CN114560805A - Synthetic method of nitrogen-containing heterocyclic compound and intermediate thereof - Google Patents
Synthetic method of nitrogen-containing heterocyclic compound and intermediate thereof Download PDFInfo
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- CN114560805A CN114560805A CN202210068542.7A CN202210068542A CN114560805A CN 114560805 A CN114560805 A CN 114560805A CN 202210068542 A CN202210068542 A CN 202210068542A CN 114560805 A CN114560805 A CN 114560805A
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- Prior art keywords
- nitrogen
- containing heterocyclic
- compound
- heterocyclic compound
- independently
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- -1 nitrogen-containing heterocyclic compound Chemical class 0.000 title claims abstract description 55
- 238000010189 synthetic method Methods 0.000 title claims abstract description 12
- 238000006552 photochemical reaction Methods 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims description 30
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 22
- IUKPWYDLDSUYIB-UHFFFAOYSA-N 3-tert-butyl-2-pyridin-2-ylpyridine Chemical compound CC(C)(C)C1=CC=CN=C1C1=CC=CC=N1 IUKPWYDLDSUYIB-UHFFFAOYSA-N 0.000 claims description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- 229940125782 compound 2 Drugs 0.000 claims description 13
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 12
- 229940125904 compound 1 Drugs 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 229910052741 iridium Inorganic materials 0.000 claims description 9
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 9
- 238000010511 deprotection reaction Methods 0.000 claims description 8
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical group 0.000 claims description 7
- 239000011941 photocatalyst Substances 0.000 claims description 7
- 229910052710 silicon Inorganic materials 0.000 claims description 7
- 239000010703 silicon Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 229910052759 nickel Inorganic materials 0.000 claims description 6
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- SQMFULTZZQBFBM-UHFFFAOYSA-N bis(trimethylsilyl)silyl-trimethylsilane Chemical compound C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C SQMFULTZZQBFBM-UHFFFAOYSA-N 0.000 claims description 3
- UEEXRMUCXBPYOV-UHFFFAOYSA-N iridium;2-phenylpyridine Chemical compound [Ir].C1=CC=CC=C1C1=CC=CC=N1.C1=CC=CC=C1C1=CC=CC=N1.C1=CC=CC=C1C1=CC=CC=N1 UEEXRMUCXBPYOV-UHFFFAOYSA-N 0.000 claims description 3
- AKQNYQDSIDKVJZ-UHFFFAOYSA-N triphenylsilane Chemical compound C1=CC=CC=C1[SiH](C=1C=CC=CC=1)C1=CC=CC=C1 AKQNYQDSIDKVJZ-UHFFFAOYSA-N 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 45
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000013341 scale-up Methods 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 20
- 239000000543 intermediate Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- YCUDHDNCZHPAJK-UHFFFAOYSA-N tert-butyl 3-bromopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(Br)C1 YCUDHDNCZHPAJK-UHFFFAOYSA-N 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- SCHZCUMIENIQMY-UHFFFAOYSA-N tris(trimethylsilyl)silicon Chemical compound C[Si](C)(C)[Si]([Si](C)(C)C)[Si](C)(C)C SCHZCUMIENIQMY-UHFFFAOYSA-N 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 7
- NHDODQWIKUYWMW-UHFFFAOYSA-N 1-bromo-4-chlorobenzene Chemical compound ClC1=CC=C(Br)C=C1 NHDODQWIKUYWMW-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000002953 preparative HPLC Methods 0.000 description 5
- YGKUEOZJFIXDGI-UHFFFAOYSA-N pridopidine Chemical compound C1CN(CCC)CCC1C1=CC=CC(S(C)(=O)=O)=C1 YGKUEOZJFIXDGI-UHFFFAOYSA-N 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 description 2
- QJPJQTDYNZXKQF-UHFFFAOYSA-N 4-bromoanisole Chemical compound COC1=CC=C(Br)C=C1 QJPJQTDYNZXKQF-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- VEQPNABPJHWNSG-UHFFFAOYSA-N Nickel(2+) Chemical compound [Ni+2] VEQPNABPJHWNSG-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical compound C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
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- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 description 1
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 1
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- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 1
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- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- UTBULQCHEUWJNV-UHFFFAOYSA-N 4-phenylpiperidine Chemical class C1CNCCC1C1=CC=CC=C1 UTBULQCHEUWJNV-UHFFFAOYSA-N 0.000 description 1
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
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- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
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- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- ZTYYDUBWJTUMHW-UHFFFAOYSA-N furo[3,2-b]furan Chemical compound O1C=CC2=C1C=CO2 ZTYYDUBWJTUMHW-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 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
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
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- 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
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
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- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 230000001590 oxidative effect 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
- 125000002080 perylenyl group Chemical group C1(=CC=C2C=CC=C3C4=CC=CC5=CC=CC(C1=C23)=C45)* 0.000 description 1
- CSHWQDPOILHKBI-UHFFFAOYSA-N peryrene Natural products C1=CC(C2=CC=CC=3C2=C2C=CC=3)=C3C2=CC=CC3=C1 CSHWQDPOILHKBI-UHFFFAOYSA-N 0.000 description 1
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical class C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 229950003764 pridopidine Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- MHOZZUICEDXVGD-UHFFFAOYSA-N pyrrolo[2,3-d]imidazole Chemical compound C1=NC2=CC=NC2=N1 MHOZZUICEDXVGD-UHFFFAOYSA-N 0.000 description 1
- RQGPLDBZHMVWCH-UHFFFAOYSA-N pyrrolo[3,2-b]pyrrole Chemical compound C1=NC2=CC=NC2=C1 RQGPLDBZHMVWCH-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- ONCNIMLKGZSAJT-UHFFFAOYSA-N thieno[3,2-b]furan Chemical compound S1C=CC2=C1C=CO2 ONCNIMLKGZSAJT-UHFFFAOYSA-N 0.000 description 1
- VJYJJHQEVLEOFL-UHFFFAOYSA-N thieno[3,2-b]thiophene Chemical compound S1C=CC2=C1C=CS2 VJYJJHQEVLEOFL-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/24—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention relates to a nitrogen-containing heterocyclic compound and a synthesis method of an intermediate thereof. The synthesis method of the intermediate comprises the following steps: reacting compound 1
And compound 2
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthetic method of a nitrogen-containing heterocyclic compound and an intermediate thereof.
