Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Synthesis method of tibolone intermediate T6

A synthetic method and intermediate technology, applied in the field of preparation of steroidal compounds, can solve the problems of harsh Birch reduction conditions, cumbersome method steps, and high production costs, and achieve environmental protection and large-scale production, avoiding the use of dangerous metal reagents , the effect of shortening the reaction steps

Pending Publication Date: 2022-04-12
ZHEJIANG XIANJU JUNYE PHARM CO LTD +1
View PDF4 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the third, fourth, and fifth synthetic methods have short steps, the raw material nandrolone or its precursor acid removal is expensive and the production cost is high
However, the first step of the method is cumbersome, and the Birch reduction conditions are harsh.

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
  • Synthesis method of tibolone intermediate T6
  • Synthesis method of tibolone intermediate T6
  • Synthesis method of tibolone intermediate T6

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Dissolve TLW (50.0 g, HPLC content ≥ 98%) in acetic anhydride (500 mL) solution, add concentrated sulfuric acid (2.0 g), and stir at room temperature for 6 hours. TLC detects that the reaction is complete, stop the reaction, concentrate to a paste, add ethyl acetate (500 mL) and water (200 mL), separate the layers, extract the aqueous layer with ethyl acetate (200 mL), separate the layers, combine the organic phases, and saturated salt Wash with water (200 mL), separate the layers, dry and concentrate to give T4B as a yellow solid, 57.0 g.

Embodiment 2

[0027] T4B (57.0 g) was dissolved in methanol (570 mL) solution, sodium borohydride (6.3 g) was added, 0 o The reaction was carried out at C for 1 hour, TLC detected that the reaction was complete, adjusted the pH to neutral with dilute hydrochloric acid, concentrated to a paste, added ethyl acetate (570 mL) and water (280 mL), separated, and the aqueous layer was ethyl acetate (280 mL) Extract, separate layers, combine organic phases, wash with saturated brine (280 mL), separate layers, dry, and concentrate to obtain T5B as a yellow solid, 57.0 g.

Embodiment 3

[0029] Dissolve T5B (57.0 g) in dichloromethane (300 mL) solution, add acetic anhydride (57.0 g), add triethylamine (28.5 g), and stir at room temperature for 12 hours. TLC detected that the reaction was complete, adding sodium bicarbonate solution to quench the reaction, filtering, spinning the filtrate to a paste, adding ethyl acetate (570 mL) and water (280 mL), separating the layers, and extracting the aqueous layer with ethyl acetate (280 mL) , separate layers, combine organic phases, wash with saturated brine (280 mL), separate layers, dry, and concentrate to obtain crude yellow solid T6, 62.0 g. The crude product of T6 was placed in methanol (310 mL), heated to reflux, naturally cooled to room temperature, stirred and crystallized, and filtered to obtain T6 as a white solid, 55.8 g, with an HPLC purity of 99%.

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

A synthesis method of a tibolone intermediate T6 comprises the following steps: 1) ring-opening reaction: dissolving TLW in acetic anhydride, using protonic acid or Lewis acid as a catalyst, performing heating reflux reaction, and after the reaction is finished, concentrating, dissolving in an organic solvent, washing with water, layering, drying and concentrating to obtain T4B; 2) reduction reaction: dissolving T4B in methanol, adding sodium borohydride at 0-50 DEG C, and after the reaction is finished, quenching with diluted hydrochloric acid, concentrating, dissolving with an organic solvent, washing with water, layering, drying and concentrating to obtain T5B; and 3) esterification reaction: dissolving T5B in an organic solvent such as dichloromethane, adding acetic anhydride, adding organic alkali or inorganic alkali serving as an acid-binding agent, and reacting at 0-50 DEG C until the reaction is complete. Adding an alkali solution for quenching reaction, concentrating to remove dichloromethane, adding an organic solvent for extraction, layering, washing and drying to obtain a T6 crude product, placing the T6 crude product in methanol, heating and refluxing, naturally cooling to room temperature, stirring and crystallizing, and filtering to obtain the target compound T6.

Description

technical field [0001] The invention relates to a preparation method of a steroid compound, in particular to a synthesis method of a tibolone intermediate. Background technique [0002] Tibolone is a tissue-selective modulator of estrogen activity (STEARs), which is a synthetic steroid hormone. Clinically, it is mainly used in perimenopausal and postmenopausal women to relieve vasomotor state, improve symptoms of urogenital atrophy, prevent bone loss and reduce the incidence of fractures, and improve the quality of life. [0003] In 1967, P. Wieland et al first reported the synthetic route of tibolone. The route uses dehydroepiandrosterone as a raw material to obtain tibolone through 11 steps with a total yield of 8.9%. [0004] In 1986, N.P.van Vliet et al. reported the second synthetic route of tibolone. The route uses diester T6 as the starting material to synthesize tibolone through 7 steps. The diester T6 needs to be obtained through 7 steps with the dechlorinated s...

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): C07J1/00
CPCY02P20/584
Inventor 张峥斌李纯尹金玉张杰锋吴静吴小芳
Owner ZHEJIANG XIANJU JUNYE PHARM CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com