CN114805237A - Process for producing heterocyclic compound and intermediate thereof - Google Patents
Process for producing heterocyclic compound and intermediate thereof Download PDFInfo
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- CN114805237A CN114805237A CN202210072874.2A CN202210072874A CN114805237A CN 114805237 A CN114805237 A CN 114805237A CN 202210072874 A CN202210072874 A CN 202210072874A CN 114805237 A CN114805237 A CN 114805237A
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- 238000000034 method Methods 0.000 title claims description 32
- 230000008569 process Effects 0.000 title claims description 7
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 3
- -1 imidazopyridine compound Chemical class 0.000 claims abstract description 45
- 238000002360 preparation method Methods 0.000 claims abstract description 45
- 238000006243 chemical reaction Methods 0.000 claims description 182
- 239000000543 intermediate Substances 0.000 claims description 159
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 65
- 150000001875 compounds Chemical class 0.000 claims description 46
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 31
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 29
- 239000003054 catalyst Substances 0.000 claims description 29
- 230000009471 action Effects 0.000 claims description 24
- 230000035484 reaction time Effects 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 21
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- 229910052751 metal Inorganic materials 0.000 claims description 18
- 239000002184 metal Substances 0.000 claims description 18
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 17
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 17
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 11
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 229910052763 palladium Inorganic materials 0.000 claims description 10
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 9
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000007818 Grignard reagent Substances 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 150000007530 organic bases Chemical class 0.000 claims description 7
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical group [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 229910052723 transition metal Inorganic materials 0.000 claims description 6
- 150000003624 transition metals Chemical group 0.000 claims description 6
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical group BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 3
- 229910017052 cobalt Inorganic materials 0.000 claims description 3
- 239000010941 cobalt Substances 0.000 claims description 3
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 3
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 3
- 229910052703 rhodium Inorganic materials 0.000 claims description 3
- 239000010948 rhodium Substances 0.000 claims description 3
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 239000003381 stabilizer Substances 0.000 claims description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 2
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 239000012298 atmosphere Substances 0.000 claims description 2
- 230000031709 bromination Effects 0.000 claims description 2
- 238000005893 bromination reaction Methods 0.000 claims description 2
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 2
- WXMZPPIDLJRXNK-UHFFFAOYSA-N butyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(CCCC)C1=CC=CC=C1 WXMZPPIDLJRXNK-UHFFFAOYSA-N 0.000 claims description 2
- 229940126214 compound 3 Drugs 0.000 claims description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- ZPATUOFYXSBHMN-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [H+].[H+].[H+].[Br-].[Br-].[Br-].C1=CC=NC=C1 ZPATUOFYXSBHMN-UHFFFAOYSA-N 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 2
- 102100040460 P2X purinoceptor 3 Human genes 0.000 abstract description 21
- 101710189970 P2X purinoceptor 3 Proteins 0.000 abstract description 20
- 206010011224 Cough Diseases 0.000 abstract description 9
- 208000002193 Pain Diseases 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- 239000000243 solution Substances 0.000 description 57
- 239000012074 organic phase Substances 0.000 description 25
- 230000015572 biosynthetic process Effects 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 19
- 230000002829 reductive effect Effects 0.000 description 18
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 17
- 238000004809 thin layer chromatography Methods 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- STUHQDIOZQUPGP-UHFFFAOYSA-N morpholin-4-ium-4-carboxylate Chemical compound OC(=O)N1CCOCC1 STUHQDIOZQUPGP-UHFFFAOYSA-N 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000007800 oxidant agent Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- QXIAGKWWKMKVLE-VIFPVBQESA-N 3-[(2S)-4-[(2-methylpropan-2-yl)oxycarbonyl]morpholin-2-yl]propanoic acid Chemical compound C(C)(C)(C)OC(=O)N1C[C@@H](OCC1)CCC(=O)O QXIAGKWWKMKVLE-VIFPVBQESA-N 0.000 description 6
- SIZJNOFPDHZOFR-LBPRGKRZSA-N N1(C(=O)OC(C)(C)C)C[C@H](CCC(=O)C2=C(F)C=C(C=C2F)C(=O)O)OCC1 Chemical compound N1(C(=O)OC(C)(C)C)C[C@H](CCC(=O)C2=C(F)C=C(C=C2F)C(=O)O)OCC1 SIZJNOFPDHZOFR-LBPRGKRZSA-N 0.000 description 6
- ICPHOPHSWOKLCX-JTQLQIEISA-N O=C(N1C[C@H](CCC(=O)C2=C(F)C=C(C=C2F)C(=O)O)OCC1)OC Chemical compound O=C(N1C[C@H](CCC(=O)C2=C(F)C=C(C=C2F)C(=O)O)OCC1)OC ICPHOPHSWOKLCX-JTQLQIEISA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- SEHLMRJSQFAPCJ-HNNXBMFYSA-N methyl (2s)-2-[[2-[2,6-difluoro-4-(methylcarbamoyl)phenyl]-7-methylimidazo[1,2-a]pyridin-3-yl]methyl]morpholine-4-carboxylate Chemical compound FC1=CC(C(=O)NC)=CC(F)=C1C1=C(C[C@@H]2OCCN(C2)C(=O)OC)N2C=CC(C)=CC2=N1 SEHLMRJSQFAPCJ-HNNXBMFYSA-N 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 230000001590 oxidative effect Effects 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- LWKMTSRRGUVABD-MRVPVSSYSA-N tert-butyl (2r)-2-formylmorpholine-4-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCO[C@@H](C=O)C1 LWKMTSRRGUVABD-MRVPVSSYSA-N 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- INELTYBDBBEEFJ-JTQLQIEISA-N CC(C)(C)OC(N1C[C@H](C=CC(OC)=O)OCC1)=O Chemical compound CC(C)(C)OC(N1C[C@H](C=CC(OC)=O)OCC1)=O INELTYBDBBEEFJ-JTQLQIEISA-N 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000000737 periodic effect Effects 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- UJWHQSMIRRYWEP-NSHDSACASA-N O(C(C)(C)C)C(=O)N1C[C@@H](OCC1)CCC(=O)N(C)OC Chemical compound O(C(C)(C)C)C(=O)N1C[C@@H](OCC1)CCC(=O)N(C)OC UJWHQSMIRRYWEP-NSHDSACASA-N 0.000 description 3
- 102100040479 P2X purinoceptor 2 Human genes 0.000 description 3
- 101710189968 P2X purinoceptor 2 Proteins 0.000 description 3
- 102000002294 Purinergic P2X Receptors Human genes 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 3
- 230000011514 reflex Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- JHLKSIOJYMGSMB-UHFFFAOYSA-N 1-bromo-3,5-difluorobenzene Chemical compound FC1=CC(F)=CC(Br)=C1 JHLKSIOJYMGSMB-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- RVEULISJJVSTSD-VUWPPUDQSA-N C(=O)(N1CCO[C@H](C1)CC(Br)C(=O)C1=C(F)C=C(C(=O)OC)C=C1F)OC Chemical compound C(=O)(N1CCO[C@H](C1)CC(Br)C(=O)C1=C(F)C=C(C(=O)OC)C=C1F)OC RVEULISJJVSTSD-VUWPPUDQSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
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- 101150003085 Pdcl gene Proteins 0.000 description 2
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- 229910052802 copper Inorganic materials 0.000 description 2
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- 239000011630 iodine Substances 0.000 description 2
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- 238000011813 knockout mouse model Methods 0.000 description 2
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- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
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- 239000002464 receptor antagonist Substances 0.000 description 2
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- 239000011734 sodium Substances 0.000 description 2
- FJYBLMJHXRWDAQ-MRVPVSSYSA-N tert-butyl (2r)-2-(hydroxymethyl)morpholine-4-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCO[C@@H](CO)C1 FJYBLMJHXRWDAQ-MRVPVSSYSA-N 0.000 description 2
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- GONAVIHGXFBTOZ-UHFFFAOYSA-N 3,5-difluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=CC(F)=C1 GONAVIHGXFBTOZ-UHFFFAOYSA-N 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- ORLGLBZRQYOWNA-UHFFFAOYSA-N 4-methylpyridin-2-amine Chemical compound CC1=CC=NC(N)=C1 ORLGLBZRQYOWNA-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical class [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
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- 102000004310 Ion Channels Human genes 0.000 description 1
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- 102100040444 P2X purinoceptor 1 Human genes 0.000 description 1
- 101710189973 P2X purinoceptor 1 Proteins 0.000 description 1
- 102100037603 P2X purinoceptor 5 Human genes 0.000 description 1
- 101710189969 P2X purinoceptor 5 Proteins 0.000 description 1
- 102100037606 P2X purinoceptor 6 Human genes 0.000 description 1
- 101710190089 P2X purinoceptor 6 Proteins 0.000 description 1
- 102100037602 P2X purinoceptor 7 Human genes 0.000 description 1
- 101710189965 P2X purinoceptor 7 Proteins 0.000 description 1
- 108091075598 P2X receptor family Proteins 0.000 description 1
- 206010036018 Pollakiuria Diseases 0.000 description 1
- 108010080192 Purinergic Receptors Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 1
- 230000036982 action potential Effects 0.000 description 1
- 230000009692 acute damage Effects 0.000 description 1
- 210000003626 afferent pathway Anatomy 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229950011175 aminopicoline Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 1
- 150000005232 imidazopyridines Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- NTNUDYROPUKXNA-UHFFFAOYSA-N methyl 2-(triphenyl-$l^{5}-phosphanylidene)acetate Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OC)C1=CC=CC=C1 NTNUDYROPUKXNA-UHFFFAOYSA-N 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000003040 nociceptive effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000008050 pain signaling Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 210000002243 primary neuron Anatomy 0.000 description 1
- MHZDONKZSXBOGL-UHFFFAOYSA-N propyl dihydrogen phosphate Chemical compound CCCOP(O)(O)=O MHZDONKZSXBOGL-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000012465 retentate Substances 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 210000003594 spinal ganglia Anatomy 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- NHVCNYLYDFGIJQ-UHFFFAOYSA-N tert-butyl 3,5-difluorobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC(F)=CC(F)=C1 NHVCNYLYDFGIJQ-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 210000001177 vas deferen Anatomy 0.000 description 1
- 230000006442 vascular tone Effects 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a preparation method of an imidazopyridine compound shown as a formula IV and an intermediate shown as a formula I or a formula II. The imidazopyridine compound shown in the formula IV can antagonize a P2X3 receptor, and has the effects of suppressing cough and relieving pain.
