CN104262255A - 一种不对称催化合成γ-硝基吡唑酰胺化合物的方法 - Google Patents
一种不对称催化合成γ-硝基吡唑酰胺化合物的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 24
- 238000007036 catalytic synthesis reaction Methods 0.000 title abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 38
- -1 β-unsaturated pyrazole amide Chemical class 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 150000001412 amines Chemical class 0.000 claims abstract description 22
- 239000002808 molecular sieve Substances 0.000 claims abstract description 14
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000000654 additive Substances 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 230000000996 additive effect Effects 0.000 claims abstract description 3
- 239000003446 ligand Substances 0.000 claims description 9
- 229910052761 rare earth metal Inorganic materials 0.000 claims description 9
- 238000006555 catalytic reaction Methods 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- GEKLDGQKEZAPFZ-UHFFFAOYSA-N 2-(ethylamino)-1-(3-methylphenyl)propan-1-one Chemical compound CCNC(C)C(=O)C1=CC=CC(C)=C1 GEKLDGQKEZAPFZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims 5
- YETWLUGJYKSMHM-UHFFFAOYSA-N gadolinium;trifluoromethanesulfonic acid Chemical compound [Gd].OS(=O)(=O)C(F)(F)F YETWLUGJYKSMHM-UHFFFAOYSA-N 0.000 claims 3
- 230000004913 activation Effects 0.000 claims 1
- FECRNHPJGAZUKO-UHFFFAOYSA-N erbium;trifluoromethanesulfonic acid Chemical compound [Er].OS(=O)(=O)C(F)(F)F FECRNHPJGAZUKO-UHFFFAOYSA-N 0.000 claims 1
- BGVUVBIFPBJZEI-UHFFFAOYSA-N holmium;trifluoromethanesulfonic acid Chemical compound [Ho].OS(=O)(=O)C(F)(F)F BGVUVBIFPBJZEI-UHFFFAOYSA-N 0.000 claims 1
- QUJLPICXDXFRSN-UHFFFAOYSA-N scandium;trifluoromethanesulfonic acid Chemical compound [Sc].OS(=O)(=O)C(F)(F)F QUJLPICXDXFRSN-UHFFFAOYSA-N 0.000 claims 1
- MRVDPBDPQPBGMS-UHFFFAOYSA-N trifluoromethanesulfonic acid;yttrium Chemical compound [Y].OS(=O)(=O)C(F)(F)F MRVDPBDPQPBGMS-UHFFFAOYSA-N 0.000 claims 1
- 125000004971 nitroalkyl group Chemical group 0.000 abstract description 12
- 239000003054 catalyst Substances 0.000 abstract description 8
- 238000000746 purification Methods 0.000 abstract description 6
- 230000003197 catalytic effect Effects 0.000 abstract description 5
- 150000002909 rare earth metal compounds Chemical class 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000006845 Michael addition reaction Methods 0.000 description 9
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000758 substrate Substances 0.000 description 7
- DYOBTPTUHDTANY-UHFFFAOYSA-K gadolinium(3+);trifluoromethanesulfonate Chemical compound [Gd+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F DYOBTPTUHDTANY-UHFFFAOYSA-K 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 0 C*1[C@@](C(N(*)NO)=O)N(*)CC1 Chemical compound C*1[C@@](C(N(*)NO)=O)N(*)CC1 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000003760 magnetic stirring Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 150000002910 rare earth metals Chemical class 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 2
- 229960001233 pregabalin Drugs 0.000 description 2
- HZXJVDYQRYYYOR-UHFFFAOYSA-K scandium(iii) trifluoromethanesulfonate Chemical compound [Sc+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HZXJVDYQRYYYOR-UHFFFAOYSA-K 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 150000003585 thioureas Chemical class 0.000 description 2
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 1
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 1
- 229910020366 ClO 4 Inorganic materials 0.000 description 1
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229960000794 baclofen Drugs 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- GLQOFBCJADYRKR-UHFFFAOYSA-K erbium(3+);trifluoromethanesulfonate Chemical compound [Er+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F GLQOFBCJADYRKR-UHFFFAOYSA-K 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- DBPDCYACEYLEMY-UHFFFAOYSA-K holmium(3+);trifluoromethanesulfonate Chemical compound [Ho+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F DBPDCYACEYLEMY-UHFFFAOYSA-K 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- PYZLRNMGUBDIHK-UHFFFAOYSA-N molecular hydrogen;nickel Chemical compound [Ni].[H][H] PYZLRNMGUBDIHK-UHFFFAOYSA-N 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229960002296 paroxetine Drugs 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- JPJIEXKLJOWQQK-UHFFFAOYSA-K trifluoromethanesulfonate;yttrium(3+) Chemical compound [Y+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F JPJIEXKLJOWQQK-UHFFFAOYSA-K 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/50—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
