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Process method of synthesizing tenofovir alafenamide

A technology of tenofovir alafenamide and process method, which is applied in the field of tenofovir alafenamide synthesis, can solve the problems of harsh reaction conditions, difficult process, cumbersome post-processing, etc., and achieve short reaction time , high purity, simple processing effect

Inactive Publication Date: 2017-07-07
JIANGSU CHENGXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the prior art, the reaction conditions for synthesizing tenofovir alafenamide are harsh, the process is difficult, the yield is low, and the post-treatment is cumbersome

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] A process method for synthesizing tenofovir alafenamide, including the following steps:

[0048] A. Synthesis of TAF-1

[0049] 1) Add 1.0 equivalent of (R)-9-(2-phosphate methoxypropyl)-adenine, 5 to 6 times the amount of acetonitrile, 0.8 to 1.5 equivalents of 4-dimethylaminopyridine, and triethylamine into the reactor 1.0-2.0 equivalents, 1.0-2.0 equivalents of triphenyl phosphite, heated to 50-80°C, stirred for 48 hours, and monitored the reaction by high pressure liquid chromatography;

[0050] 2) After the reaction is completed, concentrate under reduced pressure at 30~50℃ until no dripping, add 2 to 3 times the amount of ethyl acetate, add 3 to 5 times the amount of drinking water, separate the liquids, use 2 to 3 times the amount of ethyl acetate for the water phase ,extraction;

[0051] 3) Adjust the pH to 2~4 with concentrated hydrochloric acid, stir for 2~3h, filter, and rinse with 2-3 times the amount of water;

[0052] 4) Dry at 40~70℃ for 20h to obtain white solid...

Embodiment 2

[0070] Example 2: Synthesis of TAF-1

[0071] 1. Add (R)-9-(2-phosphate methoxypropyl)-adenine 100g, 1.0 equivalent, acetonitrile 500g, triethylamine 108g, 1.5 equivalent, 4-dimethylaminopyridine 85g, 1.0 into the flask Equivalent, 324g triphenyl phosphite, 1.5 equivalent, stirred for 48h, HPLC monitored the reaction;

[0072] 2. Concentrate under reduced pressure at 35-40°C until no dripping, add 300g ethyl acetate, add 400g deionized water, separate the layers, and extract the aqueous phase twice with 200g ethyl acetate;

[0073] 3. Adjust the pH to 2.0~3.0 with 12M HCl, cool to 0-5℃ and stir for 3h;

[0074] 4. Filter and rinse the filter cake with cold water (100g) twice;

[0075] 5. Put it in a blast oven at 50-60℃ and dry for 20h to obtain 110.2g of TAF-1 dry product, HPLC: 98.5%, yield 87.1%.

Embodiment 3

[0076] Example 3: Synthesis of TAF-1

[0077] 1. Add (R)-9-(2-phosphate methoxypropyl)-adenine 100g, 1.0 equivalent, acetonitrile 500g, triethylamine 108g, 1.5 equivalent, 4-dimethylaminopyridine 85g, 1.0 into the flask Equivalent, 324g triphenyl phosphite, 1.5 equivalent, stirred for 48h, HPLC monitored the reaction;

[0078] 2. Concentrate under reduced pressure at 35-40°C until no dripping, add 300g of ethyl acetate, add 400g of deionized water, separate the liquids, and extract the water phase with 200g of ethyl acetate for 2 times;

[0079] 3. Adjust the pH to 2.0~3.0 with 12M HCl, cool to 0~5℃ and stir for 3h;

[0080] 4. Filter and rinse the filter cake twice with 100g cold water;

[0081] 5. Put it in a blast oven at 50~60℃ and dry for 20 hours to obtain 105.0g of TAF-1 dry product, HPLC: 98.9%, yield 83.0%.

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PUM

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Abstract

The invention provides a process method of synthesizing tenofovir alafenamide. The tenofovir alafenamide is finally obtained through esterification, acylating chlorination, amidation and chiral splitting by taking (R)-9-(2-methoxyl propyl phosphate) adenine as an initial raw material. The process method provided by the invention is low in process cost, mild in reaction condition and simple and controllable in operating method, avoids use of a lot of toxic reagents, and is good in environment-friendly safety and stable in product quality.

Description

Technical field [0001] The invention relates to a process method for synthesizing tenofovir alafenamide, and belongs to the technical field of medicine and its intermediates. Background technique [0002] Tenofovir alafenamide fumarate (TAF) is a new type of nucleoside reverse transcriptase inhibitor (NRTI). In clinical trials, the drug has been proven to be lower than Gilead’s marketed drug Viread (Tenofovir disoproxil fumarate tablets, Viread, TDF) At one-tenth the dose, it has a very high antiviral effect and can improve kidney function and bone parameters. [0003] Synthetic route in the prior art: (R)-propylene oxide (4) is used as raw material, and (R)-propylene carbonate (5) is obtained by coupling with carbon dioxide catalyzed by a highly active zinc reagent, and then condensed with adenine to obtain the key Intermediate: (R)-9-(2-hydroxypropyl) adenine, which is compatible with 9-[(R)-2-[[bis-(isopropoxycarbonyl)oxy]methoxy]oxy Phosphine] methoxy] propyl] adenine is furt...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor 李二军祝俊吴锋华俊国许昇
Owner JIANGSU CHENGXIN PHARMA
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