KR101900374B1 - Method for synthesizing 5-(chlorophenyl)-2-furancarbothioamide compound from furoic acid - Google Patents
Method for synthesizing 5-(chlorophenyl)-2-furancarbothioamide compound from furoic acid Download PDFInfo
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- KR101900374B1 KR101900374B1 KR1020170050939A KR20170050939A KR101900374B1 KR 101900374 B1 KR101900374 B1 KR 101900374B1 KR 1020170050939 A KR1020170050939 A KR 1020170050939A KR 20170050939 A KR20170050939 A KR 20170050939A KR 101900374 B1 KR101900374 B1 KR 101900374B1
- Authority
- KR
- South Korea
- Prior art keywords
- chlorophenyl
- compound
- furancarbothioamide
- formula
- furoic acid
- Prior art date
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- -1 5-(chlorophenyl)-2-furancarbothioamide compound Chemical class 0.000 title claims abstract description 60
- 238000000034 method Methods 0.000 title claims abstract description 20
- 239000002253 acid Substances 0.000 title description 8
- 230000002194 synthesizing effect Effects 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 125000000068 chlorophenyl group Chemical group 0.000 claims abstract description 18
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 18
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 claims abstract description 13
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims abstract description 13
- PPGMCMGISXBEKC-UHFFFAOYSA-N 3-(3-chlorophenyl)furan-2-carbothioamide Chemical compound ClC=1C=CC=C(C=1)C1=C(OC=C1)C(N)=S PPGMCMGISXBEKC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 9
- KUDPGZONDFORKU-UHFFFAOYSA-N n-chloroaniline Chemical class ClNC1=CC=CC=C1 KUDPGZONDFORKU-UHFFFAOYSA-N 0.000 claims abstract description 7
- VOTVXDLPEPZGRT-UHFFFAOYSA-N 5-(2-chlorophenyl)furan-2-carboxamide Chemical compound O1C(C(=O)N)=CC=C1C1=CC=CC=C1Cl VOTVXDLPEPZGRT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 34
- 239000000460 chlorine Substances 0.000 claims description 33
- 239000000126 substance Substances 0.000 claims description 24
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- GCSAXWHQFYOIFE-UHFFFAOYSA-N dipyridin-2-yl carbonate Chemical compound C=1C=CC=NC=1OC(=O)OC1=CC=CC=N1 GCSAXWHQFYOIFE-UHFFFAOYSA-N 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 8
- MMCPOSDMTGQNKG-UHFFFAOYSA-N anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 claims description 8
- 239000004215 Carbon black (E152) Substances 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 229930195733 hydrocarbon Natural products 0.000 claims description 6
- 150000002430 hydrocarbons Chemical class 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- KQCMTOWTPBNWDB-UHFFFAOYSA-N 2,4-dichloroaniline Chemical compound NC1=CC=C(Cl)C=C1Cl KQCMTOWTPBNWDB-UHFFFAOYSA-N 0.000 claims description 5
- ASAXBSZZWZWZBV-UHFFFAOYSA-M 2-chlorobenzenediazonium;chloride Chemical compound [Cl-].ClC1=CC=CC=C1[N+]#N ASAXBSZZWZWZBV-UHFFFAOYSA-M 0.000 claims description 5
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical compound NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 claims description 3
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 claims description 3
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 claims description 3
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- UFGTXPLSPACVGS-UHFFFAOYSA-N pyridin-2-yl hydrogen carbonate Chemical compound OC(=O)OC1=CC=CC=N1 UFGTXPLSPACVGS-UHFFFAOYSA-N 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 32
- 238000003786 synthesis reaction Methods 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 7
- YOFNWWZZELAVRX-UHFFFAOYSA-N methanethione Chemical compound S=[CH+] YOFNWWZZELAVRX-UHFFFAOYSA-N 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- GUOMINFEASCICM-UHFFFAOYSA-N 5-phenylfuran-2-carboxylic acid Chemical compound O1C(C(=O)O)=CC=C1C1=CC=CC=C1 GUOMINFEASCICM-UHFFFAOYSA-N 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- PJGGWIHXGHQXMM-UHFFFAOYSA-N 5-(2-chlorophenyl)furan-2-carboxylic acid Chemical compound O1C(C(=O)O)=CC=C1C1=CC=CC=C1Cl PJGGWIHXGHQXMM-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 206010057190 Respiratory tract infections Diseases 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 4
- 238000005580 one pot reaction Methods 0.000 description 4
- HXYGTCQCDHEVBB-UHFFFAOYSA-N piperidine-1-carbothialdehyde Chemical compound S=CN1CCCCC1 HXYGTCQCDHEVBB-UHFFFAOYSA-N 0.000 description 4
- 238000007280 thionation reaction Methods 0.000 description 4
- 0 *N(*)C(c1ccc(-c2ccccc2)[o]1)=O Chemical compound *N(*)C(c1ccc(-c2ccccc2)[o]1)=O 0.000 description 3
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 3
- HGOUHLGJFUPVGS-UHFFFAOYSA-N 2-chlorobenzenediazonium Chemical compound ClC1=CC=CC=C1[N+]#N HGOUHLGJFUPVGS-UHFFFAOYSA-N 0.000 description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 3
- ZNMIEYHOIRLLES-UHFFFAOYSA-N 5-phenylfuran-2-carboxamide Chemical compound O1C(C(=O)N)=CC=C1C1=CC=CC=C1 ZNMIEYHOIRLLES-UHFFFAOYSA-N 0.000 description 3
- SFXIAQRTVLSMEJ-UHFFFAOYSA-N [5-(3,4-dichlorophenyl)furan-2-yl]-piperidin-1-ylmethanethione Chemical compound C1=C(Cl)C(Cl)=CC=C1C1=CC=C(C(=S)N2CCCCC2)O1 SFXIAQRTVLSMEJ-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- JLIDBLDQVAYHNE-LXGGSRJLSA-N 2-cis-abscisic acid Chemical compound OC(=O)/C=C(/C)\C=C\C1(O)C(C)=CC(=O)CC1(C)C JLIDBLDQVAYHNE-LXGGSRJLSA-N 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- YVTQHZDUDUCGRD-UHFFFAOYSA-N 5-bromofuran-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Br)O1 YVTQHZDUDUCGRD-UHFFFAOYSA-N 0.000 description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
- JLIDBLDQVAYHNE-YKALOCIXSA-N abscisic acid group Chemical group C\C(\C=C\[C@@]1(O)C(C)=CC(=O)CC1(C)C)=C\C(O)=O JLIDBLDQVAYHNE-YKALOCIXSA-N 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000013375 chromatographic separation Methods 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 2
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 2
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 150000003556 thioamides Chemical class 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- KGSWETKVKNOADH-UHFFFAOYSA-M 2,4-dichlorobenzenediazonium;chloride Chemical compound [Cl-].ClC1=CC=C([N+]#N)C(Cl)=C1 KGSWETKVKNOADH-UHFFFAOYSA-M 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- SDYWXFYBZPNOFX-UHFFFAOYSA-N 3,4-dichloroaniline Chemical compound NC1=CC=C(Cl)C(Cl)=C1 SDYWXFYBZPNOFX-UHFFFAOYSA-N 0.000 description 1
- HIDZXTFHMBMDCP-UHFFFAOYSA-N 3-(3-chlorophenyl)furan-2-carboxamide Chemical compound O1C=CC(C=2C=C(Cl)C=CC=2)=C1C(=O)N HIDZXTFHMBMDCP-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- BMJHNNPEPBZULA-UHFFFAOYSA-N 5-phenylfuran-2-carbaldehyde Chemical compound O1C(C=O)=CC=C1C1=CC=CC=C1 BMJHNNPEPBZULA-UHFFFAOYSA-N 0.000 description 1
- YUCYPPIIPWVJMM-UHFFFAOYSA-N 5-phenylfuran-2-carbonyl chloride Chemical compound O1C(C(=O)Cl)=CC=C1C1=CC=CC=C1 YUCYPPIIPWVJMM-UHFFFAOYSA-N 0.000 description 1
- 241000219194 Arabidopsis Species 0.000 description 1
- JXJNALMOWWTLHN-UHFFFAOYSA-N C1(=CC=CC=C1)B(O)O.B(O)O Chemical compound C1(=CC=CC=C1)B(O)O.B(O)O JXJNALMOWWTLHN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- CIZVQWNPBGYCGK-UHFFFAOYSA-N benzenediazonium Chemical class N#[N+]C1=CC=CC=C1 CIZVQWNPBGYCGK-UHFFFAOYSA-N 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229910052798 chalcogen Inorganic materials 0.000 description 1
- 150000001787 chalcogens Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 229960003280 cupric chloride Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- FCRACOPGPMPSHN-UHFFFAOYSA-N desoxyabscisic acid Natural products OC(=O)C=C(C)C=CC1C(C)=CC(=O)CC1(C)C FCRACOPGPMPSHN-UHFFFAOYSA-N 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- OUZNHXMJEBIDSZ-UHFFFAOYSA-N furan-2-carbothioamide Chemical compound NC(=S)C1=CC=CO1 OUZNHXMJEBIDSZ-UHFFFAOYSA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000005887 phenylation reaction Methods 0.000 description 1
- 230000008635 plant growth Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- IPPMOYGRGWPCNF-UHFFFAOYSA-N pyrrolidine-1-carbothialdehyde Chemical compound S=CN1CCCC1 IPPMOYGRGWPCNF-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003334 secondary amides Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 150000003511 tertiary amides Chemical class 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 238000004073 vulcanization Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/36—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
본 발명의 일 실시예는, 염화아닐린(chloroanilines)과 아질산 나트륨을 반응시켜 제조된 염화벤젠디아조늄 화합물을 2-퓨로산(2-furoic acid)과 반응시켜 5-(클로로페닐)-2-퓨로산을 제조하는 제1 단계, 상기 제1 단계에서 제조된 5-(클로로페닐)-2-퓨로산을 디-2-피리딜 카보네이트(2-DPC)로 처리하여 2-피리딜 에스테르 화합물을 제조하고, 여기에 아민을 첨가하여 5-(클로로페닐)-2-퓨란카보아미드를 제조하는 제2 단계 및 상기 제2 단계에서 제조된 5-(클로로페닐)-2-퓨란카보아미드를 로손 시약(Lawesson's reagent)으로 처리하는 제3 단계를 포함하는, 5-클로로페닐-2-퓨란카보티오아미드계 화합물의 제조방법을 제공한다.One embodiment of the present invention relates to a process for the preparation of 5- (chlorophenyl) -2-furo [gamma] -D-glucopyranoside by reacting a chlorobenzenediazonium compound prepared by reacting chloroanilines with sodium nitrite, (2-pyridyl) carbonate (2-DPC) to prepare a 2-pyridyl ester compound, which is prepared in the first step, (Chlorophenyl) -2-furanylcarboamide prepared in Step 2 and 5- (chlorophenyl) -2-furancarboamide prepared in Step 2 were dissolved in a solution of Lawesson's reagent Lawesson ' s reagent) to provide a 5-chlorophenyl-2-furancarbothioamide-based compound.
Description
본 발명은 퓨로산으로부터 5-클로로페닐-2-퓨란카르보티오아미드계 화합물을 합성하는 방법에 대한 것으로, 보다 구체적으로, 간단한 공정에 의해 퓨로산으로부터 알킬-5-(클로로페닐)-2-퓨란카르보티오아미드계 화합물을 효율적으로 제조하는 방법에 대한 것이다.The present invention relates to a process for synthesizing 5-chlorophenyl-2-furancarbothioamide-based compounds from furoic acid, and more particularly to a process for synthesizing alkyl 5- (chlorophenyl) -2- And a method for efficiently producing a furan carbothioamide-based compound.
티오아미드(thioamide) 화합물은 항인플루엔자 바이러스 특성, 항종양 특성 및 구충(anthelmintic) 특성과 같은 약학적 활성을 가진 중요한 화합물이다. Thioamide compounds are important compounds with pharmacological activity such as anti-influenza virus, antitumor and anthelmintic properties.
