CN113330006A - 以离子液体为介质的艾氟康唑的新型制备方法 - Google Patents
以离子液体为介质的艾氟康唑的新型制备方法 Download PDFInfo
- Publication number
- CN113330006A CN113330006A CN202080010297.3A CN202080010297A CN113330006A CN 113330006 A CN113330006 A CN 113330006A CN 202080010297 A CN202080010297 A CN 202080010297A CN 113330006 A CN113330006 A CN 113330006A
- Authority
- CN
- China
- Prior art keywords
- ionic liquid
- ethyl
- butyl
- efinaconazole
- methylimidazolium
- 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.)
- Granted
Links
- 239000002608 ionic liquid Substances 0.000 title claims abstract description 30
- NFEZZTICAUWDHU-RDTXWAMCSA-N efinaconazole Chemical compound N1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)CCC(=C)CC1 NFEZZTICAUWDHU-RDTXWAMCSA-N 0.000 title claims abstract description 22
- 229960003937 efinaconazole Drugs 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 239000000126 substance Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 14
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 claims abstract description 11
- 229960004130 itraconazole Drugs 0.000 claims abstract description 11
- LPKIGDXRQSIQBA-UHFFFAOYSA-N 4-methylidenepiperidine Chemical compound C=C1CCNCC1 LPKIGDXRQSIQBA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 238000005859 coupling reaction Methods 0.000 claims abstract description 6
- -1 1-ethyl-3-methylimidazolium hexafluorophosphate Chemical compound 0.000 claims description 39
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- VRFOKYHDLYBVAL-UHFFFAOYSA-M 1-ethyl-3-methylimidazol-3-ium;ethyl sulfate Chemical compound CCOS([O-])(=O)=O.CCN1C=C[N+](C)=C1 VRFOKYHDLYBVAL-UHFFFAOYSA-M 0.000 claims description 6
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 3
- LCZRPQGSMFXSTC-UHFFFAOYSA-M 1-butyl-1-methylpyrrolidin-1-ium;bromide Chemical compound [Br-].CCCC[N+]1(C)CCCC1 LCZRPQGSMFXSTC-UHFFFAOYSA-M 0.000 claims description 3
- GWQYPLXGJIXMMV-UHFFFAOYSA-M 1-ethyl-3-methylimidazol-3-ium;bromide Chemical compound [Br-].CCN1C=C[N+](C)=C1 GWQYPLXGJIXMMV-UHFFFAOYSA-M 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 150000008051 alkyl sulfates Chemical class 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 3
