CN107843656A - A kind of detection method of 2,4 thiophenol dimethyl benzene about material - Google Patents
A kind of detection method of 2,4 thiophenol dimethyl benzene about material Download PDFInfo
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- CN107843656A CN107843656A CN201610836937.1A CN201610836937A CN107843656A CN 107843656 A CN107843656 A CN 107843656A CN 201610836937 A CN201610836937 A CN 201610836937A CN 107843656 A CN107843656 A CN 107843656A
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- detection method
- thiophenol dimethyl
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- thiophenol
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- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 title claims abstract description 186
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 238000001514 detection method Methods 0.000 title claims abstract description 54
- 239000000463 material Substances 0.000 title claims abstract description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 67
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000007788 liquid Substances 0.000 claims abstract description 16
- 239000000945 filler Substances 0.000 claims abstract description 10
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 10
- 150000001768 cations Chemical class 0.000 claims abstract description 9
- 239000008363 phosphate buffer Substances 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 44
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 32
- 239000012071 phase Substances 0.000 claims description 18
- 238000010790 dilution Methods 0.000 claims description 13
- 239000012895 dilution Substances 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- 239000008346 aqueous phase Substances 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 7
- 239000007791 liquid phase Substances 0.000 claims description 6
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 6
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical group [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 5
- PNJYPDSNILRAGQ-UHFFFAOYSA-N CC1=C(C=CC=C1)C.S1C=CC(=C1)O Chemical class CC1=C(C=CC=C1)C.S1C=CC(=C1)O PNJYPDSNILRAGQ-UHFFFAOYSA-N 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 claims description 2
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 claims description 2
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 claims description 2
- 235000019837 monoammonium phosphate Nutrition 0.000 claims description 2
- 239000008055 phosphate buffer solution Substances 0.000 claims description 2
- 239000012488 sample solution Substances 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 claims description 2
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 claims description 2
- UQFSVBXCNGCBBW-UHFFFAOYSA-M tetraethylammonium iodide Chemical compound [I-].CC[N+](CC)(CC)CC UQFSVBXCNGCBBW-UHFFFAOYSA-M 0.000 claims description 2
- RXMRGBVLCSYIBO-UHFFFAOYSA-M tetramethylazanium;iodide Chemical compound [I-].C[N+](C)(C)C RXMRGBVLCSYIBO-UHFFFAOYSA-M 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims 1
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims 1
- 229940073455 tetraethylammonium hydroxide Drugs 0.000 claims 1
- LRGJRHZIDJQFCL-UHFFFAOYSA-M tetraethylazanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC LRGJRHZIDJQFCL-UHFFFAOYSA-M 0.000 claims 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 18
- -1 thiophenol dimethyl benzenes Chemical class 0.000 abstract description 6
- 230000035945 sensitivity Effects 0.000 abstract description 5
- 238000004811 liquid chromatography Methods 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 26
- 230000000052 comparative effect Effects 0.000 description 21
- 239000012535 impurity Substances 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 239000003814 drug Substances 0.000 description 11
- 238000000926 separation method Methods 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- 229960002263 vortioxetine Drugs 0.000 description 6
- 239000000872 buffer Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- YQNWZWMKLDQSAC-UHFFFAOYSA-N vortioxetine Chemical compound CC1=CC(C)=CC=C1SC1=CC=CC=C1N1CCNCC1 YQNWZWMKLDQSAC-UHFFFAOYSA-N 0.000 description 5
- AMNLXDDJGGTIPL-UHFFFAOYSA-N 2,4-dimethylbenzenethiol Chemical compound CC1=CC=C(S)C(C)=C1 AMNLXDDJGGTIPL-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 238000010829 isocratic elution Methods 0.000 description 3
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical compound CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 description 3