Description
PRIORITY INFORMATION
The present application claims priority and benefit of a patent application having patent application number 202110090536.7, filed 2021, month 01, 22 with the intellectual property office of china, and is incorporated herein by reference in its entirety.
Technical Field
The invention relates to a preparation method of heterocyclic compounds and intermediates thereof; in particular, the present invention relates to a process for the preparation of imidazopyridines and intermediates thereof.
Background
The P2X receptor is a nonselective ATP-gated ion channel receptor, a purinergic receptor, that binds extracellular ATP, which originates primarily from damaged or inflamed tissue. The receptor is widely expressed in nervous, immune, cardiovascular, skeletal, gastrointestinal, respiratory, endocrine systems, and the like, and is involved in a variety of physiological processes such as regulation of heart rhythm and contractility, regulation of vascular tone, regulation of nociception, particularly chronic pain, vasoconstriction of vas deferens during ejaculation, contraction of bladder during urination, platelet aggregation, activation of macrophages, apoptosis, and neuron-glial interactions. The P2X receptors mentioned above include seven homologous receptors: P2X1, P2X2, P2X3, P2X4, P2X5, P2X6, and P2X7, three heterologous receptors: P2X2/3, P2X4/6 and P2X 1/5.
P2X3 is a subtype of the P2X receptor family, selectively expressed in dorsal root ganglia, spinal cord and brain neurons of the nerve endings, i.e. primary sensory neurons of medium and small diameter.
Numerous studies have shown that activation of P2X3 and P2X2/3 expressed in primary sensory neurons plays an important role in acute injury, hyperalgesia and hypersensitivity in rodents. Many studies have shown that upregulation of P2X3 receptor expression can lead to hyperalgesia and is involved in pain signaling. P2X3 knockout mice show reduced pain responses and P2X3 receptor antagonists show reduced nociceptive effects in models of pain and inflammatory pain.
P2X3 is distributed in primary afferents around the airways and is capable of modulating cough. Studies have shown that ATP released from damaged or inflamed tissues of the airways acts on P2X3 receptors of primary neurons, triggering depolarization and action potentials that are transmitted to trigger cough impulses that trigger coughing. Preclinical and clinical data strongly demonstrate that the P2X3 receptor plays an important role in cough reflex hypersensitivity, leading to chronic cough. By antagonizing the binding to P2X3 receptor, the hypersensitivity reaction of cough reflex can be inhibited, thereby inhibiting excessive cough of chronic cough patients.
P2X3 was reported to be involved in afferent pathways controlling bladder volume reflexes, with a significant decrease in micturition frequency and a significant increase in bladder volume in P2X3 knockout mice. Therefore, inhibition of the binding of P2X3 receptor antagonists to P2X3 receptors has the effect of treating disorders of storage and micturition disorders, such as overactive bladder. Therefore, the P2X3 antagonist can be a potential drug for treating diseases related to overactive bladder and the like.
In addition, studies have shown that P2X3 antagonists can treat chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension or asthma, and therefore P2X3 antagonists are also expected to be new drugs for treating the above diseases.
P2X3 antagonists show great promise in a number of disease areas, and therefore, the development of P2X3 antagonists is of clinical importance.
Disclosure of Invention
The invention provides a preparation method of an imidazopyridine compound and an intermediate thereof. The preparation method has the advantages of mild conditions, stable process and simple operation, and is suitable for amplification and industrial production.
The invention provides an intermediate shown as a formula I or a formula II:
wherein the content of the first and second substances,
The R is 2a Is selected from C 1 -C 6 Alkyl or benzyl;
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
and X is selected from H or Br.
In a preferred embodiment of the invention, when R is 2 When halogen is used, the halogen is Br or I, preferably Br.
In a preferred embodiment of the present invention, R is 2a Is C 1 -C 6 An alkyl group; preferably, R is 2a Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In a preferred embodiment of the present invention, the intermediate of formula II as described hereinbefore is selected from any one of the following intermediates:
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
The R is 2a Having the definitions as described hereinbefore.
The invention also provides a preparation method of the intermediate shown in the formula II-1, which comprises the following steps:
step 1: under the action of an amino metal compound or an alkyl metal compound, an intermediate shown as a formula I and a compound shown as a formula 1 are reacted to prepare an intermediate shown as a formula II-1;
wherein, the first and the second end of the pipe are connected with each other,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
The R is 2a Having the definitions as described hereinbefore.
In the step 1, the amino metal compound is lithium diisopropylamide, lithium bistrimethylsilyl amide, potassium bistrimethylsilyl amide, sodium bistrimethylsilyl amide, preferably lithium diisopropylamide or bistrimethylsilyl amide.
In the step 1, the alkyl metal compound is methyl grignard reagent, ethyl grignard reagent, isopropyl grignard reagent or alkyl lithium compound, preferably methyl lithium or n-butyl lithium.
In the step 1, when the R is 2 In the case of halogens, the reaction is carried out under the action of an amino metal compound.
In the step 1, when the R is 2 Is carboxyl orWhen the reaction is carried out under the action of an amino metal compound or an alkyl metal compound.
In step 1, the reaction may be carried out in an organic solvent, including but not limited to diethyl ether, dichloromethane, toluene, 2-methyltetrahydrofuran or tetrahydrofuran, preferably tetrahydrofuran.
In the step 1, the reaction temperature of the reaction is-80 to 0 ℃, preferably-10 to 0 ℃ or-80 to-60 ℃.
In the step 1, the molar ratio of the compound shown in the formula I to the compound shown in the formula 1 in the reaction is 1: 1-1: 1.6, preferably 1: 1-1.2 or 1: 1.5-1: 1.6, and more preferably 1:1.2 or 1: 1.5.
In the step 1, the reaction time of the reaction is 2 to 4 hours, preferably 3 hours.
In the step 1, when the reaction is performed under the action of an alkyl lithium compound, the reaction further comprises a stabilizer, and the stabilizer is N, N' -tetramethylethylenediamine.
The invention also provides a preparation method of the intermediate shown in the formula I, which comprises the following steps;
step 2: under the action of organic alkali and a condensing agent, reacting an intermediate shown as a formula I-2 with a compound shown as a formula 2 to prepare the intermediate shown as the formula I;
wherein the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
In the step 2, the reaction temperature of the reaction is 20-25 ℃.
In the step 2, the organic base is N, N-diisopropylethylamine.
In the step 2, the condensing agent is 1-propyl phosphoric anhydride.
In the step 2, the molar ratio of the intermediate shown in the formula I-2 to the compound shown in the formula 2 is 1: 1-1: 2, preferably 1: 1.2.
