WO2022244969A1 - Method for preparing methylene lactone-based compound - Google Patents
Method for preparing methylene lactone-based compound Download PDFInfo
- Publication number
- WO2022244969A1 WO2022244969A1 PCT/KR2022/004436 KR2022004436W WO2022244969A1 WO 2022244969 A1 WO2022244969 A1 WO 2022244969A1 KR 2022004436 W KR2022004436 W KR 2022004436W WO 2022244969 A1 WO2022244969 A1 WO 2022244969A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- based compound
- phosphine
- metal
- methylene lactone
- formula
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 87
- -1 methylene lactone Chemical class 0.000 title claims abstract description 75
- 238000000034 method Methods 0.000 title claims abstract description 43
- 238000004519 manufacturing process Methods 0.000 claims abstract description 28
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 64
- 229910052751 metal Inorganic materials 0.000 claims description 57
- 239000002184 metal Substances 0.000 claims description 57
- 238000006243 chemical reaction Methods 0.000 claims description 49
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 32
- 150000004714 phosphonium salts Chemical class 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- 238000011065 in-situ storage Methods 0.000 claims description 17
- 239000007795 chemical reaction product Substances 0.000 claims description 16
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 16
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 13
- 229920002866 paraformaldehyde Polymers 0.000 claims description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims description 9
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 7
- 239000007983 Tris buffer Substances 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 7
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- 125000001475 halogen functional group Chemical group 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical group [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 238000005292 vacuum distillation Methods 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 4
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- UPDNYUVJHQABBS-UHFFFAOYSA-N phenoxy(diphenyl)phosphane Chemical compound C=1C=CC=CC=1OP(C=1C=CC=CC=1)C1=CC=CC=C1 UPDNYUVJHQABBS-UHFFFAOYSA-N 0.000 claims description 4
- 229910052727 yttrium Inorganic materials 0.000 claims description 4
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 3
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims description 3
- 229930188620 butyrolactone Natural products 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 claims description 3
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 3
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 3
- 229910001507 metal halide Inorganic materials 0.000 claims description 3
- 150000005309 metal halides Chemical class 0.000 claims description 3
- 229910001960 metal nitrate Inorganic materials 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- QAPGHLJQIVDTPT-UHFFFAOYSA-N tris(3-chlorophenyl)phosphane Chemical compound ClC1=CC=CC(P(C=2C=C(Cl)C=CC=2)C=2C=C(Cl)C=CC=2)=C1 QAPGHLJQIVDTPT-UHFFFAOYSA-N 0.000 claims description 3
- CCXTYQMZVYIQRP-UHFFFAOYSA-N tris(3-methoxyphenyl)phosphane Chemical compound COC1=CC=CC(P(C=2C=C(OC)C=CC=2)C=2C=C(OC)C=CC=2)=C1 CCXTYQMZVYIQRP-UHFFFAOYSA-N 0.000 claims description 3
- LFNXCUNDYSYVJY-UHFFFAOYSA-N tris(3-methylphenyl)phosphane Chemical compound CC1=CC=CC(P(C=2C=C(C)C=CC=2)C=2C=C(C)C=CC=2)=C1 LFNXCUNDYSYVJY-UHFFFAOYSA-N 0.000 claims description 3
- IQKSLJOIKWOGIZ-UHFFFAOYSA-N tris(4-chlorophenyl)phosphane Chemical compound C1=CC(Cl)=CC=C1P(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 IQKSLJOIKWOGIZ-UHFFFAOYSA-N 0.000 claims description 3
- UYUUAUOYLFIRJG-UHFFFAOYSA-N tris(4-methoxyphenyl)phosphane Chemical compound C1=CC(OC)=CC=C1P(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 UYUUAUOYLFIRJG-UHFFFAOYSA-N 0.000 claims description 3
- WXAZIUYTQHYBFW-UHFFFAOYSA-N tris(4-methylphenyl)phosphane Chemical compound C1=CC(C)=CC=C1P(C=1C=CC(C)=CC=1)C1=CC=C(C)C=C1 WXAZIUYTQHYBFW-UHFFFAOYSA-N 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 claims description 2
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 2
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical compound [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052788 barium Inorganic materials 0.000 claims description 2
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- XLJKHNWPARRRJB-UHFFFAOYSA-N cobalt(2+) Chemical compound [Co+2] XLJKHNWPARRRJB-UHFFFAOYSA-N 0.000 claims description 2
- JAWGVVJVYSANRY-UHFFFAOYSA-N cobalt(3+) Chemical compound [Co+3] JAWGVVJVYSANRY-UHFFFAOYSA-N 0.000 claims description 2
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052712 strontium Inorganic materials 0.000 claims description 2
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims 2
- WSWCOQWTEOXDQX-MQQKCMAXSA-M (E,E)-sorbate Chemical compound C\C=C\C=C\C([O-])=O WSWCOQWTEOXDQX-MQQKCMAXSA-M 0.000 claims 1
- 229910052742 iron Inorganic materials 0.000 claims 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 claims 1
- 229940075554 sorbate Drugs 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 6
- 239000000126 substance Substances 0.000 description 25
- 239000002585 base Substances 0.000 description 19
- 230000000052 comparative effect Effects 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 239000012535 impurity Substances 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- GSLDEZOOOSBFGP-UHFFFAOYSA-N alpha-methylene gamma-butyrolactone Chemical compound C=C1CCOC1=O GSLDEZOOOSBFGP-UHFFFAOYSA-N 0.000 description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 3
- 239000011592 zinc chloride Substances 0.000 description 3
- 235000005074 zinc chloride Nutrition 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 2
- SXAMGRAIZSSWIH-UHFFFAOYSA-N 2-[3-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,2,4-oxadiazol-5-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NOC(=N1)CC(=O)N1CC2=C(CC1)NN=N2 SXAMGRAIZSSWIH-UHFFFAOYSA-N 0.000 description 2
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 2
- ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2 ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 0.000 description 2
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 2
- LFJJGHGXHXXDFT-UHFFFAOYSA-N 3-bromooxolan-2-one Chemical compound BrC1CCOC1=O LFJJGHGXHXXDFT-UHFFFAOYSA-N 0.000 description 2
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 229910052747 lanthanoid Inorganic materials 0.000 description 2
- 150000002602 lanthanoids Chemical class 0.000 description 2
- 239000000395 magnesium oxide Substances 0.000 description 2
- 239000011572 manganese Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 150000003003 phosphines Chemical class 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000003507 refrigerant Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- MDDUHVRJJAFRAU-YZNNVMRBSA-N tert-butyl-[(1r,3s,5z)-3-[tert-butyl(dimethyl)silyl]oxy-5-(2-diphenylphosphorylethylidene)-4-methylidenecyclohexyl]oxy-dimethylsilane Chemical compound C1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C(=C)\C1=C/CP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 MDDUHVRJJAFRAU-YZNNVMRBSA-N 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- XQBKPBWQJVRMOJ-UHFFFAOYSA-N 1-bis(3-chlorophenyl)phosphoryl-3-chlorobenzene Chemical compound ClC1=CC=CC(P(=O)(C=2C=C(Cl)C=CC=2)C=2C=C(Cl)C=CC=2)=C1 XQBKPBWQJVRMOJ-UHFFFAOYSA-N 0.000 description 1
- XBBCBCRCOAMIPB-UHFFFAOYSA-N 1-bis(3-methoxyphenyl)phosphoryl-3-methoxybenzene Chemical compound COC1=CC=CC(P(=O)(C=2C=C(OC)C=CC=2)C=2C=C(OC)C=CC=2)=C1 XBBCBCRCOAMIPB-UHFFFAOYSA-N 0.000 description 1
- RJUIEUJUSTTWFW-UHFFFAOYSA-N 1-bis(3-methylphenyl)phosphoryl-3-methylbenzene Chemical compound CC1=CC=CC(P(=O)(C=2C=C(C)C=CC=2)C=2C=C(C)C=CC=2)=C1 RJUIEUJUSTTWFW-UHFFFAOYSA-N 0.000 description 1
- GJBIMMKVOGMMLP-UHFFFAOYSA-N 1-bis(4-chlorophenyl)phosphoryl-4-chlorobenzene Chemical compound C1=CC(Cl)=CC=C1P(=O)(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 GJBIMMKVOGMMLP-UHFFFAOYSA-N 0.000 description 1
- SPKBYIYIZQARNX-UHFFFAOYSA-N 1-bis(4-methylphenyl)phosphoryl-4-methylbenzene Chemical compound C1=CC(C)=CC=C1P(=O)(C=1C=CC(C)=CC=1)C1=CC=C(C)C=C1 SPKBYIYIZQARNX-UHFFFAOYSA-N 0.000 description 1
- BSRTYNDWQXVCKR-UHFFFAOYSA-N 2,2-dichlorobutane Chemical compound CCC(C)(Cl)Cl BSRTYNDWQXVCKR-UHFFFAOYSA-N 0.000 description 1
- WWSJZGAPAVMETJ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-ethoxypyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)OCC WWSJZGAPAVMETJ-UHFFFAOYSA-N 0.000 description 1
- FYELSNVLZVIGTI-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-5-ethylpyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1CC)CC(=O)N1CC2=C(CC1)NN=N2 FYELSNVLZVIGTI-UHFFFAOYSA-N 0.000 description 1
- FLOKBGAYTGLYGR-UHFFFAOYSA-N 3-bromo-5-methyloxolan-2-one Chemical compound CC1CC(Br)C(=O)O1 FLOKBGAYTGLYGR-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- YOZBGKNUPRZMAN-UHFFFAOYSA-N P(=O)(=O)[P] Chemical compound P(=O)(=O)[P] YOZBGKNUPRZMAN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 240000005924 Stenocarpus sinuatus Species 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- OTJZCIYGRUNXTP-UHFFFAOYSA-N but-3-yn-1-ol Chemical compound OCCC#C OTJZCIYGRUNXTP-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- CIJWIJSYZZLMGD-UHFFFAOYSA-N diphenylphosphoryloxybenzene Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)OC1=CC=CC=C1 CIJWIJSYZZLMGD-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- AMWRITDGCCNYAT-UHFFFAOYSA-L manganese oxide Inorganic materials [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- BFLSLERVRLOFCX-UHFFFAOYSA-N tulipanin B Natural products OC1COC(=O)C1=C BFLSLERVRLOFCX-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/365—Lactones
-
- 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
- C07D307/56—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
Definitions
- the present invention relates to an improved process for the preparation of methylene lactone-based compounds and similar derivatives.
- MBL Alpha methylene gamma butyrolactone
- Tulipalin A is a natural product contained in tulip flowers.
- MBL is a ⁇ -butyrolactone compound having an exomethylene group and is an important compound in the pharmaceutical industry because it has various physiological activities such as antitumor, antibacterial, and antifungal properties.
- Japanese Patent Laid-open Publication No. 2001-247560 discloses alpha-methylene-gamma-butyrolactone by reacting gamma butyrolactone and methanol under a manganese/magnesium oxide (Mn/MgO) catalyst.
- Mn/MgO manganese/magnesium oxide
- a method for preparing rolactone is disclosed.
- this method has a limitation in that it is difficult to use commercially because the conversion rate to formaldehyde is low.
- Korean Patent Registration No. KR 10-1427092 introduces a method of making enolate, an intermediate suggested by Murray, using sodium ethoxide and ethyl formate, but this technology is also difficult to apply to mass production due to poor filterability. is hard
- the present invention was made to solve the problems of the prior art, and does not require expensive manufacturing equipment such as a high-pressure reactor, and the reaction and post-reaction treatment are simple, and the intermediate manufacturing process is unnecessary, while reducing the process cost accordingly. , It is an object to provide a method for producing a methylene lactone-based compound in high yield.
- a method for preparing a methylene lactone-based compound involves mixing and reacting an alpha halo lactone-based compound, a phosphine-based compound, and an organic solvent, followed by cooling to obtain phospho-phosphorus represented by Formula 1 below.
- Step 1 of preparing a nium salt A second step of preparing a solution containing a methylene lactone-based compound and a phosphine-based oxide by mixing the phosphonium salt, a base, paraformaldehyde or formaldehyde, and an organic solvent, and then reacting in situ; A third step of adding a metal salt to the solution of step 2 and reacting the phosphine oxide with the metal salt to form a complex; and a fourth step of obtaining a methylene lactone-based compound represented by Formula 2 below by removing the complex from the solution in step 3 and then performing a concentration process and a vacuum distillation process.
- R 1 to R 3 are each independently a C 3 ⁇ C 4 straight-chain alkyl group, a phenyl group, a 3-chlorophenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group A oxyphenyl group or a phenoxy group, X is -F, -Cl, -Br or -I, Y is And, R 4 is a hydrogen atom or a C 1 ⁇ C 5 linear alkyl group.
- R 4 in Formula 2 is a hydrogen atom or a C 1 to C 5 linear alkyl group.
- the alpha halo lactone-based compound in step 1 may include a lactone-based compound represented by Formula 3 below.
- R 4 in Formula 3 is a hydrogen atom or a C 1 to C 5 linear alkyl group, and X is -F, -Cl, -Br or -I.
- the alpha halo lactone-based compound of step 1 may include alpha halo butyrolactone or alpha halo valerolactone.
- the phosphine-based compound of step 1 is tris (C 3-4 alkyl) phosphine, triphenylphosphine, tris (3-chlorophenyl) phosphine, tris (4-chlorophenyl) phosphine Pyne, tris(3-methylphenyl)phosphine, tris(4-methylphenyl)phosphine, tris(3-methoxyphenyl)phosphine, tris(4-methoxy-phenyl)phosphine, phenoxydiphenylphosphine and It may include at least one selected from diphenoxyphenylphosphine.
