CN115197086A - Preparation method of difluoro methoxy-containing m-diamide compound - Google Patents
Preparation method of difluoro methoxy-containing m-diamide compound Download PDFInfo
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- CN115197086A CN115197086A CN202110402017.XA CN202110402017A CN115197086A CN 115197086 A CN115197086 A CN 115197086A CN 202110402017 A CN202110402017 A CN 202110402017A CN 115197086 A CN115197086 A CN 115197086A
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- acid
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 64
- -1 diamide compound Chemical class 0.000 claims abstract description 50
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 239000002904 solvent Substances 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 18
- 229940125782 compound 2 Drugs 0.000 claims abstract description 12
- 229940126214 compound 3 Drugs 0.000 claims abstract description 10
- 229940125904 compound 1 Drugs 0.000 claims abstract description 9
- 229940125898 compound 5 Drugs 0.000 claims abstract description 5
- 238000006482 condensation reaction Methods 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 81
- 239000001257 hydrogen Substances 0.000 claims description 57
- 229910052739 hydrogen Inorganic materials 0.000 claims description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- 150000002431 hydrogen Chemical class 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 18
- 239000011737 fluorine Substances 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 13
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 13
- 239000008096 xylene Substances 0.000 claims description 13
- 239000003638 chemical reducing agent Substances 0.000 claims description 12
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 12
- XPXMKIXDFWLRAA-UHFFFAOYSA-N hydrazinide Chemical compound [NH-]N XPXMKIXDFWLRAA-UHFFFAOYSA-N 0.000 claims description 12
- 238000006722 reduction reaction Methods 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 10
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 9
- 238000005893 bromination reaction Methods 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- FKTXDTWDCPTPHK-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical group FC(F)(F)[C](F)C(F)(F)F FKTXDTWDCPTPHK-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 6
- 235000011054 acetic acid Nutrition 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 150000001340 alkali metals Chemical class 0.000 claims description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 6
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 5
- 235000019260 propionic acid Nutrition 0.000 claims description 5
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 5
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- XTEGARKTQYYJKE-UHFFFAOYSA-M Chlorate Chemical compound [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 claims description 4
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical group ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-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
- 150000003842 bromide salts Chemical class 0.000 claims description 4
- 229940117389 dichlorobenzene Drugs 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims description 4
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 4
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 4
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 3
- BZSXEZOLBIJVQK-UHFFFAOYSA-N 2-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=CC=C1C(O)=O BZSXEZOLBIJVQK-UHFFFAOYSA-N 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000005347 halocycloalkyl group Chemical group 0.000 claims description 3
- 125000006341 heptafluoro n-propyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- RPAJSBKBKSSMLJ-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;hydrochloride Chemical class Cl.OC(=O)[C@@H](N)CCC(O)=O RPAJSBKBKSSMLJ-DFWYDOINSA-N 0.000 claims description 2
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 claims description 2
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 claims description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 2
- 229910001919 chlorite Inorganic materials 0.000 claims description 2
- 229910052619 chlorite group Inorganic materials 0.000 claims description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 2
- QBWCMBCROVPCKQ-UHFFFAOYSA-N chlorous acid Chemical compound OCl=O QBWCMBCROVPCKQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 claims description 2
- PBWZKZYHONABLN-UHFFFAOYSA-N difluoroacetic acid Chemical compound OC(=O)C(F)F PBWZKZYHONABLN-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 125000004441 haloalkylsulfonyl group Chemical group 0.000 claims description 2
- 150000004679 hydroxides Chemical class 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 2
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 2
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims 1
- 238000000926 separation method Methods 0.000 abstract description 24
- 238000001816 cooling Methods 0.000 abstract description 10
- 239000000047 product Substances 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000003541 multi-stage reaction Methods 0.000 abstract description 3
- 125000001246 bromo group Chemical group Br* 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- 238000001514 detection method Methods 0.000 description 20
- 239000007788 liquid Substances 0.000 description 20
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 20
- 238000001819 mass spectrum Methods 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- 239000007787 solid Substances 0.000 description 13
- FTQWRYSLUYAIRQ-UHFFFAOYSA-N n-[(octadecanoylamino)methyl]octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NCNC(=O)CCCCCCCCCCCCCCCCC FTQWRYSLUYAIRQ-UHFFFAOYSA-N 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- UUKWKUSGGZNXGA-UHFFFAOYSA-N 3,5-dinitrobenzamide Chemical compound NC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 UUKWKUSGGZNXGA-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- GPSINNCBFURFNQ-UHFFFAOYSA-N cyclopropylhydrazine Chemical compound NNC1CC1 GPSINNCBFURFNQ-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 10
- 239000012043 crude product Substances 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 235000010265 sodium sulphite Nutrition 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 239000000575 pesticide Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- QSLZKWPYTWEWHC-UHFFFAOYSA-N broflanilide Chemical compound C=1C=CC(C(=O)NC=2C(=CC(=CC=2Br)C(F)(C(F)(F)F)C(F)(F)F)C(F)(F)F)=C(F)C=1N(C)C(=O)C1=CC=CC=C1 QSLZKWPYTWEWHC-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-UHFFFAOYSA-N 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- FUAKOESVWYJBLR-UHFFFAOYSA-N CC1=CC=CC=C1.C1CC1NN Chemical compound CC1=CC=CC=C1.C1CC1NN FUAKOESVWYJBLR-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- KWXJOFAYHXMEDR-UHFFFAOYSA-N hydrazine;toluene Chemical compound NN.CC1=CC=CC=C1 KWXJOFAYHXMEDR-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- FIARMZDBEGVMLV-UHFFFAOYSA-N 1,1,2,2,2-pentafluoroethanolate Chemical group [O-]C(F)(F)C(F)(F)F FIARMZDBEGVMLV-UHFFFAOYSA-N 0.000 description 1
- 125000006426 1-chlorocyclopropyl group Chemical group [H]C1([H])C([H])([H])C1(Cl)* 0.000 description 1
- 125000006420 1-fluorocyclopropyl group Chemical group [H]C1([H])C([H])([H])C1(F)* 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OYZWEOORLJBPMA-UHFFFAOYSA-N 3,5-difluorobenzoyl chloride Chemical compound FC1=CC(F)=CC(C(Cl)=O)=C1 OYZWEOORLJBPMA-UHFFFAOYSA-N 0.000 description 1
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 1
- USEDMAWWQDFMFY-UHFFFAOYSA-N 4-cyanobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(C#N)C=C1 USEDMAWWQDFMFY-UHFFFAOYSA-N 0.000 description 1
- CZKLEJHVLCMVQR-UHFFFAOYSA-N 4-fluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C=C1 CZKLEJHVLCMVQR-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000011365 complex material Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- PVFTVTSMZMQOLM-UHFFFAOYSA-N cyclopropane;formaldehyde Chemical compound O=C.C1CC1 PVFTVTSMZMQOLM-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- OKNLBTNZLUNRDW-UHFFFAOYSA-N hydrogen peroxide;hydrobromide Chemical compound Br.OO OKNLBTNZLUNRDW-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- QZUPTXGVPYNUIT-UHFFFAOYSA-N isophthalamide Chemical class NC(=O)C1=CC=CC(C(N)=O)=C1 QZUPTXGVPYNUIT-UHFFFAOYSA-N 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of a compound containing difluoromethoxy-diamide, which comprises the following steps: the compound 1 and the compound 2 are subjected to condensation reaction to obtain a compound 3, the compound 3 is reduced to obtain a compound 4, the compound 4 and the compound 5 are subjected to reaction to obtain a compound 6, the compound 6 and the compound 7 are subjected to reaction to obtain a compound 8, and the compound 8 is brominated to obtain the difluoromethoxy-containing diamide compound shown in the formula I. The multi-step reaction is almost quantitative, the byproducts are few, the deep cooling high-temperature reaction is avoided, the bromine atoms can be introduced into specific sites in the last step, the yield is high, the method is more suitable for industrial production, and meanwhile, the method can obtain high-purity products without separation until original medicines are synthesized or by simple solvent separation in each step.
