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A related impurity pzb of alfacalcidol and its preparation method and use

A technology of alfacalcidol, related impurities, applied in the field of chemical pharmacy

Active Publication Date: 2019-09-20
NANJING HERON PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] After retrieval, 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 PZB of alfacalcidol, which is used for the preparation of the impurity reference substance

Method used

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  • A related impurity pzb of alfacalcidol and its preparation method and use
  • A related impurity pzb of alfacalcidol and its preparation method and use
  • A related impurity pzb of alfacalcidol and its preparation method and use

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Experimental program
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Effect test

Embodiment 1

[0069] The preparation of embodiment 1 formula 4 compound

[0070] Add the compound of formula 2, namely 80g of vitamin D4, 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

[0071] The preparation of the compound of embodiment 2 formula 5

[0072] 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

[0073] The preparation of embodiment 3 formula 6 compound

[0074] 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 impurity PZB related to alfacalcidol and a preparing method thereof, and belongs to the technical field of chemical pharmaceutical. The impurity PZB is (1R,3S,5Z)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(2R,5R)-5-hydroxy-6-methylheptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol. The highly purified impurity PZB related to alfacalcidol can be applied as an impurity standard substance in alfacalcidol finished product detection and analysis, accordingly accurate locating and nature determine of an impurity in the alfacalcidol finished product detection and analysis are improved, the strengthened control over the impurity is facilitated, and thus the quality of an alfacalcidol finished product is improved. According tothe preparing method, raw materials are cheap and easy to obtain, the operation is simple, reproducibility is good, and the HPLC purity is larger 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 preparation method of PZB related to alfacalcidol, and the detection and analysis of the impurity in raw materials and preparations of alfacalcidol by using the impurity as an impurity reference substance, etc. For 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 19...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C401/00G01N30/02
Inventor 王芳袁尚郭彦飞闵涛胡永康丁伯祥王雪萌葛元丽
Owner NANJING HERON PHARM CO LTD