CN111689898A - Method for separating analgin impurity - Google Patents
Method for separating analgin impurity Download PDFInfo
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- CN111689898A CN111689898A CN202010594248.0A CN202010594248A CN111689898A CN 111689898 A CN111689898 A CN 111689898A CN 202010594248 A CN202010594248 A CN 202010594248A CN 111689898 A CN111689898 A CN 111689898A
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention provides a separation method of analgin impurities, which is characterized by comprising the following steps: (1) uniformly mixing analgin and a proportioning solvent, heating to dissolve, adding a proportioning activated carbon, performing heat filtration, and finally concentrating a filtrate; (2) dissolving the concentrated filtrate obtained in the step (1) by using methanol, separating by using a silica gel plate, selecting a target layer scraper, dissolving by using proportioning methanol, filtering, and concentrating to obtain a target crude product; (3) separating the crude product of the target product by using a prepared liquid phase, collecting a mobile phase with the maximum polar component, and concentrating to obtain target impurities; by carrying out qualitative analysis on unknown impurities, the generation reason can be traced, the generation of the impurities can be avoided by further optimizing the process, and the product quality is finally further improved.
Description
Technical Field
The invention relates to a separation method of analgin impurities, belonging to the technical field of drug synthesis.
Background
Analgin is a common prescription pharmaceutical product. Is a compound combining aminopyrine and sodium sulfite, is easy to dissolve in water, and has quicker and stronger antipyretic and analgesic effects than aminopyrine. Generally, the traditional Chinese medicine is not taken as a first-choice medicine and is only used for emergency fever abatement under the conditions of acute high fever and acute and serious illness condition without other effective antipyretics.
Analgin is an antipyretic analgesic developed at the beginning of the 20 th century, is produced firstly in the pharmaceutical factory in Shanghai five continents in China in 1950, has 60 years of production history in China, and is an important export-induced product in the pharmaceutical industry in China.
With the strict requirement on the consistency evaluation of the bulk drugs in China, the related substances of each bulk drug must be researched, when all related substance reference substances are used for positioning analgin, several unknown impurities with very high polarity are found in a finished product, and when the FDA examines the analgin product of the company, a question is raised, so that the unknown impurities need to be qualified.
The reason for the generation of the unknown impurities can be traced only after the unknown impurities are qualified, the generation of the impurities is avoided by further optimizing the process, and finally the product quality is further improved. Therefore, the qualitative research on unknown impurities is very necessary to improve the stability of product quality, and how to effectively separate the impurities in analgin becomes the subject of research.
Disclosure of Invention
The invention provides a separation method of analgin impurities, which is characterized by comprising the following steps:
(1) uniformly mixing analgin and a proportioning solvent, heating to dissolve, adding a proportioning activated carbon, performing heat filtration, and finally concentrating a filtrate;
(2) dissolving the concentrated filtrate obtained in the step (1) by using methanol, separating by using a silica gel plate, selecting a target layer scraper, dissolving by using proportioning methanol, filtering, and concentrating to obtain a target crude product;
(3) separating the crude product of the target product by using a prepared liquid phase, collecting a mobile phase with the maximum polar component, and concentrating to obtain target impurities;
the solvent selected in the step (1) is one of dichloromethane, methanol and ethanol, and is preferably methanol;
the thickness of the silica gel plate selected in the step (2) is 0.5-1.5 mm, the developing agent adopts ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1: 3-10;
the thickness of the silica gel plate is 1mm, and the volume ratio of the developing agent ethyl acetate to the petroleum ether is 1: 5;
the decoloring temperature selected in the step (1) is 40-60 ℃; the decoloring time is 0.5-1.5 h; the weight ratio of the active carbon to the solvent is 0.1-0.5%;
the preparation liquid phase mobile phase selected in the step (3) is one of methanol, water and acetonitrile;
the method for separating the analgin impurity comprises the following steps that (1) the selected decoloring temperature is 50 ℃; the decoloring time is 1 h; the weight ratio of the active carbon to the solvent is 0.3 percent;
the preparation liquid phase mobile phase selected in the step (3) is methanol and water; the volume ratio of methanol to water is 98:2,95: 5,90: 10;
the volume ratio of the prepared liquid phase mobile phase methanol to the water is 95: 5.
