Preparation method of fulvestrant intermediate

A technology for fulvestrant and an intermediate, which is applied in the field of medicinal chemical synthesis, can solve the problems such as the avoidance and removal methods are not given, it is difficult to industrialize production, the cost is lower, and the like. Purification difficulty and the effect of reducing the cost of raw materials

Active Publication Date: 2014-08-06
天津孚音生物科技发展有限公司
View PDF15 Cites 11 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] 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 (Scheme 4). Not only is the expensive LDA used in it, but the second step needs to be carried out under very strict conditions. After column purification, the yield can reach about 50%. Calculated in this way , not only the price is not cheaper than dehydronandrolone acetate, but it is also difficult to produce industrially, and the production of dehydronandrolone acetate has already been industrialized, and it has become an easy-to-obtain intermediate raw material
[0021] According to th...

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of fulvestrant intermediate
  • Preparation method of fulvestrant intermediate
  • Preparation method of fulvestrant intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Purification of 1,9-nonanediol:

[0065] Heat and melt 1 kg of industrial-grade 1,9-nonanediol, wash it with water four times, get 673 g of 1,9-nonanediol that meets the requirements, recover 297 g of unqualified 1,9-nonanediol, The loss of material in water is 30 g, and the total utilization rate of raw material is 97%.

[0066] GC: before washing: 1,8-octanediol content: 0.2143%;

[0067] After washing: 1,8-octanediol content: 0.0573%;

[0068] Recovered sample: 1,8-octanediol content: 0.2971%;

[0069] Water loss material: 1,8-octanediol content: 0.4182%;

Embodiment 2

[0071] Preparation of 9-bromo-1-nonanol (compound 2):

[0072] Add 1,9-nonanediol (1 kg) to toluene (20 L), add hydrobromic acid (40%, 2.5 L) with stirring, and heat to reflux (internal temperature 90-100°C) for 24 hrs. Stop heating, cool to 40°C, add ethyl acetate (4L) and cold water (4L), stir and separate layers, the organic phase is washed with saturated sodium bicarbonate aqueous solution and aqueous solution successively, dried with anhydrous sodium sulfate, and spin-dried to obtain 1.6 kg Add 4.8 L of n-hexane to the crude product, stir and heat to dissolve, cool and crystallize to obtain 1.1 kg 9-bromo-1-nonanol.

[0073] GC: before crystallization: product: 95.2033%, 1,9-dibromononane: 1.9985%;

[0074] After crystallization: Product: 98.8413%, 1,9-Dibromononane: None.

Embodiment 3

[0076] Preparation of compound 3:

[0077] Add 9-bromo-1-nonanol (1.1 kg), N,N-dimethylformamide (2.86 L), imidazole (363 g) into a 10 L reaction flask, add dimethyl tert- Butylchlorosilane (772 g), the temperature is lower than 20 °C, react for 1 hour, add water (5 L), toluene (1 L) in turn, stir, separate the liquids, extract the aqueous phase with toluene (1 L), mix the organic phase, the organic phase was washed with water (1L), dried over anhydrous sodium sulfate, and spin-dried under reduced pressure at 80°C to obtain 1.56 kg of product, which was directly used in the next reaction.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

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...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07J31/00
Inventor 刘文娟莫岚
Owner 天津孚音生物科技发展有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap