Unlock instant, AI-driven research and patent intelligence for your innovation.

Isomerized fused bicyclic structure and method for preparing vitamin d analogues comprising same

A technology of fused bicyclic compounds, applied in the field of preparation of vitamin D analogs containing it, can solve the problems of unsatisfactory diastereomer ratio and cis C/D ketone purity

Inactive Publication Date: 2014-10-15
HYBRIGENICS SA
View PDF3 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

They also found that repeated chromatographic separations resulted in unsatisfactory diastereomeric ratios and purity of the cis C / D ketone at the kilogram scale, and several purifications were actually required in order to increase the desired purity (95 / 05), Including recirculation of 50 / 50 mix

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
  • Isomerized fused bicyclic structure and method for preparing vitamin d analogues comprising same
  • Isomerized fused bicyclic structure and method for preparing vitamin d analogues comprising same
  • Isomerized fused bicyclic structure and method for preparing vitamin d analogues comprising same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Example 1 : (1R, 3aS, 7aR)-1-((2S)-5-(1-ethoxyethoxy)-5-methylhex-3-yn-2-yl)-7a-methylhexahydro -1H-inden-4(2H)-one (3)

[0074]

[0075] The trans ketone 2 (1 g) was stirred at reflux in THF in the presence of an excess (1.5 equiv) of NaH for 4 hours. A cis / trans ratio of 96 / 4 (determined by HPLC) was obtained. The reaction mixture was then poured into 10°C water at room temperature. The cis / trans ratio is not affected by this hydrolysis. Gel chromatography was performed on silica gel (15 wt. equivalents), eluting with a heptane / AcOEt+TEA mixture (90 / 10). This gave 680 mg (68%) of the desired cis product with a purity of greater than 99%. The collected analytical data are consistent with the structure of Equation 3.

Embodiment 2

[0077] Example 1 was repeated on an enlarged scale as follows:

[0078] 2.1. A solution of trans-ketone 2 (299 g, 0.851 mol) in THF (1.5 L) was added slowly to 60% sodium hydride (52 g, 2.16 mol) suspended in THF (1.5 I). After complete addition, the mixture was stirred at room temperature for 0.5 hours and boiled at reflux for 4 hours. The solution was then cooled and water (1.5 L) was added. The mixture was stirred and extracted with n-heptane. The organic layer was washed with water, and concentrated. The crude product was purified by flash chromatography on silica gel to give pure cis-ketone 3 (215 g, 75% yield, cis / trans ratio 97 / 3). The collected analytical data are consistent with the structure of Equation 3.

[0079] 2.2. A solution of trans ketone 2 (2.640 kg, 7.57 moles) in THF (13 L) was slowly added to 60% sodium hydride (464 g, 19.33 moles) suspended in THF (14 L). After complete addition, the mixture was stirred at room temperature for 0.5 hours and boiled a...

Embodiment 3

[0080] Example 3 : Preparation of Inecalcidol

[0081] 3.1 Formation of vinyl bromide 4

[0082] A solution of potassium bis(trimethylsilyl)amide (484 g, 2.42 mol) in tetrahydrofuran (2.2 L) was added slowly at -30°C to (bromomethyl)triphenylphosphine bromide (1.124 kg, 2.57 moles) in THF (2.2 L). After complete addition, the mixture was kept at -30°C for 1.5 hours and then heated to 0°C. Then, a solution of cis-ketone 3 (340 g, 0.975 mol) in tetrahydrofuran (0.5 L) was added at 0° C., and the mixture was stirred for 2.5 hours. Water was then added slowly while maintaining the temperature below 20°C. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The crude product was purified by flash chromatography on silica gel to afford pure vinyl bromide 4 (200 g, 48% yield).

[0083] 3.2. Condensation of aldehyde 5

[0084] A solution of tert-butyllithium (1.7 M in pentane, 1.25 L) was added dropwise to a solution o...

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 present invention relates to a method for isomerizing trans-fused bicyclic derivatives into cis-fused bicyclic derivatives, and a method for preparing vitamin D or analogs thereof comprising the isomerization step.

Description

technical field [0001] The present invention relates to novel methods for isomerizing fused bicyclic structures, and methods for preparing vitamin D analogs comprising the same. Background technique [0002] Vitamin D is a prohormone, meaning it does not have hormonal activity itself, but is converted into an active hormone by a controlled synthetic mechanism. Several forms of vitamin D have been discovered, including D1-D5. Chemically, the different forms of vitamin D are secosteroids, in which one of the bonds in the steroid ring is broken. The different forms of vitamin D have different side chains. The vitamin D receptor belongs to the nuclear receptor superfamily of steroid / thyroid hormone receptors and is expressed by cells in most organs including the brain, heart, skin, gonads, prostate and breast. Activation of vitamin D receptors in intestinal, skeletal, renal and parathyroid cells allows maintenance of blood calcium and phosphorus levels and preservation of bon...

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
Patent Type & Authority Patents(China)
IPC IPC(8): C07C49/753C07C45/67C07C35/21C07C29/10
CPCC07C2102/24C07B2200/07C07C401/00C07C45/67C07C2602/24A61P3/14C07C49/753C07C35/22C07C45/79C07C49/633
Inventor J-L·穆图F·穆顿G·佩莱格里诺J·拉费
Owner HYBRIGENICS SA
Features
  • R&D
  • Intellectual Property
  • Life Sciences
  • Materials
  • Tech Scout
Why Patsnap Eureka
  • Unparalleled Data Quality
  • Higher Quality Content
  • 60% Fewer Hallucinations
Social media
Patsnap Eureka Blog
Learn More

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

© 2025 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com