CN114920699B - Method for preparing 6-chloro-2-methyl-2H-indazol-5-amine - Google Patents
Method for preparing 6-chloro-2-methyl-2H-indazol-5-amine Download PDFInfo
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- CN114920699B CN114920699B CN202210613253.0A CN202210613253A CN114920699B CN 114920699 B CN114920699 B CN 114920699B CN 202210613253 A CN202210613253 A CN 202210613253A CN 114920699 B CN114920699 B CN 114920699B
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- organic solvent
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- YRZNRFJEBAPCCO-UHFFFAOYSA-N Cn1cc2cc(N)c(Cl)cc2n1 Chemical compound Cn1cc2cc(N)c(Cl)cc2n1 YRZNRFJEBAPCCO-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 96
- 238000004519 manufacturing process Methods 0.000 claims abstract description 20
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 14
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical group CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 7
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 claims abstract description 6
- 238000005658 halogenation reaction Methods 0.000 claims abstract description 5
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 84
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- 239000003960 organic solvent Substances 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 10
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 9
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- 229910052802 copper Inorganic materials 0.000 claims description 8
- 239000010949 copper Substances 0.000 claims description 8
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 8
- 230000002140 halogenating effect Effects 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 229910017604 nitric acid Inorganic materials 0.000 claims description 8
- 239000013110 organic ligand Substances 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 6
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 5
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 5
- 229930182821 L-proline Natural products 0.000 claims description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 5
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 5
- 229960000583 acetic acid Drugs 0.000 claims description 5
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- NCPHGZWGGANCAY-UHFFFAOYSA-N methane;ruthenium Chemical compound C.[Ru] NCPHGZWGGANCAY-UHFFFAOYSA-N 0.000 claims description 5
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 5
- 235000011009 potassium phosphates Nutrition 0.000 claims description 5
- 229960002429 proline Drugs 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 5
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- STJMRWALKKWQGH-UHFFFAOYSA-N clenbuterol Chemical compound CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(Cl)=C1 STJMRWALKKWQGH-UHFFFAOYSA-N 0.000 claims description 4
- 229960001117 clenbuterol Drugs 0.000 claims description 4
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 4
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 4
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 4
- QYJPSWYYEKYVEJ-FDGPNNRMSA-L copper;(z)-4-oxopent-2-en-2-olate Chemical compound [Cu+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O QYJPSWYYEKYVEJ-FDGPNNRMSA-L 0.000 claims description 4
- 229940076286 cupric acetate Drugs 0.000 claims description 4
- 229960003280 cupric chloride Drugs 0.000 claims description 4
- 229940045803 cuprous chloride Drugs 0.000 claims description 4
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 4
- 229940112669 cuprous oxide Drugs 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 238000006396 nitration reaction Methods 0.000 claims description 4
- -1 oxalyl diamine Chemical class 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 2
- 229910052731 fluorine Inorganic materials 0.000 claims 2
- 239000011737 fluorine Substances 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 abstract description 54
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 5
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 229910002651 NO3 Inorganic materials 0.000 abstract description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 230000026030 halogenation Effects 0.000 abstract 1
- 230000001546 nitrifying effect Effects 0.000 abstract 1
- 235000013350 formula milk Nutrition 0.000 description 61
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 23
- 239000005457 ice water Substances 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 239000007787 solid Substances 0.000 description 11
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- QMPBBNUOBOFBFS-UHFFFAOYSA-N 6-[(6-chloro-2-methylindazol-5-yl)amino]-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione Chemical compound CN1N=C(C=C(C(/N=C(\NC(N2CC3=NN(C)C=N3)=O)/N(CC(C=C(C(F)=C3)F)=C3F)C2=O)=C2)Cl)C2=C1 QMPBBNUOBOFBFS-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000007069 methylation reaction Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- IRSVDHPYXFLLDS-UHFFFAOYSA-N 2,4-dichloro-1-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C=C1Cl IRSVDHPYXFLLDS-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- SXVCMKGCWGVSSX-UHFFFAOYSA-N 6-chloro-5-nitro-1h-indazole Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC2=C1NN=C2 SXVCMKGCWGVSSX-UHFFFAOYSA-N 0.000 description 2
- 241000711573 Coronaviridae Species 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- OKOSGBYZOWWAPH-UHFFFAOYSA-N 5-chloro-2-methyl-4-nitroaniline Chemical compound CC1=CC([N+]([O-])=O)=C(Cl)C=C1N OKOSGBYZOWWAPH-UHFFFAOYSA-N 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 241001678559 COVID-19 virus Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- ZKXWKVVCCTZOLD-UHFFFAOYSA-N copper;4-hydroxypent-3-en-2-one Chemical compound [Cu].CC(O)=CC(C)=O.CC(O)=CC(C)=O ZKXWKVVCCTZOLD-UHFFFAOYSA-N 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 235000020610 powder formula Nutrition 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000005727 virus proliferation Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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Abstract
The invention discloses a method for preparing 6-chloro-2-methyl-2H-indazole-5-amine, belongs to the technical field of drug synthesis, and solves the problems of low yield, high cost and difficulty in realizing large-scale production in the existing synthesis method. The preparation method of the invention comprises the following steps: carrying out intramolecular cyclization on a compound shown in a formula III or a formula VIII after carrying out halogenation and methyl hydrazine substitution reaction to obtain a compound shown in a formula VI or a formula XI; the compound of formula VI is subjected to oxidative dehydrogenation to form nitrate, and then nitrifying reaction is carried out to obtain a compound of formula II; oxidative dehydrogenation of the compound of formula XI to obtain a compound of formula II; the compound of the formula II is subjected to catalytic hydrogenation to reduce nitro to obtain a target product. Compared with the prior report, the method has the advantages that the used raw materials and the used reagents are low in cost and easy to obtain, the selectivity is good, the yield is high, and the cost is effectively reduced; the production process is green and environment-friendly, and the safety is high; the intermediate and the product purification method are simple and are suitable for large-scale production.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a method for preparing an anti-novel coronavirus medicine intermediate 6-chloro-2-methyl-2H-indazole-5-amine.
