ES2310152B2 - PROCEDURE FOR THE PREPARATION OF 4-ARIL- 1,2,5,6-TETRAHYDROPIRIDINS. - Google Patents
PROCEDURE FOR THE PREPARATION OF 4-ARIL- 1,2,5,6-TETRAHYDROPIRIDINS. Download PDFInfo
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- ES2310152B2 ES2310152B2 ES200801026A ES200801026A ES2310152B2 ES 2310152 B2 ES2310152 B2 ES 2310152B2 ES 200801026 A ES200801026 A ES 200801026A ES 200801026 A ES200801026 A ES 200801026A ES 2310152 B2 ES2310152 B2 ES 2310152B2
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- Prior art keywords
- substituted
- unsubstituted
- palladium
- group
- piperidone
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 claims abstract description 55
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 44
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 18
- ISNKSXRJJVWFIL-UHFFFAOYSA-N (sulfonylamino)amine Chemical compound NN=S(=O)=O ISNKSXRJJVWFIL-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 239000003446 ligand Substances 0.000 claims abstract description 15
- 125000003118 aryl group Chemical group 0.000 claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 4
- 239000003960 organic solvent Substances 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims description 21
- 239000002585 base Substances 0.000 claims description 15
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 14
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 14
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 14
- -1 alkali metal alkoxides Chemical class 0.000 claims description 14
- 229910052744 lithium Inorganic materials 0.000 claims description 14
- 229910052700 potassium Inorganic materials 0.000 claims description 14
- 239000011591 potassium Substances 0.000 claims description 14
- 229910052708 sodium Inorganic materials 0.000 claims description 14
- 239000011734 sodium Substances 0.000 claims description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 229910052792 caesium Inorganic materials 0.000 claims description 8
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims description 8
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 7
- 150000001491 aromatic compounds Chemical class 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000012467 final product Substances 0.000 claims description 6
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 claims description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000002170 ethers Chemical class 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- BWHOZHOGCMHOBV-UHFFFAOYSA-N benzylideneacetone Chemical compound CC(=O)C=CC1=CC=CC=C1 BWHOZHOGCMHOBV-UHFFFAOYSA-N 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical group [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 3
- 239000003444 phase transfer catalyst Substances 0.000 claims description 3
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- 238000000859 sublimation Methods 0.000 claims description 3
- 230000008022 sublimation Effects 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
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- 150000001408 amides Chemical class 0.000 claims description 2
- 239000003125 aqueous solvent Substances 0.000 claims description 2
- 239000003849 aromatic solvent Substances 0.000 claims description 2
- JYTGFFWTQRIGNW-UHFFFAOYSA-N cesium;methanolate Chemical class [Cs+].[O-]C JYTGFFWTQRIGNW-UHFFFAOYSA-N 0.000 claims description 2
- NHGGJRABQHWCGJ-UHFFFAOYSA-M cesium;phenoxide Chemical compound [Cs+].[O-]C1=CC=CC=C1 NHGGJRABQHWCGJ-UHFFFAOYSA-M 0.000 claims description 2
- 150000001805 chlorine compounds Chemical class 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 150000002334 glycols Chemical class 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 229920005862 polyol Polymers 0.000 claims description 2
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
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- 239000008096 xylene Substances 0.000 claims description 2
- 150000002941 palladium compounds Chemical class 0.000 claims 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 125000005017 substituted alkenyl group Chemical group 0.000 claims 2
- CHHASAIQKXOAOX-UHFFFAOYSA-N 1-(2,2-dimethylpropoxy)-2,2-dimethylpropane Chemical compound CC(C)(C)COCC(C)(C)C CHHASAIQKXOAOX-UHFFFAOYSA-N 0.000 claims 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims 1
- 150000008041 alkali metal carbonates Chemical class 0.000 claims 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 1
- 229910000318 alkali metal phosphate Inorganic materials 0.000 claims 1
- NVBVGMKBMCZMFG-UHFFFAOYSA-N cesium;2-methylpropan-2-olate Chemical class [Cs+].CC(C)(C)[O-] NVBVGMKBMCZMFG-UHFFFAOYSA-N 0.000 claims 1
- XDPCFUNJJWMBFH-UHFFFAOYSA-N cesium;ethanolate Chemical class [Cs+].CC[O-] XDPCFUNJJWMBFH-UHFFFAOYSA-N 0.000 claims 1
- 238000004440 column chromatography Methods 0.000 claims 1
- 230000008020 evaporation Effects 0.000 claims 1
- 238000001704 evaporation Methods 0.000 claims 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims 1
- 125000000547 substituted alkyl group Chemical group 0.000 claims 1
- 150000005622 tetraalkylammonium hydroxides Chemical class 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000002547 new drug Substances 0.000 abstract description 4
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract 1
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- 230000004071 biological effect Effects 0.000 abstract 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 abstract 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 150000001502 aryl halides Chemical class 0.000 description 7
- SJZKULRDWHPHGG-UHFFFAOYSA-N 1-benzylpiperidin-4-one Chemical compound C1CC(=O)CCN1CC1=CC=CC=C1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 5
- SXWRTZOXMUOJER-UHFFFAOYSA-N hydron;piperidin-4-one;chloride;hydrate Chemical compound O.Cl.O=C1CCNCC1 SXWRTZOXMUOJER-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
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- ZBTMRBYMKUEVEU-UHFFFAOYSA-N 1-bromo-4-methylbenzene Chemical compound CC1=CC=C(Br)C=C1 ZBTMRBYMKUEVEU-UHFFFAOYSA-N 0.000 description 3
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- ZEMZPXWZVTUONV-UHFFFAOYSA-N 2-(2-dicyclohexylphosphanylphenyl)-n,n-dimethylaniline Chemical group CN(C)C1=CC=CC=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 ZEMZPXWZVTUONV-UHFFFAOYSA-N 0.000 description 3
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- CNXMDTWQWLGCPE-UHFFFAOYSA-N ditert-butyl-(2-phenylphenyl)phosphane Chemical group CC(C)(C)P(C(C)(C)C)C1=CC=CC=C1C1=CC=CC=C1 CNXMDTWQWLGCPE-UHFFFAOYSA-N 0.000 description 3
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- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- FHRDCMOUIACUOO-UHFFFAOYSA-N C1(=CC=C(C=C1)P(C1=CC=C(C=C1)C)C1=C(C=CC2=CC=CC=C12)C1=CC2=CC=CC=C2C=C1)C Chemical group C1(=CC=C(C=C1)P(C1=CC=C(C=C1)C)C1=C(C=CC2=CC=CC=C12)C1=CC2=CC=CC=C2C=C1)C FHRDCMOUIACUOO-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- VIWVGCYRRRLVGC-UHFFFAOYSA-N N1CCC(=CC1)C=1C=C2CC=NC2=CC1 Chemical compound N1CCC(=CC1)C=1C=C2CC=NC2=CC1 VIWVGCYRRRLVGC-UHFFFAOYSA-N 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- YIPGRMJWWBWENN-UHFFFAOYSA-N [2-(1-diphenylphosphanylnaphthalen-2-yl)naphthalen-1-yl]-diphenylphosphane Chemical group C1=CC=CC=C1P(C=1C2=CC=CC=C2C=CC=1C=1C(=C2C=CC=CC2=CC=1)P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 YIPGRMJWWBWENN-UHFFFAOYSA-N 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004404 heteroalkyl group Chemical group 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 239000003041 laboratory chemical Substances 0.000 description 1
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical class [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UNHGSHHVDNGCFN-UHFFFAOYSA-N naratriptan Chemical compound C=12[CH]C(CCS(=O)(=O)NC)=CC=C2N=CC=1C1CCN(C)CC1 UNHGSHHVDNGCFN-UHFFFAOYSA-N 0.000 description 1
- 229960005254 naratriptan Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 238000010651 palladium-catalyzed cross coupling reaction Methods 0.000 description 1
- 229960002296 paroxetine Drugs 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—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 one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Procedimiento de preparación de 4-aril-1,2,5,6-tetrahidropiridinas de fórmula (I) donde Ar es un sustituyente aromático o heteroaromático sustituido o no sustituido, por reacción de una 4-piperidona (II), con un compuesto de fórmula Ar-X, donde Ar tiene los significados descritos anteriormente, y X se selecciona del grupo cloro, bromo, iodo, o sulfonato; una sulfonilhidrazina R'-SO_{2}NHNH_{2}, donde R' es un grupo arilo sustituido o no sustituido; una base; en presencia de un catalizador de paladio, constituido por un complejo de paladio y un ligando; en un disolvente orgánico o en un medio acuoso. Los compuestos (I) tienen utilidad como esqueletos en procesos de descubrimiento de nuevos fármacos y como intermedios en la síntesis de moléculas con actividad biológica.Preparation Procedure 4-aryl-1,2,5,6-tetrahydropyridines of formula (I) where Ar is an aromatic substituent or substituted or unsubstituted heteroaromatic, by reaction of a 4-piperidone (II), with a compound of formula Ar-X, where Ar has the meanings described above, and X is selected from the group chlorine, bromine, iodine, or sulfonate; a sulfonylhydrazine R'-SO2 NHNH2, where R 'is an aryl group substituted or unsubstituted; one base; in the presence of a palladium catalyst, consisting of a palladium complex and a ligand; in an organic solvent or in an aqueous medium. The Compounds (I) have utility as skeletons in processes of discovery of new drugs and as intermediates in the synthesis of molecules with biological activity.
Description
Procedimiento para la preparación de 4-aril-1,2,5,6-tetrahidropiridinas.Procedure for the preparation of 4-aryl-1,2,5,6-tetrahydropyridines.
La invención se relaciona con la síntesis de compuestos químicos utilizados en la preparación de fármacos y moléculas con aplicación terapéutica. En particular la invención se refiere a un procedimiento para la obtención de derivados de 4-arilpiperidina, estructura presente en un gran número de moléculas bioactivas y utilizada extensamente en procesos de descubrimiento de nuevos fármacos, mediante un proceso de acoplamiento cruzado promovido por un catalizador de paladio, en presencia de una base y partir de una 4-piperidona, un halogenuro de arilo y una sulfonilhidrazina en un disolvente orgánico o en medio acuoso.The invention relates to the synthesis of chemical compounds used in the preparation of drugs and molecules with therapeutic application. In particular the invention is refers to a procedure for obtaining derivatives of 4-arylpiperidine, structure present in a large number of bioactive molecules and widely used in processes of discovery of new drugs, through a process of cross coupling promoted by a palladium catalyst, in presence of a base and starting with a 4-piperidone, an aryl halide and a sulfonylhydrazine in a solvent organic or in aqueous medium.
La estructura de 4-arilpiperidina (V) está considerada como una estructura privilegiada en química médica debido a su capacidad para proporcionar ligandos capaces de asociarse con una amplia variedad de receptores. Por ello la subestructura de 4-arilpiperidina (V) viene siendo empleada de forma continuada en programas de investigación de descubrimiento de nuevos fármacos. En este sentido, disponer de métodos eficaces de síntesis de 4-arilpiperidinas con estructuras diversas es del mayor interés.The structure of 4-arylpiperidine (V) is considered as a privileged structure in medical chemistry due to its ability to provide ligands capable of associating with a broad variety of receptors Therefore the substructure of 4-arylpiperidine (V) has been used continued in discovery research programs of new drugs In this regard, have effective methods of synthesis of 4-arylpiperidines with structures Various is of the greatest interest.
