CN112830929B - Process for preparing pyrazoloateroaryl compounds - Google Patents
Process for preparing pyrazoloateroaryl compounds Download PDFInfo
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- CN112830929B CN112830929B CN202011309194.5A CN202011309194A CN112830929B CN 112830929 B CN112830929 B CN 112830929B CN 202011309194 A CN202011309194 A CN 202011309194A CN 112830929 B CN112830929 B CN 112830929B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 114
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 125000006239 protecting group Chemical group 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 12
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 10
- 230000002378 acidificating effect Effects 0.000 claims description 10
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 5
- 229910017604 nitric acid Inorganic materials 0.000 claims description 5
- 239000011591 potassium Substances 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 7
- -1 cyano, amino Chemical group 0.000 description 84
- 125000000623 heterocyclic group Chemical group 0.000 description 48
- 125000000217 alkyl group Chemical group 0.000 description 44
- 125000000753 cycloalkyl group Chemical group 0.000 description 39
- 125000001072 heteroaryl group Chemical group 0.000 description 37
- 125000003118 aryl group Chemical group 0.000 description 35
- 125000001424 substituent group Chemical group 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 125000003545 alkoxy group Chemical group 0.000 description 23
- 229910052736 halogen Inorganic materials 0.000 description 22
- 150000002367 halogens Chemical group 0.000 description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 125000001188 haloalkyl group Chemical group 0.000 description 17
- 150000003839 salts Chemical class 0.000 description 16
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 125000004093 cyano group Chemical group *C#N 0.000 description 11
- 125000002947 alkylene group Chemical group 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 9
- 125000003342 alkenyl group Chemical group 0.000 description 9
- 125000000304 alkynyl group Chemical group 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 102000002689 Toll-like receptor Human genes 0.000 description 7
- 108020000411 Toll-like receptor Proteins 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 125000006413 ring segment Chemical group 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 125000003282 alkyl amino group Chemical group 0.000 description 5
- 125000004414 alkyl thio group Chemical group 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 125000000000 cycloalkoxy group Chemical group 0.000 description 5
- 125000005366 cycloalkylthio group Chemical group 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- 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 5
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 5
- 125000003396 thiol group Chemical class [H]S* 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 3
- 150000004678 hydrides Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000005051 trimethylchlorosilane Substances 0.000 description 3
- 238000005406 washing Methods 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
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 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 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000710781 Flaviviridae Species 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N Propene Chemical group CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 150000004645 aluminates Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 150000002431 hydrogen Chemical class 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
- 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
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 244000005700 microbiome Species 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
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- 235000011056 potassium acetate Nutrition 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
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 238000003786 synthesis reaction Methods 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229940044616 toll-like receptor 7 agonist Drugs 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-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
- 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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 102100039390 Toll-like receptor 7 Human genes 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000004888 barrier function Effects 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
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- 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
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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
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- 239000011630 iodine Substances 0.000 description 1
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- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
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- 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
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- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
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- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present disclosure provides methods for preparing pyrazoloaryl compounds. Specifically, the disclosure provides a method for preparing a compound shown as a general formula (I), wherein each substituent of the general formula (I) is defined as the specification. The preparation process has simple route and can reduce the production cost.
Description
Technical Field
The present disclosure relates to processes for preparing pyrazoloateroaryl compounds and intermediates thereof.
Background
Toll-like receptors (TLRs) are an important class of protein molecules involved in innate immunity. TLRs are non-catalytic receptors for single bodies to span membranes, are usually expressed in sentinel cells such as macrophages and dendritic cells, and recognize structurally conserved molecules produced by microorganisms. Once these microorganisms break through physical barriers such as skin or gut mucosa, they are recognized by TLRs and activate immune cell responses (Mahla, RS. et al, Front immunol.4:248 (2013)). The immune system has the ability to broadly recognize pathogenic microorganisms, in part due to the widespread existence of Toll-like immune receptors.
