CN113493470A - 一种盐酸羟考酮注射液杂质a的制备方法 - Google Patents
一种盐酸羟考酮注射液杂质a的制备方法 Download PDFInfo
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- CN113493470A CN113493470A CN202010199445.2A CN202010199445A CN113493470A CN 113493470 A CN113493470 A CN 113493470A CN 202010199445 A CN202010199445 A CN 202010199445A CN 113493470 A CN113493470 A CN 113493470A
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- Prior art keywords
- acid
- sodium
- oxycodone hydrochloride
- hydrochloride injection
- potassium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000012535 impurity Substances 0.000 title claims abstract description 36
- BQNSLJQRJAJITR-UHFFFAOYSA-N 1,1,2-trichloro-1,2-difluoroethane Chemical compound FC(Cl)C(F)(Cl)Cl BQNSLJQRJAJITR-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 229960003617 oxycodone hydrochloride Drugs 0.000 title claims abstract description 27
- 238000002347 injection Methods 0.000 title claims abstract description 24
- 239000007924 injection Substances 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 16
- 229960002085 oxycodone Drugs 0.000 claims abstract description 12
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 claims abstract description 11
- 230000002378 acidificating effect Effects 0.000 claims abstract description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 5
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-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
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 238000005575 aldol reaction Methods 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- NVDYPYBOQNGGBF-UHFFFAOYSA-M magnesium;2-methylpropan-2-olate;bromide Chemical compound [Br-].CC(C)(C)O[Mg+] NVDYPYBOQNGGBF-UHFFFAOYSA-M 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 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
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- 229930182821 L-proline Natural products 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- RBGLVWCAGPITBS-UHFFFAOYSA-L bis(trifluoromethylsulfonyloxy)tin Chemical compound [Sn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F RBGLVWCAGPITBS-UHFFFAOYSA-L 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
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 239000003729 cation exchange resin Substances 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 229940071870 hydroiodic acid Drugs 0.000 claims description 2
- BDAGIHXWWSANSR-NJFSPNSNSA-N hydroxyformaldehyde Chemical compound O[14CH]=O BDAGIHXWWSANSR-NJFSPNSNSA-N 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- RTKCPZYOLXPARI-UHFFFAOYSA-N magnesium;2-methylpropan-2-olate Chemical compound [Mg+2].CC(C)(C)[O-].CC(C)(C)[O-] RTKCPZYOLXPARI-UHFFFAOYSA-N 0.000 claims description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- MKNZKCSKEUHUPM-UHFFFAOYSA-N potassium;butan-1-ol Chemical compound [K+].CCCCO MKNZKCSKEUHUPM-UHFFFAOYSA-N 0.000 claims description 2
- AWDMDDKZURRKFG-UHFFFAOYSA-N potassium;propan-1-olate Chemical compound [K+].CCC[O-] AWDMDDKZURRKFG-UHFFFAOYSA-N 0.000 claims description 2
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 claims description 2