El rango de potencial aplicación de compuestos basados en la estructura de 4-arilpiperidina es muy diverso y abarca entre otras:The range of potential application of compounds based on the structure of 4-arylpiperidine is very diverse and covers among others:
- tratamiento del asma (Levell, J.; Astles, P.; Eastwood, P.; Cairns, J.; Houille, O.; Aldous, S.; Merriman, G.; Whiteley, B.; Pribish, J.; Czekaj, M.; Liang, G.; Maignan, S.; Guilloteau, J-.P.; Dupuy, A.; Davidson, J.; Harrison, T.; Morley, A.; Watson, S.; Fenton, G.; McCarthy, C.; Romano, J.; Mathew, R.; Engers, D.; Gardyan, M.; Sides, K.; Kwong, J.; Tsay, J.; Rebello, S.; Shen, L.; Wang, J.; Luo, Y.; Giardino, O.; Lim, H-.K.; Smith, K.; Pauls, H. Bioorg. Med. Chem. 2005, 13, 2859-2872).- asthma treatment (Levell, J .; Astles, P .; Eastwood, P .; Cairns, J .; Houille, O .; Aldous, S .; Merriman, G .; Whiteley, B .; Pribish, J .; Czekaj, M .; Liang, G .; Maignan, S .; Guilloteau, J-.P .; Dupuy, A .; Davidson, J .; Harrison, T .; Morley, A .; Watson, S .; Fenton, G .; McCarthy, C .; Romano, J .; Mathew, R .; Engers, D .; Gardyan, M .; Sides, K .; Kwong, J .; Tsay, J .; Rebello, S .; Shen, L .; Wang, J .; Luo, Y .; Giardino, O .; Lim, H-.K .; Smith, K .; Pauls, H. Bioorg. Med. Chem . 2005 , 13 , 2859-2872).
- la hipertensión (Cody, W. L.; Holsworth, D. D.; Powell, N. A.; Jalaie, M.; Zhang, E.; Wang, W.; Samas, B.; Bryant, J.; Ostroski, R.; Ryan, M. J.; Edmunds, J. J. Bioorg. Med. Chem. 2005, 13, 59-68).- hypertension (Cody, WL; Holsworth, DD; Powell, NA; Jalaie, M .; Zhang, E .; Wang, W .; Samas, B .; Bryant, J .; Ostroski, R .; Ryan, MJ; Edmunds, JJ Bioorg. Med. Chem . 2005 , 13 , 59-68).
- la depresión (Martin, L. L.; Klioze, S. S.; Worm, M.; Crichlow, C. A. J. Med. Chem. 1979, 22, 1347-1354).- depression (Martin, LL; Klioze, SS; Worm, M .; Crichlow, CA J. Med. Chem . 1979 , 22 , 1347-1354).
- las migrañas (Filla, S. A.; Mathes, B. M.; Johnson, K. W.; Phebus, L. A.; Cohen, M. L.; Nelson, D. L.; Zgombick, J. M.; Erickson, J. A.; Schenck, K. W.; Wainscott, D. B.; Brancheck, T. A.; Schaus, J. M. J. Med. Chem. 2003, 46, 3060-3071).- migraines (Filla, SA; Mathes, BM; Johnson, KW; Phebus, LA; Cohen, ML; Nelson, DL; Zgombick, JM; Erickson, JA; Schenck, KW; Wainscott, DB; Brancheck, TA; Schaus, JM J. Med. Chem . 2003 , 46 , 3060-3071).
- las infecciones bacterianas (Quesnelle, C. A.; Gill, P.; Roy, S.; Dodier, M.; Marinier, A.; Martel, A.; Snyder, L. B.; D'Andrea, S. V.; Bronson, J. J.; Frosco, M.; Beaulieu, D.; Warr, G. A.; DenBleyker, K. L.; Stickle, T. M.; Yang, H.; Chaniewski, S. E.; Ferraro, C. A.; Taylor, D.; Russell, J. W.; Santone, K. S.; Clarke, J.; Drain, R. L.; Knipe, J. O.; Mosure, K.; Barrett, J. F. Bioorg. Med. Chem. Lett. 2005, 15, 2728-2733);- bacterial infections (Quesnelle, CA; Gill, P .; Roy, S .; Dodier, M .; Marinier, A .; Martel, A .; Snyder, LB; D'Andrea, SV; Bronson, JJ; Frosco, M .; Beaulieu, D .; Warr, GA; DenBleyker, KL; Stickle, TM; Yang, H .; Chaniewski, SE; Ferraro, CA; Taylor, D .; Russell, JW; Santone, KS; Clarke, J. ; Drain, RL; Knipe, JO; Mosure, K .; Barrett, JF Bioorg. Med. Chem. Lett . 2005 , 15 , 2728-2733);
- la hiperplasia benigna de próstata (Barrow, J. C.; Nantermet, P. G.; Selnick, H. G.; Glass, K. L.; Riffle, K. E.; Gilbert, K. F.; Steele, T. G.; Homnick, C. F.; Freidinger, R. M.; Ransom, R. W.; Kling, P.; Reiss, D.; Broten, T. P.; Schorn, T. W.; Chang, R. S. L.; O'Malley, S. S.; Olah, T. V.; Ellis, J. D.; Banish, A.; Kassahun, K.; Leppert, P.; Nagarathnam, D.; Forray, C. J. Med. Chem. 2000, 43, 2703-2718).- benign prostatic hyperplasia (Barrow, JC; Nantermet, PG; Selnick, HG; Glass, KL; Riffle, KE; Gilbert, KF; Steele, TG; Homnick, CF; Freidinger, RM; Ransom, RW; Kling, P .; Reiss, D .; Broten, TP; Schorn, TW; Chang, RSL; O'Malley, SS; Olah, TV; Ellis, JD; Banish, A .; Kassahun, K .; Leppert, P .; Nagarathnam, D .; Forray, C. J. Med. Chem . 2000 , 43 , 2703-2718).
- desórdenes relacionados con los estrógenos (Tan, Q.; Birzin, E. T.; Chan, W.; Yang, Y. T.; Pai, L-.Y.; Hayes, E. C.; DaSilva, C. A.; DiNinno, F.; Rohrer, S. P.; Schaeffer, J. M.; Hammond, M. L. Bioorg. Med. Chem. Lett. 2004, 14, 3747-3751).- estrogen-related disorders (Tan, Q .; Birzin, ET; Chan, W .; Yang, YT; Pai, L-.Y .; Hayes, EC; DaSilva, CA; DiNinno, F .; Rohrer, SP; Schaeffer, JM; Hammond, ML Bioorg. Med. Chem. Lett . 2004 , 14 , 3747-3751).
- enfermedades neurodegenerativas tales como la enfermedad de Alzheimer (Wenzel, B.; Sorger, D.; Heintz, K.; Scheunemann, M.; Schliebs, R.; Steinbach, J.; Sabri, O. Eur. J. Med. Chem. 2005, 40, 1197-1205) o el Parkinson (Guzikowski, A. P.; Tamiz, A. P.; Acosta-Burruel, M.; Hong-Bae, S.; Cai, S. X.; Hawkinson, J. E.; Keana, J. F. W.; Kesten, S. R.; Shipp, C. T.; Tran, M.; Whittemore, E. R.; Woodward, R. M.; Wright, J. L.; Zhou, Z-.L. J. Med. Chem. 2000, 43, 984-994).- neurodegenerative diseases such as Alzheimer's disease (Wenzel, B .; Sorger, D .; Heintz, K .; Scheunemann, M .; Schliebs, R .; Steinbach, J .; Sabri, O. Eur. J. Med. Chem . 2005 , 40 , 1197-1205) or Parkinson's (Guzikowski, AP; Sieve, AP; Acosta-Burruel, M .; Hong-Bae, S .; Cai, SX; Hawkinson, JE; Keana, JFW; Kesten, SR; Shipp, CT; Tran, M .; Whittemore, ER; Woodward, RM; Wright, JL; Zhou, Z-.L. J. Med. Chem . 2000 , 43 , 984-994).
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- antagonistas de receptores de opiáceos con aplicación en el tratamiento desórdenes crónicos como la obesidad (Díaz, N.; Benvenga, M.; Emmerson, P.; Favors, R.; Mangold, M.; McKinzie, J.; Patel, N.; Peters, S.; Quimby, S.; Shannon, A.; Siegel, M.; Statnick, M.; Thomas, E.; Woodland, J.; Surface, P.; Mitch, C. Bioorg. Med. Chem. Lett. 2005, 15, 3844-3848).- Opioid receptor antagonists with application in the treatment of chronic disorders such as obesity (Díaz, N .; Benvenga, M .; Emmerson, P .; Favors, R .; Mangold, M .; McKinzie, J .; Patel, N .; Peters, S .; Quimby, S .; Shannon, A .; Siegel, M .; Statnick, M .; Thomas, E .; Woodland, J .; Surface, P .; Mitch, C. Bioorg. Med. Chem. Lett . 2005 , 15 , 3844-3848).
Entre los fármacos en uso poseedores de la unidad de 4-arilpiperidina pueden destacarse por ejemplo el Naratriptan - potente analgésico para el tratamiento de las migrañas, o la Paroxetina - un antidepresivo muy utilizado.Among the drugs in use possessing the 4-arylpiperidine unit can be highlighted by example Naratriptan - powerful analgesic for the treatment of Migraines, or Paroxetine - a widely used antidepressant.
Las 4-aril-1,2,5,6-tetrahidropiridinas (I) son derivados de 4-arilpiperidina particularmente interesantes, ya que pueden ser transformados por hidrogenación en 4-arilpiperidinas o derivatizados a estructuras más complejas aprovechando la presencia del doble enlace mediante diversos procesos como son alquilaciones (Díaz, N.; Benvenga, M.; Emmerson, P.; Favors, R.; Mangold, M.; McKinzie, J.; Patel, N.; Peters, S.; Quimby, S.; Shannon, A.; Siegel, M.; Statnick, M.; Thomas, E.; Woodland, J.; Surface, P.; Mitch, C. Bioorg. Med. Chem. Lett. 2005, 15, 3844-3848), u oxidación (Bursavich, M. G.; Rich, D. H. Org. Lett. 2001, 3, 2625).The 4-aryl-1,2,5,6-tetrahydropyridines (I) are particularly interesting derivatives of 4-arylpiperidine, since they can be transformed by hydrogenation into 4-arylpiperidines or derivatized to more complex structures taking advantage of the presence of the double bond by various processes such as alkylations (Díaz, N .; Benvenga, M .; Emmerson, P .; Favors, R .; Mangold, M .; McKinzie, J .; Patel, N .; Peters, S .; Quimby, S. ; Shannon, A .; Siegel, M .; Statnick, M .; Thomas, E .; Woodland, J .; Surface, P .; Mitch, C. Bioorg. Med. Chem. Lett . 2005 , 15 , 3844-3848 ), or oxidation (Bursavich, MG; Rich, DH Org. Lett . 2001 , 3, 2625).
