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Propofol ester derivative containing amino carboxylic acid amide structure, its preparation method and its purpose

A technology of aminocarboxylic acid amide and propofol, which is applied to the preparation of carboxylic acid amide, the preparation of organic compounds, and medical preparations containing active ingredients, etc. It can solve the problems of poor water solubility, achieve stable aqueous solution, and have cheap and easy-to-obtain raw materials , reducing the effect of the first-pass effect

Active Publication Date: 2012-03-21
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The propofol ester derivatives can overcome the disadvantage of poor water solubility of propofol, and after entering the body, except propofol can be released quickly, the rest of the released components are mostly endogenous nutrients of the human body without obvious toxicity

Method used

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  • Propofol ester derivative containing amino carboxylic acid amide structure, its preparation method and its purpose
  • Propofol ester derivative containing amino carboxylic acid amide structure, its preparation method and its purpose
  • Propofol ester derivative containing amino carboxylic acid amide structure, its preparation method and its purpose

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Dissolve 20 g of propofol (formula II) in 50 ml of triethylamine, add 14 g of succinic anhydride and 0.02 g of dimethylaminopyridine, stir at room temperature for 16 h, and distill the reaction solution under reduced pressure to remove excess triethylamine , the residue was washed into 100 ml of water, and the pH value was adjusted to 1 with 6 N hydrochloric acid, a large amount of white precipitate was precipitated, filtered and dried under reduced pressure to obtain the crude product of propofol succinic acid monoester intermediate (Ⅲ), washed with cyclohexane / Recrystallization from ethyl acetate gave 23.5 g of needle-like crystals, the reaction yield was 75.4%, and mp: 103-104°C.

Embodiment 2

[0041] Dissolve 20 g of propofol in 100 ml of dichloromethane, add 13.3 g of succinic acid and 0.02 g of dimethylaminopyridine, then add 23.2 g of DCC and stir at room temperature for 6 h, then filter off the white solid in the reaction solution , the filtrate was washed once with 150 ml of 6N hydrochloric acid, the organic layer was separated, and the solvent was evaporated under reduced pressure to obtain a light yellow solid of propofol succinate monoester intermediate (Ⅲ), which was recrystallized from cyclohexane / ethyl acetate 26.6 g of white needle-like crystals were obtained, the yield was 85%, and mp: 102-103°C.

Embodiment 3

[0043] Weigh 1 g of the propofol succinic acid monoester intermediate (Ⅲ) of Example 1 into a 25 ml single-necked bottle, add 10 ml of dry dichloromethane, and quickly add 2 g of freshly distilled oxalyl chloride, and pass through a drying tube React at room temperature for 2 h. After the HCl is completely released, evaporate the solvent and low-volatile substances to dryness on a rotary evaporator to obtain the crude propofol succinic acid monoester chloride, which can be used directly.

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Abstract

The invention relates to a propofol ester derivative containing an amino carboxylic acid amide structure, its preparation method and its purpose. The derivative has a following formula (I), in the formula, M is H, NH4 or pharmaceutically acceptable alkali metal element or alkali earth metal element, n=1-3, m=1-7, x=1 / 2-1. 2,6-diisopropyl phenol (II) is taken as a raw material, reacted with diacid or the corresponding anhydride to obtain a 2,6-diisopropyl phenol monoester intermediate, and continuously reacted with amino carboxylic acid to obtain the corresponding product (I). The propofol ester derivative can be used for preparing injection type central inhibition medicaments for generating effects of calmness, hypnosis and / or anaesthesia on animals and human, and is capable of improving the water-solubility of propofol, reducing the toxic and side effects of original drug and analogous prodrug, increasing the stability of profrug in vitro and increasing the application scope. The preparation method is simple which has industrial application value.

Description

technical field [0001] The present invention relates to a derivative of 2,6-diisopropylphenol (propofol) and its preparation method, as well as an injection-type central inhibitory drug that can produce sedation, hypnosis and / or anesthesia on animals / humans use in . Background technique [0002] Propofol (chemical name: 2,6-diisopropylphenol) is a drug widely used clinically for the induction and maintenance of general anesthesia and ICU sedation. It has the characteristics of fast onset of action, fast metabolic inactivation, and mild post-anesthesia effect. Since the first clinical report was made in 1977, it has been gradually promoted and used all over the world. Since the solubility of propofol in water is only 146mg / L, the preparations that are still widely used clinically in various countries in the world are based on 1% propofol, 10% soybean oil, 2.25% glycerin and 1.2% refined egg yolk lecithin A formulated O / W emulsion. In the United States, 0.005% edetate disod...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/47C07C231/02A61K31/222A61P25/20A61P23/00
Inventor 郑虎翁玲玲刘进张文胜杨俊
Owner SICHUAN UNIV
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