KR102481697B1 - Preparing method of ectoine and Ectoine prepared by the same method - Google Patents
Preparing method of ectoine and Ectoine prepared by the same method Download PDFInfo
- Publication number
- KR102481697B1 KR102481697B1 KR1020220018050A KR20220018050A KR102481697B1 KR 102481697 B1 KR102481697 B1 KR 102481697B1 KR 1020220018050 A KR1020220018050 A KR 1020220018050A KR 20220018050 A KR20220018050 A KR 20220018050A KR 102481697 B1 KR102481697 B1 KR 102481697B1
- Authority
- KR
- South Korea
- Prior art keywords
- acid
- ectoin
- reaction
- sodium
- solution
- Prior art date
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- WQXNXVUDBPYKBA-YFKPBYRVSA-N ectoine Chemical compound CC1=[NH+][C@H](C([O-])=O)CCN1 WQXNXVUDBPYKBA-YFKPBYRVSA-N 0.000 title claims abstract description 72
- 238000000034 method Methods 0.000 title claims abstract description 48
- WQXNXVUDBPYKBA-UHFFFAOYSA-N Ectoine Natural products CC1=NCCC(C(O)=O)N1 WQXNXVUDBPYKBA-UHFFFAOYSA-N 0.000 title abstract description 5
- OGNSCSPNOLGXSM-VKHMYHEASA-N L-2,4-diaminobutyric acid Chemical compound NCC[C@H](N)C(O)=O OGNSCSPNOLGXSM-VKHMYHEASA-N 0.000 claims abstract description 35
- 238000004519 manufacturing process Methods 0.000 claims abstract description 26
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 24
- -1 ectoine compound Chemical class 0.000 claims abstract description 20
- 230000008569 process Effects 0.000 claims abstract description 18
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 15
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims abstract description 9
- 229930182816 L-glutamine Natural products 0.000 claims abstract description 8
- 238000010924 continuous production Methods 0.000 claims abstract description 7
- LGRFSURHDFAFJT-UHFFFAOYSA-N phthalic anhydride Chemical compound C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 43
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- JMKLVQRQCLMCIN-VIFPVBQESA-N (2s)-5-amino-2-(1,3-dioxoisoindol-2-yl)-5-oxopentanoic acid Chemical compound C1=CC=C2C(=O)N([C@@H](CCC(=O)N)C(O)=O)C(=O)C2=C1 JMKLVQRQCLMCIN-VIFPVBQESA-N 0.000 claims description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 26
- 239000003153 chemical reaction reagent Substances 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
- 239000002585 base Substances 0.000 claims description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- 238000007167 Hofmann rearrangement reaction Methods 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 18
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 18
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 17
- 229910052740 iodine Inorganic materials 0.000 claims description 17
- 239000011630 iodine Substances 0.000 claims description 17
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 16
- 239000011259 mixed solution Substances 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 13
- 150000002366 halogen compounds Chemical class 0.000 claims description 13
- 150000007530 organic bases Chemical class 0.000 claims description 13
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 12
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 12
- 239000007795 chemical reaction product Substances 0.000 claims description 11
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 11
- 150000007529 inorganic bases Chemical class 0.000 claims description 11
- 238000010992 reflux Methods 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 9
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 9
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 9
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 9
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 9
- 150000007524 organic acids Chemical class 0.000 claims description 9
- 235000005985 organic acids Nutrition 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- LRIUKPUCKCECPT-UHFFFAOYSA-N [hydroxy(phenyl)-$l^{3}-iodanyl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OI(O)C1=CC=CC=C1 LRIUKPUCKCECPT-UHFFFAOYSA-N 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- PEZNEXFPRSOYPL-UHFFFAOYSA-N (bis(trifluoroacetoxy)iodo)benzene Chemical compound FC(F)(F)C(=O)OI(OC(=O)C(F)(F)F)C1=CC=CC=C1 PEZNEXFPRSOYPL-UHFFFAOYSA-N 0.000 claims description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 7
- 239000012312 sodium hydride Substances 0.000 claims description 7
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 claims description 6
- BBMCTIGTTCKYKF-UHFFFAOYSA-N 1-heptanol Chemical compound CCCCCCCO BBMCTIGTTCKYKF-UHFFFAOYSA-N 0.000 claims description 6
- YIWUKEYIRIRTPP-UHFFFAOYSA-N 2-ethylhexan-1-ol Chemical compound CCCCC(CC)CO YIWUKEYIRIRTPP-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 6
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 claims description 6
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 claims description 6
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 6
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 claims description 6
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 6
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 claims description 6
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 241000801593 Pida Species 0.000 claims description 5
- 239000011260 aqueous acid Substances 0.000 claims description 5
- 238000010923 batch production Methods 0.000 claims description 5
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 5
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical group [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- IBJMAUSPTVZWBK-UHFFFAOYSA-N [2-(2,2-dimethylpropanoyloxy)-3-iodophenyl] 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC1=CC=CC(I)=C1OC(=O)C(C)(C)C IBJMAUSPTVZWBK-UHFFFAOYSA-N 0.000 claims description 4
- SUYFTODEECUFSU-UHFFFAOYSA-N [methoxy(phenyl)-$l^{3}-iodanyl] 4-methylbenzenesulfonate Chemical compound C=1C=CC=CC=1I(OC)OS(=O)(=O)C1=CC=C(C)C=C1 SUYFTODEECUFSU-UHFFFAOYSA-N 0.000 claims description 4
- 150000001339 alkali metal compounds Chemical class 0.000 claims description 4
- 150000001341 alkaline earth metal compounds Chemical class 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- OQWAXRPJEPTTSZ-UHFFFAOYSA-N [(2,3,4,5,6-pentafluorophenyl)-(2,2,2-trifluoroacetyl)oxy-$l^{3}-iodanyl] 2,2,2-trifluoroacetate Chemical compound FC1=C(F)C(F)=C(I(OC(=O)C(F)(F)F)OC(=O)C(F)(F)F)C(F)=C1F OQWAXRPJEPTTSZ-UHFFFAOYSA-N 0.000 claims description 3
- KCSMJUHAWHWVMR-UHFFFAOYSA-N [acetyloxy-(2-nitrophenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1[N+]([O-])=O KCSMJUHAWHWVMR-UHFFFAOYSA-N 0.000 claims description 3
- HHJIDOMMYDNFCA-UHFFFAOYSA-N [acetyloxy-(4-methylphenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=C(C)C=C1 HHJIDOMMYDNFCA-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- WACNXHCZHTVBJM-UHFFFAOYSA-N 1,2,3,4,5-pentafluorobenzene Chemical compound FC1=CC(F)=C(F)C(F)=C1F WACNXHCZHTVBJM-UHFFFAOYSA-N 0.000 claims description 2
- BWDBEAQIHAEVLV-UHFFFAOYSA-N 6-methylheptan-1-ol Chemical compound CC(C)CCCCCO BWDBEAQIHAEVLV-UHFFFAOYSA-N 0.000 claims description 2
- 229940008099 dimethicone Drugs 0.000 claims 1
- 239000004205 dimethyl polysiloxane Substances 0.000 claims 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 13
- 238000006462 rearrangement reaction Methods 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract description 3
- 238000007670 refining Methods 0.000 abstract 1
- 238000004904 shortening Methods 0.000 abstract 1
- 238000007086 side reaction Methods 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 238000000354 decomposition reaction Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000003507 refrigerant Substances 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- BLCJBICVQSYOIF-UHFFFAOYSA-N 2,2-diaminobutanoic acid Chemical compound CCC(N)(N)C(O)=O BLCJBICVQSYOIF-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 229920002674 hyaluronan Polymers 0.000 description 3
- 229960003160 hyaluronic acid Drugs 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 3
- 229940011051 isopropyl acetate Drugs 0.000 description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- HDPNBNXLBDFELL-UHFFFAOYSA-N 1,1,1-trimethoxyethane Chemical compound COC(C)(OC)OC HDPNBNXLBDFELL-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 2
- 206010013774 Dry eye Diseases 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 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 description 2
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- 108090000340 Transaminases Proteins 0.000 description 1
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- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
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- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 108010023417 cholesterol dehydrogenase Proteins 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
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- 238000006297 dehydration reaction Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000000835 electrochemical detection Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229940116332 glucose oxidase Drugs 0.000 description 1
- 235000019420 glucose oxidase Nutrition 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 229940046892 lead acetate Drugs 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
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- 229930014626 natural product Natural products 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 238000007867 post-reaction treatment Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
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- 230000002265 prevention Effects 0.000 description 1
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- 238000009938 salting Methods 0.000 description 1
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- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 108010085346 steroid delta-isomerase Proteins 0.000 description 1
- 230000004488 tear evaporation Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Images
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
본 발명은 엑토인인 (S)-1,4,5,6-테트라하이드로-2-메틸-4-피리미딘카르복실산을 낮은 비용으로 대량생산할 수 있는 제조방법에 관한 것이다.The present invention relates to a method for mass-producing ectoin (S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid at a low cost.
엑토인(Ectoine)은 (S)-1,4,5,6-테트라하이드로-2-메틸-4-피리미딘카르복실산으로써, 여러 종의 박테리아에서 발견되는 천연화합물이다. 극한 환경(예를 들어 소금호수, 온천, 영구 빙설 등)에 사는 미생물로부터 얻어진 천연물질로서 극한환경에서 스스로를 보호하기 위해 천연물질 엑토인을 형성한다. 엑토인의 분자구조는 하기 화학식 1에 의해 나타낼 수 있다.Ectoine is (S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid, a natural compound found in several species of bacteria. It is a natural substance obtained from microorganisms living in extreme environments (for example, salt lakes, hot springs, permanent ice and snow, etc.) and forms natural substances ectoin to protect itself in extreme environments. The molecular structure of ectoin can be represented by Formula 1 below.
[화학식 1][Formula 1]
엑토인은 친수성 미생물에서 고농도로 발견되며, 자연계에서 호염성 박테리아 예컨데 할로모나스 엘롱가타(Halomonas elongate)를 통한 박테리아 과정을 통해서 자연적으로 생산되는 복소환 아미노산이다.( E. A. Galinski et al., Eur. J. Biochem., 149(1985) pages 135-139.) Ectoin is a heterocyclic amino acid that is found in high concentrations in hydrophilic microorganisms and is naturally produced through bacterial processes by halophilic bacteria such as Halomonas elongate in nature (EA Galinski et al., Eur. J Biochem., 149 (1985) pages 135-139.)
엑토인은 할로모나스 엘롱가타로 불리는 호열성 박테리아로부터 추출될 수 있고, 여기서 엑토인은 박테리아에서 삼투압을 보상하고 생체중합체를 안정화시켜 탈수, 고온 및 UV-손상으로부터 박테리아를 보호한다. Ectoin can be extracted from a thermophilic bacterium called Halomonas elongata, wherein ectoin compensates for osmotic pressure in the bacteria and stabilizes biopolymers to protect the bacteria from dehydration, high temperature and UV-damage.
엑토인은 보습력이 탁월하며, 항산화제(antioxidant)나 방부제(preservative)없이도 매우 높은 안정성을 유지하며, 화장품용으로 사용가능한 제품이며 머크(Merck)사에서 로나케어 히드로인(RonaCare® hydroine) 제품이 판매되고 있는 실정이다. Ectoin has excellent moisturizing power, maintains very high stability without antioxidants or preservatives, and can be used for cosmetics. Merck's RonaCare® hydroine product is It is currently on sale.
그 외에도 미세먼지의 영향에 의해 유발된 폐질환의 치료가 국제 공개특허공보 WO 2005-002556에 기술되어 있고, 바이오센서에서의 엑토인에 의한 글루코오스 옥시다아제의 안정화가 국제 공개특허공보 WO 2007-097653에 기재되어 있으며, 효소 활성의 전기화학적 검출을 목적으로 콜레스테롤 디히드로게나아제를 포함하는 콜레스테롤 바이오센서에서의 시약으로 국제 공개특허공보 WO 2007-132226에서 보고된 바 있다. In addition, treatment of lung diseases caused by the influence of fine dust is described in International Patent Publication WO 2005-002556, and stabilization of glucose oxidase by ectoin in a biosensor is disclosed in International Patent Publication WO 2007-097653 It has been described and reported in International Patent Publication No. WO 2007-132226 as a reagent in a cholesterol biosensor including cholesterol dehydrogenase for the purpose of electrochemical detection of enzyme activity.
최근에는 안과학적으로 사용 가능함이 밝혀지고 있는데, 유럽 등록특허 EP0671161 B1에서는 피부의 수분함량을 증가시키는 화장품에서 보습제로 사용될 수 있는 것을 기재하고 있고, DE 102014007423에서는 엑토인을 함유하는 눈의 염증 치료용 조성물이 개시되어 있다. 이 특허에서는 건성각 결막염(Kerotoconjunctivities sicca)을 치료하는 것이 히알루논산(Hyaluronic acid) 용액으로 치료하는 것보다 다소 효과적이라는 것이 밝혀짐으로써 기존의 인공눈물로 사용되었던 히알루논산과 더불어 엑토인의 사용범위가 더 넓어질 수 있다는 것을 의미한다. Recently, it has been found that it can be used in ophthalmology, and European registered patent EP0671161 B1 describes that it can be used as a moisturizer in cosmetics that increase the moisture content of the skin, and DE 102014007423 for treating inflammation of the eye containing ectoin A composition is disclosed. In this patent, it was found that treating keratoconjunctivitis sicca is somewhat more effective than treating with a hyaluronic acid solution, thereby extending the range of use of ectoin along with hyaluronic acid, which was used as an artificial tear. This means it can be wider.
히알루논산과 엑토인을 같이 사용하면, 눈물의 증발로부터 보호가 오래지속 되며, 안구 건조증 즉 건조 증후군(sicca syndrome)의 치료 또는 예방, 결막염(conjunctivitis) 그리고 고초열(hayfever)의 치료 및 예방에 적합한 것으로 보고되고 있다. The combination of hyaluronic acid and ectoin provides long-lasting protection against tear evaporation and is suitable for the treatment or prevention of dry eye syndrome (sicca syndrome), conjunctivitis and hayfever. It is reported as
엑토인의 제조방법을 살펴보면, 현재는 주로 생합성경로(Biosynthetic pathway)로 생산하고 있으며, 독일의 비톱(Bitop AG)사가 유일하다. 엑토인 생합성은 디아미노부타이릭산(DABA) 아미노트랜스퍼라제(EctB), 아세틸트랜스퍼라제(EctA) 그리고 엑토인 신터세이즈(EctC)를 사용하는 방법이며, 하기 제조방법에 자세하게 개시되어 있다(하기 반응식 1 참조). Looking at the manufacturing method of ectoin, it is currently mainly produced through the biosynthetic pathway, and Germany's Bitop AG is the only one. Ectoin biosynthesis is a method using diaminobutyric acid (DABA) aminotransferase (EctB), acetyltransferase (EctA) and ectoin synthetase (EctC), and is disclosed in detail in the following preparation method (the following reaction scheme 1).
[반응식 1][Scheme 1]
원개발사인 비톱사가 개발한 방법으로써, 바이오밀킹(Biomilking)이라고도 불리우며, 생산품 용액을 전기영동과 크로마토그래피, 여과 후 농축 결정화를 진행하여 얻으며, 최근에는 H. elongata의 연속적인 발효공정으로 대량생산 방법을 개발하였다고 보고하고 있다. 이 공정을 영구 밀킹(permanent milking) 프로세스라 불리우고 있다. It is a method developed by Bitop, the original developer, and is also called Biomilking. The product solution is obtained by electrophoresis, chromatography, and filtration followed by concentration and crystallization. It is reported that the method has been developed. This process is called the permanent milking process.
또한, 비톱사는 아미노아실레이즈를 이용한 하기 반응식 2에 따른 제조방법을 개발한 바 있으나, 합성공정이 길어서 엑토인의 제조원가와 경제성 면에서는 비효율적인 방법이다. In addition, Bitop has developed a manufacturing method according to Scheme 2 below using aminoacylase, but it is an inefficient method in terms of manufacturing cost and economic feasibility of ectoin because the synthesis process is long.
[반응식 2] [Scheme 2]
중국 등록특허 CN108003105에서는 아세틸-L-글루타민을 이용하여 엑토인을 합성하는 방법을 기술하고 있는데, 대량생산에는 적합하지 않은 디사이클로헥산카보디이미드(DCC), 소듐하이드라이드(NaH), 트리에틸실란(Et3SiH)을 사용하는 공정이어서 소량으로는 제조 가능하지만, 대량생산에는 적합하지 않은 방법이다(하기 반응식 3 참조). Chinese registered patent CN108003105 describes a method for synthesizing ectoin using acetyl-L-glutamine, but dicyclohexanecarbodiimide (DCC), sodium hydride (NaH), triethylsilane, Since it is a process using (Et 3 SiH), it can be produced in small quantities, but is not suitable for mass production (see Scheme 3 below).
[반응식 3][Scheme 3]
상기 문헌들의 문제점을 해결하고자, 본 발명에서는 경제적인 방법과 대량생산에 적합한 방법을 강구하였으며, 새로운 제조방법을 개발하게 되었다.In order to solve the problems of the above documents, in the present invention, an economical method and a method suitable for mass production were sought, and a new manufacturing method was developed.
본 발명은 상기 종래 기술의 문제를 해결하기 위하여 안출된 것으로서, 고압반응기 같은 고가의 제조설비가 불필요하면서도, 반응 및 반응 후 처리가 간편하며, 공정을 획기적으로 줄임으로써 효율적으로 엑토인 화합물을 제조하는 방법을 제공하는 것을 목적으로 한다.The present invention has been made to solve the problems of the prior art, and expensive manufacturing equipment such as a high-pressure reactor is unnecessary, the reaction and post-reaction treatment are simple, and the process is dramatically reduced to efficiently produce an ectoin compound. It aims to provide a method.
이와 같은 본 발명의 해결 과제를 달성하기 위한 엑토인의 제조방법은 L-글루타민과 프탈산무수물을 염기 수용액 하에서 반응시켜서 프탈릭-L-글루타민을 제조하는 1단계; 하이포할라이트(hypohalite) 또는 하이퍼발란트아이오딘(Hypervalent iodine) 시약 존재 하에서, 상기 프탈릭-L-글루타민을 호프만 재배열 반응(또는 호프만 분해반응)을 수행하여 (S)-4-아미노-2-(프탈릴)-부타노익산을 합성한 후, 탈보호화 반응을 수행하여 (S)-2,4-디아미노 부타노익산 또는 이의 염을 제조하는 2단계; 상기 (S)-2,4-디아미노 부타노익산 또는 이의 염을 반응용매와 혼합하여 혼합액을 제조하고, 상기 혼합액을 염기성 조건에서 환류 교반하여 고리화 반응을 수행한 후, 농축 및 결정화 공정을 수행하여 하기 화학식 1로 표시되는 엑토인을 수득하는 3단계;를 포함하는 공정을 수행하여 엑토인((S)-1,4,5,6-테트라하이드로-2-메틸-4-피리미딘카르복실산)을 제조할 수 있다.The method for producing ectoin to achieve the object of the present invention includes a first step of preparing phthalic-L-glutamine by reacting L-glutamine and phthalic anhydride in an aqueous base solution; In the presence of hypohalite or hypervalent iodine reagent, the phthalic-L-glutamine is subjected to a Hoffman rearrangement reaction (or a Hoffman degradation reaction) to (S)-4-amino-2 After synthesizing -(phthalyl)-butanoic acid, a second step of preparing (S)-2,4-diaminobutanoic acid or a salt thereof by performing a deprotection reaction; The (S) -2,4-diamino butanoic acid or its salt is mixed with a reaction solvent to prepare a mixed solution, and a cyclization reaction is performed by stirring the mixed solution under reflux under basic conditions, followed by concentration and crystallization. ectoin ((S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecar boxylic acid) can be prepared.
본 발명의 바람직한 일실시예로서, 상기 2단계의 호프만 재배열 반응(또는 호프만 분해반응) 및 탈보호화 반응은 연속식(continuous) 공정 또는 배치식(batch) 공정으로 수행할 수 있다.As a preferred embodiment of the present invention, the two-step Hofmann rearrangement reaction (or Hoffman decomposition reaction) and deprotection reaction may be carried out in a continuous process or a batch process.
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[화학식 1][Formula 1]
본 발명의 바람직한 일실시예로서, 상기 2단계의 호프만 재배열 반응(또는 호프만 분해반응) 및 탈보호화 반응은 연속식(continuous) 공정 또는 배치식(batch) 공정으로 수행할 수 있다.As a preferred embodiment of the present invention, the two-step Hofmann rearrangement reaction (or Hoffman decomposition reaction) and deprotection reaction may be carried out in a continuous process or a batch process.
본 발명의 바람직한 일실시예로서, 상기 2단계를 배치식 공정으로 수행시, 상기 2단계는, 하이포할라이트(hypohalite) 또는 하이퍼발란트아이오딘(Hypervalent iodine) 시약 존재 하에서, 상기 프탈릭-L-글루타민을 호프만 재배열 반응을 수행한 후, 추출, 농축, 결정화시켜서 (S)-4-아미노-2-(프탈릴)-부타노익산을 수득하는 2-1단계; 및 상기 (S)-4-아미노-2-(프탈릴)-부타노익산을 탈보호화 반응시킨 후 농축 및 결정화하여 (S)-2,4-디아미노 부타노익산 또는 이의 염을 제조하는 2-2단계;를 수행할 수도 있다.As a preferred embodiment of the present invention, when the second step is performed as a batch process, the second step is performed in the presence of hypohalite or hypervalent iodine reagent, the phthalic-L -Step 2-1 of obtaining (S)-4-amino-2-(phthalyl)-butanoic acid by subjecting glutamine to Hoffman rearrangement reaction, followed by extraction, concentration, and crystallization; and 2 for preparing (S)-2,4-diaminobutanoic acid or a salt thereof by concentrating and crystallizing the (S)-4-amino-2-(phthalyl)-butanoic acid after deprotection. -Step 2; can also be performed.
본 발명의 바람직한 일실시예로서, 1단계의 상기 염기 수용액은 유기염기 및 무기염기 중에서 선택된 1종 이상을 포함할 수 있다. As a preferred embodiment of the present invention, the aqueous base solution in the first step may include at least one selected from organic bases and inorganic bases.
본 발명의 바람직한 일실시예로서, 1단계의 상기 유기염기는 트리에틸아민, 디이소프로필에틸아민, 다이메틸아민, 피리딘 및 다이에틸아민 중에서 선택된 1종 이상을 포함할 수 있다.As a preferred embodiment of the present invention, the organic base of step 1 may include at least one selected from triethylamine, diisopropylethylamine, dimethylamine, pyridine, and diethylamine.
본 발명의 바람직한 일실시예로서, 1단계의 상기 무기염기는 중탄산나트륨, 탄산나트륨, 중탄산칼륨, 탄산칼륨, 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 in step 1 is sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium-t-butoxide, potassium-t-butoxide, sodium hydride, sodium methoxide, sodium At least one selected from ethoxide, lithium hydride, lithium hydroxide, lithium-t-butoxide, lithium methoxide, lithium ethoxide, sodium hydroxide and potassium hydroxide may be included.
본 발명의 바람직한 일실시예로서, 2단계 또는 2-1단계의 상기 하이퍼발란트 아이오딘 시약, (다이아세톡시아이오도)벤젠(PIDA), 비스(트리플루오로아세톡시)아이오도벤젠(PIFA), 비스(t-부틸카보닐옥시)아이오도벤젠(PhI(Piv)2), 아세트산 납(Lead IV acetate), [하이드록시(토실옥시)아이오도]벤젠(HTIB), [메톡시(토실옥시)아이오도]벤젠(MTIB) 및 4-(디아세톡시아이오도)톨루엔, 2-나이트로-(다이아세톡시아이오도)벤젠, 2-나이트로-(비스(트리플루오로아세톡시)아이오도벤젠, (다이아세톡시아이오도)펜타플루오로벤젠(C6F5I(OAc)2), 비스(트리플루오로아세톡시)아이오도펜타플루오로벤젠(C6F5I(CF3)2), 다이메톡시아이오도)벤젠(PIMA) 및 다이에톡시아이오도)벤젠(PIEA) 중에서 선택된 1종 이상을 포함할 수 있다. As a preferred embodiment of the present invention, the hypervalant iodine reagent of step 2 or step 2-1, (diacetoxyiodo) benzene (PIDA), bis (trifluoroacetoxy) iodobenzene (PIFA) ), bis(t-butylcarbonyloxy)iodobenzene (PhI(Piv) 2 ), lead IV acetate, [hydroxy(tosyloxy)iodo]benzene (HTIB), [methoxy(tosyl oxy)iodo]benzene (MTIB) and 4-(diacetoxyiodo)toluene, 2-nitro-(diacetoxyiodo)benzene, 2-nitro-(bis(trifluoroacetoxy)io Dobenzene, (diacetoxyiodo)pentafluorobenzene (C 6 F 5 I(OAc) 2 ), bis(trifluoroacetoxy)iodopentafluorobenzene (C 6 F 5 I(CF 3 ) 2 ), dimethoxyiodo)benzene (PIMA) and diethoxyiodo)benzene (PIEA).
본 발명의 바람직한 일실시예로서, 2단계의 상기 하이퍼발란트 아이오딘 시약의 사용량은 상기 프탈릴-L-글루타민 대비 0.9 ~ 3.0 당량비로 사용할 수 있다.As a preferred embodiment of the present invention, the amount of the hypervalant iodine reagent used in the second step may be used in an equivalent ratio of 0.9 to 3.0 compared to the phthalyl-L-glutamine.
