CN114105811A - New etomidate impurity, preparation method and application thereof - Google Patents

New etomidate impurity, preparation method and application thereof Download PDF

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CN114105811A
CN114105811A CN202010896594.4A CN202010896594A CN114105811A CN 114105811 A CN114105811 A CN 114105811A CN 202010896594 A CN202010896594 A CN 202010896594A CN 114105811 A CN114105811 A CN 114105811A
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impurity
formula
etomidate
preparation
acid
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邓声菊
王田园
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Beijing Sihuan Pharmaceutical Co Ltd
Benxi Hengkang Pharmaceutical Co Ltd
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Beijing Sihuan Pharmaceutical Co Ltd
Benxi Hengkang Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C241/00—Preparation of compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/26—Conditioning of the fluid carrier; Flow patterns
    • G01N30/28—Control of physical parameters of the fluid carrier
    • G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/86—Signal analysis
    • G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information

Abstract

The invention provides a novel etomidate impurity with a structure shown as a formula I and a preparation method thereof,

Description

New etomidate impurity, preparation method and application thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a novel etomidate impurity, and a preparation method and application thereof.
Background
Etomidate is an intravenous anesthetic used for general anesthesia induction, and the industrial preparation route of Etomidate according to literature reports (modern applied medicine, 1997, (1): 30-31, 19970201; US3354173A, 19671121) is as follows:
Figure BDA0002658649790000011
in the above synthetic route, in step 5, namely the synthetic reaction of etomidate, once the product PM-1 in step 1 is remained, nitrosamine compounds are generated when the remained PM-1 participates in the reaction in step 5. Nitrosamines have a carcinogenic risk and belong to the "queue of attention" material mentioned in the guidelines of the international conference on harmonization (ICH) for registration of drugs for human use, for the assessment and control of DNA reactive (mutagenic) impurities in drugs to limit potential carcinogenic risk.
Therefore, it is necessary to monitor the impurities of nitrosamine compound (such as the impurities with the structure shown in formula I) generated by the preparation method, so as to ensure the safety of etomidate preparation.
Disclosure of Invention
The invention aims to provide a novel etomidate impurity with a structure shown as a formula I,
Figure BDA0002658649790000021
it is also an object of the present invention to provide a process for the preparation of the impurity of formula I, comprising the steps of: weighing required amount of (R) -2- ((1-phenethyl) amino) ethyl acetate and nitrosation reagent, reacting in the presence of acid reagent to generate impurity of formula I,
Figure BDA0002658649790000022
in a preferred embodiment of the present invention, the reaction is performed in an organic solvent system, and the organic solvent is selected from any one of acetonitrile, dichloromethane, DMF, chloroform, or a combination thereof.
In a preferred embodiment of the present invention, the nitrosation reagent is selected from any one of sodium nitrite, potassium nitrite, ethyl nitrite, methyl nitrite, nitrous acid, or a combination thereof.
In a preferred embodiment of the invention, the molar ratio of the reaction mass (R) -2- ((1-phenylethyl) amino) ethyl acetate to the nitrosating agent is 1:2 to 1:6, preferably 1:3 to 1: 5.
In a preferred embodiment of the present invention, the acidic reagent is selected from an organic acid or an inorganic acid.
In a preferred technical scheme of the invention, the organic acid is selected from any one of p-toluenesulfonic acid, benzoic acid, trifluoroacetic acid and trichloroacetic acid or a combination thereof; the inorganic acid is selected from any one of hydrochloric acid, sulfuric acid and nitric acid or the combination of the hydrochloric acid, the sulfuric acid and the nitric acid.
In a preferred technical scheme of the invention, a reaction material (R) -2- ((1-phenethyl) amino) ethyl acetate: the molar ratio of the acidic reagents is 1:1 to 1:3, preferably 1: 2.
In the preferred technical scheme of the invention, the reaction temperature is 10-50 ℃, and preferably 20-30 ℃.
In a preferred technical scheme of the invention, the reaction time is not less than 5 hours, preferably not less than 8 hours.
In the preferred technical scheme of the invention, the impurity of the formula I is prepared after separation.
In the preferable technical scheme of the invention, the separation steps comprise extraction and concentration.
In a preferred embodiment of the present invention, the extraction solvent is selected from any one of ethyl acetate, chloroform, dichloromethane, isopropyl acetate, or a combination thereof.
In a preferred embodiment of the present invention, the concentration is selected from vacuum concentration or atmospheric concentration.
