KR102000754B1 - Bicyclic Bridgehead Phosphoramidite Derivatives, Preparation Method and Uses Thereof - Google Patents
Bicyclic Bridgehead Phosphoramidite Derivatives, Preparation Method and Uses Thereof Download PDFInfo
- Publication number
- KR102000754B1 KR102000754B1 KR1020170145932A KR20170145932A KR102000754B1 KR 102000754 B1 KR102000754 B1 KR 102000754B1 KR 1020170145932 A KR1020170145932 A KR 1020170145932A KR 20170145932 A KR20170145932 A KR 20170145932A KR 102000754 B1 KR102000754 B1 KR 102000754B1
- Authority
- KR
- South Korea
- Prior art keywords
- alkyl
- aryl
- reaction
- cycloalkyl
- formula
- Prior art date
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- 150000008300 phosphoramidites Chemical class 0.000 title claims abstract description 28
- 125000002619 bicyclic group Chemical group 0.000 title claims description 12
- 238000002360 preparation method Methods 0.000 title description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- -1 cyclic phosphoramidite Chemical class 0.000 claims abstract description 47
- 238000007037 hydroformylation reaction Methods 0.000 claims abstract description 40
- 150000001336 alkenes Chemical class 0.000 claims abstract description 38
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 230000008569 process Effects 0.000 claims abstract description 15
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 32
- 125000006651 (C3-C20) cycloalkyl group Chemical group 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 239000000126 substance Substances 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 125000006736 (C6-C20) aryl group Chemical group 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 150000002466 imines Chemical class 0.000 claims description 17
- 239000010948 rhodium Substances 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 239000007789 gas Substances 0.000 claims description 10
- 229910052698 phosphorus Inorganic materials 0.000 claims description 10
- 239000011574 phosphorus Substances 0.000 claims description 10
- 229910052703 rhodium Inorganic materials 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 9
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- 229910052723 transition metal Inorganic materials 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 229910010082 LiAlH Inorganic materials 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 5
- 150000003624 transition metals Chemical class 0.000 claims description 5
- DEQUKPCANKRTPZ-UHFFFAOYSA-N (2,3-dihydroxyphenyl)-phenylmethanone Chemical compound OC1=CC=CC(C(=O)C=2C=CC=CC=2)=C1O DEQUKPCANKRTPZ-UHFFFAOYSA-N 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 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 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- JVJQPDTXIALXOG-UHFFFAOYSA-N nitryl fluoride Chemical group [O-][N+](F)=O JVJQPDTXIALXOG-UHFFFAOYSA-N 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 238000007654 immersion Methods 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 abstract description 22
- 230000009257 reactivity Effects 0.000 abstract description 17
- 239000000376 reactant Substances 0.000 abstract description 12
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 125000000524 functional group Chemical group 0.000 abstract description 4
- 230000035484 reaction time Effects 0.000 abstract description 4
- 230000008859 change Effects 0.000 abstract description 2
- 150000001923 cyclic compounds Chemical class 0.000 abstract 1
- 238000005984 hydrogenation reaction Methods 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 61
- 150000001299 aldehydes Chemical class 0.000 description 51
- 239000003446 ligand Substances 0.000 description 34
- 239000000047 product Substances 0.000 description 15
- 239000003960 organic solvent Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 239000000758 substrate Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- YIYBRXKMQFDHSM-UHFFFAOYSA-N 2,2'-Dihydroxybenzophenone Chemical group OC1=CC=CC=C1C(=O)C1=CC=CC=C1O YIYBRXKMQFDHSM-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000006317 isomerization reaction Methods 0.000 description 5
- CTMHWPIWNRWQEG-UHFFFAOYSA-N 1-methylcyclohexene Chemical compound CC1=CCCCC1 CTMHWPIWNRWQEG-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000002274 desiccant Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229910052987 metal hydride Inorganic materials 0.000 description 4
- 150000004681 metal hydrides Chemical class 0.000 description 4
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 229940117389 dichlorobenzene Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- WNXRLBAHEACYJZ-UHFFFAOYSA-N C(C)(C)(C)C=1C(=C(C(=O)C2=C(C(=CC(=C2)C(C)(C)C)C(C)(C)C)O)C=C(C1)C(C)(C)C)O.C(C)(C)(C)C=1C(=C(C(=O)C2=C(C(=CC(=C2)C(C)(C)C)C(C)(C)C)O)C=C(C1)C(C)(C)C)O Chemical compound C(C)(C)(C)C=1C(=C(C(=O)C2=C(C(=CC(=C2)C(C)(C)C)C(C)(C)C)O)C=C(C1)C(C)(C)C)O.C(C)(C)(C)C=1C(=C(C(=O)C2=C(C(=CC(=C2)C(C)(C)C)C(C)(C)C)O)C=C(C1)C(C)(C)C)O WNXRLBAHEACYJZ-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 229910017052 cobalt Inorganic materials 0.000 description 2
- 239000010941 cobalt Substances 0.000 description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 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 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 125000002347 octyl 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])[H] 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GRWFGVWFFZKLTI-IUCAKERBSA-N (-)-α-pinene Chemical compound CC1=CC[C@@H]2C(C)(C)[C@H]1C2 GRWFGVWFFZKLTI-IUCAKERBSA-N 0.000 description 1
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 1
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- UQRONKZLYKUEMO-UHFFFAOYSA-N 4-methyl-1-(2,4,6-trimethylphenyl)pent-4-en-2-one Chemical group CC(=C)CC(=O)Cc1c(C)cc(C)cc1C UQRONKZLYKUEMO-UHFFFAOYSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- DGJMHKMYSDYOFP-MRXNPFEDSA-N C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O Chemical compound C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O DGJMHKMYSDYOFP-MRXNPFEDSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- CZAFIFBJBFDMTP-UHFFFAOYSA-N N-[(4-bromophenyl)methyl]-2-[4-(2-phenylethylsulfamoyl)phenoxy]acetamide Chemical compound Brc1ccc(CNC(=O)COc2ccc(cc2)S(=O)(=O)NCCc2ccccc2)cc1 CZAFIFBJBFDMTP-UHFFFAOYSA-N 0.000 description 1
- 238000006619 Stille reaction Methods 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000005840 aryl radicals Chemical group 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 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
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([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
- 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
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- 238000007866 imination reaction Methods 0.000 description 1
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- 229910052740 iodine Inorganic materials 0.000 description 1
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- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000010496 migratory insertion reaction Methods 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
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- 125000002524 organometallic group Chemical group 0.000 description 1
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- 238000007254 oxidation reaction Methods 0.000 description 1
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
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Abstract
본 발명은 두 고리 구조를 갖는 포스포라미다이트 유도체, 이의 제조방법 및 그 용도에 관한 것으로, 보다 구체적으로는 두 고리 포스포라미다이트 유도체, 이의 제조방법 및 이를 이용한 3치환 올레핀의 하이드로포밀화 반응을 통한 알데하이드의 제조방법에 관한 것이다. 본 발명에 따른 브리포스 리간드는 입체적 전자적 성질의 변화를 도모함으로써, 그동안 반응성과 내부알데하이드 선택성을 얻지 못했던 3치환 올레핀 하이드로포밀화 반응에 적합한 촉매 시스템을 개발하여 좋은 반응성과 3차-탄소 내부알데하이드 선택성을 구현해 내었다. 본 발명에 따른 tBu브리포스의 경우, 기존의 3치환 올레핀 하이드로포밀화 반응에 비해 상대적으로 낮은 압력과 짧은 반응시간이라는 온화한 반응조건에서 반응이 진행되었으며, 고리화합물 및 선형화합물 모두 좋은 반응성과 내부알데하이드 선택성을 나타낼 뿐만 아니라, 하이드로포밀화 반응에서 문제점으로 제기되는 수소화 반응에 대한 저항성을 나타내었으며, 반응물질 내 존재하는 작용기에 대해 작용기의 변화없는 내성을 보여줌으로서, 3치환 올레핀 하이드로포밀화 반응에 유용하다.The present invention relates to a phosphoramidite derivative having two ring structures, a process for preparing the same, and a use thereof, and more particularly to a process for producing two cyclic phosphoramidite derivatives, a process for producing the same and a process for hydroformylation To a process for the production of aldehydes. The inventors of the present invention have developed a catalyst system suitable for the tri-substituted olefin hydroformylation reaction, which has not achieved the reactivity and the internal aldehyde selectivity, by changing the stereophonic electronic properties, and has found that good reactivity and tertiary-carbon internal aldehyde selectivity . In the case of the tBu brieose according to the present invention, the reaction proceeded under mild reaction conditions such as relatively low pressure and short reaction time as compared with the existing tri-substituted olefin hydroformylation reaction, and both the cyclic compound and the linear compound had good reactivity and the internal aldehyde And exhibited resistance to the hydrogenation reaction posed as a problem in the hydroformylation reaction and showed resistance to the change of the functional groups with respect to the functional groups present in the reactant, so that it was useful for the tri-substituted olefin hydroformylation reaction Do.
Description
본 발명은 두 고리 구조를 갖는 포스포라미다이트 유도체, 이의 제조방법 및 그 용도에 관한 것으로, 보다 구체적으로는 두 고리 포스포라미다이트 유도체, 이의 제조방법 및 이를 이용한 3치환 올레핀의 하이드로포밀화 반응을 통한 알데하이드의 제조방법에 관한 것이다. The present invention relates to a phosphoramidite derivative having two ring structures, a process for preparing the same, and a use thereof, and more particularly to a process for producing two cyclic phosphoramidite derivatives, a process for producing the same and a process for hydroformylation To a process for the production of aldehydes.
하이드로포밀화는 1938년 로렌(Roelen)에 의해 개발된 반응으로 올레핀을 기질로 하여 일산화탄소와 수소 그리고 촉매를 통해 알데하이드를 제조하는 반응이다. 생성물인 알데하이드는 추가적인 화학반응을 통해 알코올, 아민, 카복실산 및 유도체로 변환되어 고분자 재료, 세제, 향수 및 약 등 화학산업에서 다양하게 활용되고 있으며, 현재 매년 수백만톤의 알데하이드가 세계적으로 생산되고 있다.Hydroformylation is a reaction developed by Roelen in 1938, in which olefins are used as substrates to produce aldehydes through carbon monoxide, hydrogen, and catalysts. Aldehyde, which is a product, is converted into alcohols, amines, carboxylic acids and derivatives through additional chemical reactions, which are widely used in the chemical industry such as polymer materials, detergents, fragrances and drugs. Currently, millions of tons of aldehydes are produced worldwide every year.
하이드로포밀화 반응의 경우 주로 코발트(Co), 및 로듐(Rh) 전이금속에 리간드와 배위결합한 촉매를 이용하여 반응이 진행되며 이 촉매는 반응에서 일산화탄소 및 수소와 함께 산화성 첨가(Oxidative addition), 위치변화 삽입(Migratory insertion), 환원성 제거(Reductive elimination)의 반응경로를 거쳐 반응물질인 올레핀을 알데하이드로 변환시킨다. 생성물인 알데하이드의 경우 반응물질이 1치환 올레핀인 경우에는 촉매와 올레핀과의 결합 위치에 따라 선형-알데하이드와 가지형-알데하이드의 두 가지 구조 이성질체를 얻게 된다. In the case of hydroformylation reaction, the reaction is mainly carried out using a catalyst coordinated with a ligand to cobalt (Co) and rhodium (Rh) transition metal. The catalyst is oxidized in addition to carbon monoxide and hydrogen in the reaction, The reactant, olefin, is converted to an aldehyde through a reaction pathway of migratory insertion and reduction elimination. In the case of the aldehyde as the product, when the reactant is a mono-substituted olefin, two structural isomers, linear-aldehyde and branched-aldehyde, are obtained depending on the position of the bond between the catalyst and the olefin.
한편 3치환 올레핀의 경우에는 sp2-탄소 위치에서 두 종류의 내부 알데하이드인 3차-탄소 내부 알데하이드와 4차-탄소 내부 알데하이드가 만들어지고, 반응물질의 이성질화를 통한 말단 알데하이드가 만들어지게 된다. 최근 연구 동향은 이러한 올레핀 기질로부터 하이드로포밀화 반응을 진행하여 생성물인 알데하이드를 선택적으로 얻어내는 연구가 진행 중이며, 1치환 올레핀의 경우 높은 반응성과 선택성의 알데하이드를 얻는 하이드로포밀화 반응이 보고된 반면(Robert Franke et al., Chem. Rev. Vol. 112, pp. 5675-5732, 2012). 3치환 올레핀의 하이드로포밀화 반응의 경우 기존의 1,2치환 올레핀 보다 반응성이 현저하게 저하되며, 이성질화(isomerization)을 통해 내부 알데하이드가 아닌 말단 알데하이드가 얻어지게 되므로 선택적으로 내부 알데하이드를 얻기 매우 어려운 실정이다. 현재까지 보고된 3치환 올레핀의 하이드로포밀화 반응은 고온, 고압의 조건이 필요하며, 선택적인 내부 알데하이드를 얻지 못하고 높은 비율의 이성질화를 통한 말단 알데하이드를 생산하고 있다On the other hand, in the case of tri-substituted olefins, two kinds of internal aldehydes, the tert-carbon internal aldehyde and the quaternary-carbon internal aldehyde, are produced at the sp2-carbon position, and the terminal aldehyde is formed through isomerization of the reactant. Recent studies have shown that hydroformylation reactions from these olefinic substrates proceed to selectively obtain aldehydes. In the case of mono-substituted olefins, hydroformylation reactions to obtain aldehydes with high reactivity and selectivity have been reported Robert Franke et al., Chem. Rev. Vol. 112, pp. 5675-5732, 2012). In the hydroformylation reaction of tri-substituted olefins, the reactivity is markedly lower than that of the conventional 1,2-substituted olefins, and a terminal aldehyde which is not an internal aldehyde is obtained through isomerization, so that it is very difficult to obtain the internal aldehyde selectively It is true. The reported hydroformylation of tri-substituted olefins to date requires high temperature and high pressure conditions and produces terminal aldehydes through a high proportion of isomerization without obtaining selective internal aldehydes
현재까지 보고된 3치환 올레핀 하이드로포밀화 반응을 정리하면, 먼저 1993년 Santos 연구팀에서 보고한 알파-파이넨(a-pinene)을 반응물질로 하여 각각 로듐과 코발트 촉매를 이용해 3치환 올레핀 하이드로포밀화 반응이 있다( E.N. dos Santos, J. Mol . Catal . 1993, 83, 51). 연구 결과 전체적으로 80% 이하의 낮은 수율과 3차-탄소 내부 알데하이드에 대한 낮은 선택성을 보여주었다. 2001년에는 Breit교수 연구팀에서 포스파벤젠리간드를 이용하여 알파-파이넨의 하이드로포밀화 반응을 진행하였다. 고압의 일산화탄소 및 수소가 사용된 반응이며 3차-탄소 내부알데하이드의 선택성은 높았지만 반응성이 매우 좋지 않은 결과를 보고하였다( B. Breit, Chem. Eur. J., 2001, 7, 3106). 2007년 Santos 연구팀은 기존의 알파-파이넨을 반응물질로 하여 다른 촉매를 통해 높은 반응성을 확인하였다( E.N. dos Santos, Applied Catalysis A. 2007, 326, 219). 그러나, 80기압의 높은 가스압력이 필요하고 40% 정도의 이성질체를 얻으며 낮은 수준의 3차-탄소 내부 알데하이드 선택성의 결과를 보여주었다. The three-substituted olefin hydroformylation reactions reported so far are summarized as follows. First, a-pinene, which was reported by Santos and colleagues in 1993, is reacted with rhodium and cobalt catalysts to form tri-substituted olefins (EN Dos Santos, J. Mol . Catal . 1993, 83, 51). Overall, the results showed low yields of less than 80% and low selectivity for tertiary-carbon internal aldehydes. In 2001, Prof. Breit and colleagues conducted hydroformylation of alpha-phonene using phosphabenzene ligand. (B. Breit, Chem. Eur. J., 2001, 7, 3106), which is a reaction using high-pressure carbon monoxide and hydrogen and a high selectivity for tertiary-carbon internal aldehyde. In 2007, Santos and colleagues identified a high reactivity of the existing alpha-phyinene as a reactant through other catalysts (EN Dos Santos, Applied Catalysis A. 2007, 326, 219). However, high gas pressures of 80 atmospheres are required and 40% of the isomers are obtained, resulting in low levels of tertiary-carbon internal aldehyde selectivity.
