CN118620007A - Chiral tetradentate phosphine ligand compound, and preparation method and application thereof - Google Patents
Chiral tetradentate phosphine ligand compound, and preparation method and application thereof Download PDFInfo
- Publication number
- CN118620007A CN118620007A CN202410682078.XA CN202410682078A CN118620007A CN 118620007 A CN118620007 A CN 118620007A CN 202410682078 A CN202410682078 A CN 202410682078A CN 118620007 A CN118620007 A CN 118620007A
- Authority
- CN
- China
- Prior art keywords
- compound
- chiral
- independently
- phosphine ligand
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title claims abstract description 70
- 239000003446 ligand Substances 0.000 title claims abstract description 63
- 150000001875 compounds Chemical class 0.000 title claims abstract description 60
- 229910000073 phosphorus hydride Inorganic materials 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 11
- 150000003624 transition metals Chemical group 0.000 claims abstract description 6
- -1 nitro, methyl Chemical group 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 229910052723 transition metal Inorganic materials 0.000 claims description 7
- 229940125904 compound 1 Drugs 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 4
- MKIJJIMOAABWGF-UHFFFAOYSA-N methyl 2-sulfanylacetate Chemical compound COC(=O)CS MKIJJIMOAABWGF-UHFFFAOYSA-N 0.000 claims description 4
- 125000004437 phosphorous atom Chemical group 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 150000001414 amino alcohols Chemical class 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 229910052707 ruthenium Inorganic materials 0.000 claims description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
- 229940125898 compound 5 Drugs 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 229910052702 rhenium Inorganic materials 0.000 claims description 2
- 229910052720 vanadium Inorganic materials 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 36
- 150000002576 ketones Chemical class 0.000 abstract description 13
- 230000009257 reactivity Effects 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 14
- 239000011261 inert gas Substances 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 239000003814 drug Substances 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 150000001298 alcohols Chemical class 0.000 description 7
- 239000012298 atmosphere Substances 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 150000002431 hydrogen Chemical group 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000003197 catalytic effect Effects 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- 238000006845 Michael addition reaction Methods 0.000 description 2
- 150000008062 acetophenones Chemical class 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000007366 cycloisomerization reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000006735 epoxidation reaction Methods 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000005913 hydroamination reaction Methods 0.000 description 2
- 238000006197 hydroboration reaction Methods 0.000 description 2
- 238000005669 hydrocyanation reaction Methods 0.000 description 2
- 238000006459 hydrosilylation reaction Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229910052741 iridium Inorganic materials 0.000 description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 2
- JRTIUDXYIUKIIE-KZUMESAESA-N (1z,5z)-cycloocta-1,5-diene;nickel Chemical compound [Ni].C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 JRTIUDXYIUKIIE-KZUMESAESA-N 0.000 description 1
- VPSSPAXIFBTOHY-LURJTMIESA-N (2s)-2-amino-4-methylpentan-1-ol Chemical group CC(C)C[C@H](N)CO VPSSPAXIFBTOHY-LURJTMIESA-N 0.000 description 1
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 1
- VNNDVNZCGCCIPA-FDGPNNRMSA-N (z)-4-hydroxypent-3-en-2-one;manganese Chemical compound [Mn].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O VNNDVNZCGCCIPA-FDGPNNRMSA-N 0.000 description 1
- FSJSYDFBTIVUFD-SUKNRPLKSA-N (z)-4-hydroxypent-3-en-2-one;oxovanadium Chemical compound [V]=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FSJSYDFBTIVUFD-SUKNRPLKSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- HTPMVSFJFDRBTB-UHFFFAOYSA-M C[O-].[Na+].[OH-].[K+] Chemical compound C[O-].[Na+].[OH-].[K+] HTPMVSFJFDRBTB-UHFFFAOYSA-M 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 238000005865 alkene metathesis reaction Methods 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 238000005937 allylation reaction Methods 0.000 description 1
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 1
- 229960001372 aprepitant Drugs 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000006717 asymmetric allylation reaction Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- UDGHXQPQKQPSBB-UHFFFAOYSA-N benzenesulfonic acid;4-[4-[(4-chlorophenyl)-pyridin-2-ylmethoxy]piperidin-1-yl]butanoic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1.C1CN(CCCC(=O)O)CCC1OC(C=1N=CC=CC=1)C1=CC=C(Cl)C=C1 UDGHXQPQKQPSBB-UHFFFAOYSA-N 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 229960001105 bepotastine besilate Drugs 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- OJFSXZCBGQGRNV-UHFFFAOYSA-N carbinoxamine Chemical compound C=1C=CC=NC=1C(OCCN(C)C)C1=CC=C(Cl)C=C1 OJFSXZCBGQGRNV-UHFFFAOYSA-N 0.000 description 1
- 229960000428 carbinoxamine Drugs 0.000 description 1
- GGRQQHADVSXBQN-FGSKAQBVSA-N carbon monoxide;(z)-4-hydroxypent-3-en-2-one;rhodium Chemical compound [Rh].[O+]#[C-].[O+]#[C-].C\C(O)=C\C(C)=O GGRQQHADVSXBQN-FGSKAQBVSA-N 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 238000005356 chiral GC Methods 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000005366 cycloalkylthio group Chemical group 0.000 description 1
- 229930007927 cymene Natural products 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- FAQSSRBQWPBYQC-VGKOASNMSA-N dioxomolybdenum;(z)-4-hydroxypent-3-en-2-one Chemical compound O=[Mo]=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FAQSSRBQWPBYQC-VGKOASNMSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960002866 duloxetine Drugs 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical group [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000005350 fused silica glass Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 238000005930 hydroaminomethylation reaction Methods 0.000 description 1
- 238000007037 hydroformylation reaction Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 229910052743 krypton Inorganic materials 0.000 description 1
