WO2013115595A1 - Method for preparing compound by novel michael addition reaction using water or various acids as additive - Google Patents
Method for preparing compound by novel michael addition reaction using water or various acids as additive Download PDFInfo
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- WO2013115595A1 WO2013115595A1 PCT/KR2013/000829 KR2013000829W WO2013115595A1 WO 2013115595 A1 WO2013115595 A1 WO 2013115595A1 KR 2013000829 W KR2013000829 W KR 2013000829W WO 2013115595 A1 WO2013115595 A1 WO 2013115595A1
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- acid
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 40
- 238000000034 method Methods 0.000 title claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 239000002253 acid Substances 0.000 title claims abstract description 13
- 238000006845 Michael addition reaction Methods 0.000 title claims abstract description 9
- 239000000654 additive Substances 0.000 title abstract description 9
- 150000007513 acids Chemical class 0.000 title abstract description 8
- 230000000996 additive effect Effects 0.000 title abstract description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 29
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 25
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 10
- -1 amine compound Chemical class 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 150000002825 nitriles Chemical class 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical group 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
- 239000011369 resultant mixture Substances 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 235000019270 ammonium chloride Nutrition 0.000 description 8
- IRSJDVYTJUCXRV-UHFFFAOYSA-N ethyl 2-bromo-2,2-difluoroacetate Chemical compound CCOC(=O)C(F)(F)Br IRSJDVYTJUCXRV-UHFFFAOYSA-N 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 230000035484 reaction time Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 0 CC1CC*CC1 Chemical compound CC1CC*CC1 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012776 electronic material Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000004973 liquid crystal related substance Substances 0.000 description 3
- 239000000575 pesticide Substances 0.000 description 3
- AYORTOFSIKLNIK-UHFFFAOYSA-N 1-n-[2-(dimethylamino)ethyl]-2-n,2-n-dimethylpropane-1,2-diamine Chemical compound CN(C)C(C)CNCCN(C)C AYORTOFSIKLNIK-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohex-2-enone Chemical compound O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 description 2
- YVPKMLFMDHSTKJ-UHFFFAOYSA-N diethyl 2,2-difluoropentanedioate Chemical compound CCOC(=O)CCC(F)(F)C(=O)OCC YVPKMLFMDHSTKJ-UHFFFAOYSA-N 0.000 description 2
- CKXPGHFIUHPUEK-UHFFFAOYSA-N ethyl 4-cyano-2,2-difluorobutanoate Chemical compound CCOC(=O)C(F)(F)CCC#N CKXPGHFIUHPUEK-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- DMQSHEKGGUOYJS-UHFFFAOYSA-N n,n,n',n'-tetramethylpropane-1,3-diamine Chemical compound CN(C)CCCN(C)C DMQSHEKGGUOYJS-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 150000004812 organic fluorine compounds Chemical class 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- FEWIGMWODIRUJM-HWKANZROSA-N (E)-4-hexen-3-one Chemical compound CCC(=O)\C=C\C FEWIGMWODIRUJM-HWKANZROSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GTEXIOINCJRBIO-UHFFFAOYSA-N 2-[2-(dimethylamino)ethoxy]-n,n-dimethylethanamine Chemical compound CN(C)CCOCCN(C)C GTEXIOINCJRBIO-UHFFFAOYSA-N 0.000 description 1
- UXGVMFHEKMGWMA-UHFFFAOYSA-N 2-benzofuran Chemical compound C1=CC=CC2=COC=C21 UXGVMFHEKMGWMA-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- ZPGPXBUARFMVIU-UHFFFAOYSA-N 3-ethyl-4,4-difluoroheptane Chemical compound C(C)C(C(CCC)(F)F)CC ZPGPXBUARFMVIU-UHFFFAOYSA-N 0.000 description 1
- MGTZCLMLSSAXLD-UHFFFAOYSA-N 5-oxohexanoic acid Chemical compound CC(=O)CCCC(O)=O MGTZCLMLSSAXLD-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000005513 chalcones Nutrition 0.000 description 1
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- UJTPZISIAWDGFF-UHFFFAOYSA-N ethenylsulfonylbenzene Chemical compound C=CS(=O)(=O)C1=CC=CC=C1 UJTPZISIAWDGFF-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- TVQFBZSFRXWHQN-UHFFFAOYSA-N ethyl 2,2-difluoro-2-(3-oxocyclohexyl)acetate Chemical compound CCOC(=O)C(F)(F)C1CCCC(=O)C1 TVQFBZSFRXWHQN-UHFFFAOYSA-N 0.000 description 1
- MVCFRKLRZBEPSV-UHFFFAOYSA-N ethyl 2,2-difluoro-3-methyl-5-oxoheptanoate Chemical compound CCOC(=O)C(F)(F)C(C)CC(=O)CC MVCFRKLRZBEPSV-UHFFFAOYSA-N 0.000 description 1
- IDZAHYPHKSGTBU-UHFFFAOYSA-N ethyl 2,2-difluoro-3-methyl-5-oxopentanoate Chemical compound CCOC(=O)C(F)(F)C(C)CC=O IDZAHYPHKSGTBU-UHFFFAOYSA-N 0.000 description 1
- YFIYHDGAHONZRV-UHFFFAOYSA-N ethyl 2,2-difluoro-5-oxohexanoate Chemical compound CCOC(=O)C(F)(F)CCC(C)=O YFIYHDGAHONZRV-UHFFFAOYSA-N 0.000 description 1
- HBWOULPMYYITAQ-UHFFFAOYSA-N ethyl 4-(benzenesulfonyl)-2,2-difluorobutanoate Chemical compound CCOC(=O)C(F)(F)CCS(=O)(=O)C1=CC=CC=C1 HBWOULPMYYITAQ-UHFFFAOYSA-N 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- FEWIGMWODIRUJM-UHFFFAOYSA-N hex-4-en-3-one Natural products CCC(=O)C=CC FEWIGMWODIRUJM-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- UKODFQOELJFMII-UHFFFAOYSA-N pentamethyldiethylenetriamine Chemical compound CN(C)CCN(C)CCN(C)C UKODFQOELJFMII-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
- C07B37/02—Addition
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/64—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/62—Use of additives, e.g. for stabilisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the present invention relates to a method for preparing a compound of Formula 1, which can be used as an intermediate such as pharmaceuticals, pesticides, electronic materials or liquid crystals, through a new Michael-addition reaction using water or various acids as an additive. will be.
- Compounds of the general formula (1) have various skeletons and have biological activities, and thus are widely used as intermediates for synthesizing pharmaceuticals, pesticides, electronic materials or liquid crystal materials.
- A is R 1 -C ( ⁇ O) —, nitrile, substituted or unsubstituted C 1 -C 10 alkylsulfonyl, or substituted or unsubstituted C 6 -C 10 arylsulfonyl, wherein R 1 is hydrogen; Substituted or unsubstituted C 1 -C 10 alkyl; Substituted or unsubstituted C 3 -C 10 cycloalkyl; Substituted or unsubstituted C 6 -C 10 aryl; Substituted or unsubstituted 5-membered to 10-membered heteroaryl; And substituted or unsubstituted C 1 -C 5 alkoxy, or when A is bonded to R 3, A, R 3 and the carbons to which they are each bonded together are saturated with an oxo ( ⁇ O) group. Or unsaturated C 6 -C 10 cycloalkyl,
- R2, R3 and R4 are each independently hydrogen; Substituted or unsubstituted C 1 -C 10 alkyl; Substituted or unsubstituted C 3 -C 10 cycloalkyl; Substituted or unsubstituted C 6 -C 10 aryl; Substituted or unsubstituted 5- to 10-membered heteroaryl; Substituted or unsubstituted C 1 -C 5 alkoxy; Nitrile; And substituted or unsubstituted C 1 -C 10 alkyl sulfonyl,
- R5 and R6 are each independently hydrogen; Halogen (ie, F, Cl, Br, or I); And substituted or unsubstituted C 1 -C 4 alkyl,
- P 1 is selected from the group consisting of benzyl, methyl, ethyl, i-propyl and t-butyl groups.
