CN104114530B - 羟基羧酸酰胺化合物的制法和新型的芳基硼酸化合物 - Google Patents
羟基羧酸酰胺化合物的制法和新型的芳基硼酸化合物 Download PDFInfo
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- CN104114530B CN104114530B CN201380009468.0A CN201380009468A CN104114530B CN 104114530 B CN104114530 B CN 104114530B CN 201380009468 A CN201380009468 A CN 201380009468A CN 104114530 B CN104114530 B CN 104114530B
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- Prior art keywords
- carboxylic acid
- compound
- hydroxy carboxylic
- catalyst
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- -1 hydroxy carboxylic acid amide compound Chemical class 0.000 title claims abstract description 101
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 98
- 150000001408 amides Chemical class 0.000 claims abstract description 38
- 150000001412 amines Chemical class 0.000 claims abstract description 36
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 33
- 239000002904 solvent Substances 0.000 claims description 15
- 150000003335 secondary amines Chemical class 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 230000009257 reactivity Effects 0.000 claims description 7
- 239000004215 Carbon black (E152) Substances 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 229930195733 hydrocarbon Natural products 0.000 claims description 5
- 150000002430 hydrocarbons Chemical class 0.000 claims description 5
- 150000004982 aromatic amines Chemical class 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 150000003973 alkyl amines Chemical class 0.000 claims description 3
- 230000018044 dehydration Effects 0.000 claims description 3
- 238000006297 dehydration reaction Methods 0.000 claims description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 3
- 150000003974 aralkylamines Chemical class 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000005265 dialkylamine group Chemical group 0.000 claims description 2
- 125000005266 diarylamine group Chemical group 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 description 49
- 150000001875 compounds Chemical class 0.000 description 46
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 37
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 23
- 239000002253 acid Substances 0.000 description 18
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 17
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 16
