CN113533574A - Composition for drug synthesis and detection method of p-toluenesulfonyl chloride in composition - Google Patents
Composition for drug synthesis and detection method of p-toluenesulfonyl chloride in composition Download PDFInfo
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- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 title claims abstract description 191
- 238000001514 detection method Methods 0.000 title claims abstract description 63
- 239000000203 mixture Substances 0.000 title claims abstract description 38
- 239000003814 drug Substances 0.000 title abstract description 14
- 229940079593 drug Drugs 0.000 title abstract description 14
- 230000015572 biosynthetic process Effects 0.000 title abstract description 11
- 238000001308 synthesis method Methods 0.000 title description 2
- 229940126062 Compound A Drugs 0.000 claims abstract description 36
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 26
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims abstract description 23
- 235000019796 monopotassium phosphate Nutrition 0.000 claims abstract description 23
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 16
- 239000008055 phosphate buffer solution Substances 0.000 claims abstract description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000000945 filler Substances 0.000 claims abstract description 6
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 6
- 239000012085 test solution Substances 0.000 claims description 34
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 14
- FGDQGIKMWOAFIK-UHFFFAOYSA-N acetonitrile;phosphoric acid Chemical compound CC#N.OP(O)(O)=O FGDQGIKMWOAFIK-UHFFFAOYSA-N 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 11
- 238000002347 injection Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 7
- 238000010829 isocratic elution Methods 0.000 claims description 7
- 238000010828 elution Methods 0.000 claims description 6
- 230000014759 maintenance of location Effects 0.000 claims description 6
- 238000010812 external standard method Methods 0.000 claims description 4
- 239000000243 solution Substances 0.000 abstract description 60
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 238000011002 quantification Methods 0.000 abstract description 7
- 239000000523 sample Substances 0.000 description 45
- 239000003085 diluting agent Substances 0.000 description 35
- 239000013558 reference substance Substances 0.000 description 35
- 239000011550 stock solution Substances 0.000 description 29
- 238000007865 diluting Methods 0.000 description 25
- 239000002994 raw material Substances 0.000 description 23
- 239000012071 phase Substances 0.000 description 19
- 238000012360 testing method Methods 0.000 description 17
- 238000005303 weighing Methods 0.000 description 14
- 239000012088 reference solution Substances 0.000 description 13
- 239000012488 sample solution Substances 0.000 description 11
- 238000004090 dissolution Methods 0.000 description 10
- 239000012535 impurity Substances 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- 230000015556 catabolic process Effects 0.000 description 6
- 238000006731 degradation reaction Methods 0.000 description 6
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 5
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- 238000010811 Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Methods 0.000 description 2
- 238000007872 degassing Methods 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 231100000167 toxic agent Toxicity 0.000 description 2
- 239000003440 toxic substance Substances 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
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- 238000005516 engineering process Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000008832 photodamage Effects 0.000 description 1
- 238000005173 quadrupole mass spectroscopy Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
Abstract
The invention belongs to the technical field of drug detection, and particularly relates to a composition for drug synthesis and a detection method of paratoluensulfonyl chloride in the composition. The invention provides a composition containing a compound A, which contains not more than 0.05 percent of tosyl chloride by weight, wherein the structural formula of the compound A is as follows:
the invention also provides a method for detecting the content of the tosyl chloride in the composition by using the high performance liquid chromatography, and the chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filler for the chromatographic column; the potassium dihydrogen phosphate buffer solution is used as a mobile phase A, and the acetonitrile is used as a mobile phase B. The method provided by the invention has good system applicability and specificity, detection limit and quantification limit, linearity and range, precision, accuracy and solution stability, can realize accurate detection of the content of the tosyl chloride in the composition, and has good application prospect.
Description
Technical Field
The invention belongs to the technical field of drug detection, and particularly relates to a composition for drug synthesis and a detection method of paratoluensulfonyl chloride in the composition.
Background
Compound (I)
Is a raw material for drug synthesis, which can be used for introducing a four-membered ring in drug synthesis. However, the starting material usually contains impurity p-toluenesulfonyl chloride. Tosyl chloride is a toxic compound that is irritating and damaging to the liver. Therefore, it is necessary to control the quality of the raw material and detect the content of p-toluenesulfonyl chloride as an impurity.
