CN111807954A - 一种辛波莫德中间体的制备方法 - Google Patents
一种辛波莫德中间体的制备方法 Download PDFInfo
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- CN111807954A CN111807954A CN201910282666.3A CN201910282666A CN111807954A CN 111807954 A CN111807954 A CN 111807954A CN 201910282666 A CN201910282666 A CN 201910282666A CN 111807954 A CN111807954 A CN 111807954A
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- Prior art keywords
- reaction
- compound
- acid
- anhydrous
- chloride
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- KIHYPELVXPAIDH-HNSNBQBZSA-N 1-[[4-[(e)-n-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-c-methylcarbonimidoyl]-2-ethylphenyl]methyl]azetidine-3-carboxylic acid Chemical compound CCC1=CC(C(\C)=N\OCC=2C=C(C(C3CCCCC3)=CC=2)C(F)(F)F)=CC=C1CN1CC(C(O)=O)C1 KIHYPELVXPAIDH-HNSNBQBZSA-N 0.000 title abstract description 12
- 229950005693 siponimod Drugs 0.000 title abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 64
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 13
- 238000005886 esterification reaction Methods 0.000 claims abstract description 7
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 7
- 230000003647 oxidation Effects 0.000 claims abstract description 5
- 230000032050 esterification Effects 0.000 claims abstract description 4
- 238000006692 trifluoromethylation reaction Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 26
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical group 0.000 claims description 8
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 claims description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 8
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 7
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 claims description 6
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 6
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 6
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- -1 oleum Chemical compound 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000003377 acid catalyst Substances 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 4
