CN114716380A - Efficient phase transfer catalytic 4-substituted pyrazolone compound asymmetric fluorination method - Google Patents
Efficient phase transfer catalytic 4-substituted pyrazolone compound asymmetric fluorination method Download PDFInfo
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- CN114716380A CN114716380A CN202210339561.9A CN202210339561A CN114716380A CN 114716380 A CN114716380 A CN 114716380A CN 202210339561 A CN202210339561 A CN 202210339561A CN 114716380 A CN114716380 A CN 114716380A
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- -1 4-substituted pyrazolone compound Chemical class 0.000 title claims abstract description 44
- 238000003682 fluorination reaction Methods 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 30
- 230000003197 catalytic effect Effects 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 22
- 241000157855 Cinchona Species 0.000 claims abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 235000021513 Cinchona Nutrition 0.000 claims abstract description 8
- 229930013930 alkaloid Natural products 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 150000003797 alkaloid derivatives Chemical class 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 109
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 104
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 229940125890 compound Ia Drugs 0.000 claims description 7
- DWBOSISZPCOPFS-UHFFFAOYSA-N 2-nitroacetonitrile Chemical compound [O-][N+](=O)CC#N DWBOSISZPCOPFS-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 5
- FNXLCIKXHOPCKH-UHFFFAOYSA-N bromamine Chemical compound BrN FNXLCIKXHOPCKH-UHFFFAOYSA-N 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 3
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- KMPWYEUPVWOPIM-LSOMNZGLSA-N cinchonine Chemical group C1=CC=C2C([C@@H]([C@H]3N4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-LSOMNZGLSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 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
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000006267 biphenyl group Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 150000008282 halocarbons Chemical group 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 239000011698 potassium fluoride Substances 0.000 claims description 2
- 235000003270 potassium fluoride Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- WZKSXHQDXQKIQJ-UHFFFAOYSA-N F[C](F)F Chemical compound F[C](F)F WZKSXHQDXQKIQJ-UHFFFAOYSA-N 0.000 claims 1
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims 1
- 238000003408 phase transfer catalysis Methods 0.000 abstract description 5
- 239000000758 substrate Substances 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 109
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 62
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 51
- 238000005160 1H NMR spectroscopy Methods 0.000 description 50
- 239000007787 solid Substances 0.000 description 40
- 238000004128 high performance liquid chromatography Methods 0.000 description 37
- 238000004293 19F NMR spectroscopy Methods 0.000 description 35
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 35
- 239000000047 product Substances 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 12
- 239000003054 catalyst Substances 0.000 description 7
- 239000000084 colloidal system Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 125000001153 fluoro group Chemical group F* 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 230000033444 hydroxylation Effects 0.000 description 4
- 238000005805 hydroxylation reaction Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229940051880 analgesics and antipyretics pyrazolones Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 102100034452 Alternative prion protein Human genes 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 1
- 108700020129 Human immunodeficiency virus 1 p31 integrase Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 108091000054 Prion Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 1
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- 239000003905 agrochemical Substances 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012025 fluorinating agent Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229940124524 integrase inhibitor Drugs 0.000 description 1
- 239000002850 integrase inhibitor Substances 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
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- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000004090 neuroprotective agent Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
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- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0245—Nitrogen containing compounds being derivatives of carboxylic or carbonic acids
- B01J31/0247—Imides, amides or imidates (R-C=NR(OR))
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0271—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds also containing elements or functional groups covered by B01J31/0201 - B01J31/0231
-
- 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
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- 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
- Y02P20/584—Recycling of catalysts
Abstract
The invention discloses a high-efficiency phase transfer catalytic 4-substituted pyrazolone compound asymmetric fluorination method, which comprises the following specific steps: uniformly stirring and mixing the 4-substituted pyrazolone compound, the phase transfer catalyst and the electrophilic fluorination reagent in a solvent, adding alkali, and stirring and reacting at-78-60 ℃ to obtain the chiral alpha-fluoropyrazolone compound. The method uses a phase transfer catalysis strategy and utilizes a cinchona alkaloid derived phase transfer catalyst to successfully realize the wide, high-efficiency and high-enantioselectivity asymmetric fluorination reaction of the 4-substituted pyrazolone compound. The method has the advantages of mild reaction conditions, simple operation, good substrate applicability, environmental friendliness and low cost, and is suitable for large-scale industrial production.
Description
Technical Field
The invention belongs to the technical field of phase transfer catalysis and organic synthesis, and particularly relates to a high-efficiency phase transfer catalysis 4-substituted pyrazolone compound asymmetric fluorination method.
Background
Pyrazolone is a five-membered heterocyclic compound containing two nitrogen atoms, and is a core structure of many natural products and compounds with biological activity. In particular, pyrazole-5-ketone compounds have the effects of killing insects, resisting bacteria, relieving pain, resisting inflammation, resisting tumors and the like, have been found to have an inhibitory effect on CD80, have a strong inhibitory effect on protease-resistant prion protein accumulation, and can also be used as cytokines, p38 kinase inhibitors, neuroprotective agents, HIV-1 integrase inhibitors, antipyretics and the like (Progress in Chemistry,2020,32, 1710). On the other hand, fluorine-containing compounds play an increasingly important role in medicine, agricultural chemicals, life science, and material science, and at present, more than 25% of small molecule drugs on the market contain fluorine atoms (org. process res.dev.2020,24,470). However, fluorine atoms cannot be obtained from natural products, and the preparation of fluorine-containing chiral compounds has been the focus of attention and research of organic fluorine chemists. The introduction of chiral fluorine atoms by asymmetric catalytic methods is one of the most direct and efficient methods for obtaining fluorine-containing chiral compounds (chem. rev.,2015,115,826). Of these, complex metal catalysis (J.Am.chem.Soc.2002,124,14530) and organic catalysis (Science 2011,334,1681) are the two most representative asymmetric fluorination schemes. However, for pyrazolone, an important structural unit, there are very few methods for introducing chiral fluorine atoms by asymmetric catalysis. Majoram et al first developed an asymmetric michael addition/fluorination two-step cascade of pyrazolones in 2012 to introduce chiral fluorine atoms at the 4-position of pyrazolones (chem. eur.j.2012,18,14255), and subsequently wang paul et al developed an asymmetric F-C addition/fluorination two-step cascade to introduce chiral fluorine atoms at the 4-position of pyrazolones (org. lett.2015,17,5168). However, these works have introduced a chiral center in the first step of the reaction, and the actual fluorination step is a diastereoselective fluorination process. In 2016, King Baker et al reported a direct asymmetric fluorination of 4-substituted pyrazolones using quinine cinchona-base as the catalyst (10 mol%), cesium carbonate as the base, but the enantioselectivity of the reaction was not high (35-81% ee), requiring 3-5 days of reaction time, and an ultra-low temperature of-60 ℃. It is clear that the high catalyst usage, the harsh reaction conditions and the low enantioselectivity limit the applicability of this process in practical production.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a high-efficiency phase transfer catalysis 4-substituted pyrazolone compound asymmetric fluorination method, which uses a phase transfer catalysis strategy and utilizes cinchona alkaloid derived phase transfer catalysts to successfully realize the wide, high-efficiency and high-enantioselectivity 4-substituted pyrazolone compound asymmetric fluorination reaction.
The invention adopts the following technical scheme for solving the technical problems: a high-efficiency phase transfer catalytic 4-substituted pyrazolone compound asymmetric fluorination method is characterized by comprising the following specific steps: stirring and mixing 4-substituted pyrazolone compound Ia, a phase transfer catalyst and an electrophilic fluorination reagent in a solvent uniformly, adding alkali, and stirring and reacting at-78-60 ℃ to obtain a chiral alpha-fluoropyrazolone compound Ib, wherein the reaction equation in the preparation process is as follows:
wherein R is1Is phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is F, Cl, Br, I, methoxyl or C1-4Alkyl, nitro, acetonitrile or trifluoromethyl, R2Is methyl, ethyl or substituted ethyl, the substituent on the substituted ethyl is phenyl, substituted phenyl, naphthyl or alkynyl, and the substituent on the substituted phenyl benzene ring is F, Cl, Br, I, methoxy or C1-4Alkyl, nitro, acetonitrile or trifluoromethyl, R3Is C1-4Alkyl, phenyl, substituted phenyl or naphthyl, wherein the substituent on the benzene ring of the substituted phenyl is F, Cl, Br, I, methoxy or C1-4Alkyl, nitro, acetonitrile, O-CH2-O (methylenedioxy) or trifluoromethyl;
the phase transfer catalyst is cinchonine derivative IIa or IIb, and the corresponding structural formula is as follows:
wherein R is3Is H or methoxy, R4Is tert-butyl, adamantyl, isopropyl, benzyl or substituted aryl;
the structural formula of the electrophilic fluorinating reagent is as follows:
wherein R is6Is H, methoxy, methyl, chlorine, bromine or iodine.
Further limited, the specific synthesis process of the phase transfer catalyst cinchona alkaloid cinchonine derivative IIa or IIb is as follows: primary amine reacts with bromoacetyl bromide to generate bromoamide, and then further reacts with cinchona alkaloid in tetrahydrofuran to obtain a phase transfer catalyst cinchona alkaloid cinchonine derivative IIa or IIb; the corresponding synthetic route is as follows:
further defined, the solvent is a halogenated hydrocarbon, an aromatic hydrocarbon, an alkane, or an ether; preferably one or more of toluene, trifluorotoluene, chloroform, p-xylene, mesitylene or n-hexane.
Further defined, the base is an organic base or an aqueous inorganic base; preferably an aqueous inorganic base solution which is an aqueous combination of one or more of sodium carbonate, dipotassium hydrogen phosphate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium fluoride or potassium acetate.
Further limiting the reaction temperature to-20-25 ℃.
Further limiting, the dosage of the phase transfer catalyst is 0.01-10 mol% of that of the 4-substituted pyrazolone compound Ia; preferably 0.5 to 1 mol%.
Further limiting, the feeding molar ratio of the electrophilic fluorinating reagent to the 4-substituted pyrazolone compound Ia is 1-2: 1.
Further limiting, the reaction time is 10 min-1 h.
Compared with the prior art, the invention has the following advantages and beneficial effects: the invention effectively realizes the asymmetric electrophilic fluorination reaction of the 4-substituted pyrazolone compound by using the cheap and easily-obtained chiral phase transfer catalyst, has extremely high yield and high enantioselectivity (the highest 98% ee), and can be completed within 10min to 1 h. The method provides an efficient synthesis way for preparing the alpha-fluoro pyrazolone compound with optical activity. The reaction product in the fluorination method is easy to separate in a reaction system, the fluorination efficiency can still be kept high when the fluorination reaction product is amplified to gram level, and meanwhile, the phase transfer catalyst can be recycled for multiple times and keeps a good catalytic effect. The method has the advantages of mild reaction conditions, simple operation, good substrate applicability, environmental friendliness and low cost, and is suitable for large-scale industrial production.