본 발명의 바람직한 일실시예로서, 2단계 또는 2-1단계의 호프만 재배열 반응(호프만 분해 반응)을 하이퍼발란트 아이오딘 시약 하에서 수행시, 유기용매와 물의 혼합용매 하에서 수행하며, 상기 유기용매는 아세토니트릴, 테트라하이드로퓨란, 디메틸포름아마이드, 디메틸설폭사이드, 디메틸아세트아마이드, 아세톤, 에틸아세테이트, 메틸아세테이트, 아이소프로필아세테이트, 부틸아세테이트, 메틸렌클로라이드 및 N-메틸피롤리돈 중에서 선택된 1종 이상을 포함할 수 있다.As a preferred embodiment of the present invention, when the 2-step or 2-1 step Hofmann rearrangement reaction (Hoffman decomposition reaction) is performed in a HyperValant iodine reagent, it is performed in a mixed solvent of an organic solvent and water, and the organic solvent is at least one selected from acetonitrile, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, acetone, ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, methylene chloride and N-methylpyrrolidone can include
본 발명의 바람직한 일실시예로서, 2단계 또는 2-1단계의 호프만 재배열 반응(호프만 분해 반응)을 상기 하이포할라이트 존재 하에서 수행시에는 용매로서 물을 사용할 수 있다. As a preferred embodiment of the present invention, when the 2-step or 2-1-step Hofmann rearrangement reaction (Hoffman decomposition reaction) is performed in the presence of the hypohalite, water may be used as a solvent.
본 발명의 바람직한 일실시예로서, 상기 하이포할라이트는 할로겐 화합물과 알칼리 용액의 반응생성물이며, 하이포할라이트 존재 하에서 상기 호프만 재배열 반응(호프만 분해 반응) 수행시, 프탈릴-L-글루타민 및 물의 혼합액에 알칼리 용액과 할로겐 화합물을 투입하면 하이포할라이트가 생성된다.As a preferred embodiment of the present invention, the hypohalite is a reaction product of a halogen compound and an alkali solution, and when the Hofmann rearrangement reaction (Hoffman decomposition reaction) is performed in the presence of hypohalite, phthalyl-L-glutamine and water When an alkali solution and a halogen compound are added to the mixed solution, hypohalite is produced.
본 발명의 바람직한 일실시예로서, 상기 할로겐 화합물은 염소 또는 브롬을 포함하고, 상기 알칼리 용액은 알칼리 금속 화합물의 수용액 및 알칼리 토금속 화합물 수용액을 포함할 수 있다.As a preferred embodiment of the present invention, the halogen compound may include chlorine or bromine, and the alkali solution may include an aqueous solution of an alkali metal compound and an aqueous solution of an alkaline earth metal compound.
본 발명의 바람직한 일실시예로서, 할로겐 화합물 투입량은 프탈릴-L-글루타민 및 할로겐 화합물을 1 : 1 ~ 5 몰비로 사용할 수 있다. As a preferred embodiment of the present invention, the input amount of the halogen compound is phthalyl-L-glutamine and the halogen compound in a 1: 1 to 5 molar ratio.
본 발명의 바람직한 일실시예로서, 2단계 또는 2-2단계의 상기 탈보호 반응은 산 수용액 또는 염기 수용액 하에서 수행할 수 있다.As a preferred embodiment of the present invention, the deprotection reaction in step 2 or step 2-2 may be performed in an aqueous acid solution or an aqueous base solution.
본 발명의 바람직한 일실시예로서, 탈보호 반응에 사용되는 상기 산 수용액은 염산, 황산, 브롬산, 술폰산, 벤젠술폰산, 켐퍼술폰산, 아세트산, 트리플루오로 아세트산, 메탄설폰산, 인산 및 유기산 중에서 선택된 1종 이상을 포함할 수 있다.As a preferred embodiment of the present invention, the aqueous acid solution used in the deprotection reaction is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, sulfonic acid, benzenesulfonic acid, camphorsulfonic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, phosphoric acid and organic acids. One or more may be included.
본 발명의 바람직한 일실시예로서, 탈보호 반응에 사용되는 상기 염기 수용액은 하이드라진 화합물을 포함할 수 있고, 상기 하이드라진 화합물은 하이드라진 무수물 또는 하이드라진 수화물을 포함할 수 있다.As a preferred embodiment of the present invention, the aqueous base solution used in the deprotection reaction may include a hydrazine compound, and the hydrazine compound may include hydrazine anhydride or hydrazine hydrate.
본 발명의 바람직한 일실시예로서, 2단계 또는 2-2단계의 상기 (S)-2,4-디아미노 부타노익산염은 (S)-2,4-디아미노 부타노익산을 황산, 초산, 인산, 트리플루오로 아세트산, 브롬산, 벤젠술폰산, 캠퍼술폰산 및 유기산 중에서 선택된 1종 이상을 포함하는 산용액으로 염처리하여 제조할 수 있다.As a preferred embodiment of the present invention, the (S) -2,4-diamino butanoic acid salt of step 2 or 2-2 is (S) -2,4-diamino butanoic acid in sulfuric acid, acetic acid , Phosphoric acid, trifluoroacetic acid, hydrobromic acid, benzenesulfonic acid, camphorsulfonic acid, and can be prepared by salt treatment with an acid solution containing at least one selected from organic acids.
본 발명의 바람직한 일실시예로서, 2단계 수행 후 별도의 정제 공정 없이 3단계를 수행할 수도 있다.As a preferred embodiment of the present invention, after performing the second step, the third step may be performed without a separate purification process.
본 발명의 바람직한 일실시예로서, 3단계의 염기성 조건은 (S)-2,4-디아미노부타노익산 또는 이의 염 대비 1.0 ~ 3.0 당량비의 염기를 상기 혼합액에 투입하여 형성시킬 수 있다.As a preferred embodiment of the present invention, the basic condition of the third step may be formed by introducing a base in an equivalent ratio of 1.0 to 3.0 to (S) -2,4-diaminobutanoic acid or a salt thereof into the mixed solution.
본 발명의 바람직한 일실시예로서, 3단계의 상기 염기는 유기염기 및 무기염기 중에서 선택된 1종 이상을 포함하고, 상기 유기염기는 트리에틸아민, 디이소프로필에틸아민, 다이메틸아민, 피리딘, 다이에틸아민 중에서 선택된 1종 이상을 포함할 수 있으며, 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 base of step 3 includes at least one selected from organic bases and inorganic bases, and the organic base is triethylamine, diisopropylethylamine, dimethylamine, pyridine, It may include at least one selected from ethylamine, and the inorganic base is sodium-t-butoxide, potassium-t-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, lithium hydride, lithium hydroxide Side, lithium-t-butoxide, lithium methoxide, lithium ethoxide, sodium hydroxide and potassium hydroxide may include at least one selected from.
본 발명의 바람직한 일실시예로서, 3단계의 상기 반응용매는 메탄올, 에탄올, 프로판올, 이소프로판올, n-부탄올, 이소부탄올, sec-부탄올, tert-부탄올, 펜탄올, 헥산올, 헵탄올, 옥탄올, 아이소옥탄올 및 2-에틸헥산올 중에서 선택된 1종 이상을 포함할 수 있다.As a preferred embodiment of the present invention, the reaction solvent in step 3 is methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, pentanol, hexanol, heptanol, and octanol. , isooctanol and 2-ethylhexanol.
본 발명의 바람직한 일실시예로서, 3단계의 상기 혼합액은 (S)-2,4-디아미노부타노익산 또는 이의 염 대비 1.0 ~ 3.0 당량비의 트리알킬오르소아세테이트(Trialkylorthoacetate) 또는 알킬아세트이미데이트(Alkylacetimidate)를 포함할 수 있다.As a preferred embodiment of the present invention, the mixed solution in step 3 is (S) -2,4-diaminobutanoic acid or a salt thereof in an amount of 1.0 to 3.0 equivalent ratio of trialkylorthoacetate or alkylacetimidate. (Alkylacetimidate) may be included.
본 발명의 바람직한 일실시예로서, 상기 알킬아세트이미데이트는 하기 화학식 5로 표시되는 화합물을 포함할 수 있다.As a preferred embodiment of the present invention, the alkylacetimidate may include a compound represented by Formula 5 below.
[화학식 5][Formula 5]
CH3C(=NH)OR·HClCH 3 C(=NH)OR HCl
화학식 5에서, R은 C1~C8의 직쇄형 알킬기이다. In Formula 5, R is a C 1 to C 8 straight-chain alkyl group.
본 발명의 바람직한 일실시예로서, 본 발명의 엑토인 제조방법은, 3단계에서 수득한 엑토인을 염산, 황산, 초산, 인산, 트리플루오로아세트산, 브롬산, 벤젠술폰산, 캠퍼술폰산 및 유기산 중에서 선택된 1종 이상을 포함하는 산용액으로 염 처리하는 공정을 더 수행할 수도 있다.As a preferred embodiment of the present invention, in the method for preparing ectoin of the present invention, the ectoin obtained in step 3 is mixed with hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, trifluoroacetic acid, hydrobromic acid, benzenesulfonic acid, camphorsulfonic acid and organic acids. A process of salt treatment with an acid solution containing at least one selected species may be further performed.
본 발명의 바람직한 일실시예로서, 3단계의 고리화 반응은 50 ~ 180℃에서 2 ~ 48 시간 동안 수행할 수 있다.As a preferred embodiment of the present invention, the three-step cyclization reaction may be performed at 50 to 180 ° C. for 2 to 48 hours.
본 발명의 바람직한 일실시예로서, 앞서 설명한 제조방법을 통해서, 전체 수율 40.0% 이상 및 순도 99.0% 이상인 엑토인((S)-1,4,5,6-테트라하이드로-2-메틸-4-피리미딘카르복실산 화합물)을 제조할 수 있다. As a preferred embodiment of the present invention, ectoin ((S)-1,4,5,6-tetrahydro-2-methyl-4- having a total yield of 40.0% or more and a purity of 99.0% or more through the above-described preparation method pyrimidine carboxylic acid compound) can be prepared.
본 발명의 다른 목적은 앞서 설명한 제조방법으로 제조한 고수율, 고순도의 엑토인을 제공하는데 있다.Another object of the present invention is to provide high-yield, high-purity ectoin prepared by 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, 반응조건이 압력이 불필요하며 제조공정이 단순하면서도 간결하며, 높은 수율 및 높은 순도로 목적 화합물인 엑토인을 높은 생산성, 상업적으로 제조할 수 있다.The manufacturing method of the present invention can effectively purify (or remove) reaction by-products generated during the manufacturing process in the same manufacturing process without a separate purification process, the reaction conditions do not require pressure, the manufacturing process is simple and concise, and the high Ectoin, the target compound, can be produced commercially with high yield and high purity.
도 1은 실시예 1에서 합성한 프탈릴-L-글루타민의 1H NMR 및 13C NMR 측정 데이터이다.
도 2는 실시예 1에서 합성한 (S)-4-아미노-2-(2-프탈릴)-부타노익산의 1H NMR 및 13C NMR 측정 데이터이다.
도 3은 실시예 1에서 합성한 (S)-2,4-디아미노 부타노익산의 1H NMR 및 13C NMR 측정 데이터이다.
도 4는 실시예 1에서 합성한 (S)-1,4,5,6-테트라하이드로-2-메틸-4-피리미딘카르복실산의 1H NMR 및 13C NMR 측정 데이터이다.1 is 1 H NMR and 13 C NMR measurement data of phthalyl-L-glutamine synthesized in Example 1.
Figure 2 is 1 H NMR and 13 C NMR measurement data of (S) -4-amino-2- (2-phthalyl) -butanoic acid synthesized in Example 1.
3 is 1 H NMR and 13 C NMR measurement data of (S) -2,4-diamino butanoic acid synthesized in Example 1.
4 is 1 H NMR and 13 C NMR measurement data of (S) -1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid synthesized in Example 1.
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 변형예들이 있을 수 있음을 이해하여야 한다.Therefore, the configuration of the embodiment 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 발표된 엑토인 제조공정 보다 불순물의 정제(또는 제거)가 용이하면서도, 반응 중에 정제가 어려운 불순물이 생성되지 않으며, 고순도의 엑토인 화합물을 높은 수율로 제조에 적합하며 대량 합성 공정에 유리한 발명에 관한 것이다. The present invention is easier to purify (or remove) impurities than the conventionally announced ectoin manufacturing process, does not produce impurities that are difficult to purify during the reaction, and is suitable for manufacturing high-purity ectoin compounds in high yield, and is suitable for mass synthesis process. It is about an advantageous invention.
