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Propofol water-soluble naphthenic phosphate ester derivative

A technology of propofol and bisphosphonic acid, applied in the field of medicinal chemistry, to avoid injection pain and embolism, increase solubility, and reduce side effects

Inactive Publication Date: 2014-02-19
CHENGDU UNIVERSITY OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After entering the human body, this type of compound can be hydrolyzed to release propofol quickly, exert an anesthetic effect, and effectively overcome the disadvantage of poor water solubility of propofol

Method used

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  • Propofol water-soluble naphthenic phosphate ester derivative
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  • Propofol water-soluble naphthenic phosphate ester derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Embodiment 1: Preparation of propofol-1-chlorocyclopropyl ether

[0024]

[0025] Under nitrogen protection, sodium hydride (2.5 g, dispersed in mineral oil, 60% by mass, 61.6 mmol) was suspended in anhydrous tetrahydrofuran (100 mL) while stirring, and propofol was added in batches at 0 °C (10.0 g, 56.0 mmol), the resulting mixture was stirred for 10 minutes, and a solution of 1-chloro-1-iodocyclopropane (12.5 g, 61.6 mmol) in tetrahydrofuran (10 mL) was added dropwise. After the dropwise addition was completed, stirring was continued at room temperature for 6 hours. Filter, evaporate solvent under reduced pressure, residue recrystallizes with the mixed solvent of sherwood oil and ethyl acetate (V 石油醚 :V 乙酸乙酯 =6:1), dried to obtain 12.6 g of white solid, yield 89.1%, HPLC purity: 99.4% (254 nm). 1 H NMR (400 MHz, CDCl 3 ( m, 2H).

Embodiment 2

[0026] Embodiment 2: Preparation of O-[1-(propofol-O base)]cycloprop-1-yl monoester phosphoric acid

[0027]

[0028] A mixture of propofol-1-chlorocyclopropyl ether (12.0 g, 47.5 mmol), phosphoric acid (5.6 g, 57.0 mmol), triethylamine (5.8 g, 57.0 mmol), ethanol (100 mL) was heated to 70 °C for 3 hours. Concentrate the solvent under reduced pressure (-0.09 MPa, 40 °C) until white crystals precipitate, then cool with ice-water mixture, filter, and dry to obtain 9.3 g of white solid, yield 62.0%, HPLC purity: 97.6% (254 nm) . 1 H NMR (400MHz, DMSO-d 6 ( m, 2H).

Embodiment 3

[0029] Example 3: Preparation of O-[1-(propofol-O base)]cycloprop-1-yl monoester phosphate disodium

[0030]

[0031] Dissolve O-[1-(propofol-O-yl)]cycloprop-1-yl monoester phosphoric acid (4.5 g, 14.3 mmol) in water (30 mL), add sodium hydroxide (1.15 g, 28.6 mmol). Stirring was continued at room temperature for 1 hour, water was evaporated under reduced pressure, and dried to obtain 5.1 g of white solid, yield 100.0%, HPLC purity: 98.3% (254 nm). 1 H NMR (400MHz, D 2 O) δ: 7.35-7.19 (m, 2H), 6.93-6.62 (m, 1H), 3.20-3.12 (m, 2H), 1.25 (d, 12H), 0.84-0.79 (m, 2H), 0.72-0.66 (m, 2H).

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Abstract

The present invention relates to a propofol water-soluble naphthenic phosphate ester derivative represented by a formula I, and a preparation method thereof, wherein n in the formula is 1 or 2 or 3 or 4, and each Z is independently selected from hydrogen, alkali metal ions and amine. Compared to the propofol original drug, the propofol water-soluble naphthenic phosphate ester derivative has characteristics of good water solubility, fast effect and longer action effect. The propofol water-soluble naphthenic phosphate ester derivative can be used as anesthetics for injection.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a new class of propofol cycloalkyl phosphate derivatives and physiologically acceptable salts thereof. [0002] Background technique [0003] Propofol (2,6-diisopropylphenol, propofol), a short intravenous general anesthetic, has the advantages of fast onset of anesthesia induction, rapid recovery, no obvious accumulation, and complete functional recovery, postoperative nausea and vomiting Advantages such as low rate. However, due to the steric hindrance of the isopropyl group, propofol has poor water solubility and can only be administered in the form of emulsion clinically. The disadvantages of emulsions are obvious: injection causes pain; larger oil droplets may cause embolism; it is difficult to add other drugs in the preparation; poor stability, etc. These limit the clinical use of propofol. [0004] In view of the above reasons, the inventors have designed...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/117A61K31/661A61P23/00
Inventor 周立宏曾庆乐
Owner CHENGDU UNIVERSITY OF TECHNOLOGY
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