US20020032353A1 - Process for preparing 3-hydroxybenzyl alcohol - Google Patents
Process for preparing 3-hydroxybenzyl alcohol Download PDFInfo
- Publication number
- US20020032353A1 US20020032353A1 US09/949,214 US94921401A US2002032353A1 US 20020032353 A1 US20020032353 A1 US 20020032353A1 US 94921401 A US94921401 A US 94921401A US 2002032353 A1 US2002032353 A1 US 2002032353A1
- Authority
- US
- United States
- Prior art keywords
- carboxylic acid
- chloroformate
- alcohol
- process according
- mol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- OKVJCVWFVRATSG-UHFFFAOYSA-N 3-hydroxybenzyl alcohol Chemical compound OCC1=CC=CC(O)=C1 OKVJCVWFVRATSG-UHFFFAOYSA-N 0.000 title claims abstract description 77
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 25
- 150000001734 carboxylic acid salts Chemical class 0.000 claims abstract description 25
- HTKPPYYBNUEPML-UHFFFAOYSA-N [3-(chloromethyl)phenyl] carbonochloridate Chemical compound ClCC1=CC=CC(OC(Cl)=O)=C1 HTKPPYYBNUEPML-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000006136 alcoholysis reaction Methods 0.000 claims abstract description 18
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 3
- 150000005690 diesters Chemical class 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 230000008569 process Effects 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 claims description 14
- GQLSEYOOXBRDFZ-UHFFFAOYSA-N 2-pyridin-3-ylpyrrolidine-1-carbaldehyde Chemical compound O=CN1CCCC1C1=CC=CN=C1 GQLSEYOOXBRDFZ-UHFFFAOYSA-N 0.000 claims description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 5
- PLCRZQUPBNZBHN-UHFFFAOYSA-N [3-(dichloromethyl)phenyl] carbonochloridate Chemical class ClC(Cl)C1=CC=CC(OC(Cl)=O)=C1 PLCRZQUPBNZBHN-UHFFFAOYSA-N 0.000 claims description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims 1
- -1 lithium aluminum hydride Chemical compound 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 239000000203 mixture Substances 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 150000001298 alcohols Chemical class 0.000 description 8
- 150000001735 carboxylic acids Chemical class 0.000 description 7
- 238000010626 work up procedure Methods 0.000 description 7
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 6
- IJFXRHURBJZNAO-UHFFFAOYSA-N 3-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC(O)=C1 IJFXRHURBJZNAO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 235000011054 acetic acid Nutrition 0.000 description 6
- 150000001733 carboxylic acid esters Chemical class 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 5
- 125000001931 aliphatic group Chemical group 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-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
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229910052784 alkaline earth metal Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical group OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
- 239000000920 calcium hydroxide Substances 0.000 description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 2
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 2
- 239000000347 magnesium hydroxide Substances 0.000 description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 2
- 150000002736 metal compounds Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 150000003018 phosphorus compounds Chemical class 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 239000010936 titanium Substances 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
- OFTGOQQEEHLKBY-UHFFFAOYSA-N (3-hydroxyphenyl)methyl formate Chemical compound OC1=CC=CC(COC=O)=C1 OFTGOQQEEHLKBY-UHFFFAOYSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- RELMFMZEBKVZJC-UHFFFAOYSA-N 1,2,3-trichlorobenzene Chemical class ClC1=CC=CC(Cl)=C1Cl RELMFMZEBKVZJC-UHFFFAOYSA-N 0.000 description 1
- VTBOTOBFGSVRMA-UHFFFAOYSA-N 1-Methylcyclohexanol Chemical class CC1(O)CCCCC1 VTBOTOBFGSVRMA-UHFFFAOYSA-N 0.000 description 1
- NHWQMJMIYICNBP-UHFFFAOYSA-N 2-chlorobenzonitrile Chemical compound ClC1=CC=CC=C1C#N NHWQMJMIYICNBP-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- OOQLHRQZISYCMS-UHFFFAOYSA-N 3-[(2-nitrophenyl)sulfanyloxymethyl]phenol Chemical compound OC1=CC=CC(COSC=2C(=CC=CC=2)[N+]([O-])=O)=C1 OOQLHRQZISYCMS-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical group OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical class ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- OHJMTUPIZMNBFR-UHFFFAOYSA-N biuret Chemical compound NC(=O)NC(N)=O OHJMTUPIZMNBFR-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical class B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 150000001639 boron compounds Chemical class 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 150000005753 chloropyridines Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 150000001896 cresols Chemical class 0.000 description 1
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 150000004816 dichlorobenzenes Chemical class 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- 238000005868 electrolysis reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000003622 immobilized catalyst Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- MJGFBOZCAJSGQW-UHFFFAOYSA-N mercury sodium Chemical compound [Na].[Hg] MJGFBOZCAJSGQW-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229950006238 nadide Drugs 0.000 description 1
- 150000004780 naphthols Chemical class 0.000 description 1
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- CQRYARSYNCAZFO-UHFFFAOYSA-N o-hydroxybenzyl alcohol Natural products OCC1=CC=CC=C1O CQRYARSYNCAZFO-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- BVJSUAQZOZWCKN-UHFFFAOYSA-N p-hydroxybenzyl alcohol Chemical compound OCC1=CC=C(O)C=C1 BVJSUAQZOZWCKN-UHFFFAOYSA-N 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910001023 sodium amalgam Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003464 sulfur compounds Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FAGUFWYHJQFNRV-UHFFFAOYSA-N tetraethylenepentamine Chemical compound NCCNCCNCCNCCN FAGUFWYHJQFNRV-UHFFFAOYSA-N 0.000 description 1
- 229910052716 thallium Inorganic materials 0.000 description 1
- BKVIYDNLLOSFOA-UHFFFAOYSA-N thallium Chemical compound [Tl] BKVIYDNLLOSFOA-UHFFFAOYSA-N 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003739 xylenols Chemical class 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
- C07C67/11—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond being mineral ester groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/001—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
- C07C37/0555—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group being esterified hydroxy groups
Definitions
- the present invention relates to a process for preparing 3-hydroxybenzyl alcohol from 3-chloromethylphenyl chloroformate.