- C07C205/53—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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 ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D231/16—Halogen atoms or nitro radicals
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种不对称催化合成γ-硝基吡唑酰胺化合物的方法，采用硝基烷烃和α,β-不饱和吡唑酰胺为原料，手性氧化胺与稀土金属化合物形成的络合物为催化剂，
Description
技术领域
本发明涉及手性氧化胺-稀土金属络合物催化α,β-不饱和吡唑酰胺与硝基烷烃的不对称Michael加成反应合成γ-硝基吡唑酰胺的方法。
背景技术
γ-硝基吡唑酰胺化合物在有机合成中占有很重要的地位，它不但可以在碱的催化下与甲醇发生甲酯化反应，操作简单，合成效率高，还可以通过简单的化学反应转化为γ-氨基酸、2-吡啶酮以及2-吡咯烷酮等具有生物活性的化合物。目前已有一些不对称催化合成γ-硝基吡唑酰胺的报道。
Carlos F.Barbas III等利用硫脲衍生物XIV为手性催化剂，氯仿为溶剂，在-20℃下实现了下列硝基烯与吡唑酰胺的不对称Michael加成反应，产物可获得34％-99％的收率、10:1->20:1的d.r值(d.r值：含有两个及以上手性中心的化合物的非对映选择性)和78％-97％的ee值(Angew.Chem.Int.Ed.2012,51,5381)。
Long Lu等利用硫脲衍生物2d为手性催化剂，甲苯为溶剂，在室温下实现了下列硝基烷烃与三氟甲基取代的吡唑酰胺的不对称Michael加成反应，产物可获得71％-91％的收率、4.4:1–9.9:1的d.r值(d.r值：含有两个及以上手性中心的化合物的非对映选择性)和80％-93％的ee值(ACS Catal.2013,3,502)。
Shuji Kanemasa等利用R,R-DBFOX/Ph*Ni(ClO4)2*3H2O(A)和2,2,6,6-tetramethylpiperidine(TMP)作为组合催化剂，硝基甲烷与四氢呋喃(v/v＝1/1)为混合溶剂，在-20℃至室温下实现了下列硝基甲烷对不饱和吡唑酰胺的不对称Michael加成反应，产物可获得39％-97％的收率和77％-97％的ee值(J.Am.Chem.Soc.2002,124,13394)。
综上所述，Carlos F.Barbas III的催化反应体系中，反应须在-20℃进行，会耗费很多能量；Long Lu的催化反应体系中，α,β-不饱和酰胺扩展的底物都是端位有三氟甲基取代的，限制比较大；Shuji Kanemasa的催化反应体系中，反应前需要在-78℃活化，并且扩展的16个底物中，有11个底物的反应温度为-20℃，3个底物需要0℃，仅仅只有两个底物可以在室温下反应，有11个底物的反应时间需要96h，其中有6个底物反应时间需要168h，并且收率也并不理想，反应完成后需先用饱和氯化铵洗涤产品后才柱层析分离纯化，反应条件苛刻，操作复杂，硝基甲烷的用量太大(0.1mmolα,β-不饱和吡唑酰胺化合物需要用9.1mmol硝基甲烷)，最重要的是所得的反应结果并不好。所以一种高效、操作简单、节约能源并利于环境的方法亟需被发展。
发明内容
本发明的目的是发展不对称催化α,β-不饱和吡唑酰胺化合物与硝基烷烃的Michael加成反应，提供一种高效、操作简单、节约能源并利于环境的合成γ-硝基吡唑酰胺化合物的方法。
本发明的方案是：一种不对称催化合成γ-硝基吡唑酰胺化合物的方法，其特征在于以硝基烷烃和α,β-不饱和吡唑酰胺为原料，手性氧化胺与稀土金属化合物形成的络合物为催化剂，分子筛为添加剂，二氯甲烷为溶剂，于25-50℃，常压下反应12-120h，TLC检测反应，硅胶柱层析分离，得手性γ-硝基吡唑酰胺化合物，其中：
硝基烷烃的结构为RCH2NO2，R＝H,CH3,Et,Bn；
α,β-不饱和吡唑酰胺化合物的结构为：
R1＝C6H5,4-FC6H4,4-ClC6H4,4-BrC6H4,4-MeC6H4,4-MeOC6H4,3-BrC6H4,3-MeC6H4,2-BrC6H4,2-MeOC6H4,3,4–Cl2C6H3,3,4-(MeO)2C6H3,2-Furyl,2-Thienyl,CH3,Pr,Pent,iBu,EtO,EtOOC；R2＝CH3,Ph；R3＝H,Cl,Br,I；
手性氧化胺配体的结构为：
n＝1,2；R＝Ph-,2,6-Me2C6H3-,2,6-Et2C6H3-,2,6-iPr2C6H3-,Ph2CH-；
稀土金属化合物为：三氟甲磺酸钆[Gd(OTf)3]、三氟甲磺酸钪[Sc(OTf)3]、三氟甲磺酸钬[Ho(OTf)3]、三氟甲磺酸镱[Yb(OTf)3]、三氟甲磺酸铒[Er(OTf)3]、三氟甲磺酸钇[Y(OTf)3]；
硝基烷烃与α,β-不饱和吡唑酰胺化合物的摩尔比是1.86:1-55.8:1,最佳摩尔比是9.3:1。
