WO2023032654A1 - Production method for 4-bromoisothiazolinone derivative and 4-bromoisothiazolinone derivative - Google Patents
Production method for 4-bromoisothiazolinone derivative and 4-bromoisothiazolinone derivative Download PDFInfo
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- WO2023032654A1 WO2023032654A1 PCT/JP2022/030945 JP2022030945W WO2023032654A1 WO 2023032654 A1 WO2023032654 A1 WO 2023032654A1 JP 2022030945 W JP2022030945 W JP 2022030945W WO 2023032654 A1 WO2023032654 A1 WO 2023032654A1
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- WIPO (PCT)
- Prior art keywords
- bromoisothiazolinone
- derivative
- producing
- solvent
- formula
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 60
- -1 isothiazolinone compound Chemical class 0.000 claims abstract description 52
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000003125 aqueous solvent Substances 0.000 claims abstract description 14
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
- 239000012046 mixed solvent Substances 0.000 claims abstract description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 99
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 39
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 38
- 229910052794 bromium Inorganic materials 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 38
- 239000002904 solvent Substances 0.000 claims description 33
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 26
- 238000005893 bromination reaction Methods 0.000 claims description 26
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 20
- 230000031709 bromination Effects 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 239000002002 slurry Substances 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 10
- 238000001953 recrystallisation Methods 0.000 claims description 9
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 abstract 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 47
- 239000000243 solution Substances 0.000 description 47
- 239000012043 crude product Substances 0.000 description 43
- 239000007864 aqueous solution Substances 0.000 description 41
- 239000007787 solid Substances 0.000 description 39
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 35
- 239000012044 organic layer Substances 0.000 description 28
- 229940100555 2-methyl-4-isothiazolin-3-one Drugs 0.000 description 26
- BEGLCMHJXHIJLR-UHFFFAOYSA-N methylisothiazolinone Chemical compound CN1SC=CC1=O BEGLCMHJXHIJLR-UHFFFAOYSA-N 0.000 description 26
- 239000000203 mixture Substances 0.000 description 26
- 239000011259 mixed solution Substances 0.000 description 23
- 229910000029 sodium carbonate Inorganic materials 0.000 description 22
- 238000010438 heat treatment Methods 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- UEFCKYIRXORTFI-UHFFFAOYSA-N 1,2-thiazolidin-3-one Chemical compound O=C1CCSN1 UEFCKYIRXORTFI-UHFFFAOYSA-N 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- PRIJDALNOVDQCY-UHFFFAOYSA-N 4-bromo-2-methyl-1,2-thiazol-3-one Chemical compound CN1SC=C(Br)C1=O PRIJDALNOVDQCY-UHFFFAOYSA-N 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000003242 anti bacterial agent Substances 0.000 description 6
- 238000010813 internal standard method Methods 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 230000003472 neutralizing effect Effects 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000003849 aromatic solvent Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- MGIYRDNGCNKGJU-UHFFFAOYSA-N isothiazolinone Chemical group O=C1C=CSN1 MGIYRDNGCNKGJU-UHFFFAOYSA-N 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 4
- GUUULVAMQJLDSY-UHFFFAOYSA-N 4,5-dihydro-1,2-thiazole Chemical compound C1CC=NS1 GUUULVAMQJLDSY-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- SJXPQSRCFCPWQQ-UHFFFAOYSA-N 2-methyl-1,2-thiazol-2-ium-3-ol;chloride Chemical compound Cl.CN1SC=CC1=O SJXPQSRCFCPWQQ-UHFFFAOYSA-N 0.000 description 2
- 229940031629 2-methyl-4-isothiazolin-3-one hydrochloride Drugs 0.000 description 2
- YIROYDNZEPTFOL-UHFFFAOYSA-N 5,5-Dimethylhydantoin Chemical compound CC1(C)NC(=O)NC1=O YIROYDNZEPTFOL-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 229920001131 Pulp (paper) Polymers 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 2
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 2
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 2
- 239000010985 leather Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000003973 paint Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229940090181 propyl acetate Drugs 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 229960002317 succinimide Drugs 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- 239000004753 textile Substances 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- WJUKOGPNGRUXMG-UHFFFAOYSA-N 1,2-dibromo-1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)(Br)C(Cl)(Cl)Br WJUKOGPNGRUXMG-UHFFFAOYSA-N 0.000 description 1
- HHBCEKAWSILOOP-UHFFFAOYSA-N 1,3-dibromo-1,3,5-triazinane-2,4,6-trione Chemical compound BrN1C(=O)NC(=O)N(Br)C1=O HHBCEKAWSILOOP-UHFFFAOYSA-N 0.000 description 1
- ZPQOPVIELGIULI-UHFFFAOYSA-N 1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1 ZPQOPVIELGIULI-UHFFFAOYSA-N 0.000 description 1
- OOWNNCMFKFBNOF-UHFFFAOYSA-N 1,4-ditert-butylbenzene Chemical compound CC(C)(C)C1=CC=C(C(C)(C)C)C=C1 OOWNNCMFKFBNOF-UHFFFAOYSA-N 0.000 description 1
- NJQJGRGGIUNVAB-UHFFFAOYSA-N 2,4,4,6-tetrabromocyclohexa-2,5-dien-1-one Chemical compound BrC1=CC(Br)(Br)C=C(Br)C1=O NJQJGRGGIUNVAB-UHFFFAOYSA-N 0.000 description 1
- WDZJNLOCKSPDFK-UHFFFAOYSA-N 2-(2,4,4-trimethylpentan-2-yl)-1,2-thiazol-3-one Chemical compound CC(C)(C)CC(C)(C)N1SC=CC1=O WDZJNLOCKSPDFK-UHFFFAOYSA-N 0.000 description 1
- HSFILUIYMMOOFQ-UHFFFAOYSA-N 2-(2-phenylethyl)-1,2-thiazol-3-one Chemical compound O=C1C=CSN1CCC1=CC=CC=C1 HSFILUIYMMOOFQ-UHFFFAOYSA-N 0.000 description 1
- QRADPXNAURXMSB-UHFFFAOYSA-N 2-bromo-1,1-dioxo-1,2-benzothiazol-3-one Chemical compound C1=CC=C2S(=O)(=O)N(Br)C(=O)C2=C1 QRADPXNAURXMSB-UHFFFAOYSA-N 0.000 description 1
- MARXMDRWROUXMD-UHFFFAOYSA-N 2-bromoisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(Br)C(=O)C2=C1 MARXMDRWROUXMD-UHFFFAOYSA-N 0.000 description 1
- HHPJKICDWHTLAV-UHFFFAOYSA-N 2-cyclohexyl-1,2-thiazol-3-one Chemical compound O=C1C=CSN1C1CCCCC1 HHPJKICDWHTLAV-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- ICLPUQPXRDUIMR-UHFFFAOYSA-N 3,4,5,6,7,8,9,10-octahydro-2h-pyrimido[1,2-a]azepin-5-ium;bromide Chemical compound Br.C1CCCCN2CCCN=C21 ICLPUQPXRDUIMR-UHFFFAOYSA-N 0.000 description 1
- NEGRLRUBLMLKTB-UHFFFAOYSA-N 4,5-dibromo-1,2-thiazol-3-one Chemical compound OC1=NSC(Br)=C1Br NEGRLRUBLMLKTB-UHFFFAOYSA-N 0.000 description 1
- SXUVTENOOOIQCY-UHFFFAOYSA-N 4-bromo-2-octyl-1,2-thiazol-3-one Chemical compound CCCCCCCCN1SC=C(Br)C1=O SXUVTENOOOIQCY-UHFFFAOYSA-N 0.000 description 1
- IZCQKQHIGBJWFQ-UHFFFAOYSA-N ClB(Cl)Cl.Br.Br.Br Chemical compound ClB(Cl)Cl.Br.Br.Br IZCQKQHIGBJWFQ-UHFFFAOYSA-N 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- DCTSMHZSJYOAKR-UHFFFAOYSA-L O[Cr](Br)(=O)=O.C1=CC=NC=C1 Chemical compound O[Cr](Br)(=O)=O.C1=CC=NC=C1 DCTSMHZSJYOAKR-UHFFFAOYSA-L 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 208000002029 allergic contact dermatitis Diseases 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- AXDDAQHKIQWFDG-UHFFFAOYSA-N b3596 Chemical compound Br[Br-]Br.CCCCN1C=C[N+](C)=C1 AXDDAQHKIQWFDG-UHFFFAOYSA-N 0.000 description 1
- KTLFENNEPHBKJD-UHFFFAOYSA-K benzyl(trimethyl)azanium;tribromide Chemical compound [Br-].[Br-].[Br-].C[N+](C)(C)CC1=CC=CC=C1.C[N+](C)(C)CC1=CC=CC=C1.C[N+](C)(C)CC1=CC=CC=C1 KTLFENNEPHBKJD-UHFFFAOYSA-K 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GSQACUNMFGRAKY-UHFFFAOYSA-N bromine;1,4-dioxane Chemical compound [Br].C1COCCO1 GSQACUNMFGRAKY-UHFFFAOYSA-N 0.000 description 1
- RGVBVVVFSXWUIM-UHFFFAOYSA-M bromo(dimethyl)sulfanium;bromide Chemical compound [Br-].C[S+](C)Br RGVBVVVFSXWUIM-UHFFFAOYSA-M 0.000 description 1
- XNNQFQFUQLJSQT-UHFFFAOYSA-N bromo(trichloro)methane Chemical compound ClC(Cl)(Cl)Br XNNQFQFUQLJSQT-UHFFFAOYSA-N 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- 239000004566 building material Substances 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000004035 construction material Substances 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 231100000206 health hazard Toxicity 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VDCLSGXZVUDARN-UHFFFAOYSA-N molecular bromine;pyridine;hydrobromide Chemical compound Br.BrBr.C1=CC=NC=C1 VDCLSGXZVUDARN-UHFFFAOYSA-N 0.000 description 1
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- JPMIIZHYYWMHDT-UHFFFAOYSA-N octhilinone Chemical compound CCCCCCCCN1SC=CC1=O JPMIIZHYYWMHDT-UHFFFAOYSA-N 0.000 description 1
- DSNHSQKRULAAEI-UHFFFAOYSA-N para-diethylbenzene Natural products CCC1=CC=C(CC)C=C1 DSNHSQKRULAAEI-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- SRUQAUMZABEGJF-UHFFFAOYSA-M sodium;6-bromo-1,3-diaza-5-azanidacyclohex-6-ene-2,4-dione Chemical compound [Na+].BrC1=NC(=O)NC(=O)[N-]1 SRUQAUMZABEGJF-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- NBNBICNWNFQDDD-UHFFFAOYSA-N sulfuryl dibromide Chemical compound BrS(Br)(=O)=O NBNBICNWNFQDDD-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- SFLXUZPXEWWQNH-UHFFFAOYSA-K tetrabutylazanium;tribromide Chemical compound [Br-].[Br-].[Br-].CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC SFLXUZPXEWWQNH-UHFFFAOYSA-K 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- ZKWDCFPLNQTHSH-UHFFFAOYSA-N tribromoisocyanuric acid Chemical compound BrN1C(=O)N(Br)C(=O)N(Br)C1=O ZKWDCFPLNQTHSH-UHFFFAOYSA-N 0.000 description 1
- PRXNKYBFWAWBNZ-UHFFFAOYSA-N trimethylphenylammonium tribromide Chemical compound Br[Br-]Br.C[N+](C)(C)C1=CC=CC=C1 PRXNKYBFWAWBNZ-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 235000019801 trisodium phosphate Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
- C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Definitions
- the present invention relates to a method for producing a 4-bromoisothiazolinone derivative, and a 4-bromoisothiazolinone derivative obtained by the production method.
- Antibacterial agents are used in various situations such as industrial preservatives, construction materials, paints, adhesives, leather, paper pulp, cooling towers, industrial oils, textiles, cleaning aids, cosmetics, and household products. It is used. As an antibacterial agent, the development of a safer antibacterial agent with a low possibility of causing health hazards such as allergic contact dermatitis is desired. 4-bromoisothiazolinone derivatives belong to isothiazoline antibacterial agents and are reported to have bactericidal and antibacterial activities (see, for example, Patent Document 1).
- a 4-bromoisothiazolinone derivative can be produced by brominating an isothiazolinone compound unsubstituted at the 4-position, and is described, for example, in Patent Documents 1 to 3 and Non-Patent Documents 1 and 2.
- Patent Documents 1 to 3 and Non-Patent Documents 1 and 2. none of these methods are necessarily satisfactory in terms of reaction yield, product purity, etc., and are difficult to put into practical use.
- Patent Document 1 describes a bromination reaction of 2-methyl-4-isothiazolin-3-one in a dichloroethane solvent using bromine (1 equivalent) to give the desired 4-bromo-2-methyl-4-
- the yield of isothiazolin-3-one is stated to be only 14%.
- 2-(1,1,3,3-tetramethylbutyl)-4-isothiazolin-3-one is brominated using N-bromosuccinimide (2 equivalents) in a chloroform solvent, the desired product yield is stated as 54%.
- Non-Patent Document 1 describes a bromination reaction of 2-cyclohexyl-4-isothiazolin-3-one using bromine (1 equivalent) and a bromine reaction of 2-(2-phenylethyl)-4-isothiazolin-3-one. (3 equivalents), the desired 2-alkyl-4-bromo-4-isothiazolin-3-one derivatives are obtained in yields of 75% and 63%, respectively.
- the addition of an excess amount of bromine in the same reaction results in the by-production of a 2-alkyl-4,5-dibromo-4-isothiazolin-3-one derivative in which the 5-position of the isothiazoline ring is also brominated.
- Patent Document 2 2-octyl-4-isothiazolin-3-one is subjected to a bromination reaction in an N,N-dimethylformamide solvent using 3 equivalents of bromine to give the desired 4-bromo-2- Octyl-4-isothiazolin-3-one is reported to be obtained in high yields of 93%, but 4,5-dibromo-4-isothiazolin-3-one formed when excess bromine is used. No mention is made of by-products of on-derivatives. When an excessive amount of bromine is used, a step of treating the highly reactive excessive bromine after completion of the reaction is required, and it cannot be said to be an efficient production method from the viewpoint of economy.
- Non-Patent Document 2 N,N-di- ⁇ -methylbenzyl-3,3-dithiodipropionamide is reacted with sulfuryl chloride, followed by bromination in a dichloromethane solvent using bromine. , the desired 2-(S)- ⁇ -methylbenzyl-4-bromo-4-isothiazolin-3-one is obtained in a yield of 72%, but the isothiazoline ring is chlorinated at the 5-position.
- 2-(S)- ⁇ -methylbenzyl-4-bromo-5-chloro-4-isothiazolin-3-one is produced as a by-product, and the method cannot necessarily be said to have good selectivity.
- Patent Document 3 discloses that 4-bromo-2-[1-(3-chlorophenyl)-1-methylethyl]-4-isothiazolin-3-one, which is an intermediate for the production of herbicidally active compounds, has a corresponding 4-position free Bromination of substituted 2-[1-(3-chlorophenyl)-1-methylethyl]-4-isothiazolin-3-one with 1 equivalent of bromine in acetic acid in 88% yield
- the raw material used is a bulky and highly fat-soluble substituent containing an aromatic group such as 1-(3-chlorophenyl)-1-methylethyl group on the nitrogen atom at the 2-position. have.
- An object of the present invention is to provide a method for producing a highly pure 4-bromoisothiazolinone derivative with good selectivity and yield, and a 4-bromoisothiazolinone derivative obtained by the production method.
- the present invention uses formula (1) (Wherein, R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms.)
- a method for producing a 4-bromoisothiazolinone derivative represented by formula (2) (Wherein R is the same as formula (1)), an isothiazolinone compound or a chemically acceptable salt thereof is brominated in an aqueous solvent or a mixed solvent of an aqueous solvent and an organic solvent.
- the purification method in step b) is preferably a method by recrystallization or slurry washing.
- the solvent used for recrystallization or slurry washing is preferably at least one of ethyl acetate, chlorobenzene, and o-dichlorobenzene.
- the amount of the water solvent used is preferably in the range of 0.1 to 10 in weight ratio to the starting material.
- the brominating agent is preferably bromine, N-bromosuccinimide, or 1,3-dibromo-5,5-dimethylhydantoin.
- the reaction temperature in the bromination is preferably in the range of 0°C to 80°C.
- R is preferably an alkyl group having 1 to 4 carbon atoms.
- isothiazolinone compound represented by formula (2) or a chemically acceptable salt thereof, which is a 4-bromoisothiazolinone derivative represented by formula (1) and which is contained in the 4-bromoisothiazolinone derivative is less than 100 ppm.
- R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms.
- R is the same as in formula (1).
- the present inventors have found that, in a reaction for brominating a specific isothiazolinone compound unsubstituted at the 4-position using a brominating agent, in a water solvent or a mixed solvent of a water solvent and an organic solvent It was found that a 4-bromoisothiazolinone derivative selectively brominated at the 4-position can be produced in good yield by conducting the reaction in the above. Further, the present inventors have found a purification method by which a highly pure target product can be efficiently obtained by recrystallization or slurry washing of the obtained 4-bromoisothiazolinone derivative under specific conditions.
- a method for producing a 4-bromoisothiazolinone derivative according to an embodiment of the present invention comprises formula (1) (Wherein, R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms). .), comprising: formula (2) (Wherein R is the same as in formula (1)), an isothiazolinone compound (hereinafter sometimes referred to as isothiazolinone compound (2)) or a chemically acceptable salt thereof is added to an aqueous solvent. bromination using a brominating agent in a mixed solvent of an aqueous solvent and an organic solvent.
- the method for producing a 4-bromoisothiazolinone derivative comprises Step a): Formula (2) (Wherein, R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms.) An isothiazolinone compound or a chemically acceptable salt thereof represented by In a solvent, bromination using a brominating agent, formula (1) (Wherein R is the same as formula (2).) Synthesizing a 4-bromoisothiazolinone derivative represented by Step b): purifying the 4-bromoisothiazolinone derivative obtained in step a).
- alkyl group having 1 to 12 carbon atoms represented by R examples include methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, isobutyl group, tert-butyl group, cyclobutyl group, n-pentyl group, isopentyl group, neopentyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group , 2-ethylbutyl group, cyclohexyl group, n-heptyl group, cycloheptyl group, n-octyl group, cyclooctyl group, n-nonyl group, cyclononyl group, n-decyl group, cycl
- the isothiazolinone compound (2) may form a chemically acceptable salt.
- the type of salt is not particularly limited, but examples include hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate and the like. Hydrochloride is preferred because it is readily available.
- the bromination reaction in the method for producing a 4-bromoisothiazolinone derivative according to this embodiment is carried out in the presence of a water solvent.
