CN115745884A - Opioid derivatives, intermediates thereof, and processes for preparing the same - Google Patents
Opioid derivatives, intermediates thereof, and processes for preparing the same Download PDFInfo
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- CN115745884A CN115745884A CN202111027240.7A CN202111027240A CN115745884A CN 115745884 A CN115745884 A CN 115745884A CN 202111027240 A CN202111027240 A CN 202111027240A CN 115745884 A CN115745884 A CN 115745884A
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- 238000000034 method Methods 0.000 title claims description 99
- 239000000543 intermediate Substances 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 406
- 239000003960 organic solvent Substances 0.000 claims abstract description 131
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 63
- 239000003054 catalyst Substances 0.000 claims abstract description 46
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 35
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 26
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000003446 ligand Substances 0.000 claims abstract description 15
- 239000003513 alkali Substances 0.000 claims abstract description 12
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 200
- 238000006243 chemical reaction Methods 0.000 claims description 199
- 239000002904 solvent Substances 0.000 claims description 99
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 81
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 60
- -1 Alkyl radical Chemical class 0.000 claims description 55
- 239000003153 chemical reaction reagent Substances 0.000 claims description 49
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- 238000010511 deprotection reaction Methods 0.000 claims description 34
- 239000002585 base Substances 0.000 claims description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- 239000011261 inert gas Substances 0.000 claims description 30
- 230000035484 reaction time Effects 0.000 claims description 29
- 238000003476 Darzens condensation reaction Methods 0.000 claims description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 26
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 24
- 238000004519 manufacturing process Methods 0.000 claims description 24
- 239000012046 mixed solvent Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 238000005984 hydrogenation reaction Methods 0.000 claims description 22
- 238000007254 oxidation reaction Methods 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 21
- 150000001408 amides Chemical class 0.000 claims description 20
- 238000006482 condensation reaction Methods 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 17
- 238000006114 decarboxylation reaction Methods 0.000 claims description 17
- 238000006722 reduction reaction Methods 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 238000006460 hydrolysis reaction Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 15
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 14
- 230000020477 pH reduction Effects 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 13
- 239000007795 chemical reaction product Substances 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 239000007800 oxidant agent Substances 0.000 claims description 13
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 238000006467 substitution reaction Methods 0.000 claims description 12
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims description 10
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 10
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 claims description 10
- 239000003638 chemical reducing agent Substances 0.000 claims description 10
- 238000005935 nucleophilic addition reaction Methods 0.000 claims description 10
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 238000006352 cycloaddition reaction Methods 0.000 claims description 9
- 238000010520 demethylation reaction Methods 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 239000010948 rhodium Substances 0.000 claims description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 235000011054 acetic acid Nutrition 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 claims description 8
- 229940089960 chloroacetate Drugs 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 238000006264 debenzylation reaction Methods 0.000 claims description 7
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 7
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 7
- 230000001590 oxidative effect Effects 0.000 claims description 7
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 6
- 125000001033 ether group Chemical group 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 6
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 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
- 239000003223 protective agent Substances 0.000 claims description 6
- 229910052703 rhodium Inorganic materials 0.000 claims description 6
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 150000003462 sulfoxides Chemical group 0.000 claims description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical group [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 150000001348 alkyl chlorides Chemical group 0.000 claims description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 5
- HTJWUNNIRKDDIV-UHFFFAOYSA-N bis(1-adamantyl)-butylphosphane Chemical compound C1C(C2)CC(C3)CC2CC13P(CCCC)C1(C2)CC(C3)CC2CC3C1 HTJWUNNIRKDDIV-UHFFFAOYSA-N 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 239000007818 Grignard reagent Substances 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- 239000012448 Lithium borohydride Substances 0.000 claims description 4
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 claims description 4
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 4
- 150000004795 grignard reagents Chemical class 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000012038 nucleophile Substances 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- KJTULOVPMGUBJS-UHFFFAOYSA-N tert-butyl-[tert-butyl(diphenyl)silyl]oxy-diphenylsilane Chemical group C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C(C)(C)C)O[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 KJTULOVPMGUBJS-UHFFFAOYSA-N 0.000 claims description 4
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical group 0.000 claims description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- WNAHIZMDSQCWRP-UHFFFAOYSA-N dodecane-1-thiol Chemical compound CCCCCCCCCCCCS WNAHIZMDSQCWRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 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 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 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 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 2
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical group [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- RBYGDVHOECIAFC-UHFFFAOYSA-L acetonitrile;palladium(2+);dichloride Chemical compound [Cl-].[Cl-].[Pd+2].CC#N.CC#N RBYGDVHOECIAFC-UHFFFAOYSA-L 0.000 claims description 2
- 239000005456 alcohol based solvent Substances 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000007900 aqueous suspension Substances 0.000 claims description 2
- 239000012964 benzotriazole Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 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 claims description 2
- 239000004210 ether based solvent Substances 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical group C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical group COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 239000012434 nucleophilic reagent Substances 0.000 claims description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 2
- 235000011007 phosphoric acid Nutrition 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical group [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 2
- 229960002218 sodium chlorite Drugs 0.000 claims description 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 2
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical group CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 claims description 2
- 150000003573 thiols Chemical class 0.000 claims description 2
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical group ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims 2
- 239000011342 resin composition Substances 0.000 claims 2
- JVTZFYYHCGSXJV-UHFFFAOYSA-N isovanillin Chemical compound COC1=CC=C(C=O)C=C1O JVTZFYYHCGSXJV-UHFFFAOYSA-N 0.000 abstract description 6
- 239000007858 starting material Substances 0.000 abstract description 6
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 abstract description 4
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 abstract description 4
- 235000012141 vanillin Nutrition 0.000 abstract description 4
- 239000008896 Opium Substances 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 229960001027 opium Drugs 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 82
- 238000001035 drying Methods 0.000 description 47
- 229910052757 nitrogen Inorganic materials 0.000 description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 238000000746 purification Methods 0.000 description 33
- 238000000605 extraction Methods 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 29
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 28
- 238000004440 column chromatography Methods 0.000 description 27
- 238000012544 monitoring process Methods 0.000 description 19
- 238000004821 distillation Methods 0.000 description 17
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 17
- 239000000047 product Substances 0.000 description 15
- 229910052786 argon Inorganic materials 0.000 description 14
- 239000007789 gas Substances 0.000 description 14
- 230000001681 protective effect Effects 0.000 description 14
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- 229910004161 SiNa Inorganic materials 0.000 description 1
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- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 1
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- 102000048124 delta Opioid Receptors Human genes 0.000 description 1
- BADXJIPKFRBFOT-UHFFFAOYSA-N dimedone Chemical compound CC1(C)CC(=O)CC(=O)C1 BADXJIPKFRBFOT-UHFFFAOYSA-N 0.000 description 1
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- 102000048260 kappa Opioid Receptors Human genes 0.000 description 1
- CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 239000011259 mixed solution Substances 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
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- 230000036407 pain Effects 0.000 description 1
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- 125000005561 phenanthryl group Chemical group 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical class [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
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- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- 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
Abstract
The invention discloses an opium derivative, an intermediate and a preparation method thereof. The invention provides a preparation method of a compound shown as a formula A6, which comprises the following steps of S7: under the action of a palladium catalyst, a phosphine ligand shown as a formula L1 and alkali, a compound shown as a formula A5 is subjected to dearomatization cyclization reaction in an organic solvent as shown in the specification to obtainA compound represented by formula A6. The synthetic route and the intermediate of the invention can adopt cheap and easily obtained vanillin and isovanillin as starting materials to realize the preparation of opioid compounds, and provide possibility for the large-scale production of the opioid compounds.
Description
Technical Field
The invention relates to an opium derivative, an intermediate and a preparation method thereof.
Background
Naltrexone (naltrexone) with chemical structural formula
The opioid antagonist is a pure opioid receptor antagonist, has blocking effect on mu-, delta-and kappa-opioid receptors, can obviously weaken or completely block the opioid receptors, has long action time, is a class of oral medicines approved by FDA in 1984, and can be used for blocking dependence on opioid drugs and alcohol.
Buprenorphine (Buprenorphine) having the chemical formula
Is an opioid receptor partial agonist, has analgesic effects on postoperative analgesia, cancer-induced cancer pain, burns, angina pectoris or limb pain due to excessive fatigue, and the like, and has a long duration, generally 6 to 8 hours. Meanwhile, the medicine can also be used for maintaining treatment of abstinence and can break the tension of human bodies.
Structurally, the naltrexone molecule has a more complex pentacyclic skeleton and four consecutive chiral centers, whereas buprenorphine contains a more complex hexacyclic skeleton and has seven consecutive chiral centers, but naltrexone and buprenorphine have similar main skeletons and can be divergently synthesized via a common intermediate. At present, the synthesis of naltrexone and buprenorphine compounds is mainly semisynthesis realized by further chemical conversion from Thebaine (Thebaine), an alkaloid extracted from poppy, and a chemical synthesis method for preparing naltrexone and buprenorphine by using common compounds as starting materials is not reported so far.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects in the prior art, and thus, the invention provides an opioid derivative, an intermediate thereof and a preparation method thereof.
In one aspect, the present invention provides a method for preparing a compound represented by formula A6, comprising the following step S7:
under the action of a palladium catalyst, a phosphine ligand shown in a formula L1 and alkali, carrying out dearomatization cyclization reaction shown in a formula A5 in an organic solvent to obtain a compound shown in a formula A6,
wherein R is 1 And R 2 Independently H, C 1～10 Alkyl radical, C 1～10 Alkoxy radical, C 3～10 Cycloalkyl or C 6～20 An aryl group;
R 3 independently is C 1～7 Alkyl radical, C 3～7 Cycloalkyl or C 6～20 An aryl group;
R 5 、R 6 and R 7 Independently is C 1～10 Alkyl radical, C 3～10 Substituted cycloalkyl radicals or by C 1～10 Alkyl substituted C 3～10 A substituted cycloalkyl group.
In the method for preparing the compound represented by the formula A6 (hereinafter, referred to as step S7), the reaction conditions, the types of reagents, and the amounts of the dearomatization cyclization reaction may be conventional conditions, types of reagents, and amounts of reagents in the reactions of the type in the art, and the present invention is preferably as follows.
In step S7, the dearomatization cyclization reaction may be performed under the protection of an inert gas. The inert gas may be a protective gas conventional in the art, such as nitrogen and/or argon, again for example nitrogen.
In step S7, the palladium catalyst may be one or more of palladium chloride, bis (acetonitrile) palladium chloride, palladium trifluoromethanesulfonate, and palladium acetate, for example, palladium chloride.
In step S7, the molar ratio of the palladium catalyst to the compound represented by formula A5 may be 0.01 to 0.5, for example, 0.1.
In step S7, the phosphine ligand represented by formula L1 may be one or more of tri-tert-butylphosphine, tricyclohexylphosphine, and di (1-adamantyl) n-butylphosphine, for example, di (1-adamantyl) n-butylphosphine.
In step S7, the molar ratio of the phosphine ligand represented by formula L1 to the compound represented by formula A5 may be 0.01 to 0.5, for example, 0.1 to 0.5.
In step S7, the base may be an alkali metal carbonate, such as potassium carbonate.
In step S7, the organic solvent may be a sulfoxide solvent and/or an amide solvent, preferably an amide solvent. The amide may be N, N-Dimethylformamide (DMF) and/or N, N-Dimethylacetamide (DMA), preferably N, N-dimethylformamide.
In step S7, the amount of the organic solvent used may not be particularly limited as long as the reaction is not affected. The volume-to-mass ratio of the organic solvent to the compound represented by the formula A5 may be 5 to 100mL/g, for example, 10 to 30mL/g.
In step S7, the temperature of the dearomatization cyclization reaction may be from 80 ℃ to 180 ℃, such as from 100 ℃ to 130 ℃, for example, also 120 ℃.
In step S7, the progress of the dearomatization cyclization reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and the end point of the reaction is generally determined as the disappearance or no longer reaction of the compound represented by formula A5. The reaction time may be 8 to 24 hours, for example 12 hours.
In step S7, after the dearomatization cyclization reaction, a post-treatment step may be further included, which may be a post-treatment operation conventional for such reactions, for example, including one or more of extraction, drying, concentration and purification. The solvent for the extraction may be dichloromethane. The drying may be anhydrous sodium sulfate drying. The concentration may be distillation under reduced pressure. The purification may be column chromatography.
Step S7 may include the steps of: adding the organic solvent to a mixture of the palladium catalyst, the phosphine ligand represented by formula L1, a base and the compound represented by formula A5 to perform the dearomatization cyclization reaction.
In one aspect of the present invention,R 1 may be H.
In one embodiment of the present invention, R 2 May be H.
In one embodiment of the present invention, R 3 Can be C 3～7 Cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and also cyclopropyl.
In one embodiment of the present invention, the compound represented by formula A6 is preferably
In one embodiment of the present invention, the compound represented by the formula A5 is preferably
In a certain embodiment of the present invention, the method for preparing the compound represented by formula A6 may further include a method for preparing a compound represented by formula A5 below, which includes the following step S6: carrying out deprotection reaction shown as the following on the formula A5-3 in an organic solvent under the action of a deprotection reagent to obtain the compound shown as the formula A5,
wherein R is 1 、R 2 And R 3 As defined above, P is a hydroxyl protecting group.
In one embodiment of the present invention, in the method for preparing the compound represented by formula A5 (hereinafter, referred to as step S6), the reaction conditions, the types of reagents, and the amounts of the deprotection reaction may be those conventionally used in reactions of this type in the art, and the present invention is preferably as follows.
In step S6, the deprotection reaction may be performed under the protection of an inert gas. The inert gas may be a protective gas conventional in the art, such as nitrogen and/or argon, again for example nitrogen.
In step S6, the deprotection reagent may be tetrabutylammonium fluoride.
In step S6, the molar ratio of the deprotecting reagent to the compound represented by formula A5-3 may be 1 to 5, for example, 1.1.
In step S6, the organic solvent may be an ether solvent and/or a chlorinated hydrocarbon solvent, preferably an ether solvent. The ether solvent may be one or more of tetrahydrofuran, dioxane, diethyl ether and methyl tert-butyl ether (MTBE), preferably tetrahydrofuran.
In step S6, the amount of the organic solvent used may not be particularly limited as long as the reaction is not affected. The volume-to-mass ratio of the organic solvent to the compound represented by the formula A5-3 may be 5 to 100mL/g, for example, 10 to 30mL/g, and for example, 23mL/g.
In step S6, the temperature of the deprotection reaction may be 10 to 50 ℃, for example, 20 to 35 ℃.
In step S6, the progress of the deprotection reaction can be monitored by monitoring methods conventional in the art (e.g., TLC or LCMS), and the end point of the reaction is generally determined as the disappearance or no longer reaction of the compound represented by the formula A5-3. The reaction time may be 1 to 5 hours, for example 1 hour.
In step S6, after the deprotection reaction, a post-treatment step may be further included, and the post-treatment step may be a post-treatment operation that is conventional for such a reaction, and for example, includes one or more of extraction, drying, concentration, and purification. The solvent for the extraction may be dichloromethane. The drying may be anhydrous sodium sulfate drying. The concentration may be distillation under reduced pressure. The purification may be column chromatography.
Step S6 may include the steps of: the compound represented by the formula A5-3 is dissolved in the organic solvent to form a mixture solution, and the deprotection reaction is carried out by adding (preferably, dropwise adding at 0 ℃) the deprotection reagent to the mixture solution.
In one embodiment of the invention, P may be a hydroxyl protecting group as is conventional in the art, such as a silyl ether protecting group or a carbonate-based protecting group, preferably a silyl ether protecting group. The silyl ether protecting group may be a trimethylsilyl ether protecting group, a t-butyldimethylsilyl ether protecting group or a t-butyldiphenylsilyl ether protecting group (TBDPS), preferably a t-butyldiphenylsilyl ether protecting group. The carbonate protecting group may be COOEt or COOMe.
In one embodiment of the present invention, the compound represented by the formula A5-3 is preferably
In a certain embodiment of the present invention, the method for preparing the compound represented by formula A5 may further include a method for preparing a compound represented by the following formula A5-3, which includes the following step S5: carrying out a substitution reaction shown as the following on a compound shown as a formula A5-2 and a compound shown as a formula B5-2 in an organic solvent under the action of alkali to obtain a compound shown as a formula A5-3,
wherein R is 1 、R 2 、R 3 And P is as defined above.
In the method for producing the compound represented by the formula A5 (hereinafter, referred to as step S5), the reaction conditions, the kinds of reagents, and the amounts of the substitution reaction may be those conventionally used in reactions of this type in the art, and the following are preferred in the present invention.
In step S5, the substitution reaction may be performed under the protection of an inert gas. The inert gas may be a protective gas conventional in the art, such as nitrogen and/or argon, again for example nitrogen.
In step S5, the base may be an organic base, preferably triethylamine.
In step S5, the molar ratio of the base to the compound represented by formula A5-2 may be 1 to 3, for example 2.
