CN106661016B - 用于制备旋光异噁唑啉化合物的方法 - Google Patents
用于制备旋光异噁唑啉化合物的方法 Download PDFInfo
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- CN106661016B CN106661016B CN201580042943.3A CN201580042943A CN106661016B CN 106661016 B CN106661016 B CN 106661016B CN 201580042943 A CN201580042943 A CN 201580042943A CN 106661016 B CN106661016 B CN 106661016B
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- compound
- catalyst
- formula iii
- trifluoromethyl
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- 238000000034 method Methods 0.000 title claims abstract description 30
- -1 isoxazoline compound Chemical class 0.000 title description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 32
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000002367 halogens Chemical class 0.000 claims abstract description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 9
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 4
- 125000004970 halomethyl group Chemical group 0.000 claims abstract description 4
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 4
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims abstract description 3
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical group C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims abstract description 3
- 125000004775 chlorodifluoromethyl group Chemical group FC(F)(Cl)* 0.000 claims abstract description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 9
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical group [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 150000001805 chlorine compounds Chemical group 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 150000002547 isoxazolines Chemical class 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 241000157855 Cinchona Species 0.000 description 4
- DYDCUQKUCUHJBH-UWTATZPHSA-N D-Cycloserine Chemical group N[C@@H]1CONC1=O DYDCUQKUCUHJBH-UWTATZPHSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-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
- 238000004296 chiral HPLC Methods 0.000 description 4
- 238000004807 desolvation Methods 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 235000001258 Cinchona calisaya Nutrition 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 125000004438 haloalkoxy group Chemical group 0.000 description 3
