CN117567523A - 不对称氢化制备手性环胺的方法、所用催化剂和催化剂制备方法 - Google Patents
不对称氢化制备手性环胺的方法、所用催化剂和催化剂制备方法 Download PDFInfo
- Publication number
- CN117567523A CN117567523A CN202311564920.1A CN202311564920A CN117567523A CN 117567523 A CN117567523 A CN 117567523A CN 202311564920 A CN202311564920 A CN 202311564920A CN 117567523 A CN117567523 A CN 117567523A
- Authority
- CN
- China
- Prior art keywords
- catalyst
- asymmetric hydrogenation
- preparing
- cyclic amine
- chiral
- 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
- 239000003054 catalyst Substances 0.000 title claims abstract description 66
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 title claims abstract description 36
- -1 cyclic amine Chemical class 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 239000000543 intermediate Substances 0.000 claims abstract description 15
- 239000011572 manganese Substances 0.000 claims abstract description 15
- 239000003446 ligand Substances 0.000 claims abstract description 7
- 230000000536 complexating effect Effects 0.000 claims abstract description 3
- RJYMRRJVDRJMJW-UHFFFAOYSA-L dibromomanganese Chemical compound Br[Mn]Br RJYMRRJVDRJMJW-UHFFFAOYSA-L 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 79
- 239000000758 substrate Substances 0.000 claims description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- WAJNQUGXOWDSHH-UHFFFAOYSA-N cyclopenta-1,3-diene;2-cyclopenta-2,4-dien-1-ylethanamine;iron(2+) Chemical compound [Fe+2].C=1C=C[CH-]C=1.NCC[C-]1C=CC=C1 WAJNQUGXOWDSHH-UHFFFAOYSA-N 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- ODRITQGYYWHQGM-INIZCTEOSA-N ClC1=CC=C(C=C1)[C@H]1N(CCC1)C(=O)C=1C=C2C(=NC=1)NN=C2C Chemical compound ClC1=CC=C(C=C1)[C@H]1N(CCC1)C(=O)C=1C=C2C(=NC=1)NN=C2C ODRITQGYYWHQGM-INIZCTEOSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- MYKUKUCHPMASKF-VIFPVBQESA-N (S)-nornicotine Chemical compound C1CCN[C@@H]1C1=CC=CN=C1 MYKUKUCHPMASKF-VIFPVBQESA-N 0.000 claims description 4
- JIAKIQWNYAZUJD-UHFFFAOYSA-N 6,7-dihydro-5h-quinolin-8-one Chemical compound C1=CN=C2C(=O)CCCC2=C1 JIAKIQWNYAZUJD-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- MYKUKUCHPMASKF-UHFFFAOYSA-N Nornicotine Natural products C1CCNC1C1=CC=CN=C1 MYKUKUCHPMASKF-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 9
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 abstract description 8
- 229910052748 manganese Inorganic materials 0.000 abstract description 8
- 150000001412 amines Chemical class 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract 1
- 150000003053 piperidines Chemical class 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 229910052739 hydrogen Inorganic materials 0.000 description 24
- 239000001257 hydrogen Substances 0.000 description 24
- 238000003756 stirring Methods 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000011049 filling Methods 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 238000007789 sealing Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- NYNZQNWKBKUAII-KBXCAEBGSA-N (3s)-n-[5-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide Chemical compound C1[C@@H](O)CCN1C(=O)NC1=C2N=C(N3[C@H](CCC3)C=3C(=CC=C(F)C=3)F)C=CN2N=C1 NYNZQNWKBKUAII-KBXCAEBGSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000006555 catalytic reaction Methods 0.000 description 5