Background
Ensitrelvir (S-217622) was the first orally active, non-covalent, non-peptide SARS-CoV-2 3CL protease inhibitor developed by the Japanese salt field.
The salt field announced that phase IIb clinical trial analysis of the oral novel crown drug Ensitrelvir (S-217622) was completed and production sales approval was applied to the Japanese Ministry of thick students based on phase IIb clinical data, 25 days 2.
The therapeutic principle of the novel oral medicine is to prevent severe disease by inhibiting proliferation of novel coronavirus. Within 5 days of the patient's diagnosis, the oral administration is carried out 1 time a day, and the virus proliferation is hindered by continuous administration for 5 days.
The structural formula is as follows:
6-chloro-2-methyl-2H-indazol-5-amine (I) is a key intermediate for the synthesis of Ensitrelvir (S-217622). Therefore, how to synthesize the intermediate in high yield and high selectivity is important.
Patent WO2019153080 discloses a process for the preparation of 6-chloro-2-methyl-2H-indazol-5-amine (i), which is specifically synthesized as follows:
according to the method, 2-methyl-4-nitro-5-chloroaniline is used as a starting material, diazotization cyclization reaction is carried out under the action of sodium nitrite, 5-nitro-6-chloro-1H-indazole is obtained in 38.46% yield, and the intermediate is subjected to N-methylation reaction to obtain a target product N-2-methylated product, namely a compound of formula II, in 26.32% yield, and 56.39% is an N-1-methylated product. Finally, the nitro group is reduced by iron powder to obtain the compound of the formula I with 10 percent of total yield. Although the method is short, the raw materials are not supplied commercially, and the method needs customization and is high in price. N-methylation is poorly selective and mostly occurs as the 1-position methylation product. The iron powder is used for reducing nitro, so that a large amount of iron mud is produced, the iron mud is difficult to recycle and treat, a large amount of solid waste is produced, and environmental pollution is caused. All intermediates and products need to be separated and purified by column chromatography, and large-scale production is difficult to realize.
Although the prior patent (WO 2015104662, EP 3889150) discloses a different method for preparing the compound 5-nitro-6-chloro-1H-indazole, the problem of poor N-alkylation selectivity of the indazole ring is unavoidable.
Disclosure of Invention
The invention aims to provide a method for preparing 6-chloro-2-methyl-2H-indazole-5-amine, which aims to solve the problems of low yield, high cost and difficulty in realizing large-scale production in the existing synthesis method.
The technical scheme of the invention is as follows: a process for preparing 6-chloro-2-methyl-2H-indazol-5-amine comprising the steps of:
wherein R is hydrogen or hydroxy; x is X 1 Is one of chlorine, bromine and iodine; x is X 2 Is one of chlorine and bromine.
Step one: dissolving a compound of a formula III in an organic solvent, and carrying out halogenation reaction with a halogenating reagent to obtain a compound of a formula IV;
step two: dissolving the compound of the formula IV prepared in the step one in an organic solvent, and carrying out substitution reaction with methyl hydrazine to obtain a compound of the formula V, wherein the molar ratio of the compound of the formula IV to the methyl hydrazine is 1.0:2.0-10.0;
step three: dissolving the compound of the formula V prepared in the second step in an organic solvent, carrying out intramolecular cyclization reaction in the presence of a copper catalyst and an organic ligand under an alkaline condition, and extracting by using an extraction solvent to obtain a compound extract of the formula VI;
step four: oxidative dehydrogenation is carried out on the extract of the compound of the formula VI prepared in the step three under the oxygen atmosphere, and then the compound of the formula VII is obtained by salifying with nitric acid, wherein the molar ratio of the compound of the formula VI to the nitric acid is 1.0:1.0-10.0;
step five: dissolving the compound of the formula VII prepared in the step four in acid, and performing nitration reaction to obtain a compound of the formula II;
step six: and (3) dissolving the compound shown in the formula II prepared in the step (V) in an organic solvent, adding a catalyst for catalytic hydrogenation to reduce nitro, and performing post-treatment and purification to obtain the compound shown in the formula I, namely 6-chloro-2-methyl-2H-indazole-5-amine.
