Study On The Synthetic Technique Of Pure Antiestrogen Agent Fulvestrant

Fulvestrant ('Faslodex') is a new drug for curing breast cancer which was deve- loped by Astrazeneca Company. In 2002, the US Food and Drug Administration (FD- A)granted approval for fulvestrant. Since March 2004, fulvestrant has also been lice- nsed in the European Union. It is a new type of estrogen receptor antagonist, and is us- ed for the treatment of hormone receptor-positive advanced breast cancer in postmeno- pausal women with disease progression following antiestrogen therapy. The coming of fulvestrant gives a new choice for postmenopausal women with advanced breast cancer. Its processes of synthesis has not been reported at home, and there are only few literatu- res overseas. At present, the demand of fulvestrant at home mostly depends on import- ion, So developing a new process which can adapt to plant-scale production as a great deal of profit.According to references, we improved the synthetic technique on three aspects:(1) The complete acetylation of 19-Nortestosterone was achieved by three agents. Although the similar yield of these methods, the routes starting with Acetic anhydride and acetyl chloride have some disadvantages, such as expensive reagent, troublesome post treatment, and anhydrous condition. As a result, the third method which start with Isopropenyl acetate is preferred. In following synthesis of 17β-Acetyloxy-estra-4,6- diene-3-one, we conclude the mainly factor which influences the reaction, such as the dosage of DMF and the time of the reaction. The yield of the product was 92.5%.(2) In the tosylation of 4,4,5,5,5-Pentafluoropentanol, two agents are compared, and we select Benzenesulfonyl chloride at last, because of its simple operation and high yield. 2-(9-hydroxynonyl)isothiouronium was prepared by bromonation of nonane-1,9- diol with bromide, and then reacting with Thiourea, The product without post treatment reacted with 4,4,5,5,5-pentafluoropenane-1-olmesylate to give the compound 9-(4',4',5',5',5'-pentafluoropentylthio)nonan-1-ol, which was purified by reduced pressure distillation which was popular in industry。After reacting with triphenylphosphine dibromide, the (9-bromononyl)(4',4',5',5',5'-pentafluoropentyl)sulfane was extracted by n-hexane which has not been reported until now. And the yield was similar with the method related in other references.(3) 17β-Acetyloxy-estra-4,6-diene-3-onreacted with the Grignard agent of (9-bro- mononyl)(4',4',5',5',5'-pentafluoropentyl)sulfane. The product was purified by chrom- atography. And then after the aromatisation of A -ring, removing protecting group, and oxidizing the sulphide group, fulvestrant was formed. The total yield of the product is 21.8%.Some intermediates were confirmed by means of 1H-NMR; and the final product was confirmed by IR, MS, 1H-NMR, 13C-NMR. In addition, we checked the purity of Fulvestrant, which was expressed by HPLC. And the result was not less than 97.0%.The thesis emphasized the discussion on purification of the end product and inte- rmediates. This will make the production of fulvestrant possible at home.The process that we reported has some merits, such as reaction conditions are all mild, the post treatments are simple and adapt to plant-scale production.