- the organic solvent in step 1 includes at least one selected from acetonitrile, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, acetone, and N-methylpyrrolidone. can do.
- the reaction in the first step, may be performed after mixing the alpha halolactone-based compound and the phosphine-based compound in a weight ratio of 1:0.9 to 3.0.
- the first step of the reaction may be performed at 60 to 80 ° C. for 8 to 16 hours.
- the base in step 2 may include at least one selected from organic bases and inorganic bases.
- the organic base may include at least one selected from triethylamine, diisopropylethylamine, dimethylamine and diethylamine.
- the inorganic base is sodium t-butoxide, potassium t-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, lithium hydride, lithium hydroxide, lithium t-butoxide Side, lithium methoxide, lithium ethoxide, sodium hydroxide and potassium hydroxide may include at least one selected from.
- the organic solvent in step 2 includes at least one selected from acetonitrile, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, acetone, and N-methylpyrrolidone. can do.
- the in-situ reaction in the second step is performed after mixing 30 to 100 parts by weight of the base and 15 to 50 parts by weight of paraformaldehyde or formaldehyde with respect to 100 parts by weight of the upper phase phosphonium salt. can be performed.
- the two-step in-situ reaction may be performed at 60 to 80° C. for 1 to 4 hours.
- the metal salt of step 3 is a metal halide, metal sulfate, metal nitrate, metal perchlorate, metal bicarbonate, metal carbonate, metal acetate, metal citrate, metal benzoate salt, a hydrate or These organic sorbates may be included.
- the metal of the metal salt may be an alkali metal, an alkaline earth metal, a transition metal or a lanthanide metal.
- the metal salt in step 3 may be added in an amount of 1.50 to 3.00 equivalents per 1 equivalent of the phosphine compound in step 1.
- the methylene lactone-based compound represented by Formula 2 having a yield of 70% or more and a purity of 98% or more can be prepared through the above-described preparation method.
- the manufacturing method of the present invention can effectively purify (or remove) reaction byproducts generated during the manufacturing process in the same manufacturing process without a separate purification process, and a separate intermediate synthesis process through an in-situ synthesis process. And since a drying process is not performed, a methylene lactone-based compound with a high yield and high purity can be produced with high productivity and commerciality, while the manufacturing process is simple.
- the present invention relates to an invention in which the purification (or removal) of impurities is easier than in the conventional methylene lactone-based compound manufacturing process, suitable for producing high-purity methylene lactone-based compounds in high yield, and advantageous for large-scale synthesis processes, phosphonium salts Step 1 to prepare;
- the phosphonium salt in step 1 is a process of mixing and reacting an alpha halolactone-based compound and a phosphine-based compound, followed by cooling to obtain a phosphonium salt represented by Formula 1 below.
- each of R 1 to R 3 is independently a C 3 to C 4 straight-chain alkyl group, a phenyl group, a 3-chlorophenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 3-methoxyphenyl group, a 4- A methoxyphenyl group or a phenoxy group, preferably each of R 1 to R 3 is independently a C 3 to C 4 straight-chain alkyl group, a phenyl group or a phenoxy group, more preferably each of R 1 to R 3 is independently C It is a 3 -C 4 straight-chain alkyl group or a phenyl group.
- X in Formula 1 is -F, -Cl, -Br or -I, preferably -Cl, -Br or -I, more preferably -Br.
- Y in Formula 1 is to be.
- R 4 is a hydrogen atom or a C 1 to C 5 linear alkyl group, preferably a hydrogen atom or a C 1 to C 2 linear alkyl group.
- the alpha halo lactone-based compound of step 1 may include a lactone-based compound represented by Formula 3 below.
- R 4 in Formula 3 is a hydrogen atom or a C 1 to C 5 straight-chain alkyl group, preferably a hydrogen atom or a C 1 to C 2 straight-chain alkyl group.
- X is -F, -Cl, -Br or -I, preferably X is -Cl, -Br or -I.
- alpha halo lactone-based compound of step 1 may include alpha halo butyrolactone or alpha halo valerolactone.
- the phosphine-based compound of step 1 is tris (C 3 ⁇ 4 alkyl) phosphine, triphenylphosphine, tris (3-chlorophenyl) phosphine, tris (4-chlorophenyl) phosphine, tris (3- methylphenyl)phosphine, tris(4-methylphenyl)phosphine, tris(3-methoxyphenyl)phosphine, tris(4-methoxy-phenyl)phosphine, phenoxydiphenylphosphine and diphenoxyphenylphosphine It includes at least one selected from among, preferably at least one selected from tris (C 3 ⁇ 4 alkyl) phosphine, triphenylphosphine, phenoxydiphenylphosphine and diphenoxyphenylphosphine, More preferably, at least one selected from tris(C 3-4 alkyl)phosphine and trip
- the organic solvent in step 1 may include at least one selected from acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, dimethylacetamide, acetone, and N-methylpyrrolidone.
- the alpha halolactone compound and the phosphine compound are mixed at a weight ratio of 1:0.9 to 3.0, preferably at a weight ratio of 1:1.2 to 2.5, and more preferably at a weight ratio of 1:1.5 to 2.0.
- the reaction can be carried out.
- the mixing amount of the phosphine-based compound is less than 0.9 weight ratio, there may be a problem in that the yield of the desired final reaction product is low, and when it is used in excess of 3.0 weight ratio, a large amount of impurities are generated by the unreacted phosphine-type compound, resulting in the desired final reaction product. There may be a problem with low purity.
- the reaction of the first step is carried out with slow stirring at 60 ⁇ 80 °C for 8 ⁇ 16 hours, preferably 60 ⁇ 75 °C for 8 ⁇ 14 hours, more preferably 65 ⁇ 72 °C for 9 ⁇ 13 hours
- the reaction temperature is less than 60 °C, the reaction time takes too long and there is a problem of poor commerciality, and if it exceeds 80 °C, the phosphonium salt synthesis time is short, but a large amount of unwanted reaction products (impurities) may be generated. It is preferable to carry out the reaction within the above range.
- step 2 is a process of synthesizing a methylene lactone-based compound through an in-situ reaction, in which the phosphonium salt, base, paraformaldehyde or formaldehyde and an organic solvent obtained in step 1 are mixed. Then, when an in-situ reaction is performed, a methylene lactone-based compound and a phosphine-based oxide are formed.
- step 1 alpha-bromo butyrolactone is used as an alpha halolactone-based compound and triphenylphosphine is used as a phosphine-based compound to prepare a phosphonium salt.
- phosphonium salt and a base are reacted, phosphonium ylide is synthesized, and phosphonium ylide reacts with aldehyde to synthesize a methylene lactone-based compound.
- An in-situ reaction is performed in the second step will perform
- a phosphine-based oxide is formed as an addition reaction product as a reaction product in addition to the methylene lactone-based compound.
- the phosphine-based oxide is an oxide of a phosphine-based compound used in step 1, for example, tris (C 3-4 alkyl) phosphine oxide, triphenylphosphine oxide, tris (3-chlorophenyl) phosphine oxide, Tris (4-chlorophenyl) phosphine oxide, tris (3-methylphenyl) phosphine oxide, tris (4-methylphenyl) phosphine oxide, tris (3-methoxyphenyl) phosphine oxide, tris (4-methoxy- Phenyl) may include at least one selected from phosphine oxide, phenoxydiphenylphosphine oxide and diphenoxyphenylphosphine oxide.
- the base may include at least one selected from organic bases and inorganic bases.
- the organic base may include at least one selected from triethylamine, diisopropylethylamine, dimethylamine and diethylamine, and preferably one selected from triethylamine, dimethylamine and diethylamine. may contain more than
- the inorganic base is sodium t-butoxide, potassium t-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, lithium hydride, lithium hydroxide, lithium t-butoxide, lithium methoxide, lithium It may contain at least one selected from among ethoxide, sodium hydroxide and potassium hydroxide, preferably sodium methoxide, sodium ethoxide, lithium hydride, lithium hydroxide, sodium hydroxide and potassium hydroxide It may include one or more selected from rockside.
- the amount of the base may be 30 to 100 parts by weight, preferably 30 to 60 parts by weight, more preferably 40 to 55 parts by weight, based on 100 parts by weight of the phosphonium salt. If it is less than 30 parts by weight, there may be a problem in that the synthesis yield of the methylene lactone-based compound is low due to the small amount of ylide synthesis, and if the amount of base used exceeds 100 parts by weight, the unreacted base acts as an impurity due to excessive use, resulting in methylene lactone-based Since there may be a problem of lowering the purity of the compound, it is good to use it within the above range.
- the amount of paraformaldehyde or formaldehyde used is 15 to 50 parts by weight, preferably 15 to 30 parts by weight, more preferably 18 to 30 parts by weight based on 100 parts by weight of the phosphonium salt. , If the amount thereof is less than 15 parts by weight, there may be a problem in that the synthesis yield for the methylene lactone-based compound is lowered, and if the amount thereof exceeds 50 parts by weight, the unreacted aldehyde acts as an impurity rather than the methylene lactone-based compound. Since there may be a problem of lowering the purity, it is good to use it within the above range.
- the organic solvent of the second step is selected from tetrahydrofuran, diethyl ether, 1,4-dioxane, toluene, acetonitrile, dichloromethane, ethyldichloroethane, diisopropyl ether, t-butylmethyl ether and ethyl acetate It may include one or more, preferably one or more selected from tetrahydrofuran, 1,4-dioxane, and acetonitrile.
- the second-step in-situ reaction is carried out at 60 to 80 ° C for 1 to 4 hours, preferably at 60 to 75 ° C for 1 to 3 hours, more preferably at 65 to 75 ° C for 1 to 3 hours. It is preferable, and if the reaction temperature is less than 60 °C, the synthesis time of the methylene lactone-based compound is too long and there may be a problem with low yield, and if the reaction temperature exceeds 80 °C, unwanted impurities are generated and there is a problem of low purity. Therefore, it is preferable to perform the in-situ reaction in the above temperature range.
- step 3 is a process of synthesizing a complex (or complex) by reacting the phosphine-based oxide, which is an addition reaction product of step 2, with a metal salt.
- the metal salt is a metal halide (e.g., fluoride, chloride, bromide or iodide), metal sulfate, metal nitrate, metal perchlorate, metal bicarbonate, metal carbonate, metal acetate, metal citrate, metal benzoate salt , hydrates thereof or organic sorbates thereof.
- a metal halide e.g., fluoride, chloride, bromide or iodide
- the metal of the metal salt may include an alkali metal, an alkaline earth metal, a transition metal or a lanthanide metal, and preferably, the metal of the metal salt is lithium, sodium, potassium, magnesium, calcium, barium, strontium, samirium (III ), zinc, iron(II), iron(III), manganese(II), cobalt(II), cobalt(III), nickel, copper(I) or copper(II).
- the metal salt may include at least one selected from zinc chloride and magnesium chloride.
- the amount of the metal salt added per equivalent of the phosphine-based compound based on the phosphine-based compound used in the first step may be used in a weight ratio of 0.25 to 5.0, preferably 1.5 to 3.0.
- the equivalence ratio of the metal salt input is less than 0.25 equivalence ratio, the complex is not sufficiently formed, and the remaining phosphine oxide acts as an impurity, which may cause a problem of low purity of the desired final product.
- the residual metal salt acts as an impurity, there may be a problem of lowering the purity of the species product, so it is good to use it within the above range.
- reaction of the phosphine-based oxide and the metal salt in the third step is 0 to 130 ° C, preferably 20 to 120 ° C, more preferably 20 to 40 ° C for 5 to 24 hours, preferably 6 to 18 hours while stirring slowly. can be done over time.
- Step 4 is a process for obtaining a methylene lactone-based compound represented by Formula 2 below by removing the complex formed in the reaction solution in Step 3 and performing a concentration and vacuum distillation process.
- R 4 in Formula 2 is a hydrogen atom or a C 1 to C 5 straight-chain alkyl group, preferably a hydrogen atom or a C 1 to C 2 straight-chain alkyl group.
- step 3 As a method for removing the complex synthesized in step 4 in step 3, methods such as filtration, decantation, and/or centrifugation generally used in the art may be used.
- each of the four-step concentration process and vacuum distillation process can be performed by a general concentration and vacuum distillation method used in the art.
- the methylene lactone-based compound represented by Formula 2 prepared by performing the above process has a yield of 60% or more, preferably a yield of 70% or more, more preferably 70 to 95% when calculated based on Equation 1 below A methylene lactone-based compound can be obtained in a yield of
- the methylene lactone-based compound represented by Formula 2 or Formula 3 prepared by performing the above process has a purity of 98% or more, preferably 98.5% to 99.9%, more preferably 98.8 to 99.9% when analyzed by chromatography.
- a methylene lactone-based compound can be obtained with a high purity of %.
- Example 1-1 Preparation of methylene lactone-based compound represented by Chemical Formula 2-1
- each of R 1 , R 2 , and R 3 is a phenyl group
- X is -Br
- Y is And
- R 4 is a hydrogen atom.
- R 4 in Formula 2-1 is a hydrogen atom.
- each of R 1 , R 2 , and R 3 is a phenyl group, X is -Br, and Y is , and R 4 is -CH 3 .
- R 4 in Formula 2-2 is -CH 3 .
- a methylene lactone-based compound represented by Chemical Formula 1-1 was prepared in the same manner as in Example 1, but as shown in Tables 1 and 2 below, by varying the content of the phosphine-based compound, base, etc. introduced in steps 1 to 3 Examples 3 to 10 and Comparative Examples 1 to 8 were carried out, respectively.