In the preferred technical scheme of the invention, the impurity of the formula I is prepared after separation and purification.
In a preferred technical scheme of the invention, the purification step is column chromatography or reduced pressure distillation.
In a preferred technical scheme of the invention, the column chromatography step comprises the following steps: (1) adding silica gel into the crude product of the impurity in the formula I, dissolving the crude product in a solvent 1, and concentrating the crude product to a solid; (2) adding the solid obtained in the step (1) into a silica gel column, and sequentially eluting with a solvent 2 and a solvent 3; (3) collecting eluate, and concentrating under reduced pressure.
In the preferred technical scheme of the invention, the silica gel is selected from 100-400 meshes, preferably 300-400 meshes.
In a preferred technical scheme of the invention, the solvent 1 for column chromatography is selected from any one of ethyl acetate, dichloromethane, acetonitrile, methanol and acetone or a combination thereof.
In a preferred technical scheme of the invention, the solvent 2 for column chromatography is selected from any one of n-hexane, n-heptane, petroleum ether or a combination thereof.
In a preferred technical scheme of the invention, the solvent 3 for column chromatography is selected from any one of ethyl acetate, n-hexane, petroleum ether, acetone and n-heptane or a combination thereof. Preferably a mixture of ethyl acetate to n-hexane, ethyl acetate to n-heptane, acetone to n-hexane and acetone to petroleum ether in a volume ratio of 1:5 to 1:15, preferably 1: 10.
It is also an object of the present invention to provide the use of an impurity of formula I as a standard or reference.
In a preferred technical scheme of the invention, the formula I is used as a standard substance or a reference substance for qualitatively or quantitatively detecting the quality and purity of etomidate or an intermediate thereof.
In a preferred technical scheme of the invention, the quantitative detection method adopts high performance liquid chromatography-mass spectrometry.
In a preferred embodiment of the present invention, the determination conditions of the hplc-mass spectrometry are as follows: octadecylsilane chemically bonded silica is used as a filling agent; performing linear gradient elution with 0.1% formic acid water as mobile phase A and methanol as mobile phase B at flow rate of 0.1-1 ml/min; the column temperature is 20-40 ℃; the mass to charge ratio of 237.0/105.0 was chosen as the detected ion pair.
Figure BDA0002658649790000041
In the preferred technical scheme of the invention, the flow rate is 0.5ml per minute; the column temperature was 30 ℃.
The invention also aims to provide an etomidate pharmaceutical composition with high safety, wherein the pharmaceutical composition contains etomidate or pharmaceutically acceptable salt thereof and the impurity of the formula I with the content of not more than 1 ppm.
In a preferred technical scheme of the invention, the content of impurities in the formula I in the pharmaceutical composition is not higher than 0.4 ppm.
In a preferred embodiment of the present invention, the pharmaceutically acceptable salt is selected from any one of mesylate, esylate, benzenesulfonate, fumarate, tartrate, hydrobromide, phosphate, hydrochloride, and sulfate.
One of the purposes of the invention is also to provide an etomidate pharmaceutical preparation with high safety, which consists of an etomidate pharmaceutical composition with high safety and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition contains etomidate or a pharmaceutically acceptable salt thereof and the content of the impurity of the formula I is not higher than 1 ppm.
In a preferred embodiment of the invention, the impurity content of the formula I in the preparation composition is not higher than 0.4 ppm.
In a preferred technical scheme of the invention, the pharmaceutical preparation is an injection, and more preferably is an injection emulsion.
It is another object of the present invention to provide a kit having anesthetic activity comprising the etomidate pharmaceutical composition or preparation with high safety and other drugs.
In a preferred technical scheme of the invention, the other drugs are selected from any one of lidocaine, butorphanol, propofol, scopolamine, midazolam, sufentanil, remifentanil, misoprostol, diazepam, pancuronium, atropine, ketamine and thiopentasodium or a combination thereof.
Unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the balance being weight/weight percent.
Compared with the prior art, the invention has the following beneficial technical effects:
according to the invention, nitrosamine impurities with carcinogenic risks and structures shown as formula I are prepared, characterized and confirmed for the first time, and the impurities shown as formula I are used as reference substances or standard substances for controlling the purity and quality of etomidate and a preparation intermediate thereof, so that the purity and quality of etomidate are ensured, the medicine quality is ensured, and the safety of clinical medication and the life health of patients are ensured.
Drawings