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 16
- 229960002510 mandelic acid Drugs 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 230000000694 effects Effects 0.000 description 14
- 239000000758 substrate Substances 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- 229960004365 benzoic acid Drugs 0.000 description 8
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 7
- 239000005711 Benzoic acid Substances 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- WGQKYBSKWIADBV-UHFFFAOYSA-N aminomethyl benzene Natural products NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 7
- 235000010233 benzoic acid Nutrition 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- UYVXZUTYZGILQG-UHFFFAOYSA-N methoxyboronic acid Chemical compound COB(O)O UYVXZUTYZGILQG-UHFFFAOYSA-N 0.000 description 7
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- 239000004327 boric acid Substances 0.000 description 6
- 238000006555 catalytic reaction Methods 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 6
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 150000003141 primary amines Chemical class 0.000 description 5
- BWLBGMIXKSTLSX-UHFFFAOYSA-N 2-hydroxyisobutyric acid Chemical compound CC(C)(O)C(O)=O BWLBGMIXKSTLSX-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 description 4
- 230000006340 racemization Effects 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 4
- JKRDADVRIYVCCY-UHFFFAOYSA-N 2-hydroxyoctanoic acid Chemical compound CCCCCCC(O)C(O)=O JKRDADVRIYVCCY-UHFFFAOYSA-N 0.000 description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 238000005576 amination reaction Methods 0.000 description 3
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- QPKFVRWIISEVCW-UHFFFAOYSA-N 1-butane boronic acid Chemical compound CCCCB(O)O QPKFVRWIISEVCW-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 2
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 2
- IDWRJRPUIXRFRX-UHFFFAOYSA-N 3,5-dimethylpiperidine Chemical compound CC1CNCC(C)C1 IDWRJRPUIXRFRX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- QIPHSSYCQCBJAX-UHFFFAOYSA-N propan-2-ylboronic acid Chemical compound CC(C)B(O)O QIPHSSYCQCBJAX-UHFFFAOYSA-N 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 229960004889 salicylic acid Drugs 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- UHDDEIOYXFXNNJ-UHFFFAOYSA-N (3,4,5-trifluorophenyl)boronic acid Chemical compound OB(O)C1=CC(F)=C(F)C(F)=C1 UHDDEIOYXFXNNJ-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- YAXWOADCWUUUNX-UHFFFAOYSA-N 1,2,2,3-tetramethylpiperidine Chemical compound CC1CCCN(C)C1(C)C YAXWOADCWUUUNX-UHFFFAOYSA-N 0.000 description 1
