KR20240006335A - Method for producing lactic acid - Google Patents
Method for producing lactic acid Download PDFInfo
- Publication number
- KR20240006335A KR20240006335A KR1020220083267A KR20220083267A KR20240006335A KR 20240006335 A KR20240006335 A KR 20240006335A KR 1020220083267 A KR1020220083267 A KR 1020220083267A KR 20220083267 A KR20220083267 A KR 20220083267A KR 20240006335 A KR20240006335 A KR 20240006335A
- Authority
- KR
- South Korea
- Prior art keywords
- lactic acid
- compound
- group
- equiv
- dcm
- Prior art date
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 title claims abstract description 114
- 239000004310 lactic acid Substances 0.000 title claims abstract description 57
- 235000014655 lactic acid Nutrition 0.000 title claims abstract description 57
- 238000004519 manufacturing process Methods 0.000 title description 19
- 238000002360 preparation method Methods 0.000 claims description 97
- 238000006243 chemical reaction Methods 0.000 claims description 61
- -1 aromatic thiol Chemical class 0.000 claims description 55
- AIJULSRZWUXGPQ-UHFFFAOYSA-N Methylglyoxal Chemical compound CC(=O)C=O AIJULSRZWUXGPQ-UHFFFAOYSA-N 0.000 claims description 46
- 150000001875 compounds Chemical class 0.000 claims description 46
- 239000002904 solvent Substances 0.000 claims description 29
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 239000003054 catalyst Substances 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 125000001931 aliphatic group Chemical group 0.000 claims description 12
- 150000007970 thio esters Chemical class 0.000 claims description 12
- 229930182843 D-Lactic acid Natural products 0.000 claims description 11
- 229940022769 d- lactic acid Drugs 0.000 claims description 11
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- UENWRTRMUIOCKN-UHFFFAOYSA-N benzyl thiol Chemical compound SCC1=CC=CC=C1 UENWRTRMUIOCKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- 125000006819 (C2-60) heteroaryl group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 4
- 238000000034 method Methods 0.000 abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 219
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 155
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 50
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 238000004440 column chromatography Methods 0.000 description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 239000007864 aqueous solution Substances 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- 239000003960 organic solvent Substances 0.000 description 25
- 239000000377 silicon dioxide Substances 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 229940125904 compound 1 Drugs 0.000 description 20
- 239000013067 intermediate product Substances 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 16
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 14
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 14
- 125000001424 substituent group Chemical group 0.000 description 12
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 8
- 235000001258 Cinchona calisaya Nutrition 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 229960000948 quinine Drugs 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 6
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000000855 fermentation Methods 0.000 description 6
- 230000004151 fermentation Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 6
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- QJDUDPQVDAASMV-UHFFFAOYSA-M sodium;ethanethiolate Chemical compound [Na+].CC[S-] QJDUDPQVDAASMV-UHFFFAOYSA-M 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 4
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 4
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 4
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- 229940126657 Compound 17 Drugs 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 4
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 4
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 4
- 229940125797 compound 12 Drugs 0.000 description 4
- 229940126543 compound 14 Drugs 0.000 description 4
- 229940125758 compound 15 Drugs 0.000 description 4
- 229940126142 compound 16 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 239000004626 polylactic acid Substances 0.000 description 4
- 239000011975 tartaric acid Substances 0.000 description 4
- 235000002906 tartaric acid Nutrition 0.000 description 4
- 150000003573 thiols Chemical class 0.000 description 4
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 3
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 3
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 3
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 3
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 3
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 3
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- 239000011630 iodine Substances 0.000 description 1
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- SFMJNHNUOVADRW-UHFFFAOYSA-N n-[5-[9-[4-(methanesulfonamido)phenyl]-2-oxobenzo[h][1,6]naphthyridin-1-yl]-2-methylphenyl]prop-2-enamide Chemical compound C1=C(NC(=O)C=C)C(C)=CC=C1N1C(=O)C=CC2=C1C1=CC(C=3C=CC(NS(C)(=O)=O)=CC=3)=CC=C1N=C2 SFMJNHNUOVADRW-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 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 1
- 230000003287 optical effect Effects 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- MPQXHAGKBWFSNV-UHFFFAOYSA-N oxidophosphanium Chemical group [PH3]=O MPQXHAGKBWFSNV-UHFFFAOYSA-N 0.000 description 1
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- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- XPPWLXNXHSNMKC-UHFFFAOYSA-N phenylboron Chemical group [B]C1=CC=CC=C1 XPPWLXNXHSNMKC-UHFFFAOYSA-N 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
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- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- JUYUYCIJACTHMK-UHFFFAOYSA-N quinoline-8-sulfonyl chloride Chemical compound C1=CN=C2C(S(=O)(=O)Cl)=CC=CC2=C1 JUYUYCIJACTHMK-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 125000003011 styrenyl group Chemical group [H]\C(*)=C(/[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
- JLBRGNFGBDNNSF-UHFFFAOYSA-N tert-butyl(dimethyl)borane Chemical group CB(C)C(C)(C)C JLBRGNFGBDNNSF-UHFFFAOYSA-N 0.000 description 1
- WMXCDAVJEZZYLT-UHFFFAOYSA-N tert-butylthiol Chemical compound CC(C)(C)S WMXCDAVJEZZYLT-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical group CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 1
- WXRGABKACDFXMG-UHFFFAOYSA-N trimethylborane Chemical group CB(C)C WXRGABKACDFXMG-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/50—Use of additives, e.g. for stabilisation
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
- C07C59/08—Lactic acid
Abstract
본 발명은 거울상 이성질체 과잉율이 높은 젖산 제조 방법에 관한 것이다.The present invention relates to a process for producing lactic acid with a high enantiomeric excess.
Description
본 발명은 젖산 제조 방법에 관한 것이다.The present invention relates to a method for producing lactic acid.
젖산(락트산; Lactic acid)은 생분해성 고분자인 PLA(polylactic acid)를 비롯한 다양한 화학 물질(acrylic acid, pyruvic acid, propylene glycol, 2,3-petnaedione 등)의 합성에 feedstock으로 사용될 수 있는 플랫폼 화학 물질이다. 화학 산업에서 젖산은 그 자체로 활용도가 높을 뿐만 아니라, 젖산의 원료인 탄수화물, 글리세롤 또한 비석유계 탄소원으로 주목 받고 있어, 추가적인 이산화탄소 배출없이 화학 물질을 지속 가능한 방법으로 생산하다는 점에서 의미가 있다. Lactic acid is a platform chemical that can be used as a feedstock for the synthesis of various chemicals (acrylic acid, pyruvic acid, propylene glycol, 2,3-petnaedione, etc.), including polylactic acid (PLA), a biodegradable polymer. am. Not only is lactic acid highly useful in the chemical industry, but its raw materials, carbohydrates and glycerol, are also attracting attention as non-petroleum carbon sources, which is meaningful in that it produces chemicals in a sustainable way without additional carbon dioxide emissions.
상업 공정에서 젖산의 제조 공정은 주로 탄수화물(Glucose, Fructose)의 발효를 통해 생산된다. 발효는 비산소 조건에서 진행되는데, 배치당 대략 2 내지 4일의 반응 시간이 필요하고, 반응의 최적 pH를 유지하기 위해 alkali base들이 추가적으로 첨가되어야 하는 단점이 있다. 또한, 반응 종료 후, 약 10 wt% 정도의 저농도 젖산이 생성되어, 이들의 분리 정제에 많은 에너지와 화학 물질이 소모된다. 이와 같은 발효 공정을 통한 젖산 제조 공정의 문제점은 결과적으로 젖산 생산량을 저해하게 된다. 따라서, 지속 가능한 화학 원료로서 젖산의 활용도를 증진시키기 위해서는 젖산 생산 방법 개선을 위한 다각화된 노력이 필요하다.In commercial processes, lactic acid is mainly produced through fermentation of carbohydrates (glucose, fructose). Fermentation is carried out under non-oxygen conditions, and has the disadvantage of requiring a reaction time of approximately 2 to 4 days per batch and requiring additional alkali bases to be added to maintain the optimal pH for the reaction. In addition, after completion of the reaction, low concentration lactic acid of about 10 wt% is produced, and a lot of energy and chemicals are consumed for its separation and purification. The problem of the lactic acid production process through this fermentation process ultimately inhibits lactic acid production. Therefore, in order to increase the utilization of lactic acid as a sustainable chemical raw material, diversified efforts are needed to improve lactic acid production methods.
한편, 젖산은 두 가지의 enantiomer인 D-락트산, L-락트산의 형태로 존재한다. L-락트산은 PLA의 주 원료로 사용되며, 현재 상용화된 PLA는 주로 L-락트산으로 제조된 것이다. D-락트산은 PLA 제조 시, L-락트산과 함께 사용되어 열적 특성 및 생분해 속도를 개선할 수 있고, 제약 산업에서 전구체로서 활용 가치가 높은 것으로 알려져 있다. 이처럼, L-락트산 뿐만 아니라, D-락트산을 생산하기 위한 전략 개발의 필요성을 증가시키고 있다.Meanwhile, lactic acid exists in the form of two enantiomers, D-lactic acid and L-lactic acid. L-lactic acid is used as the main raw material for PLA, and currently commercialized PLA is mainly manufactured from L-lactic acid. D-lactic acid can be used together with L-lactic acid when manufacturing PLA to improve thermal properties and biodegradation speed, and is known to have high utility as a precursor in the pharmaceutical industry. As such, the need to develop strategies to produce not only L-lactic acid but also D-lactic acid is increasing.
그러나, 현재 젖산 제조 공정은 바이오매스로부터의 발효 공정이 지배적이며, 발효 공정을 통한 젖산 제조는 L-락트산의 제조에 집중되어 있다. 이에 발효 공정을 대체하면서, 특정 enantiomer의 생산성을 높이기 위해 촉매를 이용한 화학적 제조 방법에 대한 연구가 계속적으로 요구되고 있다.However, the current lactic acid production process is dominated by a fermentation process from biomass, and the production of lactic acid through the fermentation process is focused on the production of L-lactic acid. Accordingly, while replacing the fermentation process, research on chemical production methods using catalysts to increase the productivity of specific enantiomers is continuously required.
이에 본 발명에서는, 거울상 이성질체 과잉율이 높으면서 양산화에 적합한 젖산 제조 방법을 제공하고자 한다. Accordingly, the present invention seeks to provide a method for producing lactic acid that has a high enantiomeric excess and is suitable for mass production.
본 발명은 용매 중에서, 촉매 존재 하에 메틸글리옥살(methylglyoxal) 및 지방족 또는 방향족 싸이올계 화합물을 반응시켜 티오에스터(thioester)를 제조하는 단계(단계 1); 및 상기 티오에스터(thioester)를 젖산으로 전환하는 단계(단계 2)를 포함하고, 상기 촉매는 하기 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이들의 염인, 젖산 제조 방법을 제공한다:The present invention relates to preparing a thioester by reacting methylglyoxal and an aliphatic or aromatic thiol-based compound in a solvent in the presence of a catalyst (step 1); and converting the thioester into lactic acid (step 2), wherein the catalyst is a compound represented by the following formula (1) or formula (2) or a salt thereof:
[화학식 1][Formula 1]
[화학식 2][Formula 2]
상기 화학식 1 및 화학식 2에서,In Formula 1 and Formula 2,
R1은 수소, 히드록시기, 또는 치환 또는 비치환된 C1-60 알콕시이고,R 1 is hydrogen, a hydroxy group, or substituted or unsubstituted C 1-60 alkoxy,
R2는 치환 또는 비치환된 C1-60 알킬, 또는 치환 또는 비치환된 C1-60 알케닐이고,R 2 is substituted or unsubstituted C 1-60 alkyl, or substituted or unsubstituted C 1-60 alkenyl,
L은 단일 결합, -O-, -OCO-, -NH-CO-, -NH-CO-NH-, -NH-CS-NH-, -NH-SOO-, 또는 -NH-COO-이고,L is a single bond, -O-, -OCO-, -NH-CO-, -NH-CO-NH-, -NH-CS-NH-, -NH-SOO-, or -NH-COO-,
R3는 수소, 히드록시기, 아미노기, 치환 또는 비치환된 C1-60 알킬, 치환 또는 비치환된 C6-60 아릴, 또는 치환 또는 비치환된 N, O 및 S로 구성되는 군으로부터 선택되는 어느 하나 이상의 헤테로원자를 포함하는 C2-60 헤테로아릴이다.R 3 is hydrogen, a hydroxy group, an amino group, substituted or unsubstituted C 1-60 alkyl, substituted or unsubstituted C 6-60 aryl, or substituted or unsubstituted any selected from the group consisting of N, O and S. It is C 2-60 heteroaryl containing one or more heteroatoms.
이하, 본 발명의 이해를 돕기 위하여 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail to aid understanding.
본 명세서에서, 또는 는 다른 치환기에 연결되는 결합을 의미한다. In this specification, or means a bond connected to another substituent.
본 명세서에서 "치환 또는 비치환된" 이라는 용어는 중수소; 할로겐기; 니트릴기; 니트로기; 히드록시기; 카보닐기; 에스테르기; 이미드기; 아미노기; 포스핀옥사이드기; 알콕시기; 아릴옥시기; 알킬티옥시기; 아릴티옥시기; 알킬술폭시기; 아릴술폭시기; 실릴기; 붕소기; 알킬기; 사이클로알킬기; 알케닐기; 아릴기; 아르알킬기; 아르알케닐기; 알킬아릴기; 알킬아민기; 아랄킬아민기; 헤테로아릴아민기; 아릴아민기; 아릴포스핀기; 또는 N, O 및 S 원자 중 1개 이상을 포함하는 헤테로고리기로 이루어진 군에서 선택된 1개 이상의 치환기로 치환 또는 비치환되거나, 상기 예시된 치환기 중 2 이상의 치환기가 연결된 치환 또는 비치환된 것을 의미한다. 예컨대, "2 이상의 치환기가 연결된 치환기"는 비페닐기일 수 있다. 즉, 비페닐기는 아릴기일 수도 있고, 2개의 페닐기가 연결된 치환기로 해석될 수 있다.As used herein, the term “substituted or unsubstituted” refers to deuterium; halogen group; Nitrile group; nitro group; hydroxyl group; carbonyl group; ester group; imide group; amino group; Phosphine oxide group; Alkoxy group; Aryloxy group; Alkylthioxy group; Arylthioxy group; Alkyl sulphoxy group; Aryl sulfoxy group; silyl group; boron group; Alkyl group; Cycloalkyl group; alkenyl group; Aryl group; Aralkyl group; Aralkenyl group; Alkylaryl group; Alkylamine group; Aralkylamine group; heteroarylamine group; Arylamine group; Arylphosphine group; or substituted or unsubstituted with one or more substituents selected from the group consisting of heterocyclic groups containing one or more of N, O and S atoms, or substituted or unsubstituted with two or more of the above-exemplified substituents linked. . For example, “a substituent group in which two or more substituents are connected” may be a biphenyl group. That is, the biphenyl group may be an aryl group, or it may be interpreted as a substituent in which two phenyl groups are connected.
본 명세서에서 카보닐기의 탄소수는 특별히 한정되지 않으나, 탄소수 1 내지 40인 것이 바람직하다. 구체적으로 하기와 같은 구조의 치환기가 될 수 있으나, 이에 한정되는 것은 아니다.In this specification, the carbon number of the carbonyl group is not particularly limited, but is preferably 1 to 40 carbon atoms. Specifically, the substituent may have the following structure, but is not limited thereto.
본 명세서에 있어서, 에스테르기는 에스테르기의 산소가 탄소수 1 내지 25의 직쇄, 분지쇄 또는 고리쇄 알킬기 또는 탄소수 6 내지 25의 아릴기로 치환될 수 있다. 구체적으로, 하기 구조식의 치환기가 될 수 있으나, 이에 한정되는 것은 아니다.In the present specification, the oxygen of the ester group may be substituted with a straight-chain, branched-chain, or ring-chain alkyl group having 1 to 25 carbon atoms or an aryl group having 6 to 25 carbon atoms. Specifically, it may be a substituent of the following structural formula, but is not limited thereto.
본 명세서에 있어서, 이미드기의 탄소수는 특별히 한정되지 않으나, 탄소수 1 내지 25인 것이 바람직하다. 구체적으로 하기와 같은 구조의 치환기가 될 수 있으나, 이에 한정되는 것은 아니다.In this specification, the carbon number of the imide group is not particularly limited, but is preferably 1 to 25 carbon atoms. Specifically, the substituent may have the following structure, but is not limited thereto.
본 명세서에 있어서, 실릴기는 구체적으로 트리메틸실릴기, 트리에틸실릴기, t-부틸디메틸실릴기, 비닐디메틸실릴기, 프로필디메틸실릴기, 트리페닐실릴기, 디페닐실릴기, 페닐실릴기 등이 있으나 이에 한정되지 않는다.In the present specification, the silyl group specifically includes trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, vinyldimethylsilyl group, propyldimethylsilyl group, triphenylsilyl group, diphenylsilyl group, phenylsilyl group, etc. However, it is not limited to this.
본 명세서에 있어서, 붕소기는 구체적으로 트리메틸붕소기, 트리에틸붕소기, t-부틸디메틸붕소기, 트리페닐붕소기, 페닐붕소기 등이 있으나 이에 한정되지 않는다.In the present specification, the boron group specifically includes trimethyl boron group, triethyl boron group, t-butyldimethyl boron group, triphenyl boron group, and phenyl boron group, but is not limited thereto.
본 명세서에 있어서, 할로겐기의 예로는 불소, 염소, 브롬 또는 요오드가 있다.In this specification, examples of halogen groups include fluorine, chlorine, bromine, or iodine.
본 명세서에 있어서, 상기 알킬기는 직쇄 또는 분지쇄일 수 있고, 탄소수는 특별히 한정되지 않으나 1 내지 40인 것이 바람직하다. 일 실시상태에 따르면, 상기 알킬기의 탄소수는 1 내지 20이다. 또 하나의 실시상태에 따르면, 상기 알킬기의 탄소수는 1 내지 10이다. 또 하나의 실시상태에 따르면, 상기 알킬기의 탄소수는 1 내지 6이다. 알킬기의 구체적인 예로는 메틸, 에틸, 프로필, n-프로필, 이소프로필, 부틸, n-부틸, 이소부틸, tert-부틸, sec-부틸, 1-메틸-부틸, 1-에틸-부틸, 펜틸, n-펜틸, 이소펜틸, 네오펜틸, tert-펜틸, 헥실, n-헥실, 1-메틸펜틸, 2-메틸펜틸, 4-메틸-2-펜틸, 3,3-디메틸부틸, 2-에틸부틸, 헵틸, n-헵틸, 1-메틸헥실, 사이클로펜틸메틸, 사이클로헥틸메틸, 옥틸, n-옥틸, tert-옥틸, 1-메틸헵틸, 2-에틸헥실, 2-프로필펜틸, n-노닐, 2,2-디메틸헵틸, 1-에틸-프로필, 1,1-디메틸-프로필, 이소헥실, 2-메틸펜틸, 4-메틸헥실, 5-메틸헥실 등이 있으나, 이들에 한정되지 않는다.In the present specification, the alkyl group may be straight chain or branched, and the number of carbon atoms is not particularly limited, but is preferably 1 to 40. According to one embodiment, the carbon number of the alkyl group is 1 to 20. According to another embodiment, the carbon number of the alkyl group is 1 to 10. According to another embodiment, the carbon number of the alkyl group is 1 to 6. Specific examples of alkyl groups include methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1-methyl-butyl, 1-ethyl-butyl, pentyl, n. -pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl , n-heptyl, 1-methylhexyl, cyclopentylmethyl, cyclohexylmethyl, octyl, n-octyl, tert-octyl, 1-methylheptyl, 2-ethylhexyl, 2-propylpentyl, n-nonyl, 2,2 -Dimethylheptyl, 1-ethyl-propyl, 1,1-dimethyl-propyl, isohexyl, 2-methylpentyl, 4-methylhexyl, 5-methylhexyl, etc., but is not limited to these.
본 명세서에 있어서, 상기 알케닐기는 직쇄 또는 분지쇄일 수 있고, 탄소수는 특별히 한정되지 않으나, 2 내지 40인 것이 바람직하다. 일 실시상태에 따르면, 상기 알케닐기의 탄소수는 2 내지 20이다. 또 하나의 실시상태에 따르면, 상기 알케닐기의 탄소수는 2 내지 10이다. 또 하나의 실시상태에 따르면, 상기 알케닐기의 탄소수는 2 내지 6이다. 구체적인 예로는 비닐, 1-프로페닐, 이소프로페닐, 1-부테닐, 2-부테닐, 3-부테닐, 1-펜테닐, 2-펜테닐, 3-펜테닐, 3-메틸-1-부테닐, 1,3-부타디에닐, 알릴, 1-페닐비닐-1-일, 2-페닐비닐-1-일, 2,2-디페닐비닐-1-일, 2-페닐-2-(나프틸-1-일)비닐-1-일, 2,2-비스(디페닐-1-일)비닐-1-일, 스틸베닐기, 스티레닐기 등이 있으나 이들에 한정되지 않는다.In the present specification, the alkenyl group may be straight chain or branched, and the number of carbon atoms is not particularly limited, but is preferably 2 to 40. According to one embodiment, the alkenyl group has 2 to 20 carbon atoms. According to another embodiment, the alkenyl group has 2 to 10 carbon atoms. According to another embodiment, the alkenyl group has 2 to 6 carbon atoms. Specific examples include vinyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 3-methyl-1- Butenyl, 1,3-butadienyl, allyl, 1-phenylvinyl-1-yl, 2-phenylvinyl-1-yl, 2,2-diphenylvinyl-1-yl, 2-phenyl-2-( Naphthyl-1-yl) vinyl-1-yl, 2,2-bis (diphenyl-1-yl) vinyl-1-yl, stilbenyl group, styrenyl group, etc., but are not limited to these.
본 명세서에 있어서, 사이클로알킬기는 특별히 한정되지 않으나, 탄소수 3 내지 60인 것이 바람직하며, 일 실시상태에 따르면, 상기 사이클로알킬기의 탄소수는 3 내지 30이다. 또 하나의 실시상태에 따르면, 상기 사이클로알킬기의 탄소수는 3 내지 20이다. 또 하나의 실시상태에 따르면, 상기 사이클로알킬기의 탄소수는 3 내지 6이다. 구체적으로 사이클로프로필, 사이클로부틸, 사이클로펜틸, 3-메틸사이클로펜틸, 2,3-디메틸사이클로펜틸, 사이클로헥실, 3-메틸사이클로헥실, 4-메틸사이클로헥실, 2,3-디메틸사이클로헥실, 3,4,5-트리메틸사이클로헥실, 4-tert-부틸사이클로헥실, 사이클로헵틸, 사이클로옥틸 등이 있으나, 이에 한정되지 않는다.In the present specification, the cycloalkyl group is not particularly limited, but preferably has 3 to 60 carbon atoms, and according to one embodiment, the cycloalkyl group has 3 to 30 carbon atoms. According to another embodiment, the carbon number of the cycloalkyl group is 3 to 20. According to another embodiment, the carbon number of the cycloalkyl group is 3 to 6. Specifically, cyclopropyl, cyclobutyl, cyclopentyl, 3-methylcyclopentyl, 2,3-dimethylcyclopentyl, cyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 2,3-dimethylcyclohexyl, 3, Examples include, but are not limited to, 4,5-trimethylcyclohexyl, 4-tert-butylcyclohexyl, cycloheptyl, and cyclooctyl.
본 명세서에 있어서, 아릴기는 특별히 한정되지 않으나 탄소수 6 내지 60인 것이 바람직하며, 단환식 아릴기 또는 다환식 아릴기일 수 있다. 일 실시상태에 따르면, 상기 아릴기의 탄소수는 6 내지 30이다. 일 실시상태에 따르면, 상기 아릴기의 탄소수는 6 내지 20이다. 상기 아릴기가 단환식 아릴기로는 페닐기, 바이페닐기, 터페닐기 등이 될 수 있으나, 이에 한정되는 것은 아니다. 상기 다환식 아릴기로는 나프틸기, 안트라세닐기, 페난트릴기, 파이레닐기, 페릴레닐기, 크라이세닐기, 플루오레닐기 등이 될 수 있으나, 이에 한정되는 것은 아니다.In the present specification, the aryl group is not particularly limited, but preferably has 6 to 60 carbon atoms, and may be a monocyclic aryl group or a polycyclic aryl group. According to one embodiment, the aryl group has 6 to 30 carbon atoms. According to one embodiment, the aryl group has 6 to 20 carbon atoms. The aryl group may be a monocyclic aryl group, such as a phenyl group, biphenyl group, or terphenyl group, but is not limited thereto. The polycyclic aryl group may be a naphthyl group, anthracenyl group, phenanthryl group, pyrenyl group, perylenyl group, chrysenyl group, fluorenyl group, etc., but is not limited thereto.
본 명세서에 있어서, 플루오레닐기는 치환될 수 있고, 치환기 2개가 서로 결합하여 스피로 구조를 형성할 수 있다. 상기 플루오레닐기가 치환되는 경우, 등이 될 수 있다. 다만, 이에 한정되는 것은 아니다.In the present specification, the fluorenyl group may be substituted, and two substituents may be combined with each other to form a spiro structure. When the fluorenyl group is substituted, It can be etc. However, it is not limited to this.
본 명세서에 있어서, 헤테로고리기는 이종 원소로 O, N, Si 및 S 중 1개 이상을 포함하는 헤테로고리기로서, 탄소수는 특별히 한정되지 않으나, 탄소수 2 내지 60인 것이 바람직하다. 헤테로고리기의 예로는 티오펜기, 퓨란기, 피롤기, 이미다졸기, 티아졸기, 옥사졸기, 옥사디아졸기, 트리아졸기, 피리딜기, 비피리딜기, 피리미딜기, 트리아진기, 아크리딜기, 피리다진기, 피라지닐기, 퀴놀리닐기, 퀴나졸린기, 퀴녹살리닐기, 프탈라지닐기, 피리도 피리미디닐기, 피리도 피라지닐기, 피라지노 피라지닐기, 이소퀴놀린기, 인돌기, 카바졸기, 벤조옥사졸기, 벤조이미다졸기, 벤조티아졸기, 벤조카바졸기, 벤조티오펜기, 디벤조티오펜기, 벤조퓨라닐기, 페난쓰롤린기(phenanthroline), 이소옥사졸릴기, 티아디아졸릴기, 페노티아지닐기 및 디벤조퓨라닐기 등이 있으나, 이들에만 한정되는 것은 아니다.In the present specification, the heterocyclic group is a heterocyclic group containing one or more of O, N, Si, and S as a heterogeneous element, and the number of carbon atoms is not particularly limited, but is preferably 2 to 60 carbon atoms. Examples of heterocyclic groups include thiophene group, furan group, pyrrole group, imidazole group, thiazole group, oxazole group, oxadiazole group, triazole group, pyridyl group, bipyridyl group, pyrimidyl group, triazine group, and acridyl group. , pyridazine group, pyrazinyl group, quinolinyl group, quinazoline group, quinoxalinyl group, phthalazinyl group, pyrido pyrimidinyl group, pyrido pyrazinyl group, pyrazino pyrazinyl group, isoquinoline group, indole group , carbazole group, benzooxazole group, benzoimidazole group, benzothiazole group, benzocarbazole group, benzothiophene group, dibenzothiophene group, benzofuranyl group, phenanthroline group, isoxazolyl group, thiadia These include, but are not limited to, a zolyl group, a phenothiazinyl group, and a dibenzofuranyl group.
본 명세서에 있어서, 아르알킬기, 아르알케닐기, 알킬아릴기, 아릴아민기 중의 아릴기는 전술한 아릴기의 예시와 같다. 본 명세서에 있어서, 아르알킬기, 알킬아릴기, 알킬아민기 중 알킬기는 전술한 알킬기의 예시와 같다. 본 명세서에 있어서, 헤테로아릴아민 중 헤테로아릴은 전술한 헤테로고리기에 관한 설명이 적용될 수 있다. 본 명세서에 있어서, 아르알케닐기 중 알케닐기는 전술한 알케닐기의 예시와 같다. 본 명세서에 있어서, 아릴렌은 2가기인 것을 제외하고는 전술한 아릴기에 관한 설명이 적용될 수 있다. 본 명세서에 있어서, 헤테로아릴렌은 2가기인 것을 제외하고는 전술한 헤테로고리기에 관한 설명이 적용될 수 있다. 본 명세서에 있어서, 탄화수소 고리는 1가기가 아니고, 2개의 치환기가 결합하여 형성한 것을 제외하고는 전술한 아릴기 또는 사이클로알킬기에 관한 설명이 적용될 수 있다. 본 명세서에 있어서, 헤테로고리는 1가기가 아니고, 2개의 치환기가 결합하여 형성한 것을 제외하고는 전술한 헤테로고리기에 관한 설명이 적용될 수 있다.In this specification, the aryl group among the aralkyl group, aralkenyl group, alkylaryl group, and arylamine group is the same as the example of the aryl group described above. In this specification, the aralkyl group, alkylaryl group, and alkylamine group are the same as the examples of the alkyl group described above. In the present specification, the description regarding the heterocyclic group described above may be applied to heteroaryl among heteroarylamines. In this specification, the alkenyl group among the aralkenyl groups is the same as the example of the alkenyl group described above. In the present specification, the description of the aryl group described above can be applied, except that arylene is a divalent group. In the present specification, the description of the heterocyclic group described above can be applied, except that heteroarylene is a divalent group. In the present specification, the description of the aryl group or cycloalkyl group described above can be applied, except that the hydrocarbon ring is not monovalent and is formed by combining two substituents. In the present specification, the description of the heterocyclic group described above can be applied, except that the heterocycle is not a monovalent group and is formed by combining two substituents.
본 명세서에서, “젖산”은 “락트산”과 동의어이다. In this specification, “lactic acid” is synonymous with “lactic acid.”
메틸글리옥살(methylglyoxal, 또는 pyruvaldehyde)로부터 젖산을 제조하는 과정은 일례로 다음과 같다:For example, the process for producing lactic acid from methylglyoxal (or pyruvaldehyde) is as follows:
[반응식 1][Scheme 1]
상기 반응식 1에서, In Scheme 1 above,
R은 치환 또는 비치환된 C1-20 알킬, 또는 치환 또는 비치환된 C6-60 아릴이다.R is substituted or unsubstituted C 1-20 alkyl, or substituted or unsubstituted C 6-60 aryl.
이하, 각 단계를 구체적으로 설명한다.Hereinafter, each step will be described in detail.
(단계 1)(Step 1)
본 발명의 젖산 제조 방법에 있어서, 단계 1은 용매 중에서, 촉매 존재 하에 메틸글리옥살(methylglyoxal) 및 지방족 또는 방향족 싸이올계 화합물을 반응시켜 티오에스터(thioester)를 수득하는 단계이다. In the lactic acid production method of the present invention, step 1 is a step of obtaining a thioester by reacting methylglyoxal and an aliphatic or aromatic thiol-based compound in a solvent in the presence of a catalyst.
구체적으로, 본 발명은 메틸글리옥살(methylglyoxal)과 싸이올계 화합물의 반응을 통한 젖산을 제조하는 방법에 있어서, 상기 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이의 염인, 퀴니딘(quinidine), 퀴닌(quinine), 신코닌(cinchonine), 신코니딘(cinchonidine) 및 이의 유도체를 촉매로 이용하여 카이랄한 젖산을 제조하는 방법에 관한 것이다. Specifically, the present invention relates to a method for producing lactic acid through the reaction of methylglyoxal and a thiol-based compound, including the compound represented by Formula 1 or Formula 2 or a salt thereof, quinidine, quinine ( It relates to a method of producing chiral lactic acid using quinine, cinchonine, cinchonidine, and their derivatives as catalysts.
메틸글리옥살과 싸이올계 화합물이 반응하여 거울상 선택적인 티오에스터(thioester)를 생성하는데, 이 과정에서 촉매에 의해 카르보닐 탄소의 친전자성(electrophilicity)이 향상되어 중간체의 α-양성자의 산성도를 증가시키게 되고, 상기 α-양성자는 탈양성자화되어 입체 선택적으로 재양성자화 됨으로써, 입체 선택성이 높은 젖산을 제조할 수 있다. 본 발명에 사용되는 상기 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이의 염은 전자적으로 풍부한 환경을 제공하면서, 입체적 구조를 가져 반응물의 입체 선택적 접촉을 유도하여, 특정한 입체적 구조를 가지는 젖산을 생성하는데 유리한 역할을 한다.Methylglyoxal and a thiol-based compound react to produce an enantioselective thioester. In this process, the electrophilicity of the carbonyl carbon is improved by the catalyst, increasing the acidity of the α-proton of the intermediate. As a result, the α-proton is deprotonated and stereoselectively reprotonated, thereby producing lactic acid with high stereoselectivity. The compound represented by Formula 1 or Formula 2 or its salt used in the present invention provides an electronically rich environment and has a three-dimensional structure, which is advantageous for producing lactic acid with a specific three-dimensional structure by inducing stereoselective contact with reactants. It plays a role.
상기와 같이, 본 발명은 상업적 양산화가 가능하면서도 거울상 선택성(enantioselectivity)이 높은, 즉 거울상 이성질체 과잉률(enantiomeric excess)이 높은 젖산 제조 방법을 제공한다. As described above, the present invention provides a method for producing lactic acid that can be commercially mass-produced and has high enantioselectivity, that is, high enantiomeric excess.
바람직하게는, R1은 수소, 히드록시기, 또는 메톡시이다.Preferably, R 1 is hydrogen, a hydroxy group, or methoxy.
바람직하게는, R2는 에틸 또는 비닐이다.Preferably, R 2 is ethyl or vinyl.
바람직하게는, R3는 수소, 히드록시기, 아미노기, 메틸, tert-부틸, 페닐, 또는 퀴놀린이고; 상기 페닐, 및 퀴놀린은 각각 독립적으로, 비치환되거나, 또는 하나 이상의 할로겐, 메틸, 트리플루오로메틸, 또는 메톡시로 치환된다.Preferably, R 3 is hydrogen, a hydroxy group, an amino group, methyl, tert-butyl, phenyl, or quinoline; The phenyl and quinoline are each independently unsubstituted or substituted with one or more halogen, methyl, trifluoromethyl, or methoxy.
상기 화학식 1 또는 화학식 2로 표시되는 화합물, 또는 이들의 염의 대표적인 예는 다음과 같다:Representative examples of compounds represented by Formula 1 or Formula 2, or salts thereof, are as follows:
상기 화학식 1 또는 화학식 2로 표시되는 화합물, 또는 이들의 염의 제조 방법은 후술할 실시예에서 구체화될 수 있다.Methods for producing the compounds represented by Formula 1 or Formula 2, or salts thereof, may be specified in examples to be described later.
한편, 본 발명의 젖산 제조 방법에서 사용 가능한 용매는 반응물인 메틸글리옥살, 싸이올계 화합물 및 촉매에 대한 용해성이 높은 것이라면 제한되지 않고 사용할 수 있다. 이러한 용매의 예로는 극성 용매 및 비극성 용매가 있을 수 있다. 극성 용매는, 극성 비양자성 용매 또는 극성 양자성 용매일 수 있다. 용매의 비제한적인 예로는, 톨루엔, 자일렌, 벤젠, 스티렌, 아니솔, 클로로벤젠, 디클로로벤젠, 클로로포름, 디클로로메탄(DCM), 디클로로에탄, 메틸 아세테이트, 에틸 아세테이트, 부틸 아세테이트, 메틸 에테르 케톤(MEK), 메틸 이소부틸 케톤(MIBK), 아세톤, 에틸렌 글리콜, 에탄올, 메탄올, 프로판올, 부탄올, 헥산, 시클로헥산, 디메톡시에탄, 메틸 tert-부틸 에테르(MTBE), 디에틸 에테르, 아디포니트릴, N,N-디메틸포름아미드(DMF), 디메틸설폭사이드(DMSO), N,N-디메틸아세트아미드(DMAc), 디옥산, 니트로메탄, 니트로벤젠, 피리딘, 이황화탄소(carbon disulfide), 테트라히드로퓨란(THF), 메틸테트라히드로퓨란, N-메틸 피롤리돈(NMP), 아세토니트릴, 물, 및 이의 혼합물로 구성되는 군으로부터 선택되는 1종 이상을 포함한다.Meanwhile, the solvent usable in the lactic acid production method of the present invention is not limited as long as it has high solubility in the reactants methylglyoxal, thiol-based compound, and catalyst. Examples of such solvents may include polar solvents and non-polar solvents. The polar solvent may be a polar aprotic solvent or a polar protic solvent. Non-limiting examples of solvents include toluene, xylene, benzene, styrene, anisole, chlorobenzene, dichlorobenzene, chloroform, dichloromethane (DCM), dichloroethane, methyl acetate, ethyl acetate, butyl acetate, methyl ether ketone ( MEK), methyl isobutyl ketone (MIBK), acetone, ethylene glycol, ethanol, methanol, propanol, butanol, hexane, cyclohexane, dimethoxyethane, methyl tert-butyl ether (MTBE), diethyl ether, adiponitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMAc), dioxane, nitromethane, nitrobenzene, pyridine, carbon disulfide, tetrahydrofuran (THF), methyltetrahydrofuran, N-methyl pyrrolidone (NMP), acetonitrile, water, and mixtures thereof.
바람직하게는, 용매는 메틸글리옥살 농도가 0.01 M 내지 2.0 M이 되도록 사용한다. 메틸글리옥살 농도가 0.01 M 미만이 되도록 용매를 사용할 경우, 용매 자체 비용 문제 및 정제 공정에서 추가적인 비용이 발생할 수 있고, 2.0 M 초과가 되도록 용매를 사용할 경우, 반응물과 촉매를 완전히 용해시키지 못하여 반응이 제대로 진행되지 않을 수 있다. 보다 바람직하게는, 용매는 메틸글리옥살 농도가 0.02 M 이상, 0.03 M 이상, 0.04 M 이상, 또는 0.05 M이면서, 1.5 M 이하, 1.0 M 이하, 0.7 M 이하, 0.5 M 이하, 0.3 M 이하, 0.4 M 이하, 또는 0.5 M 이하가 되도록 사용될 수 있다.Preferably, the solvent is used so that the methylglyoxal concentration is 0.01 M to 2.0 M. If the solvent is used so that the methylglyoxal concentration is less than 0.01 M, the problem of the cost of the solvent itself and additional costs may occur in the purification process, and if the solvent is used so that the concentration is more than 2.0 M, the reaction may not be completed because the reactants and catalyst cannot be completely dissolved. It may not proceed properly. More preferably, the solvent has a methylglyoxal concentration of at least 0.02 M, at least 0.03 M, at least 0.04 M, or 0.05 M, and at most 1.5 M, at most 1.0 M, at most 0.7 M, at most 0.5 M, at most 0.3 M, and at most 0.4 M. It can be used to be M or less, or 0.5 M or less.