- 229960002429 proline Drugs 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 229910052979 sodium sulfide Inorganic materials 0.000 claims description 2
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims description 2
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 claims description 2
- RCOSUMRTSQULBK-UHFFFAOYSA-N sodium;propan-1-olate Chemical compound [Na+].CCC[O-] RCOSUMRTSQULBK-UHFFFAOYSA-N 0.000 claims description 2
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 claims description 2
- 229910000018 strontium carbonate Inorganic materials 0.000 claims description 2
- UUCCCPNEFXQJEL-UHFFFAOYSA-L strontium dihydroxide Chemical compound [OH-].[OH-].[Sr+2] UUCCCPNEFXQJEL-UHFFFAOYSA-L 0.000 claims description 2
- 229910001866 strontium hydroxide Inorganic materials 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims 1
- 229940023913 cation exchange resins Drugs 0.000 claims 1
- -1 hydroxyketone compound Chemical class 0.000 abstract description 6
- 238000001819 mass spectrum Methods 0.000 abstract description 4
- 238000005882 aldol condensation reaction Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 238000012790 confirmation Methods 0.000 abstract description 2
- 239000007791 liquid phase Substances 0.000 abstract description 2
- 230000005311 nuclear magnetism Effects 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 238000011160 research Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000012074 organic phase Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000007787 solid Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000005406 washing 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102000003840 Opioid Receptors Human genes 0.000 description 2
- 108090000137 Opioid Receptors Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 239000003957 anion exchange resin Substances 0.000 description 2
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- 150000004679 hydroxides Chemical class 0.000 description 2
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- FQXXSQDCDRQNQE-UHFFFAOYSA-N markiertes Thebain Natural products COC1=CC=C2C(N(CC3)C)CC4=CC=C(OC)C5=C4C23C1O5 FQXXSQDCDRQNQE-UHFFFAOYSA-N 0.000 description 2
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- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
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- 239000000741 silica gel Substances 0.000 description 2
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- XWZCREJRXRKIRQ-UHFFFAOYSA-M sodium;heptane-1-sulfonate;hydrate Chemical compound O.[Na+].CCCCCCCS([O-])(=O)=O XWZCREJRXRKIRQ-UHFFFAOYSA-M 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- FQXXSQDCDRQNQE-VMDGZTHMSA-N thebaine Chemical compound C([C@@H](N(CC1)C)C2=CC=C3OC)C4=CC=C(OC)C5=C4[C@@]21[C@H]3O5 FQXXSQDCDRQNQE-VMDGZTHMSA-N 0.000 description 2
- 229930003945 thebaine Natural products 0.000 description 2
- DTQVDTLACAAQTR-DYCDLGHISA-N trifluoroacetic acid-d1 Chemical compound [2H]OC(=O)C(F)(F)F DTQVDTLACAAQTR-DYCDLGHISA-N 0.000 description 2
- RSSHKMSIEMOBQX-KFIKYVJASA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C RSSHKMSIEMOBQX-KFIKYVJASA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
