CN108164521A - A kind of Parecoxib Sodium degradation impurity and its preparation, detection method and application - Google Patents
A kind of Parecoxib Sodium degradation impurity and its preparation, detection method and application Download PDFInfo
- Publication number
- CN108164521A CN108164521A CN201810173211.3A CN201810173211A CN108164521A CN 108164521 A CN108164521 A CN 108164521A CN 201810173211 A CN201810173211 A CN 201810173211A CN 108164521 A CN108164521 A CN 108164521A
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- Prior art keywords
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- lithium
- parecoxib sodium
- compound
- degradation impurity
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- ICJGKYTXBRDUMV-UHFFFAOYSA-N trichloro(6-trichlorosilylhexyl)silane Chemical compound Cl[Si](Cl)(Cl)CCCCCC[Si](Cl)(Cl)Cl ICJGKYTXBRDUMV-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 239000012535 impurity Substances 0.000 title claims abstract description 45
- 229960003925 parecoxib sodium Drugs 0.000 title claims abstract description 45
- 230000015556 catabolic process Effects 0.000 title claims abstract description 41
- 238000006731 degradation reaction Methods 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 238000001514 detection method Methods 0.000 title claims abstract description 16
- 238000004587 chromatography analysis Methods 0.000 claims abstract description 6
- 239000007791 liquid phase Substances 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 7
- 239000012071 phase Substances 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 6
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 5
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000004458 analytical method Methods 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- AUALQMFGWLZREY-UHFFFAOYSA-N acetonitrile;methanol Chemical compound OC.CC#N AUALQMFGWLZREY-UHFFFAOYSA-N 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical group [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 235000011056 potassium acetate Nutrition 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000337 buffer salt Substances 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- LEKSIJZGSFETSJ-UHFFFAOYSA-N cyclohexane;lithium Chemical compound [Li]C1CCCCC1 LEKSIJZGSFETSJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 2
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 claims description 2
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 claims description 2
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims 2
- ZZPNDIHOQDQVNU-UHFFFAOYSA-N 2-hydroxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(O)OC1(C)C ZZPNDIHOQDQVNU-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims 1
- 229910000160 potassium phosphate Inorganic materials 0.000 claims 1
- 235000011009 potassium phosphates Nutrition 0.000 claims 1
- 238000011160 research Methods 0.000 abstract description 11
- 238000003860 storage Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 230000007246 mechanism Effects 0.000 abstract description 3
- 206010061623 Adverse drug reaction Diseases 0.000 abstract description 2
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 abstract description 2
- 238000004806 packaging method and process Methods 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 22
- 238000000034 method Methods 0.000 description 12
- 239000013558 reference substance Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 239000004744 fabric Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- ZXIRUKJWLADSJS-UHFFFAOYSA-N 5-methyl-3,4-diphenyl-1,2-oxazole Chemical class CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=CC=C1 ZXIRUKJWLADSJS-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 229960002004 valdecoxib Drugs 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 0 CCC(C)(C=C*(S(Cl)=O)=C)c1c(C)[o]nc1-c1ccccc1 Chemical compound CCC(C)(C=C*(S(Cl)=O)=C)c1c(C)[o]nc1-c1ccccc1 0.000 description 1
- JLJNFXQUYRMRAS-UHFFFAOYSA-N CCC(NS(c(cc1)ccc1-c1c(C)[o]nc1-c1ccccc1)(=O)=O)=C Chemical compound CCC(NS(c(cc1)ccc1-c1c(C)[o]nc1-c1ccccc1)(=O)=O)=C JLJNFXQUYRMRAS-UHFFFAOYSA-N 0.000 description 1
- GGKIMKVNYBTBLU-UHFFFAOYSA-N CCC(NS(c(cc1)ccc1-c1c(C)[o]nc1C1=CC=CCC1)(=O)=O)=O Chemical compound CCC(NS(c(cc1)ccc1-c1c(C)[o]nc1C1=CC=CCC1)(=O)=O)=O GGKIMKVNYBTBLU-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WJEIYVAPNMUNIU-UHFFFAOYSA-N [Na].OC(O)=O Chemical compound [Na].OC(O)=O WJEIYVAPNMUNIU-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- -1 alcohol ester Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- DAJLHNABGVYSOO-UHFFFAOYSA-N boric acid;2,3-dimethylbutane-2,3-diol Chemical class OB(O)O.CC(C)(O)C(C)(C)O DAJLHNABGVYSOO-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical class C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- NCCOOTMRZHTROF-UHFFFAOYSA-N ethylphosphanium;bromide Chemical class [Br-].CC[PH3+] NCCOOTMRZHTROF-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 150000002641 lithium Chemical class 0.000 description 1
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 238000005220 pharmaceutical analysis Methods 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000007686 potassium Nutrition 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- HPWDMRBYGBDHTQ-UHFFFAOYSA-M sodium propanoylazanide Chemical compound [Na+].CCC([NH-])=O HPWDMRBYGBDHTQ-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses degradation impurities of Parecoxib Sodium shown in formula I and preparation method thereof, solve the problems, such as that there has been no Parecoxib Sodium degradation impurity researchs in the prior art.The highly effective liquid phase chromatography detection method of application and the degradation impurity the invention also discloses the degradation impurity.The present invention provides the foundation for the Mechanism Study of the quality research of Parecoxib Sodium, research on standard, stability study, adverse drug reaction；Meanwhile the production for Parecoxib Sodium, packaging, storage, transport and the selection of application conditions provide foundation.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of Parecoxib Sodium degradation impurity and its preparation, detection side
Method and application.
