WO2008093955A1 - Process for the efficient preparation of 3-hydroxytetrahydrofuran - Google Patents
Process for the efficient preparation of 3-hydroxytetrahydrofuran Download PDFInfo
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- WO2008093955A1 WO2008093955A1 PCT/KR2008/000395 KR2008000395W WO2008093955A1 WO 2008093955 A1 WO2008093955 A1 WO 2008093955A1 KR 2008000395 W KR2008000395 W KR 2008000395W WO 2008093955 A1 WO2008093955 A1 WO 2008093955A1
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- WIPO (PCT)
- Prior art keywords
- cyclization
- formula
- ether
- halo
- polyethylene glycol
- Prior art date
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- XDPCNPCKDGQBAN-UHFFFAOYSA-N 3-hydroxytetrahydrofuran Chemical compound OC1CCOC1 XDPCNPCKDGQBAN-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 238000000034 method Methods 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 43
- 239000003960 organic solvent Substances 0.000 claims abstract description 29
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 64
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 57
- 239000002904 solvent Substances 0.000 claims description 32
- 150000002148 esters Chemical class 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 17
- 239000011541 reaction mixture Substances 0.000 claims description 17
- 239000002202 Polyethylene glycol Substances 0.000 claims description 14
- 229920001223 polyethylene glycol Polymers 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000009835 boiling Methods 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- POAOYUHQDCAZBD-UHFFFAOYSA-N 2-butoxyethanol Chemical compound CCCCOCCO POAOYUHQDCAZBD-UHFFFAOYSA-N 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- 229920001451 polypropylene glycol Polymers 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 claims description 6
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 3
- JJHHIJFTHRNPIK-UHFFFAOYSA-N Diphenyl sulfoxide Chemical compound C=1C=CC=CC=1S(=O)C1=CC=CC=C1 JJHHIJFTHRNPIK-UHFFFAOYSA-N 0.000 claims description 3
- 229910003018 M(BH4)n Inorganic materials 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 3
- KZTYYGOKRVBIMI-UHFFFAOYSA-N diphenyl sulfone Chemical compound C=1C=CC=CC=1S(=O)(=O)C1=CC=CC=C1 KZTYYGOKRVBIMI-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 abstract description 26
- 238000006243 chemical reaction Methods 0.000 abstract description 13
- 239000007858 starting material Substances 0.000 abstract description 8
- 239000003929 acidic solution Substances 0.000 abstract description 5
- 238000003756 stirring Methods 0.000 description 28
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
- 238000004821 distillation Methods 0.000 description 19
- 238000001914 filtration Methods 0.000 description 15
- 239000012279 sodium borohydride Substances 0.000 description 12
- 229910000033 sodium borohydride Inorganic materials 0.000 description 12
- XDPCNPCKDGQBAN-BYPYZUCNSA-N (3s)-oxolan-3-ol Chemical compound O[C@H]1CCOC1 XDPCNPCKDGQBAN-BYPYZUCNSA-N 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- ARXKVVRQIIOZGF-UHFFFAOYSA-N 1,2,4-butanetriol Chemical compound OCCC(O)CO ARXKVVRQIIOZGF-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- 238000010992 reflux Methods 0.000 description 8
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 7
- 229910010277 boron hydride Inorganic materials 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229910010272 inorganic material Inorganic materials 0.000 description 6
- 239000011147 inorganic material Substances 0.000 description 6
- -1 lithium aluminum hydride Chemical compound 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Chemical class 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- FUDDLSHBRSNCBV-UHFFFAOYSA-N 4-hydroxyoxolan-2-one Chemical compound OC1COC(=O)C1 FUDDLSHBRSNCBV-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- RTSODCRZYKSCLO-UHFFFAOYSA-N malic acid monomethyl ester Natural products COC(=O)C(O)CC(O)=O RTSODCRZYKSCLO-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- JLQZBFCQUPAOJC-UHFFFAOYSA-N oxolane-2,4-diol Chemical compound OC1COC(O)C1 JLQZBFCQUPAOJC-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- IQDXPPKWNPMHJI-BYPYZUCNSA-N (3s)-4-chlorobutane-1,3-diol Chemical compound OCC[C@H](O)CCl IQDXPPKWNPMHJI-BYPYZUCNSA-N 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (1R)-1,3-butanediol Natural products CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229960001830 amprenavir Drugs 0.000 description 1
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 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
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- ZAJNMXDBJKCCAT-YFKPBYRVSA-N ethyl (3s)-4-chloro-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@H](O)CCl ZAJNMXDBJKCCAT-YFKPBYRVSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 231100001231 less toxic Toxicity 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
- 229910001386 lithium phosphate 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
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- WMRINGSAVOPXTE-BYPYZUCNSA-N methyl (3s)-4-chloro-3-hydroxybutanoate Chemical compound COC(=O)C[C@H](O)CCl WMRINGSAVOPXTE-BYPYZUCNSA-N 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 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
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- CPWJKGIJFGMVPL-UHFFFAOYSA-K tricesium;phosphate Chemical compound [Cs+].[Cs+].[Cs+].[O-]P([O-])([O-])=O CPWJKGIJFGMVPL-UHFFFAOYSA-K 0.000 description 1
- TWQULNDIKKJZPH-UHFFFAOYSA-K trilithium;phosphate Chemical compound [Li+].[Li+].[Li+].[O-]P([O-])([O-])=O TWQULNDIKKJZPH-UHFFFAOYSA-K 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
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
-
- 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 chiral
- the present invention relates to a process for the commercial- scale preparation of chiral 3-hydroxytetrahydrofuran with high optical purity, without sacrificing optical purity of the starting material.
- [2] 3 -Hydroxy tetrahydrofuran is useful as synthesis intermediate of medicines, agri- chemicals, and the like. Especially, it is used as key intermediate in the synthesis of amprenavir, a protease inhibitor used to treat HIV infection.
- Currently known preparation processes of 3-hydroxytetrahydrofuran are as follows.
- 1,2,4-butanetriol was obtained from malic diester, 3-hydroxy- -butyrolactone, tetrahy- drofuran-2,4-diol, and the like.
- 1,2,4-butanetriol was prepared from reduction of the malic diester. But, the reduction is undesirable in reaction yield and the purification process of the product is complicated.
- 1,2,4-butanetriol may be prepared by reducing 3-hydroxy- -butyrolactone or chiral tetrahydrofuran- 2,4-diol in the presence of a reducing agent such as sodium borohydride.
- This method comprises the steps of reducing 4-halo-3-hydroxybutyric ester in an water-miscible organic solvent such as tetrahydrofuran, using sodium borohydride, to obtain 4-halo-l,3-butanediol, and cyclizing the resultant compound in an acidic solution to obtain chiral 3-hydroxytetrahydrofuran.