- Formula 1 has an advantage of being useful in the synthesis of various organic compounds because it has an ester skeleton that can be easily substituted with other substrates. Therefore, the research on the manufacturing method of the formula (1) is extensive, various synthesis methods have been developed by organic synthetic chemists and reported in many documents.
- A, R2 to R6 and P 1 are the same as defined in Formula 1, and X is halogen (ie F, Cl, Br, or I).
- the conventional Michael-addition reaction using only copper powder has a problem of requiring a relatively long reaction time, and has a disadvantage in that it is difficult to obtain the compound of Formula 1 in high yield due to the generation of impurities.
- the present invention provides a new preparation of the compound of formula (I).
- the present invention in the preparation of the following Chemical Formula 1 compound by the Michael-addition reaction of the following Chemical Formula 2 and the Chemical Formula 3 in the presence of a copper powder, reacting water or an acid or a mixture thereof
- A is R 1 -C ( ⁇ O) —, nitrile, substituted or unsubstituted C 1 -C 10 alkylsulfonyl, or substituted or unsubstituted C 6 -C 10 arylsulfonyl, wherein R 1 is hydrogen; Substituted or unsubstituted C 1 -C 10 alkyl; Substituted or unsubstituted C 3 -C 10 cycloalkyl; Substituted or unsubstituted C 6 -C 10 aryl; Substituted or unsubstituted 5-membered to 10-membered heteroaryl; And substituted or unsubstituted C 1 -C 5 alkoxy, or when A is bonded to R 3, A, R 3 and the carbons to which they are each bonded together are saturated with an oxo ( ⁇ O) group. Or unsaturated C 6 -C 10 cycloalkyl,
- R2, R3 and R4 are each independently hydrogen; Substituted or unsubstituted C 1 -C 10 alkyl; Substituted or unsubstituted C 3 -C 10 cycloalkyl; Substituted or unsubstituted C 6 -C 10 aryl; Substituted or unsubstituted 5- to 10-membered heteroaryl; Substituted or unsubstituted C 1 -C 5 alkoxy; Nitrile; And substituted or unsubstituted C 1 -C 10 alkyl sulfonyl,
- R5 and R6 are each independently hydrogen; Halogen (ie, F, Cl, Br, or I); And substituted or unsubstituted C 1 -C 4 alkyl,
- P 1 is selected from the group consisting of benzyl group, methyl group, ethyl group, i-propyl group and t-butyl group,
- X is halogen (ie, F, Cl, Br, or I).
- 'alkyl' refers to a straight or branched carbon chain having 1 to 10 (or 1 to 4) carbon atoms. Specifically, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl, isohexyl and the like can be included.
- cycloalkyl refers to a saturated or partially unsaturated mono- or poly-carbocyclic ring having 3 to 10 ring carbon atoms. Specifically, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and the like can be included.
- Aryl in the present invention refers to an aromatic mono- or poly-carbocyclic ring having 6 to 10 ring carbon atoms. Specifically, phenyl, naphthalenyl, or the like may be included.
- heteroaryl refers to an aromatic ring composed of 5 to 10 ring constituent atoms including 1 to 2 oxygen, nitrogen or sulfur as a hetero atom.
- furan, pyran, isobenzofuran, chroman, and the like may be included.
- 'alkoxy' refers to a group in which linear or branched carbon chain terminal oxygen of 1 to 5 carbon atoms is bonded. Specifically, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, pentoxy, neo-pentoxy and the like are included. Can be.
- A, and R1 to R6 are substituted groups, it is chloro, iodo, bromo, methyl, ethyl, n-propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, butoxy, And one or more substituents selected from acetyl.
- A is R 1 -C ( ⁇ O) —, nitrile, substituted or unsubstituted C 1 -C 10 alkylsulfonyl, or substituted or unsubstituted C 6 -C 10 arylsulfonyl, wherein R 1 is hydrogen; Substituted or unsubstituted C 1 -C 5 alkyl; Substituted or unsubstituted C 3 -C 6 cycloalkyl; Substituted or unsubstituted C 6 -C 8 aryl; Substituted or unsubstituted 5-membered to 8-membered heteroaryl; And substituted or unsubstituted C 1 -C 5 alkoxy, or, when A is bonded to R 3, A, R 3 and the carbons to which they are bonded together, together with an oxo ( ⁇ O) group Forms a substituted saturated or unsaturated C 6 -C 10 cycloalkyl,
- R2, R3 and R4 are each independently hydrogen; Substituted or unsubstituted C 1 -C 5 alkyl; Substituted or unsubstituted C 3 -C 6 cycloalkyl; Substituted or unsubstituted C 6 -C 8 aryl; Substituted or unsubstituted 5- to 8-membered heteroaryl; Substituted or unsubstituted C 1 -C 5 alkoxy; Nitrile; And substituted or unsubstituted C 1 -C 10 alkyl sulfonyl.
- the method for preparing the compound of Formula 1 according to the present invention is characterized by using water or various acids as an additive in Michael-addition reaction of the compound of Formula 2 and compound of Formula 3 in the presence of copper powder.
- the compound of formula 1 may be prepared, for example, via Scheme 1 below.
- a is copper powder, additives (water or various acids), amine compounds and solvents,
- R2, R3, R4, R5, R6, P 1 and X are as defined above.
- the amount of copper powder is not particularly limited, but in consideration of various conditions, it is preferable to use 1.0 to 6.0 equivalents with respect to 1 mole of the compound of formula 2, and 2.0. It is more preferable to use it in the range equivalent or more.
- water or various acids or mixtures thereof are used as specific additives of the reaction.
- Acids usable in the present invention include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; Or organic acids such as formic acid, acetic acid, tartaric acid, or the like, may be used alone or in combination of two or more thereof.
- water or acetic acid as the additive.
- the amount of water or acid used as the additive is preferably in the range of 0.1 to 6 equivalents, and more preferably in the range of 0.1 to 1 equivalents, based on 1 mol of the compound of Formula 2.
- Formula 1 compound preparation method of the present invention can be carried out in the presence of an amine compound.
- N, N, N ', N'- tetramethylethylenediamine (TMEDA; N, N, N ', N '-Tetramethylethylenediamine), N, N, N', N'- tetramethyl-1,3- Propanediamine (TMPDA; N, N, N ', N' -tetramethyl-1,3-propanediamine), N, N, N', N ', N'- pentamethyldiethylenetriamine (PMDTA; N, N, N ', N', N'- Pentamethyldiethylenetriamine), 2- (dimethylamino) ethyl ether, N, N -dimethyl-2- (4-methyl - 1-1 - piperazylyl
- An amine compound such as ethanamine ( N, N- dimethyl-2- (4-methyl-1-1-piperazylyl) ethanamine)
- the amount of the amine compound used is preferably in the range of 0.1 to 6 equivalents, and more preferably in the range of 0.1 to 1 equivalents based on 1 mole of the compound of Formula 2 above.
- TMEDA is typically used.
- the solvent used in the method for preparing the compound of formula 1 of the present invention is a conventional organic solvent, acetonitrile, aliphatic nitriles, halogenated aliphatic hydrocarbons (eg dichloromethane, dichloroethane, etc.) or cyclized ethers (eg tetrahydrofuran) , 1,4-dioxane, etc.), but is not limited thereto.
- tetrahydrofuran is typically used.
- Michael-addition reaction of the compound of Formula 2 and Formula 3 may be carried out at any temperature in the range from 15 °C to reflux temperature.
- the reaction time of the present invention may vary depending on the conditions of the reactants, the type of solvent, the amount of the solvent, and the like, but the reaction time can be significantly reduced as compared to the conventional method under the same conditions. TLC, 1 H NMR, HPLC, GC, etc. After confirming that the starting compound of the general formula (2) is all consumed, the reaction is terminated. After the reaction is completed, the solvent is distilled off under reduced pressure, and then the compound of Formula 1 may be separated and purified through a conventional method such as column chromatography.
