CN110041334B - Preparation method of aminophenol compound - Google Patents
Preparation method of aminophenol compound Download PDFInfo
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- CN110041334B CN110041334B CN201910030672.XA CN201910030672A CN110041334B CN 110041334 B CN110041334 B CN 110041334B CN 201910030672 A CN201910030672 A CN 201910030672A CN 110041334 B CN110041334 B CN 110041334B
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- -1 aminophenol compound Chemical class 0.000 title claims abstract description 73
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000007800 oxidant agent Substances 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 66
- 125000000217 alkyl group Chemical group 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 22
- 239000000126 substance Substances 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 239000012973 diazabicyclooctane Substances 0.000 claims description 2
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 229910021516 thallium(I) hydroxide Inorganic materials 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical group CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 4
- OILAIQUEIWYQPH-UHFFFAOYSA-N cyclohexane-1,2-dione Chemical compound O=C1CCCCC1=O OILAIQUEIWYQPH-UHFFFAOYSA-N 0.000 abstract description 3
- 230000001590 oxidative effect Effects 0.000 abstract description 3
- 230000009471 action Effects 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 125000001072 heteroaryl group Chemical group 0.000 description 19
- 125000000623 heterocyclic group Chemical group 0.000 description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 125000003118 aryl group Chemical group 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [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 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 125000006413 ring segment Chemical group 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical class NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 5
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 150000007942 carboxylates Chemical class 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000003282 alkyl amino group Chemical group 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 description 4
- 125000005366 cycloalkylthio group Chemical group 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 125000003226 pyrazolyl group Chemical group 0.000 description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 3
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 2
- 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 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- 125000005916 2-methylpentyl group Chemical group 0.000 description 2
- 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 2
- 125000005917 3-methylpentyl group Chemical group 0.000 description 2
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 description 2
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [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 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- 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 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RVWUHFFPEOKYLB-UHFFFAOYSA-N 2,2,6,6-tetramethyl-1-oxidopiperidin-1-ium Chemical compound CC1(C)CCCC(C)(C)[NH+]1[O-] RVWUHFFPEOKYLB-UHFFFAOYSA-N 0.000 description 1
- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003764 2,4-dimethylpentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004337 3-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- ADLVDYMTBOSDFE-UHFFFAOYSA-N 5-chloro-6-nitroisoindole-1,3-dione Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC2=C1C(=O)NC2=O ADLVDYMTBOSDFE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 101710120843 Indoleamine 2,3-dioxygenase 1 Proteins 0.000 description 1
- 229910019093 NaOCl Inorganic materials 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 125000004431 deuterium atom Chemical group 0.000 description 1
- XXECWTBMGGXMKP-UHFFFAOYSA-L dichloronickel;2-diphenylphosphanylethyl(diphenyl)phosphane Chemical compound Cl[Ni]Cl.C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 XXECWTBMGGXMKP-UHFFFAOYSA-L 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005047 dihydroimidazolyl group Chemical group N1(CNC=C1)* 0.000 description 1
- 125000005052 dihydropyrazolyl group Chemical group N1(NCC=C1)* 0.000 description 1
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- DZFYOYRNBGNPJW-UHFFFAOYSA-N ethoxythallium Chemical compound [Tl+].CC[O-] DZFYOYRNBGNPJW-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000002638 heterogeneous catalyst Substances 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- YOCBOYPGZVFUCQ-UHFFFAOYSA-L nickel(2+);tricyclohexylphosphane;dichloride Chemical compound Cl[Ni]Cl.C1CCCCC1P(C1CCCCC1)C1CCCCC1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 YOCBOYPGZVFUCQ-UHFFFAOYSA-L 0.000 description 1
- ZBRJXVVKPBZPAN-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dichloride Chemical compound [Cl-].[Cl-].[Ni+2].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 ZBRJXVVKPBZPAN-UHFFFAOYSA-L 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- WXHIJDCHNDBCNY-UHFFFAOYSA-N palladium dihydride Chemical compound [PdH2] WXHIJDCHNDBCNY-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010526 radical polymerization reaction Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of an aminophenol compound. Specifically, the amino compound and cyclohexanedione are used for preparing the aminophenol compound under the action of an oxidant TEMPO, so that the preparation method is high in reaction yield, high in product purity, easy to purify and beneficial to industrial production.
Description
Technical Field
The invention belongs to the field of medicines, and relates to a preparation method of an aminophenol compound.
Background
Aminophenol compounds are an important class of chemical substances and can be used as intermediates for the preparation of pharmaceutically active substances and the like.
In the prior art, a plurality of methods for preparing aminophenol compounds exist, but most of the methods are not suitable for industrial production due to low reaction yield, complex treatment after reaction, difficult separation and purification and the like. For example, CN1938261A discloses a method for preparing aminophenol compounds, comprising reacting a cyclohexanedione compound with an amine compound under neutral or basic conditions, and in the presence or absence of a dehydrogenation reagent.
The aminophenol compounds can be used for preparing various active substances, such as antitumor drugs. Wherein the IDO (Indoleamine-pyrrole-2, 3-dioxygenase, indolamine-pyrorol-2, 3-dioxygenase) inhibitor is an antitumor drug with wide application prospect. A large number of studies at present show that IDO is highly expressed in leukemia cells, so that local T cell proliferation is inhibited, T-cell mediated immune reaction is inhibited, T-cell activation signal transduction is inhibited, and the attack of tumor cells escaping from an immune system is mediated. WO2016169421 discloses a novel IDO inhibitor having a compound structure represented by formula (I) which exhibits excellent IDO inhibitory effect. The existing preparation method of the compound I has low yield, and the product of multi-step reaction needs to be purified by column chromatography, so that the cost is high, the operation is complex, the amplification is difficult, and the industrial production is severely limited.
PCT/CN2018/095371 (application No. 2018.07.12) describes a novel process for the preparation of compounds of formula I,
in the reaction route, the imidazoisoindolylaminophenol A is an important intermediate, and the quality of the intermediate directly influences the preparation and purification difficulty of subsequent products. The preparation method mainly comprises the step of reacting an amino compound with cyclohexanedione in the presence of oxygen, and has the disadvantages of incomplete reaction, low yield, poor product purity and great difficulty in purifying subsequent products.
2,2,6, 6-tetramethyl piperidine oxide (hereinafter referred to as TEMPO) is a stable nitroxide radical and has wide application in the fields of chemistry, biology, food industry, agriculture and the like. It can be used as reversible end-capping agent for free radical polymerization, and can also be used as heterogeneous catalyst for oxidation reaction of various alcohols and polyols. TEMPO is also an important oxidation catalyst, used in some specific chemical reactions, such as the oxidation of primary alcohols to aldehydes, with high selectivity, without further oxidation of the reaction to organic acids; oxidizing the secondary alcohol to a ketone; can also be used for preparing optically active alpha-amino aldehyde.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a novel preparation method of an aminophenol compound.
The invention provides a preparation method of a compound shown as a formula II, which comprises the step of reacting a compound shown as a formula III with a compound shown as a formula IV in the presence of TEMPO,
wherein R is1And R2The same or different, each of which is independently selected from the group consisting of hydrogen atom, alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally substituted with one or more substituents selected from the group consisting of alkyl group, halogen group, hydroxy group, amino group, nitro group, cyano group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; or,
R1and R2Together with the adjacent nitrogen atom form a 5-or 6-membered heterocyclic ring, preferably pyrrolidinyl, piperidinyl, or piperazinyl, optionally substituted with 1-3R3Substituted;
R3the same or different, and each is independently selected from the group consisting of alkyl, halo, hydroxy, amino, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, and fused ring groups, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and fused ring groups are optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, amino, nitro, cyano, and alkoxy,
wherein the condensed ring group is formed by condensing a group selected from cycloalkyl, heterocyclyl, aryl and heteroaryl with 1-2 groups independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl. For example, the compound may be a fused product of a 5-or 6-membered heteroaryl group, a 5-or 6-membered heterocyclic group and 1 to 2 members independently selected from a phenyl group, a 5-or 6-membered heteroaryl group, and a 5-or 6-membered heterocyclic group, and the 5-or 6-membered heteroaryl group and the heterocyclic group are preferably nitrogen-containing heteroaryl groups and heterocyclic groups.
