CN114349648A - Preparation method of chiral amine compound - Google Patents
Preparation method of chiral amine compound Download PDFInfo
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- CN114349648A CN114349648A CN202111524360.8A CN202111524360A CN114349648A CN 114349648 A CN114349648 A CN 114349648A CN 202111524360 A CN202111524360 A CN 202111524360A CN 114349648 A CN114349648 A CN 114349648A
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- Prior art keywords
- compound
- oac
- optionally substituted
- chiral amine
- reaction
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- -1 amine compound Chemical class 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 33
- 239000003054 catalyst Substances 0.000 claims abstract description 30
- 229910052751 metal Inorganic materials 0.000 claims abstract description 29
- 239000002184 metal Substances 0.000 claims abstract description 29
- 229910052707 ruthenium Inorganic materials 0.000 claims abstract description 29
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims abstract description 28
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 claims abstract description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229940126062 Compound A Drugs 0.000 claims abstract description 14
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000005695 Ammonium acetate Substances 0.000 claims abstract description 10
- 229940043376 ammonium acetate Drugs 0.000 claims abstract description 10
- 235000019257 ammonium acetate Nutrition 0.000 claims abstract description 10
- 150000001412 amines Chemical class 0.000 claims abstract description 9
- 150000003863 ammonium salts Chemical class 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 238000005580 one pot reaction Methods 0.000 claims abstract description 5
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims abstract description 5
- KWIPUXXIFQQMKN-UHFFFAOYSA-N 2-azaniumyl-3-(4-cyanophenyl)propanoate Chemical compound OC(=O)C(N)CC1=CC=C(C#N)C=C1 KWIPUXXIFQQMKN-UHFFFAOYSA-N 0.000 claims abstract description 4
- BURBNIPKSRJAIQ-UHFFFAOYSA-N 2-azaniumyl-3-[3-(trifluoromethyl)phenyl]propanoate Chemical compound OC(=O)C(N)CC1=CC=CC(C(F)(F)F)=C1 BURBNIPKSRJAIQ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229940090948 ammonium benzoate Drugs 0.000 claims abstract description 4
- 229940063284 ammonium salicylate Drugs 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 28
- 239000000243 solution Substances 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- 238000010791 quenching Methods 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000003446 ligand Substances 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- XJJVPYMFHXMROQ-UHFFFAOYSA-N [4-[5-bis(3,5-dimethylphenyl)phosphanyl-1,3-benzodioxol-4-yl]-1,3-benzodioxol-5-yl]-bis(3,5-dimethylphenyl)phosphane Chemical compound CC1=CC(C)=CC(P(C=2C=C(C)C=C(C)C=2)C=2C(=C3OCOC3=CC=2)C=2C(=CC=C3OCOC3=2)P(C=2C=C(C)C=C(C)C=2)C=2C=C(C)C=C(C)C=2)=C1 XJJVPYMFHXMROQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 230000000171 quenching effect Effects 0.000 claims description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- ZNORAFJUESSLTM-UHFFFAOYSA-N [4-[5-bis(3,5-ditert-butyl-4-methoxyphenyl)phosphanyl-1,3-benzodioxol-4-yl]-1,3-benzodioxol-5-yl]-bis(3,5-ditert-butyl-4-methoxyphenyl)phosphane Chemical compound C1=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=C1P(C=1C(=C2OCOC2=CC=1)C=1C(=CC=C2OCOC2=1)P(C=1C=C(C(OC)=C(C=1)C(C)(C)C)C(C)(C)C)C=1C=C(C(OC)=C(C=1)C(C)(C)C)C(C)(C)C)C1=CC(C(C)(C)C)=C(OC)C(C(C)(C)C)=C1 ZNORAFJUESSLTM-UHFFFAOYSA-N 0.000 claims description 4
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 3
- IOPQYDKQISFMJI-UHFFFAOYSA-N [1-[2-bis(4-methylphenyl)phosphanylnaphthalen-1-yl]naphthalen-2-yl]-bis(4-methylphenyl)phosphane Chemical compound C1=CC(C)=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC(C)=CC=1)C=1C=CC(C)=CC=1)C1=CC=C(C)C=C1 IOPQYDKQISFMJI-UHFFFAOYSA-N 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- NMLZYEWNUCRSRJ-UHFFFAOYSA-L [1-(2-diphenylphosphanylnaphthalen-1-yl)naphthalen-2-yl]-diphenylphosphane;ruthenium(2+);diacetate Chemical compound [Ru+2].CC([O-])=O.CC([O-])=O.C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 NMLZYEWNUCRSRJ-UHFFFAOYSA-L 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 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 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 239000012266 salt solution Substances 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 6
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000004904 shortening Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 23
- 239000008346 aqueous phase Substances 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 239000012043 crude product Substances 0.000 description 10
- 101000686031 Homo sapiens Proto-oncogene tyrosine-protein kinase ROS Proteins 0.000 description 7
- 102100023347 Proto-oncogene tyrosine-protein kinase ROS Human genes 0.000 description 7
- 230000021736 acetylation Effects 0.000 description 5
- 238000006640 acetylation reaction Methods 0.000 description 5
- 239000012300 argon atmosphere Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000003517 fume Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000004293 19F NMR spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 229940076840 Tropomyosin receptor kinase inhibitor Drugs 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000009987 spinning Methods 0.000 description 4