2012년에 Mathey 연구팀은 자체 개발한 리간드를 활용하여 3치환 올레핀 하이드로포밀화 반응을 진행하여, 총 3가지 종류의 3치환 올레핀을 이용하여 하이드로포밀화 반응을 진행한 결과, 전체적으로 낮거나 적당한 반응성과 낮은 선택성의 3차-탄소 내부알데하이드 비율을 보고하였다(F. Mathey, Organometallics, 2012, 31, 2186). 2013년에는 E. V. Gusevskaya 연구팀에서 알파-파이넨의 하이드로포밀화 반응을 트라이페닐포스파이트 리간드를 사용하여 고압과 장시간의 반응을 통해 진행하였다. 그 결과 좋은 반응성은 얻어내었지만 내부알데하이드의 선택성이 낮았으며, 용매로 사용한 에탄올로 인해 진행된 추가적인 화학반응으로 순수한 알데하이드를 얻어내지 못하였다(Elena V. Gusevskaya, ChemCatChem, 2013, 5, 1884). 지금까지 보고된 3치환 올레핀을 이용하여 하이드로포밀화 반응을 진행한 결과 전반적으로 낮거나 적당한 반응성을 보였으며 반응조건 역시 높은 가스압력 혹은 긴 반응시간 등이 필요하였다. 또한, 모두 적지 않은 이성질체를 생성하였으며 3차-탄소 내부 알데하이드의 낮은 선택성을 보여줌으로써 선택적인 하이드로포밀화 반응에 대해 성공적인 사례는 없는 실정이다.In 2012, Mathey and his colleagues conducted a tri-substituted olefin hydroformylation reaction using a proprietary ligand and conducted hydroformylation reactions using three types of tri-substituted olefins. As a result, Reported a low selectivity tertiary-carbon internal aldehyde ratio (F. Mathey, Organometallics , 2012, 31 , 2186). In 2013, EV Gusevskaya and colleagues carried out the hydroformylation of alpha-phyene using a triphenylphosphite ligand at high pressure and for a long time. As a result, good reactivity was obtained but the selectivity of the internal aldehyde was low, and pure aldehyde could not be obtained due to the additional chemical reaction proceeded by the ethanol used as the solvent (Elena V. Gusevskaya, ChemCat Chem , 2013, 5 , 1884). As a result of the hydroformylation reaction using the tri-substituted olefins reported so far, the reaction was generally low or moderate, and the reaction conditions required high gas pressure or long reaction time. In addition, there are no successful examples of selective hydroformylation reactions by producing all too few isomers and showing low selectivity of tertiary-carbon internal aldehydes.
따라서 이전에 보고된 연구결과에도 보였듯이, 3치환 올레핀의 하이드로포밀화 반응의 경우, 반응과정 중 일어나는 이성질화 현상을 제어하고 본래의 내부 올레핀 위치에서 생성되는 3차-탄소 내부 알데하이드를 선택적으로 얻어내는 것이 매우 중요하며 도전적인 부분이다.Thus, as has been shown previously in the reported results, in the case of the hydroformylation of tri-substituted olefins, the tertiary-carbon internal aldehyde generated at the original internal olefin site is selectively removed It is a very important and challenging part.
한편 본 발명자들은 대한민국 특허 제10-1574071호에서 두 고리 구조를 갖는 포스포라미다이트를 개발하였으며, 상기 촉매가 Rh-촉매 콘쥬게이트 첨가 반응(Rh(I)-catalyzed conjugate addition) 및 Pd-촉매 스틸레 커플링 반응(Pd(0)- catalyzed Stille coupling)에 적용시 종래 선형 인 리간드에 비해 빠른 반응속도를 보여 극적인 리간드 촉진 효과(LAE, ligand acceleration effect)를 가지고 있음을 확인한 바 있다.Meanwhile, the present inventors have developed a phosphoramidite having two ring structures in Korean Patent No. 10-1574071, and have found that the above-mentioned catalyst can be used for Rh-catalyzed conjugate addition (Rh (I) -catalyzed conjugate addition) and Pd- (Pd (0) - catalyzed Stille coupling) has a dramatic increase in ligand acceleration effect (LAE) compared to conventional linear ligands.
이러한 기술 배경하에, 본 발명자들은 3치환 올레핀의 하이드로 포밀화 반응을 제어하여 3차-탄소 내부 알데하이드를 선택적으로 제조할 수 있는 시스템을 개발하기 위하여 예의 노력한 결과, 두 고리 구조를 갖는 포스포라미다이트 유도체를 촉매로 사용할 경우, 반응수율이 높을 뿐만 아니라, 3차-탄소 내부 알데하이드를 선택적으로 대량 생산할 수 있는 것을 확인하고 본 발명을 완성하게 되었다.Under these technical backgrounds, the present inventors have made intensive efforts to develop a system capable of selectively producing a tertiary-carbon internal aldehyde by controlling the hydroformylation reaction of a tri-substituted olefin. As a result, the present inventors have found that a phosphoramidite Derivative as a catalyst, it was found that not only the reaction yield was high but also the tertiary-carbon internal aldehyde could be selectively mass-produced, thereby completing the present invention.
본 배경기술 부분에 기재된 상기 정보는 오직 본 발명의 배경에 대한 이해를 향상시키기 위한 것이며, 이에 본 발명이 속하는 기술분야에서 통상의 지식을 가지는 자에게 있어 이미 알려진 선행기술을 형성하는 정보를 포함하지 않을 수 있다.The information described in the Background section is intended only to improve the understanding of the background of the present invention and thus does not include information forming a prior art already known to those skilled in the art .
본 발명의 목적은 두 고리 구조를 갖는 포스포라미다이트(bicyclic bridgehead phosphoramidite) 유도체를 제공하는 것이다.It is an object of the present invention to provide a bicyclic bridgehead phosphoramidite derivative having two ring structures.
본 발명의 다른 목적은 두 고리 구조를 갖는 포스포라미다이트(bicyclic bridgehead phosphoramidite) 유도체의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for producing a bicyclic bridgehead phosphoramidite derivative having two ring structures.
본 발명의 또 다른 목적은 두 고리 구조를 갖는 포스포라미다이트(bicyclic bridgehead phosphoramidite) 유도체의 용도를 제공하는 것이다.It is another object of the present invention to provide a use of a bicyclic bridgehead phosphoramidite derivative having two ring structures.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 두 고리 구조를 갖는 포스포라미다이트 유도체(bicyclic bridgehead phophoramidite derivatives)를 제공한다:In order to achieve the above object, the present invention provides bicyclic bridgehead phophoramidite derivatives having two ring structures represented by the following formula (1)
[화학식 1][Chemical Formula 1]
상기 화학식 1에서,In Formula 1,
R’ 및 R’‘는 각각 독립적으로 (C1-20) 알킬 또는 할로겐이고;R 'and R " are each independently (C1-20) alkyl or halogen;
a 및 b는 각각 독립적으로 1 내지 4의 정수이되, a와 b는 동시에 0이 아니며,a and b are each independently an integer of 1 to 4, a and b are not 0 at the same time,
R은 수소, (C1-C20)알킬, (C3-C20)사이클로알킬, (C6-C20)아릴, (C7-C20)바이사이클로알킬 또는 방향족고리가 융합된 (C3-C20)사이클로알킬이고; R is (C3-C20) cycloalkyl fused with hydrogen, (C1-C20) alkyl, (C3-C20) cycloalkyl, (C6-C20) aryl, (C7-C20) bicycloalkyl or aromatic ring;
상기 R의 아릴, 사이클로알킬, 아릴 및 바이사이클로알킬은 각각 (C1-C20)알킬, (C3-C20)시클로알킬, (C1-C20)알콕시, 할로겐, 할로(C1-C20)알킬, (C6-C20)아릴 및 (C1-C20)알킬(C6-C20)아릴로 이루어진 군으로부터 선택되는 하나 이상의 치환체로 더 치환될 수 있다.The aryl, cycloalkyl, aryl and bicycloalkyl of R are each independently selected from the group consisting of (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, (C 1 -C 20) alkoxy, C20) aryl and (C1-C20) alkyl (C6-C20) aryl.
본 발명은 또한, 1) 하기 화학식 2의 다이하이드록시벤조페논과 하기 화학식 3의 일차아민 화합물을 반응시켜 하기 화학식 4의 이민 화합물을 제조하는 단계;The present invention also provides a process for preparing an imine compound represented by the following formula (4): (1) reacting a dihydroxybenzophenone represented by the following formula (2) with a primary amine compound represented by the following formula (3)
2) 하기 화학식 4의 이민 화합물을 환원시켜 하기 화학식 5의 이차아민 화합물을 제조하는 단계; 및2) reducing an imine compound of the following formula (4) to prepare a secondary amine compound of the following formula (5); And
3) 하기 화학식 5의 이차아민 화합물과 화학식 6의 포스포러스 화합물을 반응시켜 하기 화학식 1의 두 고리 구조를 갖는 포스포라미다이트를 제조하는 단계;3) reacting a secondary amine compound represented by the following formula (5) with a phosphorus compound represented by the following formula (6) to produce phosphoramidite having two ring structures represented by the following formula (1);
를 포함하는 하기 화학식 1의 두 고리 구조를 갖는 포스포라미다이트(bicyclic bridgehead phosphoramidite) 유도체의 제조방법을 제공한다:A bicyclic bridgehead phosphoramidite derivative having two ring structures represented by the following formula (1): < EMI ID = 1.0 >
[화학식 1][Chemical Formula 1]
[화학식 2](2)
[화학식 3](3)
[화학식 4][Chemical Formula 4]
[화학식 5][Chemical Formula 5]
[화학식 6][Chemical Formula 6]
상기 화학식 1, 2, 3, 4, 5 및 6에서,In the
R’ 및 R’‘는 각각 독립적으로 (C1-20) 알킬 또는 할로겐이고;R 'and R " are each independently (C1-20) alkyl or halogen;
a 및 b는 각각 독립적으로 1 내지 4의 정수이되, a와 b는 동시에 0이 아니며,a and b are each independently an integer of 1 to 4, a and b are not 0 at the same time,
R은 수소, (C1-C20)알킬, (C3-C20)사이클로알킬, (C6-C20)아릴, (C7-C20)바이사이클로알킬 또는 방향족고리가 융합된 (C3-C20)사이클로알킬이고, 상기 R의 아릴, 사이클로알킬, 아릴 및 바이사이클로알킬은 각각 (C1-C20)알킬, (C3-C20)시클로알킬, (C1-C20)알콕시, 할로겐, 할로(C1-C20)알킬, (C6-C20)아릴 및 (C1-C20)알킬(C6-C20)아릴로 이루어진 군으로부터 선택되는 하나 이상의 치환체로 더 치환될 수 있고;R is (C3-C20) cycloalkyl fused with hydrogen, (C1-C20) alkyl, (C3-C20) cycloalkyl, (C1-C20) alkyl, (C3-C20) cycloalkyl, (C1-C20) alkoxy, halogen, halo ) Aryl and (C1-C20) alkyl (C6-C20) aryl;
R15, R16 및 R17은 각각 독립적으로 다이(C1-C20)알킬아미노, (C1-C20)알콕시 또는 할로겐이다.R15, R16 and R17 are each independently a di (C1-C20) alkylamino, (C1-C20) alkoxy or halogen.
본 발명은 또한, 3치환 올레핀을 반응기질로 하고, 상기 두 고리 구조를 갖는 포스포라미다이트 유도체를 촉매로 하는 하이드로포밀화 반응을 통한 알데하이드의 제조방법을 제공한다.The present invention also provides a process for preparing an aldehyde by hydroformylation reaction using a tri-substituted olefin as a reaction substrate and a phosphoramidite derivative having the two-ring structure as a catalyst.
본 발명에 따른 두 고리 구조를 갖는 포스포라미다이트 유도체는 포스포라미다이트는 금속 d-오비탈과 P-N 결합의 σ*-오비탈 사이의 각도의 변화로 인해 π-결합력을 증가시킨 강한 π-받개 리간드로서, 낮은 산화상태의 전이금속을 촉매로 이용하는 화학반응에 적용시 반응의 활성도를 현저하게 증가시키는 효과가 있다.The phosphoramidite derivative having two ring structures according to the present invention is a strong π-acceptor ligand which increases the π-bonding force due to the change in the angle between the metal d-orbital and the σ * -orientation of the PN bond , It has an effect of remarkably increasing the activity of the reaction when applied to a chemical reaction using a transition metal having a low oxidation state as a catalyst.
특히, 본 발명의 두 고리 구조를 갖는 포스포라미다이트는 기하구속된 인 리간드로, 3치환 올레핀을 반응물질로 하는 하이드로포밀화 반응에서 3차-탄소 내부 알데하이드의 선택성 및 생산 수율을 높이는데 유용하다.In particular, the phosphoramidite having two ring structures of the present invention is a geometrically bound phosphorus ligand, and is useful for increasing the selectivity and production yield of the tert-carbon internal aldehyde in a hydroformylation reaction using a tri-substituted olefin as a reactant .
도 1은 본 발명의 일 실시예에서 합성한 두 고리 구조를 갖는 포스포라미다이트 유도체 및 기존 공지 리간드의 3치환 올레핀 반응물질에 대한 생산 수율을 정리한 것이다.
도 2는 본 발명의 일 실시예에서 합성한 tBu브리포스(3,5-MeOPh) 리간드의 결정 구조를 나타낸 것이다.