In certain embodiments, the compound of formula II is
The compound of formula III is
The compound of formula IV is
Wherein n is an integer of 0, 1,2 or 3.
In certain embodiments, the compound of formula II is
The compound of formula III is
The compound of formula IV is
Wherein R is4The same or different and each is independently selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
m is an integer of 0, 1,2, 3 or 4.
In certain embodiments, the compound of formula II is
The compound of formula III is
The compound of formula IV is
In certain preferred embodiments, the compound of formula II is
The compound of formula III is
The molar ratio of the compound shown in the formula III to TEMPO can be 1: 0.1-1: 7, and preferably 1: 1.2-1: 3.
The molar ratio of the compound shown in the formula III to the compound shown in the formula IV can be 1: 0.7-1: 100, and preferably 1: 2-1: 4.
The solvent for the reaction may be a conventional solvent, and for example, may be one or more of dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, methyltetrahydrofuran, dioxane, toluene, xylene, dimethyl sulfoxide, diethyl ether, isopropyl ether, methyl tert-butyl ether, acetonitrile, propionitrile, isopropanol, propanol, ethanol, methanol, and water.
The reaction temperature may be from 0 ℃ to 200 ℃, preferably from 20 ℃ to 100 ℃.
In certain embodiments, other oxidizing agents besides TEMPO may also be present in the reaction to facilitate the reaction. The other oxidant may be, for example, oxygen, NaOCl, t-BuOCl, CuCl, or the like.
In certain embodiments, TEMPO can be added to the reaction system all at once, or in multiple portions, such as two, three, or four portions.
In another aspect, the present invention provides a method for preparing a compound represented by formula I or a pharmaceutically acceptable salt thereof, comprising the step of preparing a compound represented by formula II by the method of the present invention.
Further, the preparation method of the compound shown in the formula I or the pharmaceutically acceptable salt thereof further comprises the step of preparing the compound shown in the formula V by using the compound shown in the formula II as a reactant.
Wherein X is a leaving group selected from the group consisting of-Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methylsulfonyloxy, p-toluenesulfonyloxy, phenylsulfonyloxy, acetoxy or phosphate, -SR, -SO2R, R are C1~C6An alkyl group; x is preferably-Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy, p-toluenesulfonyloxy or benzenesulfonyloxy.
Further, the method also comprises the step of carrying out coupling reaction on the compound shown in the formula V and the compound shown in the formula VI in the presence of a catalyst to prepare the compound shown in the formula VII.
Wherein X may be selected from the group consisting of-Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, p-toluenesulfonyloxy, benzenesulfonyloxy, acetoxy or phosphate, -SR, -SO2R, R are C1~C6An alkyl group; x is preferably-Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy, p-toluenesulfonyloxy or benzenesulfonyloxy;
y may be selected from-BF3K、-BRaRb、-Sn(Rc)qor-Zn-X';
Raand RbIndependently selected from-OH, alkyl, alkoxy or optionally substituted C1~C6Monohydric and dihydric alcohols, or RaAnd RbForm a ring together, RcIndependently selected from C1~C6Alkyl, X' is selected from-Cl、-Br、-I;
q is an integer of 0, 1,2, 3 or 4;
R5selected from hydrogen or hydroxyl protecting groups.
In certain preferred embodiments, Y is selected from BF3K and BRaRbThe BRaRbIn RaAnd RbIndependently selected from-OH, alkyl, alkoxy, or BRaRbIs pinacol boronate, i.e.
The catalyst may comprise PdLp、PdCl2Lp、Pd(OAc)2Lp、Pd2(dba)3Lp、Pd(II)Lp、Pd(0)、NiCl2Lp、Ni(COD)2Lp、NiCl2(NEt3)2Or NiCl2(bipy) wherein L is a phosphine-containing ligand, which may be PPh, or an N-heterocyclic carbene ligand3、dppf、PCy3、tBu3P、P(OMe)3Dppe or dppb, p is independently an integer selected from 0, 1,2, 3 or 4.
