A kind of preparation method of adefovir dipivoxil hydroxymethyl impurity

A technology of adefovir dipivoxil and ester hydroxymethyl, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of wasting raw materials, and achieve the effects of reducing environmental protection costs, saving costs, and reducing damage

Active Publication Date: 2018-06-22
FUJIAN COSUNTER PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] According to literature and structural formula analysis, the adefovir dipivoxil hydroxymethyl impurity can be obtained by the reaction of adefovir dipivoxil and formaldehyde.

Method used

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  • A kind of preparation method of adefovir dipivoxil hydroxymethyl impurity
  • A kind of preparation method of adefovir dipivoxil hydroxymethyl impurity
  • A kind of preparation method of adefovir dipivoxil hydroxymethyl impurity

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Experimental program
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Effect test

specific Embodiment approach

[0056] An adefovir dipivoxil hydroxymethyl impurity is prepared from the following raw materials through the following steps carried out in sequence according to the following weight ratio;

[0057]

[0058] Its chemical reaction formula is as follows:

[0059]

[0060] Put N-methylpyrrolidone, adefovir, triethylamine, and chloromethyl pivalate in turn into the reaction flask, stir, heat, control the temperature at 60±3°C, and react for 3 hours. After the reaction is complete, cool to room temperature. Add ethyl acetate, stir, and filter. The filtrate was washed with water, the organic layer was retained, the aqueous layer was separated, and the aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined. The organic layer was washed twice with water, and the aqueous layer was discarded. The ethyl acetate layer was extracted twice with 2mol / L hydrochloric acid, the lower layer of hydrochloric acid layer (to prepare adefovir dipivoxil), the ...

Embodiment 1

[0064] Put 5.2g of N-methylpyrrolidone, 1.6g of adefovir A-4, 2.05g of triethylamine, and 4.4g of chloromethyl pivalate into a 250ml reaction bottle in sequence, stir, heat, and control the temperature at 60±3°C. React for 3h and cool to 30±5°C. Add 70ml of ethyl acetate, stir for 1h, and filter. The filtrate was transferred to a separatory funnel, added 20ml of drinking water to wash, the organic layer was retained, the water layer was separated, transferred to a separatory funnel, the water layer was extracted twice with ethyl acetate (20ml of ethyl acetate each time), and the organic layers were combined. The organic layer was washed twice with drinking water in a separating funnel (40ml of drinking water each time), and the water layer was discarded. The ethyl acetate organic layer was extracted twice with 2mol / L hydrochloric acid (the dosage of 2mol / L hydrochloric acid was 20ml each time), the lower hydrochloric acid layer was reserved (to prepare adefovir dipivoxil), th...

Embodiment 2

[0076] Put 104g of N-methylpyrrolidone, 32g of adefovir A-4, 41g of triethylamine, and 88g of chloromethyl pivalate into a 1L reaction bottle in sequence, stir, heat, control the temperature at 60±3°C, react for 3 hours, and cool to 30±5°C. Add 700ml of ethyl acetate, stir for 1h, and filter. The filtrate was transferred to a separatory funnel, added 400ml of drinking water to wash, the organic layer was retained, the water layer was separated, transferred to a separatory funnel, the water layer was extracted twice with ethyl acetate (400ml of each ethyl acetate consumption), and the organic layers were combined. The organic layer was washed twice with drinking water in a separating funnel (400ml of drinking water each time), and the water layer was discarded. The ethyl acetate organic layer was extracted twice with 2mol / L hydrochloric acid (the amount of 2mol / L hydrochloric acid was 400ml each time), the lower hydrochloric acid layer was reserved (to prepare adefovir dipivox...

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Abstract

A preparing method of a hydroxymethyl impurity of adefovir dipivoxil is provided. The method includes S1) a step of preparing crude hydroxymethyl impurity of the adefovir dipivoxil, with the crude hydroxymethyl impurity being prepared from 2.5-4.0 parts by weight of N-methyl-2-pyrrolidone, 1.0 part by weight of adefovir A-4, 1.0-1.5 parts by weight of triethylamine and 2.0-3.6 parts by weight of chloromethyl pivalate, S2) a step of filtering a crude adefovir dipivoxil compound solution for purification, and S3) a step of subjecting the crude adefovir dipivoxil compound dry product prepared in the step S2) to secondary crystallization for purification.

Description

technical field [0001] The invention relates to a preparation method of adefovir dipivoxil hydroxymethyl impurity, belonging to the technical field of pharmaceutical chemical synthesis. Background technique [0002] Adefovir dipivoxil is an acyclic analogue of 5'-monophosphate deoxy vidarabine, a nucleoside viral reverse enzyme inhibitor, and a precursor of Adefovir, which is hydrolyzed into Adefovir in vivo Antiviral effect. Adefovir dipivoxil was developed by GileadSciences of the United States, and was approved by the FDA on September 20, 2002. The specification is 10 mg / tablet. It is clinically used for the treatment of adult chronic hepatitis B, and the trade name is Hepsera. On March 11, 2003, the European Union approved the drug to be marketed, and adefovir dipivoxil has been marketed in many countries at present. It was launched in China for the first time in April 2005, and it is mainly used for the treatment of adult chronic hepatitis B patients with liver functi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561G01N30/02
CPCC07F9/65616G01N30/02
Inventor 洪锋贞卓茂峰杨敏姚建堤吴卫华伍虹蓉陈仕魁冯彬
Owner FUJIAN COSUNTER PHARMA CO LTD
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