Background technology
The research and development of Te Naishi Pharmacia companies it is first can intravenously administrable and intramuscular injection specific cyclooxygenase-2
(COX-2) water-soluble prodrug of inhibitor Valdecoxib (valdecoxib) belongs to the former times dry goods town in anti-arthritic
Pain medicine can be clinically used for the treatment of moderate or severe postoperative acute pain.Special resistance to active ingredient is Parecoxib Sodium
(Parecoxib Sodium), N- [[4- (5- methyl -3- phenyl -4- isoxazolyls) phenyl] sulfonyl] propionamide sodium salt.
The Parecoxib Sodium synthetic route of document report is more, and the difference of each process route is mainly reflected in intermediate 3,4-
The preparation process of diphenyl -5- methylisoxazoles has difference.Pa Rui is thought in the factor analyses such as combined reaction condition, industrialization degree
The industrial synthesis technique of former times cloth sodium be with 3,4- diphenyl -5- methylisoxazoles be raw material, through chlorosulfonation, ammonolysis, it is propionating,
The preparation of Parecoxib Sodium is realized into salt, synthetic route is as follows：
Comprehensive literature research contents and synthesis technology think that highly basic involved in the preparation process of Parecoxib Sodium walks
Suddenly, moreover, Parecoxib Sodium structure belongs to alkali compounds in itself, alkaline condition may cause propionamide in its structure etc. living
Property group storage, transport or use during degrade, for example, the hydrolytic degradation of Parecoxib Sodium.
At present, it is less for the research data of Parecoxib Sodium degradation impurity, only in document Current
The oxidation impurities of Parecoxib Sodium are described in Pharmaceutical Analysis, 2017,13,271-278 and are hydrolyzed miscellaneous
Matter.Therefore, we study process contaminants issuable in technique same during Parecoxib Sodium technical study
When, its degradation impurity is investigated, it is intended to for Parecoxib Sodium quality research and further formulate rational quality mark
Standard provides guidance, for the storage of Parecoxib Sodium finished product, transport, the condition of links such as uses to provide foundation, guarantee drug
Quality, stability and the drug safety of patient.
Invention content
It is an object of the present invention to：Design feature for Parecoxib Sodium and its production, packing and storing,
The degradation impurity introduced in transportational process may cause the problem of quality, stability and drug risk of drug, provide a kind of pa
The degradation impurity of auspicious former times cloth sodium is follow-up preparation process improvement, quality research, stability study and the packet of Parecoxib Sodium
It fills selection of storage and transportation conditions etc. and basis is provided.
The second object of the present invention is：The preparation method of the degradation impurity is provided.
The third object of the present invention is：The application of the degradation impurity is provided.
The fourth object of the present invention is：The reference preparation for including the degradation impurity is provided.
The fifth object of the present invention is：The highly effective liquid phase chromatography detection method of the degradation impurity is provided.
To achieve the above object, the technical solution adopted by the present invention is：
A kind of Parecoxib Sodium degradation impurity of the present invention has the structure as shown in formula I：
Preferably, it is compound of formula I pharmaceutically acceptable salt, solvate.
The preparation method of degradation impurity of the present invention is included under alkali effect, and II compound of formula occurs in a solvent
Ring closure reaction prepares type I compound：
Further, the alkali is selected from alkyllithium derivatives, lithium amide derivative；Wherein, alkyllithium derivatives are selected from just
Any one or combination in butyl lithium, s-butyl lithium, lithium methide, tert-butyl lithium, hexyl lithium, cyclohexyl lithium, phenyl lithium；Ammonia
Base lithium derivative is selected from one or more of lithium diisopropylamine, two (trimethyl silicon substrate) lithium amides, preferably diisopropyl
Lithium amide.