- this process is not satisfactory in yield (58 to 68%).
- U.S. Patent No. 6,359,155 discloses a process comprising the steps of reducing chiral 4-halo-3-hydroxybutyric ester in an water-immiscible organic solvent such as toluene and ethyl acetate, using sodium borohydride, treating the resultant reaction mixture with water and an acid to obtain an aqueous solution of 4-halo-l,3-butanediol, and then cyclizing 4-halo-l,3-butanediol to obtain chiral 3-hydroxytetrahydrofuran.
- this method provides relatively high reaction yield (80 to 82%), it required long reaction time (40 hours or longer) and a complicated extraction (continuous extraction at 7O 0 C) for the purification. For this reason, this method has a low productivity, on the whole.
- An object of the present invention is to provide a process for the efficient preparation of 3-hydroxytetrahydrofuran.
- Another object of the present invention is to provide a process for the efficient preparation of chiral 3-hydroxytetrahydrofuran with a high optical purity of 99.0% ee or better, without sacrificing optical purity of the starting material.
- the targeted chiral 3-hydroxytetrahydrofuran is prepared in high yield and with high optical purity of 99.0% ee or better, without sacrificing chirality of the starting material.
- the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran comprising cyclizing 4-halo-l,3-butanediol either neat or in an organic solvent, by heating to 75 0 C to 18O 0 C.
- the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the cyclization is performed in the presence of a base.
- the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the cyclization is performed at 9O 0 C to 15O 0 C.
- the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the cyclization is performed at 100 0 C to 13O 0 C.
- the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the organic solvent used in the cyclization has a boiling point in the range from 75 0 C to 15O 0 C or from 21O 0 C to 600 0 C, more preferably from 9O 0 C to 15O 0 C or from 25O 0 C to 600 0 C, most preferably from 100 0 C to 15O 0 C or from 28O 0 C to 600 0 C.
- the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the chirality of the starting material is preserved during the cyclization and the resultant 3 -hydroxy tetrahydrofuran has a high optical purity of 99.0% ee or better.
- the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran which comprises a) reducing 4-halo-3-hydroxybutyric ester to obtain chiral 4-halo-l,3-butanediol, b) cyclizing the resultant compound either neat or in an organic solvent, by heating to 75 0 C to 18O 0 C, and c) recovering 3 -hydroxy tetrahydrofuran from the resultant reaction mixture.
- the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the 4-halo-3-hydroxybutyric ester is ethyl-4-halo-3-hydroxybutyrate or methyl-4-halo-3-hydroxybutyrate.
- the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the reduction in the step a) is performed in the presence of M(BH 4 ) n (where M is an alkali metal or an alkaline earth metal, and n is 1 or 2) or a mixture thereof with methanol.
- the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein said M is sodium and the proportion of M(BH 4 ) n : methanol is from 1:0.5 to 1:2.
- the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the cyclization is performed neat without using a solvent.
- 3 -hydroxy tetrahydrofuran can be prepared with high optical purity, without sacrificing optical purity of the starting material.
- 3 -hydroxy tetrahydrofuran having high optical purity of 99% ee or better can be prepared in high yield, without sacrificing chirality.
- chiral 4-halo-l,3-butanediol represented by the formula 2 can be used in the following cyclization process in crude form, without any purification.
- the cyclization is performed either neat or in an organic condition, instead of using an acidic solution, the complicated procedure of extraction or concentration of aqueous solution can be avoided.
- the process for the preparation of 3 -hydroxy tetrahydrofuran according to the present invention is carried out conveniently in mild condition. This means that the process for the preparation of 3 -hydroxy tetrahydrofuran with high optical purity in accordance with the present invention can be applied for commercial- scale production.
- the present inventors performed various experiments in order to find an alternative to the cyclization of 3 -hydroxy tetrahydrofuran in an acidic solution. As a result, they found out that 4-halo-l,3-butanediol can be cyclized into 3 -hydroxy tetrahydrofuran either in the presence of an organic solvent or neat without using a solvent. They confirmed that yield and reaction time of the cyclization of 4-halo-l,3-butanediol are greatly dependent on reaction temperature. Specifically, cyclization was hardly carried out below 75 0 C. The reaction was initiated at 75 0 C to 9O 0 C and activated at 9O 0 C or higher, most preferably at 100 0 C or higher.
- R is an ester forming group, preferably Ci-C 4 alkyl.
- 4-halo-3-hydroxybutyric ester comprises: [40] a) reducing 4-halo-3-hydroxybutyric ester represented by the formula 3 to obtain
- X is a halogen atom (F, Cl, Br or I) and R is an ester forming group, preferably Ci-C 4 alkyl.
- the process according to the present invention is particularly useful for the preparation of chiral 3-hydroxytetrahydrofuran.
- the target compound 3 -hydroxy tetrahydrofuran is prepared from chiral 4-halo-3-hydroxybutyric ester with a high optical purity of 99.0% ee or better.
- Examples of a reducing agent that can used for the reduction include borane-methyl sulfide complex, borane-tetrahydrofuran complex, diborane, lithium aluminum hydride, metal salt of boron hydride, and a mixture of metal salt of boron hydride and methanol.
- a mixture of alkali metal salt of boron hydride and methanol or a mixture of alkaline earth metal salt of boron hydride and methanol is more preferred.
- a mixture of sodium borohydride and methanol is further more preferred.
- a mixture of metal salt of boron hydride and methanol forms a metal salt of methoxy borohydride in the reaction solution, in situ.
- a mixture of sodium borohydride and methanol is the most preferred.
- the metal salt of boron hydride is used in 0.5 to 2.0 equivalents, preferably in 0.8 to 1.2 equivalents, based on compound represented by the formula 3.
- Methanol is used in 0.5 to 2.0 equivalents, preferably in 0.8 to 1.5 equivalents, based on the metal salt of boron hydride.
- the solvent used for the reduction is not particularly limited, but one commonly used in the related art may be used. Specifically, an aliphatic or aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether, an ester or an alcohol may be used. Among them, a less toxic and inexpensive organic solvent is preferred. For example, toluene, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, etc. may be used.
- the solvent may be used in an amount of 1 to 10 equivalents, preferably 2 to 5 equivalents, based on the weight of the compound represented by the formula 3.
- the reaction is performed normally at 0 to 100 0 C, preferably at 20 to 7O 0 C.
- the ester protecting group R is not particularly limited, but may be a general protecting group. Alkyl is preferred, Ci-C 4 alkyl is more preferred, and ethyl or methyl is further more preferred.
- 4-halo-3-hydroxybutyric ester can be used in the following cyclization in crude form without special purification. In addition to simplified process, this contributes to improvement of yield.
