CN115677733A - Compound for pranoprofen quality research and preparation method and application thereof - Google Patents
Compound for pranoprofen quality research and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a compound for researching the quality of pranoprofen, a preparation method and application thereof, and relates to the technical field of biological medicines. The compound is hydrogen oxide-, (E)‑2‑[1‑[3‑(10H-9-oxa-1-azaanthracen-6-yl) -2, 3-dimethoxyallyl]‑10H-9-oxa-1-azaanthracen-1-cation-6-yl]And (3) sodium propionate. The specific preparation method of the compound comprises the following steps: carrying out ketal reaction on the pranoprofen intermediate under the catalysis of sodium methoxide to generate a compound II, then carrying out rearrangement reaction on the compound II under the strong alkali condition to generate a compound III, removing hydrogen from the compound III to generate a compound IV, and then reacting the compound IV with pranoprofen to generate the compound. The compound can be applied to the process of pranoprofen preparation and impurity analysis, and can be used for pertinently tracking specific impurities, thereby being beneficial to the quality research of pranoprofen and having great significance to the pharmacokinetic and pharmacological toxicology researches.
Description
Technical Field
The application relates to the technical field of biomedicine, in particular to a compound for researching the quality of pranoprofen, and a preparation method and application thereof.
Background
Pranoprofen (2-5H- [1] benzopyran [2,3-b ] pyridin-7-yl propionic acid) (PP) is a nonsteroidal anti-inflammatory analgesic, and can mainly inhibit the activity of cyclooxygenase in vivo to reduce the biosynthesis of prostaglandin, thereby playing the roles of antipyresis, analgesia and anti-inflammatory. Internationally, pranoprofen formulations include tablets, oral solutions and eye drops. In recent years, there have been many attempts to develop nanoliposomes and nanogels for the treatment of skin diseases; or try to prepare it into nanogels and nanoparticles for the treatment of eye diseases.
However, at present, many kinds of impurities exist in the preparation process of pranoprofen, and if the impurities cannot be characterized, the researches such as product quality monitoring, quality research, pharmacology, toxicology and the like are affected.
In summary, it is necessary to understand the specific structure of impurities in the pranoprofen preparation process.
Disclosure of Invention
The invention aims to provide a compound for impurity positioning, standard limit establishment and pharmacological and toxicological research in a pranoprofen quality research process, in particular to a novel pranoprofen impurity, which is applied to the processes of pranoprofen preparation and impurity analysis and used for pertinently tracking and positioning and impurity limit calibration of the specific impurity.
In one aspect, the present application provides a compound for use in a pranoprofen mass study, the compound having a structural formula as shown in formula (I):
r is selected from Na + 、Mg 2+ 、K + 、Ca 2+ One kind of (1).
In a preferred embodiment, R is Na + The molecular formula of the compound for the pranoprofen mass study is C 32 H 28 N 2 O 6 NaOH, molecular weight 576.58, chemical name of said compound being hydro-oxy-, (E)-2-[1-[3-(10H-9-oxa-1-azaanthracen-6-yl) -2, 3-dimethoxyallyl]-10H-9-oxa-1-azaanthracen-1-cation-6-yl]And (3) sodium propionate.
On the other hand, the application also provides a preparation method of the compound for the pranoprofen mass study, which comprises the following steps:
firstly, carrying out rearrangement reaction and hydrogen extraction reaction on a compound II to generate a compound IV;
step two, reacting the compound IV with pranoprofen to obtain the compound for the pranoprofen mass study;
the structure of the compound II is shown as a formula (II), and the structure of the compound IV is shown as a formula (IV):
r is selected from Na + 、Mg 2+ 、K + 、Ca 2+ One kind of (1).
Preferably, R is Na + 。
Preferably, compound II undergoes a rearrangement reaction to produce compound III, the alpha hydrogen of the alkene of compound III is acidic, and the compound III is hydrogenated to alpha carbocation under strongly alkaline conditions, i.e., to produce compound IV.
Wherein compound III is represented by formula (III):
In a preferred embodiment, R in formula (II) is Na + The compound II is 1- (5H- [ 1)]Benzopyran [2,3-b]Pyridin-7-yl) -1, 1-dimethoxypropane-2-acetic acid sodium salt, wherein the compound IV is (Z) -3- (5H-benzopyran [2,3-b ]]Pyridin-7-yl) -2, 3-dimethoxyallyl, said compound III being (Z) -7- (1, 2-dimethoxypropyl-1-en-1-yl) -5H-benzopyran [2,3-b]Pyridine.
Further, the step one and/or the step two is/are performed under alkaline conditions, which are formed by adding a strong base.
Preferably, the strong base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide and potassium tert-butoxide.
Further, the strong base includes sodium hydroxide.
Further, the sodium hydroxide is a sodium hydroxide solution, and the concentration of the sodium hydroxide solution is 10% -40% m/v.
Preferably, the concentration of the sodium hydroxide solution in the first step is 20-40% m/v, and the concentration of the sodium hydroxide solution in the second step is 20-40% m/v; more preferably, the concentration of the sodium hydroxide solution in the first step is 30% m/v, and the concentration of the sodium hydroxide solution in the second step is 30% m/v.
The addition amount of the sodium hydroxide solution is 10-30% of the total volume.
Further, the reaction temperature of the first step is 20-40 ℃, and the reaction time is 3-5 h.
Preferably, the reaction temperature is 25-30 ℃, and the reaction time is 4 h.
Further, the mass ratio of the compound II to the pranoprofen is 1: (0.6-0.8).
Preferably, the mass ratio of the compound II to the pranoprofen is 1.
Preferably, the molar ratio of the compound IV to pranoprofen in the second step is 1: (0.9-1.3); more preferably, the molar ratio of the compound IV to pranoprofen in the second step is 1: (1.05-1.1).
Further, the reaction temperature of the second step is 20-40 ℃, and the reaction time is 1-4 h.
Preferably, the reaction temperature is 25-30 ℃, and the reaction time is 2 h.