the analgin impurity obtained by the method provided by the invention is subjected to structure confirmation:
nuclear magnetic resonance spectroscopy
The instrument model is as follows: BrukeraVIIII 400M nuclear magnetic resonance apparatus
And (3) testing conditions are as follows: a solvent DMSO; 298K
And (3) testing items: 1H, 13C, DEPT135, COSY, HSQC, HMBC
The structure of the map is confirmed in attached figures 1-6, and the test results are shown in tables 1 and 2 below.
TABLE 1 NMR 1H, COSY spectral data List
1H-NMR gave 6 sets of peaks with an integration ratio (low to high field) of 2: 2: 1: 2: 3: 3. from the chemical shifts, coupling constants and COSY correlations:
a.7.46(2H, m) is a proton signal peak at the 2, 2' position, and a cosy spectrum shows that the 7.46 is directly related to 7.38 and 7.24.
b.7.38(2H, m) is the 3, 3' position proton signal peak, and cosy spectrum shows that 7.38 and 7.46 have direct correlation.
c.7.24(1H, m) is the 1-position proton signal peak, and cosy spectrum shows that 7.24 and 7.46 have direct correlation.
d.3.82(2H, s) is the 8-position proton signal peak.
e.2.87(3H, s) is the 9-position proton signal peak.
f.2.74(3H, s) is the 10-position proton signal peak.
TABLE 2 data List of NMR 13C, HSQC, HMBC spectra
13C-NMR gave 10 sets of peaks. The structure of the product contains 2 kinds of primary carbons, 1 kind of secondary carbons, 3 kinds of tertiary carbons and 4 kinds of quaternary carbons according to chemical shift and corresponding hydrogen spectrum. 30-50 are saturated carbon signals, and 120-165 are unsaturated carbon signals.
a.162.00 is the 5-carbon signal peak, quaternary carbon.
b.137.40 is the 7-carbon signal peak, quaternary carbon, HMBC indicates 137.40 is remotely correlated with 3.82, 2.87.
c.135.84 is the 4-carbon signal peak, quaternary carbon, HMBC indicates 135.84 is remotely correlated with 7.46, 7.38.
d.129.30 is the peak of the 2, 2' carbon signal, tertiary carbon, HSQC shows 129.30 has direct correlation with 7.46, HMBC shows 129.30 has remote correlation with 7.46, 7.24.
e.129.30 is the 2, 2' carbon signal peak, tertiary carbon, HSQC showed 129.30 directly correlated with 7.46, HMBC showed 129.30 remotely correlated with 7.46, 7.24.
f.125.86 is the 1-carbon signal peak, tertiary carbon, HSQC indicates 125.86 is directly related to 7.24, HMBC indicates 125.86 is remotely related to 7.38 protons.
g.123.58 is the 6-carbon signal peak, quaternary carbon, HMBC indicates 123.58 is remotely correlated with 3.82, 2.74.
h.123.10 is the 3, 3' carbon signal peak, tertiary carbon, HSQC shows 123.10 has direct correlation with 7.38, HMBC shows 123.10 has remote correlation with 7.38,7.24 protons.
i.47.99 is the 8-carbon signal peak, secondary carbon, and HSQC shows 47.99 is directly related to 3.82.
j.38.16 is the 9 carbon signal peak, primary carbon, HSQC indicates 38.16 is directly related to 2.87.
k.33.03 is the 10 carbon signal peak, primary carbon, HSQC indicates 33.03 is directly related to 2.74.
From the NMR spectrum, the NMR data of this product were consistent with the structure.
