CN109970752B - Synthesis method of chiral 4-spiro pyrazole compound - Google Patents
Synthesis method of chiral 4-spiro pyrazole compound Download PDFInfo
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- CN109970752B CN109970752B CN201910284007.3A CN201910284007A CN109970752B CN 109970752 B CN109970752 B CN 109970752B CN 201910284007 A CN201910284007 A CN 201910284007A CN 109970752 B CN109970752 B CN 109970752B
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 58
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 239000002253 acid Substances 0.000 claims abstract description 15
- 239000011230 binding agent Substances 0.000 claims abstract description 11
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000010189 synthetic method Methods 0.000 claims abstract description 3
- -1 p-toluenesulfonyl group Chemical group 0.000 claims description 22
- 239000003054 catalyst Substances 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 239000012071 phase Substances 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 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
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003480 eluent Substances 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 125000001302 tertiary amino group Chemical group 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000003377 acid catalyst Substances 0.000 claims description 2
- 239000003513 alkali Substances 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
- 230000001588 bifunctional effect Effects 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 238000010828 elution Methods 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- 150000007527 lewis bases Chemical group 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 18
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000004809 thin layer chromatography Methods 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 238000012544 monitoring process Methods 0.000 abstract description 2
- 239000000575 pesticide Substances 0.000 abstract description 2
- 125000003226 pyrazolyl group Chemical group 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 140
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 102
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 35
- 238000005160 1H NMR spectroscopy Methods 0.000 description 35
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 35
- 238000004296 chiral HPLC Methods 0.000 description 35
- 238000004458 analytical method Methods 0.000 description 33
- 238000011017 operating method Methods 0.000 description 22
- 150000002989 phenols Chemical class 0.000 description 21
- 238000006555 catalytic reaction Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 12
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 12
- 239000012265 solid product Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 230000003197 catalytic effect Effects 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- ARWPTNHLVQOQQM-UHFFFAOYSA-N 2-methoxy-6-[(4-methylphenyl)sulfonyl-phenylmethyl]phenol Chemical compound COc1cccc(C(c2ccccc2)S(=O)(=O)c2ccc(C)cc2)c1O ARWPTNHLVQOQQM-UHFFFAOYSA-N 0.000 description 2
- JWAZRIHNYRIHIV-UHFFFAOYSA-N 2-naphthol Chemical compound C1=CC=CC2=CC(O)=CC=C21 JWAZRIHNYRIHIV-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000006362 organocatalysis Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 description 1
- IATQNRSIWRHGFK-UHFFFAOYSA-N 2-[(4-chlorophenyl)-(4-methylphenyl)sulfonylmethyl]-6-methoxyphenol Chemical compound ClC1=CC=C(C=C1)C(C1=C(C(=CC=C1)OC)O)S(=O)(=O)C1=CC=C(C)C=C1 IATQNRSIWRHGFK-UHFFFAOYSA-N 0.000 description 1
- AUYFFJVZJUCPEA-UHFFFAOYSA-N 2-[(4-fluorophenyl)-(4-methylphenyl)sulfonylmethyl]-6-methoxyphenol Chemical compound FC1=CC=C(C=C1)C(C1=C(C(=CC=C1)OC)O)S(=O)(=O)C1=CC=C(C)C=C1 AUYFFJVZJUCPEA-UHFFFAOYSA-N 0.000 description 1
- VBBXYOIXIJUYNM-UHFFFAOYSA-N 2-[(4-methylphenyl)sulfonyl-phenylmethyl]phenol Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C=1C(=CC=CC=1)O)C1=CC=CC=C1 VBBXYOIXIJUYNM-UHFFFAOYSA-N 0.000 description 1
- DELHAEZPRFOKRH-UHFFFAOYSA-N 2-[furan-2-yl-(4-methylphenyl)sulfonylmethyl]-6-methoxyphenol Chemical compound O1C(=CC=C1)C(C1=C(C(=CC=C1)OC)O)S(=O)(=O)C1=CC=C(C)C=C1 DELHAEZPRFOKRH-UHFFFAOYSA-N 0.000 description 1
- WQCPMGVKKIXIDS-UHFFFAOYSA-N 2-methoxy-6-[(2-methoxyphenyl)-(4-methylphenyl)sulfonylmethyl]phenol Chemical compound CC1=CC=C(C=C1)S(=O)(=O)C(C2=C(C(=CC=C2)OC)O)C3=CC=CC=C3OC WQCPMGVKKIXIDS-UHFFFAOYSA-N 0.000 description 1
- UDQBHOCVBFRIHV-UHFFFAOYSA-N 2-methoxy-6-[(2-methylphenyl)-(4-methylphenyl)sulfonylmethyl]phenol Chemical compound CC1=CC=C(C=C1)S(=O)(=O)C(C2=C(C(=CC=C2)OC)O)C3=CC=CC=C3C UDQBHOCVBFRIHV-UHFFFAOYSA-N 0.000 description 1
- DGBOXPGESGBIPW-UHFFFAOYSA-N 2-methoxy-6-[(3-methoxyphenyl)-(4-methylphenyl)sulfonylmethyl]phenol Chemical compound COC1=C(C(=CC=C1)C(S(=O)(=O)C1=CC=C(C)C=C1)C1=CC(=CC=C1)OC)O DGBOXPGESGBIPW-UHFFFAOYSA-N 0.000 description 1
- OHOVSQHGWXLIAE-UHFFFAOYSA-N 2-methoxy-6-[(3-methylphenyl)-(4-methylphenyl)sulfonylmethyl]phenol Chemical compound COC1=C(C(=CC=C1)C(S(=O)(=O)C1=CC=C(C)C=C1)C=1C=C(C=CC=1)C)O OHOVSQHGWXLIAE-UHFFFAOYSA-N 0.000 description 1
- JWQZMSVTGPFIKP-UHFFFAOYSA-N 2-methoxy-6-[(4-methylphenyl)-(4-methylphenyl)sulfonylmethyl]phenol Chemical compound COC1=C(C(=CC=C1)C(S(=O)(=O)C1=CC=C(C)C=C1)C1=CC=C(C=C1)C)O JWQZMSVTGPFIKP-UHFFFAOYSA-N 0.000 description 1
- MVNBENGMWLZXBE-UHFFFAOYSA-N 2-methoxy-6-[(4-methylphenyl)sulfonyl-[2-(trifluoromethyl)phenyl]methyl]phenol Chemical compound COC1=C(C(=CC=C1)C(C1=C(C=CC=C1)C(F)(F)F)S(=O)(=O)C1=CC=C(C)C=C1)O MVNBENGMWLZXBE-UHFFFAOYSA-N 0.000 description 1
- GNJCBRIKYWVSBU-UHFFFAOYSA-N 2-methoxy-6-[(4-methylphenyl)sulfonyl-[3-(trifluoromethyl)phenyl]methyl]phenol Chemical compound COC1=C(C(=CC=C1)C(C1=CC(=CC=C1)C(F)(F)F)S(=O)(=O)C1=CC=C(C)C=C1)O GNJCBRIKYWVSBU-UHFFFAOYSA-N 0.000 description 1
- QZQZZUPGGOWHMH-UHFFFAOYSA-N 2-methoxy-6-[(4-methylphenyl)sulfonyl-[4-(trifluoromethyl)phenyl]methyl]phenol Chemical compound COC1=C(C(=CC=C1)C(C1=CC=C(C=C1)C(F)(F)F)S(=O)(=O)C1=CC=C(C)C=C1)O QZQZZUPGGOWHMH-UHFFFAOYSA-N 0.000 description 1
- QGKYRJKHYCYZHX-UHFFFAOYSA-N 2-methoxy-6-[(4-methylphenyl)sulfonyl-naphthalen-1-ylmethyl]phenol Chemical compound COC1=C(C(=CC=C1)C(S(=O)(=O)C1=CC=C(C)C=C1)C1=CC=CC2=CC=CC=C12)O QGKYRJKHYCYZHX-UHFFFAOYSA-N 0.000 description 1
- DKMYMKIUSNCXSE-UHFFFAOYSA-N 2-methoxy-6-[(4-methylphenyl)sulfonyl-naphthalen-2-ylmethyl]phenol Chemical compound COC1=C(C(=CC=C1)C(S(=O)(=O)C1=CC=C(C)C=C1)C1=CC2=CC=CC=C2C=C1)O DKMYMKIUSNCXSE-UHFFFAOYSA-N 0.000 description 1
- GQWQDMQTIBEILI-UHFFFAOYSA-N 2-methoxy-6-[(4-methylphenyl)sulfonyl-thiophen-2-ylmethyl]phenol Chemical compound COC1=C(C(=CC=C1)C(S(=O)(=O)C1=CC=C(C)C=C1)C=1SC=CC=1)O GQWQDMQTIBEILI-UHFFFAOYSA-N 0.000 description 1
- VZRQGGVXSLPJLI-UHFFFAOYSA-N 4-bromo-2,5-diphenyl-1H-pyrazol-3-one Chemical compound O=C1C(Br)=C(C=2C=CC=CC=2)NN1C1=CC=CC=C1 VZRQGGVXSLPJLI-UHFFFAOYSA-N 0.000 description 1
- RISFPTQSEUGRGK-UHFFFAOYSA-N 4-bromo-2-phenyl-5-propan-2-yl-1H-pyrazol-3-one Chemical compound O=C1C(Br)=C(C(C)C)NN1C1=CC=CC=C1 RISFPTQSEUGRGK-UHFFFAOYSA-N 0.000 description 1
- JRDWFXHNLRHLNC-UHFFFAOYSA-N 4-bromo-2-phenyl-5-propyl-1H-pyrazol-3-one Chemical compound O=C1C(Br)=C(CCC)NN1C1=CC=CC=C1 JRDWFXHNLRHLNC-UHFFFAOYSA-N 0.000 description 1
- SGANUMROSCBQPU-UHFFFAOYSA-N 4-bromopyrazol-3-one Chemical compound BrC1=CN=NC1=O SGANUMROSCBQPU-UHFFFAOYSA-N 0.000 description 1
- YWJHAHMZBIFPER-UHFFFAOYSA-N 5-methoxy-2-[(4-methylphenyl)sulfonyl-phenylmethyl]phenol Chemical compound COC=1C=CC(=C(C=1)O)C(S(=O)(=O)C1=CC=C(C)C=C1)C1=CC=CC=C1 YWJHAHMZBIFPER-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229950011260 betanaphthol Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000008040 ionic compounds Chemical class 0.000 description 1
- 239000002608 ionic liquid Substances 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a synthetic method of a chiral 4-spiro pyrazole compound shown in a formula (3), which comprises the following steps: in a water-oil two-phase system, raw materials, namely a compound phenol shown as a formula (1) and a compound shown as a formula (2), react under the action of an acid-binding agent and a chiral catalystAnd tracking and monitoring by TLC (thin layer chromatography) until the reaction is complete, and carrying out aftertreatment on the obtained reaction liquid to obtain the chiral 4-spiro pyrazole compound chiral compound shown in the formula (3). The invention has the advantages that: the chiral 4-spirocyclic pyrazole structure is an important structural unit, widely exists in the fields of pesticides and medicines, and has wide application prospect. The synthesis method has the advantages of mild conditions, high yield, good asymmetric selectivity, wide range of reaction substrates, cheap and easily-obtained reaction reagents and strong operability.
Description
(I) technical field
The invention relates to a method for synthesizing a chiral 4-spirocyclic pyrazole compound, in particular to a method for synthesizing the chiral 4-spirocyclic pyrazole compound by asymmetric domino ring-closure of raw materials 2-naphthol and 2- (aryl (p-toluenesulfonyl) methyl) phenol under catalysis of chiral tertiary amine-azoic acid in a water-oil two-phase system.
(II) background of the invention
70% of the existing new small molecule drugs contain at least one chiral center, so the development of a method for efficiently constructing chiral molecules is one of the important missions of synthetic chemists. The asymmetric synthesis catalyzed by organic small molecules is still in the interest of asymmetric catalysis, which is a high-efficiency asymmetric catalysis method developed after organometallic catalysis and enzyme catalysis. Compared with organic metal catalysis, the organic small molecular catalyst is generally stable to water and air, simple and convenient in reaction operation and easy for industrial amplification, and more importantly, the organic small molecular catalyst does not contain toxic metal, which is particularly important in drug synthesis. Compared with enzyme catalysis, small molecule catalysis has no strong substrate and reaction specificity like enzyme catalysis, one catalyst can catalyze several kinds of reactions, and the reaction substrate adaptability is relatively good. Just because of their unique advantages over other catalytic approaches, small organic molecule catalysis based on different catalytic mechanisms has been under great development over the last decade. As one of the important branches of organic small molecule catalysis, asymmetric reaction based on hydrogen bond catalysis also meets the requirements of larger generationMeanwhile, catalysts containing hydrogen bond donors (such as urea, thiourea, azosquaric acid, guanidine, phosphonic acid and the like) in various structures have been designed, show excellent chiral induction effect in a plurality of asymmetric catalytic reactions, and become an important synthesis strategy for constructing carbon-carbon bonds and carbon-heteroatom bonds. (A. Berkessel and H.
Asymmetric Organocatalysis,Wiley VCH,Weinheim,2005.；P.I.Dalko,Enantioselective Organocatalysis,Wiley-VCH,Weinheim,2007.)。
In recent years, Water-Oil two-phase (Water-Oil phases) has become an important reaction system in organic synthesis, and has received much attention because it enables organic compounds and Water-soluble ionic compounds to be separated or combined efficiently and rapidly during the reaction process. The asymmetric catalytic reaction under the water-oil two-phase system has important research and practical values. In the present research, the organic reaction based on the water-oil two-phase system mainly promotes the reaction of the organic substrate and the ionic reactant by the quaternary ammonium salt and crown ether phase transfer catalyst. For asymmetric organic catalysis in two-phase systems, it is currently limited to ionic liquids. Therefore, the development of more asymmetric catalytic systems based on two phases has important practical significance.
Disclosure of the invention
The invention aims to provide a method for synthesizing chiral 4-spiro pyrazole compounds in water and oil phases.