Preferably, the solvent in the step one and/or the step two is selected from one or more of methanol, ethanol, isopropanol and ethyl acetate; more preferably, the solvent is methanol.
More preferably, said dissolving of compound II is 0.16 g per 1 mL of methanol.
Further, the preparation method of the compound II comprises the following steps: the 7- (2-chloropropyl) -5H-1 benzopyran 2,3-B pyridine is subjected to ketal reaction under the catalysis of a catalyst, wherein the catalyst is selected from one or more of sodium methoxide, sodium ethoxide and sodium tert-butoxide.
Preferably, the catalyst is sodium methoxide.
The 7- (2-chloropropoyl) -5H-1 benzopyran 2,3-B pyridine CAS:146330-68-9.
Preferably, the reaction conditions of the ketal reaction include: the reaction temperature is 20-40 ℃, and the reaction time is 3-6 h.
Preferably, the preparation method of the compound for the pranoprofen mass study further comprises a purification step.
More preferably, the purification step comprises one or more of acid-base neutralization, washing, silica gel column elution separation and petroleum ether beating.
In a preferred embodiment, a method for preparing a pranoprofen mass study compound comprises the steps of:
firstly, carrying out ketal reaction on 7- (2-chloropropyl) -5H-1 benzopyran 2,3-B pyridine under the catalysis of sodium methoxide to obtain a compound II, carrying out rearrangement reaction on the compound II under the alkaline condition formed by sodium hydroxide to generate a compound III, and carrying out hydrogen removal reaction on the compound III to generate a compound IV;
and step two, reacting the compound IV with pranoprofen under the alkaline condition formed by sodium hydroxide to obtain the compound for the pranoprofen mass study.
The compound II is 1- (5H- [ 1)]Benzopyran [2,3-b]Pyridin-7-yl) -1, 1-dimethoxypropan-2-acetic acid sodium salt, said compound III being (Z) -7- (1, 2-dimethoxypropyl-1-en-1-yl) -5H-benzopyran [2,3-b]Pyridine, the compound IV is (Z) -3- (5H-benzopyran [2, 3-b)]Pyridin-7-yl) -2, 3-dimethoxyallyl, said pranoprofen impurity being hydroxy-, (ii) pranoprofenE)-2-[1-[3-(10H-9-oxa-1-azaanthracen-6-yl) -2, 3-dimethoxyallyl]-10H-9-oxa-1-azaanthracen-1-cation-6-yl]And (3) sodium propionate.
In another aspect, the present application also provides the use of a compound as described above or a compound prepared by a method as described above for the preparation of a product for identifying the quality of pranoprofen.
The compound for the pranoprofen quality study in the application can be used as a new pranoprofen impurity in the pranoprofen synthesis process, the pharmacokinetic and pharmacological toxicology studies related to the compound are blank, and the compound is generally controlled as an unknown impurity in the current pranoprofen impurity study process.
In a preferred embodiment, the reaction mechanism involved in this application is as follows:
the compound I (namely pranoprofen intermediate, 7- (2-chloropropionyl) -5H-1 benzopyran 2,3-B pyridine) is subjected to ketal reaction under the catalysis of sodium methoxide to generate a compound II. And the compound II is subjected to rearrangement reaction under a strong alkali condition to generate a compound III. Wherein, the alpha-hydrogen of the alkene of the compound III is acidic, and is extracted into alpha carbocation under the condition of strong alkalinity, namely the compound IV is generated. Because the carbocation of the compound IV is unstable, the compound V (namely pranoprofen) is easy to attack the nitrogen atom in pyridine, and the quaternary amine can be hydroxylated under the strong alkaline condition, thereby generating the compound hydroxide of the application (A), (B), (C)E)-2-[1-[3-(10H-9-oxa-1-azaanthracen-6-yl) -2, 3-dimethoxyallyl]-10H-9-oxa-1-azaanthracen-1-cation-6-yl]And (3) sodium propionate.
The invention has the following beneficial effects:
1. the application discovers a new compound for the pranoprofen quality research for the first time, and the structure of the compound is represented;
2. the application provides a preparation method of a compound for the mass research of pranoprofen, wherein the purity is up to 98.7%, and the yield is up to 69.5%;
3. the novel pranoprofen mass research compound provided by the application can be used as a novel pranoprofen impurity to be applied to the process of pranoprofen preparation and impurity analysis, and the specific impurity is calibrated according to the targeted tracking and positioning and the impurity limit, so that the mass research of the pranoprofen is facilitated, and the novel pranoprofen mass research compound has great significance for the research of pharmacokinetics and pharmacological toxicology.
Drawings
The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the application and together with the description serve to explain the application and not to limit the application. In the drawings:
FIG. 1 shows pranoprofen impurity 1 H, spectrogram;
FIG. 2 is 1 H- 1 A H correlation spectrum (COSY) spectrum comprising FIG. 2-A, FIG. 2-B and FIG. 2-C;
FIG. 3 shows pranoprofen impurity 13 C-NMR spectrum;
FIG. 4 is 13 C- 1 An H correlation spectra (HSQC) plot, including FIG. 4-A, FIG. 4-B, and FIG. 4-C;
FIG. 5 is a remote 13 C- 1 An H correlation Spectrum (HMBC) plot, including FIG. 5-A, FIG. 5-B, and FIG. 5-C;
FIG. 6 is an ESI mass spectrum negative ion mode mass spectrum (ammonium acetate) plot;
FIG. 7 is an ESI mass spectrum, negative ion mode mass spectrum (ammonium acetate) plot;
FIG. 8 is an ESI mass spectrum negative ion mode mass spectrum (ammonium acetate) plot;
FIG. 9 is an ESI mass spectrum negative ion mode mass spectrum (ammonium acetate) diagram.
