JP2004292425A - Method for producing glycidyl phthalimide - Google Patents
Method for producing glycidyl phthalimide Download PDFInfo
- Publication number
- JP2004292425A JP2004292425A JP2003331875A JP2003331875A JP2004292425A JP 2004292425 A JP2004292425 A JP 2004292425A JP 2003331875 A JP2003331875 A JP 2003331875A JP 2003331875 A JP2003331875 A JP 2003331875A JP 2004292425 A JP2004292425 A JP 2004292425A
- Authority
- JP
- Japan
- Prior art keywords
- phthalimide
- optically active
- alkali metal
- epihalohydrin
- producing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- GZPUHNGIERMRFC-UHFFFAOYSA-N 4-(oxiran-2-ylmethyl)isoindole-1,3-dione Chemical compound O=C1NC(=O)C2=C1C=CC=C2CC1CO1 GZPUHNGIERMRFC-UHFFFAOYSA-N 0.000 title claims abstract description 60
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 37
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims abstract description 67
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 43
- -1 alkali metal salt Chemical class 0.000 claims abstract description 41
- 239000002904 solvent Substances 0.000 claims abstract description 40
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 22
- 239000003960 organic solvent Substances 0.000 claims abstract description 15
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims abstract description 14
- 150000008041 alkali metal carbonates Chemical class 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 239000013543 active substance Substances 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 13
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical group [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- 150000001340 alkali metals Chemical group 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 4
- 150000003509 tertiary alcohols Chemical class 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005456 alcohol based solvent Substances 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 claims description 3
- 150000003333 secondary alcohols Chemical group 0.000 claims description 3
- 238000005580 one pot reaction Methods 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 3
- 229910052801 chlorine Inorganic materials 0.000 claims 3
- 239000000460 chlorine Substances 0.000 claims 3
- 239000004210 ether based solvent Substances 0.000 claims 2
- KHXUWBTUFGABBI-UHFFFAOYSA-N 4-(3-hydroxypropyl)isoindole-1,3-dione Chemical compound OCCCC1=CC=CC2=C1C(=O)NC2=O KHXUWBTUFGABBI-UHFFFAOYSA-N 0.000 claims 1
- 229940006460 bromide ion Drugs 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 150000002500 ions Chemical class 0.000 claims 1
- 230000001476 alcoholic effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 238000000034 method Methods 0.000 description 37
- 230000003287 optical effect Effects 0.000 description 25
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 12
- KXHPPCXNWTUNSB-UHFFFAOYSA-M benzyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1=CC=CC=C1 KXHPPCXNWTUNSB-UHFFFAOYSA-M 0.000 description 10
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- GZPUHNGIERMRFC-SSDOTTSWSA-N 4-[[(2r)-oxiran-2-yl]methyl]isoindole-1,3-dione Chemical compound O=C1NC(=O)C2=C1C=CC=C2C[C@@H]1CO1 GZPUHNGIERMRFC-SSDOTTSWSA-N 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- BRLQWZUYTZBJKN-VKHMYHEASA-N (-)-Epichlorohydrin Chemical compound ClC[C@H]1CO1 BRLQWZUYTZBJKN-VKHMYHEASA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- GZPUHNGIERMRFC-ZETCQYMHSA-N 4-[[(2s)-oxiran-2-yl]methyl]isoindole-1,3-dione Chemical compound O=C1NC(=O)C2=C1C=CC=C2C[C@H]1CO1 GZPUHNGIERMRFC-ZETCQYMHSA-N 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- KBRVYEPWGIQEOF-UHFFFAOYSA-N 2-(3-chloro-2-hydroxypropyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CC(CCl)O)C(=O)C2=C1 KBRVYEPWGIQEOF-UHFFFAOYSA-N 0.000 description 4
- CETWDUZRCINIHU-UHFFFAOYSA-N 2-heptanol Chemical compound CCCCCC(C)O CETWDUZRCINIHU-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RZKSECIXORKHQS-UHFFFAOYSA-N Heptan-3-ol Chemical compound CCCCC(O)CC RZKSECIXORKHQS-UHFFFAOYSA-N 0.000 description 4
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 4
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 4
- AQIXEPGDORPWBJ-UHFFFAOYSA-N pentan-3-ol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- BRLQWZUYTZBJKN-GSVOUGTGSA-N (+)-Epichlorohydrin Chemical compound ClC[C@@H]1CO1 BRLQWZUYTZBJKN-GSVOUGTGSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- QNVRIHYSUZMSGM-UHFFFAOYSA-N hexan-2-ol Chemical compound CCCCC(C)O QNVRIHYSUZMSGM-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 150000003138 primary alcohols Chemical class 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000013076 target substance Substances 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- IAQQDIGGISSSQO-UHFFFAOYSA-N 2-(4-fluorophenyl)piperidine Chemical compound C1=CC(F)=CC=C1C1NCCCC1 IAQQDIGGISSSQO-UHFFFAOYSA-N 0.000 description 1
- AGIBHMPYXXPGAX-UHFFFAOYSA-N 2-(iodomethyl)oxirane Chemical compound ICC1CO1 AGIBHMPYXXPGAX-UHFFFAOYSA-N 0.000 description 1
- QNVRIHYSUZMSGM-LURJTMIESA-N 2-Hexanol Natural products CCCC[C@H](C)O QNVRIHYSUZMSGM-LURJTMIESA-N 0.000 description 1
- FOILINVEQJRMPF-UHFFFAOYSA-M 2-hydroxypropyl(trimethyl)azanium;iodide Chemical compound [I-].CC(O)C[N+](C)(C)C FOILINVEQJRMPF-UHFFFAOYSA-M 0.000 description 1
- ASNHGEVAWNWCRQ-UHFFFAOYSA-N 4-(hydroxymethyl)oxolane-2,3,4-triol Chemical compound OCC1(O)COC(O)C1O ASNHGEVAWNWCRQ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- NJSSICCENMLTKO-HRCBOCMUSA-N [(1r,2s,4r,5r)-3-hydroxy-4-(4-methylphenyl)sulfonyloxy-6,8-dioxabicyclo[3.2.1]octan-2-yl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@H]1C(O)[C@@H](OS(=O)(=O)C=2C=CC(C)=CC=2)[C@@H]2OC[C@H]1O2 NJSSICCENMLTKO-HRCBOCMUSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- UUZYBYIOAZTMGC-UHFFFAOYSA-M benzyl(trimethyl)azanium;bromide Chemical compound [Br-].C[N+](C)(C)CC1=CC=CC=C1 UUZYBYIOAZTMGC-UHFFFAOYSA-M 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- ZMCUDHNSHCRDBT-UHFFFAOYSA-M caesium bicarbonate Chemical compound [Cs+].OC([O-])=O ZMCUDHNSHCRDBT-UHFFFAOYSA-M 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- GCIHJOGYEHDJEC-UHFFFAOYSA-N cesium;isoindole-1,3-dione Chemical compound [Cs].C1=CC=C2C(=O)NC(=O)C2=C1 GCIHJOGYEHDJEC-UHFFFAOYSA-N 0.000 description 1
- 229940115457 cetyldimethylethylammonium bromide Drugs 0.000 description 1
- XENVCRGQTABGKY-ZHACJKMWSA-N chlorohydrin Chemical compound CC#CC#CC#CC#C\C=C\C(Cl)CO XENVCRGQTABGKY-ZHACJKMWSA-N 0.000 description 1
- 239000012045 crude solution Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- VUFOSBDICLTFMS-UHFFFAOYSA-M ethyl-hexadecyl-dimethylazanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)CC VUFOSBDICLTFMS-UHFFFAOYSA-M 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 125000003055 glycidyl group Chemical group C(C1CO1)* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000011346 highly viscous material Substances 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- DEGPIRUPAKWDBU-UHFFFAOYSA-N isoindole-1,3-dione;sodium Chemical compound [Na].C1=CC=C2C(=O)NC(=O)C2=C1 DEGPIRUPAKWDBU-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 229910000032 lithium hydrogen carbonate Inorganic materials 0.000 description 1
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- QQZOPKMRPOGIEB-UHFFFAOYSA-N n-butyl methyl ketone Natural products CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 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
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- ZRLVQFQTCMUIRM-UHFFFAOYSA-N potassium;2-methylbutan-2-olate Chemical compound [K+].CCC(C)(C)[O-] ZRLVQFQTCMUIRM-UHFFFAOYSA-N 0.000 description 1
- MKNZKCSKEUHUPM-UHFFFAOYSA-N potassium;butan-1-ol Chemical compound [K+].CCCCO MKNZKCSKEUHUPM-UHFFFAOYSA-N 0.000 description 1
- AWDMDDKZURRKFG-UHFFFAOYSA-N potassium;propan-1-olate Chemical compound [K+].CCC[O-] AWDMDDKZURRKFG-UHFFFAOYSA-N 0.000 description 1
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- CGRKYEALWSRNJS-UHFFFAOYSA-N sodium;2-methylbutan-2-olate Chemical compound [Na+].CCC(C)(C)[O-] CGRKYEALWSRNJS-UHFFFAOYSA-N 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- RCOSUMRTSQULBK-UHFFFAOYSA-N sodium;propan-1-olate Chemical compound [Na+].CCC[O-] RCOSUMRTSQULBK-UHFFFAOYSA-N 0.000 description 1
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- SZEMGTQCPRNXEG-UHFFFAOYSA-M trimethyl(octadecyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCCCC[N+](C)(C)C SZEMGTQCPRNXEG-UHFFFAOYSA-M 0.000 description 1
- HADKRTWCOYPCPH-UHFFFAOYSA-M trimethylphenylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C1=CC=CC=C1 HADKRTWCOYPCPH-UHFFFAOYSA-M 0.000 description 1
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- Epoxy Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
本発明は、医薬品や農薬、生理活性物質の合成中間体として重要なグリシジルフタルイミド、殊にグリシジルフタルイミドの光学活性体の製造法に関する。 The present invention relates to a method for producing glycidyl phthalimide, particularly an optically active form of glycidyl phthalimide, which is important as a synthetic intermediate for pharmaceuticals, agricultural chemicals, and physiologically active substances.
