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

Novel method for the preparation of intermediates useful for the synthesis of vitamin d analogues

A compound and halogen technology, applied in the field of manufacturing calcipotriol or calcipotriol monohydrate, can solve the problems of difficult removal, increased chromatography steps, etc.

Active Publication Date: 2010-06-02
科奥制药有限公司
View PDF8 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The Wittig process using phosphorane IV has a number of disadvantages, especially when carried out on a large scale: a) during the C═C-bond formation reaction, triphenylphosphine oxide is formed as a by-product, which is difficult to remove from the reaction mixture remove
The formation of triphenylphosphine oxide currently adds an additional chromatographic step to the above method

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
  • Novel method for the preparation of intermediates useful for the synthesis of vitamin d analogues
  • Novel method for the preparation of intermediates useful for the synthesis of vitamin d analogues
  • Novel method for the preparation of intermediates useful for the synthesis of vitamin d analogues

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0174] In another aspect, the invention relates to 20(R), 1(S), 3(R)-bis(tertiary) obtained by a process comprising reacting a compound of general structure IIIa with a phosphonate of general structure VII. Butyldimethylsilyloxy)-20-(3'-cyclopropyl-3'-oxoprop-1'(E)-enyl)-9,10-depregna-5(E) , 7(E), 10(19)-triene.

[0175] In another aspect, the invention relates to 20(R), 1(S), 3(R)-bis(tertiary) obtained by a process comprising reacting a compound of general structure IIIb with a phosphonate of general structure VII. Butyldimethylsilyloxy)-20-(3'-cyclopropyl-3'-oxoprop-1'(E)-enyl)-9,10-depregna-5(Z) , 7(E), 10(19)-triene.

[0176] In another aspect, the invention relates to 20(R), 1(S), 3(R)-bis(R), obtained by a process comprising reacting a compound of general structure VIa or VIb with a phosphonate of general structure VII. (tert-butyldimethylsilyloxy)-20-(3'-cyclopropyl-3'-oxoprop-1'(E)-enyl)-9,10-depregna-5( E), SO of 7(E), 10(19)-triene 2 adduct.

[0177] In a pres...

Embodiment 1

[0231] 20(R), 1(S), 3(R)-bis(tert-butyldimethylsilyloxy)-20-(3'-cyclopropyl-3'-oxopropane-1'(E )-alkenyl)-9,10-depregna-5(E),7(E),10(19)-triene

[0232] Compound Va(R 1 , R 2 = tert-butyldimethylsilyl)

[0233] Diethyl (2-cyclopropyl-2-oxoethyl)phosphonate (compound VII / R 3 , R 4 = ethyl) (46.0 g, 209 mmol), 1(S), 3(R)-bis(tert-butyldimethyl) prepared according to M.J. Calverley, Tetrahedron, Vol. 43, p. 20, pp. 4609-4619 1987 Methylsilyloxy)-20(S)-formyl-9,10-depregna-5(E),7(E),10(19)-triene (compound IIIa / R 1 , R 2 = tert-butyldimethylsilyl) (72.2g, 126mmol), toluene (1100ml), water (122ml), tetrabutylammonium bromide (3.13g) and sodium hydroxide solution 27.7% (128.0g) The mixture was stirred at 30°C for about one hour, then at room temperature (15-25°C) overnight. When the reaction was complete as judged by HPLC [ColumnLiChrosorb Si 60 5 μm 250 x 4 mm from Merck, flow rate 1.5 ml / min, detection at 270 nm, hexane / ethyl acetate 100:2 (v:v)], water was added ( 500ml)...

Embodiment 1A

[0235]20(R), 1(S), 3(R)-bis(tert-butyldimethylsilyloxy)-20-(3'-cyclopropyl-3'-oxopropane-1'(E )-alkenyl)-9,10-depregna-5(E),7(E),10(19)-triene

[0236] Compound Va(R 1 , R 2 = tert-butyldimethylsilyl)

[0237] To (2-cyclopropyl-2-oxoethyl) phosphonic acid diethyl ester (compound VII / R 3 , R 4 =ethyl) (1.51 g) in THF (16 ml) was added NaHMDS (sodium hexamethyldisilazane) (3.2 ml, 2M in THF) over 10 minutes below -50 °C, and Stir for another 3-4 hours, then add 1(S),3(R)-bis(tert-butyldimethylsilyloxy)-20(S)-formyl-9 below -50 °C, 10-pregna-5(E), 7(E), 10(19)-triene (compound IIIa / R 1 , R 2 = tert-butyldimethylsilyl) (2 g) in THF (3 ml). The reaction was stirred at below -50°C for an additional 2 hours before the temperature was allowed to warm to room temperature overnight, and then at -25°C for 2 hours. The reaction was checked for completion by HPLC [ColumnLiChrosorb Si 60 5 μm 250×4 mm from Merck, flow rate 1.5 ml / min, detection at 270 nm, hexane / ethyl acetate 100:2...

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 novel methods for the preparation of intermediates which are useful in the synthesis of cacipotriol. The present invention relates further to the use of intermediatesproduced with said methods for making calcipotriol or calcipotriol monohydrate.

Description

technical field [0001] The present invention relates to can be used for synthesizing calcipotriol {(5Z, 7E, 22E, 24S)-24-cyclopropyl-9,10-broken bile-5,7,10(19),22-tetraene-1α- Novel intermediates of 3β-24-triol} and methods for their preparation. The invention further relates to the use of the intermediate prepared by this process for the manufacture of calcipotriol or calcipotriol monohydrate. Background technique [0002] Calcipotriene or calcipotriene (Structure I) [CAS112965-21-6] showed potent activity in inhibiting undesirable proliferation of epidermal keratinocytes [F.A.C.M. Castelijins, M.J. Gerritsen, I.M.J.J. van Vlijmen-Willems, P.J. van Erp , P.C.M. van de Kerkhof; Acta Derm. Venereol. 79, 11, 1999]. The efficacy of calcipotriol (Ia) and calcipotriol monohydrate (Ib) in the treatment of psoriasis has been shown in a number of clinical trials [D.M.Ashcroft et al.; Brit.Med.J.320, 963-67, 2000], and calcipotriol is commonly used in several commercially availab...

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): C07B37/00C07C401/00
CPCC07C401/00C07D333/72C07C2101/02C07C2601/02C07B37/00
Inventor E·T·汉森T·P·萨布勒M·J·卡尔弗利H·佩得森H-J·W·德森
Owner 科奥制药有限公司
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