Existen diversas metodologías para la síntesis de 4-aril-1,2,5,6-tetrahidropiridinas (I). En general el punto de partida es una 4-piperidona N-protegida (II), a partir de la cual las 4-aril-1,2,5,6-tetrahidropiridinas (I) pueden obtenerse mediante varias estrategias.There are various methodologies for the synthesis of 4-aryl-1,2,5,6-tetrahydropyridines (I). In general, the starting point is a 4-piperidone N- protected (II), from which the 4-aryl-1,2,5,6-tetrahydropyridines (I) can be obtained by various strategies.
- El procedimiento más clásico implica la adición de un nucleófilo fuerte, típicamente un organomagnesiano o un sistema aromático electrónicamente muy rico, a una 4-piperidona N-protegida (II), seguido por deshidratación (a) Sakamuri, S.; Enyedy, I. J.; Kozikowski, A. P.; Zaman, W. A.; Johnson, K. M.; Wang, S. Bioorg. Med. Chem. Lett. 2001, 11, 495; (b) Lee, J. S.; Yong, S. C.; Moon, H. C.; Koh, H. Y.; Bong, Y. C.; Pae, A. N. Bioorg. Med. Chem. Lett. 2003, 13, 4117; (c) Filla, S. A., Mathes, B. M., Johnson, K. W., Phebus, L. A., Cohen, M. L., Nelson, D. L., Zgombick, J. M., Erickson, J. A., Schenck, K. W., Wainscott, D. B., Branchek, T. A., Schaus, J. M., J. Med. Chem. 2003, 46, 3060. (d) Hampson, L. J.; Arden, C.; Agius, L.; Ganotidis, M.; Kosmopoulou, M. N.; Tiraidis, C.; Elemes, Y.; Sakarellos, C.; Leonidasm, D. D.; Oikonomakos, N. G. Bioorg. Med. Chem. 2006, 14, 7835). Esta estrategia carece de generalidad y en los últimos años ha sido reemplazada por métodos que implican reacciones de acoplamiento cruzado catalizadas por especies de Pd.- The most classic procedure involves the addition of a strong nucleophile, typically an organomagnesian or an electronically rich aromatic system, to an N-protected 4-piperidone (II), followed by dehydration (a) Sakamuri, S .; Enyedy, IJ; Kozikowski, AP; Zaman, WA; Johnson, KM; Wang, S. Bioorg. Med. Chem. Lett . 2001 , 11 , 495; (b) Lee, JS; Yong, SC; Moon, HC; Koh, HY; Bong, YC; Pae, AN Bioorg. Med. Chem. Lett . 2003 , 13 , 4117; (c) Filla, SA, Mathes, BM, Johnson, KW, Phebus, LA, Cohen, ML, Nelson, DL, Zgombick, JM, Erickson, JA, Schenck, KW, Wainscott, DB, Branchek, TA, Schaus, JM , J. Med. Chem . 2003 , 46 , 3060. (d) Hampson, LJ; Arden, C .; Agius, L .; Ganotidis, M .; Kosmopoulou, MN; Tiraidis, C .; Elemes, Y .; Sakarellos, C .; Leonidasm, DD; Oikonomakos, NG Bioorg. Med. Chem . 2006 , 14 , 7835). This strategy lacks generality and in recent years it has been replaced by methods that involve cross-coupling reactions catalyzed by Pd species.
- Existen dos rutas alternativas para obtener 4-aril-1,2,5,6-tetrahidropiridinas (I) a partir de 4-piperidonas mediante reacciones de acoplamiento catalizadas por Pd:- There are two alternative routes to obtain 4-aryl-1,2,5,6-tetrahydropyridines (I) from 4-piperidones by reactions coupling catalyzed by Pd:
- i)i)
- Conversión del grupo funcional cetona de la 4-piperidona en el reactivo electrófilo de la reacción de acoplamiento cruzado mediante su transformación en un enoltriflato, seguido de reacción de acoplamiento con un organometálico, tal como un ácido boronico o un estannano [(a) M. G. Bursavich, C. W. West, D. H. Rich, Org. Lett. 2001, 3, 2317; (b) W. L. Cody, D. D. Holsworth, N. A. Powell, M. Jalaie, E. Zhang, W. Wang, B. Samas, J. Bryant, R. Ostroski, M. J. Ryan, J. J. Edmunds, Bioorg. Med. Chem. 2005, 13, 5; (c) J. Levell, P. Astles, P. Eastwood, J. Cairns, O. Houille, S. Aldous, G. Merriman, B. Whiteley, J. Pribish, M. Czekaj, G. Liang, S. Maignan, J.-P. Guilloteau, A. Dupuy, J. Davidson, T. Harrison, A. Morley, S. Watson, G. Fenton, C. McCarthy, J. Romano, R. Mathew, D. Engers, M. Gardyan, K. Sides, J. Kwong, J. Tsay, S. Rebello, L. Shen, J. Wang, Y. Luo, O. Giardino, H.-K. Lim, K. Smith, H. Pauls, Bioorg. Med. Chem. 2005, 13, 2859; (d) J. S. Lee, Y. S. Cho, M. H. Chang, H. Y. Koh, B. Y. Chungb, A. N. Pae, Bioorg. Med. Chem. Lett. 2003, 13, 4117].Conversion of the 4-piperidone ketone functional group into the electrophilic reagent of the cross-coupling reaction by transformation into an enoltriflate, followed by a coupling reaction with an organometallic, such as a boronic acid or a stannan [(a) MG Bursavich , CW West, DH Rich, Org. Lett . 2001 , 3 , 2317; (b) WL Cody, DD Holsworth, NA Powell, M. Jalaie, E. Zhang, W. Wang, B. Samas, J. Bryant, R. Ostroski, MJ Ryan, JJ Edmunds, Bioorg. Med. Chem . 2005 , 13 , 5; (c) J. Levell, P. Astles, P. Eastwood, J. Cairns, O. Houille, S. Aldous, G. Merriman, B. Whiteley, J. Pribish, M. Czekaj, G. Liang, S. Maignan , J.-P. Guilloteau, A. Dupuy, J. Davidson, T. Harrison, A. Morley, S. Watson, G. Fenton, C. McCarthy, J. Romano, R. Mathew, D. Engers, M. Gardyan, K. Sides, J. Kwong, J. Tsay, S. Rebello, L. Shen, J. Wang, Y. Luo, O. Giardino, H.-K. Lim, K. Smith, H. Pauls, Bioorg. Med. Chem . 2005 , 13 , 2859; (d) JS Lee, YS Cho, MH Chang, HY Koh, BY Chungb, AN Pae, Bioorg. Med. Chem. Lett . 2003 , 13 , 4117].
- ii)ii)
- Preparación de un vinilorganometálico a partir de la 4-piperidona, seguido de reacción de acoplamiento catalizada por Pd con un halogenuro de arilo [Acoplamiento de Suzuki: (a) P. L. Eastwood, Tetrahedron Lett. 2000, 41, 3705; (b) G. N. Boice, C. G. Savarin, J. A. Murry, K. Conrad, L. Matty, Edw G. Corley, . H. Smitrovich, D. Hughes, Tetrahedron 2004, 60, 11367; (c) N. Díaz, M. Benvenga, P. Emmerson, R. Favors, M. Mangold, J. McKinzie, N. Patel, S. Peters, S. Quimby, H. Shannon, M. Siegel, M. Statnick, E. Thomas, J. Woodland, P. Surface, C. Mitch, Bioorg. Med. Chem. Lett. 2005, 15, 3844; (d) Y. Jiang, C.-A. Chen, K. Lu, I. Daniewska, J. DeLeon, R. Kong, C. Forray, B. Li, L. G. Hegde, T. D. Wolinsky, D. A. Craig, J. M. Wetzel, K. Andersen, M. R. Marzabadi, J. Med. Chem., 2007, 50, 3870. Acoplamiento de Stille: e) J. S. Kiely, E. Laborde, L. E. Lesheski, R. A. Bucsh, J. Heterocycl, Chem. 1991, 28, 1581; (e) Q. Tan, E. T. Birzin, W. Chan, Y. T. Yang, L-.Y. Pai, E. C. Hayes, C. A. DaSilva, F. DiNinno, S. P. Rohrer, J. M. Schaeffer, M. L. Hammond, Bioorg. Med. Chem. Lett. 2004, 14, 3747; (f) D. Kim, L. Wang, J. J. Hale, C. L. Lynch, R. J. Budhu, M. MacCoss, S. G. Mills, L. Malkowitz, S. L. Gould, J. A. DeMartino, M. S. Springer, D. Hazuda, M. Miller, J. Kessler, R. C. Hrin, G. Carver, A. Carella, K. Henry, J. Lineberger, W. A. Schleif, E. A. Emini, Bioorg. Med. Chem. Lett. 2005, 15, 2129; (g) K. Yoshida, K. Nakayama, N. Kuru, S. Kobayashi, M. Ohtsuka, M. Takemura, K. Hoshino, H. Kanda, J. Z. Zhang, V. J. Lee, W. J. Watkins, Bioor. Med. Chem. 2006, 14, 1993. Acoplamiento de Hiyama: C. Morrill, N. S. Mani, Org. Lett. 2007, 9, 1505].Preparation of a vinyl organometallic from 4-piperidone, followed by coupling reaction catalyzed by Pd with an aryl halide [Suzuki Coupling: (a) PL Eastwood, Tetrahedron Lett . 2000 , 41 , 3705; (b) GN Boice, CG Savarin, JA Murry, K. Conrad, L. Matty, Edw G. Corley,. H. Smitrovich, D. Hughes, Tetrahedron 2004 , 60 , 11367; (c) N. Díaz, M. Benvenga, P. Emmerson, R. Favors, M. Mangold, J. McKinzie, N. Patel, S. Peters, S. Quimby, H. Shannon, M. Siegel, M. Statnick , E. Thomas, J. Woodland, P. Surface, C. Mitch, Bioorg. Med. Chem. Lett . 2005 , 15 , 3844; (d) Y. Jiang, C.-A. Chen, K. Lu, I. Daniewska, J. DeLeon, R. Kong, C. Forray, B. Li, LG Hegde, TD Wolinsky, DA Craig, JM Wetzel, K. Andersen, MR Marzabadi, J. Med. Chem ., 2007 , 50 , 3870. Stille coupling: e) JS Kiely, E. Laborde, LE Lesheski, RA Bucsh, J. Heterocycl, Chem . 1991 , 28 , 1581; (e) Q. Tan, ET Birzin, W. Chan, YT Yang, L-.Y. Pai, EC Hayes, CA DaSilva, F. DiNinno, SP Rohrer, JM Schaeffer, ML Hammond, Bioorg. Med. Chem. Lett . 2004 , 14 , 3747; (f) D. Kim, L. Wang, JJ Hale, CL Lynch, RJ Budhu, M. MacCoss, SG Mills, L. Malkowitz, SL Gould, JA DeMartino, MS Springer, D. Hazuda, M. Miller, J. Kessler, RC Hrin, G. Carver, A. Carella, K. Henry, J. Lineberger, WA Schleif, EA Emini, Bioorg. Med. Chem. Lett . 2005 , 15 , 2129; (g) K. Yoshida, K. Nakayama, N. Kuru, S. Kobayashi, M. Ohtsuka, M. Takemura, K. Hoshino, H. Kanda, JZ Zhang, VJ Lee, WJ Watkins, Bioor. Med. Chem . 2006 , 14 , 1993. Hiyama coupling: C. Morrill, NS Mani, Org. Lett . 2007 , 9 , 1505].