Detailed Description
The present disclosure will now be described in detail by way of example with reference to the accompanying drawings, in order to more clearly illustrate the general concepts of the present disclosure. In the following description, numerous specific details are set forth in order to provide a more thorough understanding of the present invention. It will be apparent, however, to one skilled in the art, that the present invention may be practiced without one or more of these specific details. In other instances, well-known features have not been described in order to avoid obscuring the invention.
Among them, the compound II can be obtained by purchase, and can also be synthesized in the following manner:
performing ketal reaction on 7- (2-chloropropionyl) -5H-1 benzopyran 2 and 3-B pyridine under the catalysis of sodium methoxide to obtain a compound II, wherein the reaction temperature is 20-40 ℃, and the reaction time is 3-6H.
The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer.
In the following embodiments, reagents or instruments used are not indicated by manufacturers, and are all conventional products available by commercial purchase, unless otherwise specified.
Example 1 Synthesis method
(1) Adding 65ml of methanol and 10.5 g of compound II into a 250ml three-neck flask, stirring and dissolving at room temperature, dropwise adding 10ml of 30% sodium hydroxide aqueous solution at the temperature of 25-30 ℃, controlling the temperature for 20min, and keeping the temperature at 25-30 ℃ for reaction for 4 h after dropwise adding;
(2) After the reaction is finished, continuously dropwise adding a methanol solution of pranoprofen (the methanol solution is prepared by dissolving 8.3 g of pranoprofen in 58 ml of methanol), controlling the temperature to be 25-30 ℃, completing dropwise adding within 30 min, and keeping the temperature of 25-30 ℃ for reaction for 2 h after the dropwise adding is finished;
(3) Concentrating under reduced pressure below 50 ℃ to recover methanol, after the methanol is recovered, controlling the temperature to be 10-15 ℃, dropwise adding 10% dilute hydrochloric acid to adjust the pH to 3-5, continuing to crystallize for 2 hours, filtering 10mL of ethanol to wash a filter cake, and drying the filter cake under reduced pressure below 40 ℃;
(4) A chromatographic column with the diameter of 3 cm is adopted, 78 g of silica gel is filled, dichloromethane methanol solution is washed (V dichloromethane: V methanol =2 1), the dried filter cake is added after uniform washing, 13 g of anhydrous sodium sulfate is paved on the column after the completion of the addition, dichloromethane methanol solution (V dichloromethane: V methanol = 2) is used for elution, the first eluate is collected, after the collection of the first eluate is completed, the first eluate is concentrated to be dry under reduced pressure below 40 ℃,50 mL petroleum ether methanol solution is beaten (45 mL petroleum ether; 5mL methanol) for 1 hour, the first eluate is filtered, and the filter cake is dried under reduced pressure at 40 ℃ to obtain the target product hydro-oxidation- (the target product is hydro-xy-) (5 mL methanol)E)-2-[1-[3-(10H-9-oxa-1-azaanthracen-6-yl) -2, 3-dimethoxyallyl]-10H-9-oxa-1-azaanthracen-1-cation-6-yl]Sodium propionate, 98.7% pure, 69.5% yield.
The compound II is 1- (5H- [1] benzopyran [2,3-b ] pyridine-7-yl) -1, 1-dimethoxypropane-2-sodium acetate.
Example 2 Synthesis method
(1) Adding 65ml of methanol and 10.5 g of compound II into a 250ml three-neck flask, stirring and dissolving at room temperature, dropwise adding 12 ml of 30% potassium hydroxide aqueous solution at the temperature of 25-30 ℃, keeping the temperature for 20min, and reacting at 25-30 ℃ for 3 h after dropwise adding;
(2) After the reaction is finished, continuously dropwise adding a methanol solution of pranoprofen (the methanol solution is prepared by dissolving 7 g of pranoprofen in 58 ml of methanol), controlling the temperature to be 25-30 ℃, completing dropwise adding within 30 min, and keeping the temperature of 25-30 ℃ for reaction for 1 h after the dropwise adding is finished;
(3) Concentrating under reduced pressure below 50 ℃ to recover methanol, after the methanol is recovered, controlling the temperature to be 10-15 ℃, dropwise adding 10% diluted hydrochloric acid to adjust the pH to 3-5, continuing to crystallize for 2 h, filtering 10mL of ethanol to wash a filter cake, and drying the filter cake under reduced pressure below 40 ℃;
(4) The method comprises the following steps of filling 78 g of silica gel into a chromatographic column with the diameter of 3 cm, washing with dichloromethane methanol solution (V dichloromethane: V methanol = 2), adding the dried filter cake after uniform washing, paving 13 g of anhydrous sodium sulfate on the chromatographic column after the completion of the addition, eluting with dichloromethane methanol solution (V dichloromethane: V methanol = 2)E)-2-[1-[3-(10H-9-oxa-1-azaanthracen-6-yl) -2, 3-dimethoxyallyl]-10H-9-oxa-1-azaanthracen-1-cation-6-yl]Sodium propionate, 96.9% purity, 57.3% yield.
The compound II is 1- (5H- [1] benzopyran [2,3-b ] pyridine-7-yl) -1, 1-dimethoxypropane-2-sodium acetate.
Example 3 Synthesis method
(1) Adding 65ml of methanol and 10.5 g of compound II into a 250ml three-necked flask, stirring and dissolving at room temperature, dropwise adding 15 ml of 30% sodium methoxide methanol solution at the temperature of 25-30 ℃,20min, and keeping the temperature at 25-30 ℃ for reaction for 3 h after dropwise adding;
(2) After the reaction is finished, continuously dropwise adding a methanol solution of pranoprofen (the methanol solution is prepared by dissolving 6.5 g of pranoprofen in 58 ml of methanol), controlling the temperature to be 25-30 ℃, completing dropwise adding within 30 min, and keeping the temperature of 25-30 ℃ for reaction for 3 h after the dropwise adding is finished;
(3) Concentrating under reduced pressure below 50 ℃ to recover methanol, after the methanol is recovered, controlling the temperature to be 10-15 ℃, dropwise adding 10% diluted hydrochloric acid to adjust the pH to 3-5, continuing to crystallize for 2 h, filtering 10mL of ethanol to wash a filter cake, and drying the filter cake under reduced pressure below 40 ℃;
(4) The method comprises the following steps of filling 78 g of silica gel into a chromatographic column with the diameter of 3 cm, washing with dichloromethane methanol solution (V dichloromethane: V methanol = 2), adding the dried filter cake after uniform washing, paving 13 g of anhydrous sodium sulfate on the chromatographic column after the completion of the addition, eluting with dichloromethane methanol solution (V dichloromethane: V methanol = 2)E)-2-[1-[3-(10H-9-oxa-1-azaanthracen-6-yl) -2, 3-dimethoxyallyl]-10H-9-oxa-1-azaanthracene-1-cation-6-yl]Sodium propionate, 96.7% purity, 53.4% yield.