In step S5, the organic solvent may be a chlorinated alkane and/or an amide, preferably a chlorinated alkane. The chlorinated hydrocarbon solvent may be one or more of dichloromethane, 1,2-dichloroethane and chloroform, preferably dichloromethane.
In step S5, the amount of the organic solvent used may not be particularly limited as long as the reaction is not affected. The volume-to-mass ratio of the organic solvent to the compound represented by the formula A5-2 may be 5 to 100mL/g, for example, 10 to 30mL/g, and for example, 13mL/g.
In step S5, the molar ratio of the compound represented by formula B5-2 to the compound represented by formula A5-2 may be 1 to 3, for example, 2.
In step S5, the temperature of the substitution reaction may be 10 to 50 ℃, for example, 20 to 35 ℃.
In step S5, the progress of the substitution reaction can be monitored by monitoring methods conventional in the art (e.g., TLC or LCMS), and the end point of the reaction is generally determined as the disappearance or no longer reaction of the compound represented by the formula A5-2. The reaction time may be 4 to 12 hours, for example 6 hours.
In step S5, after the substitution reaction, a post-treatment step may be further included, and the post-treatment step may be one or more of post-treatment operations conventional for such a reaction, including, for example, extraction, drying, concentration, and purification. The solvent for the extraction may be dichloromethane. The drying may be anhydrous sodium sulfate drying. The concentration may be distillation under reduced pressure. The purification may be column chromatography.
Step S5 may comprise the steps of: dissolving the compound represented by the formula A5-2 in the organic solvent to form a mixture solution, and adding (preferably, dropwise adding at 0 ℃) the compound represented by the formula B5-2 and a basic deprotection reagent to the mixture solution to carry out the substitution reaction.
In one embodiment of the present invention, the compound represented by the formula A5-2 is preferably
In a certain embodiment of the present invention, the method for preparing the compound represented by formula A5-3 may further include a method for preparing a compound represented by the following formula A5-2, which includes the following step S4: under the action of a rhodium catalyst and a ligand, carrying out asymmetric hydrogenation reaction on the compound shown in the formula A5-1 and hydrogen in an organic solvent to obtain the compound shown in the formula A5-2,
wherein R is 1 、R 2 And P is as defined above.
In the method for preparing the compound represented by the formula A5-2 (hereinafter, referred to as step S4), the reaction conditions, the types of reagents, and the amounts of the asymmetric hydrogenation reaction may be those conventionally used in reactions of this type in the art, and the present invention is preferably as follows.
In step S4, the organic solvent may be one or more of an alcohol solvent, an ether solvent, an aromatic hydrocarbon solvent, a nitrile solvent, a halogenated alkane solvent, a sulfoxide solvent, and an amide solvent, and is preferably an alcohol solvent. The alcoholic solvent may be one or more of methanol, ethanol, n-propanol and isopropanol, preferably methanol.
In step S4, the amount of the organic solvent used may not be particularly limited as long as the reaction is not affected. The volume-to-mass ratio of the organic solvent to the compound represented by the formula A5-1 may be 1 to 20mL/g, for example, 2.5 to 10mL/g and, for example, 7.5mL/g.
In step S4, the rhodium catalyst may be Rh (nbd) 2 BF 4 。
In step S4, the molar ratio of the rhodium catalyst to the compound represented by the formula A5-1 may be 0.001 to 0.1, for example, 0.01.
In step S4, the ligand can be (2R,2 'R,3R,3') R) -WingPhos
In step S4, the molar ratio of the ligand to the compound represented by formula A5-1 may be 0.001 to 0.1, for example, 0.01.
In step S4, the asymmetric hydrogenation reaction may be carried out under a pressure which is conventional in such reactions in the art, such as from 1atm to 50atm, and further such as 400psi.
In step S4, the temperature of the asymmetric hydrogenation reaction may be 10 ℃ to 50 ℃, for example, 35 ℃.
In step S4, the progress of the asymmetric hydrogenation reaction can be monitored by monitoring methods conventional in the art (e.g., TLC or LCMS), and the disappearance or no longer reaction of the compound represented by the formula A5-1 is generally used as the end point of the reaction. The reaction time may be 10-24 hours, for example 15 hours.
In step S4, after the asymmetric hydrogenation reaction, a post-treatment step may be further included, which may be a post-treatment operation conventional for such reactions, for example, including one or more of hydrogen substitution, concentration, and purification. The concentration may be distillation under reduced pressure. The purification may be column chromatography.
In one embodiment of the present invention, the compound represented by the formula A5-1 is preferably
In a certain embodiment of the present invention, the method for preparing the compound represented by formula A5-2 may further include a method for preparing a compound represented by the following formula A5-1, which includes the following step S3: in POCl 3 Subjecting a compound represented by the formula A4 to a cyclization reaction in an organic solvent as shown below to obtain a compound represented by the formula A5-1,
wherein R is 1 、R 2 And P is as defined above.
In the method for producing the compound represented by the formula A5-1 (hereinafter, referred to as step S3), the reaction conditions, the kinds of reagents, and the amounts of the reagents used in the cyclization reaction may be those which are conventional in the art, and the following are preferred in the present invention.
In step S3, the cyclization reaction may be performed under the protection of an inert gas. The inert gas may be a protective gas conventional in the art, such as nitrogen and/or argon, again for example nitrogen.
In step S3, the POCl 3 The molar ratio to the compound of formula A4 may be 2.0 to 4.0, for example 3.0.
In step S3, the organic solvent may be a chlorinated alkane solvent and/or an amide solvent, preferably a chlorinated alkane solvent. The chlorinated hydrocarbon solvent may be one or more of dichloromethane, 1,2-dichloroethane and chloroform, preferably dichloromethane.
In step S3, the amount of the organic solvent used may not be particularly limited as long as the reaction is not affected. The volume-to-mass ratio of the organic solvent to the compound represented by the formula A4 may be 5 to 20mL/g, for example, 8mL/g.
In step S3, the temperature of the cyclization reaction may be 50 to 85 ℃, for example 75 ℃.
In step S3, the progress of the cyclization reaction can be monitored by monitoring methods conventional in the art, (e.g., TLC or HPLC), and is generally determined as the end point of the reaction when the compound of formula A4 disappears. The reaction time may be 1 to 12 hours, for example 3 hours.
In step S3, after the cyclization reaction, a post-treatment step may be further included, which may be a post-treatment operation conventional for such a reaction, for example, including one or more of extraction, drying, concentration and purification. The solvent for the extraction may be dichloromethane. The drying may be anhydrous sodium sulfate drying. The concentration may be distillation under reduced pressure.
In one embodiment of the present invention, the compound represented by formula A4 is preferably
In a certain embodiment of the present invention, the method for preparing the compound represented by formula A5-1 may further include a method for preparing a compound represented by formula A4 below, which includes the following step S2: under the action of alkali and a hydroxyl protecting agent P-Hal, carrying out condensation reaction on a compound shown as a formula A3 in an organic solvent to obtain a compound shown as a formula A4,
wherein R is 1 、R 2 And P are as defined above, hal is halogen.
In the method for producing the compound represented by the formula A4 (hereinafter, referred to as step S2), the reaction conditions, the kinds of reagents, and the amounts of the condensation reaction may be those conventionally used in the reaction of this type in the art, and the following are preferred in the present invention.
In step S2, the condensation reaction may be performed under the protection of an inert gas. The inert gas may be a protective gas conventional in the art, such as nitrogen and/or argon, again for example nitrogen.
In step S2, the base may be an organic base, such as a pyridine base or an imidazole base, such as imidazole.
In step S2, the molar ratio of the base to the compound of formula A3 may be 1 to 3, for example 2.
In step S2, the hydroxy protecting agent P-Hal may be tri-tert-butyldiphenylsilicon chloride or tert-butyldiphenylsilicon chloride, preferably tert-butyldiphenylsilicon chloride.
In step S2, the molar ratio of the hydroxy protecting agent P-Hal to the compound of formula A3 may be 1 to 2, for example 1.2.
In step S2, the organic solvent may be a chlorinated alkane and/or an amide, preferably a chlorinated alkane. The chlorinated hydrocarbon solvent may be one or more of dichloromethane, 1,2-dichloroethane and chloroform, preferably dichloromethane.
In step S2, the amount of the organic solvent used may not be particularly limited as long as the reaction is not affected. The volume-to-mass ratio of the organic solvent to the compound represented by the formula A3 may be 1 to 10mL/g, for example, 3 to 6mL/g.
In step S2, the temperature of the condensation reaction may be 10 to 30 ℃, for example 20 ℃.
In step S2, the progress of the condensation reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and is generally determined as the end point of the reaction when the compound of formula A3 disappears. The time for the condensation reaction may be 5 to 12 hours, for example 8 hours.
In step S2, after the condensation reaction, a post-treatment step may be further included, which may be a post-treatment operation conventional for such reactions, including, for example, one or more of extraction, drying, concentration and purification. The solvent for the extraction may be dichloromethane. The drying may be anhydrous sodium sulfate drying. The concentration may be distillation under reduced pressure. The purification may be column chromatography.
In one embodiment of the present invention, the compound represented by formula A3 is preferably
In a certain embodiment of the present invention, the method for preparing the compound represented by formula A4 may further include a method for preparing a compound represented by formula A3 below, which includes the following step S1: carrying out condensation reaction of a compound shown in a formula 1 and a compound shown in a formula A2 in an organic solvent under the action of a catalyst to obtain a compound shown in a formula A3,
wherein R is 1 And R 2 The definition of (A) is as described above.
In the method for producing the compound represented by the formula A3 (hereinafter, referred to as step S1), the reaction conditions, the kinds of reagents, and the amounts of the condensation reaction may be those conventionally used in the reaction of this type in the art, and the following are preferred in the present invention.
In step S1, the condensation reaction may be performed under the protection of an inert gas. The inert gas may be a protective gas conventional in the art, such as nitrogen and/or argon, again for example nitrogen.
In step S1, the catalyst may be one or more of "Dicyclohexylcarbodiimide (DCC) and 4-Diaminopyridine (DMAP)", 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium Hexafluorophosphate (HATU), and Carbonyldiimidazole (CDI), preferably "dicyclohexylcarbodiimide and 4-diaminopyridine". The molar ratio of dicyclohexylcarbodiimide to 4-diaminopyridine may be from 1 to 2, for example 1.
In step S1, the molar ratio of the catalyst to the compound of formula A2 may be 1 to 3, for example 2.4.
In step S1, the molar ratio of the compound represented by formula A1 to the compound represented by formula A2 may be 1 to 3, for example, 1.05.
In step S1, the organic solvent may be a chlorinated alkane and/or an amide, preferably a chlorinated alkane. The chlorinated hydrocarbon solvent may be one or more of dichloromethane, 1,2-dichloroethane and chloroform, preferably dichloromethane. The amount of the organic solvent to be used is not particularly limited as long as the reaction proceeds.
In step S1, the temperature of the condensation reaction may be 10 to 30 ℃, for example 20 ℃.
In step S1, the progress of the condensation reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and is generally determined as the end point of the reaction when the compound of formula A2 disappears. The time for the condensation reaction may be 8 to 24 hours, for example 12 hours.
In step S1, after the condensation reaction, a post-treatment step may be further included, which may be a post-treatment operation conventional for such reactions, including, for example, one or more of extraction, drying, concentration and purification. The solvent for the extraction may be dichloromethane. The drying may be anhydrous sodium sulfate drying. The concentration may be distillation under reduced pressure. The purification may be column chromatography.
In one embodiment of the present invention, the compound represented by formula A2 is preferably
In a certain embodiment of the present invention, the method for preparing the compound represented by formula A3 may further include a method for preparing a compound represented by formula A2 below, which includes the following step S0: under the action of an oxidant, carrying out Pinnick oxidation reaction on the compound shown in the formula A2-3 in an organic solvent to obtain the compound shown in the formula A2, namely,
wherein R is 1 And R 2 The definition of (c) is as described above.
In the method for producing the compound represented by the formula A2 (hereinafter, referred to as step S0), the conditions, kinds of reagents and amounts used in the Pinnick oxidation reaction may be those conventional in the art, and the present invention is preferably as follows.
In step S0, the oxidant can be an inorganic oxidant commonly used in the Pinnick oxidation reaction, and sodium chlorite is preferred.
In step S0, the molar ratio of the oxidizing agent to the compound represented by formula A2-3 may be 1 to 3, for example, 1.2.
In step S0, the solvent may be a mixed solvent of an organic solvent and water, wherein all the organic solvents may be one or more of ether solvents or alcohol solvents, such as one or more of tetrahydrofuran, 1,4-dioxane and tert-butanol, preferably tert-butanol. The volume ratio of the organic solvent to water can be 1 (5-10), such as 1.
In step S0, the amount of the solvent used may not be particularly limited as long as the reaction is not affected. The volume-mass ratio of the solvent to the compound represented by the formula A2-3 may be 5 to 20mL/g.
In step S0, the temperature of the Pinnick oxidation reaction may be 15 to 35 ℃, for example 20 ℃.
In step S0, the progress of the Pinnick oxidation reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and is generally determined as the end point of the reaction when the compound of formula A2-3 disappears.
In step S0, after the Pinnick oxidation reaction, a post-treatment step may be further included, which may be a post-treatment operation conventional for such reactions, including, for example, one or more of extraction, drying, concentration, and purification. The solvent for the extraction may be dichloromethane. The drying may be anhydrous sodium sulfate drying. The concentration may be distillation under reduced pressure. The purification may be petroleum ether pulping.
In a certain embodiment of the present invention, the method for preparing the compound represented by formula A2 may further include a method for preparing a compound represented by the following formula A2-3, which includes the steps of: carrying out recarburization reaction on the compound shown as the formula A2-2 to obtain the compound shown as the formula A2;
wherein the recarburization reaction comprises the following steps: (i) Under the action of alkali, carrying out Darzens reaction on the compound shown as the formula A2-2 and chloroacetate in an organic solvent to obtain a Darzens reaction product; (ii) Carrying out hydrolysis reaction on the Darzens reaction product under the action of alkali to obtain a hydrolysis reaction product; (iii) Carrying out decarboxylation reaction on the hydrolysis reaction product in a solvent under the action of acid to obtain a compound shown as a formula A2-3;
wherein R is 1 And R 2 The definition of (A) is as described above.
In the method for preparing the compound represented by the formula A2-3, the reaction conditions, the types of reagents, and the amounts of the Darzens reaction, the hydrolysis reaction, and the decarboxylation reaction in the recarburization reaction may be conventional conditions, types of reagents, and amounts of the reactions in this type of reaction in the art, and the following are preferred in the present invention.
In the recarburization reaction, the Darzens reaction can be carried out under the protection of inert gas. The inert gas may be a protective gas conventional in the art, such as nitrogen and/or argon, again for example nitrogen.
In the recarburization reaction, in the Darzens reaction, the chloroacetate may be methyl chloroacetate or ethyl chloroacetate, such as ethyl chloroacetate.
In the recarburisation reaction, the equivalent weight of the chloroacetate in the Darzens reaction is 1.2 to 2.0, for example 1.3.
In the recarburization reaction, in the Darzens reaction, the base may be sodium or potassium alkyl alkoxide, such as one or more of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and further such as sodium methoxide.
In the recarburization reaction, the molar ratio of the base to the compound represented by the formula A2-2 in the Darzens reaction may be 1.2 to 2.0, for example, 1.3.
In the recarburization reaction, the organic solvent in the Darzens reaction may be an alcohol solvent and/or an ether solvent, such as an alcohol solvent, and further such as methanol. The amount of the organic solvent to be used is not particularly limited as long as the reaction proceeds.
The temperature of the Darzens reaction in the recarburisation reaction may be in the range 0 to 35 c, for example 25 c.
In the recarburization reaction, the Darzens reaction time may be 1 to 5 hours, for example, 3 hours.
In the recarburization reaction, the Darzens reaction may include the steps of: the compound represented by the formula A2-2 is dissolved in the organic solvent to form a mixture solution, and the chloroacetate and the base are added (preferably in an ice water bath or an ice salt bath) to the mixture solution to perform the Darzens reaction.
In the recarburization reaction, the base in the hydrolysis reaction may be an alkali metal hydroxide, such as sodium hydroxide and/or potassium hydroxide, preferably potassium hydroxide.
In the recarburization reaction, the molar ratio of the base to the compound represented by the formula A2-2 in the hydrolysis reaction may be 1 to 3, for example, 1.3.
In the recarburization reaction, the temperature of the hydrolysis reaction may be 10 to 30 ℃, for example, 25 ℃.
In the recarburization reaction, the hydrolysis reaction may be carried out for 3 to 5 hours, for example, for 4 hours.
In the recarburization reaction, the decarboxylation reaction can be carried out under the protection of inert gas. The inert gas may be a protective gas conventional in the art, such as nitrogen and/or argon, again for example nitrogen.
