CN103232387A - Tirofiban hydrochloride impurity, preparation method and detection method of impurity - Google Patents
Tirofiban hydrochloride impurity, preparation method and detection method of impurity Download PDFInfo
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- CN103232387A CN103232387A CN2013101480478A CN201310148047A CN103232387A CN 103232387 A CN103232387 A CN 103232387A CN 2013101480478 A CN2013101480478 A CN 2013101480478A CN 201310148047 A CN201310148047 A CN 201310148047A CN 103232387 A CN103232387 A CN 103232387A
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- 229960004929 tirofiban hydrochloride Drugs 0.000 title claims abstract description 52
- HWAAPJPFZPHHBC-FGJQBABTSA-N tirofiban hydrochloride Chemical compound O.Cl.C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 HWAAPJPFZPHHBC-FGJQBABTSA-N 0.000 title claims abstract description 52
- 239000012535 impurity Substances 0.000 title claims abstract description 41
- 238000001514 detection method Methods 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 239000002994 raw material Substances 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 14
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 11
- 230000003647 oxidation Effects 0.000 claims description 10
- 238000007254 oxidation reaction Methods 0.000 claims description 10
- 238000001228 spectrum Methods 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 238000009835 boiling Methods 0.000 claims description 8
- 230000006378 damage Effects 0.000 claims description 8
- 238000006386 neutralization reaction Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000005303 weighing Methods 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 239000000872 buffer Substances 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- -1 inorganic acid salt Chemical class 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 claims description 2
- 239000012670 alkaline solution Substances 0.000 claims description 2
- 150000001793 charged compounds Chemical class 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000013558 reference substance Substances 0.000 claims description 2
- 230000004044 response Effects 0.000 claims description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims 4
- 238000001819 mass spectrum Methods 0.000 abstract description 4
- 239000013078 crystal Substances 0.000 abstract 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 10
- COKMIXFXJJXBQG-NRFANRHFSA-N tirofiban Chemical compound C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 COKMIXFXJJXBQG-NRFANRHFSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- 229960003425 tirofiban Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical group [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000002087 whitening effect Effects 0.000 description 3
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 2
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 208000007814 Unstable Angina Diseases 0.000 description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 229940127218 antiplatelet drug Drugs 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 238000005100 correlation spectroscopy Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 2
- 238000005570 heteronuclear single quantum coherence Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 238000004237 preparative chromatography Methods 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
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- 208000011580 syndromic disease Diseases 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- FCWGIFCVCCHGTK-BYPYZUCNSA-N (2S)-butane-2-sulfonamide Chemical compound C[C@@H](CC)S(=O)(=O)N FCWGIFCVCCHGTK-BYPYZUCNSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000015795 Platelet Membrane Glycoproteins Human genes 0.000 description 1
- 108010010336 Platelet Membrane Glycoproteins Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229940000279 aggrastat Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000009172 bursting Effects 0.000 description 1
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- 208000029078 coronary artery disease Diseases 0.000 description 1
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- 229910017604 nitric acid Inorganic materials 0.000 description 1
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- 230000036470 plasma concentration Effects 0.000 description 1
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- 235000019260 propionic acid Nutrition 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- Investigating Or Analysing Biological Materials (AREA)
- Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
Abstract
The invention discloses a tirofiban hydrochloride impurity. The tirofiban hydrochloride impurity is a compound which is not reported in the exiting documents; and the tirofiban hydrochloride impurity can be taken as a comparison product for analyzing tirofiban hydrochloride impurities. The structure of the tirofiban hydrochloride impurity is determined by identifying and detecting via a high resolution mass spectrum and a nuclear magnetic resonance spectrum; and the absolute structure of the tirofiban hydrochloride impurity is also detected via single crystal diffraction. The invention also discloses a preparation method and a detection method of the tirofiban hydrochloride impurity.
Description
Technical field
The present invention relates to a kind of Tirofiban hydrochloride impurity and preparation thereof, detection method, belong to the synthetic field of medicine.
