CN112920064A - Salbutamol impurity compound and preparation method, detection method and application thereof - Google Patents
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- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
- C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
- C07C217/70—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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Abstract
The invention discloses a salbutamol impurity compound and a preparation method, a detection method and application thereof, belonging to the technical field of medicines.
Description
Technical Field
The invention relates to a salbutamol impurity compound and a preparation method, a detection method and application thereof, belonging to the technical field of medicines.
Background
The chemical name of salbutamol is 1- (4-hydroxy-3-hydroxymethyl phenyl) -2- (tert-butylamino) ethanol, and the structural formula is shown as formula III:
salbutamol, also known as kechuanning, is a selective beta 2 adrenoceptor agonist and is used to treat asthmatic bronchitis and other conditions. The medicine has high selectivity, definite clinical effect and long action duration. Although the salbutamol also has potential toxic and side effects so as to cause adverse reactions, the generation of the adverse reactions is greatly related to impurities in the salbutamol besides the pharmacological activity of the salbutamol. In the production and storage processes of salbutamol, process impurities and degradation impurities are inevitably generated, and the quality of the medicine is influenced. Therefore, the discovery, preparation and detection of the impurities have important significance on the quality and the medication safety of the salbutamol.
From the reports of salbutamol, after intensive studies on salbutamol for decades, various pharmaceutical enterprises and scientific research institutes have found some impurities that may be present in salbutamol and have conducted detailed studies on the impurities. Impurities possibly existing in the salbutamol and related raw material medicines (the salbutamol sulfate and the levosalbutamol hydrochloride) are collected and carried by pharmacopoeias of various countries, wherein the second part of the pharmacopoeias 2015 of China collects one impurity of the salbutamol, and the structural formula is shown as a formula IV:
more than ten impurities are collected in the european pharmacopoeia EP9.0, and have several structures of formula V, formula VI, formula VII, formula VIII and formula IX, and the structures of the several impurities are as follows:
besides the above impurities, the USP40-NF36 also contains an impurity having a structural formula shown in formula X:
the salbutamol has a molecular structure with 2 alcoholic hydroxyl groups, 1 phenolic hydroxyl group and 1 amino group, which are more active, and most of impurities possibly existing in the salbutamol bulk drug are generated by the reaction of the active groups, wherein the generation of the formula IV, the formula V, the formula VI and the formula X is related to the alcoholic hydroxyl groups, the generation of the formula VII and the formula VIII is related to the amino groups, and the generation of the formula IX is related to the phenolic hydroxyl groups.
Disclosure of Invention
With the development of the synthetic route of salbutamol and the continuous and intensive quality research, the inventors discovered a new impurity, which is generated by alkyl substitution reaction of phenolic hydroxyl group in the molecular structure of salbutamol. The inventors prepared the impurities through the procedures of enrichment, separation, purification and the like, and finally determined the structure of the impurities by means of detection and analysis means such as mass spectrum, nuclear magnetism and the like.
The technical problem to be solved by the invention is to provide a salbutamol impurity compound, a preparation method, a detection method and an application thereof, which can better control the quality of salbutamol and improve the safety of medicines.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
an impurity compound of salbutamol, the structural formula is as shown in formula I:
in order to solve the technical problems, the technical scheme adopted by the invention is as follows:
the salbutamol impurity compound is used as a related substance reference substance in the quality control of salbutamol substances.
The technical scheme of the invention is further improved as follows: the albuterol substance is albuterol and salt thereof, levosalbutamol and salt thereof, and dextrosalbutamol and salt thereof.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a preparation method of a salbutamol impurity compound takes a compound of a formula II and halogenated ethane as raw materials, and takes inorganic base or organic base as an acid-binding agent to prepare the impurity in an organic solvent, wherein the chemical name of the compound of the formula II is 2- [ benzyl (tert-butyl) amino]-1- [ 4-hydroxy-3- (hydroxymethyl) phenyl]Ethanol, the reaction equation is as follows:
。
the technical scheme of the invention is further improved as follows: the halogenated ethane is one or more of chloroethane, bromoethane and iodoethane, and the molar ratio of the compound shown in the formula II to the halogenated ethane is 1: 0.8-1: 2.5.
The technical scheme of the invention is further improved as follows: the acid-binding agent is one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, ammonia water, triethylamine and pyridine; the molar ratio of the compound shown in the formula II to the acid-binding agent is 1: 1-1: 3.
