CN116262729A - Etomidate impurity compound, preparation method and application thereof - Google Patents
Etomidate impurity compound, preparation method and application thereof Download PDFInfo
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- CN116262729A CN116262729A CN202111532813.1A CN202111532813A CN116262729A CN 116262729 A CN116262729 A CN 116262729A CN 202111532813 A CN202111532813 A CN 202111532813A CN 116262729 A CN116262729 A CN 116262729A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention belongs to the technical field of chemical medicines, and particularly relates to an etomidate impurity compound, a preparation method and application thereof, wherein the compound can be used as an impurity reference substance for controlling the quality of etomidate and is beneficial to improving the quality control of corresponding medicines. Meanwhile, the invention provides a preparation method of the etomidate impurity compound.
Description
Technical Field
The invention belongs to the technical field of chemical medicines, and particularly relates to an etomidate impurity compound, a preparation method and application thereof.
Background
Etomidate (Etomidate) is a fast acting intravenous anesthetic with short duration and is characterized by high efficacy, low toxicity and slight influence on cardiovascular and respiratory systems. Etomidate is non-barbital intravenous sedative, is hydroxylation salt of imidazole, and has the structural formula shown in formula III, and molecular formula C 14 H 16 N 2 O 2 Molecular weight 244.29. The chemical name is (+) -1- (alpha-methylbenzyl) imidazole-5-carboxylic acid ethyl ester.
To date, the main processes reported in the literature for the preparation of etomidate have inevitably required an oxidative dehydrosulfhydrylation step.
Patent US3354173A, US3991072A, WO2014048568A1 reports the use of two different oxidant systems to effect the oxidative desulfurization step, respectively a concentrated nitric acid catalytic system, a hydrogen peroxide catalytic system. The advantage of using a concentrated nitric acid oxidation system is that the purity of the obtained product is higher, but the disadvantage of the method is more remarkable: the reaction process generates a large amount of poisonous gas nitrogen dioxide, pollutes the environment and has potential safety hazard. The hydrogen peroxide oxidation system can effectively avoid the generation of toxic gases, but can generate more side reaction impurities. The research of etomidate related impurities and the research of quality control are recently reported by looking up the literature. Therefore, the research on etomidate related impurities, the preparation of impurity reference substances, and the method has important significance for improving the quality control of etomidate.
Disclosure of Invention
1. Object of the invention
The invention aims to provide a kind of impurity compound for etomidate quality control research and provides a preparation method of the impurity compound with simple process.
2. Problems to be solved
Impurity compounds of formula I and formula II may be produced in etomidate synthesis process, and may remain in etomidate bulk drug. At present, no standard product is sold, no document report exists, and whether the existing analysis method can detect and control the impurity compound cannot be determined. Aiming at the problem that potential impurities possibly exist in etomidate in the prior art and effective quality control cannot be performed, corresponding impurity reference substances are obtained, and the method is beneficial to obtaining products with higher quality.
3. Technical proposal
In order to solve the problems, the invention is realized by the following technical scheme:
the invention provides etomidate impurity compounds, which have the structural formula:
further, the purity of the etomidate impurity compounds is 95-100%.
The invention provides a preparation method of the impurity compound, which comprises the following synthetic route:
the preparation method takes sulfydryl etomidate as a raw material, solvent solution is added, and the mixture is dropwise added into an oxidant under the stirring condition for temperature control reaction; and after the reaction is finished, separating and purifying to obtain the impurity compounds shown in the formulas I and II.
Further, the solvent is an organic solvent or an alkaline aqueous solution.
Further, the organic solvent is ethanol, dichloromethane, tetrahydrofuran or acetic acid.
Further, the alkaline aqueous solution is sodium hydroxide or potassium hydroxide aqueous solution.
Further, the oxidant is one or a combination of nitric acid and hydrogen peroxide.
Further, a proper amount of catalyst may be added to the oxidizing agent.
Further, the added catalyst is sodium nitrite or tungstic acid
Further, the reaction temperature is 10-70 ℃.
3. Advantageous effects
Compared with the prior art, the invention has the beneficial effects that:
(1) The etomidate impurity compound disclosed by the invention has higher purity, meets the requirements of impurity reference substances in quality control, can be used for development and verification of an etomidate analysis method, and is beneficial to improvement of the etomidate quality standard, so that the product quality of etomidate is better controlled.
(2) The preparation method of the etomidate impurity compound has simple process, the purity of the prepared impurity compound is 95-100%, and the preparation method can provide qualified impurity reference substances for quality control of etomidate.
Drawings
FIG. 1 is a mass spectrum of etomidate impurity compound (formula I) obtained in example 4 of the present invention;
FIG. 2 is a mass spectrum of etomidate impurity compound (formula II) obtained in example 4 of the present invention;
FIG. 3 is a nuclear magnetic resonance spectrum of etomidate impurity compound (formula I) obtained in example 4 of the present invention;
FIG. 4 is a nuclear magnetic resonance hydrogen spectrum of etomidate impurity compound (formula II) obtained in example 4 of the present invention;
FIG. 5 is a nuclear magnetic resonance spectrum of etomidate impurity compound (formula I) obtained in example 4 of the present invention;
FIG. 6 is a nuclear magnetic resonance spectrum of etomidate impurity compound (formula II) obtained in example 4 of the present invention;
FIG. 7 is a high performance liquid chromatogram of etomidate impurity compound (formula I) obtained in example 4 of the present invention;
FIG. 8 is a high performance liquid chromatogram of etomidate impurity compound (formula II) obtained in example 4 of the present invention;
FIG. 9 is a high performance liquid chromatogram of crude etomidate of the present invention;
fig. 10 is a high performance liquid chromatogram of a finished etomidate of the present invention.
