Efficient synthesis technology of tenofovir alafenamide

A technology of tenofovir alafenamide and synthesis process, which is applied in the field of high-efficiency synthesis process of antiviral drug tenofovir alafenamide, can solve the problems of difficult condition control, long operation time, cumbersome operation, etc. Achieve the effect of improving yield and purity, less consumption of raw materials, and high chemical purity

Inactive Publication Date: 2019-08-09
石家庄凯赛医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] This process also has the problems of long operation time, cumbersome operation, low yield and difficult condition control, and poor practicability

Method used

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  • Efficient synthesis technology of tenofovir alafenamide
  • Efficient synthesis technology of tenofovir alafenamide
  • Efficient synthesis technology of tenofovir alafenamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] The preparation of compound tenofovir monophenyl ester: anhydrous tenofovir (50.0g, 0.18mol) is stirred with pyridine (500ml) at room temperature to form a turbid solution, adding triphenyl phosphite (162.0g, 0.52mol) , the reaction temperature is 50-115°C; the temperature is raised gradually, the temperature rise range is 5-10°C / hour, and the reaction time is 6 hours. Cool to room temperature, filter, wash the filter cake with acetone (50ml), and dry the filter cake at 60-70°C for 4 hours to obtain 50.7 g of tenofovir monophenyl ester as a white solid, with a yield of 82.5%.

Embodiment 2

[0046] Add 1 equivalent of triphenyl phosphite to the filtered mother liquor in Example 1, and the other operations are the same, and 62.0 g of tenofovir monophenyl ester is prepared, with a yield of 98.0%.

Embodiment 3

[0048] The operation of Example 2 was repeated to obtain 61.4 g of tenofovir monophenyl ester, with a yield of 97.0%.

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PUM

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Abstract

The invention discloses an efficient synthesis technology of tenofovir alafenamide. The efficient synthesis technology comprises the steps that A, tenofovir reacts with triphenyl phosphite under an alkali catalysis condition to prepare tenofovir monophenyl ester, wherein the initial reaction temperature is 50-70 DEG C, the reaction temperature rises according to the gradient of 5-10 DEG C/h, and the total reaction duration is 6-10 h; B, the tenofovir monpohenyl ester is subjected to acylating chlorination to prepare tenofovir phenyl ester phosphoryl chloride; C, the tenofovir phenyl ester phosphoryl chloride is isomerized, then the isomerized tenofovir phenyl ester phosphoryl chloride reacts with an L-alanine isopropyl ester compound to prepare a target compound, wherein methylbenzene andother non-polar solvents are adopted for an isomerization solvent. The prepared tenofovir alafenamide has high purity and high yield, the technology operation is simple, the cost is low, complicated technology operation and purification means like using chiral resolution agents are omitted, and the efficient synthesis technology is very suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a high-efficiency synthesis process of an antiviral drug tenofovir alafenamide. Background technique [0002] Gilead has developed tenofovir alafenamide fumarate (TAF), chemical name 9-[(R)-2-[[(S)-1-[[( S)-(isopropoxycarbonyl) ethyl] amino] phenoxyphosphinyl] methoxy] propyl] adenine fumarate for the treatment of AIDS virus (HIV) infection and hepatitis B virus infection, TAF has been proven to have a very high antiviral effect at a dose lower than 1 / 10 of Gilead's marketed drug tenofovir disoproxil fumarate (TDF), and at the same time reduce the damage to the kidneys and bones. toxic side effect. [0003] At present, four compound drugs containing TAF for the treatment of AIDS have been approved by the US FDA for marketing; in addition, a drug for treating hepatitis B (HBV) with TAF as the active ingredient was also approved for marketing by the US FDA in November ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor 李志安
Owner 石家庄凯赛医药科技有限公司
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