In order to achieve the purpose, the invention adopts the following technical scheme:
a synthetic method of a chiral 4-spirocyclic pyrazole compound shown in formula (3) comprises the following steps:
in a water-oil two-phase system, taking a compound shown in a formula (1) and a compound shown in a formula (2) as raw materials, reacting at 20-30 ℃ under the action of an acid-binding agent and a chiral catalyst, tracking and monitoring by TLC (thin layer chromatography) until the reaction is complete, and carrying out aftertreatment on the obtained reaction liquid to obtain a chiral 4-spiro pyrazole compound shown in a formula (3); the ratio of the amount of the compound represented by the formula (1) to the amount of the compound represented by the formula (2) and the acid-binding agent is 0.2-5: 1: 0.5 to 20; the amount ratio of the chiral catalyst to the compound represented by the formula (1) is 0.01 to 100: 100, respectively; the chiral catalyst is a bifunctional tertiary amine-azodicarbonic acid catalyst, which comprises a tertiary amine group containing a hydrogen bond donor azodicarbonic acid group and Lewis base function; the acid-binding agent is inorganic alkali; the water-oil two-phase system is prepared by mixing water and an organic solvent in a volume ratio of 1: 0.05-10 parts by weight;
the reaction formula is as follows:
in the formula (1), Ts represents a p-toluenesulfonyl group;
in the formula (1) or (3),
R1is H, methoxy, ethoxy or halogen;
R2is C1-20Alkyl, furyl, thienyl, naphthyl, phenyl or phenyl substituted with one or more substituents each independently being methyl, methoxy, trifluoromethyl or halogen;
in the formula (2) or the formula (3),
R3is C1-20Alkyl, naphthyl, phenyl or phenyl substituted with one or more substituents each independently being methyl, ethyl or halogen.
R4Is C1-20Alkyl or phenyl groups.
Still further, the chiral catalyst is preferably one of compounds represented by the following formulas (4) to (7):
in the formula (4) or (5), the carbon atom marked with x is a chiral carbon atom;
in the formula (4), (5), (6) or (7),
R5、R8、R11or R14Each independently is C1～C20Or phenyl or benzyl substituted with one or more substituents each independently being trifluoromethyl, nitro or halogen;
R6、R7、R9or R10Each independently is C1～C10Alkyl groups of (a);
R12or R15Each independently is ethyl or vinyl;
R13or R16Each independently is H, hydroxy or methoxy.
Still further, more preferably, the chiral catalyst is selected from one of the following:
further, the ratio of the amount of the compound represented by the formula (1) to the amount of the compound represented by the formula (2) and the acid-binding agent is preferably 0.5 to 2: 1:1 to 10.
Further, in the water-oil two-phase system, the organic solvent is selected from dichloromethane, chloroform, 1, 2-dichloroethane, diethyl ether, toluene, ethyl acetate or isopropyl acetate.
Further, the acid-binding agent is sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide or disodium hydrogen phosphate.
Further, the post-treatment method of the reaction solution comprises the following steps: after the reaction is finished, separating the reaction liquid, taking the organic phase, concentrating under reduced pressure, and then performing silica gel column chromatography separation, wherein the volume ratio of petroleum ether to ethyl acetate is 1-30: the mixed solution of 1 is used as eluent to carry out gradient elution, eluent containing a target compound is collected, the solvent is evaporated and dried, and the chiral 4-spiro pyrazole compound shown in the formula (3) is obtained.
Compared with the prior art, the invention has the beneficial effects that:
according to the synthesis method, a chiral catalyst containing at least one tertiary amine and a nitrilic acid functional group is used as a catalytic system, the reaction is carried out in water and oil phases, the product chiral 4-spiropyrazole compound is obtained through post-treatment separation, the synthesis method is mild in condition, high in yield, good in asymmetric selectivity, wide in range of reaction substrates, cheap and easily available in reaction reagents, and the chiral 4-spiropyrazole structure is an important structural unit, widely exists in the fields of pesticides and medicines, and has a wide application prospect.
(IV) detailed description of the preferred embodiments
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.
Example 1:
the catalysts (7) -b (0.01mmol, 6.3mg), 6-methoxy-2- (phenyl (p-toluenesulfonyl) methyl) phenol (0.1mmol, 36.8mg), 4-bromopyrazolone (0.13mmol, 33.0mg), potassium carbonate (0.26mmol, 36mg), chloroform (1.5ml), water (0.15ml) were added in this order to a dry 10ml reaction tube, the reaction tube was closed, stirred at room temperature for 24h with a magnetic stirrer, TLC showed complete consumption of 6-methoxy-2- (phenyl (p-toluenesulfonyl) methyl) phenol, and the reaction solution was CH2Cl2Extracting and separating liquid, taking organic phase, concentrating under reduced pressure, separating by using a silica gel chromatographic column, and mixing petroleum ether and ethyl acetate in a volume ratio of 1-20: 1 as eluent, collecting the eluent containing the target compound, evaporating the solvent and drying to obtain 37.0mg (yield 95%) of a white solid product,1H NMR(500MHz,CDCl3)7.34(q,J＝1.8Hz,1H),7.33(dd,J＝2.1,1.1Hz,1H),7.32-7.27(m,3H),7.27-7.23(m,4H),7.12-7.07(m,1H),7.02(dd,J＝8.1,7.5Hz,1H),6.94(dt,J＝8.2,1.0Hz,1H),6.79(dt,J＝7.5,1.1Hz,1H),5.16(s,1H),3.96(s,3H),2.40(s,3H).13C NMR(126MHz,CDCl3)168.04,158.08,148.25,144.83,136.98,133.76,129.10,128.58,128.48,128.47,127.84,125.18,123.00,119.11,117.47,112.66,92.32,56.19,55.34,13.11, by chiral HPLC analysis, with the specific conditions (IA-H, 15% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 9.2min, tR8.4min, 90:10, 98% ee.
The same reactants were taken according to example 1 and reacted under the same operating procedures with the following catalysts (7) -b in place of 0.01mmol, respectively, to obtain the results shown in Table 1 below:
in Table 1, the superscriptsaThe results show the yield of the separation,bshows that the diastereoselectivity is obtained by chiral high performance liquid chromatographycIndicating that the corresponding selectivity is obtained by chiral high performance liquid chromatography analysis.
TABLE 1
| Numbering | Catalyst and process for preparing same | Reaction time (h) | Yield (%)a | dr valueb | ee value (%)c |
| 1 | (4)-a | 24 | 92 | 66:34 | -60 |
| 2 | (5)-a | 24 | 95 | 70:30 | -67 |
| 3 | (6)-a | 24 | 92 | 85:15 | 96 |
| 4 | (6)-b | 24 | 90 | 82:18 | 90 |
| 5 | (7)-a | 24 | 93 | 84:14 | 96 |
| 6 | (7)-b | 24 | 95 | 90:10 | 96 |
| 7 | (7)-c | 24 | 93 | 80:20 | 92 |
| 8 | (7)-d | 24 | 60 | 79:21 | 94 |
| 9 | (7)-e | 24 | 95 | 88:12 | 92 |
| 10 | (7)-f | 24 | 92 | 75:25 | 80 |
| 11 | (7)-g | 24 | 87 | 75:25 | 81 |
The same reactants were taken according to example 1 and reacted under the same procedure with 0.26mol of the following inorganic bases, respectively, instead of potassium carbonate, with the results shown in Table 2 below:
TABLE 2
In Table 2, superscriptaThe results show the yield of the separation,bshows that the diastereoselectivity is obtained by chiral high performance liquid chromatographycShows that the corresponding selectivity is obtained by chiral high performance liquid chromatography analysis
The same reaction mixture was taken out according to example 1 and subjected to the same operation in the presence of 1.5ml of the following organic solvent in place of chloroform, respectively, to obtain the results shown in Table 3 below:
TABLE 3
Upper labelaThe results show the yield of the separation,bshows that the diastereoselectivity is obtained by chiral high performance liquid chromatographycShows that the corresponding selectivity is obtained by chiral high performance liquid chromatography analysis,erepresents 1.5ml chloroform as the sole solventfRepresenting 1.5ml of water as the sole solvent.
