CN109134601A - A kind of impurity of bortezomib and preparation method thereof - Google Patents
A kind of impurity of bortezomib and preparation method thereof Download PDFInfo
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- CN109134601A CN109134601A CN201710450796.4A CN201710450796A CN109134601A CN 109134601 A CN109134601 A CN 109134601A CN 201710450796 A CN201710450796 A CN 201710450796A CN 109134601 A CN109134601 A CN 109134601A
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- bortezomib
- sample
- alkali
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- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 title claims abstract description 76
- 229960001467 bortezomib Drugs 0.000 title claims abstract description 75
- 239000012535 impurity Substances 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims description 137
- 238000000034 method Methods 0.000 claims description 52
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 25
- 239000000523 sample Substances 0.000 claims description 23
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 21
- 239000003513 alkali Substances 0.000 claims description 18
- 230000021736 acetylation Effects 0.000 claims description 16
- 238000006640 acetylation reaction Methods 0.000 claims description 16
- 238000000746 purification Methods 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- 230000014759 maintenance of location Effects 0.000 claims description 11
- 238000012360 testing method Methods 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- -1 dichloromethane Alkane Chemical class 0.000 claims description 8
- 239000013074 reference sample Substances 0.000 claims description 8
- 238000004587 chromatography analysis Methods 0.000 claims description 7
- 238000005259 measurement Methods 0.000 claims description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- 238000012937 correction Methods 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 238000010812 external standard method Methods 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 238000010813 internal standard method Methods 0.000 claims description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- 238000003379 elimination reaction Methods 0.000 claims description 2
- 238000013215 result calculation Methods 0.000 claims description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical class CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims 1
- 150000003927 aminopyridines Chemical class 0.000 claims 1
- 235000013399 edible fruits Nutrition 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 7
- 238000010998 test method Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 239000000243 solution Substances 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000012071 phase Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000008186 active pharmaceutical agent Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 239000012488 sample solution Substances 0.000 description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000000945 filler Substances 0.000 description 6
- 239000003550 marker Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- ODLMAHJVESYWTB-UHFFFAOYSA-N ethylmethylbenzene Natural products CCCC1=CC=CC=C1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 108010022579 ATP dependent 26S protease Proteins 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 238000010606 normalization Methods 0.000 description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 3
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- YHQXBTXEYZIYOV-UHFFFAOYSA-N 3-methylbut-1-ene Chemical compound CC(C)C=C YHQXBTXEYZIYOV-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000007445 Chromatographic isolation Methods 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 2
- 229940079156 Proteasome inhibitor Drugs 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000003207 proteasome inhibitor Substances 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000000306 recurrent effect Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- ZAZPDOYUCVFPOI-UHFFFAOYSA-N 2-methylpropylboronic acid Chemical compound CC(C)CB(O)O ZAZPDOYUCVFPOI-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003217 anti-cancerogenic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229960001713 canagliflozin Drugs 0.000 description 1
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- MLVFYXKWIBURLH-UHFFFAOYSA-N chloromethane;dichloromethane Chemical class ClC.ClCCl MLVFYXKWIBURLH-UHFFFAOYSA-N 0.000 description 1
- 238000010954 commercial manufacturing process Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- YVHPHQBRUPLYOS-UHFFFAOYSA-N dichloromethane;methane Chemical compound C.ClCCl YVHPHQBRUPLYOS-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000005096 hematological system Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 238000005220 pharmaceutical analysis Methods 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
Abstract
The present invention relates to impurity of bortezomib and preparation method thereof, and the purposes of reference standard and the test method of bortezomib and its impurity are controlled as bortezomib quality, the quality of bortezomib bulk pharmaceutical chemicals can be improved.
Description
Technical field
The invention belongs to pharmaceutical chemistry and Pharmaceutical Analysis fields, and in particular to impurity of bortezomib and preparation method thereof,
As well as bortezomib quality controls the purposes of reference standard and the test method of bortezomib and its impurity.
Background technique
Bortezomib (Bortezomib), chemical name are [(1R)-3- methyl-1-[[(2S)-1- oxygen-3- phenyl-2-
[(pyrazinecarbonyl) amino] propyl] amino] butyl]-boric acid, CAS:179324-69-7, structural formula is shown in formula I.
Bortezomib, trade name Bortezomib (Velcade) are by Millennium Pharmaceuticals of the U.S. (Millennium
Pharmaceuticals) a kind of dipeptide boronic acid albuminoid enzyme body inhibitor and first protease for clinic of research and development
Body inhibitor is currently used primarily in the treatment of Huppert's disease (MM) and lymphoma mantle cell (MCL).The drug was in 2003
Food and Drug Adminstration of the US (FDA) approval is obtained May, for treating recurrent and Refractory Multiple Myeloma.Then exist
The countries such as Europe, Australia, Malaysia and China list successively, for treating recurrent and refractory multiple marrow
Tumor.
Bortezomib as a kind of new and effective single-minded proteasome inhibitor, reversibly with 26S proteasome knot
It closes, the degradation channel of blocks protein, to prevent the malignant proliferation of tumour cell.26S proteasome is a kind of big protein
Complex, the degradable protein by ubiquitination.Ubiquitin-proteasome channel is to adjusting in differential protein concentration in the cell
It plays an important role, to maintain the stabilization of intracellular environment.Proteolysis will affect intracellular multilevel signal series connection, this to just
The destruction of normal intracellular environment will lead to the death of cell.And the hydrolysis of differential protein can be prevented to the inhibition of 26S proteasome.
In vitro test proves that bortezomib has cytotoxicity to a plurality of types of cancer cells, in addition to the treatment to Huppert's disease,
Also have to the kinds of tumors such as jacket cell type lymthoma and other B cell type lymthoma, Hodgkin lymphomas stronger antitumor
Activity, while also there is chemotherapy resistance, being first all has anticarcinogenic effect to hematological system and entity malignant tumour
Proteasome inhibitor, therefore, important drugs of the bortezomib as oncotherapy have broad application prospects and study valence
Value.
Preparation patent WO2005097809(patent families CN1960996) a kind of preparation method of bortezomib is disclosed,
This method with (1S, 2S, 3R, 5S)-pinane diol-L-phenylalanine-L-Leu boric acid ester hydrochloride (Formula VII) be raw material,
Under O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid (TBTU) effect, it is coupled with piperazinecarboxylic acid (Formula VIII)
Intermediate (1S, 2S, 3R, 5S)-pinane diol-N- (the 2- pyrazinecarbonyl)-L-phenylalanine-L-Leu borate (formula of obtaining
IX it), then with isobutaneboronic acid (Formula X) is deprotected in acid condition up to bortezomib (Formulas I), further passes through recrystallization etc.
Means of purification can prepare high-purity bortezomib, and synthetic route is as follows:
It is known in the art for human administration's security consideration, needed before a kind of commercialization of active pharmaceutical ingredient (API) product
The extremely low lower limit of the identification of non-characteristic impurity in toxicology is established by country and international management organization.In general, every kind miscellaneous
The limitation of matter less than about 0.15% weight ratio.The limitation of unidentified and/or non-characteristic impurity is considerably lower, typically less than
0.1% weight ratio.
It is also known that, the impurity in bortezomib or any active pharmaceutical ingredient (API) may be from API itself in this field
Degradation (this is related to the stability of pure API during storage) and manufacturing process, including chemical synthesis.Process impurity includes
Chemical derivative, synthesising by-product and the catabolite of impurity contained in unreacted raw material, raw material.
In addition to stability, the purity of the API of business manufacture is also obviously commercialized necessary condition.In commercial manufacturing process
The impurity of middle introducing must be limited in indivisible, and preferably be substantially absent.For example, used for API manufacturer
international conference on harmonization of technical requirements for human
Use (" ICH ") Q7A guidelines are by providing the quality of raw material, controlling technological parameter, such as temperature, pressure, time and chemistry
Metering than and be added purification step in autofrettage, such as crystallization, distillation and extract make process impurity be maintained at setting limit with
Under.
The product of chemical reaction is seldom the single compound with the enough purity for meeting pharmaceutical standards.Byproduct of reaction
And how much raw material used in the reaction exist in product mixtures.In API such as bortezomib preparation process
Certain stages, it is often necessary to its purity be analyzed by HPLC, TLC or GC analytic approach, to measure whether it is suitable for continuing to process
It is used in drug with final.API do not need it is absolutely pure because absolutely pure is usual not achievable theory target.On the contrary,
Purity rubric is set to ensure that API is as free from foreign meter as possible, and therefore as safe as possible for clinical application.As described above,
In the U.S., Food and Drug Administration (food and drug control) guide is recommended, and the amount of some impurity only limits
In lower than 0.1%.
Impurity usually is identified with spectrum and/or other physical methods, then obtains the spot in a peak position or TLC plate
Point identifies impurity later, such as identifies by its relative position in chromatogram that the relative position in chromatogram becomes
" retention time ".According to instrument use condition and many other factors, retention time daily or even all exists among one day
Variation.Accurately identifying for impurity is influenced in order to reduce these variations, it is usually miscellaneous to identify with " relative retention time (RRT) "
Matter.The RRT of impurity is the retention time with its retention time divided by main peak.
Known in the art, reference standard can be used for the qualitative of reference standard compound in unknown mixture and quantitative,
When the solution of the known concentration of reference standard and unknown mixture are analyzed with same technique, reference standard is " external standard ", can be with
The amount of compound described in mixture is measured by comparing the response intensity of detector.
As it is known to the person skilled in the art, by understanding its chemical structure and route of synthesis, and pass through identification finished product
Impurity and determine that the amount of the impurity of finished product greatly reinforces the control of process impurity.
Currently, having preparation or purification process that more documents and materials report bortezomib.Bortezomib prepares patent
WO2005097809 describes preparation and its purification process of bortezomib, which uses ethyl acetate or methyl tertiary butyl ether(MTBE)
Recrystallization is purified, and purification effect is unobvious.Other patent WO2009036281, WO2011098963, CN101812026,
There is also the same problems by CN105601705, CN104822688, CN103897028 etc., and also not publicly closes in document report
In the control method of bortezomib impurity.
Therefore, in existing bortezomib technology of preparing, it is not high that there are product purities, lacks the control etc. to single impurity
Shortcoming.Aiming at the shortcomings in the prior art, the present invention studies the Control of Impurities in bortezomib product, preparation
The bortezomib impurity i.e. Formula V compounds and Formula IV compound that do not identified before two kinds, the two compounds may be
Formed during the synthesis process or storage of bortezomib, with regard to known to applicant, the two compounds never by independently prepared and
It is separated with bortezomib, therefore, we have invented be used for bortezomib purity for the two compounds as impurity reference standard
Analyze quantitative method.
Summary of the invention
The purpose of the present invention is to provide a kind of Formula V compounds, are the degradation impurity of bortezomib, i.e. (S, Z)-N-
[1- (3- methyl butene ammonia) -1- oxygen -3- phenyl-propane -2- base] pyrazine -2- formamide.
Above-mentioned Formula V compound is separated into the purity at least 50%, or at least 60% purity in some embodiments,
Perhaps at least 70% purity perhaps at least 80 purity perhaps at least 90% purity perhaps to 95% purity or at least
96% purity, perhaps at least 97% purity perhaps at least 98% purity or at least 99% purity.The purity is generally
The purity of HPLC area normalization method.
The present invention also provides the preparation methods of a kind of Formula V compound and Formula IV compound, include the following steps:
(1), it at least one organic solvent, at least one acetylation reagent and a kind of alkali acetylation Formula II compound, obtains
To formula III compound.
(2), at least one organic solvent, elimination reaction is carried out at least one alkali and formula III compound, obtains formula
IV compound.
(3), formula IV compound separated using at least one means of purification, purified, respectively obtain Formula V compound and
Formula IV compound.
Wherein, organic solvent described in step (1) and (2) is selected from methylene chloride, tetrahydrofuran and dioxane.
Wherein, acetylation reagent described in step (1) is selected from acetic anhydride, acetic acid and chloroacetic chloride, preferably acetic anhydride.
Wherein, the molar ratio of acetylation reagent and Formula II compound is 1 ~ 200:1, preferably 1 ~ 10:1 in step (1), more
Preferably 3:1.
Wherein, alkali described in step (1) and (2) is selected from triethylamine, pyridine, morpholine, 4-dimethylaminopyridine, 1,8- phenodiazine
Miscellaneous two ring (5.4.0), 11 carbon -7- alkene and 1,5- diazabicylo [4.3.0] nonyl- 5- alkene are preferably selected from triethylamine and 4- bis-
Methylamino pyridine.
Wherein, alkali described in step (1) and (2) is selected from triethylamine and 4-dimethylaminopyridine；Alkali and Formula II in step (1)
The molar ratio of compound is 0.1 ~ 100:1, preferably 1 ~ 10:1, more preferably 3:1；Alkali and formula III compound in step (2)
Molar ratio is 0.1 ~ 100:1, preferably 1 ~ 10:1, more preferably 2:1.
Wherein, step (3) means of purification is selected from preparation chromatography and conventional column chromatography.
The present invention also provides the preparation methods of another Formula V compound and Formula IV compound, include the following steps:
(1), at least one organic solvent, at least one acetylation reagent and a kind of alkali while acetylation and cancelling II
Compound obtains formula IV compound.
(2), formula IV compound separated using at least one means of purification, purified, respectively obtain Formula V compound and
Formula IV compound.
