CN119039348A - Chiral biaryl nitrogen-phosphorus ligand compound and synthetic method and application thereof - Google Patents
Chiral biaryl nitrogen-phosphorus ligand compound and synthetic method and application thereof Download PDFInfo
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- CN119039348A CN119039348A CN202411203776.3A CN202411203776A CN119039348A CN 119039348 A CN119039348 A CN 119039348A CN 202411203776 A CN202411203776 A CN 202411203776A CN 119039348 A CN119039348 A CN 119039348A
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- Prior art keywords
- reaction
- hydrogen
- phenyl
- alkoxy
- nitrogen
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 70
- 239000003446 ligand Substances 0.000 title claims abstract description 63
- -1 biaryl nitrogen-phosphorus Chemical compound 0.000 title claims abstract description 58
- 238000010189 synthetic method Methods 0.000 title description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 47
- 239000001257 hydrogen Substances 0.000 claims abstract description 47
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 42
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 25
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 22
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 22
- 150000002367 halogens Chemical class 0.000 claims abstract description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 21
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 20
- 125000003118 aryl group Chemical group 0.000 claims abstract description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 14
- 150000001345 alkine derivatives Chemical group 0.000 claims abstract description 13
- 238000005859 coupling reaction Methods 0.000 claims abstract description 11
- 238000007259 addition reaction Methods 0.000 claims abstract description 6
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 6
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 claims abstract 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 20
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 14
- 238000006722 reduction reaction Methods 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 claims description 12
- 239000005052 trichlorosilane Substances 0.000 claims description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 238000010898 silica gel chromatography Methods 0.000 claims description 10
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 9
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 9
- 238000006555 catalytic reaction Methods 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- 239000012453 solvate Substances 0.000 claims description 9
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 8
- 238000005886 esterification reaction Methods 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 150000001502 aryl halides Chemical class 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 125000003944 tolyl group Chemical group 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- 150000007514 bases Chemical class 0.000 claims description 5
- 239000003480 eluent Substances 0.000 claims description 5
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 claims description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 3
- 150000004677 hydrates Chemical class 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 239000002244 precipitate Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000003725 azepanyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- LGVUAXNPXVXCCW-UHFFFAOYSA-M cesium;2,2-dimethylpropanoate Chemical compound [Cs+].CC(C)(C)C([O-])=O LGVUAXNPXVXCCW-UHFFFAOYSA-M 0.000 claims description 2
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 2
- 238000010790 dilution Methods 0.000 claims description 2
- 239000012895 dilution Substances 0.000 claims description 2
- 238000010828 elution Methods 0.000 claims description 2
- 125000004494 ethyl ester group Chemical group 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- 150000003951 lactams Chemical class 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical group [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 150000002527 isonitriles Chemical class 0.000 claims 5
- 238000007074 heterocyclization reaction Methods 0.000 claims 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- XMSZANIMCDLNKA-UHFFFAOYSA-N methyl hypofluorite Chemical compound COF XMSZANIMCDLNKA-UHFFFAOYSA-N 0.000 claims 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 9
- 229910021589 Copper(I) bromide Inorganic materials 0.000 abstract description 7
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 abstract description 7
- 150000003934 aromatic aldehydes Chemical class 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 125000002252 acyl group Chemical group 0.000 abstract description 2
- 230000009257 reactivity Effects 0.000 abstract description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical group OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 78
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- 229910052799 carbon Inorganic materials 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 238000001228 spectrum Methods 0.000 description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 12
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 229910052698 phosphorus Inorganic materials 0.000 description 12
- 239000011574 phosphorus Substances 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 238000004679 31P NMR spectroscopy Methods 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000011914 asymmetric synthesis Methods 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 6
- 238000010200 validation analysis Methods 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 150000003248 quinolines Chemical class 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical group 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 3
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 3
- YUWBVKYVJWNVLE-UHFFFAOYSA-N [N].[P] Chemical class [N].[P] YUWBVKYVJWNVLE-UHFFFAOYSA-N 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 2
- WXYYACUWOMKZQC-UHFFFAOYSA-N 1-benzyl-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=CC=C1 WXYYACUWOMKZQC-UHFFFAOYSA-N 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-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
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- 150000005347 biaryls Chemical group 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 229920001971 elastomer Polymers 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 2
- NHVWTZOWDLOBBS-UHFFFAOYSA-N (2-methoxynaphthalen-1-yl)boronic acid Chemical compound C1=CC=CC2=C(B(O)O)C(OC)=CC=C21 NHVWTZOWDLOBBS-UHFFFAOYSA-N 0.000 description 1
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 1
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 1
- DPRJPRMZJGWLHY-HNGSOEQISA-N (e,3r,5s)-7-[5-(4-fluorophenyl)-3-propan-2-yl-1-pyrazin-2-ylpyrazol-4-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)/C=C/C=1C(C(C)C)=NN(C=2N=CC=NC=2)C=1C1=CC=C(F)C=C1 DPRJPRMZJGWLHY-HNGSOEQISA-N 0.000 description 1
- MSQCQINLJMEVNJ-UHFFFAOYSA-N 1-chloroisoquinoline Chemical compound C1=CC=C2C(Cl)=NC=CC2=C1 MSQCQINLJMEVNJ-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- QUMCIHKVKQYNPA-RUZDIDTESA-N C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC Chemical compound C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC QUMCIHKVKQYNPA-RUZDIDTESA-N 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 238000005937 allylation reaction Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000008365 aromatic ketones Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000000110 cooling liquid Substances 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 1
- 238000005828 desilylation reaction Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000005485 electric heating Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- FPULFENIJDPZBX-UHFFFAOYSA-N ethyl 2-isocyanoacetate Chemical compound CCOC(=O)C[N+]#[C-] FPULFENIJDPZBX-UHFFFAOYSA-N 0.000 description 1
- 239000003777 experimental drug Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000000524 functional group Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- MUJNAWXXOJRNGK-UHFFFAOYSA-N n-[3-(6-methyl-1,2,3,4-tetrahydrocarbazol-9-yl)propyl]cyclohexanamine Chemical compound C1=2CCCCC=2C2=CC(C)=CC=C2N1CCCNC1CCCCC1 MUJNAWXXOJRNGK-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PFGVNLZDWRZPJW-OPAMFIHVSA-N otamixaban Chemical compound C([C@@H](C(=O)OC)[C@@H](C)NC(=O)C=1C=CC(=CC=1)C=1C=C[N+]([O-])=CC=1)C1=CC=CC(C(N)=N)=C1 PFGVNLZDWRZPJW-OPAMFIHVSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/62—Isoquinoline or hydrogenated isoquinoline ring systems
-
- 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
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
- B01J31/2447—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/08—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms with acylated ring nitrogen atom
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
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- C07F7/02—Silicon compounds
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- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
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Abstract
The invention relates to chiral biaryl nitrogen-phosphorus ligand compounds, a synthesis method and application thereof, wherein in the general formula I, R 1 is selected from aryl, alkyl, alkoxy, halogen and hydrogen, and R 2 is selected from acyl substituentR 6 is selected from alkoxy and nitrogen heterocyclic group, R 3 is selected from hydrogen, alkyl, phenyl and substituted phenyl, R 4 is selected from halogen and hydrogen, R 5 is selected from aryl, substituted aryl and alkoxy, R 1 is selected from aryl, alkyl, alkoxy, halogen and hydrogen in general formulas II-III, R 2 is selected from alkyl, trifluoromethanesulfonic acid group and hydrogen, R 3 is selected from hydrogen, alkyl, phenyl and substituted phenyl, R 4 is selected from halogen and hydrogen, R 5 is selected from aryl, substituted aryl and alkoxy, the chiral ligand of ligand 9a as A 3 coupling reaction can be well matched with cuprous bromide to compensate the existing terminal alkyne substrate only to be a substrate with larger steric hindrance group, the reactivity of aromatic aldehyde is low, the enantioselectivity is controlled poorly and the like, and the ligand 10b can be matched with cuprous bromide to catalyze the enantioselective addition reaction of alkyne to quinoline salt.
