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Preparation method of tenofovir alafenamide

A technology of tenofovir alafenamide and phenol, which is applied in the field of preparation of tenofovir alafenamide, can solve the problem of no large-scale supply of starting materials, achieve low cost, avoid operating procedures, The effect of simplifying the reaction steps

Active Publication Date: 2017-05-10
安庆多辉生物科技有限公司
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

This method has certain reference significance, but the starting material (1) does not have a large-scale supply, and needs to be synthesized through two-step reactions

Method used

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  • Preparation method of tenofovir alafenamide
  • Preparation method of tenofovir alafenamide
  • Preparation method of tenofovir alafenamide

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preparation example Construction

[0038] see figure 1 , a kind of preparation method of tenofovir alafenamide, concrete steps are as follows:

[0039] (1) PMPA is heated and reacted with chlorination reagents to obtain PMPA-2Cl; the chemical reaction formula is as follows:

[0040] (1);

[0041] (2) PMPA-2Cl was reacted with phenol and L-alanine isopropyl ester successively to obtain TAF-RS through a one-pot method; the chemical reaction formula is as follows:

[0042] (2);

[0043] (3) TAF-RS is purified to obtain tenofovir alafenamide; the chemical reaction formula is as follows:

[0044] (3).

[0045] The step (1) is reacted in an organic solvent or a solvent-free system; the organic solvent is acetonitrile, toluene or benzene.

[0046] The chlorination reagent can be selected from one of thionyl chloride, phosphorus trichloride, non-chlorinated phosphorus, and oxalyl chloride; further, preferably thionyl chloride;

[0047] The one-pot method in the step (2) is to react PMPA-2Cl with phenol in t...

Embodiment 1

[0052] A kind of preparation method of tenofovir alafenamide, concrete steps are as follows:

[0053] (1) PMPA is heated and reacted with chlorination reagents to obtain PMPA-2Cl; the chemical reaction formula is as follows:

[0054] (1);

[0055] Add PMPA (5g, 17.8mmol) to 25ml of acetonitrile, add thionyl chloride 10ml at room temperature, stir and heat up to reflux reaction for 2 hours, the solid in the system dissolves, sample is added to anhydrous methanol to monitor the complete conversion of raw materials ; The reaction solution is concentrated under reduced pressure, and the removal of solvent to obtain the foamy solid PMPA-2Cl weighs 6.5g;

[0056] (2) PMPA-2Cl was reacted with phenol and L-alanine isopropyl ester successively to obtain TAF-RS through a one-pot method; the chemical reaction formula is as follows:

[0057] (2);

[0058] Add 60ml of dichloromethane, 5g of PMPA-2Cl and 5.6g (55.2mmol) of triethylamine into a clean 250ml three-necked flask. After t...

Embodiment 2

[0063] A kind of preparation method of tenofovir alafenamide, concrete steps are as follows:

[0064] (1) PMPA is heated and reacted with chlorination reagents to obtain PMPA-2Cl; the chemical reaction formula is as follows:

[0065] (1);

[0066] PMPA (5g, 17.8mmol) was added to 20ml of thionyl chloride, stirred and heated to reflux for 1.5 hours. After the reaction, the solid in the system was dissolved, and samples were added to anhydrous methanol to monitor the complete conversion of raw materials. The reaction solution was concentrated to dryness under reduced pressure to obtain a foamy solid PMPA-2Cl, weighing 6.7 g;

[0067] (2) PMPA-2Cl was reacted with phenol and L-alanine isopropyl ester successively to obtain TAF-RS through a one-pot method; the chemical reaction formula is as follows:

[0068] (2);

[0069] Add 60ml of dichloromethane, 5g of PMPA-2Cl and 5.6g (55.2mmol) of triethylamine into a clean 250ml three-necked flask. After the addition, stir and cool...

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Abstract

The invention discloses a preparation method of tenofovir alafenamide. The preparation method comprises the following specific steps: carrying out heating reaction on PMPA and a chlorination agent to obtain PMPA-2Cl; enabling the PMPA-2Cl to react with phenol and L-alanine isopropyl ester in sequence through a one pot method to obtain TAF-RS; purifying the TAF-RS to obtain the tenofovir alafenamide, wherein the chlorination agent is one of sulfoxide chloride, phosphorus chloride, phosphorus pentachloride and oxalyl chloride; the one pot method is to enable the PMPA-2Cl to react with the phenol first in an organic solvent under a condition of -30 to -20 DEG C under existence of organic alkali, and then add the L-alanine isopropyl ester for reaction. According to the synthesis process provided by the invention, the complicated operation process is avoided, the reaction steps are simplified; furthermore, as the raw materials are readily available, the reactions are mild, and the cost is relatively low, the preparation method is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of tenofovir alafenamide. Background technique [0002] Tenofovir disoproxil fumarate (TDF) {9-R-[(2-phosphonomethoxy)propyl]adenine} is a potent in vitro and in vivo inhibitor of human immunodeficiency virus type 1 (HIV-1) replication agent, a nucleotide antiviral drug. It can not only inhibit the synthesis of enzymes required for virus replication, but also participate in the competition as a substrate analog, incorporate into the DNA of the virus replication, block the extension of the DNA chain, and thereby inhibit the replication of the virus. Antiviral drugs have become one of the eye-catching drugs in the global pharmaceutical market. [0003] Tenofovir alafenamide fumarate (TAF) is a newer generation tenofovir (TFV) prodrug than tenofovir disoproxil fumarate (TDF). Clinical data show that: TAF dose is 10 times smaller than TDF and has the sa...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor 赵跃陈力谭学优袁利
Owner 安庆多辉生物科技有限公司
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