- 239000010949 copper Substances 0.000 claims description 4
- 238000005658 halogenation reaction Methods 0.000 claims description 4
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 4
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 claims description 4
- PUGUQINMNYINPK-UHFFFAOYSA-N tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1 PUGUQINMNYINPK-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 4
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 claims description 4
- 239000011592 zinc chloride Substances 0.000 claims description 4
- 235000005074 zinc chloride Nutrition 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 3
- UYCAUPASBSROMS-AWQJXPNKSA-M sodium;2,2,2-trifluoroacetate Chemical compound [Na+].[O-][13C](=O)[13C](F)(F)F UYCAUPASBSROMS-AWQJXPNKSA-M 0.000 claims description 3
- ZPTVNYMJQHSSEA-UHFFFAOYSA-N 4-nitrotoluene Chemical compound CC1=CC=C([N+]([O-])=O)C=C1 ZPTVNYMJQHSSEA-UHFFFAOYSA-N 0.000 claims description 2
- JZVUAOCDNFNSGQ-UHFFFAOYSA-N 7-methoxy-2-phenyl-1h-quinolin-4-one Chemical compound N=1C2=CC(OC)=CC=C2C(O)=CC=1C1=CC=CC=C1 JZVUAOCDNFNSGQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 2
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 claims description 2
- RJYSYRSELCQCSO-UHFFFAOYSA-M cesium;2,2,2-trifluoroacetate Chemical compound [Cs+].[O-]C(=O)C(F)(F)F RJYSYRSELCQCSO-UHFFFAOYSA-M 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 2
- 229940112669 cuprous oxide Drugs 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 230000002140 halogenating effect Effects 0.000 claims description 2
- 230000026030 halogenation Effects 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 2
- VMVNZNXAVJHNDJ-UHFFFAOYSA-N methyl 2,2,2-trifluoroacetate Chemical compound COC(=O)C(F)(F)F VMVNZNXAVJHNDJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- CUNPJFGIODEJLQ-UHFFFAOYSA-M potassium;2,2,2-trifluoroacetate Chemical compound [K+].[O-]C(=O)C(F)(F)F CUNPJFGIODEJLQ-UHFFFAOYSA-M 0.000 claims description 2
