CN109485616B - Etodolac photodegradation impurity and preparation method thereof - Google Patents
Etodolac photodegradation impurity and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the field of biological medicines, and particularly relates to etodolac photodegradation impurities and a preparation method thereof. The invention adopts the steps of dissolving etodolac in an organic solvent, carrying out light irradiation destruction under the aerobic condition, and separating and purifying by adopting supercritical fluid chromatography to obtain high-purity etodolac photodegradation impurities. The total yield of the etodolac photodegradation impurities obtained by the invention exceeds 48%, the purification yield of the supercritical fluid chromatography exceeds 90%, and the purity of the etodolac photodegradation impurities is as high as 99.01%.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to etodolac photodegradation impurities and a preparation method thereof.
Background
Etodolac (etodolac) is a pyranose carboxylic acid steroid anti-inflammatory agent, inhibits the synthesis of Prostaglandin (PG) by blocking the activity of cyclooxygenase, and has anti-inflammatory, antipyretic and analgesic effects. Is clinically used for treating postoperative pain and relieving the symptoms of rheumatoid arthritis and osteoarthritis. Meanwhile, the wide use of medicines has become an emerging environmental pollution factor. Research and control of various impurity items in pharmaceutical production are essential.
Xumeiju et al (high performance liquid chromatography for measuring the content of etodolac, Guangdong chemical, 2013,40, (5)19-23) disclose that etodolac is subjected to acid destruction, alkali destruction, oxidation destruction, light destruction and thermal destruction tests respectively, and components after the destruction tests are detected to obtain a high performance liquid chromatogram after the destruction tests, but corresponding impurity items are not given.
Poeuphorbia lathyris, (high performance liquid chromatography for determining related substances in an etodolac sustained-release tablet, China pharmacy, No. 16, No. 17, 2005, 1330-1332) discloses four impurities of a plurality of etodolac sustained-release tablet damage tests and high performance liquid chromatography detection conditions thereof.
From the above, etodolac has poor stability, is damaged by acid, alkali, light, heat and the like, can generate dozens of impurities, has potential threat to clinical medication due to the generation of the impurities, and in order to better realize the economic and social benefits of the medicine, each impurity must be strictly controlled in the standard, and the definition of each impurity item is a problem which is urgently needed to be solved.
Disclosure of Invention
The invention aims to provide an etodolac photodegradation impurity compound, which has a structural formula shown in formula I.
The invention also provides a preparation method of the impurity compound of formula I, wherein the impurity compound of formula I photodegradation is obtained by dissolving the etodolac sample, then destroying the etodolac sample by illumination and purifying the etodolac sample. The reaction formula is shown below. The inventor further researches and discovers that the etodolac with the formula I photodegradation impurity compound may be further degraded, and the etodolac solution after being damaged by illumination needs to be purified to obtain the impurity compound with the formula I with high purity. However, the compound of formula i impurity prepared by normal phase chromatography or reverse phase chromatography is easily degraded in the post-treatment process. The inventor adopts supercritical fluid chromatography to purify the compound with the impurity of formula I, and improves the mobile phase, so that the yield and the purity of the compound with the impurity of formula I can be effectively improved, and the compound with the impurity of formula I can be further effectively prevented from being degraded again.
The preparation method for the etodolac photodegradation impurity compound of the formula I provided by the invention comprises the following steps:
(1) dissolving etodolac in an organic solvent, and performing illumination damage on an etodolac solution to obtain an etodolac illumination damage solution;
(2) purifying the etodolac light irradiation destruction liquid obtained in the step (1) by supercritical fluid chromatography, and collecting elution effluent liquid containing a target product;
(3) and (3) quickly concentrating and evaporating the elution effluent obtained in the step (2) to dryness to obtain the etodolac photodegradation impurity compound of the formula I.
Preferably, the organic solvent in step (1) is one or more of polar aprotic solvent or C1-C4 alkanol, and more preferably, the organic solvent is tetrahydrofuran, ethyl acetate, acetonitrile, ethanol or methanol.