In the prior art, a method for detecting the content of p-toluenesulfonyl chloride in p-toluenesulfonic acid-2-thiophene ethyl ester by using a high performance liquid chromatography-triple quadrupole mass spectrometry combined method (UPLC-MS/MS) is provided (DOI: 10.16155/j.0254-1793.2020.11.19). However, the method requires derivatization of p-toluenesulfonyl chloride and aniline before detection, and is complex in operation, and the method is designed for a chemical system with the main component of toluenesulfonic acid-2-thiophene ethyl ester, and the selected chromatographic conditions and mass spectrum conditions are not suitable for the raw materials for drug synthesis, which have completely different main chemical components. And the method must adopt UPLC-MS/MS, and the cost is higher than that of the common liquid chromatogram, thus being not beneficial to the large-scale application in the production.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a composition for drug synthesis and a detection method of p-toluenesulfonyl chloride, wherein the content of the p-toluenesulfonyl chloride in a raw material can be accurately detected by liquid chromatography by optimizing chromatographic conditions and a non-derivatization method, so that the quality of the raw material is controlled.
A composition comprising compound A, which comprises not more than 0.05% by weight of tosyl chloride,
wherein the structural formula of the compound A is as follows:
preferably, in the HPLC chromatogram, the retention time of the compound A is 1-3min, and the retention time of the tosyl chloride is 8-12 min;
the chromatographic conditions of the HPLC chromatogram were: octadecylsilane chemically bonded silica is used as a filler for the chromatographic column; the potassium dihydrogen phosphate buffer solution is used as a mobile phase A, and the acetonitrile is used as a mobile phase B.
Preferably, its HPLC chromatogram is shown in FIG. 1B.
Preferably, in HPLC chromatographic detection, the composition is dissolved by acetonitrile-phosphoric acid with the volume ratio of 100 (0.05-0.2) to prepare a test solution;
and/or, the concentration of the composition in the test solution is 0.3-0.7 mg/ml.
Preferably, the concentration of the potassium dihydrogen phosphate in the potassium dihydrogen phosphate buffer solution is 2.5-3.0g/L, and the pH of the potassium dihydrogen phosphate buffer solution is adjusted to 2.5-3.5 by using phosphoric acid;
and/or the volume ratio of the mobile phase A to the mobile phase B is (40-60) to (60-40);
and/or, in HPLC chromatographic detection, the elution mode is isocratic elution;
and/or, the chromatographic conditions further comprise: the flow rate is 0.8-1.2ml per minute; the column temperature is 25-35 ℃; the detection wavelength is 220-250 nm; controlling the temperature of a sample injection disc to be 6-10 ℃; the sample volume is 10-25 μ l.
The invention also provides a method for detecting paratoluensulfonyl chloride in the composition, which comprises the following steps:
(1) formulating said composition into a test solution;
(2) detecting an HPLC chromatogram of the test solution, and calculating the content of the tosyl chloride;
wherein, the chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filler for the chromatographic column; the potassium dihydrogen phosphate buffer solution is used as a mobile phase A, and the acetonitrile is used as a mobile phase B.
Preferably, in the step (1), the composition is dissolved by acetonitrile-phosphoric acid with the volume ratio of 100 (0.05-0.2) to prepare a test solution;
and/or, the concentration of the composition in the test solution is 0.3-0.7 mg/ml.
Preferably, in the step (2), the concentration of the potassium dihydrogen phosphate in the potassium dihydrogen phosphate buffer solution is 2.5-3.0g/L, and the pH of the potassium dihydrogen phosphate buffer solution is adjusted to 2.5-3.0 by using phosphoric acid;
and/or the volume ratio of the mobile phase A to the mobile phase B is (40-60) to (60-40);
and/or, in HPLC chromatographic detection, the elution mode is isocratic elution.
Preferably, in step (2), the chromatographic conditions further comprise: the flow rate is 0.8-1.2ml per minute; and/or the column temperature is 25-35 ℃; and/or, the detection wavelength is 220-250 nm; and/or controlling the temperature of a sample injection disc to be 6-10 ℃; and/or, the sample amount is 10-25 mul.
Preferably, in the step (2), the content of the tosyl chloride is calculated by an external standard method according to peak area.