Detailed Description
The following detailed description of specific embodiments of the present invention will be provided in conjunction with the technical solutions to enable those skilled in the art to better understand the present invention.
Example 1
Synthesis of bromoamides
To dichloromethane (15mL) containing aniline (10mmol) was added potassium carbonate (2.1g,15mmol) in water (20 mL). The mixture was then cooled to 0 ℃ and bromoacetyl bromide (1.3mL, 15mmol) was added to 3mL dichloromethane and mixed, added dropwise, and the reaction was continued for 1 h. After the reaction was complete the two phases were separated and the aqueous phase was extracted three times with dichloromethane (3X15 mL); the organic phase was washed twice with water, once with saturated brine, dried over anhydrous sodium sulfate and spin-dried to give product S1 in 95% yield. Bromo-amides S2 to S16 with different structures were synthesized using the same method, and the reaction yield and compound structure were as follows:
example 2
Preparation of IIa-1
Mixing cinchonine (1.0g, 3.4mmol) and corresponding bromoamide (3.4mmol), adding THF (tetrahydrofuran) 30mL, heating and refluxing for 2h, controlling the reaction by thin-layer chromatography, cooling after the reaction is finished, and spin-drying the solvent. The dried solid was dissolved in methylene chloride (2 mL), and diethyl ether (25mL) was added dropwise to the solution to precipitate the solid. And (4) carrying out suction filtration on the precipitate, washing with diethyl ether, and finally drying and weighing to obtain the product.
White solid, mp: 196 ℃ plus 201 ℃; [ alpha ] to]D 25 42.0(c 0.20,CHCl3)；1H NMR(400MHz,DMSO-d6) δ11.04(d,J＝5.5Hz,1H),8.98(d,J＝4.5Hz,1H),8.25–8.02(m,2H),7.87–7.70(m, 4H),7.60(ddd,J＝8.4,6.8,1.4Hz,1H),7.50–7.38(m,2H),7.21(td,J＝7.4,1.2Hz,1H), 6.79(dd,J＝15.5,3.4Hz,1H),6.21–5.91(m,2H),5.37–5.13(m,2H),4.80(dd,J＝16.1, 12.1Hz,1H),4.66(d,J＝15.9Hz,1H),4.34(dt,J＝39.0,10.2Hz,3H),3.96–3.83(m,1H), 3.76–3.59(m,1H),2.87(q,J＝8.7Hz,1H),2.23(t,J＝11.9Hz,1H),2.02–1.85(m,3H), 1.20–0.98(m,1H).13C NMR(101MHz,DMSO-d6)δ163.22,150.65,148.05,145.14, 138.24,137.06,130.39,129.89,129.62,127.51,125.14,124.83,123.60,120.63,120.10, 117.68,66.01,65.19,59.70,59.59,57.60,37.58,26.62,23.39,20.59,11.76。
Examples 3 to 16 were carried out in the same manner as in example 2 except that IIa-1 was replaced with phase transfer catalyst structures IIa-2 to IIa-15 shown in the following Table, and the results are shown in Table 1.
Table 1 Experimental results of the synthesized phase transfer catalyst
Relative melting point, optical rotation and nuclear magnetic data for the phase transfer catalyst:
IIa-2: white solid, mp: 88 to 92 ℃; [ alpha ] to]D 25 92.5(c 0.20,CHCl3)；1H NMR(400MHz, DMSO-d6)δ10.95(d,J＝5.5Hz,1H),8.99(d,J＝4.5Hz,1H),8.32–8.13(m,2H),8.10– 7.69(m,6H),7.68–7.49(m,3H),7.41(ddd,J＝8.4,6.8,1.4Hz,1H),6.90(d,J＝3.5Hz, 1H),6.20(q,J＝6.5,4.8Hz,1H),6.05(ddd,J＝17.2,10.2,6.7Hz,1H),5.38–5.21(m,2H), 5.06(d,J＝15.9Hz,1H),4.84(dd,J＝16.1,12.1Hz,1H),4.58–4.21(m,3H),3.98(t,J＝ 11.4Hz,1H),3.87–3.70(m,1H),3.65–3.52(m,2H),2.98–2.82(m,1H),2.24(t,J＝11.9 Hz,1H),1.96(d,J＝8.5Hz,3H),1.75(td,J＝5.9,5.2,2.6Hz,2H),1.06(d,J＝8.8Hz,1H). 13C NMR(101MHz,DMSO-d6)δ164.26,150.65,148.06,145.24,137.11,134.24,132.29, 130.32,129.86,128.77,128.28,127.43,127.05,126.84,126.77,126.05,124.87,123.70, 123.13,122.91,120.62,117.67,67.48,66.11,65.42,59.57,57.56,37.60,26.64,25.60,23.43, 20.68,11.77。
IIa-3: light yellow solid, mp: 213-215 ℃; [ alpha ] to]D 25 74.5(c 0.20,CHCl3)；1H NMR(400MHz, DMSO-d6)δ10.38(q,J＝4.8,3.6Hz,1H),8.99(d,J＝4.5Hz,1H),8.27(d,J＝8.5Hz,1H), 8.08(d,J＝8.4Hz,1H),7.93–7.66(m,2H),7.52(t,J＝7.7Hz,1H),7.30(t,J＝7.6Hz, 1H),7.19(d,J＝7.6Hz,2H),6.95(dd,J＝16.5,3.9Hz,1H),6.20–5.95(m,2H),5.29(dd, J＝14.1,3.3Hz,2H),5.04(s,1H),4.76(d,J＝15.6Hz,1H),4.52–4.31(m,2H),4.16(t,J ＝11.5Hz,1H),3.97(t,J＝11.7Hz,1H),3.78(q,J＝15.5,12.4Hz,1H),2.86(q,J＝8.9Hz, 1H),2.66–2.44(m,6H),2.13(q,J＝11.8Hz,1H),1.92(dd,J＝20.2,6.8Hz,4H),1.31– 0.81(m,9H).13C NMR(101MHz,DMSO-d6)δ164.18,150.65,148.07,145.27,141.72, 137.01,132.51,130.28,129.89,128.42,127.50,126.67,124.88,123.92,120.55,117.66, 66.21,65.28,59.59,58.86,57.01,37.60,26.65,24.81,23.38,20.80,15.19,11.73。
IIa-4: white solid, mp: 196 ℃ plus 201 ℃; [ alpha ] to]D 25 69.4(c 0.20,CHCl3)；1H NMR(400MHz, DMSO-d6)δ8.97(d,J＝4.5Hz,1H),8.47(d,J＝7.4Hz,1H),8.25(d,J＝8.4Hz,1H),8.09 (d,J＝8.3Hz,1H),7.90–7.73(m,2H),7.71–7.55(m,1H),6.78(dd,J＝16.1,3.7Hz,1H), 6.08–5.88(m,2H),5.34–5.09(m,2H),4.57(d,J＝15.9Hz,1H),4.45–4.19(m,4H),3.84 (t,J＝11.3Hz,1H),3.69–3.52(m,1H),2.81(q,J＝8.8Hz,1H),2.07(q,J＝11.3,8.1Hz, 10H),1.89(q,J＝9.4,7.6Hz,3H),1.67(s,6H),1.03–0.93(m,1H).13C NMR(101MHz, DMSO-d6)δ163.79,150.67,148.04,145.25,137.02,130.30,129.96,127.48,124.83,123.89, 120.53,117.60,66.07,64.64,59.48,59.02,57.23,52.69,49.05,37.55,36.33,29.26,26.66, 23.36,20.67,11.74。
IIa-5: white solid, mp: 190 ℃ and 195 ℃; [ alpha ] to]D 25 88.0(c 0.20,CHCl3)；1H NMR(400MHz, DMSO-d6)δ9.44(t,J＝5.8Hz,1H),8.97(d,J＝4.5Hz,1H),8.23–8.03(m,2H),7.86– 7.69(m,2H),7.61(ddd,J＝8.4,6.8,1.3Hz,1H),7.46–7.18(m,6H),6.79(dd,J＝15.4,3.6 Hz,1H),6.07–5.90(m,2H),5.34–5.16(m,2H),4.64(d,J＝15.9Hz,1H),4.55–4.44(m, 3H),4.40–4.20(m,3H),3.88(dd,J＝24.4,13.1Hz,1H),3.62(dq,J＝16.6,8.4,7.5Hz, 1H),2.83(q,J＝8.9Hz,1H),2.16(t,J＝11.9Hz,1H),1.91(q,J＝8.7,7.1Hz,3H),1.04– 0.82(m,2H).13C NMR(101MHz,DMSO-d6)δ164.49,150.58,148.04,145.20,138.57, 137.06,130.28,129.84,128.95,128.05,127.70,127.65,127.58,124.84,123.65,120.51, 117.61,66.04,65.12,59.59,59.01,57.38,42.94,37.55,26.62,23.37,20.63,11.74。
IIa-6: light yellow solid, mp: 133-136 ℃; [ alpha ] to]D 25 50.0(c 0.20,CHCl3)；1H NMR(400MHz, DMSO-d6)δ10.82(s,1H),8.98(d,J＝4.5Hz,1H),8.12(dd,J＝27.2,8.5Hz,2H),8.01– 7.89(m,2H),7.86–7.67(m,3H),7.53(t,J＝7.7Hz,1H),6.86(dd,J＝15.7,3.4Hz,1H), 6.18–5.86(m,2H),5.38–5.12(m,2H),4.90(d,J＝16.0Hz,1H),4.80–4.59(m,1H),4.53 –4.07(m,3H),3.84(dt,J＝76.3,11.7Hz,2H),2.86(q,J＝8.8Hz,1H),2.16(q,J＝11.9Hz, 1H),1.93(d,J＝8.4Hz,3H),1.07–0.92(m,1H).13C NMR(101MHz,DMSO-d6)δ 165.02,150.62,148.07,145.18,137.02,133.95,132.93(t,J＝9.2Hz),130.30,129.91, 128.19–126.33(m),124.87,124.34,123.75,121.61,120.57,117.67,66.12,65.35,59.60, 59.06,57.32,37.56,26.58,23.34,20.71,11.74.19F NMR(376MHz,DMSO-d6)δ-59.52(s, 3F)。