- XGPOMXSYOKFBHS-UHFFFAOYSA-M sodium;trifluoromethanesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C(F)(F)F XGPOMXSYOKFBHS-UHFFFAOYSA-M 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 239000000463 material Substances 0.000 abstract description 5
- 230000031709 bromination Effects 0.000 abstract description 4
- 238000005893 bromination reaction Methods 0.000 abstract description 4
- XIWQGDFYIINJLV-UHFFFAOYSA-N 4-cyclohexyl-3-(trifluoromethyl)benzoic acid Chemical compound FC(F)(F)C1=CC(C(=O)O)=CC=C1C1CCCCC1 XIWQGDFYIINJLV-UHFFFAOYSA-N 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 abstract description 2
- HHNHBFLGXIUXCM-GFCCVEGCSA-N cyclohexylbenzene Chemical compound [CH]1CCCC[C@@H]1C1=CC=CC=C1 HHNHBFLGXIUXCM-GFCCVEGCSA-N 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000010410 layer Substances 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000005311 nuclear magnetism Effects 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- GPBPFDPENZHCPR-UHFFFAOYSA-N 4-bromo-3-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(Br)C(C(F)(F)F)=C1 GPBPFDPENZHCPR-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- LZJHACNNMBYMSO-UHFFFAOYSA-N 1,1-dimethyl-3-propylurea Chemical compound CCCNC(=O)N(C)C LZJHACNNMBYMSO-UHFFFAOYSA-N 0.000 description 1
- RWXUNIMBRXGNEP-UHFFFAOYSA-N 1-bromo-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1Br RWXUNIMBRXGNEP-UHFFFAOYSA-N 0.000 description 1
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- HVAPLSNCVYXFDQ-UHFFFAOYSA-N 3,3-dimethyl-1-(trifluoromethyl)-1$l^{3},2-benziodoxole Chemical group C1=CC=C2C(C)(C)OI(C(F)(F)F)C2=C1 HVAPLSNCVYXFDQ-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical group CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- MFLLMKMFWIUACU-UHFFFAOYSA-N trifluoromethanethiol Chemical group FC(F)(F)S MFLLMKMFWIUACU-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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Abstract
本发明涉及一种辛波莫德中间体的制备方法,属于药物化学领域。所述制备方法包括,以环己基苯为起始物料,经过傅克酰化,溴化,氧化,酯化,三氟甲基化,水解等反应得到4‑环己基‑3‑三氟甲基苯甲酸;本发明提供的技术方案操作简便,易于实施,反应条件温和,收率高,纯度高,成本低,适合工业化生产。
Description
技术领域
本发明涉及药物化学领域,具体涉及一种辛波莫德中间体的制备方法。
背景技术