反应的最佳催化剂是手性氧化胺L6(n＝2，R＝2,6-iPr2C6H3-)与三氟甲磺酸钆[Gd(OTf)3]形成的络合物，手性氧化胺与稀土金属化合物的摩尔比为0.8:1.0-1.5:1.0,最佳摩尔比是1.2:1.0；
分子筛450℃下活化3小时，0.1mmol的α,β-不饱和吡唑酰胺对应的分子筛量为10-100mg；
二氯甲烷经GaH2回流干燥处理，0.1mmol的α,β-不饱和吡唑酰胺对应的量为6.2mmol；
反应温度为30℃；
反应时间为72-96h。
与背景技术相比，本发明具有如下突出优势：
1.操作简便，催化剂不需要活化，产物易与催化剂、添加剂、原料分离。
2.反应转化率和对映选择性高，反应收率高达99％，对映选择性高达99％ee。
3.反应体系简单清洁，无需酸、碱添加剂。
4.反应条件温和，常压30℃下反应。
5.硝基烷烃的用量较少，节约原料。
具体实施方式
实施例1：手性氧化胺与稀土金属络合物催化不对称α,β-不饱和吡唑酰胺与硝基烷烃的Michael加成反应
在反应容器中加入稀土金属化合物(序号1-11:0.01mmol,序号12-16:0.0075mmol)、手性氧化胺配体(序号1-11:0.012mmol,序号12-16:0.009mmol)、α,β-不饱和吡唑酰胺1a(0.1mmol)、分子筛30mg、搅拌子，置换氮气3次后加入二氯甲烷(6.2mmol)、硝基甲烷(序号1-11:5.6mmol,序号12-16:0.93mmol)，于25-50℃搅拌12-120h。TLC监测反应。柱层析分离纯化，产物的对映体过量用高效液相色谱(Daicel chiralcel IE，V正己烷:V异丙醇＝90：10，流速1.0mL/min)测定，见表1。反应式和手性氧化胺配体结构如下：
表一.手性氧化胺与稀土金属络合物催化不对称α,β-不饱和吡唑酰胺和硝基甲烷的不对称Michael加成反应条件优化(n.d.：未检测)
实施例2：手性氧化胺L6-Gd(OTf)3络合物催化不对称α,β-不饱和吡唑酰胺与硝基烷烃的Michael加成反应
在反应容器中加入Gd(OTf)3(序号1-16,20-23,25-27:0.0075mmol,序号17-19,24:0.01mmol)、手性氧化胺L6(序号1-16,20-23,25-27:0.009mmol,序号17-19,24:0.012mmol)(手性氧化胺L6与三氟甲磺酸钆(Gd(OTf)3)的摩尔比为1.2:1.0)、α,β-不饱和酰胺(0.1mmol)、分子筛(序号1-16,20-27:30mg,序号18:100mg,序号17,19:60mg)、搅拌子，置换氮气3次后加入6.2mmol二氯甲烷和0.93mmol硝基烷烃，30℃下搅拌72h。柱层析分离纯化，产物的对映体过量用手性高效液相色谱测定，反应式如下：
反应结果见表2：(d.r:含有两个及以上手性中心的化合物的非对映选择性)
表2.手性氧化胺L6-Gd(OTf)3络合物催化不对称α,β-不饱和吡唑酰胺与硝基烷烃的Michael加成反应
| 序号 | R,R1,R2,R3 | 收率(％) | 对映选择性(％ee) |
| 1 | H,C6H5,CH3,H | 99 | 99 |
| 2 | H,4-FC6H4,CH3,H | 99 | 99 |
| 3 | H,4-ClC6H4,CH3,H | 98 | 98 |
| 4 | H,4-BrC6H4,CH3,H | 96 | 98 |
| 5 | H,4-MeC6H4,CH3,H | 95 | 99 |
| 6 | H,4-MeOC6H4,CH3,H | 89 | 99 |
| 7 | H,3-BrC6H4,CH3,H | 98 | 98 |
| 8 | H,3-MeC6H4,CH3,H | 96 | 99 |
| 9 | H,2-BrC6H4,CH3,H | 99 | 99 |
| 10 | H,2-MeOC6H4,CH3,H | 99 | 99 |
| 11 | H,3,4–Cl2C6H3,CH3,H | 96 | 99 |
| 12 | H,3,4-(MeO)2C6H3,CH3,H | 83 | 99 |
| 13 | H,2-Furyl,CH3,H | 56 | 97 |
| 14 | H,2-Thienyl,CH3,H | 58 | 98 |
| 15 | H,CH3,CH3,H | 69 | 98 |
| 16 | H,Pr,CH3,H | 87 | 98 |
| 17 | H,Pent,CH3,H | 65 | 98 |
| 18 | H,iBu,CH3,H | 77 | 98 |
| 19 | H,EtO,CH3,H | 53 | 95 |
| 20 | H,EtOOC,CH3,H | 67 | 95 |
| 21 | H,4-ClC6H4,CH3,Cl | 94 | 99 |
| 22 | H,4-ClC6H4,CH3,Br | 96 | 99 |
| 23 | H,4-ClC6H4,CH3,I | 97 | 99 |
| 24 | H,4-ClC6H4,C6H5,H | 39 | 81 |
| 25 | CH3,4-ClC6H4,CH3,H | 94 | 98/98(d.r.1.6/1) |
| 26 | Et,4-ClC6H4,CH3,H | 87 | 99/98(d.r.1.2/1) |
| 27 | PhCH2,4-ClC6H4,CH3,H | 98 | 99/98(d.r.1.1/1) |