For example, the catalyst may be Pd (PPh)3)2Cl2、Pd(PPh3)4、Pd(dppf)Cl2Pd/C, Pd (OAc)2、PCy3/Pd2(dba)3、NiCl2(dppf)、NiCl2(PPh3)2、Ni{P(OMe)3}2Cl2、NiCl2(PCy3)2、NiCl2(dppe),NiCl2(dppb),NiCl2(NEt3)2、NiCl2(bipy)、NiCl2·6H2O、NiCl2Or Ni (COD)2Pd (PPh) is preferred3)2Cl2、Pd(PPh3)4、Pd(dppf)Cl2Pd/C, Pd (OAc)2、PCy3/Pd2(dba)3More preferably Pd (PPh)3)2Cl2。
In certain embodiments, the reaction is carried out in the presence of an alkaline substance, preferably Na2CO3,Ba(OH)2、K3PO4、Cs2CO3、K2CO3、TlOH、KF、CsF、Bu4F. One or more of NaOH, KOH, triethylamine, DIPEA, DABCO, NaOR, KOR and TlOR, wherein R is independently selected from C1~C6An alkyl group. Wherein NaOR, KOR or TlOR may be NaOMe, NaOEt, KOtBu or TlOEt, for example. The alkaline substance is more preferably Na2CO3Or K2CO3One or more of (a).
The solvent for the reaction may be a conventional solvent, and for example, may be one or more of dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, dioxane, toluene, dimethylsulfoxide, acetonitrile, propionitrile, isopropanol, ethanol, water, preferably one or more of dimethylformamide, dioxane, water, more preferably a combination of dioxane and water.
In certain embodiments, R5Is a hydroxyl protecting group. The preparation method also comprises the step of removing the hydroxyl protecting group of the compound shown in the formula VII.
According to the invention, the amino compound and cyclohexanedione are used for preparing the aminophenol compound under the action of the oxidizing agent TEMPO, the reaction is complete, the reaction yield is high, the reaction conditions are mild, the prepared aminophenol compound has excellent purity, and the purification operation is greatly simplified.
When the method disclosed by the invention is applied to the preparation of the compound intermediate shown in the formula I, the prepared aminophenol intermediate is high in yield and purity, so that the subsequent reaction does not need complicated and time-consuming purification steps such as column passing and the like, the post-treatment process is simplified, the production efficiency is greatly improved, and the method is more suitable for industrial production.
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, with piperidinyl, pyrrolidinyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl.
The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate, preferably phenyl.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably imidazolyl, pyrazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl or thiazolyl.
Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
The term "fused ring group" means a group formed by fusing a group selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl with 1 to 2 groups independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, and non-limiting examples thereof include:
the term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
The term "haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.
The term "deuterated alkyl" refers to an alkyl group substituted with a deuterium atom, wherein alkyl is as defined above.
The term "hydroxy" refers to an-OH group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to the group-NH2。
The term "cyano" refers to — CN.
The term "nitro" means-NO2。
The term "carboxy" refers to-C (O) OH.
The term "aldehyde" refers to — CHO.
The term "carboxylate" refers to-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
The term "acyl halide" refers to a compound containing a group that is-C (O) -halogen.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
Detailed Description
The present invention will be explained in detail with reference to specific examples below, so that those skilled in the art can more fully understand the specific examples of the present invention to illustrate the technical solutions of the present invention, and not to limit the present invention in any way.
Example 1
Compound a (177g, 0.495mol, prepared according to the disclosure of WO 2016169421) was dissolved in 1.5L dichloromethane, 300mL 1, 4-dioxane was added, concentrated hydrochloric acid (412mL, 4.95mol) was added dropwise with cooling in an ice water bath, warmed to room temperature, and the reaction was stirred for 2 hours. After completion of the reaction, 600mL of water was added to the reaction mixture, and the aqueous phase was separated by extraction. Dissolving sodium hydroxide (215g, 5.38mol) in 215mL of water, slowly dropping the water phase into the water phase, adjusting the pH value to 8-9, extracting the water phase with dichloromethane, combining organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 144.8g of a compound b, wherein the product is directly subjected to the next reaction without purification.
Example 2
128.6g of compound b were subjected to chiral preparation (separation conditions: chiral preparation column Superchiral S-AY (Chiralway),2cm I.D.. times.25 cm Length,5 um; mobile phase: CO2EtOH/DEA 60/40/0.05(v/v/v), flow rate: 50g/min), collecting target components, in the process, preparing a column without blockage, and concentrating under reduced pressure to obtain a compound b' 55g, wherein the optical purity is as follows: 99.4%, chemical purity: 99.2 percent.