In the step 2, the molar ratio of the intermediate shown in the formula I-2 to the organic base compound is 1: 2-4, preferably 1: 2.8-3.2, and more preferably 1:3.
In the step 2, the molar ratio of the intermediate shown in the formula I-2 to the condensing agent is 1: 1-1: 2, preferably 1: 1.5.
In the step 2, the reaction time of the reaction is 14 to 18 hours, preferably 16 hours.
In the step 2, the reaction is carried out in dichloromethane.
According to an embodiment of the invention, the preparation method of the intermediate shown in the formula I also comprises a preparation method of the intermediate shown in the formula I-2, and the preparation method of the intermediate shown in the formula I-2 comprises the following steps:
and step 3: preparing an intermediate shown as a formula I-1 by carrying out reduction reaction on a compound shown as a formula 3;
and 4, step 4: under the action of inorganic base, hydrolyzing the intermediate shown as the formula I-1 to prepare an intermediate shown as the formula I-2;
wherein the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
In the step 3, the reaction further comprises hydrogen.
In the step 3, the reaction further comprises palladium on carbon.
In the step 3, the reaction temperature of the reaction is 20-25 ℃.
In the step 3, the pressure of hydrogen in the reaction is 0.8 to 1.2 atm, preferably 1 atm.
In the step 3, the mass ratio of the palladium carbon to the compound 3 is 1:18 to 1:22, preferably 1: 20.
In the step 3, the reaction time of the reaction is 22 to 26 hours, preferably 24 hours.
In step 4, the inorganic base is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide.
In the step 4, the reaction temperature of the reaction is 20-25 ℃.
In the step 4, the molar ratio of the intermediate shown in the formula I-1 to the inorganic base is 1: 1-1: 4, preferably 1:2.
In the step 4, the reaction time of the reaction is 14 to 18 hours, preferably 16 hours.
In the step 4, the reaction is carried out in methanol.
The invention also provides a preparation method of the intermediate shown in the formula II-1A, wherein the intermediate shown in the formula II-1A is prepared from the intermediate shown in the formula II-1, and the preparation method of the intermediate shown in the formula II-1A comprises the following steps;
and 5: under the action of a catalyst and organic base, reacting the intermediate shown as the formula II-1 with carbon monoxide and a compound shown as the formula 4 to obtain an intermediate shown as the formula II-1A;
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
the R is 2 Is halogen;
the R is 2a Having the definitions as described hereinbefore.
In the step 5, the catalyst transition metal catalyst includes palladium metal catalyst, ruthenium metal catalyst, iron metal catalyst, cobalt metal catalyst, nickel metal catalyst, rhodium metal catalyst, preferably palladium metal catalyst;
preferably, the palladium catalyst comprises tetrakis (triphenylphosphine) palladium, palladium acetate, bis (triphenylphosphine) palladium dichloride, 1-bis (diphenylphosphino) ferrocene palladium chloride, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, 1, 4-bis (diphenylphosphinobutane) palladium dichloride, and more preferably the palladium metal catalyst is 1, 1-bis (diphenylphosphino) ferrocene palladium chloride.
In step 5, the organic base includes, but is not limited to, triethylamine or N, N-diisopropylethylamine, preferably triethylamine.
In the step 5, the reaction is carried out in pressurized carbon monoxide, and the pressure of the carbon monoxide is 40-50 psi, preferably 45 psi.
In the step 5, the reaction temperature of the reaction is 55-65 ℃.
In the step 5, the reaction time is 22 to 26 hours, preferably 24 hours.
The invention also provides a preparation method of the intermediate shown in the formula II-1A, which comprises the following steps;
and 6: under the action of alkali, reacting the intermediate shown as the formula II-1 with the compound shown as the formula 5 to obtain an intermediate shown as the formula II-1A;
wherein, the first and the second end of the pipe are connected with each other,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
the R is 2 Is a carboxyl group;
the R is 2a Having the definitions as described hereinbefore.
In the step 6, the molar ratio of the intermediate shown in the formula II-1 to the compound shown in the formula 5 is 1: 1-1: 2, preferably 1: 1.5.
In the step 6, the reaction temperature of the reaction is 20-25 ℃.
In the step 6, the alkali is sodium bicarbonate.
In the step 6, the reaction is carried out in N, N-dimethylformamide.
In the step 6, the reaction time is 22 to 26 hours, preferably 24 hours.
The invention also provides a preparation method of the intermediate shown in the formula II-2, wherein the intermediate shown in the formula II-2 is prepared from the intermediate shown in the formula II-1A, and the preparation method of the intermediate shown in the formula II-2 comprises the following steps:
and 7: removing the intermediate protecting group PG shown as the formula II-1A 1 To obtain a product of removing a protecting group; reacting the product of removing the protecting group with a compound shown as a formula 6 under the action of alkali to obtain an intermediate shown as a formula II-2;
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
the R is 2a Having the definitions as described hereinbefore.
In the step 7, the molar ratio of the intermediate shown in the formula II-1A to the compound shown in the formula 6 is 1: 1-1: 2, preferably 1: 1.5.
In the step 7, the intermediate protecting group PG shown as the formula II-1A is removed 1 Under the action of hydrochloric acid.
In the step 7, the intermediate protecting group PG shown as the formula II-1A is removed 1 Under reaction with hydrogen.
In the step 7, the reaction temperature of the reaction is 20-25 ℃.
In step 7, the base includes, but is not limited to, triethylamine or N, N-diisopropylethylamine, preferably triethylamine.
In the step 7, the reaction of the deprotected group is carried out in 1, 4-dioxane.
In the step 7, the reaction time of the deprotection group is 2 to 4 hours, preferably 3 hours.
In the step 7, the reaction of the product of the deprotection group and the compound shown in the formula 6 is carried out in dichloromethane under the action of alkali.
In the step 7, the reaction time of the reaction between the product of the deprotection group and the compound shown in the formula 6 under the action of the base is 10 to 14 hours, preferably 12 hours.
The invention also provides a preparation method of the intermediate shown in the formula II-3, wherein the intermediate shown in the formula II-3 is prepared from the intermediate shown in the formula II-2, and the preparation method of the intermediate shown in the formula II-3 comprises the following steps:
and 8: reacting the intermediate shown as the formula II-2 with a bromination reagent to obtain an intermediate shown as the formula II-3;
wherein R is 2a Having the definitions as described hereinbefore.
In step 8, the brominating agent includes N-bromosuccinimide, dibromohydantoin, pyridine tribromide, copper bromide or liquid bromine, preferably liquid bromine.
In the step 8, the molar ratio of the intermediate shown in the formula II-2 to the brominating reagent is 1: 1-1: 3, preferably 1: 1.2.
In the step 8, the reaction is carried out in dichloromethane.
In the step 8, the reaction temperature of the reaction is 20-25 ℃.
In the step 8, the reaction time of the reaction is 0.5 to 2 hours, preferably 1 hour.
The invention also provides a preparation method of the intermediate shown in the formula III, the intermediate shown in the formula III is prepared from the intermediate shown in the formula II-3, and the preparation method of the intermediate shown in the formula III comprises the following steps:
and step 9: reacting the intermediate shown as the formula II-3 with the compound shown as the formula 7 to obtain an intermediate shown as the formula III;
wherein the content of the first and second substances,
the R is 2a Having the definitions as described hereinbefore.
In the step 9, the molar ratio of the intermediate shown in the formula II-3 to the compound shown in the formula 7 in the reaction is 1: 1-1: 3, preferably 1:2.
In step 9, the reaction may be carried out in an organic solvent conventional in the art, including but not limited to acetonitrile, dimethylsulfoxide, ethanol, N-dimethylacetamide, N-dimethylformamide, N-methylpyrrolidone, 1, 4-dioxane, N-propanol or N-butanol, preferably acetonitrile.
In the step 9, the reaction temperature of the reaction is 110 to 130 ℃, preferably 120 ℃.
In the step 9, the reaction time of the reaction is 22 to 26 hours, preferably 24 hours.
The invention also provides a preparation method of the imidazopyridine compound shown in the formula IV, which comprises the following steps:
step 10: reacting the intermediate shown in the formula III with methylamine to obtain a compound shown in the formula IV;
wherein the content of the first and second substances,
said R is 2a Having the definitions as described hereinbefore.
In the step 10, the molar ratio of the intermediate shown in the formula III to methylamine is 1: 4-1: 6, preferably 1: 5.
In the step 10, the reaction temperature of the reaction is 20-25 ℃.
In the step 10, the reaction is carried out in methanol.
In the step 10, the reaction time of the reaction is 4 to 6 hours, preferably 5 hours.