- 3-Hydroxybenzyl alcohol is a valuable intermediate for the preparation of pharmaceutical active compounds.
- 3-hydroxybenzoic acid can be reduced using lithium aluminum hydride, using organic aluminum or boron compounds, or by means of electrolysis to give 3-hydroxybenzyl alcohol.
- a similar reaction is the reduction of 3-hydroxybenzoic esters to 3-hydroxybenzyl alcohol, which can be carried out using aluminum hydrides or boron hydrides.
- a disadvantage of all of these processes is that relatively expensive materials such as 3-hydroxybenzoic acid, 3-hydroxybenzaldehyde, or derivatives thereof have to be used as starting material.
- the 3-chloromethylphenyl chloroformate to be used according to the invention is known from the literature. It can be obtained, for example, by phosgenation of m-cresol and subsequent side-chain chlorination of the resulting 3-methylphenyl chloroformate.
- catalysts for the phosgenation it is possible to use, for example, dimethylformamide and phosphorus compounds such as triphenylphosphine.
- Additives that can be used in the side-chain chlorination of the 3-methylphenyl chloroformate are, for example, pyridine, pyridine derivatives such as methylpyridines or chloropyridines, amides such as acetamide or benzamide, biuret, urea, cyclic lactams, urethanes, amines or polyamines such as urotropin, ethanolamine, or tetraethylenepentamine, phosphorus compounds such as phosphorus trichloride or phosphorus pentachloride, or sulfur compounds such as diaryl sulfides and diary disulfides.
- pyridine pyridine derivatives such as methylpyridines or chloropyridines
- amides such as acetamide or benzamide
- biuret urea
- cyclic lactams urethanes
- amines or polyamines such as urotropin, ethanolamine, or tetraethylenepentamine
- chlorinating agent in the side-chain chlorination of 3-methylphenyl chloroformate it is possible to use, for example, chlorine or sulfuryl chloride.
- the process of the invention is advantageously carried out using 3-chloromethylphenyl chloroformate containing less than 1% by weight of 3-methylphenyl chloroformate that has not been chlorinated in the side chain and less than 5% by weight of more highly chlorinated 3-bischloromethylphenyl chloroformate.
- the 3-chloromethylphenyl chloroformate is, according to the invention, acidolyzed using a carboxylic acid or a carboxylic acid salt.
- the product of this reaction is the diester of 3-hydroxybenzyl alcohol with the carboxylic acid used.
- aliphatic carboxylic acids are, for example, carboxylic acids having linear or branched alkyl radicals having from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms. Examples that may be mentioned are formic acid, acetic acid, propionic acid, butyric acid, and 2-methylpropionic acid.
- Suitable cycloaliphatic carboxylic acids are, for example, those having from 4 to 11 carbon atoms, preferably from 4 to 7 carbon atoms. Examples that may be mentioned are cyclopropanecarboxylic acid, cyclopentanecarboxylic acid, and cyclohexanecarboxylic acid.
- Aromatic carboxylic acids that can be used are, for example, those having from 7 to 12 carbon atoms, preferably from 7 to 10 carbon atoms.
- An example that may be mentioned is benzoic acid.
- the aliphatic and cycloaliphatic carboxylic acids may optionally bear, for example, from one to three additional substituents, for example, halogen atoms such as fluorine, chlorine, and/or bromine, preferably fluorine and/or chlorine.
- additional substituents for example, halogen atoms such as fluorine, chlorine, and/or bromine, preferably fluorine and/or chlorine.
- the aromatic carboxylic acids can likewise bear, for example, from one to three substituents, for example, halogen atoms such as fluorine, chlorine, and/or bromine and/or C 1 -C 6 -alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, hexyl, and/or cyclohexyl.
- substituents for example, halogen atoms such as fluorine, chlorine, and/or bromine and/or C 1 -C 6 -alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, hexyl, and/or cyclohexyl.
- carboxylic acid salts it is possible to use, for example, salts of alkali metals and alkaline earth metals and ammonium salts. Preference is given to alkali metal salts such as sodium salts and ammonium salts.
- the acid part of the carboxylic acid salts can correspond to the above-described aliphatic, cycloaliphatic, and aromatic carboxylic acids.
- carboxylic acid and/or carboxylic acid salt depends on the way in which the reactants 3-chloromethylphenyl chloroformate and carboxylic acid and/or carboxylic acid salt are brought into contact.