본 발명의 엑토인 제조방법은 바람직한 일례로서 하기 방정식 4에 나타낸 바와 같이, 화학식 2로 표현되는 프탈릴-L-글루타민을 제조하고, 이를 호프만 분해반응(Hofman Degradation) 또는 호프만 재배열반응(Hofmann Rearrangement Reaction)을 수행하여 화학식 3으로 표시되는 (S)-4-아미노-(2-프탈릴)부타노익산을 제조한 후, 이를 탈보호화 반응 수행하여 화학식 4로 표시되는 (S)-2,4-디아미노 부타노익산 제조한 다음, 이를 고리화반응을 수행하여서 최종 목적화합물인 화학식 1로 표현되는 엑토인을 제조하는 방법에 관한 것이다. As a preferred example, the method for preparing ectoin of the present invention prepares phthalyl-L-glutamine represented by Chemical Formula 2, as shown in Equation 4 below, and performs Hofman Degradation or Hofmann Rearrangement Reaction) to prepare (S)-4-amino-(2-phthalyl)butanoic acid represented by Formula 3, and then subjected to deprotection reaction to obtain (S)-2,4 represented by Formula 4 - It relates to a method for producing ectoin represented by Chemical Formula 1, which is the final target compound, by preparing diamino butanoic acid and then performing a cyclization reaction thereon.
[반응식 4][Scheme 4]
본 발명의 엑토인 제법에 대해 좀 더 구체적으로 설명하면, L-글루타민과 프탈산무수물을 염기 수용액 하에서 반응시켜서 프탈릭-L-글루타민을 제조하는 1단계; 하이포할라이트(hypohalite) 또는 하이퍼발란트 아이오딘 시약 존재 하에서, 상기 프탈릭-L-글루타민을 호프만 재배열 반응을 수행하여 (S)-4-아미노-2-(프탈릴)-부타노익산을 합성한 후, 탈보호화 반응을 수행하여 (S)-2,4-디아미노 부타노익산 또는 이의 염을 제조하는 2단계; 상기 (S)-2,4-디아미노 부타노익산 또는 이의 염을 반응용매와 혼합하여 혼합액을 제조하고, 상기 혼합액을 염기성 조건에서 환류 교반하여 고리화 반응을 수행한 후, 농축 및 결정화 공정을 수행하여 하기 화학식 1로 표시되는 엑토인을 수득하는 3단계;를 포함하는 공정을 수행할 수 있다.More specifically, the method for preparing ectoin of the present invention includes a first step of preparing phthalic-L-glutamine by reacting L-glutamine and phthalic anhydride in an aqueous base solution; In the presence of hypohalite or hypervalant iodine reagent, the phthalic-L-glutamine is subjected to a Hofmann rearrangement reaction to obtain (S)-4-amino-2-(phthalyl)-butanoic acid. After the synthesis, a second step of performing a deprotection reaction to prepare (S) -2,4-diamino butanoic acid or a salt thereof; The (S) -2,4-diamino butanoic acid or its salt is mixed with a reaction solvent to prepare a mixed solution, and a cyclization reaction is performed by stirring the mixed solution under reflux under basic conditions, followed by concentration and crystallization. A process including three steps of obtaining ectoin represented by the following Chemical Formula 1 may be performed.
또한, 3단계에서 수득한 엑토인을 염산, 황산, 초산, 인산, 트리플루오로아세트산, 브롬산, 벤젠술폰산, 캠퍼술폰산 및 유기산 중에서 선택된 1종 이상을 포함하는 산용액으로 염 처리하는 공정을 더 수행할 수도 있다.In addition, a step of salting the ectoin obtained in step 3 with an acid solution containing at least one selected from hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, trifluoroacetic acid, hydrobromic acid, benzenesulfonic acid, camphorsulfonic acid, and organic acids is further performed. can also be done
1단계의 출발물질인 L-글루타민과 프탈산 무수물은 상기 상업적으로 구입 가능한 것을 사용할 수 있으며, 이의 종류를 특별하게 한정하지 않는다.As the starting materials of the first step, L-glutamine and phthalic anhydride may be used commercially available, and the types are not particularly limited.
1 단계의 상기 염기 수용액은 유기염기 및 무기염기 중에서 선택된 1종 이상을 포함할 수 있다. 이때, 상기 유기염기는 트리에틸아민, 디이소프로필에틸아민, 피리딘, 다이메틸아민 및 다이에틸아민 중에서 선택된 1종 이상을 포함할 수 있다. 또한, 상기 무기염기는 중탄산나트륨, 탄산나트륨, 중탄산칼륨, 탄산칼륨, 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.The base aqueous solution of step 1 may include at least one selected from organic bases and inorganic bases. In this case, the organic base may include at least one selected from triethylamine, diisopropylethylamine, pyridine, dimethylamine, and diethylamine. In addition, the inorganic base is sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium-t-butoxide, potassium-t-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, lithium hydride, lithium hydroxide Side, lithium-t-butoxide, lithium methoxide, lithium ethoxide, sodium hydroxide and potassium hydroxide may include at least one selected from.
그리고, 염기 수용액 내 염기의 함량은 출발물질인 L-글루타민 1몰을 기준으로 1 ~ 5몰, 바람직하게는 1.01 ~ 2.00몰, 더욱 바람직하게는 1.02 ~ 1.50 몰의 양으로 포함할 수 있다.In addition, the amount of the base in the aqueous base solution may be included in an amount of 1 to 5 moles, preferably 1.01 to 2.00 moles, and more preferably 1.02 to 1.50 moles based on 1 mole of L-glutamine as a starting material.
또한, 1단계는 환류 교반 조건에서 L-글루타민과 프탈산 무수물을 반응시켜 수행할 수 있다.In addition, step 1 may be performed by reacting L-glutamine and phthalic anhydride under reflux stirring conditions.
다음으로, 2단계의 호프만 재배열 반응(또는 호프만 분해 반응) 및 탈보호화 반을을 연속적으로 수행하거나, 또는 단속적으로 수행할 수 있으며, 일례를 들면, 1단계에서 수득한 프탈릭-L-글루타민을 호프만 재배열 반응(또는 호프만 분해 반응) 을 수행하여 (S)-4-아미노-2-(프탈릴)-부타노익산을 합성한 후, 탈보호화 반응을 수행하여 (S)-2,4-디아미노 부타노익산 또는 이의 염을 제조하는 공정을 1개의 반응기에서 연속적으로 수행할 수 있다.Next, the two-step Hofmann rearrangement reaction (or Hoffman degradation reaction) and the deprotection half may be performed continuously or intermittently, for example, phthalic-L-glutamine obtained in step 1. (S)-4-amino-2-(phthalyl)-butanoic acid was synthesized by performing a Hofmann rearrangement reaction (or a Hofmann decomposition reaction), followed by a deprotection reaction to (S)-2,4 -The process of producing diamino butanoic acid or its salt can be continuously carried out in one reactor.
또는 1단계에서 수득한 프탈릭-L-글루타민을 호프만 재배열 반응을 호프만 재배열 반응을 수행한 후, 추출, 농축, 결정화시켜서 (S)-4-아미노-2-(프탈릴)-부타노익산을 수득하는 2-1단계; 및 상기 (S)-4-아미노-2-(프탈릴)-부타노익산을 탈보호화 반응시킨 후 농축 및 결정화하여 ((S)-2,4-디아미노 부타노익산 또는 이의 염을 제조하는 2-2단계;를 수행할 수 있다.Alternatively, the phthalic-L-glutamine obtained in step 1 was subjected to a Hofmann rearrangement reaction, followed by extraction, concentration, and crystallization to form (S)-4-amino-2-(phthalyl)-butanoic acid. Step 2-1 to obtain Iksan; And the (S) -4-amino-2- (phthalyl) -butanoic acid is deprotected, concentrated and crystallized to produce ((S) -2,4-diaminobutanoic acid or a salt thereof Step 2-2; can be performed.
상기 (S)-4-아미노-2-(프탈릴)-부타노익산은 핵심 중간체 화합물로서, 이를 순수하게 분리하고 구조규명을 한 보고가 지금까지 없었다. 따라서 본 발명에서 신규로 합성 및 구조 규명을 하였고, 구조 규명 데이터를 본 발명에 제시하였다.The (S) -4-amino-2- (phthalyl) -butanoic acid is a key intermediate compound, so far there has been no report on its pure isolation and structural identification. Therefore, synthesis and structural elucidation were newly performed in the present invention, and structural elucidation data were presented in the present invention.
2단계(또는 2-1단계)의 호프만 재배열 반응(호프만 분해 반응)을 하이퍼발란트 아이오딘 시약 하에서 수행시, 유기용매와 물의 혼합용매 하에서 수행할 수 있다. When the 2-step (or 2-1 step) Hofmann rearrangement reaction (Hoffman decomposition reaction) is performed under HyperValant iodine reagent, it can be performed under a mixed solvent of organic solvent and water.
하이퍼발란트 아이오딘 시약 하에서의 호프만 재배열 반응(호프만 분해 반응)의 바람직한 일례를 들면, 하기 반응식 5와 같다.A preferred example of the Hofmann rearrangement reaction (Hoffman decomposition reaction) under Hypervalant iodine reagent is shown in Scheme 5 below.
[반응식 5][Scheme 5]
상기 하이퍼발란트 아이도딘 시약은, (다이아세톡시아이오도)벤젠(PIDA), 비스(트리플루오로아세톡시)아이오도벤젠(PIFA), 비스(t-부틸카보닐옥시)아이오도벤젠(PhI(Piv)2), 아세트산 납(Lead IV acetate), [하이드록시(토실옥시)아이오도]벤젠(HTIB, 코져시약(Koser’s reagent)), [메톡시(토실옥시)아이오도]벤젠(MTIB) 및 4-(디아세톡시아이오도)톨루엔, 2-나이트로-(다이아세톡시아이오도)벤젠, 2-나이트로-(비스(트리플루오로아세톡시)아이오도벤젠, (다이아세톡시아이오도)펜타플루오로벤젠(C6F5I(OAc)2), 비스(트리플루오로아세톡시)아이오도펜타플루오로벤젠(C6F5I(CF3)2), 다이메톡시아이오도)벤젠(PIMA) 및 다이에톡시아이오도)벤젠(PIEA) 중에서 선택된 1종 이상을 포함할 수 있다. The Hypervalant idodine reagent is (diacetoxyiodo)benzene (PIDA), bis(trifluoroacetoxy)iodobenzene (PIFA), bis(t-butylcarbonyloxy)iodobenzene ( PhI (Piv) 2 ), lead IV acetate, [hydroxy(tosyloxy)iodo]benzene (HTIB, Koser's reagent), [methoxy(tosyloxy)iodo]benzene (MTIB ) and 4-(diacetoxyiodo)toluene, 2-nitro-(diacetoxyiodo)benzene, 2-nitro-(bis(trifluoroacetoxy)iodobenzene, (diacetoxyiodo) Fig.) Pentafluorobenzene (C 6 F 5 I(OAc) 2 ), bis(trifluoroacetoxy)iodopentafluorobenzene (C 6 F 5 I(CF 3 ) 2 ), dimethoxyiodo ) benzene (PIMA) and diethoxyiodo) benzene (PIEA).
그리고, 하이퍼발란트 아이오딘 시약 함유 용액 내 하이퍼발란트 아이오딘 시약의 사용량은 상기 프탈릴-L-글루타민 대비 0.9 ~ 3.0 당량비로, 바람직하게는 1 : 1.5 ~ 2.0 당량비로, 더욱 바람직하게는 1 : 1.0 ~ 1.4 당량비로 혼합한 후 반응을 수행할 수 있다. 이때, 하이퍼발란트계 아이오딘 시약의 당량비가 0.9 미만이면 목적하는 반응 생성물 수율이 낮은 문제가 있을 수 있고, 3.0 당량비를 초과하여 사용하면 과사용된 하이퍼발란트 아이오딘 시약이 불순물로 작용하여 목적하는 최종 반응생성물의 순도가 떨어지는 문제가 있을 수 있고, 제조단가가 크게 상승하는 문제가 발생하게 된다. In addition, the amount of HyperValant iodine reagent used in the solution containing the HyperValant iodine reagent is in an equivalent ratio of 0.9 to 3.0, preferably in an equivalent ratio of 1: 1.5 to 2.0, more preferably in an equivalent ratio of 1 to 1 : The reaction can be performed after mixing in an equivalent ratio of 1.0 to 1.4. At this time, if the equivalence ratio of the hypervalant iodine reagent is less than 0.9, there may be a problem in that the yield of the desired reaction product is low. There may be a problem in that the purity of the reaction product is lowered, and a problem in that the manufacturing cost is greatly increased.
또한, 하이퍼발란트 아이오딘 시약 하에서 반응시에 사용되는 상기 유기용매는 아세토니트릴, 테트라하이드로퓨란, 디메틸포름아마이드, 디메틸설폭사이드, 디메틸아세트아마이드, 아세톤, 에틸아세테이트, 메틸아세테이트, 아이소프로필아세테이트, 부틸아세테이트, 메틸렌클로라이드 및 N-메틸피롤리돈 중에서 선택된 1종 이상을 포함할 수 있으며, 바람직하게는 아세토니트릴 및 에틸아세테이트를 1 : 0.5 ~ 2.0 부피비로 포함할 수도 있다.In addition, the organic solvent used in the reaction under the hypervalant iodine reagent is acetonitrile, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, acetone, ethyl acetate, methyl acetate, isopropyl acetate, butyl At least one selected from among acetate, methylene chloride and N-methylpyrrolidone may be included, and preferably acetonitrile and ethyl acetate may be included in a volume ratio of 1:0.5 to 2.0.