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 1
- QARRCHMPOZWNED-UHFFFAOYSA-N 2,2,6-trimethylpiperidine Chemical compound CC1CCCC(C)(C)N1 QARRCHMPOZWNED-UHFFFAOYSA-N 0.000 description 1
- XDIAMRVROCPPBK-UHFFFAOYSA-N 2,2-dimethylpropan-1-amine Chemical group CC(C)(C)CN XDIAMRVROCPPBK-UHFFFAOYSA-N 0.000 description 1
- GELMWIVBBPAMIO-UHFFFAOYSA-N 2-methylbutan-2-amine Chemical group CCC(C)(C)N GELMWIVBBPAMIO-UHFFFAOYSA-N 0.000 description 1
- SPVVMXMTSODFPU-UHFFFAOYSA-N 3-methyl-n-(3-methylbutyl)butan-1-amine Chemical compound CC(C)CCNCCC(C)C SPVVMXMTSODFPU-UHFFFAOYSA-N 0.000 description 1
- 235000011437 Amygdalus communis Nutrition 0.000 description 1
- HUXCJNFTAXPKPG-UHFFFAOYSA-N C(C)(C)N(C(C)C)CCCC1=C(C=CC=C1)OB(O)O Chemical class C(C)(C)N(C(C)C)CCCC1=C(C=CC=C1)OB(O)O HUXCJNFTAXPKPG-UHFFFAOYSA-N 0.000 description 1
- KNDGHJNYFYPOCJ-UHFFFAOYSA-N CC1(N(C(CCC1)(C)C)CC1=C(C=CC=C1)OB(O)O)C Chemical compound CC1(N(C(CCC1)(C)C)CC1=C(C=CC=C1)OB(O)O)C KNDGHJNYFYPOCJ-UHFFFAOYSA-N 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical group NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 241000220304 Prunus dulcis Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 235000020224 almond Nutrition 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 125000005619 boric acid group Chemical group 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- DDTBPAQBQHZRDW-UHFFFAOYSA-N cyclododecane Chemical compound C1CCCCCCCCCCC1 DDTBPAQBQHZRDW-UHFFFAOYSA-N 0.000 description 1
- LJAVDFCIOLVDIY-UHFFFAOYSA-N cyclododecylcyclododecane Chemical group C1CCCCCCCCCCC1C1CCCCCCCCCCC1 LJAVDFCIOLVDIY-UHFFFAOYSA-N 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical class C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 1
- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical compound OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- BMFVGAAISNGQNM-UHFFFAOYSA-N isopentylamine Chemical compound CC(C)CCN BMFVGAAISNGQNM-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- OBYVIBDTOCAXSN-UHFFFAOYSA-N n-butan-2-ylbutan-2-amine Chemical compound CCC(C)NC(C)CC OBYVIBDTOCAXSN-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- ZZJKGVPMLGIOTF-UHFFFAOYSA-N n-pentan-2-ylpentan-2-amine Chemical compound CCCC(C)NC(C)CCC ZZJKGVPMLGIOTF-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000005002 naphthylamines Chemical class 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