- a methylene lactone-based compound represented by Chemical Formula 1-1 was prepared in the same manner as in Example 2, but the content of the phosphine-based compound, base, etc. introduced in steps 1 to 3 was changed as shown in Table 1 below to obtain Example 11 was carried out.
- Comparative Example 7 in which the metal salt was used at a weight ratio of less than 0.25 in step 3, compared to Example 9, it was confirmed that there was a problem in that the purity was rapidly lowered, and the metal salt was used at a weight ratio of more than 5.00 Comparative Example In the case of 8, compared to Example 10, there was a problem that the purity was lowered.
- the method for producing the methylene lactone system described above is not limited to the configuration and method of the above-described embodiments, but all or part of each embodiment is selectively applied so that various modifications can be made. They may be configured in combination.
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Abstract
The present invention relates to a method for preparing a methylene lactone-based compound and, more specifically, compared with a conventional process for preparing a methylene lactone-based compound, enables the preparation of a specific methylene lactone-based compound with high yield and high purity while simplifying a preparation process.
Description
본 발명은 메틸렌 락톤계 화합물 및 유사한 유도체의 개선된 제조방법에 관한 것이다.The present invention relates to an improved process for the preparation of methylene lactone-based compounds and similar derivatives.
알파 메틸렌 감마 부티로락톤(이하, "MBL"로 칭함)은 튜율립알린A(Tulipalin A)으로 불리우며, 튜율립 꽃에 들어 있는 천연물이다. MBL은 엑소메틸렌(exomethylene)기를 갖는 감마부티로락톤(γ-butyrolactone) 화합물로써 항종양성, 항세균성, 항진균성등의 다양한 생리활성을 가지고 있으므로 제약산업에서 중요한 화합물이다. Alpha methylene gamma butyrolactone (hereinafter referred to as “MBL”) is called Tulipalin A and is a natural product contained in tulip flowers. MBL is a γ-butyrolactone compound having an exomethylene group and is an important compound in the pharmaceutical industry because it has various physiological activities such as antitumor, antibacterial, and antifungal properties.
MBL의 제조방법은 종래 다수의 특허 등에 개시되어 있는데, 일본 공개특허 제2001-247560호에는 감마 부티로락톤과 메탄올을 망간/마그네슘 옥사이드(Mn/MgO) 촉매 하에서 반응시켜 알파-메틸렌-감마-부티로락톤을 제조하는 방법을 개시하고 있다. 그러나 이 방법은 포름알데히드로의 전환율이 낮기 때문에 상업적으로 이용하기 어려운 한계가 있다. A method for preparing MBL has been previously disclosed in a number of patents. Japanese Patent Laid-open Publication No. 2001-247560 discloses alpha-methylene-gamma-butyrolactone by reacting gamma butyrolactone and methanol under a manganese/magnesium oxide (Mn/MgO) catalyst. A method for preparing rolactone is disclosed. However, this method has a limitation in that it is difficult to use commercially because the conversion rate to formaldehyde is low.
MBL의 다른 제조방법으로 호모프로파질 알코올과 일산화탄소를 니켈이나 팔라듐 촉매 하에서 반응시키는 방법이 있다. 그러나, 니켈 촉매를 사용하는 경우에는 아세틸렌 중합이나 이중결합 이동과 같은 부반응이 진행하며 수율도 낮아 공업적 생산에 적용하기 어렵다. 또한 팔라듐 촉매를 사용하면 수율은 개선될 수 있지만, 촉매의 회수가 어렵다는 단점이 있다(J. Am. Chem. Soc. 1981, 제 103권, p7520). As another method for preparing MBL, there is a method of reacting homopropargyl alcohol and carbon monoxide in the presence of a nickel or palladium catalyst. However, in the case of using a nickel catalyst, side reactions such as acetylene polymerization or double bond transfer proceed, and the yield is also low, making it difficult to apply to industrial production. In addition, although the yield can be improved by using a palladium catalyst, there is a disadvantage in that recovery of the catalyst is difficult (J. Am. Chem. Soc. 1981, Vol. 103, p7520).
이 외의 방법들도 고온고압 또는 초임계 유체를 이용한 방법 등이 있으나 대량생산 방법으로는 적합하지 않다. 일반적으로 실험실 수준에서는 Murray가 개발한 문헌(Synthesis, January 1985, p35-38)과 Akkapeddi가 1979년에 발표한 논문(Macromolecules, Vol. 12, No. 4, July-August 1979)에 개시된 내용으로 합성을 진행하지만, Murray 방법은 염기로 소듐하이드라이드(NaH)를 사용하기에 대량생산에 적용하기에는 다소 무리가 있고, Akkapeddi의 방법은 염기로 소듐하이드라이드 대신에 소듐에톡사이드(NaOEt)를 사용하는 장점은 있지만 여과성이 좋지 않아 생산에 적용하기는 힘들다. Other methods include methods using high-temperature, high-pressure or supercritical fluids, but are not suitable for mass production. In general, at the laboratory level, synthesis is carried out according to the contents disclosed in the literature developed by Murray (Synthesis, January 1985, p35-38) and the paper published by Akkapeddi in 1979 (Macromolecules, Vol. 12, No. 4, July-August 1979). However, Murray's method uses sodium hydride (NaH) as a base, so it is somewhat difficult to apply to mass production, and Akkapeddi's method uses sodium ethoxide (NaOEt) instead of sodium hydride as a base. Although it has advantages, it is difficult to apply it to production due to poor filterability.
또한, 대한민국 등록특허 KR 10-1427092호에서 소듐에톡사이드와 에틸포메이트를 사용하여 Murray가 제시한 중간체인 엔올레이트를 만드는 방법이 소개되어 있는데, 이 기술 역시 여과성이 좋지 않아 대량 생산에 적용하기는 힘들다.In addition, Korean Patent Registration No. KR 10-1427092 introduces a method of making enolate, an intermediate suggested by Murray, using sodium ethoxide and ethyl formate, but this technology is also difficult to apply to mass production due to poor filterability. is hard
따라서, 상업적 생산을 염두에 두고 제조공정과 제조시간을 줄여 보다 효율적으로 메틸렌 락톤계 화합물을 대량 생산이 가능한 새로운 제조방법이 필요한 실정이다. Therefore, there is a need for a new manufacturing method capable of mass-producing methylene lactone-based compounds more efficiently by reducing the manufacturing process and manufacturing time with commercial production in mind.
본 발명은 상기 종래 기술의 문제를 해결하기 위하여 안출된 것으로서, 고압반응기 같은 고가의 제조설비가 불필요하며, 반응 및 반응 후의 처리가 간편하며, 중간체 제조공정이 불필요하여, 이에 따른 공정비용이 절감되면서도, 높은 수율로 메틸렌 락톤계 화합물을 제조하는 방법을 제공하는 것을 목적으로 한다.The present invention was made to solve the problems of the prior art, and does not require expensive manufacturing equipment such as a high-pressure reactor, and the reaction and post-reaction treatment are simple, and the intermediate manufacturing process is unnecessary, while reducing the process cost accordingly. , It is an object to provide a method for producing a methylene lactone-based compound in high yield.
이와 같은 본 발명의 해결 과제를 달성하기 위한 메틸렌 락톤계 화합물의 제조방법은 알파 할로 락톤계 화합물, 포스핀계 화합물 및 유기용매를 혼합 및 반응을 수행한 후, 냉각시켜서 하기 화학식 1로 표시되는 포스포늄염을 제조하는 1단계; 상기 포스포늄염, 염기, 파라포름알데히드 또는 포름알데히드, 및 유기용매를 혼합한 후, 인시투(in-situ) 반응시켜서 메틸렌 락톤계 화합물 및 포스핀계 산화물을 포함하는 용액을 제조하는 2단계; 2단계의 용액에 금속염을 투입하여, 포스핀계 산화물과 금속염을 반응시켜서 복합체를 형성시키는 3단계; 및 3단계를 수행한 용액 내 상기 복합체를 제거한 후, 농축 공정 및 진공증류 공정을 수행하여 하기 화학식 2로 표시되는 메틸렌 락톤계 화합물을 수득하는 4단계;를 포함하는 공정을 수행한다.In order to achieve the object of the present invention, a method for preparing a methylene lactone-based compound involves mixing and reacting an alpha halo lactone-based compound, a phosphine-based compound, and an organic solvent, followed by cooling to obtain phospho-phosphorus represented by Formula 1 below. Step 1 of preparing a nium salt; A second step of preparing a solution containing a methylene lactone-based compound and a phosphine-based oxide by mixing the phosphonium salt, a base, paraformaldehyde or formaldehyde, and an organic solvent, and then reacting in situ; A third step of adding a metal salt to the solution of step 2 and reacting the phosphine oxide with the metal salt to form a complex; and a fourth step of obtaining a methylene lactone-based compound represented by Formula 2 below by removing the complex from the solution in step 3 and then performing a concentration process and a vacuum distillation process.
[화학식 1][Formula 1]
화학식 1에 있어서, R1 내지 R3 각각은 독립적으로 C3~C4의 직쇄형 알킬기, 페닐기, 3-클로로페닐기, 3-메틸페닐기, 4-메틸페닐기, 3-메톡시페닐기, 4-메톡시페닐기 또는 페녹시기이며, X는 -F, -Cl, -Br 또는 -I이고, Y는
이며, R4는 수소원자 또는 C1 ~ C5의 직쇄형 알킬기이다.In Formula 1, R 1 to R 3 are each independently a C 3 ~ C 4 straight-chain alkyl group, a phenyl group, a 3-chlorophenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group A oxyphenyl group or a phenoxy group, X is -F, -Cl, -Br or -I, Y is And, R 4 is a hydrogen atom or a C 1 ~ C 5 linear alkyl group.
[화학식 2][Formula 2]
화학식 2의 R4는 수소원자 또는 C1 ~ C5의 직쇄형 알킬기이다.R 4 in Formula 2 is a hydrogen atom or a C 1 to C 5 linear alkyl group.
본 발명의 바람직한 일실시예로서, 1단계의 상기 알파 할로 락톤계 화합물은 하기 화학식 3으로 표시되는 락톤계 화합물을 포함할 수 있다.As a preferred embodiment of the present invention, the alpha halo lactone-based compound in step 1 may include a lactone-based compound represented by Formula 3 below.
[화학식 3][Formula 3]
화학식 3의 R4는 수소원자 또는 C1 ~ C5의 직쇄형 알킬기이며, X는 -F, -Cl, -Br 또는 -I이다.R 4 in Formula 3 is a hydrogen atom or a C 1 to C 5 linear alkyl group, and X is -F, -Cl, -Br or -I.
본 발명의 바람직한 일실시예로서, 1단계의 상기 알파 할로 락톤계 화합물은 알파 할로 부티로락톤 또는 알파 할로 발레로락톤을 포함할 수 있다.As a preferred embodiment of the present invention, the alpha halo lactone-based compound of step 1 may include alpha halo butyrolactone or alpha halo valerolactone.
본 발명의 바람직한 일실시예로서, 1단계의 포스핀계 화합물은 트리스(C3~4 알킬)포스핀, 트리페닐포스핀, 트리스(3-클로로페닐)포스핀, 트리스(4-클로로페닐)포스핀, 트리스(3-메틸페닐)포스핀, 트리스(4-메틸페닐)포스핀, 트리스(3-메톡시페닐)포스핀, 트리스(4-메톡시-페닐)포스핀, 페녹시다이페닐포스핀 및 다이페녹시페닐포스핀 중에서 선택된 1종 이상을 포함할 수 있다. As a preferred embodiment of the present invention, the phosphine-based compound of step 1 is tris (C 3-4 alkyl) phosphine, triphenylphosphine, tris (3-chlorophenyl) phosphine, tris (4-chlorophenyl) phosphine Pyne, tris(3-methylphenyl)phosphine, tris(4-methylphenyl)phosphine, tris(3-methoxyphenyl)phosphine, tris(4-methoxy-phenyl)phosphine, phenoxydiphenylphosphine and It may include at least one selected from diphenoxyphenylphosphine.
본 발명의 바람직한 일실시예로서, 1단계의 상기 유기용매는 아세토니트릴, 테트라하이드로퓨란, 디메틸포름아마이드, 디메틸설폭사이드, 디메틸아세트아마이드, 아세톤 및 N-메틸피롤리돈 중에서 선택된 1종 이상을 포함할 수 있다.As a preferred embodiment of the present invention, the organic solvent in step 1 includes at least one selected from acetonitrile, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, acetone, and N-methylpyrrolidone. can do.
본 발명의 바람직한 일실시예에로서, 1단계는 알파 할로 락톤계 화합물 및 포스핀계 화합물을 1 : 0.9 ~ 3.0 중량비로 혼합한 후, 반응을 수행할 수 있다.As a preferred embodiment of the present invention, in the first step, the reaction may be performed after mixing the alpha halolactone-based compound and the phosphine-based compound in a weight ratio of 1:0.9 to 3.0.
본 발명의 바람직한 일실시예로서, 1단계의 반응은 60 ~ 80℃에서 8 ~ 16시간 동안 수행할 수 있다. As a preferred embodiment of the present invention, the first step of the reaction may be performed at 60 to 80 ° C. for 8 to 16 hours.
본 발명의 바람직한 일실시예로서, 2단계의 상기 염기는 유기염기 및 무기염기 중에서 선택된 1종 이상을 포함할 수 있다.As a preferred embodiment of the present invention, the base in step 2 may include at least one selected from organic bases and inorganic bases.
본 발명의 바람직한 일실시예로서, 상기 유기염기는 트리에틸아민, 디이소프로필에틸아민, 다이메틸아민 및 다이에틸아민 중에서 선택된 1종 이상을 포함할 수 있다. As a preferred embodiment of the present invention, the organic base may include at least one selected from triethylamine, diisopropylethylamine, dimethylamine and diethylamine.
