CN108484499B - 由羟胺和炔烃制备多取代异喹啉衍生物的方法 - Google Patents
由羟胺和炔烃制备多取代异喹啉衍生物的方法 Download PDFInfo
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- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 238000000034 method Methods 0.000 title claims abstract description 35
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 title abstract description 24
- 150000001345 alkine derivatives Chemical class 0.000 title abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 38
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims abstract description 32
- 235000011056 potassium acetate Nutrition 0.000 claims abstract description 16
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 4
- 239000010948 rhodium Substances 0.000 claims abstract description 4
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 4
- -1 diaryl alkyne compound Chemical class 0.000 claims description 18
- 239000007864 aqueous solution Substances 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 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
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000005580 one pot reaction Methods 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 239000011521 glass Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 238000010992 reflux Methods 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 28
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 14
- 239000000758 substrate Substances 0.000 abstract description 12
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- 238000007363 ring formation reaction Methods 0.000 abstract description 5
- 125000001424 substituent group Chemical group 0.000 abstract description 5
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 abstract description 4
- 229910052736 halogen Inorganic materials 0.000 abstract description 4
- 150000002367 halogens Chemical class 0.000 abstract description 4
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- 230000018044 dehydration Effects 0.000 abstract description 2
- 238000006297 dehydration reaction Methods 0.000 abstract description 2
- 239000001103 potassium chloride Substances 0.000 abstract description 2
- 235000011164 potassium chloride Nutrition 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 abstract 1
- 239000000047 product Substances 0.000 description 31
- 239000003208 petroleum Substances 0.000 description 21
- 238000000926 separation method Methods 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000003480 eluent Substances 0.000 description 15
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 15
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
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- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 12
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- JRXXLCKWQFKACW-UHFFFAOYSA-N biphenylacetylene Chemical compound C1=CC=CC=C1C#CC1=CC=CC=C1 JRXXLCKWQFKACW-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- JVVPBUVHDUEYKV-UHFFFAOYSA-N 1-benzyl-3,4-diphenylisoquinoline Chemical compound N=1C(C=2C=CC=CC=2)=C(C=2C=CC=CC=2)C2=CC=CC=C2C=1CC1=CC=CC=C1 JVVPBUVHDUEYKV-UHFFFAOYSA-N 0.000 description 6
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000002994 raw material Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000011068 loading method Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
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- 150000002466 imines Chemical class 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
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- 239000000126 substance Substances 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- HGJNRQMRLNGOJH-UHFFFAOYSA-N 1-(4-chlorophenyl)isoquinoline Chemical compound C1=CC(Cl)=CC=C1C1=NC=CC2=CC=CC=C12 HGJNRQMRLNGOJH-UHFFFAOYSA-N 0.000 description 1
- WSXUXTVJTIPBAF-UHFFFAOYSA-N 1-bromo-3-[2-(3-bromophenyl)ethynyl]benzene Chemical group BrC1=CC=CC(C#CC=2C=C(Br)C=CC=2)=C1 WSXUXTVJTIPBAF-UHFFFAOYSA-N 0.000 description 1