- the compound of formula 1 may be prepared using water or various acids or mixtures thereof, which have not been tried so far, as an additive, and the reaction time may be significantly shortened and the synthesis yield may be increased as compared with the prior art. . Therefore, by using the manufacturing method of the present invention it is possible to commercially mass-produce the compound of formula (1) useful as intermediates such as pharmaceuticals, pesticides, electronic materials or liquid crystal materials.
- the yield (23%) and the improvement of the yield of 34% compared to the reaction time (3 hours) of the prior art ( J. Fluorine Chem . 2003 , 121 , 105) and the reaction time of 2 hours can be achieved.
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Abstract
Description
본 발명은, 의약품이나 농약, 전자재료 또는 액정 등의 중간체로 사용될 수 있는 화학식 1의 화합물을 물 또는 다양한 산을 첨가제로 이용한 새로운 마이클-첨가 반응(Michael-addition reaction)을 통하여 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing a compound of Formula 1, which can be used as an intermediate such as pharmaceuticals, pesticides, electronic materials or liquid crystals, through a new Michael-addition reaction using water or various acids as an additive. will be.
화학식 1의 화합물은 다양한 골격을 가지고 있고, 또한 생물학적 활성을 가지고 있기 때문에 의약품이나 농약, 전자재료 또는 액정재료 등을 합성하는 중간체로서 많이 사용되고 있다.Compounds of the general formula (1) have various skeletons and have biological activities, and thus are widely used as intermediates for synthesizing pharmaceuticals, pesticides, electronic materials or liquid crystal materials.
[화학식 1][Formula 1]
상기 화학식 1에서, In Chemical Formula 1,
A는 R1-C(=O)-, 니트릴, 치환 또는 비치환 C1-C10 알킬설포닐, 또는 치환 또는 비치환 C6-C10 아릴설포닐이고, 여기서 R1은 수소; 치환 또는 비치환 C1-C10 알킬; 치환 또는 비치환 C3-C10 시클로알킬; 치환 또는 비치환 C6-C10 아릴; 치환 또는 비치환 5-원(5-membered) 내지 10-원(10-membered) 헤테로아릴; 및 치환 또는 비치환 C1-C5 알콕시로 이루어진 군에서 선택되고, 또는, A가 R3에 결합되는 경우, A, R3 및 이들이 각각 결합된 탄소들은 함께, 옥소(=O) 그룹으로 치환된 포화 또는 불포화 C6-C10 시클로알킬을 형성하고,A is R 1 -C (═O) —, nitrile, substituted or unsubstituted C 1 -C 10 alkylsulfonyl, or substituted or unsubstituted C 6 -C 10 arylsulfonyl, wherein R 1 is hydrogen; Substituted or unsubstituted C 1 -C 10 alkyl; Substituted or unsubstituted C 3 -C 10 cycloalkyl; Substituted or unsubstituted C 6 -C 10 aryl; Substituted or unsubstituted 5-membered to 10-membered heteroaryl; And substituted or unsubstituted C 1 -C 5 alkoxy, or when A is bonded to R 3, A, R 3 and the carbons to which they are each bonded together are saturated with an oxo (═O) group. Or unsaturated C 6 -C 10 cycloalkyl,
R2, R3 및 R4는 각각 독립적으로 수소; 치환 또는 비치환 C1-C10 알킬; 치환 또는 비치환 C3-C10 시클로알킬; 치환 또는 비치환 C6-C10 아릴; 치환 또는 비치환 5-원 내지 10-원 헤테로아릴; 치환 또는 비치환 C1-C5 알콕시; 니트릴; 및 치환 또는 비치환 C1-C10 알킬 설포닐로 이루어진 군에서 선택되며, R2, R3 and R4 are each independently hydrogen; Substituted or unsubstituted C 1 -C 10 alkyl; Substituted or unsubstituted C 3 -C 10 cycloalkyl; Substituted or unsubstituted C 6 -C 10 aryl; Substituted or unsubstituted 5- to 10-membered heteroaryl; Substituted or unsubstituted C 1 -C 5 alkoxy; Nitrile; And substituted or unsubstituted C 1 -C 10 alkyl sulfonyl,
R5 및 R6은 각각 독립적으로 수소; 할로겐(즉, F, Cl, Br, 또는 I); 및 치환 또는 비치환 C1-C4 알킬로 이루어진 군에서 선택되고,R5 and R6 are each independently hydrogen; Halogen (ie, F, Cl, Br, or I); And substituted or unsubstituted C 1 -C 4 alkyl,
P1는 벤질기, 메틸기, 에틸기, i-프로필기 및 t-부틸기로 이루어진 군에서 선택된다.P 1 is selected from the group consisting of benzyl, methyl, ethyl, i-propyl and t-butyl groups.
화학식 1은 다른 기질로 쉽게 치환할 수 있는 에스터 골격을 가지고 있기 때문에 다양한 유기 화합물 합성에 유용하게 사용되는 장점을 가지고 있다. 따라서 화학식 1의 제조 방법에 대한 연구는 광범위하게 이루어져 있고, 유기 합성 화학자들에 의해 다양한 합성법이 개발되어 많은 문헌에 보고되어 있다.Formula 1 has an advantage of being useful in the synthesis of various organic compounds because it has an ester skeleton that can be easily substituted with other substrates. Therefore, the research on the manufacturing method of the formula (1) is extensive, various synthesis methods have been developed by organic synthetic chemists and reported in many documents.
화학식 1 화합물 중에서 유기불소 유도체를 가진 화합물이 활발히 연구되고 있는데, 특히 Itsumaro Kumadaki 그룹 (Setsunan University, Japan)에서 많이 연구되고 있다. 그러나 마이클-첨가 반응을 통해 이런 유기불소 유도체를 가진 화합물을 합성하는 데에는 많은 한계점들이 존재한다. 그러한 한계점들로는 첫째, 과량의 구리 분말 사용(6 당량 이상), 둘째, 비교적 긴 반응 시간(1 내지 7시간), 마지막으로 비교적 낮은 수율(20 내지 70%)을 들 수 있다. 이는 기존의 반응을 이용하여 대량으로 합성할 때 비용 및 시간 등의 측면에서 문제가 될 수 있다 [Chem. Pharm. Bull. 1999, 47, 1023; Chem. Pharm. Bull. 2000, 48, 1023; J. Fluorine Chem. 2003, 121, 105; J. Fluorine Chem. 2004, 125, 509].Compounds having organofluorine derivatives in the compound of Formula 1 have been actively studied, especially in the Itsumaro Kumadaki group (Setsunan University, Japan). However, there are many limitations in synthesizing compounds with these organofluorine derivatives through the Michael-addition reaction. Such limitations include firstly the use of excess copper powder (more than 6 equivalents), secondly, a relatively long reaction time (1-7 hours) and finally a relatively low yield (20-70%). This can be a problem in terms of cost and time when synthesizing in large quantities using existing reactions [ Chem. Pharm. Bull . 1999 , 47 , 1023; Chem. Pharm. Bull . 2000 , 48 , 1023; J. Fluorine Chem . 2003 , 121 , 105; J. Fluorine Chem . 2004 , 125 , 509].
화학식 1 화합물을 합성할 수 있는 것으로 알려진 방법의 일 예로서, 구리 분말을 이용하여 하기 화학식 2 화합물과 화학식 3 화합물을 마이클-첨가 반응하는 방법이 있다. As an example of a method known to be capable of synthesizing the compound of Formula 1, there is a method of Michael-adding a compound of Formula 2 and a compound of Formula 3 using copper powder.
[화학식 2][Formula 2]
[화학식 3][Formula 3]
상기에서, A, R2 내지 R6 및 P1은 상기 화학식 1에서 정의한 바와 동일하고, X는 할로겐(즉, F, Cl, Br, 또는 I)이다.In the above, A, R2 to R6 and P 1 are the same as defined in Formula 1, and X is halogen (ie F, Cl, Br, or I).