Further, the organic solvent used in the first step is selected from one or more of dichloromethane, dichloroethane, chloroform, chlorobenzene, cyclohexane, benzene and acetonitrile; the halogenating reagent used in the first step is selected from one of thionyl chloride, sulfonyl chloride, N-chlorosuccinimide, clenbuterol, dibromohydantoin, N-bromosuccinimide and phosphorus tribromide.
Further, the organic solvent used in the second step is selected from one or more of dichloromethane, dichloroethane, toluene, methyl tert-butyl ether, methanol, ethanol, isopropanol, acetonitrile and N, N-dimethylformamide.
Further, the organic solvent used in the third step is selected from one or more of toluene, dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide; the alkali used in the third step is selected from one or a mixture of more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and potassium phosphate; the copper catalyst used in the third step is selected from one or more of cuprous chloride, cuprous bromide, cuprous iodide, cuprous trifluoromethane sulfonate, cupric acetylacetonate, cuprous oxide, cupric acetate and cupric chloride; the organic ligand used in the third step is selected from one or more of N, N '-dimethylethylenediamine, N' -tetramethylethylenediamine, ethylenediamine, L-proline, 1, 10-phenanthroline and oxalyl diamine; the extraction solvent used in the third step is selected from one or more of dichloromethane, dichloroethane, chloroform, methyl tertiary butyl ether, ethyl acetate and toluene.
Further, the acid used in the fifth step is one or a mixture of two of glacial acetic acid and concentrated sulfuric acid.
Further, the organic solvent used in the step six is selected from one or a mixture of more of dichloromethane, methanol, ethanol, isopropanol and tetrahydrofuran; the catalyst used in the step six is selected from one or a mixture of a plurality of Raney nickel, platinum carbon and ruthenium carbon.
A process for preparing 6-chloro-2-methyl-2H-indazol-5-amine comprising the steps of:
wherein R is hydrogen or hydroxy; x is X 1 Is one of chlorine, bromine and iodine; x is X 2 Is one of chlorine and bromine.
Step one: dissolving a compound of a formula VIII in a solvent, and carrying out halogenation reaction with a halogenating reagent to obtain a compound of a formula IX;
step two: dissolving the compound of the formula IX prepared in the step one in an organic solvent, and carrying out substitution reaction with methyl hydrazine to obtain a compound of the formula X, wherein the molar ratio of the compound of the formula IV to the methyl hydrazine is 1.0:2.0-10.0;
step three: dissolving the compound of formula X prepared in the second step in an organic solvent, carrying out intramolecular cyclization reaction in the presence of a copper catalyst and an organic ligand under alkaline conditions, and extracting by using an extraction solvent to obtain a compound extract of formula XI;
step four: oxidative dehydrogenation of the extract of the compound of the formula XI prepared in the step three in an oxygen atmosphere to obtain a compound of the formula II;
step five: and (3) dissolving the compound of the formula II prepared in the step (IV) in an organic solvent, carrying out catalytic hydrogenation to reduce nitro, and purifying by post-treatment to obtain the compound of the formula I, namely 6-chloro-2-methyl-2H-indazole-5-amine.
Further, the organic solvent used in the first step is selected from one or more of dichloromethane, dichloroethane, chloroform, chlorobenzene, cyclohexane, benzene and acetonitrile; the halogenating reagent used in the first step is selected from one of thionyl chloride, sulfonyl chloride, N-chlorosuccinimide, clenbuterol, dibromohydantoin, N-bromosuccinimide and phosphorus tribromide.
Further, the organic solvent used in the second step is selected from one or more of dichloromethane, dichloroethane, toluene, methyl tert-butyl ether, methanol, ethanol, isopropanol, acetonitrile and N, N-dimethylformamide.
Further, the organic solvent used in the third step is selected from one or more of toluene, dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide; the alkali used in the third step is selected from one or a mixture of more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and potassium phosphate; the copper catalyst used in the third step is selected from one or more of cuprous chloride, cuprous bromide, cuprous iodide, cuprous trifluoromethane sulfonate, cupric acetylacetonate, cuprous oxide, cupric acetate and cupric chloride; the organic ligand used in the third step is selected from one or a mixture of more of N, N '-dimethylethylenediamine, N' -tetramethylethylenediamine, ethylenediamine, L-proline, 1, 10-phenanthroline and oxalyl diamine; the extraction solvent used in the third step is selected from one or more of dichloromethane, dichloroethane, chloroform, methyl tertiary butyl ether, ethyl acetate and toluene.