- QFRLNLXZHMUYHO-UHFFFAOYSA-N 1-chloro-4-[2-(4-chlorophenyl)ethynyl]benzene Chemical group C1=CC(Cl)=CC=C1C#CC1=CC=C(Cl)C=C1 QFRLNLXZHMUYHO-UHFFFAOYSA-N 0.000 description 1
- HFFUXLCRPYMGFM-UHFFFAOYSA-N 1-fluoro-4-[2-(4-fluorophenyl)ethynyl]benzene Chemical group C1=CC(F)=CC=C1C#CC1=CC=C(F)C=C1 HFFUXLCRPYMGFM-UHFFFAOYSA-N 0.000 description 1
- YKUOFMNGWLZXHA-UHFFFAOYSA-N 1-methoxy-4-[2-(4-methoxyphenyl)ethynyl]benzene Chemical group C1=CC(OC)=CC=C1C#CC1=CC=C(OC)C=C1 YKUOFMNGWLZXHA-UHFFFAOYSA-N 0.000 description 1
- VWGHYYQMOXOCCI-UHFFFAOYSA-N 1-methyl-3-[2-(3-methylphenyl)ethynyl]benzene Chemical group CC1=CC=CC(C#CC=2C=C(C)C=CC=2)=C1 VWGHYYQMOXOCCI-UHFFFAOYSA-N 0.000 description 1
- OFDOCXDLDQXWIX-UHFFFAOYSA-N 1-methyl-4-[2-(4-methylphenyl)ethynyl]benzene Chemical group C1=CC(C)=CC=C1C#CC1=CC=C(C)C=C1 OFDOCXDLDQXWIX-UHFFFAOYSA-N 0.000 description 1
- OLMMGNRXOABKEG-UHFFFAOYSA-N 1-tert-butyl-4-[2-(4-tert-butylphenyl)ethynyl]benzene Chemical group C1=CC(C(C)(C)C)=CC=C1C#CC1=CC=C(C(C)(C)C)C=C1 OLMMGNRXOABKEG-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- NKSZCPBUWGZONP-UHFFFAOYSA-N 3,4-dihydroisoquinoline Chemical compound C1=CC=C2C=NCCC2=C1 NKSZCPBUWGZONP-UHFFFAOYSA-N 0.000 description 1
- UICBHOXXGLYZJH-UHFFFAOYSA-N 5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium Chemical compound C1=CC=C2CC[N+]3=CC4=CC=CC=C4C=C3C2=C1 UICBHOXXGLYZJH-UHFFFAOYSA-N 0.000 description 1
- HPGQMTLUWJMIOC-UHFFFAOYSA-N 6-methoxy-3,4-bis(4-methoxyphenyl)-1-[(4-methoxyphenyl)methyl]isoquinoline Chemical compound COC=1C=C2C(=C(N=C(C2=CC=1)CC1=CC=C(C=C1)OC)C1=CC=C(C=C1)OC)C1=CC=C(C=C1)OC HPGQMTLUWJMIOC-UHFFFAOYSA-N 0.000 description 1
- DAYQIUHIVOMIRU-UHFFFAOYSA-N 6-methyl-3,4-bis(4-methylphenyl)-1-[(4-methylphenyl)methyl]isoquinoline Chemical compound CC=1C=C2C(=C(N=C(C2=CC=1)CC1=CC=C(C=C1)C)C1=CC=C(C=C1)C)C1=CC=C(C=C1)C DAYQIUHIVOMIRU-UHFFFAOYSA-N 0.000 description 1
- REBSLLVSURRARQ-UHFFFAOYSA-N 7-bromo-3,4-bis(3-bromophenyl)-1-[(3-bromophenyl)methyl]isoquinoline Chemical compound BrC1=CC=C2C(=C(N=C(C2=C1)CC1=CC(=CC=C1)Br)C1=CC(=CC=C1)Br)C1=CC(=CC=C1)Br REBSLLVSURRARQ-UHFFFAOYSA-N 0.000 description 1
