JP4384840B2 - Method for producing amide - Google Patents
Method for producing amide Download PDFInfo
- Publication number
- JP4384840B2 JP4384840B2 JP2002151176A JP2002151176A JP4384840B2 JP 4384840 B2 JP4384840 B2 JP 4384840B2 JP 2002151176 A JP2002151176 A JP 2002151176A JP 2002151176 A JP2002151176 A JP 2002151176A JP 4384840 B2 JP4384840 B2 JP 4384840B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- substituent
- oxime
- reaction
- amide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000001408 amides Chemical class 0.000 title claims description 39
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 74
- -1 phosphine compound Chemical class 0.000 claims description 52
- 150000002923 oximes Chemical class 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 32
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 31
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 150000003304 ruthenium compounds Chemical class 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 17
- 238000006462 rearrangement reaction Methods 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000012046 mixed solvent Substances 0.000 claims description 10
- 239000012327 Ruthenium complex Substances 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 8
- 239000012530 fluid Substances 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 230000001737 promoting effect Effects 0.000 claims description 2
- 230000008707 rearrangement Effects 0.000 claims 2
- 239000010410 layer Substances 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 125000003545 alkoxy group Chemical group 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- FDNYHBASQZFVBL-UHFFFAOYSA-N 3-(4-fluorophenyl)-1h-pyrazole-5-carboxylic acid Chemical compound N1C(C(=O)O)=CC(C=2C=CC(F)=CC=2)=N1 FDNYHBASQZFVBL-UHFFFAOYSA-N 0.000 description 10
- 125000002947 alkylene group Chemical group 0.000 description 10
- 150000007942 carboxylates Chemical group 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- 125000004437 phosphorous atom Chemical group 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 7
- 239000007795 chemical reaction product Substances 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000003710 aryl alkyl group Chemical group 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 229910001413 alkali metal ion Inorganic materials 0.000 description 5
- 125000000732 arylene group Chemical group 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- DMRVBCXRFYZCPR-UHFFFAOYSA-L cycloocta-1,5-diene;ruthenium(2+);dichloride Chemical compound Cl[Ru]Cl.C1CC=CCCC=C1 DMRVBCXRFYZCPR-UHFFFAOYSA-L 0.000 description 5
- 238000004817 gas chromatography Methods 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 4
- APEJMQOBVMLION-UHFFFAOYSA-N cinnamamide Chemical compound NC(=O)C=CC1=CC=CC=C1 APEJMQOBVMLION-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 229910052707 ruthenium Inorganic materials 0.000 description 4
- VTWKXBJHBHYJBI-VURMDHGXSA-N (nz)-n-benzylidenehydroxylamine Chemical compound O\N=C/C1=CC=CC=C1 VTWKXBJHBHYJBI-VURMDHGXSA-N 0.000 description 3
- VYIBCOSBNVFEIW-UHFFFAOYSA-N 3-phenylpropanamide Chemical compound NC(=O)CCC1=CC=CC=C1 VYIBCOSBNVFEIW-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- YJJICPMBHQLVQL-UHFFFAOYSA-N [2-[bis(hydroxymethyl)phosphanyl]ethyl-(hydroxymethyl)phosphanyl]methanol Chemical compound OCP(CO)CCP(CO)CO YJJICPMBHQLVQL-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- APEJMQOBVMLION-VOTSOKGWSA-N trans-cinnamamide Chemical compound NC(=O)\C=C\C1=CC=CC=C1 APEJMQOBVMLION-VOTSOKGWSA-N 0.000 description 3
- OMKVNJSMQNSORI-UHFFFAOYSA-N 3-bis(3-sulfophenyl)phosphanylbenzenesulfonic acid tetrahydrate Chemical group C1=CC(=CC(=C1)S(=O)(=O)O)P(C2=CC(=CC=C2)S(=O)(=O)O)C3=CC(=CC=C3)S(=O)(=O)O.O.O.O.O OMKVNJSMQNSORI-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000006237 Beckmann rearrangement reaction Methods 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 0 CC(CC(C)P*c1ccc(*C*c2ccc(*)cc2)cc1)P*c1ccc(*)cc1 Chemical compound CC(CC(C)P*c1ccc(*C*c2ccc(*)cc2)cc1)P*c1ccc(*)cc1 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- HBBGRARXTFLTSG-UHFFFAOYSA-N Lithium ion Chemical compound [Li+] HBBGRARXTFLTSG-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N binaphthyl group Chemical group C1(=CC=CC2=CC=CC=C12)C1=CC=CC2=CC=CC=C12 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 description 2
- MQIFHIKMMJGXTL-UHFFFAOYSA-N bis(dihydroxymethyl)phosphanylmethanediol Chemical compound OC(O)P(C(O)O)C(O)O MQIFHIKMMJGXTL-UHFFFAOYSA-N 0.000 description 2
- NCMHKCKGHRPLCM-UHFFFAOYSA-N caesium(1+) Chemical compound [Cs+] NCMHKCKGHRPLCM-UHFFFAOYSA-N 0.000 description 2