Further, the organic solvent used in the fifth step is selected from one or more of dichloromethane, methanol, ethanol, isopropanol and tetrahydrofuran; the catalyst used in the fifth step is selected from one or a mixture of a plurality of Raney nickel, platinum carbon and ruthenium carbon.
The beneficial effects of the invention are as follows:
(1) The raw materials and the auxiliary materials and the reagents used in the method are low in cost and easy to obtain, and the used reagents are conventional reagents, so that the cost can be effectively reduced;
(2) The method has the advantages of simple process, good selectivity, high yield, short production time and lower production cost;
(3) The method has the advantages that no metal residue is produced, the catalyst can be repeatedly recycled and reused, the three-waste emission is reduced, and the production process is environment-friendly;
(4) According to the method, nitrate is directly used for nitration, nitric acid is not needed to be added in the nitration reaction process, so that the yield and safety are greatly improved, and the exhaust emission is reduced;
(5) The intermediate and the product of the method do not need chromatographic purification, and the purification method is simple and can realize large-scale production.
Detailed Description
The present invention will be described in detail with reference to the following specific embodiments.
Example 1: a process for preparing 6-chloro-2-methyl-2H-indazol-5-amine comprising the steps of:
wherein R is hydroxyl, X1 and X2 are chlorine.
Step one: the compound of formula IIIa (50.0 g,0.28 mol) was dissolved in 250mL of methylene chloride and thionyl chloride (47.0 g,0.40 mol) was added dropwise with cooling in an ice water bath. After the completion of the dropwise addition, the ice bath was removed, and the temperature was slowly raised to reflux, and the reaction was continued for 3 hours. The solvent and the excessive thionyl chloride are recovered by normal pressure distillation, and then the compound of formula IVa 2, 4-dichlorobenzyl chloride (52.6 g) is obtained by reduced pressure distillation, and the yield is 96.1%.
Step two: a40% aqueous solution of methylhydrazine (107.2 g,0.93 mol) and 100mL ethanol were added to the flask under nitrogen, and 2, 4-dichlorobenzyl chloride (52.0 g,0.27 mol) as a compound of formula IVa was added dropwise. After the completion of the dropwise addition, the temperature was raised to reflux, and the reaction was continued for 1 hour. The reaction mixture was concentrated under reduced pressure to recover the solvent and excess methyl hydrazine, diluted with dichloromethane, washed with saturated sodium bicarbonate solution and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated to remove the solvent to give the compound of formula va (51.4 g), yield 92.8%. HNMR (600 mhz, dmso-d 6) delta ppm 7.51-7.50 (m, 2H), 7.36 (d, j= 6.0,1H), 3.59 (s, 2H), 3.36 (br, 2H), 2.42 (s, 3H); MS (EI) m/z=205.08 [ M+H ]] + 。
Step three: to the reaction flask was added under nitrogen (5.0 g,24.38 mmol), potassium carbonate (8.4 g,60.95 mmol), 1, 10-phenanthroline (440 mg,2.44 mmol), cuprous iodide (232 mg,1.22 mmol) and 150mL dioxane. The reaction system was warmed to reflux for 18 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated to recover the solvent. The residue was diluted with dichloromethane, washed sequentially with dilute ammonia and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered to give a dichloromethane solution of the compound of formula VI, which was used directly in the next reaction.
Step four: the dichloromethane solution of the compound in the formula VI obtained in the previous step is stirred and reacted for 2 hours at room temperature under an oxygen atmosphere. 98% concentrated nitric acid (2.3 g,36.57 mmol) was added dropwise with cooling in an ice water bath. After completion of the dropwise addition, the reaction was continued for 2 hours, and was filtered, and the cake was rinsed with a small amount of methylene chloride and dried to obtain an off-white solid powder of the compound of formula VII (3.8 g) in a yield of 68%. HNMR (600 mhz, dmso-d 6) delta ppm 8.37 (s, 1H), 7.72 (d, j=6.0 hz, 1H), 7.64 (s, 1H), 6.99 (d, j=6.0 hz, 1H), 4.13 (s, 3H); MS (EI) m/z=167.06 [ M+H ]] + 。
Step five: 40g of concentrated sulfuric acid was added to the reaction flask. The compound of formula VII (10.0 g,43.55 mmol) was added in portions with cooling in an ice-water bath. After the addition was completed, the reaction was continued for 5 hours. The reaction solution is slowly poured into ice water, stirred and dispersed uniformly, filtered, and the filter cake is leached to be neutral by water, and dried to obtain the white solid powder compound (8.5 g) with the yield of 92.3 percent. HNMR (600 mhz, cdcl 3) delta ppm 8.32 (s, 1H), 8.12 (s, 1H), 7.82 (s, 1H), 4.26 (s, 3H); MS (EI) m/z=212.04 [ M+H ]] + 。
Step six: to the pressure-resistant reaction vessel, a compound of formula II (5.0 g,23.63 mmol) and 100mL of ethanol were added, and Raney nickel catalyst (0.5 g, 0.10W/W) was added. The nitrogen is replaced three times, then the hydrogen is replaced and pressurized to 1.5MPa, and then the temperature is raised to 40-45 ℃ by heating, and the reaction is continued for 6 hours. After the reaction was completed, nitrogen was substituted and filtered, and the filtrate was concentrated and substituted with methyl t-butyl ether. The mixture was cooled in an ice-water bath, stirred for 2 hours, filtered and dried to give the compound of formula I as an off-white solid powder (3.6 g) in 83.8% yield. HNMR (600 mhz, cdcl 3) delta ppm 7.68 (s, 1H), 7.61 (s, 1H), 6.87 (s, 1H), 4.12 (s, 3H), 3.95 (br, 2H); MS (EI) m/z=182.10 [ M+H ]] + 。
Example 2: a process for preparing 6-chloro-2-methyl-2H-indazol-5-amine comprising the steps of:
wherein R is hydroxyl, X1 and X2 are bromine.
