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Synthesis method and application of fospropofol sodium and intermediates thereof

A technology of fospropofol sodium and its synthesis method, which is applied in the field of drug synthesis and application, can solve the problems of large side effects and low biological safety, and achieve the effects of simple operation, high yield and mild conditions

Active Publication Date: 2021-09-21
RINGPU TIANJIN BIOLOGICAL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] However, in the traditional process, the synthesis of such compounds often uses chlorobromomethane as a highly toxic reagent, which has large side effects and low biological safety.

Method used

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  • Synthesis method and application of fospropofol sodium and intermediates thereof
  • Synthesis method and application of fospropofol sodium and intermediates thereof
  • Synthesis method and application of fospropofol sodium and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] A kind of preparation method of water-soluble propofol prodrug fospropofol sodium, its preparation method comprises the following steps:

Embodiment 1-a

[0046] Dissolve compound A (propofol) in DMF (5V: the volume mass ratio of DMF to compound A is 5 mL / g), add potassium carbonate (2.0eq: the molar ratio of potassium carbonate to compound A is 2.0), Cool the reaction solution to 0-5°C, add CH dropwise under stirring 3 I(2.0eq:CH 3 The molar ratio of I to Compound A is 2.0) in DMF (1V: DMF vs. CH 3 The volume to mass ratio of I is 1mL / g) solution. After the dropwise addition, it was raised to room temperature for 2-3h reaction, monitored by TLC plate layer. After the reaction was completed, the reaction solution was diluted into ice water, and a large amount of solid was precipitated, filtered and dried to obtain the compound The crude product of B, with a mass yield of 106.8%, was directly used in the next reaction without further purification.

Embodiment 1-b

[0048] Dissolve compound B in DMF (5V: the volume mass ratio of DMF to compound B is 5 mL / g), add phosphorus pentachloride (1.0eq: the molar ratio of phosphorus pentachloride to compound B is 1.0), and heat React at 70°C for 3-4 hours, monitor with TLC plate, filter after the reaction is completed, concentrate the filtrate, add water and ethyl acetate to the remaining liquid, separate the liquid, and use 1M HCl solution and saturated NaHCO for the organic phase respectively 3 The solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a crude compound C with a mass yield of 115.9%.

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Abstract

The invention provides a synthesis method of fospropofol sodium and intermediates thereof, the fospropofol sodium comprises an intermediate B and an intermediate C, the invention also provides application of the fospropofol sodium prepared by the synthesis method in an anesthetic sedative for animals. The synthesis method of fospropofol disodium avoids the use of a highly toxic reagent bromochloromethane, and has high safety; the prepared fosfopropofol intermediate is mild in reaction condition and simple and convenient to operate, the mass yield is greater than 97%, industrial production is easy, and a propofol prodrug prepared from fosfopropofol sodium synthesized by the synthesis method can generate the same clinical effect as that of a commercially available propofol emulsion injection, and the myocardial inhibition reaction caused by fospropofol anesthesia does not occur.

Description

technical field [0001] The invention belongs to the field of drug synthesis and application, and relates to the synthesis and application of a propofol prodrug. Background technique [0002] Propofol is a phenol derivative that has sedative and hypnotic effects after intravenous injection. It has been widely used for induction and maintenance of anesthesia or sedation. Propofol injection has been approved for use in animals in China. Propofol Injection is a kind of fat emulsion, in addition to causing local pain after injection, it may also cause blood vessel embolism. As a fat emulsion, it will bring inconvenience during transportation, storage and use. Fospropofol sodium and its hydrate are a water-soluble prodrug of propofol. After intravenous administration, the prodrug is metabolized by alkaline phosphatase on the surface of endothelial cells to produce the active drug propofol. It quickly reaches equilibrium in the brain tissue, thereby exerting a dose-dependent sedat...

Claims

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Application Information

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IPC IPC(8): C07C41/22C07C41/16C07F9/09A61K31/661A61P23/00A61P25/20C07C43/225C07C43/205
CPCC07C41/22C07C41/16C07F9/091A61K31/661A61P23/00A61P25/20C07C43/225C07C43/205
Inventor 梁莉刘爱玲李亚玲张玉良李守军吴燕子
Owner RINGPU TIANJIN BIOLOGICAL PHARMA
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