CN115197086B - Preparation method of difluoromethoxy-containing m-diamide compound - Google Patents
Preparation method of difluoromethoxy-containing m-diamide compound Download PDFInfo
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- CN115197086B CN115197086B CN202110402017.XA CN202110402017A CN115197086B CN 115197086 B CN115197086 B CN 115197086B CN 202110402017 A CN202110402017 A CN 202110402017A CN 115197086 B CN115197086 B CN 115197086B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 83
- 238000006243 chemical reaction Methods 0.000 claims abstract description 74
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
- 239000002904 solvent Substances 0.000 claims abstract description 31
- 229940125782 compound 2 Drugs 0.000 claims abstract description 14
- 229940126214 compound 3 Drugs 0.000 claims abstract description 11
- 229940125904 compound 1 Drugs 0.000 claims abstract description 10
- 229940125898 compound 5 Drugs 0.000 claims abstract description 6
- 238000006482 condensation reaction Methods 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 80
- 239000001257 hydrogen Substances 0.000 claims description 63
- 229910052739 hydrogen Inorganic materials 0.000 claims description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- -1 chloro, bromo, iodo Chemical group 0.000 claims description 44
- 230000008569 process Effects 0.000 claims description 43
- 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 34
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 29
- 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
- 239000003054 catalyst Substances 0.000 claims description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- 239000003638 chemical reducing agent Substances 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 16
- 239000011737 fluorine Substances 0.000 claims description 16
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 15
- 238000006722 reduction reaction Methods 0.000 claims description 15
- 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
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000005893 bromination reaction Methods 0.000 claims description 11
- XPXMKIXDFWLRAA-UHFFFAOYSA-N hydrazinide Chemical compound [NH-]N XPXMKIXDFWLRAA-UHFFFAOYSA-N 0.000 claims description 11
- 239000008096 xylene Substances 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 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 group [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
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 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
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 8
- 239000007800 oxidant agent Substances 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 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
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 6
- 235000011054 acetic acid Nutrition 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 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
- 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 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
- 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 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 125000005347 halocycloalkyl group Chemical group 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
- 239000000126 substance Substances 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
- 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
- 239000003513 alkali Substances 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
- 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
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 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
- 125000006552 (C3-C8) cycloalkyl 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
- 150000001340 alkali metals Chemical class 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
- 125000006341 heptafluoro n-propyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)* 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
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 2
- 125000004749 (C1-C6) haloalkylsulfinyl group Chemical group 0.000 claims description 2
- 125000004741 (C1-C6) haloalkylsulfonyl 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 compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- 229910001513 alkali metal bromide Inorganic materials 0.000 claims description 2
- 229910000272 alkali metal oxide Inorganic materials 0.000 claims description 2
- 229910001616 alkaline earth metal bromide Inorganic materials 0.000 claims description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 2
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 claims description 2
- 229910001919 chlorite Inorganic materials 0.000 claims description 2
- 229910052619 chlorite group Inorganic materials 0.000 claims description 2
- QBWCMBCROVPCKQ-UHFFFAOYSA-N chlorous acid Chemical compound OCl=O QBWCMBCROVPCKQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 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
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 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
- 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
- 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
- 239000000463 material Substances 0.000 claims 3
- 230000001590 oxidative effect Effects 0.000 claims 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000000926 separation method Methods 0.000 abstract description 10
- 239000000047 product Substances 0.000 abstract description 7
- 238000001816 cooling Methods 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 5
- 125000001246 bromo group Chemical group Br* 0.000 abstract description 3
- 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
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 35
- 238000001514 detection method Methods 0.000 description 20
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 20
- 238000004949 mass spectrometry Methods 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 20
- FTQWRYSLUYAIRQ-UHFFFAOYSA-N n-[(octadecanoylamino)methyl]octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NCNC(=O)CCCCCCCCCCCCCCCCC FTQWRYSLUYAIRQ-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 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
- HWDVTQAXQJQROO-UHFFFAOYSA-N cyclopropylazanide Chemical compound [NH-]C1CC1 HWDVTQAXQJQROO-UHFFFAOYSA-N 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
- 238000001035 drying Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 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
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 235000010265 sodium sulphite Nutrition 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 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
- 238000010438 heat treatment Methods 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 239000000575 pesticide Substances 0.000 description 3
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- 238000005406 washing Methods 0.000 description 3
- IZEJJNNRCNMNJJ-UHFFFAOYSA-N C1(CC1)N.CC1=CC=CC=C1 Chemical compound C1(CC1)N.CC1=CC=CC=C1 IZEJJNNRCNMNJJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- 230000007613 environmental effect Effects 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
- 230000001105 regulatory effect Effects 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
- 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
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 239000003153 chemical reaction reagent 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
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 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
- 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
- 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
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Abstract
The invention provides a preparation method of a difluoro methoxy meta-diamide compound, 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 reacted to obtain a compound 6, the compound 6 and the compound 7 are reacted to obtain a compound 8, and the compound 8 is brominated to obtain the difluoromethoxy-containing m-diamide compound shown in the formula I. The multi-step reaction is almost quantitative reaction, few by-products and no deep-cooling high-temperature reaction, 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 route can obtain high-purity products without separation until raw medicines are synthesized in each step or through simple solvent separation.
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 methoxy-containing m-diamide compound.
Background
The metadiamide compound represented by Broflanilide has the characteristics of unique action mechanism, novel action target point, environmental friendliness and the like, so that the metadiamide compound becomes increasingly a research hotspot of pesticide companies at home and abroad, and the Broflanilide compound becomes one of the most potential pesticide research and development directions.
In the first reaction step, the synthesized difluoromethoxy m-diamide compound disclosed in CN105873901A needs strong alkali lithium diisopropylamide, has high cost, needs deep cooling at-70 ℃, is difficult to industrialize, has a single-step yield of only 34%, and is not beneficial to industrialized production; the synthesis disclosed in WO2014161850A1 contains difluoromethoxy-m-diamides (route two), which requires protection on the amino group first and then deprotection twice, and finally the target compound is obtained, which is complex in operation and liable to cause raw material waste.