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- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Abstract
本发明涉及一种羟基羧酸酰胺化合物的制法,其中,以R3B(OH)2表示的烷基硼酸(式中R3为伯烷基)或式(1)的芳基硼酸化合物作为催化剂,对α‑或β‑羟基羧酸化合物与胺化合物进行酰胺缩合,从而得到羟基羧酸酰胺化合物。(式(1)中,‑(CH2)nNR1R2键合于邻位或对位,n为1或2,R1为叔烷基,R2为仲烷基或叔烷基,‑NR1R2可以形成环。)
Description
技术领域
本发明涉及羟基羧酸酰胺化合物的制法和新型的芳基硼酸化合物。
背景技术
一直以来,利用芳基硼酸催化剂的酰胺缩合是众所周知的。例如,在专利文献1的39页记载了作为芳基硼酸催化剂的2-(二异丙基氨基甲基)苯基硼酸和2-(2,2,6,6-四甲基哌啶基甲基)苯基硼酸等,在42~43页记载了下述反应例:将2-(二异丙基氨基甲基)苯基硼酸作为催化剂,进行羧酸化合物与胺化合物的酰胺缩合,从而得到对应的羧酸酰胺化合物。
此外,在非专利文献1中记载了下述反应例:将具有吸电子性取代基的芳基硼酸化合物3,4,5-三氟苯基硼酸作为催化剂,进行羧酸化合物与胺化合物的酰胺缩合,从而得到对应的羧酸酰胺化合物。例如,在光学活性的α-羟基羧酸化合物与苄胺的酰胺缩合中,在甲苯回流下以高收率得到羧酸酰胺化合物而基本上不发生外消旋化。
现有技术文献
专利文献
专利文献1:国际公开第2004/113351号小册子
非专利文献
非专利文献1:J.Org.Chem.,1996,vol.61,p4196-4197
发明内容
发明要解决的课题
但是,专利文献1中并未对α-羟基羧酸化合物与胺化合物的酰胺缩合进行研究,关于在这样的酰胺缩合中何种结构的催化剂有用也没有记载和暗示。另一方面,非专利文献1中虽然记载了α-羟基羧酸化合物与胺化合物的酰胺缩合的示例,但仅仅使用了3,4,5-三氟苯基硼酸作为催化剂,因此,在这样的酰胺缩合中,具有优于3,4,5-三氟苯基硼酸的催化活性和通用性的催化剂的结构自不必说,关于这种催化剂是否存在这一点也没有记载和暗示。
本发明是为了解决这样的课题而进行的,其主要目的在于提供一种在α-或β-羟基羧酸化合物与胺化合物的酰胺缩合中与以往相比不仅羧酸酰胺化合物的收率高、而且反应底物的通用性也高的物质。
用于解决课题的方案
为了达到上述目的,本发明人在α-或β-羟基羧酸化合物与胺化合物的酰胺缩合中尝试了各种结构的烷基硼酸或芳基硼酸化合物作为催化剂,结果发现,在使用具有无支链烷基的烷基硼酸或邻位具有特定的氨基烷基的芳基硼酸化合物时,收率高、反应底物的通用性也高,由此完成了本发明。
即,本发明的羧酸酰胺化合物的制法为,将R3B(OH)2表示的烷基硼酸(式中R3为伯烷基)或式(1)的芳基硼酸化合物(式(1)中,-(CH2)nNR1R2键合于邻位或对位,n为1或2,R1为叔烷基,R2为仲烷基或叔烷基,-NR1R2可以形成环)作为催化剂,对α-或β-羟基羧酸化合物与胺化合物进行酰胺缩合,从而得到羟基羧酸酰胺化合物。
此外,本发明的新型的芳基硼酸化合物由式(2)表示。
(式(2)中,n为1或2,R1为叔烷基,R2为仲烷基或叔烷基,-NR1R2可以形成环。)
发明的效果
根据本发明的羧酸酰胺化合物的制法,与以往相比不仅羧酸酰胺化合物的收率高,而且反应底物的通用性也高。得到这样的效果的理由可以考虑如下(参照下式)。下式中,作为芳基硼酸化合物以2-(2,2,6,6-四甲基哌啶基甲基)苯基硼酸为例、作为羟基羧酸化合物以扁桃酸为例、作为胺化合物以苯基乙胺为例进行说明。首先,羟基羧酸化合物与芳基硼酸化合物反应,容易地形成式中所示的中间体。接下来,芳基硼酸化合物的大体积的氨基将胺化合物活化,促进胺化合物对于该中间体的亲核攻击,生成羟基羧酸酰胺化合物和芳基硼酸化合物。这样,由于中间体容易生成以及芳基硼酸化合物促进胺化合物的亲核攻击,因而认为反应性提高、羧酸酰胺化合物的收率提高,反应底物的通用性也提高。
具体实施方式
本发明的羧酸酰胺化合物的制法中,将R3B(OH)2表示的烷基硼酸(式中R3为伯烷基)或上述式(1)的芳基硼酸化合物作为催化剂,对α-或β-羟基羧酸化合物与胺化合物进行酰胺缩合,从而得到羟基羧酸酰胺化合物。
R3为伯烷基,优选碳原子数为1~20的伯烷基,可以举出例如甲基、乙基、正丙基、正丁基、异丁基、正戊基等。其中,特别优选甲基、正丁基。式(1)中,n为1或2即可,若考虑芳基硼酸化合物的获得容易性则n优选为1。R1为叔烷基,R2为仲烷基或叔烷基,-NR1R2可以形成环。作为仲烷基,优选碳原子数为3~20的仲烷基,可以举出例如异丙基、仲丁基、仲戊基、仲己基、环丙基、环丁基、环戊基、环己基等。作为叔烷基,优选碳原子数为4~20的叔烷基,可以举出例如叔丁基、叔戊基、叔己基等。-NR1R2形成环的情况下,优选在含氮杂环的氮的两侧的碳上具有1个或2个烷基,可以举出例如2,2,6,6-四甲基哌啶基、2,2,6-三甲基哌啶基、2,2,5,5-四甲基吡咯烷基、2,2,5-三甲基吡咯烷基等。