In the recarburization reaction and the decarboxylation reaction, the acid can be one or more of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and potassium dihydrogen phosphate, and potassium dihydrogen phosphate is preferred.
In the recarburization reaction and the decarboxylation reaction, the acid may be a 10-50% acid solution, for example, a 50% potassium dihydrogen phosphate solution.
In the recarburization reaction, the molar ratio of the acid to the compound represented by the formula A2-2 in the decarboxylation reaction may be 1.5 to 5.0, for example, 1.5.
In the recarburization reaction, in the decarboxylation reaction, the solvent may be a mixed solvent of an organic solvent and water, wherein the organic solvent may be one or more of an alcohol solvent, an ether solvent or an amide solvent, preferably a mixed solvent of an ether solvent and water, for example, a mixed solvent of tetrahydrofuran and water.
In the recarburization reaction, the temperature of the decarboxylation reaction may be 60 ℃.
The progress of the decarboxylation reaction in the recarburization reaction can be monitored by monitoring methods conventional in the art (e.g., TLC or LCMS), typically at the end of the reaction when the hydrolysis reaction product disappears. The decarboxylation reaction may be carried out for a period of 8 to 36 hours, for example 24 hours.
In one embodiment of the present invention, the compound represented by the formula A2-2 is preferably
In one embodiment of the present invention, the compound represented by the formula A2-3 is preferably
In another aspect, the present invention also provides a method for preparing a compound represented by formula A7, which comprises the following step S8: under the action of a hydrogen source and a palladium catalyst, carrying out debenzylation protection reaction on a compound shown as a formula A6 in an organic solvent to obtain a compound shown as a formula A7;
R 1 、R 2 and R 3 The definition of (A) is as described above.
In the method for preparing the compound represented by the formula A7 (hereinafter, referred to as step S8), the reaction conditions, the types of reagents, and the amounts of the debenzylation protection reaction may be conventional conditions, types of reagents, and amounts of reagents in reactions of this type in the art, and the following are preferred in the present invention.
In step S8, the compound represented by formula A6 may be prepared according to the method for preparing a compound represented by formula A6 as described above.
In step S8, the debenzylation protection reaction may be performed under the protection of an inert gas. The inert gas may be a protective gas conventional in the art, such as nitrogen and/or argon, again for example nitrogen.
In step S8, the hydrogen source is hydrogen gas and/or sodium hydride, such as sodium hydride.
In step S8, the molar ratio of the hydrogen source to the compound represented by formula A6 may be 1.05 to 2.0, for example, 1.5.
In step S8, the palladium catalyst is one or more of dry palladium carbon, palladium hydroxide, palladium chloride and palladium acetate, such as palladium chloride.
In step S8, the molar ratio of the palladium catalyst to the compound represented by formula A6 may be 0.02 to 0.1, for example, 0.05.
In step S8, the organic solvent is an ether solvent or an amide solvent, preferably an ether solvent, such as tetrahydrofuran.
In step S8, the amount of the organic solvent used may not be particularly limited as long as the reaction is not affected. The volume-to-mass ratio of the organic solvent to the compound represented by the formula A6 may be 10 to 50mL/g, for example, 20 to 30mL/g.
In step S8, the temperature of the reaction for removing the benzyl protecting group may be 40 to 70 ℃, for example, 50 ℃.
In step S8, the progress of the reaction for removing the benzyl protecting group can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and is generally determined as the end point of the reaction when the compound represented by formula A6 disappears. The debenzylation protection reaction may be carried out for a period of time of 4 to 24 hours, for example 6 hours.
In one embodiment of the present invention, the compound represented by formula A6 is preferably
In one embodiment of the present invention, the compound represented by formula A7 is preferably
In step S8, after the debenzylation protection reaction, a post-treatment step may be further included, and the post-treatment step may be a post-treatment operation conventional for such a reaction, for example, including one or more of adjustment of system pH, extraction, drying, concentration, and purification. The pH can be adjusted by using a saturated potassium dihydrogen phosphate solution. The pH of the adjustment system may be 6. The solvent for the extraction may be dichloromethane. The drying may use anhydrous sodium sulfate. The concentration may be distillation under reduced pressure. The purification may be column chromatography.
In another aspect, the present invention also provides a method for preparing a compound represented by formula A9, which includes the following step S11: carrying out acidification reaction on the water suspension of the compound shown in the formula A8 under the action of acid to obtain an acidification reaction product, then carrying out oxidation reaction on the acidification reaction product in an organic solvent under the action of an oxidant to obtain a compound shown in the formula A9,
wherein R is 1 、R 2 And R 3 The definition of (A) is as described above.
In the method for producing the compound represented by the formula A9 (hereinafter, referred to as step S11), the reaction conditions, the types of reagents, and the amounts of the acidification reaction and the oxidation reaction may be those conventionally used in the art, and the types and amounts of the reagents are preferred in the present invention.
In step S11, in the acidification reaction, the acid may be one or more of sulfuric acid, hydrochloric acid, acetic acid and formic acid, such as hydrochloric acid and/or acetic acid. The hydrochloric acid may be 5% to 20% hydrochloric acid, for example 10% hydrochloric acid. The acetic acid may be 5% to 20% acetic acid, for example 10% acetic acid.
In the step S11, the amount of the acid in the acidification reaction is preferably about 1 to 2, for example, 2.
In step S11, the acidification reaction is carried out under ice-water bath or ice-salt bath conditions, such as an ice-water bath, again for example at 0 ℃.
In step S11, after the acidification reaction, a post-treatment step may be further included, and the post-treatment step may be a post-treatment operation conventional for such reactions, for example, including one or more of extraction, drying, and concentration. The solvent for the extraction may be dichloromethane. The drying may use anhydrous sodium sulfate. The concentration may be distillation under reduced pressure.
In step S11, in the oxidation reaction, the oxidizing agent may be hydrogen peroxide and/or m-chloroperoxybenzoic acid, such as m-chloroperoxybenzoic acid (mCPBA).
In step S11, in the oxidation reaction, the molar ratio of the oxidant to the compound represented by formula A8 may be 1 to 2, for example, 1.1.
In step S11, in the oxidation reaction, the organic solvent may be a chloroalkane solvent. The chloroalkane solvent can be one or more of dichloromethane, 1,2 dichloroethane, and chloroform, preferably dichloromethane.
In step S11, the temperature of the oxidation reaction may be 10 to 30 ℃, for example, 25 ℃.
In step S11, the progress of the oxidation reaction can be monitored by monitoring methods conventional in the art, (e.g., TLC or HPLC), and is generally determined as the end point of the reaction when the compound of formula A8 disappears. The reaction time may be 3 to 8 hours, for example 4 hours.
In step S11, after the oxidation reaction, a post-treatment step may be further included, and the post-treatment step may be a post-treatment operation that is conventional for such a reaction, and includes, for example, one or more of adjustment of the pH of the system, extraction, drying, concentration, and purification. Saturated sodium bicarbonate can be used for adjusting the pH. The pH of the adjustment system may be 8. The solvent for the extraction may be dichloromethane. The drying may use anhydrous sodium sulfate. The concentration may be distillation under reduced pressure. The purification may be column chromatography.
In one embodiment of the present invention, the compound represented by the formula A8 is preferably
In one embodiment of the present invention, the compound represented by formula A9 is preferably
In a certain embodiment of the present invention, the method for preparing the compound represented by formula A9 may further include a method for preparing a compound represented by formula A8 below, which includes the following step S10: subjecting formula A8-1 to a cyclization reaction in an organic solvent under the action of a cyclization agent to obtain the compound shown in formula A8,
wherein R is 1 、R 2 And R 3 The definition of (A) is as described above.
In the method for producing the compound represented by the formula A8 (hereinafter, referred to as step S10), the reaction conditions, the kinds of reagents, and the amounts used in the cyclization reaction may be those which are conventional in the art, and the following are preferred in the present invention.
In step S10, the cyclization reaction may be performed under an inert gas atmosphere. The inert gas may be a protective gas conventional in the art, such as nitrogen and/or argon, again for example nitrogen.
In step S10, the cyclizing reagent may be one or more of N, N-dimethylformamide dimethyl acetal, p-toluic acid, sodium methoxide and sodium ethoxide, and N, N-dimethylformamide dimethyl acetal is preferred.
In step S10, the organic solvent may be a chlorinated alkane solvent. The chloroalkane solvent may be one or more of dichloromethane, 1,2 dichloroethane, and chloroform, preferably dichloromethane. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected.
In step S10, the temperature of the cyclization reaction may be 20 to 35 ℃, for example 25 ℃.
In step S10, the progress of the cyclization reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and is generally determined as the end point of the reaction when the compound of formula A8-1 disappears. The time for the reduction reaction may be 8 to 24 hours, for example 10 hours.
In step S10, after the cyclization reaction, a post-treatment step may be further included, which may be a post-treatment operation conventional for such a reaction, for example, including one or more of extraction, drying, concentration and purification. The solvent for the extraction may be dichloromethane. The drying may be anhydrous sodium sulfate drying. The concentration may be distillation under reduced pressure. The purification may be column chromatography.
In a certain embodiment of the present invention, the compound represented by the formula A8-1 is preferably
In a certain embodiment of the present invention, the method for preparing the compound represented by formula A8 may further include a method for preparing a compound represented by the following formula A8-1, which includes the following step S9: carrying out a reduction reaction shown in the following formula A7 in an organic solvent under the action of a reducing agent to obtain the compound shown in the formula A8-1,
wherein R is 1 、R 2 And R 3 The definition of (c) is as described above.
In the method for producing the compound represented by the formula A8-1 (hereinafter, referred to as step S9), the reaction conditions, the kind of the reagent, and the amount of the reduction reaction may be those conventionally used in the art, and the kind of the reagent and the amount of the reagent are preferred in the present invention.
In step S9, the reduction reaction may be performed under the protection of an inert gas. The inert gas may be a protective gas conventional in the art, such as nitrogen and/or argon, again for example nitrogen.
In step S9, the compound represented by formula A7 may be prepared according to the above-described method for preparing the compound represented by formula A7.
In step S9, the reducing agent may be an alkali metal borohydride and/or lithium aluminum hydride. The alkali metal borohydride can be sodium borohydride and/or lithium borohydride, preferably lithium borohydride.
In step S9, the molar ratio of the reducing agent to the compound represented by formula A7 may be 3 to 6, for example, 5.0.
In step S9, the organic solvent may be an ether solvent, such as tetrahydrofuran. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected.
In step S9, the temperature of the reduction reaction may be from-5 to 35 deg.C, such as from 10 to 30 deg.C, and further such as 25 deg.C.
In step S9, the progress of the reduction reaction can be monitored by a conventional monitoring method in the art (e.g., TLC or LCMS), and is generally defined as the end point of the reaction when the compound represented by formula 7 disappears. The time for the reduction reaction may be 10 to 18 hours, for example 12 hours.
Step S9 may include the steps of: the compound represented by the formula A7 is dissolved in the organic solvent to form a mixture solution, and the reducing agent is added (preferably, at 0 ℃) to the mixture solution to perform the reduction reaction.
In one embodiment of the present invention, the compound represented by formula A7 is preferably
In another aspect, the present invention also provides a use of a compound represented by formula A9 as an intermediate in the preparation of a compound represented by formula a10 or a11, which comprises the following scheme 1 or scheme 2:
scheme 1, which comprises the following step S12: hydrogenating a compound shown as a formula A9 in an organic solvent with hydrogen under the action of a catalyst to obtain a compound shown as a formula A10,
wherein R is 1 、R 2 And R 3 As defined above;
scheme 2, which comprises the following steps S12 and S13, wherein the step S12 is the same as the scheme 1;
step S13: carrying out deprotection reaction on the compound shown in the formula A10 in an organic solvent under the action of a deprotection reagent to obtain the compound shown in the formula A11,
wherein R is 1 、R 2 And R 3 The definition of (c) is as described above.
In the schemes 1 and 2, the reaction conditions, the kinds of reagents, and the amounts of the hydrogenation reaction and the deprotection reaction may be those conventionally used in the art, and the present invention is preferably as follows.
In step S12, the catalyst may be raney nickel and/or a palladium catalyst, preferably a palladium catalyst, and further preferably 5% palladium/barium sulfate, where "%" is the mass percentage of the total mass of palladium and barium sulfate.
In step S12, the mass percentage of the catalyst to the compound represented by formula A9 may be 30 to 50%.
In step S12, the organic solvent may be an alcohol solvent. The alcoholic solvent may be methanol and/or ethanol, preferably methanol.
In step S12, the amount of the organic solvent used may not be particularly limited as long as the reaction is not affected.
In step S12, the pressure of the hydrogenation reaction may be 1 to 1.5atm, for example, 1atm.
In step S12, the temperature of the hydrogenation reaction may be 20 to 35 deg.C, for example 25 deg.C.
In step S12, the progress of the hydrogenation reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and is generally determined as the end point of the reaction when the compound of formula A9 disappears. The hydrogenation reaction time may be 3 to 10 hours, for example 8 hours.
In step S12, after the hydrogenation reaction, a post-treatment step may be further included, which may be a post-treatment operation conventional for such reactions, including, for example, one or more of extraction, drying, concentration and purification. The solvent for the extraction may be dichloromethane. The drying may use anhydrous sodium sulfate. The concentration may be distillation under reduced pressure. The purification may be column chromatography.
In one embodiment of the present invention, the compound represented by the formula A9 is preferably
In step S13, the deprotection reaction may be performed under the protection of an inert gas. The inert gas may be a protective gas conventional in the art, such as nitrogen and/or argon, again for example nitrogen.
In step S13, the deprotection reagent may be boron trichloride and/or boron tribromide, preferably boron tribromide.
In step S13, the molar ratio of the deprotecting reagent to the compound represented by formula a10 may be 5 to 10, for example 8.
In step S13, the organic solvent may be a chlorinated alkane, preferably dichloromethane. The amount of the organic solvent to be used is not particularly limited as long as the reaction proceeds.
In step S13, the deprotection reaction is carried out at a temperature of-20 to 25 deg.C, for example, 10 deg.C.
In step S13, the progress of the deprotection reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and is generally used as the end point of the reaction when the compound represented by formula A10 disappears. The deprotection reaction may be carried out for a period of 5 to 10 hours, for example 8 hours.
In step S13, after the deprotection, a post-treatment step may be further included, and the post-treatment step may be one or more of post-treatment operations, such as extraction, drying, concentration and purification, which are conventional for such reactions. The solvent for the extraction may be dichloromethane. The drying may use anhydrous sodium sulfate. The concentration may be distillation under reduced pressure. The purification may be column chromatography.
In one embodiment of the present invention, the compound represented by formula A10 is preferably
In another aspect, the present invention also provides a method for preparing a compound represented by formula B2-3, comprising the steps of: subjecting a compound represented by the formula B2-2 to a recarburization reaction as shown below to obtain a compound represented by the formula B2-3,
wherein R is 8 And R 9 Independently H, C 1～10 Alkyl radical, C 1～10 Alkoxy radical, C 3～10 Cycloalkyl, benzyl or C 6～20 An aryl group; r 10 Is halogen, C 1～6 Alkyl radical, C 1～6 Cycloalkyl or C 6～20 An aryl group; r is 11 And R 12 Independently H, C 1～10 Alkyl radical, C 1～10 Alkoxy radical, C 3～10 Cycloalkyl or C 6～20 An aryl group;
the conditions and operation of the recarburization reaction are the same as those described above.
In one embodiment of the present invention, R 8 Can be C 1～10 Alkyl radicals, e.g. C 1～4 Alkyl, again for example methyl.
In one embodiment of the present invention, R 9 May be a benzyl group.
In one embodiment of the present invention, R 10 May be a halogen, such as Br.
In one embodiment of the present invention, R 11 May be H.
In one embodiment of the present invention, R 12 May be H.
In one embodiment of the present invention, the compound represented by the formula B2-2 is preferably
In one embodiment of the present invention, the compound represented by the formula B2-3 is preferably
In another aspect, the present invention also provides a method for preparing a compound represented by formula A5-1, comprising the following step S3: it comprises the following steps S3: in POCl 3 Subjecting a compound represented by the formula A4 to a cyclization reaction in an organic solvent as shown below to obtain a compound represented by the formula A5-1,
wherein R is 1 、R 2 And P are as defined above, and the conditions and operation of the cyclization reaction are as defined above.
In another aspect, the present invention provides a method for preparing a compound represented by formula A8-1, comprising the following step S9: under the protection of inert gas and the action of a reducing agent, carrying out the reduction reaction shown as the following on the compound shown as the formula A7 in an organic solvent to obtain the compound shown as the formula A8-1,
wherein R is 1 、R 2 And R 3 As defined above, and the conditions and operation of the reduction reaction are as defined above.
In another aspect, the present invention also provides a method for preparing a compound represented by formula a13, which includes the following step S15: carrying out nucleophilic addition reaction on the compound shown in the formula A12 in an organic solvent under the action of a nucleophilic reagent to obtain a compound shown in a formula A13;
wherein R is 1 、R 2 And R 3 As defined above, R 4 Is C 1～10 Alkyl radical, C 3～10 Cycloalkyl or C 6～20 And (4) an aryl group.