- 235000011009 potassium phosphates Nutrition 0.000 description 3
- CESBAYSBPMVAEI-UHFFFAOYSA-N 3,5-dimethylbenzenethiol Chemical compound CC1=CC(C)=CC(S)=C1 CESBAYSBPMVAEI-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical compound CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 description 1
- IDKCKPBAFOIONK-UHFFFAOYSA-N 3,4-dimethylbenzenethiol Chemical compound CC1=CC=C(S)C=C1C IDKCKPBAFOIONK-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- LRSHEODYZMWLHC-UHFFFAOYSA-N C1(=CC=CC=C1)O.[S].C1(=CC=CC=C1)C Chemical compound C1(=CC=CC=C1)O.[S].C1(=CC=CC=C1)C LRSHEODYZMWLHC-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- VEMXDEHLAOUMJI-UHFFFAOYSA-N [S].C1(=CC(=CC=C1)C)C Chemical compound [S].C1(=CC(=CC=C1)C)C VEMXDEHLAOUMJI-UHFFFAOYSA-N 0.000 description 1
- FGDQGIKMWOAFIK-UHFFFAOYSA-N acetonitrile;phosphoric acid Chemical compound CC#N.OP(O)(O)=O FGDQGIKMWOAFIK-UHFFFAOYSA-N 0.000 description 1
- 229940107816 ammonium iodide Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical class [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- 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
-
- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
Landscapes
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
Abstract
The present invention provides a kind of high-efficiency liquid chromatography method for detecting of 2,4 thiophenol dimethyl benzene about material.Liquid chromatogram measuring condition used is：For chromatographic column using octadecylsilane chemically bonded silica as filler, mobile phase is the phosphate buffer methanol containing cation pair.This method has the advantages that method is simple and convenient, and specificity is good, high sensitivity, reproducible, is suitable in 2,4 thiophenol dimethyl benzenes the qualitative and quantitative detection about material.
Description
Technical field
The present invention relates to detection method, and in particular to a kind of to analyze 2,4- thiophenol dimethyl benzenes with high performance liquid chromatography separation
Method about material.
Background technology
2,4- thiophenol dimethyl benzenes, also known as 2,4- dimethylbenzene thiol, are a kind of conventional medicine intermediate, its structural formula
It is as follows：
Molecular formula：C8H10S, molecular weight：138.23.
2,4- thiophenol dimethyl benzenes are most commonly used to synthesize antidepressant-Vortioxetine, according to 2,4- thiophenol dimethyl benzenes
Process route, it is understood that there may be impurity have 3- methylbenzene phenyl-sulfhydrates, 4- methylbenzene phenyl-sulfhydrates, 2,5- thiophenol dimethyl benzenes, 3,4- bis-
Methylbenzene phenyl-sulfhydrate, 3,5- thiophenol dimethyl benzenes, 2,6- thiophenol dimethyl benzenes.The presence of these impurity will produce a series of secondary anti-
Should, the purity of product is finally largely effected on, subsequently complicated technique will be needed to be isolated and purified.Such as document 1：Stability-
indicating reversed-phase HPLC method development and characterization of
Impurities in vortioxetine utilizing LC-MS, IR and NMR (Lei Liu et al., Journal
of Pharmaceutical and Biomedical Analysis,117:325-332,2015) disclose synthesis Vortioxetine
4 kinds of routes in the impurity and accessory substance that are related to, synthetic route is as follows：
Can be seen that route 1-3 using 2,4- thiophenol dimethyl benzenes from above-mentioned route is that intermediate synthesizes Vortioxetine,
Wherein the 2 of route 3,4 thiophenol dimethyl benzenes (SMB) cause product due to there may be the thiophenol dimethyl benzene (SMB-1) of impurity 2,6
Middle impurity Imp-E is produced.Therefore document 1 determines each impurity (A-H) in product Vortioxetine by high performance liquid chromatography,
Impurity that may be present and caused side reaction in raw material are speculated with this.
However, document 1 is only capable of reflecting in raw material the impurity that may contain, it is not provided with a kind of directly to miscellaneous in raw material
The method that matter is controlled by, and prior art does not disclose yet and is suitable for the relevant material of analysis detection 2,4- thiophenol dimethyl benzenes
Method.In order to reduce the generation of side reaction, improve product yield and purity, avoid it is follow-up it is complicated isolate and purify process, having must
Quality control is carried out to 2,4- thiophenol dimethyl benzenes raw material.