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 4
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 3
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 2
- 229960004891 lapatinib Drugs 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 description 1
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 108091005682 Receptor kinases Proteins 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 102000005937 Tropomyosin Human genes 0.000 description 1
- 108010030743 Tropomyosin Proteins 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- QKGYJVXSKCDGOK-UHFFFAOYSA-N hexane;propan-2-ol Chemical compound CC(C)O.CCCCCC QKGYJVXSKCDGOK-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 230000000508 neurotrophic effect Effects 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- VKJVXYWGRYQADR-UHFFFAOYSA-N s-tert-butylthiohydroxylamine Chemical compound CC(C)(C)SN VKJVXYWGRYQADR-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- CESUXLKAADQNTB-UHFFFAOYSA-N tert-butanesulfinamide Chemical compound CC(C)(C)S(N)=O CESUXLKAADQNTB-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/40—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/68—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D227/00—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00
- C07D227/02—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00 with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D227/06—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00 with only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D227/08—Oxygen atoms
- C07D227/087—One doubly-bound oxygen atom in position 2, e.g. lactams
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The embodiment of the invention discloses a preparation method of a chiral amine compound, which takes a compound A as a raw material to obtain a corresponding chiral amine compound B or chiral amine compound C through one-step reaction in the presence of a ruthenium-based metal catalyst, ammonium salt and hydrogen; the ruthenium-based metal catalyst is: ru (OAc)2(L) or [ RuCl (p-cymene) (L)]And Cl, wherein ammonium salt is selected from at least one of ammonium acetate, ammonium benzoate or ammonium salicylate. The invention realizes the direct and efficient synthesis of the optically pure lopertinib key intermediate I or the analogue thereof by one-step reaction. Compared with the prior art, the method has the advantages of greatly shortening the process flow, reducing the production cost and environmental pollution, improving the yield of key intermediates, facilitating industrial application and finally assisting the green process of related active compoundsIt is used for preparation.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a method for preparing chiral amine compounds by a one-step method.
Background
Reotretinib (lopertib) is a broad-spectrum new generation of TRKI (tropomyosin receptor kinase inhibitor) that inhibits the activities of ROS1 (sarcoma carcinogen-receptor tyrosine kinase), TRK (tropomyosin receptor kinase), and ALK (anaplastic lymphoma kinase), and is currently in clinical stage II. It can overcome the mutation of various genes which generate resistance to other TRKIs and kill various tumor cells carrying ROS1 or NTRK (neurotrophic receptor tyrosine kinase) gene fusion, thereby having potential to treat ROS1 positive non-small cell lung cancer and ROS1, NTRK and ALK positive solid tumors. Phase I clinical data named TRIDENT-1 for Reotretinib to treat ROS1 fusion non-small cell lung cancer are published on the ASCO congress at 9/1 in 2020, and the medicine is prompted to have good tolerance and effectiveness on patients with late ROS1 fusion positive non-small cell lung cancer. 8/12/2020, the U.S. food and drug administration awards the repotnectinib the title "breakthrough therapy" for the treatment of ROS1 positive metastatic non-small cell lung cancer.
Compound S is a third generation TRKI developed on the basis of lopatinib and lapatinib, can overcome multiple gene mutations that confer resistance to other TRKI, exhibits better ability to inhibit tumor growth than lapatinib in mouse experiments, and has oral potential (j.med.chem.2021,64,15503).
Optically pure (R) -I is a key intermediate for the preparation of lopinib and the active compound S, and the currently reported synthesis of this intermediate is as follows:
(1) the document CN 108026109 a reports route one: starting from commercially available aldehydes, the hydrochloride of the chiral amine I is obtained in three steps. This route uses a stoichiometric and expensive chiral prosthetic group (R) -tert-butylsulfinamide and the grignard reagent addition is not added in one step stereochemically controlled and purification by column chromatography only gives the amine intermediate in the desired configuration in 58% yield. The whole route is long, the yield is low, the production cost is high, and the produced waste is more.
(2) WO 2019/201282 Al; PCT/CN2019/083086 literature reports route two: chiral amine I is obtained from commercially available ketone through four steps, the route uses stoichiometric and expensive chiral auxiliary group (S) -tert-butyl sulfinamide, tetrahydrofuran solution of lithium triethylborohydride and corrosive reagent boron tribromide are slowly dripped at low temperature, and the reaction operation and the post-treatment are complicated. The whole route is long, the yield is low, the production cost is high, and the produced waste is more.