グリシジルフタルイミド、殊にグリシジルフタルイミドの光学活性体は、各種光学活性な医薬品製造において重要な合成中間体としての利用が見込まれる。
一般に光学活性な医薬品およびその中間体には９８％ｅｅ以上の光学純度が求められている。従って、グリシジルフタルイミドの光学活性体を高い光学純度でかつ容易に製造する方法の確立が重要な課題である。
これまでに、グリシジルフタルイミドのラセミ体の一般的な製造手法として、フタルイミドカリウムをエピクロロヒドリンのラセミ体溶媒中で還流させる方法（非特許文献１参照）や、ＤＭＦ溶媒中、フタルイミドカリウムとエピクロロヒドリンのラセミ体を等量ずつ用いて反応させる方法（非特許文献２参照）などが開発されている。更に、ヨウ化テトラｎ−ブチルアンモニウムおよび炭酸カリウム存在下、フタルイミドとエピクロロヒドリンを反応させる際にマイクロ波オーブンを用いられることを特徴とする製造法（非特許文献３参照）も開発されている。
一方、グリシジルフタルイミドの光学活性体の製造方法としては、フタルイミドを光学活性なエピクロロヒドリン溶媒中で還流することによって光学活性なＮ-（３-クロロ-２-ヒドロキシプロピル）フタルイミドを得て、これを単離精製し、更にテトラヒドロフラン溶媒中、水素化ナトリウムを加えて環化させる方法（例えば、特許文献１参照）が報告されている。また、（Ｓ）−グリシジルフタルイミドについて、特許文献２に開示はあるものの、その具体的製法が示されていない。
Generally, optically active pharmaceuticals and their intermediates are required to have an optical purity of 98% ee or more. Therefore, it is important to establish a method for easily producing an optically active form of glycidyl phthalimide with high optical purity.
Heretofore, as a general method for producing a racemic glycidyl phthalimide, a method of refluxing potassium phthalimide in a racemic solvent of epichlorohydrin (see Non-Patent Document 1), and a method of preparing an emulsion of potassium phthalimide and epichlorohydrin in a DMF solvent. A method has been developed in which a reaction is performed using an equal amount of a racemic chlorohydrin (see Non-Patent Document 2). Further, a production method characterized by using a microwave oven when reacting phthalimide and epichlorohydrin in the presence of tetra-n-butylammonium iodide and potassium carbonate has been developed (see Non-Patent Document 3). I have.
On the other hand, as a method for producing an optically active form of glycidylphthalimide, phthalimide is refluxed in an optically active epichlorohydrin solvent to obtain optically active N- (3-chloro-2-hydroxypropyl) phthalimide. A method has been reported in which this is isolated and purified, and further cyclized by adding sodium hydride in a tetrahydrofuran solvent (for example, see Patent Document 1). Patent Document 2 discloses (S) -glycidyl phthalimide, but does not show a specific production method.
上記のラセミ体合成の手法を用いて、フタルイミドカリウムと溶媒量のエピハロヒドリンの光学活性体を還流させる（非特許文献１）と、エピハロヒドリンの光学純度が低下し、その結果グリシジルフタルイミドの光学純度が低下する。またＤＭＦ溶媒中、エピクロロヒドリンの光学活性体（９９％ｅｅ）とフタルイミドカリウムを反応させるとラセミ化が進行するため、得られたグリシジルフタルイミドの光学活性体の光学純度（６３％ｅｅ）は満足できるものではない（比較例１参照）。
一方、フタルイミドを用いてマイクロ波オーブン中で反応させる手法（非特許文献３）は、満足できる収率（５０％）で得られていない。
エピクロロヒドリンの光学活性体とフタルイミドを還流下で反応させる手法（例えば、特許文献１参照）では、中間体のＮ-（３-クロロ-２-ヒドロキシプロピル）フタルイミドを単離精製する必要があるのみならず、その収率およびグリシジルフタルイミドの収率も低く、満足できるものではない。
When the optically active isomer of potassium phthalimide and a solvent amount of epihalohydrin is refluxed using the above-mentioned method of racemic synthesis (Non-Patent Document 1), the optical purity of epihalohydrin decreases, and as a result, the optical purity of glycidyl phthalimide decreases. I do. In addition, racemization proceeds when an optically active form of epichlorohydrin (99% ee) is reacted with potassium phthalimide in a DMF solvent, so that the optical purity of the obtained optically active form of glycidyl phthalimide (63% ee) is Not satisfactory (see Comparative Example 1).
On the other hand, the technique of reacting in a microwave oven using phthalimide (Non-Patent Document 3) has not been obtained in a satisfactory yield (50%).
In a method of reacting an optically active form of epichlorohydrin with phthalimide under reflux (for example, see Patent Document 1), it is necessary to isolate and purify an intermediate N- (3-chloro-2-hydroxypropyl) phthalimide. Not only that, but also the yield and the yield of glycidyl phthalimide are low and unsatisfactory.
本発明者らは、上記の課題を解決すべく鋭意検討を行った結果、アルコール溶媒存在下、エピクロロヒドリンの光学活性体とフタルイミドのアルカリ金属塩を反応させることにより、グリシジルフタルイミドの光学活性体が高収率、かつ高光学純度で得られることを見出した。また、同様にして、エピクロロヒドリンのラセミ体とフタルイミドのアルカリ金属塩を反応させることにより、グリシジルフタルイミドのラセミ体を簡便に収率良く得ることができることも判明した。
また、フタルイミドとエピハロヒドリンを有機溶媒中で、アルカリ金属炭酸塩、アルカリ金属炭酸水素塩または４級アンモニウム塩の存在下反応させ、得られるＮ-（３-ハロ-２-ヒドロキシプロピル）フタルイミドに金属アルコキシドを用いて閉環させることにより、グリシジルフタルイミドのラセミ体または光学活性体を簡便に収率良く、そして光学活性体においては高光学純度で得ることができることも判明した。
The present inventors have conducted intensive studies to solve the above problems, and as a result, in the presence of an alcohol solvent, by reacting an optically active form of epichlorohydrin with an alkali metal salt of phthalimide, the optical activity of glycidyl phthalimide It was found that the compound was obtained in high yield and high optical purity. Similarly, it was also found that a racemic glycidylphthalimide can be easily obtained with a high yield by reacting a racemic epichlorohydrin with an alkali metal salt of phthalimide.