The preparation method of degradation impurity of the present invention includes III compound of formula under the conditions of catalyst 1 with connecting boric acid frequency
That alcohol ester reacts, and coupling reaction then, which occurs, with IV compound of formula under the conditions of catalyst 2 prepares type I compound：
Wherein, X is selected from chlorine, bromine, iodine.
Wherein, prepared by the method for the synthesized reference US2003105334 of II compound of formula；The synthesis of IV compound of formula
With reference to Advanced Synthesis and Catalysis, 2002,344 (10), prepared by the method for 1146-1151.
Further, the catalyst 1 and catalyst 2 independently selected from palladium, tetrakis triphenylphosphine palladium, Pd/C,
Any one or a few in palladium bichloride, [bis- (diphenylphosphino) ferrocene of 1,1'-] palladium chloride.
Further, it is carried out under the conditions of the reaction alkalinity that the catalyst 1 and catalyst 2 are catalyzed, the alkali is selected from phosphoric acid
Any one or a few in potassium, potassium acetate, sodium acetate, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate.
The present invention the Parecoxib Sodium degradation impurity as shown in formula I detection Parecoxib Sodium intermediate, bulk pharmaceutical chemicals and/
Or the application in preparation.Mechanism Study of the degradation impurity available for Parecoxib Sodium adverse reaction, Parecoxib Sodium intermediate,
Application in the quality standard research and quality control of bulk pharmaceutical chemicals and preparation production as reference substance.
A kind of reference for detecting impurity content in Parecoxib Sodium intermediate, bulk pharmaceutical chemicals and/or preparation of the present invention
Reagent, including the Parecoxib Sodium degradation impurity as shown in formula I.
A kind of high performance liquid chromatography for detecting Parecoxib Sodium degradation impurity of the present invention, chromatographic condition are：Color
It is the analysis chromatographic column using C8, C18 or phenyl bonded silica as filler to compose column, using acetonitrile or acetonitrile-methanol as mobile phase A, with
The buffer salt solution that pH is 2.8~3.2 is Mobile phase B, is eluted according to isocratic or gradient elution program.
Compared with prior art, the present invention has the following effects that：
The present invention provides the Parecoxib Sodium degradation impurities as shown in formula I, are quality research, the standard of Parecoxib Sodium
Research, stability study, adverse drug reaction Mechanism Study provide the foundation；Meanwhile it is the production of Parecoxib Sodium, packet
Dress, storage, transport and the selection of application conditions provide foundation.The quality standard that the degradation impurity can be produced in bulk pharmaceutical chemicals and preparation
Application in research and quality control as reference substance.
The present invention also provides the preparation method of Parecoxib Sodium degradation impurity, this method synthetic route is short, reaction condition
Mildly, easy to operate, Parecoxib Sodium degradation impurity purity obtained is high, the preparation available for impurity reference substance.
The detection method of the present invention is easy to operate, as a result accurately, Parecoxib Sodium can be made to reach baseline point with its degradation impurity
From.
Description of the drawings
Fig. 1 be formula I shown in Parecoxib Sodium degradation impurity hydrogen nuclear magnetic resonance spectrogram (1H-NMR)。
Fig. 2 is the mass spectrogram (MS) of the Parecoxib Sodium degradation impurity shown in formula I.
Fig. 3 is Parecoxib Sodium of the present invention (24.243min) and the high performance liquid chromatography of its degradation impurity (44.524min)
Figure.
Specific embodiment
The present invention provides detailed description below and makes more detailed description to present disclosure, but the present invention
Subject area is not limited to specific examples below, and every the content of present invention that is based on is to compound group, reaction reagent, behaviour
Technology, the technique that the equivalent replacement or combination that work, reaction step etc. are made are realized all belong to the scope of the present invention.
Embodiment 1
The preparation of type I compound is present embodiments provided, reaction equation is as follows：
Concrete operations are：II compound of 2.5g formulas, 30mL dry tetrahydrofurans are added in round-bottomed flask successively, nitrogen
11mL n-BuLis (1.6M) are slowly added in reaction solution under protection, -78 DEG C of cryogenic conditions, after adding, continue to be stirred to react
2h；Reaction solution is to slowly warm up to room temperature reaction overnight.Saturated ammonium chloride solution is slowly added into reaction solution, reaction, second is quenched
Acetoacetic ester extracts, and organic layer is dry, concentration, and residue column chromatography obtains type I compound (R=H) as a white solid, about
0.56g, yield：24%；HPLC purity：96.3%.