本发明的羧酸酰胺化合物的制法中,作为反应底物的α-或β-羟基羧酸化合物只要是α位或β位具有羟基的羧酸化合物则无特别限定,例如α-羟基羧酸可以表示为RCH(OH)COOH(R为烷基或芳基)。该情况下,烷基优选碳原子数为1~20的烷基,可以举出例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、叔戊基、新戊基、己基、异己基、仲己基、叔己基、新己基、庚基、辛基、双(2-乙基己基)、癸基、十六烷基、环丙基、环丁基、环戊基、环己基等。芳基可以举出例如苯基、甲苯基、二甲苯基、萘基等。这样的烷基和芳基可以适宜具有取代基。作为取代基,可以举出卤素、氰基、硝基等。此外,也可以使用羟基所键合的碳为不对称碳原子的光学活性的α-羟基羧酸。该情况下,利用本发明的制法得到的羧酸酰胺化合物维持了光学活性。此外,作为β-羟基羧酸的具体例,可以举出水杨酸等。
在本发明的羧酸酰胺化合物的制法中,作为另一个反应底物的胺化合物为伯胺或仲胺。作为伯胺,可以举出甲胺、乙胺、正丙胺、异丙胺、正丁胺、异丁胺、仲丁胺、叔丁胺、正戊胺、异戊胺、仲戊胺、叔戊胺、新戊胺等烷基胺;环丙胺、环丁胺、环戊胺、环己胺、环十二烷胺等环烷基胺;苄胺、苯乙胺、二苯甲胺等芳烷基胺;苯胺、萘胺等芳基胺等。作为仲胺,可以举出二甲胺、二乙胺、二正丙胺、二异丙胺、二正丁胺、二异丁胺、二仲丁胺、二叔丁胺、二正戊胺、二异戊胺、二仲戊胺、二叔戊胺、二新戊胺、甲基乙胺、异丙基乙胺等二烷基胺;二环丙胺、二环丁胺、二环戊胺、二环己胺、二环十二烷胺等二环烷基胺;二苄胺、二苯乙胺等二芳烷基胺;二苯胺、二萘胺等二芳基胺;哌啶、吡咯烷、吗啉等环状胺等。这样的伯胺或仲胺可以适宜具有取代基。例如,作为烷基所具有的取代基,可以举出卤素、氰基、硝基等;作为环烷基或芳烷基、芳基、环状胺所具有的取代基,可以举出卤素、烷基、氰基、硝基等。
本发明的羧酸酰胺化合物的制法在使用反应性低的物质作为羟基羧酸化合物和胺化合物时有用。作为反应性低的羟基羧酸化合物,例如可以举出上述RCH(OH)COOH的R为长链烷基(例如正己基)的化合物等。此外,作为反应性低的胺化合物,例如除了仲胺(例如二正丁胺或哌啶)外,伯胺还可以举出环烷基胺(例如环十二烷胺)或芳基胺(例如苯胺)等。在使用这样的反应性低的底物的情况下,即便利用非专利文献1中记载的3,4,5-三氟苯基硼酸作为催化剂,酰胺缩合也几乎不进行,或者即便进行也仅仅以低收率得到羧酸酰胺化合物。与此相对,若使用式(1)的芳基硼酸化合物作为催化剂,则酰胺缩合容易地进行,能够以高收率得到羧酸酰胺化合物。
本发明的羧酸酰胺化合物的制法中,优选在弱酸性条件(pH4~5)下进行酰胺缩合。这是因为,式(1)的芳基硼酸化合物在中性~碱性条件下容易分解,酰胺缩合有可能不会充分进行,但在弱酸性条件下不存在这种可能性(或者较小)。该情况下,优选添加与胺化合物相比为过量的羟基羧酸化合物,或者使反应活性比羟基羧酸化合物低的其它羧酸化合物(例如苯甲酸等芳香族羧酸)共存。前者在羟基羧酸化合物的成本比较低的情况下优选采用;后者在羟基羧酸化合物比较昂贵而其它羧酸化合物比该羟基羧酸化合物廉价的情况下优选采用。
本发明的羧酸酰胺化合物的制法中,烷基硼酸或芳基硼酸化合物的用量相对于胺化合物1mol优选0.1mol%~50mol%、更优选1mol%~20mol%。
本发明的羧酸酰胺化合物的制法中,反应溶剂只要是不影响酰胺缩合的溶剂则没有特别限定,优选例如烃系溶剂、醇系溶剂、腈系溶剂、硝基系溶剂。作为烃系溶剂,可以举出己烷、庚烷、辛烷、壬烷、甲苯、二甲苯等。需要说明的是,也可以向烃系溶剂中添加少量的水。有时通过添加水,反应的再现性会提高。作为醇系溶剂,可以举出异丙醇等。作为腈系溶剂,可以举出丁腈、丙腈等。作为硝基系溶剂,可以举出硝基甲烷、硝基乙烷等。此外,也可以使用它们的混合溶剂。在使用极性高的羟基羧酸和胺的情况下,若利用烃系溶剂则溶解度低,因而反应难以进行,所以优选利用异丙醇之类的醇系溶剂。
本发明的羧酸酰胺化合物的制法中,反应温度可考虑反应速度等适宜设定即可,例如,优选在20℃~200℃的范围进行设定,更优选在60℃~160℃的范围进行设定。此外,酰胺缩合中与羧酸酰胺化合物一同会生成水,为了提高羧酸酰胺化合物的收率,优选有效地进行脱水。例如,优选使反应温度为溶剂的回流温度(即沸点),一边共沸脱水一边进行回流。
本发明的羧酸酰胺化合物的制法中,反应时间根据反应底物、反应温度等适宜设定即可,通常为几分钟~几十小时。需要说明的是,酰胺缩合可以进行至反应底物完全被消耗为止,但随着反应进行、反应底物的消失速度变得极慢的情况下,有时也优选即便反应底物未完全被消耗、也终止反应并取出羧酸酰胺化合物的做法。
本发明的羧酸酰胺化合物的制法中,为了分离作为目标的羧酸酰胺化合物,只要适用通常已知的分离手法即可。例如,在将反应混合物中的反应溶剂减压浓缩后,用柱色谱或重结晶等进行精制,从而能够分离作为目标的羧酸酰胺化合物。
实施例
[参考例]
下面说明作为催化剂使用的2-(2,2,6,6-四甲基哌啶基甲基)苯基硼酸(下文中称为催化剂C)的合成步骤。该化合物为已知化合物。