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- BJQWBACJIAKDTJ-UHFFFAOYSA-N tetrabutylphosphanium Chemical compound CCCC[P+](CCCC)(CCCC)CCCC BJQWBACJIAKDTJ-UHFFFAOYSA-N 0.000 claims description 3
- RKHXQBLJXBGEKF-UHFFFAOYSA-M tetrabutylphosphanium;bromide Chemical compound [Br-].CCCC[P+](CCCC)(CCCC)CCCC RKHXQBLJXBGEKF-UHFFFAOYSA-M 0.000 claims description 3
- GNPWBXOERPGDFI-UHFFFAOYSA-M 1-butyl-3-methylpyridin-1-ium;bromide Chemical compound [Br-].CCCC[N+]1=CC=CC(C)=C1 GNPWBXOERPGDFI-UHFFFAOYSA-M 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 abstract description 7
- 230000035484 reaction time Effects 0.000 abstract description 5
- 238000010923 batch production Methods 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 229940121375 antifungal agent Drugs 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- ZXMGHDIOOHOAAE-UHFFFAOYSA-N 1,1,1-trifluoro-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)NS(=O)(=O)C(F)(F)F ZXMGHDIOOHOAAE-UHFFFAOYSA-N 0.000 description 4
- FRZPYEHDSAQGAS-UHFFFAOYSA-M 1-butyl-3-methylimidazol-3-ium;trifluoromethanesulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)F.CCCC[N+]=1C=CN(C)C=1 FRZPYEHDSAQGAS-UHFFFAOYSA-M 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 208000010195 Onychomycosis Diseases 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 201000005882 tinea unguium Diseases 0.000 description 4
- IXLWEDFOKSJYBD-UHFFFAOYSA-M 1-ethyl-3-methylimidazol-3-ium;methanesulfonate Chemical compound CS([O-])(=O)=O.CC[N+]=1C=CN(C)C=1 IXLWEDFOKSJYBD-UHFFFAOYSA-M 0.000 description 3
- ZPTRYWVRCNOTAS-UHFFFAOYSA-M 1-ethyl-3-methylimidazol-3-ium;trifluoromethanesulfonate Chemical compound CC[N+]=1C=CN(C)C=1.[O-]S(=O)(=O)C(F)(F)F ZPTRYWVRCNOTAS-UHFFFAOYSA-M 0.000 description 3
- XGMSENVPQPNOHF-UHFFFAOYSA-N 4-methylidenepiperidine;hydrochloride Chemical compound Cl.C=C1CCNCC1 XGMSENVPQPNOHF-UHFFFAOYSA-N 0.000 description 3
- 241001480043 Arthrodermataceae Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 3
- 239000003429 antifungal agent Substances 0.000 description 3
- 230000037304 dermatophytes Effects 0.000 description 3
- UCQFCFPECQILOL-UHFFFAOYSA-N diethyl hydrogen phosphate Chemical compound CCOP(O)(=O)OCC UCQFCFPECQILOL-UHFFFAOYSA-N 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- NFRBUOMQJKUACC-UHFFFAOYSA-N triethyl(pentyl)azanium Chemical compound CCCCC[N+](CC)(CC)CC NFRBUOMQJKUACC-UHFFFAOYSA-N 0.000 description 3