- the cyclization of 4-halo-l,3-butanediol represented by the formula 2 is performed at a temperature of about 75 0 C or higher. Considering that the target compound 3 -hydroxy tetrahydrofuran has a boiling point of about 18O 0 C, the cyclization is performed in the temperature range from 75 0 C to 18O 0 C. More preferably, the cyclization is performed in the temperature range from 9O 0 C to 15O 0 C. Most preferably, the cyclization is performed in the temperature range from 100 0 C to 13O 0 C.
- the cyclization may be performed either in the presence of an organic solvent or neat without using a solvent.
- the organic solvent has a boiling point of at least 75 0 C.
- the organic solvent has a boiling point of at least 9O 0 C.
- the organic solvent has a boiling point in the range from 100 to 15O 0 C or from 21O 0 C to 600 0 C.
- an organic solvent having a boiling point in the range from 100 to 15O 0 C or from 21O 0 C to 600 0 C is the most preferred, in view of reaction rate, reaction yield and separation of the solvent from the target compound.
- Specific examples of available organic solvent include an aliphatic or aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether, an ester and an alcohol.
- benzene, toluene, xylene, C 2 -C 4 alcohols e.g., ethanol, propanol, isopropanol, 1-butanol, 2-butanol and ?-butanol
- 1,2-dichloroe thane ethyl acetate
- 1,4-dioxane etc.
- a mixture solvent of the above- mentioned solvents may be used.
- Preferable solvents are toluene, xylene and C 3 -C 4 alcohols.
- organic solvent having a boiling point in the range from 100 to 150 0 C
- the organic solvent is first recovered by distillation under reduced pressure, and then the target compound 3 -hydroxy tetrahydrofuran is obtained at higher temperature.
- Use of an organic solvent having a boiling point higher than 210 0 C provides the advantage that the target compound can be recovered first through distillation under reduced pressure.
- organic solvent include polyethylene glycol, polyethylene glycol butyl ether, polyethylene glycol dimethyl ether, polyethylene glycol methyl ether, polypropylene glycol, polypropylene glycol monobutyl ether, diphenyl ether, dibenzyl ether, phenyl sulfone and phenyl sulfoxide.
- the organic solvent is used in 0.5 to 20 equivalents, preferably in 2 to 5 equivalents, based on the weight of the compound represented by the formula 2.
- the cyclization can also be performed neat without using an organic solvent. After performing cyclization in neat condition, the target compound 3 -hydroxy tetrahydrofuran can be obtained simply through distillation under reduced pressure.
- the cyclization may be performed in the presence of a base.
- a base increases reaction rate to some extent.
- Available bases are not particularly limited, but various inorganic and organic bases may be used.
- inorganic base include an alkali metal salt.
- an alkali carbonate, an alkali bicarbonate or an alkali phosphate may be used.
- lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, etc. may be used.
- Preferred examples of organic base include alkyl- or aryl-substituted amine.
- tri- methylamine, triethylamine, tripropylamine, tributylamine, triphenylamine, diisopro- pylethylamine, dicyclohexylamine, dibenzylamine, benzylamine, etc. may be used.
- the base is used in 0.5 to 10 equivalents, preferably in 1.0 to 2 equivalents, based on the weight of the 4-halo-l,3-butanediol compound represented by the formula 2.
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Abstract
Disclosed is a process for the efficient preparation of 3-hydroxytetrahydrofuran. In particular, the present invention provides a process for the preparation of 3-hydroxytetrahydrofuran by performing cyclization of 4-halo-1,3-butanediol either neat or in an organic solvent by heating to 75°C to 18O°C. In the present invention, acidic solution is not used in the cyclization and, thus, the reaction environment is improved. Further, the cyclization product 3-hydroxytetrahydrofuran is purified by a simple process. In addition, according to the present invention, chirality of the starting material is substantially maintained. Consequently, chiral 3-hydroxytetrahydrofuran with a high optical purity of 99.0% ee or better can be prepared economically, in high yield.
Description
Description
PROCESS FOR THE EFFICIENT PREPARATION OF 3-HYDROXYTETRAHYDROFURAN
Technical Field
[1] The present invention relates to a process for the preparation of chiral
3-hydroxytetrahydrofuran. More particularly, the present invention relates to a process for the commercial- scale preparation of chiral 3-hydroxytetrahydrofuran with high optical purity, without sacrificing optical purity of the starting material. Background Art
[2] 3 -Hydroxy tetrahydrofuran is useful as synthesis intermediate of medicines, agri- chemicals, and the like. Especially, it is used as key intermediate in the synthesis of amprenavir, a protease inhibitor used to treat HIV infection. Currently known preparation processes of 3-hydroxytetrahydrofuran are as follows.
[3] There was proposed a process for preparing 3-hydroxytetrahydrofuran through cyc- lodehydrogenation of 1,2,4-butanetriol in the presence of a catalyst such as p - toluenesulfonic acid or strongly acidic cation exchange resin having a sulfate group as ion-exchange group [J. Org. Chem. 1983, vol. 48, p. 2767-2769; Korean Patent Publication No. 10-2006-0067620; Japanese Patent Laid-open No. 2006-36710]. However, the starting material 1,2,4-butanetriol has many problems in synthesis. Generally, 1,2,4-butanetriol was obtained from malic diester, 3-hydroxy- -butyrolactone, tetrahy- drofuran-2,4-diol, and the like. Typically, 1,2,4-butanetriol was prepared from reduction of the malic diester. But, the reduction is undesirable in reaction yield and the purification process of the product is complicated. Alternatively, 1,2,4-butanetriol may be prepared by reducing 3-hydroxy- -butyrolactone or chiral tetrahydrofuran- 2,4-diol in the presence of a reducing agent such as sodium borohydride. However, this method is economically unfavorable because 3-hydroxy- -butyrolactone or tetrahy- drofuran-2,4-diol is relatively expensive [J. Org. Chem. 1983, vol. 48, p. 2767-2769; WO 99/44976; Japanese Patent Laid-open No. 2006-36710].
[4] As an alternative, a process for the preparation of chiral 3-hydroxytetrahydrofuran by protecting the hydroxy group of malic diester with ?-butyl, reducing the same using lithium aluminum hydride (LAH) to obtain 2-?-butoxybutane-l,4-diol, deprotecting the resultant compound in the presence of an acid catalyst, and then performing cyclode- hydrogenation has been proposed [Org. Biomol. Chem. 2004, vol. 2, p. 2061-2070]. However, this process is complicated and difficult to handle. And, since expensive lithium aluminum hydride is used as reducing agent, it seems to be inapplicable to commercial- scale production.