In conclusion, the method for preparing the roptinib key intermediate chiral amine I reported in the prior art has the defects of long overall route, low yield, high production cost, more generated waste materials and the like.
Disclosure of Invention
In order to solve the defects of the prior art, the invention provides a novel preparation method of chiral amine compounds, which starts from simple and easily available raw materials, can realize one-step preparation of optically pure chiral amine compounds under a chiral metal catalyst, thereby shortening the reaction flow, reducing the production cost and the environmental pollution, and finally assisting the green and economic preparation of related active compounds.
The technical purpose of the invention is realized by the following technical scheme:
a preparation method of a chiral amine compound takes a compound A as a raw material, and corresponding chiral amine compound B or chiral amine compound C is obtained through one-step reaction in the presence of a ruthenium-based metal catalyst, ammonium salt and hydrogen;
wherein, the group R in the compound A and the chiral amine compound B is selected from alkyl, alkyl with H optionally substituted, cycloalkyl, H optionally substitutedCycloalkyl, aryl optionally substituted by H, aralkyl optionally substituted by H, heteroaryl optionally substituted by H, carboxy, -CnH2nCOOH、-COOR1and-CnH2nCOOR1Wherein n is an integer of 1 to 4, R1Is alkyl, H optionally substituted alkyl, aryl or H optionally substituted aryl;
in the chiral amine compound C, n is an integer of 1-4;
the ruthenium-based metal catalyst is as follows: ru (OAc)2(L) or [ RuCl (p-cymene) (L)]Cl, wherein L has the structure of formula II, III or IV:
in the general formula II, Ar is Ph (i.e. Segphos), 3,5-Me2C6H3(i.e., DM-Segphos), 4-MeO-3,5-tBu2C6H2(i.e., DTBM-Segphos) or other aryl groups; in formula III, Ar is Ph (i.e., BINAP), 4-Me-C6H4(i.e., tolBINAP),3,5-Me2C6H3(i.e., xylBINAP) or other aryl; in formula IV, Ar is Ph (i.e., C)3*-TunePhos)，3,5-Me2C6H3(i.e. C)3*-DM-TunePhos)，4-MeO-3,5-tBu2C6H2(i.e. C)3-DTBM-TunePhos) or other aryl group; or one of the S configuration ligands corresponding to the above compounds;
the ammonium salt is selected from at least one of ammonium acetate, ammonium benzoate or ammonium salicylate.
It will be appreciated by those skilled in the art that in the above reaction, the selection of the corresponding R-configured ligand or S-configured ligand results in a chiral compound of the corresponding configuration.
Further, in one embodiment of the present invention, the ruthenium-based metal catalyst is selected from Ru (OAc)2[(R)-Segphos]、Ru(OAc)2[(R)-DM-Segphos]、Ru(OAc)2[(R)-DTBM-Segphos]、Ru(OAc)2[(R)-BINAP]、Ru(OAc)2[(R)-tolBINAP]、Ru(OAc)2[(R)-xylBINAP]、Ru(OAc)2[(R)-C3*-TunePhos]、Ru(OAc)2[(R)-C3*-DM-TunePhos]、Ru(OAc)2[(R)-C3*-DTBM-TunePhos]、[RuCl(p-cymene)((R)-Segphos)]Cl、[RuCl(p-cymene)((R)-DM-Segphos)]Cl、[RuCl(p-cymene)((R)-BINAP))]Cl and S-configuration ligand corresponding to each compound.
Further, in one embodiment of the present invention, the reaction is performed in an organic solvent, and the organic solvent is an alcohol. As a more specific embodiment, at least one selected from the group consisting of methanol, ethanol, isopropanol, trifluoroethanol, and hexafluoroisopropanol is used, and the amount of the organic solvent used is 2mL to 10mL per millimole of compound a.
Further, in one of the preferred embodiments of the present invention, the group R in the compound A and the chiral amine compound B is selected from the group consisting of C1-C10 alkyl, H optionally substituted C1-C10 alkyl, C3-C6 cycloalkyl, H optionally substituted C3-C6 cycloalkyl, phenyl, H optionally substituted phenyl with halogen, aralkyl, carboxyl, -C6nH2nCOOH、-COOR1、-CnH2nCOOR1And one of the groups X1, X2, X3, X4, X5 and X6 shown in the formula, wherein n is an integer of 1-4, and R is1Is methyl, ethyl or propyl;
further, in a more preferred embodiment of the present invention, the group R in the compound A and the chiral amine compound B is selected from methyl, ethyl, propyl, butyl, isopropyl, cyclohexyl, tert-butyl, methylenecarboxyl, phenyl wherein H is optionally substituted by halogen, benzyl, phenethyl, carboxyl, -CH2COOH、-CH2CH2COOH、-CH2CH2CH2COOH、-COOCH3、-COOCH2CH3、-CH2COOCH3、-CH2COOCH3、-CH2COOCH2CH3、-CH2COOCH2CH2CH3and-CH2CH2COOCH2CH3One kind of (1).