- MQHLMHIZUIDKOO-OKZBNKHCSA-N (2R,6S)-2,6-dimethyl-4-[(2S)-2-methyl-3-[4-(2-methylbutan-2-yl)phenyl]propyl]morpholine Chemical compound C1=CC(C(C)(C)CC)=CC=C1C[C@H](C)CN1C[C@@H](C)O[C@@H](C)C1 MQHLMHIZUIDKOO-OKZBNKHCSA-N 0.000 description 2
- LSCNANBNVFQJDJ-PRHODGIISA-N (2r,3r)-2-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl)butane-2,3-diol Chemical compound C([C@@](O)([C@H](O)C)C=1C(=CC(F)=CC=1)F)N1C=NC=N1 LSCNANBNVFQJDJ-PRHODGIISA-N 0.000 description 2
- CCEYVAPCYYFRMO-UHFFFAOYSA-N 1,3-didecyl-2-methylimidazol-1-ium Chemical compound CCCCCCCCCCN1C=C[N+](CCCCCCCCCC)=C1C CCEYVAPCYYFRMO-UHFFFAOYSA-N 0.000 description 2
- PUHVBRXUKOGSBC-UHFFFAOYSA-M 1-butyl-3-methylimidazol-3-ium;methanesulfonate Chemical compound CS([O-])(=O)=O.CCCC[N+]=1C=CN(C)C=1 PUHVBRXUKOGSBC-UHFFFAOYSA-M 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- YVRDQOHBFMPIOR-UHFFFAOYSA-N CCCCN1C=CC=C(C)C1.Br Chemical compound CCCCN1C=CC=C(C)C1.Br YVRDQOHBFMPIOR-UHFFFAOYSA-N 0.000 description 2
- KKUKTXOBAWVSHC-UHFFFAOYSA-N Dimethylphosphate Chemical compound COP(O)(=O)OC KKUKTXOBAWVSHC-UHFFFAOYSA-N 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-O Imidazolium Chemical compound C1=C[NH+]=CN1 RAXXELZNTBOGNW-UHFFFAOYSA-O 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-O Pyrrolidinium ion Chemical compound C1CC[NH2+]C1 RWRDLPDLKQPQOW-UHFFFAOYSA-O 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229960003204 amorolfine Drugs 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- INDFXCHYORWHLQ-UHFFFAOYSA-N bis(trifluoromethylsulfonyl)azanide;1-butyl-3-methylimidazol-3-ium Chemical compound CCCCN1C=C[N+](C)=C1.FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F INDFXCHYORWHLQ-UHFFFAOYSA-N 0.000 description 2
- XSGKJXQWZSFJEJ-UHFFFAOYSA-N bis(trifluoromethylsulfonyl)azanide;butyl(trimethyl)azanium Chemical compound CCCC[N+](C)(C)C.FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F XSGKJXQWZSFJEJ-UHFFFAOYSA-N 0.000 description 2
- 229960003749 ciclopirox Drugs 0.000 description 2