Route one:
route two:
The process referenced Broflanilide also enables the synthesis of compounds containing difluoromethoxy-m-diamides, mainly by the following three routes.
Route three:
In particular, route three has the problems that the process route is long, bisamide is generated when the original medicine is finally synthesized, the consumption of acid is at least 2.4 times of that of amine, and alkali is added to remove water for hydrolysis, and meanwhile, the recovery operation of the acid is increased.
Route four:
the fourth route has the problem of long process route, the yield of the heptafluoroisopropyl in the eighth step is only 63%, the purification is difficult, and the expensive NBS reagent is used in the final bromination of the original medicine.
Route five:
The route five is the same as the route one, and has the problems of strong alkali, low yield, difficult industrialization and the like.
As described above, the conventional methods for synthesizing difluoromethoxy-containing m-diamide compounds and the reference Broflanilide have disadvantages such as environmental friendliness, low yield and difficulty in purification, so that development of more suitable synthesis processes is highly demanded.
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 difluoro methoxy-containing m-diamide compound.
To achieve the purpose, the invention adopts the following technical scheme:
In one aspect, the invention provides a preparation method of a difluoromethoxy-containing m-diamide compound shown in a formula I, which comprises the following steps:
(1) The condensation reaction of the compound 1 and the compound 2 is carried out to obtain a compound 3 (nitro amide for short in the invention), and the reaction formula is as follows:
(2) The compound 3 is subjected to a reduction reaction to obtain a compound 4 (amino amide for short in the invention), and the reaction formula is as follows:
(3) Compound 4 and compound 5 are reacted to obtain compound 6 (abbreviated as cyclopropylamide in the present invention) of the following formula:
(4) Compound 6 and compound 7 are reacted to obtain compound 8 (abbreviated as bisamide in the present invention), the reaction formula is as follows:
(5) The compound 8 is brominated to obtain a difluoromethoxy-containing meta-diamide compound shown in the formula I, and the reaction formula is as follows:
wherein Z 1、Z2、Z3、Z4、Z5 is independently selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, C 1-C6 alkyl, C 1-C6 cycloalkyl, C 1-C6 haloalkyl, C 1-C6 halocycloalkyl, C 1-C6 alkoxy, C 1-C6 haloalkoxy, C 1-C6 alkylsulfinyl, C 1-C6 haloalkylsulfinyl, C 1-C6 alkylsulfonyl, or C 1-C6 haloalkylsulfonyl;
r 1 is selected from hydrogen or fluorine;
R 2 is selected from hydrogen, C 1-C6 alkyl, C 1-C6 haloalkyl, C 3-C8 cycloalkyl or C 3-C8 halocycloalkyl;
R 3 is selected from hydrogen or halogen;
W 1 and W 2 are independently an oxygen atom or a sulfur atom.
The synthesis route is shorter, the multi-step reaction is quantitative reaction, few by-products are produced, the deep cooling and high temperature are avoided, the introduction of bromine atoms into specific sites can be realized in the last step, the yield is high, the method is more suitable for industrial production, and meanwhile, the route can obtain high-purity products without separation until raw medicines are synthesized in each step or through simple solvent separation.
The alkyl group according to the present invention means an alkyl group in a straight-chain or branched form, 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 the alkyl group is replaced with one or more halogen atoms. Alkoxy refers to a group having an oxygen atom attached to the end of the alkyl group, such as methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, and the like. Haloalkoxy refers to a group in which a hydrogen atom on the alkoxy group is replaced with one or more halogen atoms. Halogen is F, cl, br or I.
The term "C 1-C6 alkyl" as used herein refers to straight or branched chain alkyl groups having 1 to 6 carbon atoms and includes, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and the like. The term "C 1-C6 alkoxy" refers to straight or branched chain alkoxy groups having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, n-propoxy, isopropoxy, and t-butoxy groups, and the like. "C 1-C6 haloalkyl" refers to a straight or branched chain alkyl group of 1 to 6 carbon atoms substituted with a halogen atom and includes, without limitation, trifluoromethyl, difluoromethyl, 1-trifluoroethyl, pentafluoroethyl, heptafluoro-n-propyl, heptafluoro-isopropyl and the like. "C 1-C6 haloalkoxy" refers to straight or branched chain alkoxy groups of 1 to 6 carbon atoms substituted with halogen atoms, including without limitation trifluoromethoxy, difluoromethoxy, 2-trifluoroethoxy, pentafluoroethoxy, heptafluoro-n-propoxy, heptafluoroisopropoxy and the like. The term "C 3-C8 cycloalkyl" as used herein refers to cyclic alkyl groups having 3 to 8 carbon atoms and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The term "C 3-C8 halocycloalkyl" as used herein refers to a cyclic alkyl group having 3 to 8 carbon atoms substituted with halogen on the ring and includes, without limitation, 1-chlorocyclopropyl, 1-fluorocyclopropyl, perfluorocyclopropyl, 1-chlorocyclobutyl, 1-chlorocyclopentyl, and the like.
In the present invention, C 1-C6、C3-C8 and the like preceding the specific group represent the number of carbon atoms contained in the group, for example, C 1-C6 represents a group whose number of carbon atoms may be 1, 2, 3, 4,5 or 6, C 3-C8 represents a group whose number of carbon atoms may be 3, 4,5, 6, 7 or 8, C 2-C4 represents a group whose number of carbon atoms may be 2, 3 or 4, and the like.
In the present invention, Z 1、Z2、Z3、Z4、Z5 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, isobutyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, trifluoromethyl, pentafluoroethyl, heptafluoro-n-propyl, heptafluoro-isopropyl, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, methylsulfinyl, trifluoromethylsulfinyl, methylsulfonyl or trifluoromethylsulfonyl, as a preferred embodiment; r 2 is 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, monochloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoroisopropyl, cyclopropyl, cyclobutyl, cyclopentyl, perfluorocyclopropyl, perfluorocyclobutyl or perfluorocyclopentyl; r 3 is selected from hydrogen, fluorine or chlorine.
