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Preparation method and application of process impurity of tenofovir alafenamide fumarate

A technology of fumarate and propionate, which is applied in the field of drug synthesis and can solve the problems of no process impurity reports

Inactive Publication Date: 2019-08-06
BEIJING CREATRON INST OF PHARMA RES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, no process impurities have been reported for this route

Method used

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  • Preparation method and application of process impurity of tenofovir alafenamide fumarate
  • Preparation method and application of process impurity of tenofovir alafenamide fumarate
  • Preparation method and application of process impurity of tenofovir alafenamide fumarate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Example 1: (S)-isopropyl 2-(((R,S)-((((R)-1-(6-amino-9H-9-purinyl)-2-propyl)oxy) Synthesis of methyl)(methoxy)phosphinyl)amino)propionate.

[0081] Add 50ml of methanol and 10ml of purified water to a 250ml three-necked flask, and add 5.92g of 9-[(R)-2-[[(R,S)-[[(S)-1-(isopropoxycarbonyl) under stirring Ethyl] amino] phenoxyphosphinyl] methoxy] propyl] adenine fumarate (TAF-3), under nitrogen protection, cool down to 10-20°C, add 1.20g of NaOH, complete addition, stir overnight. Add 100ml of dichloromethane, 50ml of purified water, separate the liquids, collect the organic phase, and distill under reduced pressure to obtain a solid crude product, which will be purified by column chromatography. The elution ratio is: methanol:dichloromethane=1:20, collect The eluent was 230ml in total, temperature controlled at 30-40°C, vacuum degree: -0.08MPa, distilled under reduced pressure, and the solvent was distilled until no distillate was distilled to obtain 0.67g of yellow oi...

Embodiment 2

[0082]Example 2: (S)-isopropyl 2-(((R,S)-((((R)-1-(6-amino-9H-9-purinyl)-2-propyl)oxy) Separation of methyl)(methoxy)phosphinyl)amino)propionate

[0083] 0.67g (S)-isopropyl 2-(((R,S)-((((R)-1-(6-amino-9H-9-purinyl)-2-propyl)oxy)methyl Base) (methoxy)phosphinyl)amino)propionate was added to 50ml of ethanol for dissolution, and the sample was separated by supercritical fluid chromatography (model: MD-2018Plus). Column model: DAICEL CHIRALCEL AS-H (0.46cm I.D.x 25cm L), column temperature 35°C, detection wavelength: 220nm, injection concentration: 20mg / ml, CO 2 / EtOH=70 / 30, flow rate 2.0ml / min, time 10 minutes. After separation, the collected liquids were combined, controlled at a temperature of 30-40°C, vacuum: -0.08MPa, distilled under reduced pressure, and distilled off the solvent until no distillate was distilled to obtain 300.3 mg of (S)-isopropyl 2-(((S) -((((R)-1-(6-amino-9H-9-purinyl)-2-propyl)oxy)methyl)(methoxy)phosphinyl)amino)propionate (compound B free base), o...

Embodiment 3

[0084] Example 3: (S)-isopropyl 2-(((R)-((((R)-1-(6-amino-9H-9-purinyl)-2-propyl)oxy)methyl ) Synthesis of (methoxy)phosphinyl)amino)propionate fumarate (compound A).

[0085] Add 10ml of acetonitrile to a 50ml three-necked flask, and add 300.3mg of (S)-isopropyl 2-(((R)-((((R)-1-(6-amino-9H-9-purine Base)-2-propyl)oxy)methyl)(methoxy)phosphinyl)amino)propionate, 84.1mg fumaric acid, under nitrogen protection, heated to reflux, and kept stirring for 2 hours. Control the temperature at 30-40°C, vacuum degree: -0.08MPa, distill under reduced pressure, and distill off the solvent until no distillate is distilled to obtain Compound A, 345.7 mg of white powder, yield: 89.94%. 1 H-NMR (400Mz, DMSO-d 6 )δ: 13.146 (br, s, 2H), 8.141 (s, 1H), 8.097 (s, 1H), 7.201 (br, s, 2H), 6.638 (s, 2H), 5.092 (dd, J=10.4Hz , J=21.6Hz, 1H), 4.890~4.874(m, 1H), 4.249~4.184(m, 2H), 3.949~3.908(m, 1H), 3.783~3.728(m, 2H), 3.672~3.645(m , 1H), 3.461(d, J=10.8Hz, 3H), 1.209(d, J=7.2Hz, 3H), 1.170(d, ...

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Abstract

The present invention relates to a process impurity of tenofovir levamide amine fumarate 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine hemifumarate, and a preparation method thereof. The impurity is selected from a compound A (S)- isopropyl-2-(((R)-((((R)-1-(6-amino-9H-9-purinyl)-2-propyl)oxy)methyl)(methoxy)phosphinyl)amino)propanoate fumarate andthe like.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and relates to process impurities in the production process of raw materials and their preparation, in particular to the process impurities of tenofovir alafenamide fumarate and a preparation method thereof. Background technique [0002] Hepatitis B has become a global public health problem. About 2 billion people in the world have been infected with hepatitis B virus (HBV), and 500,000 to 700,000 people die each year from liver failure, cirrhosis, and hepatocellular carcinoma caused by HBV infection. The number of people with chronic hepatitis B virus infection in my country is about 130 million. Studies have shown that a large number of patients in my country die each year due to acute or chronic hepatitis B. [0003] At present, the key to the treatment of this disease is still antiviral treatment, and antiviral drugs are divided into two categories, namely nucleosides and interferons,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561G01N30/02G01N30/06G01N30/54G01N30/36
CPCC07B2200/07C07F9/65616G01N30/02G01N30/06G01N30/36G01N30/54G01N2030/027G01N2030/062G01N2030/065
Inventor 贾慧娟陈岩任晓慧武凯洋
Owner BEIJING CREATRON INST OF PHARMA RES CO LTD
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