- PBMWWPGTTCGBCR-UHFFFAOYSA-N 7-methyl-3,4-bis(3-methylphenyl)-1-[(3-methylphenyl)methyl]isoquinoline Chemical compound CC1=CC=C2C(=C(N=C(C2=C1)CC1=CC(=CC=C1)C)C=1C=C(C=CC=1)C)C=1C=C(C=CC=1)C PBMWWPGTTCGBCR-UHFFFAOYSA-N 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- 239000002028 Biomass Substances 0.000 description 1
- 238000006407 Bischler-Napieralski reaction Methods 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 235000011096 Papaver Nutrition 0.000 description 1
- 240000001090 Papaver somniferum Species 0.000 description 1
- 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 description 1
- 238000006796 Pomeranz-Fritsch reaction Methods 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- LFYJSSARVMHQJB-QIXNEVBVSA-N bakuchiol Chemical compound CC(C)=CCC[C@@](C)(C=C)\C=C\C1=CC=C(O)C=C1 LFYJSSARVMHQJB-QIXNEVBVSA-N 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 229930013397 isoquinoline alkaloid Natural products 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical class C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 description 1
- 238000005648 named reaction Methods 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000005693 optoelectronics Effects 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种由羟胺和炔烃制备多取代异喹啉衍生物的方法。该方法使用二芳基炔烃化合物II和羟胺为底物,在三价铑作为催化剂和醋酸钾作为碱的条件下,在氮气环境下于乙醇中140℃进行反应而得到结构通式I所示的多取代异喹啉衍生物。该方法经济、便捷,对多种底物,包括各种带烷基或卤素,给电子基的底物均适用,使得该体系能够得到取代基多样化的异喹啉类化合物;反应无需额外添加氧化剂,通过脱水即可完成环化过程。反应的原子利用率较高,整个过程所产生的副产物只有水和催化量的氯化钾,对环境没有污染。
Description
技术领域
本发明属于精细化工产品催化合成领域,涉及一种由羟胺和炔烃制备多取代异喹啉衍生物的方法。
背景技术
异喹啉衍生物广泛存在于自然界中,是已知最大的一类生物碱类型。许多异喹啉生物碱由于其突出的生物活性而被用作药物,例如从罂粟中提取出来的罂粟碱是一种重要的解痉药。很多具有生物活性的较复杂的生物碱,如吗啡烷类和原小檗碱类等也都含有异喹啉骨架。由于其独特的药理活性,作为一种优势结构的异喹啉骨架,成为药物开发中广泛使用的构筑单元。例如,某些1,3-二取代的异喹啉衍生物具有抗疟活性(Micale,N.etal.Bioorg.Med.Chem.2009,17,6505)。某些异喹啉衍生物还是生物体内某些受体的激动剂(Reux,B.et al.Bioorg.Med.Chem.2009,17,4441),被用作RNA聚合酶的抑制剂,起到抗病毒作用(Hendricks,R.T.et al.Bioorg.Med.Chem.Lett.2009,19,410)。此外,异喹啉的N原子具有良好的配位能力,使得异喹啉衍生物被广泛用作配体。例如,某些铱的异喹啉配合物由于具有突出的光电性质而被用于制造有机发光二极管(Ho,C.L.etal.Adv.Funct.Mater.2008,18,319)。由于异喹啉的刚性共平面结构,其骨架也是联萘型手性配体的常用构筑单元(Clayden,J.et al.J.Am.Chem.Soc.2009,131,5331)。综合上述异喹啉衍生物的多种用途发现,改变异喹啉上取代基,可以明显影响异喹啉环的性质和功能,便于调控其药效或配位能力。