The present invention provides a novel composition for drug synthesis, which can be used for the synthesis of drugs containing the structural unit of compound a. The weight percentage of the toxic compound tosyl chloride in the composition is not higher than 0.05 percent, thereby ensuring the safety of the synthesized drug. In order to control the content of the tosyl chloride in the composition, the invention optimizes the chromatographic conditions, the preparation conditions of the test solution and the like in the high performance liquid chromatography, can accurately detect the content of impurity tosyl chloride and has strong specificity and stability.
In addition, the acyl chloride compounds are easily degraded in water, so that in an aqueous system, tosyl chloride is unstable, which is not favorable for accurate detection. In a preferred embodiment of the present invention, acetonitrile-phosphoric acid is used as a diluent in which tosyl chloride is not easily degraded; furthermore, the mobile phase is pH to 2.5-3.5, under which conditions the degradation of methanesulfonyl chloride is very slow; on the other hand, the detection process of the present invention has a fast off-peak time, which further reduces the degradation of tosyl chloride. By combining the factors, the technical scheme of the invention can well solve the problem that tosyl chloride is easy to degrade, and further improve the detection accuracy.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a superimposed spectrum of a blank solvent, a special solution, a reference solution and a test solution; wherein: (A) the chromatogram is a chromatogram of a special solution, (B) the chromatogram of a test solution, (C) the chromatogram of a reference solution, and (D) the chromatogram of a blank solution;
FIG. 2 is a chromatogram for detecting a sample solution and a reference solution at a wavelength of 225nm in Experimental example 1;
FIG. 3 is a chromatogram for detecting a test solution and a control solution at a wavelength of 245nm in Experimental example 1;
FIG. 4 is a superimposed spectrum of the white solvent, the reference solution and the test solution under each degradation condition in Experimental example 2;
FIG. 5 is a spectrum obtained by stacking the blank, detection limit and quantification limit of tosyl chloride in Experimental example 2;
FIG. 6 shows the results of the linear measurement of p-toluenesulfonyl chloride in Experimental example 2.
Detailed Description
The reagents and materials used in the examples and experimental examples of the present invention, which are not specifically described, are commercially available products, and are specifically shown in the following table:
wherein the structural formula of the compound A is as follows:
the structural formula of the compound B is as follows:
example 1 method for detecting content of tosyl chloride in raw material containing Compound A
The steps of this example are as follows:
step 1: taking a raw material sample containing the compound A, ultrasonically dissolving the sample by using acetonitrile-phosphoric acid (100:0.1) and diluting to prepare a solution containing 0.5mg of the compound A in each 1ml as a sample solution;
step 2: p-toluenesulfonyl chloride was precisely weighed, dissolved in acetonitrile-phosphoric acid (100:0.1) and diluted to a solution containing about 0.25. mu.g of toluenesulfonyl chloride per 1ml, as a control solution.
And step 3: octadecylsilane chemically bonded silica is used as filler (such as ACE Excel 3C18-PFP,4.6 mm × 150mm, 3 μm or chromatographic column with equivalent efficiency), potassium dihydrogen phosphate buffer (2.72 g of potassium dihydrogen phosphate is weighed, 1000ml of water is added for dissolution, the pH value is adjusted to 3.0 by phosphoric acid) is used as mobile phase A, acetonitrile is used as mobile phase B, and the elution is carried out at 50:50 isocratic volume ratio and the flow rate is 1.0ml per minute; the column temperature is 30 ℃; the detection wavelength is 245 nm; the temperature of the sample feeding plate was controlled to 8 ℃. Precisely measuring 15 μ l of reference solution and sample solution, injecting into liquid chromatograph, and recording chromatogram.
And 4, step 4: if a peak of the tosyl chloride exists in a chromatogram of the test solution, the content of the tosyl chloride is calculated by an external standard method according to the peak area.
The chromatogram of the test solution obtained by the detection in this example is shown in FIG. 1B and the chromatogram of the control solution is shown in FIG. 1C.
EXAMPLE 2 composition of drug Synthesis starting Material
This example provides a pharmaceutical raw material composition containing compound a, which was tested for p-toluenesulfonyl chloride using the method of example 1, but not exceeding 0.05% by weight.
Experimental example 1 chromatographic conditions are preferred
This experimental example screens the chromatographic conditions of the method for detecting the content of tosyl chloride in a raw material containing compound a. Other operation methods and conditions not specifically described are the same as those in example 1.