The compound II is 1- (5H- [1] benzopyran [2,3-b ] pyridine-7-yl) -1, 1-dimethoxypropane-2-sodium acetate.
Example 4 synthetic methods
(1) Adding 65ml of methanol and 10.5 g of compound II into a 250ml three-necked flask, stirring and dissolving at room temperature, dropwise adding 17 ml of 30% sodium ethoxide methanol solution at the temperature of 25-30 ℃, keeping the temperature for 20min, and reacting at the temperature of 25-30 ℃ for 5h after dropwise adding;
(2) After the reaction is finished, continuously dropwise adding a methanol solution of pranoprofen (the methanol solution is prepared by dissolving 8.3 g of pranoprofen in 58 ml of methanol), controlling the temperature to be 25-30 ℃, completing dropwise adding within 30 min, and keeping the temperature of 25-30 ℃ for reaction for 4 hours after the dropwise adding is finished;
(3) Concentrating under reduced pressure below 50 ℃ to recover methanol, after the methanol is recovered, controlling the temperature to be 10-15 ℃, dropwise adding 10% diluted hydrochloric acid to adjust the pH to 3-5, continuing to crystallize for 2 h, filtering 10mL of ethanol to wash a filter cake, and drying the filter cake under reduced pressure below 40 ℃;
(4) The method comprises the following steps of filling 78 g of silica gel into a chromatographic column with the diameter of 3 cm, washing with dichloromethane methanol solution (V dichloromethane: V methanol = 2), adding the dried filter cake after uniform washing, paving 13 g of anhydrous sodium sulfate on the chromatographic column after the completion of the addition, eluting with dichloromethane methanol solution (V dichloromethane: V methanol = 2)E)-2-[1-[3-(10H-9-oxa-1-azaanthracen-6-yl) -2, 3-dimethoxyallyl]-10H-9-oxa-1-azaanthracen-1-cation-6-yl]Sodium propionate, 96.3% purity, 55.4% yield.
The compound II is 1- (5H- [1] benzopyran [2,3-b ] pyridine-7-yl) -1, 1-dimethoxypropane-2-sodium acetate.
Example 5 confirmation of pranoprofen impurity structure
1. Nuclear magnetic resonance spectroscopy
The instrument model is as follows: bruker Avance III HD 400MHz nuclear magnetic resonance spectrometer
And (3) testing conditions: solvent CD 3 OD
1 1 H nuclear magnetic resonance spectrum ( 1 H-NMR）
1.1 1 H nuclear magnetic resonance spectrogram
Of pranoprofen impurities 1 The spectrum H is shown in figure 1; 1 H- 1 the H correlation spectrum (COSY) is shown in FIG. 2 (including FIG. 2-A, FIG. 2-B and FIG. 2-C).
1.2 Measured data
The measurement data are shown in Table 1 and formula (2).
Table 1 pranoprofen impurity in CD 3 In OD 1 H-NMR data
1.3 1 H-NMR spectrum analysis
According to the COSY spectrum combined with the HSQC spectrum, pranoprofen impurity can be detected 1 Attribution of an H spectrum:
(1) 1 <xnotran> H 19 , 1 ∶ 1 ∶ 1 ∶ 1 ∶ 1 ∶ 1 ∶ 1 ∶ 1 ∶ 1 ∶ 1 ∶ 1 ∶ 1 ∶ 2 ∶ 2 ∶ 2 ∶ 1 ∶ 3 ∶ 3 ∶ 3, . </xnotran>
(2) Delta 8.10 hydrogen is a group of double peaks, and the number of protons is 1; COSY spectra show that this hydrogen is associated with a δ 7.17 hydrogen 34, assigned a hydrogen at position 33; the HSQC spectra show that this hydrogen is associated with carbon (. Delta.146.98), confirming a 33-hydrogen, confirming correct assignment.
(3) Delta 7.75 hydrogen is a group of double peaks, and the proton number is 1; COSY spectra show that this hydrogen is associated with a δ 7.17 hydrogen 34, assigned a hydrogen at position 35; the HSQC spectra show that this hydrogen is associated with carbon (. Delta.140.88), confirming a hydrogen at position 35, confirming correct assignment.
(4) Hydrogen at delta 7.54 is a group of broad doublets, and the number of protons is 1; COSY spectra show that this hydrogen is associated with δ 6.34 hydrogen 3, assigned as hydrogen at position 2; the HSQC spectra show that this hydrogen is associated with carbon (. Delta.136.96), confirming a hydrogen at position 2, confirming correct assignment.
(5) Hydrogen at δ 7.46 is a broad set of singlet with a proton number of 1, assigned as hydrogen at position 39; the HSQC spectra showed that this hydrogen was associated with carbon (. Delta.130.26), confirming the 39-position hydrogen, confirming the correct assignment.
(6) Hydrogen at delta 7.45 is a group of wide double peaks, and the number of protons is 1; COSY spectra show that this hydrogen is associated with the δ 7.13 hydrogen 28, assigned a 27-position hydrogen; the HSQC spectra show that this hydrogen is associated with carbon (. Delta.129.57), confirming a 27-position hydrogen, confirming correct assignment.
