WO2023147779A1 - 一种哒嗪酮衍生物制备方法及其中间体 - Google Patents
一种哒嗪酮衍生物制备方法及其中间体 Download PDFInfo
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- WO2023147779A1 WO2023147779A1 PCT/CN2023/074589 CN2023074589W WO2023147779A1 WO 2023147779 A1 WO2023147779 A1 WO 2023147779A1 CN 2023074589 W CN2023074589 W CN 2023074589W WO 2023147779 A1 WO2023147779 A1 WO 2023147779A1
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- Prior art keywords
- acid
- compound
- organic solvent
- present
- acetate
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 title abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 31
- 150000001875 compounds Chemical class 0.000 claims description 197
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 126
- 239000002253 acid Substances 0.000 claims description 82
- 239000003960 organic solvent Substances 0.000 claims description 82
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 74
- 238000006243 chemical reaction Methods 0.000 claims description 73
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 72
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 58
- -1 N,N-dimethylacetamide Amide Chemical group 0.000 claims description 53
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 50
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- 238000003756 stirring Methods 0.000 claims description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 38
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 38
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 36
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 28
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical group CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 26
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 26
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 26
- 229960000583 acetic acid Drugs 0.000 claims description 26
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical group [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 26
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 23
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical group [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims description 22
- GUSWJGOYDXFJSI-UHFFFAOYSA-N 3,6-dichloropyridazine Chemical compound ClC1=CC=C(Cl)N=N1 GUSWJGOYDXFJSI-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 20
- 235000011054 acetic acid Nutrition 0.000 claims description 20
- 239000007800 oxidant agent Substances 0.000 claims description 20
- 239000001632 sodium acetate Substances 0.000 claims description 19
- 235000017281 sodium acetate Nutrition 0.000 claims description 19
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 18
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 18
- 229910001961 silver nitrate Inorganic materials 0.000 claims description 18
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 16
- 238000010992 reflux Methods 0.000 claims description 16
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 15
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 15
- 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 14
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 14
- 235000019253 formic acid Nutrition 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 13
- 235000010288 sodium nitrite Nutrition 0.000 claims description 13
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical group CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 12
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 11
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical group O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 11
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims description 11
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 11
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 11
- 229910017604 nitric acid Inorganic materials 0.000 claims description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 10
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 9
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 9
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 9
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 9
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- HSOGVWWWGVFXGF-UHFFFAOYSA-N ethyl n-(2-cyanoacetyl)carbamate Chemical compound CCOC(=O)NC(=O)CC#N HSOGVWWWGVFXGF-UHFFFAOYSA-N 0.000 claims description 9
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 9
- 235000011056 potassium acetate Nutrition 0.000 claims description 9
- LLHKCFNBLRBOGN-UHFFFAOYSA-N propylene glycol methyl ether acetate Chemical compound COCC(C)OC(C)=O LLHKCFNBLRBOGN-UHFFFAOYSA-N 0.000 claims description 9
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 claims description 8
- KGEXISHTCZHGFT-UHFFFAOYSA-N 4-azaniumyl-2,6-dichlorophenolate Chemical compound NC1=CC(Cl)=C(O)C(Cl)=C1 KGEXISHTCZHGFT-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- 239000011261 inert gas Substances 0.000 claims description 8
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 8
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical group OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical group CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 7
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Chemical group CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 7
- 239000004677 Nylon Substances 0.000 claims description 7
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 7
- 229940011051 isopropyl acetate Drugs 0.000 claims description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 7
- 229920001778 nylon Polymers 0.000 claims description 7
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 claims description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 6
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 claims description 6
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000012362 glacial acetic acid Substances 0.000 claims description 6
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical group OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 6
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 6
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims description 6
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 5
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 235000006408 oxalic acid Nutrition 0.000 claims description 5
- 239000004304 potassium nitrite Substances 0.000 claims description 5
- 235000010289 potassium nitrite Nutrition 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
- 239000011734 sodium Substances 0.000 claims description 5
- CAMXVZOXBADHNJ-UHFFFAOYSA-N ammonium nitrite Chemical compound [NH4+].[O-]N=O CAMXVZOXBADHNJ-UHFFFAOYSA-N 0.000 claims description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical class IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000011698 potassium fluoride Substances 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 239000005695 Ammonium acetate Substances 0.000 claims description 3
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 claims description 3
- 235000019257 ammonium acetate Nutrition 0.000 claims description 3
- 229940043376 ammonium acetate Drugs 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- GZUXJHMPEANEGY-BJUDXGSMSA-N bromomethane Chemical class Br[11CH3] GZUXJHMPEANEGY-BJUDXGSMSA-N 0.000 claims 1
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical class [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 14
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 50
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 37
- 239000012065 filter cake Substances 0.000 description 26
- 239000012043 crude product Substances 0.000 description 20
- 238000011282 treatment Methods 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 19
- 239000008213 purified water Substances 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
- 238000005481 NMR spectroscopy Methods 0.000 description 16
- 239000000543 intermediate Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 239000007787 solid Substances 0.000 description 12
- 238000004809 thin layer chromatography Methods 0.000 description 12
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 11
- HNRMPXKDFBEGFZ-UHFFFAOYSA-N 2,2-dimethylbutane Chemical compound CCC(C)(C)C HNRMPXKDFBEGFZ-UHFFFAOYSA-N 0.000 description 10
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 10
- PFEOZHBOMNWTJB-UHFFFAOYSA-N 3-methylpentane Chemical compound CCC(C)CC PFEOZHBOMNWTJB-UHFFFAOYSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical compound CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 9
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- 239000012141 concentrate Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
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- 206010045261 Type IIa hyperlipidaemia Diseases 0.000 description 7
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- 108010028554 LDL Cholesterol Proteins 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 235000011118 potassium hydroxide Nutrition 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 230000001590 oxidative effect Effects 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- HJFWDABAASVHOC-ISLPBHIQSA-N 2-[3,5-dichloro-4-[[(7R)-1-oxo-7-(trideuteriomethyl)-2,5,6,7-tetrahydrocyclopenta[d]pyridazin-4-yl]oxy]phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile Chemical compound ClC=1C=C(C=C(C=1OC=1C2=C(C(NN=1)=O)[C@@H](CC2)C([2H])([2H])[2H])Cl)N1N=C(C(NC1=O)=O)C#N HJFWDABAASVHOC-ISLPBHIQSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
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- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
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- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229940127355 PCSK9 Inhibitors Drugs 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 241000720974 Protium Species 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
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- 238000010828 elution Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 1
- 229960000815 ezetimibe Drugs 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- WHGLQYBALPTZNJ-UHFFFAOYSA-N furan;oxolane Chemical compound C1CCOC1.C=1C=COC=1 WHGLQYBALPTZNJ-UHFFFAOYSA-N 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
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- 125000006239 protecting group Chemical group 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- FDBYIYFVSAHJLY-UHFFFAOYSA-N resmetirom Chemical compound N1C(=O)C(C(C)C)=CC(OC=2C(=CC(=CC=2Cl)N2C(NC(=O)C(C#N)=N2)=O)Cl)=N1 FDBYIYFVSAHJLY-UHFFFAOYSA-N 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
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- 108090000721 thyroid hormone receptors Proteins 0.000 description 1
- 102000004217 thyroid hormone receptors Human genes 0.000 description 1
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- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/14—Adipic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
Definitions
- the present invention relates to the field of medicine, in particular, the present invention relates to a preparation method of pyridazinone derivatives and an intermediate thereof and a preparation method of the intermediate.
- FH Classic familial hypercholestememia
- LDL-C Low Density Lipoprotein-Cholesterol
- LDL-C Low Density Lipoprotein-Cholesterol
- statins are the drug of choice for treatment, which can not only reduce LDL-C levels, but also improve the prognosis of FH patients.
- Patients who do not respond well to statin therapy or have adverse reactions can be treated in combination with the cholesterol absorption inhibitor ezetimibe.
- PCSK9 inhibitors can be added to patients who still fail to meet the above-mentioned treatments.
- HeFH has corresponding treatment methods, many patients (up to 40% of HeFH patients) still cannot reach the cholesterol (LDL-C) level after these treatments, and the accumulation of cholesterol in their body becomes a lifelong burden.
- Thyroid hormone receptors are divided into ⁇ and ⁇ subtypes. Thyroid hormones can promote cholesterol metabolism after binding to ⁇ subtype receptors. Accordingly, in recent years, a variety of thyroid hormone analogs or thyromimetic drugs that selectively stimulate the ⁇ subtype have been developed.
- Compound patent WO2019240938A1 describes a compound of formula (I), which belongs to thyroxine beta receptor agonist and is intended to be used in the treatment of primary hypercholesterolemia in adults, and discloses the preparation method at the same time.
- the purpose of the present invention is to provide a method for preparing pyridazinone derivatives.
- the method has easy-to-obtain raw materials and simple steps, crystallization is used for purification in the whole synthesis process, no silica gel column chromatography is used, the cost is low, the intermediate has good stability, high purity and high yield, and is suitable for large-scale industrial production.
- Another object of the present invention is to provide an intermediate for preparing pyridazinone derivatives.
- Another object of the present invention is to provide the preparation method of the intermediate for the preparation of pyridazinone derivatives.
- the present invention provides a compound represented by formula (1E), formula (1H) or a pharmaceutically acceptable salt thereof,
- the invention provides a method for preparing a compound of formula (1F), comprising the following steps,
- Compound 1E reacts with 3,6-dichloropyridazine, water, silver nitrate, acid A and oxidant at 55-65°C to obtain compound 1F.
- compound 1E and 3,6-dichloropyridazine add water, heat up to 30-40°C, add silver nitrate, heat up to 55-65°C, add acid A and oxidant, at 70- Compound 1F was obtained by reaction at 80°C.
- the acid A is selected from trifluoroacetic acid, pentafluoroacetic acid, heptafluoropropionic acid, sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, formic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid Acid;
- the acid A is selected from trifluoroacetic acid;
- the oxidizing agent is selected from ammonium persulfate, potassium persulfate, sodium persulfate, tert-butanol peroxy , hydrogen peroxide; in some embodiments of the present invention, the oxidizing agent is selected from ammonium persulfate; in some embodiments of the present invention, the concentration of the ammonium persulfate is 0.1-1g/mL.
- the molar ratio of the compound 1E and 3,6-dichloropyridazine is 1:0.9-5.0; in some embodiments of the present invention, the compound 1E and 3,6-dichloropyridazine
- the molar ratio of oxazine is 1:1.0-2.0; Some implementations of the present invention In the scheme, the molar ratio of compound 1E and silver nitrate is 1:0.2-2.0; in some embodiments of the present invention, the molar ratio of compound 1E and silver nitrate is 1:0.4-1.0; in some embodiments of the present invention , the molar ratio of compound 1E to acid A is 1:0.05-2.0; in some embodiments of the present invention, the molar ratio of compound 1E to acid A is 1:0.1-1.0.
- the intermediate raw material 3,6-dichloro-1,2,4,5-tetrazine was used to prepare 1F.
- the intermediate raw material 3,6-Dichloro-1,2,4,5-tetrazine has high cost, poor stability, and low yield of final product, so it is not suitable for industrial production.
- the invention provides a method for preparing a compound of formula (1E), comprising the following steps,
- compound 1D is stirred and reacted at 120-150°C to obtain compound 1E.
- post-treatment and drying steps are also included, and the post-treatment is to add Organic solvent F, organic solvent A, crystallize at room temperature, and filter; in some embodiments of the present invention, compound 1D is stirred and reacted at 130-140°C to obtain compound 1E; in some embodiments of the present invention, the Post-treatment is to add organic solvent F and organic solvent A at 30-40°C, crystallize at room temperature, filter, and collect the filter cake.