- This bromination reaction may be carried out using only water as a solvent, or may be carried out in a mixed solvent of water and an organic solvent which hardly affects the reaction.
- organic solvents used for bromination include halogen solvents such as chloroform, dichloromethane and carbon tetrachloride; amide solvents such as dimethylformamide and dimethylacetamide; or toluene, xylene, mesitylene, chlorobenzene, o-dichlorobenzene and the like.
- Aromatic solvents and the like are included. From the viewpoint of good yield, it is preferable to use an aromatic solvent, and it is more preferable to use chlorobenzene or o-dichlorobenzene.
- the amount of water may be, for example, in the range of 0.1 to 10 in weight ratio to the raw material.
- the mixing ratio of water and the organic solvent is not particularly limited. A mixing ratio appropriately selected from the range of 1 may be used.
- the brominating agent used in the bromination reaction includes bromine, bromine-1,4-dioxane complex, N-bromosuccinimide (hereinafter sometimes referred to as NBS), 1,3-dibromo-5,5- dimethylhydantoin (hereinafter sometimes referred to as DBH), tribromoisocyanuric acid, dibromoisocyanuric acid (hereinafter sometimes referred to as DBI), monosodium bromoisocyanurate, tetrabutylammonium tribromide, bromotrichloromethane, 1,2-dibromo-1,1,2,2-tetrachloroethane, carbon tetrabromide, trimethylphenylammonium tribromide, benzyltrimethylammonium tribromide, tetrapropylammonium nonabromide, pyridinium bromide perbromide, pyridinium bromochromate, 1 -butyl-3-methylimi
- the amount of the brominating agent to be used is preferably 0.5 to 2 molar equivalents relative to the amount of isothiazolinone compound (2) or a chemically acceptable salt thereof as a starting material, resulting in good selectivity and yield. more preferably 0.8 to 1.5 molar equivalents.
- the method of contacting the isothiazolinone compound (2) or a chemically acceptable salt thereof with the brominating agent is not particularly limited.
- a brominating agent may be added to a chemically acceptable salt thereof and mixed using a stirring device such as a mechanical stirrer.
- the bromination reaction can be carried out at a reaction temperature appropriately selected from the range of 0°C to the reflux temperature of the solvent, and from the viewpoint of good selectivity and yield, the reaction temperature is selected from the range of 0°C to 80°C. It is preferable to carry out at The reaction time may be, for example, 1 to 48 hours.
- the 4-bromoisothiazolinone derivative (1) obtained by general post-treatment operations such as extraction and concentration may contain impurities.
- Impurities include an unreacted raw material isothiazolinone compound (2) having similar chemical properties to the target 4-bromoisothiazolinone derivative (1) or a chemically acceptable salt thereof, as well as an isothiazolinone ring and a compound in which the 5-position of is brominated, and a compound in which the 4- and 5-positions are brominated.
- NBS or DBH is used as a brominating agent, succinimide or 5,5-dimethylhydantoin may remain. Therefore, it is difficult to remove these impurities and obtain a highly purified target product at a high recovery rate by a general purification method.
- Step b) is a step of purifying the 4-bromoisothiazolinone derivative (1) obtained by the bromination reaction. This is a step for obtaining the isothiazolinone derivative (1) at a high recovery rate.
- the solvent used in step b it is preferable to use a halogen solvent, an ester solvent, an aromatic solvent, or the like.
- halogen-based solvents include chloroform, dichloromethane, dichloroethane, and carbon tetrachloride.
- ester solvents include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate and the like.
- aromatic solvents include toluene, xylene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, nitrobenzene and the like.
- chloroform, dichloromethane, carbon tetrachloride, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate, toluene, chlorobenzene or o-dichlorobenzene are preferred in terms of good yield (recovery), and ethyl acetate , chlorobenzene and o-dichlorobenzene are more preferred.
- the conditions for recrystallization in step b) will be explained.
- the 4-bromoisothiazolinone derivative (1) mixed with the solvent is dissolved by heating, and then cooled to precipitate the highly pure 4-bromoisothiazolinone derivative (1).
- the amount of the solvent to be used is an amount appropriately selected from the range of, for example, 10% by weight to 1000% by weight with respect to the weight of the 4-bromoisothiazolinone derivative (1) obtained in step a).
- 4-bromoisothiazolinone derivative (1) is preferably added in the minimum amount of solvent that completely dissolves it.
- the temperature during heating can be appropriately selected from the range of 25° C. to the reflux temperature of the solvent. There is no particular limitation on the temperature for cooling, and although it may be cooled in an ice bath, it may be allowed to cool to room temperature (eg, 18 to 28°C).
- High-purity 4-bromoisothiazolinone derivative (1) can be precipitated by suspending 4-bromoisothiazolinone derivative (1) in a solvent.
- the amount of the solvent to be used is appropriately selected from the range of, for example, 10% by weight to 1000% by weight with respect to the weight of the 4-bromoisothiazolinone derivative (1) obtained in step a). be able to.
- the suspension can be carried out at a reaction temperature appropriately selected, for example, from the range of -20°C to the reflux temperature of the solvent.
- a highly pure 4-bromoisothiazolinone derivative (1) can be isolated by filtering the precipitated solid.
- the method of filtration is not particularly limited, and for example, it may be carried out by appropriately selecting from natural filtration, vacuum filtration, centrifugal filtration, etc. according to the reaction scale and the like. Vacuum filtration and centrifugal filtration are preferred because they are efficient and can shorten the time.
- step b The higher the purity of the 4-bromoisothiazolinone derivative (1) used in step b), the more efficiently a highly pure target product can be obtained.
- NBS or DBH is used as the brominating agent
- succinimide and 5,5-dimethylhydantoin generated from NBS and DBH, respectively are preferably removed as much as possible before recrystallization or slurry washing.
- a method for removing these impurities for example, a method of washing the reaction mixture with a basic aqueous solution after completion of the bromination reaction can be exemplified.
- Basic aqueous solutions include, for example, sodium acetate aqueous solution, potassium acetate aqueous solution, sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium carbonate aqueous solution, potassium carbonate aqueous solution, sodium hydrogen carbonate aqueous solution, potassium hydrogen carbonate aqueous solution, trisodium phosphate aqueous solution, An aqueous solution of tripotassium phosphate and the like can be mentioned.
- step b) may be repeated until the 4-bromoisothiazolinone derivative (1) reaches the desired purity.
- a method for producing a 4-bromoisothiazolinone derivative according to an embodiment of the present invention is a method for producing a 4-bromoisothiazolinone derivative useful as an active ingredient of a fungicide or an antibacterial agent with good selectivity, yield and purity. is useful as
- a 4-bromoisothiazolinone derivative that can be produced with high yield and high purity by the method for producing a 4-bromoisothiazolinone derivative according to an embodiment of the present invention is useful as an active ingredient of a disinfectant and an antibacterial agent. It can be used in various fields such as industrial preservatives, building materials, paints, adhesives, leather, paper pulp, cooling towers, industrial oils, textiles, cleaning aids, cosmetics and household products.
- the 4-bromoisothiazolinone derivative represented by the above formula (1) produced by the method for producing a 4-bromoisothiazolinone derivative according to an embodiment of the present invention is an isothiazolinone compound represented by the above formula (2) or its
- the content of chemically acceptable salts is less than 100 ppm.
- Formula (1) (Wherein, R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms.)
- a method for producing a 4-bromoisothiazolinone derivative represented by formula (2) (Wherein R is the same as formula (1)), an isothiazolinone compound or a chemically acceptable salt thereof is brominated in an aqueous solvent or a mixed solvent of an aqueous solvent and an organic solvent.
- [5] A method for producing a 4-bromoisothiazolinone derivative according to any one of [1] to [4], A method for producing a 4-bromoisothiazolinone derivative, wherein the amount of the water solvent used is in the range of 0.1 to 10 in weight ratio to the starting material.
- [6] A method for producing a 4-bromoisothiazolinone derivative according to any one of [1] to [5], A method for producing a 4-bromoisothiazolinone derivative, wherein the brominating agent is bromine, N-bromosuccinimide, or 1,3-dibromo-5,5-dimethylhydantoin.
- [7] A method for producing a 4-bromoisothiazolinone derivative according to any one of [1] to [6], A method for producing a 4-bromoisothiazolinone derivative, wherein the reaction temperature in the bromination is in the range of 0°C to 80°C.
- [8] A method for producing a 4-bromoisothiazolinone derivative according to any one of [1] to [7], A method for producing a 4-bromoisothiazolinone derivative, wherein said R is an alkyl group having 1 to 4 carbon atoms.
- a 4-bromoisothiazolinone derivative represented by formula (1) which is an isothiazolinone compound represented by formula (2) included in the 4-bromoisothiazolinone derivative, or a chemically acceptable salt thereof content is less than 100 ppm, 4-bromoisothiazolinone derivative.
- R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms.
- R is the same as in formula (1).
- the composition and yield of crude products were determined by the 1 H-NMR internal standard method.
- the 1 H-NMR internal standard method a predetermined amount of 1,4-di-tert-butylbenzene is added as an internal standard substance to the crude product, and chloroform or a mixed solution of chloroform and dimethylformamide is added to obtain a substantially homogeneous solution. A portion of this solution was sampled, diluted with deuterated chloroform, and subjected to 1 H-NMR measurement. From the integrated values in the obtained 1 H-NMR spectrum, the ratio of the target substance and starting material to the internal standard substance was calculated, and the composition and yield were determined.
- Example 4 After adding water (2.30 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.00 g, 8.68 mmol), bromine (0.53 mL, 10.4 mmol) was added for 10 minutes. dripped over. This mixed solution was stirred at room temperature for 3 hours. After neutralizing the reaction solution by adding a 20 wt% aqueous sodium carbonate solution, it was extracted with ethyl acetate (15 mL x 3 times), and each organic layer was separated with a 1:1 mixture of 20 wt% sodium carbonate aqueous solution and saturated brine ( 2 mL each). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.60 g).
- Example 7 After adding water (75.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 100.19 g, 435 mmol), bromine (27.0 mL, 524 mmol) was added over 2.5 hours. Dripped. This mixed solution was stirred at room temperature for 1 hour. A 20% by weight sodium carbonate aqueous solution was added to the reaction solution to neutralize it, then saturated brine (200 mL) was added, and the mixture was extracted with ethyl acetate (350 mL ⁇ 3 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired crude product (78.57 g).
- Example 8> After adding water (150.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 200.09 g, 869 mmol), bromine (54.0 mL, 1.05 mol) was added over 5 hours. Dripped. This mixed solution was stirred at room temperature for 1 hour. After neutralizing the reaction solution by adding a 20% by weight aqueous sodium carbonate solution, saturated brine (400 mL) was added, and the mixture was extracted with ethyl acetate (500 mL ⁇ 4 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired crude product (159.33 g).
- Example 9 After adding water (3.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 4.00 g, 17.4 mmol), bromine (1.07 mL, 20.9 mmol) was added at 40°C. was added dropwise over 10 minutes. This mixed solution was stirred at 40° C. for 2 hours. A saturated aqueous sodium carbonate solution was added to the reaction solution to neutralize it, saturated brine (8 mL) was added, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (3.14 g).
- Example 11 After adding water (7.50 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 10.02 g, 43.5 mmol), bromine (2.70 mL, 52.4 mmol) was added for 45 minutes. dripped over. The mixed solution was stirred overnight (12 hours) at room temperature. A saturated sodium carbonate aqueous solution was added to the reaction solution to neutralize it, then a saturated saline solution (20 mL) was added, and the mixture was extracted with methyl isobutyl ketone (35 mL ⁇ 3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (7.85 g).
- Example 12 After adding water (7.50 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 10.02 g, 43.5 mmol), bromine (2.70 mL, 52.4 mmol) was added for 45 minutes. dripped over. The mixed solution was stirred overnight at room temperature. A saturated sodium carbonate aqueous solution was added to the reaction solution to neutralize it, then a saturated saline solution (20 mL) was added, and the mixture was extracted with chlorobenzene (35 mL ⁇ 3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (7.57 g).
- Example 13> After adding water (7.50 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 10.03 g, 43.5 mmol), bromine (2.70 mL, 52.4 mmol) was added for 45 minutes. dripped over. The mixed solution was stirred overnight at room temperature. A saturated aqueous sodium carbonate solution was added to the reaction solution for neutralization, then saturated brine (20 mL) was added, and the mixture was extracted with o-dichlorobenzene (35 mL ⁇ 3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (7.53 g).
- Example 17 After adding water (10.0 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 10.11 g, 43.9 mmol), bromine (2.75 mL, 53.3 mmol) in chlorobenzene ( 20.0 mL) solution was added dropwise over 30 minutes. The mixed solution was stirred overnight at room temperature. Saturated saline (50 mL) was added to the reaction solution, which was then neutralized with a saturated aqueous sodium carbonate solution and then extracted with chlorobenzene (50 mL x 4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (8.06 g).
- Example 18 After adding water (1.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.02 g, 8.75 mmol), bromine (0.54 mL, 10.5 mmol) in chlorobenzene ( 4.0 mL) solution was added dropwise over 30 minutes. The mixed solution was stirred overnight at room temperature. Saturated saline (10 mL) was added to the reaction solution, which was then neutralized with a saturated aqueous sodium carbonate solution and then extracted with chlorobenzene (10 mL x 4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.61 g).
- Example 19 After adding water (2.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.03 g, 8.81 mmol), o- Dichlorobenzene (4.0 mL) solution was added dropwise over 30 minutes. This mixed solution was stirred at room temperature for 6 hours. Saturated saline (10 mL) was added to the reaction solution, which was then neutralized with saturated aqueous sodium carbonate solution and then extracted with o-dichlorobenzene (10 mL ⁇ 4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.86 g).
- Example 20 After adding water (4.40 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.02 g, 8.75 mmol), bromine (0.54 mL, 10.5 mmol) was added for 10 minutes. dripped over. This mixed solution was stirred at room temperature for 3 hours. A saturated aqueous sodium carbonate solution was added to the reaction solution to neutralize it, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL ⁇ 4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.66 g). As a result of analysis by 1 H-NMR internal standard method, the composition and yield were as follows. Table 1 shows the results.
- Example 21 After adding water (2.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.02 g, 8.78 mmol), bromine (0.54 mL, 10.5 mmol) in chlorobenzene ( 4.0 mL) solution was added dropwise over 30 minutes. The mixed solution was stirred overnight at room temperature. A saturated sodium carbonate aqueous solution was added to the reaction solution to neutralize it, then a saturated saline solution (10 mL) was added, and the mixture was extracted with chlorobenzene (10 mL ⁇ 4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.62 g). As a result of analysis by 1 H-NMR internal standard method, the composition and yield were as follows. Table 1 shows the results.
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Abstract
Provided is a method for selectively producing a high-purity 4-bromoisothiazolinone derivative at a good yield. Provided is a method for producing a 4-bromoisothiazolinone derivative represented by formula (1) (in which R is a hydrogen atom or a C1–12 alkyl group). The method involves using a brominating agent to brominate an isothiazolinone compound represented by formula (2) (in which R is the same as in formula (1)) or a chemically acceptable salt thereof in an aqueous solvent or a mixed solvent of an aqueous solvent and an organic solvent.
Description
本発明は、４－ブロモイソチアゾリノン誘導体の製造方法、およびその製造方法により得られる４－ブロモイソチアゾリノン誘導体に関する。
The present invention relates to a method for producing a 4-bromoisothiazolinone derivative, and a 4-bromoisothiazolinone derivative obtained by the production method.
抗菌剤（防腐剤）は、工業用防腐剤、建築用資材、塗料、接着剤、皮革、紙パルプ、冷却塔、工業用オイル、繊維、洗浄助剤、化粧品、家庭用品等の様々な場面で使用されている。抗菌剤としては、アレルギー性接触皮膚炎等の健康被害を引き起こす可能性の低い、より安全な抗菌剤の開発が切望されている。４－ブロモイソチアゾリノン誘導体は、イソチアゾリン系抗菌剤に属し、殺菌活性や抗菌活性を有することが報告されている（例えば、特許文献１参照）。４－ブロモイソチアゾリノン誘導体は、４位が無置換のイソチアゾリノン化合物を臭素化することによって製造することができ、例えば、特許文献１～３や非特許文献１，２等に記載されているが、いずれの方法も、反応の収率や生成物の純度等の点で必ずしも満足できるものではなく、実用化が困難であった。
Antibacterial agents (preservatives) are used in various situations such as industrial preservatives, construction materials, paints, adhesives, leather, paper pulp, cooling towers, industrial oils, textiles, cleaning aids, cosmetics, and household products. It is used. As an antibacterial agent, the development of a safer antibacterial agent with a low possibility of causing health hazards such as allergic contact dermatitis is desired. 4-bromoisothiazolinone derivatives belong to isothiazoline antibacterial agents and are reported to have bactericidal and antibacterial activities (see, for example, Patent Document 1). A 4-bromoisothiazolinone derivative can be produced by brominating an isothiazolinone compound unsubstituted at the 4-position, and is described, for example, in Patent Documents 1 to 3 and Non-Patent Documents 1 and 2. However, none of these methods are necessarily satisfactory in terms of reaction yield, product purity, etc., and are difficult to put into practical use.
例えば、特許文献１には、２－メチル－４－イソチアゾリン－３－オンの臭素（１当量）を用いたジクロロエタン溶媒中での臭素化反応において、目的の４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの収率が、わずか１４％であると記載されている。また、２－（１，１，３，３－テトラメチルブチル）－４－イソチアゾリン－３－オンをクロロホルム溶媒中でＮ－ブロモスクシンイミド（２当量）を用いて臭素化した場合には、目的物の収率は５４％と記載されている。
For example, Patent Document 1 describes a bromination reaction of 2-methyl-4-isothiazolin-3-one in a dichloroethane solvent using bromine (1 equivalent) to give the desired 4-bromo-2-methyl-4- The yield of isothiazolin-3-one is stated to be only 14%. Further, when 2-(1,1,3,3-tetramethylbutyl)-4-isothiazolin-3-one is brominated using N-bromosuccinimide (2 equivalents) in a chloroform solvent, the desired product yield is stated as 54%.