Description
Technical Field
The invention belongs to the technical field of pesticide synthesis, relates to a preparation method of a m-diamide compound, and particularly relates to a preparation method of a Broflanilide-like difluoro methoxyl-containing m-diamide compound.
Background
The m-diamide compound represented by Broflanilide increasingly becomes a research hotspot of pesticide companies at home and abroad due to the characteristics of unique action mechanism, novel action target and environmental friendliness, and the Broflanilide compound becomes one of the most potential pesticide research and development directions.
In the synthesis of the difluoromethoxy diamide compound disclosed in CN105873901A (route I), strong base lithium diisopropylamide is used in the first-step reaction process, the cost is high, deep cooling at-70 ℃ is required, the industrialization is difficult, the single-step yield is only 34%, and the industrial production is not facilitated; the synthesis of the difluoromethoxy-containing diamide compound disclosed in WO2014161850A1 (route two) requires amino group protection and then deprotection twice, and finally obtains the target compound, and the operation is complex and raw material waste is easily caused.
Route one:
and a second route:
the synthesis of the difluoromethoxy-diamide compound can also be carried out by referring to the Broflanilide process, and the following three routes are mainly adopted.
And a third route:
particularly, the third problem of the route is that the process route is long, bisamide is generated when the raw pesticide is finally synthesized, the dosage of acid is at least 2.4 times of that of amine, alkali is added for hydrolysis, and the recovery operation of acid is increased.
And a fourth route:
the fourth route also has the problem of long process route, the yield of heptafluoro isopropyl in the eighth step is only 63 percent, the purification is difficult, and expensive NBS reagent is used when the original medicine is finally synthesized by bromination.
Route five:
the fifth route is the same as the first route, and has the problems of strong alkali requirement, low yield, difficult industrialization and the like.
As described above, conventional methods for synthesizing difluoromethoxy-containing isophthalamide compounds or Broflanilide have disadvantages such as environmental pollution, low yield, and difficulty in purification, and therefore, development of a more suitable synthesis process is urgently required.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of a m-diamide compound, in particular to a preparation method of a difluoromethoxy-containing m-diamide compound.
In order to achieve the purpose, the invention adopts the following technical scheme:
on one hand, the invention provides a preparation method of a difluoromethoxy-containing m-diamide compound shown in formula I, which comprises the following steps:
(1) Compound 1 and compound 2 are condensed to obtain compound 3 (in the present invention, referred to as nitroamide for short), the reaction formula is as follows:
(2) The compound 3 is subjected to reduction reaction to obtain a compound 4 (referred to as aminoamide in the invention for short), and the reaction formula is as follows:
(3) Compound 4 is reacted with compound 5 to give compound 6 (referred to herein simply as cyclopropylaminoamide) according to the following reaction scheme:
(4) Compound 6 reacts with compound 7 to give compound 8 (abbreviated as bisamide in the present invention) according to the following reaction formula:
(5) Brominating the compound 8 to obtain a difluoromethoxy-containing m-diamide compound shown in the formula I, wherein the reaction formula is as follows:
wherein Z 1 、Z 2 、Z 3 、Z 4 、Z 5 Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro and C 1 -C 6 Alkyl radical, C 1 -C 6 A cycloalkyl group, a,C 1 -C 6 Haloalkyl, C 1 -C 6 Halogenocycloalkyl, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylsulfinyl radical, C 1 -C 6 Haloalkylsulfinyl radical, C 1 -C 6 Alkylsulfonyl or C 1 -C 6 A haloalkylsulfonyl group;
R 1 selected from hydrogen or fluorine;
R 2 selected from hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl or C 3 -C 8 A halocycloalkyl group;
R 3 selected from hydrogen or halogen;
W 1 and W 2 Independently an oxygen atom or a sulfur atom.
The synthetic route of the invention is shorter, the multi-step reaction is quantitative reaction, the by-product is less, the deep cooling high temperature is avoided, the bromine atom can be introduced into the specific site in the last step, the yield is high, the invention is more suitable for industrialized production, and simultaneously, the route can obtain the high-purity product without separation until the original medicine is synthesized or by simple solvent separation in each step.
The alkyl group in the present invention means a straight-chain or branched alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and the like. Haloalkyl refers to a group in which a hydrogen atom on an alkyl group is replaced with one or more halogen atoms. Alkoxy means a group having an oxygen atom attached to the terminal of an alkyl group, such as methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, and the like. Haloalkoxy refers to a group in which a hydrogen atom on an alkoxy group is replaced with one or more halogen atoms. Halogen is F, cl, br or I.
The term "C" as used herein 1 -C 6 Alkyl "refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, including, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentylIsopentyl, n-hexyl, and the like. The term "C 1 -C 6 Alkoxy "means a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, and the like. "C 1 -C 6 Haloalkyl "refers to a straight or branched chain alkyl group of 1 to 6 carbon atoms substituted with a halogen atom, including without limitation trifluoromethyl, difluoromethyl, 1-trifluoroethyl, pentafluoroethyl, heptafluoro-n-propyl, heptafluoro-isopropyl, and the like. ' C 1 -C 6 Haloalkoxy "means a straight or branched chain alkoxy group of 1 to 6 carbon atoms substituted with a halogen atom, and includes, without limitation, trifluoromethoxy, difluoromethoxy, 2-trifluoroethoxy, pentafluoroethoxy, heptafluoro-n-propoxy, heptafluoro-isopropoxy, and the like. The term "C" as used herein 3 -C 8 Cycloalkyl "refers to a cyclic alkyl group having 3 to 8 carbon atoms and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The term "C" as used in the present invention 3 -C 8 Halocycloalkyl "refers to a cyclic alkyl group of 3 to 8 carbon atoms having halogen substitution in the ring, including without limitation 1-chlorocyclopropyl, 1-fluorocyclopropyl, perfluorocyclopropyl, 1-chlorocyclobutyl, 1-chlorocyclopentyl, and the like.
In the present invention, C before the specific group 1 -C 6 、C 3 -C 8 Etc. represent the number of carbon atoms contained in the radical, e.g. C 1 -C 6 Represents a group having 1,2, 3, 4, 5 or 6 carbon atoms, C 3 -C 8 Represents a group having 3, 4, 5, 6, 7 or 8 carbon atoms, C 2 -C 4 Represents a group in which the number of carbon atoms may be 2, 3 or 4, and so on.
