CN100351257C - Method for producing pyridoxine or an acid addition salt thereof - Google Patents
Method for producing pyridoxine or an acid addition salt thereof Download PDFInfo
- Publication number
- CN100351257C CN100351257C CNB2003801077227A CN200380107722A CN100351257C CN 100351257 C CN100351257 C CN 100351257C CN B2003801077227 A CNB2003801077227 A CN B2003801077227A CN 200380107722 A CN200380107722 A CN 200380107722A CN 100351257 C CN100351257 C CN 100351257C
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- China
- Prior art keywords
- compound
- water
- acid
- methyl
- vit
- 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.)
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- 239000002253 acid Substances 0.000 title claims abstract description 57
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 150000003839 salts Chemical class 0.000 title claims abstract description 40
- 229940011671 vitamin b6 Drugs 0.000 title abstract description 5
- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- 235000008160 pyridoxine Nutrition 0.000 title abstract 3
- 239000011677 pyridoxine Substances 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 67
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 33
- 239000000203 mixture Substances 0.000 claims abstract description 20
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims description 52
- 239000011726 vitamin B6 Substances 0.000 claims description 35
- 235000019158 vitamin B6 Nutrition 0.000 claims description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- 238000001556 precipitation Methods 0.000 claims description 26
- 239000003795 chemical substances by application Substances 0.000 claims description 22
- 239000011541 reaction mixture Substances 0.000 claims description 20
- 238000002425 crystallisation Methods 0.000 claims description 15
- 230000008025 crystallization Effects 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 230000008859 change Effects 0.000 claims description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 230000003197 catalytic effect Effects 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 150000007522 mineralic acids Chemical class 0.000 claims description 5
- POAOYUHQDCAZBD-UHFFFAOYSA-N 2-butoxyethanol Chemical compound CCCCOCCO POAOYUHQDCAZBD-UHFFFAOYSA-N 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 2
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 238000005698 Diels-Alder reaction Methods 0.000 abstract description 7
- BAKUAUDFCNFLBX-UHFFFAOYSA-N 4,7-dihydro-1,3-dioxepine Chemical compound C1OCC=CCO1 BAKUAUDFCNFLBX-UHFFFAOYSA-N 0.000 abstract description 2
- PUMREIFKTMLCAF-UHFFFAOYSA-N 4-methyl-1,3-oxazole Chemical compound CC1=COC=N1 PUMREIFKTMLCAF-UHFFFAOYSA-N 0.000 abstract 1
- -1 nitro, amino Chemical group 0.000 description 71
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 34
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- 239000007787 solid Substances 0.000 description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- 239000012452 mother liquor Substances 0.000 description 12
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 230000009466 transformation Effects 0.000 description 9
- 238000001816 cooling Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 5
- 150000004292 cyclic ethers Chemical class 0.000 description 5
- 238000007701 flash-distillation Methods 0.000 description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000011707 mineral Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 230000002349 favourable effect Effects 0.000 description 4
- 125000005816 fluoropropyl group Chemical group [H]C([H])(F)C([H])([H])C([H])([H])* 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 241001550224 Apha Species 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000000526 short-path distillation Methods 0.000 description 3
- 239000006200 vaporizer Substances 0.000 description 3
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000010306 acid treatment Methods 0.000 description 2
- 239000011260 aqueous acid Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000011552 falling film Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 description 2
- 239000012433 hydrogen halide Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006219 1-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 description 1
- 125000004779 2-chloro-2-fluoroethyl group Chemical group [H]C([H])(*)C([H])(F)Cl 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- KKZUMAMOMRDVKA-UHFFFAOYSA-N 2-chloropropane Chemical group [CH2]C(C)Cl KKZUMAMOMRDVKA-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- YTTFFPATQICAQN-UHFFFAOYSA-N 2-methoxypropan-1-ol Chemical compound COC(C)CO YTTFFPATQICAQN-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 1
- JDFDHBSESGTDAL-UHFFFAOYSA-N 3-methoxypropan-1-ol Chemical compound COCCCO JDFDHBSESGTDAL-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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- ZKBNUNIVNISNDB-UHFFFAOYSA-N [Cl].FC Chemical compound [Cl].FC ZKBNUNIVNISNDB-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical class CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000000470 constituent Substances 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
- 238000010511 deprotection reaction Methods 0.000 description 1
- 125000004774 dichlorofluoromethyl group Chemical group FC(Cl)(Cl)* 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000006077 hetero Diels-Alder cycloaddition reaction Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- VZUGBLTVBZJZOE-KRWDZBQOSA-N n-[3-[(4s)-2-amino-1,4-dimethyl-6-oxo-5h-pyrimidin-4-yl]phenyl]-5-chloropyrimidine-2-carboxamide Chemical compound N1=C(N)N(C)C(=O)C[C@@]1(C)C1=CC=CC(NC(=O)C=2N=CC(Cl)=CN=2)=C1 VZUGBLTVBZJZOE-KRWDZBQOSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- SHNUBALDGXWUJI-UHFFFAOYSA-N pyridin-2-ylmethanol Chemical class OCC1=CC=CC=N1 SHNUBALDGXWUJI-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 230000000630 rising effect Effects 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000005059 solid analysis Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- YTZKOQUCBOVLHL-UHFFFAOYSA-N tert-butylbenzene Chemical compound CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
- C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
- C07D213/67—2-Methyl-3-hydroxy-4,5-bis(hydroxy-methyl)pyridine, i.e. pyridoxine
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention relates to a method for producing pyridoxine and the acid addition salts thereof, said method comprising the following steps: i. the Diels-Alder adduct (I) of 4-methyloxazole and a 4,7-dihydro-1,3-dioxepin is dissolved in a mixture of an organic solvent which can be at least partially mixed with water, and water, and the solution of (I) thus obtained is treated at an elevated temperature, optionally in the presence of a catalytically active quantity of an acid, until at least part of the compound (I) is converted into the corresponding 1,5-dihydro-8-methyl-[1,3]dioxepin-[5,6c]pyridin-9-ol (II); ii. the compound (II) of the solution obtained in step i., or the acid addition salt of said compound, is precipitated by adding a precipitant, and the compound (II) or the acid addition salt thereof is isolated; and iii. the compound (II) obtained in step i., or the acid addition salt thereof, is converted into pyridoxine or an acid addition salt thereof.
Description
The present invention relates to a kind of method for preparing Vit B6 and its acid salt.
