CN116874387A - Novel preparation method of oxo-pyridine compound and key intermediate - Google Patents
Novel preparation method of oxo-pyridine compound and key intermediate Download PDFInfo
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- CN116874387A CN116874387A CN202310738615.3A CN202310738615A CN116874387A CN 116874387 A CN116874387 A CN 116874387A CN 202310738615 A CN202310738615 A CN 202310738615A CN 116874387 A CN116874387 A CN 116874387A
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- -1 oxo-pyridine compound Chemical class 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- 239000003814 drug Substances 0.000 claims abstract description 8
- 200000000007 Arterial disease Diseases 0.000 claims abstract description 3
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 41
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- 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 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 235000011181 potassium carbonates Nutrition 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- 239000007821 HATU Substances 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QPQGTZMAQRXCJW-UHFFFAOYSA-N [chloro(phenyl)phosphoryl]benzene Chemical compound C=1C=CC=CC=1P(=O)(Cl)C1=CC=CC=C1 QPQGTZMAQRXCJW-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 239000003446 ligand Substances 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- PAQZWJGSJMLPMG-UHFFFAOYSA-N propylphosphonic anhydride Substances CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 3
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000012317 TBTU Substances 0.000 claims description 2
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229910052805 deuterium Inorganic materials 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 238000011282 treatment Methods 0.000 claims description 2
- 230000002792 vascular Effects 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 15
- 239000012043 crude product Substances 0.000 abstract description 14
- 239000000126 substance Substances 0.000 abstract description 8
- 238000000746 purification Methods 0.000 abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 238000007126 N-alkylation reaction Methods 0.000 abstract description 2
- 238000010934 O-alkylation reaction Methods 0.000 abstract description 2
- 201000010099 disease Diseases 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 abstract description 2
- 238000004134 energy conservation Methods 0.000 abstract 1
- 230000007613 environmental effect Effects 0.000 abstract 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 1
- 230000002093 peripheral effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 13
- 239000002904 solvent Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 229940125904 compound 1 Drugs 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- FCCRKNYAZJHMME-UHFFFAOYSA-N tert-butyl 4-amino-2-fluorobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(N)C=C1F FCCRKNYAZJHMME-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 229940127219 anticoagulant drug Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000004808 supercritical fluid chromatography Methods 0.000 description 2
- CLJQXSMSVHCCST-UHFFFAOYSA-N tert-butyl 4-amino-2-(trifluoromethyl)benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(N)C=C1C(F)(F)F CLJQXSMSVHCCST-UHFFFAOYSA-N 0.000 description 2
- LLOXEUOQRNPJJK-UHFFFAOYSA-N tert-butyl 4-amino-2-chlorobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(N)C=C1Cl LLOXEUOQRNPJJK-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- DFPYXQYWILNVAU-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1.C1=CC=C2N(O)N=NC2=C1 DFPYXQYWILNVAU-UHFFFAOYSA-N 0.000 description 1
- HFFNRRVTKJCKGM-UHFFFAOYSA-N 2,5-dimethoxypyridine Chemical compound COC1=CC=C(OC)N=C1 HFFNRRVTKJCKGM-UHFFFAOYSA-N 0.000 description 1
- MMWFMFZFCKADEL-UHFFFAOYSA-N 2-fluoro-4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1F MMWFMFZFCKADEL-UHFFFAOYSA-N 0.000 description 1
- ASMGZJJSJBTIQV-UHFFFAOYSA-N 4-[5-chloro-2-[4-(trifluoromethyl)triazol-1-yl]phenyl]-5-methoxy-1H-pyridin-2-one Chemical compound COC1=CNC(=O)C=C1C1=C(C=CC(Cl)=C1)N1C=C(N=N1)C(F)(F)F ASMGZJJSJBTIQV-UHFFFAOYSA-N 0.000 description 1
- XYWIPYBIIRTJMM-IBGZPJMESA-N 4-[[(2S)-2-[4-[5-chloro-2-[4-(trifluoromethyl)triazol-1-yl]phenyl]-5-methoxy-2-oxopyridin-1-yl]butanoyl]amino]-2-fluorobenzamide Chemical compound CC[C@H](N1C=C(OC)C(=CC1=O)C1=C(C=CC(Cl)=C1)N1C=C(N=N1)C(F)(F)F)C(=O)NC1=CC(F)=C(C=C1)C(N)=O XYWIPYBIIRTJMM-IBGZPJMESA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 244000248349 Citrus limon Species 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- WURBFLDFSFBTLW-UHFFFAOYSA-N benzil Chemical group C=1C=CC=CC=1C(=O)C(=O)C1=CC=CC=C1 WURBFLDFSFBTLW-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 239000007805 chemical reaction reactant Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical compound C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- RIVIDPPYRINTTH-UHFFFAOYSA-N n-ethylpropan-2-amine Chemical compound CCNC(C)C RIVIDPPYRINTTH-UHFFFAOYSA-N 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
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- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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Abstract
The invention relates to a novel route for preparing oxo-pyridine compounds shown in a formula (I) and key intermediates thereof. The novel route provided by the invention can greatly reduce the generation of isomer impurities, improve the selectivity of reaction chirality and N/O-alkylation selectivity, improve the yield, especially has the meaning of chemical resolution on the novel structure of R1 which is a non-hydrogen group, and the obtained crude product does not need to carry out chiral purification (SFC) with high cost, has the advantages of reduced cost, short production period, energy conservation and environmental protection, is suitable for preparing the medicaments for treating and/or preventing diseases related to the FXI a receptor, and provides a new thought for preparing the medicaments for treating and/or preventing cerebrovascular arterial diseases and/or peripheral arterial diseasesAnd (5) a road.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry preparation, and particularly relates to a novel preparation method of an oxo-pyridine compound and a key intermediate thereof.
Background
Thromboembolic disorders are diseases caused by abnormal blood clots formed in blood vessels during survival of humans and animals. Drugs of FXIa target, which have been studied as a hotspot of anticoagulants in recent years, can block endogenous pathways and inhibit amplification of the coagulation cascade, thereby having an antithrombotic effect. Wherein, based on BAY-2433334 anticoagulants of Bayer pharmacy, shi Beikang is subjected to a great deal of structural modification and technological research, and aims to provide a variety which has better effect and is more suitable for industrialized amplified production.
Particularly, in the preparation research process of anticoagulant derivative drugs shown in the following formula (I), the compound patent of Bayer pharmacy and the technological patent method thereof are difficult to obtain high-yield and high-purity crude drugs.
。
Patent WO 2014/154794 and WO 2017/005725 disclose the synthesis of such compounds starting from 2, 5-dimethoxypyridine, using a linear synthesis strategy to synthesize the target compound through nine steps, not only in a lengthy route, but also in a high racemization easily, with a low overall yield, wherein the crude product has a synthesis step yield of only 70% and is a racemate, requiring cumbersome post-treatment and purification procedures, and separating isomers by HPLC or chiral Supercritical Fluid Chromatography (SFC), which is time-consuming and expensive, and not suitable for industrial scale-up.
In patent CN 111770917A, a polymerization type synthesis strategy is disclosed, the main synthesis steps are shown below, key intermediates of the compound of formula (XVI-CF 3)/(XVI-Cl) and the compound of formula (XIX) are respectively synthesized, crude products of the compound 1/the compound 2 are generated through condensation reaction, and then impurities are separated through chemical purification and forward chromatography. The total reaction is subjected to six steps, the longest step is four, the reaction period is shortened, and the crude product is filtered and the solvent is evaporated, and then the crude product of the crude drug in an amorphous form is obtained at a high ee-value of 85% ee to 93% ee.
Although the polymeric synthetic route of this patent is overall superior to the linear synthetic strategy, when R 1 When a substituent exists at a position, particularly when alkyl is substituted, a product with high chiral purity cannot be obtained by a chemical synthesis method even if a CN 111770917A synthesis thought is adopted, and an ee-value still needs to be obtained by chromatographic column resolution>98% of the product. Combining the above factors, the difficulty in subsequent purification and risk of product quality control of the series of compounds represented by formula (I) above remains currentThe technical problem to be solved is urgent.
Disclosure of Invention
In order to solve the technical problems in the prior art and improve the yield and ee value, the invention is more suitable for industrial production, and discloses a novel preparation method for oxo-pyridine compounds and a key intermediate thereof.
In one aspect, the present invention provides an intermediate of formula (II):
wherein:
R 2 、R 3 、R 4 、R 5 independently selected from hydrogen, halogen, alkoxy or haloalkyl;
x is selected from F, cl, br or I.
Preferably, R is as defined above 2 、R 3 、R 4 、R 5 Independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl;
and/or X is independently selected from Cl or Br.
Preferably, the intermediate of formula (II) above comprises the following structure:
,
wherein R is 2 、R 3 、R 4 、R 5 Is defined as above.