IIa-7: white solid, mp: 172-176 ℃; [ alpha ] of]D 25 35.6(c 0.20,CHCl3)；1H NMR(400MHz, DMSO-d6)δ10.67(s,1H),8.99(d,J＝4.5Hz,1H),8.27–8.05(m,2H),7.85–7.65(m,4H), 7.57–7.41(m,2H),7.31(td,J＝7.7,1.7Hz,1H),6.87(d,J＝3.2Hz,1H),6.17(t,J＝3.2 Hz,1H),6.02(ddd,J＝17.2,10.1,6.8Hz,1H),5.38–5.15(m,2H),4.88(d,J＝16.0Hz, 1H),4.67(dd,J＝16.1,12.0Hz,1H),4.41(t,J＝10.5Hz,1H),4.28(t,J＝9.6Hz,2H),3.92 (t,J＝11.4Hz,1H),3.80–3.65(m,1H),2.86(q,J＝8.7Hz,1H),2.33–2.14(m,1H),1.95 (s,3H),1.10–0.94(m,1H).13C NMR(101MHz,DMSO-d6)δ163.93,150.63,148.08, 145.21,137.05,135.12,133.47,130.32,129.90,129.12,128.85,128.61,127.35,124.87, 123.85,120.59,119.64,117.67,66.18,65.34,60.23,59.67,59.27,57.56,37.57,26.60,23.39, 20.68,14.57,11.75。
IIa-8: milky white solid, mp: 129-134 ℃; [ alpha ] of]D 25 66.4(c 0.20,CHCl3)；1H NMR(400MHz, DMSO-d6)δ11.09(d,J＝3.6Hz,1H),8.98(d,J＝4.5Hz,1H),8.24(dt,J＝8.8,2.2Hz,1H), 8.09(dd,J＝8.5,1.2Hz,1H),7.81(ddd,J＝9.5,5.7,1.7Hz,2H),7.57(ddd,J＝8.4,6.8,1.4 Hz,1H),7.05(d,J＝2.2Hz,2H),6.80(dd,J＝15.9,3.6Hz,1H),6.37(t,J＝2.2Hz,1H), 6.17–5.92(m,2H),5.77(s,1H),5.28(ddt,J＝14.9,3.1,1.4Hz,2H),4.95–4.80(m,1H), 4.69(d,J＝15.9Hz,1H),4.44–4.21(m,3H),4.00–3.87(m,1H),3.78(s,8H),3.38(s,2H), 2.86(q,J＝8.8Hz,1H),2.51(p,J＝1.8Hz,1H),2.22(t,J＝11.9Hz,1H),2.04–1.87(m, 3H),1.16–0.96(m,1H).13C NMR(101MHz,DMSO-d6)δ163.32,161.12,150.66,148.06, 145.17,139.90,137.05,130.38,129.90,127.40,124.83,123.72,120.63,117.65,98.43,96.92, 65.91,65.35,59.63,59.56,57.54,55.76,55.42,37.56,26.60,23.39,20.63,11.75。
IIa-9: white solid, mp: 172-177 ℃; [ alpha ] to]D 25 35.6(c 0.20,CHCl3)；1H NMR(400MHz, DMSO-d6)δ10.45(d,J＝6.3Hz,1H),8.97(d,J＝4.5Hz,1H),8.25–7.97(m,2H),7.88– 7.71(m,2H),7.65–7.35(m,9H),7.32–7.23(m,1H),6.74(dd,J＝15.0,3.2Hz,1H),6.04 –5.70(m,2H),5.31–4.96(m,2H),4.68(d,J＝15.6Hz,1H),4.44–4.07(m,3H),3.82(dt, J＝51.6,11.2Hz,2H),3.54–3.40(m,1H),2.77(q,J＝8.8Hz,1H),2.10(q,J＝12.1Hz, 1H),1.97–1.71(m,3H),0.96–0.78(m,1H).13C NMR(101MHz,DMSO-d6)δ163.59, 150.60,148.06,145.18,139.14,138.26,137.01,133.52,131.08,130.28,129.89,129.19, 128.99,128.61,127.93,127.80,127.77,127.54,124.87,123.90,120.48,117.63,66.18,65.42, 59.41,57.24,37.55,26.53,23.35,20.69,11.72。
IIa-10: white solid, mp: 145-150 ℃; [ alpha ] to]D 25 76.4(c 0.20,CHCl3)；1H NMR(400MHz, DMSO-d6)δ11.34(s,1H),8.98(d,J＝4.5Hz,1H),8.31(dd,J＝8.6,3.3Hz,1H),8.22(d,J ＝2.0Hz,1H),8.08(dd,J＝8.5,1.2Hz,1H),7.86–7.73(m,3H),7.71–7.64(m,2H),7.59 –7.48(m,5H),7.46–7.37(m,1H),6.81(dd,J＝15.9,3.7Hz,1H),6.17(q,J＝5.8,4.4Hz, 1H),6.02(ddd,J＝17.3,10.2,6.8Hz,1H),5.33–5.20(m,2H),5.00(d,J＝15.8Hz,1H), 4.78(d,J＝15.6Hz,1H),4.54–4.19(m,3H),4.08–3.98(m,1H),3.83–3.65(m,1H),2.87 (d,J＝8.4Hz,1H),2.29–2.14(m,1H),1.92(d,J＝12.0Hz,3H),1.10–0.97(m,1H).13C NMR(101MHz,DMSO-d6)δ170.79,163.37,150.67,148.07,145.22,141.47,140.27, 138.87,137.04,130.36,130.21,129.83,129.56,128.30,127.43,127.09,124.85,123.83, 123.43,120.64,119.15,118.50,117.65,65.88,65.54,60.24,59.71,59.43,57.55,37.57, 26.62,23.43,21.25,20.69,14.56,11.75。
IIa-11: white solid, mp: 216 ℃ and 222 ℃; [ alpha ] of]D 25 64.5(c 0.20,CHCl3)；1H NMR(400MHz, DMSO-d6)δ10.41(s,1H),8.99(d,J＝4.5Hz,1H),8.27–8.03(m,2H),7.88–7.74(m,2H), 7.51(ddd,J＝8.4,6.8,1.3Hz,1H),7.43(d,J＝7.9Hz,2H),7.31(dtd,J＝21.0,7.4,1.6Hz, 2H),6.88(d,J＝3.4Hz,1H),6.15–5.95(m,2H),5.45–5.12(m,2H),5.00–4.61(m,2H), 4.48–4.21(m,3H),3.82(dt,J＝74.1,11.5Hz,2H),3.31–3.13(m,1H),2.87(q,J＝8.8Hz, 1H),2.17(q,J＝12.3Hz,1H),1.93(d,J＝13.1Hz,3H),1.16(dd,J＝21.0,6.8Hz,6H), 1.04(dt,J＝15.4,9.0Hz,1H).13C NMR(101MHz,DMSO-d6)δ164.15,150.65,148.07, 145.23,144.06,137.08,133.38,130.34,129.91,127.82,127.51,127.47,126.51,124.88, 123.76,120.57,117.67,66.21,65.21,59.67,59.26,57.42,37.59,27.74,26.64,23.97,23.84, 23.39,20.69,11.75。
IIa-12: white solid, mp: 179-184 ℃; [ alpha ] to]D 25 21.5(c 0.20,CHCl3)；1H NMR(400MHz, DMSO-d6)δ10.34(d,J＝6.3Hz,1H),8.99(d,J＝4.5Hz,1H),8.32–8.19(m,1H),8.09 (dd,J＝8.5,1.2Hz,1H),7.86–7.73(m,2H),7.62–7.46(m,2H),7.30(dddd,J＝28.2,13.7, 7.4,1.8Hz,3H),6.87(dd,J＝16.1,3.6Hz,1H),6.19–5.93(m,2H),5.37–5.20(m,2H), 4.93(d,J＝16.2Hz,1H),4.69(d,J＝16.3Hz,1H),4.49–4.32(m,2H),4.22(d,J＝9.8Hz, 1H),3.95(t,J＝11.4Hz,1H),3.85–3.66(m,1H),2.86(q,J＝8.8Hz,1H),2.23–2.09(m, 1H),1.97–1.82(m,3H),1.39(d,J＝1.5Hz,10H),0.99(d,J＝12.1Hz,1H).13C NMR(101 MHz,DMSO-d6)δ164.81,150.65,148.09,147.17,145.30,137.05,134.52,131.91,130.31, 129.92,128.35,127.51,127.11,124.93,123.94,120.58,117.66,66.29,65.39,65.10,59.66, 59.28,57.22,37.61,35.28,31.45,31.40,26.68,23.38,20.76,15.65,11.74。
IIa-13: milky white solid, mp: 181-186 ℃; [ alpha ] to]D 25 46.3(c 0.20,CHCl3)；1H NMR(400MHz, DMSO-d6)δ11.05(d,J＝3.9Hz,1H),8.98(d,J＝4.5Hz,1H),8.26(d,J＝8.3Hz,1H), 8.09(dd,J＝8.5,1.3Hz,1H),7.88–7.69(m,4H),7.62(ddd,J＝8.3,6.8,1.4Hz,1H),7.46 (dd,J＝8.7,1.8Hz,2H),6.80(dd,J＝16.0,3.6Hz,1H),6.18–5.90(m,2H),5.28(ddd,J＝ 14.6,3.1,1.4Hz,2H),4.87(t,J＝14.3Hz,1H),4.69(d,J＝15.8Hz,1H),4.43–4.21(m, 3H),3.95(d,J＝11.1Hz,1H),3.73(q,J＝9.3Hz,1H),2.86(q,J＝8.8Hz,1H),2.51(p,J＝ 1.8Hz,1H),2.34–2.06(m,1H),1.94(t,J＝8.2Hz,3H),1.29(s,9H),1.05(q,J＝8.0,6.4 Hz,1H).13C NMR(101MHz,DMSO-d6)δ170.79,162.91,150.63,148.05,147.51,145.24, 145.19,137.06,135.70,130.34,129.86,127.57,126.16,126.00,124.83,123.76,120.67, 120.60,119.90,117.65,65.91,65.39,60.23,59.63,59.47,57.51,37.57,34.64,31.62,26.61, 23.41,21.25,20.65,14.57,11.75。
IIa-14: light yellow solid, mp: 263-267 ℃; [ alpha ] to]D 25 26.5(c 0.20,CHCl3)；1H NMR(400MHz, DMSO-d6)δ10.32(s,1H),8.80(d,J＝4.5Hz,1H),7.94(d,J＝9.2Hz,1H),7.77(d,J＝4.6 Hz,1H),7.54–7.18(m,6H),6.87(d,J＝3.3Hz,1H),6.12–5.88(m,2H),5.36–5.18(m, 2H),4.84(d,J＝16.8Hz,1H),4.72–4.39(m,3H),4.23(t,J＝11.0Hz,1H),3.74(dt,J＝ 31.7,11.1Hz,2H),3.42(s,3H),2.85(q,J＝8.7Hz,1H),2.17–1.81(m,4H),1.37(s,9H), 0.91(d,J＝6.9Hz,1H).13C NMR(101MHz,DMSO-d6)δ165.16,158.36,147.72,146.80, 144.21,143.92,137.02,134.28,131.80,131.72,128.23,127.41,126.92,126.15,122.78, 120.82,117.66,101.91,66.59,64.05,60.79,59.52,57.31,56.13,37.73,35.28,31.44,26.83, 23.32,20.96,11.75。
IIb-1: white solid, mp: 215 ℃ to 220 ℃; [ alpha ] to]D 25-11.3(c 0.20,CHCl3)；1H NMR(400MHz, DMSO-d6)δ10.39(s,1H),8.98(d,J＝4.5Hz,1H),8.21(dd,J＝8.6,1.3Hz,1H),8.08(dd, J＝8.4,1.2Hz,1H),7.84–7.68(m,2H),7.61–7.43(m,2H),7.30(dddd,J＝26.6,12.1,7.3, 1.9Hz,3H),6.88(d,J＝4.1Hz,1H),6.14(t,J＝3.5Hz,1H),5.66(ddd,J＝17.4,10.7,5.6 Hz,1H),5.34–4.98(m,2H),4.96–4.64(m,2H),4.47(q,J＝10.6,9.9Hz,2H),4.30(dt,J ＝12.6,3.2Hz,1H),4.00(dd,J＝12.6,10.2Hz,1H),3.90–3.77(m,1H),2.88(s,1H),2.22 –1.89(m,4H),1.38(s,9H),1.15–0.96(m,1H).13C NMR(101MHz,DMSO-d6)δ164.97, 150.64,148.05,147.19,145.38,138.58,134.53,131.89,130.35,129.96,128.33,127.48, 127.46,127.14,124.72,123.69,120.49,116.17,65.96,64.51,60.40,59.31,56.21,37.29, 35.27,31.40,25.76,25.26,21.55。
Example 17
Preparation of 4-substituted pyrazolone asymmetric fluorination product Ib-1
A10 mL single-neck reaction flask was charged with 0.0324g (0.1mmol) of pyrazolone substrate Ia-1, NFSI 0.0346 g (0.11mmol) and 0.0025g (0.005mmol) of phase transfer catalyst IIa-1, respectively. At 0 deg.C, 2mL of toluene was added, followed by 0.2mL of 30 wt% K2CO3After the reaction was vigorously stirred for 10min with an aqueous solution, the reaction was substantially completed by TLC (thin layer chromatography). The product was isolated by column chromatography using 10:1 petroleum ether/ethyl acetate by volume ratio. White solid, mp: 58 to 63 ℃; [ alpha ] to]D 25 13.6(c 0.41,CHCl3)；97％yield,37％ee.1H NMR(400MHz, Chloroform-d)δ7.85–7.66(m,2H),7.61–7.46(m,2H),7.35(dq,J＝9.3,2.6,1.8Hz,3H), 7.26–7.12(m,2H),7.08–6.87(m,4H),6.81–6.65(m,2H),3.61–3.21(m,2H).13C NMR (101MHz,Chloroform-d)δ166.88(d,J＝21.5Hz),152.99(d,J＝13.9Hz),135.78,130.05, 128.82,128.72,128.29,128.27,128.01,127.74,127.29,126.84,125.54,125.53,124.80, 118.19,95.27,93.28,40.05(d,J＝26.0Hz).19F NMR(376MHz,Chloroform-d)δ-162.21 (s,1F).HPLC conditions:Chiralcel AS-H column(250×4.6mm),hexane/i-PrOH＝90/10, 1mL/min,254nm,τR(major)＝5.83min,τR(minor)＝5.21min。
Examples 18 to 31 were carried out in the same manner as in example 17 except that IIa-1 was replaced with phase transfer catalysts IIa-2 to IIa-15, and the results are shown in Table 2.
TABLE 2 preparation of asymmetric pyrazolone fluorination products Ib-1 with different catalysts
Examples 32-37 were carried out as in example 28, but using the temperatures listed in the table below instead of 0 ℃ and the results are given in table 3.
TABLE 3 preparation of pyrazolone fluorination product Ib-1 at different temperatures
Examples 38 to 47 were carried out in the same manner as in example 35, except that the bases listed in the following table were used instead of 30% by weight of K2CO3The results are shown in Table 4.
TABLE 4 preparation of pyrazolone fluorination products Ib-1 Using different bases
Examples 48-54 were carried out as in example 43, but using the solvents listed in the table below instead of toluene, and the results are given in table 5.
TABLE 5 preparation of pyrazolone hydroxylation product Ib-1 Using various solvents
Examples 55-59 were carried out in the same manner as in example 43 except that the concentrations of the 4-substituted pyrazolone compounds listed in the following table were used instead of the original concentrations, and the results are shown in Table 6.
TABLE 6 preparation of hydroxylation product Ib-1 using different concentrations
Examples 60-63 were carried out as in example 58, but using the amounts of catalyst listed in the table below instead of the original catalyst amount, the results are shown in table 7.
TABLE 7 preparation of pyrazolone hydroxylation product Ib-1 with varying amounts of catalyst
Examples 64-67 were carried out as in example 62, but using the electrophilic fluorinating reagents listed in the table below in place of the electrophilic fluorinating reagent, and the results are given in table 8.
TABLE 8 preparation of pyrazolone hydroxylation product Ib-1 Using different fluorinating Agents
Examples 68 to 101 were carried out in the same manner as in example 17 except that 4-substituted pyrazolones Ia-2 to Ia-36 shown in the following Table were used in place of the primary substrate Ia-1, and the results are shown in Table 9.
TABLE 9 preparation of optically active fluorinated products Ib-2 to Ib-35 using different 4-substituted pyrazolones
Example 68
Ib-2, white solid, mp: 140 ℃ and 144 ℃; [ alpha ] to]D 25 95.1(c 0.43,CHCl3)；95％yield,94％ee.1H NMR(400MHz,Chloroform-d)δ7.94–7.85(m,2H),7.77–7.65(m,2H),7.56–7.45(m, 3H),7.42–7.33(m,2H),7.24–7.13(m,1H),6.22(t,J＝2.3Hz,1H),6.00(d,J＝2.3Hz, 2H),3.68–3.37(m,8H).13C NMR(101MHz,Chloroform-d)δ168.07(d,J＝21.3Hz), 160.50,154.21(d,J＝13.7Hz),136.96,131.87(d,J＝12.1Hz),131.11,129.58(d,J＝1.7 Hz),129.05,128.87,126.67,126.66,125.88,119.17,107.40,100.87,96.15,94.17,55.03, 41.36(d,J＝26.3Hz).19F NMR(376MHz,Chloroform-d)δ-161.82(s,1F).HPLC conditions:Chiralcel AS-H column(250×4.6mm),hexane/i-PrOH＝95/5,1mL/min, 254nm,τR(major)＝7.54min,τR(minor)＝8.28min。
Example 69
Ib-3, light yellow solid, mp: 102-106 ℃; [ alpha ] to]D 25 55.6(c 0.54,CHCl3)；98％yield,87％ee.1H NMR(400MHz,Chloroform-d)δ7.94–7.82(m,2H),7.72–7.60(m,2H),7.59–7.44(m, 3H),7.38(dd,J＝8.7,7.5Hz,4H),7.26–7.16(m,2H),7.02(d,J＝8.0Hz,2H),3.73–3.48 (m,2H).13C NMR(101MHz,Chloroform-d)δ166.50(d,J＝21.4Hz),152.86(d,J＝13.7 Hz),135.65,133.19(d,J＝10.7Hz),130.33,129.38,128.18,127.91,125.58,125.56,125.13, 124.30,124.26,122.78(q,J＝272.3Hz),94.85,92.85,39.81(d,J＝26.6Hz).19F NMR(376 MHz,Chloroform-d)δ-62.76(s,3F),-162.96(s,1F).HPLC conditions:Chiralcel OJ-H column(250×4.6mm),hexane/i-PrOH＝95/5,1mL/min,254nm,τR(major)＝8.32min, τR(minor)＝7.76min。
Example 70
Ib-4, light yellow solid, mp: 102-106 ℃; [ alpha ] to]D 25 55.6(c 0.54,CHCl3)；98％yield,87％ee. 1H NMR(400MHz,Chloroform-d)δ7.93–7.83(m,2H),7.80–7.66(m,2H),7.61–7.48 (m,3H),7.45–7.33(m,2H),7.25–7.17(m,1H),6.61(tt,J＝8.8,2.3Hz,1H),6.52–6.30 (m,2H),3.70–3.37(m,2H).13C NMR(101MHz,Chloroform-d)δ167.41(d,J＝21.3Hz), 163.86(d,J＝12.7Hz),161.38(d,J＝12.8Hz),153.87(d,J＝13.7Hz),136.72,133.83, 131.46,129.26,128.99,126.60,126.58,126.15,119.18,113.02(d,J＝25.6Hz),103.69(t,J ＝25.1Hz),95.55,93.55,40.55(d,J＝27.5Hz).19F NMR(376MHz,Chloroform-d)δ -109.16(s,2F),-162.68(s,1F).HPLC conditions:Chiralcel OJ-H column(250×4.6mm), hexane/i-PrOH＝95/5,1mL/min,254nm,τR(major)＝8.32min,τR(minor)＝7.76min。
Example 71
Ib-5, light yellow solid, mp: 117 ℃ and 121 ℃; [ alpha ] to]D 25 27.6(c 0.51,CHCl3)；97％yield,80％ee. 1H NMR(400MHz,Chloroform-d)δ8.02–7.82(m,4H),7.78–7.65(m,2H),7.62–7.46 (m,3H),7.43–7.31(m,2H),7.25–7.17(m,1H),7.14–6.94(m,2H),3.81–3.55(m,2H). 13C NMR(101MHz,Chloroform-d)δ167.24(d,J＝21.3Hz),153.70(d,J＝13.8Hz), 147.62,137.68,137.57,136.61,131.57,131.01,129.32,129.01,128.93,128.92,126.58, 126.56,126.22,123.52,118.98,95.55,93.55,40.73(d,J＝27.2Hz).19F NMR(376MHz, Chloroform-d)δ-162.65(s,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm), hexane/i-PrOH＝90/10,1mL/min,254nm,τR(major)＝10.02min,τR(minor)＝12.02 min。
Example 72
Ib-6, light yellow colloid; [ alpha ] to]D 25 110.7(c 0.58,CHCl3)；95％yield,84％ee.1H NMR(400 MHz,Chloroform-d)δ7.90–7.80(m,2H),7.71–7.60(m,2H),7.57–7.46(m,3H),7.44– 7.30(m,3H),7.21(ddt,J＝8.6,7.2,1.2Hz,2H),7.15–7.04(m,2H),3.72–3.47(m,2H). 13C NMR(101MHz,Chloroform-d)δ167.58(d,J＝21.5Hz),153.93(d,J＝13.7Hz), 136.65,133.31,131.39,131.29–130.81(m),129.21,129.16,129.14,128.92,128.90,126.88 (q,J＝3.8Hz),126.63,126.61,126.09,125.23–124.39(m),95.91,93.91,40.81(d,J＝26.8 Hz).19F NMR(376MHz,Chloroform-d)δ-62.90(s,3F),-163.34(s,1F).HPLC conditions: Chiralcel OJ-H column(250×4.6mm),hexane/i-PrOH＝95/5,1mL/min,254nm,τR (major)＝10.40min,τR(minor)＝8.67min。
Example 73