그리고, 2단계(또는 2-1단계)의 상기 호프만 재배열 반응(또는 호프만 분해 반응)을 하이퍼발란트 아이도딘 시약 존재 하에서, 수행시에는 상기 호프만 재배열 반응(또는 호프만 분해 반응)은 -20 ~ 40℃에서 1 ~ 24시간 동안, 바람직하게는 -10 ~ 30℃에서 1 ~ 12시간 동안, 더욱 바람직하게는 0 ~ 10℃에서 1 ~ 6시간 동안 교반시키면서 수행하는 것이 좋으며, 이때 반응온도가 -10℃ 미만이면 반응온도가 너무 낮아 교반이 어려울 수 있으며, 반응온도가 40℃를 넘어가면 고리화 반응이 진행되어 불순물이 증가하는 결과가 발생할 수 있으므로 상기 범위 내에서 반응을 수행하는 것이 좋다. In addition, when the Hofmann rearrangement reaction (or Hoffman decomposition reaction) of step 2 (or step 2-1) is performed in the presence of Hypervalant idodine reagent, the Hoffman rearrangement reaction (or Hoffman decomposition reaction) is - It is good to carry out stirring at 20 ~ 40 ℃ for 1 ~ 24 hours, preferably -10 ~ 30 ℃ for 1 ~ 12 hours, more preferably 0 ~ 10 ℃ for 1 ~ 6 hours, at which time the reaction temperature If the reaction temperature is less than -10 ° C, stirring may be difficult because the reaction temperature is too low, and if the reaction temperature exceeds 40 ° C, the cyclization reaction may proceed and impurities may increase, so it is preferable to carry out the reaction within the above range. .
또한, 2단계 또는 2-1단계의 호프만 재배열 반응(호프만 분해 반응)을 상기 하이포할라이트 존재 하에서 수행시에는 용매로서 물을 사용할 수 있다. In addition, when the 2-step or 2-1-step Hofmann rearrangement reaction (Hoffman decomposition reaction) is performed in the presence of the hypohalite, water may be used as a solvent.
그리고, 상기 하이포할라이트(hypohalite)는 할로겐 화합물과 알칼리 용액의 반응생성물이며, 하이포할라이트 존재 하에서 상기 호프만 재배열 반응(호프만 분해 반응) 수행시, 프탈릴-L-글루타민 및 물의 혼합액에 알칼리 용액과 할로겐 화합물을 투입하면 하이포할라이트가 생성된다.In addition, the hypohalite is a reaction product of a halogen compound and an alkali solution, and when the Hofmann rearrangement reaction (Hoffman decomposition reaction) is performed in the presence of hypohalite, an alkali solution is added to a mixture of phthalyl-L-glutamine and water. When a halogen compound is added, hypohalite is produced.
상기 하이포할라이트(hypohalite) 용액은 차아염소산, 차아브롬산, 차아염소산나트륨 또는 차아브롬산나트륨을 포함할 수 있다.The hypohalite solution may include hypochlorous acid, hypobromic acid, sodium hypochlorite or sodium hypobromite.
그리고, 상기 할로겐 화합물은 염소 또는 브롬을 포함할 수 있다.And, the halogen compound may include chlorine or bromine.
상기 알칼리 용액은 알칼리 효과를 갖는 알칼리 금속 화합물의 수용액 또는 알칼리 토금속 화합물의 수용액이 사용될 수 있다. As the alkali solution, an aqueous solution of an alkali metal compound having an alkali effect or an aqueous solution of an alkaline earth metal compound may be used.
상기 알칼리 금속 화합물 수용액 또는 알칼리 토금속 화합물의 수용액은 수산화물, 탄산염, 탄산수소염, 인산염, 인산수소, 인산이수소, 수산화나트륨, 수산화칼륨, 탄산나트륨 및/또는 탄산칼륨을 포함하는 수용액일 수 있다. The alkali metal compound aqueous solution or alkaline earth metal compound aqueous solution may be an aqueous solution containing hydroxide, carbonate, hydrogen carbonate, phosphate, hydrogen phosphate, dihydrogen phosphate, sodium hydroxide, potassium hydroxide, sodium carbonate and/or potassium carbonate.
하이포할라이트 존재 하에서 호프만 재배열 반응(호프만 분해 반응)의 간략한 메카니즘의 일례를 들면, 하기 반응식 6과 같다. An example of a simple mechanism of the Hofmann rearrangement reaction (Hoffman decomposition reaction) in the presence of hypohalite is shown in Scheme 6 below.
[반응식 6][Scheme 6]
상기 할로겐 화합물은 상기 프탈릴-L-글루타민 1몰을 기준으로 1 ~ 5몰, 바람직하게는 1.01 ~ 2.00몰, 더욱 바람직하게는 1.02 ~ 1.5몰의 양으로 사용할 수 있다.The halogen compound may be used in an amount of 1 to 5 moles, preferably 1.01 to 2.00 moles, and more preferably 1.02 to 1.5 moles, based on 1 mole of the phthalyl-L-glutamine.
그리고, 2단계(또는 2-1단계)의 상기 호프만 재배열 반응(또는 호프만 분해 반응)을 하이포할라이트 존재 하에서, 수행시에는 상기 호프만 재배열 반응(또는 호프만 분해 반응)은 15 ~ 35℃에서 20분 ~ 60분간 교반 후, 60 ~ 90℃에서 30분 ~ 3시간 동안 교반시키면서 수행할 수 있으며, 바람직하게는 20 ~ 30℃에서 20분 ~ 40분간 교반 후, 70 ~ 80℃에서 40분 ~ 2시간 동안 교반시키면서 수행하는 것이 좋다.In addition, when the Hofmann rearrangement reaction (or Hoffman decomposition reaction) of step 2 (or step 2-1) is performed in the presence of hypohalite, the Hoffman rearrangement reaction (or Hoffman decomposition reaction) is performed at 15 to 35 ° C. After stirring for 20 to 60 minutes, it can be performed while stirring at 60 to 90 ° C for 30 minutes to 3 hours, preferably after stirring at 20 to 30 ° C for 20 minutes to 40 minutes, then at 70 to 80 ° C for 40 minutes to It is preferable to carry out with stirring for 2 hours.
다음으로, 2 단계(또는 2-2단계)의 탈보호화 반응은 산 수용액 또는 염기 수용액하에서 수행할 수 있다.Next, the 2-step (or 2-2 step) deprotection reaction may be performed in an aqueous acid solution or an aqueous base solution.
산을 사용하는 탈보호 반응은 강산용액을 이용해서 수행할 수 있는데, 상기 강산 용액은 염산, 황산, 브롬산, 술폰산, 벤젠술폰산, 켐퍼술폰산, 아세트산, 트리플루오로 아세트산, 메탄설폰산, 인산 및 유기산 중에서 선택된 1종 이상을 포함할 수 있다. 그리고, 사용되는 강산 용액의 양은 (S)-4-아미노-(2-프탈릴)-부타노익산 무게 대비 1~100배까지 사용할 수 있으며, 바람직하게는 1~50배가 적당하며, 더 바람직하게는 1~15배 사이가 적당하다.The deprotection reaction using an acid can be carried out using a strong acid solution, wherein the strong acid solution is hydrochloric acid, sulfuric acid, hydrobromic acid, sulfonic acid, benzenesulfonic acid, camphorsulfonic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, phosphoric acid and At least one selected from organic acids may be included. And, the amount of the strong acid solution used can be used up to 1 to 100 times the weight of (S) -4-amino- (2-phthalyl) -butanoic acid, preferably 1 to 50 times, more preferably is suitable between 1 and 15 times.
그리고, 염기를 사용하는 탈보호 반응은 하이드라진 화합물을 이용해서 수행할 수 있는데, 반응에서 사용되는 하이드라진 화합물은 하이드라진 무수물 또는 하이드라진 수화물이 사용할 수 있으며, 사용되는 하이드라진의 양은 (S)-4-아미노-(2-프탈릴)-부타노익산 무게 대비 1~100배까지 사용할 수 있으며, 바람직하게는 1~50배가 적당하며, 더 바람직하게는 1~20배 사이가 적당하다.And, the deprotection reaction using a base can be carried out using a hydrazine compound, The hydrazine compound used in the reaction can be hydrazine anhydride or hydrazine hydrate, and the amount of hydrazine used can be 1 to 100 times the weight of (S)-4-amino-(2-phthalyl)-butanoic acid. , Preferably between 1 and 50 times is appropriate, and more preferably between 1 and 20 times is appropriate.
탈보호화 반응의 구체적인 예를 들면, (S)-4-아미노-(2-프탈릴)-부타노익산 및 물을 혼합하여 혼합액을 제조한 후, 상기 혼합액에 하이드라진 화합물을 투입하여 탈보호화 반응을 수행할 수 있다.For a specific example of the deprotection reaction, after preparing a mixed solution by mixing (S)-4-amino-(2-phthalyl)-butanoic acid and water, a hydrazine compound is added to the mixed solution to perform a deprotection reaction. can be done
그리고, 상기 탈보호화 반응은 45 ~ 70℃ 하에서, 바람직하게는 50 ~ 60℃ 하에서 5 ~ 10시간 동안, 바람직하게는 6 ~ 8시간 동안 수행할 수 있다.Also, the deprotection reaction may be carried out at 45 to 70°C, preferably at 50 to 60°C for 5 to 10 hours, preferably 6 to 8 hours.
또한, 2단계에서 탈보호화 반응을 수행하여 제조한 (S)-2,4-디아미노 부타노익산은 황산, 초산, 인산, 트리플루오로아세트산, 브롬산, 벤젠술폰산, 캠퍼술폰산 및 유기산 중에서 선택된 1종 이상을 포함하는 산 용액으로 염처리하여 (S)-2,4-디아미노 부타노익산 염으로 제조할 수도 있다. In addition, (S) -2,4-diamino butanoic acid prepared by performing the deprotection reaction in step 2 is selected from sulfuric acid, acetic acid, phosphoric acid, trifluoroacetic acid, hydrobromic acid, benzenesulfonic acid, camphorsulfonic acid and organic acids. (S) -2,4-diamino butanoic acid salt may be prepared by salt treatment with an acid solution containing one or more.
그리고, 2단계(또는 2-2단계)를 수행하여 수득된 화합물인 ((S)-2,4-디아미노 부타노익산 또는 이의 염)에 대한 정제 공정을 수행한 후, 3단계를 수행할 수도 있으며, 또는 2단계에서 수득한 상기 수득물에 대한 별도의 정제 공정 수행 없이 3단계를 수행할 수도 있다.Then, after performing a purification process for the compound obtained by performing step 2 (or step 2-2) ((S) -2,4-diamino butanoic acid or a salt thereof), step 3 may be performed. Alternatively, step 3 may be performed without performing a separate purification process on the product obtained in step 2.
다음으로, 본 발명의 제조방법에 있어서, 3단계는 상기 (S)-2,4-디아미노 부타노익산 또는 이의 염을 반응용매와 혼합하여 혼합액을 제조한 후, 이를 염기성화시킨 염기성 조건에서 환류 교반하여 고리화 반응을 수행하여, 화학식 1로 표시되는 화합물, 즉 엑토인을 합성하는 공정으로서, 상기 염기성 조건은, (S)-2,4-디아미노부타노익산 또는 이의 염 대비 0.9 ~ 3.0 당량비의 염기를, 바람직하게는 1.5 ~ 2.5 당량비, 더욱 바람직하게는 1.0 ~ 2.0 당량비의 염기를 상기 혼합액에 투입하여 형성시킨다.Next, in the production method of the present invention, the third step is to prepare a mixed solution by mixing the (S) -2,4-diamino butanoic acid or its salt with a reaction solvent, and then base it under basic conditions. A process of synthesizing the compound represented by Formula 1, that is, ectoin, by carrying out a cyclization reaction by stirring under reflux, wherein the basic condition is 0.9 to 0.9 to (S) -2,4-diaminobutanoic acid or salt thereof. A base in an equivalent ratio of 3.0, preferably in an equivalent ratio of 1.5 to 2.5, and more preferably in an equivalent ratio of 1.0 to 2.0 is added to the mixture to form a base.
상기 염기는 유기염기 및 무기염기 중에서 선택된 1종 이상을 포함할 수 있다.The base may include at least one selected from organic bases and inorganic bases.
3단계의 상기 유기염기는 트리에틸아민, 디이소프로필에틸아민, 다이메틸아민, 피리딘 및 다이에틸아민 중에서 선택된 1종 이상을 포함할 수 있다.The organic base of step 3 may include at least one selected from triethylamine, diisopropylethylamine, dimethylamine, pyridine, and diethylamine.
그리고, 3단계의 상기 유기염기는 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.In addition, the organic base of step 3 is sodium-t-butoxide, potassium-t-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, lithium hydride, lithium hydroxide, lithium-t - It may contain at least one selected from among butoxide, lithium methoxide, lithium ethoxide, sodium hydroxide, and potassium hydroxide.
