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Stereoselective synthesis of vitamin D analogues

A technology for compounds and mixtures, applied in the field of intermediates for preparing calcipotriol or calcipotriol monohydrate, can solve the problems of decreased yield, easy to be oxidized, lengthy processing procedures, etc., and achieve the effect of improving yield and efficiency

Active Publication Date: 2011-07-06
LEO PHARMA AS
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0012] A major technical problem in the synthesis of calcipotriol using the stereoselective reduction method stems from the fact that the unsaturated triene systems known to date as intermediates for the synthesis of calcipotriol are chemically unstable, For example, they are unstable to Lewis acidic conditions, they are relatively easily oxidized and they are usually incompatible with the typical reduction reaction conditions used
This results in reduced yields, impure products and lengthy handling procedures, especially for large-scale production

Method used

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  • Stereoselective synthesis of vitamin D analogues
  • Stereoselective synthesis of vitamin D analogues
  • Stereoselective synthesis of vitamin D analogues

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] III: X=OR 2 , R 1 , R 2 = tert-butyldimethylsilyl

[0139] 1(S), 3(R)-bis(tert-butyldimethylsilyloxy)-20(R)-(3′-cyclopropyl-3′-oxoprop-1′(E)-ene base)-9,10-broken pregnant steroid (secopregna)-5(E), 7(E), 10(19)-triene SO 2 - adduct

[0140] 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 (according to M.J. Calverley, Tetrahedron, Vol. 43, No. 20, Nos. 4609-4619 Page, 1987 prepared by the method described in) (20.0g) was dissolved in toluene (210ml) at 20°C, then water (40ml) and SO 2 (20ml). After HPLC {from Merck's column LiChrosorb Si 60 5 μm, 250 * 4mm, the flow rate of 2ml / min, detection and mass detection at 270nm, hexane / ethyl acetate 9: 1 (volume ratio)} judged that the reaction had been completed (Usually after 2-2.5 hours), a mixture of sodium hydroxide (27.7%, 60ml) and water (80ml) was added at 10-18°C until the pH of the reaction mixture was 6. The toluene phas...

preparation example 1

[0142] VII: X=OR 2 , R 1 , R 2 = hydrogen

[0143] 1(S), 3(R)-dihydroxy-20(R)-(3′-cyclopropyl-3′-oxoprop-1′(E)-enyl)-9,10-depregna -5(E), 7(E), 10(19)-triene

[0144] 20(R), 1(S), 3(R)-bis(tert-butyldimethyl Silyloxy)-20-(3'-cyclopropyl-3'-oxoprop-1'(E)-enyl)-9,10-depregna-5(E),7(E) , 10(19)-triene was dissolved in acetonitrile. Aqueous hydrofluoric acid (40%) was added and the mixture was stirred at room temperature for about 1 hour. The progress of the reaction was conveniently checked by TLC using ethyl acetate as eluent. Ethyl acetate was added to the reaction mixture and the mixture was washed with aqueous sodium hydroxide. MgSO for organic phase 4 Dried and concentrated. The formed crystals (white needles) were filtered off, washed with ethyl acetate and dried in vacuo to afford the title compound VII (X=OR 2 , R 1 , R 2 = hydrogen). 1 H NMR (CDCl 3 )VII / X=OR 2 , R 1 , R 2 = Hydrogen = 6.77(dd, 1H), 6.57(d, 1H), 6.15(d, 1H), 5.88(dd, 1H), 5.13(dd, 1H), ...

Embodiment 2

[0146] III: X=OR 2 , R 1 , R 2 = hydrogen

[0147] 1(S), 3(R)-dihydroxy-20(R)-(3′-cyclopropyl-3′-oxoprop-1′(E)-enyl)-9,10-depregna -5(E), 7(E), 10(19)-triene SO 2 - Adducts.

[0148] The method is the same as in Example 1, except that the starting material is 1(S), 3(R)-dihydroxy-20(R)-(3'-cyclopropyl-3'-oxo) prepared in Preparation Example 1 Prop-1'(E)-enyl)-9,10-segreg-5(E),7(E),10(19)-triene. 1 H NMR (CDCl 3 )III / X=OR 2 , R 1 , R 2 = Hydrogen δ = 6.80(dd, 1H), 6.15(d, 1H), 4.75(m, 2H), 4.5-3.9(m, 4H), 3.70(d, 1H), 2.60(m, 1H), 2.5- 0.8(m, 25H), 0.68(s, 3H)ppm; 13 C NMR (CDCl 3 )III / X=OR 2 , R 1 , R 2 = Hydrogen δ = 201.0, 152.1, 151.0, 133.7, 129.2, 128.3, 108.8, 67.3, 65.1, 63.6, 56.1, 55.9, 55.5, 46.5, 40.1, 39.9, 33.9, 29.8, 27.4, 23.9, 22.1, 19.5, 18.9, 12.2, 11.2ppm.

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Abstract

The present invention relates to intermediates useful for the synthesis of calcipotriol or calcipotriol monohydrate, to methods of producing said intermediates, and to methods of stereoselectively reducing said intermediates.

Description

field of invention [0001] The present invention relates to the preparation of calcipotriol {(5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-5,7,10(19) by stereoselective reduction , 22-tetraene-1α-3β-24-triol} or calcipotriol monohydrate method. The present invention further provides novel intermediates and methods of synthesizing intermediates for the preparation of calcipotriol or calcipotriol monohydrate. Background of the invention [0002] Calcipotriol or calcipotriene (structural formula I) [CAS 112965-21-6] exhibits strong activity in inhibiting undesired 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 and calcipotriol (II) monohydrate in the treatment of psoriasis has been demonstrated in many clinical trials [D.M.Ashcroft et al., Brit.Med.J.320, 963-67, 2000] and is currently in Calcipotriol is used in m...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C401/00C07D333/72C07B31/00
CPCC07D333/72Y02P20/55A61P17/06
Inventor T·P·萨布勒M·J·卡尔弗利
Owner LEO PHARMA AS
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