- SCKYRAXSEDYPSA-UHFFFAOYSA-N ciclopirox Chemical compound ON1C(=O)C=C(C)C=C1C1CCCCC1 SCKYRAXSEDYPSA-UHFFFAOYSA-N 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000000466 oxiranyl group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 2
- OPAHEYNNJWPQPX-RCDICMHDSA-N ravuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=1C1=CC=C(C#N)C=C1 OPAHEYNNJWPQPX-RCDICMHDSA-N 0.000 description 2
- 229950004154 ravuconazole Drugs 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011829 room temperature ionic liquid solvent Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- LAGQNGWYNLUQRI-UHFFFAOYSA-N trioctylmethylammonium bis(trifluoromethylsulfonyl)imide Chemical compound FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F.CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC LAGQNGWYNLUQRI-UHFFFAOYSA-N 0.000 description 2
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 2
- 229960004740 voriconazole Drugs 0.000 description 2
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 1
- KSOGGGZFEJTGPZ-UHFFFAOYSA-M 1-butyl-2,3-dimethylimidazol-3-ium;trifluoromethanesulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)F.CCCC[N+]=1C=CN(C)C=1C KSOGGGZFEJTGPZ-UHFFFAOYSA-M 0.000 description 1
- ICIVTHOGIQHZRY-UHFFFAOYSA-N 1-butyl-3-methylimidazol-3-ium;cyanoiminomethylideneazanide Chemical compound [N-]=C=NC#N.CCCCN1C=C[N+](C)=C1 ICIVTHOGIQHZRY-UHFFFAOYSA-N 0.000 description 1
- HXMUPILCYSJMLQ-UHFFFAOYSA-M 1-ethyl-3-methylimidazol-3-ium;4-methylbenzenesulfonate Chemical compound CC[N+]=1C=CN(C)C=1.CC1=CC=C(S([O-])(=O)=O)C=C1 HXMUPILCYSJMLQ-UHFFFAOYSA-M 0.000 description 1
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- UENGBOCGGKLVJJ-UHFFFAOYSA-N 2-chloro-1-(2,4-difluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CCl)C(F)=C1 UENGBOCGGKLVJJ-UHFFFAOYSA-N 0.000 description 1
- MZFQJBMXUXJUHF-UHFFFAOYSA-N 4-azabicyclo[4.1.0]heptane Chemical compound C1CNCC2CC21 MZFQJBMXUXJUHF-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- WOCZUHLPCXDWOI-UHFFFAOYSA-N CO[Si](OC)(OC)[N-][Si](OC)(OC)OC.[Gd+3].CO[Si](OC)(OC)[N-][Si](OC)(OC)OC.CO[Si](OC)(OC)[N-][Si](OC)(OC)OC Chemical compound CO[Si](OC)(OC)[N-][Si](OC)(OC)OC.[Gd+3].CO[Si](OC)(OC)[N-][Si](OC)(OC)OC.CO[Si](OC)(OC)[N-][Si](OC)(OC)OC WOCZUHLPCXDWOI-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- UHIXWHUVLCAJQL-MPBGBICISA-N albaconazole Chemical compound C([C@@](O)([C@H](N1C(C2=CC=C(Cl)C=C2N=C1)=O)C)C=1C(=CC(F)=CC=1)F)N1C=NC=N1 UHIXWHUVLCAJQL-MPBGBICISA-N 0.000 description 1
- 229950006816 albaconazole Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001449 anionic compounds Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- IEFUHGXOQSVRDQ-UHFFFAOYSA-N bis(trifluoromethylsulfonyl)azanide;1-methyl-1-propylpiperidin-1-ium Chemical compound CCC[N+]1(C)CCCCC1.FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F IEFUHGXOQSVRDQ-UHFFFAOYSA-N 0.000 description 1
- BLODSRKENWXTLO-UHFFFAOYSA-N bis(trifluoromethylsulfonyl)azanide;triethylsulfanium Chemical compound CC[S+](CC)CC.FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F BLODSRKENWXTLO-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- MKHFCTXNDRMIDR-UHFFFAOYSA-N cyanoiminomethylideneazanide;1-ethyl-3-methylimidazol-3-ium Chemical compound [N-]=C=NC#N.CCN1C=C[N+](C)=C1 MKHFCTXNDRMIDR-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000024386 fungal infectious disease Diseases 0.000 description 1
- 229910001412 inorganic anion Inorganic materials 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- YSWYYGKGAYSAOJ-UHFFFAOYSA-N phosphane Chemical compound P.P YSWYYGKGAYSAOJ-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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Abstract
本发明涉及一种以离子液体为介质的艾氟康唑的新型制备方法,其特征在于,该方法使得1‑[[(2R,3S)‑2‑(2,4‑二氟苯基)‑3‑甲基环氧乙烷基]甲基]‑1H‑1,2,4‑三唑和4‑亚甲基哌啶或其有机化学上可接受的盐进行反应,所述4‑亚甲基哌啶或其有机化学上可接受的盐在碱上被阴离子化,在离子液体化合物的存在下,与所述1‑[[(2R,3S)‑2‑(2,4‑二氟苯基)‑3‑甲基环氧乙烷基]甲基]‑1H‑1,2,4‑三唑进行偶联反应。本发明在制备艾氟康唑时,采用离子液体代替有机溶剂,从而与现有方法相比,减少了有关物质,缩短了反应时间,可以很容易地得到高纯度和高收率的最终的化合物艾氟康唑,并且非常适合批量生产。
Description
技术领域
本发明涉及一种以离子液体为介质的艾氟康唑的新型制备方法。
背景技术
爪癣(onychomycosis)也称为爪真菌病、甲真菌病,是指指甲被皮肤癣菌(dermatophytes)、非皮肤癣菌性霉菌(non-dermatophytic molds)、酵母等真菌感染而引起变形的疾病。
为了对主要由皮肤癣菌引发的爪癣进行治疗,外用抗真菌剂被广泛使用,具有代表性的外用抗真菌剂可以列举出阿莫罗芬(amorolfine)、环吡酮胺(ciclopirox)和艾氟康唑(efinaconazole)等。
然而,在这些外用抗真菌药物中,艾氟康唑(Efinaconazole)已被开发为局部涂布剂溶液剂型的制剂,其效果是原有局部涂布剂的两倍以上,因此其作为爪癣的治疗剂被广泛使用。
由此,对艾氟康唑的需求正在逐渐增加,并且目前正在研究各种经济高效的制备方法。
作为现有技术的示例,可以列举国际公开专利WO2016079728A1(专利文献1)中公开的内容(由此,专利文献1的全部内容作为本说明书的现有技术进行引用和合并)。
专利文献1中公开了如下所示的通过将2-氯-1-(2,4二氟苯基)-乙-1-酮采用催化不对称反应进行氰硅化的方法,经过共五个步骤的工艺进行制备的方法。
但是,该制备方法除了使用昂贵的手型配体之外,还具有腐蚀性,对空气和水的反应性很强,需要使用要在无水条件下进行的双(三甲氧基甲硅烷基)酰胺钆,因此该技术方法被认为是一种受限制的方法。
不仅如此,在艾氟康唑的制备步骤中,P-1和4-亚甲基哌啶盐酸盐的偶联反应时,需要使用微波炉在120℃进行反应,因此虽然适用于研究实验技术,但是作为批量生产工艺效率差。
因此,为制备作为爪癣的优异抗真菌剂的艾氟康唑,需要开发一种在维持高收率、高纯度的品质的同时,安全、高效并适用于批量生产的经济性的工艺。
(专利文献1)WO2016079728A1(2016.05.26)
发明内容
本发明的目的是提供品质满足有关物质的基准值,能够进行批量生产的高纯度和高收率的艾氟康唑的制备方法,该方法使用离子液体化合物代替溶剂作为反应媒介体(medium),不仅具有经济性而且适合批量生产,提供了一种高纯度和高收率的艾氟康唑合成的新型制法。
本发明是为了解决上述的现有技术的问题而提出的。
本发明提供一种艾氟康唑的制备方法,其特征在于,在碱和离子液体化合物的存在下,使1-[[(2R,3S)-2-(2,4-二氟苯基)-3-甲基环氧乙烷基]甲基]-1H-1,2,4-三唑和4-亚甲基哌啶或其有机化学上可接受的盐进行偶联反应。
另外,本发明提供一种艾氟康唑的制备方法,其中,所述离子液体化合物选自以下化学式Ⅲ至Ⅶ中的至少一种。
[化学式Ⅲ]
[化学式Ⅳ]
[化学式Ⅴ]
[化学式Ⅵ]
[化学式Ⅶ]
其中,R1为氢、甲基或乙基,
R2为氢、碳原子数C1-C12的烷基,
X为Cl、Br、BF4、PF6、(三氟甲烷)磺酸盐(Otf)、乙酸盐(OAc)或甲磺酸盐、或碳原子数C1-C3的烷基硫酸盐。
另外,本发明提供一种艾氟康唑的制备方法,其中,所述离子液体化合物选自1-乙基-3-甲基溴化咪唑鎓、1-乙基-3-甲基咪唑鎓六氟磷酸盐、N-丁基-N-甲基溴化吡咯鎓、N-丁基-N-甲基吡咯烷鎓六氟磷酸盐、N-丁基-3-甲基溴化吡啶、N-丁基-3-甲基六氟磷酸吡啶、四-N-丁基溴化铵、四-N-丁基六氟磷酸铵、四-N-丁基溴化鏻和四-N-丁基六氟磷酸鏻中的至少一种。
另外,本发明提供一种艾氟康唑的制备方法,其中,所述离子液体化合物为咪唑鎓类烷基硫酸盐。
另外,本发明提供一种艾氟康唑的制备方法,其中,所述离子液体化合物为1-乙基-3-甲基咪唑鎓乙基硫酸盐。
另外,本发明提供一种艾氟康唑的制备方法,其中,所述碱为选自由叔丁醇钾、叔丁醇钠、NaH、NaOH和KOH组成的组中的至少一种。
本发明在艾氟康唑的制备中采用离子液体代替有机溶剂,与现有的方法相比,不仅减少了有关物质,缩短了反应时间,而且可以容易地得到高纯度和高收率的最终化合物-艾氟康唑,非常适合大批量生产。
具体实施方式
以下,对本发明进行详细地说明。
本发明中,
在碱和离子液体化合物的存在下,使1-[[(2R,3S)-2-(2,4-二氟苯基)-3-甲基环氧乙烷基]甲基]-1H-1,2,4-三唑和4-亚甲基哌啶或其有机化学上可接受的盐进行偶联反应。
所述1-[[(2R,3S)-2-(2,4-二氟苯基)-3-甲基环氧乙烷基]甲基]-1H-1,2,4-三唑是由以下化学式Ⅰ表示的化合物,它是伏立康唑(voriconazole)、拉夫康唑(ravuconazole)、阿巴康唑(albaconazole)和艾氟康唑(efinaconazole)等三唑类抗真菌治疗剂的关键中间体,由于环氧乙烷基团的C2和C3碳原子具有手性,因此可通过多种亲核取代反应转化为各种衍生物,并可根据如WO2016079728和WO2005014583等常规的已知方法制备,或者可以商购获得。
[化学式Ⅰ]
所述4-亚甲基哌啶是由以下化学式II表示的化合物,其作为亲核试剂打开环氧乙烷环的C3,4-亚甲基哌啶可以商购获得,可以是各种有机化学盐的形态,但主要以盐酸盐的形态被广泛使用。
[化学式Ⅱ]
所述4-亚甲基哌啶或它的盐与所述1-[[(2R,3S)-2-(2,4-二氟苯基)-3-甲基环氧乙烷基]甲基]-1H-1,2,4-三唑可以按照摩尔比1-20倍使用,优选为5-15倍。
所述碱用于使4-亚甲基哌啶阴离子(anion)化,可以不受限制地使用,只要能够使得反应条件呈碱性条件即可,可以列举出选自由叔丁醇钾、叔丁醇钠、NaH、NaOH和KOH组成的组中的至少一种。
所述碱可以为4-亚甲基哌啶使用量的2-20倍,优选地,可以为5-15倍。如果碱的当量小于上述提及的当量范围,则反应会无法完成;相反地,如果大于当量范围,则可能出现产生大量杂质的现象。
所述离子液体化合物是指由于阳离子和阴离子尺寸的不对称而无法形成结晶体,从而以液体状态存在的物质。特别地,在常温下以液体存在的离子液体被称为常温离子液体(room temperature ionic liquid,RTIL)。代表性的离子液体化合物可以列举出由具有含氮环结构的有机阳离子和具有较小尺寸的无机阴离子组成的熔融盐。
所述离子液体化合物具有挥发性低、热稳定性好、离子电导率高、电化学稳定性宽、蒸气压低等特点,因此在本发明中,可以用作一种稳定、环保的溶剂来替代现有的有机溶剂。即,可以替代有机溶剂或显著减少其使用量,从而解决现有技术中使用有机溶剂导致的工艺或环境方面的多种问题。
另外,化学式I和II的化合物在没有离子液体化合物的存在下进行偶联反应时,会过量地产生各种杂质,反应时间也十分长(例如,当纯度约为50%或还存在15%以上的起始物质p-1时反应不完成),由此不仅需要更多的原料化合物和碱(如胺试剂4-MH需要15当量),并且还需要柱提纯工艺等附加的工艺,最终的工艺时间也会增加。
此外,在很长的反应时间下,可能导致反应无法完成或者因为副反应等而产生有关物质。
与此相对地,根据本发明,在反应中加入离子液体时,可以使用相对较少的碱,缩短反应时间,几乎没有杂质产生,并且与现有已知的其他反应相比,收率也非常高。也就是说,不仅可以保证反应液的纯度为80%以上,无需柱提纯工艺,通过60%乙醇结晶可以确保99.8%以上的高纯度艾氟康唑的含量为100%以上,并且使用的碱,例如4-MH,也仅需要7当量,十分经济,适合大批量生产。
在本发明中,所述离子液体化合物可以采用选自以下化学式III至VII的咪唑鎓类(imidazolium)、吡啶鎓类(pyridium)、吡咯烷鎓(pyrrolidium)类、铵类(ammonium)、鏻类(phosphonium)中的至少一种。
[化学式Ⅲ]
[化学式Ⅳ]
[化学式Ⅴ]
[化学式Ⅵ]
[化学式Ⅶ]
其中,R1为氢、甲基或乙基,
R2为氢、碳原子数C1-C12的烷基,
X为Cl、Br、BF4、PF6、(三氟甲烷)磺酸盐(Otf)、乙酸盐(OAc)或甲磺酸盐、或碳原子数C1-C3的烷基硫酸盐。
更具体地,所述X可以为选自1-乙基-3-甲基咪唑乙基硫酸盐、1-乙基-3-甲基咪唑四氟硼酸盐、1-乙基-3-甲基咪唑甲苯磺酸盐、1-乙基-3-甲基咪唑鎓甲磺酸盐、1-乙基-3-甲基咪唑鎓三氟甲磺酸盐、1-乙基-3-甲基咪唑鎓二氰胺、1-丁基-3-甲基咪唑鎓四氟硼酸盐、1-丁基-3-甲基咪唑鎓双(三氟甲基磺酰基)亚胺、1-丁基-3-甲基咪唑鎓二氰胺、1-丁基-3-甲基咪唑鎓三氟甲磺酸盐、1-丁基-3-甲基咪唑鎓甲磺酸盐、1-丁基-3-甲基咪唑鎓三氟亚甲基磺酸盐、1,3-二癸基-2-甲基咪唑鎓双(三氟甲基磺酰基)亚胺、戊基三乙基铵双(三氟亚甲基磺酰基)亚胺、1-丁基2,3-二甲基咪唑鎓三氟甲磺酸盐、1-丁基-2,3-二甲基咪唑鎓四氟硼酸盐、1-(2-羟乙基)-3-甲基咪唑鎓四氟硼酸盐、1-癸基-3-甲基咪唑鎓四氟硼酸盐、1-丁基-3-甲基吡啶鎓四氟硼酸盐、1-丁基-4-甲基吡啶鎓四氟硼酸盐、1-烯丙基-3-乙基咪唑鎓四氟硼酸盐、1-甲基-1丙基哌啶鎓双(三氟甲基磺酰基)亚胺、甲基三辛基铵双(三氟甲基磺酰基)亚胺、丁基三甲基铵双(三氟甲基磺酰基)亚胺、三乙基硫鎓双(三氟甲基磺酰基)亚胺和二乙基甲基硫鎓双(三氟甲基磺酰基)亚胺组成的组;更优选地,为1-乙基-3-甲基咪唑鎓甲磺酸盐、1-丁基-3-甲基咪唑鎓四氟硼酸盐、1-丁基-3-甲基咪唑鎓双(三氟甲基磺酰基)亚胺、1-丁基-3-甲基咪唑鎓甲磺酸盐、1-丁基-3-甲基咪唑鎓三氟亚甲基磺酸盐、1,3-二癸基-2-甲基咪唑鎓双(三氟甲基磺酰基)亚胺、戊基三乙基铵双(三氟亚甲基磺酰基)亚胺、1-丁基-2,3-二甲基咪唑鎓四氟硼酸盐、1-烯丙基-3-乙基咪唑鎓四氟硼酸盐、甲基三辛基铵双(三氟甲基磺酰基)亚胺或丁基三甲基铵双(三氟甲基磺酰基)亚胺;特别优选地,可以为1-丁基-3-甲基咪唑鎓四氟硼酸盐、1-丁基-3-甲基咪唑鎓三氟亚甲基磺酸盐、戊基三乙基铵双(三氟亚甲基磺酰基)亚胺或1-烯丙基-3-乙基咪唑鎓四氟硼酸盐中的任意一种或多种。
优选地,所述离子液体化合物可以使用1-乙基-3-甲基溴化咪唑鎓、1-乙基-3-甲基咪唑鎓六氟磷酸盐、N-丁基-N-甲基溴化吡咯鎓、N-丁基-N-甲基吡咯烷鎓六氟磷酸盐、N-丁基-3-甲基溴化吡啶、N-丁基-3-甲基六氟磷酸吡啶、四-N-丁基溴化铵,四-N-丁基六氟磷酸铵、四-N-丁基溴化鏻和四-N-丁基六氟磷酸鏻。特别优选地,使用1-乙基-3-甲基咪唑乙基硫酸盐。
所述离子溶液化合物与所述1-[[(2R,3S)-2-(2,4-二氟苯基)-3-甲基环氧乙烷基]甲基]-1H-1,2,4-三唑相比可以是其重量的3-20倍,优选地可以为3-10倍。
以下,对容易合成高纯度和高收率的艾氟康唑的制备方法的一个示例进行说明。
[反应式1]
反应式1的制备方法中,在起始原料(2R,3R)-2-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基)丁烷-2,3-二醇和吡啶溶剂下,滴加氯磷酸二乙酯并在常温下反应得到化合物。不使用反应中所使用的溶剂,在常温下反应两小时以内完成所述反应,得到磷酸二甲酯或磷酸二乙酯中间体。作为所述磷酸盐离去基可以使用二甲基磷酰基、二乙基磷酰基等,其中最优选使用二乙基磷酰基。新型中间体磷酸二乙酯反应时使用的碱可以列举出叔丁氧基化钾(KOt-Bu)、NaOH、KOH、TEA、DIPEA等,其中,最优选使用吡啶。本发明中所述反应温度在20-30℃的温度进行,在室温进行时,反应可在3小时内完成。
[反应式2]
反应式2的制备方法中,将甲醇钠的甲醇溶液滴加到磷酸二甲酯或磷酸二乙酯中间体中,在常温下反应得到化合物。不使用反应中所使用的溶剂,所述反应温度在常温下2小时内完成,得到步骤P-1的化合物。
[反应式3]
反应式3的制备方法中,反应2的P-1化合物中,代替有机溶剂,在离子液体1-乙基-3-甲基咪唑乙基硫酸盐的存在下进行反应。向该反应液中滴加4-亚甲基哌啶,在100℃的反应温度下6小时之内完成反应。所述离子液体的用量范围为化学式3的化合物重量的3-10倍,优选地,在5-10倍的范围内使用。
以下,将参考实施例更详细地描述本发明。然而,显然以下实施例仅用于对本发明的详细描述,并不用于限制权利范围。
实施例
(2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基磷酸二甲 酯的合成
在烧瓶中加入10g的(2R,3R)-2-(2,4-二氟苯基)-1-(1H-1,2,4-三唑-1-基)丁烷-2,3-二醇和50ml的吡啶后,在常温(23-28℃)下搅拌10分钟,之后滴加7.20ml的氯磷酸二乙酯。该反应液在常温下搅拌2小时后,无后处理过程,得到14.3g(95%)的(2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基磷酸二烷基酯。接着直接进行下一步反应。
1-[[(2R,3S)-2-(2,4-二氟苯基)-3-甲基环氧乙烷基]甲基]-1H-1,2,4-三唑的合 成
在(2R,3R)-3-(2,4-二氟苯基)-3-羟基-4-(1H-1,2,4-三唑-1-基)丁-2-基磷酸二甲酯反应液中加入甲醇钠溶液14.4ml,之后在常温(23-28℃)下搅拌2小时,反应完成时,用乙酸乙酯和蒸馏水进行后处理。有机层用硫酸钠脱水后,过滤。减压浓缩后,得到7.98g(90%)的1-[[(2R,3S)-2-(2,4-二氟苯基)-3-甲基环氧乙烷基]甲基]-1H-1,2,4-三唑)。
1H NMR(400MHz,CDCl3)δ1.64(3H,d),3.19(1H,q),4.41-4.48(1H,m),4.85-4.92(1H,m),6.69-6.83(2H,m),6.96-7.07(1H,m),7.81(1H,s),7.98(1H,s)
(2R,3R)-2-(2,4-二氟苯基)-3-(4-亚甲基哌啶-1-基)-1-(1H-1,2,4-三唑-1-基) 丁醇的合成
投入42.44g的4-亚甲基哌啶盐酸盐、354.01ml的氢氧化钾50%水溶液后,在常温(23~28℃)下搅拌2小时。在反应液中加入638.4ml的乙醚搅拌30分钟后,进行层分离。在有机层中加入638.4ml的精制水搅拌30分钟后,进行层分离并浓缩得到有机层。在浓缩液中加入7.98g的1-[(2R,3S)-2-(2,4-二氟苯基)-3-甲基环氧乙烷基]甲基]-1H-1,2,4-三唑、95.76ml的精制水、40ml的离子液体1-乙基-3-甲基咪唑乙基硫酸盐后,将反应液在100℃搅拌6小时。确认反应完成后,冷却至常温,加入638.4ml的乙酸乙酯、638.4ml的精制水搅拌使得层分离。在有机层中加入638.4ml的饱和氯化钠水溶液搅拌30分钟后,分离有机层。在分离后的有机层中加入无水硫酸钠脱水后,过滤并减压浓缩有机溶剂。所得化合物进行结晶,得到8.85g(80%)。
1H NMR(400MHz,CDCl3)δ0.96(3H,dd),2.1-2.5(6H,m),2.6-2.8(2H,m),2.91(1H,q),4.64(2H,s),4.80(1H,d),4.89(1H,d),5.48(1H,brs),6.7-6.8(2H,m),7.47-7.63(1H,m),7.79(1H,s),8.03(1H,s)
对比例-根据韩国注册专利10-0339166的艾氟康唑的制备方法
在1.336g的4-亚甲基哌啶盐酸盐中加入11.2ml的50%氢氧化钾水溶液,搅拌至溶解之后,用20ml的乙醚萃取该溶液3次,除去有机层的乙醚。向残余物中依次加入3ml的乙醇、251mg的所述实施例2中得到的环氧乙烷中间体(1-[[(2R,3S)-2-(2,4-二氟苯基)-3-甲基环氧乙烷基]甲基)]-1H-1,2,4-三唑)和3ml的蒸馏水,将混合物在85℃下加热回流24小时。反应完成后,将反应液冷却至室温,加入20ml的乙酸乙酯和20ml的蒸馏水分离有机相,再用20ml的乙酸乙酯另外萃取3次水相,收集的有机层用盐水(brine)洗涤后,用无水硫酸镁干燥,接着在减压条件下除去溶剂。将浓缩物通过柱色谱提纯,得到188mg(54.0%)的标题化合物。
Claims (6)
1.一种艾氟康唑的制备方法,其特征在于,在碱和离子液体化合物的存在下,使1-[[(2R,3S)-2-(2,4-二氟苯基)-3-甲基环氧乙烷基]甲基]-1H-1,2,4-三唑和4-亚甲基哌啶或其有机化学上可接受的盐进行偶联反应。
3.根据权利要求1所述的艾氟康唑的制备方法,其中,所述离子液体化合物选自1-乙基-3-甲基溴化咪唑鎓、1-乙基-3-甲基咪唑鎓六氟磷酸盐、N-丁基-N-甲基溴化吡咯鎓、N-丁基-N-甲基吡咯烷鎓六氟磷酸盐、N-丁基-3-甲基溴化吡啶、N-丁基-3-甲基六氟磷酸吡啶、四-N-丁基溴化铵、四-N-丁基六氟磷酸铵、四-N-丁基溴化鏻和四-N-丁基六氟磷酸鏻中的至少一种。
4.根据权利要求1所述的艾氟康唑的制备方法,其中,所述离子液体化合物为咪唑鎓类烷基硫酸盐。
5.根据权利要求4所述的艾氟康唑的制备方法,其中,所述离子液体化合物为1-乙基-3-甲基咪唑乙基硫酸盐。
6.根据权利要求1所述的艾氟康唑的制备方法,其中,所述碱为选自由叔丁醇钾、叔丁醇钠、NaH、NaOH和KOH组成的组中的至少一种。
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