Chromatography high sensitivity, can reflect the spy such as chemical composition and content situation simultaneously because method is easy, quick
Point, it is most wide to have become application, one of most important method.Conventional chromatography have high performance liquid chromatography (HPLC) and
Gas chromatography (GC) etc..It is smaller in view of 2,4- thiophenol dimethyl benzene molecular weight, and there is certain volatility, the application's
Inventor also attempts to use gas chromatography, is chromatographic column to the relevant thing of 2,4- thiophenol dimethyl benzenes using OP-WAX and DB-FFAP
Matter is detected, but separating effect is unsatisfactory.Therefore, the present invention will provide one kind and be suitable for separation detection 2,4- dimethyl
HPLC analytical method of the benzenethiol about material.
The content of the invention
It is an object of the invention to provide a kind of separation analysis high-efficient liquid phase color of the 2,4- thiophenol dimethyl benzenes about material
Spectrometry, so as to realize the quality control to 2,4- thiophenol dimethyl benzenes.
Inventor uses chromatographic column of the octadecylsilane chemically bonded silica for filler by test of many times, final determination,
The mixed solution of organic phase and aqueous phase as mobile phase, wherein, organic phase is selected from methanol, and aqueous phase is selected from phosphate buffer, water
Containing cation to reagent in phase, to carry out effect separation to 2,4 thiophenol dimethyl benzenes and its relevant material.
Inventor was once attempted using acetonitrile as organic phase, but was tested and found that acetonitrile-buffer solution system can not detect completely
Go out each peak.Inventor also attempts, using methanol-water as mobile phase, by the way of isocratic elution or gradient elution to be divided
From analysis, but during use gradient elution, because the associated physical property of 2,4- thiophenol dimethyl benzenes is closely similar so that 2,
4- thiophenol dimethyl benzene chromatographies impurity peaks adjacent thereto can not efficiently separate.And isocratic elution is used, it is only capable of in 60min
Separation detection goes out 2 chromatographic peaks, and retention time is long, is unfavorable for detecting.
Therefore the present invention finally determine using phosphate buffer as aqueous phase, and in aqueous phase addition cation to reagent with
Improve 2,4 thiophenol dimethyl benzenes and its relevant material separating effect.Wherein, phosphate be selected from potassium dihydrogen phosphate, sodium dihydrogen phosphate,
One or more of mixtures in ammonium dihydrogen phosphate, preferably potassium dihydrogen phosphate.Inventor was once tested with acetate or formates
Buffer solution is as mobile phase, but under low wavelength (230nm) condition determination selected by the present invention, the baseline noise of chromatogram detection compared with
Greatly.
Cation of the present invention is to selected from TBAH, tetrabutylammonium chloride, TBAB, four fourths
Base ammonium iodide, TMAH, tetramethyl ammonium chloride, 4 bromide, tetramethyl-ammonium iodide, tetraethyl hydroxide
Ammonium, etamon chloride, tetraethylammonium bromide, tetraethyl ammonium iodide etc. are applied to the one of the cation centering of slant acidity compound
Kind is several.
The volume ratio of methanol of the present invention and the phosphate buffer of cation pair is 70~55：30~45, it is excellent
Select 60：40.Inventor test find, when in mobile phase methanol ratio be less than 55%, 2,4- thiophenol dimethyl benzene retention time mistakes
It is long, it is unfavorable for detecting.And the separating degree for being more than 70%, 4- methylbenzene phenyl-sulfhydrates when methanol ratio is undesirable, 3- methylbenzene sulphur
Phenol and 4- methylbenzene phenyl-sulfhydrates can not efficiently separate.
The concentration of the phosphate buffer of the present invention is 0.05~0.1mol/L, preferably 0.05mol/L.
The mass concentration of the cation pair of the present invention is 3~4.5%, preferably 4%.The present inventor is found by experiment that,
When the mass concentration of aqueous phase cationic pair is less than 3% or more than 4.5%, 2,4- thiophenol dimethyl benzene and point at other impurities peak
It is undesirable from spending, it is not suitable for detecting.