Vit B6, especially its hydrochloride are vitamin b6 usp B
6Business form.As well-known, vitamin b6 usp B
6Be 2-methyl-3-hydroxyl-4, two (methylol) pyridines of 5-.Vit B6, especially its hydrochloride, of many uses in pharmaceutical preparation and as in the food and feed additive.
As well-known, Vit B6 prepares by wherein reacting the composition sequence that forms described pyridine ring by hetero-Diels-Alder industrial.Can be at Ullmann ' s Encyclopedia ofIndustrial Chemistry, CD-Rom the 5th edition, Wiley-VCH 1997, and Vitamins finds the summary by " Diels-Alder reaction " synthetic Vit B6 in the 8.7.1.4 chapter.
In described synthesizing, on the 5-position, have the substituent 4-Jia of alkoxyl group or itrile group Ji oxazole and suitable dienophile, particularly suitable-2-butylene-1, the derivatives reaction of 4-glycol.Especially confirmed 4,7-dihydro-1,3-two oxa- (4,7-dihydro-1,3-dioxepine DOX) is useful dienophile.In following scheme, illustrated by the Diels-Alder prepared in reaction Vit B6 of 4-first base oxazole (MOX) with two oxa- DOX:
In this scheme, Y is CN or OR
1Group, wherein R
1It is the optional alkyl that replaces.R
2And R
3Be hydrogen or the optional alkyl that replaces independently of one another.According to described reaction conditions and substituting group Y, Diels-Alder adducts I is aromizing spontaneously, perhaps at substituting group OR
1Situation under, by with the acid treatment I of catalytic amount and aromizing, to obtain Compound I I.Then under acid catalysis in the mode of routine with Compound I I deprotection to obtain Vit B6 or its acid salt.
Purity to Vit B6 has been made high request.The Vit B6 of Diels-Alder prepared in reaction that usually, will be by MOX and DOX was purified in the Vit B6 hydrochloride stage.Show that as in-house research because described by product and Vit B6 hydrochloride have closely similar chemical property, so this method is very expensive and not convenient technically.
JA 7111500 (01.04.1968) discloses the reaction product that the acetate with catalytic amount obtains in the Diels-Alder reaction to 4-methyl-5-Yi Yang Ji oxazole and DOX derivative and has carried out initial treatment, is concentrated into and makes gained mixture drying, handle described residue, the residue from alcohol-acetone is evaporated to drying once more and makes its recrystallization with the alcoholic solution of hydrochloric acid in the aqueous solution of alcohol.Because described re-crystallization step, so this method is very expensive and inconvenient.
DE-A 1445882 and US 3,250,778 disclose general formula I I type compound dissolution has been handled the solution of gained in solvents and with precipitation agent, so that Compound I I is crystallized out.Yet the solid of acquisition still must recrystallization.In addition, its productive rate can not be satisfactory.
The purpose of this invention is to provide a kind of method for preparing Vit B6, this method does not have the shortcoming of described art methods.
We have been surprised to find ought be OR with wherein Y defined above
1Compound of Formula I be dissolved in organically to small part can with the mixture of miscible solvent of water and water in, selectively in the presence of the acid of catalytically effective amount, the solution of handling the Compound I that obtains by this way under the temperature that raises has changed into the compound of formula II defined above up to part of compounds I at least, and, can realize this purpose by add precipitation agent when Compound I I or its acid salt are precipitated out from the solution that obtains by this way.In this way, can obtain Compound I I or its acid salt with high yield and highly selective.Substantially removed any impurity that causes by the Diels-Alder reaction in this stage.Simplified the final purifying process of Vit B6 or its acid salt like this.
Therefore, the present invention relates to a kind of method for preparing Vit B6 and its acid salt, it comprises:
I. with the compound dissolution of general formula I in to small part can with the mixture of miscible organic solvent of water and water in,
Wherein
R
1For the optional alkyl that replaces and
R
2And R
3Be hydrogen or the optional alkyl that replaces independently of one another, perhaps the carbon atom that connects with them forms 5-to 8-unit saturated rings,
And selectively in the presence of the acid of catalytic activity amount, under the temperature that raises, handle the solution of the I that obtains by this way, changed into Compound I I up to part of compounds I at least
R wherein
2And R
3Definition as mentioned,
Ii. by add precipitation agent with Compound I I or its acid salt from step I. precipitate the solution of acquisition, and separating compound II or its acid salt; With
Iii. with step I. the Compound I I of acquisition or its acid salt change into Vit B6 or change into the acid salt of Vit B6.
Here and hereinafter, alkyl is to have 1～10, the particularly line style of 1～6 carbon atom or the aliphatic hydrocarbyl of branching usually, and it can have one or more (for example 2 or 3) substituting group.Except halogen, the example of suitable substituents also has C
1-C
4-alkoxyl group, hydroxyl, COOH, C
1-C
4-alkylthio, nitro, amino and phenyl, and phenyl itself can have one or more C of being selected from
1-C
4-alkyl, C
1-C
4The substituting group of-alkoxy or halogen.
Has 1～10, particularly the example of the alkyl of 1～6 carbon atom is: methyl, ethyl, propyl group, the 1-methylethyl, butyl, the 1-methyl-propyl, 2-methyl-propyl or 1, the 1-dimethyl ethyl, n-pentyl, the 1-methyl butyl, the 2-methyl butyl, the 3-methyl butyl, 2, the 2-dimethyl propyl, the 1-ethyl propyl, n-hexyl, 1, the 1-dimethyl propyl, 1, the 2-dimethyl propyl, the 1-methyl amyl, the 2-methyl amyl, the 3-methyl amyl, the 4-methyl amyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 2, the 3-dimethylbutyl, 3, the 3-dimethylbutyl, the 1-ethyl-butyl, the 2-ethyl-butyl, 1,1,2-trimethylammonium propyl group, 1-ethyl-1-methyl-propyl, 1-ethyl-3-methyl-propyl, n-heptyl, 1-methyl hexyl, 2-methyl hexyl, the 1-ethyl pentyl group, the 2-ethyl pentyl group, n-octyl, 1-methylheptyl and 2-ethylhexyl.
C
1-C
4The example of-alkoxyl group is: methoxyl group, oxyethyl group, propoxy-, 1-methyl ethoxy, butoxy, 1-methyl propoxy-, 2-methyl propoxy-or 1,1-dimethyl oxyethyl group.