In the present invention, as a further preferable embodiment, Z 1、Z2、Z3、Z4、Z5 is each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methanesulfonyl or trifluoromethanesulfonyl; r 1 is selected from hydrogen or fluorine; r 2 is selected from hydrogen or methyl; r 3 is selected from hydrogen or chlorine; w 1 and W 2 are selected from oxygen.
In the present invention, particularly preferably, Z 1、Z2、Z3、Z4、Z5 is each independently selected from hydrogen, fluorine, chlorine, cyano; r 1 is selected from hydrogen or fluorine; r 2 is selected from hydrogen; r 3 is selected from hydrogen, W 1 and W 2 are 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, the molar ratio of compound 1 to compound 2 in step (1) is (1-1.5): 1, for example 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1 or 1.5:1, preferably (1.05-1.3): 1.
Preferably, the mass ratio of compound 2 to solvent in step (1) is 1 (1-5), for example 1:1、1:1.2、1:1.5、1:1.8、1:2、1:2.2、1:2.4、1:2.5、1:2.7、1:2.8、1:2.9、1:3、1:3.2、1:3.4、1:3.6、1:3.8、1:4、1:4.3、1:4.5、1:4.8 or 1:5, preferably 1 (2-4).
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, for example 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 of 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 compound 3 (nitroamide) to solvent in step (2) is 1: (2-8), preferably 1: (3-5).
Preferably, the mass ratio of compound 3 (nitroamide) to catalyst in step (2) is 1 (0.001-0.01), e.g. 1:0.001, 1:0.003, 1:0.004, 1:0.005, 1:0.006, 1:0.007, 1:0.008 or 1:0.01, preferably 1 (0.003-0.006).
Preferably, the reducing agent in the reduction reaction in 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 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 ℃, for example 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 16 hours, for example 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours or 16 hours, preferably 10 to 14 hours.
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 of 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, zinc powder or a combination of zinc powder and an acid, preferably a combination of zinc powder and an 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, preferably acetic acid and/or propionic acid.
Preferably, when the reducing agent in the step (3) is hydrogen, the catalyst is any one of palladium-carbon, platinum-carbon or Raney nickel, and is 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 (0.001-0.02), for example 1:0.001, 1:0.003, 1:0.004, 1:0.005, 1:0.006, 1:0.007, 1:0.008 or 1:0.01, preferably 1 (0.003-0.01).
Preferably, when the reducing agent in the step (3) is hydrogen, the pressure after introducing 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 compound 4 (aminoamide) to reducing agent in step (3) is 1 (1.5-6), for example 1:1.5, 1:1.8, 1:2, 1:2.5, 1:2.8, 1:3, 1:3.5, 1:3.8, 1:4, 1:4.5, 1:4.8, 1:5, 1:5.5, 1:5.8 or 1:6, preferably 1 (2-4).
Preferably, the molar ratio of compound 4 (aminoamide) to compound 5 in step (3) is from 1:1.2 to 3, for example from 1:1.2, 1:1.5, 1:1.8, 1:2, 1:2.3, 1:2.5, 1:2.8, 1:3, preferably from 1:1.6 to 2.
Preferably, the molar ratio of compound 4 (aminoamide) to acid in step (3) is from 1 (0 to 12), for example 1：0.2、1：0.4、1：0.6、1：1.2、1：1.8、1：2.4、1:3、1:3.5、1:3.8、1:4、1:4.5、1:5、1:5.5、1:6、1:6.5、1:7、1:7.5、1:8、1:9、1:10、1:11、1:12, is preferably from 1 (4 to 8).
Preferably, the temperature of the reaction in step (3) is from 25 to 150 ℃, for example 25 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃, 80 ℃ or 90 ℃, preferably from 60 to 120 ℃.
Preferably, the reaction time in step (3) is 1 to 10 hours, for example 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, the mass ratio of compound 4 (aminoamide) to solvent in step (3) is from 1:2 to 8, for example from 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, preferably from 1:4 to 6.
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, the mass ratio of compound 6 (cyclopropylamide) to solvent in step (4) is 1 (2-8), e.g. 1:2, 1:2.5, 1:2.8, 1:3, 1:3.5, 1:3.8, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5 or 1:8, preferably 1 (4-6).
Preferably, the molar ratio of compound 6 (cyclopropylamide) to compound 7 in step (4) is 1 (1-1.5), for example 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, preferably 1 (1.05-1.1).
Preferably, the temperature of the reaction in step (4) is 40 to 180 ℃, for example 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, for example 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) is finished, the next step can be carried out 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 or a combination of at least two of alkali metal bromide, alkaline earth metal bromide, hydrobromic acid, bromine and ammonium bromide, preferably sodium bromide or hydrobromic acid.
Preferably, the oxidizing agent is one or a combination of at least two of chlorine, alkali metal or alkaline earth metal perchlorate, chlorate, chlorite or hypochlorite, preferably one or a combination of at least two of sodium chlorate, sodium hypochlorite or chlorine.
Preferably, the molar ratio of compound 8 (bisamide) to bromide in step (5) is 1 (0.55-2.0), for example 1:0.55, 1:0.7, 1:0.9, 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8 or 1:2, preferably 1 (1.2-1.6).
Preferably, the molar ratio of compound 8 (bisamide) to the oxidizing agent in step (5) is 1 (0.2-2.0), e.g. 1:0.2, 1:0.4, 1:0.55, 1:0.7, 1:0.9, 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8 or 1:2, etc., preferably 1 (0.4-1.6).
Preferably, the bromination reaction of step (5) is carried out in the presence of an alkaline substance.
Preferably, the alkaline substance is one or a combination of at least two of an alkali metal or alkaline earth metal hydroxide, carbonate and bicarbonate, preferably sodium hydroxide or potassium hydroxide.
Preferably, the molar ratio of compound 8 (bisamide) to basic substance is 1 (0-3.0), for example 1:0.3, 1:0.5, 1:0.8, 1:1, 1:1.5, 1:1.8, 1:2, 1:2.2, 1:2.5, 1:2.8, 1:3, preferably 1 (0.5-2.8).