- VEZUQRBDRNJBJY-UHFFFAOYSA-N cyclohexanone oxime Chemical compound ON=C1CCCCC1 VEZUQRBDRNJBJY-UHFFFAOYSA-N 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- 150000004693 imidazolium salts Chemical class 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000543 intermediate Substances 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
- 229910001416 lithium ion Inorganic materials 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 2
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 2
- FVZVCSNXTFCBQU-UHFFFAOYSA-N phosphanyl Chemical group [PH2] FVZVCSNXTFCBQU-UHFFFAOYSA-N 0.000 description 2
- 229910001414 potassium ion Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229910001415 sodium ion Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 2
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- FZENGILVLUJGJX-NSCUHMNNSA-N (E)-acetaldehyde oxime Chemical compound C\C=N\O FZENGILVLUJGJX-NSCUHMNNSA-N 0.000 description 1
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 1
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 1
- SYLMLKKURPTCSO-UHFFFAOYSA-N 1-phosphanylethylphosphane Chemical compound CC(P)P SYLMLKKURPTCSO-UHFFFAOYSA-N 0.000 description 1
- PWBRLMKOCGLZAH-UHFFFAOYSA-N 2-(4-ethylphenyl)acetaldehyde Chemical compound CCC1=CC=C(CC=O)C=C1 PWBRLMKOCGLZAH-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- FWFZRPMNAAFGBA-UHFFFAOYSA-N 2-phosphanylethylphosphane Chemical compound PCCP FWFZRPMNAAFGBA-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- QSHYGLAZPRJAEZ-UHFFFAOYSA-N 4-(chloromethyl)-2-(2-methylphenyl)-1,3-thiazole Chemical compound CC1=CC=CC=C1C1=NC(CCl)=CS1 QSHYGLAZPRJAEZ-UHFFFAOYSA-N 0.000 description 1
- 241000486679 Antitype Species 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- PHJHAXJPICUEFV-UHFFFAOYSA-N [1-[bis(hydroxymethyl)phosphanyl]ethyl-(hydroxymethyl)phosphanyl]methanol Chemical compound OCP(CO)C(C)P(CO)CO PHJHAXJPICUEFV-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 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 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 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 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000003935 n-pentoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004957 naphthylene group Chemical group 0.000 description 1
- 229940078487 nickel acetate tetrahydrate Drugs 0.000 description 1
- OINIXPNQKAZCRL-UHFFFAOYSA-L nickel(2+);diacetate;tetrahydrate Chemical compound O.O.O.O.[Ni+2].CC([O-])=O.CC([O-])=O OINIXPNQKAZCRL-UHFFFAOYSA-L 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- SJYNFBVQFBRSIB-UHFFFAOYSA-N norbornadiene Chemical compound C1=CC2C=CC1C2 SJYNFBVQFBRSIB-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- WQIQNKQYEUMPBM-UHFFFAOYSA-N pentamethylcyclopentadiene Chemical compound CC1C(C)=C(C)C(C)=C1C WQIQNKQYEUMPBM-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical class C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 description 1
- VIHDTGHDWPVSMM-UHFFFAOYSA-N ruthenium;triphenylphosphane Chemical compound [Ru].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 VIHDTGHDWPVSMM-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- AKXUUJCMWZFYMV-UHFFFAOYSA-M tetrakis(hydroxymethyl)phosphanium;chloride Chemical compound [Cl-].OC[P+](CO)(CO)CO AKXUUJCMWZFYMV-UHFFFAOYSA-M 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は、医薬品或いはその合成中間体、農薬或いはその合成中間体、等として広く利用されるアミドの製造方法に関する。詳しくは、オキシムの転位反応によるアミドの製造方法に関する。
【０００２】
【従来の技術】
従来、オキシムの転位反応によるアミドの製造方法は公知である。オキシムを、強酸の存在下でアミドへ転位せしめる反応は、ベックマン転位と称され、例えば、シクロヘキサノンオキシムからε−カプロラクタムを製造する際に利用されるなど、工業的に有用な反応である。当該転位反応において硫酸等の強酸は触媒として用いられるが、反応にはオキシムに対して等量以上の強酸が必要である。そして生成したアミドは、強酸との塩を形成するので、反応終了後の反応混合物からアミドを回収するにはアミドを強酸から遊離させる工程が必要であり、このときに環境に負荷のかかる強酸のアルカリ塩が大量に副生する。したがって、この強酸を用いるベックマン転位を利用したアミドの製造法は、工業的に有利な方法とはいい難い。
上記の触媒として強酸を用いる方法の問題点を解決し得る方法として、オキシムからアミドへの転位反応の触媒として酢酸ニッケル四水和物を用いる方法［Ｊｏｕｒｎａｌ ｏｆ Ａｍｅｒｉｃａｎ Ｃｈｅｍｉｃａｌ Ｓｏｃｉｅｔｙ、８３，１９８３（１９６１）］、転位反応の触媒として過レニウム酸と複素環化合物からなる塩を用いる方法［特開平９−３０１９５１号公報］等が知られている。
これらの方法では、目的とするアミドが好収率で得られるが、レニウムなど高価な金属がかなりの量必要であり、これらの金属は使用後通常再使用不可能なために触媒費用が非常に大きくなる。また多量の溶媒を使用するため生産性が低いという問題がある。以上のことから工業的生産においては経済的に不利である。
【０００３】
【発明が解決しようとする課題】
本発明は、オキシムを転位反応せしめてアミドを製造する方法において、上記従来法の問題点を解決した方法、即ち、アミドの工業的生産において環境への負荷が大きい副生物を大量に生じることなく、比較的容器効率の高い経済的で簡便な方法を提供することを課題とする。
【０００４】
【課題を解決するための手段】
本発明者は、上記課題を解決するために鋭意研究を行った。その結果、オキシムを転位反応せしめてアミドを製造する際に、オキシムを、親水性ホスフィン化合物及びルテニウム化合物の存在下、多相系溶媒中で０〜２００℃で撹拌下に混合して反応させると、溶媒の使用量を少なくしても目的のアミドを選択的に製造でき、また反応に強酸を使用しないので大量の副生成物が発生することがないことを見出した。
また多相系溶媒として水及び水と混和しない有機溶媒の混合溶媒を用いると、反応終了後の反応混合物から本発明の転位反応を触媒する親水性ホスフィン化合物及びルテニウム化合物から形成される化合物を含む水層を容易に分離して反応に再使用できることを見出し、本発明を完成するに至った。
【０００５】
即ち本発明は、オキシムを転位反応せしめてアミドを製造するに当たり、多相系溶媒中、親水性ホスフィン化合物及びルテニウム化合物の存在下に反応を行うことを特徴とするアミドの製造方法に関する。