No obstante, estas rutas sintéticas requieren varios pasos de reacción, la utilización de cantidades estequiométricas de reactivos organometálicos, el empleo de atmósfera inerte y disolventes secos, y la protección del grupo N-H de la 4-piperidona.However, these synthetic routes require several reaction steps, the use of quantities stoichiometric organometallic reagents, the use of inert atmosphere and dry solvents, and group protection N-H of 4-piperidone.
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La reacción de acoplamiento cruzado catalizado por paladio de tosilhidrazonas con halogenuros de arilo es un método eficaz de síntesis de olefinas polisustituidas (J. Barluenga, P. Moriel, C. Valdés, F. Aznar, Angew. Chem. Int. Ed 2007, 46, 5587). Sin embargo, no ha sido aplicada a la preparación de 4-aril-1,2,5,6-tetrahidropiridinas.The palladium-catalyzed cross-coupling reaction of tosylhydrazones with aryl halides is an effective method of synthesizing polysubstituted olefins (J. Barluenga, P. Moriel, C. Valdés, F. Aznar, Angew. Chem. Int. Ed 2007 , 46 , 5587). However, it has not been applied to the preparation of 4-aryl-1,2,5,6-tetrahydropyridines.
Esta invención proporciona un procedimiento para la preparación de 4-aril-1,2,5,6-tetrahidropiridinas de fórmula general (I) mediante una reacción que utiliza como reactivos de partida directamente una 4-piperidona o su clorhidrato, y un compuesto aromático que contiene un grupo saliente que puede ser un halógeno o un sulfonato, en presencia de una sulfonilhidrazina, una base y un catalizador de Paladio, en un disolvente orgánico o acuoso. Es posible llevar a cabo la reacción utilizando 4-piperidona con el N-H libre (R = H) o su clorhidrato, lo que presenta gran interés, ya que facilita la posterior derivatización del sistema. El esquema general se presenta en la Ecuación 1.This invention provides a method for the preparation of 4-aryl-1,2,5,6-tetrahydropyridines of general formula (I) by a reaction that uses as starting reagents directly a 4-piperidone or its hydrochloride, and an aromatic compound containing a group projection that can be a halogen or a sulphonate, in the presence of a sulfonylhydrazine, a base and a palladium catalyst, in a organic or aqueous solvent. It is possible to carry out the reaction using 4-piperidone with the N-H free (R = H) or its hydrochloride, which is of great interest, since which facilitates the subsequent derivatization of the system. The scheme general is presented in Equation 1.
En la ecuación 1, las 4-aril,1,2,5,6-tetrahidropiridinas (I) se sintetizan en una reacción en la que una 4-piperidona (II) o su clorhidrato se hace reaccionar con el compuesto aromático (III) poseedor de un grupo saliente en presencia de la sulfonilhidrazina (IV), de una base y un catalizador de paladio, generado a partir de un compuesto de paladio y un ligando.In equation 1, the 4-aryl, 1,2,5,6-tetrahydropyridines (I) are synthesized in a reaction in which a 4-piperidone (II) or its hydrochloride is made react with the aromatic compound (III) possessing a group protrusion in the presence of sulfonylhydrazine (IV), from a base and a palladium catalyst, generated from a compound of Palladium and a ligand.
Respecto de la 4-piperidona (II), R se selecciona del grupo consistente en hidrógeno, alquilo sustituido o no sustituido, alquenilo sustituido o no sustituido, arilo sustituido o no sustituido, heteroalquilo sustituido o no sustituido, arilalquilo sustituido o no sustituido, heteroarilalquilo sustituido o no sustituido, acilo, alcoxicarbonilo, aminocarbonilo.Regarding 4-piperidone (II), R is selected from the group consisting of hydrogen, alkyl substituted or unsubstituted, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl substituted, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, acyl, alkoxycarbonyl, aminocarbonyl.
Respecto del compuesto aromático (III):Regarding the aromatic compound (III):
Ar se selecciona del grupo consistente en arilo sustituido o no sustituido, heteroarilo sustituido o no sustituido,Ar is selected from the group consisting of aryl substituted or unsubstituted, heteroaryl substituted or not replaced,
El grupo saliente X puede ser F, Cl, Br, I, triflato, tosilato, nonaflato o mesilato. Preferiblemente se emplean Br o Cl.The leaving group X can be F, Cl, Br, I, triflate, tosylate, nonaflato or mesylate. Preferably it they use Br or Cl.
Respecto de la sulfonilhidrazina (IV), R' puede ser arilo sustituido o no sustituido o alquilo sustituido o no sustituido. Preferiblemente se emplea la tosilhidrazina, (R' = p-tolilo).With respect to sulfonylhydrazine (IV), R 'can be substituted or unsubstituted aryl or substituted or unsubstituted alkyl. Preferably tosylhydrazine is used, (R '= p -tolyl).
Entre las bases adecuadas para su empleo se encuentran los alcóxidos de metales alcalinos, tales como los tert-butóxidos de litio, sodio, potasio o cesio, los metóxidos de litio, sodio, potasio o cesio y los etóxidos de litio, sodio, potasio o cesio, los fenóxidos de metales alcalinos tales como fenóxido de litio, sodio, potasio, o cesio, los hidróxidos de metales alcalinos (litio, sodio, potasio o cesio) los carbonatos de metales alcalinos (litio, sodio, potasio o cesio) y los fosfatos de metales alcalinos (litio, sodio, potasio o cesio) Preferiblemente se emplea como base tert-butóxido de litio.Among the appropriate bases for its use are find alkali metal alkoxides, such as tert-butoxides of lithium, sodium, potassium or cesium, lithium, sodium, potassium or cesium methoxides and lithium ethoxides, sodium, potassium or cesium, alkali metal phenoxides such such as lithium, sodium, potassium, or cesium phenoxide, the hydroxides of alkali metals (lithium, sodium, potassium or cesium) carbonates of alkali metals (lithium, sodium, potassium or cesium) and phosphates of alkali metals (lithium, sodium, potassium or cesium) Preferably Lithium tert-butoxide base is used.
Las reacciones pueden llevarse a cabo en presencia o en ausencia de catalizadores de transferencia de fase, dependiendo de la naturaleza de la base. Los catalizadores de transferencia de fase que se pueden emplear se seleccionan del grupo de las sales de amonio cauternarias, tales como hidróxidos de tetraalquilamonio, fluoruros de tetraalquilamonio, cloruros de tetraalquilamonio, bromuros de tetraalquilamonio, e ioduros de tetraalquilamonio.The reactions can be carried out in presence or absence of phase transfer catalysts, depending on the nature of the base. The catalysts of phase transfer that can be used are selected from the group of the cauternary ammonium salts, such as hydroxides of tetraalkylammonium, tetraalkylammonium fluorides, chlorides of tetraalkylammonium, tetraalkylammonium bromides, and iodides of tetraalkylammonium
La reacción tiene lugar en presencia de un catalizador de paladio. El catalizador de paladio se genera en el medio de reacción por adición independiente del complejo precursor de paladio y el ligando. Alternativamente, el catalizador de paladio puede sintetizarse previamente y añadirse a continuación al medio de reacción.The reaction takes place in the presence of a palladium catalyst The palladium catalyst is generated in the reaction medium by independent addition of the precursor complex of palladium and ligand. Alternatively, the catalyst of Palladium can be previously synthesized and then added to the reaction medium
Una serie no limitativa de complejos precursores de paladio incluye complejos de paladio (0) de alquenos y dienos y sales de paladio (II), entre ellos [bis-di(benciliden)acetona)]paladio (0), [tris-di(benciliden)acetona]dipaladio (0), tetrakis-(trifenilfosfina)-paladio (0), acetato de paladio (II). Cualquiera de los precursores mencionados puede incluir disolvente de cristalización. También puede emplearse como precursor Paladio soportado en carbón. Muy preferiblemente se empleará [tris-di(benciliden)acetona]dipaladio (0) como complejo de paladio precursor.A non-limiting series of complex precursors Palladium includes palladium complexes (0) of alkenes and dienes and Palladium salts (II), including [bis-di (benzylidene) acetone)] palladium (0), [tris-di (benzylidene) acetone] dipaladium (0), tetrakis- (triphenylphosphine) -palladium (0), acetate of palladium (II). Any of the forerunners mentioned may include crystallization solvent. It can also be used as Palladium precursor supported on carbon. Very preferably it will employ [tris-di (benzylidene) acetone] dipaladium (0) as a palladium precursor complex.
El complejo de paladio se compleja posteriormente con un ligando adicional para constituir el catalizador de paladio. Una serie de ejemplos de ligandos útiles, que no debe considerarse limitativa, se muestra a continuación, e incluye:The palladium complex is complex subsequently with an additional ligand to constitute the palladium catalyst A series of examples of useful ligands, which should not be considered limiting, shown below, and It includes:
Tri(t-butil)fosfina (P(t-Bu)3), triciclohexilfosfina, PPh3, P(o-Tol)3, 1,1'-bis(difenilfosfino)ferroceno (DPPF), 1,1'-bis(difenilfosfino)-2,2'-binaftilo (B1NAP), 1,1' -bis(dip-tolilfosfino)-2,2'-binaftilo (Tol-BINAP), 2-Diciclohexilfosfino-2',4',6'-triisopropilbifenilo (X-Phos), 2-Diterbutilfosfmo-2',4',6'-triisopropilbifenilo, 2-Diciclohexilfosfino-2'-(N,N-dimetilamino)bifenilo (DavePhos), 2-Ditertbutilfosfinobifenilo (JohnPhos), 2-Diciclohexilfosfino-2',6'-dimetoxibifenilo (S-Phos);Tri (t-butyl) phosphine (P (t-Bu) 3), tricyclohexylphosphine, PPh3, P (o-Tol) 3, 1,1'-bis (diphenylphosphino) ferrocene (DPPF), 1,1'-bis (diphenylphosphino) -2,2'-binaphthyl (B1NAP), 1.1 ' -bis (dip-tolylphosphino) -2,2'-binaphthyl (Tol-BINAP), 2-Dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (X-Phos), 2-Diterbutylphosphmo-2 ', 4', 6'-triisopropylbiphenyl, 2-Dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl (DavePhos), 2-Ditertbutylphosphinobiphenyl (JohnPhos), 2-Dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (S-Phos);
Preferiblemente se emplean como ligandos fosfinas mondentadas voluminosas y electrónicamente ricas, como JohnPhos, DavePhos o X-Phos o carbenos N-heterocíclicos. Muy preferiblemente se empleará X-Phos como ligando.Preferably, voluminous and electronically rich phosphine-linked phosphines are used as JohnPhos, DavePhos or X-Phos or N- heterocyclic carbons. Most preferably, X-Phos will be used as a ligand.
En general, la relación molar paladio:ligando puede ser variable, oscilando entre 1:1 a 1:4 Preferiblemente se emplea una relación paladio:ligando, 1:2.In general, the palladium molar ratio: ligand it can be variable, ranging from 1: 1 to 1: 4 Preferably it is employs a palladium: ligand, 1: 2 ratio.
