CN114716391A - Methazolamide impurity and preparation method and application thereof - Google Patents

Methazolamide impurity and preparation method and application thereof Download PDF

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CN114716391A
CN114716391A CN202210450074.XA CN202210450074A CN114716391A CN 114716391 A CN114716391 A CN 114716391A CN 202210450074 A CN202210450074 A CN 202210450074A CN 114716391 A CN114716391 A CN 114716391A
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methazolamide
impurity
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CN114716391B (en
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沈杞容
陶颉
刘玲
胡秀波
马小明
宣燕红
刘锐
贺亚平
胡玉婷
宋存珍
李福高
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Hangzhou Qianyuan Baoling Pharmaceutical Co ltd
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Abstract

The invention provides unknown methazolamide impurities, and preparation, analysis methods and applications thereof, and belongs to the field of organic synthetic drug chemistry. The invention discloses two new impurity compounds in methazolamide and preparation and analysis methods thereof for the first time, and the impurity samples prepared by the preparation method have high purity, simple and efficient operation, moderate reaction conditions, strong safety and easy control, and are suitable for preparing impurities as reference substances to monitor the product quality.

Description

Methazolamide impurity and preparation method and application thereof
Technical Field
The invention relates to the field of organic synthetic pharmaceutical chemistry, and particularly relates to methazolamide impurity and a preparation method and application thereof.
Background
Methazolamide, synonym azodicarbonamide, foreign trade name: naptazane, english name: methazolamide, United states Pharmacopeia, has been previously documented. The product is a carbonic anhydrase inhibitor-type anti-glaucoma drug, and is mainly used for clinically treating chronic open-angle glaucoma, acute angle closure glaucoma, secondary glaucoma, ocular tension reduction in ophthalmic surgery, and the like.
For example, chinese patent application 200510050599.0 discloses a method for preparing methazolamide, which comprises using 5-amino-2-mercapto-1, 3, 4-thiadiazole as raw material, subjecting to condensation, acetylation, methylation, oxidation, amination reaction to obtain a crude methazolamide product, refining to obtain a refined methazolamide product, adding sodium hypochlorite in the oxidation and amination reaction process, reacting in the presence of iron chloride catalyst, and subjecting the intermediate obtained by the reaction to amination reaction to obtain a crude methazolamide product; adding a 5% NaOH solution into the crude methazolamide product, adjusting the pH value to 4-5 to obtain a precipitate, washing and drying to obtain a finished product; wherein the reaction temperature is controlled between 35 ℃ and 50 ℃ during the oxidation reaction. The reaction formula is as follows:
Figure BDA0003617972960000011
impurities are inevitably produced during the synthesis, processing and storage of the azomethine, and may cause potential toxicity during use. Therefore, it is necessary to investigate the impurities in the product of the methazolamide and to limit its content in the final product. In each large pharmacopoeia, the content of a single impurity is required to be controlled to be less than 0.10%, so that the content of part of impurities is small, and the impurities are difficult to separate and confirm, so that a standard product cannot be obtained to perform quality control on the impurities. Further improvement of methazolamide hybrid mass spectrum is required, and the quality control level of methazolamide is improved.
Disclosure of Invention
As mentioned above, the identification of the structure of the impurity is the basic requirement for drug registration, and in order to further improve the quality of methazolamide, the content of the impurity in the drug methazolamide is controlled.
One of the purposes of the invention is to provide a methazolamide impurity compound shown as the following formula (I),
Figure BDA0003617972960000021
the compound of the formula (I) can be used as a standard substance in methazolamide finished product detection and analysis, and is favorable for strengthening the safety control of medicines.
The inventors have found that the compound of formula (I) is an unknown impurity which has not been found so far in the production of methazolamide, and is generated by reacting a sulfonyl chloride intermediate with an impurity, benzylamine.
Figure BDA0003617972960000022
It is therefore another object of the present invention to provide a process for the preparation of the impurity compound of formula (I), said process comprising the steps of:
(1) mixing sulfonyl chloride intermediate, benzylamine, alkali and solvent, and reacting to obtain reaction liquid;
(2) and (2) concentrating the reaction liquid obtained in the step (1) under reduced pressure until the reaction liquid is dried, and eluting the reaction liquid through a column to obtain the impurity compound shown in the formula (I).