Further, the hydrogen in the structure of the above intermediate may be substituted with at least 1 deuterium.
Further, the above intermediates include the following compounds:
、/>、、/>。
further, the invention provides application of the intermediate or pharmaceutically acceptable salt thereof in preparing standard substances, reference substances or medicines for treating or preventing vascular arterial diseases.
In another aspect, the present invention provides a method for preparing an oxopyridine compound represented by formula (i), comprising the following reaction steps:
wherein,,
R x selected from fluorine, chlorine or trifluoromethyl;
R 1 selected from alkyl or deuterated alkyl;
R 2 、R 3 、R 4 、R 5 independently selected from hydrogen, halogen, alkoxy or haloalkyl;
step 1: reacting an intermediate shown in a formula (II) or a pharmaceutically acceptable salt thereof with a compound shown in a formula (III) to obtain a compound shown in a formula (IV);
step 2: carrying out hydrolysis reaction on the compound of the formula (IV) to obtain a compound of the formula (V);
step 3: the compound of formula (V) undergoes condensation reaction to obtain the compound of formula (I).
Further preferably, in the above method:
R 1 selected from methyl or deuterated methyl;
and/or R 2 、R 3 、R 4 、R 5 Independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl.
Further, the above step 1 includes the following reaction conditions:
the reaction conditions include a base selected from an organic base or an inorganic base; preferably, the base comprises any one or more than two of tetramethylguanidine, triethylamine, DBU, DIPEA, pyridine, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide; more preferably, the base comprises any one or more than two of tetramethylguanidine, triethylamine, DBU, DIPEA, potassium carbonate and cesium carbonate;
the reaction solvent of the reaction conditions is selected from organic solvents; preferably, the organic solvent comprises any one or more than two of isopropanol, ethanol, acetone, DMF, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane;
optionally, the molar ratio of compound of formula (II) to base in step 1 is 1:1 to 3, preferably 1:2;
optionally, the reaction temperature in the step 1 is 0 ℃ to 60 ℃, preferably 20 ℃ to 40 ℃, and more preferably 26 to 32 ℃;
optionally, the reaction time in the step 1 is 1 to 10 hours, preferably 4 to 6 hours.
Further, the above step 2 includes the following reaction conditions:
the reaction conditions include an acid selected from an organic acid or an inorganic acid; preferably, the acid comprises any one or more than two of hydrochloric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, acetic acid and hydrobromic acid; more preferably, the base comprises any one or more of hydrochloric acid, trifluoroacetic acid and sulfuric acid;
the reaction solvent of the reaction conditions is selected from organic solvents; preferably, the organic solvent comprises any one or more than two of isotetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetone, methanol, ethanol, isopropanol and DMF;
optionally, the molar ratio of compound of formula (IV) to acid in step 2 is 1:30, preferably 10:20, a step of;
optionally, the reaction temperature in the step 2 is-20 ℃ to 40 ℃, preferably-10 ℃ to 10 ℃, more preferably-5 ℃ to 5 ℃;
optionally, the reaction time in the step 2 is 1-8 hours, preferably 2-4 hours.
Further, the above step 3 includes the following reaction conditions:
the reaction conditions include a base selected from an organic base or an inorganic base; preferably, the base comprises any one or more than two of triethylamine, DBU, DIPEA, tetramethyl guanidine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide; more preferably, the base comprises any one or more than two of triethylamine, DBU, DIPEA, tetramethyl guanidine, potassium carbonate and cesium carbonate;
the reaction conditions include condensing agent and ligand; preferably, the condensing agent and the ligand comprise any one or more than two of EDCI, HOBT and HATU, HBTU, DCC, CDI, T3P, DPP-Cl, HCTU, TBTU, DMAP; more preferably, the base comprises any one or more than two of EDCI, HOBT, HATU, HBTU;
the reaction solvent of the reaction conditions is selected from organic solvents; preferably, the organic solvent comprises any one or more than two of isotetrahydrofuran, DCM, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, ethanol, isopropanol, DMF and DMAC;
optionally, the molar ratio of compound of formula (V) to base in step 3 is 1:1 to 5, preferably 1:3, a step of;
optionally, the reaction temperature in the step 3 is 0 ℃ to 60 ℃, preferably 20 ℃ to 40 ℃, and more preferably 26 to 32 ℃;
optionally, the reaction time in the step 3 is 1 to 10 hours, preferably 4 to 6 hours.
Term interpretation:
"alkyl" refers to lower alkyl, specifically containing a C1-C16 saturated branched or straight chain alkyl. The alkyl moiety in "alkylcarbonyl" is to be interpreted identically.