由于异喹啉类化合物具有上述突出的性质和广泛的应用,关于它的合成技术就一直受到有机合成化学家的关注。从19世纪末开始多种利用缩合环化反应合成异喹啉的方法就被开发出来,其中有许多人名反应(Kurti,L.;Czako,B.,StrategicApplications ofNamed Reactions in Organic Synthesis.Background andDetailedMechanisms.Elsevier Academic Press:2005.)。比如Bischler-Napieralski反应,是利用2-芳基乙胺与酰氯或酸酐反应生成酰胺,进而在P2O5等脱水剂作用下环化生成3,4-二氢异喹啉,然后在Pd/C等条件下脱氢生成异喹啉。类似的Pictet-Spengler反应则利用2-芳基乙胺与醛生成的亚胺作为底物,进而环化成四氢异喹啉。而Pomeranz-Fritsch反应则用带亚胺和缩醛双官能团的底物成环。这些最经典的方法虽然被使用的时间较长,但它们往往需要强酸条件,对环境污染较大,不符合绿色化学和可持续发展的需求;并且这些方法对底物的适用性较窄,往往只能合成带有特定取代基的异喹啉衍生物,已经不能满足现代药物开发中构建多样化分子库的需求。近十几年来,许多的化学工作者也发展了一系列方法来构建异喹啉类化合物。Larock等发展了一系列基于2-炔基苯甲醛参与的串联反应来构建异喹啉等杂环的方法(Zeni,G.;Larock,R.C.Chem.Rev.2006,106,4644),然而该方法需要预先使用卤代苯和端炔合成相应底物,合成步骤较繁琐,并且产生大量的含卤素副产物,对环境不友好。Fagnou(Guimond,N.;Fagnou,K.J.Am.Chem.Soc.2009,131,12050.),Miura(Fukutani,T.;Umeda,N.;Hirano,K.;Satoh,T.;Miura,M.Chem.Commun.2009,5141.)先后报道了铑催化合成异喹啉的反应体系,这些反应体系均是通过对碳氢键的活化而直接进行反应,避免了含卤素副产物的生成。但是,这些体系均需要较复杂的路线合成含氮底物,且均加入了当量的醋酸铜作氧化剂,整个反应条件有待优化。之后Cheng(Parthasarathy,K.;Cheng,C.H.J.Org.Chem.2009,74,9359.),Chiba(Too,P.C.;Wang,Y.F.;Chiba,S.Org.Lett.2010,12,5688.)和Li(Zhang,X.;Zhao,J.;Li,X.;etal.Adv.Synth.Catal.2011,353,719.)等均在底物设计上使用内置氧化剂,但其肟类底物仍需较复杂的合成得到,反应体系仍不理想。因此,开发更为便捷、高效而绿色的异喹啉合成体系成为有机合成化学家探索的目标之一。这其中涉及两个重要的问题:一是如何开发使用常见原料即可完成的合成体系,二是如何在合成过程中尽可能地减少对环境不友好的副产物产生。
发明内容
本发明的目的是提供一种由羟胺和炔烃制备多取代异喹啉衍生物的方法。
本发明提供的制备式I所示化合物(也即多取代异喹啉衍生物)的方法,包括如下步骤:将式II所示二芳基炔烃化合物、羟胺的水溶液或盐酸羟胺、碱及催化剂混匀进行“一锅法”反应,反应完毕得到所述式I所示化合物;
所述式I、式II中,R为供电子取代基,具体可为碳原子数总数为1-5的烷基、碳原子总数为1-5的烷氧基、氟、氯、溴或氢;更具体可为甲基、甲氧基、叔丁基;
所述碱为醋酸钾、醋酸钠、醋酸铯或碳酸钾,优选醋酸钾。
所述催化剂为三价铑催化剂,为[Cp*RhCl2]2,其中,Cp*为五甲基环戊二烯负离子。
所述羟胺源为羟胺的水溶液或盐酸羟胺,优选羟胺的水溶液。所述羟胺水溶液为羟胺的质量浓度为20%至80%的水溶液,优选50%的水溶液,其投料摩尔用量以其中所含羟胺的投料摩尔用量计,为所述式II所示二芳基炔烃化合物的2.0~4.5倍,优选3.0倍。
所述催化剂的投料摩尔用量为所述式II所示二芳基炔烃化合物的0.5~2.5%,优选1.0%。
所述碱的投料摩尔用量为所述式II所示二芳基炔烃化合物的0.2~1.0倍,优选0.5倍。