Background
The nitrogen-containing heterocyclic compound has a very important research position in the technical field of pharmaceutical chemistry. On the one hand, nitrogen-containing heterocyclic compounds are easy to structurally modify and convenient for introducing various functional groups, so that the nitrogen-containing heterocyclic compounds play an important role in drug design in the past decades. On the other hand, many drug lead molecules contain nitrogen-containing heterocyclic compound structures, and partial nitrogen-containing heterocyclic compounds are found to have certain biological activities, such as anticancer, antioxidation, antibiosis, antivirus, antifungal, anti-inflammatory and the like, and can be used as important synthetic building blocks of bioactive molecules.
The literature is concerned with the synthesis and evaluation of a series of 4-phenylpiperidines and 4-phenylpiperazines as ligands for the D2 receptor and the discovery of the dopaminergic stabiliser 4- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine (Huntexil, Pridopidine, ACR 16). The synthetic route involving compound 11 is shown below:
the compound 4 and N-tert-butyloxycarbonyl-4-piperidone generate a compound 5 under the action of N-butyllithium; deprotecting and dehydrating the compound 5 under the action of trifluoroacetic acid to obtain a compound 6; reacting the compound 6 with methyl chloroformate under the action of triethylamine to obtain a compound 7; oxidizing the compound 7 with m-chloroperoxybenzoic acid to obtain a compound 8; catalytically hydrogenating the compound 8 to obtain a compound 9; deacetylating the compound 9 with hydrochloric acid to obtain a compound 10; the compound 10 reacts with a halide under the action of potassium carbonate to obtain a compound 11(4- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine or 4- [3- (methylsulfonyl) phenyl ] -1-benzylpiperidine).
The synthetic method has a long route, uses national supervision hypertoxic (methyl chloroformate), simultaneously needs reactions with potential safety hazards such as catalytic hydrogenation and the like, has high cost of raw materials and equipment, and is not beneficial to industrial scale-up production.
Disclosure of Invention
Based on the method, the invention provides a synthetic method of the nitrogen-containing heterocyclic compound and the intermediate thereof, which has the advantages of short route, safe operation and low cost and is convenient for industrial scale-up production.
In a first aspect of the present invention, there is provided a method for synthesizing an intermediate of a nitrogen-containing heterocyclic compound, comprising the steps of:
carrying out photochemical reaction on the compound 1 and the compound 2 to prepare the intermediate;
the structure of compound 1 is shown below:
the structure of compound 2 is shown below:
the structure of the intermediate is shown as follows:
wherein, Y1、Y2、Y3、Y4、Y5Each independently is CH2Or NR, and at least one is NR; r represents a protecting group;
X1、X2each independently is halogen;
ar is C6-C10 aryl or C5-C10 heteroaryl;
R1、R2each independently of the others hydrogen, halogen, cyano, hydroxy, C1-C6 alkoxy or-S (O)2R3，R3Is C1-C6 alkyl.
In one embodiment, the light source used for the photochemical reaction is a blue light lamp with 8W-12W.
In one embodiment, the conditions of the photochemical reaction include: the reaction is carried out in the presence of a solvent, an organic iridium complex photocatalyst, a nickel reagent, a silicon reagent and a base.
In one embodiment, the solvent is selected from one or more of ethylene glycol dimethyl ether, acetonitrile, N-dimethylacetamide, and N, N-dimethylformamide; and/or the alkali is selected from one or more of sodium carbonate, potassium carbonate and lithium hydroxide; and/or
The silicon reagent is selected from one or more of triethylsilane, tri (trimethylsilyl) silane and triphenylsilane; and/or
The organic iridium complex photocatalyst is one or two of tris (2-phenylpyridine) iridium and [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridyl N ] phenyl-C ] iridium hexafluorophosphate (III); and/or
The nickel reagent is [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] nickel (II) dichloride.