그리고, 3단계의 상기 반응용매는 유기용매로서, 메탄올, 에탄올, 프로판올, 이소프로판올, n-부탄올, 이소부탄올, sec-부탄올, tert-부탄올, 펜탄올, 헥산올, 헵탄올, 옥탄올, 아이소옥탄올 및 2-에틸헥산올 중에서 선택된 1종 이상을 포함할 수 있다.And, the reaction solvent in step 3 is an organic solvent, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, pentanol, hexanol, heptanol, octanol, isooctane It may include at least one selected from ol and 2-ethylhexanol.
또한, 상기 혼합액은 (S)-2,4-디아미노부타노익산 또는 이의 염 대비 1.0 ~ 5.0 당량비, 바람직하게는 1.0 ~ 3.0 당량비의 트리알킬오르소아세테이트(Trialkylorthoacetate) 또는 알킬아세트이미데이트(Alkylacetimidate)을 포함할 수 있다.In addition, the mixed solution is (S) -2,4-diaminobutanoic acid or a salt thereof in an equivalent ratio of 1.0 to 5.0, preferably 1.0 to 3.0 equivalent ratio of trialkylorthoacetate or alkylacetimidate. ) may be included.
그리고, 상기 알킬아세트이미데이트는 하기 화학식 5로 표시되는 화합물을 포함할 수 있다.And, the alkylacetimidate may include a compound represented by Formula 5 below.
[화학식 5][Formula 5]
CH3C(=NH)OR·HClCH 3 C(=NH)OR HCl
화학식 5에서, R은 C1~C8의 직쇄형 알킬기이다. In Formula 5, R is a C 1 to C 8 straight-chain alkyl group.
3단계의 상기 고리화 반응은 50~ 180℃에서 1 ~ 24시간 동안, 바람직하게는 50 ~ 150℃에서 18시간 동안, 더욱 바람직하게는 60 ~ 120℃에서 12시간 동안 교반시키면서 수행하는 것이 좋으며, 이때 반응온도가 150℃ 이상 되면 최종 화합물 색이 어두워지는 결과가 발생할 수 있으므로 상기 범위내에서 반응을 수행하는 것이 좋다. The three-step cyclization reaction is carried out at 50 to 180 ° C for 1 to 24 hours, preferably at 50 to 150 ° C for 18 hours, more preferably at 60 to 120 ° C for 12 hours while stirring, At this time, if the reaction temperature is higher than 150 ° C., the color of the final compound may become dark, so it is preferable to carry out the reaction within the above range.
그리고, 3단계의 고리화 반응 후, 당업계에서 사용하는 일반적인 농축 및 결정화 공정을 수행하여 결정화된 엑토인을 수득할 수 있다.And, after the three-step cyclization reaction, a general concentration and crystallization process used in the art may be performed to obtain crystallized ectoin.
또한, 상기 결정화 공정시 사용하는 용매는 직쇄형 또는 분쇄형 C1 ~ C8 알콜류, 메틸아세테이트, 에틸아세테이트, 아이소프로필아세테이트, 부틸아세테이트, 아세토니트릴, 테트라하이드로퓨란, 메틸렌클로라이드 및 아세톤 중에서 선택된 1종 이상을 포함할 수 있다. In addition, the solvent used in the crystallization process is at least one selected from straight-chain or pulverized C1-C8 alcohols, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, methylene chloride, and acetone. can include
또한, 3단계의 반응 후 얻어진 엑토인은 유리염기 및 금속염 일수 있으며, 상기 금속염의 상기 금속은 알카리금속, 알카리토금속, 전이금속 또는 란탄족금속일 수 있고, 바람직하게는 금속은 나트륨, 칼륨 또는 칼슘일 수 있으며, 이들의 수화물 또는 이들의 유기솔베이트를 포함할 수 있다.In addition, ectoin obtained after the reaction in step 3 may be a free base or a metal salt, and the metal of the metal salt may be an alkali metal, an alkaline earth metal, a transition metal, or a lanthanide metal. Preferably, the metal is sodium, potassium, or calcium. , and may include hydrates thereof or organic sorbates thereof.
위와 같은 공정을 수행하여 제조한 엑토인 화합물은 각 단계별 분리공정 또는 연속공정으로 진행하여 하기 수학식 1에 의거하여 계산시, 전체 수율이 40% 이상, 바람직하게는 45% 이상일 수 있다. The total yield of the ectoin compound prepared by performing the above process may be 40% or more, preferably 45% or more, when calculated based on Equation 1 below by proceeding through a step-by-step separation process or a continuous process.
[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 엑토인은 액체 크로마토그래피 분석시 90% 이상, 바람직하게는 순도 98.0% ~ 99.9%, 더욱 바람직하게는 99.0 ~ 99.9%의 높은 순도로 엑토인 화합물을 수득할 수 있다. In addition, the ectoin prepared by performing the above process can obtain an ectoin compound with a high purity of 90% or more, preferably 98.0% to 99.9%, more preferably 99.0 to 99.9%, when analyzed by liquid chromatography. can
이하, 본 발명을 구체적인 실시예에 의해 설명한다. 단 이하의 실시예들은 본 발명을 예시하기 위한 일례일 뿐, 본 발명의 범위가 이들로 한정되지는 않는다. 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.
[실시예][Example]
실시예 1 : 엑토인의 제조Example 1: Preparation of Ectoin
(1) 프탈릴-L-글루타민의 제조(1) Preparation of phthalyl-L-glutamine
1000mL 3구 라운드 플라스크에 콘덴서를 연결하고 냉매를 순환시킨 후 L-글루타민 146g, 중탄산 나트륨 100g, 증류수 500g 그리고 프탈릭산 무수물 148g을 투입하고 3시간 동안 환류 교반한다. 반응종결을 TLC로 확인하고 반응기 내부온도를 0 ~ 5℃까지 서서히 냉각한 다음 1시간 동안 교반한 후 여과를 수행하였다. After connecting a condenser to a 1000mL three-necked round flask and circulating a refrigerant, 146g of L-glutamine, 100g of sodium bicarbonate, 500g of distilled water, and 148g of phthalic anhydride were added, followed by refluxing and stirring for 3 hours. After confirming the completion of the reaction by TLC, the temperature inside the reactor was slowly cooled to 0 to 5° C., followed by stirring for 1 hour, followed by filtration.
다음으로, 열풍 건조기에서 60℃에서 12시간 동안 건조하여 프탈릴-L-글루타민 248.6g(수율 90%)를 수득하였다. 이때, 수율은 하기 수학식 1에 의거하여 측정한 것이며, 수득한 프탈릴-L-글루타민에 대한 1H NMR과 13C NMR 측정결과는 하기와 같으며, 이를 통해서 화학식 2로 표시되는 화합물을 합성되었음을 확인할 수 있었다. 1H NMR 및 13C NMR 측정 데이타는 도 1에 나타내었다.Next, 248.6 g of phthalyl-L-glutamine (yield: 90%) was obtained by drying at 60° C. for 12 hours in a hot air dryer. At this time, the yield was measured based on Equation 1 below, and the 1 H NMR and 13 C NMR measurement results for the obtained phthalyl-L-glutamine are as follows, through which the compound represented by Formula 2 was synthesized I was able to confirm that it was. 1 H NMR and 13 C NMR measurement data are shown in FIG. 1 .
1 H NMR(DMSO-d6) : δ 7.96-7.88(m, 4H), δ 7.22(s, 1H), δ 6.74(s, 1H), δ 4.78-4.75(dd, 1H), δ 2.41-2.29(m, 2H), δ 2.12-2.09(t, 2H) 1 H NMR (DMSO-d6) : δ 7.96-7.88 (m, 4H), δ 7.22 (s, 1H), δ 6.74 (s, 1H), δ 4.78-4.75 (dd, 1H), δ 2.41-2.29 ( m, 2H), δ 2.12-2.09 (t, 2H)
13 C NMR(DMSO-d6) : δ 173.77, δ 170.94, δ 167.94, δ 135.30, δ 131.68, δ 123.85, δ 51.78, δ 31.82, δ 24.45 13 C NMR (DMSO-d6): δ 173.77, δ 170.94, δ 167.94, δ 135.30, δ 131.68, δ 123.85, δ 51.78, δ 31.82, δ 24.45
[수학식 1][Equation 1]
수율(%) = (반응생성물의 실제 수득량/반응생성물의 이론적 수득량)×100%Yield (%) = (actual yield of reaction product/theoretical yield of reaction product) × 100%
(2) (S)-4-아미노-2-(2-프탈릴)-부타노익산의 제조(2) Preparation of (S) -4-amino-2- (2-phthalyl) -butanoic acid
100mL 2구 라운드 플라스크에 콘덴서를 연결하고 냉매를 순환시킨 후, 앞서 제조한 프탈릴-L-글루타민 5g, 증류수 9mL, 아세토니트릴 18mL 및 에틸아세테이트 18mL를 투입하고 0 ~ 5℃에서 교반을 수행했다. After connecting a condenser to a 100mL two-necked round flask and circulating the refrigerant, 5g of phthalyl-L-glutamine, 9mL of distilled water, 18mL of acetonitrile and 18mL of ethyl acetate were added and stirred at 0 to 5 °C.
다음으로, 프탈릴-L-글루타민 1당량 대비하여, 하이퍼발란트 아이오딘 시약인 (다이아세톡시아이오도)벤젠(PIDA)을 1.2 당량비인 7g을 반응기에 투입하고 2시간 동안 교반을 수행했다. Next, compared to 1 equivalent of phthalyl-L-glutamine, 7 g of 1.2 equivalent ratio of (diacetoxyiodo)benzene (PIDA), a hypervalant iodine reagent, was added to the reactor and stirred for 2 hours.
다음으로, 반응종결을 TLC로 확인하고 반응기 내부온도를 0 ~ 2℃ 사이로 조절하고, 30분간 교반한 다음 여과한 후, 열풍건조기에서 60℃에서 12시간 동안 건조하여 (S)-4-아미노-(2-프탈릴)부타노익산 3.59g(수율 80.0%)을 수득하였다. 이의 1H NMR과 13C NMR 측정결과는 하기와 같으며, 1H NMR 및 13C NMR 측정 데이타는 도 2에 나타내었다.Next, the completion of the reaction was confirmed by TLC, the temperature inside the reactor was adjusted to between 0 and 2 ° C, stirred for 30 minutes, filtered, and dried in a hot air dryer at 60 ° C for 12 hours to (S) -4-amino- (2-phthalyl) butanoic acid 3.59g (yield 80.0%) was obtained. The 1 H NMR and 13 C NMR measurement results thereof are as follows, and the 1 H NMR and 13 C NMR measurement data are shown in FIG. 2 .
1 H NMR(D 2 O) : δ 7.77-7.68(m, 4H), δ 4.62-4.59(t, 1H), δ 3.04-2.92(m, 2H), δ 2.45-2.35(m, 1H), δ 2.30-2.21(m, 1H) 1 H NMR (D 2 O): δ 7.77-7.68 (m, 4H), δ 4.62-4.59 (t, 1H), δ 3.04-2.92 (m, 2H), δ 2.45-2.35 (m, 1H), δ 2.30-2.21(m, 1H)
13 C NMR(D 2 O) : δ 174.66, δ 169.97, δ 134.88, δ 131.09, δ 123.53, δ 52.09, δ 37.42, δ 27.73 13 C NMR (D 2 O): δ 174.66, δ 169.97, δ 134.88, δ 131.09, δ 123.53, δ 52.09, δ 37.42, δ 27.73
(3) (S)-2,4-디아미노 부타노익산의 제조(3) Preparation of (S) -2,4-diamino butanoic acid
500mL 3구 라운드 플라스크에 콘덴서를 연결하고 냉매를 순환시킨 후에, 앞서 제조한 (S)-4-아미노-(2-프탈릴)-부타노익산 48.5g, 탄산나트륨 15.5g, 증류수 280mL을 투입한 후 교반을 수행했다. 다음으로, 50 중량% 농도의 하이드라진 수화물 20g을 넣고 50 ~ 55℃에서 7시간 동안 교반하였다. After connecting a condenser to a 500mL three-necked round flask and circulating the refrigerant, 48.5g of (S)-4-amino-(2-phthalyl)-butanoic acid, 15.5g of sodium carbonate, and 280mL of distilled water were added thereto. Agitation was performed. Next, 20 g of hydrazine hydrate at a concentration of 50% by weight was added and stirred at 50 to 55 ° C. for 7 hours.
다음으로, 반응종결을 TLC로 확인하고 묽은 염산용액을 반응액에 넣어서 pH를 중성으로 조절한 후 반응 부산물인 프탈하이드라자이드를 여과하여 제거하고 여액을 온도 30℃ 이하에서 감압 농축하였다. Next, the completion of the reaction was confirmed by TLC, diluted hydrochloric acid solution was added to the reaction solution to adjust the pH to neutral, and phthalhydrazide, a reaction by-product, was removed by filtration, and the filtrate was concentrated under reduced pressure at a temperature of 30 ° C or lower.
