Ixabepilone

Ixabepilone is an orally bioavailable microtubule inhibitor, which binds to tubulin and promotes tubulin polymerization and microtubule stabilization, thereby arrests cells in the G2-M phase of the cell cycle and induces tumor cell apoptosis.

Preparation of Ixabepilone Example-48: Preparation of (lS, 3S, 7S, 10R, HS, 12S, 16R)-7, ll-dihydroxy- 8, 8, 10, 12, 16-pentamethyl-3-[(lE)-l-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-17-oxa- 4-azabicyclo [14.1.0] heptadecane-5, 9-dione (Ixabepilone) Chloroform (45 ml) was added to (4S, 7R, 8S, 9S, 16S, Z)-4, 8-dihydroxy-5, 5, 7, 9, 13- pentamethyl- 16-((E)- 1 -(2-methylthiazol-4-yl)prop- 1 -en-2-yl)azacyclohexadec- 13 -ene- 2, 6-dione compound of formula G (0.43 gm) at 25-30°C under nitrogen atmosphere and stirred for 10 min at the same temperature. Cooled the reaction mixture to -15°C to -20°C and m-chloro perbenzoic acid (0.23 gm) was added and stirred for 4 hrs at the same temperature. Dichloromethane and 7percent aqueous sodium bicarbonate solution were added to the reaction mixture. Raised the temperature of the reaction mixture to 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with 7percent aqueous sodium bicarbonate solution, followed by with 25percent aqueous sodium sulfite solution and then finally with 5percent aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure. The obtained residue was purified by preparative HPLC to get the title compound. Yield: 0.31 gm; Purity by HPLC: 99.0percent.Example-52: Preparation of (lS, 3S, 7S, 10R, HS, 12S, 16R)-7, ll-dihydroxy- 8, 8, 10, 12, 16-pentamethyl-3-[(lE)-l-methyl-2-(2-methyl-4-thiazolyl)ethenyI]-17-oxa- 4-azabicyclo[14.1.0]heptadecane-5, 9-dione (Ixabepilone) A mixture of (3S, 6R, 7S, 8S)-l l-((2R, 3S)-3-((S, E)-2-amino-3-methyl-4-(2- methylthiazol-4-yl)but-3-enyl)-2-methyloxiran-2-yl)-3, 7-dihydroxy-4, 4, 6, 8-tetramethyl- 5-oxoundecanoic acid compound of formula K (3 gm) and dimethyl formamide (30 ml) was stirred for 10 min at 25-30°C under nitrogen atmosphere. Acetonitrile (480 ml) was added to the reaction mixture at 25-30°C. Cooled the reaction mixture to 0-5°C, 1- hydroxybenzotriazole (0.23 gm) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.2 gm) were added. Raised the temperature of the reaction mixture to 25- 30°C and stirred for 12 hrs at the same temperature. Water and ethyl acetate were added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with water followed by with aqueous sodium bicarbonate solution and then finally with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure and then high vacuum was applied to get the title compound. Yield: 3.2 gm.

Antineoplastic; antimitotic.