- 125000004441 haloalkylsulfonyl group Chemical group 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229960000948 quinine Drugs 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 description 2
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 2
- 125000006771 (C1-C6) haloalkylthio group Chemical group 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- LKUDPHPHKOZXCD-UHFFFAOYSA-N 1,3,5-trimethoxybenzene Chemical compound COC1=CC(OC)=CC(OC)=C1 LKUDPHPHKOZXCD-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- IYGDLOMSJZQSGY-UHFFFAOYSA-N 1,2,4,5-tetrachloro-3,6-bis(chloromethyl)benzene Chemical compound ClCC1=C(Cl)C(Cl)=C(CCl)C(Cl)=C1Cl IYGDLOMSJZQSGY-UHFFFAOYSA-N 0.000 description 1
- WTBYGXCRADGSLY-UHFFFAOYSA-N 1,4-bis(bromomethyl)-2,3,5,6-tetrafluorobenzene Chemical compound FC1=C(F)C(CBr)=C(F)C(F)=C1CBr WTBYGXCRADGSLY-UHFFFAOYSA-N 0.000 description 1
- PGFAKOSRZYDFLR-UHFFFAOYSA-N 1,4-bis(chloromethyl)-2,3,5,6-tetramethylbenzene Chemical compound CC1=C(C)C(CCl)=C(C)C(C)=C1CCl PGFAKOSRZYDFLR-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- 125000004797 2,2,2-trichloroethoxy group Chemical group ClC(CO*)(Cl)Cl 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical class CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 235000021513 Cinchona Nutrition 0.000 description 1
- DYDCUQKUCUHJBH-UHFFFAOYSA-N D-Cycloserine Natural products NC1CONC1=O DYDCUQKUCUHJBH-UHFFFAOYSA-N 0.000 description 1
- 229910020261 KBF4 Inorganic materials 0.000 description 1
- 229910021135 KPF6 Inorganic materials 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229910020667 PBr3 Inorganic materials 0.000 description 1
- 229910019201 POBr3 Inorganic materials 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 229910006121 SOBr2 Inorganic materials 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229960003077 cycloserine Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000004774 dichlorofluoromethyl group Chemical group FC(Cl)(Cl)* 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- CZXGXYBOQYQXQD-UHFFFAOYSA-N methyl benzenesulfonate Chemical class COS(=O)(=O)C1=CC=CC=C1 CZXGXYBOQYQXQD-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
- C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/14—Nitrogen atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