Type I compound：1H-NMR(CD3COCD3,400MHz)：δ=8.04 (d, J=8.0Hz, 1H), 7.90 (s, 1H),
7.72 (d, J=4.0Hz, 1H), 7.47~7.40 (m, 5H), 3.10 (q, J=8.0Hz, 2H), 2.57 (s, 3H), 1.29 (t, J
=8.0Hz, 3H) ppm.
MS-ESI(m/z):351.3(M-H)-。
Embodiment 2
The preparation of formula III compound is present embodiments provided, reaction equation is as follows：
Concrete operations are：Successively by bromo- 2- methoxycarbonyl groups benzsulfamide (the preparation method bibliography of 4.5g 4-
Bioorganic＆Medicinal Chemistry Letters 19 (2009) 6855-6861), 40mL dry tetrahydrofurans add
Enter into round-bottomed flask, 0 DEG C is cooled under nitrogen protective condition, (1.0M, tetrahydrofuran are molten by 45mL ethyl phosphonium bromides magnesium solution
Liquid) it is slowly dropped into reaction solution, after dripping off, after continuing stirring 30 minutes, reaction solution is to slowly warm up to room temperature, is stirred to react
Overnight.It adds in 20mL water quenchings into reaction solution to go out reaction, ethyl acetate extraction, organic layer drying, concentration, residue progress column layer
Analysis purifying obtains III compound of 1.5g formulas.
Embodiment 3
The preparation of type I compound is present embodiments provided, reaction equation is as follows：
By III compound of 1.5g formulas, 1.7g connection boric acid pinacol esters, 0.3g [1,1'- bis- (diphenylphosphines) two in embodiment 2
Luxuriant iron] palladium chloride, 1.2g potassium acetates, 20ml Isosorbide-5-Nitraes-dioxane be added in round-bottomed flask, under nitrogen protection, will react
Liquid is to slowly warm up to 100 DEG C and reacts 5 hours, and reaction solution is cooled to room temperature, is filtered, and filtrate concentration, residue carries out column chromatography
Subsequent reactions are carried out after purification.
Successively by above-mentioned product, IV compound of 1.2g formulas, 0.2g tetrakis triphenylphosphine palladiums, 10mL ethyl alcohol, 5mL 2M carbonic acid
Sodium solution is added in round-bottomed flask, and back flow reaction is to slowly warm up under stirring condition.TLC monitors reaction process.By reaction solution
It is cooled to room temperature, adds in 20mL saturated salt solutions, ethyl acetate extraction, organic layer drying, concentration, it is pure that residue carries out column chromatography
Change obtains type I compound as a white solid, about 0.5g, two step total recoverys：26%；HPLC purity：97.8%.
Embodiment 4
The present embodiment provides the highly effective liquid phase chromatography detection methods of the auspicious former times cloth sodium light degradation impurity of pa.
Detecting instrument：1260 high performance liquid chromatograph of Agilent
Chromatographic condition：Chromatographic column is Agilengt Eclipse XDB-C18 4.6*150mm 5um；Column temperature is 40 DEG C；Stream
Speed is 1.0ml/min；Detection wavelength is 215nm, with acetonitrile -0.01mol/L disodium phosphate solns (30：70) it is mobile phase etc.
Degree elution, wherein 0.01mol/L disodium phosphate solns phosphoric acid tune pH to 3.0.Its dosage is 30：70.
The preparation of sample：Parecoxib Sodium 25mg is taken to put in 50ml volumetric flasks, 40% acetonitrile solution is added to dissolve and dilutes quarter
Degree, shake up to get.
The preparation of reference substance：Type I compound 11mg, Parecoxib Sodium 23mg is taken to put in same 50ml volumetric flasks, adds 40%
Acetonitrile solution dissolves and dilutes scale, shake up to get.
Detection method：Sample and each 10 μ l injections liquid chromatograph of reference substance solution are taken, is measured by the chromatographic condition, note
Chromatogram is recorded, completes to measure；Gained chromatogram is as shown in Figure 3.
The results show that baseline separation can be reached using the auspicious former times cloth sodium of the present embodiment method and its light degradation impurity, detect
Rapidly, as a result accurately.
Embodiment 5
The present embodiment provides the highly effective liquid phase chromatography detection methods of the auspicious former times cloth sodium light degradation impurity of pa.
Detecting instrument：1260 high performance liquid chromatograph of Agilent
The preparation of sample：Parecoxib Sodium 25mg is taken to put in 50ml volumetric flasks, 40% acetonitrile solution is added to dissolve and dilutes quarter
Degree, shake up to get
The preparation of reference substance：Type I compound 11mg, Parecoxib Sodium 25mg is taken to put in same 50ml volumetric flasks, adds 40%
Acetonitrile solution dissolves and dilutes scale, shake up to get.