The alkyl that replaces is particularly:
C
1-C
6-haloalkyl, chloromethyl for example, dichloromethyl, trichloromethyl, methyl fluoride, difluoromethyl, trifluoromethyl, the chlorine methyl fluoride, dichlorofluoromethyl, chlorodifluoramethyl-, the 2-fluoro ethyl, the 2-chloroethyl, the 2-bromotrifluoromethane, 2-iodine ethyl, 2,2-two fluoro ethyls, 2,2, the 2-trifluoroethyl, 2-chloro-2-fluoro ethyl, 2-chloro-2,2-two fluoro ethyls, 2,2-two chloro-2-fluoro ethyls, 2,2,2-three chloroethyls, pentafluoroethyl group, the 2-fluoropropyl, the 3-fluoropropyl, 2,2-two fluoropropyls, 2,3-two fluoropropyls, the 2-chloropropyl, the 3-chloropropyl, 2,3-two chloropropyls, the 2-bromopropyl, the 3-bromopropyl, 3,3, the 3-trifluoro propyl, 3,3,3-three chloropropyls, 2,2,3,3,3-five fluoropropyls, seven fluoropropyls, 1-(methyl fluoride)-2-fluoro ethyl, 1-(chloromethyl)-2-chloroethyl, 1-(brooethyl)-2-bromotrifluoromethane, 4-fluorine butyl, the 4-chlorobutyl, 4-brombutyl or nine fluorine butyl;
C
1-C
4-alkoxy-C
1-C
4-alkyl, methoxymethyl for example, ethoxyl methyl, the propoxy-methyl, (1-methyl ethoxy) methyl, butoxymethyl, (1-methyl propoxy-) methyl, (2-methyl propoxy-)-methyl, (1,1-dimethyl oxyethyl group) methyl, 2-(methoxyl group) ethyl, 2-(oxyethyl group) ethyl, 2-(propoxy-) ethyl, 2-(1-methyl ethoxy) ethyl, 2-(butoxy) ethyl, 2-(1-methyl propoxy-) ethyl, 2-(2-methyl propoxy-) ethyl, 2-(1,1-dimethyl oxyethyl group) ethyl, 2-(methoxyl group) propyl group, 2-(oxyethyl group) propyl group, 2-(propoxy-) propyl group, 2-(1-methyl ethoxy) propyl group, 2-(butoxy) propyl group, 2-(1-methyl propoxy-) propyl group, 2-(2-methyl propoxy-) propyl group, 2-(1,1-dimethyl oxyethyl group) propyl group, 3-(methoxyl group) propyl group, 3-(oxyethyl group)-propyl group, 3-(propoxy-) propyl group, 3-(1-methyl ethoxy) propyl group, 3-(butoxy) propyl group, 3-(1-methyl propoxy-) propyl group, 3-(2-methyl propoxy-) propyl group, 3-(1,1-dimethyl oxyethyl group) propyl group, 2-(methoxyl group) butyl, 2-(oxyethyl group) butyl, 2-(propoxy-) butyl, 2-(1-methyl ethoxy) butyl, 2-(butoxy) butyl, 2-(1-methyl propoxy-) butyl, 2-(2-methyl propoxy-) butyl, 2-(1,1-dimethyl oxyethyl group) butyl, 3-(methoxyl group) butyl, 3-(oxyethyl group) butyl, 3-(propoxy-) butyl, 3-(1-methyl ethoxy) butyl, 3-(butoxy) butyl, 3-(1-methyl propoxy-) butyl, 3-(2-methyl propoxy-) butyl, 3-(1,1-dimethyl oxyethyl group) butyl, 4-(methoxyl group) butyl, 4-(oxyethyl group) butyl, 4-(propoxy-) butyl, 4-(1-methyl ethoxy) butyl, 4-(butoxy) butyl, 4-(1-methyl propoxy-) butyl, 4-(2-methyl propoxy-) butyl or 4-(1,1-dimethyl oxyethyl group) butyl, and C
1-C
4-alkylthio-C
1-C
4-alkyl, methylthiomethyl for example, the ethylmercapto group methyl, the rosickyite ylmethyl, (1-methyl ethylmercapto group) methyl, the butylthio methyl, (1-methyl-prop sulfenyl) methyl, (2-methyl-prop sulfenyl) methyl, (1,1-dimethyl ethylmercapto group) methyl, 2-(methylthio group) ethyl, 2-(ethylmercapto group) ethyl, 2-(rosickyite base) ethyl, 2-(1-methyl ethylmercapto group) ethyl, 2-(butylthio) ethyl, 2-(1-methyl-prop sulfenyl) ethyl, 2-(2-methyl-prop sulfenyl) ethyl, 2-(1,1-dimethyl ethylmercapto group) ethyl, 2-(methylthio group) propyl group, 2-(ethylmercapto group) propyl group, 2-(rosickyite base) propyl group, 2-(1-methyl ethylmercapto group) propyl group, 2-(butylthio) propyl group, 2-(1-methyl-prop sulfenyl) propyl group, 2-(2-methyl-prop sulfenyl) propyl group, 2-(1,1-dimethyl ethylmercapto group) propyl group, 3-(methylthio group) propyl group, 3-(ethylmercapto group) propyl group, 3-(rosickyite base) propyl group, 3-(1-methyl ethylmercapto group) propyl group, 3-(butylthio) propyl group, 3-(1-methyl-prop sulfenyl) propyl group, 3-(2-methyl-prop sulfenyl) propyl group, 3-(1,1-dimethyl ethylmercapto group) propyl group, 2-(methylthio group) butyl, 2-(ethylmercapto group) butyl, 2-(rosickyite base) butyl, 2-(1-methyl ethylmercapto group) butyl, 2-(butylthio) butyl, 2-(1-methyl-prop sulfenyl) butyl, 2-(2-methyl-prop sulfenyl) butyl, 2-(1,1-dimethyl ethylmercapto group) butyl, 3-(methylthio group) butyl, 3-(ethylmercapto group) butyl, 3-(rosickyite base) butyl, 3-(1-methyl ethylmercapto group) butyl, 3-(butylthio) butyl, 3-(1-methyl-prop sulfenyl) butyl, 3-(2-methyl-prop sulfenyl) butyl, 3-(1,1-dimethyl ethylmercapto group) butyl, 4-(methylthio group) butyl, 4-(ethylmercapto group) butyl, 4-(rosickyite base) butyl, 4-(1-methyl ethylmercapto group) butyl, 4-(butylthio) butyl, 4-(1-methyl-prop sulfenyl) butyl, 4-(2-methyl-prop sulfenyl) butyl or 4-(1,1-dimethyl ethylmercapto group) butyl.