- B01J2231/32—Addition reactions to C=C or C-C triple bonds
- B01J2231/324—Cyclisations via conversion of C-C multiple to single or less multiple bonds, e.g. cycloadditions
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Abstract
本发明涉及一种用于制备具有式(I)的化合物的方法
其中A1和A2是C‑H，或A1和A2中之一是C‑H并且另一个是N；R1是C1‑C4烷基、C1‑C4卤烷基或C3‑C6环烷基；每个R2独立地是溴、氯、氟或三氟甲基；R3是氢；R4是氢、卤素、甲基、卤甲基或氰基；或R3和R4一起形成一个桥接1,3‑丁二烯基团；R5是氯二氟甲基或三氟甲基；n是2或3；通过以下来制备：使一种具有式(II)的化合物
其中A1、A2、R1、R2、R3、R4、R5和n是如在上述式(I)之下所定义的，与羟胺、一种碱和一种手性催化剂反应，其特征在于该手性催化剂是一种具有式(III)的二聚手性催化剂其中R6、R7、R8、R9、R10和X是如在权利要求1中所定义的。
Description
本发明涉及一种用于制备具有环丝氨酸取代基的旋光异噁唑啉化合物(其可用作杀有害生物剂)的方法，并且涉及用于在所述过程中使用的催化剂。
例如在WO 2013/069731中描述了使用手性催化剂来制备旋光异噁唑啉化合物的方法。具有环丝氨酸取代基的旋光异噁唑啉化合物显示出了两种立构中心，立构中心构型对于化合物的生物活性十分重要。根据WO 2013/069731的单体的催化剂是基于金鸡纳生物碱并且针对异噁唑啉的形成显示出了高度的对映体选择性。然而，可以观察到环丝氨酸立构中心的显著的外消旋作用，该外消旋作用减少了反应的选择性并且因此减少了所希望的旋光产物的产量。尤其针对大规模生产这是一个显著的缺点。
因此，本发明的目的是提供一种用于制备具有环丝氨酸取代基的旋光异噁唑啉化合物的方法，该方法通过使用新型催化剂来改善所希望产物的对映体选择性。
因此，根据本发明，提供了一种用于制备具有式I的化合物的方法
其中
A1和A2是C-H，或A1和A2中之一是C-H并且另一个是N；
R1是C1-C4烷基、C1-C4卤烷基或C3-C6环烷基；
每个R2独立地是溴、氯、氟或三氟甲基；
R3是氢；
R4是氢、卤素、甲基、卤甲基或氰基；
或R3和R4一起形成一个桥接1,3-丁二烯基团；
R5是氯二氟甲基或三氟甲基；
n是2或3；
通过以下来制备：使一种具有式II的化合物
其中
A1、A2、R1、R2、R3、R4、R5和n是如在上述式I之下所定义的，
与羟胺、一种碱和一种手性催化剂反应，其特征在于该手性催化剂是一种具有式III的二聚手性催化剂
其中
每个R6是乙基或乙烯基；
R7、R8、R9和R10是卤素、氰基、C1-C6烷基、C1-C6卤烷基、C1-C6烷氧基、C1-C6卤烷氧基、C1-C6烷硫基、C1-C6卤烷硫基、C1-C6烷基磺酰基或C1-C6卤烷基磺酰基；
并且X是一种卤素阴离子、BF4 -、PF6 -、HSO4 -或一种C1-C3烷基磺酸盐、苯磺酸盐或甲基-苯磺酸盐。
取代基的定义中出现的烷基基团可以是直连或支链并且例如是甲基、乙基、正丙基、正丁基、正戊基、正己基、异丙基、正丁基、仲丁基、异丁基或叔丁基。烷氧基、卤烷基、卤烷氧基、烷基磺酰基和卤烷基磺酰基基团是衍生自所提及的烷基基团。
卤素通常是氟、氯、溴或碘，优选是氟、溴或氯。相应地，这也应用于与其他含义相结合的卤素，例如卤烷基或卤烷氧基。
卤烷基基团优选地具有一个从1至4个碳原子的链长。卤烷基是，例如氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、2,2,2-三氟乙基、2-氟乙基、2-氯乙基、五氟乙基、1,1-二氟-2,2,2-三氯乙基、2,2,3,3-四氟乙基和2,2,2-三氯乙基；优选三氯甲基、二氟氯甲基、二氟甲基、三氟甲基、以及二氯氟甲基。
烷氧基是，例如甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基；优选是甲氧基和乙氧基。卤烷氧基是，例如氟甲氧基、二氟甲氧基、三氟甲氧基、2,2,2-三氟乙氧基、1,1,2,2-四氟乙氧基、2-氟乙氧基、2-氯乙氧基、2,2-二氟乙氧基和2,2,2-三氯乙氧基，优选是二氟甲氧基、2-氯乙氧基和三氟甲氧基。烷硫基是，例如甲硫基、乙硫基、丙硫基、异丙硫基、正丁硫基、异丁硫基、仲丁硫基或叔丁硫基，优选是甲硫基和乙硫基。
在本发明的方法中，具有式III的化合物是优选的，其中X是卤代氨基、BF4 -或HSO4 -。
优选的C1-C3烷基磺酸盐和甲基-苯磺酸盐是甲磺酸盐、乙磺酸盐、丙磺酸盐、苯磺酸盐和4-甲基-苯磺酸盐。
如果n是2，具有式I的化合物优选是由具有式Ia的化合物表示的
根据本发明的方法尤其适用于制备具有式I的化合物，其中
A1和A2是C-H；
R1是C1-C4烷基；
每个R2独立地是氯、氟或少三氟甲基；优选是氯或氟；
R3是氢；
R4是氢、卤素、甲基、卤甲基或氰基；优选是甲基；
R5是三氟甲基；并且
n是2或3。
具有式III的二聚手性催化剂
其中
每个R6是乙基或乙烯基；
