WO2007132990A1 - Process for the preparation of chiral glycidylphthalimide in highly optical purity - Google Patents
Process for the preparation of chiral glycidylphthalimide in highly optical purity Download PDFInfo
- Publication number
- WO2007132990A1 WO2007132990A1 PCT/KR2007/002154 KR2007002154W WO2007132990A1 WO 2007132990 A1 WO2007132990 A1 WO 2007132990A1 KR 2007002154 W KR2007002154 W KR 2007002154W WO 2007132990 A1 WO2007132990 A1 WO 2007132990A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- glycidylphthalimide
- formula
- set forth
- amino
- acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 52
- 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 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 230000003287 optical effect Effects 0.000 title abstract description 37
- -1 N-(3-substituted-2-hydroxypropyl)phthalimide Chemical class 0.000 claims abstract description 30
- 239000002253 acid Substances 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 claims abstract description 15
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 15
- 150000002924 oxiranes Chemical class 0.000 claims abstract description 7
- 239000002585 base Substances 0.000 claims description 12
- 229910052783 alkali metal Inorganic materials 0.000 claims description 9
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
- 150000003512 tertiary amines Chemical class 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 150000001805 chlorine compounds Chemical group 0.000 claims 1
- 229940098779 methanesulfonic acid Drugs 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 18
- 239000007858 starting material Substances 0.000 abstract description 10
- 230000000717 retained effect Effects 0.000 abstract description 7
- 238000000746 purification Methods 0.000 abstract description 5
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical compound CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 abstract 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 15
- 229910000160 potassium phosphate Inorganic materials 0.000 description 15
- 235000011009 potassium phosphates Nutrition 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 11
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical group ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 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 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000006482 condensation reaction Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- ZCPJBHYNOFIAPJ-AENDTGMFSA-N (2s)-1-amino-3-chloropropan-2-ol;hydrochloride Chemical compound Cl.NC[C@H](O)CCl ZCPJBHYNOFIAPJ-AENDTGMFSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 239000003495 polar organic solvent Substances 0.000 description 4
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- RTSAOAOFVDUPRN-AENDTGMFSA-N (2s)-1-amino-3-chloropropan-2-ol;methanesulfonic acid Chemical compound CS(O)(=O)=O.NC[C@H](O)CCl RTSAOAOFVDUPRN-AENDTGMFSA-N 0.000 description 2
- CYJBWQFWXJKKMS-UHFFFAOYSA-N 1-amino-3-chloropropan-2-ol Chemical compound NCC(O)CCl CYJBWQFWXJKKMS-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229910000318 alkali metal phosphate Inorganic materials 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- ZMCUDHNSHCRDBT-UHFFFAOYSA-M caesium bicarbonate Chemical compound [Cs+].OC([O-])=O ZMCUDHNSHCRDBT-UHFFFAOYSA-M 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 description 2
- 229910001386 lithium phosphate Inorganic materials 0.000 description 2
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- CPWJKGIJFGMVPL-UHFFFAOYSA-K tricesium;phosphate Chemical compound [Cs+].[Cs+].[Cs+].[O-]P([O-])([O-])=O CPWJKGIJFGMVPL-UHFFFAOYSA-K 0.000 description 2
- TWQULNDIKKJZPH-UHFFFAOYSA-K trilithium;phosphate Chemical compound [Li+].[Li+].[Li+].[O-]P([O-])([O-])=O TWQULNDIKKJZPH-UHFFFAOYSA-K 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910000316 alkaline earth metal phosphate Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- GVALZJMUIHGIMD-UHFFFAOYSA-H magnesium phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GVALZJMUIHGIMD-UHFFFAOYSA-H 0.000 description 1
- 239000004137 magnesium phosphate Substances 0.000 description 1
- 229910000157 magnesium phosphate Inorganic materials 0.000 description 1
- 229960002261 magnesium phosphate Drugs 0.000 description 1
- 235000010994 magnesium phosphates Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- ODHXBMXNKOYIBV-UHFFFAOYSA-N triphenylamine Chemical compound C1=CC=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 ODHXBMXNKOYIBV-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
- A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
- A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
- A01N43/12—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings condensed with a carbocyclic ring
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
- A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
- A01N43/20—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom three- or four-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the present invention relates to a process for the preparation of glycidylphthalimide.
- the present invention relates to a process for the preparation of chiral glycidylphthalimide with high optical purity without decrease of the optical purity of the starting material.
- Glycidylphthalimide is widely used as an intermediate of medicines, agrochemicals or physiologically active materials. Conventional methods for preparing glycidylphthalimide known in the art are as follows.
- U.S. Patent No. 6,875,875 disclosed a method for preparing glycidylphthalimide by reacting optically active epichlorohydrin with an alkali metal salt of phthalimide in an alcohol solvent, or by reacting optically active epihalohydrin with phthalimide in the presence of an inorganic salt (e.g., alkali metal carbonate or alkali metal hydrogencarbonate) or a quaternary ammonium salt to obtain N - (3-halo-2-hydroxypropyl)phthalimide, and then by cyclizing the obtained product with alkali metal alkoxide.