- liquid carboxylic acids when used, these can advantageously also serve as solvents for the acidolysis reaction, and in this case preference is thus given to using from 1 to 20 mol of carboxylic acid (particularly from 1 to 10 mol of carboxylic acid) and from 1 to 5 mol of carboxylic acid salt (particularly from 1 to 2 mol of carboxylic acid salt), in each case per mol of 3-chloromethylphenyl chloroformate.
- the carboxylic acid salt is brought directly into contact with 3-chloromethylphenyl chloroformate in the presence or absence of a carboxylic acid, 1 mol of carboxylic acid salt is consumed by the acidolysis of the chloroformate group and 1 mol is consumed by acidolysis of the chloromethyl group, so that in this case 2 mol of carboxylic acid salt are stoichiometrically required for complete acidolysis.
- preference is given to using from 2 to 5 mol of carboxylic acid salt (particularly from 2 to 3 mol of carboxylic acid salt) per 1 mol of 3-chloromethylphenyl chloroformate.
- the carboxylic acid salt can either be used as such or can be prepared in situ from a carboxylic acid and a base.
- Suitable bases are, for example, alkali metal hydroxides and alkaline earth metal hydroxides, alkali metal carbonates and alkaline earth metal carbonates, and ammonia.
- suitable bases are NaOH, KOH, LiOH, Na 2 CO 3 , K 2 CO 3 , Mg(OH) 2 , Ca(OH) 2 , and/or NH 3 . Preference is given to adding carboxylic acid salt as such.
- the reaction of 3-chloromethylphenyl chloroformate with the carboxylic acid and/or the carboxylic acid salt according to the invention can be carried out in the presence or absence of an inert solvent.
- suitable solvents are aromatic and chloroaromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, chlorotoluenes, dichlorobenzenes, and trichlorobenzenes, etherified aromatics such as anisole, substituted anisoles, and phenethole, aromatic nitrites such as benzonitrile, tolunitriles, and chlorobenzonitrile, hydrogenated aromatic hydrocarbons such as decalin, and/or aliphatic polyethers such as 1,2-dimethoxyethane.
- the acidolysis is preferably carried out in an excess of liquid carboxylic acid as solvent.
- the acidolysis according to the invention can, for example, be carried out at temperatures in the range from 20 to 200° C., preferably from 50 to 150° C.
- the pressure during the acidolysis reaction can be superatmospheric, subatmospheric, or atmospheric. Preference is given to pressures in the range from 0.9 to 3 bar.
- the diesters prepared in the first reaction step can be isolated from the reaction mixture by, for example, distillation or aqueous work-up. Any inorganic salts obtained here can be removed by washing with water and the diester can be isolated by phase separation.
- diesters of 3-hydroxybenzyl alcohol are obtained as a result of the acidolysis carried out in the first step.
- These diesters generally contain, as a result of partial hydrolysis in the aqueous work-up and/or as a result of water present in the acidolysis reaction, a certain proportion of a monoester of 3-hydroxybenzyl alcohol, but this is converted into 3-hydroxybenzyl alcohol in the same way as the diester in the subsequent alcoholysis.
- the monoester content can be, for example, up to 50% by weight.
- these diesters are converted into 3-hydroxybenzyl alcohol by reaction with an alcohol (i.e., alcoholysis).
- an alcohol i.e., alcoholysis
- Alcohols which can be used for this alcoholysis are, for example, aliphatic alcohols having from 1 to 12 carbon atoms or cycloaliphatic alcohols having from 5 to 12 carbon atoms. Preference is given to linear and branched aliphatic alcohols having from 1 to 6 carbon atoms and alcohols having from 5 to 8 carbon atoms. Examples that may be mentioned are methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, t-butanol, n-pentanol, n-hexanol, cyclohexanol, and methylcyclohexanols.
- aromatic alcohols having, for example, from 6 to 10 carbon atoms, e.g., phenol, cresols, xylenols, and naphthols, as alcohols.
- the aliphatic, cycloaliphatic, and aromatic alcohols may be substituted, for example, by halogen atoms such as fluorine, chlorine, or bromine, preferably fluorine or chlorine. If substituted, the alcohols can bear one or more substituents.
- the stoichiometrically required amount of alcohol to be used is 2 mol per mol of diester of 3-hydroxybenzyl alcohol.
- it is advantageous to shift the equilibria towards 3-hydroxybenzyl alcohol for example, by using an excess of alcohol or by removing (e.g., by distillation) the alcohol carboxylate formed, in order to achieve complete conversion into the desired 3-hydroxybenzyl alcohol.
- Catalysts that can be used are, for example, those that are known for alcoholysis of carboxylic esters, for example, bases, acids, and metal salts or metal compounds.
- bases are alkali metal hydroxides and alkaline earth metal hydroxides, alkali metal carbonates and alkaline earth metal carbonates, amines, and phosphines, particularly LiOH, NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , Mg(OH) 2 , and Ca(OH) 2 .
- acids are mineral acids, carboxylic acids, and sulfonic acids, particularly H 2 SO 4 , H 3 PO 4 , HCl, HBr, HI, acetic acid, propionic acid, and benzoic acid.
- Suitable metal salts and metal compounds are, for example, salts and compounds of thallium, tin, and titanium, e.g., TINO 3 , (butyl) 2 SnO, and Ti(O-phenyl) 4 .
- the catalysts can also be present in immobilized form, for example, in the form of basic or acidic ion exchangers that, for example, bear amine or HSO 3 functions or the appropriate metal as cation.