- 229950003970 larotrectinib Drugs 0.000 description 5
- DPNGWXJMIILTBS-UHFFFAOYSA-N myosmine Chemical class C1CCN=C1C1=CC=CN=C1 DPNGWXJMIILTBS-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229910000510 noble metal Inorganic materials 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229960002715 nicotine Drugs 0.000 description 3
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 102100035108 High affinity nerve growth factor receptor Human genes 0.000 description 2
- 101000596894 Homo sapiens High affinity nerve growth factor receptor Proteins 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 230000003044 adaptive effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 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
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 150000003235 pyrrolidines Chemical class 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QOGXQLSFJCIDNY-UHFFFAOYSA-N 2-chloro-5-fluoropyridine Chemical compound FC1=CC=C(Cl)N=C1 QOGXQLSFJCIDNY-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 102100024456 Cyclin-dependent kinase 8 Human genes 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 101000980937 Homo sapiens Cyclin-dependent kinase 8 Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- KUXDQQMEFBFTGX-UHFFFAOYSA-N [N].P Chemical compound [N].P KUXDQQMEFBFTGX-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 150000008365 aromatic ketones Chemical class 0.000 description 1
- DLGYNVMUCSTYDQ-UHFFFAOYSA-N azane;pyridine Chemical compound N.C1=CC=NC=C1 DLGYNVMUCSTYDQ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003571 electronic cigarette Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- QKGYJVXSKCDGOK-UHFFFAOYSA-N hexane;propan-2-ol Chemical compound CC(C)O.CCCCCC QKGYJVXSKCDGOK-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- OEBIHOVSAMBXIB-SJKOYZFVSA-N selitrectinib Chemical compound C[C@@H]1CCC2=NC=C(F)C=C2[C@H]2CCCN2C2=NC3=C(C=NN3C=C2)C(=O)N1 OEBIHOVSAMBXIB-SJKOYZFVSA-N 0.000 description 1
- 229940121609 selitrectinib Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 108010064884 trkA Receptor Proteins 0.000 description 1
- 102000015533 trkA Receptor Human genes 0.000 description 1
- 230000004614 tumor growth Effects 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
- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
- B01J2231/645—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of C=C or C-C triple bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种不对称氢化制备手性环胺所用催化剂和催化剂制备方法,为五羰基溴化锰与手性配体络合而成。本发明还公开了一种不对称氢化方法制备手性环胺的方法及其应用。本发明的起始原料为各种环亚胺类化合物,该类化合物可由已报导方法制备所得;将该类化合物用手性锰催化剂进行不对称氢化反应得到手性环胺类化合物。对应选择性最高可达≥99%ee,利用本发明的方法,可高效、高选择性地制备一系列手性吡咯烷或手性哌啶化合物,该方法可用于工业上制备重要的手性胺类药物中间体,具有重要的实用价值及应用前景。
Description
技术领域
本发明属于化学催化反应技术领域,具体涉及一种不对称氢化制备手性环胺的方法、所用催化剂和催化剂制备方法。
背景技术
手性吡咯烷分子是一类重要的手性合成砌块,可用于合成多种药物,天然产物,农药的中间体。如烟草,电子烟中的有效成分尼古丁,也可作为一种杀虫剂使用;以及新型杀虫剂S-毒藜碱。
在药物合成领域,如新抗癌药物Selitrectinib是一种新一代选择性TRK抑制剂,它可以通过抑制TRKA受体激酶,达到抑制肿瘤细胞生长;2017年中国上市的抗癌药物Larotrectinib,该药物通过靶向NTRK基因来恢复TRK正常功能,从而阻止肿瘤细胞的生长和蔓延,该药物适用于多种癌症;活性药物MSC2530818是一种有效,选择性,抑制CDK8的抑制剂,有抗直肠癌的作用。