The invention also provides a preparation method of the intermediate shown in the formula 3, wherein the preparation method of the intermediate shown in the formula 3 comprises the following steps;
step 11: reacting the intermediate shown as the formula 3-1 with a dess-martin oxidant to obtain an intermediate shown as the formula 3-2; reacting the intermediate shown as the formula 3-2 with a compound shown as a formula 8 to obtain an intermediate shown as a formula 3;
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
In the step 11, the molar ratio of the intermediate shown in the formula 3-1 to the dess-martin oxidant is 1: 1-2, preferably 1: 1.2.
In the step 11, the reaction temperature of the intermediate shown as the formula 3-1 and the dess-Martin oxidant is 20-25 ℃.
In the step 11, the reaction time of the intermediate shown in the formula 3-1 and the dess-martin oxidant is 1-3 hours, preferably 2 hours.
In the step 11, the reaction of the intermediate shown as the formula 3-1 and a dess-martin oxidant is carried out in dichloromethane.
In the step 11, the molar ratio of the intermediate shown in the formula 3-2 to the compound 8 is 1: 1-1: 2, preferably 1: 1.1.
In the step 11, the reaction temperature of the intermediate shown in the formula 3-1 and the compound 8 is 20-25 ℃.
In the step 11, the reaction time of the intermediate shown in the formula 3-1 and the compound 8 is 14 to 18 hours, preferably 16 hours.
In the step 11, the reaction of the intermediate shown as the formula 3-1 and a dess-martin oxidant is carried out in dichloromethane.
Terms and definitions
Unless otherwise indicated, the terms and definitions used in the present application, including in the specification and claims of the present application, are as follows.
It will be understood by those skilled in the art that, according to the convention used in the art, in the structural formulae of the present application,for delineating chemical bonds, which are the points at which moieties or substituents are attached to a core structure or a backbone structure.
The term "C 1 -C 6 Alkyl "is understood to mean a straight-chain or branched, saturated monovalent hydrocarbon radical having 1,2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl group, a 1-ethylpropyl group, a 1, 2-dimethylpropyl group, a neopentyl group, a 1, 1-dimethylpropyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-ethylbutyl group, a 1-ethylbutyl group, a 3, 3-dimethylbutyl group, a 2, 2-dimethylbutyl group, a 1, 1-dimethylbutyl group, a 2, 3-dimethylbutyl group, a 1, 3-dimethylbutyl group or a 1, 2-dimethylbutyl group, or the like, or isomers thereof. In particular, the radicals have 1,2 or 3 carbon atoms ("C) 1 -C 3 Alkyl groups) such as methyl, ethyl, n-propyl or isopropyl.
The term "metal alkyl compound" refers to a compound formed by direct bonding of a metal atom to an alkyl carbon atomAn organic compound. The alkyl group includes, but is not limited to, alkyl or cycloalkyl, such as C 1 -C 6 An alkyl group. Including but not limited to potassium, sodium, lithium, magnesium, or aluminum. The alkyl metal compound includes but is not limited to grignard reagent, alkyl lithium compound.
The term "amino metal compound" refers to a compound formed by a metal atom covalently or coordinately bound to an amino group, the "amino group being primary (i.e., -NH) 2 ) Secondary (i.e., -NRH) and tertiary (i.e., -NRR) amines, said R including but not limited to C 1 -C 6 Including but not limited to potassium, sodium, lithium or magnesium, and amino metal compounds including but not limited to lithium diisopropylamide, lithium bistrimethylsilyl amide, potassium bistrimethylsilyl amide, sodium amide, potassium amide, lithium amide.
The term "halo" or "halogen" is fluorine, chlorine, bromine and iodine.
The term "catalyst" refers to any substance or agent that can affect, induce, increase or promote the reactivity or reaction of a compound.
The term "transition metal catalyst" refers to any metal having an electron in its d orbital, for example a metal selected from groups 3-12 of the periodic table or the lanthanide series of elements. Catalysts useful in the process of the present invention include atoms, ions, salts or complexes of transition metals from groups 8 to 11 of the periodic Table. "groups 3 to 12 of the periodic Table of the elements" means the groups of the periodic Table numbered according to the IUPAC method. Thus, group 8-11 transition metals include iron, ruthenium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver, and gold. Such catalysts include, but are not limited to, CuI, CuCl, CuBr 2 、Cu 2 Cl 2 、Cu 2 O、Cu、Pd 2 (dba) 2 、Pd/C、PdCl 2 、Pd(OAc) 2 、(CH 3 CN) 2 PdCl 2 、Pd[P(C 6 H 5 ) 3 ] 4 、NiCl 2 [P(C 6 H 5 )] 2 And Ni (COD) 2 。
The term "R 2a -I "means containing R 2a The iodine reagent of (1).
In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.
Detailed Description
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Unless otherwise specified, the compounds of the present invention are structurally defined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). NMR shift in units of 10 -6 (ppm). Solvents for NMR measurement were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and an internal standard was Tetramethylsilane (TMS).
Abbreviations of the present invention are defined as follows:
m: molar concentration, e.g. 1M hydrochloric acid for 1mol/L hydrochloric acid solution
DIPEA: also can be written as DIEA, diisopropylethylamine, i.e., N-diisopropylethylamine
DMF: n, N-dimethylformamide
DCM: methylene dichloride
Et 3 N: triethylamine
Dess-Martin: dess-martin oxidizer
T 3 P: 1-Propylphosphoric acid anhydride
LDA: lithium diisopropylamide
n-BuLi: n-butyl lithium
TMEDA: n, N, N ', N' -tetramethylethylenediamine
NaHCO 3 : sodium bicarbonate
THF: tetrahydrofuran (THF)
Pd(dppf)Cl 2 :1, 1-bis (diphenylphosphino) ferrocene palladium chloride
LC-MS: liquid chromatography-mass spectrometry
TLC: thin layer chromatography
Preparation 1: preparation of intermediate (S) -tert-butyl 2- (3- (methoxy (methyl) amino) -3-oxopropyl) morpholine-4-carboxylate (A)
The synthetic route of the target intermediate a is shown below:
the first step is as follows: synthesis of tert-butyl (R) -2-formylmorpholine-4-carboxylate (A-2)
To a 2L three-necked flask were added (R) -tert-butyl 2-hydroxymethylmorpholine-4-carboxylate (A-1) (107g,491mmol) and dichloromethane (1L). The reaction temperature was adjusted to 0-5 ℃ and Dess-Martin reagent (250g,590mmol) was added slowly in portions while maintaining the reaction temperature at 0-5 ℃ and the reaction was continued at 0-5 ℃ with stirring for 0.5 h. The reaction temperature was adjusted to 20-25 ℃ and stirring was continued for 2h, TLC showed the starting material reaction was complete. The reaction was slowly poured into saturated solution sodium bicarbonate (1L) and stirred for 0.5h, filtered, separated and the organic phase collected. The organic phase was washed with a saturated sodium bicarbonate solution (1L. times.2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give tert-butyl (R) -2-formylmorpholine-4-carboxylate (A-2) as a colorless oil (100g, 95% yield).
The second step is that: synthesis of (S) -2- (3-methoxy-3-oxoprop-1-en-1-yl) morpholine-4-carboxylic acid tert-butyl ester (A-3)
In a 2L three-necked flask were added (R) -2-formylmorpholine-4-carboxylic acid tert-butyl ester (A-2) (100g,460mmol) and dichloromethane (1L). The reaction temperature was adjusted to 20-25 ℃ and the starting material was allowed to react completely by TLC, with slow addition of the methoxycarbonylmethylenetriphenylphosphine (171g,511mmol) in portions while maintaining the reaction temperature at 20-25 ℃ and continued stirring at 20-25 ℃ for 16 h. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to give tert-butyl (S) -2- (3-methoxy-3-oxoprop-1-en-1-yl) morpholine-4-carboxylate (A-3) as a colorless oil (65g, 51.6% yield).
1 H NMR(400MHz,Chloroform-d)δ6.83(ddd,J=15.9,4.2,1.0Hz,0.76H),6.16–6.07(m,1H),5.87(dt,J=11.8,1.2Hz,0.24H),4.18–3.80(m,4H),3.74(s,1.0Hz,3H),3.64–3.53(m,1H),3.05–2.85(m,1H),2.75–2.55(m,1H),1.47(t,J=1.6Hz,9H).