实施例3：放大量实验1
在装有磁力搅拌装置的圆底烧瓶中，加入氧化胺配体L6(0.24mmol)、三氟甲磺酸钆(0.2mmol)、序号2中不饱和酰胺(0.976g，4mmol)、分子筛1.2g，抽换氮气3次，然后加入186mmol二氯甲烷、37.2mmol硝基甲烷，30℃下搅拌96h。硅胶柱层析分离，得到催化产物为白色固体，1.217g，收率：99％；利用高效液相色谱(Daicel chiralcel IE，V正己烷:V异 丙醇＝90：10，流速1.0mL/min)测定，得到产物的对映选择性ee值99％。
实施例4：放大量实验2
在装有磁力搅拌装置的圆底烧瓶中，加入氧化胺配体L6(0.36mmol)、三氟甲磺酸钆(0.3mmol)、序号3中不饱和酰胺(1.04g，4mmol)、分子筛1.2g，抽换氮气3次，然后加入186mmol二氯甲烷、37.2mmol硝基甲烷，30℃下搅拌72h。硅胶柱层析分离，得到催化产物为白色固体，1.278g，收率：99％；利用高效液相色谱(Daicel chiralcel IE，V正己烷:V异 丙醇＝90：10，流速1.0mL/min)测定，得到产物的对映选择性ee值98％。
实施例5：放大量实验3
在装有磁力搅拌装置的圆底烧瓶中，加入氧化胺配体L6(0.72mmol)、三氟甲磺酸钆(0.6mmol)、序号18中不饱和酰胺(1.236g，6mmol)、分子筛6.5g，抽换氮气3次，然后加入325.5mmol二氯甲烷、55.8mmol硝基甲烷，30℃下搅拌72h。硅胶柱层析分离，得到催化产物为无色液体，1.34g，收率：83％；利用高效液相色谱(Daicel chiralcel IE，V正己烷:V异丙醇＝90：10，流速1.0mL/min)测定，得到产物的对映选择性ee值99％。
γ-硝基吡唑酰胺化合物在合成中的应用：
实施例6：催化产物的酯化反应
催化反应完成后(起始α,β-不饱和吡唑酰胺为0.1mmol)，往盛有3b和3a反应液的试管中分别加入DBU(0.067mmol)和甲醇(2.5mmol),在室温下搅拌过夜。柱层析分离纯化，利用高效液相色谱分析(3a:Daicel chiralcel IB，V正己烷:V异丙醇＝90:10，流速1.0mL/min)、(3b:Daicel chiralcel IC，V正己烷:V异丙醇＝95:5，流速0.8mL/min)。结果如下：
5a和5b可以按照文献报道的方法合成药物分子，巴氯芬和帕罗西汀(Org.Lett.2012,14,1516)。
由于脂肪类的酯类化合物不便于检测和分离纯化，所以采取了分步的方式来完成酯化的过程：在反应容器中加入3t(46.2mg,0.173mmol，98％ee，)，然后依次加入7.8mmol二氯甲烷、DBU(0.1mmol)、甲醇(3.72mmol)，室温下搅拌5h。柱层析分离纯化，利用高效液相色谱分析(Daicel chiralcel IE，V正己烷:V异丙醇＝95:5，流速1.0mL/min)，产物收率95％，对映体选择性98％ee。结果如下：
实施例7：普瑞巴林的合成
中国科学院成都有机化学有限公司公布了消旋的5c转化为消旋的6c的方法。他们用的是雷尼镍-H2作为氢化试剂对5c进行了还原关环，以97％的收率得到6c，虽然结果很好，但是操作复杂，并且过程中用到雷尼镍、氢气这些危险的试剂(CN 102115449A.06,07,2011)。
在这里我们提供了下列由5c合成6c的方法：该法反应条件温和、操作简单、反应高效
在装有磁力搅拌装置的圆底烧瓶中，加入5c(68.82mg,0.34mmol)、NiCl2·6H2O(80.6mg,0.34mmol)、EtOH(33.9mmol)，然后置于冰浴中5分钟，然后慢慢加入NaBH4(140.9mg,3.74mmol)，反应溶液继续在冰浴下搅拌2小时。然后加入1mL乙醇淬灭反应，回到室温，往反应液中加入1mL 6mol/L的氢氧化钠溶液，继续搅拌1h。1h后，往反应液中加入2mol/L的盐酸溶液，调节PH值小于7，然后用二氯甲烷(4x 6mL)萃取，合并有机层，用无水硫酸钠干燥，接着抽滤旋干既得产物6c，收率：95％，利用高效液相色谱分析(Daicel chiralcelAD-H，V正己烷:V异丙醇＝96：4，流速1.0mL/min)，得到产物的对映选择性ee值97％。
化合物6c按照文献的报道(Tetrahedron,2011,67,636)，在6mol/L盐酸中，100℃下回流10小时，便可以以95％的收率拿到普瑞巴林的盐酸盐并且ee值得到保持。
Claims (11)
1.一种不对称催化合成γ-硝基吡唑酰胺化合物的方法，其特征在于：以α,β-不饱和吡唑酰胺和硝基烷烃为原料，手性氧化胺与稀土金属化合物形成的络合物为催化剂，分子筛为添加剂，二氯甲烷为溶剂，于25-50℃,常压下反应12-120h，得手性γ-硝基吡唑酰胺化合物，其中：硝基烷烃的结构为RCH2NO2,R＝H,CH3,Et,Bn；
α,β-不饱和吡唑酰胺的结构为：
R1＝C6H5,4-FC6H4,4-ClC6H4,4-BrC6H4,4-MeC6H4,4-MeOC6H4,3-BrC6H4,3-MeC6H4,2-BrC6H4,2-MeOC6H4,3,4–Cl2C6H3,3,4-(MeO)2C6H3,2-Furyl,2-Thienyl,CH3,Pr,Pent,iBu,EtO,EtOOC；R2＝CH3,Ph；R3＝H,Cl,Br,I；