Preferably, the illumination intensity in the step (1) is 3000-6000 Lx, and the illumination time is 10-20 h.
Preferably, the photodisruption described in step (1) is carried out under aerobic conditions. More preferably, the aerobic condition is that etodolac is dissolved in an organic solvent, and then is added with hydrogen peroxide solution for light damage; or dissolving etodolac in organic solvent, and introducing air or oxygen when the etodolac is damaged by illumination.
Preferably, hydrogen peroxide is added after the etodolac sample is dissolved in the step (1), wherein the mass concentration of the hydrogen peroxide is 1-5%, and the addition volume of the hydrogen peroxide is 0.5-1.5% of the volume of the etodolac solution. After the etodolac sample is dissolved, a proper amount of hydrogen peroxide solution is added, so that the photodegradation degree of the etodolac can be increased, and the etodolac can be converted into the photodegradation impurity compound shown in the formula I to a greater extent. When the amount of the hydrogen peroxide is too large, etodolac is more oxidized and damaged, and the occurrence of photodegradation reaction is inhibited.
Preferably, in step (2), the supercritical fluid chromatographic packing is bare silica gel, diol-based, amino-based, amide-based or zwitterionic chromatographic packing; more preferably, the supercritical fluid chromatography filler is a bare silica gel, diol silica gel matrix filler.
Preferably, the control range of the supercritical fluid chromatography is 30-35 ℃, and the pressure control range of the chromatographic system is 100-300 bar.
The chromatographic mobile phase in the step (2) adopts supercritical CO2Modifiers and additives. The modifier is one or more of polar aprotic solvent or C1-C4 alkanol, the additive is C1-C3 monobasic acid, more preferably, the modifier is one or more of tetrahydrofuran, acetonitrile, ethanol and methanol, and the additive is formic acid or acetic acid.
More preferably, the modifier is added in an amount of supercritical CO21.5-15% of the volume of the additive, and the addition amount of the additive is supercritical CO20.01-0.5% of the volume.
Preferably, the step (3) is carried out under the condition of keeping out light, and the temperature is controlled to be 20-30 ℃.
In a preferred embodiment, a method for preparing etodolac photodegradation impurities comprises the steps of:
(1) dissolving an etodolac sample in an organic solvent to prepare a solution with a certain concentration, adding a hydrogen peroxide solution with the mass concentration of 1-5% into the solution, and uniformly mixing to obtain an etodolac solution to be destroyed; placing the etodolac to-be-destroyed liquid in an illumination box to destroy the etodolac, wherein the illumination intensity is 3000-6000 Lx, and the illumination time is 10-20 h to obtain the etodolac illumination destruction liquid; sampling and detecting by HPLC.
(2) Purifying the etodolac photodisruption solution by supercritical fluid chromatography, wherein the supercritical fluid chromatography mobile phase is A, B, and the phase A is CO2The phase B is a mixed solution of a modifier and an additive, the control range of the supercritical fluid chromatography is 30-35 ℃, and the control range of the chromatographic system is 100-300 bar; and collecting elution effluent containing the target product by adopting a gradient elution program.
(3) And (3) quickly decompressing, concentrating and evaporating the elution effluent liquid obtained in the step (2) to dryness at the temperature of 20-30 ℃ in a dark place to obtain the photodegradation impurity shown in the formula I.
Preferably, the organic solvent in step (1) is tetrahydrofuran, ethyl acetate, acetonitrile, ethanol or methanol;
preferably, the adding amount of the hydrogen peroxide in the step (1) is 0.5-1.5% of the volume of the solution to be destroyed of the etodolac.
Preferably, the supercritical fluid chromatographic filler in the step (2) is naked silica gel, diol-based, amino-based, amide-based or zwitterionic chromatographic filler; more preferably the supercritical fluid chromatography filler is a bare silica gel or a silica gel diol matrix filler.
Preferably, the phase B modifier in the step (2) is one or more of polar aprotic solvent or C1-C4 alkanol, the additive is C1-C3 monobasic acid, more preferably, the phase B modifier is one or more of tetrahydrofuran, acetonitrile, ethanol and methanol, and the additive is formic acid or acetic acid.