- Catalysts can, for example, be used in amounts of from 0.05 to 10 mol % (preferably from 0.5 to 3 mol %), based on the diester of 3-hydroxybenzyl alcohol. If relatively small amounts of catalyst within these ranges are used, the work-up of the reaction mixture from the alcoholysis is simplified.
- mol % refers to the active functional groups of the catalyst.
- the alcoholysis of the invention is preferably carried out using acidic catalysts such as H 2 SO 4 , H 3 PO 4 , HCl, Hbr, or acidic ion exchangers.
- acidic catalysts such as H 2 SO 4 , H 3 PO 4 , HCl, Hbr, or acidic ion exchangers.
- the alcoholysis of the diester of 3-hydroxybenzyl alcohol can be carried out in the presence or absence of inert solvents.
- inert solvents for example, it is possible to use the same solvents that have been mentioned above for the acidolysis of 3-chloromethylphenyl chloroformate by means of carboxylic acid and/or its salts.
- the acidolysis is preferably carried out without addition of solvents.
- Mixtures of various alcohols can also be used as alcohols and mixtures of various catalysts can be used as catalysts.
- the alcoholysis of the diester of 3-hydroxybenzyl alcohol can be carried out, for example, at temperatures in the range from 0 to 200° C., preferably from 50 to 150° C.
- the pressure in the alcoholysis reaction can be superatmospheric, subatmospheric, or atmospheric. Preference is given to atmospheric pressure, subatmospheric pressures that may be necessary for distilling off a relatively high-boiling carboxylic ester, and superatmospheric pressures that may be necessary for overcoming an azeotrope. Accordingly, the reaction pressure is, for example, from 0.01 to 10 bar, preferably from 0.1 to 5 bar.
- each of the two substeps can be carried out continuously, batchwise, or semicontinuously in portions.
- the carboxylic acid e.g., acetic acid
- the carboxylic acid salt e.g., sodium acetate
- the carboxylic acid salt is then added to the fully reacted mixture and the mixture is stirred hot. This results in acidolysis of the chloromethyl group.
- the acetic diester of 3-hydroxybenzyl alcohol is obtained after, for example, aqueous work-up.
- the carboxylic acid present as solvent is distilled from the reaction mixture and the residue obtained is stirred with water to remove the salts.
- part of the diester can be deacylated to form a monoester of hydroxybenzyl alcohol.
- This monoacylation product of 3-hydroxybenzyl alcohol is obtained in admixture with the diester. It is one of the intermediates in the subsequent alcoholysis of the diester to form 3-hydroxybenzyl alcohol, so that it is likewise converted into the desired product 3-hydroxybenzyl alcohol.
- Catalyst and an excess of alcohol are then added to the diester that has been prepared and the carboxylic ester (e.g., methyl or ethylacetate) formed is distilled off as an azeotrope with the alcohol.
- carboxylic ester e.g., methyl or ethylacetate
- further alcohol can be introduced into the reaction mixture continuously or semicontinuously in portions during the distillation to achieve complete conversion.
- the alcohol is then evaporated together with remaining carboxylic ester. The residue that remains an, if necessary, be purified by recrystallization.
- a mixture of carboxylic acid e.g., acetic acid
- its salt e.g., sodium acetate
- 3-chloromethylphenyl chloroformate is metered in hot.
- the acetic diester of 3-hydroxybenzyl alcohol is also obtained in this way and this can then be alcoholyzed as described above.
- the process of the invention has a series of advantages.
- Second, the process requires simple auxiliaries such as carboxylic acids, carboxylic acid salts, and alcohols that are available at low cost and require no particular measures in their handling. For this reason, the process of the invention enables 3-hydroxybenzyl alcohol to be obtained in a significantly simpler and cheaper way than hitherto.
- the 3-hydroxybenzyl alcohol thereby prepared could be isolated in pure form by evaporation of the methanol and recrystallization, for example, from benzene or carbon tetrachloride.
Abstract
3-Hydroxybenzyl alcohol can be prepared in a simple and inexpensive way by subjecting 3-chloromethylphenyl chloroformate to an acidolysis with a carboxylic acid or a carboxylic acid salt and subsequently subjecting the reaction product of the first step to an alcoholysis.
Description
- The present invention relates to a process for preparing 3-hydroxybenzyl alcohol from 3-chloromethylphenyl chloroformate. 3-Hydroxybenzyl alcohol is a valuable intermediate for the preparation of pharmaceutical active compounds.
- Various methods of preparing 3-hydroxybenzyl alcohol are known.
- These methods start from 3-hydroxybenzaldehyde, 3-hydroxybenzoic acid, or derivatives of these compounds. To convert them into 3-hydroxybenzyl alcohol, the starting compounds are reduced.
- For example, 3-hydroxybenzoic acid can be reduced using lithium aluminum hydride, using organic aluminum or boron compounds, or by means of electrolysis to give 3-hydroxybenzyl alcohol. A similar reaction is the reduction of 3-hydroxybenzoic esters to 3-hydroxybenzyl alcohol, which can be carried out using aluminum hydrides or boron hydrides.
- For the reduction of 3-hydroxybenzaldehyde to 3-hydroxybenzyl alcohol, it is possible to use the following reagents: lithium aluminum hydride, sodium borohydride, zinc borohydride, tin dichloride plus magnesium, sodium amalgam, or polymer-bound nicotinamide-adenine dinucleotide in the H form (NADH). This reaction can also be carried out as a catalytic hydrogenation, e.g., using Raney nickel catalysts or platinum catalysts. The catalytic reduction of benzyl ethers of 3-hydroxybenzyl alcohol is similar.
