The Synthetic Technique Of Fulvestrant And Its Intermediates And The Synthesis Of Phosphate Prodrug

Fulvestrant (’Faslodex’) is a new drug for curing breast cancer which was deve-loped by Astrazeneca Company. In2002, the US Food and Drug Administration (FD-A)granted approval for fulvestrant. Since March2004, 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. In order toimprove the synthesis of Fulvestrant. We have also studied the synthesis process of the(7a,17b)-7-(9-Bromononyl)-estra-1,3,5(10)-triene-3,17-diol17-acetate.According to references, we improved the synthetic technique on three aspects:(1) The complete acetylation of19-Nortestosterone was achieved by three agents.Although the similar yield of these methods, the routes starting with Acetic anhydrideand acetyl chloride have some disadvantages, such as expensive reagent, troublesomepost treatment, and anhydrous condition. As a result, the third method which start withIsopropenyl acetate is preferred. In following synthesis of17β-Acetyloxy-estra-4,6-diene-3-one, we conclude the mainly factor which influences the reaction, such as thedosage of DMF and the time of the reaction. The yield of the product was92.5%.(2) In the tosylation of4,4,5,5,5-Pentafluoropentanol, two agents are compared,and we select Benzenesulfonyl chloride at last, because of its simple operation and highyield.2-(9-hydroxynonyl)isothiouronium was prepared by bromonation of nonane-1,9-diol with bromide, and then reacting with Thiourea, The product without post treatmentreacted with4,4,5,5,5-pentafluoropenane-1-olmesylate to give the compound9-(4’,4’,5’,5’,5’-pentafluoropentylthio)nonan-1-ol, which was purified by reduced pressuredistillation which was popular in industry.After reacting with triphenylphosphine dibromide, the (9-bromononyl)(4’,4’,5’,5’,5’-pentafluoropentyl)sulfane was extractedby n-hexane which has not been reported until now. And the yield was similar with themethod related in other references.(3) The Dienone with a Grignard reagent can react Michael addition. We studied tofind that the reaction temperature greatly affects the format of the yield of the additionreaction. We find its format addition product is obtained in a yield of90%of theoptimum reaction conditions.Some intermediates were confirmed by means of1H-NMR; and the final productwas confirmed by IR, MS,1H-NMR,13C-NMR. In addition, we checked the purity ofFulvestrant, which was expressed by HPLC. And the result was not less than97.0%.In order to improve the stability and the orally active of Fulvestrant, we havedesigned and synthesized the derivative of Fulvestrant. The structure of thecompounds were confirmed by means of1H-NMR and MS。Under The action ofphosphatase,The phosphate ester prodrug can completely release the phosphate esterderivatives from the experiment in vitro.