Step one: the compound of formula IIIb (50.0 g,0.23 mol) was dissolved in 500mL cyclohexane and phosphorus tribromide (21.6 g,0.08 mol) was added dropwise with cooling in an ice water bath. After the completion of the dropwise addition, the ice bath was removed, and the temperature was slowly raised to room temperature, and the reaction was continued for 5 hours. The solvent and excess phosphorus tribromide were recovered by atmospheric distillation, followed by distillation under reduced pressure to give the compound of formula IVb (58.3 g) in 89.2% yield.
Step two: a40% aqueous methylhydrazine solution (42.2 g,0.36 mol) and 100mL methylene chloride were added dropwise to the flask under nitrogen (52.0 g,0.18 mol). After the completion of the dropwise addition, stirring was carried out at room temperature, and the reaction was continued for 1 hour. The reaction mixture was diluted with dichloromethane and purified water, and the organic phase was separated, washed with saturated sodium hydrogencarbonate solution and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated to remove the solvent to give the compound of formula vb (36.9 g), yield 82.1%. MS (EI) m/z=248.95 [ M+H ]] + 。
Step three: to the reaction flask was added the compound of formula vb (5.0 g,20.00 mmol), sodium hydroxide (2.0 g,50.00 mmol), N, N' -dimethylethylenediamine (176 mg,2.00 mmol), cuprous triflate (362 mg,1.00 mmol) and 150mL N-methylpyrrolidone under nitrogen. The reaction system is heated to 120 ℃ to react for 12 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated to recover the solvent. The residue was diluted with toluene, washed sequentially with dilute ammonia water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered to give an ethyl acetate solution of the compound of formula VI, which was used directly in the next reaction.
Step four: the ethyl acetate solution of the compound of formula VI obtained in the previous step is stirred at room temperature in air for reaction for 5 hours. 98% concentrated nitric acid (6.3 g,0.10 mol) was added dropwise under cooling in an ice-water bath. After the completion of the dropwise addition, the temperature was raised to reflux and water separation, the reaction was carried out for 2 hours, the reaction was cooled to room temperature, the filtration was carried out, the filter cake was rinsed with a small amount of toluene, and the compound of the powder formula VII (2.9. 2.9 g) was obtained as an off-white solid by drying, with a yield of 63%.
Step five: glacial acetic acid (6.0 g,0.10 mol) and 40g of concentrated sulfuric acid were added to the reaction flask. The compound of formula VII (10.0 g,43.55 mmol) was added in portions with cooling in an ice-water bath. After the addition was completed, the reaction was continued for 5 hours. The reaction solution is slowly poured into ice water, stirred and dispersed uniformly, filtered, and the filter cake is leached to be neutral by water, and dried to obtain white-like solid powder compound of formula II (8.2 g), and the yield is 88.6%.
Step six: to the pressure-resistant reaction vessel, the compound of formula II (5.0 g,23.63 mmol) and 100mL of tetrahydrofuran were added, and a 5% platinum carbon catalyst (0.025 g, 0.05W/W) was added. After the nitrogen gas was replaced three times, the hydrogen gas was replaced and pressurized to 2.0MPa, and the reaction was continued at room temperature for 12 hours. After the reaction was completed, nitrogen was substituted and filtered, and the filtrate was concentrated and substituted with methyl t-butyl ether. The mixture was cooled in an ice-water bath, stirred for 2 hours, filtered and dried to give the compound of formula I as an off-white solid powder (3.8 g) in 88.5% yield. HNMR (600 mhz, cdcl 3) delta ppm 7.68 (s, 1H), 7.61 (s, 1H), 6.87 (s, 1H), 4.12 (s, 3H), 3.95 (br, 2H); MS (EI) m/z=182.10 [ M+H ]] + 。
Example 3: a process for preparing 6-chloro-2-methyl-2H-indazol-5-amine comprising the steps of:
wherein R is hydrogen, X1 is iodine, and X2 is chlorine.