这几种药物中都含有手性吡咯烷砌块,制备手性吡咯烷是合成这些药物的关键步骤。目前制备手性吡咯烷的方法主要有贵金属催化,如周其林课题组在2015年发表的工作(J.Am.Chem.Soc.2015,137,90-93),周其林等人报导用金属铱催化剂对带有取代基的麦斯明衍生物进行不对称氢化,因为取代基可以降低麦斯明分子上的两个氮原子对催化活性中心的配位作用,但由于吡啶氮配位的影响,不能直接对麦斯明进行氢化;张绪穆等人使用其设计的金属铱催化剂(Nature Communications,2023,14,3718,CN 116102464),是先对芳香酮进行不对称氢化,再进行化学方法关环的方法合成尼古丁,而非直接对环亚胺不对称氢化制备去甲基烟碱。其具有反应步骤长,选择性差,收率低的缺陷,同时使用贵金属催化会造成生产成本的增加和重金属残留问题。Harald Groger等人利用酶催化制备Larotrectinib中间体(Org.Process Res.Dev.2022,26,2067-2074),但是生物酶催化反应,产物分离提纯比较困难,生物酶容易失活,并且该工作所催化的底物只有三种,这可能是由于酶对底物的适配性专一,应用范围不广泛。还有一些药物合成的报导,将环亚胺直接氢化为混旋产物再进行拆分(European Journal of Medicinal Chemistry 235(2022)114303),但这种最传统的方法会造成一半以上的原料浪费。
发明内容
由于锰为非贵金属,价格便宜,制备成本低,通过设计新型手性配体,调节锰催化不对称氢化环亚胺成为单一手性的胺,具有反应路线短,成本低的特点,具有潜在的药物合成以及天然化合物合成的价值;因此,本发明的目的在于提供一种不对称氢化制备手性环胺的方法、所用催化剂和催化剂制备方法,本发明合成了几种新型的PNN型手性膦氮配体,与Mn(CO)5Br反应合成了手性锰催化剂,利用手性锰催化剂对环亚胺不对称氢化,实现了温和条件下、高选择性合成手性吡咯烷类化合物,在药物合成中具有广泛的应用前景。
本发明的技术方案:
一种不对称氢化制备手性环胺所用催化剂,为五羰基溴化锰与手性配体络合而成,所述催化剂包括以下四种分别为Mn-1、Mn-2、Mn-3和Mn-4,其结构式为:
一种不对称氢化制备手性环胺所用催化剂制备方法,包括以下步骤:
S1、1-S-二苯基膦-2-R-氨基乙基二茂铁与6,7-二氢喹啉-8-(5H)-酮溶解在有机溶剂中,在酸性环境,还原剂作用下反应生成(RC,SP)-N-5,6,7,8-四氢喹啉基-1-(2-二芳基膦基)二茂铁基乙基胺;
化学反应式为:
S2、(RC,SP)-N-5,6,7,8-四氢喹啉基-1-(2-二芳基膦基)二茂铁基乙基胺与Mn(CO)5Br在有机溶剂中反应生成催化剂和Mn-1、Mn-2、Mn-3和Mn-4。
化学反应式为:
优选的,S1中所述1-S-二苯基膦-2-R-氨基乙基二茂铁与6,7-二氢喹啉-8-(5H)-酮的摩尔比为0.9:1-2:1;
S1中有机溶剂为二氯甲烷、1,4-二氧六环、四氢呋喃、乙腈、1,2-二氯乙烷,所述有机溶剂用量为每克6,7-二氢喹啉-8-(5H)-酮所需溶剂的量为20ml-100ml;
S1中添加酸产生酸性环境,所述酸为甲酸、乙酸、三氟乙酸,酸的的用量是1-S-二苯基膦-2-R-氨基乙基二茂铁所用摩尔量的10%-100%;
S1中所用还原剂为硼氢化钠、氰基硼氢化钠或三乙酰氧基硼氢化钠,1-S-二苯基膦-2-R-氨基乙基二茂铁与还原剂的摩尔为1:1-1:5;
S1中反应温度为0℃-80℃,反应时间为2h-24h。
优选的,S2中(RC,SP)-N-5,6,7,8-四氢喹啉基-1-(2-二芳基膦基)二茂铁基乙基胺与Mn(CO)5Br的摩尔比为1:1-2:1;
S2中有机溶剂为四氢呋喃、2-甲基四氢呋喃、乙二醇二甲醚、甲苯或甲基叔丁基醚,所述有机溶剂用量为每克Mn(CO)5Br所需溶剂的量为100ml-400ml;
S2中反应温度为20℃-100℃,反应时间为2h-24h;
S2的反应在惰性气体或氮气保护下进行。
一种不对称氢化制备手性环胺的方法,化学反应方程式如下:
其中化学通式a,b中,R表示苯环、吡啶环、带有取代基的苯环或带有取代基的吡啶环,n=1-2,代表含有4-5个碳原子的环。
优选的,催化剂的添加量为底物a摩尔量的0.05%-5%;
不对称氢化反应温度为40-110℃,不对称氢化反应的压力为0.5Mpa-8Mpa。
优选的,还添加助催化剂,所述助催化剂包括叔丁醇钾、叔丁醇钠、碳酸钠、碳酸钾、氢氧化钾或氢氧化钠,所述助催化剂的添加量为为底物a摩尔量的10%-50%。
优选的,所述催化剂为Mn-5,所述的助催化剂为叔丁醇钾。
优选的,用于制备去甲基烟碱、S-毒藜碱、Larotrectinib中间体、Selitrectinib中间体和MSC2530818中间体。
优选的,R为:
一种不对称氢化制备手性环胺所用催化剂制备方法,当R为吡啶环,n=1时,用于制备尼古丁的前体——去甲基烟碱,制备方法如下式:
一种不对称氢化制备手性环胺所用催化剂制备方法,当R为吡啶环,n=2时,用于制备S-毒藜碱,制备方法如下式:
一种不对称氢化制备手性环胺所用催化剂制备方法,当R为2,5-二氟苯基,n=1时,用于制备Larotrectinib中间体,制备方法如下式:
一种不对称氢化制备手性环胺所用催化剂制备方法,当R为3-(2-氯-5-氟吡啶)-基或3-2-甲氧基-5-氟吡啶,n=1时,用于制备Selitrectinib中间体,制备方法如下式:
一种不对称氢化制备手性环胺所用催化剂制备方法,当R为4-氯苯基,n=1时,该方法可用于制备药物MSC2530818的中间体,制备方法如下式:
本发明的有益效果:
本发明提供了四种手性锰催化剂,用于手性环亚胺类化合物的不对成氢化,制备手性环胺类化合物,该方法易于实现工业化放大,后处理简单,绿色环保;由于锰为非贵金属,价格便宜,该方法成本更低;催化剂光学选择性较高,所得产品无需进行拆分即可满足下游产品要求。
具体实施方式
为更进一步阐述本发明为实现预定发明目的所采取的技术手段及功效,以下结合较佳实施例,对依据本发明的具体实施方式、结构、特征及其功效,详细说明如后。
催化剂制备实施例:锰催化剂Mn-1、Mn-2、Mn-3和Mn-4的制备
(1)制备(RC,SP)-1-(2-二芳基膦基)二茂铁基乙胺(参照Organometallics 2014,33,2109-2114.)
如上式所示,将1(2.57g,10mmol)溶于20mL甲基叔丁基醚中,氮气保护下,在0℃下向其中逐滴滴加1.3M叔丁基锂的正戊烷溶液(8.5mL,11.05mol),滴加完毕后升至室温搅拌1.5h。
将体系降温至-80℃,向体系中滴加三氯化磷(1.57g,11.46mmol)于1mL甲基叔丁基醚中的溶液,滴加完毕后,将体系升至室温搅拌4h。
再将体系降温至-80℃,滴加25mmol ArLi在甲基叔丁基醚中的悬浊液(在氮气保护,-40℃下,由等摩尔量的ArBr和正丁基锂在甲基叔丁基醚中反应制得;当ArBr为溴代-3,5-2-均三联苯时,制备芳基锂时的溶剂为四氢呋喃,反应温度为-80℃),滴加完毕后,使体系缓慢从-80℃降至室温,反应过夜,用饱和氯化铵溶液溶液猝灭,乙酸乙酯萃取,收集有机相,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,蒸干溶剂,得到3粗产品,用硅胶色谱柱进行纯化,得到3纯产品。
3-1:Ar=2-naphatlene,橙色泡状固体,产率60%;
3-2:Ar=3,5-Ph2-C6H3,黄色泡状固体,产率71%;
3-3:Ar=3,5-Me2-4-OMe-C6H2,橙色泡状固体,产率68%。
3-4:Ar=3,5-tBu2-C6H3,黄色泡状固体,产率52%;
(2)1-S-二芳基膦-2-R-氨基乙基二茂铁的制备(参照Angew.Chem.Int.Ed.2022,e202202814.)