The third step: synthesis of (S) -tert-butyl 2- (3-methoxy-3-oxopropyl) morpholine-4-carboxylate (A-4)
(S) -2- (3-methoxy-3-oxoprop-1-en-1-yl) morpholine-4-carboxylic acid tert-butyl ester (A-3) (65g,240mmol), methanol (650mL) were added to a 2L single-neck flask, the reaction system was purged with nitrogen 3 times, Pd/C (3.25g) was added, the reaction system was purged with hydrogen 3 times, the reaction temperature was adjusted to 20-25 ℃ and stirred under 1atm hydrogen atmosphere for 24h, TLC showed complete reaction of the starting materials. The reaction system was purged with nitrogen 3 times, and filtered to obtain a methanol solution of tert-butyl (S) -2- (3-methoxy-3-oxopropyl) morpholine-4-carboxylate (A-4) (65.5g, yield 100%) which was used directly in the next step.
1 H NMR(400MHz,Chloroform-d)δ3.90–3.65(m,3H),3.59(s,3H),3.44–3.33(m,1H),3.33–3.22(m,1H),2.83(t,J=13.2Hz,1H),2.50(t,J=22.0Hz,1H),2.45–2.24(m,2H),1.78–1.61(m,2H),1.40–1.36(m,9H)。
The fourth step: synthesis of (S) -3- (4- (tert-butoxycarbonyl) morpholin-2-yl) propionic acid (A-5)
A2L three-necked flask was charged with a solution of (S) -tert-butyl 2- (3-methoxy-3-oxopropyl) morpholine-4-carboxylate (A-4) (65.5g, 240mmol) in methanol (650mL), 65mL of water were added, the reaction temperature was adjusted to 20-25 deg.C, lithium hydroxide monohydrate (20.1g,479mmol) was slowly added while maintaining the reaction temperature at 20-25 deg.C, and the reaction was stirred for a further 16h at 20-25 deg.C. The dry methanol was concentrated under reduced pressure, 400mL of water was added, the aqueous phase was washed with ethyl acetate (200 mL. times.2), the temperature of the aqueous phase was adjusted to 0-5 ℃, the pH was adjusted to 4-5 with 4M aqueous HCl under stirring, the aqueous phase was extracted with dichloromethane (400 mL. times.3), the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (S) -3- (4- (tert-butoxycarbonyl) morpholin-2-yl) propionic acid (A-5) as a colorless oil (61g, 98% yield).
1 H NMR(400MHz,Chloroform-d)δ3.97–3.69(m,3H),3.46(td,J=11.7,2.8Hz,1H),3.41–3.32(m,1H),2.97-2.81(m,1H),2.67–2.38(m,J=21.0,16.7,9.5Hz,3H),1.76(qd,J=9.9,8.6,6.1Hz,2H),1.44(s,9H).
The fifth step: synthesis of (S) -tert-butyl 2- (3- (methoxy (methyl) amino) -3-oxopropyl) morpholine-4-carboxylate (A)
In a 2L three-necked flask were charged (S) -3- (4- (tert-butoxycarbonyl) morpholin-2-yl) propionic acid (A-5) (61g,235mmol), N, O-dimethylhydroxylamine hydrochloride (27.5g,282mmol) and dichloromethane (610mL), and the reaction temperature was adjusted to 0-5 ℃. DIEA (91g,706mmol) and 1-propylphosphoric anhydride (50% DMF solution, 225g, 353mmol) were slowly added dropwise to the reaction mixture. The reaction internal temperature was adjusted to 20-25 ℃ and stirred for 16 h. 500mL of a saturated sodium bicarbonate solution was slowly added dropwise to the reaction solution, and the organic phase was separated and collected. The organic phase is washed with 500mL of saturated sodium bicarbonate solution and concentrated to dryness under reduced pressure. To the disabledTo the retentate, 360mL of ethyl acetate was added, followed by saturated NH 4 Washed with Cl (300 mL. times.3), and the organic phase was concentrated to dryness under reduced pressure to give (S) -tert-butyl 2- (3- (methoxy (methyl) amino) -3-oxopropyl) morpholine-4-carboxylate (A) as a colorless oil (60g, 84% yield).
1 H NMR(400MHz,Chloroform-d)δ3.96–3.74(m,3H),3.67(s,3H),3.46(td,J=11.7,2.9Hz,1H),3.36(td,J=7.9,6.8,4.2Hz,1H),3.16(s,3H),2.98–2.83(m,1H),2.55(dd,J=13.8,6.6Hz,3H),1.87–1.70(m,2H),1.44(s,9H)。
Preparation 2: preparation of intermediate (S) -tert-butyl 2- (3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B)
The synthetic route of the target intermediate B is shown below:
the first step is as follows: synthesis of tert-butyl (S) -2- (3- (4-bromo-2, 6-difluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-1)
Adding 3, 5-difluorobromobenzene (57.9g,300mmol) and anhydrous tetrahydrofuran (600mL) into a 2L three-necked flask under nitrogen atmosphere, adjusting the reaction temperature to-10-0 ℃, slowly dropwise adding lithium diisopropylamide (150mL,300mmol,2mol/L tetrahydrofuran solution) while maintaining the reaction temperature at-10-0 ℃, after the reaction liquid is continuously stirred for 1h, slowly dropwise adding tetrahydrofuran (120mL) solution of (S) -2- (3- (methoxy (methyl) amino) -3-oxopropyl) morpholine-4-carboxylic acid tert-butyl ester (A) (60g,198mmol) into the solution, and continuously stirring at-10-0 ℃ for 2h, wherein TLC shows that the reaction is complete. Slowly dropwise adding saturated NH into the reaction liquid 4 Cl solution (500mL), the reaction was warmed to room temperature, diluted with 500mL ethyl acetate and partitionedThe aqueous phase is extracted with 500mL of ethyl acetate, the combined organic phases are saturated with NH 4 Cl (1L) was washed, and the collected organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:5) to give (S) -tert-butyl 2- (3- (4-bromo-2, 6-difluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-1) (65g, yield 74.8%) as a white solid.
LC-MS,M/Z:334.1[M+H] +
The second step is that: synthesis of (S) -tert-butyl 2- (3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B)
Tert-butyl (S) -2- (3- (4-bromo-2, 6-difluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-1) (65g, 150mmol) was dissolved in methanol (650mL), triethylamine (45.4g, 449mmol) and 1, 1-bis (diphenylphosphino) ferrocene palladium chloride (5.48g, 7.48mmol) were added, vacuum was applied, nitrogen was applied three times, carbon monoxide was applied three times, and the reaction was carried out at 55-65 ℃ for 24h under carbon monoxide (45 psi). TLC showed the reaction was complete, the reaction was concentrated to dryness, then water (650mL) was added, neutralized with citric acid, then extracted with ethyl acetate (650mL × 2), combined with organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound (S) -tert-butyl 2- (3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B) (56g, 90% yield) as a brown oil.
LC-MS,M/Z:314.2[M+H] + 。
Preparation 3: preparation of intermediate (S) -tert-butyl 2- (3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B)
The synthetic route of the target intermediate B is shown below:
the first step is as follows: synthesis of (S) -tert-butyl 2- (3- (4-bromo-2, 6-difluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-2)
Under nitrogen atmosphere, 3, 5-difluorobromobenzene (9.6g,50mmol) and anhydrous tetrahydrofuran (100mL) are added into a 250mL three-necked flask, the reaction temperature is adjusted to-80 to-60 ℃, lithium diisopropylamide (25mL,50mmol,2mol/L tetrahydrofuran solution) is slowly dripped while maintaining the reaction temperature at-80 to-60 ℃, after the reaction liquid is continuously stirred for 1h, a tetrahydrofuran (20mL) solution of (S) -2- (3- (methoxy (methyl) amino) -3-oxopropyl) morpholine-4-carboxylic acid tert-butyl ester (A) (10g,33mmol) is slowly dripped into the solution, and the TLC shows that the reaction is complete after the reaction is continuously stirred for 2h at-80 to-60 ℃. Slowly dropwise adding saturated NH into the reaction liquid 4 Cl solution (100mL), the reaction was warmed to room temperature, diluted with 100mL ethyl acetate, separated and the aqueous phase extracted with 100mL ethyl acetate, the combined organic phases saturated NH 4 Cl (200mL) was washed, and the collected organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:5) to give (S) -tert-butyl 2- (3- (4-bromo-2, 6-difluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-2) (7.46g, 52% yield) as a white solid.