또한, 2-위치 및 5- 위치가 치환된 다양한 퓨란 화합물들이 자연계에 존재하며, 이들의 히드라지드(hydrazide) 유도체는 살균성, 제초성(herbicidal) 등을 포함하는 다양한 활성을 나타낸다. 이러한 유도체들 중, 2,5-치환된 퓨란 골격(2,5-disubstituted furan skeleton)을 갖는 화합물인 5-(3,4-디클로로페닐)퓨란-2-일](피페리딘-1-일)메탄티온{[5-(3,4-dichlorophenyl)furan-2-yl](piperidin-1-yl) methanethione}(DFPM)은 낙엽산(abscisic acid)(ABA) 종속성 유전자의 발현을 하향 조절하고(downregulate), ABA 신호의 변환(transduction)을 억제한다. 최근 DFPM은 애기 장대(Arabidopsis) 식물의 뿌리에서 특정의 성장 정지(growth arrest) 특성을 가진다는 것이 알려졌다.Also, various furan compounds substituted in 2-position and 5-position exist in nature, and their hydrazide derivatives exhibit various activities including bactericidal, herbicidal and the like. Of these derivatives, compounds having a 2,5-disubstituted furan skeleton such as 5- (3,4-dichlorophenyl) furan-2-yl] (piperidin- (DFPM) down-regulates the expression of the abscisic acid (ABA) dependency gene and the expression of the abscisic acid (ABA) downregulate, and suppress the transduction of the ABA signal. It has recently been found that DFPM has a specific growth arrest characteristic in the roots of Arabidopsis plants.
한편, 5-(클로로페닐)-2-퓨란카르보티오아미드[5-(chlorophenyl)-2-furancarbothioamide]의 합성은, 5-(클로로페닐)-2-퓨로산[5-(chlorophenyl)-2-furoic acid]의 제조, 아미드 전환 및 아미드의 가황(thionation)으로 이루어진다. On the other hand, the synthesis of 5- (chlorophenyl) -2-furancarbothioamide [5- (chlorophenyl) -2-furancarbothioamide] -furoic acid], amide conversion and thionation of the amide.
일반적으로, 5-페닐-2-퓨로산은 2-퓨란카르복스알데하이드(2-furancarboxaldehyde)의 메르바인 페닐화(Meerwein phenylation)에 의해 얻어지는 5-페닐-2-퓨르알데하이드(5-phenyl-2-furaldehyde)의 산화에 의해 제조된다. 또한, 5-페닐-2-퓨로산은, 벤젠디아조늄염(benzenediazonium salt)을 이용한 2-퓨로산(2-furoic acid)의 디아조화(diazotization)에 의해 제조되거나, 마이크로파의 조사(microwave irradiation) 또는 공기 중에서 Pd/C 촉매를 이용한 5-브로모-2-퓨로산(5-bromo-2-furoic acid)과 테트라페닐보레이트 나트륨(sodium tetraphenylborate)의 교차 결합 반응(cross-coupling reaction)에 의해 제조된다.Generally, 5-phenyl-2-furoic acid is a 5-phenyl-2-furaldehyde obtained by Meerwein phenylation of 2-furancarboxaldehyde ). ≪ / RTI > In addition, 5-phenyl-2-furoic acid may be prepared by diazotization of 2-furoic acid with benzenediazonium salt or by microwave irradiation or Is prepared by cross-coupling reaction of 5-bromo-2-furoic acid and sodium tetraphenylborate in air using a Pd / C catalyst .
5-페닐-2-퓨란카르복스아미드(5-phenyl-2-furancarboxamide)는 일반적으로, 아민(amine)을 이용한 5-페닐-2-퓨로일 클로라이드(5-phenyl-2-furoyl chloride)의 아실 치환(acyl substitution)에 의해 합성되며, 5-페닐-2-퓨로일 클로라이드는 5-페닐-2-퓨로산(5-phenyl-2-furoic acid)과 염화티오닐(thionyl chloride)의 반응으로부터 유도된다. 염화페닐술포닐(phenylsulfonyl chloride)를 이용한 5-페닐-2-퓨로산과 아릴아민(arylamine)의 원포트 반응(one-pot reaction)에 의해서도 N-아릴-5-페닐-2-퓨란카르복스아마이드(N-aryl-5-phenyl-2-furancarboxamide)가 얻어질 수 있다. 한편, EDCl/HOBt를 이용한 5-브로모-2-퓨로산(5-bromo-2-furoic acid)과 아릴아민(arylamine)의 축합반응에 의해서 N-아릴-5-브로모-2-퓨란카르복스아마이드(N-aryl-5-bromo-2-furancarboxamide)가 얻어질 수 있다. 이러한 아미드들은 Pd(PPh3)4의 존재 하에서 페닐보론산(phenylboronic acid)과 커플링되어 N-아릴-5-페닐-2-퓨란카르복스아마이드(N-aryl-5-phenyl-2-furancarboxamide)를 제공한다. 5-페닐-2-퓨란카르복스아마이드(5-phenyl-2-furancarboxamide)가 그에 대응되는 티오아미드(thioamide)로 전환(conversion)되는 반응은, 일반적으로 2,4-비스(4-메톡시페닐)-1,3,2,4-디티아포스페탄 2,4-디설파이드[2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiaphosphetane 2,4-disulfide](Lawesson's reagent)을 이용하여 이루어지는데, 이는 카르보닐 기(carbonyl group)의 가황(thionation)에 광범위하게 사용되었다.5-phenyl-2-furancarboxamide is generally prepared by reacting an acyl of 5-phenyl-2-furoyl chloride with an amine 5-phenyl-2-furoyl chloride is synthesized by acyl substitution and is derived from the reaction of 5-phenyl-2-furoic acid with thionyl chloride do. One-pot reaction of 5-phenyl-2-furoic acid with arylamine using phenylsulfonyl chloride gave N-aryl-5-phenyl-2-furancarboxamide ( N-aryl-5-phenyl-2-furancarboxamide) can be obtained. On the other hand, by the condensation reaction of 5-bromo-2-furoic acid with arylamine using EDCl / HOBt, N-aryl-5-bromo-2- N-aryl-5-bromo-2-furancarboxamide can be obtained. These amides are Pd (PPh 3) is coupled with boronic acid (phenylboronic acid) in the presence of 4 N- aryl-5-phenyl-2-furan-carboxamide amide (N-aryl-5-phenyl -2-furancarboxamide) Lt; / RTI > The reaction in which 5-phenyl-2-furancarboxamide is converted to the corresponding thioamide is generally carried out by reacting 2,4-bis (4-methoxyphenyl) (2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiaphosphetane 2,4-disulfide] (Lawesson's reagent) , Which is widely used for thionation of carbonyl groups.
그러나, DFPM을 포함하는 5-(클로로페닐)-2-퓨란카르보티오아미드[5-(chlorophenyl)-2-furancarbo-thioamide]의 합성은 보고된 바 없다.However, the synthesis of 5- (chlorophenyl) -2-furancarbo-thioamide containing DFPM has not been reported.
본 발명의 일 실시예는, 온화한 조건(mild condition)에서 퓨로산으로부터 5-클로로페닐-2-퓨란카르보티오아미드계 화합물을 효율적으로 합성하는 방법을 제공하고자 한다.One embodiment of the present invention is to provide a method for efficiently synthesizing a 5-chlorophenyl-2-furancarbothioamide-based compound from furoic acid in a mild condition.
본 발명의 다른 일 실시예는, 온화한 조건(mild condition)에서 퓨로산으로부터 알킬-5-(클로로페닐)-2-퓨로카르보티오아미드 화합물을 효율적으로 제조하는 방법을 제공하고자 한다. 보다 구체적으로, 본 발명의 다른 일 실시예는, 퓨로산으로부터, 식물 성장 억제 특성을 갖는 N,N-디알킬-5-(클로로페닐)-2-퓨로카르보티오아미드 화합물을 제조하는 방법을 제공하고자 한다.Another embodiment of the present invention is to provide a process for efficiently producing an alkyl-5- (chlorophenyl) -2-furacarbothioamide compound from furoic acid under mild conditions. More specifically, another embodiment of the present invention is a method for producing an N, N-dialkyl-5- (chlorophenyl) -2-furacarbothioamide compound having plant growth inhibitory properties from furosilic acid .
이러한 과제를 해결하기 위해, 본 발명의 일 실시예는, 염화아닐린(chloroaniline)과 아질산 나트륨(sodium nitrite)을 반응시켜 제조된 염화벤젠디아조늄(chlorobenzenediazonium) 화합물을 2-퓨로산(2-furoic acid)과 반응시켜 5-(클로로페닐)-2-퓨로산[5-(chlorophenyl)-2-furoic acid]을 제조하는 제1 단계; 상기 제1 단계에서 제조된 5-(클로로페닐)-2-퓨로산[5-(chlorophenyl)-2-furoic acid]을 디-2-피리딜 카보네이트(di-2-pyridyl carbonate)(2-DPC)로 처리하여 2-피리딜 에스테르(2-pyridyl esters) 화합물을 제조하고, 여기에 아민을 첨가하여 5-(클로로페닐)-2-퓨란카보아미드[5-(chlorophenyl)-2-furancarboamide]를 제조하는 제2 단계; 및 상기 제2 단계에서 제조된 5-(클로로페닐)-2-퓨란카보아미드를 로손 시약(Lawesson's reagent)으로 처리하는 제3 단계;를 포함하는, 5-클로로페닐-2-퓨란카보티오아미드[5-(chlorophenyl)-2-furancarbothioamide]계 화합물의 제조방법을 제공한다.In order to solve the above problems, an embodiment of the present invention relates to a method for producing a chlorobenzenediazonium compound prepared by reacting chloroaniline with sodium nitrite in the presence of 2-furoic acid ) To produce 5- (chlorophenyl) -2-furoic acid [5- (chlorophenyl) -2-furoic acid]; 2-furoic acid [5- (chlorophenyl) -2-furoic acid] prepared in the first step was dissolved in di-2-pyridyl carbonate (2-DPC ) To prepare a 2-pyridyl esters compound which is then reacted with 5- (chlorophenyl) -2-furancarboamide A second step of manufacturing; And a third step of treating the 5- (chlorophenyl) -2-furan-carbamoide prepared in the second step with Lawesson's reagent to obtain 5-chlorophenyl-2-furancarbothioamide [ 5- (chlorophenyl) -2-furancarbothioamide] compound.
상기 제1 단계는 하기 반응식 1로 표현된다.The first step is represented by the following reaction formula (1).
[반응식 1] [Reaction Scheme 1]
여기서, R1 및 R2는 각각 독립적으로 수소 또는 염소(Cl)이며, R1 및 R2 중 적어도 하나는 염소(Cl)이다.Wherein R 1 and R 2 are each independently hydrogen or chlorine (Cl), and at least one of R 1 and R 2 is chlorine (Cl).
상기 제2 단계는 하기 반응식 2로 표현된다.The second step is represented by the following reaction formula (2).
[반응식 2][Reaction Scheme 2]
여기서, R3 및 R4는 이들과 연결된 질소 원자(N)와 함께 고리를 형성하거나, 또는, R3 및 R4는 각각 독립적으로 수소, 직쇄형 탄화수소 및 고리형 탄화수소 중 어느 하나이며, 이 때 R3 및 R4 중 적어도 하나는 수소가 아니다.Wherein R 3 and R 4 together with the nitrogen atom (N) connected to them form a ring, or R 3 and R 4 are each independently any one of hydrogen, straight chain hydrocarbon and cyclic hydrocarbon, At least one of R < 3 > and R < 4 > is not hydrogen.
상기 제3 단계는 하기 반응식 3으로 표현된다.The third step is represented by the following reaction formula (3).
[반응식 3][Reaction Scheme 3]
상기 5-클로로페닐-2-퓨란카보티오아미드계 화합물은 하기 화학식 1로 표현된다.The 5-chlorophenyl-2-furancarbothioamide compound is represented by the following formula (1).
[화학식 1][Chemical Formula 1]
여기서, R1 및 R2는 각각 독립적으로 수소 또는 염소(Cl)이며, R1 및 R2 중 적어도 하나는 염소(Cl)이다. Wherein R 1 and R 2 are each independently hydrogen or chlorine (Cl), and at least one of R 1 and R 2 is chlorine (Cl).