According to a specific embodiment of the present invention, in the step (1), the reaction conditions are: stirring at room temperature for 2-5 hr, heating to 40-70 deg.C, and stirring for 0.5-3 hr. Preferably, the reaction conditions are: after stirring at room temperature for 3.5 hours, the temperature was raised to 50 ℃ and the mixture was stirred for 1.5 hours.
According to a specific embodiment of the present invention, in step (1), the base includes, but is not limited to, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine and the like, preferably sodium carbonate. The solvent may be a solvent conventional in the art, such as water, an alcohol solvent, an ester solvent, an ether solvent, etc., and preferably a non-hydroxyl solvent, such as tetrahydrofuran, dichloromethane, etc.
According to one embodiment of the invention, in step (2), the column used is a C18 chromatography column.
According to a specific embodiment of the invention, in the step (2), the eluent is a mixed solution of n-hexane and ethyl acetate, preferably a mixed solution of n-hexane and ethyl acetate in a volume ratio of 1: 1.
The sulfonyl chloride intermediate has a structural formula:
Figure BDA0003617972960000031
the structural formula of the benzylamine is as follows:
Figure BDA0003617972960000032
still another object of the present invention is to provide a methazolamide impurity compound represented by the following formula (II),
Figure BDA0003617972960000033
the compound shown in the formula (II) can be used as a standard substance in methazolamide finished product detection and analysis, and is favorable for strengthening the safety control of medicines.
The inventors have found that the compound of formula (II) is an unknown impurity which has not been found so far in the production of methazolamide, and is generated by the reaction of methazolamide with sulfonyl chloride intermediates.
Figure BDA0003617972960000034
It is therefore a further object of the present invention to provide a process for the preparation of an impurity compound of formula (II), said process comprising the steps of:
methazolamide is dissolved in a solvent, and the impurity compound (II) is separated by a DAC50 system.
According to a specific embodiment of the present invention, the solvent is at least one selected from methanol, acetonitrile, and water, preferably methanol, and more preferably 80% methanol.
According to a specific embodiment of the present invention, the specific steps of the separation are: separating for the first time, collecting the part containing impurity compound (II), concentrating under reduced pressure to obtain crude product, separating for the second time, and collecting impurity compound (II).
Further, according to a specific embodiment of the present invention, the conditions of the first separation are:
a chromatographic column: a reversed phase C18 column;
flow rate: 45.0-55.0 mL/min;
ultraviolet wavelength: 285 and 295 nm;
mobile phase: mixed mobile phase of sodium sulfate and acetonitrile.
Preferably:
and (3) chromatographic column: a reversed phase C18 column;
flow rate: 50.0 mL/min;
ultraviolet wavelength: 290 nm;
mobile phase: the volume ratio is 75: 25 mM 20mM sodium sulfate and acetonitrile.
Further, according to a specific embodiment of the present invention, the conditions of the second separation are:
a chromatographic column: a reversed phase C18 column;
flow rate: 45.0-55.0 mL/min;
ultraviolet wavelength: 285 and 295 nm;
mobile phase: formic acid-water and acetonitrile.
Preferably:
a chromatographic column: a reversed phase C18 column;
flow rate: 50.0 mL/min;
ultraviolet wavelength: 290 nm;
mobile phase: the volume ratio is 75: 25 of mixed mobile phase of 0.1% formic acid-water and acetonitrile.
Another preparation method of the impurity compound shown in the structure of the formula (II) comprises the following steps: mixing methazolamide, triethylamine and a solvent, stirring, adding a sulfonyl chloride intermediate for reaction, adding water and dichloromethane for extraction, concentrating an organic layer, performing silica gel column chromatography on the obtained organic layer, eluting the solvent by ethyl acetate and ethanol in a volume ratio of 5-15:1, and collecting an impurity compound (II).
Preferably, the elution solvent is ethyl acetate and ethanol in a volume ratio of 10: 1.