Step one: the compound of formula IIIc (50.0 g,0.20 mol) is added to 200mL of cyclohexane followed by N-chlorosuccinimide (29.4 g,0.22 mol) and benzoyl peroxide (284 mg,2 mmol) in sequence. The reaction system was warmed to reflux and the reaction was continued for 20 hours. Cooling to room temperature, filtering to remove insoluble matters, washing the filtrate with saturated sodium bicarbonate solution and saturated saline water in sequence, drying with anhydrous sodium sulfate, filtering and concentrating to obtain a compound of the formula IVc, and directly using the compound in the next reaction.
Step two: a40% aqueous solution of methylhydrazine (230.0 g,2.00 mol) was added dropwise to a reaction flask under nitrogen protection, followed by 300mL of an N, N-dimethylformamide solution of the compound of formula IVc. After the completion of the dropwise addition, the reaction was continued at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and purified water, and the organic phase was separated, washed with saturated sodium bicarbonate solution and saturated saline, and then with anhydrous sulfuric acidAfter drying the sodium, the solvent was removed by concentration to give the compound of formula vc (49.1 g) in 82.8% yield. MS (EI) m/z=296.98 [ M+H ]] + 。
Step three: to the reaction flask was added the compound of formula VC (5.0 g,16.86 mmol), potassium phosphate (7.2 g,633.72 mmol), L-proline (195 mg,1.69 mmol), copper acetate (168 mg,0.84 mmol) and 150mL toluene under nitrogen. The reaction system was warmed to reflux for 24 hours. Insoluble matters are removed by filtration, the filtrate is washed by dilute ammonia water and saturated sodium chloride solution in sequence, and after being dried by anhydrous sodium sulfate, toluene solution of the compound shown in the formula VI is obtained by filtration and is directly used for the next reaction.
Step four: the toluene solution of the compound of formula VI obtained in the previous step is stirred at room temperature for reaction for 2 hours under an oxygen atmosphere. 98% concentrated nitric acid (2.3 g,36.57 mmol) was added dropwise with cooling in an ice water bath. After the completion of the dropwise addition, the temperature was raised to reflux and water separation, the reaction was continued for 2 hours, cooled to room temperature, filtered, and the filter cake was rinsed with a small amount of toluene and dried to obtain an off-white solid powder compound of formula VII (3.0 g) in 78% yield. HNMR (600 mhz, dmso-d 6) delta ppm 8.37 (s, 1H), 7.72 (d, j=6.0 hz, 1H), 7.64 (s, 1H), 6.99 (d, j=6.0 hz, 1H), 4.13 (s, 3H); MS (EI) m/z=167.06 [ M+H ]] + 。
Step five: 50mL of glacial acetic acid was added to the reaction flask. The compound of formula VII (10.0 g,43.55 mmol) was added in portions with cooling in an ice-water bath. After the addition was completed, the temperature was slowly raised to 50℃and the reaction was continued for 10 hours. Acetic acid is recovered by decompression concentration, the remainder is slowly poured into ice water, after stirring and dispersing uniformly, filtration is carried out, filter cakes are leached to be neutral by water, and white solid powder-like compound (7.1 g) is obtained by drying, and the yield is 89.8%.
Step six: to the pressure-resistant reaction vessel were added the compound of formula II (5.0 g,23.63 mmol) and 100mL of methylene chloride, and 5% ruthenium-carbon catalyst (0.025 g, 0.05W/W) was added. After the nitrogen gas was replaced three times, the hydrogen gas was replaced and pressurized to 2.0MPa, and then the reaction was continued at room temperature for 10 hours. After the reaction was completed, nitrogen was substituted and filtered, and the filtrate was concentrated and substituted with methyl t-butyl ether. The mixture was cooled in an ice-water bath, stirred for 2 hours, filtered and dried to give the compound of formula I as an off-white solid powder (3.9. 3.9 g) in a yield of 90.9%. HNMR (600 MHz, CDCl 3) delta ppm 7.68 (s, 1H), 7.61 (s, 1H), 6.87 (s, 1H), 4.12(s,3H),3.95(br,2H)；MS(EI):m/z＝182.10[M+H] + 。
Example 4: a process for preparing 6-chloro-2-methyl-2H-indazol-5-amine comprising the steps of:
wherein R is hydrogen; x1 bromine; x2 is bromine.
Step one: compound VIII a (20.0 g,79.85 mmol) was added to 140mL of acetonitrile followed by N-bromosuccinimide (14.9 g,83.84 mmol) and azobisisobutyronitrile (131 mg,0.80 mmol) in sequence. The reaction system was warmed to reflux and the reaction was continued for 6 hours. Cooled to room temperature, insoluble materials were removed by filtration, and the filtrate was concentrated to recover the solvent. Dichloromethane was added for dilution, washed with saturated sodium bicarbonate solution and saturated brine in this order, dried over anhydrous sodium sulfate, and filtered to obtain a dichloromethane solution of the compound of formula Xa, which was used directly in the next reaction.