다음으로 감압 농축액에 아이소프로필에테르를 넣어서 결정화시킨 후 여과한 후 열풍건조기에서 60℃에서 12시간 동안 건조하여 결정화된 (S)-2,4-디아미노 부타노익산 14.8g(수율 64.3%)을 수득하였다. 그리고, 이의 1H NMR과 13C NMR 측정결과는 하기와 같으며, 1H NMR 및 13C NMR 측정 데이타는 도 3에 나타내었다.Next, crystallize by adding isopropyl ether to the concentrate under reduced pressure, filter it, and dry it in a hot air dryer at 60 ° C for 12 hours to obtain 14.8 g (yield 64.3%) of (S) -2,4-diamino butanoic acid crystallized. obtained. In addition, the 1 H NMR and 13 C NMR measurement results thereof are as follows, and the 1 H NMR and 13 C NMR measurement data are shown in FIG. 3 .
1 H NMR(D 2 O) : δ 3.75-3.71(t, 1H), δ 3.16-3.03(m, 2H), δ 2.13-2.08(q, 2H) 1 H NMR (D 2 O): δ 3.75-3.71 (t, 1H), δ 3.16-3.03 (m, 2H), δ 2.13-2.08 (q, 2H)
13 C NMR(D 2 O) : δ 172, δ 51.58, δ 36.55, δ 27.92 13 C NMR (D 2 O): δ 172, δ 51.58, δ 36.55, δ 27.92
(4) (S)-1,4,5,6-테트라하이드로-2-메틸-4-피리미딘카르복실산의 제조(4) Preparation of (S) -1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid
500mL 2구 라운드 플라스크에 콘덴서를 연결하고 냉매를 순환시킨 후, 앞서 제조한 (S)-2,4-디아미노 부타노익산 11.81g, 트리에틸아민 10.2g, 메탄올 120mL 및 트리메틸오르소아세테이트 24.1g 을 투입하고 65℃에서 12시간 동안 환류 교반하여 고리화 반응을 수행하였다. After connecting a condenser to a 500mL two-necked round flask and circulating the refrigerant, 11.81g of (S)-2,4-diaminobutanoic acid, 10.2g of triethylamine, 120mL of methanol and 24.1g of trimethylorthoacetate prepared above was added and stirred under reflux at 65° C. for 12 hours to perform a cyclization reaction.
다음으로, 반응종결을 TLC로 확인하고 반응액을 상온(23~25℃)으로 냉각한 후, 감압 농축하여 용매를 제거하였다. 잔류물에 메탄올 50mL와 에틸아세테이트 110mL를 넣고 상온(20 ~ 25℃)에서 2시간 동안 교반한 후 여과를 실시하여 최종 목적화합물 엑토인 10.24g(수율 72%)를 수득하였다. 또한 수득된 엑토인을 액체크로마토그래피로 분석하여 순도 99.3%임을 확인하였으며, 1H NMR과 13C NMR 측정결과는 하기와 같으며, 1H NMR 및 13C NMR 측정 데이타는 도 4에 나타내었다. 이를 통해서, 화학식 1로 표시되는 (S)-1,4,5,6-테트라하이드로-2-메틸-4-피리미딘카르복실산이 합성되었음을 확인할 수 있었다.Next, the completion of the reaction was confirmed by TLC, the reaction solution was cooled to room temperature (23-25 ° C), and then concentrated under reduced pressure to remove the solvent. 50 mL of methanol and 110 mL of ethyl acetate were added to the residue, stirred at room temperature (20 to 25 ° C) for 2 hours, and then filtered to obtain 10.24 g of ectoin (72% yield) as the final target compound. In addition, the obtained ectoin was analyzed by liquid chromatography to confirm that the purity was 99.3%. 1 H NMR and 13 C NMR measurement results were as follows, and 1 H NMR and 13 C NMR measurement data were shown in FIG. Through this, it was confirmed that (S) -1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid represented by Formula 1 was synthesized.
1 H NMR(D 2 O) : δ 3.95-3.92(t, 1H), δ 3.35-3.30(m, 1H), δ 3.20-3.12(m, 1H), δ 2.10(s, 3H), δ 2.04-1.93(m, 2H) 1 H NMR (D 2 O): δ 3.95-3.92 (t, 1H), δ 3.35-3.30 (m, 1H), δ 3.20-3.12 (m, 1H), δ 2.10 (s, 3H), δ 2.04- 1.93 (m, 2H)
13 C NMR(D 2 O) : δ 176.66, δ 160.40, δ 53.08, δ 37.11, δ 21.30, δ 18.06 13 C NMR (D 2 O): δ 176.66, δ 160.40, δ 53.08, δ 37.11, δ 21.30, δ 18.06
[화학식 1][Formula 1]
실시예 2 ~ 실시예 6 : 엑토인의 제조Examples 2 to 6: Preparation of Ectoin
상기 실시예 1과 동일한 방법으로 엑토인을 제조하되, (S)-4-아미노-2-(2-프탈릴)부타노익산을 제조시, 하기 표 1과 같이 투입되는 하이퍼발란트 아이오딘 시약(HVI reagent)의 종류와 당량을 달리하여 (S)-4-아미노-2-(2-프탈릴)부타노익산을 각각 제조하고, 이를 이용하여 엑토인을 각각 제조하여 실시예 2 ~ 6을 각각 실시하였다.Ectoin was prepared in the same manner as in Example 1, but when preparing (S) -4-amino-2- (2-phthalyl) butanoic acid, hypervalant iodine reagent added as shown in Table 1 below (S) -4-amino-2- (2-phthalyl) butanoic acid was prepared by varying the type and equivalent weight of the (HVI reagent), and ectoin was prepared using the same to prepare Examples 2 to 6 each was carried out.
실시예 7: 엑토인의 제조Example 7: Preparation of Ectoin
상기 실시예 1과 동일한 방법으로 (1) 프탈릴-L-글루타민, (2) (S)-4-아미노-2-(2-프탈릴)-부타노익산 및 (3) (S)-2,4-디아미노 부타노익산을 제조하였다.In the same manner as in Example 1, (1) phthalyl-L-glutamine, (2) (S)-4-amino-2-(2-phthalyl)-butanoic acid and (3) (S)-2 ,4-diamino butanoic acid was prepared.
다음으로, 500mL 2구 라운드 플라스크에 콘덴서를 연결하고 냉매를 순환시킨 후 상기 (S)-2,4-디아미노 부타노익산 11.81g, 트리에틸아민 10.2g, 메탄올 120mL 그리고 하기 화학식 5-1로 표시되는 알킬아세트이미데이트 염산 13.6g, 트리에틸아민 20.24g을 투입하고 24시간 동안 환류 교반하여 고리화 반응을 수행하였다. Next, after connecting a condenser to a 500mL two-necked round flask and circulating the refrigerant, 11.81 g of (S) -2,4-diamino butanoic acid, 10.2 g of triethylamine, 120 mL of methanol and the following formula 5-1 13.6 g of the indicated alkylacetimidate hydrochloric acid and 20.24 g of triethylamine were added and stirred under reflux for 24 hours to perform a cyclization reaction.
[화학식 5-1][Formula 5-1]
CH3C(=NH)OR·HClCH 3 C(=NH)OR HCl
화학식 5-1에서, R은 에틸기이다.In Formula 5-1, R is an ethyl group.
다음으로, 반응종결을 TLC로 확인하고 반응액을 상온으로 냉각한 후 감압농축하여 용매를 제거한다. 잔류물에 메탄올 50mL와 아세톤 110mL를 넣고 1시간 동안 환류한 다음 온도를 상온(20 ~ 25℃)으로 냉각 후 동일 온도에서 1시간 동안 교반 후 여과를 실시하여 최종 목적화합물 엑토인 9.67g(수율 68%)를 수득하였다.Next, the completion of the reaction is confirmed by TLC, the reaction solution is cooled to room temperature, and the solvent is removed by concentrating under reduced pressure. After adding 50 mL of methanol and 110 mL of acetone to the residue, refluxing for 1 hour, cooling the temperature to room temperature (20 ~ 25 ℃), stirring at the same temperature for 1 hour, and filtering to obtain 9.67 g of the final target compound, ectoin (yield: 68 %) was obtained.
실시예 8Example 8
상기 실시예 1과 동일한 방법으로 (1) 프탈릴-L-글루타민, (2) (S)-4-아미노-2-(2-프탈릴)-부타노익산 및 (3) (S)-2,4-디아미노 부타노익산을 제조하였다.In the same manner as in Example 1, (1) phthalyl-L-glutamine, (2) (S)-4-amino-2-(2-phthalyl)-butanoic acid and (3) (S)-2 ,4-diamino butanoic acid was prepared.
다음으로, 실시예 1과 동일한 방법으로 (S)-1,4,5,6-테트라하이드로-2-메틸-4-피리미딘카르복실산(엑토인)을 합성하되, 트리에틸아민 10.2g 대신 소듐 메톡사이드 6.8g을 사용하여 고리화 반응을 수행하였다.Next, (S) -1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid (ectoin) was synthesized in the same manner as in Example 1, but instead of 10.2 g of triethylamine A cyclization reaction was performed using 6.8 g of sodium methoxide.
실시예 9Example 9
상기 실시예 1과 동일한 방법으로 (1) 프탈릴-L-글루타민, (2) (S)-4-아미노-2-(2-프탈릴)-부타노익산 및 (3) (S)-2,4-디아미노 부타노익산을 제조하였다.In the same manner as in Example 1, (1) phthalyl-L-glutamine, (2) (S)-4-amino-2-(2-phthalyl)-butanoic acid and (3) (S)-2 ,4-diamino butanoic acid was prepared.
다음으로, 실시예 1과 동일한 방법으로 (S)-1,4,5,6-테트라하이드로-2-메틸-4-피리미딘카르복실산(엑토인)을 합성하되, 트리에틸아민 10.2g 대신 30 부피% 농도의 소듐 메톡사이드(용매:메탄올) 22.5g을 사용하여 고리화 반응을 수행하였다.Next, (S) -1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid (ectoin) was synthesized in the same manner as in Example 1, but instead of 10.2 g of triethylamine A cyclization reaction was performed using 22.5 g of sodium methoxide (solvent: methanol) at a concentration of 30% by volume.
(1a) = (다이아세톡시아이오도)벤젠(PIDA)
(1b) = 비스(트리플루오로아세톡시)아이오도벤젠
(1c) = 비스(t-부틸카보닐옥시)아이오도벤젠
(1d) = [하이드록시(토실옥시)아이오도]벤젠
(1e) = [메톡시(토실옥시)아이오도]벤젠
(1f) = 아세트산 납
(2) 프탈릴-L-글루타민 1 당량에 대한 당량비
(3) 수율은 하기 수학식 1에 의거하여 측정
[수학식 1]
수율(%) = (반응생성물의 실제 수득량/반응생성물의 이론적 수득량)X100%(1) HyperValant iodine reagent (HVI reagent)
(1a) = (diacetoxyiodo)benzene (PIDA)
(1b) = bis(trifluoroacetoxy)iodobenzene
(1c) = bis(t-butylcarbonyloxy)iodobenzene
(1d) = [hydroxy(tosyloxy)iodo]benzene
(1e) = [methoxy(tosyloxy)iodo]benzene
(1f) = lead acetate
(2) Equivalent ratio with respect to 1 equivalent of phthalyl-L-glutamine
(3) Yield is measured according to Equation 1 below
[Equation 1]
Yield (%) = (actual yield of reaction product / theoretical yield of reaction product)
실시예 10: 엑토인의 제조(연속공정)Example 10: Preparation of ectoin (continuous process)
실시예 1과 동일한 방법으로 (1) 프탈릴-L-글루타민을 제조하였다.(1) Phthalyl-L-glutamine was prepared in the same manner as in Example 1.
다음으로, 1L 3구 라운드 플라스크에 콘덴서를 연결하고 냉매를 순환시킨 후 프탈릴-L-글루타민 28g과 증류수 350mL을 투입하고 0 ~ 5℃에서 교반하였다. Next, after connecting a condenser to a 1L three-necked round flask and circulating a refrigerant, 28 g of phthalyl-L-glutamine and 350 mL of distilled water were added and stirred at 0 to 5 °C.
다음으로, 프탈릴-L-글루타민 1몰 기준으로 수산화나트륨(NaOH) 49.33몰(20g)과 브롬 12.35몰(20g)을 넣고 20 ~ 25℃에서 30분 동안 교반한 다음 70 ~ 80℃에서 1시간 동안 교반하여 호프만 재배열반응을 수행하였다.Next, 49.33 moles (20 g) of sodium hydroxide (NaOH) and 12.35 moles (20 g) of bromine were added based on 1 mole of phthalyl-L-glutamine, stirred at 20 to 25 ° C for 30 minutes, and then stirred at 70 to 80 ° C for 1 hour. While stirring, a Hofmann rearrangement reaction was performed.