Background technology
Tirofiban hydrochloride, its chemical name is: (S)-2-butyl sulfonamide base-3-(4-([4-(piperidin-4-yl) butoxy] phenyl) propionic acid is the hydrochloride of Tirofiban, and its structural formula (I) is:
Formula I.
The International Nonproprietary Name of Tirofiban is Tirofiban (trade(brand)name Aggrastat), is a kind of antiplatelet drug. and it belongs to a kind of antiplatelet drug that is named as the glycoprotein iib/iiia inhibitor. and Tirofiban is that first origin can be traced back to one based on the drug candidate of pharmacophore virtual screening.Tirofiban is a kind of reversibility antagonist of platelet glycoprotein IIb/IIIa acceptor of non-peptide class, and this receptor is the main platelet surface acceptor relevant with the platelet aggregation process.Tirofiban hydrochloride stops Fibrinogen to be combined with glycoprotein iib/iiia, thereby the crosslinked and hematoblastic gathering of blocking platelet.Platelet activation, adhesion and gathering are the key initial steps of atheromatous plaque bursting surface artery thrombosis, and thrombosis is that acute coronary ischemic syndromes is the main physiopathology problem of unstable angina pectoris and myocardial infarction and coronary artery postangioplasty heart ischemia complication.In vitro tests shows, Tirofiban hydrochloride can suppress the platelet aggregation that adenosine diphosphate (ADP) (ADP) induces and the bleeding time (BT) that prolongs health volunteer and patients with coronary heart disease, and this shows that Tirofiban hydrochloride can potent inhibition platelet function.The time of suppressing parallels with the plasma concentration of medicine.Stop using behind the Tirofiban hydrochloride injection liquid, platelet function returns to baseline values rapidly.Tirofiban hydrochloride is the non-peptide class platelet surface glycoprotein glycoprotein iib/iiia receptor antagonist of first listing by Merck company exploitation, has efficient, highly selective, advantage such as reversible.Went on the market in the U.S. first in 1998, went on the market in China in 2004, the clinical acute coronary artery syndrome that is used for the treatment of, comprise unstable angina pectoris, non Q wave myocardial infarction patient, the patient of pass through percutaneous transluminal coronary urethroptasty or atherosclerotic plaque surgical blanking, this mechanism of drug action uniqueness, clinical efficacy is definite, security good.However, Tirofiban hydrochloride also has potential toxicity, thereby causes untoward reaction.The generation of untoward reaction also has very big relation except outside the Pass the pharmacologically active with Tirofiban itself has with the impurity that exists in the Tirofiban hydrochloride.Therefore carry out to standard impurity research, and it is controlled in a safety, rational limits, will be directly connected to quality and the security of Tirofiban hydrochloride.
At present abroad less to the bibliographical information of the impurity research of Tirofiban hydrochloride, not domestic not appearing in the newspapers.Therefore, be badly in need of it is studied, to improve the quality of Tirofiban hydrochloride product.
Summary of the invention
The object of the present invention is to provide a kind of impurity of Tirofiban hydrochloride, it has as the described structure of formula II:
Formula II, described formula II molecular formula is C
22H
35ClN
2O
5S.
The contriver investigates in the test at the impurity of Tirofiban hydrochloride, detect above-mentioned impurity, this impurity all detects in bulk drug and preparation thereof and their pressure degraded test, storage process, and particularly bulk drug and preparation thereof all have generation in oxidation, high temperature, with processes such as salt acid treatment.Therefore, identify, synthesize this impurity by detection, structure, not only can provide foundation for the quality control of product, and can be used for the qualitative and quantitative analysis of Tirofiban hydrochloride production, this impurity of storage.
The described impurity of formula II can acid destroys by Tirofiban hydrochloride is carried out, alkali destroys, high temperature destroys or oxidation destruction obtains.Wherein: acid destroys and refers to that the Tirofiban hydrochloride raw material after the boiling water bath heating, adds the alkali neutralization again under acid solution.