In the method for producing the compound represented by formula a13 (hereinafter, referred to as step S15), the reaction conditions, the types of reagents, and the amounts of the nucleophilic addition reaction may be those conventionally used in reactions of this type in the art, and the following are preferred in the present invention.
In step S15, the nucleophilic addition reaction may be performed under the protection of an inert gas; the inert gas may be a protective gas conventional in the art, such as nitrogen and/or argon, again for example nitrogen.
In step S15, the nucleophile may be a grignard reagent and/or a lithium reagent, preferably a grignard reagent.
In step S15, the molar ratio of the nucleophile to the compound of formula a12 may be 5 to 10, for example 7.
In step S15, the organic solvent may be an ether solvent and/or a substituted aromatic hydrocarbon solvent, such as an aromatic hydrocarbon solvent, and further such as toluene.
In step S15, the amount of the organic solvent used may not be particularly limited as long as the reaction is not affected. The volume to mass ratio of the organic solvent to the compound of formula a12 may be that of such reactions in the art, for example, 5 to 100mL/g, and further for example, 40 to 60mL/g.
In step S15, the temperature of the nucleophilic addition reaction may be from-5 to 35 deg.C, such as from 10 to 30 deg.C, and further such as 25 deg.C.
In step S15, the progress of the nucleophilic addition reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and the end point of the reaction is generally determined as the disappearance or no longer reaction of the compound represented by formula A12. The nucleophilic addition reaction may be carried out for a period of 4 to 10 hours, for example 6 hours.
In step S15, after the nucleophilic addition reaction, a post-treatment step may be further included, which may be a post-treatment operation conventional for such reactions, including, for example, one or more of quenching, extraction, drying, concentration, and purification. The quenching can be performed by adding saturated ammonium chloride solution into the system. The extracted organic solvent may be ethyl acetate. The solvent for the washing may be a saturated sodium chloride solution. The drying may be carried out using anhydrous sodium sulfate. The concentration may be distillation under reduced pressure. The purification may be column chromatography.
In one embodiment of the present invention, R 4 Can be C 1～4 Alkyl, preferably tert-butyl.
In one embodiment of the present invention, the compound represented by formula A12 is preferably
In one embodiment of the present invention, the compound represented by formula A13 is preferably
In a certain embodiment of the present invention, the method for preparing the compound represented by formula a13 may further include a method for preparing a compound represented by formula a12 below, which includes the following step S14: performing cycloaddition reaction on the compound shown in the formula A8 and methyl vinyl ketone to obtain a compound shown in a formula A12,
R 1 、R 2 and R 3 The definition of (A) is as described above.
In the method for producing the compound represented by formula a12 (hereinafter, referred to as step S14), the reaction conditions, the kinds of reagents, and the amounts of the cycloaddition reaction may be those which are conventional in the art, and the following are preferred in the present invention.
In step S14, the compound represented by formula A8 may be prepared according to the above-described method for preparing a compound represented by formula A8.
In step S14, the volume-to-mass ratio of the methyl vinyl ketone to the compound represented by formula A8 may be 0.5 to 5mL/100mg, for example, 3mL/100mg.
In step S14, the temperature of the cycloaddition reaction may be 70 to 90 ℃, for example 80 ℃.
In step S14, the progress of the cycloaddition reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and is generally determined as the end point of the reaction when the compound of formula A8 disappears. The cycloaddition reaction may be carried out for a period of time of 4 to 16 hours, for example 6 hours.
In step S14, after the cycloaddition reaction, the method may further comprise a post-treatment step, which may be a conventional post-treatment operation for such a reaction, such as direct concentration and purification. The concentration may be distillation under reduced pressure. The purification may be column chromatography.
In one embodiment of the present invention, the compound represented by the formula A8 is preferably
In another aspect, the present invention also provides a method for preparing a compound represented by formula a14, which includes the following step S16: subjecting the compound represented by the formula A13 to a hydrogenation reaction with hydrogen in an organic solvent in the presence of a catalyst to obtain a compound represented by the formula A14,
the hydrogenation reaction is carried out at a pressure of 5 to 30atm, for example 10atm.
Wherein R is 1 、R 2 、R 3 And R 4 The definition of (A) is as described above.
In the method for producing the compound represented by the formula a14 (hereinafter, referred to as step S16), the reaction conditions, the kind of the reagent, and the amount of the hydrogenation reaction may be those conventionally used in the art, and the kind of the reagent, and the amount are preferably as follows.
In step S16, the compound represented by formula a13 may be prepared according to the above-described method for preparing the compound represented by formula a 13.
In step S16, the catalyst may be a metal catalyst, such as a palladium catalyst, and further such as palladium on carbon.
In step S16, the molar ratio of the catalyst to the compound represented by formula a13 may be 0.03 to 0.2; such as 0.1.
In step S16, the organic solvent may be an ether and/or alcohol solvent, such as an alcohol solvent, such as ethanol and/or isopropanol, and further such as isopropanol.
In step S16, the amount of the organic solvent used may not be particularly limited as long as the reaction is not affected.
In step S16, the temperature of the hydrogenation reaction may be 50-80 deg.C, for example 70 deg.C.
In step S16, the progress of the hydrogenation reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and the end point of the reaction is generally determined as the disappearance or no longer reaction of the compound represented by formula A13. The hydrogenation reaction time may be 8 to 16 hours, for example 10 hours.
In one embodiment of the present invention, the compound represented by formula A13 is preferably
In one embodiment of the present invention, the compound represented by formula A14 is preferably
In another aspect, the present invention also provides a method for preparing a compound represented by formula a15, which includes the following step S17: subjecting the compound represented by the formula A14 to demethylation reaction in an organic solvent under the action of a base and a thiol to obtain the compound represented by the formula A15,
wherein R is 1 、R 2 、R 3 And R 4 The definition of (A) is as described above.
In the method for producing the compound represented by the formula a15 (hereinafter, referred to as step S17), the reaction conditions, the kinds of reagents, and the amounts of the demethylation reaction may be those conventionally used in reactions of this type in the art, and the present invention is preferably as follows.
In step S17, the compound represented by formula a14 may be prepared according to the above-described method for preparing a compound represented by formula a 14.
In step S17, the demethylation reaction may be performed under the protection of an inert gas; the inert gas may be a protective gas conventional in the art, such as nitrogen and/or argon, again for example nitrogen.
In step S17, the base may be an alcoholic base, such as sodium tert-butoxide and/or potassium tert-butoxide.
In step S17, the mercaptan may be an alkyl mercaptan, such as n-dodecyl mercaptan.
In step S17, the molar ratio of the base to the compound a14 may be 1.8 to 3.0, for example, 2.0.
In step S17, the organic solvent may be an amide and/or sulfoxide-based solvent, such as DMSO and/or DMF.
In step S17, the amount of the organic solvent used may not be particularly limited as long as the reaction is not affected.
In step S17, the temperature of the demethylation reaction may be in the range of 100 to 130 deg.C, for example 120 deg.C.
In step S17, the progress of the demethylation reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and the end point of the reaction is generally the disappearance or no longer reaction of the compound of formula A14. The time for the reduction reaction may be 1 to 3 hours, for example 2 hours.
Step S17, after the demethylation reaction, may further comprise a post-treatment step, which may be one or more of the post-treatment operations conventional for such reactions, including, for example, extraction, drying, concentration, and purification. The solvent for the extraction may be ethyl acetate. The drying may be anhydrous sodium sulfate drying. The concentration may be distillation under reduced pressure. The purification may be column chromatography.
In one embodiment of the present invention, the compound represented by formula A14 is preferably
In one embodiment of the present invention, the compound represented by formula A15 is preferably
In another aspect, the present invention also provides a method for preparing a compound represented by formula A8, which includes the following steps S1 to S10:
wherein R is 1 、R 2 、R 3 And P are as defined above, and the conditions and operations of the steps S1 to S10 are as defined above.
In another aspect, the present invention also provides a method for preparing a compound represented by formula a11, which includes the following steps S11 to S13:
wherein R is 1 、R 2 And R 3 The above-mentioned definitions of (1) and (2) are the same as those described above, and the conditions and operations of step S11 to step S13 are the same as those described above.
On the other hand, the present invention also provides a method for preparing a compound represented by formula a15, which comprises the following steps S14 to S17:
wherein R is 1 、R 2 、R 3 And R 4 The conditions and operations of the steps S14 to S17 are as described above.
In another aspect, the present invention also provides a compound represented by formula A5-1:
wherein R is 1 、R 2 And P is as defined above.
In another aspect, the present invention also provides a compound represented by formula A5-2:
wherein R is 1 、R 2 And P is as defined above.
In another aspect, the present invention also provides a compound represented by formula A5-3:
wherein R is 1 、R 2 、R 3 And P is as defined above.
In another aspect, the invention also provides a compound of formula A5:
wherein R is 1 、R 2 And R 3 The definition of (A) is as described above.
In another aspect, the present invention also provides a compound represented by formula A6:
wherein R is 1 、R 2 And R 3 The definition of (A) is as described above.
In another aspect, the present invention also provides a compound represented by formula A7:
wherein R is 1 、R 2 And R 3 The definition of (A) is as described above.
In another aspect, the invention also provides a compound of formula A8:
wherein R is 1 、R 2 And R 3 The definition of (A) is as described above.
In another aspect, the invention also provides a compound of formula A8:
wherein R is 1 、R 2 And R 3 The definition of (A) is as described above.
In another aspect, the invention also provides a compound of formula A9:
wherein R is 1 、R 2 And R 3 The definition of (A) is as described above.
In another aspect, the present invention also provides a compound represented by formula a 10:
wherein R is 1 、R 2 And R 3 The definition of (A) is as described above.
In another aspect, the invention also provides a compound of formula a 12:
wherein R is 1 、R 2 And R 3 The definition of (A) is as described above.
In another aspect, the present invention also provides a compound represented by formula a 13:
wherein R is 1 、R 2 、R 3 And R 4 The definition of (A) is as described above.
In one embodiment of the present invention, the compounds represented by the formula A5-1, A5-2, A5-3, A5, A6, A7, A8-1, A8, A9, A10, A12 or A13 may each be selected from the following compounds:
in the present invention, "alkyl" includes straight-chain alkyl and branched-chain alkyl.
In the present invention, "alkoxy" means a group-O-R X Wherein R is X Is an alkyl group as defined above.
In the present invention, "cycloalkyl" means a monovalent saturated cyclic alkyl group, preferably having 3 to 7 ring carbon atoms, more preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In the present invention, "aryl" refers to a group having a 4n +2 aromatic ring system (e.g., 6, 10, or 14 p electrons shared in the cyclic array). Aryl of 6 to 14 carbon atoms, such as phenyl, naphthyl, phenanthryl, or anthracyl, is preferred.
In the present invention, "room temperature" or "normal temperature" means 10 to 30 ℃ such as 25 ℃.
In the present invention, "ice-water bath" or "ice-salt bath" means-5 to 5 ℃ for example, 0 ℃.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the synthetic route and the intermediate of the invention can adopt cheap and easily obtained vanillin and isovanillin as starting materials to realize the preparation of opioid compounds, and provide possibility for the large-scale production of the opioid compounds.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. Experimental procedures without specifying specific conditions in the following examples were selected in accordance with conventional procedures and conditions, or in accordance with commercial instructions.
Example 1: a compound represented by formula 1 (4- (2-aminoethyl) -2-methoxyphenol)
2-methoxy-4- (2-nitrovinyl) phenol (2-methoxy-4- (2-nitrovinyl) phenol):
adding 250mL of nitromethane (5 mL of nitromethane/1 g of vanillin), preheating to 110 ℃, adding vanillin (50g, 0.3286mol and 1eq.), adding ethylenediamine (0.25mL, 0.003744mol and 0.01eq.) after complete dissolution, transferring to a 1L round-bottom flask after 2 hours of reaction while the solution is hot, distilling under reduced pressure until no solvent exists, adding 100mL of MeOH/H 2 O =1:1 mixed solvent slurried for 2H, filtered, and treated with 50mL MeOH/H 2 The cake was washed twice with the mixed solvent O, the filter cake was collected and dried to give a nitroene product as an orange-yellow powder, 2-methoxy-4- (2-nitrovinyl) phenol (57.7 g,90% yield).
1 H NMR(500MHz,CDCl 3 )δ7.96(d,J＝13.3Hz,1H),7.52(d,J＝13.5Hz,1H),7.14(d,J＝7.7Hz,1H),7.04–6.94(m,2H),6.05(s,1H),3.96(s,3H).
13 C NMR(126MHz,CDCl 3 )δ149.88,147.19,139.63,135.14,125.07,122.56,115.42,110.25,56.24.
HRMS(ESI+):m/z calculated for C 9 H 8 NO 4 [M+H] + :194.0459,found:194.0460.
4- (2-aminoethyl) -2-methoxyphenol (4- (2-aminoethyl) -2-methoxyphenol):
2-methoxy-4- (2-nitrovinyl) phenol (57.7g, 0.2956mol, 1eq.), 480mL of a mixed solvent of THF/MeOH =7:1, cooled to 0 ℃ and NaBH added portionwise 4 (17.4g, 0.4611mol, 1.56eq.) and after addition, the reaction was allowed to return to room temperature. After the reaction is completed, cooling the reaction system to 0 ℃, adding 1M HCl solution to quench the reaction and adjusting the pH value to about 7, evaporating the organic solvent, adding ethyl acetate to extract, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain an oily substance. The oily matter was dissolved in methanol and transferred to a hydrogenation vessel, and palladium on carbon (6 g,10 mol%) was added thereto, and the reaction was carried out overnight at 40 ℃ under normal pressure. After the reaction was completed, the reaction mixture was filtered through celite, the filter cake was washed with methanol three times, the filtrates were combined, vacuum distilled and then slurried with dichloromethane, filtered, the filter cake was washed with dichloromethane, and the filter cake was collected and dried to obtain an off-white powdery phenethylamine-based product, 4- (2-aminoethyl) -2-methoxyphenol (39.0 g,80% yield).
1 H NMR(500MHz,CD 3 OD)δ6.85(s,1H),6.77(d,J＝8.0Hz,1H),6.70(dd,J＝8.0,1.8Hz,1H),3.86(s,3H),3.12(t,J＝7.6Hz,2H),2.86(t,J＝7.5Hz,2H).
13 C NMR(126MHz,CD 3 OD)δ147.88,145.39,127.85,120.87,115.12,111.88,54.98,40.93,33.17.
HRMS(ESI+):m/z calculated for C 9 H 14 NO 2 [M+H] + :168.1019,found:168.1022.
Example 2: a compound (2- (3- (benzyloxy) -2-bromo-4-methoxyphenyl) acetic acid) represented by the formula 2
A compound represented by the formula 2-1 (2-bromo-3-hydroxy-4-methoxybenzadhehyde)
3-hydroxy-4-methoxybenzaldehyde (10.0g, 0.0657mol, 1.0eq.) was dissolved in 100mL of DCM, the temperature was reduced to 0 ℃, NBS (12.8g, 0.0723mol, 1.1eq.) was added in portions, and the reaction was continued at room temperature after 1 hour at low temperature. After the reaction, the temperature is reduced to 10 ℃, saturated sodium chloride solution is added, the mixture is stirred for 0.5 hour and then filtered, filter cake is washed by water for 2 times, and the compound 2 (14.6 g,96 percent yield) is obtained after drying. The organic phases in the filtrate can be combined for several batches and then purified by recrystallization to obtain the compound 2-1.
1 H NMR(500MHz,CD 3 OD)δ10.20(s,1H),7.47(d,J＝8.6Hz,1H),7.05(d,J＝8.5Hz,1H),3.96(s,3H).
13 C NMR(126MHz,CD 3 OD)δ191.20,153.23,127.05,121.49,113.22,109.36,55.52.
HRMS(ESI+):m/z calculated for C 8 H 8 BrO 3 [M+H] + :230.9651,found:230.9642.
A compound represented by the formula 2-2 (3- (benzoyloxy) -2-bromo-4-methoxybenzaldehyde)
Compound 2-1 (14.6 g,0.0631mol, 1.0eq.) was dissolved in 100mL of DMF, and the solution was cooled to 0 ℃ and K was added 2 CO 3 (10.5g, 0.0757mol, 1.2eq.) and BnBr (8.2mL, 0.0694mol, 1.1eq.), reacted at low temperature for 1 hour and then returned to room temperature to continue the reaction. After the reaction is finished, filtering is carried out, a filter cake is washed by dichloromethane, a large part of filtrate is removed by rotation, a saturated sodium chloride solution and triethylamine (0.96mL, 0.00694mol and 0.11eq.) are added, stirring is carried out for 0.5 hour, dichloromethane is used for extraction for three times, dichloromethane is dried by rotation to obtain an oily substance, a saturated sodium chloride solution is added, stirring is carried out to obtain a white solid, filtering and drying are carried out to obtain a compound 2-2 (18.8g and 93 percent yield).
