KR100639551B1 - Process of the preparation of 5-(substituted phenylalkyl)amino salicylic acid derivatives - Google Patents
Process of the preparation of 5-(substituted phenylalkyl)amino salicylic acid derivatives Download PDFInfo
- Publication number
- KR100639551B1 KR100639551B1 KR1020050068879A KR20050068879A KR100639551B1 KR 100639551 B1 KR100639551 B1 KR 100639551B1 KR 1020050068879 A KR1020050068879 A KR 1020050068879A KR 20050068879 A KR20050068879 A KR 20050068879A KR 100639551 B1 KR100639551 B1 KR 100639551B1
- Authority
- KR
- South Korea
- Prior art keywords
- benzoic acid
- acetoxy
- methyl ester
- acid methyl
- mmole
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 65
- 125000003884 phenylalkyl group Chemical group 0.000 title claims abstract description 22
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical class NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 title abstract description 18
- 238000002360 preparation method Methods 0.000 title description 102
- 230000008569 process Effects 0.000 title description 4
- -1 aminosalicylic acid compound Chemical class 0.000 claims abstract description 56
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 229960004909 aminosalicylic acid Drugs 0.000 claims abstract description 12
- 125000003277 amino group Chemical group 0.000 claims abstract description 6
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims abstract description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 229910000085 borane Inorganic materials 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 229940113720 aminosalicylate Drugs 0.000 abstract description 9
- 229960004963 mesalazine Drugs 0.000 abstract description 9
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 abstract description 8
- 239000000178 monomer Substances 0.000 abstract description 7
- YGCZTXZTJXYWCO-UHFFFAOYSA-N 3-phenylpropanal Chemical compound O=CCCC1=CC=CC=C1 YGCZTXZTJXYWCO-UHFFFAOYSA-N 0.000 abstract description 4
- 238000006268 reductive amination reaction Methods 0.000 abstract description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 100
- 239000007787 solid Substances 0.000 description 93
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 80
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 40
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 34
- DYFBMSXWGMOJAN-UHFFFAOYSA-N methyl 2-acetyloxy-5-aminobenzoate Chemical compound COC(=O)C1=CC(N)=CC=C1OC(C)=O DYFBMSXWGMOJAN-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000005711 Benzoic acid Substances 0.000 description 19
- 235000010233 benzoic acid Nutrition 0.000 description 19
- 239000000543 intermediate Substances 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 229940093499 ethyl acetate Drugs 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 208000012902 Nervous system disease Diseases 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 7
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 208000025966 Neurological disease Diseases 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- DTUQWGWMVIHBKE-UHFFFAOYSA-N phenylacetaldehyde Chemical group O=CCC1=CC=CC=C1 DTUQWGWMVIHBKE-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
- 230000003412 degenerative effect Effects 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 4
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 208000006011 Stroke Diseases 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 150000002466 imines Chemical class 0.000 description 3
- LWISUSRGCCJRSS-UHFFFAOYSA-N methyl 2-acetyloxy-5-(3-phenylpropanoylamino)benzoate Chemical compound COC(C1=C(C=CC(=C1)NC(CCC1=CC=CC=C1)=O)OC(C)=O)=O LWISUSRGCCJRSS-UHFFFAOYSA-N 0.000 description 3
- HJANGZGIPVONLT-UHFFFAOYSA-N methyl 2-acetyloxy-5-[(2-cyclohexylacetyl)amino]benzoate Chemical compound COC(C1=C(C=CC(=C1)NC(CC1CCCCC1)=O)OC(C)=O)=O HJANGZGIPVONLT-UHFFFAOYSA-N 0.000 description 3
- QSUSKDKCSQQOOW-UHFFFAOYSA-N methyl 2-acetyloxy-5-[3-(4-methylphenyl)propanoylamino]benzoate Chemical compound CC1=CC=C(C=C1)CCC(=O)NC2=CC(=C(C=C2)OC(=O)C)C(=O)OC QSUSKDKCSQQOOW-UHFFFAOYSA-N 0.000 description 3
- ASJBNNFCUZPJRL-UHFFFAOYSA-N methyl 2-acetyloxy-5-[3-[4-(trifluoromethyl)phenyl]propanoylamino]benzoate Chemical compound COC(C1=C(C=CC(=C1)NC(CCC1=CC=C(C=C1)C(F)(F)F)=O)OC(C)=O)=O ASJBNNFCUZPJRL-UHFFFAOYSA-N 0.000 description 3
- DUIDWDGWXOMWDG-UHFFFAOYSA-N methyl 2-acetyloxy-5-[3-[4-(trifluoromethyl)phenyl]propylamino]benzoate Chemical compound CC(=O)OC1=C(C=C(C=C1)NCCCC2=CC=C(C=C2)C(F)(F)F)C(=O)OC DUIDWDGWXOMWDG-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000006116 polymerization reaction Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- NTURQZFFJDCTMZ-UHFFFAOYSA-N 1-(2-bromoethyl)-4-nitrobenzene Chemical group [O-][N+](=O)C1=CC=C(CCBr)C=C1 NTURQZFFJDCTMZ-UHFFFAOYSA-N 0.000 description 2
- GXMWLJKTGBZMBH-UHFFFAOYSA-N 2-(2,4-dichlorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(Cl)C=C1Cl GXMWLJKTGBZMBH-UHFFFAOYSA-N 0.000 description 2
- ZVVWZNFSMIFGEP-UHFFFAOYSA-N 2-(4-ethoxyphenyl)acetic acid Chemical compound CCOC1=CC=C(CC(O)=O)C=C1 ZVVWZNFSMIFGEP-UHFFFAOYSA-N 0.000 description 2
- MOMFXATYAINJML-UHFFFAOYSA-N 2-Acetylthiazole Chemical group CC(=O)C1=NC=CS1 MOMFXATYAINJML-UHFFFAOYSA-N 0.000 description 2
- JIGQWPODMPJHFB-UHFFFAOYSA-N 2-aminooxy-5-[3-(4-nitrophenyl)propyl]benzoic acid Chemical compound C1=C(C(O)=O)C(ON)=CC=C1CCCC1=CC=C([N+]([O-])=O)C=C1 JIGQWPODMPJHFB-UHFFFAOYSA-N 0.000 description 2
- NBGAYCYFNGPNPV-UHFFFAOYSA-N 2-aminooxybenzoic acid Chemical class NOC1=CC=CC=C1C(O)=O NBGAYCYFNGPNPV-UHFFFAOYSA-N 0.000 description 2
- BMULRORAIYVLEA-UHFFFAOYSA-N 2-hydroxy-5-[2-(4-nitrophenyl)ethylamino]benzoic acid Chemical compound C1=C(O)C(C(=O)O)=CC(NCCC=2C=CC(=CC=2)[N+]([O-])=O)=C1 BMULRORAIYVLEA-UHFFFAOYSA-N 0.000 description 2
- VNKBKWSRMXEWHM-UHFFFAOYSA-N 2-hydroxy-5-[3-[4-(trifluoromethyl)phenyl]propylamino]benzoic acid Chemical compound C1=C(O)C(C(=O)O)=CC(NCCCC=2C=CC(=CC=2)C(F)(F)F)=C1 VNKBKWSRMXEWHM-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- LEMITQMCXRQLGX-UHFFFAOYSA-N 5-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethylamino]-2-hydroxybenzoic acid Chemical compound C1=C(O)C(C(=O)O)=CC(NCCC=2C=C(F)C(=CC=2)C(F)(F)F)=C1 LEMITQMCXRQLGX-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- FWHYAYNTBAMKQX-UHFFFAOYSA-N COC(C1=C(C(=CC=C1)NC(CC1=CC=C(C=C1)N(C)C)=O)OOC(C)=O)=O Chemical compound COC(C1=C(C(=CC=C1)NC(CC1=CC=C(C=C1)N(C)C)=O)OOC(C)=O)=O FWHYAYNTBAMKQX-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- 238000006845 Michael addition reaction Methods 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 2
- 230000002920 convulsive effect Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- ZGNQYBTXDFCVEW-UHFFFAOYSA-N methyl 2-acetyloxy-5-(2-cyclohexylethylamino)benzoate Chemical compound COC(C1=C(C=CC(=C1)NCCC1CCCCC1)OC(C)=O)=O ZGNQYBTXDFCVEW-UHFFFAOYSA-N 0.000 description 2
- YXGGPGNZJGJJOB-UHFFFAOYSA-N methyl 2-acetyloxy-5-[2-(2-methylphenyl)ethylamino]benzoate Chemical compound COC(C1=C(C=CC(=C1)NCCC1=C(C=CC=C1)C)OC(C)=O)=O YXGGPGNZJGJJOB-UHFFFAOYSA-N 0.000 description 2
- SVEBBEVTCQUNCS-UHFFFAOYSA-N methyl 2-acetyloxy-5-[[2-(2-methylphenyl)acetyl]amino]benzoate Chemical compound COC(C1=C(C=CC(=C1)NC(CC1=C(C=CC=C1)C)=O)OC(C)=O)=O SVEBBEVTCQUNCS-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- QQUGTTJYNYXZSW-UHFFFAOYSA-N 1-(3-bromopropyl)-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(CCCBr)C=C1 QQUGTTJYNYXZSW-UHFFFAOYSA-N 0.000 description 1
- SRXJZMLETPOSSJ-UHFFFAOYSA-N 1-bromo-2-propylbenzene Chemical compound CCCC1=CC=CC=C1Br SRXJZMLETPOSSJ-UHFFFAOYSA-N 0.000 description 1
- UCHCAUUKJXSNAT-UHFFFAOYSA-N 1-nitro-4-prop-2-enylbenzene Chemical compound [O-][N+](=O)C1=CC=C(CC=C)C=C1 UCHCAUUKJXSNAT-UHFFFAOYSA-N 0.000 description 1
- RKSHYZZUJFUXEY-UHFFFAOYSA-N 1-prop-1-enyl-4-(trifluoromethyl)benzene Chemical compound CC=CC1=CC=C(C(F)(F)F)C=C1 RKSHYZZUJFUXEY-UHFFFAOYSA-N 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- QPKZIGHNRLZBCL-UHFFFAOYSA-N 2-(2,4-difluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(F)C=C1F QPKZIGHNRLZBCL-UHFFFAOYSA-N 0.000 description 1
- RPTRFSADOICSSK-UHFFFAOYSA-N 2-(2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC=C1F RPTRFSADOICSSK-UHFFFAOYSA-N 0.000 description 1
- RZWGTXHSYZGXKF-UHFFFAOYSA-N 2-(2-methylphenyl)acetic acid Chemical compound CC1=CC=CC=C1CC(O)=O RZWGTXHSYZGXKF-UHFFFAOYSA-N 0.000 description 1
- YCAKYFIYUHHCKW-UHFFFAOYSA-N 2-(3,4-difluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(F)C(F)=C1 YCAKYFIYUHHCKW-UHFFFAOYSA-N 0.000 description 1
- JVOHBPFLXAVCDU-UHFFFAOYSA-N 2-(3,4-difluorophenyl)propanoic acid Chemical compound OC(=O)C(C)C1=CC=C(F)C(F)=C1 JVOHBPFLXAVCDU-UHFFFAOYSA-N 0.000 description 1
- IGGNSAVLXJKCNH-UHFFFAOYSA-N 2-(3,5-difluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC(F)=CC(F)=C1 IGGNSAVLXJKCNH-UHFFFAOYSA-N 0.000 description 1
- YEAUYVGUXSZCFI-UHFFFAOYSA-N 2-(3-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(F)=C1 YEAUYVGUXSZCFI-UHFFFAOYSA-N 0.000 description 1
- MGKPFALCNDRSQD-UHFFFAOYSA-N 2-(4-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(F)C=C1 MGKPFALCNDRSQD-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- TYOCDHCKTWANIR-UHFFFAOYSA-N 2-[2-(trifluoromethyl)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=CC=C1C(F)(F)F TYOCDHCKTWANIR-UHFFFAOYSA-N 0.000 description 1
- LUIOBGWYVHPKRC-UHFFFAOYSA-N 2-[2-fluoro-4-(trifluoromethyl)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=C(C(F)(F)F)C=C1F LUIOBGWYVHPKRC-UHFFFAOYSA-N 0.000 description 1
- OIVIPAUIJVTMGM-UHFFFAOYSA-N 2-[2-fluoro-5-(trifluoromethyl)phenyl]acetic acid Chemical compound OC(=O)CC1=CC(C(F)(F)F)=CC=C1F OIVIPAUIJVTMGM-UHFFFAOYSA-N 0.000 description 1
- PAWSKKHEEYTXSA-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]acetic acid Chemical compound OC(=O)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 PAWSKKHEEYTXSA-UHFFFAOYSA-N 0.000 description 1
- BLXXCCIBGGBDHI-UHFFFAOYSA-N 2-[3-(trifluoromethyl)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=CC(C(F)(F)F)=C1 BLXXCCIBGGBDHI-UHFFFAOYSA-N 0.000 description 1
- ZFOWDXKJQNNLMW-UHFFFAOYSA-N 2-[3-fluoro-4-(trifluoromethyl)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=C(C(F)(F)F)C(F)=C1 ZFOWDXKJQNNLMW-UHFFFAOYSA-N 0.000 description 1
- LQIBHDUPSIQRPV-UHFFFAOYSA-N 2-[3-fluoro-5-(trifluoromethyl)phenyl]acetic acid Chemical compound OC(=O)CC1=CC(F)=CC(C(F)(F)F)=C1 LQIBHDUPSIQRPV-UHFFFAOYSA-N 0.000 description 1
- ZMTIBXQPXBUWPQ-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=C(OC(F)(F)F)C=C1 ZMTIBXQPXBUWPQ-UHFFFAOYSA-N 0.000 description 1
- MQXZEKTWPSSQAU-UHFFFAOYSA-N 2-[4-[(dimethylamino)methyl]phenyl]acetic acid Chemical compound CN(C)CC1=CC=C(CC(O)=O)C=C1 MQXZEKTWPSSQAU-UHFFFAOYSA-N 0.000 description 1
- BMUFUJMVNODTAD-UHFFFAOYSA-N 2-[4-fluoro-2-(trifluoromethyl)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=C(F)C=C1C(F)(F)F BMUFUJMVNODTAD-UHFFFAOYSA-N 0.000 description 1
- MGQPQAYFSXCYPW-UHFFFAOYSA-N 2-[4-fluoro-3-(trifluoromethyl)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=C(F)C(C(F)(F)F)=C1 MGQPQAYFSXCYPW-UHFFFAOYSA-N 0.000 description 1
- GWWZRGDMAFXULO-UHFFFAOYSA-N 2-[5-fluoro-2-(trifluoromethyl)phenyl]acetic acid Chemical compound OC(=O)CC1=CC(F)=CC=C1C(F)(F)F GWWZRGDMAFXULO-UHFFFAOYSA-N 0.000 description 1
- AAJLPPDFIRPBDA-UHFFFAOYSA-N 2-cyclohexyl-2-phenylacetic acid Chemical compound C=1C=CC=CC=1C(C(=O)O)C1CCCCC1 AAJLPPDFIRPBDA-UHFFFAOYSA-N 0.000 description 1
- BKMYMPRJVYTJMQ-UHFFFAOYSA-N 2-hydroxy-5-[2-(2-methylphenyl)ethylamino]benzoic acid Chemical compound CC1=CC=CC=C1CCNC1=CC=C(O)C(C(O)=O)=C1 BKMYMPRJVYTJMQ-UHFFFAOYSA-N 0.000 description 1
- CMGSFYWEHNDRRO-UHFFFAOYSA-N 2-hydroxy-5-[3-(4-methylphenyl)propylamino]benzoic acid Chemical compound C1=CC(C)=CC=C1CCCNC1=CC=C(O)C(C(O)=O)=C1 CMGSFYWEHNDRRO-UHFFFAOYSA-N 0.000 description 1
- LODHFNUFVRVKTH-ZHACJKMWSA-N 2-hydroxy-n'-[(e)-3-phenylprop-2-enoyl]benzohydrazide Chemical compound OC1=CC=CC=C1C(=O)NNC(=O)\C=C\C1=CC=CC=C1 LODHFNUFVRVKTH-ZHACJKMWSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical group O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- LDYGRLNSOKABMM-UHFFFAOYSA-N 3-(p-tolyl)propionic acid Chemical compound CC1=CC=C(CCC(O)=O)C=C1 LDYGRLNSOKABMM-UHFFFAOYSA-N 0.000 description 1
- XBTCPZFLSHWRKF-UHFFFAOYSA-N 5-(2-cyclohexylethylamino)-2-hydroxybenzoic acid Chemical compound C1(CCCCC1)CCNC=1C=CC(=C(C(=O)O)C1)O XBTCPZFLSHWRKF-UHFFFAOYSA-N 0.000 description 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Natural products OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- WFVQHGKNBHBCTI-UHFFFAOYSA-N [Br].ON=O Chemical compound [Br].ON=O WFVQHGKNBHBCTI-UHFFFAOYSA-N 0.000 description 1
- QHKAWMRUYQORMY-UHFFFAOYSA-N [N+](=O)([O-])C=CC1=CC=CC=C1.[N+](=O)([O-])C1=CC=C(C=C)C=C1 Chemical compound [N+](=O)([O-])C=CC1=CC=CC=C1.[N+](=O)([O-])C1=CC=C(C=C)C=C1 QHKAWMRUYQORMY-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- AIWXJLPLVDPBHE-UHFFFAOYSA-N amino 2-hydroxybenzoate Chemical class NOC(=O)C1=CC=CC=C1O AIWXJLPLVDPBHE-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
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- 239000003814 drug Substances 0.000 description 1
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- ULITUPMHIDVLLV-UHFFFAOYSA-N formonitrile;sodium Chemical compound [Na].N#C ULITUPMHIDVLLV-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- SXRYPFTWTPYPRA-UHFFFAOYSA-N methyl 2-acetyloxy-5-[3-(4-methylphenyl)propylamino]benzoate Chemical compound COC(C1=C(C=CC(=C1)NCCCC1=CC=C(C=C1)C)OC(C)=O)=O SXRYPFTWTPYPRA-UHFFFAOYSA-N 0.000 description 1
- ONWPLBKWMAUFGZ-UHFFFAOYSA-N methyl 2-acetyloxybenzoate Chemical compound COC(=O)C1=CC=CC=C1OC(C)=O ONWPLBKWMAUFGZ-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- CLOXAWYNXXEWBT-UHFFFAOYSA-N tert-butyl n-(3-oxocyclopentyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(=O)C1 CLOXAWYNXXEWBT-UHFFFAOYSA-N 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/44—Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/64—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by singly-bound oxygen atoms
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
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Abstract
Description
도 1은 실시예에서 제조된 2-하이드록시-5-[2-(4-트라이플루오로메틸페네틸아미노)]벤조산의 중간체의 수소 핵자기 공명(H NMR) 스펙트럼.1 is a hydrogen nuclear magnetic resonance (H NMR) spectrum of the intermediate of 2-hydroxy-5- [2- (4-trifluoromethylphenethylamino)] benzoic acid prepared in the Examples.
도 2는 실시예에서 제조된 2-하이드록시-5-[2-(4-트라이플루오로메틸페네틸아미노)]벤조산의 수소 핵자기 공명(H-NMR) 스펙트럼.2 is a hydrogen nuclear magnetic resonance (H-NMR) spectrum of 2-hydroxy-5- [2- (4-trifluoromethylphenethylamino)] benzoic acid prepared in the Examples.
도 3은 실시예에서 제조된 2-하이드록시-5-[2-(4-트라이플루오로메틸페닐프로필아미노)]벤조산의 중간체의 수소 핵자기 공명(H-NMR) 스펙트럼. 3 is a hydrogen nuclear magnetic resonance (H-NMR) spectrum of the intermediate of 2-hydroxy-5- [2- (4-trifluoromethylphenylpropylamino)] benzoic acid prepared in the Example.
도 4는 실시예에서 제조된 2-하이드록시-5-[2-(4-트라이플루오로메틸페닐프로필아미노)]벤조산의 수소 핵자기 공명(H-NMR) 스펙트럼. 4 is a hydrogen nuclear magnetic resonance (H-NMR) spectrum of 2-hydroxy-5- [2- (4-trifluoromethylphenylpropylamino)] benzoic acid prepared in the Examples.
본 발명은 급성 및 퇴행성 뇌신경계 질환의 예방 및 치료에 유용한 하기 화학식Ⅰ로 표시되는 5-(치환된 페닐알킬)아미노살리실산 화합물의 제조방법에 관한 것이다.The present invention relates to a process for the preparation of 5- (substituted phenylalkyl) aminosalicylic acid compounds represented by the following formula (I) useful for the prevention and treatment of acute and degenerative neurological diseases.
<화학식Ⅰ><Formula I>
상기 식 중에서, R은 수소 또는 할로겐(halogen)기, 할로알킬(haloalkyl)기, 니트로(nitro)기, 알킬(alkyl)기, 아릴(aryl)기, 알콕시(alkoxy)기, 아민(amine)기이며, n은 1또는 2로 표현되는 화합물이다. In the above formula, R is a hydrogen or halogen group, haloalkyl group, nitro group, alkyl group, aryl group, alkoxy group, amine group And n is a compound represented by 1 or 2.
대한민국 공개특허 제2003-0058934호에는 5-(치환된 페닐알킬)아미노살리실산화합물이 급성 및 퇴행성 뇌신경계 질환의 예방 및 치료에 유용한 물질로써, 알츠하이머병, 파킨슨씨병 및 헌팅턴씨병 등의 퇴행성 뇌신경계 질환, 간질 등의 경련성 뇌신경계 질환과 뇌졸중 등의 허혈성 뇌신경계 질환의 예방 및 치료 등에 유효한 것으로 기재되어 있어 상기 화합물의 제조는 학계 및 산업계의 관심이 크다.Korean Unexamined Patent Publication No. 2003-0058934 discloses 5- (substituted phenylalkyl) aminosalicylic acid compound as a useful substance for the prevention and treatment of acute and degenerative neurological diseases, including degenerative neurological diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease. It has been described as effective for the prevention and treatment of convulsive neurological diseases such as epilepsy and stroke, and ischemic cerebral nervous system diseases such as stroke.
상기 화합물 제조에 대해서 대한민국 공개특허 제2003-0058934호에 5-(4-나이트로페네틸)아미노살리실산과 5-(4-나이트로페닐프로필)아미노살리실산을 제조 하는 방법이 기재되어 있으며 상세하게는 하기 반응식 I에 도시한 바와 같다.Regarding the preparation of the compound, Korean Patent Publication No. 2003-0058934 discloses a method for preparing 5- (4-nitrophenethyl) aminosalicylic acid and 5- (4-nitrophenylpropyl) aminosalicylic acid. As shown in Scheme I below.
<반응식 I>Scheme I
상기 반응식 I에서는, 5-(4-나이트로페네틸)아미노살리실산과 5-(4-나이트로페닐프로필)아미노살리실산을 아미노살리실산과 2-(4-나이트로페닐)에틸브로마이드 또는 3-(4-나이트로페닐)프로필브로마이드 화합물과의 트리에틸아민과 디메틸포름아마이드 용매 하에서 반응시켜 치환 반응 메커니즘으로 목적물을 제조하는 방법을 보여주고 있다.In Scheme I, 5- (4-nitrophenethyl) aminosalicylic acid and 5- (4-nitrophenylpropyl) aminosalicylic acid are substituted with aminosalicylic acid and 2- (4-nitrophenyl) ethylbromide or 3- (4 Triethylamine with a nitrophenyl) propyl bromide compound and a dimethylformamide solvent are shown to prepare a target product as a substitution reaction mechanism.