(7) Hydrogen at delta 7.32 is a group of wide double peaks, and the number of protons is 1; COSY spectra show that this hydrogen is associated with δ 6.34 hydrogen 3, being assigned the hydrogen at position 4; HSQC spectra showed that this hydrogen was associated with carbon (. Delta.139.31), confirming a hydrogen at position 4, confirming correct assignment.
(8) Hydrogen at delta 7.17 is a group of double peaks, and the number of protons is 1; COSY spectra show that this hydrogen is associated with a δ 7.75 hydrogen 35, a δ 8.10 hydrogen 33, assigned a hydrogen at position 34; the HSQC spectra show that this hydrogen is associated with carbon (. Delta.121.64), confirming a hydrogen at position 34, confirming correct assignment.
(9) Hydrogen at δ 7.13 is a set of doublets with a proton number of 1; COSY spectra show that this hydrogen is associated with the δ 7.45 hydrogen 27, being assigned the 28-position hydrogen; the HSQC spectra show that this hydrogen is associated with carbon (. Delta.117.65), confirming a 28-position hydrogen, confirming correct assignment.
(10) Hydrogen at delta 7.09 is a group of double peaks, the number of protons is 1, and the hydrogen is assigned to 8 positions; the HSQC spectra show that this hydrogen is associated with carbon (. Delta.131.01), confirming a hydrogen at position 8, confirming correct assignment.
(11) Hydrogen at delta 7.02 is a group of double peaks, and the number of protons is 1; COSY spectra show that this hydrogen is associated with the δ 6.75 hydrogen 11, assigned a hydrogen at position 10; the HSQC spectra show that this hydrogen is associated with carbon (. Delta.127.88), confirming a hydrogen at position 10, confirming correct assignment.
(12) Delta 6.75 hydrogen is a group of double peaks, and the proton number is 1; COSY spectra show that this hydrogen is associated with δ 7.02 hydrogen 10, being assigned the 11-position hydrogen; the HSQC spectra show that this hydrogen is associated with carbon (. Delta.117.39), confirming a hydrogen at position 11, confirming correct assignment.
(13) Hydrogen at delta 6.34 is a group of triplet peaks, and the number of protons is 1; COSY spectra show that this hydrogen is associated with δ 7.32 hydrogen 4, δ 7.54 hydrogen 2, assigned as hydrogen at position 3; the HSQC spectra show that this hydrogen is associated with carbon (. Delta.108.68), confirming a hydrogen at position 3, confirming correct assignment.
(14) Hydrogen at δ 5.08 is a group of single peaks, proton number is 2, and assignment is hydrogen at 19 position; the HSQC spectra show that this hydrogen is associated with carbon (. Delta.44.88), confirming a 19-hydrogen, confirming correct assignment.
(15) Hydrogen at δ 4.16 is a group of single peaks, proton number is 2, assigned as hydrogen at position 37; the HSQC spectra show that this hydrogen is associated with carbon (. Delta.28.57), confirming a hydrogen at position 37, confirming correct assignment.
(16) δ 3.80 hydrogen is a group of singlet with proton number 2, assigned as hydrogen at position 6; the HSQC spectra show that this hydrogen is associated with carbon (. Delta.32.61), confirming a 6-position hydrogen, confirming correct assignment.
(17) Hydrogen at delta 3.58 is a group of quartet peaks, and the number of protons is 1; COSY spectra show that this hydrogen is associated with the δ 1.38 hydrogen 16, assigned a hydrogen at position 15; the HSQC spectra showed that this hydrogen was associated with carbon (. Delta.45.91), confirming a 15-position hydrogen, confirming correct assignment.
(18) The hydrogen at delta 3.47 is a group of single peaks, the proton number is 3, and the assignment is the hydrogen at 25 position; the HSQC spectra show that this hydrogen is associated with carbon (. Delta.59.24), confirming a 25-position hydrogen, confirming correct assignment.
(19) Delta 3.40 hydrogen is a group of single peaks, proton number is 3, and 22-position hydrogen is assigned; the HSQC spectra show that this hydrogen is associated with carbon (. Delta.58.94), confirming a 22-position hydrogen, confirming correct assignment.
(20) δ 1.38 hydrogen is a set of doublets with a proton number of 3; COSY spectra show that this hydrogen is associated with the δ 3.58 hydrogen 15, assigned a hydrogen at position 16; the HSQC spectra show that this hydrogen is associated with carbon (. Delta.19.21), confirming a 16-position hydrogen, confirming correct assignment.
(21) Because the product adopts deuterated methanol as a nuclear magnetic solvent and active hydrogen is exchanged, hydroxyl (OH) on 1 position - ) No peak appears, which is a normal phenomenon.
2 13 C nuclear magnetic resonance spectroscopy
2.1 13 C nuclear magnetic resonance spectrogram
Of pranoprofen impurity 13 The C-NMR spectrum is shown in FIG. 3; 13 C- 1 h correlation spectra (HSQC) see FIG. 4 (including FIG. 4-A, FIG. 4-B, and FIG. 4-C), remote 13 C- 1 The H correlation spectrum (HMBC) is shown in FIG. 5 (including FIG. 5-A, FIG. 5-B and FIG. 5-C).
2.2 Measured data
The measurement data are shown in Table 2 and formula (3).
Table 2 pranoprofen impurity in CD 3 In OD 13 C-NMR data
2.3 13 C-NMR spectrum analysis
Pranoprofen impurity having 32 carbons in the molecular structure 13 The C spectrum shows 31 sets of carbon peaks, indicating that there may be overlapping signals in the spectrum. The overall judgment shows that the map information conforms to the molecular structure of the pranoprofen impurity. From the HSQC spectrum and the HMBC spectrum, the following analyses were performed:
(1) An aliphatic carbon peak at δ 19.21, associated with δ 1.38 hydrogen 16 in the HSQC spectrum, assigned to the methyl carbon at position 16; the HMBC spectrum showed that this carbon peak was correlated remotely with δ 3.58 hydrogen 15, confirming a methyl carbon at position 16, confirming correct assignment.