In one embodiment, the conditions of the photochemical reaction include: reacting for 10 to 20 hours at the temperature of between 20 and 30 ℃.
In one embodiment, Y1、Y2、Y3、Y4、Y5Selected from one of the following groups:
(i)Y1is NR, Y2、Y3、Y4And Y5Is CH2；
(ii)Y2Is NR, Y1、Y3、Y4And Y5Is CH2；
(iii)Y4Is NR, Y1、Y2、Y3And Y5Is CH2；
(iv)Y1And Y3Is NR, Y4、Y2And Y5Is CH2。
In one embodiment, X1、X2is-Br.
In one embodiment, Ar has the structural features shown below:
wherein, Y6Each independently selected from CH or N.
In one embodiment, R1、R2Each independently is a hydroxyl group or a C1-C3 alkoxy group.
In a second aspect of the invention, there is provided a method for synthesizing a nitrogen-containing heterocyclic compound, comprising the steps of:
preparing said intermediate according to the synthetic method of the first aspect;
carrying out deprotection reaction on the intermediate to prepare the nitrogen-containing heterocyclic compound;
the structure of the nitrogen-containing heterocyclic compound is shown as follows:
wherein, Ar and R1And R2Is as defined in claim 1;
W1、W2、W3、W4、W5each independently is CH2Or NH, and at least one is NH.
In one embodiment, the deprotection reaction is carried out in the presence of an acid.
The synthesis method realizes the synthesis of the nitrogen-containing heterocyclic compound and the intermediate thereof by taking the compound 1 and the compound 2 with specific structures as initial raw materials and combining photochemical reaction. Meanwhile, the synthetic method has the advantages of short route, mild reaction conditions, no need of pressurization or adoption of controlled reagents, safe and simple operation, cheap and easily-obtained starting raw materials and convenience for industrial scale-up production.
Detailed Description
The synthesis method of the nitrogen-containing heterocyclic compound and the intermediate thereof according to the present invention will be described in further detail below with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
In the present invention, "first aspect", "second aspect", etc. are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or quantity, nor are they to be construed as implicitly indicating the importance or quantity of the technical features indicated. Also, "first," "second," etc. are used for non-exhaustive enumeration of description purposes only and should not be construed as constituting a closed limitation to the number.
In the present invention, the technical features described in the open type include a closed technical solution composed of the listed features, and also include an open technical solution including the listed features.
In the present invention, the numerical intervals are regarded as continuous, and include the minimum and maximum values of the range and each value between the minimum and maximum values, unless otherwise specified. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range-describing features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein.
In the present invention, the percentage content refers to both mass percentage for solid-liquid mixing and solid-solid phase mixing and volume percentage for liquid-liquid phase mixing, unless otherwise specified.
In the present invention, the percentage concentrations are, unless otherwise specified, the final concentrations. The final concentration refers to the ratio of the additive component in the system to which the component is added.
In the present invention, the temperature parameter is not particularly limited, and may be a constant temperature treatment or a treatment within a certain temperature range. The constant temperature process allows the temperature to fluctuate within the accuracy of the instrument control.
In the present invention, "halogen" means F, Cl, Br or I.
In the present invention, "aryl" means an aromatic hydrocarbon group derived by removing one hydrogen atom from an aromatic ring compound, and may be a monocyclic aryl group, or a condensed ring aryl group, or a polycyclic aryl group, at least one of which is an aromatic ring system for a polycyclic ring species. For example, "C6-C10 aryl" refers to aryl groups containing 6 to 10 carbon atoms, which at each occurrence, may be independently C6, C7, C8, C9, or C10 aryl. Suitable examples include, but are not limited to: benzene, biphenyl, naphthalene, anthracene, phenanthrene, perylene, triphenylene, and derivatives thereof.
In the present invention, "heteroaryl" means that at least one carbon atom is replaced with a non-carbon atom, which may be a N atom, an O atom, an S atom, or the like, in addition to an aryl group. For example, "C5-C10 heteroaryl" refers to heteroaryl groups containing 5 to 10 carbon atoms, which at each occurrence, may be independently of each other, C5 heteroaryl, C6 heteroaryl, C7 heteroaryl, C8 heteroaryl, C9 heteroaryl, or C10 heteroaryl. Suitable examples include, but are not limited to: furan, benzofuran, thiophene, benzothiophene, pyrrole, pyrazole, triazole, imidazole, oxazole, oxadiazole, thiazole, tetrazole, indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furopyrrole, furofuran, thienofuran, benzisoxazole, benzisothiazole, benzimidazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, quinoline, isoquinoline, phthalazine, quinoxaline, phenanthridine, primadine, quinazoline, and quinazolinone.