手性氧化胺配体的结构为：
n＝1,2；R＝Ph-,2,6-Me2C6H3-,2,6-Et2C6H3-,2,6-iPr2C6H3-,Ph2CH-；
稀土金属化合物为：三氟甲磺酸钆[Gd(OTf)3]、三氟甲磺酸钪[Sc(OTf)3]、三氟甲磺酸钬[Ho(OTf)3]、三氟甲磺酸镱[Yb(OTf)3]、三氟甲磺酸铒[Er(OTf)3]、三氟甲磺酸钇[Y(OTf)3]；
硝基烷烃与α,β-不饱和吡唑酰胺化合物的摩尔比是1.86:1-55.8:1；
手性氧化胺与稀土金属化合物的摩尔比为0.8:1.0-1.5:1.0；
分子筛的量为:0.1mmol的α,β-不饱和吡唑酰胺需分子筛为10-100mg；
二氯甲烷与α,β-不饱和吡唑酰胺化合物的摩尔比为3.1:1.0-7.8:1.0。
2.按权利要求1所述的方法，其特征在于硝基烷烃与α,β-不饱和吡唑酰胺化合物的摩尔比为9.3:1。
3.按权利要求1所述的方法，其特征在于稀土金属化合物是三氟甲磺酸钆[Gd(OTf)3]。
4.按权利要求1所述的方法，其特征在于手性氧化胺配体是n＝2,R＝2,6-iPr2C6H3-。
5.按权利要求1所述的方法，其特征在于手性氧化胺配体和三氟甲磺酸钆[Gd(OTf)3]的摩尔比为1.2:1。
6.按权利要求1所述的方法，α,β-不饱和吡唑酰胺化合物与稀土金属化合物的摩尔比为20:1-10:1。
7.按权利要求1所述的方法，其特征在于0.1mmolα,β-不饱和吡唑酰胺化合物需要分子筛30-100mg。
8.按权利要求1所述的方法，其特征在于0.1mmolα,β-不饱和吡唑酰胺化合物需要二氯甲烷6.2mmol。
9.按权利要求1所述的方法，其特征在于分子筛须450℃活化3h，二氯甲烷需CaH2干燥回流1h。
10.按权利要求1所述的方法，其特征在于反应温度为30℃。
11.按权利要求10所述的方法，其特征在于反应时间为72-96h。
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| CN201410486209.3A CN104262255A (zh) | 2014-09-22 | 2014-09-22 | 一种不对称催化合成γ-硝基吡唑酰胺化合物的方法 |
| CN201510075076.5A CN105985292B (zh) | 2014-09-22 | 2015-02-12 | 一种不对称催化合成γ-硝基吡唑酰胺化合物的方法 |
| CN201510291876.0A CN105418502B (zh) | 2014-09-22 | 2015-06-01 | 一种用于合成帕罗西汀的中间体及其制备方法和用途 |
| PCT/CN2015/081341 WO2016045415A1 (zh) | 2014-09-22 | 2015-06-12 | 一种不对称催化合成硝基吡唑酰胺化合物的方法 |
| JP2017512956A JP2017530956A (ja) | 2014-09-22 | 2015-06-12 | ニトロピラゾールアミド化合物の不斉触媒合成方法 |
| EP15844037.0A EP3199525A4 (en) | 2014-09-22 | 2015-06-12 | Method for asymmetrically catalyzed synthesis of nitropyrazole amide compound |
| US15/511,243 US10464899B2 (en) | 2014-09-22 | 2015-06-12 | Asymmetrically catalyzed synthesis method of nitropyrazole amide compound |
| JP2017513185A JP2017529343A (ja) | 2014-09-22 | 2015-06-15 | パロキセチンを合成するための中間体およびその製造方法と用途 |
| US15/511,244 US9796675B1 (en) | 2014-09-22 | 2015-06-15 | Intermediate for synthesizing paroxetine, method for preparing the same, and uses thereof |
| EP15844676.5A EP3199526A4 (en) | 2014-09-22 | 2015-06-15 | Intermediate for use in synthesizing paroxetine, preparation method for the intermediate, and uses thereof |
| PCT/CN2015/081422 WO2016045416A1 (zh) | 2014-09-22 | 2015-06-15 | 一种用于合成帕罗西汀的中间体及其制备方法和用途 |
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| WO2016045415A1 (zh) * | 2014-09-22 | 2016-03-31 | 浙江九洲药业股份有限公司 | 一种不对称催化合成硝基吡唑酰胺化合物的方法 |