Further, in one of preferred embodiments of the present invention, the compound a is selected from one of the compounds a1, a2, A3, a4, a5, a6, a7, A8, a9 and a 10:
further, in one embodiment of the present invention, the molar ratio of the compound a to the ruthenium-based metal catalyst is 1:0.01 to 1: 0.001, and the molar ratio of the compound A to the ammonium salt is 1:2-1: 4.
Further, in one embodiment of the present invention, the hydrogen pressure during the reaction is 30 to 60atm, and the reaction temperature is 60 to 100 ℃.
Further, in one embodiment of the present invention, the reaction time is 12 to 48 hours.
Further, in one embodiment of the present invention, after the reaction is completed, a quenching solution is added to quench the reaction, wherein the quenching solution is a saturated sodium bicarbonate solution or other weak alkaline inorganic salt solution, and the quenching solution is used in an amount of 10-30mL per millimole of compound a.
Further, in one embodiment of the present invention, the reaction further comprises a process of extracting the organic phase with an organic solvent and drying.
The embodiment of the invention has the following beneficial effects:
the invention takes a readily available compound A as a substrate, and reductive amination participated by ruthenium-based metal catalyst and ammonium salt can realize one-step reaction to directly and efficiently synthesize an optically pure compound B or C, wherein the compound B is a lopinib key intermediate I or an analogue thereof. The ruthenium-based metal catalyst is simple and convenient to prepare, the used chiral ligand and metal precursor are cheap and easy to obtain, the using amount of the catalyst used in the reaction can be reduced to 0.1%, and the reaction scale is easy to amplify. Compared with the method for synthesizing the intermediate I in the prior art, the method avoids the use of expensive and stoichiometric optically pure tert-butyl sulfenamide, can greatly shorten the process flow, reduce the production cost and environmental pollution caused by protecting group operation, improve the yield of key intermediates, is easy for industrial application, and finally assists in green and economic preparation of related active compounds.
Detailed Description
In order to better understand the content of the present invention, the following further description is made in conjunction with specific embodiments to clearly and completely describe the technical solutions in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The reagents used in the examples are all conventional commercially available reagents, and the technical means used in the examples are conventional means well known to those skilled in the art.
In the following examples 1 to 19, the reaction product was protected by acetylation and the enantiomeric excess ee, resolution conditions, were determined by high performance liquid chromatography: daicel Chiralpak OD-3, Hexane i-PrOH 95:5, v 1.0mL/min, T25 ℃, UV 210nm, T1＝12.183min,t2＝18.044min。
Example 1
To a 2mL reaction flask, under an argon atmosphere in a glove box, was added a ruthenium-based metal catalyst Ru (OAc)2[(R)-Segphos](0.001mmol), Compound A1(0.1mmol), ammonium acetate (0.2mmol) and methanol (0.5mL), the reaction flask was placed in an autoclave and hydrogen gas at 40 atmospheres was introduced. The reaction kettle is placed in an oil bath at the temperature of 80 ℃ to be stirred and reacted for 24 hours, and the compound B1 is obtained. After the reaction, the hydrogen in the kettle was carefully released in a fume hood, 2mL of saturated sodium bicarbonate solution was added to quench the reaction, 3mL of dichloromethane was used for three extractions, the organic phases were combined, dried over anhydrous sodium sulfate, and filteredThen decompressing and spin-drying the solvent to obtain a crude product.
The crude product is dissolved again in 5mL of dichloromethane and washed with 1M hydrochloric acid solution and the aqueous phase is separated off. Saturated sodium bicarbonate solution was then added to the aqueous phase until no gas was produced. The aqueous phase is subsequently separated off and extracted with dichloromethane, the organic phase is collected and dried over anhydrous sodium sulfate, filtered and the solvent is finally dried by spinning to give the pure product B1. The product yields and enantiomeric excess results are shown in table 1.
Compound B1 nuclear magnetism:
1H NMR(400MHz,CDCl3)δ6.83(td,J＝8.5,3.0Hz,1H),6.75(dd,J＝8.8,4.9Hz,1H),6.68(dd,J＝9.0,2.9Hz,1H),4.26(q,J＝6.6Hz,1H),1.47(d,J＝6.7Hz,3H).
13C NMR(100MHz,CDCl3)δ156.0(d,J＝236.1Hz),153.47,128.90(d,J＝6.5Hz),117.74(d,J＝7.7Hz),114.57(d,J＝22.5Hz),113.54(d,J＝23.3Hz),51.38,23.63.
19F NMR(400MHz,CDCl3)δ-125.955.
example 2
The operating conditions and procedure were as in example 1 except that 0.2mmol of ammonium acetate was replaced by 0.2mmol of ammonium salicylate. The product yields and enantiomeric excess results are shown in table 1.
Example 3
The operating conditions and procedure were as in example 1, except that 0.2mmol of ammonium acetate was replaced by 0.2mmol of ammonium benzoate. The product yields and enantiomeric excess results are shown in table 1.
