CN112430215B - Etomidate emulsion injection impurity and preparation method thereof - Google Patents
Etomidate emulsion injection impurity and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the field of medicinal chemistry, and particularly relates to etomidate emulsion injection impurities and a preparation method thereof. The new impurity is 1- ((R) -1-phenylethyl) -1H-imidazole-5-carboxylic acid glyceride. In addition, the invention provides a preparation method of the impurity, the etomidate sodium salt and the acetone condensed glycerol are condensed by a condensing agent, extracted and subjected to column chromatography to obtain an intermediate etomidate acetone condensed glyceride, and the intermediate is subjected to acid hydrolysis, column chromatography and preparative liquid phase separation to obtain the new etomidate impurity.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to etomidate emulsion injection impurities and a preparation method thereof.
Background material
Etomidate is known by the chemical name (+) -1- (alpha-methylbenzyl) imidazole-5-carboxylic acid ethyl ester, and the structural formula of the etomidate is shown as follows:
etomidate is an imidazole derivative, is a non-barbiturate intravenous anesthetic with short-time action, has the advantages of quick response, stable anesthesia, quick recovery, slight interference on heart vessels, cerebral protection and the like, and is widely applied to anesthesia induction maintenance and long-term sedation of critically ill patients.
Etomidate is mainly used in two dosage forms: (1) water aqua: etomidate is added into propylene glycol with certain concentration to be dissolved to prepare the injection. (2) Fat emulsion: etomidate is dissolved in soybean oil, medium chain triglyceride, glycerin water, etc. to prepare the injection.
The research on impurities is the main content of drug research and development, and the safety, effectiveness and quality controllability of drugs are directly influenced throughout the research and development of drugs. Therefore, the research on the impurities in etomidate is of great significance.
Disclosure of Invention
The invention aims to provide a new etomidate impurity and a preparation method thereof, the impurity can be generated by the reaction of a degradation product etomidate acid in an etomidate fatty emulsion injection and an auxiliary material glycerol, and the invention provides a powerful support for the quality research and quality control of the etomidate emulsion injection.
The invention mainly aims to provide a new impurity in an etomidate emulsion injection, namely 1- ((R) -1-phenethyl) -1H-imidazole-5-carboxylic glyceride, which has a chemical structure shown in a formula I:
another object of the present invention is to provide a process for the preparation of new etomidate impurities represented by formula I, wherein the compound of formula II is condensed with acetone to obtain a compound of formula III, and the compound of formula III is hydrolyzed by acid to obtain new etomidate impurities represented by formula I, comprising two steps:
step 1: stirring sodium etomidate (compound of formula II), acetone-glycerol acetal, condensing agent and condensation activator in a solvent at room temperature for reaction, adding water and ethyl acetate for extraction after the reaction is finished, obtaining an organic phase, washing the organic phase with acid washing, alkali washing and saturated saline water in sequence, and concentrating the organic phase to dryness under reduced pressure to obtain an intermediate etomidate acetone-glycerol acetal (compound of formula III).
Step 2: heating and refluxing etomidate acetonide glyceride, a solvent and a catalytic amount of acid for reaction, concentrating the solvent after the reaction is finished, and performing column chromatography and preparative high performance liquid chromatography to obtain new etomidate impurities.
The further technical scheme of the invention is as follows:
the condensing agent in the step 1 is selected from one or more of dicyclohexylcarbodiimide, diisopropylcarbodiimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and preferably 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
The condensation activator in the step 1 is selected from one or more of 4-dimethylamino pyridine, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole and 4-pyrrolidinyl pyridine, and preferably is 4-dimethylamino pyridine.
The solvent in the step 1 is one or more selected from dichloromethane, tetrahydrofuran, N-dimethylformamide and acetonitrile.
The molar ratio of the condensing agent in the step 1 is 1.0-1.5 times that of etomidate sodium salt, and the molar ratio of the condensation activating agent is 0.25-0.5 times that of etomidate sodium salt.