Many diseases, disorders are associated with abnormalities of TLRs, such as melanoma, non-small cell lung cancer, hepatocellular carcinoma, basal cell carcinoma (basalcellcarcinosoma), renal cell carcinoma, myeloma, allergic rhinitis, asthma, Chronic Obstructive Pulmonary Disease (COPD), ulcerative colitis, liver fibrosis, HBV, Flaviviridae (Flaviviridae) virus, HCV, HPV, RSV, SARS, HIV or viral infection of the influenza, and the like. Therefore, agonists of TLRs are promising for the treatment of related diseases.
Related TLR7 agonist patent applications are currently available, such as WO2005025583, WO2007093901, WO2008011406, WO2009091032, WO2010077613, WO2010133882, WO2011031965, WO 2012080730.
WO2018095426 discloses a pharmaceutical compound with lower concentration of onset, better selectivity (selective to TLR7, no activation to TLR 8), and more significant activation effect, and at the same time, it is a safer and more effective TLR7 agonist with weak inhibition to CYP. As shown in formula (I).
In view of the considerations of simplifying the preparation process and reducing the production cost, the present disclosure provides a novel method for preparing the compound represented by the formula (I).
Disclosure of Invention
The disclosure provides a process for the preparation of a compound of formula (I),
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
the method comprises the following steps: a step of reacting a compound represented by the formula (I-A) with a compound represented by the formula (I-B) to form a compound represented by the formula (I-C),
wherein:
ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
g is CH or N;
X 1 is alkylene or S (O) m Wherein said alkylene is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, and heterocyclyl;
L 1 is selected from-NR 4 -、-O-、-S-、-C(O)-、-C(O)-OR 4 、-S(O) m -、-N(R 4 )C(O)-、-C(O)N(R 4 )-、-N(R 4 )S(O) 2 -、-S(O) 2 N(R 4 ) -and a covalent bond;
R 1 selected from the group consisting of alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 、-C(O)R 5 、-S(O) m R 5 、-NR 6 R 7 and-C (O) NR 6 R 7 Is substituted with one or more substituents of (1);
R 2 the same OR different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 、-C(O)R 5 、-S(O) m R 5 、-NR 6 R 7 and-C (O) NR 6 R 7 Is substituted with one or more substituents of (1);
L 2 is an alkylene group OR a covalent bond, wherein said alkylene group is optionally substituted with a substituent selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 、-C(O)R 5 、-S(O) m R 5 、-NR 6 R 7 and-C (O) NR 6 R 7 Is substituted with one or more substituents of (a);
R 3 selected from haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 、-C(O)R 5 、-S(O) m R 5 、-NR 6 R 7 and-C (O) NR 6 R 7 Wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 、-C(O)R 8 、-S(O) m R 8 、-NR 9 R 10 and-C (O) NR 9 R 10 Is substituted with one or more substituents of (1);
R 4 selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;
R 5 selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, amino groups, hydroxyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups；
R 6 And R 7 Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a-C (O) R 8 、-S(O) m R 8 and-C (O) NR 9 R 10 (ii) a Wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
or, said R 6 And R 7 Reacting together with the attached nitrogen atom to form a heterocyclic group, wherein said heterocyclic group optionally contains 1 to 2 identical or different heteroatoms selected from N, O and S in addition to 1 nitrogen atom, and said heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;
R 8 selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, amino groups, hydroxyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;
R 9 and R 10 Are the same or different and are each independently selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, amino groups, hydroxyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;
x is halogen;
n is 0, 1,2, 3 or 4; and is
m is 0, 1 or 2.
Further, the aforementioned reaction is carried out under basic conditions, and the basic reagent is preferably selected from triethylamine, N-diisopropylethylamine or pyridine.