R3 및 R4는 이들과 연결된 질소 원자(N)와 함께 고리를 형성하거나, 또는, R3 및 R4는 각각 독립적으로 수소, 직쇄형 탄화수소 및 고리형 탄화수소 중 어느 하나이며, 이 때 R3 및 R4 중 적어도 하나는 수소가 아니다. R 3 and R 4 form a ring together with the nitrogen atom (N) connected thereto, or R 3 and R 4 are each independently any one of hydrogen, straight chain hydrocarbon and cyclic hydrocarbon, wherein R 3 And R < 4 > are not hydrogen.
상기 5-클로로페닐-2-퓨란카보티오아미드계 화합물은 화학식 2 내지 12 중 어느 하나로 표현될 수 있다.The 5-chlorophenyl-2-furancarbothioamide-based compound may be represented by any one of formulas (2) to (12).
상기 염화아닐린은 2,4-디클로로아닐린(2,4-dichloroaniline), 2-클로로아닐린(2-chloroaniline), 3-클로로아닐린(3-chloroaniline), 4-클로로아닐린(4-chloroaniline) 및 3,4-디클로로아닐린(3,4-dichloroaniline) 중 어느 하나이다.The aniline chloride can be prepared by reacting 2,4-dichloroaniline, 2-chloroaniline, 3-chloroaniline, 4-chloroaniline, 4-dichloroaniline. ≪ / RTI >
상기 아민은 피페리딘(piperidine), 디에틸아민(diethylamine), 시클로프로필아민(cyclopropylamine), 피롤리딘(pyrrolidine) 및 모르폴린(morpholine) 중 어느 하나이다. The amine is any one of piperidine, diethylamine, cyclopropylamine, pyrrolidine, and morpholine.
상기 염화벤젠디아조늄(chlorobenzenediazonium) 화합물은 염화벤젠디아조늄 염화물(chlorobenzenediazonium chloride)이다.The chlorobenzenediazonium compound is a chlorobenzenediazonium chloride.
본 발명의 일 실시예에 따르면, 온화한 반응조건에서 퓨로산으로부터 5-클로로페닐-2-퓨란카르보티오아미드계 화합물이 효율적으로 합성될 수 있다. 또한, 본 발명의 일 실시예에 따르면, 온화한 반응조건에서 퓨로산으로부터 알킬-5-(클로로페닐)-2-퓨로카르보티오아미드 화합물이 효율적으로 제조될 수 있다. 특히, 본 발명의 일 실시예에 따르면, N,N-디알킬-5-(클로로페닐)-2-퓨란카르보티오아미드 화합물이 합성될 수 있다.According to one embodiment of the present invention, 5-chlorophenyl-2-furancarbothioamide-based compounds can be efficiently synthesized from furoic acid under mild reaction conditions. Further, according to one embodiment of the present invention, an alkyl-5- (chlorophenyl) -2-furocarbothioamide compound can be efficiently produced from furoic acid under mild reaction conditions. In particular, according to one embodiment of the present invention, N, N-dialkyl-5- (chlorophenyl) -2-furancarbothioamide compounds can be synthesized.
또한, 본 발명의 일 실시예에 따르면, 2-퓨로산으로부터 3단계 반응에 의하여 5-(클로로페닐)-2-퓨란카르보티오아미드계 화합물이 합성될 수 있다.Further, according to one embodiment of the present invention, a 5- (chlorophenyl) -2-furancarbothioamide-based compound can be synthesized by a three-step reaction from 2-furoic acid.
본 발명의 일 실시예 따르면, 반응의 모든 단계들이 온화한 조건에서 수행될 수 있으며, 5-페닐-2-퓨로산의 5-페닐-2-퓨란카르보아미드로의 전환은 한 단계 반응으로 이루어질 수 있다.According to one embodiment of the present invention, all steps of the reaction can be carried out under mild conditions and the conversion of 5-phenyl-2-furoic acid to 5-phenyl-2-furancarbamides can be carried out in one step reaction have.
본 발명의 일 실시예에 따르면, 다양한 구조를 갖는 5-(클로로페닐)-2-퓨란카르보티오아미드 유도체가 높은 수득율로 제조될 수 있다.According to one embodiment of the present invention, 5- (chlorophenyl) -2-furancarbothioamide derivatives having various structures can be prepared with high yields.
본 발명의 이점 및 특징, 그리고 그것들을 달성하는 방법은 후술되어 있는 실시예들을 참조하면 명확해질 것이다. 그러나 본 발명은 이하에서 개시되는 실시예들에 한정되는 것이 아니라 서로 다른 다양한 형태로 구현될 것이며, 실시예들은 단지 본 발명의 개시가 완전하도록 하며, 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에게 발명의 범주를 완전하게 알려주기 위해 제공되는 것이다. 본 발명의 범위는 청구항의 범주에 의해 정의될 뿐이다. Advantages and features of the present invention and methods of achieving them will become apparent with reference to the embodiments described hereinafter. The present invention will now be described more fully hereinafter with reference to the accompanying drawings, in which preferred embodiments of the present invention are shown. However, the present invention is not limited to the embodiments described below, It is provided to inform the person completely of the scope of the invention. The scope of the present invention is defined only by the scope of the claims.
시간 관계에 대한 설명에 있어서, 예를 들어, '~후에', '~에 이어서', '~다음에', '~전에' 등으로 시간적 선후 관계가 설명되는 경우, '바로' 또는 '직접'이 사용되지 않는 이상 연속적이지 않은 경우도 포함할 수 있다.In the description of the time relation, for example, if the temporal relationship is described by 'after', 'after', 'after', 'before', etc., May not be continuous unless they are not used.
이하, 실시예를 참조하여 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail with reference to examples.
본 발명의 일 실시예에 따르면, 3단계 반응에 의해 5-클로로페닐-2-퓨란카보티오아미드[5-(chlorophenyl)-2-furancarbothioamide]계 화합물을 제조할 수 있다.According to one embodiment of the present invention, a 5-chlorophenyl-2-furancarbothioamide compound can be prepared by a three-step reaction.
구체적으로, 본 발명의 일 실시예에 따른 5-클로로페닐-2-퓨란카보티오아미드계 화합물의 제조방법은, 염화아닐린(chloroanilines)과 아질산 나트륨(sodium nitrite)을 반응시켜 제조된 염화벤젠디아조늄(chlorobenzenediazonium) 화합물을 2-퓨로산(2-furoic acid)과 반응시켜 5-(클로로페닐)-2-퓨로산[5-(chlorophenyl)-2-furoic acid]을 제조하는 제1 단계, 제1 단계에서 제조된 5-(클로로페닐)-2-퓨로산을 디-2-피리딜 카보네이트(di-2-pyridyl carbonate)(2-DPC)로 처리하여 2-피리딜 에스테르(2-pyridyl esters) 화합물을 제조하고, 여기에 아민을 첨가하여 5-(클로로페닐)-2-퓨란카보아미드[5-(chlorophenyl)-2-furancarboamide]를 제조하는 제2 단계 및 제2 단계에서 제조된 5-(클로로페닐)-2-퓨란카보아미드를 로손 시약(Lawesson's reagent)으로 처리하는 제3 단계를 포함한다.Specifically, a method for preparing a 5-chlorophenyl-2-furancarbothioamide compound according to an embodiment of the present invention is a method for producing a 5-chlorophenyl-2-furancarbothioamide compound by reacting chloranilines with sodium nitrite, (chlorophenyl) -2-furoic acid] by reacting a chlorobenzenediazonium compound with 2-furoic acid to produce a 5- (chlorophenyl) -2-furoic acid, 2-pyridyl esters prepared by treating the 5- (chlorophenyl) -2-furoic acid prepared in the above step with di-2-pyridyl carbonate (2-DPC) 2-furancarboamide] was prepared in the same manner as in Example 1, except that 5- (chlorophenyl) -2-furancarboamide was prepared by adding an amine thereto to prepare 5- (chlorophenyl) Chlorophenyl) -2-furancarbonamide with Lawesson ' s reagent.
제1 단계는 하기 반응식 1로 표현될 수 있다.The first step can be represented by the following reaction formula 1.
[반응식 1] [Reaction Scheme 1]
구체적으로, 제1 단계에서는, 염화아닐린(chloroanilines)(일반식 I)과 아질산 나트륨(sodium nitrite)을 반응시켜 염화벤젠디아조늄(chlorobenzene-diazonium) 화합물(일반식 II)을 제조하고, 이를 2-퓨로산(2-furoic acid)과 반응시켜 5-(클로로페닐)-2-퓨로산[5-(chlorophenyl)-2-furoic acid](일반식 III)을 제조한다.Specifically, in the first step, a chlorobenzene-diazonium compound (Formula II) is prepared by reacting chloroanilines (Formula I) with sodium nitrite, which is then reacted with 2- 5- (chlorophenyl) -2-furoic acid (Formula III) is prepared by reacting 2-furoic acid with 5- (chlorophenyl) -2-furoic acid.
반응식 1에서, R1 및 R2는 각각 독립적으로 수소 또는 염소(Cl)이며, R1 및 R2 중 적어도 하나는 염소(Cl)이다. 예를 들어, 염화아닐린(일반식 I)의 2-, 3- 및 4- 위치 중 어느 한 곳 또는 두 곳에 염소(Cl) 원자가 치환될 수 있다.In Scheme 1, R 1 and R 2 are each independently hydrogen or chlorine (Cl), and at least one of R 1 and R 2 is chlorine (Cl). For example, chlorine (Cl) atoms may be substituted at either or both of the 2-, 3- and 4-positions of aniline chloride (Formula I).
본 발명의 일 실시예에 따르면, 제1 단계에서 사용되는 염화아닐린(일반식 I)은 2,4-디클로로아닐린(2,4-dichloroaniline), 2-클로로아닐린(2-chloroaniline), 3-클로로아닐린(3-chloroaniline), 4-클로로아닐린(4-chloroaniline) 및 3,4-디클로로아닐린(3,4-dichloroaniline) 중 어느 하나이다.According to one embodiment of the present invention, the chlorinated aniline (general formula I) used in the first step is 2,4-dichloroaniline, 2-chloroaniline, 3- Is one of 3-chloroaniline, 4-chloroaniline and 3,4-dichloroaniline.
또한, 염화벤젠디아조늄(chlorobenzenediazonium) 화합물(일반식 II)로, 예를 들어, 염화벤젠디아조늄 염화물(chlorobenzenediazonium chloride)이 있다.Also, chlorobenzenediazonium chloride compound (formula II) is, for example, chlorobenzenediazonium chloride.
제2 단계는 하기 반응식 2로 표현될 수 있다. The second step can be represented by the following reaction formula (2).
[반응식 2][Reaction Scheme 2]
제2 단계에서는, 제1 단계에서 제조된 5-(클로로페닐)-2-퓨로산[5-(chlorophenyl)-2-furoic acid](일반식 III)을 디-2-피리딜 카보네이트(di-2-pyridyl carbonate)(2-DPC)로 처리하여 2-피리딜 에스테르(2-pyridyl esters) 화합물(일반식 IV)을 제조하고, 여기에 아민(R3R4NH)을 첨가하여 5-(클로로페닐)-2-퓨란카보아미드[5-(chlorophenyl)-2-furancarboamide](일반식 V)를 제조한다. In the second step, the 5- (chlorophenyl) -2-furoic acid (formula III) prepared in the first step is reacted with di-2-pyridyl carbonate 2-pyridyl carbonate (2-DPC) to prepare a 2-pyridyl esters compound (Formula IV), to which an amine (R 3 R 4 NH) Chlorophenyl) -2-furancarboamide (formula V).
반응식 2에서, R1 및 R2는 각각 독립적으로 수소 또는 염소(Cl)이며, R1 및 R2 중 적어도 하나는 염소(Cl)이다.In Scheme 2, R 1 and R 2 are each independently hydrogen or chlorine (Cl), and at least one of R 1 and R 2 is chlorine (Cl).