Preferably, the bromination reaction in step (5) is carried out at a temperature of 0 to 150 ℃, for example 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 period of time of from 0.5 to 8 hours, for example from 0.5 hours, 0.6 hours, 0.8 hours, 1 hour, 1.5 hours, 1.8 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours or 8 hours, preferably from 1 to 2 hours.
After the reaction in the step (5) is finished, separating the reaction liquid while the reaction liquid is hot, adding sodium sulfite solution into an organic layer for washing, then adding hydrochloric acid to adjust the pH to 4-5, then separating the solution, concentrating the organic layer to obtain a light yellow product crude product, and then recrystallizing the light yellow product by an organic solvent and drying to obtain a white solid, namely the product. The organic solvent used for the recrystallization is one or a combination of at least two of dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, ethyl acetate, methanol, ethanol and 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 reaction, few by-products are generated, 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 more than 90%, the yield is high, the preparation method is more suitable for industrial production, and meanwhile, the route can obtain high-purity products without separation until the original medicine is synthesized or through simple solvent separation.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
In the present invention, the starting material, compound 2, is prepared by the method disclosed in reference to EP2319830 A1.
The overall synthesis 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 was prepared wherein Z 1、Z2、Z4 and Z 5 are hydrogen, Z 3 is fluorine, R 1 is fluorine, R 2 and R 3 are hydrogen, and W 1 and W 2 are 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 1 is F), 265.2g of toluene and 53.9g (0.26 mol) of compound 1 are sequentially added, the mixture is heated to 110 ℃ for reaction for 4 hours, 40g of 10% sodium carbonate solution is slowly added after being cooled slightly, the mixture is stirred for 30min at 80 ℃ and separated when the mixture is hot, and 367.6g of an organic layer with 26.7% of nitroamide content and 99.3% of yield are obtained.
Mass spectrometry detection: LC/MS [ M+1]: m/z=495;
(2) Sequentially adding 367.6g of the organic layer obtained in the step (1) and 0.29g of 10% palladium-carbon catalyst into a 1L autoclave, hydrogenating to a pressure of 0.5MPa, reacting for 10 hours at 100 ℃, filtering, drying and removing filtrate to obtain 361.2g of amino-amide toluene solution, wherein the amino-amide content is 24.9%, and the yield is 97.6%.
Mass spectrometry detection: LC/MS [ M+1]: m/z=465;
(3) 361.2g (content: 24.9%,0.194 mol) of the amino-amide toluene solution obtained in the step (2), 22.4g (0.31 mol) of cyclopropylamide 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 the dropwise addition, the hot filtration is carried out, the pH of the filtrate is adjusted to 7 by 160g of 20% sodium hydroxide solution at 50 ℃, the solution is separated while the hot, and 382.3g of cyclopropylamide toluene solution is obtained, the content of cyclopropylamide is 25.1%, and the yield is 95.5%.
Mass spectrometry detection: LC/MS [ M+1]: m/z=519;
(4) 382.3g (content 25.1%,0.185 mol) of cyclopropylamide toluene solution obtained in the step (3) and 32.7g (0.2 mol) of 4-fluorobenzoyl chloride are sequentially added into a 500mL reaction kettle, 40g of 20% sodium hydroxide solution is slowly added after the reaction is carried out for 5h at the temperature of 100 ℃, stirring is carried out for 30min at the temperature of 80 ℃, 403.6g of organic phase is obtained after hot separation, the content of bisamide is 29.2%, and the yield is 99.5%.
Mass spectrometry detection: LC/MS [ M+1]: m/z=641;
(5) In a 500mL reaction vessel, 403.6g (content 29.2%,0.184 mol) of the organic phase obtained in the 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, after the temperature is raised to 70 ℃, 54.1g of 14.5% sodium chlorate solution is dropwise added, after the dropwise addition, the reaction is continued for 1h, the solution is separated while the solution is hot, the organic phase is washed with 50g of 7.5% sodium sulfite solution at 70 ℃, the pH value is adjusted to 5 by 12.9g of concentrated hydrochloric acid, the solution is separated while the solution is hot again, 138.7g of light yellow crude product is obtained after the concentration of the organic phase, the crude product is dissolved in 180mL toluene for recrystallization, and the white solid is obtained after the drying, the content is 99.2%, and the yield is 92.6%.
Mass spectrometry detection: LC/MS [ M+1]: m/z=720;
H NMR (400 MHz, DMSO-d 6) data were as follows (δ[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 was prepared wherein Z 1、Z2、Z4 and Z 5 are hydrogen, Z 3 is chlorine, R 1、R2 and R 3 are hydrogen, W 1 and W 2 are oxygen, i.e
The preparation method comprises the following steps:
(1) In a 500mL reaction vessel, 62.0g (0.2 mol) of compound 2 (R 1 is hydrogen), 186.0g of dimethylbenzene and 49.8g (0.24 mol) of compound 1 are sequentially added, the mixture is heated to 120 ℃ for reaction for 6 hours, 40g of 10% sodium hydroxide solution is slowly added after the mixture is cooled slightly, the mixture is stirred for 30 minutes at 80 ℃, the organic layer is cooled to room temperature after the mixture is separated while the mixture is hot, then the mixture is placed in an ice machine for stirring for 3 hours at 5 ℃, 93.1g of nitroamide yellow solid is obtained after the mixture is filtered and dried, and the content is 98.5%, and the yield is 96.3%.
Mass spectrometry 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, hydrogenation is carried out to a pressure of 2.5MPa, the reaction is carried out for 12 hours at a temperature of 60 ℃, filtration is carried out, the filtrate is concentrated to obtain a grey solid, 89.7g is dried, the content is 98.5%, and the yield is 99.1%.