Wherein, organic solvent described in step (1) is selected from methylene chloride, tetrahydrofuran and dioxane.
Wherein, acetylation reagent described in step (1) is selected from acetic anhydride, acetic acid and chloroacetic chloride, preferably acetic anhydride.
Wherein, the molar ratio of acetylation reagent and Formula II compound is 1 ~ 200:1, preferably 1 ~ 10:1 in step (1), more
Preferably 5:1.
Wherein, alkali described in step (1) is selected from triethylamine, pyridine, morpholine, 4-dimethylaminopyridine, 1,8- diaza two
11 carbon -7- alkene of ring (5.4.0) and 1,5- diazabicylo [4.3.0] nonyl- 5- alkene, preferably 4-dimethylaminopyridine.
Wherein, the molar ratio of alkali and Formula II compound is 0.1 ~ 100:1, preferably 1 ~ 10:1 in step (1), more preferably
5:1。
Wherein, step (2) means of purification is selected from preparation chromatography and conventional column chromatography.
In a specific embodiment, the isolation and purification method of above-mentioned Formula V compound and Formula IV compound, further
Include the following steps:
(1) above-mentioned formula IV compound single solvent or mixed solvent are dissolved；
(2) optionally, it is chromatographed using conventional column by the formula IV compound of dissolution, eluent is made by single solvent or mixed solvent
Elution separation is carried out, the Formula V compound and Formula IV compound of purifying are respectively obtained.
(3) optionally, the formula IV compound of dissolution is flowed by single solvent or mixed solvent using preparation chromatographic column
Dynamic phase is separated, and the Formula V compound and Formula IV compound of purifying are respectively obtained.
In above-mentioned purification step, wherein solvent described in step (1) include methylene chloride, chloroform, tetrahydrofuran,
Ethyl acetate, n-hexane, normal heptane, petroleum ether or their mixed liquor etc.；Eluent described in step (2) includes ethyl acetate
With n-hexane mixed liquor or ethyl acetate and normal heptane mixed liquor or ethyl acetate and petroleum ether mixed liquor, methylene chloride and just
Hexane mixed liquor or methylene chloride and normal heptane mixed liquor or methylene chloride and petroleum ether mixed liquor etc.；Described in step (3)
Mobile phase includes ethyl acetate and n-hexane mixed liquor or ethyl acetate and normal heptane mixed liquor or ethyl acetate and petroleum ether
Mixed liquor, methylene chloride and n-hexane mixed liquor or the mixing of methylene chloride and normal heptane mixed liquor or methylene chloride and petroleum ether
Liquid etc..
The present invention also provides the purposes that a kind of Formula V compound and Formula IV compound are used to control bortezomib quality.
The present invention also provides a kind of methods of measurement bortezomib and its impurity, this method comprises:
(1) a kind of bortezomib sample is provided；
(2) a kind of Formula V compound containing known quantity and/or characteristic is provided or/and Formula IV compound makees reference sample；
(3) with the presence of chromatography determination bortezomib sample compound of formula V or/and Formula IV compound or/and amount and/or
The amount of bortezomib.
In said determination method, the preferred high performance liquid chromatography of chromatography (HPLC) method.It measures and determines boron for assistant
Rice sample compound of formula V or/and the presence of Formula IV compound or/and the high performance liquid chromatography (HPLC) of amount generally comprise
External standard method, internal standard method, principal component Self-control method of the correction up factor etc., the specific operation process of these methods all this fields are normal
The knowledge of rule.The determination includes the test result calculations or contrast V chemical combination according to bortezomib sample and reference sample
The presence and/or amount of object or/and Formula IV compound in bortezomib sample.It is described calculating be this field routine knowledge with
Calculation formula.The content of the Formula V compound or/and Formula IV compound that detect in the bortezomib sample of actual production is normal
Light absorbing impurty is advised hereinafter, being not more than 0.1%.
The present invention also provides a kind of methods of measurement bortezomib and its impurity, this method comprises:
(1) a kind of bortezomib solution is provided and makees test sample；
(2) solution for providing a kind of Formula V compound containing known quantity and/or characteristic or/and Formula IV compound is made referring to sample
Product；
(3) with HPLC measurement (1) test sample and/or (2) reference product, determine bortezomib sample compound of formula V,
Or/and the presence or/and amount of Formula IV compound.
In the above method, the determination refers to be used according to the test result of bortezomib test sample and reference sample
The principal component Self-control method of external standard method, internal standard method or the correction up factor calculates or judges Formula V compound or/and Formula IV chemical combination
Presence and/or amount of the object in bortezomib sample.