Further, phthalimide and epihalohydrin are reacted in an organic solvent in the presence of an alkali metal carbonate, an alkali metal bicarbonate or a quaternary ammonium salt, and the resulting N- (3-halo-2-hydroxypropyl) phthalimide is reacted with a metal alkoxide. It has also been found that by performing ring closure using, a racemic or optically active form of glycidyl phthalimide can be easily obtained with high yield, and the optically active form can be obtained with high optical purity.
即ち、本発明は、下記式（１）
下記式（２）
で表されるフタルイミドのアルカリ金属塩と、下記式（３）
で表されるエピハロヒドリンをアルコール溶媒中で反応させるか；あるいは
フタルイミドとエピハロヒドリン（３）を有機溶媒中で、アルカリ金属炭酸塩、アルカリ金属炭酸水素塩または下記式（４）
Ｒ1Ｒ2Ｒ3Ｒ4Ｎ+Ｘ- （４）
（式中、Ｒ１、Ｒ２、Ｒ３およびＲ４は互いに異なっていてもよい炭素数１〜１６のアルキル基、アルケニル基、アラルキル基またはアリール基を表し、そしてＸ−は塩素イオン、臭素イオン、よう素イオン、硫酸水素イオンまたは水酸イオンを表す。）
で表される第４級アンモニウム塩の存在下、反応させ、下記式（５）
で表されるＮ-（３-ハロ-２-ヒドロキシプロピル）フタルイミドを得、次いで、アルカリ金属アルコキシドにより環化反応させることを特徴とする該グリシジルフタルイミド（１）の製造法に関する。
That is, the present invention provides the following formula (1)
The following equation (2)
An alkali metal salt of phthalimide represented by the following formula (3):
Reacting epihalohydrin represented by the following formula in an alcohol solvent; or reacting phthalimide and epihalohydrin (3) in an organic solvent with an alkali metal carbonate, an alkali metal bicarbonate or the following formula (4)
R 1 R 2 R 3 R 4 N + X - (4)
(Wherein, R 1 , R 2 , R 3 and R 4 represent an alkyl group, an alkenyl group, an aralkyl group or an aryl group which may be different from each other, and X − represents a chlorine ion, bromine Ion, iodine ion, hydrogen sulfate ion or hydroxyl ion.)
In the presence of a quaternary ammonium salt represented by the following formula (5)
The present invention relates to a process for producing the glycidyl phthalimide (1), characterized by obtaining N- (3-halo-2-hydroxypropyl) phthalimide represented by the formula:
本発明は、またフタルイミドのアルカリ金属塩（２）とエピハロヒドリン（３）をアルコール溶媒中で反応させることを特徴とするグリシジルフタルイミド（１）の製造法に関する（以下この発明を便宜上、方法Ａに関する発明と略記する。）。
本発明は、特にフタルイミドのアルカリ金属塩（２）に対して、エピハロヒドリン（３）の光学活性体をアルコール溶媒中で反応させることを特徴とするグリシジルフタルイミド（１）の光学活性体の製造法に関する。
The present invention also relates to a method for producing glycidyl phthalimide (1), which comprises reacting an alkali metal salt of phthalimide (2) with epihalohydrin (3) in an alcoholic solvent (hereinafter referred to as the invention relating to method A for convenience of the present invention). Abbreviated.).
The present invention particularly relates to a method for producing an optically active glycidylphthalimide (1), which comprises reacting an optically active epihalohydrin (3) with an alkali metal salt of phthalimide (2) in an alcohol solvent. .
本発明は、また方法Ａにおいて、第４級アンモニウム塩（４）を添加することを特徴とするグリシジルフタルイミド（１）またはその光学活性体の製造法にも関する。 The present invention also relates to a method for producing glycidyl phthalimide (1) or an optically active form thereof, which comprises adding a quaternary ammonium salt (4) in method A.
本発明は、またフタルイミドとエピハロヒドリン（３）を有機溶媒中で、アルカリ金属炭酸塩、アルカリ金属炭酸水素塩または第４級アンモニウム塩（４）の存在下、反応させ、Ｎ-（３-ハロ-２-ヒドロキシプロピル）フタルイミド（５）を得、次いで、アルカリ金属アルコキシドにより環化反応を行うことを特徴とするグリシジルフタルイミド（１）の製造法にも関する（以下この発明を便宜上、方法Ｂに関する発明と略記する。）。
また、本発明は、上記方法Ｂの第一のステップにより得られるＮ-（３-ハロ-２-ヒドロキシプロピル）フタルイミド（５）を単離することなく、反応系にアルカリ金属アルコキシドを加えて、いわゆるワンポットで第二のステップである環化反応を行うことを特徴とする、グリシジルフタルイミド（１）の製造法に関する。
The present invention also relates to the reaction of phthalimide and epihalohydrin (3) in an organic solvent in the presence of an alkali metal carbonate, an alkali metal bicarbonate or a quaternary ammonium salt (4) to form N- (3-halo- The present invention also relates to a method for producing glycidyl phthalimide (1), characterized in that 2-hydroxypropyl) phthalimide (5) is obtained, and then a cyclization reaction is performed with an alkali metal alkoxide. Abbreviated.).
Further, the present invention provides a method of adding an alkali metal alkoxide to a reaction system without isolating N- (3-halo-2-hydroxypropyl) phthalimide (5) obtained in the first step of the method B, The present invention relates to a method for producing glycidyl phthalimide (1), which comprises performing a cyclization reaction as a second step in a so-called one pot.
更に、本発明は、有機溶媒中において、アルカリ金属炭酸塩、アルカリ金属炭酸水素塩または第４級アンモニウム塩（４）の存在下、フタルイミドとエピハロヒドリン（３）とを縮合反応させることを特徴とするＮ-（３-ハロ-２-ヒドロキシプロピル）フタルイミド（５）の製造法にも関する。 Further, the present invention is characterized in that a phthalimide and epihalohydrin (3) are subjected to a condensation reaction in an organic solvent in the presence of an alkali metal carbonate, an alkali metal bicarbonate or a quaternary ammonium salt (4). The present invention also relates to a method for producing N- (3-halo-2-hydroxypropyl) phthalimide (5).
本発明は、特に方法Ｂにおいて、エピハロヒドリン（３）が光学活性体であること、あるいは光学活性なエピハロヒドリンがエピクロロヒドリンであることを特徴とするグリシジルフタルイミド（１）の光学活性体の製造法に関する。更には、これらの光学活性なエピハロヒドリンを用いるＮ-（３-ハロ-２-ヒドロキシプロピル）フタルイミド（５）の光学活性体の製造方法に関する。 The present invention provides a method for producing an optically active form of glycidyl phthalimide (1), which is characterized in that, in method B, the epihalohydrin (3) is an optically active substance or the optically active epihalohydrin is epichlorohydrin. About. Further, the present invention relates to a method for producing an optically active N- (3-halo-2-hydroxypropyl) phthalimide (5) using these optically active epihalohydrins.
本発明によれば、グリシジルフタルイミド、特にその光学活性体を高収率、高光学純度で製造することができる。 ADVANTAGE OF THE INVENTION According to this invention, glycidyl phthalimide, especially its optically active substance can be manufactured with high yield and high optical purity.
方法（Ａ）で用いられるフタルイミドのアルカリ金属塩（２）は、イミドの窒素原子にアルカリ金属原子が結合したものであり、フタルイミドナトリウム、フタルイミドカリウム、フタルイミドセシウムなどが挙げられるが、フタルイミドカリウムが望ましい。
方法（Ａ）で用いられるエピハロヒドリン（３）としては、エピクロロヒドリン、エピブロモヒドリンおよびエピヨードヒドリン、特にそれらの光学活性体が挙げられるが、特に好ましくはエピクロロヒドリンの光学活性体である。
エピハロヒドリンの使用量は、フタルイミドのアルカリ金属塩（２）に対して１〜４当量であり、好ましくは２〜３当量である。
方法（Ａ）で用いられるアルコール溶媒としては、メタノール、エタノール、１−プロパノール、１−ブタノール、１−ペンタノール、１−ヘキサノールなどの１級アルコール類、イソプロパノール、２−ブタノール、２−ペンタノール、３−ペンタノール、２−ヘキサノール、シクロヘキサノール、２−ヘプタノール、３−ヘプタノールなどの２級アルコール類や、ｔｅｒｔ−ブタノール、ｔｅｒｔ−ペンタノールなどの３級アルコール類などが挙げられるが、好ましくは２級および３級アルコール類であり、更に好ましくはイソプロパノール、２−ブタノールおよびｔｅｒｔ−ブタノールである。
アルコール溶媒の使用量は、フタルイミドのアルカリ金属塩（２）に対して２〜２０倍（ｗ／ｗ）が適量である。
The alkali metal salt of phthalimide (2) used in the method (A) is one in which an alkali metal atom is bonded to a nitrogen atom of the imide, and examples thereof include sodium phthalimide, potassium phthalimide, and cesium phthalimide, and potassium phthalimide is preferable. .