- the organic solvent F is selected from dichloromethane, methyl acetate, acetonitrile, toluene, ethyl acetate, isopropyl acetate, acetone, 2-methyltetrahydrofuran, tetrahydrofuran, 1,4- Dioxane, dimethyl carbonate, propylene glycol methyl ether acetate, dimethyl nylon acid;
- the organic solvent F is selected from dichloromethane, methyl acetate, dimethyl carbonate , propylene glycol methyl ether acetate, dimethyl nylon acid; in some embodiments of the present invention, the organic solvent F is selected from dichloromethane; in some embodiments of the present invention, the organic solvent A is selected from alkyl Hydrocarbons or esters; In some embodiments of the present invention, the organic solvent A is selected from n-pentane, n-hexane, n-heptane, petroleum
- a method for preparing a compound of formula (1E) further includes the following steps,
- the organic solvent F is selected from dichloromethane, methyl acetate, acetonitrile, toluene, ethyl acetate, isopropyl acetate, acetone, 2-methyltetrahydrofuran, tetrahydrofuran, 1,4- Dioxane, dimethyl carbonate, propylene glycol methyl ether acetate, dimethyl nylon acid;
- the organic solvent F is selected from dichloromethane, methyl acetate, dimethyl carbonate , propylene glycol methyl ether acetate, dimethyl nylon acid; in some embodiments of the present invention, the organic solvent F is selected from dichloromethane; in some embodiments of the present invention, the acid A is selected from trifluoroacetic acid , pentafluoroacetic acid, heptafluoropropionic acid, hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, benz
- the molar ratio of compound 1C to acid A is 1:3.0-30.0; in some embodiments of the present invention, the molar ratio of compound 1C to acid A is 1:3.0-10.0.
- a method for preparing a compound of formula (1E) further includes the following steps,
- Compound 1B reacts with a deuterated reagent in the presence of an organic base to obtain Compound 1C.
- the deuterated reagent is selected from deuteroiodomethane, deuterobromomethane, deuterochloromethane, D3-p-toluenesulfonyl methyl ester, D3-methylsulfonyl methyl ester; some of the present invention In an embodiment, the deuterated reagent is selected from deuterated methyl iodide.
- the molar ratio of the compound 1B and the base is 1:1.00-5.05; in some embodiments of the present invention, the molar ratio of the compound 1B and the base is 1:1.05-2.05; the present invention In some embodiments of the present invention, the molar ratio of the compound 1B to the deuterated reagent is 1:0.9-5.0; in some embodiments of the present invention, the molar ratio of the compound 1B to the deuterated reagent is 1:1.0-2.5.
- the base is selected from sodium methoxide, potassium ethoxide, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium acetate, potassium acetate, K 3 PO 4 , K 2 CO 3 , KHCO 3 , Cs 2 CO 3 , Na 2 CO 3 , NaHCO 3 , KF, pyridine, triethylamine, N,N-diisopropylethylamine, DBU; in some embodiments of the present invention, the base is selected from Sodium methylate, potassium ethylate, potassium tert-butoxide, sodium tert-butoxide; In some embodiments of the present invention, the alkali is selected from potassium tert-butoxide; In some embodiments of the present invention, the catalyst is tetrabutylsulfuric acid Ammonium hydrogen; In some embodiments of the present invention, the organic solvent E is selected from tetrahydro
- the molar ratio of the compound 1A and the base is 1:0.001-0.5; in some embodiments of the present invention, the molar ratio of the compound 1A and the base is 1:0.01-0.25; the present invention In some embodiments of the present invention, the molar ratio of the compound 1A and tert-butyl acrylate is 1:0.8-6.0; in some embodiments of the present invention, the molar ratio of the compound 1A and tert-butyl acrylate is 1:1.0- 3.0.
- the present invention also provides a preparation method of a compound of formula (I), comprising the following steps,
- the organic solvent B is selected from dimethylsulfoxide, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoramide, N- Methylpyrrolidone; In some embodiments of the present invention, the organic solvent B is selected from N,N-dimethylacetamide.
- compound 1L is reacted at 100-130° C. in the presence of organic solvent B and lye B to obtain compound I; in some embodiments of the present invention, compound 1L is reacted in the presence of organic solvent B and lye B Compound I was obtained by reacting at 110-120°C in the presence of the present invention; in some embodiments of the present invention, compound 1L was reacted at 115°C in the presence of organic solvent B and lye B to obtain Compound I.
- the molar ratio of the compound 1L to the lye B is 1:0.5-1:5.0; in some embodiments of the present invention, the molar ratio of the compound 1L to the lye B is 1: 0.5-1:4.5; in some embodiments of the present invention, the molar ratio of compound 1L and lye B is 1:1-1:4.5; in some embodiments of the present invention, the compound 1L and lye B The molar ratio of is 1:2-1:4.5; In some embodiments of the present invention, the molar ratio of described compound 1L and lye B is 1:1-3:4.5; In some embodiments of the present invention, described The molar ratio of compound 1L to lye B is 1:0.5-1:4.0; in some embodiments of the present invention, the molar ratio of compound 1L to lye B is 1:0.5-1:3.5; some of the present invention In an embodiment, the molar ratio of the compound 1L to the lye B is 1:0.5-1:3.0; in some
- compound 1L in the presence of organic solvent B and lye B, compound 1L also includes post-treatment and purification steps after the reaction to obtain compound I; in some embodiments of the present invention, the post-treatment is at 55 At -65°C, add water, filter, wash for the first time, add organic solvent D and water, crystallize at 5-15°C, filter, wash for the second time, and dry to obtain the crude product of compound I; some implementations of the present invention
- the purification is to mix the crude product of compound I with absolute ethanol, stir and react at 70-80°C for 3-6h, cool down to 0-10°C for crystallization, filter, wash and dry after completion to obtain compound I;
- the first washing is carried out with N,N-dimethylacetamide;
- the organic solvent D is formic acid, acetic acid, oxalic acid, propionic acid; some of the present invention
- the organic solvent D is acetic acid; in some embodiments
- a preparation method of a compound of formula (I) further includes the following steps,
- Dissolve compound 1K in water and organic solvent D add acid B and stir, add lye A and lye B in sequence, and finally add N-cyanoacetylurethane to obtain compound 1L after reaction.
- compound 1K is dissolved in water and organic solvent D, at -5-5°C, acid B is added, after stirring the reaction, lye A is added, after the reaction is complete, lye B is added, and finally N -Cyanoacetylurethane, heated to 5-15°C, after reaction, compound 1L was obtained.
- the organic solvent D is selected from formic acid, acetic acid, oxalic acid, propionic acid; in some embodiments of the present invention, the organic solvent D is selected from acetic acid; in some embodiments of the present invention , the acid B is selected from hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, perchloric acid; in some embodiments of the present invention, the acid B is selected from hydrochloric acid; in some embodiments of the present invention, the lye A is Nitrate, described nitrite is selected from sodium nitrite, potassium nitrite, ammonium nitrite; In some embodiments of the present invention, described nitrite is selected from sodium nitrite; In some embodiments of the present invention, the The concentration of the sodium nitrite is 0.3-0.6g/mL; in some embodiments of the present invention, the lye B is acetate, and the acetate is selected from sodium acetate, potassium nitrite, ammonium
- the molar ratio of the compound 1K and N-cyanoacetylurethane is 1:0.9-5.0; in some embodiments of the present invention, the compound 1K and N-cyanoacetylurethane
- the molar ratio of the compound 1K is 1:1.0-3.0; in some embodiments of the present invention, the molar ratio of the compound 1K and the base A is 1:1.0-10.0; in some embodiments of the present invention, the compound 1K and the base A
- the molar ratio is 1:1.1-3.0.
- the base added in the compound patent (WO2019240938A1) is pyridine, the post-treatment is extracted with ethyl acetate, and the product I is obtained by concentration.
- water is added to directly crystallize, the post-treatment is simple and easy to scale up, and the product yield and purity are higher.
- a preparation method of a compound of formula (I) further includes the following steps,
- the lye C is selected from potassium hydroxide solution, sodium hydroxide solution, lithium hydroxide solution, potassium tert-butoxide solution, lithium tert-butoxide solution, sodium carbonate solution, potassium carbonate solution, Cesium Carbonate Solution;
- the lye C is selected from potassium hydroxide; in some embodiments of the present invention, the lye C is selected from sodium hydroxide; in some embodiments of the present invention, the mass concentration of potassium hydroxide 0.1-0.2g/mL;
- the organic solvent C is selected from anhydrous methanol, absolute ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, toluene, acetone , methyl isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl sulfoxide, N,
- the reflux reaction temperature is 70-90°C; in some embodiments of the present invention, the reflux reaction temperature is 75-85°C; in some embodiments of the present invention, the reflux reaction The temperature is 80 ⁇ 5°C; in some embodiments of the present invention, the reflux reaction temperature is 80°C.
- compound 1H is mixed with lye C and organic solvent C, and heated to reflux for 15-20 h to obtain the racemate of compound 1K; the racemate of compound 1K is then post-treated and Refined, and finally resolved by chiral SFC to obtain compound 1K.
- the post-treatment is cooling to 20-30°C, adding water, adjusting the pH of the solution to 8-9, extracting, washing, drying, and filtering; in some embodiments of the present invention, the refining is The crude product obtained after post-treatment was dissolved in dioxane solution, crystallized at room temperature, filtered, and purified 2-3 times, and vacuum-dried.
- a preparation method of a compound of formula (I) further includes the following steps,
- step (b) Dissolve compound 1G obtained in step (a) with glacial acetic acid, add benzoic anhydride, dry after the reaction, heat up to 115-125°C for 15-20 hours, and obtain compound 1H after post-treatment.
- the organic solvent B is selected from dimethylsulfoxide, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoramide, N- Methylpyrrolidone; In some embodiments of the present invention, the organic solvent B is selected from N,N-dimethylacetamide.
- the post-treatment is to concentrate the reaction solution under reduced pressure at 60-65°C, add absolute ethanol, slowly add the mixed solution into water, stir rapidly to precipitate solids, centrifuge, and wash to obtain the compound 1H.
- the molar ratio of the compound 1F, 4-amino-2,6-dichlorophenol to cesium carbonate is 1-5:1-5:1.0-10; in some embodiments of the present invention , the molar ratio of the compound 1F, 4-amino-2,6-dichlorophenol and cesium carbonate is 2-3:2-3:3.0-5.0; in some embodiments of the present invention, the benzoic anhydride and The molar ratio of compound 1F is 1-5:1-5; in some embodiments of the present invention, the molar ratio of benzoic anhydride to compound 1F is 2-3:2.2-3.5;
- a preparation method of a compound of formula (I) further includes the following steps,
- Compound 1E is reacted with 3,6-dichloropyridazine, water, silver nitrate, acid A and an oxidizing agent at 55-65°C to obtain compound 1F.
- compound 1E and 3,6-dichloropyridazine add water, heat up to 30-40°C, add silver nitrate, heat up to 55-65°C, add acid A and oxidant, at 70- Compound 1F was obtained by reaction at 80°C.
- the acid A is selected from trifluoroacetic acid, pentafluoroacetic acid, heptafluoropropionic acid, sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, formic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid Acid;
- the acid A is selected from trifluoroacetic acid;
- the oxidizing agent is selected from ammonium persulfate, potassium persulfate, sodium persulfate, tert-butanol peroxy , hydrogen peroxide; in some embodiments of the present invention, the oxidizing agent is selected from ammonium persulfate; in some embodiments of the present invention, the concentration of the ammonium persulfate is 0.1-1g/mL.
