CN103232387B - 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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- 229960004929 tirofiban hydrochloride Drugs 0.000 title claims abstract description 51
- 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 51
- 239000012535 impurity Substances 0.000 title claims abstract description 41
- 238000001514 detection method Methods 0.000 title claims abstract description 19
- 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
- 239000000243 solution Substances 0.000 claims description 15
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 13
- 239000003513 alkali Substances 0.000 claims description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 12
- 238000009835 boiling Methods 0.000 claims description 8
- 238000006386 neutralization reaction Methods 0.000 claims description 8
- 230000001590 oxidative effect Effects 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 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
- 230000006378 damage Effects 0.000 claims description 6
- -1 inorganic acid salt Chemical class 0.000 claims description 4
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 4
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 4
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims description 3
- 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
- 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
- 239000000741 silica gel Substances 0.000 claims 1
- 229910002027 silica gel Inorganic materials 0.000 claims 1
- 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 9
- 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
- 238000001228 spectrum Methods 0.000 description 8
- 229960003425 tirofiban Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 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
- 238000000034 method Methods 0.000 description 5
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical group [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 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
- 239000000377 silicon dioxide Substances 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
- 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
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000004237 preparative chromatography Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 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
- 238000005160 1H NMR spectroscopy Methods 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
- 0 C*(C(C)=O)NS(C)* Chemical compound C*(C(C)=O)NS(C)* 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
- 238000001816 cooling Methods 0.000 description 1
- 238000007887 coronary angioplasty Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
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- 229940125672 glycoprotein IIb/IIIa inhibitor Drugs 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 Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
- Investigating Or Analysing Biological Materials (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 glycoprotein iib/iiia inhibitor. and Tirofiban is that first origin can be traced back to a drug candidate based on 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 during platelet aggregation.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 heart ischemia complication after unstable angina pectoris and myocardial infarction and Coronary angioplasty.In vitro tests demonstration, Tirofiban hydrochloride can suppress the platelet aggregation of adenosine diphosphate (ADP) (ADP) induction and extend the bleeding time (BT) of 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 after tirofiban hydrochloride injection solution, platelet function returns to rapidly baseline values.Tirofiban hydrochloride is developed by Merck company, is the non-peptide class Platelet surface glycoprotein glycoprotein iib/iiia receptor antagonist of first listing, has efficient, highly selective, the advantage such as reversible.Within 1998, in the U.S., go on the market first, 2004 in Discussion on Chinese Listed, the clinical acute coronary artery syndrome that is used for the treatment of, the patient who comprises unstable angina pectoris, non Q wave myocardial infarction patient, percutaneous transluminal coronary urethroptasty or atherosclerotic plaque surgical blanking, this mechanism of drug action is unique, clinical efficacy is definite, security good.However, Tirofiban hydrochloride also has potential toxicity, thereby causes untoward reaction.The generation of untoward reaction, except outside the Pass the pharmacologically active with Tirofiban itself has, also has very big relation with the impurity existing in Tirofiban hydrochloride.Therefore carry out impurity research to standard, and be controlled in a safety, rational limits, will be directly connected to quality and the security of Tirofiban hydrochloride.
Less to the bibliographical information of the impurity research of Tirofiban hydrochloride abroad at present, the domestic report that has no.Therefore, be badly in need of it to study, 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 the structure as described in formula II:
Formula II, described formula II molecular formula is C
22h
35clN
2o
5s.
Contriver investigates in test at the impurity of Tirofiban hydrochloride, detect above-mentioned impurity, this impurity all detects in bulk drug and preparation thereof and their pressure Degrading experiment, storage process, and particularly bulk drug and preparation thereof all have generation in the processes such as oxidation, high temperature, salt adding acid treatment.Therefore, by detection, Structural Identification, synthetic this impurity, not only can provide foundation for the quality control of product, and the qualitative and quantitative analysis of this impurity in can producing, store for Tirofiban hydrochloride.
Impurity described in formula II can by Tirofiban hydrochloride is carried out, acid destroys, alkali destroys, high temperature destroys or Oxidative demage obtains.Wherein: acid destroys and to refer to that Tirofiban hydrochloride raw material is under acid solution after boiling water bath heating, then adds alkali neutralization.
Alkali destroys and to refer to that Tirofiban hydrochloride raw material is under alkaline solution after boiling water bath heating, then adds alkali neutralization.
High temperature destroys and to refer to that Tirofiban hydrochloride raw material puts placing response in baking oven.