Preferably, the modifier is added in an amount of supercritical CO21.5-15% of the volume of the additive, and the addition amount of the additive is supercritical CO20.01-0.5% of the volume.
Preferably, the elution process of the supercritical fluid chromatography purification of step (2) is gradient elution, and the elution gradient is shown in table 1:
TABLE 1 supercritical fluid chromatography elution gradient chart
In another preferred embodiment, a method for preparing etodolac photodegradation impurities comprises the steps of:
(1) dissolving an etodolac sample in an organic solvent to prepare a solution with a certain concentration to obtain an etodolac to-be-destroyed solution, placing the etodolac to-be-destroyed solution in an illumination box for destruction, introducing air or oxygen under stirring conditions, wherein the illumination intensity is 3000-6000 Lx, and the illumination time is 10-20 h to obtain the etodolac illumination destruction solution; sampling and detecting by HPLC.
(2) Purifying the etodolac photodisruption solution by supercritical fluid chromatography, wherein the supercritical fluid chromatography mobile phase is A, B, A is CO2The phase B is a mixed solution of a modifier and an additive, the control range of the supercritical fluid chromatography is 30-35 ℃, and the control range of the chromatographic system is 100-300 bar; and collecting elution effluent containing the target product by adopting a gradient elution program.
(3) And (3) quickly decompressing, concentrating and evaporating the elution effluent liquid obtained in the step (2) to dryness at the temperature of 20-30 ℃ in a dark place to obtain the photodegradation impurity shown in the formula I.
Preferably, the organic solvent in step (1) is tetrahydrofuran, ethyl acetate, acetonitrile, ethanol or methanol;
preferably, the supercritical fluid chromatographic filler in the step (2) is naked silica gel, diol-based, amino-based, amide-based or zwitterionic chromatographic filler; more preferably the supercritical fluid chromatography filler is a bare silica gel or a silica gel diol matrix filler.
Preferably, the phase B modifier in the step (2) is one or more of polar aprotic solvent or C1-C4 alkanol, the additive is C1-C3 monobasic acid, more preferably, the phase B modifier is one or more of tetrahydrofuran, acetonitrile, ethanol and methanol, and the additive is formic acid or acetic acid.
Preferably, the modifier is added in an amount of supercritical CO21.5-15% of the volume of the additive, and the addition amount of the additive is supercritical CO20.01-0.5% of the volume.
Preferably, the elution process of the supercritical fluid chromatography purification in step (2) is gradient elution, and the elution gradient is shown in table 1.
According to the detection method of the compound of the formula I, the etodolac photodegradation impurity compound of the formula I can be detected by high performance liquid chromatography, and the relative retention time is 0.95-0.97. The HPLC used in the present invention is purchased from Saimer Feishell science and technology. The chromatographic conditions were as follows:
HPLC instrument model: Thermo-Ultimate 3000;
a chromatographic column: Thermo-Hypersil-5 μm,4.6 x 150 mm;
mobile phase: phase a is 0.6% H3PO4Aqueous solution, b phase 0.6% H3PO4Acetonitrile solution; gradient elution.
The elution gradient is shown in table 2:
TABLE 2 elution gradient for HPLC detection of impurity compounds of formula I
Detection wavelength: 280nm
Flow rate: 1.0mL/min
Column temperature: 30 deg.C
The technical advantages of the invention are as follows:
(1) the light damage process of etodolac is assisted by introducing oxygen or air or adding hydrogen peroxide, so that the light degradation effect of etodolac can be enhanced, and the content of light degradation impurities is increased, so that the content of the compound of formula I etodolac light degradation impurities exceeds 50%.
(2) Using supercritical fluid chromatography with supercritical CO2And the mixture of the modifier and the additive is a mobile phase, so that the separation efficiency of the etodolac photodegradation impurity compound of formula I is high, and the sample yield is high.