非特許文献１には、２－シクロヘキシル－４－イソチアゾリン－３－オンの臭素（１当量）を用いた臭素化反応、および２－（２－フェニルエチル）－４－イソチアゾリン－３－オンの臭素（３当量）を用いた臭素化反応において、目的とする２－アルキル－４－ブロモ－４－イソチアゾリン－３－オン誘導体が、それぞれ７５％および６３％の収率で得られると記載されているが、同反応において過剰量の臭素を添加すると、イソチアゾリン環の５位も臭素化された２－アルキル－４，５－ジブロモ－４－イソチアゾリン－３－オン誘導体が副生することが報告されている。
Non-Patent Document 1 describes a bromination reaction of 2-cyclohexyl-4-isothiazolin-3-one using bromine (1 equivalent) and a bromine reaction of 2-(2-phenylethyl)-4-isothiazolin-3-one. (3 equivalents), the desired 2-alkyl-4-bromo-4-isothiazolin-3-one derivatives are obtained in yields of 75% and 63%, respectively. However, it has been reported that the addition of an excess amount of bromine in the same reaction results in the by-production of a 2-alkyl-4,5-dibromo-4-isothiazolin-3-one derivative in which the 5-position of the isothiazoline ring is also brominated. there is
特許文献２には、２－オクチル－４－イソチアゾリン－３－オンに対して３当量の臭素を用いてＮ，Ｎ－ジメチルホルムアミド溶媒中で臭素化反応を行い、目的の４－ブロモ－２－オクチル－４－イソチアゾリン－３－オンが９３％の高収率で得られる旨、記載されているが、過剰量の臭素を用いた際に生成する４，５－ジブロモ－４－イソチアゾリン－３－オン誘導体の副生に関しては一切記述されていない。過剰量の臭素を使用した場合、反応性の高い余剰の臭素を反応終了後に処理する工程が必要であり、経済性の観点からも効率の良い製造方法とは言えない。
In Patent Document 2, 2-octyl-4-isothiazolin-3-one is subjected to a bromination reaction in an N,N-dimethylformamide solvent using 3 equivalents of bromine to give the desired 4-bromo-2- Octyl-4-isothiazolin-3-one is reported to be obtained in high yields of 93%, but 4,5-dibromo-4-isothiazolin-3-one formed when excess bromine is used. No mention is made of by-products of on-derivatives. When an excessive amount of bromine is used, a step of treating the highly reactive excessive bromine after completion of the reaction is required, and it cannot be said to be an efficient production method from the viewpoint of economy.
非特許文献２には、Ｎ，Ｎ－ジ－α－メチルベンジル－３，３－ジチオジプロピオンアミドにスルフリルクロリドを反応させた後、続いて臭素を用いたジクロロメタン溶媒中での臭素化反応において、目的とする２－（Ｓ）－α－メチルベンジル－４－ブロモ－４－イソチアゾリン－３－オンが収率７２％で得られると記載されているが、イソチアゾリン環の５位が塩素化された２－（Ｓ）－α－メチルベンジル－４－ブロモ－５－クロロ－４－イソチアゾリン－３－オンが副生することが報告されており、必ずしも選択性の良い方法とは言えない。また、副生成物を分離する工程が必要であり、経済性の観点からも効率の良い方法とは言えない。また、２－エチル－４－ブロモ－４－イソチアゾリン－３－オンの合成も記載されているが、収率は５６％であり、満足できるものではない。
In Non-Patent Document 2, N,N-di-α-methylbenzyl-3,3-dithiodipropionamide is reacted with sulfuryl chloride, followed by bromination in a dichloromethane solvent using bromine. , the desired 2-(S)-α-methylbenzyl-4-bromo-4-isothiazolin-3-one is obtained in a yield of 72%, but the isothiazoline ring is chlorinated at the 5-position. However, it has been reported that 2-(S)-α-methylbenzyl-4-bromo-5-chloro-4-isothiazolin-3-one is produced as a by-product, and the method cannot necessarily be said to have good selectivity. Moreover, a step of separating by-products is required, and it cannot be said that this is an efficient method from the viewpoint of economy. Also the synthesis of 2-ethyl-4-bromo-4-isothiazolin-3-one is described, but the yield is 56% which is not satisfactory.
特許文献３には、除草活性化合物の製造中間体である４－ブロモ－２－［１－（３－クロロフェニル）－１－メチルエチル］－４－イソチアゾリン－３－オンが、対応する４位無置換体の２－［１－（３－クロロフェニル）－１－メチルエチル］－４－イソチアゾリン－３－オンを酢酸中で１当量の臭素を用いて臭素化することにより、８８％の収率で合成できることが記載されているが、用いる原料が、２位の窒素原子上に１－（３－クロロフェニル）－１－メチルエチル基のような芳香族基を含む嵩高く脂溶性の高い置換基を有する。
Patent Document 3 discloses that 4-bromo-2-[1-(3-chlorophenyl)-1-methylethyl]-4-isothiazolin-3-one, which is an intermediate for the production of herbicidally active compounds, has a corresponding 4-position free Bromination of substituted 2-[1-(3-chlorophenyl)-1-methylethyl]-4-isothiazolin-3-one with 1 equivalent of bromine in acetic acid in 88% yield Although it is described that it can be synthesized, the raw material used is a bulky and highly fat-soluble substituent containing an aromatic group such as 1-(3-chlorophenyl)-1-methylethyl group on the nitrogen atom at the 2-position. have.
なお、特許文献１～３および非特許文献１，２に記載の臭素化方法は、反応を有機溶媒中で行っており、水溶媒の存在下で反応を行った例は一切記載されていない。
In addition, in the bromination methods described in Patent Documents 1 to 3 and Non-Patent Documents 1 and 2, the reaction is performed in an organic solvent, and no example of the reaction in the presence of a water solvent is described.
本発明の目的は、高純度の４－ブロモイソチアゾリノン誘導体を、選択性および収率よく製造する方法、およびその製造方法により得られる４－ブロモイソチアゾリノン誘導体を提供することにある。
An object of the present invention is to provide a method for producing a highly pure 4-bromoisothiazolinone derivative with good selectivity and yield, and a 4-bromoisothiazolinone derivative obtained by the production method.
本発明は、式（１）
（式中、Ｒは、水素原子または炭素数１～１２のアルキル基を表す。）で示される４－ブロモイソチアゾリノン誘導体を製造する方法であって、
式（２）
（式中、Ｒは、式（１）と同じである。）で示されるイソチアゾリノン化合物またはその化学的に許容される塩を、水溶媒中または水溶媒と有機溶媒との混合溶媒中で臭素化剤を用いて臭素化する、４－ブロモイソチアゾリノン誘導体の製造方法である。
The present invention uses formula (1)
(Wherein, R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms.) A method for producing a 4-bromoisothiazolinone derivative represented by
formula (2)
(Wherein R is the same as formula (1)), an isothiazolinone compound or a chemically acceptable salt thereof is brominated in an aqueous solvent or a mixed solvent of an aqueous solvent and an organic solvent. A method for producing a 4-bromoisothiazolinone derivative by bromination using an agent.
式（２）
formula (2)
前記４－ブロモイソチアゾリノン誘導体の製造方法において、工程ａ）：前記式（２）で示されるイソチアゾリノン化合物またはその化学的に許容される塩を、前記水溶媒中または水溶媒と有機溶媒との混合溶媒中で、前記臭素化剤を用いて臭素化し、前記式（１）で示される４－ブロモイソチアゾリノン誘導体を合成する工程と、工程ｂ）：前記工程ａ）で得られた４－ブロモイソチアゾリノン誘導体を精製する工程と、を含むことが好ましい。
In the method for producing a 4-bromoisothiazolinone derivative, step a): the isothiazolinone compound represented by the formula (2) or a chemically acceptable salt thereof is added in the water solvent or in a water solvent and an organic solvent. a step of synthesizing the 4-bromoisothiazolinone derivative represented by the formula (1) by bromination in a mixed solvent using the brominating agent; and step b): the 4- obtained in step a). and purifying the bromoisothiazolinone derivative.
前記４－ブロモイソチアゾリノン誘導体の製造方法において、前記工程ｂ）における精製する方法が、再結晶またはスラリー洗浄による方法であることが好ましい。
In the method for producing a 4-bromoisothiazolinone derivative, the purification method in step b) is preferably a method by recrystallization or slurry washing.
前記４－ブロモイソチアゾリノン誘導体の製造方法において、前記再結晶またはスラリー洗浄に使用する溶媒が、酢酸エチル、クロロベンゼン、およびｏ－ジクロロベンゼンのうちの少なくとも１つであることが好ましい。
In the method for producing a 4-bromoisothiazolinone derivative, the solvent used for recrystallization or slurry washing is preferably at least one of ethyl acetate, chlorobenzene, and o-dichlorobenzene.
前記４－ブロモイソチアゾリノン誘導体の製造方法において、使用する前記水溶媒の量が、原料に対する重量比で０．１から１０の範囲であることが好ましい。
In the method for producing a 4-bromoisothiazolinone derivative, the amount of the water solvent used is preferably in the range of 0.1 to 10 in weight ratio to the starting material.
前記４－ブロモイソチアゾリノン誘導体の製造方法において、前記臭素化剤が、臭素、Ｎ－ブロモスクシンイミド、または１，３－ジブロモ－５，５－ジメチルヒダントインであることが好ましい。
In the method for producing a 4-bromoisothiazolinone derivative, the brominating agent is preferably bromine, N-bromosuccinimide, or 1,3-dibromo-5,5-dimethylhydantoin.
前記４－ブロモイソチアゾリノン誘導体の製造方法において、前記臭素化における反応温度が、０℃から８０℃の範囲であることが好ましい。
In the method for producing a 4-bromoisothiazolinone derivative, the reaction temperature in the bromination is preferably in the range of 0°C to 80°C.
前記４－ブロモイソチアゾリノン誘導体の製造方法において、前記Ｒが、炭素数１～４のアルキル基であることが好ましい。
In the method for producing a 4-bromoisothiazolinone derivative, R is preferably an alkyl group having 1 to 4 carbon atoms.
式（１）で示される４－ブロモイソチアゾリノン誘導体であって、前記４－ブロモイソチアゾリノン誘導体に含まれる式（２）で示されるイソチアゾリノン化合物またはその化学的に許容される塩の含有量が１００ｐｐｍ未満である、４－ブロモイソチアゾリノン誘導体である。
（式中、Ｒは、水素原子または炭素数１～１２のアルキル基を表す。）
（式中、Ｒは、式（１）と同じである。）
Content of the isothiazolinone compound represented by formula (2) or a chemically acceptable salt thereof, which is a 4-bromoisothiazolinone derivative represented by formula (1) and which is contained in the 4-bromoisothiazolinone derivative is less than 100 ppm.
(Wherein, R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms.)
(Wherein, R is the same as in formula (1).)
本発明により、高純度の４－ブロモイソチアゾリノン誘導体を、選択性および収率よく製造する方法、およびその製造方法により得られる４－ブロモイソチアゾリノン誘導体を提供することができる。
According to the present invention, it is possible to provide a method for producing a highly pure 4-bromoisothiazolinone derivative with good selectivity and yield, and a 4-bromoisothiazolinone derivative obtained by the production method.
本発明の実施の形態について以下説明する。本実施形態は本発明を実施する一例であって、本発明は本実施形態に限定されるものではない。
An embodiment of the present invention will be described below. This embodiment is an example of implementing the present invention, and the present invention is not limited to this embodiment.
本発明者らは、鋭意検討を重ねた結果、４位が無置換の特定のイソチアゾリノン化合物を、臭素化剤を用いて臭素化する反応において、水溶媒中または水溶媒と有機溶媒との混合溶媒中で反応を行うことにより、４位が選択的に臭素化された４－ブロモイソチアゾリノン誘導体が、収率よく製造できることを見出した。さらに、得られた４－ブロモイソチアゾリノン誘導体を特定の条件下で再結晶またはスラリー洗浄することにより、高純度の目的物が効率よく得られる精製方法を見出した。
As a result of extensive studies, the present inventors have found that, in a reaction for brominating a specific isothiazolinone compound unsubstituted at the 4-position using a brominating agent, in a water solvent or a mixed solvent of a water solvent and an organic solvent It was found that a 4-bromoisothiazolinone derivative selectively brominated at the 4-position can be produced in good yield by conducting the reaction in the above. Further, the present inventors have found a purification method by which a highly pure target product can be efficiently obtained by recrystallization or slurry washing of the obtained 4-bromoisothiazolinone derivative under specific conditions.
本発明の実施形態に係る４－ブロモイソチアゾリノン誘導体の製造方法は、
式（１）
（式中、Ｒは、水素原子または炭素数１～１２のアルキル基を表す。）で示される４－ブロモイソチアゾリノン誘導体（以下、４－ブロモイソチアゾリノン誘導体（１）と称することがある。）を製造する方法であって、
式（２）
（式中、Ｒは、式（１）と同じである。）で示されるイソチアゾリノン化合物（以下、イソチアゾリノン化合物（２）と称することがある。）またはその化学的に許容される塩を、水溶媒中または水溶媒と有機溶媒との混合溶媒中で臭素化剤を用いて臭素化する方法である。
A method for producing a 4-bromoisothiazolinone derivative according to an embodiment of the present invention comprises
formula (1)
(Wherein, R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms). .), comprising:
formula (2)
(Wherein R is the same as in formula (1)), an isothiazolinone compound (hereinafter sometimes referred to as isothiazolinone compound (2)) or a chemically acceptable salt thereof is added to an aqueous solvent. bromination using a brominating agent in a mixed solvent of an aqueous solvent and an organic solvent.
式（１）
式（２）
formula (1)
formula (2)
また、本発明の実施形態に係る４－ブロモイソチアゾリノン誘導体の製造方法は、
工程ａ）：式（２）
（式中、Ｒは、水素原子または炭素数１～１２のアルキル基を表す。）で示されるイソチアゾリノン化合物またはその化学的に許容される塩を、水溶媒中または水溶媒と有機溶媒との混合溶媒中で、臭素化剤を用いて臭素化し、式（１）
（式中、Ｒは、式（２）と同じである。）で示される４－ブロモイソチアゾリノン誘導体を合成する工程と、
工程ｂ）：工程ａ）で得られた４－ブロモイソチアゾリノン誘導体を精製する工程と、を含む方法であってもよい。 Further, the method for producing a 4-bromoisothiazolinone derivative according to an embodiment of the present invention comprises
Step a): Formula (2)
(Wherein, R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms.) An isothiazolinone compound or a chemically acceptable salt thereof represented by In a solvent, bromination using a brominating agent, formula (1)
(Wherein R is the same as formula (2).) Synthesizing a 4-bromoisothiazolinone derivative represented by
Step b): purifying the 4-bromoisothiazolinone derivative obtained in step a).
工程ａ）：式（２）
工程ｂ）：工程ａ）で得られた４－ブロモイソチアゾリノン誘導体を精製する工程と、を含む方法であってもよい。 Further, the method for producing a 4-bromoisothiazolinone derivative according to an embodiment of the present invention comprises
Step a): Formula (2)
Step b): purifying the 4-bromoisothiazolinone derivative obtained in step a).
イソチアゾリノン化合物（２）および４－ブロモイソチアゾリノン誘導体（１）の置換基Ｒの定義について説明する。
The definition of the substituent R of the isothiazolinone compound (2) and the 4-bromoisothiazolinone derivative (1) will be explained.
Ｒで表される炭素数１～１２のアルキル基としては、例えば、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、シクロプロピル基、ｎ－ブチル基、イソブチル基、ｔｅｒｔ－ブチル基、シクロブチル基、ｎ－ペンチル基、イソペンチル基、ネオペンチル基、１－エチルプロピル基、ｎ－ヘキシル基、イソヘキシル基、１，１－ジメチルブチル基、２，２－ジメチルブチル基、３，３－ジメチルブチル基、２－エチルブチル基、シクロヘキシル基、ｎ－ヘプチル基、シクロヘプチル基、ｎ－オクチル基、シクロオクチル基、ｎ－ノニル基、シクロノニル基、ｎ－デシル基、シクロデシル基、ｎ－ウンデシル基、シクロウンデシル基、ｎ－ドデシル基、シクロドデシル基等の、直鎖状、分岐鎖状または環状の炭素数１～１２のアルキル基が挙げられる。収率が良い点で、炭素数１～４のアルキル基が好ましく、メチル基がより好ましい。
Examples of the alkyl group having 1 to 12 carbon atoms represented by R include methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, isobutyl group, tert-butyl group, cyclobutyl group, n-pentyl group, isopentyl group, neopentyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group , 2-ethylbutyl group, cyclohexyl group, n-heptyl group, cycloheptyl group, n-octyl group, cyclooctyl group, n-nonyl group, cyclononyl group, n-decyl group, cyclodecyl group, n-undecyl group, cycloun Linear, branched or cyclic alkyl groups having 1 to 12 carbon atoms such as decyl group, n-dodecyl group and cyclododecyl group can be mentioned. An alkyl group having 1 to 4 carbon atoms is preferred, and a methyl group is more preferred, in terms of good yield.
イソチアゾリノン化合物（２）は、化学的に許容される塩を形成していてもよい。塩の種類としては、特に制限されないが、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硝酸塩、硫酸塩等が挙げられる。入手が容易である点で、塩酸塩が好ましい。
The isothiazolinone compound (2) may form a chemically acceptable salt. The type of salt is not particularly limited, but examples include hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate and the like. Hydrochloride is preferred because it is readily available.
４－ブロモイソチアゾリノン誘導体の製造方法について説明する。
A method for producing a 4-bromoisothiazolinone derivative will be explained.
本実施形態に係る４－ブロモイソチアゾリノン誘導体の製造方法における臭素化反応は、水溶媒の存在下で実施する。この臭素化反応は、水のみを溶媒として用いて実施してもよいし、水と反応に害をほとんど及ぼさない有機溶媒との混合溶媒中で実施してもよい。臭素化に用いる有機溶媒としては、例えば、クロロホルム、ジクロロメタン、四塩化炭素等のハロゲン系溶媒、ジメチルホルムアミド、ジメチルアセトアミド等のアミド系溶媒、またはトルエン、キシレン、メシチレン、クロロベンゼン、ｏ－ジクロロベンゼン等の芳香族系溶媒等が挙げられる。収率が良い点で、芳香族系溶媒を用いることが好ましく、クロロベンゼンまたはｏ－ジクロロベンゼンを用いることがより好ましい。
The bromination reaction in the method for producing a 4-bromoisothiazolinone derivative according to this embodiment is carried out in the presence of a water solvent. This bromination reaction may be carried out using only water as a solvent, or may be carried out in a mixed solvent of water and an organic solvent which hardly affects the reaction. Examples of organic solvents used for bromination include halogen solvents such as chloroform, dichloromethane and carbon tetrachloride; amide solvents such as dimethylformamide and dimethylacetamide; or toluene, xylene, mesitylene, chlorobenzene, o-dichlorobenzene and the like. Aromatic solvents and the like are included. From the viewpoint of good yield, it is preferable to use an aromatic solvent, and it is more preferable to use chlorobenzene or o-dichlorobenzene.