所述反应在溶剂中进行;所述溶剂为甲醇、乙醇、正丙醇或异丙醇,优选乙醇。
所述反应步骤中,温度为130~150℃,优选140℃;时间为12~24小时,优选18小时,该反应时间视不同式II所示反应物不同而变化。反应是否完毕可通过薄层色谱或者气相色谱进行监测。
在反应完毕后,可将反应体系按照常规方法进行分离提纯,优选的分离方式为:将反应之后的原液转移到圆底烧瓶中,转移时可用一些乙酸乙酯或二氯甲烷冲洗原容器,以减少损失;加入一定量100~200目的硅胶,减压浓缩除去溶剂得到含产物的硅胶;使用100~200目的硅胶和石油醚装柱,使用干法上柱;先用石油醚作为洗脱剂进行洗脱,用薄层色谱监测,待未反应的II原料洗脱出之后,用石油醚-乙酸乙酯混合溶剂进行洗脱,石油醚和乙酸乙酯的比例视反应物和产物的极性而不同,需要通过薄层色谱的结果进行估计,乙酸乙酯的体积分数一般为2~10%;收集包含反应产物I的溶液,旋蒸掉溶剂后真空干燥,称重并计算产率。对于固体产物,可以通过重结晶的方式来获得更高的纯度,一般重结晶的方式是在样品中加入一定量的二氯乙烷,加热使得样品完全溶解,再向其中加入不良溶剂正己烷,并让其缓慢挥发,可得到产物的单晶。
本发明提供的合成多取代异喹啉衍生物的方法,具有以下特点:(1)经济。反应原料的羟胺和炔烃,是常用的化工原料,所使用的碱和溶剂亦非常的廉价易得,所使用的催化剂虽然不廉价,但所需加入量很少,反应所得的产物为高附加值的杂环化合物。(2)便捷。反应只需一步、一次投料和一次分离步骤即可得到最终产物,由于反应具有很高的化学选择性,使得分离过程亦非常简单。(3)普适。反应对多种底物,包括各种带烷基或卤素,给电子基的底物均适用,使得该体系能够得到取代基多样化的异喹啉类化合物;且在反应物用量为0.5~10mmol的范围内均得到了很好的实践。(4)绿色。溶剂为甲醇或乙醇,低毒且可以从生物质中再生。更重要的是,反应无需额外添加氧化剂,通过脱水即可完成环化过程。反应的原子利用率较高,整个过程所产生的副产物只有水和催化量的氯化钾,对环境没有污染。
附图说明
图1为实施例1所得目标产物的核磁共振氢谱图。
图2为实施例1所得目标产物的核磁共振碳谱图。
图3为实施例2所得目标产物的核磁共振氢谱图。
图4为实施例2所得目标产物的核磁共振碳谱图。
图5为实施例3所得目标产物的核磁共振氢谱图。
图6为实施例3所得目标产物的核磁共振碳谱图。
图7为实施例7所得目标产物的核磁共振氢谱图。
图8为实施例7所得目标产物的核磁共振碳谱图。
具体实施方式
下面结合具体实施例对本发明作进一步阐述,但本发明并不限于以下实施例。所述方法如无特别说明均为常规方法。所述材料如无特别说明均能从公开商业途径而得。
下述实施例在反应结束后进行柱分离可按照各种常规方法进行,如可按照如下方法进行:
将反应之后的原液转移到圆底烧瓶中,转移时用乙酸乙酯冲洗原容器,以减少损失;加入一定量100~200目的硅胶,减压浓缩除去溶剂得到含产物的硅胶;使用100~200目的硅胶和石油醚装柱,干法上柱;先用石油醚作为洗脱剂进行洗脱,用薄层色谱监测,待未反应的式II原料洗脱出之后,用石油醚-乙酸乙酯混合溶剂进行洗脱,石油醚和乙酸乙酯的比例视反应物和产物的极性而不同,需要通过薄层色谱的结果进行估计,乙酸乙酯的体积分数一般为2~10%;收集包含反应产物I的溶液,旋蒸掉溶剂后真空干燥,称重并计算产率。对于固体产物,可以通过重结晶的方式来获得更高的纯度,一般重结晶的方式是在样品中加入一定量的二氯乙烷,加热使得样品完全溶解,再向其中加入不良溶剂正己烷,并让其缓慢挥发,可得到产物的单晶。
实施例1
依次称取0.1782g二苯乙炔(1.0mmol)、184μL 50%的羟胺水溶液(3.0mmol)、0.0062g[Cp*RhCl2]2(0.01mmol)、0.0491g醋酸钾(0.5mmol)于含磁性搅拌子的25mL封管中,加入4.0mL乙醇。在氮气条件下将封管密封,放入140℃的油浴中搅拌18小时。反应结束后用石油醚-乙酸乙酯作为洗脱剂进行柱分离,得到白色固体0.1595g,目标产物1-苯甲基-3,4-二苯基异喹啉的分离产率为86%。图1和图2分别为该实施例制备所得产品的核磁共振氢谱和碳谱,由图可知,该化合物结构正确。
实施例2
依次称取0.2063g二(4-甲基苯基)乙炔(1.0mmol)、184μL 50%的羟胺水溶液(3.0mmol)、0.0062g[Cp*RhCl2]2(0.01mmol)、0.0491g醋酸钾(0.5mmol)于含磁性搅拌子的25mL封管中,加入4.0mL乙醇。在氮气条件下将封管密封,放入140℃的油浴中搅拌18小时。反应结束后用石油醚-乙酸乙酯作为洗脱剂进行柱分离,得到淡黄色固体0.1879g,目标产物6-甲基-1-(4-甲基苯甲基)-3,4-二(4-甲基苯基)异喹啉的分离产率为88%。图3和图4分别为该实施例制备所得产品的核磁共振氢谱和碳谱,由图可知,该化合物结构正确。