그러나, 단순히 구리분말만을 사용하는 기존의 마이클-첨가 반응은 비교적 긴 반응 시간을 필요로 하는 문제가 있고, 불순물 생성 등으로 인해 화학식 1 화합물을 높은 수율로 얻기 힘들다는 단점이 있다.However, the conventional Michael-addition reaction using only copper powder has a problem of requiring a relatively long reaction time, and has a disadvantage in that it is difficult to obtain the compound of Formula 1 in high yield due to the generation of impurities.
본 발명은 화학식 1 화합물을 높은 수율로 제조할 수 있는 새로운 제법을 제공하는 것을 그 목적으로 한다.It is an object of the present invention to provide a novel process for producing a compound of formula 1 in high yield.
따라서 본 발명은 화학식 1 화합물의 새로운 제법을 제공한다. 본 발명에 따르면, 구리 분말의 존재 하에 하기 화학식 2 화합물과 하기 화학식 3 화합물의 마이클-첨가 반응(Michael-addition reaction)을 통해 하기 화학식 1 화합물을 제조함에 있어서, 물 또는 산 또는 이들의 혼합물을 반응 혼합물에 첨가하는 것을 특징으로 하는 화학식 1 화합물의 제조방법이 제공된다:Thus, the present invention provides a new preparation of the compound of formula (I). According to the present invention, in the preparation of the following Chemical Formula 1 compound by the Michael-addition reaction of the following Chemical Formula 2 and the Chemical Formula 3 in the presence of a copper powder, reacting water or an acid or a mixture thereof There is provided a process for the preparation of the compound of formula 1, which is added to the mixture:
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
상기에서, In the above,
A는 R1-C(=O)-, 니트릴, 치환 또는 비치환 C1-C10 알킬설포닐, 또는 치환 또는 비치환 C6-C10 아릴설포닐이고, 여기서 R1은 수소; 치환 또는 비치환 C1-C10 알킬; 치환 또는 비치환 C3-C10 시클로알킬; 치환 또는 비치환 C6-C10 아릴; 치환 또는 비치환 5-원(5-membered) 내지 10-원(10-membered) 헤테로아릴; 및 치환 또는 비치환 C1-C5 알콕시로 이루어진 군에서 선택되고, 또는, A가 R3에 결합되는 경우, A, R3 및 이들이 각각 결합된 탄소들은 함께, 옥소(=O) 그룹으로 치환된 포화 또는 불포화 C6-C10 시클로알킬을 형성하고,A is R 1 -C (═O) —, nitrile, substituted or unsubstituted C 1 -C 10 alkylsulfonyl, or substituted or unsubstituted C 6 -C 10 arylsulfonyl, wherein R 1 is hydrogen; Substituted or unsubstituted C 1 -C 10 alkyl; Substituted or unsubstituted C 3 -C 10 cycloalkyl; Substituted or unsubstituted C 6 -C 10 aryl; Substituted or unsubstituted 5-membered to 10-membered heteroaryl; And substituted or unsubstituted C 1 -C 5 alkoxy, or when A is bonded to R 3, A, R 3 and the carbons to which they are each bonded together are saturated with an oxo (═O) group. Or unsaturated C 6 -C 10 cycloalkyl,
R2, R3 및 R4는 각각 독립적으로 수소; 치환 또는 비치환 C1-C10 알킬; 치환 또는 비치환 C3-C10 시클로알킬; 치환 또는 비치환 C6-C10 아릴; 치환 또는 비치환 5-원 내지 10-원 헤테로아릴; 치환 또는 비치환 C1-C5 알콕시; 니트릴; 및 치환 또는 비치환 C1-C10 알킬 설포닐로 이루어진 군에서 선택되며,R2, R3 and R4 are each independently hydrogen; Substituted or unsubstituted C 1 -C 10 alkyl; Substituted or unsubstituted C 3 -C 10 cycloalkyl; Substituted or unsubstituted C 6 -C 10 aryl; Substituted or unsubstituted 5- to 10-membered heteroaryl; Substituted or unsubstituted C 1 -C 5 alkoxy; Nitrile; And substituted or unsubstituted C 1 -C 10 alkyl sulfonyl,
R5 및 R6은 각각 독립적으로 수소; 할로겐(즉, F, Cl, Br, 또는 I); 및 치환 또는 비치환 C1-C4 알킬로 이루어진 군에서 선택되고,R5 and R6 are each independently hydrogen; Halogen (ie, F, Cl, Br, or I); And substituted or unsubstituted C 1 -C 4 alkyl,
P1은 벤질기, 메틸기, 에틸기, i-프로필기 및 t-부틸기로 이루어진 군에서 선택되며,P 1 is selected from the group consisting of benzyl group, methyl group, ethyl group, i-propyl group and t-butyl group,
X는 할로겐(즉, F, Cl, Br, 또는 I)이다.X is halogen (ie, F, Cl, Br, or I).
본 발명에서 ‘알킬’은 탄소수 1 내지 10(또는 1 내지 4)의 직쇄상 또는 분지상의 탄소사슬을 일컫는다. 구체적으로는, 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, sec-부틸, t-부틸, 펜틸, 네오-펜틸, 헥실, 이소헥실 등이 포함될 수 있다.In the present invention, 'alkyl' refers to a straight or branched carbon chain having 1 to 10 (or 1 to 4) carbon atoms. Specifically, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl, isohexyl and the like can be included.
본 발명에서 ‘시클로알킬’은 3 내지 10개의 고리 탄소 원자를 갖는 포화 또는 부분 불포화된 모노- 또는 폴리-카보시클릭 고리를 일컫는다. 구체적으로는, 시클로펜틸, 시클로펜테닐, 시클로헥실, 시클로헥세닐, 시클로헵틸 등이 포함될 수 있다.In the present invention, "cycloalkyl" refers to a saturated or partially unsaturated mono- or poly-carbocyclic ring having 3 to 10 ring carbon atoms. Specifically, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and the like can be included.
본 발명에서 ‘아릴’은 6 내지 10개의 고리 탄소 원자를 갖는 방향족 모노- 또는 폴리-카보시클릭 고리를 일컫는다. 구체적으로는, 페닐, 나프탈레닐 등이 포함될 수 있다. "Aryl" in the present invention refers to an aromatic mono- or poly-carbocyclic ring having 6 to 10 ring carbon atoms. Specifically, phenyl, naphthalenyl, or the like may be included.
본 발명에서‘헤테로아릴’은 헤테로 원자로서 1 내지 2개의 산소, 질소 또는 황을 포함하여 5 내지 10개의 고리 구성 원자로 이루어진 방향족 고리를 일컫는다. 구체적으로 퓨란, 피란, 이소벤조퓨란, 크로멘 등이 포함될 수 있다. In the present invention, "heteroaryl" refers to an aromatic ring composed of 5 to 10 ring constituent atoms including 1 to 2 oxygen, nitrogen or sulfur as a hetero atom. Specifically, furan, pyran, isobenzofuran, chroman, and the like may be included.
본 발명에서 ‘알콕시’는 탄소수 1 내지 5의 직쇄상 또는 분지상의 탄소사슬 말단 산소가 결합된 그룹을 일컫는다. 구체적으로는, 메톡시, 에톡시, n-프로폭시, i-프로폭시, n-부톡시, i-부톡시, sec-부톡시, t-부톡시, 펜톡시, 네오-펜톡시 등이 포함될 수 있다.In the present invention, 'alkoxy' refers to a group in which linear or branched carbon chain terminal oxygen of 1 to 5 carbon atoms is bonded. Specifically, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, pentoxy, neo-pentoxy and the like are included. Can be.