Alkali destroys and refers to that the Tirofiban hydrochloride raw material after the boiling water bath heating, adds the alkali neutralization again under alkaline solution.
High temperature destroys and to refer to that the Tirofiban hydrochloride raw material puts placing response in the baking oven.
Oxidation destroys and refers to that the Tirofiban hydrochloride raw material adds, and puts on the water-bath and reacts.
In a representative instance of the present invention, the described impurity of formula II can by Tirofiban hydrochloride, hydrogen peroxide are put together, reacting by heating makes.
In another representative instance of the present invention, the described impurity of formula II can by Tirofiban hydrochloride, hydrogen peroxide, hydrochloric acid are put together, reacting by heating makes.
In another representative instance of the present invention, the described impurity of formula II can by Tirofiban hydrochloride, hydrogen peroxide, alkali are put together, reacting by heating makes.
In another representative instance of the present invention, the described impurity of formula II can be by making Tirofiban hydrochloride reacting by heating in the environment of secluding air not.
In another representative instance of the present invention, the described impurity of formula II can by Tirofiban hydrochloride, hydrochloric acid are put together, reacting by heating makes in the environment of secluding air not.
In another representative instance of the present invention, the described impurity of formula II can by Tirofiban hydrochloride, alkali are put together, reacting by heating makes in the environment of secluding air not.
In an example of the present invention, it is raw materials weighing 14mg that described acid destroys, and adds 1mol/L hydrochloric acid soln 4ml, and boiling water bath heated about 20 hours, adds 1mol/L sodium hydroxide solution 4ml neutralization again; It is raw materials weighing 14mg that described alkali destroys, and adds 1mol/L sodium hydroxide solution 4ml, and boiling water bath heated about 20 hours, adds 1mol/L hydrochloric acid soln 4ml neutralization again; It is raw materials weighing 14mg that high temperature destroys, and puts in 220 ℃ of baking ovens and places 2 hours; It is raw materials weighing 14mg that described oxidation destroys, and adds 6% hydrogen peroxide 2ml, puts on the water-bath reaction and volatilizes solvent.
In addition, the present invention also provides a kind of inorganic acid salt, organic acid salt of formula II compound, and wherein said mineral acid is selected from hydrochloric acid, sulfuric acid, nitric acid; Described organic acid is selected from formic acid, acetic acid, oxalic acid, phenylformic acid, tartrate, citric acid, oxysuccinic acid.
The structure authentication method that another object of the present invention provides a kind of formula II compound adopts high resolution mass spectrum and NMR (Nuclear Magnetic Resonance) spectrum (NMR (Nuclear Magnetic Resonance) spectrum specifically comprises hydrogen spectrum, heavy water exchange hydrogen spectrum, carbon spectrum, DEPT, COSY, HSQC, HMBC) structure of compound (II) to be inferred and definite.
Wherein, formula II compound 1H NMR (600MHz, DMSO) δ (ppm): 12.91 (s, 1H, COOH), 9.00 (s, 1H, NH
2), 8.74 (s, 1H, NH
2), 7.61 (d, 1H, NH), 7.35 (d, 1H, Ar), 7.20 (dd, 1H, Ar), 7.05 (d, 1H, Ar), 3.99 (m, 2H, CH
2), 3.94 (m, 1H, CH), 3.19 (d, 2H, CH
2), 2.97 (dd, 1H, CH
2), 2.77 (t, 2H, CH
2), 2.66 (dd, 1H, CH
2), 2.58 (m, 2H, CH
2), 1.75 (d, 2H, CH
2), 1.70 (m, 2H, CH
2), 1.50 (m, 1H, CH), 1.42 (m, 2H, CH
2), 1.33 (m, 2H, CH
2), 1.28 (m, 2H, CH
2), 1.26 (m, 2H, CH
2), 1.11 (m, 2H, CH
2), 0.73 (t, 3H, CH
3), each peak ± 0.1ppm wherein.