水の量は、例えば、原料に対する重量比で、０．１から１０の範囲とすればよい。臭素化反応を水と有機溶媒との混合溶媒中で実施する場合、水と有機溶媒との混合比は特に制限はないが、例えば、容量比で、水：有機溶媒＝１：１０から１０：１の範囲から適宜選ばれた混合比で実施すればよい。
The amount of water may be, for example, in the range of 0.1 to 10 in weight ratio to the raw material. When the bromination reaction is carried out in a mixed solvent of water and an organic solvent, the mixing ratio of water and the organic solvent is not particularly limited. A mixing ratio appropriately selected from the range of 1 may be used.
臭素化反応で使用する臭素化剤としては、臭素、臭素－１，４－ジオキサンコンプレックス、Ｎ－ブロモスクシンイミド（以下、ＮＢＳと表記することもある。）、１，３－ジブロモ－５，５－ジメチルヒダントイン（以下、ＤＢＨと表記することもある。）、トリブロモイソシアヌル酸、ジブロモイソシアヌル酸（以下、ＤＢＩということもある）、ブロモイソシアヌル酸一ナトリウム、三臭化テトラブチルアンモニウム、ブロモトリクロロメタン、１，２－ジブロモ－１，１，２，２－テトラクロロエタン、四臭化炭素、トリメチルフェニルアンモニウムトリブロミド、ベンジルトリメチルアンモニウムトリブロミド、テトラプロピルアンモニウムノナブロミド、ピリジニウムブロミドペルブロミド、ブロモクロム酸ピリジニウム、１－ブチル－３－メチルイミダゾリウムトリブロミド、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン三臭化水素塩、Ｎ－ブロモフタルイミド、Ｎ－ブロモサッカリン、Ｎ－ブロモアセトアミド、三臭化ホウ素、三臭化リン、ブロモジメチルスルホニウムブロミド、５，５－ジブロモメルドラム酸、２，４，４，６－テトラブロモ－２，５－シクロヘキサジエノン、ビス（２，４，６－トリメチルピリジン）ブロモニウムヘキサフルオロホスファート、トリメチルシリルブロミド、スルフリルブロミド、臭化水素等が挙げられる。入手が容易であり、収率が良い点で、臭素、Ｎ－ブロモスクシンイミドまたは１，３－ジブロモ－５，５－ジメチルヒダントインが好ましく、臭素がより好ましい。
The brominating agent used in the bromination reaction includes bromine, bromine-1,4-dioxane complex, N-bromosuccinimide (hereinafter sometimes referred to as NBS), 1,3-dibromo-5,5- dimethylhydantoin (hereinafter sometimes referred to as DBH), tribromoisocyanuric acid, dibromoisocyanuric acid (hereinafter sometimes referred to as DBI), monosodium bromoisocyanurate, tetrabutylammonium tribromide, bromotrichloromethane, 1,2-dibromo-1,1,2,2-tetrachloroethane, carbon tetrabromide, trimethylphenylammonium tribromide, benzyltrimethylammonium tribromide, tetrapropylammonium nonabromide, pyridinium bromide perbromide, pyridinium bromochromate, 1 -butyl-3-methylimidazolium tribromide, 1,8-diazabicyclo[5.4.0]-7-undecene hydrobromide, N-bromophthalimide, N-bromosaccharin, N-bromoacetamide, tribromide Boron chloride, phosphorus tribromide, bromodimethylsulfonium bromide, 5,5-dibromomeldrum acid, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, bis(2,4,6-trimethylpyridine ) bromonium hexafluorophosphate, trimethylsilyl bromide, sulfuryl bromide, hydrogen bromide and the like. Bromine, N-bromosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin is preferred, and bromine is more preferred, in view of easy availability and good yield.
臭素化剤の使用量は、原料であるイソチアゾリノン化合物（２）またはその化学的に許容される塩の量に対して０．５から２モル当量であることが好ましく、選択性および収率が良い点で０．８から１．５モル当量であることがより好ましい。
The amount of the brominating agent to be used is preferably 0.5 to 2 molar equivalents relative to the amount of isothiazolinone compound (2) or a chemically acceptable salt thereof as a starting material, resulting in good selectivity and yield. more preferably 0.8 to 1.5 molar equivalents.
イソチアゾリノン化合物（２）またはその化学的に許容される塩に臭素化剤と接触させる方法に特に制限はなく、例えば、水溶媒中または水溶媒と有機溶媒との混合溶媒中でイソチアゾリノン化合物（２）またはその化学的に許容される塩に臭素化剤を添加して、メカニカルスターラー等の撹拌装置を使用して混合すればよい。
The method of contacting the isothiazolinone compound (2) or a chemically acceptable salt thereof with the brominating agent is not particularly limited. Alternatively, a brominating agent may be added to a chemically acceptable salt thereof and mixed using a stirring device such as a mechanical stirrer.
臭素化反応は、０℃から溶媒還流温度の範囲から適宜選ばれた反応温度で実施することができるが、選択性や収率が良い点で、０℃から８０℃の範囲から選ばれる反応温度で実施することが好ましい。反応時間は、例えば、１から４８時間とすればよい。
The bromination reaction can be carried out at a reaction temperature appropriately selected from the range of 0°C to the reflux temperature of the solvent, and from the viewpoint of good selectivity and yield, the reaction temperature is selected from the range of 0°C to 80°C. It is preferable to carry out at The reaction time may be, for example, 1 to 48 hours.
臭素化反応終了後に、抽出や濃縮等の一般的な後処理操作により得られる４－ブロモイソチアゾリノン誘導体（１）は不純物を含むことがある。不純物としては、目的とする４－ブロモイソチアゾリノン誘導体（１）と化学的性質が似通った、未反応の原料のイソチアゾリノン化合物（２）またはその化学的に許容される塩の他に、イソチアゾリノン環の５位が臭素化された化合物や４位と５位の２箇所が臭素化された化合物等が挙げられる。また、臭素化剤としてＮＢＳやＤＢＨを用いた場合には、スクシンイミドや５，５－ジメチルヒダントインが残存する場合がある。したがって、一般的な精製方法では、これらの不純物を除去し、高純度の目的物を回収率良く得ることは困難である。
After the bromination reaction is completed, the 4-bromoisothiazolinone derivative (1) obtained by general post-treatment operations such as extraction and concentration may contain impurities. Impurities include an unreacted raw material isothiazolinone compound (2) having similar chemical properties to the target 4-bromoisothiazolinone derivative (1) or a chemically acceptable salt thereof, as well as an isothiazolinone ring and a compound in which the 5-position of is brominated, and a compound in which the 4- and 5-positions are brominated. Further, when NBS or DBH is used as a brominating agent, succinimide or 5,5-dimethylhydantoin may remain. Therefore, it is difficult to remove these impurities and obtain a highly purified target product at a high recovery rate by a general purification method.
工程ｂ）は、臭素化反応によって得られた４－ブロモイソチアゾリノン誘導体（１）を精製する工程であり、特定の溶媒中で再結晶またはスラリー洗浄を施すことによって、高純度の４－ブロモイソチアゾリノン誘導体（１）を回収率良く得る工程である。
Step b) is a step of purifying the 4-bromoisothiazolinone derivative (1) obtained by the bromination reaction. This is a step for obtaining the isothiazolinone derivative (1) at a high recovery rate.
工程ｂ）に使用する溶媒としては、ハロゲン系溶媒、エステル系溶媒または芳香族系溶媒等を用いることが好ましい。
As the solvent used in step b), it is preferable to use a halogen solvent, an ester solvent, an aromatic solvent, or the like.
ハロゲン系溶媒としては、例えば、クロロホルム、ジクロロメタン、ジクロロエタン、四塩化炭素等が挙げられる。エステル系溶媒としては、例えば、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ブチル、酢酸イソブチル、酢酸ｔｅｒｔ－ブチル等が挙げられる。芳香族系溶媒としては、例えば、トルエン、キシレン、クロロベンゼン、ｏ－ジクロロベンゼン、ｍ－ジクロロベンゼン、ニトロベンゼン等が挙げられる。これらの溶媒の中でも、収率（回収率）が良い点で、クロロホルム、ジクロロメタン、四塩化炭素、酢酸エチル、酢酸プロピル、酢酸ブチル、酢酸イソブチル、トルエン、クロロベンゼンまたはｏ－ジクロロベンゼンが好ましく、酢酸エチル、クロロベンゼン、ｏ－ジクロロベンゼンがより好ましい。
Examples of halogen-based solvents include chloroform, dichloromethane, dichloroethane, and carbon tetrachloride. Examples of ester solvents include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate and the like. Examples of aromatic solvents include toluene, xylene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, nitrobenzene and the like. Among these solvents, chloroform, dichloromethane, carbon tetrachloride, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate, toluene, chlorobenzene or o-dichlorobenzene are preferred in terms of good yield (recovery), and ethyl acetate , chlorobenzene and o-dichlorobenzene are more preferred.
工程ｂ）で再結晶を行う場合の条件について説明する。溶媒と混合した４－ブロモイソチアゾリノン誘導体（１）を、加温して溶解させた後、冷却することにより、高純度の４－ブロモイソチアゾリノン誘導体（１）を析出させることができる。使用する溶媒の量は、工程ａ）で得られた４－ブロモイソチアゾリノン誘導体（１）の重量に対して、例えば、１０重量％から１０００重量％の範囲から適宜選ばれた量であって、４－ブロモイソチアゾリノン誘導体（１）を完全に溶解させる最少量の溶媒を加えることが望ましい。加熱の際の温度は２５℃から溶媒還流温度の範囲から適宜選ばれた反応温度で実施することができる。冷却の際の温度に特に制限はなく、氷浴中で冷却してもよいが、室温（例えば、１８～２８℃）まで放冷してもよい。
The conditions for recrystallization in step b) will be explained. The 4-bromoisothiazolinone derivative (1) mixed with the solvent is dissolved by heating, and then cooled to precipitate the highly pure 4-bromoisothiazolinone derivative (1). The amount of the solvent to be used is an amount appropriately selected from the range of, for example, 10% by weight to 1000% by weight with respect to the weight of the 4-bromoisothiazolinone derivative (1) obtained in step a). , 4-bromoisothiazolinone derivative (1) is preferably added in the minimum amount of solvent that completely dissolves it. The temperature during heating can be appropriately selected from the range of 25° C. to the reflux temperature of the solvent. There is no particular limitation on the temperature for cooling, and although it may be cooled in an ice bath, it may be allowed to cool to room temperature (eg, 18 to 28°C).
工程ｂ）でスラリー洗浄を行う場合の条件について説明する。４－ブロモイソチアゾリノン誘導体（１）を、溶媒中で懸濁させることによって、高純度の４－ブロモイソチアゾリノン誘導体（１）を析出させることができる。使用する溶媒の量は、工程ａ）で得られた４－ブロモイソチアゾリノン誘導体（１）の重量に対して、例えば、１０重量％から１０００重量％の範囲から適宜選ばれた量で実施することができる。懸濁の際の温度は、例えば、－２０℃から溶媒還流温度の範囲から適宜選ばれた反応温度で実施することができる。
The conditions for slurry washing in step b) will be explained. High-purity 4-bromoisothiazolinone derivative (1) can be precipitated by suspending 4-bromoisothiazolinone derivative (1) in a solvent. The amount of the solvent to be used is appropriately selected from the range of, for example, 10% by weight to 1000% by weight with respect to the weight of the 4-bromoisothiazolinone derivative (1) obtained in step a). be able to. The suspension can be carried out at a reaction temperature appropriately selected, for example, from the range of -20°C to the reflux temperature of the solvent.
工程ｂ）の終了後は、析出した固体をろ別することにより、高純度の４－ブロモイソチアゾリノン誘導体（１）を単離することができる。ろ過の方法については特に制限はなく、例えば、自然ろ過、減圧ろ過、遠心ろ過等から、反応スケール等に合わせて適宜選択して実施すればよい。効率が良く、時間が短縮できる点で、減圧ろ過や遠心ろ過が好ましい。
After step b) is completed, a highly pure 4-bromoisothiazolinone derivative (1) can be isolated by filtering the precipitated solid. The method of filtration is not particularly limited, and for example, it may be carried out by appropriately selecting from natural filtration, vacuum filtration, centrifugal filtration, etc. according to the reaction scale and the like. Vacuum filtration and centrifugal filtration are preferred because they are efficient and can shorten the time.
工程ｂ）に用いる４－ブロモイソチアゾリノン誘導体（１）は、純度が高い方が効率よく高純度の目的物を得ることができる。臭素化剤としてＮＢＳまたはＤＢＨを用いた場合に、ＮＢＳやＤＢＨからそれぞれ生じるスクシンイミドや５，５－ジメチルヒダントインは、再結晶またはスラリー洗浄の操作の前に可能な限り除去しておくことが好ましい。これらの不純物を除去する方法としては、例えば、臭素化反応終了後に塩基性水溶液により反応混合物を洗浄操作する方法等を例示することができる。塩基性水溶液としては、例えば、酢酸ナトリウム水溶液、酢酸カリウム水溶液、水酸化ナトリウム水溶液、水酸化カリウム水溶液、炭酸ナトリウム水溶液、炭酸カリウム水溶液、炭酸水素ナトリウム水溶液、炭酸水素カリウム水溶液、リン酸三ナトリウム水溶液、リン酸三カリウム水溶液等が挙げられる。
The higher the purity of the 4-bromoisothiazolinone derivative (1) used in step b), the more efficiently a highly pure target product can be obtained. When NBS or DBH is used as the brominating agent, succinimide and 5,5-dimethylhydantoin generated from NBS and DBH, respectively, are preferably removed as much as possible before recrystallization or slurry washing. As a method for removing these impurities, for example, a method of washing the reaction mixture with a basic aqueous solution after completion of the bromination reaction can be exemplified. Basic aqueous solutions include, for example, sodium acetate aqueous solution, potassium acetate aqueous solution, sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium carbonate aqueous solution, potassium carbonate aqueous solution, sodium hydrogen carbonate aqueous solution, potassium hydrogen carbonate aqueous solution, trisodium phosphate aqueous solution, An aqueous solution of tripotassium phosphate and the like can be mentioned.
工程ｂ）の操作は、４－ブロモイソチアゾリノン誘導体（１）が所望の純度に到達するまで繰り返し実施してもよい。
The operation of step b) may be repeated until the 4-bromoisothiazolinone derivative (1) reaches the desired purity.
本発明の実施形態に係る４－ブロモイソチアゾリノン誘導体の製造方法は、殺菌剤、抗菌剤の有効成分として有用な４－ブロモイソチアゾリノン誘導体を、選択性、収率および純度良く製造する方法として有用である。
A method for producing a 4-bromoisothiazolinone derivative according to an embodiment of the present invention is a method for producing a 4-bromoisothiazolinone derivative useful as an active ingredient of a fungicide or an antibacterial agent with good selectivity, yield and purity. is useful as
本発明の実施形態に係る４－ブロモイソチアゾリノン誘導体の製造方法によって収率良く高純度で製造できる４－ブロモイソチアゾリノン誘導体は、殺菌剤、抗菌剤の有効成分として有用であり、例えば、工業用防腐剤、建築用資材、塗料、接着剤、皮革、紙パルプ、冷却塔、工業用オイル、繊維、洗浄助剤、化粧品や家庭用品等の様々な場面で使用することができる。
A 4-bromoisothiazolinone derivative that can be produced with high yield and high purity by the method for producing a 4-bromoisothiazolinone derivative according to an embodiment of the present invention is useful as an active ingredient of a disinfectant and an antibacterial agent. It can be used in various fields such as industrial preservatives, building materials, paints, adhesives, leather, paper pulp, cooling towers, industrial oils, textiles, cleaning aids, cosmetics and household products.
本発明の実施形態に係る４－ブロモイソチアゾリノン誘導体の製造方法によって製造される上記式（１）で示される４－ブロモイソチアゾリノン誘導体は、上記式（２）で示されるイソチアゾリノン化合物またはその化学的に許容される塩の含有量が１００ｐｐｍ未満である。
The 4-bromoisothiazolinone derivative represented by the above formula (1) produced by the method for producing a 4-bromoisothiazolinone derivative according to an embodiment of the present invention is an isothiazolinone compound represented by the above formula (2) or its The content of chemically acceptable salts is less than 100 ppm.
本明細書は、以下に示す実施形態を含む。
［１］式（１）
（式中、Ｒは、水素原子または炭素数１～１２のアルキル基を表す。）で示される４－ブロモイソチアゾリノン誘導体を製造する方法であって、
式（２）
（式中、Ｒは、式（１）と同じである。）で示されるイソチアゾリノン化合物またはその化学的に許容される塩を、水溶媒中または水溶媒と有機溶媒との混合溶媒中で臭素化剤を用いて臭素化する、４－ブロモイソチアゾリノン誘導体の製造方法。
The present specification includes the embodiments shown below.
[1] Formula (1)
(Wherein, R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms.) A method for producing a 4-bromoisothiazolinone derivative represented by
formula (2)
(Wherein R is the same as formula (1)), an isothiazolinone compound or a chemically acceptable salt thereof is brominated in an aqueous solvent or a mixed solvent of an aqueous solvent and an organic solvent. A method for producing a 4-bromoisothiazolinone derivative by bromination using an agent.
［１］式（１）
式（２）
[1] Formula (1)
formula (2)
［２］［１］に記載の４－ブロモイソチアゾリノン誘導体の製造方法であって、
工程ａ）：前記式（２）で示されるイソチアゾリノン化合物またはその化学的に許容される塩を、前記水溶媒中または水溶媒と有機溶媒との混合溶媒中で、前記臭素化剤を用いて臭素化し、前記式（１）で示される４－ブロモイソチアゾリノン誘導体を合成する工程と、
工程ｂ）：前記工程ａ）で得られた４－ブロモイソチアゾリノン誘導体を精製する工程と、
を含む、４－ブロモイソチアゾリノン誘導体の製造方法。 [2] A method for producing a 4-bromoisothiazolinone derivative according to [1],
Step a): The isothiazolinone compound represented by the formula (2) or a chemically acceptable salt thereof is subjected to bromination using the brominating agent in the aqueous solvent or a mixed solvent of the aqueous solvent and the organic solvent. a step of synthesizing a 4-bromoisothiazolinone derivative represented by the formula (1);
Step b): Purifying the 4-bromoisothiazolinone derivative obtained in step a);
A method for producing a 4-bromoisothiazolinone derivative, comprising:
工程ａ）：前記式（２）で示されるイソチアゾリノン化合物またはその化学的に許容される塩を、前記水溶媒中または水溶媒と有機溶媒との混合溶媒中で、前記臭素化剤を用いて臭素化し、前記式（１）で示される４－ブロモイソチアゾリノン誘導体を合成する工程と、
工程ｂ）：前記工程ａ）で得られた４－ブロモイソチアゾリノン誘導体を精製する工程と、
を含む、４－ブロモイソチアゾリノン誘導体の製造方法。 [2] A method for producing a 4-bromoisothiazolinone derivative according to [1],
Step a): The isothiazolinone compound represented by the formula (2) or a chemically acceptable salt thereof is subjected to bromination using the brominating agent in the aqueous solvent or a mixed solvent of the aqueous solvent and the organic solvent. a step of synthesizing a 4-bromoisothiazolinone derivative represented by the formula (1);
Step b): Purifying the 4-bromoisothiazolinone derivative obtained in step a);
A method for producing a 4-bromoisothiazolinone derivative, comprising:
［３］［２］に記載の４－ブロモイソチアゾリノン誘導体の製造方法であって、
前記工程ｂ）における精製する方法が、再結晶またはスラリー洗浄による方法である、４－ブロモイソチアゾリノン誘導体の製造方法。 [3] A method for producing a 4-bromoisothiazolinone derivative according to [2],
A method for producing a 4-bromoisothiazolinone derivative, wherein the purification method in the step b) is a method by recrystallization or slurry washing.