In some embodiments, it is more desirable to control the reaction temperature of the compound of formula (I-A) with the compound of formula (I-B) below zero. In some embodiments, the compound of formula (I-A) is reacted with the compound of formula (I-B) at a temperature of-20 ℃ to-50 ℃. In some embodiments, the compound of formula (I-A) is reacted with the compound of formula (I-B) at a temperature of-20 deg.CTo-35 ℃. In some embodiments, the compound of formula (I-A) is reacted with the compound of formula (I-B) at a temperature of-35 ℃ to-40 ℃. In some embodiments, the compound of formula (I-A) is reacted with the compound of formula (I-B) at a temperature of-30 ℃ to-40 ℃. In an alternative embodiment, the compound of formula (I) wherein R is 3 Is a heterocyclic group, said heterocyclic group being optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl.
In an alternative embodiment, the compound of formula (I) wherein R is 3 is-NR 6 R 7 ，R 6 And R 7 And the nitrogen atom connected with the heterocyclic group form a heterocyclic group, wherein the heterocyclic group optionally contains 1-2 same or different heteroatoms selected from N, O and S besides 1 nitrogen atom, and the heterocyclic group is optionally substituted by one or more substituents selected from alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl.
In an alternative embodiment, said compound of formula (I), wherein said ring a is selected from phenyl and pyridyl, preferably from phenyl.
In an alternative embodiment, the compound of formula (I), wherein the pyridyl is selected from the group consisting of
In an alternative embodiment, the compound of formula (I), wherein X is 1 Is an alkylene group.
In an alternative embodiment, the compound of formula (I) is a compound of formula (II):
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
the preparation method comprises the following steps: a step of reacting a compound represented by the formula (I-A) with a compound represented by the formula (II-B) or a salt thereof to form a compound represented by the formula (II-C),
g, L therein 1 ～L 2 、X、R 1 ～R 2 、R 6 ～R 7 And n is as defined in formula (I).
In an alternative embodiment, the compound of formula (I) wherein G is N.
In an alternative embodiment, the compound of formula (I), wherein L is 2 Is an alkylene group.
In an alternative embodiment, the compound of formula (I) is a compound of formula (III):
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
the preparation method comprises the following steps: a step of reacting a compound represented by the formula (II-A) with a compound represented by the formula (III-B) or a salt thereof to form a compound represented by the formula (III-C),
wherein:
s is 0, 1 or 2;
L 1 、X、R 1 ～R 2 and n is as defined in formula (I).
In an alternative embodiment, the compound of formula (I), wherein L is 1 Selected from-O-, -NR 4 -, -C (O) -and-C (O) N (R) 4 )-，R 4 Is a hydrogen atom or an alkyl group.
In some embodiments, R in the compound of formula (la) 4 Is selected from C 1-6 An alkyl group.
In an alternative embodiment, the compound of formula (I) wherein R is 1 Is an alkyl group optionally substituted with one or more alkoxy groups.
In an alternative embodiment, the compound of formula (I) wherein R is 2 The same or different, and each independently is a hydrogen atom or a halogen.
Typical compounds of the present disclosure include, but are not limited to:
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
the preparation method comprises the following steps: a step of reacting a compound represented by the formula (II-A) with a compound represented by the formula (B) or a salt thereof to form a compound represented by the formula (C),
wherein X is as defined in formula (I).
Preferably, the method for preparing the compound shown in the general formula (I) further comprises the step of reacting the compound shown in the formula (I-C) with the compound shown in the formula (I-D) under basic conditions to form the compound shown in the formula (I-E), wherein a reagent under basic conditions is preferably selected from triethylamine, N-diisopropylethylamine or pyridine,
wherein, W 1 、W 2 Are each selected from a hydrogen atom or an amino protecting group, or W 1 And W 2 Together form an amino protecting group.
In some embodiments, the compound of formula (I-C) is reacted with the compound of formula (I-D) under basic conditions as follows:
the reagent under basic conditions is preferably selected from triethylamine, N-diisopropylethylamine or pyridine, wherein W is 1 、W 2 Are each selected from a hydrogen atom or an amino protecting group, or W 1 And W 2 Together form an amino protecting group.
In some embodiments, the amino protecting group is selected from t-butyloxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl or phthaloyl.
