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Novel preparation process of tenofovir alafenamide fumarate

A technology of tenofovir alafenamide and hemifumaric acid, which is applied in the field of new preparation technology of tenofovir alafenamide hemifumarate, can solve the problem of high content of three pairs of diastereoisomers , Difficult to get effective control and other issues

Active Publication Date: 2018-08-24
科兴生物制药股份有限公司
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

In the existing synthesis process, the content of enantiomers can be controlled by the preparation method (such as WO2002008241A2), but the three pairs of diastereoisomers of tenofovir alafenamide are difficult to be effectively controlled
Therefore, the content of the three pairs of diastereomers in the crude product of tenofovir alafenamide is relatively high

Method used

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  • Novel preparation process of tenofovir alafenamide fumarate
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  • Novel preparation process of tenofovir alafenamide fumarate

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preparation example Construction

[0040] For the preparation method of tenofovir alafenamide, refer to US Patent Document US7803788. like figure 1 As shown, using the above-mentioned HPLC detection method to detect, in the tenofovir alafenamide crude product raw material used in the present invention, the content of tenofovir alafenamide is 88.28%, and the content of isomer I (peak 1) The content was 1.86%, the content of isomer II (peak 2) was 0.83%, and the content of isomer III (peak 3) was 1.25%. In addition, Impurity 1 (Peak 4), Impurity 2 (Peak 5) and Impurity 3 (Peak 6) could be resolved.

[0041] The novel preparation process of tenofovir alafenamide hemifumarate provided by the present invention can effectively remove non-enantiomers and other impurities, and the preparation of tenofovir alafenamide hemifumarate of the present invention The method includes the steps of:

[0042] (1) refining of tenofovir alafenamide

[0043] Add the crude product of tenofovir alafenamide into isobutanol, heat to d...

Embodiment 1

[0050] In the present embodiment, the preparation method of tenofovir alafenamide hemifumarate comprises the following steps:

[0051](1) refining of tenofovir alafenamide

[0052] Add 100 g of tenofovir alafenamide crude product (HPLC purity 88.28%) into 500 ml of isobutanol, heat to dissolve, then add 1000 ml of acetonitrile and n-hexane mixed solution (the volume ratio of acetonitrile and n-hexane is 6:4) After stirring evenly, the temperature was slowly lowered to 5° C., stirred and crystallized at 60 rpm for 2 hours, the filter cake was filtered and rinsed with cold acetonitrile, and then vacuum-dried to obtain the refined product of tenofovir alafenamide, with a yield of 86.3%.

[0053] The HPLC detection result of tenofovir alafenamide refined product is as follows figure 2 Shown, the content of main peak tenofovir alafenamide is 98.13%, the content of isomer I (peak 1) is 0.52%, the content of isomer II (peak 2) is 0.97%, isomer III The content of (Peak 3) was 0.16%...

Embodiment 2

[0058] In the present embodiment, the preparation method of tenofovir alafenamide hemifumarate comprises the following steps:

[0059] (1) refining of tenofovir alafenamide

[0060] Add tenofovir alafenamide crude product 100g (HPLC purity 88.28%) into 800ml isobutanol, heat to dissolve, then add acetonitrile and n-hexane mixed solution 1500ml (the volume ratio of acetonitrile and n-hexane is 2:1) After stirring evenly, the temperature was slowly lowered to 5°C, stirred and crystallized at 40 rpm for 3 hours, the filtered cake was rinsed with cold acetonitrile and then vacuum-dried to obtain the refined product of tenofovir alafenamide with a yield of 81.6%.

[0061] The HPLC detection result of tenofovir alafenamide refined product shows that the content of main peak tenofovir alafenamide is 98.06%, the content of isomer I (peak 1) is 0.48%, isomer II ( The content of peak 2) was 0.93%, and the content of isomer III (peak 3) was 0.26%.

[0062] (2) Preparation of tenofovir ...

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Abstract

The invention discloses a novel preparation process of tenofovir alafenamide fumarate, and in particular provides a preparation method of the tenofovir alafenamide fumarate. The method comprises the steps of adding a crude tenofovir alafenamide product into isobutanol, dissolving by heating, and then adding a mixed solution of acetonitrile and n-hexane for refining; then, adding the obtained tenofovir alafenamine refined product and fumaric acid into acetonitrile, salifying and crystallizing to obtain the tenofovir alafenamide fumarate. After the method provided by the invention is adopted, diastereomer impurities in crude tenofovir alafenamide product can be effectively removed, and the high-quality tenofovir alafenamide fumarate can be obtained.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a novel preparation process of tenofovir alafenamide hemifumarate. Background technique [0002] Tenofovir alafenamide fumarate (tenofovir alafenamide fumarate) is a new type of nucleotide reverse transcriptase inhibitor developed by Gilead, USA, for the treatment of chronic hepatitis B virus infection and compensatory Hepatic disease, chemical name 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy ]Propyl]adenine hemifumarate. The structure of tenofovir alafenamide hemifumarate is as follows: [0003] [0004] Tenofovir alafenamide is an oral prodrug of tenofovir (TFV), which is rapidly transformed into tenofovir after oral administration, which is phosphorylated into tenofovir diphosphate under the action of cellular kinases Salt inhibits HIV and HBV activity by competitively binding to natural deoxyribose substrates to inhibit viral poly...

Claims

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Application Information

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IPC IPC(8): C07F9/6561C07C51/41C07C57/15
CPCC07C51/412C07F9/65616C07C57/15
Inventor 崔宁郝志海张允王翠翠仇渡先
Owner 科兴生物制药股份有限公司
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