- an inorganic salt e.g., alkali metal carbonate or alkali metal hydrogencarbonate
- a quaternary ammonium salt e.g., a quaternary ammonium salt
- the method requires excessive use of the expensive optically active epichlorohydrin in an amount of 3 times or 2 times of the alkali metal phthalimide or phthalimide.
- some of glycidylphthalimide synthesized undergoes decomposition by the addition of water after completion of the cyclization reaction.
- the optical purity of the starting material is somewhat reduced because selectivity is not distinguishable. Accordingly, the resultant glycidylphthalimide has an optical purity of 98%ee or less. For these reasons, the industrial-scale synthesis of glycidylphthalimide having high optical purity of 98%ee or higher, preferably 99%ee or higher is being demanded. Disclosure of Invention Technical Problem
- An object of the present invention is to provide a process for the efficient preparation of chiral glycidylphthalimide with high optical purity of 99%ee or higher.
- the process of the present invention makes it possible to prepare the targeted glycidylphthalimide with an optical purity of 99%ee or higher, while chirality of the starting material is retained.
- a process for the preparation of chiral glycidylphthalimide which comprises the steps of a) reacting an optically active 3-substituted l-amino-2-propanol acid addition salt with phthalic anhydride in a presence of a base to obtain N -
- l-amino-2-propanol acid addition salt is l-amino-3-halo-propanol acid addition salt including l-amino-3-halo-2-propanol hydrochloride salt, l-amino-3-halo-2-propanol hydrobromide salt, l-amino-3-halo-2-propanol hydroiodide salt or l-amino-3-halo-2-propanol methanesulfonic acid salt.
- glycidylphthalimide can be prepared with high optical purity, while the optical purity of the starting material is substantially retained.
- the resultant target compound can be prepared with high optical purity, while the chirality of the chiral compound represented by Formula 2, which is used as the starting material, is not reduced. Consequently, glycidylphthalimide can be prepared with the optical purity of 99%ee or higher in high yield, while the optical purity of the starting material is retained.
- the compound of formula 4 obtained from the condensation of the optically active 3-substiuted l-amino-2-propanol acid addition salt of formula 2 with phthalic anhydride of formula 3 is applicable to the subsequent cyclization reaction, without any special purification.
- the present invention relates to a process for the preparation of glycidylphthalimide, which comprises the steps of a) reacting an optically active 3-substituted l-amino-2-propanol acid addition salt (or acid salt) with phthalic anhydride in a presence of a base to obtain N-(3-sustituted-2-hydroxypropyl)phthalimide and b) subjecting the obtained compound to an epoxide cyclization reaction to prepare the glycidylphthalimide in an optically pure form.
- the present invention relates to a process for the preparation of chiral glycidylphthalimide having formula 1, which comprises the steps of a) reacting an optically active 3-substituted l-amino-2-propanol acid addition salt of formula 2 with phthalic anhydride of formula 3 in a presence of a base to obtain N - (3-sustituted-2-hydroxypropyl)phthalimide of formula 4 and b) subjecting the obtained compound of formula 4 to an epoxide cyclization reaction to prepare the targeted chiral glycidylphthalimide having formula 1.
- the glycidylphthalimide of formula 1 is easily isolated through recrystallization and has optical purity of 99%ee or higher while the optical purity of the starting material is retained.
- N-(3-substituted-2-hydroxypropyl)phthalimide of formula 4 is obtained from the condensation of an optically active 3-substituted l-amino-2-propanol acid addition salt of formula 2 with phthalic anhydride of formula 3.
- the 3-substituted l-amino-2-propanol acid addition salt of formula 2 is firstly converted, with aid of a base, to a free basic form and then takes part in the condensation with phthalic anhydride of formula 3.
- the phthalic anhydride of formula 3 is added in an amount of 0.9-1.5 equivalents, preferably in an amount of 1-1.2 equivalents, based on the 3-substituted l-amino-2-propanol acid addition salt of formula 2.
- the condensation reaction is carried out in the presence of a base.
- a base As a based to be used in the condensation reaction, an organic base or an inorganic base may be used.
- Preferred examples of the organic base include a tertiary amine represented by R R R N, wherein R , R and R represent each inde- pendently C -C alkyl, C -C alkenyl, C -C arylalkyl or C -C alkylaryl.
- tertiary amine examples include trimethylamine, triethylamine, tributylamine, triphenylamine and diisopropylethylamine.
- an alkali metal salt may be used as an inorganic base.
- alkali metal carbonate, alkali metal bicarbonate or alkali metal phosphate may be used as an inorganic base.
- lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; lithium bicarbonate, sodium bicarbonate, potassium bicarbonate and cesium bicarbonate; and lithium phosphate, sodium phosphate, potassium phosphate and cesium phosphate may be used. Most preferable is trialkylamine.
- the base is added in an amount of 1-10 equivalents, preferably in an amount of 1-5 equivalents, most preferably in an amount of 1.1-2 equivalents, based on the 3-substituted l-amino-2-propanol acid addition salt of formula 2.
- the condensation reaction is carried out in an organic solvent system.
- An organic solvent well known in the art may be widely used in the condensation reaction.