In the above method, HPLC detection method be can be used: octadecylsilane chemically bonded silica is filler, and Detection wavelength is
270nm selects Suitable flow that test is mutually made to meet custom requirements, chromatogram is recorded, with area normalization method calculated purity.
In short, the present invention provides a kind of isolated bortezomib degradation impurity, i.e. Formula V compound and Formula V compound
With the preparation method of Formula IV compound and both as the purposes of bortezomib reference standard.Therefore, the present invention efficiently solves
The control shortcoming in the prior art lacked to single impurity, the quality for further control bortezomib provide guarantor
Barrier.
Detailed description of the invention
Fig. 1 is the typical HPLC chromatogram of the marker solution of the bortezomib of embodiment 6.
Fig. 2 is the typical HPLC chromatogram of the marker solution of the Formula V compound of embodiment 6.
Fig. 3 is the typical HPLC chromatogram of the marker solution of the formula III compound of embodiment 6.
Specific embodiment
The following examples are not limited the scope of the invention for further understanding and illustrating the present invention.
General operation
The preparation of Formula II compound, such as according to document " Synthesis and Characterization of Organic
Impurities in Bortezomib Anhydride Produced by a Convergent Technology " (Sci
Pharm.2012;The method preparation reported in 80:67-75), its full text introducing present invention is used to refer to, in addition, can also pass through
Commercial sources are bought.
The instrument that mass spectral analysis uses is 1200 highly effective liquid phase chromatographic system of Agilent, Agilent company G6410A string
Join triple level four bars mass spectrographs, ion source uses electric spray ion source, positive ion mode.The HPLC eluent of shunting allows big
About 1 μ g/ml enters mass spectrometric ion source.
The instrument that nuclear magnetic resonance spectroscopy uses is 600 nuclear magnetic resonance spectrometer of Bruker Avance, is using deuterated solvent
DMSO-d6.TMS is used as the resonance (δ 1H 0.00) and solvent internal reference of a proton, and DMSO-d6 is as carbon resonance
Internal standard (δ 13C 39.10-40.10).
The present invention uses following contracting word, and has following meaning:
Embodiment 1: the HPLC analysis method of bortezomib
It takes bortezomib appropriate, adds 0.1% phosphoric acid solution/acetonitrile (50:50) mixed liquor to dissolve in right amount, with 0.1% phosphoric acid solution/second
The solution in every 1ml containing about 1mg is made in the dilution of nitrile (50:50) mixed liquor, as test solution, by high performance liquid chromatography
(two V D of annex of Chinese Pharmacopoeia version in 2015) measurement.It is filler with octadecylsilane chemically bonded silica, column temperature is 25 DEG C,
Flow velocity is 1.0ml/min, Detection wavelength 270nm, and using 0.1% phosphoric acid solution as mobile phase A, acetonitrile is pressed as Mobile phase B
Following table ratio does linear gradient elution (ratio is its volume ratio), and number of theoretical plate is calculated by bortezomib should be not less than 3000.Essence
Close 20 μ l of measurement test solution injects liquid chromatograph, records chromatogram, calculates the pure of bortezomib with area normalization method
Degree.When necessary, system peak area or solvent peak area can be deducted by blank control.
Embodiment 2: the preparation of formula IV compound
1, the preparation of formula III compound
Formula II compound (10g, 28.1mmol) and triethylamine (8.5g, 84.0mmol) are dissolved in 200ml methylene chloride, nitrogen
Reaction system is replaced, 0-5 DEG C of temperature control, is slowly added to acetic anhydride (8.6g, 84.2mmol), is reacted at room temperature about 10 hours, TLC detection
Fully reacting stops reaction.Reaction solution is poured slowly into ice water, liquid separation, water phase extracts primary, merging dichloro with methylene chloride
Methane layer, then be washed with brine twice, anhydrous magnesium sulfate dries, filters, and is concentrated to dryness to obtain formula III compound, off-white color
Powder, HPLC:96.3%.
2, the preparation of formula IV compound
Formula III compound (10g, 25.1mmol) is dissolved in 200ml tetrahydrofuran, reaction system with nitrogen is stirred at room temperature
Under, it is slowly added to DMAP(6.1g, 49.9mmol), it reacts at room temperature about 3 hours, TLC detects fully reacting, stops reaction.It will be anti-
Liquid is answered to be poured slowly into the mixed liquor of ethyl acetate and water, liquid separation, water phase is extracted with ethyl acetate twice, combined ethyl acetate
Layer twice with 0.5N acid rinsing, then is washed with brine once, and anhydrous sodium sulfate dries, filters, and is concentrated to dryness to obtain formula IV
Compound, clear yellow viscous object.