R3 및 R4는 이들과 연결된 질소 원자(N)와 함께 고리를 형성할 수 있다. 또는, R3 및 R4는 각각 독립적으로 수소, 직쇄형 탄화수소 및 고리형 탄화수소 중 어느 하나일 수 있으며, 이 때, R3 및 R4 중 적어도 하나는 수소가 아니다.R 3 and R 4 may form a ring together with the nitrogen atom (N) linked thereto. Alternatively, R 3 and R 4 may each independently be hydrogen, a linear hydrocarbon, or a cyclic hydrocarbon. At least one of R 3 and R 4 is not hydrogen.
본 발명의 일 실시예에 따르면, 아민(R3R4NH)은 피페리딘(piperidine), 디에틸아민(diethylamine), 시클로프로필아민(cyclopropylamine), 피롤리딘(pyrrolidine) 및 모르폴린(morpholine) 중 어느 하나이다.According to one embodiment of the present invention, the amine (R 3 R 4 NH) is selected from the group consisting of piperidine, diethylamine, cyclopropylamine, pyrrolidine, and morpholine ).
제3 단계는 하기 반응식 3으로 표현될 수 있다.The third step can be represented by the following reaction formula (3).
[반응식 3][Reaction Scheme 3]
제3 단계에서는, 제2 단계에서 제조된 5-(클로로페닐)-2-퓨란카보아미드(일반식 V)를 로손 시약(Lawesson's reagent)으로 처리한다. 5-(클로로페닐)-2-퓨란카보아미드(일반식 V)를 로손 시약(Lawesson's reagent)으로 처리함으로써 5-클로로페닐-2-퓨란카보티오아미드[5-(chlorophenyl)-2-furancarbothioamide]계 화합물(일반식 VI)이 합성된다.In a third step, the 5- (chlorophenyl) -2-furancarboamide (Formula V) prepared in the second step is treated with Lawesson's reagent. Treatment of 5- (chlorophenyl) -2-furancarbothioamide [Formula 5] with 5-chlorophenyl-2-furancarboamide (Formula V) with Lawesson's reagent Compound (VI) is synthesized.
반응식 3에서, R1, R2, R3 및 R4는 상기에서 설명한 바와 같다.In Scheme 3, R 1 , R 2 , R 3 and R 4 are as described above.
본 발명의 일 실시예에 따른 제조방법으로 제조되는 5-클로로페닐-2-퓨란카보티오아미드계 화합물(일반식 VI)은 하기 화학식 1로 표현될 수 있다.The 5-chlorophenyl-2-furancarbothioamide compound (formula VI) prepared by the production method according to one embodiment of the present invention can be represented by the following formula (1).
[화학식 1][Chemical Formula 1]
여기서, R1 및 R2는 각각 독립적으로 수소 또는 염소(Cl)이며, R1 및 R2 중 적어도 하나는 염소(Cl)이다. Wherein R 1 and R 2 are each independently hydrogen or chlorine (Cl), and at least one of R 1 and R 2 is chlorine (Cl).
한편, R3 및 R4는 이들과 연결된 질소 원자(N)와 함께 고리를 형성할 수 있다. 또는, R3 및 R4는 각각 독립적으로 수소, 직쇄형 탄화수소 및 고리형 탄화수소 중 어느 하나이며, 이 때 R3 및 R4 중 적어도 하나는 수소가 아니다. On the other hand, R 3 and R 4 may form a ring together with the nitrogen atom (N) connected thereto. Or R 3 and R 4 are each independently any one of hydrogen, a linear hydrocarbon and a cyclic hydrocarbon, wherein at least one of R 3 and R 4 is not hydrogen.
본 발명의 일 실시예에 따른 제조방법으로 제조되는 5-클로로페닐-2-퓨란카보티오아미드계 화합물은 하기 화학식 2 내지 12 중 어느 하나로 표현될 수 있다.The 5-chlorophenyl-2-furancarbothioamide compound produced by the process according to one embodiment of the present invention can be represented by any one of the following formulas (2) to (12).
[화학식 2](2)
[화학식 3](3)
[화학식 4][Chemical Formula 4]
[화학식 5][Chemical Formula 5]
[화학식 6][Chemical Formula 6]
[화학식 7](7)
[화학식 8][Chemical Formula 8]
[화학식 9][Chemical Formula 9]
[화학식 10][Chemical formula 10]
[화학식 11](11)
[화학식 12][Chemical Formula 12]
Lawesson 시약은 2,4-비스(4-메톡시페닐)-1,2,3,4-디티아디포스페탄-2,4-디설파이드[2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide]로, 하기 화학식 13으로 표시될 수 있다.Lawesson's reagent is 2,4-bis (4-methoxyphenyl) -1,3,4-dithiadiophosphane-2,4-disulfide. 2,4-dithiadiphosphetane-2,4-disulfide] represented by the following formula (13).
[화학식 13][Chemical Formula 13]
이하, 구체적인 제조예를 참조하여 본 발명을 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail with reference to specific production examples.
제조예에서는, 염화아닐린(chloroanilines)과 아질산 나트륨(sodium nitrite)에 의해 형성된 염화벤젠디아조늄(chlorobenzenediazonium) 염을 2-퓨로산(2-furoic acid)과 반응시켜 5-위치가 치환된 5-(클로로페닐)-2-퓨로산[5-(chlorophenyl)-2-furoic acid]를 합성할 수 있다. 합성된 화합물을 디-2-피리딜 카보네이트(di-2-pyridyl carbonate)(2-DPC)로 처리하여 2-피리딜 에스테르(2-pyridyl esters)로 전환시킨 후, 여기에 아민은 첨가함으로써 친핵성 아실 치환반응에 의해 5-(클로로페닐)-2-퓨란카보아미드[5-(chlorophenyl)-2-furancarboamide]를 원포트(one-pot) 반응으로 합성할 수 있다. 이와 같이 얻어진 화합물을 0.5 당량의 로손 시약(Lawesson's reagent)으로 처리하여 다양한 구조를 갖는 5-클로로페닐-2-퓨란카보티오아미드[5-(chlorophenyl)-2-furancarbothioamide]계 화합물들을 온화한 조건에서 높은 수득율로 합성할 수 있다.In the preparation examples, chlorobenzenediazonium salt formed by chloroanilines and sodium nitrite was reacted with 2-furoic acid to obtain 5-substituted (5- Chlorophenyl) -2-furoic acid [5- (chlorophenyl) -2-furoic acid] can be synthesized. The synthesized compound is converted to 2-pyridyl esters by treatment with di-2-pyridyl carbonate (2-DPC) 5- (chlorophenyl) -2-furancarboamide can be synthesized by a one-pot reaction by nucleophilic acylation reaction. The thus obtained compound is treated with 0.5 equivalent of Lawesson's reagent to give 5-chlorophenyl-2-furancarbothioamide compounds having various structures at a high temperature under mild conditions . ≪ / RTI >
보다 구체적으로, 본 발명의 제조예에 따르면, 5-클로로페닐-2-퓨란카보티오아미드계 화합물은 하기 반응식 4에 따라 합성될 수 있다.More specifically, according to the preparation examples of the present invention, 5-chlorophenyl-2-furancarbothioamide-based compounds can be synthesized according to the following Reaction Scheme 4.
[반응식 4][Reaction Scheme 4]
반응식 4에 있어서, 염화 아닐린은 일반식 1로 표현되며, 염화 아닐린(일반식 1)의 치환기 R은 기호 a, b, c, d로 표시된다. 여기서, "a"는 2- 위치에 치환된 염소(2-Cl)를 표시하며, "b"는 4- 위치에 치환된 염소(4-Cl)를 표시하며, "c"는 2,4- 위치에 치환된 두 개의 염소(2,4-di-Cl)를 표시하며, "d"는 3,4- 위치에 치환된 두 개의 염소(3,4-di-Cl)를 표시한다.In Scheme 4, the aniline chloride is represented by the general formula 1, and the substituent R of the aniline chloride (general formula 1) is represented by the symbols a, b, c, and d. Here, "a" represents chlorine (2-Cl) substituted at the 2-position, "b" represents chlorine (4-Cl) substituted at the 4-position, "c" (2,4-di-Cl), and "d" represents two chlorine (3,4-di-Cl) substituted at the 3,4-position.
아민 화합물은 R'NH2 또는 R2'NH로 표시되며(R'NH2 or R2'NH), 그 치환기인 R'는 기호 e, f, g, h, i로 표시된다. 여기서, "e"는 고리형 C3H5(c-C3H5)를 표시하며, "f"는 에틸기(C2H5)를 표시하며, "g"는 고리를 형성하는 -(CH2)4-를 표시하며, "h"는 고리를 형성하는 -(CH2)5-를 표시하며, "i"는 고리를 형성하는 -(CH2)2O(CH2)2-를 표시한다.The amine compound is represented by R'NH 2 or R 2 'NH (R'NH 2 or R 2 ' NH), and the substituent R 'is represented by the symbols e, f, g, h and i. Represents a cyclic C 3 H 5 (cC 3 H 5 ), "f" represents an ethyl group (C 2 H 5 ), "g" represents a - (CH 2 ) 4 -, "h" represents - (CH 2 ) 5 - to form a ring, and "i" represents - (CH 2 ) 2 O (CH 2 ) 2 - to form a ring.
(1) 제1 단계(1) Step 1
먼저, 2-퓨로산(2-furoic acid)을 염화벤젠디아조늄 염(chlorobenzene-diazonium salts)(2a-d; 일반식 2로 표현되며 치환기가 a 내지 d인 화합물)으로 처리하여 5-(클로로페닐)-2-퓨로산[5-(chlorophenyl)-2-furoic acid](3a-d; 일반식 3으로 표현되며 치환기가 a 내지 d인 화합물)을 제조하였다.First, 2-furoic acid is treated with chlorobenzene-diazonium salts (2a-d, compounds of the formula 2 and substituents a to d) to give 5- (chloro Phenyl] -2-furoic acid [5- (chlorophenyl) -2-furoic acid] (3a-d; a compound represented by the general formula 3 and having substituents a to d).
구체적으로, 0℃의 염산 수용액(aqueous HCl solution)에서 아질산나트륨(sodium nitrite)이 염화아닐린(chloroanilines)(1a-d; 일반식 1로 표현되며 치환기가 a 내지 d인 화합물)에 첨가되어, 대응되는 일반식 2의 화합물(2a-d)이 제조되었다. 2-퓨로산과 촉매 용량의 염화 제2 구리(copper(II) chloride)가 일반식 2의 화합물(2a-d)과 혼합되어, 퓨란 고리의 5-위치에서의 페닐화(phenylation)와 함께 위치선택성(regioselective)이 높은 전자친화성(electrophilic) 치환이 이루어졌다. 이 반응은 수시간(several hours) 내에 완료되었으며, 통상적인 정제(work-up) 및 재결정(recrystallization) 후 56-65%의 수득율로 일반식 3의 화합물(3a-d)이 수득되었다(수득율, 3a: 57%, 3b: 56%, 3c: 62%, 3d: 65%).Specifically, sodium nitrite is added to chloroanilines (1a-d, compounds represented by general formula 1 and substituents a to d) in an aqueous HCl solution at 0 ° C, (2a-d) of the general formula 2 was prepared. 2-furoic acid and a catalytic amount of copper (II) chloride are mixed with the compound (2a-d) of the general formula 2 to give a compound of the formula (regioselective) electrophilic substitution was achieved. This reaction was completed within several hours and compound (3a-d) of general formula 3 was obtained with a yield of 56-65% after conventional work-up and recrystallization (yield, 3a: 57%, 3b: 56%, 3c: 62%, 3d: 65%).
(2) 제2 단계(2) Step 2
다음, 아민에 의해 2-피리딜 5-(클로로페닐)-2-퓨로에이트[2-pyridyl 5-(chlorophenyl)-2-furoate] 중간체(intermediate)(일반식 4의 화합물)가 아실 치환(acyl substitution)되어, 5-(클로로페닐)-2-퓨로카르복스아미드(일반식 5의 화합물)가 만들어졌다. Then, the amine is reacted with 2-pyridyl 5- (chlorophenyl) -2-furoate intermediate (compound of the general formula 4) acyl to give 5- (chlorophenyl) -2-furocarboxamide (compound of general formula 5).