"cycloalkyl" means a C3-C10 cycloalkyl group, preferably a C3-C6 cycloalkyl group.
"halogen" means fluorine, chlorine, bromine, iodine.
The terms "above" and "below" include the same.
DBU:1, 8-diazabicyclo undec-7-ene
DIPEA: isopropyl ethylamine
T3P: 1-propylphosphoric acid cyclic anhydride
DPP-Cl: diphenylphosphinoyl chloride
EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
HOBT 1-hydroxybenzotriazole
HBTU benzotriazol-N, N, N ', N' -tetramethyluronium hexafluorophosphate
HATU 2- (7-Azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate
DCC N, N' -dicyclohexylcarbodiimide
Compared with the prior art, the invention has the following advantages:
the synthetic route of the invention can improve the ratio of N-alkylation to O-alkylation to a certain extent, and meanwhile, the intermediate formula (V) with the ee-value higher than 99% is obtained through chemical resolution of the intermediate formula (V) compound; finally obtaining a target compound shown in a formula (I) through condensation reaction; the ee value of formula (I) is maintained above 99%. So that the chemical resolution method of the compound of the formula (I) can be applied in the process of technical amplification without resolution by high chiral Supercritical Fluid Chromatography (SFC).
Detailed Description
The present invention will be described in further detail with reference to the following examples and test examples, which are only for the purpose of illustrating the technical aspects of the present invention, but are not to be construed as limiting the present invention, and any equivalent substitution in the art according to the present disclosure is intended to be within the scope of the present invention.
The compounds of the present invention, stereoisomers or pharmaceutically acceptable salts thereof may be prepared by the synthetic routes of the examples, and the conventional conditions of the reaction starting materials and reaction solvents may be adjusted according to the substituents or salt-forming requirements, which may be accomplished by one skilled in the art based on the present disclosure. In addition, the column chromatography of the present invention refers to silica gel column chromatography unless otherwise specified, and the eluting solvent may be a single or mixed eluting solvent determined by combining the reaction solvent with common knowledge or common means of a person skilled in the art.
The structure of the compound is nuclear magnetic resonance 1 H NMR) or liquid chromatography-mass spectrometry (LC-M)S) to determine.
The liquid chromatography-mass spectrometer (LC-MS) is Agilent G6120B (matched with liquid phase Agilent 1260); nuclear magnetic resonance apparatus 1 H NMR) of Bruker AVANCE-400 or Bruker AVANCE-800, nuclear magnetic resonance 1 H NMR) shift [ ]δ) Given in parts per million (ppm), the internal standard is Tetramethylsilane (TMS), the chemical shift is 10 -6 (ppm) is given as a unit.
The term "room temperature" according to the invention means a temperature between 10 and 30 ℃.
The mixed solvent used in the examples of the present invention refers to a volume ratio unless otherwise specified.
The term "20ml ethyl acetate" according to the invention: the n-heptane 1:2 solvent "refers to 20ml of the mixed solvent (ethyl acetate: n-heptane 1:2, v/v)". Similar writing is similarly interpreted.
Example 1: preparation of (S) -4- (2- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) butyramide) -2-fluoro-N-methylbenzamide (compound 1):
step 1: preparation of 4-nitro-2-fluorobenzoic acid diphenyl methyl ester
1.85g (10.0 mmol) of 2-fluoro-4-nitrobenzoic acid is taken and dissolved in 20ml of tetrahydrofuran, 2.21g (12.0 mmol) of benzhydrol is added, the mixture is cooled to below 0 ℃, 5.24g (20.0 mmol) of triphenylphosphine is added, 4.04g (20.0 mmol) of DIAD diluted with 5ml of tetrahydrofuran is then added dropwise, and after the addition, the mixture is stirred and reacted for 1 hour at 0-5 ℃, the mixture is stirred and reacted for 30 minutes at room temperature. After the reaction, water is added to terminate the reaction, EA is added to extract, the organic phase is washed with 5% of lemon acid, saturated sodium bicarbonate, water, saturated saline, anhydrous sodium sulfate and concentrated to obtain crude products. Purification by ethyl acetate in petroleum ether 1:3 column chromatography gave 2.71g of white solid in 77.0% yield, 98.16% purity.