Ib-7, white solid, mp: 85-89 ℃; [ alpha ] to]D 25 46.5(c 0.42,CHCl3)；96％yield,83％ee.1H NMR(400MHz,Chloroform-d)δ7.81(dq,J＝6.9,1.2Hz,2H),7.72–7.62(m,3H),7.59– 7.44(m,3H),7.43–7.29(m,4H),7.25–7.18(m,1H),3.82–3.52(m,2H).13C NMR(101 MHz,Chloroform-d)δ167.19(d,J＝21.4Hz),153.71(d,J＝13.5Hz),136.46,132.86(d,J ＝10.6Hz),131.73(q,J＝33.6Hz),131.65,130.33,129.33,128.98,126.60,126.58,126.28, 122.78(q,J＝272.8Hz),122.04,122.00,121.96,95.41,93.40,40.61(d,J＝27.2Hz).19F NMR(376MHz,Chloroform-d)δ-63.10(s,6F),-164.38(s,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝98/2,1mL/min,254nm,τR(major)＝ 22.00min,τR(minor)＝18.38min。
Example 74
Ib-8, light yellow solid, mp: 165-169 ℃ of reaction; [ alpha ] to]D 25 56.7(c 0.72,CHCl3)；96％yield,87％ee. 1H NMR(400MHz,Chloroform-d)δ7.88–7.73(m,4H),7.48–7.30(m,5H),7.23–7.17 (m,1H),3.57(tt,J＝15.2,1.8Hz,1H),3.29(ddt,J＝26.9,15.1,1.6Hz,1H).13C NMR(101 MHz,Chloroform-d)δ165.72(d,J＝22.6Hz),153.29(d,J＝13.7Hz),153.22,146.02, 143.59,143.55,141.35,138.81,137.60,135.99,130.45,128.06,127.98,125.60,125.58, 125.10,117.98,104.31(t,J＝18.1Hz),92.43,90.40,28.68,27.29(d,J＝26.7Hz).19F NMR (376MHz,Chloroform-d)δ-139.19–-139.75(m,2F),-153.43(t,J＝20.8Hz,1F),-161.83 (dd,J＝21.0,14.2Hz,2F),-170.79(t,J＝10.5Hz,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝90/10,1mL/min,254nm,τR(major)＝5.04 min,τR(minor)＝5.54min。
Example 75
Ib-9, light yellow colloid; [ alpha ] of]D 25 48.2(c 0.41,CHCl3)；99％yield,92％ee.1H NMR(400MHz, Chloroform-d)δ7.95–7.86(m,2H),7.74–7.62(m,2H),7.57–7.46(m,3H),7.40–7.33 (m,2H),7.20(t,J＝7.4Hz,1H),7.00(t,J＝7.9Hz,1H),6.67(ddd,J＝8.3,2.6,0.9Hz,1H), 6.49(dt,J＝7.5,1.2Hz,1H),6.38(t,J＝2.1Hz,1H),3.69–3.51(m,2H),3.49(s,3H).13C NMR(101MHz,Chloroform-d)δ168.05(d,J＝21.5Hz),159.39,154.19(d,J＝13.8Hz), 136.93,131.32,131.20,131.14,129.53,129.52,129.42,129.10,128.88,126.69,126.68, 125.92,122.23,119.30,114.59,114.42,96.28,94.29,54.92,41.21(d,J＝26.3Hz).19F NMR (376MHz,Chloroform-d)δ-162.10(s,1F).HPLC conditions:Chiralcel OJ-H column(250 ×4.6mm),hexane/i-PrOH＝80/20,1mL/min,254nm,τR(major)＝8.86min,τR(minor) ＝13.25min。
Example 76
Ib-10, white solid, mp: 86-89 ℃; [ alpha ] to]D 25 56.7(c 0.42,CHCl3)；98％yield,92％ee.1H NMR(400MHz,Chloroform-d)δ7.72(dq,J＝8.4,1.5Hz,4H),7.40–7.24(m,5H),7.17– 7.06(m,1H),6.89–6.63(m,2H),6.38(dd,J＝9.0,4.4Hz,1H),3.72–3.27(m,2H),3.09(s, 3H).13C NMR(101MHz,Chloroform-d)δ167.19(d,J＝21.8Hz),155.19–153.34(m), 152.72,152.70,136.12,128.70,128.68,127.88,127.44,125.45,125.43,124.73,119.58, 117.97,117.64(d,J＝23.6Hz),114.14(d,J＝22.7Hz),109.48(d,J＝8.4Hz),94.88,92.89, 53.74,34.19(d,J＝27.1Hz).19F NMR(376MHz,Chloroform-d)δ-124.15(s,1F), -164.47(s,1F).HPLC conditions:Chiralcel OJ-H column(250×4.6mm),hexane/i-PrOH＝ 95/5,1mL/min,254nm,τR(major)＝17.41min,τR(minor)＝16.05min。
Example 77
Ib-11, colorless colloid; [ alpha ] to]D 25 112.3(c 0.42,CHCl3)；99％yield,90％ee.1H NMR(400MHz, Chloroform-d)δ7.78(d,J＝8.5Hz,1H),7.75–7.62(m,4H),7.59–7.50(m,2H),7.47– 7.38(m,1H),7.39–7.29(m,5H),7.25–7.21(m,1H),7.21–7.11(m,3H),4.10–3.95(m, 2H).13C NMR(101MHz,Chloroform-d)δ168.52(d,J＝21.8Hz),154.84(d,J＝13.9Hz), 136.85,133.63,132.02,130.92,129.68,129.66,129.20,128.82,128.76,128.53,126.76, 126.67,126.65,125.87,125.86,125.60,124.82,123.64,119.24,96.54,94.55,37.30(d,J＝ 26.4Hz).19F NMR(376MHz,Chloroform-d)δ-163.17(s,1F).HPLC conditions:Chiralcel OJ-H column(250×4.6mm),hexane/i-PrOH＝90/10,1mL/min,254nm,τR(major)＝ 15.19min,τR(minor)＝12.76min。
Example 78
Ib-12, white solid, mp: 103-107 ℃; [ alpha ] to]D 25 53.8(c 0.62,CHCl3)；98％yield,90％ee. 1H NMR(400MHz,Chloroform-d)δ7.82–7.70(m,2H),7.67–7.58(m,2H),7.51–7.40 (m,3H),7.39–7.26(m,3H),7.18–7.12(m,1H),6.90(d,J＝1.7Hz,2H),3.53–3.25(m, 2H).13C NMR(101MHz,Chloroform-d)δ166.40(d,J＝21.5Hz),152.85(d,J＝13.6Hz), 135.52,132.91,132.81,132.68,130.78,130.46,128.22,128.07,128.06,127.96,125.60, 125.58,125.23,121.68,118.42,94.52,92.51,39.14(d,J＝27.0Hz).19F NMR(376MHz, Chloroform-d)δ-163.81(s,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm), hexane/i-PrOH＝80/20,1mL/min,254nm,τR(major)＝4.51min,τR(minor)＝5.43 min。
Example 79
Ib-13, brown yellow solid, mp: 104-108 ℃; [ alpha ] of]D 25 48.2(c 0.40,CHCl3)；98％yield,90％ee. 1H NMR(400MHz,Chloroform-d)δ7.87–7.77(m,2H),7.65–7.54(m,2H),7.48–7.37 (m,3H),7.33–7.23(m,2H),7.14–7.04(m,1H),6.81(d,J＝7.8Hz,2H),6.74–6.64(m, 2H),3.68–3.30(m,2H),2.10(s,3H).13C NMR(101MHz,Chloroform-d)δ168.14(d,J＝ 21.5Hz),154.24(d,J＝13.9Hz),137.63,136.96,131.13,129.80,129.49,129.14,129.11, 128.86,126.71,126.69,126.60,125.90,119.39,96.39,94.41,40.71(d,J＝26.0Hz),21.07. 19F NMR(376MHz,Chloroform-d)δ-161.89(s,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝98/2,1mL/min,254nm,τR(major)＝9.65min, τR(minor)＝8.49min。
Example 80
Ib-14, light yellow solid, mp: 80-84 ℃; [ alpha ] to]D 25 27.4(c 0.38,CHCl3)；99％yield,92％ee.1H NMR(400MHz,Chloroform-d)δ7.98(tdd,J＝6.3,2.9,1.1Hz,4H),7.57–7.36(m,5H), 7.30–7.20(m,1H),1.88(d,J＝22.6Hz,3H).13C NMR(101MHz,Chloroform-d)δ168.65 (d,J＝22.0Hz),155.61(d,J＝14.5Hz),137.42,131.26,129.05,129.01,128.54,128.53, 126.69,126.67,125.77,118.80,93.70,91.77,29.70,21.42(d,J＝26.5Hz).19F NMR(376 MHz,Chloroform-d)δ-163.74(s,1H).HPLC conditions:Chiralcel AD-H column(250×4.6 mm),hexane/i-PrOH＝98/2,0.8mL/min,254nm,τR(major)＝11.02min,τR(minor)＝ 8.59min。
Example 81
Ib-15, colorless oil; [ alpha ] to]D 25 64.5(c 0.31,CHCl3)；92％yield,94％ee.1H NMR(400 MHz,Chloroform-d)δ8.03–7.82(m,4H),7.56–7.38(m,5H),7.24(d,J＝7.5Hz,1H), 5.54–5.32(m,1H),5.22–4.92(m,2H),3.18–2.89(m,2H).13C NMR(101MHz, Chloroform-d)δ167.90(d,J＝21.7Hz),154.26(d,J＝13.9Hz),137.23,131.23,129.06, 128.99,128.94,126.63,126.62,126.37,126.26,125.82,122.71,118.94,95.41,93.43,39.16 (d,J＝26.1Hz).19F NMR(376MHz,Chloroform-d)δ-164.30(s,1F).HPLC conditions: Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝90/10,1mL/min,254nm,τR (major)＝5.54min,τR(minor)＝4.95min。
Example 82
Ib-16, colorless oil; [ alpha ] to]D 25 57.3(c 0.25,CHCl3)；94％yield,89％ee.1H NMR(400 MHz,Chloroform-d)δ7.95(ddt,J＝15.4,7.9,1.2Hz,4H),7.58–7.39(m,5H),7.30–7.26 (m,1H),3.27(ddd,J＝15.8,8.1,2.8Hz,1H),3.12(ddd,J＝15.8,7.5,2.8Hz,1H),1.93(t,J ＝2.7Hz,1H).13C NMR(101MHz,Chloroform-d)δ165.82(d,J＝21.0Hz),152.35(d,J＝ 13.4Hz),136.08,130.33,128.07,127.99,127.56,127.54,125.56,125.54,124.94,118.04, 92.99,91.00,72.12(d,J＝19.0Hz),71.90(d,J＝2.6Hz),24.30(d,J＝34.1Hz).19F NMR (376MHz,Chloroform-d)δ-164.40(s,1F).HPLC conditions:Chiralcel AD-H column(250 ×4.6mm),hexane/i-PrOH＝80/20,1mL/min,254nm,τR(major)＝5.85min,τR(minor) ＝5.19min。
Example 83
Ib-17, colorless oil; [ alpha ] to]D 25 29.6(c 0.21,CHCl3)；95％yield,72％ee.1H NMR(400 MHz,Chloroform-d)δ7.67–7.59(m,2H),7.40–7.30(m,2H),7.29–7.23(m,3H),7.21– 7.12(m,3H),3.65–3.10(m,2H),2.14(d,J＝1.6Hz,3H).13C NMR(101MHz, Chloroform-d)δ136.97,130.65,130.55,129.76,128.87,128.77,128.06,125.65,118.96, 95.52,93.56,13.83.13C NMR(101MHz,Chloroform-d)δ167.79(d,J＝21.0Hz),157.01(d, J＝16.4Hz),39.41(d,J＝26.1Hz).19F NMR(376MHz,Chloroform-d)δ-167.08(s,1F). HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝99/1,1mL/ min,254nm,τR(major)＝＝16.00min,τR(minor)＝13.90min。
Example 84
Ib-18, white solid, mp: 131 ℃ and 135 ℃; [ alpha ] to]D 25 79.5(c 0.41,CHCl3)；99％yield,92％ee.1H NMR(400MHz,Chloroform-d)δ7.76–7.65(m,3H),7.59(dt,J＝9.6,2.1Hz,1H),7.48 (td,J＝8.1,5.7Hz,1H),7.39(dd,J＝8.6,7.4Hz,2H),7.25–7.18(m,2H),6.23(t,J＝2.3 Hz,1H),6.01(d,J＝2.3Hz,2H),3.71–3.32(m,8H).13C NMR(101MHz,Chloroform-d) δ167.96(d,J＝21.3Hz),164.16,161.70,160.57,153.18(dd,J＝13.9,3.2Hz),136.78, 131.72,131.60,131.56,131.47,130.82,130.74,128.92,126.07,122.50,122.48,122.45, 119.17,118.14(d,J＝21.3Hz),114.50–112.27(m),107.43,100.77,95.88,93.89,55.06, 41.33(d,J＝26.1Hz).19F NMR(376MHz,Chloroform-d)δ-110.99(s,1F),-162.34(s,1F). HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝90/10,1mL/ min,254nm,τR(major)＝＝6.84min,τR(minor)＝7.63min。
Example 85
Ib-19, white solid, mp: 122-126 ℃; [ alpha ] to]D 25 64.3(c 0.40,CHCl3)；97％yield,86％ee.1H NMR(400MHz,Chloroform-d)δ7.89–7.78(m,2H),7.77–7.62(m,2H),7.54–7.43(m, 2H),7.43–7.33(m,2H),7.25–7.15(m,1H),6.23(t,J＝2.3Hz,1H),6.00(d,J＝2.3Hz, 2H),3.65–3.33(m,8H).13C NMR(101MHz,Chloroform-d)δ167.96(d,J＝21.4Hz), 160.60,153.32(d,J＝14.0Hz),137.26,136.85,131.80,131.69,129.40,128.94,128.04, 128.02,127.92,127.90,126.06,119.19,107.52,100.68,95.99,94.01,55.11,41.39(d,J＝ 26.2Hz).19F NMR(376MHz,Chloroform-d)δ-162.48(s,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝98/2,1mL/min,254nm,τR(major)＝＝21.46min,τR(minor)＝17.56min。
Example 86
Ib-20, light yellow solid, mp: 131 ℃ and 135 ℃; [ alpha ] to]D 25 27.5(c 0.57,CHCl3)；98％yield,86％ee. 1H NMR(400MHz,Chloroform-d)δ7.80–7.60(m,2H),7.43(ddd,J＝8.2,1.8,1.0Hz, 1H),7.41–7.31(m,3H),7.24–7.13(m,1H),6.92(d,J＝8.1Hz,1H),6.23(t,J＝2.3Hz, 1H),6.11–5.94(m,4H),3.63–3.35(m,8H).13C NMR(101MHz,Chloroform-d)δ167.90 (d,J＝21.6Hz),160.49,153.86,153.72,150.13,148.43,136.96,132.02,131.90,128.83, 125.78,123.71,123.69,122.05,122.02,119.10,108.65,107.53,106.24,101.71,100.61, 96.25,94.27,55.09,41.61(d,J＝26.3Hz).19F NMR(376MHz,Chloroform-d)δ-161.64(s, 1F).HPLC conditions:Chiralcel AS-H column(250×4.6mm),hexane/i-PrOH＝80/20,1 mL/min,254nm,τR(major)＝＝8.45min,τR(minor)＝10.87min。
Example 87
Ib-21, light yellow solid, mp: 78-81 ℃; [ alpha ] to]D 25 43.2(c 0.40,CHCl3)；93％yield,92％ee. 1H NMR(400MHz,Chloroform-d)δ7.98(d,J＝8.1Hz,2H),7.73(dd,J＝8.4,6.9Hz,4H), 7.46–7.35(m,2H),7.23(d,J＝7.5Hz,1H),6.23(t,J＝2.3Hz,1H),5.98(d,J＝2.3Hz, 2H),3.57–3.32(m,8H).13C NMR(101MHz,Chloroform-d)δ167.98(d,J＝21.1Hz), 160.62,152.98(d,J＝14.1Hz),136.73,132.47(q,J＝32.8Hz),128.98,126.92,126.91, 126.22,125.97,125.93,123.67(q,J＝1651.3,817.3Hz),119.22,107.53,100.64,95.78, 93.79,55.04,41.29(d,J＝26.0Hz).19F NMR(376MHz,Chloroform-d)δ-62.99(s,3F), -162.75(s,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH ＝90/10,1mL/min,254nm,τR(major)＝＝7.44min,τR(minor)＝6.46min。
Example 88
Ib-22, white colloid; [ alpha ] to]D 25 52.5(c 0.42,CHCl3)；97％yield,90％ee.1H NMR(400MHz, Chloroform-d)δ7.82(d,J＝8.0Hz,2H),7.78–7.66(m,2H),7.45–7.30(m,4H),7.24– 7.09(m,1H),6.22(t,J＝2.3Hz,1H),6.01(d,J＝2.2Hz,2H),3.46(s,8H),3.07–2.84(m, 1H),1.30(dd,J＝6.9,1.1Hz,6H).13C NMR(101MHz,Chloroform-d)δ168.05(d,J＝21.4 Hz),160.44,154.31(d,J＝13.8Hz),152.41,137.02,132.07,131.95,128.84,127.18,127.12, 126.79,126.78,125.78,119.16,107.39,100.93,96.21,94.23,55.00,41.43(d,J＝26.2Hz), 34.21,23.75,23.74.19F NMR(376MHz,Chloroform-d)δ-161.86(s,1F).HPLC conditions: Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝80/20,1mL/min,254nm,τR (major)＝＝5.80min,τR(minor)＝4.77min。
Example 89
Ib-23, white solid, mp: 140 ℃ to 144 ℃; [ alpha ] to]D 25 37.2(c 0.38,CHCl3)；98％yield,90％ee. 1H NMR(400MHz,Chloroform-d)δ8.04–7.89(m,2H),7.79–7.69(m,4H),7.69–7.61 (m,2H),7.54–7.46(m,2H),7.44–7.34(m,3H),7.25–7.19(m,1H),6.23(t,J＝2.3Hz, 1H),6.05(d,J＝2.3Hz,2H),3.69–3.49(m,2H),3.47(s,6H).13C NMR(101MHz, Chloroform-d)δ168.12(d,J＝21.3Hz),160.55,154.03(d,J＝14.0Hz),143.75,139.90, 137.01,131.97(d,J＝11.8Hz),129.05,128.92,128.44,128.43,128.18,127.64,127.18, 127.16,127.12,125.94,119.23,107.53,100.85,96.22,94.24,55.09,41.52(d,J＝26.2Hz). 19F NMR(376MHz,Chloroform-d)δ-162.05(s,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝80/20,1mL/min,254nm,τR(major)＝＝11.16 min,τR(minor)＝8.91min。
Example 90
Ib-24, white solid, mp: 145-150 ℃; [ alpha ] to]D 25 38.1(c 0.31,CHCl3)；93％yield,89％ee. 1H NMR(400MHz,Chloroform-d)δ7.95(d,J＝8.3Hz,2H),7.82–7.64(m,4H),7.46– 7.35(m,2H),7.31–7.18(m,1H),6.23(t,J＝2.3Hz,1H),5.97(d,J＝2.3Hz,2H),3.66– 3.37(m,8H).13C NMR(101MHz,Chloroform-d)δ167.96(d,J＝21.2Hz),160.69,152.52 (d,J＝14.1Hz),136.63,133.51,133.49,132.71,131.58,131.47,129.04,127.01,127.00, 126.39,119.23,118.15,114.22,107.59,100.52,95.64,93.65,41.32(d,J＝26.0Hz),55.12. 19F NMR(376MHz,Chloroform-d)δ-163.05(s,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝80/20,1mL/min,254nm,τR(major)＝10.41 min,τR(minor)＝13.74min。
Example 91
Ib-25, white solid, mp: 132-135 ℃; [ alpha ] to]D 25 42.3(c 0.40,CHCl3)；98％yield,92％ee. 1H NMR(400MHz,Chloroform-d)δ7.73(d,J＝8.0Hz,2H),7.68–7.57(m,2H),7.35– 7.26(m,2H),7.23(d,J＝8.0Hz,2H),7.16–7.07(m,1H),6.14(t,J＝2.3Hz,1H),5.94(d, J＝2.3Hz,2H),3.55–3.32(m,8H),2.36(s,3H).13C NMR(101MHz,CDCl3)δ168.07(d, J＝21.5Hz),160.49,154.33(d,J＝13.9Hz),141.63,137.03,132.06,131.93,129.79, 128.86,126.81,126.66,126.64,125.82,119.20,107.49,100.79,96.30,94.32,55.08,41.46(d, J＝26.2Hz),21.68.19F NMR(376MHz,Chloroform-d)δ-161.91(s,1F).HPLC conditions: Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝98/2,1mL/min,254nm,τR (major)＝＝18.71min,τR(minor)＝14.22min。
Example 92
Ib-26, white solid, mp: 114-119 ℃; [ alpha ] to]D 25 51.2(c 0.41,CHCl3)；99％yield,95％ee. 1H NMR(400MHz,Chloroform-d)δ7.90(d,J＝1.9Hz,1H),7.72(d,J＝7.8Hz,1H),7.68 –7.60(m,2H),7.59–7.50(m,1H),7.30(dt,J＝10.3,7.7Hz,3H),7.16(q,J＝7.4,6.2Hz, 1H),6.16(t,J＝2.3Hz,1H),5.93(d,J＝2.3Hz,2H),3.55–3.31(m,8H).13C NMR(101 MHz,Chloroform-d)δ166.91(d,J＝21.3Hz),159.55,151.92(d,J＝13.8Hz),135.74, 132.91,131.02–130.16(m),129.50,127.90,125.06,124.16(d,J＝2.0Hz),122.18,118.15, 106.44,99.85,94.80,92.82,54.04,40.28(d,J＝26.0Hz).19F NMR(376MHz, Chloroform-d)δ-162.59(s,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm), hexane/i-PrOH＝90/10,1mL/min,254nm,τR(major)＝6.60min,τR(minor)＝7.38 min。
Example 93
Ib-27, white solid,mp：148-152℃；[α]D 25 21.2(c 0.40,CHCl3)；98％yield,96％ee. 1H NMR(400MHz,Chloroform-d)δ7.79–7.62(m,2H),7.50(dt,J＝8.6,1.5Hz,1H),7.43 –7.32(m,3H),7.25–7.15(m,1H),6.97(d,J＝8.4Hz,1H),6.23(t,J＝2.3Hz,1H),6.04(d, J＝2.3Hz,2H),3.98(s,3H),3.94(s,3H),3.62–3.39(m,8H).1 13C NMR(101MHz, CDCl3)δ168.00(d,J＝21.4Hz),160.51,154.12(d,J＝13.8Hz),151.71,149.52,136.99, 132.06(d,J＝12.1Hz),128.85,125.86,122.47,120.80,120.77,119.32,110.86,108.54, 107.59,100.67,96.35,94.37,56.06,55.09,41.78.9F NMR(376MHz,Chloroform-d)δ -161.65(s,1F).(d,J＝26.2Hz).HPLC conditions:Chiralcel AD-H column(250×4.6mm), hexane/i-PrOH＝80/20,1mL/min,254nm,τR(major)＝9.20min,τR(minor)＝10.84 min。
example 94
Ib-28, white colloid; [ alpha ] to]D 25 17.8(c 0.40,CHCl3)；98％yield,94％ee.1H NMR(400MHz, Chloroform-d)δ7.76–7.64(m,3H),7.59(dt,J＝9.7,2.1Hz,1H),7.48(td,J＝8.1,5.7Hz, 1H),7.43–7.33(m,2H),7.25–7.17(m,2H),6.23(t,J＝2.3Hz,1H),6.01(d,J＝2.3Hz, 2H),3.63–3.39(m,8H).13C NMR(101MHz,Chloroform-d)δ167.99(d,J＝21.2Hz), 164.19,161.73,160.60,153.20(d,J＝10.9Hz),136.81,132.33–131.31(m),130.81(d,J＝ 8.1Hz),128.95,126.10,122.53,122.51,122.49,119.20,118.17(d,J＝21.3Hz),113.40(d,J ＝23.3Hz),107.46,100.80,95.90,93.92,55.08,41.36(d,J＝26.2Hz).19F NMR(376MHz, Chloroform-d)δ-111.00(s,1F),-162.32(s,1F).HPLC conditions:Chiralcel AD-H column (250×4.6mm),hexane/i-PrOH＝90/10,1mL/min,254nm,τR(major)＝6.62min,τR (minor)＝7.34min。
Example 95
Ib-29, white solid, mp: 63-67 ℃; [ alpha ] to]D 25 39.5(c 0.40,CHCl3)；98％yield,80％ee.1H NMR(400MHz,Chloroform-d)δ8.20–8.06(m,2H),7.95(s,1H),7.83–7.68(m,2H), 7.51–7.31(m,2H),7.34–7.26(m,1H),6.23(t,J＝2.3Hz,1H),5.99(d,J＝2.3Hz,2H), 3.61–3.40(m,8H).13C NMR(101MHz,Chloroform-d)δ167.89(d,J＝21.2Hz),160.78, 152.06(d,J＝14.4Hz),136.58,132.48(q,J＝33.9Hz),131.91–131.45(m),129.12, 126.54,126.35,124.17,123.99,107.78,100.45,95.45,93.46,55.04,41.45(d,J＝25.6Hz). 19F NMR(376MHz,Chloroform-d)δ-62.99(s,6F),-164.91(s,1F).HPLC conditions: Chiralcel AS-H column(250×4.6mm),hexane/i-PrOH＝95/5,1mL/min,254nm,τR (major)＝4.38min,τR(minor)＝3.82min。
Example 96
Ib-30, brown colloid; [ alpha ] to]D 25 19.3(c 0.40,CHCl3)；98％yield,92％ee.1H NMR(400MHz, Chloroform-d)δ8.00–7.87(m,4H),7.67–7.60(m,2H),7.57–7.49(m,3H),6.21(t,J＝ 2.3Hz,1H),5.98(d,J＝2.3Hz,2H),3.61–3.35(m,8H).13C NMR(101MHz, Chloroform-d)δ168.33(d,J＝21.6Hz),160.56,154.82(d,J＝13.9Hz),139.69,131.52, 131.49,129.17,128.23–126.91(m),126.80,126.78,126.15,126.12,118.45,107.42,100.75, 96.18,94.19,55.05,41.37(d,J＝26.1Hz).19F NMR(376MHz,Chloroform-d)δ-62.25(s, 3F),-161.37(s,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane /i-PrOH＝80/20,1mL/min,254nm,τR(major)＝6.06min,τR(minor)＝6.40min。
Example 97
Ib-31, white colloid; [ alpha ] to]D 25 57.1(c 0.40,CHCl3)；92％yield,83％ee.1H NMR(400MHz, Chloroform-d)δ7.90–7.72(m,2H),7.57–7.33(m,3H),6.25(t,J＝2.3Hz,1H),5.96(d,J ＝2.2Hz,2H),3.56–3.41(m,8H).13C NMR(101MHz,Chloroform-d)δ167.53(d,J＝ 21.6Hz),159.72,154.90(d,J＝14.1Hz),144.05(dd,J＝12.0,4.1Hz),142.66–140.89(m), 141.46–138.89(m),138.50–137.16(m),136.44–134.59(m),130.55,128.21,128.08, 128.07,125.71,125.70,106.75,99.60,93.51,91.53,54.06,39.96(d,J＝26.0Hz).19F NMR (376MHz,Chloroform-d)δ-142.54–143.00(m,2F),-151.62–152.05(m,1F),-160.88(s, 1F),-160.92–161.16(m,2F).HPLC conditions:Chiralcel AD-H column(250×4.6mm), hexane/i-PrOH＝90/10,1mL/min,254nm,τR(major)＝5.46min,τR(minor)＝6.08 min。
Example 98
Ib-32, brown oil; [ alpha ] to]D 25 43.2(c 0.40,CHCl3)；97％yield,92％ee.1H NMR(400 MHz,Chloroform-d)δ7.88–7.71(m,4H),7.58–7.37(m,5H),7.10–6.94(m,3H),6.86– 6.71(m,2H),3.64–3.39(m,2H).13C NMR(101MHz,Chloroform-d)δ167.21(d,J＝21.7 Hz),153.70(d,J＝14.0Hz),138.56,130.47,128.81,128.62,128.50,128.17,128.04(d,J＝ 1.8Hz),127.43,127.04,125.75(d,J＝1.8Hz),125.07(q,J＝3.8Hz),117.49,95.38,93.38, 40.16(d,J＝26.0Hz).19F NMR(376MHz,Chloroform-d)δ-62.27(s,3F),-162.06(s,1F). HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝99/1,1mL/ min,254nm,τR(major)＝9.62min,τR(minor)＝7.28min。
Example 99
Ib-33, white solid; mp: 73-76 ℃; [ alpha ] to]D 25 58.1(c 0.40,CHCl3)；97％yield,90％ee.1H NMR(400MHz,Chloroform-d)δ8.01–7.76(m,4H),7.54–7.33(m,5H),6.13(t,J＝2.3 Hz,1H),5.92(d,J＝2.3Hz,2H),3.55–3.42(m,2H),3.40(s,6H).13C NMR(101MHz, CDCl3)δ168.23(d,J＝21.6Hz),160.59,154.76(d,J＝14.1Hz),137.40,131.69,131.56, 131.48,131.21,129.54,129.24,129.18,126.82,126.80,123.02–121.87(m),121.84,115.94 –115.33(m),107.44,100.78,96.26,94.27,55.05,41.43(d,J＝26.2Hz).19F NMR(376 MHz,Chloroform-d)δ-62.71(s,3F),-161.76(s,1F).HPLC conditions:Chiralcel AD-H column(250×4.6mm),hexane/i-PrOH＝93/7,1mL/min,254nm,τR(major)＝5.27min, τR(minor)＝5.89min。
Example 100
Ib-34, brown oil; [ alpha ] to]D 25 31.2(c 0.40,CHCl3)；97％yield,92％ee.1H NMR(400 MHz,Chloroform-d)δ7.97–7.82(m,2H),7.57–7.44(m,5H),7.32–7.20(m,1H),7.03 (ddt,J＝7.5,1.7,0.9Hz,1H),6.22(t,J＝2.3Hz,1H),6.01(d,J＝2.3Hz,2H),3.65–3.34 (m,8H),2.37(s,3H).13C NMR(101MHz,Chloroform-d)δ168.08(d,J＝21.3Hz),160.53, 154.14(d,J＝13.8Hz),138.87,136.88,132.00,131.88,131.08,129.67,129.65,129.06, 128.72,126.79,126.70,126.68,119.94,116.57,107.45,100.89,96.15,94.17,55.06,41.39(d, J＝26.3Hz),21.55.19F NMR(376MHz,Chloroform-d)δ-161.88(s,1F).HPLC conditions: Chiralcel OJ-H column(250×4.6mm),hexane/i-PrOH＝98/2,1mL/min,254nm,τR (major)＝16.66min,τR(minor)＝19.44min。
Example 101
Ib-35, white solid; mp: 81-85 ℃; [ alpha ] to]D 25 31.2(c 0.40,CHCl3)；96％yield,98％ee.1H NMR(400MHz,Chloroform-d)δ7.85(dd,J＝6.7,3.0Hz,2H),7.57–7.37(m,3H),7.24–7.03(m,3H),6.95–6.74(m,2H),3.84(ddd,J＝11.2,6.9,4.2Hz,1H),3.61–3.31(m,2H), 1.86–1.72(m,1H),1.72–1.52(m,4H),1.31–0.98(m,6H).13C NMR(101MHz, Chloroform-d)δ168.54(d,J＝20.8Hz),152.91(d,J＝13.7Hz),130.54,130.13,129.02, 128.25,127.71,126.30,126.29,96.54,94.56,52.84,40.76(d,J＝26.1Hz),30.13,30.00, 25.22,25.08.19F NMR(376MHz,Chloroform-d)δ-165.69(s,1F).HPLC conditions: Chiralcel OJ-H column(250×4.6mm),hexane/i-PrOH＝99/1,0.5mL/min,254nm,τR (major)＝15.05min,τR(minor)＝12.07min。。
Example 102
Preparation of (R) -pyrazolone chiral fluorination product Ib-27 (catalyst recycle)
Weighing 1mmol of 4-substituted pyrazolone Ia-27, adding 0.5mol percent of phase transfer catalyst IIa-12, putting into a 100mL reaction bottle, adding 38wt percent of K2HPO45mL of aqueous solution, 50mL of toluene, 1.05mmol of NFSI (first charge) are added with stirring at 20 ℃. After the reaction is carried out for 30min, HPLC is used for measuring the conversion rate and ee value of the reaction, 1mmol of 4-substituted pyrazolone Ia-27 and 1.05mmol of NFSI (second feeding) are further added into the system, the reaction is continuously stirred for 30min, and the feeding is continued after the conversion rate and ee value of the reaction are measured by HPLC. The reaction is carried out for ten times in total, and each timeThe reaction time, conversion and ee value of the charge are shown in Table 10.