R7、R8、R9和R10是卤素、氰基、C1-C6烷基、C1-C6卤烷基、C1-C6烷氧基、C1-C6卤烷氧基、C1-C6烷硫基、C1-C6卤烷硫基、C1-C6烷基磺酰基或C1-C6卤烷基磺酰基；
并且
X是卤代氨基、BF4 -或PF6 -；是新颖的并且是尤其被开发用于根据本发明的方法。因此，具有式III的二聚手性催化剂代表了本发明的另外的目的。
优选的具有式III的催化剂是以下那些，其中
每个R6是乙烯基；
取代基R7、R8、R9和R10中的每一个具有相同的含义并且代表卤素，并且X是氯化物、溴化物或BF4 -，特别是氯化物或溴化物。
尤其优选的具有式III的催化剂是以下那些，其中
每个R6是乙烯基；
取代基R7、R8、R9和R10中的每一个具有相同的含义并且代表氟或氯，尤其是氟；并且X是氯化物或溴化物。
具有式III的催化剂可以通过以下来制备
使一种具有式IV的化合物
其中
R6是乙基或乙烯基；
与一种具有式V的化合物发生反应
其中R6、R7、R8、R9、R10和X是如针对以上具有式III的化合物所定义的。该方法优选在有机溶剂中进行，例如甲苯或乙腈或甲醇。例如在WO2013/069731中，描述了单体手性催化剂的制备方法。根据本发明，所述的方法可类似地用来制备具有式III的催化剂。具有式IV的化合物是已知的，并且是可商购的或可以根据已知的方法来制备。
例如，具有式V的化合物可以通过使具有式(VI)的化合物
与一种适合的卤化试剂(例如SOCl2、POCl3、SOBr2、POBr3、PBr3、PCl3、HBr或HCl)发生反应来制备。
另外，具有式V的化合物可以例如通过使具有式(VII)的化合物
(其中R7、R8、R9和R10是如在上述式V之下所定义的)与一种适合的卤化试剂(例如Cl2、Br2、NCS或NBS)发生反应来制备。
另外，具有式V的化合物可以例如通过使具有式(VIII)的化合物
(其中R7、R8、R9和R10是如在上述式V之下所定义的)与一种适合的卤甲基化试剂(例如CH2O/HCl、CH2O/HCl/ZnCl2、CH2O/HBr)发生反应来制备。
例如可以根据WO 2011/067272，具体是在18、19页上方案3中显示的来制备具有式II的化合物。
根据本发明的方法优选是在适合的有机溶剂(例如二氯甲烷、1,2-二氯乙烷、甲苯、氯苯、氯仿、甲基叔丁基醚、异丙醇、乙醇、四氢呋喃、2-甲基四氢呋喃、乙腈、丙腈、2-甲基丙腈、丁腈，优选是1,2-二氯乙烷、2-甲基四氢呋喃、乙腈或二氯甲烷)中，在-78℃至60℃之间的温度(优选在-20℃和+20℃之间)下，并且以例如0.1M至1M之间的稀释度进行的。该反应时间通常是在30分钟和48小时之间，优选在1小时和4小时之间。催化剂的量通常是从0.01至0.4摩尔当量，优选是从0.02至0.2摩尔当量。羟胺的量是从1至10当量，优选是从1.0至1.2当量。此类反应通常是在一种碱的存在下进行。适合的碱包括碱性氢氧化物，例如氢氧化锂、氢氧化钠或氢氧化钾，优选氢氧化钠，以在0.05和2当量之间的常用量。优选地，使用的碱的量是从0.05至1.0当量。该反应可以在水的存在下进行。
制备实例：
以下缩写用于本节：s＝单峰；bs＝宽单峰；d＝二重峰；dd＝双二重峰；dt＝双三重峰；t＝三重峰；tt＝三三重峰；q＝四重峰；sept＝七重峰；m＝多重峰；Me＝甲基；Et＝乙基；Pr＝丙基；Bu＝丁基；M.p.＝熔点；RT＝保留时间；M＝分子质量。
以下的LC-MS方法用来表征这些化合物：
方法A
光谱记录在来自沃特斯公司的质谱仪(SQD或ZQ单四极杆质谱仪)上，其装备有一种电喷射源(极性：正离子或负离子，毛细管：3.00kV，锥孔范围：30-60V，萃取器：2.00V，源温度：150℃，去溶剂化温度：350℃，锥孔气体流量：0L/Hr，去溶剂化气体流量：650L/Hr，质量范围：100至900Da)和一种来自沃特斯公司的Acquity UPLC：二元泵，加热柱室以及二极管阵列检测器。溶剂脱气装置，二元泵，加热柱室以及二极管阵列检测器。柱：沃特斯UPLCHSS T3，1.8μm，30x2.1mm，温度：60℃，DAD波长范围(nm)：210至500，溶剂梯度：A＝水+5％MeOH+0.05％HCOOH，B＝乙腈+0.05％HCOOH：梯度：梯度：0min 0％B，100％A；1.2-1.5min100％B；流量(ml/min)0.85。
方法B
光谱记录在来自沃特斯公司的质谱仪(SQD或ZQ单四极杆质谱仪)上，其装备有一种电喷射源(极性：正离子或负离子，毛细管：3.00kV，锥孔范围：30-60V，萃取器：2.00V，源温度：150℃，去溶剂化温度：350℃，锥孔气体流量：0L/Hr，去溶剂化气体流量：650L/Hr，质量范围：100至900Da)和一种来自沃特斯公司的Acquity UPLC：二元泵，加热柱室以及二极管阵列检测器。溶剂脱气装置，二元泵，加热柱室以及二极管阵列检测器。柱：沃特斯UPLCHSS T3，1.8μm，30x2.1mm，温度：60℃，DAD波长范围(nm)：210至500，溶剂梯度：A＝水+5％MeOH+0.05％HCOOH，B＝乙腈+0.05％HCOOH：梯度：梯度：0min 0％B，100％A；2.7-3.0min100％B；流量(ml/min)0.85。
手性HPLC是在沃特斯UPLC–Hclass，DAD检测器沃特斯UPLC上进行，采用柱DaicelID，5μl，0.46cm x 25cm，流动相：Hept/EtOAc 70/30，流速：1.0mL/min，检测：265nm，样品浓度：1mg/mL在DCM/iPrOH 50/50中，注入：2μl。自由基代表甲基基团。