将3(3.4mmol)溶于5mL乙酸酐中,在氮气保护下,升温至50℃反应3h,在旋转蒸发仪上除去乙酸酐,得到粗产物4。
向粗产物4中加入10mL异丙醇,再加入7.5mL浓氨水,在氮气保护下升温至60℃反应12h,冷却至室温,乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,得到粗产品5,通过硅胶色谱柱纯化,得到纯产物5。
注:当Ar=5-Ph2-C6H3时,向粗产物4中加入10mL四氢呋喃,10mL甲醇胺溶液,氮气保护下升温至60℃反应12h,冷却至室温,乙酸乙酯萃取,饱和氯化钠溶液洗涤,无水硫酸钠干燥,得到粗产品5,通过硅胶色谱柱纯化,得到纯产物5。
5-1:Ar=2-naphatlene,橙色泡状固体,产率40%;
5-2:Ar=3,5-Ph2-C6H3,黄色泡状固体,产率20%;
5-3:Ar=3,5-Me2-4-OMe-C6H2,橙色泡状固体,产率67%。
5-4:Ar=3,5-tBu2-C6H3,黄色泡状固体,产率60%;
步骤(1)、(2)采用的是现有技术,步骤(3)开始是本发明的技术方案。
(3)(RC,SP)-N-5,6,7,8-四氢喹啉基-1-(2-二芳基膦基)二茂铁基乙基胺(催化剂配体)的制备:
将5(2.3mmol),6(0.35g,2.4mmol)溶于14mL 1,2-二氯乙烷中,加入三乙酰氧基硼氢化钠(1.5g,7mmol,3equiv),乙酸(69mg,1.15mmol,0.5equiv),在氮气保护下,30℃搅拌,反应过夜,而后用饱和碳酸氢钠溶液猝灭反应,二氯甲烷分三次萃取,收集有机相,将有机相用饱和氯化钠洗涤,无水硫酸钠干燥,蒸干溶剂,得到7粗品,将7粗品通过硅胶色谱柱纯化,得到纯净的7。
7-1:Ar=2-naphatlene,黄色泡状固体,产率71%。
1H NMR(400MHz,CDCl3)δ8.25(d,J=9.7Hz,1H),8.11(s,1H),7.87(d,J=6.4Hz,2H),7.81(d,J=8.0Hz,1H),7.71–7.56(m,4H),7.48–7.37(m,3H),7.35–7.18(m,2H),6.76–6.57(m,2H),4.64(s,1H),4.41(s,1H),4.30(s,1H),4.05(d,J=19.9Hz,5H),3.90(s,1H),3.82(s,1H),2.39–2.22(m,1H),1.96(d,J=16.4Hz,1H),1.81(d,J=20.6Hz,2H),1.72(d,J=5.4Hz,3H),1.62(s,1H).
13C NMR(101MHz,CDCl3)δ157.35,146.30,138.20,138.11,136.94,136.30,136.18,136.01,135.31,135.22,133.53,133.14,133.03,132.87,132.81,132.67,132.30,132.13,131.87,131.77,129.50,129.31,128.24,127.93,127.74,127.50,127.43,127.37,126.82,126.76,126.27,125.72,125.67,122.49,121.09,99.32,99.08,74.79,74.72,71.72,71.68,70.85,69.67,69.29,69.25,68.86,54.02,47.52,47.45,30.72,29.80,28.36,26.99,26.55,19.51,18.48,17.99.
7-2:Ar=3,5-Ph2-C6H3,黄色泡状固体,产率70%。
1H NMR(400MHz,CDCl3)δ8.72(d,J=2.4Hz,1H),8.15–8.06(m,3H),8.01(s,1H),7.87(s,1H),7.84(s,1H),7.68(d,J=7.4Hz,4H),7.63(d,J=9.0Hz,2H),7.45(dd,J=13.2,6.7Hz,8H),7.35(td,J=15.3,7.3Hz,8H),6.97(d,J=7.3Hz,1H),6.76(d,J=3.8Hz,1H),4.75(s,1H),4.69(d,J=5.5Hz,1H),4.39(s,1H),4.32(s,5H),4.06(s,1H),3.91(s,1H),3.00(t,J=5.7Hz,1H),2.83–2.78(m,1H),2.34(d,J=16.5Hz,1H),2.23–2.07(m,3H),1.88(s,1H),1.74(d,J=5.5Hz,3H).
13C NMR(101MHz,CDCl3)δ196.88,157.96,149.15,148.21,146.56,141.59,141.46,140.87,140.84,140.74,140.19,140.13,137.71,137.28,136.49,136.25,136.21,135.23,132.37,129.46,129.35,129.25,129.15,129.04,128.91,128.72,128.32,127.94,127.53,127.30,127.20,127.04,121.12,98.66,98.56,74.01,73.85,70.54,70.44,70.31,70.06,69.94,65.31,54.39,53.57,46.50,39.71,29.15,28.75,27.01,22.70,18.65,18.44.
7-3:Ar=3,5-Me2-4-OMe-C6H2,黄色泡状固体,产率74%。
1H NMR(400MHz,CDCl3)δ8.29(s,1H),7.21(dd,J=20.3,10.8Hz,3H),7.04–6.94(m,1H),6.78(d,J=7.2Hz,2H),5.33(s,1H),4.67(d,J=51.0Hz,1H),4.25(d,J=27.1Hz,2H),4.03(d,J=12.0Hz,5H),3.83(d,J=8.5Hz,1H),3.77(s,3H),3.60(d,J=8.5Hz,3H),2.57–2.42(m,2H),2.42–2.27(m,8H),2.02(d,J=18.4Hz,7H),1.71(s,3H),1.40(s,1H),1.30(d,J=12.3Hz,1H).