- Polar organic solvents such as alcohol, tetrahydrofuran, dioxane, acetone, N,N - dimethylformaldehyde and dimethylsulfoxide, or low polar organic solvents such as aromatic hydrocarbon, ether and C -C halogenated hydrocarbon may be used as an organic solvent.
- Preferable is an aprotic organic solvent. More preferable is an aromatic hydrocarbon such as toluene.
- the organic solvent is preferably used in an amount of 3 to 15 times (w/w) of the 3-substituted l-amino-2-propanol acid addition salt of formula 2.
- Various leaving groups may be substituted at the C3 position of the 3-substiuted l-amino-2-propanol acid addition salt having formula 2.
- the leaving group may be a halogen group or a sulfonyl group represented by
- R is C -C alkyl; C -C aryl; or C -C aryl substituted with nitro, methyl
- V 4 1 10 J 6 10 J 6 10 J J ethyl, fluoro or chloro).
- Preferred examples of the sulfonyl group include methanesulfonyl, p-toluenesulfonyl, benzenesulfonyl, trifluoromethanesulfonyl or n itrobenzenesulfonyl. l-Amino-3-halo-2-proanol acid addition salt is preferred.
- l-amino-3-chloro-2-propanol acid addition salt l-amino-3-bromo-2-propanol acid addition salt or l-amino-3-iodo-2-propanol acid addition salt may be used.
- Most preferable is l-amino-3-chloro-2-propanol acid addition salt.
- C -C alkylaryl sulfonic acid C -C arylalkyl sulfonic acid or C -C carboxylic acid
- Preferable is C -C alkyl sulfonic acid, C -C aryl sulfonic acid, C -C
- the compound of formula 4 produced from the condensation reaction may be directly subjected to a cyclization reaction after evaporation of the solvent under reduced pressure, without any further special purification. Therefore, the condensation and the subsequent cyclization may be carried out as a one-pot reaction. This simplifies the reaction procedure and improves the production yield.
- the cyclization reaction is also carried out in the presence of a base.
- a base for an organic base, the tertiary amine mentioned in the above may be used.
- An inorganic base is more preferable.
- the inorganic base include an alkali metal salt and an alkaline earth metal salt.
- alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, alkali metal phosphate or alkaline earth metal phosphate may be used.
- lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, magnesium phosphate and calcium phosphate may be used.
- Potassium phosphate is most preferable.
- the base is added in an amount of 1-10 equivalents, preferably in an amount of 1-5 equivalents, most preferably in an amount of 1.5-3 equivalents, based on the 3-substituted l-amino-2-propanol acid addition salt of formula 2.
- the cyclization reaction is also carried out in an organic solvent system.
- Polar organic solvents such as acetonitrile, tetrahydrofuran, acetone, N,N- dimethylformaldehyde and dimethylsulfoxide, or low polar organic solvents such as aromatic hydrocarbon, ether and C 1 -C 4 halogenated hydrocarbon may be used.
- An aprotic organic solvent is preferable.
- Aromatic hydrocarbon or C 1 -C 4 halogenated hy- drocarbon is more preferable. Most preferable is 1,2-Dichloroethane.
- the organic solvent is used in an amount of 3 to 15 times (w/w) of the 3-substituted l-amino-2-propnaol acid addition salt of formula 2.
- the glycidylphthalimide of formula 1 obtained from the cyclization reaction may be purified throughout common workup processes (extraction, drying and solvent evaporation) and recrystallization.
- a solvent to be used in the recrystallization a single solvent system or a mixed solvent system may be used. According to the method disclosed in U.S. Patent No. 6,875,875, the recrystallization was carried out using a mixed solvent of ethyl acetate/hexane.
- C -C alcohol such as methanol, ethanol, propanol, isopropanol or butanol may be used in the recrystallization.
- recrystallization under ethanol gave highly optical pure glycidylphthalimide of formula 1.
- the most important advantage of the process for preparation of glycidylphthalimide in accordance with the present invention is that the optical purity of the starting material is substantially completely retained. That is, the resultant target compound is prepared in an optically pure form, without any decrease of the chirality of the chiral compound of formula 2. Consequently, glycidylphthalimide with high optical purity of 99%ee or higher is prepared in high yield, while the optical purity of the starting material is retained. Further, overall reactions are carried out under mild conditions and in a single reaction vessel without any special purification. This increases the yield of the target compound.
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Abstract
The present invention relates to a process for the preparation of highly optical pure glycidylphthalimide. More particularly, the present invention relates to a process for the preparation of chiral glycidylphthalimide, which comprises the steps of reacting an optically active 3-susbstituted 1-amino-2-propanol acid addition salt with phthalic anhydride in a presence of a base to obtain N-(3-substituted-2-hydroxypropyl)phthalimide and subjecting the obtained compound to an epoxide cyclization reaction to prepare the targeted glycidylphthalimide. According to the process, the chirality of the starting material is substantially retained throughout overall procedures. Therefore, the process can prepare the targeted glycidylphthalimide in an optically pure form having 99%ee or higher. And, the reactions are carried out under mild conditions through overall procedures and in a single reaction vessel without any special purification. This increases the yield of the target compound.