Mass spectrometry
The instrument comprises the following steps: waters, liquid phase: AcquisytArc; mass spectrum: AcquisytQDa
Solvent: methanol
An ionization mode: ESI (-)
TABLE 3 Mass spectrometric results
As can be seen from FIG. 7, the mass-to-charge ratio of the [ M-H ] -peak of the product was 296.07. The molecular weight of the product free substance is 297.08, which is the same as the molecular weight of the presumed structure.
Comprehensive analysis
The compound contains 15 hydrogen and 12 carbons, wherein the primary carbon is 2, the secondary carbon is 1, the tertiary carbon is 5, and the quaternary carbon is 4 by combining nuclear magnetic and mass spectrometry; the mass spectrum positive ion mode shows that the mass-to-charge ratio of the excimer ion peak [ M-H ] peak of the compound is 296.07, and the compound is presumed to have the structural formula as follows through comprehensive analysis:
drawings
FIG. 1 shows nuclear magnetic hydrogen spectrum;
FIG. 2 is a nuclear magnetic carbon spectrum;
FIG. 3 shows the spectrum of Dept 135;
FIG. 4 is a COSY spectrum;
FIG. 5 is a spectrum of HSQC;
FIG. 6 HMBC spectrogram;
FIG. 7 is a high resolution mass spectrum.
Detailed Description
The present invention is further described below with reference to examples.
Example 1
Add 1g of analgin to dichloromethane (50mL) and stir well, add activated carbon (0.04g, 0.1%) and stir at 40 ℃ for 0.5 h. Hot filtering, and concentrating the filtrate to obtain crude product.
The residue was dissolved in 10ml of methanol, and then the samples were spread on 10 20cm by 20cm gf254 silica gel plates with a thickness of 0.5mm using 1:3 (by volume) ethyl acetate and petroleum ether as developing agents for plate separation. Finally, the bottom layer is collected, stirred and extracted by 20ml of methanol, filtered and concentrated for later use.
Pure methanol is used as a mobile phase for preparing the liquid phase, the concentrated residue is dissolved by the mobile phase, then the sample is loaded for preparation, the mobile phase of the target substance is collected, concentrated and analyzed by TLC, and the number of impurity points is very large.
Example 2
Add 1g analgin to methanol (50mL), stir well, add activated carbon (0.12g, 0.3%), stir at 50 ℃ for 1 h. Hot filtering, and concentrating the filtrate to obtain crude product.
The residue was dissolved in 10ml of methanol, and then the samples were spread on 10 20cm x 20cm gf254 silica gel plates 1mm thick using 1:5 (by volume) ethyl acetate and petroleum ether as developing agents for plate separation. Finally, the bottom layer is collected, stirred and extracted by 20ml of methanol, filtered and concentrated for later use.
Methanol and water (volume ratio) 98:2 are used as a preparation liquid phase, the residue after concentration is dissolved by the mobile phase, then the sample is loaded for preparation, the target mobile phase is collected and concentrated to obtain 8.7mg of light yellow solid, and TLC still has obvious impurity points.
Example 3
Add 1g analgin to methanol (50mL), stir well, add activated carbon (0.12g, 0.3%), stir at 50 ℃ for 1 h. Hot filtering, and concentrating the filtrate to obtain crude product.
The residue was dissolved in 10ml of methanol, and then the samples were spread on 10 20cm x 20cm gf254 silica gel plates 1mm thick using 1:5 (by volume) ethyl acetate and petroleum ether as developing agents for plate separation. Finally, the bottom layer is collected, stirred and extracted by 20ml of methanol, filtered and concentrated for later use.
Using methanol and water with a volume ratio of 95:5 as a preparation liquid phase, dissolving the concentrated residue with the mobile phase, then loading the sample for preparation, collecting a target mobile phase, performing TLC analysis for purity, concentrating to obtain 10.5mg of off-white solid, and performing structure confirmation, wherein the spectrogram is shown in attached figures 1-7.
Example 4
Add 1g analgin to methanol (50mL), stir well, add activated carbon (0.12g, 0.3%), stir at 50 ℃ for 1 h. Hot filtering, and concentrating the filtrate to obtain crude product.