FIG. 1 of impurities of formula I1H NMR spectrum
FIG. 2 of impurities of formula I13C NMR spectrum
FIG. 3 MS spectra of impurities of formula I
FIG. 4 HPLC-MS of the impurity of formula I
FIG. 5 HPLC-MS spectra of etomidate related substances using impurities of formula I as control (sample 1)
Detailed Description
The present invention is illustrated by the following examples, which should be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Other insubstantial modifications and adaptations of the present invention can be made without departing from the scope of the present invention.
Example 1Preparation of the impurity of formula I
At 20-30 ℃, adding 50ml of acetonitrile into 5g of (R) -2- ((1-phenethyl) amino) ethyl acetate for dissolution, adding 6.66g of sodium nitrite and 9.18g of p-toluenesulfonic acid, keeping the temperature at 20-30 ℃, stirring for 14h, and detecting the completion of the reaction by TLC. Purified water (100g) was added to the reaction mixture, extracted with ethyl acetate (60 ml. times.2), the organic phases were combined, washed with purified water (100ml), and the organic phase was collected. The organic phase was concentrated at 45-50 ℃ under reduced pressure to give a yellow liquid.
The concentrated yellow liquid was loaded by a dry method, 10g of silica gel (300-400 mesh) was added, 50ml of ethyl acetate was added, and the mixture was concentrated under reduced pressure at 45 to 50 ℃. 50g of silica gel (300-400 mesh) was added to the column. Elution with n-hexane (200ml) was performed, followed by ethyl acetate: n-hexane (1: 10) (550ml) was eluted, and the eluate was collected and concentrated at 45 to 50 ℃ under reduced pressure to give 2.09g of a yellow liquid, yield 36.7%, HPLC purity (method below) 96.5%.
And (3) purity determination: taking a proper amount of the reaction product, precisely weighing, adding ethanol-water (50:50) to dissolve and quantitatively dilute into a solution containing about 2mg of the reaction product in each 1ml, and taking the solution as a test solution. Measuring by high performance liquid chromatography, using octadecylsilane chemically bonded silica as filler (YMC C)18100 mm. times.4.6 mm, 3 μm), 5g/L ammonium carbonate solution as mobile phase A and acetonitrile as mobile phase B, gradient elution was performed according to Table 1 below at a flow rate of 2.0ml per minute, a column temperature of 35 ℃ and a detection wavelength of 210 nm. Precisely measuring 10 mu l of test solution, injecting the test solution into a liquid chromatograph, and recording a chromatogram, wherein the purity of a main peak in the chromatogram of the test solution is not lower than 95.0 percent according to the calculation of an area normalization method.
TABLE 1
Figure BDA0002658649790000071
Structural identification is shown in FIGS. 1-3:
1H NMR(600MHz，DMSO)δ1.100～1.124ppm(3H，t，J＝7.2Hz)，δ1.808～1.820ppm(3H，d，J＝7.2Hz)，δ3.982～4.019ppm(2H，m)，δ4.055～4.082ppm(1H，d，J＝16.2H)，δ4.187～4.214ppm(1H，d，J＝16.2H)，δ5.839～5.875ppm(1H，m)，δ7.329～7.349(1H，m)，δ7.353～7.713(4H，m)。
13C NMR(600MHz，DMSO)：δ13.84ppm，δ18.85ppm，δ45.41ppm，δ60.75ppm，δ61.75ppm，δ127.17ppm(2C)，δ128.09ppm，δ128.66ppm(2C)，δ139.18ppm，δ165.45pp。
MS:[M+H]+＝236.9。
example 2 detection of Etomidate related substances by the use of impurities of formula I as control
Taking a proper amount of etomidate samples of different batches (3 batches), precisely weighing, adding a methanol solution for dissolving, and quantitatively diluting to prepare a solution containing about 100mg of etomidate in each 1ml as a test solution; an appropriate amount of the impurity of formula I synthesized in the examples was weighed precisely, dissolved in methanol solution and diluted quantitatively to give a solution containing about 40ng per 1ml as a control solution. According to the determination of high performance liquid chromatography-mass spectrometry, octadecylsilane chemically bonded silica is used as a filling agent (a chromatographic column with 3.0mm multiplied by 100mm and 3.5 mu m or equivalent performance); linear gradient elution was performed according to table 2 below using 0.1% formic acid water as mobile phase a and methanol as mobile phase B at a flow rate of 0.5ml per minute; the column temperature was 30 ℃. Using a mass spectrometer, electrospray positive ion mode (ESI)+) Performing multi-reaction monitoring (MRM), and selecting a mass-to-charge ratio of 237.0/105.0 as a detection ion pair (the source temperature is 550 ℃; ion spray voltage 5500 volts). Precisely measuring 5 mu l of a test solution and a reference solution, respectively injecting the test solution and the reference solution into a liquid chromatography-mass spectrometer, recording a chromatogram, wherein if an impurity peak of formula 1 exists in the chromatogram of the test solution, the peak area is calculated according to an external standard method, and the peak area does not exceed 0.4 ppm.
TABLE 2
Figure BDA0002658649790000091
The results of the impurity determination of formula I are shown in Table 3:
TABLE 3 results of etomidate related substances detected by the impurities of formula I as control
Item Mass to charge ratio Sample 1 Sample 2 Sample 3
Impurity of formula 1 237.0/105.0 Not detected out Not detected out Not detected out