In the present invention, Z is a preferable embodiment 1 、Z 2 、Z 3 、Z 4 、Z 5 Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutylButyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, trifluoromethyl, pentafluoroethyl, heptafluoro-n-propyl, heptafluoro-isopropyl, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, methylsulfinyl, trifluoromethylsulfinyl, methylsulfonyl or trifluoromethylsulfonyl; r 2 Selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, neopentyl, isopentyl, 4-methyl-2-pentyl, n-hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoroisopropyl, cyclopropyl, cyclobutyl, cyclopentyl, perfluorocyclopropyl, perfluorocyclobutyl or perfluorocyclopentyl; r 3 Selected from hydrogen, fluorine or chlorine.
In the present invention, as a more preferable embodiment, Z 1 、Z 2 、Z 3 、Z 4 、Z 5 Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylsulfonyl or trifluoromethylsulfonyl; r 1 Selected from hydrogen or fluorine; r 2 Selected from hydrogen or methyl; r 3 Selected from hydrogen or chlorine; w is a group of 1 And W 2 Selected from oxygen.
In the present invention, particularly preferably, Z 1 、Z 2 、Z 3 、Z 4 、Z 5 Each independently selected from hydrogen, fluorine, chlorine, cyano; r 1 Selected from hydrogen or fluorine; r 2 Selected from hydrogen; r 3 Selected from hydrogen, W 1 And W 2 Selected from oxygen.
Preferably, the solvent for the condensation reaction in step (1) is any one or a combination of at least two of dichloromethane, 1, 2-dichloroethane, chloroform, benzene, toluene, xylene, chlorobenzene or dichlorobenzene, preferably toluene and/or xylene.
Preferably, in step (1), the molar ratio of compound 1 to compound 2 is (1 to 1.5): 1, for example, 1.
Preferably, in step (1), the mass ratio of the compound 2 to the solvent is 1 (1 to 5), such as 1.
Preferably, the temperature of the reaction in step (1) is 40 to 180 ℃, e.g. 40 ℃,50 ℃,60 ℃,80 ℃,100 ℃, 120 ℃, 140 ℃, 150 ℃, 170 ℃ or 180 ℃, preferably 110 to 140 ℃.
Preferably, the reaction time in step (1) is 3 to 8 hours, such as 3 hours, 3.3 hours, 3.5 hours, 3.8 hours, 4 hours, 4.5 hours, 4.8 hours, 5 hours, 5.3 hours, 5.5 hours, 5.8 hours, 6 hours, 6.5 hours, 6.8 hours, 7 hours, 7.5 hours, 7.8 hours or 8 hours, preferably 4 to 6 hours.
Preferably, the solvent for the reaction in step (2) is one or a combination of at least two of methanol, ethanol, acetonitrile, benzene, toluene, xylene, chlorobenzene and ethyl acetate, preferably methanol, toluene and ethyl acetate.
Preferably, the catalyst for the reduction reaction in step (2) is any one of palladium carbon, platinum carbon or raney nickel, and is preferably palladium carbon or platinum carbon catalyst.
Preferably, the mass ratio of the compound 3 (nitroamide) to the solvent in the step (2) is 1: (2 to 8), preferably 1: (3-5).
Preferably, the mass ratio of the compound 3 (nitroamide) to the catalyst in the step (2) is 1 (0.001-0.01), such as 1.
Preferably, the reducing agent in the reduction reaction in the step (2) is hydrogen.
Preferably, the pressure after the hydrogen gas is introduced in the reduction reaction in the step (2) is controlled to be 0.1 to 3.0MPa, for example, 0.1MPa, 0.3MPa, 0.5MPa, 0.7MPa, 0.9MPa, 1.1MPa, 1.3MPa, 1.5MPa, 1.7MPa, 1.9MPa, 2MPa, 2.2MPa, 2.5MPa, 2.8MPa or 3MPa, preferably 0.5 to 2.5MPa.
Preferably, the temperature of the reduction reaction in step (2) is 25 to 120 ℃, such as 25 ℃,30 ℃,40 ℃,50 ℃,60 ℃, 70 ℃,80 ℃, 90 ℃,100 ℃, 110 ℃ or 120 ℃, preferably 40 to 100 ℃.
Preferably, the time of the reduction reaction in step (2) is 8 to 16h, such as 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h or 16h, preferably 10 to 14h.
Preferably, the solvent for the reaction in step (3) is one or a combination of at least two of tetrahydrofuran, dichloromethane, methanol, ethyl acetate, 1, 2-dichloroethane, toluene or xylene, preferably one or a combination of at least two of methanol, ethyl acetate or toluene.
Preferably, the reducing agent for the reaction in step (3) is one or a combination of at least two of hydrogen, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride, and zinc powder, or a combination of zinc powder and acid, preferably a combination of zinc powder and acid or hydrogen.
Preferably, the acid in step (3) is one or a combination of at least two of hydrochloric acid, sulfuric acid, formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid and difluoroacetic acid, and is preferably acetic acid and/or propionic acid.
Preferably, when the reducing agent in step (3) is hydrogen, the catalyst is any one of palladium carbon, platinum carbon or raney nickel, preferably palladium carbon or platinum carbon catalyst.
Preferably, when the reducing agent in step (3) is hydrogen, the mass ratio of the aminoamide to the catalyst is 1 (0.001 to 0.02), for example 1.
Preferably, when the reducing agent in the step (3) is hydrogen, the pressure after the introduction of hydrogen is controlled to be 0.1 to 3.0MPa, for example, 0.1MPa, 0.3MPa, 0.5MPa, 0.7MPa, 0.9MPa, 1.1MPa, 1.3MPa, 1.5MPa, 1.7MPa, 1.9MPa, 2MPa, 2.2MPa, 2.5MPa, 2.8MPa or 3MPa, preferably 0.5 to 2.5MPa.
Preferably, the molar ratio of the compound 4 (aminoamide) to the reducing agent in step (3) is 1 (1.5 to 6), such as 1.
Preferably, in step (3), the molar ratio of compound 4 (aminoamide) to compound 5 is 1.
Preferably, the molar ratio of compound 4 (aminoamide) to acid in step (3) is 1 (0 to 12), such as 1:0.2, 1:0.4, 1:0.6, 1:1.2, 1:1.8, 1:2.4, 1.
Preferably, the temperature of the reaction in step (3) is in the range of 25 to 150 ℃, e.g. 25 ℃,30 ℃,40 ℃,50 ℃,60 ℃, 70 ℃,80 ℃ or 90 ℃, preferably 60 to 120 ℃.
Preferably, the reaction time in step (3) is 1 to 10 hours, such as 1 hour, 1.5 hours, 1.8 hours, 2 hours, 2.5 hours, 2.8 hours, 3 hours, 3.3 hours, 3.5 hours, 4.5 hours, 5.5 hours, 6.5 hours, 7.5 hours, 8.5 hours, 9.5 hours or 10 hours, preferably 1.5 to 6 hours.