The further technical scheme of the invention is as follows:
the acid in the catalytic amount in the step 2 is one or more selected from hydrochloric acid, trifluoroacetic acid, formic acid and p-toluenesulfonic acid, and preferably the p-toluenesulfonic acid.
The catalytic amount of acid in step 2 is 0.2-0.5 times the weight of the compound of formula III.
In view of the fact that the discovery of new etomidate impurities has important significance for the quality research and quality control of etomidate emulsion injection, the inventors also claimed the application of the structure of the compound of formula I as an impurity reference in the content analysis and quality control of etomidate emulsion injection.
The beneficial technical effects of the invention are as follows:
the invention provides a new etomidate impurity which has important significance for quality research and quality control of etomidate emulsion injection and a preparation method thereof. The preparation method is simple to operate, and the prepared new etomidate impurity can be used as a reference substance for qualitative and quantitative analysis, so that quality control of the etomidate emulsion injection is guaranteed.
Description of the drawings:
FIG. 1 is a graph showing the application of a compound of formula I as an impurity control in the determination of related substances of etomidate emulsion injection.
Detailed Description
The following examples are given to further illustrate the embodiments of the present invention. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Example (b):
this example provides a process for the preparation of a novel etomidate impurity (compound of formula I) comprising two steps:
example 1:
step 1:
to a 500mL single-necked flask were added etomidate sodium salt (20g), methylene chloride (300mL), followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (19.20g), 4-dimethylaminopyridine (2.57g), and acetonide (11.10g), and the mixture was stirred at room temperature for 20 hours. After the reaction, water (200mL) was added to the reaction mixture, and the layers were separated, and the organic layer was collected, followed by extraction of the aqueous phase with ethyl acetate (300mL), and the organic layers were combined, followed by washing with 10% aqueous citric acid (100 mL/time) 2 times, extraction of the aqueous phase with ethyl acetate (100 mL/time) 3 times, and the organic layers were combined, washed with 200mL of saturated aqueous sodium bicarbonate solution, followed by 200mL of saturated brine, and the organic layer was collected and concentrated to dryness to give 23.2g of an oil.
Step 2:
the oily substance (23.2g), methanol (300ml) and p-toluenesulfonic acid (4.64g) were charged into a 500ml single-neck flask, and the mixture was heated to 65 ℃ to reflux and reacted for 58 hours. After the reaction is finished, the solvent is concentrated under reduced pressure to obtain colorless oily substance, column chromatography (silica gel, 100 meshes and 200 meshes) is carried out to obtain 11.99g of yellow oily substance, and the yellow oily substance is separated by preparative high performance liquid chromatography to obtain new etomidate impurity.
Nuclear magnetic data (QUNANTUM-I-500MHz NMR spectrometer, internal standard: TMS solvent: DMSO-d)6) As follows:
1H-NMRδ(ppm)：1.843(d,J＝7.1Hz,3H)、3.504(m,2H)、3.712(m,1H)、4.048(m,1H)、4.180(m,1H)、4.6359(s,1H)、4.9399(s,1H)、6.262(q,J＝7.1Hz,1H)、7.209(m,2H)、7.269(m,1H)、7.331(m,2H)、7.717(d,J＝1.0Hz,1H)、8.270(d,J＝1.1Hz,1H)；
13C-NMRδ(ppm)：δ(ppm)：21.727(CH3)，54.733(CH)，62.513(CH2)，65.676(CH2)，69.213(CH)，121.875(C)，125.859*2(CH)，127.513(CH)，128.546*2(CH)，137.644(CH)，140.811(CH)，142.094(C)，159.601(C)。
2D-NMR-related fragment signals: deltaH4.048(m,1H), 4.180(m,1H) and δH3.712(m,1H) protons1H-1H COSY is related; and deltaC65.676(CH2) Is related to the carbon resonance peak HSQC of deltaC62.513(CH2)、δC159.601(C), HMBC. DeltaH3.712(m,1H) and δC159.601(C) has no HMBC correlation signal.