(3) The post-treatment method for supercritical fluid chromatographic purification is simple and rapid, has strong pertinence, and effectively prevents the sample from being degraded again, and by adopting the technical scheme of the invention, the total yield of the formula I etodolac photodegradation impurities exceeds 48%, the supercritical fluid chromatographic purification yield exceeds 90%, and the purity of the formula I etodolac photodegradation impurities is as high as 99.01%.
Drawings
FIG. 1 is the photo-damage profile of etodolac of example 1;
FIG. 2 is a photo-damage spectrum of etodolac of comparative example 1;
FIG. 3 is the supercritical fluid chromatography purification profile of example 11 photo-disruption of samples with respect to etodolac, with peak positions of target products at retention times of 8.81;
figure 4 is an HPLC detection profile of example 11 etodolac photodegradation impurities.
Detailed Description
The present invention is described in further detail below with reference to specific examples, it is to be understood that the following examples are for illustrative purposes only and are not intended to limit the present invention, which will be apparent to those of ordinary skill in the art to which the present invention pertains.
The raw material etodolac sample used in the embodiment of the invention is provided by Shandong New era pharmaceutical industry Co., Ltd, and the HPLC purity is 99.06%; other raw materials used, unless otherwise specified, are those commonly used in the art and are commercially available.
Example 1: preparation of impurity compounds of formula I
Dissolving an etodolac sample in acetonitrile to prepare 100ml of 10mg/ml acetonitrile solution, adding 1ml of hydrogen peroxide solution with the mass fraction of 3%, and uniformly mixing to obtain etodolac solution to be destroyed; placing the etodolac to-be-destroyed liquid in an illumination destruction box, setting the temperature at 20 ℃, and carrying out illumination destruction for 15h at an illumination intensity of 5000Lx to obtain an etodolac illumination destruction liquid; a sample was taken for HPLC and the HPLC purity of the impurity compound of formula I was 60.91%.
Example 2: preparation of impurity compounds of formula I
Dissolving an etodolac sample in tetrahydrofuran to prepare 100ml of 15mg/ml tetrahydrofuran solution, adding 5ml of hydrogen peroxide solution with the mass fraction of 1%, and uniformly mixing to obtain etodolac solution to be destroyed; placing the etodolac to-be-destroyed liquid in an illumination destruction box, setting the temperature at 30 ℃, and carrying out illumination destruction for 20h at an illumination intensity of 3000Lx to obtain an etodolac illumination destruction liquid; a sample was taken for HPLC and the HPLC purity of the compound of formula I as an impurity was 57.45%.
Example 3: preparation of impurity compounds of formula I
Dissolving an etodolac sample in ethyl acetate to prepare 100ml of 10mg/ml ethyl acetate solution, adding 0.5ml of hydrogen peroxide solution with the mass fraction of 5%, and uniformly mixing to obtain etodolac to-be-destroyed solution; placing the etodolac to-be-destroyed liquid in an illumination destruction box, and carrying out illumination destruction for 10h at the set temperature of 25 ℃ and the illumination intensity of 6000Lx to obtain the etodolac illumination destruction liquid; a sample was taken for HPLC and the HPLC purity of the impurity compound of formula I was 55.65%.
Example 4: preparation of impurity compounds of formula I
Dissolving an etodolac sample in ethanol to prepare 100ml of 20mg/ml ethanol solution, adding 1.5ml of hydrogen peroxide solution with the mass fraction of 5%, and uniformly mixing to obtain etodolac solution to be destroyed; placing the etodolac to-be-destroyed liquid in an illumination destruction box, setting the temperature at 20 ℃, and carrying out illumination destruction for 15h at an illumination intensity of 5000Lx to obtain an etodolac illumination destruction liquid; a sample was taken for HPLC and the HPLC purity of the impurity compound of formula I was 53.76%.
Example 5: preparation of impurity compounds of formula I
Dissolving etodolac in methanol to prepare a methanol solution of 5mg/ml, uniformly mixing to obtain an etodolac solution to be destroyed, placing the etodolac in an illumination destruction box, continuously introducing air while stirring, setting the temperature at 20 ℃, and carrying out illumination destruction for 15h at an illumination intensity of 5000Lx to obtain an etodolac illumination destruction solution; a sample was taken for HPLC and the HPLC purity of the impurity compound of formula I was 50.89%.