LC-MS,M/Z:334.1[M+H] +
The second step is that: synthesis of (S) -tert-butyl 2- (3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B)
Tert-butyl (S) -2- (3- (4-bromo-2, 6-difluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-2) (7.46g, 17.2mmol) was dissolved in methanol (75mL), triethylamine (5.13g, 51.6mmol) and 1, 1-bis (diphenylphosphino) ferrocene palladium chloride (0.63g, 0.86mmol) were added, vacuum was applied, nitrogen was applied three times, carbon monoxide was applied three times, and the reaction was carried out under carbon monoxide (45psi) at 55-65 ℃ for 24 h. TLC showed completion of the reaction, concentrated to dryness, then added water (100mL), neutralized with citric acid, then extracted with ethyl acetate (100mL × 2), combined with organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound (S) -tert-butyl 2- (3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B) (6.6g, 93% yield) as a brown oil.
LC-MS,M/Z:314.2[M+H] + 。
Preparation 4: preparation of intermediate (S) -tert-butyl 2- (3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B)
The synthetic route of the target intermediate B is shown below:
the first step is as follows: synthesis of (S) -4- (3- (4- (tert-butoxycarbonyl) morpholin-2-yl) propionyl) -3, 5-difluorobenzoic acid (B-3)
Under a nitrogen atmosphere, 3, 5-difluorobenzoic acid (6.26g,39.2mmol), TMEDA (10.0g,87mmol) and anhydrous tetrahydrofuran (100mL) were added to a 250mL three-necked flask, the reaction temperature was adjusted to-10 to 0 ℃, n-butyllithium (35mL,87mmol,2.5mol/L n-hexane solution) was slowly added dropwise while maintaining the reaction temperature at-10 to 0 ℃, the reaction solution was stirred for 0.5 hour, then a tetrahydrofuran (20mL) solution of tert-butyl (A) (10g,33mmol) of (S) -2- (3- (methoxy (methyl) amino) -3-oxopropyl) morpholine-4-carboxylate was slowly added dropwise, and the reaction was stirred for 2 hours at-10 to 0 ℃ by TLC. Water (100mL) was slowly added dropwise to the reaction solution, the reaction solution was allowed to warm to room temperature, the pH of the aqueous phase was adjusted to 4-5 with 1M aqueous hydrochloric acid, 100mL of ethyl acetate was added, the aqueous phase was separated and extracted with 100mL of ethyl acetate, the organic phases were combined, and the collected organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (S) -4- (3- (4- (tert-butoxycarbonyl) morpholin-2-yl) propionyl) -3, 5-difluorobenzoic acid (B-3) (6.72g, yield 51%) as a white solid.
LC-MS,M/Z:300.1[M+H] +
The second step is that: synthesis of (S) -tert-butyl 2- (3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B)
(S) -4- (3- (4- (tert-butoxycarbonyl) morpholin-2-yl) propionyl) -3, 5-difluorobenzoic acid (B-3) (6.72g, 16.8mmol) was dissolved in N, N-dimethylformamide (70mL), and sodium hydrogencarbonate (2.82g, 33.6mmol) and iodomethane (3.57g, 25.2mmol) were added to react at 20-25 ℃ for 24 hours. TLC showed completion of the reaction, added water (100mL) to the reaction solution, then extracted with ethyl acetate (100mL × 2), combined the organic phases, washed with saturated sodium bicarbonate solution (300mL × 2) and saturated sodium chloride solution (300mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound (S) -tert-butyl 2- (3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B) as a brown oil (5.9g, 85% yield).
LC-MS,M/Z:314.2[M+H] + 。
Preparation 5: preparation of intermediate tert-butyl (S) -2- (3- (4- (4-tert-butoxycarbonyl) -2, 6-difluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-Bu)
The synthetic route of the target intermediate B-Bu is shown as follows:
the first step is as follows: synthesis of tert-butyl (S) -2- (3- (4- (4-tert-butoxycarbonyl) -2, 6-difluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-Bu)
Under a nitrogen atmosphere, 3, 5-difluorobenzoic acid tert-butyl ester (10.6g,49.5mmol) and anhydrous tetrahydrofuran (100mL) are added into a 250mL three-necked flask, the reaction temperature is adjusted to-10-0 ℃, lithium diisopropylamide (24.8mL,49.5mmol,2mol/L n-hexane solution) is slowly added dropwise while maintaining the reaction temperature at-10-0 ℃, after the reaction solution is continuously stirred for 1h, a tetrahydrofuran (20mL) solution of (S) -2- (3- (methoxy (methyl) amino) -3-oxopropyl) morpholine-4-carboxylic acid tert-butyl ester (A) (10g,33mmol) is slowly added dropwise into the solution, and the reaction is continuously stirred for 3h at-10-0 ℃, and TLC shows that the reaction is complete. Saturated ammonium chloride solution (100mL) was slowly added dropwise to the reaction solution, the reaction solution was warmed to room temperature, 100mL of ethyl acetate was added to dilute, the aqueous phase was separated and extracted with 100mL of ethyl acetate, the combined organic phases were washed with saturated ammonium chloride solution (200mL), the collected organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:5) to give (S) -tert-butyl 2- (3- (4- (4-tert-butoxycarbonyl) -2, 6-difluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-Bu) as a white solid (7.06g, yield 47%).
LC-MS,M/Z:356.2[M+H] + 。
Preparation 6: preparation of intermediate methyl (2S) -2- (2-bromo-3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C)
The synthetic route of the target intermediate C is shown below:
the first step is as follows: synthesis of methyl (S) -2- (3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C-1)
To a 2L three-necked flask were added tert-butyl (S) -2- (3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B) (56g,135mmol) and 1, 4-dioxane (150mL) under a nitrogen atmosphere, and the reaction temperature was adjusted to 20 to 25 ℃. A solution of HCl in 1, 4-dioxane (135mL,4mol/L) was added slowly to the solution, the reaction temperature was maintained at 20-25 deg.C, the reaction was stirred for an additional 3h, and LC-MS showed completion of the reaction. The reaction mixture was concentrated to dryness under reduced pressure, methylene chloride (600mL) was added to the residue, the temperature of the reaction mixture was adjusted to 0-5 ℃, triethylamine (41.1g,406mmol) was slowly added dropwise, followed by methyl chloroformate (19.2g,203 mmol). The reaction temperature is adjusted to 20-25 ℃, the reaction solution is stirred for 12h at 20-25 ℃, and TLC shows that the reaction is complete. Adding 400mL of saturated sodium chloride solution into the reaction solution, separating the solution and collecting an organic phase, wherein the organic phase is saturated NH 1L 4 Washed with Cl and the organic phase was concentrated to dryness to give (S) -methyl 2- (3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C-1) as a brown oil (47g, 93% yield).
LC-MS,M/Z:372.1[M+H] + 。
The second step is that: synthesis of methyl (2S) -2- (2-bromo-3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C)
To a 1L three-necked flask were added methyl (S) -2- (3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C-1) (47g,127mmol), dichloromethane (470mL) and a 33% solution of hydrogen bromide in acetic acid (1.55g,6.33 mmol). The reaction temperature was adjusted to 20-25 deg.C, liquid bromine (24.27g,152mmol) was slowly added dropwise to the reaction solution, the reaction was stirred at 20-25 deg.C for 1h, TLC indicated complete reaction. 300mL of saturated sodium bisulfite solution and 400mL of saturated sodium bicarbonate solution were added to the reaction system. The organic phase was separated and collected, washed with 400mL of a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:3) to give (2S) -2- (2-bromo-3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylic acid methyl ester (C) as a brown oil (50g, yield 88%).
LC-MS,M/Z:450.0[M+H] + 。
Preparation 7: preparation of intermediate methyl (2S) -2- (2-bromo-3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C)
The synthetic route of the target intermediate C is shown below:
the first step is as follows: synthesis of (S) -3, 5-difluoro-4- (3- (4- (methoxycarbonyl) morpholin-2-yl) propionyl) benzoic acid (C-2)
To a 250mL three-necked flask, tert-butyl (S) -2- (3- (4- (tert-butoxycarbonyl) -2, 6-difluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-4) (7.06g,15.5mmol) and 1, 4-dioxane (20mL) were added under a nitrogen atmosphere, and the reaction temperature was adjusted to 20-25 ℃. A solution of hydrochloric acid in 1, 4-dioxane (16.0mL,4mol/L) was slowly added to the solution, the reaction temperature was maintained at 20-25 deg.C, and the reaction was continued with stirring for 15 h. The reaction mixture was concentrated to dryness under reduced pressure, methylene chloride (70mL) was added to the residue, the temperature of the reaction mixture was adjusted to 0-5 deg.C, triethylamine (5.5g,54.3mmol) was slowly added dropwise, followed by methyl chloroformate (1.9g,23.3 mmol). The reaction temperature is adjusted to 20-25 ℃, and the reaction liquid is stirred for 12h at 20-25 ℃. To the reaction solution was added 100mL of water, the pH of the aqueous phase was adjusted to 4-5 with 5M hydrochloric acid solution, the phases were separated and the organic phase was collected, the aqueous phase was extracted with dichloromethane (100mL × 2), and the combined organic phases were concentrated to dryness to give (S) -3, 5-difluoro-4- (3- (4- (methoxycarbonyl) morpholin-2-yl) propionyl) benzoic acid (C-2) (4.3g, 78% yield) as a white solid.