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- 206010067484 Adverse reaction Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
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- 239000000556 agonist Substances 0.000 description 1
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- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- HSJKGGMUJITCBW-UHFFFAOYSA-N beta-hydroxybutyraldehyde Natural products CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 1
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- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
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- FPLYNRPOIZEADP-UHFFFAOYSA-N octylsilane Chemical group CCCCCCCC[SiH3] FPLYNRPOIZEADP-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明属于化工领域，具体涉及一种盐酸羟考酮注射液杂质A的制备方法。在酸性或碱性条件下，羟考酮发生Aldol缩合反应生成β羟基酮类化合物，即得到杂质A。本发明的的合成工艺所需试剂易得，反应条件温和易于控制，操作简便，得到杂质易纯化且液相纯度高，经核磁和质谱确认结构，可以用于盐酸羟考酮注射液质量研究。
Description
技术领域：
本发明属于化工领域，具体涉及一种盐酸羟考酮注射液杂质A的制备方法。
背景技术：
羟考酮(oxycodone)为阿片受体纯激动剂，是由生物碱蒂巴因(thebaine)提取物合成的阿片类中枢神经止痛药。对脑和脊髓的阿片受体具有亲和力，羟考酮的作用类似***。该药具有生物利用度高，镇痛效果好，不良反应小等特点，在临床上其单、复方制剂广泛用于中到重度疼痛的治疗。
盐酸羟考酮注射液在加速试验和长期稳定性试验过程中，随时间的延长会生成一较大杂质。经Q-TOF LC/MS一级质谱和二级质谱推测，杂质为盐酸羟考酮羟醛二聚体，即为杂质A。
杂质在药品的质量控制方面有重要意义，制备高纯度杂质对照品成为建立杂质检测方法的关键，高纯度的杂质对于原料药及其制剂质量的有效控制具有重要的意义。
目前羟考酮注射液杂质A制备方法未见相关文献报道，急需开发一种合成路线简单且制备样品纯度高的合成方法。
发明内容：
本发明为了解决现有技术存在的问题，通过实验发现在酸性或碱性条件下，羟考酮发生自身缩合(Aldol缩合反应)生成β羟基酮类化合物，即得到杂质A。
本发明提供一种盐酸羟考酮注射液杂质A的制备方法，所述的方法包括羟考酮在酸性或碱性条件下进行Aldol反应。
在上述的盐酸羟考酮注射液杂质A的制备方法中，在酸性条件下进行Aldol反应，所述酸选自硫酸、盐酸、氢溴酸、氢碘酸、磷酸、硝酸、高氯酸、对甲苯磺酸、苯磺酸、阳离子交换树脂、乙酸、三氟乙酸、L-脯氨酸、三氟化硼、三甲基铝、四氯化钛、三氟甲磺酸锡、氯化铝、氯化镍等质子酸和路易斯酸的一种或多种。
进一步的，在上述的盐酸羟考酮注射液杂质A的制备方法中，所述的酸优选为对甲苯磺酸和四氯化钛，更优选为四氯化钛。
在上述的盐酸羟考酮注射液杂质A的制备方法中，所述的酸性条件的pH为1-4。
在上述的盐酸羟考酮注射液杂质A的制备方法中，所述在酸条件下的反应温度为0-30℃，优选为0-10℃；
在上述的盐酸羟考酮注射液杂质A的制备方法中，在碱性条件下进行Aldol反应，所述碱选自氢氧化钠、氢氧化钾、氢氧化锶、氢氧化锂、氢氧化钡、氢氧化钙、氢氧化铯、碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、碳酸锶、碳酸铯、硫化钠、氢化钠、丁基锂、(六氢)吡啶、喹啉、甲醇钠、乙醇钠、丙醇钠、异丙醇钠、正丁醇钠、叔丁醇钠、甲醇钾、乙醇钾、丙醇钾、异丙醇钾、正丁醇钾、叔丁醇钾、二乙胺、三正丁胺、三丙基胺、二异丙基胺、二异丙基乙胺、叔丁醇铝、叔丁氧基溴化镁、三乙胺、二甲基吡啶等金属氧化物、氢氧化物，有机胺类化合物以及阴离子交换树脂中的一种或几种；进一步，所述碱优选为乙醇钠和叔丁氧基溴化镁，更优选为叔丁氧基溴化镁。
在上述的盐酸羟考酮注射液杂质A的制备方法中，所述的碱性条件的pH为8-14；所述在碱条件下的反应温度为0-80℃。
本发明的有益技术效果：
本发明的的合成工艺所需试剂易得，反应条件温和易于控制，操作简便，得到杂质易纯化且液相纯度高，经核磁和质谱确认结构，可以用于盐酸羟考酮注射液质量研究。
附图说明：
附图1：杂质A用于羟考酮的检测制备实施例：
盐酸羟考酮购买自北京华素制药股份有限公司
实施例
羟考酮在碱性或酸性条件下，发生自身缩合(Aldol缩合反应)生成β羟基酮类化合物，即得到杂质A，反应式如下：
实施例1
将5.00g盐酸羟考酮和40ml水加至反应瓶，搅拌溶解，滴加氨水调pH至9-10，用二氯甲烷萃取三次(20ml/次)，合并有机相，用20ml水洗一次，有机相用无水硫酸镁干燥，抽滤，滤液减压蒸除溶剂，得到4.38g类白色固体。
另取0.71g镁屑、15ml四氢呋喃加至反应瓶，搅拌下先滴加3ml 2.73g溴乙烷溶于15ml四氢呋喃的溶液，至反应引发，继续滴加，加毕，回流30分钟，将反应液冷却至0℃，滴加1.85g叔丁醇，加毕，于0-5℃保温搅拌1小时。
计时毕，于0-5℃滴加4.38g羟考酮碱基溶于25ml四氢呋喃的溶液，加毕，先于0-5℃保温搅拌6小时，后室温搅拌16小时。
将反应液冷却至0-5℃，滴加100ml水，搅拌30分钟，用二氯甲烷萃取三次(50ml/次)，合并有机相，用50ml水洗一次，有机相用无水硫酸镁干燥，抽滤，滤液减压蒸除溶剂，得到3.72g黄色固体，加入100ml无水乙醇加热溶解，后室温搅拌4小时，抽滤，滤饼于30-35℃真空干燥16小时，得到1.93g淡黄色固体，HPLC：97.6％。
1H NMR(500MHz,DMSO-d6+CF3COOD)δ:6.88(d,1H),6.81(d,1H),6.79(d,1H),6.680(d,1H),5.19(s,1H),4.63(s,1H),3.88(s,3H),3.84(s,3H),3.76(d,1H),3.53(d,1H),3.50(d,1H),3.42(d,1H),3.34(d,1H),3.20(m,1H),3.10(m,1H),3.05(d,1H),2.98(d,1H),2.913(s,3H),2.842(s,3H),2.722(d,1H),2.55(m,2H),2.46(d,1H),2.38(d,1H),2.13(d,1H),1.58(d,1H),1.53(d,1H),1.462(d,1H),1.39(m,2H),1.21(m,1H).