前記工程ｂ）における精製する方法が、再結晶またはスラリー洗浄による方法である、４－ブロモイソチアゾリノン誘導体の製造方法。 [3] A method for producing a 4-bromoisothiazolinone derivative according to [2],
A method for producing a 4-bromoisothiazolinone derivative, wherein the purification method in the step b) is a method by recrystallization or slurry washing.
［４］［３］に記載の４－ブロモイソチアゾリノン誘導体の製造方法であって、
前記再結晶またはスラリー洗浄に使用する溶媒が、酢酸エチル、クロロベンゼン、およびｏ－ジクロロベンゼンのうちの少なくとも１つである、４－ブロモイソチアゾリノン誘導体の製造方法。 [4] A method for producing a 4-bromoisothiazolinone derivative according to [3],
A method for producing a 4-bromoisothiazolinone derivative, wherein the solvent used for recrystallization or slurry washing is at least one of ethyl acetate, chlorobenzene, and o-dichlorobenzene.
前記再結晶またはスラリー洗浄に使用する溶媒が、酢酸エチル、クロロベンゼン、およびｏ－ジクロロベンゼンのうちの少なくとも１つである、４－ブロモイソチアゾリノン誘導体の製造方法。 [4] A method for producing a 4-bromoisothiazolinone derivative according to [3],
A method for producing a 4-bromoisothiazolinone derivative, wherein the solvent used for recrystallization or slurry washing is at least one of ethyl acetate, chlorobenzene, and o-dichlorobenzene.
［５］［１］～［４］のいずれか一つに記載の４－ブロモイソチアゾリノン誘導体の製造方法であって、
使用する前記水溶媒の量が、原料に対する重量比で０．１から１０の範囲である、４－ブロモイソチアゾリノン誘導体の製造方法。 [5] A method for producing a 4-bromoisothiazolinone derivative according to any one of [1] to [4],
A method for producing a 4-bromoisothiazolinone derivative, wherein the amount of the water solvent used is in the range of 0.1 to 10 in weight ratio to the starting material.
使用する前記水溶媒の量が、原料に対する重量比で０．１から１０の範囲である、４－ブロモイソチアゾリノン誘導体の製造方法。 [5] A method for producing a 4-bromoisothiazolinone derivative according to any one of [1] to [4],
A method for producing a 4-bromoisothiazolinone derivative, wherein the amount of the water solvent used is in the range of 0.1 to 10 in weight ratio to the starting material.
［６］［１］～［５］のいずれか一つに記載の４－ブロモイソチアゾリノン誘導体の製造方法であって、
前記臭素化剤が、臭素、Ｎ－ブロモスクシンイミド、または１，３－ジブロモ－５，５－ジメチルヒダントインである、４－ブロモイソチアゾリノン誘導体の製造方法。 [6] A method for producing a 4-bromoisothiazolinone derivative according to any one of [1] to [5],
A method for producing a 4-bromoisothiazolinone derivative, wherein the brominating agent is bromine, N-bromosuccinimide, or 1,3-dibromo-5,5-dimethylhydantoin.
前記臭素化剤が、臭素、Ｎ－ブロモスクシンイミド、または１，３－ジブロモ－５，５－ジメチルヒダントインである、４－ブロモイソチアゾリノン誘導体の製造方法。 [6] A method for producing a 4-bromoisothiazolinone derivative according to any one of [1] to [5],
A method for producing a 4-bromoisothiazolinone derivative, wherein the brominating agent is bromine, N-bromosuccinimide, or 1,3-dibromo-5,5-dimethylhydantoin.
［７］［１］～［６］のいずれか一つに記載の４－ブロモイソチアゾリノン誘導体の製造方法であって、
前記臭素化における反応温度が、０℃から８０℃の範囲である、４－ブロモイソチアゾリノン誘導体の製造方法。 [7] A method for producing a 4-bromoisothiazolinone derivative according to any one of [1] to [6],
A method for producing a 4-bromoisothiazolinone derivative, wherein the reaction temperature in the bromination is in the range of 0°C to 80°C.
前記臭素化における反応温度が、０℃から８０℃の範囲である、４－ブロモイソチアゾリノン誘導体の製造方法。 [7] A method for producing a 4-bromoisothiazolinone derivative according to any one of [1] to [6],
A method for producing a 4-bromoisothiazolinone derivative, wherein the reaction temperature in the bromination is in the range of 0°C to 80°C.
［８］［１］～［７］のいずれか一つに記載の４－ブロモイソチアゾリノン誘導体の製造方法であって、
前記Ｒが、炭素数１～４のアルキル基である、４－ブロモイソチアゾリノン誘導体の製造方法。 [8] A method for producing a 4-bromoisothiazolinone derivative according to any one of [1] to [7],
A method for producing a 4-bromoisothiazolinone derivative, wherein said R is an alkyl group having 1 to 4 carbon atoms.
前記Ｒが、炭素数１～４のアルキル基である、４－ブロモイソチアゾリノン誘導体の製造方法。 [8] A method for producing a 4-bromoisothiazolinone derivative according to any one of [1] to [7],
A method for producing a 4-bromoisothiazolinone derivative, wherein said R is an alkyl group having 1 to 4 carbon atoms.
［９］式（１）で示される４－ブロモイソチアゾリノン誘導体であって、前記４－ブロモイソチアゾリノン誘導体に含まれる式（２）で示されるイソチアゾリノン化合物またはその化学的に許容される塩の含有量が１００ｐｐｍ未満である、４－ブロモイソチアゾリノン誘導体。
（式中、Ｒは、水素原子または炭素数１～１２のアルキル基を表す。）
（式中、Ｒは、式（１）と同じである。）
[9] A 4-bromoisothiazolinone derivative represented by formula (1), which is an isothiazolinone compound represented by formula (2) included in the 4-bromoisothiazolinone derivative, or a chemically acceptable salt thereof content is less than 100 ppm, 4-bromoisothiazolinone derivative.
(Wherein, R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms.)
(Wherein, R is the same as in formula (1).)
以下、実施例および比較例を挙げ、本発明をより具体的に詳細に説明するが、本発明は、以下の実施例に限定されるものではない。
The present invention will be described in more specific detail below with reference to examples and comparative examples, but the present invention is not limited to the following examples.
［１Ｈ－ＮＭＲ測定］
１Ｈ－ＮＭＲの測定には、Ｂｒｕｋｅｒ ＡＳＣＥＮＤ ＨＤ（４００ＭＨｚ；ＢＲＵＫＥＲ製）を用いた。１Ｈ－ＮＭＲは、重クロロホルム（ＣＤＣｌ３）を測定溶媒とし、内部標準物質としてテトラメチルシラン（ＴＭＳ）を用いて測定した。化合物の純度は測定した１Ｈ－ＮＭＲの積分比から算出した。また、試薬類は市販品等を用いた。 [ 1 H-NMR measurement]
Bruker ASCEND HD (400 MHz; manufactured by BRUKER) was used for 1 H-NMR measurement. 1 H-NMR was measured using deuterated chloroform (CDCl 3 ) as a measurement solvent and tetramethylsilane (TMS) as an internal standard substance. The purity of the compound was calculated from the integral ratio of the measured 1 H-NMR. Commercially available reagents and the like were used.
１Ｈ－ＮＭＲの測定には、Ｂｒｕｋｅｒ ＡＳＣＥＮＤ ＨＤ（４００ＭＨｚ；ＢＲＵＫＥＲ製）を用いた。１Ｈ－ＮＭＲは、重クロロホルム（ＣＤＣｌ３）を測定溶媒とし、内部標準物質としてテトラメチルシラン（ＴＭＳ）を用いて測定した。化合物の純度は測定した１Ｈ－ＮＭＲの積分比から算出した。また、試薬類は市販品等を用いた。 [ 1 H-NMR measurement]
Bruker ASCEND HD (400 MHz; manufactured by BRUKER) was used for 1 H-NMR measurement. 1 H-NMR was measured using deuterated chloroform (CDCl 3 ) as a measurement solvent and tetramethylsilane (TMS) as an internal standard substance. The purity of the compound was calculated from the integral ratio of the measured 1 H-NMR. Commercially available reagents and the like were used.
実施例２０，２１、比較例１，２では、１Ｈ－ＮＭＲ内部標準法により粗生成物の組成と収率を求めた。１Ｈ－ＮＭＲ内部標準法は、粗生成物に対し、内部標準物質として１，４－ジ－ｔｅｒｔ－ブチルベンゼンを所定量加え、クロロホルムまたはクロロホルムとジメチルホルムアミドとの混合溶液を加えて略均一な溶液とした。この溶液の一部を採取して重クロロホルムで希釈し、１Ｈ－ＮＭＲ測定を行った。得られた１Ｈ－ＮＭＲスペクトルにおける積分値から、内部標準物質に対する目的物および原料の物質量比を計算し、組成と収率を求めた。
In Examples 20 and 21 and Comparative Examples 1 and 2, the composition and yield of crude products were determined by the 1 H-NMR internal standard method. In the 1 H-NMR internal standard method, a predetermined amount of 1,4-di-tert-butylbenzene is added as an internal standard substance to the crude product, and chloroform or a mixed solution of chloroform and dimethylformamide is added to obtain a substantially homogeneous solution. A portion of this solution was sampled, diluted with deuterated chloroform, and subjected to 1 H-NMR measurement. From the integrated values in the obtained 1 H-NMR spectrum, the ratio of the target substance and starting material to the internal standard substance was calculated, and the composition and yield were determined.
＜実施例１＞
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，２．００ｇ，８．６８ｍｍｏｌ）に水（４．４０ｇ）を加えた後、臭素（０．５３０ｍＬ，１０．４ｍｍｏｌ）を１０分間かけて滴下した。この混合溶液を室温（１８～２８℃）で１．５時間撹拌した。反応溶液に２０重量％炭酸ナトリウム水溶液を加えて中和した後、酢酸エチル（１０ｍＬ×３回）で抽出し、各有機層を飽和食塩水（各１ｍＬ）で洗浄した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．６８ｇ）を得た。 <Example 1>
After adding water (4.40 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.00 g, 8.68 mmol), bromine (0.530 mL, 10.4 mmol) was added for 10 minutes. dripped over. This mixed solution was stirred at room temperature (18-28° C.) for 1.5 hours. After neutralizing the reaction solution by adding a 20% by weight aqueous sodium carbonate solution, it was extracted with ethyl acetate (10 mL×3 times), and each organic layer was washed with saturated brine (1 mL each). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.68 g).
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，２．００ｇ，８．６８ｍｍｏｌ）に水（４．４０ｇ）を加えた後、臭素（０．５３０ｍＬ，１０．４ｍｍｏｌ）を１０分間かけて滴下した。この混合溶液を室温（１８～２８℃）で１．５時間撹拌した。反応溶液に２０重量％炭酸ナトリウム水溶液を加えて中和した後、酢酸エチル（１０ｍＬ×３回）で抽出し、各有機層を飽和食塩水（各１ｍＬ）で洗浄した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．６８ｇ）を得た。 <Example 1>
After adding water (4.40 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.00 g, 8.68 mmol), bromine (0.530 mL, 10.4 mmol) was added for 10 minutes. dripped over. This mixed solution was stirred at room temperature (18-28° C.) for 1.5 hours. After neutralizing the reaction solution by adding a 20% by weight aqueous sodium carbonate solution, it was extracted with ethyl acetate (10 mL×3 times), and each organic layer was washed with saturated brine (1 mL each). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.68 g).
得られた粗生成物に酢酸エチル（約２ｍＬ）を加え、加温して溶解させた後、室温まで冷却し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（１．４４ｇ，収率：８６％，純度：９９．９％）を得た。１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）：δ８．０７（ｓ，１Ｈ），３．４２（ｓ，３Ｈ）。結果を表１に示す。
Ethyl acetate (about 2 mL) was added to the obtained crude product, dissolved by heating, cooled to room temperature, and the precipitated solid was separated by filtration to give 4-bromo-2-methyl-4- A white solid of isothiazolin-3-one (1.44 g, yield: 86%, purity: 99.9%) was obtained. 1 H-NMR (400 MHz, CDCl 3 ): δ 8.07 (s, 1H), 3.42 (s, 3H). Table 1 shows the results.
＜実施例２＞
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，１２．０ｇ，５２．１ｍｍｏｌ）に水（２６．４ｇ）を加えた後、２５℃以下の水浴下で冷却しながら臭素（３．２０ｍＬ，６２．５ｍｍｏｌ）を４５分間かけて滴下した。この混合溶液を室温で３時間撹拌した。反応溶液に２０重量％炭酸ナトリウム水溶液を加えて中和した後、酢酸エチル（４０ｍＬ×３）で抽出し、各有機層を、２０重量％炭酸ナトリウム水溶液と飽和食塩水の１：１混合液（各２ｍＬ）で洗浄した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（９．５０ｇ）を得た。 <Example 2>
After adding water (26.4 g) to 2-methyl-4-isothiazolin-3-one (50% by weight aqueous solution, 12.0 g, 52.1 mmol), bromine (3 .20 mL, 62.5 mmol) was added dropwise over 45 minutes. This mixed solution was stirred at room temperature for 3 hours. After neutralizing the reaction solution by adding a 20 wt% aqueous sodium carbonate solution, it was extracted with ethyl acetate (40 mL x 3), and each organic layer was treated with a 1:1 mixture of 20 wt% sodium carbonate aqueous solution and saturated brine ( 2 mL each). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (9.50 g).
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，１２．０ｇ，５２．１ｍｍｏｌ）に水（２６．４ｇ）を加えた後、２５℃以下の水浴下で冷却しながら臭素（３．２０ｍＬ，６２．５ｍｍｏｌ）を４５分間かけて滴下した。この混合溶液を室温で３時間撹拌した。反応溶液に２０重量％炭酸ナトリウム水溶液を加えて中和した後、酢酸エチル（４０ｍＬ×３）で抽出し、各有機層を、２０重量％炭酸ナトリウム水溶液と飽和食塩水の１：１混合液（各２ｍＬ）で洗浄した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（９．５０ｇ）を得た。 <Example 2>
After adding water (26.4 g) to 2-methyl-4-isothiazolin-3-one (50% by weight aqueous solution, 12.0 g, 52.1 mmol), bromine (3 .20 mL, 62.5 mmol) was added dropwise over 45 minutes. This mixed solution was stirred at room temperature for 3 hours. After neutralizing the reaction solution by adding a 20 wt% aqueous sodium carbonate solution, it was extracted with ethyl acetate (40 mL x 3), and each organic layer was treated with a 1:1 mixture of 20 wt% sodium carbonate aqueous solution and saturated brine ( 2 mL each). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (9.50 g).
得られた粗生成物に酢酸エチル（約１１ｍＬ）を加え、加温して溶解させた後、室温まで冷却し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（８．０９ｇ，収率：８０％，純度：９９．９％）を得た。結果を表１に示す。
Ethyl acetate (about 11 mL) was added to the resulting crude product, dissolved by heating, cooled to room temperature, and the precipitated solid was filtered off to give 4-bromo-2-methyl-4- A white solid of isothiazolin-3-one (8.09 g, yield: 80%, purity: 99.9%) was obtained. Table 1 shows the results.
＜実施例３＞
２－メチル－４－イソチアゾリン－３－オン（５０％重量水溶液，２．００ｇ，８．６８ｍｍｏｌ）に水（４．４０ｇ）を加えた後、臭素（０．５３ｍＬ，１０．４ｍｍｏｌ）を１０分間かけて滴下した。この混合溶液を室温で３時間撹拌した。反応溶液に飽和炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（９ｍＬ）を加え、酢酸エチル（１０ｍＬ×４回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．６２ｇ）を得た。 <Example 3>
After water (4.40 g) was added to 2-methyl-4-isothiazolin-3-one (50% weight aqueous solution, 2.00 g, 8.68 mmol), bromine (0.53 mL, 10.4 mmol) was added for 10 minutes. dripped over. This mixed solution was stirred at room temperature for 3 hours. A saturated aqueous sodium carbonate solution was added to the reaction solution to neutralize it, saturated brine (9 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.62 g).
２－メチル－４－イソチアゾリン－３－オン（５０％重量水溶液，２．００ｇ，８．６８ｍｍｏｌ）に水（４．４０ｇ）を加えた後、臭素（０．５３ｍＬ，１０．４ｍｍｏｌ）を１０分間かけて滴下した。この混合溶液を室温で３時間撹拌した。反応溶液に飽和炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（９ｍＬ）を加え、酢酸エチル（１０ｍＬ×４回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．６２ｇ）を得た。 <Example 3>
After water (4.40 g) was added to 2-methyl-4-isothiazolin-3-one (50% weight aqueous solution, 2.00 g, 8.68 mmol), bromine (0.53 mL, 10.4 mmol) was added for 10 minutes. dripped over. This mixed solution was stirred at room temperature for 3 hours. A saturated aqueous sodium carbonate solution was added to the reaction solution to neutralize it, saturated brine (9 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.62 g).
得られた粗生成物に酢酸エチル（約２ｍＬ）を加え、加温して溶解させた後、室温まで冷却し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（１．２８ｇ，収率：７６％，純度：９９．９％）を得た。結果を表１に示す。
Ethyl acetate (about 2 mL) was added to the obtained crude product, dissolved by heating, cooled to room temperature, and the precipitated solid was separated by filtration to give 4-bromo-2-methyl-4- A white solid of isothiazolin-3-one (1.28 g, yield: 76%, purity: 99.9%) was obtained. Table 1 shows the results.