【０００６】
【発明の実施の様態】
本発明を以下に詳しく説明する。
本発明に用いられるオキシムとしては、例えば、一般式（１）：
【０００７】
【化３】
【０００８】
上記一般式（１）中、Ｒ1及びＲ2で表される置換基を有していてもよいアルキル基としては、例えば、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、ペンチル基、ヘキシル基等の炭素数１〜６の直鎖状及び分岐鎖状のアルキル基、並びに当該アルキル基が有する水素原子の１個以上を、水酸基、アルコキシ基（例えば、メトキシ基、エトキシ基、イソプロポキシ基等の炭素数１〜４の直鎖状及び分岐鎖状のアルコキシ基）、後述する置換基を有していてもよいアルケニル基、後述する置換基を有していてもよいシクロアルキル基、後述する置換基を有していてもよいシクロアルケニル基及び後述する置換基を有していてもよいアリール基からなる群より選ばれる基に置換したものが挙げられる。置換基を有していてもよいアルケニル基としては、２−ブテニル基、３−ブテニル基、ビニル基等の炭素数２〜４の直鎖状及び分岐鎖状のアルケニル基並びに当該アルケニル基が有する水素原子の１個以上を、水酸基、前述のアルコキシ基、前述の置換基を有していてもよいアルキル基、後述する置換基を有していてもよいシクロアルキル基、後述する置換基を有していてもよいシクロアルケニル基及び後述する置換基を有していてもよいアリール基からなる群より選ばれる基に置換したものが挙げられる。置換基を有していてもよいシクロアルキル基としては、例えば、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロオクチル基等の炭素数５〜８のシクロアルキル基、並びに当該シクロアルキル基が有する水素原子の１個以上を、水酸基、前述のアルコキシ基、前述の置換基を有していてもよいアルキル基、前述の置換基を有していてもよいアルケニル基、後述する置換基を有していてもよいシクロアルケニル基及び後述する置換基を有していてもよいアリール基からなる群より選ばれる基に置換したものが挙げられる。置換基を有していてもよいシクロアルケニル基としては、前述の炭素数５〜８のシクロアルキル基における隣接する炭素原子間の結合の少なくとも１つが二重結合であるシクロアルケニル基、並びに当該シクロアルケニル基が有する水素原子の１個以上を、水酸基、前述のアルコキシ基、前述の置換基を有していてもよいアルキル基、前述の置換基を有していてもよいアルケニル基、前述の置換基を有していてもよいシクロアルキル基及び後述する置換基を有していてもよいアリール基からなる群より選ばれる基に置換したものが挙げられる。また置換基を有していてもよいアリール基としては、例えば、フェニル基及びナフチル基並びにこれらが有する水素原子の１個以上を、水酸基、前述のアルコキシ基、前述の置換基を有していてもよいアルキル基、前述の置換基を有していてもよいアルケニル基、前述の置換基を有していてもよいシクロアルキル基及び前述の置換基を有していてもよいシクロアルケニル基からなる群より選ばれる基に置換したものが挙げられる。
【０００９】
また、Ｒ1とＲ2が一緒になってそれらが結合する炭素原子と共に環を形成する基としては、例えば、エチレン基、トリメチレン基、テトラメチレン基、ペンタメチレン基及びヘキサメチレン基等の炭素数２〜６のアルキレン基、当該アルキレン基において隣接する炭素原子間に二重結合を１個以上有するもの、当該アルキレン基のメチレン鎖が窒素原子及び／又は酸素原子によって中断されているもの（例えば、Ｒ2とＲ3が一緒になってそれらが結合する炭素原子と共にピペリジン環、モルホリン環等の複素環を形成するもの）、並びにこれらが有する水素原子の１個以上を、水酸基、前述のアルコキシ基、前述の置換基を有していてもよいアルキル基、前述の置換基を有していてもよいアルケニル基、前述の置換基を有していてもよいシクロアルキル基、前述の置換基を有していてもよいシクロアルケニル基、前述の置換基を有していてもよいアリール基等からなる群より選ばれる基に置換したもの等を挙げることができる。
【００１０】
本発明に用いられるオキシムは、上記の例に限定されず、またシン型及びアンチ型の立体構造についても特に制限はない。
【００１１】
本発明によって、反応に用いたオキシムに応じて、当該オキシムがベックマン転位したアミドを製造することができる。例えば、上記一般式（１）で示されるオキシムから一般式（２）：
【００１２】
【化４】
【００１３】
本発明では水溶性のルテニウム錯体を形成し得る親水性ホスフィン化合物及びルテニウム化合物を用いて転位反応を行う。
【００１４】
親水性ホスフィン化合物は、親水性であってルテニウム原子又はそのイオンとともに錯体を形成し得る化合物であり、公知のものを広く適用できる。当該親水性ホスフィン化合物は、分子中にリン原子を１個又は２個以上含むもののいずれであってもよく、好ましくは分子中にリン原子を１個又は２個含むものである。
【００１５】
分子中にリン原子を１個含む親水性ホスフィン化合物としては、例えば、一般式（３）：
【００１６】
【化５】
【００１７】
【化６】
【００１８】
【化７】
【００１９】
【化８】
【００２０】
【化９】
【００２１】
【化１０】
【００２２】
上記一般式（３）においてＲ3で表されるスルホナト基及びカルボキシラート基からなる群より選ばれる置換基を１個以上有するアリール基は、好ましくはスルホナト基及びカルボキシラート基からなる群より選ばれる置換基を１個又は２個有するフェニル基、ナフチル基、ビフェニリル基及びビナフチリル基であり、スルホナト基及びカルボキシラート基からなる群より選ばれる置換基を１個以上有する炭素数１〜６のアルキル基は、好ましくはスルホナト基及びカルボキシラート基からなる群より選ばれる置換基を１個有する炭素数１〜４のアルキル基であり、炭素数１〜６のヒドロキシアルキル基は、好ましくはヒドロキシメチル基、ヒドロキシエチル基、３−ヒドロキシプロピル基、２−ヒドロキシプロピル基、４−ヒドロキシブチル基等の炭素数１〜４のヒドロキシアルキル基である。尚、スホナト基及びカルボキシラート基が有するアルカリ金属イオンとしては、具体的には、リチウムイオン、ナトリウムイオン、カリウムイオン及びセシウムイオンが挙げられる。
【００２３】
一般式（３）のＲ3で表される上記式（４）で表される基において式中Ｒ6表でされる１〜１８のアルキル基は直鎖状又は分岐鎖状であってもよい。また上記式（５）で表される基において式中Ｍ3で表されるアルカリ金属イオンは、具体的には、リチウムイオン、ナトリウムイオン、カリウムイオン及びセシウムイオンである。また式（７）で表される基において式中のＲ7で表される炭素数１〜６のアルキレン基は直鎖状又は分岐鎖状であってもよい。
【００２４】
上記一般式（３）において、式中のＲ7及びＲ8で表される置換基を有していてもよいアルキル基及び置換基を有していてもよいアリール基には、上記Ｒ6で示される基が包含される。その他の置換基を有していてもよいアルキル基としては、例えば、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、ｎ−ペンチル基及びｎ−ヘキシル基等の炭素数１〜６の直鎖状又は分岐鎖状のアルキル基並びに当該アルキル基が有する水素原子の１個以上を、水酸基、ニトロ基、アミノ基及びハロゲン原子からなる群より選ばれる置換基に置換したもの等が挙げられ、置換基を有していてもよいアリール基としては、例えば、フェニル基、ナフチル基、ビフェニル基、フェニルナフチル基及びビナフチル基並びにこれらが前記置換基を有していてもよいアルキル基及びアルコキシ基並びに水酸基からなる群より選ばれる置換基を１個以上有するもの等（具体的には、例えば、置換基を有していてもよいフェニル基としては、フェニル基、トリル基、キシリル基、メシチル基、クミル基、メトキシフェニル基、ヒドロキシフェニル基、ヒドロキシトリル基等）が挙げられ、置換基を有していてもよいアラルキル基としては、例えば、前記置換基を有していてもよいアルキル基に前記置換基を有していてもよいアリール基が置換したもの等〔具体的には、例えば、ベンジル基、フェネチル基、フェニルプロピル基、トリルメチル基、キシリルメチル基、（ヒドロキシフェニル）メチル基等〕が挙げられ、置換基を有していてもよいアルコキシ基としては、例えば、メトキシ基、エトキシ基、ｎ−プロピルオキシ基、イソプロピルオキシ基、ｎ−ブチルオキシ基、イソブチルオキシ基、ｎ−ペンチルオキシ基、ｎ−ヘキシルオキシ基等の炭素数１〜６の直鎖状又は分岐鎖状のアルコキシ基並びに当該アルコキシ基が有する水素原子の１個以上を、水酸基、ニトロ基、アミノ基及びハロゲン原子等からなる群より選ばれる置換基を１個以上有するもの等が挙げられる。
【００２５】
分子中にリン原子を１個含む親水性ホスフィン化合物は上記式（２）で示される化合物に限定されない。
【００２６】
分子中にリン原子を１個含む親水性ホスフィン化合物の具体例としては、例えば、以下の化合物を挙げることができる。
【００２７】
【化１１】
【化１２】
【化１３】
【化１４】
【００３１】
【化１５】
【００３２】
【化１６】
【化１７】
【００３４】
【化１８】
【化１９】
【化２０】
【化２１】
【００３８】
【化２２】
【００３９】
【化２３】
【００４０】
【化２４】
【化２５】
【化２６】
また、分子中にリン原子を２個含む親水性ホスフィン化合物としては、例えば、式（９）：
【００４４】
Ｒ9Ｒ10Ｐ−Ａ−ＰＲ11Ｒ12 （９）
［式中、Ｒ9、Ｒ10、Ｒ11及びＲ12は互いに同じか或いは異なってそれぞれ置換基を有していてもよいアルキル基、アルコキシ基、アリール基又はアラルキル基を表し、Ａは置換基を有していてもよいアルキレン基；置換基を有していてもよいアリーレン基；又は式（１０）：
【００４５】
【化２７】
【００４６】
式（９）中のＲ11、Ｒ12、Ｒ13及びＲ14で表される置換基を有していてもよいアルキル基、アルコキシ基、アリール基及びアラルキル基は、上記式（３）におけるＲ4及びＲ5と同様である。
【００４７】
また式（９）中のＡで表される置換基を有していてもよいアルキレン基としては、例えば、メチレン基；エチレン基、トリメチレン基、テトラメチレン基、ペンタメチレン基及びヘキサメチレン基等のポリメチレン基；これらがアルキル基、アルコキシ基、アリール基及びアラルキル基〔上記式（３）におけるＲ4及びＲ5のアルキル基、アルコキシ基、アラルキル基及びアリール基と同様〕並びにスルホナト基及びカルボキシラート基からなる群から選ばれる少なくとも１個の置換基を有していてもよいアルキレン基等が挙げられる。置換基を有していてもよいアリーレン基としては、フェニレン基、ナフチレン基、ビフェニリレン基及びビナフチリレン基並びにこれらがアルキル基、アルコキシ基、アラルキル基及びアリール基〔上記式（３）におけるＲ4及びＲ5のアルキル基、アルコキシ基、アラルキル基及びアリール基と同様〕並びにスルホナト基及びカルボキシラート基からなる群から選ばれる少なくとも１個の置換基を有していてもよいアリーレン基が挙げられる。