Gradient chromatography condition：It is filler (such as Agilengt Eclipse XDB-C18 with octadecyl silane；
150mm×4.6mm,5μm).Detection wavelength is 215nm, and column temperature is 40 DEG C, and flow velocity is 1.0ml per minute.
Mobile phase A：Acetonitrile-methanol (4：1)
Mobile phase B：0.1% phosphoric acid solution
Gradient elution time sequencing is as follows:
Detection method：Sample and each 10 μ l injections liquid chromatograph of reference substance solution are taken, is measured by the chromatographic condition, note
Chromatogram is recorded, completes to measure.
The results show that baseline separation can be reached using the auspicious former times cloth sodium of the present embodiment method and its light degradation impurity, detect
Rapidly, as a result accurately.
Above-described embodiment is only one of the preferred embodiment of the present invention, should not be taken to limit the protection model of the present invention
Enclose, as long as the present invention body design thought and that mentally makes have no the change of essential meaning or polishing, solved
The technical issues of it is still consistent with the present invention, should all be included within protection scope of the present invention.
Claims (10)
1. a kind of Parecoxib Sodium degradation impurity, which is characterized in that there is the structure as shown in formula I：
2. degradation impurity according to claim 1, which is characterized in that for compound of formula I pharmaceutically acceptable salt, solvent
Compound.
3. the preparation method of degradation impurity according to claim 1 or 2, which is characterized in that be included under alkali effect, formula II
Compound occurs ring closure reaction and prepares type I compound in a solvent：
4. preparation method according to claim 3, which is characterized in that the alkali is selected from alkyllithium derivatives, lithium amide spreads out
Biology；Wherein, alkyllithium derivatives be selected from n-BuLi, s-butyl lithium, lithium methide, tert-butyl lithium, hexyl lithium, cyclohexyl lithium,
Any one or a few in phenyl lithium；Lithium amide derivative is selected from lithium diisopropylamine, two (trimethyl silicon substrate) lithium amides
One or more of, preferred lithium diisopropylamine.
5. the preparation method of degradation impurity according to claim 1 or 2, which is characterized in that urged including III compound of formula
It is reacted under the conditions of agent 1 with even boric acid pinacol ester, coupling reaction system then occurs with IV compound of formula under the conditions of catalyst 2
Standby type I compound：
Wherein, X is selected from chlorine, bromine, iodine.
6. preparation method according to claim 5, which is characterized in that the catalyst 1, catalyst 2 independently selected from
It is arbitrary in palladium, tetrakis triphenylphosphine palladium, Pd/C, palladium bichloride, [bis- (diphenylphosphino) ferrocene of 1,1'-] palladium chloride
It is one or more of.
7. preparation method according to claim 5 or 6, which is characterized in that the catalyst 1 and catalyst 2 are catalyzed anti-
It answers and is carried out under alkaline condition, the alkali is in potassium phosphate, potassium acetate, sodium acetate, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate
Any one or a few.
8. degradation impurity as claimed in claim 1 or 2 is in detection Parecoxib Sodium intermediate, bulk pharmaceutical chemicals and/or preparation
Using.
9. the reference reagent of impurity content in a kind of detection Parecoxib Sodium intermediate, bulk pharmaceutical chemicals and/or preparation, will including right
Seek the impurity described in 1 or 2.
10. a kind of highly effective liquid phase chromatography detection method of the Parecoxib Sodium degradation impurity described in claims 1 or 2, feature exist
In chromatographic condition is：Chromatographic column is the analysis chromatographic column using C8, C18 or phenyl bonded silica as filler, with acetonitrile or acetonitrile-
Methanol is mobile phase A, using the buffer salt solution that pH is 2.8~3.2 as Mobile phase B, is carried out according to isocratic or gradient elution program
Elution.
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| CN110642801A (en) * | 2019-09-20 | 2020-01-03 | 深圳市祥根生物科技有限公司 | Preparation method of parecoxib meta-isomer impurity |
| CN111257441A (en) * | 2019-12-31 | 2020-06-09 | 河南润弘制药股份有限公司 | Method for detecting impurities in parecoxib sodium synthesis process |
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Denomination of invention: A Paricoxib Sodium Degradation Impurity and Its Preparation, Detection Method and Application Granted publication date: 20201113 Pledgee: Bank of Chengdu science and technology branch of Limited by Share Ltd. Pledgor: CHENGDU SINO-STRONG PHARMACEUTICAL Co.,Ltd. Registration number: Y2024980024385 |