7-4:Ar=3,5-tBu2-C6H3,黄色泡状固体,产率83%。
1H NMR(400MHz,CDCl3)δ8.32(d,J=4.3Hz,1H),7.43–7.33(m,3H),7.14(d,J=9.1Hz,2H),7.04(d,J=7.8Hz,2H),6.93(dd,J=7.5,4.8Hz,1H),4.58(s,1H),4.29(dd,J=12.8,9.4Hz,2H),4.04(s,5H),3.89(t,J=4.4Hz,1H),3.67(s,1H),2.48–2.37(m,1H),2.28(dt,J=16.5,5.3Hz,1H),1.69(d,J=6.2Hz,3H),1.45(s,1H),1.31(s,22H),1.08(s,18H).
13C NMR(101MHz,CDCl3)δ158.18,150.69,150.58,149.81,149.74,149.69,146.78,139.24,139.18,136.54,132.45,129.86,129.65,126.94,126.76,126.53,126.42,125.56,122.59,121.40,121.10,99.16,98.92,76.25,76.17,71.01,70.97,69.48,69.03,69.00,68.70,54.85,47.68,47.59,35.04,34.87,34.62,31.53,31.38,31.31,28.41,26.94,26.89,22.75,22.71,19.52,17.76,14.26,14.22.
(4)催化剂的制备
将(RC,SP)-N-5,6,7,8-四氢喹啉基-1-(2-二芳基膦基)二茂铁基乙基胺(各种催化剂配体)(4.48mmol),五羰基溴化锰(1.35g,4.93mmol)溶于190mL 2-甲基四氢呋喃中,氮气保护下升温至80℃,反应8h,冷却至室温,用10mL二氯甲烷溶解,过滤除去不溶物,向滤液中加入大量正己烷直至析出固体,搅拌0.5h后过滤,所得固体即为催化剂Mn-1—Mn-4。
7-4:Ar=3,5-tBu2-C6H3,黄色粉末,产率75%;
7-1:Ar=2-naphatlene,黄色粉末,产率66%;
7-2:Ar=5-Ph2-C6H3,黄色粉末,产率65%;
7-3:Ar=3,5-Me2-4-OMe-C6H2,橙色粉末,产率64%。
实施例1-实施例5为不对称氢化制备手性环胺所用催化剂制备方法。
实施例1:R为吡啶环,n=1时,
将催化剂Mn-4(9.6mg,0.0086mmol),叔丁醇钾(0.1g,1mmol)添加至反应釜中,添加完毕后加入2.5mL甲醇搅拌溶解。再向反应釜中加入底物a-1(5mmol,0.73g),随后将反应釜密封,并用氢气置换三次,再向反应釜中充入5Mpa氢气,开启搅拌,升温至80℃后反应16h。反应完毕后将反应釜冷却至室温,缓缓放出氢气,NMR测得转化率为94.1%,HPLC测得ee值99.8%。
b-1:浅黄色油状液体,1H NMR(400MHz,CDCl3)δ8.55(s,1H),8.42(d,J=4.4Hz,1H),7.72(d,J=7.8Hz,1H),7.21(dd,J=7.6,4.9Hz,1H),4.22–4.12(m,1H),4.07(s,1H),3.24–3.12(m,1H),3.04(dd,J=16.5,8.7Hz,1H),2.27–2.13(m,1H),1.99–1.80(m,2H),1.71(dq,J=12.1,8.6Hz,1H).
13C NMR(101MHz,CDCl3)δ148.56,148.45,138.58,134.47,123.46,60.09,46.55,33.75,25.17.
OJ-H色谱柱,检测波长254nm,流动相为正己烷:异丙醇=95:5,包含0.1%乙二胺,流速0.9mL/min,S型tR=15.5min,R型tR=14.6min。
根据实施例1对催化剂的筛选实验:以a-1为标准底物,对催化剂Mn-1—Mn-4催化性能筛选见表1
表1
根据实施例1所提供的方法,上表中每一项反应的方法操作基本与实施例1中的方法操作相同,区别为所使用的催化剂不同,催化剂用量不同,反应温度不同,反应时间不同。
以反应效果最佳项11为例,最佳催化剂为Mn-4:
将催化剂Mn-4(2.8mg,0.0025mmol),叔丁醇钾(0.1g,1mmol)添加至反应釜中,添加完毕后加入2.5mL甲醇搅拌溶解。再向反应釜中加入底物a-1(5mmol,0.73g),随后将反应釜密封,并用氢气置换三次,再向反应釜中充入5Mpa氢气,开启搅拌,升温至80℃后反应16h。反应完毕后将反应釜冷却至室温,缓缓放出氢气,NMR测得转化率为96.1%,HPLC测得ee值99.4%。
实施例2:S-毒藜碱的制备
将催化剂Mn-4(9.8mg,0.0087mmol,1.7%mol),叔丁醇钾(0.11mg,0.1mmol,20%mol)添加至反应釜中,添加完毕后加入2.5mL甲醇搅拌溶解。再向反应釜中加入底物a-2(0.5mmol,80mg),随后将反应釜密封,并用氢气置换三次,再向反应釜中充入5Mpa氢气,开启搅拌,升温至80℃后反应16h。反应完毕后将反应釜冷却至室温,缓缓放出氢气,NMR测得转化率为89.3%,HPLC测得ee值90.7%。
b-2:红色油状液体,1H NMR(400MHz,CDCl3)δ8.57(s,1H),8.46(d,J=4.0Hz,1H),7.74(d,J=7.8Hz,1H),7.24(dd,J=7.7,4.8Hz,1H),3.70–3.57(m,1H),3.18(s,1H),2.88–2.69(m,1H),1.90(d,J=9.8Hz,1H),1.78(d,J=11.2Hz,1H),1.67(d,J=11.7Hz,1H),1.60–1.48(m,3H),1.26(d,J=11.7Hz,1H).