In the liquid phase chromatogram condition of the present invention, column temperature is 20~40 DEG C, preferably 30 DEG C.
In the liquid phase chromatogram condition of the present invention, Detection wavelength 230nm.Each impurity and 2,4- dimethyl benzene sulphur in the present invention
Phenol has UV absorption, and with reference to absorption curve, present invention selection Detection wavelength is 230nm.
In the liquid phase chromatogram condition of the present invention, flow velocity is 0.8~1.2ml/min, preferably 1.0ml/min.
Detection method of the present invention, it can be realized by the following method：
1) take 2,4- thiophenol dimethyl benzene samples appropriate, add methanol dilution to be made in every 1ml containing about 2,4- dimethyl benzene sulphur
Phenol 2mg solution；
2) flow velocity for setting mobile phase is 0.8-1.2ml/min, and Detection wavelength 230nm, the column temperature of chromatographic column is 20-40
℃；
3) precision measures sample solution 10-20 μ l 1), injects liquid chromatograph, completes the measure about material.
The side of the relevant material of high performance liquid chromatography separation measure 2,4- thiophenol dimethyl benzene bulk drugs of the present invention
Method is simple and convenient, and specificity is good, and high sensitivity is reproducible, is suitable in 2,4- thiophenol dimethyl benzenes about the qualitative of material
With quantitative detection, particularly suitable for separation detection 3- methylbenzene phenyl-sulfhydrates, 4- methylbenzene phenyl-sulfhydrates, 2,5- thiophenol dimethyl benzenes, 3,4-
The contents about material such as thiophenol dimethyl benzene, 3,5- thiophenol dimethyl benzenes, 2,6- thiophenol dimethyl benzenes, originated to control with it
The quality of final medicine such as Vortioxetine prepared by raw material or intermediate provides powerful guarantee.
Brief description of the drawings
Fig. 1 is the HPLC chromatogram of system suitability solution in comparative example 1；
Fig. 2 is the HPLC chromatogram of system suitability solution in comparative example 2；
Fig. 3 is the HPLC chromatogram of system suitability solution in comparative example 3；
Fig. 4 is the HPLC chromatogram of system suitability solution in comparative example 4；
Fig. 5 is the HPLC chromatogram of system suitability solution in comparative example 5；
Fig. 6 is the HPLC chromatogram of system suitability solution in embodiment 1；
Fig. 7 is the HPLC chromatogram of the system suitability solution of test number 1 in embodiment 2；
Fig. 8 is the HPLC chromatogram of the system suitability solution of test number 2 in embodiment 2；
Fig. 9 is the HPLC chromatogram of the system suitability solution of test number 3 in embodiment 2；；
Figure 10 is the HPLC chromatogram of the system suitability solution of test number 4 in embodiment 2；
Figure 11 is the HPLC chromatogram of the system suitability solution of test number 5 in embodiment 2；
Figure 12 is the HPLC chromatogram of the system suitability solution of test number 6 in embodiment 2；
Figure 13 is the HPLC chromatogram of the system suitability solution of test number 7 in embodiment 2；
Figure 14 is the HPLC chromatogram of the system suitability solution of test number 8 in embodiment 2；
Figure 15 is the HPLC chromatogram of the system suitability solution of test number 9 in embodiment 2；
Figure 16 is the HPLC chromatogram of the system suitability solution of test number 10 in embodiment 2；
Figure 17 is the HPLC chromatogram of the system suitability solution of test number 11 in embodiment 2；
Figure 18 is the HPLC chromatogram of the system suitability solution of test number 12 in embodiment 2；
Figure 19 is the HPLC chromatogram of sample 1 in embodiment 4；
Figure 20 is the HPLC chromatogram of sample 2 in embodiment 4.
Embodiment
The present invention is described in further detail by following examples to present disclosure, can not be used to limit this
The protection domain of invention.