[5] U.S. Patent No. 5,780,649 discloses a process for the preparation of
3 -hydroxy tetrahydrofuran from easily available and inexpensive 4-halo-3-hydroxybutyric ester. This method comprises the steps of reducing 4-halo-3-hydroxybutyric ester in an water-miscible organic solvent such as tetrahydrofuran, using sodium borohydride, to obtain 4-halo-l,3-butanediol, and cyclizing the resultant compound in an acidic solution to obtain chiral 3-hydroxytetrahydrofuran. However, this process is not satisfactory in yield (58 to 68%).
[6] As an improvement of the above method, U.S. Patent No. 6,359,155 discloses a process comprising the steps of reducing chiral 4-halo-3-hydroxybutyric ester in an water-immiscible organic solvent such as toluene and ethyl acetate, using sodium borohydride, treating the resultant reaction mixture with water and an acid to obtain an aqueous solution of 4-halo-l,3-butanediol, and then cyclizing 4-halo-l,3-butanediol to obtain chiral 3-hydroxytetrahydrofuran. Although this method provides relatively high reaction yield (80 to 82%), it required long reaction time (40 hours or longer) and a complicated extraction (continuous extraction at 7O0C) for the purification. For this reason, this method has a low productivity, on the whole.
[7] In both U.S. Patent Nos. 5,780,649 and6,359, 155, cyclization is performed under acidic solution condition. Acid is harmful to the human body and the use thereof needs to be restricted as much as possible. Particularly, in large-scale production, an acidic condition is difficult to handle. In addition, cyclization in aqueous solution makes the purification of 3-hydroxytetrahydrofuran complicated.
[8] To conclude, the methods disclosed in U.S. Patent Nos. 5,780,649 and 6,359,155 involve at least one of the following problems: i) unsatisfactory yield, ii) long reaction time (40 hours or longer), iii) unfavorable working condition due to use of acid, and iv) difficulty in purification of the target compound due to use of aqueous solution. Disclosure of Invention Technical Problem
[9] An object of the present invention is to provide a process for the efficient preparation of 3-hydroxytetrahydrofuran.
[10] Another object of the present invention is to provide a process for the efficient preparation of chiral 3-hydroxytetrahydrofuran with a high optical purity of 99.0% ee or better, without sacrificing optical purity of the starting material. According to a preferred embodiment of the present invention, the targeted chiral 3-hydroxytetrahydrofuran is prepared in high yield and with high optical purity of 99.0% ee or better, without sacrificing chirality of the starting material. Technical Solution
[11] In one aspect, the present invention provides a process for the preparation of
3 -hydroxy tetrahydrofuran comprising cyclizing 4-halo-l,3-butanediol either neat or in an organic solvent, by heating to 750C to 18O0C.
[12] In a preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the cyclization is performed in the presence of a base.
[13] In another preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the cyclization is performed at 9O0C to 15O0C.
[14] In still another preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the cyclization is performed at 1000C to 13O0C.
[15] In yet another preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the organic solvent used in the cyclization has a boiling point in the range from 750C to 15O0C or from 21O0C to 6000C, more preferably from 9O0C to 15O0C or from 25O0C to 6000C, most preferably from 1000C to 15O0C or from 28O0C to 6000C.
[16] In still yet another preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the chirality of the starting material is preserved during the cyclization and the resultant 3 -hydroxy tetrahydrofuran has a high optical purity of 99.0% ee or better.
[17] In a further preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran which comprises a) reducing 4-halo-3-hydroxybutyric ester to obtain chiral 4-halo-l,3-butanediol, b) cyclizing the resultant compound either neat or in an organic solvent, by heating to 750C to 18O0C, and c) recovering 3 -hydroxy tetrahydrofuran from the resultant reaction mixture.
[18] In another further preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the 4-halo-3-hydroxybutyric ester is ethyl-4-halo-3-hydroxybutyrate or methyl-4-halo-3-hydroxybutyrate.
[19] In still another further preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the reduction in the step a) is performed in the presence of M(BH4)n (where M is an alkali metal or an alkaline earth metal, and n is 1 or 2) or a mixture thereof with methanol.
[20] In yet another further preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein said M is sodium and the proportion of M(BH4)n : methanol is from 1:0.5 to 1:2.
[21] In still yet another further preferred embodiment, the present invention provides a process for the preparation of 3 -hydroxy tetrahydrofuran wherein the cyclization is performed neat without using a solvent.
Advantageous Effects
[22] According to the process for the preparation of chiral 3 -hydroxy tetrahydrofuran of the present invention, 3 -hydroxy tetrahydrofuran can be prepared with high optical purity, without sacrificing optical purity of the starting material. Specifically, from the starting material represented by the formula 2 and/or formula 3, 3 -hydroxy tetrahydrofuran having high optical purity of 99% ee or better can be prepared in high yield, without sacrificing chirality. And, chiral 4-halo-l,3-butanediol represented by the formula 2 can be used in the following cyclization process in crude form, without any purification. Further, since the cyclization is performed either neat or in an organic condition, instead of using an acidic solution, the complicated procedure of extraction or concentration of aqueous solution can be avoided. In addition, by performing the cyclization in neat condition and using an organic solvent having a boiling point higher than that of the target compound, chiral 3 -hydroxy tetrahydrofuran can be purified simply through distillation under reduced pressure. Accordingly, the process for the preparation of 3 -hydroxy tetrahydrofuran according to the present invention is carried out conveniently in mild condition. This means that the process for the preparation of 3 -hydroxy tetrahydrofuran with high optical purity in accordance with the present invention can be applied for commercial- scale production. Mode for the Invention
[23] The present inventors performed various experiments in order to find an alternative to the cyclization of 3 -hydroxy tetrahydrofuran in an acidic solution. As a result, they found out that 4-halo-l,3-butanediol can be cyclized into 3 -hydroxy tetrahydrofuran either in the presence of an organic solvent or neat without using a solvent. They confirmed that yield and reaction time of the cyclization of 4-halo-l,3-butanediol are greatly dependent on reaction temperature. Specifically, cyclization was hardly carried out below 750C. The reaction was initiated at 750C to 9O0C and activated at 9O0C or higher, most preferably at 1000C or higher. Surprisingly, the chirality of 3 -hydroxy tetrahydrofuran was preserved during the cyclization. As a result, it was confirmed that 3 -hydroxy tetrahydrofuran can be prepared with high optical purity (99.0% ee or better).
