Phosphoryl carboxylic acid propofol ester derivative and preparation method thereof

A technology of phosphoryl carboxylic acid and phosphoryl mercaptocarboxylic acid, which is applied in phosphorous organic compounds, chemical instruments and methods, drug combinations, etc., can solve the problem of high industrialization cost, difficult preparation method of water-soluble prodrug, and low yield and other problems, to achieve the effect of fast onset, reduction or removal of injection pain, and high yield

Active Publication Date: 2010-01-27
HANGZHOU ADAMERCK PHARMLABS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The preparation method disclosed in this patent is difficult to realize its water-soluble prodrug on drugs that cannot withstand high temperature conditions, otherwise the yield is very low and the cost of industrialization is high

Method used

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  • Phosphoryl carboxylic acid propofol ester derivative and preparation method thereof
  • Phosphoryl carboxylic acid propofol ester derivative and preparation method thereof
  • Phosphoryl carboxylic acid propofol ester derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Synthesis of Propofol 2-Chloroacetate

[0036]

[0037] method one:

[0038] In a 500ml four-neck round-bottomed flask, install a mechanical stirrer, a nitrogen gas introduction device, a condenser tube and a thermometer, add 8.9g (0.05mol) 2,6-diisopropylphenol, 100mlTHF, 2.4g (0.1 mol) sodium hydride, and the reaction solution was stirred below 10°C until no bubbles were generated. (3.0mol, 225.88ml) chloroacetyl chloride was added dropwise to the reaction solution, followed by gas phase until the reaction was complete, the suspension was filtered, the filter cake was washed with THF, THF was concentrated under reduced pressure, and the remaining oil was vacuum (0-1 torr) , b.p=80°C) distillation to obtain propofol 2-chloroacetate.

[0039] Method Two:

[0040] Cool the chloroform solution of 33.88g (0.3mol) of chloroacetyl chloride with an ice bath to lower the temperature of the solution to below 5°C, then add the fine powder of 2,6-diisopropylsodium phenate i...

Embodiment 2

[0043] Synthesis of α-disodium phosphothioglycolate propofol

[0044]

[0045] In the three-necked flask, add sodium thiophosphate (72.03g, 0.2mol), propofol 2-chloroacetate (56.05g, 0.22mol) and 160ml of distilled water at one time, stir, and under ice water cooling, the temperature in the flask is natural Decrease to about 15°C, dropwise add 120ml of dimethyl sulfoxide (DMSO), the reaction temperature rises gradually, not exceeding 20°C, after the addition is complete, continue to stir until the reaction is complete to obtain a product solution; continue to add 95% ethanol dropwise to the solution 260ml, left for a while, overnight, to obtain a solid. Washed once with 45ml of alcohol, dried in a vacuum oven (30 inches Hg, 45° C.) for 48 hours to obtain a white solid α-disodium phosphothioglycolate propofol.

[0046] 1 H-NMR (D6-DMSO-D2O): δ1.29(d, 12H, 4CH3); 3.12(m, 2H, 2CH); 3.5(s, 2H, CH2); 6.91(t, H, CH); 7.31 (d, 2H, 2CH).

Embodiment 3

[0048] Synthesis of Propofol α-Disodium Phosphoryloxyacetate

[0049]

[0050] In a three-necked flask, add sodium phosphate (76.02g, 0.2mol), 2-propofol chloroacetate (56.05g, 0.22mol) and 160ml of distilled water at one time, stir, and under ice water cooling, the temperature in the flask naturally drops to At about 15°C, add 120ml of dimethyl sulfoxide (DMSO) dropwise, and the reaction temperature rises gradually, not exceeding 20°C. After the addition is complete, continue to stir until the reaction is complete to obtain a product solution; continue to add 260ml of 95% ethanol dropwise to the solution, Leave it for a while, overnight, to get a solid. Washed once with 45ml of alcohol, dried in a vacuum oven (30 inchesHg, 45° C.) for 48 hours to obtain a white solid α-disodium phosphooxyacetate propofol.

[0051] 1 H-NMR (D6-DMSO-D2O): δ1.29 (d, 12H, 4CH3,); 3.12 (m, 2H, 2CH); 4.97 (s, 2H, CH2); 6.91 (t, H, CH); 7.31 (d, 2H, 2CH).

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Abstract

The invention relates to a phosphoryl carboxylic acid propofol ester derivative which has the general formula (I). The method comprises the following steps: propofol reacts with 2-halogenated carboxylic acid and a derivative thereof by alkali to obtain corresponding ester and then the product reacts with phosphoric acid or thiophosphoric acid and the derivative thereof by dissolvent to obtain a water-soluble product or the propofol reacts with a 2-halogenated carboxylic acid phosphate ester derivative by the alkali to obtain the corresponding ester and then the ester is catalyzed, hydrogenated and salified to obtain the water-soluble product (I). The preparation method has mild reaction condition, high yield, simple operation and industrialized prospect, and a prepared oral preparation has the characteristics of high bioavailability, rapid absorption, high stability, and the like; and auxiliary materials with safety defects, such as a surface active agent, and the like can not be added into the prepared injection, thereby improving the stability of the preparation, reducing or removing injection pain, increasing the compliance of patients, overcoming the defects of propofol emulsion and having the advantage of obvious effect. The invention has the structural general formula (I).

Description

technical field [0001] The invention belongs to the field of chemical industry and pharmacy, and relates to a phosphoryl carboxylate propofol derivative and a preparation method thereof. It is used to solve the problems of its preparation and administration caused by the low water solubility of propofol. technical background [0002] Propofol is a fast-acting short-acting intravenous anesthetic. Because of its advantages of fast onset, rapid recovery, and no accumulation after continuous infusion, it has become the first drug for induction and maintenance of anesthesia, and is widely used in neurosurgery anesthesia, pediatric anesthesia, monitoring anesthesia, and sedation in ICU wards. However, due to its poor water solubility, fat emulsion injections are made by pharmaceutical methods, but as liquid emulsions, there are disadvantages such as thermodynamic and kinetic instability, easy contamination and microbial growth, and inconvenient storage and use. Injection pain is...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/165C07F9/09A61K31/683A61K31/661A61P23/00
Inventor 漆又毛揭清张冯敏
Owner HANGZHOU ADAMERCK PHARMLABS INC
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