Detailed Description
The invention is further described below in connection with specific examples, which, however, one skilled in the art will understand, are for illustration only and should not be construed as limiting the scope of the invention. All modifications, equivalent substitutions, improvements, etc. which are within the spirit and principles of the present invention are intended to be included within the scope of the present invention.
In the examples, if no specific conditions are noted, the process is carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The term "HPLC" refers to high performance liquid chromatography.
In the present invention, the operation temperature, if not limited, is carried out at room temperature.
In the following examples, the purity is HPLC purity unless otherwise specified.
The invention is further described below in connection with specific embodiments.
Example 1
The preparation method of the etomidate impurity compound comprises the following steps:
to the reaction flask was added 2.0g of mercaptoetomidate, 20ml of tetrahydrofuran was added, and the solution was stirred. The resulting solution was added dropwise to 5.0g of a 30% hydrogen peroxide solution, and the dropping speed was controlled. After the dripping, stirring and reacting for 5 hours at about 55 ℃. After the reaction is finished, the reaction liquid is extracted by methylene dichloride, washed by water and concentrated under reduced pressure, and crude products of the impurity compounds are obtained. Separating and purifying by column chromatography to obtain 0.43g of impurity compound of formula I with purity of 95.2%; 0.55g of impurity compound II with purity of 96.8%.
Example 2
The preparation method of the etomidate impurity compound comprises the following steps:
to the reaction flask was added 2.0g of mercaptoetomidate, and 10ml of methylene chloride was added thereto and the mixture was dissolved by stirring. The resulting solution was added dropwise to 6.0g of a 30% hydrogen peroxide solution (0.1 g of tungstic acid was added), and the dropping speed was controlled. After the dripping, stirring and reacting for 10 hours at about 40 ℃. After the reaction is finished, the reaction liquid is extracted by methylene dichloride, washed by water and concentrated under reduced pressure, and crude products of the impurity compounds are obtained. Separating and purifying by column chromatography to obtain 0.37g of impurity compound of formula I with purity of 95.8%; 0.49g of impurity compound of formula II, purity 96.2%.
Example 3
The preparation method of the etomidate impurity compound comprises the following steps:
to the reaction flask was added 5.0g of mercaptoetomidate, and 30ml of acetic acid was added thereto and the mixture was dissolved by stirring. The resulting solution was added dropwise to a 30% hydrogen peroxide solution of 10.0. 10.0 g, and the dropping speed was controlled. After the dripping, stirring and reacting for 3 hours at about 65 ℃. After the reaction is finished, the reaction liquid is extracted by methylene dichloride, washed by water, decompressed and concentrated to obtain crude products of the impurity compounds. Preparing, separating and purifying to obtain etomidate impurity compounds with the formula I of 1.27g and the purity of 95.2 percent; impurity compound formula II 1.15g, purity 96.8%.
Example 4
The embodiment provides an impurity compound reference substance in quality control of etomidate preparation process, and the preparation method comprises the following steps:
sodium hydroxide 0.15g is added into a reaction bottle, purified water 5ml is added into the reaction bottle for stirring and dissolving, and mercaptoetomidate 5.0g is added into the reaction bottle for stirring and dissolving for standby. The resulting solution was added dropwise to 20g of a 30% hydrogen peroxide solution, and the dropping rate was controlled. After the dripping, stirring and reacting for 12 hours at about 50 ℃. After the reaction is finished, the reaction liquid is extracted by methylene dichloride, washed by water and concentrated under reduced pressure, and crude products of the impurity compounds are obtained. Preparing and purifying by a separation method to obtain 1.23g of impurity compound of the formula I and 98.1% of purity; impurity compound of formula II 1.57 g, 99.3% purity.
Claims (10)
1. An etomidate impurity compound, which is characterized in that: the structural formula is as follows:
2. etomidate impurity compound according to claim 1, characterized in that: the purity of the impurity compounds is 95% -100%.
3. A process for the preparation of etomidate impurity compounds according to claim 1 or 2, characterized in that: sulfydryl etomidate is dissolved in a solvent, and is dropwise added into an oxidant under stirring to react under temperature control; and after the reaction is finished, separating and purifying to obtain the etomidate impurity compound, wherein the reaction formula is as follows:
4. a process for the preparation of etomidate impurity compounds according to claim 3, characterized in that: the solvent is an organic solvent or an alkaline aqueous solution.
5. A process for the preparation of etomidate impurity compounds according to claim 3 or 4, characterized in that: the organic solvent is ethanol, dichloromethane, tetrahydrofuran or acetic acid.
6. A process for the preparation of etomidate impurity compounds according to claim 3 or 4, characterized in that: the alkaline aqueous solution is sodium hydroxide aqueous solution or potassium hydroxide aqueous solution.
7. A process for the preparation of etomidate impurity compounds according to claim 3, characterized in that: the oxidant is one or a combination of nitric acid and hydrogen peroxide.
8. A process for the preparation of etomidate impurity compounds according to claim 3 or 7, characterized in that: an appropriate amount of catalyst may be added to the oxidizing agent.
9. A process for the preparation of etomidate impurity compounds according to claim 3, characterized in that: the reaction temperature is 10-70 ℃.
10. Use of an etomidate impurity compound according to claim 1 or 2, characterized in that: the impurity compound is used as an impurity reference substance and applied to the quality control of etomidate.
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| CN116265442A (en) * | 2021-12-16 | 2023-06-20 | 燃点(南京)生物医药科技有限公司 | Preparation method of etomidate |
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| CN116265442A (en) * | 2021-12-16 | 2023-06-20 | 燃点(南京)生物医药科技有限公司 | Preparation method of etomidate |
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