El catalizador se emplea en cantidades "catalíticas", es decir en cantidad inferior a estequiométrica en relación con los reactivos. La cantidad de catalizador útil oscila entre un 10% molar a un 0.1% molar en relación a la cantidad de 4-piperidona (II). Preferiblemente se emplea entre un 1% molar y un 5% molar en relación a la cantidad de 4-piperidona.The catalyst is used in quantities "catalytic," that is, less than stoichiometric in relation to reagents. The amount of useful catalyst ranges from 10% molar to 0.1% molar in relation to the quantity of 4-piperidone (II). Preferably used between 1% molar and 5% molar in relation to the amount of 4-piperidone
La relación molar entre la 4-piperidona (II), el halogenuro de arilo (III) y la hidrazona (W) puede ser variable, pudiendo emplearse un exceso de cualquiera de los tres reactivos. Preferiblemente se utiliza una relación 1:1:1 de 4-piperidona (II), halogenuro de arilo (III) e hidrazina (IV).The molar relationship between 4-piperidone (II), aryl halide (III) and the Hydrazone (W) can be variable, and an excess of any of the three reagents. Preferably a 1: 1: 1 ratio of 4-piperidone (II), halide of aryl (III) and hydrazine (IV).
La cantidad de base empleada puede ser cualquier cantidad que permita la formación del producto final. Preferiblemente una cantidad que oscile entre la relación molar base:4-piperidona 2:1 a 5:1. Muy preferiblemente se emplea una cantidad que oscile entre una relación molar base:4-piperidona (II) 2:1 a 3:1.The amount of base employed can be any amount that allows the formation of the final product. Preferably an amount that oscillates between the molar ratio base: 4-piperidone 2: 1 to 5: 1. Very preferably it employs an amount that oscillates between a molar ratio base: 4-piperidone (II) 2: 1 to 3: 1.
La reacción puede llevarse a cabo en cualquier disolvente que no interfiera con la formación del producto foral. Pueden emplearse disolventes tanto próticos como apróticos, o combinaciones de ellos. Una relación no limitante de disolvente apróticos adecuados incluye éteres como 1,4-dioxano y tetrahidrofurano, disolventes aromáticos como tolueno y xileno, amidas polares apróticas como dimetilformamida o N-metilpirrolidinona. La relación de disolvente próticos incluye, pero no está limitada, a agua, alcoholes alifáticos como metanol, etanol y tert-butanol, y también glicoles y polioles. En una realización aún más preferida el disolvente empleado es dioxano.The reaction can be carried out in any solvent that does not interfere with the formation of the foral product. Both protic and aprotic solvents, or combinations thereof, can be used. A non-limiting ratio of suitable aprotic solvents includes ethers such as 1,4-dioxane and tetrahydrofuran, aromatic solvents such as toluene and xylene, aprotic polar amides such as dimethylformamide or N- methylpyrrolidinone. The protic solvent ratio includes, but is not limited to, water, aliphatic alcohols such as methanol, ethanol and tert-butanol, and also glycols and polyols. In an even more preferred embodiment, the solvent used is dioxane.
La cantidad de disolvente empleado puede ser cualquier cantidad, preferiblemente que disuelva al menos parcialmente a los reactivos. Una concentración apropiada está típicamente en el rango de concentraciones 0.1 molar a 1.0 molar en relación a la 4-piperidona (II) de partida. Otras cantidades de disolvente también pueden ser adecuadas de acuerdo con las necesidades específicas de cada proceso particular, determinabas por el experto en la técnica.The amount of solvent used can be any amount, preferably that dissolves at least partially to reagents. An appropriate concentration is typically in the concentration range 0.1 molar to 1.0 molar in ratio to the starting 4-piperidone (II). Other amounts of solvent may also be suitable according with the specific needs of each particular process, you determined by the person skilled in the art.
Los reactivos se mezclan o se adicionan al disolvente en cualquier orden. La reacción se puede llevar a cabo en atmósfera inerte de nitrógeno o argón. No obstante, se ha observado que la reacción en atmósfera de aire conduce a los productos finales con rendimientos comparables, por lo que el empleo de la atmósfera inerte lo puede decidir el experto en la técnica. Las condiciones de la reacción pueden ser cualquiera que proporcione el producto final. En general la temperatura de reacción de la siguiente invención oscila desde 20ºC a 150ºC. Preferiblemente entre 70ºC y 120ºC. El proceso puede llevarse a cabo a cualquier presión. Preferiblemente el proceso se lleva a cabo a presión atmosférica. El tiempo de reacción de la presente invención es el tiempo necesario para alcanzar la máxima conversión posible de 4-piperidona (II) en el producto fmal (I). Típicamente el tiempo de reacción depende de la reacción particular y oscila entre 1 h y 40 h. Preferiblemente el tiempo de reacción oscila entre 3 y 24 horas.Reagents are mixed or added to the solvent in any order. The reaction can be carried out. in an inert atmosphere of nitrogen or argon. However, it has observed that the reaction in air atmosphere leads to final products with comparable yields, so the use of the inert atmosphere can be decided by the expert in the technique. The reaction conditions can be any that Provide the final product. In general the reaction temperature of the following invention ranges from 20 ° C to 150 ° C. Preferably between 70 ° C and 120 ° C. The process can lead to out at any pressure. Preferably the process takes out at atmospheric pressure. The reaction time of the present invention is the time needed to achieve maximum conversion possible 4-piperidone (II) in the final product (I). Typically the reaction time depends on the reaction. particular and ranges between 1 h and 40 h. Preferably the time of reaction ranges from 3 to 24 hours.
La reacción a la que se refiere la presente invención puede llevarse a cabo en cualquier reactor convencional. Pueden emplearse reactores continuos, semi-continuos y discontinuos. El calentamiento puede efectuarse de forma convencional o utilizando energía de microondas.The reaction referred to herein The invention can be carried out in any conventional reactor. Continuous, semi-continuous reactors can be used and discontinuous. The heating can be done in a way conventional or using microwave energy.
El aislamiento del producto final se efectúa mediante métodos convencionales conocidos por los expertos en la técnica, incluyendo destilación, cristalización, sublimación y cromatografía. Preferiblemente el producto se aísla por dilución de la mezcla de reacción a un volumen al menos tres veces superior en un disolvente apropiado, seguido de filtración por celita y eliminación de los volátiles a presión reducida. Una relación no limitativa de disolventes incluye hidrocarburos como pentano o hexano, éteres como éter dietílico, tert-butil metil éter o dioxano, disolventes clorados como diclorometano o cloroformo o combinaciones de ellos. Alternativamente el producto puede aislarse por filtración a través de celita de la mezcla de reacción seguida de eliminación de los volátiles a presión reducida. El producto (I) obtenido puede purificarse mediante métodos convencionales conocidos por el experto en la técnica, incluyendo destilación, cristalización, sublimación y cromatografía en gel de sílice.The final product is insulated by conventional methods known to those skilled in the technique, including distillation, crystallization, sublimation and chromatography Preferably the product is isolated by dilution of the reaction mixture at a volume at least three times higher in an appropriate solvent, followed by filtration by celite and removal of volatiles under reduced pressure. A relationship not Limiting solvents include hydrocarbons such as pentane or hexane, ethers such as diethyl ether, tert-butyl methyl ether or dioxane, chlorinated solvents such as dichloromethane or chloroform or combinations of them. Alternatively the product it can be isolated by filtration through celite from the mixture of reaction followed by removal of volatiles under reduced pressure. The product (I) obtained can be purified by methods conventional techniques known to those skilled in the art, including distillation, crystallization, sublimation and gel chromatography of silica.
El rendimiento del producto final puede variar en función de los reactivos, el catalizador empleado y las condiciones de reacción. En la presente invención el rendimiento se refiere al porcentaje molar de 4-ariltetrahidropiridina (I) obtenida en relación con la cantidad de 4-piperidona (II) inicial. En general el rendimiento es superior al 50 por ciento, y en la mayor parte de los casos superior al 80 por ciento.The performance of the final product may vary. depending on the reagents, the catalyst used and the reaction conditions In the present invention the performance is refers to the molar percentage of 4-aryltetrahydropyridine (I) obtained in relation with the amount of initial 4-piperidone (II). In overall performance is greater than 50 percent, and in the highest part of the cases greater than 80 percent.
La metodología objeto de la invención permite acceder a la estructura de 4-ariltetrahidropiridina en un único paso de reacción a partir de la 4-piperidona, sin el empleo de cantidades estequiométricas de metales, sin la necesidad de emplear disolventes y atmósfera anhidros, y sin necesidad de proteger el grupo N-H. Además, la reacción transcurre con elevados rendimientos y presenta gran generalidad y tolerancia de grupos funcionales.The methodology object of the invention allows access the structure of 4-aryltetrahydropyridine in a single reaction step from the 4-piperidone, without the use of quantities stoichiometric metal, without the need to use anhydrous solvents and atmosphere, and without the need to protect the N-H group. In addition, the reaction proceeds with high yields and presents great generality and tolerance of functional groups.
Presenta una aplicación potencial en aquellos sectores en los que se generen compuestos químicos como, por ejemplo, en la preparación de fármacos y moléculas con aplicación terapéutica, en el descubrimiento de nuevos fármacos y en su implementación a gran escala.It presents a potential application in those sectors in which chemical compounds are generated, such as example, in the preparation of drugs and molecules with application therapeutic, in the discovery of new drugs and in their large scale implementation
Los siguientes ejemplos sirven para ilustrar la invención sin que deban ser considerados como limitativos del alcance de la misma.The following examples serve to illustrate the invention without being considered as limiting the scope of it.
Consideraciones generales: Las reacciones se llevan a cabo en tubos de reacción equipados con tapones roscados de cierre hermético con una llave lateral de salida de aire y sistema de reflujo. El dioxano se seca utilizando los procedimientos descritos en D. Perrin Purification of Laboratory Chemicals, Pergamon Press Ltd. 1980, 2^{nd} Ed. Los complejos de paladio y los ligandos utilizados son comerciales y se utilizan sin purificación posterior. El terbutóxido de litio comercial se almacena en un matraz en atmósfera de nitrógeno y se pesa al aire. Los halogenuros de arilo y las 4-piperidonas son comerciales y se utilizan sin purificación posterior. La tosilhidrazina es comercial y se emplea sin purificación posterior. Los espectros de Resonancia Magnética Nuclear (NMR) se obtuvieron a 400 ó 300 MHz para ^{1}H y 100 ó 75 MHz para ^{13}C, con tetrametilsilano como estándar interno para ^{1}H y la señal residual del disolvente como para ^{13}C. Los desplazamientos químicos se denotan en ppm y las constantes de acoplamiento en Hz. Los datos se indican como s=singlete, d=doblete, t=triplete, c=cuatriplete y m=multiplete o no resuelto. Los espectros de masas se obtuvieron por impacto electrónico (70 eV). General considerations : The reactions are carried out in reaction tubes equipped with threaded seals with a side air outlet and reflux system. The dioxane is dried using the procedures described in D. Perrin Purification of Laboratory Chemicals , Pergamon Press Ltd. 1980, 2d Ed. Palladium complexes and ligands used are commercial and are used without further purification. Commercial lithium terbutoxide is stored in a flask under a nitrogen atmosphere and weighed in the air. Aryl halides and 4-piperidones are commercial and are used without further purification. Tosylhydrazine is commercial and is used without further purification. Nuclear Magnetic Resonance (NMR) spectra were obtained at 400 or 300 MHz for 1 H and 100 or 75 MHz for 13 C, with tetramethylsilane as internal standard for 1 H and the residual signal of the solvent as for 13 C. The chemical shifts are denoted in ppm and the coupling constants in Hz. The data are indicated as s = singlet, d = doublet, t = triplet, c = quadriplete and m = multiplet or unresolved. Mass spectra were obtained by electronic impact (70 eV).
