Novel crystal form of tenofovir ester maleate, preparation method and pharmaceutical application thereof

A technology of tenofovir dipivoxil and ester maleate, applied in the field of -phosphinoylmethoxy], can solve problems such as restricting industrialized large-scale production, stability problems and the like

Inactive Publication Date: 2011-03-16
BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the above-mentioned studies have certain improvements in stability, for industrialized large-scale production processes, there are still problems in stability, and because the amount of

Method used

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  • Novel crystal form of tenofovir ester maleate, preparation method and pharmaceutical application thereof
  • Novel crystal form of tenofovir ester maleate, preparation method and pharmaceutical application thereof
  • Novel crystal form of tenofovir ester maleate, preparation method and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1 Synthesis and crystallization purification of (R)-9-[2-bis(pivaloyloxymethyl)phosphonomethoxypropyl]adenine (tenofovir dipivoxil)

[0028] Mix PMPA (5g), chloromethyl tert-butyl ester (13.79mL), triethylamine (7.64mL) and N-methylpyrrolidone (19g) under nitrogen protection and heat to 60±3°C (no more than 65 ℃). After 2 hours, TLC (dichloromethane / methanol=15 / 1), showed that the starting material had disappeared. Lower the temperature of the reactant to room temperature (25±2°C), add ethyl acetate (50mL) and water (30mL) and stir for 30 minutes, separate the liquids, continue to back-extract the aqueous phase once with ethyl acetate (50mL), and combine ethyl acetate The ester phase was washed once with saturated aqueous sodium chloride (20 mL), and dried over anhydrous sodium sulfate to remove water. At a temperature not higher than 50°C, the organic solvent was evaporated in vacuo to obtain 10 g of a viscous yellow oil, which was purified by column to obtai...

Embodiment 2

[0091] White foamy solid (3 g), maleic acid (0.34 g), and ethanol (20 mL) were heated to 50° C. and stirred for 1 hour, then filtered while hot. The mother liquor was evaporated in vacuo to remove the organic solvent at a temperature of 30° C. to obtain a slightly yellow oil (3.3 g). Dissolve the oil with hot ethyl acetate (200 mL, temperature about 50°C), mix and cool to room temperature, add seed crystals, place at 10°C, filter after 12 hours, wash with a small amount of ethyl acetate to obtain a white solid.

Embodiment 3

[0093] White foamy solid (3 g), maleic acid (0.39 g), and ethanol (20 mL) were heated to 60°C and stirred for 1 hour, then filtered while hot. The mother liquor was evaporated in vacuo to remove the organic solvent at a temperature of 30° C. to obtain a slightly yellow oil (3.3 g). Dissolve the oil with hot ethyl acetate (200 mL, temperature about 40°C), mix and cool to room temperature, add seed crystals, place at 10°C, filter after 18 hours, wash with a small amount of ethyl acetate to obtain a white solid.

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Abstract

The invention provides a novel crystal form of a tenofovir maleate, a preparation method and a pharmaceutical application thereof. The novel crystal form in a salt form facilitates the more stable presence of the tenofovir ester. A study on the stability of the crystal form shows that the novel crystal form of the tenofovir ester maleate is more stable than that reported in previous documents and is excellent in flowability. The novel crystal form tremendously improves the stability during industrial production and flowability and compressibility during preparation, and greatly meets the needs of industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to (R)-9-[2-bis(pivaloyloxymethyl)phosphonomethoxypropyl]adenine maleate (English name is 9-[2- A new crystal form of (R)-[bis[pivaloyloxymethoxy]-phosphinoylmethoxy]propyl]adenine maleate (hereinafter referred to as tenofovir disoproxil maleate), its preparation method and its application in the preparation of medicines. Background technique [0002] Tenofovir disoproxil fumarate (tenofovir diSOProxilfumarate), chemical name (R)-[[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphine Its structural formula of acid diisopropoxycarbonyloxy methyl ester fumarate is as shown in formula one, is the nucleotide reverse transcriptase inhibitor developed by U.S. Gilead Sciences company, is the prodrug of tenofovir (PMPA), Its structural formula is shown in Formula 2. It was first launched in the United States in 2001. It is mainly used clinically to treat human immunodeficiency virus (HIV...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61K31/675A61P31/18A61P31/20
Inventor 袁建栋徐安佗
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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