根据WO 2013/069731来制备(XI)。
将[2,3,5,6-四氟-4-(羟甲基)苯基]甲醇XV(5.0g)与在乙酸中的HBr(5.7mol/L，41ml)混合。将该合成的深橙色溶液在环境温度下搅拌16小时。添加10mL的乙酸并且搅拌再继续20小时。处理(work up)：将橙色悬浮液用乙酸乙酯进行稀释-->橙色溶液。将该溶液转移至另外的漏斗中并且将其滴加至冷的饱和Na2CO3溶液中(气体释放)。在添加结束时，将该反应化合物再搅拌20分钟。然后将水层(悬浮液)用乙酸乙酯萃取两次。将该有机层用饱和的Na2CO3溶液洗涤两次并且用盐水洗涤一次。然后将其经Na2SO4干燥、过滤并且蒸发以给出呈淡黄色固体的7.5g的产物XVI。
1H NMR(400MHz,CDCl3)δ＝4.52(s,4H)。19F NMR(376MHz,CDCl3)δ＝142.36。
将无水乙腈(200ml)添加至奎宁(6.5g，西格玛奥德里奇(Sigma Aldrich))和1,4-双(溴甲基)-2,3,5,6-四氟-苯(12.5g)的混合物中并且将其在40℃下，在氩气下搅拌过夜。将固体过滤，并且用乙腈洗涤两次并用二乙醚洗涤一次。将其在减压下干燥以给出呈米色固体的18.0g的产物XVII。
1H NMR(400MHz,DMSO)δ＝8.83(d,2H,J＝4.4),8.02(d,2H,J＝8.3),7.80-7.79(m,2H),7.51(d,2H,J＝4.9),7.44(br.s,2H),6.81(br.s,2H),6.58(br.s,2H),5.82-5.76(m,2H),5.62(d,2H,J＝12.8),5.13-5.03(m,4H),4.83(d,2H,J＝12.8),4.20(br.s,6H),4.03(s,6H),3.86(br.s,2H),3.68(br.s,2H),2.87(br.s,2H),2.24(br.s,2H),2.17(br.s,2H),2.05(d,2H),1.89(br.s,2H),1.44(t,2H)。
LC-MS(ES+):m/z＝413(M-569)RT＝0.76(方法A)
将1,2,4,5-四氯-3,6-双(氯甲基)苯(482mg)和奎宁(1.0g，西格玛奥德里奇(Sigma Aldrich))与无水乙腈(15ml)进行混合。将该反应混合物在室温下搅拌一晚并且在65℃下搅拌5天。然后将其进行过滤并且将固体用冷的乙腈洗涤两次以给出呈米色固体的959mg的产物XIX。
1H NMR(400MHz,DMSO)δ＝8.83(d,2H,J＝4.4),8.02(d,2H,J＝9.2),7.80(d,2H,J＝4.4),7.50(d,2H),7.40(m,2H),6.99(d,2H),6.60(br.s,2H),5.89-5.74(m,4H),5.08-5.00(m,6H),4.51-4.45(m,3H),4.26-4.24(m,2H),4.07-4.00(m,7H),3.77(br.s,2H),2.78(d,2H),2.17(br.s,2H),2.07(m,4H),1.98(br.s,2H),1.84(br.s,2H),1.41-1.38(m,2H)。LC-MS(ES-):m/z＝445(M-513)RT＝0.83(方法A)
将1,4-双(氯甲基)-2,3,5,6-四甲基-苯(428mg)和奎宁(1.2g，西格玛奥德里奇(Sigma Aldrich))与无水乙腈(18.5mL)在氩气下进行混合。将其在室温下搅拌过夜并且在55℃下搅拌2天。将反应混合物冷却至室温并且缓慢倒入二乙醚中。将悬浮液过滤以给出呈浅棕色固体的1.07g的XXI。
1H NMR(400MHz,DMSO)δ＝8.85-8.83(m,2H),8.02(d,3H,J＝9.2),7.82(t,2H,J＝2x5.4),7.52-7.49(m,4H),7.04(d,1H,J＝3.7),6.98(d,1H,J＝3.7),6.78(d,2H,J＝12.1),5.81-5.72(m,4H),5.09-5.00(m,5H),4.86(d,2H,J＝14.3),4.23(br.s,4H),4.04(d,6H,J＝12.1),3.55(d,4H,J＝9.9),3.37-1.37(m,24H)。LC-MS(ES-):m/z＝484(M-394)RT＝0.72(方法A)
向在乙腈(4ml)中的XVII的悬浮液(500mg，0.508mmol)中添加KBF4(0.320g，2.54mmol)。将该反应混合物在室温搅拌2.5天。将乙醚添加至反应混合物中。将生成的沉淀物滤出并且用水洗涤。将该沉淀物溶解于甲醇和二氯甲烷的混合物中，并且在减压下蒸发以提供呈米色固体的XXXII(474mg)。
IR(薄膜)1621、1496、1292、1241、1025cm-1
向在乙腈(4ml)中的催化剂XVII的悬浮液(500mg，0.508mmol)中添加KPF6(0.467g，2.54mmol)。将该反应混合物在室温搅拌2.5天。将乙醚添加至反应混合物中。将生成的沉淀物滤出并且用水洗涤。将该沉淀物溶解于甲醇和二氯甲烷的混合物中，并且在减压下蒸发以提供呈棕色固体的XXXIII(433mg)。
IR(薄膜)1621、1497、1293、1241、1026、928、826cm-1
将根据本发明的催化剂的选择性与根据现有技术的结构上接近的催化剂进行比较。结果在下表1中给出(自由基代表甲基基团)：