- DNNSSWSSYDEUBZ-UHFFFAOYSA-N krypton atom Chemical compound [Kr] DNNSSWSSYDEUBZ-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 125000005394 methallyl group Chemical group 0.000 description 1
- BNFDLGUZDIWYJK-UHFFFAOYSA-N n,n-dimethyl-2-[(4-methylphenyl)-phenylmethoxy]ethanamine;hydrochloride Chemical compound [Cl-].C=1C=C(C)C=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 BNFDLGUZDIWYJK-UHFFFAOYSA-N 0.000 description 1
- 229910052754 neon Inorganic materials 0.000 description 1
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 1
- BMGNSKKZFQMGDH-FDGPNNRMSA-L nickel(2+);(z)-4-oxopent-2-en-2-olate Chemical compound [Ni+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O BMGNSKKZFQMGDH-FDGPNNRMSA-L 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QVYRGXJJSLMXQH-UHFFFAOYSA-N orphenadrine Chemical compound C=1C=CC=C(C)C=1C(OCCN(C)C)C1=CC=CC=C1 QVYRGXJJSLMXQH-UHFFFAOYSA-N 0.000 description 1
- 229960003941 orphenadrine Drugs 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a chiral tetradentate phosphine ligand compound, a preparation method and application thereof. The chiral tetradentate phosphine ligand compound provided by the invention has the advantages of simple synthetic route, low cost and stable air. After the chiral tetradentate phosphine ligand and the transition metal form a complex, the complex is applied to the efficient asymmetric hydrogenation of various prochiral ketones; in the reaction process, the method shows excellent reactivity and enantioselectivity and has wide application prospect.
Description
Technical Field
The invention relates to the technical field of asymmetric catalysis, and particularly provides a chiral tetradentate phosphine ligand compound, a preparation method and application thereof in asymmetric hydrogenation reaction and similar reactions.
Background
Chiral compounds are widely found in natural products, bioactive molecules, and clinical drug molecules (or key intermediates thereof). In the field of new medicine research, 820 kinds of medicines are chiral molecules in more than 1200 kinds of medicines, and the ratio of the medicines is nearly seven. Chiral drug research has been very rapid in recent years, and various large drug research and development companies develop small molecular drug species. The proportion of compounds of single chirality gradually increases. The importance of chiral research is self-evident. Among all chiral compounds, chiral alcohols belong to a common class of chiral molecules and are widely applied to the fields of small molecule medicines, pesticides, natural compounds and functional materials. The asymmetric hydrogenation reaction catalyzed by the organic metal has the advantages of mild reaction condition, high efficiency, high selectivity, wide substrate application range and the like, and is widely focused and studied intensively. However, the central factor affecting the efficiency of asymmetric catalytic hydrogenation is a catalyst, which consists of a metal center and a ligand, and the available transition metal species are limited due to the limitation of the periodic table of elements, so that the development of novel chiral ligands is actually the most fundamental research topic in the field of asymmetric hydrogenation, throughout the entire history of asymmetric hydrogenation.
In asymmetric hydrogenation reactions, the structure of chiral ligands has an important influence on the activity and stereoselectivity of the reaction, so chemists can realize fine control over the reaction through reasonable ligand electrical and steric design. However, none of the ligands solves all the problems, and thus the development of chiral ligands and asymmetric catalytic systems with high efficiency, high selectivity and wide substrate applicability would be a constant topic. Although chiral phosphine ligands are now very abundant in both species and number, each ligand has its unique properties, and therefore, the development of novel chiral multidentate phosphine ligands is of great importance.
Disclosure of Invention
The invention aims to provide a chiral tetradentate phosphine ligand compound, a preparation method and application thereof. After the chiral tetradentate phosphine ligand and the transition metal form a complex, the complex is applied to efficient asymmetric hydrogenation (especially aromatic ketone compounds) of various prochiral ketones, the reaction obtains excellent reactivity and enantioselectivity under a higher conversion number, and the complex has excellent reactivity and enantioselectivity in the reaction process and wide application prospect. The chiral tetradentate phosphine ligand provided by the invention has the advantages of simple synthesis, easily available raw materials, stability in air atmosphere, high catalytic activity, high stereoselectivity and easiness in realizing industrial production.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
in one aspect, the invention provides a chiral tetradentate phosphine ligand compound (abbreviated as f-thiophamidol), which has a structure shown in a formula (I):
Wherein each R 1 is independently alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, or heteroaryl, or two R 1 together with the attached P atom form a heterocyclyl;
l 1 and L 2 are each independently selected from -NR2-C(＝O)-、-C(＝O)-NR2-、-C(＝O)-C(＝O)-、-((C(R3)2)q-C(＝O))x-、-C(＝O)-(C(R3)2)q)x- or- (C (R 3)2)q)x -;
q and x are independently selected from 0,1, 2, 3, 4, 5 or 6;
Each R 3 is independently H, -F, -Cl, -Br, -I, -CN, -CHO, nitro, alkoxy, alkylthio, haloalkyl, alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, or heteroaryl; or R 3 on two adjacent carbon atoms may form, together with the attached C, a cycloalkyl or aryl group of C 3-6;
Each R 2 is independently H or alkyl;
Each of R 1、R2 and R 3 is independently further mono-or polysubstituted with identical or different substituents; the substituents are selected from hydrogen, -F, -Cl, -Br, -I, -NH 2, -CN, -CHO, nitro, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl, C 4-12 heterocycloalkyl, C 6-12 aryl, C 5-12 heteroaryl or C 1-6 alkyl. The substituents of the invention may optionally be further substituted with-F, -Cl, -Br-I, -NH 2, -CN, -CHO, nitro, C 1-6 alkoxy C 1-6 alkylthio, C 3-12 cycloalkyl, C 4-12 heterocycloalkyl, C 6-12 aryl, C 5-12 heteroaryl or C 1-6 alkyl.