Embodiment 3: the one kettle way preparation of formula IV compound
1, the preparation of formula IV compound
Formula II compound (10g, 28.1mmol) and DMAP(17.1g, 140.0mmol) is dissolved in 200ml tetrahydrofuran, nitrogen
Reaction system is replaced, 0-5 DEG C of temperature control, is slowly added to acetic anhydride (14.3g, 140.1mmol), is reacted at room temperature about 6 hours, TLC inspection
Fully reacting is surveyed, reaction is stopped.Reaction solution is poured slowly into the mixed liquor of ethyl acetate and water, liquid separation, water phase acetic acid second
Ester extracts twice, combined ethyl acetate layer, twice with 0.5N acid rinsing, then is washed with brine primary, anhydrous sodium sulfate drying,
Filtering, is concentrated to dryness to obtain formula IV compound, clear yellow viscous object.
2, the preparation of formula IV compound
Formula II compound (10g, 28.1mmol) and DBU(17.1g, 112.4mmol) is dissolved in 200ml methylene chloride, nitrogen
Reaction system is replaced, 0-5 DEG C of temperature control, is slowly added to acetic anhydride (11.5g, 112.6mmol), is reacted at room temperature about 8 hours, TLC inspection
Fully reacting is surveyed, reaction is stopped.Reaction solution is poured slowly into ice water, liquid separation, water phase extracts primary, merging two with methylene chloride
Chloromethanes layer, then be washed with brine twice, anhydrous magnesium sulfate dries, filters, and is concentrated to dryness to obtain formula IV compound, and yellow is viscous
Thick object.
Embodiment 4: the preparation of Formula V compound
1, the preparation of Formula V compound
2 step 2 compound of formula IV of embodiment is dissolved in ethyl acetate, is made using the mixed system of ethyl acetate and petroleum ether
Eluent, the conventional column chromatographic purifying through 200-300 mesh silicone filler separate (S, Z)-N- [1- (3- methyl butene ammonia) -1-
Oxygen -3- phenyl-propane -2- base] pyrazine -2- formamide (Formula V compound), HPLC:97.7%.
It is 361 that the peak M+H+, which is the peak 339, M+Na+, in mass spectrum [ESI-MS, m/z].
13C NMR (600MHz, DMSO) δ (ppm): 169.2,162.8,148.3,144.4,143.9,143.8,
137.5,129.6,128.5,126.9,120.2,119.2,54.1,38.2,25.1,23.4,23.3；
1H NMR (600MHz, DMSO) δ (ppm): 9.60-9.62 (1H, d), 9.13 (1H, d), 8.89 (1H, d),
8.75-8.77(2H,m),7.16-7.27(5H,m),6.39-6.43(1H,m),5.02-5.06(1H,m),4.55-4.58
(1H,m),3.07-3.14(2H,m),2.72-2.78(1H,m),0.92-0.97(6H,dd)。
2, the preparation of Formula V compound
2 step 2 compound of formula IV of embodiment is dissolved in appropriate ethyl acetate, using preparation chromatographic isolation (chromatographic column:
Santai SepaFlash 80g 40-63 μm), using n-hexane as mobile phase A, ethyl acetate as Mobile phase B, by A/B=
80:20 is eluted, flow velocity: 10ml/min, collects target component, (S, Z)-N- [1- (3- methyl butene is concentrated under reduced pressure
Ammonia) -1- oxygen -3- phenyl-propane -2- base] pyrazine -2- formamide (Formula II compound), HPLC:99.6%.
Embodiment 5: the preparation of Formula IV compound
1, the preparation of Formula IV compound
The formula IV compound prepared in 2 step 2 of embodiment is dissolved in appropriate ethyl acetate, using ethyl acetate and petroleum ether
Mixed system makees eluent, and the conventional column chromatographic purifying through 200-300 mesh silicone filler separates (S, E)-N- [1- (3- methyl
Butylene ammonia) -1- oxygen -3- phenyl-propane -2- base] -2 formamide (Formula IV compound) of pyrazine, HPLC:98.5%.
It is 361 that the peak M+H+, which is the peak 339, M+Na+, in mass spectrum [ESI-MS, m/z].