1 H NMR(500MHz,CDCl 3 )δ10.26(s,1H),7.75(s,1H),7.55(d,J＝7.3Hz,2H),7.38(dt,J＝23.4,7.2Hz,3H),6.98(d,J＝8.7Hz,1H),5.05(s,2H),3.96(s,4H).
13 C NMR(126MHz,CDCl 3 )δ191.20,158.90,145.20,136.72,128.63,128.55,128.47,127.49,126.73,123.69,111.03,74.93,56.45.
HRMS(ESI+):m/z calculated for C 15 H 13 BrNaO 3 [M+Na] + :342.9940,found:342.9943.
A compound represented by the formula 2-3 (2- (3- (benzyloxy) -2-bromo-4-methoxyphenyl) acetaldehyde)
Compound 2-2 (18.8g, 0.0587mol, 1.0eq.) was weighed into a 500mL three-necked flask, nitrogen was purged three times, 100mL of ultra-dry methanol was added, the temperature was lowered to 0 ℃, ethyl chloroacetate (8.0mL, 0.0763mol, 1.3eq.) and a solution of sodium methoxide in methanol (15.2mL, 0.0763mol, 1.3eq.) were added slowly and reacted at low temperature. After the reaction was completed, KOH solution (4.3 g,0.0763mol,1.3 eq.) was added, and the mixture was stirred at room temperature for about 0.5 hour, whereupon a large amount of white solid precipitated, placed in a refrigerator and left to stand for 0.5 hour, filtered, washed with cold methanol: washing the filter cake twice with a mixed solvent of dichloromethane =1:1, and drying the filter cake to obtain the organic potassium salt. Adding organic potassium salt to KH 2 PO 4 (12.0 g,0.0881mol,1.5 eq.) of THF/H 2 Heating to 60 deg.C in O mixed solution, reacting for 24 hr, extracting with ethyl acetate, drying with anhydrous sodium sulfate, and spin-drying oily compound 2-3 (14.2g, 72% yield) of organic solvent
1 H NMR(500MHz,CDCl 3 )δ9.73(d,J＝1.7Hz,1H),7.55(d,J＝7.3Hz,2H),7.41–7.32(m,3H),6.98(d,J＝8.4Hz,1H),6.89(d,J＝8.4Hz,1H),5.04(s,2H),3.88(s,3H),3.83(d,J＝1.2Hz,2H).
13 C NMR(126MHz,CDCl 3 )δ199.12,153.33,145.86,137.15,128.58,128.48,128.26,126.71,125.59,121.26,111.61,74.73,56.29,50.26.
HRMS(ESI+):m/z calculated for C 16 H 15 BrNaO 3 [M+Na] + :357.0097,found:357.0093.
A compound (2- (3- (benzyloxy) -2-bromo-4-methoxyphenyl) acetic acid) represented by the formula 2
Transferring compound 2-3 (14.2g, 0.0423mol,1.0 eq.) to 500mL egg-shaped flask, adding 20mL tert-butanol and 10mL isoamylene, cooling to 0 deg.C, and slowly adding NaClO 2 (4.6g, 0.0508mol, 1.2eq.) and NaH 2 PO 4 (40.6g, 0.3384mol,8.0 eq.) was mixed with an aqueous solution (150 mL), and the reaction was then allowed to return to room temperature. Extracting with ethyl acetate after the reaction is finished, drying with anhydrous sodium sulfate, and rotating to remove the solventObtaining oily matter, pulping with petroleum ether, filtering, washing the filter cake once with petroleum ether, and drying the filter cake to obtain a white powdery compound 2 (13.5g, 91 percent yield).
1 H NMR(500MHz,CDCl 3 )δ7.56(d,J＝7.5Hz,2H),7.36(dt,J＝27.4,7.3Hz,3H),7.04(d,J＝8.4Hz,1H),6.87(d,J＝8.4Hz,1H),5.03(s,2H),3.87(s,3H),3.82(s,2H).
13 C NMR(126MHz,CDCl 3 )δ177.31,153.17,145.60,137.22,128.52,128.43,128.17,126.58,126.51,121.39,111.30,74.65,56.21,41.15.
HRMS(ESI+):m/z calculated for C 16 H 15 BrNaO 4 [M+Na] + :373.0046,found:373.0051.
Example 3 the compound represented by the formula 3 (2- (3- (phenyloxy) -2-bromo-4-methoxyphenyl) -N- (4-hydroxy-3-methoxyphenyl) acetamide)
A clean dry round-bottomed flask equipped with a stirrer was charged with the compound represented by formula 2 (10.7 g,30.5 mmol) and the compound represented by formula 1 (5.35g, 32mmol), the whole system was purged with nitrogen three times, dried methylene chloride (50 mL) was added, the system was cooled to 0 ℃ and dicyclohexylcarbodiimide (7.0 g,36.6 mmol) and 4-dimethylaminopyridine (6.4 mL,36.6 mmol) were slowly added dropwise, and after completion of the dropwise addition, the system was kept at 0 ℃ for stirring for 30 minutes and then warmed to room temperature for stirring for 12 hours. After completion of the reaction, the reaction was quenched by addition of water (50 mL). The system was extracted three times with dichloromethane (100 mL. Times.3). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent was a mixed solvent of ethyl acetate/petroleum ether = 1:1) to give the product compound 3 as a white solid (11.8g, 78% yield).
1 H NMR(500MHz,CDCl 3 )δ7.55(d,J＝7.1Hz,2H),7.38(t,J＝7.3Hz,2H),7.33(t,J＝7.3Hz,1H),6.98(d,J＝8.4Hz,1H),6.83(d,J＝8.4Hz,1H),6.76(d,J＝8.0Hz,1H),6.61(d,J＝1.7Hz,1H),6.52(dd,J＝8.0,1.7Hz,1H),5.59(s,1H),5.41(s,1H),5.01(s,2H),3.88(s,3H),3.82(s,3H),3.63(s,2H),3.44(q,J＝6.8Hz,2H),2.66(t,J＝6.9Hz,2H).
13 C NMR(126MHz,CDCl 3 )δ170.05,153.20,146.76,145.78,144.35,137.19,130.53,128.54,128.44,128.23,127.77,126.57,121.40,121.23,114.47,111.76,111.23,74.67,56.28,56.04,43.89,40.90,35.27.
HRMS(ESI+):m/z calculated for C 25 H 27 BrNO 5 [M+H] + :500.1067,found:500.1072.
Example 4: a compound represented by the formula 4 (2- (3- (benzoyloxy) -2-bromo-4-methoxyphenyl) -N- (4- ((tert-butylpropylphenyl) oxy) -3-methoxyphentyl) acetamide)
A clean dry round bottom flask equipped with a stirrer was charged with the compound represented by formula 3 (1.28g, 2.66mmol) and imidazole (362mg, 5.32mmol), the whole system was purged with nitrogen three times, dried dichloromethane (6 mL) was added, tert-butyldiphenylsilyl chloride (0.83mL, 3.2mmol) was slowly added dropwise at normal temperature, and after completion of the addition, the system was stirred at room temperature for 8 hours. After the reaction was complete, the reaction was quenched by addition of water (20 mL). The system was extracted three times with dichloromethane (30 mL. Times.3). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent was a mixed solvent of ethyl acetate/petroleum ether = 1:1) to give the product compound 4as a white foamy solid (1.76g, 90% yield).
1 H NMR(500MHz,CDCl 3 )δ7.71(d,J＝6.6Hz,4H),7.55(d,J＝6.8Hz,2H),7.44–7.31(m,9H),6.94(d,J＝8.3Hz,1H),6.78(d,J＝8.3Hz,1H),6.59(d,J＝7.9Hz,1H),6.52(s,1H),6.32(d,J＝7.3Hz,1H),5.43(s,1H),5.02(s,2H),3.82(s,3H),3.61(s,2H),3.52(s,3H),3.39(d,J＝6.0Hz,2H),2.60(t,J＝6.3Hz,2H),1.11(s,9H).
13 C NMR(126MHz,CDCl 3 )δ169.92,153.05,150.53,145.55,143.61,137.06,135.42,133.66,131.92,129.66,128.53,128.39,128.19,127.66,127.54,126.54,121.17,120.55,120.10,112.74,111.56,74.59,56.15,55.40,43.79,40.84,35.19,26.73,19.84.
HRMS(ESI+):m/z calculated for C 41 H 44 BrNO 5 SiNa[M+Na] + :760.2064,found:760.2068.
Example 5: a compound represented by the formula 5 ((R) - (1- (3- (phenyloxy) -2-bromo-4-methoxybenzyl) -7-hydroxy-6-methoxy-3,4-dihydroquinolin-2 (1H) -yl) (cyclopropyl) methanone)
A compound 1- (3- (benzyliloxy) -2-bromo-4-methoxybenzyl) -7- ((tert-butyldiphenylsilyl) oxy) -6-methoxy-3,4-dihydroquinoleine represented by formula 5-1
Compound 4 (500mg, 0.68mmol) was added to a clean dry Schlenk tube equipped with a stirrer, nitrogen was purged three times through the system, dry dichloroethane (4 mL) was added, phosphorus oxychloride (0.19mL, 2.0 mmol) was slowly added dropwise at normal temperature, and after completion of the addition, the system was heated to 75 ℃ and stirred for 3 hours. After completion of the reaction, the system was cooled to room temperature and quenched by addition of saturated sodium bicarbonate (10 mL). The system was extracted three times with dichloromethane (30 mL. Times.3). The organic phases were combined and dried over anhydrous sodium sulfate and concentrated to give 5-1 as a pale yellow foamy solid, which was used directly for the next step without further purification.
HRMS(ESI+):m/z calculated for C 21 H 23 BrNO 6 [M+H] + :464.0703,found:464.0707.
The compound (R) -1- (3- (benzoyloxy) -2-bromo-4-methoxybenzyl) -7- ((tert-butyldiphenylsilyl) oxy) -6-methoxy-1,2,3,4-tetrahydroquinoline represented by the formula 5-2
To a clean, dry 25mL round bottom flask equipped with a stir bar were added (2R, 2'R,3R,3' R) -WingPhos (2.0mg, 3.2. Mu. Mol) and Rh (nbd) 2 BF 4 (2.1 mg, 3.2. Mu. Mol), followed by addition of methanol (1.5 mL), stirring at ordinary temperature for 15 minutes, followed by addition of a methanol solution of compound 5-1 (200mg, 0.28mmol) and placing in an autoclave to replace hydrogen gas three times, the whole system was reacted at 35 ℃ under a pressure of 400psi for 15 hours. After the reaction was complete, concentration gave the desired product 5-2 (180mg, 90% yield).
80％ee:Chiral OD-H column,iPrOH/Hexane＝90:10,1.0mL/min,210nm UV detector,t1＝14.48min(minor),t2＝17.56min(Major).
HRMS(ESI+):m/z calculated for C 41 H 45 BrNO 4 Si[M+H] + :722.2296,found:722.2300.
A compound represented by the formula 5-3 ((R) - (1- (3- (phenyloxy) -2-bromo-4-methoxybenzyl) -7- ((tert-butylphenylsilyl) oxy) -6-methoxy-3,4-dihydroisoquinolin-2 (1H) -yl) (cyclopropy) meth-one)
A clean dry round bottom flask equipped with a stir bar was charged with compound 5-2 (457mg, 0.68mmol), the whole system was purged with nitrogen three times, dried dichloromethane (6 mL) was added, and the system was cooled to 0 deg.C and cyclopropanecarbonyl chloride (0.12mL, 1.36mmol) and triethylamine (0.19mL, 1.36mmol) were slowly added dropwise. After the completion of the dropwise addition, the system was warmed to room temperature and stirred for 6 hours. After the reaction was complete, the reaction was quenched by addition of water (20 mL). The system was extracted three times with dichloromethane (20 mL. Times.3). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent was a mixed solvent of ethyl acetate/petroleum ether = 1:1) to give the product compound 5-3 as a white foamy solid (330mg, 61% yield).
1 H NMR(400MHz,CDCl 3 )δ7.75(dd,J＝22.3,6.1Hz,4H),7.59(d,J＝7.0Hz,2H),7.41(dt,J＝22.3,6.9Hz,9H),6.77(d,J＝11.1Hz,2H),6.68(d,J＝8.1Hz,1H),6.56(s,1H),5.09(d,J＝9.5Hz,1H),4.98(s,2H),4.78(d,J＝8.1Hz,1H),3.84(s,3H),3.73(s,3H),3.09–2.99(m,1H),2.92–2.73(m,3H),2.59(d,J＝15.3Hz,1H),1.16(s,9H),0.92(s,1H),0.63(d,J＝5.0Hz,1H),0.37(d,J＝6.1Hz,2H),0.00(d,J＝5.7Hz,1H).
13 C NMR(101MHz,CDCl 3 )δ172.81,152.76,149.79,145.51,143.72,137.23,135.71,135.66,133.61,133.40,130.31,129.90,128.66,128.48,128.31,127.80,127.31,127.06,120.79,118.55,112.66,111.63,74.79,56.32,56.00,54.94,42.62,35.33,28.27,26.88,19.89,10.69,7.62,7.31.
HRMS(ESI+):m/z calculated for C 41 H 47 BrNO 7 Si[M+H] + :790.2558,found:790.2559.
A compound represented by the formula 5 ((R) - (1- (3- (phenyloxy) -2-bromo-4-methoxybenzyl) -7-hydroxy-6-methoxy-3,4-dihydroquinolin-2 (1H) -yl) (cyclopropy) methane)
A clean dry round bottom flask equipped with a stirrer was charged with compound 5-3 (260mg, 0.33mmol), the whole system was purged with nitrogen three times, dry THF (6 mL) was added, and tetrabutylammonium fluoride (0.39mL, 0.39mmol, 1N) was slowly added dropwise by cooling the system to 0 ℃. After completion of the dropwise addition, the system was warmed to room temperature and stirred for 1 hour. The system was directly concentrated and purified by column chromatography (eluent was a mixed solvent of ethyl acetate/petroleum ether = 1:2) to give the product compound 5 as a white foamy solid (170mg, 94% yield).
1 H NMR(400MHz,CDCl 3 )δ7.55(t,J＝10.4Hz,2H),7.35(dt,J＝21.8,6.7Hz,3H),7.00(s,1H),6.79(q,J＝8.4Hz,2H),6.60(s,1H),5.59(s,1H),5.40(d,J＝10.1Hz,1H),5.00(s,2H),4.81(dd,J＝12.8,4.9Hz,1H),3.84(t,J＝14.0Hz,6H),3.44–3.34(m,1H),3.11(ddd,J＝33.9,18.8,11.2Hz,2H),2.92–2.79(m,1H),2.65(d,J＝15.3Hz,1H),1.11(d,J＝4.3Hz,1H),0.86(d,J＝53.8Hz,1H),0.67(dd,J＝15.0,6.2Hz,1H),0.42(dd,J＝14.4,7.8Hz,2H),0.09(dd,J＝13.2,6.8Hz,1H).
13 C NMR(101MHz,CDCl 3 )δ172.90,152.87,145.88,145.59,144.26,137.15,130.20,129.43,128.64,128.49,128.29,127.18,126.15,120.84,112.75,111.74,110.96,74.83,56.33,56.10,55.21,42.80,35.54,28.32,10.80,7.69,7.39.
HRMS(ESI+):m/z calculated for C 29 H 31 BrNO 5 [M+H] + :552.1380,found:552.1375.
Example 6: the compound represented by formula 6 (4 bS, 9R) -4- (phenyloxy) -11- (cyclopropanecarbyl) -3,6-dimethoxy-9,10-dihydo-7H-9, 4b- (epiethano) phenyl-thren-7-one)
A clean, dry 250mL Schlenk tube was charged with palladium chloride (106mg, 0.6 mmol), bis (1-adamantyl) n-butylphosphine (215mg, 0.6 mmol), potassium carbonate (2.5g, 18mmol) and compound 5 (3.3g, 6.0mmol). The whole system was purged with nitrogen three times, followed by addition of N, N-dimethylformamide (100 mL). The whole reaction system was stirred at 120 ℃ for 12 hours. After completion of the reaction, the system was cooled to room temperature, dichloromethane (100 mL) was added, and the crude system was filtered through celite, concentrated and purified by column chromatography (eluent is a mixed solvent of dichloromethane/methanol =150 from 1 to 100) to give compound 6 (1.75g, 63% yield) as a yellow solid product.
1 H NMR(400MHz,CDCl 3 )δ7.51(d,J＝6.9Hz,2H),7.42(t,J＝6.9Hz,2H),7.37(d,J＝6.7Hz,1H),7.27(d,J＝13.2Hz,1H),6.88(q,J＝8.4Hz,2H),6.34(d,J＝6.9Hz,1H),5.52(d,J＝3.5Hz,1H),5.33(dd,J＝20.9,9.7Hz,1H),5.13(dd,J＝40.8,11.6Hz,1H),4.34–4.01(m,1H),3.89(s,3H),3.39(d,J＝21.1Hz,3H),3.20(dd,J＝15.1,10.6Hz,1H),3.12(d,J＝17.8Hz,1H),3.01–2.62(m,1H),2.42(dd,J＝49.6,13.2Hz,1H),1.83(s,1H),1.00(dd,J＝16.3,10.9Hz,2H),0.92–0.66(m,3H).
13 C NMR(101MHz,CDCl 3 )δ180.94,172.78,159.45,151.94,151.65,146.34,137.49,130.58,128.73,128.57,128.16,127.36,127.24,124.48,124.31,122.09,121.99,120.27,119.73,112.39,74.22,60.40,56.02,54.82,51.83,44.16,40.66,39.24,38.93,37.81,14.24,12.16,11.58,7.75.
HRMS(ESI+):m/z calculated for C 29 H 30 NO 5 [M+H] + :472.2118,found:472.2117.
Example 7: the compound represented by formula 7 ((4 bS, 9R) -11- (cyclopropanecarbonyl) -4-hydroxy-3,6-dimethoxy-9,10-dihydro-7H-9,4b- (epiethano) phenylanthren-7-one)
A clean dry round bottom flask was charged with palladium chloride (15mg, 0.085mmol) and sodium hydride (102mg, 2.55mmol,60% in mineral oil). The whole system was purged with nitrogen three times, followed by addition of a tetrahydrofuran solution (20 mL) of compound 6 (750mg, 1.7mmol). The whole reaction system was stirred at 50 ℃ for 6 hours. After completion of the reaction, the system was cooled to room temperature, water (20 mL) and a saturated potassium dihydrogen phosphate solution (10 mL) were added to adjust the pH of the system to 6, and the crude system was extracted three times with dichloromethane (20 mL. Times.3). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent dichloromethane/methanol =100 mixed solvent) to give the product compound 7 as a yellow foamy solid (442mg, 73% yield).
1 H NMR(400MHz,CDCl 3 )δ7.54(s,1H),6.75(d,J＝8.1Hz,1H),6.62(d,J＝8.2Hz,1H),6.35(d,J＝17.0Hz,2H),5.52(s,1H),5.20(s,1H),4.34(dd,J＝13.6,4.2Hz,1H),4.03(dd,J＝12.6,4.4Hz,1H),3.86(d,J＝11.3Hz,3H),3.73(s,3H),3.41–3.03(m,3H),2.62(dd,J＝28.3,11.7Hz,2H),1.14–0.61(m,5H).
13 C NMR(101MHz,CDCl 3 )δ181.10,172.87,172.64,159.59,151.64,145.66,143.73,128.65,127.67,122.83,122.03,119.99,119.84,119.29,109.97,56.39,54.98,53.51,51.92,43.91,40.82,40.16,38.82,37.96,37.69,37.07,12.18,11.61,7.74.
HRMS(ESI+):m/z calculated for C 22 H 24 NO 5 [M+H] + :382.1649,found:382.1648.
Example 8: a compound represented by the formula 8 ((4R, 7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-2,3,4,7a-tetrahydro-1H-4,12-methanozofuro [3,2-e ] isoquinoline)
A solution of lithium aluminum hydride (2.1mL, 2.1mmol, 1N) was added to a solution of debenzylation product 7 (160mg, 0.42mmol) in tetrahydrofuran under a nitrogen atmosphere at 0 ℃. The whole system was stirred at 0 ℃ for 1 hour, and the throat was raised to room temperature and stirred for 12 hours. After completion of the reaction, the reaction was quenched by addition of saturated sodium potassium tartrate (5 mL), and the system was extracted three times with ethyl acetate (20 mL. Times.3). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated and dried to give a solid (crude product) as a pale yellow foam which was used directly in the next reaction.
The crude product obtained above was transferred to a clean and dry Schlenk tube, the system was purged with nitrogen three times, and dry dichloromethane (5 mL) was added at ordinary temperature, followed by N, N-dimethyldimethylacetal (0.28mL, 2.1mmol). The whole was stirred at room temperature for 10 hours, directly concentrated and purified by column chromatography (eluent is a mixed solvent of dichloromethane/methanol = 30) to give the product compound 8 as a yellow foam solid (87mg, 59% yield).
1 H NMR(500MHz,CD 3 OD)δ6.81(d,J＝8.2Hz,1H),6.73(d,J＝8.3Hz,1H),6.02(d,J＝6.6Hz,1H),5.42(s,1H),5.24(d,J＝6.6Hz,1H),4.70(d,J＝6.9Hz,1H),3.84(s,3H),3.66(s,3H),3.55(t,J＝13.8Hz,2H),3.44(d,J＝7.6Hz,1H),3.25(d,J＝6.9Hz,3H),2.45(td,J＝13.9,4.9Hz,1H),1.95(d,J＝13.5Hz,1H),1.25–1.15(m,1H),0.85–0.75(m,2H),0.52(d,J＝4.5Hz,2H).
13 C NMR(126MHz,CD 3 OD)δ156.11,146.06,144.74,133.46,125.55,121.29,115.92,96.27,89.00,61.65,57.26,55.86,45.95,30.74,7.10,5.02,4.78.
HRMS(ESI+):m/z calculated for C 22 H 26 NO 3 [M+H] + :352.1907,found:352.1910.
Example 9: a compound represented by the formula 9 ((4R,4aS, 7aR, 12bS) -3- (cyclopropropylethyl) -4a-hydroxy-9-methoxy-2,3, 4a-tetrahydro-1H-4,12-methanobenzofuro [3,2-e ] isoquinolin-7 (7 aH) -one)
To a suspension of compound 8 (51mg, 0.13mmol) in water (5 mL) under an open ice-water bath was added 10% diluted hydrochloric acid until the pH was 2. The whole was then extracted five times with dichloromethane (10 mL × 5), the organic phases were combined and dried over anhydrous sodium sulfate, concentrated and dried to give the hydrochloride salt.
To this aqueous acetic acid solution of hydrochloride (5 mL,10% aqueous solution) was added m-chloroperoxybenzoic acid (30mg, 0.17mmol) in portions. After the addition was complete, the system was warmed to room temperature and stirred for 4 hours. After the reaction was completed, saturated sodium bicarbonate (10 mL) was slowly added to adjust the pH of the system to 8. The system was extracted four times with dichloromethane (10 mL. Times.4). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent dichloromethane/methanol =100 mixed solvent) to give the product compound 9 as a yellow foamy solid (31mg, 67% yield).
1 H NMR(400MHz,CDCl 3 )δ6.64(dt,J＝26.8,8.1Hz,3H),6.18(d,J＝10.0Hz,1H),4.71(s,1H),3.83(s,3H),3.37(d,J＝4.9Hz,1H),3.13(d,J＝18.6Hz,1H),2.83–2.70(m,1H),2.56(dd,J＝18.5,5.5Hz,1H),2.44(t,J＝9.7Hz,3H),2.25(t,J＝10.8Hz,1H),1.69(d,J＝12.2Hz,1H),0.88(d,J＝5.7Hz,1H),0.58(d,J＝7.0Hz,2H),0.17(d,J＝3.4Hz,2H).
13 C NMR(101MHz,CDCl 3 )δ194.36,147.71,144.52,142.81,134.77,130.80,125.07,119.62,115.33,87.25,67.71,61.85,59.19,57.01,47.34,43.70,29.73,23.24,9.41,4.17,3.94.
HRMS(ESI+):m/z calculated for C 21 H 24 NO 4 [M+H] + :354.1700,found:354.1705.
Example 10: a compound represented by formula 10 ((4R, 4aS,7aR, 12bS) -3- (cyclopropylmethyl) -4a-hydroxy-9-methoxy-2,3, 4a,5,6-hexahydro-1H-4,12-methanozofuro [3,2-e ] isoquinolin-7 (7 aH) -one)
A clean, dry 25mL round bottom flask was charged with Compound 9 (31mg, 0.088mmol) and Palladium/barium sulfate (5% on BaSO) 4 15mg, 8mol%), followed by addition of methanol (5 mL), and hydrogen gas was purged from the entire system three times (normal pressure: 1 atm), and reacted under the normal pressure condition for 8 hours at normal temperature. After completion of the reaction, it was directly concentrated and purified by column chromatography (eluent is a mixed solvent of dichloromethane/methanol = 100) to give the product compound a10 (30mg, 96% yield) as a colorless oil.
1 H NMR(400MHz,CDCl 3 )δ6.68(d,J＝8.1Hz,1H),6.60(d,J＝8.1Hz,1H),4.67(s,1H),3.88(s,3H),3.21(s,1H),3.10–2.95(m,2H),2.77–2.53(m,2H),2.41(d,J＝6.1Hz,3H),2.29(d,J＝14.3Hz,1H),2.13(dd,J＝11.8,9.5Hz,1H),1.88(d,J＝12.7Hz,1H),1.60(dd,J＝28.9,12.8Hz,2H),0.87(d,J＝3.7Hz,1H),0.55(d,J＝7.2Hz,2H),0.15(d,J＝3.6Hz,2H).
13 C NMR(101MHz,CDCl 3 )δ208.53,145.15,143.07,129.63,124.94,119.49,115.18,90.50,70.27,62.21,59.32,57.00,50.88,43.81,36.26,31.62,30.74,29.78,22.80,9.43,4.11,3.94.
HRMS(ESI+):m/z calculated for C 21 H 26 NO 4 [M+H] + :356.1856,found:356.1860.
Example 11: the compound shown as formula 11, naltrexone ((4R, 4aS,7aR, 12bS) -3- (cyclopropylmethyl) -4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanozofuro- [3,2-e ] isoquinolin-7 (7 aH) -one)
Compound 10 (11mg, 0.031mmol) is added to a clean dry schleck tube, the system is purged with nitrogen three times and dry dichloromethane (3 mL) is added. The whole system was cooled to-20 ℃ and then boron tribromide (24 μ L,0.25 mmol) was slowly added dropwise, the system was warmed to 10 ℃ and stirred for 5 hours. After completion of the reaction, the system was cooled to 0 ℃ and saturated ammonium chloride (5 mL) was added, and the system was extracted four times with dichloromethane (10 mL. Times.4). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent is a mixed solvent of dichloromethane/methanol = 50) to give product 11 as a white solid (6 mg,56% yield).
1 H NMR(500MHz,CDCl 3 )δ6.72(d,J＝8.0Hz,1H),6.58(d,J＝7.9Hz,1H),4.69(s,1H),3.20(d,J＝4.8Hz,1H),3.11–2.98(m,2H),2.71(d,J＝7.7Hz,1H),2.57(dd,J＝18.3,5.5Hz,1H),2.49–2.37(m,3H),2.32(d,J＝14.4Hz,1H),2.17(dd,J＝12.1,9.1Hz,1H),1.89(d,J＝13.1Hz,1H),1.62(ddd,J＝27.4,19.5,6.8Hz,2H),0.87(d,J＝6.9Hz,1H),0.55(d,J＝7.6Hz,2H),0.15(d,J＝4.5Hz,2H).
13 C NMR(126MHz,CDCl 3 )δ210.13,143.60,138.95,129.11,124.34,120.07,118.09,90.72,70.38,62.17,59.35,51.18,43.76,36.33,31.51,30.77,29.84,22.78,9.52,4.15,3.96.
HRMS(ESI+):m/z calculated for C 20 H 24 NO 4 [M+H] + :342.1700,found:342.1703.
Example 12: a compound represented by formula 12, 1- ((4R, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4, 7a-hexahydro-4a, 7-ethaneo-4,12-methanozofuro [3,2-e ] isoquinolin-14-yl) ethan-1-one
Compound 8 (100mg, 0.285mmol) was added to a clean, dry Schlenk tube, the system was purged with nitrogen three times and methyl vinyl ketone (3 mL) was added. The system was warmed to 80 ℃ and stirred for 6 hours. After the reaction was completed, the system was cooled to room temperature, concentrated and purified by column chromatography (eluent is a mixed solvent of dichloromethane/methanol = 60) to obtain product 12 (78mg, 65% yield) as a white foamy solid.
1 H NMR(500MHz,CDCl 3 )δ6.61(d,J＝8.0Hz,1H),6.51(d,J＝7.9Hz,1H),5.88(d,J＝8.6Hz,1H),5.58(d,J＝8.7Hz,1H),4.58(s,1H),3.80(s,3H),3.59(s,4H),3.10(d,J＝18.4Hz,1H),2.97(dd,J＝21.7,8.8Hz,2H),2.73(d,J＝7.2Hz,1H),2.41(t,J＝18.2Hz,4H),2.14(s,3H),1.98(s,1H),1.84(d,J＝12.2Hz,1H),1.44–1.32(m,1H),0.82(s,1H),0.50(t,J＝7.3Hz,2H),0.13(s,2H).
13 C NMR(126MHz,CDCl 3 )δ209.51,149.78,148.06,141.89,136.19,134.22,128.17,125.97,119.46,116.17,113.58,95.34,81.38,59.77,57.04,56.68,53.57,50.74,48.18,44.11,43.19,33.53,30.64,30.01,23.32,9.38,4.30,3.47.
HRMS(ESI+):m/z calculated for C 26 H 32 NO 4 [M+H] + :422.2326,found:422.2331.
Example 13: a compound represented by formula 13 (2- ((4R, 4aS,7S,7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4, 7a-hexahydro-4a, 7-ethanol-4,12-methanozofuro [3,2-e ] isoquinolin-14-yl) -3,3-dimethylbutan-2-ol)
Compound 12 (54mg, 0.128mmol) was added to a clean dry Schlenk tube, the system was purged with nitrogen three times and dry toluene (3 mL) was added. The whole system was cooled to 0 ℃ and tert-butylmagnesium chloride (1.7M, 0.53mL, 0.897mmol) was slowly added dropwise, after which the system was warmed to room temperature and stirred for 5 hours. After completion of the reaction, the system was cooled to 0 ℃ and saturated ammonium chloride (5 mL) was added, and the system was extracted four times with ethyl acetate (15 mL. Times.4). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent is a mixed solvent of petroleum ether/ethyl acetate = 10) to obtain compound 13 (36mg, 59% yield) as a colorless oily product while recovering the starting material (8mg, 15% yield). The yield of this reaction based on starting material was therefore (71%, brsm).
1 H NMR(500MHz,CDCl 3 )δ6.61(d,J＝8.1Hz,1H),6.49(d,J＝8.1Hz,1H),5.99(d,J＝8.8Hz,1H),5.65(s,1H),5.44(d,J＝8.9Hz,1H),4.56(s,1H),3.79(d,J＝20.6Hz,6H),3.49(d,J＝6.5Hz,1H),3.09(d,J＝18.4Hz,1H),2.97(dd,J＝12.5,8.8Hz,1H),2.66(dd,J＝11.8,4.6Hz,1H),2.46–2.31(m,4H),2.15(t,J＝8.6Hz,1H),1.97–1.80(m,2H),1.04–0.81(m,15H),0.59–0.44(m,2H),0.22–0.08(m,2H).
13 C NMR(126MHz,CDCl 3 )δ148.18,141.79,135.65,134.87,128.61,124.93,119.34,113.81,99.11,84.61,78.51,60.50,59.66,56.93,56.87,55.36,47.23,45.98,44.22,43.20,39.82,34.10,32.30,26.78,23.23,19.75,9.63,4.47,3.30.
HRMS(ESI+):m/z calculated for C 30 H 42 NO 4 [M+H] + :480.3108,found:480.3111.
Example 14: a compound represented by formula 14 (2- ((4R, 4aR,7S,7aR, 12bS) -3- (cyclopropylmethyl) -7,9-dimetoxy-1, 2,3,4,5,6, 7a-octahydro-4a,7-ethano-4,12-methanozofuro [3,2-e ] isoquinolin-6-yl) -3,3-dimethylbutan-2-ol)
Into a clean and dry 25mL round-bottomed flask, compound 13 (18mg, 0.038mmol), 10% by weight of Pd/C (5mg, 0.0047mmol) and isopropanol (5 mL) were charged, and the reaction vessel was placed, and the system was purged with hydrogen three times and raised to a hydrogen pressure of 10atm. The system was then warmed to 70 ℃ and reacted under this hydrogen pressure for 14 hours. After the reaction was complete, the system was filtered through celite and washed with dichloromethane, and the organic phase was concentrated to give compound 14 as a white foamy solid (18mg, 99% yield), which was subjected to the subsequent reaction without purification.
1 H NMR(500MHz,CDCl 3 )δ6.70(d,J＝8.1Hz,1H),6.55(d,J＝8.1Hz,1H),5.92(s,1H),4.43(d,J＝1.5Hz,1H),3.87(s,3H),3.55(s,3H),3.03–2.95(m,2H),2.93–2.85(m,1H),2.60(dd,J＝11.7,5.2Hz,1H),2.38–2.19(m,4H),2.15(t,J＝9.8Hz,1H),1.97(td,J＝12.7,5.6Hz,1H),1.87–1.74(m,2H),1.67(dd,J＝12.9,2.4Hz,1H),1.36(s,3H),1.03(s,9H),0.88(t,J＝6.9Hz,1H),0.79(td,J＝13.2,6.7Hz,1H),0.75–0.67(m,1H),0.53–0.42(m,2H),0.11(d,J＝3.5Hz,2H).