도 3은 본 발명의 일 실시예에서 합성한 tBu브리포스(3,5-MeOPh) 리간드를 이용하여 다양한 3치환 올레핀을 반응물질로 한 하이드로포밀화 반응 결과를 정리한 것이다.FIG. 1 shows the production yields of a phosphoramidite derivative having two ring structures synthesized in an embodiment of the present invention and a known ligand with respect to a tri-substituted olefin reactant.
Figure 2 shows the crystal structure of a synthesized tBu briFose (3,5-MeOPh) ligand in one embodiment of the present invention.
FIG. 3 is a table summarizing the results of hydroformylation reaction using various trisubstituted olefins as a reaction material using tBu brioose (3,5-MeOPh) ligand synthesized in one embodiment of the present invention.
다른 식으로 정의되지 않는 한, 본 명세서에서 사용된 모든 기술적 및 과학적 용어들은 본 발명이 속하는 기술분야에서 숙련된 전문가에 의해서 통상적으로 이해되는 것과 동일한 의미를 갖는다. 일반적으로 본 명세서에서 사용된 명명법은 본 기술분야에서 잘 알려져 있고 통상적으로 사용되는 것이다. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is well known and commonly used in the art.
본 발명에 기재된 용어 「알킬」은 탄소 및 수소 원자만으로 구성된 1가의 직쇄 또는 분쇄 포화 탄화수소 라디칼을 의미하는 것으로, 이러한 알킬 라디칼의 예는 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, t-부틸, 펜틸, 헥실, 옥틸, 도데실 등을 포함하지만 이에 한정되지는 않는다.The term " alkyl " as used herein refers to a monovalent straight or branched saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms. Examples of such alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Butyl, pentyl, hexyl, octyl, dodecyl, and the like.
본 발명에 기재된 용어 「알콕시」는 -O-알킬 라디칼을 의미하는 것으로, 여기서 '알킬'은 상기 정의한 바와 같다. 이러한 알콕시 라디칼의 예는 메톡시, 에톡시, 이소프로폭시, 부톡시, 이소부톡시, t-부톡시 등을 포함하지만 이에 한정되지는 않는다.The term " alkoxy " as used in the present invention means an -O-alkyl radical, where 'alkyl' is as defined above. Examples of such alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy and the like.
본 발명에 기재된 용어 「사이클로알킬」는 하나의 고리로 구성된 1가의 지환족 알킬 라디칼을 의미하는 것으로, 사이클로알킬의 예는 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸, 사이클로옥틸, 사이클로노닐, 사이클로데실 등을 포함하지만 이에 한정되지는 않는다.The term " cycloalkyl " as used in the present invention means a monovalent alicyclic alkyl radical consisting of one ring, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclo Nonyl, cyclodecyl, and the like.
본 발명에 기재된 용어 「아릴」는 하나의 수소 제거에 의해서 방향족 탄화수소로부터 유도된 유기 라디칼로, 각 고리에 적절하게는 4 내지 7개, 바람직하게는 5 또는 6개의 고리원자를 포함하는 단일 또는 융합고리계를 포함하며, 다수개의 아릴이 단일결합으로 연결되어 있는 형태까지 포함한다. 구체적인 예로 페닐, 나프틸, 비페닐, 안트릴, 인데닐(indenyl), 플루오레닐 등을 포함하지만, 이에 한정되지는 않는다.The term " aryl ", as used herein, refers to an organic radical derived from an aromatic hydrocarbon by the removal of one hydrogen, with a single or fused ring containing, suitably, 4 to 7, preferably 5 or 6 ring atoms in each ring A ring system, and a form in which a plurality of aryls are connected by a single bond. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, and the like.
본 발명에 기재된 용어 「바이사이클로알킬」는 포화 또는 부분적으로 불포화된 융합 두 고리형(bicyclic) 또는 브릿지된(bridged) 다중고리형 고리 라디칼을 의미하는 것으로, 바이사이클로알킬의 예는 바이사이클로[2.2.1]헵틸, 바이사이클로[2.2.2]옥틸, 바이사이클로[3.1.1]헵틸, 바이사이클로[3.2.1]옥틸, 바이사이클로[3.3.1]노닐, 바이사이클로[3.3.2]데실 등을 포함하지만 이에 한정되지는 않는다.The term " bicycloalkyl ", as used herein, refers to a saturated or partially unsaturated fused two bicyclic or bridged multicyclic ring radical, examples of bicycloalkyl being bicyclo [2.2 3] heptyl, bicyclo [3.3.1] octyl, bicyclo [3.3.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] But are not limited to.
본 발명에 기재된 용어 「할로겐」은 불소, 염소, 브롬 또는 요오드 원자를 의미한다.The term " halogen " as used in the present invention means a fluorine, chlorine, bromine or iodine atom.
본 발명에 기재된 용어 「할로알킬」는 상기 정의된 할로겐 원자로 치환된 알킬라디칼을 의미하는 것으로, 할로알킬의 예는 플루오로메틸, 디플루오로메틸, 트리플루오로메틸, 플루오로에틸, 디플루오로에틸, 브로모프로필 등을 포함하지만 이에 한정되지는 않는다.The term " haloalkyl " as used herein refers to an alkyl radical substituted with a halogen atom as defined above, examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoro Ethyl, bromopropyl, and the like.
본 발명에 기재된 용어 「알킬아릴」는 상기 정의된 알킬 라디칼로 치환된 아릴 라디칼을 의미한다. 알킬아릴 라디칼의 예는 톨릴, 크실릴, 메시틸 등을 포함하지만, 이에 한정되지는 않는다.The term " alkylaryl " as defined in the present invention means an aryl radical substituted with an alkyl radical as defined above. Examples of alkylaryl radicals include, but are not limited to, tolyl, xylyl, mesityl, and the like.
본 발명에 기재된 용어 「방향족고리가 융합된 사이클로알킬」는 방향족 탄화수소 환이 상기 정의된 사이클로알킬 라디칼의 두 개의 인접한 탄소 원자에 융합됨을 의미한다.The term "cycloalkyl fused with an aromatic ring" as used herein means that an aromatic hydrocarbon ring is fused to two adjacent carbon atoms of a cycloalkyl radical as defined above.
본 발명에 기재된 용어 「3차-탄소 내부 알데하이드」는 3치환 올레핀의 이성질화 없이 하이드로포밀화 반응을 통해 제조되는 알데하이드를 의미한다. 바람직하게는, 하기 반응식 1에서 이성질화(isomerization)를 통해 생산되는 아래 패널의 알데하이드가 아닌, 윗 패널의 알데하이드를 의미한다.(체크 요망)The term " tertiary-carbon internal aldehyde " as used in the present invention means an aldehyde prepared via a hydroformylation reaction without isomerization of tri-substituted olefins. Preferably, it refers to the upper panel aldehyde rather than the aldehyde of the lower panel produced via isomerization in
[반응식 1][Reaction Scheme 1]
본 발명에서는 두 고리 구조를 갖는 포스포라미다이트 유도체의 3치환 올레핀의 하이드로포밀화 반응에서의 촉매 효과를 확인하고자 하였다. In the present invention, the catalytic effect of the phosphoramidite derivative having two ring structures in the hydroformylation reaction of the tri-substituted olefin was examined.
즉, 본 발명의 일 실시예에서는 본 발명자가 기존 특허(대한민국특허 제10-1574071)에서 개발한 브리포스 리간드의 구조를 변화시켜 입체 및 전자제어를 통해 새로운 구조의 브리포스 리간드를 합성하였다. 즉, 브리포스를 합성하는데 기본이 되는 골격인 2,2’-다이하이드록시벤조페논의 오쏘(ortho-)와 파라(para-) 위치에 수소 대신 3차-부틸 혹은 염소를 치환하면서 기존의 2,2’-다이하이드록시벤조페논에 비해 변형된 구조를 얻었고, 변형된 기본 골격을 통해 각각의 변형된 tBu브리포스 와 Cl브리포스를 합성하였다. That is, in one embodiment of the present invention, the present inventors have modified the structure of the biphospholys ligand developed in the existing patent (Korean Patent No. 10-1574071) to synthesize a new structure of the biphos ligand through stereoscopic and electronic control. That is, the ortho- and para-positions of 2,2'-dihydroxybenzophenone, which is the basic skeleton for synthesizing the bifurc, are substituted with tert-butyl or chlorine instead of hydrogen at the para- , 2'-dihydroxybenzophenone, and synthesized the modified tBu and Cl brios through modified basic frameworks.
신규 합성한 브리포스 유도체, 기존에 개발한 브리포스 및 상업적으로 판매되는 리간드를 이용하여 1-메틸사이클로헥센(1-methylcyclohexene)을 3치환 올레핀 기질로 하여 하이드로포밀화 반응을 실시한 결과, 본 발명에서 합성한 브리포스 유도체가 알데하이드의 생산능이 뛰어날 뿐만 아니라, 3차-탄소 내부 알데하이드의 선택성 역시 탁월한 것을 확인하였다(도 1). As a result of hydroformylation reaction using 1-methylcyclohexene as a tri-substituted olefin substrate using a newly synthesized bifunctional derivative, a previously developed bifurcate and a commercially available ligand, It was confirmed that the synthesized bryophous derivatives not only excelled in the ability to produce aldehyde, but also had excellent selectivity for tertiary-carbon internal aldehyde (Fig. 1).
따라서, 본 발명은 일 관점에서 하기 화학식 1로 표시되는 두 고리 구조를 갖는 포스포라미다이트 유도체(bicyclic bridgehead phophoramidite derivatives)에 관한 것이다:Accordingly, the present invention relates, in one aspect, to bicyclic bridgehead phophoramidite derivatives having two ring structures represented by the following formula (1): < EMI ID =
[화학식 1][Chemical Formula 1]
상기 화학식 1에서,In
R’ 및 R’‘는 각각 독립적으로 (C1-20) 알킬 또는 할로겐이고;R 'and R " are each independently (C1-20) alkyl or halogen;
a 및 b는 각각 독립적으로 1 내지 4의 정수이되, a와 b는 동시에 0이 아니며,a and b are each independently an integer of 1 to 4, a and b are not 0 at the same time,
R은 수소, (C1-C20)알킬, (C3-C20)사이클로알킬, (C6-C20)아릴, (C7-C20)바이사이클로알킬 또는 방향족고리가 융합된 (C3-C20)사이클로알킬이고; R is (C3-C20) cycloalkyl fused with hydrogen, (C1-C20) alkyl, (C3-C20) cycloalkyl, (C6-C20) aryl, (C7-C20) bicycloalkyl or aromatic ring;
상기 R의 아릴, 사이클로알킬, 아릴 및 바이사이클로알킬은 각각 (C1-C20)알킬, (C3-C20)시클로알킬, (C1-C20)알콕시, 할로겐, 할로(C1-C20)알킬, (C6-C20)아릴 및 (C1-C20)알킬(C6-C20)아릴로 이루어진 군으로부터 선택되는 하나 이상의 치환체로 더 치환될 수 있다.The aryl, cycloalkyl, aryl and bicycloalkyl of R are each independently selected from the group consisting of (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, (C 1 -C 20) alkoxy, C20) aryl and (C1-C20) alkyl (C6-C20) aryl.
본 발명에 있어서, 상기 R은 하기 구조로부터 선택되는 것을 특징할 수 있다:In the present invention, R may be selected from the following structures:
상기 구조에서,In the above structure,
R1 및 R2는 각각 독립적으로 수소, (C1-C20)알킬, (C6-C20)아릴, (C3-C20)사이클로알킬이고, 상기 R1 및 R2의 알킬은 (C6-C20)아릴 또는 (C1-C20)알킬(C6-C20)아릴로 더 치환될 수 있고;(C1-C20) alkyl, (C6-C20) aryl, (C3-C20) cycloalkyl and the alkyl of R1 and R2 is (C6-C20) aryl or ) Alkyl (C6-C20) aryl;
R3 내지 R7은 각각 독립적으로 수소, (C1-C20)알킬, (C1-C20)알콕시, 할로겐, 할로(C1-C20)알킬 또는 (C6-C20)아릴이고; R3 to R7 are each independently hydrogen, (C1-C20) alkyl, (C1-C20) alkoxy, halogen, halo (C1-C20) alkyl or (C6-C20) aryl;
n은 1 내지 5의 정수이다.n is an integer of 1 to 5;
본 발명에 있어서, 상기 화학식 1의 두 고리 구조를 갖는 포스포라미다이트 유도체는 하기 구조로부터 선택될 수 있으나, 이에 한정되는 것은 아니다:In the present invention, the phosphoramidite derivative having two ring structures of
본 발명의 다른 관점에서 다음의 단계를 포함하는 두 고리 구조를 갖는 포스포라미다이트 유도체의 제조방법에 관한 것이다:In another aspect of the present invention, there is provided a process for preparing a phosphoramidite derivative having two ring structures, comprising the steps of:
1) 하기 화학식 2의 다이하이드록시벤조페논과 하기 화학식 3의 일차아민 화합물을 반응시켜 하기 화학식 4의 이민 화합물을 제조하는 단계;1) reacting a dihydroxybenzophenone represented by the following
2) 하기 화학식 4의 이민 화합물을 환원시켜 하기 화학식 5의 이차아민 화합물을 제조하는 단계; 및2) reducing an imine compound of the following formula (4) to prepare a secondary amine compound of the following formula (5); And
3) 하기 화학식 5의 이차아민 화합물과 화학식 6의 포스포러스 화합물을 반응시켜 하기 화학식 1의 두 고리 구조를 갖는 포스포라미다이트를 제조하는 단계;3) reacting a secondary amine compound represented by the following formula (5) with a phosphorus compound represented by the following formula (6) to produce phosphoramidite having two ring structures represented by the following formula (1);
[화학식 1][Chemical Formula 1]
[화학식 2](2)
[화학식 3](3)
[화학식 4][Chemical Formula 4]
[화학식 5][Chemical Formula 5]
[화학식 6][Chemical Formula 6]
상기 화학식 1, 2, 3, 4, 5 및 6에서,In the
R’ 및 R’‘는 각각 독립적으로 (C1-20) 알킬 또는 할로겐이고;R 'and R " are each independently (C1-20) alkyl or halogen;
a 및 b는 각각 독립적으로 1 내지 4의 정수이되, a와 b는 동시에 0이 아니며,a and b are each independently an integer of 1 to 4, a and b are not 0 at the same time,
R은 수소, (C1-C20)알킬, (C3-C20)사이클로알킬, (C6-C20)아릴, (C7-C20)바이사이클로알킬 또는 방향족고리가 융합된 (C3-C20)사이클로알킬이고, 상기 R의 아릴, 사이클로알킬, 아릴 및 바이사이클로알킬은 각각 (C1-C20)알킬, (C3-C20)시클로알킬, (C1-C20)알콕시, 할로겐, 할로(C1-C20)알킬, (C6-C20)아릴 및 (C1-C20)알킬(C6-C20)아릴로 이루어진 군으로부터 선택되는 하나 이상의 치환체로 더 치환될 수 있고;R is (C3-C20) cycloalkyl fused with hydrogen, (C1-C20) alkyl, (C3-C20) cycloalkyl, (C1-C20) alkyl, (C3-C20) cycloalkyl, (C1-C20) alkoxy, halogen, halo ) Aryl and (C1-C20) alkyl (C6-C20) aryl;
R15, R16 및 R17은 각각 독립적으로 다이(C1-C20)알킬아미노, (C1-C20)알콕시 또는 할로겐이다.R15, R16 and R17 are each independently a di (C1-C20) alkylamino, (C1-C20) alkoxy or halogen.