The technical scheme of the invention is further improved as follows: the organic solvent is one or more of dichloromethane, chloroform, methanol, ethanol, n-propanol, isopropanol, acetonitrile, tetrahydrofuran, ethyl acetate, toluene, DMSO and DMF, and the dosage of the organic solvent is 50-150 mg solute/g solvent.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a method for detecting salbutamol impurity compounds adopts high performance liquid chromatography to carry out qualitative or quantitative analysis on impurities in salbutamol, and the detection conditions comprise:
a chromatographic column: reverse-phase octadecylsilane chemically bonded silica gel column; detecting the wavelength of 210-400 nm; the mobile phase comprises a mobile phase A and a mobile phase B; mobile phase A: an aqueous phase containing buffer salts, pH 3.0; mobile phase B: methanol or acetonitrile; the mobile phase is eluted by a gradient method:
0-10 min, mobile phase A: 85%, mobile phase B: 15 percent;
10-45 min, mobile phase A: 85 → 70%, mobile phase B: 15 → 30%;
45-55 min, mobile phase A: 70%, mobile phase B: 30 percent;
55-56 min, mobile phase A: 70 → 85%, mobile phase B: 30 → 15%;
56-66 min, mobile phase A: 85%, mobile phase B: 15 percent;
the detection step comprises:
(1) preparing a test solution and a reference solution;
(2) respectively detecting the test solution and the reference solution;
the test solution is salbutamol or salt, solvate or hydrate thereof to be detected.
The technical scheme of the invention is further improved as follows: the detection wavelength is 220 nm.
The technical scheme of the invention is further improved as follows: the water phase containing buffer salt is dipotassium hydrogen phosphate-phosphoric acid buffer salt; the concentration of the potassium dihydrogen phosphate in the buffer salt is 0.02 mol/L.
Due to the adoption of the technical scheme, the invention has the technical progress that:
according to the invention, a new impurity is obtained through detailed research on the salbutamol, and the impurity is successfully prepared, so that more comprehensive and accurate information is provided for the research on the salbutamol impurity, and a new direction is provided for accurately controlling the impurity and obtaining the salbutamol with higher safety, reliability and definite curative effect.
Drawings
FIG. 1 is a mass spectrum of an impurity compound of salbutamol of example 1 of the present invention;
FIG. 2 shows the NMR spectrum of salbutamol as an impurity compound in example 1 of the present invention (1H-NMR）；
FIG. 3 is the NMR spectrum of salbutamol as an impurity compound in example 1 of the present invention: (13C-NMR）；
FIG. 4 is a chromatogram of an impurity compound of salbutamol of example 1 according to the present invention;
FIG. 5 is a chromatogram of the impurity compound salbutamol and salbutamol sulphate salt of example 4 of the present invention;
FIG. 6 is a structural formula of a salbutamol impurity compound of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the following examples:
example 1
1g of 2- [ benzyl (tert-butyl) amino ] -1- [ 4-hydroxy-3- (hydroxymethyl) phenyl ] ethanol and 15ml of methanol are added into a 50ml three-necked bottle, 0.9g of potassium carbonate and 0.72g of bromoethane are added, and the mixture is stirred and heated to 35-40 ℃ for reaction for 24 hours. Filtering while hot, concentrating the filtrate at 40-50 deg.C under reduced pressure to dryness, adding 5ml ethanol into the concentrated residue, heating to reflux, stirring for dissolving, cooling to-5-0 deg.C, stirring for crystallizing for 3 hr, filtering, and vacuum drying at 50-60 deg.C for 8 hr to obtain 0.65g of salbutamol impurity with purity of 99.377%, and its spectrogram is shown in figure 4, and yield is 59.9%.
Confirmation of chemical structure
Mass spectrometry was performed on an Agilent technologies 6120 mass spectrometer with methanol as solvent. The spectrum is shown in figure 1.
Calculated molecular weight: 357.0, MS M/e (M + H): 358.0.
nuclear magnetic resonance hydrogen spectrum (1H-NMR) was carried out on a Bruker AVANCE-400 nuclear magnetic resonance spectrometer using DMSO-d6 as solvent. The spectrogram is shown in the attached figureAs shown in fig. 2.