Un reactor en atmósfera de nitrógeno se carga con 2-diciclohexilfosfino-2',4',6'-triisopropilbiphenilo (X-phos) (0.02 mmol, 23.8 mg), tris(dibencilidenacetona)dipalladio(0) (0.005 mmol, 4.57 mg), t-butoxido de litio (2.4 mmol, 192.2 mg), tosylhydrazina (IV) (1 mmol, 186 mg), la 4-piperidona (II) correspondiente (1.1 mmol) y dioxano (4 mL). La mezcla se agita, y después de 5 minutos se añade el halogenuro de arilo (III) (1 mmol). El sistema se calienta a 110ºC con agitación y reflujo. La reacción se monitoriza por cromatografía de gases/espectrometría de masas (GC/MS) siguiendo la desaparición del halogenuro de arilo. Cuando la reacción se ha completado, la mezcla de reacción se enfría a temperatura ambiente y se añaden 15 mL de pentano con agitación. La mezcla se filtra a través de celita y el filtrado se concentra por eliminación de los disolventes a presión reducida. El crudo de reacción se seca a alto vacío proporcionando la 4-ariltetrahidropiridina esencialmente pura. Si es necesario, el residuo se purifica por cromatografía en gel de sílice.A nitrogen atmosphere reactor is charged with 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (X-phos) (0.02 mmol, 23.8 mg), tris (dibenzylidenacetone) dipalladium (0) (0.005 mmol, 4.57 mg ), lithium t -butoxide (2.4 mmol, 192.2 mg), tosylhydrazine (IV) (1 mmol, 186 mg), the corresponding 4-piperidone (II) (1.1 mmol) and dioxane (4 mL). The mixture is stirred, and after 5 minutes the aryl halide (III) (1 mmol) is added. The system is heated to 110 ° C with stirring and reflux. The reaction is monitored by gas chromatography / mass spectrometry (GC / MS) following the disappearance of the aryl halide. When the reaction is complete, the reaction mixture is cooled to room temperature and 15 mL of pentane is added with stirring. The mixture is filtered through celite and the filtrate is concentrated by removal of the solvents under reduced pressure. The reaction crude is dried under high vacuum to provide essentially pure 4-aryltetrahydropyridine. If necessary, the residue is purified by silica gel chromatography.
Siguiendo el procedimiento descrito, empleando 127.1 mg de N-etil-4-piperidona y 170 mg de 4-bromotolueno.Following the procedure described, using 127.1 mg of N- ethyl-4-piperidone and 170 mg of 4-bromotoluene.
Rendimiento 80%.80% yield.
HRMS (EI): calcd. para C_{14}H_{19}N: 201.1512; encontrado: 201.1507; ^{1}H NMR (CDCl_{3}, 300 MHz): \delta = 1.17 (t, ^{3}J = 7.2 Hz, 3H), 2.34 (s, 311), 2.50-2.60 (m, 4H), 2.68-2.72 (m, 2H), 3.15-3.16 (m, 2H), 6.04 (br. s, 1H), 7.13 (d, ^{3}J= 8.1 Hz, 2H), 7.30 (d, ^{3}J = 8.1 Hz, 2H); ^{13}C NMR (CDCl_{3}, 75 MHz): \delta = 12.2 (CH_{3}), 20.9 (CH_{3}), 28.0 (CH_{2}), 50.0 (CH_{2}), 51.9 (CH_{2}), 52.7 (CH_{2}), 120.9 (CH), 124.6 (CH), 128.8 (CH), 134.7 (C), 136.4 (C), 138.0 (C).HRMS (EI): calcd. for C 14 H 19 N: 201.1512; Found: 201.1507; 1 H NMR (CDCl 3, 300 MHz): δ = 1.17 (t, 3 J = 7.2 Hz, 3H), 2.34 (s, 311), 2.50-2.60 (m, 4H) , 2.68-2.72 (m, 2H), 3.15-3.16 (m, 2H), 6.04 (br. S, 1H), 7.13 (d, 3 J = 8.1 Hz, 2H), 7.30 (d, ^ 3} J = 8.1 Hz, 2H); 13 C NMR (CDCl 3, 75 MHz): δ = 12.2 (CH 3), 20.9 (CH 3), 28.0 (CH 2), 50.0 (CH 2) , 51.9 (CH2), 52.7 (CH2), 120.9 (CH), 124.6 (CH), 128.8 (CH), 134.7 (C), 136.4 (C), 138.0 (C).
Siguiendo el procedimiento descrito empleando 127.1 mg de N-etil-4-piperidona y 161,9 mg de 2-bromotiofeno.Following the procedure described using 127.1 mg of N- ethyl-4-piperidone and 161.9 mg of 2-bromothiophene.
Rendimiento 79%. Purificado por cromatografía flash en gel de sílice empleando hexano como eluyente. Rf=0.54.Yield 79%. Purified by chromatography flash on silica gel using hexane as eluent. Rf = 0.54.
HRMS (EI): calcd. para C_{11}H_{15}NS: 193.0925; encontrado: 193.0922; ^{1}H NMR (CDCl_{3}, 300 MHz): \delta = 1.15 (t, ^{3}J = 7.2 Hz, 3H), 2.49-2.61 (m, 411), 2.67-2.71 (m, 2H), 3.12-3.14 (m, 2H), 6.07-6.11 (m, 1H), 6.94-6.95 (m, 2H), 7.10-7.12 (m, 1H); ^{13}C NMR (CDCl_{3}, 75 MHz): \delta = 12.3 (CH_{3}), 28.4 (CH_{2}), 49.7 (CH_{2}), 51.9 (CH_{2}), 52.4 (CH_{2}), 120.9 (CH), 121.6 (CH), 123.1 (CH), 127.1 (CH), 129.6 (C), 145.3 (C).HRMS (EI): calcd. for C 11 H 15 NS: 193.0925; Found: 193.0922; 1 H NMR (CDCl 3, 300 MHz): δ = 1.15 (t, 3 J = 7.2 Hz, 3H), 2.49-2.61 (m, 411), 2.67-2.71 (m, 2H), 3.12-3.14 (m, 2H), 6.07-6.11 (m, 1H), 6.94-6.95 (m, 2H), 7.10-7.12 (m, 1H); 13 C NMR (CDCl 3, 75 MHz): δ = 12.3 (CH 3), 28.4 (CH 2), 49.7 (CH 2), 51.9 (CH 2) , 52.4 (CH2), 120.9 (CH), 121.6 (CH), 123.1 (CH), 127.1 (CH), 129.6 (C), 145.3 (C).
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Siguiendo el procedimiento descrito empleando 127.1 mg de N-etil-4-piperidona y 195 mg de 5-bromoindol.Following the procedure described using 127.1 mg of N- ethyl-4-piperidone and 195 mg of 5-bromoindole.
Rendimiento 80%. Purificado por cromatografía flash en gel de sílice empleando hexano como eluyente. Rf =0.54.80% yield. Purified by chromatography flash on silica gel using hexane as eluent. Rf = 0.54.
HRMS (EI): calcd. para C_{15}H_{18}N_{2}: 226.1470; encontrado: 226.1472; ^{1}H NMR (CDCl_{3}, 300 MHz): \delta = 1.21 (t, ^{3}J = 7.2 Hz, 3H), 2.59 (c, ^{3}J = 7.2 Hz, 2H), 2.71-2.77 (m, 4H), 3.20-3.21 (m, 2H), 6.06 (br. s, 1H), 6.51-6.55 (m, 1H), 7.14 (m, 1H), 7.30 (m, 2H), 7.65 (m, 1H), 8.80 (br. s, 1H); ^{13}C NMR (CDCl_{3}, 75 MHz): \delta = 12.2 (CH_{3}), 28.6 (CH_{2}), 50.2 (CH_{2}), 52.0 (CH_{2}), 52.8 (CH_{2}), 102.5 (CH), 110.7 (CH), 116.8 (CH), 119.6 (CH), 119.8 (CH), 124.6 (CH), 127.8 (C), 133.0 (C), 135.1 (C). 135.8 (C).HRMS (EI): calcd. for C 15 H 18 N 2: 226.1470; Found: 226.1472; 1 H NMR (CDCl 3, 300 MHz): δ = 1.21 (t, 3 J = 7.2 Hz, 3H), 2.59 (c, 3 J = 7.2 Hz, 2H) , 2.71-2.77 (m, 4H), 3.20-3.21 (m, 2H), 6.06 (br. S, 1H), 6.51-6.55 (m, 1H), 7.14 (m, 1H), 7.30 (m, 2H) , 7.65 (m, 1H), 8.80 (br. S, 1H); 13 C NMR (CDCl 3, 75 MHz): δ = 12.2 (CH 3), 28.6 (CH 2), 50.2 (CH 2), 52.0 (CH 2) , 52.8 (CH_2), 102.5 (CH), 110.7 (CH), 116.8 (CH), 119.6 (CH), 119.8 (CH), 124.6 (CH), 127.8 (C), 133.0 (C), 135.1 (C). 135.8 (C).
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Siguiendo el procedimiento descrito empleando 189.1 mg de N-bencil-4-piperidona y 170 mg de 4-bromotolueno.Following the procedure described using 189.1 mg of N- benzyl-4-piperidone and 170 mg of 4-bromotoluene.
Rendimiento 93%.93% yield.
HRMS: calcd. para C_{19}H_{19}N: 263.1669; encontrado: 263.1672.HRMS: calcd. for C 19 H 19 N: 263.1669; Found: 263.1672.
^{1}H-NMR (300 MHz, CDCl_{3}) \delta (ppm) = 7.41-7.39 (d, J=7.8Hz, 2H), 7.36-7.33 (m, 2H), 7.31-7.27 (m, 3H), 6.07-6.05 (m, 1H), 3.67 (s, 2H), 3.21-3.19 (m, 2H), 2.77-2.72 (m, 2H), 2.60-2.58 (m, 2H).1 H-NMR (300 MHz, CDCl 3) δ (ppm) = 7.41-7.39 (d, J = 7.8Hz, 2H), 7.36-7.33 (m, 2H), 7.31-7.27 (m , 3H), 6.07-6.05 (m, 1H), 3.67 (s, 2H), 3.21-3.19 (m, 2H), 2.77-2.72 (m, 2H), 2.60-2.58 (m, 2H).
^{13}C-NMR (300 MHz, CDCl_{3}) \delta (ppm) = 138.2 (C), 138.0 (C), 136.5 (C), 134.7 (C), 129.1 (2xCH), 128.8, (2xCH), 128.2 (2xCH), 127.0 (CH), 124.7 (2xCH), 120.9 (CH), 62.7 (CH_{2}), 53.2 (CH_{2}), 49.9 (CH_{2}), 27.9 (CH_{2}), 21.0 (CH_{3}).13 C-NMR (300 MHz, CDCl 3) δ (ppm) = 138.2 (C), 138.0 (C), 136.5 (C), 134.7 (C), 129.1 (2xCH), 128.8, (2xCH), 128.2 (2xCH), 127.0 (CH), 124.7 (2xCH), 120.9 (CH), 62.7 (CH2), 53.2 (CH2), 49.9 (CH2), 27.9 (CH2), 21.0 (CH3).