The example of 5-to 8-unit ring is a carbon ring group, for example cyclohexyl, suberyl, ring octyl group, and heterocyclic group, for example 2-oxa-cyclopentyl, 2-oxa-cyclohexyl etc.
R among formula I and the MOX
1Preferably unsubstituted C
1-C
6-alkyl, particularly ethyl, n-propyl, normal-butyl.
R among formula DOX, I and the II
2Group is hydrogen preferably.R among formula DOX, I and the II
3Group preferably is different from hydrogen and particularly unsubstituted C
1-C
10-alkyl, C
1-C
4-alkoxy-C
1-C
4-alkyl or C
1-C
4-alkylthio-C
1-C
4-alkyl.Especially, R
3Be unsubstituted C
1-C
6-alkyl, particularly sec.-propyl or 2-butyl.
In step I. in Compound I be dissolved in organically to small part can with the mixture of miscible solvent of water and water in.Can refer to described solvent and can absorb at least 10wt%, particularly 20wt%, the more preferably water of 50wt% at least at least with water is miscible to small part, to form homogeneous phase (room temperature).
The example of suitable solvent is acyclic ethers and ether alcohol, cyclic ethers and C
1-C
5-alkanol.The example of acyclic ethers is a diethyl ether, 1,2-bi-methoxy ethane, diglyme, triglyme etc.The example of ether alcohol is 2-methyl cellosolve, 2-or 3-methoxypropanol.The example of cyclic ethers is diox and tetrahydrofuran (THF) (THF) particularly.
C
1-C
5The example of-alkanol is methyl alcohol, ethanol, n-propyl alcohol, propyl carbinol, Virahol, 2-butanols, the trimethyl carbinol and Pentyl alcohol.
Preferably to small part can be C with the miscible organic solvent of water
1-C
4-alkanol and cyclic ethers, particularly cyclic ethers, and wherein preferred tetrahydrofuran (THF).
The organic solvent that especially preferably has unlimited and water miscibility.
The concentration of Compound I is generally 5～60wt% in described solution, is in particular 10～50wt%.
Verified when step I. in the water that is reflected at have that productive rate and the purity for the product II that obtains among the step I i. all is favourable when carrying out down.Be used for step I. solvent mixture preferably contain in every mol Compound I 0.5～10mol water, particularly 2～6mol water.
Can by acid, preferably by pKa be 1.5～6.5 weak acid, especially the aliphatic carboxylic acid (for example formic acid, acetate and propionic acid) by preferably having 1～4 carbon atom, especially come the conversion of catalytic cpd I to Compound I I by acetate.If necessary, the amount of described acid is preferably 0.01～1mol in every mol Compound I, is in particular 0.05～0.5mol, more preferably 0.1～0.3mol.
Described I usually above 30 ℃, is preferably 40～100 ℃ to the required temperature of the conversion of II, is in particular 50～70 ℃.
Preferably carry out I and changed into Compound I I up at least 10%, special at least 20% Compound I to the conversion of II.In principle, can after changing into II fully, I carry out described reaction.Yet verified when with I to the conversion of II only so that many parts transformation efficiency, preferred 80% transformation efficiency at the most, particularly 50% transformation efficiency is favourable at the most.
Under acid catalyzed situation, according to required temperature, realize that the reaction times of described transformation efficiency needs is generally at least 1 hour, preferably at least 2 hours, be in particular 2 hours～8 hours.Described reaction process can (for example pass through HPLC) in a manner known way by those skilled in the art and determine.
As selection, also can under the situation that does not have acid, realize the conversion of I to II.With regard to temperature of reaction, same being suitable for as indicated above.Usually, only need the long reaction times, be generally at least 2 hours, be in particular at least 4 hours～12 hours.
When having realized the conversion of desirable Compound I, add precipitation agent with precipitation Compound I I.Astoundingly, I proceeds to the conversion of II in described precipitation process, thereby finishes in precipitation, can realize that Compound I is generally at least 90% to the conversion of Compound I I, and particularly at least 95%.
Precipitation agent is can reduce Compound I I to be used for step I in principle. deliquescent all reagent of solvent/water mixture.
When Compound I I precipitated as neutral compound, the available solvability reduced reagent particularly aliphatic series and clicyclic hydrocarbon, for example hexane, heptane, isohexane, octane, hexanaphthene, and the aliphatic hydrocrbon fraction is sherwood oil or petroleum fractions and its mixture for example.
In a preferred embodiment, described precipitation agent is a mineral acid, for example sulfuric acid, phosphoric acid or hydrogen halide, and it is selectively with the form of aqueous acids.Then Compound I I is precipitated out as sl. sol. acid salt.Preferred acidic precipitation agent is a hydrogenchloride, and it is selectively with the form of its aqueous acids, but preferred especially gaseous hydrogen chloride.
Should be understood that when mineral acid is when the described precipitation agent, especially when the use hydrogen halide amount of described acid makes described acid equivalent at least corresponding to the mole number of Compound I I.Preferably with 5mol%, the preferred described acid of excessive use of 10mol%, particularly 10～80mol%, especially 20～80mol% at least at least.
Under the situation of liquid precipitation agent, can by in any required mode with step I. the solution of acquisition and precipitant mix are added described precipitation agent.Yet, preferably described precipitation agent is joined step I. and in the solution of acquisition.In principle, described precipitation agent can add with portion.Yet, preferably with many parts or interior with described precipitation agent adding step I in the long relatively time (for example 0.5～5 hour especially is 1～3 hour). and in the solution of acquisition.
Should be understood that usually with step I. add this precipitation agent in the solution of acquisition and the described precipitant mix.The device that is applicable to this is familiar with to those skilled in the art.The example of suitable device comprises the stirring tank with following characteristics: have and be used to remove the interchanger of heat of crystallization and one or more levels agitator (for example cross-arm agitator or have the slurry formula turbine of pitch) is housed, perhaps under the situation of gaseous state precipitation agent disc agitator is housed especially.
When adding described precipitation agent, verified useful especially is (for example 30～100 ℃ at first at elevated temperatures, preferred 40～80 ℃, be in particular 50～70 ℃) the adding precipitation agent, and during adding described precipitation agent or afterwards the mixture with gained is cooled to low temperature, for example-20 to+30 ℃, particularly-10 to+20 ℃, especially-10 to+10 ℃.Especially, verifiedly usefully during adding described precipitation agent, the inclusion of described reactor is cooled to moderate temperature, for example 40～10 ℃, and after this interpolations end, continue to be cooled to desirable outlet temperature.Subsequently, usually this outlet temperature is kept certain hour, to realize the complete crystallization of Compound I I or its acid salt.Described rate of cooling is preferably 50～5K/h, is in particular 40～10K/h.