- the molar ratio of the compound 1E and 3,6-dichloropyridazine is 1:0.9-5.0; in some embodiments of the present invention, the compound 1E and 3,6-dichloropyridazine
- the molar ratio of oxazine is 1:1.0-2.0; Some implementations of the present invention In the scheme, the molar ratio of compound 1E and silver nitrate is 1:0.2-2.0; in some embodiments of the present invention, the molar ratio of compound 1E and silver nitrate is 1:0.4-1.0; in some embodiments of the present invention , the molar ratio of compound 1E to acid A is 1:0.05-2.0; in some embodiments of the present invention, the molar ratio of compound 1E to acid A is 1:0.1-1.0.
- the second scheme of the present invention a preparation method of a compound of formula (1F), comprises the following steps,
- the acid A is selected from trifluoroacetic acid, pentafluoroacetic acid, heptafluoropropionic acid, sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, formic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid; Ammonium sulfate, potassium persulfate, sodium persulfate, tert-butanol peroxy, hydrogen peroxide;
- the third scheme of the present invention a preparation method of a compound of formula (1E), comprises the following steps,
- the post-processing is to add organic solvent F and organic solvent A at 20-50 ° C, crystallize at room temperature, and filter;
- the organic solvent F is selected from dichloromethane, methyl acetate, dimethyl carbonate, propylene glycol methyl ether acetate, dimethyl nylon acid, acetonitrile, toluene, ethyl acetate, isopropyl acetate, acetone, 2- Methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane;
- the acid A is selected from trifluoroacetic acid, pentafluoroacetic acid, heptafluoropropionic acid, hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, benzenesulfonic acid, methanesulfonic acid, P-toluenesulfonic acid;
- the organic solvent A is selected from normal pentane, normal hexane, normal heptane, sherwood oil, 2-methylpentane, 3-methylpentane, 2,3-dimethylbutan
- the deuterated reagent is selected from deuteroiodomethane, deuterobromomethane, deuterochloromethane, D 3 -p-toluenesulfonyl methyl ester, D 3 -methylsulfonyl methyl ester; preferably deuteroiodomethane;
- the base is selected from sodium methoxide, potassium ethoxide, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium acetate, potassium acetate, K 3 PO 4 , K 2 CO 3 , KHCO 3 , Cs 2 CO 3 , Na 2 CO 3 , NaHCO 3 , KF, pyridine, triethylamine, N,N-diisopropylethyl Amine, DBU; Potassium tert-butoxide;
- the catalyst is tetrabutylammonium bisulfate;
- the organic solvent E is selected from tetrahydrofuran, N,N-dimethylacetamide, dimethylformamide, acetonitrile, acetone, Methyl isobutyl ketone, toluene, pyridine, dichloromethane, ethyl acetate, 2-methyltetrahydrofuran or 1,4-d
- the fourth scheme of the present invention a preparation method of a compound of formula (I), comprises the following steps,
- the organic solvent B is selected from dimethylsulfoxide, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoramide, N-methylpyrrolidone; preferably N,N - dimethylacetamide;
- the organic solvent D is selected from formic acid, acetic acid, oxalic acid, propionic acid; preferably acetic acid;
- the acid B is selected from hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, perchloric acid; preferably hydrochloric acid;
- the lye A is nitrous acid Salt, the nitrite is selected from sodium nitrite, potassium nitrite, ammonium nitrite; preferred sodium nitrite;
- the lye B is acetate, the acetate is selected from sodium acetate, potassium acetate, acetic acid Ammonium; preferably sodium acetate;
- the lye C is selected from potassium hydroxide solution, sodium hydroxide solution, lithium hydroxide solution, potassium tert-butoxide solution, lithium tert-butoxide solution, sodium carbonate solution, potassium carbonate solution, cesium carbonate solution; preferably potassium hydroxide , sodium hydroxide;
- the organic solvent C is anhydrous methanol, absolute ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, toluene, acetone, methyl isobutyl ketone, tetrahydrofuran Furan, 2-methyltetrahydrofuran, dimethylsulfoxide, N,N-dimethylacetamide, hexamethylphosphoramide, N-methylpyrrolidone; preferably absolute ethanol, absolute methanol;
- the organic solvent B is selected from dimethylsulfoxide, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoramide, N-methylpyrrolidone; preferably N,N - dimethylacetamide;
- the acid A is selected from trifluoroacetic acid, pentafluoroacetic acid, heptafluoropropionic acid, sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, formic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid; preferably trifluoroacetic acid;
- the oxidizing agent is selected from ammonium persulfate, potassium persulfate, sodium persulfate, tert-butanol peroxy, hydrogen peroxide; preferably ammonium persulfate.
- the fifth scheme of the present invention a method for preparing a compound of formula (I), comprises the following steps,
- the acid A is selected from trifluoroacetic acid, pentafluoroacetic acid, heptafluoropropionic acid, sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, formic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid; preferably trifluoroacetic acid;
- Said oxidant is selected from ammonium persulfate, potassium persulfate, sodium persulfate, tert-butanol peroxy, hydrogen peroxide; preferred ammonium persulfate;
- the organic solvent B is selected from dimethylsulfoxide, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoramide, N-methylpyrrolidone; preferably N,N - dimethylacetamide;
- step (3) compound 1H obtained in step (2) is mixed with lye C and organic solvent C, and refluxed to obtain compound 1K;
- the lye C is selected from potassium hydroxide solution, sodium hydroxide solution, lithium hydroxide solution, potassium tert-butoxide solution, lithium tert-butoxide solution, sodium carbonate solution, potassium carbonate solution, cesium carbonate solution; preferably potassium hydroxide , sodium hydroxide;
- the organic solvent C is anhydrous methanol, absolute ethanol, n-propanol, isopropanol, tert-butanol, n-butanol, toluene, acetone, methyl isobutyl ketone, tetrahydrofuran, 2-methyl Tetrahydrofuran, dimethylsulfoxide, N,N-dimethylacetamide, hexamethylphosphoramide, N-methylpyrrolidone; preferably absolute ethanol, absolute methanol;
- step (3) dissolve the compound 1K obtained in step (3) in water and organic solvent D, add acid B and stir, add lye A and lye B in turn, and finally add N-cyanoacetylurethane to obtain after reaction Compound 1L;
- the organic solvent D is selected from formic acid, acetic acid, oxalic acid, propionic acid; preferably acetic acid;
- the acid B is selected from hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, perchloric acid; preferably hydrochloric acid;
- the lye A is nitrous acid Salt, the nitrite is selected from sodium nitrite, potassium nitrite, ammonium nitrite; preferred sodium nitrite;
- the lye B is acetate, the acetate is selected from sodium acetate, potassium acetate, acetic acid Ammonium; preferably sodium acetate;
- the organic solvent B is selected from dimethylsulfoxide, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoramide, N-methylpyrrolidone; preferably N,N -Dimethylacetamide; the lye B is acetate, and the acetate is selected from sodium acetate, potassium acetate, ammonium acetate; preferably sodium acetate.
- the method of the present invention has easy-to-obtain raw materials and simple steps, and the entire synthesis process is purified by crystallization without using silica gel column chromatography or other preparation chromatographic methods.
- the cost is low, the intermediate has good stability, high purity and high yield, and is suitable for large-scale industrial production.
- the compound of the general formula involved in the present invention has a chiral center
- the compound of the general formula may be a racemate or an optical isomer unless clearly indicated.
- the inert gas refers to a gas that does not participate in the reaction, such as nitrogen.
- the elements carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the elements carbon, hydrogen, oxygen involved in the groups and compounds of the present invention , sulfur or nitrogen are optionally further replaced by 1 to 5 of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D, also known as deuterium ), tritium (T, also known as tritium), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes
- the isotopes of nitrogen include 32 S, 33 S, 34 S and 36 S, the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine are 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.
- an acid refers to a compound whose cations are all hydrogen ions when it is ionized in an aqueous solution, and can be divided into inorganic acids and organic acids.
- the acid selected in the present invention is organic acid or inorganic acid, organic acid such as trifluoroacetic acid, pentafluoroacetic acid, heptafluoropropionic acid, etc.; inorganic acid such as hydrochloric acid, nitric acid, etc.
- an alkali refers to a substance in which all the anions ionized in aqueous solution are OH- .
- the alkali selected in the present invention is as sodium nitrite, potassium nitrite, sodium acetate, potassium acetate, potassium hydroxide, sodium hydroxide, sodium methylate, potassium ethylate, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, K 3 PO 4 , K 2 CO 3 , KHCO 3 , Cs 2 CO 3 , Na 2 CO 3 , NaHCO 3 , KF, pyridine, triethylamine, N,N-diisopropylethylamine, DBU, etc.
- NMR nuclear magnetic resonance
- MS mass spectroscopy
- HPLC HPLC-based high pressure liquid chromatography
- the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
- the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.20mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. -0.5mm.
- the known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology Waiting for the company.
- the crude product is mixed with 2L of dichloromethane and 2L of petroleum ether for later use.
- the fifth step 3,5-dichloro-4-((4-chloro-5-(methyl-d3)-6,7-dihydro-5H-cyclopentane[d]pyridazin-1-yl) Oxy)aniline (1G)3,5-dichloro-4-((4-chloro-5-(methyl-d3)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)oxy)aniline (1G)
- the seventh step 4-(4-amino-2,6-dichlorophenoxy)-7-(methyl-d3)-2,5,6,7-tetrahydro-1H-cyclopentyl[d] Pyridazin-1-one (1K racemate)
- Mobile phase A: CO2, B: Methanol; Gradient: B 40%; Flow rate: 200mL/min; Back pressure: 100bar;
- the ninth step (R, Z)-(2-cyano-2-(2-(3,5-dichloro-4-)((7-(methyl-d3)-1-oxo-2, 5,6,7-Tetrahydro-1H-cyclopentyl[d]pyridazin-4-yl)oxy)phenyl)hydrazono-4-acetyl)carbamate (1L)
- the filter cake was dried at 55 ⁇ 5°C and vacuum ⁇ -0.07MPa for about 17 hours to obtain 1L of intermediate with a weight of 2.6327kg.
- the yield was 87.3% based on 1K (purity: 98.18%).
- the filter cake was dried at 55 ⁇ 5°C and vacuum ⁇ -0.07MPa for about 16 hours to obtain 1L of intermediate with a weight of 1.845kg. Overweight, the yield was 100% (purity: 98.64%).
- the fine wet product was vacuum-dried at 55 ⁇ 5°C and vacuum ⁇ -0.07MPa for about 17 hours to obtain the finished product I.
- the yield was 2.02555kg in 1L, and the yield was 85.0% (purity: 99.74%).
- the fine wet product was vacuum-dried at 55 ⁇ 5°C and vacuum ⁇ -0.07MPa for about 12 hours to obtain the finished product I.
- the yield was 1L, the weight was 1.582kg, and the yield was 82.6% (purity: 99.23%).