Mass spectrometry detection: LC/MS [ M+1]: m/z=447;
(3) Into a 500ml autoclave, 46.9g (0.1 mol) of aminoamide, 0.14g of 10% Pd-C, 12.9g (0.18 mol) of cyclopropylaldehyde, 24g (0.4 mol) of acetic acid and 237.6g of methanol were charged. 3 times with nitrogen and then hydrogen to 0.5MPa. Heating to 100 ℃, cooling the reaction kettle to 40 ℃ after reacting for 6 hours, filtering, leaching the catalyst with methanol, combining organic phases, and then decompressing to remove the solvent. 150ml toluene and 50ml water are added into the residue, the PH=7-8 is regulated by 30% sodium hydroxide, the mixture is separated when the mixture is hot, the organic layer is placed at 0-5 ℃ and stirred for 3 hours, the mixture is filtered and dried to obtain 46.4g of light yellow cyclopropylamide, the content is 98.6%, and the yield is 91.5%.
Mass spectrometry detection: LC/MS [ M+1]: m/z=501;
(4) 50.0g (0.1 mol) of cyclopropylamide, 300g of toluene and 20.8g (0.11 mol) of 4-chlorobenzoyl chloride are sequentially added into a 500mL reaction kettle, 40g of 10% sodium carbonate solution is slowly added after the reaction is carried out for 3 hours at the temperature of 110 ℃, the mixture is stirred for 30 minutes at the temperature of 80 ℃ and then is separated into 366.8g of organic phase while the mixture is hot, the organic phase is reserved, the bisamide content is 17.2%, and the yield is 98.6%.
Mass spectrometry detection: LC/MS [ M+1]: m/z=640;
(5) In a 500mL reaction vessel, 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 were sequentially added, 8.5g (0.119 mol) of chlorine gas was introduced after heating to 90 ℃, the reaction was continued for 2 hours after passing, the hot separated liquid was washed with 50g of 7.5% sodium sulfite solution at 90 ℃, the pH was adjusted to 4 by 13.8g of concentrated hydrochloric acid, the hot separated liquid was again, 76.5g of a pale yellow crude product was obtained after concentrating the organic phase, the crude product was dissolved in 90mL of isopropanol for recrystallization, and a white solid product was obtained after drying, the content was 67.4g, the yield was 99.2%, and 94.1%.
Mass spectrometry detection: LC/MS [ M+1]: m/z=719;
h NMR (400 MHz, DMSO-d 6) data were as follows (δ[ppm])：1H NMR(400MHz,DMSO-d6)δ[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 was prepared wherein Z 1、Z2、Z4 and Z 5 are hydrogen, Z 3 is cyano, R 1 is fluoro, R 2、R3 is hydrogen, W 1 and W 2 are oxygen, i.e
The preparation method comprises the following steps:
(1) In a 250mL reaction kettle, 65.4g (0.2 mol) of compound 2 (R 1 is fluorine), 130.8g of toluene and 43.6g (0.21 mol) of compound 1 are sequentially added, the mixture is heated to 110 ℃ for reaction for 6 hours, 40g of 10% sodium carbonate solution is slowly added after the mixture is cooled slightly, the mixture is stirred for 30 minutes at 80 ℃, the organic layer is cooled to room temperature after hot liquid separation, then the mixture is placed in an ice machine and stirred for 3 hours at 0 ℃, and 96.4g of nitroamide yellow solid with the content of 98.2% and the yield of 95.8% is obtained after filtration and drying.
Mass spectrometry 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, hydrogenation is carried out to a pressure of 2.5MPa, reaction is carried out for 14h at a temperature of 40 ℃, filtration is carried out, filtrate is concentrated to obtain a grey solid, 93.2g of amino amide is obtained after drying, the content is 98.6%, and the yield is 99.0%.
Mass spectrometry detection: LC/MS [ M+1]: m/z=465;
(3) Into a 500mL autoclave, 46.9g (0.1 mol), 0.47g of 10% Pt-C, 12.9g (0.18 mol) of cyclopropylaldehyde, 29.6g (0.4 mol) of propionic acid, and 281.4g of toluene were charged. The mixture was replaced 3 times with nitrogen and then hydrogen was introduced to 2.5MPa. Heating to 120 ℃, cooling the reaction kettle to 40 ℃ after reacting for 4 hours, filtering, leaching the catalyst by toluene, combining organic phases and then decompressing to remove the solvent. To the residue was added 150mL toluene, 50mL water, ph=7 with 30% sodium hydroxide, the solution was separated while hot, the organic layer was stirred at 0 ℃ for 3 hours, filtered, and dried to give 48.9g of pale yellow cyclopropylamide, content 98.2%, yield 92.8%.
Mass spectrometry detection: LC/MS [ M+1]: m/z=519;
(4) 51.8g (0.1 mol), 259g of 1, 2-dichloroethane and 17.7g (0.105 mol) of 4-cyanobenzoyl chloride are sequentially added into a 500mL reaction kettle, 40g of 10% sodium carbonate solution is slowly added after the reaction is carried out for 4 hours at the temperature of 80 ℃, the mixture is stirred for 30 minutes at the temperature of 80 ℃ and then separated into 332.9g of organic phase when the mixture is hot, the organic phase is ready for use, the content of bisamide is 19.3%, and the yield is 99.3%.
Mass spectrometry detection: LC/MS [ M+1]: m/z=648;
(5) In a 500mL reaction vessel, 332.9g (content 19.1%,0.099 mol) of the organic phase obtained in the step (4), 12.3g (0.119 mol) of sodium bromide, 2.1g (0.049 mol) of NaOH and 30g of water are sequentially added, after the temperature is raised to 40 ℃, 82.2g of 14.5% sodium hypochlorite solution is dropwise added, the reaction is continued for 1.5 hours after the completion of the dropwise addition, the organic phase is separated into a liquid while hot, 50g of 7.5% sodium sulfite solution is used for washing at 50 ℃, and 11.9g of concentrated hydrochloric acid is used for regulating the pH to 4 at the moment, the liquid while hot is separated again, 74.9g of light yellow crude product is obtained after the organic phase is concentrated, the crude product is dissolved in 60mL of methanol for recrystallization, and a white solid product with 67.5g and the content of 99.2% is obtained after the drying, and the yield is 93.2%.