본 발명에서 A, 및 R1 내지 R6가 치환된 그룹인 경우, 이는 클로로, 요오도, 브로모, 메틸, 에틸, n-프로필, 이소프로필, 부틸, 메톡시, 에톡시, 프로폭시, 부톡시, 및 아세틸 중에서 선택된 하나 이상의 치환체로 치환된 것임을 의미한다.In the present invention, when A, and R1 to R6 are substituted groups, it is chloro, iodo, bromo, methyl, ethyl, n-propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, butoxy, And one or more substituents selected from acetyl.
본 발명의 일 구체예에 따르면, 상기 화학식 1 및 2에서 독립적으로, According to an embodiment of the present invention, independently in the formula 1 and 2,
A는 R1-C(=O)-, 니트릴, 치환 또는 비치환 C1-C10 알킬설포닐, 또는 치환 또는 비치환 C6-C10 아릴설포닐이고, 여기서 R1은 수소; 치환 또는 비치환 C1-C5 알킬; 치환 또는 비치환 C3-C6 시클로알킬; 치환 또는 비치환 C6-C8 아릴; 치환 또는 비치환 5-원(5-membered) 내지 8-원(8-membered) 헤테로아릴; 및 치환 또는 비치환 C1-C5 알콕시로 이루어진 군에서 보다 바람직하게 선택되고, 또는, A가 R3에 결합되는 경우, A, R3 및 이들이 각각 결합된 탄소들은 함께, 옥소(=O) 그룹으로 치환된 포화 또는 불포화 C6-C10 시클로알킬을 형성하고,A is R 1 -C (═O) —, nitrile, substituted or unsubstituted C 1 -C 10 alkylsulfonyl, or substituted or unsubstituted C 6 -C 10 arylsulfonyl, wherein R 1 is hydrogen; Substituted or unsubstituted C 1 -C 5 alkyl; Substituted or unsubstituted C 3 -C 6 cycloalkyl; Substituted or unsubstituted C 6 -C 8 aryl; Substituted or unsubstituted 5-membered to 8-membered heteroaryl; And substituted or unsubstituted C 1 -C 5 alkoxy, or, when A is bonded to R 3, A, R 3 and the carbons to which they are bonded together, together with an oxo (═O) group Forms a substituted saturated or unsaturated C 6 -C 10 cycloalkyl,
R2, R3 및 R4는 각각 독립적으로 수소; 치환 또는 비치환 C1-C5 알킬; 치환 또는 비치환 C3-C6 시클로알킬; 치환 또는 비치환 C6-C8 아릴; 치환 또는 비치환 5-원 내지 8-원 헤테로아릴; 치환 또는 비치환 C1-C5 알콕시; 니트릴; 및 치환 또는 비치환 C1-C10 알킬 설포닐로 이루어진 군에서 보다 바람직하게 선택된다.R2, R3 and R4 are each independently hydrogen; Substituted or unsubstituted C 1 -C 5 alkyl; Substituted or unsubstituted C 3 -C 6 cycloalkyl; Substituted or unsubstituted C 6 -C 8 aryl; Substituted or unsubstituted 5- to 8-membered heteroaryl; Substituted or unsubstituted C 1 -C 5 alkoxy; Nitrile; And substituted or unsubstituted C 1 -C 10 alkyl sulfonyl.
본 발명에 따른 상기 화학식 1 화합물의 제조방법은 상기 화학식 2 화합물과 화학식 3 화합물을 구리 분말의 존재 하에 마이클-첨가 반응함에 있어서 물 또는 다양한 산을 첨가제로 사용하는 것을 특징으로 한다. 본 발명의 일 구체예에 따르면, 예컨대 다음 반응식 1을 통하여 화학식 1 화합물이 제조될 수 있다.The method for preparing the compound of Formula 1 according to the present invention is characterized by using water or various acids as an additive in Michael-addition reaction of the compound of Formula 2 and compound of Formula 3 in the presence of copper powder. According to one embodiment of the present invention, the compound of formula 1 may be prepared, for example, via Scheme 1 below.
[반응식 1]Scheme 1
상기 반응식 1에서,In Scheme 1,
a는 구리 분말, 첨가제(물 또는 다양한 산), 아민 화합물 및 용매이고,a is copper powder, additives (water or various acids), amine compounds and solvents,
A, R2, R3, R4, R5, R6, P1 및 X는 상기에서 정의한 바와 같다.A, R2, R3, R4, R5, R6, P 1 and X are as defined above.
본 발명의 화학식 1 화합물 제조방법에 있어서, 구리 분말의 사용량에는 특별한 제한을 두지 않으나, 여러 가지 여건을 고려하였을 때 상기 화학식 2 화합물 1몰에 대하여 1.0 내지 6.0 당량 범위로 사용하는 것이 바람직하고, 2.0 당량 이상의 범위로 사용하는 것이 보다 바람직하다.In the method for preparing the compound of formula 1 of the present invention, the amount of copper powder is not particularly limited, but in consideration of various conditions, it is preferable to use 1.0 to 6.0 equivalents with respect to 1 mole of the compound of formula 2, and 2.0. It is more preferable to use it in the range equivalent or more.
본 발명의 화학식 1 화합물 제조방법에서는 반응의 특정 첨가제로서 물 또는 다양한 산 또는 이들의 혼합물을 이용한다. 본 발명에서 사용가능한 산으로는 염산, 황산, 질산, 인산 등의 무기산; 또는 포름산, 초산, 주석산 등의 유기산을 단독으로 또는 2종 이상 혼합하여 사용할 수 있으며, 특히 반응의 안정성 및 편의성 등을 고려할 때, 상기 첨가제로서 물 또는 초산을 사용하는 것이 바람직하다. 본 발명에 있어서 상기 첨가제로서 물 또는 산의 사용량은 상기 화학식 2 화합물 1몰에 대하여 0.1 내지 6 당량의 범위인 것이 바람직하고, 0.1 내지 1 당량 범위로 사용하는 것이 보다 바람직하다.In the method for preparing the compound of formula 1 of the present invention, water or various acids or mixtures thereof are used as specific additives of the reaction. Acids usable in the present invention include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; Or organic acids such as formic acid, acetic acid, tartaric acid, or the like, may be used alone or in combination of two or more thereof. In particular, in consideration of stability and convenience of the reaction, it is preferable to use water or acetic acid as the additive. In the present invention, the amount of water or acid used as the additive is preferably in the range of 0.1 to 6 equivalents, and more preferably in the range of 0.1 to 1 equivalents, based on 1 mol of the compound of Formula 2.
본 발명의 화학식 1 화합물 제조방법은 아민 화합물의 존재 하에서 수행될 수 있다. 이 경우, N,N,N’,N’-테트라메틸에틸렌디아민(TMEDA; N,N,N’,N’-Tetramethylethylenediamine), N,N,N’,N’-테트라메틸-1,3-프로판디아민(TMPDA; N,N,N’,N’-Tetramethyl-1,3-propanediamine), N,N,N’,N’,N’-펜타메틸디에틸렌트리아민(PMDTA; N,N,N’,N’,N’-Pentamethyldiethylenetriamine), 2-(디메틸아미노)에틸 에테르(2-(Dimethylamino)ethyl ether), N,N-디메틸-2-(4-메틸-1-1-피페라질릴)에탄아민(N,N-dimethyl-2-(4-methyl-1-1-piperazylyl)ethanamine) 등의 아민 화합물을 사용할 수 있으나 이에 한정되는 것은 아니다. 아민 화합물의 사용량은 상기 화학식 2 화합물 1몰에 대하여 0.1 내지 6 당량 범위로 사용하는 것이 바람직하고, 0.1 내지 1 당량 범위로 사용하는 것이 보다 바람직하다. 본 발명의 일 구체예에서는 대표적으로 TMEDA를 사용한다.Formula 1 compound preparation method of the present invention can be carried out in the presence of an amine compound. In this case, N, N, N ', N'- tetramethylethylenediamine (TMEDA; N, N, N ', N '-Tetramethylethylenediamine), N, N, N', N'- tetramethyl-1,3- Propanediamine (TMPDA; N, N, N ', N' -tetramethyl-1,3-propanediamine), N, N, N', N ', N'- pentamethyldiethylenetriamine (PMDTA; N, N, N ', N', N'- Pentamethyldiethylenetriamine), 2- (dimethylamino) ethyl ether, N, N -dimethyl-2- (4-methyl - 1-1 - piperazylyl An amine compound such as ethanamine ( N, N- dimethyl-2- (4-methyl-1-1-piperazylyl) ethanamine) may be used, but is not limited thereto. The amount of the amine compound used is preferably in the range of 0.1 to 6 equivalents, and more preferably in the range of 0.1 to 1 equivalents based on 1 mole of the compound of Formula 2 above. In one embodiment of the present invention, TMEDA is typically used.