그러나 상기 방법으로 제조되는 경우 출발물질인 2-(4-나이트로페닐)에틸브로마이드 또는 3-(4-나이트로페닐)프로필브로마이드 화합물이 아미노살리실산 중의 아민기가 염기로 작용하여 5-(4-나이트로페네틸)아미노살리실산 또는 3-(4-나이트로페닐)프로필브로마이드가 치환 반응(substitution reaction)이 아닌 수소화 브롬으로 제거 반응(elimination reaction) 되어, 하기 화학식Ⅲ의 표현되는 나이트로스티렌(4-nitrostyrene) 혹은 1-알릴-4-나이트로벤젠(1-allyl-4-nitrobenze ne)으로 생성되는 문제점이 있다. 이와 같이 생성된 하기 화학식Ⅲ의 모노머(monom er)는 일반적인 재결정법으로는 제거가 용이하지 않으며, 또한 연속적으로 중합반응(polymerization)이 진행되어 많은 중합체 및 올리고머, 다이머 등 많은 불순물이 생성되고 이를 제거하기 위해서는 컬럼 혹은 증류 등의 복잡한 정제 공정을 거쳐야 하기 때문에, 이에 따른 수율의 감소, 낮은 순도의 목적 화합물 제조 및 제조비용의 상승 등으로 상업적 제조방법으로는 여러 가지 문제점을 내포하고 있다.However, when prepared by the above method, the starting material 2- (4-nitrophenyl) ethylbromide or 3- (4-nitrophenyl) propylbromide compound acts as a base for the amine group in the aminosalicylic acid, resulting in 5- (4-knight Lofenethyl) aminosalicylic acid or 3- (4-nitrophenyl) propylbromide is removed by nitric hydride bromine instead of substitution reaction, whereby nitrostyrene (4- nitrostyrene) or 1-allyl-4-nitrobenzene (1-allyl-4-nitrobenze ne) is a problem that is produced. The monomer of the general formula (III) thus produced is not easy to be removed by a general recrystallization method, and also polymerization is continuously performed to generate a large number of impurities such as many polymers, oligomers, and dimers, and remove them. In order to perform a complex purification process such as column or distillation, there are various problems in the commercial production method due to the reduction of the yield, the production of the target compound of low purity and the increase of the production cost.
<화학식Ⅲ><Formula III>
뿐만 아니라, 대한민국 공개특허 제2003-0058934호에 제시되어 있는 방법으로 진행하기 위해서는 출발물질의 수급에 제한이 많고 특히 상기 방법에서 출발물질로 사용하고 있는 3-(4-나이트로페닐)프로필브로마이드 화합물의 경우 상업적으로 수급에 어려움이 있어 상대적으로 가격이 높기 때문에 결국은 목적하는 화합물에 대한 제조 원가의 상승부분으로 작용하여 산업화에 적용하기 위한 제조 방법을 개발하는 데에 더욱 불리한 요소가 될 수밖에 없다. In addition, in order to proceed with the method disclosed in Korean Patent Laid-Open Publication No. 2003-0058934, there are many restrictions on supply and demand of starting materials, and in particular, 3- (4-nitrophenyl) propyl bromide compound used as starting material in the above method. In the case of the commercial supply and demand is difficult because of the relatively high price in the end will act as a rising part of the manufacturing cost for the desired compound will be further disadvantageous to develop a manufacturing method for applying to industrialization.
이에 본 발명자들은 생산의 용이성과 화학식Ⅲ에서 제시된 모노머(monomer) 생성 문제를 원천적으로 해결하기 위하여 본 발명자들이 연구를 한 결과, 알킬 5-(치환된 페닐알킬)아미노살리실레이트(alkyl 5-(substituted phenylalkyl)amino salicylate)를 중간체로 사용하여 제조함으로써 고 순도 및 고 수율의 목적 화합물을 얻을 수 있음을 확인하고 발명을 완성하였다.Therefore, the inventors of the present inventors have conducted research to solve the problem of the production of monomer and the monomer production presented in the formula (III). As a result, the alkyl 5- (substituted phenylalkyl) aminosalicylate (alkyl 5- ( By using substituted phenylalkyl) amino salicylate) as an intermediate, it was confirmed that the target compound of high purity and high yield was obtained, and the invention was completed.
본 발명의 목적은 불순물로 작용하던 상기 화학식Ⅲ의 모노머(monomer) 생성을 원천적으로 방지한 5-(치환된 페닐알킬)아미노살리실산(5-(substituted phenylalkyl)amino salicylic acid)의 신규 제조방법을 제공하여 상업적 규모로 생산이 가능하고 고 순도 및 고 수율로 목적 화합물을 얻을 수 있는 제조방법을 제공하는데 그 목적이 있다. SUMMARY OF THE INVENTION An object of the present invention is to provide a novel method for preparing 5- (substituted phenylalkyl) amino salicylic acid, which originally prevented the formation of the monomer of Formula III, which acted as an impurity. The purpose of the present invention is to provide a production method that can be produced on a commercial scale and obtain a target compound in high purity and high yield.
상기의 목적을 달성하기 위하여 본 발명은 하기 화학식 II으로 표현되는 알킬 5-(치환된 페닐알킬)아미노살리실레이트(alkyl 5-(substituted phenylalkyl) amino salicylate)를 중간체로 제조한 후, 목적 화합물을 제조하였으며 중간체 제조는 하기 반응식 II에 제시되어 있는 것처럼 세 가지 경로로 제조하였다.In order to achieve the above object, the present invention is to prepare an alkyl 5- (substituted phenylalkyl) amino salicylate represented by the following formula (II) as an intermediate, the target compound Intermediate preparation was made in three routes as shown in Scheme II below.
<화학식Ⅱ><Formula II>
상기 식 중에서, R은 수소 또는 할로겐(halogen)기, 할로알킬(haloalkyl)기, 니트로(nitro)기, 하이드록시(hydroxy)기, 알킬(alkyl)기, 아릴(aryl)기, 알콕시 (alkoxy)기, 아민(amine)기이며, n은 1 또는 2로 표현되며, A는 수소 혹은 알킬이고, B는 수소 혹은 아세틸로 표현되는 화합물이다. Wherein R is a hydrogen or a halogen group, a haloalkyl group, a nitro group, a hydroxy group, an alkyl group, an aryl group, an alkoxy A group is an amine group, n is represented by 1 or 2, A is hydrogen or alkyl, and B is hydrogen or acetyl.
<반응식 II> Scheme II
상기 식 중에서, R은 수소 또는 할로겐(halogen)기, 할로알킬(haloalkyl)기, 니트로(nitro)기, 하이드록시(hydroxy)기, 알킬(alkyl)기, 아릴(aryl)기, 알콕시(alkoxy)기, 아민(amine)기이며, n은 1 또는 2로 표현되고, A는 수소 혹은 알킬이고, B는 수소 혹은 아세틸로 표현되는 화합물이다. Wherein R is hydrogen or a halogen group, haloalkyl group, nitro group, hydroxy group, alkyl group, aryl group, alkoxy Group is an amine group, n is represented by 1 or 2, A is hydrogen or alkyl, and B is hydrogen or acetyl.
상기 공정들을 상세하게 설명하면 다음과 같다. The processes are described in detail as follows.
[경로 1]은 두 단계를 통하여 화학식 II으로 표현되는 중간체를 합성하였다. Path 1 synthesized an intermediate represented by Formula II through two steps.
[경로 1 a]는 상기 식 R로 치환된 2-페닐아세트산 및 3-페닐프로필산을 싸이오닐클로라이드 혹은 삼염화인, 오염화인 등의 무기산 클로라아드를 사용하거나, 혹은 커플링 시약으로 다이싸이클로헥사다이이마이드(dicyclohexylcarbodiimide, 이하 DCC)를 사용하여 알킬 5-아미노살리실산과 에스테르 반응하는 단계,[Path 1 a] is a 2-cycloacetic acid and 3-phenylpropyl acid substituted with the above formula R using thioyl chloride or inorganic acid chlorad such as phosphorus trichloride, phosphorus pentachloride, or dicyclohexan as a coupling reagent. Ester reaction with alkyl 5-aminosalicylic acid using dicyclohexylcarbodiimide (DCC),
[경로 1 b]는 [경로 1 a]에서 제조된 아미드를 보레인을 사용하여 선택적으로 수소화 반응을 하여 중간체를 제조하는 단계로 이루어져 있다.Path 1 b consists of a step of selectively hydrogenating the amide prepared in Path 1 a using borane to prepare an intermediate.
상기 경로의 단계 1에서 커플링 시약으로 다이싸이클로헥사다이이마이드(DCC)를 사용할 경우 상기 식 R로 치환된 2-페닐아세트산 및 3-페닐프로필산 대비 0.8에서 1.5 몰 비를 사용하고 더욱 바람직하게는 1.0 몰비를 사용하고, 촉매로 톨루엔 설폰 산을 상기 식 R로 치환된 2-페닐아세트산 및 3-페닐프로필산 대비 0.1에서 0.5 몰 비를 사용하여 아미드 화합물을 얻었다. 단계 2에서 제조된 아미드를 테트라히드로퓨란 용매에 녹인 후 1몰 농도의 테트라히드로퓨란 표준 용매에 희석된 보레인을 상기 식 R로 치환된 2-페닐아세트산 및 3-페닐프로필산 대비 1에서 3몰 비를 사용하여 화학식 II로 표현되는 중간체를 얻었다. 이때, 반응 온도는 20 ~ 80도에서 실행하였으며 더욱 바람직하게는 50 ~ 70도에서 제조하는 것이다.When dicyclohexadiimide (DCC) is used as the coupling reagent in step 1 of the above route, a molar ratio of 0.8 to 1.5 relative to 2-phenylacetic acid and 3-phenylpropyl acid substituted with the above formula R is used, more preferably. An amide compound was obtained by using a 1.0 molar ratio and using a toluene sulfonic acid as a catalyst from 0.1 to 0.5 molar ratio relative to 2-phenylacetic acid and 3-phenylpropyl acid substituted with the above formula R. The amide prepared in
[경로 2]는 한 단계를 통하여 화학식 II로 표현되는 중간체를 합성하였다.
상기 식 R로 치환된 2-페닐아세트 알데하이드 혹은 3-페닐프로필 알데하이드를 5-아미노-살리실산과 환원 아민화 반응(reductive amination)을 하여 하기 화학식Ⅱ의 알킬 5-(치환된 페닐알킬)아미노살리실레이트(alkyl 5-(substituted phenylalkyl)amino salicylate)의 중간체 화합물을 제조하였다. 이때 5-아미노-살리실산를 상기 식 R로 치환된 2-페닐아세트 알데하이드 혹은 3-페닐프로필 알데하이드를 5-아미노-살리실산 대비 0.8에서 1.2 몰 비를 사용하여 이민이 제조되며 생성된 이민은 분리 없이 인시이튜(insitu)로 수소화 반응하여 중간체를 제조하였다. 이때, 이민을 환원하는 시약으로 시안화수소화 붕소나트륨을 사용하여 고 수율의 중간체 아민을 얻을 수 있었으며 이때 사용한 시안화수소화 붕소나트륨의 몰 비는 R로 치환된 2-페닐아세트 알데하이드 혹은 3-페닐프로필 알데하이드 대비 1에서 3몰 비를 사용하였다.2-phenylacetaldehyde or 3-phenylpropyl aldehyde substituted with the above formula R is subjected to reductive amination with 5-amino-salicylic acid to give an alkyl 5- (substituted phenylalkyl) aminosalicyl of formula (II) Intermediate compounds of the rate (alkyl 5- (substituted phenylalkyl) amino salicylate) were prepared. In this case, imine is prepared using 2-phenylacetaldehyde or 3-phenylpropyl aldehyde substituted with 5-amino-salicylic acid by the above formula R using 0.8 to 1.2 molar ratio of 5-amino-salicylic acid, and the generated imine is in situ without separation. The intermediate was prepared by hydrogenation with (insitu). At this time, a high yield of intermediate amine was obtained using sodium cyanide boride as a reagent for reducing imine, and the molar ratio of sodium cyanide boride used was compared to 2-phenylacetaldehyde or 3-phenylpropyl aldehyde substituted with R. A molar ratio of 1 to 3 was used.
[경로 3]은 마이클 첨가반응(michael addition)을 통해 중간체를 합성했다.
반응식 II에 도시된 바와 같이, 상기 식 R로 치환된 스틸렌 혹은 아릴 벤젠을 5-아미노-살리실산과 마이클 첨가반응(michael addition)을 하여 중간체 화합물을 제조하였다. 이때, 5-아미노-살리실산을 R로 치환된 스틸렌 혹은 아릴 벤젠을 5-아미노-살리실산 대비 1에서 1.5몰 비를 사용하여 중간체를 제조하였다. As shown in Scheme II, an intermediate compound was prepared by Michael addition of styrene or aryl benzene substituted with Formula R with 5-amino-salicylic acid. In this case, an intermediate was prepared using styrene or aryl benzene substituted with 5-amino-salicylic acid with R in a ratio of 1 to 1.5 moles relative to 5-amino-salicylic acid.
이와 같이, 세 가지 경로로 제조된 알킬 5-(치환된 페닐알킬)아미노살리실레이트(alkyl 5-(substituted phenylalkyl)amino salicylate)의 중간체를 염산으로 가수분해하여 목적 화합물을 얻을 수 있다. 이때, 사용되는 염산은 1에서 12몰 농도의 염산을 사용하였으며 사용량은 5-(치환된 페닐알킬)아미노살리실레이트(alkyl 5-(substituted phenylalkyl)amino salicylate) 대비 5 ~ 20 부피비를 사용하여 목적 화합물을 제조하였다. 그리고 반응 온도는 50 ~ 100도에서 제조 가능하며 더욱 바람직하게는 80에서 100도에서 제조하며, 반응 시간은 5시간에서 15시간 반응하여 목적 화합물을 제조하였다. 수득된 화합물을 에틸 아세테이트 또는 디에틸에테르 등의 비양자성 극성 용매를 이용하여 재결정하면 고품질의 상기 화학식 I의 화합물을 얻을 수 있으며, 중간체 제조 및 목적물 제조 과정은 별도의 정제공정을 거치지 않고 연속 공정으로 다음 반응을 진행함으로써 보다 경제적으로 제조를 할 수 있었다.As such, the intermediate of the alkyl 5- (substituted phenylalkyl) amino salicylate prepared by three routes can be hydrolyzed with hydrochloric acid to obtain the target compound. At this time, the hydrochloric acid used was 1 to 12 moles of hydrochloric acid, and the amount used was 5 to 20 volume ratio compared to 5- (substituted phenylalkyl) amino salicylate. The compound was prepared. The reaction temperature may be prepared at 50 to 100 degrees, more preferably at 80 to 100 degrees, and the reaction time is 5 to 15 hours to prepare the target compound. When the obtained compound is recrystallized using an aprotic polar solvent such as ethyl acetate or diethyl ether, a high quality compound of formula (I) can be obtained, and intermediate production and target production can be carried out in a continuous process without undergoing a separate purification process. By proceeding with the next reaction, production could be made more economically.
이와 같이, 본 발명은 선행기술에서 사용된 원료물질과 비교하여 상대적으로 가격이 저렴하며, 모든 공정단계는 이미 일반화된 반응들로 구성되어 전체적으로 온화한 반응조건하에서 진행되어 산업화에 용이한 공정단계로 되어 있음을 특징으로 한다.As such, the present invention is relatively inexpensive compared to the raw materials used in the prior art, and all the process steps are made up of generalized reactions, which are generally processed under mild reaction conditions, and thus are easy to industrialize. It is characterized by the presence.
다음은 본 발명의 실시 예를 들어 보다 구체적으로 설명하고자 한다. 다만, 하기 실시 예는 본 발명의 예시에 불과한 것으로서 본 발명의 범위를 이들로 한정하는 것은 아니다. The following will be described in more detail with reference to embodiments of the present invention. However, the following examples are only examples of the present invention, and the scope of the present invention is not limited thereto.
1. [경로 1]을 이용한 5-(치환된 페닐알킬)아미노살리실산 제조방법 [실시예 1 ~ 93]1. Preparation method of 5- (substituted phenylalkyl) aminosalicylic acid using [Path 1]
<실시예 1> 2-아세톡시-5-[2-(2-트라이플루오로메틸페닐아세틸아미노)]벤조 산메틸에스테르 제조Example 1 Preparation of 2-acetoxy-5- [2- (2-trifluoromethylphenylacetylamino)] benzoic acid methyl ester
질소 대기압하의 실온에서 무수 염화 메틸렌 (30.0 mL)에 2-아세톡시-5-아미노벤조산메틸에스테르(1.06 g, 5.07 mmole)와 2-트라이프루오로메틸페닐아세트산 (1.14 g, 5.57 mmloe), 다이싸이클로헥사카보다이이마이드(DCC)(1.14 g, 5.55 mmole)를 첨가하였다. 반응 혼합액을 실온에서 2시간 동안 교반하였다. 생성된 부유물을 여과하여 제거하고 염화 메틸렌을 감압 하에서 제거하였다. 잔류물을 메탄올/에틸아세테이트/헥산 하에서 재결정함으로써 2-아세톡시-5-[2-(2-트라이플루오로메틸페닐아세틸아미노)]벤조산메틸에스테르 1.84g (91%)를 얻었다. 1H NMR (DMSO-d6) 8.18~8.29 (d,1H), 7.78~7.84 (q,1H), 7.66~7.72 (d, 1H), 7.60~7.66 (t, 1H), 7.50~7.54 (d, 1H), 7.44~7.50 (t, 1H), 7.12~7.20 (d, 1H), 4.80 (s, 2H), 3.80 (s, 3H), 2.25 (s, 3H) 2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole), 2-trifluoromethylphenylacetic acid (1.14 g, 5.57 mmloe), dicyclo, in anhydrous methylene chloride (30.0 mL) at room temperature under nitrogen atmosphere. Hexacarbodiimide (DCC) (1.14 g, 5.55 mmole) was added. The reaction mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered off and methylene chloride was removed under reduced pressure. The residue was recrystallized under methanol / ethyl acetate / hexane to give 1.84 g (91%) of 2-acetoxy-5- [2- (2-trifluoromethylphenylacetylamino)] benzoic acid methyl ester. 1 H NMR (DMSO-d 6 ) 8.18-8.29 (d, 1H), 7.78-7.84 (q, 1H), 7.66-7.72 (d, 1H), 7.60-7.72 (t, 1H), 7.50-7.54 (d , 1H), 7.44-7.50 (t, 1H), 7.12-7.20 (d, 1H), 4.80 (s, 2H), 3.80 (s, 3H), 2.25 (s, 3H)
<실시예 2> 2-아세톡시-5-[2-(2-트라이플루오로메틸페네틸아미노)]벤조산메틸에스테르 제조Example 2 Preparation of 2-acetoxy-5- [2- (2-trifluoromethylphenethylamino)] benzoic acid methyl ester
실온에서 테트라하이드로퓨란 (10.0 mL)에 2-아세톡시-5-[2-(2-트라이플루오로메틸페닐아세틸아미노)]벤조산메틸에스테르 (1.30 g, 3.29 mmole)와 보레인테트라하이드론퓨란 1몰 표준용액 (20.0 mL)을 첨가했다. 그리고 70°C로 2시간동안 가열하였다. 반응 종결 후에 1몰 염산으로 적정한 후, 에틸아세테이트로 추출하고, 소금물로 세척하였다. 유기층은 감압 증류를 통하여 용매를 제거하였다. 잔류물을 메탄올/에틸아세테이트/헥산 하에서 재결정함으로써 2-아세톡시-5-[2-(2-트라이플루오로메틸페네틸아미노)]벤조산메틸에스테르 1.13g (90%)를 흰색 고체로 얻었다. 1H NMR (CDCl6) 7.60~7.68 (d, 1H), 7.44~7.50 (t, 1H), 7.30~7.38 (d, H), 7.16~7.22 (d, 1H), 6.86~6.92 (d, 1H), 6.70~6.77 (q, 1H), 3.84 (s, 3H), 3.38~3.44 (t, 2H), 3.06~3.10 (t, 2H), 2.50 (s, 3H)Tetrahydrofuran (10.0 mL) at room temperature in 2-acetoxy-5- [2- (2-trifluoromethylphenylacetylamino)] benzoic acid methyl ester (1.30 g, 3.29 mmole) and 1 mole of boranetetrahydrofuran Standard solution (20.0 mL) was added. And heated to 70 ° C. for 2 hours. After completion of the reaction, the mixture was titrated with 1 mol hydrochloric acid, extracted with ethyl acetate, and washed with brine. The organic layer was removed from the solvent by distillation under reduced pressure. The residue was recrystallized under methanol / ethylacetate / hexane to give 1.13 g (90%) of 2-acetoxy-5- [2- (2-trifluoromethylphenethylamino)] benzoic acid methyl ester as a white solid. 1 H NMR (CDCl 6 ) 7.60 ~ 7.68 (d, 1H), 7.44 ~ 7.50 (t, 1H), 7.30 ~ 7.38 (d, H), 7.16 ~ 7.22 (d, 1H), 6.86 ~ 6.92 (d, 1H ), 6.70 ~ 6.77 (q, 1H), 3.84 (s, 3H), 3.38 ~ 3.44 (t, 2H), 3.06 ~ 3.10 (t, 2H), 2.50 (s, 3H)
<실시예 3> 2-하이드록시-5-[2-(2-트라이플루오로메틸페네틸아미노)]벤조산 제조Example 3 Preparation of 2-hydroxy-5- [2- (2-trifluoromethylphenethylamino)] benzoic acid
실온에서 6몰 염산 (40.0 mL)에 2-아세톡시-5-[2-(2-트라이플루오로메틸페네틸아미노)]벤조산메틸에스테르 (1.00 g, 3.07 mmole), 페닐아세트산 (10.0 mL)을 첨가하였다. 반응 혼합액을 환류하여 10시간 교반하였다. 진공 하에서 용매를 제거한 후 잔류물을 에테르와 물로 세척하였고, 2-하이드록시-5-[2-(2-트라이플루오로메틸페네틸아미노)]벤조산 0.80g (80%)를 회색 고체로 얻었다. 1H NMR (DMSO-d6) 7.66~7.70 (d, 1H), 7.58~7.64 (t, 1H), 7.50~7.55 (d, 1H), 6.94~7.00 (d, 1H), 6.84~6.90 (q, 1H), 6.72~6.77 (d, 1H), 3.17~3.23 (t, 2H), 2.96~3.02 (t, 2H)2-acetoxy-5- [2- (2-trifluoromethylphenethylamino)] benzoic acid methyl ester (1.00 g, 3.07 mmole) and phenylacetic acid (10.0 mL) were added to 6 mol hydrochloric acid (40.0 mL) at room temperature. Added. The reaction mixture was refluxed and stirred for 10 hours. After removal of the solvent under vacuum the residue was washed with ether and water and 0.80 g (80%) of 2-hydroxy-5- [2- (2-trifluoromethylphenethylamino)] benzoic acid was obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 7.66 ~ 7.70 (d, 1H), 7.58 ~ 7.64 (t, 1H), 7.50 ~ 7.55 (d, 1H), 6.94 ~ 7.00 (d, 1H), 6.84 ~ 6.90 (q , 1H), 6.72 ~ 6.77 (d, 1H), 3.17 ~ 3.23 (t, 2H), 2.96 ~ 3.02 (t, 2H)