Example 4
Except that 0.001mmol of ruthenium-based metal catalyst Ru (OAc)2[(R)-Segphos]Change to 0.001mmol Ru (OAc)2[(R)-DM-Segphos]In addition, the other operating conditions and procedures were the same as in example 1. The product yields and enantiomeric excess results are shown in table 1.
Example 5
Except that 0.001mmol of ruthenium-based metal catalyst Ru (OAc)2[(R)-Segphos]Replacement by 0.001 mmoleRu (OAc)2[(R)-DTBM-Segphos]In addition, the other operating conditions and procedures were the same as in example 1. The product yields and enantiomeric excess results are shown in table 1.
Example 6
Except that 0.001mmol of ruthenium-based metal catalyst Ru (OAc)2[(R)-Segphos]Replacement by 0.001 mmoleRu (OAc)2[(R)-BINAP]In addition, the other operating conditions and procedures were the same as in example 1. The product yields and enantiomeric excess results are shown in table 1.
Example 7
Except that 0.001mmol of ruthenium-based metal catalyst Ru (OAc)2[(R)-Segphos]Replacement by 0.001 mmoleRu (OAc)2[(R)-tolBINAP]In addition, the other operating conditions and procedures were the same as in example 1. The product yields and enantiomeric excess results are shown in table 1.
Example 8
Except that 0.001mmol of ruthenium-based metal catalyst Ru (OAc)2[(R)-Segphos]Replacement by 0.001 mmoleRu (OAc)2[(R)-xylBINAP]In addition, the other operating conditions and procedures were the same as in example 1. The product yields and enantiomeric excess results are shown in table 1.
Example 9
Except that 0.001mmol of ruthenium-based metal catalyst Ru (OAc)2[(R)-Segphos]Replacement by 0.001 mmoleRu (OAc)2[(R)-C3*-TunePhos]In addition, the other operating conditions and procedures were the same as in example 1. The product yields and enantiomeric excess results are shown in table 1.
Example 10
Except that 0.001mmol of ruthenium-based metal catalyst Ru (OAc)2[(R)-Segphos]Replacement by 0.001 mmoleRu (OAc)2[(R)-C3*-DM-TunePhos]In addition, the other operating conditions and procedures were the same as in example 1. The product yields and enantiomeric excess results are shown in table 1.
Example 11
Except that 0.001mmol of ruthenium-based metal catalyst Ru (OAc)2[(R)-Segphos]Replacement by 0.001 mmoleRu (OAc)2[(R)-C3*-DTBM-TunePhos]In addition, the other operating conditions and procedures were the same as in example 1. The product yields and enantiomeric excess results are shown in table 1.
Example 12
Except that 0.001mmol of ruthenium-based metal catalyst Ru (OAc)2[(R)-Segphos]Instead, 0.001mmol [ RuCl (p-cymene) ((R) -Segphos)]The operating conditions and procedures were the same as in example 1 except for Cl. The product yields and enantiomeric excess results are shown in table 1.
Example 13
Except that 0.001mmol of ruthenium-based metal catalyst Ru (OAc)2[(R)-Segphos]Instead, 0.001mmol [ RuCl (p-cymene) ((R) -DM-Segphos)]The operating conditions and procedures were the same as in example 1 except for Cl. The product yields and enantiomeric excess results are shown in table 1.
Example 14
Except that 0.001mmol of ruthenium-based metal catalyst Ru (OAc)2[(R)-Segphos]Change to 0.001mmol [ RuCl (p-cymene) ((R) -BINAP)]The operating conditions and procedures were the same as in example 1 except for Cl. The product yields and enantiomeric excess results are shown in table 1.
Example 15
The procedure is as in example 1 except that 0.5mL of the solvent methanol is replaced with 0.5mL of trifluoroethanol. The product yields and enantiomeric excess results are shown in table 1.
Example 16
The procedure is as in example 1 except that 0.5mL of methanol as solvent is replaced by 0.5mL of ethanol. The product yields and enantiomeric excess results are shown in table 1.
Example 17
The procedure is as in example 1 except that 0.5mL of the solvent methanol is replaced with 0.5mL of isopropanol. The product yields and enantiomeric excess results are shown in table 1.
Example 18
Except that 0.001mmol of ruthenium-based metal catalyst Ru (OAc)2[(R)-Segphos]Change to 0.001mmol Ru (OAc)2[(S)-Segphos]In addition, the other operating conditions and procedures were the same as in example 1. The product yields and enantiomeric excess results are shown in table 1.
Table 1.