구체적으로, 염화메틸렌(methylene chloride) 용매에 용해된 일반식 3의 화합물 용액에, 디-2-피리딜 카보네이트(di-2-pyridyl carbonate)(2-DPC)가 첨가되어, 대응되는 카르복시 무수물(carboxylic anhydride)의 혼합물이 얻어졌으며, 이는 다시 촉매 용량의 4-(디메틸아미노)피리딘[4-(dimethylamino)pyridine](4-DMAP) 으로 처리되어 일반식 4의 화합물로 전환되었다. 예를 들어, 0.1 당량의 4-DMAP의 존재하에서 5-(3,4-디클로로페닐)-2-퓨로산(5-(3,4-dichlorophenyl)-2-furoic acid)(일반식 3d의 화합물)이 2-DPC와 반응되어 95%의 수득율로 2-피리딜 5-(3,4-디클로로페닐)-2-퓨로에이트[2-pyridyl 5-(3,4-dichlorophenyl)-2-furoate] (일반식 4d의 화합물)가 얻어졌다. 피리딘 고리의 1H NMR 값은 δ 8.46 (dd, J = 4.9, 1.6 Hz, 1H), 7.82-7.89 (m, 1H), 7.24-7.31 (m, 2H)에서 측정되었고, 일반식 4d의 화합물에 대한 FT-IR 카보닐 신축 피크(FT-IR carbonyl stretching peak)는 1739 cm-1에서 측정되었다. Specifically, di-2-pyridyl carbonate (2-DPC) is added to a solution of a compound of the general formula 3 dissolved in a methylene chloride solvent to give the corresponding carboxylic anhydride ( carboxylic anhydride was obtained which was again treated with a catalytic amount of 4- (dimethylamino) pyridine (4-DMAP) and converted to the compound of formula 4. (3,4-dichlorophenyl) -2-furoic acid (compound of the general formula (3d) in the presence of 0.1 equivalent of 4-DMAP, ) Was reacted with 2-DPC to give 2-pyridyl 5- (3,4-dichlorophenyl) -2-furoate with 95% yield. (Compound of the general formula 4d) was obtained. The 1 H NMR values of the pyridine ring were measured at δ 8.46 (dd, J = 4.9, 1.6 Hz, 1H), 7.82-7.89 (m, 1H), 7.24-7.31 The FT-IR carbonyl stretching peak (FT-IR carbonyl stretching peak) was measured at 1739 cm -1 .
일반식 5의 화합물 합성은, 일반식 4의 화합물에 대한 분리 없이, 원포트 공정(one-pot process)로 수행된다. 즉, 0℃의 염화메틸렌(methylene chloride) 용매로 된 일반식 4의 화합물 용액에 아민이 직접 첨가되었고, 0.5시간(hour)동안 반응 후, 반응이 완료되었다. 통상적인 기본 정제(work-up) 및 크로마토그래피에 의한 분리에 의해 81-96%의 수득율로 일반식 5의 화합물이 수득되었다.The synthesis of the compound of the general formula 5 is carried out in a one-pot process without separation of the compound of the general formula 4. [ Namely, the amine was directly added to a solution of the compound of the general formula 4 in a methylene chloride solvent at 0 ° C, and the reaction was completed after 0.5 hour. By conventional basic work-up and chromatographic separation, the compound of general formula 5 was obtained with a yield of 81-96%.
(3) 제3 단계(3) Step 3
카르복실기의 효율적인 가황제(thionating agent)인 로손 시약(Lawesson's reagent)를 이용하여 일반식 5의 화합물이 5-(클로로페닐)-2-퓨란카르보티오아미드[N,N-dialkyl-5-(chlorophenyl)-2-furancarbothioamide](일반식 6)로 변환되었다.Using Lawesson's reagent, an efficient thionating agent of the carboxyl group, the compound of formula 5 is reacted with 5- (chlorophenyl) -2-furancarbothioamide [N, N-dialkyl-5- ) -2-furancarbothioamide] (Formula 6).
구체적으로, 염화메틸렌(methylene chloride) 용매로 된 일반식 5의 화합물 용액에 로손 시약(Lawesson's reagent)이 첨가되면, 디티오포스핀 일라이드(dithiophosphine ylide)의 황 원자(S)가 일반식 5의 화합물에 있는 카보닐기의 탄소 원자를 공격하여 티아옥사포스페탄(thiaoxaphosphetane)이 형성된다. 이 중간체(intermediate)에서 환제거가 일어나(cycloeliminated), 일반식 6의 화합물과 메타티오포스포네이트(metathiophosphonate)(p-MeOC6H4POS)가 형성된다. 로손 시약(Lawesson's reagent)를 이용한 일반식 5의 화합물에 대한 가황(thionation)은 상온에서 0.5 내지 3.5 시간에 완료되었으며, 크로마토그래피 분리 후 87-96%의 수득율로 일반식 6의 화합물이 수득되었다. Specifically, when Lawesson's reagent is added to a solution of a compound of the general formula 5 of a methylene chloride solvent, the sulfur atom (S) of the dithiophosphine ylide is reacted with the compound of the general formula 5 To attack the carbon atom of the carbonyl group in the thiooxaphosphetane to form thiaoxaphosphetane. At this intermediate cycloeliminated, the compound of formula 6 and metathiophosphonate ( p -MeOC 6 H 4 POS) are formed. The thionation of the compound of general formula 5 using Lawesson's reagent was completed in 0.5-3.5 hours at room temperature and the compound of general formula 6 was obtained with a yield of 87-96% after chromatographic separation.
한편, N-시클로프로필-5-(4-클로로페닐)-2-퓨란카르복스아미드(N-cyclopropyl-5-(4-chlorophenyl)-2-furancarboxamide)(일반식 5be)의 경우, 상온에서 48시간 이상 염화메틸렌에서 가황이 느리게 진행되어, 73%의 수득율로 N-시클로프로필-5-(4-클로로페닐)-2-퓨란카보티오아미드(N-cyclopropyl-5-(4-chlorophenyl)-2-furancarbothioamide)(일반식 6be)가 수득되었다. 그러나, 대응되는 일반식 5be의 화합물의 반응은 THF에서 완료되었으며, 1.5 시간 후 65℃에서 90%의 수득율로 화합물 6b가 수득되었다.On the other hand, in the case of N-cyclopropyl-5- (4-chlorophenyl) -2-furancarboxamide (formula 5be) (4-chlorophenyl) -2 (4-chlorophenyl) -2-naphthyridine was obtained at a yield of 73% -furancarbothioamide (general formula 6be). However, the reaction of the corresponding compound of general formula 5be was completed in THF, and compound 6b was obtained after 1.5 hours at 65 DEG C with a yield of 90%.
이하, 화학식 2 내지 12로 표현되는 화합물은 다음과 같이 합성된다.Hereinafter, the compounds represented by formulas (2) to (12) are synthesized as follows.
<합성예 1> ≪ Synthesis Example 1 &
[5-(2,4-디클로로페닐)퓨란-2-일](피페리딘-1-일)메탄티온{[5-(2,4-dichlorophenyl)furan-2-yl] (piperidin-1-yl)methanethione}(일반식 6ch)의 합성2-yl] (piperidin-1-yl) methanethion {[5- (2,4-dichlorophenyl) furan- yl) methanethione} (General Formula 6ch) Synthesis of
(1) 제1 단계(1) Step 1
5-(2,4-디클로로페닐)-2-퓨로산[5-(2,4-dichlorophenyl)-2-furoic acid](일반식 3c)의 제조Preparation of 5- (2,4-dichlorophenyl) -2-furoic acid [5- (2,4-dichlorophenyl) -2-furoic acid]
10 mL의 물(H2O)에 3.37 g의 2,4-디클로로아닐린[2,4-dichloroaniline](일반식 1c)이 분산되어 이루어진 2,4-디클로로아닐린 분산액(3.37 g, 20.8 mmol)에, 0℃에서 18%의 염산 용액(HCl solution) 8 mL가 첨가되었다. 20분간 교반 후, 10 mL의 물(H2O)에 1.44 g의 아질산나트륨(sodium nitrite)이 용해되어 이루어진 아질산나트륨 용액(1.44 g, 20.9 mmol)이 첨가되어, 그 혼합물이 다시 20분간 교반되었다. 그 결과물인 2,4-디클로로벤젠디아조늄 클로라이드(2,4-dichlorobenzenediazonium chloride) 용액에, 7 mL의 아세톤(acetone)에 1.46 g의 2-퓨로산(2-furoic acid)이 용해되어 이루어진 2-퓨로산 용액(1.46 g, 13.0 mmol)이 첨가되고, 5 mL의 물(H2O)에 523 mg의 염화 제2 구리[copper(II) chloride]가 용해되어 이루어진 염화 제2 구리 용액(523 mg, 3.9 mmol)이 첨가되었다. 그 혼합물은 0℃ 내지 상온의 온도에서 6시간 동안 교반되었다. 아세톤(acetone)이 증발되어 제거된 후, 혼합액이 50 mL의 염수(brine)에 투여(poured)된 다음, 30 mL의 에틸 아세테이트(ethyl acetate)로 3회 추출되었다. 추출된 유기층 상(combined organic phases)이 무수 황산 마그네슘(anhydrous MgSO4)에서 건조되고, 여과되고, 진공에서(in vacuo) 농축되었다(concentrated). 그 잔류물이 n-헥산(n-hexane)으로 세정되고, 50%의 EtOAc/n-hexane에서 재결정되어 황색 고체상의 일반식 3c의 화합물이 합성되었다(2.08 g, 62%). 화합물 3c에 대한 측정 결과는 다음과 같다. mp 223-225℃; 1H NMR(300 MHz, CD3COCD3) δ 13.58 (s, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.58 (dd, J = 8.6, 1.6 Hz, 1H), 7.33 (d, J = 3.6 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H); 13C NMR(75 MHz, CD3COCD3) δ 159.3, 151.7, 145.3, 134.3, 131.3, 130.5, 129.9, 128.0, 127.0, 118.9, 113.1; Ms m/z (%) 256 (M+, 16), 214 (40), 212 (67), 183 (40), 151 (38), 149 (100).To a 2,4-dichloroaniline dispersion (3.37 g, 20.8 mmol) in which 3.37 g of 2,4-dichloroaniline (Formula 1c) was dispersed in 10 mL of water (H 2 O) , 8 mL of 18% hydrochloric acid solution (HCl solution) was added at 0 占 폚. After stirring for 20 minutes, sodium nitrite solution (1.44 g, 20.9 mmol) in which 1.44 g of sodium nitrite was dissolved in 10 mL of water (H 2 O) was added and the mixture was stirred again for 20 minutes . To the resulting solution of 2,4-dichlorobenzenediazonium chloride was added 2.46 g of 2-furoic acid dissolved in 7 mL of acetone. A cupric chloride solution (523 mg, 1.46 g, 13.0 mmol) in which 523 mg of cupric (II) chloride was dissolved in 5 mL of water (H 2 O) , 3.9 mmol). The mixture was stirred at a temperature of 0 ° C to room temperature for 6 hours. The acetone was evaporated off and the mixture was poured into 50 mL of brine and extracted three times with 30 mL of ethyl acetate. The combined organic phases were dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was washed with n-hexane and recrystallized from 50% EtOAc / n-hexane to synthesize the compound of formula 3c (2.08 g, 62%) as a yellow solid. The measurement results for Compound 3c are as follows. mp 223-225 [deg.] C; 1 H NMR (300 MHz, CD 3 COCD 3) δ 13.58 (s, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.58 (dd, J = 8.6, 1.6 Hz, 1H), 7.33 (d, J = 3.6 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H); 13 C NMR (75 MHz, CD 3 COCD 3 )? 159.3, 151.7, 145.3, 134.3, 131.3, 130.5, 129.9, 128.0, 127.0, 118.9, 113.1; Ms m / z (%) 256 (M + , 16), 214 (40), 212 (67), 183 (40), 151 (38), 149 (100).