(for example by filter or by centrifugation) the solid chemical compound II that will obtain by this way removes from described mother liquor subsequently, in a manner known way.Confirmed that in addition the belt filtration can be used for the successive reaction.
With regard to being further purified, can wash described crystal in the mode of routine.For this reason, be particularly useful for step I. organic solvent be useful.The amount of described washing liq is counted 0.5～3 weight part with the dried crystals of every weight part usually, is in particular 1～2.5 weight part.
Usually, the mother liquor that is produced by precipitating action and any washing liq will be handled and be recycled in the described reaction or be conducted to during other uses by the distillation mode.In step I. middle use cyclic ethers has the following advantages in addition: can steam during described processing and desolventize-water azeotrope and be directly used in step I once more. in.
The Compound I I that can in a manner known way step I i. be obtained changes into Vit B6 or its acid salt, changes into its hydrochloride especially.The prior art of quoting from the outset in principle and from DE-A 1445882, US 3,525,749, DE-A 1545943, know the method that is used for this purpose especially.The method that is similar to these as description among DE-A 1620045 or the GB 1293843 is suitable equally.
Usually, by mode II is changed into Vit B6 with mineral acid treatment II.This can easily provide the acid salt of described II.Be preferable over and in aqueous mineral acid, carry out the conversion of II or its acid salt under the temperature of rising to Vit B6.Preferred aqueous inorganic acid is a hydrochloric acid.
The concentration of described mineral acid is preferably 0.01～1mol/l, is in particular 0.05～0.5mol/l.Usually the concentration (determining with described neutral compound) with Compound I I is adjusted to 10～50wt%, particularly 15～40wt%.
When II being changed into the acid salt of described Vit B6 by use aqueous inorganic acid, particularly aqueous hydrochloric acid, the verified advantageously compound R that will between the described reaction period, form
2R
3C=O removes from described reaction mixture.Be applicable to all Compound I I on this methodological principle, and have nothing to do, and therefore constitute the part of theme of the present invention with its preparation method.
Usually by carrying out mode that gas puies forward with suitable inert substance and/or steam with compound R
2R
3C=O removes from described reaction mixture, and this is because this compound is volatile.Preferably steam is infeeded described reaction mixture to remove compound R
2R
3C=O, described steam are selectively to mix with liquid water.Also can additionally introduce steam and introduce liquid water subsequently.Based on 1 weight part Compound I I (determining with described neutral compound), the amount of introducing water (steam and optional liquid water) is generally 1～50 weight part, and preferred 2～20 weight parts are in particular 4～10 weight parts.Usually select the amount of liquid water so that the amount of the water of introducing by steam is at least 1 weight part based on 1 weight part Compound I I.
In the method, verified usefully is 0.5 * 10 at the pressure that reduces, preferred peak pressure
5Pa, particularly 0.1 to 0.5 * 10
5Carry out the reaction among the step I ii. under the Pa pressure.The temperature of described reaction needed is preferably 40～80 ℃ usually above 30 ℃, especially 40～70 ℃, is in particular 50～70 ℃.
When the described reaction mixture of cooling, so described Vit B6 is with its acid salt crystallization, especially with crystal of hydrochloride.
In a preferred embodiment of the invention, the reaction mixture of heat still concentrated up to the content of the Vit B6 of determining with described acid salt be 20wt% at least, be in particular 20～35wt%.Higher concentrating degree is fine in principle, for example concentrate the solubility limit that reaches under this temperature or the higher temperature, but this is not favourable.Preferably be concentrated into the feasible degree that is no more than the solubility limit of described Vit B6.
Subsequently, from described reaction mixture, obtain Vit B6 by crystallization with described acid salt.Described crystallization can be carried out II therein and carry out or carry out in independent reaction vessel in the container that Vit B6 transforms.
Before described crystallization, can adopt gac that still hot reaction mixture is handled.For this reason, will be preferably under at least 40 ℃ of temperature, especially under at least 50 ℃ of temperature the solution of the described still heat of (for example 50～100 ℃) by being filled with the tower of gac.Can be absorbed with colored foreign like this.
In order to make the acid salt crystallization of described Vit B6, the solution of the Vit B6 acid salt of cooling gained.Described outlet temperature is usually less than 20 ℃, preferably is lower than 10 ℃, is in particular 10～0 ℃.In order to ensure crystallization uniformly and the crystalline high purity that causes thus, rate of cooling is no more than 20K/h, 10K/h especially usually.Especially, rate of cooling is 2K/h～10K/h.
Described crystallization can be carried out in being applicable to this any conventional equipment in principle.Especially, the device (for example stirring tank) that is used to carry out suspension crystallization has been proved to be available.These stirring tanks preferably have the external heat exchanger that is used to remove heat of crystallization.
Obtain described Vit B6 acid salt by filtration and/or centrifugation in a manner known way.In order to remove the mother liquor of attachment removal, can carry out conventional purification operations to described crystal, for example adopt the washing step of water, aqueous inorganic acid and/or alcohol.
The described Vit B6 acid salt that obtains as crystal has especially high purity.The productive rate that obtains when adopting art methods based on the productive rate of used Compound I I.
Concentrated mother liquor and the optional aqueous cleaning liquid that is used to be purified can cause the further crystallization of Vit B6 acid salt.The Vit B6 acid salt of gained has low relatively purity, yet it is enough to be used in many application, is used in particular for as fodder additives.Yet advantageously the crystal that will obtain by this way is recirculated in the still hot reaction mixture of step I ii. acquisition, and can improve the productive rate of primary crystal by this way.
Be OR with DOX with Y wherein by the reaction scheme that provides according to beginning at elevated temperatures in a manner known way
1MOX reaction and the compound of preparation general formula I.
The temperature of reaction that described conversion needs is generally at least 110 ℃, preferably at least 120 ℃, is in particular at least 140 ℃.They preferably are no more than 200 ℃, and 180 ℃ especially, especially 170 ℃.
With regard to the reaction of MOX and DOX, advantageously use based on the excessive DOX of required stoichiometry.Therefore preferably with DOX: the MOX mol ratio be at least 2: 1, be in particular at least 5: 1, MOX and DOX be conducted to described reaction zone in more preferably 5: 1～20: 1.