<실시예 4> 2-아세톡시-5-[2-(3-트라이플루오로메틸페닐아세틸아미노)]벤조산메틸에스테르 제조Example 4 Preparation of 2-acetoxy-5- [2- (3-trifluoromethylphenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.57 mmole)과 3-트라이플루오로메틸페닐아세트산 (1.14 g, 5.57 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(3-트라이플루오로메틸페닐아세틸아미노)]벤조산메틸에스테르 1.76g (88%)을 흰색 고체로 얻었다. 1H NMR (DMSO-d6) 8.18~8.24 (d, 1H), 7.82~7.86 (q, 1H), 7.69 (s, 1H), 7.59~7.64 (t, 2H), 7.52~7.58 (t, 1H), 7.12~7.19 (d, 1H), 3.85 (s, 2H), 3.80 (s, 3H), 2.25 (s, 3H)2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.57 mmole) with 3-trifluoromethylphenylacetic acid (1.14 g, 5.57 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole) Using the same method as in <Example 1>, 1.76 g (88%) of 2-acetoxy-5- [2- (3-trifluoromethylphenylacetylamino)] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (DMSO-d 6 ) 8.18-8.24 (d, 1H), 7.82-7.86 (q, 1H), 7.69 (s, 1H), 7.59-7.74 (t, 2H), 7.52-7.58 (t, 1H ), 7.12-7.19 (d, 1H), 3.85 (s, 2H), 3.80 (s, 3H), 2.25 (s, 3H)
<실시예 5> 2-아세톡시-5-[2-(3-트라이플루오로메틸페네틸아미노)]벤조산메틸에스테르 제조Example 5 Preparation of 2-acetoxy-5- [2- (3-trifluoromethylphenethylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(3-트라이플루오로메틸페닐아세틸아미노)]벤조산메틸에스테르 (1.50 g, 3.79 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(3-트라이플루오로메틸페네틸아미노)]벤조산메틸에스테르 1.33g (92%)를 흰색 고체로 얻었다. 1H NMR (CDCl6) 7~7.53 (d, 1H) 7.44~7.47 (d, 1H), 7.40~7.44 (d, 1H), 7.35~7.40 (t, 1H), 7.14~7.32 (d, 1H), 6.84~6.92 (d, 1H), 6.69~6.74 (q, 1H), 3.83 (s, 3H), 3.38~3.44 (t, 2H), 2.93~2.98 (t, 2H), 2.30 (s, 3H)2-Acetoxy-5- [2- (3-trifluoromethylphenylacetylamino)] benzoic acid methyl ester (1.50 g, 3.79 mmole) was carried out in the same manner as in <Example 2> to give 2-acetoxy- 1.33 g (92%) of 5- [2- (3-trifluoromethylphenethylamino)] benzoic acid methyl ester were obtained as a white solid. 1 H NMR (CDCl 6 ) 7 ~ 7.53 (d, 1H) 7.44 ~ 7.47 (d, 1H), 7.40 ~ 7.44 (d, 1H), 7.35 ~ 7.40 (t, 1H), 7.14 ~ 7.32 (d, 1H) , 6.84 ~ 6.92 (d, 1H), 6.69 ~ 6.74 (q, 1H), 3.83 (s, 3H), 3.38 ~ 3.44 (t, 2H), 2.93 ~ 2.98 (t, 2H), 2.30 (s, 3H)
<실시예 6> 2-하이드록시-5-[2-(3-트라이플루오로페네틸아미노)]벤조산 제조Example 6 Preparation of 2-hydroxy-5- [2- (3-trifluorophenethylamino)] benzoic acid
2-아세톡시-5-[2-(3-트라이플루오로메틸페네틸아미노)]벤조산메틸에스테르 (1.20 g, 3.69 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(3-트라이플루오로페네틸아미노)]벤조산 0.98g (82%)를 회색 고체로 얻었다. 1H NMR (DMSO-d6) 7.50~7.62 (m, 4H), 7.02 (s, 1H), 6.53~6.58 (d, 1H), 6.44~6.50 (d, 1H), 3.15~3.22 (t, 2H), 2.87~2.94 (t, 2H)2-hydroxy using 2-acetoxy-5- [2- (3-trifluoromethylphenethylamino)] benzoic acid methyl ester (1.20 g, 3.69 mmole) in the same manner as in <Example 3> 0.98 g (82%) of -5- [2- (3-trifluorophenethylamino)] benzoic acid was obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 7.50 ~ 7.62 (m, 4H), 7.02 (s, 1H), 6.53 ~ 6.58 (d, 1H), 6.44 ~ 6.50 (d, 1H), 3.15 ~ 3.22 (t, 2H ), 2.87-2.94 (t, 2H)
<실시예 7> 2-아세톡시-5-[2-(4-트라이플루오로메톡시아세틸아미노)]벤조산메틸에스테르 제조Example 7 Preparation of 2-acetoxy-5- [2- (4-trifluoromethoxyacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 4-트라이플루오로메톡시페닐아세트산(1.21 g, 5.55 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(4-트라이플루오로메톡시아세틸아미노)]벤조산메틸에스테르 1. 72g (77%)를 흰색 고체로 얻었다. 1H NMR (DMSO-d6) 7.14~7.24 (m, 5H), 6.83~6.95 (d, 1H), 6.70~6.75 (m, 1H), 3.95 (s, 2H), 3.85 (s, 3H), 2.32 (s, 3H)2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) with 4-trifluoromethoxyphenylacetic acid (1.21 g, 5.55 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole ) Was prepared in the same manner as in <Example 1>, and 2-acetoxy-5- [2- (4-trifluoromethoxyacetylamino)] benzoic acid methyl ester 1.72g (77%) was obtained as a white solid. Got it. 1 H NMR (DMSO-d 6 ) 7.14 ~ 7.24 (m, 5H), 6.83 ~ 6.95 (d, 1H), 6.70 ~ 6.75 (m, 1H), 3.95 (s, 2H), 3.85 (s, 3H), 2.32 (s, 3 H)
<실시예 8> 2-아세톡시-5-[2-(4-트라이플루오로메톡시페네틸아미노)]벤조산메틸에스테르 제조Example 8 Preparation of 2-acetoxy-5- [2- (4-trifluoromethoxyphenethylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(4-트라이플루오로메톡시아세틸아미노)]벤조산메틸에스테르 (1.50 g, 3.79 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(4-트라이플루오로메톡시페네틸아미노)]벤조산메틸에스테르 1.54g (95%)를 흰색 고체로 얻었다. 1H NMR (CDCl6) 7.14~7.24 (m, 5H), 6.83~6.95 (d, 1H), 6.70~6.75 (m, 1H), 3.85 (s, 3H), 3.33~3.42 (t, 2H), 2.85~2.95 (t, 2H), 2.32 (s, 3H)2-Acetoxy-5- [2- (4-trifluoromethoxyacetylamino)] benzoic acid methyl ester (1.50 g, 3.79 mmole) was carried out in the same manner as in <Example 2> to give 2-acetoxy- 1.54 g (95%) of 5- [2- (4-trifluoromethoxyphenethylamino)] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.14 ~ 7.24 (m, 5H), 6.83 ~ 6.95 (d, 1H), 6.70 ~ 6.75 (m, 1H), 3.85 (s, 3H), 3.33 ~ 3.42 (t, 2H), 2.85-2.95 (t, 2H), 2.32 (s, 3H)
<실시예 9> 2-하이드록시-5-[2-(4-트라이플루오로메톡시페네틸아미노)]벤조산 제조Example 9 Preparation of 2-hydroxy-5- [2- (4-trifluoromethoxyphenethylamino)] benzoic acid
2-아세톡시-5-[2-(4-트라이플루오로메톡시페네틸아미노)]벤조산메틸에스테르 (1.40 g, 3.07 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(4-트라이플루오로메톡시페네틸아미노)]벤조산 1.23g (88%)를 회색 고체로 얻었다. 1H NMR (DMSO-d6) 7.35~7.40 (d, 2H), 7.20~7.26 (d, 2H), 6.95~7.00 (d, 1H), 6.85~6.89 (q, 1H), 6.71~6.80 (d, 1H), 3.27~3.13 (t, 2H), 2.75~2.90 (t, 2H)2-hydroxy using 2-acetoxy-5- [2- (4-trifluoromethoxyphenethylamino)] benzoic acid methyl ester (1.40 g, 3.07 mmole) in the same manner as in <Example 3> 1.23 g (88%) of -5- [2- (4-trifluoromethoxyphenethylamino)] benzoic acid were obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 7.35-7.40 (d, 2H), 7.20-7.26 (d, 2H), 6.95-7.00 (d, 1H), 6.85-6.89 (q, 1H), 6.71-6.80 (d , 1H), 3.27-3.13 (t, 2H), 2.75-2.90 (t, 2H)
<실시예 10> 2-아세톡시-5-[2-(2,4-다이플루오로페닐아세틸아미노)]벤조산메틸에스테르 제조Example 10 Preparation of 2-acetoxy-5- [2- (2,4-difluorophenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 2,4-다이플루오로페닐아세트산 (1.04 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2,4-다이플루오로페닐아세틸아미노)]벤조산메틸에스테르 1.51g (82%) 를 흰색 고체로 얻었다. 1H NMR (DMSO-d6) 7.14~7.18 (d, 1H), 7.08~7.14 (t, 1H), 6.84~6.90 (d, 1H), 6.74~6.82 (m, 2H), 6.66~6.72 (q, 1H), 3.90 (s, 2H), 3.80 (s, 3H), 2.25 (s, 3H)2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) with 2,4-difluorophenylacetic acid (1.04 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 1.5 ml (2-%) of 2-acetoxy-5- [2- (2,4-difluorophenylacetylamino)] benzoic acid methyl ester was prepared by the same method as in <Example 1>. Obtained as a solid. 1 H NMR (DMSO-d 6 ) 7.14 ~ 7.18 (d, 1H), 7.08 ~ 7.14 (t, 1H), 6.84 ~ 6.90 (d, 1H), 6.74 ~ 6.82 (m, 2H), 6.66 ~ 6.72 (q , 1H), 3.90 (s, 2H), 3.80 (s, 3H), 2.25 (s, 3H)
<실시예 11> 2-아세톡시-5-[2-(2,4-다이플루오로페네틸아미노)]벤조산메틸에스테르 제조 <Example 11> Methyl ester of 2-acetoxy-5- [2- (2,4-difluorophenethylamino)] benzoate
2-아세톡시-5-[2-(2,4-다이플루오로페닐아세틸아미노)]벤조산메틸에스테르 (1.30 g, 3.29 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2,4-다이플루오로페네틸아미노)]벤조산메틸에스테르 1.07g (93%)를 흰색 고체로 얻었다. 1H NMR (CDCl6) 7.14~7.18 (d, 1H), 7.08~7.14 (t, 1H), 6.84~6.90 (d, 1H), 6.74~6.82 (m, 2H), 6.66~6.72 (q, 1H), 3.80 (s, 3H), 3.25~3.40 (t, 2H), 2.80~2.90 (t, 2H), 2.25 (s, 3H)2-Acetoxy-5- [2- (2,4-difluorophenylacetylamino)] benzoic acid methyl ester (1.30 g, 3.29 mmole) was used to carry out the same procedure as in <Example 2> to give 2-acetyl. 1.07 g (93%) of methoxy-5- [2- (2,4-difluorophenethylamino)] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.14 ~ 7.18 (d, 1H), 7.08 ~ 7.14 (t, 1H), 6.84 ~ 6.90 (d, 1H), 6.74 ~ 6.82 (m, 2H), 6.66 ~ 6.72 (q, 1H ), 3.80 (s, 3H), 3.25-3.40 (t, 2H), 2.80-2.90 (t, 2H), 2.25 (s, 3H)
<실시예 12> 2-하이드록시-5-[2-(2,4-다이플루오로페네틸아미노)]벤조산의 제조 Example 12 Preparation of 2-hydroxy-5- [2- (2,4-difluorophenethylamino)] benzoic acid
2-아세톡시-5-[2-(2,4-다이플루오로페네틸아미노)]벤조산메틸에스테르 (0.90 g, 3.07 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(2,4-다이플루오로페네틸아미노)]벤조산 0.81g (90%)를 회색 고체로 얻었다. 1H NMR (DMSO-d6) 7.30~7.38 (q, 1H), 7.08~7.16 (m, 1H), 6.94~7.00 (m, 2H), 6.84~6.90 (m, 1H), 6.72~6.76 (d, 1H), 3.10~3.20 (t, 2H), 2.70~2.90 (t, 2H)2-Hydroxy-5- [2- (2,4-difluorophenethylamino)] benzoic acid methyl ester (0.90 g, 3.07 mmole) was used to carry out the same procedure as in <Example 3>. 0.81 g (90%) of oxy-5- [2- (2,4-difluorophenethylamino)] benzoic acid was obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 7.30 ~ 7.38 (q, 1H), 7.08 ~ 7.16 (m, 1H), 6.94 ~ 7.00 (m, 2H), 6.84 ~ 6.90 (m, 1H), 6.72 ~ 6.76 (d , 1H), 3.10-3.20 (t, 2H), 2.70-2.90 (t, 2H)
<실시예 13> 2-아세톡시-5-[2-(3-플루오로페닐아세틸아미노)]벤조산메틸에스테르 제조 Example 13 Preparation of 2-acetoxy-5- [2- (3-fluorophenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 3-플루오로페닐아세트산 (0.93 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(3-플루오로페닐아세틸아미노)]벤조산메틸에스테르 1.65g (94%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 7.10~7.16 (d, 1H), 6.84~6.90 (d, 1H), 6.62~6.74 (m, 5H), 3.95 (s, 2H), 3.80 (s, 3H), 2.30 (s, 3H)2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole), 3-fluorophenylacetic acid (0.93 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole) Using the same method as in <Example 1>, 1.65 g (94%) of 2-acetoxy-5- [2- (3-fluorophenylacetylamino)] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (DMSO-d 6 ) 7.10 ~ 7.16 (d, 1H), 6.84 ~ 6.90 (d, 1H), 6.62 ~ 6.74 (m, 5H), 3.95 (s, 2H), 3.80 (s, 3H), 2.30 (s, 3 H)
<실시예 14> 2-아세톡시-5-[2-(3-플루오로페네틸아미노)]벤조산메틸에스테르 제조Example 14 Preparation of 2-Acetoxy-5- [2- (3-fluorophenethylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(3-플루오로페닐아세틸아미노)]벤조산메틸에스테르 (1.50 g, 3.79 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(3-플루오로페네틸아미노)]벤조산메틸에스테르 1.14g (91%)를 흰색 고체로 얻었다. 1H NMR (CDCl6) 7.10~7.16 (d, 1H), 6.84~6.90 (d, 1H), 6.62~6.74 (m, 5H), 3.80 (s, 3H), 3.30~3.40 (t, 2H), 2.80~2.90 (t, 2H), 2.30 (s, 3H)2-acetoxy-5 was prepared by the same method as in <Example 2>, using 2-acetoxy-5- [2- (3-fluorophenylacetylamino)] benzoic acid methyl ester (1.50 g, 3.79 mmole). 1.14 g (91%) of-[2- (3-fluorophenethylamino)] benzoic acid methyl ester were obtained as a white solid. 1 H NMR (CDCl 6 ) 7.10 ~ 7.16 (d, 1H), 6.84 ~ 6.90 (d, 1H), 6.62 ~ 6.74 (m, 5H), 3.80 (s, 3H), 3.30 ~ 3.40 (t, 2H), 2.80-2.90 (t, 2H), 2.30 (s, 3H)
<실시예 15> 2-하이드록시-5-[2-(3-플루오로페네틸아미노)]벤조산 제조Example 15 Preparation of 2-hydroxy-5- [2- (3-fluorophenethylamino)] benzoic acid
2-아세톡시-5-[2-(3-플루오로페네틸아미노)]벤조산메틸에스테르 (1.00 g, 3.63 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(3-플루오로페네틸아미노)]벤조산 0.85g (85%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 6.93~7.03 (m, 5H), 6.86~6.90 (q, 1H), 6.71~6.75 (d, 1H), 3.10~3.30 (t, 2H), 2.70~2.90 (t, 2H)2-hydroxy-5 was carried out in the same manner as in <Example 3> using 2-acetoxy-5- [2- (3-fluorophenethylamino)] benzoic acid methyl ester (1.00 g, 3.63 mmole) 0.85 g (85%) of-[2- (3-fluorophenethylamino)] benzoic acid were obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 6.93 ~ 7.03 (m, 5H), 6.86 ~ 6.90 (q, 1H), 6.71 ~ 6.75 (d, 1H), 3.10 ~ 3.30 (t, 2H), 2.70 ~ 2.90 (t , 2H)
<실시예 16> 2-아세톡시-5-[2-(3,4-다이플루오로페닐아세틸아미노)]벤조산메틸에스테르 제조 Example 16 Preparation of 2-acetoxy-5- [2- (3,4-difluorophenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 3,4-다이플루오로페닐아세트산 (1.04g, 6.04mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(3,4-다이플루오로페닐아세틸아미노)]벤조산메틸에스테르 1.35g (73%)를 흰색 고체로 얻었다. 1H NMR (DMSO-d6) 7.14~7.20 (d, 1H), 7.04~7.12 (m, 1H), 6.97~7.03 (m, 1H), 6.84~6.93 (m, 2H), 6.68~6.74 (q, 1H), 3.90 (s, 2H), 3.84 (s, 3H), 2.30 (s, 3H)2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) with 3,4-difluorophenylacetic acid (1.04 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 1,35 g (73%) of methyl acetate of 2-acetoxy-5- [2- (3,4-difluorophenylacetylamino)] benzoic acid by the same method as in Example 1 using mmole). Obtained as a solid. 1 H NMR (DMSO-d 6 ) 7.14-7.20 (d, 1H), 7.04-7.72 (m, 1H), 6.97-7.03 (m, 1H), 6.84-6.63 (m, 2H), 6.68-6.74 (q , 1H), 3.90 (s, 2H), 3.84 (s, 3H), 2.30 (s, 3H)
<실시예 17> 2-아세톡시-5-[2-(3,4-다이플루오로페네틸아미노)]벤조산메틸에스테르 제조Example 17 Preparation of 2-acetoxy-5- [2- (3,4-difluorophenethylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(3,4-다이플루오로페닐아세틸아미노)]벤조산메틸에스테르 (1.20 g, 3.04 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(3,4-다이플루오로페네틸아미노)]벤조산메틸에스테르 0.95g (90%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.14~7.20 (d, 1H), 7.04~7.12 (m, 1H), 6.97~7.03 (m, 1H), 6.84~6.93 (m, 2H), 6.68~6.74 (q, 1H), 3.84 (s, 3H), 3.34~3.40 (t, 2H), 2.82~2.90 (t, 2H), 2.30 (s, 3H)2-acetoxy-5- [2- (3,4-difluorophenylacetylamino)] benzoic acid methyl ester (1.20 g, 3.04 mmole) was used to carry out the same procedure as described in <Example 2>. 0.95 g (90%) of methoxy-5- [2- (3,4-difluorophenethylamino)] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.14 ~ 7.20 (d, 1H), 7.04 ~ 7.12 (m, 1H), 6.97 ~ 7.03 (m, 1H), 6.84 ~ 6.93 (m, 2H), 6.68 ~ 6.74 (q, 1H ), 3.84 (s, 3H), 3.34-3.40 (t, 2H), 2.82-2.90 (t, 2H), 2.30 (s, 3H)
<실시예 18> 2-하이드록시-5-[2-(3,4-다이플루오로페네틸아미노)]벤조산의 제조Example 18 Preparation of 2-hydroxy-5- [2- (3,4-difluorophenethylamino)] benzoic acid
2-아세톡시-5-[2-(3,4-다이플루오로페네틸아미노)]벤조산메틸에스테르 (0.80 g, 2.73 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시- 5-[2-(3,4-다이플루오로페네틸아미노)]벤조산 0.65g (81%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 7.20~7.36 (m, 2H), 7.05 (s, 1H), 6.94~7.00 (d, 1H0, 6.84~6.90 (d, 1H), 6.70~6.80 (d, 1H), 3.10~3.20 (t, 1H), 2.70~2.90 (t, 2H)2-Hydroxy-5- [2- (3,4-difluorophenethylamino)] benzoic acid methyl ester (0.80 g, 2.73 mmole) was used in the same manner as in <Example 3> to give 2-hydroxy. 0.65 g (81%) of hydroxy-5 [2- (3,4-difluorophenethylamino)] benzoic acid was obtained as a white solid. 1 H NMR (DMSO-d 6 ) 7.20 ~ 7.36 (m, 2H), 7.05 (s, 1H), 6.94 ~ 7.00 (d, 1H0, 6.84 ~ 6.90 (d, 1H), 6.70 ~ 6.80 (d, 1H) , 3.10-3.20 (t, 1H), 2.70-2.90 (t, 2H)
<실시예 19> 2-아세톡시-5-[2-(3,5-다이플루오로페닐아세틸아미노)]벤조산메틸에스테르 제조 Example 19 Preparation of 2-Acetoxy-5- [2- (3,5-difluorophenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 3,5-다이플루오로페닐아세트산 (1.04g, 6.04mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(3,5-다이플루오로페닐아세틸아미노)]벤조산메틸에스테르 1.63g (88%)를 흰색 고체로 얻었다. 1H NMR (DMSO-d6) 7.20~7.36 (m, 2H), 7.05 (s, 1H), 6.94~7.00 (d, 1H), 6.84~6.90 (d, 1H), 6.70~6.80 (d, 1H), 3.95 (s, 2H), 3.80 (s, 3H), 2.30 (s, 3H)2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) with 3,5-difluorophenylacetic acid (1.04 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 1,63 g (88%) of 2-acetoxy-5- [2- (3,5-difluorophenylacetylamino)] benzoic acid methyl ester was prepared using the same method as in <Example 1>. Obtained as a solid. 1 H NMR (DMSO-d 6 ) 7.20 ~ 7.36 (m, 2H), 7.05 (s, 1H), 6.94 ~ 7.00 (d, 1H), 6.84 ~ 6.90 (d, 1H), 6.70 ~ 6.80 (d, 1H ), 3.95 (s, 2H), 3.80 (s, 3H), 2.30 (s, 3H)
<실시예 20> 2-아세톡시-5-[2-(3,5-다이플루오로페네틸아미노)]벤조산메틸에스테르 제조Example 20 Preparation of 2-acetoxy-5- [2- (3,5-difluorophenethylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(3,5-다이플루오로페닐아세틸아미노)]벤조산메틸에스테르 (1.50 g, 3.79 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세 톡시-5-[2-(3,5-다이플루오로페네틸아미노)]벤조산메틸에스테르 1.26g (95%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.20~7.36 (m, 2H), 7.05 (s, 1H), 6.94~7.00 (d, 1H), 6.84~6.90 (d, 1H), 6.70~6.80 (d, 1H), 3.80 (s, 3H), 3.10~3.20 (t, 1H), 2.70~2.90 (t, 2H), 2.30 (s, 3H)2-acetoxy-5- [2- (3,5-difluorophenylacetylamino)] benzoic acid methyl ester (1.50 g, 3.79 mmole) was used for the same procedure as in <Example 2> to give 2-acetyl. 1.26 g (95%) of methoxy-5- [2- (3,5-difluorophenethylamino)] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.20 ~ 7.36 (m, 2H), 7.05 (s, 1H), 6.94 ~ 7.00 (d, 1H), 6.84 ~ 6.90 (d, 1H), 6.70 ~ 6.80 (d, 1H), 3.80 (s, 3H), 3.10-3.20 (t, 1H), 2.70-2.90 (t, 2H), 2.30 (s, 3H)