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Abstract
提供了一种哒嗪酮衍生物制备方法及其中间体和中间体的制备方法，所述方法原料易得、步骤简单，成本低，中间体稳定性好、纯度高、收率高，适宜大规模工业化生产。
Description
本发明涉及医药领域，具体的，本发明涉及一种哒嗪酮衍生物制备方法及其中间体和中间体的制备方法。
经典的家族性高胆固醇血症(Familial Hypercholestemlemia,FH)是一种常染色体(共)显性遗传病，主要临床表现为血清低密度脂蛋白胆固醇(Low Density Lipoprotein-Cholesterol，LDL-C)水平明显升高，以及皮肤/腱黄色瘤，可导致早发的心血管疾病。常见的FH分为杂合子家族性高胆固醇血症(HeFH)和更罕见的纯合子家族性高胆固醇血症(HoFH)。据统计，HeFH的患病率高达0.2％-0.48％。FH通常是由于LDL受体(LDLR)的失活性突变引起。临床用药上，他汀类药物为治疗的首选药物，不仅可以降低LDL-C水平，还可以改善FH患者的预后。对他汀类药物治疗效果不好或者有不良反应的患者可联合胆固醇吸收抑制剂依折麦布进行治疗。对上述治疗仍不达标的患者可加用PCSK9抑制剂。尽管HeFH有相应治疗的治疗方式，但许多患者(多达40％的HeFH患者)在这些治疗后依旧无法让胆固醇(LDL-C)水平达标，他们体内胆固醇的累积成为终身负担。
甲状腺激素受体分为α和β两种亚型。甲状腺激素与β亚型受体结合后可促进胆固醇代谢。据此，近年开发出多种选择性激动β亚型的甲状腺激素类似物或拟甲状腺素药物。由Madrigal公司开发的口服激动剂MGL-3196，临床结果显示可显著降低患者体内LDL-C的水平，改善代谢综合征(例如胰岛素抵抗和血脂异常)和脂肪肝疾病(包括脂毒性和炎症)。
化合物专利WO2019240938A1中描述了一种式(I)化合物，属于甲状腺素β受体激动剂，拟用于拟用于治疗成人原发性高胆固醇血症，同时公开了制备方法，
但是该制备方法存在中间体稳定性差、纯化难度大，需要多步过柱纯化不利于工业使用，反应条件不利于放大生产，收率低，成本高昂等缺点。
发明内容
本发明的目的是提供一种哒嗪酮衍生物制备方法。
所述方法原料易得、步骤简单，整个合成工艺都用结晶纯化，没有用到硅胶柱层析，成本低，中间体稳定性好、纯度高、收率高，适宜大规模工业化生产。
本发明的另一个目的是提供了一种制备哒嗪酮衍生物的中间体。
本发明的另一个目的是提供了所述制备哒嗪酮衍生物的中间体的制备方法。
本发明提供了一种式(1E)、式(1H)所示化合物或其药学上可接受的盐，
本发明提供了一种式(1F)化合物的制备方法，包括以下步骤，
化合物1E与3,6-二氯哒嗪、水、硝酸银反应后，加酸A和氧化剂，反应得到化合物1F。
化合物1E与3,6-二氯哒嗪、水、硝酸银，在55～65℃加酸A和氧化剂，反应得到化合物1F。
本发明的一些实施方案中，将化合物1E与3,6-二氯哒嗪，加水，升温至30-40℃，加硝酸银，升温至55-65℃，加酸A和氧化剂，在70-80℃下反应得到化合物1F。
本发明的一些实施方案中，所述酸A选自三氟乙酸、五氟乙酸、七氟丙酸、硫酸、盐酸、磷酸、硝酸、甲酸、乙酸、苯磺酸、甲磺酸、对甲苯磺酸；本发明的一些实施方案中，所述酸A选自三氟乙酸；本发明的一些实施方案中，所述氧化剂选自过硫酸铵、过硫酸钾、过硫酸钠、过氧叔丁醇、过氧化氢；本发明的一些实施方案中，所述氧化剂选自过硫酸铵；本发明的一些实施方案中，所述过硫酸铵的浓度为0.1-1g/mL。
本发明的一些实施方案中，所述化合物1E和3,6-二氯哒嗪摩尔比为1:0.9-5.0；本发明的一些实施方案中，所述化合物1E和3,6-二氯哒嗪摩尔比为1:1.0-2.0；本发明的一些实施
方案中，所述化合物1E和硝酸银摩尔比为1:0.2-2.0；本发明的一些实施方案中，所述化合物1E和硝酸银摩尔比为1:0.4-1.0；本发明的一些实施方案中，所述化合物1E和酸A摩尔比为1:0.05-2.0；本发明的一些实施方案中，所述化合物1E和酸A摩尔比为1:0.1-1.0。
化合物专利(WO2019240938A1)中使用中间原料3,6-二氯-1,2,4,5-四嗪制备1F，与本发明中间原料3,6-二氯哒嗪相比，中间原料3,6-二氯-1,2,4,5-四嗪的成本高，稳定性差，最终产物收率低，不宜工业化生产。
本发明提供了一种式(1E)化合物的制备方法，包括以下步骤，
将化合物1D在100～180℃下搅拌反应，得到化合物1E。
本发明的一些实施方案中，将化合物1D，在120～150℃下搅拌反应，得到化合物1E，所述搅拌反应后还包括后处理和干燥步骤，所述后处理为在20～50℃下加入有机溶剂F、有机溶剂A，室温下析晶，过滤；本发明的一些实施方案中，将化合物1D，在130～140℃下搅拌反应，得到化合物1E；本发明的一些实施方案中，所述后处理为在30～40℃下加入有机溶剂F、有机溶剂A，室温下析晶，过滤，收集滤饼。
本发明的一些实施方案中，所述有机溶剂F选自二氯甲烷、乙酸甲酯、乙腈、甲苯、乙酸乙酯、乙酸异丙酯、丙酮、2-甲基四氢呋喃、四氢呋喃、1,4-二氧六环、碳酸二甲酯、丙二醇甲醚乙酸酯、尼龙酸二甲酯；本发明的一些实施方案中，所述有机溶剂F选自二氯甲烷、乙酸甲酯、碳酸二甲酯、丙二醇甲醚乙酸酯、尼龙酸二甲酯；本发明的一些实施方案中，所述有机溶剂F选自二氯甲烷；本发明的一些实施方案中，所述有机溶剂A选自烷基烃类或者酯类；本发明的一些实施方案中，所述有机溶剂A选自正戊烷、正己烷、正庚烷、石油醚、2-甲基戊烷、3-甲基戊烷、2，3-二甲基丁烷、2，2-二甲基丁烷、乙酸甲酯、碳酸二甲酯、丙二醇甲醚乙酸酯、尼龙酸二甲酯、乙酸乙酯、乙酸异丙酯；本发明的一些实施方案中，所述有机溶剂A选自正戊烷、正己烷、正庚烷、石油醚、2-甲基戊烷、3-甲基戊烷、2，3-二甲基丁烷和2，2-二甲基丁烷；本发明的一些实施方案中，所述有机溶剂A选自正己烷；本发明的一些实施方案中，所述干燥为在40～60℃，真空度≤-0.07MPa下将所述过滤处理后的滤饼进行干燥；本发明的一些实施方案中，所述干燥为在45～55℃，真空度≤-0.07MPa下将所述过滤处理后的滤饼进行干燥。
本发明的一些实施方案中，一种式(1E)化合物的制备方法，还包括以下步骤，
化合物1C与有机溶剂F和酸A回流反应得到化合物1D。
化合物1C与有机溶剂F和酸A，回流反应，减压浓缩，打浆，过滤，干燥，得到化合物1D。
本发明的一些实施方案中，所述有机溶剂F选自二氯甲烷、乙酸甲酯、乙腈、甲苯、乙酸乙酯、乙酸异丙酯、丙酮、2-甲基四氢呋喃、四氢呋喃、1,4-二氧六环、碳酸二甲酯、丙二醇甲醚乙酸酯、尼龙酸二甲酯；本发明的一些实施方案中，所述有机溶剂F选自二氯甲烷、乙酸甲酯、碳酸二甲酯、丙二醇甲醚乙酸酯、尼龙酸二甲酯；本发明的一些实施方案中，所述有机溶剂F选自二氯甲烷；本发明的一些实施方案中，所述酸A选自三氟乙酸、五氟乙酸、七氟丙酸、盐酸、硫酸、磷酸、甲酸、苯磺酸、甲磺酸、对甲苯磺酸；本发明的一些实施方案中，所述酸A选自三氟乙酸、五氟乙酸、七氟丙酸；本发明的一些实施方案中，所述酸A选自三氟乙酸；本发明的一些实施方案中，所述有机溶剂A选自烷基烃类或者酯类；本发明的一些实施方案中，所述有机溶剂A选自正戊烷、正己烷、正庚烷、石油醚、2-甲基戊烷、3-甲基戊烷、2,3-二甲基丁烷、2,2-二甲基丁烷、乙酸甲酯、碳酸二甲酯、丙二醇甲醚乙酸酯、尼龙酸二甲酯、乙酸乙酯、乙酸异丙酯；本发明的一些实施方案中，所述有机溶剂A选自正戊烷、正己烷、正庚烷、石油醚、2-甲基戊烷、3-甲基戊烷、2,3-二甲基丁烷、2,2-二甲基丁烷；本发明的一些实施方案中，所述有机溶剂A选自正己烷；本发明的一些实施方案中，所述干燥为在40～60℃，真空度≤-0.07MPa下将所述过滤处理后的滤饼进行干燥；本发明的一些实施方案中，所述干燥为在45～55℃，真空度≤-0.07MPa下将所述过滤处理后的滤饼进行干燥。
本发明的一些实施方案中，所述化合物1C和酸A的摩尔比为1:3.0-30.0；本发明的一些实施方案中，所述化合物1C和酸A的摩尔比为1:3.0～10.0。
本发明的一些实施方案中，一种式(1E)化合物的制备方法，还包括以下步骤，
化合物1B在有机碱存在下，与氘代试剂反应，得到化合物1C。
本发明的一些实施方案中，所述氘代试剂选自氘代碘甲烷、氘代溴甲烷、氘代氯甲烷、D3-对甲苯磺酰甲酯、D3-甲磺酰甲酯；本发明的一些实施方案中，所述氘代试剂选自氘代碘甲烷。
本发明的一些实施方案中，所述化合物1B和碱的摩尔比为1:1.00-5.05；本发明的一些实施方案中，所述化合物1B和碱的摩尔比为1:1.05-2.05；本发明的一些实施方案中，所述化合物1B和氘代试剂的摩尔比为1:0.9-5.0；本发明的一些实施方案中，所述化合物1B和氘代试剂的摩尔比为1:1.0～2.5。
本发明的一些实施方案中，还包括以下步骤，
将化合物1A、碱和催化剂加入到有机溶剂E中，惰性气体保护下加入丙烯酸叔丁酯，反应完全后得到化合物1B。
本发明的一些实施方案中，所述碱选自甲醇钠、乙醇钾、叔丁醇钾、叔丁醇钠、叔丁醇锂、乙酸钠、乙酸钾、K3PO4、K2CO3、KHCO3、Cs2CO3、Na2CO3、NaHCO3、KF、吡啶、三乙胺、N,N-二异丙基乙胺、DBU；本发明的一些实施方案中，所述碱选自甲醇钠、乙醇钾、叔丁醇钾、叔丁醇钠；本发明的一些实施方案中，所述碱选自叔丁醇钾；本发明的一些实施方案中，所述催化剂为四丁基硫酸氢铵；本发明的一些实施方案中，所述有机溶剂E选自四氢呋喃、N,N-二甲基乙酰胺、二甲基甲酰胺、乙腈、丙酮、甲基异丁酮、甲苯、吡啶、二氯甲烷、乙酸乙酯、2-甲基四氢呋喃或1，4-二氧六环；本发明的一些实施方案中，所述有机溶剂E选自四氢呋喃、N,N-二甲基乙酰胺、二甲基甲酰胺、乙腈、丙酮；本发明的一些实施方案中，所述有机溶剂E选自四氢呋喃。
本发明的一些实施方案中，所述化合物1A和碱的摩尔比为1:0.001-0.5；本发明的一些实施方案中，所述化合物1A和碱的摩尔比为1:0.01～0.25；本发明的一些实施方案中，所述化合物1A和丙烯酸叔丁酯的摩尔比为1:0.8-6.0；本发明的一些实施方案中，所述化合物1A和丙烯酸叔丁酯的摩尔比为1:1.0-3.0。