- Further methods of forming 3-hydroxybenzyl alcohol are cleavage of (3-hydroxyphenyl)methyl formate and (3-hydroxyphenyl)methyl 2-nitrobenzenesulfenate.
- A disadvantage of all of these processes is that relatively expensive materials such as 3-hydroxybenzoic acid, 3-hydroxybenzaldehyde, or derivatives thereof have to be used as starting material. In addition, it is frequently necessary to employ reducing agents or catalytic hydrogenations, which are complicated or expensive.
- There is therefore still a need for a process for preparing 3-hydroxybenzyl alcohol simply and inexpensively.
- We have now found a process for preparing 3-hydroxybenzyl alcohol comprising
- (a) subjecting 3-chloromethylphenyl chloroformate to an acidolysis with a carboxylic acid or a carboxylic acid salt, and
- (b) carrying out an alcoholysis of the reaction product of the acidolysis step.
- The 3-chloromethylphenyl chloroformate to be used according to the invention is known from the literature. It can be obtained, for example, by phosgenation of m-cresol and subsequent side-chain chlorination of the resulting 3-methylphenyl chloroformate. As catalysts for the phosgenation, it is possible to use, for example, dimethylformamide and phosphorus compounds such as triphenylphosphine. Additives that can be used in the side-chain chlorination of the 3-methylphenyl chloroformate are, for example, pyridine, pyridine derivatives such as methylpyridines or chloropyridines, amides such as acetamide or benzamide, biuret, urea, cyclic lactams, urethanes, amines or polyamines such as urotropin, ethanolamine, or tetraethylenepentamine, phosphorus compounds such as phosphorus trichloride or phosphorus pentachloride, or sulfur compounds such as diaryl sulfides and diary disulfides.
- As chlorinating agent in the side-chain chlorination of 3-methylphenyl chloroformate, it is possible to use, for example, chlorine or sulfuryl chloride.
- The process of the invention is advantageously carried out using 3-chloromethylphenyl chloroformate containing less than 1% by weight of 3-methylphenyl chloroformate that has not been chlorinated in the side chain and less than 5% by weight of more highly chlorinated 3-bischloromethylphenyl chloroformate.
- The 3-chloromethylphenyl chloroformate is, according to the invention, acidolyzed using a carboxylic acid or a carboxylic acid salt. The product of this reaction is the diester of 3-hydroxybenzyl alcohol with the carboxylic acid used.
- According to the invention, a broad range of aliphatic, cycloaliphatic, and aromatic carboxylic acids can be used as carboxylic acid. Suitable aliphatic carboxylic acids are, for example, carboxylic acids having linear or branched alkyl radicals having from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms. Examples that may be mentioned are formic acid, acetic acid, propionic acid, butyric acid, and 2-methylpropionic acid.
- Suitable cycloaliphatic carboxylic acids are, for example, those having from 4 to 11 carbon atoms, preferably from 4 to 7 carbon atoms. Examples that may be mentioned are cyclopropanecarboxylic acid, cyclopentanecarboxylic acid, and cyclohexanecarboxylic acid.
- Aromatic carboxylic acids that can be used are, for example, those having from 7 to 12 carbon atoms, preferably from 7 to 10 carbon atoms. An example that may be mentioned is benzoic acid.
- The aliphatic and cycloaliphatic carboxylic acids may optionally bear, for example, from one to three additional substituents, for example, halogen atoms such as fluorine, chlorine, and/or bromine, preferably fluorine and/or chlorine.
- The aromatic carboxylic acids can likewise bear, for example, from one to three substituents, for example, halogen atoms such as fluorine, chlorine, and/or bromine and/or C1-C6-alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, hexyl, and/or cyclohexyl.
- As carboxylic acid salts, it is possible to use, for example, salts of alkali metals and alkaline earth metals and ammonium salts. Preference is given to alkali metal salts such as sodium salts and ammonium salts. The acid part of the carboxylic acid salts can correspond to the above-described aliphatic, cycloaliphatic, and aromatic carboxylic acids.
- The amount of carboxylic acid and/or carboxylic acid salt to be used depends on the way in which the reactants 3-chloromethylphenyl chloroformate and carboxylic acid and/or carboxylic acid salt are brought into contact.
- If, for example, only one carboxylic acid is brought into contact with 3-chloromethylphenyl chloroformate, only the chloroformate group reacts with the carboxylic acid and the chloromethyl group remains largely unaltered. The chloromethyl group can then also be reacted by subsequent addition of carboxylic acid salt. The stoichiometrically required amounts of carboxylic acid and carboxylic acid salt are in this case each time 1 mol per mol of 3-chloromethylphenyl chloroformate. When liquid carboxylic acids are used, these can advantageously also serve as solvents for the acidolysis reaction, and in this case preference is thus given to using from 1 to 20 mol of carboxylic acid (particularly from 1 to 10 mol of carboxylic acid) and from 1 to 5 mol of carboxylic acid salt (particularly from 1 to 2 mol of carboxylic acid salt), in each case per mol of 3-chloromethylphenyl chloroformate.