본 발명의 일 실시예에 따른 상기 화학식 6의 포스포러스 화합물은 보다 바람직하게는 하기 화학식 7의 헥사알킬포스포러스 트리아미드, 화학식 8의 포스파이트 또는 화학식 9의 포스포러스 트라이할라이드일 수 있다.The phosphorus compound of formula (6) according to an embodiment of the present invention may more preferably be a hexaalkylphosphorus triamide of the following formula (7), a phosphite of the formula (8) or a phosphorus trihalide of the formula (9).
[화학식 7](7)
[화학식 8][Chemical Formula 8]
[화학식 9][Chemical Formula 9]
상기 화학식 7, 8 및 9에서, R21, R22 및 R23은 각각 독립적으로 (C1-C20)알킬이고, X는 할로겐이다.In the general formulas (7), (8) and (9), R21, R22 and R23 are each independently (C1-C20) alkyl and X is halogen.
본 발명에 있어서, 상기 화학식 3의 일차아민 화합물은 하기 구조로부터 선택되는 것을 특징으로 할 수 있다:In the present invention, the primary amine compound of
상기 구조에서,In the above structure,
R1 및 R2는 각각 독립적으로 수소, (C1-C20)알킬, (C6-C20)아릴, (C3-C20)사이클로알킬이고, 상기 R1 및 R2의 알킬은 (C6-C20)아릴 또는 (C1-C20)알킬(C6-C20)아릴로 더 치환될 수 있고;(C1-C20) alkyl, (C6-C20) aryl, (C3-C20) cycloalkyl and the alkyl of R1 and R2 is (C6-C20) aryl or ) Alkyl (C6-C20) aryl;
R3 내지 R7은 각각 독립적으로 수소, (C1-C20)알킬, (C1-C20)알콕시, 할로겐, 할로(C1-C20)알킬 또는 (C6-C20)아릴이고; R3 to R7 are each independently hydrogen, (C1-C20) alkyl, (C1-C20) alkoxy, halogen, halo (C1-C20) alkyl or (C6-C20) aryl;
n은 1 내지 5의 정수이다.n is an integer of 1 to 5;
상업적으로 이용가능한 화학식 2의 2,2'-디하이드록시벤조페논을 화학식 3의 1차아민 화합물과 반응시켜 화학식 4의 이민 화합물을 제조한다. 화합물 2의 2,2'-디하이드록시벤조페논의 내부 수소 결합은 화학식 4의 이민 화합물의 형성을 상당히 촉진시키고, 생성된 화학식 4의 이민 화합물은 축방향 화합물(axial compounds)과 키랄 금속 착화합물(chiral-at-metal complexes)의 입체선택적 생성(stereoselective generation)을 위해 사용된다.A commercially available 2,2'-dihydroxybenzophenone of formula (2) is reacted with a primary amine compound of formula (3) to produce an imine compound of formula (4). The internal hydrogen bonding of the 2,2'-dihydroxybenzophenone of
본 발명의 일 실시예에 따른 화학식 3의 1차아민 화합물은 화학식 2의 2,2'-디하이드록시벤조페논에 대하여 과량 사용하며, 바람직하게는 화학식 2의 2,2'-디하이드록시벤조페논 1당량에 대하여 1.1 내지 100당량으로 사용한다.The primary amine compound of
본 발명의 일 실시예에 따른 화학식 4의 이민 화합물을 제조하기 위한 반응온도는 화학식 3의 일차아민 화합물의 종류에 따라 조절될 수 있으며, 바람직하게는 상온 내지 250℃에서 수행된다. 예를 들어 일차아민 화합물로 사이클로알킬아민을 사용한 경우 상온에서 진행되었으나, 아닐린을 사용한 경우에는 온도를 상승시키는 것이 필요했다. 또한, 전자-결핍 친환체가 도입된 아닐린을 사용한 경우에는 수율을 향상시키기 위하여 마이크로웨이브를 조사하기도 하였다.The reaction temperature for preparing the imine compound of
본 발명의 일 실시예에 따른 상기 화학식 4의 이민 화합물의 제조는 유기 용매 하에서 또는 니트(neat)로도 이루어질 수 있으며, 상기 반응물질을 용해할 수 있는 것이라면 유기용매에 제한을 둘 필요는 없다. 니트(neat)라함은 유기 용매를 사용하지 않고 상기 화학식 2의 다이하이드록시벤조페논과 화학식 3의 일차아민 화합물을 섞어 상기 이민화 반응을 수행하는 것이다. 상기 반응의 용매로는 메탄올, 에탄올, 이소프로판올, 부탄올, 아세톤, 에틸 아세테이트, 아세토니트릴, 이소프로필 에테르, 메틸에틸케톤, 메틸렌 클로라이드, 다이클로로벤젠, 클로로벤젠, 다이클로로에탄, 테트라하이드로퓨란, 톨루엔, 벤젠, 크실렌, 메시틸렌(mesitylene), 다이메틸포름아미드, 및 다이메틸설폭사이드 등으로 이루어진 군으로부터 선택되는 불활성 용매인 것이 반응물의 용해성 및 제거의 용이성을 고려할 때 바람직하며, 메탄올, 에탄올 또는 이들의 혼합용매를 사용하는 것이 더욱 바람직하다.The imine compound of
상기 생성된 화학식 4의 이민 화합물의 분리 정제 없이 별도의 정제과정 없이 다음 반응에 사용하거나, 필요에 따라 정제과정을 거칠 수도 있다.The resulting imine compound of formula (4) can be used in the next reaction without purification and without purification, or may be subjected to purification if necessary.
생성된 화학식 4의 이민 화합물을 환원제를 사용하여 환원시켜 화학식 5의 이차아민 화합물을 제조한다.The resulting imine compound of formula (4) is reduced using a reducing agent to prepare a secondary amine compound of formula (5).
본 발명의 일 실시예에 따른 환원제는 금속수소화물을 사용할 수 있으며, 바람직하게는 NaBH4, NaBH(OAc)3, NaBH2(OAc)2, NaBH3OAc, NaBH3CN, KBH4, KBH(OAc), LiAlH4, B2H6 및 DIBAL-H(Diisobutylaluminium hydride)으로 구성된 군으로부터 선택되는 하나 이상을 사용할 수 있고, 보다 바람직하게는 NaBH4 또는 LiAlH4를 사용할 수 있다.The reducing agent according to an embodiment of the present invention can be a metal hydride. Preferably, the reducing agent is NaBH 4 , NaBH (OAc) 3 , NaBH 2 (OAc) 2 , NaBH 3 OAc, NaBH 3 CN, KBH 4 , KBH OAc), LiAlH 4 , B 2 H 6 and DIBAL-H (Diisobutylaluminium hydride), and more preferably NaBH 4 or LiAlH 4 can be used.
본 발명의 일 실시예에 따른 환원제의 함량은 제한되는 것은 아니나, 화학식 4의 이민 화합물에 대하여 동등 또는 과량 사용하며, 바람직하게는 화학식 4의 이민 화합물 1당량에 대하여 1 내지 100당량으로 사용한다.The amount of the reducing agent according to one embodiment of the present invention is not limited, but the same or an excess amount is used for the imine compound of the formula (4), preferably 1 to 100 equivalents based on 1 equivalent of the imine compound of the formula (4).
본 발명의 일 실시예에 따른 화학식 5의 이차아민 화합물을 제조하기 위한 반응온도는 상온 내지 250 ℃에서 수행된다.The reaction temperature for preparing the secondary amine compound of Formula 5 according to an embodiment of the present invention is from room temperature to 250 ° C.
본 발명의 일 실시예에 따른 상기 화학식 5의 이차아민 화합물의 제조는 유기 용매 하에서 이루어질 수 있으며, 상기 반응물질을 용해할 수 있는 것이라면 유기용매에 제한을 둘 필요는 없다. 상기 반응의 용매로는 메탄올, 에탄올, 이소프로판올, 아세톤, 에틸 아세테이트, 아세토니트릴, 이소프로필 에테르, 메틸에틸케톤, 메틸렌 클로라이드, 다이클로로벤젠, 클로로벤젠, 다이클로로에탄, 테트라하이드로퓨란, 톨루엔, 벤젠 및 크실렌으로 이루어진 군으로부터 선택되는 불활성 용매인 것이 반응물의 용해성 및 제거의 용이성을 고려할 때 바람직하며, 메탄올, 에탄올 또는 이들의 혼합용매를 사용하는 것이 더욱 바람직하다.The preparation of the secondary amine compound of Formula 5 according to an embodiment of the present invention may be carried out in an organic solvent, and the organic solvent is not limited as long as it can dissolve the reaction material. The solvent of the reaction may be selected from the group consisting of methanol, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, isopropyl ether, methyl ethyl ketone, methylene chloride, dichlorobenzene, chlorobenzene, dichloroethane, tetrahydrofuran, Xylene. It is more preferable to use an inert solvent selected from the group consisting of methanol, ethanol or a mixed solvent thereof in view of the solubility and ease of removal of the reactants.
상기 화학식 5의 이차아민 화합물과 화학식 6의 포스포러스 화합물을 반응시켜 화학식 1의 두고리 구조를 갖는 포스포라미다이트를 제조한다.The secondary amine compound of Formula 5 and the phosphorus compound of Formula 6 are reacted to prepare phosphoramidite having a tripod structure of
본 발명의 일 실시예에 따른 화학식 6의 포스포러스 화합물은 화학식 5의 이차아민 화합물에 대하여 과량 사용하며, 바람직하게는 화학식 5의 이차아민 화합물 1당량에 대하여 1 내지 20 당량으로 사용한다.The phosphorus compound of Formula 6 according to an embodiment of the present invention is used in an excess amount relative to the secondary amine compound of Formula 5, preferably 1 to 20 equivalents based on 1 equivalent of the secondary amine compound of Formula 5.
본 발명의 일 실시예에 따른 화학식 1의 두고리 구조를 갖는 포스포라미다이트를 제조하기 위한 반응온도는 -78 내지 100 ℃에서 수행된다.The reaction temperature for preparing the phosphoramidite having the triply structure of
본 발명의 일 실시예에 따른 상기 화학식 1의 두고리 구조를 갖는 포스포라미다이트의 제조는 유기 용매 하에서 이루어질 수 있으며, 상기 반응물질을 용해할 수 있는 것이라면 유기용매에 제한을 둘 필요는 없다. 상기 반응의 용매로는 메탄올, 에탄올, 이소프로판올, 아세톤, 에틸 아세테이트, 아세토니트릴, 이소프로필 에테르, 메틸에틸케톤, 메틸렌 클로라이드, 다이클로로벤젠, 클로로벤젠, 다이클로로에탄, 테트라하이드로퓨란, 톨루엔, 벤젠 및 크실렌 등을 사용할 수 있다.The preparation of phosphoramidite having a tripod structure according to an embodiment of the present invention can be carried out in an organic solvent. The organic solvent is not limited as long as it can dissolve the reactant. The solvent of the reaction may be selected from the group consisting of methanol, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, isopropyl ether, methyl ethyl ketone, methylene chloride, dichlorobenzene, chlorobenzene, dichloroethane, tetrahydrofuran, Xylene, and the like.
본 발명의 일 실시예에 따른 반응은 TLC 등을 통하여 출발물질이 모두 소모되었음을 확인 후 반응을 완결시키도록 한다. 반응이 완결되면 필요에 따라 감압 하에서 용매를 증류시킨 후, 관 크로마토그래피 등의 통상의 방법을 통하여 목적물을 분리 정제할 수 있다.In the reaction according to an embodiment of the present invention, the starting material is completely consumed through TLC or the like, and the reaction is completed. After the reaction is completed, the solvent can be distilled off under reduced pressure if necessary, and the desired product can be separated and purified through a conventional method such as column chromatography.
한편 본 발명의 다른 실시예에서는 본 발명에서 합성한 두 고리 구조를 갖는 포스포라미다이트 유도체가 다양한 종류의 3치환 올레핀을 기질로 하는 하이드로포밀화 반응에서도 그 효롸를 나타내는지를 확인하고자 하였다.In another embodiment of the present invention, it has been attempted to confirm whether the phosphoramidite derivative having two ring structures synthesized in the present invention is effective in the hydroformylation reaction using various kinds of tri-substituted olefins as substrates.
즉, 본 발명의 다른 실시예에서는 tBu브리포스(3,5-MeOPh) 리간드를 이용하여 다양한 3치환 올레핀 하이드로포밀화 반응을 실시한 결과, 도 3에 개시된 바와 같이 주로 99% 이상의 좋은 반응성과 70% 이상의 내부 알데하이드 선택성을 확인할 수 있었다. That is, in another embodiment of the present invention, various tri-substituted olefin hydroformylation reactions were carried out using tBu briPose (3,5-MeOPh) ligand. As shown in FIG. 3, The internal aldehyde selectivity was confirmed.
따라서, 본 발명은 또 다른 관점에서, 하기 화학식 1로 표시되는 두 고리 구조를 갖는 포스포라미다이트 유도체(bicyclic bridgehead phophoramidite derivatives) 및 로듐 또는 팔라듐 전이금속 촉매를 포함하는 올리핀계화합물의 하이드로포밀화 반응용 촉매 조성물에 관한 것이다:Accordingly, in another aspect, the present invention relates to a process for the hydroformylation of an olefinic compound comprising a bicyclic bridgehead phophoramidite derivative having two ring structures represented by the following formula (1) and a rhodium or palladium transition metal catalyst ≪ / RTI >
[화학식 1][Chemical Formula 1]
상기 화학식 1에서,In
R’ 및 R’‘는 각각 독립적으로 (C1-20) 알킬 또는 할로겐이고;R 'and R " are each independently (C1-20) alkyl or halogen;
a 및 b는 각각 독립적으로 1 내지 4의 정수이되, a와 b는 동시에 0이 아니며,a and b are each independently an integer of 1 to 4, a and b are not 0 at the same time,
R은 수소, (C1-C20)알킬, (C3-C20)사이클로알킬, (C6-C20)아릴, (C7-C20)바이사이클로알킬 또는 방향족고리가 융합된 (C3-C20)사이클로알킬이고; R is (C3-C20) cycloalkyl fused with hydrogen, (C1-C20) alkyl, (C3-C20) cycloalkyl, (C6-C20) aryl, (C7-C20) bicycloalkyl or aromatic ring;
상기 R의 아릴, 사이클로알킬, 아릴 및 바이사이클로알킬은 각각 (C1-C20)알킬, (C3-C20)시클로알킬, (C1-C20)알콕시, 할로겐, 할로(C1-C20)알킬, (C6-C20)아릴 및 (C1-C20)알킬(C6-C20)아릴로 이루어진 군으로부터 선택되는 하나 이상의 치환체로 더 치환될 수 있음The aryl, cycloalkyl, aryl and bicycloalkyl of R are each independently selected from the group consisting of (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, (C 1 -C 20) alkoxy, C20) aryl and (C1-C20) alkyl (C6-C20) aryl.