本发明还提供一种式(I)化合物的制备方法，包括如下步骤，
化合物1L在有机溶剂B和碱液B存在下，反应得到化合物I。
本发明的一些实施方案中，所述有机溶剂B选自二甲亚砜、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、六甲基磷酰胺、N-甲基吡咯烷酮；本发明的一些实施方案中，所述有机溶剂B选自N,N-二甲基乙酰胺。
本发明的一些实施方案中，化合物1L在有机溶剂B和碱液B存在下，在100-130℃下反应得到化合物I；本发明的一些实施方案中，化合物1L在有机溶剂B和碱液B存在下，在110-120℃下反应得到化合物I；本发明的一些实施方案中，化合物1L在有机溶剂B和碱液B存在下，在115℃下反应得到化合物I。
本发明的一些实施方案中，所述化合物1L与碱液B的摩尔比为1:0.5-1:5.0；本发明的一些实施方案中，所述化合物1L与碱液B的摩尔比为1:0.5-1:4.5；本发明的一些实施方案中，所述化合物1L与碱液B的摩尔比为1:1-1:4.5；本发明的一些实施方案中，所述化合物1L与碱液B的摩尔比为1:2-1:4.5；本发明的一些实施方案中，所述化合物1L与碱液B的摩尔比为1:1-3:4.5；本发明的一些实施方案中，所述化合物1L与碱液B的摩尔比为1:0.5-1:4.0；本发明的一些实施方案中，所述化合物1L与碱液B的摩尔比为1:0.5-1:3.5；本发明的一些实施方案中，所述化合物1L与碱液B的摩尔比为1:0.5-1:3.0；本发明的一些实施方案中，所述化合物1L与碱液B的摩尔比为1:1.0-2.5；本发明的一些实施方案中，所述化合物1L与碱液B的摩尔比为1:1.0-2.0。
本发明的一些实施方案中，化合物1L在有机溶剂B和碱液B存在下，反应后还包括后处理和精制步骤，得到化合物I；本发明的一些实施方案中，所述后处理为在55-65℃下，加水，过滤，第一次洗涤，加入有机溶剂D和水，在5-15℃下析晶，过滤，第二次洗涤，干燥，得到化合物I的粗品；本发明的一些实施方案中，所述精制为将化合物I的粗品与无水乙醇混合，在70-80℃下搅拌反应3-6h，降温至0-10℃下析晶，完成后过滤、洗涤，干燥，得到化合物I；本发明的一些实施方案中，所述第一次洗涤采用N,N-二甲基乙酰胺进行洗涤；所述有机溶剂D为甲酸、乙酸、乙二酸、丙酸；本发明的一些实施方案中，所述有机溶剂D为乙酸；本发明的一些实施方案中，所述第二次洗涤分别采用水和无水乙醇进行洗涤。
化合物专利(WO2019240938A1)中合成化合物I通过制备型HPLC纯化，和上一步一起两步收率只有20-30％，收率低；而本发明工艺中此两步收率高达70-80％。
本发明的一些实施方案中，一种式(I)化合物的制备方法，还包括以下步骤，
化合物1K溶于水和有机溶剂D中，加酸B搅拌，依次加碱液A和碱液B，最后加入N-氰基乙酰尿烷，反应后得到化合物1L。
本发明的一些实施方案中，化合物1K溶于水和有机溶剂D中，在-5-5℃下，加酸B，搅拌反应后加碱液A，反应完全后加碱液B，最后加入N-氰基乙酰尿烷，升温至5-15℃，反应后得到化合物1L。
本发明的一些实施方案中，所述有机溶剂D选自甲酸、乙酸、乙二酸、丙酸；本发明的一些实施方案中，所述有机溶剂D选自乙酸；本发明的一些实施方案中，所述酸B选自盐酸、硝酸、硫酸、磷酸、高氯酸；本发明的一些实施方案中，所述酸B选自盐酸；本发明的一些实施方案中，所述碱液A为亚硝酸盐，所述亚硝酸盐选自亚硝酸钠、亚硝酸钾、亚硝酸铵；本发明的一些实施方案中，所述亚硝酸盐选自亚硝酸钠；本发明的一些实施方案中，所述亚硝酸钠的浓度为0.3-0.6g/mL；本发明的一些实施方案中，所述碱液B为乙酸盐，所述乙酸盐选自乙酸钠、乙酸钾、乙酸铵；本发明的一些实施方案中，所述乙酸盐选自乙酸钠；本发明的一些实施方案中，所述乙酸钠的浓度为0.1-0.3g/mL。
本发明的一些实施方案中，所述化合物1K和N-氰基乙酰尿烷的摩尔比为1:0.9-5.0；本发明的一些实施方案中，所述化合物1K和N-氰基乙酰尿烷的摩尔比为1:1.0-3.0；本发明的一些实施方案中，所述化合物1K和碱A的摩尔比为1:1.0-10.0；本发明的一些实施方案中，所述化合物1K和碱A的摩尔比为1:1.1-3.0。
化合物专利(WO2019240938A1)中添加的碱为吡啶，后处理采用乙酸乙酯萃取，浓缩得到产物I。而本发明工艺反应结束加水直接析晶，后处理简单易于放大，且产物收率和纯度更高。
本发明的一些实施方案中，一种式(I)化合物的制备方法，还包括以下步骤，
化合物1H与碱液C和有机溶剂C混合，回流反应，得到化合物1K。
本发明的一些实施方案中，所述碱液C选自氢氧化钾溶液、氢氧化钠溶液、氢氧化锂溶液、叔丁醇钾溶液、叔丁醇锂溶液、碳酸钠溶液、碳酸钾溶液、碳酸铯溶液；本发明的一些实
施方案中，所述碱液C选自氢氧化钾；本发明的一些实施方案中，所述碱液C选自氢氧化钠；本发明的一些实施方案中，所述氢氧化钾的质量浓度为0.1-0.2g/mL；本发明的一些实施方案中，所述有机溶剂C选自无水甲醇、无水乙醇、正丙醇、异丙醇、叔丁醇、正丁醇、甲苯、丙酮、甲基异丁酮、四氢呋喃、2-甲基四氢呋喃、二甲亚砜、N,N-二甲基乙酰胺、六甲基磷酰胺、N-甲基吡咯烷酮；本发明的一些实施方案中，所述有机溶剂C选自无水乙醇；本发明的一些实施方案中，所述有机溶剂C选自无水甲醇。
本发明的一些实施方案中，所述回流反应温度为70-90℃；本发明的一些实施方案中，所述回流反应温度为75-85℃；本发明的一些实施方案中，所述回流反应温度为80±5℃；本发明的一些实施方案中，所述回流反应温度为80℃。
本发明的一些实施方案中，将化合物1H，与碱液C和有机溶剂C混合，加热回流反应15-20h，得到化合物1K的消旋体；所述化合物1K的消旋体再经过后处理和精制，最后经过手性SFC拆分，得到化合物1K。
本发明的一些实施方案中，所述后处理为降温至20-30℃，加水，调节溶液pH至8-9，萃取，洗涤，干燥，过滤；本发明的一些实施方案中，所述精制为将后处理后得到的粗品用二氧六环溶液溶清，在室温下析晶，过滤；重复精制2-3次，真空干燥。
本发明的一些实施方案中，一种式(I)化合物的制备方法，还包括以下步骤，
化合物1F、4-氨基-2,6-二氯苯酚在有机溶剂B和碳酸铯存在下，在惰性气体保护下，反应得到化合物1G；
化合物1G在冰乙酸存在下，与苯甲酸酐反应得到化合物1H。
化合物专利(WO2019240938A1)中使用碘化亚铜催化制备1G，收率低，且可能有金属铜残留，还需要过柱子纯化；而本工艺直接在碱性下取代反应得到1G，三步粗品连投得到1k消旋体，结晶纯化，三步叠缩反应更适宜工业化生产；另外，化合物专利中制备1K消旋体化合物，三步收率只有20-25％；而本发明工艺制备1K消旋体化合物的三步收率可以达到30-40％；且化合物1H保护基不同，更易析晶，大大简化后处理工艺。
本发明的一些实施方案中，具体包括以下步骤，
(a)、将化合物1F、4-氨基-2,6-二氯苯酚与有机溶剂B混合，加入碳酸铯，在氮气保护下，加热到90-95℃下反应18-22h，得到化合物1G；
(b)、将步骤(a)得到的化合物1G用冰乙酸溶清，加入苯甲酸酐，反应结束后干燥，升温至115-125℃下反应15-20h，经过后处理得到化合物1H。
本发明的一些实施方案中，所述有机溶剂B选自二甲亚砜、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、六甲基磷酰胺、N-甲基吡咯烷酮；本发明的一些实施方案中，所述有机溶剂B选自N,N-二甲基乙酰胺。
本发明的一些实施方案中，所述后处理为在60-65℃下，减压浓缩反应液，加无水乙醇，将混合溶液缓慢加入到水中，快速搅拌析出固体，离心，洗涤，得到化合物1H。
本发明的一些实施方案中，所述化合物1F、4-氨基-2,6-二氯苯酚与碳酸铯的摩尔比为1-5:1-5:1.0-10；本发明的一些实施方案中，所述化合物1F、4-氨基-2,6-二氯苯酚与碳酸铯的摩尔比为2-3:2-3:3.0-5.0；本发明的一些实施方案中，所述苯甲酸酐与化合物1F的摩尔比为1-5:1-5；本发明的一些实施方案中，所述苯甲酸酐与化合物1F的摩尔比为2-3:2.2-3.5；
本发明的一些实施方案中，一种式(I)化合物的制备方法，还包括以下步骤，
化合物1E与3,6-二氯哒嗪、水、硝酸银反应后，加酸A和氧化剂，反应得到化合物1F。
将化合物1E与3,6-二氯哒嗪，加水、硝酸银，在55～65℃加酸A和氧化剂，反应得到化合物1F。
本发明的一些实施方案中，将化合物1E与3,6-二氯哒嗪，加水，升温至30-40℃，加硝酸银，升温至55-65℃，加酸A和氧化剂，在70-80℃下反应得到化合物1F。
本发明的一些实施方案中，所述酸A选自三氟乙酸、五氟乙酸、七氟丙酸、硫酸、盐酸、磷酸、硝酸、甲酸、乙酸、苯磺酸、甲磺酸、对甲苯磺酸；本发明的一些实施方案中，所述酸A选自三氟乙酸；本发明的一些实施方案中，所述氧化剂选自过硫酸铵、过硫酸钾、过硫酸钠、过氧叔丁醇、过氧化氢；本发明的一些实施方案中，所述氧化剂选自过硫酸铵；本发明的一些实施方案中，所述过硫酸铵的浓度为0.1-1g/mL。
本发明的一些实施方案中，所述化合物1E和3,6-二氯哒嗪摩尔比为1:0.9-5.0；本发明的一些实施方案中，所述化合物1E和3,6-二氯哒嗪摩尔比为1:1.0-2.0；本发明的一些实施
方案中，所述化合物1E和硝酸银摩尔比为1:0.2-2.0；本发明的一些实施方案中，所述化合物1E和硝酸银摩尔比为1:0.4-1.0；本发明的一些实施方案中，所述化合物1E和酸A摩尔比为1:0.05-2.0；本发明的一些实施方案中，所述化合物1E和酸A摩尔比为1:0.1-1.0。
本发明的第一个方案，一种式(1E)、式(1H)所示化合物或其药学上可接受的盐，
本发明的第二个方案，一种式(1F)化合物的制备方法，包括以下步骤，
化合物1E与3,6-二氯哒嗪、水、硝酸银反应后，加酸A和氧化剂，反应得到化合物1F。
化合物1E与3,6-二氯哒嗪、水、硝酸银，在55～65℃加酸A和氧化剂，反应得到化合物1F；