13C-NMR(125MHz,DMSO-d6+CF3COOD)δ:207.75,146.70,145.04,143.26,142.21,130.69,128.23,122.98,122.06,120.60,118.79,116.08,115.17,91.03,89.79,71.95,70.12,70.07,67.15,66.41,56.73,56.58,49.85,49.69,47.64,47.27,44.58,41.40,41.29,31.73,29.31,27.56,25.33,24.87,23.64,23.54.
Q-TOF LC-MS(m/z):631.3007[M+H]+.
实施例2
将5.00g盐酸羟考酮和40ml水加至反应瓶，搅拌溶解，滴加氨水调pH至9-10，用二氯甲烷萃取三次(20ml/次)，合并有机相，用20ml水洗一次，有机相用无水硫酸镁干燥，抽滤，滤液减压蒸除溶剂，得到4.45g类白色固体。
将上述固体用180ml无水乙醇溶解，加入4.00g20％乙醇钠，加热回流至反应完全。反应完毕，外温于30-35℃下减压蒸除溶剂，加入100ml二氯甲烷，搅拌下滴加50ml水，分液，有机相用水洗涤三次(50ml/次)，有机相用无水硫酸镁干燥，抽滤，滤液减压蒸除溶剂，得到3.12g黄色固体。加入90ml无水乙醇加热溶解，后室温搅拌4小时，抽滤，滤饼于30-35℃真空干燥16小时，得到1.73g淡黄色固体，HPLC：97.3％。
实施例3
将5.00g盐酸羟考酮和40ml水加至反应瓶，搅拌溶解，滴加氨水调pH至9-10，用二氯甲烷萃取三次(20ml/次)，合并有机相，用20ml水洗一次，有机相用无水硫酸镁干燥，抽滤，滤液减压蒸除溶剂，得到4.36g类白色固体。
氮气保护下，将上述固体和200ml二氯甲烷加至500ml反应瓶，冰水浴降温并于0-5℃加入1.60g三乙胺和4.12g四氯化钛，加毕，于0-5℃保温搅拌3小时。
计时毕，于0-5℃依次滴加300ml二氯甲烷和200ml水，搅拌，滴加氨水使pH值至8-9，分液，水相再用二氯甲烷萃取两次(100ml/次)，合并有机相，用水洗两次(100ml/次)，有机相用无水硫酸镁干燥，抽滤，滤液减压蒸除溶剂，得到4.52g黄色泡沫状固体。
柱层析：以100-200目硅胶湿法装柱，取4.50g样品以10ml二氯甲烷溶解湿法上样，流动相以甲醇/二氯甲烷为洗脱剂梯度洗脱，收集目标产物，减压蒸除溶剂，得到1.82g类白色固体，HPLC：98.8％。
实施例4
将5.00g盐酸羟考酮和40ml水加至反应瓶，搅拌溶解，滴加氨水调pH至9-10，用二氯甲烷萃取三次(20ml/次)，合并有机相，用20ml水洗一次，有机相用无水硫酸镁干燥，抽滤，滤液减压蒸除溶剂，得到4.46g类白色固体。
将上述固体和200ml二氯甲烷加至250ml反应瓶，冰水浴降温并于0-5℃加入2.70g对甲基苯磺酸，加毕，于0-5℃保温搅拌3小时。
计时毕，于0-5℃滴加氨水使pH值至8-9，分液，水相再用二氯甲烷萃取两次(100ml/次)，合并有机相，用水洗两次(100ml/次)，有机相用无水硫酸镁干燥，抽滤，滤液减压蒸除溶剂，得到4.12g黄色泡沫状固体。
