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Preparation method of high-stability adefovir dipivoxil

An adefovir dipivoxil, high-stability technology, applied in the field of drug synthesis, can solve the problems of thermal instability, poor stability and small particle size of raw materials

Pending Publication Date: 2019-08-20
BEIJING JIMEITANG MEDICINE RES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, according to the process parameters of the original research patent CN1216062, the obtained bulk drug (anhydrous crystal type) is thermally unstable and easy to hydrolyze; the stability is poor and the shelf life is short; the particle size is small and the fluidity is poor, which is not conducive to the use of subsequent preparations

Method used

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  • Preparation method of high-stability adefovir dipivoxil
  • Preparation method of high-stability adefovir dipivoxil
  • Preparation method of high-stability adefovir dipivoxil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Add 5.20kg (2w / w) of acetonitrile into a 50L reactor, add 2.60kg (1eq) of compound 1 and 4.24kg (3.5eq) of bromotrimethylsilane under stirring, raise the temperature to 65±5°C, and keep the reaction for 2 hours. Concentrate the organic phase under reduced pressure at 45±5°C until no liquid distills out, add 7.80kg (3w / w) of purified water to dissolve the organic phase, raise the temperature to 55±5°C and stir for 0.5 hours; add 30% NaOH aqueous solution dropwise to the 50L reaction kettle Adjust the pH to 2.5-3.5, raise the temperature to 75±5°C and keep stirring for 2 hours; cool down to 3±3°C and keep stirring for 3 hours; centrifuge, and filter the cake with 2.60kg (1w / w) of purified water and 1.30kg of ethanol (0.5 w / w) washing; add 10.40kg (4w / w) of purified water to the 50L reactor, add filter cake under stirring, heat up to 75±5°C, beat for 2 hours; cool down to 3±3°C for 3 hours; centrifuge , the filter cake was washed with 2.60kg (1w / w) of purified water; the f...

Embodiment 2

[0058] Add 5.20kg (2w / w) of DMF to the 50L reactor, add 2.60kg (1eq) of compound 1 and 1.72kg (2eq) of trimethylchlorosilane under stirring, raise the temperature to 55±5°C, and keep the reaction for 2 hours. Concentrate the organic phase under reduced pressure at 45±5°C until no liquid distills out, add 7.80kg (3w / w) of purified water to dissolve the organic phase, raise the temperature to 55±5°C and stir for 0.5 hours; add 30% NaOH aqueous solution dropwise to the 50L reaction kettle Adjust the pH to 2.5-3.5, raise the temperature to 75±5°C and keep stirring for 2 hours; cool down to 3±3°C and keep stirring for 3 hours; centrifuge, and filter the cake with 2.60kg (1w / w) of purified water and 1.30kg of ethanol (0.5 w / w) washing; add 10.40kg (4w / w) of purified water to the 50L reactor, add filter cake under stirring, heat up to 75±5°C, beat for 2 hours; cool down to 3±3°C for 3 hours; centrifuge , the filter cake was washed with 2.60kg (1w / w) of purified water; the filter cake...

Embodiment 3

[0064] Add 5.20kg (2w / w) of tetrahydrofuran into a 50L reactor, add 2.60kg (1eq) of compound 1 and 7.92kg (5eq) of iodotrimethylsilane under stirring, raise the temperature to 75±5°C, and keep the reaction for 2 hours. Concentrate the organic phase under reduced pressure at 45±5°C until no liquid distills out, add 7.80kg (3w / w) of purified water to dissolve the organic phase, raise the temperature to 55±5°C and stir for 0.5 hours; add 30% NaOH aqueous solution dropwise to the 50L reaction kettle Adjust the pH to 2.5-3.5, raise the temperature to 75±5°C and keep stirring for 2 hours; cool down to 3±3°C and keep stirring for 3 hours; centrifuge, and filter the cake with 2.60kg (1w / w) of purified water and 1.30kg of ethanol (0.5 w / w) washing; add 10.40kg (4w / w) of purified water to the 50L reactor, add filter cake under stirring, heat up to 75±5°C, beat for 2 hours; cool down to 3±3°C for 3 hours; centrifuge , the filter cake was washed with 2.60kg (1w / w) of purified water; the f...

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PUM

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Abstract

The invention belongs to the field of pharmaceutical synthesis. A preparation method of high-stability adefovir dipivoxil is characterized by comprising the following steps: 1) a compound 1 undergoestrimethylbromosilane substitution, followed by hydrolysis with a NaOH aqueous solution to obtain a compound 2; 2) the compound 2 and a compound 3 are catalyzed by triethylamine in N-methylpyrrolidoneto obtain a compound 4; 3) the compound 4 is refined to obtain a compound 5, namely [[2-(6-amino-9H-purine-9-yl)ethoxy]methyl]phosphodi(pivaloyloxymethyl)ester. The preparation method of high-stability adefovir dipivoxil has advantages of good stability of bulk drugs and simple production process, and is suitable for large-scale commercial production.

Description

technical field [0001] The present invention relates to a method for the treatment of adult chronic hepatitis B with evidence of active replication of hepatitis B virus, accompanied by sustained elevation of serum aminotransferase (ALT or AST) or liver histologically active lesions of liver function compensation The preparation method of the patient, specifically relates to the preparation method of adefovir dipivoxil, and belongs to the field of drug synthesis. Background technique [0002] Adefovir dipivoxil is the precursor of Adefovir, which exerts antiviral effect after being hydrolyzed into Adefovir in vivo. Adefovir dipivoxil is a thermally unstable drug that is prone to hydrolysis. Nucleotide analog antiviral drugs which are used for long-term treatment of chronic hepatitis B. In addition, adefovir dipivoxil has the characteristics of low incidence of drug resistance, late occurrence of drug resistance, good long-term drug safety, and high clinical efficiency. The...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
CPCC07F9/65616C07B2200/13
Inventor 李培何杰姜爱斌王辉
Owner BEIJING JIMEITANG MEDICINE RES CO LTD
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