(2) An aliphatic carbon peak at δ 28.57, associated with δ 4.16 hydrogen 37 in HSQC spectrum, assigned to the methylene carbon at position 37; the HMBC spectrum showed that this carbon peak was correlated remotely with the δ 7.46 hydrogens 39, 7.75 hydrogens 35, confirming a methylene carbon at position 37, confirming correct assignment.
(3) An aliphatic carbon peak at δ 32.61, associated with δ 3.80 hydrogen 6 in the HSQC spectrum, assigned to the methylene carbon at position 6; the HMBC spectrum showed that this carbon peak was correlated remotely with δ 7.09 hydrogen 8, 7.32 hydrogen 4, confirming a methylene carbon at position 6, confirming correct assignment.
(4) An aliphatic carbon peak at δ 44.88, associated with δ 5.08 hydrogen 19 in the HSQC spectrum, assigned to the methylene carbon at position 19; the HMBC spectrum showed that this carbon peak was correlated remotely with δ 7.54 hydrogen 2, confirming a methylene carbon at position 19, confirming correct assignment.
(5) An aliphatic carbon peak at δ 45.91, associated with δ 3.58 hydrogen 15 in HSQC spectrum, assigned to the methine carbon at position 15; the HMBC spectrum shows that this carbon peak is remotely correlated with δ 1.38 hydrogen 16, δ 7.02 hydrogen 10, δ 7.09 hydrogen 8, confirming a 15-position methine carbon, confirming correct assignment.
(6) The aliphatic carbon peak at δ 58.94, associated with δ 3.40 hydrogen 22 in the HSQC spectrum, was assigned as the methyl carbon at position 22.
(7) The fatty carbon peak at δ 59.24, associated with δ 3.47 hydrogen 25 in the HSQC spectrum, was assigned to the methyl carbon at position 25.
(8) An aromatic carbon peak at δ 108.68, associated with δ 6.34 hydrogen 3 in HSQC spectrum, assigned as the methine carbon at position 3; the HMBC spectrum showed that this carbon peak was correlated remotely with δ 7.54 hydrogen 2, confirming a methine carbon at position 3, confirming correct assignment.
(9) The aromatic carbon peak at δ 117.39, associated with δ 6.75 hydrogen 11 in the HSQC spectrum, is assigned to the methine carbon at position 11.
(10) The aromatic carbon peak at δ 117.65, associated with δ 7.13 hydrogen 28 in the HSQC spectrum, is assigned as the methine carbon at position 28.
(11) The aromatic carbon peak at δ 117.74, with no HSQC signal, was remotely correlated with δ 4.16 hydrogen 37, δ 7.17 hydrogen 34, as shown in the HMBC spectrum, and was assigned to the 36-position quaternary carbon.
(12) The aromatic carbon peak at δ 121.17, without HSQC signal, was remotely associated with δ 4.16 hydrogen 37, δ 7.13 hydrogen 28, and was assigned as quaternary carbon at position 38, as shown in the HMBC spectrum.
(13) An aromatic carbon peak at δ 121.64, associated with δ 7.17 hydrogen 34 in the HSQC spectrum, assigned to the methine carbon at position 34; the HMBC spectrum showed that this carbon peak was correlated remotely with the δ 8.10 hydrogen 33, confirming a methine carbon at position 34, confirming correct assignment.
(14) The aromatic carbon peak of delta 127.46, without HSQC signal, is remotely associated with delta 3.80 hydrogen 6, delta 6.75 hydrogen 11, delta 7.09 hydrogen 8, and is assigned as quaternary carbon at position 7, as shown in HMBC spectra.
(15) An aromatic carbon peak of δ 127.88, associated with δ 7.02 hydrogen 10 in HSQC spectrum, assigned to the methine carbon at position 10; the HMBC spectrum shows that this carbon peak is remotely correlated with δ 3.58 hydrogen 15, δ 6.75 hydrogen 11, δ 7.09 hydrogen 8, confirming a 10-position methine carbon, confirming correct assignment.
(16) There is a signal overlap of the aromatic carbon peaks for δ 129.57, one of which, in the HSQC spectrum, is associated with δ 7.45 hydrogen 27, assigned to the methine carbon at position 27; the HMBC spectrum showed that this carbon peak was remotely correlated with δ 7.13 hydrogen 28, δ 7.46 hydrogen 39, confirming the 27-position methine carbon, confirming correct assignment. In addition, δ 129.57 contains another signal, which in HMBC spectra shows that this carbon peak is remotely associated with δ 7.13 hydrogen 28, δ 7.45 hydrogen 27, δ 7.46 hydrogen 39, and is assigned as a quaternary carbon at position 26.
(17) An aromatic carbon peak at δ 130.26, associated with δ 7.46 hydrogen 39 in HSQC spectrum, assigned as the methine carbon at position 39; the HMBC spectrum showed that this carbon peak was remotely correlated with δ 4.16 hydrogens 37, δ 7.45 hydrogens 27, confirming a methine carbon at position 39, confirming correct assignment.
(18) An aromatic carbon peak of δ 131.01, associated with δ 7.09 hydrogen 8 in HSQC spectrum, assigned to the methine carbon at position 8; the HMBC spectra show that the carbon peak is remotely correlated with delta 3.58 hydrogen 15, delta 3.80 hydrogen 6, delta 7.02 hydrogen 10, and confirms that the carbon peak is 8 methine carbon, and the attribution is correct.
(19) The aromatic carbon peak of delta 133.19, without HSQC signal, is shown in HMBC spectra and is remotely associated with delta 3.80 hydrogen 6, delta 6.34 hydrogen 3, and is assigned as the quaternary carbon at position 5.
(20) Delta 133.87, without HSQC signal, was remotely correlated with delta 1.38 hydrogen 16, delta 3.58 hydrogen 15, delta 6.75 hydrogen 11 in the HMBC spectrum, assigned to the 9-position quaternary carbon.