加入120ml无水乙醇加热溶解，后室温搅拌4小时，抽滤，滤饼于30-35℃真空干燥16小时，得到2.13g淡黄色固体，HPLC：98.1％。
实施例5：杂质A用于羟考酮检测
高效液相色谱法(中国药典2015年版四部通则0512)试验，用辛烷基硅烷键合硅胶为填充剂(InertSustainTM C8，4.6mm×250mm，5μm或效能相当的色谱柱)；以0.11％一水合庚烷磺酸钠溶液(用磷酸调节pH值至1.8)-甲醇-乙腈(85:10:5)为流动相A，以0.13％一水合庚烷磺酸钠溶液(用磷酸调节pH值至1.8)-甲醇-乙腈(60:5:35)为流动相B，按下表进行梯度洗脱；流速为每分钟1.5ml；检测波长为206nm；柱温为40℃。
精密称取杂质A适量，置量瓶中，用醋酸溶液溶解并稀释制成每1ml含1mg的溶液，备用。精密量取20ul，注入液相色谱仪，采用峰面积归一法进行含量计算，详细信息见图1。高纯度的杂质A可以很好的用于羟考酮注射液的质量控制。
Claims (9)
1.一种盐酸羟考酮注射液杂质A的制备方法，其特征在于，所述的方法包括羟考酮在酸性或碱性条件下进行Aldol反应，
2.根据权利要求1所述的盐酸羟考酮注射液杂质A的制备方法，其特征在于，所述酸性所用的酸选自硫酸、盐酸、氢溴酸、氢碘酸、磷酸、硝酸、高氯酸、对甲苯磺酸、苯磺酸、阳离子交换树脂、乙酸、三氟乙酸、L-脯氨酸、三氟化硼、三甲基铝、四氯化钛、三氟甲磺酸锡、氯化铝、氯化镍等质子酸、路易斯酸的一种或多种。
3.根据权利要求2所述的盐酸羟考酮注射液杂质A的制备方法，其特征在于，所述的酸优选为对甲苯磺酸和四氯化钛。
4.根据权利要求1所述的盐酸羟考酮注射液杂质A的制备方法，其特征在于，所述在酸条件下的反应温度为0-30℃。
5.根据权利要求4所述的盐酸羟考酮注射液杂质A的制备方法，其特征在于，所述在酸条件下的反应温度为1-10℃。
6.根据权利要求1所述的盐酸羟考酮注射液杂质A的制备方法，其特征在于，所述碱性所用的碱选自氢氧化钠、氢氧化钾、氢氧化锶、氢氧化锂、氢氧化钡、氢氧化钙、氢氧化铯、碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、碳酸锶、碳酸铯、硫化钠、氢化钠、丁基锂、吡啶、喹啉、甲醇钠、乙醇钠、丙醇钠、异丙醇钠、正丁醇钠、叔丁醇钠、甲醇钾、乙醇钾、丙醇钾、异丙醇钾、正丁醇钾、叔丁醇钾、二乙胺、三正丁胺、三丙基胺、二异丙基胺、二异丙基乙胺、叔丁醇铝、叔丁氧基溴化镁、三乙胺、二甲基吡啶中的一种或几种。
7.根据权利要求6所述的盐酸羟考酮注射液杂质A的制备方法，其特征在于，所述碱为乙醇钠和叔丁氧基溴化镁。
8.根据权利要求7所述的盐酸羟考酮注射液杂质A的制备方法，其特征在于，所述碱为叔丁氧基溴化镁。
9.根据权利要求1所述的盐酸羟考酮注射液杂质A的制备方法，其特征在于，所述在碱条件下的反应温度为0-80℃。
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