본 발명의 화학식 1 화합물 제조방법에 사용되는 용매는 통상의 유기 용매이며, 아세토니트릴, 지방족 니트릴류, 할로겐화 지방족 탄화수소류(예컨대, 디클로로메탄, 디클로로에탄 등) 또는 고리화 에테르 (예컨대, 테트라히드로퓨란, 1,4-디옥산 등)를 사용할 수 있으나, 이에 한정되는 것은 아니다. 본 발명의 일 구체예에서는 대표적으로 테트라히드로퓨란을 사용한다.The solvent used in the method for preparing the compound of formula 1 of the present invention is a conventional organic solvent, acetonitrile, aliphatic nitriles, halogenated aliphatic hydrocarbons (eg dichloromethane, dichloroethane, etc.) or cyclized ethers (eg tetrahydrofuran) , 1,4-dioxane, etc.), but is not limited thereto. In one embodiment of the present invention, tetrahydrofuran is typically used.
상기 화학식 2 화합물과 화학식 3 화합물의 마이클-첨가 반응은 15℃ 내지 환류 온도까지의 범위 내의 어느 온도에서도 수행될 수 있다. Michael-addition reaction of the compound of Formula 2 and Formula 3 may be carried out at any temperature in the range from 15 ℃ to reflux temperature.
본 발명의 반응 시간은 반응물질, 용매의 종류 및 용매의 양 등의 조건에 따라 달라질 수 있으나, 동등한 조건의 종래 방법에 비해서는 반응시간을 대폭 줄일 수 있다. TLC, 1H NMR, HPLC, GC 등을 통하여 출발물질인 화학식 2 화합물이 모두 소모되었음을 확인한 후 반응을 종결시킨다. 반응이 종결되면 감압하에서 용매를 증류시킨 후, 컬럼 크로마토그래피 등의 통상의 방법을 통하여 화학식 1 화합물을 분리 및 정제할 수 있다.The reaction time of the present invention may vary depending on the conditions of the reactants, the type of solvent, the amount of the solvent, and the like, but the reaction time can be significantly reduced as compared to the conventional method under the same conditions. TLC, 1 H NMR, HPLC, GC, etc. After confirming that the starting compound of the general formula (2) is all consumed, the reaction is terminated. After the reaction is completed, the solvent is distilled off under reduced pressure, and then the compound of Formula 1 may be separated and purified through a conventional method such as column chromatography.
본 발명에 따르면, 지금까지 시도된 바가 없는 물 또는 다양한 산 또는 그의 혼합물을 첨가제로 이용하여 화학식 1 화합물을 제조할 수 있고, 선행 기술과 비교하여 획기적으로 반응시간을 단축시키고 합성 수율을 높일 수 있다. 따라서 본 발명의 제조방법을 활용하여 약품이나 농약, 전자재료 또는 액정재료 등의 중간체로 유용한 화학식 1 화합물을 상업적으로 대량생산할 수 있다.According to the present invention, the compound of formula 1 may be prepared using water or various acids or mixtures thereof, which have not been tried so far, as an additive, and the reaction time may be significantly shortened and the synthesis yield may be increased as compared with the prior art. . Therefore, by using the manufacturing method of the present invention it is possible to commercially mass-produce the compound of formula (1) useful as intermediates such as pharmaceuticals, pesticides, electronic materials or liquid crystal materials.
이상에서 설명한 바와 같은 본 발명에 대해 하기의 실시예를 통하여 더욱 상세히 설명하겠는 바, 하기의 실시예들은 본 발명에 대한 이해를 돕기 위한 것으로서 본 발명의 범위가 여기에 국한된 것은 아니다.The present invention as described above will be described in more detail with reference to the following examples, the following examples are provided to help the understanding of the present invention is not limited to the scope of the present invention.
실시예 1: 디에틸 2,2-디플루오로펜탄디오에이트(Diethyl 2,2-difluoropentanedioate)의 합성Example 1 Synthesis of Diethyl 2,2-difluoropentanedioate
구리 분말(700 mg)과 테트라히드로퓨란(5.8 mL)을 반응 용기에 넣고 50 ℃에서 교반시킨 뒤, 여기에 에틸 아크릴레이트(0.50 g)와 에틸 브로모디플루오로아세테이트(2.53 g)를 첨가하고, TMEDA(0.29 g)와 초산(0.27 g)을 차례로 적가한 뒤, 0.5시간 동안 반응시킨 후 반응을 종결하였다. 결과 혼합액에 10% 암모늄클로라이드 수용액을 첨가하고, 구리 잔류물을 제거하기 위해 결과 혼합액을 셀라이트 패드를 이용하여 여과한 후, 메틸 t-부틸에테르로 추출하여 디에틸 2,2-디플루오로펜탄디오에이트(1.09 g, 수율: 97.4%)를 수득하였다. Copper powder (700 mg) and tetrahydrofuran (5.8 mL) were placed in a reaction vessel and stirred at 50 ° C, to which ethyl acrylate (0.50 g) and ethyl bromodifluoroacetate (2.53 g) were added, TMEDA (0.29 g) and acetic acid (0.27 g) were added dropwise, followed by reaction for 0.5 hours, and then the reaction was terminated. 10% ammonium chloride aqueous solution was added to the resultant mixture, and the resultant mixture was filtered through a pad of celite to remove copper residue, followed by extraction with methyl t-butylether to diethyl 2,2-difluoropentane. Dioate (1.09 g, yield: 97.4%) was obtained.
또한, 상기 방법과 동일하게 하되 초산 대신 물(0.10 g)을 사용하여 디에틸 2.2-디플루오로펜탄디오에이트(1.08 g, 수율: 96.4%)를 수득하였다.In the same manner as above, but diethyl 2.2-difluoropentanedioate (1.08 g, yield: 96.4%) was obtained using water (0.10 g) instead of acetic acid.
실시예 2: 에틸 2,2-디플루오로-2-(3-옥소시클로헥실)아세테이트(Ethyl 2,2-difluoro-2-(3-oxocyclohexyl)acetate)의 합성Example 2: Synthesis of ethyl 2,2-difluoro-2- (3-oxocyclohexyl) acetate (Ethyl 2,2-difluoro-2- (3-oxocyclohexyl) acetate)
구리 분말(1.65 g)과 테트라히드로퓨란(7.60 mL)을 반응 용기에 넣고 환류조건하에 교반시킨 뒤, 여기에 2-시클로헥센-1-온(0.50 g)과 에틸 브로모디플루오로아세테이트(2.64 g)를 첨가하고, TMEDA(0.30 g)와 초산(0.28 g)을 차례로 적가한 뒤, 4시간 동안 반응시킨 후 반응을 종결하였다. 결과 혼합액에 10% 암모늄클로라이드 수용액을 첨가하고, 구리 잔류물을 제거하기 위해 결과 혼합액을 셀라이트 패드를 이용하여 여과한 후, 메틸 t-부틸에테르로 추출하여 에틸 2,2-디플루오로-2-(3-옥소시클로헥실)아세테이트(1.12 g, 수율: 97.8%)를 수득하였다.Copper powder (1.65 g) and tetrahydrofuran (7.60 mL) were placed in a reaction vessel and stirred under reflux conditions, followed by 2-cyclohexen-1-one (0.50 g) and ethyl bromodifluoroacetate (2.64 g). ) Was added dropwise, TMEDA (0.30 g) and acetic acid (0.28 g) were added dropwise, followed by reaction for 4 hours and then terminated. 10% aqueous ammonium chloride solution was added to the resultant mixture, and the resultant mixture was filtered through a pad of celite to remove copper residue, followed by extraction with methyl t-butylether to give ethyl 2,2-difluoro-2. -(3-oxocyclohexyl) acetate (1.12 g, yield: 97.8%) was obtained.