Example 6: preparation of impurity compounds of formula I
Dissolving an etodolac sample in acetonitrile to prepare 100ml of 10mg/ml acetonitrile solution, adding 5ml of hydrogen peroxide solution with the mass fraction of 5%, and uniformly mixing to obtain etodolac solution to be destroyed; placing the etodolac to-be-destroyed liquid in an illumination destruction box, setting the temperature at 20 ℃, and carrying out illumination destruction for 15h at an illumination intensity of 5000Lx to obtain an etodolac illumination destruction liquid; a sample was taken for HPLC and the HPLC purity of the compound of formula I as an impurity was 16.73%.
Example 7: purification of the impurity Compound of formula I
Purifying etodolac photo-disruption solution by supercritical fluid chromatography with chromatographic column size of 19mm × 150mm, filler of naked silica gel and particle size of 5 μm, and eluent of A-CO2B is 5% ethanol and 0.1% formic acid; the detection wavelength is 280nm, the flow rate is 60ml/min, the column temperature is 33 ℃, and the system back pressure is 120 bar; loading 10ml of etodolac light damage liquid (with HPLC purity of 60.91%), running an elution gradient table in table 1, collecting elution effluent containing a target product, and sampling and detecting; and (3) quickly concentrating the elution effluent to be dry under the condition of water bath at 25 ℃ in a dark place under reduced pressure to obtain the impurity compound shown in the formula I, wherein the purification yield is 91.4%, and the HPLC purity is 98.56%.
Example 8: purification of the impurity Compound of formula I
Purifying etodolac light damage liquid by supercritical fluid chromatography, wherein the size of a chromatographic column is 19mm × 150mm, the filler is diol-based silica gel, the particle size is 5 μm, and the eluent is A-CO2B is 10% acetonitrile and 0.01% acetic acid; the detection wavelength is 280nm, the flow rate is 60ml/min, the column temperature is 30 ℃, and the system back pressure is 300 bar; loading 10ml of etodolac light damage liquid (HPLC purity is 57.45%), running an elution gradient table in table 1, collecting elution effluent containing a target product, and sampling and detecting; and (3) quickly concentrating the elution effluent to be dry under the condition of water bath at 20 ℃ in a dark place under reduced pressure to obtain the impurity compound shown in the formula I, wherein the purification yield is 92.3%, and the HPLC purity is 98.86%.
Example 9: purification of the impurity Compound of formula I
Purifying etodolac light damage liquid by supercritical fluid chromatography, wherein the size of a chromatographic column is 19mm × 150mm, the filler is amino silica gel, the particle size is 10 μm, and the eluent is A-CO2B is 1.5% tetrahydrofuran and 0.3% formic acid; the detection wavelength is 280nm, the flow rate is 60ml/min, the column temperature is 35 ℃, and the system back pressure is 200 bar; loading 10ml of etodolac light damage liquid (HPLC purity is 53.76%), running an elution gradient table in table 1, collecting elution effluent containing a target product, and sampling and detecting; subjecting the eluate to 30 deg.C water bathAnd (4) quickly concentrating under reduced pressure to dryness in a dark place to obtain the impurity compound shown in the formula I, wherein the purification yield is 90.1 percent, and the HPLC purity is 98.54 percent.
Example 10: purification of the impurity Compound of formula I
Purifying etodolac photo-disruption solution by supercritical fluid chromatography with chromatographic column size of 19mm × 150mm, filler of amide silica gel and particle size of 5 μm, and eluent of A-CO2B is 15% methanol and 0.5% acetic acid; the detection wavelength is 280nm, the flow rate is 60ml/min, the column temperature is 33 ℃, and the system back pressure is 150 bar; loading 10ml of etodolac light damage liquid (with HPLC purity of 60.91%), running an elution gradient table in table 1, collecting elution effluent containing a target product, and sampling and detecting; and (3) quickly concentrating the elution effluent to be dry under the condition of water bath at 25 ℃ in a dark place under reduced pressure to obtain the impurity compound shown in the formula I, wherein the purification yield is 91.6%, and the HPLC purity is 98.02%.