【００４８】
分子中にリン原子を２個含む親水性ホスフィン化合物は、上記式（９）で示される化合物に限定されるものではない。分子中にリン原子を２個含む親水性ホスフィン化合物の具体例としては、例えば、以下の化合物を挙げることができる。
【００４９】
【化２８】
【化２９】
【化３０】
【化３１】
【化３２】
【化３３】
【化３４】
【化３５】
【化３６】
【化３７】
【化３８】
【化３９】
【化４０】
【化４１】
【化４２】
尚、親水性ホスフィン化合物は、従来公知の方法に従って調製することができる。
【００６５】
また本発明に使用するルテニウム化合物におけるルテニウムの原子価は特に限定されず、ルテニウムが０価の原子又は陽イオンであるルテニウム化合物を使用できる。ルテニウム化合物の具体例としては、例えば、ジクロロ（１，５−シクロオクタジエン）ルテニウム（II）、ジクロロビス（トリフェニルホスフィン）ルテニウム（II）等を挙げることができるが、これらに限定されない。
【００６６】
また本発明においては、親水性ホスフィン化合物とルテニウム化合物を反応に使用するが、本発明においてはこれらから形成される水溶性のルテニウム錯体が本発明の転位反応の触媒として作用すると容易に予想される。したがって本発明において親水性ホスフィン化合物とルテニウム化合物のそれぞれを反応系に添加して転位反応を行うほか、親水性ホスフィン化合物とルテニウム化合物とから水溶性のルテニウム錯体を調製し、得られた水溶性ルテニウム錯体を用いて反応を実施することもできる。水溶性ルテニウム錯体の調整方法は特に限定されず、従来公知の方法を適用することができ、例えば、上記の親水性ホスフィン化合物及びルテニウム化合物を溶媒中で反応させた後、溶媒を除去し、得られた固体を再結晶等により精製する方法が挙げられる。尚、こうして得られる水溶性ルテニウム錯体は、水溶性である限りにおいて、上記親水性ホスフィン化合物以外に、他の配位子を含んでいてもよい。他の配位子としては、具体的には、例えば、トリフェニルホスフィン、１，５−シクロオクタジエン、ハロゲンイオン（塩素イオン、臭素イオン又はヨウ素イオン）、２，２‘−ジピリジル、ｐ−シメン、ＣＯ、トリシクロヘキシルホスフィン、シクロペンタジエン、ペンタメチルシクロペンタジエン、エチレンジアミン及びノルボルナジエン等、従来公知の遷移金属錯体に含まれる配位子を挙げることができる。
【００６７】
本発明における親水性ホスフィン化合物及びルテニウム化合物の使用量は、ルテニウム化合物の量が、原料のオキシム１モルに対して通常０．０００１〜０．２モル、好ましくは０．００１〜０．１モルとなるように用いられ、親水性ホスフィン化合物はそれが分子中に有するルテニウムと配位結合を形成し得るリン原子の数により異なり一義的に決定することはできないがルテニウム化合物１モルに対して通常１モル以上、好ましくは１．１〜２０モルである。
【００６８】
本発明のオキシムのアミドへの転位反応は、多相系溶媒中で行われる。多相系溶媒とは、互いに混和しない２種以上の溶媒の組み合わせからなり、静置状態でそれぞれの溶媒層に層分離する混合溶媒である。具体的には、例えば、水、有機溶媒及びイオン性流体から選ばれる少なくとも２種類の互いに混和しない溶媒を組み合わせて用いた混合溶媒である。有機溶媒としては、例えば、ｎ−ヘキサン等の脂肪族炭化水素、ベンゼン、トルエン及びキシレン等の芳香族炭化水素、ジクロロメタン、クロロホルム等のハロゲン化炭化水素、テトラリン等の脂環式炭化水素、ジエチルエーテル等のエーテル類等が挙げられ、イオン性流体としては、例えば、Ｎ，Ｎ’−ジアルキル置換イミダゾリウム＝テトラフルオロボラート、Ｎ，Ｎ’−ジアルキル置換イミダゾリウム＝ヘキサフルオロホスファート、Ｎ−アルキル置換ピリジニウム＝ヘキサフルオロホスファート等が挙げられる。ここで、水、有機溶媒及びイオン性流体の組み合わせは、本発明における親水性ホスフィン化合物及びルテニウム化合物から形成される水溶性のルテニウム化合物と目的物のアミドをそれぞれ異なる溶媒層に溶解して容易に分離できるような組み合わせが好ましく、アミドの溶解特性に応じて決定すればよい。
【００６９】
特に好ましくは多相系溶媒として水及び水と混和しない有機溶媒の混合溶媒を用いる。水及び水と混和しない有機溶媒の混合溶媒を用いると、目的物のアミドの多くは、水にも有機溶媒にも溶解しにくいので、反応終了後、得られた反応混合物を冷却し、次いで濾過すれば、生成物のアミドを濾滓として分離できる。そして濾液は、これを水層と有機溶媒層とに分液すれば、水層として親水性ホスフィン化合物及びルテニウム化合物から形成される水溶性のルテニウム錯体を含む水溶液が得られ、そして有機溶媒層として残存アミド及び副生物を溶解した溶液が得られる。アミド及び副生物類が水及び有機溶媒のいずれにも溶解し得る場合には、水層と有機溶媒層を分液した後、更に水層から生成アミド及び副生物類を有機溶媒で抽出してもよい。尚、このようにして得られる水層をそのまま本発明のオキシムの転位反応に用いることにより、当該水層に含まれる水溶性のルテニウム錯体が転位反応を促進する触媒として再使用できる。即ち、反応終了後の反応混合物から水層を分離し、当該水層に含まれる親水性ホスフィン化合物及びルテニウム化合物から形成される水溶性ルテニウム錯体を、親水性ホスフィン化合物及びルテニウム化合物に代えて反応に利用することができる。
【００７０】
多相系溶媒の使用量は特に限定されないが、オキシム１重量部に対して通常０．５〜１００重量部、好ましくは２〜２０重量部である。
【００７１】
本発明の反応の反応温度は、通常０〜２００℃の範囲でよく、好ましくは５０〜１５０℃である。反応時間は特に制限はない。
【００７２】
本発明のアミドの製造法を実施するには、反応器にオキシム、親水性ホスフィン化合物、ルテニウム化合物及び多相系溶媒を仕込んだ後、上記反応温度にて攪拌すればよい。尚反応は、低酸素状態もしくは酸素が存在しない条件下で実施するのが好ましく、窒素やアルゴン等の不活性な気体の雰囲気下で実施することが好ましい。また、反応に用いる化合物が液体であるときには脱気した後に使用するのが好ましい。
【００７３】
更に本発明に用いるオキシムが分子中にエチレン性の不飽和結合を有するとき、水素雰囲気下で反応を行うことにより、オキシムのアミドへの転位反応とオキシムが分子中に有する不飽和結合の水素化を１工程の反応で実施することができる。例えば、上記一般式（１）で示されるオキシムにおいて式中のＲ1及び／又はＲ2が置換基を有していてもよいアルケニル基及び置換基を有していてもよいシクロアルケニル基からなる群より選ばれる基であるとき、生成物である一般式（２）で示されるアミドにおいて当該アルケニル基及びシクロアルケニル基の不飽和結合が水素で飽和されてアルキル基及びシクロアルキル基に転化したアミドを製造することができる。
【００７４】
水素雰囲気下で転位反応を行うときの水素圧は、通常０．１〜１０ＭＰａ、好ましくは２〜６ＭＰａである。
【００７５】
本発明では、上記のようにオキシムが分子中にエチレン性の不飽和結合を有する場合でも、水素を使用しなければ不飽和結合を有したアミドを得ることができる。
【００７６】
以下、実施例により本発明を更に詳細に説明するが、本発明はこれに限定されるものではない。
【００７７】
尚、以下の実施例におけるガスクロマトグラフィーの分析条件は次の通りである。
＜ガスクロマトグラフィー分析条件＞
カラム：ＤＢ−１（Ｊ＆Ｗサイエンス社製）
キャリアガス及び流量：ヘリウム、４０ｍｌ／分
カラム温度：８０℃から２５０℃まで５℃／分で昇温した後、２５０℃で３０分間保持。
【００７８】
参考例１
Ｉｎｏｒｇａｎｉｃ Ｃｈｉｍｉｃａ Ａｃｔａ，２４０，３６７（１９９５）の記載に従って、次のようにして親水性ホスフィン化合物を製造した。
テトラエチル−エチレンジホスフォナート５．０ｇ（１６．５ミリモル）をジエチルエーテル５０ｍｌ中で水素化アルミニウムリチウム２．０ｇ（５２．７ミリモル）と反応させて１，２−ジホスフィノエタン０．８９ｇ（９．４３ミリモル）を得た。得られたジホスフィノエタン０．８９ｇをトルエン中、パラホルムアルデヒド１．１７ｇ（３９ミリモル）と反応させて、１，２−ビス［ジ（ヒドロキシメチル）ホスフィノ］エタン１．９８ｇ（９．２５ミリモル、収率５５％）を得た。
【００７９】
参考例２
小宮らのＣｈｅｍ．Ｃｏｍｍｕｎ．，４８９，１９９９の記載に従って、次のようにして親水性ホスフィン化合物を製造した。
８０重量％テトラヒドロキシメチルホスホニウム＝クロリド水溶液（試薬）２．５ｇ（１０．５ミリモル）から水を除去し、トリエチルアミン１２．０ｍｌを加えて混合した。得られた混合物を濾過して不溶物を除き、次いで濾液を濃縮し、残渣を乾燥させた。得られた固形物をエタノールに溶解し、エーテルを加えて沈殿を生成させた後、濾過し、得られた沈澱物を乾燥してトリス（ジヒドロキシメチル）ホスフィン０．８０ｇ（６．４５ミリモル、収率６１％）を得た。
【００８０】
実施例１
２０ｍｌステンレス製オートクレーブ［ガラス内筒つき、耐圧ガラス工業（株）製］内をアルゴンガスで満たし、ベンズアルデヒドオキシム０．５１ｇ（４．２ミリモル）、水２．５ｍｌ及びベンゼン２．５ｍｌを仕込み、更に市販のトリナトリウム＝トリ（３−スルホナトフェニル）ホスフィン・４水和物（試薬、ＳＴＲＥＭ社製）０．０５０ｇ（０．０８８ミリモル）及びジクロロ（１，５−シクロオクタジエン）ルテニウム（II）０．００４ｇ（０．０１４ミリモル）を加えた。次いでオートクレーブ内をアルゴンで置換して密閉し、１００℃に昇温して同温度で２４時間攪拌して反応させた。反応終了後、オートクレーブ内容物を冷却して取り出し、濾過した。濾滓として得られた結晶をガスクロマトグラフィーにて分析した結果、反応生成物の割合はベンズアミド：ベンズアルデヒド：ベンズアルデヒドオキシム：その他（ガスクロマトグラムのピーク面積比、以下ＧＣ面積比）＝４２：２７：１０：２１であった。
【００８１】
実施例２
実施例１においてベンズアルデヒドオキシムに代えてシンナムアルデヒドオキシム０．５ｇ（３．５ミリモル）を用いた以外は実施例１と同様に行った。その結果、反応生成物の割合はケイ皮酸アミド：シンナムアルデヒドオキシム：ケイ皮酸ニトリル：その他（ＧＣ面積比）＝４６：１３：１６：２５であった。