[24] In order to evaluate the effect of HCl on the cyclization of 4-halo-l,3-butanediol, the present inventors performed the cyclization in the presence of a base. Surprisingly enough, the rate of the cyclization increased to some extent, instead of decreasing. Such a result indicates that the HCl produced during the cyclization does not have a significant effect on the reaction. In other words, this contradicts the theory that the HCl produced during the cyclization of 4-halo-l,3-butanediol changes the reaction
solution into acidic condition and thereby accelerates the cyclization. [25] The process for the preparation of 3 -hydroxy tetrahydrofuran represented by the formula 1 below according to the present invention comprises cyclizing
4-halo-l,3-butanediol represented by the formula 2 either neat or in an organic solvent, by heating to 750C to 18O0C: [26] Formula 1
[30] wherein * represents a chiral center and X is a halogen atom (F, Cl, Br or I).
[31] The preparation of 3 -hydroxy tetrahydrofuran through cyclization of
4-halo-l,3-butanediol represented by the formula 2 is summarized in the following
Scheme 1: [32] Scheme 1
[34] wherein * represents a chiral center and X is a halogen atom (F, Cl, Br or I).
[35] 4-Halo-l,3-butanediol may be prepared in high yield by reducing chiral
4-halo-3-hydroxybutyric ester represented by the formula 3. The reduction is also performed with high yield, without sacrificing optical purity. [36] Formula 3
[38] In the formula 3, * represents a chiral center, X is a halogen atom (F, Cl, Br or I) and
R is an ester forming group, preferably Ci-C4 alkyl. [39] The entire process of preparing 3 -hydroxy tetrahydrofuran from
4-halo-3-hydroxybutyric ester comprises: [40] a) reducing 4-halo-3-hydroxybutyric ester represented by the formula 3 to obtain
4-halo-l,3-butanediol represented by the formula 2; [41] b) cyclizing the resultant compound represented by the formula 2 either neat or in an organic solvent, by heating to 750C to 18O0C; and
[42] c) recovering 3 -hydroxy tetrahydrofuran represented by the formula 1 from the resultant reaction mixture. [43] The entire process of preparing 3 -hydroxy tetrahydrofuran from
4-halo-3-hydroxybutyric ester represented by the formula 3 is summarized in the following Scheme 2: [44] Scheme 2 heating in organic or neat condition to perform cyclization
[46] wherein * represents a chiral center, X is a halogen atom (F, Cl, Br or I) and R is an ester forming group, preferably Ci-C4 alkyl.
[47] During the reduction of the 4-halo-3-hydroxybutyric ester and the cyclization by heating, no substantial degradation of chirality was observed. Accordingly, the process according to the present invention is particularly useful for the preparation of chiral 3-hydroxytetrahydrofuran. According to a preferred embodiment of the present invention, the target compound 3 -hydroxy tetrahydrofuran is prepared from chiral 4-halo-3-hydroxybutyric ester with a high optical purity of 99.0% ee or better.
[48] Hereinafter, the present invention is described in further detail.
[49] 4-Halo-3-hydroxybutyric ester represented by the formula 3 is reduced to
4-halo- 1 ,3-butanediol.
[50] Examples of a reducing agent that can used for the reduction include borane-methyl sulfide complex, borane-tetrahydrofuran complex, diborane, lithium aluminum hydride, metal salt of boron hydride, and a mixture of metal salt of boron hydride and methanol. A mixture of alkali metal salt of boron hydride and methanol or a mixture of alkaline earth metal salt of boron hydride and methanol is more preferred. A mixture of sodium borohydride and methanol is further more preferred. A mixture of metal salt of boron hydride and methanol forms a metal salt of methoxy borohydride in the reaction solution, in situ. A mixture of sodium borohydride and methanol is the most preferred. The metal salt of boron hydride is used in 0.5 to 2.0 equivalents, preferably in 0.8 to 1.2 equivalents, based on compound represented by the formula 3. Methanol is used in 0.5 to 2.0 equivalents, preferably in 0.8 to 1.5 equivalents, based on the metal salt of boron hydride. According to experimental results, when sodium borohydride was used alone in 1 equivalent based on the compound represented by the formula 3, about 48 hours of reaction time was required. But, when a mixture of 1 equivalent of sodium borohydride and 1 equivalent of methanol was used, the reaction was completed in about 20 hours.
[51] The solvent used for the reduction is not particularly limited, but one commonly used
in the related art may be used. Specifically, an aliphatic or aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether, an ester or an alcohol may be used. Among them, a less toxic and inexpensive organic solvent is preferred. For example, toluene, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, etc. may be used. The solvent may be used in an amount of 1 to 10 equivalents, preferably 2 to 5 equivalents, based on the weight of the compound represented by the formula 3. The reaction is performed normally at 0 to 1000C, preferably at 20 to 7O0C.
[52] In the 4-halo-3-hydroxybutyric ester represented by the formula 3, the ester protecting group R is not particularly limited, but may be a general protecting group. Alkyl is preferred, Ci-C4 alkyl is more preferred, and ethyl or methyl is further more preferred.
[53] 4-Halo-l,3-butanediol represented by the formula 2 obtained from the reduction of
4-halo-3-hydroxybutyric ester can be used in the following cyclization in crude form without special purification. In addition to simplified process, this contributes to improvement of yield.
[54] The cyclization of 4-halo-l,3-butanediol represented by the formula 2 is performed at a temperature of about 750C or higher. Considering that the target compound 3 -hydroxy tetrahydrofuran has a boiling point of about 18O0C, the cyclization is performed in the temperature range from 750C to 18O0C. More preferably, the cyclization is performed in the temperature range from 9O0C to 15O0C. Most preferably, the cyclization is performed in the temperature range from 1000C to 13O0C.
[55] The cyclization may be performed either in the presence of an organic solvent or neat without using a solvent. The organic solvent has a boiling point of at least 750C. Preferably, the organic solvent has a boiling point of at least 9O0C. Most preferably, the organic solvent has a boiling point in the range from 100 to 15O0C or from 21O0C to 6000C. Use of an organic solvent having a boiling point in the range from 15O0C to 21O0C is recommended to be avoided, if possible. It is because the purification of the target compound 3 -hydroxy tetrahydrofuran (boiling point = ~180°C) by distillation may become difficult. Accordingly, as described above, an organic solvent having a boiling point in the range from 100 to 15O0C or from 21O0C to 6000C is the most preferred, in view of reaction rate, reaction yield and separation of the solvent from the target compound. Specific examples of available organic solvent include an aliphatic or aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent, an ether, an ester and an alcohol. For example, benzene, toluene, xylene, C2-C4 alcohols (e.g., ethanol, propanol, isopropanol, 1-butanol, 2-butanol and ?-butanol), 1,2-dichloroe thane, ethyl acetate, 1,4-dioxane, etc., may be used. Also, a mixture solvent of the above- mentioned solvents may be used. Preferable solvents are toluene, xylene and C3-C4 alcohols. When an organic solvent having a boiling point in the range from 100 to
1500C is used, the organic solvent is first recovered by distillation under reduced pressure, and then the target compound 3 -hydroxy tetrahydrofuran is obtained at higher temperature. Use of an organic solvent having a boiling point higher than 2100C provides the advantage that the target compound can be recovered first through distillation under reduced pressure. Examples of organic solvent include polyethylene glycol, polyethylene glycol butyl ether, polyethylene glycol dimethyl ether, polyethylene glycol methyl ether, polypropylene glycol, polypropylene glycol monobutyl ether, diphenyl ether, dibenzyl ether, phenyl sulfone and phenyl sulfoxide. The organic solvent is used in 0.5 to 20 equivalents, preferably in 2 to 5 equivalents, based on the weight of the compound represented by the formula 2.
