Preparation method of tenofovir alafenamide hemifumarate

A technology of tenofovir alafenamide and hemi-fumarate, which is applied in the preparation of carboxylate, the preparation of carboxylate, the preparation of organic compounds, etc. Problems such as poor operability, to avoid process operation and purification methods, to achieve the effect of accurate ratio and precise control

Inactive Publication Date: 2018-03-13
YANGTZE RIVER PHARM GRP CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, in the patent reported by the original research company, there is a purification process using simulated fluidized bed chromatography technology for chiral separation of phosphorus, but its equipment dependence is large, operability is poor, cost is high, and it is not conducive to large-scale industrial production

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] The preparation of formula TAF-M1 compound

[0039] Add 4L of acetonitrile to the 10L reaction flask, then add TAF-SM1 (500g), DMAP (213g), Et 3 N (352g), triphenyl phosphite (810g), heat up to 70-80°C for reflux reaction for 65-72 hours after addition; 30°C), add water (2000g) and EA (1500ml), stir to dissolve, separate layers, extract the water phase with 1500ml*3 EA three times, adjust the pH value of the water phase to 1-2 (about 160°C) with concentrated hydrochloric acid at 20-30°C -170ml), stirred for 30 minutes, cooled to 0-10 to crystallize for 1-2 hours after the solid was precipitated, filtered, rinsed with 1% dilute hydrochloric acid (0-10°C), filtered and dried, and the wet cake was beaten with 1.5L of DCM After 2-3 hours, it was filtered and air-dried at normal pressure for 24-30 hours, and 474 g of white solid was collected, namely the compound of formula TAF-M1, with a purity of more than 98% by HPLC.

Embodiment 2

[0041] The preparation of formula TAF-M2 compound

[0042] Acyl chloride step: 2.4L of toluene was added to a 5L reaction flask, TAF-M1 (400g, prepared according to the method in Example 1) was added, heated to 70-80°C under nitrogen protection, and thionyl chloride (262g ), keep warm at 70-80°C and react for 40-50 hours, control the temperature below 75°C, concentrate under reduced pressure until no obvious fraction comes out, under the protection of nitrogen, cool down to 20-40°C, add 1600ml of dichloromethane, stir and disperse, stand-by;

[0043] Isolation step: Add 2.4L of dichloromethane into a 5L reaction flask, add TAF-SM2 (646g) and potassium bicarbonate (441g) to free at 15-25°C for 5-10 hours, filter, drain, and control the temperature for 30- Concentrate to dryness under reduced pressure at 40°C, and take it twice with 400ml*2 of new dichloromethane, and add 2.4L of new dichloromethane to the residue.

[0044] Reaction steps: Cool to -25~-15°C under nitrogen prot...

Embodiment 3

[0048] The preparation of formula TAF-M2 compound

[0049] Acyl chloride step: 2.4L of chlorobenzene was added to a 5L reaction flask, TAF-M1 (400g, prepared according to the method in Example 1) was added, the temperature was lowered to 70-80°C under nitrogen protection, and thionyl chloride was slowly added dropwise ( 262g), after adding, keep warm at 70-80°C and react for 50-60 hours, control the temperature below 75°C, concentrate under reduced pressure until no obvious fraction comes out, add 400ml of chlorobenzene, concentrate under reduced pressure until no obvious fraction comes out, under nitrogen protection, Cool down to 20-40°C, add 1600ml of dichloromethane, stir to disperse, and set aside;

[0050] Isolation step: Add 2.4L of dichloromethane into a 5L reaction flask, add TAF-SM2 (646g) and potassium bicarbonate (441g) to free at 15-25°C for 5-10 hours, filter, drain, and control the temperature for 30- Concentrate to dryness under reduced pressure at 40°C, and ta...

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Abstract

The invention discloses a preparation method of tenofovir alafenamide hemifumarate. The preparation method comprises the following steps of: reacting tenofovir with triphenyl phosphite under the condition of alkali catalysis to prepare tenofovir phenol ester; preparing tenofovir alafenamide through acylating chlorination and a reaction with L-alanine isopropyl ester; preparing tenofovir alafenamide hemifumarate by a special salt-forming process with fumaric acid. The tenofovir alafenamide hemifumarate prepared by the process is accurate in control of a salt type ratio, and simple in process operation, and avoids complex process operation and purification means such as chiral resolution, the total purity can reach 99% or more, and indexes of related substances are qualified.

Description

technical field [0001] The invention belongs to the field of pharmacy, and specifically relates to a preparation method of tenofovir alafenamide hemifumarate, using tenofovir as a starting material, through the directional synthesis of a special phosphorus chiral atom and unique Salt-forming process to prepare tenofovir alafenamide hemifumarate. Background technique [0002] Hepatitis B virus (HBV) infection is a worldwide epidemic. According to the report of the World Health Organization, about 2 billion people in the world have been infected with HBV, of which 350 million people are chronic HBV infected people, and about 1 million people die of HBV every year. Liver failure and cirrhosis caused by HBV infection. The 2006 national epidemiological survey of hepatitis B showed that the HBsAg carrier rate of the general population aged 1 to 59 in my country was 7.18%, but the HBsAg carrier rate of children under 5 years old was only 0.96%. According to this calculation, ther...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561C07C51/41C07C57/15
CPCC07F9/65616C07C51/412C07C57/15
Inventor 倪海华徐浩宇蔡伟宋亚李浩李连友郝秀斌黄淑萍周崴海阴启明
Owner YANGTZE RIVER PHARM GRP CO LTD
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