13C NMR(101MHz,CDCl3)δ148.58,140.19,134.49,123.56,59.69,47.50,34.46,25.38,25.04.
AD-H色谱柱,检测波长254nm,流动相为正己烷:异丙醇=90:10,包含0.1%三乙胺,流速1mL/min,R型tR=9.0min,S型tR=9.2min。
实施例3:Larotrectinib中间体的制备
将催化剂Mn-4(9.8mg,0.0087mmol,0.17%mmol),叔丁醇钾(0.11g,1mmol,20%mmol)添加至反应釜中,添加完毕后加入2.5mL甲醇搅拌溶解。再向反应釜中加入底物a-3(5mmol,0.9g),随后将反应釜密封,并用氢气置换三次,再向反应釜中充入5Mpa氢气,开启搅拌,升温至80℃后反应16h。反应完毕后将反应釜冷却至室温,缓缓放出氢气,NMR测得转化率为99.3%,HPLC测得ee值97.7%。
b-3:黄色油状液体,1H NMR(400MHz,CDCl3)δ7.27(ddd,J=9.1,5.3,2.4Hz,1H),6.97(td,J=9.2,4.5Hz,1H),6.91–6.82(m,1H),4.42(t,J=7.5Hz,1H),3.24–3.12(m,1H),3.06(dd,J=9.8,7.8Hz,1H),2.28(td,J=13.1,7.7Hz,1H),2.03–1.96(m,1H),1.95–1.76(m,2H),1.63(dt,J=16.1,7.8Hz,1H).
13C NMR(101MHz,CDCl3)δ160.08,157.70,157.57,155.18,134.59,134.53,134.43,134.36,116.14,116.05,115.89,115.81,114.25,114.19,114.14,114.05,114.00,113.94,113.90,113.81,55.48,46.81,33.19,25.52.
AD-H色谱柱,检测波长254nm,流动相为正己烷:异丙醇=95:5,包含0.1%三乙胺,流速1mL/min,R型tR=5.3min,S型tR=6.0min。
实施例41:Selitrectinib中间体的第一种制备
将催化剂Mn-4(9.8mg,0.0087mmol,4.3%mmol),叔丁醇钾(4.5mg,0.04mmol,20%mmol)添加至反应釜中,添加完毕后加入2.5mL甲醇搅拌溶解。再向反应釜中加入底物a-4(0.2mmol,39.7mg),随后将反应釜密封,并用氢气置换三次,再向反应釜中充入5Mpa氢气,开启搅拌,升温至40℃后反应48h。反应完毕后将反应釜冷却至室温,缓缓放出氢气,NMR测得转化率为83.4%,HPLC测得ee值99.6%。
b-4:无色油状液体,1H NMR(400MHz,CDCl3)δ8.06(d,J=2.5Hz,1H),7.83(dd,J=8.9,2.6Hz,1H),4.46(t,J=7.3Hz,1H),3.11(h,J=9.7Hz,2H),2.40(dq,J=14.6,7.4Hz,1H),2.02(d,J=30.6Hz,1H),1.82(p,J=7.0Hz,2H),1.50(dq,J=14.3,7.2Hz,1H).
13C NMR(101MHz,CDCl3)δ160.56,158.02,144.07,142.69,142.66,135.04,134.78,123.91,123.69,57.77,47.08,33.02,25.50.
AD-H色谱柱,检测波长254nm,流动相为正己烷:异丙醇=95:5,包含0.1%三乙胺,流速1mL/min,R型tR=8.1min,S型tR=10.8min。
实施例42:Selitrectinib中间体的第二种制备
将催化剂Mn-4(9.8mg,0.0087mmol,1.7%mmol),叔丁醇钾(11.2mg,0.1mmol,20%mmol)添加至反应釜中,添加完毕后加入2.5mL甲醇搅拌溶解。再向反应釜中加入底物a-5(0.5mmol,97mg),随后将反应釜密封,并用氢气置换三次,再向反应釜中充入5Mpa氢气,开启搅拌,升温至80℃后反应16h。反应完毕后将反应釜冷却至室温,缓缓放出氢气,NMR测得转化率为100.0%,HPLC测得ee值96.2%。
b-5:无色油状液体,1H NMR(400MHz,CDCl3)δ7.89(d,J=2.6Hz,1H),7.60(dd,J=8.5,2.6Hz,1H),4.38(t,J=7.6Hz,1H),4.02–3.93(m,3H),3.66(s,1H),3.24(dt,J=13.5,6.9Hz,1H),3.17–3.05(m,1H),2.27(qd,J=12.9,7.6Hz,1H),1.98–1.83(m,2H),1.69(qd,J=15.7,7.7Hz,1H).
13C NMR(101MHz,CDCl3)δ157.40,156.82,154.38,131.18,130.93,123.92,123.69,56.66,53.81,46.50,31.79,25.07.