Example 3
Dissolving compounds b' (77.3g, 300mmol) and c (100.9g, 900mmol) in 1150mL of ethanol, heating to 60 ℃, adding TEMPO (93.75g, 600mmol) in batches into the reaction system, stirring for reaction for 12 hours, cooling the reaction liquid to 0-10 ℃, stirring for 1 hour, filtering, leaching the filter cake with methyl tert-butyl ether, collecting the filter cake, and drying in vacuum to obtain compound d (141.6g, off-white solid), yield: 67.5% and 97% chemical purity.
Example 4
Compound d (141.6g, 405mol) was dissolved in 2.8L of dichloromethane. The temperature is reduced to 0 ℃, pyridine (160.2g, 2025mmol) is added, and Tf is added dropwise2O (148.5g, 526mmol), and the reaction was stirred for 1 hour with heat preservation. After the reaction is finished, adding 2L of water into the reaction solution, adjusting the pH value to 2-3 by using 1M hydrochloric acid, standing for layering, separating an organic phase, extracting a water phase by using dichloromethane, combining the organic phase, drying over anhydrous magnesium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a compound e (195g, brown foamy solid) with chemical purity: 97.99 percent, and the product is directly subjected to the next reaction without purification.
Example 5
Compound e (65g, 135mmol) and compound f (64.3g, 270mmol, prepared as disclosed in CN 105189461A) were dissolved in 1300mL of a mixed solvent of 1, 4-dioxane and water (V: V ═ 5:1), and sodium carbonate (42.9g, 405mmol) and Pd (dppf) Cl were added in that order2(9.9g, 13.5mmol), heated to reflux under argon and stirred for 3 hours. After the reaction, the reaction solution was cooled to room temperature, 325mL of water was added, the mixture was stirred at room temperature for 30min, filtered, the filter cake was rinsed with water, the filter cake was collected, dispersed with 1.2L of methanol, concentrated hydrochloric acid (34mL) was added, stirred for 30min, concentrated to remove methanol, 1.8L of water was added, stirred for 30min, filtered, the solid was rinsed with water, the aqueous phases were combined, back-extracted with ethyl acetate (600 mL. times.2), the aqueous phase was collected, saturated NaHCO was used for the extraction, and the resulting mixture was concentrated in vacuo3Adjusting the pH value of the solution to be alkaline, separating out a solid, filtering to obtain a solid, washing with water, and drying in vacuum to obtain 41g of a compound I, wherein the yield is 68.5%, and the chemical purity is as follows: 98.6%, optical purity: 99.8 percent.
Comparative example
First step of
Compound b' (75g, 292mmol) prepared according to example 2 was dissolved in 2L ethanol, compound C (49.1g, 438mmol) and 10% Pd/C7.5 g were added sequentially, the temperature was raised to 75 deg.C, air was introduced, and the reaction was stirred for 28 hours. After the reaction is finished, filtering to remove Pd/C, leaching a filter cake with methanol, concentrating the filtrate under reduced pressure, adding 500mL of ethanol into the residue to dissolve, adding 2.5L of methyl tert-butyl ether, stirring to separate out a solid, filtering, collecting the filter cake, and drying to obtain 54.1g of a compound d, yield: 53%, chemical purity: 89.8 percent.
Second step of
Compound d (54.1g, 0.155mol) was dissolved in 700mL of dichloromethane. Cooling to 0 deg.C, adding pyridine (61.3g, 0.775mol), and adding Tf dropwise2O (56.8g, 0.201 mol). The reaction mixture was warmed to room temperature and stirred for 1 hour. After the reaction is finished, adding 60mL of water into the reaction solution, adjusting the pH value to 2 by using 1M hydrochloric acid, standing for layering, separating an organic phase, extracting a water phase by using dichloromethane, and combining the organic phaseThe phases were dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography (eluent: DCM: MeOH ═ 10:1) to give compound e 41g, yield: 55%, chemical purity: 92.76 percent.