바람직하게는, 촉매는 메틸글리옥살 기준 1 mol% 이상으로 사용된다. 촉매의 양이 메틸글리옥살 기준 1 mol% 미만인 경우, 반응 속도가 느려질 수 있으며, 보다 바람직하게는, 촉매는 메틸글리옥살 기준 1.5 mol% 이상, 2 mol% 이상, 2.5 mol% 이상, 3 mol% 이상, 3.5 mol% 이상, 4 mol% 이상, 4.5 mol% 이상, 또는 5 mol% 이상으로 사용될 수 있다. 또한, 본 발명의 효과를 구현하기 위한 촉매 사용량의 상한은 특별한 제한이 없으나, 일례로 150 mol% 이하, 120 mol% 이하, 또는 100 mol% 이하로 사용될 수 있다.Preferably, the catalyst is used in an amount of at least 1 mol% based on methylglyoxal. If the amount of catalyst is less than 1 mol% based on methylglyoxal, the reaction rate may be slow, and more preferably, the catalyst is present in an amount of 1.5 mol% or more, 2 mol% or more, 2.5 mol% or more, or 3 mol% based on methylglyoxal. It may be used in an amount of 3.5 mol% or more, 4 mol% or more, 4.5 mol% or more, or 5 mol% or more. In addition, there is no particular limitation on the upper limit of the amount of catalyst used to realize the effect of the present invention, but for example, it may be 150 mol% or less, 120 mol% or less, or 100 mol% or less.
한편, 본 발명에서 메틸글리옥살과 반응하는 지방족 또는 방향족 싸이올 화합물의 종류는, 상기 반응식 1과 같은 싸이올 에스터 생성이 가능한 물질이면 특별한 제한이 없다. 또한, 본 명세서에서 싸이올계 화합물이란, -SH 작용기를 포함하는 물질로서, 하나 이상의 할로겐으로 치환된 지방족 또는 방향족 싸이올계 화합물을 포함한다. 지방족 또는 방향족 싸이올계 화합물의 구체적인 예로는 벤질 싸이올, tert-부틸 싸이올, 또는 퍼푸릴 싸이올 등이 있다. Meanwhile, in the present invention, the type of aliphatic or aromatic thiol compound that reacts with methylglyoxal is not particularly limited as long as it is a material capable of producing a thiol ester as shown in Scheme 1 above. Additionally, in this specification, a thiol-based compound refers to a substance containing a -SH functional group and includes an aliphatic or aromatic thiol-based compound substituted with one or more halogens. Specific examples of aliphatic or aromatic thiol-based compounds include benzyl thiol, tert-butyl thiol, or furfuryl thiol.
바람직하게는, 지방족 또는 방향족 싸이올계 화합물은 메틸글리옥살 대비 0.5 내지 10 당량으로 사용된다. 지방족 또는 방향족 싸이올이 메틸글리옥살 대비 0.5 당량 미만으로 사용될 경우, 젖산의 수율이 매우 낮아 목적하는 생산성을 달성하지 못할 수 있고, 10 당량 초과로 사용될 경우, 잔여 화합물의 분리 공정에 과도한 비용이 소모될 수 있다. 보다 바람직하게는, 상기 지방족 또는 방향족 싸이올계 화합물은 메틸글리옥살 대비 0.6 당량 이상, 0.7 당량 이상, 0.8 당량 이상, 0.9 당량 이상, 또는 1.0 당량 이상이면서, 9 당량 이하, 8 당량 이하, 7 당량 이하, 6 당량 이하, 5 당량 이하, 4 당량 이하, 3 당량 이하, 또는 2 당량 이하사용될 수 있다. Preferably, the aliphatic or aromatic thiol-based compound is used in an amount of 0.5 to 10 equivalents relative to methylglyoxal. If aliphatic or aromatic thiol is used in less than 0.5 equivalents compared to methylglyoxal, the yield of lactic acid may be very low and the desired productivity may not be achieved, and if used in excess of 10 equivalents, excessive costs are incurred in the separation process of the remaining compounds. It can be. More preferably, the aliphatic or aromatic thiol-based compound is present in an amount of 0.6 equivalents or more, 0.7 equivalents or more, 0.8 equivalents or more, 0.9 equivalents or more, or 1.0 equivalents or more, and 9 equivalents or less, 8 equivalents or less, or 7 equivalents or less compared to methylglyoxal. , 6 equivalents or less, 5 equivalents or less, 4 equivalents or less, 3 equivalents or less, or 2 equivalents or less may be used.
바람직하게는, 상기 반응은 -30 ℃ 내지 100 ℃에서 진행한다. 반응 온도가 -30 ℃ 미만인 경우, 반응이 진행되지 않을 수 있고, 100 ℃ 초과인 경우 부반응 또는 반응물의 분해, 용매의 휘발 등이 있을 수 있다. 또한, 높은 광학 활성과 수율을 얻기 위해서는, -25 ℃ 이상, -20 ℃ 이상, -15 ℃ 이상, -10 ℃ 이상, -5 ℃, 또는 0 ℃ 이상이면서, 90 ℃ 이하, 80 ℃ 이하, 70 ℃ 이하, 60 ℃ 이하, 또는 50 ℃ 이하에서 진행하는 것이 바람직하다.Preferably, the reaction proceeds at -30°C to 100°C. If the reaction temperature is below -30°C, the reaction may not proceed, and if it is above 100°C, there may be side reactions, decomposition of reactants, volatilization of solvent, etc. In addition, in order to obtain high optical activity and yield, the temperature is -25 ℃ or higher, -20 ℃ or higher, -15 ℃ or higher, -10 ℃ or higher, -5 ℃, or 0 ℃ or higher, but 90 ℃ or lower, 80 ℃ or lower, 70 ℃ or higher. It is preferable to proceed at ℃ or lower, 60 ℃ or lower, or 50 ℃ or lower.
(단계 2)(Step 2)
본 발명의 단계 2는 단계 1에서 제조된 상기 티오에스터를 젖산으로 전환하는 단계이다. Step 2 of the present invention is a step of converting the thioester prepared in Step 1 into lactic acid.
단계 1에서 제조된 생성물은, 상기 반응식 1에서 확인할 수 있는 바와 같이, α-히드록시 티오에스터 구조를 가진다. 이를 젖산으로 전환하기 위해서는, 당업계에 널리 알려진 바와 같이 티오에스터의 가수 분해를 적용할 수 있으며, 일례로 티오에스터를 산 혹은 염기 수용액을 처리하여 황 작용기를 물로 대체하여 제조한다. The product prepared in Step 1 has an α-hydroxy thioester structure, as can be seen in Scheme 1 above. To convert this to lactic acid, hydrolysis of the thioester can be applied, as is widely known in the art. For example, the thioester is prepared by treating the aqueous acid or base solution and replacing the sulfur functional group with water.
또한, 본 발명에 따른 젖산 제조 방법은 생성물을 회수하기 위하여 침전, 용매재결정, 반응추출, 실리카 컬럼 크로마토그래피 등을 수행하여 정제하는 단계를 추가로 포함할 수 있으나, 이에 제한되지 않는다. In addition, the method for producing lactic acid according to the present invention may further include a purification step by performing precipitation, solvent recrystallization, reaction extraction, silica column chromatography, etc. to recover the product, but is not limited thereto.
본 발명의 젖산 제조 방법에 따라 제조된 젖산은 L-락트산 및 D-락트산을 포함하고, 상기 L-락트산 또는 D-락트산의 거울상 이성질체 과잉률(enatiomeric excess)이 5% 이상이다. “거울상 이성질체 과잉률”은 거울상체 혼합물에서 하나의 거울상체가 다른 거울상체보다 어느 정도로 존재하는지 판단하는 척도이다. 본 발명에 따른 제조 방법을 통해 생성되는 젖산은 거울상 이성질체의 혼합물로, L-락트산 및 D-락트산의 혼합물이다. 즉, 본 발명에서 거울상 이성질체 과잉률은 L-락트산 또는 D-락트산을 기준으로 하여, 혼합물 내 거울상 이성질체 함량의 비율을 의미한다. 거울상 이성질체 과잉률의 산출 방법은 후술할 실시예에서 보다 구체화한다. 보다 바람직하게는, 거울상 이성질체 과잉률이 6% 이상, 7% 이상, 8% 이상, 9% 이상, 10% 이상, 11% 이상, 또는 12% 이상이다.Lactic acid prepared according to the lactic acid production method of the present invention includes L-lactic acid and D-lactic acid, and the enatiomeric excess of L-lactic acid or D-lactic acid is 5% or more. “Enantiomeric excess” is a measure that determines the extent to which one enantiomer exists over another in an enantiomeric mixture. Lactic acid produced through the production method according to the present invention is a mixture of enantiomers, and is a mixture of L-lactic acid and D-lactic acid. That is, in the present invention, the enantiomeric excess ratio refers to the ratio of the enantiomeric content in the mixture based on L-lactic acid or D-lactic acid. The method for calculating the enantiomeric excess ratio will be described in more detail in the Examples described later. More preferably, the enantiomeric excess is 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 11% or more, or 12% or more.
본 발명의 젖산 제조 방법에 따르면, 친환경 적이며 경제적으로 선택적으로 카이랄한 젖산을 제조할 수 있다 According to the lactic acid production method of the present invention, chiral lactic acid can be selectively produced in an environmentally friendly and economical manner.
이하, 본 발명의 구현예를 하기의 실시예에서 보다 상세하게 설명한다. 단, 하기의 실시예는 본 발명의 구현예를 예시하는 것일 뿐, 본 발명의 내용이 하기의 실시예에 의하여 한정되는 것은 아니다. Hereinafter, embodiments of the present invention will be described in more detail in the following examples. However, the following examples only illustrate embodiments of the present invention, and the content of the present invention is not limited by the following examples.
제조예 1: 화합물 1의 제조Preparation Example 1: Preparation of Compound 1
Quinine(1 equiv)과 sodium ethanethiolate(4 equiv)을 DMF에 녹인 후 110 ℃에서 overnight 동안 반응시켰다. 반응이 종료된 후 NH4Cl 수용액으로 pH7로 맞춘 뒤 ethyl acetate로 추출하였다. 추출한 유기용매를 소금물로 씻고 Na2SO4로 말린 후 실리카 컬럼 크로마토 그래피로 정제하여 화합물 1을 제조하였다. (수율: 67%)Quinine (1 equiv) and sodium ethanethiolate (4 equiv) were dissolved in DMF and reacted at 110°C overnight. After the reaction was completed, the pH was adjusted to 7 with NH 4 Cl aqueous solution and extracted with ethyl acetate. Compound 1 was prepared by washing the extracted organic solvent with salt water, drying it with Na 2 SO 4 and purifying it by silica column chromatography. (yield: 67%)
1H NMR (600 MHz, CD3OD) δ 8.55 (d, 1H), 7.86 (d, 1H), 7.58 (d, 1H), 7.29 (dd, 1H), 7.25 (d, 1H), 5.74-5.68 (m, 1H), 5.48 (d, 1H), 4.95-4.92 (m, 1H), 3.69-3.64 (m, 1H), 3.28-3.27 (m, 2H), 3.09-3.04 (m, 2H), 2.71-2.62 (m, 2H), 2.34-2.29 (m, 1H), 1.86-1.79 (m, 2H), 1.76-1.74 (m, 1H), 1.58-1.52 (m, 1H), 1.42-1.37 (m, 1H) ppm 1 H NMR (600 MHz, CD 3 OD) δ 8.55 (d, 1H), 7.86 (d, 1H), 7.58 (d, 1H), 7.29 (dd, 1H), 7.25 (d, 1H), 5.74-5.68 (m, 1H), 5.48 (d, 1H), 4.95-4.92 (m, 1H), 3.69-3.64 (m, 1H), 3.28-3.27 (m, 2H), 3.09-3.04 (m, 2H), 2.71 -2.62 (m, 2H), 2.34-2.29 (m, 1H), 1.86-1.79 (m, 2H), 1.76-1.74 (m, 1H), 1.58-1.52 (m, 1H), 1.42-1.37 (m, 1H) ppm
제조예 2: 화합물 2의 제조Preparation Example 2: Preparation of Compound 2
Quinine(1 equiv)을 THF(terahydrofuran)에 용해시킨 뒤 0 ℃에서 교반하였다. TEA(triethylamine, 2.3 equiv)와 methanesulfonyl chloride(1.9 equiv)을 넣고 상온에서 overnight동안 교반하였다. TLC(thin layer chromatography)로 quinine이 모두 소비되었는지 확인하고 NaHCO3 수용액을 넣고 유기용매는 증발시켰다. 물층을 DCM(dichloromethane)으로 추출하고 용매를 증발시켰다. 남은 잔여물은 물에 녹인 뒤 tartaric acid(0.99 equiv) 넣고 1시간 동안 reflux 하였다. 반응이 종료된 후, 고체 NaHCO3를 기체 방출이 없을 때까지 천천히 넣고 DCM으로 추출하였다. 유기 용매를 MgSO4로 말린 뒤 short column chromatograph로 정제하여 중간 생성물 2-a을 제조하였다. (수율: 70%) After dissolving quinine (1 equiv) in THF (terahydrofuran), It was stirred at ℃. TEA (triethylamine, 2.3 equiv) and methanesulfonyl chloride (1.9 equiv) were added and stirred at room temperature overnight. After confirming that all quinine was consumed by TLC (thin layer chromatography), NaHCO 3 aqueous solution was added, and the organic solvent was evaporated. The water layer was extracted with DCM (dichloromethane) and the solvent was evaporated. The remaining residue was dissolved in water, then tartaric acid (0.99 equiv) was added and refluxed for 1 hour. After the reaction was completed, solid NaHCO 3 was slowly added until no gas was evolved and extracted with DCM. The organic solvent was dried with MgSO 4 and purified using a short column chromatograph to prepare intermediate product 2-a. (yield: 70%)
중간 생성물 2-a(1 equiv)와 sodium ethanethiolate(4 equiv)을 DMF에 녹인 후 110 ℃에서 overnight 동안 반응시켰다. 반응이 종료된 후, NH4Cl 수용액으로 pH 7로 맞춘 뒤 ethyl acetate로 추출하였다. 추출한 유기용매를 소금물로 씻고 Na2SO4로 말린 후 column chromatograph로 정제하여 화합물 2를 제조하였다. (수율: 19%)After dissolving intermediate product 2-a (1 equiv) and sodium ethanethiolate (4 equiv) in DMF, The reaction was carried out overnight at ℃. After the reaction was completed, the pH was adjusted to 7 with NH 4 Cl aqueous solution and extracted with ethyl acetate. Compound 2 was prepared by washing the extracted organic solvent with salt water, drying it with Na 2 SO 4 and purifying it by column chromatography. (yield: 19%)
1H NMR (400 MHz, CDCl3) δ 8.67 (d, 1H), 8.00 (d, 1H), 7.72 (s, 1H), 7.38-7.33 (m, 2H), 5.74-5.64 (m, 1H), 4.98-4.90 (m, 3H), 3.20-3.00 (m, 3H), 2.74-2.60 (m, 2H), 2.34-2.20 (m, 1H), 1.70-1.22 (m, 5H), 0.94-0.84 (m, 1H) ppm 1 H NMR (400 MHz, CDCl 3 ) δ 8.67 (d, 1H), 8.00 (d, 1H), 7.72 (s, 1H), 7.38-7.33 (m, 2H), 5.74-5.64 (m, 1H), 4.98-4.90 (m, 3H), 3.20-3.00 (m, 3H), 2.74-2.60 (m, 2H), 2.34-2.20 (m, 1H), 1.70-1.22 (m, 5H), 0.94-0.84 (m) , 1H)ppm
제조예 3: 화합물 3의 제조Preparation Example 3: Preparation of Compound 3
Quinidine(1 equiv)과 sodium ethanethiolate(4 equiv)을 DMF에 녹인 후 110 ℃에서 overnight 동안 반응시켰다. 반응이 종료된 후, NH4Cl 수용액으로 pH 7로 맞춘 뒤 ethyl acetate로 추출하였다. 추출한 유기용매를 소금물로 씻고 Na2SO4로 말린 후 column chromatograph로 정제하여 화합물 3을 제조하였다. (수율: 47%)After dissolving quinidine (1 equiv) and sodium ethanethiolate (4 equiv) in DMF, The reaction was carried out overnight at ℃. After the reaction was completed, the pH was adjusted to 7 with NH 4 Cl aqueous solution and extracted with ethyl acetate. Compound 3 was prepared by washing the extracted organic solvent with salt water, drying it with Na 2 SO 4 and purifying it by column chromatography. (Yield: 47%)
1H NMR (400 MHz, CD3OD) δ 8.59 (d, 1H), 7.90 (d, 1H), 7.64 (d, 1H), 7.33 (dd, 1H), 7.26 (d, 1H), 6.21-6.13 (m, 1H), 5.59 (d, 1H), 5.15-5.05 (m, 2H), 3.68-3.60 (m, 1H), 3.08-3.04 (m, 1H), 2.97-2.93 (m, 2H), 2.88-2.80 (m, 1H), 2.38-2.30 (m, 1H), 2.26-2.22 (m, 1H), 1.85 (s, 1H), 1.69-1.53 (m, 2H), 1.12-1.04 (m, 1H) ppm 1H NMR (400 MHz, CD 3 OD) δ 8.59 (d, 1H), 7.90 (d, 1H), 7.64 (d, 1H), 7.33 (dd, 1H), 7.26 (d, 1H), 6.21-6.13 (m, 1H), 5.59 (d, 1H), 5.15-5.05 (m, 2H), 3.68-3.60 (m, 1H), 3.08-3.04 (m, 1H), 2.97-2.93 (m, 2H), 2.88 -2.80 (m, 1H), 2.38-2.30 (m, 1H), 2.26-2.22 (m, 1H), 1.85 (s, 1H), 1.69-1.53 (m, 2H), 1.12-1.04 (m, 1H) ppm
제조예 4: 화합물 4의 제조Preparation Example 4: Preparation of Compound 4
