Synthesis method of potential impurities in production of tenofovir alafenamide hemifumarate

A technology for amides and compounds, applied in the field of synthesis of potential impurities, can solve problems such as no literature reports, and achieve the effect of improving production technology and improving product internal control quality

Active Publication Date: 2018-06-01
SHENZHEN KEXING PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Three impurities of tenofovir alafenamide fumarate were reported in CN201510943798: tenofovir alafenamide isopropyl ester impurity (TAF-impurity H), tenofovir alafenamide diphenyl ester impurity (TAF-impurity I), the synthetic method of tenofovir alafenamide diamide impurity (TAF-impurity J), but the synthesis route and the preparation method of TAF-impurity A~F impurity are still not seen in the literature so far

Method used

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  • Synthesis method of potential impurities in production of tenofovir alafenamide hemifumarate
  • Synthesis method of potential impurities in production of tenofovir alafenamide hemifumarate
  • Synthesis method of potential impurities in production of tenofovir alafenamide hemifumarate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Embodiment 1, synthetic TAF-impurity A

[0065]

[0066] Add 120ml of tetrahydrofuran to a 500ml reaction flask, add 9-[(R)-2-[[(S)-[[(S)-1-(tert-butyloxycarbonyl)ethyl]amino]phenoxyoxy Phosphino]methoxy]propyl]adenine 10g was added dropwise to a tetrahydrofuran solution of 2 mol / L sodium bis(trimethylsilyl)amide, the reaction was monitored by TLC, and the reaction was quenched by acetic acid. Tetrahydrofuran was concentrated under reduced pressure and purified by column chromatography with V dichloromethane:V methanol at 2:1 to obtain a white solid impurity 9-[(R)-2-[[(S)-[[(S)-1-propane Acid] amino] phenoxyphosphinyl] methoxy] propyl] adenine (TAF-impurity A) 6.0 g, yield 68%, purity greater than 98%.

[0067] Structural Confirmation Data:

[0068] TAF-impurity A mass spectrum data: m / z M+1:435.2[C18H23N6O5P+].

[0069] NMR data: H NMR (400MHz, d6-DMSO)

[0070] δ10.92(brs,1H),δ8.22(s,1H),δ8.16(s,1H),δ7.36-7.32(t,4H),δ7.18-7.16(t,1H),

[0071] δ7.09-7.07(d,2H)...

Embodiment 2

[0073] Embodiment 2, synthetic TAF-impurity B

[0074]

[0075] Add 500ml of toluene to a 1L reaction flask, add 50g of 9-[(R)-2-[[(phenoxyphosphinyl)methoxy]propyl]adenine and raise the temperature to 90°C to reflux and divide water until no Obvious moisture comes out, slowly add 30g of thionyl chloride dropwise, keep warm at 80°C for 20 hours, concentrate under reduced pressure until no obvious fraction comes out, cool down to room temperature under nitrogen protection, add 200ml of dichloromethane, stir and disperse, transfer to the dropping funnel stand-by.

[0076] Add 2000ml of dichloromethane into a 5L reaction flask, add 100g of N-benzyloxycarbonyl-L-alanine-N-hydroxysuccinimide ester, cool to -15°C under nitrogen protection, and slowly add chloride , DBU was added dropwise, and the reaction was completed at room temperature for 20 hours. Add 10% aqueous solution of sodium dihydrogen phosphate, let the saturated sodium chloride solution stand for stratification, c...

Embodiment 3

[0081] Embodiment 3, synthesis TAF-impurity C, TAF-impurity D, TAF-impurity E

[0082]

[0083] Add 500ml of toluene to a 1L reaction flask, add 50g of tenofovir and raise the temperature to 90°C to reflux and divide the water until no obvious water comes out, slowly add 30g of thionyl chloride dropwise, keep warm at 80°C for 20 hours, and decompress Concentrate until no obvious fraction comes out, then cool down to room temperature under nitrogen protection, add 200ml of dichloromethane, stir and disperse for later use.

[0084] Add 500ml of dichloromethane into a 3L reaction flask, add 32g of L-alanine isopropyl hydrochloride and 40g of potassium bicarbonate, add 50g of anhydrous sodium sulfate to free at room temperature for 4 hours, filter and drain, under nitrogen protection Cool to -15°C, slowly add triethylamine and the above-mentioned chlorinated compound, keep warm for reaction after adding, and monitor the completion of the reaction by TLC. Add 10% aqueous soluti...

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PUM

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Abstract

The invention discloses a preparation method of potential impurities and degradation impurities in the production technology of tenofovir alafenamide hemifumarate. Illustrating the impurity spectrogram of the tenofovir alafenamide hemifumarate plays a guiding role in improving the production technology and enhancing the internal control quality of the product.

Description

technical field [0001] The invention relates to a method for synthesizing potential impurities in the production of tenofovir alafenamide hemifumarate. Background technique [0002] Tenofovir alafenamide (TAF, GS-7340) is an RNA-dependent DNA polymerase inhibitor and an oral prodrug of tenofovir (TFV). Similar to tenofovir disoproxil, TAF is converted into TFV in cells and is currently mainly used to treat AIDS, and has shown good anti-HBV efficacy in phase III clinical trials. Because the clinical dosage is much lower than TDF, it greatly reduces the serious adverse reactions caused by long-term administration of TDF, and can improve renal function and bone safety parameters, so it is widely favored. The prospect of long-term or even life-long anti-HIV should not be underestimated. [0003] According to Birkus et al., 2016. Intracellular Activation of Tenofovir Alafenamide and the Effect of Viral and Host Protease Inhibitors. AntimicrobAgents Chemother 60:316-322 and A.S.R...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor 吴聪泉马鸿杰张浩杨文杰
Owner SHENZHEN KEXING PHARM CO LTD
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