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Alkaline amino acid ester salt of propofol

A technology of propofol basicity and amino acid ester, applied in the field of medicine, can solve the problems of difficult to obtain practical application, short compound induction time and duration, and achieve the effects of easy large-scale preparation, good water solubility and low cost

Inactive Publication Date: 2014-06-25
HAISCO PHARMA GRP INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] In 2003, Altomare et al. announced several cyclic amino acid ester propofol prodrugs (Highly water-soluble derivatives of the anesthetic agent propofol: in vitro and in vitro evaluation of cyclic amino acid esters, European Journal of Pharmaceutical Sciences, 2003, 20: 17-26), it is believed that the L-proamino acid ester of propofol may develop into a prodrug, but there is no follow-up report
[0010] Chinese invention patent CN 102020574 A discloses derivatives of propofol γ-aminobutyrate, but the derivatives of γ-aminobutyrate have no relevant biological activity, and the induction time and duration of some compounds are extremely short (several seconds to several More than ten seconds), it is difficult to obtain practical application

Method used

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  • Alkaline amino acid ester salt of propofol
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  • Alkaline amino acid ester salt of propofol

Examples

Experimental program
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Effect test

Embodiment 1

[0046] Embodiment 1: the synthesis of propofol histidine ester hydrochloride

[0047] Dissolve histidine (24g, 0.16mol) in a mixed solvent of 2M NaOH solution (300ml) and 1,4-dioxane (200ml), cool down to 0°C, and add di-tert-dicarbonate dropwise to the above system Butyl ester (176g, 0.805mol) in 1, 4-dioxane (200ml) was added dropwise and stirred overnight at 25°C. Add water (500ml) to the reaction system, stir, and extract the aqueous phase with petroleum ether three times (500ml×3). Add appropriate amount of citric acid (200g) to adjust the water phase to weak acidity (pH=6). The aqueous phase was extracted twice with ethyl acetate (500ml×2), and the organic phases were combined and washed three times with saturated brine (500ml×3). Dry over magnesium sulfate, filter, and wash the filter cake with ethyl acetate. The filtrate was concentrated to obtain N-Boc-protected histidine (Boc-His(Boc)-OH), a white solid, weight: 50 g, yield: 89%.

[0048] Propofol (37.6g, 0.211mo...

Embodiment 2

[0056] Embodiment 2: the synthesis of propofol arginine hydrochloride

[0057] Dissolve arginine (21g, 0.121mol) in a mixed solvent of 2M NaOH solution (300ml) and 1,4-dioxane (100ml), then cool down to 0°C, and add dicarbonate dicarbonate dropwise to the above system The solution of tert-butyl ester (92.5g, 0.424mol) in 1,4-dioxane (100ml) was added dropwise and stirred overnight at 25°C. Add water (500ml) to the reaction system, stir, and extract the aqueous phase with petroleum ether three times (200ml×3). Add appropriate amount of citric acid (200g) to adjust the pH value of the aqueous phase to weak acidity (PH=6). The aqueous phase was extracted twice with ethyl acetate (200ml×2), and the organic phases were combined and washed three times with saturated brine (200ml×3). Dry over magnesium sulfate, filter, and wash the filter cake with ethyl acetate. Concentrate filtrate, obtain the arginine (Boc-Arg(Boc) of N-Boc protection 2 )-OH), white solid, weight: 46g, yield: ...

Embodiment 3

[0066] Embodiment 3: the synthesis of propofol ornithine hydrochloride

[0067] Ornithine hydrochloride (37.6g, 0.183mol) was dissolved in a mixed solvent of 2M NaOH solution (350ml) and 1,4-dioxane (150ml), then cooled to 0°C, and added dropwise to the above system Di-tert-butyl dicarbonate (120g, 0.550mol) in 1,4-dioxane (200ml) was added dropwise and stirred overnight at 25°C. Add water (500ml) to the reaction system, stir, and extract the aqueous phase with petroleum ether three times (500ml×3). Add appropriate amount of citric acid (80g) to adjust the pH value of the aqueous phase to weak acidity (PH=6). The aqueous phase was extracted twice with ethyl acetate (500ml×2), and the organic phases were combined and washed three times with saturated brine (500ml×3). Dry over magnesium sulfate, filter, and wash the filter cake with ethyl acetate. The filtrate was concentrated to obtain N-Boc-protected ornithine (Boc-Orn(Boc)-OH), a white solid, weight: 56 g, yield: 92%. . ...

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Abstract

The invention discloses an alkaline amino acid ester salt of propofol, a preparation method and applications thereof. The preparation method comprises the following steps: taking alkaline amino acid as the raw material, subjecting alkaline amino acid to carry out reactions with ditertbutyl dicarbonate ester in an alkaline condition so as to obtain N-Boc alkaline amino acid, then subjecting the N-Boc alkaline amino acid to carry out condensation reactions with propofol in the presence of DCC / DMAP, and finally removing the Boc protection groups in an acidic condition so as to obtain the pharmaceutically-acceptable propofol alkaline amino acid ester salt represented by the structural formula I. The propofol alkaline amino acid ester salt can be used to prepare drugs for tranquilizing, hypnotics, and narcotics, has a good solubility in water, can release propofol in human body to generate pharmaceutical activity, is capable of being made into different dosage forms to apply to the clinic, and overcomes the shortages brought by single using of propofol. The synthesis method has the advantages of simple operation, available raw material, low cost, and strong versatility.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a basic amino acid ester salt of propofol, a preparation method thereof and their application in the preparation of sedative hypnotic and anesthetic drugs. Background technique [0002] Propofol, also known as 2, 6-diisopropylphenol (Propofol, formula II), is a widely used systemic intravenous anesthetic. It has rapid onset, short action time, quick and complete recovery; few adverse reactions, no accumulation in the body, no organ toxicity, and no sequelae; wide application range (can be used for anesthesia induction, maintenance and auxiliary epidural anesthesia), dosage Easy to master and other excellent features. Therefore, propofol has been more and more widely used in clinical surgical anesthesia, especially suitable for induction and maintenance of surgical operations and outpatient biopsies and various surgical anesthesia, and can also be used in cardiac, pediatric, neurosurgery ...

Claims

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Application Information

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IPC IPC(8): C07D233/64C07C279/14C07C277/08C07C229/26C07C227/18A61K31/4172A61K31/223A61P25/20A61P23/00
CPCC07D233/64C07C227/18C07C229/26C07C269/04C07C269/06C07C271/22C07C277/08C07C279/14C07C279/24
Inventor 邹永陈大峰陈洪王勇袁辛娅
Owner HAISCO PHARMA GRP INC
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