Because described starting material is generally liquid under described reaction conditions, therefore in liquid phase, carry out the reaction of MOX and DOX usually.Can selectively organic solvent be added described reaction mixture.The example of suitable solvent is aliphatic series and cycloaliphatic hydrocarbon for example hexane, octane, hexanaphthene, technologic hydrocarbon mixture is petroleum fractions for example, aromatic hydrocarbon is toluene, dimethylbenzene, cumene, tert.-butylbenzene etc. for example, and aliphatic series and alicyclic ethers for example diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran (THF), diox, and the mixture of these solvents.In a preferred embodiment, (based on the total amount of starting material, percentage of solvents＜10wt% operates especially＜5wt%) in the presence of organic solvent.
Advantageously, from reaction zone, discharge the reaction of carrying out MOX and DOX with successive technology by the product materials flow that continuously MOX and DOX is conducted to reaction zone and will contains Compound I continuously.About productive rate and the purity of I, verified is favourable when reaction zone is arranged so that its back-mixing with inapparent product and reactant.Can realize that so described reactant narrower residence time in reaction zone distributes.
The method that is used to realize inapparent back-mixing be to those skilled in the art be familiar with and be described in the literature, for example at Chemische Reaktionstechnik, 1 volume, second edition, Georg Thieme Verlag, Stuttgart 1999,9 chapters are particularly in the 331st～342 page.Usually, flow through the desirable inapparent back-mixing of realization by reaction zone with successive with at least two reaction order that are linked in sequence.
Preparing in first embodiment of I continuously, described reaction zone is arranged at least 2 grades stirring tank group.
Preparing in another embodiment of I continuously, reaction zone is arranged to not have product round-robin flow tube.Preferably, described flow tube is characterised in that Bodenstein value B
0〉=5, preferably be Bodenstein value B
0Be 50～200, be in particular 100～150.The length that described flow tube preferably has: the footpath is than being at least 5: 1, preferably at least 10: 1, be in particular 10: 1～1000: 1.
Preferably make the transformation efficiency of MOX be no more than 70%, particularly 60% with the residence time in the selective reaction district.Yet, carry out described reaction usually and be at least 20%, preferably at least 40% up to the transformation efficiency of MOX.The required for this reason residence time is generally 30 minutes～and 5 hours, be in particular 60 minutes～3 hours.
Described reaction under atmospheric pressure or under elevated pressure is for example clung to, preferably clung to up to 150 up to 200 is carried out usually.When described reaction zone is arranged to the stirring tank group, under atmospheric pressure or at the pressure that raises a little or reduce for example operate under 0.8 crust～50 crust, preferred 0.9 crust～10 crust usually.When described reaction zone is arranged to flow tube, verified usefully elevated pressure for example 10～200 the crust, preferred 50～150 the crust, especially 60～120 the crust under react.
(for example by the distillation approach) handles the reactor effluent (product materials flow) that contains Compound I in a manner known way.Can from target compound I, remove low boilers for example MOX and DOX like this.
Astoundingly, can realize the good especially productive rate of target compound I when removing volatile constituent when described product materials flow being carried out flash distillation.
For flash distillation, leave described reaction zone enter be in low pressure for example be lower than 500 millibars pressure, preferably be lower than 100 millibars, be in particular 1～20 millibar zone after at once with the reactor effluent decompression of described still heat.Temperature in the described vaporizer zone is preferably 30～160 ℃, is in particular 40～100 ℃.Especially, under the situation that needn't introduce heat in addition, carry out described flash distillation.Can for example in gas-liquid separator, carry out described flash distillation in a manner known way.
In flash vaporization process, with at least 30%, preferred at least 40%, for example 40～95%, particularly 40～80%, especially 50～70% low boilers (for example unconverted reactant II and the III) evaporation usually that is contained in the described product materials flow.As for being further purified, preferably described residue is carried out short-path distillation, for example at thin-film evaporator such as falling-film evaporator, as fall materials flow vaporizer (falling-streamevaporator), swivel pipe falling-film evaporator, perhaps rotatory evaporator is for example in the Sambay vaporizer.Temperature in the described short-path distillation is no more than 160 ℃ usually, 140 ℃ especially, is preferably 80～140 ℃.With regard to pressure, as mentioned at described same being suitable for of flash distillation.As selection, also can handle by short-path distillation specially in mode described here.The residence time in the described decompression evaporator is generally 1 minute～and 30 minutes, be in particular 2 minutes～10 minutes.
Can obtain by this way to contain and be less than 10%, preferably be less than 5%, be in particular the product I of 1% low boilers.The low boilers of Huo Deing is made up of MOX and DOX and used any organic solvent substantially by this way, and therefore can recirculation enter in the described reaction zone.
The following examples are intended to illustrate the present invention, rather than restriction the present invention.
Embodiment 1
1.3-sec.-propyl-1,5-dihydro-[1,3]-two oxa--3-methyl-4-n-butoxy-7-oxa--2-azabicyclo [2.2.1]-2-heptene (DAA) changes into 1,5-dihydro-3-sec.-propyl-8-methyl-[1,3]-two oxa--[5,6-c]-pyridine-9-phenol is as described hydrochloride (DOPHCl).
Variation scheme a:
148.5g DAA is dissolved in the 380g tetrahydrofuran (THF) and with it mixes with 45g water and 5.1g Glacial acetic acid.Under 60 ℃ and normal atmosphere, stirred this solution 4 hours.The transformation efficiency that the analysis of described reaction mixture is presented at based on DAA under the selectivity of DOP97% is 43%.
In 1.5 hours, 0.9mol gaseous state HCl is infeeded in the solution that starts from by this way obtaining under 60 ℃ of temperature.During described interpolation, this mixture of restir not.During this period, described mixture is cooled to 20 ℃ and the formation of described solid.Filter the solid that obtains by this way and use a small amount of ice-cold tetrahydrofuran (THF) (based on the solid that obtains, about 1.5 weight parts) washing by suction filter.By this way, obtaining according to ultimate analysis is pure and chromatic number is the 113g crystal of APHA 38.This is corresponding to 87.5% productive rate (pure solid).
Described mother liquor contains other DOPHCl and a spot of Vit B6 hydrochloride.
With regard to whole mixture (comprising mother liquor), the mole rate of recovery 99% (3% the Vit B6 hydrochloride productive rate) productive rate of DOPHCl down is 96%.