ESI-MS:m/z=352.1(M+H) + 。
Step 2: preparation of 4-amino-2-fluorobenzoic acid diphenyl methyl ester
2.70g (7.69 mmol) of 4-nitro-2-fluorobenzoic acid diphenyl methyl ester is taken and dissolved in 30ml of acetic acid, 1.72g (30.76 mmol) of iron powder is added, after the reaction is carried out for 1 hour at the temperature of 65 ℃, TLC is monitored to complete, 3V water is added to terminate the reaction, EA is added for extraction, the organic phase is sequentially used, saturated sodium bicarbonate is washed, water is washed, saturated salt is washed, anhydrous sodium sulfate is dried, and the solvent is evaporated to dryness to obtain 608mg of crude product. To the crude product was taken 50ml ethyl acetate: the n-heptane 1:1 solvent was recrystallized, filtered, the filter cake washed with n-heptane and dried in vacuo to give 2.08g of a pale grey solid in 84.3% yield and 98.12% purity.
ESI-MS:m/z=322.1(M+H) + 。
Step 3: preparation of (R) -4- (2-bromobutyramide) -2-fluorobenzoic acid dibenzoyl ester
973mg (5.86 mmol) of (R) -2-bromo-3-propionic acid was dissolved in 10ml of tetrahydrofuran, 1.57g (4.88 mmol) of diphenyl methyl 4-amino-2-fluorobenzoate was added, cooled to below 0℃and 1.39g (17.58 mmol) of pyridine was added, then 6.21g (9.76 mmol) of 1-propylphosphoric anhydride (50% ethyl acetate solution) diluted with 10ml of tetrahydrofuran was added dropwise thereto, and the mixture was stirred at 0 to 5℃for 10 minutes after the addition and stirred at room temperature for 30 minutes. After the completion of the reaction, water was added to terminate the reaction, EA was added to extract, and the organic phase was washed with 5% citric acid, saturated sodium bicarbonate, water, saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 1.68g of crude product. 10ml of ethyl acetate was added to the crude product and stirred at room temperature for 2 hours, and the mixture was filtered, the filter cake was washed with ethyl acetate, and the filter cake was dried in vacuo to give 1.65g of a white solid, yield 71.8% and purity 97.51%.
ESI-MS:m/z=470.1(M+H) + 。
Step 4: preparation of (S) -4- (2- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) butyrylamido) -2-fluorobenzoic acid diphenylmethyl ester
1.65g (4.46 mmol) of 4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one, 50ml of isopropanol and 20ml of acetone were mixed, 1.54g (13.38 mmol) of tetramethylguanidine was added, and the mixture was stirred for 5 minutes, 2.51g (5.36 mmol) of dibenzoyl (R) -4- (2-bromobutyramide) -2-fluorobenzoate was added, and the mixture was stirred at room temperature overnight. After the completion of the reaction, saturated ammonium chloride was added to terminate the reaction, ethyl acetate was added to extract, the organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 4.26g of crude product. Purification by column, eluent (ethyl acetate: petroleum ether=1:2) and collection of the product afforded 2.58g of a white solid. The yield thereof was found to be 76.2% and the purity thereof was found to be 97.62%.
ESI-MS:m/z=760.2(M+H) + 。
Step 5: preparation of (S) -4- (2- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) butyramide) -2-fluorobenzoic acid
2.58g (3.41 mmol) of (S) -4- (2- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) butyryl) -2-fluorobenzoic acid diphenyl methyl ester was dissolved in 25mL of tetrahydrofuran, and the mixture was cooled to about 0℃and monitored at an internal temperature, 7.78g (68.25 mmol) of trifluoroacetic acid was slowly added dropwise, and after TLC detection for 0.5H, the reaction was completed, water was added to terminate the reaction, EA extraction was added, the organic phase was used sequentially, saturated sodium bicarbonate was used, water was used, saturated brine was used, anhydrous sodium sulfate was dried, and the solvent was evaporated to dryness to give 2.36g of crude product. To the crude product, 15ml of ethyl acetate was added, and the mixture was stirred well, the solids were removed by filtration, and the mother liquor was concentrated and then 20ml of ethyl acetate was used: n-heptane 1:2 solvent was stirred at room temperature for 2 hours, filtered, the filter cake washed with n-heptane and dried in vacuo to give 1.86g of a white solid with a yield of 91.9%, an ee-value of 99.28% and a purity of 97.32%.