In addition, the present invention also provides a kind of detection method of formula II compound, described detection method is to adopt reverse phase liquid chromatography, chromatographic column is that bonded silica gels such as C18, C8, phenyl are the analytical column of filler, detector is UV-detector, be moving phase with acetonitrile and phosphoric acid buffer, detect according to degree such as grade and gradient elution program.Preferably, described phosphoric acid buffer has added triethylamine, diethylamine.The pH value control of phosphoric acid buffer is in 5.5～7.5 scopes.
In specific examples of the present invention, by the reaction solution of formula I compound after above-mentioned acid destruction, alkali destruction, high temperature destruction or oxidation destroy carried out the liquid-phase chromatography method analysis.Wherein use chromatographic column: Inertsil ODS-3250*4.6mm, particle diameter 5 μ m; Column temperature: 30 ℃, flow velocity: 1.0ml/min, moving phase: the A acetonitrile, B0.025mol/L potassium dihydrogen phosphate (regulating pH6.5 with triethylamine): acetonitrile (8:2), moving phase according to the form below gradient elution program:
Description of drawings
Fig. 1 is the high resolution mass spectrum figure of compound (II).
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of compound (II).
Fig. 3 is the carbon-13 nmr spectra figure of compound (II).
Fig. 4 destroys back need testing solution compound (II) liquid chromatographic detection figure for Tirofiban hydrochloride with acid.
Fig. 5 is that Tirofiban hydrochloride destroys back need testing solution compound (II) liquid chromatographic detection figure with alkali.
Fig. 6 is that Tirofiban hydrochloride destroys back need testing solution compound (II) liquid chromatographic detection figure with high temperature.
Fig. 7 is that Tirofiban hydrochloride destroys back need testing solution compound (II) liquid chromatographic detection figure with oxidation.
Embodiment:
Embodiment 1: the preparation of compound (II)
Get Tirofiban hydrochloride bulk drug 0.5g, add 3% hydrogen peroxide 1ml, 2mol hydrochloric acid 1ml stirred 24 hours down at 60 ℃, after the cooling, filtered, and solid got compound (II) in 2 hours with 5% acetonitrile 8ml recrystallization, 40 ℃ of vacuum-dryings.Compound (II) is 98% with its purity of liquid chromatography for measuring.
High resolution magnetic substance spectrum detects and obtains accurate molecular ion peak quality is 474.1960 ± 0.01, and high resolution mass spectrum figure sees accompanying drawing 1, and elementary composition is C
22H
35ClN
2O
5S, mass spectrometric detection gained quasi-molecular ions does not comprise hydrochloride, with Tirofiban molecular formula C
22H
36N
2O
5S relatively lacks a H in the molecular formula, many Cl illustrate that this Tirofiban hydrochloride oxidation impurities is that a H is replaced by a Cl in the Tirofiban molecule.The molecular formula that is compound (II) is C
22H
35ClN
2O
5S.
Nucleus magnetic resonance adopts hydrogen spectrum, heavy water exchange hydrogen spectrum, carbon spectrum, DEPT, COSY, HSQC, HMBC to this compound test, and proton nmr spectra is seen accompanying drawing 2, and carbon-13 nmr spectra is seen accompanying drawing 3.
Embodiment 2: get Tirofiban hydrochloride 5g, add 6% superoxol 15ml, 50～60 ℃ were heated 15 hours under stirring, and filtered.Solid adds 5% acetonitrile 75ml, being heated to backflow and making dissolving, adds gac 0.3g, insulation absorption 15 minutes, and filtered while hot, filtrate is left standstill crystallization, filters, and 40 ℃ of vacuum-dryings of solid got whitening compound (II) in 2 hours.
Embodiment 3: get Tirofiban hydrochloride 200mg, add 1mol/L sodium hydroxide solution 4ml, 50～60 ℃ of heating of water-bath 20 hours add 1mol/L hydrochloric acid soln 4ml again.Reaction solution separates by preparative chromatography ((30:70) is moving phase with acetonitrile-water, is weighting agent with the octadecylsilane chemically bonded silica, detects wavelength 227nm) after adding the %10 dilution in acetonitrile.Collect the effluent liquid of compound (II), put and volatilize solvent in the Rotary Evaporators, obtain whitening compound (II).