[56] The cyclization can also be performed neat without using an organic solvent. After performing cyclization in neat condition, the target compound 3 -hydroxy tetrahydrofuran can be obtained simply through distillation under reduced pressure.
[57] As described earlier, the cyclization may be performed in the presence of a base. The addition of a base increases reaction rate to some extent. Available bases are not particularly limited, but various inorganic and organic bases may be used. Examples of inorganic base include an alkali metal salt. For example, an alkali carbonate, an alkali bicarbonate or an alkali phosphate may be used. Specifically, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, cesium phosphate, etc. may be used. Preferred examples of organic base include alkyl- or aryl-substituted amine. Specifically, tri- methylamine, triethylamine, tripropylamine, tributylamine, triphenylamine, diisopro- pylethylamine, dicyclohexylamine, dibenzylamine, benzylamine, etc. may be used. The base is used in 0.5 to 10 equivalents, preferably in 1.0 to 2 equivalents, based on the weight of the 4-halo-l,3-butanediol compound represented by the formula 2.
[58] The following examples illustrate the present invention and are not intended to limit the same.
[59] Example 1
[60] 61.5 g (1.626 mol) of sodium borohydride was dissolved in 694 mL of toluene, and
52 g (1.626 mol) of methanol was added drop wise at room temperature for 1 hour. Subsequently, 300 g (1.807 mol, 99.3% ee) of ethyl (S)-4-chloro-3-hydroxybutyrate was added, and stirring was performed at room temperature for 12 hours. The reaction mixture was cooled below 100C and, after adding 183 g of 36% HCl dropwise, the solvent was removed by distillation under reduced pressure below 400C. Using 800 mL of methanol, concentration under reduced pressure was performed for 3 times below 40 C. 800 mL of dichloromethane was added to the resultant residue. After filtering off
solid inorganic materials and removing the solvent under reduced pressure, 220 g of (S )-4-chloro-l,3-butanediol was obtained as oil (yield = 98%).
[61] Example 2
[62] 800 mL of toluene was added to 220 g ( 1.774 mol) of (S)-4-chloro- 1 ,3-butanediol prepared in Example 1, and stirring was performed for 16 hours under reflux. The reaction mixture was cooled to room temperature and, after adding 37.6 g (0.355 mol) of Na2CO3 and 1 g (0.055 mol) of water, stirring was further performed for 30 minutes. After removing solid by filtering, the solvent was recovered by concentration under reduced pressure, and the residue was further distilled under reduced pressure. 138 g of colorless (S)-3-hydroxytetrahydrofuran was obtained (yield = 88%, optical purity = 99.55% ee).
[63] Example 3
[64] 61.5 g (1.626 mol) of sodium borohydride was dissolved in 694 mL of toluene, and
52 g (1.626 mol) of methanol was added drop wise at room temperature for 1 hour. Subsequently, 300 g (1.807 mol, 99.3% ee) of ethyl (#)-4-chloro-3-hydroxybutyrate was added, and stirring was performed at room temperature for 12 hours. The reaction mixture was cooled below 1O0C and, after adding 183 g of 36% HCl dropwise, the solvent was removed by distillation under reduced pressure below 4O0C. Using 800 mL of methanol, concentration under reduced pressure was performed for 3 times below 4O0C. 800 mL of dichloromethane was added to the resultant residue. After filtering off solid inorganic materials and removing the solvent under reduced pressure, 218 g of (R )-4-chloro-l,3-butanediol was obtained as oil (yield = 97%).
[65] Example 4
[66] 800 mL of toluene was added to 218 g (1.758 mol) of (#)-4-chloro-l,3-butanediol prepared in Example 3, and stirring was performed for 16 hours under reflux. The reaction mixture was cooled to room temperature and, after adding 37.3 g (0.352 mol) of Na2CO3 and 1 g (0.055 mol) of water, stirring was further performed for 30 minutes. After removing solid by filtering, the solvent was recovered by concentration under reduced pressure, and the residue was further distilled under reduced pressure. 137 g of colorless (/?)-3-hydroxytetrahydrofuran was obtained (yield = 88%, overall yield = 85%, optical purity = 99.52% ee).
[67] Example 5
[68] 41.0 g (1.084 mol) of sodium borohydride and 200 g (1.205 mol, 99.3% ee) of ethyl (
S)-4-chloro-3-hydroxybutyrate were dissolved in 400 g of tetrahydrofuran, and 34.7 g (1.084 mol) of methanol was added dropwise at room temperature for 1 hour. After stirring at room temperature for 10 hours, the reaction mixture was cooled below 1O0C. Then, after adding 122 g of 36% HCl dropwise, the solvent was removed by distillation under reduced pressure below 4O0C. Using 550 mL of methanol, concentration
under reduced pressure was performed for 3 times below 4O0C. 550 mL of di- chloromethane and 20 g of Na2SO4 were added to the resultant residue, and stirring was performed for 30 minutes. After filtering off solid inorganic materials and removing the solvent under reduced pressure, 144 g of (S)-4-chloro-l,3-butanediol was obtained as oil (yield = 96%).
[69] Example 6
[70] 550 mL of toluene was added to 144 g (1.161 mol) of (S)-4-chloro-l,3-butanediol prepared in Example 5, and stirring was performed for 16 hours under reflux. The reaction mixture was cooled to room temperature and, after adding 24.6 g (0.232 mol) of Na2CO3 and 0.5 g (0.028 mol) of water, stirring was further performed for 30 minutes. After removing solid by filtering, the solvent was recovered by concentration under reduced pressure, and the residue was further distilled under reduced pressure. 91 g of colorless (S)-3-hydroxytetrahydrofuran was obtained (yield = 89%, overall yield = 85%, optical purity = 99.45% ee).