Preferably, in step (3), the mass ratio of compound 4 (aminoamide) to the solvent is 1.
Preferably, the solvent for the reaction in step (4) is any one or a combination of at least two of dichloromethane, 1, 2-dichloroethane, chloroform, benzene, toluene, xylene, chlorobenzene or dichlorobenzene, preferably 1, 2-dichloroethane or toluene.
Preferably, in the step (4), the mass ratio of the compound 6 (cyclopropylamino amide) to the solvent is 1 (2 to 8), such as 1.
Preferably, in step (4), the molar ratio of compound 6 (cyclopropylamino amide) to compound 7 is 1 (1-1.5), for example 1.
Preferably, the temperature of the reaction in step (4) is 40 to 180 ℃, e.g. 40 ℃,50 ℃,60 ℃,80 ℃,100 ℃, 120 ℃, 140 ℃, 150 ℃, 170 ℃ or 180 ℃, preferably 80 to 110 ℃.
Preferably, the reaction time in step (4) is 1 to 6 hours, such as 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours or 6 hours, preferably 3 to 5 hours.
After the reaction in the step (4) of the present invention is completed, the next step can be performed without separation after the post-treatment.
Preferably, the bromination reaction of step (5) is carried out in the presence of bromide and an oxidizing agent.
Preferably, the bromide is one of or a combination of at least two of a bromide salt of an alkali metal, a bromide salt of an alkaline earth metal, hydrobromic acid, bromine, ammonium bromide, preferably sodium bromide or hydrobromic acid.
Preferably, the oxidizing agent is chlorine gas, one or a combination of at least two of perchlorate, chlorate, chlorite or hypochlorite of alkali metal or alkaline earth metal, preferably one or a combination of at least two of sodium chlorate, sodium hypochlorite or chlorine gas.
Preferably, in step (5), the molar ratio of the compound 8 (bisamide) to the bromide is 1 (0.55-2.0), for example, 1.
Preferably, in step (5), the molar ratio of the compound 8 (bisamide) to the oxidizing agent is 1 (0.2 to 2.0), such as 1.
Preferably, the bromination reaction in step (5) is carried out in the presence of a basic substance.
Preferably, the alkaline substance is one or a combination of at least two of hydroxides, carbonates and bicarbonates of alkali metals or alkaline earth metals, preferably sodium hydroxide or potassium hydroxide.
Preferably, the molar ratio of the compound 8 (bisamide) to the basic substance is 1 (0 to 3.0), such as 1.
Preferably, the temperature of the bromination reaction in step (5) is 0 to 150 ℃, e.g., 0 ℃,5 ℃,10 ℃, 20 ℃, 25 ℃,30 ℃,40 ℃,50 ℃,60 ℃, 70 ℃,80 ℃, 90 ℃,100 ℃, 110 ℃, 120 ℃, 130 ℃, 140 ℃ or 150 ℃, preferably 40 to 90 ℃.
Preferably, the bromination reaction in step (5) is carried out for a time of 0.5 to 8 hours, such as 0.5 hour, 0.6 hour, 0.8 hour, 1 hour, 1.5 hour, 1.8 hour, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours or 8 hours, preferably 1 to 2 hours.
In the invention, after the reaction in the step (5) is finished, the reaction solution is separated while hot, the organic layer is washed by adding a sodium sulfite solution, then hydrochloric acid is added for pH to 4-5, then liquid separation is carried out, the organic layer is concentrated to obtain a light yellow product crude product, and then white solid, namely the product, is obtained after organic solvent recrystallization and drying. The organic solvent used for recrystallization is one or a combination of at least two of dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, ethyl acetate, methanol, ethanol, isopropanol), preferably toluene, methanol or isopropanol.
Compared with the prior art, the invention has the following beneficial effects:
in the preparation method, the multi-step reaction is almost quantitative, the byproducts are few, the deep cooling high-temperature reaction is avoided, the introduction of bromine atoms into specific sites can be realized in the last step, the yield of each step in the preparation method is over 90 percent, the yield is high, the preparation method is more suitable for industrial production, and meanwhile, the route can obtain a high-purity product without separation until the original medicine is synthesized or by simple solvent separation in each step.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
In the present invention, the preparation of said starting material, compound 2, is referred to the process disclosed in EP2319830 A1.
The overall synthetic route of the invention is as follows:
the following examples all utilize this route to complete the preparation of the compounds.
Example 1
In this example, a compound of the structure wherein Z is prepared 1 、Z 2 、Z 4 And Z 5 Is hydrogen, Z 3 Is fluorine, R 1 Is fluorine, R 2 And R 3 Is hydrogen, W 1 And W 2 Is oxygen, i.e.
The preparation method comprises the following steps:
(1) In a 500mL reaction vessel, 65.4g (0.2 mol) of Compound 2 (R) were sequentially added 1 F), 265.2g of toluene and 53.9g (0.26 mol) of compound 1 were heated to 110 ℃ to react for 4 hours, after cooling slightly, 40g of a 10% sodium carbonate solution was slowly added thereto, and the mixture was stirred at 80 ℃ for 30 minutes and separated while hot to obtain 367.6g of an organic layer having a nitroamide content of 26.7% and a yield of 99.3%.
Mass spectrum detection: LC/MS [ M +1]: m/z =495;
(2) 367.6g of the organic layer obtained in the step (1) and 0.29g of 10% palladium-carbon catalyst are sequentially put into a 1L autoclave, the mixture is hydrogenated to 0.5MPa pressure, reacted for 10 hours at 100 ℃, filtered, and the filtrate is dried and dehydrated to obtain 361.2g of aminoamide toluene liquid, wherein the content of aminoamide is 24.9%, and the yield is 97.6%.
Mass spectrum detection: LC/MS [ M +1]: m/z =465;
(3) 361.2g (content: 24.9%,0.194 mol) of aminoamide toluene solution obtained in step (2), 22.4g (0.31 mol) of cyclopropanecarbaldehyde and 25.5g (0.392 mol) of zinc powder are sequentially added into a 500mL reaction kettle, 47.1g (0.784 mol) of acetic acid is dropwise added at 60 ℃, the reaction is continued for 2 hours after dropwise addition, the mixture is filtered while hot, the pH of the filtrate is adjusted to 7 by 160g of 20% sodium hydroxide solution at 50 ℃, liquid separation is carried out while hot, 382.3g of cyclopropylaminoamide toluene solution is obtained, the content of cyclopropylaminoamide is 25.1%, and the yield is 95.5%.
Mass spectrum detection: LC/MS [ M +1]: m/z =519;
(4) And (2) sequentially adding 382.3g (content: 25.1%,0.185 mol) of the cyclopropylamino amide toluene solution obtained in the step (3) and 32.7g (0.2 mol) of 4-fluorobenzoyl chloride into a 500mL reaction kettle, raising the temperature to 100 ℃, reacting for 5 hours, slowly adding 40g of 20% sodium hydroxide solution, stirring at 80 ℃ for 30 minutes, and separating while hot to obtain 403.6g of an organic phase for later use, wherein the content of bisamide is 29.2%, and the yield is 99.5%.