다음으로, 실온(20~25℃)으로 냉각하고 혼합물에 6M 염산 용액을 투입 및 교반하여 산성화한 다음 여과하고 여액을 농축하여 농축잔류물을 수득한 다음, 상기 농축잔류물에 추가로 35 부피% 농도의 염산 25mL를 넣고 3시간 동안 환류교반하여 탈보호화 반응을 수행하였다. 반응종결을 TLC로 확인하고 실온으로 냉각한 다음 반응 부산물인 프탈릭산을 여과하여 제거하고 수층을 아이소프로필에테르로 세척하였다. 다음으로, 수층을 완전 농축한 후 톨루엔을 이용해서 재농축하여 (S)-2,4-디아미노 부타노익산을 포함하는 농축잔류물을 수득한 다음, 정제 없이 다음 반응을 연속적으로 진행하였다. Next, it was cooled to room temperature (20-25 ° C), acidified by adding and stirring a 6M hydrochloric acid solution to the mixture, filtered, and concentrated the filtrate to obtain a concentrated residue, and then added 35% by volume to the concentrated residue. A deprotection reaction was performed by adding 25 mL of concentrated hydrochloric acid and stirring under reflux for 3 hours. After confirming the completion of the reaction by TLC, the mixture was cooled to room temperature, and phthalic acid, a reaction by-product, was removed by filtration, and the aqueous layer was washed with isopropyl ether. Next, the aqueous layer was completely concentrated and re-concentrated using toluene to obtain a concentrated residue containing (S) -2,4-diamino butanoic acid, and then the following reaction was continuously performed without purification.
다음으로 상기 농축잔류물에 트리메틸오르소아세테이트 32g, 트리에틸아민 12.7g과 무수 메탄올 280mL를 투입한 후 65℃에서 5시간 동안 환류 교반하여 고리화 반응을 수행하였다. Next, 32 g of trimethylorthoacetate, 12.7 g of triethylamine, and 280 mL of anhydrous methanol were added to the concentrated residue, followed by reflux stirring at 65° C. for 5 hours to perform a cyclization reaction.
반응종결을 TLC로 확인한 후 용매를 감압농축하여 제거한 후 잔류물에 메탄올 10mL와 에틸아세테이트 25mL를 넣고 상온(20 ~ 25℃)에서 2시간 동안 교반 후 여과를 실시하여 최종 목적화합물 엑토인 7.93g(수율 55%, 프탈릴-L-글루타민으로부터 수율)를 수득하였다. 또한, 수득된 엑토인을 액체크로마토그래피로 분석하여 순도 99.3%임을 확인하였다.After confirming the completion of the reaction by TLC, the solvent was concentrated under reduced pressure to remove it, and 10 mL of methanol and 25 mL of ethyl acetate were added to the residue, stirred at room temperature (20 ~ 25 ° C) for 2 hours, and then filtered to obtain 7.93 g of the final target compound, ectoin (
상기와 같이 설명된 실시예 제조방법은 상기 설명된 실시예들의 구성과 방법이 한정되게 적용될 수 있는 것이 아니라, 상기 실시예들은 다양한 변형(당량비, 반응시간, 중간체 분리 및 연속공정 등)이 이루어질 수 있도록 각 실시예들의 전부 또는 일부가 선택적으로 조합되어 구성될 수도 있다. The method for preparing the examples described above is not limited to the configuration and method of the examples described above, but various modifications (equivalent ratio, reaction time, intermediate separation and continuous process, etc.) can be made in the examples. All or part of each embodiment may be configured by selectively combining so as to be.
Claims (14)
하이포할라이트(hypohalite) 또는 하이퍼발란트아이오딘(Hypervalent iodine) 시약 존재 하에서, 상기 프탈릭-L-글루타민을 호프만 재배열 반응을 수행하여 (S)-4-아미노-2-(프탈릴)-부타노익산을 합성한 후, 탈보호화 반응을 수행하여 (S)-2,4-디아미노 부타노익산 또는 이의 염을 제조하는 2단계;
상기 (S)-2,4-디아미노 부타노익산 또는 이의 염을 반응용매와 혼합하여 혼합액을 제조하고, 상기 혼합액을 염기성 조건에서 환류 교반하여 고리화 반응을 수행한 후, 농축 및 결정화 공정을 수행하여 하기 화학식 1로 표시되는 엑토인을 수득하는 3단계;를 포함하는 공정을 수행하며,
상기 2단계의 호프만 재배열 반응 및 탈보호화 반응은 연속식(continuous) 공정 또는 배치식(batch) 공정으로 수행하는 것을 특징으로 하는 엑토인의 제조방법;
[화학식 1]
A first step of preparing phthalic-L-glutamine by reacting L-glutamine and phthalic anhydride in an aqueous base solution;
(S)-4-amino-2-(phthalyl)- After synthesizing butanoic acid, a second step of preparing (S) -2,4-diamino butanoic acid or a salt thereof by performing a deprotection reaction;
The (S) -2,4-diamino butanoic acid or its salt is mixed with a reaction solvent to prepare a mixed solution, and a cyclization reaction is performed by stirring the mixed solution under reflux under basic conditions, followed by concentration and crystallization. Performing a process including three steps to obtain ectoin represented by Formula 1 below;
A method for producing ectoin, characterized in that the two-step Hofmann rearrangement reaction and deprotection reaction are carried out in a continuous process or a batch process;
[Formula 1]
하이포할라이트(hypohalite) 또는 하이퍼발란트아이오딘(Hypervalent iodine) 시약 존재 하에서, 상기 프탈릭-L-글루타민을 호프만 재배열 반응을 수행한 후 추출, 농축, 결정화시켜서 (S)-4-아미노-2-(프탈릴)-부타노익산을 수득하는 2-1단계; 및
상기 (S)-4-아미노-2-(프탈릴)-부타노익산을 탈보호화 반응시킨 후 농축 및 결정화하여 (S)-2,4-디아미노 부타노익산 또는 이의 염을 제조하는 2-2단계;를 수행하는 것을 특징으로 하는 엑토인의 제조방법.
The method of claim 1, when the two steps are performed as a batch process, the two steps,
In the presence of hypohalite or hypervalent iodine reagent, the phthalic-L-glutamine was subjected to a Hofmann rearrangement reaction, followed by extraction, concentration, and crystallization of (S)-4-amino- Step 2-1 to obtain 2-(phthalyl)-butanoic acid; and
After deprotection of the (S) -4-amino-2- (phthalyl) -butanoic acid, concentration and crystallization to produce (S) -2,4-diaminobutanoic acid or a salt thereof 2- Step 2; Method for producing ectoin, characterized in that performing.
상기 유기염기는 트리에틸아민, 디이소프로필에틸아민, 다이메틸아민, 피리딘 및 다이에틸아민 중에서 선택된 1종 이상을 포함하며,
상기 무기염기는 중탄산나트륨, 탄산나트륨, 중탄산칼륨, 탄산칼륨, 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 엑토인의 제조방법.
The method of claim 1, wherein the aqueous base solution in the first step contains at least one selected from organic bases and inorganic bases,
The organic base includes at least one selected from triethylamine, diisopropylethylamine, dimethylamine, pyridine, and diethylamine,
The inorganic base is sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium-t-butoxide, potassium-t-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, lithium hydride, lithium hydroxide, A method for producing ectoin comprising at least one selected from lithium-t-butoxide, lithium methoxide, lithium ethoxide, sodium hydroxide and potassium hydroxide.
The method of claim 1 or 2, wherein the hypervalant iododine reagent, (diacetoxy iodo) benzene (PIDA), bis (trifluoroacetoxy) iodobenzene (PIFA), bis (t -Butylcarbonyloxy)iodobenzene (PhI(Piv) 2 ), lead IV acetate, [hydroxy(tosyloxy)iodo]benzene (HTIB), [methoxy(tosyloxy)iodo] Benzene (MTIB) and 4-(diacetoxyiodo)toluene, 2-nitro-(diacetoxyiodo)benzene, 2-nitro-(bis(trifluoroacetoxy)iodobenzene, Setoxyiodo)pentafluorobenzene (C 6 F 5 I(OAc) 2 ), bis(trifluoroacetoxy)iodopentafluorobenzene (C 6 F 5 I(CF 3 ) 2 ), dimethicone A method for producing ectoin comprising at least one selected from toxiaiodo)benzene (PIMA) and diethoxyiodo)benzene (PIEA).
[Claim 5] The method for preparing ectoin according to claim 4, wherein the amount of the HyperValant iodine reagent used in the second step is 0.9 to 3.0 equivalent to the phthalyl-L-glutamine.
상기 할로겐 화합물은 염소 또는 브롬을 포함하고,
상기 알칼리 용액은 알칼리 금속 화합물의 수용액 및 알칼리 토금속 화합물 수용액을 용매로 포함하며,
할로겐 화합물 사용량은 프탈릭-L-글루타민 및 할로겐 화합물을 1 : 1 ~ 5 몰비로 포함하는 알칼리 용액을 포함하는 것을 특징으로 하는 엑토인의 제조방법.
The method of claim 1 or 2, wherein the hypohalite (Hypohalite) is a reaction product of a halogen compound and an alkali solution,
The halogen compound includes chlorine or bromine,
The alkali solution includes an aqueous solution of an alkali metal compound and an aqueous solution of an alkaline earth metal compound as a solvent,
A method for producing ectoin, characterized in that the amount of halogen compound used includes an alkali solution containing phthalic-L-glutamine and a halogen compound in a molar ratio of 1:1 to 5.
산 수용액은 염산, 황산, 브롬산, 술폰산, 벤젠술폰산, 켐퍼술폰산, 아세트산, 트리플루오로 아세트산, 메탄설폰산, 인산 및 유기산 중에서 선택된 1종 이상을 포함하며,
상기 염기 수용액은 하이드라진 화합물은 하이드라진 무수물 또는 하이드라진 수화물을 포함하는 하이드라진 화합물을 포함하는 것을 특징으로 하는 엑토인의 제조방법.
The method of claim 1 or 2, wherein the deprotection reaction is carried out in an aqueous acid solution or an aqueous base solution,
The aqueous acid solution contains at least one selected from hydrochloric acid, sulfuric acid, hydrobromic acid, sulfonic acid, benzenesulfonic acid, camphorsulfonic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, phosphoric acid and organic acids,
The method for preparing ectoin, wherein the aqueous base solution contains a hydrazine compound including hydrazine anhydride or hydrazine hydrate.
The method of claim 1 or 2, wherein the (S) -2,4-diamino butanoic acid salt is (S) -2,4-diamino butanoic acid in sulfuric acid, acetic acid, phosphoric acid, trifluoroacetic acid A method for preparing (S) -2,4-diaminobutanoic acid salt, characterized in that it is produced by salt treatment with an acid solution containing at least one selected from hydrobromic acid, benzenesulfonic acid, camphorsulfonic acid and organic acids.
상기 염기는 유기염기 및 무기염기 중에서 선택된 1종 이상을 포함하고,
상기 유기염기는 트리에틸아민, 디이소프로필에틸아민, 다이메틸아민, 피리딘, 다이에틸아민 중에서 선택된 1종 이상을 포함하며,
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 엑토인의 제조방법.
The basic condition of claim 1, wherein the basic condition of step 3 is formed by introducing a base in an equivalent ratio of 1.0 to 3.0 to (S) -2,4-diaminobutanoic acid or a salt thereof into the mixed solution,
The base includes at least one selected from organic bases and inorganic bases,
The organic base includes at least one selected from triethylamine, diisopropylethylamine, dimethylamine, pyridine, 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, lithium methoxide, A method for producing ectoin comprising at least one selected from lithium ethoxide, sodium hydroxide and potassium hydroxide.
The reaction solvent of claim 1, wherein the reaction solvent in the third step is methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, pentanol, hexanol, heptanol, octanol, isooctanol and 2-ethylhexanol.
상기 알킬아세트이미데이트는 하기 화학식 5로 표시되는 화합물을 포함하는 것을 특징으로 하는 엑토인의 제조방법.
[화학식 5]
CH3C(=NH)OR·HCl
화학식 5에서, R은 C1~C8의 직쇄형 알킬기이다.
The method of claim 1, wherein the mixed solution of step 3 is (S) -2,4-diaminobutanoic acid or its salt in an equivalent ratio of 1.0 to 3.0 trialkylorthoacetate (Trialkylorthoacetate) or alkylacetimidate (Alkylacetimidate) Including,
The method for producing ectoin, characterized in that the alkylacetimidate comprises a compound represented by the following formula (5).
[Formula 5]
CH 3 C(=NH)OR HCl
In Formula 5, R is a C 1 to C 8 straight-chain alkyl group.
The method of claim 1, wherein the ectoin obtained in step 3 is salt-treated with an acid solution containing at least one selected from hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, trifluoroacetic acid, hydrobromic acid, benzenesulfonic acid, camphorsulfonic acid and organic acids. Method for producing ectoin, characterized in that further performing the step of.
The method for preparing ectoin according to claim 1, wherein, after performing the second step, the third step is performed without a separate purification process.
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