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Preparation method of propofol tenofovir degradation impurity

A technology of tenofovir and alafenol, which is applied in the field of preparation of tenofovir alafenamide degradation impurities, can solve the problems of long reaction time, complex post-processing, cumbersome operation, etc., and achieve simple raw materials, simple post-processing, and reaction The effect of easily controllable conditions

Pending Publication Date: 2021-07-13
HINYE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The purpose of the present invention is to overcome the technical problems of long reaction time, cumbersome operation, complicated post-processing and high cost in the synthesis of tenofovir alafenamide degrading impurity compound formula II in the prior art, and provide a tenofovir alafenamide The preparation method of degradation impurity, this preparation method is simple, quick and the impurity that makes has high purity, can be used as impurity standard substance to control the quality standard of tenofovir

Method used

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  • Preparation method of propofol tenofovir degradation impurity
  • Preparation method of propofol tenofovir degradation impurity
  • Preparation method of propofol tenofovir degradation impurity

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0033] A preparation method for tenofovir alafenamide degrading impurities, comprising the following steps:

[0034] Step 1. Add 5.0g of tenofovir alafenamide free base and 50mL of dichloromethane into the reaction flask, and stir to dissolve; another 2.9g of potassium carbonate is stirred and dissolved with 20mL of water, and then incubated at 25°C for 15 hours. After completion, let stand to separate layers, discard the dichloromethane layer, and control the internal temperature of the aqueous phase layer to 10-30°C.

[0035] S2. After being purified by high-pressure preparative chromatography, the component solutions containing materials were collected and freeze-dried to obtain 3.8 g of white solid tenofovir alafenamide degraded impurity compound I, with a HPLC purity of 99.15%; wherein the high-pressure preparative chromatography was washed with isocratic For separation, the mobile phase was 3% pure acetonitrile aqueous solution, the flow rate was 15 mL / min, and the injec...

Embodiment 2～4

[0037] A preparation method of tenofovir alafenamide degrading impurities is substantially the same as in Example 1, and the difference is that the mol ratio of tenofovir alafenamide free base to potassium carbonate (expressed with A in table 1) is different, See Table 1 for details.

[0038] The impact of different feed ratios on the product yield in table 1

[0039]

[0040]

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Abstract

The invention discloses a preparation method of a propofol tenofovir degradation impurity. According to the preparation method, propofol tenofovir free alkali and an aqueous solution containing an alkaline substance are used as raw materials, dichloromethane is used as a reaction solvent, and in a reaction system with a specific alkaline substance, reaction temperature and the like, the conversion rate of the raw materials in the reaction liquid is as high as 90.0% or above, and the reaction selectivity is relatively high; and after layering, an obtained water layer is purified through medium-pressure preparative chromatography, the purity of a target product is up to 99% or above, the target product can be used as an impurity reference substance, and important guiding significance is provided for quality standard control and safe medication of the propofol tenofovir.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, more specifically, relate to a kind of preparation method of tenofovir alafenamide degrading impurity. Background technique [0002] Tenofovir Alafenamide Fumurate (TAF) is a targeted prodrug of the nucleotide reverse transcriptase inhibitor Tenofovir (Tenofovir), developed by Gilead Sciences in the United States under the trade name Vemlidy, released in 2016 It was approved for marketing in the United States in November for the once-a-day treatment of chronic hepatitis B virus (HBV) infection in adult patients with compensated liver disease, and was approved for marketing in China in November 2018. The chemical name of TAF is N-[(S)-[[[(R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy]methyl](phenoxy) Phosphoryl]-L-alanine isopropyl ester, (2E)-2-butenedioate (2:1), its chemical structure is as follows: [0003] [0004] In the process of synthesizing TAF, it is often accompanied by th...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
CPCC07B2200/07C07F9/65616
Inventor 邹湘祁马晓宁廖正华黄明强谢明成
Owner HINYE PHARM CO LTD