Note: s single peak; d, double peak; q quartet; m multiplets; dd doublet of doublets; heptad hept;
example 2:
step 1:
to a 500mL one-necked flask were added etomidate sodium salt (20g), methylene chloride (300mL), followed by dicyclohexylcarbodiimide (17.3g), 1-hydroxybenzotriazole (5.7g), and acetonide (11.10g), and stirred at room temperature for 20 hours. After the reaction, water (200mL) was added to the reaction mixture, and the layers were separated, and the organic layer was collected, followed by extraction of the aqueous phase with ethyl acetate (300mL), and the organic layers were combined, followed by washing with 10% aqueous citric acid (100 mL/time) 2 times, extraction of the aqueous phase with ethyl acetate (100 mL/time) 3 times, and the organic layers were combined, washed with 200mL of saturated aqueous sodium bicarbonate solution and 200mL of saturated brine, and the organic layer was collected and concentrated to dryness to give 20.1g of an oil.
Step 2:
the oily substance (20.1g), methanol (300ml) and trifluoroacetic acid (4.02g) were added to a 500ml single-neck flask, and the mixture was heated to 65 ℃ to reflux and reacted for 58 hours. After the reaction is finished, the solvent is concentrated under reduced pressure to obtain colorless oily matter, column chromatography (silica gel, 100 meshes and 200 meshes) is carried out to obtain 10.0g of yellow oily matter, and the yellow oily matter is separated by preparative high performance liquid chromatography to obtain new etomidate impurities.
Example 3:
step 1:
to a 500mL one-necked flask were added etomidate sodium salt (20g), methylene chloride (300mL), followed by diisopropylcarbodiimide (15.9g), 1-hydroxybenzotriazole (2.84g), and acetonide (11.10g), and the mixture was stirred at room temperature for 20 hours. After the reaction, water (200mL) was added to the reaction mixture, and the layers were separated, and the organic layer was collected, followed by extraction of the aqueous phase with ethyl acetate (300mL), and the organic layers were combined, followed by washing with 10% aqueous citric acid (100 mL/time) 2 times, extraction of the aqueous phase with ethyl acetate (100 mL/time) 3 times, and the organic layers were combined, washed with 200mL of saturated aqueous sodium bicarbonate solution, followed by 200mL of saturated brine, and the organic layer was collected and concentrated to dryness to give 20.5g of an oil.
Step 2:
the oily substance (20.5g), methanol (300ml) and hydrochloric acid (10.25g) were added to a 500ml single-neck flask, and the mixture was heated to 65 ℃ to reflux and reacted for 58 hours. After the reaction is finished, the solvent is concentrated under reduced pressure to obtain colorless oily substance, column chromatography (silica gel, 100 meshes and 200 meshes) is carried out to obtain 11.0g of yellow oily substance, and the yellow oily substance is separated by preparative high performance liquid chromatography to obtain new etomidate impurity.
Example 4: the application of the compound shown in the formula I as an impurity reference substance in measuring related substances of etomidate emulsion injection.
Chromatographic conditions are as follows: octadecylsilane bonded silica gel as a packing material (Agilent Eclipse XDB C184.6X 250mm, 5 μm, or equivalent performance column); acetonitrile-potassium dihydrogen phosphate solution (0.68 g potassium dihydrogen phosphate is taken, water is added for dissolution and dilution to 1000ml, the pH value is adjusted to 2.5 by phosphoric acid) (20:80) is taken as a mobile phase A, acetonitrile-water (90:10) is taken as a mobile phase B, tetrahydrofuran-water (80:20) is taken as a mobile phase C, and gradient elution is carried out according to the following table; flow rate was 1.5ml per minute; the detection wavelength is 220 nm; the column temperature was 50 ℃.
Test solution: etomidate emulsion injection is taken as a test solution.
Impurity control solution: an appropriate amount of the compound of formula I was diluted with methanol-water (60:40) to give a solution containing about 4. mu.g of the compound per 1ml, which was used as an impurity control solution.
The determination method comprises the following steps: precisely measuring 10 μ l of each of the sample solution and the impurity reference solution, respectively injecting into a liquid chromatograph, and recording chromatogram. If an impurity (formula I) peak exists in the chromatogram of the test solution, the impurity content is not more than 0.2 percent according to the calculation of the peak area by an external standard method.