Examples of the epihalohydrin (3) used in the method (A) include epichlorohydrin, epibromohydrin, and epiiodohydrin, particularly, optically active forms thereof, and particularly preferably, the optical activity of epichlorohydrin. Body.
The amount of epihalohydrin used is 1 to 4 equivalents, preferably 2 to 3 equivalents, relative to the alkali metal salt of phthalimide (2).
Examples of the alcohol solvent used in the method (A) include primary alcohols such as methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol and 1-hexanol, isopropanol, 2-butanol, 2-pentanol, Secondary alcohols such as 3-pentanol, 2-hexanol, cyclohexanol, 2-heptanol and 3-heptanol, and tertiary alcohols such as tert-butanol and tert-pentanol are exemplified. And tertiary alcohols, more preferably isopropanol, 2-butanol and tert-butanol.
The appropriate amount of the alcohol solvent used is 2 to 20 times (w / w) the alkali metal salt of phthalimide (2).
方法（Ａ）で用いられる第４級アンモニウム塩（４）の具体例としては、塩化ベンジルトリメチルアンモニウム、塩化ジアリルジメチルアンモニウム、臭化ベンジルトリメチルアンモニウム、臭化ｎ−オクチルトリメチルアンモニウム、臭化ステアリルトリメチルアンモニウム、臭化セチルジメチルエチルアンモニウム、よう化テトラｎ−ブチルアンモニウム、よう化β−メチルコリン、硫酸水素テトラ−ｎ−ブチルアンモニウムおよびフェニルトリメチルアンモニウムヒドロキシドなどが挙げられるが、これらに限定されない。
方法（Ａ）の反応は、第４級アンモニウム塩（４）を添加することにより反応が加速され、目的物のグリシジルフタルイミド（１）あるいはその光学活性体の収率を向上させることができる。
第４級アンモニウム塩（４）の量は、フタルイミドのアルカリ金属塩（２）に対して触媒量でよく、０．００５〜０．１当量が好ましい。
Specific examples of the quaternary ammonium salt (4) used in the method (A) include benzyltrimethylammonium chloride, diallyldimethylammonium chloride, benzyltrimethylammonium bromide, n-octyltrimethylammonium bromide, and stearyltrimethylammonium bromide. Cetyldimethylethylammonium bromide, tetra-n-butylammonium iodide, β-methylcholine iodide, tetra-n-butylammonium hydrogensulfate, phenyltrimethylammonium hydroxide, and the like, but are not limited thereto.
The reaction of the method (A) is accelerated by adding the quaternary ammonium salt (4), and the yield of the target product, glycidylphthalimide (1) or an optically active form thereof can be improved.
The amount of the quaternary ammonium salt (4) may be a catalytic amount with respect to the alkali metal salt of phthalimide (2), and is preferably 0.005 to 0.1 equivalent.
方法（Ａ）の反応温度は−１０〜６０℃が好ましく、更に好ましくは０〜３０℃である。−１０℃未満では反応が抑制されるので適切ではない。また、反応温度が６０℃を超えると、副反応が進行して収率低下の原因となったり、使用されるエピハロヒドリンが光学活性体の場合、エピハロヒドリンの光学活性体のラセミ化が進行して、得られるグリシジルフタルイミド（１）の光学活性体の光学純度が低下するなど、好ましくない。
方法（Ａ）に関する発明の利点は、反応終了後にアルコール溶媒を留去し、抽出溶媒を加えて水洗するという、非常に簡便な操作で目的のグリシジルフタルイミド（１）、殊にその光学活性体が高収率で、かつ高光学純度で得られることにある。抽出溶媒としては、目的物（１）が溶解する非水溶性有機溶媒であれば特に限定されず、酢酸メチル、酢酸エチルなどの酢酸エステルや、塩化メチレン、クロロホルム、１，２−ジクロロエタンなどのハロゲン系溶媒などが挙げられる。必要であれば、晶析およびカラムクロマトグラフィーなどの精製を行ってもよい。
The reaction temperature of the method (A) is preferably from -10 to 60C, more preferably from 0 to 30C. If the temperature is lower than −10 ° C., the reaction is suppressed, so that it is not appropriate. When the reaction temperature exceeds 60 ° C., a side reaction proceeds to cause a decrease in yield, or when the epihalohydrin used is an optically active substance, racemization of the optically active epihalohydrin proceeds, It is not preferable because the optical purity of the obtained glycidyl phthalimide (1) optically active substance is reduced.
An advantage of the invention relating to the method (A) is that the objective glycidyl phthalimide (1), particularly its optically active substance, can be obtained by a very simple operation of distilling off the alcohol solvent after completion of the reaction, adding an extraction solvent and washing with water. It is to be obtained in high yield and high optical purity. The extraction solvent is not particularly limited as long as it is a water-insoluble organic solvent in which the target substance (1) is dissolved. Examples of the extraction solvent include acetates such as methyl acetate and ethyl acetate, and halogens such as methylene chloride, chloroform and 1,2-dichloroethane. System solvents and the like. If necessary, purification such as crystallization and column chromatography may be performed.
次に方法（Ｂ）について説明する。
方法（Ｂ）で用いられる式（３）で表されるエピハロヒドリンの具体例としては、発明方法Ａで用いられるものと同じである。エピハロヒドリン（３）の使用量は、フタルイミドに対して好ましくは１〜３当量であり、より好ましくは１〜２当量である。
Next, the method (B) will be described.
Specific examples of the epihalohydrin represented by the formula (3) used in the method (B) are the same as those used in the invention method A. The amount of epihalohydrin (3) used is preferably 1 to 3 equivalents, more preferably 1 to 2 equivalents to phthalimide.
方法（Ｂ）で用いられるアルカリ金属炭酸塩としては、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、および炭酸セシウムなどが挙げられ、アルカリ炭酸水素塩としては、炭酸水素リチウム、炭酸水素ナトリウム、炭酸水素カリウム、および炭酸水素セシウムなどが挙げられるが、これらに限定されない。アルカリ金属炭酸塩およびアルカリ金属炭酸水素塩は、含水物または無水物のどちらを用いてもよいが、グリシジルフタルイミド（１）の光学活性体が所望であれば、無水物が好ましい。
アルカリ金属炭酸塩またはアルカリ金属炭酸水素塩の量は、フタルイミドに対して化学量論量または触媒量のどちらでもよく、０．０１〜３当量が好ましい。
方法Ｂで用いられる第４級アンモニウム塩（４）の具体例としては、発明方法Ａで用いられるものと同じである。
第４級アンモニウム塩（４）の量は、フタルイミドに対して触媒量でよく、０．００５〜０．１当量が好ましい。第４級アンモニウム塩（４）を上記アルカリ金属炭酸塩またはアルカリ金属炭酸水素塩と併用することにより、本反応（Ｂ）がより促進され、より高収率で目的物（１）を得ることができる。
Examples of the alkali metal carbonate used in the method (B) include lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Examples of the alkali hydrogen carbonate include lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, And cesium bicarbonate, but are not limited thereto. As the alkali metal carbonate and the alkali metal bicarbonate, either a hydrate or an anhydride may be used. If an optically active form of glycidyl phthalimide (1) is desired, an anhydride is preferable.
The amount of the alkali metal carbonate or alkali metal bicarbonate may be either stoichiometric or catalytic with respect to phthalimide, and is preferably 0.01 to 3 equivalents.
Specific examples of the quaternary ammonium salt (4) used in Method B are the same as those used in Invention Method A.