ESI-MS:m/z=594.1(M+H) + 。
Step 6: preparation of (S) -4- (2- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) butyramide) -2-fluoro-N-methylbenzamide
1.0g (1.675 mmol) of (S) -4- (2- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) butyryl) -2-fluorobenzoic acid was dissolved in 10mL of DMAC, 226mg (3.35 mmol) of methylamine hydrochloride, 953mg (2.52 mmol) of HBTU were added, the temperature was lowered to about 5℃and monitored by internal temperature, 1.1g (8.38 mmol) of DIPEA was slowly added dropwise, after maintaining the reaction at 5-10℃for 1 hour, TLC detection was complete, 30mL of water was slowly added to terminate the reaction, and after stirring and beating for 1 hour, a solid was obtained by filtration, and after air-blast drying, 1.06g of crude product was obtained. Then 20ml of ethyl acetate: n-heptane 1:2 solvent was stirred at room temperature for 2 hours, filtered, the filter cake washed with n-heptane and dried in vacuo to give 838mg of a white solid in 82.6% yield, ee-value 99.21% purity 97.38%.
ESI-MS:m/z=607.2(M+H) + 。
1 H NMR (400 MHz, DMSO-d6) δ: 10.82 (s, 1H), 9.16 (d, J = 1.1 Hz, 1H), 8.13 – 8.06 (m, 1H), 7.89 – 7.80 (m, 2H), 7.79 (d, J = 2.0 Hz, 1H), 7.70 – 7.60 (m, 2H), 7.37 (dd, J = 8.5, 2.0 Hz, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.52 (t, J = 7.8 Hz, 1H), 3.25 (s, 3H), 2.76 (d, J = 4.6 Hz, 3H), 2.18 – 2.02 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H)。
Example 2: preparation of (S) -4- (2- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) butyrylamido) -2-fluoro-N- (methyl-d 3) benzamide (Compound 2)
The preparation method is the same as that of example 1, and the methylamine hydrochloride in step 4 is replaced by deuterated methylamine hydrochloride, so that the title compound 2 can be prepared with a yield of 85%, an ee-value of 99.26% and a purity of 97.69%.
ESI-MS:m/z=610.2(M+H) + 。
1 H NMR (400 MHz, DMSO-d6) δ: 10.79 (s, 1H), 9.14 (d, J = 1.1 Hz, 1H), 8.06 (d, J = 3.4 Hz, 1H), 7.92 – 7.81 (m, 2H), 7.81 – 7.76 (m, 1H), 7.70 – 7.60 (m, 2H), 7.37 (dd, J = 8.6, 2.0 Hz, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.51 (d, J = 8.6 Hz, 1H), 3.25 (s, 3H), 2.19 – 1.99 (m, J = 7.1 Hz, 2H), 0.78 (t, J = 7.2 Hz, 3H)。
Example 3: preparation of Compound 3
The preparation method is the same as that of example 1, and the tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced by tert-butyl 4-amino-2- (trifluoromethyl) benzoate, so that the title compound 3 with ee-value of 99.36% and purity of 97.56% can be obtained.
ESI-MS:m/z=657.2(M+H) + 。
1 H NMR (400 MHz, DMSO-d6) δ: 10.82 (s, 1H), 9.16 (d, J = 1.1 Hz, 1H), 8.18 – 8.12 (m, 1H), 7.98 – 7.90 (m, 2H), 7.85 (d, J = 2.0 Hz, 1H), 7.70 – 7.60 (m, 2H), 7.37 (dd, J = 8.5, 2.0 Hz, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.53 (t, J = 7.8 Hz, 1H), 3.26 (s, 3H), 2.77 (d, J = 4.6 Hz, 3H), 2.18 – 2.02 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H)。
Example 4: preparation of Compound 4
The preparation method is the same as that of example 1, the tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced by tert-butyl 4-amino-2- (trifluoromethyl) benzoate, and the methylamine hydrochloride in step 4 is replaced by deuterated methylamine hydrochloride, so that the title compound 4 can be prepared, wherein the ee-value is 99.02%, and the purity is 98.38%.
ESI-MS:m/z=660.2(M+H) + 。
1 H NMR (400 MHz, DMSO-d6) δ: 10.82 (s, 1H), 9.15 (d, J = 1.1 Hz, 1H), 8.19 – 8.12 (m, 1H), 7.98 – 7.91 (m, 2H), 7.85 (d, J = 2.0 Hz, 1H), 7.70 – 7.60 (m, 2H), 7.37 (dd, J = 8.5, 2.0 Hz, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.53 (t, J = 7.8 Hz, 1H), 3.26 (s, 3H), 2.18 – 2.02 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H)。
Example 5: preparation of Compound 5
The preparation method is the same as that of example 1, and the tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced by tert-butyl 4-amino-2-chlorobenzoate, so that the title compound 5 can be prepared, wherein the ee-value is 98.98%, and the purity is 98.46%.