AD-H色谱柱,检测波长254nm,流动相为正己烷:异丙醇=95:5,包含0.1%三乙胺,流速1mL/min,R型tR=6.8min,S型tR=5.7min。
实施例5:活性药物MSC2530818的中间体的制备
将催化剂Mn-4(9.8mg,0.0087mmol,1.7%mmol),叔丁醇钾(11.2mg,0.1mmol,20%mmol)添加至反应釜中,添加完毕后加入2.5mL甲醇搅拌溶解。再向反应釜中加入底物a-5(0.5mmol,90mg),随后将反应釜密封,并用氢气置换三次,再向反应釜中充入5Mpa氢气,开启搅拌,升温至80℃后反应16h。反应完毕后将反应釜冷却至室温,缓缓放出氢气,NMR测得转化率为92.9%,HPLC测得ee值95.8%。
b-6:黄色油状液体,1H NMR(400MHz,CDCl3)δ7.38–7.22(m,4H),4.13(t,J=7.8Hz,1H),3.21(dd,J=14.8,9.0Hz,2H),3.04(dd,J=16.6,8.4Hz,1H),2.27–2.14(m,1H),1.98–1.80(m,2H),1.74–1.60(m,1H).
13C NMR(101MHz,CDCl3)δ142.43,132.59,128.49,128.07,61.92,46.72,34.20,25.34.
AD-H色谱柱,检测波长254nm,流动相为正己烷:异丙醇=95:5,包含0.1%三乙胺,流速1mL/min,R型tR=7.7min,S型tR=8.2min。
实施例6:底物适应性筛选
为了进一步探究催化剂的适用性,下表是对Mn-4催化剂对底物的适应性筛选。下表中的底物被不对称氢化后所生成的手性环亚胺,有很多具有潜在的药物合成的应用价值。
将催化剂Mn-4(9.8mg,0.0087mmol),叔丁醇钾(底物摩尔量的20%)添加至反应釜中,添加完毕后加入2.5mL甲醇搅拌溶解。再向反应釜中加入底物a-7—a-24,随后将反应釜密封,并用氢气置换三次,再向反应釜中充入5Mpa氢气,开启搅拌,升温至80℃后反应16h。反应完毕后将反应釜冷却至室温,缓缓放出氢气,使用NMR测得转化率,HPLC测得ee值,如下表2所示。
表2
注:[a]催化剂的摩尔量为底物摩尔量的0.5%
[b]催化反应的温度为100℃。
根据实施例6所提供的方法,其特点是在每项底物的不对称氢化实验中,催化剂的用量不变,为9.8mg(0.0087mmol)。
根据实施例6所提供的方法,调整催化剂与底物比例的方法是催化剂用量不变,溶剂体积不变,对底物的摩尔量进行增减,达到调整催化剂与底物摩尔比的效果。
根据实施例6所提供的方法,叔丁醇钾的用量为底物摩尔量的20%。
以上所述,仅是本发明的较佳实施例而已,并非对本发明作任何形式上的限制,虽然本发明已以较佳实施例揭示如上,然而并非用以限定本发明,任何本领域技术人员,在不脱离本发明技术方案范围内,当可利用上述揭示的技术内容做出些许更动或修饰为等同变化的等效实施例,但凡是未脱离本发明技术方案内容,依据本发明的技术实质对以上实施例所作的任何简介修改、等同变化与修饰,均仍属于本发明技术方案的范围。
Claims (10)
1.一种不对称氢化制备手性环胺所用催化剂,其特征在于,为五羰基溴化锰与手性配体络合而成,所述催化剂包括以下四种分别为Mn-1、Mn-2、Mn-3和Mn-4,其结构式为:
2.一种不对称氢化制备手性环胺所用催化剂制备方法,其特征在于,包括以下步骤:
S11、1-S-二苯基膦-2-R-氨基乙基二茂铁与6,7-二氢喹啉-8-(5H)-酮溶解在有机溶剂中,在酸性环境,还原剂作用下反应生成(RC,SP)-N-5,6,7,8-四氢喹啉基-1-(2-二芳基膦基)二茂铁基乙基胺;
S12、(RC,SP)-N-5,6,7,8-四氢喹啉基-1-(2-二芳基膦基)二茂铁基乙基胺与Mn(CO)5Br在有机溶剂中反应生成催化剂Mn-1、Mn-2、Mn-3和Mn-4。
3.根据权利要求2所述的不对称氢化制备手性环胺所用催化剂制备方法,其特征在于,S11中所述1-S-二苯基膦-2-R-氨基乙基二茂铁与6,7-二氢喹啉-8-(5H)-酮的摩尔比为0.9:1-2:1;
S11中有机溶剂为二氯甲烷、1,4-二氧六环、四氢呋喃、乙腈、1,2-二氯乙烷,所述有机溶剂用量为每克6,7-二氢喹啉-8-(5H)-酮所需溶剂的量为20ml-100ml;
S11中添加酸产生酸性环境,所述酸为甲酸、乙酸、三氟乙酸,酸的的用量是1-S-二苯基膦-2-R-氨基乙基二茂铁所用摩尔量的10%-100%;
S11中所用还原剂为硼氢化钠、氰基硼氢化钠或三乙酰氧基硼氢化钠,1-S-二苯基膦-2-R-氨基乙基二茂铁与还原剂的摩尔为1:1-1:5;
S11中反应温度为0℃-80℃,反应时间为2h-24h。
4.根据权利要求3所述的不对称氢化制备手性环胺所用催化剂制备方法,其特征在于,S12中(RC,SP)-N-5,6,7,8-四氢喹啉基-1-(2-二芳基膦基)二茂铁基乙基胺与Mn(CO)5Br的摩尔比为1:1-2:1;
S12中有机溶剂为四氢呋喃、2-甲基四氢呋喃、乙二醇二甲醚、甲苯或甲基叔丁基醚,所述有机溶剂用量为每克Mn(CO)5Br所需溶剂的量为100ml-400ml;
S12中反应温度为20℃-100℃,反应时间为2h-24h;
S12的反应在惰性气体或氮气保护下进行。
5.一种不对称氢化制备手性环胺的方法,其特征在于,化学反应方程式如下:
所用催化剂为权利要求1-4任一项所述催化剂;
其中化学通式a,b中,R表示苯环、吡啶环、带有取代基的苯环或带有取代基的吡啶环,n=1-2,代表含有4-5个碳原子的环。
6.根据权利要求5所述的不对称氢化制备手性环胺的方法,其特征在于,催化剂的添加量为底物a摩尔量的0.05%-5%;
不对称氢化反应温度为40-110℃,不对称氢化反应的压力为0.5Mpa-8Mpa。
7.根据权利要求5所述的不对称氢化制备手性环胺的方法,其特征在于,还添加助催化剂,所述助催化剂包括叔丁醇钾、叔丁醇钠、碳酸钠、碳酸钾、氢氧化钾或氢氧化钠,所述助催化剂的添加量为为底物a摩尔量的10%-50%。
