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Preparation method of fumaric acid tenofovir alafenamide

A technology of tenofovir fumarate and alafenamide, which is applied in the field of medicine and can solve problems such as affecting product yield and difficulty in purification

Active Publication Date: 2018-08-17
科兴生物制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] In the patent CN107522743, tenofovir alafenamide fumarate needs multiple refinements to improve the chemical purity, and there are technical difficulties that are difficult to purify, and multiple refinements affect the product yield

Method used

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  • Preparation method of fumaric acid tenofovir alafenamide
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  • Preparation method of fumaric acid tenofovir alafenamide

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preparation example Construction

[0032] In order to solve the above-mentioned technical problems, the invention provides a kind of preparation method of tenofovir alafenamide fumarate, comprising the following steps:

[0033] (1) Esterification: add acid-binding agent, (R)-tenofovir, triphenyl phosphite, the first organic solvent into the reactor, reflux reaction for 60-80h, after the reaction is over, concentrate under reduced pressure to remove the first Organic solvent, cool the residue to room temperature, add water, ethyl acetate, stir to dissolve, separate layers, extract the water phase with ethyl acetate, adjust the pH value of the water phase to 2-3 with concentrated hydrochloric acid, cool down and crystallize, filter, and use Rinse with dilute hydrochloric acid with a mass fraction of 1%, then stir with dichloromethane at room temperature, filter, rinse with dichloromethane, and dry under atmospheric pressure to obtain TAF-1;

[0034] (2) Halogenation: under the protection of inert gas, add TAF-1 a...

Embodiment 1

[0070] The preparation method of tenofovir alafenamide fumarate comprises the following steps:

[0071] (1) Esterification: add acid-binding agent, (R)-tenofovir, triphenyl phosphite, the first organic solvent into the reactor, reflux reaction for 70h, after the reaction is over, concentrate under reduced pressure to remove the first organic solvent , the residue was cooled to room temperature, added water, ethyl acetate, stirred to dissolve, layered, the aqueous phase was extracted with ethyl acetate, and the aqueous phase was adjusted to a pH value of 2-3 with concentrated hydrochloric acid with a mass fraction of 36%, cooling and crystallization , filtered, rinsed with dilute hydrochloric acid with a mass fraction of 1%, then stirred at room temperature with dichloromethane (the (R)-tenofovir and the first organic solvent, the water, the ethyl acetate , the weight ratio of the dichloromethane is 1:9:3:8:7), filtered, washed with dichloromethane, and air-dried at normal pres...

Embodiment 2

[0077] The preparation method of tenofovir alafenamide fumarate comprises the following steps:

[0078] (1) Esterification: add acid-binding agent, (R)-tenofovir, triphenyl phosphite, the first organic solvent into the reactor, reflux reaction for 70h, after the reaction is over, concentrate under reduced pressure to remove the first organic solvent , the residue is cooled to room temperature, add water, ethyl acetate, stir to dissolve, separate layers, extract the water phase with ethyl acetate, adjust the pH value of the water phase to 2-3 with concentrated hydrochloric acid with a mass fraction of 36%, cool down and crystallize , filtered, rinsed with dilute hydrochloric acid with a mass fraction of 1%, then stirred at room temperature with dichloromethane (the (R)-tenofovir and the first organic solvent, the water, the ethyl acetate , the weight ratio of the dichloromethane is 1:9:3:8:7), filtered, washed with dichloromethane, and air-dried at normal pressure to obtain TAF...

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Abstract

The invention provides a preparation method of fumaric acid tenofovir alafenamide. By esterification reaction, halogenating reaction, condensation reaction, refining and salt forming reaction, the fumaric acid tenofovir alafenamide which is high in yield, easy to purify and suitable for industrial mass production is obtained.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular, the invention relates to a preparation method of tenofovir alafenamide fumarate. Background technique [0002] Tenofovir alafenamide fumarate was launched in the United States in November 2016 for the treatment of adult patients with chronic hepatitis B (HBV) infection; it was approved for marketing in Japan in December 2016, and the indication is to inhibit chronic hepatitis B patients Viral replication in patients with hepatitis B virus replication activity and abnormal liver function; in January 2017, it was approved for marketing in 28 EU member states, Norway and Iceland, for adults and adolescents (age ≥ 12 years) with chronic hepatitis B (HBV) age and body weight ≥ 35 kg) infected persons. [0003] The chemical name of tenofovir alafenamide fumarate (TAF) is 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl ) ethyl] amino] phenoxyphosphinyl] methoxy] propyl] adenine fumarate, is...

Claims

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Application Information

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IPC IPC(8): C07F9/6561C07C51/41C07C57/15
CPCC07C51/412C07F9/65616C07C57/15
Inventor 郝志海仇渡先张允王翠翠崔宁
Owner 科兴生物制药股份有限公司
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