- If, for example, the carboxylic acid salt is brought directly into contact with 3-chloromethylphenyl chloroformate in the presence or absence of a carboxylic acid, 1 mol of carboxylic acid salt is consumed by the acidolysis of the chloroformate group and 1 mol is consumed by acidolysis of the chloromethyl group, so that in this case 2 mol of carboxylic acid salt are stoichiometrically required for complete acidolysis. In this case, preference is given to using from 2 to 5 mol of carboxylic acid salt (particularly from 2 to 3 mol of carboxylic acid salt) per 1 mol of 3-chloromethylphenyl chloroformate.
- The carboxylic acid salt can either be used as such or can be prepared in situ from a carboxylic acid and a base. Suitable bases are, for example, alkali metal hydroxides and alkaline earth metal hydroxides, alkali metal carbonates and alkaline earth metal carbonates, and ammonia. Examples of suitable bases are NaOH, KOH, LiOH, Na2CO3, K2CO3, Mg(OH)2, Ca(OH)2, and/or NH3. Preference is given to adding carboxylic acid salt as such.
- It is also possible to use mixtures of various carboxylic acids and various carboxylic acid salts. However, preference is given to using one carboxylic acid and one of its salts.
- The reaction of 3-chloromethylphenyl chloroformate with the carboxylic acid and/or the carboxylic acid salt according to the invention can be carried out in the presence or absence of an inert solvent. Examples of suitable solvents are aromatic and chloroaromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, chlorotoluenes, dichlorobenzenes, and trichlorobenzenes, etherified aromatics such as anisole, substituted anisoles, and phenethole, aromatic nitrites such as benzonitrile, tolunitriles, and chlorobenzonitrile, hydrogenated aromatic hydrocarbons such as decalin, and/or aliphatic polyethers such as 1,2-dimethoxyethane.
- The acidolysis is preferably carried out in an excess of liquid carboxylic acid as solvent.
- The acidolysis according to the invention can, for example, be carried out at temperatures in the range from 20 to 200° C., preferably from 50 to 150° C.
- The pressure during the acidolysis reaction can be superatmospheric, subatmospheric, or atmospheric. Preference is given to pressures in the range from 0.9 to 3 bar.
- The diesters prepared in the first reaction step can be isolated from the reaction mixture by, for example, distillation or aqueous work-up. Any inorganic salts obtained here can be removed by washing with water and the diester can be isolated by phase separation.
- According to the invention, diesters of 3-hydroxybenzyl alcohol are obtained as a result of the acidolysis carried out in the first step. These diesters generally contain, as a result of partial hydrolysis in the aqueous work-up and/or as a result of water present in the acidolysis reaction, a certain proportion of a monoester of 3-hydroxybenzyl alcohol, but this is converted into 3-hydroxybenzyl alcohol in the same way as the diester in the subsequent alcoholysis. The monoester content can be, for example, up to 50% by weight.
- According to the invention, these diesters are converted into 3-hydroxybenzyl alcohol by reaction with an alcohol (i.e., alcoholysis).
- Alcohols which can be used for this alcoholysis are, for example, aliphatic alcohols having from 1 to 12 carbon atoms or cycloaliphatic alcohols having from 5 to 12 carbon atoms. Preference is given to linear and branched aliphatic alcohols having from 1 to 6 carbon atoms and alcohols having from 5 to 8 carbon atoms. Examples that may be mentioned are methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, t-butanol, n-pentanol, n-hexanol, cyclohexanol, and methylcyclohexanols.
- It is also possible to use aromatic alcohols having, for example, from 6 to 10 carbon atoms, e.g., phenol, cresols, xylenols, and naphthols, as alcohols.
- The aliphatic, cycloaliphatic, and aromatic alcohols may be substituted, for example, by halogen atoms such as fluorine, chlorine, or bromine, preferably fluorine or chlorine. If substituted, the alcohols can bear one or more substituents.
- The stoichiometrically required amount of alcohol to be used is 2 mol per mol of diester of 3-hydroxybenzyl alcohol. However, since equilibria between the diester, the two monodeacylated intermediates, 3-hydroxybenzyl alcohol, the alcohol added, and the respective carboxylic ester of the alcohol are generally established, it is advantageous to shift the equilibria towards 3-hydroxybenzyl alcohol, for example, by using an excess of alcohol or by removing (e.g., by distillation) the alcohol carboxylate formed, in order to achieve complete conversion into the desired 3-hydroxybenzyl alcohol. Since in the case of removal of alcohol carboxylate by distillation, azeotropes composed of the alcohol and its carboxylic ester are frequently present, it is advantageous in both cases to use the alcohol in excess, for example, in amounts of from 2.1 to 20 mol (preferably from 2.5 to 10 mol) per mol of diester of 3-hydroxybenzyl alcohol.
- To accelerate the alcoholysis of the diester, catalysts can be added. Catalysts that can be used are, for example, those that are known for alcoholysis of carboxylic esters, for example, bases, acids, and metal salts or metal compounds. Examples of suitable bases are alkali metal hydroxides and alkaline earth metal hydroxides, alkali metal carbonates and alkaline earth metal carbonates, amines, and phosphines, particularly LiOH, NaOH, KOH, Na2CO3, K2CO3, Mg(OH)2, and Ca(OH)2. Examples of acids are mineral acids, carboxylic acids, and sulfonic acids, particularly H2SO4, H3PO4, HCl, HBr, HI, acetic acid, propionic acid, and benzoic acid. Suitable metal salts and metal compounds are, for example, salts and compounds of thallium, tin, and titanium, e.g., TINO3, (butyl)2SnO, and Ti(O-phenyl)4.