Description
Description
PROCESS FOR THE PREPARATION OF CHIRAL GLY- CIDYLPHTHALIMIDE IN HIGHLY OPTICAL PURITY
Technical Field
[1] The present invention relates to a process for the preparation of glycidylphthalimide.
More particularly, the present invention relates to a process for the preparation of chiral glycidylphthalimide with high optical purity without decrease of the optical purity of the starting material. Background Art
[2] Most of recently developed or commercially available medicines are optically active substances. This is attributed to the fact that conventional racemic medicines often cause side effects or exhibit low therapeutic effects. Various efforts are made to develop medicines with high optical purity in a pure stereo-isomeric form in order to increase stability and therapeutic efficacy of the medicines. In order to synthesize the medicines having high optical purity, the optical purity of the corresponding intermediates should be high. As the optical purity is higher, the price of the compound is even more expensive. Thus, compounds having high optical purity of 99%ee or higher are of great value.
[3] Glycidylphthalimide is widely used as an intermediate of medicines, agrochemicals or physiologically active materials. Conventional methods for preparing glycidylphthalimide known in the art are as follows.
[4] There was disclosed a method for preparing glycidylphthalimide, comprising reacting phthalimide with epichlorohydrin in a presence of tetra-n-butylammonium iodide and potassium carbonate inside a microwave oven (Synlett, 1996, p873-874). However, the method fails to produce the target compound in a satisfactory yield.
[5] There was disclosed another method for preparing glycidylphthalimide by refluxing potassium phthalimide under an epichlorohydrin solvent (J. Org. Chem. 1963, vol. 28, pl589-1593; J. Am. Chem. Soc. 1995, vol. 117, pi 1220-11229). However, the method suffers from the disadvantages that optical purity of the glycidylphthalimide decreases due to racemization that takes place during refluxing epihalohydrin in the presence of potassium phthalimide. Further, excessive use of the expensive optically active epihalohydrin as a solvent deteriorates the price competitiveness.
[6] There was disclosed a method for preparingglycidylphthalimide by reacting epichlorohydrin with potassium phthalimide in aN,N-dimethylformaldehyde solvent ( HeIv. Chim. Acta 1990, vol. 73, p912-915). The method reduces the amount of epichlorohydrin to be used. However, when optically active epichlorohydrin (99%ee)
reacts with potassium phthalimide in a polar aprotic solvent such as N,N- dimethylamide, selectivity decreases and racemization takes place. Consequently, the resultant glycidylphthalimide has poor optical purity (63%ee), which is not adequate for medicines.
[7] As an alterative, there was disclosed a method for preparing optically active glycidylphthalimide by coupling optically active glycidol with phthalimide in a presence of diethylazodicarboxylate and triphenylphosphine that are Mitsunobu reagents ( Tetrahedron Asymmetry, 1996, vol. 7, pl641-1648 and Tetrahedron, 2004, vol. 60, p7679-7692). However, the method has a problem that purification of the resultant optically active glycidylphthalimide is not easy due to the byproducts of the Mitsunobu reactions. Therefore, the method is not applicable to industrial-scale production.
[8] Recently, U.S. Patent No. 6,875,875 disclosed a method for preparing glycidylphthalimide by reacting optically active epichlorohydrin with an alkali metal salt of phthalimide in an alcohol solvent, or by reacting optically active epihalohydrin with phthalimide in the presence of an inorganic salt (e.g., alkali metal carbonate or alkali metal hydrogencarbonate) or a quaternary ammonium salt to obtain N - (3-halo-2-hydroxypropyl)phthalimide, and then by cyclizing the obtained product with alkali metal alkoxide. According to the method, chiral glycidylphthalimide is obtained in high optical purity of 98%ee. However, the method requires excessive use of the expensive optically active epichlorohydrin in an amount of 3 times or 2 times of the alkali metal phthalimide or phthalimide. Further, in the synthesis of the glycidylphthalimide from N-(3-halo-2-hydroxypropyl)phthalimide, some of glycidylphthalimide synthesized undergoes decomposition by the addition of water after completion of the cyclization reaction. In addition, the optical purity of the starting material is somewhat reduced because selectivity is not distinguishable. Accordingly, the resultant glycidylphthalimide has an optical purity of 98%ee or less. For these reasons, the industrial-scale synthesis of glycidylphthalimide having high optical purity of 98%ee or higher, preferably 99%ee or higher is being demanded. Disclosure of Invention Technical Problem
[9] An object of the present invention is to provide a process for the efficient preparation of chiral glycidylphthalimide with high optical purity of 99%ee or higher. The process of the present invention makes it possible to prepare the targeted glycidylphthalimide with an optical purity of 99%ee or higher, while chirality of the starting material is retained. Technical Solution
[10] According to a preferred embodiment of the present invention, there is provided a
process for the preparation of chiral glycidylphthalimide, which comprises the steps of a) reacting an optically active 3-substituted l-amino-2-propanol acid addition salt with phthalic anhydride in a presence of a base to obtain N -
(3-sustituted-2-hydroxypropyl)phthalimide and b) subjecting the obtained compound to an epoxide cyclization reaction to prepare the chiral glycidylphthalimide.