First, solution preparation
Test solution: precisely weighing 10mg of the sample, placing the sample in a 20ml measuring flask, ultrasonically dissolving the sample by using acetonitrile-phosphoric acid (100:0.1), diluting the sample to a scale, and shaking the sample uniformly to obtain the test solution.
Control solution: an appropriate amount of p-toluenesulfonyl chloride is precisely weighed, placed in a measuring flask, added with acetonitrile-phosphoric acid (100:0.1) for ultrasonic dissolution and diluted to prepare a solution containing about 0.25 mu g of p-toluenesulfonyl chloride in each 1 ml.
Selection of initial experimental conditions
Because hydrolysis of p-toluenesulfonyl chloride can be inhibited under acidic conditions, acetonitrile-phosphoric acid (100:0.1) is used as a diluent, and a potassium dihydrogen phosphate buffer solution with the pH value of 3.0 is used as an aqueous phase in a mobile phase; because the p-toluenesulfonyl chloride reacts with methanol but not acetonitrile, the organic phase in the mobile phase adopts acetonitrile; because the mobile phase contains water, in order to reduce the contact time of the paratoluensulfonyl chloride and the water, an isocratic elution mode is adopted without gradient elution.
The initial experimental conditions were: selecting ACE Excel 3C18-PFP (angiotensin converting enzyme) with the volume ratio of 4.6 to 150mm 3 mu m for a chromatographic column, isocratically eluting for 15min at the ratio of mobile phase A to mobile phase B of 50:50, and carrying out column temperature: 30 ℃, injection volume: 15 μ l, flow rate: 1.0ml/min, sample tray temperature: the detection wavelength was 225nm at 8 ℃.
Chromatograms of the test solution and the reference solution obtained by isocratic elution at 225nm are shown in FIG. 2, and it can be seen from the chromatogram that impurities in the test solution interfere with the detection of tosyl chloride.
Third, optimization of detection wavelength
The preferred experimental conditions are: selecting ACE Excel 3C18-PFP (angiotensin converting enzyme) with the volume ratio of 4.6 to 150mm 3 mu m for a chromatographic column, isocratically eluting for 15min at the ratio of mobile phase A to mobile phase B of 50:50, and carrying out column temperature: 30 ℃, injection volume: 15 μ l, flow rate: 1.0ml/min, detection wavelength: 245nm, sample tray temperature: at 8 ℃.
Chromatogram obtained by isocratic elution of the test solution and the reference solution at the wavelength of 245nm is shown in fig. 3, and it can be seen from the chromatogram that the base line is smoother at the wavelength of 245nm, the response of the tosyl chloride is higher, and impurities in the test solution do not interfere with the detection of the tosyl chloride. From this result, it was found that the effect of using the maximum ultraviolet absorption wavelength of p-toluenesulfonyl chloride of 245nm as the detection wavelength is more excellent in the detection of p-toluenesulfonyl chloride in the raw material containing compound A.
Experimental example 2 methodological verification
First, system applicability and specificity
1. Solution preparation
Blank solvent (diluent): acetonitrile-phosphoric acid (100: 0.1): weighing 1000ml of acetonitrile and 1ml of phosphoric acid, uniformly mixing, and performing ultrasonic degassing to obtain the product.
Mobile phase A: 20mM potassium dihydrogen phosphate (pH 3.0): weighing 2.72g of potassium dihydrogen phosphate, adding 1000ml of water for dissolving, adjusting the pH value to 3.0 by using phosphoric acid, filtering, and performing ultrasonic degassing to obtain the potassium dihydrogen phosphate.
Compound B control stock: accurately weighing compound B as reference, placing into a measuring flask, adding diluent, ultrasonic dissolving, and diluting to obtain solution containing about 0.1mg of compound B per 1 ml.
P-toluenesulfonic acid control stock solution: precisely weighing a proper amount of p-toluenesulfonic acid reference substance, placing into a measuring flask, adding a diluent for ultrasonic dissolution, and diluting to prepare a solution containing about 0.1mg of p-toluenesulfonic acid in each 1 ml.