Step two: a40% aqueous solution of methylhydrazine (46.0 g,0.40 mol) was added to the flask under nitrogen protection, followed by dropwise addition of an acetonitrile solution of the compound of formula IX a obtained in the above step. After completion of the dropwise addition, the reaction was continued for 3 hours. Then methyl tert-butyl ether and saturated sodium hydrogencarbonate solution were added to separate an organic phase, which was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to remove the solvent to give the compound of formula Xa (20.6 g), yield 87.5%. HNMR (600 mhz, dmso-d 6) delta ppm 8.18 (s, 1H), 7.96 (s, 1H), 3.65 (s, 2H), 3.49 (br, 2H), 2.52 (s, 3H); MS (EI) m/z=293.94 [ M+H ]] + 。
Step three: to the reaction flask was added the compound of formula Xa (5.0 g,16.98 mmol), diisopropylethylamine (4.4 g,33.95 mmol), copper acetylacetonate (222 mg,0.85 mmol), oxalyldibenzylamine (487 mg,1.70 mmol) and 100mL of N, N-dimethylformamide under nitrogen. The reaction system was warmed to 90℃and continued for 20 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to recover the solvent. The residue was diluted with dichloroethane, washed sequentially with dilute aqueous ammonia and saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered to give a dichloroethane solution of the compound of formula XI, which was used directly in the next reaction.
Step four: the dichloroethane solution of the compound of formula XI obtained in the above step was stirred at room temperature under an oxygen atmosphere for reaction for 1 hour. The reaction system was concentrated under reduced pressure to recover the solvent to obtain a crude solid product, which was recrystallized from ethanol, filtered and dried to obtain an off-white solid powder of the compound of formula II (2.8 g) in 78.5% yield.
Step five: to the pressure-resistant reaction vessel, a compound of formula II (5.0 g,23.63 mmol) and 100mL of methanol were added, and Raney nickel catalyst (0.5 g, 0.10W/W) was added. The nitrogen is replaced three times, then the hydrogen is replaced and pressurized to 1.5MPa, and then the temperature is raised to 40-45 ℃ by heating, and the reaction is continued for 6 hours. After the reaction was completed, nitrogen was substituted and filtered, and the filtrate was concentrated and substituted with methyl t-butyl ether. The mixture was cooled in an ice-water bath, stirred for 2 hours, filtered and dried to give the compound of formula I as an off-white solid powder (3.8 g) in 88.5% yield. HNMR (600 mhz, cdcl 3) delta ppm 7.68 (s, 1H), 7.61 (s, 1H), 6.87 (s, 1H), 4.12 (s, 3H), 3.95 (br, 2H); MS (EI) m/z=182.10 [ M+H ]] + 。
Claims (10)
1. A process for preparing 6-chloro-2-methyl-2H-indazol-5-amine, characterized by comprising the steps of:
step one: dissolving a compound of a formula III in an organic solvent, and carrying out halogenation reaction with a halogenating reagent to obtain a compound of a formula IV;
wherein R is hydrogen or hydroxy; x is X 1 Is one of fluorine, chlorine, bromine and iodine; x is X 2 Is one of chlorine and bromine;
step two: dissolving the compound of the formula IV prepared in the step one in an organic solvent, and carrying out substitution reaction with methyl hydrazine to obtain a compound of the formula V, wherein the molar ratio of the compound of the formula IV to the methyl hydrazine is 1.0:2.0-10.0;
step three: dissolving the compound of the formula V prepared in the second step in an organic solvent, carrying out intramolecular cyclization reaction in the presence of a copper catalyst and an organic ligand under an alkaline condition, and extracting by using an extraction solvent to obtain a compound extract of the formula VI;
step four: oxidative dehydrogenation is carried out on the extract of the compound of the formula VI prepared in the step three under the oxygen atmosphere, and then the compound of the formula VII is obtained by salifying with nitric acid, wherein the molar ratio of the compound of the formula VI to the nitric acid is 1.0:1.0-10.0;
step five: dissolving the compound of the formula VII prepared in the step four in acid, and performing nitration reaction to obtain a compound of the formula II;
step six: dissolving the compound of the formula II prepared in the step five in an organic solvent, adding a catalyst to catalyze, hydrogenate and reduce nitro, and purifying by post-treatment to obtain the compound of the formula I, namely 6-chloro-2-methyl-2H-indazol-5-amine:
2. a process for preparing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 1, characterized in that: the organic solvent used in the first step is selected from one or more of dichloromethane, dichloroethane, chloroform, chlorobenzene, cyclohexane, benzene and acetonitrile; the halogenating reagent used in the first step is selected from one of thionyl chloride, sulfonyl chloride, N-chlorosuccinimide, clenbuterol, dibromohydantoin, N-bromosuccinimide and phosphorus tribromide.