Claims (10)

1. A novel etomidate impurity with a structure shown as a formula I,
Figure FDA0002658649780000011
2. a process for the preparation of the impurity of formula i according to claim 1, comprising the steps of: weighing required amount of (R) -2- ((1-phenethyl) amino) ethyl acetate and nitrosation reagent, reacting in the presence of acid reagent to generate impurity of formula I,
Figure FDA0002658649780000012
3. the preparation method of claim 2, wherein the reaction is carried out in an organic solvent system, and the organic solvent is selected from any one of acetonitrile, dichloromethane, DMF, chloroform or a combination thereof; the nitrosation reagent is any one or combination of sodium nitrite, potassium nitrite, ethyl nitrite, methyl nitrite and nitrous acid; preferably, the reaction mass (R) -ethyl 2- ((1-phenylethyl) amino) acetate to nitrosylating agent molar ratio is from 1:2 to 1:6, preferably from 1:3 to 1: 5; the acidic reagent is selected from organic acid or inorganic acid; reaction mass (R) -ethyl 2- ((1-phenylethyl) amino) acetate: the molar ratio of the acidic reagents is 1:1-1:3, preferably 1: 2; more preferably, the reaction temperature is from 10 ℃ to 50 ℃, preferably from 20 ℃ to 30 ℃.
4. A process according to claim 3, characterized in that the impurity of formula i is isolated and obtained; preferably, the separation step is extraction and concentration.
5. The process of claim 4, wherein the impurity of formula I is isolated and purified to obtain the compound; preferably, the purification step is column chromatography or distillation under reduced pressure; preferably, the column chromatography step comprises: (1) adding silica gel into the crude product of the impurity in the formula I, dissolving the crude product in a solvent 1, and concentrating the crude product to a solid; (2) adding the solid obtained in the step (1) into a silica gel column, and sequentially eluting with a solvent 2 and a solvent 3; (3) collecting eluate, and concentrating under reduced pressure.
6. Use of an impurity of formula i as defined in claim 1 as a standard or control; preferably, the formula i is used as a standard or control for qualitative or quantitative determination of the quality and purity of etomidate or an intermediate thereof.
7. The use of claim 6, wherein the quantitative detection method employs high performance liquid chromatography-mass spectrometry; preferably, the determination conditions of the high performance liquid chromatography-mass spectrometry are as follows: octadecylsilane chemically bonded silica is used as a filling agent; performing linear gradient elution with 0.1% formic acid water as mobile phase A and methanol as mobile phase B at flow rate of 0.1-1 ml/min; the column temperature is 20-40 ℃; selecting a mass-to-charge ratio of 237.0/105.0 as a detection ion pair;
Figure FDA0002658649780000021
more preferably, the flow rate is 0.5ml per minute; the column temperature was 30 ℃.
8. Etomidate pharmaceutical composition with high safety, which comprises etomidate or a pharmaceutically acceptable salt thereof and an impurity of formula I as defined in claim 1 in an amount of not more than 1 ppm; preferably, the impurity level of formula I is not higher than 0.4 ppm.
9. An etomidate pharmaceutical preparation with high safety, which consists of an etomidate pharmaceutical composition with high safety and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition contains etomidate or a pharmaceutically acceptable salt thereof and an impurity with the formula I as described in claim 1, wherein the impurity content is not higher than 1 ppm; preferably, the impurity level of formula I is not higher than 0.4 ppm.
10. A pharmaceutical pack having anaesthetic activity comprising the highly safe etomidate pharmaceutical composition or formulation of any of claims 8 or 9 and a further medicament.
CN202010896594.4A 2020-08-31 2020-08-31 New etomidate impurity, preparation method and application thereof Pending CN114105811A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110922361A (en) * 2019-11-21 2020-03-27 武汉大安制药有限公司 Etomidate oxidation impurity and preparation method thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110922361A (en) * 2019-11-21 2020-03-27 武汉大安制药有限公司 Etomidate oxidation impurity and preparation method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
敖玲玲: "高效液相色谱法测定依托咪酯异构体杂质", 《广州化学》, vol. 39, no. 2, pages 45 - 47 *

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