본 발명의 바람직한 일실시예로서, 상기 무기염기는 소듐 t-부톡사이드, 포타슘 t-부톡사이드, 소듐 하이드라이드, 소듐 메톡사이드, 소듐 에톡사이드, 리튬 하이드라이드, 리튬 하이드록사이드, 리튬 t-부톡사이드, 리튬 메톡사이드, 리튬 에톡사이드, 소듐 하이드록사이드 및 포타슘 하이드록사이드 중에서 선택된 1종 이상을 포함할 수 있다.As a preferred embodiment of the present invention, the inorganic base is sodium t-butoxide, potassium t-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, lithium hydride, lithium hydroxide, lithium t-butoxide Side, lithium methoxide, lithium ethoxide, sodium hydroxide and potassium hydroxide may include at least one selected from.
본 발명의 바람직한 일실시예로서, 2단계의 상기 유기용매는 아세토니트릴, 테트라하이드로퓨란, 디메틸포름아마이드, 디메틸설폭사이드, 디메틸아세트아마이드, 아세톤 및 N-메틸피롤리돈 중에서 선택된 1종 이상을 포함할 수 있다.As a preferred embodiment of the present invention, the organic solvent in step 2 includes at least one selected from acetonitrile, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, acetone, and N-methylpyrrolidone. can do.
본 발명의 바람직한 일실시예로서, 2단계의 인시투 반응은 상상기 포스포늄염 100 중량부에 대하여, 상기 염기 30 ~ 100 중량부 및 파라포름알데히드 또는 포름알데히드 15 ~ 50 중량부로 혼합한 후 반응을 수행할 수 있다.As a preferred embodiment of the present invention, the in-situ reaction in the second step is performed after mixing 30 to 100 parts by weight of the base and 15 to 50 parts by weight of paraformaldehyde or formaldehyde with respect to 100 parts by weight of the upper phase phosphonium salt. can be performed.
본 발명의 바람직한 일실시예로서, 2단계의 인시투 반응은 60 ~ 80℃에서 1 ~ 4 시간 동안 수행할 수 있다.As a preferred embodiment of the present invention, the two-step in-situ reaction may be performed at 60 to 80° C. for 1 to 4 hours.
본 발명의 바람직한 일실시예로서, 3단계의 금속염은 금속 할라이드, 금속 설페이트, 금속 나이트레이트, 금속 퍼클로레이트, 금속 바이카보네이트, 금속 카보네이트, 금속 아세테이트, 금속 시트레이트, 금속 벤조에이트염, 이들의 수화물 또는 이들의 유기솔베이트를 포함할 수있다.As a preferred embodiment of the present invention, the metal salt of step 3 is a metal halide, metal sulfate, metal nitrate, metal perchlorate, metal bicarbonate, metal carbonate, metal acetate, metal citrate, metal benzoate salt, a hydrate or These organic sorbates may be included.
본 발명의 바람직한 일실시예로서, 금속염의 상기 금속은 알카리금속, 알카리토금속, 전이금속 또는 란탄족금속일 수 있다.As a preferred embodiment of the present invention, the metal of the metal salt may be an alkali metal, an alkaline earth metal, a transition metal or a lanthanide metal.
본 발명의 바람직한 일실시예로서, 3단계의 금속염은 1단계의 포스핀계 화합물 1당량 당 1.50 ~ 3.00 당량으로 투입할 수 있다.As a preferred embodiment of the present invention, the metal salt in step 3 may be added in an amount of 1.50 to 3.00 equivalents per 1 equivalent of the phosphine compound in step 1.
본 발명의 바람직한 일실시예로서, 앞서 설명한 제조방법을 통해서, 수율 70% 이상 및 순도 98% 이상인 상기 화학식 2로 표시되는 메틸렌 락톤계 화합물을 제조할 수 있다.As a preferred embodiment of the present invention, the methylene lactone-based compound represented by Formula 2 having a yield of 70% or more and a purity of 98% or more can be prepared through the above-described preparation method.
본 발명의 제조방법은 제조공정 중에 발생하는 반응부산물을 별도의 정제과정 없이, 동일 제조 공정에서 효과적으로 정제(또는 제거)할 수 있고, 인시투(in-situ) 합성 공정을 통해 별도의 중간체 합성 공정 및 이로 인한 건조 공정을 수행하지 않으므로, 제조공정이 단순하면서도, 높은 수율 및 높은 순도의 메틸렌 락톤계 화합물을 높은 생산성, 상업성으로 제조할 수 있다. The manufacturing method of the present invention can effectively purify (or remove) reaction byproducts generated during the manufacturing process in the same manufacturing process without a separate purification process, and a separate intermediate synthesis process through an in-situ synthesis process. And since a drying process is not performed, a methylene lactone-based compound with a high yield and high purity can be produced with high productivity and commerciality, while the manufacturing process is simple.
본 발명을 좀 더 구체적으로 설명하기 전에, 본 명세서 및 청구범위에 사용된 용어나 단어는 통상적이거나 사전적인 의미로 한정되어서는 아니되며, 발명을 가장 최선의 방법으로 설명하기 위해 용어의 개념을 적절하게 정의할 수 있다는 원칙에 입각하여 본 발명의 기술적 사상에 부합하는 의미와 개념으로 해석되어야만 한다.Before describing the present invention in more detail, the terms or words used in this specification and claims should not be limited to their usual or dictionary meanings, and the concept of terms is appropriately used to describe the invention in the best way. It should be interpreted as a meaning and concept consistent with the technical spirit of the present invention based on the principle that it can be defined in the following way.
따라서, 본 명세서에 기재된 실시예의 구성은 본 발명의 바람직한 하나의 예에 불과할 뿐이고, 본 발명의 기술적 사상을 모두 대변하는 것은 아니므로, 본 출원시점에 있어서 이들을 대체할 수 있는 다양한 균등물과 변형 예들이 있을 수 있음을 이해하여야 한다.Therefore, the configuration of the embodiments described in this specification is only one preferred example of the present invention, and does not represent all of the technical spirit of the present invention, so various equivalents and modifications that can replace them at the time of the present application It should be understood that there may be
본 발명은 종래 메틸렌 락톤계 화합물 제조공정 보다 불순물의 정제(또는 제거)가 용이하면서도, 고순도의 메텔렌 락톤계 화합물을 높은 수율로 제조에 적합하며 대량합성공정에 유리한 발명에 관한 것으로서, 포스포늄염을 제조하는 1단계; 상기 포스포늄염, 염기, 파라포름알데히드 또는 포름알데히드 및 유기용매을 혼합한 후, 인시투(in-situ) 반응시켜서 메틸렌 락톤계 화합물 및 포스핀계 산화물을 포함하는 용액을 제조하는 2단계; 2단계의 용액에 금속염을 투입하여, 포스핀계 산화물과 금속염을 반응시켜서 복합체를 형성시키는 3단계; 및 3단계를 수행한 용액 내 상기 복합체를 제거한 후, 농축 공정 및 진공증류 공정을 수행하여 메틸렌 락톤계 화합물을 수득하는 4단계;를 포함하는 공정을 수행하여, 고순도의 메텔렌 락톤계 화합물을 높은 수율로 제조할 수 있다.The present invention relates to an invention in which the purification (or removal) of impurities is easier than in the conventional methylene lactone-based compound manufacturing process, suitable for producing high-purity methylene lactone-based compounds in high yield, and advantageous for large-scale synthesis processes, phosphonium salts Step 1 to prepare; A second step of preparing a solution containing a methylene lactone-based compound and a phosphine-based oxide by mixing the phosphonium salt, base, paraformaldehyde or formaldehyde and an organic solvent, and then reacting in situ; A third step of adding a metal salt to the solution of step 2 and reacting the phosphine oxide with the metal salt to form a complex; and a fourth step of obtaining a methylene lactone-based compound by removing the complex from the solution in step 3 and then performing a concentration process and a vacuum distillation process to obtain a high-purity methylene lactone-based compound. It can be produced in yield.
1단계의 상기 포스포늄염은, 알파 할로 락톤계 화합물 및 포스핀계 화합물을 혼합 및 반응을 수행한 후, 냉각시켜서 하기 화학식 1로 표시되는 포스포늄염을 수득하는 공정이다.The phosphonium salt in step 1 is a process of mixing and reacting an alpha halolactone-based compound and a phosphine-based compound, followed by cooling to obtain a phosphonium salt represented by Formula 1 below.
[화학식 1][Formula 1]
상기 화학식 1에 있어서, R1 내지 R3 각각은 독립적으로 C3~C4의 직쇄형 알킬기, 페닐기, 3-클로로페닐기, 3-메틸페닐기, 4-메틸페닐기, 3-메톡시페닐기, 4-메톡시페닐기 또는 페녹시기이며, 바람직하게는 R1 내지 R3 각각은 독립적으로 C3~C4의 직쇄형 알킬기, 페닐기 또는 페녹시기이며, 더욱 바람직하게는 R1 내지 R3 각각은 독립적으로 C3~C4의 직쇄형 알킬기 또는 페닐기이다.In Formula 1, each of R 1 to R 3 is independently a C 3 to C 4 straight-chain alkyl group, a phenyl group, a 3-chlorophenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 3-methoxyphenyl group, a 4- A methoxyphenyl group or a phenoxy group, preferably each of R 1 to R 3 is independently a C 3 to C 4 straight-chain alkyl group, a phenyl group or a phenoxy group, more preferably each of R 1 to R 3 is independently C It is a 3 -C 4 straight-chain alkyl group or a phenyl group.
또한, 화학식 1의 X는 -F, -Cl, -Br 또는 -I이고, 바람직하게는 -Cl, -Br 또는 -I이며, 더욱 바람직하게는 -Br이다.In addition, X in Formula 1 is -F, -Cl, -Br or -I, preferably -Cl, -Br or -I, more preferably -Br.
또한, 화학식 1의 Y는 
이다. 그리고, R4는 수소원자 또는 C1 ~ C5의 직쇄형 알킬기이고, 바람직하게는 수소원자 또는 C1 ~ C2의 직쇄형 알킬기이다.In addition, Y in Formula 1 is to be. And, R 4 is a hydrogen atom or a C 1 to C 5 linear alkyl group, preferably a hydrogen atom or a C 1 to C 2 linear alkyl group.
1단계의 상기 알파 할로 락톤계 화합물은 하기 화학식 3으로 표시되는 락톤계 화합물을 포함할 수 있다.The alpha halo lactone-based compound of step 1 may include a lactone-based compound represented by Formula 3 below.
[화학식 3][Formula 3]
화학식 3의 R4는 수소원자 또는 C1 ~ C5의 직쇄형 알킬기이며, 바람직하게는 수소원자 또는 C1 ~ C2의 직쇄형 알킬기이다. X는 -F, -Cl, -Br 또는 -I이고, 바람직하게는 X는 -Cl, -Br 또는 -I이다.R 4 in Formula 3 is a hydrogen atom or a C 1 to C 5 straight-chain alkyl group, preferably a hydrogen atom or a C 1 to C 2 straight-chain alkyl group. X is -F, -Cl, -Br or -I, preferably X is -Cl, -Br or -I.
또한, 1단계의 상기 알파 할로 락톤계 화합물은 알파 할로 부티로락톤 또는 알파 할로 발레로락톤을 포함할 수 있다.In addition, the alpha halo lactone-based compound of step 1 may include alpha halo butyrolactone or alpha halo valerolactone.
또한, 1단계의 상기 포스핀계 화합물은 트리스(C3~4 알킬)포스핀, 트리페닐포스핀, 트리스(3-클로로페닐)포스핀, 트리스(4-클로로페닐)포스핀, 트리스(3-메틸페닐)포스핀, 트리스(4-메틸페닐)포스핀, 트리스(3-메톡시페닐)포스핀, 트리스(4-메톡시-페닐)포스핀, 페녹시다이페닐포스핀 및 다이페녹시페닐포스핀 중에서 선택된 1종 이상을 포함하며, 바람직하게는 트리스(C3~4 알킬)포스핀, 트리페닐포스핀, 페녹시다이페닐포스핀 및 다이페녹시페닐포스핀 중에서 선택된 1종 이상을 포함하고, 더욱 바람직하게는 트리스(C3~4 알킬)포스핀 및 트리페닐포스핀 중에서 선택된 1종 이상을 포함할 수 있다. In addition, the phosphine-based compound of step 1 is tris (C 3 ~ 4 alkyl) phosphine, triphenylphosphine, tris (3-chlorophenyl) phosphine, tris (4-chlorophenyl) phosphine, tris (3- methylphenyl)phosphine, tris(4-methylphenyl)phosphine, tris(3-methoxyphenyl)phosphine, tris(4-methoxy-phenyl)phosphine, phenoxydiphenylphosphine and diphenoxyphenylphosphine It includes at least one selected from among, preferably at least one selected from tris (C 3 ~ 4 alkyl) phosphine, triphenylphosphine, phenoxydiphenylphosphine and diphenoxyphenylphosphine, More preferably, at least one selected from tris(C 3-4 alkyl)phosphine and triphenylphosphine may be included.
또한, 1단계의 상기 유기용매는 아세토니트릴, 테트라하이드로퓨란, 디메틸포름아마이드, 디메틸설폭사이드, 디메틸아세트아마이드, 아세톤 및 N-메틸피롤리돈 중에서 선택된 1종 이상을 포함할 수 있다.In addition, the organic solvent in step 1 may include at least one selected from acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, dimethylacetamide, acetone, and N-methylpyrrolidone.