Change scheme b:
In the stirring tank with chuck and vapour cooler (disc agitator), 1200g DAA is dissolved in 1467g tetrahydrofuran (THF) and the 320g water.Add the spissated acetate of 37g (Glacial acetic acid).Stirred this solution 4 hours down at 60 ℃.In specific agitator output rating is under the 1.6W/kg reaction mixture, below 214g gaseous state HCl is infeeded described solution from this agitator in 2 hours.Cause DOPHCl to come out like this as solid precipitation.Simultaneously, with 30K/h described solution is cooled to 30 ℃ from 60 ℃, and with 10K/h it is cooled to 20 ℃ from 30 ℃ afterwards.After being metered into HCl and finishing, further cool off this suspension to 0 ℃ with 20K/h.Subsequently, use suction filter that described solid is removed from mother liquor, with the cold tetrahydrofuran (THF) washing of 1320g, and dry under the pressure that reduces.Obtain 850g exsiccant white solid.Solid analysis shows the purity＞99.5wt% based on DOPHCl, is 92.2% based on the productive rate of used pure DAA.Described solid APHA chromatic number is 3.In described mother liquor, find the DOPHCl of 0.8wt% and the VB6HCl of 1.5wt%.Cause overall yield＞98% like this based on DOPHCl and the VB6HCl of used pure DAA.
In order to handle described mother liquor, under the pressure that reduces, steam and remove described solvent to obtain not acidiferous THF-water azeotrope at cat head.Second step that it is used for reacting/precipitating, and can not cause the loss of productive rate or purity.
2.DOPHCl change into the Vit B6 hydrochloride
Variation scheme a:
In the reaction vessel of water distilling apparatus was housed, (variation scheme a) the middle DOPHCl that obtains was dissolved in the 0.1M hydrochloric acid to obtain the concentration of about 13wt% with step 1 to be accompanied by heating.Subsequently, when keeping described temperature, described pressure is reduced to 400 millibars, and kept this temperature in addition 2 hours.During this period, isobutyric aldehyde and water steamed as azeotrope remove.HPLC to still hot reaction soln analyzes demonstration based on used DOPHCl, and the productive rate of Vit B6 hydrochloride is 94%.When being cooled to 0 ℃, the Vit B6 crystal of hydrochloride is come out.Leach this crystal and use a small amount of ice-cold salt acid elution.The degree of purity of production of Huo Deing＞92% by this way.
Change scheme b:
The DOPHCl that 442g is derived from the THF-humidity in stage 1 (variation scheme b) under 50 ℃ is dissolved in its amount and causes concentration to be about in 0.1 mole hydrochloride of 28wt%.Subsequently, the pressure in this device is reduced to 200 millibars, with first steam (T=120 ℃) be that liquid water infeeds then, meanwhile described compound is heated to about 60 ℃.The isobutyric aldehyde that obtains the residue of tetrahydrofuran (THF) like this and removed by steaming subsequently-water azeotrope.Infeed enough steam and water, make that the mass ratio of water and DOPHCl is 6: 1.The time of infeeding of steam and water is about 3 hours.Subsequently, no longer infeeding steam also is concentrated into this mixture based on the concentration of Vit B6 hydrochloride for about 32wt%.
Solution with described still heat under about 55～60 ℃ temperature passes through the gac tower.The stirring tank that uses the paddle stirrer (energy input 0.25watt/kg) that 3-level belt pitch is housed subsequently is the still hot solution to 0 ℃ of (about 10K/h) cooling gained lentamente.Obtain the Vit B6 hydrochloride that crystallizes out like this.
Described solid is leached and wash by suction filter with a small amount of frozen water (based on 1 weight part solid, the water of 0.5 weight part).Cause purity to obtain 208g (based on DOPHCl) Vit B6 hydrochloride like this with＞99%.
Described mother liquor still contains the VB6HCl of the 8wt% that has an appointment, and it can reclaim with solid part by concentrated mother liquor and subsequent crystallisation under the pressure that reduces.
Embodiment 2 (contrast): under the condition of not adding water, DAA is changed into DOPHCl
0.5mol DAA is dissolved in the 380g tetrahydrofuran (THF) and with it mixes with the 5.1g Glacial acetic acid.Under 60 ℃ and normal atmosphere, stirred this solution 2.5 hours.By HPLC the transformation efficiency that the analysis of this reaction mixture is presented at based on DAA under 38% selectivity of DOP is about 9%.
Subsequently, (change scheme and a) under the described condition 0.9mol gaseous state HCl is infeeded described reaction mixture in embodiment 1, step 1.Obtain the DOPHCl that crystallizes out like this.Leach this solid as mentioned above also with a small amount of tetrahydrofuran (THF) washing.Obtain the crystalline product that the 100g chromatic number is APHA416 by this way.Considering the product part that is contained in the mother liquor, is 84% based on the selectivity of DOPHCl.The mole rate of recovery only is 84%.
Embodiment 3
Under no acid catalyzed condition, DAA is changed into DOPHCl
0.5mol DAA is dissolved in the 380g tetrahydrofuran (THF) and with it mixes with 45g water.Under 60 ℃ and normal atmosphere, stirred this solution 4 hours.Being presented at based on DAA transformation efficiency under 55% selectivity of DOP by HPLC to the analysis of this reaction mixture is 15%.
With embodiment 1 (change scheme a), the mode described of step 1 infeeds 0.9mol gaseous state HCl in the reaction mixture that obtains by this way.When cooling, crystallization goes out DOPHCl.Leaching the solid that obtains by this way by suction filter also washs with a small amount of tetrahydrofuran (THF).Obtain the DOPHCl that the 75g chromatic number is APHA 54 by this way.
With regard to whole batch of materials, the selectivity based on the formation of DOPHCl under the mole rate of recovery 97% (2% Vit B6 hydrochloride) is 95%.
Claims (16)
1. method for preparing Vit B6 or its acid salt, it comprises:
I. with the compound dissolution of general formula I in to small part can with the mixture of miscible organic solvent of water and water in,
Wherein
R
1For the optional alkyl that replaces and
R
2And R
3Be hydrogen or the optional alkyl that replaces, perhaps R independently of one another
2And R
3The carbon atom that connects with them forms 5-to 8-unit saturated rings,
And selectively in the presence of the acid of catalytic activity amount, in being higher than the solution of handling the I that obtains by this way under 30 ℃ to 100 ℃ the temperature, changed into Compound I I up to part of compounds I at least
R wherein
2And R
3Definition as mentioned,
Ii. by add precipitation agent with Compound I I or its acid salt from step I. precipitate the solution of acquisition, and separating compound II or its acid salt; With
Iii. the Compound I I that step I i. is obtained or its acid salt change into Vit B6 or change into the acid salt of Vit B6.