P-toluenesulfonyl chloride control stock solution: precisely weighing p-toluenesulfonyl chloride reference substance, placing into a measuring flask, adding diluent, ultrasonically dissolving, and diluting to obtain a solution containing about 0.1mg of p-toluenesulfonyl chloride in each 1 ml.
P-toluenesulfonic acid methyl ester control stock solution: accurately weighing methyl p-toluenesulfonate reference substance, placing into a measuring flask, adding diluent, ultrasonically dissolving, and diluting to obtain a solution containing about 0.1mg of methyl p-toluenesulfonate in each 1 ml.
A special solution: precisely weighing about 10mg of the compound A reference substance, placing the compound A reference substance into a 20ml measuring flask, adding a proper amount of diluent for ultrasonic dissolution, precisely weighing 0.5ml of each of the compound B and the p-toluenesulfonic acid impurity reference substance stock solution, 50 mu l of each of the p-toluenesulfonyl chloride and the p-toluenesulfonic acid methyl ester impurity reference substance stock solution, and diluting with the diluent to a constant volume to obtain the compound A.
Test solution: taking about 10mg of a raw material sample containing the compound A, precisely weighing, placing in a 20ml measuring flask, ultrasonically dissolving with a proper amount of diluent, diluting to scale, preparing into a solution containing 0.5mg of the raw material in each 1ml, and shaking up to obtain the final product.
P-toluenesulfonyl chloride reference stock solution 2: 2.5ml of a paratoluensulfonyl chloride reference substance stock solution is precisely measured and placed in a 100ml measuring flask, and a diluent is added to dilute the solution to prepare a solution containing about 2.5 mu g of paratoluensulfonyl chloride in each 1 ml.
Control solution: a proper amount of paratoluensulfonyl chloride reference substance stock solution is precisely measured, and the solution is placed in a measuring flask and diluted by a diluent to prepare solution containing about 0.25 mu g of paratoluensulfonyl chloride in each 1 ml.
2. The result of the detection
The blank solvent, the special solution, the reference solution and the test solution were subjected to the detection under the chromatographic conditions of example 1. The results are shown in FIG. 1.
For the blank solvent: the chromatogram of the blank solvent does not have interference peaks at the position of the p-toluenesulfonyl chloride peak.
For the proprietary solutions: it is known that impurity compound B, p-toluenesulfonic acid and methyl p-toluenesulfonate do not interfere with the detection of p-toluenesulfonyl chloride, the degree of separation between p-toluenesulfonyl chloride and adjacent impurity peaks is 18.5 and greater than 1.5, the theoretical plate number of p-toluenesulfonyl chloride peak is 13668, and the tailing factor is 1.0.
For the control solutions: the number of theoretical plates of the tosyl chloride is 13678, the tailing factor is 1.1, the reference solution is continuously injected for 6 times, the peak area RSD is 0.3 percent and less than 10.0 percent, and the RSD of the retention time is 0.08 percent and less than 1.0 percent.
The results show that the method of the invention has good applicability and specificity.
Second, degradation specificity
1. Solution preparation
High temperature failure test solution: precisely weighing 10.35mg of a raw material sample containing the compound A, placing the sample in a headspace bottle, placing the headspace bottle in a forced air drying oven at 80 ℃ for 24h, adding a diluent, transferring the mixture into a 20ml measuring flask, diluting to scale, and shaking up to obtain the compound A.
High wet break test solution: precisely weighing 10.44mg of a raw material sample containing the compound A, placing the sample in a 20ml measuring flask, opening the measuring flask, placing the sample in a constant-temperature constant-humidity test box with 92.5% RH at 25 ℃ for 24h, adding a proper amount of diluent, ultrasonically dissolving and diluting the sample to scale, and shaking up to obtain the compound A.
Light damage test solution: precisely weighing 10.06mg of a raw material sample containing the compound A, placing the sample in a 20ml transparent measuring flask, and placing the sample in an illumination box (the illumination is 5000 +/-500 lux, and the ultraviolet energy is 90 uw/cm)2) Standing for 24h, adding appropriate amount of diluent, ultrasonic dissolving, diluting to scale, and shaking.
Damp-heat Damp test solution: precisely weighing 10.16mg of a raw material sample containing the compound A, placing the sample in a 20ml measuring flask, opening the measuring flask, placing the sample in a constant-temperature constant-humidity test box with 40 ℃ and 75% RH for 24h, adding a proper amount of diluent, ultrasonically dissolving and diluting the sample to scale, and shaking up to obtain the compound A.