Description
Technical Field
The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to chiral biaryl nitrogen-phosphorus ligand compounds, and a synthetic method and application thereof.
Background
The information disclosed in the background of the invention is only for enhancement of understanding of the general background of the invention and is not necessarily to be taken as an admission or any form of suggestion that this information forms the prior art already known to a person of ordinary skill in the art.
Chiral ligands play an important role in the regulation of the reactivity and enantioselectivity of asymmetric catalytic reactions. Therefore, the development of efficient synthetic methods for chiral ligands is of great importance. Quinap is a class of classical axial chiral biaryl nitrogen phosphorus ligands designed and synthesized by the Brown team. Since the discovery in 1993 Quinap has become an important subclass of nitrogen-phosphorus ligands, the construction of an axial chiral biaryl backbone from 1-chloroisoquinoline and (2-methoxynaphthalen-1-yl) boronic acid by palladium-catalyzed Suzuki coupling reactions, followed by a series of functional group transformations to finally give the racemic Quinap, and finally resolution of the racemate by using stoichiometric chiral palladium complexes to finally give optically pure Quinap, which shows unique steric control in several enantioselective reactions such as hydroboration, allylation, cycloaddition, a 3 coupling reactions, etc. Some developments have also been made in the approach to obtain optically pure Quinap, such as chiral sulfoxide-assisted strategies (Synlett 2007,17, 2655-2658), palladium-catalyzed dynamic kinetic phosphorylation reactions (j.am. Chem. Soc.2013,135,16829-16832,ACS Catal.2016,6,3955-3964, adv. Synth. Catalyst.2019, 361, 441-444) and catalytic enantioselective oxynitrides (angel. Chem. Int. Ed.2023,62, e 202309272).
At present, quinap derivatives are not fully developed, so that the derivatives are used as chiral ligands and have great limitation in some asymmetric catalytic reactions, and the characteristics of low reaction activity, large substrate limitation and the like are shown. Accordingly, there is a great interest in developing a new method for efficient de novo synthesis Quinap. The synthesis strategy can conveniently construct a series Quinap derivative with various structures and substituents, and has important significance for researching the relationship between the space effect and the electronic effect of the ligand in asymmetric catalytic reaction.
Disclosure of Invention
Aiming at the requirements of the prior art, the invention aims to provide a chiral biaryl nitrogen phosphorus ligand compound, a synthesis method and application thereof, and the invention proves that the biaryl nitrogen phosphorus ligand (1) with multiple chiralities has excellent stereoselectivity effect in asymmetric three-component coupling reaction of terminal alkyne, aldehyde and amine, which is obviously superior to Quinap, and (2) has excellent stereoselectivity effect in enantioselective addition reaction of copper-catalyzed alkyne to quinoline salt, which is obviously superior to Quinap.
Specifically, the invention provides the following technical scheme:
In a first aspect of the present invention, there is provided a class of biaryl nitrogen phosphorus ligand compounds having axial chirality, or pharmaceutically acceptable salts, solvates and hydrates thereof, said biaryl nitrogen phosphorus ligand compounds having the structure shown in formula I:
Wherein R 1 is a substituent group on the benzene ring of the isoquinoline part of the parent structure, the number of the substituent groups is one or two, and R 1 is selected from aryl, alkyl, alkoxy, halogen and hydrogen;
R 2 is selected from acyl substituents R 6 is selected from alkoxy and nitrogen heterocyclic;
R 3 is selected from hydrogen, alkyl, phenyl, and substituted phenyl;
R 4 is selected from halogen and hydrogen;
r 5 is selected from aryl, substituted aryl, and alkoxy.
Preferably, the R 1 is selected from the group consisting of hydrogen, C 1-C3 alkyl, C 1-C3 alkoxy, halogen, and phenyl.
Preferably, when R 1 is phenyl, R 1 shares two carbon atoms with the benzene ring to form a fused ring.
Preferably, when the number of R 1 is two, R 1 is selected from C 1-C3 alkyl or phenyl.
Preferably, the R 1 is selected from hydrogen, methyl, methoxy, fluoro, chloro and bromo.
Preferably, the substitution position of R 1 is selected from the group consisting of positions 5, 6, 7 and 8 on isoquinoline, and when the number of R 1 is one, the preferred positions are positions 5 and 7, and when the number of R 1 is two, the preferred positions are positions 6 and 8.
Preferably, the R 2 is selected from one of ethyl ester group, lactam and heteroatom lactam.
Preferably, the R 3 is selected from hydrogen, phenyl and phenyl substituted with at least one of methyl, methoxy, halogen.
Preferably, R 3 is selected from the group consisting of phenyl, 4-tolyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, and hydrogen.
Preferably, the R 4 is selected from 6-bromo and hydrogen.
Preferably, R 5 is selected from the group consisting of C 1-C3 alkoxy, phenyl, substituted phenyl and naphthyl, wherein the substituted phenyl is substituted with at least one group selected from the group consisting of C 1-C4 alkyl, C 1-C3 alkoxy, halogen, the preferred substitution positions being positions 3, 4 and 5, wherein the preferred substitution position is position 4 when the substituent is one, and positions 3 and 5 when the substituent is two;
preferably, R 5 is selected from ethoxy, phenyl, naphthyl, methylphenyl, methoxyphenyl, tert-butylphenyl, chlorophenyl.
Preferably, the R 6 is selected from the group consisting of C 1-C3 alkoxy and five to seven membered nitrogen heterocyclyl.
Preferably, R 6 is selected from ethoxy, piperidinyl, pyrrolidinyl, azepanyl, morpholinyl, thiomorpholinyl, wherein the carbonyl group is attached with oxygen and nitrogen.
Preferably, the pharmaceutically acceptable salts are those which are group-modified to improve the physicochemical properties of the chiral biaryl nitrogen phosphorus ligand, typically those formed from the chiral biaryl nitrogen phosphorus ligand with inorganic salts such as hydrochloric acid, sulfuric acid, nitric acid or hydrobromic acid, and with organic acids such as methanesulfonic acid, toluenesulfonic acid, citric acid or trifluoroacetic acid.
Preferably, the compounds of formula I include the following structures:
In a second aspect of the present invention, there is provided a method for preparing the chiral biaryl nitrogen phosphorus ligand compound of the first aspect, comprising the steps of:
S1, mixing an isonitrile compound, an aryl halide, an alkaline compound and a catalyst in an organic solvent to perform a heterocyclic reaction;
s2, removing the organic solvent after the reaction, and purifying to obtain the compound shown in the general formula I.
Preferably, in the step S1, the molar ratio of the isonitrile compound to the aryl halide is 1:1.5-1:2.
Preferably, in step S1, the isonitrile compound isThe aryl halide is
Preferably, in step S1, the alkaline compound is selected from one or more of cesium carbonate, cesium pivalate, potassium carbonate, and sodium carbonate, and more preferably, the alkaline compound is cesium carbonate.
Preferably, in the step S1, the molar ratio of the basic compound to the isonitrile compound is 1-1.5:1, and more preferably, the molar ratio of the basic compound to the isonitrile compound is 1.2:1.
Preferably, in step S1, the organic solvent is selected from one or more of toluene, chlorobenzene, xylene, and 1, 4-dioxane, and further preferably, the organic solvent is toluene.
Preferably, in the step S1, the catalyst is selected from one or more of palladium acetate and triphenylphosphine, and further preferably, the catalyst is obtained by mixing palladium acetate and triphenylphosphine according to a molar ratio of 1:2;
Preferably, in the step S1, the reaction temperature of the heterocyclic reaction is 70-85 ℃, the reaction time is 2-3.5 h, and more preferably, the reaction temperature of the heterocyclic reaction is 80 ℃ and the reaction time is 3h.
Preferably, in step S2, the purification specifically includes the operations of subjecting the mixture from which the organic solvent is removed to extraction, drying, filtration, concentration and silica gel column chromatography in this order.