【００８２】
実施例３
実施例１と同様のオートクレーブ内をアルゴンガスで満たし、シンナムアルデヒドオキシム０．５１ｇ（４．２ミリモル）、水２．５ｍｌ及びベンゼン２．５ｍｌを仕込み、更に参考例１で得た１，２−ビス［ジ（ヒドロキシメチル）ホスフィノ］エタン０．０６５ｇ（０．３ミリモル）及びジクロロ（１，５−シクロオクタジエン）ルテニウム（II）０．００４ｇ（０．０１４ミリモル）を加えた。次いでオートクレーブ内をアルゴンで置換して密閉した後、水素を導入して水素圧３ＭＰａとし、１００℃に昇温して同温度で２４時間攪拌して反応させた。反応終了後、オートクレーブ内容物を冷却し、内容物を取り出し濾過した。濾過で得られた結晶をガスクロマトグラフィーにて分析した結果、反応生成物の割合はケイ皮酸アミド：ケイ皮酸ニトリル：シンナムアルデヒドオキシム：その他（ＧＣ面積比）＝７３：１２：６：９であった。
【００８３】
実施例４
実施例３において１，２−ビス［ジ（ヒドロキシメチル）ホスフィノ］エタンに代えて市販のトリナトリウム＝トリ（３−スルホナトフェニル）ホスフィン・４水和物（試薬、ＳＴＲＥＭ社製）０．０５０ｇ（０．０８８ミリモル）を用いた以外は実施例３と同様に行った。その結果、反応生成物の割合は、３−フェニルプロピオンアミド：その他（ＧＣ面比）＝５９：４１であった。尚、原料のシンナムアルデヒドオキシムは検出されなかった。
【００８４】
実施例５
実施例３において１，２−ビス［ジ（ヒドロキシメチル）ホスフィノ］エタンに代えて参考例３で得たトリス（ジヒドロキシメチル）ホスフィン０．００３ｇ（０．０２４ミリモル）を用い、更にエチレンジアミン０．０１８ｇ（０．２９１ミリモル）をオートクレーブに仕込んだ以外は実施例３と同様に行った。その結果、反応生成物の割合はケイ皮酸アミド：ケイ皮酸ニトリル：その他（ＧＣ面積比）＝５７：３１：１２であった。尚、原料のシンナムアルデヒドオキシムは検出されなかった。
【００８５】
実施例６
実施例１と同様のオートクレーブ内をアルゴンガスで満たし、シンナムアルデヒドオキシム０．２７１ｇ（１．８４ミリモル）、水２．５ｍｌ及びベンゼン２．５ｍｌを仕込み、更に参考例１で得た１，２−ビス［ジ（ヒドロキシメチル）ホスフィノ］エタン０．１４５ｇ（０．６７７ミリモル）及びジクロロ（１，５−シクロオクタジエン）ルテニウム（II）０．０６８６ｇ（０．２４５ミリモル）を加えた。次いでオートクレーブ内をアルゴンで置換して密閉した後、水素を導入して水素圧３ＭＰａとし、１００℃に昇温して同温度で２４時間攪拌して反応させた。反応終了後、オートクレーブ内容物を冷却し、内容物を取り出し濾過した。濾過で得られた結晶をガスクロマトグラフィーにて分析した結果、反応生成物の割合は３−フェニルプロピオンアミド：ケイ皮酸アミド：シンナムアルデヒドオキシム：その他（ＧＣ面積比）＝８０：０．１：約０（トレース）：１９．９であった。
【００８６】
また反応終了後の濾過操作によって得られた濾液を水層と有機層に分液し、得られた水層を用いて当該水層に含まれる１，２−ビス［ジ（ヒドロキシメチル）ホスフィノ］エタン及びジクロロ（１，５−シクロオクタジエン）ルテニウム（II）を再使用して上記と同様の反応を行った。即ち、上記と同様のオートクレーブに分液して得られた水層、シンナムアルデヒドオキシム０．２７１ｇ（１．８４ミリモル）及びベンゼン２．５ｍｌを仕込んだ以外は、上記と同様にして反応、後処理及び分析を行った。その結果、反応生成物の割合は３−フェニルプロピオンアミド：ケイ皮酸アミド：シンナムアルデヒドオキシム：その他（ＧＣ面比）＝７８：１．７：約０（トレース）：２０．３であった。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing amides widely used as pharmaceuticals or synthetic intermediates thereof, agricultural chemicals or synthetic intermediates thereof, and the like. Specifically, the present invention relates to a method for producing an amide by an oxime rearrangement reaction.
[0002]
[Prior art]
Conventionally, a method for producing an amide by an oxime rearrangement reaction is known. A reaction in which an oxime is rearranged to an amide in the presence of a strong acid is called a Beckmann rearrangement, and is an industrially useful reaction, for example, used in the production of ε-caprolactam from cyclohexanone oxime. In the rearrangement reaction, a strong acid such as sulfuric acid is used as a catalyst, but the reaction requires an equal amount or more of a strong acid relative to the oxime. The produced amide forms a salt with a strong acid, and thus a step of liberating the amide from the strong acid is necessary to recover the amide from the reaction mixture after the reaction is completed. A large amount of alkali salt is by-produced. Therefore, this amide production method using Beckmann rearrangement using a strong acid is not an industrially advantageous method.
As a method that can solve the problems of the method using a strong acid as the catalyst, a method using nickel acetate tetrahydrate as a catalyst for the rearrangement reaction from oxime to amide [Journal of American Chemical Society, 83, 1983 (1961) ], A method using a salt of perrhenic acid and a heterocyclic compound as a catalyst for the rearrangement reaction [JP-A-9-301951] and the like are known.
These methods give the desired amides in good yields, but require a significant amount of expensive metals such as rhenium, and these metals are usually not reusable after use, so the catalyst costs are very high. growing. In addition, since a large amount of solvent is used, there is a problem that productivity is low. From the above, industrial production is economically disadvantageous.
[0003]
[Problems to be solved by the invention]
The present invention provides a method for producing amides by rearrangement reaction of oximes, which is a method that solves the above-mentioned problems of the conventional method, that is, without producing a large amount of by-products that have a large environmental impact in industrial production of amides. An object of the present invention is to provide an economical and simple method with relatively high container efficiency.
[0004]
[Means for Solving the Problems]
The present inventor has intensively studied to solve the above problems. As a result, when the oxime is rearranged to produce an amide, the oxime is reacted in the presence of a hydrophilic phosphine compound and a ruthenium compound in a multiphase solvent at 0 to 200 ° C. with stirring. It has been found that even if the amount of the solvent used is reduced, the target amide can be selectively produced, and since no strong acid is used in the reaction, a large amount of by-products are not generated.