所述酸A选自三氟乙酸、五氟乙酸、七氟丙酸、硫酸、盐酸、磷酸、硝酸、甲酸、乙酸、苯磺酸、甲磺酸、对甲苯磺酸；所述氧化剂选自过硫酸铵、过硫酸钾、过硫酸钠、过氧叔丁醇、过氧化氢；
本发明的第三个方案，一种式(1E)化合物的制备方法，包括以下步骤，
将化合物1D，在100～180℃下搅拌反应，得到化合物1E；
所述搅拌反应后还包括后处理和干燥步骤，所述后处理为在20～50℃下加入有机溶剂F、有机溶剂A，室温下析晶，过滤；
还包括以下步骤，
化合物1C与有机溶剂F和酸A，回流反应，减压浓缩，打浆，过滤，干燥，得到化合物1D；
所述有机溶剂F选自二氯甲烷、乙酸甲酯、碳酸二甲酯、丙二醇甲醚乙酸酯、尼龙酸二甲酯、乙腈、甲苯、乙酸乙酯、乙酸异丙酯、丙酮、2-甲基四氢呋喃、四氢呋喃、1,4-二氧六环；所述酸A选自三氟乙酸、五氟乙酸、七氟丙酸、盐酸、硫酸、磷酸、甲酸、苯磺酸、甲磺酸、对甲苯磺酸；所述有机溶剂A选自正戊烷、正己烷、正庚烷、石油醚、2-甲基戊烷、3-甲基戊烷、2，3-二甲基丁烷和2，2-二甲基丁烷、乙酸甲酯、碳酸二甲酯、丙二醇甲醚乙酸酯、尼龙酸二甲酯、乙酸乙酯、乙酸异丙酯；所述干燥为在40～60℃，真空度≤-0.07MPa下将所述过滤处理后的滤饼进行干燥；
还包括以下步骤，
化合物1B在碱存在下，与氘代试剂反应，得到化合物1C；
所述氘代试剂选自氘代碘甲烷、氘代溴甲烷、氘代氯甲烷、D3-对甲苯磺酰甲酯、D3-甲磺酰甲酯；优选氘代碘甲烷；
还包括以下步骤，
将化合物1A、碱和催化剂加入到有机溶剂E中，惰性气体保护下加入丙烯酸叔丁酯，反应完全后得到化合物1B；
所述碱选自甲醇钠、乙醇钾、叔丁醇钾、叔丁醇钠、叔丁醇锂、乙酸钠、乙酸钾、K3PO4、K2CO3、KHCO3、Cs2CO3、Na2CO3、NaHCO3、KF、吡啶、三乙胺、N,N-二异丙基乙
胺、DBU；优选叔丁醇钾；所述催化剂为四丁基硫酸氢铵；所述有机溶剂E选自四氢呋喃、N,N-二甲基乙酰胺、二甲基甲酰胺、乙腈、丙酮、甲基异丁酮、甲苯、吡啶、二氯甲烷、乙酸乙酯、2-甲基四氢呋喃或1,4-二氧六环。
本发明的第四个方案，一种式(I)化合物的制备方法，包括如下步骤，
化合物1L在有机溶剂B和碱液B存在下，反应得到化合物I；
所述有机溶剂B选自二甲亚砜、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、六甲基磷酰胺、N-甲基吡咯烷酮；优选N,N-二甲基乙酰胺；
还包括以下步骤，
化合物1K溶于水和有机溶剂D中，加酸B搅拌，依次加碱液A和碱液B，最后加入N-氰基乙酰尿烷，反应后得到化合物1L；
所述有机溶剂D选自甲酸、乙酸、乙二酸、丙酸；优选乙酸；所述酸B选自盐酸、硝酸、硫酸、磷酸、高氯酸；优选盐酸；所述碱液A为亚硝酸盐，所述亚硝酸盐选自亚硝酸钠、亚硝酸钾、亚硝酸铵；优选亚硝酸钠；所述碱液B为乙酸盐，所述乙酸盐选自乙酸钠、乙酸钾、乙酸铵；优选乙酸钠；
还包括以下步骤，
化合物1H与碱液C和有机溶剂C混合，回流反应，得到化合物1K；
所述碱液C选自氢氧化钾溶液、氢氧化钠溶液、氢氧化锂溶液、叔丁醇钾溶液、叔丁醇锂溶液、碳酸钠溶液、碳酸钾溶液、碳酸铯溶液；优选氢氧化钾、氢氧化钠；所述有机溶剂C为无水甲醇、无水乙醇、正丙醇、异丙醇、叔丁醇、正丁醇、甲苯、丙酮、甲基异丁酮、四氢呋
喃、2-甲基四氢呋喃、二甲亚砜、N,N-二甲基乙酰胺、六甲基磷酰胺、N-甲基吡咯烷酮；优选为无水乙醇、无水甲醇；
还包括以下步骤，
化合物1F、4-氨基-2,6-二氯苯酚在有机溶剂B和碳酸铯存在下，在惰性气体保护下，反应得到化合物1G；
化合物1G在冰乙酸存在下，与苯甲酸酐反应得到化合物1H；
所述有机溶剂B选自二甲亚砜、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、六甲基磷酰胺、N-甲基吡咯烷酮；优选N,N-二甲基乙酰胺；
还包括以下步骤，
化合物1E与3,6-二氯哒嗪、水、硝酸银反应后，加酸A和氧化剂，反应得到化合物1F。
将化合物1E与3,6-二氯哒嗪，加水、硝酸银，在55～65℃加酸A和氧化剂，反应得到化合物1F；
所述酸A选自三氟乙酸、五氟乙酸、七氟丙酸、硫酸、盐酸、磷酸、硝酸、甲酸、乙酸、苯磺酸、甲磺酸、对甲苯磺酸；优选三氟乙酸；所述氧化剂选自过硫酸铵、过硫酸钾、过硫酸钠、过氧叔丁醇、过氧化氢；优选过硫酸铵。
本发明的第五个方案，一种式(I)化合物的制备方法，包括如下步骤，
(1)、将化合物1E与3,6-二氯哒嗪，加水、硝酸银反应后，加酸A和氧化剂，反应得到化合物1F；
所述酸A选自三氟乙酸、五氟乙酸、七氟丙酸、硫酸、盐酸、磷酸、硝酸、甲酸、乙酸、苯磺酸、甲磺酸、对甲苯磺酸；优选三氟乙酸；所述氧化剂选自过硫酸铵、过硫酸钾、过硫酸钠、过氧叔丁醇、过氧化氢；优选过硫酸铵；
(2)、将步骤(1)得到的化合物1F、4-氨基-2,6-二氯苯酚在有机溶剂B和碳酸铯存在下，在惰性气体保护下，反应得到化合物1G；
化合物1G在冰乙酸存在下，与苯甲酸酐反应得到化合物1H；
所述有机溶剂B选自二甲亚砜、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、六甲基磷酰胺、N-甲基吡咯烷酮；优选N,N-二甲基乙酰胺；
(3)、将步骤(2)得到的化合物1H与碱液C和有机溶剂C混合，回流反应，得到化合物1K；
所述碱液C选自氢氧化钾溶液、氢氧化钠溶液、氢氧化锂溶液、叔丁醇钾溶液、叔丁醇锂溶液、碳酸钠溶液、碳酸钾溶液、碳酸铯溶液；优选氢氧化钾、氢氧化钠；所述有机溶剂C为无水甲醇、无水乙醇、正丙醇、异丙醇、叔丁醇、正丁醇、甲苯、丙酮、甲基异丁酮、四氢呋喃、2-甲基四氢呋喃、二甲亚砜、N,N-二甲基乙酰胺、六甲基磷酰胺、N-甲基吡咯烷酮；优选为无水乙醇、无水甲醇；
(4)、将步骤(3)得到的化合物1K溶于水和有机溶剂D中，加酸B搅拌，依次加碱液A和碱液B，最后加入N-氰基乙酰尿烷，反应后得到化合物1L；
所述有机溶剂D选自甲酸、乙酸、乙二酸、丙酸；优选乙酸；所述酸B选自盐酸、硝酸、硫酸、磷酸、高氯酸；优选盐酸；所述碱液A为亚硝酸盐，所述亚硝酸盐选自亚硝酸钠、亚硝酸钾、亚硝酸铵；优选亚硝酸钠；所述碱液B为乙酸盐，所述乙酸盐选自乙酸钠、乙酸钾、乙酸铵；优选乙酸钠；
(5)、化合物1L在有机溶剂B和碱液B存在下，反应得到化合物I；
所述有机溶剂B选自二甲亚砜、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、六甲基磷酰胺、N-甲基吡咯烷酮；优选N,N-二甲基乙酰胺；所述碱液B为乙酸盐，所述乙酸盐选自乙酸钠、乙酸钾、乙酸铵；优选乙酸钠。
本发明的有益效果：
本发明所述方法原料易得、步骤简单，整个合成工艺都用结晶纯化，没有用到硅胶柱层析或其他制备色谱方法，成本低，中间体稳定性好、纯度高、收率高，适宜大规模工业化生产。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明涉及的通式化合物存在手性中心时，除明确标示外，通式化合物可以是消旋体，也可以是旋光异构体。
本发明中，所述惰性气体是指不参与反应的气体，如氮气。
本发明所述基团和化合物中所涉及的元素碳、氢、氧、硫、氮或卤素均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的元素碳、氢、氧、硫或氮任选进一步被1至5个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，硫的同位
素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。
酸在化学上是指在水溶液中电离时产生的阳离子都是氢离子的化合物，可分为无机酸、有机酸。本发明所选取的酸为有机酸或无机酸，有机酸如三氟乙酸、五氟乙酸、七氟丙酸等；无机酸如盐酸、硝酸等。
碱在酸碱电离理论中，碱指在水溶液中电离出的阴离子全部都是OH-的物质。本发明所选取的碱如亚硝酸钠、亚硝酸钾、乙酸钠、乙酸钾、氢氧化钾、氢氧化钠、甲醇钠、乙醇钾、叔丁醇钾、叔丁醇钠、叔丁醇锂、K3PO4、K2CO3、KHCO3、Cs2CO3、Na2CO3、NaHCO3、KF、吡啶、三乙胺、N,N-二异丙基乙胺、DBU等等。
以下结合实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-
6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)；
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
实施例1
(R)-2-(3,5-二氯-4-((7-(甲基-d3)-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈
(R)-2-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
第一步：三叔丁基丁烷-1,3,3-三羧酸酯-4,4,4-d3(1C)
tri-tert-butyl butane-1,3,3-tricarboxylate-4,4,4-d3(1C)
方法一：
1000L反应釜中，加入720L四氢呋喃、90.0kg 1A、2.33kg叔丁醇钾和1.41kg四丁基硫酸氢铵，加毕，氮气保护下降温0～10℃，控温10℃以下滴加53.3kg丙烯酸叔丁酯，加毕，保温反应1小时，TLC监控(正己烷/乙酸乙酯(v/v)＝10:1)原料基本转化完全，向反应液加入49.0kg叔丁醇钾，控温0～10℃，将62.0kg氘代碘甲烷滴加至反应液中，加毕，
继续反应1小时后，TLC监控(正己烷/乙酸乙酯(v/v)＝10:1)原料基本转化完全。反应液中加入115kg 10％氯化铵溶液，用乙酸乙酯(150L×2)萃取水相，合并有机相用200L饱和氯化钠水溶液洗涤一次，分液，50±5℃减压浓缩有机相至无馏分后，得到143.0kg淡黄色油状液体，收率：95.1％。
1H NMR(400MHz,DMSO)δ2.14-2.10(m 2H),1.92-1.88(m,2H),1.39(s,27H).