[71] Example 7
[72] 41.0 g (1.084 mol) of sodium borohydride and 200 g (1.205 mol, 99.3% ee) of ethyl (
S)-4-chloro-3-hydroxybutyrate were dissolved in 400 g of isopropanol, and 34.7 g (1.084 mol) of methanol was added dropwise at room temperature for 1 hour. After stirring at room temperature for 12 hours, the reaction mixture was cooled below 1O0C. Then, after adding 122 g of 36% HCl dropwise, the solvent was removed by distillation under reduced pressure below 4O0C. Using 500 mL of methanol, concentration under reduced pressure was performed for 3 times below 4O0C. Stirring was performed after adding 550 mL of isopropanol to the resultant residue. After filtering off solid inorganic materials, 147 g of (S)-4-chloro-l,3-butanediol was obtained as oil (yield = 98%).
[73] Example 8
[74] An isopropanol solution containing 147 g (1.182 mol) of (S)-4-chloro-l,3-butanediol obtained in Example 7 was stirred for 22 hours under reflux. After cooling the reaction mixture to room temperature, 24.6 g (0.232 mol) of Na2CO3 and 0.5 g (0.028 mol) of water were added, and stirring was performed for 30 minutes. After filtering, the solvent was recovered by concentration under reduced pressure, and the residue was further distilled under reduced pressure. 89 g of colorless (S)-3-hydroxytetrahydrofuran was obtained (yield = 87%, overall yield = 85%, optical purity = 99.43% ee).
[75] Example 9
[76] 400 mL of 1,4-dioxane was added to 100 g (0.806 mol) of (S
)-4-chloro-l,3-butanediol obtained in Example 1, and stirring was performed for 20 hours under reflux. After cooling the reaction mixture to room temperature, 24.6 g (0.232 mol) of Na2CO3 and 0.5 g (0.028 mol) of water were added, and stirring was
performed for 30 minutes. After filtering, the solvent was concentrated under reduced pressure. The resultant residue was distilled under reduced pressure to obtain 58 g of colorless (S)-3-hydroxytetrahydrofuran (yield = 82%, optical purity = 99.42% ee).
[77] Example 10
[78] While stirring 220 g (1.774 mol) of (S)-4-chloro-l,3-butanediol prepared in Example
1 at 11O0C in neat condition without a solvent, distillation under reduced pressure was performed for 6 hours. The resultant compound was diluted in 200 mL of toluene and, after adding 37.6 g (0.355 mol) Of Na2CO3 and 1 g (0.055 mol) of water, stirring was performed for 30 minutes. After filtering, distillation under reduced pressure was performed to obtain 130 g of colorless (S)-3-hydroxytetrahydrofuran (yield = 83%, overall yield = 82%, optical purity = 99.45% ee).
[79] Example 11
[80] 200 g (1.613 mol) of (S)-4-chloro-l,3-butanediol prepared in Example 1 was added to 600 g of polyethylene glycol, and distillation under reduced pressure was performed at 11O0C for 4 hours, while stirring. The resultant compound was diluted in 200 mL of toluene and, after adding 34.2 g (0.323 mol) of Na2CO3 and 0.6 g (0.033 mol) of water, stirring was performed for 30 minutes. After filtering, distillation under reduced pressure was performed to obtain 125 g of colorless (S)-3-hydroxytetrahydrofuran (yield = 88%, optical purity = 99.61% ee).
[81] Example 12
[82] 200 g (1.613 mol) of (S)-4-chloro-l,3-butanediol prepared in Example 1 was added to 600 g of polyethylene glycol dimethyl ether, and distillation under reduced pressure was performed at 11O0C for 5 hours, while stirring. The resultant compound was diluted in 200 mL of toluene and, after adding 34.2 g (0.323 mol) of Na2CO3 and 0.6 g (0.033 mol) of water, stirring was performed for 30 minutes. After filtering, distillation under reduced pressure was performed to obtain 126 g of colorless (S )-3-hydroxytetrahydrofuran (yield = 90%, optical purity = 99.46% ee).
[83] Example 13
[84] 200 g (1.613 mol) of (S)-4-chloro-l,3-butanediol prepared in Example 1 was added to 600 g of polypropylene glycol monobutyl ether, and distillation under reduced pressure was performed at 11O0C for 4 hours, while stirring. The resultant compound was diluted in 200 mL of toluene and, after adding 34.2 g (0.323 mol) of Na2CO3 and 0.6 g (0.033 mol) of water, stirring was performed for 30 minutes. After filtering, distillation under reduced pressure was performed to obtain 123 g of colorless (S )-3-hydroxytetrahydrofuran (yield = 86%, optical purity = 99.45% ee).
[85] Example 14
[86] 800 mL of toluene and 197.5 g (1.951 mol) of triethylamine were added to 220 g
(1.774 mol) of (S)-4-chloro-l,3-butanediol prepared in Example 1, and stirring was
performed for 16 hours under reflux. The reaction mixture was cooled to room temperature and filtered to remove solid. After recovering the solvent by concentrating under reduced pressure, the residue was further distilled under reduced pressure to obtain 136 g of colorless (S) -3 -hydroxy tetrahydrofuran (yield = 87%, optical purity = 99.5% ee).
[87] Example 15
[88] 700 mL of toluene and 149 g (1.774 mol) of NaHCO3 were added to 200 g (1.613 mol) of (S)-4-chloro-l,3-butanediol prepared in Example 1, and stirring was performed for 16 hours under reflux. The reaction mixture was cooled to room temperature and filtered to remove solid. After recovering the solvent by concentrating under reduced pressure, the residue was further distilled under reduced pressure to obtain 121 g of colorless (S)-3-hydroxytetrahydrofuran (yield = 85%, overall yield = 83%, optical purity = 99.54% ee).
[89] Example 16
[90] 61.5 g (1.626 mol) of sodium borohydride was dissolved in 694 mL of toluene, and
275.6 g (1.807 mol, 99.3% ee) of methyl (S)-4-chloro-3-hydroxybutyrate was added. After adding 52 g (1.626 mol) of methanol drop wise at room temperature for 1 hour, stirring was performed at room temperature for 12 hours. The reaction mixture was cooled below 1O0C and, after adding 183 g of 36% HCl dropwise, the solvent was removed by distillation under reduced pressure below 4O0C. Using 800 mL of methanol, concentration under reduced pressure was performed below 4O0C for 3 times. 800 mL of dichloromethane was added to the resultant residue. After filtering off solid inorganic materials, the solvent was removed under reduced pressure to obtain 220 g of (S)-4-chloro-l,3-butanediol as oil (yield = 98%).
[91] Example 17
[92] 800 mL of toluene was added to 22O g (1.774 mol) of (S)-4-chloro- 1 ,3-butanediol prepared in Example 16, and stirring was performed for 16 hours under reflux. The reaction mixture was cooled below 1O0C and, after adding 37.6 g (0.355 mol) of Na2 CO3 and 1 g (0.055 mol) of water, stirring was further performed for 30 minutes. After filtering off solid inorganic materials, the solvent was recovered by distillation under reduced pressure. The residue was further distilled under reduced pressure to obtain 136 g of colorless (S)-3-hydroxytetrahydrofuran (yield = 87%, optical purity = 99.5% ee).