3. A process according to claim 1 or 2 for the preparation of 6-chloro-2-methyl-2H-indazol-5-amine, characterized in that: the organic solvent used in the second step is selected from one or more of dichloromethane, dichloroethane, toluene, methyl tert-butyl ether, methanol, ethanol, isopropanol, acetonitrile and N, N-dimethylformamide.
4. A process for preparing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 3, characterized in that: the organic solvent used in the third step is selected from one or more of toluene, dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide; the alkaline reagent used in the third step is selected from one or a mixture of more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and potassium phosphate; the copper catalyst used in the third step is selected from one or more of cuprous chloride, cuprous bromide, cuprous iodide, cuprous trifluoromethane sulfonate, cupric acetylacetonate, cuprous oxide, cupric acetate and cupric chloride; the organic ligand used in the third step is selected from one or more of N, N '-dimethylethylenediamine, N' -tetramethylethylenediamine, ethylenediamine, L-proline, 1, 10-phenanthroline and oxalyl diamine; the extraction solvent used in the third step is selected from one or more of dichloromethane, dichloroethane, chloroform, methyl tertiary butyl ether, ethyl acetate and toluene.
5. A process for preparing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 4, characterized in that: the acid used in the fifth step is one or a mixture of two of glacial acetic acid and concentrated sulfuric acid; the organic solvent used in the step six is selected from one or a mixture of more of dichloromethane, methanol, ethanol, isopropanol and tetrahydrofuran; the catalyst used in the step six is selected from one or a mixture of a plurality of Raney nickel, platinum carbon and ruthenium carbon.
6. A process for preparing 6-chloro-2-methyl-2H-indazol-5-amine, characterized by comprising the steps of:
step one: dissolving a compound of a formula VIII in a solvent, and carrying out halogenation reaction with a halogenating reagent to obtain a compound of a formula IX;
wherein R is hydrogen or hydroxy; x is X 1 Is one of fluorine, chlorine, bromine and iodine; x is X 2 Is one of chlorine and bromine;
step two: dissolving the compound of the formula IX prepared in the step one in an organic solvent, and carrying out substitution reaction with methyl hydrazine to obtain a compound of the formula X, wherein the molar ratio of the compound of the formula IV to the methyl hydrazine is 1.0:2.0-10.0;
step three: dissolving the compound of formula X prepared in the second step in an organic solvent, carrying out intramolecular cyclization reaction in the presence of a copper catalyst and an organic ligand under alkaline conditions, and extracting by using an extraction solvent to obtain a compound extract of formula XI;
step four: oxidative dehydrogenation of the extract of the compound of the formula XI prepared in the step three in an oxygen atmosphere to obtain a compound of the formula II;
step five: dissolving the compound of the formula II prepared in the step four in an organic solvent, catalyzing, hydrogenating and reducing nitro, and purifying to obtain the compound of the formula I, namely 6-chloro-2-methyl-2H-indazol-5-amine:
7. a process for preparing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 6, characterized in that: the organic solvent used in the first step is selected from one or more of dichloromethane, dichloroethane, chloroform, chlorobenzene, cyclohexane, benzene and acetonitrile; the halogenating reagent used in the first step is selected from one of thionyl chloride, sulfonyl chloride, N-chlorosuccinimide, clenbuterol, dibromohydantoin, N-bromosuccinimide and phosphorus tribromide.
8. A process for preparing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 6 or 7, characterized in that: the organic solvent used in the second step is selected from one or more of dichloromethane, dichloroethane, toluene, methyl tert-butyl ether, methanol, ethanol, isopropanol, acetonitrile and N, N-dimethylformamide.
9. A process for preparing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 8, characterized in that: the organic solvent used in the third step is selected from one or more of toluene, dioxane, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide; the alkaline reagent used in the third step is selected from one or a mixture of more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and potassium phosphate; the copper catalyst used in the third step is selected from one or more of cuprous chloride, cuprous bromide, cuprous iodide, cuprous trifluoromethane sulfonate, cupric acetylacetonate, cuprous oxide, cupric acetate and cupric chloride; the organic ligand used in the third step is selected from one or a mixture of more of N, N '-dimethylethylenediamine, N' -tetramethylethylenediamine, ethylenediamine, L-proline, 1, 10-phenanthroline and oxalyl diamine; the extraction solvent used in the third step is selected from one or more of dichloromethane, dichloroethane, chloroform, methyl tertiary butyl ether, ethyl acetate and toluene.
10. A process for preparing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 9, characterized in that: the organic solvent used in the fifth step is selected from one or more of dichloromethane, methanol, ethanol, isopropanol and tetrahydrofuran; the catalyst used in the fifth step is selected from one or a mixture of a plurality of Raney nickel, platinum carbon and ruthenium carbon.
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