Further preferably, the method for preparing the compound shown in the general formula (I) further comprises the step of carrying out nucleophilic substitution reaction on the compound shown in the formula (I-E) and the compound shown in the formula (I-F) under alkaline conditions to obtain the compound shown in the general formula (I-G), wherein reagents of the alkaline conditions are preferably selected from sodium, potassium, n-butyl lithium, lithium diisopropylamide and lithium bistrimethylsilyl amide,
wherein, ring A, G, L 1 ～L 2 、X、X 1 、R 1 ～R 3 And n is as defined in formula (I).
In some embodiments, the reaction of a compound of formula (I-E) with a compound of formula (I-F) under basic conditions is as follows:
the reagent under alkaline conditions is preferably selected from sodium, potassium, n-butyllithium, lithium diisopropylamide, lithium bistrimethylsilyl amide.
In some embodiments, the reaction of a compound of formula (I-E) with a compound of formula (I-F) under basic conditions is as follows:
the reagent under alkaline conditions is preferably selected from sodium, potassium, n-butyllithium, lithium diisopropylamide, lithium bistrimethylsilyl amide.
The method for preparing the compound shown in the general formula (I) further comprises the step of removing a protecting group of the compound shown in the general formula (I-G) under an acidic condition to obtain the compound shown in the general formula (I), wherein a reagent under the acidic condition is preferably selected from hydrogen chloride, 1, 4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid and trimethylchlorosilane (Me) 3 SiCl), trimethylsilyl trifluoromethanesulfonate (TMSOTf),
wherein, W 1 、W 2 Are each selected from an amino protecting group, or W 1 And W 2 Together form an amino protecting group; ring A, G, L 1 ～L 2 、X、X 1 、R 1 ～R 3 And n is as defined in formula (I).
In some embodiments, the compound of formula (I-G) is deprotected under acidic conditions to provide a compound of general formula (I) by the following steps:
the reagent for the acidic conditions is preferably selected from hydrogen chloride, 1, 4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, trimethylchlorosilane (Me) 3 SiCl), trimethylsilyl trifluoromethanesulfonate (TMSOTf).
In other embodiments, the deprotection of a compound of formula (I-G) under acidic conditions to provide a compound of general formula (I) is as follows:
the reagent under acidic conditions is preferably selected from hydrogen chloride, 1, 4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, trimethylchlorosilane (Me) 3 SiCl), trimethylsilyl trifluoromethanesulfonate (TMSOTf).
In some embodiments, the present disclosure provides a process for preparing a compound of formula (I):
wherein, G, L 1 ～L 2 、X、R 1 、R 2 、R 6 、R 7 And n is as defined in formula (I).
In an alternative embodiment, the present disclosure is directed to a process for preparing a compound of formula (I):
wherein, G, L 1 ～L 2 、X、R 1 、R 2 、R 6 、R 7 And n is as defined in formula (I).
In an alternative embodiment, the present disclosure is directed to a process for preparing a compound of formula (I):
wherein L is 1 、X、R 1 、R 2 And n is as defined in formula (I).
In an alternative embodiment, the present disclosure is directed to a process for preparing a compound of formula (I):
in an alternative embodiment, the present disclosure provides a process for preparing a compound of formula (I):
further, the compound shown as B-1 can be prepared by the following steps:
the present disclosure also provides compounds of formula (I-B):
In an alternative embodiment, is a compound of formula (I-B) which is:
In an alternative embodiment, the compound of formula (I-B) is:
wherein s is 0, 1 or 2; r 2 And n is as defined in formula (I).
