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A kind of directional synthesis method and application of isomer impurity of alfacalcidol

A technology of alfacalcidol and isomers, applied in the field of chemical pharmacy

Active Publication Date: 2019-09-10
NANJING HERON PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] After searching, there is no bibliographical report about the synthesis of this impurity, therefore, it is of great practical significance to provide a synthetic method of the isomer impurity PY2 of alfacalcidol, which is used for the preparation of the impurity reference substance

Method used

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  • A kind of directional synthesis method and application of isomer impurity of alfacalcidol
  • A kind of directional synthesis method and application of isomer impurity of alfacalcidol
  • A kind of directional synthesis method and application of isomer impurity of alfacalcidol

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Experimental program
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Embodiment 1

[0067] The preparation of embodiment 1 formula 4 compound

[0068] Add the compound of formula 2, 80g of vitamin D3, 5L of dichloromethane, and 35g of imidazole into the reaction flask, keep away from light, and add 47g of tert-butyldimethylsilyl chloride dropwise at 0-5°C; React at 30°C, monitor by TLC until the reaction of the raw materials is complete, wash with water, stir and dry with anhydrous sodium sulfate, and obtain a solution of the compound of formula 3; cool the solution of the compound of formula 3 in methylene chloride to below -20°C, and stir in the dark, Add 300 g of sulfur dioxide gas, monitor by TLC until the reaction of the raw materials is complete, concentrate under reduced pressure, and concentrate the mother liquor in vacuo to obtain a brown oily substance, namely 115 g of the compound of formula 4.

Embodiment 2

[0069] The preparation of the compound of embodiment 2 formula 5

[0070] Add 115g of the compound of formula 4, 140g of sodium bicarbonate, and 1.5L of 95% ethanol into the reaction flask, keep away from light, protect with argon, heat to reflux for about 2-3h, monitor by TLC until the reaction of the raw materials is complete, concentrate, and add acetic acid to the residue 1.5 L of ethyl ester and 1.5 L of water were stirred until the solids were completely dissolved, left to stand, separated, the organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a light yellow transparent oil, namely 100 g of the compound of formula 5.

Embodiment 3

[0071] The preparation of embodiment 3 formula 6 compound

[0072] Add 2L of dichloromethane, 1.5L of acetonitrile, 100g of the compound of formula 5, and 90g of N-methylmorpholine oxide into the reaction bottle, heat to reflux, add 20g of selenium dioxide, reflux for 2-3h, monitor by TLC, and cool to room temperature , adding 1.5 L of water, stirring and standing for liquid separation, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a dark brown oily substance, namely 101 g of the compound of formula 6.

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Abstract

The invention discloses an isomer impurity PY2, namely, (5Z,7E)-9,10-secocholesta-5,7,10(19)-triene-1 beta,3 beta-diol, of alfacalcidol and a preparation method of the isomer impurity and belongs to the technical field of chemical pharmacy. The high-purity related impurity PY2 of alfacalcidol can be used as an impurity standard substance in detection and analysis of an alfacalcidol product, so that accurate positioning and quality determination of the impurity in the detection and analysis of the alfacalcidol product are improved, control on the impurity can be strengthened, and the quality ofthe alfacalcidol product can be improved. The method is simple to operate and good in repeatability, raw materials are cheap and easy to obtain, and the HPLC purity is higher than or equal to 99.5%.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and specifically relates to a method for preparing an alfacalcidol isomer impurity PY2, and using the impurity as an impurity reference substance, detection and analysis in alfacalcidol raw materials and preparations Analysis and other quality control purposes. Background technique [0002] Alfacalcidol, chemical name: 9,10-cyclocholesteryl-5Z,7E,10(19)-triene-1α,3β-diol. The chemical formula is: [0003] . [0004] It was first developed by Bone Care International, and has been approved for marketing in Israel, Germany, Japan, and Italy. The products of Danish LEO Pharmaceutical Company are widely sold all over the world. They are mostly used for calcium metabolism disorders caused by vitamin D metabolic disorders. They are clinically used for osteoporosis, chronic renal insufficiency, hypoparathyroidism, and anti-vitamin D. Rickets, osteomalacia, etc. [0005] Since 1997, domes...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C401/00G01N30/02
Inventor 袁尚王芳胡永康闵涛王林郭彦飞
Owner NANJING HERON PHARM CO LTD
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