Embodiment 4: get Tirofiban hydrochloride 100mg, put in 220 ℃ of baking ovens and placed 2 hours, take out.The gained solid dissolves with 10% acetonitrile, and solution is separated by preparative chromatography ((30:70) is moving phase with acetonitrile-water, is weighting agent with the octadecylsilane chemically bonded silica, detects wavelength 227nm).Collect the effluent liquid of compound (II), put and volatilize solvent in the Rotary Evaporators, obtain whitening compound (II).
Embodiment 5: compound (II) is as the application of liquid chromatographic detection impurity reference substance
Be used for to analyze Tirofiban hydrochloride bulk drug and preparation thereof study on the stability, influence factor test, etc. test relate to the detection of this impurity.Liquid-phase chromatography method uses chromatographic column: Inertsil ODS-3250*4.6mm, particle diameter 5 μ m; Column temperature: 30 ℃, flow velocity: 1.0ml/min, moving phase: the A acetonitrile, B0.025mol/L potassium dihydrogen phosphate (regulating pH6.5 with triethylamine): acetonitrile (8:2), moving phase according to the form below gradient elution program:
The liquid-phase chromatographic analysis data are seen accompanying drawing 4-7.
Claims (10)
1. the impurity of a Tirofiban hydrochloride and salt thereof, solvate, described impurity has as the described structure of formula II:
Formula II, the molecular formula of described formula II compound are C
22H
35ClN
2O
5S.
2. impurity as claimed in claim 1, it has
1HNMR (600MHz, DMSO) δ (ppm): 12.91 (s, 1H, COOH), 9.00 (s, 1H, NH
2), 8.74 (s, 1H, NH
2), 7.61 (d, 1H, NH), 7.35 (d, 1H, Ar), 7.20 (dd, 1H, Ar), 7.05 (d, 1H, Ar), 3.99 (m, 2H, CH
2), 3.94 (m, 1H, CH), 3.19 (d, 2H, CH
2), 2.97 (dd, 1H, CH
2), 2.77 (t, 2H, CH
2), 2.66 (dd, 1H, CH
2), 2.58 (m, 2H, CH
2), 1.75 (d, 2H, CH
2), 1.70 (m, 2H, CH
2), 1.50 (m, 1H, CH), 1.42 (m, 2H, CH
2), 1.33 (m, 2H, CH
2), 1.28 (m, 2H, CH
2), 1.26 (m, 2H, CH
2), 1.11 (m, 2H, CH
2), 0.73 (t, 3H, CH
3), each peak ± 0.1ppm wherein.
3. impurity as claimed in claim 1 or 2 and salt thereof, solvate, it has high resolution magnetic substance spectrum and detects that to obtain accurate molecular ion peak quality be 474.1960 ± 0.01.
4. as each described impurity of claim 1-3 and salt thereof, solvate, wherein said salt is inorganic acid salt or organic acid salt.
5. the preparation method of impurity as claimed in claim 1 comprises that Tirofiban hydrochloride is carried out acid destruction, alkali destruction, high temperature destruction or oxidation destruction to be obtained.
6. the preparation method of impurity as claimed in claim 5, wherein: acid destroys and refers to that the Tirofiban hydrochloride raw material after the boiling water bath heating, adds the alkali neutralization again under acid solution; Alkali destroys and refers to that the Tirofiban hydrochloride raw material after the boiling water bath heating, adds the alkali neutralization again under alkaline solution; High temperature destroys and to refer to that the Tirofiban hydrochloride raw material puts placing response in the baking oven; Oxidation destroys and refers to that the Tirofiban hydrochloride raw material adds, and puts on the water-bath and reacts.