It is a further object of the present invention to provide the use of the impurity compounds of formula (I) and formula (II) for the quality control of methazolamide.
The final object of the invention is to provide a method for detecting methazolamide impurities, which is characterized in that the impurity compound of formula (I) and/or the impurity compound of formula (II) are/is used as standard substances, and the detection is carried out according to the following steps:
preparation of a sample solution: taking solution of mobile phase A and B at a ratio of 18:82 as solvent, dissolving sample at concentration of 0.1-10mg/ml, preferably 5mg/ml
Preparation of a standard solution: solvent the same sample solution, with concentration of 0.1-10 μ g/ml, preferably 5 μ g/ml
A chromatographic column: phenyl column
Mobile phase A acetonitrile
Mobile phase B potassium dihydrogen phosphate (6.8g/L)
Gradient elution:
Time B(%)
0 80-85
10 80-85
30 38-42
35 38-42
35.1 80-85
45 80-85
wavelength: 290/250
Flow rate: 0.8-1.2mL/min
Sample introduction amount: 5 μ L.
The invention achieves the following beneficial effects:
1) the invention discloses the structures of the unknown impurity compounds of the methazolamide formulas (I) and (II) for the first time, and has important significance for the quality research of the methazolamide;
2) the invention discloses a preparation method of methazolamide unknown impurity compounds of formula (I) and formula (II) for the first time, and the impurity samples prepared by the preparation method have high purity, simple and efficient operation, moderate reaction conditions, strong safety and easy control, and are suitable for impurity preparation as reference substances to monitor the product quality.
Drawings
FIG. 1 mass spectrum of impurity (I);
FIG. 2 hydrogen spectrum of impurity (I);
FIG. 3 impurity (I) C13A spectrogram;
FIG. 4 Infrared Spectrum of impurity (I);
FIG. 5 UV spectrum of impurity (I);
FIG. 6 liquid phase spectrum of impurity (II);
fig. 7 mass spectrum (positive Ion) of Impurity (II);
FIG. 8 mass spectrum of impurity (II) (negative ions);
FIG. 9 Infrared Spectrum of impurity (II);
FIG. 10 UV spectrum of impurity (II);
FIG. 11 hydrogen spectrum of impurity (II);
FIG. 12 impurity (II) C13A spectrogram;
FIG. 13 DEPT-135 carbon spectrum of impurity (II);
FIG. 14 is a two-dimensional hydrogen spectrum (H-H COSY) diagram of impurity (II);
FIG. 15 two-dimensional hydrocarbon correlation (HSQC) plot of impurity (II);
FIG. 16 impurity (II) two-dimensional hydrocarbon correlation (HMBC) plot.
Detailed Description
The following exemplary reactions serve to illustrate the invention. The invention is protected by the technical scheme that simple replacement or improvement and the like of the invention are made by those skilled in the art. The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
EXAMPLE 1 preparation of the impurity Compound of formula (I)
(1) 2.05g of sulfonyl chloride intermediate, 0.87g of benzylamine, 0.86g of sodium carbonate and 20mL of tetrahydrofuran were added to the reaction flask, and the mixture was stirred at room temperature for 3.5 hours, then heated to 50 ℃ and stirred for 1.5 hours.
(2) Concentrating the dried reaction solution under reduced pressure, purifying with silica gel column to obtain eluent of n-hexane and ethyl acetate (1:1), concentrating, and removing the solution to obtain white solid impurity compound (I)0.8g with purity of 98% and yield of 70%.
Example 2 structural characterization of impurity Compound (I)
2.1 Pop data:
UV-Visλ(CH3OH)nm:258,295(λmax);IR(KBr)νmax cm-1:3070(s,br),2865(m),2801(m,sh),1590(s),1490(s),1455(s,sh),1400(s),1359(s),1323(s);1H NMR(500MHz;DMSO-d6;TMS)ppm:δH 2.96(3H,s,H-7),3.84(3H,s,H-8),4.24(2H,d,H-10),7.218-7.302(5H,m,H-12/12’/13/13’/14),9.30(1H,t,9-NH);13C NMR(125MHz;DMSO-d6;TMS)ppm:δC 26.38(C-7),38.23(C-8),46.33(C-11),127.37(C-14),127.80and 128.19(C-12/12’/13/13’),155.33(C-5),164.28(C-2),179.74(C-6);ms([M+H]+)m/z:327.0590(Calc.327.0580).