The amount of the quaternary ammonium salt (4) may be a catalytic amount based on phthalimide, and is preferably 0.005 to 0.1 equivalent. By using the quaternary ammonium salt (4) in combination with the above-mentioned alkali metal carbonate or alkali metal bicarbonate, the reaction (B) is further promoted, and the desired product (1) can be obtained in higher yield. it can.
方法（Ｂ）で用いられる有機溶媒は、フタルイミドやエピハロヒドリン（３）と反応するもの（アミン類、カルボン酸類、グリシジル基）以外であれば特に限定されないが、グリシジルフタルイミド（１）の光学活性体が所望であれば、アルコール類、エーテル類またはこれらの混合溶媒が好ましく用いられる。アルコール系溶媒としては、メタノール、エタノール、１-プロパノール、１-ブタノール、１-ペンタノール、１-ヘキサノールなどの１級アルコール類、イソプロパノール、２-ブタノール、２-ペンタノール、３-ペンタノール、２-ヘキサノール、シクロヘキサノール、２-ヘプタノール、３-ヘプタノールなどの２級アルコール類や、ｔｅｒｔ-ブタノール、ｔｅｒｔ-ペンタノールなどの３級アルコール類などが挙げられるが、好ましくはメタノール、イソプロパノール、およびｔｅｒｔ-ブタノールである。一方、エーテル系溶媒としては、ジエチルエーテル、ジブチルエーテル、ｔｅｒｔ-ブチルメチルエーテル、１，２-ジメトキシエタン、１，４-ジオキサン、テトラヒドロフラン（ＴＨＦ）などが挙げられるが、好ましくはＴＨＦおよび１，４-ジオキサンである。 The organic solvent used in the method (B) is not particularly limited as long as it is other than those that react with phthalimide or epihalohydrin (3) (amines, carboxylic acids, glycidyl groups). The optically active glycidyl phthalimide (1) is preferably used. If desired, alcohols, ethers or mixed solvents thereof are preferably used. Examples of alcohol solvents include primary alcohols such as methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol and 1-hexanol, isopropanol, 2-butanol, 2-pentanol, 3-pentanol, Secondary alcohols such as -hexanol, cyclohexanol, 2-heptanol, and 3-heptanol; and tertiary alcohols such as tert-butanol and tert-pentanol. Among them, methanol, isopropanol, and tert- Butanol. On the other hand, examples of the ether solvent include diethyl ether, dibutyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran (THF), and the like. -Dioxane.
溶媒の混合比については特に限定されない。溶媒の量は、フタルイミドに対して２〜２０倍（ｗ／ｗ）が好ましい。 The mixing ratio of the solvent is not particularly limited. The amount of the solvent is preferably 2 to 20 times (w / w) of phthalimide.
方法（Ｂ）の第二ステップで用いられるアルカリ金属アルコキシドとしては、ナトリウムメトキシド、カリウムメトキシド、ナトリウムエトキシド、カリウムエトキシド、ナトリウムｎ-プロポキシド、カリウムｎ-プロポキシド、ナトリウムイソプロポキシド、カリウムイソプロポキシド、ナトリウムｎ-ブトキシド、カリウムｎ-ブトキシド、ナトリウムｔｅｒｔ-ブトキシド、カリウムｔｅｒｔ-ブトキシド、ナトリウムｔｅｒｔ-アミラート、カリウムｔｅｒｔ-アミラート、ナトリウムｎ-ヘキシラート、およびカリウムｎ-ヘキシラートなどが好ましく挙げられるが、これらに限定されない。 The alkali metal alkoxide used in the second step of the method (B) includes sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, potassium n-propoxide, sodium isopropoxide, Preferred examples include potassium isopropoxide, sodium n-butoxide, potassium n-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amylate, potassium tert-amylate, sodium n-hexylate, and potassium n-hexylate. However, it is not limited to these.
アルカリ金属アルコキシドは、フタルイミドとエピハロヒドリン（３）との縮合反応が完結してＮ-（３-ハロ-２-ヒドロキシプロピル）フタルイミド（５）得られてから添加される。フタルイミドとエピハロヒドリン（３）との縮合反応時にアルカリ金属アルコキシドを添加すると、副生成物の増加により目的物の収率が低下し、特に光学活性体が所望の場合は光学純度が低下する（比較例５参照）。アルカリ金属アルコキシド添加方法は、そのまま数回に分けて加える方法や、本反応で使用するアルコール系またはエーテル系に溶解させてからゆっくりと加える方法などが挙げられる。
方法（Ｂ）の反応温度は−１０〜６０℃が好ましく、更に好ましくは０〜５０℃である。
The alkali metal alkoxide is added after the condensation reaction between phthalimide and epihalohydrin (3) is completed and N- (3-halo-2-hydroxypropyl) phthalimide (5) is obtained. When an alkali metal alkoxide is added during the condensation reaction between phthalimide and epihalohydrin (3), the yield of the target product decreases due to an increase in by-products, and the optical purity decreases particularly when an optically active substance is desired (Comparative Example) 5). Examples of the method of adding the alkali metal alkoxide include a method in which the alkali metal alkoxide is added in several portions as it is, and a method in which the alkali metal alkoxide is slowly added after dissolving in the alcohol or ether used in the present reaction.
The reaction temperature of the method (B) is preferably from -10 to 60C, more preferably from 0 to 50C.
アルカリ金属炭酸塩、アルカリ金属炭酸水素塩または第４級アンモニウム塩（４）の存在下、有機溶媒中で、好ましくはアルコール系またはエーテル溶媒中でフタルイミドとエピハロヒドリン（３）またはその光学活性体とを反応させ、生成物を晶析または、カラムクロマトグラフィ等の手段により単離精製することによってＮ-（３-ハロ-２-ヒドロキシプロピル）フタルイミド（５）を高収率またはその光学活性体を高収率、高光学純度で得ることができる。従って、この化合物（５）は、グリシジルフタルイミドおよび他の有用な物質の中間製造原料として極めて重要である。 In the presence of an alkali metal carbonate, an alkali metal bicarbonate or a quaternary ammonium salt (4), a phthalimide and epihalohydrin (3) or an optically active substance thereof are reacted in an organic solvent, preferably in an alcohol or ether solvent. The N- (3-halo-2-hydroxypropyl) phthalimide (5) is obtained in a high yield or a high yield of its optically active product by reacting and isolating and purifying the product by means of crystallization or column chromatography. Rate and high optical purity. Therefore, this compound (5) is very important as an intermediate raw material for glycidyl phthalimide and other useful substances.
方法（Ｂ）に関する発明の第一の利点は、比較的安価な原料を安価な溶媒中で反応を行うことができ、反応終了後は溶媒を留去した後に抽出溶媒を加えて水洗するという、非常に簡便な後処理操作で目的のグリシジルフタルイミド（１）、殊にその光学活性体が高純度かつ高光学純度で得ることができることである。この場合、抽出溶媒としては、目的物（１）が溶解する非水溶性有機溶媒であれば特に限定されず、酢酸メチル、酢酸エチルなどの酢酸エステルや、塩化メチレン、クロロホルム、１，２-ジクロロエタンなどのハロゲン系溶媒などを用いることができ、必要に応じ、晶析およびカラムクロマトグラフィーなどの精製を行うことができる。
また、第二の利点として、フタルイミドとエピハロヒドリン（３）またはその光学活性体を反応させることによって得られるＮ-（３-ハロ-２-ヒドロキシプロピル）フタルイミド（５）またはその光学活性体の単離精製を行わずに、そのままアルカリ金属アルコキシドを加えることによって目的のグリシジルフタルイミド（１）またはその光学活性体を得ることができる点にある。
The first advantage of the invention relating to the method (B) is that a relatively inexpensive raw material can be reacted in an inexpensive solvent, and after completion of the reaction, the solvent is distilled off, followed by adding an extraction solvent and washing with water. The objective glycidyl phthalimide (1), particularly its optically active substance, can be obtained with high purity and high optical purity by a very simple post-treatment operation. In this case, the extraction solvent is not particularly limited as long as it is a water-insoluble organic solvent in which the target substance (1) is dissolved, and may be an acetate such as methyl acetate or ethyl acetate, methylene chloride, chloroform, 1,2-dichloroethane. Halogenated solvents such as can be used, and if necessary, purification such as crystallization and column chromatography can be performed.