2. The result of the detection
The solutions obtained by subjecting the blank solvent, the reference solution and the sample solution to high temperature, high humidity, moist heat and light irradiation were examined under the chromatography conditions described in example 1. The results are shown in FIG. 4.
The result shows that no p-toluenesulfonyl chloride is detected after the test solution is damaged by conditions such as high temperature, high humidity, damp heat, light and the like.
The above results show that the method of the present invention has good specificity of degradation.
Third, detection limit and quantification limit
1. Solution preparation
Quantitative limiting solution: precisely measuring a proper amount of reference solution, and continuously diluting with a diluent until the S/N of the paratoluensulfonyl chloride chromatographic peak is between 10 and 30.
Detection limiting solution: precisely measuring a proper amount of limiting solution, and continuously diluting with a diluent until the S/N of the paratoluensulfonyl chloride chromatographic peak is between 3 and 8.
2. The result of the detection
The signal-to-noise ratio of the p-toluenesulfonyl chloride in the detection limit solution is within the range of 3-8, and the results are shown in Table 1. The signal to noise ratio of the p-toluenesulfonyl chloride in the quantitative limiting solution is within the range of 10-30, the RSD of the peak area of the 6-pin quantitative limiting solution p-toluenesulfonyl chloride is 3.8% and less than 10%, the quantitative limiting concentration is lower than 50% of the limiting concentration, and the results are shown in Table 2. The chromatograms of the detection limiting solution and the quantification limiting solution are shown in fig. 5.
TABLE 1 examination result table of detection limit and quantitative limit of p-toluenesulfonyl chloride signal-to-noise ratio
| Name (R) | Concentration (μ g/ml) | Corresponding to the concentration of the test sample% | Corresponding to the limit concentration% | S/N |
| Detection limit | 0.0059 | 0.0012 | 2.37 | 4.8 |
| Limit of quantification | 0.0177 | 0.0035 | 7.10 | 15.9 |
TABLE 2 Table of quantitative limiting SNR and peak area investigation results for tosyl chloride
The above results indicate that the detection limit and the quantification limit of the method of the present invention are low, which indicates that the method of the present invention has a high sensitivity.
Four, linearity and range
1. Solution preparation
Linear 50% (limiting concentration) solution: precisely measuring 1ml of paratoluensulfonyl chloride reference substance stock solution, placing the paratoluensulfonyl chloride reference substance stock solution into a 20ml measuring flask, and diluting the paratoluensulfonyl chloride reference substance stock solution to a scale by using a diluent to obtain the paratoluensulfonyl chloride reference substance.
Linear 80% (limiting concentration) solution: precisely measuring 1.6ml of paratoluensulfonyl chloride reference substance stock solution, placing the paratoluensulfonyl chloride reference substance stock solution into a 20ml measuring flask, and diluting the paratoluensulfonyl chloride reference substance stock solution to a scale by using a diluent to obtain the p-toluenesulfonyl chloride reference substance.
Linear 100% (limiting concentration) solution: precisely measuring 2ml of paratoluensulfonyl chloride reference substance stock solution, placing the paratoluensulfonyl chloride reference substance stock solution into a 20ml measuring flask, and diluting the paratoluensulfonyl chloride reference substance stock solution to a scale by using a diluent to obtain the paratoluensulfonyl chloride reference substance.
Linear 150% (limiting concentration) solution: precisely measuring 3ml of paratoluensulfonyl chloride reference substance stock solution, placing the paratoluensulfonyl chloride reference substance stock solution into a 20ml measuring flask, and diluting the paratoluensulfonyl chloride reference substance stock solution to a scale by using a diluent to obtain the paratoluensulfonyl chloride reference substance.
2. The result of the detection
The above linear solution was tested according to the chromatographic conditions of example 1. The results of the linear p-toluenesulfonyl chloride test are shown in Table 3 and FIG. 6.
TABLE 3 Linear test results for p-toluenesulfonyl chloride
The results show that the peak area and the concentration of the p-toluenesulfonyl chloride are linearly related. Furthermore, as can be seen from the linear equation, the standard curve is almost through the origin, which indicates that little degradation of tosyl chloride occurs as measured by the method of example 1. Therefore, the detection method can realize accurate quantitative detection of the tosyl chloride.