方法二：
50L反应釜中，加入16L四氢呋喃、2000g 1A、102g叔丁醇钾和32g Bu4NHSO4，加毕，氮气保护下降温0～10℃，控温10℃以下滴加1185g丙烯酸叔丁酯，约1-2小时加毕，保温反应1小时，TLC监控(正己烷/乙酸乙酯(v/v)＝12:1)原料基本转化完全，向反应液加入1090g叔丁醇钾，控温0～10℃，将1407g氘代碘甲烷滴加至反应液中，约1小时加毕，继续反应1小时后，TLC监控(正己烷/乙酸乙酯(v/v)＝12:1)原料基本转化完全。反应液中加入10L 10％氯化铵溶液，用乙酸乙酯(8L×2)萃取水相，合并有机相用10L饱和氯化钠水溶液洗涤一次，分液，有机相用1.5kg无水硫酸钠干燥，过滤除去硫酸钠，50±5℃减压浓缩有机相至无馏分后得到3.756kg淡黄色油状液体，粗品超重，收率按照100％计。
第二步：丁烷-1,3,3-三羧酸-4,4,4-d3酸(1D)
butane-1,3,3-tricarboxylic-4,4,4-d3acid(1D)
方法一：
1000L反应釜中，加入200L二氯甲烷、143.0kg 1C和160L三氟乙酸，加毕，升温40～45℃回流反应约12小时，TLC监控(正己烷/乙酸乙酯(v/v)＝10:1)原料转化完全。将反应液50±5℃减压浓缩至无明显馏分后，加入100L正己烷打浆2.0小时，过滤，洗涤，收集滤饼。滤饼于50±5℃，干燥约16小时。收料得白色固体65.5kg中间体1D，收率约85.7％(纯度：95％)。
1H NMR(400MHz,DMSO)δ12.66-12.00(brs,3H),2.20-2.15(m,2H),1.97-1.92(m,2H).
LCMS m/z＝192.1[M-H]+
方法二：
50L玻璃反应釜中，加入8L二氯甲烷、3756g 1C和6L三氟乙酸，加毕，升温35～40℃回流反应约16小时，TLC监控(正己烷/乙酸乙酯(v/v)＝12:1)原料转化完全。将反应
液50±5℃减压浓缩至无明显馏分后，加入2L正己烷打浆0.5小时，过滤，正己烷洗涤，收集滤饼。滤饼于50±5℃、真空≤-0.07MPa干燥约16小时。收料得白色固体1280g中间体1D，两步收率约72％(纯度：95％)。
1H NMR(400MHz,DMSO)δ12.66-12.00(brs,3H),2.20-2.15(m,2H),1.97-1.92(m,2H).
LCMS m/z＝192.1[M-H]+
第三步：2-(甲基-d3)戊二酸(1E)
2-(methyl-d3)pentanedioic acid(1E)
5L反应瓶中，加入1280g 1D，开启搅拌升温至130～140℃下反应约5小时。将反应液冷却至30～40℃，先加入1.5L二氯甲烷，搅拌约10分钟后，再加入1.5L正己烷，室温下搅拌析晶约16小时，过滤，滤饼用正己烷洗涤，收集滤饼。滤饼于50±5℃、真空≤-0.07MPa干燥约16小时。收料得白色固体900g中间体1E，收率约91％(纯度：97％)。
1H NMR(400MHz,DMSO)δ12.09(brs,2H),2.32-2.23(m,1H),2.21-2.19(m,2H),1.78-1.74(m,1H),1.58-1.52(m,1H).
LCMS m/z＝148.1[M-H]+
第四步：1,4-二氯-5-(甲基-d3)-6,7-二氢-5H-环戊[d]哒嗪(1F)
1,4-dichloro-5-(methyl-d3)-6,7-dihydro-5H-cyclopenta[d]pyridazine(1F)
向100L反应釜中，加入纯化水22L，开启搅拌，加入1998g 3,6-二氯哒嗪、2000g 1E开启加热，升温至35℃。待内温升至35℃±5℃，加入1146g硝酸银。开启加热，内温升至60℃，加入306g三氟乙酸，开始滴加(NH4)2S2O8水溶液(将10.70kg(NH4)2S2O8溶于26L纯化水中)，反应放出气体并伴随放热，控制内温于75℃±5℃。滴加完成后，保持内温75℃±5℃，继续反应半小时后，取样TLC监控(EA:PE＝1:4)至3,6-二氯哒嗪消失。
降温至40℃，加入30L甲基叔丁基醚萃取，分液，水相再用15L甲基叔丁基醚萃取一次，合并有机相，水相中加入12.5L氨水后再用10L甲基叔丁基醚萃取一次，合并有机相，用15L饱和氯化钠溶液洗涤有机相一次，4kg无水硫酸钠干燥有机相，过滤浓缩得到粗品。
粗品用2L二氯甲烷和2L石油醚混合后待用，柱子用6kg硅胶(200-300目)填充，用石油醚洗脱后进行上样，先用30～40L石油醚洗脱，后用EA：PE＝1:10～1:20进行洗脱，收集产物点，浓缩洗脱相大部分后有大量固体析出，浓缩剩余3L左右溶剂后降至10℃打浆1h后进行过滤，得到目标产物1F，滤液可适当进行回收，产品于35℃±5℃真空干燥约18h，得白色固体产品0.842kg，收率约40％(纯度：98.0％)。
1H NMR(400MHz,DMSO)δ3.48-3.46(m,1H),3.20-3.13(m,1H),3.01-2.94(m,1H),2.38-2.33(m,1H),1.84-1.78(m,1H).
LCMS m/z＝206.1[M+1]+
第五步：3,5-二氯-4-((4-氯-5-(甲基-d3)-6,7-二氢-5H-环戊烷[d]哒嗪-1-基)氧基)苯胺(1G)3,5-dichloro-4-((4-chloro-5-(methyl-d3)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)oxy)aniline(1G)
向100L玻璃反应釜中，加入22L N,N-二甲基乙酰胺，开启搅拌，加入2736g 1F、2600g 4-氨基-2,6-二氯苯酚，溶清，并加入6488g Cs2CO3，氮气置换三次，开启加热，升温至90～95℃搅拌反应约20小时。取样送检，反应至1F含量<3.0％。
搅拌下，反应液冷却至30℃后，加入20L甲苯。继续降温至20℃，加入35L 5％的氯化钠溶液搅拌，静置分液，再以甲苯(10L×2)萃取水相，合并有机相，再用5％的氯化钠溶液(20L×2)洗涤有机相，有机相用无水硫酸钠3.0kg干燥，过滤，有机相减压浓缩得粗品1G，超重油状物，收率按100％计，直接下一步。
1H NMR(400MHz,DMSO)δ6.71-6.70(d,2H),5.66(s,2H),3.45-3.43(m,1H),3.16-2.97(m,2H),2.45-2.40(m,1H),1.87-1.83(m,1H).
LCMS m/z＝347.0[M+1]+
第六步：N-(3,5-二氯-4-((7-(甲基-d3)-1-氧代-2,5,6,7-四氢-1H-环戊烷[d]哒嗪-4-基)氧基)苯基)苯甲酰胺(1H)
N-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)benzamide(1H)
将上步粗品4.62kg 1G用冰乙酸25.0L溶清并加入100L反应釜中，加入苯甲酸酐3300g，开启搅拌，室温下反应约4小时，TLC(正己烷/乙酸乙酯＝5/1)监控至1G消失后，然后再加入2722g无水乙酸钠，升温到120℃搅拌反应约18小时。
反应液降温至60～65℃，减压浓缩除去大部分乙酸，浓缩完毕后向残余液中加入10L无水乙醇混合均匀，然后将该混合溶液缓慢加入到250L水中，加入过程中保持快速搅拌状态，加入过程中有大量固体析出，加完后继续搅拌约0.5小时，离心，滤饼纯化水(20L×2)洗涤，得粗品1H，超重，收率按照100％计，直接下一步。
1H NMR(400MHz,DMSO)δ12.07(s,1H),10.55(s,1H),8.04(s,2H),7.98-7.95(m,2H),7.63-7.50(m,3H),3.29-3.25(m,1H),3.02-2.90(m,2H),2.39-2.36(m,1H),1.75-1.72(m,1H).
LCMS m/z＝433.1[M+1]+
第七步：4-(4-氨基-2,6-二氯苯氧基)-7-(甲基-d3)-2,5,6,7-四氢-1H-环戊基[d]哒嗪-1-酮(1K消旋体)
4-(4-amino-2,6-dichlorophenoxy)-7-(methyl-d3)-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-1-one(1K消旋体)
方法一：
100L反应釜中，搅拌下加入上步粗品5.76kg 1H、氢氧化钾溶液(2606g KOH溶于19.5L纯化水中)和6.0L无水乙醇加毕，80±5℃加热回流反应约16小时，中控原料反应完全。
降温至25℃，加入30L水，用氯化铵固体调pH到8-9，加入35.0L乙酸乙酯搅拌，分液，水相用乙酸乙酯(15.0L×2)萃取，合并有机相，用5％的氯化钠水溶液(25L×2)洗涤，有机相用无水硫酸钠3.0Kg干燥，过滤，有机相浓缩至无明显馏分流出，得粗品。
将粗品和含水10％的二氧六环溶液7.0L加热溶清，冷却至室温，搅拌析晶约16小时，过滤得湿品，再重复精制二次，50℃下真空干燥约12小时，得黄色固体1507g，三步(第五、六、七步三步)总收率34.5％(纯度：98.5％)。
1H NMR(400MHz,DMSO)δ11.98(s,1H),6.67(m,2H),5.60(s,2H),3.30-3.19(m,1H),3.03-2.93(m,1H),2.90-2.70(m,1H),2.35(m,1H),1.69(m,1H).
LCMS m/z＝329.0[M+1]+
方法二：
100L反应釜中，搅拌下加入上步粗品1.0kg 1H、氢氧化钠溶液(1.12kg NaOH溶于10kg纯化水中)和4.46kg无水甲醇加毕，80±5℃加热回流反应约12小时，中控原料1H基本反应完全。
降温至25℃，加入10kg水和10kg乙酸乙酯搅拌，分液，水相用10kg乙酸乙酯(萃取，合并有机相，用10kg 5％的氯化钠水溶液洗涤，有机相用无水硫酸钠3.0kg干燥，过滤，有机相浓缩至无明显馏分流出，得粗品。
将粗品和含水10％的二氧六环溶液2.0L加热溶清，冷却至室温，搅拌析晶约6小时，过滤得湿品，再重复精制二次，50℃下真空干燥约12小时，得黄色固体228g，三步(第五、六、七步三步)总收率35.0％(纯度：98.0％)。
第八步：(R)-4-(4-氨基-2,6-二氯苯氧基)-7-(甲基-d3)-2,5,6,7-四氢-1H-环戊基[d]哒嗪-1-酮(1K)(R)-4-(4-amino-2,6-dichlorophenoxy)-7-(methyl-d3)-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-1-one(1K)
取3298g消旋体用于手性拆分，分离后得到两个光学异构体：
化合物1K(保留时间：1.583s，1230g,类白色固体，ee％＝99.60％，收率37.3％)；
化合物1K-1(保留时间：1.926s，1255g,类白色固体，ee％＝99.76％，收率38.1％)。
拆分条件：
仪器:MGⅢpreparative SFC；柱:Whelk O1(S,S),300×50mm I.D.,10μm；
流动相:A：CO2，B：甲醇；梯度:B 40％；流量:200mL/min；背压:100bar；
柱温:38℃；波长:220nm；周期:4.5min；样品制备:消旋体溶解于甲醇/二氯甲烷中制得50mg/ml；注射:17ml/针。
化合物1K
1H NMR(400MHz,DMSO)δ11.98(s,1H),6.67(s,2H),5.60(s,2H),3.30-3.19(m,1H),3.03-2.93(m,1H),2.90-2.70(m,1H),2.35(dtd,1H),1.69(ddt,1H).