- The catalysts can also be present in immobilized form, for example, in the form of basic or acidic ion exchangers that, for example, bear amine or HSO3 functions or the appropriate metal as cation.
- Catalysts can, for example, be used in amounts of from 0.05 to 10 mol % (preferably from 0.5 to 3 mol %), based on the diester of 3-hydroxybenzyl alcohol. If relatively small amounts of catalyst within these ranges are used, the work-up of the reaction mixture from the alcoholysis is simplified.
- In the case of immobilized catalysts, the term mol % refers to the active functional groups of the catalyst.
- The alcoholysis of the invention is preferably carried out using acidic catalysts such as H2SO4, H3PO4, HCl, Hbr, or acidic ion exchangers.
- The alcoholysis of the diester of 3-hydroxybenzyl alcohol can be carried out in the presence or absence of inert solvents. For example, it is possible to use the same solvents that have been mentioned above for the acidolysis of 3-chloromethylphenyl chloroformate by means of carboxylic acid and/or its salts. However, the acidolysis is preferably carried out without addition of solvents.
- Mixtures of various alcohols can also be used as alcohols and mixtures of various catalysts can be used as catalysts.
- The alcoholysis of the diester of 3-hydroxybenzyl alcohol can be carried out, for example, at temperatures in the range from 0 to 200° C., preferably from 50 to 150° C.
- The pressure in the alcoholysis reaction can be superatmospheric, subatmospheric, or atmospheric. Preference is given to atmospheric pressure, subatmospheric pressures that may be necessary for distilling off a relatively high-boiling carboxylic ester, and superatmospheric pressures that may be necessary for overcoming an azeotrope. Accordingly, the reaction pressure is, for example, from 0.01 to 10 bar, preferably from 0.1 to 5 bar.
- The process of the invention can be carried out in various embodiments. In principle, each of the two substeps can be carried out continuously, batchwise, or semicontinuously in portions.
- In a preferred embodiment, the carboxylic acid (e.g., acetic acid) is placed in the reaction vessel and heated to reflux temperature, and 3-chloromethylphenyl chloroformate is then metered in while stirring, with essentially only the chloroformate group being acidolyzed. The carboxylic acid salt (e.g., sodium acetate) is then added to the fully reacted mixture and the mixture is stirred hot. This results in acidolysis of the chloromethyl group. In this way, the acetic diester of 3-hydroxybenzyl alcohol is obtained after, for example, aqueous work-up.
- In the aqueous work-up, for example, the carboxylic acid present as solvent is distilled from the reaction mixture and the residue obtained is stirred with water to remove the salts.
- As a result of hydrolysis during this work-up, and also as a result of hydrolysis by water that may be present in the acidolysis reaction, part of the diester can be deacylated to form a monoester of hydroxybenzyl alcohol. This monoacylation product of 3-hydroxybenzyl alcohol is obtained in admixture with the diester. It is one of the intermediates in the subsequent alcoholysis of the diester to form 3-hydroxybenzyl alcohol, so that it is likewise converted into the desired product 3-hydroxybenzyl alcohol.
- Catalyst and an excess of alcohol (e.g., methanol or ethanol) are then added to the diester that has been prepared and the carboxylic ester (e.g., methyl or ethylacetate) formed is distilled off as an azeotrope with the alcohol. If desired, further alcohol can be introduced into the reaction mixture continuously or semicontinuously in portions during the distillation to achieve complete conversion. After the reaction, the alcohol is then evaporated together with remaining carboxylic ester. The residue that remains an, if necessary, be purified by recrystallization.
- In another preferred embodiment, a mixture of carboxylic acid (e.g., acetic acid) and its salt (e.g., sodium acetate) is placed in a reaction vessel and 3-chloromethylphenyl chloroformate is metered in hot. After complete reaction and aqueous work-up, the acetic diester of 3-hydroxybenzyl alcohol is also obtained in this way and this can then be alcoholyzed as described above.
- Due to the change to a completely novel starting material for this purpose, the process of the invention has a series of advantages. First, readily available and inexpensive 3-chloromethylphenyl chloroformate is used as starting material. Second, the process requires simple auxiliaries such as carboxylic acids, carboxylic acid salts, and alcohols that are available at low cost and require no particular measures in their handling. For this reason, the process of the invention enables 3-hydroxybenzyl alcohol to be obtained in a significantly simpler and cheaper way than hitherto.
- The following example further illustrates details for the process of this invention. The invention, which is set forth in the foregoing disclosure, is not to be limited either in spirit or scope by this example. Those skilled in the art will readily understand that known variations of the conditions of the following procedure can be used. Unless otherwise noted, all temperatures are degrees Celsius and all percentages are percentages by weight.