Further, each R 1 is independently C 1-6 alkyl, C 3-12 cycloalkyl, C 2-12 heterocyclyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, or C 1-12 heteroaryl, or two R 1 together with the attached P atom form a C 2-12 heterocyclyl. Further, each R 1 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, phenylmethyl, or the like; each R 1 is independently further mono-or polysubstituted with identical or different substituents; the substituent is selected from hydrogen, -F, -Cl, -Br, -I, -NH 2, -CN, -CHO, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidinyl and the like.
Further, each R 3 is independently H, -F, -Cl, -Br, -I, -CN, -CHO, nitro, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 alkyl, C 3-12 cycloalkyl, C 2-12 heterocyclyl, C 6-12 aryl, C 6-12 arylC 1-6 alkyl, or C 1-12 heteroaryl; or R 3 on two adjacent carbon atoms may form together with the attached C a cycloalkyl group of C 3-6 or a C 6-12 aryl group. Further, each R 3 is independently H, -F, -Cl, -Br, -I, -CN, -CHO, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, phenylmethyl, or the like.
Further, each R 2 is independently H or C 1-6 alkyl. Further, each R 2 is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, etc.
Further, L 1 and L 2 are each independently selected from the following substructures:
further, the invention provides a chiral tetradentate phosphine ligand compound, the structure of which is shown as a formula (II):
Wherein each R 1 and R 3 has the meaning as described in the present invention.
Further, the invention provides a chiral tetradentate phosphine ligand compound, the structure of which is shown as a formula (III):
Wherein each R 1 and R 3 has the meaning as described in the present invention.
Further, the compounds of the present invention are selected from one of the following structures:
in another aspect, the invention provides a method for preparing a chiral tetradentate phosphine ligand compound, comprising the following specific steps:
S1, condensing the compound 1 and the compound 5 at a high temperature to obtain a compound 2;
S2, sequentially reacting the compound 2 with sodium hydroxide and acetic acid, and removing an ester group protecting group to obtain a compound 3;
s3, condensing the compound 3 with the compound 4 to obtain a compound shown in a formula (I);
Wherein each R 1、L1、L2 and R 3 has the meaning as described in the present invention.
In another aspect, the invention provides a method for preparing a chiral tetradentate phosphine ligand compound, comprising the following specific steps:
s1, condensing the compound 1 with methyl thioglycolate at a high temperature to obtain a compound 6;
S2, sequentially reacting the compound 6 with sodium hydroxide and acetic acid, and removing an ester group protecting group to obtain a compound 7;
s3, condensing the compound 7 with chiral amino alcohol 8 to obtain a compound shown in a formula (III);
Wherein each R 1 and R 3 has the meaning as described in the present invention.
Further, in S1, compound 1, methyl thioglycolate and tetrahydrofuran were added to a sealed tube equipped with a magnetic stirrer, heated in an oil bath at 120 ℃ overnight, after the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, half-saturated brine was added, then extraction was performed with ethyl acetate, the organic phases were combined, backwashed with half-saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by flash column chromatography to give a yellow solid as compound 6.
Further, the step S2 is: compound 6, sodium hydroxide, ethanol and water were added to a flask equipped with a magnetic stirrer, and after reacting at room temperature for 2 hours, excess acetic acid was added dropwise to the flask until the system became acidic. The residue was dissolved in ethyl acetate, half-saturated brine was added, followed by extraction with ethyl acetate, and the organic phases were combined, backwashed with half-saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a yellow oil as compound 7.
Further, the step S3 is: compound 7 was dissolved in anhydrous dichloromethane, triethylamine, chiral amino alcohol and benzotriazole-N, N' -tetramethylurea Hexafluorophosphate (HBTU) were added at room temperature, and reacted at room temperature for 12 hours. After the reaction, the reaction solution was concentrated and separated by column chromatography to obtain a pale yellow solid which was a compound represented by formula (III).