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Siguiendo el procedimiento descrito empleando 189.1 mg de N-bencil-4-piperidona y 189.9 mg de 1-cloro-4-bromobenceno.Following the procedure described using 189.1 mg of N- benzyl-4-piperidone and 189.9 mg of 1-chloro-4-bromobenzene.
Rendimiento 89%.Yield 89%.
HRMS: calcd. para C_{18}H_{18}ClN: 283.1122; encontrado: 283.1121.HRMS: calcd. for C 18 H 18 ClN: 283.1122; Found: 283.1121.
^{1}H-NMR (400 MHz, CDCl_{3}) \delta (ppm) = 7.39-.38 (m, 2H), 7.36-7.35 (m, 1H), 7.35-7.34 (m, 1H), 7.33-7.32 (m, 2H), 7.31-7.30 (m, 2H), 7.28-7.27 (m, 1H), 6.09- 6.07 (m, 111), 3.67 (s, 2H), 3.21-3.18 (m, 211), 2.76-2.72 (t, J=5.8Hz, 211), 2.55-2.54 (m, 2H).1 H-NMR (400 MHz, CDCl 3) δ (ppm) = 7.39-.38 (m, 2H), 7.36-7.35 (m, 1H), 7.35-7.34 (m, 1H), 7.33-7.32 (m, 2H), 7.31-7.30 (m, 2H), 7.28-7.27 (m, 1H), 6.09- 6.07 (m, 111), 3.67 (s, 2H), 3.21-3.18 (m, 211 ), 2.76-2.72 (t, J = 5.8Hz, 211), 2.55-2.54 (m, 2H).
^{13}C-NMR (300 MHz, CDCl_{3}) \delta (ppm) = 139.2 (C), 138.0 (C), 133.9 (C), 132.5 (C), 129.2 (2xCH), 128.3, (2xCH), 128.2 (2xCH), 127.1 (CH), 126.1(2xCH), 122.4 (CH), 62.6 (CH_{2}), 53.2 (CH_{2}), 49.8 (CH_{2}), 27.9 (CH_{2}).13 C-NMR (300 MHz, CDCl 3) δ (ppm) = 139.2 (C), 138.0 (C), 133.9 (C), 132.5 (C), 129.2 (2xCH), 128.3, (2xCH), 128.2 (2xCH), 127.1 (CH), 126.1 (2xCH), 122.4 (CH), 62.6 (CH2), 53.2 (CH2), 49.8 (CH2), 27.9 (CH2).
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Siguiendo el procedimiento descrito empleando 189.1 mg de N-bencil-4-piperidona y 186 mg de 4-bromoanisol.Following the procedure described using 189.1 mg of N- benzyl-4-piperidone and 186 mg of 4-bromoanisole.
Rendimiento 99%.99% yield.
HRMS: calcd. para C_{19}H_{21}NO: 279.1612; encontrado: 279.1615.HRMS: calcd. for C 19 H 21 NO: 279.1612; Found: 279.1615.
^{1}H-NMR (400 MHz, CDCl_{3}) \delta (ppm) = 7.44-7.42 (d, J=7.88Hz, 2H), 7.40-7.35 (m, 4H), 7.33-7.31 (d, J=6.5Hz, 1H), 6.90-6.87 (d, J=68.8Hz, 2H), 6.03-6.01 (m, 1H), 3.82 (s, 311), 3.67 (s, 2H), 3.21-3.19 (m, 2H), 2.76-2.73 (t, J=5.8Hz, 2H), 2.59-2.57 (m, 2H).1 H-NMR (400 MHz, CDCl 3) δ (ppm) = 7.44-7.42 (d, J = 7.88Hz, 2H), 7.40-7.35 (m, 4H), 7.33-7.31 (d , J = 6.5Hz, 1H), 6.90-6.87 (d, J = 68.8Hz, 2H), 6.03-6.01 (m, 1H), 3.82 (s, 311), 3.67 (s, 2H), 3.21-3.19 ( m, 2H), 2.76-2.73 (t, J = 5.8Hz, 2H), 2.59-2.57 (m, 2H).
^{13}C-NMR (300 MHz, CDCl_{3}) \delta (ppm) = 158.6 (C), 138.2 (C), 134.2 (C), 133.4 (C), 129.2 (2xCH), 128.2, (2xCH), 127.0 (CH), 125.8 (2xCH), 120.1 (CH), 113.5 (2xCH), 62.7 (CH_{2}), 55.1 (CH_{3}), 53.2 (CH_{2}), 49.9 (CH_{2}), 28.0 (CH_{2}).13 C-NMR (300 MHz, CDCl 3) δ (ppm) = 158.6 (C), 138.2 (C), 134.2 (C), 133.4 (C), 129.2 (2xCH), 128.2, (2xCH), 127.0 (CH), 125.8 (2xCH), 120.1 (CH), 113.5 (2xCH), 62.7 (CH2), 55.1 (CH3), 53.2 (CH2), 49.9 (CH2), 28.0 (CH2).
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Siguiendo el procedimiento descrito empleando 189.1 mg de N-bencil-4-piperidona y 181 mg de 3-bromobenzonitrilo.Following the procedure described using 189.1 mg of N -benzyl-4-piperidone and 181 mg of 3-bromobenzonitrile.
Rendimiento 98%.98% yield.
HRMS (El): calcd. para C_{19}H_{18}N_{2}: 274.1465; encontrado: 274.1462.HRMS (El): calcd. for C 19 H 18 N 2: 274.1465; Found: 274.1462.
^{1}H-NMR (300 MHz, CDCl_{3}) \delta (ppm) = 2.55 (m, 2H), 2.75 (t, ^{3}J= 5.7 Hz, 2H), 3.20 (m, 211), 3.66 (s, 2H), 6.15 (m, 1H), 7.29 (d, ^{3}J = 6.9 Hz, 1H), 7.34-7.44 (m, 5H), 7.52 (d, ^{3}J= 7,9 Hz, 1H), 7.62 (d, ^{3}J= 7.9 Hz, 111), 7.66 (s, 1H); ^{13}C-NMR (75 MHz, CDCl_{3}) \delta (ppm) = 27.8 (CH_{2}), 49.4 (CH_{2}), 52.9 (CH_{2}), 62.4 (CH_{2}), 112.2 (C), 118.8 (CH), 124.2 (CH), 127.0 (CH), 128.0 (CH), 128.1 (CH), 128.3 (2xCH), 129.0 (2xCH), 130.1 (CH), 133.0 (C), 137.8 (C), 141.7 (C), 150.4 (C).1 H-NMR (300 MHz, CDCl 3) δ (ppm) = 2.55 (m, 2H), 2.75 (t, 3 J = 5.7 Hz, 2H), 3.20 (m, 211 ), 3.66 (s, 2H), 6.15 (m, 1H), 7.29 (d, 3 J = 6.9 Hz, 1H), 7.34-7.44 (m, 5H), 7.52 (d, 3 J = 7.9 Hz, 1H), 7.62 (d, 3 J = 7.9 Hz, 111), 7.66 (s, 1H); <13> C-NMR (75 MHz, CDCl3) [delta] (ppm) = 27.8 (CH2), 49.4 (CH2), 52.9 (CH2), 62.4 (CH_ { 2}), 112.2 (C), 118.8 (CH), 124.2 (CH), 127.0 (CH), 128.0 (CH), 128.1 (CH), 128.3 (2xCH), 129.0 (2xCH), 130.1 (CH), 133.0 (C), 137.8 (C), 141.7 (C), 150.4 (C).
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Siguiendo el procedimiento descrito empleando 189.1 mg de N-bencil-4-piperidona y 146 mg de 3-bromofurano.Following the procedure described using 189.1 mg of N- benzyl-4-piperidone and 146 mg of 3-bromofuran.
Rendimiento 98%.98% yield.
HRMS: calcd. para C_{16}H_{17}NO: 239.1305; encontrado: 239.1301.HRMS: calcd. for C 16 H 17 NO: 239.1305; Found: 239.1301.
^{1}H-NMR (400 MHz, CDCl_{3}) \delta (ppm) = 7.452-7.34(m, 6H), 7.32-7.30 (d, J= 6.9Hz, 1H), 6.53 (s, 1H), 5.95-5.92 (m, 1H), 3.66 (s, 2H), 3.17-3.16 (d, J= 4''Hz, 2H), 2.72-2.70 (t, J=5.8Hz, 2H), 2.45-2.44 (m, 2H).1 H-NMR (400 MHz, CDCl 3) δ (ppm) = 7.452-7.34 (m, 6H), 7.32-7.30 (d, J = 6.9Hz, 1H), 6.53 (s, 1H ), 5.95-5.92 (m, 1H), 3.66 (s, 2H), 3.17-3.16 (d, J = 4``Hz, 2H), 2.72-2.70 (t, J = 5.8Hz, 2H), 2.45- 2.44 (m, 2H).
^{13}C-NMR (300 MHz, CDCl_{3}) \delta (ppm) = 143.1 (CH), 138.24 (C), 137.8 (CH), 129.1 (2xCH), 128.2 (2xCH), 127.1 (CH), 126.9 (C), 120.0 (CH), 107.2 (CH), 62.7 (CH_{2}), 52.9 (CH_{2}), 49.5 (CH_{2}), 27.6 (CH_{2}).13 C-NMR (300 MHz, CDCl 3) δ (ppm) = 143.1 (CH), 138.24 (C), 137.8 (CH), 129.1 (2xCH), 128.2 (2xCH), 127.1 (CH), 126.9 (C), 120.0 (CH), 107.2 (CH), 62.7 (CH2), 52.9 (CH2), 49.5 (CH2), 27.6 (CH2).
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Siguiendo el procedimiento descrito empleando 189.1 mg de N-bencil-4-piperidona y 158 mg de 3-bromopiridina.Following the procedure described using 189.1 mg of N- benzyl-4-piperidone and 158 mg of 3-bromopyridine.
Rendimiento 99%.99% yield.
HRMS: calcd. para C_{17}H_{18}N_{2}: 250.1465; encontrado: 250.1465.HRMS: calcd. for C 17 H 18 N 2: 250.1465; Found: 250.1465.
^{1}H-NMR (300 MHz, CDCl_{3}) \delta (ppm) = 8.67 (s, 1H), 8.53-8.51 (d, J=5Hz, 1H), 7.65-7.64 (d, J= 7.6Hz, 111), 7.39-7.26 (m, 5H), 7.22-7.19 (m, 1H), 6.16-6.13 (m, 1H), 3.67 (s, 2H), 3.22-3.19 (m, 2H), 2.77-2.73 (t, J=5.9Hz, 2H), 2.59-2.56 (m, 2H).1 H-NMR (300 MHz, CDCl 3) δ (ppm) = 8.67 (s, 1H), 8.53-8.51 (d, J = 5Hz, 1H), 7.65-7.64 (d, J = 7.6Hz, 111), 7.39-7.26 (m, 5H), 7.22-7.19 (m, 1H), 6.16-6.13 (m, 1H), 3.67 (s, 2H), 3.22-3.19 (m, 2H), 2.77 -2.73 (t, J = 5.9Hz, 2H), 2.59-2.56 (m, 2H).