- 100 parts by weight of acetic acid were placed in a reaction vessel and stirred at 120° C. 60.3 parts by weight of 3-chloromethylphenyl chloroformate (assay according to GC area: 98.0%) were then metered in over a period of 1 hour. The mixture was then stirred for another 1 hour at 120-125° C., after which it was cooled to 80° C. 31.9 parts by weight of sodium acetate were then added while stirring and the mixture was stirred under reflux for another 7 hours. After the major part of the acetic acid still present had been distilled off, first at atmospheric pressure and finally under reduced pressure down to 22 mbar, the residue was taken up in 100 parts by weight of water, and the organic phase was separated off and washed once more with 22 parts by weight of water. The aqueous phases were discarded. This gave 58.2 parts by weight of an oily product that, according to GC analysis, contained 78.3% of the acetic diester of 3-hydroxybenzyl alcohol and 19.2% of a monoacetylated derivative of 3-hydroxybenzyl alcohol.
- This mixture was admixed with 55.4 parts by weight of methanol and 0.58 parts by weight of concentrated sulfuric acid and refluxed in a column (10 theoretical plates). Over a period of 4 hours, 75 parts by eight of methanol/methyl acetate azeotrope were taken off and the same amount of methanol was added to the reaction mixture in the bottom of the column. This gave 104.8 parts by weight of a methanolic solution of 3-hydroxybenzyl alcohol containing 32.2% of 3-hydroxybenzyl alcohol (HPLC). The yield was thus 94.4% of theory based on the amount of 3-chloromethylphenyl chloroformate used.
- The 3-hydroxybenzyl alcohol thereby prepared could be isolated in pure form by evaporation of the methanol and recrystallization, for example, from benzene or carbon tetrachloride.
Claims (10)
1. A process for preparing 3-hydroxybenzyl alcohol comprising
(a) subjecting 3-chloromethylphenyl chloroformate to an acidolysis with a carboxylic acid or a carboxylic acid salt, and
(b) carrying out an alcoholysis of the reaction product of the acidolysis step.
2. A process according to claim 1 wherein the 3-chloromethylphenyl chloroformate contains less than 1 % by weight of 3-methylphenyl chloroformate that has not been chlorinated in the side chain and less than 5% by weight of more highly chlorinated 3-bischloromethylphenyl chloroformate.
3. A process according to claim 1 wherein the acidolysis is carried out using (i) a carboxylic acid containing linear or branched alkyl radicals having from 1 to 12 carbon atoms or (ii) a cycloaliphatic carboxylic acid containing from 4 to 11 carbon atoms or (ii) an aromatic carboxylic acid containing from 7 to 12 carbon atoms.
4. A process according to claim 1 wherein 1 to 20 mol of a carboxylic acid is brought into contact with 3-chloromethylphenyl chloroformate and 1 to 5 mol of a carboxylic acid salt is subsequently added.
5. A process according to claim 1 wherein 2 to 5 mol of a carboxylic acid salt is brought directly into contact with 3-chloromethylphenyl chloroformate.
6. A process according to claim 1 wherein the acidolysis is carried out at temperatures in the range from 20 to 200° C. and pressures in the range from 0.9 to 3 bar.
7. A process according to claim 1 wherein the alcoholysis is carried out using an aliphatic alcohol having from 1 to 18 carbon atoms, a cycloaliphatic alcohol having from 5 to 12 carbon atoms, or an aromatic alcohol having from 6 to 11 carbon atoms.
8. A process according to claim 1 wherein the alcoholysis is carried out using from 2.1 to 20 mol of an alcohol per 1 mol of the diester of 3-hydroxybenzyl alcohol formed in the first step.
9. A process according to claim 1 wherein the alcoholysis is carried out in the presence of a catalyst.
10. A process according to claim 1 wherein the alcoholysis is carried out at temperatures in the range from 0 to 200° C. and at pressures in the range from 0.01 to 10 bar.
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Application Number | Priority Date | Filing Date | Title |
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DE10044910.7 | 2000-09-12 | ||
DE10044910A DE10044910A1 (en) | 2000-09-12 | 2000-09-12 | Process for the preparation of 3-hydroxybenzyl alcohol |
DE10044910 | 2000-09-12 |
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US20020032353A1 true US20020032353A1 (en) | 2002-03-14 |
US6380441B1 US6380441B1 (en) | 2002-04-30 |
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US09/949,214 Expired - Fee Related US6380441B1 (en) | 2000-09-12 | 2001-09-07 | Process for preparing 3-hydroxybenzyl alcohol |
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US (1) | US6380441B1 (en) |
EP (1) | EP1186587A1 (en) |
JP (1) | JP2002114726A (en) |
DE (1) | DE10044910A1 (en) |
HU (1) | HUP0103642A3 (en) |
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US3420868A (en) * | 1963-08-29 | 1969-01-07 | Hooker Chemical Corp | Side chain halogenated alkylphenyl haloformates |
US3732315A (en) * | 1970-05-13 | 1973-05-08 | Basf Ag | Production of aromatic hydroxyaldehydes |
US4069340A (en) * | 1976-01-30 | 1978-01-17 | Hooker Chemicals & Plastics Corporation | Immonium salts and derivatives thereof |
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2000
- 2000-09-12 DE DE10044910A patent/DE10044910A1/en not_active Withdrawn
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- 2001-09-04 EP EP01120695A patent/EP1186587A1/en not_active Withdrawn
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US6380441B1 (en) | 2002-04-30 |
EP1186587A1 (en) | 2002-03-13 |
DE10044910A1 (en) | 2002-03-21 |
JP2002114726A (en) | 2002-04-16 |
HUP0103642A3 (en) | 2002-12-28 |
HU0103642D0 (en) | 2001-11-28 |
HUP0103642A2 (en) | 2002-07-29 |
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