化合物N-(4-环己基-3-三氟甲基-苄氧基)-乙亚氨酸乙酯(式I)是合成药学上活性化合物1-{4-[1-(4-环己基-3-三氟甲基-苄氧基亚氨基)-乙基-苄基(benxyl)}-氮杂环丁烷-3-羧酸(辛波莫德)的中间体。
辛波莫德是可用于治疗免疫疾病例如多发性硬化的鞘氨醇-1-磷酸酯(“S1P”)调节剂。合成辛波莫德的方法参见中国专利申请CN 104105687 A和WO2017120124A1。
现有技术中,CN 104105687 A公开的辛波莫德制备方法,其中间体是以2-溴三氟甲苯为原料,经格氏反应,钯催化氢化,二溴海因溴代,再格氏反应制得。由于该方法需要使用格氏试剂且还需要使用活性极高的丁基锂试剂,其反应安全性较差,不利于工业放大。WO2017120124A1公开的中间体制备方法中,是以4-溴-3-三氟甲基苯甲酸为原料,经一步铃木反应,一步钯催化氢化反应制得。由于该方法需要使用两次钯催化剂,其反应成本较高,且底物4-溴-3-三氟甲基苯甲酸成本较高,进一步限制了该路线的工业应用。
因此,仍然需要研究辛波莫德及其中间体,以获得具有操作简便,易于实施,反应条件温和,收率高,纯度高,成本低,适合工业化生产的制备方法。
发明内容
本发明提供一种辛波莫德中间体的制备方法,该中间体其结构如化合物A05所示:
本发明提供了一种辛波莫德关键中间体4-环己基-3-三氟甲基苯甲酸(即A05)的合成方法。该方法以环己基苯为起始物料,经过傅克酰化,溴化,氧化,酯化,三氟甲基化,水解等反应得到4-环己基-3-三氟甲基苯甲酸。该化合物可经还原,溴代,缩合等反应制得辛波莫德中间体N-(4-环己基-3-三氟甲基-苄氧基)-乙亚氨酸乙酯(式I):
其中X为卤素,R为C1-C6的烷基。
本发明的一种制备化合物A05的方法包括,在反应溶剂中,在铜催化剂存在下,化合物A04和三氟甲基化试剂进行反应,再经过水解反应,制得化合物A05;
其中X为卤素,R为C1-C6的烷基。在一些实施方式中,X为溴,R为甲基或乙基。
在一些实施方式中,所述溶剂为DMF,DMAc,NMP和DMPU中的至少一种。
在一些实施方式中,所述反应的反应温度为50℃-200℃;或者所述反应的反应温度为100℃-200℃;或者所述反应的反应温度为140℃-160℃;或者所述反应的反应温度为150℃。
在一些实施方式中,所述铜催化剂为碘化亚铜,溴化亚铜,氯化亚铜,氧化亚铜和铜粉中的至少一种。
在一些实施方式中,所述三氟甲基化试剂为三氟乙酸钠,三氟乙酸锂,三氟乙酸钾,三氟乙酸铯,三氟乙酸甲酯,三氟乙酸乙酯,梅本试剂,三氟甲磺酸钠,三氟甲基亚磺酸钠,togin试剂和三氟甲基三甲基硅烷中的至少一种。
在一些实施方式中,所述水解反应是在碱性条件下进行的。
在一些实施方式中,水解反应的碱性试剂为氢氧化钠,氢氧化锂,氢氧化钾,氢氧化铯,碳酸锂,碳酸钠,碳酸钾,碳酸铯,氧化钙,氧化镁,氢氧化钙和氢氧化镁中至少一种。
在一些实施方式中,水解反应的温度为20℃-120℃;或者水解反应的温度为20℃-100℃;或者水解反应的温度为40℃-80℃;或者水解反应的温度为50℃-70℃;或者水解反应的温度为60℃。
在一些实施方式中,化合物A04是通过化合物A03在酸催化剂的作用下酯化反应生成的,
其中X为卤素,R为C1-C6的烷基。在一些实施方式中,X为溴,R为甲基或乙基。
在一些实施方式中,所述酸催化剂为硫酸,磷酸,多聚磷酸,五氧化二磷,浓盐酸,甲磺酸,对甲苯磺酸,甲磺酰氯,对甲苯磺酰氯,三氟甲磺酸和三氟甲磺酸酐中的至少一种。
在一些实施方式中,所述酯化反应的溶剂为C1-C6的醇。
在一些实施方式中,酯化反应的溶剂为甲醇或乙醇。
在一些实施方式中,所述反应的温度为溶剂的回流温度。
在一些实施方式中,化合物A03是通过化合物A02在溶剂中氧化反应生成的,
其中X为卤素。在一些实施方式中,X为溴。
在一些实施方式中,所述溶剂为二恶烷,THF,乙醚,甲基叔丁基醚,乙二醇二甲醚,甲醇,乙醇,异丙醇,二氯甲烷,氯仿,四氯化碳和1,2-二氯乙烷中至少一种。
在一些实施方式中,所述氧化反应的氧化试剂为次溴酸钠,二溴海因,NBS,NBA和溴素中至少一种。
在一些实施方式中,所述反应温度在0℃-30℃;或者所述反应温度在5℃-25℃。
在一些实施方式中,化合物A02是通过化合物A01在催化剂作用下卤化反应生成的,其中X为卤素,
在一些实施方式中,所述催化剂为四氯化锡,无水氯化锡,无水氯化锌,无水氯化铁,无水三氟甲磺酸钪,三氟化硼,三氟化硼-乙醚,无水溴化铝,硫酸,发烟硫酸,五氧化二磷,多聚磷酸和三氧化硫中至少一种。
在一些实施方式中,所述卤化反应的卤化试剂为二溴海因,NBS,NBA和溴素中至少一种。
在一些实施方式中,所述反应的反应温度在0℃-50℃;或者所述反应的反应温度为室温。
在一些实施方式中,化合物A01是通过化合物A00在催化剂作用下酰化反应生成的,