The residue was dissolved in 10ml of methanol, and then the samples were spread on 10 20cm x 20cm gf254 silica gel plates 1mm thick using 1:5 (by volume) ethyl acetate and petroleum ether as developing agents for plate separation. Finally, the bottom layer is collected, stirred and extracted by 20ml of methanol, filtered and concentrated for later use.
The preparation was carried out by dissolving the above concentrated residue in a mobile phase using methanol and water at a ratio of 90:10 (by volume), collecting the desired mobile phase, and concentrating to obtain 12.5mg of a yellow oil, which was analyzed by TLC for a large number of impurities.
Example 5
Add 1g analgin to ethanol (50mL), stir well, add activated carbon (0.2g, 0.5%), stir at 60 ℃ for 1.5 h. Hot filtering, and concentrating the filtrate to obtain crude product.
The residue was dissolved in 10ml of methanol, and then the sample was spread on 10 20cm by 20cm gf254 silica gel plates with a thickness of 1.5mm using 1:10 (volume ratio) ethyl acetate and petroleum ether as developing agents for plate separation. Finally, the bottom layer is collected, stirred and extracted by 20ml of methanol, filtered and concentrated for later use.
And (3) using pure acetonitrile as a preparation liquid phase mobile phase, dissolving the concentrated residue by using the mobile phase, then loading the sample for preparation, collecting a target substance mobile phase, concentrating, and analyzing by TLC (thin layer chromatography) for more impurities.
Claims (8)
1. The method for separating the analgin impurities is characterized by comprising the following steps of:
(1) uniformly mixing analgin and a proportioning solvent, heating to dissolve, adding a proportioning activated carbon, performing heat filtration, and finally concentrating a filtrate;
(2) dissolving the concentrated filtrate obtained in the step (1) by using methanol, separating by using a silica gel plate, selecting a target layer scraper, dissolving by using proportioning methanol, filtering, and concentrating to obtain a target crude product;
(3) separating the crude product of the target product by using a prepared liquid phase, collecting the mobile phase with the maximum polar component, and concentrating to obtain the target impurity.
2. The method for separating analgin impurity as claimed in claim 1, wherein:
the solvent selected in the step (1) is one of dichloromethane, methanol and ethanol.
3. The method for separating analgin impurity as set forth in claim 1 or 2, wherein: the solvent selected was methanol.
4. The method for separating analgin impurity as claimed in claim 1, wherein: the thickness of the silica gel plate selected in the step (2) is 0.5-1.5 mm, ethyl acetate and petroleum ether are adopted as the developing agent, and the volume ratio of ethyl acetate to petroleum ether is 1:3 to 10.
5. The method for separating analgin impurity as claimed in claim 1 or 4, wherein: the thickness of the silica gel plate is 1mm, and the volume ratio of developing agent ethyl acetate to petroleum ether is 1: 5.
6. the method for separating analgin impurity as claimed in claim 1, wherein:
the decoloring temperature selected in the step (1) is 40-60 ℃; the decoloring time is 0.5-1.5 h; the weight ratio of the active carbon to the solvent is 0.1-0.5%;
the preparation liquid phase mobile phase selected in the step (3) is one of methanol, water and acetonitrile.
7. The method for separating analgin impurity of claim 1 or 6, wherein:
the decoloring temperature selected in the step (1) is 50 ℃; the decoloring time is 1 h; the weight ratio of the active carbon to the solvent is 0.3 percent;
the preparation liquid phase mobile phase selected in the step (3) is methanol and water; the volume ratio of methanol to water is 98:2,95: 5,90: 10.
8. The method for separating analgin impurity of claim 1 or 6, wherein:
preparing a liquid phase mobile phase methanol and water volume ratio of 95: 5.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010594248.0A CN111689898A (en) | 2020-06-24 | 2020-06-24 | Method for separating analgin impurity |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010594248.0A CN111689898A (en) | 2020-06-24 | 2020-06-24 | Method for separating analgin impurity |
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| CN111689898A true CN111689898A (en) | 2020-09-22 |
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