ESI-MS:m/z=623.1(M+H) + 。
1 H NMR (400 MHz, DMSO-d6) δ: 10.82 (s, 1H), 9.16 (d, J = 1.1 Hz, 1H), 8.16 – 8.10 (m, 1H), 7.96 – 7.88 (m, 2H), 7.84 (d, J = 2.0 Hz, 1H), 7.70 – 7.60 (m, 2H), 7.37 (dd, J = 8.5, 2.0 Hz, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.52 (t, J = 7.8 Hz, 1H), 3.26 (s, 3H), 2.76 (d, J = 4.6 Hz, 3H), 2.18 – 2.02 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H)。
Example 6: preparation of Compound 6
The preparation method is the same as that of example 1, the tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced by tert-butyl 4-amino-2-chlorobenzoate, and the methylamine hydrochloride in step 4 is replaced by deuterated methylamine hydrochloride, so that the title compound 6 can be prepared, wherein the ee-value is 99.16%, and the purity is 98.12%.
ESI-MS:m/z=626.1(M+H) + 。
1 H NMR (400 MHz, DMSO-d6) δ: 10.81 (s, 1H), 9.16 (d, J = 1.1 Hz, 1H), 8.16 – 8.10 (m, 1H), 7.96 – 7.89 (m, 2H), 7.84 (d, J = 2.0 Hz, 1H), 7.70 – 7.60 (m, 2H), 7.37 (dd, J = 8.5, 2.0 Hz, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.52 (t, J = 7.8 Hz, 1H), 3.26 (s, 3H), 2.18 – 2.06 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H).
Example 7: preparation of Compound 7
The preparation method is the same as that of example 1, and the tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced by tert-butyl 4-amino-2- (methoxy) benzoate, so that the title compound 7 with ee-value of 98.69% and purity of 98.60% can be obtained.
ESI-MS:m/z=619.2(M+H) + 。
1 H NMR (400 MHz, DMSO-d6) δ: 10.82 (s, 1H), 9.16 (d, J = 1.1 Hz, 1H), 8.13 – 8.06 (m, 1H), 7.89 – 7.80 (m, 2H), 7.79 (d, J = 2.0 Hz, 1H), 7.70 – 7.60 (m, 2H), 7.37 (dd, J = 8.5, 2.0 Hz, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.52 (t, J = 7.8 Hz, 1H), 3.86 (s, 3H), 3.25 (s, 3H), 2.76 (d, J = 4.6 Hz, 3H), 2.18 – 2.02 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H)。
Example 8: preparation of Compound 8
The preparation method is the same as that of example 1, the tert-butyl 4-amino-2-fluorobenzoate in step 1 is replaced by tert-butyl 4-amino-2- (methoxy) benzoate, and methylamine hydrochloride in step 4 is replaced by deuterated methylamine hydrochloride, so that the title compound 8 can be obtained, wherein the ee-value is 98.76%, and the purity is 98.82%.
ESI-MS:m/z=622.2(M+H) + 。
1 H NMR (400 MHz, DMSO-d6) δ: 10.81 (s, 1H), 9.17 (d, J = 1.1 Hz, 1H), 8.13 – 8.08 (m, 1H), 7.89 – 7.81 (m, 2H), 7.79 (d, J = 2.0 Hz, 1H), 7.70 – 7.60 (m, 2H), 7.37 (dd, J = 8.5, 2.0 Hz, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 5.53 (t, J = 7.8 Hz, 1H), 3.86 (s, 3H), 3.25 (s, 3H), 2.18 – 2.02 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H)。
Comparative example 1: preparation of (S) -4- (2- (4- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) butyramide) -2-fluoro-N-methylbenzamide (compound 1):
compound 1 was synthesized according to the synthetic strategy disclosed in patent CN 111770917A and finally purified to give the title compound 1 having an ee-value 82.12% and purity of 96.26%. Since the crystallization process of compound 1 cannot form a synergistic crystal of the enantiomer, the chiral isomer of compound 1 (R-configuration compound 1) cannot be removed in the refinement process.
By the route provided by this patent, as in example 1, intermediate formula (V) with ee-value higher than 98% was obtained by chemical resolution of structural formula (V), thereby achieving the target API of high ee-value and high chemical purity of compound 1.