13C NMR (600MHz, DMSO) δ (ppm): 168.5,163.0,148.2,144.4,143.9,143.8,
137.9,129.6,128.6,126.9,120.1,120.7,54.6,37.6,28.9,23.3,23.3；
1H NMR (600MHz, DMSO) δ (ppm): 9.95-9.96 (1H, d), 9.11 (1H, d), 8.88 (1H, d),
8.80-8.81(1H,m),8.75(1H,m),7.15-7.26(5H,m),6.54-6.58(1H,m),5.25-5.28(1H,
m),4.76-4.79(1H,m),3.08-3.16(2H,m),2.26-2.34(1H,m),0.97-0.98(6H,dd)。
2, the preparation of Formula IV compound
The formula IV compound prepared in 2 step 2 of embodiment is dissolved in appropriate ethyl acetate, using preparation chromatographic isolation (chromatography
Column: Santai SepaFlash 80g 40-63 μm), using n-hexane as mobile phase A, ethyl acetate is as Mobile phase B, by A/
B=80:20 is eluted, flow velocity: 10ml/min, collects target component, (S, E)-N- [1- (3- methyl butene is concentrated under reduced pressure
Ammonia) -1- oxygen -3- phenyl-propane -2- base] -2 formamide (formula III compound) of pyrazine, HPLC:99.8%.
Embodiment 6: the qualitative and quantitative analysis of bortezomib, Formula V compound or/and Formula IV compound
A. chromatographic condition
Chromatographic column & filler: octadecylsilane chemically bonded silica is the chromatographic column (Waters of filler
Symmetry C18,5 μm, 4.6mm × 250mm)
Column temperature: 25 DEG C
Detection wavelength: 270nm
Sample volume: 20 μ l
Flow velocity: 1.0ml/min
Mobile phase: using 0.1% phosphoric acid solution as mobile phase A, with acetonitrile mobile phase B, according to the form below ratio does linear gradient elution (ratio
Example is its volume ratio).
B. the marker solution for identifying bortezomib, Formula V compound or/and Formula IV compound is prepared
Take bortezomib, Formula V compound or/and Formula IV compound appropriate respectively, respectively with 0.1% phosphoric acid solution/acetonitrile
(50:50) mixed liquor, which is dissolved in right amount and diluted, is configured to solution that concentration is about 0.1mg/ml to get each marker solution.It will be each
Marker solution, which is injected separately into chromatographic column, to be measured, and records chromatogram to get respective retention time.In above-mentioned chromatographic condition
Under, the retention time of bortezomib is about that 11.736min(chromatogram is shown in Fig. 1)；Formula IV the retention time of the compound is about
29.993min(chromatogram is shown in Fig. 2)；Formula V the retention time of the compound is about that 31.286min(chromatogram is shown in Fig. 3).According to ability
The knowledge in domain, it will be understood that it can reach between bortezomib, Formula V compound or/and each substance of Formula IV compound and efficiently separate,
Therefore the chromatographic condition can accurately identify bortezomib, Formula V compound or/and Formula IV compound.
C. sample solution is prepared
Bortezomib is dissolved with appropriate 0.1% phosphoric acid solution/acetonitrile (50:50) mixed liquor, and is diluted to point of concentration about 1mg/ml
The bortezomib sample solution of analysis.
D. 1% sample solution is prepared
Take sample solution in C to be diluted to concentration about 1%(10 μ g/ml with 0.1% phosphoric acid solution/acetonitrile (50:50) mixed liquor) examination
Sample solution.
E. it measures
By in the 1% sample solution injecting chromatograph of the sample solution of C and D, chromatogram is recorded.
Impurity is positioned with external standard method, the amount of impurity is calculated by the principal component Self-control method of the correction up factor.
Ai is the peak area of impurity i, and A1 is the main peak area of 1% sample solution canagliflozin, and fi is the correction factor of impurity i.
Claims (22)
1. a kind of Formula V compound,
。
2. a kind of method for preparing the compound as shown in claim 1 Formula V, it is characterised in that: described method includes following steps:
(1) it at least one organic solvent, at least one acetylation reagent and a kind of alkali acetylation Formula II compound, obtains
Formula III compound；
(2) at least one organic solvent, elimination reaction is carried out at least one alkali and formula III compound, obtains formula IV
Close object；
(3) formula IV compound separated using at least one means of purification, purified, respectively obtain Formula V compound and Formula IV
Compound
。
3. method according to claim 2, it is characterised in that: organic solvent described in step (1) and (2) is selected from dichloromethane
Alkane, tetrahydrofuran and dioxane.
4. method according to claim 2, it is characterised in that: acetylation reagent described in step (1) is selected from acetic anhydride, acetic acid
And chloroacetic chloride, preferably acetic anhydride.