Mass spectrum detection: LC/MS [ M +1]: m/z =641;
(5) In a 500mL reaction kettle, 403.6g (content: 29.2%,0.184 mol) of the organic phase obtained in step (4), 53.6g (0.265 mol) of 40% hydrobromic acid, 30g of water and 14.2g (0.34 mol) of NaOH are sequentially added, the temperature is raised to 70 ℃, 54.1g of 14.5% sodium chlorate solution is dropwise added, the reaction is continued for 1h after the dropwise addition, liquid separation is carried out while hot, 50g of 7.5% sodium sulfite solution is used for washing the organic phase at 70 ℃, the pH is adjusted to 5 by 12.9g of concentrated hydrochloric acid, liquid separation is carried out again while hot, 138.7g of pale yellow crude product is obtained after the organic phase is concentrated, the crude product is dissolved in 180mL of toluene for recrystallization, 123.5g of white solid is obtained after drying, the content is 99.2%, and the yield is 92.6%.
Mass spectrum detection: LC/MS [ M +1]: m/z =720;
h NMR (400MHz, DMSO-d 6) data were as follows (. Delta. [ ppm ]): 10.32 (s, 1H), 7.90 (s, 1H), 7.67-7.51 (m, 4H), 7.38-7.33 (m, 3H), 7.15-7.09 (m, 2H), 3.70 (d, J =20.0hz, 2h), 1.06-1.01 (m, 1H), 0.41 (d, J =8.0hz, 2h), 0.09 (br s, 2H).
Example 2
In this example, a compound of the structure wherein Z is prepared 1 、Z 2 、Z 4 And Z 5 Is hydrogen, Z 3 Is chlorine, R 1 、R 2 And R 3 Is hydrogen, W 1 And W 2 Is oxygen, i.e.
The preparation method comprises the following steps:
(1) In a 500mL reaction kettle, sequentially adding62.0g (0.2 mol) of Compound 2 (R) 1 Hydrogen), 186.0g of xylene and 49.8g (0.24 mol) of the compound 1 are heated to 120 ℃ for reaction for 6h, after slight cooling, 40g of 10% sodium hydroxide solution is slowly added, the mixture is stirred at 80 ℃ for 30min, the organic layer is cooled to room temperature after liquid separation while the mixture is hot, then the mixture is placed in an ice maker for stirring for 3h at 5 ℃, and 93.1g of yellow solid of the nitroamide with the content of 98.5 percent is obtained after filtration and drying, and the yield is 96.3 percent.
Mass spectrum detection: LC/MS [ M +1]: m/z =477;
(2) 95.2g (0.2 mol) of nitroamide, 0.59g of 10% palladium-carbon catalyst and 285.6g of methanol are sequentially put into a 1L autoclave, the mixture is hydrogenated to 2.5MPa pressure, reacted for 12 hours at 60 ℃, filtered, and the filtrate is concentrated to obtain a grey solid, 89.7g of the grey solid is obtained after drying, the content is 98.5%, and the yield is 99.1%.
Mass spectrum detection: LC/MS [ M +1]: m/z =447;
(3) 46.9g (0.1 mol) of aminoamide, 0.14g 10% Pd-C, 12.9g (0.18 mol) of cyclopropanecarboxaldehyde, 24g (0.4 mol) of acetic acid and 237.6g of methanol were charged in a 500ml autoclave. The mixture was purged with nitrogen 3 times, and then charged with hydrogen to 0.5MPa. Heating to 100 ℃, reacting for 6 hours, cooling the reaction kettle to 40 ℃, filtering, leaching the catalyst with methanol, combining organic phases, and removing the solvent under reduced pressure. 150ml of toluene and 50ml of water were added to the residue, the PH was adjusted to 7 to 8 with 30% sodium hydroxide, liquid was separated while hot, the organic layer was stirred at 0 to 5 ℃ for 3 hours, filtered, and dried to obtain 46.4g of pale yellow cyclopropylamino amide, the content was 98.6%, and the yield was 91.5%.
Mass spectrum detection: LC/MS [ M +1]: m/z =501;
(4) 50.0g (0.1 mol) of cyclopropylamino amide, 300g of toluene and 20.8g (0.11 mol) of 4-chlorobenzoyl chloride are sequentially added into a 500mL reaction kettle, the temperature is raised to 110 ℃ for reaction for 3 hours, 40g of 10% sodium carbonate solution is slowly added, after stirring at 80 ℃ for 30 minutes, liquid separation is carried out while hot to obtain 366.8g of an organic phase for later use, the bisamide content is 17.2%, and the yield is 98.6%.
Mass spectrum detection: LC/MS [ M +1]: m/z =640;
(5) And (2) sequentially adding 366.8g (content: 17.5%,0.099 mol) of the organic phase obtained in the step (4), 16.3g (0.158 mol) of sodium bromide, 30g of water and 18.3g (0.277 mol) of KOH into a 500mL reaction kettle, heating to 90 ℃, introducing 8.5g (0.119 mol) of chlorine, continuously reacting for 2 hours after the reaction is finished, carrying out liquid separation while hot, washing the organic phase with 50g of 7.5% sodium sulfite solution at 90 ℃, adjusting the pH to 4 with 13.8g of concentrated hydrochloric acid, carrying out liquid separation while hot again, concentrating the organic phase to obtain 76.5g of light yellow crude product, dissolving the crude product into 90mL isopropanol for recrystallization, and drying to obtain 67.4g of a white solid product with the content of 99.2% and the yield of 94.1%.
Mass spectrum detection: LC/MS [ M +1]: m/z =719;
h NMR (400MHz, DMSO-d 6) data were as follows (. Delta. [ ppm ]): 1H NMR (400MHz, DMSO-d 6) delta [ ppm ]:10.31 (s, 1H), 7.90 (s, 1H), 7.68-7.48 (m, 3H), 7.33 (t, J =72.0Hz, 2H), 7.32 (brs, 6H), 3.69 (d, J =16.8Hz, 2H), 1.02 (brs, 1H), 0.41 (d, J =7.7Hz, 2H), 0.09 (s, 2H).
Example 3
In this example, a compound of the structure wherein Z is prepared 1 、Z 2 、Z 4 And Z 5 Is hydrogen, Z 3 Is cyano, R 1 Is fluorine, R 2 、R 3 Is hydrogen, W 1 And W 2 Is oxygen, i.e.
The preparation method comprises the following steps:
(1) Into a 250mL reaction vessel, 65.4g (0.2 mol) of Compound 2 (R) were sequentially added 1 Fluorine), 130.8g of toluene and 43.6g (0.21 mol) of the compound 1 are heated to 110 ℃ for reaction for 6h, after slight cooling, 40g of 10% sodium carbonate solution is slowly added, stirring is carried out at 80 ℃ for 30min, the organic layer is cooled to room temperature after liquid separation is carried out while the solution is hot, then the mixture is placed in an ice maker for stirring at 0 ℃ for 3h, and 96.4g of yellow solid of nitroamide with the content of 98.2% is obtained after filtration and drying, and the yield is 95.8%.