Comparative example 1-3
1st, medicine and reagent
The medicine of table 1 and reagent list
2nd, key instrument
The key instrument list of table 2
3rd, detection method
System suitability solution：Precision weighs 3- methylbenzene phenyl-sulfhydrates 10.30mg, 4- methylbenzene phenyl-sulfhydrate 11.40mg, and 3,5- bis-
Methylbenzene phenyl-sulfhydrate 10.01mg, 3,4- thiophenol dimethyl benzene 10.09mg, 2,5- thiophenol dimethyl benzene 10.25mg, 2,4- dimethyl
Benzenethiol 10.16mg, 2,6- thiophenol dimethyl benzene 10.21mg are placed in same 50ml measuring bottles, accurate with methanol dilution to scale
Draw above-mentioned solution 2.5ml to put in 50ml measuring bottles, produced with methanol dilution to scale.
Liquid chromatographic detection condition：It is filler (Kromasil, 100-5C18,5 μ with octadecylsilane chemically bonded silica
m,250*4.6mm)；Using water-methanol as mobile phase；Flow velocity is 1.0ml per minute；Detection wavelength is 230nm；30 DEG C of column temperature.Ladder
It is as follows to spend elution program：
20 μ l injection liquid chromatographs are measured, number of theoretical plate is not less than 3000 by 2,4- thiophenol dimethyl benzenes meter, each component
Between separating degree should meet the requirements.
4th, result
High performance liquid chromatography detection is carried out according to above-mentioned condition, as a result as Figure 1-3.It can be seen that 2,4-
Thiophenol dimethyl benzene and its chromatographic peak peak adjacent thereto about material overlap each other, and separating effect is very poor.Supposition is probably 2,
The associated physical property of 4- thiophenol dimethyl benzenes is closely similar so that is difficult to effectively divide in above-mentioned each material of chromatographic condition
From.
Comparative example 4
1st, medicine and reagent
With comparative example 1
2nd, key instrument
With comparative example 1
3rd, detection method
System suitability solution：With comparative example 1.
Liquid chromatographic detection condition：It is filler (Kromasil, 100-5C18,5 μ with octadecylsilane chemically bonded silica
m,250*4.6mm)；With water-methanol (40:60) it is mobile phase；Flow velocity is 1.0ml per minute；Detection wavelength is 230nm；Column temperature
30℃.20 μ l injection liquid chromatographs are measured, number of theoretical plate presses 2,4- thiophenol dimethyl benzenes meter not less than 3000, between each component
Separating degree should meet the requirements.
4th, result
High performance liquid chromatography detection is carried out according to above-mentioned condition, as a result as shown in Figure 4.Used it can be seen that working as
Isocratic elution, separation detection is only capable of in 60min and goes out 2 chromatographic peaks, retention time is long, is unfavorable for detecting.
Comparative example 5
1st, medicine and reagent
With comparative example 1
2nd, key instrument
With comparative example 1
3rd, detection method
System suitability solution：With comparative example 1.
Liquid chromatographic detection condition：It is filler (Kromasil, 100-5C18,5 μ with octadecylsilane chemically bonded silica
m,250*4.6mm)；4% TBAH solution-acetonitrile (50 is contained with 0.05mol/L potassium dihydrogen phosphates:50) it is flowing
Phase；Flow velocity is 1.0ml per minute；Detection wavelength is 230nm；30 DEG C of column temperature.Measure 20 μ l injection liquid chromatographs, number of theoretical plate
By 2,4- thiophenol dimethyl benzenes meter not less than 3000, the separating degree between each component should meet the requirements.
4th, result
High performance liquid chromatography detection is carried out according to above-mentioned condition, as a result as shown in Figure 5.It can be seen that acetonitrile-
Phosphate-buffered salt system can only detect 4 chromatographic peaks, equally be unfavorable for being kept completely separate for relevant material.
Embodiment 1
1st, medicine and reagent
With comparative example 1
2nd, key instrument
With comparative example 1
3rd, detection method
System suitability solution：Precision weighs 3- methylbenzene phenyl-sulfhydrates 10.30mg, 4- methylbenzene phenyl-sulfhydrate 11.40mg, and 3,5- bis-
Methylbenzene phenyl-sulfhydrate 10.01mg, 3,4- thiophenol dimethyl benzene 10.09mg, 2,5- thiophenol dimethyl benzene 10.25mg, 2,4- dimethyl
Benzenethiol 10.16mg, 2,6- thiophenol dimethyl benzene 10.21mg are placed in same 50ml measuring bottles, accurate with methanol dilution to scale
Draw above-mentioned solution 2.5ml to put in 50ml measuring bottles, produced with methanol dilution to scale.