LC-MS,M/Z:358.1[M+H] +
The second step is that: synthesis of methyl (S) -2- (3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C-1)
(S) -3, 5-difluoro-4- (3- (4- (methoxycarbonyl) morpholin-2-yl) propionyl) benzoic acid (C-2) (4.3g, 12.1mmol) was dissolved in N, N-dimethylformamide (43mL), and reacted with sodium bicarbonate (2.0g, 24.2mmol) and iodomethane (2.57g, 18.2mmol) at 20-25 ℃ for 24 hours. TLC showed completion of the reaction, and water (100mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100mL × 2), organic phase was combined, washed with saturated sodium bicarbonate solution (300mL × 2) and saturated sodium chloride solution (300mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give methyl (S) -2- (3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C-1) (3.32g, 73% yield) as a white oily compound.
LC-MS,M/Z:372.1[M+H] +
The third step: synthesis of methyl (2S) -2- (2-bromo-3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C)
A100 mL three-necked flask was charged with methyl (S) -2- (3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C-1) (3.32g,8.83mmol), dichloromethane (40mL) and 33% acetic acid hydrogen bromide solution (0.11g,0.45 mmol). The reaction temperature was adjusted to 20-25 deg.C, liquid bromine (1.7g,10.6mmol) was slowly added dropwise to the reaction solution, the reaction was stirred at 20-25 deg.C for 1h, TLC indicated complete reaction. To the reaction system were added 30mL of a saturated sodium bisulfite solution and 40mL of a saturated sodium bicarbonate solution. The organic phase was separated and collected, washed with 40mL of a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:3) to give (2S) -2- (2-bromo-3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylic acid methyl ester (C) (3.6g, yield 91%) as a brown oil.
LC-MS,M/Z:450.0[M+H] + 。
Preparation 8: preparation of intermediate methyl (S) -2- ((2- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (D)
The synthetic route of the target intermediate D is shown below:
the first step is as follows: synthesis of methyl (S) -2- ((2- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (D)
To a 1L reaction flask was added (2S) -methyl 2- (2-bromo-3-oxo-3- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C) (50g,111mmol), 2-amino-4-methylpyridine (24.0g, 222mmol) and acetonitrile (500mL), the reaction flask was closed, the reaction temperature was adjusted to 120 ℃ and stirred for 24h, filtered under cooling to room temperature, the filtrate was concentrated to dryness under reduced pressure, and finally purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:1) to give (S) -methyl 2- ((2- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate as a yellow solid, (S) - (2-bromo-3-oxo-3-methyl) morpholine-4-carboxylate D) (25g, yield 47%).
LC-MS,M/Z:460.2[M+H] + 。
Example 1: preparation of methyl (S) -2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (1)
The synthetic route of the target compound 1 is shown below:
the first step is as follows: preparation of methyl (S) -2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate Synthesis of (1)
To a 100mL reaction flask was added (S) -methyl 2- ((2- (2, 6-difluoro-4- (methoxycarbonyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (D) (8g,16.7mmol), methanol (16 mL). To the reaction solution was added a 33% solution of methylamine in methanol (7.8g, 83mmol), the reaction temperature was adjusted to 20-25 ℃ and stirred for 5 h. TLC indicated the reaction was complete. The reaction solution was concentrated under reduced pressure to dryness, and purified by silica gel column chromatography to give methyl (S) -2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (1) (7.7g, yield 97%) as a yellow solid.
1 H NMR(400MHz,Chloroform-d)δ8.13(d,J=7.1Hz,1H),7.62(ddd,J=9.6,5.6,2.1Hz,1H),7.32(dt,J=2.0,1.1Hz,1H),7.00(s,1H),6.64(dd,J=7.1,1.7Hz,1H),3.95–3.68(m,3H),3.62(s,3H),3.54–3.47(m,1H),3.37–3.27(m,1H),3.02(d,J=4.8,0.9Hz,3H),3.00–2.78(m,3H),2.55(dd,J=13.0,10.6Hz,1H),2.37(d,J=1.1Hz,3H).
LC-MS,M/Z:459.2[M+H] + 。
Claims (22)
1. An intermediate of formula I or formula II:
wherein the content of the first and second substances,
The R is 2a Is selected from C 1 -C 6 Alkyl or benzyl;
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
and X is selected from H or Br.
2. The intermediate of formula II according to claim 1,
when R is 2 When halogen is used, the halogen is Br or I, preferably Br;
and/or, said R 2a Is C 1 -C 6 An alkyl group; preferably, R is 2a Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
3. The intermediate of claim 1 or claim 2, wherein the intermediate of formula II is selected from any one of the following intermediates:
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
The R is 2a Having the definition as claimed in claim 1 or claim 2.
4. A process for the preparation of an intermediate of formula II-1, as defined in claim 3, comprising the steps of:
step 1: under the action of an amino metal compound or an alkyl metal compound, an intermediate shown as a formula I and a compound shown as a formula 1 are reacted to prepare an intermediate shown as a formula II-1;
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
The R is 2a Having the definition as claimed in claim 1 or claim 2.
5. A process for the preparation of an intermediate of formula I as defined in claim 1, comprising the steps of:
step 2: under the action of organic alkali and a condensing agent, reacting an intermediate shown as a formula I-2 with a compound shown as a formula 2 to prepare the intermediate shown as the formula I;
wherein the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
6. The method for preparing the intermediate shown in the formula I according to claim 5, wherein the method for preparing the intermediate shown in the formula I further comprises a method for preparing the intermediate shown in the formula I-2, and the method for preparing the intermediate shown in the formula I-2 comprises the following steps:
and step 3: preparing an intermediate shown as a formula I-1 by carrying out reduction reaction on a compound shown as a formula 3;
and 4, step 4: under the action of inorganic base, hydrolyzing the intermediate shown in the formula I-1 to prepare an intermediate shown in the formula I-2;
wherein the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
7. A method for preparing an intermediate shown as a formula II-1A in an intermediate shown as a formula II-1A according to claim 3, wherein the intermediate shown as the formula II-1A is prepared from an intermediate shown as a formula II-1, and the method for preparing the intermediate shown as the formula II-1A comprises the following steps:
and 5: under the action of a catalyst and organic base, reacting the intermediate shown as the formula II-1 with carbon monoxide and a compound shown as the formula 4 to obtain an intermediate shown as the formula II-1A;
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
the R is 2 Is halogen;
the R is 2a Having the definition as claimed in claim 1 or claim 2.
8. A method for preparing an intermediate shown as a formula II-1A in an intermediate shown as a formula II-1A according to claim 3, wherein the intermediate shown as the formula II-1A is prepared from an intermediate shown as a formula II-1, and the method for preparing the intermediate shown as the formula II-1A comprises the following steps:
step 6: under the action of alkali, reacting the intermediate shown as the formula II-1 with the compound shown as the formula 5 to obtain an intermediate shown as the formula II-1A;
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
the R is 2 Is a carboxyl group;
the R is 2a Having the definition as claimed in claim 1 or claim 2.
9. A method for preparing an intermediate shown as a formula II-2 in an intermediate shown as a formula II-2 according to claim 3, wherein the intermediate shown as the formula II-2 is prepared from an intermediate shown as a formula II-1A, and the method for preparing the intermediate shown as the formula II-2 comprises the following steps:
and 7: removing a compound represented by the formula II-1AIntermediate protecting group PG 1 To obtain a product of removing a protecting group; reacting the product of removing the protecting group with a compound shown as a formula 6 under the action of alkali to obtain an intermediate shown as a formula II-2;
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
said R is 2a Having the definition as set forth in claim 1 or claim 2.
10. A method for preparing an intermediate shown as a formula II-3 in an intermediate shown as a formula II-3 according to claim 3, wherein the intermediate shown as the formula II-3 is prepared from an intermediate shown as a formula II-2, and the method for preparing the intermediate shown as the formula II-3 comprises the following steps:
and 8: reacting the intermediate shown as the formula II-2 with a bromination reagent to obtain an intermediate shown as the formula II-3;
wherein R is 2a Has the definition as claimed in claim 1 or claim 2.