Example 11: purification of the impurity Compound of formula I
Purifying etodolac light damage liquid by supercritical fluid chromatography, wherein the size of a chromatographic column is 19mm × 150mm, the filler is diol-based silica gel, the particle size is 5 μm, and the eluent is A-CO2B is 10% methanol and 0.1% acetic acid; the detection wavelength is 280nm, the flow rate is 60ml/min, the column temperature is 33 ℃, and the system back pressure is 120 bar; loading 10ml of etodolac light damage liquid (with HPLC purity of 60.91%), running an elution gradient table in table 1, collecting elution effluent containing a target product, and sampling and detecting; and (3) quickly concentrating the elution effluent liquid to be dry under the condition of water bath at 25 ℃ in a dark place under reduced pressure to obtain the impurity compound shown in the formula I, wherein the purification yield is 94.5%, and the HPLC purity is 99.01%.
Example 12: purification of the impurity Compound of formula I
Purifying etodolac photo-disruption solution by supercritical fluid chromatography with chromatographic column size of 19mm × 150mm, filler of naked silica gel and particle size of 10 μm, and eluent of A-CO2B is 10% methanol; the detection wavelength is 280nm, the flow rate is 60ml/min, the column temperature is 33 ℃, and the system back pressure is 150 bar; loading 10ml of the etodolac light damage solution (HPLC purity 60.91%), running the elution gradient table in Table 1, and collecting the elution effluent containing the target productSampling and detecting; and (3) quickly concentrating the elution effluent to be dry under the condition of water bath at 25 ℃ in a dark place under reduced pressure to obtain the impurity compound shown in the formula I, wherein the purification yield is 72.8 percent, and the HPLC purity is 96.33 percent.
Example 13: purification of the impurity Compound of formula I
Purifying etodolac light damage liquid by supercritical fluid chromatography, wherein the size of a chromatographic column is 19mm × 150mm, the filler is zwitterionic chromatographic filler, the particle size is 10 μm, and the eluent is A-CO2B is 10% isopropanol and 0.1% formic acid; the detection wavelength is 280nm, the flow rate is 60ml/min, the column temperature is 33 ℃, and the system back pressure is 120 bar; loading 10ml of etodolac light damage liquid (with HPLC purity of 60.91%), running an elution gradient table in table 1, collecting elution effluent containing a target product, and sampling and detecting; and (3) quickly concentrating the elution effluent to be dry under the condition of water bath at 25 ℃ in a dark place under reduced pressure to obtain the impurity compound shown in the formula I, wherein the purification yield is 80.6%, and the HPLC purity is 97.76%.
Comparative example 1: preparation of impurity compounds of formula I
Dissolving an etodolac sample in acetonitrile to prepare 100ml of acetonitrile solution of 10mg/ml, and uniformly mixing to obtain etodolac solution to be destroyed; placing the etodolac to-be-destroyed liquid in an illumination destruction box, setting the temperature at 20 ℃, and carrying out illumination destruction for 15h at an illumination intensity of 5000Lx to obtain an etodolac illumination destruction liquid; a sample was taken for HPLC and the HPLC purity of the compound of formula I as an impurity was 5.88%.
Comparative example 2: purification of the impurity Compound of formula I
Using reversed phase high performance liquid chromatography, and optionally
Filling material, DAC-50 preparing column system; eluent: a-purified water and B-acetonitrile, respectively adding 0.1% acetic acid; detection wavelength: 280 nm; flow rate: 50 mL/min; loading 10mL of etodolac light damage liquid (the HPLC purity is 60.91%), running a gradient elution program in the table 3, and collecting elution effluent containing a target product; sampling and detecting; concentrating the eluate in water bath at 25 deg.C under dark condition, quickly concentrating under reduced pressure until no acetonitrile flows out, and collecting the eluateThe concentrated solution is frozen and dried in vacuum to obtain the impurity compound shown in the formula I, the purification yield is 59.7 percent, and the HPLC purity is 87.36 percent.
TABLE 3 reversed-phase HPLC elution gradient chart
The structure of the prepared etodolac photodegradation impurity compound of the formula I is confirmed:
HR ESI-MS(m/z):320.2069[M+H]+；
1H NMR(500MHz,CDCl3)H:7.98(s,NH),7.49(d,J＝7.7Hz,1H),7.39(t,J＝7.6Hz,1H),7.25(d,J＝7.4Hz,1H),2.77(dq,J＝7.5,1.0Hz,2H),1.26(t,J＝7.5Hz,3H),4.45(t,J＝12.0Hz,1H),4.16(ddd,J＝13.5,4.7,2.1Hz,1H),3.17(m,1H),2.47(dd,J＝14.7,3.4Hz,1H),3.18(d,J＝14.6Hz,1H),2.86(d,J＝14.6Hz,1H),2.11(dq,J＝14.4,7.3Hz,1H),1.96(dq,J＝12.7,6.4Hz,1H),1.13(t,J＝7.5Hz,3H).
13C NMR(125MHz,CDCl3)C:204.6(C),177.5(C),172.0(C),142.8(C),138.9(C),133.5(C),132.1(CH),128.7(CH),124.7(CH),80.7(C),63.7(CH2),42.9(CH2),35.9(CH2),30.5(CH2),23.6(CH2),14.2(CH3),7.9(CH3).
Claims (7)
1. a preparation method of an etodolac photodegradation impurity compound, the structural formula of the etodolac photodegradation impurity compound is shown in a formula I,
a formula I;
the preparation method comprises the following steps:
(1) dissolving etodolac in an organic solvent, and illuminating the etodolac solution to obtain an etodolac illumination destruction liquid;
(2) purifying the etodolac light irradiation destruction liquid obtained in the step (1) by supercritical fluid chromatography, and collecting elution effluent liquid containing a target product;
(3) quickly concentrating and evaporating the elution effluent obtained in the step (2) to dryness to obtain an etodolac photodegradation impurity compound of formula I;
wherein, the irradiation destruction in the step (1) is carried out under the aerobic condition, and the aerobic condition refers to that etodolac is dissolved in an organic solvent, and hydrogen peroxide solution is added for irradiation destruction; or dissolving etodolac in organic solvent, and introducing air or oxygen when the etodolac is damaged by illumination; the mass concentration of the hydrogen peroxide is 1-5%, and the adding volume of the hydrogen peroxide is 0.5-1.5% of the volume of the etodolac solution;
the supercritical fluid chromatographic mobile phase in the step (2) is supercritical CO2Adding modifier and additive; the modifier is one or more of polar aprotic solvent or C1-C4 alkanol, and the additive is C1-C3 monoacid; the addition amount of the modifier is supercritical CO21.5-15% of the volume of the additive, and the addition amount of the additive is supercritical CO20.01-0.5% of the volume.
2. The preparation method according to claim 1, wherein the organic solvent in step (1) is one or more of polar aprotic solvents or C1-C4 alkanols.
3. The method according to claim 1, wherein the organic solvent in step (1) is tetrahydrofuran, ethyl acetate, acetonitrile, ethanol or methanol.
4. The preparation method according to claim 1, wherein the illumination intensity in the step (1) is 3000-6000 Lx, and the illumination time is 10-20 h.
5. The method according to claim 1, wherein the supercritical fluid chromatography packing of step (2) is bare silica gel, diol-based, amino-based, amide-based or zwitterionic chromatography packing.
6. The method of claim 1, wherein the supercritical fluid chromatography filler of step (2) is a bare silica gel or silica gel matrix filler.
7. The preparation method according to claim 1, wherein the modifier is one or more of tetrahydrofuran, acetonitrile, ethanol and methanol, and the additive is formic acid or acetic acid.
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