Fifthly, precision
The method of example 1 was followed, and 6 consecutive injections of the control solution were performed, and the peak areas of the 6 detection results were examined, and the results are shown in Table 4.
TABLE 4 Table of examination results of precision peak area of sample injection for control solutions
The results show that in 6 chromatogram of the control solution, RSD of the peak area of p-toluenesulfonyl chloride is 0.3% and less than 10.0%, and RSD of retention time is 0.08% and less than 1.0%. The method of the invention thus has good precision.
Sixthly, repeatability
1. Solution preparation
Adding a standard test sample solution # 1: taking 10.28mg of a raw material sample containing the compound A, placing the sample in a 20ml measuring flask, adding a proper amount of diluent for ultrasonic dissolution, adding 2ml of paratoluensulfonyl chloride reference substance stock solution, diluting to a scale with the diluent, and shaking up to obtain the compound A.
Adding a standard test sample solution # 2: taking 10.25mg of a raw material sample containing the compound A, placing the sample in a 20ml measuring flask, adding a proper amount of diluent for ultrasonic dissolution, adding 2ml of paratoluensulfonyl chloride reference substance stock solution, diluting to a scale with the diluent, and shaking up to obtain the compound A.
Adding a standard test sample solution # 3: taking 10.31mg of a raw material sample containing the compound A, placing the sample in a 20ml measuring flask, adding a proper amount of diluent for ultrasonic dissolution, adding 2ml of paratoluensulfonyl chloride reference substance stock solution, diluting to a scale with the diluent, and shaking up to obtain the compound A.
Adding a standard test article solution # 4: taking 10.31mg of a raw material sample containing the compound A, placing the sample in a 20ml measuring flask, adding a proper amount of diluent for ultrasonic dissolution, adding 2ml of paratoluensulfonyl chloride reference substance stock solution, diluting to a scale with the diluent, and shaking up to obtain the compound A.
Adding a standard test sample solution # 5: taking 10.35mg of a raw material sample containing the compound A, placing the sample in a 20ml measuring flask, adding a proper amount of diluent for ultrasonic dissolution, adding 2ml of paratoluensulfonyl chloride reference substance stock solution, diluting to a scale with the diluent, and shaking up to obtain the compound A.
Adding a standard test sample solution # 6: taking 10.13mg of a raw material sample containing the compound A, placing the sample in a 20ml measuring flask, adding a proper amount of diluent for ultrasonic dissolution, adding 2ml of paratoluensulfonyl chloride reference substance stock solution, diluting to a scale with the diluent, and shaking up to obtain the compound A.
2. The result of the detection
The above-mentioned labeled test sample solution was measured in accordance with the method of example 1, and the content of tosyl chloride in 6 parts of the labeled test sample solution was calculated by the external standard method, and the results are shown in Table 5.
TABLE 5 Table of results of repeatability test on tosyl chloride
The result shows that the detection result RSD of 6 parts of the solution added with the standard test sample is 0 and less than 10.0 percent. The detection method of the invention has good repeatability.
Seventh, accuracy
Detecting the content of the paratoluensulfonyl chloride in the solution of the standard sample, and calculating the recovery rate of the paratoluensulfonyl chloride. The results are shown in Table 6.
TABLE 6 Table of p-toluenesulfonyl chloride accuracy examination results
Under the limit concentration of 100%, the recovery rate of the paratoluensulfonyl chloride is between 90.0% and 110.0%, and the recovery rate RSD is 0.6% and less than 10.0%, which shows that the detection method has high accuracy.
Eighth, solution stability
1. Solution preparation
Preparing a test solution and a reference solution according to the method, standing at 8 ℃ for 12 hours, injecting 15 mu l of sample at 0h, 2h, 4h, 8h and 12h respectively, and recording a chromatogram.
2. The result of the detection
For the test article solutions: in the verification time, no new impurity is added to interfere the detection of the tosyl chloride, and the RSD of the p-toluenesulfonyl chloride peak area is less than or equal to 10.0 percent.
For control solutions: the results of peak area for p-toluenesulfonyl chloride are shown in Table 7.