Example 2:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-ethoxy-2-phenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 37.0mg (yield 93%) of a white solid product,1H NMR(500MHz,CDCl3)7.35–7.32(m,1H),7.32(dd,J＝2.1,1.1Hz,1H),7.31–7.29(m,1H),7.29–7.25(m,3H),7.25–7.23(m,3H),7.13–7.06(m,1H),6.99(dd,J＝8.2,7.4Hz,1H),6.97–6.90(m,1H),6.77(dt,J＝7.4,1.2Hz,1H),5.14(s,1H),4.21(q,J＝7.0Hz,2H),2.40(s,3H),1.49(t,J＝7.0Hz,3H).13C NMR(126MHz,CDCl3)168.18,158.29,148.52,144.14,137.01,133.92,129.13,128.59,128.47,128.45,127.94,125.18,122.93,119.12,117.44,114.13,92.30,64.80,55.41,14.93,13.17. analysis by chiral HPLC, with the specific conditions (ID, 15% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 10.5min, tR9.9min, 86:14dr, 92% ee.
Example 3:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 5-methoxy-2- (phenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 36.5mg (yield 95%) of a white solid product,1H NMR(500MHz,CDCl3)7.37–7.30(m,4H),7.30–7.24(m,4H),7.23(dd,J＝6.1,1.8Hz,2H),7.12–7.08(m,1H),7.07–7.03(m,1H),6.92(dd,J＝1.8,1.1Hz,1H),,5.13(s,1H),3.94(s,3H),2.40(s,3H).13C NMR(126MHz,CDCl3)167.63,157.43,147.55,145.20,136.81,132.82,129.50,129.00,128.71,128.62,128.58,125.29,120.26,119.07,116.12,114.42,92.50,56.44,55.05,13.06, by chiral HPLC, with specific conditions (IC, 15% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 10.5min, tR9.9min, 97:3dr, 93% ee.
Example 4:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-4-bromo-2- (4-methylphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 44mg (yield 95%) of the product as a white solid,1H NMR(500MHz,CDCl3)7.37–7.28(m,5H),7.28–7.24(m,2H),7.24–7.21(m,2H),7.12–7.04(m,2H),6.95–6.88(m,1H),,5.13(s,1H),3.94(s,3H),2.39(s,3H).13C NMR(126MHz,CDCl3)167.67,157.47,147.59,145.24,136.84,132.85,129.03,128.75,128.66,128.62,128.15,125.32,120.30,119.11,116.15,114.45,92.54,56.47,55.08,13.10 by chiral HPLC analysis, with the specific conditions (OD-H, 4% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 17.0min, tR(times) 20min, 80:20dr, 98% ee.
Example 5:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (4-fluorophenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operation were the same as in example 1 to give 38.1mg (yield 95%) of a white solid product,1H NMR(500MHz,CDCl3)7.41–7.36(m,2H),7.27(dd,J＝8.7,7.3Hz,2H),7.21(dd,J＝8.5,5.4Hz,2H),7.11(t,J＝7.4Hz,1H),7.04–6.92(m,4H),6.74(d,J＝7.5Hz,1H),5.13(s,1H),3.95(s,3H),2.38(s,3H).13C NMR(126MHz,CDCl3)167.96,162.70(d, J-247.6 Hz),158.13,148.13,144.87,136.96,130.86(d, J-8.3 Hz),129.68(d, J-3.1 Hz),128.68,127.79,125.30,123.14,118.97,117.27,115.47(d, J-21.6 Hz),112.78,92.13,56.20,54.61,13.07. analysis by chiral HPLC, with the specific conditions (IA, 15% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 9.4min, tR8.5min, 82:18dr, 98% ee.
Example 6:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (4-chlorophenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 38.9mg (yield 93%) of a solid product,1H NMR(500MHz,CDCl3)1H NMR(500MHz,CDCl3)7.41–7.37(m,2H),7.30–7.27(m,2H),7.27–7.24(m,2H),7.19–7.16(m,2H),7.14–7.10(m,1H),7.04–6.99(m,1H),6.94(d,J＝8.2Hz,1H),6.73(dt,J＝7.6,1.1Hz,1H),5.11(s,1H),3.96(s,3H),2.37(s,3H).13C NMR(126MHz,CDCl3)167.83,158.09,148.15,144.89,136.93,134.41,132.54,130.50,128.68,127.55,125.34,123.18,119.00,117.24,112.85,91.96,56.19,54.65,13.03, by chiral HPLC, with the specific conditions (IA, 15% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 10.1min, tR9.1min, 82:18dr, 98% ee.
Example 7:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (4-trifluoromethylphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operation were the same as in example 1 to give 37.5mg (yield 83%) of a solid product,1H NMR(500MHz,CDCl3)7.55(d,J＝8.1Hz,2H),7.36(d,J＝8.1Hz,2H),7.32–7.29(m,2H),7.28–7.23(m,2H),7.14–7.09(m,1H),7.06–7.01(m,1H),6.96(d,J＝8.2Hz,1H),6.74(dt,J＝7.5,1.1Hz,1H),5.19(s,1H),3.96(s,3H),2.39(s,3H).13C NMR(126MHz,CDCl3)167.68,158.05,148.26,144.98,138.25,136.75,130.68(q, J ═ 32.6Hz),129.64,128.69,127.09,125.49,125.41(q, J ═ 3.6Hz),123.86(q, J ═ 272.8Hz),123.32,119.07,117.21,112.97,91.95,56.21,54.98,13.07. analysis by chiral HPLC was carried out with the specific conditions (IC, 4% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 24.8min, tR21.8min, 88:12dr, 96% ee.
Example 8:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (3-trifluoromethylphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and the operation were the same as in example 1 to obtain a solid product 43.0mg (yield 95%),1H7.54–7.49(m,2H),7.44–7.40(m,2H),7.38–7.33(m,2H),7.28–7.23(m,2H),7.12–7.09(m,1H),7.04(dd,J＝8.2,7.5Hz,1H),6.96(dt,J＝8.2,1.0Hz,1H),6.74(dt,J＝7.4,1.1Hz,1H),5.19(s,1H),3.96(s,3H),2.39(s,3H).13C NMR(126MHz,CDCl3)167.72,158.06,148.27,144.98,136.83,135.26,132.64,130.90(q, J ═ 32.6Hz),128.65,127.02,125.81(q, J ═ 3.7Hz),125.37(q, J ═ 3.5),125.35,123.79(q, J ═ 271),123.38,118.91,117.16,113.01,92.02,56.21,55.05,13.07. analysis by chiral HPLC was carried out with the specific conditions (IC, 5% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 14min, tR(times) 11.5min, 81:19dr, 96% ee.