LCMS m/z＝329.1[M+1]+
化合物1K-1
1H NMR(400MHz,DMSO)δ11.98(s,1H),6.68(d,2H),5.60(s,2H),3.29-3.18(m,1H),2.97(tdd,1H),2.90-2.72(m,1H),2.35(dtd,1H),1.69(ddt,1H).
LCMS m/z＝329.0[M+1]+
第九步：(R,Z)-(2-氰基-2-(2-(3,5-二氯-4-)((7-(甲基-d3)-1-氧代-2,5,6,7-四氢-1H-环戊基[d]哒嗪-4-基)氧基)苯基)亚肼基-4-乙酰基)氨基甲酸乙酯(1L)
ethyl(R,Z)-(2-cyano-2-(2-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate(1L)
方法一：
100L反应釜中，搅拌下加入16.0kg乙酸、4.0kg纯化水和2.0kg 1K。降温至0±5℃，再加入盐酸2.36kg，加毕，保温0±5℃搅拌约20分钟，控温0±5℃滴加亚硝酸钠溶液(0.5kg亚硝酸钠溶于1.0kg纯化水)，滴毕，保温0±5℃反应2小时。控温5±5℃滴加乙酸钠溶液(1.5kg乙酸钠溶于6.0kg纯化水)，滴毕，再加入0.99kg N-氰基乙酰尿烷，加毕，升温至10±5℃反应约2小时后，取样HPLC监控，此后每间隔约2小时取样，HPLC检测1K含量≤1.0％，停止反应。
反应结束后，控温10±5℃，将30.0kg纯化水加入至反应釜中，加毕，控温10±5℃继续搅拌1小时；过滤，滤饼用3.0kg纯化水洗涤。滤饼与12.6kg无水乙醇加入100L反应釜中，升温至50±5℃下，搅拌约1小时。降温至20±5℃，搅拌0.5小时，过滤，滤饼用1.26kg无水乙醇洗涤一次。
滤饼于55±5℃、真空≤-0.07MPa干燥约17小时，收料得中间体1L，重量为2.6327kg。收率以1K计，收率为87.3％(纯度：98.18％)。
1H NMR(400MHz,DMSO)δ12.08(d,2H),10.88(s,1H),7.99(s,2H),4.21(q,2H),3.30-3.17(m,1H),3.08-2.95(m,1H),2.95-2.80(m,1H),2.38(ddd,1H),1.78-1.63(m,1H),1.28(t,3H).
LCMS m/z＝496.1[M+1]+
方法二：
100L反应釜中，搅拌下加入10.0kg乙酸、2.4kg纯化水和1.20kg 1K。降温至0±5℃，再加入盐酸1.42kg，加毕，保温0±5℃搅拌约30分钟，控温0±5℃滴加亚硝酸钠溶液(0.334kg亚硝酸钠溶于0.6kg纯化水)，滴毕，保温0±5℃反应2小时。控温5±5℃滴加乙
酸钠溶液(1100kg乙酸钠溶于3.6kg纯化水)，滴毕，再加入0.683kg N-氰基乙酰尿烷，加毕，升温至10±5℃反应约2小时后，取样HPLC监控，HPLC检测1K含量≤1.0％，停止反应。
反应结束后，控温10±5℃，将18.0kg纯化水加入至反应釜中，加毕，控温10±5℃继续搅拌1小时；过滤，滤饼用4.0kg乙酸乙酯洗涤。
滤饼于55±5℃、真空≤-0.07MPa干燥约16小时，收料得中间体1L，重量为1.845kg。超重，收率为100％(纯度：98.64％)。
第十步：(R)-2-(3,5-二氯-4-((7-(甲基-d3)-1-氧代-2,5,6,7-四氢-1H-环戊[d]哒嗪-4-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈(I)
(R)-2-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile(I)
方法一：
100L反应釜中，搅拌下加入12.40kg N,N-二甲基乙酰胺、2.6269kg 1L和0.54kg乙酸钠。加毕，升温，保持内温115±5℃反应约2小时后取样HPLC监控，此后每间隔约2小时取样，HPLC检测1L含量≤1.0％，停止反应。
反应结束后，降温至60±5℃，向反应液加入0.788kg纯化水，加毕，趁热过滤，用1.24kg N,N-二甲基乙酰胺洗涤，滤液转入100L反应釜中。控温60±5℃加入0.39kg乙酸和13.66kg纯化水，加毕后，降温至10±5℃下搅拌析晶约2小时。过滤，滤饼用2.63kg纯化水洗涤、2.11kg无水乙醇洗涤，抽干收集滤饼，得到I粗品(收率按照100％计算)。直接用于下一步反应。
100L反应釜中，搅拌下加入12.35kg无水乙醇和上步全量的I粗品，升温至75℃±5℃，搅拌反应约4小时。降温至5±5℃，搅拌析晶约12小时，过滤，滤饼用乙醇洗涤二次，每次用量1.05kg，得I精湿品。
精湿品于55±5℃、真空≤-0.07MPa真空干燥约17小时，得到I成品，收率以1L计，重量为2.02555kg，收率85.0％(纯度：99.74％)。
1H NMR(400MHz,DMSO)δ13.26(s,1H),12.09(s,1H),7.79(s,2H),3.32-3.24(m,1H),3.10-2.99(m,1H),2.96-2.88(m,1H),2.45-2.31(m,1H),1.77-1.69(m,1H).
LCMS m/z＝450.0[M+1]+。
方法二：
100L反应釜中，搅拌下加入8.53kg N,N-二甲基乙酰胺、1.831kg 1L和0.434kg乙酸钠。加毕，升温，保持内温120±5℃反应约2小时后取样HPLC监控，HPLC检测1L含量≤1.0％，停止反应。
反应结束后，降温至20±5℃，加入0.52kg乙酸，将反应液加入50.0kg冰水中，大量固体析出。过滤，滤饼用纯化水洗涤、2.11kg无水乙醇洗涤，抽干收集滤饼，得到I粗品(收率按照100％计算)。直接用于下一步反应。
100L反应釜中，搅拌下加入10.0kg无水异丙醇和上步全量的I粗品，升温至80℃±5℃，搅拌反应约3小时。降温至5±5℃，搅拌析晶约12小时，过滤，滤饼用异丙醇洗涤二次，得I精湿品。
精湿品于55±5℃、真空≤-0.07MPa真空干燥约12小时，得到I成品，收率以1L计，重量为1.582kg，收率82.6％(纯度：99.23％)。
Claims (18)
- 一种式(1E)、式(1H)所示化合物或其药学上可接受的盐，
- 一种式(1F)化合物的制备方法，其特征在于，包括以下步骤，
化合物1E与3,6-二氯哒嗪、水、硝酸银反应后，加酸A和氧化剂，反应得到化合物1F。 - 一种制备权利要求1或2中所述式(1E)化合物的方法，其特征在于，包括以下步骤，
将化合物1D在100～180℃下搅拌反应，得到化合物1E。 - 根据权利要求3所述的制备方法，其特征在于，还包括以下步骤，
化合物1C与有机溶剂F和酸A回流反应得到化合物1D。 - 根据权利要求4所述的制备方法，其特征在于，所述有机溶剂F选自二氯甲烷、乙酸甲酯、碳酸二甲酯、丙二醇甲醚乙酸酯、尼龙酸二甲酯、乙腈、甲苯、乙酸乙酯、乙酸异丙酯、丙酮、2-甲基四氢呋喃、四氢呋喃、1,4-二氧六环；所述酸A选自三氟乙酸、五氟乙酸、七氟丙酸、盐酸、硫酸、磷酸、甲酸、苯磺酸、甲磺酸、对甲苯磺酸。
- 根据权利要求4所述的制备方法，其特征在于，还包括以下步骤，
化合物1B在碱存在下，与氘代试剂反应，得到化合物1C。 - 根据权利要求6所述的制备方法，其特征在于，所述氘代试剂选自氘代碘甲烷、氘代溴甲烷、氘代氯甲烷、D3-对甲苯磺酰甲酯、D3-甲磺酰甲酯。
- 根据权利要求6所述的制备方法，其特征在于，还包括以下步骤，
将化合物1A、碱和催化剂加入到有机溶剂E中，惰性气体保护下加入丙烯酸叔丁酯反应，得到化合物1B。 - 根据权利要求6或8所述的制备方法，其特征在于，所述碱选自甲醇钠、乙醇钾、叔丁醇钾、叔丁醇钠、叔丁醇锂、乙酸钠、乙酸钾、K3PO4、K2CO3、KHCO3、Cs2CO3、Na2CO3、NaHCO3、KF、吡啶、三乙胺、N,N-二异丙基乙胺、DBU；所述催化剂为四丁基硫酸氢铵；所述有机溶剂E选自四氢呋喃、N,N-二甲基乙酰胺、二甲基甲酰胺、乙腈、丙酮、甲基异丁酮、甲苯、吡啶、二氯甲烷、乙酸乙酯、2-甲基四氢呋喃或1,4-二氧六环。
- 一种式(I)化合物的制备方法，其特征在于，包括如下步骤，
化合物1L在有机溶剂B和碱液B存在下，反应得到化合物I；所述有机溶剂B选自二甲亚砜、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、六甲基磷酰胺、N-甲基吡咯烷酮。 - 根据权利要求10所述制备方法，其特征在于，还包括以下步骤，
化合物1K溶于水和有机溶剂D中，加酸B搅拌，依次加碱液A和碱液B，N-氰基乙酰尿烷，反应后得到化合物1L。 - 根据权利要求10或11所述制备方法，其特征在于，所述有机溶剂D选自甲酸、乙酸、乙二酸、丙酸；所述酸B选自盐酸、硝酸、硫酸、磷酸、高氯酸；所述碱液A为亚硝酸盐，所述亚硝酸盐选自亚硝酸钠、亚硝酸钾、亚硝酸铵；所述碱液B为乙酸盐，所述乙酸盐选自乙酸钠、乙酸钾、乙酸铵。
- 根据权利要求11所述制备方法，其特征在于，还包括以下步骤，
化合物1H与碱液C和有机溶剂C混合，回流反应，得到化合物1K。 - 根据权利要求13所述制备方法，其特征在于，所述碱液C选自氢氧化钾溶液、氢氧化钠溶液、氢氧化锂溶液、叔丁醇钾溶液、叔丁醇锂溶液、碳酸钾溶液、碳酸铯溶液；所述有机溶剂C选自无水甲醇、无水乙醇、正丙醇、异丙醇、叔丁醇、正丁醇、甲苯、丙酮、甲基异丁酮、四氢呋喃、2-甲基四氢呋喃、二甲亚砜、N,N-二甲基乙酰胺、六甲基磷酰胺、N-甲基吡咯烷酮。
- 根据权利要求13所述制备方法，其特征在于，还包括以下步骤，
化合物1F、4-氨基-2,6-二氯苯酚在有机溶剂B和碳酸铯存在下，在惰性气体保护下，反应得到化合物1G；化合物1G在冰乙酸存在下，与苯甲酸酐反应得到化合物1H。 - 根据权利要求15所述制备方法，其特征在于，所述有机溶剂B选自二甲亚砜、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、六甲基磷酰胺、N-甲基吡咯烷酮。
- 根据权利要求15所述制备方法，其特征在于，还包括以下步骤，
化合物1E与3,6-二氯哒嗪、水、硝酸银反应后，加酸A和氧化剂，反应得到化合物1F。 - 根据权利要求2或17所述制备方法，其特征在于，所述酸A选自三氟乙酸、五氟乙酸、七氟丙酸、硫酸、盐酸、磷酸、硝酸、甲酸、乙酸、苯磺酸、甲磺酸、对甲苯磺酸；所述氧化剂选自过硫酸铵、过硫酸钾、过硫酸钠、过氧叔丁醇、过氧化氢。
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