[11] According to more preferred embodiment of the present invention, there is provided a process for the preparation of glycidylphthalimide, wherein 3-substituted l-amino-2-propanol acid addition salt is l-amino-3-halo-propanol acid addition salt including l-amino-3-halo-2-propanol hydrochloride salt, l-amino-3-halo-2-propanol hydrobromide salt, l-amino-3-halo-2-propanol hydroiodide salt or l-amino-3-halo-2-propanol methanesulfonic acid salt.
[12] According to even more preferred embodiment, there is provided a process for the preparation of glycidylphthalimide, wherein the l-amino-3-halo-2-propanol acid addition salt is l-amino-3-halo-2-propanol methanesulfonic acid salt.
[13] According to another preferred embodiment, there is provided a process for the preparation of glycidylphthalimide, wherein the base in the step a) is an organic base.
[14] According to yet another preferred embodiment, there is provided a process for the preparation of glycidylphthalimide, wherein the base in the step a) is a tertiary amine.
[15] According to further another preferred embodiment, there is provided a process for the preparation of glycidylphthalimide, wherein the epoxide cyclization of the step b) is carried out in a presence of a base.
[16] According to further yet another preferred embodiment, there is provided a process for the preparation of glycidylphthalimide, wherein the epoxide cyclization of the step b) is carried out in a presence of an inorganic base. Advantageous Effects
[17] According to the process of the present invention, glycidylphthalimide can be prepared with high optical purity, while the optical purity of the starting material is substantially retained. Particularly, the resultant target compound can be prepared with high optical purity, while the chirality of the chiral compound represented by Formula 2, which is used as the starting material, is not reduced. Consequently, glycidylphthalimide can be prepared with the optical purity of 99%ee or higher in high yield, while the optical purity of the starting material is retained. And, the compound of formula 4 obtained from the condensation of the optically active 3-substiuted l-amino-2-propanol acid addition salt of formula 2 with phthalic anhydride of formula 3 is applicable to the subsequent cyclization reaction, without any special purification. The subsequent cyclization reaction is performed under mild condition. Therefore, the process for the preparation of glycidylphthalimide in accordance with the present
invention is carried out under the mild condition and proceeds as one-pot reaction, throughout overall processes. This means that the process in accordance with the present invention is useful for industrial-scale production of glycidylphthalimide with high optical purity. Mode for the Invention
[18] The present invention relates to a process for the preparation of glycidylphthalimide, which comprises the steps of a) reacting an optically active 3-substituted l-amino-2-propanol acid addition salt (or acid salt) with phthalic anhydride in a presence of a base to obtain N-(3-sustituted-2-hydroxypropyl)phthalimide and b) subjecting the obtained compound to an epoxide cyclization reaction to prepare the glycidylphthalimide in an optically pure form.
[19] More particularly, the present invention relates to a process for the preparation of chiral glycidylphthalimide having formula 1, which comprises the steps of a) reacting an optically active 3-substituted l-amino-2-propanol acid addition salt of formula 2 with phthalic anhydride of formula 3 in a presence of a base to obtain N - (3-sustituted-2-hydroxypropyl)phthalimide of formula 4 and b) subjecting the obtained compound of formula 4 to an epoxide cyclization reaction to prepare the targeted chiral glycidylphthalimide having formula 1. The glycidylphthalimide of formula 1 is easily isolated through recrystallization and has optical purity of 99%ee or higher while the optical purity of the starting material is retained.
[20] Formula 1
[22] Formula 2
[24] Formula 3
[26] Formula 4
[28] In the formula 1 to 4, * represents a chiral center, X represents a leaving group and Y represents sulfonyl, halogen or carboxyl group. [29] The process for the preparation of chiral glycidylphthalimide in the accordance with the present invention can be summarized in the following scheme 1 :
[30] Scheme 1
Cychzation
[32] As shown in the scheme 1, N-(3-substituted-2-hydroxypropyl)phthalimide of formula 4 is obtained from the condensation of an optically active 3-substituted l-amino-2-propanol acid addition salt of formula 2 with phthalic anhydride of formula 3. The 3-substituted l-amino-2-propanol acid addition salt of formula 2 is firstly converted, with aid of a base, to a free basic form and then takes part in the condensation with phthalic anhydride of formula 3. The phthalic anhydride of formula 3 is added in an amount of 0.9-1.5 equivalents, preferably in an amount of 1-1.2 equivalents, based on the 3-substituted l-amino-2-propanol acid addition salt of formula 2. In order to convert the 3-substiuted l-amino-2-propanol acid addition salt of formula 2 into a free basic form, the condensation reaction is carried out in the presence of a base. As a based to be used in the condensation reaction, an organic base or an inorganic base may be used. Preferred examples of the organic base include a tertiary amine represented by R R R N, wherein R , R and R represent each inde-
pendently C -C alkyl, C -C alkenyl, C -C arylalkyl or C -C alkylaryl. Specific
1 16 2 16 7 16 7 16 examples of the tertiary amine include trimethylamine, triethylamine, tributylamine, triphenylamine and diisopropylethylamine. As an inorganic base, an alkali metal salt may be used. For example, alkali metal carbonate, alkali metal bicarbonate or alkali metal phosphate may be used. Specifically, lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; lithium bicarbonate, sodium bicarbonate, potassium bicarbonate and cesium bicarbonate; and lithium phosphate, sodium phosphate, potassium phosphate and cesium phosphate may be used. Most preferable is trialkylamine. The base is added in an amount of 1-10 equivalents, preferably in an amount of 1-5 equivalents, most preferably in an amount of 1.1-2 equivalents, based on the 3-substituted l-amino-2-propanol acid addition salt of formula 2.