In addition, when a mixed solvent of water and an organic solvent immiscible with water is used as the multiphase solvent, a compound formed from the hydrophilic phosphine compound and the ruthenium compound that catalyzes the rearrangement reaction of the present invention from the reaction mixture after completion of the reaction is included. It has been found that the aqueous layer can be easily separated and reused in the reaction, and the present invention has been completed.
[0005]
That is, the present invention relates to a method for producing an amide, which comprises carrying out a reaction in the presence of a hydrophilic phosphine compound and a ruthenium compound in a multiphase solvent when an oxime is rearranged to produce an amide.
[0006]
[Mode for Carrying Out the Invention]
The present invention is described in detail below.
Examples of the oxime used in the present invention include the general formula (1):
[0007]
[Chemical 3]
[0008]
In the general formula (1), R 1 And R 2 As the alkyl group which may have a substituent represented by, for example, carbon such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, pentyl group, hexyl group, etc. A linear or branched alkyl group of 1 to 6 and one or more hydrogen atoms of the alkyl group are substituted with a hydroxyl group, an alkoxy group (for example, methoxy group, ethoxy group, isopropoxy group, etc.) 1-4 linear and branched alkoxy groups), an alkenyl group which may have a substituent which will be described later, a cycloalkyl group which may have a substituent which will be described later, and a substituent which will be described later. What substituted by the group chosen from the group which consists of the aryl group which may have the cycloalkenyl group which may have and the substituent mentioned later may be mentioned. Examples of the alkenyl group which may have a substituent include linear and branched alkenyl groups having 2 to 4 carbon atoms such as 2-butenyl group, 3-butenyl group and vinyl group, and the alkenyl group. One or more hydrogen atoms have a hydroxyl group, the above-described alkoxy group, an alkyl group which may have the above-described substituent, a cycloalkyl group which may have a substituent which will be described later, or a substituent which will be described later. And a group selected from the group consisting of an optionally substituted cycloalkenyl group and an aryl group which may have a substituent described later. Examples of the cycloalkyl group which may have a substituent include a cycloalkyl group having 5 to 8 carbon atoms such as a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group, and a hydrogen that the cycloalkyl group has. One or more of the atoms have a hydroxyl group, the above-described alkoxy group, an alkyl group that may have the above-described substituent, an alkenyl group that may have the above-described substituent, or a substituent that will be described later. Examples thereof include those substituted with a group selected from the group consisting of a cycloalkenyl group which may be substituted and an aryl group which may have a substituent which will be described later. The cycloalkenyl group which may have a substituent includes a cycloalkenyl group in which at least one of the bonds between adjacent carbon atoms in the above-described cycloalkyl group having 5 to 8 carbon atoms is a double bond, and the cycloalkenyl group. One or more hydrogen atoms of the alkenyl group are substituted with a hydroxyl group, the above-described alkoxy group, an alkyl group that may have the above-described substituent, an alkenyl group that may have the above-described substituent, or the above-described substitution. What substituted by the group chosen from the group which consists of the cycloalkyl group which may have group, and the aryl group which may have the substituent mentioned later may be mentioned. Examples of the aryl group which may have a substituent include, for example, a phenyl group, a naphthyl group, and one or more hydrogen atoms included in these having a hydroxyl group, the above-described alkoxy group, and the above-described substituent. An alkyl group which may have the above-mentioned substituent, an cycloalkyl group which may have the above-mentioned substituent, and a cycloalkenyl group which may have the above-mentioned substituent Examples thereof include those substituted with a group selected from the group.
[0009]
R 1 And R 2 Examples of the group that together form a ring with the carbon atom to which they are bonded include an alkylene group having 2 to 6 carbon atoms such as an ethylene group, trimethylene group, tetramethylene group, pentamethylene group, and hexamethylene group, The alkylene group having one or more double bonds between adjacent carbon atoms, or a methylene chain of the alkylene group interrupted by a nitrogen atom and / or an oxygen atom (for example, R 2 And R Three Together with a carbon atom to which they are bonded to form a heterocyclic ring such as a piperidine ring or a morpholine ring), and one or more of these hydrogen atoms have a hydroxyl group, the aforementioned alkoxy group, or the aforementioned substituent. An alkyl group that may have a substituent, an alkenyl group that may have a substituent as described above, a cycloalkyl group that may have a substituent as described above, and a substituent that may have a substituent as described above. Examples thereof include those substituted with a group selected from the group consisting of a cycloalkenyl group and an aryl group which may have the above-described substituent.
[0010]
The oxime used in the present invention is not limited to the above examples, and there is no particular limitation on the syn-type and anti-type three-dimensional structures.
[0011]
According to the present invention, an amide in which the oxime is Beckmann rearranged can be produced according to the oxime used in the reaction. For example, from the oxime represented by the general formula (1), the general formula (2):
[0012]
[Formula 4]
[0013]
In the present invention, the rearrangement reaction is performed using a hydrophilic phosphine compound and a ruthenium compound capable of forming a water-soluble ruthenium complex.
[0014]
The hydrophilic phosphine compound is a compound which is hydrophilic and can form a complex with a ruthenium atom or an ion thereof, and widely known compounds can be applied. The hydrophilic phosphine compound may be one containing one or more phosphorus atoms in the molecule, and preferably one or two phosphorus atoms in the molecule.
[0015]
Examples of the hydrophilic phosphine compound containing one phosphorus atom in the molecule include, for example, the general formula (3):
[0016]
[Chemical formula 5]
[0017]
[Chemical 6]
[0018]
[Chemical 7]
[0019]
[Chemical 8]
[0020]
[Chemical 9]
[0021]
[Chemical Formula 10]
[0022]
In the general formula (3), R Three The aryl group having at least one substituent selected from the group consisting of a sulfonate group and a carboxylate group represented by the formula (1) preferably has one or two substituents selected from the group consisting of a sulfonate group and a carboxylate group The alkyl group having 1 to 6 carbon atoms, which is a phenyl group, a naphthyl group, a biphenylyl group and a binaphthyl group and has one or more substituents selected from the group consisting of a sulfonate group and a carboxylate group, is preferably a sulfonate group and a carboxylate. A C1-C4 alkyl group having one substituent selected from the group consisting of groups, preferably a C1-C6 hydroxyalkyl group, preferably a hydroxymethyl group, a hydroxyethyl group, a 3-hydroxypropyl group , 2-hydroxypropyl group, 4-hydroxybutyl group, etc. Is a Shiarukiru group. In addition, as an alkali metal ion which a sulfonate group and a carboxylate group have, a lithium ion, a sodium ion, a potassium ion, and a cesium ion are specifically mentioned.
[0023]
R in general formula (3) Three In the group represented by the above formula (4) represented by 6 The alkyl groups 1 to 18 represented in the table may be linear or branched. In the group represented by the above formula (5), M in the formula Three Specifically, the alkali metal ions represented by are lithium ion, sodium ion, potassium ion, and cesium ion. In the group represented by the formula (7), R in the formula 7 The alkylene group having 1 to 6 carbon atoms represented by may be linear or branched.
[0024]
In the general formula (3), R in the formula 7 And R 8 In the alkyl group which may have a substituent represented by the above and the aryl group which may have a substituent, the above R 6 The group shown by is included. Examples of the alkyl group which may have other substituents include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, n-pentyl group and n-hexyl group. A linear or branched alkyl group having 1 to 6 carbon atoms and one or more hydrogen atoms of the alkyl group as a substituent selected from the group consisting of a hydroxyl group, a nitro group, an amino group, and a halogen atom. Examples of the aryl group which may have a substituent include, for example, a phenyl group, a naphthyl group, a biphenyl group, a phenylnaphthyl group, a binaphthyl group, and those having the substituent. Those having one or more substituents selected from the group consisting of a good alkyl group, alkoxy group and hydroxyl group (specifically, for example, they may have a substituent) Examples of the phenyl group include a phenyl group, a tolyl group, a xylyl group, a mesityl group, a cumyl group, a methoxyphenyl group, a hydroxyphenyl group, a hydroxytolyl group, etc., and examples of the aralkyl group that may have a substituent include For example, an alkyl group which may have the above-described substituent is substituted with an aryl group which may have the above-mentioned substituent [specifically, for example, a benzyl group, a phenethyl group, a phenylpropyl group, etc. , Tolylmethyl group, xylylmethyl group, (hydroxyphenyl) methyl group, etc.], and examples of the alkoxy group which may have a substituent include a methoxy group, an ethoxy group, an n-propyloxy group, and an isopropyloxy group. , N-butyloxy group, isobutyloxy group, n-pentyloxy group, n-hexyloxy group, etc. 6 linear or branched alkoxy groups and at least one hydrogen atom of the alkoxy group has at least one substituent selected from the group consisting of a hydroxyl group, a nitro group, an amino group, a halogen atom, and the like. And the like.