In another alternative embodiment, the compound of formula (I-B) is:
the present disclosure also provides a process for preparing a compound represented by formula (I-B) or a salt thereof, the process comprising: a step of converting the compound represented by formula 3 into the compound represented by formula 5 by reacting with the compound represented by formula 4,
wherein, the compound shown in the formula 3 reacts with the compound shown in the formula 4 to form a compound shown in the formula M,
subsequently, the compound shown in the formula M and a hydride source are subjected to reduction reaction to obtain the compound shown in the formula 5, wherein the hydride source is preferably at least one of lithium aluminum tetrahydride, lithium triethylborohydride, diisobutylaluminum hydride, sodium cyanoborohydride, sodium borohydride, sodium dihydrobis (2-methoxyethoxy) aluminate and hydrogen/metal catalyst,
wherein, ring A, L 2 、X 1 、R 2 、R 3 And n is as defined in formula (I); w 1 、W 2 As defined in formulas (I-E).
Further, the method for preparing the compound shown in the formula (I-B) also comprises the step of removing the protecting group of the compound shown in the formula 5 to obtain the compound shown in the formula (I-B),
and a step of reacting the compound represented by the formula 1 with the compound represented by the formula 2 under basic conditions to form a compound represented by the formula 3,
wherein, ring A, L 2 、X、X 1 、R 2 、R 3 And n is as defined in formula (I); w 1 、W 2 As defined in formulas (I-E).
In some embodiments, the present disclosure provides a method of preparing a compound of formula (I-B):
in some alternative embodiments, the present disclosure provides a method of preparing a compound of formula (I-B):
in some alternative embodiments, the present disclosure provides a method of preparing a compound of formula (I-B):
in some alternative embodiments, the present disclosure provides a method of preparing a compound of formula (I-B):
another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, prepared according to the foregoing method, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
The "amino protecting group" described in this disclosure is a group known in the art as being suitable for amino protection, see amino protecting Groups in the literature ("Protective Groups in Organic Synthesis", 5th.ed.t.w.greene & p.g.m.wuts). Illustratively, the amino protecting group is selected from t-butoxycarbonyl, acetyl, benzyl, allyl, or p-methoxybenzyl, or, together with the nitrogen atom to which it is bound, forms a lactam, such as phthaloyl. The mode of removing the protecting group can also refer to the mode of removing the protecting group in the literature ("Protective Groups in Organic Synthesis", 5th.ed.t.w.greene & p.g.m.wuts), and the relevant contents are introduced into the present specification. Illustratively, the benzyl group is removed by a hydrogen/metal catalyst selected from, but not limited to, at least one of palladium on carbon, palladium hydroxide, platinum oxide, palladium on alumina, platinum on activated carbon, and raney nickel, preferably palladium on carbon, palladium hydroxide; the removal of the tert-butyloxycarbonyl (Boc) group under acidic conditions, the reagents providing the acidic conditions are preferably selected from methanesulfonic acid, hydrochloric acid, trifluoroacetic acid.
The hydride source of the present disclosure is well known or determinable to those skilled in the art and is selected from, but not limited to, at least one of lithium aluminum tetrahydride, lithium triethylborohydride, diisobutylaluminum hydride, sodium borohydride, sodium dihydrobis (2-methoxyethoxy) aluminate, hydrogen gas/metal catalyst. Further, the metal catalyst is selected from at least one of palladium carbon, palladium hydroxide, platinum oxide, palladium on alumina, platinum on activated carbon and raney nickel, but is not limited thereto, and preferably is palladium carbon, palladium hydroxide.
The salt of the compound represented by the formula (I-B) in the disclosure is a substance formed by reacting the compound represented by the formula (I-B) with an acid, wherein the acid can be hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid and the like, and hydrochloric acid is preferred.
The reagents that provide basic conditions in the present disclosure include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, lithium bistrimethylsilylamide, potassium acetate, sodium t-butoxide, potassium t-butoxide, and sodium N-butoxide, and inorganic bases including, but not limited to, sodium, potassium, sodium hydride, potassium phosphate, sodium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, and lithium hydroxide.
The reagents of the present disclosure that provide acidic conditions include, but are not limited to, hydrogen chloride, 1, 4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me 3 SiCl、TMSOTf。
The above reaction is preferably carried out in a solvent including, but not limited to: acetic acid, methanol, ethanol, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, and water or N, N-dimethylformamide.