Mass spectrometry detection: LC/MS [ M+1]: m/z=727;
h NMR (400 MHz, DMSO-d 6) data were as follows (δ[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 was prepared wherein Z 1、Z3、Z5 is hydrogen, Z 2、Z4 is fluorine, R 1、R2、R3 is hydrogen, W 1 and W 2 are oxygen, i.e
The preparation method comprises the following steps:
(1) In a 500mL reaction vessel, 62.0g (0.2 mol) of compound 2 (R 1 is hydrogen), 186.0g of dimethylbenzene and 49.8g (0.24 mol) of compound 1 are sequentially added, the mixture is heated to 140 ℃ for reaction for 5 hours, 40g of 10% sodium hydroxide solution is slowly added after the mixture is cooled slightly, the mixture is stirred for 30 minutes at 80 ℃, the organic layer is cooled to room temperature after the mixture is separated while the mixture is hot, then the mixture is placed in an ice machine for stirring for 3 hours at 5 ℃, 93.1g of nitroamide yellow solid is obtained after the mixture is filtered and dried, and the content is 98.5%, and the yield is 96.3%.
Mass spectrometry 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, hydrogenation is carried out to a pressure of 1.5MPa, the reaction is carried out for 12 hours at a temperature of 60 ℃, filtration is carried out, the filtrate is concentrated to obtain a grey solid, 89.7g is dried, the content is 98.5%, and the yield is 99.1%.
Mass spectrometry detection: LC/MS [ M+1]: m/z=447;
(3) In a 500mL reaction kettle, 44.7g (0.1M mol), 223.5g of ethyl acetate, 14.3g (0.2 mol) of cyclopropylaldehyde and 26g (0.4 mol) of zinc powder are sequentially added, 48g (0.8 mol) of acetic acid is dropwise added after 60 ℃, the reaction is continued for 1.5h after the dropwise addition, filtration is carried out while the mixture is hot, the filtrate is concentrated to obtain yellow solid, 50mL of toluene is added to be heated to 90 ℃ for dissolving, 50mL of water is added, 5.9g of 30% sodium hydroxide solution is used for adjusting the pH value to 8, the mixture is separated while the mixture is hot, the organic layer is placed at 0 ℃ for stirring for 3h, filtration and drying are carried out, and 48.6g of light yellow cyclopropylamide is obtained after the mixture is dried, the content is 98.6%, and the yield is 95.9%.
Mass spectrometry detection: LC/MS [ M+1]: m/z=501;
(4) 50.0g (0.1 mol) of cyclopropylamide, 200g of 1, 2-dichloroethane and 19.4g (0.108 mol) of 3, 5-difluorobenzoyl chloride are sequentially added into a 500mL reaction kettle, 40g of 10% sodium carbonate solution is slowly added after the temperature is raised to 80 ℃ for reaction for 4 hours, and 267.9g of organic phase is obtained after stirring for 30min at 80 ℃ and hot liquid separation, wherein the content of bisamide is 23.7%, and the yield is 99.3%.
Mass spectrometry detection: LC/MS [ M+1]: m/z=641;
(5) In a 500mL reaction vessel, 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 are sequentially added, after the temperature is raised to 70 ℃, 82.2g of 14.5% sodium hypochlorite solution is dropwise added, after the dropwise addition, the reaction is continued for 1.5h, the organic phase is separated into a liquid while being hot, 50g of 7.5% sodium sulfite solution is used for washing at 50 ℃, the pH value of the organic phase is adjusted to 5 by using 11.9g of concentrated hydrochloric acid while being hot, 75.2g of light yellow crude product is obtained after the organic phase is concentrated, the crude product is dissolved in 60mL of methanol for recrystallization, and the white solid product is obtained after the drying, and the content is 99.2% and the yield is 93.2%.
Mass spectrometry detection: LC/MS [ M+1]: m/z=720;
h NMR (400 MHz, DMSO-d 6) data were as follows (δ[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, refer to example two in CN 104245665B)
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 step 4 in example 1, and the mixture was stirred under ice for 10 minutes. 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, which was extracted with ethyl acetate, and then the organic layer was dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, the solvent was removed under reduced pressure, and the concentrated residue was purified by silica gel column chromatography to give 0.93g of a solid (yield 80%).
Comparative example 2 (bromine method, reference to method in CN 102491910A)
To a 100mL reaction vessel, 32g (0.05 mol) of the bisamide (namely, 2-fluoro-3- (N- (cyclopropylmethyl) -4-fluorobenzamide) -N- (2- (difluoromethoxy) -4- (heptafluoroisopropyl) phenyl) benzamide) obtained in the step 4 in example 1 and 50mL of 1, 2-dichloroethane were sequentially added, 8.8g (0.055 mol) of bromine was added dropwise at 20 ℃ for 30min, and the reaction was continued for 1h after the completion of the dropwise addition; 7.4g (0.065 mol) of hydrogen peroxide is added dropwise, the solvent is removed after the reaction is continued for 6 hours after the dripping is completed, and 40mL of isopropanol is crystallized to obtain 29.1g of white solid with the yield of 81 percent.
Comparative example 3 (Hydrogen bromide Hydrogen peroxide method, see method in CN 109704976A)
To a 100mL reaction vessel, 32g (0.05 mol) of the bisamide (namely, 2-fluoro-3- (N- (cyclopropylmethyl) -4-fluorobenzamide) -N- (2- (difluoromethoxy) -4- (heptafluoroisopropyl) phenyl) benzamide) obtained in the 4 th step in example 1 and 50mL of 1, 2-dichloroethane were sequentially added, the temperature was raised to 50 ℃, 7.4g (0.065 mol) of 30% hydrogen peroxide was added dropwise, the reaction was continued for 1h after the completion of the addition, and no reaction was monitored in a liquid phase.