In the present invention, the term "alkyl" refers to a monovalent residue of a saturated hydrocarbon containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof, which has lost one hydrogen atom. Phrases encompassing this term, such as "C1-C6 alkyl" refer to alkyl groups containing 1 to 6 carbon atoms, which at each occurrence, may be independently C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl. Suitable examples include, but are not limited to: methyl (Me, -CH)3) Ethyl (Et, -CH)2CH3) 1-propyl (n-Pr, n-propyl, -CH)2CH2CH3) 2-propyl (i-Pr, i-propyl, -CH (CH)3)2) 1-butyl (n-Bu, n-butyl, -CH)2CH2CH2CH3) 2-methyl-1-propyl (i-Bu, i-butyl, -CH)2CH(CH3)2)、2-butyl (s-Bu, s-butyl, -CH (CH)3)CH2CH3) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH)3)3) 1-pentyl (n-pentyl, -CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH3) CH2CH2CH3), 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) 1-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3)。
In the present invention, "alkoxy" refers to a group of the structure-O-alkyl, i.e. an alkyl group as defined above is connected to an adjacent group via an oxygen atom. Phrases comprising this term, such as "C1-C6 alkoxy" refer to alkyl moieties containing 1 to 6 carbon atoms which, at each occurrence, may be independently C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy, C6 alkoxy. Suitable examples include, but are not limited to: methoxy (-O-CH)3or-OMe), ethoxy (-O-CH)2CH3or-OEt) and tert-butoxy(-O-C(CH3)3or-OtBu).
In the present invention, "-" denotes a connection site.
The invention provides a method for synthesizing an intermediate of a nitrogen-containing heterocyclic compound, which comprises the following steps:
carrying out photochemical reaction on the compound 1 and the compound 2 to prepare the intermediate;
the structure of compound 1 is shown below:
the structure of compound 2 is shown below:
the structure of the intermediate is shown as follows:
wherein, Y1、Y2、Y3、Y4、Y5Each independently is CH2Or NR, and at least one is NR; r represents a protecting group;
X1、X2each independently is halogen;
ar is C6-C10 aryl or C5-C10 heteroaryl;
R1、R2each independently of the others hydrogen, halogen, cyano, hydroxy, C1-C6 alkoxy or-S (O)2R3，R3Is C1-C6 alkyl.
In one specific example, the light source used for the photochemical reaction is a blue light lamp with 8W-12W. Specifically, the power of the light source used for the photochemical reaction includes, but is not limited to: 8W, 9W, 10W, 11W and 12W. It is understood that the blue light lamp refers to a lamp source emitting blue light, and the blue light refers to light with a wavelength of 480-500 nm. Specifically, the blue light lamp may be a blue LED lamp.
In one specific example, the distance between the blue light lamp and the reactant is 2cm to 5 cm.
In one specific example, the conditions of the photochemical reaction include: the reaction is carried out in the presence of a solvent, an organic iridium complex photocatalyst, a nickel reagent, a silicon reagent and a base.
Specifically, the solvent is selected from one or more of ethylene glycol dimethyl ether, acetonitrile, N-dimethylacetamide and N, N-dimethylformamide. Further, the solvent is ethylene glycol dimethyl ether.
Specifically, the base is selected from one or more of sodium carbonate, potassium carbonate and lithium hydroxide. Further, the base is sodium carbonate.
Specifically, the silicon reagent is selected from one or more of triethylsilane, tris (trimethylsilyl) silane, and triphenylsilane. Further, the silicon reagent is tris (trimethylsilyl) silane.
Specifically, the organic iridium complex photocatalyst is one or two selected from tris (2-phenylpyridine) iridium and iridium (III) hexafluorophosphate [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] (CAS: 870987-63-6). Further, the organic iridium complex photocatalyst is [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridyl N ] phenyl-C ] iridium (III) hexafluorophosphate.
Specifically, the nickel reagent is [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] nickel (II) dichloride.
In one specific example, the conditions of the photochemical reaction include: the method comprises the steps of taking ethylene glycol dimethyl ether as a solvent, and reacting in the presence of [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridyl N1, N1] bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridyl N ] phenyl-C ] iridium (III) hexafluorophosphate, [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridyl N1, N1] nickel (II) dichloride, tri (trimethylsilyl) silane and alkali.
In one specific example, the molar ratio of the compound 2 to the compound 1 is 1 (1-1.5).
In one specific example, the molar ratio of the compound 2, [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridinyl N ] phenyl-C ] iridium (III) hexafluorophosphate, [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] nickel (II) dichloride to tris (trimethylsilyl) silane is 1 (0.005-0.015): 0.01-0.02): 0.8-1.2.
In one specific example, the molar ratio of the compound 2 to the base is 1 (1.5-3).
In one specific example, the amount of ethylene glycol dimethyl ether is 5mL to 15mL per 1mmol of compound 2.
In one specific example, the conditions of the photochemical reaction include: reacting for 10 to 20 hours at the temperature of between 20 and 30 ℃. Specifically, the temperature of the photochemical reaction includes, but is not limited to: 20 ℃, 21 ℃, 22 ℃, 23 ℃,24 ℃, 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃ and 30 ℃. Specifically, the photochemical reaction time includes, but is not limited to: 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h and 20 h.