Example 9:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (2-trifluoromethylphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operation were the same as in example 1 to give 38mg (yield 84%) of the product, 7.62(d, J ═ 7.8Hz,1H), 7.59-7.48 (m,3H),7.38(t, J ═ 7.6Hz,1H), 7.33-7.24 (m,3H), 7.16-7.11 (m,1H), 7.04-6.91 (m,2H),6.64(d, J ═ 7.5Hz,1H),5.39(s,1H),4.12(s,3H),3.98(s,3H),2.21(s,3H).13C NMR(126MHz,CDCl3)166.98,158.36,147.54,144.86,137.30,134.10,133.63,131.52,129.37,128.67,128.39(q, J ═ 29.2Hz),128.19,125.43(q, J ═ 5.7Hz),125.24,124.23(q, J ═ 272.08),123.60,119.15,117.30,112.69,90.12,56.19,49.81,12.71. analysis by chiral HPLC, specific conditions were (ID, 15% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 12.3min, tR(times) 8.1min, 96:4dr, 99% ee.
Example 10:
the difference from the embodiment 1 is that: the substrate used is substituted benzeneThe phenol was 6-methoxy-2- (4-methylphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 38.7mg (yield 97%),1H NMR(500MHz,CDCl3)7.38(ddd,J＝8.7,2.0,1.1Hz,2H),7.29–7.24(m,2H),7.15–7.08(m,5H),7.04–6.98(m,1H),6.93(dt,J＝8.3,1.0Hz,1H),6.78(dt,J＝7.6,1.1Hz,1H),5.13(s,1H),3.96(s,3H),2.39(s,3H),2.29(s,3H).13C NMR(126MHz,CDCl3)168.12,158.15,148.16,144.79,138.19,137.09,130.66,129.17,128.98,128.55,128.15,125.12,122.94,119.13,117.46,112.59,92.31,56.18,55.02,21.07,13.09. analysis by chiral HPLC was carried out with the specific conditions (IA, 15% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 9.9min, tR8.8min, 85:15dr, 94% ee.
Example 11:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (3-methylphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 38.2mg (yield 96%),1H NMR(500MHz,CDCl3)7.39–7.34(m,2H),7.28–7.24(m,2H),7.20–7.15(m,1H),7.11–7.00(m,5H),6.93(d,J＝7.9Hz,1H),6.79(dd,J＝7.3,0.9Hz,1H),5.13(s,1H),3.96(s,3H),2.40(s,3H),2.27(s,3H).13C NMR(126MHz,CDCl3)168.11,158.16,148.21,144.80,138.12,137.05,133.71,129.62,129.20,128.56,128.35,127.91,126.16,125.13,122.96,119.08,117.55,112.61,92.34,56.18,55.29,21.26,13.09. analysis by chiral HPLC was carried out with the specific conditions (IA, 5% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 12.2min, tR13.8min, 85:15dr, 96% ee.
Example 12:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (2-methylphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 36.6mg (yield 92%) of the product,1H NMR(500MHz,CDCl3)7.40(d,J＝7.8Hz,2H),7.30–7.26(m,2H),7.19–7.10(m,5H),7.01(t,J＝7.8Hz,1H),6.92(d,J＝8.1Hz,1H),6.70(d,J＝7.5Hz,1H),5.44(s,1H),3.97(s,3H),2.36(s,3H),2.30(s,3H).13C NMR(126MHz,CDCl3)168.00,159.14,148.09,144.77,137.16,136.34,133.25,130.77,130.05,129.09,128.67,128.05,125.98,125.20,123.05,119.13,117.58,112.39,91.09,56.18,51.38,19.45,13.14. analysis by chiral HPLC, with the specific conditions (IA, 5% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 13.5min, tR(times) 11.9min, 95:5dr, 96% ee.
Example 13:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (3-methoxyphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 40.3mg (yield 97%) of the product,1H NMR(500MHz,CDCl3)7.52(dd,J＝8.7,1.2Hz,2H),7.31–7.27(m,2H),7.23(ddd,J＝7.7,6.1,1.7Hz,2H),7.11(ddt,J＝8.6,7.2,1.2Hz,1H),7.03(t,J＝7.8Hz,1H),6.96–6.91(m,2H),6.84–6.74(m,2H),5.53(s,1H),3.95(s,3H),3.65(s,3H),2.33(s,3H).13C NMR(126MHz,CDCl3)167.78,158.88,157.26,148.13,144.84,137.51,130.00,129.18,128.60,127.64,124.79,123.43,122.68,120.52,118.71,117.82,112.35,109.53,91.15,56.13,55.08,48.11,12.95 by chiral HPLC analysis, with the specific conditions (IA, 7% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 15.5min, tR(times) 17.5min, 87:13dr, 97% ee.
Example 14:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (2-methoxyphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 39.8mg (yield 96%),1H NMR(500MHz,CDCl3)7.52–7.44(m,2H),7.28–7.18(m,4H),7.10–7.06(m,1H),7.00(dd,J＝8.1,7.5Hz,1H),6.93–6.88(m,2H),6.79(dt,J＝7.6,1.1Hz,1H),6.74(dd,J＝8.2,1.1Hz,1H),5.50(s,1H),3.92(s,3H),3.62(s,3H),2.30(s,3H).13C NMR(126MHz,CDCl3)167.81,158.92,157.29,148.17,144.87,137.54,130.05,129.22,128.64,127.67,124.83,123.46,122.71,120.56,118.75,117.86,112.37,109.56,91.19,56.16,55.11,48.14,12.99. analysis by chiral HPLC, with the specific conditions (IC, 15% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 26min, tR(times) ═ 20.2min, 95:15dr, 98% ee.
Example 15:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (3, 4-methyleneoxyphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operation were the same as in example 1 to give 41.1mg (yield 96%),1H NMR(500MHz,CDCl3)7.47(dt,J＝8.7,1.6Hz,2H),7.31–7.27(m,2H),7.14–7.10(m,1H),7.01(t,J＝7.8Hz,1H),6.92(d,J＝8.1Hz,1H),6.79–6.68(m,4H),5.89(dd,J＝9.9,1.4Hz,2H),5.07(s,1H),3.95(s,3H),2.36(s,3H).13C NMR(126MHz,CDCl3)168.07,158.13,148.04,147.75,147.66,144.80,137.18,128.63,128.03,127.42,125.14,123.02,122.68,118.97,117.42,112.69,109.49,108.13,101.11,92.18,56.16,55.10,13.05 by chiral HPLC analysis, with the specific conditions (IA, 4% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 37.0min, tR(times) 39.8min, 80:20dr, 94% ee.
Example 16:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (1-naphthyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operation were the same as in example 1 to give 41.7mg (yield 96%),1H NMR(500MHz,CDCl3)7.83–7.73(m,3H),7.43–7.35(m,3H),7.26–7.22(m,1H),7.14–7.08(m,2H),7.06–6.97(m,4H),6.93(d,J＝8.1Hz,1H),6.78(d,J＝7.5Hz,1H),5.89(s,1H),3.95(s,3H),2.41(s,3H).13C NMR(125MHz,CDCl3)167.46,158.71,148.16,144.95,136.81,133.54,131.88,131.62,129.12,128.72,128.49,128.38,128.18,126.48,125.63,125.25,125.13,123.16,121.40,119.25,118.06,112.51,90.88,56.14,50.36,13.13, by chiral HPLC, with the specific conditions (IA, 15% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 15.8min, tR10.6min, 96:4dr, 99% ee.