首先,向烧瓶中加入2-溴苄基溴(10mmol)、碳酸钾(22mmol)、碘化钾(11mmol)、3-戊酮(20mL)和2,2,6,6-四甲基哌啶(22mmol),加热回流2天。自然冷却至室温后,通过过滤去除不溶物。将滤液用水清洗2次,用氯仿提取水层。将有机层全部合在一起并用硫酸钠进行干燥,之后减压浓缩。用柱色谱法(NH硅胶、己烷)对所得到的粗产物进行精制,以收率92%得到作为目标的胺化合物、即1-溴-2-(2,2,6,6-四甲基哌啶基甲基)苯。
接下来,向所得到的胺化合物(10mmol)的THF(8.5mL)溶液中加入TMEDA(20mmol),冷却至-78℃。向该溶液中缓慢地滴加BuLi的1.5M己烷溶液(30mmol)。将该溶液于-78℃搅拌1.5小时后,加入B(OMe)3(60mmol),升温至室温并搅拌8小时。向该反应混合物中加入水,进一步搅拌15分钟后,用水清洗。用氯仿提取水层后,将有机层全部合在一起并用硫酸钠干燥,并减压浓缩,从而得到作为目标的催化剂C。
[实验例1~12]
使用表1所示的各种催化剂,进行扁桃酸与2-苯基乙胺的酰胺缩合,从而得到对应的羧酸酰胺化合物。下面说明其合成步骤。向20mL烧瓶中加入2-苯基乙胺(2.5mmol)、扁桃酸(2.5mmol或3.0mmol)、催化剂(参见表1、0.25mmol)和甲苯(10mL),安装填充有干燥的分子筛3A(约3g)的柱(小型索氏提取器)。将该溶液脱水加热回流8小时(油浴的温度:约130℃)后,自然冷却至室温。将甲苯减压蒸馏除去,用柱色谱法(硅胶,己烷-乙酸乙酯3:1)对所得到的粗产物进行精制,得到作为目标的羧酸酰胺化合物。其结果示于表1。需要说明的是,实验例5、6相当于本发明的实施例,其它实验例相当于比较例。
[表1]
由表1可知,与使用了催化剂A、B、D、E、F的实验例1~4、7~12相比,使用了催化剂C的实验例5、6的反应活性高,以高收率得到了羧酸酰胺化合物。具体地说,在苯基硼酸的单个或两个邻位具有二异丙基氨基甲基的催化剂A、B和作为硼酸的催化剂F的情况下,与催化剂C相比反应促进效果小。此外,在苯基硼酸的两个邻位具有2,2,6,6-四甲基哌啶基甲基的催化剂D和在苯基硼酸的3,4,5位具有氟原子的催化剂E的情况下,与催化剂C相比反应促进效果略小。与此相对,在苯基硼酸的单个邻位具有2,2,6,6-四甲基哌啶基甲基的催化剂C可以看作是在N上带有2个叔烷基的化合物,但与其它催化剂相比反应促进效果大。
此外,在使用了催化剂C的例中,在使用了与2-苯基乙胺等摩尔的扁桃酸的实验例5中,催化剂C的分解发生了41%,但在以2-苯基乙胺的1.2倍摩尔使用了扁桃酸的实验例6中,反应液为弱酸性,能够将催化剂C的分解大致抑制为零。另外,在使用了催化剂D的例中,在使用了与2-苯基乙胺等摩尔的扁桃酸的实验例7中,催化剂D的分解也发生了54%,但在以2-苯基乙胺的1.2倍摩尔使用了扁桃酸的实验例8中,虽然反应液为弱酸性,但只能将催化剂D的分解抑制为16%。需要说明的是,催化剂C、D的分解物是-B(OH)2变为了-H的物质。
[实验例13~48]
使用表2和表3所示的各种催化剂,进行各种α-羟基羧酸化合物与各种胺化合物的酰胺缩合,从而得到对应的羧酸酰胺化合物。合成步骤依照实验例1~12。但是,实验例15中,添加苯甲酸(1.0当量)而在弱酸性条件下实施反应;实验例47中,添加苯甲酸(0.10当量),在二甲苯(沸点144℃)中在弱酸性条件下实施反应。其结果示于表2和表3。需要说明的是,实验例14、15、19、22、26、32、37、40、43、46、47相当于本发明的实施例,其它实验例相当于比较例。
[表2]
[表3]
由表2和表3可知,在所有的酰胺缩合中,催化剂C均显示出优异的反应活性。由此可知,对于使用了催化剂C的α-羟基羧酸化合物与胺化合物的酰胺缩合,与其它催化剂相比不仅羧酸酰胺化合物的收率高,而且反应底物的通用性也高。
具体地说,实验例13、14、16、17中,作为α-羟基羧酸化合物使用了扁桃酸,作为胺化合物使用了反应性低的作为仲胺的3,5-二甲基哌啶,结果在催化剂A、D的情况下收率不足10%,在催化剂E的情况下收率为零,与此相对在催化剂C的情况下收率为46%。特别是,催化剂D、E在表1所示的酰胺缩合(作为胺化合物使用了作为伯胺的2-苯基乙胺)中收率比较高,与此相对,此处则止于低收率,因此很难说反应底物的通用性高。此外,实验例15中,为了抑制催化剂C的分解,添加了比扁桃酸廉价的苯甲酸而进行反应,结果收率为99%,看到了显著的效果。由此可知:催化剂C即使在使用仲胺作为胺化合物的情况下也能够容易地促进酰胺缩合。
实验例18~20中,作为α-羟基羧酸化合物使用了扁桃酸,作为胺化合物使用了具有大体积的烷基的环十二烷胺,结果在催化剂A、E的情况下收率停留于30%左右,与此相对,在催化剂C的情况下收率为74%,与其它催化剂相比可看到更高的反应促进效果。
实验例21~23中,作为α-羟基羧酸化合物使用了扁桃酸,作为胺化合物使用了二苯甲胺,结果在催化剂A、E的情况下收率为80%左右,为比较高的值,与此相对,在催化剂C的情况下收率为99%,看到了更高的反应促进效果。
实验例24~29中,作为α-羟基羧酸化合物使用了2-羟基辛酸,作为胺化合物使用了2-苯基乙胺,结果收率按照催化剂F、催化剂A、催化剂B、催化剂E、催化剂D、催化剂C的顺序升高。该酰胺缩合中,在催化剂C的情况下收率为95%,与其它催化剂相比也看到了更高的反应促进效果。
实验例30~35中,作为α-羟基羧酸化合物使用了2-羟基辛酸,作为胺化合物使用了反应性低的苯胺,结果在催化剂E、F的情况下反应基本上未进行,与此相对,在其它催化剂的情况下反应进行,收率按照催化剂B、催化剂D、催化剂A、催化剂C的顺序升高。该酰胺缩合中,在催化剂C的情况下收率为51%,与其它催化剂相比也看到了高的反应促进效果。