The nuclear magnetism and mass spectrum data for intermediates produced by the methods of the examples above for compounds 1-8 are shown in the following table:
/>
the above embodiment is only one of the preferred embodiments of the present invention, and should not be used to limit the scope of the present invention, but all the insubstantial modifications or color changes made in the main design concept and spirit of the present invention are still consistent with the present invention, and all the technical problems to be solved are included in the scope of the present invention.
Claims (10)
1. An intermediate of formula (II) or a pharmaceutically acceptable salt thereof:
,
wherein:
R 2 、R 3 、R 4 、R 5 independently selected from hydrogen, halogen, alkoxy or haloalkyl;
x is selected from F, cl, br or I.
2. An intermediate, or a pharmaceutically acceptable salt thereof, as claimed in claim 1,
the R is 2 、R 3 、R 4 、R 5 Independently selected from hydrogen, fluorine, chlorine, methoxy, ethoxy or trifluoromethyl;
and/or X is independently selected from Cl or Br.
3. The intermediate of claim 1, or a pharmaceutically acceptable salt thereof, wherein the intermediate of formula (II) comprises the structure:
,
wherein R is 2 、R 3 、R 4 、R 5 Is defined as corresponding to claims 1-2.
4. An intermediate or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 wherein hydrogen in the structure of the intermediate may be substituted with at least 1 deuterium.
5. An intermediate according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the intermediate comprises the following compounds:
、/>、、/>。
6. the use of the intermediate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 for a standard, a control or in the manufacture of a medicament for the treatment or prophylaxis of vascular arterial disease.
7. A method for preparing an oxo-pyridine compound shown in a formula (I), which is characterized by comprising the following reaction steps:
wherein,,
R x selected from fluorine, chlorine or trifluoromethyl;
R 1 selected from alkyl or deuterated alkyl;
R 2 、R 3 、R 4 、R 5 independently selected from hydrogen, halogen, alkoxy or haloalkyl;
step 1: reacting an intermediate shown in a formula (II) or a pharmaceutically acceptable salt thereof with a compound shown in a formula (III) to obtain a compound shown in a formula (IV);
step 2: carrying out hydrolysis reaction on the compound of the formula (IV) to obtain a compound of the formula (V);
step 3: the compound of formula (V) undergoes condensation reaction to obtain the compound of formula (I).
8. The method of claim 7, wherein step 1 comprises the following reaction conditions:
the reaction conditions include a base selected from an organic base or an inorganic base; preferably, the base comprises any one or more than two of tetramethylguanidine, triethylamine, DBU, DIPEA, pyridine, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide;
the reaction solvent of the reaction conditions is selected from organic solvents; preferably, the organic solvent comprises any one or more than two of isopropanol, ethanol, acetone, DMF, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane;
optionally, the molar ratio of compound of formula (II) to base in step 1 is 1: 1-3;
optionally, the reaction temperature in the step 1 is 0-60 ℃;
optionally, the reaction time of the step 1 is 1-10 hours.
9. The method of claim 7, wherein step 2 comprises the following reaction conditions:
the reaction conditions include an acid selected from an organic acid or an inorganic acid; preferably, the acid comprises any one or more than two of hydrochloric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, acetic acid and hydrobromic acid;
the reaction solvent of the reaction conditions is selected from organic solvents; preferably, the organic solvent comprises any one or more than two of isotetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetone, methanol, ethanol, isopropanol and DMF;
optionally, the molar ratio of compound of formula (IV) to acid in step 2 is 1:30;
optionally, the reaction temperature in the step 2 is-20-40 ℃;
optionally, the reaction time of the step 2 is 1-8 hours.
10. The method of claim 7, wherein step 3 comprises the following reaction conditions:
the reaction conditions include a base selected from an organic base or an inorganic base; preferably, the base comprises any one or more than two of triethylamine, DBU, DIPEA, tetramethyl guanidine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide;
the reaction conditions include condensing agent and ligand; preferably, the condensing agent and the ligand comprise any one or more than two of EDCI, HOBT and HATU, HBTU, DCC, CDI, T3P, DPP-Cl, HCTU, TBTU, DMAP;
the reaction solvent of the reaction conditions is selected from organic solvents; preferably, the organic solvent comprises any one or more than two of isotetrahydrofuran, DCM, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, ethanol, isopropanol, DMF and DMAC;
optionally, the molar ratio of compound of formula (V) to base in step 3 is 1: 1-5;
optionally, the reaction temperature in the step 3 is 0-60 ℃;
optionally, the reaction time of the step 3 is 1-10 hours.
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