Production method of labelled vitamin D2 internal standard compound

A technology for internal standard compounds and vitamins, which can be applied in the fields of isotope introduction into organic compounds, organic chemistry methods, compounds of elements in Group 4/14 of the periodic table, etc., and can solve problems such as low yields

Inactive Publication Date: 2019-09-24
无锡贝塔医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method has good reaction selectivity, but the yield is lo

Method used

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  • Production method of labelled vitamin D2 internal standard compound
  • Production method of labelled vitamin D2 internal standard compound
  • Production method of labelled vitamin D2 internal standard compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Add the following formula (IV-1) amide phosphorus salt compound (1.10 g, 2 mmol) into diethyl ether (10 mL), replace with nitrogen, start stirring, control the temperature at -20°C, and slowly add n-butyllithium in n-hexane (2.5M, 1.6 mL, 4 mol), the solution turned red. After the dropwise addition, the temperature was raised to room temperature, and the reaction was stirred for 2 hours; then the reaction solution was cooled to -20°C, and the following formula (Ⅲ) aldehyde (0.89 g , 2 mmol) solution in diethyl ether, the red color of the solution disappears, the reaction is stirred at constant temperature for 2 hours, warmed up to room temperature and stirred overnight; the reaction is quenched by adding dilute hydrochloric acid, the organic phase is separated, the aqueous phase is extracted with diethyl ether, the organic phase is combined, and anhydrous sulfuric acid Dry over magnesium; concentrate the organic phase, and purify by silica gel column chromatography (petr...

Embodiment 2

[0043] Add the following formula (IV-1) amide phosphorus salt compound (1.10 g, 2 mmol) into THF (10 mL), replace with nitrogen, start stirring, control the temperature at -20°C, and slowly add n-butyllithium in n-hexane solution (2.5M, 1.6 mL, 4 mol), the solution turned red. After the dropwise addition, the temperature was raised to 0°C, and the reaction was stirred for 2 hours; then the reaction solution was cooled to -20°C, and the aldehyde of the following formula (Ⅲ-1) was slowly added (0.89 g, 2 mmol) solution in THF, the red color of the solution disappeared, stirred at constant temperature for 2 hours, warmed up to room temperature and stirred overnight; quenched the reaction by adding dilute hydrochloric acid, extracted twice with ether, combined the organic phases, and dried over anhydrous magnesium sulfate ; Concentrate the organic phase and purify by silica gel column chromatography (petroleum ether / ethyl acetate: 5 / 1) to obtain 0.62 g of an intermediate of the fol...

Embodiment 3

[0051] Add the following formula (IV-1) amide phosphorus salt compound (1.10 g, 2 mmol) into THF (10 mL), replace with nitrogen, start stirring, control the temperature at -20°C, and slowly add n-butyllithium in n-hexane solution (2.5M, 1.6 mL, 4 mol), the solution turned red. After the dropwise addition, the temperature was raised to 0°C, and the reaction was stirred for 2 hours; then the reaction solution was cooled to -20°C, and the aldehyde of the following formula (Ⅲ-1) was slowly added (0.89 g, 2 mmol) solution in THF, the red color of the solution disappeared, stirred at constant temperature for 2 hours, warmed up to room temperature and stirred overnight; quenched the reaction by adding dilute hydrochloric acid, extracted twice with ether, combined the organic phases, and dried over anhydrous magnesium sulfate ; Concentrate the organic phase and purify by silica gel column chromatography (petroleum ether / ethyl acetate: 5 / 1) to obtain 0.62 g of the intermediate of the fo...

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Abstract

The invention relates to a production method of a labelled vitamin D2 internal standard compound. The production method of the labelled vitamin D2 internal standard compound comprises the following steps of firstly, subjecting a gamma-amide phosphonium salt compound as shown in a formula (IV) in the specification and an aldehyde as shown in a formula (III) in the specification to a reaction at -40 DEG to 0 DEG C to obtain an intermediate as shown in a formula (V) in the specification; then adding a Boc anhydride and a catalyst, carrying out a reaction, and then adding an isotope labelled methyl Grignard reagent dropwise to obtain an intermediate as shown in a formula (VI) in the specification; and then adding tetrabutylammonium fluoride, and carrying out a reaction to obtain a finished product, namely, the labelled vitamin D2 internal standard compound. The production method of the labelled vitamin D2 internal standard compound has the advantage that the produced labelled vitamin D2 internal standard compound can be used for 25-hydroxyvitamin D2, 1,25-dihydroxyvitamin D2 and tandem mass spectrometry for detecting the content of VD in human serum by means of the 25-hydroxyvitamin D2 and the 1,25-dihydroxyvitamin D2.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a labeled internal standard compound of vitamin D2, which belongs to the field of organic synthesis. Background technique [0002] Vitamin D (Vitamin D, VD) is a kind of fat-soluble steroid hormone precursor. The basic chemical structure is cholesterol. It has anti-rickets effect. It is also called anti-rickets vitamin. The most important members of the vitamin D family are VD2 (ergocalciferol) and VD3 (cholecalciferol). Both D2 and D3 from different sources need to be transported to the liver through blood circulation, and are first converted into 25-hydroxyvitamin D (25-(OH)VD) under the action of liver enzymes, which is the main storage form of VD in the body. 25-(OH)VD is then transported to the kidney, where it undergoes a second hydroxylation to form 1,25-dihydroxyvitamin D (1,25-(OH)2VD), which is the most active VD. [0003] The following formula ...

Claims

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Application Information

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IPC IPC(8): C07C401/00C07F7/18C07B59/00
CPCC07B59/001C07B2200/05C07C401/00C07C2601/14C07C2602/24C07F7/1804C07F7/1892
Inventor 朱称古张敏颜盛旺李刚
Owner 无锡贝塔医药科技有限公司
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