Oxidative demage refers to that Tirofiban hydrochloride raw material adds, and puts on water-bath and reacts.
In a representative instance of the present invention, the impurity described in formula II can be by putting together Tirofiban hydrochloride, hydrogen peroxide, reacting by heating makes.
In another representative instance of the present invention, the impurity described in formula II can be by putting together Tirofiban hydrochloride, hydrogen peroxide, hydrochloric acid, reacting by heating makes.
In another representative instance of the present invention, the impurity described in formula II can be by putting together Tirofiban hydrochloride, hydrogen peroxide, alkali, reacting by heating makes.
In another representative instance of the present invention, the impurity described in formula II can be by making Tirofiban hydrochloride reacting by heating in the environment of isolated air not.
In another representative instance of the present invention, the impurity described in formula II can be by putting together Tirofiban hydrochloride, hydrochloric acid, in the environment of isolated air not, reacting by heating makes.
In another representative instance of the present invention, the impurity described in formula II can be by putting together Tirofiban hydrochloride, alkali, in the environment of isolated air not, reacting by heating makes.
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 heats approximately 20 hours, then adds 1mol/L sodium hydroxide solution 4ml neutralization; It is raw materials weighing 14mg that described alkali destroys, and adds 1mol/L sodium hydroxide solution 4ml, and boiling water bath heats approximately 20 hours, then adds 1mol/L hydrochloric acid soln 4ml neutralization; It is raw materials weighing 14mg that high temperature destroys, and puts in 220 ℃ of baking ovens and places 2 hours; Described Oxidative demage is raw materials weighing 14mg, adds 6% hydrogen peroxide 2ml, puts and on water-bath, reacts and volatilize 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.
A kind of Structural Identification method that another object of the present invention is to provide 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) that the structure of compound (II) is inferred and determined.
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 the analytical column that the bonded silica gels such as C18, C8, phenyl are filler, detector is UV-detector, take acetonitrile and phosphoric acid buffer as moving phase, according to degree such as grade and gradient elution program, detect.Preferably, described phosphoric acid buffer has added triethylamine, diethylamine.The pH value of phosphoric acid buffer is controlled in 5.5～7.5 scopes.
In specific examples of the present invention, by by formula I compound, the reaction solution after above-mentioned acid destruction, alkali destruction, high temperature destruction or Oxidative demage carries out 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: 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:
Accompanying drawing explanation
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 is need testing solution compound (II) liquid chromatographic detection figure after Tirofiban hydrochloride destroys with acid.
Fig. 5 is need testing solution compound (II) liquid chromatographic detection figure after Tirofiban hydrochloride destroys with alkali.
Fig. 6 is need testing solution compound (II) liquid chromatographic detection figure after Tirofiban hydrochloride destroys with high temperature.
Fig. 7 is need testing solution compound (II) liquid chromatographic detection figure after Oxidative demage for Tirofiban hydrochloride.
Embodiment:
Embodiment 1: the preparation of compound (II)
Get Tirofiban hydrochloride bulk drug 0.5g, add 3% hydrogen peroxide 1ml, 2mol hydrochloric acid 1ml stirs 24 hours at 60 ℃, cooling after, filter, 5% acetonitrile 8ml recrystallization solid for, 40 ℃ of vacuum-dryings 2 hours must compound (II).Compound (II) is 98% by its purity of liquid chromatography for measuring.
It is 474.1960 ± 0.01 that high resolution magnetic mass spectrometric detection obtains accurate molecular ion peak quality, and high resolution mass spectrum figure is shown in 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 comparison, a few H in molecular formula, many Cl, illustrate that this Tirofiban hydrochloride oxidation impurities is that in Tirofiban molecule, a H is replaced by a Cl.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 shown in accompanying drawing 2, and carbon-13 nmr spectra is shown in accompanying drawing 3.
Embodiment 2: get Tirofiban hydrochloride 5g, add 6% superoxol 15ml, stir lower 50～60 ℃ of heating 15 hours, filter.Solid adds 5% acetonitrile 75ml, is heated to backflow and makes to dissolve, and adds gac 0.3g, insulation absorption 15 minutes, and filtered while hot, the standing crystallization of filtrate, filters, and 40 ℃ of vacuum-dryings of solid obtain whitening compound (II) for 2 hours.