In another aspect, the present invention provides a chiral catalyst, which is a complex formed by complexing the chiral tetradentate phosphine ligand compound of the present invention with a transition metal salt. Further, the transition metal is selected from Ru, rh, pd, ir, fe, co, ni, cu, sc, ti, V, cr, mn, ag and Re. The transition metal salt used may be RuX3、RuHX(L)2(diphosphine)、RuX2(L)2(diphosphine)、Ru(arene)X2(diphosphine)、Ru(ary1group)X2、Ru(RCOO)2(diphsphine)、Ru(methallyl)2(diphine)、Ru(ary1group)X2(PPh3)3、Ru(COD)(COT)、Ru(COD)(COT)X、RuX2(cymene)、Ru(COD)n、Ru(arylgroup)X2(diphosphine)、RuC12(COD)、[Ru(COD)2]X、RuX2(diphosphine)、RuC12(＝CHR)(PR'3)2、Ru(ArH)C12、Ru(COD)(methallyl)2、Rh(CO)2C12、[Rh(NBD)2]BF4、[Rh(NBD)C1]2、[Rh(COD)C1]2、[Rh(COD)2]X、Rh(acac)(CO)2、Rh(ethylene)2(acac)、[Rh(ethylene)2C1]2、RhC1(PPh3)3、PdX2、Pd(PPh3)4、Pd(allyl)Cl、IrX3、[Ir(NBD)2)C1]2、[Ir(COD)C1]2、Ir(COD)X、FeX2、FeX3、Ni(acac)2、NiX2、[Ni(allyl)X]2、Ni(COD)2、CuX、CuX2、MoO2(acac)2、ScX2、Ti(OiPr)4、VO(acac)2、CrX2、CrX3、MnX2、Mn(acac)2、MeReO3.
In another aspect, the present invention provides the use of a chiral tetradentate phosphine ligand compound of the present invention in the preparation of a chiral catalyst.
In another aspect, the invention provides a chiral tetradentate phosphine ligand compound and application of the chiral tetradentate phosphine ligand compound in catalyzing asymmetric catalytic reaction. Further, the asymmetric reaction is an asymmetric hydrogenation reaction of prochiral ketone compounds, and is used for synthesizing chiral alcohols. The asymmetric reaction is as follows: asymmetric hydrogenation, asymmetric transfer hydrogenation, asymmetric hydroamination, asymmetric hydrocyanation, asymmetric hydrosilation, asymmetric hydroboration, asymmetric allylation, asymmetric coupling, asymmetric cyclization, asymmetric Michael addition, asymmetric epoxidation, asymmetric Aldol, asymmetric Mannich, asymmetric Diels-Alder, asymmetric cycloisomerization, hydroformylation, hydrosilation, hydroboration, hydrohydroxylation, hydroamination, hydrocyanation, isomerisation formylation, hydroaminomethylation, transfer hydrogenation, allylation, olefin metathesis, cycloisomerization, asymmetric coupling, michael addition, asymmetric epoxidation, kinetic resolution, and [ m+n ] cyclization. The prochiral ketone compounds include simple aryl alkyl ketone, conjugated ketene, alpha-hydroxy aryl alkyl ketone, alpha-amino aryl alkyl ketone, alpha-chloro aryl alkyl ketone, beta-keto ester, aryl (hetero) aryl ketone, etc.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl.
The term "aryl" refers to a6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl.
Substituted phenyl means phenyl having at least one substituent, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
The ligand disclosed by the invention is a novel chiral tetradentate phosphine ligand, and has the advantages of simple synthesis, easy modification, good stability and the like. The metal complex of the ligand shows excellent catalytic activity and extremely high enantioselectivity in the asymmetric hydrogenation reaction of ketone, can efficiently reduce prochiral ketone such as alpha, beta-unsaturated ketone, simple aryl alkyl ketone, alpha-hydroxyaryl alkyl ketone, alpha-amino aryl alkyl ketone, alpha-chloro aryl alkyl ketone, beta-keto ester, aryl (hetero) aryl ketone and the like into corresponding chiral alcohol, and has important industrial application value.
The ligand has the following advantages: 1. the synthesis is simple. Most chiral ligands can be prepared by only 4-6 steps of reaction, and the yield is high; 2. the ligand is stable. The series of ligands are insensitive to water and oxygen, and are convenient to store and use; 3. the ligand is easily modified. A series of chiral tetradentate ligands with rich structures can be quickly and efficiently synthesized through the combination and replacement of the connecting units, and steric hindrance and electric regulation are realized. 4. High catalytic activity and high selectivity. The catalyst shows extremely high catalytic activity and excellent stereoselectivity in asymmetric hydrogenation of ketone.
The invention provides a chiral tetradentate phosphine ligand, a preparation method and application thereof, wherein the chiral tetradentate phosphine ligand based on ferrocene skeleton is constructed as the ligand to be in-situ complexed with metallic iridium to prepare the chiral catalyst, the metallic complex is applied to asymmetric catalytic reaction, especially to asymmetric hydrogenation of ketone, and experimental results show that the asymmetric hydrogenation reaction with high reactivity and high stereoselectivity can be realized under higher conversion number.
The tetradentate ligand developed by the invention has excellent performance in asymmetric hydrogenation of a series of prochiral ketones, can efficiently prepare a series of chiral alcohols, and has high enantioselectivity, high yield and high conversion number (TON). Most ketone substrates can achieve a conversion of 99% or more and an ee value of 99% or more at a catalyst level of 0.01mol% (S/c=10000). The ligand and the corresponding catalytic hydrogenation method can be used for synthesizing key chiral fragments of Ezetimine、Duloxetine、Aprepitant、Crizotinib、bepotastine besilate、carbinoxamine、orphenadine、neobenodine and other medicaments, and have important application value and wide industrial application prospect.