＜実施例４＞
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，２．００ｇ，８．６８ｍｍｏｌ）に水（２．３０ｇ）を加えた後、臭素（０．５３ｍＬ，１０．４ｍｍｏｌ）を１０分間かけて滴下した。この混合溶液を室温で３時間撹拌した。反応溶液に２０重量％炭酸ナトリウム水溶液を加えて中和した後、酢酸エチル（１５ｍＬ×３回）で抽出し、各有機層を２０重量％炭酸ナトリウム水溶液と飽和食塩水の１：１混合液（各２ｍＬ）で洗浄した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．６０ｇ）を得た。 <Example 4>
After adding water (2.30 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.00 g, 8.68 mmol), bromine (0.53 mL, 10.4 mmol) was added for 10 minutes. dripped over. This mixed solution was stirred at room temperature for 3 hours. After neutralizing the reaction solution by adding a 20 wt% aqueous sodium carbonate solution, it was extracted with ethyl acetate (15 mL x 3 times), and each organic layer was separated with a 1:1 mixture of 20 wt% sodium carbonate aqueous solution and saturated brine ( 2 mL each). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.60 g).
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，２．００ｇ，８．６８ｍｍｏｌ）に水（２．３０ｇ）を加えた後、臭素（０．５３ｍＬ，１０．４ｍｍｏｌ）を１０分間かけて滴下した。この混合溶液を室温で３時間撹拌した。反応溶液に２０重量％炭酸ナトリウム水溶液を加えて中和した後、酢酸エチル（１５ｍＬ×３回）で抽出し、各有機層を２０重量％炭酸ナトリウム水溶液と飽和食塩水の１：１混合液（各２ｍＬ）で洗浄した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．６０ｇ）を得た。 <Example 4>
After adding water (2.30 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.00 g, 8.68 mmol), bromine (0.53 mL, 10.4 mmol) was added for 10 minutes. dripped over. This mixed solution was stirred at room temperature for 3 hours. After neutralizing the reaction solution by adding a 20 wt% aqueous sodium carbonate solution, it was extracted with ethyl acetate (15 mL x 3 times), and each organic layer was separated with a 1:1 mixture of 20 wt% sodium carbonate aqueous solution and saturated brine ( 2 mL each). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.60 g).
得られた粗生成物に酢酸エチル（約２ｍＬ）を加え、加温して溶解させた後、室温まで冷却し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（１．３２ｇ，収率：７９％，純度：９９．９％）を得た。結果を表１に示す。
Ethyl acetate (about 2 mL) was added to the obtained crude product, dissolved by heating, cooled to room temperature, and the precipitated solid was separated by filtration to give 4-bromo-2-methyl-4- A white solid of isothiazolin-3-one (1.32 g, yield: 79%, purity: 99.9%) was obtained. Table 1 shows the results.
＜実施例５＞
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，２．００ｇ，８．６８ｍｍｏｌ）に水（１．５０ｇ）を加えた後、臭素（０．５３ｍＬ，１０．４ｍｍｏｌ）を１０分間かけて滴下した。この混合溶液を室温で３時間撹拌した。反応溶液に２０重量％炭酸ナトリウム水溶液を加えて中和した後、酢酸エチル（１５ｍＬ×３回）で抽出し、各有機層を２０重量％炭酸ナトリウム水溶液と飽和食塩水の１：１混合液（各２ｍＬ）で洗浄した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．６２ｇ）を得た。 <Example 5>
After adding water (1.50 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.00 g, 8.68 mmol), bromine (0.53 mL, 10.4 mmol) was added for 10 minutes. dripped over. This mixed solution was stirred at room temperature for 3 hours. After neutralizing the reaction solution by adding a 20 wt% aqueous sodium carbonate solution, it was extracted with ethyl acetate (15 mL x 3 times), and each organic layer was separated with a 1:1 mixture of 20 wt% sodium carbonate aqueous solution and saturated brine ( 2 mL each). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.62 g).
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，２．００ｇ，８．６８ｍｍｏｌ）に水（１．５０ｇ）を加えた後、臭素（０．５３ｍＬ，１０．４ｍｍｏｌ）を１０分間かけて滴下した。この混合溶液を室温で３時間撹拌した。反応溶液に２０重量％炭酸ナトリウム水溶液を加えて中和した後、酢酸エチル（１５ｍＬ×３回）で抽出し、各有機層を２０重量％炭酸ナトリウム水溶液と飽和食塩水の１：１混合液（各２ｍＬ）で洗浄した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．６２ｇ）を得た。 <Example 5>
After adding water (1.50 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.00 g, 8.68 mmol), bromine (0.53 mL, 10.4 mmol) was added for 10 minutes. dripped over. This mixed solution was stirred at room temperature for 3 hours. After neutralizing the reaction solution by adding a 20 wt% aqueous sodium carbonate solution, it was extracted with ethyl acetate (15 mL x 3 times), and each organic layer was separated with a 1:1 mixture of 20 wt% sodium carbonate aqueous solution and saturated brine ( 2 mL each). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.62 g).
得られた粗生成物に酢酸エチル（約２ｍＬ）を加え、加温して溶解させた後、室温まで冷却し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（１．３５ｇ，収率：８０％，純度：９９．９％）を得た。結果を表１に示す。
Ethyl acetate (about 2 mL) was added to the obtained crude product, dissolved by heating, cooled to room temperature, and the precipitated solid was separated by filtration to give 4-bromo-2-methyl-4- A white solid of isothiazolin-3-one (1.35 g, yield: 80%, purity: 99.9%) was obtained. Table 1 shows the results.
＜実施例６＞
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，１００．２３ｇ，４３５ｍｍｏｌ）に水（７５．００ｇ）を加えた後、臭素（２７．０ｍＬ，５２４ｍｍｏｌ）を２．５時間かけて滴下した。この混合溶液を室温で１時間撹拌した。反応溶液に２０重量％炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（２００ｍＬ）を加え、酢酸エチル（３５０ｍＬ×３回）で抽出した。合一した有機層を無水硫酸ナトリウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（７８．４５ｇ）を得た。 <Example 6>
After adding water (75.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 100.23 g, 435 mmol), bromine (27.0 mL, 524 mmol) was added over 2.5 hours. Dripped. This mixed solution was stirred at room temperature for 1 hour. A 20% by weight sodium carbonate aqueous solution was added to the reaction solution to neutralize it, then saturated brine (200 mL) was added, and the mixture was extracted with ethyl acetate (350 mL×3 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired crude product (78.45 g).
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，１００．２３ｇ，４３５ｍｍｏｌ）に水（７５．００ｇ）を加えた後、臭素（２７．０ｍＬ，５２４ｍｍｏｌ）を２．５時間かけて滴下した。この混合溶液を室温で１時間撹拌した。反応溶液に２０重量％炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（２００ｍＬ）を加え、酢酸エチル（３５０ｍＬ×３回）で抽出した。合一した有機層を無水硫酸ナトリウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（７８．４５ｇ）を得た。 <Example 6>
After adding water (75.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 100.23 g, 435 mmol), bromine (27.0 mL, 524 mmol) was added over 2.5 hours. Dripped. This mixed solution was stirred at room temperature for 1 hour. A 20% by weight sodium carbonate aqueous solution was added to the reaction solution to neutralize it, then saturated brine (200 mL) was added, and the mixture was extracted with ethyl acetate (350 mL×3 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired crude product (78.45 g).
得られた粗生成物に酢酸エチル（約７０ｍＬ）を加え、加温して溶解させた後、室温まで冷却し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（６７．０４ｇ，収率：７９％，純度：９９．９％）を得た。結果を表１に示す。
Ethyl acetate (about 70 mL) was added to the resulting crude product, dissolved by heating, cooled to room temperature, and the precipitated solid was filtered off to give 4-bromo-2-methyl-4- A white solid of isothiazolin-3-one (67.04 g, yield: 79%, purity: 99.9%) was obtained. Table 1 shows the results.
＜実施例７＞
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，１００．１９ｇ，４３５ｍｍｏｌ）に水（７５．００ｇ）を加えた後、臭素（２７．０ｍＬ，５２４ｍｍｏｌ）を２．５時間かけて滴下した。この混合溶液を室温で１時間撹拌した。反応溶液に２０重量％炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（２００ｍＬ）を加え、酢酸エチル（３５０ｍＬ×３回）で抽出した。合一した有機層を無水硫酸ナトリウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（７８．５７ｇ）を得た。 <Example 7>
After adding water (75.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 100.19 g, 435 mmol), bromine (27.0 mL, 524 mmol) was added over 2.5 hours. Dripped. This mixed solution was stirred at room temperature for 1 hour. A 20% by weight sodium carbonate aqueous solution was added to the reaction solution to neutralize it, then saturated brine (200 mL) was added, and the mixture was extracted with ethyl acetate (350 mL×3 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired crude product (78.57 g).
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，１００．１９ｇ，４３５ｍｍｏｌ）に水（７５．００ｇ）を加えた後、臭素（２７．０ｍＬ，５２４ｍｍｏｌ）を２．５時間かけて滴下した。この混合溶液を室温で１時間撹拌した。反応溶液に２０重量％炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（２００ｍＬ）を加え、酢酸エチル（３５０ｍＬ×３回）で抽出した。合一した有機層を無水硫酸ナトリウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（７８．５７ｇ）を得た。 <Example 7>
After adding water (75.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 100.19 g, 435 mmol), bromine (27.0 mL, 524 mmol) was added over 2.5 hours. Dripped. This mixed solution was stirred at room temperature for 1 hour. A 20% by weight sodium carbonate aqueous solution was added to the reaction solution to neutralize it, then saturated brine (200 mL) was added, and the mixture was extracted with ethyl acetate (350 mL×3 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired crude product (78.57 g).
得られた粗生成物に酢酸エチル（５０ｍＬ）を加え、氷冷下で１時間スラリー洗浄し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（７１．６０ｇ，収率：８５％，純度：９９．９％）を得た。結果を表１に示す。
Ethyl acetate (50 mL) was added to the resulting crude product, the slurry was washed under ice cooling for 1 hour, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazolin-3-one. A white solid (71.60 g, yield: 85%, purity: 99.9%) was obtained. Table 1 shows the results.
＜実施例８＞
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，２００．０９ｇ，８６９ｍｍｏｌ）に水（１５０．００ｇ）を加えた後、臭素（５４．０ｍＬ，１．０５ｍｏｌ）を５時間かけて滴下した。この混合溶液を室温で１時間撹拌した。反応溶液に２０重量％炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（４００ｍＬ）を加え、酢酸エチル（５００ｍＬ×４回）で抽出した。合一した有機層を無水硫酸ナトリウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１５９．３３ｇ）を得た。 <Example 8>
After adding water (150.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 200.09 g, 869 mmol), bromine (54.0 mL, 1.05 mol) was added over 5 hours. Dripped. This mixed solution was stirred at room temperature for 1 hour. After neutralizing the reaction solution by adding a 20% by weight aqueous sodium carbonate solution, saturated brine (400 mL) was added, and the mixture was extracted with ethyl acetate (500 mL×4 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired crude product (159.33 g).
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，２００．０９ｇ，８６９ｍｍｏｌ）に水（１５０．００ｇ）を加えた後、臭素（５４．０ｍＬ，１．０５ｍｏｌ）を５時間かけて滴下した。この混合溶液を室温で１時間撹拌した。反応溶液に２０重量％炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（４００ｍＬ）を加え、酢酸エチル（５００ｍＬ×４回）で抽出した。合一した有機層を無水硫酸ナトリウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１５９．３３ｇ）を得た。 <Example 8>
After adding water (150.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 200.09 g, 869 mmol), bromine (54.0 mL, 1.05 mol) was added over 5 hours. Dripped. This mixed solution was stirred at room temperature for 1 hour. After neutralizing the reaction solution by adding a 20% by weight aqueous sodium carbonate solution, saturated brine (400 mL) was added, and the mixture was extracted with ethyl acetate (500 mL×4 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired crude product (159.33 g).
得られた粗生成物に酢酸エチル（１００ｍＬ）を加え、氷冷下で３０分間スラリー洗浄し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（１４６．６７ｇ，収率：８７％，純度：９９．８％）を得た。結果を表１に示す。
Ethyl acetate (100 mL) was added to the resulting crude product, the slurry was washed for 30 minutes under ice-cooling, and the precipitated solid was filtered off to give 4-bromo-2-methyl-4-isothiazolin-3-one. A white solid (146.67 g, yield: 87%, purity: 99.8%) was obtained. Table 1 shows the results.
＜実施例９＞
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，４．００ｇ，１７．４ｍｍｏｌ）に水（３．００ｇ）を加えた後、４０℃で臭素（１．０７ｍＬ，２０．９ｍｍｏｌ）を１０分かけて滴下した。この混合溶液を４０℃で２時間撹拌した。反応溶液に飽和炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（８ｍＬ）を加え、酢酸エチル（２０ｍＬ×３回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（３．１４ｇ）を得た。 <Example 9>
After adding water (3.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 4.00 g, 17.4 mmol), bromine (1.07 mL, 20.9 mmol) was added at 40°C. was added dropwise over 10 minutes. This mixed solution was stirred at 40° C. for 2 hours. A saturated aqueous sodium carbonate solution was added to the reaction solution to neutralize it, saturated brine (8 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (3.14 g).
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，４．００ｇ，１７．４ｍｍｏｌ）に水（３．００ｇ）を加えた後、４０℃で臭素（１．０７ｍＬ，２０．９ｍｍｏｌ）を１０分かけて滴下した。この混合溶液を４０℃で２時間撹拌した。反応溶液に飽和炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（８ｍＬ）を加え、酢酸エチル（２０ｍＬ×３回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（３．１４ｇ）を得た。 <Example 9>
After adding water (3.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 4.00 g, 17.4 mmol), bromine (1.07 mL, 20.9 mmol) was added at 40°C. was added dropwise over 10 minutes. This mixed solution was stirred at 40° C. for 2 hours. A saturated aqueous sodium carbonate solution was added to the reaction solution to neutralize it, saturated brine (8 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (3.14 g).
得られた粗生成物に酢酸エチル（約３ｍＬ）を加え、加温して溶解させた後、室温まで冷却し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（２．６７ｇ，収率：７９％，純度９９．９％）を得た。結果を表１に示す。
Ethyl acetate (about 3 mL) was added to the resulting crude product, dissolved by heating, cooled to room temperature, and the precipitated solid was filtered off to give 4-bromo-2-methyl-4- A white solid of isothiazolin-3-one (2.67 g, yield: 79%, purity 99.9%) was obtained. Table 1 shows the results.
＜実施例１０＞
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，４．００ｇ，１７．４ｍｍｏｌ）に水（２．００ｇ）を加えた後、４０℃で臭素（１．０７ｍＬ，２０．９ｍｍｏｌ）を１０分かけて滴下した。この混合溶液を４０℃で５時間撹拌した。反応溶液に飽和炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（８ｍＬ）を加え、酢酸エチル（２０ｍＬ×３回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（３．０４ｇ）を得た。 <Example 10>
After adding water (2.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 4.00 g, 17.4 mmol), bromine (1.07 mL, 20.9 mmol) was added at 40°C. was added dropwise over 10 minutes. This mixed solution was stirred at 40° C. for 5 hours. A saturated aqueous sodium carbonate solution was added to the reaction solution to neutralize it, saturated brine (8 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (3.04 g).
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，４．００ｇ，１７．４ｍｍｏｌ）に水（２．００ｇ）を加えた後、４０℃で臭素（１．０７ｍＬ，２０．９ｍｍｏｌ）を１０分かけて滴下した。この混合溶液を４０℃で５時間撹拌した。反応溶液に飽和炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（８ｍＬ）を加え、酢酸エチル（２０ｍＬ×３回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（３．０４ｇ）を得た。 <Example 10>
After adding water (2.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 4.00 g, 17.4 mmol), bromine (1.07 mL, 20.9 mmol) was added at 40°C. was added dropwise over 10 minutes. This mixed solution was stirred at 40° C. for 5 hours. A saturated aqueous sodium carbonate solution was added to the reaction solution to neutralize it, saturated brine (8 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (3.04 g).
得られた粗生成物に酢酸エチル（約４ｍＬ）を加え、加温して溶解させた後、室温まで冷却し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（２．６９ｇ，収率：８０％，純度９９．９％）を得た。結果を表１に示す。
Ethyl acetate (about 4 mL) was added to the resulting crude product, dissolved by heating, cooled to room temperature, and the precipitated solid was filtered off to give 4-bromo-2-methyl-4- A white solid of isothiazolin-3-one (2.69 g, yield: 80%, purity 99.9%) was obtained. Table 1 shows the results.
＜実施例１１＞
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，１０．０２ｇ，４３．５ｍｍｏｌ）に水（７．５０ｇ）を加えた後、臭素（２．７０ｍＬ，５２．４ｍｍｏｌ）を４５分かけて滴下した。この混合溶液を室温で一晩（１２時間）撹拌した。反応溶液に飽和炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（２０ｍＬ）を加え、メチルイソブチルケトン（３５ｍＬ×３回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（７．８５ｇ）を得た。 <Example 11>
After adding water (7.50 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 10.02 g, 43.5 mmol), bromine (2.70 mL, 52.4 mmol) was added for 45 minutes. dripped over. The mixed solution was stirred overnight (12 hours) at room temperature. A saturated sodium carbonate aqueous solution was added to the reaction solution to neutralize it, then a saturated saline solution (20 mL) was added, and the mixture was extracted with methyl isobutyl ketone (35 mL×3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (7.85 g).
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，１０．０２ｇ，４３．５ｍｍｏｌ）に水（７．５０ｇ）を加えた後、臭素（２．７０ｍＬ，５２．４ｍｍｏｌ）を４５分かけて滴下した。この混合溶液を室温で一晩（１２時間）撹拌した。反応溶液に飽和炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（２０ｍＬ）を加え、メチルイソブチルケトン（３５ｍＬ×３回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（７．８５ｇ）を得た。 <Example 11>
After adding water (7.50 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 10.02 g, 43.5 mmol), bromine (2.70 mL, 52.4 mmol) was added for 45 minutes. dripped over. The mixed solution was stirred overnight (12 hours) at room temperature. A saturated sodium carbonate aqueous solution was added to the reaction solution to neutralize it, then a saturated saline solution (20 mL) was added, and the mixture was extracted with methyl isobutyl ketone (35 mL×3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (7.85 g).
得られた粗生成物にメチルイソブチルケトン（約８ｍＬ）を加え、加温して溶解させた後、室温まで冷却し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（６．７０ｇ，収率：７９％，純度９９．９％）を得た。結果を表１に示す。
Methyl isobutyl ketone (about 8 mL) was added to the obtained crude product, dissolved by heating, cooled to room temperature, and the precipitated solid was filtered off to give 4-bromo-2-methyl-4 -isothiazolin-3-one as a white solid (6.70 g, yield: 79%, purity 99.9%). Table 1 shows the results.
