Preparation method of tenofovir dipifuratate

Abstract

The invention provides a preparation method for tenofovir dipifuratate. The tenofovir dipifuratate which is high in yield and easy to purify and is suitable for industrialized mass production is obtained through the reactions of etherifying, hydrolyzing, condensing and refining.

Description

technical field

[0001] The invention relates to the technical field of medicine, in particular, the invention relates to a preparation method of tenofovir disoproxil. Background technique

[0002] Tenofovir is a nucleotide antiviral drug, which is an analogue of adenosine 5'-monophosphate, but its oral absorption is poor, and it is almost not absorbed through the gastrointestinal tract. Tenofovir disoproxil is its ester prodrug, which has water solubility after forming an ester, which improves oral absorption and its uptake by cells. Tenofovir dipivoxil is similar in structure to adefovir dipivoxil, but has the characteristics of good tolerance, low rebound rate after drug withdrawal, and low nephrotoxicity.

[0003] Chronic hepatitis B is one of the most common chronic infectious diseases in my country, and its pathogenic agent is hepatitis B virus. Patients with chronic hepatitis B can progress to liver fibrosis, cirrhosis, decompensated cirrhosis, and HCC.

[0004] The...

Examples

preparation example Construction

[0038] The present invention provides a kind of preparation method of tenofovir disoproxil, and described preparation method comprises the steps:

[0039] S01 etherification: Add (R)-9-(2-hydroxypropyl)adenine and N-methylpyrrolidone in sequence in the reactor, and slowly add magnesium tert-butoxide under constant stirring; after raising the temperature, slowly add Diethyl p-toluenesulfonyloxymethyl phosphate, stop heating after reacting to (R)-9-(2-hydroxypropyl)adenine completely, cool down to room temperature naturally; add acetic acid to the system, adjust under stirring pH value until the reaction system is clarified; then slowly add the above reaction solution into ethyl acetate under rapid stirring, solids are precipitated, stirred, and centrifuged; the filter cake is beaten with 20L dichloromethane, centrifuged, and the filtrate is reduced at a certain temperature Concentrate under pressure without distillate, add cyclohexane to the residue, concentrate until there is ...

Embodiment approach 1

[0073] Embodiment 1. This embodiment provides a kind of preparation method of tenofovir disoproxil, and described preparation method comprises the following steps:

[0074] S01 etherification: Add (R)-9-(2-hydroxypropyl)adenine and N-methylpyrrolidone in sequence in the reactor, and slowly add magnesium tert-butoxide under constant stirring; after raising the temperature, slowly add Diethyl p-toluenesulfonyloxymethyl phosphate, stop heating after reacting to (R)-9-(2-hydroxypropyl)adenine completely, cool down to room temperature naturally; add acetic acid to the system, adjust under stirring pH value until the reaction system is clarified; then slowly add the above reaction solution into ethyl acetate under rapid stirring, solids are precipitated, stirred, and centrifuged; the filter cake is beaten with 20L dichloromethane, centrifuged, and the filtrate is reduced at a certain temperature Concentrate under pressure without distillate, add cyclohexane to the residue, concentra...

Embodiment 1

[0089] Embodiment 1: This embodiment provides a kind of preparation method of tenofovir disoproxil, and described preparation method comprises the following steps:

[0090] S01 etherification: Add 5kg (R)-9-(2-hydroxypropyl)adenine and 20L N-methylpyrrolidone in sequence in the reaction kettle, slowly add 7.5kg magnesium tert-butoxide under uniform stirring, and start heating. After raising the temperature to 70°C, slowly add 10kg of diethyl p-toluenesulfonyloxymethyl phosphate, and the addition is completed in about 30 minutes. Keep the reaction temperature at about 79°C for continuous reaction until (R)-9-(2-hydroxy After the reaction of propyl) adenine is complete, stop heating, and cool to room temperature naturally; add acetic acid to the system, adjust the pH value to 7.0 under stirring, and the stirring reaction system is clarified; then slowly add the above reaction solution to 150L under rapid stirring In ethyl acetate, solids were precipitated, stirred, and centrifug...