通用程序(基于WO 2013/069731)：
将0.32mmol的XXIV(E/Z>99:1，R/S＝99:1)溶解于4mL的二氯甲烷中。添加0.06mmol或0.03mmol的催化剂(如下所示)。将反应混合物冷却至-20℃，顺序地添加0.7mmol的10M氢氧化钠溶液、0.054ml的水和0.64mmol的50％的水性羟胺。将反应混合物在-20℃下大力搅拌20h并且通过手性HPLC(非对映异构体的比例)和1H NMR(转化)进行分析。
表1：与现有技术中已知的催化剂的对比数据：
(*)起始材料的86％的转化。对于所有其他运行，观察到了起始材料的高于>95％的转化。
根据WO 2011/104089和WO 2011/067272的化合物XXX
根据WO 2002/05953的化合物XXXI
表2：在不同的反应条件下根据本发明的催化剂的实例
通用程序：
将0.32mmol的XXIV(E/Z>99:1，R/S＝99:1)溶解于4mL的二氯甲烷中。添加催化剂0.06mmol。将反应混合物冷却至-20℃，顺序地添加0.7mmol的10M氢氧化钠溶液、0.054ml的水和0.64mmol的50％的水性羟胺。将反应混合物在-20℃下大力搅拌20h并且通过手性HPLC(非对映异构体的比例)和1H NMR(转化)进行分析。
对于所有运行，观察到了起始材料的高于>95％的转化。
表3：在不同的反应条件下根据本发明的催化剂的选择性：
通用程序：
将XXVI(E/Z>99:1，R/S>99:1)和催化剂XVII在给定溶剂中在反应温度下进行搅拌。顺序地添加碱的水性5-10M溶液和50％的水性羟胺。将该反应混合物在给定温度下大力搅拌。对其通过手性HPLC(非对映异构体的比例)和1H NMR使用1,3,5-三甲氧基苯作为标准品(产量确定)进行分析。
Claims (7)
1.一种用于制备具有式I的化合物的方法
其中
A1和A2是C-H，或A1和A2中之一是C-H并且另一个是N；
R1是C1-C4烷基、C1-C4卤烷基或C3-C6环烷基；
每个R2独立地是溴、氯、氟或三氟甲基；
R3是氢；
R4是氢、卤素、甲基、卤甲基或氰基；
或R3和R4一起形成一个桥接1,3-丁二烯基团；
R5是氯二氟甲基或三氟甲基；
n是2或3；
通过以下来制备：使一种具有式II的化合物
其中
A1、A2、R1、R2、R3、R4、R5和n是如在上述式I之下所定义的，与羟胺、一种碱和一种手性催化剂反应，其特征在于该手性催化剂是一种具有式III的二聚手性催化剂
其中
每个R6是乙烯基；
取代基R7、R8、R9和R10中的每一个具有相同的含义并且代表卤素，并且X是氯离子或溴离子或BF4-或PF6 -。
2.根据权利要求1所述的方法，其中在具有式III的催化剂中
每个R6是乙烯基；
取代基R7、R8、R9和R10中的每一个具有相同的含义并且代表氟或氯；并且
X是氯离子或溴离子。
3.根据权利要求1所述的方法，其中羟胺的量是从1至10当量。
4.根据权利要求1所述的方法，其中碱的量是从0.05至2当量。
5.根据权利要求1所述的方法，其中催化剂的量是从0.01至0.4当量。
6.一种具有式III的化合物
其中
每个R6是乙烯基；
取代基R7、R8、R9和R10中的每一个具有相同的含义并且代表卤素，并且X是氯离子或溴离子或BF4-或PF6 -。
7.根据权利要求6所述的具有式III的化合物，其中
每个R6是乙烯基；
取代基R7、R8、R9和R10中的每一个具有相同的含义并且代表氟或氯；并且
X是氯离子或溴离子。
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| PCT/EP2015/067894 WO2016023787A1 (en) | 2014-08-11 | 2015-08-04 | Process for the preparation of optically active isoxazoline compounds |
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| CN102822168A (zh) * | 2010-02-25 | 2012-12-12 | 先正达参股股份有限公司 | 制备异恶唑啉衍生物的方法 |
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| CN102822168A (zh) * | 2010-02-25 | 2012-12-12 | 先正达参股股份有限公司 | 制备异恶唑啉衍生物的方法 |
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| EP3180336B1 (en) | 2018-09-26 |
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| EP3180336A1 (en) | 2017-06-21 |
| SI3180336T1 (sl) | 2019-01-31 |
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| BR112017002507B1 (pt) | 2021-05-04 |
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