＜実施例１２＞
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，１０．０２ｇ，４３．５ｍｍｏｌ）に水（７．５０ｇ）を加えた後、臭素（２．７０ｍＬ，５２．４ｍｍｏｌ）を４５分かけて滴下した。この混合溶液を室温で一晩撹拌した。反応溶液に飽和炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（２０ｍＬ）を加え、クロロベンゼン（３５ｍＬ×３回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（７．５７ｇ）を得た。 <Example 12>
After adding water (7.50 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 10.02 g, 43.5 mmol), bromine (2.70 mL, 52.4 mmol) was added for 45 minutes. dripped over. The mixed solution was stirred overnight at room temperature. A saturated sodium carbonate aqueous solution was added to the reaction solution to neutralize it, then a saturated saline solution (20 mL) was added, and the mixture was extracted with chlorobenzene (35 mL×3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (7.57 g).
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，１０．０２ｇ，４３．５ｍｍｏｌ）に水（７．５０ｇ）を加えた後、臭素（２．７０ｍＬ，５２．４ｍｍｏｌ）を４５分かけて滴下した。この混合溶液を室温で一晩撹拌した。反応溶液に飽和炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（２０ｍＬ）を加え、クロロベンゼン（３５ｍＬ×３回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（７．５７ｇ）を得た。 <Example 12>
After adding water (7.50 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 10.02 g, 43.5 mmol), bromine (2.70 mL, 52.4 mmol) was added for 45 minutes. dripped over. The mixed solution was stirred overnight at room temperature. A saturated sodium carbonate aqueous solution was added to the reaction solution to neutralize it, then a saturated saline solution (20 mL) was added, and the mixture was extracted with chlorobenzene (35 mL×3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (7.57 g).
得られた粗生成物にクロロベンゼン（約７ｍＬ）を加え、加温して溶解させた後、室温まで冷却し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（６．２９ｇ，収率：７５％，純度９９．９％）を得た。結果を表１に示す。
Chlorobenzene (about 7 mL) was added to the obtained crude product, dissolved by heating, cooled to room temperature, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazoline. A white solid of -3-one (6.29 g, yield: 75%, purity 99.9%) was obtained. Table 1 shows the results.
＜実施例１３＞
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，１０．０３ｇ，４３．５ｍｍｏｌ）に水（７．５０ｇ）を加えた後、臭素（２．７０ｍＬ，５２．４ｍｍｏｌ）を４５分かけて滴下した。この混合溶液を室温で一晩撹拌した。反応溶液に飽和炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（２０ｍＬ）を加え、ｏ－ジクロロベンゼン（３５ｍＬ×３回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（７．５３ｇ）を得た。 <Example 13>
After adding water (7.50 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 10.03 g, 43.5 mmol), bromine (2.70 mL, 52.4 mmol) was added for 45 minutes. dripped over. The mixed solution was stirred overnight at room temperature. A saturated aqueous sodium carbonate solution was added to the reaction solution for neutralization, then saturated brine (20 mL) was added, and the mixture was extracted with o-dichlorobenzene (35 mL×3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (7.53 g).
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，１０．０３ｇ，４３．５ｍｍｏｌ）に水（７．５０ｇ）を加えた後、臭素（２．７０ｍＬ，５２．４ｍｍｏｌ）を４５分かけて滴下した。この混合溶液を室温で一晩撹拌した。反応溶液に飽和炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（２０ｍＬ）を加え、ｏ－ジクロロベンゼン（３５ｍＬ×３回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（７．５３ｇ）を得た。 <Example 13>
After adding water (7.50 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 10.03 g, 43.5 mmol), bromine (2.70 mL, 52.4 mmol) was added for 45 minutes. dripped over. The mixed solution was stirred overnight at room temperature. A saturated aqueous sodium carbonate solution was added to the reaction solution for neutralization, then saturated brine (20 mL) was added, and the mixture was extracted with o-dichlorobenzene (35 mL×3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (7.53 g).
得られた粗生成物にｏ－ジクロロベンゼン（約７ｍＬ）を加え、加温して溶解させた後、室温まで冷却し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（６．４９ｇ，収率：７７％，純度９９．８％）を得た。結果を表１に示す。
o-Dichlorobenzene (about 7 mL) was added to the resulting crude product, dissolved by heating, cooled to room temperature, and the precipitated solid was filtered off to give 4-bromo-2-methyl- A white solid of 4-isothiazolin-3-one (6.49 g, yield: 77%, purity 99.8%) was obtained. Table 1 shows the results.
＜実施例１４＞
２－メチル－４－イソチアゾリン－３－オン塩酸塩（１．０１ｇ，６．６４ｍｍｏｌ）に水（４．００ｇ）を加えた後、臭素（０．３８ｍＬ，７．３７ｍｍｏｌ）を１５分間かけて滴下した。この混合溶液を室温で１時間撹拌した。反応溶液に飽和食塩水（５ｍＬ）を加え、次いで２０重量％炭酸ナトリウム水溶液で中和した後、酢酸エチル（１０ｍＬ×４回）で抽出した。合一した有機層を無水硫酸ナトリウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．２１ｇ）を得た。 <Example 14>
After adding water (4.00 g) to 2-methyl-4-isothiazolin-3-one hydrochloride (1.01 g, 6.64 mmol), bromine (0.38 mL, 7.37 mmol) was added dropwise over 15 minutes. bottom. This mixed solution was stirred at room temperature for 1 hour. Saturated saline (5 mL) was added to the reaction solution, which was then neutralized with a 20% by weight sodium carbonate aqueous solution and then extracted with ethyl acetate (10 mL×4 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.21 g).
２－メチル－４－イソチアゾリン－３－オン塩酸塩（１．０１ｇ，６．６４ｍｍｏｌ）に水（４．００ｇ）を加えた後、臭素（０．３８ｍＬ，７．３７ｍｍｏｌ）を１５分間かけて滴下した。この混合溶液を室温で１時間撹拌した。反応溶液に飽和食塩水（５ｍＬ）を加え、次いで２０重量％炭酸ナトリウム水溶液で中和した後、酢酸エチル（１０ｍＬ×４回）で抽出した。合一した有機層を無水硫酸ナトリウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．２１ｇ）を得た。 <Example 14>
After adding water (4.00 g) to 2-methyl-4-isothiazolin-3-one hydrochloride (1.01 g, 6.64 mmol), bromine (0.38 mL, 7.37 mmol) was added dropwise over 15 minutes. bottom. This mixed solution was stirred at room temperature for 1 hour. Saturated saline (5 mL) was added to the reaction solution, which was then neutralized with a 20% by weight sodium carbonate aqueous solution and then extracted with ethyl acetate (10 mL×4 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.21 g).
得られた粗生成物に酢酸エチル（約１ｍＬ）を加え、加温して溶解させた後、室温まで冷却し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（１．０４ｇ，収率：８０％，純度：９９．９％）を得た。結果を表１に示す。
Ethyl acetate (about 1 mL) was added to the resulting crude product, dissolved by heating, cooled to room temperature, and the precipitated solid was filtered off to give 4-bromo-2-methyl-4- A white solid of isothiazolin-3-one (1.04 g, yield: 80%, purity: 99.9%) was obtained. Table 1 shows the results.
＜実施例１５＞
２－メチル－４－イソチアゾリン－３－オン塩酸塩（１．００ｇ，６．６２ｍｍｏｌ）に水（３．００ｇ）を加えた後、臭素（０．３９５ｍＬ，７．６６ｍｍｏｌ）を１５分間かけて滴下した。この混合溶液を室温で３時間撹拌した。反応溶液に飽和食塩水（５ｍＬ）を加え、次いで２０重量％炭酸ナトリウム水溶液で中和した後、酢酸エチル（１０ｍＬ×４回）で抽出した。合一した有機層を無水硫酸ナトリウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．１８ｇ）を得た。 <Example 15>
After adding water (3.00 g) to 2-methyl-4-isothiazolin-3-one hydrochloride (1.00 g, 6.62 mmol), bromine (0.395 mL, 7.66 mmol) was added dropwise over 15 minutes. bottom. This mixed solution was stirred at room temperature for 3 hours. Saturated saline (5 mL) was added to the reaction solution, which was then neutralized with a 20% by weight sodium carbonate aqueous solution and then extracted with ethyl acetate (10 mL×4 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.18 g).
２－メチル－４－イソチアゾリン－３－オン塩酸塩（１．００ｇ，６．６２ｍｍｏｌ）に水（３．００ｇ）を加えた後、臭素（０．３９５ｍＬ，７．６６ｍｍｏｌ）を１５分間かけて滴下した。この混合溶液を室温で３時間撹拌した。反応溶液に飽和食塩水（５ｍＬ）を加え、次いで２０重量％炭酸ナトリウム水溶液で中和した後、酢酸エチル（１０ｍＬ×４回）で抽出した。合一した有機層を無水硫酸ナトリウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．１８ｇ）を得た。 <Example 15>
After adding water (3.00 g) to 2-methyl-4-isothiazolin-3-one hydrochloride (1.00 g, 6.62 mmol), bromine (0.395 mL, 7.66 mmol) was added dropwise over 15 minutes. bottom. This mixed solution was stirred at room temperature for 3 hours. Saturated saline (5 mL) was added to the reaction solution, which was then neutralized with a 20% by weight sodium carbonate aqueous solution and then extracted with ethyl acetate (10 mL×4 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.18 g).
得られた粗生成物に酢酸エチル（約１ｍＬ）を加え、加温して溶解させた後、室温まで冷却し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（０．９９ｇ，収率：７７％，純度：９９．９％）を得た。結果を表１に示す。
Ethyl acetate (about 1 mL) was added to the resulting crude product, dissolved by heating, cooled to room temperature, and the precipitated solid was filtered off to give 4-bromo-2-methyl-4- A white solid of isothiazolin-3-one (0.99 g, yield: 77%, purity: 99.9%) was obtained. Table 1 shows the results.
＜実施例１６＞
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，２．０７ｇ，８．９９ｍｍｏｌ）に水（２．００ｇ）を加えた後、臭素（０．５６ｍＬ，１０．９ｍｍｏｌ）のクロロベンゼン（４．０ｍＬ）溶液を３０分間かけて滴下した。この混合溶液を室温で一晩撹拌した。反応溶液に飽和食塩水（１０ｍＬ）を加え、次いで飽和炭酸ナトリウム水溶液で中和した後、クロロベンゼン（１０ｍＬ×４回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．７９ｇ）を得た。 <Example 16>
After adding water (2.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.07 g, 8.99 mmol), bromine (0.56 mL, 10.9 mmol) in chlorobenzene ( 4.0 mL) solution was added dropwise over 30 minutes. The mixed solution was stirred overnight at room temperature. Saturated saline (10 mL) was added to the reaction solution, which was then neutralized with a saturated aqueous sodium carbonate solution and then extracted with chlorobenzene (10 mL x 4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.79 g).
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，２．０７ｇ，８．９９ｍｍｏｌ）に水（２．００ｇ）を加えた後、臭素（０．５６ｍＬ，１０．９ｍｍｏｌ）のクロロベンゼン（４．０ｍＬ）溶液を３０分間かけて滴下した。この混合溶液を室温で一晩撹拌した。反応溶液に飽和食塩水（１０ｍＬ）を加え、次いで飽和炭酸ナトリウム水溶液で中和した後、クロロベンゼン（１０ｍＬ×４回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．７９ｇ）を得た。 <Example 16>
After adding water (2.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.07 g, 8.99 mmol), bromine (0.56 mL, 10.9 mmol) in chlorobenzene ( 4.0 mL) solution was added dropwise over 30 minutes. The mixed solution was stirred overnight at room temperature. Saturated saline (10 mL) was added to the reaction solution, which was then neutralized with a saturated aqueous sodium carbonate solution and then extracted with chlorobenzene (10 mL x 4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.79 g).
得られた粗生成物にクロロベンゼン（約２ｍＬ）を加え、加温して溶解させた後、室温まで冷却し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（１．５４ｇ，収率：８８％，純度：９９．９％）を得た。結果を表１に示す。
Chlorobenzene (about 2 mL) was added to the obtained crude product, dissolved by heating, cooled to room temperature, and the precipitated solid was separated by filtration to obtain 4-bromo-2-methyl-4-isothiazoline. -3-one was obtained as a white solid (1.54 g, yield: 88%, purity: 99.9%). Table 1 shows the results.
＜実施例１７＞
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，１０．１１ｇ，４３．９ｍｍｏｌ）に水（１０．０ｇ）を加えた後、臭素（２．７５ｍＬ，５３．３ｍｍｏｌ）のクロロベンゼン（２０．０ｍＬ）溶液を３０分間かけて滴下した。この混合溶液を室温で一晩撹拌した。反応溶液に飽和食塩水（５０ｍＬ）を加え、次いで飽和炭酸ナトリウム水溶液で中和した後、クロロベンゼン（５０ｍＬ×４回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（８．０６ｇ）を得た。 <Example 17>
After adding water (10.0 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 10.11 g, 43.9 mmol), bromine (2.75 mL, 53.3 mmol) in chlorobenzene ( 20.0 mL) solution was added dropwise over 30 minutes. The mixed solution was stirred overnight at room temperature. Saturated saline (50 mL) was added to the reaction solution, which was then neutralized with a saturated aqueous sodium carbonate solution and then extracted with chlorobenzene (50 mL x 4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (8.06 g).
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，１０．１１ｇ，４３．９ｍｍｏｌ）に水（１０．０ｇ）を加えた後、臭素（２．７５ｍＬ，５３．３ｍｍｏｌ）のクロロベンゼン（２０．０ｍＬ）溶液を３０分間かけて滴下した。この混合溶液を室温で一晩撹拌した。反応溶液に飽和食塩水（５０ｍＬ）を加え、次いで飽和炭酸ナトリウム水溶液で中和した後、クロロベンゼン（５０ｍＬ×４回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（８．０６ｇ）を得た。 <Example 17>
After adding water (10.0 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 10.11 g, 43.9 mmol), bromine (2.75 mL, 53.3 mmol) in chlorobenzene ( 20.0 mL) solution was added dropwise over 30 minutes. The mixed solution was stirred overnight at room temperature. Saturated saline (50 mL) was added to the reaction solution, which was then neutralized with a saturated aqueous sodium carbonate solution and then extracted with chlorobenzene (50 mL x 4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (8.06 g).
得られた粗生成物にクロロベンゼン（約８ｍＬ）を加え、加温して溶解させた後、室温まで冷却し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（６．８７ｇ，収率：８１％，純度：９９．９％）を得た。結果を表１に示す。
Chlorobenzene (about 8 mL) was added to the obtained crude product, dissolved by heating, cooled to room temperature, and the precipitated solid was filtered off to obtain 4-bromo-2-methyl-4-isothiazoline. -3-one was obtained as a white solid (6.87 g, yield: 81%, purity: 99.9%). Table 1 shows the results.
＜実施例１８＞
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，２．０２ｇ，８．７５ｍｍｏｌ）に水（１．００ｇ）を加えた後、臭素（０．５４ｍＬ，１０．５ｍｍｏｌ）のクロロベンゼン（４．０ｍＬ）溶液を３０分間かけて滴下した。この混合溶液を室温で一晩撹拌した。反応溶液に飽和食塩水（１０ｍＬ）を加え、次いで飽和炭酸ナトリウム水溶液で中和した後、クロロベンゼン（１０ｍＬ×４回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．６１ｇ）を得た。 <Example 18>
After adding water (1.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.02 g, 8.75 mmol), bromine (0.54 mL, 10.5 mmol) in chlorobenzene ( 4.0 mL) solution was added dropwise over 30 minutes. The mixed solution was stirred overnight at room temperature. Saturated saline (10 mL) was added to the reaction solution, which was then neutralized with a saturated aqueous sodium carbonate solution and then extracted with chlorobenzene (10 mL x 4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.61 g).
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，２．０２ｇ，８．７５ｍｍｏｌ）に水（１．００ｇ）を加えた後、臭素（０．５４ｍＬ，１０．５ｍｍｏｌ）のクロロベンゼン（４．０ｍＬ）溶液を３０分間かけて滴下した。この混合溶液を室温で一晩撹拌した。反応溶液に飽和食塩水（１０ｍＬ）を加え、次いで飽和炭酸ナトリウム水溶液で中和した後、クロロベンゼン（１０ｍＬ×４回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．６１ｇ）を得た。 <Example 18>
After adding water (1.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.02 g, 8.75 mmol), bromine (0.54 mL, 10.5 mmol) in chlorobenzene ( 4.0 mL) solution was added dropwise over 30 minutes. The mixed solution was stirred overnight at room temperature. Saturated saline (10 mL) was added to the reaction solution, which was then neutralized with a saturated aqueous sodium carbonate solution and then extracted with chlorobenzene (10 mL x 4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.61 g).
得られた粗生成物にクロロベンゼン（約２ｍＬ）を加え、加温して溶解させた後、室温まで冷却し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（１．３４ｇ，収率：７９％，純度：９９．９％）を得た。結果を表１に示す。
Chlorobenzene (about 2 mL) was added to the obtained crude product, dissolved by heating, cooled to room temperature, and the precipitated solid was separated by filtration to obtain 4-bromo-2-methyl-4-isothiazoline. -3-one was obtained as a white solid (1.34 g, yield: 79%, purity: 99.9%). Table 1 shows the results.
＜実施例１９＞
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，２．０３ｇ，８．８１ｍｍｏｌ）に水（２．００ｇ）を加えた後、臭素（０．５５ｍＬ，１０．７ｍｍｏｌ）のｏ－ジクロロベンゼン（４．０ｍＬ）溶液を３０分間かけて滴下した。この混合溶液を室温で６時間撹拌した。反応溶液に飽和食塩水（１０ｍＬ）を加え、次いで飽和炭酸ナトリウム水溶液で中和した後、ｏ－ジクロロベンゼン（１０ｍＬ×４回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．８６ｇ）を得た。 <Example 19>
After adding water (2.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.03 g, 8.81 mmol), o- Dichlorobenzene (4.0 mL) solution was added dropwise over 30 minutes. This mixed solution was stirred at room temperature for 6 hours. Saturated saline (10 mL) was added to the reaction solution, which was then neutralized with saturated aqueous sodium carbonate solution and then extracted with o-dichlorobenzene (10 mL×4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.86 g).