Drawings
FIG. 1 Nuclear magnetic resonance Spectrometry for ligand L2
FIG. 2 Nuclear magnetic resonance Spectrometry for ligand L8
The invention will be further illustrated with reference to specific examples. These examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
Detailed Description
The application will be described in further detail below with reference to the drawings by means of specific embodiments. In the following embodiments, numerous specific details are set forth in order to provide a better understanding of the present application. However, one skilled in the art will readily recognize that some of the features may be omitted in various situations, or replaced by other materials, methods. In some cases, some operations related to the present application are not shown or described in the specification in order to avoid flooding the core of the present application with excessive descriptions, and detailed descriptions of the related operations are not necessary for those skilled in the art, and they are fully understood from the descriptions in the specification and the general knowledge in the art
Furthermore, the described features, operations, or characteristics of the description may be combined in any suitable manner in various embodiments. Also, various steps or acts in the method descriptions may be interchanged or modified in a manner apparent to those of ordinary skill in the art. Thus, the various orders in the description and drawings are for clarity of description of only certain embodiments, and are not meant to be required orders unless otherwise indicated.
The numbering of the components itself, e.g. "first", "second", etc., is used herein merely to distinguish between the described objects and does not have any sequential or technical meaning.
The invention aims to solve the technical problem of providing a chiral tetradentate phosphine ligand, a preparation method and application thereof, and the chiral tetradentate phosphine ligand and metallic iridium forming catalyst provided by the invention are applied to asymmetric hydrogenation of ketone, and the reaction obtains excellent reaction activity and enantioselectivity under higher conversion number.
The application of the catalyst in catalyzing asymmetric hydrogenation of aromatic ketone compounds is shown as follows:
In one embodiment, the compound of formula a may be at least one of a1 to a 14:
in one embodiment, the chiral alcohol of formula b may be at least one of b1 to b 14:
In one embodiment, the method of preparing the catalyst may include: the transition metal precursor and the ligand f-thiophamidol are mixed in a solvent to obtain a catalyst.
In one embodiment, the asymmetric hydrogenation reaction may be carried out in an alcoholic solvent.
In one embodiment, the basic compound is added in an amount of 5.0 to 10.0% molar equivalents of the compound of formula a.
In one embodiment, the strong base condition may be formed by adding at least one of potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, potassium methoxide, sodium methoxide potassium hydroxide to the aprotic solvent.
In one embodiment, the pressure of hydrogen at the time of the reaction may be 30-50atm.
In one embodiment, the catalyst may be used in an amount of 0.01 molar equivalents of the compound of formula a. Preferably, the catalyst is used in an amount of 5X 10 -5 molar equivalents of the compound of formula I.
In one embodiment, the reaction time may be 12-48 hours.
In one embodiment, the reaction is carried out in an oxygen-free environment.
In one embodiment, the oxygen-free environment is an inert gas atmosphere.
In one embodiment, the inert gas is at least one of nitrogen, helium, neon, argon, krypton, and xenon. Preferably, the inert gas is nitrogen.
In the application, inert gas is introduced into the reaction system, mainly to form an anaerobic environment, and if the anaerobic environment can be ensured, the inert gas can be not used; in one implementation of the application, even though inert gas is used, a substantial portion of the overall reaction environment is hydrogen, e.g., greater than 99% hydrogen, with the remainder being inert gas.
The application discloses chiral alcohol obtained by the preparation method.
The application uses f-thiophamidol ligand high-efficiency asymmetric catalytic hydrogenation method to reduce alkyl aryl ketone compound, divergently synthesizes chiral alcohol derivative shown in structural formula b, and the obtained product has high optical purity and can be used as intermediate of various bioactive compounds.
The application is further illustrated by the following examples. The following examples are merely illustrative of the present application and should not be construed as limiting the application.
Ligand preparation example, ligand L2 is taken as an example:
S1, compound 1 (335 mg,1 mmol), methyl thioglycolate (212 mg,2 mmol) and tetrahydrofuran (2 mL) were added to a tube sealed with a magnetic stirrer, heated overnight in an oil bath at 120℃and after the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate (5 mL), half-saturated brine (10 mL) was added, followed by extraction with ethyl acetate (10 mL), the organic phases were combined, backwashed with half-saturated brine (10 mL), dried over anhydrous sodium sulfate (3 g), concentrated, and separated by flash column chromatography to give Compound 6 (413 mg,75% yield) as a yellow solid.
S2: to a flask equipped with a magnetic stirrer, compound 6 (413 mg), sodium hydroxide (200 mg), ethanol (3 mL) and water (3 mL) were added, and after reacting at room temperature for 2 hours, excess acetic acid was added dropwise to the flask until the system became acidic (3 to 4). The residue was dissolved in ethyl acetate (5 mL), half-saturated brine (10 mL) was added, followed by extraction with ethyl acetate (10 mL), and the organic phases were combined, backwashed with half-saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give compound 7 (369 mg,93% yield) as a yellow oil, which was directly subjected to the next reaction without purification.
Further, the step S3 is: compound 7 (369 mg) was dissolved in anhydrous dichloromethane (2 mL), and triethylamine (202. Mu.L), L-tertiary leucinol (117 mg) and benzotriazole-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU) (380 mg) were added at room temperature and reacted at room temperature for 12 hours. After the completion of the reaction, the reaction mixture was concentrated and separated by column chromatography to give compound L2 (316 mg,71% yield) as a pale yellow solid.