7. as the preparation method of claim 5 or 6 described impurity, wherein: it is raw materials weighing 14mg that acid destroys, and adds 1mol/L hydrochloric acid soln 4ml, and boiling water bath heated about 20 hours, adds 1mol/L sodium hydroxide solution 4ml neutralization again; It is raw materials weighing 14mg that described alkali destroys, and adds 1mol/L sodium hydroxide solution 4ml, and boiling water bath heated about 20 hours, adds 1mol/L hydrochloric acid soln 4ml neutralization again; It is raw materials weighing 14mg that high temperature destroys, and puts in 220 ℃ of baking ovens and places 2 hours; It is raw materials weighing 14mg that described oxidation destroys, and adds 6% hydrogen peroxide 2ml, puts on the water-bath reaction and volatilizes solvent.
8. as the detection method of each described impurity of claim 1-3, adopt reverse phase liquid chromatography, chromatographic column is that bonded silica gels such as C18, C8, phenyl are the analytical column of filler, detector is UV-detector, be moving phase with acetonitrile and phosphoric acid buffer, detect according to degree such as grade and gradient elution program; Preferably, described phosphoric acid buffer has added triethylamine, diethylamine; The pH value control of phosphoric acid buffer is in 5.5～7.5 scopes.
9. detection method as claimed in claim 8, wherein use chromatographic column: Inertsil ODS-3250*4.6mm, particle diameter 5 μ m, column temperature: 30 ℃, flow velocity: 1.0ml/min; Moving phase: the A acetonitrile, B0.025mol/L potassium dihydrogen phosphate (regulating pH6.5 with triethylamine): acetonitrile=8:2, moving phase according to the form below gradient elution program:
10. as the application as the impurity reference substance in the degraded of Tirofiban hydrochloride and quality examination thereof of each described impurity of claim 1-4 and salt thereof, solvate.
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| CN104086478A (en) * | 2014-07-15 | 2014-10-08 | 武汉武药科技有限公司 | Impurity compound in tirofiban hydrochloride and preparation method of impurity compound |
| CN106596788A (en) * | 2016-12-26 | 2017-04-26 | 上海微谱化工技术服务有限公司 | Method for separating and detecting cardio-cerebrovascular drug S-configuration tirofiban |
| CN108440393A (en) * | 2018-03-20 | 2018-08-24 | 成都倍特药业有限公司 | Method for detecting impurities in tirofiban material impurity, impurity preparation and material |
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| CN104086478A (en) * | 2014-07-15 | 2014-10-08 | 武汉武药科技有限公司 | Impurity compound in tirofiban hydrochloride and preparation method of impurity compound |
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| CN106596788A (en) * | 2016-12-26 | 2017-04-26 | 上海微谱化工技术服务有限公司 | Method for separating and detecting cardio-cerebrovascular drug S-configuration tirofiban |
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| CN108440393A (en) * | 2018-03-20 | 2018-08-24 | 成都倍特药业有限公司 | Method for detecting impurities in tirofiban material impurity, impurity preparation and material |
| CN112578030A (en) * | 2019-09-29 | 2021-03-30 | 扬子江药业集团四川海蓉药业有限公司 | Method for detecting enantiomer in tirofiban hydrochloride injection |
| CN112578030B (en) * | 2019-09-29 | 2022-10-04 | 扬子江药业集团四川海蓉药业有限公司 | Method for detecting enantiomer in tirofiban hydrochloride injection |
| CN110988158A (en) * | 2019-11-25 | 2020-04-10 | 鲁南制药集团股份有限公司 | Method for detecting related substances of tirofiban hydrochloride injection |
| CN112816282A (en) * | 2020-12-29 | 2021-05-18 | 江苏慧聚药业有限公司 | Tirofiban hydrochloride related substance and preparation and detection method thereof |
| CN115598257A (en) * | 2022-11-04 | 2023-01-13 | 华夏生生药业（北京）有限公司（Cn） | Method for detecting multiple impurities in tirofiban hydrochloride injection |
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