1H-NMR（DMSO-d6，400MHz）：δ7.43（d，J=7.6Hz，2H），7.20~7.32（m，4H），6.98（d，J=8.4Hz，1H），6.79（d，J=8.4Hz，1H），4.90~4.93（t，J=5.6Hz，1H），4.73（d，J=5.6Hz，2H），4.37（s，1H），4.10~4.18（m，1H），3.95~4.00（m，2H），3.92（d，J=15.6Hz，1H），3.69（d，J=15.6Hz，1H），2.67~2.73（m，1H），2.56~2.61（m，1H），1.30（t，J=13.6Hz，3H），1.06（m，9H）。
Nuclear magnetic resonance carbon spectrum (13C-NMR) was carried out on a nuclear magnetic resonance spectrometer model Bruker AVANCE-400 with DMSO-d6 as solvent. The spectrum is shown in figure 3.
Therefore, the structural formula of the impurity compound is confirmed to be formula I, as shown in the attached figure 6.
Example 2
10g of 2- [ benzyl (tert-butyl) amino ] -1- [ 4-hydroxy-3- (hydroxymethyl) phenyl ] ethanol and 200ml of ethyl acetate are added into a 500ml three-necked bottle, 6.0g of potassium carbonate and 8.2g of iodoethane are added, and the mixture is stirred and heated to 35-40 ℃ for reaction for 24 hours. Cooling to 20-25 ℃, adding 100ml of water for washing and separating liquid, adding 100ml of saturated sodium chloride for washing and separating liquid into the organic phase, concentrating the organic phase at 40-50 ℃ under reduced pressure until the organic phase is dried, adding 30ml of methanol into the concentrated residue, heating to reflux, stirring for dissolving, cooling to-5-0 ℃, stirring for crystallizing for 3 hours, filtering, and drying in vacuum at 50-60 ℃ for 8 hours to obtain 5.8g of salbutamol impurity, wherein the purity is 99.121%, and the yield is 53.5%.
Example 3
A500 ml three-necked flask was charged with 10g of 2- [ benzyl (t-butyl) amino ] -1- [ 4-hydroxy-3- (hydroxymethyl) phenyl ] ethanol and 200ml of methylene chloride, and then 6.3g of pyridine and 7.0g of bromoethane were added thereto, followed by stirring, heating and refluxing for 24 hours. Cooling to 20-25 ℃, adding 100ml of water for washing and separating liquid, adding 100ml of saturated sodium chloride for washing and separating liquid into the organic phase, concentrating the organic phase at 35-40 ℃ under reduced pressure until the organic phase is dried, adding 30ml of methanol into the concentrated residue, heating to reflux, stirring for dissolving, cooling to-5-0 ℃, stirring for crystallizing for 3 hours, filtering, and drying in vacuum at 50-60 ℃ for 8 hours to obtain 6.0g of salbutamol impurity, wherein the purity is 99.340%, and the yield is 55.3%.
Example 4 detection of Salbutamol impurity Compound
The checking method comprises the following steps: the determination is carried out by referring to high performance liquid chromatography (the four-part general regulation 0512 in the 2015 edition of Chinese pharmacopoeia).
The instrument comprises the following steps: LC-2030 high performance liquid chromatograph (Shimadzu Japan)
A chromatographic column: waters Xbridge Shield RP18, 4.6 mm. times.150 mm, 3.5 μm
Mobile phase A: dissolving 0.02mol/L potassium dihydrogen phosphate, and adding phosphoric acid to adjust pH to 3.0.
Mobile phase B: acetonitrile
Column temperature: sample volume at 30 ℃: 20 μ l detection wavelength: flow rate at 220 nm: 1ml/min
Elution procedure:
| time (min) | Mobile phase A% | Mobile |
| 0 | 85 | 15 |
| 10 | 85 | 15 |
| 45 | 70 | 30 |
| 55 | 70 | 30 |
| 56 | 85 | 15 |
| 66 | 85 | 15 |
And (3) sample determination:
taking a proper amount of each salbutamol sulfate and an impurity compound (formula I) reference substance, adding a mobile phase A to dissolve and dilute the salbutamol sulfate and the impurity compound (formula I) until each 1ml of the solution contains 0.1mg of the mixed solution of the salbutamol sulfate and 1 mu g of the impurity compound, and shaking up the solution to obtain a system applicability solution. And precisely measuring 20 mu l of system applicability solution, injecting into a liquid chromatograph, and recording a chromatogram.
Precisely weighing about 10mg of impurity compound (formula I), placing in a 100ml volumetric flask, adding mobile phase B to dissolve and dilute to scale, and shaking up to obtain solution containing 0.1mg per 1ml as reference solution. Precisely measuring 20 μ l of the reference solution, injecting into a liquid chromatograph, and recording chromatogram.