8.根据权利要求7所述的不对称氢化制备手性环胺的方法,其特征在于,所述催化剂为Mn-4,所述的助催化剂为叔丁醇钾。
9.根据权利要求5所述的不对称氢化制备手性环胺的方法,其特征在于,用于制备去甲基烟碱、S-毒藜碱、Larotrectinib中间体、Selitrectinib中间体和MSC2530818中间体。
10.根据权利要求5所述的不对称氢化制备手性环胺的方法,其特征在于,R为:
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311564920.1A CN117567523A (zh) | 2023-11-22 | 2023-11-22 | 不对称氢化制备手性环胺的方法、所用催化剂和催化剂制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311564920.1A CN117567523A (zh) | 2023-11-22 | 2023-11-22 | 不对称氢化制备手性环胺的方法、所用催化剂和催化剂制备方法 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117567523A true CN117567523A (zh) | 2024-02-20 |
Family
ID=89895018
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311564920.1A Pending CN117567523A (zh) | 2023-11-22 | 2023-11-22 | 不对称氢化制备手性环胺的方法、所用催化剂和催化剂制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117567523A (zh) |
-
2023
- 2023-11-22 CN CN202311564920.1A patent/CN117567523A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Zhang et al. | Site-selective functionalization of remote aliphatic C–H bonds via C–H metallation | |
Wang et al. | Recent progress in Ru (II)-catalyzed C–H activations with oxidizing directing groups | |
JP2710632B2 (ja) | 光学活性な第二アミンの製造方法 | |
Berkessel et al. | Pentacoordinated manganese (III) dihydrosalen complexes as biomimetic oxidation catalysts | |
CN112778218B (zh) | 一种壳聚糖负载铜催化剂制备喹唑酮及其衍生物的方法 | |
CN111171037A (zh) | 手性螺3,2’-吡咯烷氧化吲哚骨架化合物、制备方法及用途、中间体及制备方法 | |
US6486337B2 (en) | Ruthenium-disphosphine complexes and their use as catalysts | |
CN113880750A (zh) | 一种手性3-取代-3-芳基氧化吲哚类化合物的合成方法 | |
CN112961194A (zh) | 一种含面手性二茂铁的pno配体及其应用 | |
CN117567523A (zh) | 不对称氢化制备手性环胺的方法、所用催化剂和催化剂制备方法 | |
CN113200905B (zh) | 一种手性吲哚酮类衍生物及其合成方法 | |
CN114437143B (zh) | 一种吡啶基桥联双四唑廉价金属配合物及其制备和应用 | |
CN111116450B (zh) | 一种轴手性萘胺方酰胺类有机催化剂及其制备方法和应用 | |
CN110590859B (zh) | 一种锰络合物、制备方法及其应用 | |
CN107880022B (zh) | 一种手性含咪唑吡啶酰胺类的化合物及其制备方法和应用 | |
Głuszyńska et al. | Enantioselective modification of the Pomeranz–Fritsch–Bobbitt synthesis of tetrahydroisoquinoline alkaloids synthesis of (−)-salsolidine and (−)-carnegine | |
CN111825508B (zh) | 一种二氢化9-菲胺类化合物的制备方法及其制得的手性产品 | |
CN113717098B (zh) | 一种非氢气参与选择性催化氢化喹啉类化合物合成四氢喹啉类化合物的方法 | |
CN110776470A (zh) | 一种铱催化喹唑啉酮化合物不对称氢化合成手性3,4-二氢喹唑啉酮的方法 | |
CN114437092B (zh) | 一种手性四氢咔唑类多环衍生物及其制备方法与应用 | |
CN117820316B (zh) | 一种手性吲哚并二氢吡啶并吲哚类化合物及其合成方法 | |
CN114591369B (zh) | 一种亚磷酰胺配体及其制备方法、应用 | |
CN118026793A (zh) | 一种光学纯α-芳基手性胺化合物的制备方法及其应用 | |
JP3563347B2 (ja) | ホモアリル型アミンの合成方法とキラルジルコニウム触媒 | |
CN108484673B (zh) | 席夫碱Mn配合物、制备及其在催化烯烃环氧化中的应用 |
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 |