实验例36~38中,作为α-羟基羧酸化合物使用了2-羟基异丁酸,作为胺化合物使用了2-苯基乙胺,结果在催化剂A、C、E的情况下收率均为80%以上,催化剂C与催化剂E匹敌,收率为99%,看到了高的反应促进效果。
实验例39~41中,作为α-羟基羧酸化合物使用了光学活性的2-羟基-3-苯基丙酸,作为胺化合物使用了2-苯基乙胺,结果在催化剂A、E的情况下收率均为60%~70%,与此相对,催化剂C定量地得到羧酸酰胺化合物,而且还能够维持光学纯度。
实验例42~44中,作为α-羟基羧酸化合物使用了2-羟基-3-苯基丙酸,作为胺化合物使用了作为仲胺的3,5-二甲基哌啶,结果催化剂E的收率为22%,催化剂A的收率为50%,与此相对催化剂C定量地得到了羧酸酰胺化合物。
实验例45、46、48中,作为α-羟基羧酸化合物使用了2-羟基-3-苯基丙酸,作为胺化合物使用了作为仲胺的二正丁胺,结果在催化剂E的情况下反应基本上未进行,催化剂A的收率也仅为5%,与此相对,催化剂C的收率为23%。在使用催化剂C并少量添加了苯甲酸的实验例47中,收率提高至77%。
[实验例49]
实验例14中,使用催化剂C,作为α-羟基羧酸化合物使用了扁桃酸,作为胺化合物使用了作为仲胺的3,5-二甲基哌啶,结果反应定量地进行。与此相对,实验例49中,如下式所示,代替实验例14的扁桃酸而使用2-苯基丙酸并在相同的反应条件下实施酰胺缩合。结果,对应的羧酸酰胺化合物仅得到了18%。由此可知,催化剂C并不是在任何的羧酸化合物与胺化合物的酰胺缩合中均可进行促进,而是特异性地促进α-羟基羧酸化合物与胺化合物的酰胺缩合。需要说明的是,实验例49相当于本发明的比较例。
由以上的实验例的结果可知,使用了催化剂C的α-羟基羧酸化合物与胺化合物的酰胺缩合与其它催化剂相比不仅羧酸酰胺化合物的收率高,而且反应底物的通用性也高。此外,催化剂C并不是在任何的羧酸化合物与胺化合物的酰胺缩合中均可进行促进,而是特异性地促进α-羟基羧酸化合物与胺化合物的酰胺缩合。另外可知,催化剂C在弱酸性条件(例如过量使用α-羟基羧酸化合物的情况或加入与α-羟基羧酸化合物不同的苯甲酸等反应性低的酸的情况)下能有效地抑制自身的分解。
[实验例50~54]
在扁桃酸与2-苯乙胺的酰胺缩合中,如表4所示进行催化剂量的研究。将反应时间固定为8小时,使催化剂量从10mol%阶段性地减少至1mol%,结果催化剂量越少则收率越低。但是,即便是1mol%,通过将反应时间延长为14小时,反应也可良好地进行,以98%得到了羧酸酰胺化合物。需要说明的是,实验例50~54均相当于实施例。
[表4]
[实验例55~57]
合成四甲基哌啶基甲基键合于间位、对位的催化剂,如表5所示研究扁桃酸与3,5-二甲基哌啶的酰胺缩合中的催化活性。其结果,取代基键合于间位的催化剂即使添加苯甲酸(10mol%)也发生分解,无法得到作为目标的羧酸酰胺化合物,与此相对,取代基键合于邻位的催化剂或键合于对位的催化剂未发生分解,反应良好地进行。需要说明的是,实验例55、57相当于实施例,实验例56相当于比较例。
[表5]
对于取代基键合于间位、对位的催化剂(参照表5的实施例56、57),根据上述催化剂C的合成步骤代替2-溴苄基溴而利用3-溴苄基溴或4-溴苄基溴进行合成。此外,取代基键合于对位的催化剂在其原状态下1H NMR光谱宽且为形状复杂,无法确认结构。因此,对于取代基键合于对位的催化剂,通过在甲苯中于室温与频哪醇反应30分钟,从而将硼酸部位转换为频哪醇酯,然后确认其结构。该频哪醇酯的1H NMR数据如下所示。1H NMR(CDCl3,400MHz)δ0.99(s,24H),1.44-1.64(m,6H),3.73(s,2H),6.97(d,J=7.8 Hz,2H),7.30(d,J=7.8 Hz,2H).
[实验例58]
研究酒石酸与苄胺的酰胺缩合(参照下式)。酒石酸的极性高,因此使用异丙醇(沸点82℃)作为反应溶剂(油浴的温度100℃),结果溶解于溶剂中,反应良好地进行。需要说明的是,实验例58相当于实施例。
[实验例59~61]
如表6所示,在扁桃酸与3,5-二甲基哌啶(1当量)的酰胺缩合中,使用各种烷基硼酸作为催化剂并对它们的催化活性进行了研究。下面,以实验例59为例对其酰胺缩合的步骤进行说明。在20mL烧瓶中量取扁桃酸(1.25mmol)、甲基硼酸(0.125mmol)和苯甲酸(0.125mmol),溶解于甲苯(10mL)中。向该溶液中加入3,5-二甲基哌啶(1.25mmol)和水(50μL),于室温搅拌10分钟。对该烧瓶安装填充有干燥的分子筛3A(约2g)的柱(小型索氏提取器)和冷却管。将该溶液脱水加热回流14小时(油浴的温度:约130℃)后,冷却至室温。将甲苯减压蒸馏除去,用柱色谱法(硅胶,己烷-乙酸乙酯3:1)对所得到的粗产物进行精制,得到作为目标的酰胺化合物297mg(收率96%)。其结果示于表6。此外,实验例60、61分别使用正丁基硼酸、异丙基硼酸作为催化剂,依照实验例59进行反应。其结果也示于表6。
由研究的结果可知,甲基硼酸和正丁基硼酸在本反应中显示出优异的催化活性。另一方面,在使用异丙基硼酸的情况下收率低。此外,在甲基硼酸催化剂的反应中,添加苯甲酸(10mol%)来实施反应,结果反应性提高。虽然表6中未示出,但在添加苯甲酸50mol%的情况下,即使将甲基硼酸的量减至1mol%,反应也良好地进行。需要说明的是,实验例59、60相当于实施例。
[表6]
[实验例62~82]