technical field

[0001] The invention relates to the technical field of medicine, in particular, the invention relates to a preparation method of tenofovir disoproxil. Background technique

[0002] Tenofovir is a nucleotide antiviral drug, which is an analogue of adenosine 5'-monophosphate, but its oral absorption is poor, and it is almost not absorbed through the gastrointestinal tract. Tenofovir disoproxil is its ester prodrug, which has water solubility after forming an ester, which improves oral absorption and its uptake by cells. Tenofovir dipivoxil is similar in structure to adefovir dipivoxil, but has the characteristics of good tolerance, low rebound rate after drug withdrawal, and low nephrotoxicity.

[0003] Chronic hepatitis B is one of the most common chronic infectious diseases in my country, and its pathogenic agent is hepatitis B virus. Patients with chronic hepatitis B can progress to liver fibrosis, cirrhosis, decompensated cirrhosis, and HCC.

[0004] The...

Examples

preparation example Construction

[0038] The present invention provides a kind of preparation method of tenofovir disoproxil, and described preparation method comprises the steps:

[0039] S01 etherification: Add (R)-9-(2-hydroxypropyl)adenine and N-methylpyrrolidone in sequence in the reactor, and slowly add magnesium tert-butoxide under constant stirring; after raising the temperature, slowly add Diethyl p-toluenesulfonyloxymethyl phosphate, stop heating after reacting to (R)-9-(2-hydroxypropyl)adenine completely, cool down to room temperature naturally; add acetic acid to the system, adjust under stirring pH value until the reaction system is clarified; then slowly add the above reaction solution into ethyl acetate under rapid stirring, solids are precipitated, stirred, and centrifuged; the filter cake is beaten with 20L dichloromethane, centrifuged, and the filtrate is reduced at a certain temperature Concentrate under pressure without distillate, add cyclohexane to the residue, concentrate until there is ...

Embodiment approach 1

[0073] Embodiment 1. This embodiment provides a kind of preparation method of tenofovir disoproxil, and described preparation method comprises the following steps:

[0074] S01 etherification: Add (R)-9-(2-hydroxypropyl)adenine and N-methylpyrrolidone in sequence in the reactor, and slowly add magnesium tert-butoxide under constant stirring; after raising the temperature, slowly add Diethyl p-toluenesulfonyloxymethyl phosphate, stop heating after reacting to (R)-9-(2-hydroxypropyl)adenine completely, cool down to room temperature naturally; add acetic acid to the system, adjust under stirring pH value until the reaction system is clarified; then slowly add the above reaction solution into ethyl acetate under rapid stirring, solids are precipitated, stirred, and centrifuged; the filter cake is beaten with 20L dichloromethane, centrifuged, and the filtrate is reduced at a certain temperature Concentrate under pressure without distillate, add cyclohexane to the residue, concentra...

Embodiment 1

[0089] Embodiment 1: This embodiment provides a kind of preparation method of tenofovir disoproxil, and described preparation method comprises the following steps:

[0090] S01 etherification: Add 5kg (R)-9-(2-hydroxypropyl)adenine and 20L N-methylpyrrolidone in sequence in the reaction kettle, slowly add 7.5kg magnesium tert-butoxide under uniform stirring, and start heating. After raising the temperature to 70°C, slowly add 10kg of diethyl p-toluenesulfonyloxymethyl phosphate, and the addition is completed in about 30 minutes. Keep the reaction temperature at about 79°C for continuous reaction until (R)-9-(2-hydroxy After the reaction of propyl) adenine is complete, stop heating, and cool to room temperature naturally; add acetic acid to the system, adjust the pH value to 7.0 under stirring, and the stirring reaction system is clarified; then slowly add the above reaction solution to 150L under rapid stirring In ethyl acetate, solids were precipitated, stirred, and centrifug...

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