[33] The condensation reaction is carried out in an organic solvent system. An organic solvent well known in the art may be widely used in the condensation reaction. Polar organic solvents such as alcohol, tetrahydrofuran, dioxane, acetone, N,N - dimethylformaldehyde and dimethylsulfoxide, or low polar organic solvents such as aromatic hydrocarbon, ether and C -C halogenated hydrocarbon may be used as an organic solvent. Preferable is an aprotic organic solvent. More preferable is an aromatic hydrocarbon such as toluene. The organic solvent is preferably used in an amount of 3 to 15 times (w/w) of the 3-substituted l-amino-2-propanol acid addition salt of formula 2.
[34] Various leaving groups may be substituted at the C3 position of the 3-substiuted l-amino-2-propanol acid addition salt having formula 2. For example, the leaving group may be a halogen group or a sulfonyl group represented by
(wherein R is C -C alkyl; C -C aryl; or C -C aryl substituted with nitro, methyl,
V 4 1 10 J 6 10 J 6 10 J J ethyl, fluoro or chloro). Preferred examples of the sulfonyl group include methanesulfonyl, p-toluenesulfonyl, benzenesulfonyl, trifluoromethanesulfonyl or n itrobenzenesulfonyl. l-Amino-3-halo-2-proanol acid addition salt is preferred. For example, l-amino-3-chloro-2-propanol acid addition salt, l-amino-3-bromo-2-propanol acid addition salt or l-amino-3-iodo-2-propanol acid addition salt may be used. Most preferable is l-amino-3-chloro-2-propanol acid addition salt. For the formation of the acid addition salt, hydrochloric acid, hy- drobromic acid, hydroiodic acid, C -C alkyl sulfonic acid, C -C aryl sulfonic acid, C
J 1 10 J 6 10 J
-C alkylaryl sulfonic acid, C -C arylalkyl sulfonic acid or C -C carboxylic acid may be used. Preferable is C -C alkyl sulfonic acid, C -C aryl sulfonic acid, C -C
1 10 6 10 7 11 alkylaryl sulfonic acid or C -C arylalkyl sulfonic acid. l-Amino-3-halo-2-propanol
methanesulfonate is most preferable.
[35] The compound of formula 4 produced from the condensation reaction may be directly subjected to a cyclization reaction after evaporation of the solvent under reduced pressure, without any further special purification. Therefore, the condensation and the subsequent cyclization may be carried out as a one-pot reaction. This simplifies the reaction procedure and improves the production yield.
[36] The cyclization reaction is also carried out in the presence of a base. For an organic base, the tertiary amine mentioned in the above may be used. An inorganic base is more preferable. Examples of the inorganic base include an alkali metal salt and an alkaline earth metal salt. Preferably, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, alkali metal phosphate or alkaline earth metal phosphate may be used. Specifically, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, magnesium phosphate and calcium phosphate may be used. Potassium phosphate is most preferable. The base is added in an amount of 1-10 equivalents, preferably in an amount of 1-5 equivalents, most preferably in an amount of 1.5-3 equivalents, based on the 3-substituted l-amino-2-propanol acid addition salt of formula 2.
[37] The cyclization reaction is also carried out in an organic solvent system. Polar organic solvents such as acetonitrile, tetrahydrofuran, acetone, N,N- dimethylformaldehyde and dimethylsulfoxide, or low polar organic solvents such as aromatic hydrocarbon, ether and C 1 -C 4 halogenated hydrocarbon may be used. An aprotic organic solvent is preferable. Aromatic hydrocarbon or C 1 -C 4 halogenated hy- drocarbon is more preferable. Most preferable is 1,2-Dichloroethane. Preferably, the organic solvent is used in an amount of 3 to 15 times (w/w) of the 3-substituted l-amino-2-propnaol acid addition salt of formula 2.
[38] The glycidylphthalimide of formula 1 obtained from the cyclization reaction may be purified throughout common workup processes (extraction, drying and solvent evaporation) and recrystallization. As a solvent to be used in the recrystallization, a single solvent system or a mixed solvent system may be used. According to the method disclosed in U.S. Patent No. 6,875,875, the recrystallization was carried out using a mixed solvent of ethyl acetate/hexane. In addition to the mixed solvent system, C -C alcohol such as methanol, ethanol, propanol, isopropanol or butanol may be used in the recrystallization. According to a specific example of the invention, recrystallization under ethanol gave highly optical pure glycidylphthalimide of formula 1.
