A kind of preparation method of fulvestrant intermediate

Abstract

The invention provides a preparation method of a fulvestrant intermediate. The preparation method of the fulvestrant intermediate is characterized in that a water extraction starting material 1,9-nonanediol is adopted for controlling the content of 1,8-octylene glycol, an antioxidant is added for reducing byproducts which are generated by Michael addition and difficult to purify and pH value is regulated for reducing production of aromatized impurities difficult to remove, so that a route for preparing fulvestrant by virtue of the fulvestrant intermediate has the advantages that a final product is difficult to purify, the cost is low and industrialization can be easily realized. The prepared fulvestrant intermediate lays a key foundation for obtaining a route for synthesizing fulvestrant which is easy to purify and easy for industrialization.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and relates to a preparation method of a fulvestrant intermediate. Background technique [0002] Fulvestrant, molecular formula C 32 h 47 f 5 o 3 S, the chemical name is 7-α-[9-(4,4,5,5,5-pentafluoropentasulfinyl)nonyl]estra-1,3,5-(10)-triene- 3,17-β-diol, the structural formula is as follows: [0003] [0004] Fulvestrant is a new type of anti-breast cancer drug developed by Astrazeneca. It is mainly used for the treatment of postmenopausal advanced breast cancer who are ineffective in the treatment of anti-estrogen therapy and estrogen receptor positive. Since it was launched in the United States in 2002 and approved in Europe in 2004, its good curative effect and relatively small side effects have enabled postmenopausal women with breast cancer to see the gospel. In view of the large demand and high price of fulvestrant, a large number of people cannot afford...

AI Technical Summary

Problems solved by technology

[0016] Chinese patents CN102227441, CN201110163041, CN201110273964, CN201110278101 and U.S. Patent US20100174101 are all based on compound B as the core, or connected to long chains or short chains. Although the starting material estradiol of compound B1 is relatively cheap, it can be achieved Compound B1 still needs three steps (Scheme4). Not only does it use expensive LDA, but the second step needs to be carried out under very strict conditions. After column purification, the yield can reach about 50%. In this way, Not only is the price not cheaper than dehydronandrolone acetate, but it is also difficult to industrialize production, while the production of dehydronandrolone acetate has already been industrialized and has become an easily available intermediate raw material

[0019] According to the existing technology, we can conclude that it is the most economical method to use dehydronandrolone acetate as the mother nucleus, and to introduce pentafluoropentanol after the addition of Michael, and the route Scheme1 has become our current First choice, and the synthesis of intermediate compound X is one of the keys in the whole route, and many impurities that are strictly restricted in the Fulvestrant Pharmacopoeia are also derivatives produced during the synthesis of this intermediate, although US4659516 and WO2006015081 There is a certain description of its synthesis, but there is no explanation for the avoidance and removal of key impurities, and whether the route to synthesize fulvestrant using this intermediate as a starting material is easy to industrialize and whether the cost is Being able to go lower plays an important role

Images