그리고, 1단계의 혼합 및 반응은 알파 할로 락톤계 화합물 및 포스핀계 화합물을 1 : 0.9 ~ 3.0 중량비로, 바람직하게는 1 : 1.2 ~ 2.5 중량비로, 더욱 바람직하게는 1 : 1.5 ~ 2.0 중량비로 혼합한 후, 반응을 수행할 수 있다. 이때, 포스핀계 화합물 혼합량이 0.9 중량비 미만이면 목적하는 최종 반응생성물 수율이 낮은 문제가 있을 수 있고, 3.0 중량비를 초과하여 사용하면 미반응 포스핀계 화합물에 의해 불순물이 다량 발생하여 목적하는 최종 반응생성물의 순도가 낮은 문제가 있을 수 있다.In the mixing and reaction of step 1, the alpha halolactone compound and the phosphine compound are mixed at a weight ratio of 1:0.9 to 3.0, preferably at a weight ratio of 1:1.2 to 2.5, and more preferably at a weight ratio of 1:1.5 to 2.0. After that, the reaction can be carried out. At this time, if the mixing amount of the phosphine-based compound is less than 0.9 weight ratio, there may be a problem in that the yield of the desired final reaction product is low, and when it is used in excess of 3.0 weight ratio, a large amount of impurities are generated by the unreacted phosphine-type compound, resulting in the desired final reaction product. There may be a problem with low purity.
그리고, 1단계의 반응은 60 ~ 80℃에서 8 ~ 16시간 동안, 바람직하게는 60 ~ 75℃에서 8 ~ 14시간 동안, 더욱 바람직하게는 65 ~ 72℃에서 9 ~ 13시간 동안 천천히 교반시키면서 수행하는 것이 좋으며, 이때, 반응 온도가 60℃ 미만이면 반응 시간이 너무 오래 걸려서 상업성이 떨어지는 문제가 있고, 80℃를 초과하면 포스포늄염 합성 시간은 짧으나 원치 않는 반응생성물(불순물)이 다량 발생할 수 있으므로 상기 범위 내에서 반응을 수행하는 것이 좋다.And, the reaction of the first step is carried out with slow stirring at 60 ~ 80 ℃ for 8 ~ 16 hours, preferably 60 ~ 75 ℃ for 8 ~ 14 hours, more preferably 65 ~ 72 ℃ for 9 ~ 13 hours At this time, if the reaction temperature is less than 60 ℃, the reaction time takes too long and there is a problem of poor commerciality, and if it exceeds 80 ℃, the phosphonium salt synthesis time is short, but a large amount of unwanted reaction products (impurities) may be generated. It is preferable to carry out the reaction within the above range.
다음으로, 2단계는 인시투(in-situ) 반응을 통한 메틸렌 락톤계 화합물을 합성하는 공정으로서, 상기 1단계에서 수득한 포스포늄염, 염기, 파라포름알데히드 또는 포름알데히드 및 유기용매를 혼합한 후, 인시투 반응을 수행하면 메틸렌 락톤계 화합물 및 포스핀계 산화물이 형성된다. Next, step 2 is a process of synthesizing a methylene lactone-based compound through an in-situ reaction, in which the phosphonium salt, base, paraformaldehyde or formaldehyde and an organic solvent obtained in step 1 are mixed. Then, when an in-situ reaction is performed, a methylene lactone-based compound and a phosphine-based oxide are formed.
이해를 돕기 위해 하기 반응식 1의 예를 들면, 1단계에서 알파 할로 락톤계 화합물로서, 알파브로모 부티로락톤을 사용하고, 포스핀계 화합물로서 트리페닐포스핀을 사용하여 포스포늄염을 제조한 후, 상기 포스포늄염과 염기와 반응시키면 포스포늄 일라이드(Phosphonuim ylide)가 합성되고, 포스포늄 일라이드가 알데히드와 반응하여 메틸렌 락톤계 화합물이 합성되는 인시투(in-situ) 반응을 2단계에서 수행하게 된다. For better understanding, in the following Reaction Scheme 1, in step 1, alpha-bromo butyrolactone is used as an alpha halolactone-based compound and triphenylphosphine is used as a phosphine-based compound to prepare a phosphonium salt. , When the phosphonium salt and a base are reacted, phosphonium ylide is synthesized, and phosphonium ylide reacts with aldehyde to synthesize a methylene lactone-based compound. An in-situ reaction is performed in the second step will perform
[반응식 1][Scheme 1]
그리고, 이러한 인시투 반응에서 메틸렌 락톤계 화합물 외에 반응생성물로서 포스핀계 산화물이 부가반응생성물로 형성하게 된다. And, in this in-situ reaction, a phosphine-based oxide is formed as an addition reaction product as a reaction product in addition to the methylene lactone-based compound.
상기 포스핀계 산화물은 1단계에서 사용하는 포스핀계 화합물의 산화물로서, 예를 들면, 트리스(C3~4 알킬)포스핀옥사이드, 트리페닐포스핀옥사이드, 트리스(3-클로로페닐)포스핀옥사이드, 트리스(4-클로로페닐)포스핀옥사이드, 트리스(3-메틸페닐)포스핀옥사이드, 트리스(4-메틸페닐)포스핀옥사이드, 트리스(3-메톡시페닐)포스핀옥사이드, 트리스(4-메톡시-페닐)포스핀옥사이드, 페녹시다이페닐포스핀옥사이드 및 다이페녹시페닐포스핀옥사이드 중에서 선택된 1종 이상을 포함할 수 있다. The phosphine-based oxide is an oxide of a phosphine-based compound used in step 1, for example, tris (C 3-4 alkyl) phosphine oxide, triphenylphosphine oxide, tris (3-chlorophenyl) phosphine oxide, Tris (4-chlorophenyl) phosphine oxide, tris (3-methylphenyl) phosphine oxide, tris (4-methylphenyl) phosphine oxide, tris (3-methoxyphenyl) phosphine oxide, tris (4-methoxy- Phenyl) may include at least one selected from phosphine oxide, phenoxydiphenylphosphine oxide and diphenoxyphenylphosphine oxide.
그리고, 2단계에서 상기 염기는 유기염기 및 무기염기 중에서 선택된 1종 이상을 포함할 수 있다. In step 2, the base may include at least one selected from organic bases and inorganic bases.
상기 유기염기는 트리에틸아민, 디이소프로필에틸아민, 다이메틸아민 및 다이에틸아민 중에서 선택된 1종 이상을 포함할 수 있으며, 바람직하게는 트리에틸아민, 다이메틸아민 및 다이에틸아민 중에서 선택된 1종 이상을 포함할 수 있다.The organic base may include at least one selected from triethylamine, diisopropylethylamine, dimethylamine and diethylamine, and preferably one selected from triethylamine, dimethylamine and diethylamine. may contain more than
그리고, 상기 무기염기는 소듐 t-부톡사이드, 포타슘 t-부톡사이드, 소듐 하이드라이드, 소듐 메톡사이드, 소듐 에톡사이드, 리튬 하이드라이드, 리튬 하이드록사이드, 리튬 t-부톡사이드, 리튬 메톡사이드, 리튬 에톡사이드, 소듐 하이드록사이드 및 포타슘 하이드록사이드 중에서 선택된 1종 이상을 포함할 수 있고, 바람직하게는 소듐 메톡사이드, 소듐 에톡사이드, 리튬 하이드라이드, 리튬 하이드록사이드, 소듐 하이드록사이드 및 포타슘 하이드록사이드 중에서 선택된 1종 이상을 포함할 수 있다.And, the inorganic base is sodium t-butoxide, potassium t-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, lithium hydride, lithium hydroxide, lithium t-butoxide, lithium methoxide, lithium It may contain at least one selected from among ethoxide, sodium hydroxide and potassium hydroxide, preferably sodium methoxide, sodium ethoxide, lithium hydride, lithium hydroxide, sodium hydroxide and potassium hydroxide It may include one or more selected from rockside.
그리고, 상기 염기의 사용량은 상기 포스포늄염 100 중량부에 대하여, 30 ~ 100 중량부를, 바람직하게는 30 ~ 60 중량부를, 더욱 바람직하게는 40 ~ 55 중량부를 사용할 수 있으며, 이때, 염기 사용량이 30 중량부 미만이면 일라이드 합성량이 적어서 메틸렌 락톤계 화합물에 대한 합성 수율이 낮아지는 문제가 있을 수 있고, 염기 사용량이 100 중량부를 초과하면 과량 사용으로서 오히려 미반응 염기가 불순물로 작용하여 메틸렌 락톤계 화합물 순도가 낮아지는 문제가 있을 수 있으므로 상기 범위 내로 사용하는 것이 좋다.The amount of the base may be 30 to 100 parts by weight, preferably 30 to 60 parts by weight, more preferably 40 to 55 parts by weight, based on 100 parts by weight of the phosphonium salt. If it is less than 30 parts by weight, there may be a problem in that the synthesis yield of the methylene lactone-based compound is low due to the small amount of ylide synthesis, and if the amount of base used exceeds 100 parts by weight, the unreacted base acts as an impurity due to excessive use, resulting in methylene lactone-based Since there may be a problem of lowering the purity of the compound, it is good to use it within the above range.
그리고, 상기 파라포름알데히드 또는 포름알데히드의 사용량은 상기 포스포늄염 100 중량부에 대하여, 15 ~ 50 중량부를, 바람직하게는 15 ~ 30 중량부를, 더욱 바람직하게는 18 ~ 30 중량부를 사용하는 것이 좋으며, 이의 사용량이 15 중량부 미만이면 메틸렌 락톤계 화합물에 대한 합성 수율이 낮아지는 문제가 있을 수 있고, 이의 사용량이 50 중량부를 초과하면 과량 사용으로서 오히려 미반응 알데히드가 불순물로 작용하여 메틸렌 락톤계 화합물 순도가 낮아지는 문제가 있을 수 있으므로 상기 범위 내로 사용하는 것이 좋다.And, the amount of paraformaldehyde or formaldehyde used is 15 to 50 parts by weight, preferably 15 to 30 parts by weight, more preferably 18 to 30 parts by weight based on 100 parts by weight of the phosphonium salt. , If the amount thereof is less than 15 parts by weight, there may be a problem in that the synthesis yield for the methylene lactone-based compound is lowered, and if the amount thereof exceeds 50 parts by weight, the unreacted aldehyde acts as an impurity rather than the methylene lactone-based compound. Since there may be a problem of lowering the purity, it is good to use it within the above range.
그리고, 2단계의 유기용매는 테트라하이드로퓨란, 다이에틸에테르, 1,4-다이옥세인, 톨루엔, 아세토니트릴, 디클로로메탄, 에틸디클로로에탄, 디이소프로필 에테르, t-부틸메틸에테르 및 에틸아세테이트 중에서 선택된 1종 이상을 포함할 수 있으며, 바람직하게는 테트라하이드로퓨란, 1,4-다이옥세인 및 아세토니트릴 중에서 선택된 1종 이상을 포함할 수 있다.And, the organic solvent of the second step is selected from tetrahydrofuran, diethyl ether, 1,4-dioxane, toluene, acetonitrile, dichloromethane, ethyldichloroethane, diisopropyl ether, t-butylmethyl ether and ethyl acetate It may include one or more, preferably one or more selected from tetrahydrofuran, 1,4-dioxane, and acetonitrile.
그리고, 2단계의 인시투 반응은 60 ~ 80℃에서 1 ~ 4 시간 동안, 바람직하게는 60 ~ 75℃에서 1 ~ 3 시간 동안, 더욱 바람직하게는 65 ~ 75℃에서 1 ~ 3 시간 동안 수행하는 것이 좋으며, 반응 온도가 60℃ 미만이면 메틸렌 락톤계 화합물 합성 시간이 너무 길어지고, 수율이 낮은 문제가 있을 수 있고, 반응 온도가 80℃를 초과하면 원치 않는 불순물이 발생하여 순도가 낮은 문제가 있을 수 있으므로 상기 온도 범위에서 인시투 반응을 수행하는 것이 좋다.And, the second-step in-situ reaction is carried out at 60 to 80 ° C for 1 to 4 hours, preferably at 60 to 75 ° C for 1 to 3 hours, more preferably at 65 to 75 ° C for 1 to 3 hours. It is preferable, and if the reaction temperature is less than 60 ℃, the synthesis time of the methylene lactone-based compound is too long and there may be a problem with low yield, and if the reaction temperature exceeds 80 ℃, unwanted impurities are generated and there is a problem of low purity. Therefore, it is preferable to perform the in-situ reaction in the above temperature range.
다음으로, 3단계는 2단계의 부가반응생성물인 상기 포스핀계 산화물을 금속염과 반응시켜 복합체(또는 착화물)로 합성시키는 공정이다.Next, step 3 is a process of synthesizing a complex (or complex) by reacting the phosphine-based oxide, which is an addition reaction product of step 2, with a metal salt.