(21) An aromatic carbon peak at δ 136.96, associated with δ 7.54 hydrogen 2 in the HSQC spectrum, assigned to the methine carbon at position 2; the HMBC spectra show that the carbon peak is remotely correlated with delta 6.34 hydrogen 3 and delta 7.32 hydrogen 4, which is confirmed to be the methine carbon at the 2-position, confirming the correct assignment.
(22) An aromatic carbon peak at δ 139.31, associated with δ 7.32 hydrogen 4 in the HSQC spectrum, assigned to the methine carbon at position 4; the HMBC spectrum showed that this carbon peak was correlated remotely with δ 7.54 hydrogen 2, confirming a methine carbon at the 4-position, confirming correct assignment.
(23) An aromatic carbon peak at δ 140.88, associated with δ 7.75 hydrogen 35 in HSQC spectrum, assigned as the methine carbon at position 35; the HMBC spectrum showed that this carbon peak was remotely correlated with δ 4.16 hydrogen 37, δ 8.10 hydrogen 33, confirming the 35-position methine carbon, confirming correct assignment.
(24) The aromatic carbon peak at δ 142.66, with no HSQC signal, was remotely correlated with δ 3.40 hydrogen 22, δ 5.08 hydrogen 19, as shown in the HMBC spectrum, and was assigned to the 20-position quaternary carbon.
(25) An aromatic carbon peak at δ 146.98, associated with δ 8.10 hydrogen 33 in the HSQC spectrum, assigned to the methine carbon at position 33; the HMBC spectrum showed that this carbon peak was remotely correlated with δ 7.17 hydrogen 34, δ 7.75 hydrogen 35, confirming the 33-position methine carbon, confirming correct assignment.
(26) The aromatic carbon peak at δ 148.12, with no HSQC signal seen, is shown in the HMBC spectrum to be remotely associated with δ 3.47 hydrogen 25, δ 5.08 hydrogen 19, δ 7.45 hydrogen 27, δ 7.46 hydrogen 39, and is assigned to the quaternary carbon at position 23.
(27) The aromatic carbon peak of δ 152.60, no HSQC signal was seen, which was remotely associated with δ 4.16 hydrogen 37, δ 7.13 hydrogen 28, δ 7.45 hydrogen 27, δ 7.46 hydrogen 39, and was assigned as the quaternary carbon at position 29, as shown in the HMBC spectra.
(28) The aromatic carbon peak of delta 155.57, for which no HSQC signal was seen, was assigned as the 12-position quaternary carbon, as shown in the HMBC spectra, which was remotely associated with delta 3.80 hydrogen 6, delta 6.75 hydrogen 11, delta 7.02 hydrogen 10, delta 7.09 hydrogen 8.
(29) The aromatic carbon peak at δ 159.49, without the HSQC signal, was remotely correlated with δ 4.16 hydrogen 37, δ 7.75 hydrogen 35 in the HMBC spectrum, and was assigned to the quaternary carbon at position 31.
(30) The aromatic carbon peak of δ 164.93, not seen as HSQC signal, was remotely associated with δ 3.80 hydrogen 6, δ 5.08 hydrogen 19, δ 7.32 hydrogen 4, δ 7.54 hydrogen 2, and was assigned quaternary carbon at position 14, as shown in the HMBC spectrum.
(31) The carboxylic acid carbon peak at δ 178.86, no HSQC signal was seen, and it was shown in the HMBC spectrum to be remotely correlated with δ 1.38 hydrogens 16, δ 3.58 hydrogens 15, assigned as quaternary carbon at position 17.
2. Mass Spectrum (MS)
The instrument model is as follows: agilent 1200RRLC-6520 Accurate-Mass Q-Tof
And (3) testing conditions are as follows: ESI
1. Mass spectrogram
The ESI mass spectra of pranoprofen impurity are shown in fig. 6-9.
1.2 Measured data
The mass spectrometry and the attribution of the pranoprofen impurity are shown in table 3.
Table 3 mass spectrometric analysis and attribution of pranoprofen impurities
| Content providing method and apparatus | Positive ion | Negative ion |
| Ratio of nucleus to nucleus | 577 | 553 |
| Attribution | [M+H]+ | [M-Na]- |
1.3 Mass Spectrometry Positive ion fragmentation information
The results show that: the excimer ion peak of the sample measured by the mass spectrum positive ion mode is [ M + H ]] + Mass to charge ratio ofm/zIs 577; the peak of the quasi-molecular ion of the sample is [ M-Na ] measured by a mass spectrum negative ion mode] - Mass to charge ratio ofm/zIs 553. Thus, M was found to be 576, consistent with the exact molecular weight of the pranoprofen impurity (576).
EXAMPLE 5 use of the object Compounds in the preparation of quality standards
In this example, the target compound hydro-oxidation-, (E)-2-[1-[3-(10H-9-oxa-1-azaanthracen-6-yl) -2, 3-dimethoxyallyl]-10H-9-oxa-1-azaanthracen-1-cation-6-yl]The method for obtaining the location Relative Retention Time (RRT) and the correction factor (f) of the sodium propionate is to obtain the location Relative Retention Time (RRT) and the correction factor (f) of the target compound by using the method of this embodiment, and further perform the location and the formulation of the relevant pranoprofen quality standard, so as to better control the pranoprofen quality.
The chromatographic conditions include: the chromatographic column is Shimadzu-Inertsil-ODS-3; the specification is 4.6 multiplied by 250mm,5um; + a detection wavelength of 275nm; the column temperature is 25 ℃; the flow rate is 1.0ml/min; the sample injection amount is 20ul; the running time is 60min; the mobile phase is A:0.1mol/L ammonium acetate (pH adjusted to 4.5 with acetic acid), B: and (3) acetonitrile.
The elution procedure is shown in table 4.