(2) 제2 단계(2) Step 2
[5-(2,4-디클로로페닐)퓨란-2-일](피페리딘-1-일)메타톤{[5-(2,4-dichlorophenyl)furan-2-yl](piperidin-1-yl)methanone}(일반식 5ch)의 합성[2,4-dichlorophenyl] furan-2-yl] (piperidin-1-yl) yl) methanone} (General Formula 5ch) Synthesis of
일반식 3c의 화합물 771 mg(3.0 mmol)이 18 mL의 염화메틸렌(methylene chloride)에 분산되어 이루어진, 일반식 3c의 화합물로 된 분산액(771 mg, 3.0 mmol)에, 649 mg의 디-2-피리딜 카보네이트(di-2-pyridyl carbonate)(649 mg, 3.0 mmol) 및 37 mg의 4-DMAP(37 mg, 0.3 mmol)가 상온에서 첨가되었다. 3시간 동안 교반 후, 그 혼합물이 0℃로 냉각되고, 326 μL의 피페리딘(piperidine)(326 μL, 3.3 mmol)이 그 결과물인 2-피리딜 5-(2,4-디클로로페닐)-2-퓨로에이트[2-pyridyl 5-(2,4-dichlorophenyl)-2-furoate]에 2분 이상 동안 천천히 첨가되었다. 30분 이상 교반 후, 그 혼합물이 40 mL의 포화 탄산수소나트륨(NaHCO3) 용액에 투여된(poured) 다음, 25 mL의 메틸렌 클로라이드(methylene chloride)로 3회 추출되었다. 농축된 잔류물이, 50%의 EtOAc/n-hexane을 사용하는 단경로 실리카겔 컬럼 크로마토그래피(short pathway silica gel column chromatography)에 의해 정제되어 일반식 5ch의 화합물이 합성되었다(856 mg, 88%). 일반식 5ch의 화합물에 대한 측정 결과는 다음과 같다. mp 87-89℃; 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 8.5, 2.0 Hz, 1H), 7.14 (d, J = 3.6 Hz, 1H), 7.02 (d, J = 3.6 Hz, 1H), 3.68-3.86 (m, 4H), 1.61-1.79 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 159.0, 150.0, 147.6, 134.1, 131.3, 130.6, 129.0, 127.4, 127.1, 117.2, 112.2, 26.2, 24.7 (overlapped); Ms m/z (%) 327 (M+ +4, 10), 325 (M+ +2, 64), 323 (M+, 100), 241 (69), 239 (95), 185 (56), 183 (92).To a dispersion (771 mg, 3.0 mmol) of the compound of the general formula 3c, in which 771 mg (3.0 mmol) of the compound of the general formula 3c was dispersed in 18 mL of methylene chloride, 649 mg of di- Di-2-pyridyl carbonate (649 mg, 3.0 mmol) and 37 mg of 4-DMAP (37 mg, 0.3 mmol) were added at room temperature. After stirring for 3 hours, the mixture was cooled to 0 C and 326 L of piperidine (326 L, 3.3 mmol) was added to the resulting 2-pyridyl 5- (2,4-dichlorophenyl) - Was slowly added to the 2-pyridyl 5- (2,4-dichlorophenyl) -2-furoate for at least 2 minutes. After stirring for over 30 minutes, the mixture was poured into 40 mL of saturated sodium bicarbonate (NaHCO 3 ) solution and then extracted three times with 25 mL of methylene chloride. The concentrated residue was purified by short pathway silica gel column chromatography using 50% EtOAc / n-hexane to synthesize a compound of general formula 5ch (856 mg, 88%). . The measurement results for the compounds of the general formula 5ch are as follows. mp 87-89 [deg.] C; 1 H NMR (300 MHz, CDCl 3) δ 7.77 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 8.5, 2.0 Hz, 1H), 7.14 (d, J = 3.6 Hz, 1H), 7.02 (d, J = 3.6 Hz, 1H), 3.68-3.86 (m, 4H), 1.61-1.79 (m, 6H); 13 C NMR (75 MHz, CDCl 3 )? 159.0, 150.0, 147.6, 134.1, 131.3, 130.6, 129.0, 127.4, 127.1, 117.2, 112.2, 26.2, 24.7 (overlapped); Ms m / z 327 (M + +4, 10), 325 (M + +2, 64), 323 (M + , 100), 241 (69), 239 (95) 183 (92).
(3) 제3 단계(3) Step 3
[5-(2,4-디클로로페닐)퓨란-2-일](피페리딘-1-일)메탄티온{[5-(2,4-dichlorophenyl)furan-2-yl] (piperidin-1-yl)methanethione}(일반식 6ch)의 합성2-yl] (piperidin-1-yl) methanethion {[5- (2,4-dichlorophenyl) furan- yl) methanethione} (General Formula 6ch) Synthesis of
일반식 5ch의 화합물 778 mg(2.4 mmol)가 12 mL의 염화메틸렌(methylene chloride)에 용해되어 이루어진 일반식 5ch의 화합물 용액(778 mg, 2.4 mmol)에, 486 mg(1.2 mmol)의 Lawesson's reagent(486 mg, 1.2 mmol)가 상온에서 첨가되고, 그 혼합물이 5시간 동안 교반되었다. 염화메틸렌(methylene chloride)이 증발되어 제거된 후, 그 잔류물이, 30%의 EtOAc/n-hexane을 용리액(eluent)으로 사용하는 실리카겔 컬럼 크로마토그래피(silica gel column chromatography)로 처리되어 일반식 6ch의 화합물이 합성되었다(767 mg, 94%). 농축된 잔류물(concentrated residue)이 10%의 EtOAc/n-hexane으로 재결정되어, 황색 고체상의 일반식 6ch로 표현되는 화합물이 얻어졌다. 일반식 6ch의 화합물에 대한 측정 결과는 다음과 같다. mp 106-107℃; 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.30 (dd, J = 8.6, 2.1 Hz, 1H), 7.13 (d, J = 3.7 Hz, 1H), 7.11 (d, J = 3.7 Hz, 1H), 4.22-4.38 (m, 2H), 3.82-3.92 (m, 2H), 1.71-1.86 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 184.4, 151.8, 149.3, 134.1, 131.4, 130.7, 128.8, 127.5, 127.1, 118.9, 113.0, 54.1, 52.0, 27.1, 25.9, 24.3; Ms m/z (%) 343 (M+ +4, 10), 341 (M+ +2, 69), 339 (M+, 100), 240 (63), 238 (96), 183 (30).488 mg (1.2 mmol) of Lawesson ' s reagent (1.2 mmol) was added to a solution of the compound of general formula 5-ch (778 mg, 2.4 mmol) in which 778 mg (2.4 mmol) of the compound of general formula 5 was dissolved in 12 mL of methylene chloride 486 mg, 1.2 mmol) was added at room temperature, and the mixture was stirred for 5 hours. After the methylene chloride was evaporated and removed, the residue was treated with silica gel column chromatography using 30% EtOAc / n-hexane as the eluent to give 6ch Was synthesized (767 mg, 94%). The concentrated residue was recrystallized from 10% EtOAc / n-hexane to give the compound represented by the general formula 6ch in the form of a yellow solid. The measurement results for the compounds of the general formula 6ch are as follows. mp 106-107 [deg.] C; 1 H NMR (300 MHz, CDCl 3) δ 7.73 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.30 (dd, J = 8.6, 2.1 Hz, 1H), 7.13 (d, J = 3.7 Hz, 1H), 7.11 (d, J = 3.7 Hz, 1H), 4.22-4.38 (m, 2H), 3.82-3.92 (m, 2H), 1.71-1.86 (m, 6H); 13 C NMR (75 MHz, CDCl 3) δ 184.4, 151.8, 149.3, 134.1, 131.4, 130.7, 128.8, 127.5, 127.1, 118.9, 113.0, 54.1, 52.0, 27.1, 25.9, 24.3; Ms m / z (%) 343 (M + +4, 10), 341 (M + +2, 69), 339 (M + , 100), 240 (63), 238 (96), 183 (30).
[화학식 2] 일반식 6ch의 화합물[Chemical Formula 2] Compound of general formula 6 ch
<합성예 2-11>≪ Synthesis Example 2-11 &
제1 단계에서 사용된 염화아닐린과 제2 단계에서 적용된 아민 화합물의 종류를 다르게 하여, 합성예 1과 동일한 방법으로 합성예 2-11에 따른 화합물이 합성되었다.The compound according to Synthesis Example 2-11 was synthesized in the same manner as in Synthesis Example 1, except that the kinds of the aniline chloride used in the first step and the amine compound used in the second step were different.
합성예 1 내지 11에 있어서, 제1 단계에서 사용된 염화아닐린과 제2 단계에서 적용된 아민 화합물은 하기 표 1과 같다.In Synthesis Examples 1 to 11, the aniline chloride used in the first step and the amine compound used in the second step are shown in Table 1 below.
표 1에서, 괄호로 표시된 것은 각각 합성되는 화합물에 대한 기호이다.In Table 1, parentheses are symbols for compounds to be synthesized, respectively.
<합성예 2>≪ Synthesis Example 2 &
N,N-디에틸-5-(2-클로로페닐)-2-(퓨란카보티오아미드)[N,N-Diethyl-5-(2-chlorophenyl)-2-furancarbothioamide](일반식 6af)의 제조Preparation of N, N-diethyl-5- (2-chlorophenyl) -2- (furancarbothioamide) [N, N-Diethyl-5- (2-chlorophenyl) -2-furancarbothioamide]
mp 87-88℃; 1H NMR (300 MHz, CDCl3) δ 7.78 (dd, J = 7.8, 1.6 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.30-7.37 (m, 1H), 7.24-7.30 (m, 2H), 7.15 (d, J = 3.6 Hz, 1H), 3.93-4.19 (m, 2H), 3.82-3.93 (m, 2H), 1.30-1.50 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 184.2, 152.0, 150.5, 131.0, 130.9, 128.9, 128.6, 128.1, 127.0, 120.2, 113.0, 48.1 (overlapped), 14.3, 11.2; Ms m/z (%) 295 (M++2, 15), 293 (M+, 38), 223 (40), 221 (100), 207 (44), 149 (30).mp 87-88 [deg.] C; 1 H NMR (300 MHz, CDCl 3) δ 7.78 (dd, J = 7.8, 1.6 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.30-7.37 (m, 1H), 7.24-7.30 ( m, 2H), 7.15 (d, J = 3.6 Hz, 1H), 3.93-4.19 (m, 2H), 3.82-3.93 (m, 2H), 1.30-1.50 (m, 6H); 13 C NMR (75 MHz, CDCl 3) δ 184.2, 152.0, 150.5, 131.0, 130.9, 128.9, 128.6, 128.1, 127.0, 120.2, 113.0, 48.1 (overlapped), 14.3, 11.2; Ms m / z (%) 295 (M + +2, 15), 293 (M + , 38), 223 (40), 221 (100), 207 (44), 149 (30).
[화학식 3] 일반식 6af의 화합물The compound of the general formula 6af
<합성예 3>≪ Synthesis Example 3 &
[5-(2-클로로페닐)퓨란-2-일](피페리딘-1-일)메탄티온{[5-(2-Chlorophenyl) furan-2-yl](piperidin-1-yl)methanethione}(일반식 6ah)의 제조2-yl] (piperidin-1-yl) methanethione The title compound was prepared according to the procedure described in Example 1, (General formula 6ah)
mp 78-79℃; 1H NMR (300 MHz, CDCl3) δ 7.78 (dd, J = 7.8, 1.7 Hz, 1H), 7.45 (dd, J = 7.9, 1.3 Hz, 1H), 7.29-7.34 (m, 1H), 7.21-7.27 (m, 1H), 7.15 (d, J = 3.6 Hz, 1H), 7.12 (d, J = 3.6 Hz, 1H), 4.18-4.34 (m, 2H), 3.90-4.05 (m, 2H), 1.73-1.84 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 184.5, 151.7, 150.4, 130.9, 129.0, 128.6, 128.1, 127.0, 119.4 (overlapped), 112.8, 53.9, 52.0, 27.0, 26.0, 24.4; Ms m/z (%) 307 (M++2, 39), 305 (M+, 100), 223 (14), 221 (39), 204 (98), 149 (40).mp 78-79 [deg.] C; 1 H NMR (300 MHz, CDCl 3) δ 7.78 (dd, J = 7.8, 1.7 Hz, 1H), 7.45 (dd, J = 7.9, 1.3 Hz, 1H), 7.29-7.34 (m, 1H), 7.21- 1H), 7.27 (m, 1H), 7.15 (d, J = 3.6 Hz, 1H), 7.12 (d, J = 3.6 Hz, 1H), 4.18-4.34 (m, 2H), 3.90-4.05 -1.84 (m, 6H); 13 C NMR (75 MHz, CDCl 3) δ 184.5, 151.7, 150.4, 130.9, 129.0, 128.6, 128.1, 127.0, 119.4 (overlapped), 112.8, 53.9, 52.0, 27.0, 26.0, 24.4; Ms m / z (%) 307 (M + +2, 39), 305 (M + , 100), 223 (14), 221 (39), 204 (98), 149 (40).