Example 17:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (2-naphthyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operation were the same as in example 1 to give 32.6mg (yield 75%),1H NMR(500MHz,CDCl3)7.83–7.73(m,3H),7.43–7.35(m,3H),7.26–7.22(m,1H),7.14–7.08(m,2H),7.06–6.97(m,4H),6.93(d,J＝8.1Hz,1H),6.78(d,J＝7.5Hz,1H),5.89(s,1H),3.95(s,3H),2.41(s,3H).13C NMR(125MHz,CDCl3)171.04,158.41,147.67,145.05,137.65,133.20,132.46,128.95,127.93,127.75,127.39,127.19,126.65,126.55,125.99,125.50,123.19,119.06,117.91,91.82,56.87,56.20,14.57 analysis by chiral HPLC, with the specific conditions (OD-H, 50% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 9.5min, tR35.5min, 68:32dr, 99% ee.
Example 18:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (2-furyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 34.4mg (yield 92%) of the product,1H NMR(500MHz,CDCl3)7.63(dt,J＝8.8,1.6Hz,2H),7.36–7.29(m,3H),7.19–7.13(m,1H),7.05–7.00(m,1H),6.92(t,J＝7.4Hz,2H),6.34–6.28(m,2H),5.34(s,0H),5.23(s,1H),3.94(s,3H),2.33(s,3H).13C NMR(126MHz,CDCl3)167.53,157.88,148.91,144.85,142.92,137.40,128.87,128.70,125.74,125.16,123.10,118.94,117.30,113.05,110.74,109.58,90.42,56.19,48.56,12.97, by chiral HPLC, with the specific conditions (IC, 15% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 26min, tR17.6min, 83:17dr, 85% ee.
Example 19:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (2-thienyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 35.5mg (yield 91%),1H NMR(500MHz,CDCl3)7.50(dt,J＝8.8,1.6Hz,2H),7.32–7.27(m,2H),7.21(dd,J＝5.1,1.2Hz,1H),7.15–7.11(m,1H),7.04–7.00(m,2H),6.98–6.89(m,3H),5.42(s,1H),3.95(s,3H),2.37(s,3H).13C NMR(126MHz,CDCl3)167.62,157.72,147.70,144.77,137.11,135.90,128.64,127.79,127.61,127.16,125.83,125.20,123.09,119.03,117.32,113.05,91.90,56.19,50.14,13.05. analysis by chiral HPLC, with the specific conditions (IC, 15% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 25.2min, tR19.2min, 87:13dr, 92% ee.
Example 20:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (methyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 18.0mg (yield 56%),1H NMR(500MHz,CDCl3)7.92–7.82(m,2H),7.45–7.36(m,2H),7.24–7.16(m,1H),6.96(td,J＝7.8,5.9Hz,1H),6.87–6.75(m,2H),3.90(s,3H),3.87(q,J＝7.5Hz,1H),2.20(s,3H),1.43(d,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)168.52,158.98,146.64,144.57,137.64,130.66,128.87,125.22,122.94,118.73,115.83,112.26,91.35,56.12,43.15,14.09,12.94, by chiral HPLC analysis, with the specific conditions (IC, 10% iPrOH in hexane, flow rate 1.0ml/min): tR(main) 12.5min, tR49.5min, 66:34dr, 60% ee.
Example 21:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (ethyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 21.8mg (yield 65%) of the product,1H NMR(500MHz,CDCl3)7.86–7.83(m,2H),7.42–7.37(m,2H),7.21–7.17(m,1H),6.94(dd,J＝8.6,7.1Hz,1H),6.83(d,J＝8.1Hz,2H),3.89(s,3H),3.75–3.66(m,1H),2.20(s,3H),2.04–1.96(m,2H),0.99(t,J＝7.5Hz,3H).13C NMR(125MHz,CDCl3)168.37,159.41,146.54,144.65,137.63,130.17,128.90,125.27,122.72,118.82,116.30,112.18,90.55,56.09,50.37,23.37,12.97,12.38 by chiral HPLC analysis, with specific conditions (IC, 10% iPrOH in hexane, flow rate 1.0ml/min): tR(main ═12.6min,tR(times) 61.8min, 83:17dr, 60% ee.
Example 22:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 2- (phenyl (p-toluenesulfonyl) methyl) phenol, and other reaction conditions and operation were the same as in example 1,
33.2mg (yield 94%) of the product are obtained,1H NMR(500MHz,CDCl3)7.26–7.23(m,3H),7.20–7.11(m,8H),6.99–6.94(m,3H),5.01(s,1H),2.26(s,3H).13C NMR(125MHz,CDCl3)168.44,160.01,158.56,136.99,134.06,129.46,129.07,128.60,128.51,128.48,128.15,126.62,125.62,125.19,122.21,119.01,110.51,92.02,55.15,13.05 by chiral HPLC analysis, with the specific conditions (IA, 10% iPrOH in hexane, flow rate 1.0ml/min): tR(main) 11.3min, tR7.0min, 72:18dr, 50% ee.
Example 23:
the difference from the embodiment 1 is that: the substrate-substituted phenol used was 2- (2-methoxyphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 36.9mg (yield 96%),1H NMR(500MHz,CDCl3)7.48–7.42(m,2H),7.22–7.16(m,4H),7.12–7.06(m,2H),7.03–6.92(m,3H),6.84(td,J＝7.5,1.1Hz,1H),6.67(d,J＝8.2Hz,1H),5.38(s,1H),3.53(s,3H),2.20(s,3H).13C NMR(125MHz,CDCl3)168.16,159.88,159.27,157.27,137.57,129.88,129.24,129.20,128.66,126.40,125.97,124.79,123.71,121.94,120.58,118.61,110.48,109.55,90.87,55.11,47.84,12.94, by chiral HPLC analysis, with the specific conditions (ID, 20% iPrOH in hexane, flow rate 1.0ml/min): tR(main) ═ 13.3min, tR(times) 20.5min, 83:17dr,61％ee。
Example 24:
the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2- (4-fluorophenyl) -5-methylpyrazolone, and other reaction conditions and operation were the same as in example 1 to obtain 33.4mg (yield 83%),1H NMR(500MHz,CDCl3)7.31–7.22(m,7H),7.05–6.99(m,1H),6.93(t,J＝8.7Hz,3H),6.78(d,J＝7.5Hz,1H),5.16(s,1H),3.96(s,3H),2.40(s,3H).13C NMR(126MHz,CDCl3)168.00,160.01(d, J ═ 244.6Hz),158.29,148.25,144.86,133.72,133.07(d, J ═ 2.7Hz),129.10,128.53,128.51,127.73,123.09,120.96(d, J ═ 8.1Hz),117.49,115.36(d, J ═ 22.7Hz),112.71,92.35,56.21,55.42,13.10. analysis by chiral HPLC, specific conditions were (IA, 10% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 10.4min, tR9.7min, 89:11dr, 98% ee.
Example 25:
the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2- (4-bromophenyl) -5-methylpyrazolone, and the other reaction conditions and operating procedures were the same as in example 1, whereby 36.5mg (yield 79%) of the product was obtained,1H NMR(500MHz,CDCl3)7.39–7.33(m,2H),7.30–7.25(m,5H),7.22(dd,J＝7.5,1.9Hz,2H),7.02(t,J＝7.8Hz,1H),6.94(s,1H),6.78(d,J＝7.5Hz,1H),5.15(s,1H),3.96(s,3H),2.40(s,3H).13C NMR(126MHz,CDCl3)168.01,158.50,148.17,144.83,136.05,133.60,131.61,129.02,128.55,128.50,127.64,123.12,120.25,117.99,117.46,112.70,92.34,56.18,55.43,13.11. analysis by chiral HPLC, with the specific conditions (AD-H, 10% iPrOH in hexane, flow rate 1.0ml/min): tR(main) 10.1min, tR(times) 8.4min, 99:1dr, 98% ee.