2.2 Mass Spectroscopy, Hydrogen Spectroscopy, carbon Spectroscopy, Infrared characterization and ultraviolet characterization plots are shown in FIGS. 1-5.
EXAMPLE 3 preparation of the impurity Compound of formula (II)
A sample of methazolamide was dissolved in 80% methanol and isolated as impurity C by the DAC50 manufacturing system. The method specifically comprises the following steps:
(1) first separation: the separation preparation conditions are reverse phase C18 column (10um), flow rate is 50.0mL/min, ultraviolet wavelength is 290nm, mobile phase is a mixed mobile phase of 20mM sodium sulfate and acetonitrile, and the volume ratio is 75: sodium sulfate improves the peak profile of the chromatographic separation. The fraction containing impurity C was collected (RT ═ 45 min) and then concentrated under reduced pressure to give crude impurity C.
(2) And (3) second separation: again through the same C18 column, flow rate 50.0mL/min, uv wavelength 290nm, in a volume ratio of 75: the mixed mobile phase of 25.1% formic acid-water and acetonitrile was further purified for desalting, and the impurity C fraction was collected (RT ═ 45 min) and lyophilized to give a pure sample (172 mg).
EXAMPLE 4 preparation of the impurity Compound of formula (II)
15g of methazolamide, 7.78g of triethylamine and 50ml of DMF are added, the mixture is stirred at-20 ℃, 20.32g of sulfonyl chloride intermediate is added to react for 5 hours, 500ml of water and 300ml of dichloromethane are added, extraction is carried out, and an organic layer is concentrated. The obtained organic layer was subjected to silica gel column chromatography using ethyl acetate as an eluting solvent: the impurity compound (II) is collected with the ethanol ratio of 10:1, the purity of 98 percent and the yield of 60 percent.
Example 5 structural characterization of impurity Compound (II)
2.1 Pop data:
UV-Visλ(CH3OH)nm:202,255,292(λmax);IR(KBr)νmax cm-1:3455(m,br),2931(m),2853(m),1731(s),1495(s),1379(s),1308(s);1H NMR(500MHz;DMSO-d6;TMS)ppm:δH 2.25(6H,s,H-7/7’),3.86(6H,s,H-8/8’);13C NMR(125MHz;DMSO-d6;TMS)ppm:δC26.38(C-7/7’),38.00(C-8/8’),158.88(C-5/5’),164.42(C-2/2’),179.52(C-6/6’);ms([M+H]+)m/z:455.9884(Calc.455.9883);ms([2M+H]+)m/z:910.9678(Calc.910.9693);ms([M-H]-)m/z:453.9790(Calc.453.9737);([M-CH3CO]-)m/z:411.9683(Calc.411.9632).
2.2 liquid phase spectrogram, mass spectrum, infrared characterization, ultraviolet characterization, hydrogen spectrum and carbon spectrum are shown in FIGS. 6-16.
Figure BDA0003617972960000071
Figure BDA0003617972960000081
Example 6
And (3) detecting the content of impurities in the methazolamide medicine by taking the impurities prepared in the examples 1 and 4 as standard substances.
A detection step: methazolamide analysis method
Preparation of a sample solution: taking solution with mobile phase A and B at a ratio of 18:82 as solvent, dissolving sample at concentration of 0.5mg/ml
Preparation of a standard solution: solvent same sample solution with concentration of 5 μ g/ml
A chromatographic column: agilent phenyl column
Mobile phase A acetonitrile
Mobile phase B potassium dihydrogen phosphate (6.8g/L)
Gradient elution:
Time B(%)
0 82
10 82
30 40
35 40
35.1 82
45 82
wavelength: 290/250
Flow rate: 1mL/min
Sample introduction amount: 5 μ L
And (3) detection results: the content of impurity I is about 0.03-0.05%, and the content of impurity II is about 0.06-0.12%. The impurity preparation method provided by the invention is simple, can be used as a standard substance to realize effective detection of corresponding impurities in methazolamide medicines, and further enhances the quality control of methazolamide medicines.