In addition, regarding the structure of compound 1:
it will be appreciated that R represents a protecting group, optionally an amino protecting group as is known in the art. In one specific example, R is t-butyloxycarbonyl (-BOC).
In one specific example, Y1、Y2、Y3、Y4、Y5Selected from one of the following groups:
(i)Y1is NR, Y2、Y3、Y4And Y5Is CH2；
(ii)Y2Is NR, Y1、Y3、Y4And Y5Is CH2；
(iii)Y4Is NR, Y1、Y2、Y3And Y5Is CH2；
(iv)Y1And Y3Is NR, Y4、Y2And Y5Is CH2。
Further, the air conditioner is provided with a fan,
has the following structural characteristics:
in one particular example, compound 1 is selected from the following compounds:
further, with respect to the structure of compound 2:
understandably, R1、R2And X2The position attached to Ar is not limited and may be ortho, meta or para.
In one specific example, X1、X2Each independently is-Cl, -Br or-I. Further, X1、X2is-Br.
In one specific example, Ar has the structural features shown below:
wherein, Y6Each independently selected from CH or N.
In one specific example, Ar is phenyl or pyridyl. Further, Ar is phenyl.
In one specific example, R1、R2Each independently of the other is hydrogen, -Cl, hydroxy, -C1-C3 alkoxy or-S (O)2R3，R3Is C1-C2 alkyl. Further, R1Is hydrogen, R2is-Cl, hydroxy, C1-C3 alkoxy or-S (O)2R3，R3Is C1-C2 alkyl.
In one specific example, R1、R2Each independently is a hydroxyl group or a C1-C3 alkoxy group.
In one particular example, compound 2 is selected from the following compounds:
in one particular example, the intermediate is selected from the following compounds:
the invention provides a synthetic method of a nitrogen-containing heterocyclic compound, which comprises the following steps:
the intermediates were prepared according to the synthetic methods described above
Carrying out deprotection reaction on the intermediate to prepare the nitrogen-containing heterocyclic compound
Wherein, Ar and R1And R2The definition of (1) is as above; w1、W2、W3、W4、W5Each independently is CH2Or NH, and at least one is NH. Understandably, W1、W2、W3、W4、W5And Y1、Y2、Y3、Y4、Y5And correspondingly.
In one specific example, the deprotection reaction is carried out in the presence of an acid.
In one specific example, the acid is hydrochloric acid. Further, the molar ratio of the acid to the intermediate is (50-340): 1. Furthermore, the molar ratio of the acid to the intermediate is (55-65): 1 or (330-340): 1.
In one specific example, the deprotection reaction conditions include: the temperature is 15-25 ℃, and the time is 0.5-2 h.
It will be appreciated that a co-solvent, such as dichloromethane, may suitably be added for the deprotection reaction.
In one specific example, the nitrogen-containing heterocyclic compound is selected from the following compounds:
specific examples are as follows.
EXAMPLE Synthesis of Compound 3A
Under nitrogen protection, tert-butyl 3-bromopiperidine-1-carboxylate (compound 1A) (896mg,3.40mmol,1.3eq), 4-bromochlorobenzene (compound 2A) (500mg,2.61mmol,1.00eq), [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridinyl N ] phenyl-C ] iridium (III) hexafluorophosphate (29.3mg,0.01eq), [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] nickel (II) dichloride (15.6mg,0.015eq), tris (trimethylsilyl) silane (650mg,1.00eq), sodium carbonate (554mg,2.00eq) and 26 ml of ethylene glycol dimethyl ether were added to a 40 ml reaction flask, a distance of 3 cm from the reaction flask was irradiated with a 10W blue LED lamp, and the mixture was stirred at 25 ℃ for 14 hours. After the reaction was complete as monitored by LCMS, the mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was isolated by preparative HPLC to give Compound 3A (320mg, 99.5% purity, 41.2% yield) as a yellow solid.
1H NMR:(400MHz,CDCl3)δ7.28(d,J＝8.8Hz,2H),7.16(d,J＝8.4Hz,2H),4.15-4.12(m,2H),2.77-2.65(m,3H),2.01-1.77(m,1H),1.76(dt,J＝2.9Hz,6.2Hz,1H),1.65-1.57(m,2H),1.48(s,9H)。
LC-MS:(M-55)+:240.0。
HPLC:99.5％purity(220nm,Rt＝3.081min)。
EXAMPLE Synthesis of Compound A1
A mixture of Compound 3A (20.0mg, 67.6. mu. mol,1.00eq) and hydrochloric acid/ethyl acetate (4M,1mL) was stirred at 15 ℃ for 2 hours. After the reaction was completed by LCMS monitoring, the reaction was concentrated to give Compound A1(15mg, 64.3. mu. mol, 99.5% pure, 95.1% yield) as a white solid.
