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Selective enzymatic esterification and solvolysis of epimeric vitamin D analog and separation of the epimers

A technology for epimers and vitamins, which is applied in the field of separation of mixed epimers of vitamin D analogues, and can solve problems such as difficult effective separation and close retention time

Inactive Publication Date: 2005-07-13
TEVA PHARMA IND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The difficulty in chromatographic separation is that the two C-24 hydroxyl epimers do not have significantly different affinities for the adsorbent, so their retention times are too close to be effectively separated in one chromatographic step

Method used

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  • Selective enzymatic esterification and solvolysis of epimeric vitamin D analog and separation of the epimers
  • Selective enzymatic esterification and solvolysis of epimeric vitamin D analog and separation of the epimers
  • Selective enzymatic esterification and solvolysis of epimeric vitamin D analog and separation of the epimers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Example 1 - Selective enzymatic esterification

[0072] to the stirred R 1 = R 2 = tert-butyldimethylsilyl and R 3 =C-24 epimer of structure III of the cyclopropyl alcohol mixture (20gr, 31.2mmol) and vinyl acetate (5.8ml, 62.4mmol) in n-hexane (60ml) was added 0.56gr of Alcaligenes Is lipase. The mixture was stirred at 25 ± 3°C for 3 hours, after which HPLC analysis indicated essentially complete conversion of epimer C-24(R) to acetate. Residual unesterified C-24(S) alcohol was >99% diastereomeric excess (HPLC). The solution was filtered and concentrated to dryness. Chromatography of the residue on pretreated silica gel, eluting with 5% ethyl acetate in n-hexane followed by ethyl acetate, gave the C-24 acetate compound IV (11gr) and the C-24 alcohol compound V ( 7.4gr).

[0073] compound

Embodiment 2

[0074] Example 2 - Selective enzymatic esterification

[0075] 0.5 g of Alcaligenes lipase was immobilized on 4 g Eupergit C (Rohm, Germany) according to known methods recommended by the supplier. To the R containing 0.3g (0.47mmol) 1 = R 2 = tert-butyldimethylsilyl and R 3 = cyclopropyl C-24 epimer alcohol mixture III (65:35 isomer ratio), 0.43ml (4.7mmol) vinyl acetate and 3.57ml n-hexane in a round bottom flask was added 400mg of immobilized enzyme. The mixture was stirred at 35°C for 4 hours, after which HPLC analysis indicated the presence of 30% Compound IV, 35% Compound VIII and 35% unreacted Compound V.

Embodiment 3

[0076] Example 3 - Selective enzymatic esterification

[0077] To the R containing 100mg (0.16mmol) 1 = R 2 = tert-butyldimethylsilyl and R 3 = Mixed C-24 epimers (65:35 isomer ratio) of the C-24 alcohol of structure III of cyclopropyl, 0.044 ml (0.47 mmol) of vinyl acetate and 1.5 ml of diisopropyl ether 10 mg of Alcaligenes lipase was added to the vial. The mixture was stirred at room temperature for 2 hours, after which HPLC analysis indicated the presence of 65% compound IV and 35% compound V.

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Abstract

Provided is a method of selectively enzymatically esterifying or selectively enzymatically solvolyzing epimers of analogs of vitamin D having a stereogenic center at C-24 that has a free or esterified OH group. The metod can be used, for example, for separating mixed epimers of the vitamin D analog.

Description

field of invention [0001] The present invention relates to methods for the selective enzymatic esterification and selective enzymatic solvolysis of the C-24 epimer of vitamin D analogues and esters thereof. The present invention further relates to a method of isolating mixed epimers of a vitamin D analog comprising a selective enzymatic esterification step or a selective enzymatic solvolysis step. [0002] related application [0003] This application claims priority to US Provisional Patent Application 60 / 348,082, filed January 10, 2002, and US Provisional Patent Application 60 / 349,977, filed January 18, 2002. Background of the invention [0004] Since its discovery as vitamin D 3 The hormonally active metabolite form of 1α, 25-dihydroxyvitamin D 3 (1,25-(OH) 2 D. 3 ) Since then, many analogues have been prepared in order to obtain active substances with a hypocalcemic effect. Much effort has been devoted to the modification of the vitamin D side chain. While the 1α ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P7/62C12N9/20C12P7/18C12P41/00
CPCC12P7/18C12P41/004C12P7/62C12N9/0004
Inventor E·夏皮罗A·费斯曼R·埃芬伯格A·迈蒙A·施瓦茨
Owner TEVA PHARMA IND LTD
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