Detailed description of the invention
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-propanal, and mixtures thereofMethylpentyl, 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, 2-ethylhexyl-hexyl, 5-ethylhexyl-ethyl, 2-ethylhexyl-pentyl, 2-ethylhexyl-ethyl-pentyl, 2-ethylhexyl-pentyl, 3-pentyl, 2-ethylhexyl-ethyl-pentyl, 2-pentyl, 3-pentyl, 2-ethyl-pentyl, 2-pentyl, 3-ethylhexyl-octyl, 3-ethyl-pentyl, 2, 3-pentyl, 2,3, 2,3, 2,3, 2, or, 2, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, various branched chain isomers thereof, and the like. 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. Alkyl groups may be substituted OR unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably independently optionally selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -OR 5 、-C(O)R 5 、-S(O) m R 5 、-NR 6 R 7 and-C (O) NR 6 R 7 Is substituted with one or more substituents.
The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group having 2 residues derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, which is a straight or branched chain group containing from 1 to 20 carbon atomsPreferably an alkylene group having 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) 2 -), 1-ethylidene (-CH (CH) 3 ) -), 1, 2-ethylene (-CH) 2 CH 2 ) -, 1-propylene (-CH (CH) 2 CH 3 ) -), 1, 2-propylene (-CH) 2 CH(CH 3 ) -), 1, 3-propylene (-CH) 2 CH 2 CH 2 -) 1, 4-butylene (-CH 2 CH 2 CH 2 CH 2 -) and the like. Alkylene groups may be substituted OR unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably independently optionally selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -OR 5 、-C(O)R 5 、-S(O) m R 5 、-NR 6 R 7 and-C (O) NR 6 R 7 Is substituted with one or more substituents.
The term "alkenyl" refers to a hydrocarbon group having one or more fewer hydrogen atoms in the olefin molecule. The alkenyl group may be substituted OR unsubstituted, and when substituted, the substituent is preferably one OR more groups independently selected from hydrogen atom, alkyl group, alkoxy group, halogen, haloalkyl group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -OR 5 、-C(O)R 5 、-S(O) m R 5 、-NR 6 R 7 and-C (O) NR 6 R 7 Is substituted with one or more substituents of (a);
the term "alkynyl" refers to a hydrocarbon containing a carbon-carbon triple bond in the molecule. Alkynyl groups may be substituted OR unsubstituted, and when substituted, the substituents are preferably one OR more groups independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 、-C(O)R 5 、-S(O) m R 5 、-NR 6 R 7 and-C (O) NR 6 R 7 Is substituted with one or more substituents.
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, preferably from 3 to 10 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 3 to 10 ring atoms, of which 1-4 is a heteroatom; more preferably from 5 to 6 ring atoms; of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1, 2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
the heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently optionally selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyNitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -OR 5 、-C(O)R 5 、-S(O) m R 5 、-NR 6 R 7 and-C (O) NR 6 R 7 Is substituted with one or more substituents.
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 ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
aryl groups may be substituted OR unsubstituted, and when substituted, the substituents are preferably one OR more groups independently optionally selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, -OR 5 、-C(O)R 5 、-S(O) m R 5 、-NR 6 R 7 and-C (O) NR 6 R 7 Is substituted with one or more substituents.
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 10 membered, more preferably 5 or 6 membered, for example furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, tetrazolyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
heteroaryl 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, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, -OR 5 、-C(O)R 5 、-S(O) m R 5 、-NR 6 R 7 and-C (O) NR 6 R 7 Is substituted with one or more substituents.
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 substituents independently selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. The term "hydroxy" refers to an-OH group.
The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to-NH 2 。
The term "cyano" refers to — CN.
Term "Nitro "means-NO 2 。
The term "oxo" refers to ═ O.
"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.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salt" refers to salts of the disclosed compounds which are safe and effective for use in a mammal and which possess the requisite biological activity, and are selected from the group consisting of, but not limited to, hydrochloride and sulfate salts.