The applicant states that the present invention is described by way of the above examples for the preparation of the difluoromethoxy-containing isopolyamide 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 practiced by relying on the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
Claims (80)
1. The preparation method of the difluoromethoxy-containing m-diamide compound shown in the 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, wherein the reaction formula is as follows:
(2) The compound 3 is subjected to reduction reaction to obtain a compound 4, wherein the reaction formula is as follows:
(3) Compound 4 is reacted with compound 5 to give compound 6, which has the following formula:
(4) Compound 6 and compound 7 are reacted to give compound 8, which has the following reaction formula:
(5) The compound 8 is brominated to obtain a difluoromethoxy-containing meta-diamide compound shown in the formula I, and the reaction formula is as follows:
wherein Z 1、Z2、Z3、Z4、Z5 is independently selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, C 1-C6 alkyl, C 1-C6 cycloalkyl, C 1-C6 haloalkyl, C 1-C6 halocycloalkyl, C 1-C6 alkoxy, C 1-C6 haloalkoxy, C 1-C6 alkylsulfinyl, C 1-C6 haloalkylsulfinyl, C 1-C6 alkylsulfonyl, or C 1-C6 haloalkylsulfonyl;
r 1 is selected from hydrogen or fluorine;
R 2 is selected from hydrogen, C 1-C6 alkyl, C 1-C6 haloalkyl, C 3-C8 cycloalkyl or C 3-C8 halocycloalkyl;
R 3 is selected from hydrogen or halogen;
W 1 and W 2 are independently an oxygen atom or a sulfur atom.
2. The production method according to claim 1, wherein Z 1、Z2、Z3、Z4、Z5 is each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, isobutyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, trifluoromethyl, pentafluoroethyl, heptafluoro-n-propyl, heptafluoro-isopropyl, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, methylsulfinyl, trifluoromethylsulfinyl, methylsulfonyl or trifluoromethylsulfonyl; r 2 is 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, monochloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoroisopropyl, cyclopropyl, cyclobutyl, cyclopentyl, perfluorocyclopropyl, perfluorocyclobutyl or perfluorocyclopentyl; r 3 is selected from hydrogen, fluorine or chlorine.
3. The method of claim 1, wherein Z 1、Z2、Z3、Z4、Z5 is each independently selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methanesulfonyl, or trifluoromethanesulfonyl; r 1 is selected from hydrogen or fluorine; r 2 is selected from hydrogen or methyl; r 3 is selected from hydrogen or chlorine; w 1 and W 2 are selected from oxygen.
4. The method of claim 1, wherein Z 1、Z2、Z3、Z4、Z5 is each independently selected from hydrogen, fluoro, chloro, cyano; r 1 is selected from hydrogen or fluorine; r 2 is selected from hydrogen; r 3 is selected from hydrogen, W 1 and W 2 are selected from oxygen.
5. The method according to claim 1, wherein the condensation reaction of step (1) is carried out in a solvent which is any one or a combination of at least two of dichloromethane, 1, 2-dichloroethane, chloroform, benzene, toluene, xylene, chlorobenzene or dichlorobenzene.
6. The method according to claim 5, wherein the solvent is toluene and/or xylene.
7. The process according to claim 1, wherein the molar ratio of compound 1 to compound 2 in step (1) is 1 to 1.5:1.
8. The process according to claim 7, wherein the molar ratio of compound 1 to compound 2 in step (1) is 1.05 to 1.3.
9. The preparation method according to claim 1, wherein the mass ratio of the compound 2 to the solvent in the step (1) is 1 (1-5).
10. The preparation method according to claim 9, wherein the mass ratio of the compound 2 to the solvent in the step (1) is 1 (2-4).
11. The process according to claim 1, wherein the temperature of the reaction in step (1) is 40 to 180 ℃.
12. The process of claim 11, wherein the temperature of the reaction in step (1) is 110 to 140 ℃.
13. The process according to claim 1, wherein the reaction time in step (1) is 3 to 8 hours.
14. The process of claim 13, wherein the reaction time in step (1) is 4 to 6 hours.
15. The process according to claim 1, wherein the reaction in step (2) is carried out in a solvent which is one or a combination of at least two of methanol, ethanol, acetonitrile, benzene, toluene, xylene, chlorobenzene and ethyl acetate.
16. The method of claim 15, wherein the solvent is methanol, toluene, or ethyl acetate.
17. The method according to claim 1, wherein the reduction reaction in step (2) is performed in the presence of a catalyst selected from the group consisting of palladium on carbon, platinum on carbon and Raney nickel.
18. The method of claim 17, wherein the catalyst is a palladium on carbon or platinum on carbon catalyst.
19. The preparation method according to claim 1, wherein the mass ratio of the compound 3 to the solvent in the step (2) is 1 (2-8).
20. The preparation method according to claim 19, wherein the mass ratio of the compound 3 to the solvent in the step (2) is 1 (3-5).
21. The preparation method according to claim 17, wherein the mass ratio of the compound 3 to the catalyst in the step (2) is 1 (0.001-0.01).
22. The method according to claim 1, wherein the reducing agent in the reduction reaction in the step (2) is hydrogen.
23. The method according to claim 22, wherein the pressure after the introduction of hydrogen in the reduction reaction in the step (2) is controlled to be 0.1 to 3.0MPa.
24. The method according to claim 23, wherein the pressure after the introduction of hydrogen in the reduction reaction in the step (2) is controlled to be 0.5 to 2.5MPa.
25. The method according to claim 1, wherein the temperature of the reduction reaction in the step (2) is 25 to 120 ℃.
26. The method according to claim 25, wherein the temperature of the reduction reaction in step (2) is 40 to 100 ℃.
27. The method according to claim 1, wherein the time of the reduction reaction in the step (2) is 8 to 16 hours.
28. The method according to claim 27, wherein the time of the reduction reaction in the step (2) is 10 to 14 hours.
29. The method of claim 1, wherein the reaction of step (3) is performed in a solvent selected from one or a combination of at least two of tetrahydrofuran, dichloromethane, methanol, ethyl acetate, 1, 2-dichloroethane, toluene, and xylene.
30. The method of claim 29, wherein the solvent is one or a combination of at least two of methanol, ethyl acetate, or toluene.
31. The process of claim 1, wherein the reaction of step (3) is carried out in the presence of a reducing agent which is one or a combination of at least two of hydrogen, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride, zinc powder, or a combination of zinc powder and an acid.