13 C NMR(126MHz,CDCl 3 )δ147.04,141.79,133.06,129.08,119.26,114.18,96.88,80.90,79.50,59.68,58.43,57.01,52.73,46.33,44.04,43.83,40.53,36.08,35.91,33.59,29.89,29.84,26.57,23.00,20.21,18.32,9.66,4.31,3.39.
HRMS(ESI+):m/z calculated for C 30 H 44 NO 4 [M+H] + :482.3265,found:482.3269.
Example 15: the compound Buprenorphine represented by formula 15 (4R, 4aR,7S,7aR, 12bS) -3- (cyclopropylmethyl) -6- (2-hydroxy-3,3-dimethylbutan-2-yl) -7-methoxy-1,2,3,4,5,6, 7a-octahydro-4a,7-ethano-4,12-methanobenzofuro [3,2-e ] isoquinolin-9-ol)
A clean dry Schlenk tube was charged with potassium tert-butoxide (11mg, 0.1mmol), the system was purged with nitrogen three times and dry N, N-dimethylformamide (1.5 mL) was added. The system was heated to 50 ℃ and n-dodecyl mercaptan (24. Mu.L, 0.1 mmol) was added. The system was stirred for 5 minutes, and a solution of compound 14 (18mg, 0.037mmol) in N, N-dimethylformamide (1.5 mL) was added. The whole system is heated to 120 ℃ for reaction for 2 hours. After the reaction was completed, the system was cooled to room temperature and potassium dihydrogen phosphate solution (50%, 5 mL) was added to adjust the pH to 4, saturated sodium bicarbonate solution was added to adjust the pH to 9, and the system was extracted four times with ethyl acetate (10 mL. Times.4). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent mixed solvent of petroleum ether/ethyl acetate = 4:1) to give the final product compound 15 buprenorphine (14mg, 81% yield).
1 H NMR(500MHz,CDCl 3 )δ6.69(d,J＝8.0Hz,1H),6.51(d,J＝8.0Hz,1H),5.92(s,1H),4.45(s,1H),3.53(s,3H),2.98(d,J＝18.9Hz,2H),2.89(t,J＝10.2Hz,1H),2.62(dd,J＝11.5,4.7Hz,1H),2.26(dddd,J＝36.9,30.5,15.9,7.8Hz,6H),1.98(td,J＝12.6,5.4Hz,1H),1.84(t,J＝12.4Hz,1H),1.75(td,J＝12.8,6.0Hz,1H),1.70–1.57(m,1H),1.36(s,3H),1.31(d,J＝13.8Hz,2H),1.03(s,9H),0.88(t,J＝5.9Hz,1H),0.80(s,1H),0.70(t,J＝12.3Hz,1H),0.53–0.42(m,2H),0.11(d,J＝3.6Hz,2H).
13 C NMR(126MHz,CDCl 3 )δ145.56,137.36,132.72,128.51,119.74,116.50,97.23,80.98,79.67,59.66,58.43,52.67,46.64,43.85,40.54,36.15,35.76,33.56,32.07,29.84,29.78,26.56,23.08,22.84,20.25,18.35,14.27,9.60,4.31,3.40.
HRMS(ESI+):m/z calculated for C 29 H 42 NO 4 [M+H] + :468.3108,found:468.3112.
Claims (32)
1. A method for producing a compound represented by formula A6, comprising the step S7 of: under the action of a palladium catalyst, a phosphine ligand shown in a formula L1 and alkali, a compound shown in a formula A5 is subjected to dearomatization cyclization reaction in an organic solvent to obtain a compound shown in a formula A6,
wherein R is 1 And R 2 Independently H, C 1～10 Alkyl radical, C 1～10 Alkoxy radical, C 3～10 Cycloalkyl or C 6～20 An aryl group;
R 3 independently is C 1～7 Alkyl radical, C 3～7 Cycloalkyl or C 6～20 An aryl group;
R 5 、R 6 and R 7 Independently is C 1～10 Alkyl radical, C 3～10 Substituted cycloalkyl radicals or by C 1～10 Alkyl substituted C 3～10 A substituted cycloalkyl group.
2. The method according to claim 1, wherein the reaction mixture,
in step S7, the palladium catalyst is one or more of palladium chloride, bis (acetonitrile) palladium chloride, palladium trifluoromethanesulfonate and palladium acetate, for example, palladium chloride;
and/or, in step S7, the molar ratio of the palladium catalyst to the compound represented by formula A5 is 0.01 to 0.5, for example 0.1;
and/or, in step S7, the phosphine ligand represented by formula L1 is one or more of tri-tert-butylphosphine, tricyclohexylphosphine, and bis (1-adamantyl) n-butylphosphine, such as bis (1-adamantyl) n-butylphosphine;
and/or, in step S7, the molar ratio of the phosphine ligand represented by formula L1 to the compound represented by formula A5 is 0.01 to 0.5, for example 0.1 to 0.5;
and/or, in step S7, the base is an alkali metal carbonate, such as potassium carbonate;
and/or, in step S7, the organic solvent is a sulfoxide-based solvent and/or an amide-based solvent, such as N, N-dimethylformamide and/or N, N-dimethylacetamide, preferably N, N-dimethylformamide;
and/or in step S7, the volume mass ratio of the organic solvent to the compound shown in the formula A5 is 5-100 mL/g, for example 10-30 mL/g;
and/or, in step S7, the temperature of the dearomatization cyclization reaction is 80 ℃ to 180 ℃, for example 100 ℃ to 130 ℃;
and/or, in step S7, the reaction time of the dearomatization cyclization reaction is 8-24 hours, such as 12 hours;
and/or step S7 comprises the steps of: adding the organic solvent to a mixture of the palladium catalyst, the phosphine ligand represented by formula L1, a base and the compound represented by formula A5 to perform the dearomatization cyclization reaction;
and/or, R 1 Is H; the compound of the formula A6 is preferably
And/or, R 2 Is H; a compound of the formula A5Preferred examples of the substances
And/or, R 3 Is C 3～7 Cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and also cyclopropyl.
3. The method of claim 1, further comprising the steps of:
and step S4: under the action of a rhodium catalyst and a ligand, carrying out asymmetric hydrogenation reaction on the compound shown in the formula A5-1 and hydrogen in an organic solvent to obtain the compound shown in the formula A5-2,
step S5: carrying out a substitution reaction shown as the following on a compound shown as a formula A5-2 and a compound shown as a formula B5-2 in an organic solvent under the action of alkali to obtain a compound shown as a formula A5-3,
step S6: carrying out deprotection reaction shown as the following on the formula A5-3 in an organic solvent under the action of a deprotection reagent to obtain the compound shown as the formula A5,
wherein R is 1 、R 2 And R 3 As defined in claim 1, P is a hydroxyl protecting group.
4. The method according to claim 3,
in step S4, the organic solvent is one or more of an alcohol solvent, an ether solvent, an aromatic hydrocarbon solvent, a nitrile solvent, a halogenated alkane solvent, a sulfoxide solvent and an amide solvent, for example, one or more of methanol, ethanol, n-propanol and isopropanol, preferably methanol;
and/or, in step S4, the volume-to-mass ratio of the organic solvent to the compound represented by the formula A5-1 is 1 to 20mL/g, such as 2.5 to 10mL/g, and further such as 7.5mL/g;
and/or, in step S4, the rhodium catalyst is Rh (nbd) 2 BF 4 ；
And/or, in step S4, the molar ratio of the rhodium catalyst to the compound of formula A5-1 is 0.001 to 0.1, for example 0.01;
and/or, in step S4, the ligand is (2R,2 'R,3R,3' R) -WingPhos;
and/or, in step S4, the molar ratio of said ligand to said compound of formula A5-1 is between 0.001 and 0.1, for example 0.01;
and/or, in step S4, the asymmetric hydrogenation reaction is at a pressure of from 1atm to 50atm, such as 400psi;
and/or, in step S4, the temperature of the asymmetric hydrogenation reaction is 10 ℃ to 50 ℃, for example, 35 ℃;
and/or, in step S4, the reaction time of the asymmetric hydrogenation reaction is 10 to 24 hours, for example 15 hours;
and/or, in step S5, the base is an organic base, preferably triethylamine;
and/or, in step S5, the molar ratio of the base to the compound of formula A5-2 is 1 to 3, for example 2;
and/or, in step S5, the organic solvent is a chlorinated alkane and/or an amide, such as one or more of dichloromethane, 1,2-dichloroethane and chloroform, preferably dichloromethane;
and/or, in step S5, the volume-to-mass ratio of the organic solvent to the compound represented by the formula A5-2 is 5 to 100mL/g, such as 10 to 30mL/g, and such as 13mL/g;
and/or, in step S5, the molar ratio of the compound represented by the formula B5-2 to the compound represented by the formula A5-2 is 1 to 3, for example 2;
and/or, in step S5, the temperature of the substitution reaction is 10-50 ℃, for example 20-35 ℃;
and/or, in step S5, the reaction time of the substitution reaction is 4 to 12 hours, for example 6 hours;
and/or, step S5 comprises the steps of: dissolving the compound shown as the formula A5-2 in the organic solvent to form a mixture solution, and adding the compound shown as the formula B5-2 and an alkaline deprotection reagent into the mixture solution to carry out the substitution reaction;
and/or in step S6, the deprotection reagent is tetrabutylammonium fluoride;
and/or, in step S6, the molar ratio of the deprotecting reagent to the compound of formula A5-3 is 1 to 5, e.g. 1.1;
and/or, in step S6, the organic solvent is an ether solvent and/or a chlorinated hydrocarbon solvent, such as one or more of tetrahydrofuran, dioxane, diethyl ether and methyl tert-butyl ether, preferably tetrahydrofuran;
and/or, in step S6, the volume-to-mass ratio of the organic solvent to the compound represented by the formula A5-3 is 5 to 100mL/g, such as 10 to 30mL/g, and such as 23mL/g;
and/or, in step S6, the temperature of the deprotection reaction is 10 to 50 ℃, for example 20 to 35 ℃;
and/or, in step S6, the reaction time of the deprotection reaction is 1 to 5 hours, for example, 1 hour;
and/or, step S6 comprises the steps of: dissolving the compound shown in the formula A5-3 in the organic solvent to form a mixture solution, and adding the deprotection reagent into the mixture solution to perform deprotection reaction;
and/or P is a silyl ether protecting group or a carbonate-based protecting group, such as a trimethylsilyl ether protecting group, a t-butyldimethylsilyl ether protecting group, a t-butyldiphenylsilyl ether protecting group, COOEt or COOMe, preferably a t-butyldiphenylsilyl ether protecting group.
5. The method of claim 3, further comprising the step S3 of: in POCl 3 Subjecting a compound represented by the formula A4 to a cyclization reaction in an organic solvent as shown below to obtain a compound represented by the formula A5-1,
wherein R is 1 And R 2 Is defined as in claim 1 and P is defined as in claim 3.
6. The method according to claim 5,
in step S3, the POCl 3 The molar ratio to the compound represented by the formula A4 is 2.0 to 4.0, for example, 3.0;
and/or, in step S3, the organic solvent is a chlorinated alkane solvent and/or an amide solvent, such as one or more of dichloromethane, 1,2-dichloroethane and chloroform, preferably dichloromethane;
and/or in step S3, the volume-to-mass ratio of the organic solvent to the compound shown in the formula A4 is 5-20 mL/g, such as 8mL/g;
and/or, in step S3, the temperature of the cyclization reaction is 50 to 85 ℃, for example 75 ℃;
and/or, in step S3, the reaction time of the cyclization reaction is 1 to 12 hours, for example 3 hours;
and/or the compound shown as the formula A4 is
The compound shown as the formula A5-1 is
7. The method of claim 5, further comprising the steps of:
step S0: under the action of an oxidant, carrying out Pinnick oxidation reaction on the compound shown in the formula A2-3 in an organic solvent to obtain the compound shown in the formula A2, namely,
step S1: carrying out condensation reaction of a compound shown in a formula 1 and a compound shown in a formula A2 in an organic solvent under the action of a catalyst to obtain a compound shown in a formula A3,
step S2: under the action of alkali and a hydroxyl protecting agent P-Hal, carrying out condensation reaction on a compound shown as a formula A3 in an organic solvent to obtain a compound shown as a formula A4,
wherein R is 1 And R 2 Is defined according to claim 1, P is defined according to claim 4, and Hal is halogen.
8. The method according to claim 7,
in step S0, the oxidizing agent is sodium chlorite;
and/or, in step S0, the molar ratio of the oxidizing agent to the compound of formula A2-3 is 1 to 3, for example 1.2;
and/or, in the step S0, the solvent is a mixed solvent of an organic solvent and water, wherein all the organic solvents are one or more of ether solvents or alcohol solvents, such as one or more of tetrahydrofuran, 1,4-dioxane and tert-butyl alcohol, preferably tert-butyl alcohol; the volume ratio of the organic solvent to the water can be 1 (5-10), such as 1;
and/or in the step S0, the volume-mass ratio of the organic solvent to the compound shown in the formula A2-3 is 5-20 mL/g;
and/or, in step S0, the temperature of the Pinnick oxidation reaction is 15 to 35 ℃, e.g. 20 ℃;
and/or in the step S1, the catalyst is one or more of dicyclohexylcarbodiimide and 4-diaminopyridine, 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate and carbonyldiimidazole, preferably dicyclohexylcarbodiimide and 4-diaminopyridine, and the molar ratio of the dicyclohexylcarbodiimide to the 4-diaminopyridine is 1-2;
and/or, in step S1, the molar ratio of the catalyst to the compound of formula A2 is 1 to 3, for example 2.4;
and/or, in step S1, the molar ratio of the compound of formula A1 to the compound of formula A2 is 1 to 3, for example 1.05;
and/or, in step S1, the organic solvent is a chlorinated alkane and/or an amide, such as one or more of dichloromethane, 1,2-dichloroethane and chloroform, preferably dichloromethane;
and/or, in step S1, the temperature of the condensation reaction is 10 to 30 ℃, for example 20 ℃;
and/or, in step S1, the condensation reaction is carried out for a reaction time of 8 to 24 hours, for example 12 hours
And/or, in step S2, the base is an organic base, such as a pyridine base or an imidazole base, such as imidazole;
and/or, in step S2, the molar ratio of the base to the compound of formula A3 is 1 to 3, for example 2;
and/or, in step S2, the hydroxyl protecting agent P-Hal is tri-tert-butyldiphenylsilicon chloride or tert-butyldiphenylsilicon chloride, preferably tert-butyldiphenylsilicon chloride;
and/or, in step S2, the molar ratio of the hydroxy protecting agent P-Hal to the compound of formula A3 is 1 to 2, for example 1.2;
and/or, in step S2, the organic solvent is a chlorinated alkane and/or an amide, such as one or more of dichloromethane, 1,2-dichloroethane and chloroform, preferably dichloromethane;
and/or in step S2, the volume-to-mass ratio of the organic solvent to the compound shown in the formula A3 is 1-10 mL/g, for example, 3-6 mL/g;
and/or, in step S2, the temperature of the condensation reaction is 10 to 30 ℃, for example 20 ℃;
and/or, in step S2, the reaction time of the condensation reaction is 5 to 12 hours, for example 8 hours.
9. The method according to claim 7, further comprising a method for preparing a compound represented by the following formula A2-3, which comprises the steps of: carrying out recarburization reaction on the compound shown as the formula A2-2 to obtain the compound shown as the formula A2;
wherein the recarburization reaction comprises the following steps: (i) Under the action of alkali, carrying out Darzens reaction on the compound shown as the formula A2-2 and chloroacetate in an organic solvent to obtain a Darzens reaction product; (ii) Carrying out hydrolysis reaction on the Darzens reaction product under the action of alkali to obtain a hydrolysis reaction product; (iii) Carrying out decarboxylation reaction on the hydrolysis reaction product in a solvent under the action of acid to obtain a compound shown as a formula A2-3;
wherein R is 1 And R 2 Is as defined in claim 1.