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，２．０３ｇ，８．８１ｍｍｏｌ）に水（２．００ｇ）を加えた後、臭素（０．５５ｍＬ，１０．７ｍｍｏｌ）のｏ－ジクロロベンゼン（４．０ｍＬ）溶液を３０分間かけて滴下した。この混合溶液を室温で６時間撹拌した。反応溶液に飽和食塩水（１０ｍＬ）を加え、次いで飽和炭酸ナトリウム水溶液で中和した後、ｏ－ジクロロベンゼン（１０ｍＬ×４回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．８６ｇ）を得た。 <Example 19>
After adding water (2.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.03 g, 8.81 mmol), o- Dichlorobenzene (4.0 mL) solution was added dropwise over 30 minutes. This mixed solution was stirred at room temperature for 6 hours. Saturated saline (10 mL) was added to the reaction solution, which was then neutralized with saturated aqueous sodium carbonate solution and then extracted with o-dichlorobenzene (10 mL×4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.86 g).
得られた粗生成物にｏ－ジクロロベンゼン（約２ｍＬ）を加え、加温して溶解させた後、室温まで冷却し、析出した固体をろ別することにより、４－ブロモ－２－メチル－４－イソチアゾリン－３－オンの白色固体（１．４６ｇ，収率：８５％，純度：９９．８％）を得た。結果を表１に示す。
o-Dichlorobenzene (about 2 mL) was added to the resulting crude product, dissolved by heating, cooled to room temperature, and the precipitated solid was filtered off to give 4-bromo-2-methyl- A white solid of 4-isothiazolin-3-one (1.46 g, yield: 85%, purity: 99.8%) was obtained. Table 1 shows the results.
＜実施例２０＞
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，２．０２ｇ，８．７５ｍｍｏｌ）に水（４．４０ｇ）を加えた後、臭素（０．５４ｍＬ，１０．５ｍｍｏｌ）を１０分間かけて滴下した。この混合溶液を室温で３時間撹拌した。反応溶液に飽和炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（１０ｍＬ）を加え、酢酸エチル（１０ｍＬ×４回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．６６ｇ）を得た。１Ｈ－ＮＭＲ内部標準法による分析の結果、組成と収率は以下の通りであった。結果を表１に示す。 <Example 20>
After adding water (4.40 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.02 g, 8.75 mmol), bromine (0.54 mL, 10.5 mmol) was added for 10 minutes. dripped over. This mixed solution was stirred at room temperature for 3 hours. A saturated aqueous sodium carbonate solution was added to the reaction solution to neutralize it, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.66 g). As a result of analysis by 1 H-NMR internal standard method, the composition and yield were as follows. Table 1 shows the results.
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，２．０２ｇ，８．７５ｍｍｏｌ）に水（４．４０ｇ）を加えた後、臭素（０．５４ｍＬ，１０．５ｍｍｏｌ）を１０分間かけて滴下した。この混合溶液を室温で３時間撹拌した。反応溶液に飽和炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（１０ｍＬ）を加え、酢酸エチル（１０ｍＬ×４回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．６６ｇ）を得た。１Ｈ－ＮＭＲ内部標準法による分析の結果、組成と収率は以下の通りであった。結果を表１に示す。 <Example 20>
After adding water (4.40 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.02 g, 8.75 mmol), bromine (0.54 mL, 10.5 mmol) was added for 10 minutes. dripped over. This mixed solution was stirred at room temperature for 3 hours. A saturated aqueous sodium carbonate solution was added to the reaction solution to neutralize it, saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.66 g). As a result of analysis by 1 H-NMR internal standard method, the composition and yield were as follows. Table 1 shows the results.
組成：４－ブロモ－２－メチル－４－イソチアゾリン－３－オン；９３．５％
２－メチル－４－イソチアゾリン－３－オン；０．０％
収率：９１％ Composition: 4-bromo-2-methyl-4-isothiazolin-3-one; 93.5%
2-methyl-4-isothiazolin-3-one; 0.0%
Yield: 91%
２－メチル－４－イソチアゾリン－３－オン；０．０％
収率：９１％ Composition: 4-bromo-2-methyl-4-isothiazolin-3-one; 93.5%
2-methyl-4-isothiazolin-3-one; 0.0%
Yield: 91%
＜実施例２１＞
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，２．０２ｇ，８．７８ｍｍｏｌ）に水（２．００ｇ）を加えた後、臭素（０．５４ｍＬ，１０．５ｍｍｏｌ）のクロロベンゼン（４．０ｍＬ）溶液を３０分間かけて滴下した。この混合溶液を室温で一晩撹拌した。反応溶液に飽和炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（１０ｍＬ）を加え、クロロベンゼン（１０ｍＬ×４回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．６２ｇ）を得た。１Ｈ－ＮＭＲ内部標準法による分析の結果、組成と収率は以下の通りであった。結果を表１に示す。 <Example 21>
After adding water (2.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.02 g, 8.78 mmol), bromine (0.54 mL, 10.5 mmol) in chlorobenzene ( 4.0 mL) solution was added dropwise over 30 minutes. The mixed solution was stirred overnight at room temperature. A saturated sodium carbonate aqueous solution was added to the reaction solution to neutralize it, then a saturated saline solution (10 mL) was added, and the mixture was extracted with chlorobenzene (10 mL×4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.62 g). As a result of analysis by 1 H-NMR internal standard method, the composition and yield were as follows. Table 1 shows the results.
２－メチル－４－イソチアゾリン－３－オン（５０重量％水溶液，２．０２ｇ，８．７８ｍｍｏｌ）に水（２．００ｇ）を加えた後、臭素（０．５４ｍＬ，１０．５ｍｍｏｌ）のクロロベンゼン（４．０ｍＬ）溶液を３０分間かけて滴下した。この混合溶液を室温で一晩撹拌した。反応溶液に飽和炭酸ナトリウム水溶液を加えて中和した後、飽和食塩水（１０ｍＬ）を加え、クロロベンゼン（１０ｍＬ×４回）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．６２ｇ）を得た。１Ｈ－ＮＭＲ内部標準法による分析の結果、組成と収率は以下の通りであった。結果を表１に示す。 <Example 21>
After adding water (2.00 g) to 2-methyl-4-isothiazolin-3-one (50 wt% aqueous solution, 2.02 g, 8.78 mmol), bromine (0.54 mL, 10.5 mmol) in chlorobenzene ( 4.0 mL) solution was added dropwise over 30 minutes. The mixed solution was stirred overnight at room temperature. A saturated sodium carbonate aqueous solution was added to the reaction solution to neutralize it, then a saturated saline solution (10 mL) was added, and the mixture was extracted with chlorobenzene (10 mL×4 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.62 g). As a result of analysis by 1 H-NMR internal standard method, the composition and yield were as follows. Table 1 shows the results.
組成：４－ブロモ－２－メチル－４－イソチアゾリン－３－オン；９５．０％
２－メチル－４－イソチアゾリン－３－オン；０．０％
収率：９０％ Composition: 4-bromo-2-methyl-4-isothiazolin-3-one; 95.0%
2-methyl-4-isothiazolin-3-one; 0.0%
Yield: 90%
２－メチル－４－イソチアゾリン－３－オン；０．０％
収率：９０％ Composition: 4-bromo-2-methyl-4-isothiazolin-3-one; 95.0%
2-methyl-4-isothiazolin-3-one; 0.0%
Yield: 90%
＜比較例１＞
２－メチル－４－イソチアゾリン－３－オン（１．００ｇ，８．６８ｍｍｏｌ）の酢酸エチル（１７．０ｍＬ）溶液に、臭素（０．４５ｍＬ，８．７６ｍｍｏｌ）をゆっくりと滴下した後、８０℃で８時間加熱攪拌した。反応溶液を減圧下に濃縮し、クロロホルム（２５ｍＬ）および水（１０ｍＬ）を添加した後、３０分間撹拌した。この混合溶液をクロロホルム（１０ｍＬ×３回）で抽出し、合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．４９ｇ）を得た。１Ｈ－ＮＭＲ内部標準法による分析の結果、組成と収率は以下の通りであった。結果を表１に示す。 <Comparative Example 1>
After slowly dropping bromine (0.45 mL, 8.76 mmol) into a solution of 2-methyl-4-isothiazolin-3-one (1.00 g, 8.68 mmol) in ethyl acetate (17.0 mL), was heated and stirred for 8 hours. The reaction solution was concentrated under reduced pressure, chloroform (25 mL) and water (10 mL) were added, and the mixture was stirred for 30 minutes. This mixed solution was extracted with chloroform (10 mL x 3 times), and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.49 g). . As a result of analysis by 1 H-NMR internal standard method, the composition and yield were as follows. Table 1 shows the results.
２－メチル－４－イソチアゾリン－３－オン（１．００ｇ，８．６８ｍｍｏｌ）の酢酸エチル（１７．０ｍＬ）溶液に、臭素（０．４５ｍＬ，８．７６ｍｍｏｌ）をゆっくりと滴下した後、８０℃で８時間加熱攪拌した。反応溶液を減圧下に濃縮し、クロロホルム（２５ｍＬ）および水（１０ｍＬ）を添加した後、３０分間撹拌した。この混合溶液をクロロホルム（１０ｍＬ×３回）で抽出し、合一した有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．４９ｇ）を得た。１Ｈ－ＮＭＲ内部標準法による分析の結果、組成と収率は以下の通りであった。結果を表１に示す。 <Comparative Example 1>
After slowly dropping bromine (0.45 mL, 8.76 mmol) into a solution of 2-methyl-4-isothiazolin-3-one (1.00 g, 8.68 mmol) in ethyl acetate (17.0 mL), was heated and stirred for 8 hours. The reaction solution was concentrated under reduced pressure, chloroform (25 mL) and water (10 mL) were added, and the mixture was stirred for 30 minutes. This mixed solution was extracted with chloroform (10 mL x 3 times), and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired crude product (1.49 g). . As a result of analysis by 1 H-NMR internal standard method, the composition and yield were as follows. Table 1 shows the results.
組成：４－ブロモ－２－メチル－４－イソチアゾリン－３－オン；８５．２％
２－メチル－４－イソチアゾリン－３－オン；６．７％
収率：７６％ Composition: 4-bromo-2-methyl-4-isothiazolin-3-one; 85.2%
2-methyl-4-isothiazolin-3-one; 6.7%
Yield: 76%
２－メチル－４－イソチアゾリン－３－オン；６．７％
収率：７６％ Composition: 4-bromo-2-methyl-4-isothiazolin-3-one; 85.2%
2-methyl-4-isothiazolin-3-one; 6.7%
Yield: 76%
＜比較例２＞
２－メチル－４－イソチアゾリン－３－オン（１．０２ｇ，８．８６ｍｍｏｌ）の酢酸（１５．０ｍＬ）溶液に、氷冷下で臭素（０．４６ｍＬ，８．８９ｍｍｏｌ）をゆっくりと滴下した後、氷冷下（０～５℃）で１時間撹拌し、さらに室温で１７時間撹拌した。反応溶液に水（１０ｍＬ）を加え、酢酸エチル（１５ｍＬ×３回）で抽出した。合一した有機層を飽和炭酸水素ナトリウム水溶液（１４ｍＬ）、飽和チオ硫酸ナトリウム水溶液（１４ｍＬ）および水（５ｍＬ）で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．３１ｇ）を得た。１Ｈ－ＮＭＲ内部標準法による分析の結果、組成と収率は以下の通りであった。結果を表１に示す。 <Comparative Example 2>
To a solution of 2-methyl-4-isothiazolin-3-one (1.02 g, 8.86 mmol) in acetic acid (15.0 mL) was slowly added dropwise bromine (0.46 mL, 8.89 mmol) under ice cooling. , under ice-cooling (0-5° C.) for 1 hour, and further stirred at room temperature for 17 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL x 3 times). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (14 mL), saturated aqueous sodium thiosulfate solution (14 mL) and water (5 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude target product (1.31 g). As a result of analysis by 1 H-NMR internal standard method, the composition and yield were as follows. Table 1 shows the results.
２－メチル－４－イソチアゾリン－３－オン（１．０２ｇ，８．８６ｍｍｏｌ）の酢酸（１５．０ｍＬ）溶液に、氷冷下で臭素（０．４６ｍＬ，８．８９ｍｍｏｌ）をゆっくりと滴下した後、氷冷下（０～５℃）で１時間撹拌し、さらに室温で１７時間撹拌した。反応溶液に水（１０ｍＬ）を加え、酢酸エチル（１５ｍＬ×３回）で抽出した。合一した有機層を飽和炭酸水素ナトリウム水溶液（１４ｍＬ）、飽和チオ硫酸ナトリウム水溶液（１４ｍＬ）および水（５ｍＬ）で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下に濃縮することにより、目的物の粗生成物（１．３１ｇ）を得た。１Ｈ－ＮＭＲ内部標準法による分析の結果、組成と収率は以下の通りであった。結果を表１に示す。 <Comparative Example 2>
To a solution of 2-methyl-4-isothiazolin-3-one (1.02 g, 8.86 mmol) in acetic acid (15.0 mL) was slowly added dropwise bromine (0.46 mL, 8.89 mmol) under ice cooling. , under ice-cooling (0-5° C.) for 1 hour, and further stirred at room temperature for 17 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL x 3 times). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (14 mL), saturated aqueous sodium thiosulfate solution (14 mL) and water (5 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude target product (1.31 g). As a result of analysis by 1 H-NMR internal standard method, the composition and yield were as follows. Table 1 shows the results.
組成：４－ブロモ－２－メチル－４－イソチアゾリン－３－オン；７４．０％
２－メチル－４－イソチアゾリン－３－オン；４．７％
収率：５６％ Composition: 4-bromo-2-methyl-4-isothiazolin-3-one; 74.0%
2-methyl-4-isothiazolin-3-one; 4.7%
Yield: 56%
２－メチル－４－イソチアゾリン－３－オン；４．７％
収率：５６％ Composition: 4-bromo-2-methyl-4-isothiazolin-3-one; 74.0%
2-methyl-4-isothiazolin-3-one; 4.7%
Yield: 56%
このように、実施例の方法によって、高純度の４－ブロモイソチアゾリノン誘導体を、選択性および収率よく製造することができた。
Thus, by the method of the example, a highly pure 4-bromoisothiazolinone derivative could be produced with good selectivity and yield.
Claims (9)
- 式（１）
式（２）
formula (2)
- 請求項１に記載の４－ブロモイソチアゾリノン誘導体の製造方法であって、
工程ａ）：前記式（２）で示されるイソチアゾリノン化合物またはその化学的に許容される塩を、前記水溶媒中または水溶媒と有機溶媒との混合溶媒中で、前記臭素化剤を用いて臭素化し、前記式（１）で示される４－ブロモイソチアゾリノン誘導体を合成する工程と、
工程ｂ）：前記工程ａ）で得られた４－ブロモイソチアゾリノン誘導体を精製する工程と、
を含むことを特徴とする４－ブロモイソチアゾリノン誘導体の製造方法。 A method for producing a 4-bromoisothiazolinone derivative according to claim 1,
Step a): The isothiazolinone compound represented by the formula (2) or a chemically acceptable salt thereof is subjected to bromination with the brominating agent in the aqueous solvent or in the mixed solvent of the aqueous solvent and the organic solvent. a step of synthesizing a 4-bromoisothiazolinone derivative represented by the formula (1);
Step b): a step of purifying the 4-bromoisothiazolinone derivative obtained in step a);
A method for producing a 4-bromoisothiazolinone derivative, comprising: - 請求項２に記載の４－ブロモイソチアゾリノン誘導体の製造方法であって、
前記工程ｂ）における精製する方法が、再結晶またはスラリー洗浄による方法であることを特徴とする４－ブロモイソチアゾリノン誘導体の製造方法。 A method for producing a 4-bromoisothiazolinone derivative according to claim 2,
A method for producing a 4-bromoisothiazolinone derivative, wherein the purification method in the step b) is a method by recrystallization or slurry washing. - 請求項３に記載の４－ブロモイソチアゾリノン誘導体の製造方法であって、
前記再結晶またはスラリー洗浄に使用する溶媒が、酢酸エチル、クロロベンゼン、およびｏ－ジクロロベンゼンのうちの少なくとも１つであることを特徴とする４－ブロモイソチアゾリノン誘導体の製造方法。 A method for producing a 4-bromoisothiazolinone derivative according to claim 3,
A method for producing a 4-bromoisothiazolinone derivative, wherein the solvent used for recrystallization or slurry washing is at least one of ethyl acetate, chlorobenzene, and o-dichlorobenzene. - 請求項１～４のいずれか一項に記載の４－ブロモイソチアゾリノン誘導体の製造方法であって、
使用する前記水溶媒の量が、原料に対する重量比で０．１から１０の範囲であることを特徴とする４－ブロモイソチアゾリノン誘導体の製造方法。 A method for producing a 4-bromoisothiazolinone derivative according to any one of claims 1 to 4,
A method for producing a 4-bromoisothiazolinone derivative, wherein the amount of the water solvent used is in the range of 0.1 to 10 by weight relative to the raw material. - 請求項１または２に記載の４－ブロモイソチアゾリノン誘導体の製造方法であって、
前記臭素化剤が、臭素、Ｎ－ブロモスクシンイミド、または１，３－ジブロモ－５，５－ジメチルヒダントインであることを特徴とする４－ブロモイソチアゾリノン誘導体の製造方法。 A method for producing a 4-bromoisothiazolinone derivative according to claim 1 or 2,
A method for producing a 4-bromoisothiazolinone derivative, wherein the brominating agent is bromine, N-bromosuccinimide, or 1,3-dibromo-5,5-dimethylhydantoin. - 請求項１または２に記載の４－ブロモイソチアゾリノン誘導体の製造方法であって、
前記臭素化における反応温度が、０℃から８０℃の範囲であることを特徴とする４－ブロモイソチアゾリノン誘導体の製造方法。 A method for producing a 4-bromoisothiazolinone derivative according to claim 1 or 2,
A method for producing a 4-bromoisothiazolinone derivative, wherein the reaction temperature in the bromination is in the range of 0°C to 80°C. - 請求項１または２に記載の４－ブロモイソチアゾリノン誘導体の製造方法であって、
前記Ｒが、炭素数１～４のアルキル基であることを特徴とする４－ブロモイソチアゾリノン誘導体の製造方法。 A method for producing a 4-bromoisothiazolinone derivative according to claim 1 or 2,
A method for producing a 4-bromoisothiazolinone derivative, wherein said R is an alkyl group having 1 to 4 carbon atoms. - 式（１）で示される４－ブロモイソチアゾリノン誘導体であって、前記４－ブロモイソチアゾリノン誘導体に含まれる式（２）で示されるイソチアゾリノン化合物またはその化学的に許容される塩の含有量が１００ｐｐｍ未満であることを特徴とする、４－ブロモイソチアゾリノン誘導体。
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