Example 19
An enlarged gram-scale experiment was performed in this example on substrate a 1:
glove box under argon atmosphere, a 30mL reaction flask was charged with Compound A1(7.0mmol,1078mg), ammonium acetate (2.0equiv,14.0mmol,1078mg), Ru (OAc)2[(R)-Segphos](0.1 mol%, 0.007mmol,5.8mg) and methanol (12.0 mL). The reaction bottle is put into a high-pressure hydrogenation reaction kettle and filled with hydrogen gas with 40 atmospheric pressure. The reaction kettle is placed in an oil bath at the temperature of 80 ℃ to be stirred and reacted for 48 hours, and the compound B1 is obtained. After the reaction was completed, the reaction vessel was taken out of the oil bath and allowed to cool to room temperature. The reactor was carefully purged of hydrogen in a fume hood, the reaction was spin dried, then dissolved in 15mL of dichloromethane and washed with saturated sodium bicarbonate solution, the organic phase was separated with a separatory funnel, then dried over anhydrous sodium sulfate, filtered, and finally the solvent was spin dried to give the crude product.
The crude product is dissolved again in 15mL of dichloromethane and washed with 1M hydrochloric acid solution and the aqueous phase is separated off. Saturated sodium bicarbonate solution was then added to the aqueous phase until no gas was produced. The aqueous phase was subsequently separated and extracted with dichloromethane, the organic phase was collected, dried over anhydrous sodium sulphate, filtered and the solvent was finally spun off to give a white solid (1.02g) with a yield of 94% by nuclear magnetic assay and an enantiomeric excess e.e. 97% by HPLC after protection of the product by acetylation.
Example 20
To a 2mL reaction flask, under an argon atmosphere in a glove box, was added a ruthenium-based metal catalyst Ru (OAc)2[(R)-Segphos](0.001mmol), Compound A2(0.1mmol), ammonium acetate (0.2mmol) and methanol (0.5mL), the reaction flask was placed in an autoclave and hydrogen gas at 40 atmospheres was introduced. The reaction kettle is placed in an oil bath at the temperature of 80 ℃ to be stirred and reacted for 24 hours, and the compound B2 is obtained. After the reaction is finished, the hydrogen in the kettle is carefully released in a fume hood, 2mL of saturated sodium bicarbonate solution is added to quench the reaction, 3mL of dichloromethane is used for extraction for three times, organic phases are combined, anhydrous sodium sulfate is used for drying, and after filtration, the solvent is dried in a rotary manner under reduced pressure to obtain a crude product. The crude product is dissolved again in 5mL of dichloromethane and washed with 1M hydrochloric acid solution and the aqueous phase is separated off. Saturated sodium bicarbonate solution was then added to the aqueous phase until no gas was produced. The aqueous phase is subsequently separated off and extracted with dichloromethane, the organic phase is collected and dried over anhydrous sodium sulfate, filtered and finally the solvent is dried by spinning to give the pure product B2, which is protected by acetylation and then the enantiomeric excess is determined by HPLC.
B2: light brown solid, 15.9mg, 94% yield, greater than 99% ee.
1H NMR(400MHz,CDCl3)δ6.83(td,J＝8.5,3.0Hz,1H),6.74(dd,J＝8.8,4.9Hz,1H),6.64(dd,J＝9.0,3.0Hz,1H),3.95(t,J＝7.0Hz,1H),1.77(ddd,J＝20.9,13.7,6.5Hz,2H),0.92(s,3H).
13C NMR(100MHz,CDCl3)δ156.97,154.62,153.55(d,J＝1.9Hz),127.65(d,J＝6.5Hz),117.71(d,J＝7.7Hz),116.61–112.03(m),58.00(d,J＝1.1),29.47,10.68.
19F NMR(400MHz,CDCl3)δ-126.29.
Example 21
Ruthenium-based gold was added to a 2mL reaction flask under an argon atmosphere in a glove boxGenus catalyst Ru (OAc)2[(R)-Segphos](0.001mmol), Compound A3(0.1mmol), ammonium acetate (0.2mmol) and methanol (0.5mL), the reaction flask was placed in an autoclave and hydrogen gas at 40 atmospheres was introduced. The reaction kettle is placed in an oil bath at the temperature of 80 ℃ to be stirred and reacted for 24 hours, and the compound B3 is obtained. After the reaction is finished, the hydrogen in the kettle is carefully released in a fume hood, 2mL of saturated sodium bicarbonate solution is added to quench the reaction, 3mL of dichloromethane is used for extraction for three times, organic phases are combined, anhydrous sodium sulfate is used for drying, and after filtration, the solvent is dried in a rotary manner under reduced pressure to obtain a crude product. The crude product is dissolved again in 5mL of dichloromethane and washed with 1M hydrochloric acid solution and the aqueous phase is separated off. Saturated sodium bicarbonate solution was then added to the aqueous phase until no gas was produced. The aqueous phase is subsequently separated off and extracted with dichloromethane, the organic phase is collected and dried over anhydrous sodium sulfate, filtered and finally the solvent is dried by spinning to give the pure product B3, which is protected by acetylation and then the enantiomeric excess is determined by HPLC.
B3: light brown solid, 17.0mg, 94% yield, 99% ee.
1H NMR(400MHz,CDCl3)δ6.83(td,J＝8.5,3.1Hz,1H),6.74(dd,J＝8.8,4.9Hz,1H),6.64(dd,J＝9.0,3.0Hz,1H),4.13–3.88(m,1H),1.90–1.53(m,2H),1.54–1.14(m,3H),0.93(t,J＝7.3Hz,3H).
13C NMR(100MHz,CDCl3)δ157.00,154.65,153.54(d,J＝2.0Hz),127.98(d,J＝6.5Hz),117.75(d,J＝7.7Hz),114.45(dd,J＝22.8,12.8Hz),56.29(d,J＝1.2Hz),38.67,19.43,13.85.
19F NMR(400MHz,CDCl3)δ-126.239.
Example 22
To a 2mL reaction flask, under an argon atmosphere in a glove box, was added a ruthenium-based metal catalyst Ru (OAc)2[(R)-Segphos](0.001mmol), Compound A5(0.1mmol), ammonium acetate (0.2mmol) and methanol(0.5mL), the reaction flask was placed in a high pressure hydrogenation reactor and charged with hydrogen to 40 atmospheres. The reaction kettle is placed in an oil bath at the temperature of 80 ℃ to be stirred and reacted for 24 hours, and the compound B5 is obtained. After the reaction is finished, the hydrogen in the kettle is carefully released in a fume hood, 2mL of saturated sodium bicarbonate solution is added to quench the reaction, 3mL of dichloromethane is used for extraction for three times, organic phases are combined, anhydrous sodium sulfate is used for drying, and after filtration, the solvent is dried in a rotary manner under reduced pressure to obtain a crude product. The crude product is dissolved again in 5mL of dichloromethane and washed with 1M hydrochloric acid solution and the aqueous phase is separated off. Saturated sodium bicarbonate solution was then added to the aqueous phase until no gas was produced. The aqueous phase is subsequently separated off and extracted with dichloromethane, the organic phase is collected and dried over anhydrous sodium sulfate, filtered and finally the solvent is dried by spinning to give the pure product B5, which is protected by acetylation and then the enantiomeric excess is determined by HPLC.
B5: light brown solid, 19.5mg, 89% yield, 99% ee.
1H NMR(400MHz,CDCl3)δ7.45–7.28(m,5H),6.97–6.65(m,2H),6.47(dd,J＝9.2,2.6Hz,1H),5.25(s,1H).
13C NMR(100MHz,CDCl3)δ157.08,154.73,153.83(d,J＝1.9Hz),142.59,129.12,128.10,127.18(d,J＝6.5Hz),126.90,118.01(d,J＝7.7Hz),115.05(t,J＝23.1Hz),59.69.
19F NMR(400MHz,CDCl3)δ-125.499.
The above disclosure is only for the purpose of illustrating the preferred embodiments of the present invention, and it is therefore to be understood that the invention is not limited by the scope of the appended claims.
Claims (10)
1. A preparation method of a chiral amine compound is characterized in that a compound A is used as a raw material, and a corresponding chiral amine compound B or chiral amine compound C is obtained through one-step reaction in the presence of a ruthenium-based metal catalyst, ammonium salt and hydrogen;
wherein the group R in compound A and chiral amine compound B is selected from alkyl, H optionally substituted alkyl, cycloalkyl, H optionally substituted cycloalkyl, aryl, H optionally substituted aryl, aralkyl, H optionally substituted aralkyl, heteroaryl, H optionally substituted heteroaryl, carboxy, -CnH2nCOOH、-COOR1and-CnH2nCOOR1Wherein n is an integer of 1 to 4, R1Is alkyl, H optionally substituted alkyl, aryl or H optionally substituted aryl;
in the chiral amine compound C, n is an integer of 1-4;
the ruthenium-based metal catalyst is as follows: ru (OAc)2(L) or [ RuCl (p-cymene) (L)]Cl, wherein L has the structure of formula II, formula III or formula IV:
in the general formula II, Ar is Ph, 3,5-Me2C6H3，4-MeO-3,5-tBu2C6H2Or other aryl groups; in the general formula III, Ar is Ph, 4-Me-C6H4，3,5-Me2C6H3Or other aryl groups; in the general formula IV, Ar is Ph, 3,5-Me2C6H3，4-MeO-3,5-tBu2C6H2Or other aryl groups; or one of the S configuration ligands corresponding to the above compounds;
the ammonium salt is selected from at least one of ammonium acetate, ammonium benzoate or ammonium salicylate.
2. The method according to claim 1, wherein the ruthenium-based metal catalyst is selected from the group consisting of Ru (OAc)2[(R)-Segphos]、Ru(OAc)2[(R)-DM-Segphos]、Ru(OAc)2[(R)-DTBM-Segphos]、Ru(OAc)2[(R)-BINAP]、Ru(OAc)2[(R)-tolBINAP]、Ru(OAc)2[(R)-xylBINAP]、Ru(OAc)2[(R)-C3*-TunePhos]、Ru(OAc)2[(R)-C3*-DM-TunePhos]、Ru(OAc)2[(R)-C3*-DTBM-TunePhos]、[RuCl(p-cymene)((R)-Segphos)]Cl、[RuCl(p-cymene)((R)-DM-Segphos)]Cl、[RuCl(p-cymene)((R)-BINAP))]Cl and S-configuration ligand corresponding to each compound.
3. The process according to claim 1, wherein the reaction is carried out in an organic solvent which is an alcohol solvent, and the amount of the organic solvent is 2 to 10mL per mmol of Compound A.
4. The production method according to claim 3, wherein the alcoholic solvent is at least one selected from the group consisting of methanol, ethanol, isopropanol, trifluoroethanol and hexafluoroisopropanol.
5. The process according to claim 1, wherein the R group in the compound A and the chiral amine compound B is selected from the group consisting of C1-C10 alkyl, H optionally substituted C1-C10 alkyl, C3-C6 cycloalkyl, H optionally substituted C3-C6 cycloalkyl, phenyl, H optionally substituted phenyl with halogen, aralkyl, carboxyl, -CnH2nCOOH、-COOR1、-CnH2nCOOR1One of groups X1, X2, X3, X4, X5 and X6 shown in the following formula, wherein n is an integer from 1 to 4, and R is1Is methyl, ethyl or propyl;
6. the process according to claim 5, wherein the R groups in the compound A and the chiral amine compound B are selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, and the like,Cyclohexyl, tert-butyl, methylenecarboxy, phenyl optionally substituted by halogen H, benzyl, phenethyl, carboxy, -CH2COOH、-CH2CH2COOH、-CH2CH2CH2COOH、-COOCH3、-COOCH2CH3、-CH2COOCH3、-CH2COOCH3、-CH2COOCH2CH3、-CH2COOCH2CH2CH3and-CH2CH2COOCH2CH3One kind of (1).
7. The method according to claim 5, wherein the compound A is one selected from the group consisting of compounds A1, A2, A3, A4, A5, A6, A7, A8, A9 and A10:
8. the production method according to claim 1, wherein the molar ratio of the compound a to the ruthenium-based metal catalyst is 1:0.01 to 1: 0.001, and the molar ratio of the compound A to the ammonium salt is 1:2-1: 4.
9. The preparation method according to claim 1, wherein the hydrogen pressure during the reaction is 30 to 60atm, and the reaction temperature is 60 to 100 ℃.
10. The method according to claim 1, wherein after completion of the reaction, a quenching solution is added to quench the reaction, and the quenching solution is a saturated sodium bicarbonate solution or other weakly alkaline inorganic salt solution.
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| WO2024098464A1 (en) * | 2022-11-11 | 2024-05-16 | 深圳先进技术研究院 | PREPARATION METHOD FOR OPTICALLY PURE α-ARYL CHIRAL AMINE COMPOUND, AND USE THEREOF |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016055015A1 (en) * | 2014-10-11 | 2016-04-14 | 浙江华海药业股份有限公司 | Method for preparing sitagliptin intermediate via asymmetrical reduction method |
| CN109851506A (en) * | 2019-01-30 | 2019-06-07 | 凯特立斯（深圳）科技有限公司 | The asymmetric reduction amination of ruthenium-double-phosphine catalyst catalysis simple ketone prepares chiral primary amine |
| CN112300047A (en) * | 2019-08-01 | 2021-02-02 | 凯特立斯（深圳）科技有限公司 | Method for synthesizing chiral lactam by tandem reduction amine |
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| CN114349648B (en) * | 2021-12-14 | 2024-08-09 | 深圳先进技术研究院 | Preparation method of chiral amine compound |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016055015A1 (en) * | 2014-10-11 | 2016-04-14 | 浙江华海药业股份有限公司 | Method for preparing sitagliptin intermediate via asymmetrical reduction method |
| CN109851506A (en) * | 2019-01-30 | 2019-06-07 | 凯特立斯（深圳）科技有限公司 | The asymmetric reduction amination of ruthenium-double-phosphine catalyst catalysis simple ketone prepares chiral primary amine |
| CN112300047A (en) * | 2019-08-01 | 2021-02-02 | 凯特立斯（深圳）科技有限公司 | Method for synthesizing chiral lactam by tandem reduction amine |
Non-Patent Citations (1)
| Title |
|---|
| 高爽: "过渡金属催化酮直接不对称还原胺化合成伯胺及其衍生物", 硕士电子期刊工程科技I辑, pages 23 - 27 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023109213A1 (en) * | 2021-12-14 | 2023-06-22 | 深圳先进技术研究院 | Method for preparing chiral amine compound |
| WO2024098464A1 (en) * | 2022-11-11 | 2024-05-16 | 深圳先进技术研究院 | PREPARATION METHOD FOR OPTICALLY PURE α-ARYL CHIRAL AMINE COMPOUND, AND USE THEREOF |
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