CN108164521B - Parecoxib sodium degradation impurity, and preparation method, detection method and application thereof - Google Patents
Parecoxib sodium degradation impurity, and preparation method, detection method and application thereof Download PDFInfo
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- CN108164521B CN108164521B CN201810173211.3A CN201810173211A CN108164521B CN 108164521 B CN108164521 B CN 108164521B CN 201810173211 A CN201810173211 A CN 201810173211A CN 108164521 B CN108164521 B CN 108164521B
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses parecoxib sodium degradation impurities shown in a formula I and a preparation method thereof, and solves the problem that parecoxib sodium degradation impurities are not researched in the prior art. The invention also discloses application of the degradation impurity and a high performance liquid chromatography detection method of the degradation impurity. The invention provides a foundation for the quality research, the standard research, the stability research and the mechanism research of adverse drug reactions of parecoxib sodium; meanwhile, a basis is provided for the selection of production, packaging, storage, transportation and application conditions of the parecoxib sodium.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to parecoxib sodium degradation impurities, and preparation and detection methods and application thereof.
Background
The tolterone is a water-soluble prodrug of valdecoxib (valdecoxib) which is a specific cyclooxygenase-2 (COX-2) inhibitor and can be intravenously and intramuscularly developed by Pharmacia, belongs to a coxib analgesic in antiarthritic drugs, and can be clinically used for treating moderate or severe postoperative acute pain. The effective component of the tablet is Parecoxib Sodium (Parecoxib Sodium), N- [ [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonyl ] propionamide Sodium salt.
The parecoxib sodium synthesis routes reported in the literature are more, and the difference of each process route is mainly reflected in the difference of the preparation process of the intermediate 3, 4-diphenyl-5-methylisoxazole. The factor analysis of comprehensive reaction conditions, industrialization degree and the like considers that the industrial synthesis process of the parecoxib sodium takes 3, 4-diphenyl-5-methylisoxazole as a raw material and realizes the preparation of the parecoxib sodium through the steps of chlorosulfonation, aminolysis, propionylation, salification and the like, and the synthesis route is as follows:
according to the comprehensive literature research content and the analysis of synthetic processes, the preparation process of the parecoxib sodium is considered to involve a strong alkali step, and the parecoxib sodium structure belongs to a basic compound, and the basic condition can cause the degradation of active groups such as propionamide in the structure during storage, transportation or use, for example, the hydrolytic degradation of the parecoxib sodium.
At present, research data on impurities degraded by parecoxib sodium are less, and oxidation impurities and hydrolysis impurities of parecoxib sodium are only described in the documents CurrentPharmaceutical Analysis,2017,13, 271-278. Therefore, in the process of parecoxib sodium process research, process impurities possibly generated in the process are researched, meanwhile, degradation impurities of the parecoxib sodium are investigated, the purpose is to provide guidance for parecoxib sodium quality research and further formulation of reasonable quality standards, provide basis for conditions of various links such as storage, transportation and use of parecoxib sodium finished products, and guarantee quality and stability of medicines and medication safety of patients.
Disclosure of Invention
One of the objects of the present invention is: aiming at the structural characteristics of parecoxib sodium and the problem that degradation impurities introduced in the processes of production, packaging storage and transportation of parecoxib sodium can cause the quality, stability and medication risk of medicines, the parecoxib sodium degradation impurities are provided, and a foundation is provided for the subsequent preparation process improvement, quality research, stability research, packaging storage and transportation condition selection and the like of parecoxib sodium.
The second purpose of the invention is: provides a preparation method of the degradation impurity.
The third purpose of the invention is that: provides the application of the degraded impurities.
The fourth purpose of the invention is that: a reference formulation comprising the degrading impurity is provided.
The fifth purpose of the invention is that: provides a high performance liquid chromatography detection method for the degraded impurities.
In order to achieve the purpose, the invention adopts the technical scheme that:
the parecoxib sodium degradation impurity has a structure shown as a formula I:
preferably, the compound is a pharmaceutically acceptable salt or solvate of the formula I.
The preparation method for degrading impurities comprises the following steps of carrying out a ring-closing reaction on a compound shown in a formula II in a solvent under the action of alkali to prepare a compound shown in a formula I:
further, the base is selected from any one or combination of n-butyl lithium, sec-butyl lithium, methyl lithium, tert-butyl lithium, hexyl lithium, cyclohexyl lithium and phenyl lithium, and an aminolithium derivative; wherein, the lithium amide derivative is selected from one or more of lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and lithium diisopropylamide is preferred.
The preparation method of the impurity degradation comprises the following steps that a compound shown in a formula III reacts with pinacol diboron under the condition of a catalyst 1, and then the compound is coupled with a compound shown in a formula IV under the condition of a catalyst 2 to prepare a compound shown in a formula I:
wherein X is selected from chlorine, bromine and iodine.
Wherein, the synthesis of the compound of formula II is prepared according to the method of US 2003105334; synthesis of Compounds of formula IV the compounds of formula IV are prepared by the method of Advanced Synthesis and Catalysis,2002,344(10), 1146-1151.
Further, the catalyst 1 and the catalyst 2 are respectively and independently selected from any one or more of palladium acetate, palladium tetrakis (triphenylphosphine), Pd/C, palladium chloride and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride.
Further, the reaction catalyzed by the catalyst 1 and the catalyst 2 is carried out under alkaline conditions, and the alkali is any one or more of potassium phosphate, potassium acetate, sodium acetate, potassium carbonate, sodium carbonate, cesium carbonate and lithium carbonate.
The parecoxib sodium degradation impurity shown in the formula I is applied to detection of parecoxib sodium intermediates, raw material medicines and/or preparations. The degraded impurities can be used for mechanism research of parecoxib sodium adverse reactions, quality standard research of parecoxib sodium intermediate, bulk drug and preparation production and application as a reference substance in quality control.
The reference reagent for detecting the impurity content in the parecoxib sodium intermediate, the bulk drug and/or the preparation comprises parecoxib sodium degradation impurities shown as a formula I.
The high performance liquid chromatography for detecting parecoxib sodium degradation impurities provided by the invention has the following chromatographic conditions: the chromatographic column is an analytical chromatographic column taking C8, C18 or phenyl bonded silica gel as a filler, acetonitrile or acetonitrile-methanol as a mobile phase A and a buffer salt solution with the pH of 2.8-3.2 as a mobile phase B, and elution is carried out according to an isocratic or gradient elution program.
Compared with the prior art, the invention has the following effects:
the parecoxib sodium degradation impurity shown as the formula I provides a foundation for quality research, standard research, stability research and mechanism research of adverse drug reactions of parecoxib sodium; meanwhile, a basis is provided for the selection of production, packaging, storage, transportation and application conditions of the parecoxib sodium. The degradation impurity can be used as a reference substance in quality standard research and quality control of raw material medicine and preparation production.
The invention also provides a preparation method of the parecoxib sodium degradation impurity, the method is short in synthetic route, mild in reaction condition and simple and convenient to operate, and the prepared parecoxib sodium degradation impurity is high in purity and can be used for preparing an impurity reference substance.
The detection method is simple and convenient to operate, accurate in result and capable of enabling parecoxib sodium and degradation impurities thereof to achieve baseline separation.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of parecoxib sodium degradation impurity shown in formula I (I) < CHEM >1H-NMR)。
FIG. 2 is a Mass Spectrum (MS) of parecoxib sodium degradation impurity shown in formula I.
FIG. 3 is a high performance liquid chromatogram of parecoxib sodium (24.243min) and its degradation impurities (44.524 min).
Detailed Description
The present invention provides the following embodiments to explain the present invention in more detail, but the scope of the subject matter of the present invention is not limited to the following embodiments, and all the techniques and processes realized by equivalent substitutions or combinations of compound groups, reagents, operations, reaction steps, etc. based on the present invention belong to the scope of the present invention.
Example 1
This example provides the preparation of a compound of formula I, which is represented by the following reaction scheme:
the specific operation is as follows: sequentially adding 2.5g of a compound shown in the formula II and 30mL of dry tetrahydrofuran into a round-bottom flask, slowly adding 11mL of n-butyllithium (1.6M) into the reaction solution at the low temperature of-78 ℃ under the protection of nitrogen, and continuously stirring for reaction for 2h after the addition is finished; the reaction was slowly warmed to room temperature and reacted overnight. The reaction was quenched by slowly adding saturated ammonium chloride solution to the reaction solution, extracted with ethyl acetate, the organic layer was dried, concentrated, and the residue was column chromatographed to give the compound of formula i (R ═ H) as a white solid, about 0.56g, yield: 24 percent; HPLC purity: 96.3 percent.
A compound of formula I:1H-NMR(CD3COCD3,400MHz)：＝8.04(d,J＝8.0Hz,1H),7.90(s,1H),7.72(d,J＝4.0Hz,1H),7.47～7.40(m,5H),3.10(q,J＝8.0Hz,2H),2.57(s,3H),1.29(t,J＝8.0Hz,3H)ppm。
MS-ESI(m/z):351.3(M-H)-。
example 2
This example provides the preparation of a compound of formula III, having the following reaction scheme:
the specific operation is as follows: 4.5g of 4-bromo-2-methoxycarbonylbenzenesulfonamide (preparation method reference Bioorganic & Medicinal Chemistry Letters 19 (2009)) and 6855-. Adding 20mL of water into the reaction solution to quench the reaction, extracting with ethyl acetate, drying an organic layer, concentrating, and carrying out column chromatography purification on the residue to obtain 1.5g of the compound shown in the formula III.
Example 3
This example provides the preparation of a compound of formula I, which is represented by the following reaction scheme:
adding 1.5g of the compound shown in the formula III in example 2, 1.7g of pinacol diboron, 0.3g of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, 1.2g of potassium acetate and 20ml of 1, 4-dioxane into a round-bottom flask, slowly heating the reaction liquid to 100 ℃ under the protection of nitrogen, reacting for 5 hours, cooling the reaction liquid to room temperature, filtering, concentrating the filtrate, and carrying out column chromatography purification on the residues to carry out subsequent reaction.
The product, 1.2g of the compound of formula IV, 0.2g of tetrakis (triphenylphosphine) palladium, 10mL of ethanol, and 5mL of 2M sodium carbonate solution were added to a round bottom flask in sequence, and the temperature was slowly raised to reflux with stirring. TLC monitored the progress of the reaction. The reaction was cooled to room temperature, 20mL of saturated brine was added, extraction was performed with ethyl acetate, the organic layer was dried and concentrated, and the residue was purified by column chromatography to give the compound of formula i as a white solid, about 0.5g, with two-step overall yield: 26 percent; HPLC purity: 97.8 percent.
Example 4
This example provides a high performance liquid chromatography detection of the photodegradable impurities of sodium palbociclate.
A detection instrument: agilent 1260 high performance liquid chromatograph
Chromatographic conditions are as follows: the chromatographic column is Agilength Eclipse XDB-C184.6 x 150mm 5 um; the column temperature was 40 ℃; the flow rate is 1.0 ml/min; the detection wavelength is 215nm, acetonitrile-0.01 mol/L disodium hydrogen phosphate solution (30: 70) is used as a mobile phase for isocratic elution, wherein the pH value of the 0.01mol/L disodium hydrogen phosphate solution is adjusted to 3.0 by phosphoric acid. The dosage of the composition is 30: 70.
preparation of a sample: and (3) putting 25mg of parecoxib sodium into a 50ml volumetric flask, adding 40% acetonitrile solution to dissolve and dilute the parecoxib sodium, and shaking up to obtain the parecoxib sodium.
Preparation of control: and (3) taking 11mg of the compound shown in the formula I and 23mg of parecoxib sodium, placing the compound and the parecoxib sodium in a same 50ml volumetric flask, adding 40% acetonitrile solution to dissolve and dilute the mixture to scale, and shaking up the mixture to obtain the parecoxib sodium.
Detection method: injecting 10 μ l of each of the sample solution and the reference solution into a liquid chromatograph, measuring according to the chromatographic conditions, recording a chromatogram, and finishing the measurement; the resulting chromatogram is shown in FIG. 3.
The result shows that the base line separation of the sodium reoxib and the photodegradable impurities can be achieved by adopting the method of the embodiment, the detection is rapid, and the result is accurate.
Example 5
This example provides a high performance liquid chromatography detection of the photodegradable impurities of sodium palbociclate.
A detection instrument: agilent 1260 high performance liquid chromatograph
Preparation of a sample: putting 25mg of parecoxib sodium into a 50ml volumetric flask, adding 40% acetonitrile solution to dissolve and dilute the solution, and shaking up to obtain the parecoxib sodium liquid
Preparation of control: and (3) putting 11mg of the compound shown in the formula I and 25mg of parecoxib sodium into a same 50ml volumetric flask, adding 40% acetonitrile solution to dissolve and dilute the mixture to scale, and shaking up the mixture to obtain the parecoxib sodium.
Gradient chromatographic conditions: octadecyl-bonded silica gel was used as a filler (e.g., Agilengt Eclipse XDB-C18; 150 mm. times.4.6 mm,5 μm). The detection wavelength was 215nm, the column temperature was 40 ℃ and the flow rate was 1.0ml per minute.
Mobile phase A: acetonitrile-methanol (4: 1)
Mobile phase B: 0.1% phosphoric acid solution
The gradient elution time sequence is as follows:
| time (min) | Mobile phase A% | Mobile |
| 0 | 20 | 80 |
| 3 | 20 | 80 |
| 22 | 65 | 35 |
| 27 | 65 | 35 |
| 28 | 20 | 80 |
| 35 | 20 | 80 |
Detection method: and (3) injecting 10 mu l of each of the sample solution and the reference solution into a liquid chromatograph, measuring according to the chromatographic conditions, recording a chromatogram, and finishing the measurement.
The result shows that the base line separation of the sodium reoxib and the photodegradable impurities can be achieved by adopting the method of the embodiment, the detection is rapid, and the result is accurate.
The above-mentioned embodiment is only one of the preferred embodiments of the present invention, and should not be used to limit the scope of the present invention, but all the insubstantial modifications or changes made within the spirit and scope of the main design of the present invention, which still solve the technical problems consistent with the present invention, should be included in the scope of the present invention.
Claims (2)
1. A preparation method of parecoxib sodium degradation impurities is characterized in that the degradation impurities have a structure shown as a formula I, and the preparation method comprises the following steps: sequentially adding 2.5g of a compound shown in the formula II and 30mL of dry tetrahydrofuran into a round-bottom flask, slowly adding 11mL of n-butyllithium 1.6M into the reaction solution at the low temperature of-78 ℃ under the protection of nitrogen, and continuously stirring for reaction for 2 hours after the addition; slowly heating the reaction solution to room temperature for reaction overnight; the reaction formula is as follows:
2. the method of claim 1, wherein the degradative impurity is a pharmaceutically acceptable salt of the compound of formula I.
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| CN108828127A (en) * | 2018-06-21 | 2018-11-16 | 上药东英（江苏）药业有限公司 | Liquid-phase chromatography method in relation to substance in a kind of detection Parecoxib Sodium and synthetic intermediate |
| CN110642801A (en) * | 2019-09-20 | 2020-01-03 | 深圳市祥根生物科技有限公司 | Preparation method of parecoxib meta-isomer impurity |
| CN111257441B (en) * | 2019-12-31 | 2022-07-29 | 河南润弘制药股份有限公司 | Method for detecting impurities in parecoxib sodium synthesis process |
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| WO1996025405A1 (en) * | 1995-02-13 | 1996-08-22 | G.D. Searle & Co. | Substituted isoxazoles for the treatment of inflammation |
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| CN106908525A (en) * | 2017-01-16 | 2017-06-30 | 山东省药学科学院 | A kind of analysis method for determining SC 69124 intermediate and SC 69124 about material |
| CN109568277A (en) * | 2019-01-30 | 2019-04-05 | 成都欣捷高新技术开发股份有限公司 | Citric acid is preparing application in SC 69124 sodium freeze-dried preparation composition and combinations thereof and preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2003029230A1 (en) * | 2001-10-02 | 2003-04-10 | Pharmacia Corporation | Method for preparing benzenesulfonyl compounds |
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| WO1997038986A1 (en) * | 1996-04-12 | 1997-10-23 | G.D. Searle & Co. | Substituted benzenesulfonamide derivatives as prodrugs of cox-2 inhibitors |
| CN104557755A (en) * | 2015-01-04 | 2015-04-29 | 成都克莱蒙医药科技有限公司 | Synthesis method for parecoxib sodium impurity |
| CN106908525A (en) * | 2017-01-16 | 2017-06-30 | 山东省药学科学院 | A kind of analysis method for determining SC 69124 intermediate and SC 69124 about material |
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