^{13}C-NMR (300 MHz, CDCl_{3}) \delta (ppm) = 148.0 (CH), 146.5 (CH), 137.9 (C), 136.1 (C), 132.3 (C), 132.0, (CH), 129.1 (2xCH), 128.2 (2xCH), 127.1 (CH), 123.72 (CH), 123.0 (CH), 62.7 (CH_{2}), 53.1 (CH_{2}), 49.6 (CH_{2}), 27.67 (CH_{2}).13 C-NMR (300 MHz, CDCl 3) δ (ppm) = 148.0 (CH), 146.5 (CH), 137.9 (C), 136.1 (C), 132.3 (C), 132.0, (CH), 129.1 (2xCH), 128.2 (2xCH), 127.1 (CH), 123.72 (CH), 123.0 (CH), 62.7 (CH2), 53.1 (CH2), 49.6 (CH2), 27.67 (CH2).
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Siguiendo el procedimiento descrito, empleando p-bromotolueno (85.5 mg, 0.5 mmol), y clorhidrato de 4-piperidinona monohidrato (84.5 mg, 0.55 mmol).Following the procedure described, using p- bromotoluene (85.5 mg, 0.5 mmol), and 4-piperidinone hydrochloride monohydrate (84.5 mg, 0.55 mmol).
Rendimiento 94%.94% yield.
^{1}H-NMR (400 MHz, CDCl_{3}) \delta (ppm) = 2.36 (s, 3H), 2.56 (m, 2H), 3.21 (m, 2H), 3.63 (m, 2H), 6.05 (m, 1H), 7.14 (d, ^{3}J = 10.7 Hz, 2H), 7.27 (d, ^{3}J = 10.7 Hz, 2H); ^{13}C-NMR (100 MHz, CDCl_{3}) \delta (ppm) = 20.9 (CH_{3}), 26.4 (CH_{2}), 42.4 (CH_{2}), 44.2 (CH_{2}), 120.1 (CH), 124.6 (2xCH), 129.0 (2xCH), 135.2 (C), 137.0 (C), 137.6 (C).1 H-NMR (400 MHz, CDCl 3) δ (ppm) = 2.36 (s, 3H), 2.56 (m, 2H), 3.21 (m, 2H), 3.63 (m, 2H), 6.05 (m, 1H), 7.14 (d, 3 J = 10.7 Hz, 2H), 7.27 (d, 3 J = 10.7 Hz, 2H); 13 C-NMR (100 MHz, CDCl 3) δ (ppm) = 20.9 (CH 3), 26.4 (CH 2), 42.4 (CH 2), 44.2 (CH_ { 2}), 120.1 (CH), 124.6 (2xCH), 129.0 (2xCH), 135.2 (C), 137.0 (C), 137.6 (C).
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Siguiendo el procedimiento descrito, empleando p-bromoanisol (93.5 mg, 0.5 mmol), y clorhidrato de 4-piperidinona monohidrato (84.5 mg, 0.55 mmol).Following the procedure described, using p- bromoanisole (93.5 mg, 0.5 mmol), and 4-piperidinone hydrochloride monohydrate (84.5 mg, 0.55 mmol).
Rendimiento 90%.Yield 90%.
HRMS (EI): calcd. para C_{12}H_{15}NO: 189.1148; encontrado: 189.1143.HRMS (EI): calcd. for C 12 H 15 NO: 189.1148; Found: 189.1143.
^{1}H-NMR (400 MHz, CDCl_{3}) \delta (ppm) = 2.45 (m, 211), 3.12 (m, 2H), 3.54 (m, 2H), 3.82 (s, 311), 6.05 (m, 1H), 6.85 (d, ^{3}J = 8.7 Hz, 2H), 7.33 (d, ^{3}J = 8.7 Hz, 2H); ^{13}C-NMR (100 MHz, CDCl_{3}) \delta (ppm) = 27.1 (CH_{2}), 42.8 (CH_{2}), 44.8 (CH_{2}), 55.0 (CH_{3}), 113.5 (2xCH), 120.8 (CH), 125.6 (2xCH), 133.5 (C), 134.5 (C), 158.6 (C).1 H-NMR (400 MHz, CDCl 3) δ (ppm) = 2.45 (m, 211), 3.12 (m, 2H), 3.54 (m, 2H), 3.82 (s, 311), 6.05 (m, 1H), 6.85 (d, 3 J = 8.7 Hz, 2H), 7.33 (d, 3 J = 8.7 Hz, 2H); <13> C-NMR (100 MHz, CDCl3) [delta] (ppm) = 27.1 (CH2), 42.8 (CH2), 44.8 (CH2), 55.0 (CH_ { 3}), 113.5 (2xCH), 120.8 (CH), 125.6 (2xCH), 133.5 (C), 134.5 (C), 158.6 (C).
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Siguiendo el procedimiento descrito, empleando 3-bromobenzonitrile (91.0 mg, 0.5 mmol) y clorhidrato de 4-piperidinona monohidrato (84.5 mg, 0.55 mmol).Following the procedure described, using 3-bromobenzonitrile (91.0 mg, 0.5 mmol) and 4-piperidinone hydrochloride monohydrate (84.5 mg, 0.55 mmol).
Rendimiento 93%.93% yield.
HRMS (EI): calcd. para C_{12}H_{12}N_{2}: 184.0995; encontrado: 184.0992.HRMS (EI): calcd. for C 12 H 12 N 2: 184.0995; Found: 184.0992.
^{1}H-NMR (400 MHz, CDCl_{3}) \delta (ppm) = 2.41 (m, 211), 3.10 (m, 211), 3.55 (m, 2H), 6.19 (m, 111), 7.40 (t, ^{3}J = 7.7 Hz, 111), 7.48 (d, ^{3}J = 7.7 Hz, 111), 7.57 (d, ^{3}J = 7.7 Hz, 1H), 7.60 (s, 111); ^{13}C-NMR (100 MHz, CDCl_{3}) \delta (ppm) = 27.6 (CH_{2}), 43.1 (CH_{2}), 45.5 (CH_{2}), 112.5 (C), 119.0 (CH), 126.0 (CH), 128.6 (CH), 129.1 (CH), 130.2 (CH), 133.6 (C), 140.3 (C), 142.4 (C).1 H-NMR (400 MHz, CDCl 3) δ (ppm) = 2.41 (m, 211), 3.10 (m, 211), 3.55 (m, 2H), 6.19 (m, 111), 7.40 (t, 3 J = 7.7 Hz, 111), 7.48 (d, 3 J = 7.7 Hz, 111), 7.57 (d, 3 J = 7.7 Hz, 1H), 7.60 ( s, 111); 13 C-NMR (100 MHz, CDCl 3) δ (ppm) = 27.6 (CH 2), 43.1 (CH 2), 45.5 (CH 2), 112.5 (C) , 119.0 (CH), 126.0 (CH), 128.6 (CH), 129.1 (CH), 130.2 (CH), 133.6 (C), 140.3 (C), 142.4 (C).
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Siguiendo el procedimiento descrito, 2-bromotiofeno (63.3 mg, 0.5 mmol) y clorhidrato de 4-piperidinona monohidrato (84.5 mg, 0.55 mmol).Following the procedure described, 2-Bromothiophene (63.3 mg, 0.5 mmol) and hydrochloride 4-piperidinone monohydrate (84.5 mg, 0.55 mmol).
Rendimiento 70%.70% yield.
HRMS (EI): calcd. para C_{9}H_{11}NS: 165.0607; encontrado: 165.0601.HRMS (EI): calcd. for C_ {9} H_ {NS} NS: 165.0607; Found: 165.0601.
^{1}H NMR (300 MHz, CDCl_{3}): \delta = 2.45 (m, 2H), 3.08 (m, 2H), 3.49 (m, 2H), 6.14 (m, 1H), 6.99 (m, 2H), 7.11 (m, 1H); ^{13}C NMR (75 MHz, CDCl_{3}): \delta = 27.7 (CH_{2}), 42.9 (CH_{2}), 45.0 (CH_{2}), 121.3 (CH), 122.4 (CH), 123.0 (CH), 127.1 (CH), 129.8 (C), 145.8 (C).1 H NMR (300 MHz, CDCl 3): δ = 2.45 (m, 2H), 3.08 (m, 2H), 3.49 (m, 2H), 6.14 (m, 1H), 6.99 (m, 2H), 7.11 (m, 1H); 13 C NMR (75 MHz, CDCl 3): δ = 27.7 (CH2), 42.9 (CH2), 45.0 (CH2), 121.3 (CH), 122.4 (CH), 123.0 (CH), 127.1 (CH), 129.8 (C), 145.8 (C).
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Siguiendo el procedimiento descrito, 5-bromoindole (98.0 mg, 0.5 mmol) y clorhidrato de 4-piperidinona monohidrato (84.5 mg, 0.55 mmol).Following the procedure described, 5-Bromoindole (98.0 mg, 0.5 mmol) and hydrochloride 4-piperidinone monohydrate (84.5 mg, 0.55 mmol).
Rendimiento 76%.Yield 76%.
HRMS (EI): calcd. para C_{13}H_{14}N_{2}: 198.1152; encontrado: 198.1149.HRMS (EI): calcd. for C 13 H 14 N 2: 198.1152; Found: 198.1149.
^{1}H NMR (300 MHz, CDCl_{3}): \delta = 2.50 (m, 2H), 3.24 (m, 2H), 3.68 (m, 2H), 6.16 (m, 1H), 6.74 (m, 1H), 7.19 (m, 1H), 7.30 (m, 2H), 7.57 (m, 111), 8.49 (br. s, IH); ^{13}C NMR (75 MHz, CDCl_{3}): \delta = 28.3 (CH_{2}), 43.5 (CH_{2}), 45.6 (CH_{2}), 102.7 (CH), 110.7 (CH), 116.7 (CH), 119.6 (CH), 121.8 (CH), 124.5 (CH), 127.9 (C), 133.6 (C), 135.1 (C). 136.1 (C).1 H NMR (300 MHz, CDCl 3): δ = 2.50 (m, 2H), 3.24 (m, 2H), 3.68 (m, 2H), 6.16 (m, 1H), 6.74 (m, 1H), 7.19 (m, 1H), 7.30 (m, 2H), 7.57 (m, 111), 8.49 (br. S, IH); 13 C NMR (75 MHz, CDCl 3): δ = 28.3 (CH 2), 43.5 (CH2), 45.6 (CH2), 102.7 (CH), 110.7 (CH), 116.7 (CH), 119.6 (CH), 121.8 (CH), 124.5 (CH), 127.9 (C), 133.6 (C), 135.1 (C). 136.1 (C).
Claims (24)
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| BARLUENGA et al., Angewandte Chemie Int. Ed. 2007, vol. 46, páginas 5587-5590. Willey InterScience. "{}N-Tosylhydrazones as reagents for cross-coupling reactions: A route to polysubstituted olefins"{}. * |
| MORRILL et al., Organic Letters 2007, vol. 9, n$^{o}$ 8, páginas 1505-1508. American Chemical Society. "{}Synthesis of 4-arylpiperidines from 1-benzyl-4-piperidone: Application of the Saphiro reaction and alkenylsilane cross-coupling"{}, todo el documento. * |
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