Example 26:
the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2- (4-bromophenyl) -5-methylpyrazolone, and the other reaction conditions and operating procedures were the same as in example 1, to give 40.7mg (yield 88%) of the product,1H NMR(500MHz,CDCl3)7.55(t,J＝2.0Hz,1H),7.33(ddd,J＝8.2,2.1,1.0Hz,1H),7.28–7.24(m,3H),7.21–7.16(m,3H),7.07(t,J＝8.1Hz,1H),7.02–6.98(m,1H),6.92(d,J＝8.2Hz,1H),6.76(dt,J＝7.6,1.1Hz,1H),5.13(s,1H),3.94(s,3H),2.38(s,3H).13C NMR(125MHz,CDCl3)168.09,158.58,148.15,144.84,138.12,133.52,129.94,129.04,128.61,128.56,127.99,127.67,123.15,122.26,121.59,117.47,117.11,112.71,92.40,56.21,55.47,13.14, by chiral HPLC, with specific conditions (IC, 10% iPrOH in hexane, flow rate 1.0ml/min): tR(main) ═ 13.3min, tR10.8min, 98:2dr, 98% ee.
Example 27:
the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2- (2, 3, 4,5, 6-pentafluorophenyl) -5-methylpyrazolone, other reaction conditions and operating procedures were the same as in example 1, giving 42.9mg (yield 91%),1H NMR(500MHz,CDCl3)7.37–7.32(m,3H),7.26–7.21(m,2H),7.03(t,J＝7.8Hz,1H),6.94(d,J＝8.1Hz,1H),6.77(dt,J＝7.6,1.1Hz,1H),5.20(s,1H),3.98(s,3H),2.38(s,3H),1.30(d,J＝14.3Hz,1H).13C NMR(126MHz,CDCl3)168.69,159.88,147.81,144.89,144.81-144.63(m),142.76-142.57(m),140.67-140.40(m),138.81-138.51(m),136.79-136.51(m),133.21,129.18,128.74,128.73,127.70,123.34,117.41,112.60,111.50-111.24(m),90.51,56.14,55.50,13.13. analysis by chiral HPLC, specific conditions are (IC, 10% iPrOH in hexane, flow rate 1.0ml/min):tR(main) ═ 19.3min, tR17.9min, 90:10dr, 99% ee.
Example 28:
the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2- (4-methylphenyl) -5-methylpyrazolone, and the other reaction conditions and operating procedures were the same as in example 1, giving 33.4mg (yield 84%),1H NMR(500MHz,CDCl3)7.30–7.23(m,5H),7.19(d,J＝8.5Hz,2H),7.03(dd,J＝20.3,8.1Hz,3H),6.93(d,J＝8.1Hz,1H),6.79(d,J＝7.5Hz,1H),5.15(s,1H),3.96(s,3H),2.39(s,3H),2.28(s,3H).13C NMR(126MHz,CDCl3)167.90,157.89,148.29,144.82,134.94,134.53,133.81,129.12,128.46,128.43,127.89,122.95,119.26,117.48,112.66,92.31,56.19,55.30,20.88,13.08. analysis by chiral HPLC, with the specific conditions (IC, 10% iPrOH in hexane, flow rate 1.0ml/min): tR(main) 22.3min, tR(times) 20.3min, 92:8dr, 98% ee.
Example 29:
the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2- (2-ethylphenyl) -5-methylpyrazolone, and the other reaction conditions and operating procedures were the same as in example 1, giving 33.6mg (yield 81%),1H NMR(500MHz,CDCl3)7.33–7.30(m,2H),7.26–7.19(m,7H),7.08–7.04(m,1H),7.00–6.95(m,1H),6.90(d,J＝8.1Hz,1H),6.75(dt,J＝7.5,1.1Hz,1H),5.22(s,1H),3.93(s,3H),3.08(hept,J＝7.0Hz,1H),1.49(d,J＝6.8Hz,3H),1.41(d,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3)168.26,164.80,148.36,144.91,137.13,134.01,129.12,128.53,128.43,128.40,127.93,125.07,122.85,119.12,117.55,112.94,93.13,56.31,55.53,28.18,21.30,20.06 analysis by chiral HPLC, with the specific conditions (ID, 7% iPrOH in h)exane,flow rate 1.0ml/min):tR(main) 21.2min, tR24.9min, 85:815dr, 95% ee.
Example 30:
the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2- (2-naphthyl) -5-methylpyrazolone, and other reaction conditions and operation procedures were the same as in example 1 to give 41.7mg (yield 96%),1H NMR(500MHz,CDCl3)8.38(d,J＝1.9Hz,1H),8.11(dd,J＝8.9,2.2Hz,1H),7.94–7.84(m,3H),7.50(dddd,J＝20.9,8.1,6.9,1.3Hz,2H),7.38–7.33(m,3H),7.24–7.20(m,2H),7.10–7.06(m,1H),6.99–6.89(m,2H),5.40(t,J＝0.9Hz,1H),3.97(s,3H),1.65(s,3H).13C NMR(126MHz,CDCl3)171.12,158.61,147.58,144.95,135.19,134.99,133.42,131.16,128.99,128.79,128.47,128.21,127.98,127.60,127.28,126.53,125.50,123.10,118.23,117.80,116.15,112.61,91.83,56.71,56.13,14.43, by chiral HPLC analysis, with the specific conditions (ID, 10% iPrOH in hexane, flow rate 1.0ml/min): tR(main) 20.9min, tR16.3min, 80:20dr, 94% ee.
Example 31:
the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2-cyclohexyl-5-methylpyrazolone, and the other reaction conditions and operating procedures were the same as in example 1, giving 35.1mg (yield 90%) of the product,1H NMR(500MHz,CDCl3)7.30–7.27(m,3H),7.18(dd,J＝6.6,2.9Hz,2H),6.96(dd,J＝8.1,7.5Hz,1H),6.88(d,J＝8.1Hz,1H),6.73(dt,J＝7.5,1.1Hz,1H),,5.03(s,1H),3.93(s,3H),3.52–3.44(m,1H),2.27(s,3H),1.75–1.65(m,2H),1.62–1.51(m,3H),1.27–1.00(m,5H),0.88–0.81(m,1H).13C NMR(125MHz,CDCl3)168.59,156.35,148.35,144.75,133.82,129.20,128.35,128.23,128.12,122.69,117.34,112.33,92.45,56.06,54.88,51.98,30.32,29.73,25.21,25.19,25.09,12.97, analysis by chiral HPLC, with specific conditions (ID, 10% iPrOH in hexane, flow rate 1.0ml/min): tR(main) 11.2min, tR9.4min, 82:18dr, 98% ee.