Quinidine(1 equiv) 및 PPh3(triphenylphosphine)(1.3 equiv)을 THF에 용해시켜 0 ℃에서 교반하였다. DIAD(diisopropyl azodicarboxylate)(1.1 equiv)을 넣고 0도에서 15분간 교반하였다. p-Nitrobenzoic acid(1.1 equiv)을 THF에 녹여 dropwise 하였다. 용액의 온도를 상온으로 올려 overnight동안 교반하였다. 용매를 모두 증발시키고 혼합물을 diethylether에 녹여 NaHCO3 포화 수용액으로 세척하였다. K2CO3(2 equiv)을 최소한의 물에 녹여 유기 용매에 넣었다. 메탄올을 소량 넣어 유기용매와 물이 잘 섞일 수 있도록 해준 뒤 1시간 30분동안 상온에서 교반하였다. 반응이 종료되면 유기용매를 증발시킨 뒤 ethyl acetate 로 추출하였다. 유기 용매를 소금물로 씻어주고 column chromatograph를 통해 중간 생성물(epi-quinidine) 4-a를 제조하였다. (수율: 15%)Quinidine (1 equiv) and PPh 3 (triphenylphosphine) (1.3 equiv) were dissolved in THF to obtain 0 It was stirred at ℃. DIAD (diisopropyl azodicarboxylate) (1.1 equiv) was added and stirred at 0 degrees for 15 minutes. p-Nitrobenzoic acid (1.1 equiv) was dissolved in THF and applied dropwise. The temperature of the solution was raised to room temperature and stirred overnight. All solvents were evaporated, the mixture was dissolved in diethylether and washed with saturated aqueous NaHCO 3 solution. K 2 CO 3 (2 equiv) was dissolved in minimal water and added to the organic solvent. A small amount of methanol was added to allow the organic solvent and water to mix well, and then stirred at room temperature for 1 hour and 30 minutes. When the reaction was completed, the organic solvent was evaporated and extracted with ethyl acetate. The organic solvent was washed with salt water, and the intermediate product (epi-quinidine) 4-a was prepared through column chromatography. (yield: 15%)
중간 생성물 4-a(1 equiv)과 sodium ethanethiolate(4 equiv)을 DMF에 녹인 후 110 ℃에서 overnight 동안 반응시켰다. 반응이 종료된 후, NH4Cl 수용액으로 pH 7로 맞춘 뒤 ethyl acetate로 추출하였다. 추출한 유기용매를 소금물로 씻고 Na2SO4로 말린 후 column chromatograph로 정제하여 화합물 4를 제조하였다. (수율: 40 %)Intermediate product 4-a (1 equiv) and sodium ethanethiolate (4 equiv) were dissolved in DMF and reacted at 110°C overnight. After the reaction was completed, the pH was adjusted to 7 with NH 4 Cl aqueous solution and extracted with ethyl acetate. Compound 4 was prepared by washing the extracted organic solvent with salt water, drying it with Na 2 SO 4 and purifying it by column chromatography. (Yield: 40%)
1H NMR (400 MHz, CDCl3) δ 8.65 (d, 1H), 8.59 (d, 1H), 7.76 (s, 1H), 7.46-7.28 (m, 2H), 5.86-5.78 (m, 1H), 5.08-4.98 (m, 2H), 4.90 (d, 1H), 3.18-3.08 (m, 1H), 2.96-2.76 (m, 3H), 2.32-2.24 (m, 1H), 1.67 (s, 1H), 1.57-1.45 (m, 2H), 1.36-1.18 (m, 2H), 1.05-0.97 (m, 1H) ppm 1 H NMR (400 MHz, CDCl 3 ) δ 8.65 (d, 1H), 8.59 (d, 1H), 7.76 (s, 1H), 7.46-7.28 (m, 2H), 5.86-5.78 (m, 1H), 5.08-4.98 (m, 2H), 4.90 (d, 1H), 3.18-3.08 (m, 1H), 2.96-2.76 (m, 3H), 2.32-2.24 (m, 1H), 1.67 (s, 1H), 1.57-1.45 (m, 2H), 1.36-1.18 (m, 2H), 1.05-0.97 (m, 1H) ppm
제조예 5: 화합물 5의 제조Preparation Example 5: Preparation of Compound 5
Cinchonidine(1 equiv)을 THF에 용해시킨 뒤 0 ℃에서 교반하였다. TEA(2.3 equiv)와 methanesulfonyl chloride(1.9 equiv)을 넣고 상온에서 4시간 동안 교반하였다. TLC로 cinchonidine 이 모두 소비되었는지 확인하고 NaHCO3 수용액을 넣고 유기 용매는 증발시켰다. 물층을 DCM으로 추출하고 용매를 증발시켰다. 남은 잔여물은 물에 녹인 뒤 tartaric acid(0.99 equiv) 넣고 overnight동안 reflux 하였다. 반응이 종료된 후, 고체 NaHCO3를 기체 방출이 없을 때까지 천천히 넣고 DCM으로 추출하였다. 유기 용매를 MgSO4로 말린 뒤 short column chromatograph로 정제하여 화합물 5를 제조하였다. (수율: 40%)Cinchonidine (1 equiv) was dissolved in THF and then It was stirred at ℃. TEA (2.3 equiv) and methanesulfonyl chloride (1.9 equiv) were added and stirred at room temperature for 4 hours. TLC confirmed whether all cinchonidine was consumed, NaHCO 3 aqueous solution was added, and the organic solvent was evaporated. The water layer was extracted with DCM and the solvent was evaporated. The remaining residue was dissolved in water, tartaric acid (0.99 equiv) was added, and refluxed overnight. After the reaction was completed, solid NaHCO 3 was slowly added until no gas was evolved and extracted with DCM. Compound 5 was prepared by drying the organic solvent with MgSO 4 and purifying it using a short column chromatograph. (Yield: 40%)
1H NMR (400 MHz, CDCl3) δ 8.92 (d, 1H), 8.36 (d, 1H), 8.15 (d, 1H), 7.73 (t, 1H), 7.58 (t, 1H), 7.52 (d, 1H), 5.80-5.70 (m, 1H), 5.18 (d, 1H), 5.04-4.94 (m, 2H), 3.33-3.21 (m, 2H), 3.12-3.04 (m, 1H), 2.75-2.81 (m, 2H), 2.40-2.30 (m, 1H), 1.70-1.62 (m, 3H), 1.47-1.41 (m, 1H), 1.04-0.96 (m, 1H) ppm 1 H NMR (400 MHz, CDCl 3 ) δ 8.92 (d, 1H), 8.36 (d, 1H), 8.15 (d, 1H), 7.73 (t, 1H), 7.58 (t, 1H), 7.52 (d, 1H), 5.80-5.70 (m, 1H), 5.18 (d, 1H), 5.04-4.94 (m, 2H), 3.33-3.21 (m, 2H), 3.12-3.04 (m, 1H), 2.75-2.81 ( m, 2H), 2.40-2.30 (m, 1H), 1.70-1.62 (m, 3H), 1.47-1.41 (m, 1H), 1.04-0.96 (m, 1H) ppm
제조예 6: 화합물 6의 제조Preparation Example 6: Preparation of Compound 6
Cinchonine(1 equiv)을 THF에 용해시킨 뒤 0oC에서 교반한다. TEA(2.3 equiv)와 methanesulfonyl chloride(1.9 equiv)을 넣고 상온에서 overnight 동안 교반하였다. TLC로 cinchonine 이 모두 소비되었는지 확인하고 NaHCO3 수용액을 넣고 유기 용매는 증발시켰다. 물층을 DCM으로 추출하고 용매를 증발시켰다. 남은 잔여물은 물에 녹인 뒤 tartaric acid(0.99 equiv) 넣고 1 시간 동안 reflux 하였다. 반응이 종료된 후, 고체 NaHCO3를 기체방출이 없을 때까지 천천히 넣고 DCM으로 추출하였다. 유기 용매를 MgSO4로 말린 뒤 short column chromatograph로 정제하여 화합물 6을 제조하였다. (수율: 53%)Cinchonine (1 equiv) was dissolved in THF and stirred at 0 o C. TEA (2.3 equiv) and methanesulfonyl chloride (1.9 equiv) were added and stirred at room temperature overnight. TLC confirmed whether all cinchonine was consumed, NaHCO 3 aqueous solution was added, and the organic solvent was evaporated. The water layer was extracted with DCM and the solvent was evaporated. The remaining residue was dissolved in water, then tartaric acid (0.99 equiv) was added and refluxed for 1 hour. After the reaction was completed, solid NaHCO 3 was slowly added until no gas was evolved and extracted with DCM. Compound 6 was prepared by drying the organic solvent with MgSO 4 and purifying it using a short column chromatograph. (yield: 53%)
1H NMR (600 MHz, CDCl3) δ 8.91 (d, 1H), 8.34 (d, 1H), 8.14 (d, 1H), 7.74-7.71 (m, 1H), 7.59-7.56 (m, 1H), 7.53 (d, 1H), 5.95-5.89 (m, 1H), 5.17-5.11 (m, 3H), 3.05-2.93 (m, 5H), 2.36-2.32 (m, 1H), 1.71-1.70 (m, 1H), 1.63-1.52 (m, 2H), 1.36-1.31 (m, 1H), 1.03-0.99 (m, 1H) ppm 1 H NMR (600 MHz, CDCl 3 ) δ 8.91 (d, 1H), 8.34 (d, 1H), 8.14 (d, 1H), 7.74-7.71 (m, 1H), 7.59-7.56 (m, 1H), 7.53 (d, 1H), 5.95-5.89 (m, 1H), 5.17-5.11 (m, 3H), 3.05-2.93 (m, 5H), 2.36-2.32 (m, 1H), 1.71-1.70 (m, 1H) ), 1.63-1.52 (m, 2H), 1.36-1.31 (m, 1H), 1.03-0.99 (m, 1H) ppm
제조예 7: 화합물 7의 제조Preparation Example 7: Preparation of Compound 7
제조예 1에서 제조한 화합물 1(1 equiv)를 DMF에 녹였다. TIPSCI(triisopropylsilyl chloride)와 imidazole을 용액에 넣고 질소 환경으로 만들었다. 상온에서 overnight동안 교반하였다. 반응이 끝나면 용액을 ethyl acetate로 묽혀 NaHCO3 수용액으로 세척하였다. 유기 용매를 Na2SO4로 말리고 column chromatograph로 정제하여 중간 생성물 7-a를 제조하였다. (수율: 91%)Compound 1 (1 equiv) prepared in Preparation Example 1 was dissolved in DMF. TIPSCI (triisopropylsilyl chloride) and imidazole were added to the solution and a nitrogen environment was created. It was stirred overnight at room temperature. After the reaction was completed, the solution was diluted with ethyl acetate and washed with NaHCO 3 aqueous solution. The organic solvent was dried with Na 2 SO 4 and purified by column chromatography to prepare intermediate product 7-a. (yield: 91%)
얻어진 중간 생성물 7-a(1.1 equiv)를 DCM에 녹여 0 ℃로 cool down 시켰다. TEA(2 equiv)와 benzoic chloride(1.1 equiv)를 넣고 상온에서 overnight동안 교반하였다. TLC로 반응물이 모두 소비된 것이 확인되면 반응용액을 NaHCO3 수용액으로 씻어준 뒤 용매를 증발시켰다. 남겨진 잔여물을 MeCN에 녹이고 0 ℃로 온도는 낮추었다. HF in pyridine(5 equiv)을 넣고 0 ℃에서 30분 교반하였다. 반응이 종료되면 남아있는 HF를 NaHCO3 수용액으로 quenching하였다. 반응 혼합물에서 MeCN을 증발시킨 뒤 ethyl acetate로 추출하였다. 추출한 유기 용매를 Na2SO4로 말리고 column chromatograph로 정제하여 화합물 7을 제조하였다. (수율: 85%)Dissolve the obtained intermediate product 7-a (1.1 equiv) in DCM and obtain 0 It was cooled down to ℃. TEA (2 equiv) and benzoic chloride (1.1 equiv) were added and stirred overnight at room temperature. When it was confirmed by TLC that all the reactants were consumed, the reaction solution was washed with NaHCO 3 aqueous solution and the solvent was evaporated. The remaining residue was dissolved in MeCN and the temperature was lowered to 0°C. HF in pyridine (5 equiv) was added and stirred at 0°C for 30 minutes. When the reaction was completed, the remaining HF was quenched with NaHCO 3 aqueous solution. MeCN was evaporated from the reaction mixture and extracted with ethyl acetate. Compound 7 was prepared by drying the extracted organic solvent with Na 2 SO 4 and purifying it by column chromatography. (yield: 85%)
1H NMR (400 MHz, CDCl3) δ 8.67 (d, 1H), 8.13 (d, 2H), 7.99 (d, 1H), 7.82 (d, 1H), 7.62-7.58 (m, 1H), 7.49 (t, 2H), 7.37 (d, 1H), 7.28 (dd, 1H), 6.87 (d, 1H), 5.81-5.73 (m, 1H), 5.05-4.97 (m, 2H), 3.49-3.47 (m, 1H), 3.42-3.36 (m, 1H), 3.28-3.17 (m, 1H), 2.85-2.65 (m, 2 H), 1.94-1.86 (m, 4H), 1.66-1.62 (m, 2H) ppm 1H NMR (400 MHz, CDCl 3 ) δ 8.67 (d, 1H), 8.13 (d, 2H), 7.99 (d, 1H), 7.82 (d, 1H), 7.62-7.58 (m, 1H), 7.49 ( t, 2H), 7.37 (d, 1H), 7.28 (dd, 1H), 6.87 (d, 1H), 5.81-5.73 (m, 1H), 5.05-4.97 (m, 2H), 3.49-3.47 (m, 1H), 3.42-3.36 (m, 1H), 3.28-3.17 (m, 1H), 2.85-2.65 (m, 2H), 1.94-1.86 (m, 4H), 1.66-1.62 (m, 2H) ppm
제조예 8: 화합물 8의 제조Preparation Example 8: Preparation of Compound 8
30w% mineral oil 현탁액 KH(3 equiv)을 THF에 녹여 0 ℃로 온도를 낮추어 교반하였다. Quininie(1 equiv)을 THF에 녹여 천천히 넣었다. 0 ℃에서 30분 동안 교반하고 온도를 50 ℃로 올려 30분간 더 교반하였다. 다시 0 ℃로 용액의 온도를 낮추고 methyl iodide(1.05 equiv)을 dropwise 하였다. 반응용액의 온도를 상온으로 올리고 overnight 동안 교반하였다. 반응이 종료되면 반응용액의 온도를 0℃로 낮추어 남은 KH를 물로 quenching 하였다. 일부 유기 용매를 증발시키고 ethyl acetate로 추출하였다. 유기 용매를 소금물로 씻은 뒤 Na2SO4로 말렸다. 얻어진 반응 혼합물을 column chromatograph로 정제하여 중간 생성물 8-a를 제조하였다. (수율: 69%) Dissolve 30w% mineral oil suspension KH (3 equiv) in THF and The temperature was lowered to ℃ and stirred. Quininie (1 equiv) was dissolved in THF and slowly added. 0 Stir for 30 minutes at ℃ and lower the temperature to 50℃. The temperature was raised to ℃ and stirred for an additional 30 minutes. 0 again The temperature of the solution was lowered to ℃ and methyl iodide (1.05 equiv) was added dropwise. The temperature of the reaction solution was raised to room temperature and stirred overnight. When the reaction was completed, the temperature of the reaction solution was lowered to 0°C and the remaining KH was quenched with water. Some organic solvents were evaporated and extracted with ethyl acetate. The organic solvent was washed with salt water and dried with Na 2 SO 4 . The obtained reaction mixture was purified by column chromatography to prepare intermediate product 8-a. (yield: 69%)
중간 생성물 8-a(1 equiv)와 sodium ethanethiolate(4.4 equiv)을 DMF에 녹여 110 ℃에서 4일동안 교반하였다. 반응이 종료되면 NH4Cl 포화수용액을 넣고 ethyl acetate로 추출하였다. 유기 용매를 소금물고 씻고 Na2SO4로 말려 column chromatograph로 화합물 8을 제조하였다. (수율: 30%)Intermediate product 8-a (1 equiv) and sodium ethanethiolate (4.4 equiv) were dissolved in DMF and stirred at 110°C for 4 days. When the reaction was completed, saturated NH 4 Cl aqueous solution was added and extracted with ethyl acetate. The organic solvent was washed with salt water, dried with Na 2 SO 4 , and compound 8 was prepared by column chromatography. (yield: 30%)
1H NMR (400 MHz, CDCl3) δ 8.75 (d, 1H), 8.06-8.02 (m, 2H), 7.41-7.37 (m, 2H), 5.94 (s, 1H), 5.67-5.59 (m, 1H), 5.18-5.06 (m, 1H), 4.12-4.02 (m, 1H), 3.65-3.57 (m, 2H), 3.55-3.47 (m, 1H), 3.38-3.28 (m, 1H), 2.76-2.72 (m, 1H), 2.24-2.12 (m, 3H), 1.98-1.90 (m, 1H), 1.53-1.47 (m, 1H) ppm 1H NMR (400 MHz, CDCl 3 ) δ 8.75 (d, 1H), 8.06-8.02 (m, 2H), 7.41-7.37 (m, 2H), 5.94 (s, 1H), 5.67-5.59 (m, 1H) ), 5.18-5.06 (m, 1H), 4.12-4.02 (m, 1H), 3.65-3.57 (m, 2H), 3.55-3.47 (m, 1H), 3.38-3.28 (m, 1H), 2.76-2.72 (m, 1H), 2.24-2.12 (m, 3H), 1.98-1.90 (m, 1H), 1.53-1.47 (m, 1H) ppm
제조예 9: 화합물 9의 제조Preparation Example 9: Preparation of Compound 9
제조예 1에서 제조한 화합물 1(1 equiv)을 메탄올에 녹인 후 Pd/C(0.1 equiv)을 넣었다. 수소 기체(3 bar)를 채워준 뒤 상온에서 3시간 동안 교반하였다. 반응이 종료되면 celite filter로 고체를 거른 뒤 column chromatograph로 정제하여 화합물 9을 제조하였다. (수율: 31%)Compound 1 (1 equiv) prepared in Preparation Example 1 was dissolved in methanol, and then Pd/C (0.1 equiv) was added. After filling with hydrogen gas (3 bar), the mixture was stirred at room temperature for 3 hours. When the reaction was completed, the solid was filtered through a celite filter and purified using a column chromatograph to prepare compound 9. (yield: 31%)
1H NMR (400 MHz, CD3OD) δ 8.59 (d, 1H), 7.90 (d, 1H), 7.63 (d, 1H), 7.33 (dd, 1H), 7.26 (d, 1H), 5.53 (d, 1H), 3.68-3.64 (m, 1H), 3.28-3.10 (m, 2H), 2.78-2.62 (m, 1H), 2.46-2.42 (m, 1H), 1.92-1.80 (m, 3H), 1.60-1.52 (m, 2H), 1.45-1.35 (m, 1H), 1.32-1.22 (m, 2H), 0.85-0.67 (t, 3H) ppm 1H NMR (400 MHz, CD 3 OD) δ 8.59 (d, 1H), 7.90 (d, 1H), 7.63 (d, 1H), 7.33 (dd, 1H), 7.26 (d, 1H), 5.53 (d) , 1H), 3.68-3.64 (m, 1H), 3.28-3.10 (m, 2H), 2.78-2.62 (m, 1H), 2.46-2.42 (m, 1H), 1.92-1.80 (m, 3H), 1.60 -1.52 (m, 2H), 1.45-1.35 (m, 1H), 1.32-1.22 (m, 2H), 0.85-0.67 (t, 3H) ppm
제조예 10: 화합물 10의 제조Preparation Example 10: Preparation of Compound 10
제조예 6에서 제조한 화합물 6(1 equiv)을 THF에 용해시킨 뒤 0 ℃에서 교반하였다. TEA(4 equiv)와 methanesulfonyl chloride(2 equiv)을 넣고 상온에서 3시간 동안 교반하였다. 반응이 종료되면 유기 용매는 증발시키고 NaHCO3수용액과 DCM으로 추출하고 유기층을 MgSO4로 말린 뒤 column chromatograph로 정제하여 중간 생성물 10-a를 제조하였다. (수율: 79%). Compound 6 (1 equiv) prepared in Preparation Example 6 was dissolved in THF and stirred at 0°C. TEA (4 equiv) and methanesulfonyl chloride (2 equiv) were added and stirred at room temperature for 3 hours. When the reaction was completed, the organic solvent was evaporated, extracted with NaHCO 3 aqueous solution and DCM, and the organic layer was dried with MgSO 4 and purified by column chromatography to prepare intermediate product 10-a. (Yield: 79%).
중간 생성물 10-a(1 equiv)를 DMF에 용해시킨 뒤 질소 환경으로 만들어 주었다. Sodium azide(3.7 equiv)을 넣고 80 ℃에서 3시간동안 교반하였다. 온도를 상온으로 낮추어 overnight동안 교반하였다. DMF를 증발시킨 뒤 NaOH수용액과 DCM으로 추출하였다. 추출한 유기층을 증발시키고 THF에 용해시켰다. PPh3(2 equiv)을 넣고 50 ℃에서 3시간동안 교반한 뒤 물을 넣고 overnight동안 교반하였다. 반응이 종료되면 용매를 증발시키고 HCl수용액에 녹여 DCM으로 씻어준다. 물층에 NaOH수용액을 넣어 pH12로 맞춘 뒤 DCM으로 추출하였다. 추출한 유기층은 MgSO4로 말린 뒤 column chromatograph로 정제하여 중간 생성물 10-b를 제조하였다. (수율: 33%) Intermediate product 10-a (1 equiv) was dissolved in DMF and then created in a nitrogen environment. Add sodium azide (3.7 equiv) and add 80% It was stirred at ℃ for 3 hours. The temperature was lowered to room temperature and stirred overnight. After evaporating DMF, it was extracted with NaOH aqueous solution and DCM. The extracted organic layer was evaporated and dissolved in THF. Add PPh 3 (2 equiv) and add 50 After stirring at ℃ for 3 hours, water was added and stirred overnight. When the reaction is completed, the solvent is evaporated, dissolved in HCl aqueous solution, and washed with DCM. NaOH aqueous solution was added to the water layer to adjust pH to 12 and then extracted with DCM. The extracted organic layer was dried with MgSO 4 and purified by column chromatography to prepare intermediate product 10-b. (yield: 33%)
중간 생성물 10-b(1 equiv)를 THF에 용해시킨 뒤 질소 환경으로 만들어 주었다. Phenyl isothiocyanate(1 equiv)을 넣고 상온에서 overnight동안 교반하였다. 반응이 종료되면 column chromatograph로 정제하여 화합물 10을 제조하였다. (수율: 39%)Intermediate product 10-b (1 equiv) was dissolved in THF and then created in a nitrogen environment. Phenyl isothiocyanate (1 equiv) was added and stirred overnight at room temperature. When the reaction was completed, compound 10 was prepared by purification using column chromatography. (Yield: 39%)
1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.46 (d, 1H), 8.12 (d, 1H), 7.67 (dt, 2H), 7.42-7.25 (m, 4H), 7.09 (s, 1H), 6.68 (s, 1H), 5.92-5.74 (m, 1H), 4.96-4.80 (m, 2H), 3.43-3.31 (m, 1H), 2.88-2.65 (m, 4H), 2.21-2.01 (m, 2H), 1.78-1.54 (m, 4H) ppm 1H NMR (400 MHz, CDCl 3 ) δ 8.87 (s, 1H), 8.46 (d, 1H), 8.12 (d, 1H), 7.67 (dt, 2H), 7.42-7.25 (m, 4H), 7.09 ( s, 1H), 6.68 (s, 1H), 5.92-5.74 (m, 1H), 4.96-4.80 (m, 2H), 3.43-3.31 (m, 1H), 2.88-2.65 (m, 4H), 2.21- 2.01 (m, 2H), 1.78-1.54 (m, 4H) ppm
제조예 11: 화합물 11의 제조Preparation Example 11: Preparation of Compound 11
Quinine(1 equiv)을 THF에 용해시킨 뒤 0℃에서 교반하였다. TEA(2.3 equiv)와 methanesulfonyl chloride(1.9 equiv)을 넣고 상온에서 overnight동안 교반하였다. TLC로 quinine 이 모두 소비되었는지 확인하고 NaHCO3 수용액을 넣고 유기 용매는 증발시켰다. 물층을 DCM으로 추출하고 용매를 증발시켰다. 남은 잔여물은 물에 녹인 뒤 tartaric acid(0.99 equiv) 넣고 1시간 동안 reflux 하였다. 반응이 종료 후 고체 NaHCO3를 기체방출이 없을 때까지 천천히 넣고 DCM으로 추출하였다. 유기 용매를 MgSO4로 말린 뒤 short column chromatograph로 정제하여 중간 생성물 11-a를 제조하였다. (수율: 70 %) Quinine (1 equiv) was dissolved in THF and stirred at 0°C. TEA (2.3 equiv) and methanesulfonyl chloride (1.9 equiv) were added and stirred overnight at room temperature. TLC confirmed whether all quinine was consumed, NaHCO 3 aqueous solution was added, and the organic solvent was evaporated. The water layer was extracted with DCM and the solvent was evaporated. The remaining residue was dissolved in water, then tartaric acid (0.99 equiv) was added and refluxed for 1 hour. After the reaction was completed, solid NaHCO 3 was slowly added until no gas was evolved and extracted with DCM. The organic solvent was dried with MgSO 4 and purified using a short column chromatograph to prepare intermediate product 11-a. (Yield: 70%)
중간 생성물 11-a(1 equiv)를 THF에 용해시킨 뒤 0 ℃에서 교반하였다. TEA(4 equiv)와 methanesulfonyl chloride(2 equiv)을 넣고 상온에서 overnight동안 교반하였다. 반응이 종료되면 유기 용매는 증발시키고 NaHCO3수용액과 DCM으로 추출하고 유기층을 MgSO4로 말린 뒤 column chromatograph로 정제하여 중간 생성물 11-b를 제조하였다. (수율: 80%)Intermediate product 11-a (1 equiv) was dissolved in THF and stirred at 0°C. TEA (4 equiv) and methanesulfonyl chloride (2 equiv) were added and stirred overnight at room temperature. When the reaction was completed, the organic solvent was evaporated, extracted with NaHCO 3 aqueous solution and DCM, and the organic layer was dried with MgSO 4 and purified by column chromatography to prepare intermediate product 11-b. (yield: 80%)
중간 생성물 11-b(1 equiv)를 DMF에 용해시킨 뒤 질소환경으로 만들어준다. Sodium azide(3.7 equiv)을 넣고 80℃에서 3시간동안 교반하였다. 온도를 상온으로 낮추어 overnight동안 교반하였다. DMF를 증발시킨 뒤 NaOH수용액과 DCM으로 추출하였다. 추출한 유기층을 증발시키고 THF에 용해시켰다. PPh3(2 equiv)을 넣고 50 ℃에서 3시간동안 교반한 뒤 물을 넣고 overnight동안 교반하였다. 반응이 종료되면 용매를 증발시키고 HCl수용액에 녹여 DCM으로 세척하였다. 물층에 NaOH수용액을 넣어 pH12로 맞춘 뒤 DCM으로 추출하였다. 추출한 유기층은 MgSO4로 말린 뒤 column chromatograph로 정제하여 화합물 11을 제조하였다. (수율: 41%)Intermediate product 11-b (1 equiv) is dissolved in DMF and then created in a nitrogen environment. Sodium azide (3.7 equiv) was added and stirred at 80°C for 3 hours. The temperature was lowered to room temperature and stirred overnight. After evaporating DMF, it was extracted with NaOH aqueous solution and DCM. The extracted organic layer was evaporated and dissolved in THF. PPh 3 (2 equiv) was added and stirred at 50°C for 3 hours, then water was added and stirred overnight. When the reaction was completed, the solvent was evaporated, dissolved in HCl aqueous solution, and washed with DCM. NaOH aqueous solution was added to the water layer to adjust pH to 12 and then extracted with DCM. The extracted organic layer was dried with MgSO 4 and purified by column chromatography to prepare compound 11. (Yield: 41%)
1H NMR (400 MHz, CDCl3) δ 8.74 (d, 1H), 8.03 (d, 1H), 7.58-7.48 (m, 2H), 7.38 (dd, 1H), 5.94-5.85 (m, 1H), 5.11-5.05 (m, 2H), 4.69-4.67 (m, 1H), 3.97 (s, 1H), 3.08-2.92 (m, 5H), 2.31-2.25 (m, 1H), 1.98 (bs, 2H), 1.61-1.53 (m, 3H), 1.18-1.12 (m, 1H), 0.98-0.90 (m, 1H) ppm 1 H NMR (400 MHz, CDCl 3 ) δ 8.74 (d, 1H), 8.03 (d, 1H), 7.58-7.48 (m, 2H), 7.38 (dd, 1H), 5.94-5.85 (m, 1H), 5.11-5.05 (m, 2H), 4.69-4.67 (m, 1H), 3.97 (s, 1H), 3.08-2.92 (m, 5H), 2.31-2.25 (m, 1H), 1.98 (bs, 2H), 1.61-1.53 (m, 3H), 1.18-1.12 (m, 1H), 0.98-0.90 (m, 1H) ppm
제조예 12: 화합물 12의 제조Preparation Example 12: Preparation of Compound 12
제조예 11에서 제조한 화합물 11(1 equiv)을 DMF에 용해시키고 sodium ethanthiolate(4 equiv)을 넣었다. 질소환경으로 만들어 준 뒤 110 ℃에서 overnight동안 교반하였다. 반응이 종료된 후 NH4Cl 수용액으로 pH7로 맞춘 뒤 ethyl acetate로 추출하였다. 추출한 유기 용매를 소금물로 씻고 Na2SO4로 말린 후 실리카 컬럼 크로마토 그래피로 정제하여 화합물 12를 제조하였다. (수율: 35 %)Compound 11 (1 equiv) prepared in Preparation Example 11 was dissolved in DMF and sodium ethhanthiolate (4 equiv) was added. After creating a nitrogen environment, it was stirred overnight at 110°C. After the reaction was completed, the pH was adjusted to 7 with NH 4 Cl aqueous solution and extracted with ethyl acetate. The extracted organic solvent was washed with salt water, dried with Na 2 SO 4 and purified by silica column chromatography to prepare Compound 12. (Yield: 35%)
1H NMR (600 MHz, CD3OD) δ 8.69 (d, 1H), 7.97 (d, 1H), 7.61 (d, 1H), 7.55 (d, 1H), 7.42 (dd, 1H), 6.02-5.96 (m, 1H), 5.21-5.15 (m, 2H), 3.70-3.66 (m, 1H), 3.53-3.49 (m, 1H), 3.29-3.25 (m, 1H), 3.01-2.99 (m, 1H), 2.89-2.84 (m, 1H), 2.65-2.63 (m, 1H), 2.26-2.21 (m, 1H), 2.10-2.01 (m, 2H), 1.92-1.89 (m, 1H), 1.86-1.81 (m, 1H) ppm 1 H NMR (600 MHz, CD 3 OD) δ 8.69 (d, 1H), 7.97 (d, 1H), 7.61 (d, 1H), 7.55 (d, 1H), 7.42 (dd, 1H), 6.02-5.96 (m, 1H), 5.21-5.15 (m, 2H), 3.70-3.66 (m, 1H), 3.53-3.49 (m, 1H), 3.29-3.25 (m, 1H), 3.01-2.99 (m, 1H) , 2.89-2.84 (m, 1H), 2.65-2.63 (m, 1H), 2.26-2.21 (m, 1H), 2.10-2.01 (m, 2H), 1.92-1.89 (m, 1H), 1.86-1.81 ( m, 1H) ppm
제조예 13: 화합물 13의 제조Preparation Example 13: Preparation of Compound 13
제조예 5에서 제조한 화합물 5(1 equiv)를 THF에 용해시킨 뒤 0 ℃에서 교반하였다. TEA(4 equiv)와 methanesulfonyl chloride(2 equiv)을 넣고 상온에서 4시간동안 교반하였다. 반응이 종료되면 유기 용매는 증발시키고 NaHCO3수용액과 DCM으로 추출하고 유기층을 MgSO4로 말린 뒤 column chromatograph로 정제하여 중간 생성물 13-a를 제조하였다. (수율: 80%)Compound 5 (1 equiv) prepared in Preparation Example 5 was dissolved in THF and stirred at 0°C. TEA (4 equiv) and methanesulfonyl chloride (2 equiv) were added and stirred at room temperature for 4 hours. When the reaction was completed, the organic solvent was evaporated, extracted with NaHCO 3 aqueous solution and DCM, and the organic layer was dried with MgSO 4 and purified by column chromatography to prepare intermediate product 13-a. (yield: 80%)
중간 생성물 13-a(1 equiv)를 DMF에 용해시킨 뒤 질소환경으로 만들어 주었다. Sodium azide(3.7 equiv)을 넣고 80 ℃에서 3시간동안 교반하였다. 온도를 상온으로 낮추어 overnight동안 교반하였다. DMF를 증발시킨 뒤 NaOH수용액과 DCM으로 추출하였다. 추출한 유기층을 증발시키고 THF에 용해시켰다. PPh3(2 equiv)을 넣고 50 ℃에서 3시간동안 교반한 뒤 물을 넣고 overnight동안 교반하였다. 반응이 종료되면 용매를 증발시키고 HCl수용액에 녹여 DCM으로 세척하였다. 물층에 NaOH수용액을 넣어 pH12로 맞춘 뒤 DCM으로 추출하였다. 추출한 유기층은 MgSO4로 말린 뒤 column chromatograph로 정제하여 화합물 13을 제조하였다. (수율: 56%)Intermediate product 13-a (1 equiv) was dissolved in DMF and then created in a nitrogen environment. Sodium azide (3.7 equiv) was added and stirred at 80°C for 3 hours. The temperature was lowered to room temperature and stirred overnight. After evaporating DMF, it was extracted with NaOH aqueous solution and DCM. The extracted organic layer was evaporated and dissolved in THF. PPh 3 (2 equiv) was added and stirred at 50°C for 3 hours, then water was added and stirred overnight. When the reaction was completed, the solvent was evaporated, dissolved in HCl aqueous solution, and washed with DCM. NaOH aqueous solution was added to the water layer to adjust pH to 12 and then extracted with DCM. The extracted organic layer was dried with MgSO 4 and purified by column chromatography to prepare compound 13. (Yield: 56%)
1H NMR (400 MHz, CDCl3) δ 8.92 (d, 2H), 8.22 (d, 2H), 8.14 (d, 2H), 7.70 (d, 2H), 7.58 (d, 1H), 7.41 (d, 1H), 6.01-5.93 (m, 1H), 5.12-5.04 (m, 2H), 4.73-4.69 (m, 1H), 3.28-3.20 (m, 1H), 3.07-2.91 (m, 2H), 2.70-2.64 (m, 1H), 2.58-2.48 (m, 1H), 2.32-2.16 (m, 2H), 1.92-1.88 (m, 1H), 1.71-1.45 (m, 3H) ppm 1 H NMR (400 MHz, CDCl 3 ) δ 8.92 (d, 2H), 8.22 (d, 2H), 8.14 (d, 2H), 7.70 (d, 2H), 7.58 (d, 1H), 7.41 (d, 1H), 6.01-5.93 (m, 1H), 5.12-5.04 (m, 2H), 4.73-4.69 (m, 1H), 3.28-3.20 (m, 1H), 3.07-2.91 (m, 2H), 2.70- 2.64 (m, 1H), 2.58-2.48 (m, 1H), 2.32-2.16 (m, 2H), 1.92-1.88 (m, 1H), 1.71-1.45 (m, 3H) ppm
제조예 14: 화합물 14의 제조Preparation Example 14: Preparation of Compound 14
제조예 11에서 제조한 화합물 11(1 equiv)을 DCM에 용해시키고 질소 환경으로 만들어 0 ℃에서 교반하였다. Benzoyl chloride(2 equiv)을 dropwise 하였다. TEA(3 equiv)을 넣고 상온에서 overnight 동안 교반하였다. 반응이 종료되면 NaHCO3 수용액과 소금물고 씻어주고 MgSO4로 건조하였다. 실리카 컬럼크로마토그래피를 통해 정제하여 화합물 14를 제조하였다. (수율: 33%)Compound 11 (1 equiv) prepared in Preparation Example 11 was dissolved in DCM, created in a nitrogen environment, and stirred at 0°C. Benzoyl chloride (2 equiv) was added dropwise. TEA (3 equiv) was added and stirred overnight at room temperature. When the reaction was completed, it was washed with NaHCO 3 aqueous solution and salt water and dried with MgSO 4 . Compound 14 was prepared by purification through silica column chromatography. (yield: 33%)
1H NMR (600 MHz, CDCl3) δ 8.78 (d, 1H), 7.98 (d, 1H), 7.68 (d, 3H), 7.49-7.43 (m, 2H), 7.39 (t, 2H), 7.33 (dd, 1H), 6.23-6.18 (m, 2H), 6.01-5.95 (m, 1H), 5.14-5.09 (m, 2H), 3.97 (s, 3H), 3.55-3.51 (m, 1H), 3.20-3.16 (m, 1H), 3.00-2.94 (m, 1H), 2.85-2.82 (m, 1H), 2.63-2.58 (m, 1H), 2.35-2.34 (m, 1H), 2.09-2.04 (m, 1H), 1.91-1.87 (m, 1H), 1.82-1.77 (m, 1H), 1.65-1.62 (m, 1H), 1.56-1.51 (m, 1H) ppm 1H NMR (600 MHz, CDCl 3 ) δ 8.78 (d, 1H), 7.98 (d, 1H), 7.68 (d, 3H), 7.49-7.43 (m, 2H), 7.39 (t, 2H), 7.33 ( dd, 1H), 6.23-6.18 (m, 2H), 6.01-5.95 (m, 1H), 5.14-5.09 (m, 2H), 3.97 (s, 3H), 3.55-3.51 (m, 1H), 3.20- 3.16 (m, 1H), 3.00-2.94 (m, 1H), 2.85-2.82 (m, 1H), 2.63-2.58 (m, 1H), 2.35-2.34 (m, 1H), 2.09-2.04 (m, 1H) ), 1.91-1.87 (m, 1H), 1.82-1.77 (m, 1H), 1.65-1.62 (m, 1H), 1.56-1.51 (m, 1H) ppm
제조예 15: 화합물 15의 제조Preparation Example 15: Preparation of Compound 15
제조예 11에서 제조한 화합물 11(1 equiv)을 DCM에 용해시키고 질소 환경으로 만들어 0 ℃에서 교반하였다. TEA(3 equiv)을 넣고 3,5-bis(trifluoromethyl)-phenyl carboxylic acid chloride(1.2 equiv)을 dropwise 하였다. 상온에서 overnight 동안 교반하였다. 반응이 종료되면 NaHCO3 수용액 DCM으로 추출하였다. DCM으로 여러 차례 추출한뒤 MgSO4로 말린다. 실리카 컬럼크로마토그래피를 통해 정제하여 화합물 15를 제조하였다. (수율: 81%)Compound 11 (1 equiv) prepared in Preparation Example 11 was dissolved in DCM, created in a nitrogen environment, and stirred at 0°C. TEA (3 equiv) was added, and 3,5-bis(trifluoromethyl)-phenyl carboxylic acid chloride (1.2 equiv) was added dropwise. It was stirred overnight at room temperature. When the reaction was completed, it was extracted with NaHCO 3 aqueous solution DCM. After extraction with DCM several times, it is dried with MgSO 4 . Compound 15 was prepared by purification through silica column chromatography. (yield: 81%)
1H NMR (400 MHz, CDCl3) δ 8.65 (d, 1H), 8.16 (s, 1H), 7.95 (s, 1H), 7.90 (d, 1H), 7.65 (d, 1H), 7.38 (d, 1H), 7.32 (dd, 1H), 6.88 (d, 1H), 6.23 (t, 1H), 5.98-5.88 (m, 1H), 5.13-5.05 (m, 2H), 3.97 (s, 3H), 3.57-3.51 (m, 1H), 3.20-3.12 (m, 1H), 2.98-2.92 (m, 1H), 2.82-2.76 (m, 1H), 2.63-2.55 (m, 1H), 2.36-2.30 (m, 1H), 2.12-2.06 (m, 1H), 1.92-1.88 (m, 1H), 1.84-1.74 (m, 1H), 1.60-1.54 (m, 2H) ppm 1 H NMR (400 MHz, CDCl 3 ) δ 8.65 (d, 1H), 8.16 (s, 1H), 7.95 (s, 1H), 7.90 (d, 1H), 7.65 (d, 1H), 7.38 (d, 1H), 7.32 (dd, 1H), 6.88 (d, 1H), 6.23 (t, 1H), 5.98-5.88 (m, 1H), 5.13-5.05 (m, 2H), 3.97 (s, 3H), 3.57 -3.51 (m, 1H), 3.20-3.12 (m, 1H), 2.98-2.92 (m, 1H), 2.82-2.76 (m, 1H), 2.63-2.55 (m, 1H), 2.36-2.30 (m, 1H), 2.12-2.06 (m, 1H), 1.92-1.88 (m, 1H), 1.84-1.74 (m, 1H), 1.60-1.54 (m, 2H) ppm
제조예 16: 화합물 16의 제조Preparation Example 16: Preparation of Compound 16
제조예 11에서 제조한 화합물 11(1 equiv)을 THF에 용해시키고 phenyl isothiocyanate THF용액(1 equiv)을 천천히 넣은 뒤 상온에서 overnight동안 교반하였다. 반응이 끝나면 실리카 컬럼크로마토그래피로 정제하여 화합물 16을 제조하였다. (수율: 89%)Compound 11 (1 equiv) prepared in Preparation Example 11 was dissolved in THF, phenyl isothiocyanate THF solution (1 equiv) was slowly added, and stirred at room temperature overnight. After the reaction was completed, compound 16 was prepared by purification using silica column chromatography. (yield: 89%)
1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.73 (d, 1H), 8.31 (d, 1H), 8.04 (s, 1H), 7.93 (d, 1H), 7.57 (s, 1H), 7.40-7.24 (m, 3H), 7.16 (d, 1H), 6.57 (t, 1H), 6.04-5.96 (m, 1H), 5.14-5.02 (m, 2H), 4.05-4.01 (m, 1H), 3.92 (s, 3H), 3.56-3.48 (m, 1H), 2.96-2.74 (m, 2H), 2.45-2.37 (m, 1H), 2.26-2.18 (m, 1H), 1.96-1.86 (m, 1H), 1.79-1.67 (m, 2H), 1.49-1.41 (m, 1H), 1.22-1.16 (m, 1H) ppm 1H NMR (400 MHz, DMSO-d 6 ) δ 9.54 (s, 1H), 8.73 (d, 1H), 8.31 (d, 1H), 8.04 (s, 1H), 7.93 (d, 1H), 7.57 ( s, 1H), 7.40-7.24 (m, 3H), 7.16 (d, 1H), 6.57 (t, 1H), 6.04-5.96 (m, 1H), 5.14-5.02 (m, 2H), 4.05-4.01 ( m, 1H), 3.92 (s, 3H), 3.56-3.48 (m, 1H), 2.96-2.74 (m, 2H), 2.45-2.37 (m, 1H), 2.26-2.18 (m, 1H), 1.96- 1.86 (m, 1H), 1.79-1.67 (m, 2H), 1.49-1.41 (m, 1H), 1.22-1.16 (m, 1H) ppm
제조예 17: 화합물 17의 제조Preparation Example 17: Preparation of Compound 17
제조예 11에서 제조한 화합물 11(1 equiv)을 THF에 용해시키고 phenyl isocyanate(1 equiv)을 천천히 넣은 뒤 상온에서 overnight동안 교반하였다. 반응이 끝나면 실리카 컬럼크로마토그래피로 정제하여 화합물 17을 제조하였다. (수율: 94%)Compound 11 (1 equiv) prepared in Preparation Example 11 was dissolved in THF, phenyl isocyanate (1 equiv) was slowly added, and stirred at room temperature overnight. After the reaction was completed, compound 17 was prepared by purification using silica column chromatography. (yield: 94%)
1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, 1H), 8.35 (s, 1H), 7.92 (d, 1H), 7.72 (d, 1H), 7.38-7.32 (m, 2H), 7.19 (t, 2H), 6.86 (t, 1H), 6.71 (d, 1H), 6.06-5.96 (m, 1H), 5.60-5.55 (m, 1H), 5.14-5.02 (m, 2H), 3.78 (s, 3H), 2.92-2.80 (m, 2H), 2.64-2.56 (m, 1H), 2.46-2.34 (m, 1H), 2.26-2.20 (m, 1H), 2.05-1.97 (m, 1H), 1.80-1.76 (m, 1H), 1.68-1.60 (m, 1H), 1.50-1.36 (m, 2H) ppm 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.70 (d, 1H), 8.35 (s, 1H), 7.92 (d, 1H), 7.72 (d, 1H), 7.38-7.32 (m, 2H), 7.19 (t, 2H), 6.86 (t, 1H), 6.71 (d, 1H), 6.06-5.96 (m, 1H), 5.60-5.55 (m, 1H), 5.14-5.02 (m, 2H), 3.78 ( s, 3H), 2.92-2.80 (m, 2H), 2.64-2.56 (m, 1H), 2.46-2.34 (m, 1H), 2.26-2.20 (m, 1H), 2.05-1.97 (m, 1H), 1.80-1.76 (m, 1H), 1.68-1.60 (m, 1H), 1.50-1.36 (m, 2H) ppm
제조예 18: 화합물 18의 제조Preparation Example 18: Preparation of Compound 18
제조예 11에서 제조한 화합물 11(1 equiv)을 DCM에 용해시키고 질소환경으로 만들어준다. TEA(1 equiv)을 넣고 methanesulfonyl chloride(1 equiv)을 dropwise 하였다. 상온에서 overnight동안 교반하고 반응이 종료되면 NaHCO3수용액과 DCM으로 추출하였다. 추출한 유기층을 MgSO4로 말린 뒤 실리카 컬럼크로마토그래피로 정제하여 화합물 18을 제조하였다. (수율: 64 %)Compound 11 (1 equiv) prepared in Preparation Example 11 was dissolved in DCM and created in a nitrogen environment. TEA (1 equiv) was added, and methanesulfonyl chloride (1 equiv) was added dropwise. It was stirred overnight at room temperature, and when the reaction was completed, it was extracted with NaHCO 3 aqueous solution and DCM. The extracted organic layer was dried with MgSO 4 and purified by silica column chromatography to prepare compound 18. (Yield: 64%)
1H NMR (600 MHz, CDCl3) δ 8.79 (d, 1H), 8.04 (d, 1H), 7.42-7.39 (m, 2H), 7.34 (d, 1H), 5.93-5.87 (m, 1H), 5.07-5.04 (m, 2H), 3.97 (s, 3H), 3.27 (bs, 1H), 2.99-2.85 (m, 2H), 2.61-2.59 (m, 1H), 2.52-2.46 (m, 4H), 2.27-2.24 (s, 1H), 2.16-2.11 (m, 1H), 1.89 (s, 1H), 1.65-1.44 (m, 5H) ppm 1 H NMR (600 MHz, CDCl 3 ) δ 8.79 (d, 1H), 8.04 (d, 1H), 7.42-7.39 (m, 2H), 7.34 (d, 1H), 5.93-5.87 (m, 1H), 5.07-5.04 (m, 2H), 3.97 (s, 3H), 3.27 (bs, 1H), 2.99-2.85 (m, 2H), 2.61-2.59 (m, 1H), 2.52-2.46 (m, 4H), 2.27-2.24 (s, 1H), 2.16-2.11 (m, 1H), 1.89 (s, 1H), 1.65-1.44 (m, 5H) ppm
제조예 19: 화합물 19의 제조Preparation Example 19: Preparation of Compound 19
제조예 11에서 제조한 화합물 11(1 equiv)을 DCM에 용해시키고 질소환경으로 만들어준다. TEA(1 equiv)을 넣고 tosyl chloride DCM용액(1 equiv)을 dropwise 하였다. 상온에서 overnight동안 교반하고 반응이 종료되면 NaHCO3수용액과 DCM으로 추출하였다. 추출한 유기층을 MgSO4로 말린 뒤 실리카 컬럼크로마토그래피로 정제하여 화합물 19를 제조하였다. (수율: 75%)Compound 11 (1 equiv) prepared in Preparation Example 11 was dissolved in DCM and created in a nitrogen environment. TEA (1 equiv) was added and tosyl chloride DCM solution (1 equiv) was added dropwise. It was stirred overnight at room temperature, and when the reaction was completed, it was extracted with NaHCO 3 aqueous solution and DCM. The extracted organic layer was dried with MgSO 4 and purified by silica column chromatography to prepare compound 19. (yield: 75%)
1H NMR (400 MHz, CDCl3) δ 8.52 (d, 1H), 7.85 (d, 1H), 7.31-7.27 (m, 1H), 7.19-7.15 (m, 2H), 7.11-7.06 (m, 2H), 6.69 (d, 2H), 5.94-5.85 (m, 1H), 5.07-5.01 (m, 3H), 3.94 (s, 3H), 3.22 (bs, 1H), 2.98-2.88 (m, 2H), 2.57-2.46 (m, 2H), 2.28-2.22 (m, 1H), 2.14 (s, 3H),1.89 (s, 1H), 1.69-1.54 (m, 4H), 1.51-1.43 (m, 1H) ppm 1H NMR (400 MHz, CDCl 3 ) δ 8.52 (d, 1H), 7.85 (d, 1H), 7.31-7.27 (m, 1H), 7.19-7.15 (m, 2H), 7.11-7.06 (m, 2H) ), 6.69 (d, 2H), 5.94-5.85 (m, 1H), 5.07-5.01 (m, 3H), 3.94 (s, 3H), 3.22 (bs, 1H), 2.98-2.88 (m, 2H), 2.57-2.46 (m, 2H), 2.28-2.22 (m, 1H), 2.14 (s, 3H), 1.89 (s, 1H), 1.69-1.54 (m, 4H), 1.51-1.43 (m, 1H) ppm
제조예 20: 화합물 20의 제조Preparation Example 20: Preparation of Compound 20
제조예 11에서 제조한 화합물 11(1 equiv)을 DCM에 용해시키고 질소환경으로 만들어준다. TEA(1 equiv)을 넣고 3,5-bis(trifluoromethyl)benzenesulfonylchloride(1 equiv)을 dropwise 하였다. 상온에서 overnight동안 교반하고 반응이 종료되면 물과 DCM으로 추출하였다. 추출한 유기층을 MgSO4로 말린 뒤 실리카 컬럼크로마토그래피로 정제하여 compelx 20을 제조하였다. (수율: 66%)Compound 11 (1 equiv) prepared in Preparation Example 11 was dissolved in DCM and created in a nitrogen environment. TEA (1 equiv) was added, and 3,5-bis(trifluoromethyl)benzenesulfonylchloride (1 equiv) was added dropwise. It was stirred overnight at room temperature, and when the reaction was completed, it was extracted with water and DCM. The extracted organic layer was dried with MgSO 4 and purified by silica column chromatography to prepare compelx 20. (Yield: 66%)
1H NMR (400 MHz, CDCl3) δ 8.51 (d, 1H), 7.85 (d, 1H), 7.71 (s, 2H), 7.59 (s, 1H), 7.33-7.28 (m, 1H), 7.13 (d, 1H), 7.07 (d, 1H), 5.97-5.85 (m, 1H), 5.18 (bs, 1H), 5.11-5.05 (m, 2H), 3.95 (s, 3H), 3.30 (bs, 1H), 3.00-2.82 (m, 2H), 2.62-2.43 (m, 2H), 2.30-2.17 (m, 2H), 1.95 (s, 1H), 1.65-1.44 (m, 3H) ppm 1H NMR (400 MHz, CDCl 3 ) δ 8.51 (d, 1H), 7.85 (d, 1H), 7.71 (s, 2H), 7.59 (s, 1H), 7.33-7.28 (m, 1H), 7.13 ( d, 1H), 7.07 (d, 1H), 5.97-5.85 (m, 1H), 5.18 (bs, 1H), 5.11-5.05 (m, 2H), 3.95 (s, 3H), 3.30 (bs, 1H) , 3.00-2.82 (m, 2H), 2.62-2.43 (m, 2H), 2.30-2.17 (m, 2H), 1.95 (s, 1H), 1.65-1.44 (m, 3H) ppm
제조예 21: 화합물 21의 제조Preparation Example 21: Preparation of Compound 21
제조예 14에서 제조한 화합물 14(1 equiv)를 DCM에 용해시켜 -78 ℃에서 교반시켰다. 1M BBr3 DCM용액(5 equiv)을 dropwise한 뒤 상온에서 overnight동안 교반하였다. 반응이 종료되면 얼음 항온조에서 NaOH수용액으로 quenching하였다. 수용액을 DCM으로 씻어준 뒤 물을 증발시켰다. Crude 생성물을 메탄올에서 재결정하여 화합물 21을 제조하였다. (수율: 45%)Compound 14 (1 equiv) prepared in Preparation Example 14 was dissolved in DCM and stirred at -78°C. 1M BBr 3 DCM solution (5 equiv) was added dropwise and stirred overnight at room temperature. When the reaction was completed, it was quenched with NaOH aqueous solution in an ice thermostat. The aqueous solution was washed with DCM and the water was evaporated. Compound 21 was prepared by recrystallizing the crude product from methanol. (Yield: 45%)
1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.95 (d, 1H), 8.64 (s, 1H), 7.85-7.79 (m, 1H), 7.70-7.60 (m, 2H), 7.52-7.40 (m, 2H), 7.30 (d, 1H), 6.06-5.96 (m, 1H), 5.85-5.78 (m, 1H), 5.10-5.01 (m, 2H), 3.56-3.47 (m, 1H), 2.99-2.91 (m, 1H), 2.87-2.80 (m, 1H), 2.45-2.31 (m, 2H), 2.23-2.17 (m, 1H), 2.12-2.04 (m, 1H), 1.77-1.70 (m, 1H), 1.65-1.56 (m, 1H), 1.48-1.40 (m, 1H), 1.28-1.21 (m, 1H) ppm 1H NMR (400 MHz, DMSO-d 6 ) δ 10.04 (s, 1H), 8.95 (d, 1H), 8.64 (s, 1H), 7.85-7.79 (m, 1H), 7.70-7.60 (m, 2H) ), 7.52-7.40 (m, 2H), 7.30 (d, 1H), 6.06-5.96 (m, 1H), 5.85-5.78 (m, 1H), 5.10-5.01 (m, 2H), 3.56-3.47 (m , 1H), 2.99-2.91 (m, 1H), 2.87-2.80 (m, 1H), 2.45-2.31 (m, 2H), 2.23-2.17 (m, 1H), 2.12-2.04 (m, 1H), 1.77 -1.70 (m, 1H), 1.65-1.56 (m, 1H), 1.48-1.40 (m, 1H), 1.28-1.21 (m, 1H) ppm
제조예 22: 화합물 22의 제조Preparation Example 22: Preparation of Compound 22
제조예 15에서 제조한 화합물 15(1 equiv)를 DCM에 용해시켜 -78 ℃에서 교반시켰다. 1M BBr3 DCM용액(5 equiv)을 dropwise한 뒤 상온에서 overnight동안 교반하였다. 반응이 종료되면 얼음 항온조에서 NaOH수용액으로 quenching하였다. 수용액을 DCM으로 씻어준 뒤 물을 증발시켰다. Crude 생성물을 메탄올에서 재결정하여 화합물 22을 제조하였다. (수율: 55%)Compound 15 (1 equiv) prepared in Preparation Example 15 was dissolved in DCM and stirred at -78°C. 1M BBr 3 DCM solution (5 equiv) was added dropwise and stirred overnight at room temperature. When the reaction was completed, it was quenched with NaOH aqueous solution in an ice thermostat. The aqueous solution was washed with DCM and the water was evaporated. Compound 22 was prepared by recrystallizing the crude product from methanol. (yield: 55%)
1H NMR (400 MHz, CDCl3) δ 8.62 (d, 1H), 7.98-7.89 (m, 3H), 7.66 (d, 1H), 7.34 (d, 1H), 7.05-6.94 (m, 3H), 6.06-5.96 (m, 1H), 5.77 (bs, 1H), 5.22-5.16 (m, 2H), 3.59-3.54 (m, 1H), 3.30-3.19 (m, 2H), 2.96-2.85 (m, 2H), 2.45 (s, 1H), 2.02-1.94 (m, 2H), 1.86-1.76 (m, 1H), 1.70-1.61 (m, 1H), 1.53-1.47 (m, 1H) ppm 1 H NMR (400 MHz, CDCl 3 ) δ 8.62 (d, 1H), 7.98-7.89 (m, 3H), 7.66 (d, 1H), 7.34 (d, 1H), 7.05-6.94 (m, 3H), 6.06-5.96 (m, 1H), 5.77 (bs, 1H), 5.22-5.16 (m, 2H), 3.59-3.54 (m, 1H), 3.30-3.19 (m, 2H), 2.96-2.85 (m, 2H) ), 2.45 (s, 1H), 2.02-1.94 (m, 2H), 1.86-1.76 (m, 1H), 1.70-1.61 (m, 1H), 1.53-1.47 (m, 1H) ppm
제조예 23: 화합물 23의 제조Preparation Example 23: Preparation of Compound 23
제조예 16에서 제조한 화합물 16(1 equiv)을 DCM에 용해시켜 -78 ℃에서 교반시켰다. 1M BBr3 DCM용액(5 equiv)을 dropwise한 뒤 상온에서 overnight동안 교반하였다. 반응이 종료되면 얼음 항온조에서 NaOH수용액으로 quenching하였다. DCM과 ethyl acetate로 추출하여 실리카 컬럼 크로마토 그래피로 정제하여 화합물 23을 제조하였다. (수율: 34%)Compound 16 (1 equiv) prepared in Preparation Example 16 was dissolved in DCM and stirred at -78°C. 1M BBr 3 DCM solution (5 equiv) was added dropwise and stirred overnight at room temperature. When the reaction was completed, it was quenched with NaOH aqueous solution in an ice thermostat. Compound 23 was prepared by extraction with DCM and ethyl acetate and purification by silica column chromatography. (yield: 34%)
1H NMR (600 MHz, CD3OD) δ 8.61 (d, 1H), 7.97 (d, 1H), 7.91 (d, 1H), 7.48 (d, 1H), 7.36 (dd, 1H), 7.31-7.28 (m, 2H), 7.23-7.21 (m, 2H), 7.17-7.15 (m, 1H), 6.70 (d, 1H), 6.01-5.95 (m, 1H), 5.10-5.03 (m, 2H), 3.59-3.54 (m, 1H), 3.24-3.19 (m, 1H), 2.95 (dd, 1H), 2.58-2.51 (m, 2H), 2.35-2.31 (m, 1H), 2.05-2.00 (m, 1H), 1.95-1.89 (m, 2H), 1.86-1.84 (m, 1H), 1.63-1.57 (m, 1H) ppm 1 H NMR (600 MHz, CD 3 OD) δ 8.61 (d, 1H), 7.97 (d, 1H), 7.91 (d, 1H), 7.48 (d, 1H), 7.36 (dd, 1H), 7.31-7.28 (m, 2H), 7.23-7.21 (m, 2H), 7.17-7.15 (m, 1H), 6.70 (d, 1H), 6.01-5.95 (m, 1H), 5.10-5.03 (m, 2H), 3.59 -3.54 (m, 1H), 3.24-3.19 (m, 1H), 2.95 (dd, 1H), 2.58-2.51 (m, 2H), 2.35-2.31 (m, 1H), 2.05-2.00 (m, 1H) , 1.95-1.89 (m, 2H), 1.86-1.84 (m, 1H), 1.63-1.57 (m, 1H) ppm
제조예 24: 화합물 24의 제조Preparation Example 24: Preparation of Compound 24
제조예 17에서 제조한 화합물 17(1 equiv)를 DCM에 용해시켜 -78 ℃에서 교반시켰다. 1M BBr3 DCM용액(5 equiv)을 dropwise한 뒤 상온에서 overnight동안 교반하였다. 반응이 종료되면 얼음 항온조에서 NaOH수용액으로 quenching하였다. DCM과 ethyl acetate로 추출하여 실리카 컬럼 크로마토 그래피로 정제하여 화합물 24을 제조하였다. (수율: 47%)Compound 17 (1 equiv) prepared in Preparation Example 17 was dissolved in DCM and stirred at -78°C. 1M BBr 3 DCM solution (5 equiv) was added dropwise and stirred overnight at room temperature. When the reaction was completed, it was quenched with NaOH aqueous solution in an ice thermostat. Compound 24 was prepared by extraction with DCM and ethyl acetate and purification by silica column chromatography. (Yield: 47%)
1H NMR (600 MHz, CD3OD) δ 8.63 (d, 1H), 7.91 (d, 1H), 7.64 (d, 1H), 7.49 (d, 1H), 7.35 (dd, 1H), 7.32-7.31 (m, 2H), 7.24-7.22 (m, 2H), 6.98-6.93 (m, 1H), 6.03-5.97 (m, 1H), 5.76 (d, 1H), 5.13-5.07 (m, 2H), 3.55 (q, 1H), 3.17-3.12 (m, 1H), 3.04 (dd, 1H), 2.73-2.69 (m, 1H), 2.62-2.57 (m, 1H), 2.41-2.37 (m, 1H), 2.16-2.12 (m, 1H), 1.94-1.85 (m, 2H), 1.69-1.62 (m, 2H) ppm 1 H NMR (600 MHz, CD 3 OD) δ 8.63 (d, 1H), 7.91 (d, 1H), 7.64 (d, 1H), 7.49 (d, 1H), 7.35 (dd, 1H), 7.32-7.31 (m, 2H), 7.24-7.22 (m, 2H), 6.98-6.93 (m, 1H), 6.03-5.97 (m, 1H), 5.76 (d, 1H), 5.13-5.07 (m, 2H), 3.55 (q, 1H), 3.17-3.12 (m, 1H), 3.04 (dd, 1H), 2.73-2.69 (m, 1H), 2.62-2.57 (m, 1H), 2.41-2.37 (m, 1H), 2.16 -2.12 (m, 1H), 1.94-1.85 (m, 2H), 1.69-1.62 (m, 2H) ppm
제조예 25: 화합물 25의 제조Preparation Example 25: Preparation of Compound 25
제조예 18에서 제조한 화합물 18(1 equiv)를 DCM에 용해시켜 -78 ℃에서 교반시켰다. 1M BBr3 DCM용액(5 equiv)을 dropwise한 뒤 상온에서 overnight동안 교반하였다. 반응이 종료되면 얼음 항온조에서 NaOH수용액으로 quenching하였다. 물을 증발시키고 메탄올과 다이에티에터로 재결정하고 DMF로 celite filter 하였다. 실리카 컬럼 크로마토그래피로 정제하여 화합물 25를 제조하였다. (수율: 28%)Compound 18 (1 equiv) prepared in Preparation Example 18 was dissolved in DCM and stirred at -78°C. 1M BBr 3 DCM solution (5 equiv) was added dropwise and stirred overnight at room temperature. When the reaction was completed, it was quenched with NaOH aqueous solution in an ice thermostat. The water was evaporated, recrystallized with methanol and diether, and celite filtered with DMF. Compound 25 was prepared by purification by silica column chromatography. (Yield: 28%)
1H NMR (400 MHz, CD3OD) δ 8.70-8.68 (m, 1H), 7.97 (d, 1H), 7.58-7.55 (m, 2H), 7.41 (dd, 1H), 6.00-5.91 (m, 1H), 5.34 (bs, 1H), 5.18-5.08 (m, 2H), 3.58-3.50 (m, 1H), 3.13 (t, 1H), 2.79-2.68 (m, 3H), 2.53-2.47 (m, 1H), 2.45 (s, 3H), 2.22-2.14 (m, 2H), 2.01-1.71 (m, 5H) ppm 1 H NMR (400 MHz, CD 3 OD) δ 8.70-8.68 (m, 1H), 7.97 (d, 1H), 7.58-7.55 (m, 2H), 7.41 (dd, 1H), 6.00-5.91 (m, 1H), 5.34 (bs, 1H), 5.18-5.08 (m, 2H), 3.58-3.50 (m, 1H), 3.13 (t, 1H), 2.79-2.68 (m, 3H), 2.53-2.47 (m, 1H), 2.45 (s, 3H), 2.22-2.14 (m, 2H), 2.01-1.71 (m, 5H) ppm
제조예 26: 화합물 26의 제조Preparation Example 26: Preparation of Compound 26
제조예 19에서 제조한 화합물 19(1 equiv)를 DCM에 용해시켜 -78 ℃에서 교반시켰다. 1M BBr3 DCM용액(5 equiv)을 dropwise한 뒤 상온에서 overnight동안 교반하였다. 반응이 종료되면 얼음 항온조에서 NaOH수용액으로 quenching하였다. Ethyl acetate로 추출하여 실리카 컬럼 크로마토 그래피로 정제하여 화합물 26을 제조하였다. (수율: 15%)Compound 19 (1 equiv) prepared in Preparation Example 19 was dissolved in DCM to -78 Stirred at °C. 1M BBr 3 DCM solution (5 equiv) was added dropwise and stirred overnight at room temperature. When the reaction was completed, it was quenched with NaOH aqueous solution in an ice thermostat. Compound 26 was prepared by extraction with ethyl acetate and purification by silica column chromatography. (yield: 15%)
1H NMR (600 MHz, CD3OD) δ 8.35 (d, 1H), 7.71 (d, 1H), 7.28-7.23 (m, 3H), 7.14 (d, 2H), 6.64 (d, 2H), 5.99-5.93 (m, 1H), 5.09-5.05 (m, 2H), 3.31-3.19 (m, 1H), 3.16-3.12 (m, 1H), 2.91 (dd, 1H), 2.49-2.48 (d, 2H), 2.35-2.30 (m, 1H), 2.19-2.13 (m, 1H), 1.88 (s, 1H), 1.82-1.76 (m, 1H), 1.75-1.67 (m, 1H), 1.64-1.59 (m, 1H) ppm 1 H NMR (600 MHz, CD 3 OD) δ 8.35 (d, 1H), 7.71 (d, 1H), 7.28-7.23 (m, 3H), 7.14 (d, 2H), 6.64 (d, 2H), 5.99 -5.93 (m, 1H), 5.09-5.05 (m, 2H), 3.31-3.19 (m, 1H), 3.16-3.12 (m, 1H), 2.91 (dd, 1H), 2.49-2.48 (d, 2H) , 2.35-2.30 (m, 1H), 2.19-2.13 (m, 1H), 1.88 (s, 1H), 1.82-1.76 (m, 1H), 1.75-1.67 (m, 1H), 1.64-1.59 (m, 1H)ppm
제조예 27: 화합물 27의 제조Preparation Example 27: Preparation of Compound 27
제조예 20에서 제조한 화합물 20(1 equiv)를 DCM에 용해시켜 -78oC에서 교반시켰다. 1M BBr3 DCM용액(5 equiv)을 dropwise한 뒤 상온에서 overnight동안 교반하였다. 반응이 종료되면 얼음 항온조에서 NaOH수용액으로 quenching하였다. DCM로 추출하여 MgSO4로 말린다. 실리카 컬럼 크로마토그래피로 정제하여 화합물 27을 제조하였다. (수율: 30%)Compound 20 (1 equiv) prepared in Preparation Example 20 was dissolved in DCM and stirred at -78 o C. 1M BBr 3 DCM solution (5 equiv) was added dropwise and stirred overnight at room temperature. When the reaction was completed, it was quenched with NaOH aqueous solution in an ice thermostat. Extracted with DCM and dried with MgSO 4 . Compound 27 was prepared by purification by silica column chromatography. (yield: 30%)
1H NMR (600 MHz, CD3OD) δ 8.37 (d, 1H), 7.77 (s, 2H), 7.67 (d, 2H), 7.29-7.23 (m, 3H), 6.02-5.97 (m, 1H), 5.14-5.08 (m, 3H), 3.11-3.02 (m, 1H), 2.92 (dd, 1H), 2.55-2.50 (m, 2H), 2.36 (s, 1H), 2.28-2.24 (m, 1H), 1.93 (s, 1H), 1.86-1.74 (m, 2H), 1.67-1.62 (m, 1H) ppm 1 H NMR (600 MHz, CD 3 OD) δ 8.37 (d, 1H), 7.77 (s, 2H), 7.67 (d, 2H), 7.29-7.23 (m, 3H), 6.02-5.97 (m, 1H) , 5.14-5.08 (m, 3H), 3.11-3.02 (m, 1H), 2.92 (dd, 1H), 2.55-2.50 (m, 2H), 2.36 (s, 1H), 2.28-2.24 (m, 1H) , 1.93 (s, 1H), 1.86-1.74 (m, 2H), 1.67-1.62 (m, 1H) ppm
제조예 28: 화합물 28의 제조Preparation Example 28: Preparation of Compound 28
제조예 12에서 제조한 화합물 12(1 equiv)를 메탄올에 용해시킨 뒤 di-tert-butyl dicarbonate(2.5 equiv)을 넣은 뒤 상온에서 overnight동안 교반하였다. 반응이 끝나면 용매를 제거하고 물과 DCM으로 추출하고 Na2SO4로 말린 뒤 실리카 컬럼크로마토그래피로 정제하여 화합물 28을 제조하였다. (수율: 42%)Compound 12 (1 equiv) prepared in Preparation Example 12 was dissolved in methanol, di-tert-butyl dicarbonate (2.5 equiv) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was removed, extracted with water and DCM, dried with Na 2 SO 4 and purified by silica column chromatography to prepare Compound 28. (Yield: 42%)
1H NMR (600 MHz, CD3OD) δ 8.59 (d, 1H), 7.90 (d, 1H), 7.61 (m, 1H), 7.44 (d, 1H), 7.39-7.27 (m, 1H), 6.02-6.00 (m, 1H), 5.44 (d, 1H), 5.10-5.04 (m, 2H), 3.39-3.35 (m, 1H),3.12-3.05 (m, 1H), 2.96-2.92 (m, 1H), 2.57-2.47 (m, 2H), 2.36-2.28 (m, 1H), 2.08-2.12 (m, 1H), 1.84-1.78 (m, 2H), 1.64-1.54 (m, 2H), 1.52-1.48 (m, 1H), 1.41 (s, 9H) ppm 1 H NMR (600 MHz, CD 3 OD) δ 8.59 (d, 1H), 7.90 (d, 1H), 7.61 (m, 1H), 7.44 (d, 1H), 7.39-7.27 (m, 1H), 6.02 -6.00 (m, 1H), 5.44 (d, 1H), 5.10-5.04 (m, 2H), 3.39-3.35 (m, 1H),3.12-3.05 (m, 1H), 2.96-2.92 (m, 1H) , 2.57-2.47 (m, 2H), 2.36-2.28 (m, 1H), 2.08-2.12 (m, 1H), 1.84-1.78 (m, 2H), 1.64-1.54 (m, 2H), 1.52-1.48 ( m, 1H), 1.41 (s, 9H) ppm
제조예 29: 화합물 29의 제조Preparation Example 29: Preparation of Compound 29
제조예 13에서 제조한 화합물 13(1 equiv)을 질소환경에서 DCM에 용해시킨 뒤 TEA(1 equiv)을 넣는다. Tosyl chloride DCM용액(1 equiv)을 dropwise하고 상온에서 overnight동안 교반하였다. 반응이 종료되면 NaHCO3수용액과 DCM으로 추출하고 유기층을 모아 실리카 컬럼크로마토그래피로 정제하여 화합물 29를 제조하였다. (수율: 64%)Compound 13 (1 equiv) prepared in Preparation Example 13 was dissolved in DCM in a nitrogen environment, and then TEA (1 equiv) was added. Tosyl chloride DCM solution (1 equiv) was added dropwise and stirred overnight at room temperature. When the reaction was completed, extraction was performed with NaHCO 3 aqueous solution and DCM, and the organic layer was collected and purified by silica column chromatography to prepare compound 29. (yield: 64%)
1H NMR (400 MHz, CD3OD) δ 8.37 (d, 1H), 8.00 (d, 1H), 7.70 (d, 1H), 7.51 (t, 1H), 7.38 (t, 1H), 7.17 (d, 1H), 6.93 (d, 2H), 6.39 (d, 2H), 5.80-5.71 (m, 1H), 5.02 (bs, 1H,), 4.88-4.82 (m, 2H), 3.15-3.10 (m, 1H), 2.94-2.86 (m, 1H), 2.67-2.61 (m, 1H), 2.28-2.18 (m, 2H), 2.08-1.98 (m, 2H), 1.86 (s, 3H), 1.63-1.32 (m, 4H) ppm 1H NMR (400 MHz, CD 3 OD) δ 8.37 (d, 1H), 8.00 (d, 1H), 7.70 (d, 1H), 7.51 (t, 1H), 7.38 (t, 1H), 7.17 (d) , 1H), 6.93 (d, 2H), 6.39 (d, 2H), 5.80-5.71 (m, 1H), 5.02 (bs, 1H,), 4.88-4.82 (m, 2H), 3.15-3.10 (m, 1H), 2.94-2.86 (m, 1H), 2.67-2.61 (m, 1H), 2.28-2.18 (m, 2H), 2.08-1.98 (m, 2H), 1.86 (s, 3H), 1.63-1.32 ( m, 4H)ppm
제조예 30: 화합물 30의 제조Preparation Example 30: Preparation of Compound 30
제조예 13에서 제조한 화합물 13(1 equiv)을 DCM에 용해시키고 질소환경으로 만들어준다. TEA(1 equiv)을 넣고 3,5-bis(trifluoromethyl)benzenesulfonylchloride(1 equiv)을 dropwise 하였다. 상온에서 overnight동안 교반하고 반응이 종료되면 물과 DCM으로 추출하였다. 추출한 유기층을 MgSO4로 말린 뒤 실리카 컬럼크로마토그래피로 정제하여 compelx 30을 제조하였다. (수율: 26%)Compound 13 (1 equiv) prepared in Preparation Example 13 was dissolved in DCM and created in a nitrogen environment. TEA (1 equiv) was added, and 3,5-bis(trifluoromethyl)benzenesulfonylchloride (1 equiv) was added dropwise. It was stirred overnight at room temperature, and when the reaction was completed, it was extracted with water and DCM. The extracted organic layer was dried with MgSO 4 and purified by silica column chromatography to prepare compelx 30. (yield: 26%)
1H NMR (400 MHz, CD3OD) δ 8.45 (d, 1H), 8.19 (s, 1H), 8.02 (d, 1H), 7.92 (s, 1H), 7.70 (d, 1H), 7.58-7.50 (m, 3H), 7.45-7.41 (m, 1H), 7.24-7.20 (m, 1H), 5.90-5.81 (m, 1H), 5.18 (bs, 1H), 4.98-4.92 (m, 2H), 3.29-3.22 (m, 1H), 2.98-2.90 (m, 1H), 2.79-2.73 (m, 1H), 2.40-2.14 (m, 4H), 1.78-1.60 (m, 3H), 1.51-1.44 (m, 1H) ppm 1 H NMR (400 MHz, CD 3 OD) δ 8.45 (d, 1H), 8.19 (s, 1H), 8.02 (d, 1H), 7.92 (s, 1H), 7.70 (d, 1H), 7.58-7.50 (m, 3H), 7.45-7.41 (m, 1H), 7.24-7.20 (m, 1H), 5.90-5.81 (m, 1H), 5.18 (bs, 1H), 4.98-4.92 (m, 2H), 3.29 -3.22 (m, 1H), 2.98-2.90 (m, 1H), 2.79-2.73 (m, 1H), 2.40-2.14 (m, 4H), 1.78-1.60 (m, 3H), 1.51-1.44 (m, 1H) ppm
제조예 31: 화합물 31의 제조Preparation Example 31: Preparation of Compound 31
제조예 13에서 제조한 화합물 13(1 equiv)을 DCM에 용해시키고 질소환경을 만들어준다. Quinoline-8-sulfonyl chloride DCM(1 equiv)용액을 dropwise 하고 TEA(1 equiv)를 넣는다. 상온에서 overnight동안 교반한 뒤 물과 DCM으로 추출하였다. 추출한 유기층은 실리카 컬럼크로마토그래피로 정제하여 화합물 31을 제조하였다. (수율: 59%)Compound 13 (1 equiv) prepared in Preparation Example 13 was dissolved in DCM and a nitrogen environment was created. Add quinoline-8-sulfonyl chloride DCM (1 equiv) solution dropwise and add TEA (1 equiv). After stirring overnight at room temperature, the mixture was extracted with water and DCM. The extracted organic layer was purified by silica column chromatography to prepare compound 31. (Yield: 59%)
1H NMR (400 MHz, CDCl3) δ 8.75 (bs, 1H), 8.05 (d, 1H), 7.92-7.88 (m, 2H), 7.64 (d,1H), 7.48-7.44 (m, 2H), 7.36-7.23 (m, 1H), 6.92-6.78 (m, 3H), 6.01-5.92 (m, 1H), 5.26-5.04 (m, 3H), 3.40-3.30 (m, 1H), 2.97-2.85 (m, 2H), 2.53-2.50 (m, 1H), 2.43-2.26 (m, 3H), 1.95-1.76 (m, 4H), 1.57-1.48 (m, 1H) ppm 1 H NMR (400 MHz, CDCl 3 ) δ 8.75 (bs, 1H), 8.05 (d, 1H), 7.92-7.88 (m, 2H), 7.64 (d, 1H), 7.48-7.44 (m, 2H), 7.36-7.23 (m, 1H), 6.92-6.78 (m, 3H), 6.01-5.92 (m, 1H), 5.26-5.04 (m, 3H), 3.40-3.30 (m, 1H), 2.97-2.85 (m) , 2H), 2.53-2.50 (m, 1H), 2.43-2.26 (m, 3H), 1.95-1.76 (m, 4H), 1.57-1.48 (m, 1H) ppm
제조예 32: 화합물 32의 제조Preparation Example 32: Preparation of Compound 32
제조예 13에서 제조한 화합물 13(1 equiv)을 THF에 용해시키고 phenyl isocyanate(1 equiv)을 천천히 넣은 뒤 상온에서 overnight동안 교반하였다. 반응이 끝나면 실리카 컬럼크로마토그래피로 정제하여 화합물 32을 제조하였다. (수율: 76%)Compound 13 (1 equiv) prepared in Preparation Example 13 was dissolved in THF, phenyl isocyanate (1 equiv) was slowly added, and stirred at room temperature overnight. After the reaction was completed, compound 32 was prepared by purification using silica column chromatography. (Yield: 76%)
1H NMR (400 MHz, CDCl3) δ 8.84 (d, 1H), 8.57 (d, 1H), 8.11 (d, 1H), 7.93 (bs, 1H), 7.75-7.70 (m, 1H), 7.64-7.60 (m, 1H), 7.38-7.33 (m, 2H), 7.30-7.24 (m, 1H), 7.05 (d, 2H), 6.69-6.65 (m, 1H), 6.56 (bs, 1H), 5.94-5.85 (m, 1H), 5.08-5.02 (m, 2H), 3.39-3.32 (m, 1H), 3.05-3.96 (m, 2H), 2.62-2.58 (m, 1H), 2.52-2.45 (m, 1H), 2.29-2.23 (m, 1H), 1.94-1.70 (m, 5H), 1.50-1.42 (m, 1H) ppm 1H NMR (400 MHz, CDCl 3 ) δ 8.84 (d, 1H), 8.57 (d, 1H), 8.11 (d, 1H), 7.93 (bs, 1H), 7.75-7.70 (m, 1H), 7.64- 7.60 (m, 1H), 7.38-7.33 (m, 2H), 7.30-7.24 (m, 1H), 7.05 (d, 2H), 6.69-6.65 (m, 1H), 6.56 (bs, 1H), 5.94- 5.85 (m, 1H), 5.08-5.02 (m, 2H), 3.39-3.32 (m, 1H), 3.05-3.96 (m, 2H), 2.62-2.58 (m, 1H), 2.52-2.45 (m, 1H) ), 2.29-2.23 (m, 1H), 1.94-1.70 (m, 5H), 1.50-1.42 (m, 1H) ppm
제조예 33: 화합물 33의 제조Preparation Example 33: Preparation of compound 33
제조예 13에서 제조한 화합물 13(1 equiv)을 THF에 용해시키고 3,5-bis(trifluoromethtyl)phenyl isothiocyanate(1 equiv)을 천천히 넣은 뒤 상온에서 overnight동안 교반하였다. 반응이 끝나면 실리카 컬럼크로마토그래피로 정제하여 화합물 33을 제조하였다. (수율: 52%)Compound 13 (1 equiv) prepared in Preparation Example 13 was dissolved in THF, 3,5-bis(trifluoromethtyl)phenyl isothiocyanate (1 equiv) was slowly added, and the mixture was stirred at room temperature overnight. After the reaction was completed, compound 33 was prepared by purification using silica column chromatography. (Yield: 52%)
1H NMR (400 MHz, CDCl3) δ 8.79-8.77 (m, 1 H), 8.42-8.39 (m, 1H), 8.05 (d, 1H), 7.75-7.60 (m, 4H), 7.34-7.32 (m, 1H), 6.60 (bs, 1H), 5.94-5.84 (m, 1H), 5.11-5.05 (m, 2H), 3.50-3.42 (m, 1H), 3.09-2.92 (m, 2H), 2.76-2.74 (m, 1H), 2.59-2.51 (m, 1H), 2.34-3.29 (m, 1H), 2.03-1.94 (m, 1H), 1.89-1.85 (m, 1H), 1.71-1.60 (m, 2H), 1.50-1.42 (m, 1H) ppm 1H NMR (400 MHz, CDCl 3 ) δ 8.79-8.77 (m, 1H), 8.42-8.39 (m, 1H), 8.05 (d, 1H), 7.75-7.60 (m, 4H), 7.34-7.32 ( m, 1H), 6.60 (bs, 1H), 5.94-5.84 (m, 1H), 5.11-5.05 (m, 2H), 3.50-3.42 (m, 1H), 3.09-2.92 (m, 2H), 2.76- 2.74 (m, 1H), 2.59-2.51 (m, 1H), 2.34-3.29 (m, 1H), 2.03-1.94 (m, 1H), 1.89-1.85 (m, 1H), 1.71-1.60 (m, 2H) ), 1.50-1.42 (m, 1H) ppm
제조예 34: 화합물 34의 제조Preparation Example 34: Preparation of Compound 34
제조예 13에서 제조한 화합물 13(1 equiv)을 THF에 용해시키고 4-methoxyphenyl isothiocyanate(1 equiv)을 천천히 넣은 뒤 상온에서 overnight동안 교반하였다. 반응이 끝나면 실리카 컬럼크로마토그래피로 정제하여 화합물 34을 제조하였다. (수율: 63%)Compound 13 (1 equiv) prepared in Preparation Example 13 was dissolved in THF, 4-methoxyphenyl isothiocyanate (1 equiv) was slowly added, and the mixture was stirred at room temperature overnight. After the reaction was completed, compound 34 was prepared by purification using silica column chromatography. (yield: 63%)
1H NMR (400 MHz, CDCl3) δ 8.86 (d, 1H), 8.58 (d, 1H), 8.11 (d, 1H), 7.75-7.71 (m, 1H), 7.65-7.61 (m, 1H), 7.57-7.51(m, 1H), 7.24-7.20(m, 1H), 6.96-6.94 (m, 1H), 6.88-6.85 (m, 1H), 6.66 (t, 1H), 6.19 (bs, 1H), 5.94-5.85 (m, 1H), 5.08-5.03 (m, 1H), 3.80 (s, 3H), 3.38-3.28 (m, 1H), 3.06-2.97 (m, 2H), 2.61-2.47 (m, 2H), 2.31-2.23 (m, 1H), 1.90-1.72 (m, 4H), 1.52-1.42 (m, 1H) ppm 1 H NMR (400 MHz, CDCl 3 ) δ 8.86 (d, 1H), 8.58 (d, 1H), 8.11 (d, 1H), 7.75-7.71 (m, 1H), 7.65-7.61 (m, 1H), 7.57-7.51(m, 1H), 7.24-7.20(m, 1H), 6.96-6.94 (m, 1H), 6.88-6.85 (m, 1H), 6.66 (t, 1H), 6.19 (bs, 1H), 5.94-5.85 (m, 1H), 5.08-5.03 (m, 1H), 3.80 (s, 3H), 3.38-3.28 (m, 1H), 3.06-2.97 (m, 2H), 2.61-2.47 (m, 2H) ), 2.31-2.23 (m, 1H), 1.90-1.72 (m, 4H), 1.52-1.42 (m, 1H) ppm
실시예 1-1Example 1-1
(단계 1)(Step 1)
상기 제조예 1에서 제조한 화합물 1(20 mol%)을 DMF(Dimethylformamide)에 0.1 M 농도로 녹였다. 상기 용액에 메틸글리옥살(methylglyoxal) 1 당량, 벤질 싸이올(benzyl thiol)을 2 당량으로 각각 투입하고 상온에서 18시간 동안 교반하였다. 반응이 완료된 후 사용한 용매를 감압 하에 제거하고 실리카 컬럼 크로마토 그래피를 통해 정제하여 티오에스터를 제조하였다.Compound 1 (20 mol%) prepared in Preparation Example 1 was dissolved in DMF (Dimethylformamide) at a concentration of 0.1 M. 1 equivalent of methylglyoxal and 2 equivalents of benzyl thiol were added to the solution and stirred at room temperature for 18 hours. After the reaction was completed, the used solvent was removed under reduced pressure and purified through silica column chromatography to prepare a thioester.
(단계 2)(Step 2)
상기 티오에스터를 물에 녹인 후, 염기를 첨가하고 100 ℃에서 1시간 동안 환류하였다. 반응이 완료된 후 DCM으로 씻어주어 벤질 싸이올을 회수하였다. 물 층을 산성화(acidify) 한 뒤, EA(ethyl acetate)로 추출하여 젖산을 제조하였다.After dissolving the thioester in water, a base was added and refluxed at 100°C for 1 hour. After the reaction was completed, the benzyl thiol was recovered by washing with DCM. The water layer was acidified and extracted with EA (ethyl acetate) to prepare lactic acid.
실시예 1-2 내지 1-40Examples 1-2 to 1-40
화합물 1 및 DCM 대신 하기 표 1에 기재된 화합물 및 용매를 사용한 것을 제외하고는 상기 실시예 1과 동일한 방법으로 젖산을 제조하였다.Lactic acid was prepared in the same manner as Example 1, except that the compounds and solvents listed in Table 1 below were used instead of Compound 1 and DCM.
실시예 2-1 내지 2-11Examples 2-1 to 2-11
DCM 대신 하기 표 2에 기재된 용매를 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 젖산을 제조하였다.Lactic acid was prepared in the same manner as Example 1, except that the solvent listed in Table 2 below was used instead of DCM.
비교예Comparative example
촉매를 사용하지 않고, 용매는 toluene을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 젖산을 제조하였다.Lactic acid was prepared in the same manner as in Example 1, except that toluene was used as a solvent without using a catalyst.
상기 실시예 및 비교예에서 사용된 용매는 다음과 같다.The solvents used in the above examples and comparative examples are as follows.
DMF(Dimethylformamide), DCM(Dichloromethane), MeOH(Methanol), H2O, THF(Tetrahydrofuran), DMSO(Dimethyl sulfoxide), NMP(N-methyl-2-pyrrolidone), Toluene, CF3-toluene, Acetone, p-xylene, DMAc(N,N-Dimethylacetamide), NMF(N-methylformamide)DMF (Dimethylformamide), DCM (Dichloromethane), MeOH (Methanol), H 2 O, THF (Tetrahydrofuran), DMSO (Dimethyl sulfoxide), NMP (N-methyl-2-pyrrolidone), Toluene, CF 3 -toluene, Acetone, p-xylene, DMAc(N,N-Dimethylacetamide), NMF(N-methylformamide)
실험예Experiment example
(1) 젖산의 수율 및 거울상 이성질체 과잉률(1) Yield and enantiomeric excess of lactic acid
반응 후 존재하는 화합물들은 실리카 컬럼 크로마토그래피(EA2/Hx98 -> EA10/Hx90)로 정제하여 확보된 무게로 수율을 계산하였다.The compounds present after the reaction were purified by silica column chromatography (EA2/Hx98 -> EA10/Hx90), and the yield was calculated based on the obtained weight.
정제한 화합물의 1H-NMR을 측정하고, 젖산과 hemithioacetal 형태의 화합물의 적분비를 이용하여 환산 질량으로 계산하였다. 1 H-NMR of the purified compound was measured, and the converted mass was calculated using the integral ratio of lactic acid and the hemithioacetal compound.
거울상 이성질체 과잉률은 생성물을 컬럼 크로마토그래피로 분리하여 chiral HPLC 장비로 분석한 후, ee 값을 하기 식 1과 같이 계산하였다.The enantiomeric excess ratio was calculated by separating the product by column chromatography and analyzing it with chiral HPLC equipment, and then calculating the ee value as shown in Equation 1 below.
HPLC 장비는 Agilent 1260 Series G1322A Degasser, Agilent 1200 Series G1312A Bin Pump, Agilent 1100 Series G1314A VWD Detector를 사용하였으며, column 관으로 DAICEL CHIRALPAK AS-H(Particle size 5 μm, Dimension 4.6 mm Φ * 250 mmL)를 사용하였다. 이동상은 5 % isopropyl alcohol/95 % Hexane 으로 설정하였고, Flow rate는 1.0 mL/min이며, UV 254 nm에서 측정하였다. HPLC equipment used was Agilent 1260 Series G1322A Degasser, Agilent 1200 Series G1312A Bin Pump, and Agilent 1100 Series G1314A VWD Detector, and DAICEL CHIRALPAK AS-H (Particle size 5 μm, Dimension 4.6 mm Φ * 250 mmL) was used as a column tube. did. The mobile phase was set to 5% isopropyl alcohol/95% hexane, the flow rate was 1.0 mL/min, and measured at UV 254 nm.
[식 1][Equation 1]
거울상 이성질체 과잉률(ee) = [|(L-락트산)-(D-락트산)|]/[(L-락트산)+(D-락트산)] * 100Enantiomeric excess ratio (ee) = [|(L-lactic acid)-(D-lactic acid)|]/[(L-lactic acid)+(D-lactic acid)] * 100
상기 표 1 및 표 2에 기재된 바와 같이, 메틸글리옥살과 지방족 또는 방향족 싸이올계 화합물의 반응을 통해 젖산을 제조하는 방법에 있어서, 본 발명에 따른 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이의 염을 촉매로 사용하는 경우, 거울상이성질체 과잉률이 높으면서 젖산의 수율 또한 높아, 선택적으로 카이랄한 젖산을 제조할 수 있었다.As shown in Tables 1 and 2 above, in the method of producing lactic acid through the reaction of methylglyoxal and an aliphatic or aromatic thiol-based compound, the compound represented by Formula 1 or Formula 2 according to the present invention or a salt thereof When used as a catalyst, the enantiomeric excess ratio was high and the yield of lactic acid was also high, making it possible to selectively produce chiral lactic acid.
Claims (11)
상기 티오에스터(thioester)를 젖산으로 전환하는 단계(단계 2)를 포함하고,
상기 촉매는 하기 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이들의 염인,
젖산 제조 방법:
[화학식 1]
[화학식 2]
상기 화학식 1 및 화학식 2에서,
R1은 수소, 히드록시기, 또는 치환 또는 비치환된 C1-60 알콕시이고,
R2는 치환 또는 비치환된 C1-60 알킬, 또는 치환 또는 비치환된 C1-60 알케닐이고,
L은 단일 결합, -O-, -OCO-, -NH-CO-, -NH-CO-NH-, -NH-CS-NH-, -NH-SOO-, 또는 -NH-COO-이고,
R3는 수소, 히드록시기, 아미노기, 치환 또는 비치환된 C1-60 알킬, 치환 또는 비치환된 C6-60 아릴, 또는 치환 또는 비치환된 N, O 및 S로 구성되는 군으로부터 선택되는 어느 하나 이상의 헤테로원자를 포함하는 C2-60 헤테로아릴이다.
Preparing a thioester by reacting methylglyoxal and an aliphatic or aromatic thiol-based compound in a solvent in the presence of a catalyst (step 1); and
Converting the thioester to lactic acid (step 2),
The catalyst is a compound represented by Formula 1 or Formula 2 below, or a salt thereof,
Lactic acid preparation method:
[Formula 1]
[Formula 2]
In Formula 1 and Formula 2,
R 1 is hydrogen, a hydroxy group, or substituted or unsubstituted C 1-60 alkoxy,
R 2 is substituted or unsubstituted C 1-60 alkyl, or substituted or unsubstituted C 1-60 alkenyl,
L is a single bond, -O-, -OCO-, -NH-CO-, -NH-CO-NH-, -NH-CS-NH-, -NH-SOO-, or -NH-COO-,
R 3 is hydrogen, a hydroxy group, an amino group, substituted or unsubstituted C 1-60 alkyl, substituted or unsubstituted C 6-60 aryl, or substituted or unsubstituted any selected from the group consisting of N, O and S. It is C 2-60 heteroaryl containing one or more heteroatoms.
R1은 수소, 히드록시기, 또는 메톡시인,
젖산 제조 방법.
According to paragraph 1,
R 1 is hydrogen, a hydroxyl group, or methoxy,
How to make lactic acid.
R2는 에틸 또는 비닐인,
젖산 제조 방법.
According to paragraph 1,
R 2 is ethyl or vinyl,
How to make lactic acid.
R3는 수소, 히드록시기, 아미노기, 메틸, tert-부틸, 페닐, 또는 퀴놀린이고,
상기 페닐, 및 퀴놀린은 각각 독립적으로, 비치환되거나, 또는 하나 이상의 할로겐, 메틸, 트리플루오로메틸, 또는 메톡시로 치환된,
젖산 제조 방법.
According to paragraph 1,
R 3 is hydrogen, hydroxy group, amino group, methyl, tert-butyl, phenyl, or quinoline,
The phenyl and quinoline are each independently unsubstituted or substituted with one or more halogen, methyl, trifluoromethyl, or methoxy,
How to make lactic acid.
상기 화학식 1 또는 화학식 2로 표시되는 화합물, 또는 이들의 염은 하기로 구성되는 군으로부터 선택되는 어느 하나인,
젖산 제조 방법:
According to paragraph 1,
The compound represented by Formula 1 or Formula 2, or a salt thereof, is any one selected from the group consisting of:
Lactic acid preparation method:
상기 용매는 메틸글리옥살 농도가 0.01 M 내지 2.0 M이 되도록 사용하는,
젖산 제조 방법.
According to paragraph 1,
The solvent is used so that the methylglyoxal concentration is 0.01 M to 2.0 M,
How to make lactic acid.
상기 촉매는 메틸글리옥살 기준 1 mol% 이상으로 사용되는,
젖산 제조 방법.
According to paragraph 1,
The catalyst is used in an amount of 1 mol% or more based on methylglyoxal,
How to make lactic acid.
상기 지방족 또는 방향족 싸이올계 화합물은 메틸글리옥살 대비 0.5 내지 10 당량으로 사용되는,
젖산 제조 방법.
According to paragraph 1,
The aliphatic or aromatic thiol-based compound is used in an amount of 0.5 to 10 equivalents compared to methylglyoxal,
How to make lactic acid.
상기 지방족 또는 방향족 싸이올계 화합물은 벤질 싸이올인,
젖산 제조 방법.
According to paragraph 1,
The aliphatic or aromatic thiol-based compound is benzyl thiol,
How to make lactic acid.
상기 반응은 -30 ℃ 내지 100 ℃에서 진행하는,
젖산 제조 방법.
According to paragraph 1,
The reaction proceeds from -30 ℃ to 100 ℃,
How to make lactic acid.
상기 젖산은 L-락트산 및 D-락트산을 포함하고,
상기 L-락트산 또는 D-락트산의 거울상 이성질체 과잉률이 5% 이상인,
젖산 제조 방법.
According to paragraph 1,
The lactic acid includes L-lactic acid and D-lactic acid,
The enantiomeric excess ratio of the L-lactic acid or D-lactic acid is 5% or more,
How to make lactic acid.
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