The purity or content of the compound is determined by HPLC detection, and compound characterization data is obtained by analyzing a nuclear magnetic resonance spectrum; reagents used in the present disclosure may be commercially available.
Detailed Description
The present disclosure will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present disclosure, and the spirit and scope of the present disclosure are not limited thereto.
Example 1:
step 1: 4- (pyrrolyl 1-methyl) benzaldehyde (59.6g) was dissolved in 500ml of ethanol, and BocNHNH was added 2 (41.6g) and acetic acid (1.05g), heating and refluxing for reaction, cooling after TLC detection reaction, and concentrating the reaction solution to obtain 67.0g of a product with the purity of 98% and the yield of 70.1%.
1 H NMR(CDCl 3 ,400M):1.53(s,9H),1.76-1.80(m,4H),2.49-2.52(m,4H),3.61(s,2H),7.31(d,J＝8.4Hz,2H),7.60(d,J＝8.4Hz,2H),7.79(s,1H),8.16(brs,1H).
And 2, step: the product (15.2g) from the previous step was dissolved in tetrahydrofuran (106 ml)/acetic acid (76ml), cooled and NaBH added 3 CN (9.45g), stirring for reaction, after TLC detection reaction, concentrating the reaction solution for dissolving in ethyl acetate (190ml), adding sodium hydroxide (4N, 150ml), separating, extracting with ethyl acetate, washing with saturated saline, drying, and concentrating to obtain 15.1g of product with purity of 89%, yield of 98.7%.
1 H NMR(CDCl 3 ,400M):1.46(s,9H),1.78-1.83(m,4H),2.54-2.57(m,4H),3.63(s,2H),3.96(d,J＝5.2Hz,2H),4.16(brs,1H),6.05(brs,1H),7.26-7.30(m,4H).
And step 3: dissolving the product (15.1g) obtained in the last step in 8.3M HCl/ethanol (100ml), after the heating reaction is finished, cooling and filtering to obtain white solid, then washing with ethanol, and drying to obtain the product (10.5 g), the purity is 98 percent, and the yield is 76.3 percent.
Example 2:
adding a compound of formula B-1 (26.2g), ethanol (1500mL) and triethylamine (29.7g) into a three-necked flask at-35 ℃, stirring for reacting for 1h, adding a compound of formula II-A1 (20.1g), adding p-methoxybenzylamine (65.8g) after the stirring reaction is finished, adding methyl tert-butyl ether (1500mL) after the stirring reaction is finished, stirring, filtering, washing with ethyl acetate, and drying to obtain a yellow solid.
The yellow solid was dissolved in dichloromethane/water (250ml/250ml) with stirring, the solution was separated, washed with 25% ammonium chloride solution, separated, dried, concentrated, and purified by column chromatography to give 30.5g, 96% purity, 70.0% yield.
Example 3:
the compound (21.7g) obtained in example 2 was dissolved in n-butanol (200mL), 18.9g of sodium n-butoxide (or a sodium n-butoxide solution prepared from 4.5g of Na and 14.57g of n-butanol) was added, the reaction was refluxed, after completion of the TLC detection reaction, the reaction mixture was cooled, methyl tert-butyl ether (200mL) and a 15% sodium chloride solution (200mL) were added and stirred, liquid separation was carried out, extraction was carried out with methyl tert-butyl ether, the pH was adjusted to 7 to 8 with a 30% ammonium chloride solution, liquid separation was carried out, the organic layer was washed with a saturated sodium chloride solution, dried, filtered and concentrated to 23g, with a purity of 96% and a yield of 98.0%.
Example 4:
the compound (23g) obtained in example 3 was dissolved in trifluoroacetic acid (150ml), and after completion of the reflux reaction, cooling and concentration were carried out, and 200ml of dichloromethane was added to the residue to dissolve it, and the pH was adjusted to 7 to 8 with a saturated sodium bicarbonate solution, followed by liquid separation, dichloromethane extraction, drying, concentration, and column chromatography purification to obtain 12g of a product with a purity of 97% and a yield of 68.6%.