[0025]
The hydrophilic phosphine compound containing one phosphorus atom in the molecule is not limited to the compound represented by the above formula (2).
[0026]
Specific examples of the hydrophilic phosphine compound containing one phosphorus atom in the molecule include the following compounds.
[0027]
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[0031]
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[0032]
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[0034]
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[0038]
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[0039]
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[0040]
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Moreover, as a hydrophilic phosphine compound containing two phosphorus atoms in the molecule, for example, the formula (9):
[0044]
R 9 R Ten P-A-PR 11 R 12 (9)
[Wherein R 9 , R Ten , R 11 And R 12 Represents an alkyl group, an alkoxy group, an aryl group or an aralkyl group which may be the same or different from each other and may have a substituent, and A represents an alkylene group which may have a substituent; An arylene group which may be present; or formula (10):
[0045]
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[0046]
R in formula (9) 11 , R 12 , R 13 And R 14 An alkyl group, an alkoxy group, an aryl group and an aralkyl group which may have a substituent represented by R in the above formula (3) Four And R Five It is the same.
[0047]
Examples of the alkylene group optionally having a substituent represented by A in formula (9) include a methylene group; an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, and the like. Polymethylene group; these are alkyl group, alkoxy group, aryl group and aralkyl group [R in the above formula (3) Four And R Five And an alkylene group that may have at least one substituent selected from the group consisting of a sulfonate group and a carboxylate group. Examples of the arylene group which may have a substituent include a phenylene group, a naphthylene group, a biphenylylene group, a binaphthylylene group, and an alkyl group, an alkoxy group, an aralkyl group, and an aryl group [R in the above formula (3) Four And R Five And an arylene group optionally having at least one substituent selected from the group consisting of a sulfonate group and a carboxylate group.
[0048]
The hydrophilic phosphine compound containing two phosphorus atoms in the molecule is not limited to the compound represented by the above formula (9). Specific examples of the hydrophilic phosphine compound containing two phosphorus atoms in the molecule include the following compounds.
[0049]
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The hydrophilic phosphine compound can be prepared according to a conventionally known method.
[0065]
Further, the valence of ruthenium in the ruthenium compound used in the present invention is not particularly limited, and a ruthenium compound in which ruthenium is a zero-valent atom or cation can be used. Specific examples of the ruthenium compound include, but are not limited to, dichloro (1,5-cyclooctadiene) ruthenium (II), dichlorobis (triphenylphosphine) ruthenium (II), and the like.
[0066]
In the present invention, a hydrophilic phosphine compound and a ruthenium compound are used for the reaction. In the present invention, a water-soluble ruthenium complex formed from these compounds is easily expected to act as a catalyst for the rearrangement reaction of the present invention. . Therefore, in the present invention, each of the hydrophilic phosphine compound and the ruthenium compound is added to the reaction system to perform the rearrangement reaction, and a water-soluble ruthenium complex is prepared from the hydrophilic phosphine compound and the ruthenium compound. The reaction can also be carried out using a complex. The method for preparing the water-soluble ruthenium complex is not particularly limited, and a conventionally known method can be applied. For example, after the above-described hydrophilic phosphine compound and ruthenium compound are reacted in a solvent, the solvent is removed to obtain The method of refine | purifying the obtained solid by recrystallization etc. is mentioned. The water-soluble ruthenium complex thus obtained may contain other ligands in addition to the hydrophilic phosphine compound as long as it is water-soluble. Specific examples of other ligands include triphenylphosphine, 1,5-cyclooctadiene, halogen ion (chlorine ion, bromine ion or iodine ion), 2,2′-dipyridyl, and p-cymene. , CO, tricyclohexylphosphine, cyclopentadiene, pentamethylcyclopentadiene, ethylenediamine, norbornadiene, and the like include ligands contained in conventionally known transition metal complexes.
[0067]
The use amount of the hydrophilic phosphine compound and the ruthenium compound in the present invention is such that the amount of the ruthenium compound is usually 0.0001 to 0.2 mol, preferably 0.001 to 0.1 mol, relative to 1 mol of the raw material oxime. The hydrophilic phosphine compound differs depending on the number of phosphorus atoms that can form a coordination bond with ruthenium in the molecule and cannot be determined uniquely, but usually 1 per mole of ruthenium compound. More than mol, preferably 1.1 to 20 mol.
[0068]
The oxime of the present invention to amide Rearrangement reaction Is carried out in a multiphase solvent. The multiphase solvent is a mixed solvent that is composed of a combination of two or more solvents that are immiscible with each other and separates into respective solvent layers in a stationary state. Specifically, for example, it is a mixed solvent using a combination of at least two types of immiscible solvents selected from water, organic solvents and ionic fluids. Examples of the organic solvent include aliphatic hydrocarbons such as n-hexane, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane and chloroform, alicyclic hydrocarbons such as tetralin, and diethyl ether. Examples of ionic fluids include N, N′-dialkyl-substituted imidazolium = tetrafluoroborate, N, N′-dialkyl-substituted imidazolium = hexafluorophosphate, N-alkyl. Substituted pyridinium = hexafluorophosphate and the like. Here, a combination of water, an organic solvent and an ionic fluid can be easily obtained by dissolving the water-soluble ruthenium compound formed from the hydrophilic phosphine compound and the ruthenium compound in the present invention and the target amide in different solvent layers. Combinations that can be separated are preferable, and may be determined according to the solubility characteristics of the amide.
[0069]
Particularly preferably, a mixed solvent of water and an organic solvent immiscible with water is used as the multiphase solvent. When a mixed solvent of water and an organic solvent immiscible with water is used, most of the target amide is difficult to dissolve in water or an organic solvent. Therefore, after completion of the reaction, the obtained reaction mixture is cooled and then filtered. The product amide can then be separated as a filter cake. And if the filtrate is separated into an aqueous layer and an organic solvent layer, an aqueous solution containing a water-soluble ruthenium complex formed from a hydrophilic phosphine compound and a ruthenium compound is obtained as the aqueous layer, and as the organic solvent layer A solution in which residual amide and by-products are dissolved is obtained. When amides and by-products can be dissolved in both water and organic solvents, the aqueous layer and the organic solvent layer are separated, and then the produced amides and by-products are extracted from the aqueous layer with an organic solvent. Also good. By using the aqueous layer thus obtained as it is for the oxime rearrangement reaction of the present invention, the water-soluble ruthenium complex contained in the aqueous layer can be reused as a catalyst for promoting the rearrangement reaction. That is, the aqueous layer is separated from the reaction mixture after completion of the reaction, and the water-soluble ruthenium complex formed from the hydrophilic phosphine compound and ruthenium compound contained in the aqueous layer is replaced with the hydrophilic phosphine compound and ruthenium compound. Can be used.
[0070]
Although the usage-amount of a multiphase type solvent is not specifically limited, It is 0.5-100 weight part normally with respect to 1 weight part of oximes, Preferably it is 2-20 weight part.
[0071]
The reaction temperature of the reaction of the present invention is usually in the range of 0 to 200 ° C, preferably 50 to 150 ° C. The reaction time is not particularly limited.
[0072]
In order to carry out the method for producing an amide of the present invention, an oxime, a hydrophilic phosphine compound, a ruthenium compound, and a multiphase solvent are charged into a reactor and then stirred at the reaction temperature. The reaction is preferably carried out in a low oxygen state or in the absence of oxygen, and is preferably carried out in an atmosphere of an inert gas such as nitrogen or argon. Further, when the compound used for the reaction is liquid, it is preferably used after deaeration.