In a third aspect of the present invention, there is provided a class of biaryl nitrogen phosphorus ligand compounds having multiple chiralities, or pharmaceutically acceptable salts, solvates and hydrates thereof, said compounds having the structure shown in formula II or III:
Wherein R 1 is selected from aryl, alkyl, alkoxy, halogen, and hydrogen;
R 2 is selected from alkyl, triflate, and hydrogen;
R 3 is selected from the group consisting of hydrogen, alkyl, phenyl, and substituted phenyl, wherein the substituted phenyl is selected from the group consisting of phenyl substituted with at least one of halogen and alkoxy;
R 4 is selected from halogen and hydrogen;
R 5 is selected from aryl, substituted aryl, and alkoxy;
The halogen is preferably fluorine, chlorine or bromine, the alkyl is preferably C 1-C3 alkyl, the alkoxy is preferably C 1-C3 alkoxy, and the aryl is preferably phenyl.
Preferably, when R 1 is 7-methyl, R 3 is 4-tolyl, R 4 is hydrogen, and R 5 is phenyl, R 2 is selected from one of hydrogen, methyl, isopropyl, and trifluoromethanesulfonic acid.
Preferably, the pharmaceutically acceptable salts are those which are group-modified to improve the physicochemical properties of the chiral biaryl nitrogen phosphorus ligand, typically those formed from the chiral biaryl nitrogen phosphorus ligand with inorganic salts such as hydrochloric acid, sulfuric acid, nitric acid or hydrobromic acid, and with organic acids such as methanesulfonic acid, toluenesulfonic acid, citric acid or trifluoroacetic acid.
Preferably, the compounds of formula II, III include the following structures:
According to a fourth aspect of the present invention, there is provided a method for preparing the chiral biaryl nitrogen phosphorus ligand compound according to the third aspect, comprising the steps of:
S1, mixing a compound shown in a general formula I with sodium hydroxide to perform hydrolysis reaction in a solvent to prepare acid;
S2, mixing the acid obtained in the step S1, (S) -BINOL, EDCI and 4-dimethylaminopyridine to perform esterification reaction in an organic solvent to obtain phenol ester with an SS configuration and phenol ester with an RS configuration;
S3, dissolving phenol ester, triethylamine and trichlorosilane in an SS configuration in an organic solvent for reduction reaction to obtain a compound shown in a general formula II;
S4, dissolving the phenol ester with the RS configuration, triethylamine and trichlorosilane in an organic solvent for reduction reaction to obtain the compound shown in the general formula III.
Preferably, in the step S1, the molar ratio of the compound shown in the general formula I to sodium hydroxide is 1:3-15, and more preferably, the molar ratio of the compound shown in the general formula I to sodium hydroxide is 1:10.
Preferably, in the step S1, the solvent is selected from one or more of ethanol and methanol, and more preferably, the solvent is obtained by mixing ethanol and water according to a volume ratio of 1:1.
Preferably, in the step S1, the temperature of the hydrolysis reaction is 65-85 ℃ and the time is 8-15 h, and more preferably, the temperature of the hydrolysis reaction is 80 ℃ and the time is 10h.
Preferably, in step S1, after the hydrolysis reaction is finished, the diluted reaction solution is first adjusted to pH 2 with hydrochloric acid solution, and then filtered, washed and dried in sequence, wherein the filtered precipitate is washed with a washing solution comprising ethanol and water in a volume ratio of 1:3.
Preferably, in step S2, the molar ratio of the acid (S) -BINOL, EDCI and 4-dimethylaminopyridine obtained in step S1 is 1:1.05:2:2.
Preferably, in step S2, the organic solvent is dichloromethane.
Preferably, in the step S2, the esterification reaction is carried out for 10-15 hours at room temperature, and more preferably, the reaction time of the esterification reaction is 12 hours.
Preferably, in step S2, the mixture after the esterification reaction is separated by silica gel column chromatography, and more preferably, the eluent of the silica gel column chromatography is a petroleum ether/ethyl acetate elution system with a volume ratio of 1:2-2:1.
Preferably, in step S3, the molar ratio of the phenol ester, triethylamine and trichlorosilane in the SS configuration is 1:30:10.
Preferably, in step S4, the molar ratio of the phenolic ester of RS configuration, triethylamine and trichlorosilane is 1:30:10.
Preferably, in steps S3 and S4, the organic solvent is toluene.
Preferably, in the steps S3 and S4, the reaction temperature of the reduction reaction is 90-120 ℃ and the time is 8-15 h, and more preferably, the reaction temperature of the reduction reaction is 110 ℃ and the time is 12h.
Preferably, in steps S3 and S4, the mixture after the reduction reaction is subjected to dilution, quenching, filtration, drying, concentration and silica gel column chromatography in this order.
In a fifth aspect of the invention, there is provided the use of a biaryl nitrogen phosphorus ligand compound having multiple chiralities as described in the third aspect as a catalyst ligand in an asymmetric catalytic reaction.
Preferably, the asymmetric catalytic reaction includes, but is not limited to, an asymmetric three-component coupling reaction (a 3 coupling reaction), which is preferably an asymmetric three-component coupling reaction of terminal alkyne, aldehyde, and amine, and an addition reaction of alkyne to quinoline salt.
In some embodiments of the invention, biaryl nitrogen phosphorus ligand compounds with multiple chiralities described herein are combined with cuprous bromide as chiral ligands in catalytic systems for asymmetric three-component coupling reactions of terminal alkynes, aldehydes and amines. This reaction requires high enantioselectivity, whereas the ligands provided by the invention are capable of significantly increasing the optical purity of the product (ee values up to 98%).
In some embodiments of the invention, biaryl nitrogen phosphorus ligand compounds having multiple chiralities described herein are complexed with copper catalysts to catalyze the enantioselective addition reaction of alkynes to quinoline salts. Can effectively improve the stereoselectivity of the catalytic reaction and has better effect than the traditional Quinap ligand.
Therefore, the biaryl nitrogen-phosphorus ligand compound with multiple chiralities plays a key role in regulating stereochemistry in a catalytic system, and helps a catalyst to realize a high-selectivity catalytic process.
The beneficial effects obtained by the above one or more technical schemes of the invention are as follows:
(1) The preparation method of the compound shown in the general formula I is a strategy of slave synthesis, breaks through the limitation that the axial chiral biaryl skeleton can only be constructed through Suzuki coupling reaction in the past, can realize the diversity synthesis of Quinap derivatives, reduces the number of reaction steps in the synthesis process compared with the existing synthesis method, and has certain step economy.
(2) The compound shown in the general formulas II and III is a multi-chiral biaryl nitrogen-phosphorus ligand, the original synthesis method of chiral Quinap with similar structure is invented by Brown team, and the stoichiometric chiral palladium complex is needed in the process, so that the cost is high. The invention can split through chiral binaphthol derivatives, simultaneously obtain two optical pure diastereomers, greatly reduce the reaction cost and have higher economic benefit.