[93] The invention has been described in detail with reference to preferred embodiments thereof. However, it will be appreciated by those skilled in the art that changes may be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims
[1] A process for the preparation of 3 -hydroxy tetrahydrofuran represented by formula 1, which comprises cyclizing 4-halo-l,3-butanediol represented by formula 2 either neat or in an organic solvent, by heating to from 750C to 18O0C: formula 1
[2] The process of claim 1, wherein the cyclization is performed in the presence of a base.
[3] The process of claim 1, wherein the cyclization is performed at 9O0C to 15O0C.
[4] The process of claim 1, wherein the cyclization is performed at 1000C to 13O0C.
[5] The process of claim 1, wherein the organic solvent used in the cyclization has a boiling point in a range of from 750C to 15O0C or from 21O0C to 6000C.
[6] The process of claim 1, wherein the 4-halo-3-hydroxybutyric ester represented by formula 2 is optically active.
[7] The process of claim 1, wherein the organic solvent used in the cyclization is benzene, toluene, xylene, C2-C4 alcohol, 1,2-dichloroethane, ethyl acetate, 1,4-dioxane, polyethylene glycol, polyethylene glycol butyl ether, polyethylene glycol dimethyl ether, polyethylene glycol methyl ether, polypropylene glycol, polypropylene glycol monobutyl ether, diphenyl ether, dibenzyl ether, phenyl sulfone or phenyl sulfoxide.
[8] The process of claim 7, wherein the organic solvent used in the cyclization is toluene, xylene, C3-C4 alcohol, polyethylene glycol, polyethylene glycol butyl ether, polyethylene glycol dimethyl ether, polyethylene glycol methyl ether, polypropylene glycol, polypropylene glycol monobutyl ether, diphenyl ether, dibenzyl ether, phenyl sulfone or phenyl sulfoxide.
[9] The process of claim 1, wherein the cyclization is performed neat without using a solvent.
[10] The process of claim 1, which comprises: a) reducing 4-halo-3-hydroxybutyric ester represented by formula 3 to obtain 4-halo-l,3-butanediol represented by formula 2; b) cyclizing the compound represented by formula 2 either neat or in an organic
solvent, by heating to from 750C to 18O0C; and c) recovering 3 -hydroxy tetrahydrofuran represented by formula 1 from a reaction mixture of the step b): formula 1
OH X^^C°0R wherein * represents a chiral center, X is a halogen atom (F, Cl, Br or I) and R is an ester forming group.
[11] The process of claim 10, wherein the reduction in the step a) is performed in the presence of M(BH4)n (where M is an alkali metal or an alkaline earth metal, and n is 1 or 2) or a mixture thereof with methanol.
[12] The process of claim 11, wherein said M is sodium and the proportion of M(BH4
)n : methanol is from 1:0.5 to 1:2.
[13] The process of claim 10, wherein said R is Ci-C4 alkyl.
[14] The process of claim 13, wherein said R is ethyl or methyl.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102477019A (en) * | 2010-11-26 | 2012-05-30 | 苏州凯达生物医药技术有限公司 | Novel method for preparing S-3-hydroxytetrahydrofuran |
| WO2016021192A1 (en) * | 2014-08-08 | 2016-02-11 | Eisai R&D Management Co., Ltd. | Process for production of (s)-(tetrahydrofuran-3-yl)hydrazine |
| CN105669608A (en) * | 2016-02-29 | 2016-06-15 | 苏州艾缇克药物化学有限公司 | Preparing method of (S)-3-hydroxy tetrahydrofuran |
| CN113956130A (en) * | 2021-11-23 | 2022-01-21 | 东莞理工学院 | Synthetic method of R- (-) -1, 3-butanediol |
| CN114195743A (en) * | 2021-12-02 | 2022-03-18 | 厦门弘毅元素科技有限公司 | Synthesis method of (S) -3-hydroxytetrahydrofuran |
| CN115611829A (en) * | 2021-07-13 | 2023-01-17 | 中化医药有限公司 | Preparation method of (S) -3-hydroxytetrahydrofuran |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5780649A (en) * | 1995-09-08 | 1998-07-14 | Takasago International Corporation | Process for preparing optically active cyclic compounds |
| WO2000063199A1 (en) * | 1999-04-15 | 2000-10-26 | Kaneka Corporation | Process for the preparation of 3-hydroxytetrahydrofuran |
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- 2007-02-01 KR KR1020070010639A patent/KR100877849B1/en active IP Right Grant
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| US5780649A (en) * | 1995-09-08 | 1998-07-14 | Takasago International Corporation | Process for preparing optically active cyclic compounds |
| WO2000063199A1 (en) * | 1999-04-15 | 2000-10-26 | Kaneka Corporation | Process for the preparation of 3-hydroxytetrahydrofuran |
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| YUASA Y. AND TSURUTA H.: "Practical Sytheses of (S)-4-Hydroxytetrahydrofuran-2-one, (S)-3-Hydroxytetrahydrofuran and Their (R)-Enantiomers", LIEBIGS ANNALEN / RECUEIL, vol. 9, 1997, pages 1877 - 1879, XP002929637 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102477019A (en) * | 2010-11-26 | 2012-05-30 | 苏州凯达生物医药技术有限公司 | Novel method for preparing S-3-hydroxytetrahydrofuran |
| WO2016021192A1 (en) * | 2014-08-08 | 2016-02-11 | Eisai R&D Management Co., Ltd. | Process for production of (s)-(tetrahydrofuran-3-yl)hydrazine |
| CN105669608A (en) * | 2016-02-29 | 2016-06-15 | 苏州艾缇克药物化学有限公司 | Preparing method of (S)-3-hydroxy tetrahydrofuran |
| CN115611829A (en) * | 2021-07-13 | 2023-01-17 | 中化医药有限公司 | Preparation method of (S) -3-hydroxytetrahydrofuran |
| CN113956130A (en) * | 2021-11-23 | 2022-01-21 | 东莞理工学院 | Synthetic method of R- (-) -1, 3-butanediol |
| CN113956130B (en) * | 2021-11-23 | 2023-12-19 | 东莞理工学院 | Synthetic method of R- (-) -1, 3-butanediol |
| CN114195743A (en) * | 2021-12-02 | 2022-03-18 | 厦门弘毅元素科技有限公司 | Synthesis method of (S) -3-hydroxytetrahydrofuran |
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| KR100877849B1 (en) | 2009-01-15 |
| KR20080072206A (en) | 2008-08-06 |
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