The compound of formula I is used as an impurity reference substance to determine the detection results of related substances of different batches of etomidate emulsion injection, and the chromatogram is shown in figure 1.
| Batch number | S20190802 | S20190803 | S20190804 |
| Results | 0.088％ | 0.074％ | 0.071％ |
Claims (10)
1. A process for the preparation of a compound of formula I by condensing a compound of formula II with acetone glycerol to obtain a compound of formula III, and acid hydrolyzing the compound of formula III to obtain a novel etomidate impurity of formula I, comprising the steps of:
step 1: stirring a compound of a formula II, acetone glycerol, a condensing agent and a condensation activating agent in a solvent at room temperature for reaction, adding water and ethyl acetate for extraction after the reaction is finished to obtain an organic phase, washing the organic phase with acid, alkali and saturated saline water in sequence, and concentrating the organic phase under reduced pressure until the organic phase is dried to obtain a compound of a formula III;
step 2: heating a compound shown in the formula III, a solvent and a catalytic amount of acid for reaction, concentrating the solvent under reduced pressure after the reaction is finished, and carrying out column chromatography and separation to obtain a compound shown in the formula I.
2. The method according to claim 1, wherein the condensing agent used in step 1 is one or more selected from dicyclohexylcarbodiimide, diisopropylcarbodiimide, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
3. The method according to claim 2, wherein the condensing agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
4. The preparation method according to claim 1, wherein the condensation activator is one or more selected from 4-dimethylaminopyridine, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole and 4-pyrrolidinyl pyridine.
5. The process according to claim 4, wherein the condensation activator is 4-dimethylaminopyridine.
6. The preparation method according to claim 1, wherein the solvent in step 1 is one or more selected from dichloromethane, tetrahydrofuran, N-dimethylformamide and acetonitrile.
7. The preparation method of claim 1, wherein in step 1, the molar ratio of the condensing agent is 1.0-1.5 times of the molar ratio of the etomidate sodium salt, and the molar ratio of the condensation activating agent is 0.25-0.5 times of the molar ratio of the compound of formula II.
8. The preparation method according to claim 1, wherein the catalytic amount of the acid in step 2 is selected from one or more of hydrochloric acid, trifluoroacetic acid, formic acid and p-toluenesulfonic acid.
9. The method of claim 1, wherein the catalytic amount of acid of step 2 is p-toluenesulfonic acid.
10. The process of claim 1, wherein the catalytic amount of the acid used in step 2 is 0.2 to 0.5 times the weight of the compound of formula III.
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| CN103145554A (en) * | 2013-02-22 | 2013-06-12 | 玛耀生物医药（上海）有限公司 | Preparation method of 1-decanoyl-rac-glycerol compound |
| CN105055310A (en) * | 2015-08-30 | 2015-11-18 | 四川百利药业有限责任公司 | Etomidate composition used for injection and preparing method thereof |
| CN107445898A (en) * | 2016-05-30 | 2017-12-08 | 四川海思科制药有限公司 | N substituted imidazole carboxylic acid ester compounds and preparation method thereof and purposes in medicine |
| CN109553610A (en) * | 2018-12-21 | 2019-04-02 | 江西富祥药业股份有限公司 | A kind of preparation method of emtricitabine isomers |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103145554A (en) * | 2013-02-22 | 2013-06-12 | 玛耀生物医药（上海）有限公司 | Preparation method of 1-decanoyl-rac-glycerol compound |
| CN105055310A (en) * | 2015-08-30 | 2015-11-18 | 四川百利药业有限责任公司 | Etomidate composition used for injection and preparing method thereof |
| CN107445898A (en) * | 2016-05-30 | 2017-12-08 | 四川海思科制药有限公司 | N substituted imidazole carboxylic acid ester compounds and preparation method thereof and purposes in medicine |
| CN109553610A (en) * | 2018-12-21 | 2019-04-02 | 江西富祥药业股份有限公司 | A kind of preparation method of emtricitabine isomers |
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