[39] The most important advantage of the process for preparation of glycidylphthalimide
in accordance with the present invention is that the optical purity of the starting material is substantially completely retained. That is, the resultant target compound is prepared in an optically pure form, without any decrease of the chirality of the chiral compound of formula 2. Consequently, glycidylphthalimide with high optical purity of 99%ee or higher is prepared in high yield, while the optical purity of the starting material is retained. Further, overall reactions are carried out under mild conditions and in a single reaction vessel without any special purification. This increases the yield of the target compound.
[40] EXAMPLES
[41] Example 1
[42] 25.00 g of (S)-l-amino-3-chloro-2-propanol methanesulfonic acid salt (0.123 mol),
25.34 g of phthalic anhydride (0.123 mol), 18.63 ml of triethylamine (0.134 mol) and 121 ml of toluene were added into a reaction vessel. After stirring for 2 hours at 110-120°C, the solvent was removed under reduced pressure. Subsequently, 64.51 g of potassium phosphate (0.304 mol) and 121 ml of 1,2-dichloroethane were added to the reaction vessel. The mixture was stirred for 14 hours at 80°C. The reaction mixture was cooled to 0°C. After 100 ml of water was added to dissolve potassium phosphate, the solution was extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 17.91 g of the targeted (S)-glycidylphthalimide (yield: 72%, optical purity: 99.5%ee) as a white crystal.
[43] Melting point: 100-102°C
[44] 1H NMR (CDCl3, 300 MHz): δ 7.70-8.00 (m, 4H), 3.95 (dd, IH, J=14.4Hz, 5.1Hz),
3.79 (dd, IH), 3.22-3.26 (m, 1 H), 2.80 (dd, IH), 2.67 (dd, IH, J=7.8Hz, 2.4Hz)
[45] The optical purity (%ee) of glycidylphthalimide was confirmed from high speed liquid chromatography (HPLC). CHRALPAC AD™ Column (0.46 cm x 25 cm, available from Daicel Co., Ltd) was used. The mobile phase was a mixed solvent of n - hexane/isopropanol (90/10 (Wv)) and was flown at a velocity of 1 ml/min. Detection was performed at 254 nm. The (S) isomer was detected at 14.2 minutes and the (R) isomer was detected at 19.2 minutes.
[46] Example 2
[47] 25.00 g of (S)-l-amino-3-chloro-2-propanol methanesulfonic acid salt (0.123 mol),
25.34 g of phthalic anhydride (0.123 mol), 18.63 ml of triethylamine (0.134 mol) and 121 ml of toluene were added into a reaction vessel. After stirring for 2 hours at 110-120°C, the organic layer was washed with water at room temperature. After drying with anhydrous magnesium sulfate, the solvent was removed under reduced pressure. Subsequently, 64.51 g of potassium phosphate (0.304 mol) and 121 ml of
1,2-dichloroethane were added to the reaction vessel. The mixture was stirred for 14 hours at 80°C. The reaction mixture was cooled to 0°C. After 100 ml of water was added to dissolve potassium phosphate, the solution was extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 18.12 g of the targeted (S)-glycidylphthalimide (yield: 73%, optical purity: 99.5%ee) as a white crystal.
[48] Example 3
[49] 25.00 g of (S)-l-amino-3-chloro-2-propanol hydrochloride (0.171 mol), 25.34 g of phthalic anhydride (0.171 mol), 28.64 ml of triethylamine (0.206 mol) and 171 ml of toluene were added into a reaction vessel. After stirring for 2 hours at 110-120°C, the solvent was removed under reduced pressure. Subsequently, 90.86 g of potassium phosphate (0.342 mol) and 171 ml of 1,2-dichloroethane were added to the reaction vessel. The mixture was stirred for 14 hours at 80°C. The reaction mixture was cooled to 0°C. After 100 ml of water was added to dissolve potassium phosphate, the solution was extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 24.01 g of the targeted (S)-glycidylphthalimide (yield: 69%, optical purity: 99.5%ee) as a white crystal.
[50] Example 4
[51] 25.00 g of (S)-l-amino-3-chloro-2-propanol hydrochloride (0.171 mol), 25.34 g of phthalic anhydride (0.171 mol), 28.64 ml of triethylamine (0.206 mol) and 171 ml of toluene were added into a reaction vessel. After stirring for 2 hours at 110-120°C, the solvent was removed under reduced pressure. Subsequently, 90.86 g of potassium phosphate (0.342 mol) and 171 ml of acetonitrile were added to the reaction vessel. The mixture was stirred for 14 hours at 80°C. The reaction mixture was cooled to 0°C. After 100 ml of water was added to dissolve potassium phosphate, the solution was extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 22.34 g of the targeted (S)-glycidylphthalimide (yield: 64%, optical purity: 99.5%ee) as a white crystal.