(3) The compound shown in the general formulas II and III provided by the invention is a chiral biaryl nitrogen-phosphorus ligand, and researches prove that the stereoselectivity effect in various asymmetric catalytic reactions is far better than that of a similar ligand Quinap.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 shows nuclear magnetic resonance hydrogen (a), carbon (b) and phosphorus (c) spectra of compound 3a prepared according to the present invention;
FIG. 2 shows nuclear magnetic resonance hydrogen (a), carbon (b) and phosphorus (c) spectra of compound 4a prepared according to the present invention;
FIG. 3 shows nuclear magnetic resonance hydrogen (a), carbon (b) and phosphorus (c) spectra of compound 7a prepared according to the present invention;
FIG. 4 shows nuclear magnetic resonance hydrogen (a), carbon (b) and phosphorus (c) spectra of compound 8a prepared according to the present invention;
FIG. 5 shows nuclear magnetic resonance hydrogen (a), carbon (b) and phosphorus (c) spectra of compound 9a prepared according to the present invention;
FIG. 6 shows nuclear magnetic resonance hydrogen (a), carbon (b) and phosphorus (c) spectra of compound 10a prepared according to the present invention;
FIG. 7 shows nuclear magnetic resonance hydrogen (a), carbon (b) and phosphorus (c) spectra of compound 9b prepared according to the present invention;
FIG. 8 shows nuclear magnetic resonance hydrogen (a), carbon (b) and phosphorus (c) spectra of compound 10b prepared according to the present invention;
FIG. 9 shows nuclear magnetic resonance hydrogen (a), carbon (b) and phosphorus (c) spectra of compound 9c prepared according to the present invention;
FIG. 10 shows nuclear magnetic resonance hydrogen (a), carbon (b) and phosphorus (c) spectra of compound 10c prepared according to the present invention;
FIG. 11 shows nuclear magnetic resonance hydrogen (a), carbon (b), phosphorus (c) and fluorine (d) spectra of compound 10d prepared according to the present invention;
FIG. 12 is a high performance liquid chromatogram of asymmetric A 3 reaction product 5a of 9a as a ligand;
FIG. 13 is a high performance liquid chromatogram of enantioselective synthesis of propargylamine product 6a with 10b as a ligand.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail with reference to specific embodiments.
The purity, the place of production and the model and the place of production of the experimental reagent used in the invention are shown in tables 1 and 2 respectively.
Table 1 laboratory apparatus
| Name of the name | Model number | Production area |
| Rotary evaporator | YRE-5299 | Gongyi Metro Limited for Instrument |
| Low-temperature cooling liquid circulating pump | DLSB-5L/20 | Gongyi Metro Limited for Instrument |
| Circulating water type multipurpose vacuum pump | SHZ-D(III) | Gongyi Metro Limited for Instrument |
| Electric heating constant temperature drum air-drying box | DHG-9140A | Gongyi Metro Limited for Instrument |
| Magnetic heating stirrer | MR Hei-Tec | Shanghai Bajiu Utility Co., ltd |
| Dark box type ultraviolet analyzer | ZF-20D | Gongyi Metro Limited for Instrument |
| Numerical control ultrasonic cleaner | KQ3200DE | Undergrouse Ultraco Undergrouse |
| Electronic balance | FA2004B | Shanghai Tianmei balance instruments Co., ltd |
| Vacuum drying oven | DZF-6020 | Shanghai BoXie Co Ltd |
| Nuclear magnetic resonance spectrometer | BrukerDRX400 | Bruke science and technology Co Ltd |
| High performance liquid chromatograph | G71269A | Agilent technologies Co Ltd |
Table 2 experimental drugs and reagents
In the examples below, the abbreviations represent the meanings of CDCl 3, deuterated chloroform, 1 H NMR, hydrogen nuclear magnetic resonance spectroscopy, 13 C NMR, carbon nuclear magnetic resonance spectroscopy, 31 P NMR, phosphorus nuclear magnetic resonance spectroscopy, 19 F NMR, fluorine nuclear magnetic resonance spectroscopy, HRMS (ESI), high resolution mass spectrometry (electrospray ionization), EDCI, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, (S) -BINOL, S-1,1' -bi-2-naphthol, DIPEA, N-diisopropylethylamine, [ alpha ] 33 D, optical rotation of the compound at 33 ℃, HPLC, high performance liquid chromatograph, PE, petroleum ether, EA, ethyl acetate.
1A-1p' synthesis:
The method comprises the steps of condensing and formylating ethyl isocyanoacetate which is easy to obtain and aromatic aldehyde or aromatic ketone which are used as starting materials, and further dehydrating to obtain a series of products, wherein the reaction equation is shown in the figure:
Selecting substrates with different substituents to perform a series of reactions to obtain compounds 1a-1p', wherein 17 compounds are all reported compounds;
Synthesis of 2q-2 y:
the first step is trifluoro methyl sulfonation reaction:
Second step, phosphorylation reaction
Through the two steps of conversion, substrates with different substituents are selected for serial reactions to synthesize 2q-2y, and 9 compounds are obtained in total and are all reported compounds.
Example 1 this example provides a process for the preparation of a compound of formula I
In a flask equipped with a magnetic stirrer and a rubber stopper, compound 2, pd (OAc) 2、PPh3、Cs2CO3, and toluene were added. The system was rapidly sealed, replaced three times with nitrogen and stirred for 5min at 80 ℃. Dissolving the compound 1 into toluene, and adding the compound into the system within 3-5 hours through a syringe pump. The mixture was cooled to room temperature, and the reaction system was concentrated, diluted with ethyl acetate, transferred to a separating funnel, and extracted with saturated brine and ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE: ea=1:1 to 1:3) to give compound 3 as a white solid.
Substrates with different substituents are selected for reaction to obtain a series of compounds 3, 26 compounds 3 (3 a-3 y) are obtained, and the reaction yield ranges from 31% to 98%. Wherein, the compound 3b-3y is reacted on the scale of 0.5mmol of the raw material 1.
Example 2 this example provides the preparation of Compound 3a and validation data
To a 500mL flask equipped with a magnetic stirrer and a rubber stopper was added 2a(15mmol),Pd(OAc)2(224mg,1.0mmol),PPh3(524mg,2.0mmol),Cs2CO3(3.91g,12mmol), toluene (200 mL). The system was rapidly sealed, replaced three times with nitrogen and stirred for 5min at 80 ℃. 1a (10 mmol) was dissolved in 200mL of toluene and added to the system by syringe pump over 5h. The mixture was cooled to room temperature, and the reaction system was concentrated, diluted with ethyl acetate (200 mL), transferred to a 1000mL separating funnel, and extracted three times with saturated brine (200 mL) and ethyl acetate (200 mL). The combined organic phases were dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Purification by column chromatography (PE: ea=1:1 to 1:3) gave compound 3a (6.06 g, 96% yield, melting point) as a white solid ：254-256℃).1H NMR(400MHz,CDCl3)δ8.35(dd,J＝11.0,8.7Hz,1H),8.17–8.05(m,3H),7.96(d,J＝8.2Hz,1H),7.57–7.43(m,4H),7.40(d,J＝8.6Hz,1H),7.36–7.25(m,6H),7.10–7.05(m,2H),7.02(s,1H),6.92(d,J＝8.6Hz,1H),6.87(td,J＝7.4,1.5Hz,1H),6.72(td,J＝7.7,3.0Hz,2H),4.09–4.02(m,2H),2.47(s,3H),2.27(s,3H),0.98(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ167.3,156.7(d,JC-P＝5.1Hz),141.1,140.3(d,JC-P＝10.1Hz),138.4,137.8,134.9(d,JC-P＝3.0Hz),133.0,132.92(d,JC-P＝10.1Hz),132.9,132.7(d,JC-P＝2.0Hz),132.5,132.3(d,JC-P＝105.0Hz),131.7(d,JC-P＝3.0Hz),131.67(d,JC-P＝105.0Hz),131.2(d,JC-P＝10.1Hz),130.8(d,JC-P＝101.0Hz),130.19,130.17,130.1,129.6,129.2,129.1,129.0(d,JC-P＝8.1Hz),128.6(d,JC-P＝9.1Hz),128.2(d,JC-P＝13.1Hz),128.16,128.0,127.2(d,JC-P＝15.2Hz),126.8(d,JC-P＝12.1Hz),126.5,125.9,61.0,21.7,21.4,13.9.31P NMR(162MHz,CDCl3)δ30.8.HRMS(ESI)calcd for C42H34NO3PNa[M+Na]+654.2169,found 654.2167.