[화학식 4] 일반식 6ah의 화합물[Chemical Formula 4] Compound of general formula 6ah
<합성예 4>≪ Synthesis Example 4 &
N-시클로프로필-5-(4-클로로페닐)-2-퓨란카보티오아미드[N-Cyclopropyl-5-(4-chlorophenyl)-2-furancarbothioamide](일반식 6be)의 제조Preparation of N-cyclopropyl-5- (4-chlorophenyl) -2-furancarbothioamide [N-Cyclopropyl-5- (4-chlorophenyl) -2-furancarbothioamide]
mp 109-110℃; 1H NMR (300 MHz, CDCl3) δ 7.87 (br s, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 3.7Hz, 1H), 7.39 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 3.7 Hz, 1H), 3.31-3.40 (m, 1H), 1.01-1.08 (m, 2H), 0.79-0.85 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 183.6, 153.9, 151.5, 134.7, 129.2, 128.0, 125.7, 119.8, 108.9, 28.1, 7.6; Ms m/z (%) 279 (M++2, 12), 277 (M+, 33), 264 (38), 262 (100), 223 (11), 221 (32), 149 (34).mp 109-110 [deg.] C; 1 H NMR (300 MHz, CDCl 3) δ 7.87 (br s, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 3.7Hz, 1H), 7.39 (d, J = 8.6 2H), 6.71 (d, J = 3.7 Hz, 1H), 3.31-3.40 (m, 1H), 1.01-1.08 (m, 2H), 0.79-0.85 (m, 2H); 13 C NMR (75 MHz, CDCl3) δ 183.6, 153.9, 151.5, 134.7, 129.2, 128.0, 125.7, 119.8, 108.9, 28.1, 7.6; Ms m / z (%) 279 (M + +2, 12), 277 (M + , 33), 264 (38), 262 (100), 223 (11), 221 (32), 149 (34).
[화학식 5] 일반식 6be의 화합물[Chemical Formula 5] Compound of general formula 6be
<합성예 5>≪ Synthesis Example 5 &
[5-(4-클로로페닐)퓨란-2-일](피롤리딘-1-일)메탄티온{[5-(4-Chlorophenyl) furan-2-yl](pyrrolidin-1-yl)methanethione}(일반식 6bg)의 제조Furan-2-yl] (pyrrolidin-1-yl) methanethione}, was prepared in the same manner as in [5- (4-chlorophenyl) furan- (General formula 6bg)
mp 142-143℃; 1H NMR (300 MHz, CDCl3) δ 7.61 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 3.6 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 3.6 Hz, 1H), 4.09-4.16 (m, 2H), 4.04-4.09 (m, 2H), 2.10-2.18 (m, 2H), 2.03-2.10 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 179.8, 154.0, 152.3, 134.3, 129.2, 128.4, 125.5, 121.7, 107.9, 55.0, 53.6, 27.0, 23.8; Ms m/z (%) 293 (M++2, 35), 291 (M+, 100), 258 (42), 222 (61), 149 (46).mp 142-143 [deg.] C; 1 H NMR (300 MHz, CDCl 3) δ 7.61 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 3.6 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 6.72 (d , J = 3.6 Hz, 1H), 4.09-4.16 (m, 2H), 4.04-4.09 (m, 2H), 2.10-2.18 (m, 2H), 2.03-2.10 (m, 2H); 13 C NMR (75 MHz, CDCl3) δ 179.8, 154.0, 152.3, 134.3, 129.2, 128.4, 125.5, 121.7, 107.9, 55.0, 53.6, 27.0, 23.8; Ms m / z (%) 293 (M + +2, 35), 291 (M + , 100), 258 (42), 222 (61), 149 (46).
[화학식 6] 일반식 6bg의 화합물The compound of the formula 6bg
<합성예 6>≪ Synthesis Example 6 &
[5-(4-클로로페닐)퓨란-2-일](피페리딘-1-일)메탄티온{[5-(4-Chlorophenyl) furan-2-yl](piperidin-1-yl)methanethione}(일반식 6bh)의 제조Furan-2-yl] (piperidin-1-yl) methanethione The title compound was prepared according to the procedure described in Example 1, (General formula 6bh)
mp 111-112℃; 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 3.6 Hz, 1H), 6.69 (d, J = 3.6 Hz, 1H), 4.10-4.38 (m, 2H), 3.82-4.10 (m, 2H), 1.75-1.90 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 184.3, 152.9, 151.9, 134.1, 129.1, 128.5, 125.4, 120.0, 107.6, 53.7, 52.0, 27.2, 25.9, 24.4; Ms m/z (%) 307 (M++2, 38), 305 (M+, 100), 223 (15), 221 (39), 149 (32).mp 111-112 [deg.] C; 1 H NMR (300 MHz, CDCl 3) δ 7.59 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 3.6 Hz, 1H), 6.69 (d , J = 3.6 Hz, 1H), 4.10-4.38 (m, 2H), 3.82-4.10 (m, 2H), 1.75-1.90 (m, 6H); 13 C NMR (75 MHz, CDCl 3) δ 184.3, 152.9, 151.9, 134.1, 129.1, 128.5, 125.4, 120.0, 107.6, 53.7, 52.0, 27.2, 25.9, 24.4; Ms m / z (%) 307 (M + +2, 38), 305 (M + , 100), 223 (15), 221 (39), 149 (32).
[화학식 7] 일반식 6bh의 화합물[Chemical Formula 7] Compound of general formula 6bh
<합성예 7>≪ Synthesis Example 7 &
[5-(2,4-디클로로페닐)퓨란-2-일](피롤리딘-1-일)메탄티온{[5-(2,4-Dichlorophenyl)furan-2-yl](pyrrolidin-1-yl)methanethione}(일반식 6cg)의 제조2-yl] (pyrrolidin-l-yl) methanethion {[5- (2,4-Dichlorophenyl) furan- yl) methanethione} (general formula 6cg)
mp 172-174℃; 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 3.7 Hz, 1H), 7.33 (dd, J = 8.5, 2.0 Hz, 1H), 7.15 (d, J = 3.7 Hz, 1H), 4.02-4.12 (m, 4H), 2.02-2.16 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 179.9, 152.1, 150.5, 134.3, 131.6, 130.8, 128.8, 127.5, 127.1, 121.0, 113.3, 55.1, 53.7, 27.0, 23.8; Ms m/z (%) 329 (M++4, 11), 327 (M++2, 69), 325 (M+, 100), 292 (43), 258 (41), 256 (59), 183 (30).mp 172-174 [deg.] C; 1 H NMR (300 MHz, CDCl 3) δ 7.73 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 3.7 Hz, 1H), 7.33 (dd J = 8.5, 2.0 Hz, 1H), 7.15 (d, J = 3.7 Hz, 1H), 4.02-4.12 (m, 4H), 2.02-2.16 (m, 4H); 13 C NMR (75 MHz, CDCl 3) δ 179.9, 152.1, 150.5, 134.3, 131.6, 130.8, 128.8, 127.5, 127.1, 121.0, 113.3, 55.1, 53.7, 27.0, 23.8; Ms m / z 329 (M + +4, 11), 327 (M + +2, 69), 325 (M + , 100), 292 (43), 258 (41) 183 (30).
[화학식 8] 일반식 6cg의 화합물The compound of the general formula 6cg
<합성예 8>≪ Synthesis Example 8 &
[5-(2,4-디클로로페닐)퓨란-2-일](모르폴리노)메탄티온{[5-(2,4-Dichlorophenyl)furan-2-yl](morpholino)methanethione}(일반식 6ci)의 제조(2,4-dichlorophenyl) furan-2-yl] (morpholino) methanethione} (general formula 6ci )
mp 163-165℃; 1H NMR (300 MHz, CDCl3) δ 7.69 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 8.6, 2.1 Hz, 1H), 7.19 (d, J = 3.7 Hz, 1H), 7.11 (d, J = 3.7 Hz, 1H), 4.05-4.35 (m, 4H), 3.80-3.93 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 185.1, 151.3, 149.9, 134.4, 131.5, 130.7, 128.9, 127.6, 126.9, 120.3, 113.1, 66.7, 52.1; Ms m/z (%) 345 (M++4, 10), 343 (M++2, 61), 341 (M+, 90), 259 (11), 257 (71), 255 (100), 183 (59).mp 163-165 [deg.] C; 1 H NMR (300 MHz, CDCl 3) δ 7.69 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 8.6, 2.1 Hz, 1H), 7.19 (d, J = 3.7 Hz, 1H), 7.11 (d, J = 3.7 Hz, 1H), 4.05-4.35 (m, 4H), 3.80-3.93 (m, 4H); 13 C NMR (75 MHz, CDCl 3) δ 185.1, 151.3, 149.9, 134.4, 131.5, 130.7, 128.9, 127.6, 126.9, 120.3, 113.1, 66.7, 52.1; Ms m / z% 345 (M + +4, 10), 343 (M + +2, 61), 341 (M + , 90), 259 (11), 257 183 (59).
[화학식 9] 일반식 6ci의 화합물[Chemical Formula 9] Compound of general formula 6ci
<합성예 9>≪ Synthesis Example 9 &
N,N-디에틸-5-(3,4-디클로로페닐)-2-퓨란카보티오아미드[N,N-Diethyl-5-(3,4-dichlorophenyl)-2-furancarbothioamide](일반식 6df)의 제조N, N-Diethyl-5- (3,4-dichlorophenyl) -2-furancarbothioamide (general formula 6df) Manufacturing
점성의 액체(viscous liquid); 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J = 1.1 Hz, 1H), 7.45-7.49 (m, 2H), 7.24 (d, J = 3.6 Hz, 1H), 6.73 (d, J = 3.6 Hz, 1H), 4.03-4.13 (m, 2H), 3.72-3.82 (m, 2H), 1.35-1.50 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 183.9, 152.6, 151.6, 133.3, 132.1, 130.9, 129.9, 125.8, 123.2, 120.3, 108.6, 48.1 (overlapped), 14.3, 11.2; Ms m/z (%) 331 (M++4, 4), 329 (M++2, 25), 327 (M+, 36), 259 (10), 257 (71), 255 (100), 183 (12).Viscous liquid; 1 H NMR (300 MHz, CDCl 3) δ 7.73 (d, J = 1.1 Hz, 1H), 7.45-7.49 (m, 2H), 7.24 (d, J = 3.6 Hz, 1H), 6.73 (d, J = 3.6 Hz, 1H), 4.03-4.13 (m, 2H), 3.72-3.82 (m, 2H), 1.35-1.50 (m, 6H); 13 C NMR (75 MHz, CDCl 3) δ 183.9, 152.6, 151.6, 133.3, 132.1, 130.9, 129.9, 125.8, 123.2, 120.3, 108.6, 48.1 (overlapped), 14.3, 11.2; Ms m / z 331 (M + +4, 4), 329 (M + +2, 25), 327 (M + , 36), 259 (10), 257 (71) 183 (12).