1H NMR:(400MHz,DMSO-d6)δ9.08(br s,1H),7.41(d,J＝8.4Hz,2H),7.32(d,J＝8.4Hz,2H),,3.30-3.25(m,3H),3.03-2.98(m,2H),2.89-2.83(m,1H),1.88-1.65(m,4H)。
LC-MS:(M+H)+:196.2。
HPLC:99.5％purity(220nm,Rt＝2.306min)。
EXAMPLE three Synthesis of Compound 3B
Under nitrogen protection, tert-butyl 3-bromopiperidine-1-carboxylate (compound 1A) (68.4mg,0.260mmol,1.30eq), 4-bromochlorobenzene (compound 2B) (34.4mg,0.200mmol,1.00eq), [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridinn ] phenyl-C ] iridium (III) hexafluorophosphate (2.24mg,0.01eq), [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] nickel (II) dichloride (1.19mg,0.015eq), tris (trimethylsilyl) silane (49.7mg,1.00eq), sodium carbonate (42.4mg,2.00eq) and 2ml of ethylene glycol dimethyl ether were added to a 15ml reaction flask, a distance of 3 cm from the reaction flask was irradiated with a 10W blue LED lamp, and the mixture was stirred at 25 ℃ for 14 hours. After the reaction was complete as monitored by LCMS, the mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was isolated by preparative HPLC to give Compound 3B (25mg, 97.3% purity, 45.1% yield) as a white solid.
H NMR:(400MHz,CDCl3)δ9.21(s,1H),7.03(d,J＝8.4Hz,2H),6.68(d,J＝8.4Hz,2H),3.96-3.88(m,2H),2.66-2.52(m,3H),1.82(d,J＝12.4Hz,1H),1.70-1.65(m,1H),1.59-1.50(m,1H),1.46-1.43(m,1H),1.39(s,9H)。
LC-MS:(M-55)+:222.0。
HPLC:97.3％purity(220nm,Rt＝1.815min)。
Example Synthesis of Tetracompound A2
A mixture of Compound 3B (20.0mg, 72.1. mu. mol,1.00eq) and hydrochloric acid/ethyl acetate (4M,1mL) was stirred at 15 ℃ for 2 hours. After the reaction was completed by LCMS monitoring, the reaction was concentrated to give Compound A2(15mg, 69.0. mu. mol, 98.3% purity, 95.7% yield) as a white solid.
1H NMR:(400MHz,DMSO-d6)δ9.37(s,1H),9.03(br s,1H),7.05(d,J＝8.4Hz,2H),7.72(d,J＝8.4Hz,2H),3.26-3.18(m,2H),2.92-2.81(m,3H),1.86-1.57(m,4H)。
LC-MS:(M+H)+:178.2。
HPLC:98.3％purity(220nm,Rt＝1.162min)。
EXAMPLE five Synthesis of Compound 3C
Under nitrogen protection, tert-butyl 3-bromopiperidine-1-carboxylate (compound 1A) (68.4mg,0.260mmol,1.30eq), 4-bromochlorobenzene (compound 2C) (38.0mg,0.200mmol,1.00eq), [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridinyl N ] phenyl-C ] iridium (III) hexafluorophosphate (2.24mg,0.01eq), [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] nickel (II) dichloride (1.19mg,0.015eq), tris (trimethylsilyl) silane (49.7mg,1.00eq), sodium carbonate (42.4mg,2.00eq) and 2ml of ethylene glycol dimethyl ether were added to a 15ml reaction flask, a distance of 3 cm from the reaction flask was irradiated with a 10W blue LED lamp, and the mixture was stirred at 25 ℃ for 14 hours. After the reaction was complete as monitored by LCMS, the mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was isolated by preparative HPLC to give Compound 3C (22mg, 98.8% purity, 37.3% yield) as a white solid.
1H NMR:(400MHz,CDCl3)δ7.25-7.20(m,3H),7.10(d,J＝7.2Hz,1H),4.18-4.11(m,2H),2.78-2.65(m,3H),2.03-2.00(m,1H),1.78-1.74(m,1H),1.63-1.57(m,2H),1.48(s,9H)。
LC-MS:(M-55)+:240.0。
HPLC:98.8％purity(220nm,Rt＝3.015min)。
Example Synthesis of hexacompound A3
A mixture of Compound 3C (20.0mg, 67.6. mu. mol,1.00eq) and hydrochloric acid/ethyl acetate (4M,1mL) was stirred at 15 ℃ for 2 hours. After the reaction was completed by LCMS monitoring, the reaction was concentrated to give Compound A3(15mg, 69.0. mu. mol, 98.6% purity, 95.7% yield) as a pink oil.
