bestrabucil

Originator

Atrimustine,Onbio Inc.

Manufacturing Process

Preparation of 3-hydroxy-1,3,5(10)-estratriene-17β-[4-{p-[bis(2- chloroethyl)amino]phenyl}butyryloxy]acetate:
Preparation of 3-hydroxy-1,3,5(10)-estratriene-17β-monobromoacetate. 10 g of 1,3,5(10)-estratriene-3,17β-diol was dissolved in 400 ml of anhydrous tetrahydrofuran (THF), and then, 8.8 g of pyridine was added. A solution of 22.5 g of monobromoacetyl bromide in 74 g of carbon tetrachloride was added dropwise to the resulting solution at about -5°C to -7°C. The mixture was kept for one night. After the reaction, the resulting precipitate was separated by a filtration. The solvent was distilled off from the filtrate. The residue was dissolved in ether and recrystallized from ether to obtain 1,3,5(10)-estratriene-3,17β-bis(monobromoacetate). 2 g of the product was dissolved in 900 ml of methanol and the solution was cooled to -5°C. A solution of 0.24 g of K2CO3 in 20 ml of water was added dropwise to the resulting solution. After the reaction for 30 minutes, 1000 ml of water was added and the resulting precipitate was separated and dried. It was confirmed that the product was 3-hydroxy-1,3,5(10)-estradiene-17β-monobromoacetate by the elementary analysis and the IR spectrum.
Preparation of 3-hydroxy-1,3,5(10)-estratriene-17β-[4{p-[bis(2- chloroethyl)amino]phenyl}butyryloxy]acetate:
200 mg of silver [4-{p-[bis(2-chloroethyl)amino]phenyl}butyrate (silver salt of Chlorambucil) was added in 10 ml of DMSO to form a white colloidal solution. Then, 190.8 mg of 3-hydroxy-1,3,5(10)-estratriene-17β- monobromoacetate was added and the mixture was stirred at room temperature for 64 hours in the dark. The precipitate was changed to yellowish green color. A small amount of acetone was added and the precipitate was separated by a filtration through G-4 filter. The precipitate was changed from yellowish green color to blackish green color by the irradiation of light. The filtrate was colorless and transparent. DMSO was distilled off under a reduced pressure on a water bath at 80°C and 100 ml of water was added to precipitate white crystals. The crystals were kept for 1 hour to remove DMSO and the crystals were separated through G-4 filter and thoroughly washed with distilled water and dried under a reduced pressure in a desiccator. A crude yield was 330.5 mg.
Purification of the product 330.5 mg of crude crystals were dissolved in a mixed solvent of 50 vol. parts of cyclohexane and 10 vol. parts of ethyl acetate. The solution was slowly passed through a column filling 40 g of silica gel and the product was gradually separated to obtain 188.2 mg (yield: 62.86%) of pure product. It was confirmed that the product was 3-hydroxy-1,3,5(10)-estratriene-17β-[4{p-[bis(2-chloroethyl)amino]phenyl} butyryloxy]acetate by the elementary analysis and the IR spectrum.

Therapeutic Function

Antineoplastic

Safety Profile

An experimental teratogen. Otherexperimental reproductive effects. Human mutation datareported. When heated to decomposition it emits toxicfumes of Cl- and NOx.