Also, as a second advantage, isolation of N- (3-halo-2-hydroxypropyl) phthalimide (5) or its optically active substance obtained by reacting phthalimide with epihalohydrin (3) or its optically active substance. The point is that the desired glycidyl phthalimide (1) or its optically active substance can be obtained by adding the alkali metal alkoxide as it is without purification.
以下の実施例によって本発明を具体的に説明するが、本発明はこれらの実施例によって限定されるものではない。 The present invention will be specifically described by the following examples, but the present invention is not limited to these examples.
実施例１
反応槽にフタルイミドカリウム５０．０ｇ（０．２７ｍｏｌ）、塩化ベンジルトリメチルアンモニウム５．００ｇ（０．０２７ｍｏｌ）、イソプロパノール（５００ｍＬ）を入れて１０℃に冷却した後に（Ｒ）−エピクロロヒドリン７４．９ｇ（０．８１ｍｏｌ）を加えた。冷却したまま４６時間撹拌を行った後、溶媒を留去し、濃縮残渣に酢酸エチル２５０ｍＬを加え、水２５０ｍＬで洗浄した。酢酸エチルを留去後、（Ｒ）−グリシジルフタルイミドの粗体（光学純度９７％ｅｅ）を得、更に酢酸エチル−ヘキサンより晶析することによって目的の（Ｒ）−グリシジルフタルイミド４５．６ｇ（収率８３％、光学純度９８％ｅｅ）を白色結晶として得た。
融点 １００−１０２℃
比旋光度 ［α］D 25 −９．７°（ｃ２．０，ＣＨＣｌ3）
1ＨＮＭＲ（ＣＤＣｌ3，２７０ＭＨｚ）δ２．７０（ｄｄ，１Ｈ），２．８１（ｄｄ，１Ｈ），３．２１−３．２８（ｍ，１Ｈ），３．８１（ｄｄ，１Ｈ），３．９７（ｄｄ，１Ｈ），７．２７−７．９１（ｍ，４Ｈ）
Example 1
50.0 g (0.27 mol) of potassium phthalimide, 5.00 g (0.027 mol) of benzyltrimethylammonium chloride, and isopropanol (500 mL) were placed in a reaction vessel, and the mixture was cooled to 10 ° C and then cooled to (R) -epichlorohydrin. 9 g (0.81 mol) were added. After stirring for 46 hours while cooling, the solvent was distilled off, and 250 mL of ethyl acetate was added to the concentrated residue, followed by washing with 250 mL of water. After the ethyl acetate was distilled off, a crude product of (R) -glycidylphthalimide (optical purity 97% ee) was obtained, and 45.6 g of the desired (R) -glycidylphthalimide was obtained by crystallization from ethyl acetate-hexane. 83%, optical purity 98% ee) were obtained as white crystals.
Melting point 100-102 ° C
Specific rotation [α] D 25 -9.7 ° (c2.0, CHCl 3 )
1 H NMR (CDCl 3 , 270 MHz) δ 2.70 (dd, 1 H), 2.81 (dd, 1 H), 3.21-3.28 (m, 1 H), 3.81 (dd, 1 H), 97 (dd, 1H), 7.27-7.91 (m, 4H)
なお、光学純度（％ｅｅ）は高速液体クロマトグラフィー法を用い、そのエリア比より算出した。その条件を以下に示す。
カラム：ダイセル化学工業（株）製 ＣＨＩＲＡＬＰＡＣ ＡＤ（０．４６ｃｍφ×２５ｃｍＬ）
移動相：ｎ−ヘキサン／イソプロパノール（９０／１０（ｖ／ｖ））
流速：１．０ｍＬ／ｍｉｎ．
検出器：ＵＶ２２０ｎｍ
保持時間：（Ｓ）体＝１７．９分、（Ｒ）体＝２５．５分
The optical purity (% ee) was calculated from the area ratio using a high performance liquid chromatography method. The conditions are shown below.
Column: CHIRALPAC AD (0.46 cmφ × 25 cmL) manufactured by Daicel Chemical Industries, Ltd.
Mobile phase: n-hexane / isopropanol (90/10 (v / v))
Flow rate: 1.0 mL / min.
Detector: UV 220nm
Retention time: (S) form = 17.9 minutes, (R) form = 25.5 minutes
実施例２
反応槽にフタルイミドカリウム５．００ｇ（２７．０ｍｍｏｌ）、塩化ベンジルトリメチルアンモニウム０．５０ｇ（２．７０ｍｍｏｌ）、ｔｅｒｔ−ブチルアルコール（５０ｍＬ）を入れた後に（Ｓ）−エピクロロヒドリン６．５３ｇ（５４．０ｍｍｏｌ）を加えた。２０℃で２４時間撹拌を行った後、溶媒を留去し、濃縮残渣に酢酸エチル３０ｍＬを加え、水２０ｍＬで洗浄した。酢酸エチルを留去することによって目的の（Ｓ）−グリシジルフタルイミドの粗体（定量値３．９５ｇ、収率７２％、光学純度９７％ｅｅ）を白色固体として得た。
Example 2
After putting 5.00 g (27.0 mmol) of potassium phthalimide, 0.50 g (2.70 mmol) of benzyltrimethylammonium chloride, and tert-butyl alcohol (50 mL) into the reaction vessel, 6.53 g of (S) -epichlorohydrin ( 54.0 mmol) was added. After stirring at 20 ° C. for 24 hours, the solvent was distilled off, and 30 mL of ethyl acetate was added to the concentrated residue, followed by washing with 20 mL of water. Ethyl acetate was distilled off to obtain a crude product of (S) -glycidylphthalimide (quantitative value: 3.95 g, yield: 72%, optical purity: 97% ee) as a white solid.
実施例３
反応槽にフタルイミドカリウム５．００ｇ（２７．０ｍｍｏｌ）、塩化ベンジルトリメチルアンモニウム０．５０ｇ（２．７０ｍｍｏｌ）、メタノール（５０ｍＬ）を入れた後に（Ｒ）−エピクロロヒドリン９．９９ｇ（８１．０ｍｍｏｌ）を加えた。２０℃で１５時間撹拌を行った後、溶媒を留去し、濃縮残渣に酢酸エチル３０ｍＬを加え、水２０ｍＬで洗浄した。酢酸エチルを留去することによって目的の（Ｒ）−グリシジルフタルイミドの粗体（定量値３．７４ｇ、収率６８％、光学純度９９％ｅｅ）を白色固体として得た。
Example 3
After putting 5.00 g (27.0 mmol) of potassium phthalimide, 0.50 g (2.70 mmol) of benzyltrimethylammonium chloride and methanol (50 mL) into the reaction tank, 9.99 g (81.0 mmol) of (R) -epichlorohydrin was added. ) Was added. After stirring at 20 ° C. for 15 hours, the solvent was distilled off, and 30 mL of ethyl acetate was added to the concentrated residue, followed by washing with 20 mL of water. Ethyl acetate was distilled off to obtain a crude product of (R) -glycidylphthalimide (quantity: 3.74 g, yield: 68%, optical purity: 99% ee) as a white solid.
比較例１
反応槽にフタルイミドカリウム５．００ｇ（２７．０ｍｍｏｌ）、塩化ベンジルトリメチルアンモニウム０．５０ｇ（２．７０ｍｍｏｌ）、ＤＭＦ（５０ｍＬ）を入れた後に（Ｒ）−エピクロロヒドリン５．００ｇ（５４．０ｍｍｏｌ）を加えた。室温で１６時間撹拌を行った後、溶媒を留去し、濃縮残渣に酢酸エチル３０ｍＬを加え、水２０ｍＬで洗浄した。酢酸エチルを留去することによって目的の（Ｒ）−グリシジルフタルイミドの粗体（定量値４．４８ｇ、収率８２％、光学純度６３％ｅｅ）を白色固体として得た。
以下に比較例１と同様な反応において、種々の溶媒を用いたときの比較例を示す。
Comparative Example 1
After putting 5.00 g (27.0 mmol) of potassium phthalimide, 0.50 g (2.70 mmol) of benzyltrimethylammonium chloride and DMF (50 mL) into the reaction tank, 5.00 g (54.0 mmol) of (R) -epichlorohydrin was added. ) Was added. After stirring at room temperature for 16 hours, the solvent was distilled off, and 30 mL of ethyl acetate was added to the concentrated residue, followed by washing with 20 mL of water. Ethyl acetate was distilled off to obtain the desired crude (R) -glycidylphthalimide (quantity: 4.48 g, yield: 82%, optical purity: 63% ee) as a white solid.