<실시예 21> 2-하이드록시-5-[2-(3,5-다이플루오로페네틸아미노)]벤조산 제조Example 21 Preparation of 2-hydroxy-5- [2- (3,5-difluorophenethylamino)] benzoic acid
2-아세톡시-5-[2-(3,5-다이플루오로페네틸아미노)]벤조산메틸에스테르 (1.10 g, 3.75 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(3,5-다이플루오로페네틸아미노)]벤조산 0.90g (82%)를 흰색 고체로 얻었다. 1H NMR (DMSO-d6) 7.26~7.36 (t, 1H), 7.20~7.28 (t, 1H), 7.10~7.14 (q, 1H), 6.98~7.02 (d, 1H), 6.84~6.90 (q. 1H), 6.70~6.78 (d, 1H), 3.10~3.20 (t, 2H), 2.80~2.90 (t, 2H)2-Acetoxy-5- [2- (3,5-difluorophenethylamino)] benzoic acid methyl ester (1.10 g, 3.75 mmole) was used for the same procedure as in <Example 3> to give 2-hydroxy. 0.90 g (82%) of oxy-5- [2- (3,5-difluorophenethylamino)] benzoic acid was obtained as a white solid. 1 H NMR (DMSO-d 6 ) 7.26 ~ 7.36 (t, 1H), 7.20 ~ 7.28 (t, 1H), 7.10 ~ 7.14 (q, 1H), 6.98 ~ 7.02 (d, 1H), 6.84 ~ 6.90 (q 1H), 6.70 ~ 6.78 (d, 1H), 3.10 ~ 3.20 (t, 2H), 2.80 ~ 2.90 (t, 2H)
<실시예 22> 2-아세톡시-5-[2-(2-플루오로페닐아세틸아미노)]벤조산메틸에스테르 제조Example 22 Preparation of 2-Acetoxy-5- [2- (2-fluorophenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 2-플루오로페닐아세트산 (0.93 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2-플루오로페닐아세틸아미노)]벤조산메틸에스테르 1.48g (85%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 7.10~7.18 (d, 1H), 6.84~6.90 (d, 1H), 6.60~6.78 (m, 5H), 3.90 (s, 2H), 3.80 (s, 3H), 2.30 (s, 3H) 2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole), 2-fluorophenylacetic acid (0.93 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole) Using the same method as in <Example 1>, 1.48 g (85%) of 2-acetoxy-5- [2- (2-fluorophenylacetylamino)] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (DMSO-d 6 ) 7.10 ~ 7.18 (d, 1H), 6.84 ~ 6.90 (d, 1H), 6.60 ~ 6.78 (m, 5H), 3.90 (s, 2H), 3.80 (s, 3H), 2.30 (s, 3 H)
<실시예 23> 2-아세톡시-5-[2-(2-플루오로페네틸아미노)]벤조산메틸에스테르 제조Example 23 Preparation of 2-Acetoxy-5- [2- (2-fluorophenethylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(2-플루오로페닐아세틸아미노)]벤조산메틸에스테르 (1.10 g, 2.72 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2-플루오로페네틸아미노)]벤조산메틸에스테르 0.85g (92%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.10~7.18 (d, 1H), 6.84~6.90 (d, 1H), 6.60~6.78 (m, 5H), 3.80 (s, 3H), 3.20~3.40 (t, 2H), 2.70~2.90 (t, 2H), 2.30 (s, 3H) 2-acetoxy-5 by the same method as in <Example 2> using 2-acetoxy-5- [2- (2-fluorophenylacetylamino)] benzoic acid methyl ester (1.10 g, 2.72 mmole) 0.85 g (92%) of-[2- (2-fluorophenethylamino)] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.10 ~ 7.18 (d, 1H), 6.84 ~ 6.90 (d, 1H), 6.60 ~ 6.78 (m, 5H), 3.80 (s, 3H), 3.20 ~ 3.40 (t, 2H), 2.70 ~ 2.90 (t, 2H), 2.30 (s, 3H)
<실시예 24> 2-하이드록시-5-[2-(2-플루오로페네틸아미노)]벤조산 제조Example 24 Preparation of 2-hydroxy-5- [2- (2-fluorophenethylamino)] benzoic acid
2-아세톡시-5-[2-(2-플루오로페네틸아미노)]벤조산메틸에스테르 (0.75 g, 2.72 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(2-플루오로페네틸아미노)]벤조산 0.63g (84%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 6.60~7.10 (m, 5H), 6.83~6.95 (q, 1H), 6.70~6.80 (d, 1H), 3.10~3.30 (t, 2H), 2.70~3.00 (t, 2H)2-hydroxy-5 was carried out in the same manner as in <Example 3> using 2-acetoxy-5- [2- (2-fluorophenethylamino)] benzoic acid methyl ester (0.75 g, 2.72 mmole) 0.63 g (84%) of-[2- (2-fluorophenethylamino)] benzoic acid were obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 6.60 ~ 7.10 (m, 5H), 6.83 ~ 6.95 (q, 1H), 6.70 ~ 6.80 (d, 1H), 3.10 ~ 3.30 (t, 2H), 2.70 ~ 3.00 (t , 2H)
<실시예 25> 2-아세톡시-5-[2-(2,4-다이클로로페닐아세틸아미노)]벤조산메틸에스테르 제조Example 25 Preparation of 2-acetoxy-5- [2- (2,4-dichlorophenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 2,4-다이클로로페닐아세트산 (1.23 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2,4-다이클로로페닐아세틸아미노)]벤조산메틸에스테르 1.63g (81 %)를 흰색 고체로 얻었다. 1H NMR (DMSO-d6) 7.32~7.40 (d, 1H), 7.12~7.20 (m, 2H), 7.08~7.12 (d, 1H), 6.84~6.90 (d, 1H), 6.68~6.72 (q, 1H), 3.95 (s, 2H), 3.80 (s, 3H), 2.25 (s, 3H) 2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) with 2,4-dichlorophenylacetic acid (1.23 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole ) Was prepared in the same manner as in <Example 1>, and 1.63 g (81%) of 2-acetoxy-5- [2- (2,4-dichlorophenylacetylamino)] benzoic acid methyl ester was obtained as a white solid. Got it. 1 H NMR (DMSO-d 6 ) 7.32 ~ 7.40 (d, 1H), 7.12 ~ 7.20 (m, 2H), 7.08 ~ 7.12 (d, 1H), 6.84 ~ 6.90 (d, 1H), 6.68 ~ 6.72 (q , 1H), 3.95 (s, 2H), 3.80 (s, 3H), 2.25 (s, 3H)
<실시예 26> 2-아세톡시-5-[2-(2,4-다이클로로페네틸아미노)]벤조산메틸에스테르 제조Example 26 Preparation of 2-Acetoxy-5- [2- (2,4-dichlorophenethylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(2,4-다이클로로페닐아세틸아미노)]벤조산메틸에스테르 (1.50 g, 3.79 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2,4-다이클로로페네틸아미노)]벤조산메틸에스테르 1.35g (93%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.32~7.40 (d, 1H), 7.12~7.20 (m, 2H), 7.08~7.12 (d, 1H), 6.84~6.90 (d, 1H), 6.68~6.72 (q, 1H), 3.80 (s, 3H), 3.30~3.40 (t, 2H), 2.90~3.00 (t, 2H), 2.25 (s, 3H) 2-acetoxy-5- [2- (2,4-dichlorophenylacetylamino)] benzoic acid methyl ester (1.50 g, 3.79 mmole) was used to carry out the same procedure as described in <Example 2>. 1.35 g (93%) of -5- [2- (2,4-dichlorophenethylamino)] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.32 ~ 7.40 (d, 1H), 7.12 ~ 7.20 (m, 2H), 7.08 ~ 7.12 (d, 1H), 6.84 ~ 6.90 (d, 1H), 6.68 ~ 6.72 (q, 1H ), 3.80 (s, 3H), 3.30-3.40 (t, 2H), 2.90-3.00 (t, 2H), 2.25 (s, 3H)
<실시예 27> 2-하이드록시-5-[2-(2,4-다이클로로페네틸아미노)]벤조산 제조Example 27 Preparation of 2-hydroxy-5- [2- (2,4-dichlorophenethylamino)] benzoic acid
2-아세톡시-5-[2-(2,4-다이클로로페네틸아미노)]벤조산메틸에스테르 (1.25 g, 3.83 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(2,4-다이클로로페네틸아미노)]벤조산 1.06g (85%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.49 (s, 1H), 7.20~7.40 (m, 2H), 6.97~7.10 (d, 1H), 6.80~6.90 (q, 1H), 6.70~6.80 (d, 1H), 3.10~3.30 (s, 2H), 2.80~3.00 (s, 2H)2-hydroxy using 2-acetoxy-5- [2- (2,4-dichlorophenethylamino)] benzoic acid methyl ester (1.25 g, 3.83 mmole) in the same manner as in <Example 3> 1.06 g (85%) of -5- [2- (2,4-dichlorophenethylamino)] benzoic acid were obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 7.49 (s, 1H), 7.20 ~ 7.40 (m, 2H), 6.97 ~ 7.10 (d, 1H), 6.80 ~ 6.90 (q, 1H), 6.70 ~ 6.80 (d, 1H ), 3.10-3.30 (s, 2H), 2.80-3.00 (s, 2H)
<실시예 28> 2-아세톡시-5-[2-(2-메틸페닐)아세틸아미노]벤조산메틸에스테르 제조Example 28 Preparation of 2-acetoxy-5- [2- (2-methylphenyl) acetylamino] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 2-메틸페닐아세트산 (0.91 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC)(1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2-메틸페닐)아세틸아미노]벤조산메틸에스테르 1.57g (76%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 7.10~7.20 (m, 5H), 6.84~6.88 (d, 1H), 6.66~6.72 (q, 1H), 3.95 (s, 2H), 3.80 (s, 3H), 2.35 (s, 3H), 2.26 (s, 3H)2-Acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole), 2-methylphenylacetic acid (0.91 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole) In the same manner as in <Example 1>, 1.57 g (76%) of 2-acetoxy-5- [2- (2-methylphenyl) acetylamino] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (DMSO-d 6 ) 7.10-7.20 (m, 5H), 6.84-6.88 (d, 1H), 6.66-6.72 (q, 1H), 3.95 (s, 2H), 3.80 (s, 3H), 2.35 (s, 3H), 2.26 (s, 3H)
<실시예 29> 2-아세톡시-5-[2-(2-메틸페닐)에틸아미노]벤조산메틸에스테르 제조Example 29 Preparation of 2-acetoxy-5- [2- (2-methylphenyl) ethylamino] benzoic acid methyl ester
2-아세톡시-5-[2-(2-메틸페닐아세틸아미노)]벤조산메틸에스테르 (1.40 g, 3.54 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2-메틸페닐)에틸아미노]벤조산메틸에스테르 1.05g (91%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.10~7.20 (m, 5H), 6.84~6.88 (d, 1H), 6.66~6.72 (q, 1H), 3.80 (s, 3H), 3.25~3.40 (t, 2H), 2.80~3.00 (t, 2H), 2.35 (s, 3H), 2.26 (s, 3H)2-Acetoxy-5- [2- (2-methylphenylacetylamino)] benzoic acid methyl ester (1.40 g, 3.54 mmole) was used to carry out the same procedure as in <Example 2> to give 2-acetoxy-5- [ 1.05 g (91%) of 2- (2-methylphenyl) ethylamino] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.10-7.20 (m, 5H), 6.84-6.88 (d, 1H), 6.66-6.72 (q, 1H), 3.80 (s, 3H), 3.25-3.40 (t, 2H), 2.80-3.00 (t, 2H), 2.35 (s, 3H), 2.26 (s, 3H)
<실시예 30> 2-하이드록시-5-[2-(2-메틸페닐)에틸아미노]벤조산 제조Example 30 Preparation of 2-hydroxy-5- [2- (2-methylphenyl) ethylamino] benzoic acid
2-아세톡시-5-[2-(2-메틸페닐)에틸아미노]벤조산메틸에스테르 (0.95 g, 3.50 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(2-메틸페닐)에틸아미노]벤조산 0.75g (79%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.13~7.20 (d, 1H), 7.00~7.20 (m, 4H), 6.85~6.98 (d, 1H), 6.70~6.80 (d, 1H), 3.10~3.20 (t, 2H), 2.80~2.90 (t, 2H), 2.29 (s, 3H)2-hydroxy-5- [was carried out in the same manner as in <Example 3> using 2-acetoxy-5- [2- (2-methylphenyl) ethylamino] benzoic acid methyl ester (0.95 g, 3.50 mmole). 0.75 g (79%) of 2- (2-methylphenyl) ethylamino] benzoic acid was obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 7.13 ~ 7.20 (d, 1H), 7.00 ~ 7.20 (m, 4H), 6.85 ~ 6.98 (d, 1H), 6.70 ~ 6.80 (d, 1H), 3.10 ~ 3.20 (t , 2H), 2.80-2.90 (t, 2H), 2.29 (s, 3H)
<실시예 31> 2-아세톡시-5-[2-(2-플루오로-3-트라이플루오로메틸페닐아세틸아미노)]벤조산메틸에스테르 제조Example 31 Preparation of 2-Acetoxy-5- [2- (2-fluoro-3-trifluoromethylphenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 2-플루오로-3-트라이플루오로메틸아세트산 (1.34 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2-플루오로-3-트라이플루오로메틸아세틸아미노)]벤조산메틸에스테르 1.61g (77%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 7.42~7.50 (t, 1H), 7.34~7.40 (t, 1H), 7.10~7.18 (m, 2H), 6.84~6.90 (d, 1H), 6.68~6.74 (q, 1H), 3.95 (s, 2H), 3.80 (s. 3H), 2.30 (s, 3H) 2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) and 2-fluoro-3-trifluoromethylacetic acid (1.34 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole) and 1.61 g of 2-acetoxy-5- [2- (2-fluoro-3-trifluoromethylacetylamino)] benzoic acid methyl ester using the same method as in <Example 1>. (77%) was obtained as a white solid. 1 H NMR (DMSO-d 6 ) 7.42 ~ 7.50 (t, 1H), 7.34 ~ 7.40 (t, 1H), 7.10 ~ 7.18 (m, 2H), 6.84 ~ 6.90 (d, 1H), 6.68 ~ 6.74 (q , 1H), 3.95 (s, 2H), 3.80 (s. 3H), 2.30 (s, 3H)
<실시예 32> 2-아세톡시-5-[2-(2-플루오로-3-트라이플루오로메틸페닐아미노)]벤조산메틸에스테르 제조 Example 32 Preparation of 2-Acetoxy-5- [2- (2-fluoro-3-trifluoromethylphenylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(2-플루오로-3-트라이플루오로메틸아세틸아미노)]벤조산메틸에스테르 (1.50 g, 3.79 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2-플루오로-3-트라이플루오로메틸페닐아미노)]벤조산메틸에스테르 1.44g (95%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.42~7.50 (t, 1H), 7.34~7.40 (t, 1H), 7.10~7.18 (m, 2H), 6.84~6.90 (d, 1H), 6.68~6.74 (q, 1H), 3.80 (s. 3H), 3.30~3.40 (t, 2H), 2.90~3.00 (t, 2H), 2.30 (s, 3H) 2-acetoxy-5- [2- (2-fluoro-3-trifluoromethylacetylamino)] benzoic acid methyl ester (1.50 g, 3.79 mmole) was used for the same procedure as in <Example 2> 1.44 g (95%) of 2-acetoxy-5- [2- (2-fluoro-3-trifluoromethylphenylamino)] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.42 ~ 7.50 (t, 1H), 7.34 ~ 7.40 (t, 1H), 7.10 ~ 7.18 (m, 2H), 6.84 ~ 6.90 (d, 1H), 6.68 ~ 6.74 (q, 1H ), 3.80 (s. 3H), 3.30-3.40 (t, 2H), 2.90-3.00 (t, 2H), 2.30 (s, 3H)
<실시예 33> 2-하이드록시-5-[2-(2-플루오로-3-트라이플루오로메틸페닐아미 노)]벤조산 제조 Example 33 Preparation of 2-hydroxy-5- [2- (2-fluoro-3-trifluoromethylphenylamino)] benzoic acid
2-아세톡시-5-[2-(2-플루오로-3-트라이플루오로메틸페닐아미노)]벤조산메틸에스테르 (1.34 g, 3.90 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(2-플루오로-3-트라이플루오로메틸페닐아미노]벤조산 1.19g (89%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.60~7.70 (t, 1H), 7.50~7.60 (t, 1H), 7.07 (s, 1H), 6.90~6.98 (d, 1H) 6.70~6.80 (d, 1H), 3.20~3.30 (t, 2H), 2.90~3.00 (t, 2H)2-acetoxy-5- [2- (2-fluoro-3-trifluoromethylphenylamino)] benzoic acid methyl ester (1.34 g, 3.90 mmole) was used to carry out the same procedure as in <Example 3>. 1.19 g (89%) of -hydroxy-5- [2- (2-fluoro-3-trifluoromethylphenylamino] benzoic acid was obtained as a gray solid, 1 H NMR (DMSO-d 6 ) 7.60 to 7.70 (t , 1H), 7.50 ~ 7.60 (t, 1H), 7.07 (s, 1H), 6.90 ~ 6.98 (d, 1H) 6.70 ~ 6.80 (d, 1H), 3.20 ~ 3.30 (t, 2H), 2.90 ~ 3.00 ( t, 2H)
<실시예 34> 2-아세톡시-5-[2-(3,5-비스트라이플루오로메틸페닐아세틸아미노)]벤조산메틸에스테르 제조 Example 34 Preparation of 2-acetoxy-5- [2- (3,5-bistrifluoromethylphenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 3,5-비스트라이플루오로메틸페닐아세트산 (1.64g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(3,5-비스트라이플루오로메틸페닐아세틸아미노)]벤조산메틸에스테르 1.85g (79%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 8.21 (s, 1H), 8.04 (s, 1H), 7.99 (s, 2H), 7.80~7.83 (d, 1H), 7.10~7.10 (d, 1H), 3.97 (s, 2H), 3.79 (s, 3H), 2.26 (s, 3H)2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) with 3,5-bistrifluoromethylphenylacetic acid (1.64 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole) using the same method as in <Example 1> to give 1.85 g (79%) of 2-acetoxy-5- [2- (3,5-bistrifluoromethylphenylacetylamino)] benzoic acid methyl ester Was obtained as a white solid. 1 H NMR (DMSO-d 6 ) 8.21 (s, 1H), 8.04 (s, 1H), 7.99 (s, 2H), 7.80-7.83 (d, 1H), 7.10-7.10 (d, 1H), 3.97 ( s, 2H), 3.79 (s, 3H), 2.26 (s, 3H)
<실시예 35> 2-아세톡시-5-[2-(3,5-비스트라이플루오로메틸페네틸아미노)]벤조산메틸에스테르의 제조 Example 35 Preparation of 2-Acetoxy-5- [2- (3,5-bistrifluoromethylphenethylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(3,5-비스트라이플루오로메틸페닐아세틸아미노)]벤조산메틸에스테르 (1.60 g, 4.05 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(3,5-비스트라이플루오로메틸페네틸아미노)]벤조산메틸에스테르 1.71g (94%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.77 (s, 1H), 7.60~7.70 (s, 1H), 7.10~7.20 (d, 1H), 6.80~7.00 (d, 1H), 6.60~6.80 (d, 1H), 3.80 (s, 3H), 3.40~3.50 (t, 2H), 3.00~3.10 (t, 2H), 2.30 (s, 3H)2-acetoxy-5- [2- (3,5-bistrifluoromethylphenylacetylamino)] benzoic acid methyl ester (1.60 g, 4.05 mmole) was used for the same procedure as in <Example 2>, and 2- 1.71 g (94%) of acetoxy-5- [2- (3,5-bistrifluoromethylphenethylamino)] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.77 (s, 1H), 7.60 to 7.70 (s, 1H), 7.10 to 7.20 (d, 1H), 6.80 to 7.00 (d, 1H), 6.60 to 6.80 (d, 1H), 3.80 (s, 3H), 3.40-3.50 (t, 2H), 3.00-3.10 (t, 2H), 2.30 (s, 3H)
<실시예 36> 2-하이드록시-5-[2-(3,5-비스트라이플루오로메틸페네틸아미노)]벤조산의 제조 Example 36 Preparation of 2-hydroxy-5- [2- (3,5-bistrifluoromethylphenethylamino)] benzoic acid
2-아세톡시-5-[2-(3,5-비스트라이플루오로메틸페네틸아미노)]벤조산메틸에스테르 (1.60 g, 4.07 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(3,5-비스트라이플루오로메틸페네틸아미노)]벤조산 1.34g (84%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.97 (s, 2H), 7.89 (s, 1H), 7.28 (s, 1H), 7.10~7.20 (t, 1H), 6.80~6.90 (d, 1H), 3.35~3.50 (t, 2H), 3.00~3.16 (t, 2H)2-acetoxy-5- [2- (3,5-bistrifluoromethylphenethylamino)] benzoic acid methyl ester (1.60 g, 4.07 mmole) was used to carry out the same procedure as in <Example 3>. 1.34 g (84%) of -hydroxy-5- [2- (3,5-bistrifluoromethylphenethylamino)] benzoic acid were obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 7.97 (s, 2H), 7.89 (s, 1H), 7.28 (s, 1H), 7.10-7.20 (t, 1H), 6.80-6.70 (d, 1H), 3.35- 3.50 (t, 2H), 3.00-3.16 (t, 2H)
<실시예 37> 5-[2-(4-플루오로페닐프로피오닐아미노)]-2-아세톡시]벤조산메 틸에스테르 제조 Example 37 Preparation of 5- [2- (4-fluorophenylpropionylamino)]-2-acetoxy] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 4-플루오로페닐프로필산 (1.01g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 5-[2-(4-플루오로페닐프로피오닐아미노)]-2-아세톡시]벤조산메틸에스테르 1.52g (81%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 8.16~8.20 (d, 1H), 7.78~7.84 (q, 1H), 7.22~7.30 (t, 2H), 7.12~7.16 (d, 1H), 7.04~7.10 (t, 2H), 3.80 (s, 3H), 2.86~2.94 (t, 2H), 2.60~2.66 (t, 2H), 2.24 (s, 3H) 2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) with 4-fluorophenylpropyl acid (1.01 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole) Was carried out in the same manner as in <Example 1> to obtain 1.52 g (81%) of 5- [2- (4-fluorophenylpropionylamino)]-2-acetoxy] benzoic acid methyl ester as a white solid. . 1 H NMR (DMSO-d 6 ) 8.16-8.20 (d, 1H), 7.78-7.84 (q, 1H), 7.22-7.30 (t, 2H), 7.12-7.16 (d, 1H), 7.04-7.10 (t , 2H), 3.80 (s, 3H), 2.86-2.94 (t, 2H), 2.60-2.66 (t, 2H), 2.24 (s, 3H)