Mass spectrum detection: LC/MS [ M +1]: m/z =495;
(2) 98.8g (0.2 mol) of nitroamide, 0.49g of 10% platinum-carbon catalyst and 496g of ethyl acetate are sequentially put into a 1L autoclave, the mixture is hydrogenated to 2.5MPa pressure, reacted for 14h at 40 ℃, filtered, and the filtrate is concentrated to obtain a grey solid which is dried to obtain 93.2g of aminoamide with the content of 98.6% and the yield of 99.0%.
Mass spectrum detection: LC/MS [ M +1]: m/z =465;
(3) Into a 500mL autoclave were charged 46.9g (0.1 mol) of aminoamide, 0.47g 10% by weight of Pt-C, 12.9g (0.18 mol) of cyclopropanecarbaldehyde, 29.6g (0.4 mol) of propionic acid, and 281.4g of toluene. The mixture was purged with nitrogen 3 times, and then charged with hydrogen to 2.5MPa. Heating to 120 ℃, cooling the reaction kettle to 40 ℃ after reacting for 4 hours, filtering, leaching the catalyst with toluene, combining organic phases, and removing the solvent under reduced pressure. To the residue were added 150mL of toluene and 50mL of water, the pH =7 was adjusted with 30% sodium hydroxide, liquid was separated while hot, and the organic layer was left to stand at 0 ℃ and stirred for 3 hours, filtered, and dried to obtain 48.9g of pale yellow cyclopropylamino amide, which was 98.2% in content and 92.8% in yield.
Mass spectrum detection: LC/MS [ M +1]: m/z =519;
(4) 51.8g (0.1 mol) of cyclopropylamino amide, 259g of 1, 2-dichloroethane and 17.7g (0.105 mol) of 4-cyanobenzoyl chloride are sequentially added into a 500mL reaction kettle, the temperature is raised to 80 ℃ to react for 4 hours, 40g of a 10% sodium carbonate solution is slowly added, the mixture is stirred at 80 ℃ for 30 minutes, and then liquid separation is carried out while hot to obtain 332.9g of an organic phase for later use, wherein the content of bisamide is 19.3%, and the yield is 99.3%.
Mass spectrum detection: LC/MS [ M +1]: m/z =648;
(5) And (2) sequentially adding 332.9g (with the content of 19.1 percent and the mol of 0.099) of the organic phase obtained in the step (4), 12.3g (with the mol of 0.119 mol) of sodium bromide, 2.1g (with the mol of 0.049 mol) of NaOH and 30g of water into a 500mL reaction kettle, heating to 40 ℃, dropwise adding 82.2g of 14.5 percent sodium hypochlorite solution, continuously reacting for 1.5h after dropwise adding, carrying out liquid separation while hot, washing the organic phase with 50g of 7.5 percent sodium sulfite solution at 50 ℃, adjusting the pH to 4 with 11.9g of concentrated hydrochloric acid, carrying out liquid separation again while hot, concentrating the organic phase to obtain 74.9g of light yellow crude product, dissolving the crude product into 60mL of methanol for recrystallization, and drying to obtain 67.5g of a white solid product with the content of 99.2 percent and the yield of 93.2 percent.
Mass spectrum detection: LC/MS [ M +1]: m/z =727;
h NMR (400MHz, DMSO-d 6) data were as follows (. Delta. [ ppm ]): 10.32 (s, 1H), 7.92 (s, 1H), 7.81-7.76 (m, 2H), 7.72 (d, J =8.0hz, 2h), 7.54 (s, 1H), 7.51-7.47 (m, 3H), 7.31 (4, J =74.4hz, 2h), 3.79 (d, J =6.4hz, 2h), 1.07-0.99 (m, 1H), 0.45-0.41 (m, 2H), 0.16 (br s, 2H).
Example 4
In this example, a compound of the structure wherein Z is prepared 1 、Z 3 、Z 5 Is hydrogen, Z 2 、Z 4 Is fluorine, R 1 、R 2 、R 3 Is hydrogen, W 1 And W 2 Is oxygen, i.e.
The preparation method comprises the following steps:
(1) Into a 500mL reaction vessel, 62.0g (0.2 mol) of Compound 2 (R) was added in order 1 Hydrogen), 186.0g of xylene and 49.8g (0.24 mol) of the compound 1 are heated to 140 ℃ for reaction for 5 hours, after slight cooling, 40g of 10% sodium hydroxide solution is slowly added, stirring is carried out at 80 ℃ for 30 minutes, the organic layer is cooled to room temperature after liquid separation is carried out while the organic layer is hot, then the mixture is placed in an ice maker for stirring at 5 ℃ for 3 hours, and after filtration and drying, 93.1g of yellow solid of nitroamide with the content of 98.5 percent and the yield of 96.3 percent are obtained.
Mass spectrum detection: LC/MS [ M +1]: m/z =477;
(2) 95.2g (0.2 mol) of nitroamide, 0.59g of 10% palladium-carbon catalyst and 285.6g of methanol are sequentially put into a 1L autoclave, the mixture is hydrogenated to 1.5MPa pressure, reacted for 12 hours at 60 ℃, filtered, and the filtrate is concentrated to obtain a grey solid, and the grey solid is dried to obtain 89.7g with the content of 98.5% and the yield of 99.1%.
Mass spectrum detection: LC/MS [ M +1]: m/z =447;
(3) 44.7g (0.1 mol) of amino amide, 223.5g of ethyl acetate, 14.3g (0.2 mol) of cyclopropane formaldehyde and 26g (0.4 mol) of zinc powder are sequentially added into a 500mL reaction kettle, 48g (0.8 mol) of acetic acid is dropwise added at 60 ℃, reaction is continued for 1.5h after dropwise addition is finished, filtration is carried out while the solution is hot, the filtrate is concentrated to obtain yellow solid, 50mL of toluene is added and heated to 90 ℃ for dissolution and cleaning, 50mL of water is added, 5.9g of 30% sodium hydroxide solution is added to adjust the pH value to 8, liquid separation is carried out while the solution is hot, the organic layer is stirred for 3h at 0 ℃, and filtration and drying is carried out to obtain 48.6g of light yellow cyclopropyl amino amide, the content is 98.6%, and the yield is 95.9%.
Mass spectrum detection: LC/MS [ M +1]: m/z =501;
(4) 50.0g (0.1 mol) of cyclopropylamino amide, 200g of 1, 2-dichloroethane and 19.4g (0.108 mol) of 3, 5-difluorobenzoyl chloride are sequentially added into a 500mL reaction kettle, the temperature is raised to 80 ℃ for reaction for 4 hours, 40g of 10% sodium carbonate solution is slowly added, the mixture is stirred at 80 ℃ for 30 minutes, and then liquid separation is carried out while hot to obtain 267.9g of an organic phase for later use, wherein the content of bisamide is 23.7%, and the yield is 99.3%.
