3, —CH2OP(O)(OCH2Ph)2, CH3CH2C(O)—, —CH2O(CO)CH2N(CH2CH2)2NCH3, —CH2O(CO)CH2N(CH2CH3)2, —C(O)CH2N(CH3)2, —C(O)CH(CH3)NHCOOC(CH3)3;
• and
• R5 is selected from the group consisting of phenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-fluorophenyl, 4-triflourotoluene, 2-furanyl, 2-thienyl, phenylethene, 2-furanyl-CH═CH—, (CH3)2CHCH2—, C6H11—CH2—, (CH3)2CH—, PhCH2CH2—, C6HII—CH2CH2—, CH3CH2CH2—, 4—Cl-phenyl-, 2-fluorophenyl-, 3-fluoro-phenyl- and 4—CH3-phenyl- with a compound of formula (II)
• wherein:
• E is a member of the group consisting of
• L1 is a bifunctional group;
• Y1 is selected from among O, S or NR7;
• R6 and R7 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-19 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
• and
• J1 is selected from the group consisting of OH and leaving groups;
• under conditions sufficient to form a blocked intermediate of the formula (III)
• b) deprotecting said blocked intermediate with about an equimolar amount of a secondary amine under conditions sufficient to form a compound of formula (IV):