EXAMPLE 3 this example provides a procedure for the preparation of Compound 4a
A250 mL dry flask equipped with a magnetic stirrer was charged with 3a (6.31 g,10.0 mmol), sodium hydroxide (4.0 g,100 mmol), ethanol/H 2 O=1/1 (150 mL). Stirred at 80 ℃ for 10h and cooled to room temperature after the reaction was completed. The reaction solution was poured into a 1000mL beaker and the pH was adjusted to 2 with hydrochloric acid solution. The precipitate was filtered and washed with ethanol/H 2 o=1/3 (50 mL). The product was dried to give light grey solid 4a (5.79 g, yield 96％).1H NMR(400MHz,CDCl3)δ8.06(dd,J＝8.7,2.3Hz,1H),8.00(d,J＝8.3Hz,1H),7.74–7.59(m,4H),7.47–7.26(m,12H),7.17(s,1H),7.13–7.08(m,1H),7.6–7.04(m,1H),6.98(td,J＝7.7,2.9Hz,2H),2.47(s,3H),2.31(s,3H).13C NMR(101MHz,CDCl3)δ165.2,155.1(d,JC-P＝5.1Hz),142.2(d,JC-P＝8.1Hz),139.3,137.6,136.6,136.1,134.9(d,JC-P＝2.0Hz),134.8,132.8,132.4,132.2(d,JC-P＝11.1Hz),131.9(d,JC-P＝108.1Hz),131.8(d,JC-P＝10.1Hz),131.7(d,JC-P＝2.0Hz),131.3(d,JC-P＝104.0Hz),131.1(d,JC-P＝3.0Hz),131.0(d,JC-P＝102.0Hz),130.4(d,JC-P＝10.1Hz),129.8,129.7,129.4(d,JC-P＝13.1Hz),129.2(d,JC-P＝13.1Hz),129.0,128.8(d,JC-P＝5.1Hz),128.5,128.4,128.3,127.7(d,JC-P＝12.1Hz),127.5,127.2(d,JC-P＝14.1Hz),126.4,21.8,21.5.31P NMR(162MHz,CDCl3)δ29.5.HRMS(ESI)calcd for C40H30NO3PNa[M+Na]+626.1856,found 626.1845.
Example 4 this example provides a procedure for the preparation of Compounds 7a and 8a
A50 mL dry flask was equipped with a magnetic stirrer and 4a (603.0 mg,1.0 mmol), (S) -BINOL (300.4 mg,1.05 mmol), EDCI (383.4 mg,2.0 mmol), 4-dimethylaminopyridine (244.3 mg,2.0 mmol) dichloromethane (20 mL) was added. Stir at room temperature for 12h. The reaction mixture was directly subjected to column chromatography on silica gel (PE/ea=1/2 to 2/1) to give the desired product as a white solid 7a (400.8 mg, yield 46％)1H NMR(400MHz,CDCl3)δ8.27(dd,J＝11.0,8.7Hz,1H),8.19–8.10(m,3H),8.04(d,J＝8.9Hz,1H),8.00(d,J＝8.1Hz,1H),7.94(d,J＝8.2Hz,1H),7.61–7.56(m,1H),7.55(d,J＝8.9Hz,1H),7.52(d,J＝8.8Hz,1H),7.50–7.44(m,2H),7.40(dd,J＝7.9,1.8Hz,1H),7.30–7.27(m,2H),7.25–7.16(m,8H),7.14(dd,J＝7.8,2.0Hz,1H),6.94(s,1H),6.91–6.87(m,1H),6.86–6.82(m,1H),6.82–6.78(m,1H),6.73(d,J＝8.6Hz,1H),6.69(dd,J＝7.7,2.0Hz,1H),6.65–6.57(m,2H),6.54–6.50(m,1H),6.34(s,1H),6.01(td,J＝7.8,3.0Hz,2H),2.49(s,3H),2.25(s,3H).13C NMR(101MHz,CDCl3)δ166.1,156.4(d,JC-P＝5.1Hz),152.7,148.1,140.0,139.9,138.9,138.7,137.8,134.7,134.3,133.6,133.4,133.0,132.7(d,JC-P＝11.1Hz),132.5,132.46,132.2,132.0,131.8,131.2(d,JC-P＝3.0Hz),131.0,130.9,130.87(d,JC-P＝105.0Hz),130.8,130.3,130.2,129.9,129.84(d,JC-P＝104.0Hz),129.8(d,JC-P＝4.0Hz),129.5(d,JC-P＝11.1Hz),129.3(d,JC-P＝11.1Hz),128.8,128.7,128.5,128.4,128.2,128.0,127.9,127.6,127.4,127.1,126.44,126.4,126.3(d,JC-P＝10.1Hz),126.0(d,JC-P＝10.1Hz),124.4,124.1,123.1,121.8,118.9,114.4,21.7,21.5.31PNMR(162MHz,CDCl3)δ30.1.HRMS(ESI)calcd for C60H42NO4PNa[M+Na]+894.2744,found 894.2741.
White solid 8a (392 mg, yield) 45％).1H NMR(400MHz,CDCl3)δ8.16(dd,J＝11.1,8.6Hz,1H),8.06(dd,J＝8.8,1.9Hz,1H),8.01–7.92(m,3H),7.90(d,J＝8.1Hz,1H),7.87(d,J＝8.2Hz,1H),7.72(d,J＝8.1Hz,1H),7.62(d,J＝8.9Hz,1H),7.50(t,J＝7.5Hz,1H),7.42–7.35(m,2H),7.30–7.26(m,1H),7.25–7.12(m,10H),7.10–7.03(m,3H),7.00(d,J＝8.9Hz,1H),6.93(d,J＝8.4Hz,1H),6.87(s,1H),6.82(d,J＝8.6Hz,1H),6.74–6.67(m,1H),6.45–6.39(m,1H),6.36(td,J＝7.7,2.9Hz,2H),6.25(dd,J＝7.8,2.0Hz,1H),6.14(s,1H),2.27(s,3H),2.16(s,3H).13C NMR(101MHz,CDCl3)δ165.7,156.7(d,JC-P＝5.1Hz),152.3,148.0,140.4(d,JC-P＝10.1Hz),139.0,138.6,137.4,135.3,134.8(d,JC-P＝2.0Hz),134.1,133.7,133.3,132.8,132.7,132.6,132.4,132.0,131.7(d,JC-P＝107.1Hz),131.5(d,JC-P＝3.0Hz),131.4(d,JC-P＝105.0Hz),131.2(d,JC-P＝11.1Hz),130.7(d,JC-P＝103.0Hz),130.3(d,JC-P＝3.0Hz),129.9,129.8,129.77,129.6,129.2(d,JC-P＝11.1Hz),128.9,128.89,128.7,128.6,128.4(d,JC-P＝9.1Hz),128.22,128.2,128.19,128.1,128.06,128.0,127.3(d,JC-P＝12.1Hz),127.1,126.9,126.5,126.4,126.3(d,JC-P＝10.0Hz),125.9,125.5,123.2,121.9,118.9,114.5,21.7,21.3.31P NMR(162MHz,CDCl3)δ30.5.HRMS(ESI)calcd for C60H42NO4PNa[M+Na]+894.2744,found 894.2702.
Example 5 this example provides the preparation of Compound 9a and validation data
To a 50mL dry flask at 0deg.C was added 7a (218 mg,0.25 mmol), triethylamine (1.05 mL,7.5 mmol), trichlorosilane (250 uL,2.5 mmol), and toluene (7.5 mL). The reaction mixture was heated at 110 ℃ for 12h. After cooling to room temperature, the mixture was diluted with ethyl acetate and quenched with a small amount of saturated sodium bicarbonate. The resulting suspension was filtered through celite, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography using PE/ea=10/1 as eluent gave 9a (173.2 mg, 81% yield, melting point) as a white solid ：271-273℃).[α]33 D＝124.0(c 1.00,CHCl3).1H NMR(400MHz,CDCl3)δ7.95–7.91(m,3H),7.88(d,J＝8.2Hz,1H),7.64(d,J＝8.5Hz,1H),7.55(td,J＝8.6,8.0,2.5Hz,2H),7.47(dd,J＝8.5,3.6Hz,1H),7.44–7.39(m,2H),7.32–7.18(m,10H),7.16–7.03(m,10H),7.00–6.87(m,4H),6.77(dd,J＝7.9,2.0Hz,1H),5.63(s,1H),2.40(s,3H),2.07(s,3H).13C NMR(101MHz,CDCl3)δ165.8,158.6(d,JC-P＝5.1Hz),152.0,148.2,143.0,142.7,138.82,138.8,137.4,137.35,137.2,136.8(d,JC-P＝12.1Hz),135.6(d,JC-P＝15.2Hz),134.8,134.1,133.8,133.65(d,JC-P＝13.1Hz),133.6,133.57(d,JC-P＝20.2Hz),132.9(d,JC-P＝7.1Hz),132.6,132.58,132.1,130.12,129.9,129.8,129.78,129.6,129.0,128.95,128.9,128.8,128.4,128.2(d,JC-P＝2.0Hz),128.17(d,JC-P＝18.2Hz),128.0,127.97,127.7,126.9,126.8(d,JC-P＝2.0Hz),126.75,126.7,126.5,126.4,126.2,125.9,125.2,123.3,123.2,122.3,118.9,114.9,21.6,21.4.31P NMR(162MHz,CDCl3)δ-12.4.HRMS(ESI)calcd for C60H42NO3PNa[M+Na]+878.2795,found 878.2767.