10. The method according to claim 9,
and/or, in the recarburisation reaction, in the Darzens reaction, the chloroacetate is methyl chloroacetate or ethyl chloroacetate, such as ethyl chloroacetate;
and/or, in the recarburisation reaction, in the Darzens reaction, the chloroacetate has an equivalent weight of 1.2 to 2.0, e.g. 1.3;
and/or, in the recarburization reaction, in the Darzens reaction, the base is sodium or potassium alkyl alkoxide, such as one or more of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and further such as sodium methoxide;
and/or, in the recarburization reaction, the molar ratio of the base to the compound of formula A2-2 in the Darzens reaction is 1.2 to 2.0, e.g. 1.3;
and/or, in the recarburization reaction, in the Darzens reaction, the organic solvent is an alcohol solvent and/or an ether solvent, such as methanol;
and/or, in the recarburisation reaction, the temperature of the Darzens reaction is between 0 and 35 ℃, for example 25 ℃;
and/or, in the recarburisation reaction, the Darzens reaction is carried out for a reaction time of 1 to 5 hours, for example 3 hours;
and/or, in the recarburization reaction, the Darzens reaction comprises the following steps: dissolving the compound represented by the formula A2-2 in the organic solvent to form a mixture solution, adding the chloroacetate and the base to the mixture solution, and carrying out the Darzens reaction;
and/or, in the recarburization reaction, in the hydrolysis reaction, the alkali is an alkali metal hydroxide, such as sodium hydroxide and/or potassium hydroxide;
and/or, in the recarburization reaction, the molar ratio of the base to the compound represented by the formula A2-2 in the hydrolysis reaction is 1 to 3, such as 1.3;
and/or, in the recarburization reaction, the temperature of the hydrolysis reaction is 10-30 ℃, such as 25 ℃;
and/or, in the recarburization reaction, the reaction time of the hydrolysis reaction is 3 to 5 hours, such as 4 hours;
and/or, in the recarburization reaction and the decarboxylation reaction, the acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and potassium dihydrogen phosphate, and potassium dihydrogen phosphate is preferred;
and/or, in the recarburization reaction and the decarboxylation reaction, the acid is 10-50% acid solution, such as 50% potassium dihydrogen phosphate solution;
and/or in the recarburization reaction and the decarboxylation reaction, the molar ratio of the acid to the compound shown in the formula A2-2 is 1.5-5.0;
and/or in the recarburization reaction and the decarboxylation reaction, the solvent is a mixed solvent of an organic solvent and water, wherein the organic solvent is one or more of an alcohol solvent, an ether solvent or an amide solvent, preferably an ether solvent, such as tetrahydrofuran;
and/or in the recarburization reaction, the decarboxylation reaction is carried out at the temperature of 60 ℃;
and/or, in the recarburization reaction, the reaction time of the decarboxylation reaction is 8-36 hours, such as 24 hours;
and/or the compound shown as the formula A2-2 is
The compound shown as the formula A2-3 is
11. A method for producing a compound represented by formula A7, comprising the step S8 of: under the action of hydrogen source and palladium catalyst, carrying out debenzylation protection reaction on the compound shown as the formula A6 in an organic solvent to obtain a compound shown as a formula A7;
R 1 、R 2 and R 3 Is as defined in claim 1 or 2.
12. The method according to claim 11,
in step S8, the compound represented by formula A6 is prepared according to the method for preparing a compound represented by formula A6 as claimed in one of claims 1 to 10;
and/or, in step S8, the hydrogen source is hydrogen gas and/or sodium hydride, such as sodium hydride;
and/or, in step S8, the molar ratio of the hydrogen source to the compound represented by formula A6 is 1.05 to 2.0, for example, 1.5;
and/or, in step S8, the palladium catalyst is one or more of dry palladium carbon, palladium hydroxide, palladium chloride and palladium acetate, such as palladium chloride;
and/or, in step S8, the molar ratio of the palladium catalyst to the compound of formula A6 is 0.02 to 0.1, for example 0.05;
and/or, in step S8, the organic solvent is an ether solvent or an amide solvent, such as tetrahydrofuran;
and/or in step S8, the volume-to-mass ratio of the organic solvent to the compound represented by the formula A6 is 10 to 50mL/g, for example, 20 to 30mL/g;
and/or, in step S8, the temperature of the reaction for removing the benzyl protecting group is 40-70 ℃, for example, 50 ℃;
and/or, in step S8, the reaction time for the benzyl protecting group removal reaction is 4 to 24 hours, for example, 6 hours;
and/or the compound shown as the formula A6 is
The compound shown as the formula A7 is
13. A method for producing a compound represented by formula A9, comprising the step S11 of: under the action of acid, carrying out acidification reaction on the water suspension of the compound shown in the formula A8 to obtain an acidification reaction product, then carrying out oxidation reaction on the acidification reaction product in an organic solvent under the action of an oxidant to obtain the compound shown in the formula A9,
wherein R is 1 、R 2 And R 3 Is as defined in claim 1 or 2.
14. The method according to claim 13, wherein the step of preparing the resin composition,
in step S11, in the acidification reaction, the acid is one or more of sulfuric acid, hydrochloric acid, acetic acid and formic acid, such as hydrochloric acid and/or acetic acid;
and/or in the step S11, in the acidification reaction, the amount of the acid is preferably about 1-2 of the pH value of the system;
and/or, in the step S11, the acidification reaction is carried out under the condition of an ice water bath or an ice salt bath;
and/or, in step S11, in the oxidation reaction, the oxidizing agent is hydrogen peroxide and/or m-chloroperoxybenzoic acid;
and/or, in step S11, in the oxidation reaction, the molar ratio of the oxidizing agent to the compound represented by formula A8 is 1 to 2, for example, 1.1;
and/or, in step S11, in the oxidation reaction, the organic solvent is a chlorinated alkane solvent, such as one or more of dichloromethane, 1,2 dichloroethane and chloroform, preferably dichloromethane;
and/or, in step S11, the temperature of the oxidation reaction is 10 to 30 ℃, for example, 25 ℃;
and/or, in step S11, the reaction time of the oxidation reaction is 3 to 8 hours, for example, 4 hours;
and/or the compound shown as the formula A8 is
The compound shown as the formula A9 is
15. The method according to claim 13, wherein the step of preparing the resin composition,
the method for preparing the compound represented by formula A9 may further include a method for preparing a compound represented by formula A8 below, which includes the following step S10: subjecting formula A8-1 to a cyclization reaction in an organic solvent under the action of a cyclization agent to obtain the compound shown in formula A8,
wherein R is 1 、R 2 And R 3 Is as defined in claim 1 or 2.
16. The method according to claim 15,
in step S10, the cyclizing reagent is one or more of N, N-dimethylformamide dimethyl acetal, p-toluic acid, sodium methoxide and sodium ethoxide, preferably N, N-dimethylformamide dimethyl acetal;
and/or in step S10, the organic solvent is a chloroalkane solvent; such as one or more of dichloromethane, 1,2 dichloroethane, and chloroform;
and/or, in step S10, the temperature of the cyclization reaction is 20 to 35 ℃, for example, 25 ℃;
and/or, in step S10, the reaction time of the cyclization reaction is 8 to 24 hours, for example 10 hours.
17. The method of claim 15,
the method for preparing the compound represented by the formula A8 may further include a method for preparing a compound represented by the following formula A8-1, which includes the following step S9: subjecting the compound represented by the formula A7 to a reduction reaction in an organic solvent under the action of a reducing agent to obtain a compound represented by the formula A8-1,
wherein R is 1 、R 2 And R 3 Is as defined in claim 1 or 2.
18. The method of claim 17,
in step S9, the compound represented by formula A7 is produced according to the production method of the compound represented by formula A7 according to claim 11 or 12;
and/or, in the step S9, the reducing agent is alkali metal borohydride and/or lithium aluminum hydride; for example sodium borohydride and/or lithium borohydride, preferably lithium borohydride;
and/or, in step S9, the molar ratio of the reducing agent to the compound of formula A7 is 3 to 6, for example 5.0;
and/or, in step S9, the organic solvent is an ether solvent, such as tetrahydrofuran;
and/or, in step S9, the temperature of the reduction reaction is-5 to 35 ℃, for example 10 to 30 ℃, and further for example 25 ℃;
and/or, in step S9, the reaction time of the reduction reaction is 10 to 18 hours, for example 12 hours;
and/or step S9 comprises the steps of: dissolving the compound shown in the formula A7 in the organic solvent to form a mixture solution, and adding the reducing agent into the mixture solution to perform the reduction reaction;
and/or a compound of the formula A7The object is
The compound shown as the formula A8-1 is
19. Use of a compound of formula A9 as an intermediate in the preparation of a compound of formula a10 or a11, comprising scheme 1 or scheme 2 as follows:
scheme 1, which comprises the following step S12: carrying out hydrogenation reaction on the compound shown in the formula A9 and hydrogen in an organic solvent under the action of a catalyst to obtain the compound shown in the formula A10,
scheme 2, which comprises the following steps S12 and S13, wherein the step S12 is the same as the scheme 1;
step S13: carrying out deprotection reaction on the compound shown in the formula A10 in an organic solvent under the action of a deprotection reagent to obtain the compound shown in the formula A11,
wherein R is 1 、R 2 And R 3 Is as defined in claim 1 or 2.
20. The use according to claim 19,
in step S12, the compound represented by formula A9 is prepared according to the method for preparing a compound represented by formula A9 as claimed in one of claims 13 to 18;
in step S12, the catalyst is raney nickel and/or a palladium catalyst, preferably a palladium catalyst, and further preferably 5% palladium/barium sulfate, and the "%" is a mass percentage of the palladium in the total mass of the palladium and the barium sulfate;
and/or in step S12, the mass percent of the catalyst and the compound shown in the formula A9 is 30-50%;
and/or, in step S12, the organic solvent is an alcohol solvent, such as methanol and/or ethanol;
and/or, in step S12, the pressure of the hydrogenation reaction is 1 to 1.5atm, for example 1atm;
and/or, in step S12, the temperature of the hydrogenation reaction is 20 to 35 ℃, for example 25 ℃;
and/or, in step S12, the reaction time of the hydrogenation reaction is 3 to 10 hours, for example 8 hours;
and/or, in step S13, the deprotection reagent is boron trichloride and/or boron tribromide, preferably boron tribromide;
and/or, in step S13, the molar ratio of the deprotection reagent to the compound represented by formula a10 is 5 to 10, for example 8;
and/or, in step S13, the organic solvent is a chloroalkane, preferably dichloromethane;
and/or, in step S13, the temperature of the deprotection reaction is-20 to 25 ℃, for example, 10 ℃;
and/or, in step S13, the reaction time of the deprotection reaction is 5 to 10 hours, for example, 8 hours;
and/or the compound shown as the formula A9 is
The compound shown as the formula A10 is
21. A method for preparing a compound represented by formula B2-3, comprising the steps of: subjecting a compound represented by the formula B2-2 to a recarburization reaction as shown below to obtain a compound represented by the formula B2-3,
wherein R is 8 And R 9 Independently H, C 1～10 Alkyl radical, C 1～10 Alkoxy radical, C 3～10 Cycloalkyl, benzyl or C 6～20 An aryl group; r 10 Is halogen, C 1～6 Alkyl radical, C 1～6 Cycloalkyl or C 6～20 An aryl group; r is 11 And R 12 Independently H, C 1～10 Alkyl radical, C 1～10 Alkoxy radical, C 3～10 Cycloalkyl or C 6～20 An aryl group;
the conditions and operation of the recarburization reaction are as defined in claim 9 or 10.
22. A method for producing a compound represented by the formula A5-1, comprising the step S3 of: the method comprises the following steps S3: in POCl 3 Subjecting a compound represented by the formula A4 to a cyclization reaction in an organic solvent as shown below to obtain a compound represented by the formula A5-1,
wherein R is 1 And R 2 As defined in claim 1 or 2, P as defined in claim 3 or 4, and the conditions and operation of the cyclisation reaction as defined in claim 5 or 6.
23. A method for producing a compound represented by the formula A8-1, comprising the step S9 of: under the protection of inert gas and the action of a reducing agent, carrying out the reduction reaction shown as the following on the compound shown as the formula A7 in an organic solvent to obtain the compound shown as the formula A8-1,
wherein R is 1 、R 2 And R 3 As defined in claim 1 or 2, the conditions and operation of said reduction reaction being as defined in claim 17 or 18.
24. A method for producing a compound represented by formula a13, comprising the step S15 of: carrying out nucleophilic addition reaction on the compound shown in the formula A12 in an organic solvent under the action of a nucleophilic reagent to obtain a compound shown in a formula A13;
wherein R is 1 、R 2 And R 3 As defined in claim 1 or 2, R 4 Is C 1～10 Alkyl radical, C 3～10 Cycloalkyl or C 6～20 And (4) an aryl group.
25. The method of claim 24,
in step S15, the nucleophile is a grignard reagent and/or a lithium reagent, preferably a grignard reagent;
and/or, in step S15, the molar ratio of the nucleophile to the compound of formula a12 is 5 to 10, for example 7;
and/or, in step S15, the organic solvent is an ether solvent and/or a substituted aromatic hydrocarbon solvent, such as toluene;
and/or, in step S15, the volume-to-mass ratio of the organic solvent to the compound represented by formula a12 is 5 to 100mL/g, for example, 40 to 60mL/g;
and/or, in step S15, the temperature of the nucleophilic addition reaction is between-5 and 35 ℃, for example between 10 and 30 ℃, and for example again at 25 ℃;
and/or, in step S15, the reaction time of the nucleophilic addition reaction is 4 to 10 hours, for example 6 hours;
and/or, R 4 Is C 1～4 Alkyl, the compound represented by the formula A12 is preferably
The compound represented by the formula A13 is preferably
26. The method according to claim 24, wherein the method for producing a compound represented by formula a13 further comprises a method for producing a compound represented by the following formula a12, which comprises the following step S14: performing cycloaddition reaction on the compound shown in the formula A8 and methyl vinyl ketone to obtain a compound shown in a formula A12,
R 1 、R 2 and R 3 Is as defined in claim 1 or 2.
27. The method of claim 26,
in step S14, the compound of formula A8 is prepared according to the method for preparing a compound of formula A8 as claimed in one of claims 15 to 18;
and/or in step S14, the volume-to-mass ratio of the methyl vinyl ketone to the compound shown in the formula A8 is 0.5-5 mL/100mg, for example 3mL/100mg;
and/or, in step S14, the temperature of the cycloaddition reaction is 70 to 90 ℃, for example 80 ℃;
and/or, in step S14, the reaction time of the cycloaddition reaction is 4 to 16 hours, for example 6 hours.
28. A method for producing a compound represented by formula a14, comprising the step S16 of: subjecting the compound represented by the formula A13 to a hydrogenation reaction with hydrogen in an organic solvent in the presence of a catalyst to obtain a compound represented by the formula A14,
the hydrogenation reaction is carried out under the pressure of 5-30 atm;
wherein R is 1 、R 2 And R 3 As defined in claim 1 or 2, R 4 Is as defined in claim 24.
29. The method of claim 28,
in step S16, the compound represented by formula a13 is produced according to the production method of the compound represented by formula a13 according to any one of claims 24 to 27;
and/or, in step S16, the hydrogenation reaction is carried out at a pressure of 10 atm;
and/or, in step S16, the catalyst is a palladium catalyst, such as palladium on carbon;
and/or, in step S16, the molar ratio of the catalyst to the compound represented by formula a13 is 0.03 to 0.2; for example 0.1;
and/or, in step S16, the organic solvent is an ether and/or alcohol solvent, such as ethanol and/or isopropanol;
and/or, in step S16, the temperature of the hydrogenation reaction is 50-80 ℃, for example 70 ℃;
and/or, in step S16, the reaction time of the hydrogenation reaction is 8 to 16 hours, for example 10 hours;
and/or the compound shown as the formula A13 is
The compound shown as the formula A14 is
30. A method for preparing a compound represented by formula a15, comprising the following step S17: subjecting the compound represented by the formula A14 to demethylation reaction in an organic solvent under the action of a base and a thiol to obtain the compound represented by the formula A15,
wherein R is 1 、R 2 And R 3 As defined in claim 1 or 2, R 4 As defined in claim 24 or 25.
31. The method of claim 30, wherein the step of preparing the composition,
in step S17, the compound represented by formula a14 is produced according to the production method of the compound represented by formula a14 according to claim 28 or 29;
and/or, in step S17, the base is an alcoholic base, such as sodium tert-butoxide and/or potassium tert-butoxide;
and/or, in step S17, the mercaptan is an alkyl mercaptan, such as n-dodecyl mercaptan;
and/or, in step S17, the molar ratio of the base to the compound a14 is 1.8 to 3.0, for example 2.0;
and/or, in step S17, the organic solvent is an amide and/or sulfoxide solvent, such as DMSO and/or DMF;
and/or, in step S17, the temperature of the demethylation reaction is between 100 and 130 ℃, for example 120 ℃;
and/or, in step S17, the reaction time of the demethylation reaction is 1 to 3 hours, for example 2 hours
And/or the compound shown as the formula A14 is
The compound shown as the formula A15 is
32. A compound represented by formula A5-1, A5-2, A5-3, A5, A6, A7, A8-1, A8, A9, A10, A12 or A13:
wherein R is 1 、R 2 、R 3 And R 4 P is as defined in the claims;
preferably, the compounds represented by the formula A5-1, A5-2, A5-3, A5, A6, A7, A8-1, A8, A9, A10, A12 or A13 are each selected from the following compounds:
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