实施例3
依次称取0.2063g二(3-甲基苯基)乙炔(1.0mmol)、184μL 50%的羟胺水溶液(3.0mmol)、0.0062g[Cp*RhCl2]2(0.01mmol)、0.0491g醋酸钾(0.5mmol)于含磁性搅拌子的25mL封管中,加入4.0mL乙醇。在氮气条件下将封管密封,放入140℃的油浴中搅拌18小时。反应结束后用石油醚-乙酸乙酯作为洗脱剂进行柱分离,得到黄色固体0.1708g,目标产物7-甲基-1-(3-甲基苯甲基)-3,4-二(3-甲基苯基)异喹啉的分离产率为80%。图5和图6分别为该实施例制备所得产品的核磁共振氢谱和碳谱,由图可知,该化合物结构正确。
实施例4
依次称取0.2904g二(4-叔丁基苯基)乙炔(1.0mmol)、184μL 50%的羟胺水溶液(3.0mmol)、0.0062g[Cp*RhCl2]2(0.01mmol)、0.0491g醋酸钾(0.5mmol)于含磁性搅拌子的25mL封管中,加入4.0mL乙醇。在氮气条件下将封管密封,放入140℃的油浴中搅拌18小时。反应结束后用石油醚-乙酸乙酯作为洗脱剂进行柱分离,得到黄色固体0.2439g,目标产物6-叔丁基-1-(4-叔丁基苯甲基)-3,4-二(4-叔丁基苯基)异喹啉的分离产率为82%。
实施例5
依次称取0.2142g二(4-氟苯基)乙炔(1.0mmol)、184μL 50%的羟胺水溶液(3.0mmol)、0.0062g[Cp*RhCl2]2(0.01mmol)、0.0491g醋酸钾(0.5mmol)于含磁性搅拌子的25mL封管中,加入4.0mL乙醇。在氮气条件下将封管密封,放入140℃的油浴中搅拌18小时。反应结束后用石油醚-乙酸乙酯作为洗脱剂进行柱分离,得到黄色固体0.1794g,目标产物6-氟-1-(4-氟苯甲基)-3,4-二(4-氟苯基)异喹啉的分离产率为81%。
实施例6
依次称取0.2471g二(4-氯苯基)乙炔(1.0mmol)、184μL 50%的羟胺水溶液(3.0mmol)、0.0062g[Cp*RhCl2]2(0.01mmol)、0.0491g醋酸钾(0.5mmol)于含磁性搅拌子的25mL封管中,加入4.0mL乙醇。在氮气条件下将封管密封,放入140℃的油浴中搅拌18小时。反应结束后用石油醚-乙酸乙酯作为洗脱剂进行柱分离,得到褐色固体0.2163g,目标产物6-氯-1-(4-氯苯甲基)-3,4-二(4-氯苯基)异喹啉的分离产率为85%。
实施例7
依次称取0.3360g二(3-溴苯基)乙炔(1.0mmol)、184μL 50%的羟胺水溶液(3.0mmol)、0.0062g[Cp*RhCl2]2(0.01mmol)、0.0491g醋酸钾(0.5mmol)于含磁性搅拌子的25mL封管中,加入4.0mL乙醇。在氮气条件下将封管密封,放入140℃的油浴中搅拌18小时。反应结束后用石油醚-乙酸乙酯作为洗脱剂进行柱分离,得到褐色固体0.2611g,目标产物7-溴-1-(3-溴苯甲基)-3,4-二(3-溴苯基)异喹啉的分离产率为76%。图7和图8分别为该实施例制备所得产品的核磁共振氢谱和碳谱,由图可知,该化合物结构正确。
实施例8
依次称取0.2383g二(4-甲氧基苯基)乙炔(1.0mmol)、184μL 50%的羟胺水溶液(3.0mmol)、0.0062g[Cp*RhCl2]2(0.01mmol)、0.0491g醋酸钾(0.5mmol)于含磁性搅拌子的25mL封管中,加入4.0mL乙醇。在氮气条件下将封管密封,放入140℃的油浴中搅拌18小时。反应结束后用石油醚-乙酸乙酯作为洗脱剂进行柱分离,得到白色固体0.2261g,目标产物6-甲氧基-1-(4-甲氧基苯甲基)-3,4-二(4-甲氧基苯基)异喹啉的分离产率为92%。
实施例9
依次称取0.1782g二苯乙炔(1.0mmol)、0.2085g盐酸羟胺(3.0mmol)、0.0062g[Cp*RhCl2]2(0.01mmol)、0.3437g醋酸钾(3.5mmol)于含磁性搅拌子的25mL封管中,加入4.0mL乙醇。在氮气条件下将封管密封,放入140℃的油浴中搅拌18小时。反应结束后用石油醚-乙酸乙酯作为洗脱剂进行柱分离,得到白色固体0.1057g,目标产物1-苄基-3,4-二苯基异喹啉的分离产率为57%。
实施例10