5. method according to claim 2, it is characterised in that: alkali described in step (1) and (2) be selected from triethylamine, pyridine,
Quinoline, 4-dimethylaminopyridine, 11 carbon -7- alkene of 1,8- diazabicylo (5.4.0) and 1,5- diazabicylo [4.3.0] nonyl-
5- alkene, is preferably selected from triethylamine and 4-dimethylaminopyridine.
6. method according to claim 2, it is characterised in that: alkali described in step (1) and (2) is selected from triethylamine and 4- diformazan
Aminopyridine.
7. method according to claim 2, it is characterised in that: step (3) means of purification is selected from preparation chromatography and routine
Column chromatography.
8. method according to claim 2, it is characterised in that: acetylation reagent and Formula II compound in the step (1)
Molar ratio is 1 ~ 200:1, preferably 1 ~ 10:1, more preferably 3:1.
9. method according to claim 2, it is characterised in that: the molar ratio of alkali and Formula II compound is in the step (1)
0.1 ~ 100:1, preferably 1 ~ 10:1, more preferably 3:1；In the step (2) molar ratio of alkali and formula III compound be 0.1 ~
100:1, preferably 1 ~ 10:1, more preferably 2:1.
10. a kind of method for preparing the compound as shown in claim 1 Formula V, it is characterised in that: the method includes walking as follows
It is rapid:
(1), at least one organic solvent, at least one acetylation reagent and a kind of alkali while acetylation and cancelling II
Compound obtains formula IV compound；
(2), formula IV compound separated using at least one means of purification, purified, respectively obtain Formula V compound and Formula IV
Compound
。
11. method according to claim 10, it is characterised in that: organic solvent described in step (1) is selected from methylene chloride, four
Hydrogen furans and dioxane.
12. method according to claim 10, it is characterised in that: acetylation reagent described in step (1) is selected from acetic anhydride, second
Acid and chloroacetic chloride, preferably acetic anhydride.
13. method according to claim 10, it is characterised in that: alkali described in step (1) be selected from triethylamine, pyridine, morpholine,
4-dimethylaminopyridine, 11 carbon -7- alkene of 1,8- diazabicylo (5.4.0) and 1,5- diazabicylo [4.3.0] nonyl- 5-
Alkene, preferably 4-dimethylaminopyridine.
14. method according to claim 10, it is characterised in that: step (2) means of purification is selected from preparation chromatography and often
Advise column chromatography.
15. method according to claim 10, it is characterised in that: acetylation reagent and Formula II compound in the step (1)
Molar ratio be 1 ~ 200:1, preferably 1 ~ 10:1, more preferably 5:1.
16. method according to claim 10, it is characterised in that: the molar ratio of alkali and Formula II compound in the step (1)
For 0.1 ~ 100:1, preferably 1 ~ 10:1, more preferably 5:1.
17. the purposes of Formula V compound and Formula IV compound in control bortezomib quality as described in claim 1 ~ 16.
18. a kind of method of measurement bortezomib and its impurity, this method comprises:
(1) a kind of bortezomib sample is provided；
(2) the Formula V compound, and/or Formula IV compound for providing a kind of known quantity and/or characteristic make reference sample；
(3) with the bortezomib sample of HPLC measurement (1) and/or the reference sample of (2), Formula V in bortezomib sample is determined
Close the presence of object, and/or Formula IV compound and/or the amount of amount and/or bortezomib.
19. method according to claim 18, the HPLC method includes external standard method or internal standard method.
20. method according to claim 18, the determination includes the test knot according to bortezomib sample and reference sample
The presence and/or amount of fruit comparison or calculating formula V compound, and/or Formula IV compound in bortezomib sample.
21. according to the method for claim 20, this method are as follows: provide a kind of Formula V compound, and/or Formula IV compound is made
Reference sample obtains the relative retention time and correction factor with bortezomib by HPLC method contrast test；A kind of boron is provided
Bortezomib sample is tested with the HPLC of the same terms；According to test result and relative retention time and correction factor calculating formula Vization
Close the presence and/or amount of object, and/or Formula IV compound in bortezomib sample.
22. method according to claim 18, this method further comprises providing a kind of Formula V compound, and/or Formula IV compound
Make reference sample, is tested with HPLC；A kind of bortezomib sample is provided, is tested with the HPLC of the same terms；In bortezomib sample
It is quantitatively adding Formula V compound, and/or Formula IV compound in product, is tested with the HPLC of the same terms；According to test result calculations formula
The presence and/or amount of V compound, and/or Formula IV compound in bortezomib sample.
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| CN110372612B (en) * | 2019-08-17 | 2021-06-25 | 西安都创医药科技有限公司 | Preparation method of bortezomib derivative |
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