2. the method for claim 1, wherein step I. can containing in every mol Compound I 0.5～10mol water with the miscible organic solvent of water and the mixture of water to small part of middle use.
3. method as claimed in claim 1 or 2 is wherein in step I. and middle use is in every mol Compound I 0.01～1mol aliphatic carboxylic acid.
4. method as claimed in claim 1 or 2, wherein step I. the Compound I that the conversion of middle Compound I is proceeded up to 20～80% has changed into Compound I I.
5. method as claimed in claim 1 or 2, wherein said precipitation agent is a hydrogenchloride, it is selectively with the form of aqueous hydrochloric acid.
6. method as claimed in claim 5 wherein saidly can be selected from the miscible organic solvent of water to small part: ether, ether alcohol, C
1-C
5-alkanol and its mixture.
7. method as claimed in claim 5 wherein infeeds step I with gaseous hydrogen chloride in step I i.. the reaction mixture of acquisition.
8. method as claimed in claim 1 or 2 wherein reduces the temperature of described reaction mixture during adding described precipitation agent in step I i..
9. method as claimed in claim 1 or 2 is wherein handled Compound I I or its acid salt in being higher than under 30 ℃ to 80 ℃ the temperature with aqueous inorganic acid in step I ii..
10. method as claimed in claim 9, wherein aqueous inorganic acid is the hydrochloric acid of 0.01～1M.
11. method as claimed in claim 9 is wherein removed the compound R that forms in the described reaction from described reaction mixture in step I ii.
2R
3C=O.
12. method as claimed in claim 11 is wherein removed compound R by water vapor being infeeded described reaction mixture in step I ii.
2R
3C=O, described steam selectively mixes with liquid water.
13. method as claimed in claim 12, wherein based on 1 weight part II, the total amount of the described water that infeeds is 1～50 weight part.
14., wherein be 0.5 * 10 to the maximum as each described method in the claim 11～13
5Carry out the reaction among the step I ii. under the pressure of the reduction of Pa.
15. method as claimed in claim 9 is wherein carried out the reaction among the step I ii. under 40～70 ℃ temperature.
16. method as claimed in claim 1 or 2 wherein obtains Vit B6 by crystallization the reaction mixture that obtains from step I ii. with acid salt.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10261271.4 | 2002-12-27 | ||
| DE2002161271 DE10261271A1 (en) | 2002-12-27 | 2002-12-27 | Process for the preparation of pyridoxine or its acid addition salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1732175A CN1732175A (en) | 2006-02-08 |
| CN100351257C true CN100351257C (en) | 2007-11-28 |
Family
ID=32478029
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2003801077227A Expired - Fee Related CN100351257C (en) | 2002-12-27 | 2003-12-23 | Method for producing pyridoxine or an acid addition salt thereof |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1578752A1 (en) |
| CN (1) | CN100351257C (en) |
| AU (1) | AU2003300226A1 (en) |
| DE (1) | DE10261271A1 (en) |
| WO (1) | WO2004058774A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584692A (en) * | 2011-01-14 | 2012-07-18 | 浙江天新药业有限公司 | Preparation method of puridoxine hydrochloride |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101402600B (en) * | 2008-11-17 | 2010-08-25 | 江西天新药业有限公司 | Process for producing vitamin B6 |
| CN102295598B (en) * | 2011-07-12 | 2012-12-19 | 湖北惠生药业有限公司 | Crystallization method of vitamin B6 |
| CN104710351B (en) * | 2013-12-13 | 2017-12-26 | 大丰海嘉诺药业有限公司 | A kind of continuous preparation method of vitamin B6 |
| CN103739545B (en) * | 2014-01-20 | 2015-07-15 | 新发药业有限公司 | Simple preparation method of vitamin B6 |
| CN108586488B (en) * | 2018-03-29 | 2020-05-12 | 浙江新和成股份有限公司 | Photocatalytic synthesis method of Diels-Alder adduct as intermediate of vitamin B6 |
| CN114149442A (en) * | 2021-12-08 | 2022-03-08 | 华中药业股份有限公司 | Preparation method of impurity TS-3B |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3227721A (en) * | 1965-05-24 | 1966-01-04 | Merck & Co Inc | Process for preparing 2-methyl-3-hydroxypyridines |
| US3250778A (en) * | 1962-11-29 | 1966-05-10 | Hoffmann La Roche | Intermediates for and synthesis of vitamin b and related compounds |
-
2002
- 2002-12-27 DE DE2002161271 patent/DE10261271A1/en not_active Withdrawn
-
2003
- 2003-12-23 AU AU2003300226A patent/AU2003300226A1/en not_active Abandoned
- 2003-12-23 CN CNB2003801077227A patent/CN100351257C/en not_active Expired - Fee Related
- 2003-12-23 EP EP03799503A patent/EP1578752A1/en not_active Withdrawn
- 2003-12-23 WO PCT/EP2003/014812 patent/WO2004058774A1/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3250778A (en) * | 1962-11-29 | 1966-05-10 | Hoffmann La Roche | Intermediates for and synthesis of vitamin b and related compounds |
| US3227721A (en) * | 1965-05-24 | 1966-01-04 | Merck & Co Inc | Process for preparing 2-methyl-3-hydroxypyridines |
Non-Patent Citations (3)
| Title |
|---|
| A new dimer of Pyridoxol (VitaminB6).E.E. Harris et al.Journal of Organic Chemistry,Vol.34 No.6. 1969 * |
| 维生素B6噁唑法合成新工艺 周后元，方资婷，叶鼎彝，杨基樊，王其灼.中国医药工业杂志，第25卷第9期 1994 * |
| 维生素B6的噁唑法合成概况 周后元.医药工业，第16卷第6期 1985 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584692A (en) * | 2011-01-14 | 2012-07-18 | 浙江天新药业有限公司 | Preparation method of puridoxine hydrochloride |
| CN102584692B (en) * | 2011-01-14 | 2013-10-09 | 浙江天新药业有限公司 | Preparation method of puridoxine hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1578752A1 (en) | 2005-09-28 |
| WO2004058774A1 (en) | 2004-07-15 |
| DE10261271A1 (en) | 2004-07-08 |
| AU2003300226A1 (en) | 2004-07-22 |
| CN1732175A (en) | 2006-02-08 |
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