Position solution：3- methylbenzene phenyl-sulfhydrates, 4- methylbenzene phenyl-sulfhydrates, 3,5- thiophenol dimethyl benzenes, 3,4- dimethyl are taken respectively
Benzenethiol, 2,5- thiophenol dimethyl benzenes, 2,4- thiophenol dimethyl benzenes, 2,6- thiophenol dimethyl benzenes are appropriate, put 25ml measuring bottles respectively
In, produced with methanol dilution to scale.
Liquid chromatographic detection condition：It is filler (Kromasil, 100-5C18,5 μ with octadecylsilane chemically bonded silica
m,250*4.6mm)；4% TBAH-methanol (40 is contained with 0.05mol/L potassium phosphate buffers:60) it is flowing
Phase；Flow velocity is 1.0ml per minute；Detection wavelength is 230nm；30 DEG C of column temperature.Measure 20 μ l injection liquid chromatographs, number of theoretical plate
By 2,4- thiophenol dimethyl benzenes meter not less than 3000, the separating degree between each component should meet the requirements.
4th, result
High performance liquid chromatography detection is carried out according to above-mentioned condition, as a result as shown in table 3 and Fig. 6.In Fig. 6, peak sequence is
3- methylbenzene phenyl-sulfhydrates, 4- methylbenzene phenyl-sulfhydrates, 3,4- thiophenol dimethyl benzenes (3,5 thiophenol dimethyl benzene), 2,5- thiophenol dimethyl benzenes,
2,4- thiophenol dimethyl benzenes, 2,6- thiophenol dimethyl benzenes.Although 3,4- thiophenol dimethyl benzenes and 3,5- thiophenol dimethyl benzenes in Fig. 6
Chromatographic peak overlaps, but does not influence 2, measure of the 4- thiophenol dimethyl benzenes about material, and the separating degree between remaining each peak is good.
The 2,4- thiophenol dimethyl benzenes specificity of table 3 investigates data
Embodiment 2
The present embodiment investigates the durability of chromatographic process, medicine and reagent and master by the parameter of changing section chromatographic condition
Instrument such as comparative example 1 is wanted, and based on following chromatographic condition：It is filler with octadecylsilane chemically bonded silica
(Kromasil,100-5C18,5μm,250*4.6mm)；Using phosphate buffer-methanol containing TBAH as flowing
Phase；Flow velocity is 1.0ml per minute；Detection wavelength is 230nm；30 DEG C of column temperature.
The present embodiment investigates concentration, the concentration of phosphate buffer, phosphatic species and the phosphorus of TBAH
Influence of the chromatographic condition such as volume ratio of phthalate buffer and methanol to detecting system adaptability solution.Main investigate changes chromatogram
Condition is to 2,4- thiophenol dimethyl benzenes in system suitability solution and 3- methylbenzene phenyl-sulfhydrates, 4- methylbenzene phenyl-sulfhydrates, 3,5- dimethyl
The influence of benzenethiol, 3,4- thiophenol dimethyl benzenes, 2,5- thiophenol dimethyl benzenes, 2,6- thiophenol dimethyl benzene separating degrees.
System suitability solution：Precision weighs 3- methylbenzene phenyl-sulfhydrates 10.30mg, 4- methylbenzene phenyl-sulfhydrate 11.40mg, and 3,5- bis-
Methylbenzene phenyl-sulfhydrate 10.01mg, 3,4- thiophenol dimethyl benzene 10.09mg, 2,5- thiophenol dimethyl benzene 10.25mg, 2,4- dimethyl
Benzenethiol 10.16mg, 2,6- thiophenol dimethyl benzene 10.21mg are placed in same 50ml measuring bottles, accurate with methanol dilution to scale
Draw above-mentioned solution 2.5ml to put in 50ml measuring bottles, produced with methanol dilution to scale.