依次称取0.1782g二苯乙炔(1.0mmol)、184μL 50%的羟胺水溶液(3.0mmol)、0.0062g[Cp*RhCl2]2(0.01mmol)、0.0491g醋酸钾(0.5mmol)于含磁性搅拌子的25mL封管中,加入4.0mL乙醇。在空气条件下将封管密封,放入140℃的油浴中搅拌18小时。反应结束后用石油醚-乙酸乙酯作为洗脱剂进行柱分离,得到白色固体0.1279g,目标产物1-苯甲基-3,4-二苯基异喹啉的分离产率为69%。
实施例11
依次称取0.1782g二苯乙炔(1.0mmol)、184μL 50%的羟胺水溶液(3.0mmol)、0.0062g[Cp*RhCl2]2(0.01mmol)、0.0691g碳酸钾(0.5mmol)于含磁性搅拌子的25mL封管中,加入4.0mL乙醇。在氮气条件下将封管密封,放入140℃的油浴中搅拌18小时。反应结束后用石油醚-乙酸乙酯作为洗脱剂进行柱分离,得到白色固体0.1149g,目标产物1-苯甲基-3,4-二苯基异喹啉的分离产率为62%。
实施例12
依次称取0.1782g二苯乙炔(1.0mmol)、184μL 50%的羟胺水溶液(3.0mmol)、0.0062g[Cp*RhCl2]2(0.01mmol)、0.0491g醋酸钾(0.5mmol)于含磁性搅拌子的25mL封管中,加入2.0mL乙醇。在氮气条件下将封管密封,放入140℃的油浴中搅拌18小时。反应结束后用石油醚-乙酸乙酯作为洗脱剂进行柱分离,得到白色固体0.1353g,目标产物1-苯甲基-3,4-二苯基异喹啉的分离产率为73%。
实施例13
依次称取0.1782g二苯乙炔(1.0mmol)、184μL 50%的羟胺水溶液(3.0mmol)、0.0062g[Cp*RhCl2]2(0.01mmol)、0.0491g醋酸钾(0.5mmol)于含磁性搅拌子的25mL封管中,加入4.0mL异丙醇。在氮气条件下将封管密封,放入140℃的油浴中搅拌18小时。反应结束后用石油醚-乙酸乙酯作为洗脱剂进行柱分离,得到白色固体0.1521g,目标产物1-苯甲基-3,4-二苯基异喹啉的分离产率为82%。
对比例1
依次称取0.1782g二苯乙炔(1.0mmol)、184μL 50%的羟胺水溶液(3.0mmol)、0.0062g[Cp*RhCl2]2(0.01mmol)于含磁性搅拌子的25mL封管中,加入4.0mL乙醇。在氮气条件下将封管密封,放入140℃的油浴中搅拌18小时。没有目标产物1-苯甲基-3,4-二苯基异喹啉生成。
Claims (11)
1.一种制备式I所示化合物的方法,包括如下步骤:
将式II所示二芳基炔烃化合物、羟胺源、碱及催化剂混匀进行“一锅法”反应,反应完毕得到所述式I所示化合物;
所述式I、式II中,所述R为碳原子数总数为1-5的烷基、碳原子总数为1-5的烷氧基、氟、氯、溴或氢;
所述碱为醋酸钾、醋酸钠、醋酸铯或碳酸钾;
所述催化剂为三价铑催化剂;所述三价铑催化剂为[Cp*RhCl2]2,其中,Cp*为五甲基环戊二烯负离子;
所述羟胺源为羟胺的水溶液或盐酸羟胺;
所述羟胺源的投料摩尔用量以羟胺的投料摩尔用量计,为所述式II所示二芳基炔烃化合物的2.0~4.5倍;
所述催化剂的投料摩尔用量为所述式II所示二芳基炔烃化合物投料摩尔用量的0.5~2.5%;
所述碱的投料摩尔用量为所述式II所示二芳基炔烃化合物的0.2~1.0倍。
2.根据权利要求1所述的方法,其特征在于:所述R中,碳原子总数为1-5的烷基为甲基或叔丁基;
所述碳原子总数为1-5的烷氧基为甲氧基。
3.根据权利要求1所述的方法,其特征在于:所述羟胺的水溶液为羟胺的质量百分浓度为20%至80%的水溶液。
4.根据权利要求3所述的方法,其特征在于:所述羟胺的水溶液为为羟胺的质量百分浓度为50%的水溶液。
5.根据权利要求1所述的方法,其特征在于:所述羟胺源的投料摩尔用量以羟胺的投料摩尔用量计,为所述式II所示二芳基炔烃化合物的3.0倍;
所述催化剂的投料摩尔用量为所述式II所示二芳基炔烃化合物投料摩尔用量的1.0%;
所述碱的投料摩尔用量为所述式II所示二芳基炔烃化合物的0.5倍。
6.根据权利要求1所述的方法,其特征在于:所述反应在溶剂中进行。
7.根据权利要求6所述的方法,其特征在于:所述溶剂选自甲醇、乙醇、正丙醇和异丙醇中至少一种。
8.根据权利要求1所述的方法,其特征在于:所述反应步骤中,温度为130~150 °C;时间为12~24小时。
9.根据权利要求1所述的方法,其特征在于:所述反应步骤中,温度为140 °C;时间为18小时。
10.根据权利要求1-9任一所述的方法,其特征在于:所述反应步骤中,反应装置为开放的或密闭的反应装置或附加回流装置的反应容器。
11.根据权利要求10所述的方法,其特征在于:所述反应步骤中,反应装置为玻璃封管。
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