使用甲基硼酸催化剂对各种α-羟基羧酸与胺实施酰胺缩合。合成步骤依照实验例59进行。其结果示于表7和表8。在(S)-3-苯基乳酸的酰胺键处,完全未发生外消旋化,以高收率得到了对应的酰胺(实验例62~68)。在(R)-扁桃酸的酰胺缩合中,反应良好地进行,但是略微发生了外消旋化(实验例69~75)。通过使用二氯乙烷(沸点83℃)作为反应溶剂,能够以某种程度抑制该外消旋化。需要说明的是,在与反应性高的胺的缩合中,即使将催化剂量减至1mol%也可良好地进行反应。在2-羟基辛酸的酰胺缩合中,以高收率得到了对应的酰胺(实验例76~79)。在α位为季碳的2-羟基异丁酸与伯胺的酰胺缩合中,也以高收率得到了对应的酰胺(实验例80~82)。需要说明的是,实验例62~82相当于实施例。
[表7]
[表8]
[实验例83,84]
使用甲基硼酸催化剂对作为β-羟基羧酸的水杨酸实施酰胺缩合。合成步骤依照实验例59进行。其结果示于表9。通过使用二甲苯(沸点144℃)作为反应溶剂,反应良好地进行(实验例83)。与此相对,在未使用甲基硼酸催化剂的情况下,反应性低(实验例84)。需要说明的是,实验例83相当于实施例。
[表9]
本申请以2012年2月17日提交的日本国专利申请第2012-32400号作为优先权主张的基础,通过引用的方式使其内容全部包含在本说明书中。
工业实用性
本发明主要可用于药品化学产业,例如可在制造医药品、农药、化妆品的中间体等时进行利用。
Claims (7)
1.一种羟基羧酸酰胺化合物的制法,其中,将式(1)的芳基硼酸化合物作为催化剂,对α-羟基羧酸化合物与胺化合物进行酰胺缩合,从而得到羟基羧酸酰胺化合物,
式(1)中,-(CH2)nNR1R2键合于邻位或对位,n为1,-NR1R2为2,2,6,6-四甲基哌啶基,
所述α-羟基羧酸化合物是RCH(OH)COOH,其中R为烷基或芳基,
所述胺化合物为烷基胺、环烷基胺、芳烷基胺、芳基胺、二烷基胺、二环烷基胺、二芳烷基胺、二芳基胺或环状胺。
2.如权利要求1所述的羟基羧酸酰胺化合物的制法,其中,所述式(1)中,-(CH2)nNR1R2键合于邻位,-NR1R2为2,2,6,6-四甲基哌啶基。
3.如权利要求1或2所述的羟基羧酸酰胺化合物的制法,其中,所述胺化合物为仲胺或芳香族胺。
4.如权利要求1或2所述的羟基羧酸酰胺化合物的制法,其中,在弱酸性条件下进行所述酰胺缩合。
5.如权利要求1或2所述的羟基羧酸酰胺化合物的制法,其中,添加与所述胺化合物相比为过量的所述羟基羧酸化合物,或者使反应活性比所述羟基羧酸化合物低的羧酸化合物共存。
6.如权利要求1或2所述的羟基羧酸酰胺化合物的制法,其中,所述酰胺缩合通过在反应溶剂中共沸脱水而进行。
7.如权利要求1或2所述的羟基羧酸酰胺化合物的制法,其中,所述酰胺缩合通过在添加有水的烃系溶剂中共沸脱水而进行。
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EP1317412A1 (en) | 2000-08-18 | 2003-06-11 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
JP3589450B2 (ja) | 2001-03-13 | 2004-11-17 | 独立行政法人 科学技術振興機構 | アミド脱水縮合触媒として有用なパーフルオロアルキルフェニルホウ酸 |
US6946542B2 (en) | 2002-04-01 | 2005-09-20 | University Of Southern California | Amino amides, peptides and peptidomimetics |
CN101861325A (zh) | 2007-09-05 | 2010-10-13 | 阿尔伯塔大学理事会 | 在使用经过邻位取代的芳基硼酸进行的化学反应中对羧酸进行有机催化活化的方法 |
US8735582B2 (en) | 2009-03-11 | 2014-05-27 | National University Corporation Nagoya University | Method for producing carboxylic anhydride and arylboronic acid compound |
US9284270B2 (en) * | 2011-02-14 | 2016-03-15 | The Governers Of The University Of Alberta | Boronic acid catalysts and methods of use thereof for activation and transformation of carboxylic acids |
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JP5881189B2 (ja) | 2016-03-09 |
CN104114530A (zh) | 2014-10-22 |
WO2013122130A1 (ja) | 2013-08-22 |
EP2816026A4 (en) | 2015-03-11 |
US20150011766A1 (en) | 2015-01-08 |
IN2014DN06778A (zh) | 2015-05-22 |
JPWO2013122130A1 (ja) | 2015-05-18 |
EP2816026A1 (en) | 2014-12-24 |
US9162972B2 (en) | 2015-10-20 |
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