在一些实施方式中,所述催化剂为无水氯化铝,无水氯化锡,无水氯化锌,无水氯化铁,无水三氟甲磺酸钪,三氟化硼,三氟化硼-乙醚,无水溴化铝,硫酸,发烟硫酸,五氧化二磷,多聚磷酸和三氧化硫中至少一种。
在一些实施方式中,所述酰化反应的酰化试剂为乙酰氯,冰乙酸和乙酸酐中至少一种。
在一些实施方式中,所述反应的溶剂为二氯甲烷,硝基苯,对硝基甲苯,二硫化碳,石油醚,正己烷,环己烷,正庚烷,庚烷,四氯化碳,氯仿和1,2-二氯乙烷中的至少一种。
在一些实施方式中,所述反应的反应温度在-15℃-15℃;或者反应的反应温度在-5℃-5℃;或者反应温度为0℃。
本发明提供的一种辛波莫德中间体的制备方法,相对于现有技术而言避开了活泼的有机金属试剂(正丁基锂,格氏试剂等)与昂贵的钯催化剂的使用,解决了反应条件苛刻,安全性差,不利于工业放大,反应成本高,收率低等技术问题;本发明提供的技术方案操作简便,易于实施,反应条件温和,收率高,纯度高,成本低,适合工业化生产,达到了发明目的。
在本发明的描述中,需要理解的是,术语“第一”、“第二”仅用于描述目的,而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此,限定有“第一”、“第二”的特征可以明示或者隐含地包括一个或者更多个该特征。在本发明的描述中,“多个”的含义是两个或两个以上,除非另有明确具体的限定。
在本说明书的描述中,参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外,在不相互矛盾的情况下,本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
本发明中,如“化合物A05”和“式A05所示的化合物”和“A05”的表述,表示的是同一个化合物。
本发明中,mmol表示毫摩尔;h表示小时;g表示克;ml表示毫升;DMF表示N,N-二甲基甲酰胺;THF表示四氢呋喃;DCM表示二氯甲烷;togin试剂表示1-(三氟甲基)-3,3-二甲基-1,2-苯并碘氧杂戊环;CF3TMS表示三氟甲基三甲基硅烷;梅本试剂表示三氟甲基锍盐;DMAc表示N,N-二甲基乙酰胺;NMP表示N-甲基吡咯烷酮;DMPU表示N,N-二甲基丙烯基脲;NBS表示N-溴代丁二酰亚胺,NBA表示氮溴代乙酰胺;室温表示25℃±5℃。
具体实施方式
为了使本领域的技术人员更好地理解本发明的技术方案,下面进一步披露一些非限制实施例,对本发明作进一步的详细说明。
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。
实施例1化合物A01的制备
在0℃下向反应瓶中加入无水氯化铝9.98g,DCM 50ml,搅拌下滴加乙酰氯5.39g,搅拌10min后滴加A00 10.00g。0℃搅拌反应至HPLC检测无原料。将反应液倒入100g冰水混合物中,搅拌淬灭反应。分液,DCM萃取反应液50ml*1次,弃去水层,合并有机层。水洗有机层至pH=7,弃去水层,旋干有机层。得产品(无色油状物)A01 12.65g,收率100%。MS:[M+1]=203.14,核磁1H NMR(400MHz,CDCl3)δ7.89-7.87(d,J=8Hz,2H),7.30-7.28(d,J=8Hz,2H),2.57(s,3H),1.90-1.74(m,5H),1.48-1.23(m,6H)。
实施例2化合物A02-溴化物的制备
室温下反应瓶中加入A01 15.00g,二氯甲烷120ml,四氯化锡23.18g,搅拌下分两批加入二溴海因13.78g。室温避光搅拌反应至HPLC检测无原料。将反应液倒入120g冰水混合物,搅拌淬灭反应。分液,DCM萃取反应液120ml*1次,弃去水层,合并有机层。依次用120ml亚硫酸钠溶液(10%),120ml水洗涤有机层1次,弃去水层,旋干有机层。柱色谱分离产品,得产品(淡黄色油状物)A02-溴化物19.65g,收率94.2%。MS:[M+1]=281.05,核磁1H NMR(400MHz,CDCl3)δ8.11(s,1H),7.84-7.82(d,J=8Hz,1H),7.34-7.32(d,J=8Hz,1H),3.04-2.98(t,J=12Hz,1H),2.56(s,3H),1.90-1.77(m,5H),1.47-1.25(m,5H)。
实施例3化合物A03-溴化物的制备
室温下反应瓶中加入氢氧化钠7.11g,水50ml,搅拌下溶清并冷却至0℃,避光条件下向反应液中滴加溴素9.38g,控制滴速使内温小于5℃,避光搅拌1h制备次溴酸钠溶液。将A02-溴化物5.00g溶于二恶烷50ml中,搅拌下将上述溶液滴入新制的次溴酸钠溶液中,控制滴速使内温小于25℃,加毕后于25℃避光反应至HPLC检测无原料。向反应液中加入饱和亚硫酸钠溶液10ml淬灭反应,升温反应液至回流,向反应液中滴加硫酸调pH至1~3,反应液加水50ml搅拌下冷却至室温析晶。抽滤,水洗滤饼10ml*2次,烘干滤饼。得产品(白色粉末)A03-溴化物4.58g,收率91.0%。MS:[M-1]=281.02,核磁1H NMR(400MHz,CDCl3)δ8.28(s,1H),8.00-7.98(d,J=8Hz,1H),7.36-7.34(d,J=8Hz,1H),3.06-3.00(t,J=12Hz,1H),1.89-1.77(m,5H),1.47-1.24(m,5H)。