[화학식 10] 일반식 6df의 화합물Compound of general formula 6df
<합성예 10>≪ Synthesis Example 10 &
[5-(3,4-디클로로페닐)퓨란-2-일](피페리딘-1-일)메탄티온{[5-(3,4-Dichlorophenyl)furan-2-yl](piperidin-1-yl)methanethione}(일반식 6dh)의 제조(3,4-dichlorophenyl) furan-2-yl] (piperidin-1-yl) yl) methanethione} (general formula 6dh)
mp 111-113℃; 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J = 1.0 Hz, 1H), 7.45-7.50 (m, 2H), 7.11 (d, J = 3.6 Hz, 1H), 6.72 (d, J = 3.6 Hz, 1H), 4.22-4.35 (m, 2H), 3.80-3.92 (m, 2H), 1.76-1.90 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 184.1, 152.3, 151.5, 133.3, 132.1, 130.9, 129.9, 125.8, 123.2, 119.4, 108.5, 53.9, 52.5, 27.4, 26.1, 24.4; Ms m/z (%) 343 (M++4, 11), 341 (M++2, 69), 339 (M+, 100), 242 (10), 240 (64), 238 (99), 183 (22).mp 111-113 [deg.] C; 1 H NMR (300 MHz, CDCl 3 )? 7.72 (d, J = 1.0 Hz, 1H), 7.45-7.50 (m, 2H), 7.11 3.6 Hz, 1H), 4.22-4.35 (m, 2H), 3.80-3.92 (m, 2H), 1.76-1.90 (m, 6H); 13 C NMR (75 MHz, CDCl 3) δ 184.1, 152.3, 151.5, 133.3, 132.1, 130.9, 129.9, 125.8, 123.2, 119.4, 108.5, 53.9, 52.5, 27.4, 26.1, 24.4; Ms m / z (%) 343 (M + +4, 11), 341 (M + +2, 69), 339 (M + , 100), 242 (10), 240 (64), 238 183 (22).
[화학식 11] 일반식 6dh의 화합물The compound of the general formula 6dh
<합성예 11>≪ Synthesis Example 11 &
[5-(3,4-디클로로페닐)퓨란-2-일](모르폴리노)메탄티온{[5-(3,4-Dichlorophenyl)furan-2-yl](morpholino)methanethione}(일반식 6di)의 제조(3,4-dichlorophenyl) furan-2-yl] (morpholino) methanethione} (general formula 6di )
mp 143-145℃; 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J = 1.1 Hz, 1H), 7.45-7.49 (m, 2H), 7.18 (d, J = 3.6 Hz, 1H), 6.73 (d, J = 3.6 Hz, 1H), 4.13-4.27 (m, 4H), 3.82-3.89 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 185.0, 152.0, 151.7, 133.4, 132.4, 131.0, 129.6, 125.9, 123.3, 120.7, 108.6, 66.7, 51.3; Ms m/z (%) 345 (M++4, 10), 343 (M++2, 63), 341 (M+, 92), 308 (51), 259 (12), 257 (72), 255 (100), 183 (42).mp 143-145 [deg.] C; 1 H NMR (300 MHz, CDCl 3 )? 7.71 (d, J = 1.1 Hz, 1H), 7.45-7.49 (m, 2H), 7.18 3.6 Hz, 1H), 4.13-4.27 (m, 4H), 3.82-3.89 (m, 4H); 13 C NMR (75 MHz, CDCl 3) δ 185.0, 152.0, 151.7, 133.4, 132.4, 131.0, 129.6, 125.9, 123.3, 120.7, 108.6, 66.7, 51.3; Ms m / z (%) 345 (M + +4, 10), 343 (M + +2, 63), 341 (M + , 92), 308 (51), 259 (12), 257 255 (100), 183 (42).
[화학식 12] 일반식 6di의 화합물Compounds of general formula 6di
제조 결과 및 수득율은 하기 표 2에 표시되었다.Production results and yields are shown in Table 2 below.
표 2에서 "Entry"는 치환기의 기호를 이용하여 표시된 화합물의 기호이며, R과 R'는 치환기를 나타낸다. "Thioamides"는 합성된 화합물의 화학식을 나타내며, "Isolated yield"의 "5"와 "6"은 각각 일반식 5로 표시되는 화합물과 일반식 6으로 표시되는 화합물의 수득율을 나타낸다. 또한, 표 2의 괄호 안의 숫자는 총 수득율을 나타낸다.In Table 2, "Entry" is a symbol of a compound represented by the symbol of a substituent, and R and R 'represent a substituent. "Thioamides" represents the formula of the synthesized compound, and "5" and "6" of the "Isolated yield" represent the yields of the compound represented by the formula The numbers in parentheses in Table 2 indicate the total yield.
표 2에 개시된 바와 같이, 2-퓨로산(2-furoic acid)으로부터 다양한 5-(클로로페닐)-2-퓨란카르보티오아미드[5-(chlorophenyl)-2-furancarbothioamide]가 높은 수득율(전체 수득율 42 내지 57%)로 수득되었다. 비록, 일반식 5b와 같은 2차 아미드(secondary amide)의 가황(thionation)은 느리게 진행되었지만, 다른 3차 아미드(tertiary amide)가 대응 티오아미드로 전환되는 것은 상온에서 무리없이 진행되었다. 일반식 3의 화합물과 아민의 축합반응 및 일반식 5의 화합물에 대한 가황은, 본 발명의 일 실시예에 따른 조건에서 5-페닐 고리(5-phenyl ring)에서 클로로기의 위치에 상관없이 원활하게 진행되었다.(Chlorophenyl) -2-furancarbothioamide] was obtained from 2-furoic acid as shown in Table 2 in a high yield (overall yield 42 to 57%). Although the thionation of the secondary amide as in the general formula 5b proceeded slowly, the conversion of the other tertiary amide to the corresponding thioamide proceeded at room temperature. The condensation reaction of the compound of the general formula 3 with the amine and the vulcanization of the compound of the general formula 5 can be carried out in the 5-phenyl ring under the conditions according to one embodiment of the present invention regardless of the position of the chloro group .
Claims (9)
상기 제1 단계에서 제조된 5-(클로로페닐)-2-퓨로산[5-(chlorophenyl)-2-furoic acid]을 디-2-피리딜 카보네이트(di-2-pyridyl carbonate)(2-DPC)로 처리하여 2-피리딜 에스테르(2-pyridyl esters) 화합물을 제조하고, 여기에 아민을 첨가하여 5-(클로로페닐)-2-퓨란카보아미드[5-(chlorophenyl)-2-furancarboamide]를 제조하는 제2 단계; 및
상기 제2 단계에서 제조된 5-(클로로페닐)-2-퓨란카보아미드를 로손 시약(Lawesson's reagent)으로 처리하는 제3 단계;를 포함하고,
상기 제1 단계는 하기 반응식 1로 표현되고,
[반응식 1]
상기 제2 단계는 하기 반응식 2로 표현되고,
[반응식 2]
상기 제3 단계는 하기 반응식 3으로 표현되는, 5-클로로페닐-2-퓨란카보티오아미드계 화합물의 제조방법.
[반응식 3]
여기서, R1 및 R2는 각각 독립적으로 수소 또는 염소(Cl)이며, R1 및 R2 중 적어도 하나는 염소(Cl)이고,
R3 및 R4는 이들과 연결된 질소 원자(N)와 함께 고리를 형성하거나, 또는
R3 및 R4는 각각 독립적으로 수소, 직쇄형 탄화수소 및 고리형 탄화수소 중 어느 하나이며, 이 때 R3 및 R4 중 적어도 하나는 수소가 아니다.A chlorobenzenediazonium compound prepared by the reaction of chloroanilines with sodium nitrite was reacted with 2-furoic acid to give 5- (chlorophenyl) -2-furoic acid [5- (chlorophenyl) -2-furoic acid];
2-furoic acid [5- (chlorophenyl) -2-furoic acid] prepared in the first step was dissolved in di-2-pyridyl carbonate (2-DPC ) To prepare a 2-pyridyl esters compound which is then reacted with 5- (chlorophenyl) -2-furancarboamide A second step of manufacturing; And
And a third step of treating 5- (chlorophenyl) -2-furan-carbamoide prepared in the second step with Lawesson's reagent,
The first step is represented by the following reaction formula 1,
[Reaction Scheme 1]
The second step is represented by the following reaction formula 2,
[Reaction Scheme 2]
The third step is a process for producing a 5-chlorophenyl-2-furancarbothioamide-based compound represented by the following reaction formula (3).
[Reaction Scheme 3]
Wherein R 1 and R 2 are each independently hydrogen or chlorine (Cl), at least one of R 1 and R 2 is chlorine (Cl)
R 3 and R 4 together with the nitrogen atom (N) linked thereto form a ring, or
R 3 and R 4 are each independently any one of hydrogen, straight chain hydrocarbon and cyclic hydrocarbon, wherein at least one of R 3 and R 4 is not hydrogen.
상기 5-클로로페닐-2-퓨란카보티오아미드계 화합물은 하기 화학식 1로 표현되는 5-클로로페닐-2-퓨란카보티오아미드계 화합물의 제조방법.
[화학식 1]
여기서, R1 및 R2는 각각 독립적으로 수소 또는 염소(Cl)이며, R1 및 R2 중 적어도 하나는 염소(Cl)이고,
R3 및 R4는 이들과 연결된 질소 원자(N)와 함께 고리를 형성하거나, 또는
R3 및 R4는 각각 독립적으로 수소, 직쇄형 탄화수소 및 고리형 탄화수소 중 어느 하나이며, 이 때 R3 및 R4 중 적어도 하나는 수소가 아니다. The method according to claim 1,
Wherein the 5-chlorophenyl-2-furancarbothioamide compound is represented by the following formula (1).
[Chemical Formula 1]
Wherein R 1 and R 2 are each independently hydrogen or chlorine (Cl), at least one of R 1 and R 2 is chlorine (Cl)
R 3 and R 4 together with the nitrogen atom (N) linked thereto form a ring, or
R 3 and R 4 are each independently any one of hydrogen, straight chain hydrocarbon and cyclic hydrocarbon, wherein at least one of R 3 and R 4 is not hydrogen.
상기 5-클로로페닐-2-퓨란카보티오아미드계 화합물은 하기 화학식 2 내지 12 중 어느 하나로 표현되는 5-클로로페닐-2-퓨란카보티오아미드계 화합물의 제조방법.
[화학식 2]
[화학식 3]
[화학식 4]
[화학식 5]
[화학식 6]
[화학식 7]
[화학식 8]
[화학식 9]
[화학식 10]
[화학식 11]
[화학식 12]
The 5-chlorophenyl-2-furancarbothioamide-based compound is represented by any one of the following Chemical Formulas (2) to (12).
(2)
(3)
[Chemical Formula 4]
[Chemical Formula 5]
[Chemical Formula 6]
(7)
[Chemical Formula 8]
[Chemical Formula 9]
[Chemical formula 10]
(11)
[Chemical Formula 12]
상기 염화아닐린은 2,4-디클로로아닐린(2,4-dichloroaniline), 2-클로로아닐린(2-chloroaniline), 3-클로로아닐린(3-chloroaniline), 4-클로로아닐린(4-chloroaniline) 및 3,4-디클로로아닐린(3,4-dichloroaniline) 중 어느 하나인 5-클로로페닐-2-퓨란카보티오아미드계 화합물의 제조방법.The method according to claim 1,
The aniline chloride can be prepared by reacting 2,4-dichloroaniline, 2-chloroaniline, 3-chloroaniline, 4-chloroaniline, A process for producing a 5-chlorophenyl-2-furancarbothioamide-based compound, which is any one of 4-dichloroaniline.
상기 아민은 피페리딘(piperidine), 디에틸아민(diethylamine), 시클로프로필아민(cyclopropylamine), 피롤리딘(pyrrolidine) 및 모르폴린(morpholine) 중 어느 하나인 5-클로로페닐-2-퓨란카보티오아미드계 화합물의 제조방법.The method according to claim 1,
The amine is selected from the group consisting of piperidine, diethylamine, cyclopropylamine, pyrrolidine, and morpholine, which is 5-chlorophenyl-2-furancarbothio Amide compound.
상기 염화벤젠디아조늄(chlorobenzenediazonium) 화합물은 염화벤젠디아조늄 염화물(chlorobenzenediazonium chloride)인 5-클로로페닐-2-퓨란카보티오아미드계 화합물의 제조방법.
The method according to claim 1,
The chlorobenzenediazonium compound is a chlorobenzenediazonium chloride. The method of producing a 5-chlorophenyl-2-furancarbothioamide compound according to claim 1, wherein the chlorobenzenediazonium compound is chlorobenzenediazonium chloride.
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