Example 32:
the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2-phenyl-5-ethylpyrazolone, and the other reaction conditions and operating procedures were the same as in example 1, giving 36.6mg (yield 92%),1H NMR(500MHz,CDCl3)7.39–7.34(m,2H),7.30–7.21(m,7H),7.09(t,J＝7.4Hz,1H),7.01(t,J＝7.8Hz,1H),6.93(d,J＝8.1Hz,1H),6.78(d,J＝7.5Hz,1H),5.17(s,1H),3.96(s,3H),2.77(dd,J＝7.4,3.7Hz,2H),1.44(t,J＝7.4Hz,3H).13C NMR(126MHz,CDCl3)168.29,161.96,148.29,144.85,137.16,133.96,129.11,128.56,128.47,128.43,127.93,125.11,122.94,119.12,117.51,112.74,92.51,56.24,55.55,20.74,9.41. analysis by chiral HPLC, with the specific conditions (IA, 7% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 9.8min, tR9.4min, 94:6dr, 97% ee.
Example 33:
the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2-phenyl-5-n-propylpyrazolone, and other reaction conditions and operation were the same as in example 1, whereby 37.5mg (yield 91%) of the product was obtained,1H NMR(500MHz,CDCl3)7.35(dt,J＝8.9,1.8Hz,2H),7.29–7.23(m,7H),7.12–7.07(m,1H),7.01(t,J＝7.8Hz,1H),6.93(dt,J＝8.1,1.0Hz,1H),6.78(dt,J＝7.6,1.1Hz,1H),5.18(s,1H),3.96(s,3H),2.76–2.64(m,2H),1.95(h,J＝7.4Hz,2H),1.14(t,J＝7.4Hz,3H).13C NMR(126MHz,CDCl3)168.23,160.95,148.30,144.83,137.11,133.93,129.11,128.54,128.45,128.41,127.91,125.09,123.10,119.09,117.49,112.75,92.60,56.19,55.48,29.29,18.64,14.05. analysis by chiral HPLC, with the specific conditions (IA, 7% iPrOH in hexane, flow rate 0.7ml/min): tR(main) 9.0min, tR8.5min, 91:9dr, 87% ee.
Example 34:
the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2-phenyl-5-isopropyl pyrazolone, and other reaction conditions and operation procedures were the same as in example 1 to give 37.0mg (yield 90%),1H NMR(500MHz,CDCl3)7.33–7.30(m,2H),7.26–7.19(m,7H),7.08–7.04(m,1H),7.00–6.95(m,1H),6.90(d,J＝8.1Hz,1H),6.75(dt,J＝7.5,1.1Hz,1H),5.22(s,1H),3.93(s,3H),3.08(hept,J＝7.0Hz,1H),1.49(d,J＝6.8Hz,3H),1.41(d,J＝7.0Hz,3H).13C NMR(125MHz,CDCl3)168.26,164.80,148.36,144.91,137.13,134.01,129.12,128.53,128.43,128.40,127.93,125.07,122.85,119.12,117.55,112.94,93.13,56.31,55.53,28.18,21.30,20.06. analysis by chiral HPLC, with the specific conditions (ID, 5% iPrOH in hexane, flow rate 1.0ml/min): tR(main) 9.1min, tR10.9min, 93:7dr, 95% ee.
Example 35:
the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2-phenyl-5-phenylpyrazolone, and other reaction conditions and operation were the same as in example 1 to give 38.4mg (yield 86%),1H NMR(500MHz,CDCl3)1H NMR(500MHz,CDCl3)8.10–8.04(m,2H),7.54–7.47(m,3H),7.41–7.36(m,2H),7.30–7.25(m,5H),7.22(dd,J＝7.5,2.0Hz,2H),7.16–7.11(m,1H),7.09–7.03(m,1H),7.00(d,J＝8.1Hz,1H),6.80(dt,J＝7.4,1.2Hz,1H),5.42(s,1H),4.00(s,3H).13C NMR(125MHz,CDCl3)168.53,155.48,148.20,145.16,136.91,133.68,130.97,129.19,129.17,129.15,128.61,128.48,127.85,126.81,125.52,123.12,119.50,117.69,113.12,92.89,57.12,56.40 by chiral HPLC analysis, with the specific conditions (ID, 10% iPrOH in hexane, flow rate 1.0ml/min): tR(main) 11.4min, tR12.7min, 93:7dr, 95% ee.
Claims (6)
1. A synthetic method of a chiral 4-spiro pyrazole compound shown in a formula (3) is characterized by comprising the following steps: the synthesis method comprises the following steps:
in a water-oil two-phase system, taking a compound shown in a formula (1) and a compound shown in a formula (2) as raw materials, reacting at 20-30 ℃ under the action of an acid-binding agent and a chiral catalyst to obtain a reaction solution, and performing post-treatment to obtain a chiral 4-spiro pyrazole compound shown in a formula (3); the ratio of the amount of the compound represented by the formula (1) to the amount of the compound represented by the formula (2) and the acid-binding agent is 0.2-5: 1: 0.5 to 20; the amount ratio of the chiral catalyst to the compound represented by the formula (1) is 0.01 to 100: 100, respectively; the chiral catalyst is a bifunctional tertiary amine-azodicarbonic acid catalyst, which comprises a tertiary amine group containing a hydrogen bond donor azodicarbonic acid group and Lewis base function; the acid-binding agent is inorganic alkali; the water-oil two-phase system is prepared by mixing water and an organic solvent in a volume ratio of 1: 0.05-10 parts by weight;
in the formula (1), Ts represents a p-toluenesulfonyl group;
in the formula (1) or (3),
R1is H, methoxy, ethoxy or halogen;
R2is C1-20Alkyl, furyl, thienyl, naphthyl, phenyl or phenyl substituted by one or more substituents each independently being methyl, methoxy, tri-nFluoromethyl or halogen;
in the formula (2) or the formula (3),
R3is C1-20Alkyl, naphthyl, phenyl or phenyl substituted with one or more substituents each independently being methyl, ethyl or halogen,
R4is C1-20Alkyl or phenyl of (a);
the chiral catalyst is one of the following compounds:
in the formulae (4), (5) and (6),
R5、R8、R11each independently is C1～C20Or phenyl or benzyl substituted with one or more substituents each independently being trifluoromethyl, nitro or halogen;
R6、R7、R9or R10Each independently is C1～C10Alkyl groups of (a);
R12is ethyl or vinyl;
R13is H, hydroxyl or methoxyl.
2. The method of claim 1, wherein: the chiral catalyst is selected from one of the following:
3. the method of claim 1, wherein: the ratio of the amount of the compound represented by the formula (1) to the amount of the compound represented by the formula (2) and the acid-binding agent is 0.5-2: 1:1 to 10.
4. The method of claim 1, wherein: in the water-oil two-phase system, the organic solvent is selected from dichloromethane, chloroform, 1, 2-dichloroethane, diethyl ether, toluene, ethyl acetate or isopropyl acetate.
5. The method of claim 1, wherein: the acid-binding agent is sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide or disodium hydrogen phosphate.
6. The method of claim 1, wherein: the post-treatment method of the reaction solution comprises the following steps: after the reaction is finished, separating the reaction liquid, taking the organic phase, concentrating under reduced pressure, and then performing silica gel column chromatography separation, wherein the volume ratio of petroleum ether to ethyl acetate is 1-30: the mixed solution of 1 is used as eluent to carry out gradient elution, eluent containing a target compound is collected, the solvent is evaporated and dried, and the chiral 4-spiro pyrazole compound shown in the formula (3) is obtained.
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