1H NMR:(400MHz,DMSO-d6)δ8.87(br s,1H),7.40(s,1H),7.37(d,J＝7.6Hz,1H),7.34-7.32(m,1H),7.27-7.25(m,1H),3.29-3.09(m,3H),3.06(t,J＝12.4Hz,1H),2.97(t,J＝11.2Hz,1H),2.87(t,J＝12.4Hz,1H),1.88(d,J＝11.6Hz,2H),1.77-1.67(m,2H)。
LC-MS:(M+H)+:196.1。
HPLC:98.6％purity(220nm,Rt＝2.223min)。
EXAMPLE Synthesis of 3D Compound
Under nitrogen protection, tert-butyl 3-bromopiperidine-1-carboxylate (compound 1A) (68.6mg,0.260mmol,1.30eq), 4-bromobenezene sulfone (compound 2D) (47.0mg,0.200mmol,1.00eq), [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridyl N ] phenyl-C ] iridium (III) hexafluorophosphate (2.24mg,0.01eq), [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] nickel (II) (1.19mg,0.015eq), tris (trimethylsilyl) silane (49.7mg,1.00eq), sodium carbonate (42.4mg,2.00eq) and 2ml of ethylene glycol dimethyl ether were added to a 15ml reaction flask, a distance of 3 cm from the reaction flask was irradiated with a 10W blue LED lamp, and the mixture was stirred at 25 ℃ for 14 hours. After the reaction was complete as monitored by LCMS, the mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was isolated by preparative HPLC to give compound 3D as a pale yellow oil (10mg, 24.3. mu. mol, 95.8% purity, 12.1% yield).
1H NMR:(400MHz,CDCl3)δ7.89(d,J＝8.2Hz,2H),7.44(d,J＝8.4Hz,2H),4.38-3.98(m,2H),3.06(s,3H),2.79(s,3H),2.04(d,J＝12.0Hz,1H),1.83-1.74(m,1H),1.72-1.61(m,2H),1.48(s,9H)。
LC-MS:(M-55)+:284.0。
HPLC:95.8％purity(220nm,Rt＝3.051min)。
EXAMPLE Synthesis of Compound A4
A mixture of Compound 3D (8.00mg, 19.4. mu. mol,1.00eq) and hydrochloric acid/dioxane (4M,2mL) was stirred at 25 ℃ for 0.5 hour. After the reaction was completed by LCMS monitoring, the reaction was concentrated to give Compound A4(5mg, 17.7. mu. mol, 97.88% purity, 91.27% yield) as a white solid.
1H NMR:(400MHz,DMSO-d6)δ9.29-9.12(m,1H),9.06-8.85(m,1H),7.91(d,J＝8.4Hz,2H),7.59(d,J＝8.4Hz,2H),3.32-3.27(m,2H),3.21(s,3H),3.14-3.06(m,2H),2.96-2.83(m,1H),1.93-1.71(m,4H)。
LC-MS:(M+1)+:240.1。
HPLC:97.8％purity(220nm,Rt＝0.856min)。
EXAMPLE nine Synthesis of Compound 3E
Under nitrogen protection, tert-butyl 3-bromopiperidine-1-carboxylate (compound 1A) (827mg,3.14mmol,1.30eq), p-bromoanisole (compound 2E) (450mg,2.42mmol.1.00eq), [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridinyl N ] phenyl-C ] iridium (III) hexafluorophosphate (27.2mg,0.01eq), [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] nickel (II) (14.4mg,0.015eq), tris (trimethylsilyl) silane (602mg,1.00eq), sodium carbonate (513mg,2.00eq) and 24 ml of ethylene glycol dimethyl ether were added to a 40 ml reaction flask, a distance of 3 cm from the reaction flask was irradiated with a 10W blue LED lamp, and the mixture was stirred at 25 ℃ for 14 hours. After the reaction was complete as monitored by LCMS, the mixture was filtered and the filtrate was concentrated to give the crude product. The crude product was isolated by preparative HPLC to give compound 3E (450mg,1.54mmol, 100% purity, 45.0% yield) as a white solid.
1H NMR:(400MHz,CDCl3)δ7.16(d,J＝8.8Hz,2H),6.86(d,J＝8.4Hz,2H),4.15(br s,2H),3.80(s,3H),2.74-2.63(m,3H),2.01-1.98(m,1H),1.76-1.74(m,1H),1.61-1.56(m,2H),1.47(s,9H)。
LC-MS:(M-55)+:236.2。
HPLC:100％purity(220nm,Rt＝2.452min)。
EXAMPLE Synthesis of Compound A5
A mixture of Compound 3E (20.0mg, 68.6. mu. mol,1.00eq) and hydrochloric acid/ethyl acetate (4M,1mL) was stirred at 15 ℃ for 0.5 hour. After the reaction was completed by LCMS monitoring, the reaction was concentrated to give Compound A5(15.0mg,65.0umol, 98.7% write, 94.7% yield) as a yellow solid.
1H NMR:(400MHz,DMSO-d6)δ8.91(br s,1H),8.65(br s,1H),7.19(d,J＝8.8Hz,2H),6.90(d,J＝8.8Hz,2H),3.73(s,3H),3.26(t,J＝10.8Hz,2H),2.97-2.85(m,3H),1.85(t,J＝13.2Hz,2H),1.76-1.67(m,2H)。
LC-MS:(M+H)+:192.2。
HPLC:98.7％purity(220nm,Rt＝1.064min)。
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, so as to understand the technical solutions of the present invention specifically and in detail, but not to be understood as the limitation of the protection scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. It should be understood that the technical solutions provided by the present invention, which are obtained by logical analysis, reasoning or limited experiments, are within the scope of the appended claims. Therefore, the protection scope of the patent of the invention is subject to the content of the appended claims, and the description can be used for explaining the content of the claims.