<실시예 38> 5-[2-(4-플루오로페닐프로필아미노)]-2-아세톡시]벤조산메틸에스테르 제조Example 38 Preparation of 5- [2- (4-fluorophenylpropylamino)]-2-acetoxy] benzoic acid methyl ester
5-[2-(4-플루오로페닐프로피오닐아미노)]-2-아세톡시벤조산메틸에스테르 (1.30 g, 3.29 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 5-[2-(4-플루오로페닐프로필아미노)]-2-아세톡시]벤조산메틸에스테르 1.06g (93%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.10~7.20 (m, 3H), 6.95~7.00 (t, 2H), 6.80~6.90 (d, 1H), 6.60~6.70 (q, 1H), 3.80 (s, 3H), 3.00~3.20 (t, 2H), 2.60~2.80 (t, 2H), 2.30 (s, 3H), 1.80~2.00 (q, 2H)5- [2- (4-fluorophenylpropionylamino)]-2-acetoxybenzoic acid methyl ester (1.30 g, 3.29 mmole) was carried out in the same manner as in <Example 1>, and 5- [2- 1.06 g (93%) of (4-fluorophenylpropylamino)]-2-acetoxy] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.10-7.20 (m, 3H), 6.95-7.00 (t, 2H), 6.80-6.70 (d, 1H), 6.60-6.70 (q, 1H), 3.80 (s, 3H), 3.00 ~ 3.20 (t, 2H), 2.60 ~ 2.80 (t, 2H), 2.30 (s, 3H), 1.80 ~ 2.00 (q, 2H)
<실시예 39> 5-[2-(4-플루오로페닐프로필아미노)]-2-하이드록시]벤조산 제조Example 39 Preparation of 5- [2- (4-fluorophenylpropylamino)]-2-hydroxy] benzoic acid
5-[2-(4-플루오로페닐프로필아미노)]-2-아세톡시]벤조산메틸에스테르 (0.90 g, 3.11 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 5-[2-(4-플루오로페닐프로필아미노)]-2-하이드록시]벤조산 0.77g (85%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.10~7.20 (m, 3H), 7.00~7.05 (t, 2H), 6.90~7.00 (d, 1H), 6.73~6.90 (d, 1H), 2.90~3.00 (t, 2H), 2.60~2.70 (t, 2H), 1.75~1.90 (q, 2H)5- [2- (4-fluorophenylpropylamino)]-2-acetoxy] benzoic acid methyl ester (0.90 g, 3.11 mmole) was used for the same procedure as in <Example 3> to give 5- [2- 0.77 g (85%) of (4-fluorophenylpropylamino)]-2-hydroxy] benzoic acid were obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 7.10 ~ 7.20 (m, 3H), 7.00 ~ 7.05 (t, 2H), 6.90 ~ 7.00 (d, 1H), 6.73 ~ 6.90 (d, 1H), 2.90 ~ 3.00 (t , 2H), 2.60-2.70 (t, 2H), 1.75-1.90 (q, 2H)
<실시예 40> 2-아세톡시-5-[2-(4-에톡시페닐아세틸아미노)]벤조산메틸에스테르 제조Example 40 Preparation of 2-acetoxy-5- [2- (4-ethoxyphenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 4-에톡시페닐아세트산 (1.08 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC)(1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(4-에톡시페닐아세틸아미노)]벤조산메틸에스테르 1.49g (79%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 8.20(s, 1H), 7.80~7.90 (q, 1H), 7.20~7.30 (d, 2H), 7.10~7.20 (d, 1), 6.80~6.90 (d, 2H), 3.90~4.00 (m, 2H), 3.80 (s, 3H),3.57 (s, 2H), 2.26 (s, 3H), 1.25~1.35 (t, 3H)2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole), 4-ethoxyphenylacetic acid (1.08 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole) It was carried out in the same manner as in <Example 1> to give 1.49 g (79%) of 2-acetoxy-5- [2- (4-ethoxyphenylacetylamino)] benzoic acid methyl ester as a white solid. 1 H NMR (DMSO-d 6 ) 8.20 (s, 1H), 7.80 ~ 7.90 (q, 1H), 7.20 ~ 7.30 (d, 2H), 7.10 ~ 7.20 (d, 1), 6.80 ~ 6.90 (d, 2H ), 3.90-4.00 (m, 2H), 3.80 (s, 3H), 3.57 (s, 2H), 2.26 (s, 3H), 1.25-1.35 (t, 3H)
<실시예 41> 2-아세톡시-5-[2-(4-에톡시페네틸아미노)]벤조산메틸에스테르의 제조Example 41 Preparation of 2-acetoxy-5- [2- (4-ethoxyphenethylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(4-에톡시페닐아세틸아미노)]벤조산메틸에스테르 (1.30 g, 3.29 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(4-에톡시페네틸아미노)]벤조산메틸에스테르 1.07g (91%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.15~7.20 (d, 2H), 7.06~7.11 (d, 2H), 6.83~6.88 (t, 2H), 6.81 (s, 1H), 6.68~6.72 (q, 1H), 4.00~4.10 (q, 2H), 3.30~3.40 (t, 2H), 2.80~2.90 (t, 2H), 1.30~1.50 (t, 3H) 2-acetoxy-5 by the same method as in <Example 2> using 2-acetoxy-5- [2- (4-ethoxyphenylacetylamino)] benzoic acid methyl ester (1.30 g, 3.29 mmole) 1.07 g (91%) of-[2- (4-ethoxyphenethylamino)] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.15-7.20 (d, 2H), 7.06-7.11 (d, 2H), 6.83-6.88 (t, 2H), 6.81 (s, 1H), 6.68-6.72 (q, 1H), 4.00 ~ 4.10 (q, 2H), 3.30 ~ 3.40 (t, 2H), 2.80 ~ 2.90 (t, 2H), 1.30 ~ 1.50 (t, 3H)
<실시예 42> 2-하이드록시-5-[2-(4-에톡시페네틸아미노)]벤조산의 제조Example 42 Preparation of 2-hydroxy-5- [2- (4-ethoxyphenethylamino)] benzoic acid
2-아세톡시-5-[2-(4-에톡시페네틸아미노)]벤조산메틸에스테르 (0.90 g, 2.99 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(4-에톡시페네틸아미노)]벤조산 0.77g (86%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.10~7.20 (d, 2H), 6.90~7.00 (d, 1H), 6.83~6.90 (q, 1H), 6.80~6.83 (m, 2H), 6.70~6.75 (d, 1H), 3.90~4.00 (q, 2H), 3.10~3.20 (t, 2H), 2.70~2.80 (t, 2H), 1.25~1.35 (q, 3H)2-hydroxy-5 was carried out in the same manner as in <Example 3> using 2-acetoxy-5- [2- (4-ethoxyphenethylamino)] benzoic acid methyl ester (0.90 g, 2.99 mmole) 0.77 g (86%) of-[2- (4-ethoxyphenethylamino)] benzoic acid were obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 7.10 ~ 7.20 (d, 2H), 6.90 ~ 7.00 (d, 1H), 6.83 ~ 6.90 (q, 1H), 6.80 ~ 6.83 (m, 2H), 6.70 ~ 6.75 (d , 1H), 3.90-4.00 (q, 2H), 3.10-3.20 (t, 2H), 2.70-2.80 (t, 2H), 1.25-1.35 (q, 3H)
<실시예 43> 2-아세톡시-5-[2-(3-메틸페닐아세틸아미노)]벤조산메틸에스테르의 제조Example 43 Preparation of 2-acetoxy-5- [2- (3-methylphenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 3-메틸페닐아세트산 (0.91 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(3-메틸페닐아세틸아미노)]벤조산메틸에스테르 1.39g (80%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 8.15~8.24 (d, 1H), 7.82~7.88 (q, 1H), 7.14~7.22 (m, 2H), 7.09~7.14 (m, 2H), 7.00~7.08 (d, 1H), 3.80 (s, 3H), 3.60 (s, 2H), 2.30 (s, 3H), 2.26 (s, 3H)2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole), 3-methylphenylacetic acid (0.91 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole) In the same manner as in <Example 1>, 1.39 g (80%) of 2-acetoxy-5- [2- (3-methylphenylacetylamino)] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (DMSO-d 6 ) 8.15-8.24 (d, 1H), 7.82-7.88 (q, 1H), 7.14-7.22 (m, 2H), 7.09-7.14 (m, 2H), 7.00-7.08 (d , 1H), 3.80 (s, 3H), 3.60 (s, 2H), 2.30 (s, 3H), 2.26 (s, 3H)
<실시예 44> 2-아세톡시-5-[2-(3-메틸페네틸아미노)]벤조산메틸에스테르의 제조Example 44 Preparation of 2-Acetoxy-5- [2- (3-methylphenethylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(3-메틸페닐아세틸아미노)]벤조산메틸에스테르 (1.10 g, 2.78 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(3-메틸페네틸아미노)]벤조산메틸에스테르 0.82g (90%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.10~7.20 (m, 2H), 6.90~7.10 (t, 3H), 6.80~6.90 (d, 1H), 6.70~6.77 (d, 1H), 3.83 (s, 3H), 3.30~3.43 (t, 2H), 2.80~2.90 (t, 2H), 2.34 (s, 3H),2.29 (s, 3H) 2-acetoxy-5- [2- (3-methylphenylacetylamino)] benzoic acid methyl ester (1.10 g, 2.78 mmole) was used to carry out the same procedure as in <Example 2> to give 2-acetoxy-5- [ 0.82 g (90%) of 2- (3-methylphenethylamino)] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.10 ~ 7.20 (m, 2H), 6.90 ~ 7.10 (t, 3H), 6.80 ~ 6.90 (d, 1H), 6.70 ~ 6.77 (d, 1H), 3.83 (s, 3H), 3.30 ~ 3.43 (t, 2H), 2.80 ~ 2.90 (t, 2H), 2.34 (s, 3H), 2.29 (s, 3H)
<실시예 45> 2-하이드록시-5-[2-(3-메틸페네틸아미노)]벤조산의 제조Example 45 Preparation of 2-hydroxy-5- [2- (3-methylphenethylamino)] benzoic acid
2-아세톡시-5-[2-(3-메틸페네틸아미노)]벤조산메틸에스테르 (0.75 g, 2.76 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(3-메틸페네틸아미노)]벤조산 0.64g (85%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.10~7.20 (t, 1H), 6.93~7.10 (m, 4H), 6.83~6.95 (q, 1H), 6.70~6.80 (d, 1H), 3.10~3.25 (t, 2H), 2.70~2.85 (t, 2H), 2.28 (s, 3H) 2-Hydroxy-5- [2- (3-methylphenethylamino)] benzoic acid methyl ester (0.75 g, 2.76 mmole) was carried out in the same manner as in <Example 3>. 0.64 g (85%) of [2- (3-methylphenethylamino)] benzoic acid was obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 7.10-7.20 (t, 1H), 6.93-7.10 (m, 4H), 6.83-6.95 (q, 1H), 6.70-6.80 (d, 1H), 3.10-3.25 (t , 2H), 2.70-2.85 (t, 2H), 2.28 (s, 3H)
<실시예 46> 2-아세톡시-5-[2-(2-트라이플루오로메틸-4-플루오로페닐아세틸아미노)]벤조산메틸에스테르 제조Example 46 Preparation of 2-acetoxy-5- [2- (2-trifluoromethyl-4-fluorophenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 2-트라이플루오로메틸-4-플루오로페닐아세트산 (1.34 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2-트라이플루오로메틸-4-플루오로페닐아세틸아미노)]벤조산메틸에스테르 1.69g (81%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 8.18~8.24 (d, 1H), 7.76~7.82(q, 1H), 7.55~7.62 (m, 2H), 7.50~7.54 (m, 1H), 7.12~7.20 (d, 1H), 3.92 (s, 2H), 3.80 (s, 3H), 2.22~2.28 (s, 3H)2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) with 2-trifluoromethyl-4-fluorophenylacetic acid (1.34 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) ( 1.14 g, 5.55 mmole) was used in the same manner as in <Example 1> to give 2-acetoxy-5- [2- (2-trifluoromethyl-4-fluorophenylacetylamino)] benzoic acid methyl ester 1.69 g (81%) was obtained as a white solid. 1 H NMR (DMSO-d 6 ) 8.18-8.24 (d, 1H), 7.76-7.82 (q, 1H), 7.55-7.82 (m, 2H), 7.50-7.54 (m, 1H), 7.12-7.20 (d , 1H), 3.92 (s, 2H), 3.80 (s, 3H), 2.22-2.28 (s, 3H)
<실시예 47> 2-아세톡시-5-[2-(2-트라이플루오로메틸-4-플루오로페네틸아미노)]벤조산메틸에스테르의 제조Example 47 Preparation of 2-Acetoxy-5- [2- (2-trifluoromethyl-4-fluorophenethylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(2-트라이플루오로메틸-4-플루오로페닐아세틸아미노)]벤조산메틸에스테르 (1.50 g, 3.79 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2-트라이플루오로메틸-4-플루오로페네틸아미노)]벤조산메틸에스테르 1.39g (92%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.30~7.40 (m, 2H), 7.10~7.20 (m, 2H), 6.80~7.00 (d, 1H), 6.70~6.80 (q, 1H), 3.82 (s, 3H), 3.40 (t, 2H), 3.07 (t, 2H), 2.24 (s, 3H)The same procedure as in <Example 2> was carried out using 2-acetoxy-5- [2- (2-trifluoromethyl-4-fluorophenylacetylamino)] benzoic acid methyl ester (1.50 g, 3.79 mmole). This gave 1.39 g (92%) of 2-acetoxy-5- [2- (2-trifluoromethyl-4-fluorophenethylamino)] benzoic acid methyl ester as a white solid. 1 H NMR (CDCl 6 ) 7.30-7.40 (m, 2H), 7.10-7.20 (m, 2H), 6.80-7.00 (d, 1H), 6.70-6.80 (q, 1H), 3.82 (s, 3H), 3.40 (t, 2H), 3.07 (t, 2H), 2.24 (s, 3H)
<실시예 48> 2-하이드록시-5-[2-(2-트라이플루오로메틸-4-플루오로페네틸아미노)]벤조산 제조Example 48 Preparation of 2-hydroxy-5- [2- (2-trifluoromethyl-4-fluorophenethylamino)] benzoic acid
2-아세톡시-5-[2-(2-트라이플루오로메틸-4-플루오로페네틸아미노)]벤조산메틸에스테르 (1.30 g, 3.79 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(2-트라이플루오로메틸-4-플루오로페네틸아미노)]벤조산 1.09g (84%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.90 (s, 1H), 7.60~7.70 (t, 2H), 7.45~7.60 (m, 2H), 7.00~7.10 (d, 1H), 3.40~3.50 (t, 2H), 3.10~3.30 (t, 2H)The same procedure as in Example 3 was carried out using 2-acetoxy-5- [2- (2-trifluoromethyl-4-fluorophenethylamino)] benzoic acid methyl ester (1.30 g, 3.79 mmole). This gave 1.09 g (84%) of 2-hydroxy-5- [2- (2-trifluoromethyl-4-fluorophenethylamino)] benzoic acid as a gray solid. 1 H NMR (DMSO-d 6 ) 7.90 (s, 1H), 7.60-7.70 (t, 2H), 7.45-7.70 (m, 2H), 7.00-7.10 (d, 1H), 3.40-3.50 (t, 2H ), 3.10-3.30 (t, 2H)
<실시예 49> 2-아세톡시-5-(3-페닐프로피오닐아미노)벤조산메틸에스테르의 제조Example 49 Preparation of 2-acetoxy-5- (3-phenylpropionylamino) benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 3-페닐프로피온산 (0.90 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-(3-페닐프로피오닐아미노)벤조산메틸에스테르 1.55g (90%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 8.16~8.22 (d, 1H), 7.80~7.84 (q, 1H), 7.20~7.30 (m, 4H), 7.10~7.20 (m, 2H), 3.80 (s, 3H), 2.88~2.94 (t, 2H), 2.60~2.68 (t, 2H), 2.45 (s, 3H)2-Acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole), 3-phenylpropionic acid (0.90 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole) In the same manner as in <Example 1>, 1.55 g (90%) of 2-acetoxy-5- (3-phenylpropionylamino) benzoic acid methyl ester was obtained as a white solid. 1 H NMR (DMSO-d 6 ) 8.16-8.22 (d, 1H), 7.80-7.84 (q, 1H), 7.20-7.30 (m, 4H), 7.10-7.20 (m, 2H), 3.80 (s, 3H ), 2.88-2.94 (t, 2H), 2.60-2.68 (t, 2H), 2.45 (s, 3H)
<실시예 50> 2-아세톡시-5-(3-페닐프로필아미노)]벤조산메틸에스테르의 제조Example 50 Preparation of 2-acetoxy-5- (3-phenylpropylamino)] benzoic acid methyl ester
2-아세톡시-5-(3-페닐프로피오닐아미노)벤조산메틸에스테르 (1.20 g, 3.04 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-(3-페닐프로필아미노)]벤조산메틸에스테르 0.90g (91%)를 흰색고체로 얻었다. 1H NMR (CDCl6)7.30~7.40 (t, 2H), 7.19~7.23 (m, 3H), 7.10~7.20 (d, 1H), 6.80~7.00 (d, 1H), 6.60~6.80 (q, 1H), 3.90 (s, 3H), 3.10~3.20 (t, 2H), 2.70~2.80 (t, 2H), 2.30 (s, 3H), 1.90~2.00 (q, 2H)2-acetoxy-5- (3-phenylpropionylamino) benzoic acid methyl ester (1.20 g, 3.04 mmole) was used in the same manner as in <Example 2> to give 2-acetoxy-5- (3-phenyl Propylamino)] 0.90 g (91%) of benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.30 to 7.40 (t, 2H), 7.19 to 7.33 (m, 3H), 7.10 to 7.20 (d, 1H), 6.80 to 7.00 (d, 1H), 6.60 to 6.80 (q, 1H ), 3.90 (s, 3H), 3.10-3.20 (t, 2H), 2.70-2.80 (t, 2H), 2.30 (s, 3H), 1.90-2.00 (q, 2H)
<실시예 51> 2-하이드록시-5-(3-페닐프로필아미노)]벤조산의 제조Example 51 Preparation of 2-hydroxy-5- (3-phenylpropylamino)] benzoic acid
2-아세톡시-5-(3-페닐프로필아미노)]벤조산메틸에스테르 (0.80 g, 2.95 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-(3-페닐프로필아미노)]벤조산 0.66g (83%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 7.20~7.40 (m, 2H), 7.10~7.20 (m, 3H), 6.90~7.00 (d, 1H), 6.80~6.90 (m, 1H), 6.60~6.80 (m, 1H), 2.90~3.00 (t, 2H), 2.60~2.70 (q, 2H), 1.70~2.00 (q, 2H)2-Hydroxy-5- (3-phenylpropylamino)] benzoic acid methyl ester (0.80 g, 2.95 mmole) was carried out in the same manner as in <Example 3> to give 2-hydroxy-5- (3-phenyl Propylamino)] 0.66 g (83%) of benzoic acid was obtained as a white solid. 1 H NMR (DMSO-d 6 ) 7.20 ~ 7.40 (m, 2H), 7.10 ~ 7.20 (m, 3H), 6.90 ~ 7.00 (d, 1H), 6.80 ~ 6.90 (m, 1H), 6.60 ~ 6.80 (m , 1H), 2.90-3.00 (t, 2H), 2.60-2.70 (q, 2H), 1.70-2.00 (q, 2H)
<실시예 52> 2-아세톡시-5-[2-(3-트라이플루오로메틸-4-플루오로페닐아세틸아미노)]벤조산메틸에스테르의 제조Example 52 Preparation of 2-acetoxy-5- [2- (3-trifluoromethyl-4-fluorophenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 3-트라이플루오로메틸-4-플루오로페닐아세트산 (1.34 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(3-트라이플루오로메틸-4-플루오로페닐아세틸아미노)]벤조산메틸에스테르 1.51g (72%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 7.36~7.46 (t, 1H), 7.30~7.35 (m, 1H), 7.00~7.20 (m, 2H), 6.80~7.00 (d, 1H), 6.60~6.75 (q, 1H), 3.90 (s, 2H), 3.82 (s, 3H), 2.30 (s, 3H)2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) with 3-trifluoromethyl-4-fluorophenylacetic acid (1.34 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) ( 1.14 g, 5.55 mmole) was used in the same manner as in <Example 1> to give 2-acetoxy-5- [2- (3-trifluoromethyl-4-fluorophenylacetylamino)] benzoic acid methyl ester 1.51 g (72%) was obtained as a white solid. 1 H NMR (DMSO-d6) 7.36-7.46 (t, 1H), 7.30-7.35 (m, 1H), 7.00-7.20 (m, 2H), 6.80-7.00 (d, 1H), 6.60-6.65 (q, 1H), 3.90 (s, 2H), 3.82 (s, 3H), 2.30 (s, 3H)
<실시예 53> 2-아세톡시-5-[2-(3-트라이플루오로메틸-4-플루오로페네틸아미노)]벤조산메틸에스테르의 제조Example 53 Preparation of 2-acetoxy-5- [2- (3-trifluoromethyl-4-fluorophenethylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(3-트라이플루오로메틸-4-플루오로페닐아세틸아미노)]벤조산메틸에스테르 (1.20 g, 3.04 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(3-트라이플루오로메틸-4-플루오로페네틸아미노)]벤조산메틸에스테르 1.13g (93%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.36~7.46 (t, 1H), 7.30~7.35 (m, 1H), 7.00~7.20 (m, 2H), 6.80~7.00 (d, 1H), 6.60~6.75 (q, 1H), 3.82 (s, 3H), 3.30~3.40 (t, 2H), 2.80~2.95 (t, 2H), 2.30 (s, 3H)It was carried out in the same manner as in <Example 2> using 2-acetoxy-5- [2- (3-trifluoromethyl-4-fluorophenylacetylamino)] benzoic acid methyl ester (1.20 g, 3.04 mmole) This gave 1.13 g (93%) of 2-acetoxy-5- [2- (3-trifluoromethyl-4-fluorophenethylamino)] benzoic acid methyl ester as a white solid. 1 H NMR (CDCl 6 ) 7.36 ~ 7.46 (t, 1H), 7.30 ~ 7.35 (m, 1H), 7.00 ~ 7.20 (m, 2H), 6.80 ~ 7.00 (d, 1H), 6.60 ~ 6.75 (q, 1H ), 3.82 (s, 3H), 3.30-3.40 (t, 2H), 2.80-2.95 (t, 2H), 2.30 (s, 3H)
<실시예 54> 2-하이드록시-5-[2-(3-트라이플루오로메틸-4-플루오로페네틸아미노)]벤조산의 제조Example 54 Preparation of 2-hydroxy-5- [2- (3-trifluoromethyl-4-fluorophenethylamino)] benzoic acid