[0073]
Furthermore, when the oxime used in the present invention has an ethylenically unsaturated bond in the molecule, the reaction is carried out in a hydrogen atmosphere, whereby the rearrangement reaction of the oxime to the amide and the hydrogenation of the unsaturated bond the oxime has in the molecule. Can be carried out in a one-step reaction. For example, in the oxime represented by the general formula (1), R in the formula 1 And / or R 2 When is a group selected from the group consisting of an alkenyl group which may have a substituent and a cycloalkenyl group which may have a substituent, in the amide represented by the general formula (2) as a product, An amide in which the unsaturated bond of the alkenyl group and the cycloalkenyl group is saturated with hydrogen and converted to an alkyl group and a cycloalkyl group can be produced.
[0074]
The hydrogen pressure when the rearrangement reaction is performed in a hydrogen atmosphere is usually 0.1 to 10 MPa, preferably 2 to 6 MPa.
[0075]
In the present invention, even when the oxime has an ethylenically unsaturated bond in the molecule as described above, an amide having an unsaturated bond can be obtained unless hydrogen is used.
[0076]
EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to this.
[0077]
In addition, the analysis conditions of the gas chromatography in the following examples are as follows.
<Gas chromatography analysis conditions>
Column: DB-1 (manufactured by J & W Science)
Carrier gas and flow rate: helium, 40 ml / min
Column temperature: The temperature was raised from 80 ° C. to 250 ° C. at 5 ° C./min, and then kept at 250 ° C. for 30 minutes.
[0078]
Reference example 1
According to the description of Inorganic Chimica Acta, 240, 367 (1995), a hydrophilic phosphine compound was produced as follows.
Reacting 5.0 g (16.5 mmol) of tetraethyl-ethylene diphosphonate with 2.0 g (52.7 mmol) of lithium aluminum hydride in 50 ml of diethyl ether to give 0.89 g of 1,2-diphosphinoethane. (9.43 mmol) was obtained. 0.89 g of the obtained diphosphinoethane is reacted with 1.17 g (39 mmol) of paraformaldehyde in toluene to give 1.98 g (9.25 mmol) of 1,2-bis [di (hydroxymethyl) phosphino] ethane. Yield 55%).
[0079]
Reference example 2
Komiya et al., Chem. Commun. , 489, 1999, a hydrophilic phosphine compound was produced as follows.
Water was removed from 2.5 g (10.5 mmol) of 80 wt% tetrahydroxymethylphosphonium chloride aqueous solution (reagent), and 12.0 ml of triethylamine was added and mixed. The resulting mixture was filtered to remove insolubles, then the filtrate was concentrated and the residue was dried. The obtained solid was dissolved in ethanol and ether was added to form a precipitate, followed by filtration. The resulting precipitate was dried and 0.80 g (6.45 mmol, tris (dihydroxymethyl) phosphine was collected. 61%) was obtained.
[0080]
Example 1
A 20 ml stainless steel autoclave (with a glass inner cylinder, manufactured by Pressure Glass Industry Co., Ltd.) is filled with argon gas, charged with 0.51 g (4.2 mmol) of benzaldehyde oxime, 2.5 ml of water and 2.5 ml of benzene, Commercially available trisodium = tri (3-sulfonatophenyl) phosphine tetrahydrate (reagent, manufactured by STREM) 0.050 g (0.088 mmol) and dichloro (1,5-cyclooctadiene) ruthenium (II) 0.004 g (0.014 mmol) was added. Next, the inside of the autoclave was replaced with argon and sealed, and the temperature was raised to 100 ° C. and stirred at the same temperature for 24 hours for reaction. After completion of the reaction, the autoclave contents were cooled and removed and filtered. As a result of analyzing the crystals obtained as filter cake by gas chromatography, the ratio of the reaction product was benzamide: benzaldehyde: benzaldehyde oxime: others (gas chromatogram peak area ratio, hereinafter referred to as GC area ratio) = 42: 27: 10 : 21.
[0081]
Example 2
The same procedure as in Example 1 was performed except that 0.5 g (3.5 mmol) of cinnamaldehyde oxime was used instead of benzaldehyde oxime in Example 1. As a result, the ratio of the reaction product was cinnamic amide: cinnamaldehyde oxime: cinnamic nitrile: others (GC area ratio) = 46: 13: 16: 25.
[0082]
Example 3
The same autoclave as in Example 1 was filled with argon gas, 0.51 g (4.2 mmol) of cinnamaldehyde oxime, 2.5 ml of water and 2.5 ml of benzene were charged, and 1,2-obtained in Reference Example 1 was further obtained. 0.065 g (0.3 mmol) of bis [di (hydroxymethyl) phosphino] ethane and 0.004 g (0.014 mmol) of dichloro (1,5-cyclooctadiene) ruthenium (II) were added. Next, after the inside of the autoclave was replaced with argon and sealed, hydrogen was introduced to a hydrogen pressure of 3 MPa, the temperature was raised to 100 ° C., and the mixture was stirred at the same temperature for 24 hours for reaction. After completion of the reaction, the autoclave contents were cooled, the contents were taken out and filtered. As a result of analyzing the crystals obtained by filtration by gas chromatography, the ratio of the reaction product was cinnamic amide: cinnamic nitrile: cinnamaldehyde oxime: others (GC area ratio) = 73: 12: 6: 9 Met.
[0083]
Example 4
In Example 3, instead of 1,2-bis [di (hydroxymethyl) phosphino] ethane, commercially available trisodium = tri (3-sulfonatophenyl) phosphine tetrahydrate (reagent, manufactured by STREM) 0.050 g Example 3 was performed except that (0.088 mmol) was used. As a result, the ratio of the reaction product was 3-phenylpropionamide: others (GC plane ratio) = 59: 41. The raw material cinnamaldehyde oxime was not detected.
[0084]
Example 5
In Example 3, 0.003 g (0.024 mmol) of tris (dihydroxymethyl) phosphine obtained in Reference Example 3 was used instead of 1,2-bis [di (hydroxymethyl) phosphino] ethane, and 0.018 g of ethylenediamine was used. (0.291 mmol) was carried out in the same manner as in Example 3 except that the autoclave was charged. As a result, the ratio of the reaction product was cinnamic amide: cinnamic nitrile: other (GC area ratio) = 57: 31: 12. The raw material cinnamaldehyde oxime was not detected.
[0085]
Example 6
Same as Example 1 Autoclave The inside was filled with argon gas, cinnamaldehyde oxime 0.271 g (1.84 mmol), water 2.5 ml and benzene 2.5 ml were charged, and 1,2-bis [di (hydroxymethyl) obtained in Reference Example 1 was further added. Phosphino] ethane 0.145 g (0.677 mmol) and dichloro (1,5-cyclooctadiene) ruthenium (II) 0.0686 g (0.245 mmol) were added. Next, after the inside of the autoclave was replaced with argon and sealed, hydrogen was introduced to a hydrogen pressure of 3 MPa, the temperature was raised to 100 ° C., and the mixture was stirred at the same temperature for 24 hours for reaction. After completion of the reaction, the autoclave contents were cooled, the contents were taken out and filtered. As a result of analyzing the crystals obtained by filtration by gas chromatography, the ratio of the reaction product was 3-phenylpropionamide: cinnamic acid amide: cinnamaldehyde oxime: other (GC area ratio) = 80: 0.1: About 0 (trace): 19.9.
[0086]
Moreover, the filtrate obtained by the filtration operation after completion of the reaction is separated into an aqueous layer and an organic layer, and 1,2-bis [di (hydroxymethyl) phosphino] contained in the aqueous layer is obtained using the obtained aqueous layer. Ethane and dichloro (1,5-cyclooctadiene) ruthenium (II) were reused to carry out the same reaction as above. That is, the reaction and post-treatment were carried out in the same manner as above except that an aqueous layer obtained by separating into an autoclave similar to the above, 0.271 g (1.84 mmol) of cinnamaldehyde oxime, and 2.5 ml of benzene were charged. And analysis. As a result, the ratio of the reaction product was 3-phenylpropionamide: cinnamic acid amide: cinnamaldehyde oxime: other (GC surface ratio) = 78: 1.7: about 0 (trace): 20.3.
Claims (6)
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