Crystalline form of Adefovir dipivoxil and preparing process thereof

A technology of adefovir dipivoxil and new crystallization, applied in the field of organic chemistry

Inactive Publication Date: 2003-08-13
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the AD reported in the above literature is only provided in the form of non-crystalline (that is, amorphous)

Method used

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  • Crystalline form of Adefovir dipivoxil and preparing process thereof
  • Crystalline form of Adefovir dipivoxil and preparing process thereof
  • Crystalline form of Adefovir dipivoxil and preparing process thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0053] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples are further illustrations of the present invention rather than limitations. Embodiment 1: Preparation of form 1 crystal

[0054] Referring to WO9904774 (CN1251592A) and EP481214 Example 8

[0055] (1) Diethyl p-toluenesulfonyloxymethylphosphonate (C-1)

[0056] Add 500g (3.6mol) diethyl phosphite, 137.5g (4.5mol) paraformaldehyde, 76g triethylamine and 2100ml toluene into a 5000ml three-necked flask, heat to 85°C (85-105°C), stir for 2h, then Reflux for 2h. The temperature was lowered to 0°C and 625g of p-toluenesulfonyl chloride was added, and 474g of triethylamine was added dropwise at 0°C. After addition, stir at room temperature for 10h. Filter and wash the filter cake with 100ml×3 toluene. Combine the organic phases, successively use 700ml water, 2000ml 5% Na 2 CO 3 Aqueous solution, washed with 2000ml water. The organic layer was separated, and the solvent wa...

Embodiment 2

[0068] Form 1 Dissolve 50g of adefovir dipivoxil in 300mL of acetone to obtain a colorless and transparent solution. Evaporate the solvent to dryness in vacuo at 30-40°C to obtain an oil, gradually cool to room temperature, solidify into a white solid, grind, and dry in vacuo at 60°C After 8 hours, 49 g of a white powdery solid was obtained, which was adefovir dipivoxil in a new crystal form. Embodiment 3: the preparation of the adefovir dipivoxil of new crystal form

Embodiment 3

[0069] Form 1 Adefovir dipivoxil 50g was dissolved in 500mL isopropanol to obtain a colorless and transparent solution. The solvent was evaporated to dryness in vacuo at 30-60°C to obtain an oil, which was gradually cooled to 30°C and solidified into a white solid. Grinding, 60 ℃ vacuum drying for 8 hours to obtain 50 g of white powdery solid, which is adefovir dipivoxil in a new crystal form. Embodiment 4: the preparation of the adefovir dipivoxil of new crystal form

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Abstract

A compound Adefovir Dipivoxil (AD) in the form of anhydrous crystal for curing chronic hepatitis B is disclosed. It is just 9-[2-[bis(neopentanoyloxy methoxy)phosphorylmethoxy]ethyl] adenine. Its features are its high stability to light, moisture and heat. Its preparing process is also disclosed.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, in particular to Adefovir Dipivoxil (Adefovir Dipivoxil, abbreviated as AD, whose chemical name is 9-[2-[bis(pivaloyloxymethoxy)] ) phosphorylmethoxy] ethyl] adenine) and a method for preparing the crystal. Background technique [0002] Adefovir Dipivoxil (AD) is a new generation of nucleotide analogues known at present, and its chemical name is 9-[2-[bis(pivaloyloxymethoxy)phosphorylmethoxy ] Ethyl] adenine is adefovir (Adefovir, PMEA for short), the chemical name is the dipivaloyloxymethyl ester of 9-(2-phosphonomethoxyethyl) adenine. [0003] After oral administration, this product is rapidly hydrolyzed into adefovir in the body to exert antiviral effect. Its antiviral spectrum is very wide, including hepatitis B virus (HBV), human immunodeficiency virus (HIV) and herpes virus, and has long-acting, potent antiviral replication and unique anti-drug resi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/675A61P1/16A61P31/12C07F9/6561
Inventor 张殿镇徐莉赵健朱建强刘伍林董亚博张明华
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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