상기 금속염은 금속 할라이드(예를 들면, 플루오라이드, 클로라이드, 브로마이드 또는 요오다이드), 금속 설페이트, 금속 나이트레이트, 금속 퍼클로레이트, 금속 바이카보네이트, 금속 카보네이트, 금속 아세테이트, 금속 시트레이트, 금속 벤조에이트염, 이들의 수화물 또는 이들의 유기솔베이트를 포함할 수 있다. 그리고, 상기 금속염의 금속은 알카리금속, 알카리토금속, 전이금속 또는 란탄족금속을 포함할 수 있으며, 바람직하게는 금속염의 금속은 리튬, 나트륨, 포타슘, 마그네슘, 칼슘, 바륨, 스트론튬, 사미리움(III), 아연, 철(II), 철(III), 망간(II), 코발트(II), 코발트(III), 니켈, 구리(I) 또는 구리(II)를 포함할 수 있다. 상기 금속염의 바람직한 일구현예를 들면, 상기 금속염은 염화아연 및 염화마그네슘 중에서 선택된 1종 이상을 포함할 수 있다. The metal salt is a metal halide (e.g., fluoride, chloride, bromide or iodide), metal sulfate, metal nitrate, metal perchlorate, metal bicarbonate, metal carbonate, metal acetate, metal citrate, metal benzoate salt , hydrates thereof or organic sorbates thereof. In addition, the metal of the metal salt may include an alkali metal, an alkaline earth metal, a transition metal or a lanthanide metal, and preferably, the metal of the metal salt is lithium, sodium, potassium, magnesium, calcium, barium, strontium, samirium (III ), zinc, iron(II), iron(III), manganese(II), cobalt(II), cobalt(III), nickel, copper(I) or copper(II). For a preferred embodiment of the metal salt, the metal salt may include at least one selected from zinc chloride and magnesium chloride.
3단계에서 금속염 투입 당량은 1단계에서 사용되는 포스핀계 화합물을 기준으로 상기 포스핀계 화합물 1 당량 당 상기 금속염 0.25 ~ 5.0 댱량비로, 바람직하게는 1.5 ~ 3.0 댱량비로 사용할 수 있다. 이때, 금속염 투입 당량비가 0.25 당량비 미만이면 복합체가 충분하게 형성되지 않아서 잔류하는 포스핀계 산화물이 불순물로 작용하여 목적하는 최종 생성물의 순도가 낮은 문제가 있을 수 있고, 5.0 당량비를 초과하여 사용하면 과량 사용으로서 오히려 잔류 금속염이 불순물로 작용하여 종 생성물의 순도가 낮아지는 문제가 있을 수 있으므로 상기 범위 내로 사용하는 것이 좋다.In the third step, the amount of the metal salt added per equivalent of the phosphine-based compound based on the phosphine-based compound used in the first step may be used in a weight ratio of 0.25 to 5.0, preferably 1.5 to 3.0. At this time, if the equivalence ratio of the metal salt input is less than 0.25 equivalence ratio, the complex is not sufficiently formed, and the remaining phosphine oxide acts as an impurity, which may cause a problem of low purity of the desired final product. As such, since the residual metal salt acts as an impurity, there may be a problem of lowering the purity of the species product, so it is good to use it within the above range.
그리고, 3단계의 포스핀계 산화물과 금속염의 반응은 0 ~ 130℃, 바람직하게는 20 ~ 120℃, 더욱 바람직하게는 20 ~ 40℃에서 서서히 교반시키면서 5 ~ 24 시간 동안, 바람직하게는 6 ~ 18시간 동안 수행할 수 있다.And, the reaction of the phosphine-based oxide and the metal salt in the third step is 0 to 130 ° C, preferably 20 to 120 ° C, more preferably 20 to 40 ° C for 5 to 24 hours, preferably 6 to 18 hours while stirring slowly. can be done over time.
4단계는 3단계를 수행한 반응용액 내 형성된 복합체를 제거하고, 농축 및 진공증류 공정을 수행하여 하기 화학식 2로 표시되는 메틸렌 락톤계 화합물을 수득하는 공정이다.Step 4 is a process for obtaining a methylene lactone-based compound represented by Formula 2 below by removing the complex formed in the reaction solution in Step 3 and performing a concentration and vacuum distillation process.
[화학식 2][Formula 2]
화학식 2의 R4는 수소원자 또는 C1 ~ C5의 직쇄형 알킬기이며, 바람직하게는 수소원자 또는 C1 ~ C2의 직쇄형 알킬기이다.R 4 in Formula 2 is a hydrogen atom or a C 1 to C 5 straight-chain alkyl group, preferably a hydrogen atom or a C 1 to C 2 straight-chain alkyl group.
4단계에서 3단계에서 합성된 복합체를 제거하는 방법은 일반적으로 당업계에서 사용하는 여과, 디칸테이션(decantation) 및/또는 원심분리(centrifugation) 등의 방법을 사용할 수 있다. As a method for removing the complex synthesized in step 4 in step 3, methods such as filtration, decantation, and/or centrifugation generally used in the art may be used.
그리고, 4단계의 농축공정 및 진공 증류공정 각각은 당업계에서 사용하는 일반적인 농축, 진공증류 방법으로 수행할 수 있다.In addition, each of the four-step concentration process and vacuum distillation process can be performed by a general concentration and vacuum distillation method used in the art.
위와 같은 공정을 수행하여 제조한 화학식 2로 표시되는 메틸렌 락톤계 화합물은 하기 수학식 1에 의거하여 계산시, 수율이 60% 이상, 바람직하게는 수율 70% 이상, 더욱 바람직하게는 70 ~ 95%의 수율로 메틸렌 락톤계 화합물을 수득할 수 있다.The methylene lactone-based compound represented by Formula 2 prepared by performing the above process has a yield of 60% or more, preferably a yield of 70% or more, more preferably 70 to 95% when calculated based on Equation 1 below A methylene lactone-based compound can be obtained in a yield of
[수학식 1][Equation 1]
수율(%) = (반응생성물의 실제 수득량/반응생성물의 이론적 수득량)×100%Yield (%) = (actual yield of reaction product/theoretical yield of reaction product) × 100%
또한, 위와 같은 공정을 수행하여 제조한 화학식 2 또는 화학식 3으로 표시되는 메틸렌 락톤계 화합물은 크로마토그래피로 분석시, 98% 이상, 바람직하게는 순도 98.5% ~ 99.9%, 더욱 바람직하게는 98.8 ~ 99.9%의 높은 순도로 메틸렌 락톤계 화합물을 수득할 수 있다.In addition, the methylene lactone-based compound represented by Formula 2 or Formula 3 prepared by performing the above process has a purity of 98% or more, preferably 98.5% to 99.9%, more preferably 98.8 to 99.9% when analyzed by chromatography. A methylene lactone-based compound can be obtained with a high purity of %.
이하, 본 발명을 구체적인 실시예에 의해 설명한다. 단 이하의 실시예들은 본 발명을 예시하기 위한 일례일 뿐, 본 발명의 범위가 이들로 한정되지는 않는다. [실시예]
Hereinafter, the present invention will be described with specific examples. However, the following examples are only examples for illustrating the present invention, and the scope of the present invention is not limited thereto. [Example]
실시예 1-1: 화학식 2-1로 표시되는 메틸렌 락톤계 화합물의 제조Example 1-1: Preparation of methylene lactone-based compound represented by Chemical Formula 2-1
(1)포스포늄염의 제조(1) Manufacture of phosphonium salt
5L의 4구 라운드 플라스크에 콘덴서를 연결하고 냉매를 순환시킨 후 테트라하이드로퓨란(유기용매) 1500 mL, 알파 브로모 감마 부티로락톤 460g과 트리페닐포스핀 735g을 플라스크에 투입하였다. After connecting a condenser to a 5L four-necked round flask and circulating the refrigerant, 1500 mL of tetrahydrofuran (organic solvent), 460 g of alpha-bromo-gamma-butyrolactone, and 735 g of triphenylphosphine were added to the flask.
다음으로, 내부온도를 70℃로 승온 후 12시간 동안 교반 및 반응을 수행하였다. 반응종결을 확인한 후 상온(약 20℃~23℃)으로 냉각하고 30분간 교반 후 여과를 실시한 후, 습체를 60℃에서 8시간 건조하여 하기 화학식 1-1로 표시되는 포스포늄염 1048g(수율 88%)을 수득하였으며, 1H NMR 측정 결과는 하기와 같다. Next, after raising the internal temperature to 70 ℃, stirring and reaction were performed for 12 hours. After confirming the completion of the reaction, it was cooled to room temperature (about 20 ° C. to 23 ° C.), stirred for 30 minutes, filtered, and dried at 60 ° C. for 8 hours to obtain 1048 g of a phosphonium salt represented by the following formula 1-1 (yield: 88 %) was obtained, and the 1 H NMR measurement results are as follows.
1H NMR(CDCl3) : δ 8.01-7.94(m, 6H), δ 7.84-7.80(m, 3H), δ 7.71-7.68(m, 6H), δ 7.65-7.55(m, 1H), δ 4.87-4.81(m, 1H), δ 4.35-4.30(t, 1H), δ 3.36-3.28(m, 1H), δ 2.44-2.35(m, 1H) 1 H NMR (CDCl 3 ): δ 8.01-7.94 (m, 6H), δ 7.84-7.80 (m, 3H), δ 7.71-7.68 (m, 6H), δ 7.65-7.55 (m, 1H), δ 4.87 -4.81 (m, 1H), δ 4.35-4.30 (t, 1H), δ 3.36-3.28 (m, 1H), δ 2.44-2.35 (m, 1H)
[화학식 1-1][Formula 1-1]
화학식 1-1에 있어서, R1, R2, R3 각각은 페닐기이며, X는 -Br이고, Y는 
이며, R4는 수소원자이다. In Formula 1-1, each of R 1 , R 2 , and R 3 is a phenyl group, X is -Br, and Y is And, R 4 is a hydrogen atom.
(2) 인시투 반응 수행 및 메틸렌 락톤계 화합물 합성(2) In-situ reaction and synthesis of methylene lactone-based compounds
3L의 4구 반응플라스크에 앞서 제조한 화학식 1-1로 표시되는 포스포늄염 98.2g, 유기염기인 트리에틸아민 46.2g, 파라포름알데히드 24.1g 및 테트라하이드로퓨란 800mL를 순차적으로 넣고, 반응기 내부온도를 약 68℃로 조절한 후, 2 시간 동안 교반 및 인시투 반응을 수행하였다. 98.2 g of the phosphonium salt represented by Chemical Formula 1-1 prepared previously, 46.2 g of triethylamine as an organic base, 24.1 g of paraformaldehyde, and 800 mL of tetrahydrofuran were sequentially put into a 3 L four-necked reaction flask, and the internal temperature of the reactor After adjusting to about 68 ° C., stirring and in-situ reaction were performed for 2 hours.
다음으로, 반응종결을 TLC로 확인하고 상온으로 냉각을 수행하였다. Next, completion of the reaction was confirmed by TLC, and cooling was performed to room temperature.
다음으로, 냉각된 반응 용액에 금속염인 염화아연 62.7g을 투입한 후, 약 25℃에서 8시간 동안 교반 및 반응을 수행하여, 반응 용액 내 포스핀계 산화물과 금속염이 반응하여 복합체를 형성되도록 하였다.Next, 62.7 g of zinc chloride, which is a metal salt, was added to the cooled reaction solution, followed by stirring and reaction at about 25 ° C. for 8 hours, so that the phosphine oxide and the metal salt reacted in the reaction solution to form a complex.
다음으로, 상기 반응 용액을 여과하여 반응 용액으로부터 복합체를 제거한 후, 여액을 농축한 후 진공증류하여 무색의 하기 화학식 2-1로 표시되는 메틸렌 락톤계 화합물 19.4g(수율 86%)을 수득하였다. 이때, 수율은 하기 수학식 1에 의거하여 측정한 것이다. Next, the reaction solution was filtered to remove the complex from the reaction solution, and then the filtrate was concentrated and vacuum distilled to obtain 19.4 g (86% yield) of a colorless methylene lactone-based compound represented by Formula 2-1 below. At this time, the yield is measured based on Equation 1 below.
또한, 수득된 메틸렌 락톤계 화합물을 가스크로마토그래피로 분석하여 순도 99% 이상임을 확인하였으며, 1H NMR 측정 결과는 하기와 같다. In addition, it was confirmed that the obtained methylene lactone-based compound was analyzed by gas chromatography to have a purity of 99% or more, and the results of 1 H NMR measurement are as follows.
1H NMR(CDCl3) :δ 6.20-6.18(t, 1H), δ 5.65-5.64(t, 1H), δ 4.36-4.32(t, 2H), δ 2.99-2.94(m, 2H) 1 H NMR (CDCl 3 ) : δ 6.20-6.18 (t, 1H), δ 5.65-5.64 (t, 1H), δ 4.36-4.32 (t, 2H), δ 2.99-2.94 (m, 2H)
[수학식 1][Equation 1]
수율(%) = (반응생성물의 실제 수득량/반응생성물의 이론적 수득량)X100%Yield (%) = (actual yield of reaction product / theoretical yield of reaction product) X 100%
[화학식 2-1][Formula 2-1]
화학식 2-1의 R4는 수소원자이다.R 4 in Formula 2-1 is a hydrogen atom.
실시예 2: 화학식 2-2로 표시되는 메틸렌 락톤계 화합물의 제조Example 2: Preparation of methylene lactone-based compound represented by Chemical Formula 2-2
(1)포스포늄염의 제조(1) Manufacture of phosphonium salt
5L의 4구 라운드 플라스크에 콘덴서를 연결하고 냉매를 순환시킨 후 테트라하이드로퓨란(유기용매) 1500 mL, 알파 브로모 감마 발레로락톤(cis 및 trans 혼합물) 460g과 트리페닐포스핀 735g을 플라스크에 투입하였다. After connecting a condenser to a 5L four-necked round flask and circulating the refrigerant, 1500 mL of tetrahydrofuran (organic solvent), 460 g of alpha bromo-gamma valerolactone (cis and trans mixture) and 735 g of triphenylphosphine were added to the flask. did
다음으로, 내부온도를 70℃로 승온 후 12시간 동안 교반 및 반응을 수행하였다. 반응종결을 확인한 후 상온(약 20℃~23℃)으로 냉각하고 30분간 교반 후 여과를 실시한 후, 습체를 60℃에서 8시간 건조하여 하기 화학식 1-2로 표시되는 포스포늄염(수율 76%)을 수득하였으며, 1H NMR 측정 결과는 하기와 같다. Next, after raising the internal temperature to 70 ℃, stirring and reaction were performed for 12 hours. After confirming the completion of the reaction, it was cooled to room temperature (about 20 ° C to 23 ° C), stirred for 30 minutes, filtered, and then dried at 60 ° C for 8 hours to obtain a phosphonium salt represented by the following formula 1-2 (yield: 76%) ) was obtained, and the 1 H NMR measurement results are as follows.