Mass spectrum detection: LC/MS [ M +1]: m/z =641;
(5) And (2) sequentially adding 267.9g (content 23.7%,0.099 mol) of the organic phase obtained in the step (4), 12.3g (0.119 mol) of sodium bromide, 4.2g (0.099 mol) of NaOH and 30g of water into a 500mL reaction kettle, heating to 70 ℃, dropwise adding 82.2g of 14.5% sodium hypochlorite solution, continuously reacting for 1.5h after dropwise adding, carrying out liquid separation while hot, washing the organic phase with 50g of 7.5% sodium sulfite solution at 50 ℃, adjusting the pH to 5 with 11.9g of concentrated hydrochloric acid, carrying out liquid separation again while hot, concentrating the organic phase to obtain 75.2g of light yellow crude product, dissolving the crude product in 60mL of methanol for recrystallization, and drying to obtain 66.9g of a white solid product with the content of 99.2% and the yield of 93.2%.
Mass spectrum detection: LC/MS [ M +1]: m/z =720;
h NMR (400MHz, DMSO-d 6) data were as follows (. Delta. [ ppm ]): 10.34 (s, 1H), 7.91 (s, 1H), 7.73 (t, J =7.3hz, 1h), 7.61 (s, 1H), 7.52 (s, 1H), 7.35 (t, J =8.0hz, 1h), 7.31 (t, J =72.0hz, 1h), 7.23 (s, 2H), 7.00 (s, 2H), 3.69 (s, 2H), 1.00 (brs, 1H), 0.42 (d, J =7.2hz, 2h), 0.09 (s, 2H).
Comparative example 1 (NBS method, see example II of CN 104245865B)
To 68.5mg (1.71 mmol) of sodium hydride (content: 60%) were added 4g of N, N-dimethylformamide and 1.1g (1.72 mmol) of the bisamide (i.e., 2-fluoro-3- (N- (cyclopropylmethyl) -4-fluorobenzamide) -N- (2- (difluoromethoxy) -4- (heptafluoroisopropyl) phenyl) benzamide) obtained in the 4 th step in example 1, and the mixture was stirred for 10 minutes in an ice bath. To the reaction mixture was added 0.31g (1.80 mmol) of N-bromosuccinimide, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, the solvent was removed under reduced pressure, and then the concentrated residue was purified by silica gel column chromatography to obtain 0.93g of a solid (yield 80%).
Comparative example 2 (bromine method, see method in CN 102491910A)
Adding 32g (0.05 mol) of the product bisamide (namely 2-fluoro-3- (N- (cyclopropylmethyl) -4-fluorobenzamide) -N- (2- (difluoromethoxy) -4- (heptafluoroisopropyl) phenyl) benzamide) obtained in the step 4 in the example 1 and 50mL of 1, 2-dichloroethane in turn into a 100mL reaction kettle, dropwise adding 8.8g (0.055 mol) of bromine at 20 ℃, and continuing to react for 1h after dropwise adding for 30 min; 7.4g (0.065 mol) of hydrogen peroxide is dripped again, the reaction is continued for 6h after the dripping is finished within 1h, the solvent is removed, 40mL of isopropanol is crystallized to obtain 29.1g of white solid, and the yield is 81%.
Comparative example 3 (Hydrogen bromide hydrogen peroxide method, see CN 109704976A)
32g (0.05 mol) of the bisamide (i.e. 2-fluoro-3- (N- (cyclopropylmethyl) -4-fluorobenzamide) -N- (2- (difluoromethoxy) -4- (heptafluoroisopropyl) phenyl) benzamide) obtained in the step 4 in the example 1 and 50mL of 1, 2-dichloroethane (hereinafter referred to as "1/4 g") were added sequentially to a 100mL reaction vessel, 30% hydrogen peroxide solution was added dropwise after the temperature was raised to 50 ℃, the reaction was continued for 1 hour after the dropwise addition, and no reaction was observed in the liquid phase.
The applicant states that the present invention is illustrated by the above examples to the preparation method of difluoromethoxy group-containing m-diamide compounds of the present invention, but the present invention is not limited to the above examples, i.e. it is not meant that the present invention must be implemented by relying on the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. A preparation method of a difluoromethoxy-containing m-diamide compound shown in formula I is characterized by comprising the following steps:
(1) The compound 1 and the compound 2 are subjected to condensation reaction to obtain a compound 3, and the reaction formula is as follows:
(2) The compound 3 is subjected to reduction reaction to obtain a compound 4, and the reaction formula is as follows:
(3) Reacting compound 4 with compound 5 to obtain compound 6, wherein the reaction formula is as follows:
(4) Reacting compound 6 with compound 7 to obtain compound 8, wherein the reaction formula is as follows:
(5) Brominating the compound 8 to obtain a difluoromethoxy-containing m-diamide compound shown in the formula I, wherein the reaction formula is as follows:
wherein Z 1 、Z 2 、Z 3 、Z 4 、Z 5 Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro and C 1 -C 6 Alkyl radical, C 1 -C 6 Cycloalkyl radical, C 1 -C 6 Haloalkyl, C 1 -C 6 Halocycloalkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkylsulfinyl radical, C 1 -C 6 Haloalkylsulfinyl radical, C 1 -C 6 Alkylsulfonyl or C 1 -C 6 A haloalkylsulfonyl group;
R 1 selected from hydrogen or fluorine;
R 2 selected from hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Haloalkyl, C 3 -C 8 Cycloalkyl or C 3 -C 8 A halocycloalkyl group;
R 3 selected from hydrogen or halogen;
W 1 and W 2 Independently an oxygen atom or a sulfur atom.
2. The method of claim 1, wherein Z is 1 、Z 2 、Z 3 、Z 4 、Z 5 Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, trifluoromethyl, pentafluoroethyl, heptafluoro-n-propyl, heptafluoro-isopropyl, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, methylsulfinyl, trifluoromethylsulfinyl, methylsulfonyl or trifluoromethylsulfonyl; r 2 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, neopentyl, isopentyl, 4-methyl-2-pentyl, n-hexyl, monofluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoroisopropyl, cyclopropyl, cyclobutyl, cyclopentyl, perfluorocyclopropyl, perfluorocyclobutyl or perfluorocyclopentyl; r 3 Selected from hydrogen, fluorine or chlorine;
preferably, Z 1 、Z 2 、Z 3 、Z 4 、Z 5 Each independently selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylsulfonyl or trifluoromethylsulfonyl; r 1 Selected from hydrogen or fluorine; r is 2 Selected from hydrogen or methyl; r 3 Selected from hydrogen or chlorine; w 1 And W 2 Is selected from oxygen;
preferably, Z 1 、Z 2 、Z 3 、Z 4 、Z 5 Each independently selected from hydrogen, fluorine, chlorine, cyano; r 1 Selected from hydrogen or fluorine; r is 2 Selected from hydrogen; r 3 Selected from hydrogen, W 1 And W 2 Selected from oxygen.
3. The method according to claim 1 or 2, wherein the solvent for the condensation reaction in step (1) is any one or a combination of at least two of dichloromethane, 1, 2-dichloroethane, chloroform, benzene, toluene, xylene, chlorobenzene, or dichlorobenzene, preferably toluene and/or xylene;
preferably, the molar ratio of the compound 1 to the compound 2 in the step (1) is (1-1.5): 1, preferably (1.05-1.3): 1.