The following are partial product ligand nuclear magnetic data:
The nuclear magnetic data of the product L2 is 1H NMR(600MHz,CDCl3)δ7.60(t,J＝8.0Hz,2H),7.40(d,J＝7.4Hz,3H),7.22(d,J＝5.4Hz,3H),7.19–7.13(m,2H),6.89(d,J＝8.8Hz,1H),4.46(s,1H),4.39(d,J＝7.8Hz,2H),4.05(s,1H),3.89(s,5H),3.81(dd,J＝11.3,3.2Hz,1H),3.73(dd,J＝17.0,3.2Hz,1H),3.49(dd,J＝11.3,8.2Hz,1H),3.14(d,J＝16.9Hz,1H),3.04(d,J＝16.9Hz,1H),1.76(d,J＝6.9Hz,3H),0.97(s,9H).
The nuclear magnetic data of the product L6 is 1H NMR(600MHz,CDCl3)δ7.37(d,J＝11.8Hz,1H),7.21(s,1H),7.19–7.12(m,2H),7.06(m,1H),7.03(s,1H),6.75(d,J＝7.9Hz,1H),4.44(d,J＝2.8Hz,1H),4.40–4.32(m,2H),4.03(s,1H),3.89(s,5H),3.81(dd,J＝11.3,3.2Hz,1H),3.72(dd,J＝17.0,3.2Hz,1H),3.48(dd,J＝11.3,8.2Hz,1H),3.14(d,J＝16.9Hz,1H),3.04(d,J＝16.9Hz,1H),2.33(s,6H),2.20(s,6H),1.72(d,J＝6.9Hz,3H),0.97(s,9H).
The nuclear magnetic data of the product L8 is 1H NMR(600MHz,CDCl3)δ7.60(ddd,J＝9.5,5.8,2.1Hz,2H),7.44–7.37(m,3H),7.21(h,J＝2.2Hz,3H),7.15(td,J＝7.2,2.2Hz,2H),7.06(d,J＝8.1Hz,1H),4.48(q,J＝2.0Hz,1H),4.40(t,J＝2.6Hz,1H),4.35(qd,J＝6.8,3.2Hz,1H),4.06(dt,J＝2.4,1.0Hz,1H),3.87(s,5H),3.69(dt,J＝11.4,3.7Hz,1H),3.59(dt,J＝11.1,5.3Hz,1H),3.56–3.49(m,1H),3.21(d,J＝17.1Hz,1H),3.04(d,J＝17.1Hz,1H),2.73(d,J＝5.8Hz,1H),1.76(d,J＝6.9Hz,3H),0.97(d,J＝6.8Hz,3H),0.94(d,J＝6.8Hz,3H).
Application examples
(1) Synthesis of chiral alcohols of Structure b
Under nitrogen atmosphere, adding 0.2mmol of acetophenone derivative of the compound shown in the structural formula a, then adding 0.001mmol of metal precursor [ Ir (COD) Cl ] 2, 0.002mmol of ligand L, 0.002mmol of potassium tert-butoxide and 1.0mL of deoxidized isopropanol into a hydrogenation bottle, transferring into a pressure kettle, wherein inert gas in a reaction chamber is nitrogen, more than 99% of the reaction atmosphere is hydrogen, setting hydrogen pressure to 30atm, and reacting for 12h at 25 ℃. Then slowly releasing hydrogen, adding 10.0mL of dichloromethane for dilution, quenching with 8.0mL of water, separating an organic phase, washing the aqueous phase twice with 10.0mL of dichloromethane, then combining the organic phases, drying with anhydrous sodium sulfate, concentrating to obtain a crude product, and separating and purifying by column chromatography to obtain the clean chiral alcohol shown in the structural formula b.
(3) Product structure, yield and enantioselectivity detection
The structure of the hydrogenated product was determined by 1 H NMR and 13 C NMR spectra, the ee value (enantioselectivity) of the product was determined by HPLC (high performance liquid chromatography), the yield (yield) was analyzed by nuclear magnetic resonance hydrogen spectroscopy, and the optical rotation value of the product was determined by using a polarimeter.
The chiral alcohols of b1 to b14 were specifically synthesized in this example, and the structure of each product and its yield and enantioselectivity result were as follows:
The specific synthetic procedures of the partial products and their product structure, yield and enantioselectivity detection analysis data are schematically illustrated in this example, and are specifically as follows:
a) Synthesis of chiral cyclic alcohol represented by b1
24.0Mg of acetophenone shown in b1, namely 0.2mmol, 2 6.7.7 mg of metal precursor [ Ir (COD) Cl ] or 0.001mmol, 12.6mg of ligand L, namely 0.002mmol, 2.2mg of potassium tert-butoxide, namely 0.002mmol and 1.0mL of deoxidized isopropanol are added into a hydrogenation bottle under the inert gas atmosphere, then the mixture is transferred into an autoclave, inert gas in a reaction chamber is nitrogen, more than 99% of the reaction atmosphere is hydrogen, the hydrogen pressure is 10atm, and the reaction is carried out for 12 hours at 25 ℃. Then hydrogen is slowly released, 10.0mL of dichloromethane is added for dilution, 8.0mL of water is used for quenching, an organic phase is separated, 10.0mL of dichloromethane is used for washing two times of water phases, then the organic phases are combined, anhydrous sodium sulfate is used for drying, concentration is carried out, crude products are obtained, and the crude products are separated and purified through column chromatography to obtain clean chiral alcohol shown as a structural formula b 1.