[52] Example 5
[53] 5.00 g of (S)-l-amino-3-chloro-2-propanol hydrochloride (0.034 mol), 5.069 g of phthalic anhydride (0.034 mol), 5.73 ml of triethylamine (0.041 mol) and 34 ml of toluene were added into a reaction vessel. After stirring for 2 hours at 110-120°C, 30
ml of water was added into the reaction vessel. An organic layer was obtained by extracting with toluene. Then, the obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. Subsequently, 18.17 g of potassium phosphate (0.069 mol) and 34 ml of 1,2-dichloroethane were added to the reaction vessel. The mixture was stirred for 14 hours at 80°C. The reaction mixture was cooled to 0°C. After 100 ml of water was added to dissolve potassium phosphate, the solution was extracted with 1,2-dichloroethane to obtain an organic layer. The obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 4.68 g of the targeted (S)-glycidylphthalimide (yield: 67%, optical purity: 99.5%ee) as a white crystal.
[54] Example 6
[55] 5.00 g of (S)-l-amino-3-chloro-2-propanol hydrochloride (0.034 mol), 5.069 g of phthalic anhydride (0.034 mol), 5.73 ml of triethylamine (0.041 mol) and 34 ml of toluene were added into a reaction vessel. After stirring for 2 hours at 110-120°C, the solvent was removed under reduced pressure. Subsequently, 18.17 g of potassium phosphate (0.069 mol) and 34 ml of ΛζN-dimethylformamide were sequentially added to the reaction vessel. The mixture was stirred for 3.5 hours at 40°C. After cooling to 0°C, potassium phosphate was filtered and pH of the resultant precipitate was adjusted to 5-6 by addition of sulfuric acid. Then, an organic layer was obtained by extracting with ethyl acetate. The obtained organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was recrystallized in ethanol to obtain 4.07 g of the targeted (S)-glycidylphthalimide (yield: 59%, optical purity: 99.5%ee) as white crystals.
Claims
[1] A process for the preparation of glycidylphthalimide represented by formula 1, which comprises the steps of: a) reacting 3-substituted l-amino-2-propanol acid addition salt of formula 2 with phthalic anhydride of formula 3 in a presence of a base to obtain N - (3-substituted-2-hydroxypropyl)phthalimide of formula 4; and b) subjecting the obtained compound (4) to an epoxide cyclization reaction to prepare the targeted glycidylphthalimide of formula 1 :
Formula 1
[2] The process as set forth in claim 1, wherein the 3-substituted l-amino-2-propanol acid addition salt of formula 2 is an optically active compound.
[3] The process as set forth in claim 1, wherein X is a halogen group or a sulfonyl group represented by
, wherein R 4 is C 1 -C 10 alky Jl; C 6 -C 10 ary Jl; or C 6 -C 10 ar Jyl substituted with nitro, methyl, ethyl, fluoro or chloro.
[4] The process as set forth in claim 3, wherein X is a halogen group selected from the group consisting of chloride, bromide and iodide.
[5] The process for the preparation of glycidylphthalimide as set forth in claim 4, wherein X is chloride.
[6] The process as set forth in claim 1, wherein HY is hydrochloric acid, hy- drobromide acid, hydroiodide acid, C -C alkyl sulfonic acid, C -C aryl sulfonic acid, C -C alkylaryl sulfonic acid, C -C aiylalkyl sulfonic acid or C -
7 11 7 11 1
C carboxylic acid.
[7] The process as set forth in claim 6, wherein HY is methanesulfonic acid.
[8] The process as set forth in claim 1, wherein the 3-substituted l-amino-2-propanol acid addition salt is l-amino-3-chloro-2-propanol methanesulfonic acid salt. [9] The process as set forth in claim 1, wherein the step a) is carried out in a presence of a tertiary amine represented by R R R N (wherein R , R and R are each independently C -C alkyl, C -C alkenyl, C -C arylalkyl or C -C
^ J 1 16 J 2 16 J 7 16 J J 7 16 alkylaryl). [10] The process as set forth in claim 1, wherein the step b) is carried out in a presence of an inorganic base selected from the group consisting of an alkali metal salt and an alkaline earth metal salt.
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| KR1020060042433A KR100612779B1 (en) | 2006-05-11 | 2006-05-11 | New process for the preparation of chiral glycidylphthalimide in highly optical purity |
| KR10-2006-0042433 | 2006-05-11 |
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|---|---|---|---|---|
| CN103130780A (en) * | 2012-12-07 | 2013-06-05 | 苏州百灵威超精细材料有限公司 | Preparation method for chiral N-epoxypropyl phthalimide |
| CN108440383A (en) * | 2018-04-03 | 2018-08-24 | 浙江永太科技股份有限公司 | A kind of preparation method of Rivaroxaban intermediate |
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| US6875875B2 (en) * | 2002-09-25 | 2005-04-05 | Daiso Co., Ltd. | Process for preparing glycidylphthalimide |
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| US6875875B2 (en) * | 2002-09-25 | 2005-04-05 | Daiso Co., Ltd. | Process for preparing glycidylphthalimide |
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|---|---|---|---|---|
| CN103130780A (en) * | 2012-12-07 | 2013-06-05 | 苏州百灵威超精细材料有限公司 | Preparation method for chiral N-epoxypropyl phthalimide |
| CN108440383A (en) * | 2018-04-03 | 2018-08-24 | 浙江永太科技股份有限公司 | A kind of preparation method of Rivaroxaban intermediate |
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