Hereinafter, a comparative example using various solvents in the same reaction as in comparative example 1 will be described.
反応槽にフタルイミド２００．０ｇ（１．３６ｍｏｌ）、（Ｓ）−エピクロロヒドリン２２６．４ｇ（２．４５ｍｏｌ）、無水炭酸ナトリウム１４．４０ｇ（０．１３６ｍｏｌ）、塩化ベンジルトリメチルアンモニウム２５．２４ｇ（０．１３６ｍｏｌ）、およびイソプロパノール１．２Ｌを入れて２５℃で、２２時間反応させることによってＮ-（３-クロロ-２-ヒドロキシプロピル）フタルイミドの粗体溶液を得た。温度を１５℃まで冷却した後、カリウムｔｅｒｔ-ブトキシド１８３．０ｇ（１．６３ｍｏｌ）とイソプロパノール０．８Ｌの混合溶液を２時間かけて滴下し、そのままの温度で更に２時間攪拌した。溶媒の留去後、濃縮残渣に酢酸エチル１．３Ｌを加え、水０．６５Ｌで洗浄した。酢酸エチルの留去後、（Ｓ）−グリシジルフタルイミドの粗体を得、更に酢酸エチル−ヘキサンより晶析することによって目的の（Ｓ）−グリシジルフタルイミド２０６．３ｇ（収率７５％、化学純度９９％、光学純度９８％ｅｅ）を白色結晶として得た。
（Ｓ）−グリシジルフタルイミド
融点 ９９−１０１℃
比旋光度 ［α］Ｄ ２５ ＋１１．０°（ｃ２．０，ＣＨＣｌ３）
In a reaction tank, 200.0 g (1.36 mol) of phthalimide, 226.4 g (2.45 mol) of (S) -epichlorohydrin, 14.40 g (0.136 mol) of anhydrous sodium carbonate, and 25.24 g of benzyltrimethylammonium chloride ( 0.136 mol) and 1.2 L of isopropanol and reacted at 25 ° C. for 22 hours to obtain a crude solution of N- (3-chloro-2-hydroxypropyl) phthalimide. After the temperature was cooled to 15 ° C., a mixed solution of 183.0 g (1.63 mol) of potassium tert-butoxide and 0.8 L of isopropanol was added dropwise over 2 hours, and the mixture was further stirred at the same temperature for 2 hours. After the solvent was distilled off, 1.3 L of ethyl acetate was added to the concentrated residue, and the residue was washed with 0.65 L of water. After the ethyl acetate was distilled off, a crude product of (S) -glycidylphthalimide was obtained, and further crystallized from ethyl acetate-hexane to obtain 206.3 g of the desired (S) -glycidylphthalimide (yield 75%, chemical purity 99). %, Optical purity 98% ee) as white crystals.
(S) -glycidyl phthalimide melting point 99-101 ° C
Specific rotation [α] D 25 + 11.0 ° (c2.0, CHCl 3 )
Ｎ-（３-クロロ-２-ヒドロキシプロピル）フタルイミド
１ＨＮＭＲ（ＣＤＣｌ３，２７０ＭＨｚ）δ２．８３（ｄ，１Ｈ），３．５８−３．７３（ｍ，２Ｈ），３．８５−４．０１（ｍ，２Ｈ），４．１３−４．２１（ｍ，１Ｈ），７．７３−７．８９（ｍ，４Ｈ）
N- (3-chloro-2-hydroxypropyl) phthalimide
1 HNMR (CDCl 3, 270MHz) δ2.83 (d, 1H), 3.58-3.73 (m, 2H), 3.85-4.01 (m, 2H), 4.13-4.21 (M, 1H), 7.73-7.89 (m, 4H)
実施例５
反応槽にフタルイミド２．００ｇ（１３．６ｍｍｏｌ）、（Ｒ）−エピクロロヒドリン２．５２ｇ（２７．２ｍｍｏｌ）、無水炭酸ナトリウム１４４ｍｇ（１．３６ｍｍｏｌ）、塩化ベンジルトリメチルアンモニウム２５２ｍｇ（１．３６ｍｏｌ）、およびイソプロパノール１３ｍＬを入れて室温下、１５時間反応を行った。未反応エピクロロヒドリンの留去後、イソプロパノール１３ｍＬを加えて２０℃に冷却した。カリウムｔｅｒｔ-ブトキシド１．８３ｇ（１６．３ｍｍｏｌ）とイソプロパノール７ｍＬの混合溶液をゆっくり滴下し、２０℃で１時間攪拌した。溶媒を留去し、濃縮残渣に酢酸エチル１３ｍＬを加え、水７ｍＬで洗浄した。酢酸エチルを留去することによって目的の（Ｒ）−グリシジルフタルイミドの粗体（定量値２．１６ｇ、収率７８％、光学純度９８％ｅｅ）を白色結晶として得た。
以下に実施例５と同様な反応操作において、種々の有機溶媒、塩化ベンジルトリメチルアンモニウムと共にアルカリ金属炭酸塩またはアルカリ金属炭酸水素塩を用いた際の実施例を示す。
Example 5
In a reaction tank, 2.00 g (13.6 mmol) of phthalimide, 2.52 g (27.2 mmol) of (R) -epichlorohydrin, 144 mg (1.36 mmol) of anhydrous sodium carbonate, and 252 mg (1.36 mol) of benzyltrimethylammonium chloride. , And 13 mL of isopropanol were added and reacted at room temperature for 15 hours. After the unreacted epichlorohydrin was distilled off, 13 mL of isopropanol was added, and the mixture was cooled to 20 ° C. A mixed solution of 1.83 g (16.3 mmol) of potassium tert-butoxide and 7 mL of isopropanol was slowly added dropwise, followed by stirring at 20 ° C. for 1 hour. The solvent was distilled off, and 13 mL of ethyl acetate was added to the concentrated residue, followed by washing with 7 mL of water. Ethyl acetate was distilled off to obtain the desired crude (R) -glycidylphthalimide (quantitative value: 2.16 g, yield: 78%, optical purity: 98% ee) as white crystals.
Hereinafter, examples in which an alkali metal carbonate or an alkali metal bicarbonate is used together with various organic solvents and benzyltrimethylammonium chloride in the same reaction procedure as in Example 5 will be described.
なお、実施例１３では、塩化ベンジルトリメチルアンモニウムのみを用いた。アルカリ金属アルコキシドの添加方法としては、実施例７では、ナトリウムメトキシド（２８％メタノール溶液）を滴下し、実施例８ではカリウムtert-ブトキシドをそのまま数回に分けて添加した。
In addition, in Example 13, only benzyltrimethylammonium chloride was used. As a method for adding the alkali metal alkoxide, in Example 7, sodium methoxide (28% methanol solution) was added dropwise, and in Example 8, potassium tert-butoxide was added in several portions as it was.
実施例１４
反応槽にフタルイミド２．００ｇ（１３．６ｍｍｏｌ）、（Ｒ）−エピクロロヒドリン２．２６ｇ（２４．５ｍｍｏｌ）、無水炭酸ナトリウム０．７２ｇ（６．８０ｍｍｏｌ）、硫酸水素テトラ−ｎ−ブチルアンモニウム０．４６ｇ（１．３６ｍｏｌ）、およびイソプロパノール１３ｍＬを入れて５０℃、２３時間反応を行った後、カリウムｔｅｒｔ-ブトキシド１．８３ｇ（１６．３ｍｍｏｌ）のイソプロパノール溶液をゆっくり滴下し、２０℃で１時間攪拌した。反応終了後、後処理をすることによって目的の（Ｒ）−グリシジルフタルイミドの粗体（定量値２．２１ｇ、収率８０％、光学純度９８％ｅｅ）を白色結晶として得た。
Example 14
2.00 g (13.6 mmol) of phthalimide, 2.26 g (24.5 mmol) of (R) -epichlorohydrin, 0.72 g (6.80 mmol) of anhydrous sodium carbonate, tetra-n-butylammonium hydrogen sulfate in a reaction vessel After adding 0.46 g (1.36 mol) and 13 mL of isopropanol and reacting at 50 ° C. for 23 hours, a solution of 1.83 g (16.3 mmol) of potassium tert-butoxide in isopropanol was slowly added dropwise, and the solution was added at 20 ° C. for 1 hour. Stirred for hours. After the completion of the reaction, post-treatment was performed to obtain a target crude product of (R) -glycidylphthalimide (quantitative value: 2.21 g, yield: 80%, optical purity: 98% ee) as white crystals.