1H NMR(CDCl3) : δ 8.10-7.72(m, 16H), δ 5.36-5.25(m, 1H), δ 3.50-3.35 (m, 1H), δ 2.65-2.60(t, 1H), δ 1.33(d, 3H) 1 H NMR (CDCl 3 ): δ 8.10-7.72 (m, 16H), δ 5.36-5.25 (m, 1H), δ 3.50-3.35 (m, 1H), δ 2.65-2.60 (t, 1H), δ 1.33 (d, 3H)
[화학식 1-2][Formula 1-2]
화학식 1-2에 있어서, R1, R2, R3 각각은 페닐기이며, X는 -Br이고, Y는 
이며, R4는 -CH3이다. In Formula 1-2, each of R 1 , R 2 , and R 3 is a phenyl group, X is -Br, and Y is , and R 4 is -CH 3 .
(2) 인시투 반응 수행 및 메틸렌 락톤계 화합물 합성(2) In-situ reaction and synthesis of methylene lactone-based compounds
3L의 4구 반응플라스크에 앞서 제조한 화학식 1-2로 표시되는 포스포늄염 98.2g, 유기염기인 트리에틸아민 46.2g, 파라포름알데히드 24.1g 및 테트라하이드로퓨란 800mL를 순차적으로 넣고, 반응기 내부온도를 약 68℃로 조절한 후, 2 시간 동안 교반 및 인시투 반응을 수행하였다. 98.2 g of the phosphonium salt represented by Chemical Formula 1-2 prepared previously, 46.2 g of triethylamine as an organic base, 24.1 g of paraformaldehyde, and 800 mL of tetrahydrofuran were sequentially put into a 3 L four-necked reaction flask, and the internal temperature of the reactor After adjusting to about 68 ° C., stirring and in-situ reaction were performed for 2 hours.
다음으로, 반응종결을 TLC로 확인하고 상온으로 냉각을 수행하였다. Next, completion of the reaction was confirmed by TLC, and cooling was performed to room temperature.
다음으로, 냉각된 반응 용액에 금속염인 염화아연 62.7g을 투입한 후, 약 25℃에서 8시간 동안 교반 및 반응을 수행하여, 반응 용액 내 포스핀계 산화물과 금속염이 반응하여 복합체를 형성되도록 하였다.Next, 62.7 g of zinc chloride, which is a metal salt, was added to the cooled reaction solution, followed by stirring and reaction at about 25 ° C. for 8 hours, so that the phosphine oxide and the metal salt reacted in the reaction solution to form a complex.
다음으로, 상기 반응 용액을 여과하여 반응 용액으로부터 복합체를 제거한 후, 여액을 농축한 후 진공증류하여 무색의 하기 화학식 3-1로 표시되는 메틸렌 락톤계 화합물(수율 71%)을 수득하였다. 이때, 수율은 실시예 1과 동일한 방법으로 측정한 것이다. Next, the reaction solution was filtered to remove the complex from the reaction solution, and the filtrate was concentrated and vacuum distilled to obtain a colorless methylene lactone-based compound represented by Formula 3-1 (71% yield). At this time, the yield is measured in the same way as in Example 1.
또한, 수득된 메틸렌 락톤계 화합물을 크로마토그래피로 분석하여 순도 99% 이상임을 확인하였으며, 1H NMR 측정 결과는 하기와 같다. In addition, it was confirmed that the obtained methylene lactone-based compound was chromatographically analyzed to have a purity of 99% or more, and the results of 1 H NMR measurement are as follows.
1H NMR(CDCl3)=δ 6.23(t, 1H), δ 5.63(t, 1H), δ 4.66(m, 1 H), δ 3.10(m, 1H), δ 2.56(m, 1H), δ 1.43(d, 3H) 1 H NMR (CDCl 3 )=δ 6.23 (t, 1H), δ 5.63 (t, 1H), δ 4.66 (m, 1 H), δ 3.10 (m, 1H), δ 2.56 (m, 1H), δ 1.43(d, 3H)
[화학식 2-2][Formula 2-2]
화학식 2-2의 R4는 -CH3이다. R 4 in Formula 2-2 is -CH 3 .
실시예 3 ~ 실시예 10 및 비교예 1 ~ 8 Examples 3 to 10 and Comparative Examples 1 to 8
상기 실시예 1과 동일한 방법으로 화학식 1-1로 표시되는 메틸렌 락톤계 화합물을 제조하되, 하기 표 1 및 표 2와 같이 1단계 ~ 3단계에서 투입되는 포스핀계 화합물, 염기 등의 함량을 달리하여 실시예 3 ~ 10 및 비교예 1 ~ 8을 각각 실시하였다.A methylene lactone-based compound represented by Chemical Formula 1-1 was prepared in the same manner as in Example 1, but as shown in Tables 1 and 2 below, by varying the content of the phosphine-based compound, base, etc. introduced in steps 1 to 3 Examples 3 to 10 and Comparative Examples 1 to 8 were carried out, respectively.
실시예 11Example 11
상기 실시예 2와 동일한 방법으로 화학식 1-1로 표시되는 메틸렌 락톤계 화합물을 제조하되, 하기 표 1과 같이 1단계 ~ 3단계에서 투입되는 포스핀계 화합물, 염기 등의 함량을 달리하여 실시예 11을 실시하였다.A methylene lactone-based compound represented by Chemical Formula 1-1 was prepared in the same manner as in Example 2, but the content of the phosphine-based compound, base, etc. introduced in steps 1 to 3 was changed as shown in Table 1 below to obtain Example 11 was carried out.
| 구분division | 1단계Stage 1 | 2단계Step 2 |
3단계 Step 3 |
메틸렌 락톤계 화합물methylene lactone compounds | |||
|
포스핀계 화합물 투입 중량비(1) Introducing phosphine compounds weight ratio (1) |
포스포늄염 (중량부)phosphonium salt (parts by weight) |
염기 (중량부)base (parts by weight) |
파라포름알데하이드 (중량부)paraformaldehyde (parts by weight) |
금속염 투입 당량비(2) metal salt input equivalence ratio (2) |
종류type |
수율(3)/ 순도Yield (3) / water |
|
| 실시예 1Example 1 | 1:1.61:1.6 | 100 100 | 4747 | 24.524.5 | 2.02.0 |
화학식 2-1chemical formula 2-1 |
86.2%/ 99.3%86.2%/ 99.3% |
| 실시예 2Example 2 | 1:1.61:1.6 | 100 100 | 4747 | 24.524.5 | 2.02.0 |
화학식 2-2chemical formula 2-2 |
71.3%/ 99.1%71.3%/ 99.1% |
| 실시예 3Example 3 | 1:1.21:1.2 | 100 100 | 4747 | 24.524.5 | 2.02.0 |
화학식 2-1chemical formula 2-1 |
81.0%/ 99.0%81.0%/ 99.0% |
| 실시예 4Example 4 | 1:2.51:2.5 | 100 100 | 4747 | 24.524.5 | 2.02.0 |
화학식 2-1chemical formula 2-1 |
88.2%/ 98.6%88.2%/ 98.6% |
| 실시예 5Example 5 | 1:1.61:1.6 | 100 100 | 3535 | 24.524.5 | 2.02.0 |
화학식 2-1chemical formula 2-1 |
75.9%/ 99.5%75.9%/ 99.5% |
| 실시예 6Example 6 | 1:1.61:1.6 | 100 100 | 6060 | 24.524.5 | 2.02.0 |
화학식 2-1chemical formula 2-1 |
87.8%/ 97.7%87.8%/ 97.7% |
| 실시예 7Example 7 | 1:1.61:1.6 | 100 100 | 4747 | 18.018.0 | 2.02.0 |
화학식 2-1chemical formula 2-1 |
85.4%/ 99.1%85.4%/ 99.1% |
| 실시예 8Example 8 | 1:1.61:1.6 | 100 100 | 4747 | 30.030.0 | 2.02.0 |
화학식 2-1chemical formula 2-1 |
89.3%/ 98.5%89.3%/ 98.5% |
| 실시예 9Example 9 | 1:1.61:1.6 | 100 100 | 4747 | 24.524.5 | 1.51.5 |
화학식 2-1chemical formula 2-1 |
86.2%/ 99.1%86.2%/ 99.1% |
| 실시예 10Example 10 | 1:1.61:1.6 | 100 100 | 4747 | 24.524.5 | 3.03.0 |
화학식 2-1chemical formula 2-1 |
86.1%/ 99.4%86.1%/ 99.4% |
| 실시예 11Example 11 | 1:1.71:1.7 | 100 100 | 5252 | 28.528.5 | 2.32.3 |
화학식 2-2chemical formula 2-2 |
77.2%/ 99.0%77.2%/ 99.0% |
|
(1) 알파 할로 락톤계 화합물에 대한 중량비 (2) 1단계의 포스핀계화합물 1 당량에 대한 당량비 (3) 수율은 하기 수학식 1에 의거하여 측정 [수학식 1] 수율(%) = (반응생성물의 실제 수득량/반응생성물의 이론적 수득량)×100%(1) Weight ratio to alpha halolactone compound (2) Equivalent ratio with respect to 1 equivalent of the phosphine compound in the first step (3) Yield is measured according to Equation 1 below [Equation 1] Yield (%) = (actual yield of reaction product/theoretical yield of reaction product) × 100% |
|||||||
| 구분division | 1단계Stage 1 | 2단계Step 2 |
3단계 Step 3 |
메틸렌 락톤계 화합물methylene lactone compounds | |||
|
포스핀계 화합물 투입 중량비(1) Introducing phosphine compounds weight ratio (1) |
포스포늄염 (중량부)phosphonium salt (parts by weight) |
염기 (중량부)base (parts by weight) |
파라포름알데하이드 (중량부)paraformaldehyde (parts by weight) |
금속염 투입 당량비(2) metal salt input equivalence ratio (2) |
종류type |
수율(3)/ 순도Yield (3) / water |
|
| 비교예 1Comparative Example 1 | 1:0.851:0.85 | 100 100 | 4747 | 24.524.5 | 2.02.0 |
화학식 2-1chemical formula 2-1 |
67.8%/ 99.2%67.8%/ 99.2% |
| 비교예 2Comparative Example 2 | 1:3.51:3.5 | 100 100 | 4747 | 24.524.5 | 2.02.0 |
화학식 2-1chemical formula 2-1 |
88.4%/ 94.3%88.4%/ 94.3% |
| 비교예 3Comparative Example 3 | 1:1.61:1.6 | 100 100 | 2727 | 24.524.5 | 2.02.0 |
화학식 2-1chemical formula 2-1 |
66.7%/ 99.5%66.7%/ 99.5% |
| 비교예 4Comparative Example 4 | 1:1.61:1.6 | 100 100 | 105105 | 24.524.5 | 2.02.0 |
화학식 2-1chemical formula 2-1 |
87.6%/ 96.8%87.6%/ 96.8% |
| 비교예 5Comparative Example 5 | 1:1.61:1.6 | 100 100 | 4747 | 13.013.0 | 2.02.0 |
화학식 2-1chemical formula 2-1 |
77.9%/ 99.5%77.9%/ 99.5% |
| 비교예 6Comparative Example 6 | 1:1.61:1.6 | 100 100 | 4747 | 60.060.0 | 2.02.0 |
화학식 2-1chemical formula 2-1 |
90.4%/ 96.2%90.4%/ 96.2% |
| 비교예 7Comparative Example 7 | 1:1.61:1.6 | 100 100 | 4747 | 24.524.5 | 0.230.23 |
화학식 2-1chemical formula 2-1 |
86.2%/ 89.4%86.2%/ 89.4% |
| 비교예 8Comparative Example 8 | 1:1.61:1.6 | 100 100 | 4747 | 24.524.5 | 5.205.20 |
화학식 2-1chemical formula 2-1 |
86.1%/ 97.7%86.1%/ 97.7% |
|
(1) 알파 할로 락톤계 화합물에 대한 중량비 (2) 1단계의 포스핀계화합물 1 당량에 대한 당량비 (3) 수율은 하기 수학식 1에 의거하여 측정 [수학식 1] 수율(%) = (반응생성물의 실제 수득량/반응생성물의 이론적 수득량)×100%(1) Weight ratio to alpha halolactone compound (2) Equivalent ratio with respect to 1 equivalent of the phosphine compound in the first step (3) Yield is measured according to Equation 1 below [Equation 1] Yield (%) = (actual yield of reaction product/theoretical yield of reaction product) × 100% |
|||||||
상기 표 1 및 표 2를 살펴보면, 실시예 1 ~ 11에서 제조한 메틸렌 락톤계 화합물은 70% 이상의 수율 및 98.5% 이상의 높은 순도로 수득할 수 있음을 확인할 수 있었다.이에 반해, 1단계에서 포스핀계 화합물을 0.9 중량비 미만으로 사용한 비교예 1의 경우, 실시예 3과 비교할 때, 수율이 급격하게 감소하는 문제가 있었으며, 포스핀계 화합물을 3.0 중량비를 초과한 3.5 중량비를 사용한 비교예 2의 경우, 실시예 1 및 실시예 4와 비교할 때, 수율 증대는 높지 않으면서, 순도만 크게 감소하는 문제가 있었다.Looking at Table 1 and Table 2, it was confirmed that the methylene lactone-based compounds prepared in Examples 1 to 11 could be obtained in a yield of 70% or more and a high purity of 98.5% or more. In contrast, in the first step, the phosphine-based compound In the case of Comparative Example 1 using the compound in a weight ratio of less than 0.9, compared to Example 3, there was a problem in that the yield decreased rapidly, and in the case of Comparative Example 2 using a 3.5 weight ratio exceeding 3.0 weight ratio of the phosphine compound, Compared to Examples 1 and 4, there was a problem in that only the purity was greatly reduced while the yield increase was not high.