2-아세톡시-5-[2-(3-트라이플루오로메틸-4-플루오로페네틸아미노)]벤조산메틸에스테르 (1.00 g, 2.91 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(3-트라이플루오로메틸-4-플루오로페네틸아미노)]벤조산 0.85g (85%) 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.50~7.65 (t, 2H), 7.25~7.40 (t, 1H), 7.05 (s, 1H), 6.85~6.97 (d, 1H), 6.70~6.80 (d, 1H), 3.20~3.30 (t, 2H), 2.83~3.00 (t, 2H)2-acetoxy-5- [2- (3-trifluoromethyl-4-fluorophenethylamino)] benzoic acid methyl ester (1.00 g, 2.91 mmole) was used in the same manner as in <Example 3>. 0.85-g (85%) gray solid of 2-hydroxy-5- [2- (3-trifluoromethyl-4-fluorophenethylamino)] benzoic acid was obtained. 1 H NMR (DMSO-d 6 ) 7.50 ~ 7.65 (t, 2H), 7.25 ~ 7.40 (t, 1H), 7.05 (s, 1H), 6.85 ~ 6.97 (d, 1H), 6.70 ~ 6.80 (d, 1H ), 3.20-3.30 (t, 2H), 2.83-3.00 (t, 2H)
<실시예 55> 2-아세톡시-5-[2-(3-트라이플루오로메틸-5-플루오로페닐아세틸아미노)]벤조산메틸에스테르의 제조Example 55 Preparation of 2-acetoxy-5- [2- (3-trifluoromethyl-5-fluorophenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 3-트라이플루오로메틸-5-플루오로페닐아세트산 (1.34 g, 6.04 mmole), 다이싸이클로헥사카 보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(3-트라이플루오로메틸-5-플루오로페닐아세틸아미노)]벤조산메틸에스테르 1.72g (82%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 7.23 (s, 1H), 7.14~7.18 (d, 1H), 7.10~7.15 (d, 1H), 7.00~7.10 (d, 1H), 6.80~6.90 (d, 1H), 6.60~6.70 (q, 1H), 3.90 (s, 2H), 3.81 (s, 3H), 2.30 (s, 3H)2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) with 3-trifluoromethyl-5-fluorophenylacetic acid (1.34 g, 6.04 mmole), dicyclohexacarbaimide (DCC) (1.14 g, 5.55 mmole) was used in the same manner as in <Example 1> to give 2-acetoxy-5- [2- (3-trifluoromethyl-5-fluorophenylacetylamino)] methyl benzoate 1.72 g (82%) of ester were obtained as a white solid. 1 H NMR (DMSO-d 6 ) 7.23 (s, 1H), 7.14 ~ 7.18 (d, 1H), 7.10 ~ 7.15 (d, 1H), 7.00 ~ 7.10 (d, 1H), 6.80 ~ 6.90 (d, 1H ), 6.60-6.70 (q, 1H), 3.90 (s, 2H), 3.81 (s, 3H), 2.30 (s, 3H)
<실시예 56> 2-아세톡시-5-[2-(3-트라이플루오로메틸-5-플루오로페네틸아미노)]벤조산메틸에스테르의 제조 Example 56 Preparation of 2-Acetoxy-5- [2- (3-trifluoromethyl-5-fluorophenethylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(3-트라이플루오로메틸-5-플루오로페닐아세틸아미노)]벤조산메틸에스테르 (1.50 g, 3.79 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(3-트라이플루오로메틸-5-플루오로페네틸아미노)]벤조산메틸에스테르 1.42g (94%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.23 (s, 1H), 7.14~7.18 (d, 1H), 7.10~7.15 (d, 1H), 7.00~7.10 (d, 1H), 6.80~6.90 (d, 1H), 6.60~6.70 (q, 1H), 3.81 (s, 3H), 3.25~3.38 (t, 2H), 2.80~2.90 (t, 2H), 2.30 (s, 3H)It was carried out in the same manner as in <Example 2> using 2-acetoxy-5- [2- (3-trifluoromethyl-5-fluorophenylacetylamino)] benzoic acid methyl ester (1.50 g, 3.79 mmole) To obtain 1.42 g (94%) of methyl 2-acetoxy-5- [2- (3-trifluoromethyl-5-fluorophenethylamino)] benzoic acid as a white solid. 1 H NMR (CDCl 6 ) 7.23 (s, 1H), 7.14-7.18 (d, 1H), 7.10-7.15 (d, 1H), 7.00-7.10 (d, 1H), 6.80-6.70 (d, 1H), 6.60-6.70 (q, 1H), 3.81 (s, 3H), 3.25-3.38 (t, 2H), 2.80-2.90 (t, 2H), 2.30 (s, 3H)
<실시예 57> 2-하이드록시-5-[2-(3-트라이플루오로메틸-5-플루오로페네틸아미노)]벤조산의 제조Example 57 Preparation of 2-hydroxy-5- [2- (3-trifluoromethyl-5-fluorophenethylamino)] benzoic acid
2-아세톡시-5-[2-(3-트라이플루오로메틸-5-플루오로페네틸아미노)]벤조산메틸에스테르 (1.30 g, 3.79 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(3-트라이플루오로메틸-5-플루오로페네틸아미노)]벤조산 1.13g (87%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.80 (s, 1H), 7.50~7.60 (q, 1H), 7.44~7.50 (m, 2H), 7.35~7.46 (d, 2H), 6.90~7.00 (d, 1H), 3.50~3.40 (t, 2H), 3.10~3.20 (t, 2H)The same procedure as in Example 3 was carried out using 2-acetoxy-5- [2- (3-trifluoromethyl-5-fluorophenethylamino)] benzoic acid methyl ester (1.30 g, 3.79 mmole). This gave 1.13 g (87%) of 2-hydroxy-5- [2- (3-trifluoromethyl-5-fluorophenethylamino)] benzoic acid as a gray solid. 1 H NMR (DMSO-d 6 ) 7.80 (s, 1H), 7.50-7.70 (q, 1H), 7.44-7.50 (m, 2H), 7.35-7.46 (d, 2H), 6.90-7.00 (d, 1H ), 3.50-3.40 (t, 2H), 3.10-3.20 (t, 2H)
<실시예 58> 5-[2-(3,4-다이플루오로페닐프로피오닐아미노)]-2-아세톡시]벤조산메틸에스테르의 제조Example 58 Preparation of 5- [2- (3,4-difluorophenylpropionylamino)]-2-acetoxy] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 3,4-다이플루오로페닐프로피온산 (1.03 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 5-[2-(3,4-다이플루오로페닐프로피오닐아미노)]-2-아세톡시]벤조산메틸에스테르 1.49g (81%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 7.00~7.17 (q, 2H), 6.90~7.00 (q, 2H), 6.80~6.93 (d, 1H), 6.60~6.70 (q, 1H), 3.82 (s, 3H), 3.00~3.20 (t, 2H), 2.60~2.70 (t, 2H), 2.29 (s, 3H), 1.90~2.00(q, 2H)2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) with 3,4-difluorophenylpropionic acid (1.03 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 1.49 g (81%) of 5- [2- (3,4-difluorophenylpropionylamino)]-2-acetoxy] benzoic acid methyl ester by the same method as in Example 1 using mmole). Was obtained as a white solid. 1 H NMR (DMSO-d 6 ) 7.00 ~ 7.17 (q, 2H), 6.90 ~ 7.00 (q, 2H), 6.80 ~ 6.93 (d, 1H), 6.60 ~ 6.70 (q, 1H), 3.82 (s, 3H ), 3.00-3.20 (t, 2H), 2.60-2.70 (t, 2H), 2.29 (s, 3H), 1.90-2.00 (q, 2H)
<실시예 59> 5-[2-(3,4-다이플루오로페닐프로필아미노)]-2-아세톡시]벤조산 메틸에스테르의 제조Example 59 Preparation of 5- [2- (3,4-difluorophenylpropylamino)]-2-acetoxy] benzoic acid methyl ester
5-[2-(3,4-다이플루오로페닐프로피오닐아미노)]-2-아세톡시]벤조산메틸에스테르 (1.30 g, 3.29 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 5-[2-(3,4-다이플루오로페닐프로필아미노)]-2-아세톡시]벤조산메틸에스테르 1.09g (95%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.09~7.12 (d, 1H), 6.92~7.07 (m, 2H), 6.82~6.87 (d, 2H), 6.62~6.67 (q, 1H), 3.82 (s, 3H), 3.00~3.10 (t, 2H), 2.60~2.70 (t, 2H), 2.29 (s, 3H), 1.80~1.90 (s, 2H)5- [2- (3,4-Difluorophenylpropionylamino)]-2-acetoxy] benzoic acid methyl ester (1.30 g, 3.29 mmole) was used for the same procedure as in <Example 2>. 1.09 g (95%) of-[2- (3,4-difluorophenylpropylamino)]-2-acetoxy] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.09 ~ 7.12 (d, 1H), 6.92 ~ 7.07 (m, 2H), 6.82 ~ 6.87 (d, 2H), 6.62 ~ 6.67 (q, 1H), 3.82 (s, 3H), 3.00 ~ 3.10 (t, 2H), 2.60 ~ 2.70 (t, 2H), 2.29 (s, 3H), 1.80 ~ 1.90 (s, 2H)
<실시예 60> 5-[2-(3,4-다이플루오로페닐프로필아미노)]-2-하이드록시]벤조산의 제조Example 60 Preparation of 5- [2- (3,4-difluorophenylpropylamino)]-2-hydroxy] benzoic acid
5-[2-(3,4-다이플루오로페닐프로필아미노)]-2-아세톡시]벤조산메틸에스테르 (1.00 g, 3.41 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 5-[2-(3,4-다이플루오로페닐프로필아미노)]-2-하이드록시]벤조산 0.89g (89%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.20~7.30 (t, 2H), 7.00~7.10 (d, 2H), 6.80~6.90 (q, 1H), 6.70~6.80 (d, 1H), 2.90~3.00 (t, 2H), 2.60~2.70 (t, 2H), 1.70~1.90 (q, 2H)5- [2- (3,4-Difluorophenylpropylamino)]-2-acetoxy] benzoic acid methyl ester (1.00 g, 3.41 mmole) was used for the same procedure as in <Example 3>, and 5- 0.89 g (89%) of [2- (3,4-difluorophenylpropylamino)]-2-hydroxy] benzoic acid were obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 7.20 ~ 7.30 (t, 2H), 7.00 ~ 7.10 (d, 2H), 6.80 ~ 6.90 (q, 1H), 6.70 ~ 6.80 (d, 1H), 2.90 ~ 3.00 (t , 2H), 2.60-2.70 (t, 2H), 1.70-1.90 (q, 2H)
<실시예 61> 2-아세톡시-5-[2-(나프테닐-2일)아세틸아미노]벤조산메틸에스테 르의 제조Example 61 Preparation of 2-acetoxy-5- [2- (naphthenyl-2yl) acetylamino] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 2-나프테닐페닐아세트산 (1.12 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.12 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(나프테닐-2일)아세틸아미노]벤조산메틸에스테르 1.61g (84%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 7.70~7.80 (t, 3H), 7.56 (s, 1H), 7.30~7.46 (q, 2H), 7.20~7.30 (d, 1H), 7.10~7.18 (d, 1H), 6.80~6.85 (d, 1H), 6.55~6.65 (q, 1H), 3.85 (s, 2H), 3.77 (s, 3H), 2.26 (s, 3H) 2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole), 2-naphthenylphenylacetic acid (1.12 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.12 g, 5.55 mmole) Was carried out in the same manner as in <Example 1> to obtain 1.61 g (84%) of 2-acetoxy-5- [2- (naphthenyl-2 yl) acetylamino] benzoic acid methyl ester as a white solid. 1 H NMR (DMSO-d 6 ) 7.70 ~ 7.80 (t, 3H), 7.56 (s, 1H), 7.30 ~ 7.46 (q, 2H), 7.20 ~ 7.30 (d, 1H), 7.10 ~ 7.18 (d, 1H ), 6.80-6.85 (d, 1H), 6.55-6.65 (q, 1H), 3.85 (s, 2H), 3.77 (s, 3H), 2.26 (s, 3H)
<실시예 62> 2-아세톡시-5-[2-(나프테닐-2일)에틸아미노]벤조산메틸에스테르의 제조Example 62 Preparation of 2-acetoxy-5- [2- (naphthenyl-2 yl) ethylamino] benzoic acid methyl ester
2-아세톡시-5-(2-나프테닐아세틸아미노)벤조산메틸에스테르 (1.50 g, 3.79 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(나프테닐-2일)에틸아미노]벤조산메틸에스테르 1.24g (90%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.70~7.80 (t, 3H), 7.56 (s, 1H), 7.30~7.46 (q, 2H), 7.20~7.30 (d, 1H), 7.10~7.18 (d, 1H), 6.80~6.85 (d, 1H), 6.55~6.65 (q, 1H), 3.77 (s, 3H), 3.30~3.40 (t, 2H), 2.90~3.00 (t, 2H), 2.26 (s, 3H) 2-acetoxy-5- (2-naphthenylacetylamino) benzoic acid methyl ester (1.50 g, 3.79 mmole) was used in the same manner as in <Example 2> to give 2-acetoxy-5- [2- ( Naphthenyl-2 yl) ethylamino] benzoic acid methyl ester 1.24 g (90%) was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.70-7.80 (t, 3H), 7.56 (s, 1H), 7.30-7.46 (q, 2H), 7.20-7.30 (d, 1H), 7.10-7.18 (d, 1H), 6.80 ~ 6.85 (d, 1H), 6.55 ~ 6.65 (q, 1H), 3.77 (s, 3H), 3.30 ~ 3.40 (t, 2H), 2.90 ~ 3.00 (t, 2H), 2.26 (s, 3H)
<실시예 63> 2-하이드록시-5-[2-(나프테닐-2일)에틸아미노]벤조산의 제조Example 63 Preparation of 2-hydroxy-5- [2- (naphthenyl-2yl) ethylamino] benzoic acid
2-아세톡시-5-[2-(나프테닐-2일)에틸아미노]벤조산메틸에스테르 (1.10 g, 3.58 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(나프테닐-2일)에틸아미노]벤조산 0.87g (79%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.80~7.90 (m, 3H), 7.74 (s, 1H), 7.35~7.50 (m, 3H), 7.08 (s, 1H), 6.90~7.00 (q, 1H), 6.72~6.80 (d, 1H), 3.25~3.40 (t, 2H), 2.95~3.10 (t, 2H) 2-hydroxy-5 was carried out in the same manner as in <Example 3> using 2-acetoxy-5- [2- (naphthenyl-2yl) ethylamino] benzoic acid methyl ester (1.10 g, 3.58 mmole) 0.87 g (79%) of [2- (naphthenyl-2 yl) ethylamino] benzoic acid were obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 7.80 to 7.90 (m, 3H), 7.74 (s, 1H), 7.35 to 7.50 (m, 3H), 7.08 (s, 1H), 6.90 to 7.00 (q, 1H), 6.72 ~ 6.80 (d, 1H), 3.25-3.40 (t, 2H), 2.95-3.10 (t, 2H)
<실시예 64> 2-아세톡시-5-[2-(2-플루오로-4-트라이플루오로메틸페닐아세틸아미노)]벤조산메틸에스테르의 제조Example 64 Preparation of 2-acetoxy-5- [2- (2-fluoro-4-trifluoromethylphenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 2-플루오로-4-트라이플루오로메틸페닐아세트산 (1.34 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2-플루오로-4-트라이플루오로메틸페닐아세틸아미노)]벤조산메틸에스테르 1.59g (76%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 7.22~7.40 (m, 3H), 7.10~7.20 (d, 1H), 6.80~6.90 (d, 1H), 6.64~6.77 (q, 1H), 3.90 (s, 2H), 3.83 (s, 3H), 2.30 (s, 3H)2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) with 2-fluoro-4-trifluoromethylphenylacetic acid (1.34 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole) and 1.59 g of 2-acetoxy-5- [2- (2-fluoro-4-trifluoromethylphenylacetylamino)] benzoic acid methyl ester using the same method as in <Example 1>. (76%) was obtained as a white solid. 1 H NMR (DMSO-d 6 ) 7.22 ~ 7.40 (m, 3H), 7.10 ~ 7.20 (d, 1H), 6.80 ~ 6.90 (d, 1H), 6.64 ~ 6.77 (q, 1H), 3.90 (s, 2H ), 3.83 (s, 3H), 2.30 (s, 3H)
<실시예 65> 2-아세톡시-5-[2-(2-플루오로-4-트라이플루오로메틸페네틸아미노)]벤조산메틸에스테르의 제조Example 65 Preparation of 2-acetoxy-5- [2- (2-fluoro-4-trifluoromethylphenethylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(2-플루오로-4-트라이플루오로메틸페닐아세틸아미노)]벤조산메틸에스테르 (1.50 g, 3.79 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2-플루오로-4-트라이플루오로메틸페네틸아미노)]벤조산메틸에스테르 1.35g (89%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.22~7.40 (m, 3H), 7.10~7.20 (d, 1H), 6.80~6.90 (d, 1H), 6.64~6.77 (q, 1H), 3.83 (s, 3H), 3.30~3.40 (t, 2H), 2.90~3.00 (t, 2H), 2.30 (s, 3H)2-acetoxy-5- [2- (2-fluoro-4-trifluoromethylphenylacetylamino)] benzoic acid methyl ester (1.50 g, 3.79 mmole) was used in the same manner as in <Example 2> 1.35 g (89%) of 2-acetoxy-5- [2- (2-fluoro-4-trifluoromethylphenethylamino)] benzoic acid methyl ester were obtained as a white solid. 1 H NMR (CDCl 6 ) 7.22 ~ 7.40 (m, 3H), 7.10 ~ 7.20 (d, 1H), 6.80 ~ 6.90 (d, 1H), 6.64 ~ 6.77 (q, 1H), 3.83 (s, 3H), 3.30 ~ 3.40 (t, 2H), 2.90 ~ 3.00 (t, 2H), 2.30 (s, 3H)
<실시예 66> 2-하이드록시-5-[2-(2-플루오로-4-트라이플루오로메틸페네틸아미노)]벤조산의 제조Example 66 Preparation of 2-hydroxy-5- [2- (2-fluoro-4-trifluoromethylphenethylamino)] benzoic acid
2-아세톡시-5-[2-(2-플루오로-4-트라이플루오로메틸페네틸아미노)]벤조산메틸에스테르 (1.25 g, 3.64 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(2-플루오로-4-트라이플루오로메틸페네틸아미노)]벤조산 0.98g (78%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 7.50~7.60 (m, 2H), 7.40~7.50 (d, 2H), 7.00~7.05 (d, 1H), 6.80~6.90 (q, 1H), 6.70~6.80 (d, 1H), 3.20~3.30 (t, 2H), 2.90~2.95 (t, 2H)It was carried out in the same manner as in <Example 3> using 2-acetoxy-5- [2- (2-fluoro-4-trifluoromethylphenethylamino)] benzoic acid methyl ester (1.25 g, 3.64 mmole) To give 0.98 g (78%) of 2-hydroxy-5- [2- (2-fluoro-4-trifluoromethylphenethylamino)] benzoic acid as a white solid. 1 H NMR (DMSO-d 6 ) 7.50 ~ 7.60 (m, 2H), 7.40 ~ 7.50 (d, 2H), 7.00 ~ 7.05 (d, 1H), 6.80 ~ 6.90 (q, 1H), 6.70 ~ 6.80 (d , 1H), 3.20-3.30 (t, 2H), 2.90-2.95 (t, 2H)
<실시예 67> 2-아세톡시-5-[2-(2-트라이플루오로메틸-5-플루오로페닐아세틸아미노)]벤조산메틸에스테르의 제조Example 67 Preparation of 2-Acetoxy-5- [2- (2-trifluoromethyl-5-fluorophenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 2-트라이플루오로메틸-5-플루오로페닐아세트산 (1.34 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.34 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2-트라이플루오로메틸-5-플루오로페닐아세틸아미노)]벤조산메틸에스테르 1.72g (82%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 7.55~7.69 (m, 1H), 7.10~7.20 (d, 1H), 6.90~7.00 (m, 2H), 6.80~6.92 (d, 2H), 6.63~6.76 (q, 1H), 3.93 (s, 2H), 3.83 (s, 3H), 2.31 (s, 3H) 2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) with 2-trifluoromethyl-5-fluorophenylacetic acid (1.34 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) ( 1.34 g, 5.55 mmole) and 2-acetoxy-5- [2- (2-trifluoromethyl-5-fluorophenylacetylamino)] benzoic acid methyl ester in the same manner as in <Example 1>. 1.72 g (82%) was obtained as a white solid. 1 H NMR (DMSO-d 6 ) 7.55 ~ 7.69 (m, 1H), 7.10 ~ 7.20 (d, 1H), 6.90 ~ 7.00 (m, 2H), 6.80 ~ 6.92 (d, 2H), 6.63 ~ 6.76 (q , 1H), 3.93 (s, 2H), 3.83 (s, 3H), 2.31 (s, 3H)
<실시예 68> 2-아세톡시-5-[2-(2-트라이플루오로메틸-5-플루오로페네틸아미노)]벤조산메틸에스테르의 제조Example 68 Preparation of 2-Acetoxy-5- [2- (2-trifluoromethyl-5-fluorophenethylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(2-트라이플루오로메틸-5-플루오로페닐아세틸아미노)]벤조산메틸에스테르 (1.50 g, 3.79 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2-트라이플루오로메틸-5-플루오로페네틸아미노)]벤조산메틸에스테르 1.45g (96%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.55~7.69 (m, 1H), 7.10~7.20 (d, 1H), 6.90~7.00 (m, 2H), 6.80~6.92 (d, 2H), 6.63~6.76 (q, 1H), 3.83 (s, 3H), 3.30~3.40 (t, 2H), 3.00~3.08 (t, 2H), 2.31 (s, 3H) The same procedure as in Example 2 was carried out using 2-acetoxy-5- [2- (2-trifluoromethyl-5-fluorophenylacetylamino)] benzoic acid methyl ester (1.50 g, 3.79 mmole). To obtain 1.45 g (96%) of methyl 2-acetoxy-5- [2- (2-trifluoromethyl-5-fluorophenethylamino)] benzoic acid as a white solid. 1 H NMR (CDCl 6 ) 7.55 ~ 7.69 (m, 1H), 7.10 ~ 7.20 (d, 1H), 6.90 ~ 7.00 (m, 2H), 6.80 ~ 6.92 (d, 2H), 6.63 ~ 6.76 (q, 1H ), 3.83 (s, 3H), 3.30-3.40 (t, 2H), 3.00-3.08 (t, 2H), 2.31 (s, 3H)
<실시예 69> 2-하이드록시-5-[2-(2-트라이플루오로메틸-5-플루오로페네틸아 미노)]벤조산의 제조Example 69 Preparation of 2-hydroxy-5- [2- (2-trifluoromethyl-5-fluorophenethylamino)] benzoic acid
2-아세톡시-5-[2-(2-트라이플루오로메틸-5-플루오로페네틸아미노)]벤조산메틸에스테르 (1.35 g, 3.93 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(2-트라이플루오로메틸-5-플루오로페네틸아미노)]벤조산 1.11g (82%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.70~7.80 (q, 1H), 7.35~7.47 (d, 1H), 7.18~7.30 (t, 1H), 7.07 (s, 1H), 6.90~7.00 (q, 1H), 6.72~6.84 (d, 1H), 3.20~3.32 (t, 2H), 2.93~3.07 (t, 2H)It was carried out in the same manner as in <Example 3> using 2-acetoxy-5- [2- (2-trifluoromethyl-5-fluorophenethylamino)] benzoic acid methyl ester (1.35 g, 3.93 mmole) This gave 1.11 g (82%) of 2-hydroxy-5- [2- (2-trifluoromethyl-5-fluorophenethylamino)] benzoic acid as a gray solid. 1 H NMR (DMSO-d 6 ) 7.70-7.80 (q, 1H), 7.35-7.47 (d, 1H), 7.18-7.30 (t, 1H), 7.07 (s, 1H), 6.90-7.00 (q, 1H ), 6.72 ~ 6.84 (d, 1H), 3.20 ~ 3.32 (t, 2H), 2.93 ~ 3.07 (t, 2H)