4. The method according to any one of claims 1 to 3, wherein the mass ratio of the compound 2 to the solvent in the step (1) is 1 (1 to 5), preferably 1 (2 to 4).
5. The method of any one of claims 1 to 4, wherein the temperature of the reaction of step (1) is 40 to 180 ℃, preferably 110 to 140 ℃;
preferably, the reaction time of the step (1) is 3 to 8 hours, and preferably 4 to 6 hours.
6. The process according to any one of claims 1 to 5, wherein the solvent for the reaction in step (2) is one or a combination of at least two of methanol, ethanol, acetonitrile, benzene, toluene, xylene, chlorobenzene and ethyl acetate, preferably methanol, toluene and ethyl acetate;
preferably, the catalyst for the reduction reaction in the step (2) is any one of palladium-carbon, platinum-carbon or raney nickel, and is preferably a palladium-carbon or platinum-carbon catalyst;
preferably, the mass ratio of the compound 3 to the solvent in the step (2) is 1 (2-8), preferably 1 (3-5);
preferably, the mass ratio of the compound 3 to the catalyst in the step (2) is 1 (0.001-0.01);
preferably, the reducing agent in the reduction reaction in the step (2) is hydrogen;
preferably, the pressure after the hydrogen is introduced in the reduction reaction in the step (2) is controlled to be 0.1-3.0 MPa, and preferably 0.5-2.5MPa;
preferably, the temperature of the reduction reaction in the step (2) is 25-120 ℃, preferably 40-100 ℃;
preferably, the time of the reduction reaction in the step (2) is 8 to 16 hours, preferably 10 to 14 hours.
7. The process according to any one of claims 1 to 6, wherein the solvent for the reaction in step (3) is one or a combination of at least two of tetrahydrofuran, dichloromethane, methanol, ethyl acetate, 1, 2-dichloroethane, toluene or xylene, preferably one or a combination of at least two of methanol, ethyl acetate or toluene;
preferably, the reducing agent for the reaction in step (3) is one or a combination of at least two of hydrogen, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride and zinc powder, or a combination of zinc powder and acid, preferably a combination of zinc powder and acid or hydrogen;
preferably, the acid is one or a combination of at least two of hydrochloric acid, sulfuric acid, formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid and difluoroacetic acid, and is preferably acetic acid and/or propionic acid;
preferably, when the reducing agent in step (3) is hydrogen, the catalyst is any one of palladium carbon, platinum carbon or raney nickel, preferably palladium carbon or platinum carbon catalyst;
preferably, when the reducing agent in the step (3) is hydrogen, the mass ratio of the aminoamide to the catalyst is 1 (0.001-0.02), preferably 1 (0.003-0.01);
preferably, when the reducing agent in the step (3) is hydrogen, the pressure after the hydrogen is introduced is controlled to be 0.1-3.0 MPa, and preferably 0.5-2.5MPa;
preferably, the molar ratio of the compound 4 to the reducing agent in the step (3) is 1 (1.5-6), preferably 1 (2-4);
preferably, the molar ratio of the compound 4 to the compound 5 in the step (3) is 1;
preferably, the molar ratio of the compound 4 to the acid in the step (3) is 1 (0-12), preferably 1 (4-8);
preferably, the temperature of the reaction in the step (3) is 25-150 ℃, preferably 60-120 ℃;
preferably, the reaction time of the step (3) is 1 to 10 hours, preferably 1.5 to 6 hours;
preferably, the mass ratio of the compound 4 to the solvent in the step (3) is 1 (2-8), preferably 1 (4-6).
8. The production method according to any one of claims 1 to 7, characterized in that the solvent for the reaction in step (4) is any one of or a combination of at least two of dichloromethane, 1, 2-dichloroethane, chloroform, benzene, toluene, xylene, chlorobenzene, or dichlorobenzene, preferably 1, 2-dichloroethane or toluene;
preferably, the mass ratio of the compound 6 to the solvent in the step (4) is 1 (2-8), preferably 1 (4-6);
preferably, the molar ratio of the compound 6 to the compound 7 in the step (4) is 1 (1-1.5), preferably 1 (1.05-1.1);
preferably, the temperature of the reaction in the step (4) is 40-180 ℃, preferably 80-110 ℃;
preferably, the reaction time in step (4) is 1 to 6 hours, preferably 3 to 5 hours.
9. The production method according to any one of claims 1 to 8, wherein the bromination reaction in step (5) is carried out in the presence of a bromide and an oxidizing agent;
preferably, the bromide is one of or a combination of at least two of a bromide salt of an alkali metal, a bromide salt of an alkaline earth metal, hydrobromic acid, bromine, ammonium bromide, preferably sodium bromide or hydrobromic acid;
preferably, the oxidizing agent is chlorine gas, one or a combination of at least two of perchlorate, chlorate, chlorite or hypochlorite of alkali metal or alkaline earth metal, preferably one or a combination of at least two of sodium chlorate, sodium hypochlorite or chlorine gas.
10. The method according to any one of claims 1 to 9, wherein the molar ratio of the compound 8 to the bromide in the step (5) is 1 (0.55 to 2.0), preferably 1 (1.2 to 1.6);
preferably, the molar ratio of the compound 8 to the oxidant in the step (5) is 1 (0.2-2.0), preferably 1 (0.4-1.6);
preferably, the bromination reaction of step (5) is carried out in the presence of a basic substance;
preferably, the alkaline substance is one or a combination of at least two of hydroxides, carbonates and bicarbonates of alkali metals or alkaline earth metals, preferably sodium hydroxide or potassium hydroxide;
preferably, the molar ratio of the compound 8 to the alkaline substance is 1 (0.05-3.0), preferably 1 (0.5-2.8);
preferably, the temperature of the bromination reaction in the step (5) is 0-150 ℃, preferably 40-90 ℃;
preferably, the time of the bromination reaction in the step (5) is 0.5 to 8 hours, and preferably 1 to 2 hours.
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| CN108586279A (en) * | 2018-06-26 | 2018-09-28 | 上海泰禾国际贸易有限公司 | One inter-species diamide compound and its preparation method and application |
| CN112142621A (en) * | 2019-06-27 | 2020-12-29 | 上海泰禾国际贸易有限公司 | Meta-diamide compound and preparation method and application thereof |
| CN112430210A (en) * | 2019-08-26 | 2021-03-02 | 沈阳化工大学 | Bisamide compound and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108586279A (en) * | 2018-06-26 | 2018-09-28 | 上海泰禾国际贸易有限公司 | One inter-species diamide compound and its preparation method and application |
| CN109497062A (en) * | 2018-06-26 | 2019-03-22 | 上海泰禾国际贸易有限公司 | One inter-species diamide compound and its preparation method and application |
| CN110028423A (en) * | 2018-06-26 | 2019-07-19 | 上海泰禾国际贸易有限公司 | One inter-species diamide compound and its preparation method and application |
| CN112142621A (en) * | 2019-06-27 | 2020-12-29 | 上海泰禾国际贸易有限公司 | Meta-diamide compound and preparation method and application thereof |
| CN112430210A (en) * | 2019-08-26 | 2021-03-02 | 沈阳化工大学 | Bisamide compound and application thereof |
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