Embodiment 3: gets Tirofiban hydrochloride 200mg, adds 1mol/L sodium hydroxide solution 4ml, and 50～60 ℃ of heating of water-bath 20 hours, then add 1mol/L hydrochloric acid soln 4ml.Reaction solution passes through preparative chromatography (acetonitrile-water (30:70) of take is moving phase, take octadecylsilane chemically bonded silica as weighting agent, detects wavelength 227nm) separation after adding %10 dilution in acetonitrile.Collect the effluent liquid of compound (II), put in Rotary Evaporators and volatilize solvent, obtain whitening compound (II).
Embodiment 4: get Tirofiban hydrochloride 100mg, put in 220 ℃ of baking ovens and place 2 hours, take out.Gained solid dissolves with 10% acetonitrile, and solution is passed through to preparative chromatography (acetonitrile-water (30:70) of take is moving phase, take octadecylsilane chemically bonded silica as weighting agent, detects wavelength 227nm) separation.Collect the effluent liquid of compound (II), put in Rotary Evaporators and volatilize solvent, obtain whitening compound (II).
Embodiment 5: compound (II) is as the application of liquid chromatographic detection impurity reference substance
For 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 is used chromatographic column: Inertsil ODS-3250*4.6mm, particle diameter 5 μ m; Column temperature: 30 ℃, flow velocity: 1.0ml/min, moving phase: 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:
Liquid-phase chromatographic analysis data are shown in accompanying drawing 4-7.
Claims (11)
1. impurity and the salt thereof as described in formula II:
Formula II, the molecular formula of described formula II compound is C
22h
35clN
2o
5s.
2. impurity as claimed in claim 1 and salt thereof, 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, it has high resolution magnetic mass spectrometric detection, and to obtain accurate molecular ion peak quality be 474.1960 ± 0.01.
4. impurity as claimed in claim 1 or 2 and salt thereof, 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 to acid destruction, alkali destruction, high temperature destruction or Oxidative demage to be obtained.
6. the preparation method of impurity as claimed in claim 5, wherein: acid destroys and refers to that Tirofiban hydrochloride raw material is under acid solution after boiling water bath heating, then adds alkali neutralization; Alkali destroys and to refer to that Tirofiban hydrochloride raw material is under alkaline solution after boiling water bath heating, then adds acid neutralization; High temperature destroys and to refer to that Tirofiban hydrochloride raw material puts placing response in baking oven; Oxidative demage refers to that Tirofiban hydrochloride raw material adds, and puts on water-bath and reacts.
7. the preparation method of the impurity as described in claim 5 or 6, wherein: it is raw materials weighing 14mg that acid destroys, and adds 1mol/L hydrochloric acid soln 4ml, and boiling water bath heats approximately 20 hours, then adds 1mol/L sodium hydroxide solution 4ml neutralization; It is raw materials weighing 14mg that described alkali destroys, and adds 1mol/L sodium hydroxide solution 4ml, and boiling water bath heats approximately 20 hours, then adds 1mol/L hydrochloric acid soln 4ml neutralization; It is raw materials weighing 14mg that high temperature destroys, and puts in 220 ℃ of baking ovens and places 2 hours; Described Oxidative demage is raw materials weighing 14mg, adds 6% hydrogen peroxide 2ml, puts and on water-bath, reacts and volatilize solvent.
8. the detection method of the impurity as described in claim 1-3 any one, adopt reverse phase liquid chromatography, chromatographic column is the analytical column that C18, C8, phenyl bonded silica gel are filler, detector is UV-detector, take acetonitrile and phosphoric acid buffer as moving phase, according to degree such as grade and gradient elution program, detect.
9. as right, want the detection method of the impurity as described in 8, described phosphoric acid buffer has added triethylamine, diethylamine; The pH value of phosphoric acid buffer is controlled in 5.5～7.5 scopes.
10. 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: A acetonitrile, B0.025mol/L potassium dihydrogen phosphate: acetonitrile=8:2, described potassium dihydrogen phosphate regulates pH6.5 with triethylamine, moving phase according to the form below gradient elution program:
11. impurity as described in claim 1-4 any one and salt thereof in the degraded of Tirofiban hydrochloride and quality examination thereof as the application of impurity reference substance.
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| CN106596788B (en) * | 2016-12-26 | 2019-05-03 | 上海微谱化工技术服务有限公司 | A kind of method for separating and detecting of cardiovascular medicament tirofiban S configuration |
| 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 |
| 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 |
| CN112816282B (en) * | 2020-12-29 | 2022-04-12 | 江苏慧聚药业股份有限公司 | 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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