Example 6 this example provides the preparation of Compound 10a and validation data
In a 50mL dry flask, 8a (218 mg,0.25 mmol), triethylamine (1.05 mL,7.5 mmol), trichlorosilane (250 uL,2.5 mmol) and toluene (7.5 mL) were added. The reaction mixture was heated at 110 ℃ for 12h. After cooling to room temperature, the mixture was diluted with ethyl acetate and quenched with a small amount of saturated sodium bicarbonate. The resulting suspension was filtered through celite, dried over magnesium sulfate, and then concentrated under reduced pressure. Purification by silica gel column chromatography using PE/ea=10/1 as eluent gave 10a (171.1 mg, 80% yield, melting point) as a white solid ：266-268℃).[α]33 D＝-182.0(c 1.00,CHCl3).1H NMR(400MHz,CDCl3)δ7.89(d,J＝4.3Hz,1H),7.87–7.80(m,3H),7.62(d,J＝8.5Hz,2H),7.46–7.41(m,3H),7.38(d,J＝7.6Hz,1H),7.30–7.25(m,6H),7.23–7.16(m,4H),7.15–7.03(m,10H),7.01(d,J＝7.8Hz,1H),6.98–6.92(m,3H),6.89(d,J＝7.9Hz,1H),5.46(s,1H),2.41(s,3H),2.03(s,3H).13C NMR(101MHz,CDCl3)δ166.1,158.7(d,JC-P＝5.1Hz),152.1,148.6,143.2,142.9,139.0,138.3,137.6(d,JC-P＝13.1Hz),137.4,137.1(d,JC-P＝12.1Hz),135.7,135.5(d,JC-P＝15.2Hz),134.0(d,JC-P＝21.2Hz),133.9(d,JC-P＝14.4Hz),133.62,133.6(d,JC-P＝19.2Hz),133.59,132.9,132.8(d,JC-P＝7.1Hz),132.6,132.1,130.2,130.1(d,JC-P＝3.0Hz),129.9(d,JC-P＝3.0Hz),129.8,129.4,129.1,128.9,128.8,128.5,128.4,128.36,128.3,128.2,128.15,128.1,127.9,127.8,127.0,126.8,126.73,126.7,126.5,126.4,126.0,125.2,123.2,123.1,122.3,118.7,114.5,21.6,21.5.31PNMR(162MHz,CDCl3)δ-12.7.HRMS(ESI)calcd for C60H42NO3PNa[M+Na]+878.2795,found 878.2761.
Example 7 this example provides a procedure for the preparation of Compounds 7b and 8b
A50 mL flask equipped with a magnetic stirrer was charged with 4a (603.0 mg 1.0 mmol), (S) -MeBINOL (315.1 mg,1.05 mmol), EDCI (383.4 mg,2.0 mmol), 4-dimethylaminopyridine (244.3 mg,2.0 mmol), dichloromethane (20 mL). Stir at room temperature for 12h. The reaction mixture was directly subjected to column chromatography on silica gel (PE/ea=1/2 to 2/1) to give the desired product as a white solid (mixture 7b and 8b in a ratio of 1:1) (796.8 mg, yield 90%), the polarity of the products 7b and 8b being identical and the two could not be separated by column chromatography, so no pure spectrum was measured, which would provide characterization data of the reduced product after the reduction reaction of example 8.
Example 8 this example provides the preparation of Compounds 9b and 10b and validation data
The yields were calculated from the mixture of 7b and 8b in a 1:1 ratio of the product obtained in example 7, and the reduction products 9b, 10b obtained.
To a dry 50mL flask at 0deg.C were added 7b (110.7 mg,0.125 mmol), 8b (110.7 mg,0.125 mmol) triethylamine (1.05 mL,7.5 mmol), trichlorosilane (250 uL,2.5 mmol) and toluene (7.5 mL). The reaction mixture was heated at 110 ℃ for 12h. After cooling to room temperature, the mixture was diluted with ethyl acetate and quenched with a small amount of saturated sodium bicarbonate. The resulting suspension was filtered through celite, dried over magnesium sulfate, and then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using PE/ea=15/1 to 1/5 as eluent to give 9b (72.8 mg, 67% yield, melting point: 233-235 ℃) as a white solid, 10b (78.2 mg, 72% yield, melting point: 230-232 ℃).
White solid 9b：[α]33 D＝134.0(c 1.00,CHCl3).1H NMR(400MHz,CDCl3)δ7.94(dd,J＝8.5,4.0Hz,2H),7.85(dd,J＝8.6,5.7Hz,2H),7.67(d,J＝8.2Hz,1H),7.55(t,J＝7.5Hz,1H),7.57–7.49(m,2H),7.45(d,J＝8.6Hz,1H),7.36–7.07(m,20H),6.99(d,J＝8.5Hz,1H),6.97–6.90(m,2H),6.88(d,J＝9.0Hz,1H),6.82(d,J＝7.8Hz,1H),6.47(d,J＝7.8Hz,1H),3.35(s,3H),2.37(s,3H),2.02(s,3H).13C NMR(101MHz,CDCl3)δ165.0,158.4(d,JC-P＝6.1Hz),155.4,147.4,144.2,143.8,139.6,138.5,137.6,137.4,137.3,137.2,135.1(d,JC-P＝15.2Hz),134.1,134.0,133.8,133.79,133.7(d,JC-P＝2.0Hz),133.5(d,JC-P＝19.2Hz),132.9(d,JC-P＝7.1Hz),132.8,132.4,131.8,130.3,129.8,129.7(d,JC-P＝3.0Hz),129.5,129.4,129.0,128.7,128.6,128.5(d,JC-P＝6.1Hz),128.3,128.26,128.24,128.2(d,JC-P＝7.1Hz),128.1,128.0,127.8,127.1(d,JC-P＝3.0Hz),126.9,126.6(d,JC-P＝3.0Hz),126.4,126.3,126.2,125.8,125.2,125.1,123.2,122.3,117.5,114.0,56.6,21.6,21.4.31P NMR(162MHz,CDCl3)δ-13.9.HRMS(ESI)calcd for C61H44NO3PNa[M+Na]+892.2951,found892.2928.
