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Epimerisation of allylic alcohols

A technology of epimerization and epimerization, which is applied in the field of compounds for synthesizing vitamin D analogs, can solve the problems of undisclosed alcohol epimerization, unfavorable economy, etc., and achieves easy operation and improved overall production. efficiency, the effect of improving the productivity of the method

Inactive Publication Date: 2007-07-18
LEO PHARMA AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This epimerization process has the disadvantage that it involves two additional chemical transformations, esterification and saponification of IIIb, making the process economically unfavorable, especially on an industrial scale
[0009] WO 94 / 07853 discloses various vitamin D analogs having a hydroxyl substituent on the asymmetric allyl carbon at position 24, but does not disclose a method for epimerizing the alcohol

Method used

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  • Epimerisation of allylic alcohols
  • Epimerisation of allylic alcohols
  • Epimerisation of allylic alcohols

Examples

Experimental program
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Embodiment approach

[0076] In a preferred embodiment of the invention, the vitamin D analog fragment is represented by fragment F, G, H, J, K or L,

[0077]

[0078] where R 1 and / or R 2 may be the same or different and represent hydrogen or a hydroxyl protecting group.

[0079] In another preferred embodiment of the invention, R 1 and R 2 Represents an alkylsilyl group or hydrogen.

[0080] In another preferred embodiment of the invention, R 1 and R 2 Represents tert-butyldimethylsilyl.

[0081] In another preferred embodiment of the invention, R 3 is cyclopropyl or -C(CH 3 ) 2 -C(O)-O-CH(CH 3 ) 2 .

[0082] In a further preferred embodiment of the invention, the configuration at carbon atom C-20 of the side chain marked with an asterisk is (R) and the configuration at C-17 or a C-17 analogous position is the same as in natural vitamin D 3 in the same.

[0083] In a further preferred embodiment of the invention, the epimer is compound IIIba or an epimer mixture comprising compo...

Embodiment 1

[0137] Example 1: MC898 / MC901

[0138] 1(S), 3(R)-bis(tert-butyldimethylsilyloxy)-20(R)-(3'-cyclopropyl-3'(R)-hydroxypropyl-1'( E)-alkenyl)-9,10-seppregna-5(E),7(E),10(19)-triene (IIIb:R 1 , R 2 = tert-butyldimethylsilyl) (10 mg), THF (1 mL) and aqueous sulfuric acid (0.4 mL, pH 1.7) were mixed in a test tube. After standing overnight at room temperature, HPLC analysis (normal phase silica 20 cm analytical column, 4 mL / min, AcOEt / n-hexane 4 / 96 (v:v)) indicated the presence of about 40% of the starting epimer And about 45% of 1(S), 3(R)-bis(tert-butyldimethylsilyloxy)-20(R)-(3'-cyclopropyl-3(S)'-hydroxypropyl -1'(E)-alkenyl)-9,10-depregna-5(E),7(E),10(19)-triene (IIIa:R 1 , R 2 = tert-butyldimethylsilyl) together with about 12% of two major and less polar impurities of unknown structure.

Embodiment 2

[0140] Will contain about 95% of 1(S), 3(R)-bis(tert-butyldimethylsilyloxy)-20(R)-(3'-cyclopropyl-3'(R)-hydroxy Prop-1'(E)-enyl)-9,10-depregna-5(E),7(E),10(19)-triene (IIIb:R 1 , R 2= tert-butyldimethylsilyl) and 1 , R 2 = tert-butyldimethylsilyl) (about 12 kg) was dissolved in a mixture of acetone (58 L) and THF (58.5 L). A solution of sodium bisulfate (0.3 kg) in water (20 L) (pH 1.58) was added with stirring while maintaining an internal temperature of 20-25°C. After 220 minutes, the saturated NaHCO 3 The solution (6 L) was added to the reaction mixture. The organic solvent was mostly removed in vacuo and the residue was redissolved in ethyl acetate (100 L). The organic solution was then washed with brine (2 L saturated NaCl solution in 180 L water). Ethyl acetate was then removed in vacuo, the residue was redissolved in hexane, and the epimeric mixture was separated by silica gel column chromatography (by HPLC {column LiChrosorb Si 60 5 μm 250 x 4 mm, purchased from ...

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Abstract

The present invention relates to processes for epimerising alcohols of compounds having a hydroxyl substituent on an asymmetric allylic carbon, such as compounds useful for the synthesis of vitamin D analogues where the epimeric hydroxyl substituent is at the 24 position. The invention further relates to methods of producing intermediates useful for the synthesis of calcipotriol by said epimerisation processes.

Description

field of invention [0001] The present invention relates to a novel method of epimerization of compounds, such as those useful in the synthesis of vitamin D analogues, which have a hydroxyl substituent on an asymmetric allylic carbon, for example at position 24. The present invention further relates to the application of the intermediate produced by this method in the preparation of calcipotriol i.e. {(5Z, 7E, 22E, 24S)-24-cyclopropyl-9,10-broken cholesterol-5,7,10(19 ), 22-tetraene-1α-3β-24-triol} or calcipotriol monohydrate. Background of the invention [0002] Calcipotriol (Structure I) [CAS 112965-21-6] shows strong 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 and monohydrate (I-hydrate) calcipotriol in the treatment of psoriasis has been shown in many clinical trials [D....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C401/00C07J9/00
CPCC07J9/00C07C401/00C07C2101/02C07C2601/02
Inventor H·佩得森C·A·S·布雷丁E·T·宾德鲁普
Owner LEO PHARMA AS
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