Example 5:
adding a compound of the formula B-1 (5.0g), ethanol (250mL) and triethylamine (5.5g) into a three-necked flask at-35 ℃, stirring for reacting for 1h, adding a compound of the formula II-A1 (3.8g), after the stirring reaction is finished, introducing about 15L of ammonia gas into the reaction solution, after the stirring reaction is finished, concentrating the reaction solution, and purifying by column chromatography to obtain 4.7g of a product with the purity of 95% and the yield of 76.3%.
1 H NMR(DMSO,400M):1.71(m,4H,CH 2 ),2.51(m,4H,NCH 2 ),3.66(s,2H,CH 2 ),5.42(s,2H,CH 2 ),7.14(d,J＝8.0Hz,2H,CH),7.30(d,J＝8.0Hz,2H,CH),8.17(b-s,2H,NH),8.41(s,1H,CH).
Example 6:
the compound (4.6g) obtained in example 5 was dissolved in n-butanol (46ml), and 5.2g of sodium n-butoxide (or a sodium n-butoxide solution prepared from 1.24g of Na and 4g of n-butanol) was added thereto, followed by heating and refluxing, after completion of the TLC detection reaction, cooling, and addition of saturated NH 4 And (3) quenching the reaction by using a Cl aqueous solution, extracting by using methyl tert-butyl ether, separating, concentrating, and purifying by column chromatography to obtain a product of 3.91g, wherein the purity is 99%, and the yield is 76.6%.
Example 7:
in a 5L three-necked flask, the compound prepared according to the method of example 6 (136.0g, 0.357mol, 1.0eq) is taken, 1100mL of absolute ethyl alcohol and 1100mL of ethyl acetate are added and stirred to dissolve, the reaction solution is cooled to 0-5 ℃ in an ice bath, 268mL of 4mol/L hydrochloric acid ethanol solution is added dropwise, after the dropwise addition, the temperature is increased, stirring and crystallization are carried out, the filtration is carried out, a filter cake is rinsed by 272mL of mixed solution of absolute ethyl alcohol and ethyl acetate (v: v ═ 1:1), the filter cake is dried to obtain 135.3g, and the yield is 83.2%.
Remarking: the preparation method of the hydrogen chloride ethanol solution comprises the following steps:
weighing anhydrous ethanol, cooling to below-10 deg.C, introducing hydrogen chloride gas, stopping introducing when the weight of anhydrous ethanol is increased by more than 30%, detecting concentration, and diluting with anhydrous ethanol to 4 moL/L.
Claims (2)
1. A process for preparing a compound of formula (III-G) comprising:
wherein,
x is a chlorine atom;
R 1 is n-butyl, R 2 Is a hydrogen atom;
L 1 is-O-;
W 1 and W 2 Each independently selected from a hydrogen atom or an amino protecting group, or W 1 And W 2 Together form an amino protecting group;
n is 4 and s is 1;
wherein the first two steps of the reaction scheme are carried out under basic conditions, the basic reagent is selected from triethylamine, N-diisopropylethylamine or pyridine; the third step of the reaction route is carried out under the alkaline condition, and the alkaline reagent is selected from sodium, potassium, n-butyl lithium, lithium diisopropylamide and lithium bistrimethylsilyl amide.
2. The process according to claim 1, further comprising the step of deprotecting the amino protecting group of the compound of formula (III-G) under acidic conditions selected from the group consisting of hydrogen chloride, 1, 4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me to give the compound of general formula (III) 3 SiCl、TMSOTf，
Wherein, W 1 And W 2 Each independently selected from a hydrogen atom or an amino protecting group, and not simultaneously a hydrogen atom, or W 1 And W 2 Together forming an amino groupA protecting group; l is 1 、R 1 ～R 2 N and s are as defined in claim 1.
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