实施例4化合物A04-溴化物的制备
室温下反应瓶中加入A03-溴化物1.50g,甲醇15ml,搅拌下加入硫酸(98%)0.15g,搅拌下升温至回流,TLC检测至原料反应完全。停止反应,向反应液中加入饱和碳酸氢钠溶液15ml,EA萃取水层15ml*2次,合并有机层。依次用饱和碳酸氢钠15ml,水15ml洗涤有机层1次,弃去水层,旋干有机层,得产品(无色油状物)A04-溴化物1.49g,收率94.9%。MS:[M+1]=297.05,核磁1H NMR(400MHz,D2O)δ8.20(s,1H),7.92-7.90(d,J=8Hz,1H),7.31-7.29(d,J=8Hz,1H),3.90(s,3H),3.03-2.96(t,J=12Hz,1H),1.90-1.76(m,5H),1.51-1.25(m,5H)。
实施例5化合物A05的制备
室温下反应瓶中加入A04-溴化物2.00g,碘化亚铜12.82g,三氟乙酸钠9.15g,DMF100ml,氮气保护下升温至150℃搅拌反应。HPLC检测至原料反应完毕,停止反应,冷却反应液至室温,向反应液中加入EA 100ml搅拌均匀后抽滤,EA洗涤滤饼30ml*3次,合并滤液。水洗有机层100ml*2次,弃去水层,旋干有机层。向旋干物中加乙醇40ml,氢氧化钠0.81g,水10ml,60℃搅拌反应至HPLC检测原料反应完全。停止反应,冷却反应至室温,加盐酸(2M)20ml调pH=1~3,旋干反应液。向旋干物中加甲苯4ml,搅拌下升温至110℃,反应溶清后缓慢降温至10℃搅拌析晶,抽滤,甲苯洗涤滤饼1ml*2次,抽干滤饼,烘干滤饼。得产品(白色粉末)A05 1.36g,收率73.6%。MS:[M+1]=271.10,δ8.12(s,1H),8.14-8.12(d,J=8Hz,1H),7.72-7.70(d,J=8Hz,1H),2.86-2.80(t,J=12Hz,1H),1.79-1.24(m,10H)。
本发明的方法已经通过较佳实施例进行了描述,相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明内。
Claims (15)
2.根据权利要求1所述的方法,所述反应溶剂为DMF,DMAc,NMP和DMPU中的至少一种;所述反应的反应温度在50℃-200℃之间。
3.根据权利要求1所述的方法,所述铜催化剂为碘化亚铜,溴化亚铜,氯化亚铜,氧化亚铜和铜粉中的至少一种。
4.根据权利要求1所述的方法,所述三氟甲基化试剂为三氟乙酸钠,三氟乙酸锂,三氟乙酸钾,三氟乙酸铯,三氟乙酸甲酯,三氟乙酸乙酯,梅本试剂,三氟甲磺酸钠,三氟甲基亚磺酸钠,togin试剂和三氟甲基三甲基硅烷中的至少一种。
5.根据权利要求1所述的方法,所述水解反应是在碱性条件下进行的;水解反应的温度在20℃-120℃之间。
7.根据权利要求6所述的方法,所述酸催化剂为硫酸,磷酸,多聚磷酸,五氧化二磷,浓盐酸,甲磺酸,对甲苯磺酸,甲磺酰氯,对甲苯磺酰氯,三氟甲磺酸和三氟甲磺酸酐中的至少一种。
8.根据权利要求6所述的方法,所述酯化反应的溶剂为C1-C6的醇。
10.根据权利要求9所述的方法,所述溶剂为二恶烷,THF,乙醚,甲基叔丁基醚,乙二醇二甲醚,甲醇,乙醇,异丙醇,二氯甲烷,氯仿,四氯化碳和1,2-二氯乙烷中至少一种;所述氧化反应的氧化试剂为次溴酸钠、二溴海因,NBS,NBA和溴素中至少一种;所述反应温度在0℃-30℃之间。
12.根据权利要求11所述的方法,所述催化剂为四氯化锡,无水氯化锡,无水氯化锌,无水氯化铁,无水三氟甲磺酸钪,三氟化硼,三氟化硼-乙醚,无水溴化铝,硫酸,发烟硫酸,五氧化二磷,多聚磷酸和三氧化硫中至少一种;所述卤化反应的卤化试剂为二溴海因,NBS,NBA和溴素中至少一种。
14.根据权利要求13所述的方法,所述催化剂为无水氯化铝,无水氯化锡,无水氯化锌,无水氯化铁,无水三氟甲磺酸钪,三氟化硼,三氟化硼-乙醚,无水溴化铝,硫酸,发烟硫酸,五氧化二磷,多聚磷酸和三氧化硫中至少一种;所述酰化反应的酰化试剂为乙酰氯,冰乙酸和乙酸酐中至少一种。
15.根据权利要求14所述的方法,所述反应的溶剂为二氯甲烷,硝基苯,对硝基甲苯,二硫化碳,石油醚,正己烷,环己烷,正庚烷,庚烷,四氯化碳,氯仿和1,2-二氯乙烷中的至少一种;所述反应的反应温度在-15℃-15℃之间。
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