실시예 3: 에틸 2,2-디플루오로-3-메틸-5-옥소헵타노에이트(Ethyl 2,2-difluoro-3-methyl-5-oxoheptanoate)의 합성Example 3: Synthesis of Ethyl 2,2-difluoro-3-methyl-5-oxoheptanoate
구리 분말(1.94 g)과 테트라히드로퓨란(7.4 mL)을 반응 용기에 넣고 환류조건하에 교반시킨 뒤, 여기에 4-헥센-3-온(0.50 g)과 에틸 브로모디플루오로아세테이트(2.59 g)를 첨가하고, TMEDA(0.30 g)과 초산(0.28 g)을 차례로 첨가한 뒤, 1시간 동안 반응시킨 후 반응을 종결하였다. 결과 혼합액에 10% 암모늄클로라이드 수용액을 첨가하고, 구리 잔류물을 제거하기 위해 결과 혼합액을 셀라이트 패드를 이용하여 여과한 후, 메틸 t-부틸에테르로 추출하여 에틸 2,2-디플루오로-3-메틸-5-옥소헵타노에이트(1.04 g, 수율: 91.9%)를 수득하였다.Copper powder (1.94 g) and tetrahydrofuran (7.4 mL) were placed in a reaction vessel and stirred under reflux, followed by 4-hexen-3-one (0.50 g) and ethyl bromodifluoroacetate (2.59 g). Was added, TMEDA (0.30 g) and acetic acid (0.28 g) were added sequentially, followed by reaction for 1 hour, and then the reaction was terminated. 10% aqueous ammonium chloride solution was added to the resultant mixture, and the resultant mixture was filtered through a pad of celite to remove copper residue, followed by extraction with methyl t-butylether to give ethyl 2,2-difluoro-3. -Methyl-5-oxoheptanoate (1.04 g, yield: 91.9%) was obtained.
실시예 4: 에틸-2,2-디플루오로-5-옥소헥사노에트(Ethyl-2,2-difluoro-5-oxohexanoate)의 합성Example 4 Synthesis of Ethyl-2,2-difluoro-5-oxohexanoate
구리 분말(0.48 g)과 테트라히드로퓨란 (5.21 mL)을 반응 용기에 넣고 실온에서 교반시킨 뒤, 여기에 메틸 비닐케톤(0.25 g)과 에틸 브로모디플루오로아세테이트(1.14 mL)를 첨가하고, TMEDA(0.21 g)와 초산(0.19 g)을 차례로 첨가한 뒤, 1시간 동안 반응시킨 후 반응을 종결하였다. 결과 혼합액에 10% 암모늄클로라이드 수용액을 첨가하고, 구리 잔류물을 제거하기 위해 결과 혼합액을 셀라이트 패드를 이용하여 여과한 후, 메틸 t-부틸에테르로 추출하여 에틸-2,2-디플루오로-5-옥소헥사노에트(0.63 g, 수율: 91.0%)를 수득하였다.Copper powder (0.48 g) and tetrahydrofuran (5.21 mL) were placed in a reaction vessel and stirred at room temperature, to which methyl vinyl ketone (0.25 g) and ethyl bromodifluoroacetate (1.14 mL) were added, and TMEDA (0.21 g) and acetic acid (0.19 g) were added sequentially, followed by reaction for 1 hour, and then the reaction was terminated. 10% aqueous ammonium chloride solution was added to the resultant mixture, and the resultant mixture was filtered through a pad of celite to remove copper residues, followed by extraction with methyl t-butylether and ethyl-2,2-difluoro-. 5-oxohexanoate (0.63 g, yield: 91.0%) was obtained.
실시예 5: 에틸-4-시아노-2,2-디플루오로부타노에트(Ethyl 4-cyano-2,2-difluorobutanoate)의 합성Example 5: Synthesis of ethyl-4-cyano-2,2-difluorobutanoate
구리 분말(1.26 g)과 테트라히드로퓨란(13.8 mL)을 반응 용기에 넣고 실온에서 교반시킨 뒤, 여기에 아크릴로니트릴(0.50 g)과 에틸 브로모디플루오로아세테이트(4.78 g)를 적가하고, TMEDA(0.55 g)와 초산(0.51 g)을 차례로 첨가한 뒤, 1시간 동안 반응시킨 후 반응을 종결하였다. 결과 혼합액에 10% 암모늄클로라이드 수용액을 첨가하고, 구리 잔류물을 제거하기 위해 결과 혼합액을 셀라이트 패드를 이용하여 여과한 후, 메틸 t-부틸에테르로 추출하여 에틸-4-시아노-2,2-디플루오로부타노에트(1.52 g, 수율: 91.1%)를 수득하였다. Copper powder (1.26 g) and tetrahydrofuran (13.8 mL) were placed in a reaction vessel and stirred at room temperature, to which acrylonitrile (0.50 g) and ethyl bromodifluoroacetate (4.78 g) were added dropwise, and TMEDA (0.55 g) and acetic acid (0.51 g) were added sequentially, followed by reaction for 1 hour, and then the reaction was terminated. 10% aqueous ammonium chloride solution was added to the resultant mixture, and the resultant mixture was filtered through a pad of celite to remove copper residues, followed by extraction with methyl t-butylether and ethyl-4-cyano-2,2. -Difluorobutanoate (1.52 g, yield: 91.1%) was obtained.
또한, 상기 방법과 동일하게 하되 초산 대신 물(0.17g)을 사용하여 에틸-4-시아노-2,2-디플루오로부타노에트(1.48 g, 수율: 88.7%)를 수득하였다.In addition, ethyl-4-cyano-2,2-difluorobutanoate (1.48 g, yield: 88.7%) was obtained in the same manner as the above method, but using water (0.17 g) instead of acetic acid.
실시예 6: 에틸 2,2-디플루오로-3-메틸-5-옥소펜타노에이트(Ethyl 2,2-difluoro-3-methyl-5-oxopentanoate)의 합성Example 6 Synthesis of Ethyl 2,2-difluoro-3-methyl-5-oxopentanoate
구리 분말(1.81 g)과 테트라히드로퓨란(10.40 mL)을 반응 용기에 넣고 환류조건 하에서 교반시킨 뒤, 여기에 크로토알데히드(0.50 g)와 에틸 브로모디플루오로아세테이트(3.62 g)를 적가하고, TMEDA(0.41 g)와 초산(0.39 g)을 차례로 첨가한 뒤, 1시간 동안 반응시킨 후 반응을 종결하였다. 결과 혼합액에 10% 암모늄클로라이드 수용액을 첨가하고, 구리 잔류물을 제거하기 위해 결과 혼합액을 셀라이트 패드를 이용하여 여과한 후, 메틸 t-부틸에테르로 추출하여 에틸-4-시아노-2,2-디플루오로부타노에이트(0.79 g, 수율: 57.0%)를 수득하였다. Copper powder (1.81 g) and tetrahydrofuran (10.40 mL) were added to the reaction vessel, and the mixture was stirred under reflux conditions. To this was added dropwise crotoaldehyde (0.50 g) and ethyl bromodifluoroacetate (3.62 g). TMEDA (0.41 g) and acetic acid (0.39 g) were added sequentially, followed by reaction for 1 hour, and then the reaction was terminated. 10% aqueous ammonium chloride solution was added to the resultant mixture, and the resultant mixture was filtered through a pad of celite to remove copper residues, followed by extraction with methyl t-butylether and ethyl-4-cyano-2,2. -Difluorobutanoate (0.79 g, yield: 57.0%) was obtained.