TABLE 7 test results of solution stability of control solutions at 8 deg.C for 12h
| Name (R) | 0h | 2.2h | 4h | 8h | 12h | RSD％ |
| Control solution | 0.1784 | 0.1774 | 0.1767 | 0.1779 | 0.1775 | 0.4 |
RSD of the peak area of p-toluenesulfonyl chloride of the control solution at 8 ℃ for 12 hours was 0.4% and less than 10.0%.
The results show that the test solution and the reference solution prepared by the detection method provided by the invention have good stability.
As can be seen from the above examples and experimental examples, the present invention provides a novel pharmaceutical raw material composition and a detection method thereof. The method provided by the invention has good system applicability and specificity, detection limit and quantification limit, linearity and range, precision, accuracy and solution stability, can realize accurate detection of the content of the tosyl chloride in the composition, and has good application prospect.
Claims (10)
1. A composition comprising compound A, characterized in that it comprises not more than 0.05% by weight of tosyl chloride,
wherein the structural formula of the compound A is as follows:
2. the composition of claim 1, wherein: in an HPLC chromatogram of the compound, the retention time of the compound A is 1-3min, and the retention time of the tosyl chloride is 8-12 min;
the chromatographic conditions of the HPLC chromatogram were: octadecylsilane chemically bonded silica is used as a filler for the chromatographic column; the potassium dihydrogen phosphate buffer solution is used as a mobile phase A, and the acetonitrile is used as a mobile phase B.
3. The composition of claim 2, wherein: its HPLC chromatogram is shown in FIG. 1B.
4. The composition of claim 2, wherein: in HPLC chromatographic detection, the composition is dissolved by acetonitrile-phosphoric acid with the volume ratio of 100 (0.05-0.2) to prepare a test solution;
and/or, the concentration of the composition in the test solution is 0.3-0.7 mg/ml.
5. The composition of claim 2, wherein: the concentration of the potassium dihydrogen phosphate in the potassium dihydrogen phosphate buffer solution is 2.5-3.0g/L, and the pH of the potassium dihydrogen phosphate buffer solution is adjusted to 2.5-3.5 by using phosphoric acid;
and/or the volume ratio of the mobile phase A to the mobile phase B is (40-60) to (60-40);
and/or, in HPLC chromatographic detection, the elution mode is isocratic elution;
and/or, the chromatographic conditions further comprise: the flow rate is 0.8-1.2ml per minute; the column temperature is 25-35 ℃; the detection wavelength is 220-250 nm; controlling the temperature of a sample injection disc to be 6-10 ℃; the sample volume is 10-25 μ l.
6. A method for detecting tosyl chloride in a composition according to any of claims 1 to 5, comprising the steps of:
(1) formulating said composition into a test solution;
(2) detecting an HPLC chromatogram of the test solution, and calculating the content of the tosyl chloride;
wherein, the chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filler for the chromatographic column; the potassium dihydrogen phosphate buffer solution is used as a mobile phase A, and the acetonitrile is used as a mobile phase B.
7. The detection method according to claim 6, characterized in that: in the step (1), the composition is dissolved by acetonitrile-phosphoric acid with the volume ratio of 100 (0.05-0.2) to prepare a test solution;
and/or, the concentration of the composition in the test solution is 0.3-0.7 mg/ml.
8. The detection method according to claim 6, characterized in that: in the step (2), the concentration of the potassium dihydrogen phosphate in the potassium dihydrogen phosphate buffer solution is 2.5-3.0g/L, and the pH of the potassium dihydrogen phosphate buffer solution is adjusted to 2.5-3.0 by using phosphoric acid;
and/or the volume ratio of the mobile phase A to the mobile phase B is (40-60) to (60-40);
and/or, in HPLC chromatographic detection, the elution mode is isocratic elution.
9. The detection method according to claim 6, characterized in that: in the step (2), the chromatographic conditions further comprise: the flow rate is 0.8-1.2ml per minute; and/or the column temperature is 25-35 ℃; and/or, the detection wavelength is 220-250 nm; and/or controlling the temperature of a sample injection disc to be 6-10 ℃; and/or, the sample amount is 10-25 mul.
10. The detection method according to claim 6, characterized in that: in the step (2), the method for calculating the content of the p-toluenesulfonyl chloride is calculated by an external standard method according to the peak area.
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