White solid 10b：[α]33 D＝-120.0(c 1.00,CHCl3).1H NMR(400MHz,CDCl3)δ7.92(dd,J＝8.3,3.3Hz,2H),7.85(d,J＝9.4Hz,2H),7.73(d,J＝8.1Hz,1H),7.67(d,J＝9.0Hz,1H),7.54–7.46(m,2H),7.40–7.34(m,3H),7.32–7.27(m,3H),7.25–7.19(m,5H),7.19–7.09(m,6H),7.09–6.98(m,7H),6.87(s,1H),6.52(d,J＝7.8Hz,1H),6.45(d,J＝7.7Hz,1H),3.44(s,3H),2.30(s,3H),2.04(s,3H).13CNMR(101MHz,CDCl3)δ165.4,158.5(d,JC-P＝5.1Hz),155.4,147.3,143.5,143.2,139.8,138.4,137.9(d,JC-P＝13.1Hz),137.0,136.9(d,JC-P＝13.1Hz),135.2,135.1,134.3,134.2(d,JC-P＝21.2Hz),133.9(d,JC-P＝10.1Hz),133.6,133.2(d,JC-P＝19.2Hz),133.0,132.9,132.4,131.7,130.1,129.7,129.66,129.6,129.5,129.4,128.9,128.7,128.6,128.5,128.3(d,JC-P＝5.1Hz),128.1,128.05,128.0,127.9,127.8,127.0(d,JC-P＝3.0Hz),126.9,126.6(d,JC-P＝4.0Hz),126.55,126.4,126.3,126.1,125.9,125.2,124.7,123.2,122.2,117.6,114.1,56.8(d,JC-P＝3.0Hz),21.54,21.32.31P NMR(162MHz,CDCl3)δ-12.7.HRMS(ESI)calcd for C61H44NO3PNa[M+Na]+892.2951,found 892.2919.
Example 9 this example provides a procedure for the preparation of Compounds 7c and 8c
A dried 50mL flask was equipped with a magnetic stirrer, and 4a (603.0 mg of 1.0 mmol), (S) -i-PrBINOL (345 mg of 1.05 mmol), EDCI (383.4 mg of 2.0 mmol) 4-dimethylaminopyridine (244.3 mg of 2.0 mmol) dichloromethane (20 mL) was added. Stir at room temperature for 12h. The reaction mixture was directly chromatographed on silica gel (PE/ea=1/2 to 2/1) to give the desired product as a white solid (mixture 7c and 8c ratio 1:1) (785.4 mg, 86% yield). The same polarity of products 7c and 8c could not be separated by column chromatography, so no pure spectra were measured and characterization data for the reduced products would be provided after the reduction reaction of example 10.
Example 10 this example provides the preparation of Compounds 7c and 8c and validation data
The yields were calculated from the product obtained in example 8 as a mixture of 7c and 8c in a ratio of 1:1, and the reduction products 9c and 10c obtained individually.
To a dry 50mL flask at 0deg.C was added 7C (114.2 mg,0.125 mmol), 8C (114.2 mg,0.125 mmol) triethylamine (1.05 mL,7.5 mmol), trichlorosilane (250 uL, 2.5 mmol) and toluene (7.5 mL) and the reaction mixture was heated at 110deg.C for 12h. After cooling to room temperature, the mixture was diluted with ethyl acetate and quenched with a small amount of saturated sodium bicarbonate. The resulting suspension was filtered through celite, dried over magnesium sulfate, and then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with PE/ea=15/1 to 1/5 to give 9C (78.5 mg, 70% yield, melting point: 320 to 322 ℃) as a white solid, 10C (75.2 mg, 67% yield, melting point: 336 to 338 ℃).
White solid 9c：[α]33 D＝166.2(c 1.00,CHCl3).1H NMR(400MHz,CDCl3)δ7.89(d,J＝8.4Hz,2H),7.82(dd,J＝8.7,5.7Hz,2H),7.70(dd,J＝14.5,8.5Hz,2H),7.51(t,J＝7.6Hz,1H),7.48–7.40(m,2H),7.33–7.10(m,20H),7.08–6.99(m,3H),6.95(d,J＝8.5Hz,1H),6.69(d,J＝7.8Hz,1H),6.13(d,J＝7.8Hz,1H),4.00–3.94(m,1H),2.33(s,3H),2.05(s,3H),0.70(d,J＝6.1Hz,3H),0.61(d,J＝6.1Hz,3H).13C NMR(101MHz,CDCl3)δ164.9,158.3(d,JC-P＝7.1Hz),154.5,147.5,144.2,143.9,138.9,138.8,137.5(d,JC-P＝12.1Hz),137.4(d,JC-P＝13.1Hz),137.0,135.3,135.2,134.1,134.08,133.9(d,JC-P＝20.2Hz),133.87,133.6,133.4,133.0,132.9,132.86,132.5,131.7,130.3,129.7,129.69,129.3,129.2(d,JC-P＝3.0Hz),128.9,128.7,128.6,128.32(d,JC-P＝13.1Hz),128.31,128.3(d,JC-P＝21.2Hz),128.1,128.0,127.7,127.1(d,JC-P＝3.0Hz),126.8(d,JC-P＝6.1Hz),126.6,126.5,126.4,126.3,126.1,126.0,125.5,125.1,123.4,122.3,119.4,117.2,72.8,22.6,22.2,21.7,21.5.31P NMR(162MHz,CDCl3)δ-13.3.HRMS(ESI)calcd for C63H48NO3PNa[M+Na]+920.3264,found 960.3230.
White solid 10c：[α]33 D＝-150.0(c 1.00,CHCl3).1H NMR(400MHz,CDCl3)δ7.90(d,J＝8.6Hz,2H),7.83(d,J＝8.6Hz,2H),7.63(d,J＝8.1Hz,1H),7.57(d,J＝9.0Hz,1H),7.50–7.48(m,2H),7.38–7.31(m,3H),7.26–7.14(m,11H),7.12–6.96(m,10H),6.84–6.76(m 3H),4.23–4.17(m,1H),2.35(s,3H),1.97(s,3H),0.86(d,J＝6.1Hz,3H),0.80(d,J＝6.1Hz,3H).13C NMR(101MHz,CDCl3)δ165.4,158.3(d,JC-P＝6.1Hz),153.9,147.5,143.4,143.1,140.0,138.2(d,JC-P＝20.2Hz),138.0(d,JC-P＝13.1Hz),136.9(d,JC-P＝14.1Hz),135.4(d,JC-P＝15.2Hz),134.3(d,JC-P＝21.2Hz),134.2,133.8(d,JC-P＝8.1Hz),133.7,133.6,133.5,133.3,133.1,133.0,132.97,132.3,131.5,130.0,129.8,129.62,129.6,129.3,129.0,128.9,128.6,128.5,128.49,128.3,128.26(d,JC-P＝9.1Hz),128.1,128.0(d,JC-P＝5.1Hz),127.9,127.6,127.0(d,JC-P＝2.0Hz),126.8,126.6,126.5,126.47,126.1,125.9(d,JC-P＝9.1Hz),125.2,125.1,123.3,122.2,119.7,117.3,71.7,22.5,22.1,21.5,21.4.31P NMR(162MHz,CDCl3)δ-12.3.HRMS(ESI)calcd for C63H48NO3PNa[M+Na]+920.3264,found 960.3238.
Example 11 this example provides the preparation of Compound 10d and validation data
10A (85.5 mg,0.1 mmol) and 4-dimethylaminopyridine (24.4 mg,0.2 mmol) were added to a solution of dichloromethane (1.5 mL) and stirred under nitrogen at 0deg.C for 10min. Then trifluoromethanesulfonic anhydride (31 mg,0.11 mmol) dissolved in 0.5mL of dichloromethane was added via syringe and the mixture was stirred at 0deg.C for 5h. Column chromatography of the reaction mixture directly on silica gel (PE/ea=10/1) gave 10d (89.8 mg, 91% yield, melting point) as a white solid ：238-240℃).[α]33 D＝-140.0(c 1.00,CHCl3).1HNMR(400MHz,CDCl3)δ8.04–7.92(m,3H),7.88(d,J＝8.2Hz,1H),7.58(t,J＝7.6Hz,2H),7.47(d,J＝8.7Hz,1H),7.46–7.39(m,2H),7.36–7.28(m,6H),7.26–7.01(m,18H),6.88(s,1H),6.74(d,J＝9.0Hz,1H),2.44(s,3H),1.96(s,3H).13C NMR(101MHz,CDCl3)δ165.0,158.2(d,JC-P＝6.1Hz),147.5,145.3,143.6,143.3,140.0,138.3,137.64(d,JC-P＝12.1Hz),137.6,136.9(d,JC-P＝13.1Hz),135.1,135.0,134.1(d,JC-P＝21.2Hz),133.6,133.5,133.4,133.3,133.2,133.1,133.0,132.7,132.4,132.1,131.4,130.1,130.05,129.9(d,JC-P＝4.0Hz),129.6(d,JC-P＝3.0Hz),129.0(d,JC-P＝7.1Hz),128.5,128.4,128.2,128.15,128.1,128.05,127.8(d,JC-P＝9.1Hz),127.3,127.13,127.1,127.06,126.9,126.7,126.5,126.4,126.3(d,JC-P＝4.0Hz),125.6,125.0,122.0,121.4,119.4,118.0,(q,JC-F＝321.2Hz)21.43,21.4.31P NMR(162MHz,CDCl3)δ-13.1.19F NMR(376MHz,CDCl3)δ-74.6.HRMS(ESI)calcd for C61H42F3NO5PS[M+H]+988.2468,found 988.2443.