11. A preparation method of an intermediate shown in a formula III is characterized in that the intermediate shown in the formula III is prepared from an intermediate shown in a formula II-3, and the preparation method of the intermediate shown in the formula III comprises the following steps:
and step 9: reacting the intermediate shown as the formula II-3 with the compound shown as the formula 7 to obtain an intermediate shown as the formula III;
wherein the content of the first and second substances,
the R is 2a Having the definition as claimed in claim 1 or claim 2.
12. A preparation method of an imidazopyridine compound shown in formula IV comprises the following steps:
step 10: reacting the intermediate shown in the formula III with methylamine to obtain a compound shown in the formula IV;
wherein the content of the first and second substances,
the R is 2a Having the definition as claimed in claim 1 or claim 2.
13. The method for preparing the intermediate represented by the formula II-1 according to claim 4, wherein in the step 1,
the amino metal compound is lithium diisopropylamide, lithium bistrimethylsilyl amide, potassium bistrimethylsilyl amide, sodium bistrimethylsilyl amide, preferably lithium diisopropylamide or lithium bistrimethylsilyl amide;
optionally, the alkyl metal compound is methyl grignard reagent, ethyl grignard reagent, isopropyl grignard reagent, alkyl lithium compound, preferably methyl lithium or n-butyl lithium;
optionally, when said R is 2 In the case of halogen, the reaction is carried out under the action of an amino metal compound;
optionally, when said R is 2 Is carboxyl orWhen the reaction is carried out under the action of an amino metal compound or an alkyl metal compound;
optionally, the reaction temperature of the reaction is-80 to 0 ℃, preferably-10 to 0 ℃ or-80 to-60 ℃;
optionally, the molar ratio of the intermediate shown in the formula I to the compound shown in the formula 1 in the reaction is 1: 1-1: 1.6, preferably 1: 1-1.2 or 1: 1.5-1: 1.6, more preferably 1:1.2 or 1: 1.5;
optionally, the reaction is carried out in an organic solvent comprising diethyl ether, dichloromethane, toluene, 2-methyltetrahydrofuran or tetrahydrofuran, preferably tetrahydrofuran;
optionally, the reaction time of the reaction is 2-4 hours, preferably 3 hours;
optionally, when the reaction is carried out under the action of an alkyllithium compound, the reaction further comprises a stabilizer which is N, N' -tetramethylethylenediamine.
14. The method for preparing the intermediate shown in the formula I according to claim 5, wherein in the step 2,
the molar ratio of the intermediate shown in the formula I-2 to the compound shown in the formula 2 is 1: 1-1: 2, preferably 1: 1.2;
optionally, the molar ratio of the intermediate shown in the formula I-2 to the compound of the organic base is 1:2 to 1:4, preferably 1:2.8 to 1:3.2, and more preferably 1: 3;
optionally, the molar ratio of the intermediate shown as the formula I-2 to the condensing agent is 1: 1-1: 2, preferably 1: 1.5;
optionally, the organic base is N, N-diisopropylethylamine;
optionally, the reaction temperature of the reaction is 20-25 ℃;
optionally, the condensing agent is 1-propyl phosphoric anhydride;
optionally, the reaction is carried out in dichloromethane;
optionally, the reaction time of the reaction is 14 to 18 hours, preferably 16 hours.
15. The method for preparing the intermediate shown in the formula I according to claim 6, wherein in the step 3,
the reaction further comprises hydrogen;
optionally, the reaction further comprises palladium on carbon;
optionally, the reaction temperature of the reaction is 20-25 ℃;
optionally, the pressure of hydrogen in the reaction is 0.8 to 1.2 atmospheres, preferably 1 atmosphere;
optionally, the mass ratio of the palladium carbon to the compound 3 is 1: 18-1: 22, preferably 1: 20;
optionally, the reaction time of the reaction is 22 to 26 hours, preferably 24 hours.
16. The method for preparing the intermediate shown in the formula I according to claim 6, characterized in that in the step 4,
the inorganic base is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide;
optionally, the reaction temperature of the reaction is 20-25 ℃;
optionally, the molar ratio of the intermediate shown in the formula I-1 to the inorganic base is 1: 1-1: 4, preferably 1: 2;
optionally, the reaction is carried out in methanol;
optionally, the reaction time of the reaction is 14 to 18 hours, preferably 16 hours.
17. The method for preparing the intermediate as shown in the formula II-1A according to claim 7, characterized in that in the step 5,
the catalyst is a transition metal catalyst, and the transition metal catalyst comprises a palladium metal catalyst, a ruthenium metal catalyst, an iron metal catalyst, a cobalt metal catalyst, a nickel metal catalyst and a rhodium metal catalyst; preferably a palladium metal catalyst;
preferably, the palladium metal catalyst is tetrakis (triphenylphosphine) palladium, palladium acetate, bis (triphenylphosphine) palladium dichloride, 1-bis (diphenylphosphino) ferrocene palladium chloride, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, 1, 4-bis (diphenylphosphinobutane) palladium dichloride; more preferably, the palladium metal catalyst is 1, 1-bis (diphenylphosphino) ferrocene palladium chloride;
optionally, the organic base is triethylamine or N, N-diisopropylethylamine, preferably triethylamine;
optionally, the reaction is carried out in pressurized carbon monoxide at a pressure of 40 to 50psi, preferably 45 psi;
optionally, the reaction temperature of the reaction is 55-65 ℃;
optionally, the reaction time of the reaction is 22 to 26 hours, preferably 24 hours.
18. The method for preparing the intermediate represented by the formula II-1A according to claim 8, wherein in the step 6,
the molar ratio of the intermediate shown in the formula II-1 to the compound shown in the formula 5 is 1: 1-1: 2, preferably 1: 1.5;
optionally, the reaction temperature of the reaction is 20-25 ℃;
optionally, the base is sodium bicarbonate;
optionally, the reaction is carried out in N, N-dimethylformamide;
optionally, the reaction time of the reaction is 22 to 26 hours, preferably 24 hours.
19. The method for preparing the intermediate represented by the formula II-2 according to claim 9, wherein in the step 7,
the molar ratio of the intermediate shown in the formula II-1A to the compound shown in the formula 6 is 1: 1-1: 2, preferably 1: 1.5;
optionally, removing the intermediate protecting group PG shown as the formula II-1A 1 Under the action of hydrochloric acid;
optionally, the removal is as shown in formula II-1AIntermediate protecting group PG 1 Under reaction with hydrogen;
optionally, the reaction temperature of the reaction is 20-25 ℃;
optionally, the base is triethylamine or N, N-diisopropylethylamine, preferably triethylamine;
optionally, the reaction of the deprotected group is carried out in 1, 4-dioxane;
optionally, the reaction time for removing the protecting group is 2-4 hours, preferably 3 hours;
optionally, the reaction of the product of deprotection and the compound shown as the formula 6 is carried out in dichloromethane under the action of alkali;
optionally, the reaction time of the product of the deprotection group and the compound shown in the formula 6 under the action of alkali is 10-14 hours, preferably 12 hours.
20. The method of claim 10, wherein in step 8,
the brominating reagent is N-bromosuccinimide, dibromohydantoin, pyridine tribromide, copper bromide or liquid bromine, preferably liquid bromine;
optionally, the molar ratio of the intermediate shown in the formula II-2 to the brominating reagent is 1: 1-1: 3, preferably 1: 1.2;
optionally, the reaction is carried out in dichloromethane;
optionally, the reaction temperature of the reaction is 20-25 ℃;
optionally, the reaction time of the reaction is 0.5 to 2 hours, preferably 1 hour.
21. The method for preparing the intermediate shown in the formula III according to claim 11, wherein in the step 9,
in the reaction, the molar ratio of the intermediate shown in the formula II-3 to the compound shown in the formula 7 is 1: 1-1: 3, preferably 1: 2;
optionally, the reaction is carried out in an organic solvent comprising acetonitrile, dimethyl sulfoxide, ethanol, N-dimethylacetamide, N-dimethylformamide, N-methylpyrrolidone, 1, 4-dioxane, N-propanol or N-butanol, preferably acetonitrile;
optionally, the reaction temperature of the reaction is 110-130 ℃, preferably 120 ℃;
optionally, the reaction time of the reaction is 22 to 26 hours, preferably 24 hours.
22. The method of claim 12, wherein in step 10,
the molar ratio of the intermediate shown in the formula III to methylamine is 1: 4-1: 6, preferably 1: 5;
optionally, the reaction temperature of the reaction is 20-25 ℃;
optionally, the reaction is carried out in methanol;
optionally, the reaction time of the reaction is 4 to 6 hours, preferably 5 hours.
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