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Preparation method of propofol

A technology of propofol and isopropanol, which is applied in the novel preparation field of intravenous anesthetic propofol (Propofol), can solve the problems of harsh reaction conditions, severe reaction, difficulty in controlling, many by-products, etc. The effect of novel route and easy product

Active Publication Date: 2015-05-27
LIAONING YAOLIAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the method reported in patent US2831898 and CN200910140403.5, propofol is prepared by alkylation reaction of phenol or 2-isopropylphenol and propylene under high temperature and high pressure conditions. Many; in the method that patent US4929761 and 2010MU01862 report, take p-hydroxybenzoic acid as raw material and isopropanol through alkylation reaction, make propofol through high temperature decarboxylation under the protection of nitrogen, the required temperature of decarboxylation reaction is high, and reaction time Long, difficult to purify the product

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0021] Example 1 2,6-diisopropyl-4-nitrophenol (compound ) preparation

[0022] Slowly add 36 mL of concentrated sulfuric acid into 2.5 mL of cold water, and after cooling to room temperature, slowly add the solution dropwise to p-nitrophenol (10 g, 0.072 mol) in isopropanol (12 mL, 0.16 mol) in an ice bath In the solution, keep the temperature not exceeding 10°C during the dropwise addition, and raise the temperature to 60°C for 3 hours after the dropwise addition. Pour the reaction solution into 500 g of ice, adjust the pH to 11-13 with 20% NaOH solution, filter, wash the filtrate with petroleum ether, then adjust the pH of the water layer to 3-4 with 2mol / L HCl, precipitate solids, filter with suction, collect and filter The cake was vacuum-dried to obtain 14.3 g of the product (yield: 89.1%). 1 H-NMR (CDCl 3 ): δ 7.99 (s, 2H), 3.20 (m, 2H), 1.31 (d, 12H).

Embodiment 2

[0023] Example 2 2,6-diisopropyl-4-nitrophenol (compound ) preparation

[0024] Add 36 mL of 85% phosphoric acid to a 100 mL three-neck flask, add p-nitrophenol (10 g, 0.072 mol), stir in an ice bath, and slowly add isopropanol (12 mL, 0.16 mol) dropwise. Keep the temperature at no more than 10°C, and raise the temperature to 60°C for 3 hours after the dropwise addition. Pour the reaction solution into 500 g of ice, adjust the pH to 11-13 with 20% NaOH solution, filter, wash the filtrate with petroleum ether, and then adjust the pH of the water layer to 3-4 with 2 mol / L HCl, precipitate solid, suction filter, collect and filter The cake was vacuum-dried to obtain 13.3 g of the product (yield: 82.9%).

Embodiment 3

[0025] Example 3 2,6-diisopropyl-4-nitrophenol (compound ) preparation

[0026] Add 50 mL of 40% hydrofluoric acid into a three-necked flask, add p-nitrophenol (10 g, 0.072 mol), stir in an ice bath, and slowly add isopropanol (12 mL, 0.16 mol) dropwise. Keep the temperature at no more than 10°C, and raise the temperature to 60°C for 3 hours after the dropwise addition. Pour the reaction solution into 500 g of ice, adjust the pH to 11-13 with 20% NaOH solution, filter, wash the filtrate with petroleum ether, and then adjust the pH of the water layer to 3-4 with 2 mol / L HCl, precipitate solid, suction filter, collect and filter The cake was vacuum-dried to obtain 11.3 g of the product (yield: 70.4%).

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Abstract

The invention provides a preparation method of propofol, which includes following steps: (1) performing Friedel-crafts reaction to p-nitrophenol and isopropanol or 2-halogenated propane under catalysis of an acid to prepare a compound I; (2) performing acylation protection to the compound I to prepare a compound II; (3) performing a reduction reaction to the compound II to prepare a compound III; (4) performing a diazo-reaction to the compound III to prepare a compound IV; and (5) under a weak reducing agent condition, performing a decomposition reaction to the compound IV and meanwhile carrying out hydrolysis under an alkaline condition to obtain the propofol V. The raw materials of the preparation method are easy to obtain. The preparation method is simple in process and is high in yield.

Description

technical field [0001] The present invention relates to a kind of novel preparation method of intravenous anesthetic propofol (Propofol). Background technique [0002] Propofol (Propofol, trade name: Propofol, Diprivan), chemically named 2,6-diisopropylphenol, is a widely used short-acting intravenous anesthetic of alkylphenols, through Activates GABA receptor-chloride ion complex to exert sedative and hypnotic effects. It has excellent characteristics such as rapid onset of action, 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. Since its anesthetic activity was discovered in 1977, it has been widely used clinically. [0003] [0004] In the method reported in patent US2831898 and CN200910140403.5, propofol is prepared by alkylation reaction of phenol or 2-isopropylphenol and propylene under high t...

Claims

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Application Information

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IPC IPC(8): C07C39/06C07C37/055
CPCY02P20/55
Inventor 于航蒿海军鲍峰
Owner LIAONING YAOLIAN PHARMA
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