TABLE 4
The solution preparation comprises the following steps: the sample solution is prepared by precisely weighing about 6mg of the target compound sample, placing the sample in a 10ml volumetric flask, adding a proper amount of mobile phase, shaking up, ultrasonically dissolving, and diluting with the mobile phase to a scale; the reference solution is prepared by precisely weighing about 6mg of pranoprofen sample, placing the pranoprofen sample in a 10ml volumetric flask, adding a proper amount of mobile phase, shaking up, ultrasonically dissolving, and diluting to scale with the mobile phase.
The assay comprises: precisely measuring 20 μ l of each of the test solution and the reference solution, respectively injecting into a liquid chromatograph, and recording chromatogram.
The specific calculation formula is as follows:
correction factor: f = (S) Test article /m Test article ）/（S Reference substance /m Reference substance ）
Relative retention time (positioning): RRT = T Test article /T Reference substance
In the formula: f: a correction factor; s Test article : the peak area of the test sample; s Reference substance : peak area of control; m is a unit of Test article : sample amount of test substance (target compound as referred to herein); m is a unit of Reference substance : weighing a reference substance (pranoprofen); t is a unit of Test article : test article (target compound as referred to herein) retention time; t is a unit of Reference substance : retention time of control (pranoprofen).
The method comprises the following steps: preparing 2 parts of reference solution, measuring 5 times in the 1 st part, wherein the RSD percent of the peak area does not exceed 1.0 percent, and solving a correction factor by using the average peak area and the concentration; the 2 nd portion was measured 2 times and the average peak area and the sample weight were used to determine the calibration factor. The standard deviation of the correction factor must not exceed 1.0%.
Wherein, 2 parts of test solution are prepared, each part is tested for 2 times, the retention time of the average peak is used respectively, and the relative retention time is obtained, and the standard deviation is not over 1.0 percent.
The experimental determination RRT =2.158 f =0.576
The above description is only an example of the present application and is not intended to limit the present application. Various modifications and changes may occur to those skilled in the art to which the present application pertains. Any modification, equivalent replacement, improvement or the like made within the spirit and principle of the present application shall be included in the scope of the claims of the present application.
Claims (10)
1. A compound for use in pranoprofen mass study, wherein the structural formula of the compound is represented by formula (I):
r is selected from Na + 、Mg 2+ 、K + 、Ca 2+ To (3) is provided.
2. A method for preparing a compound for use in the pranoprofen mass study according to claim 1, comprising the steps of:
firstly, carrying out rearrangement reaction and hydrogen extraction reaction on a compound II to generate a compound IV;
step two, reacting the compound IV with pranoprofen to obtain a compound for the pranoprofen mass study according to claim 1;
the structure of the compound II is shown as a formula (II), and the structure of the compound IV is shown as a formula (IV):
r is selected from Na + 、Mg 2+ 、K + 、Ca 2+ One kind of (1).
3. The method of claim 2, wherein the first and/or second steps are performed under alkaline conditions, the alkaline conditions being formed by the addition of a strong base.
4. The method of claim 3, wherein the strong base comprises sodium hydroxide.
5. The preparation method according to claim 4, wherein the sodium hydroxide is a sodium hydroxide solution, and the concentration of the sodium hydroxide solution is 10% -40% m/v.
6. The preparation method of claim 2, wherein the reaction temperature in the first step is 20-40 ℃ and the reaction time is 3-5 h.
7. The preparation method according to claim 2, wherein the mass ratio of the compound II to the pranoprofen is 1: (0.6-0.8).
8. The preparation method of claim 2, wherein the reaction temperature in the second step is 20 ℃ to 40 ℃, and the reaction time is 1 to 4 hours.
9. The method according to claim 2, wherein the compound II is prepared by: the 7- (2-chloropropyl) -5H-1 benzopyran 2,3-B pyridine is subjected to ketal reaction under the catalysis of a catalyst, wherein the catalyst is selected from one or more of sodium methoxide, sodium ethoxide and sodium tert-butoxide.
10. Use of a compound according to claim 1 or prepared by a process according to any one of claims 2 to 9 in the preparation of a product for identifying pranoprofen quality.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5889030A (en) * | 1994-03-15 | 1999-03-30 | Senju Pharmaceutical Co., Ltd. | Method for stabilizing pranoprofen and stable liquid preparation of pranaprofen |
| CN109053749A (en) * | 2018-07-31 | 2018-12-21 | 成都译山生物科技有限公司 | A kind of pranoprofen derivative and its preparation method and application |
| CN113150004A (en) * | 2021-05-07 | 2021-07-23 | 山东瑞安药业有限公司 | Compound A3, preparation method thereof and application thereof as pranoprofen impurity |
| CN113214276A (en) * | 2021-05-07 | 2021-08-06 | 山东瑞安药业有限公司 | Compound A1, preparation method thereof and application thereof as pranoprofen impurity |
| CN113234082A (en) * | 2021-05-07 | 2021-08-10 | 山东瑞安药业有限公司 | Compound A2, preparation method thereof and application thereof as pranoprofen impurity |
-
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- 2022-12-20 CN CN202211637074.7A patent/CN115677733A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5889030A (en) * | 1994-03-15 | 1999-03-30 | Senju Pharmaceutical Co., Ltd. | Method for stabilizing pranoprofen and stable liquid preparation of pranaprofen |
| CN109053749A (en) * | 2018-07-31 | 2018-12-21 | 成都译山生物科技有限公司 | A kind of pranoprofen derivative and its preparation method and application |
| CN113150004A (en) * | 2021-05-07 | 2021-07-23 | 山东瑞安药业有限公司 | Compound A3, preparation method thereof and application thereof as pranoprofen impurity |
| CN113214276A (en) * | 2021-05-07 | 2021-08-06 | 山东瑞安药业有限公司 | Compound A1, preparation method thereof and application thereof as pranoprofen impurity |
| CN113234082A (en) * | 2021-05-07 | 2021-08-10 | 山东瑞安药业有限公司 | Compound A2, preparation method thereof and application thereof as pranoprofen impurity |
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