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Tenofovir alafenamide diastereoisomer, preparation method and application of diastereoisomer

A technology of tenofovir alafenamide and diastereoisomers, applied in chemical instruments and methods, compounds of Group 5/15 elements of the periodic table, measuring devices, etc.

Inactive Publication Date: 2020-09-04
北京华睿鼎信科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] So far there is no public report of the formula I diastereomer, so it is necessary to develop the preparation method of the formula I diastereomer, obtain the impurity reference substance and the impurity reference substance for detecting the impurity reference substance in the API. The detection method of impurity, one object of the present invention is to provide formula I diastereomer impurity, another object of the present invention is to provide the preparation method of formula I diastereomer, still another object of the present invention is to provide The diastereoisomers of formula I are used as impurity reference substances in the inspection of related substances in the quality control link in the production process of tenofovir alafenamide, and then used for tenofovir alafenamide and its Salt Quality Control

Method used

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  • Tenofovir alafenamide diastereoisomer, preparation method and application of diastereoisomer

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preparation example Construction

[0049] The preparation of embodiment 1 formula I diastereoisomer

[0050] Step 1: Preparation of formula 2 compound

[0051] Add 6g of commercially available compound of formula 1, 3.9g of phenol, 50g of acetonitrile, 4.6g of triethylamine and 10g of dicyclohexylcarbodiimide into a 250mL reaction flask, and react at 70°C for 18h. After adding water to quench, filter, and extract the filtrate with ethyl acetate 2-3 times. Collect the aqueous phase and adjust the aqueous solution to about 3.0 with hydrochloric acid, stir and crystallize for about 2 hours, filter, and dry to obtain 3.7 g of the brown yellow compound of formula 2.

[0052] Step 2: Preparation of formula I diastereoisomers

[0053] Add 3g of compound of formula 2, 25g of acetonitrile, and 2.8g of thionyl chloride into a 100mL reaction flask, heat to 85°C for 6 hours, evaporate to dryness under reduced pressure, add 25g of acetonitrile, and dropwise add 3.2g of D- A solution of isopropyl alanine dissolved in 20 g...

Embodiment 2

[0056] Example 2 The external standard method in high performance liquid chromatography detects the content of optical isomers in tenofovir alafenamide High performance liquid chromatography: Shimadzu 2030C

[0057] Column: Waters, Shield RP18, 4.6×150mm, 3.5μm

[0058] Mobile phase: mobile phase A is 0.02mol / L potassium dihydrogen phosphate buffer (pH6.0)-[tetrahydrofuran-acetonitrile (7:3)] (99:1), mobile phase B is 0.02mol / L dihydrogen phosphate Potassium buffer (pH6.0)-[tetrahydrofuran-acetonitrile (7:3)] (50:50), eluted according to the gradient elution program in Table 1.

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Abstract

The invention relates to a tenofovir alafenamide diastereomer as shown in a formula I. The invention also relates to a preparation method of the tenofovir alafenamide diastereoisomer as shown in the formula I, and application of the tenofovir alafenamide diastereomer in detection of purity of the tenofovir alafenamide and salt thereof, detection of content of optical isomers in the tenofovir alafenamide and salt thereof, and quality control in production or preparation of the tenofovir alafenamide and salt thereof. The tenofovir alafenamide diastereomer disclosed by the invention has importantsignificance for quality monitoring and standard research in industrial production of tenofovir alafenamide.

Description

technical field [0001] The present invention relates to a kind of diastereoisomer, specifically, the present invention relates to a kind of tenofovir alafenamide diastereomer as shown in formula I (hereinafter referred to as formula I diastereomer) Construct). The present invention also relates to the preparation and use of said diastereoisomers of formula I. Background technique [0002] Tenofovir Alafenamide Fumarate (TAF), chemical name 9-((R)-2-(((S)-(((S)-1-isopropoxycarbonyl- 1-oxopropyl-2-yl)amino)(phenoxy)phosphono)methoxy)propyl)-9H-purin-6-amine fumarate, is a novel nucleotide reverse transcription Enzyme inhibitors. Developed by Gilead and approved by FDA in 2016 (trade name: Vemlidy, specification 25mg, dosage form is tablet), it is used to treat HIV infection and hepatitis B in adults. [0003] Tenofovir alafenamide fumarate (TAF) is a prodrug of tenofovir, which is hydrolyzed into tenofovir in the body and then phosphorylated by cellular enzymes to form ten...

Claims

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Application Information

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IPC IPC(8): C07F9/6561G01N30/06
CPCC07F9/65616G01N30/06
Inventor 安明常珍魏俊明祝江业况斌张婵娟吕宁郎昌野蔡琳刘爱民
Owner 北京华睿鼎信科技有限公司
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