Example 6 impurity toxicity test
Performing mouse LD50 determination of oral route on impurity I and impurity II, and determining that oral LD50 of methazolamide impurity I mouse is 624 mg/kg; the oral LD50 of the methazolamide impurity II mice is 383mg/kg, which is obviously lower than that of the methazolamide.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A methazolamide impurity compound shown as the following formula (I),
Figure FDA0003617972950000011
2. the preparation method of the impurity compound shown in the structure of the formula (I) is characterized by comprising the following steps:
(1) mixing sulfonyl chloride intermediate, benzylamine, alkali and solvent, and reacting to obtain reaction liquid;
(2) and (2) concentrating the reaction liquid obtained in the step (1) under reduced pressure to dryness, and eluting through a column to obtain the impurity compound shown in the formula (I).
3. The method according to claim 2, wherein in the step (1), the reaction conditions are as follows: stirring at room temperature for 2-5 hours, heating to 40-70 ℃, and stirring for 0.5-3 hours; the alkali is sodium carbonate; the solvent is a non-hydroxyl solvent.
4. The preparation method according to claim 2, wherein in the step (2), the eluent is a mixed solution of n-hexane and ethyl acetate, preferably a mixed solution of n-hexane and ethyl acetate in a volume ratio of 1: 1.
5. A methazolamide impurity compound shown as the following formula (II),
Figure FDA0003617972950000012
6. a method for preparing an impurity compound represented by the structure of formula (II), comprising the steps of:
dissolving methazolamide in a solvent, and separating by using a DAC50 system to obtain an impurity compound (II); preferably, the specific steps of the separation are as follows: performing first separation, collecting the part containing the impurity compound (II), concentrating under reduced pressure to obtain crude product, performing second separation, and collecting the impurity compound (II); preferably, the solvent is selected from at least one of methanol, acetonitrile, water.
7. The method according to claim 6, wherein the conditions for the first separation are:
a chromatographic column: a reversed phase C18 column;
flow rate: 45.0-55.0 mL/min;
ultraviolet wavelength: 285 and 295 nm;
mobile phase: a mixed mobile phase of sodium sulfate and acetonitrile,
the conditions of the second separation are as follows:
a chromatographic column: a reversed phase C18 column;
flow rate: 45.0-55.0 mL/min;
ultraviolet wavelength: 285 and 295 nm;
mobile phase: formic acid-water and acetonitrile.
8. A method for preparing an impurity compound represented by the structure of formula (II), comprising the steps of: mixing methazolamide, triethylamine and a solvent, stirring, adding a sulfonyl chloride intermediate for reaction, adding water and dichloromethane for extraction, concentrating an organic layer, performing silica gel column chromatography on the obtained organic layer, eluting the solvents, namely ethyl acetate and ethanol in a volume ratio of 5-15:1, and collecting an impurity compound (II).
9. The impurity compound shown in the formula (I) and the impurity compound shown in the formula (II) are applied to the quality control of methazolamide.
10. A method for detecting methazolamide impurities, which is characterized in that the impurities in claim 1 and/or claim 5 are used as standard substances, and the detection is carried out according to the following steps:
preparation of a sample solution: taking solution of mobile phase A and B at a ratio of 18:82 as solvent, dissolving sample at concentration of 0.1-10mg/ml, preferably 5mg/ml
Preparation of a standard solution: solvent same product solution with concentration of 0.1-10 μ g/ml, preferably 5 μ g/ml
And (3) chromatographic column: phenyl column
Mobile phase A acetonitrile
Mobile phase B potassium dihydrogen phosphate (6.8g/L)
Gradient elution:
Time B(%) 0 80-85 10 80-85 30 38-42 35 38-42 35.1 80-85 45 80-85
wavelength: 290/250
Flow rate: 0.8-1.2mL/min
Sample introduction amount: 5 μ L.
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