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Propofol, phosphate and amino acid double salt and preparation method and application thereof

A technology of propofol phosphate and propofol dihydrogen phosphate, applied in its preparation, water-soluble prodrug-propofol phosphate amino acid double salt, application field in the preparation of sedative hypnotic and anesthetic drugs , can solve the problems of unfavorable drug safety and achieve the effects of improving water solubility and bioavailability, less environmental pollution, and reducing irritation

Inactive Publication Date: 2013-01-02
GUANGZHOU CHEM CO LTD CHINESE ACADEMY OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These two phosphoesterification modifications can improve the water solubility of propofol and improve the pharmacokinetic properties, but they all belong to a single propofol phosphate salt, and the compound of formula (5) is metabolized in vivo will release a molecule of formaldehyde (European Journal of Pharmaceutical Sciences, 2008, 34: 110-117), which is relatively unfavorable in terms of drug safety

Method used

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  • Propofol, phosphate and amino acid double salt and preparation method and application thereof
  • Propofol, phosphate and amino acid double salt and preparation method and application thereof
  • Propofol, phosphate and amino acid double salt and preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0040] Add 1.78 g (0.01 mol) of propofol, 1.52 g (0.015 mol) of triethylamine, and 10 ml of dichloromethane into a 50 ml three-necked flask equipped with a thermometer, a constant pressure dropping funnel, and a reflux condenser. Stir the reaction at 25° C. After 0.5 hours, slowly add 2.30 g (0.015 mol) of phosphorus oxychloride dropwise, and the dropwise addition is completed in about 1 hour. Complete, add water at 25°C for hydrolysis, control the reaction solution to be always acidic, stir for 2 hours, the reaction is complete, wash with water until the water layer is basically colorless, back-extract the water layer with dichloromethane, combine the organic layers, and spin dry to obtain red Brown viscous liquid, and then purified to obtain 2.01 g of white crystals of propofol dihydrogen phosphate, yield: 77.9%.

Embodiment 2

[0042] Add 1.78g (0.01mol) of propofol, 1.52g (0.015mol) of triethylamine, and 10ml of dichloromethane into a 50ml three-necked flask equipped with a thermometer, a constant pressure dropping funnel and a reflux condenser, and stir the reaction at 0°C After 0.5 hours, slowly add 2.30 g (0.015 mol) of phosphorus oxychloride dropwise, and the dropwise addition is completed in about 1 hour. Complete, add water at 0°C for hydrolysis, control the reaction solution to always be acidic, stir and react for 4 hours, the reaction is complete, wash with water until the water layer is basically colorless, back-extract the water layer with dichloromethane, combine the organic layers, and spin dry to obtain red Brown viscous liquid, and then purified to obtain 1.53 g of white crystals of propofol dihydrogen phosphate, yield: 59.3%.

Embodiment 3

[0044]Add 1.78 g (0.01 mol) of propofol, 1.52 g (0.015 mol) of triethylamine, and 10 ml of dichloromethane into a 50 ml three-necked flask equipped with a thermometer, a constant pressure dropping funnel, and a reflux condenser. Stir the reaction at 25° C. After 0.5 hours, slowly add 2.30 g (0.015 mol) of phosphorus oxychloride dropwise, and the dropwise addition is completed in about 1 hour. Complete, add water at 50°C for hydrolysis, control the reaction solution to be always acidic, stir for 1 hour, the reaction is complete, wash with water until the water layer is basically colorless, back-extract the water layer with dichloromethane, combine the organic layers, and spin dry to obtain red Brown viscous liquid, and then purified to obtain 1.89 g of white crystals of propofol dihydrogen phosphate, yield: 73.2%.

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Abstract

The invention discloses propofol, phosphate and amino acid double salt and a preparation method and application thereof. The method comprises the following steps of: reacting propofol as a raw material with a phosphorylating reagent under a basic condition to obtain a phosphorus oxychloride intermediate; hydrolyzing the phosphorus oxychloride intermediate to obtain propofol ethyl phosphoric acid;then salifying with basic amino acid and concentrating to obtain a crude product; and recrystallizing and purifying the crude product to obtain the propofol, phosphate and amino acid double salt witha structure formula shown as (1), wherein R is the basic amino acid. The medical double salt has favorable water solubility and stability and can be prepared into injections, oral solutions, capsules, tablets and the like after mixing with necessary auxiliary materials. The invention obviously improves the water solubility and the bioavailability of the propofol, reduces irritation and increases therapeutic cooperativity. The synthesis method has the advantages of simple operation, easy obtainment of the raw material, low cost and high yield.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a water-soluble prodrug-propofol phosphate amino acid double salt, its preparation method and its application in the preparation of sedative, hypnotic and anesthetic drugs. Background technique [0002] Propofol (Propofol, formula (2), also known as Propofol, Diprivan, chemical name 2,6-diisopropylphenol), is a widely used systemic intravenous anesthetic. It has the advantages of quick onset, short action time, quick and complete recovery, few adverse reactions, no sequelae, wide application range (can be used for anesthesia induction, maintenance and auxiliary epidural anesthesia), and easy to control dosage. However, propofol is a fat-soluble compound and hardly soluble in water, so its pharmacokinetic properties are not good. At present, the preparation form of fat emulsion is mainly used for intravenous administration. This fat emulsion has certain side effects,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/12C07C279/14C07D233/64
Inventor 邹永孙洪宜陈煜肖春芬刘现可
Owner GUANGZHOU CHEM CO LTD CHINESE ACADEMY OF SCI
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