Claims (11)
1. A method for synthesizing an intermediate of a nitrogen-containing heterocyclic compound is characterized by comprising the following steps:
carrying out photochemical reaction on the compound 1 and the compound 2 to prepare the intermediate;
the structure of compound 1 is shown below:
the structure of compound 2 is shown below:
the structure of the intermediate is shown as follows:
wherein, Y1、Y2、Y3、Y4、Y5Each independently is CH2Or NR, and at least one is NR; r represents a protecting group;
X1、X2each independently is halogen;
ar is C6-C10 aryl or C5-C10 heteroaryl;
R1、R2each independently of the others hydrogen, halogen, cyano, hydroxy, C1-C6 alkoxy or-S (O)2R3，R3Is C1-C6 alkyl.
2. The method for synthesizing an intermediate of a nitrogen-containing heterocyclic compound according to claim 1, wherein a light source used for the photochemical reaction is a blue light lamp of 8W to 12W.
3. The method of claim 1, wherein the photochemical reaction conditions comprise: the reaction is carried out in the presence of a solvent, an organic iridium complex photocatalyst, a nickel reagent, a silicon reagent and a base.
4. The method for synthesizing an intermediate of a nitrogen-containing heterocyclic compound according to claim 3, wherein the solvent is one or more selected from the group consisting of ethylene glycol dimethyl ether, acetonitrile, N-dimethylacetamide and N, N-dimethylformamide; and/or the alkali is selected from one or more of sodium carbonate, potassium carbonate and lithium hydroxide; and/or
The silicon reagent is selected from one or more of triethylsilane, tri (trimethylsilyl) silane and triphenylsilane; and/or
The organic iridium complex photocatalyst is one or two selected from iridium tris (2-phenylpyridine) and iridium [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] bis [3, 5-difluoro-2- [5- (trifluoromethyl) -2-pyridyl N ] phenyl-C ] hexafluorophosphate (III); and/or
The nickel reagent is [4,4 '-bis (1, 1-dimethylethyl) -2, 2' -bipyridine N1, N1] nickel (II) dichloride.
5. The method of claim 1, wherein the photochemical reaction conditions comprise: reacting for 10 to 20 hours at the temperature of between 20 and 30 ℃.
6. The method for synthesizing an intermediate of a nitrogen-containing heterocyclic compound according to any one of claims 1 to 5, wherein Y is1、Y2、Y3、Y4、Y5Selected from one of the following groups:
(i)Y1is NR, Y2、Y3、Y4And Y5Is CH2；
(ii)Y2Is NR, Y1、Y3、Y4And Y5Is CH2；
(iii)Y4Is NR, Y1、Y2、Y3And Y5Is CH2；
(iv)Y1And Y3Is NR, Y4、Y2And Y5Is CH2。
7. The method for synthesizing an intermediate of a nitrogen-containing heterocyclic compound according to any one of claims 1 to 5, wherein X is1、X2is-Br.
8. The method for synthesizing an intermediate of a nitrogen-containing heterocyclic compound according to any one of claims 1 to 5, wherein Ar has the structural characteristics shown as follows:
wherein, Y6Each independently selected from CH or N.
9. The method for synthesizing an intermediate of a nitrogen-containing heterocyclic compound according to any one of claims 1 to 5, wherein R is1、R2Each independently is a hydroxyl group or a C1-C3 alkoxy group.
10. A synthetic method of a nitrogen-containing heterocyclic compound is characterized by comprising the following steps:
preparing said intermediate according to the synthetic method of any one of claims 1 to 9;
carrying out deprotection reaction on the intermediate to prepare the nitrogen-containing heterocyclic compound;
the structure of the nitrogen-containing heterocyclic compound is shown as follows:
wherein, Ar and R1And R2Is as defined in claim 1;
W1、W2、W3、W4、W5each independently is CH2Or NH, and at least one is NH.
11. The method of claim 10, wherein the deprotection reaction is carried out in the presence of an acid.
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| US5250731A (en) * | 1992-03-17 | 1993-10-05 | E. I. Du Pont De Nemours And Company | Preparation of optically active hydrazines and amines |
| CN112218863A (en) * | 2018-03-14 | 2021-01-12 | 比奥根Ma公司 | O-glycoprotein-2-acetamido-2-deoxy-3-D-pyranosidase inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5250731A (en) * | 1992-03-17 | 1993-10-05 | E. I. Du Pont De Nemours And Company | Preparation of optically active hydrazines and amines |
| CN112218863A (en) * | 2018-03-14 | 2021-01-12 | 比奥根Ma公司 | O-glycoprotein-2-acetamido-2-deoxy-3-D-pyranosidase inhibitors |
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