TABLE 10 reaction time, conversion and ee value per charge
After the tenth charge for 30min, 30mL of ethyl acetate was added and the organic layers were combined. The organic layer was washed 2 times with water, once with saturated brine, dried over anhydrous sodium sulfate and concentrated (> 99% yield, 95.5% ee). The crude product was directly crystallized from absolute ethanol to give 3.75g of product in 81% overall yield, with an ee value of 99.7% being determined.
While there have been shown and described what are at present considered the fundamental principles of the invention, its essential features and advantages, the invention further resides in various changes and modifications which fall within the scope of the invention as claimed.
Claims (10)
1. A high-efficiency phase transfer catalytic 4-substituted pyrazolone compound asymmetric fluorination method is characterized by comprising the following specific steps: stirring and mixing 4-substituted pyrazolone compound Ia, a phase transfer catalyst and an electrophilic fluorination reagent in a solvent uniformly, adding alkali, and stirring and reacting at-78-60 ℃ to obtain a chiral alpha-fluoropyrazolone compound Ib, wherein the reaction equation in the preparation process is as follows:
wherein R is1Is phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is F, Cl, Br, I, methoxyl or C1-4Alkyl, nitro, acetonitrile or trifluoromethyl, R2Is methyl, ethyl or substituted ethyl, the substituent on the substituted ethyl is phenyl, substituted phenyl, naphthyl or alkynyl, and the substituent on the substituted phenyl benzene ring is F, Cl, Br, I, methoxy or C1-4Alkyl, nitro, acetonitrile or trifluoromethylRadical, R3Is C1-4Alkyl, phenyl, substituted phenyl or naphthyl, wherein the substituent on the benzene ring of the substituted phenyl is F, Cl, Br, I, methoxy or C1-4Alkyl, nitro, acetonitrile, methylenedioxy or trifluoromethyl;
the phase transfer catalyst is cinchonine derivative IIa or IIb, and the corresponding structural formula is as follows:
wherein R is3Is H or methoxy, R4Is tert-butyl, adamantyl, isopropyl, benzyl or substituted aryl;
the structural formula of the electrophilic fluorinating reagent is as follows:
wherein R is6Is H, methoxy, methyl, chlorine, bromine or iodine.
2. The method for efficiently phase-transfer-catalyzing the asymmetric fluorination of 4-substituted pyrazolone compounds according to claim 1, wherein the specific synthetic process of the phase-transfer catalyst cinchona alkaloid cinchonine derivative IIa or IIb is as follows: reacting primary amine with bromoacetyl bromide to generate bromoamide, and then further reacting with cinchona alkaloid in tetrahydrofuran to obtain a phase transfer catalyst cinchona alkaloid cinchonine derivative IIa or IIb; the corresponding synthetic route is as follows:
3. the method for efficiently phase-transfer catalyzing the asymmetric fluorination of 4-substituted pyrazolone compounds according to claim 1, which is characterized in that: the solvent is halogenated hydrocarbon, aromatic hydrocarbon, alkane or ether.
4. The efficient phase transfer catalyzed asymmetric fluorination method of 4-substituted pyrazolone compounds according to claim 1 or 3, which is characterized in that: the solvent is one or more of toluene, benzotrifluoride, chloroform, p-xylene, mesitylene or n-hexane.
5. The method for efficiently phase-transfer catalyzing the asymmetric fluorination of 4-substituted pyrazolone compounds according to claim 1, which is characterized in that: the alkali is organic alkali or inorganic alkali aqueous solution; the inorganic alkaline water solution is one or more aqueous solution combination of sodium carbonate, dipotassium hydrogen phosphate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium fluoride or potassium acetate.
6. The method for efficiently phase-transfer catalyzing the asymmetric fluorination of 4-substituted pyrazolone compounds according to claim 1, which is characterized in that: the reaction temperature is-20 to 25 ℃.
7. The method for efficiently phase-transfer catalyzing the asymmetric fluorination of 4-substituted pyrazolone compounds according to claim 1, which is characterized in that: the dosage of the phase transfer catalyst is 0.01-10 mol% of that of the 4-substituted pyrazolone compound Ia.
8. The method for efficiently phase-transfer catalyzing the asymmetric fluorination of 4-substituted pyrazolone compounds according to claim 1, which is characterized in that: the dosage of the phase transfer catalyst is 0.5-1 mol% of that of the 4-substituted pyrazolone compound Ia.
9. The method for efficiently phase-transfer catalyzing the asymmetric fluorination of 4-substituted pyrazolone compounds according to claim 1, which is characterized in that: the feeding molar ratio of the electrophilic fluorinating reagent to the 4-substituted pyrazolone compound Ia is 1-2: 1.
10. The method for efficiently phase-transfer catalyzing the asymmetric fluorination of 4-substituted pyrazolone compounds according to claim 1, which is characterized in that: the reaction time is 10 min-1 h.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102089304A (en) * | 2008-05-13 | 2011-06-08 | 阿斯利康(瑞典)有限公司 | Quinuclidine derivatives as muscarinic M3 receptor antagonists |
| CN102285919A (en) * | 2011-07-12 | 2011-12-21 | 浙江工业大学 | Method for preparing 4-fluorinated pyrazole derivative |
| CN104884056A (en) * | 2012-11-12 | 2015-09-02 | 雷德伍德生物科技股份有限公司 | Compounds and methods for producing a conjugate |
| WO2016109795A1 (en) * | 2014-12-31 | 2016-07-07 | Concert Pharmaceuticals, Inc. | Deuterated funapide and difluorofunapide |
| WO2020230134A1 (en) * | 2019-05-14 | 2020-11-19 | Metabomed Ltd | Acss2 inhibitors and methods of use thereof |
| CN113956202A (en) * | 2021-10-26 | 2022-01-21 | 新乡医学院 | Method for realizing asymmetric alpha-hydroxylation of pyrazolone compounds by phase transfer catalytic photosensitive molecular oxygen |
-
2022
- 2022-04-01 CN CN202210339561.9A patent/CN114716380A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102089304A (en) * | 2008-05-13 | 2011-06-08 | 阿斯利康(瑞典)有限公司 | Quinuclidine derivatives as muscarinic M3 receptor antagonists |
| CN102285919A (en) * | 2011-07-12 | 2011-12-21 | 浙江工业大学 | Method for preparing 4-fluorinated pyrazole derivative |
| CN104884056A (en) * | 2012-11-12 | 2015-09-02 | 雷德伍德生物科技股份有限公司 | Compounds and methods for producing a conjugate |
| WO2016109795A1 (en) * | 2014-12-31 | 2016-07-07 | Concert Pharmaceuticals, Inc. | Deuterated funapide and difluorofunapide |
| WO2020230134A1 (en) * | 2019-05-14 | 2020-11-19 | Metabomed Ltd | Acss2 inhibitors and methods of use thereof |
| CN113956202A (en) * | 2021-10-26 | 2022-01-21 | 新乡医学院 | Method for realizing asymmetric alpha-hydroxylation of pyrazolone compounds by phase transfer catalytic photosensitive molecular oxygen |
Non-Patent Citations (4)
| Title |
|---|
| DAE YOUNG KIM ET AL.: ""Catalytic Enantioselective Fluorination of β-Keto Esters by Phase-Transfer Catalysis Using Chiral Quaternary Ammonium Salts"", 《ORGANIC LETTERS》, vol. 4, no. 4, pages 545 - 547, XP002330794 * |
| JIE LUO ET AL.: ""Enantioselective direct fluorination and chlorination of cyclic β-ketoesters mediated by phase-transfer catalysts"", 《TETRAHEDRON LETTERS》, vol. 54, pages 2623 - 2626, XP028580391, DOI: 10.1016/j.tetlet.2013.03.028 * |
| XIAOZE BAO ET AL.: ""Asymmetric fluorination of 4-substituted pyrazolones catalyzed by quinine"", 《TETRAHEDRON: ASYMMETRY》, vol. 27, pages 436 - 441, XP029525547, DOI: 10.1016/j.tetasy.2016.03.013 * |
| YAKUN WANG ET AL.: ""Fast, highly enantioselective, and sustainable fluorination of 4-substituted pyrazolones catalyzed by amide-based phase-transfer catalysts"", 《ORGANIC CHEMISTRY FRONTIERS》, vol. 10, pages 2226 - 2233 * |
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