32. The process of claim 31 wherein the reducing agent is a combination of zinc powder and an acid or hydrogen.
33. The method of claim 31, wherein 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.
34. The method of claim 33, wherein the acid is acetic acid and/or propionic acid.
35. The method according to claim 31, wherein when the reducing agent in the step (3) is hydrogen, the catalyst is any one of palladium on carbon, platinum on carbon or raney nickel.
36. The method according to claim 35, wherein when the reducing agent in the step (3) is hydrogen, the catalyst is palladium-carbon or platinum-carbon catalyst.
37. The process according to claim 31, wherein the mass ratio of the aminoamide to the catalyst in the case where the reducing agent in the step (3) is hydrogen is 1 (0.001 to 0.02).
38. The method according to claim 37, wherein when the reducing agent in the step (3) is hydrogen, the mass ratio of the aminoamide to the catalyst is 1 (0.003 to 0.01).
39. The method according to claim 31, wherein when the reducing agent in the step (3) is hydrogen, the pressure after introducing hydrogen is controlled to be 0.1 to 3.0MPa.
40. The process according to claim 39, wherein when the reducing agent in the step (3) is hydrogen, the pressure after introducing hydrogen is controlled to be 0.5 to 2.5MPa.
41. The process according to claim 31, wherein the molar ratio of compound 4 to reducing agent in step (3) is1 (1.5-6).
42. The process according to claim 41, wherein the molar ratio of the compound 4 to the reducing agent in the step (3) is 1 (2-4).
43. The preparation method according to claim 1, wherein the molar ratio of the compound 4 to the compound 5 in the step (3) is 1:1.2-3.
44. The process of claim 43, wherein the molar ratio of compound 4 to compound 5 in step (3) is 1:1.6-2.
45. The process of claim 32, wherein the molar ratio of compound 4 to acid in step (3) is 1 (0-12).
46. The process according to claim 45, wherein the molar ratio of the compound 4 to the acid in the step (3) is 1 (4 to 8).
47. The process according to claim 1, wherein the temperature of the reaction in step (3) is 25 to 150 ℃.
48. The process of claim 47, wherein the temperature of the reaction in step (3) is 60 to 120 ℃.
49. The method according to claim 1, wherein the reaction time in the step (3) is 1 to 10 hours.
50. The process of claim 49, wherein the reaction time in step (3) is 1.5 to 6 hours.
51. The preparation method according to claim 29, wherein the mass ratio of the compound 4 to the solvent in the step (3) is 1 (2-8).
52. The process according to claim 51, wherein the mass ratio of the compound 4 to the solvent in the step (3) is 1 (4 to 6).
53. The method of claim 1, wherein the reaction of step (4) is carried out in a solvent selected from the group consisting of dichloromethane, 1, 2-dichloroethane, chloroform, benzene, toluene, xylene, chlorobenzene, and dichlorobenzene.
54. The process of claim 53 wherein the solvent is 1, 2-dichloroethane or toluene.
55. The process according to claim 53, wherein the mass ratio of the compound 6 to the solvent in the step (4) is 1 (2 to 8).
56. The process of claim 55, wherein the mass ratio of compound 6 to solvent in step (4) is 1 (4-6).
57. The process according to claim 1, wherein the molar ratio of compound 6 to compound 7 in step (4) is 1 (1-1.5).
58. The process of claim 57 wherein the molar ratio of compound 6 to compound 7 in step (4) is 1 (1.05-1.1).
59. The process according to claim 1, wherein the temperature of the reaction in step (4) is 40 to 180 ℃.
60. The process of claim 59 wherein the temperature of the reaction in step (4) is 80 to 110 ℃.
61. The method according to claim 1, wherein the reaction time in the step (4) is 1 to 6 hours.
62. The process of claim 61 wherein the time of the reaction in step (4) is 3 to 5 hours.
63. The process of claim 1, wherein the bromination reaction of step (5) is carried out in the presence of bromide and an oxidizing agent.
64. The method of claim 63, wherein the bromide is one or a combination of at least two of alkali metal bromide, alkaline earth metal bromide, hydrobromic acid, bromine, and ammonium bromide.
65. The method of claim 64, wherein the bromide is sodium bromide or hydrobromic acid.
66. The method of claim 63, wherein the oxidizing agent is one or a combination of at least two of chlorine, alkali or alkaline earth perchlorate, chlorate, chlorite or hypochlorite.
67. The method of claim 66, wherein the oxidizing agent is one or a combination of at least two of sodium chlorate, sodium hypochlorite, or chlorine gas.
68. The process of claim 63 wherein the molar ratio of compound 8 to bromide in step (5) is 1 (0.55-2.0).
69. The process of claim 68 wherein the molar ratio of compound 8 to bromide in step (5) is from 1 (1.2) to 1.6.
70. The process of claim 63 wherein the molar ratio of compound 8 to oxidant in step (5) is 1 (0.2-2.0).
71. The process of claim 63 wherein the molar ratio of compound 8 to oxidant in step (5) is 1 (0.4-1.6).
72. The process according to claim 1, wherein the bromination reaction of step (5) is carried out in the presence of an alkaline substance.
73. The method of claim 72, wherein the alkaline material is one or a combination of at least two of an alkali metal or alkaline earth metal hydroxide, carbonate and bicarbonate.
74. The method of claim 73, wherein the alkaline material is sodium hydroxide or potassium hydroxide.
75. The process of claim 72 wherein the molar ratio of compound 8 to alkaline material is 1 (0.05-3.0).
76. The process according to claim 75, wherein the molar ratio of the compound 8 to the basic substance is 1 (0.5 to 2.8).
77. The process of claim 1, wherein the bromination reaction in step (5) is carried out at a temperature of 0 to 150 ℃.
78. A method as in claim 77, wherein said bromination reaction of step (5) is carried out at a temperature of 40-90 ℃.
79. The process of claim 1, wherein the bromination reaction in step (5) is carried out for a period of 0.5 to 8 hours.
80. The process of claim 79, wherein the bromination reaction of step (5) is carried out for a period of time of 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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| 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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