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Preparation method of TAF (tenofovir alafenamide fumarate) nucleoside derivative and intermediate of TAF nucleoside derivative

A volume and compound technology, applied in the field of preparation of TAF nucleoside derivatives and its intermediates, can solve the problems of large environmental pollution, low yield, harsh reaction conditions, etc.

Active Publication Date: 2017-08-08
FUJIAN COSUNTER PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] The technical problem to be solved by the present invention is to overcome the harsh reaction conditions, low yield, However, it provides a new preparation method with mild environmental pollution, mild reaction conditions, less side reactions, high yield, and less environmental pollution, and is suitable for industrial production.

Method used

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  • Preparation method of TAF (tenofovir alafenamide fumarate) nucleoside derivative and intermediate of TAF nucleoside derivative
  • Preparation method of TAF (tenofovir alafenamide fumarate) nucleoside derivative and intermediate of TAF nucleoside derivative
  • Preparation method of TAF (tenofovir alafenamide fumarate) nucleoside derivative and intermediate of TAF nucleoside derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] The preparation of embodiment 1 compound III

[0036]

[0037] Put IV (100g, 0.348mol) in a 2L three-neck flask, add thionyl chloride (1L) under nitrogen protection, heat to an external temperature of 70 degrees and reflux for overnight reaction. TLC shows that the reaction is complete, and the solvent is directly evaporated to dryness to obtain V The crude product of light yellow solid 110g (0.341mol, yield 97.9%).

[0038]

[0039] Put 100g (0.310mol) of the crude product of V in a 2L three-neck flask, add anhydrous acetonitrile (1L) under nitrogen protection, stir to dissolve and cool to 0°C, add phenol (116g, 1.23mol), slowly rise to 25°C Reacted for 16 hours, TLC showed that the reaction was complete, quenched the reaction with saturated sodium bicarbonate solution, extracted and separated layers with dichloromethane, washed the organic phase with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness, and washed...

Embodiment 2

[0042] Embodiment 2R is methyl

[0043]

[0044] Put compound (R)-9-(2-diphenoxyphosphomethoxypropyl)adenine (III) 100g (0.228mol) in a 2L three-necked flask, add anhydrous acetonitrile (1L) under nitrogen protection , stirred to dissolve and cooled to 0 degrees, added methanol (20g), slowly rose to 25 degrees Celsius for 16 hours, TLC showed that the reaction was complete, saturated sodium bicarbonate solution quenched the reaction, dichloromethane extraction layered, organic phase with saturated chlorine Wash with sodium chloride, dry over anhydrous magnesium sulfate, filter and evaporate the solvent to obtain 83 g (0.220 mol, yield 96.6%) of the desired product II-1.

[0045] Characterization data NMR (400MHz,d 6 -DMSO):8.13(s,1H),8.11(s,1H),7.55(br,2H),7.25(m,2H),7.08(m,1H),7.03(m,2H),4.22(m, 2H), 3.95(br,1H), 3.75(m,3H), 1.02(br,3H).

Embodiment 3

[0046] The preparation of embodiment 3 compound I

[0047]

[0048] Put 83g (0.220mol) of II-1 in a 2L three-neck flask, add 1.35L of 1,4-dioxane, 1M potassium hydroxide aqueous solution (350mL, 0.35mol), stir at 25°C for 3 hours, TLC shows After the reaction is complete, add water (350mL) and extract twice with ethyl acetate (350mL). The aqueous phase is adjusted to pH=2-3 with concentrated hydrochloric acid, and solid I is precipitated. Filter, wash the filter cake with 2N hydrochloric acid, and dry it in an oven at 60 degrees. I was obtained (78 g, 0.215 mol, yield 97.7%).

[0049] Characterization data NMR (400MHz,d 6-DMSO):8.13(s,1H),8.11(s,1H), 7.55(br,2H),7.25(m,2H),7.08(m,1H),7.03(m,2H),4.22(m, 2H), 3.95(br,1H), 3.75(m,3H), 1.02(br,3H).

[0050] ESI-MS[M+H] + :364.14

[0051] Embodiment 4R is ethyl

[0052]

[0053] Put compound (R)-9-(2-diphenoxyphosphomethoxypropyl)adenine (III) 100g (0.228mol) in a 2L three-necked flask, add anhydrous acetonitrile (1L) u...

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Abstract

The invention discloses a preparation method of a TAF (tenofovir alafenamide fumarate) nucleoside derivative and an intermediate of the TAF nucleoside derivative. The method comprises the steps that in a solvent of a compound II, in the presence of alkali, stirring is performed until the reaction is completed, and a required compound I is obtained. Compared with the prior art, the preparation method has the advantages that the raw materials are cheap and are easily obtained; the reaction conditions are mild; the side reactions are few; the yield is high; the environment pollution is little; the preparation method is applicable to industrial production; a new path is provided for the preparation of the TAF key intermediate. The formulas are shown in the specification.

Description

technical field [0001] The invention relates to a preparation method of an important intermediate of tenofovir alafenamide fumarate and an intermediate thereof. Background technique [0002] Tenofovir alafenamide fumarate (tenofovir alafenamide fumarate), abbreviated as TAF, chemical name is 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxy Carbonyl) ethyl] amino] phenoxyphosphinyl] methoxy] propyl] adenine fumarate is a novel nucleotide reverse transcriptase inhibitor. [0003] [0004] The compound was developed by Gilead Sciences of the United States and launched in the United States in 2015 for the treatment of HIV infection in adults. The drug is also used to treat hepatitis B and is currently in Phase III clinical trials. This product is rapidly transformed into tenofovir after oral administration, and is phosphorylated into tenofovir diphosphate under the action of cellular kinases, which inhibits viral polymerase and inserts into the virus by competitively combining with natur...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
CPCC07F9/6561
Inventor 吴文强汤漾徐志刚吴晓峰应律李国栋
Owner FUJIAN COSUNTER PHARMA CO LTD
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