본 발명에 있어서, 상기 전이금속 촉매는 하이드로포밀화 반응에 이용될 수 있는 전이금속이면 제한없이 이용가능하나, 바람직하게는 Rh(C2H4)2(acac), Pd(dba)3 및 Rh(CO2)(acac)으로 구성된 군에서 선택된 1종 이상인 것을 특징으로 할 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the transition metal catalyst is a hydro-port one is available without a back-transition metal which can be limited using the milhwa reaction, preferably Rh (C 2 H 4) 2 (acac), Pd (dba) 3 , and Rh (CO 2 ) (acac), but the present invention is not limited thereto.
본 발명은 또한 상기 촉매 조성물의 존재 하에서 올레핀계 화합물과, 일산화탄소 및 수소의 합성기체를 반응시켜 알데히드를 제조하는 것을 특징으로 하는 올레핀계 화합물의 하이드로포밀화 방법에 관한 것이다.The present invention also relates to a process for the hydroformylation of olefinic compounds, characterized in that an aldehyde is produced by reacting an olefinic compound with a synthesis gas of carbon monoxide and hydrogen in the presence of the catalyst composition.
본 발명에 있어서, 상기 올레핀계 화합물은 3치환 올레핀인 것을 특징으로 할 수 있다.In the present invention, the olefin-based compound may be a tri-substituted olefin.
본 발명에 있어서, 상기 올레핀계 화합물은 화학식 10 또는 화학식 11로 표시되는 화합물인 것을 특징으로 할 수 있다:In the present invention, the olefin compound may be a compound represented by formula (10) or (11): < EMI ID =
[화학식 10] [Chemical formula 10]
[화학식 11] (11)
상기 화학식 10 및 11에서 R8, R9. R10 및 R11은 각각 독립적으로 수소, (C1-C20) 알킬, 불소, 염소, 브롬, 트리플루오로메틸 또는 0~5개의 치환기를 갖는 (C6-C20) 페닐기 이고, 상기 페닐기가 치환되는 경우, 치환기는 니트로, 불소, 염소, 브롬, 메틸, 에틸, 프로필, 또는 부틸기이다. In formulas (10) and (11), R 8 , R 9 . R 10 and R 11 are each independently hydrogen, (C 1 -C 20) alkyl, fluorine, chlorine, bromine, trifluoromethyl or (C 6 -C 20) phenyl group having 0-5 substituents, , The substituent is nitro, fluorine, chlorine, bromine, methyl, ethyl, propyl, or butyl group.
본 발명에 있어서, 상기 알데하이드는 3치환 올레핀의 하이드로포밀화 반응으로부터 생산되는 것이면 제한없이 이용가능하나, 바람직하게는 3차-탄소 내부 알데하이드인 것을 특징으로 할 수 있다.In the present invention, the aldehyde can be used without limitation as long as it is produced from the hydroformylation reaction of the tri-substituted olefin, but is preferably a tert-carbon internal aldehyde.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다. Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for illustrating the present invention and that the scope of the present invention is not construed as being limited by these embodiments.
상업적으로 이용가능한 화합물은 추가적인 정제 또는 건조 없이 사용하였다. 1H NMR (400 MHz), 13C NMR (100MHz) 및 31P NMR (162 MHz) 분석은 Bruker Ascend 400 또는 Bruker Avance III HD spectrometer을 사용하여 수행하였다. Mass 스펙트라는 Bruker Daltonik microTOF-Q II high-resolution mass spectrometer (ESI) 을 사용하여 분석하였다.Commercially available compounds were used without further purification or drying. 1 H NMR (400 MHz), 13 C NMR (100 MHz) and 31 P NMR (162 MHz) analyzes were performed using a Bruker Ascend 400 or Bruker Avance III HD spectrometer. Mass spectra were analyzed using a Bruker Daltonik microTOF-Q II high-resolution mass spectrometer (ESI).
[[ 실시예Example 1 내지 7]. 1 to 7]. tBu브리포스tBu Brephus 유도체의 제조 Preparation of derivatives
화합물 4a 내지 4g의 제조Preparation of compounds 4a to 4g
3,3’,5,5’-테트라-3차-부틸-2,2‘-다이하이드록시벤조피논(3,3’,5,5‘-tetra-tert-butyl-2,2’-dihydroxylbenzophenone)과 일차아민(3a 내지 3g) 10당량을 니트(neat) 조건하에서 반응을 수행하였다. 이때 반응 온도는 170℃에서 12시간동안 교반한 후, 생성되는 생성물은 컬럼관 크로마토그래피를 통해서 헥세인과 에틸아세테이트를 20:1 용리액으로 사용하여 분리하였다.3,3 ', 5,5'-tetra-tert-butyl-2,2'-dihydroxybenzophenone (3,3', 5,5'-tetra-tert-butyl-2,2'-dihydroxylbenzophenone ) And 10 equivalents of primary amines (3a to 3g) under neat conditions. At this time, the reaction temperature was maintained at 170 ° C. for 12 hours, and the resulting product was separated by column chromatography using hexane and ethyl acetate as a 20: 1 eluent.
화합물 5a 내지 5g의 제조Preparation of compounds 5a to 5g
이민화합물 1.0당량과 금속수소화물로서 LiAlH4를 3.0당량 취하여 테트라하이드로퓨란(THF) 용매하에서 4시간동안 교반기를 통해 반응을 진행하였다. 반응진행 후 과량으로 넣어준 금속수소화물시약(LiAlH4)에 에틸 아세테이트를 넣어주고 30분간 교반해준 뒤, 용매를 갑압을 통해 제거하였으며, 물과 에틸아세테이트를 이용해서 추출과정을 실시하였다. 그 다음 건조제(MgSO4)를 이용하여 건조시킨 뒤, 건조제를 제거 후 유기용매를 감압으로 제거하여 생성물을 수득하였다.1.0 equivalent of an imine compound and 3.0 equivalents of LiAlH 4 as a metal hydride were reacted in a tetrahydrofuran (THF) solvent for 4 hours through a stirrer. After the reaction, ethyl acetate was added to the excess metal hydride reagent (LiAlH 4 ), and the mixture was stirred for 30 minutes. Then, the solvent was removed through the autoclave and extraction was carried out using water and ethyl acetate. After drying with a desiccant (MgSO 4 ), the drying agent was removed, and the organic solvent was removed under reduced pressure to obtain a product.
화합물 1a 내지 1g의 제조Preparation of compounds 1a to 1g
상기 단계에서 수득한 이차아민 생성물 1.0 당량과 포스포러스 화합물(PBr3)1.1당량 그리고 염기인 트라이에틸아민(Et3N)3.3당량을 N2조건하에서 클로로폼을 용매로하여 교반기를 통해 반응을 진행하였다. 반응온도는 0 oC에서 진행하였고, 반응시간은 4시간이었다. 반응진행 후 반응 용액은 실리카를 이용하여 여과하고 이 과정에서의 용리액으로 에틸아세테이트를 이용하였다. 이후, 감압을 통해 에틸아세테이트를 제거한 뒤 에탄올을 이용하여 생성물을 침전시켰다. 침전된 생성물은 필터를 통해 분리하여 수득하였다.1.0 equivalents of the secondary amine product obtained in the above step, 1.1 equivalents of a phosphorus compound (PBr 3 ) and 3.3 equivalents of a base, triethylamine (Et 3 N) were reacted in a chloroform solvent under N 2 under a stirrer Respectively. The reaction temperature was 0 ° C and the reaction time was 4 hours. After the reaction, the reaction solution was filtered using silica, and ethyl acetate was used as an eluent in this process. Ethyl acetate was then removed through reduced pressure and the product was precipitated with ethanol. The precipitated product was isolated by filtration.
실시예 1(화합물 1a): 
흰색 고체: 1H NMR (400 MHz, CDCl3):δ ppm 7.15(d, J = 2.4 Hz, 2H), 7.00(d, J = 2.4 Hz, 2H), 4.92(d, J = 5.1 Hz, 1H), 3.07(qt, J = 11.4, 3.6 Hz, 1H), 1.83-1.67(m, 4H), 1.57(d, J = 15.9 Hz, 2H), 1.46-1.41(m, 1H), 1.38(s, 18H), 1.28(s, 18H), 1.21(dt, J = 13.1, 2.9 Hz, 2H), 1.171.01(m, 1H)White solid: 1 H NMR (400 MHz, CDCl 3): δ ppm 7.15 (d, J = 2.4 Hz, 2H), 7.00 (d, J = 2.4 Hz, 2H), 4.92 (d, J = 5.1 Hz, 1H ), 3.07 (qt, J = 11.4, 3.6 Hz, 1H), 1.83-1.67 (m, 4H), 1.57 (d, J = 15.9 Hz, 2H), 1.46-1.41 1H), 1.28 (s, 18H), 1.21 (dt, J = 13.1, 2.9 Hz, 2H), 1.171.01
13C NMR (100 MHz, CDCl3):δ ppm 146.3, 146.2, 137.9, 128.4, 128.3, 122.8, 122.1, 59.9, 59.7, 54.3, 35.1, 34.5, 34.1, 34.0, 31.7, 29.9, 26.1, 25.7 13 C NMR (100 MHz, CDCl 3 ):? Ppm 146.3, 146.2, 137.9, 128.4, 128.3, 122.8, 122.1, 59.9, 59.7, 54.3, 35.1, 34.5, 34.1, 34.0, 31.7, 29.9, 26.1, 25.7
31P NMR (162 MHz, CDCl3):δ ppm 94.9 31 P NMR (162 MHz, CDCl 3): δ ppm 94.9
HRMS(ESI) calculated for C35H52NO2P[M+H]+:550.3816,Found:550.3868HRMS (ESI) calculated for C 35 H 52 NO 2 P [M + H] + : 550.3816, Found: 550.3868
실시예 2(화합물 1b): 
흰색 고체: 1H NMR (400 MHz, CDCl3):δ ppm 7.26(d, J = 1.6 Hz, 2H), 7.20(d, J = 2.4 Hz, 2H), 7.13(dt, J = 2.2, 1.2 Hz, 1H), 7.11(q, J = 1.0 Hz, 1H), 7.09(d, J = 2.4 Hz, 2H), 7.00(tt, J = 7.4, 1.0 Hz, 1H), 5.5(d, J = 4.1 Hz, 1H), 1.39(s, 18H), 1.29(s, 18H)White solid: 1 H NMR (400 MHz, CDCl 3): δ ppm 7.26 (d, J = 1.6 Hz, 2H), 7.20 (d, J = 2.4 Hz, 2H), 7.13 (dt, J = 2.2, 1.2 Hz , 7.5 (d, J = 4.1 Hz, 2H), 7.00 (t, J = 7.4, 1.0 Hz, 1H) , 1 H), 1.39 (s, 18 H), 1.29 (s, 18 H)
13C NMR (100 MHz, CDCl3):δ ppm 146.0, 145.9, 144.8, 144.6, 144.5, 138.2(2), 129.5, 127.2(2), 123.3, 122.9, 122.8, 122.3, 120.8, 120.7, 56.3, 35.1, 34.6, 31.7, 29.9 13 C NMR (100 MHz, CDCl 3): δ ppm 146.0, 145.9, 144.8, 144.6, 144.5, 138.2 (2), 129.5, 127.2 (2), 123.3, 122.9, 122.8, 122.3, 120.8, 120.7, 56.3, 35.1 , 34.6, 31.7, 29.9
31P NMR (162 MHz, CDCl3):δ ppm 87.1 31 P NMR (162 MHz, CDCl 3): δ ppm 87.1
HRMS(ESI) calculated for C35H46NO2P[M+H]+:544.3346,Found:544.3330 HRMS (ESI) calculated for C 35
실시예 3(화합물 1c): 
흰색 고체: 1H NMR (400 MHz, CDCl3):δ ppm 7.21(d, J = 2.5 Hz, 2H), 7.12(d, J = 2.4 Hz, 2H), 6.76(dq, J = 1.6, 0.8 Hz, 2H), 6.66(tt, J = 1.5, 0.7 Hz, 1H), 5.55(d, J = 4.1 Hz, 1H), 2.26(q, J = 0.6 Hz, 6H), 1.42(s, 18H), 1.31(s, 18H)White solid: 1 H NMR (400 MHz, CDCl 3): δ ppm 7.21 (d, J = 2.5 Hz, 2H), 7.12 (d, J = 2.4 Hz, 2H), 6.76 (dq, J = 1.6, 0.8 Hz 2H), 6.66 (tt, J = 1.5, 0.7 Hz, 1H), 5.55 (d, J = 4.1 Hz, 1H), 2.26 (q, J = 0.6 Hz, 6H) (s, 18H)
13C NMR (100 MHz, CDCl3):δ ppm 146.0, 145.9, 144.7, 144.5, 144.4, 139.1, 138.1, 127.4, 127.3, 124.7, 123.2, 122.3, 118.6, 118.5, 56.4, 35.1, 34.6, 31.7, 29.9, 21.6 13 C NMR (100 MHz, CDCl 3): δ ppm 146.0, 145.9, 144.7, 144.5, 144.4, 139.1, 138.1, 127.4, 127.3, 124.7, 123.2, 122.3, 118.6, 118.5, 56.4, 35.1, 34.6, 31.7, 29.9 , 21.6
31P NMR (162 MHz, CDCl3):δ ppm 87.1 31 P NMR (162 MHz, CDCl 3): δ ppm 87.1
HRMS(ESI) calculated for C37H50NO2P[M+H]+:572.3659,Found:572.3604HRMS (ESI) calculated for C 37 H 50 NO 2 P [M + H] + : 572.3659, Found: 572.3604
실시예 4(화합물 1d): 
흰색 고체: 1H NMR (400 MHz, CDCl3):δ ppm 7.21(d, J = 2.4 Hz, 2H), 7.11(d, J = 2.4 Hz, 2H), 6.31(dd, J = 2.2, 1.1 Hz, 2H), 6.13(t, J = 2.2 Hz, 1H), 5.55(d, J = 4.1 Hz, 1H), 3.74(s, 3H), 1.41(s, 18H), 1.30(s, 18H)White solid: 1 H NMR (400 MHz, CDCl 3): δ ppm 7.21 (d, J = 2.4 Hz, 2H), 7.11 (d, J = 2.4 Hz, 2H), 6.31 (dd, J = 2.2, 1.1 Hz , 2H), 6.13 (t, J = 2.2 Hz, 1H), 5.55 (d, J = 4.1 Hz, 1H), 3.74 (s,
13C NMR (100 MHz, CDCl3):δ ppm 161.5, 146.7, 146.5 145.9, 145.8, 144.6, 138.2, 127.1(2), 123.3, 122.3, 99.2, 99.0, 95.0, 56.2, 55.4, 35.1, 34.6, 31.7, 29.9 13 C NMR (100 MHz, CDCl 3 ):? Ppm 161.5, 146.7, 146.5 145.9, 145.8, 144.6, 138.2, 127.1 (2), 123.3, 122.3, 99.2, 99.0, 95.0, 56.2, 55.4, 35.1, 34.6, 31.7 , 29.9
31P NMR (162 MHz, CDCl3):δ ppm 86.9 31 P NMR (162 MHz, CDCl 3): δ ppm 86.9
HRMS(ESI) calculated for C37H50NO4P[M+H]+:604.3557,Found:604.3532HRMS (ESI) calculated for C 37 H 50 NO 4 P [M + H] + : 604.3557, Found: 604.3532
실시예 5(화합물 1e): 
흰색 고체: 1H NMR (400 MHz, CDCl3):δ ppm 7.21(d, J = 2.4 Hz, 2H), 7.07-7.01(m, 1H), 6.97(d, J = 2.4 Hz, 2H), 6.88-6.82(m, 1H), 6.69(d, J = 7.9 Hz, 1H), 5.10(d, J = 4.2 Hz, 1H) 2.30-2.22(m, 6H), 1.43(s, 18H), 1.28(s, 18H)White solid: 1 H NMR (400 MHz, CDCl 3): δ ppm 7.21 (d, J = 2.4 Hz, 2H), 7.07-7.01 (m, 1H), 6.97 (d, J = 2.4 Hz, 2H), 6.88 (M, 6H), 1.43 (s, 18H), 1.28 (d, J = , 18H)
13C NMR (100 MHz, CDCl3):δ ppm 145.8, 145.7, 144.0, 138.1, 135.4, 132.0, 127.7, 127.6, 127.5, 126.0(2), 123.1, 122.2, 58.5, 35.1, 34.5, 31.7, 29.9, 21.0, 18.7 13 C NMR (100 MHz, CDCl 3): δ ppm 145.8, 145.7, 144.0, 138.1, 135.4, 132.0, 127.7, 127.6, 127.5, 126.0 (2), 123.1, 122.2, 58.5, 35.1, 34.5, 31.7, 29.9, 21.0, 18.7
31P NMR (162 MHz, CDCl3):δ ppm 87.3 31 P NMR (162 MHz, CDCl 3): δ ppm 87.3
HRMS(ESI) calculated for C37H50NO2P[M+H]+:604.3557,Found:604.3532HRMS (ESI) calculated for C 37 H 50 NO 2 P [M + H] + : 604.3557, Found: 604.3532
실시예 6(화합물 1f): 
흰색 고체: 1H NMR (400 MHz, CDCl3):δ ppm 7.17(d, J = 2.4 Hz, 2H), 7.02(t, J = 8.3 Hz, 1H), 6.96(d, J = 2.5 Hz, 2H), 6.55(d, J = 8.3 Hz, 2H), 5.20(d, J = 3.5 Hz, 1H), 3.63(s, 6H) 1.45(s, 18H), 1.29(s, 18H)White solid: 1 H NMR (400 MHz, CDCl 3): δ ppm 7.17 (d, J = 2.4 Hz, 2H), 7.02 (t, J = 8.3 Hz, 1H), 6.96 (d, J = 2.5 Hz, 2H ), 6.55 (d, J = 8.3 Hz, 2H), 5.20 (d, J = 3.5 Hz, 1H), 3.63 (s,
13C NMR (100 MHz, CDCl3):δ ppm 155.6, 146.1, 146.0, 143.0, 138.7, 137.6(2), 129.2, 128.7(2), 128.4, 125.5, 125.2, 122.4, 122.3, 57.7, 56.4, 35.1, 34.4, 31.8, 30.0 13 C NMR (100 MHz, CDCl 3): δ ppm 155.6, 146.1, 146.0, 143.0, 138.7, 137.6 (2), 129.2, 128.7 (2), 128.4, 125.5, 125.2, 122.4, 122.3, 57.7, 56.4, 35.1 , 34.4, 31.8, 30.0
31P NMR (162 MHz, CDCl3):δ ppm 87.8 31 P NMR (162 MHz, CDCl 3): δ ppm 87.8
HRMS(ESI) calculated for C37H50NO4P[M+H]+:604.3557,Found:604.3568HRMS (ESI) calculated for C 37 H 50 NO 4 P [M + H] + : 604.3557, Found: 604.3568
실시예 7(화합물 1g): 
흰색 고체: 1H NMR (400 MHz, CDCl3):δ ppm 7.32-7.28(m, 2H), 7.20(d, J = 2.4 Hz, 2H), 7.09(d, J = 2.4 Hz, 2H), 7.08-7.05(m, 2H), 5.52(d, J = 4.2 Hz, 1H) 1.41(s, 18H), 1.30(s, 18H), 1.29(s, 9H)White solid: 1 H NMR (400 MHz, CDCl 3): δ ppm 7.32-7.28 (m, 2H), 7.20 (d, J = 2.4 Hz, 2H), 7.09 (d, J = 2.4 Hz, 2H), 7.08 (S, 18H), 1.30 (s, 18H), 1.29 (s, 9H)
13C NMR (100 MHz, CDCl3):δ ppm 146.0(2), 145.9, 144.4, 142.2, 142.0, 138.2, 127.4, 127.3, 126.4(2), 123.2, 120.7, 120.6, 56.5, 35.1, 34.5, 34.4, 31.7, 31.5, 29.9 13 C NMR (100 MHz, CDCl 3 ):? Ppm 146.0 (2), 145.9, 144.4, 142.2, 142.0, 138.2, 127.4, 127.3, 126.4 (2), 123.2, 120.7, 120.6, 56.5, 35.1, , 31.7, 31.5, 29.9
31P NMR (162 MHz, CDCl3):δ ppm 87.2 31 P NMR (162 MHz, CDCl 3): δ ppm 87.2
HRMS(ESI) calculated for C39H54NO2P[M+H]+:600.3972,Found:600.4001HRMS (ESI) calculated for C 39 H 54 NO 2 P [M + H] + : 600.3972, Found: 600.4001
[[ 실시예Example 8 내지 11]. 8 to 11]. Cl브리포스Cl BRIFOS 유도체의 제조 Preparation of derivatives
화합물 4h 내지 4k의 제조Preparation of compounds 4h to 4k
3,3’,5,5’-테트라-3차-부틸-2,2‘-다이하이드록시벤조피논(3,3’,5,5‘-tetra-tert-butyl-2,2’-dihydroxylbenzophenone)과 일차아민(3h 내지 3k) 1.0당량을 니트(neat) 조건 또는 유기용매(부탄올)하에서 반응을 수행하였다. 이때 반응 온도는 130℃에서 12시간동안 교반한 후, 생성되는 생성물은 별도의 정제없이 다음 반응에 사용하거나, 필요에 따라 정제과정을 수행하였다.3,3 ', 5,5'-tetra-tert-butyl-2,2'-dihydroxybenzophenone (3,3', 5,5'-tetra-tert-butyl-2,2'-dihydroxylbenzophenone ) And 1.0 equivalent of primary amine (3h to 3k) under neat conditions or in an organic solvent (butanol). At this time, the reaction temperature was maintained at 130 ° C for 12 hours, and the resulting product was used in the next reaction without further purification, or purification was carried out if necessary.
화합물 5h 내지 5k의 제조Preparation of compounds 5h to 5k
이민화합물 1.0당량과 금속수소화물로서 NaBH4를 3.0당량 취하여 메탄올 용매하에서 4시간동안 교반기를 통해 반응을 진행하였다. 반응진행 후, 반응의 용매로 사용한 메탄올을 갑압을 통해 제거하였으며, 물과 에틸아세테이트를 이용해서 추출과정을 실시하였다. 그 다음 건조제(MgSO4)를 이용하여 건조시킨 뒤, 건조제를 제거 후 유기용매를 감압으로 제거하여 생성물을 수득하였다.Taking 3.0 equivalents of NaBH 4 as the imine compound with 1.0 equivalent of metal hydride and the reaction was carried out by a stirrer for 4 hours in a methanol solvent. After the reaction was completed, the methanol used as the reaction solvent was removed through the autoclave, and extraction was carried out using water and ethyl acetate. After drying with a desiccant (MgSO 4 ), the drying agent was removed, and the organic solvent was removed under reduced pressure to obtain a product.
화합물 1h 내지 1k의 제조Preparation of compounds 1h to 1k
상기 단계에서 수득한 이차아민 생성물 1.0 당량과 포스포러스 화합물(PBr3)1.1당량 그리고 염기인 트라이에틸아민(Et3N)3.3당량을 N2조건하에서 클로로폼을 용매로하여 교반기를 통해 반응을 진행하였다. 반응온도는 0 oC에서 진행하였고, 반응시간은 4시간이었다. 반응진행 후 반응 용액은 실리카를 이용하여 여과하고 이 과정에서의 용리액으로 에틸아세테이트를 이용하였다. 이후, 감압을 통해 에틸아세테이트를 제거한 뒤 에탄올을 이용하여 생성물을 침전시켰다. 침전된 생성물은 필터를 통해 분리하여 수득하였다.1.0 equivalents of the secondary amine product obtained in the above step, 1.1 equivalents of a phosphorus compound (PBr 3 ) and 3.3 equivalents of a base, triethylamine (Et 3 N) were reacted in a chloroform solvent under N 2 under a stirrer Respectively. The reaction temperature was 0 ° C and the reaction time was 4 hours. After the reaction, the reaction solution was filtered using silica, and ethyl acetate was used as an eluent in this process. Ethyl acetate was then removed through reduced pressure and the product was precipitated with ethanol. The precipitated product was isolated by filtration.
실시예 8(화합물 1h): 
1H NMR (400 MHz, CDCl3):δ ppm 7.27(d, J = 2.5 Hz, 2H), 7.03(d, J = 2.4 Hz, 2H), 4.92(d, J = 5.0 Hz, 1H) 3.15(qt, J = 11.4, 3.4 Hz, 1H), 1.76(td, J = 7.9, 6.5, 3.6 Hz, 4H), 1.62(d, J = 12.9 Hz, 1H), 1.37(qd, J = 12.7, 11.9, 3.7 Hz, 2H), 1.29-1.17(m, 2H), 1.15-1.03(m, 1H) 1 H NMR (400 MHz, CDCl 3): δ ppm 7.27 (d, J = 2.5 Hz, 2H), 7.03 (d, J = 2.4 Hz, 2H), 4.92 (d, J = 5.0 Hz, 1H) 3.15 ( J = 11.4, 3.4 Hz, 1H), 1.76 (td, J = 7.9, 6.5, 3.6 Hz, 4H), 1.62 (d, J = 3.7 Hz, 2H), 1.29-1.17 (m, 2H), 1.15-1.03 (m, 1H)
13C NMR (100 MHz, CDCl3):δ ppm 129.5, 127.2, 125.0, 60.1, 59.9, 51.3, 34.1, 34.0, 25.8, 25.4 13 C NMR (100 MHz, CDCl 3): δ ppm 129.5, 127.2, 125.0, 60.1, 59.9, 51.3, 34.1, 34.0, 25.8, 25.4
31P NMR (162 MHz, CDCl3):δ ppm 96.6 31 P NMR (162 MHz, CDCl 3): δ ppm 96.6
HRMS(ESI) calculated for C19H16Cl4NO2P[M+H,MeOH]+:494.0015,Found:494.3499 HRMS (ESI) calculated for C 19
실시예 9(화합물 1i): 
1H NMR (400 MHz, CDCl3):δ ppm 7.33(d, J = 2.5 Hz, 2H), 7.32-7.29(m, 2H), 7.14(d, J = 2.4 Hz, 2H), 7.13-7.09(m, 1H), 7.04(dq, J = 7.6, 1.1 Hz, 2H), 5.49(d, J = 4.3 Hz, 1H) 1 H NMR (400 MHz, CDCl 3): δ ppm 7.33 (d, J = 2.5 Hz, 2H), 7.32-7.29 (m, 2H), 7.14 (d, J = 2.4 Hz, 2H), 7.13-7.09 ( J = 7.6, 1.1 Hz, 2H), 5.49 (d, J = 4.3 Hz, 1H)
13C NMR (100 MHz, CDCl3):δ ppm 130.1, 129.9, 128.5, 128.4, 128.0, 125.3, 124.8, 121.7, 121.6, 54.4 13 C NMR (100 MHz, CDCl 3 ):? Ppm 130.1, 129.9, 128.5, 128.4, 128.0, 125.3, 124.8, 121.7, 121.6, 54.4
31P NMR (162 MHz, CDCl3):δ ppm 88.6 31 P NMR (162 MHz, CDCl 3): δ ppm 88.6
HRMS(ESI) calculated for C19H10Cl4NO2P[M+K]+:493.884,Found:493.9062 HRMS (ESI) calculated for C 19
실시예 10(화합물 1j): 
1H NMR (400 MHz, CDCl3):δ ppm 7.32(d, J = 2.4 Hz, 2H), 7.13(d, J = 2.5 Hz, 2H), 6.76(tq, J = 1.6, 0.8 Hz, 1H), 6.65(dq, J = 1.4, 0.7 Hz, 2H), 5.47(d, J = 4.3 Hz, 1H), 2.27(d, J = 0.7 Hz, 6H) 1 H NMR (400 MHz, CDCl 3): δ ppm 7.32 (d, J = 2.4 Hz, 2H), 7.13 (d, J = 2.5 Hz, 2H), 6.76 (tq, J = 1.6, 0.8 Hz, 1H) , 6.65 (dq, J = 1.4, 0.7 Hz, 2H), 5.47 (d, J = 4.3 Hz,
13C NMR (100 MHz, CDCl3):δ ppm 144.3, 144.2, 142.8, 142.6, 139.9, 129.8, 128.6, 128.6, 127.8, 126.6, 125.2, 119.4, 119.3, 54.5, 21.5 13 C NMR (100 MHz, CDCl 3): δ ppm 144.3, 144.2, 142.8, 142.6, 139.9, 129.8, 128.6, 128.6, 127.8, 126.6, 125.2, 119.4, 119.3, 54.5, 21.5
31P NMR (162 MHz, CDCl3):δ ppm 88.5 31 P NMR (162 MHz, CDCl 3): δ ppm 88.5
HRMS(ESI) calculated for C21H14Cl4NO2P[M+H]+:483.9596,Found:483.9605HRMS (ESI) calculated for C 21 H 14 Cl 4 NO 2 P [M + H] + : 483.9596, Found: 483.9605
실시예 11(화합물 1k): 
1H NMR (400 MHz, CDCl3):δ ppm 7.32(d, J = 2.5 Hz, 2H), 7.13(d, J = 2.5 Hz, 2H), 6.20(ddd, J = 2.4, 1.8, 0.6 Hz, 1H), 6.18(dd, J = 2.1, 0.9 Hz, 2H), 5.49(d, J = 4.2 Hz, 1H), 3.75(s, 6H) 1 H NMR (400 MHz, CDCl 3): δ ppm 7.32 (d, J = 2.5 Hz, 2H), 7.13 (d, J = 2.5 Hz, 2H), 6.20 (ddd, J = 2.4, 1.8, 0.6 Hz, (D, J = 2.1, 0.9 Hz, 2H), 5.49 (d, J = 4.2 Hz,
13C NMR (100 MHz, CDCl3):δ ppm 161.9, 144.2, 144.1, 129.9, 128.4, 128.0, 125.3, 125.2, 99.9, 99.7, 96.0, 55.6, 54.1 13 C NMR (100 MHz, CDCl 3 ):? Ppm 161.9, 144.2, 144.1, 129.9, 128.4, 128.0, 125.3, 125.2, 99.9, 99.7, 96.0, 55.6, 54.1
31P NMR (162 MHz, CDCl3):δ ppm 88.3 31 P NMR (162 MHz, CDCl 3): δ ppm 88.3
HRMS(ESI) calculated for C21H14Cl4NO4P[M+H]+:515.9495,Found:515.9483 HRMS (ESI) calculated for C 21
실시예Example 12. 두 고리 구조를 갖는 12. Having two ring structures 포스포라미다이트Phosphoramidite 유도체의 Derivative 하이드로포밀화Hydroformylation 반응에서의 효과 확인 Identify the effect of the reaction
리간드의 반응성 시험을 위해 1-Methylcyclohexene을 3치환 올레핀 기질로 하여 대한민국 특허 제10-1574071호에서 개발한 브리포스(도 3의 L9 내지 L12), 실시예 1 내지 7에서 제조한 tBu브리포스(도 3의 L13 내지 L19), 실시예 8 내지 11에서 제조한 Cl브리포스(도 3의 L20 내지 L23), 및 상업적으로 구하기 쉬운 리간드(도 3의 L1 내지 L8)를 이용하여 하이드로포밀화 반응을 실시하였다. To test the reactivity of the ligand, 1-Methylcyclohexene was used as a tri-substituted olefin substrate, and the bryophos (L9 to L12 in FIG. 3) developed in Korean Patent No. 10-1574071 and the tBu briocose (L13 to L19 in FIG. 3), Clbrifor (L20 to L23 in FIG. 3) prepared in Examples 8 to 11, and commercially available ligands (L1 to L8 in FIG. 3) were subjected to a hydroformylation reaction Respectively.
먼저 아르곤 기체로 채워진 Glove box안에서 Rh(CO)2(acac)(0.01mmol,1mol%)과 리간드(0.02 mmol, 2 mol%)를 취하여 톨루엔 용매 안에서 교반기를 통해 전이금속과 리간드가 배위 결합된 촉매로 제조한 다음, 제조된 촉매를 압력솥(autoclave) 반응기에 담은 후, 반응에 사용할 반응물질(1.0 mmol)을 담고 압력솥(autoclave) 반응기를 닫은 다음, 일산화탄소/수소 혼합가스와 압력솥 반응기를 연결관을 통해 연결한 후, 일산화탄소/수소의 혼합가스(5 bar)를 이용해서 퍼징(purging)과정을 3회 반복하여 실시하였다. 이후 일산화탄소/수소의 혼합가스(20 bar)의 압력을 가해준 뒤 100 oC로 설정된 교반기에 넣고 반응을 12시간 진행하고, 반응용기의 가스밸브를 이용해 남아있는 혼합가스를 제거한 뒤, 압력솥(autoclave) 용기를 열고, 반응혼합물을 유리바이알(20 mL)에 옮겨 담아 NMR 및 GC-MS의 분석장비를 이용하여 반응결과 분석을 실시하였다.First, Rh (CO) 2 (acac) (0.01 mmol, 1 mol%) and ligand (0.02 mmol, 2 mol%) were taken in a glove box filled with argon gas and the ligand was coordinated with a transition metal through a stirrer in a toluene solvent (1.0 mmol), the autoclave reactor was closed, and a carbon monoxide / hydrogen mixed gas and an autoclave reactor were connected to the autoclave reactor. And purging was repeated three times using a mixed gas of carbon monoxide and hydrogen (5 bar). Then, the pressure was applied to the mixed gas of carbon monoxide / hydrogen (20 bar), and the mixture was placed in an agitator set at 100 ° C for 12 hours. The remaining gas mixture was removed using a gas valve of the reaction vessel, The vessel was opened and the reaction mixture was transferred to a glass vial (20 mL) and the reaction results were analyzed using NMR and GC-MS analysis equipment.
분석결과, 기존의 상업적으로 구하기 쉬운 포스포러스 리간드 중 L1 리간드부터 L7까지의 리간드들은 낮은 반응성과 주로 70% 이하의 낮은 3차-탄소 내부 알데하이드 선택성을 보였으며, L8 리간드인 TDTBPP의 경우 65%의 변환율로 적당한 반응성을 보였지만 내부 알데하이드의 선택성면에서 65% 이하의 낮은 선택성을 나타내는 것을 확인하였다. As a result, the ligands L1 to L7 of the commercially available phosphorescent ligands exhibited low reactivity and a low tertiary-carbon internal aldehyde selectivity of mainly 70% or less, and 65% of the L8 ligand TDTBPP It was confirmed that the selectivity of the internal aldehyde exhibited low selectivity of 65% or less even though it showed moderate reactivity at conversion.
반면, 실시예 1 내지 11에서 제조한 리간드의 경우 tBu브리포스 계열의 리간드에서 좋은 반응성과 선택성을 확인하였고(L13-19), 그 중 tBu브리포스(3,5-MeOPh)(L16)의 경우, 83%의 변환율이 나타나는 것을 확인하였으며, 80% 이상의 높은 3차-탄소 내부 알데하이드 선택성을 나타내어, 가장 좋은 반응성과 선택성을 가지고 있는 것을 확인하였다. 이외에 공지 브리포스 리간드(L9-12)와 Cl브리포스 리간드(L20-23)의 경우, 좋은 반응성과 내부알데하이드 선택성을 나타내지 못하는 것을 확인하였다.On the other hand, in the case of the ligand prepared in Example 1 to 11. In the case of tBu debris was confirmed good reactivity and selectivity in the phosphine ligands of the series (L13-19), in that tBu debris Force (3,5-MeOPh) (L16) , And 83%, respectively, and showed high tertiary-carbon internal aldehyde selectivity of more than 80%, confirming the best reactivity and selectivity. In addition, it was confirmed that the known biphosphese ligands ( L9-12 ) and the Cl- biphosphese ligands ( L20-23 ) did not show good reactivity and internal aldehyde selectivity.
실시예Example 13. 13. tBu브리포스tBu Brephus (3,5-(3,5- MeOPhMeOPh ) 리간드에 대한 촉매구조 확인) Identification of the catalytic structure for the ligand
리간드와 로듐의 소스로 Rh(CO)2(acac)과 배위결합을 시킨 후, 결정을 얻어내어 X-ray 회절 분석법을 통하여 결정구조를 분석하였다.After coordination with Rh (CO) 2 (acac) as a source of ligand and rhodium, crystals were obtained and the crystal structure was analyzed by X-ray diffraction analysis.
촉매 결정은 Glove box내에서 수득 하였으며, 로듐과 리간드를 디클로로메탄에 녹여 교반기를 통해 로듐-리간드 복합체를 형성한 뒤, 헥세인과의 확산속도차이를 이용하여 수득하였다. 결정구조 분석결과 tBu브리포스리간드는 로듐촉매와 1:1의 비율로 배위결합 하며 로듐 내 CO를 1분자 방출하는것을 확인할 수 있었다(도 3).Catalyst crystals were obtained in a glove box, rhodium and ligand were dissolved in dichloromethane to form a rhodium-ligand complex through a stirrer, and then the difference in diffusion rate with hexane was used. As a result of the crystal structure analysis, it was confirmed that the tBu brioose ligand coordinated with the rhodium catalyst at a ratio of 1: 1 and released one molecule of CO in the rhodium (FIG. 3).
실시예Example 14. 14. tBu브리포스tBu Brephus (3,5-(3,5- MeOPhMeOPh ) 리간드의 다양한 ) A variety of ligands 3치환3-substitution 올레핀에 대한 For olefin 하이드로포밀화Hydroformylation 반응 확인 Confirm the reaction
실시예 12와 같은 방법으로 tBu브리포스(3,5-MeOPh)리간드를 이용하여 다양한 3치환 올레핀 하이드로포밀화 반응을 실시한 결과, 도 2에 개시된 바와 같이, 주로 99% 이상의 좋은 반응성과 70% 이상의 내부알데하이드 선택성을 확인하였다. As a result of carrying out various tri-substituted olefin hydroformylation reactions using tBu briPose (3,5-MeOPh) ligand in the same manner as in Example 12, it was found that, mainly as shown in FIG. 2, The internal aldehyde selectivity was confirmed.
선형 3치환 올레핀 반응물질 중 지방족 기질 및 알코올, 아세테이트 계열의 작용기를 가진 기질들에서 작용기의 변형없이 좋은 반응성과 3차-탄소 내부 알데하이드 선택성을 보이는 것을 확인하였다(2a-2d). 2d의 경우, 1 mol%의 촉매 반응에서 낮은 내부 알데하이드의 선택성을 보였지만, 촉매로 사용하는 로듐과 리간드의 양을 증가시켜줌으로써, 높은 선택성을 확보하였다. (2a-2d) showed good reactivity and tert-carbon internal aldehyde selectivity without modification of the functional groups in the substrates having aliphatic and alcohol and acetate series functional groups in the linear tri-substituted olefinic reactants. In the case of 2d, the selectivity of low internal aldehyde was shown by the catalytic reaction of 1 mol%, but high selectivity was obtained by increasing the amount of rhodium and ligand used as the catalyst.
고리형 3치환 올레핀의 경우, 5각 고리 및 6각 고리형 반응물질 모두 좋은 반응성과 3차-탄소 내부 알데하이드 선택성을 나타내었고고, 반응물질 내에 니트릴이나(2f) 카복실산(2g), 알코올(2k) 등 다른 작용기들이 있음에도 작용기의 변형없이 좋은 반응성과 내부 알데하이드 선택성을 나타내는 것을 확인하였다. 뿐만 아니라, 아릴그룹이 있는 반응물질에서도(2l) 좋은 반응성과 3차-탄소 내부 알데하이드 선택성을 나타내는 것을 확인하였다.In the case of the cyclic tri-substituted olefins, both of the pentagonal and hexagonal cyclic reactants exhibited good reactivity and tertiary-carbon internal aldehyde selectivity, and nitrile, (2f) carboxylic acid (2g), alcohol ), But showed good reactivity and internal aldehyde selectivity without modification of functional groups. In addition, it was confirmed that (2l) good reactivity and tertiary-carbon internal aldehyde selectivity were exhibited even in the reaction material having an aryl group.
<기질 분석><Substrate Analysis>
<기질 분석><Substrate Analysis>
기질들의 반응성 시험 결과 생성물을 정제하여 분리하여 분광학 자료를 얻어내었다. 분자량이 적어 감압을 통해 쉽게 증발하는 생성물의 경우 추가적인 환원반응을 통해 알데하이드에서 알코올로 변형시킨 뒤 그 구조를 확인하였으며, 쉽게 증발하지 않는 생성물의 경우 알데하이드의 상태로 분리해 분석하였다The reaction products of the substrates were purified and separated to obtain spectroscopic data. In the case of the product which is easily evaporated by the reduced pressure due to the low molecular weight, the structure is confirmed after the aldehyde to alcohol modification through an additional reduction reaction. In the case of the product which does not easily evaporate, the aldehyde is separated and analyzed
13C NMR (100 MHz, CDCl3):δ ppm 66.8, 41.6, 29.0, 20.8, 18.2, 12.7 1 H NMR (400 MHz, CDCl 3 ):? Ppm 3.59 (dd, 1H), 3.44 (dd, 1H), 1.74-1.66 (m, 1H), 1.53-1.47 , 3H), 0.87-0.83 (dd, 6H)
13 C NMR (100 MHz, CDCl 3 ):? Ppm 66.8, 41.6, 29.0, 20.8, 18.2, 12.7
13C NMR (100 MHz, CDCl3):δ ppm 68.6, 36.4, 36.2, 31.0, 28.4, 22.9, 22.6, 16.7 1 H NMR (400 MHz, CDCl 3): δ ppm 3.50 (dd, 1H), 3.41 (dd, 1H), 1.67-1.42 (m, 2H), 1.35-1.26 (m, 1H), 1.26-1.04 (m , ≪ / RTI > 3H), 0.96-0.86 (m, 9H)
13 C NMR (100 MHz, CDCl 3): δ ppm 68.6, 36.4, 36.2, 31.0, 28.4, 22.9, 22.6, 16.7
13C NMR (100 MHz, CDCl3):δ ppm 206.3, 60.0, 59.7, 26.5, 20.7, 20.2 1 H NMR (400 MHz, CDCl 3): δ ppm 9.82 (d, 1H), 3.98 (dd, 1H), 3.78 (dd, 1H), 2.40 (m, 1H), 2.17 (m, 1H), 2.03 ( s, 3H), 1.04 (dd, 6H)
13 C NMR (100 MHz, CDCl 3 ):? Ppm 206.3, 60.0, 59.7, 26.5, 20.7, 20.2
13C NMR (100 MHz, CDCl3):δ ppm 202.7, 170.8, 61.0, 56.8, 26.3, 20.7, 20.3, 19.7. 1 H NMR (400 MHz, CDCl 3): δ ppm 9.71 (d, 1H), 4.38 (dd, 1H), 4.27 (dd, 1H), 2.47 (m, 1H), 2.13 (m, 1H), 2.03 ( s, 3H), 1.02 (dd, 6H)
13 C NMR (100 MHz, CDCl 3 ):? Ppm 202.7, 170.8, 61.0, 56.8, 26.3, 20.7, 20.3, 19.7.
13C NMR (100 MHz, CDCl3):δ ppm 66.7, 49.9, 37.1, 35.2, 29.6, 24.1, 20.2 1 H NMR (400 MHz, CDCl 3 ):? Ppm 3.64 (dddd, 1H), 3.47 (m, 1H), 1.87-1.76 (m, 2H), 1.65-1.49 (m, 4H), 1.39-1.32 , ≪ / RTI > 1H), 1.22-1.15 (m, 1H), 1.0 (dd,
13 C NMR (100 MHz, CDCl 3 ):? Ppm 66.7, 49.9, 37.1, 35.2, 29.6, 24.1, 20.2
13C NMR (100 MHz, CDCl3):δ ppm 202.1, 118.5, 56.5, 36.1, 32.2, 26.7, 24.5, 22.0. 1 H NMR (400 MHz, CDCl 3 ):? Ppm 9.70 (m, 2H), 2.62-2.44 (m, 4H), 2.11-1.78
13 C NMR (100 MHz, CDCl 3): δ ppm 202.1, 118.5, 56.5, 36.1, 32.2, 26.7, 24.5, 22.0.
13C NMR (100 MHz, CDCl3):δ ppm 201.5, 179.8, 54.8, 43.3, 30.2, 26.9, 25.3 1 H NMR (400 MHz, CDCl 3 ):? Ppm 9.72 (d, 1H), 3.28-3.17 (m, 2H), 2.09-1.88 (m, 4H), 1.82-1.75 (m, 1 H)
13 C NMR (100 MHz, CDCl 3 ):? Ppm 201.5, 179.8, 54.8, 43.3, 30.2, 26.9, 25.3
13C NMR (100 MHz, CDCl3):δ ppm 66.2, 46.7, 35.8, 33.8, 29.7, 26.5, 26.4, 20.3 1 H NMR (400 MHz, CDCl 3): δ ppm 3.71 (dd, 1H), 3.53 (m, 1H), 1.82-1.73 (m, 2H), 1.69-1.64 (m, 2H), 1.33 (s, 1H ), 1.28-1.20 (m, 3H), 1.11-1.07 (m, 2H), 0.97 (d, 3H)
13 C NMR (100 MHz, CDCl 3): δ ppm 66.2, 46.7, 35.8, 33.8, 29.7, 26.5, 26.4, 20.3
13C NMR (100 MHz, CDCl3):δ ppm 66.4, 41.0, 39.5, 31.1, 28.9, 26.9, 26.8, 26.7, 13.5 1 H NMR (400 MHz, CDCl 3): δ ppm 3.59 (dd, 1H), 3.43 (dd, 1H), 1.71 (d, 2H), 1.62 (d, 3H), 1.47 (tt, 1H), 1.38- 1H), 1.27 (m, 1H), 1.25-1.05 (m, 4H), 1.01-0.91
13 C NMR (100 MHz, CDCl 3): δ ppm 66.4, 41.0, 39.5, 31.1, 28.9, 26.9, 26.8, 26.7, 13.5
13C NMR (100 MHz, CDCl3):δ ppm 70.1. 47.9. 41.5. 39.5. 39.1. 39.0. 33.6. 31.3. 28.1, 23.0, 22.2 1 H NMR (400 MHz, CDCl 3 ):? Ppm 3.58 (dd, 1H), 3.45 (dd, 1H), 2.31-2.25 , 2H), 1.78-1.75 (m, 1H), 1.72-1.68 (m, 1H), 1.55 (ddd, 0.73 (d, 1 H)
13 C NMR (100 MHz, CDCl 3): δ ppm 70.1. 47.9. 41.5. 39.5. 39.1. 39.0. 33.6. 31.3. 28.1, 23.0, 22.2
13C NMR (100 MHz, CDCl3):δ ppm 205.6, 69.6, 64.6, 34.0, 33.7, 31.8, 23.3, 19.7 1 H NMR (400 MHz, CDCl 3): δ ppm 9.76 (d, 1H), 3.87-3.81 (td, 1H), 2.05-2.01 (m, 1H), 1.96-1.90 (ddd, 1H), 1.81-1.63 (m, 3H), 1.40 - 1.24 (m, 3H), 1.01 (d, 3H)
13 C NMR (100 MHz, CDCl 3 ):? Ppm 205.6, 69.6, 64.6, 34.0, 33.7, 31.8, 23.3, 19.7
13C NMR (100 MHz, CDCl3):δ ppm 201.1, 135.5, 129.3, 128.9, 127.5, 66.8, 28.8, 21.2, 20.0 1 H NMR (400 MHz, CDCl 3 ): δ ppm 9.71 (d, 1H), 7.39-7.20 (m, 5H), 3,21 (dd, ), 0.79 (d, 1 H).
13 C NMR (100 MHz, CDCl 3 ):? Ppm 201.1, 135.5, 129.3, 128.9, 127.5, 66.8, 28.8, 21.2, 20.0
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적 기술은 단지 바람직한 실시 양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereto will be. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
Claims (15)
[화학식 1]
상기 화학식 1에서,
R' 및 R"는 t-부틸이고;
a 및 b는 각각 독립적으로 1 내지 4의 정수이되, a와 b는 동시에 0이 아니며,
R은 수소, (C1-C20)알킬, (C3-C20)사이클로알킬, (C6-C20)아릴, (C7-C20)바이사이클로알킬 또는 방향족고리가 융합된 (C3-C20)사이클로알킬이고;
상기 R의 아릴, 사이클로알킬, 아릴 및 바이사이클로알킬은 각각 (C1-C20)알킬, (C3-C20)시클로알킬, (C1-C20)알콕시, 할로겐, 할로(C1-C20)알킬, (C6-C20)아릴 및 (C1-C20)알킬(C6-C20)아릴로 이루어진 군으로부터 선택되는 하나 이상의 치환체로 더 치환될 수 있음.
Bicyclic bridgehead phosphoramidite derivatives having two ring structures represented by the following formula (1):
[Chemical Formula 1]
In Formula 1,
R 'and R "are t-butyl;
a and b are each independently an integer of 1 to 4, a and b are not 0 at the same time,
R is (C3-C20) cycloalkyl fused with hydrogen, (C1-C20) alkyl, (C3-C20) cycloalkyl, (C6-C20) aryl, (C7-C20) bicycloalkyl or aromatic ring;
The aryl, cycloalkyl, aryl and bicycloalkyl of R are each independently selected from the group consisting of (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, (C 1 -C 20) alkoxy, C20) aryl and (C1-C20) alkyl (C6-C20) aryl.
상기 R은 하기 구조로부터 선택되는 것을 특징으로 하는 두 고리 구조를 갖는 포스포라미다이트 유도체:
상기 구조에서,
R1 및 R2는 각각 독립적으로 수소, (C1-C20)알킬, (C6-C20)아릴, (C3-C20)사이클로알킬이고, 상기 R1 및 R2의 알킬은 (C6-C20)아릴 또는 (C1-C20)알킬(C6-C20)아릴로 더 치환될 수 있고;
R3 내지 R7은 각각 독립적으로 수소, (C1-C20)알킬, (C1-C20)알콕시, 할로겐, 할로(C1-C20)알킬 또는 (C6-C20)아릴이고;
n은 1 내지 5의 정수이다.
The method according to claim 1,
Wherein R is selected from the following structures: < RTI ID = 0.0 >
In the above structure,
(C1-C20) alkyl, (C6-C20) aryl, (C3-C20) cycloalkyl and the alkyl of R1 and R2 is (C6-C20) aryl or ) Alkyl (C6-C20) aryl;
R3 to R7 are each independently hydrogen, (C1-C20) alkyl, (C1-C20) alkoxy, halogen, halo (C1-C20) alkyl or (C6-C20) aryl;
n is an integer of 1 to 5;
The phosphoramidite derivative according to claim 2, having two ring structures selected from the following structures:
2) 하기 화학식 4의 이민 화합물을 환원시켜 하기 화학식 5의 이차아민 화합물을 제조하는 단계; 및
3) 하기 화학식 5의 이차아민 화합물과 화학식 6의 포스포러스 화합물을 반응시켜 하기 화학식 1의 두 고리 구조를 갖는 포스포라미다이트를 제조하는 단계;
를 포함하는 하기 화학식 1의 두 고리 구조를 갖는 포스포라미다이트(bicyclic bridgehead phosphoramidite) 유도체의 제조방법:
[화학식 1]
[화학식 2]
[화학식 3]
[화학식 4]
[화학식 5]
[화학식 6]
상기 화학식 1, 2, 3, 4, 5 및 6에서,
R' 및 R"는 t-부틸이고;
a 및 b는 각각 독립적으로 1 내지 4의 정수이되, a와 b는 동시에 0이 아니며,
R은 수소, (C1-C20)알킬, (C3-C20)사이클로알킬, (C6-C20)아릴, (C7-C20)바이사이클로알킬 또는 방향족고리가 융합된 (C3-C20)사이클로알킬이고, 상기 R의 아릴, 사이클로알킬, 아릴 및 바이사이클로알킬은 각각 (C1-C20)알킬, (C3-C20)시클로알킬, (C1-C20)알콕시, 할로겐, 할로(C1-C20)알킬, (C6-C20)아릴 및 (C1-C20)알킬(C6-C20)아릴로 이루어진 군으로부터 선택되는 하나 이상의 치환체로 더 치환될 수 있고;
R15, R16 및 R17은 각각 독립적으로 다이(C1-C20)알킬아미노, (C1-C20)알콕시 또는 할로겐이다.
1) reacting a dihydroxybenzophenone represented by the following formula 2 with a primary amine compound represented by the following formula 3 to prepare an imine compound represented by the following formula 4;
2) reducing an imine compound of the following formula (4) to prepare a secondary amine compound of the following formula (5); And
3) reacting a secondary amine compound represented by the following formula (5) with a phosphorus compound represented by the following formula (6) to produce phosphoramidite having two ring structures represented by the following formula (1);
Wherein the bicyclic bridgehead phosphoramidite derivative has two ring structures represented by the following formula (1): < EMI ID =
[Chemical Formula 1]
(2)
(3)
[Chemical Formula 4]
[Chemical Formula 5]
[Chemical Formula 6]
In the above Formulas 1, 2, 3, 4, 5, and 6,
R 'and R "are t-butyl;
a and b are each independently an integer of 1 to 4, a and b are not 0 at the same time,
R is (C3-C20) cycloalkyl fused with hydrogen, (C1-C20) alkyl, (C3-C20) cycloalkyl, (C1-C20) alkyl, (C3-C20) cycloalkyl, (C1-C20) alkoxy, halogen, halo ) Aryl and (C1-C20) alkyl (C6-C20) aryl;
R15, R16 and R17 are each independently a di (C1-C20) alkylamino, (C1-C20) alkoxy or halogen.
상기 화학식 3의 일차아민 화합물은 하기 구조로부터 선택되는 것을 특징으로 하는 제조방법.
상기 구조에서,
R1 및 R2는 각각 독립적으로 수소, (C1-C20)알킬, (C6-C20)아릴, (C3-C20)사이클로알킬이고, 상기 R1 및 R2의 알킬은 (C6-C20)아릴 또는 (C1-C20)알킬(C6-C20)아릴로 더 치환될 수 있고;
R3 내지 R7은 각각 독립적으로 수소, (C1-C20)알킬, (C1-C20)알콕시, 할로겐, 할로(C1-C20)알킬 또는 (C6-C20)아릴이고;
n은 1 내지 5의 정수이다.
5. The method of claim 4,
Wherein the primary amine compound of Formula 3 is selected from the following structures.
In the above structure,
(C1-C20) alkyl, (C6-C20) aryl, (C3-C20) cycloalkyl and the alkyl of R1 and R2 is (C6-C20) aryl or ) Alkyl (C6-C20) aryl;
R3 to R7 are each independently hydrogen, (C1-C20) alkyl, (C1-C20) alkoxy, halogen, halo (C1-C20) alkyl or (C6-C20) aryl;
n is an integer of 1 to 5;
5. The method according to claim 4, wherein the immersion temperature in step 1) is in the range of room temperature to 250 ° C.
5. The method of claim 4, wherein 2) the reducing agent used in the reduction of step is NaBH 4, NaBH (OAc) 3 , NaBH 2 (OAc) 2, NaBH 3 OAc, NaBH 3 CN, KBH 4, KBH (OAc) 3, LiAlH 4 , B 2 H 6, and DIBAL-H.
The method according to claim 7, wherein the reaction temperature in step 2) is from room temperature to 250 ° C.
The process according to claim 4, wherein the reaction temperature in step 3) is from -78 to 100 ° C.
The method according to claim 4, wherein the step (b) is a neat reaction or a reaction of methanol, ethanol, isopropanol, butanol, acetone, ethyl acetate, acetonitrile, isopropyl ether, methyl ethyl ketone, methylene chloride, Wherein the reaction is carried out in an inert solvent selected from the group consisting of benzene, chlorobenzene, dichloroethane, tetrahydrofuran, toluene, benzene, xylene, mesitylene, dimethylformamide, and dimethylsulfoxide.
[화학식 1]
상기 화학식 1에서,
R' 및 R"는 t-부틸이고;
a 및 b는 각각 독립적으로 1 내지 4의 정수이되, a와 b는 동시에 0이 아니며,
R은 수소, (C1-C20)알킬, (C3-C20)사이클로알킬, (C6-C20)아릴, (C7-C20)바이사이클로알킬 또는 방향족고리가 융합된 (C3-C20)사이클로알킬이고;
상기 R의 아릴, 사이클로알킬, 아릴 및 바이사이클로알킬은 각각 (C1-C20)알킬, (C3-C20)시클로알킬, (C1-C20)알콕시, 할로겐, 할로(C1-C20)알킬, (C6-C20)아릴 및 (C1-C20)알킬(C6-C20)아릴로 이루어진 군으로부터 선택되는 하나 이상의 치환체로 더 치환될 수 있음.
1. A catalyst composition for hydroformylation of an olefinic compound comprising bicyclic bridgehead phosphoramidite derivatives represented by the following formula (1) and a rhodium or palladium transition metal catalyst:
[Chemical Formula 1]
In Formula 1,
R 'and R "are t-butyl;
a and b are each independently an integer of 1 to 4, a and b are not 0 at the same time,
R is (C3-C20) cycloalkyl fused with hydrogen, (C1-C20) alkyl, (C3-C20) cycloalkyl, (C6-C20) aryl, (C7-C20) bicycloalkyl or aromatic ring;
The aryl, cycloalkyl, aryl and bicycloalkyl of R are each independently selected from the group consisting of (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, (C 1 -C 20) alkoxy, C20) aryl and (C1-C20) alkyl (C6-C20) aryl.
The catalyst according to claim 11, wherein the transition metal catalyst is at least one selected from the group consisting of Rh (C 2 H 4 ) 2 (acac), Pd (dba) 3 and Rh (CO 2 ) (acac) Composition.
A process for hydroformylation of an olefinic compound, which comprises reacting an olefinic compound with a synthesis gas of carbon monoxide and hydrogen in the presence of the catalyst composition of claim 11 to produce an aldehyde.
14. The hydroformylation process according to claim 13, wherein the olefin-based compound is a tri-substituted olefin.
[화학식 10]
[화학식 11]
상기 화학식 10 및 11에서 R8, R9. R10 및 R11은 각각 독립적으로 수소, (C1-C20) 알킬, 불소, 염소, 브롬, 트리플루오로메틸 또는 0~5개의 치환기를 갖는 (C6-C20) 페닐기 이고, 상기 페닐기가 치환되는 경우, 치환기는 니트로, 불소, 염소, 브롬, 메틸, 에틸, 프로필, 또는 부틸기이다. The hydroformylation method according to claim 14, wherein the olefin compound is a compound represented by formula (10) or (11):
[Chemical formula 10]
(11)
In formulas (10) and (11), R 8 , R 9 . R 10 and R 11 are each independently hydrogen, (C 1 -C 20) alkyl, fluorine, chlorine, bromine, trifluoromethyl or (C 6 -C 20) phenyl group having 0-5 substituents, , The substituent is nitro, fluorine, chlorine, bromine, methyl, ethyl, propyl, or butyl group.
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