Nuclear magnetic resonance analysis showed a colorless oil, 23.9mg,99% yield, 98% ee; the nuclear magnetic data of the product b1 are 1H NMR(400MHz,CDCl3)δ7.37–7.29(m,4H),7.28–7.21(m,1H),4.84(q,J＝6.4Hz,1H),2.15(s,1H),1.46(dd,J＝6.5,1.1Hz,3H).13C NMR(101MHz,CDCl3)δ145.9,128.5,127.5,125.4,70.4,25.2.[α]D20＝+50.15(c＝1.0,CHCl3).
Ee was determined by chiral GC (Supelco β -DEXTM 120, df=0.25 mm i.d. x 30cm, fused silica capillary column) carrier gas, N2 (flow 1.2 mL/min); injection temperature, 220 ℃; initial column temperature, 80 ℃; progress, 2.0 ℃/min; the final column temperature was 120 ℃, which was held for 20 minutes; detector temperature, 240 ℃; tR (R) =23.73 min (primary), tR (S) =25.03 min.
B) Synthesis of chiral cyclic alcohol shown in b1 by high conversion number
Under inert gas atmosphere, metal precursor [ Ir (COD) Cl ] 2 0.005.005 mmol and ligand L2.01 mmol are dissolved in 5mL isopropanol solution, and stirred at room temperature for 2h until complete dissolution.
2.4G of acetophenone shown in b1, namely 20mmol, 0.5mL of the catalyst solution, 448.8mg of potassium tert-butoxide, namely 0.4mmol, and 10.0mL of deoxidized isopropanol are added into a hydrogenation bottle, then the mixture is transferred into an autoclave, inert gas in a reaction chamber is nitrogen, more than 99% of the inert gas in the reaction atmosphere is hydrogen, the hydrogen pressure is 50atm, and the reaction is carried out for 48 hours at 25 ℃. Then slowly releasing hydrogen, adding 30.0mL of dichloromethane for dilution, quenching with 20.0mL of water, separating an organic phase, washing the aqueous phase twice with 30.0mL of dichloromethane, then combining the organic phases, drying with anhydrous sodium sulfate, concentrating to obtain a crude product, and separating and purifying by column chromatography to obtain the clean chiral alcohol shown as the structural formula b 1.
In summary, the chiral alcohols shown in b1 to b14 are respectively synthesized by adopting the acetophenone derivatives shown in a1 to a14 in the embodiment, and the synthesis method has the advantages of low cost and easy obtainment of raw materials, simple operation steps, high catalytic efficiency, high yield, high product enantioselectivity and the like.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (10)
1. A chiral tetradentate phosphine ligand compound or an isomer thereof, which is characterized in that the structure is shown as a formula (I):
Wherein each R 1 is independently alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, or heteroaryl, or two R 1 together with the attached P atom form a heterocyclyl;
l 1 and L 2 are each independently selected from -NR2-C(＝O)-、-C(＝O)-NR2-、-C(＝O)-C(＝O)-、-((C(R3)2)q-C(＝O))x-、-C(＝O)-(C(R3)2)q)x- or- (C (R 3)2)q)x -;
q and x are independently selected from 0,1, 2, 3, 4, 5 or 6;
Each R 3 is independently H, -F, -Cl, -Br, -I, -CN, -CHO, nitro, alkoxy, alkylthio, haloalkyl, alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, or heteroaryl; or R 3 on two adjacent carbon atoms may form, together with the attached C, a cycloalkyl or aryl group of C 3-6;
Each R 2 is independently H or alkyl;
Each of R 1、R2 and R 3 is independently further mono-or polysubstituted with identical or different substituents; the substituents are selected from hydrogen, -F, -Cl, -Br, -I, -NH 2, -CN, -CHO, nitro, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl, C 4-12 heterocycloalkyl, C 6-12 aryl, C 1-12 heteroaryl or C 1-6 alkyl.
2. The chiral tetradentate phosphine ligand compound of claim 1, wherein each R 1 is independently C 1-6 alkyl, C 3-12 cycloalkyl, C 2-12 heterocyclyl, C 6-12 aryl, C 6-12 arylc 1-6 alkyl or C 1-12 heteroaryl, or two R 1 together with the attached P atom form a C 2-12 heterocyclyl; preferably, each R 1 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, phenylmethyl, or the like; each R 1 is independently further mono-or polysubstituted with identical or different substituents; the substituent is selected from hydrogen, -F, -Cl, -Br, -I, -NH 2, -CN, -CHO, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, phenyl, naphthyl, pyridyl and pyrimidinyl;
Each R 3 is independently H, -F, -Cl, -Br, -I, -CN, -CHO, nitro, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 alkyl, C 3-12 cycloalkyl, C 2-12 heterocyclyl, C 6-12 aryl, C 6-12 arylC 1-6 alkyl or C 1-12 heteroaryl; or R 3 on two adjacent carbon atoms may form, together with the attached C, a cycloalkyl group of C 3-6 or a C 6-12 aryl group; preferably, each R 3 is independently H, -F, -Cl, -Br, -I, -CN, -CHO, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, phenyl, naphthyl, pyridinyl, pyrimidinyl or phenylmethyl;
Each R 2 is independently H or C 1-6 alkyl; preferably, each R 2 is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl.
3. The chiral tetradentate phosphine ligand compound of claim 1, wherein each of L 1 and L 2 is independently selected from one of the following substructures:
4. the chiral tetradentate phosphine ligand compound according to claim 1, wherein the structure is as follows:
Wherein each R 1 and R 3 has the meaning as defined in claim 1.