또한, 2단계에서 염기를 30 중량부 미만인 27 중량부를 사용한 비교예 3의 경우, 실시예 1 및 실시예 5와 비교할 때, 수율이 70% 미만으로 급격하게 낮아지는 문제가 있었으며, 염기를 100 중량부 초과한 105 중량부를 사용한 비교예 4의 경우, 실시예 6과 비교할 때, 순도가 오히려 낮아졌는데 이는 과량의 염기가 불순물로 작용했기 때문으로 판단됩니다.In addition, in the case of Comparative Example 3 using 27 parts by weight of less than 30 parts by weight of the base in the second step, compared to Examples 1 and 5, there was a problem that the yield was rapidly lowered to less than 70%, and the base was 100 parts by weight In the case of Comparative Example 4 using more than 105 parts by weight, compared to Example 6, the purity was rather low, which is determined because the excess base acted as an impurity.
또한, 2단계에서 파라포름알데하이드를 15 중량부 미만인 13 중량부를 사용한 비교예 5의 경우, 실시예 7과 비교할 때, 순도는 다소 높지만 수율이 낮은 문제가 있고, 파라포름알데하이드를 50 중량부를 초과한 60 중량부를 사용한 비교예 6의 경우, 실시예 8과 비교할 때, 오히려 순도가 낮아지는 문제가 있었다.In addition, in the case of Comparative Example 5 using 13 parts by weight of less than 15 parts by weight of paraformaldehyde in the second step, compared to Example 7, the purity is somewhat higher, but the yield is low, and paraformaldehyde in excess of 50 parts by weight In the case of Comparative Example 6 using 60 parts by weight, compared to Example 8, there was a problem that the purity was rather low.
그리고, 3단계에서 금속염을 0.25 댱량비 미만으로 사용한 비교예 7의 경우, 실시예 9와 비교할 때, 순도가 급격하게 낮아지는 문제가 있음을 확인할 수 있었으며, 금속염을 5.00 댱량비를 초과 사용한 비교예 8의 경우, 실시예 10과 비교할 때 오히려 순도가 낮아지는 문제가 있었다.And, in the case of Comparative Example 7 in which the metal salt was used at a weight ratio of less than 0.25 in step 3, compared to Example 9, it was confirmed that there was a problem in that the purity was rapidly lowered, and the metal salt was used at a weight ratio of more than 5.00 Comparative Example In the case of 8, compared to Example 10, there was a problem that the purity was lowered.
상기와 같이 설명된 메틸렌 락톤계의 제조방법은 상기 설명된 실시예들의 구성과 방법이 한정되게 적용될 수 있는 것이 아니라, 상기 실시예들은 다양한 변형이 이루어질 수 있도록 각 실시예들의 전부 또는 일부가 선택적으로 조합되어 구성될 수도 있다.The method for producing the methylene lactone system described above is not limited to the configuration and method of the above-described embodiments, but all or part of each embodiment is selectively applied so that various modifications can be made. They may be configured in combination.
Claims (10)
- 알파 할로 락톤계 화합물, 포스핀계 화합물 및 유기용매를 혼합 및 반응을 수행한 후, 냉각시켜서 하기 화학식 1로 표시되는 포스포늄염을 제조하는 1단계;A first step of preparing a phosphonium salt represented by Formula 1 by mixing and reacting an alpha halolactone-based compound, a phosphine-based compound, and an organic solvent, followed by cooling;상기 포스포늄염, 염기, 파라포름알데히드 또는 포름알데히드, 및 유기용매를 혼합한 후, 인시투(in-situ) 반응시켜서 메틸렌 락톤계 화합물 및 포스핀계 산화물을 포함하는 용액을 제조하는 2단계;A second step of preparing a solution containing a methylene lactone-based compound and a phosphine-based oxide by mixing the phosphonium salt, a base, paraformaldehyde or formaldehyde, and an organic solvent, and then reacting in situ;2단계의 용액에 금속염을 투입하여, 포스핀계 산화물과 금속염을 반응시켜서 복합체를 형성시키는 3단계; 및A third step of adding a metal salt to the solution of step 2 and reacting the phosphine oxide with the metal salt to form a complex; and3단계를 수행한 용액 내 상기 복합체를 제거한 후, 농축 공정 및 진공증류 공정을 수행하여 하기 화학식 2로 표시되는 메틸렌 락톤계 화합물을 수득하는 4단계;Step 4 of obtaining a methylene lactone-based compound represented by Formula 2 below by removing the complex from the solution in Step 3 and then performing a concentration process and a vacuum distillation process;를 포함하는 것을 특징으로 하는 메틸렌 락톤계 화합물의 제조방법:Method for producing a methylene lactone-based compound comprising:[화학식 1][Formula 1]
화학식 1에 있어서, R1 내지 R3 각각은 독립적으로 C3~C4의 직쇄형 알킬기, 페닐기, 3-클로로페닐기, 3-메틸페닐기, 4-메틸페닐기, 3-메톡시페닐기, 4-메톡시페닐기 또는 페녹시기이며, X는 -F, -Cl, -Br 또는 -I이고, Y는이며, R4는 수소원자 또는 C1 ~ C5의 직쇄형 알킬기이고,In Formula 1, R 1 to R 3 are each independently a C 3 ~ C 4 straight-chain alkyl group, a phenyl group, a 3-chlorophenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group A oxyphenyl group or a phenoxy group, X is -F, -Cl, -Br or -I, Y is
And, R 4 is a hydrogen atom or a C 1 ~ C 5 linear alkyl group,[화학식 2][Formula 2]
화학식 2의 R4는 수소원자 또는 C1 ~ C5의 직쇄형 알킬기이다.R 4 in Formula 2 is a hydrogen atom or a C 1 to C 5 linear alkyl group. - 제1항에 있어서, 상기 알파 할로 락톤계 화합물은 알파 할로 부티로락톤 또는 알파 할로 발레로락톤을 포함하는 것을 특징으로 하는 메틸렌 락톤계 화합물의 제조방법.The method of claim 1, wherein the alpha halo lactone compound includes alpha halo butyrolactone or alpha halo valerolactone.
- 제1항에 있어서, 1단계의 포스핀계 화합물은 트리스(C3~4 알킬)포스핀, 트리페닐포스핀, 트리스(3-클로로페닐)포스핀, 트리스(4-클로로페닐)포스핀, 트리스(3-메틸페닐)포스핀, 트리스(4-메틸페닐)포스핀, 트리스(3-메톡시페닐)포스핀, 트리스(4-메톡시-페닐)포스핀, 페녹시다이페닐포스핀 및 다이페녹시페닐포스핀 중에서 선택된 1종 이상을 포함하고, The method of claim 1, wherein the phosphine compound of step 1 is tris (C 3 ~ 4 alkyl) phosphine, triphenylphosphine, tris (3-chlorophenyl) phosphine, tris (4-chlorophenyl) phosphine, tris (3-methylphenyl)phosphine, tris(4-methylphenyl)phosphine, tris(3-methoxyphenyl)phosphine, tris(4-methoxy-phenyl)phosphine, phenoxydiphenylphosphine and diphenoxy Including at least one selected from phenylphosphine,1단계의 상기 유기용매는 아세토니트릴, 테트라하이드로퓨란, 디메틸포름아마이드, 디메틸설폭사이드, 디메틸아세트아마이드, 아세톤 및 N-메틸피롤리돈 중에서 선택된 1종 이상을 포함하는 것을 특징으로 하는 메틸렌 락톤계 화합물의 제조방법.The organic solvent in step 1 comprises at least one selected from acetonitrile, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, acetone and N-methylpyrrolidone Methylene lactone-based compound Manufacturing method of.
- 제1항에 있어서, 1단계는 알파 할로 락톤계 화합물 및 포스핀계 화합물을 1 : 0.9 ~ 3.0 중량비로 혼합한 후, 반응을 수행하는 것을 특징으로 하는 메틸렌 락톤계 화합물의 제조방법.The method for preparing a methylene lactone-based compound according to claim 1, wherein in step 1, the reaction is performed after mixing the alpha halo lactone-based compound and the phosphine-based compound in a weight ratio of 1:0.9 to 3.0.
- 제1항에 있어서, 2단계의 상기 염기는 유기염기 및 무기염기 중에서 선택된 1종 이상을 포함하고,The method of claim 1, wherein the base in step 2 includes at least one selected from organic bases and inorganic bases,상기 유기염기는 트리에틸아민, 디이소프로필에틸아민, 다이메틸아민 및 다이에틸아민 중에서 선택된 1종 이상을 포함하며,The organic base includes at least one selected from triethylamine, diisopropylethylamine, dimethylamine and diethylamine,상기 무기염기는 소듐 t-부톡사이드, 포타슘 t-부톡사이드, 소듐 하이드라이드, 소듐 메톡사이드, 소듐 에톡사이드, 리튬 하이드라이드, 리튬 하이드록사이드, 리튬 t-부톡사이드, 리튬 메톡사이드, 리튬 에톡사이드, 소듐 하이드록사이드 및 포타슘 하이드록사이드 중에서 선택된 1종 이상을 포함하는 것을 특징으로 하는 메틸렌 락톤계 화합물의 제조방법.The inorganic base is sodium t-butoxide, potassium t-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, lithium hydride, lithium hydroxide, lithium t-butoxide, lithium methoxide, lithium ethoxide , A method for producing a methylene lactone-based compound comprising at least one selected from sodium hydroxide and potassium hydroxide.
- 제1항에 있어서, 3단계의 금속염은 금속 할라이드, 금속 설페이트, 금속 나이트레이트, 금속 퍼클로레이트, 금속 바이카보네이트, 금속 카보네이트, 금속 아세테이트, 금속 시트레이트, 금속 벤조에이트염, 이들의 수화물 또는 이들의 유기솔베이트를 포함하며,The metal salt of claim 1, wherein the metal salt of step 3 is a metal halide, metal sulfate, metal nitrate, metal perchlorate, metal bicarbonate, metal carbonate, metal acetate, metal citrate, metal benzoate salt, a hydrate thereof, or an organic salt thereof. Contains sorbate,상기 금속은 리튬, 나트륨, 포타슘, 마그네슘, 칼슘, 바륨, 스트론튬, 사미리움(III), 아연, 철(II), 철(III), 망간(II), 코발트(II), 코발트(III), 니켈, 구리(I) 또는 구리(II)을 포함하는 것을 특징으로 하는 메틸렌 락톤계 화합물의 제조방법.The metal is lithium, sodium, potassium, magnesium, calcium, barium, strontium, samirium (III), zinc, iron (II), iron (III), manganese (II), cobalt (II), cobalt (III), A method for producing a methylene lactone-based compound comprising nickel, copper (I) or copper (II).
- 제1항에 있어서, 2단계는 인시투 반응은 상기 포스포늄염 100 중량부에 대하여, 상기 염기 30 ~ 100 중량부 및 파라포름알데히드 또는 포름알데히드 15 ~ 50 중량부로 혼합한 후 반응을 수행하는 것을 특징으로 하는 메틸렌 락톤계 화합물의 제조방법.The method of claim 1, wherein the second step is to perform the reaction after mixing 30 to 100 parts by weight of the base and 15 to 50 parts by weight of paraformaldehyde or formaldehyde with respect to 100 parts by weight of the phosphonium salt. Method for producing a methylene lactone-based compound characterized by
- 제1항에 있어서, 1단계의 반응은 60 ~ 80℃에서 8 ~ 16시간 동안 수행하고, The method of claim 1, wherein the first step reaction is carried out at 60 ~ 80 ℃ for 8 ~ 16 hours,2단계의 인시투 반응은 60 ~ 80℃에서 1 ~ 4 시간 동안 수행하는 것을 특징으로 하는 메틸렌 락톤계 화합물의 제조방법.The method for producing a methylene lactone-based compound, characterized in that the two-step in-situ reaction is performed at 60 to 80 ° C. for 1 to 4 hours.
- 제1항에 있어서, 3단계의 금속염은 1단계의 포스핀계 화합물 1당량 당 1.50 ~ 3.00 당량으로 투입하는 것을 특징으로 하는 메틸렌 락톤계 화합물의 제조방법.The method for preparing a methylene lactone-based compound according to claim 1, wherein the metal salt in step 3 is added in an amount of 1.50 to 3.00 equivalent per 1 equivalent of the phosphine-based compound in step 1.
- 제1항 내지 제9항 중에서 선택된 어느 한 항에 있어서, 하기 수학식 1에 의거하여 측정시 수율이 70% 이상이고, According to any one selected from claims 1 to 9, the yield is 70% or more when measured based on Equation 1 below,순도가 98% 이상인 것을 특징으로 하는 메틸렌 락톤계 화합물의 제조방법;A method for producing a methylene lactone-based compound characterized in that the purity is 98% or more;[수학식 1][Equation 1]수율(%) = (반응생성물의 실제 수득량/반응생성물의 이론적 수득량)×100%Yield (%) = (actual yield of reaction product/theoretical yield of reaction product) × 100%
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