CN115322141B - 一种不对称氢化制备手性哌甲酯类化合物的方法 - Google Patents
一种不对称氢化制备手性哌甲酯类化合物的方法 Download PDFInfo
- Publication number
- CN115322141B CN115322141B CN202211070916.5A CN202211070916A CN115322141B CN 115322141 B CN115322141 B CN 115322141B CN 202211070916 A CN202211070916 A CN 202211070916A CN 115322141 B CN115322141 B CN 115322141B
- Authority
- CN
- China
- Prior art keywords
- reaction
- methyl
- acid
- chiral
- solvent
- 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.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 title claims abstract description 11
- -1 methylphenidate compound Chemical class 0.000 title claims description 8
- 229960001344 methylphenidate Drugs 0.000 title description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000001257 hydrogen Substances 0.000 claims abstract description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 26
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Methylphenidate Chemical class C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 239000003446 ligand Substances 0.000 claims abstract description 6
- 239000000758 substrate Substances 0.000 claims abstract description 6
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 6
- 150000003624 transition metals Chemical class 0.000 claims abstract description 6
- 229910052741 iridium Inorganic materials 0.000 claims abstract description 4
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 46
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 25
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 24
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 239000007848 Bronsted acid Substances 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- 230000000996 additive effect Effects 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 239000002243 precursor Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 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
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 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
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- 150000001336 alkenes Chemical class 0.000 abstract description 16
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 12
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 abstract description 11
- 239000010948 rhodium Substances 0.000 abstract description 8
- 238000009776 industrial production Methods 0.000 abstract description 5
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 229910052703 rhodium Inorganic materials 0.000 abstract description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052707 ruthenium Inorganic materials 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 50
- 239000000047 product Substances 0.000 description 39
- 239000007858 starting material Substances 0.000 description 21
- 230000015572 biosynthetic process Effects 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 13
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 238000000605 extraction Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- VNPUDNMSZLIANG-UHFFFAOYSA-N (r)-f-binaphane Chemical compound [Fe].[CH]1[CH][CH][CH][C]1P1CC2=C3C=CC=CC3=CC=C2C(C=CC=2C3=CC=CC=2)=C3C1.[CH]1[CH][CH][CH][C]1P1CC2=C3C=CC=CC3=CC=C2C(C=CC=2C3=CC=CC=2)=C3C1 VNPUDNMSZLIANG-UHFFFAOYSA-N 0.000 description 11
- 239000012300 argon atmosphere Substances 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 239000012298 atmosphere Substances 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 239000007788 liquid Substances 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- DUGOZIWVEXMGBE-CHWSQXEVSA-N dexmethylphenidate Chemical compound C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 DUGOZIWVEXMGBE-CHWSQXEVSA-N 0.000 description 5
- 229960001042 dexmethylphenidate Drugs 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- JUMYIBMBTDDLNG-OJERSXHUSA-N hydron;methyl (2r)-2-phenyl-2-[(2r)-piperidin-2-yl]acetate;chloride Chemical compound Cl.C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 JUMYIBMBTDDLNG-OJERSXHUSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- ZNLHWEDEIKEQDK-UHFFFAOYSA-N 5-chloropentanal Chemical compound ClCCCCC=O ZNLHWEDEIKEQDK-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-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
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical group NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CRZQGDNQQAALAY-UHFFFAOYSA-N Methyl benzeneacetate Chemical compound COC(=O)CC1=CC=CC=C1 CRZQGDNQQAALAY-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 2
- 208000013403 hyperactivity Diseases 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- SOJSYOXMFGDLHY-UHFFFAOYSA-N methyl acetate;hydrochloride Chemical compound Cl.COC(C)=O SOJSYOXMFGDLHY-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229940099204 ritalin Drugs 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 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 2
- 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 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- KCOPAESEGCGTKM-UHFFFAOYSA-N 1,3-oxazol-4-one Chemical compound O=C1COC=N1 KCOPAESEGCGTKM-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- IRPGOXJVTQTAAN-UHFFFAOYSA-N 2,2,3,3,3-pentafluoropropanal Chemical compound FC(F)(F)C(F)(F)C=O IRPGOXJVTQTAAN-UHFFFAOYSA-N 0.000 description 1
- DNYWGUIJLFDIPD-UHFFFAOYSA-N 2-methoxypiperidine Chemical compound COC1CCCCN1 DNYWGUIJLFDIPD-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- KLZUFWVZNOTSEM-UHFFFAOYSA-K Aluminum fluoride Inorganic materials F[Al](F)F KLZUFWVZNOTSEM-UHFFFAOYSA-K 0.000 description 1
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 1
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- HXEACLLIILLPRG-RXMQYKEDSA-N D-pipecolic acid Chemical compound OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 description 1
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical class C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 1
- 102000010909 Monoamine Oxidase Human genes 0.000 description 1
- 108010062431 Monoamine oxidase Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- GNEKQRJQKMYNOU-UHFFFAOYSA-M [I-].CC(C)(C)[N+](C(C)(C)C)(C(C)(C)C)C(C)(C)C Chemical compound [I-].CC(C)(C)[N+](C(C)(C)C)(C(C)(C)C)C(C)(C)C GNEKQRJQKMYNOU-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-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
- 230000004913 activation Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- CECABOMBVQNBEC-UHFFFAOYSA-K aluminium iodide Chemical compound I[Al](I)I CECABOMBVQNBEC-UHFFFAOYSA-K 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- FKOASGGZYSYPBI-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)alumanyl trifluoromethanesulfonate Chemical compound [Al+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F FKOASGGZYSYPBI-UHFFFAOYSA-K 0.000 description 1
- 239000002775 capsule Substances 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
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229910001914 chlorine tetroxide Inorganic materials 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229930007927 cymene Natural products 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- DHCWLIOIJZJFJE-UHFFFAOYSA-L dichlororuthenium Chemical compound Cl[Ru]Cl DHCWLIOIJZJFJE-UHFFFAOYSA-L 0.000 description 1
- HDRXZJPWHTXQRI-BHDTVMLSSA-N diltiazem hydrochloride Chemical compound [Cl-].C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CC[NH+](C)C)C2=CC=CC=C2S1 HDRXZJPWHTXQRI-BHDTVMLSSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 230000002825 dopamine reuptake Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006056 electrooxidation reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- PSCMQHVBLHHWTO-UHFFFAOYSA-K indium(iii) chloride Chemical compound Cl[In](Cl)Cl PSCMQHVBLHHWTO-UHFFFAOYSA-K 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000006713 insertion reaction Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000005394 methallyl group Chemical group 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003287 optical effect Effects 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
- 230000020477 pH reduction Effects 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- ZYTJPPRBIGGXRO-UHFFFAOYSA-N propan-2-ylalumane Chemical compound C(C)(C)[AlH2] ZYTJPPRBIGGXRO-UHFFFAOYSA-N 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form 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
- PUGUQINMNYINPK-UHFFFAOYSA-N tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1 PUGUQINMNYINPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明提供了一种不对称氢化制备手性哌甲酯类化合物的方法。该方法在温和的条件下，以四取代烯烃为原料，以双膦配体为手性配体，以过渡金属钌、铑、铱等为催化剂，催化C＝C不饱和双键的氢化反应,从而制备出一系列手性哌甲酯衍生物。本发明的优点是：反应条件温和，氢气作为廉价易得的氢源，底物普适性好，能以较高的收率和优秀的对映选择性和非对映选择性获得目标产物，扩大量反应仍然能很好的转化并表现出优秀的选择性。因此，本发明为今后包含此结构的其他高价值化合物的工业化生产提供了一种有效的方案。
Description
技术领域
本发明属于手性合成领域，具体涉及一种不对称氢化制备手性哌甲酯类化合物的方法。
背景技术
过渡金属催化的不对称氢化将分子氢添加到前手性不饱和烯烃中，已被广泛用于构建光学纯精细化学品、农药和药物。与二取代和三取代烯烃相比，四取代烯烃的不对称氢化仍然是该领域的一大挑战。迄今为止，对空间位阻要求较低的氟代或甲基取代的四取代烯烃的不对称氢化也仅有几篇报道(如下所示)。然而，诸如官能团不兼容、反应活性差、对映选择性低以及对具有大空间位阻的底物无效等限制，仍然阻碍了不对称氢化在四取代烯烃中的应用。
哌甲酯(Methylphenidate)属中枢兴奋剂，是临床治疗注意缺陷多动障碍的一线药物，通过促进多巴胺释放、减少多巴胺再摄取及抑制单胺氧化酶活性而起作用，可显著减少多动行为，增加注意力集中能力，有效改善和治疗注意力缺乏或多动综合症(ADHD)。1944年，Panizzon等报道合成哌甲酯的四种异构体 [(±)-erythro/(±)-threo)]混合物，并于1950年以商品名利他林(Ritalin)在美国上市。
根据更进一步的临床研究表明，苏式构型(threo)对上述疾病才具有治疗作用，(2R,2’R)-苏型哌甲酯更容易进入中枢神经系统，比其对映体更具药理活性。 D-苏型哌甲酯的缓释胶囊于2005年5月26日由NOVARTIS公司通过FDA申请上市，商品名为Focalin XR。
D-苏型哌甲酯的合成根据目前的专利文献报道主要有如下几种方法：
一、手性拆分方法：参考专利和文献WO 98/52921,1998；US Patent 5,936,091,1999；Tetrahedron:Asymmetry 1998,9,2133。
二、手性合成法：
1)Novartis公司报道了第一例手性全合成D-苏型哌甲酯的方法(J.Org.Chem.1999,64,1750.)，该方法利用光学纯的噁唑啉酮手性辅助基，与5-氯戊醛发生羟醛缩合反应得到构型单一的产物，再经保护、环化、去保护等步骤得到目标化合物，其合成路线如反应式I：
2)Winkler和Davies的研究小组报道了铑催化的不对称卡宾插入反应合成 D-苏型哌甲酯的方法(J.Am.Chem.Soc.1999,121,6509；J.Am.Chem.Soc.1999, 121,6511.)。该方法十分简洁的构建了哌甲酯结构，可以通过控制催化剂的构型获得不同构型的哌甲酯衍生物，其合成路线如反应式II：
3)Matsumura小组报道了从保护的哌啶出发，先通过电化学氧化得到保护的2-甲氧基哌啶，再与苯乙酸的手性噁唑啉酮酰胺反应立体选择性构建哌甲酯衍生物，经去保护、皂化、酯化等步骤得到目标化合物(Org.Lett.1999,1,175； Tetrahedron 2000,56,7411.)。其合成路线如反应式III：
4)专利CN 102134208A报道了利用叔丁基亚磺酰胺与5-氯戊醛缩合得到叔丁基亚磺酰亚胺，然后与苯乙酸甲酯在强碱的条件下发生加成反应形成手性中间体，再通过去保护和关环反应得到D-苏型哌甲酯，光学纯度达到>97％ee。其合成路线如反应式IV：
5)Perel的研究小组以D-哌啶酸为原料，经保护、偶联反应、wittig反应、硼氢化氧化、醇氧化、甲基化和酸化等步骤得到目标化合物(J.Med.Chem.1998, 41,591)。该方法以光学纯的底物，可诱导一系列右哌甲酯衍生物的制备，其合成路线如反应式Ⅴ：
综上所述，现有技术中多采用手性拆分和手性辅基诱导的合成方法，反应路径繁琐，成本过高，原料浪费严重，因此不利于大规模工业化生产。因此，亟需提供一种高效的手性哌甲酯化合物的全新合成工艺，以期通过廉价的试剂与温和的反应条件获得较高的产物收率和选择性，最终实现(R)-2-苯基-2-((R)-哌啶-2-基) 乙酸甲酯盐酸盐的大规模工业化生产。
发明内容
本发明要解决的技术问题是提供一种高效的手性哌甲酯化合物的全新合成工艺，以期通过廉价的试剂与温和的反应条件获得较高的产物收率和选择性，最终实现(R)-2-苯基-2-((R)-哌啶-2-基)乙酸甲酯盐酸盐的大规模工业化生产。
本发明提供了一种不对称氢化制备手性哌甲酯类化合物的方法，其反应路线为：
具体地，化合物(I)在合适的溶剂中，加入手性双膦配体、过渡金属催化剂、布朗斯特酸以及添加剂，充入氢气进行不对称还原反应得到式(II)所示的化合物。
其中，化合物中R代表不同的取代基，为烷基、环烷基、芳烷基、杂环烷基；另外，上述烷基、环烷基、芳烷基、杂环烷基也具有取代基，星号(*)标记的碳原子表示手性碳原子。
作为本发明的一种优选技术方案，所用手性双膦配体选自以下至少一种：
优选为(R)-f-Binaphane或其任意对映异构体。
作为本发明的一种优选技术方案，所述过渡金属选自铱、铑、钌；其中，金属前体选自[Ir(NBD)Cl]2，[Ir(NBD)2]X，[Ir(COD)Cl]2，[Ir(COD)2]X，[Rh(NBD)2]X， [Rh(NBD)Cl]2，Rh(acac)(CO)2，[Rh(COD)Cl]2，Rh(ethylene)2(acac)， [Rh(ethylene)2Cl]2，[Rh(COD)2]X，RhCl(PPh3)3，Ru(aryl group)X2，RuX2(cymene)， RuCl2(COD)，(Ru(COD)2)X，RuX2(diphosphine)，Ru(ArH)Cl2， Ru(COD)(methallyl)2；X表示负阴离子Cl-，Br-，I-，BF4 -，ClO4 -，SbF6 -，PF6 -， TfO-，RCOO-，B(Ar)4 -；金属优选铱金属，金属前体优选[Ir(COD)Cl]2。
作为本发明的一种优选技术方案，所述反应是在溶剂中进行；所述溶剂选自甲醇、乙醇、异丙醇、甲基叔丁基醚、四氢呋喃、1,4-二氧六环、二氯甲烷、乙酸乙酯、正己烷、甲苯中的一种或任意比例的混合溶剂，优选为异丙醇。式(I) 所示的化合物与溶剂的用量比为1mmol：(10-20)mL，优选为1mmol：10mL。
作为本发明的一种优选技术方案，使用的氢气压力为10-100bar的压力，优选30-60bar的氢气压力。
作为本发明的一种优选技术方案，其特征在于，本发明所使用的反应温度选择20-100℃，其中，优选20-50℃。
作为本发明的一种优选技术方案，本发明所使用的布朗斯特酸选自苯甲酸、甲酸、三氟甲磺酸、磷酸、樟脑磺酸、对甲苯磺酸、三氟乙酸，盐酸中的至少一种或任意比例的混合物，优选为三氟乙酸。
作为本发明的一种优选技术方案，本发明所使用的添加剂选自醋酸锌、三氟甲磺酸锌、氯化锌，碘，四叔丁基碘化铵，氯化铵，四异丙氧钛，三氟化硼，氯化锂、溴化锂、异丙基铝、氯化铝、氟化铝、溴化铝、碘化铝、三氟甲磺酸铝，氯化镁、氯化铟等，优选为三氯化铝。
作为本发明的一种优选技术方案，催化剂的使用量根据氢化底物、反应条件及催化剂的种类而定，催化剂与底物的摩尔比范围为0.01mol％-10mol％，优选 0.11mol％-1mol％。
作为本发明的一种优选技术方案，反应时间一般为0.5-100h，优选16-72h。
本发明进一步提供了一种(R)-2-苯基-2-((R)-哌啶-2-基)乙酸甲酯盐酸盐的制备工艺，其特征在于，合成路线如下：
具体的，包括以下步骤：1)(S)-2-苯基-2-((R)-哌啶-2-基)乙酸甲酯(2a)与浓盐酸加热回流反应脱去甲酯，加入二氯亚砜活化后，经胺解得到甲酰胺取代的化合物3；2)化合物3在合适的溶剂中，和强碱反应在加热条件下异构化，再经水解甲酯化得到(R)-2-苯基-2-((R)-哌啶-2-基)乙酸甲酯(4)；3)化合物4与盐酸成盐得到(R)-2-苯基-2-((R)-哌啶-2-基)乙酸甲酯盐酸盐(5)。
本发明相对于现有技术具有以下有益效果：
(1)本发明提供了一种手性哌甲酯化合物的全新合成工艺，反应具有高度的稳定性和反应活性，实现了优异的立体控制，可以得到大于90％对映选择性的哌甲酯中间体，且dr值大于20：1。
(2)本发明中，不对称催化还原反应是关键步骤，使用优选的催化体系 Ir/f-Binaphane，不对称氢化反应具有非常高的反应活性，催化剂转化数(TON， turnovernumber)高达1500，并且能保持其优异的立体控制。
(3)本发明的工艺具有较高的产物收率和选择性，成本低廉，易于放大，适用于大规模工业化生产，具有极高的工业化价值。
具体实施方式
下面结合具体实施方式对本发明的技术方案进一步的说明和描述，但本发明并不限制于以下描述的具体实施例。
实施例中未注明具体条件的实验方法，通常按照常规条件以及手册中所述的条件，或按照制造厂商所建议的条件；所用材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1：(S)-2-苯基-2-((R)-哌啶-2-基)乙酸甲酯的合成
在氩气氛围下，向氢化瓶中加入[Ir(COD)Cl]2(0.3mg,0.5μmol)、 (R)-f-Binaphane(0.9mg,1.1μmol)和30μL无水二氯甲烷。反应室温搅拌30分钟后，依次加入四取代烯烃原料(23.1mg,0.1mmol)、三氯化铝(2.7mg,0.02mmol)、1mL无水异丙醇和11μL三氟乙酸。在30bar的氢气氛围下反应24h 后，原料全部转化为产物。随后缓慢释放氢气，将反应的pH值调至10，用乙酸乙酯萃取，收集有机相用无水硫酸钠干燥后减压条件下除去溶剂，然后柱层析得到目标产物(21.4mg,收率：92％，92％ee,98:2dr)。
产物为无色液体，[α]25 D＝-58.8(c 0.85,CH3OH)，HPLC条件：Chiralpak IE 柱,正己烷(包含0.05％三氟乙酸)/异丙醇＝98/2，流速：1.0mL/min，254nm， t1＝9.8min,t2＝10.1min(major),t3＝13.2min。1H NMR(600MHz,CDCl3)δ＝ 7.41(d,J＝7.0Hz,2H),7.34(t,J＝7.2Hz,2H),7.31–7.29(m,1H),3.65(s,3H), 3.46(d,J＝10.0Hz,1H),3.10(t,J＝10.0Hz,1H),2.92(d,J＝11.1Hz,1H),2.50(t,J＝11.2Hz,1H),1.81–1.79(m,2H),1.56(s,1H),1.46–1.22(m,4H).13C NMR (151MHz,CDCl3)δ＝173.0,136.1,128.9,128.7,127.8,59.0,58.3,51.9,47.0,31.1, 25.8,24.5.HRMS(ESI)m/z:[M+H]+Calcd for C14H20NO2 +＝234.1489；Found 234.1486.
实施例2：(S)-2-(3-氟苯基)-2-((R)-哌啶-2-基)乙酸甲酯的合成
在氩气氛围下，向氢化瓶中加入[Ir(COD)Cl]2(0.3mg,0.5μmol)、 (R)-f-Binaphane(0.9mg,1.1μmol)和30μL无水二氯甲烷。反应室温搅拌30分钟后，依次加入四取代烯烃原料(24.9mg,0.1mmol)、三氯化铝(2.7mg,0.02mmol)、1mL无水异丙醇和11μL三氟乙酸。在30bar的氢气氛围下反应24h 后，原料全部转化为产物。随后缓慢释放氢气，将反应的pH值调至10，用乙酸乙酯萃取，收集有机相用无水硫酸钠干燥后减压条件下除去溶剂，然后柱层析得到目标产物(23.3mg,收率：93％，93％ee,98:2dr)。
产物为无色液体，[α]25 D＝-33.1(c 1.20,CH3OH)，HPLC条件：Chiralpak IC 柱,正己烷(包含0.05％三氟乙酸)/异丙醇＝98/2，流速：0.5mL/min，254nm， t1＝13.6min(major),t2＝14.7min,t3＝17.8min.1H NMR(400MHz,CDCl3)δ＝ 7.33–7.26(m,2H),7.18–7.16(m,2H),7.02–6.97(m,1H),3.66(s,3H),3.46(d,J ＝10.0Hz,1H),3.07(td,J＝10.1,2.1Hz,1H),2.94(d,J＝11.7Hz,1H),2.52(td,J＝11.5,2.8Hz,1H),1.81–1.76(m,2H),1.60–1.56(m,1H),1.47–1.19(m,4H).13C NMR(101MHz,CDCl3)δ＝172.6,163.0(d,J＝246.9Hz),138.5(d,J＝7.3Hz), 130.2(d,J＝8.3Hz),124.6,115.5(d,J＝21.9Hz),114.9(d,J＝21.0Hz),59.0,58.0,52.0,47.0,31.0,25.7,24.4.19F NMR(376MHz,CDCl3)δ＝-112.2.HRMS(ESI)m/z: [M+H]+Calcd for C14H19FNO2 +＝252.1394；Found 252.1391.
实施例3：(S)-2-(3-氯苯基)-2-((R)-哌啶-2-基)乙酸甲酯的合成
在氩气氛围下，向氢化瓶中加入[Ir(COD)Cl]2(0.3mg,0.5μmol)、 (R)-f-Binaphane(0.9mg,1.1μmol)和30μL无水二氯甲烷。反应室温搅拌30分钟后，依次加入四取代烯烃原料(26.5mg,0.1mmol)、三氯化铝(2.7mg,0.02mmol)、1mL无水异丙醇和11μL三氟乙酸。在30bar的氢气氛围下反应24h 后，原料全部转化为产物。随后缓慢释放氢气，将反应的pH值调至10，用乙酸乙酯萃取，收集有机相用无水硫酸钠干燥后减压条件下除去溶剂，然后柱层析得到目标产物(24.3mg,收率：91％，92％ee,99:1dr)。
产物为无色液体，[α]25 D＝-48.2(c 1.26,CH3OH)，HPLC条件：Chiralpak IE 柱,正己烷(包含0.05％三氟乙酸)/异丙醇＝98/2，流速：0.5mL/min，254nm， t1＝16.7min,t2＝17.2min(major).1H NMR(400MHz,CDCl3)δ＝7.42(s,1H), 7.30–7.24(m,3H),3.66(s,3H),3.42(d,J＝10.0Hz,1H),3.07(td,J＝10.1,2.1Hz,1H),2.93(d,J＝11.7Hz,1H),2.51(td,J＝11.5,2.8Hz,1H),1.81–1.75(m,2H), 1.59–1.55(m,1H),1.47–1.18(m,4H).13C NMR(101MHz,CDCl3)δ＝172.5, 138.1,134.7,130.0,128.7,128.1,127.0,58.9,58.0,52.0,47.0,31.0,25.7,24.4.HRMS(ESI)m/z:[M+H]+Calcd for C14H19ClNO2 +＝268.1096；Found268.1099.
实施例4：(S)-2-(3-溴苯基)-2-((R)-哌啶-2-基)乙酸甲酯的合成
在氩气氛围下，向氢化瓶中加入[Ir(COD)Cl]2(0.3mg,0.5μmol)、 (R)-f-Binaphane(0.9mg,1.1μmol)和30μL无水二氯甲烷。反应室温搅拌30分钟后，依次加入四取代烯烃原料(30.9mg,0.1mmol)、三氯化铝(2.7mg,0.02mmol)、1mL无水异丙醇和11μL三氟乙酸。在30bar的氢气氛围下反应24h 后，原料全部转化为产物。随后缓慢释放氢气，将反应的pH值调至10，用乙酸乙酯萃取，收集有机相用无水硫酸钠干燥后减压条件下除去溶剂，然后柱层析得到目标产物(28.6mg,收率：92％，91％ee,99:1dr)。
产物为无色液体，[α]25 D＝-42.3(c 1.20,CH3OH)，HPLC条件：Chiralpak IC 柱,正己烷(包含0.05％三氟乙酸)/异丙醇＝98/2，流速：0.5mL/min，254nm， t1＝14.5min,t2＝15.4min(major).1H NMR(400MHz,CDCl3)δ＝7.58(t,J＝1.7 Hz,1H),7.43(ddd,J＝7.9,1.9,1.0Hz,1H),7.34(d,J＝7.8Hz,1H),7.21(t,J＝7.8Hz,1H),3.66(s,3H),3.41(d,J＝10.0Hz,1H),3.06(td,J＝10.1,2.1Hz,1H),2.94 (d,J＝11.7Hz,1H),2.52(td,J＝11.5,2.7Hz,1H),1.81–1.74(m,2H),1.59–1.56(m,1H),1.47–1.18(m,4H).13C NMR(101MHz,CDCl3)δ＝172.5,138.4,131.6, 131.1,130.3,127.4,122.9,59.0,58.0,52.0,47.0,31.0,25.7,24.4.HRMS(ESI)m/z: [M+H]+Calcd for C14H19BrNO2 +＝312.0594；Found 312.0590.
实施例5：(S)-2-(3-三氟甲基苯基)-2-((R)-哌啶-2-基)乙酸甲酯的合成
在氩气氛围下，向氢化瓶中加入[Ir(COD)Cl]2(0.3mg,0.5μmol)、 (R)-f-Binaphane(0.9mg,1.1μmol)和30μL无水二氯甲烷。反应室温搅拌30分钟后，依次加入四取代烯烃原料(29.9mg,0.1mmol)、三氯化铝(2.7mg,0.02mmol)、1mL无水异丙醇和11μL三氟乙酸。在30bar的氢气氛围下反应24h 后，原料全部转化为产物。随后缓慢释放氢气，将反应的pH值调至10，用乙酸乙酯萃取，收集有机相用无水硫酸钠干燥后减压条件下除去溶剂，然后柱层析得到目标产物(27.4mg,收率：91％，92％ee,98:2dr)。
产物为无色液体，[α]25 D＝-29.2(c 0.76,CH3OH)，HPLC条件：Chiralpak IE 柱,正己烷(包含0.05％三氟乙酸)/异丙醇＝98/2，流速：1.0mL/min，254nm， t1＝5.6min,t2＝5.8min(major),t3＝7.6min.1H NMR(400MHz,CDCl3)δ＝7.67 (s,1H),7.63(d,J＝7.7Hz,1H),7.56(d,J＝7.8Hz,1H),7.47(t,J＝7.7Hz,1H),3.67(s,3H),3.53(d,J＝9.9Hz,1H),3.12(td,J＝10.1,2.1Hz,1H),2.94(d,J＝12.4 Hz,1H),2.52(td,J＝11.5,2.7Hz,1H),1.82–1.77(m,2H),1.60–1.57(m,1H),1.47–1.22(m,4H).13C NMR(101MHz,CDCl3)δ＝172.5,137.1,132.0,131.2(q,J ＝32.4Hz),129.3,125.6(q,J＝3.8Hz),124.8(q,J＝3.6Hz),123.9(q,J＝272.0Hz),59.0,58.2,52.1,47.0,31.0,25.7,24.4.19F NMR(376MHz,CDCl3)δ＝-62.6.HRMS (ESI)m/z:[M+H]+Calcd for C15H19F3NO2 +＝302.1362；Found 302.1362.
实施例6：(S)-2-(4-甲氧基苯基)-2-((R)-哌啶-2-基)乙酸甲酯的合成
在氩气氛围下，向氢化瓶中加入[Ir(COD)Cl]2(0.3mg,0.5μmol)、 (R)-f-Binaphane(0.9mg,1.1μmol)和30μL无水二氯甲烷。反应室温搅拌30分钟后，依次加入四取代烯烃原料(26.1mg,0.1mmol)、三氯化铝(2.7mg,0.02mmol)、1mL无水异丙醇和11μL三氟乙酸。在30bar的氢气氛围下反应24h 后，原料全部转化为产物。随后缓慢释放氢气，将反应的pH值调至10，用乙酸乙酯萃取，收集有机相用无水硫酸钠干燥后减压条件下除去溶剂，然后柱层析得到目标产物(23.4mg,收率：89％，90％ee,98:2dr)。
产物为无色液体，[α]25 D＝-44.9(c 1.19,CH3OH)，HPLC条件：Chiralpak OJH 柱,正己烷(包含0.05％三氟乙酸)/异丙醇＝98/2，流速：0.8mL/min，254nm， t1＝10.0min(major),t2＝11.1min,t3＝12.4min.1H NMR(400MHz,CDCl3)δ＝δ 7.32(dt,J＝8.8,2.8Hz,2H),6.87(dt,J＝8.8,2.8Hz,2H),3.78(s,3H),3.63(s,3H), 3.39(d,J＝10.1Hz,1H),3.03(td,J＝10.2,2.1Hz,1H),2.92(d,J＝11.4Hz,1H),2.49(td,J＝11.4,2.7Hz,1H),1.80–1.76(m,2H),1.57–1.55(m,1H),1.47– 1.18(m,4H).13C NMR(101MHz,CDCl3)δ＝173.3,159.2,129.6,128.0,114.2, 59.0,57.4,55.2,51.8,47.0,31.0,25.8,24.4.HRMS(ESI)m/z:[M+H]+Calcd for C15H22NO3 +＝264.1594；Found 264.1594.
实施例7：(S)-2-((R)-哌啶-2-基)-2-(噻吩-3-基)乙酸甲酯的合成
在氩气氛围下，向氢化瓶中加入[Ir(COD)Cl]2(0.3mg,0.5μmol)、 (R)-f-Binaphane(0.9mg,1.1μmol)和30μL无水二氯甲烷。反应室温搅拌30分钟后，依次加入四取代烯烃原料(23.7mg,0.1mmol)、三氯化铝(2.7mg,0.02 mmol)、1mL无水异丙醇和11μL三氟乙酸。在30bar的氢气氛围下反应24h 后，原料全部转化为产物。随后缓慢释放氢气，将反应的pH值调至10，用乙酸乙酯萃取，收集有机相用无水硫酸钠干燥后减压条件下除去溶剂，然后柱层析得到目标产物(21.5mg,收率：90％，89％ee,99:1dr)。
产物为无色液体，[α]25 D＝-53.5(c 0.78,CH3OH)，HPLC条件：Chiralpak IE 柱,正己烷(包含0.05％三氟乙酸)/异丙醇＝98/2，流速：0.8mL/min，254nm， t1＝14.7min,t2＝15.2min(major),t3＝20.1min.1H NMR(400MHz,CDCl3)δ＝ 7.31(dd,J＝4.9,3.0Hz,1H),7.25(d,J＝1.0Hz,1H),7.16(dd,J＝4.9,1.0Hz,1H), 3.67(s,3H),3.62(d,J＝9.8Hz,1H),3.01(td,J＝10.1,2.3Hz,1H),2.95(d,J＝11.5Hz,1H),2.52(td,J＝11.4,2.7Hz,1H),1.81–1.74(m,2H),1.58–1.56(m,1H), 1.47–1.18(m,4H).13C NMR(101MHz,CDCl3)δ＝172.7,136.4,127.2,126.2, 123.4,59.1,53.7,51.9,47.0,30.9,25.8,24.4.HRMS(ESI)m/z:[M+H]+Calcd for C12H18NO2S+＝240.1053；Found 240.1050.
实施例8：(S)-2-(萘-1-基)-2-((R)-哌啶-2-基)乙酸甲酯的合成
在氩气氛围下，向氢化瓶中加入[Ir(COD)Cl]2(0.3mg,0.5μmol)、 (R)-f-Binaphane(0.9mg,1.1μmol)和30μL无水二氯甲烷。反应室温搅拌30分钟后，依次加入四取代烯烃原料(28.1mg,0.1mmol)、三氯化铝(2.7mg,0.02 mmol)、1mL无水异丙醇和11μL三氟乙酸。在60bar的氢气氛围下反应48h 后，原料全部转化为产物。随后缓慢释放氢气，将反应的pH值调至10，用乙酸乙酯萃取，收集有机相用无水硫酸钠干燥后减压条件下除去溶剂，然后柱层析得到目标产物(26.0mg,收率：92％，96％ee,97:3dr)。
产物为白色固体，[α]25 D＝-81.1(c 0.85,CH3OH)，HPLC条件：Chiralpak IE 柱,正己烷(包含0.05％三氟乙酸)/异丙醇＝98/2，流速：1.0mL/min，254nm， t1＝10.5min,t2＝12.4min(major),t3＝14.5min.1H NMR(400MHz,CDCl3)δ＝ 8.28(d,J＝8.5Hz,1H),7.86(d,J＝8.1Hz,1H),7.80(d,J＝8.2Hz,1H),7.73(d,J ＝7.2Hz,1H),7.57–7.53(m,1H),7.49(t,J＝7.7Hz,2H),4.42(d,J＝9.9Hz,1H),3.61(s,3H),3.37(t,J＝9.6Hz,1H),2.86(d,J＝10.0Hz,1H),2.50(td,J＝11.2,2.9 Hz,1H),1.96–1.84(m,2H),1.58–1.55(m,1H),1.50–1.26(m,4H).13C NMR (101MHz,CDCl3)δ＝173.2,134.0,132.5,132.4,128.8,128.2,126.6,125.8,125.6, 123.4,59.4,51.9,47.1,31.2,25.8,24.6.HRMS(ESI)m/z:[M+H]+Calcd forC18H22NO2 +＝284.1645；Found 284.1642.
实施例9：(S)-2-苯基-2-((R)-哌啶-2-基)乙酸苄酯的合成
在氩气氛围下，向氢化瓶中加入[Ir(COD)Cl]2(0.3mg,0.5μmol)、 (R)-f-Binaphane(0.9mg,1.1μmol)和30μL无水二氯甲烷。反应室温搅拌30分钟后，依次加入四取代烯烃原料(30.7mg,0.1mmol)、三氯化铝(2.7mg,0.02mmol)、1mL无水异丙醇和11μL三氟乙酸。在30bar的氢气氛围下反应24h 后，原料全部转化为产物。随后缓慢释放氢气，将反应的pH值调至10，用乙酸乙酯萃取，收集有机相用无水硫酸钠干燥后减压条件下除去溶剂，然后柱层析得到目标产物(28.1mg,收率：91％，92％ee,98:2dr)。
产物为无色液体，[α]25 D＝-16.8(c 1.15,CH3OH)，HPLC条件：ChiralpakADH 柱,正己烷(包含0.05％三氟乙酸)/异丙醇＝98/2，流速：1.0mL/min，254nm， t1＝9.9min,t2＝10.2min(major),t3＝15.2min.1H NMR(400MHz,CDCl3)δ＝ 7.42–7.40(m,2H),7.35–7.23(m,8H),5.09(dd,J＝40.8,12.5Hz,2H),3.52(d,J ＝10.0Hz,1H),3.13(t,J＝10.1Hz,1H),2.92(d,J＝11.3Hz,1H),2.50(t,J＝10.8Hz,1H),1.78–1.76(m,2H),1.57–1.55(m,1H),1.47–1.21(m,4H).13C NMR (101MHz,CDCl3)δ＝172.4,135.9,135.8,128.9,128.7,128.5,128.1,127.9,66.4, 59.0,58.4,47.0,31.0,25.7,24.4.HRMS(ESI)m/z:[M+H]+Calcd forC20H24NO2 +＝ 310.1802；Found 310.1802.
实施例10：(S)-2-苯基-2-((R)-哌啶-2-基)乙酸甲酯的扩大合成
在氩气氛围下，向氢化瓶中加入[Ir(COD)Cl]2(1.0mg,1.5μmol)、 (R)-f-Binaphane(2.7mg,3.3μmol)和90μL无水二氯甲烷。反应室温搅拌30分钟后，依次加入四取代烯烃原料(1.04g,4.5mmol)、三氯化铝(120mg,0.9mmol)、 4.5mL无水异丙醇和0.5mL三氟乙酸。在30bar的氢气氛围下反应72h后，原料全部转化为产物。随后缓慢释放氢气，将反应的pH值调至10，用乙酸乙酯萃取，收集有机相用无水硫酸钠干燥后减压条件下除去溶剂，然后柱层析得到目标产物(0.96g,收率：92％，92％ee,98:2dr)。
实施例11：(S)-2-苯基-2-((R)-哌啶-2-基)乙酰胺的合成
向一个50mL反应瓶中加入2a(466mg,2.0mmol)，10mL水和3mL浓盐酸，回流条件下搅拌过夜。待反应体系冷却后，减压条件下除去溶剂，得到淡黄色粗产品直接用于下一步反应。
在20mL反应瓶中将粗产品溶于无水二氯甲烷，在0℃摄氏度缓慢滴加二氯亚砜。搅拌半个小时后，反应体系缓慢升温至回流再搅拌2小时。减压条件下除去溶剂后将残留物溶于12mL四氢呋喃，随后在0℃缓慢滴加7M的氨甲醇溶液，反应体系升至室温后搅拌2小时。在0℃用水淬灭，加入3mL 5M盐酸溶液搅拌1小时。萃取后收集水相，用30％的氢氧化钠水溶液将pH值调至12 再用乙酸乙酯萃取。收集有机相在减压条件下除去溶剂，经过柱层析就可以得到产物3(327mg,产率:75％)
产物为白色固体。1H NMR(400MHz,CDCl3)δ＝7.40–7.26(m,5H),6.77(s, 1H),5.51(s,1H),3.30(d,J＝7.3Hz,1H),3.13–3.08(m,1H),2.99–2.95(m,1H),2.55(td,J＝12.1,2.8Hz,1H),1.86–1.79(m,2H),1.57–1.54(m,1H),1.46–1.27 (m,3H),1.21–1.14(m,1H).13CNMR(101MHz,CDCl3)δ＝174.6,136.4,128.8, 128.8,127.7,58.7,58.4,47.0,30.9,26.1,24.6.HRMS(ESI)m/z:[M+H]+Calcd for C13H19NO2 +＝219.1492；Found 219.1492.
实施例12：(R)-2-苯基-2-((R)-哌啶-2-基)乙酸甲酯的合成
在氩气氛围下，向一个50mL反应瓶中加入3(280mg,1.3mmol)，叔丁醇钾(291mg,2.6mol)和15mL甲苯，反应在70℃回流条件下搅拌24小时。在0℃用水淬灭，加入2mL 5M盐酸溶液搅拌1小时。萃取后收集水相，用30％的氢氧化钠水溶液将pH值调至12再用乙酸乙酯萃取。收集有机相在减压条件下除去溶剂，得到白色固体。
将上述白色固体溶于3mL甲醇中，向体系中加入0.5mL浓硫酸，反应在 75℃下搅拌48小时。待反应冷却后减压条件下除去溶剂，在0℃加入5mL水和5mL乙酸异丁酯。用饱和碳酸钠水溶液将pH值调至12，再用乙酸乙酯萃取。收集有机相在减压条件下除去溶剂，得到产物4(198mg,0.85mmol,收率：66％, 90％ee,96:4dr)。
产物为无色液体。[α]23 D＝+74.1(c 1.0,CH3OH)；HPLC条件：Chiralpak IE柱, 正己烷(包含0.05％三氟乙酸)/异丙醇＝98/2，流速：1.0mL/min，254nm，t1＝10.5 min,t2＝12.9min(major),t3＝14.8min.1H NMR(400MHz,CDCl3)δ＝7.33–7.24 (m,5H),3.64(s,3H),3.44(d,J＝10.1Hz,1H),3.11–3.05(m,2H),2.70(td,J＝11.9,2.8Hz,1H),1.95(s,1H),1.70–1.66(m,1H),1.59–1.56(m,1H),1.43–1.32(m, 1H),1.28–1.17(m,2H),1.00–0.91(m,1H).13C NMR(101MHz,CDCl3)δ＝ 173.8,136.4,128.6,128.5,127.5,58.99,58.7,51.9,46.8,29.9,26.1,24.3.HRMS(ESI)m/z:[M+H]+Calcd for C14H20NO2 +＝234.1489；Found234.1488.
实施例13：(R)-2-苯基-2-((R)-哌啶-2-基)乙酸甲酯盐酸盐的合成
将4(152mg,0.65mmol)溶于3mL乙酸乙酯中，向体系中加入0.5mL4 M 盐酸二氧六环溶液，搅拌半个小时。将反应体系过滤，收集滤饼，减压条件下干燥得到产物5(176mg,0.65mmol,收率：99％)。
产物为白色固体。[α]23 D＝+78.8(c 1.0,CH3OH).1H NMR(400MHz,CDCl3)δ＝10.37(br s,1H),8.90(br s,1H),7.37–7.27(m,5H),4.31(d,J＝10.2Hz,1H), 3.83(s,3H),3.73–3.63(m,2H),2.92(t,J＝12.3Hz,1H),2.16–2.06(m,1H),1.84 –1.69(m,3H),1.41–1.33(m,2H).13C NMR(101MHz,CDCl3)δ＝172.0,134.1, 129.2,128.4,128.4,59.0,53.9,53.4,45.6,25.9,22.6,21.9.HRMS(ESI)m/z: [M–Cl–]+Calcd for C14H20NO2 +＝234.1489；Found 234.1489.
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (6)
1.一种不对称氢化制备手性哌甲酯类化合物的方法，其特征在于，其反应路线为：
具体地，化合物(I)在合适的溶剂中，加入手性双膦配体、过渡金属催化剂、布朗斯特酸以及添加剂，充入氢气进行不对称还原反应得到式(II)所示的化合物；
所用手性双膦配体为：
其中，R为甲基，Ar为苯基；或R为甲基，Ar为3-氟苯基；或R为甲基，Ar为3-氯苯基；或R为甲基，Ar为3-溴苯基；或R为甲基，Ar为3-三氟甲基苯基；或R为甲基，Ar为4-甲氧基苯基；或R为甲基，Ar为噻吩-3-基；R为甲基，Ar为萘-1-基；或R为苯甲基，Ar为苯基；
所述过渡金属选自铱；金属前体选自[Ir(NBD)Cl]2，[Ir(NBD)2]X，[Ir(COD)Cl]2，[Ir(COD)2]X；X表示负阴离子Cl-，Br-或I-；所使用的添加剂选自氯化铝。
2.根据权利要求1所述的制备方法，其特征在于，所述反应是在溶剂中进行；所述溶剂选自甲醇、乙醇、异丙醇、甲基叔丁基醚、四氢呋喃、1,4-二氧六环、二氯甲烷、乙酸乙酯、正己烷、甲苯中的至少一种或任意比例的混合溶剂；式(I)所示的化合物与溶剂的用量比为1mmol：(10-20)mL。
3.根据权利要求1所述的制备方法，其特征在于，使用的氢气压力为10-100bar。
4.根据权利要求1所述的制备方法，其特征在于，所使用的反应温度选自20-100℃。
5.根据权利要求1所述的制备方法，其特征在于，所使用的布朗斯特酸选自苯甲酸、甲酸、三氟甲磺酸、磷酸、樟脑磺酸、对甲苯磺酸、三氟乙酸、盐酸中的一种或任意比例的混合物。
6.根据权利要求1所述的制备方法，其特征在于，催化剂与底物的摩尔比为0.01mol％-10mol％，反应时间为0.5-100h。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211070916.5A CN115322141B (zh) | 2022-09-01 | 2022-09-01 | 一种不对称氢化制备手性哌甲酯类化合物的方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211070916.5A CN115322141B (zh) | 2022-09-01 | 2022-09-01 | 一种不对称氢化制备手性哌甲酯类化合物的方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115322141A CN115322141A (zh) | 2022-11-11 |
| CN115322141B true CN115322141B (zh) | 2024-04-16 |
Family
ID=83929600
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211070916.5A Active CN115322141B (zh) | 2022-09-01 | 2022-09-01 | 一种不对称氢化制备手性哌甲酯类化合物的方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115322141B (zh) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5859249A (en) * | 1997-02-19 | 1999-01-12 | Takasago International Corporation | 2-phenyl-2-(2'-piperidinylidene)acetate derivative, process for manufacturing the same, and process for manufacturing optically active 2-phenyl-2-(2'-piperidinyl)acetate derivative by asymmetrically hydrogenating the same |
| US5936091A (en) * | 1997-05-22 | 1999-08-10 | Celgene Corporation | Processes and intermediates for resolving piperidyl acetamide stereoisomers |
-
2022
- 2022-09-01 CN CN202211070916.5A patent/CN115322141B/zh active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5859249A (en) * | 1997-02-19 | 1999-01-12 | Takasago International Corporation | 2-phenyl-2-(2'-piperidinylidene)acetate derivative, process for manufacturing the same, and process for manufacturing optically active 2-phenyl-2-(2'-piperidinyl)acetate derivative by asymmetrically hydrogenating the same |
| US5936091A (en) * | 1997-05-22 | 1999-08-10 | Celgene Corporation | Processes and intermediates for resolving piperidyl acetamide stereoisomers |
Non-Patent Citations (9)
| Title |
|---|
| A concise and stereoselective synthesis of (+/−)-erythro-methylphenidate;Dennis Russowsky 等;《Tetrahedron Letters》;第44卷;第2923-2926页 * |
| Ir-Catalysed Asymmetric Hydrogenation: Ligands, Substrates and Mechanism;Klas Kallstrom 等;《Chem. Eur. J.》;第12卷;第3194-3200页 * |
| Iridium-Catalyzed Asymmetric Hydrogenation of Olefins;STEPHEN J. ROSEBLADE 等;《Acc. Chem. Res.》;第40卷;第1402-1411页 * |
| Iridium-Catalyzed Asymmetric Hydrogenation of Tetrasubstituted Exocyclic Olefins: An Efficient Access to Dexmethylphenidate;Yingying Tian 等;《CCS Chem.》;第1-10页 * |
| Iridium-Catalyzed Asymmetric Hydrogenation of Unsaturated Carboxylic Acids;Shou-Fei Zhu 等;《Acc. Chem. Res.》;第50卷;第988-1001页 * |
| Quantitative structure-activity relationship studies of threo-methylphenidate analogs;Milind Misra 等;《Bioorganic & Medicinal Chemistry》;第18卷;第7221-7238页 * |
| STERICALLY STABILIZED α-ACYL FREE RADICALS: α-ISOPROPROEYCARBONYL, N-MORPHOLINOCARBONYL AND CYANO BIS(PENTACHLOROPHENYL)METHYL RADICALS.;A F Hegarty 等;《Tetrahedron Letters》;第28卷(第8期);第901-904页 * |
| Studies on the Eschenmoser coupling reaction and insights on its mechanism. Application in the synthesis of Norallosedamine and other alkaloids;Brenno A.D. Neto 等;《Tetrahedron》;第65卷;第2484-2496页 * |
| 盐酸右哌甲酯及其光学异构体的合成;张飞龙 等;《Chin. J. Org. Chem.》;第36卷;第2162-2167页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115322141A (zh) | 2022-11-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI312772B (en) | Process to chiral beta amino acid derivatives by asymmetric hydrogenation | |
| US4943635A (en) | Enantioselective reduction of ketones | |
| Nájera et al. | Enantioselective desymmetrization reactions in asymmetric catalysis | |
| JP6150179B2 (ja) | Ｒ−ビフェニルアラニノールの合成 | |
| CA2658215C (en) | An enantioselective synthesis of pyrrolidines-substituted flavones | |
| EP2029541B1 (en) | Process for preparation of enantiomerically enriched cyclic beta-aryl or heteroaryl carboxylic acids | |
| Sugimura et al. | Axial chirality control by 2, 4-pentanediol or its analogue as a simple chiral linking bridge. Highly diastereodifferentiating homocoupling of a 1-lithio-2-naphthyl ether | |
| EP2560493B1 (en) | An enantioselective process for cycloalkenyl b-substituted alanines | |
| US7109343B2 (en) | Metal catalysts and methods for making and using same | |
| US20070072905A1 (en) | Novel process for preparing dopenzil and its derivatives | |
| CN115322141B (zh) | 一种不对称氢化制备手性哌甲酯类化合物的方法 | |
| CN101391960A (zh) | 制备光学纯的2-羟基-4-芳基-丁酸乙酯的方法 | |
| EP1347960B1 (en) | Process for preparing (+) trans-4-p-fluorophenyl-3-hydroxymethyl-1 | |
| EP1607388B1 (en) | An improved manufacturing process for methylphenidate and intermediates thereof | |
| CN114644662A (zh) | 一种基于二茂铁结构的手性膦氮氮三齿配体及其应用 | |
| EP1153023B1 (en) | Process for the production of paroxetine | |
| CN112279743B (zh) | 一种手性α-氨基酸酯衍生物的合成方法 | |
| EP2762467B1 (en) | Method for producing an optically active 2-arylpiperidinium salt | |
| JP4529419B2 (ja) | 光学活性含フッ素化合物類、及びこれらの製造方法 | |
| EP1210324B1 (en) | Substituted cyclopentenes, their preparation and their use for chiral scaffolds | |
| CN101522634A (zh) | 氮杂双环烷醇衍生物的制造方法 | |
| Li et al. | Catalytic Asymmetric Hydrogenation of Ethyl 2‐(Benzo [b] thiophen‐5‐yl)‐2‐oxoacetate with Ru‐SunPhos in the Formal Synthesis of T‐588 | |
| JP3494549B2 (ja) | アミノ酸を配位子とする新規ルテニウム錯体およびそれを用いた不斉水素化方法 | |
| CA2768239A1 (en) | Processes for the synthesis of (2s, 3ar, 7as)-octahydro-1h-indole carboxylic acid as an intermediate for trandolapril | |
| CN118119596A (zh) | 一种药物中间体的制备方法 |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |