CN109836374B - Environment-friendly preparation method of vitamin B6 - Google Patents
Environment-friendly preparation method of vitamin B6 Download PDFInfo
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- CN109836374B CN109836374B CN201711213884.9A CN201711213884A CN109836374B CN 109836374 B CN109836374 B CN 109836374B CN 201711213884 A CN201711213884 A CN 201711213884A CN 109836374 B CN109836374 B CN 109836374B
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- Prior art keywords
- cyano
- vitamin
- aminopropionate
- disubstituted
- alkali
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- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 239000011726 vitamin B6 Substances 0.000 title claims abstract description 26
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 title description 12
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 title description 7
- 229940011671 vitamin b6 Drugs 0.000 title description 6
- 235000019158 vitamin B6 Nutrition 0.000 title description 5
- -1 2, 2-disubstituted-5-cyano-4, 7-dihydro-1, 3-dioxepin Chemical class 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 20
- 239000001257 hydrogen Substances 0.000 claims abstract description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 150000001728 carbonyl compounds Chemical class 0.000 claims abstract description 14
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910002091 carbon monoxide Inorganic materials 0.000 claims abstract description 13
- QNAYBMKLOCPYGJ-UHFFFAOYSA-M alaninate Chemical compound CC(N)C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-M 0.000 claims abstract description 11
- 238000006170 formylation reaction Methods 0.000 claims abstract description 11
- 238000006482 condensation reaction Methods 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 8
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 230000005494 condensation Effects 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 31
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 28
- 239000003513 alkali Substances 0.000 claims description 26
- 239000007789 gas Substances 0.000 claims description 21
- 229930003270 Vitamin B Natural products 0.000 claims description 18
- 235000019156 vitamin B Nutrition 0.000 claims description 18
- 239000011720 vitamin B Substances 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 14
- HYSSNHLBSZNTQF-UHFFFAOYSA-N 4-hydroxy-2-(hydroxymethyl)but-2-enenitrile Chemical compound OCC(C#N)=CCO HYSSNHLBSZNTQF-UHFFFAOYSA-N 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- DWKPPFQULDPWHX-UHFFFAOYSA-N methyl 2-aminopropanoate Chemical group COC(=O)C(C)N DWKPPFQULDPWHX-UHFFFAOYSA-N 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- ILYVXUGGBVATGA-UHFFFAOYSA-N 1-carboxyethylazanium;chloride Chemical compound Cl.CC(N)C(O)=O ILYVXUGGBVATGA-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N Alanine Chemical compound CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 claims description 5
- UZOOFOAVJQHYEU-UHFFFAOYSA-N C(=O)=[RhH].C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound C(=O)=[RhH].C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1 UZOOFOAVJQHYEU-UHFFFAOYSA-N 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 4
- ROBXZHNBBCHEIQ-UHFFFAOYSA-N ethyl 2-aminopropanoate Chemical compound CCOC(=O)C(C)N ROBXZHNBBCHEIQ-UHFFFAOYSA-N 0.000 claims description 4
- IYUKFAFDFHZKPI-UHFFFAOYSA-N hydron;methyl 2-aminopropanoate;chloride Chemical group Cl.COC(=O)C(C)N IYUKFAFDFHZKPI-UHFFFAOYSA-N 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 229910001882 dioxygen Inorganic materials 0.000 claims description 3
- JCXLZWMDXJFOOI-UHFFFAOYSA-N ethyl 2-aminopropanoate;hydron;chloride Chemical compound [Cl-].CCOC(=O)C(C)[NH3+] JCXLZWMDXJFOOI-UHFFFAOYSA-N 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- CDJRODYFQOGXNP-UHFFFAOYSA-N C(=O)=[RhH].P Chemical compound C(=O)=[RhH].P CDJRODYFQOGXNP-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- RJJXSCQQRYCPLW-UHFFFAOYSA-N butyl 2-aminopropanoate Chemical compound CCCCOC(=O)C(C)N RJJXSCQQRYCPLW-UHFFFAOYSA-N 0.000 claims description 2
- ODMDNPRWFGSQHZ-UHFFFAOYSA-N butyl 2-aminopropanoate hydrochloride Chemical compound Cl.CCCCOC(=O)C(C)N ODMDNPRWFGSQHZ-UHFFFAOYSA-N 0.000 claims description 2
- CPRFTFJQMGHRRM-UHFFFAOYSA-N carbon monoxide;pentane-2,4-dione;rhodium Chemical compound [Rh].[O+]#[C-].[O+]#[C-].CC(=O)CC(C)=O CPRFTFJQMGHRRM-UHFFFAOYSA-N 0.000 claims description 2
- RXPAYNWWOUGGHI-UHFFFAOYSA-K cycloocta-1,5-diene;rhodium(3+);trichloride Chemical compound Cl[Rh](Cl)Cl.C1CC=CCCC=C1 RXPAYNWWOUGGHI-UHFFFAOYSA-K 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 230000022244 formylation Effects 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- GSMUZACKUHJQDP-UHFFFAOYSA-N propyl 2-aminopropanoate Chemical compound CCCOC(=O)C(C)N GSMUZACKUHJQDP-UHFFFAOYSA-N 0.000 claims description 2
- OUVGTEGRZQSNTH-UHFFFAOYSA-N propyl 2-aminopropanoate hydrochloride Chemical compound Cl.CCCOC(=O)C(C)N OUVGTEGRZQSNTH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims 1
- 239000002351 wastewater Substances 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000009833 condensation Methods 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- FWPDSAJKWKRRJD-UHFFFAOYSA-N 5-ethoxy-4-methyl-1,3-oxazole Chemical compound CCOC=1OC=NC=1C FWPDSAJKWKRRJD-UHFFFAOYSA-N 0.000 description 4
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 4
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 4
- BDXXPIZNQMLMBS-UHFFFAOYSA-N 5-ethoxy-4-methyl-1,3-oxazole-2-carboxylic acid Chemical compound CCOC=1OC(C(O)=O)=NC=1C BDXXPIZNQMLMBS-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 229910001220 stainless steel Inorganic materials 0.000 description 3
- 239000010935 stainless steel Substances 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000006324 decarbonylation Effects 0.000 description 2
- 238000006606 decarbonylation reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- NHZMQXZHNVQTQA-UHFFFAOYSA-N pyridoxamine Chemical compound CC1=NC=C(CO)C(CN)=C1O NHZMQXZHNVQTQA-UHFFFAOYSA-N 0.000 description 2
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 2
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 2
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 2
- GYBMSOFSBPZKCX-UHFFFAOYSA-N sodium;ethanol;ethanolate Chemical compound [Na+].CCO.CC[O-] GYBMSOFSBPZKCX-UHFFFAOYSA-N 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- RUTBWJOYERVBCR-UHFFFAOYSA-N 2-propyl-4,7-dihydro-1,3-dioxepine Chemical compound CCCC1OCC=CCO1 RUTBWJOYERVBCR-UHFFFAOYSA-N 0.000 description 1
- NVJAEYMAUCBDKQ-UHFFFAOYSA-N C(=O)=[RhH].C(C)(=O)C(C(CP(CC(=O)C(C(C)=O)(C(C)=O)C(C)=O)CC(=O)C(C(C)=O)(C(C)=O)C(C)=O)=O)(C(C)=O)C(C)=O Chemical compound C(=O)=[RhH].C(C)(=O)C(C(CP(CC(=O)C(C(C)=O)(C(C)=O)C(C)=O)CC(=O)C(C(C)=O)(C(C)=O)C(C)=O)=O)(C(C)=O)C(C)=O NVJAEYMAUCBDKQ-UHFFFAOYSA-N 0.000 description 1
- KARMSTBGXAHBAY-UHFFFAOYSA-N C(=O)OCC.CC=1N=COC1OCC Chemical compound C(=O)OCC.CC=1N=COC1OCC KARMSTBGXAHBAY-UHFFFAOYSA-N 0.000 description 1
- QPNUSIVQGYFJGW-UHFFFAOYSA-N C(C)N(CC)CC.P(=O)(Cl)(Cl)Cl Chemical compound C(C)N(CC)CC.P(=O)(Cl)(Cl)Cl QPNUSIVQGYFJGW-UHFFFAOYSA-N 0.000 description 1
- MCPVXTFWLAXUKF-UHFFFAOYSA-N C1(=CC=CC=C1)[RhH](C(=O)P)(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound C1(=CC=CC=C1)[RhH](C(=O)P)(C1=CC=CC=C1)C1=CC=CC=C1 MCPVXTFWLAXUKF-UHFFFAOYSA-N 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- DLDJFQGPPSQZKI-UHFFFAOYSA-N but-2-yne-1,4-diol Chemical compound OCC#CCO DLDJFQGPPSQZKI-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- JXEMVHUBFNXQSY-UHFFFAOYSA-N diethyl 5-hydroxy-6-methylpyridine-3,4-dicarboxylate Chemical compound CCOC(=O)C1=CN=C(C)C(O)=C1C(=O)OCC JXEMVHUBFNXQSY-UHFFFAOYSA-N 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 235000008164 pyridoxal Nutrition 0.000 description 1
- 239000011674 pyridoxal Substances 0.000 description 1
- 229960003581 pyridoxal Drugs 0.000 description 1
- 235000008151 pyridoxamine Nutrition 0.000 description 1
- 239000011699 pyridoxamine Substances 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940088594 vitamin Drugs 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
- 239000002699 waste material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to vitamin B6The preparation method is environment-friendly. The method comprises the steps of using 2-cyano-2-cis-butene-1, 4-diol as an initial raw material, carrying out condensation reaction with a carbonyl compound to protect hydroxyl to obtain 2, 2-disubstituted-5-cyano-4, 7-dihydro-1, 3-dioxepin, carrying out formylation reaction with carbon monoxide and hydrogen to prepare 2, 2-disubstituted-5-cyano-6-formyl-1, 3-dioxepin, carrying out condensation with 2-aminopropionate or hydrochloride thereof, and removing the carbonyl compound to prepare the vitamin B6. The method does not use a 4-methyl-5-alkoxy oxazole intermediate which is expensive and has large wastewater amount in the production process, has the advantages of environment-friendly process, high reaction selectivity, high product purity and high atom economy, and is suitable for industrial production.
Description
Technical Field
The invention relates to vitamin B6Belonging to the technical field of pharmaceutical biochemical industry.
Background
Vitamin B6Is one of the vitamins essential to human body, plays a key role in the growth process of animals, and is widely used in the fields of medicine, food, feed additives, cosmetics industry and the like. Vitamin B6(abbreviation VB)6) In nature in the form of pyridoxine, pyridoxal and pyridoxamine. Under certain conditions, the three components can be mutually transformed in vivo. Industrially synthesized vitamin B6Typically pyridoxine hydrochloride.
The chemical synthesis method is generally adopted to produce vitamin B in industry6Preparation of vitamin B from diethyl 2-methyl-3-hydroxy-pyridine-4, 5-dicarboxylate using lithium aluminium hydride as reducing agent, as mentioned in US32277216However, lithium aluminum hydride has a large dosage, a high price, a high cost, a large potential safety hazard and inconvenient operation. At present, vitamin B is in China6The production process adopts 4-methyl-5-ethoxy oxazole route, and the total yield is increased to about 56%, such as 2009,40(2), 81-82 and 96 in Chinese medicine industry. The key of the route is a 4-methyl-5-ethoxy oxazole intermediate, which is prepared by refluxing L-alanine, excessive oxalic acid, ethanol and benzene with water to prepare N-ethoxy oxalyl-L-alanine ethyl ester, cyclizing by phosphorus oxychloride-triethylamine to obtain 4-methyl-5-ethoxy oxazole-2-ethyl formate, and reacting by waterThe 4-methyl-5-ethoxy oxazole is prepared by decarboxylation and hydrolysis, the preparation process is complicated, the energy consumption is high, dehydrating agents such as phosphorus oxychloride and the like are required to close the ring, the wastewater quantity is large, the waste salt content is high, the environmental protection is not facilitated, the atom economy is poor, and the product cost is high. In addition, the obtained product is relatively heavy in color, needs to be purified and decolored for multiple times to remove pyrrole byproducts, and is not beneficial to vitamin B6Green industrial production.
CN104628633A provides a preparation method of vitamin B6, which comprises: reacting 4-methyl-5-ethoxy-2-carboxyl oxazole with 2-n-propyl-4, 7-dihydro-1, 3-dioxepin to obtain a key intermediate compound shown in formula III for preparing vitamin B6; reacting concentrated hydrochloric acid with a compound shown in a formula III to obtain vitamin B6; the total yield was 70%. Although the process route of the method is short, the preparation process of the 4-methyl-5-ethoxy-2-carboxyl oxazole used as the raw material still needs to use phosphorus oxychloride and other cyclization reagents, and the problem of environmental protection is not fundamentally solved. In addition, the 4-methyl-5-ethoxy-2-carboxyl oxazole has poor stability, more side reactions and lower total yield.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides vitamin B6The preparation method of (1).
The method does not use a 4-methyl-5-ethoxy oxazole intermediate with high price and large wastewater amount in the preparation process, does not need high-temperature Diels-Alder addition reaction, and can be used for conveniently preparing the vitamin B6And the whole process is green and environment-friendly.
Description of terms:
vitamin B of the present invention6Is pyridoxine hydrochloride. Has a structure shown in formula I:
suffix numbers of compound names in the present invention are consistent with the corresponding structural formulae in the reaction schemes.
The technical scheme of the invention is as follows:
vitamin B6The preparation method comprises 2-The cyano-2-cis-butene-1, 4-diol is used as an initial raw material and comprises the following steps:
(1) protection reaction
Reacting 2-cyano-2-cis-butene-1, 4-diol (II) with a carbonyl compound in a solvent A in the presence of a catalyst to protect hydroxyl, so as to obtain 2, 2-disubstituted-5-cyano-4, 7-dihydro-1, 3-dioxaheptin (III); the carbonyl compound has the structure shown in formula VI below:
wherein R is2And R3Can be hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl or tert-butyl, respectively or simultaneously;
(2) formylation reaction
Preparing 2, 2-disubstituted-5-cyano-6-formyl-1, 3-dioxoheptacyclo (IV) by formylating 2, 2-disubstituted-5-cyano-4, 7-dihydro-1, 3-dioxaheptin (III) with carbon monoxide and hydrogen in a solvent B in the presence of a formylation catalyst;
(3) condensation and deprotection reactions
In an alcohol solvent, under the action of alkali, 2-disubstituted-5-cyano-6-formyl-1, 3-dioxygen heptacyclo (IV) and 2-aminopropionate or hydrochloride of 2-aminopropionate are subjected to condensation reaction to obtain 1, 5-dihydro-3, 3-disubstituted-8-methyl-9-hydroxypyrido [3,4-e ]]1, 3-dioxohepta (V), by reacting under acidic conditions a1, 5-dihydro-3, 3-disubstituted-8-methyl-9-hydroxypyrido [3,4-e ] compound]The (E) -1, 3-dioxoheptacyclo (V) is subjected to hydrolysis deprotection to remove carbonyl compound, thus preparing vitamin B6(Ⅰ)。
According to the invention, the solvent A in the step (1) is selected from one or a combination of dichloromethane, chloroform, n-hexane, cyclohexane, petroleum ether or toluene, and the mass ratio of the solvent A to the 2-cyano-2-cis-1, 4-diol (II) is (2.0-10.0): 1. Further preferably, the mass ratio of the solvent A to the 2-cyano-2-cis-buten-1, 4-diol (II) (5.0-8.0): 1.
Preferably according to the invention, in step (1), the catalyst is one or a combination of p-toluenesulfonic acid, hydrochloric acid, sulfuric acid or nitric acid; the mass ratio (0.01-0.1) of the catalyst to the 2-cyano-2-cis-buten-1, 4-diol (II) is 1. Further preferably, the mass ratio (0.03-0.08) is 1.
According to a preferred embodiment of the invention, in step (1), the molar ratio of the carbonyl compound to the 2-cyano-2-cis-1, 4-diol (II) (1.0-1.3): 1.
Preferably, according to the invention, the reaction temperature of step (1) is 10 to 100 ℃; further preferably, the reaction temperature is 25 to 85 ℃. Preferably, the reaction time of step (1) is 2 to 10 hours.
Preferably, step (2) comprises any one or more of the following conditions:
a1, wherein the solvent B in the step (2) is one or the combination of n-hexane, cyclohexane, n-heptane, petroleum ether, toluene or xylene;
a2, the mass ratio of the solvent B to the 2, 2-disubstituted-5-cyano-4, 7-dihydro-1, 3-dioxaheptin (III) (3.0-10.0) is 1. Further preferably, the mass ratio (5.0-8.0) of the solvent B to the 2, 2-disubstituted-5-cyano-4, 7-dihydro-1, 3-dioxepin (III) is 1.
a3, the catalyst is tri (triphenyl) phosphine carbonyl rhodium hydride, tri (sodium trisulfonate phenyl) phosphine carbonyl rhodium hydride, tri (triacetylacetonyl) phosphine carbonyl rhodium hydride, acetylacetone dicarbonyl rhodium, bis (1, 5-cyclooctadiene rhodium chloride); preferably tris (triphenyl) phosphinocarbonylrhodium hydride.
a4, wherein the catalyst accounts for 0.01-1.0 percent of the mass ratio of the 2, 2-disubstituted-5-cyano-4, 7-dihydro-1, 3-dioxaheptin (III).
a5, wherein the formylation reaction temperature is 50-150 ℃; further preferably, the reaction temperature is 75 to 125 ℃. Preferably, the formylation reaction temperature is 95-100 ℃ or 105-110 ℃.
a6, wherein the molar ratio of the carbon monoxide to the hydrogen is 1: 1;
a7 the pressure of the mixed gas of carbon monoxide and hydrogen is 1.0-20.0 MPa. Preferably, the pressure of the mixed gas of carbon monoxide and hydrogen is 2-4 MPa. The reaction time is 5-10 hours.
Preferably, step (3) comprises any one or more of the following conditions:
b 1: the 2-aminopropionate hydrochloride is selected from 2-aminopropionate methyl ester hydrochloride, 2-aminopropionate ethyl ester hydrochloride, 2-aminopropionate propyl ester hydrochloride and 2-aminopropionate butyl ester hydrochloride; the 2-aminopropionate is selected from methyl 2-aminopropionate, ethyl 2-aminopropionate, propyl 2-aminopropionate and butyl 2-aminopropionate; are all commercial products.
b 2: the alcohol solvent is methanol, ethanol, isopropanol, n-butanol or sec-butanol;
b 3: the mass ratio of the alcohol solvent to the 2, 2-disubstituted-5-cyano-6-formyl-1, 3-dioxoheptacyclo (5.0-15.0) is 1. More preferably, (7.0-12.0): 1.
b 4: the alkali is organic alkali or inorganic alkali, and the organic alkali is selected from sodium methoxide, sodium ethoxide, triethylamine or diethyl isopropylamine; the inorganic base is selected from potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate. Wherein the sodium methoxide is added in the form of sodium methoxide methanol solution, and the sodium methoxide methanol solution with the mass fraction of 20-35% is further preferable. The sodium ethoxide is added in the form of sodium ethoxide ethanol solution; further preferably, the mass fraction of the sodium ethoxide ethanol solution is 20-35%.
b 5: the mass ratio of the 2, 2-disubstituted-5-cyano-6-formyl-1, 3-dioxan, 2-aminopropionic acid ester hydrochloride to the alkali is 1 (1.0-1.5) to 2.0-3.5; the mass ratio of the 2, 2-disubstituted-5-cyano-6-formyl-1, 3-dioxy heptacyclo, 2-amino propionate and alkali is 1 (1.0-1.5) to (1.0-2.5).
Preferably, according to the invention, the condensation reaction temperature in step (3) is regulated in stages:
when the alkali is organic alkali, keeping the temperature at 20-40 ℃, dropwise adding 2, 2-disubstituent-5-cyano-6-formyl-1, 3-dioxetane into alcohol solvent, alkali, 2-aminopropionate hydrochloride or 2-aminopropionate methyl ester, and stirring for reaction at 45-55 ℃. The reaction time is 4-6 hours.
Maintaining the temperature at 45-55 ℃ when the alkali is inorganic alkali, dropwise adding 2, 2-disubstituent-5-cyano-6-formyl-1, 3-dioxetane into alcohol solvent, alkali, 2-aminopropionate hydrochloride or 2-aminopropionate methyl ester, and stirring for reaction at 55-75 ℃ after dropwise adding. The reaction time is 6-8 hours.
Preferably, according to the invention, after the condensation reaction in the step (3) is finished, hydrochloric acid with the mass concentration of 30-35% is added, the reflux is carried out for 3-6 hours, after the decarbonylation compound of the hydrolysis reaction is finished, the hot filtration is carried out, the solvent is recovered from the filtrate under reduced pressure, and the vitamin B is obtained after the post-treatment6And (5) producing the product. The post-treatment is carried out according to the prior art and mainly comprises the steps of decoloring, crystallizing, separating, drying and the like.
According to the invention, the hydrogen cyanide gas generated in the deprotection reaction process in the step (3) can be used for preparing 2-cyano-2-butene-1, 4-diol (II) after being collected, so that the cyclic utilization of the hydrogen cyanide gas is realized, and no harmful gas is discharged. The preferred method for collecting the hydrogen cyanide gas is: absorbing the tail gas of the reaction in the step (3) for 2-3 times by using a sodium hydroxide aqueous solution with the mass fraction of 15-30%.
The reaction route of the method is as follows:
R1is methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl,
R2、R3is hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl
The invention has the technical characteristics and excellent effects that:
1. the method of the invention uses 2-cyano-2-cis-butene-1, 4-diol as initial raw material, and the condensation reaction is carried out with carbonyl compound to protect hydroxyl group and obtain 2, 2-disubstituted-5-cyano-4, 7-dihydro-1, 3-dioxepin, then the 2, 2-disubstituted-5-cyano-6-formyl-1, 3-dioxepin is prepared with carbon monoxide and hydrogen through formylation reaction, and then the 2, 2-disubstituted-5-cyano-6-formyl-1, 3-dioxepin is condensed with 2-amino propionate or hydrochloride thereof, and the decarbonylation compound is prepared into vitamin B6. The invention is notThe 4-methyl-5-alkoxy oxazole intermediate with high price and large wastewater amount in the production process is used, the process is environment-friendly, and the wastewater amount is small. The invention firstly reacts the initial raw material and the carbonyl compound to protect the hydroxyl, thereby prolonging the service life of the catalyst and increasing the application times of the catalyst.
2. The intermediate 2, 2-disubstituted-5-cyano-6-formyl-1, 3-dioxohepta-ring obtained by the method has the advantages of high reaction activity, good reaction selectivity, high product yield and high purity. The total yield of the three steps can reach 85.8 percent based on the initial compound.
3. The invention directly uses 2-amino propionate or hydrochloride thereof to construct pyridine ring, hydrogen cyanide and carbonyl compound generated in the process can be recycled, the atom economy is high, and the method is suitable for vitamin B6Green industrial production.
Detailed Description
The following examples are provided to fully illustrate the technical aspects of the present invention in detail, but the present invention is not limited to the following examples. Based on the embodiments of the present invention, any non-inventive solutions and embodiments derived by those skilled in the art in combination with the present technical solutions belong to the protection scope of the present invention.
The raw material 2-cyano-2-cis-buten-1, 4-diol is provided by the pharmaceutical industry of Jinan Bright, the GC purity is 99.7 percent, and the raw materials 2-aminopropionic acid methyl ester hydrochloride, 2-aminopropionic acid ethyl ester hydrochloride, 2-aminopropionic acid methyl ester and 2-aminopropionic acid ethyl ester are commercially available. The starting materials and intermediates were assayed by gas chromatography, Shimadzu GC-2010PLUS, and the final product purity was determined by high performance liquid chromatography, indicated as (HPLC).
Preparation of mono, 2-disubstituted-5-cyano-4, 7-dihydro-1, 3-dioxepin (iii):
example 1: 2-n-propyl-5-cyano-4, 7-dihydro-1, 3-dioxepin (III 1, wherein R is2Is n-propyl, R3Is hydrogen) preparation
Into a 500 ml four-necked flask, 300 g of methylene chloride, 56.5 g (0.5 mol) of 2-cyano-2-cis-buten-1, 4-diol, 38.9 g (0.54 mol) of n-butyraldehyde, 0.5 g of p-toluenesulfonic acid were added and reacted at 30 to 35 ℃ for 5 hours. The layers were separated, the aqueous layer was extracted twice with dichloromethane (30 g total), the organic phases were combined, washed once with 20 g of 5% aqueous sodium carbonate solution, the organic phase was distilled at atmospheric pressure to recover dichloromethane, and then distilled under reduced pressure (120 ℃ C., 140 ℃ C., 5-10 mm Hg) to give 80.6 g of 2-n-propyl-5-cyano-4, 7-dihydro-1, 3-dioxaheptin with a GC purity of 99.7% and a yield of 96.5%.
Example 2: 2-isopropyl-5-cyano-4, 7-dihydro-1, 3-dioxepin (III 2, wherein R is2Is isopropyl, R3Is hydrogen) preparation
Into a 500 ml four-necked flask, 300 g of chloroform, 56.5 g (0.5 mol) of 2-cyano-2-cis-buten-1, 4-diol, 38.9 g (0.54 mol) of isobutyraldehyde, 0.5 g of p-toluenesulfonic acid were added and reacted at 35 to 40 ℃ for 5 hours. The layers were separated, the aqueous layer was extracted twice with chloroform (30 g total), the organic phases were combined, washed once with 20 g of 5% aqueous sodium carbonate solution, the organic phase was distilled at normal pressure to recover chloroform, and then distilled under reduced pressure (120 ℃ C., 140 ℃ C., 5-10 mm Hg) to give 80.8 g of 2-isopropyl-5-cyano-4, 7-dihydro-1, 3-dioxepin, a GC purity of 99.9%, and a yield of 96.8%.
Example 3: 2-methyl-2-ethyl-5-cyano-4, 7-dihydro-1, 3-dioxepin (III 3, wherein R is2Is methyl, R3Is ethyl) preparation
A500 ml four-necked flask was charged with 300 g of toluene, 56.5 g (0.5 mol) of 2-cyano-2-cis-buten-1, 4-diol, 39.6 g (0.55 mol) of 2-butanone, 0.5 g of 98% sulfuric acid, and reacted at 50 to 60 ℃ for 4 hours. The layers were separated, the aqueous layer was extracted twice with toluene (30 g total), the organic phases were combined, washed once with 20 g of 5% aqueous sodium carbonate solution, the organic phase was distilled at normal pressure to recover toluene, and then distilled under reduced pressure (120 ℃ C., 140 ℃ C., 5-10 mm Hg) to give 79.6 g of 2-methyl-2-ethyl-5-cyano-4, 7-dihydro-1, 3-dioxepin, a GC purity of 99.6%, and a yield of 95.3%.
Preparation of di, 2-disubstituted-5-cyano-6-formyl-1, 3-dioxaheptacyclo (IV):
example 4: 2-n-propyl-5-cyano-6-formyl-1, 3-dioxaheptacyclo (IV 1, wherein R2Is n-propyl, R3Is hydrogen) preparation
100 g of toluene, 66.8 g (0.4 mol) of 2-n-propyl-5-cyano-4, 7-dihydro-1, 3-dioxaheptin (prepared in example 1) and 300 mg of tris (triphenyl) phosphine carbonyl rhodium hydride were charged into a 500 ml stainless steel autoclave replaced with nitrogen, and after three times of replacement with nitrogen, carbon monoxide and hydrogen were introduced and the reaction was carried out for 7 hours while maintaining a temperature of 95 to 100 ℃ and a pressure of 2.0 to 2.5 MPa. Cooling to normal temperature, evacuating, replacing with nitrogen for three times, removing the reaction liquid, filtering, distilling the organic phase at normal pressure to recover toluene, and then distilling under reduced pressure (110 ℃ C., 120 ℃ C., 3-5 mm Hg) to obtain 72.6 g of 2-n-propyl-5-cyano-6-formyl-1, 3-dioxaheptanes, wherein the GC purity is 99.3%, and the yield is 93.1%.
Example 5: 2-isopropyl-5-cyano-6-formyl-1, 3-dioxaheptacyclo (IV 2, wherein R is2Is isopropyl, R3Is hydrogen) preparation
100 g of n-hexane, 66.8 g (0.4 mol) of 2-isopropyl-5-cyano-4, 7-dihydro-1, 3-dioxaheptin (prepared in example 2), 350 mg of tris (triphenyl) phosphine carbonyl rhodium hydride were charged into a 500 ml stainless steel autoclave replaced with nitrogen, and after three times of replacement with nitrogen, carbon monoxide and hydrogen were introduced and the reaction was carried out for 6 hours while maintaining the temperature at 95 to 100 ℃ and the pressure at 2.5 to 3.5 MPa. Cooling to normal temperature, evacuating, replacing with nitrogen for three times, removing the reaction liquid, filtering, distilling the organic phase at normal pressure to recover n-hexane, and then distilling under reduced pressure (110 ℃ C., 115 ℃ C., 3-5 mm Hg) to obtain 73.2 g of 2-isopropyl-5-cyano-6-formyl-1, 3-dioxaheptanes, wherein the GC purity is 99.5%, and the yield is 93.9%.
Example 6: 2-methyl-2-ethyl-5-cyano-6-formyl-1, 3-dioxoheptacyclo (IV 3, wherein R is2Is methyl, R3Is ethyl) preparation
100 g of toluene, 66.8 g (0.4 mol) of 2-methyl-2-ethyl-5-cyano-4, 7-dihydro-1, 3-dioxepin (prepared in example 3) and 300 mg of tris (triphenyl) phosphine carbonyl rhodium hydride were charged into a 500 ml stainless steel autoclave replaced with nitrogen, and after three replacements with nitrogen, carbon monoxide and hydrogen were introduced and the reaction was carried out at 95 to 100 ℃ and 2.0 to 2.5MPa for 7 hours. Cooling to normal temperature, evacuating, replacing with nitrogen for three times, removing the reaction liquid, filtering, distilling the organic phase at normal pressure to recover toluene, and then distilling under reduced pressure (110 ℃ C., 125 ℃ C., 3-5 mm Hg) to obtain 71.5 g of 2-methyl-2-ethyl-5-cyano-6-formyl-1, 3-dioxaheptanes, wherein the GC purity is 99.2%, and the yield is 91.7%.
III, vitamin B6Preparation of
The following examples 7-9 were conducted in a fume hood and the tail gas was absorbed twice with 200 g of 25% aqueous sodium hydroxide solution. The tail gas contains hydrogen cyanide, and the generated hydrogen cyanide gas can react with the 2-butyne-1, 4-diol to prepare the 2-cyano-2-cis-buten-1, 4-diol after being collected in the industrial production process, so that the cyclic utilization of the hydrogen cyanide gas is realized.
Example 7: vitamin B6Preparation of
Into a 500 ml four-necked flask, 200 g of methanol, 30.5 g (0.22 mol) of methyl 2-aminopropionate hydrochloride and 100 g of 27% sodium methoxide methanol solution were charged, and stirred, and kept at 30 to 35 ℃ to add 39.0 g (0.2 mol) of 2-n-propyl-5-cyano-6-formyl-1, 3-dioxoheptacyclo (prepared in example 4) dropwise, followed by stirring at 50 ℃ for 5 hours. Adding 80 g of 35% concentrated hydrochloric acid (hydrogen cyanide gas is generated in the process) below 50 ℃, carrying out reflux reaction for 4 hours, filtering while the solution is hot, recovering the solvent and n-butyraldehyde from the filtrate under reduced pressure, adding 40 g of ethanol and 0.2 g of activated carbon, decolorizing for 30 minutes at 70 ℃, filtering, cooling and crystallizing the filtrate, carrying out suction filtration, and drying the filter cake to obtain 38.5 g of vitamin B6The product, 99.8% pure (HPLC), 93.7% yield.
Example 8: vitamin B6Preparation of
Into a 500 ml four-necked flask, 200 g of methanol, 22.5 g (0.22 mol) of methyl 2-aminopropionate and 50 g of a 27% sodium methoxide methanol solution were charged, and the mixture was stirred and kept at 30 to 35 ℃ to add 39.0 g (0.2 mol) of 2-isopropyl-5-cyano-6-formyl-1, 3-dioxoheptacyclo (prepared in example 5) dropwise, followed by stirring at 45 ℃ for 5 hours. Then adding 35 g of 60 g below 45 DEG C% concentrated hydrochloric acid (hydrogen cyanide gas is generated in the process), reflux reaction is carried out for 4 hours, hot filtration is carried out, the solvent and isobutyraldehyde are recovered from filtrate under reduced pressure, 40 g of ethanol and 0.2 g of active carbon are added, decolorization is carried out for 30 minutes at 70 ℃, filtration is carried out, the filtrate is cooled, crystallized and filtered, and 38.9 g of vitamin B is obtained after filter cakes are dried6Product, purity 99.9% (HPLC), yield 94.7%.
Example 9: vitamin B6Preparation of
Into a 500 ml four-necked flask, 200 g of ethanol, 25.8 g (0.22 mol) of ethyl 2-aminopropionate and 35.0 g of potassium carbonate were charged, stirred, maintained at 50 ℃ and 39.0 g (0.2 mol) of 2-methyl-2-ethyl-5-cyano-6-formyl-1, 3-dioxoheptacyclo (prepared in example 6) was added dropwise, and after completion of dropwise addition, the mixture was stirred at 55 ℃ for 6 hours. Adding 80 g of 30% concentrated hydrochloric acid (hydrogen cyanide gas is generated in the process) below 55 ℃, carrying out reflux reaction for 4 hours, filtering while the solution is hot, decompressing the filtrate, recovering the solvent and 2-butanone, adding 40 g of ethanol and 0.2 g of activated carbon, decoloring for 30 minutes at 70 ℃, filtering, cooling and crystallizing the filtrate, carrying out suction filtration, and drying the filter cake to obtain 35.5 g of vitamin B6Product, purity 99.7% (HPLC), yield 86.4%.
Claims (12)
1. Vitamin B6The preparation method takes 2-cyano-2-cis-buten-1, 4-diol as an initial raw material and comprises the following steps:
(1) protection reaction
Reacting 2-cyano-2-cis-butene-1, 4-diol (II) with a carbonyl compound in a solvent A in the presence of a catalyst to protect hydroxyl, so as to obtain 2, 2-disubstituted-5-cyano-4, 7-dihydro-1, 3-dioxaheptin (III); the carbonyl compound has the structure shown in formula VI below:
wherein R is2And R3Each or both hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl or tert-butyl;
the solvent A is selected from one or a combination of dichloromethane, chloroform, normal hexane, cyclohexane, petroleum ether or toluene;
the catalyst is one or a combination of p-toluenesulfonic acid, hydrochloric acid, sulfuric acid or nitric acid;
the reaction temperature is 10-100 ℃;
(2) formylation reaction
Preparing 2, 2-disubstituted-5-cyano-6-formyl-1, 3-dioxoheptacyclo (IV) by formylating 2, 2-disubstituted-5-cyano-4, 7-dihydro-1, 3-dioxaheptin (III) with carbon monoxide and hydrogen in a solvent B in the presence of a formylation catalyst;
the solvent B is one or a combination of n-hexane, cyclohexane, n-heptane, petroleum ether, toluene or xylene;
the catalyst is tri (triphenyl) phosphine carbonyl rhodium hydride, tri (sodium trisulfonate phenyl) phosphine carbonyl rhodium hydride, tri (triacetylacetone) phosphine carbonyl rhodium hydride, acetylacetone dicarbonyl rhodium, bis (1, 5-cyclooctadiene rhodium chloride);
the formylation reaction temperature is 50-150 ℃;
(3) condensation and deprotection reactions
In an alcohol solvent, under the action of alkali, 2-disubstituted-5-cyano-6-formyl-1, 3-dioxygen heptacyclo (IV) and 2-aminopropionate or hydrochloride of 2-aminopropionate are subjected to condensation reaction to obtain 1, 5-dihydro-3, 3-disubstituted-8-methyl-9-hydroxypyrido [3,4-e ] -1, 3-dioxygen heptacyclo (V),
without isolation, under acidic conditions the 1, 5-dihydro-3, 3-disubstituted-8-methyl-9-hydroxypyrido [3,4-e ] s]The (E) -1, 3-dioxoheptacyclo (V) is subjected to hydrolysis deprotection to remove carbonyl compound, thus preparing vitamin B6；
And (4) collecting hydrogen cyanide gas generated in the deprotection reaction process in the step (3) and then using the hydrogen cyanide gas to prepare 2-cyano-2-butene-1, 4-diol (II) so as to realize the cyclic utilization of the hydrogen cyanide gas.
2. Vitamin B as claimed in claim 16The preparation method is characterized in that in the step (1), the mass ratio (2.0-10.0) of the solvent A to the 2-cyano-2-cis-buten-1, 4-diol (II) is 1.
3. Vitamin B as claimed in claim 16The preparation method is characterized in that in the step (1), the mass ratio of the catalyst to the 2-cyano-2-cis-buten-1, 4-diol (II) is (0.01-0.1): 1.
4. Vitamin B as claimed in claim 16The preparation method is characterized in that in the step (1), the molar ratio (1.0-1.3) of the carbonyl compound to the 2-cyano-2-cis-1, 4-diol (II) is 1.
5. Vitamin B as claimed in claim 16The production method of (2), wherein in the step (1), the reaction temperature is 25 to 85 ℃.
6. Vitamin B as claimed in claim 16The method of (2), wherein any one or more of the following conditions are included in the step (2):
a1, the mass ratio of the solvent B to the 2, 2-disubstituted-5-cyano-4, 7-dihydro-1, 3-dioxaheptin (III) (3.0-10.0) is 1;
a2, wherein the catalyst accounts for 0.01 to 1.0 percent of the mass of the 2, 2-disubstituted-5-cyano-4, 7-dihydro-1, 3-dioxaheptine (III);
a3, wherein the formylation reaction temperature is 75-125 ℃;
a4, wherein the molar ratio of the carbon monoxide to the hydrogen is 1: 1;
a5 the pressure of the mixed gas of carbon monoxide and hydrogen is 1.0-20.0 MPa.
7. Vitamin B as claimed in claim 16Characterized in that, in the step (2), the method isThe mass ratio of the solvent B to the 2, 2-disubstituted-5-cyano-4, 7-dihydro-1, 3-dioxaheptin (III) (5.0-8.0) is 1; the formylation reaction temperature is 95-100 ℃ or 105-110 ℃; the pressure of the mixed gas of the carbon monoxide and the hydrogen is 2-4 MPa.
8. Vitamin B as claimed in claim 16The production method of (2), wherein any one or more of the following conditions are included in the step (3):
b 1: the 2-aminopropionate hydrochloride is selected from 2-aminopropionate methyl ester hydrochloride, 2-aminopropionate ethyl ester hydrochloride, 2-aminopropionate propyl ester hydrochloride and 2-aminopropionate butyl ester hydrochloride; the 2-aminopropionate is selected from methyl 2-aminopropionate, ethyl 2-aminopropionate, propyl 2-aminopropionate and butyl 2-aminopropionate;
b 2: the alcohol solvent is methanol, ethanol, isopropanol, n-butanol or sec-butanol;
b 3: the mass ratio of the alcohol solvent to the 2, 2-disubstituted-5-cyano-6-formyl-1, 3-dioxoheptacyclo (5.0-15.0) is 1;
b 4: the alkali is organic alkali or inorganic alkali, and the organic alkali is selected from sodium methoxide, sodium ethoxide, triethylamine or diethyl isopropylamine; the inorganic base is selected from potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate;
b 5: the mass ratio of the 2, 2-disubstituted-5-cyano-6-formyl-1, 3-dioxan, 2-aminopropionic acid ester hydrochloride to the alkali is 1 (1.0-1.5) to 2.0-3.5.
9. Vitamin B as claimed in claim 16The preparation method is characterized in that in the step (3), the mass ratio of the alcohol solvent to the 2, 2-disubstituted-5-cyano-6-formyl-1, 3-dioxoheptacyclo is (7.0-12.0): 1; the mass ratio of the 2, 2-disubstituted-5-cyano-6-formyl-1, 3-dioxy heptacyclo, 2-amino propionate and alkali is 1 (1.0-1.5) to (1.0-2.5).
10. Vitamin B as claimed in claim 16Characterized in that the condensation reaction temperature in step (3) is controlled in stages：
When the alkali is organic alkali, keeping the temperature at 20-40 ℃, dropwise adding 2, 2-disubstituent-5-cyano-6-formyl-1, 3-dioxetane into an alcohol solvent, the alkali, 2-aminopropionate hydrochloride or 2-aminopropionate methyl ester, and stirring for reaction at 45-55 ℃ after dropwise adding;
maintaining the temperature at 45-55 ℃ when the alkali is inorganic alkali, dropwise adding 2, 2-disubstituent-5-cyano-6-formyl-1, 3-dioxetane into alcohol solvent, alkali, 2-aminopropionate hydrochloride or 2-aminopropionate methyl ester, and stirring for reaction at 55-75 ℃ after dropwise adding.
11. Vitamin B as claimed in claim 16The preparation method is characterized in that after the condensation reaction in the step (3) is finished, hydrochloric acid with the mass concentration of 30-35% is added, reflux is carried out for 3-6 hours, the hydrolysis reaction for removing carbonyl compounds is finished, the hot filtration is carried out, the filtrate is decompressed and the solvent is recovered, and the vitamin B is obtained after post-treatment6And (5) producing the product.
12. Vitamin B as claimed in claim 16The preparation method is characterized in that the collection method of the hydrogen cyanide gas comprises the following steps: absorbing the tail gas of the reaction in the step (3) for 2-3 times by using a sodium hydroxide aqueous solution with the mass fraction of 15-30%.
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| CN103739545A (en) * | 2014-01-20 | 2014-04-23 | 新发药业有限公司 | Simple preparation method of vitamin B6 |
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| CN103739545A (en) * | 2014-01-20 | 2014-04-23 | 新发药业有限公司 | Simple preparation method of vitamin B6 |
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| Rh-Catalyzed Asymmetric Hydroformylation of Heterocyclic Olefins Using Chiral Diphosphite Ligands. Scope and Limitations;Javier Mazuela等;《J. Org. Chem.》;20090702;第74卷(第15期);第5444页 * |
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