比較例５
反応槽にフタルイミド２．００ｇ（１３．６ｍｍｏｌ）、塩化ベンジルトリメチルアンモニウム２５２ｍｇ（１．３６ｍｏｌ）、およびイソプロパノール２５ｍＬを入れて氷冷した後、カリウムｔｅｒｔ-ブトキシド３．０５ｇ（２７．２ｍｍｏｌ）を数回に分けて加え、更に（Ｒ）−エピクロロヒドリン２．５２ｇ（２７．２ｍｍｏｌ）を加えて室温下、２６時間反応を行った。反応終了後、後処理をすることにより目的の（Ｒ）−グリシジルフタルイミドの粗体（定量値０．４５ｇ、収率１７％、光学純度９６％ｅｅ）を黄色高粘性体として得た。
Comparative Example 5
After putting 2.00 g (13.6 mmol) of phthalimide, 252 mg (1.36 mol) of benzyltrimethylammonium chloride, and 25 mL of isopropanol in a reaction vessel and cooling with ice, 3.05 g (27.2 mmol) of potassium tert-butoxide was added several times. , And 2.52 g (27.2 mmol) of (R) -epichlorohydrin was further added to carry out a reaction at room temperature for 26 hours. After completion of the reaction, post-treatment was carried out to obtain a target crude product of (R) -glycidylphthalimide (quantitative value: 0.45 g, yield: 17%, optical purity: 96% ee) as a yellow highly viscous substance.
Claims (18)
下記式（２）
で表されるフタルイミドのアルカリ金属塩と、下記式（３）
で表されるエピハロヒドリンをアルコール溶媒中で反応させるか；あるいは
フタルイミドとエピハロヒドリン（３）を有機溶媒中で、アルカリ金属炭酸塩、アルカリ金属炭酸水素塩または下記式（４）
Ｒ1Ｒ2Ｒ3Ｒ4Ｎ+Ｘ- （４）
（式中、Ｒ1、Ｒ2、Ｒ3およびＲ4は互いに異なっていてもよい炭素数１〜１６のアルキル基、アルケニル基、アラルキル基またはアリール基を表し、そしてＸ-は塩素イオン、臭素イオン、よう素イオン、硫酸水素イオンまたは水酸イオンを表す。）
で表される第４級アンモニウム塩の存在下、反応させ、下記式（５）
で表されるＮ-（３-ハロ-２-ヒドロキシプロピル）フタルイミドを得、次いで、アルカリ金属アルコキシドにより環化反応させることを特徴とする該グリシジルフタルイミド（１）の製造法。 The following equation (1)
The following equation (2)
An alkali metal salt of phthalimide represented by the following formula (3):
Reacting epihalohydrin represented by the following formula in an alcohol solvent; or reacting phthalimide with epihalohydrin (3) in an organic solvent in an alkali metal carbonate, alkali metal bicarbonate or the following formula (4):
R 1 R 2 R 3 R 4 N + X - (4)
(Wherein R 1 , R 2 , R 3 and R 4 represent an alkyl group, an alkenyl group, an aralkyl group or an aryl group which may be different from each other, and X − represents chlorine ion, bromine Ion, iodine ion, hydrogen sulfate ion or hydroxyl ion.)
In the presence of a quaternary ammonium salt represented by the following formula (5)
A method for producing the glycidyl phthalimide (1), characterized by obtaining N- (3-halo-2-hydroxypropyl) phthalimide represented by the formula: and then subjecting it to a cyclization reaction with an alkali metal alkoxide.
下記式（２）
で表されるフタルイミドのアルカリ金属塩と、下記式（３）
で表されるエピハロヒドリンをアルコール溶媒中で反応させることを特徴とする該グリシジルフタルイミド（１）の製造法。 The following formula
The following equation (2)
An alkali metal salt of phthalimide represented by the following formula (3):
A method for producing the glycidyl phthalimide (1), wherein the epihalohydrin represented by the following formula is reacted in an alcohol solvent.
Ｒ1Ｒ2Ｒ3Ｒ4Ｎ+Ｘ- （４）
（Ｒ1、Ｒ2、Ｒ3およびＲ4は互いに異なっていてもよい炭素数１〜１６のアルキル基、アルケニル基、アラルキル基またはアリール基を表し、そしてＸ-は塩素イオン、臭素イオン、よう素イオン、硫酸水素イオンまたは水酸イオンを表す。）
で表される第４級アンモニウム塩の存在下反応させることを特徴とする請求項２または３に記載のグリシジルフタルイミドまたはその光学活性体の製造法。 The following equation (4)
R 1 R 2 R 3 R 4 N + X - (4)
(R 1 , R 2 , R 3 and R 4 represent an alkyl group, an alkenyl group, an aralkyl group or an aryl group having 1 to 16 carbon atoms which may be different from each other, and X − represents a chloride ion, a bromide ion, etc. Represents elementary ion, hydrogen sulfate ion or hydroxyl ion.)
The method for producing glycidyl phthalimide or an optically active substance thereof according to claim 2 or 3, wherein the reaction is carried out in the presence of a quaternary ammonium salt represented by the formula:
フタルイミドと下記式（３）
で表されるエピハロヒドリンを有機溶媒中で、アルカリ金属炭酸塩、アルカリ金属炭酸水素塩または下記式（４）
Ｒ1Ｒ2Ｒ3Ｒ4Ｎ+Ｘ- （４）
（式中、Ｒ1、Ｒ2、Ｒ3およびＲ4は互いに異なっていてもよい炭素数１〜１６のアルキル基、アルケニル基、アラルキル基またはアリール基を表し、そしてＸ-は塩素イオン、臭素イオン、よう素イオン、硫酸水素イオンまたは水酸イオンを表す。）
で表される第４級アンモニウム塩の存在下、反応させ、下記式（５）
で表されるＮ-（３-ハロ-２-ヒドロキシプロピル）フタルイミドを得、次いで、アルカリ金属アルコキシドにより環化反応させることを特徴とする該グリシジルフタルイミド（１）の製造法。 The following formula
Phthalimide and the following formula (3)
In an organic solvent, an epihalohydrin represented by the following formula is used: an alkali metal carbonate, an alkali metal bicarbonate or the following formula (4)
R 1 R 2 R 3 R 4 N + X - (4)
(Wherein R 1 , R 2 , R 3 and R 4 represent an alkyl group, an alkenyl group, an aralkyl group or an aryl group which may be different from each other, and X − represents chlorine ion, bromine Ion, iodine ion, hydrogen sulfate ion or hydroxyl ion.)
In the presence of a quaternary ammonium salt represented by the following formula (5)
A method for producing the glycidyl phthalimide (1), characterized by obtaining N- (3-halo-2-hydroxypropyl) phthalimide represented by the formula: and then subjecting it to a cyclization reaction with an alkali metal alkoxide.
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| WO2007074686A1 (en) * | 2005-12-26 | 2007-07-05 | Kaneka Corporation | Method for producing optically active n-(3-halo-2-hydroxypropyl)phthalimide |
| JP2007297305A (en) * | 2006-04-28 | 2007-11-15 | Daiso Co Ltd | Method for producing n-(2,3-epoxy-2-methylpropyl)phthalimide |
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| WO2007074686A1 (en) * | 2005-12-26 | 2007-07-05 | Kaneka Corporation | Method for producing optically active n-(3-halo-2-hydroxypropyl)phthalimide |
| JP2007297305A (en) * | 2006-04-28 | 2007-11-15 | Daiso Co Ltd | Method for producing n-(2,3-epoxy-2-methylpropyl)phthalimide |
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