본 실시예에서는 종래 기술(J. Fluorine Chem. 2003, 121, 105)의 수득률(23%) 및 반응시간(3시간) 대비 34%의 수득률 향상 및 2시간의 반응시간 단축을 달성할 수 있었다.In this embodiment, the yield (23%) and the improvement of the yield of 34% compared to the reaction time (3 hours) of the prior art ( J. Fluorine Chem . 2003 , 121 , 105) and the reaction time of 2 hours can be achieved.
실시예 7: 에틸 2,2-디플루오로-5-엑소-3-페닐헥사노에이트(Ethyl 2,2-difluoro-5-exo-3-phenylhexanoate)의 합성Example 7: Synthesis of Ethyl 2,2-difluoro-5-exo-3-phenylhexanoate
구리 분말(0.32 g)과 테트라히드로퓨란(10.4 mL)을 반응 용기에 넣고 환류조건 하에서 교반시킨 뒤, 여기에 찰콘(chalcone)(0.50 g)과 에틸 브로모디플루오로아세테이트(1.22 g)를 적가하고, TMEDA(0.14 g)와 초산(0.13 g)을 차례로 첨가한 뒤, 1시간 동안 반응시킨 후 반응을 종결하였다. 결과 혼합액에 10% 암모늄클로라이드 수용액을 첨가하고, 구리 잔류물을 제거하기 위해 결과 혼합액을 셀라이트 패드를 이용하여 여과한 후, 메틸 t-부틸에테르로 추출하여 에틸 2,2-디플루오로-5-엑소-3-페닐헥사노에이트(833 mg, 수율: 34.8%)를 수득하였다.Copper powder (0.32 g) and tetrahydrofuran (10.4 mL) were added to the reaction vessel and stirred under reflux conditions, followed by dropwise addition of chalcone (0.50 g) and ethyl bromodifluoroacetate (1.22 g). , TMEDA (0.14 g) and acetic acid (0.13 g) were added sequentially, followed by reaction for 1 hour, and then the reaction was terminated. 10% aqueous ammonium chloride solution was added to the resultant mixture, and the resultant mixture was filtered through a pad of celite to remove copper residue, followed by extraction with methyl t-butylether and ethyl 2,2-difluoro-5. -Exo-3-phenylhexanoate (833 mg, yield: 34.8%) was obtained.
본 실시예에서는 종래 기술(J. Fluorine Chem. 2003, 121, 105)의 수득률(23%) 대비 11.8%의 수득률 향상을 달성할 수 있었다. 또한, 본반응시간(1시간) 자체는 종래 기술과 동일하였지만, 종래 기술에서는 다른 반응물들을 넣고 1시간 교반 후 TMEDA를 첨가하게 되는 반면 본 발명에서는 이러한 과정이 필요없기 때문에 총 소요시간을 실질적으로 더 단축시킬 수 있었다.In this embodiment, the yield improvement of 11.8% compared to the yield (23%) of the prior art ( J. Fluorine Chem . 2003 , 121 , 105) could be achieved. In addition, while the reaction time (1 hour) itself was the same as in the prior art, while in the prior art, TMEDA is added after stirring for 1 hour after adding other reactants, while in the present invention, the total time required is substantially longer because this process is not necessary. Could be shortened.
실시예 8: 에틸 2,2-디플루오로-4-(페닐설포닐)부타노에이트(Ethyl 2,2-difluoro-4-(phenylsulfonyl)butanoate)의 합성Example 8: Synthesis of ethyl 2,2-difluoro-4- (phenylsulfonyl) butanoate (Ethyl 2,2-difluoro-4- (phenylsulfonyl) butanoate)
구리 분말(0.40 g)과 테트라히드로퓨란(4.40 mL)를 반응 용기에 넣고 50 ℃ 에서 교반시킨 뒤, 여기에 페닐 비닐설폰(0.50 g)과 에틸 브로모디플루오로아세테이트(1.51 g)를 적가하고, TMEDA(0.17 g)와 초산(0.16 g)을 차례로 첨가한 뒤, 1시간 동안 반응시킨 후 반응을 종결하였다. 결과 혼합액에 10% 암모늄클로라이드 수용액을 첨가하고, 구리 잔류물을 제거하기 위해 결과 혼합액을 셀라이트 패드를 이용하여 여과한 후, 메틸 t-부틸에테르로 추출하여 에틸 2,2-디플루오로-4-(페닐설포닐)부타노에이트(0.74 g, 수율: 85.2%)를 합성하였다.Copper powder (0.40 g) and tetrahydrofuran (4.40 mL) were added to the reaction vessel and stirred at 50 ° C, to which phenyl vinylsulfone (0.50 g) and ethyl bromodifluoroacetate (1.51 g) were added dropwise, TMEDA (0.17 g) and acetic acid (0.16 g) were added sequentially, followed by reaction for 1 hour, and then the reaction was terminated. 10% aqueous ammonium chloride solution was added to the resultant mixture, and the resultant mixture was filtered through a pad of celite to remove copper residue, followed by extraction with methyl t-butylether to give ethyl 2,2-difluoro-4. -(Phenylsulfonyl) butanoate (0.74 g, yield: 85.2%) was synthesized.
Claims (7)
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- 2014-07-31 TN TNP2014000329A patent/TN2014000329A1/en unknown
- 2014-08-12 CO CO14176211A patent/CO7030967A2/en unknown
- 2014-08-12 MA MA37281A patent/MA35906B1/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07103159B2 (en) * | 1985-01-14 | 1995-11-08 | ネオルックス | Radionuclide metal chelate |
Non-Patent Citations (3)
| Title |
|---|
| COMELLES, JOSEP ET AL.: "Ionic and Covalent Copper(II)-Based Catalysts for Michael Additions. The Mechanism", J. ORG. CHEM., vol. 69, no. 20, October 2004 (2004-10-01), pages 6834 - 6842, XP055079825 * |
| COMELLES, JOSEP ET AL.: "Michael additions catalyzed by transition metals and lanthanide species. A review", ARKIVOC USA, INC., 26 March 2005 (2005-03-26), pages 207 - 238, XP055079823 * |
| EVANS, DAVID A. ET AL.: "Catalytic Enantioselective Michael Additions to Unsaturated Ester Derivatives Using Chiral Copper(II) Lewis Acid Complexes", ORGANIC LETTERS, vol. 1, no. 6, 1999, pages 865 - 868, XP055079828 * |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20130090360A (en) | 2013-08-13 |
| CN104159884B (en) | 2016-01-13 |
| KR101539761B1 (en) | 2015-07-28 |
| BR112014018985A8 (en) | 2017-07-11 |
| EA026411B1 (en) | 2017-04-28 |
| AU2013215796A1 (en) | 2014-08-21 |
| ZA201405598B (en) | 2015-09-30 |
| CN104159884A (en) | 2014-11-19 |
| PH12014501704B1 (en) | 2014-10-13 |
| EA201491463A1 (en) | 2014-11-28 |
| CO7030967A2 (en) | 2014-08-21 |
| MX2014009309A (en) | 2014-11-10 |
| TN2014000329A1 (en) | 2015-12-21 |
| MA35906B1 (en) | 2014-12-01 |
| AU2013215796B2 (en) | 2016-09-15 |
| MX355336B (en) | 2018-04-16 |
| MY168411A (en) | 2018-11-09 |
| PH12014501704A1 (en) | 2014-10-13 |
| PE20142331A1 (en) | 2015-01-17 |
| BR112014018985A2 (en) | 2017-06-20 |
| SG11201404396TA (en) | 2015-06-29 |
| BR112014018985B1 (en) | 2021-01-19 |
| CL2014002029A1 (en) | 2014-12-26 |
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