Example 12 this example provides asymmetric Synthesis of Compound 5a with 9a as chiral ligand
A15 mL flask, flushed with dry nitrogen, equipped with a magnetic stirrer and septum was charged with cuprous bromide (3.6 mg,0.025 mmol), 9a (25.7 mg,0.03 mmol) and activated MSMolecular sieves (300 mg). The flask was sealed and replaced with nitrogen three times. Super-dry toluene (2 mL) was added and the mixture was stirred at room temperature for 45min. Trimethylsilylacetylene (0.5 mmol), cyclohexylformaldehyde (0.5 mmol) and dibenzylamine (0.5 mmol) were dissolved in 1mL of toluene and added to the flask using a syringe. The reaction mixture was stirred at room temperature for 4d. After completion of the reaction, the reaction mixture was diluted with n-hexane (10 mL), filtered and washed with Et 2 O. Purification was performed with a silica gel column. Colorless transparent solid 5a (184.9 mg, 95%) was obtained, and after desilylation of 5a was measured 98％ee.[α]33 D＝-171.9(c 1.00,CHCl3).1H NMR(400MHz,CDCl3)δ7.29(d,J＝6.9Hz,4H),7.24–7.16(m,4H),7.15–7.09(m,2H),3.70(d,J＝13.8Hz,2H),3.25(d,J＝13.7Hz,2H),2.93(d,J＝10.4Hz,1H),2.17(d,J＝13.6Hz,1H),1.88(d,J＝11.3Hz,1H),1.63–1.42(m,4H),1.15–0.88(m,3H),0.78–0.50(m,2H),0.15(s,9H).13C NMR(101MHz,CDCl3)δ139.4,128.4,127.7,126.3,103.0,89.6,58.1,54.4,39.0,30.7,29.8,26.1,25.7,25.5,0.0.
Example 13 this example provides asymmetric Synthesis of Compounds 5b-5q with 9a as chiral ligand
The same series of compounds 5b-5q on a 0.5mmol scale and under the same conditions (aromatic aldehyde substrate reaction time extended to 6 d) and the work-up procedure gave the following Table 1 (wherein 9a as ligand vs. Quinap as enantioselective results of ligand):
TABLE 1
As can be seen from Table 1, the novel axial chiral nitrogen-phosphorus ligand 9a synthesized by the method can play a very excellent role in the asymmetric three-component coupling reaction of terminal alkyne, aldehyde and amine by matching with cuprous bromide, the ee value of the synthesized chiral propargylamine product is up to 98%, particularly, the problem of poor enantioselectivity when Quinap is used as a ligand is solved in the case of an aromatic aldehyde substrate, the ee value of the improved result is 90% or more in most cases, and the improvement range of individual examples is three times or more (5 b-5 q).
EXAMPLE 14 this example provides asymmetric Synthesis of Compound 6a with 10b as chiral ligand
A dry and nitrogen flushed 15mL flask was equipped with a magnetic stirrer and a septum to which was added cuprous bromide (1.8 mg,0.0125 mmol), 10b (13.1 mg,0.015 mmol). The flask was sealed and replaced with nitrogen three times. Dichloromethane (1 mL) was added and stirred at room temperature for 45min. The mixture was then cooled to-20 ℃ and phenylacetylene (0.25 mmol) was added. Dissolved in 0.5mL of methylene chloride, and the mixture was added to the flask by syringe and stirred for 10 minutes. During this stirring time, in a separate flask of isobutyl chloroformate (0.25 mmol). Quinoline (0.25 mmol) was added (dissolved in 1.0mL of dichloromethane) and stirred at room temperature for 10min. The quinoline salt thus formed was transferred to a flask containing copper catalyst and alkyne, followed by the addition of DIPEA (0.35 mmol) dissolved in 0.5mL of dichloromethane by syringe. The reaction mixture was stirred at-20℃for 24H, and the reaction mixture was directly chromatographed on silica gel (PE/EA) to give 6a (58.8 mg, 71% yield) as a white solid, as measured on an OD-H chiral column 92％ee.[α]33 D＝-617.6(c 1.00,CHCl3).1H NMR(400MHz,CDCl3)δ7.62(s,1H),7.24–7.16(m,3H),7.19–7.07(m,5H),7.08–6.93(m,2H),6.47(d,J＝8.4Hz,1H),6.07–5.94(m,2H),4.03–3.88(m,2H),2.01–1.84(m,1H),0.90(d,J＝6.7Hz,6H).13C NMR(101MHz,CDCl3)δ154.0,134.4,131.9,128.3,128.1,127.8,126.7,126.5,126.0,125.0,124.4,124.3,122.6,85.8,83.4,72.7,44.7,27.9,19.2.HRMS(ESI)calcd for C22H21NO2Na[M+Na]+354.1465,found 354.1457.Enantiomeric excess was determined by HPLC with a Chiralcel OD-Hcolumn(90:10n-hexane:isopropanol,1.0mL/min,254nm);minor tr＝5.29min;major tr＝6.08min;92％ee.
Example 15 unlike example 14, this example provides the results of asymmetric synthesis of compound 6a with 9a, 9b, 9c, 10a, 10c, 10d as chiral ligands
The test results show that 9a, 9b, 9c, 10a, 10c and 10d can all play a certain role in stereoselectivity as chiral ligands in the asymmetric synthesis of the compound 6a, wherein 10d can reach an ee value of 90.6%, but the overall effect comparison finds that 10b is the chiral ligand with the optimal reaction.
Example 16 this example provides an asymmetric synthesis of compounds 6b-6i using 10b as chiral ligand, on a 0.25mmol scale and with the same reaction conditions and post-treatment procedure, as shown in Table 2 below (substrate extension results of the copper-catalyzed alkyne-to-quinoline salt reaction in which 10b is the ligand):
TABLE 2
| Entry | R1 | R2 | R3 | Yield(%) | ee(%) |
| 6a | Ph | H | i-Bu | 71 | 92 |
| 6b | 2-NO2C6H4 | H | i-Bu | 63 | 90 |
| 6c | 3,4-F2C6H3 | H | i-Bu | 52 | 91 |
| 6d | Ph(CH2)2 | H | i-Bu | 40 | 92 |
| 6e | Ph | 6-MeO | i-Bu | 67 | 92 |
| 6f | Ph | 6-MeOCO | i-Bu | 55 | 91 |
| 6g | Ph | H | i-Pr | 56 | 90 |
| 6h | Ph | H | n-Pr | 67 | 90 |
| 6i | Ph | H | Bn | 41 | 89 |
As can be seen from Table 2, the novel axial chiral nitrogen-phosphorus ligand 10b synthesized by the invention can have very excellent effect in the enantioselective addition reaction of alkyne to quinoline salt by matching with cuprous bromide, and the ee value of the product is up to 90% or more in most cases, thus solving the problem of poor enantioselectivity when Quinap is used as the ligand. In the prior art, the literature reports that the ee value is only 42% when Quinap is used as a ligand, and the improvement effect is remarkable when the ligand 10b modified by the invention is used.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
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