The third step
Compound e (41g, 85mmol) and compound f (40.5g, 170mmol) were dissolved in 820mL of a mixed solvent of 1, 4-dioxane and water (V: V ═ 5:1), and sodium carbonate (27g, 255mmol) and pd (dppf) Cl were added in this order2(6.2g, 8.5mmol), heated to reflux under argon, and stirred for reaction for 3 hours. After the reaction is finished, cooling the reaction liquid to room temperature, adding 200mL of water, stirring at room temperature for 30min, filtering, leaching the filter cake with water, collecting the filter cake, dispersing with 750mL of methanol, adding concentrated hydrochloric acid (22mL), stirring for 30min, concentrating to remove methanol, adding 1.2L of water, stirring for 30min, filtering, leaching the solid with water, combining the water phases, back extracting with ethyl acetate (400mL multiplied by 2), collecting the water phase, and using saturated NaHCO to perform back extraction on the water phase and the solid phase3Adjusting the pH value of the solution to be alkaline, separating out a solid, filtering to obtain a solid, washing with water, and drying in vacuum to obtain 29.3g of a compound I, wherein the yield is 66%, and the chemical purity is as follows: 95.1%, optical purity: 99.7 percent.
Since the invention has been described in terms of specific embodiments thereof, certain modifications and equivalent variations will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Claims (10)
1. A process for the preparation of a compound of formula II comprising the step of reacting a compound of formula III with a compound of formula IV in the presence of TEMPO,
the compound of formula II is
The compound of formula III is
The compound of formula IV is
Wherein R is4Are the same or different and are each independently selected from the group consisting of lower alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, halogen, amino, nitro, hydroxy, cyano;
m is an integer of 0, 1,2, 3 or 4;
the molar ratio of the compound shown in the formula III to TEMPO is 1: 0.1-1: 7;
the molar ratio of the compound shown in the formula III to the compound shown in the formula IV is 1: 0.7-1: 100;
the solvent for the reaction is selected from one or more of dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, methyltetrahydrofuran, dioxane, toluene, xylene, dimethyl sulfoxide, diethyl ether, isopropyl ether, methyl tert-butyl ether, acetonitrile, propionitrile, isopropanol, propanol, ethanol, methanol and water.
4. The preparation method according to claim 1, wherein the molar ratio of the compound represented by the formula III to TEMPO is 1: 1.2-1: 3.
5. The preparation method according to claim 1, wherein the molar ratio of the compound represented by the formula III to the compound represented by the formula IV is 1:2 to 1: 4.
6. The method of claim 1, wherein an additional oxidizing agent is present in the reaction.
7. A process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof, comprising the step of preparing a compound of formula II according to the process of any one of claims 1 to 6,
the method also comprises the step of preparing the compound shown in the formula V by taking the compound shown in the formula II as a reactant;
the method also comprises the step of carrying out coupling reaction on the compound shown as the formula V and the compound shown as the formula VI in the presence of a catalyst to prepare the compound shown as the formula I,
wherein X is selected from-Cl and-Br-I, -F, trifluoromethanesulfonyloxy, methylsulfonyloxy, p-toluenesulfonyloxy, phenylsulfonyloxy, acetoxy or phosphate, -SR, -SO2R, R are C1~C6An alkyl group;
y is pinacol borate;
R5is hydrogen;
the catalyst is selected from Pd (PPh)3)2Cl2;
The reaction is carried out in the presence of a basic substance.
8. The process according to claim 7, wherein X is selected from the group consisting of-Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy, p-toluenesulfonyloxy and benzenesulfonyloxy.
9. The method according to claim 8, wherein the alkaline substance is Na2CO3、Ba(OH)2、K3PO4、Cs2CO3、K2CO3、TlOH、KF、CsF、Bu4F. One or more of NaOH, KOH, triethylamine, DIPEA, DABCO, NaOR, KOR and TlOR, wherein R is independently selected from C1~C6An alkyl group.
10. The method according to claim 9, wherein the alkaline substance is selected from Na2CO3Or K2CO3One or more of (a).
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CN106715440A (en) * | 2015-04-21 | 2017-05-24 | 江苏恒瑞医药股份有限公司 | Imidazo isoindole derivative, preparation method therefor and medical use thereof |
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