WO2022051984A1 - 吡非尼酮的合成方法 - Google Patents
吡非尼酮的合成方法 Download PDFInfo
- Publication number
- WO2022051984A1 WO2022051984A1 PCT/CN2020/114479 CN2020114479W WO2022051984A1 WO 2022051984 A1 WO2022051984 A1 WO 2022051984A1 CN 2020114479 W CN2020114479 W CN 2020114479W WO 2022051984 A1 WO2022051984 A1 WO 2022051984A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- pirfenidone
- mmol
- formula
- pyridone
- Prior art date
Links
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 title claims abstract description 64
- 229960003073 pirfenidone Drugs 0.000 title claims abstract description 43
- 238000001308 synthesis method Methods 0.000 title 1
- AYVIIWXJYORYKK-UHFFFAOYSA-N 5-methyl-3,4-dihydro-1h-pyridin-2-one Chemical compound CC1=CNC(=O)CC1 AYVIIWXJYORYKK-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 24
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims abstract description 23
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims abstract description 17
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000005859 coupling reaction Methods 0.000 claims abstract description 10
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000008878 coupling Effects 0.000 claims abstract description 6
- 238000010168 coupling process Methods 0.000 claims abstract description 6
- 239000010949 copper Substances 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 13
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- TTYVUTCCJNSNRL-UHFFFAOYSA-N O=C1CCC(C)=CN1C1=CC=CC=C1 Chemical compound O=C1CCC(C)=CN1C1=CC=CC=C1 TTYVUTCCJNSNRL-UHFFFAOYSA-N 0.000 claims description 11
- 229910052802 copper Inorganic materials 0.000 claims description 11
- 150000005171 halobenzenes Chemical class 0.000 claims description 10
- 239000003446 ligand Substances 0.000 claims description 8
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 7
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 7
- SWRGUMCEJHQWEE-UHFFFAOYSA-N ethanedihydrazide Chemical class NNC(=O)C(=O)NN SWRGUMCEJHQWEE-UHFFFAOYSA-N 0.000 claims description 7
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical class N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 6
- 239000005695 Ammonium acetate Chemical class 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 229940043376 ammonium acetate Drugs 0.000 claims description 6
- 235000019257 ammonium acetate Nutrition 0.000 claims description 6
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 4
- ZKXWKVVCCTZOLD-FDGPNNRMSA-N copper;(z)-4-hydroxypent-3-en-2-one Chemical compound [Cu].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O ZKXWKVVCCTZOLD-FDGPNNRMSA-N 0.000 claims description 4
- 238000005580 one pot reaction Methods 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 2
- 229910020366 ClO 4 Inorganic materials 0.000 claims description 2
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 claims description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 229910001869 inorganic persulfate Inorganic materials 0.000 claims description 2
- 150000001451 organic peroxides Chemical class 0.000 claims description 2
- FHHJDRFHHWUPDG-UHFFFAOYSA-L peroxysulfate(2-) Chemical compound [O-]OS([O-])(=O)=O FHHJDRFHHWUPDG-UHFFFAOYSA-L 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 abstract description 7
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical class [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 abstract description 6
- 150000001879 copper Chemical class 0.000 abstract description 6
- 239000013110 organic ligand Substances 0.000 abstract description 5
- 150000001555 benzenes Chemical class 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 239000003513 alkali Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000007787 solid Substances 0.000 description 26
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 239000000203 mixture Substances 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- SOHMZGMHXUQHGE-UHFFFAOYSA-N 5-methyl-1h-pyridin-2-one Chemical compound CC1=CC=C(O)N=C1 SOHMZGMHXUQHGE-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- -1 n-octyl Chemical group 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 0 *c1nnc(-c2nnc(*)[n]2)[n]1 Chemical compound *c1nnc(-c2nnc(*)[n]2)[n]1 0.000 description 3
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 3
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 3
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 3
- 235000019798 tripotassium phosphate Nutrition 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- HIKRJHFHGKZKRI-UHFFFAOYSA-N 2,4,6-trimethylbenzaldehyde Chemical compound CC1=CC(C)=C(C=O)C(C)=C1 HIKRJHFHGKZKRI-UHFFFAOYSA-N 0.000 description 2
- VQGHOUODWALEFC-UHFFFAOYSA-N 2-phenylpyridine Chemical compound C1=CC=CC=C1C1=CC=CC=N1 VQGHOUODWALEFC-UHFFFAOYSA-N 0.000 description 2
- CMBSSVKZOPZBKW-UHFFFAOYSA-N 5-methylpyridin-2-amine Chemical compound CC1=CC=C(N)N=C1 CMBSSVKZOPZBKW-UHFFFAOYSA-N 0.000 description 2
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 2
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 238000006254 arylation reaction Methods 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- DTUQWGWMVIHBKE-UHFFFAOYSA-N phenylacetaldehyde Chemical compound O=CCC1=CC=CC=C1 DTUQWGWMVIHBKE-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000003562 2,2-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- NFQGQMBFMIIIOR-UHFFFAOYSA-N 2-methoxy-5-methylpyridine Chemical compound COC1=CC=C(C)C=N1 NFQGQMBFMIIIOR-UHFFFAOYSA-N 0.000 description 1
- ZPOODPZCZLCUAN-UHFFFAOYSA-N 3,4-dihydro-1h-pyridin-2-one Chemical compound O=C1CCC=CN1 ZPOODPZCZLCUAN-UHFFFAOYSA-N 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- YGAILVDTGIMZAB-UHFFFAOYSA-N 3-pyrazol-3-ylidenepyrazole Chemical compound N1=NC=CC1=C1N=NC=C1 YGAILVDTGIMZAB-UHFFFAOYSA-N 0.000 description 1
- JFFQOKQBOFHZKF-UHFFFAOYSA-N 4,4-ditert-butyl-2-pyridin-2-yl-3h-pyridine Chemical compound C1=CC(C(C)(C)C)(C(C)(C)C)CC(C=2N=CC=CC=2)=N1 JFFQOKQBOFHZKF-UHFFFAOYSA-N 0.000 description 1
- TXNLQUKVUJITMX-UHFFFAOYSA-N 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine Chemical compound CC(C)(C)C1=CC=NC(C=2N=CC=C(C=2)C(C)(C)C)=C1 TXNLQUKVUJITMX-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- SABRUZXWLVODQU-UHFFFAOYSA-N C(CC1)CCC1c1nnc(-c2nnc(C3CCCCC3)[nH]2)[nH]1 Chemical compound C(CC1)CCC1c1nnc(-c2nnc(C3CCCCC3)[nH]2)[nH]1 SABRUZXWLVODQU-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 229910004882 Na2S2O8 Inorganic materials 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000003510 anti-fibrotic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229910001914 chlorine tetroxide Inorganic materials 0.000 description 1
- 230000037319 collagen production Effects 0.000 description 1
- 229940112669 cuprous oxide Drugs 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 125000004991 fluoroalkenyl group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 238000007832 transition metal-catalyzed coupling reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- 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
- B01J31/22—Organic complexes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Definitions
- the invention relates to a catalytic system composed of 5-methyl-3,4-dihydro-2-pyridone and halogenated benzene (chlorobenzene, bromobenzene or iodobenzene) as raw materials, in copper salt and organic ligands
- halogenated benzene chlorobenzene, bromobenzene or iodobenzene
- a process for synthesizing pirfenidone (1) in the presence of a base Compared with 5-methylpyridin-2(1H)-one, 5-methyl-3,4-dihydro-2-pyridone is more readily available and less expensive.
- the process also takes advantage of the high efficiency of a catalytic system consisting of copper(1) salts and organic ligands in the coupling of 5-methyl-3,4-dihydro-2-pyridone and halobenzene.
- copper-catalyzed air oxidation can efficiently convert the structure of 3,4-dihydro-2-pyridone to pyridin-2(1H)-one, enabling the practical synthesis of pirfenidone.
- Pirfenidone whose chemical name is 5-methyl-1-phenylpyridin-2(1H)-one, is represented by formula (1).
- Pirfenidone is a drug used to treat idiopathic pulmonary fibrosis. Has anti-fibrotic and anti-inflammatory activity, prevents collagen production and fibroblast proliferation.
- Patent DE2362958 discloses an arylation step for the synthesis of pirfenidone from intermediate (3) with iodobenzene, copper powder and inorganic base at reflux temperature in the absence of solvent.
- Patent CN1817862 discloses that CuCl promotes the pure reaction of (3) and iodobenzene in the presence of potassium carbonate at reflux temperature.
- WO2003014087 reports the synthesis of (1) by reacting intermediate (3) with bromobenzene at elevated temperature in the presence of potassium carbonate and cuprous oxide.
- WO201772216 reports the synthesis of intermediate (3) and a catalytic system consisting of copper salts and organic ligands by reacting intermediate (3) with chlorobenzene at elevated temperature in the presence of potassium carbonate (1).
- 5-Methylpyridin-2(1H)-one is usually prepared from 5-methylpyridin-2-amine or 2-methoxy-5-methylpyridine, both of which require transition metal-catalyzed coupling reactions , resulting in a higher total synthesis cost of pirfenidone.
- room temperature means a temperature from about 15°C to 35°C, preferably a temperature from about 20°C to 30°C, more preferably 25°C.
- alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 12 carbon atoms.
- Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl base, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- Octyl, n-nonyl and n-decyl.
- aryl refers to a monocyclic or polycyclic ring system in which one or more of the fused rings is aromatic.
- Representative examples of aryl groups include, but are not limited to, anthracenyl, fluoroalkenyl, indolyl, indolyl, naphthyl, and phenyl.
- the present invention provides a method for preparing pirfenidone of formula (1),
- X is selected from Cl, Br and I.
- the above-mentioned process can be carried out by separating the intermediate compound, and preferably, the process does not separate the intermediate compound, and most preferably, the above-mentioned process is carried out as a one-pot reaction, that is, it is not necessary to separate the intermediate compound, but directly. Complete conversion to pirfenidone.
- the present application is based on the discovery of a new, alternative method for the synthesis of pirfenidone of formula (1).
- the synthetic method described herein enables cost-effective preparation of pirfenidone by using inexpensive and readily available starting materials, novel catalyst systems, and reducing production time and cost.
- the invention provides a short-step method for the low-cost production of pirfenidone. To achieve a strategy based on cheap, readily available starting materials, step economy, and overall high efficiency, novel reactions are relied on at each synthetic step to build up significant molecular complexity.
- the first step is copper-catalyzed CN coupling.
- the base is any organic and inorganic base selected from TEA, DBU, DIPEA, KOH , K2CO3 , NaOH , Na2CO3 , Cs2CO3 , CsOH , K3PO4 , K2HPO4 , Na 3 PO 4 and Na 2 HPO 4 .
- the copper catalyst is selected from CuI, CuCl, CuBr, Cu2O, Cu(acac) 2 , CuCl2, CuBr2 , CuI2 , Cu(OAc) 2 , Cu(OTf )2 , Cu ( ClO4 ) 2 and CuSO 4 .
- the ligand is selected from compounds of formula (7),
- R is any alkyl and substituted/unsubstituted aryl.
- R is selected from methyl, ethyl, propyl, isopropyl and tert-butyl; and substituted/unsubstituted anthracenyl, indenyl, naphthyl and phenyl.
- the second step in the synthesis is the oxidation of 5-methyl-1-phenyl-3,4-dihydropyridin-2(1H)-one (6) to pirfenidone (1) in the presence of a copper catalyst and an oxidizing reagent .
- the copper catalyst is selected from any copper salt and its complexes such as CuI, CuCl, CuBr, Cu2O, Cu(acac) 2 , CuCl2, CuBr2 , CuI2 , Cu ( OAc )2 , Cu(OTf ) 2 , Cu(ClO 4 ) 2 and CuSO 4 .
- Oxygen, hydrogen peroxide, organic peroxide, inorganic persulfate and inorganic peroxymonosulfate are selected as oxidizing reagents.
- the overall synthesis of pirfenidone from 5-methyl-3,4-dihydro-2-pyridone (4) is accomplished in a one-pot reaction of the same catalytic system (copper salt and ligand). , complete these two steps in a single reaction vessel:
- the present invention utilizes the compound of formula (7) in the coupling reaction of C-N bond for the first time.
- the compound of formula (7) is easy to prepare, exhibits excellent selectivity and reaction efficiency in the coupling reaction of C-N bond, and is suitable for a wide range of substrates with different substituents
- reaction mixture was cooled to room temperature and extracted with ethyl acetate (300 mL) and water (100 mL). The organic mixture was dried over MgSO4 , filtered and concentrated to give a crude product in vacuo, which was dissolved in ethyl acetate and n-hexane was added to the resulting solution; the mixture was slowly cooled to 5°C while stirring, and stirred at 5°C for 1 hour. The suspension was filtered under vacuum and the resulting solid was washed with n-hexane and dried; crude pirfenidone (1) was obtained with a purity of over 95%. The beige solid was dissolved in hot water and stirred in the presence of activated carbon for 1 hour.
- the activated carbon is filtered out and washed with hot water.
- the resulting solution was slowly cooled to room temperature, then stirred at that temperature for 1 hour, cooled to 5°C, and stirred for 1 hour.
- the resulting off-white solid was filtered under vacuum, washed with cold water and dried.
- the molar yield from 5-methyl-3,4-dihydro-2-pyridone (4) to pirfenidone (1) was 71%.
- reaction mixture was cooled to room temperature and extracted with ethyl acetate (300 mL) and water (100 mL). The organic mixture was dried over MgSO4 , filtered and concentrated to give a crude product in vacuo, which was dissolved in ethyl acetate and n-hexane was added to the resulting solution; the mixture was slowly cooled to 5°C while stirring, and stirred at 5°C for 1 hour. The suspension was filtered under vacuum, and the resulting solid was washed with n-hexane and dried; crude pirfenidone (1) was obtained with a purity of over 95%. The beige solid was dissolved in hot water and stirred in the presence of activated carbon for 1 hour.
- the activated carbon is filtered out and washed with hot water.
- the resulting solution was slowly cooled to room temperature, then stirred at that temperature for 1 hour, cooled to 5°C, and stirred for 1 hour.
- the resulting white solid was filtered under vacuum, washed with cold water and dried.
- the molar yield from 5-methyl-3,4-dihydro-2-pyridone (4) to pirfenidone (1) was 72%.
- Pirfenidone (1) obtained from the above examples has the following characteristics:
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- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pyridine Compounds (AREA)
Abstract
Description
Claims (9)
- 如权利要求1所述的方法,其特征在于,步骤(a)所述碱是选自TEA、DBU、DIPEA、KOH、K 2CO 3、NaOH、Na 2CO 3、Cs 2CO 3、CsOH、K 3PO 4、K 2HPO 4、Na 3PO 4以及Na 2HPO 4。
- 如权利要求1所述的方法,所述步骤(a)和(b)的铜催化剂相同或不同,选自CuI、CuCl、CuBr、Cu 2O、Cu(acac) 2、CuCl 2、CuBr 2、CuI 2、Cu(OAc) 2、Cu(OTf) 2、Cu(ClO 4) 2和CuSO 4。
- 如权利要求1所述的方法,其特征在于,步骤(b)所述氧化剂选自氧气、过氧化氢、有机过氧化物、无机过硫酸盐和无机过氧单硫酸盐。
- 如权利要求5所述的方法,其特征在于,所述R选自甲基、乙基、丙基、异丙基和叔丁基;以及取代/非取代的蒽基、茚基、萘基和苯基。
- 一种如权利要求1-7任一项的方法,其特征在于,所述步骤(a) 和步骤(b)采用一锅法进行。
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US17/434,820 US20220251042A1 (en) | 2020-09-10 | 2020-09-10 | Total synthesis of pirfenidone |
PCT/CN2020/114479 WO2022051984A1 (zh) | 2020-09-10 | 2020-09-10 | 吡非尼酮的合成方法 |
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WO2017072216A1 (en) * | 2015-10-29 | 2017-05-04 | Procos S.P.A. | Process for the synthesis of pirfenidone |
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2020
- 2020-09-10 US US17/434,820 patent/US20220251042A1/en active Pending
- 2020-09-10 WO PCT/CN2020/114479 patent/WO2022051984A1/zh active Application Filing
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