Under each investigation chromatographic condition, take the μ l of system suitability solution 20 injection liquid chromatographs to be detected respectively, examine
Result such as table 4 is surveyed, chromatogram is as best shown in figures 7-18.Peak sequence is 3- methylbenzene phenyl-sulfhydrates, 4- methylbenzene phenyl-sulfhydrates, 3,4- dimethyl
Benzenethiol (3,5 thiophenol dimethyl benzene), 2,5- thiophenol dimethyl benzenes, 2,4- thiophenol dimethyl benzenes, 2,6- thiophenol dimethyl benzenes.
As a result show in the case of changing section chromatographic parameter, if TBAH concentration is 3-4.5wt%, phosphorus
The concentration of phthalate buffer is 0.05-0.1mol/L, and phosphate is the phosphate such as potassium dihydrogen phosphate or sodium dihydrogen phosphate, phosphate
Buffer solution is 30~45 with methanol volume ratio：70~55, the separating degree of system suitability solution is impacted less, at these
This method is still applied to the relevant material of detection 2,4- thiophenol dimethyl benzenes under part, and methods described has preferable durability.
Investigation data of the 2,4- thiophenol dimethyl benzenes of table 4 under different experimental conditions
Embodiment 3
1st, medicine and reagent
With comparative example 1
2nd, key instrument
With comparative example 1
3rd, detection method
Impurity contrast solution：Precision weighs 3- methylbenzene phenyl-sulfhydrates 11.62mg, 4- methylbenzene phenyl-sulfhydrate 14.40mg, 3,5- diformazans
Base benzenethiol 13.74mg, 2,5- thiophenol dimethyl benzene 12.98mg, 2,6- thiophenol dimethyl benzene 13.57mg put same 50ml measuring bottles
In, with methanol dilution to scale, stock solution is compareed as impurity.Precision is drawn above-mentioned solution 2.5ml and put in 50ml measuring bottles, uses first
Alcohol is diluted to scale and produces impurity contrast solution.
Need testing solution：Precision weighs 2,4- thiophenol dimethyl benzenes 0.1006g and put in 50ml measuring bottles, with methanol dilution to quarter
Degree, as need testing solution.
Liquid chromatographic detection condition：It is filler (Kromasil, 100-5C18,5 μ with octadecylsilane chemically bonded silica
m,250*4.6mm)；4% TBAH-methanol (40 is contained with 0.05mol/L potassium phosphate buffers:60) it is flowing
Phase；Flow velocity is 1.0ml per minute；Detection wavelength is 230nm；30 DEG C of column temperature.Precision measures impurity contrast solution, need testing solution
Each pin of 20 μ l continuous sample introductions 6, record peak area.
4th, result
High performance liquid chromatography detection is carried out according to above-mentioned condition, records chromatogram, as a result such as table 5 and shown.Calculate 3- first
Base benzenethiol, 4- methylbenzene phenyl-sulfhydrates, 3,5- thiophenol dimethyl benzenes, 2,5- thiophenol dimethyl benzenes, 2,6- thiophenol dimethyl benzenes, 2,4-
The RSD of thiophenol dimethyl benzene B content is respectively 1.30%, 1.39%, 1.42%, 1.37%, 0.37% and 0.52%, is respectively less than
2.0%, show that this method repeatability is good.
The repeatability of table 5. investigates data
Embodiment 4
1st, medicine and reagent
With comparative example 1
2nd, key instrument
With comparative example 1
3rd, detection method
Reference substance solution：Precision weighs 3- methylbenzene phenyl-sulfhydrates 11.62mg, 4- methylbenzene phenyl-sulfhydrate 14.40mg, 3,5- dimethyl
Benzenethiol 13.74mg, 2,5- thiophenol dimethyl benzene 12.98mg, 2,6- thiophenol dimethyl benzene 13.57mg put same 50ml measuring bottles
In, with methanol dilution to scale, stock solution is compareed as impurity.Precision is drawn above-mentioned solution 2.5ml and put in 50ml measuring bottles, uses first
Alcohol is diluted to scale and produces impurity contrast solution.
Need testing solution：Precision weighs 2,4- thiophenol dimethyl benzene 0.1061g, puts in 50ml measuring bottles, with methanol dilution extremely
Scale, produce.
Liquid chromatographic detection condition：It is filler (Kromasil, 100-5C18,5 μ with octadecylsilane chemically bonded silica
m,250*4.6mm)；4% TBAH-methanol (40 is contained with 0.05mol/L potassium phosphate buffers:60) it is flowing
Phase；Flow velocity is 1.0ml per minute；Detection wavelength is 230nm；30 DEG C of column temperature.20 μ l injection liquid chromatographs are measured, are surveyed in accordance with the law
It is fixed, in terms of area normalization method.
4th, result
High performance liquid chromatography detection is carried out according to above-mentioned condition, as a result as shown in table 6 and Figure 19-20.Can from table 6
Go out, the content of 3- methylbenzene phenyl-sulfhydrates, 3,5- dimethyl thiophenol and 2,6- thiophenol dimethyl benzene is respectively 0.011%, 0.098% He
0.032%, the sensitivity of methods described is very high.
The sample detection data of table 6.
In summary, analysis method of the present invention has special in terms of the relevant material of measure 2,4- thiophenol dimethyl benzenes
Attribute, durability and favorable reproducibility, the features such as high sensitivity.
Claims (10)
1. one kind 2, detection method of the 4- thiophenol dimethyl benzenes about material, it is characterised in that entered using high performance liquid chromatography
OK, wherein the liquid chromatogram measuring condition is：Chromatographic column is using octadecylsilane chemically bonded silica as filler, with organic phase and water
The mixed solvent of phase is as mobile phase；Organic phase in wherein described mobile phase is methanol, and aqueous phase is phosphate buffer solution, water
Containing cation to reagent in phase.
2. detection method according to claim 1, it is characterised in that the cation in aqueous phase is tetrabutyl hydrogen-oxygen to reagent
Change ammonium, tetrabutylammonium chloride, TBAB, tetrabutylammonium iodide, TMAH, tetramethyl ammonium chloride, tetramethyl
In base ammonium bromide, tetramethyl-ammonium iodide, tetraethyl ammonium hydroxide, etamon chloride, tetraethylammonium bromide, tetraethyl ammonium iodide
One or more.
3. detection method according to claim 1, it is characterised in that the volume ratio of organic phase and aqueous phase is 70~55：30~
45。
4. detection method according to claim 3, it is characterised in that the volume ratio of organic phase and aqueous phase is 60：40.
5. detection method according to claim 1, it is characterised in that the phosphate is selected from potassium dihydrogen phosphate, biphosphate
One or more of mixtures in sodium, ammonium dihydrogen phosphate, preferably potassium dihydrogen phosphate.
6. detection method according to claim 4, it is characterised in that the concentration of the phosphate buffer be 0.05~
0.1mol/L, preferably 0.05mol/L.
7. detection method according to claim 1, it is characterised in that the quality of TBAH is dense in the aqueous phase
Spend for 3~4.5%, preferably 4%.
8. detection method according to claim 1, it is characterised in that in the liquid phase chromatogram condition, Detection wavelength is
230nm。
9. detection method according to claim 1, it is characterised in that in the liquid phase chromatogram condition, column temperature is 20~40
DEG C, preferably 30 DEG C；Flow velocity is 0.8~1.2ml/min, preferably 1.0ml/min.
10. according to the detection method any one of claim 1-7, it is characterised in that comprise the steps of：
1) take 2,4- thiophenol dimethyl benzene samples appropriate, add methanol dilution to be made in every 1ml containing about 2,4- thiophenol dimethyl benzenes 2mg
Solution；
2) flow velocity for setting mobile phase is 0.8~1.2ml/min, and Detection wavelength 230nm, the column temperature of chromatographic column is 20~40
℃；
3) precision measures sample solution 10-20 μ l 1), injects liquid chromatograph, completes the measure about material.
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