Precisely weighing salbutamol sulfate about 25mg, placing in a 25ml volumetric flask, adding mobile phase A for dissolving and diluting to scale, and shaking up to obtain solution containing 1mg per 1ml as test solution. Precisely measuring 20 μ l of the sample solution, injecting into liquid chromatograph, and recording chromatogram, which is shown in figure 5. It can be seen from FIG. 5 that the impurity compound (formula I) was detected.
Claims (10)
1. An impurity compound of salbutamol, the structural formula is as shown in formula I:
2. use of the salbutamol impurity compound of claim 1 as a reference substance in the quality control of salbutamol.
3. Use of a salbutamol impurity compound according to claim 2, said salbutamol material being salbutamol and its salts, levosalbutamol and its salts, dexsalbutamol and its salts.
4. The method for preparing salbutamol impurity compound of claim 1, wherein the impurity is prepared in organic solvent by using compound of formula II and halogenated ethane as raw materials and inorganic base or organic base as acid-binding agent, wherein the chemical name of compound of formula II is 2- [ benzyl (tert-butyl) amino]-1- [ 4-hydroxy-3- (hydroxymethyl) phenyl]Ethanol, the reaction equation is as follows:
。
5. the method for preparing the salbutamol impurity compound according to claim 4, wherein the halogenated ethane is one or more of chloroethane, bromoethane and iodoethane, and the molar ratio of the compound of formula II to the halogenated ethane is 1: 0.8-1: 2.5.
6. The method of preparing a salbutamol impurity compound according to claim 4, wherein the acid scavenger is one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, ammonia, triethylamine and pyridine; the molar ratio of the compound shown in the formula II to the acid-binding agent is 1: 1-1: 3.
7. The method for preparing the salbutamol impurity compound according to claim 4, wherein the organic solvent is one or more of dichloromethane, chloroform, methanol, ethanol, n-propanol, isopropanol, acetonitrile, tetrahydrofuran, ethyl acetate, toluene, DMSO and DMF, and the amount of the organic solvent is 50-150 mg solute/g solvent.
8. The method for detecting the salbutamol impurity compound according to claim 1, wherein the impurities in the salbutamol are qualitatively or quantitatively analyzed by high performance liquid chromatography, and the detection conditions comprise:
a chromatographic column: reverse-phase octadecylsilane chemically bonded silica gel column; detecting the wavelength of 210-400 nm; the mobile phase comprises a mobile phase A and a mobile phase B; mobile phase A: an aqueous phase containing buffer salts, pH 3.0; mobile phase B: methanol or acetonitrile; the mobile phase is eluted by a gradient method:
0-10 min, mobile phase A: 85%, mobile phase B: 15 percent;
10-45 min, mobile phase A: 85 → 70%, mobile phase B: 15 → 30%;
45-55 min, mobile phase A: 70%, mobile phase B: 30 percent;
55-56 min, mobile phase A: 70 → 85%, mobile phase B: 30 → 15%;
56-66 min, mobile phase A: 85%, mobile phase B: 15 percent;
the detection step comprises:
(1) preparing a test solution and a reference solution;
(2) respectively detecting the test solution and the reference solution;
the test solution is salbutamol or salt, solvate or hydrate thereof to be detected.
9. The method for detecting a salbutamol impurity compound according to claim 8, wherein the detection wavelength is 220 nm.
10. The method for detecting a salbutamol impurity compound according to claim 8, wherein said aqueous phase containing a buffer salt is a dipotassium hydrogen phosphate-phosphate buffer salt; the concentration of the potassium dihydrogen phosphate in the buffer salt is 0.02 mol/L.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113912507A (en) * | 2021-11-05 | 2022-01-11 | 深圳市祥根生物医药有限公司 | Preparation method of salbutamol impurity |
| CN114436869A (en) * | 2022-02-15 | 2022-05-06 | 南京恒道医药科技有限公司 | Novel levosalbutamol hydrochloride impurity and preparation method thereof |
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2021
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113912507A (en) * | 2021-11-05 | 2022-01-11 | 深圳市祥根生物医药有限公司 | Preparation method of salbutamol impurity |
| CN114436869A (en) * | 2022-02-15 | 2022-05-06 | 南京恒道医药科技有限公司 | Novel levosalbutamol hydrochloride impurity and preparation method thereof |
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