| WO2016045416A1 (zh) * | 2014-09-22 | 2016-03-31 | 浙江九洲药业股份有限公司 | 一种用于合成帕罗西汀的中间体及其制备方法和用途 |
| CN106748949A (zh) * | 2017-01-13 | 2017-05-31 | 厦门大学 | 一种合成α,β不饱和酰胺化合物的方法 |
| CN112876328A (zh) * | 2021-01-15 | 2021-06-01 | 四川大学 | 一种不对称催化合成γ-氰基酰胺化合物及采用该化合物手性药物的方法 |
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| DE3680184D1 (de) * | 1985-08-10 | 1991-08-14 | Beecham Group Plc | Verfahren zur herstellung von arylpiperidincarbinol. |
| WO2009005647A2 (en) * | 2007-06-27 | 2009-01-08 | Bioverdant, Inc. | Compounds and process to prepare chiral intermediates for synthesis of paroxetine |
| CN102531825B (zh) * | 2010-12-29 | 2014-04-23 | 中国科学院大连化学物理研究所 | 一种促进丙烷转化制芳烃的方法 |
| CN102531815B (zh) * | 2011-12-22 | 2014-04-16 | 四川大学 | 一种不对称催化α,β-不饱和羰基化合物环氧化反应方法 |
| CN104262255A (zh) * | 2014-09-22 | 2015-01-07 | 四川大学 | 一种不对称催化合成γ-硝基吡唑酰胺化合物的方法 |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016045415A1 (zh) * | 2014-09-22 | 2016-03-31 | 浙江九洲药业股份有限公司 | 一种不对称催化合成硝基吡唑酰胺化合物的方法 |
| WO2016045416A1 (zh) * | 2014-09-22 | 2016-03-31 | 浙江九洲药业股份有限公司 | 一种用于合成帕罗西汀的中间体及其制备方法和用途 |
| CN105985292A (zh) * | 2014-09-22 | 2016-10-05 | 浙江九洲药业股份有限公司 | 一种不对称催化合成γ-硝基吡唑酰胺化合物的方法 |
| JP2017529343A (ja) * | 2014-09-22 | 2017-10-05 | 浙江九洲▲藥▼▲業▼股▲ふぇん▼有限公司Ｚｈｅｊｉａｎｇ Ｊｉｕｚｈｏｕ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． | パロキセチンを合成するための中間体およびその製造方法と用途 |
| CN105985292B (zh) * | 2014-09-22 | 2019-05-10 | 浙江九洲药业股份有限公司 | 一种不对称催化合成γ-硝基吡唑酰胺化合物的方法 |
| CN106748949A (zh) * | 2017-01-13 | 2017-05-31 | 厦门大学 | 一种合成α,β不饱和酰胺化合物的方法 |
| CN106748949B (zh) * | 2017-01-13 | 2019-04-09 | 厦门大学 | 一种合成α,β不饱和酰胺化合物的方法 |
| CN112876328A (zh) * | 2021-01-15 | 2021-06-01 | 四川大学 | 一种不对称催化合成γ-氰基酰胺化合物及采用该化合物手性药物的方法 |
Also Published As
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| JP2017529343A (ja) | 2017-10-05 |
| JP2017530956A (ja) | 2017-10-19 |
| CN105985292A (zh) | 2016-10-05 |
| EP3199526A1 (en) | 2017-08-02 |
| EP3199526A4 (en) | 2018-02-14 |
| US10464899B2 (en) | 2019-11-05 |
| US9796675B1 (en) | 2017-10-24 |
| EP3199525A1 (en) | 2017-08-02 |
| CN105418502A (zh) | 2016-03-23 |
| US20170283380A1 (en) | 2017-10-05 |
| CN105418502B (zh) | 2018-12-14 |
| EP3199525A4 (en) | 2018-02-14 |
| WO2016045416A1 (zh) | 2016-03-31 |
| US20170291876A1 (en) | 2017-10-12 |
| CN105985292B (zh) | 2019-05-10 |
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