CN112824381A - 一种哌啶胺的制备方法 - Google Patents
一种哌啶胺的制备方法 Download PDFInfo
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- CN112824381A CN112824381A CN201911146743.9A CN201911146743A CN112824381A CN 112824381 A CN112824381 A CN 112824381A CN 201911146743 A CN201911146743 A CN 201911146743A CN 112824381 A CN112824381 A CN 112824381A
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- compound
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- sodium
- reaction
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical compound NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 title abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 100
- 238000000034 method Methods 0.000 claims abstract description 35
- -1 sulfoxide halide Chemical class 0.000 claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 10
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 claims abstract description 7
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 claims abstract description 7
- 229960001327 pyridoxal phosphate Drugs 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000002585 base Substances 0.000 claims description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 11
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 9
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 9
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 9
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 9
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 239000006184 cosolvent Substances 0.000 claims description 6
- 150000004820 halides Chemical class 0.000 claims description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- TVRHDFJMHSSQCP-UHFFFAOYSA-M [Ir]Cl.C1CC=CCCC=C1 Chemical group [Ir]Cl.C1CC=CCCC=C1 TVRHDFJMHSSQCP-UHFFFAOYSA-M 0.000 claims description 3
- 239000007853 buffer solution Substances 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 claims description 2
- MHXHNLNQRNPZOP-UHFFFAOYSA-N CO[Ir].C1CC=CCCC=C1 Chemical class CO[Ir].C1CC=CCCC=C1 MHXHNLNQRNPZOP-UHFFFAOYSA-N 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- NJZKKQJLJHSEQN-UHFFFAOYSA-M [Rh]Cl.C1=C(C2)CCC2=C1 Chemical class [Rh]Cl.C1=C(C2)CCC2=C1 NJZKKQJLJHSEQN-UHFFFAOYSA-M 0.000 claims description 2
- XSRWPJFTHDOKTA-UHFFFAOYSA-M [Rh]Cl.C1CC=CCCC=C1 Chemical class [Rh]Cl.C1CC=CCCC=C1 XSRWPJFTHDOKTA-UHFFFAOYSA-M 0.000 claims description 2
- 235000004279 alanine Nutrition 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 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
- 239000000872 buffer Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000003840 hydrochlorides Chemical class 0.000 claims description 2
- 229910000042 hydrogen bromide 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
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 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
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 8
- 230000009471 action Effects 0.000 abstract description 7
- 238000000746 purification Methods 0.000 abstract description 7
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 238000000926 separation method Methods 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 229910019020 PtO2 Inorganic materials 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 208000004631 alopecia areata Diseases 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- GJMPSRSMBJLKKB-UHFFFAOYSA-N 3-methylphenylacetic acid Chemical compound CC1=CC=CC(CC(O)=O)=C1 GJMPSRSMBJLKKB-UHFFFAOYSA-N 0.000 description 1
- JXUWZXFVCBODAN-UHFFFAOYSA-N 5-methylpyridin-3-amine Chemical compound CC1=CN=CC(N)=C1 JXUWZXFVCBODAN-UHFFFAOYSA-N 0.000 description 1
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- NTNUDYROPUKXNA-UHFFFAOYSA-N methyl 2-(triphenyl-$l^{5}-phosphanylidene)acetate Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OC)C1=CC=CC=C1 NTNUDYROPUKXNA-UHFFFAOYSA-N 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- ISYORFGKSZLPNW-UHFFFAOYSA-N propan-2-ylazanium;chloride Chemical compound [Cl-].CC(C)[NH3+] ISYORFGKSZLPNW-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940117957 triethanolamine hydrochloride Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/04—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated
- C07C225/06—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and acyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/02—Preparation by ring-closure or hydrogenation
-
- 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
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Abstract
本发明涉及一种哌啶胺的制备方法,该方法以化合物02作为原料与三甲基卤化亚砜反应,制得化合物03,化合物03在催化剂作用下反应成环生成化合物04;化合物04在ω‑转氨酶和磷酸吡哆醛的作用下反应生成化合物05,化合物05在酸的作用下脱保护基得到化合物06;该方法避免用手性柱拆分或拆分剂拆分,原料便宜易得,步骤短,且分离纯化简单,ee值高,收率高,纯度高,操作安全,利于工业化生产。
Description
技术领域
本发明涉及药物化学领域,具体涉及一种哌啶胺的制备方法。
背景技术
哌啶胺作为重要的医药中间体,通常应用于合成药物活性化合物,如用于合成PF-06651600。
PF-06651600是一种强效的JAK3选择性抑制剂,此前已获得FDA的突破性疗法认定,用于治疗斑秃。目前,它进行治疗中重度斑秃的3期临床试验,同时还继续试验用于治疗类风湿性关节炎(RA),克罗恩病(CD)和溃疡性结肠炎(UC);PF-06651600的结构如下式所示:
现有技术中,使用5-甲基-3-氨基吡啶为原料,如WO2010048012公开了使用金属铑催化剂将吡啶环还原成哌啶环;WO2016112298公开了使用PtO2作为催化剂还原吡啶环。然而,金属催化剂价格昂贵,一般使用氢气还原,长时间高压加热氢化,反应条件苛刻。如,使用PtO2生成的铂黑易燃,生产危险。现有工艺中,多步反应需要柱层析纯化,难于放大生产。现有技术中,使用(R)-N-3,5-二硝基苯甲酰基苯甘氨酸为拆分剂,价格昂贵,同时文献(Organic Process Research&Development(2019)记载拆分剂使用时存在剧烈放热现象,生产时控制不好仍然存在安全隐患。
因此,急需寻找一种新的中间体,或者研究一种新方法用于制备PF-06651600的哌啶胺中间体,以获得具有操作简便,避免了手性拆分损失收率,原料便宜易得,步骤短,且分离纯化简单,ee值高,收率高,纯度高,环境友好的制备方法,从而更好地制备获得化合物PF-06651600。
发明内容
本发明提供一种哌啶胺的制备方法,该方法中,可以以化合物02作为原料与三甲基卤化亚砜反应,制得化合物03,化合物03在催化剂作用下反应成环生成化合物04;化合物04在ω-转氨酶和磷酸吡哆醛的作用下反应生成化合物05,化合物05在酸的作用下脱保护基得到化合物06。
第一方面,本发明提供的一种哌啶胺的制备方法,包括,在第一溶剂中,在第一碱的存在下,化合物 02与三甲基卤化亚砜反应,制得化合物03,
其中,
R1为Boc,Cbz,甲氧羰基,乙氧羰基,乙酰基,苯甲酰基,甲磺酰基,苯磺酰基,2-硝基苯磺酰基中的一种;
R2为甲基,乙基,正丙基,异丙基,苄基,叔丁基中的一种;
所述三甲基卤化亚砜为三甲基碘化亚砜、三甲基溴化亚砜、三甲基氯化亚砜中的至少一种。
在一些实施方式中,所述第一溶剂为THF、DMSO、2Me-THF、DCM、甲苯中的至少一种。
在一些实施方式中,所述第一碱为氢化钠、氨基钠、叔丁醇钾、叔丁醇钠中的至少一种,有利于更好制备获得高收率高纯度的产品。
在一些实施方式中,所述第一碱与化合物02的摩尔比为1:1-3:1;在一些实施方式中,所述第一碱与化合物02的摩尔比为1.5:1-2.5:1。
在一些实施方式中,所述三甲基卤化亚砜与化合物02的摩尔比为1:1-3:1;在一些实施方式中,所述三甲基卤化亚砜与化合物02的摩尔比为1.5:1-2.5:1,有利于更好地制备获得产品。
在一些实施方式中,所述反应的反应温度为-20℃~80℃;在一些实施方式中,所述反应的反应温度为 40℃-60℃。
在一些实施方式中,所述反应的反应时间为2h-24h;在一些实施方式中,所述反应的反应时间为5h-20h;在一些实施方式中,所述反应的反应时间为10h-15h。
第二方面,本发明提供的一种哌啶胺的制备方法,包括,化合物03在第二溶剂中,在催化剂作用下进一步反应生成化合物04
R1为Boc,Cbz,甲氧羰基,乙氧羰基,乙酰基,苯甲酰基,甲磺酰基,苯磺酰基,2-硝基苯磺酰基中的一种。
在一些实施方式中,所述第二溶剂为DCE、DCM、THF、2Me-THF、甲苯中的至少一种。
在一些实施方式中,所述催化剂为(1,5-环辛二烯)氯化铱(I)二聚体、(1,5-环辛二烯)甲氧基铱(I)二聚体、(1,5-环辛二烯)氯化铑(I)二聚体、(降冰片二烯)氯化铑(I)二聚体,其结构如下式所示:
该催化剂有利于更好地催化获得ee值高,收率高,纯度高的化合物04。
在一些实施方式中,所述催化剂与化合物03的摩尔比为0.01%~10%;在一些实施方式中,所述催化剂与化合物03的摩尔比为0.5%~3%。
在一些实施方式中,所述反应的反应温度为20℃-80℃;在一些实施方式中,所述反应的反应温度为 40℃-60℃。
第三方面,本发明提供的一种哌啶胺的制备方法,包括,化合物03在第三溶剂中与卤化物进一步反应生成化合物03-1
其中,
R1为Boc,Cbz,甲氧羰基,乙氧羰基,乙酰基,苯甲酰基,甲磺酰基,苯磺酰基,2-硝基苯磺酰基中的一种;
X为氟、氯、溴或碘中的一种。
在一些实施方式中,所述卤化物为氯化氢、溴化氢;在一些实施方式中,所述卤化物为氯化锂、溴化钠、溴化锂、碘化钠、碘化钾的至少一种与第一酸的混合物。
在一些实施方式中,所述第一酸为甲磺酸、对甲基苯磺酸,三氟甲基磺酸、硫酸中的至少一种。
在一些实施方式中,所述第三溶剂为DCM、EA、THF、二氧六环、甲苯中的至少一种。
第四方面,本发明提供的一种哌啶胺的制备方法,包括,化合物03-1在第四溶剂中和第三碱存在的条件下反应,生成化合物04-1
其中,X为氟、氯、溴或碘中的一种。
在一些实施方式中,所述第三碱为碳酸氢钠,碳酸钠,碳酸钾,氢氧化钠,三乙胺,二异丙基乙胺中的至少一种。
在一些实施方式中,所述第四溶剂为甲醇、乙醇、丙酮、四氢呋喃、二氯甲烷、甲苯,中的至少一种;在一些实施方式中,所述第四溶剂为三乙胺,二异丙基乙胺中的至少一种。直接用上述液体有机碱作溶剂,有利于更方便制备化合物04-1。
在一些实施方式中,所述第三碱与化合物03-1的摩尔比为0.8:1-3:1,在一些实施方式中,所述第三碱与化合物03-1的摩尔比为1:1-1.8:1。
第五方面,本发明提供的一种哌啶胺的制备方法,包括,在ω-转氨酶和磷酸吡哆醛存在的条件下,在助溶剂和缓冲液中,使化合物04与氨基供体接触,反应得到化合物05
R1为Boc,Cbz,甲氧羰基,乙氧羰基,乙酰基,苯甲酰基,甲磺酰基,苯磺酰基,硝基苯磺酰基中的一种。
在一些实施方式中,在ω-转氨酶和磷酸吡哆醛存在下,在所述助溶剂和缓冲溶液中,使所述化合物 04与所述氨基供体接触,在25℃-60℃、pH值8.5-11条件下反应,得到所述化合物05。
在一些实施方式中,所述氨基供体为异丙胺、丙氨酸、正丙胺、1-苯乙胺、甘氨酸、或它们的盐酸盐中的至少一种。
在一些实施方式中,所述助溶剂为二甲亚砜或乙醇或其组合。
第六方面,本发明提供的一种哌啶胺的制备方法,包括,化合物05在第五溶剂和第二酸的条件下脱保护基,通过用第四碱调节pH,制备得到化合物06
R1为Boc,Cbz,甲氧羰基,乙氧羰基,乙酰基,苯甲酰基,甲磺酰基,苯磺酰基,硝基苯磺酰基中的一种。
在一些实施方式中,所述第五溶剂为乙醇、甲醇、乙酸乙酯、二氯甲烷中的至少一种。
在一些实施方式中,所述第二酸为盐酸、硫酸、磷酸、三氟乙酸中的至少一种。
在一些实施方式中,所述第四碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾中的至少一种。
第七方面,本发明提供一种化合物,如下式化合物03、化合物03-1或化合物06所示:
其中,
R1为Boc,Cbz,甲氧羰基,乙氧羰基,乙酰基,苯甲酰基,甲磺酰基,苯磺酰基,硝基苯磺酰基中的一种;
X为氟、氯、溴或碘中的一种。
本发明提供的一种哌啶胺的制备方法,避免用手性柱拆分或拆分剂拆分,原料便宜易得,步骤短,且分离纯化简单,ee值高,收率高,纯度高,操作安全,利于工业化生产。
在本发明的描述中,需要理解的是,术语“第一”、“第二”仅用于描述目的,而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此,限定有“第一”、“第二”的特征可以明示或者隐含地包括一个或者更多个该特征。在本发明的描述中,“多个”的含义是两个或两个以上,除非另有明确具体的限定。
在本说明书的描述中,参考术语“一些实施方式”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外,在不相互矛盾的情况下,本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
本发明中,如“化合物01”和“式(01)所示的化合物”的表述,表示的是同一个化合物。
具体实施方式
为了使本领域的技术人员更好地理解本发明的技术方案,下面进一步披露一些非限制实施例,对本发明作进一步的详细说明。
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。
本发明中,mmol表示毫摩尔,h表示小时,g表示克,ml表示毫升,eq表示当量,M表示mol/L, THF表示四氢呋喃,2Me-THF表示2-甲基四氢呋喃,MeOH表示甲醇,EtOH表示乙醇,CH3CN表示乙腈,DCM表示二氯甲烷,DMF表示N,N-二甲基甲酰胺,DMSO表示二甲亚砜,PE表示石油醚,EA表示乙酸乙酯,Boc2O表示二碳酸二叔丁酯,CbzCl表示氯甲酸苄酯,TLC表示薄层色谱,LCMS表示液相色谱-质谱,NaOH表示氢氧化钠,Ms表示甲磺酰基,Ts或Tos表示对甲苯磺酰基,NH4Cl表示氯化铵,NaHCO3表示碳酸氢钠,Na2CO3表示碳酸钠,DME表示乙二醇二甲醚,TEA表示三乙胺,MeMgBr表示甲基溴化镁。
实施例1制备化合物01-1
室温下,将化合物00-1(20.0g,1.0eq)加入DCM(100mL)中,在0℃氮气保护下缓慢滴加甲氧甲酰基亚甲基三苯基膦(42.5g,1.1eq)溶于DCM(150mL)的溶液,加完后反应体系在室温下反应约20h,中控,反应结束,减压浓缩反应液,柱层析分离纯化(PE:EA=10:1~PE:EA=8:1),得到化合物01-1的无色油状液体22.66g,纯度:99.10%,收率85.5%;分析数据:
LCMS+H+:130.2,174.2。
实施例2制备化合物02-1
室温下,将化合物01-1(12.0g,1.0eq)、10%Pd/C(0.12g,10%Wt)加入甲醇(100mL)介质中,氢气置换,室温下反应5h,中控,反应结束,过滤,减压浓缩滤液得化合物02-1白色固体产物11.82g,纯度:99.02%;收率:98%;分析数据:
LCMS+H+:132.20,176.20;
1H NMR(400MHz,CDCl3)δ4.38(s,1H),3.67(s,4H),2.37(t,J=7.6Hz,2H),1.86–1.64(m,2H),1.44 (s,9H),1.14(d,J=6.6Hz,3H)。
实施例3制备化合物03-2
室温下,将叔丁醇钾(12.35g,1.65eq)加入THF(110mL)介质中,氮气保护,室温搅拌下在5min 内分批加入三甲基碘化亚砜(23.44g,1.6eq),加完后升至65℃下反应2h,转移至室温,氮气保护下缓慢滴加化合物02-1溶于THF(15mL)的溶液,滴加完毕,室温下反应20h,LCMS中控,反应结束,过滤,减压浓缩滤液,柱层析纯化(EA:EtOH=2:1)得到化合物03-2白色固体产物16.1g,纯度:99.3%,收率: 83%;分析数据:
LCMS+H+:292.20;
1H NMR(400MHz,CDCl3)δ4.61(s,1H),4.39(s,1H),3.70–3.54(m,1H),3.40(s,6H),2.24(dd,J=11.5, 7.2Hz,2H),1.76–1.64(m,2H),1.43(s,9H),1.13(d,J=6.5Hz,3H);
13C NMR(151MHz,CDCl3)δ190.26,155.45,78.85,69.52,46.55,42.24,37.26,32.71,28.48,21.55。
实施例4制备化合物04-2
室温下,将催化剂(1,5-环辛二烯)氯化铱(I)二聚体([Ir(COD)Cl]2)(45mg,0.1mmol%)加入DCE(400mL) 介质中,氮气保护下升至65℃下搅拌,预热10min后缓慢滴加化合物03-2(13.1g,1.0eq)溶于DCE(200mL) 的溶液,加完后继续在65℃下反应,18h后LCMS中控,反应结束,降至室温后减压浓缩,柱层析纯化 (PE:EA=8:1~PE:EA=5:1)得到化合物04-2白色固体产物6.9g,纯度:98.2%,收率:72%;分析数据:
LCMS+H+:114.30,158.20;
1H NMR(400MHz,CDCl3)δ4.40(d,J=18.4Hz,1H),4.29(s,1H),3.58(d,J=18.8Hz,1H),2.42(dd,J =7.4,5.9Hz,2H),2.21(dt,J=19.7,5.9Hz,1H),1.66–1.56(m,1H),1.47(s,9H),1.24(d,J=6.4Hz,3H);
13C NMR(101MHz,CDCl3)δ207.91,154.51,80.35,49.76,46.69,36.01,28.37,27.81,18.31。
实施例5制备化合物05-1
室温下,将盐酸异丙胺(16mL,4M,pH 8.5),盐酸三乙醇胺(11mL,0.1M,pH 8.5)缓冲液加入 100mL单口瓶中,室温下搅拌,加入ω-转氨酶粉(1.5g)、PLP(0.1g)和DMSO(15ml),升温至45℃,滴加化合物04-1(5.0g,1.0eq)溶于DMSO(15ml)的溶液,控制pH=9~10,保温反应14小时;反应完毕,降至室温,过滤,加入乙酸乙酯和水萃取和洗涤。减压浓缩去除有机层,得到化合物05-1无色油状物 4.9g,纯度99.13%,收率89.6%;分析数据:
LCMS+H+:115.3,159.3。
实施例6制备化合物06-1
室温下,将化合物05-1(4.0g,1.0eq)加入6mol/L的盐酸水溶液(20ml)中,搅拌升温至回流,反应14h;反应完毕,降温至10℃,加入氢氧化钠调节pH7~8,加入二氯甲烷萃取蒸干,得到化合物06-1 淡黄色油状物2.04g,纯度:99.05%,ee值99.1%,收率96.01%;分析数据:
LC-MS:M+H=115.2;
1H NMR(400MHz,DMSO-d6):δ8.24(brs,2H),5.25(brs,2H),4.43(m,1H),4.19(d,J=8.11Hz,1H),2.97 (m,2H),1.78(m,2H),1.50(m,2H),1.11(d,J=7.0Hz,3H);
13C NMR(100MHz,DMSO-d6):δ43.05,40.34,36.23,24.56,21.75,17.55。
实施例7制备化合物03-1-1
室温下,将化合物03-02(16g,55mmol)、THF(20mL)、乙酸乙酯的HCl溶液(20mL)加入到三口瓶中, N2保护下在室温下反应10min后转移至70℃下反应,反应2h后,原料反应完毕,停止反应,减压蒸干有机溶剂,柱层析纯化得到(DCM:MeOH=8:1)化合物03-1-1无色油状产物6.6g,纯度:98.1%,ee值 99.20%,收率80.2%;分析数据:
LC-MS:M+H=150.1。
实施例8制备化合物04-1
室温下,将化合物03-1-1(6g,1.0eq,40mmol)、乙腈(20mL)、三乙胺(6.06g,1.5eq,60mmol)加入反应瓶中,70℃下反应过夜后,原料反应完毕,停止反应,降至室温,加入H2O(10mL)淬灭,EtOA 萃取2次,有机相用无水硫酸钠干燥,柱层析纯化(EA:PE=1:1)得到化合物04-1无色油状产物4.01g,纯度:99.12%,ee值99.15%,收率88%;分析数据:
LC-MS:M+H=114.1。
实施例9制备化合物04-2
在室温下,将化合物04-1(2g,1.0eq,17.7mmol)、DCM(20mL)加入反应瓶中,控温20℃下加入(Boc) 2O(4.6g,1.2eq,21.2mmol),该温度下反应过夜后,原料反应完毕,停止反应,减压蒸干有机溶剂柱层析纯化(EA:PE=8:1)得到化合物04-2白色固体3.6g,纯度:98.56%,ee值99.02%,收率95%;分析数据:
LCMS+H+:114.30,158.20。
实施例10制备化合物04-3
在室温下,于100ml两口瓶中,将化合物04-1(1.8g,1.0eq,16mmol)溶解于THF(10mL),将NaOH (1.28g,2.0eq,32mmol)溶解于10ml水中加入上述反应瓶中,控温0℃下加入氯甲酸苄酯(3.26g,1.2eq, 19.2mmol),加完后室温下反应16h,反应完毕,停止反应,用乙酸乙酯30ml*2萃取,分液,有机相经2NHCl (10mL)、饱和食盐水(10mL)分别洗涤一次,无水硫酸钠干燥,柱层析纯化(EA:PE=6:1)得到化合物04-3无色油状产物3.5g,纯度:99.05%,ee值99.10%,收率90%;分析数据:
LCMS+H+:248.20。
本发明的方法已经通过较佳实施例进行了描述,相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明内。
Claims (25)
2.根据权利要求1所述的方法,其特征在于,所述第一溶剂为THF、DMSO、2Me-THF、DCM、甲苯中的至少一种。
3.根据权利要求1所述的方法,其特征在于,所述第一碱为氢化钠、氨基钠、叔丁醇钾、叔丁醇钠中的至少一种。
4.根据权利要求1所述的方法,其特征在于,所述第一碱与化合物02的摩尔比为1:1-3:1;或者摩尔比为1.5:1-2.5:1。
5.根据权利要求1所述的方法,其特征在于,所述三甲基卤化亚砜与化合物02的摩尔比为1:1-3:1;或者摩尔比为1.5:1-2.5:1。
6.根据权利要求1所述的方法,其特征在于,所述反应的反应温度为-20℃~80℃;或者反应温度为40℃-60℃。
7.根据权利要求1所述的方法,其特征在于,所述反应的反应时间为2h-24h;或者反应时间为5h-20h;或者反应时间为10h-15h。
9.根据权利要求8所述的方法,其特征在于,所述第二溶剂为DCE、DCM、THF、2Me-THF、甲苯中的至少一种。
10.根据权利要求8所述的方法,其特征在于,所述催化剂为(1,5-环辛二烯)氯化铱(I)二聚体、(1,5-环辛二烯)甲氧基铱(I)二聚体、(1,5-环辛二烯)氯化铑(I)二聚体、(降冰片二烯)氯化铑(I)二聚体。
11.根据权利要求8所述的方法,其特征在于,所述催化剂与化合物03的摩尔比为0.01%~10%;或者摩尔比为0.5%~3%。
12.根据权利要求8所述的方法,其特征在于,所述反应的反应温度为20℃-80℃;或者反应温度为40℃-60℃。
14.根据权利要求13所述的方法,其特征在于,所述卤化物为氯化氢、溴化氢;或者卤化物为氯化锂、溴化钠、溴化锂、碘化钠、碘化钾的至少一种与第一酸的混合物。
15.根据权利要求14所述的方法,其特征在于,所述第一酸为甲磺酸、对甲基苯磺酸,三氟甲基磺酸、硫酸中的至少一种。
16.根据权利要求14所述的方法,其特征在于,所述第三溶剂为DCM、EA、THF、二氧六环、甲苯中的至少一种。
18.根据权利要求17所述的方法,其特征在于,所述第四溶剂为甲醇、乙醇、丙酮、四氢呋喃、二氯甲烷、甲苯,中的至少一种;或者第四溶剂为三乙胺,二异丙基乙胺中的至少一种。
19.根据权利要求17所述的方法,其特征在于,所述第三碱与化合物03-1的摩尔比为0.8:1-3:1,或者摩尔比为1:1-1.8:1。
21.根据权利要求20所述的方法,其特征在于,在ω-转氨酶和磷酸吡哆醛存在下,在所述助溶剂和缓冲溶液中,使所述化合物04与所述氨基供体接触,在25℃-60℃、pH值8.5-11条件下反应,得到所述化合物05。
22.根据权利要求20所述的方法,其特征在于,所述氨基供体为异丙胺、丙氨酸、正丙胺、1-苯乙胺、甘氨酸、或它们的盐酸盐中的至少一种。
23.根据权利要求20所述的方法,其特征在于,所述助溶剂为二甲亚砜或乙醇或其组合。
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