<실시예 70> 2-아세톡시-5-[2-(2-플루오로-5-트라이플루오로메틸페닐아세틸아미노)]벤조산메틸에스테르의 제조Example 70 Preparation of 2-acetoxy-5- [2- (2-fluoro-5-trifluoromethylphenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 2-플루오로-5-트라이플루오로메틸페닐아세트산 (1.34 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2-플루오로-5-트라이플루오로메틸페닐아세틸아미노)]벤조산메틸에스테르 1.54g (74%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 7.40~7.53 (t, 2H), 7.00~7.20 (m, 2H), 6.83~6.93 (d, 1H), 6.64~6.77 (q, 1H), 3. 95 (s, 2H), 3.83 (s, 3H), 2.30 (s, 3H) 2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) and 2-fluoro-5-trifluoromethylphenylacetic acid (1.34 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole) and 1.54 g of 2-acetoxy-5- [2- (2-fluoro-5-trifluoromethylphenylacetylamino)] benzoic acid methyl ester using the same method as in <Example 1>. (74%) was obtained as a white solid. 1 H NMR (DMSO-d 6 ) 7.40 ~ 7.53 (t, 2H), 7.00 ~ 7.20 (m, 2H), 6.83 ~ 6.93 (d, 1H), 6.64 ~ 6.77 (q, 1H), 3. 95 (s , 2H), 3.83 (s, 3H), 2.30 (s, 3H)
<실시예 71> 2-아세톡시-5-[2-(2-플루오로-5-트라이플루오로메틸페네틸에틸아미노)]벤조산메틸에스테르의 제조 Example 71 Preparation of 2-acetoxy-5- [2- (2-fluoro-5-trifluoromethylphenethylethylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(2-플루오로-5-트라이플루오로메틸페닐아세틸아미노)]벤조산메틸에스테르 (1.50 g, 3.79 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2-플루오로-5-트라이플루오로메틸페네틸에틸아미노)]벤조산메틸에스테르 1.49g (95%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.40~7.53 (t, 2H), 7.00~7.20 (m, 2H), 6.83~6.93 (d, 1H), 6.64~6.77 (q, 1H), 3.83 (s, 3H), 3.30~3.43 (t, 2H), 2.87~3.00 (t, 2H), 2.30 (s, 3H) 2-acetoxy-5- [2- (2-fluoro-5-trifluoromethylphenylacetylamino)] benzoic acid methyl ester (1.50 g, 3.79 mmole) was used for the same procedure as in <Example 2> 1.49 g (95%) of 2-acetoxy-5- [2- (2-fluoro-5-trifluoromethylphenethylethylamino)] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.40 ~ 7.53 (t, 2H), 7.00 ~ 7.20 (m, 2H), 6.83 ~ 6.93 (d, 1H), 6.64 ~ 6.77 (q, 1H), 3.83 (s, 3H), 3.30 ~ 3.43 (t, 2H), 2.87 ~ 3.00 (t, 2H), 2.30 (s, 3H)
<실시예 72> 2-하이드록시-5-[2-(2-플루오로-5-트라이플루오로메틸페네틸아미노)]벤조산의 제조 Example 72 Preparation of 2-hydroxy-5- [2- (2-fluoro-5-trifluoromethylphenethylamino)] benzoic acid
2-아세톡시-5-[2-(2-플루오로-5-트라이플루오로메틸페네틸아미노)]벤조산메틸에스테르 (1.40 g, 3.92 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(2-플루오로-5-트라이플루오로메틸페네틸아미노)]벤조산 1.16g (83%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.55~7.66 (d, 1H), 7.51 (s, 1H), 7.21~7.30 (t, 1H), 7.00 (s, 1H), 6.80~6.90 (q, 1H), 6.60~6.75 (d, 1H), 3.20~3.30 (t, 2H), 2.90~3.00 (t, 2H) It was carried out in the same manner as in <Example 3> using 2-acetoxy-5- [2- (2-fluoro-5-trifluoromethylphenethylamino)] benzoic acid methyl ester (1.40 g, 3.92 mmole) This gave 1.16 g (83%) of 2-hydroxy-5- [2- (2-fluoro-5-trifluoromethylphenethylamino)] benzoic acid as a gray solid. 1 H NMR (DMSO-d 6 ) 7.55 ~ 7.66 (d, 1H), 7.51 (s, 1H), 7.21 ~ 7.30 (t, 1H), 7.00 (s, 1H), 6.80 ~ 6.90 (q, 1H), 6.60 ~ 6.75 (d, 1H), 3.20 ~ 3.30 (t, 2H), 2.90 ~ 3.00 (t, 2H)
<실시예 73> 2-아세톡시-5-[2-(4-플루오로페닐아세틸아미노)]벤조산메틸에스테르의 제조Example 73 Preparation of 2-Acetoxy-5- [2- (4-fluorophenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 4-플루오로페닐아세트산 (0.93 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(4-플루오로페닐아세틸아미노)]벤조산메틸에스테르 1.43g (82%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 7.05~7.18 (m, 3H), 6.90~7.00 (t, 2H), 6.80~6.90 (d, 1H), 6.60~6.73 (q, 1H), 3.90 (s, 2H), 3.81 (s, 3H), 2.28 (s, 3H)2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole), 4-fluorophenylacetic acid (0.93 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole) Was carried out in the same manner as in <Example 1> to obtain 1.43 g (82%) of 2-acetoxy-5- [2- (4-fluorophenylacetylamino)] benzoic acid methyl ester as a white solid. 1 H NMR (DMSO-d 6 ) 7.05 ~ 7.18 (m, 3H), 6.90 ~ 7.00 (t, 2H), 6.80 ~ 6.90 (d, 1H), 6.60 ~ 6.73 (q, 1H), 3.90 (s, 2H ), 3.81 (s, 3H), 2.28 (s, 3H)
<실시예 74> 2-아세톡시-5-[2-(4-플루오로페네틸아미노)]벤조산메틸에스테르의 제조Example 74 Preparation of 2-acetoxy-5- [2- (4-fluorophenethylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(4-플루오로페닐아세틸아미노)]벤조산메틸에스테르 (1.30 g, 3.29 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(4-플루오로페네틸아미노)]벤조산메틸에스테르 1.01g (93%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.05~7.18 (m, 3H), 6.90~7.00 (t, 2H), 6.80~6.90 (d, 1H), 6.60~6.73 (q, 1H), 3.81 (s, 3H), 3.24~3.38 (t, 2H), 2.80~2.89 (t, 2H), 2.28 (s, 3H)2-acetoxy-5 by the same method as in <Example 2> using 2-acetoxy-5- [2- (4-fluorophenylacetylamino)] benzoic acid methyl ester (1.30 g, 3.29 mmole) 1.01 g (93%) of-[2- (4-fluorophenethylamino)] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.05 ~ 7.18 (m, 3H), 6.90 ~ 7.00 (t, 2H), 6.80 ~ 6.90 (d, 1H), 6.60 ~ 6.73 (q, 1H), 3.81 (s, 3H), 3.24-3.38 (t, 2H), 2.80-2.89 (t, 2H), 2.28 (s, 3H)
<실시예 75> 2-하이드록시-5-[2-(4-플루오로페네틸아미노)]벤조산의 제조Example 75 Preparation of 2-hydroxy-5- [2- (4-fluorophenethylamino)] benzoic acid
2-아세톡시-5-[2-(4-플루오로페네틸아미노)]벤조산메틸에스테르 (0.90 g, 3.27 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(4-플루오로페네틸아미노)]벤조산 0.73g (81%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.13~7.27 (q, 2H), 7.00~7.05 (d, 1H), 6.90~7.00 (t, 2H), 6.80~6.90 (q, 1H), 6.70~6.78 (d, 1H), 3.22~3.30 (t, 2H), 2.80~2.90 (t, 2H)2-hydroxy-5 was carried out in the same manner as in <Example 3> using 2-acetoxy-5- [2- (4-fluorophenethylamino)] benzoic acid methyl ester (0.90 g, 3.27 mmole) 0.73 g (81%) of-[2- (4-fluorophenethylamino)] benzoic acid were obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 7.13 ~ 7.27 (q, 2H), 7.00 ~ 7.05 (d, 1H), 6.90 ~ 7.00 (t, 2H), 6.80 ~ 6.90 (q, 1H), 6.70 ~ 6.78 (d , 1H), 3.22-3.30 (t, 2H), 2.80-2.90 (t, 2H)
<실시예 76> 2-아세톡시-5-(3-p-톨릴프로피오닐아미노)벤조산메틸에스테르의 제조Example 76 Preparation of 2-Acetoxy-5- (3-p-tolylpropionylamino) benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 4-메틸페닐프로피온산 (0.99 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (0.99 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-(3-p-톨릴프로피오닐아미노)벤조산메틸에스테르 1.29g (72%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 8.17 (s, 1H), 7.70~7.80 (q, 1H), 7.00~7.20 (m, 5H), 3.78 (s, 3H), 2.80~2.90 (t, 2H), 2.50~2.65 (t, 2H), 2.24 (s, 3H), 2.22 (s, 3H) 2-Acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole), 4-methylphenylpropionic acid (0.99 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (0.99 g, 5.55 mmole) In the same manner as in <Example 1>, 1.29 g (72%) of 2-acetoxy-5- (3-p-tolylpropionylamino) benzoic acid methyl ester was obtained as a white solid. 1 H NMR (DMSO-d 6 ) 8.17 (s, 1H), 7.70-7.80 (q, 1H), 7.00-7.20 (m, 5H), 3.78 (s, 3H), 2.80-2.90 (t, 2H), 2.50-2.65 (t, 2H), 2.24 (s, 3H), 2.22 (s, 3H)
<실시예 77> 2-아세톡시-5-(3-p-톨릴프로필아미노)벤조산메틸에스테르 제조Example 77 Preparation of 2-acetoxy-5- (3-p-tolylpropylamino) benzoic acid methyl ester
2-아세톡시-5-(3-p-톨릴프로피오닐아미노)벤조산메틸에스테르 (1.10 g, 2.78 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-(3-p-톨릴프로필아미노)벤조산메틸에스테르 0.87g (92%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.00~7.20 (m, 5H), 6.80~6.90 (d, 1H), 6.60~6.70 (q, 1H), 3.85 (s, 3H), 3.00~3.20 (t, 2H), 2.60~2.75 (t, 2H), 2.33 (s, 3H), 2.27 (s, 3H), 1.80~2.00 (q, 2H) 2-Acetoxy-5- (3-p-tolylpropionylamino) benzoic acid methyl ester (1.10 g, 2.78 mmole) was carried out in the same manner as in <Example 2>, to obtain 2-acetoxy-5- (3 0.87 g (92%) of -p-tolylpropylamino) benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.00-7.20 (m, 5H), 6.80-6.70 (d, 1H), 6.60-6.70 (q, 1H), 3.85 (s, 3H), 3.00-3.20 (t, 2H), 2.60-2.75 (t, 2H), 2.33 (s, 3H), 2.27 (s, 3H), 1.80-2.00 (q, 2H)
<실시예 78> 2-하이드록시-5-(3-p-톨릴프로필아미노) 벤조산의 제조Example 78 Preparation of 2-hydroxy-5- (3-p-tolylpropylamino) benzoic Acid
2-아세톡시-5-(3-p-톨릴프로필아미노)벤조산메틸에스테르 (0.75 g, 2.63 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-(3-p-톨릴프로필아미노) 벤조산 0.65g (86%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.35 (s, 1H), 7.10~7.20 (d, 1H), 7.05 (s, 4H), 6.80~6.90 (d, 1H), 3.00~3.10 (t, 2H), 2.60~2.70 (t, 2H), 2.25 (s, 3H), 1.80~1.95 (q, 2H)2-Hydroxy-5- (3-p-tolylpropylamino) benzoic acid methyl ester (0.75 g, 2.63 mmole) was carried out in the same manner as in <Example 3>, and 2-hydroxy-5- (3- 0.65 g (86%) of p-tolylpropylamino) benzoic acid was obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 7.35 (s, 1H), 7.10-7.20 (d, 1H), 7.05 (s, 4H), 6.80-6.70 (d, 1H), 3.00-3.10 (t, 2H), 2.60 ~ 2.70 (t, 2H), 2.25 (s, 3H), 1.80 ~ 1.95 (q, 2H)
<실시예 79> 2-아세톡시-5-[3-{4-(트라이플루오로메틸)페닐}프로피오닐아미노]벤조산메틸에스테르의 제조Example 79 Preparation of 2-acetoxy-5- [3- {4- (trifluoromethyl) phenyl} propionylamino] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 4-트라이 플루오로페닐프로피온산 (1.31 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[3-{4-(트라이플루오로메틸)페닐}프로피오닐아미노]벤조산메틸에스테르 1.71g (82%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 8.14~8.24 (d, 1H), 7.78~7.84 (q, 1H), 7.60~7.68 (d, 2H), 7.44~7.50 (d, 2H), 7.12~7.18 (d, 1H), 3.80 (s, 3H), 2.98~3.04 (t, 2H), 2.66~2.72 (t, 2H), 2.26 (s, 3H) 2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) with 4-trifluorophenylpropionic acid (1.31 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole) 1.71 g (82%) of 2-acetoxy-5- [3- {4- (trifluoromethyl) phenyl} propionylamino] benzoic acid methyl ester was prepared by the same method as in Example 1. Obtained as a solid. 1 H NMR (DMSO-d 6 ) 8.14-8.24 (d, 1H), 7.78-7.84 (q, 1H), 7.60-7.68 (d, 2H), 7.44-7.50 (d, 2H), 7.12-7.18 (d , 1H), 3.80 (s, 3H), 2.98-3.04 (t, 2H), 2.66-2.72 (t, 2H), 2.26 (s, 3H)
<실시예 80> 2-아세톡시-5-(3-(4-(트라이플루오로메틸)페닐)프로필아미노)벤조산메틸에스테르의 제조 Example 80 Preparation of 2-acetoxy-5- (3- (4- (trifluoromethyl) phenyl) propylamino) benzoic acid methyl ester
2-아세톡시-5-[3-{4-(트라이플루오로메틸)페닐}프로피오닐아미노]벤조산메틸에스테르 (1.60 g, 4.05 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-(3-(4-(트라이플루오로메틸)페닐)프로필아미노)벤조산메틸에스테르 1.46g (91%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.50~7.58 (d, 2H), 7.20~7.30 (d, 2H), 7.10~7.18 (d, 1H), 6.80~6.90 (d, 1H), 6.60~6.70 (q, 1H), 3.83 (s, 3H), 3.10~3.20 (t, 2H), 2.70~2.85 (t, 2H), 2.30 (s, 3H), 1.80~2.00 (q, 2H)2-acetoxy-5- [3- {4- (trifluoromethyl) phenyl} propionylamino] benzoic acid methyl ester (1.60 g, 4.05 mmole) was used in the same manner as in <Example 2> to give 2 1.46 g (91%) of acetoxy-5- (3- (4- (trifluoromethyl) phenyl) propylamino) benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.50 ~ 7.58 (d, 2H), 7.20 ~ 7.30 (d, 2H), 7.10 ~ 7.18 (d, 1H), 6.80 ~ 6.90 (d, 1H), 6.60 ~ 6.70 (q, 1H ), 3.83 (s, 3H), 3.10-3.20 (t, 2H), 2.70-2.85 (t, 2H), 2.30 (s, 3H), 1.80-2.00 (q, 2H)
<실시예 81> 2-하이드록시-5-[3-{4-(트라이플루오로메틸)페닐}프로필아미 노] 벤조산의 제조 Example 81 Preparation of 2-hydroxy-5- [3- {4- (trifluoromethyl) phenyl} propylamino] benzoic acid
2-아세톡시-5-[3-{4-(트라이플루오로메틸)페닐}프로필아미노]벤조산메틸에스테르 (1.30 g, 3.83 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[3-{4-(트라이플루오로메틸)페닐}프로필아미노] 벤조산 1.01g (78%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.55~7.65 (d, 2H), 7.35~7.45 (d, 2H), 7.00 (s, 1H), 6.80~6.95 (t, 1H), 6.70~6.80 (d, 1H), 2.90~3.05(t, 2H), 2.70~2.80 (t, 2H), 1.80~2.00 (q, 2H) 2-acetoxy-5- [3- {4- (trifluoromethyl) phenyl} propylamino] benzoic acid methyl ester (1.30 g, 3.83 mmole) was used to carry out the same procedure as described in <Example 3>. 1.01 g (78%) of hydroxy-5- [3- {4- (trifluoromethyl) phenyl} propylamino] benzoic acid was obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 7.55 ~ 7.65 (d, 2H), 7.35 ~ 7.45 (d, 2H), 7.00 (s, 1H), 6.80 ~ 6.95 (t, 1H), 6.70 ~ 6.80 (d, 1H ), 2.90-3.05 (t, 2H), 2.70-2.80 (t, 2H), 1.80-2.00 (q, 2H)
<실시예 82> 2-아세톡시-5-[2-(2,4-다이클로로페닐아세틸아미노)]벤조산메틸에스테르의 제조Example 82 Preparation of 2-acetoxy-5- [2- (2,4-dichlorophenylacetylamino)] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 2,4-다이클로로페닐아세트산 (1.34 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2,4-다이클로로페닐아세틸아미노)]벤조산메틸에스테르 1.51g (72%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) with 2,4-dichlorophenylacetic acid (1.34 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole ) And 1.51 g (72%) of 2-acetoxy-5- [2- (2,4-dichlorophenylacetylamino)] benzoic acid methyl ester in the same manner as in <Example 1> Got it. 1 H NMR (DMSO-d 6 )
<실시예 83> 2-아세톡시-5-[2-(2,4-다이클로로페네틸아미노)]벤조산메틸에스테르의 제조Example 83 Preparation of 2-Acetoxy-5- [2- (2,4-dichlorophenethylamino)] benzoic acid methyl ester
2-아세톡시-5-[2-(2,4-다이클로로페닐아세틸아미노)]벤조산메틸에스테르 (1.20 g, 3.04 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 2-아세톡시-5-[2-(2,4-다이클로로페네틸아미노)]벤조산메틸에스테르 1.13g (93%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.36~7.46(t, 1H), 7.30~7.35(m, 1H), 7.00~7.20(m, 2H), 6.80~7.00(d, 1H), 6.60~6.75(q, 1H), 3.82(s, 3H0, 3.30~3.40(t, 2H), 2.80~2.95(t, 2H), 2.30(s, 3H)2-acetoxy-5- [2- (2,4-dichlorophenylacetylamino)] benzoic acid methyl ester (1.20 g, 3.04 mmole) was used to carry out the same procedure as described in <Example 2>. 1.13 g (93%) of -5- [2- (2,4-dichlorophenethylamino)] benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.36 ~ 7.46 (t, 1H), 7.30 ~ 7.35 (m, 1H), 7.00 ~ 7.20 (m, 2H), 6.80 ~ 7.00 (d, 1H), 6.60 ~ 6.75 (q, 1H ), 3.82 (s, 3H0, 3.30-3.40 (t, 2H), 2.80-2.95 (t, 2H), 2.30 (s, 3H)
<실시예 84> 2-하이드록시-5-[2-(2,4-다이클로로페네틸아미노)]벤조산 제조Example 84 Preparation of 2-hydroxy-5- [2- (2,4-dichlorophenethylamino)] benzoic acid
2-아세톡시-5-[2-(2,4-다이클로로페네틸아미노)]벤조산메틸에스테르 (1.00 g, 2.91 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 2-하이드록시-5-[2-(2,4-다이클로로페네틸아미노)]벤조산 0.85g (85%) 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.50~7.65(t, 2H), 7.25~7.40(t, 1H), 7.05(s, 1H), 6.85~6.97(d, 1H), 6.70~6.80(d, 1H), 3.20~3.30(t, 2H), 2.83~3.00(t, 2H)2-hydroxy using 2-acetoxy-5- [2- (2,4-dichlorophenethylamino)] benzoic acid methyl ester (1.00 g, 2.91 mmole) in the same manner as in <Example 3> 0.85-g (85%) gray solid was obtained from -5- [2- (2,4-dichlorophenethylamino)] benzoic acid. 1 H NMR (DMSO-d 6 ) 7.50 ~ 7.65 (t, 2H), 7.25 ~ 7.40 (t, 1H), 7.05 (s, 1H), 6.85 ~ 6.97 (d, 1H), 6.70 ~ 6.80 (d, 1H ), 3.20-3.30 (t, 2H), 2.83-3.00 (t, 2H)
<실시예 85> 5-[3-{3-플루오로-4-(트라이플루오로메틸페닐)아세틸아미노}-2-아세톡시]벤조산메틸에스테르의 제조 Example 85 Preparation of 5- [3- {3-fluoro-4- (trifluoromethylphenyl) acetylamino} -2-acetoxy] benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 3-플루오로-4-트라이플루오로메틸페닐아세트산 (1.34 g, 6.04 mmole), 다이싸이클로헥사카 보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 5-[3-{3-플루오로-4-(트라이플루오로메틸페닐)아세틸아미노}-2-아세톡시]벤조산메틸에스테르 1.41g (67%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 7.50~7.60 (t, 1H), 7.15~7.20 (d, 1H), 7.00~7.10 (t, 2H), 6.85~6.95 (d, 1H), 6.65~6.75 (q, 1H), 3.93 (s, 2H), 3.85 (s, 3H), 2.30 (s, 3H)2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) with 3-fluoro-4-trifluoromethylphenylacetic acid (1.34 g, 6.04 mmole), dicyclohexaka boaidimide (DCC) ( 1.14 g, 5.55 mmole) was prepared in the same manner as in <Example 1> to give 5- [3- {3-fluoro-4- (trifluoromethylphenyl) acetylamino} -2-acetoxy] benzoate 1.41 g (67%) of ester were obtained as a white solid. 1 H NMR (DMSO-d 6 ) 7.50 ~ 7.60 (t, 1H), 7.15 ~ 7.20 (d, 1H), 7.00 ~ 7.10 (t, 2H), 6.85 ~ 6.95 (d, 1H), 6.65 ~ 6.75 (q , 1H), 3.93 (s, 2H), 3.85 (s, 3H), 2.30 (s, 3H)
<실시예 86> 5-[3-플루오로-4-(트라이플루오로메틸)페네틸아미노-2-아세톡시]벤조산메틸에스테르의 제조 Example 86 Preparation of 5- [3-fluoro-4- (trifluoromethyl) phenethylamino-2-acetoxy] benzoic acid methyl ester
5-[3-(3-플루오로-4-(트라이플루오로메틸페닐)아세틸아미노)-2-아세톡시]벤조산메틸에스테르 (1.30 g, 3.29 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 5-[3-플루오로-4-(트라이플루오로메틸)페네틸아미노-2-아세톡시]벤조산메틸에스테르 1.25g (95%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.50~7.60 (t, 1H), 7.15~7.20 (d, 1H), 7.00~7.10 (t, 2H), 6.85~6.95 (d, 1H), 6.65~6.75 (q, 1H), 3.85 (s, 3H), 3.35~3.45 (t, 2H), 2.90~3.00 (t, 2H), 2.30 (s, 3H)In the same manner as in <Example 2> using 5- [3- (3-fluoro-4- (trifluoromethylphenyl) acetylamino) -2-acetoxy] benzoic acid methyl ester (1.30 g, 3.29 mmole) This was carried out to obtain 1.25 g (95%) of 5- [3-fluoro-4- (trifluoromethyl) phenethylamino-2-acetoxy] benzoic acid methyl ester as a white solid. 1 H NMR (CDCl 6 ) 7.50 ~ 7.60 (t, 1H), 7.15 ~ 7.20 (d, 1H), 7.00 ~ 7.10 (t, 2H), 6.85 ~ 6.95 (d, 1H), 6.65 ~ 6.75 (q, 1H ), 3.85 (s, 3H), 3.35-3.45 (t, 2H), 2.90-3.00 (t, 2H), 2.30 (s, 3H)
<실시예 87> 5-[3-플루오로-4-(트라이플루오로메틸)페네틸아미노]-2-하이드록시 벤조산의 제조 Example 87 Preparation of 5- [3-fluoro-4- (trifluoromethyl) phenethylamino] -2-hydroxy benzoic acid
5-[3-플루오로-4-(트라이플루오로메틸)페네틸아미노)-2-아세톡시]벤조산메틸 에스테르 (1.15 g, 3.35 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 5-[3-플루오로-4-(트라이플루오로메틸)페네틸아미노]-2-하이드록시 벤조산 1.00g (87%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.60~7.75 (t, 1H), 7.35~7.45 (d, 1H), 7.20~7.30 (d, 1H), 6.92~7.00 (s, 1H), 6.80~6.90 (q, 1H), 6.70~6.80 (d, 1H), 3.20~3.30 (t, 2H), 2.80~3.00 (t, 2H)5- [3-fluoro-4- (trifluoromethyl) phenethylamino) -2-acetoxy] benzoic acid methyl ester (1.15 g, 3.35 mmole) was used in the same manner as in <Example 3> 1.00 g (87%) of 5- [3-fluoro-4- (trifluoromethyl) phenethylamino] -2-hydroxy benzoic acid was obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 7.60 ~ 7.75 (t, 1H), 7.35 ~ 7.45 (d, 1H), 7.20 ~ 7.30 (d, 1H), 6.92 ~ 7.00 (s, 1H), 6.80 ~ 6.90 (q , 1H), 6.70 ~ 6.80 (d, 1H), 3.20 ~ 3.30 (t, 2H), 2.80 ~ 3.00 (t, 2H)
<실시예 88> 5-(2-싸이클로헥실아세틸아미노)-2-아세톡시 벤조산메틸에스테르의 제조 Example 88 Preparation of 5- (2-cyclohexylacetylamino) -2-acetoxy benzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 싸이클로헥실페닐아세트산 (0.85 g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 5-(2-싸이클로헥실아세틸아미노)-2-아세톡시 벤조산메틸에스테르 1.34g (79%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 8.22 (s, 1H), 7.78~7.86 (d, 1H), 7.08~7.18 (d, 1H), 3.80 (s, 3H), 2.25 (s, 3H), 2.30~2.40 (d, 2H), 1.60~1.75 (m, 5H), 1.10~1.30 (m, 4H), 0.90~1.05 (m, 2H) 2-Acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole), cyclohexylphenylacetic acid (0.85 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole) 1.34 g (79%) of 5- (2-cyclohexylacetylamino) -2-acetoxy benzoic acid methyl ester was obtained by the same method as in <Example 1>, to obtain a white solid. 1 H NMR (DMSO-d 6 ) 8.22 (s, 1H), 7.78-7.86 (d, 1H), 7.08-7.18 (d, 1H), 3.80 (s, 3H), 2.25 (s, 3H), 2.30- 2.40 (d, 2H), 1.60-1.75 (m, 5H), 1.10-1.30 (m, 4H), 0.90-1.05 (m, 2H)
<실시예 89> 5-(2-싸이클로헥실에틸아미노)-2-아세톡시 벤조산메틸에스테르의 제조Example 89 Preparation of 5- (2-cyclohexylethylamino) -2-acetoxy benzoic acid methyl ester
5-(2-싸이클로헥실아세틸아미노)-2-아세톡시 벤조산메틸에스테르 (1.20 g, 3.04 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 5-(2-싸이클로헥실에틸아미노)-2-아세톡시 벤조산메틸에스테르 0.70g (88%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.15~7.18 (d, 1H), 6.81~6.90 (d, 1H), 6.67~6.73 (q, 1H), 3.85 (s, 3H), 3.05~3.15 (t, 2H), 2.30 (s, 3H), 1.65~1.80 (m, 5H), 1.45~1.55 (q, 2H), 1.10~1.30 (m, 4H), 0.90~1.00 (m, 2H)5- (2-cyclohexylacetylamino) -2-acetoxy benzoic acid methyl ester (1.20 g, 3.04 mmole) was carried out in the same manner as in <Example 2> to give 5- (2-cyclohexylethylamino)- 0.70 g (88%) of 2-acetoxy benzoic acid methyl ester was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.15 ~ 7.18 (d, 1H), 6.81 ~ 6.90 (d, 1H), 6.67 ~ 6.73 (q, 1H), 3.85 (s, 3H), 3.05-3.15 (t, 2H), 2.30 (s, 3H), 1.65-1.80 (m, 5H), 1.45-1.55 (q, 2H), 1.10-1.30 (m, 4H), 0.90-1.00 (m, 2H)
<실시예 90> 5-(2-싸이클로헥실에틸아미노)-2-하이드록시 벤조산의 제조Example 90 Preparation of 5- (2-cyclohexylethylamino) -2-hydroxy benzoic acid
5-(2-싸이클로헥실에틸아미노)-2-아세톡시 벤조산메틸에스테르 (0.80 g, 3.04 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 5-(2-싸이클로헥실에틸아미노)-2-하이드록시 벤조산 0.70g (88%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 7.15 (s, 1H), 6.95~7.05 (d, 1H), 6.75~6.85 (d, 1H), 2.95~3.05 (t, 2H), 1.55~1.70 (m, 5H), 1.40~1.45 (m, 2H), 1.30~1.40 (m, 1H), 1.10~1.22 (s, 3H), 0.84~0.94 (q, 2H) 5- (2-cyclohexylethylamino) -2-acetoxy benzoic acid methyl ester (0.80 g, 3.04 mmole) was carried out in the same manner as in <Example 3>, to obtain 5- (2-cyclohexylethylamino)- 0.70 g (88%) of 2-hydroxy benzoic acid was obtained as a gray solid. 1 H NMR (DMSO-d 6 ) 7.15 (s, 1H), 6.95-7.05 (d, 1H), 6.75-6.85 (d, 1H), 2.95-3.05 (t, 2H), 1.55-1.70 (m, 5H ), 1.40-1.45 (m, 2H), 1.30-1.40 (m, 1H), 1.10-1.22 (s, 3H), 0.84-0.94 (q, 2H)
<실시예 91> 5-(4-(다이메틸아미노)페닐아세틸아미노-2-아세톡시시 벤조산메틸에스테르의 제조Example 91 Preparation of 5- (4- (dimethylamino) phenylacetylamino-2-acetoxyoxybenzoic acid methyl ester
2- 아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)과 4-다이메 틸아미노메틸페닐아세트산 (1.08g, 6.04 mmole), 다이싸이클로헥사카보다이이마이드(DCC) (1.14 g, 5.55 mmole)을 사용하여 <실시예 1>의 동일한 방법으로 실시하여 5-(4-(다이메틸아미노)페닐아세틸아미노-2-아세톡시시 벤조산메틸에스테르 1.35g( 72%)를 흰색고체로 얻었다. 1H NMR (DMSO-d6) 8.20 (s, 1H), 7.80~7.86 (d, 1H), 7.10~7.20 (t, 3H), 6.62~6.68 (d, 2H), 3.79 (s, 3H), 3.49 (s, 2H), 2.82~2.88 (d, 6H), 2.26 (s, 3H)2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) with 4-dimethylaminomethylphenylacetic acid (1.08 g, 6.04 mmole), dicyclohexacarbodiimide (DCC) (1.14 g, 5.55 mmole ) by the use <example 1> and carried out similarly to the procedures of 5- (4- (dimethylamino) -phenyl acetyl-amino-2-acetoxy-benzoic acid methyl ester was obtained when 1.35g (72%) as a white solid. 1 H NMR (DMSO-d 6 ) 8.20 (s, 1H), 7.80-7.86 (d, 1H), 7.10-7.20 (t, 3H), 6.62-6.68 (d, 2H), 3.79 (s, 3H), 3.49 (s, 2H), 2.82-2.88 (d, 6H), 2.26 (s, 3H)
<실시예 92> 5-[4-(다이메틸아미노)페네틸)아미노-2-아세톡시]벤조산메틸에스테르의 제조 Example 92 Preparation of 5- [4- (dimethylamino) phenethyl) amino-2-acetoxy] benzoic acid methyl ester
5-(4-(다이메틸아미노)페닐아세틸아미노-2-아세톡시시 벤조산메틸에스테르 (1.20 g, 3.04 mmole)을 사용하여 <실시예 2>의 동일한 방법으로 실시하여 5-[4-(다이메틸아미노)페네틸)아미노-2-아세톡시]벤조산메틸에스테르 1.00g (92%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.12~7.18 (d, 1H), 7.02~7.10 (q, 2H), 6.82~6.88 (d, 1H), 6.64~6.72 (m, 3H),3.82 (s, 3H), 3.28~3.35 (t, 2H), 2.90 (s, 6H), 2.78~2.82 (t, 2H), 2.29 (s, 3H) 5- (4- (dimethylamino) phenylacetylamino-2-acetoxyoxybenzoic acid methyl ester (1.20 g, 3.04 mmole) was used for the same procedure as in <Example 2> to give 5- [4- (di Methylamino) phenethyl) amino-2-acetoxy] benzoic acid methyl ester 1.00g (92%) was obtained as a white solid. 1 H NMR (CDCl 6 ) 7.12-7.18 (d, 1H), 7.02-7.10 (q, 2H), 6.82-6.88 (d, 1H), 6.64-6.72 (m, 3H), 3.82 (s, 3H), 3.28 ~ 3.35 (t, 2H), 2.90 (s, 6H), 2.78 ~ 2.82 (t, 2H), 2.29 (s, 3H)
<실시예 93> 5-(4-(다이메틸아미노)페네틸아미노-2-하이드록시 벤조산 제조Example 93 Preparation of 5- (4- (dimethylamino) phenethylamino-2-hydroxy benzoic acid
5-(4-(다이메틸아미노)페닐에틸아미노-2-아세톡시시 벤조산메틸에스테르 (0.90 g, 3.00 mmole)를 사용하여 <실시예 3>의 동일한 방법으로 실시하여 5-(4-(다이메틸아미노)페네틸아미노-2-하이드록시 벤조산 0.80g (89%)를 회색고체로 얻었다. 1H NMR (DMSO-d6) 8.04 (s, 1H), 7.73~7.80 (q, 1H), 7.60~7.70 (d, 2H), 7.30~7.45 (d, 2H), 7.00~7.10 (d, 1H), 3.40~3.60 (t, 2H), 3.00~3.20 (m, 8H), 1.90 (s, 1H)5- (4- (dimethylamino) phenylethylamino-2-acetoxyoxybenzoic acid methyl ester (0.90 g, 3.00 mmole) was used to carry out the same procedure as in <Example 3> to give 5- (4- ( 0.80 g (89%) of methylamino) phenethylamino-2-hydroxy benzoic acid was obtained as a gray solid, 1 H NMR (DMSO-d 6 ) 8.04 (s, 1H), 7.73-7.80 (q, 1H), 7.60 ~ 7.70 (d, 2H), 7.30-7.45 (d, 2H), 7.00-7.10 (d, 1H), 3.40-3.60 (t, 2H), 3.00-3.20 (m, 8H), 1.90 (s, 1H)
2. [경로 2]를 이용한 5-(치환된 페닐알킬)아미노살리실산 제조방법 (실시예 94, 95)2. Method for preparing 5- (substituted phenylalkyl) aminosalicylic acid using [Path 2] (Examples 94 and 95)
<실시예 94> 2-아세톡시-5-[2-(2-트라이플루오로메틸페네틸아미노)]벤조산메틸에스테르의 제조Example 94 Preparation of 2-acetoxy-5- [2- (2-trifluoromethylphenethylamino)] benzoic acid methyl ester
질소 기류 하에서 2-(4-트리플루오로메틸메틸)페닐아세트 알데히드(0.86 g, 4.56 mmol)를 2-아세톡시-5-아미노벤조산메틸에스테르 (1.06 g, 5.07 mmole)에 서서히 부가하며 부가 온도는 25도에서 40도에서 2시간 부가하였다. 2시간 상온에서 더 교반 한 후 보레인테트라하이드론퓨란 첨가했다. 그리고 시안화수소화 붕소 나트륨 (0.31 g, 5.02 mmol)을 넣고 70oC로 2시간동안 가열하였다. 반응 종결 후에 1N 염산으로 적정한 후, 에틸아세테이트로 추출하고, 소금물로 세척 하였다. 유기 층은 갑압 증류를 통하여 용매를 제거하였다. 잔류물을 메탄올/에틸아세테이트/헥산 하에서 재결정함으로써 2-아세톡시-5-[2-(2-트라이플루오로메틸페네틸아미노)] 벤조산메틸에스테르 0.94g (75%)를 흰색고체로 얻었다. 1H NMR (CDCl6) 7.60~7.68 (d, 1H), 7.44~7.50 (t, 1H), 7.30~7.38 (d, H), 7.16~7.22 (d, 1H), 6.86~6.92 (d, 1H), 6.70~6.77 (q, 1H), 3.84 (s, 3H), 3.38~3.44 (t, 2H), 3.06~3.10 (t, 2H), 2.50 (s, 3H).2- (4-trifluoromethylmethyl) phenylacetaldehyde (0.86 g, 4.56 mmol) was added slowly to 2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) under nitrogen stream and the addition temperature was It was added for 2 hours at 25 degrees and 40 degrees. After further stirring at room temperature for 2 hours, borane tetrahydrofuran was added. And sodium hydrogen cyanide (0.31 g, 5.02 mmol) was added and heated to 70 ° C. for 2 hours. After completion of the reaction, the mixture was titrated with 1N hydrochloric acid, extracted with ethyl acetate, and washed with brine. The organic layer was removed from the solvent by vacuum distillation. The residue was recrystallized in methanol / ethyl acetate / hexane to give 0.94 g (75%) of 2-acetoxy-5- [2- (2-trifluoromethylphenethylamino)] benzoic acid methyl ester as a white solid. 1 H NMR (CDCl 6 ) 7.60 ~ 7.68 (d, 1H), 7.44 ~ 7.50 (t, 1H), 7.30 ~ 7.38 (d, H), 7.16 ~ 7.22 (d, 1H), 6.86 ~ 6.92 (d, 1H ), 6.70 to 6.27 (q, 1H), 3.84 (s, 3H), 3.38 to 3.44 (t, 2H), 3.06 to 3.10 (t, 2H), 2.50 (s, 3H).
<실시예 95> 2-하이드록시-5-[2-(2-트라이플루오로메틸페네틸아미노)]벤조산 의 제조Example 95 Preparation of 2-hydroxy-5- [2- (2-trifluoromethylphenethylamino)] benzoic acid
<실시 예 3>과 동일한 방법으로 제조하였다.It prepared in the same manner as in <Example 3>.
3. [경로 3]을 이용한 5-(치환된 페닐알킬)아미노살리실산 제조방법 (실시예 96, 97)3. Method for preparing 5- (substituted phenylalkyl) aminosalicylic acid using [Path 3] (Examples 96 and 97)
<실시예 96> 2-아세톡시-5-[2-(2-트라이플루오로메틸페네틸아미노)]벤조산메틸에스테르의 제조Example 96 Preparation of 2-acetoxy-5- [2- (2-trifluoromethylphenethylamino)] benzoic acid methyl ester
질소 기류 하에서 4-트리플루오로메틸메틸 스틸렌 (0.86g,5.00mmol)를 디메틸포름아미드 (10.0 mL)에 녹인후 2-아세톡시-5-아미노벤조산메틸에스테르(1.06 g, 5.07 mmole)를 부가하였다.그리고, 중합방지제로 페노티아진 (50mg)을 넣고 105도에서 가열하였다. 12시간 반응 후 증류수 (10.0 mL)를 넣고 에테르 (10.0 mL)로 3회 추출하였다. 유기층을 무수 환산나트륨으로 건조 후 여과하고, 용매를 농출하였 다. 생성된 노란색의 오일을 헥산과 에틸 아세테이트로 컬럼 분리하였다. 농축하여 흰색의 고체를 얻고 에테르로 재결정하여 흰색의 목적 화합물(0.6g, 50%)을 얻었다. 1H NMR (CDCl6) 7.60~7.68 (d, 1H), 7.44~7.50 (t, 1H), 7.30~7.38 (d, H), 7.16~7.22 (d, 1H), 6.86~6.92 (d, 1H), 6.70~6.77 (q, 1H), 3.84 (s, 3H), 3.38~3.44 (t, 2H), 3.06~3.10 (t, 2H), 2.50 (s, 3H).4-trifluoromethylmethyl styrene (0.86 g, 5.00 mmol) was dissolved in dimethylformamide (10.0 mL) under nitrogen stream, and 2-acetoxy-5-aminobenzoic acid methyl ester (1.06 g, 5.07 mmole) was added thereto. Then, phenothiazine (50 mg) was added as a polymerization inhibitor and heated at 105 degrees. After the reaction for 12 hours, distilled water (10.0 mL) was added and extracted three times with ether (10.0 mL). The organic layer was dried over anhydrous sodium equivalents and filtered, and the solvent was concentrated. The resulting yellow oil was column separated with hexane and ethyl acetate. Concentration gave a white solid which was recrystallized with ether to obtain a white desired compound (0.6 g, 50%). 1 H NMR (CDCl 6 ) 7.60 ~ 7.68 (d, 1H), 7.44 ~ 7.50 (t, 1H), 7.30 ~ 7.38 (d, H), 7.16 ~ 7.22 (d, 1H), 6.86 ~ 6.92 (d, 1H ), 6.70 to 6.27 (q, 1H), 3.84 (s, 3H), 3.38 to 3.44 (t, 2H), 3.06 to 3.10 (t, 2H), 2.50 (s, 3H).
<실시예 97> 2-하이드록시-5-[2-(2-트라이플루오로메틸페네틸아미노)]벤조산 제조Example 97 Preparation of 2-hydroxy-5- [2- (2-trifluoromethylphenethylamino)] benzoic acid
<실시 예 3>과 동일한 방법으로 제조하였다.It prepared in the same manner as in <Example 3>.
<비교예 1>Comparative Example 1
대한민국 공개특허 제2003-0058934호에 제시된 방법으로 상기 명시된 화합물 2-하이드록시-5-(3-페닐프로필아미노)]벤조산을 합성하였다.The compound 2-hydroxy-5- (3-phenylpropylamino)] benzoic acid specified above was synthesized by the method given in Korean Laid-Open Patent Publication No. 2003-0058934.
5-아미노살리실산 (820 mg, 4,01 mmole)을 상온, 질소 기류 하에서 다이메틸포름아마이드(30.0 mL)에 넣어준 후 현탁시켰고, 10분 후에, 트라이에틸아민 (1.0 mL), 테트라부틸암모늄아이오다이드 (10 mg)을 넣어주고 30분간 교반하였다. 반응물이 완전히 녹으면 2-브로모페닐프로판을 (4.01 g, 21.6 mmole)을 넣어주고, 24시간동안 교반하였다. 반응 종결 후에 얼음을 조금씩 넣어주었고, 에틸아세테이트로 2회 추출하고 감압증류를 통하여 추출용매를 제거하였다. 얻어진 잔류물을 컬럼 크 로마토그램을 이용하여 정제하면, 2-하이드록시-5-(3-페네틸아미노)]벤조산을 (1.82g, 15.2%)를 얻어내었다.5-aminosalicylic acid (820 mg, 4,01 mmole) was added to dimethylformamide (30.0 mL) at room temperature and under a nitrogen stream, and then suspended. After 10 minutes, triethylamine (1.0 mL), tetrabutylammonium eye Odide (10 mg) was added and stirred for 30 minutes. When the reaction was completely dissolved 2-bromophenylpropane (4.01 g, 21.6 mmole) was added and stirred for 24 hours. After completion of the reaction, ice was added little by little, extracted twice with ethyl acetate, and the extraction solvent was removed by distillation under reduced pressure. The obtained residue was purified using a column chromatogram to give 2-hydroxy-5- (3-phenethylamino)] benzoic acid (1.82 g, 15.2%).
표 1> 공개특허 제 2003-0058934호에 제시된 방법과 본 발명의 반응식 II를 이용하여 화학식 I을 제조하는 방법의 장·단점 비교도표Table 1> Advantages and Disadvantages Comparison Chart for Producing Chemical Formula I Using Method of Publication No. 2003-0058934 and Scheme II of the Present Invention
상기한 바와 같이, 본 발명은 5-(치환된 페닐알킬)아미노살리실산(5-(substituted phenylalkyl)amino salicylic acid)화합물의 제조에 관한 것으로 5-(치환된 페닐알킬)아미노살리실산(5-(substituted phenylalkyl)amino salicylate) 유도체를 핵심 중간체로 사용하는 새로운 제조공정으로서, 기존의 대한민국 공개특허 제 2003-0058934호를 이용하는 방법은 반응 중에 모노머가 생성되어 이로 인하여 중합반응이 일어나고 그 때문에 반응성이 떨어지고, 그로 인한 반응시간도 오래 지속 되며, 수율이 낮고, 정제의 많은 어려움이 있다. 또한 정제에 드는 비용이 많이 소요되어, 이로 인한 생산단가가 높아지는 문제점을 갖고 있는 반면, 본 발명에서는 반응식 II의 [경로 1], [경로 2], [경로 3]을 통하여 공정이 간단하고 선행기 술 방법에서 발생 될 수 있는 모노머(monomer) 생성을 근원적으로 방지하여 저 비용 및 고 수율로 목적 화합물을 화학식 I을 간편하게 얻을 수 있고, 이러한 화학식 I은 급성 및 퇴행성 뇌신경계 질환의 예방 및 치료제로 이용 가능하며, 알츠하이머병, 파킨슨씨병 및 헌팅턴씨병 등의 퇴행성 뇌신경계 질환, 간질 등의 경련성 뇌신경계 질환 및 뇌졸중 등의 허혈성 뇌신경계 질환의 예방 및 치료 등에도 유효하게 이용될 수 있다.As described above, the present invention relates to the preparation of 5- (substituted phenylalkyl) amino salicylic acid compounds, and 5- (substituted phenylalkyl) aminosalicylic acid (5- (substituted) As a new manufacturing process using a phenylalkyl) amino salicylate) derivative as a key intermediate, the existing method using the Republic of Korea Patent Publication No. 2003-0058934 is that monomers are generated during the reaction, thereby causing a polymerization reaction, thereby reducing the reactivity, Due to the long reaction time, the yield is low, there are many difficulties in purification. In addition, the cost of purification is high, and thus, the production cost thereof is increased, whereas in the present invention, the process is simple and precedent through [path 1], [path 2], and [path 3] of Scheme II. It is possible to easily obtain the target compound of formula I at low cost and high yield by fundamentally preventing the production of monomers that may occur in the method of alcohol, which is used as a preventive and therapeutic agent for acute and degenerative neurological diseases. It can be used effectively for the prevention and treatment of degenerative brain neurological diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease, convulsive neurological system diseases such as epilepsy and ischemic cerebral nervous system diseases such as stroke.
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| GB1268465A (en) | 1969-06-25 | 1972-03-29 | Merck & Co Inc | Substituted salicylic acid compounds |
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| GB1268465A (en) | 1969-06-25 | 1972-03-29 | Merck & Co Inc | Substituted salicylic acid compounds |
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