5. The chiral tetradentate phosphine ligand compound according to claim 1, wherein said compound is selected from one of the following structures:
6. a process for the preparation of a chiral tetradentate phosphine ligand compound according to any one of claims 1 to 5, comprising the steps of:
S1, condensing the compound 1 and the compound 5 at a high temperature to obtain a compound 2;
S2, sequentially reacting the compound 2 with sodium hydroxide and acetic acid, and removing an ester group protecting group to obtain a compound 3;
s3, condensing the compound 3 with the compound 4 to obtain a compound shown in a formula (I);
Wherein each R 1、L1、L2 and R 3 has the meaning as defined in claim 1.
7. A process for the preparation of a chiral tetradentate phosphine ligand compound according to any one of claims 1 to 5, comprising the steps of:
s1, condensing the compound 1 with methyl thioglycolate at a high temperature to obtain a compound 6;
S2, sequentially reacting the compound 6 with sodium hydroxide and acetic acid, and removing an ester group protecting group to obtain a compound 7;
s3, condensing the compound 7 with chiral amino alcohol 8 to obtain a compound shown in a formula (III);
Wherein each R 1 and R 3 has the meaning as defined in claim 1.
8. A chiral catalyst, characterized in that the chiral catalyst is a complex formed after the chiral tetradentate phosphine ligand compound according to any one of claims 1to 5 is complexed with a transition metal salt; preferably, the transition metal is selected from Ru, rh, pd, ir, fe, co, ni, cu, sc, ti, V, cr, mn, ag and Re.
9. Use of a chiral tetradentate phosphine ligand compound according to any of claims 1-5 in the preparation of a chiral catalyst.
10. Use of a chiral tetradentate phosphine ligand compound according to any one of claims 1 to 5 and a catalyst prepared therefrom for catalyzing asymmetric hydrogenation reactions.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410682078.XA CN118620007A (en) | 2024-05-29 | 2024-05-29 | Chiral tetradentate phosphine ligand compound, and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410682078.XA CN118620007A (en) | 2024-05-29 | 2024-05-29 | Chiral tetradentate phosphine ligand compound, and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118620007A true CN118620007A (en) | 2024-09-10 |
Family
ID=92606377
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410682078.XA Pending CN118620007A (en) | 2024-05-29 | 2024-05-29 | Chiral tetradentate phosphine ligand compound, and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN118620007A (en) |
-
2024
- 2024-05-29 CN CN202410682078.XA patent/CN118620007A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8558017B2 (en) | Ruthenium (II) catalysts for use in stereoselective cyclopropanations | |
| CN113563370B (en) | Preparation method for preparing beta-boron-based ketone with alpha-position substituent by catalysis of chitosan loaded copper material | |
| CN101671365A (en) | Chiral spiro aminophosphine ligand compound and synthesis method as well as application thereof | |
| KR100384411B1 (en) | Chiral ligand in heteroaromatic diphosphine | |
| Wang et al. | Synthesis and application of a dual chiral [2.2] paracyclophane-based N-heterocyclic carbene in enantioselective β-boration of acyclic enones | |
| CN114315917B (en) | Chiral ferrocene PNNO tetradentate ligand and application thereof in asymmetric hydrogenation reaction | |
| CN110724164A (en) | Preparation method and application of 3-substituted chiral spiro aminophosphine ligand on pyridine ring | |
| Duan et al. | Synthesis of new alkoxy/sulfonate-substituted carbene precursors derived from [2.2] paracyclophane and their application in the asymmetric arylation of aldehydes | |
| JP2006508161A (en) | Catalytic hydrogenation of carbon-heteroatom double bonds | |
| RU2446154C2 (en) | Sulphonylated diphenylethylene diamines, synthesis method thereof and use in transfer hydrogenation catalysis | |
| Gladiali et al. | Optically active phenanthrolines in asymmetric catalysis. III. Highly efficient enantioselective transfer hydrogenation of acetophenone by chiral rhodium/3-alkyl phenanthroline catalysts. | |
| CN114478362A (en) | Preparation method of chiral pyridinol derivative | |
| CN109575060B (en) | Synthesis of spiro bisboron catalyst and application of spiro bisboron catalyst in hydrogenation reaction | |
| CN111217809B (en) | Chiral nitrogen-containing diene ligand and preparation method and application thereof | |
| Yuan et al. | A class of readily available optically pure 7, 7′-disubstituted BINAPs for asymmetric catalysis | |
| CN118620007A (en) | Chiral tetradentate phosphine ligand compound, and preparation method and application thereof | |
| WO2023077643A1 (en) | Chiral multidentate ligand and use thereof in asymmetric hydrogenation | |
| CN115536708A (en) | Chiral diphosphine ligand of ferrocene skeleton and preparation method and application thereof | |
| US7094725B2 (en) | Biphenyldiphosphine compounds | |
| JP2001526111A (en) | Catalyst compositions based on chiral ligands having molybdenum, tungsten or chromium and methods for asymmetric alkylation of allylic substrates | |
| JP3710846B2 (en) | Asymmetric hydrogenation of ketoisophorone derivatives | |
| CN110790708B (en) | Preparation method of Ailixipine intermediate | |
| CN106045985B (en) | A kind of bisoxazoline class compound and preparation method and purposes | |
| Cao et al. | Synthesis of [CNN] pincer nickel (ii) NHC chlorides and their catalytic effects on the hydrosilylation of aldehydes and ketones under mild conditions | |
| EP4257593A1 (en) | Chiral multidentate ligand and use thereof in asymmetric hydrogenation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |