CN113563306B - Preparation method of 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide - Google Patents
Preparation method of 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide Download PDFInfo
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- CN113563306B CN113563306B CN202010347047.0A CN202010347047A CN113563306B CN 113563306 B CN113563306 B CN 113563306B CN 202010347047 A CN202010347047 A CN 202010347047A CN 113563306 B CN113563306 B CN 113563306B
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- phenoxyphenyl
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- -1 4-phenoxyphenyl Chemical group 0.000 title claims abstract description 72
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 235000005152 nicotinamide Nutrition 0.000 title claims abstract description 23
- 239000011570 nicotinamide Substances 0.000 title claims abstract description 23
- 229960003966 nicotinamide Drugs 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 23
- 238000006482 condensation reaction Methods 0.000 claims abstract description 19
- 239000003054 catalyst Substances 0.000 claims abstract description 18
- 238000006317 isomerization reaction Methods 0.000 claims abstract description 18
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000003863 ammonium salts Chemical class 0.000 claims abstract description 11
- 230000008569 process Effects 0.000 claims abstract description 8
- 230000009471 action Effects 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 26
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical group [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 22
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 235000019270 ammonium chloride Nutrition 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 239000012295 chemical reaction liquid Substances 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- 230000005494 condensation Effects 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000005695 Ammonium acetate Substances 0.000 claims description 2
- 239000004254 Ammonium phosphate Substances 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 2
- 235000019257 ammonium acetate Nutrition 0.000 claims description 2
- 229940043376 ammonium acetate Drugs 0.000 claims description 2
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 claims description 2
- 229910000148 ammonium phosphate Inorganic materials 0.000 claims description 2
- 235000019289 ammonium phosphates Nutrition 0.000 claims description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 2
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 2
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 150000003003 phosphines Chemical class 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- FTEZOBLRKATKKG-UHFFFAOYSA-N 3-oxo-3-(4-phenoxyphenyl)propanamide Chemical compound NC(CC(C(C=C1)=CC=C1OC1=CC=CC=C1)=O)=O FTEZOBLRKATKKG-UHFFFAOYSA-N 0.000 abstract description 13
- VTDIWMPYBAVEDY-UHFFFAOYSA-N 1-propylpiperidine Chemical compound CCCN1CCCCC1 VTDIWMPYBAVEDY-UHFFFAOYSA-N 0.000 abstract description 5
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- VQCZEFRKZUNRPT-UHFFFAOYSA-N CCC=CC(NN1CCCCC1)=O Chemical compound CCC=CC(NN1CCCCC1)=O VQCZEFRKZUNRPT-UHFFFAOYSA-N 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- 238000001914 filtration Methods 0.000 description 22
- 239000012065 filter cake Substances 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- 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 16
- 239000000047 product Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- SJZKULRDWHPHGG-UHFFFAOYSA-N 1-benzylpiperidin-4-one Chemical compound C1CC(=O)CCN1CC1=CC=CC=C1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 10
- 239000007791 liquid phase Substances 0.000 description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 10
- 125000003277 amino group Chemical group 0.000 description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 8
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 229910001220 stainless steel Inorganic materials 0.000 description 8
- 239000010935 stainless steel Substances 0.000 description 8
- GYOMHDIHFFHNJY-UHFFFAOYSA-N 1,1-diethoxy-3-nitropropane Chemical compound CCOC(OCC)CC[N+]([O-])=O GYOMHDIHFFHNJY-UHFFFAOYSA-N 0.000 description 7
- 238000004821 distillation Methods 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- MOKDVDXMMSCFHC-UHFFFAOYSA-N 1,1-dimethoxy-3-nitropropane Chemical compound COC(OC)CC[N+]([O-])=O MOKDVDXMMSCFHC-UHFFFAOYSA-N 0.000 description 2
- MZPVEMOYADUARK-UHFFFAOYSA-N 2-(4-phenoxyphenyl)-6-(1-prop-2-enoylpiperidin-4-yl)pyridine-3-carboxamide Chemical compound NC(=O)C1=CC=C(C2CCN(CC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 MZPVEMOYADUARK-UHFFFAOYSA-N 0.000 description 2
- 229940124291 BTK inhibitor Drugs 0.000 description 2
- 201000004085 CLL/SLL Diseases 0.000 description 2
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N alpha-aminopyridine Natural products NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- 208000023738 chronic lymphocytic leukemia/small lymphocytic lymphoma Diseases 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 229960001507 ibrutinib Drugs 0.000 description 2
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000002277 temperature effect Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 241001251371 Betula chinensis Species 0.000 description 1
- XIQVNETUBQGFHX-UHFFFAOYSA-N Ditropan Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC#CCN(CC)CC)C1CCCCC1 XIQVNETUBQGFHX-UHFFFAOYSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- LTYMSROWYAPPGB-UHFFFAOYSA-N diphenyl sulfide Chemical compound C=1C=CC=CC=1SC1=CC=CC=C1 LTYMSROWYAPPGB-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 229940071705 orelabrutinib Drugs 0.000 description 1
- 229960005434 oxybutynin Drugs 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003512 tertiary amines Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention provides a preparation method of 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide, which comprises the steps of carrying out a first condensation reaction on 3, 3-dialkoxy-1-nitropropane and N-P substituent piperidine-4-ketone under the action of alkali to obtain N-P substituent-4-hydroxy-4- (1-nitro-3, 3-dialkoxy) propyl piperidine, then adding ammonium salt and 3- (4-phenoxyphenyl) -3-oxo-propionamide into a reaction solution, and carrying out a second condensation reaction to obtain 2- (4-phenoxybenzoyl) -5-nitro-5- (N-P substituent-4-hydroxy-4-yl) piperidyl N-pent-2-enamide And then under the action of a catalyst and hydrogen and under the condition of temperature programming, the 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide is obtained through reduction-cyclization reaction and isomerization reaction. The method has the advantages of cheap and easily obtained raw materials, easy operation of the technological process, low cost of the target product, high yield and purity, and suitability for industrial production.
Description
Technical Field
The invention relates to a preparation method of 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide, belonging to the technical field of pharmaceutical chemicals.
Background
2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide (I) is an important pyridine derivative and can be used for preparing orbetinib (Orelabrutinib). Orbetinib, CAS number [1655504-04-3], is a BTK inhibitor with specific selectivity developed by norcheng jianhua in china, and the national drug administration (NMPA) has accepted orbetinib (ICP-022) for the new drug marketing for treating relapsed/refractory Chronic Lymphocytic Leukemia (CLL) and relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and applied for treating tumors and autoimmune diseases, orbetinib has an overall curative effect superior to ibrutinib, a safety coefficient significantly superior to ibrutinib and zertinib, a target of the drug is more precise, and the side effects of orbetinib, such as major hemorrhage, infection and secondary malignant tumor, have the lowest occurrence probability, the lowest off-target probability and the lowest pharmaceutical dosage in all BTK inhibitors. Orbetinib has undergone multiple clinical phase I, clinical phase II and registered clinical trials for multicenter and multiple indications in china and the usa in 2019, and the obtained clinical results show good safety and curative effect, and some indications are reporting NDA.
The structural formulas of 2- (4-phenoxyphenyl) -6- (piperidin-4-) nicotinamide (I), known as 2- (4-phenoxyphenyl) -6- (piperidine-4-yl) pyridine-3-carboxamide, 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide (I) and oxybutynin are shown as follows:
at present, no relevant report of a preparation technology of 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide is found in the prior art, so that a low-cost green preparation process of the 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide is established, and the preparation method has important significance for the production of the obtinib. The invention is therefore proposed.
Disclosure of Invention
Aiming at the defects of the prior art, especially the defects of the prior art that the preparation technology of 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide is lacked, and aiming at the industrial requirement of obtinib, the invention provides a low-cost green preparation process of 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide.
The method takes the 3, 3-dialkoxy-1-nitropropane as an initial raw material, is cheap and easily obtained, has simple and convenient operation method, easy realization, safety and environmental protection, small waste water amount, low cost, high yield and selectivity and few byproducts, and is suitable for green industrial production.
Description of the terms:
a compound of formula I: 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide.
A compound of formula II: 3, 3-dialkoxy-1-nitropropane;
a compound of formula III: N-P substituent-4-hydroxy-4- (1-nitro-3, 3-dialkoxy) propylpiperidine;
a compound of formula IV: 3- (4-phenoxyphenyl) -3-oxo-propionamide;
a compound of formula V: 2- (4-phenoxybenzoyl) -5-nitro-5- (N-P substituent-4-hydroxy-4-yl) piperidinyl-N-pent-2-enamide;
the compound numbers in the specification are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula of the compound.
The technical scheme of the invention is as follows:
a method for preparing 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide comprises the following steps:
(1) in a solvent, under the action of alkali, 3, 3-dialkoxy-1-nitropropane and N-P substituent piperidine-4-ketone are subjected to a first condensation reaction to obtain a compound shown in a formula III;
wherein in the structural formula of the compounds shown in the formulas II and III, R is methyl, ethyl, propyl, isopropyl, tert-butyl or other C4H9Butyl, P is hydrogen, benzyl, o-methylbenzyl, m-methylbenzyl, P-methylbenzyl, o-chlorobenzyl or P-methoxybenzyl;
(2) adding ammonium salt and a compound shown in the formula IV into the reaction liquid containing the compound shown in the formula III obtained in the step (1), and carrying out a second condensation reaction to obtain a compound shown in the formula V;
(3) transferring the reaction mixed solution containing the compound of the formula V obtained in the step (2) into a pressure kettle, adding a catalyst, and carrying out reduction-cyclization reaction and isomerization reaction under the condition of temperature programming to obtain 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide (I);
in the method of the present invention, the steps (1), (2) and (3) can be completed by a one-pot method.
Preferably, in step (1), the base is one or a combination of sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium methoxide;
preferably, the solvent is one or a combination of water, C1-C4 lower alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, dichloroethane, dichloromethane, chloroform, acetonitrile or toluene.
According to the invention, in the step (1), the mass ratio of the solvent to the 3, 3-dialkoxy-1-nitropropane (II) is (2-15): 1.
According to a preferred embodiment of the present invention, in step (1), the molar ratio of the base, the N-P substituent piperidin-4-one and the 3, 3-dialkoxy-1-nitropropane is (1.0-1.8): 1 (1.0-1.2): 1.
Preferably, according to the invention, in step (1), the first condensation reaction temperature is-20 to 25 ℃; preferably, the first condensation reaction temperature is-10-20 ℃. The first condensation reaction time is 0.5-5 hours; the first condensation reaction time is preferably 2 to 3 hours.
According to the invention, in the step (1), the N-P substituent piperidine-4-ketone is added into the reaction system in a dropwise manner.
Preferably, in step (2), the ammonium salt is ammonium chloride, ammonium sulfate, ammonium nitrate, ammonium acetate, ammonium phosphate or ammonium bromide; preferably the ammonium salt is ammonium chloride; the molar ratio of the ammonium salt, the compound shown in the formula IV and the compound shown in the formula II is (1.0-4.0): 1.0-1.2):1, and the molar ratio of the ammonium salt, the compound shown in the formula IV and the compound shown in the formula II is preferably (2.0-3.0): 1.0-1.1): 1.
Preferably, in step (2), the second condensation reaction temperature is 20-100 ℃; preferably, the second condensation reaction temperature is 30-60 ℃. The time of the second condensation reaction is 1-8 hours; preferably, the second condensation reaction time is 3 to 5 hours.
According to the present invention, preferably, the catalyst in step (3) is composed of a main catalyst and a cocatalyst, wherein the main catalyst is a palladium-carbon catalyst; more preferably, the mass of the palladium-carbon catalyst is 0.5-10 of that of the compound shown in the formula II: 100, respectively; most preferably, the mass of the palladium-carbon catalyst is 1-5 of that of the compound shown in the formula II: 100, respectively;
preferably, the cocatalyst is tertiary amine, a pyridine compound, trisubstituted phosphine, thiophenol or thioether, preferably triethylamine, tri-n-butylamine, pyridine, 4-dimethylaminopyridine, triphenylphosphine or diphenyl sulfide, and the mass of the cocatalyst is 0.1-1.0 of that of the compound of formula II: 100, respectively; preferably 0.4 to 0.6: 100.
according to the invention, preferably, in the step (3), the reduction-cyclization reaction is carried out under the condition of hydrogen pressure, preferably, the temperature of the reduction-cyclization reaction is 0-45 ℃, and the hydrogen pressure is 0.1-1.0 MPa; further preferably, the reduction-cyclization reaction temperature is 20-40 ℃, and the hydrogen pressure is 0.4-0.6 MPa. The reduction-cyclization reaction time is 3-10 hours; further preferably, the reduction-cyclization reaction time is 4 to 8 hours.
According to the present invention, in the step (3), the isomerization reaction temperature is preferably 40 to 100 ℃, and more preferably 60 to 80 ℃. The isomerization reaction time is 1-7 hours; further preferably, the isomerization reaction time is 2 to 4 hours.
The process of the present invention is depicted as scheme 1 below:
wherein IV is 3- (4-phenoxyphenyl) -3-oxo-propionamide
Wherein R is methyl, ethyl, propyl, isopropyl, tert-butyl or other C4H9Butyl, P is hydrogen, benzyl, o-methylbenzyl, m-methylbenzyl, P-methylbenzyl, o-chlorobenzyl or P-methoxybenzyl
The invention has the technical characteristics and beneficial effects that:
1. the invention provides a preparation method of 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide, which comprises the steps of carrying out a first condensation reaction on 3, 3-dialkoxy-1-nitropropane and N-P substituent piperidine-4-ketone under the action of alkali to obtain N-P substituent-4-hydroxy-4- (1-nitro-3, 3-dialkoxy) propyl piperidine, then adding ammonium salt and 3- (4-phenoxyphenyl) -3-oxo-propionamide into a reaction solution, and carrying out a second condensation reaction to obtain 2- (4-phenoxybenzoyl) -5-nitro-5- (N-P substituent-4-hydroxy-4-yl) piperidyl N-pentyl-2- Under the action of catalyst and hydrogen and at the condition of programmed temperature rise, 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide is obtained through reduction-cyclization reaction and isomerization reaction.
2. The method utilizes methylene connected with the nitro in the 3, 3-dialkoxy-1-nitropropane to easily form carbanion under the alkaline condition, the formed carbanion is easy to condense with the carbonyl of N-P substituent piperidine-4-ketone, and the temperature effect and the concentration effect are reasonably utilized to ensure the high selectivity of the reaction. The nitro-ortho methylene activity of the 3, 3-dialkoxy-1-nitropropane is greater than the carbonyl-ortho methylene activity of the N-P substituent piperidin-4-one, and the N-P substituent piperidin-4-one is dripped at a lower temperature in combination with a low concentration effect, so that the self-condensation of the N-P substituent piperidin-4-one can be avoided, and the N-P substituent-4-hydroxy-4- (1-nitro-3, 3-dialkoxy) propylpiperidine can be obtained with high yield and high selectivity. The N-P substituent-4-hydroxy-4- (1-nitro-3, 3-dialkoxy) propyl piperidine is protected by 3, 3-dialkoxy base under the weak acid condition of ammonium salt, and is converted into corresponding aldehyde, and the aldehyde and methylene of 3- (4-phenoxyphenyl) -3-oxo-propionamide are dehydrated and condensed to obtain 2- (4-phenoxybenzoyl) -5-nitro-5- (N-P substituent-4-hydroxy-4-yl) piperidyl N-pent-2-enamide. And 3, obtaining a target product with high selectivity by utilizing the characteristic that the nitro is easy to be reduced into amino and combining a temperature programming effect and a cocatalyst. The nitro group which is easy to be reduced can be converted into amino at lower temperature, the obtained amino group can react with the phenyl carbonyl group and the carbonyl group of the amide, the selectivity of the reaction depends on the cis-trans configuration of the carbon-carbon double bond and the reaction temperature, and the amino group can react with the phenyl carbonyl group at lower temperature rather than the carbonyl group of the amide. The trans configuration of formula VA facilitates the formation of the desired product. Due to the low carbonyl reactivity of the amino and the amide, the cis-configuration cyclization shown in the formula VB requires higher temperature, and the cis-configuration shown in the formula VB can be converted into the trans-configuration shown in the formula VA in the presence of a low temperature and a cocatalyst, so that the target product is obtained with high selectivity by combining the programmed temperature effect and the cocatalyst. And when the temperature is higher, the selectivity of the subsequent reaction of the amino group obtained after the reduction of the nitro group is poor, so that the selectivity of the target product is low. If the temperature is high during the reduction-cyclization reaction, after the corresponding amino compound is obtained by nitro reduction, amino can be cyclized with carbonyl of amide at a higher temperature to form the 2-aminopyridine compound. The 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide is obtained by reduction-cyclization reaction and isomerization reaction under the condition of temperature programming.
The reaction mechanism of this step is presumed as follows:
wherein, P is hydrogen, benzyl, o-methylbenzyl, m-methylbenzyl, P-methylbenzyl, o-chlorobenzyl or P-methoxybenzyl, and G is hydrogen or P.
3. The method has the advantages of cheap and easily obtained raw materials, easy operation of the technological process, low cost of the target product, high yield and purity, and suitability for industrial production.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
The 3, 3-dialkoxy-1-nitropropane (II) used in the examples was prepared by reference to org. Synth.2000,77,236, and the other raw materials and reagents were all commercially available products. In the examples, "%" is given by weight unless otherwise specified. The yields in the examples are all molar yields.
Example 1: preparation of 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide (I)
A1000 ml four-necked flask equipped with a stirrer and a thermometer was charged with 100 g of water, 200 g of methanol, 29.8 g (0.2 mol) of 3, 3-dimethoxy-1-nitropropane, 26 g (0.26 mol) of 40% sodium hydroxide, cooled, maintained at 0 to 5 ℃ and added dropwise with a solution of 41.5 g (0.22 mol) of N-benzylpiperidin-4-one and 100 g of methanol over about 1 hour, and then stirred at 10 to 15 ℃ for reaction for 3 hours. 25 g of ammonium chloride and 51.5 g (0.202 mol) of 3- (4-phenoxyphenyl) -3-oxo-propionamide are added and the reaction is stirred at 40 to 45 ℃ for 4 hours. Transferring the obtained reaction liquid into a 1000 ml stainless steel pressure kettle, adding 0.8 g of 5% palladium carbon and 0.15 g of triphenylphosphine, replacing 3 times by nitrogen, charging hydrogen pressure to 0.4-0.5MPa, carrying out catalytic hydrogenation reaction at 30-35 ℃ for 5 hours, after the reduction-cyclization reaction is finished, carrying out isomerization reaction at 70-75 ℃ for 3 hours, cooling to room temperature, replacing 3 times by nitrogen, filtering to separate out palladium carbon, washing a filter cake by 30 g of methanol for 1 time, combining filtrate, carrying out reduced pressure distillation at 40 ℃ to recover 200 g of methanol, adding 200 g of water into the residue, filtering, adding the obtained filter cake into 200 g of 90% methanol aqueous solution, heating for recrystallization, filtering, and drying to obtain 66.5 g of 2- (4-phenoxyphenyl) -6- (piperidine-4-) based nicotinamide (I), wherein the yield is 89.1%, and the liquid phase purity is 99.8%.
The nuclear magnetic data of the product are as follows:
1H NMR(DMSO,δ,ppm)：
1.61-1.87(m，4H)，2.59-2.68(m，4H)，2.72(m，1H)，4.1(s，3H)，6.87-6.92(m，3H)， 6.98-7.06(m，3H)，7.11(m，2H),7.79-7.83(m，3H)。
example 2: preparation of 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide (I)
A1000 ml four-necked flask equipped with a stirrer and a thermometer was charged with 100 g of water, 200 g of methanol, 35.4 g (0.2 mol) of 3, 3-diethoxy-1-nitropropane, and 16.8 g (0.3 mol) of potassium hydroxide, cooled, maintained at 0 to 5 ℃ and added dropwise with a solution of 41.5 g (0.22 mol) of N-benzylpiperidin-4-one and 80 g of methanol over about 1.0 hour, and thereafter, stirred at 10 to 15 ℃ for 3 hours. 30 g of ammonium chloride and 51.5 g (0.202 mol) of 3- (4-phenoxyphenyl) -3-oxo-propionamide are added and the reaction is stirred at 40 to 45 ℃ for 4 hours. Transferring the obtained reaction liquid to a 1000 ml stainless steel pressure kettle, adding 0.8 g of 5% palladium carbon and 0.15 g of triphenylphosphine, replacing the reaction liquid with nitrogen for 3 times, then charging hydrogen to 0.4-0.5MPa, carrying out catalytic hydrogenation reaction at 25-30 ℃ for 5 hours, after the reduction-cyclization reaction is finished, carrying out isomerization reaction at 75-80 ℃ for 3 hours, cooling to room temperature, replacing the reaction liquid with nitrogen for 3 times, filtering and separating out the palladium carbon, washing a filter cake with 30 g of methanol for 1 time, combining the filtrate, carrying out reduced pressure distillation at 40 ℃ to recover 200 g of methanol, adding 200 g of water into the residue, filtering, adding the obtained filter cake into 200 g of 90% methanol aqueous solution, heating for recrystallization, filtering and drying to obtain 68.0 g of 2- (4-phenoxyphenyl) -6- (piperidine-4-) based nicotinamide (I), wherein the yield is 91.1%, and the liquid phase purity is 99.9%.
Example 3: preparation of 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide (I)
A1000 ml four-necked flask equipped with a stirrer and a thermometer was charged with 100 g of water, 200 g of methanol, 35.4 g (0.2 mol) of 3, 3-diethoxy-1-nitropropane, and 16.8 g (0.3 mol) of potassium hydroxide, cooled, maintained at 0 to 5 ℃ and added dropwise with a solution of 48.2 g (0.22 mol) of N- (4-p-methoxybenzyl) piperidin-4-one and 100 g of methanol over about 1.0 hour, after which the reaction was stirred at 15 to 20 ℃ for 3 hours. 30 g of ammonium chloride and 51.5 g (0.202 mol) of 3- (4-phenoxyphenyl) -3-oxo-propionamide are added and the reaction is stirred at 40 to 45 ℃ for 4 hours. Transferring the obtained reaction solution to a 1000 ml stainless steel pressure kettle, adding 0.8 g of 5% palladium carbon and 0.15 g of 4-dimethylamino pyridine, replacing with nitrogen for 3 times, the pressure of the charging gas is 0.4 to 0.5MPa, the catalytic hydrogenation reaction is carried out for 5 hours at the temperature of between 30 and 35 ℃, after the reduction-cyclization reaction is finished, isomerization reaction is carried out for 3 hours at 70-75 ℃, the temperature is reduced to room temperature, nitrogen is replaced for 3 times, then palladium carbon is filtered and separated out, filter cakes are washed for 1 time by 30 g of methanol, filter liquor is combined, 200 g of methanol is recovered by reduced pressure distillation at 40 ℃, 200 g of water is added into residues, filtration is carried out, the obtained filter cakes are added into 200 g of 90% methanol water solution, heating for recrystallization, filtering and drying to obtain 67.7 g of 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide (I), the yield is 90.7 percent and the liquid phase purity is 99.8 percent.
Comparative example 1: preparation of 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide (I)
A1000 ml four-necked flask equipped with a stirrer and a thermometer was charged with 100 g of water, 300 g of methanol, 29.8 g (0.2 mol) of 3, 3-dimethoxy-1-nitropropane, 41.5 g (0.22 mol) of N-benzylpiperidin-4-one, 26 g (0.26 mol) of 40% sodium hydroxide, and reacted at 10 to 15 ℃ with stirring for 3 hours. 25 g of ammonium chloride and 51.5 g (0.202 mol) of 3- (4-phenoxyphenyl) -3-oxo-propionamide are added and the reaction is stirred at 40 to 45 ℃ for 4 hours. Transferring the obtained reaction solution to a 1000 ml stainless steel pressure kettle, adding 0.8 g of 5% palladium carbon and 0.15 g of triphenylphosphine, replacing the reaction solution with nitrogen for 3 times, the pressure of the charging gas is 0.4 to 0.5MPa, the catalytic hydrogenation reaction is carried out for 5 hours at the temperature of between 30 and 35 ℃, after the reduction-cyclization reaction is finished, isomerization reaction is carried out for 3 hours at 70-75 ℃, the temperature is reduced to room temperature, nitrogen is replaced for 3 times, then palladium carbon is filtered and separated out, filter cakes are washed for 1 time by 30 g of methanol, filter liquor is combined, 200 g of methanol is recovered by reduced pressure distillation at 40 ℃, 200 g of water is added into residues, filtration is carried out, the obtained filter cakes are added into 200 g of 90% methanol water solution, heating for recrystallization, filtering and drying to obtain 47.1 g of 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide (I), the yield is 63.1 percent and the liquid phase purity is 97.6 percent.
As can be seen from comparative example 1, the dropwise addition of N-benzylpiperidin-4-one is critical to the product yield, and if N-benzylpiperidin-4-one is added to the reaction system at one time, the concentration of N-benzylpiperidin-4-one is high and intermolecular polymerization is liable to occur under alkaline conditions, resulting in a decrease in the yield.
Comparative example 2: preparation of 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide (I)
A1000 ml four-necked flask equipped with a stirrer and a thermometer was charged with 100 g of water, 200 g of methanol, 35.4 g (0.2 mol) of 3, 3-diethoxy-1-nitropropane, and 16.8 g (0.3 mol) of potassium hydroxide, cooled, maintained at 0 to 5 ℃ and added dropwise with a solution of 41.5 g (0.22 mol) of N-benzylpiperidin-4-one and 80 g of methanol over about 1.0 hour, and thereafter, stirred at 30 to 35 ℃ for reaction for 3 hours. 30 g of ammonium chloride and 51.5 g (0.202 mol) of 3- (4-phenoxyphenyl) -3-oxo-propionamide are added and the reaction is stirred at 40 to 45 ℃ for 4 hours. Transferring the obtained reaction liquid into a 1000 ml stainless steel pressure kettle, adding 0.8 g of 5% palladium carbon and 0.15 g of triphenylphosphine, replacing 3 times by nitrogen, charging hydrogen pressure to 0.4-0.5MPa, carrying out catalytic hydrogenation reaction at 30-35 ℃ for 5 hours, after the reduction-cyclization reaction is finished, carrying out isomerization reaction at 70-75 ℃ for 3 hours, cooling to room temperature, replacing 3 times by nitrogen, filtering to separate out palladium carbon, washing a filter cake by 30 g of methanol for 1 time, combining filtrate, carrying out reduced pressure distillation at 40 ℃ to recover 200 g of methanol, adding 200 g of water into the residue, filtering, adding the obtained filter cake into 200 g of 90% methanol aqueous solution, heating for recrystallization, filtering, and drying to obtain 52.5 g of 2- (4-phenoxyphenyl) -6- (piperidine-4-) based nicotinamide (I), wherein the yield is 70.3%, and the liquid phase purity is 96.9%.
As can be seen from comparative example 2, the temperature of the first condensation reaction is critical to the product yield and purity, and a high temperature of the first condensation reaction tends to result in the condensation of one molecule of 3, 3-diethoxy-1-nitropropane with two molecules of N-benzylpiperidin-4-one and two molecules of N-benzylpiperidin-4-one, resulting in a decrease in the product yield and purity.
Comparative example 3: preparation of 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide (I)
A1000 ml four-necked flask equipped with a stirrer and a thermometer was charged with 100 g of water, 200 g of methanol, 35.4 g (0.2 mol) of 3, 3-diethoxy-1-nitropropane, and 16.8 g (0.3 mol) of potassium hydroxide, cooled, maintained at 0 to 5 ℃ and added dropwise with a solution of 41.5 g (0.22 mol) of N-benzylpiperidin-4-one and 80 g of methanol over about 1.0 hour, and thereafter, stirred at 10 to 15 ℃ for 3 hours. 30 g of ammonium chloride and 51.5 g (0.202 mol) of 3- (4-phenoxyphenyl) -3-oxo-propionamide are added and the reaction is stirred at 40 to 45 ℃ for 4 hours. Transferring the obtained reaction solution to a 1000 ml stainless steel pressure kettle, adding 0.8 g of 5% palladium carbon, replacing for 3 times with nitrogen, the pressure of the charging gas is 0.4 to 0.5MPa, the catalytic hydrogenation reaction is carried out for 5 hours at the temperature of between 30 and 35 ℃, after the reduction-cyclization reaction is finished, isomerization reaction is carried out for 3 hours at 70-75 ℃, the temperature is reduced to room temperature, nitrogen is replaced for 3 times, palladium carbon is separated by filtration, filter cakes are washed for 1 time by 30 g of methanol, filter liquor is combined, 200 g of methanol is recovered by reduced pressure distillation at 40 ℃, 200 g of water is added into residues, filtration is carried out, the obtained filter cakes are added into 200 g of 90% methanol water solution, heating for recrystallization, filtering and drying to obtain the product, which contains 37.8 g of 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide (I) by a liquid phase external standard method, is difficult to separate and has a yield of 50.6 percent.
As can be seen from the comparative example 3, whether the cocatalyst triphenylphosphine is added or not is very important for the yield of the target product, and the cocatalyst can participate in the 1, 4-addition of unsaturated ketone while reducing the nitro group into the amino group, so as to obtain a conformation which is favorable for completely promoting the cyclization of the amino group and the carbonyl group, and is favorable for the pyridine cyclization reaction in molecules.
Comparative example 4: preparation of 2- (4-phenoxyphenyl) -6- (N-benzylpiperidin-4-) ylnicotinamide
A1000 ml four-necked flask equipped with a stirrer and a thermometer was charged with 100 g of water, 200 g of methanol, 35.4 g (0.2 mol) of 3, 3-diethoxy-1-nitropropane, and 16.8 g (0.3 mol) of potassium hydroxide, cooled, maintained at 0 to 5 ℃ and added dropwise with a solution of 41.5 g (0.22 mol) of N-benzylpiperidin-4-one and 80 g of methanol over about 1.0 hour, and thereafter, stirred at 10 to 15 ℃ for 3 hours. 30 g of ammonium chloride and 51.5 g (0.202 mol) of 3- (4-phenoxyphenyl) -3-oxo-propionamide are added and the reaction is stirred at 40 to 45 ℃ for 4 hours. Transferring the obtained reaction liquid to a 1000 ml stainless steel pressure kettle, adding 0.1 g of 5% palladium carbon and 0.15 g of triphenylphosphine, replacing for 3 times by nitrogen, charging hydrogen to 0.4-0.5MPa, carrying out catalytic hydrogenation reaction for 5 hours at 30-35 ℃, after the reduction-cyclization reaction is finished, carrying out isomerization reaction for 3 hours at 70-75 ℃, cooling to room temperature, replacing for 3 times by nitrogen, filtering and separating out palladium carbon, washing a filter cake for 1 time by 30 g of methanol, combining filtrates, carrying out reduced pressure distillation at 40 ℃ to recover 200 g of methanol, adding 200 g of water into the residue, filtering, adding the obtained filter cake into 200 g of 90% methanol aqueous solution, heating for recrystallization, filtering, drying to obtain 83.6 g of white solid, comparing the liquid phase peak time and carrying out LCMS analysis to obtain the product of 2- (4-phenoxyphenyl) -6- (N-benzylpiperidine-4-) based nicotinamide, the yield is 90.2 percent, and the purity of the liquid phase is 99.2 percent.
As can be seen from comparative example 4, the addition amount of the main catalyst palladium-carbon is very important for the yield of the target product, and when the addition amount of the palladium-carbon is insufficient, the benzyl group cannot be removed, the nitro group which is easy to be hydrogenated is reduced into amino group, and then the pyridine ring is formed through cyclization reaction, while the benzyl group cannot be removed.
Comparative example 5: preparation of 2- (4-phenoxyphenyl) -6- (N-benzylpiperidin-4-) ylnicotinamide
A1000 ml four-necked flask equipped with a stirrer and a thermometer was charged with 100 g of water, 200 g of methanol, 35.4 g (0.2 mol) of 3, 3-diethoxy-1-nitropropane, and 16.8 g (0.3 mol) of potassium hydroxide, cooled, maintained at 0 to 5 ℃ and added dropwise with a solution of 41.5 g (0.22 mol) of N-benzylpiperidin-4-one and 80 g of methanol over about 1.0 hour, and thereafter, stirred at 10 to 15 ℃ for 3 hours. 30 g of ammonium chloride and 51.5 g (0.202 mol) of 3- (4-phenoxyphenyl) -3-oxo-propionamide are added and the reaction is stirred at 40 to 45 ℃ for 4 hours. Transferring the obtained reaction liquid to a 1000 ml stainless steel pressure kettle, adding 0.7 g of 5% palladium carbon and 0.15 g of triphenylphosphine, replacing with nitrogen for 3 times, charging hydrogen to 0.4-0.5MPa, carrying out catalytic hydrogenation reaction at 55-60 ℃ for 5 hours, cooling to room temperature, replacing with nitrogen for 3 times, filtering to separate out palladium carbon, washing a filter cake with 30 g of methanol for 1 time, combining filtrates, distilling at 40 ℃ under reduced pressure to recover 200 g of methanol, adding 200 g of water into a residue, filtering, adding the obtained filter cake into 200 g of 90% methanol aqueous solution, heating for recrystallization, filtering and drying to obtain 61.5 g of white solid, wherein the white solid contains 29.6 g of 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide by a liquid phase external standard method. The resulting mixture was separated by semipreparative liquid phase separation and analyzed by LCMS and an additional 31.9 g of solid was 2-amino-3- (4-phenoxybenzoyl) -6- (piperidin-4-) ylpyridine.
As can be seen from comparative example 5, the temperature during the reduction-cyclization reaction is high, and after the nitro group is reduced to obtain the corresponding amino compound, the amino group can be cyclized with the carbonyl group of the amide at a higher temperature to form the 2-aminopyridine compound. Reduction-cyclization and isomerization utilize temperature programming which is critical to the selectivity of the reaction. The nitro group which is easily reduced can be converted into amino at a lower temperature, and the obtained amino group can react with the benzene carbonyl group at a lower temperature instead of the carbonyl group of the amide. And when the temperature is higher, the selectivity of the subsequent reaction of the amino group obtained after the reduction of the nitro group is poor, so that the selectivity of the target product is low.
Claims (13)
1. A method for preparing 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide comprises the following steps:
(1) carrying out a first condensation reaction on 3, 3-dialkoxy-1-nitropropane and N-P substituent piperidine-4-ketone in a solvent under the action of alkali to obtain a compound shown in a formula III;
in the structural formulas of the compounds shown in the formulas II and III, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, and P is hydrogen, benzyl, o-methylbenzyl, m-methylbenzyl, P-methylbenzyl, o-chlorobenzyl or P-methoxybenzyl;
(2) adding ammonium salt and a compound shown in the formula IV into the reaction liquid containing the compound shown in the formula III obtained in the step (1), and carrying out a second condensation reaction to obtain a compound shown in the formula V;
(3) transferring the reaction mixed solution containing the compound of the formula V obtained in the step (2) into a pressure kettle, adding a catalyst, and carrying out reduction-cyclization reaction and isomerization reaction under the condition of temperature programming to obtain 2- (4-phenoxyphenyl) -6- (piperidine-4-) nicotinamide (I); the reduction-cyclization reaction is carried out under the condition of hydrogen pressure, the catalyst consists of a main catalyst and an auxiliary catalyst, the main catalyst is a palladium-carbon catalyst, and the auxiliary catalyst is a pyridine compound or trisubstituted phosphine;
2. the method for preparing 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide according to claim 1, wherein in the step (1), the base is one or a combination of sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium methoxide.
3. The method for preparing 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide as claimed in claim 1, wherein in the step (1), the solvent is one or a combination of water, C1-C4 lower alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, dichloroethane, dichloromethane, chloroform, acetonitrile or toluene.
4. The process for producing 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide as claimed in claim 1, wherein the mass ratio of the solvent to the 3, 3-dialkoxy-1-nitropropane (II) in step (1) is (2-15): 1.
5. The process for the preparation of 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide as claimed in claim 1, wherein the molar ratio of the base, the N-P substituent piperidin-4-one and the 3, 3-dialkoxy-1-nitropropane in step (1) is (1.0-1.8): (1.0-1.2): 1.
6. The process for the preparation of 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide according to claim 1, wherein the temperature of the first condensation reaction in step (1) is-20 to 25 ℃.
7. The process for producing 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide as claimed in claim 1, wherein in the step (1), the N-P substituent piperidin-4-one is added dropwise to the reaction system.
8. The method for producing 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide according to claim 1, wherein in the step (2), the ammonium salt is ammonium chloride, ammonium sulfate, ammonium nitrate, ammonium acetate, ammonium phosphate or ammonium bromide.
9. The method for preparing 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide according to claim 1, wherein in the step (2), the molar ratio of the ammonium salt, the compound of formula IV and the compound of formula II is (1.0-4.0): (1.0-1.2): 1.
10. The process for producing 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide as claimed in claim 1, wherein in the step (2), the temperature of the second condensation is 20 to 100 ℃ and the reaction time of the second condensation is 1 to 8 hours.
11. The method for preparing 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide according to claim 1, wherein the reduction-cyclization reaction temperature in step (3) is 0 to 45 ℃ and the hydrogen pressure is 0.1 to 1.0 MPa.
12. The method for preparing 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide according to claim 1, wherein the isomerization reaction temperature in step (3) is 40 to 100 ℃ and the isomerization reaction time is 1 to 7 hours.
13. The method for preparing 2- (4-phenoxyphenyl) -6- (piperidin-4-) ylnicotinamide according to claim 1, wherein the mass of the main catalyst in the step (3) is 0.5 to 10% of the mass of the compound of formula II: 100, respectively; the mass of the cocatalyst is 0.1-1.0 of the mass of the compound of the formula II: 100.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1646502A (en) * | 2002-04-26 | 2005-07-27 | 伊莱利利公司 | Triazole derivatives as tachykinin receptor antagonists |
| CN101573357A (en) * | 2006-10-19 | 2009-11-04 | 武田药品工业株式会社 | Indole compound |
| CN104341388A (en) * | 2013-10-16 | 2015-02-11 | 上海润诺生物科技有限公司 | Aromatic amide derivative as well as preparation method and medicinal application thereof |
| CN107226805A (en) * | 2016-03-24 | 2017-10-03 | 北京天诚医药科技有限公司 | Aromatic amides analog derivative, its preparation method and its in application pharmaceutically |
| CN109485638A (en) * | 2017-09-12 | 2019-03-19 | 新发药业有限公司 | A kind of uncommon preparation method for Buddhist nun's intermediate difficult to understand |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1646502A (en) * | 2002-04-26 | 2005-07-27 | 伊莱利利公司 | Triazole derivatives as tachykinin receptor antagonists |
| CN101573357A (en) * | 2006-10-19 | 2009-11-04 | 武田药品工业株式会社 | Indole compound |
| CN104341388A (en) * | 2013-10-16 | 2015-02-11 | 上海润诺生物科技有限公司 | Aromatic amide derivative as well as preparation method and medicinal application thereof |
| CN107226805A (en) * | 2016-03-24 | 2017-10-03 | 北京天诚医药科技有限公司 | Aromatic amides analog derivative, its preparation method and its in application pharmaceutically |
| CN109485638A (en) * | 2017-09-12 | 2019-03-19 | 新发药业有限公司 | A kind of uncommon preparation method for Buddhist nun's intermediate difficult to understand |
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Denomination of invention: A method for preparing 2- (4-phenoxyphenyl) -6- (piperidin-4-) - nicotinamide Effective date of registration: 20231130 Granted publication date: 20220701 Pledgee: Dongying Branch of China CITIC Bank Co.,Ltd. Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2023980068537 |
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