CN102617455B - Preparation method of pyridoxal or pyridoxal hydrochloride - Google Patents
Preparation method of pyridoxal or pyridoxal hydrochloride Download PDFInfo
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- CN102617455B CN102617455B CN201110442237.1A CN201110442237A CN102617455B CN 102617455 B CN102617455 B CN 102617455B CN 201110442237 A CN201110442237 A CN 201110442237A CN 102617455 B CN102617455 B CN 102617455B
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- pyridoxal
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- inorganic salt
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- RADKZDMFGJYCBB-UHFFFAOYSA-N Pyridoxal Chemical compound CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 title claims abstract description 84
- 229960003581 pyridoxal Drugs 0.000 title claims abstract description 28
- 235000008164 pyridoxal Nutrition 0.000 title claims abstract description 28
- 239000011674 pyridoxal Substances 0.000 title claims abstract description 28
- FCHXJFJNDJXENQ-UHFFFAOYSA-N pyridoxal hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(C=O)=C1O FCHXJFJNDJXENQ-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims abstract description 30
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 28
- 239000001301 oxygen Substances 0.000 claims abstract description 28
- 235000008160 pyridoxine Nutrition 0.000 claims abstract description 28
- 239000011677 pyridoxine Substances 0.000 claims abstract description 28
- 150000001412 amines Chemical class 0.000 claims abstract description 25
- 230000003647 oxidation Effects 0.000 claims abstract description 24
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 24
- 229910017053 inorganic salt Inorganic materials 0.000 claims abstract description 23
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 claims abstract description 18
- 239000011764 pyridoxine hydrochloride Substances 0.000 claims abstract description 18
- 229960004172 pyridoxine hydrochloride Drugs 0.000 claims abstract description 18
- 230000003197 catalytic effect Effects 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000000694 effects Effects 0.000 claims abstract description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 26
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 14
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 14
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 7
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 7
- 229960003280 cupric chloride Drugs 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 5
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical compound OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- UJVWPZIWWKDJNH-UHFFFAOYSA-N (4-acetamido-2-hydroxyphenyl)arsonic acid Chemical compound CC(=O)NC1=CC=C([As](O)(O)=O)C(O)=C1 UJVWPZIWWKDJNH-UHFFFAOYSA-N 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 4
- IMPPGHMHELILKG-UHFFFAOYSA-N 4-ethoxyaniline Chemical compound CCOC1=CC=C(N)C=C1 IMPPGHMHELILKG-UHFFFAOYSA-N 0.000 claims description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- NWFNSTOSIVLCJA-UHFFFAOYSA-L copper;diacetate;hydrate Chemical compound O.[Cu+2].CC([O-])=O.CC([O-])=O NWFNSTOSIVLCJA-UHFFFAOYSA-L 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- FRGXNJWEDDQLFH-UHFFFAOYSA-N 4-propan-2-ylpyridine Chemical compound CC(C)C1=CC=NC=C1 FRGXNJWEDDQLFH-UHFFFAOYSA-N 0.000 claims description 2
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- 239000003570 air Substances 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- 230000008901 benefit Effects 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract description 2
- 229940011671 vitamin b6 Drugs 0.000 abstract 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- 239000003446 ligand Substances 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 230000009466 transformation Effects 0.000 description 13
- 238000001514 detection method Methods 0.000 description 12
- 238000011084 recovery Methods 0.000 description 12
- 239000007788 liquid Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 238000007039 two-step reaction Methods 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- 230000008859 change Effects 0.000 description 9
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 description 8
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 description 8
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000005515 coenzyme Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229960001327 pyridoxal phosphate Drugs 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 235000019156 vitamin B Nutrition 0.000 description 2
- 239000011720 vitamin B Substances 0.000 description 2
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000006386 Myelin Proteins Human genes 0.000 description 1
- 108010083674 Myelin Proteins Proteins 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- OMZSGWSJDCOLKM-UHFFFAOYSA-N copper(II) sulfide Chemical compound [S-2].[Cu+2] OMZSGWSJDCOLKM-UHFFFAOYSA-N 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 230000009916 joint effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000005012 myelin Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- -1 nitroxyl free radical Chemical class 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- VIHDTGHDWPVSMM-UHFFFAOYSA-N ruthenium;triphenylphosphane Chemical compound [Ru].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 VIHDTGHDWPVSMM-UHFFFAOYSA-N 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- ROBLTDOHDSGGDT-UHFFFAOYSA-M sodium;pentane-1-sulfonate Chemical compound [Na+].CCCCCS([O-])(=O)=O ROBLTDOHDSGGDT-UHFFFAOYSA-M 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Abstract
The invention discloses a preparation method of pyridoxal or pyridoxal hydrochloride. The preparation method comprises: taking pyridoxine or pyridoxine hydrochloride shown in formula (III) as the starting material and water as the reaction solvent, conducting selective oxidation on the pyridoxine or pyridoxine hydrochloride in water under the effect of a catalytic oxidation system, thus obtaining the pyridoxal or pyridoxal hydrochloride shown in formula (I). The catalytic oxidation system includes an oxygen source, a catalyst, an inorganic salt and an amine ligand. The preparation method of the invention has the advantages of high conversion rate, good selectivity, mild reaction condition, easy operation, low cost, and environmental friendliness, thus boasting good industrial application value.
Description
(1) technical field
The present invention relates to the preparation method of a kind of pyridoxal or pyridoxal hydrochloride, especially a kind of selective oxidation pyridoxol or pyridoxine hydrochloride are prepared the method for pyridoxal or pyridoxal hydrochloride.
(2) background technology
Pyridoxal hydrochloride is vitamins B
6a kind of derivative, as shown in formula I, be the key intermediate of synthetic PLP.PLP chemistry PLP by name, is called for short PLP, is vitamins B
6a kind of activeconstituents forming under the kinase whose effect of Triphosaden in cell, structural formula is as formula II:
PLP is as a coenzyme, can from more than 100 different enzyme effects in body, the biochemistry of joint effect cells in vivo is movable and metabolic.It is to maintain the normal requisite material of human immune system; Be people's bulk-growth, grow, maintain the indispensable material of balance; It is the coenzyme of liver starch Phosphation.In addition, PLP, as a coenzyme, also can be assisted the synthetic of the interior nerve amines of brain cell, accelerates the recovery of impaired brain; In auxiliary nervous system, the myelin of nerve fiber forms; Helper folic acid metabolism etc.
The following several method of bibliographical information synthesizes pyridoxal:
Method one, Ahens H; Korytnyk W. (J.Heterocycl.Chem.Vol.4,1967:625-626) reported taking pyridoxine hydrochloride as starting raw material, obtains pyridoxal, yield 77% with Manganse Dioxide selective oxidation.Method two, More Ashok. (Spectrochimica Acta Part A.Vol.72,2009:204-208) has reported with H
2o
2for oxygenant, dichloro three (triphenyl phosphorus) ruthenium mixture is that catalyst selectivity oxidation pyridoxol is pyridoxal, yield 96.66%.
Above-mentioned two kinds of methods all have weak point, and it is oxygenant that first method is used Manganse Dioxide, produces a large amount of Mn-bearing waste waters, and difficult treatment is unfriendly to environment; The second weak point is used transition metal Ru, expensive, there is no at present industrial applications and is worth, and needs further exploitation of investigators.
(3) summary of the invention
Pollute the shortcomings such as large, process is complicated for overcoming in prior art reaction, the object of this invention is to provide that a kind of transformation efficiency is high, selectivity good, reaction conditions is gentle, easy to operate, with low cost, environmentally friendly, there is the method that selective oxidation pyridoxol that good industrial applications is worth or pyridoxine hydrochloride are prepared pyridoxal or pyridoxal hydrochloride.
For achieving the above object, the present invention adopts following technical scheme:
The preparation method of a kind of pyridoxal or pyridoxal hydrochloride, described preparation method comprises: taking the pyridoxol shown in formula III or pyridoxine hydrochloride as initial feed, taking water as reaction solvent, described pyridoxol or pyridoxine hydrochloride in water under the effect of catalytic oxidation system selective oxidation make the pyridoxal shown in formula I or pyridoxal hydrochloride;
Described catalytic oxidation system comprises oxygen source, catalyzer, inorganic salt and amine part;
It is one of following that described oxygen source is selected from: air, oxygen, hydrogen peroxide;
Described catalyzer is selected from following a kind of or several combination arbitrarily: 2,2,6,6-tetramethyl piperidine-nitrogen-oxyradical, 4-hydroxyl-2,2,6,6-tetramethyl piperidine-1-oxyradical, 4-acetylaminohydroxyphenylarsonic acid 2,2,6,6-tetramethyl piperidine-1-nitroxyl free radical, 4-amino-2,2,6,6-tetramethyl piperidine-1-oxyradical;
Described inorganic salt are selected from following a kind of or several combination arbitrarily: cupric nitrate, copper sulfate, copper trifluoromethanesulfcomposite, cupric sulfide, neutralized verdigris, cupric bromide, cuprous bromide, cupric iodide, cuprous iodide, cupric chloride, cuprous chloride;
Described amine part is selected from following a kind of or several combination arbitrarily: 1，2-diaminoethane, TERTIARY BUTYL AMINE, diethylamine, triethylamine, tri-tert amine, tri-n-butylamine, 1,4-diazabicylo [2.2.2] octane, morpholine, pyridine, PA, DMAP, 4,6-dimethyl-2-pyridine amine, ammoniacal liquor, ammonium chloride, ammonium sulfate, volatile salt, bicarbonate of ammonia, 2,2 '-dipyridyl, 4-isopropyl pyridine, 4-pyridone.
The present invention is in reaction process, and pyridoxal and pyridoxal hydrochloride, in chemical equilibrium, are exactly to prepare pyridoxal therefore prepare pyridoxal hydrochloride actual.
In the present invention, described selective oxidation carries out under the effect of catalytic oxidation system, and described catalytic oxidation system is preferably made up of oxygen source, catalyzer, inorganic salt and amine part.
In the present invention, in the time that described oxygen source is air or oxygen, the pressure of described air or oxygen is 1～5 normal atmosphere, is preferably 1～2 normal atmosphere.In the time that described oxygen source is hydrogen peroxide, the consumption of described hydrogen peroxide is with H
2o
2mole number count 0.5～8 times of mole number of pyridoxol or pyridoxine hydrochloride, be preferably 1～2 times.
Catalyzer of the present invention is nitroxyl free radical, and the consumption of described catalyzer is counted 0.01～5 times of mole number of pyridoxol or pyridoxine hydrochloride with mole number, be preferably 0.05～3 times.
Inorganic salt of the present invention are mantoquita or cuprous salt, and preferably inorganic salt are one of following: cupric bromide, cupric iodide, cupric chloride, cupric nitrate.In the present invention, the consumption of described inorganic salt is counted 0.01～3 times of mole number of pyridoxol or pyridoxine hydrochloride with mole number, be preferably 0.01～1 times, more preferably 0.01～0.5 times.
Amine part of the present invention is preferably from one of following: DMAP, 4-pyridone, ammoniacal liquor, ammonium chloride, triethylamine.In the present invention, the consumption of described amine part is counted 0.01～5 times of mole number of pyridoxol or pyridoxine hydrochloride with mole number, be preferably 0.01～1 times.
In the present invention, described selective oxidation carries out under the temperature condition of 0～55 DEG C.Preferably, described selective oxidation carries out under the temperature condition of 10～30 DEG C.
The present invention can adopt ordinary method (such as liquid chromatography) monitoring reaction end, and the general reaction times is at 1～2h.
The present invention, after selective oxidation completes, can obtain pyridoxal or pyridoxal hydrochloride by column chromatography.But due to pyridoxal and pyridoxal hydrochloride unstable, difficult separation, therefore in actual applications, after selective oxidation completes, gained reaction solution adds p-ethoxyaniline reaction without separation, obtain corresponding Schiff alkali (IX), this Schiff alkali stable in properties, can supply subsequent reactions.Concrete operations can be investigated the paper ANew Synthesis of Pyridoxal-5-phosphate that Masaru Iwanami delivers, Vol.41,1968:161-165.
Compared with prior art, the method for preparing pyridoxal or pyridoxal hydrochloride of the present invention has following advantage: transformation efficiency is high, and selectivity is good, and reaction conditions gentleness is easy to operate, with low cost, environmentally friendly, has good industrial applications and is worth.
(4) embodiment
With specific embodiment, technical scheme of the present invention is described below, but protection scope of the present invention is not limited to this:
Embodiment 1
In the 25mL reaction flask with agitator and thermometer, add successively 0.085g (0.5mmol) 2,2,6,6-tetramethyl piperidine-nitrogen-oxyradical, 0.29g (2mmol) cupric bromide, 0.40g (5mmol) pyridine and 2.06g (10mmol) pyridoxine hydrochloride.Add water 5mL, temperature is controlled at 30 DEG C, opens and stirs.Then drip 2.0g (18mmol) 30% hydrogen peroxide, control temperature of reaction at 30～35 DEG C simultaneously.After dropwising, insulation continues to stir 1～2 hour at 30～35 DEG C, and gained reaction solution reaches 99% (liquid-phase condition: chromatographic column is XDB-G8 250 × 4.6mm 5um through Liquid Detection pyridoxol transformation efficiency.Moving phase is methyl alcohol: buffer=15: 85; Buffer:0.04% sodium pentanesulfonate is adjusted PH to 3 with Glacial acetic acid; Detection wavelength is 284nm), reaction preference is 98%.
In addition, get about 5mL reaction solution and directly go up silicagel column, eluent is methylene dichloride: methyl alcohol=20: 1, obtain final elutriant through gradient elution, and be concentrated into dryly, can obtain white solid pyridoxal hydrochloride, fusing point 164.1-164.8 DEG C, nuclear-magnetism characterizes as follows:
1hNMR (400MHz, DMSO), δ: 8.27 (s, 1H, CHO), 6.63 (d, 1H, CH), 5.00-5.16 (m, 2H, CH
2), 2.62 (s, 3H, CH
3).
Because pyridoxal hydrochloride is unstable, difficult separation, investigate in actual applications paper [the A New Synthesis of Pyridoxal-5-phosphate that Masaru Iwanami delivers, Vol.41,1968:161-165], reaction solution then adds p-ethoxyaniline 1.37g (10mmol), treated yellow Schiff alkali (IX) 2.10g that obtains without separating.The total recovery of two-step reaction is 88%.
Embodiment 2
Oxygen source changes 1 atmospheric oxygen into, and inorganic salt change 1.5g (10mmol) cupric nitrate into, and amine part changes 1.0g (10mmol) triethylamine into, and other operate with embodiment 1, obtain yellow solid 2.21g.Liquid Detection pyridoxol transformation efficiency reaches 99%, and reaction preference is 97%.The total recovery of two-step reaction is 89%.
Embodiment 3
Oxygen source changes 2 atmospheric oxygen into, and inorganic salt change 0.29g (2mmol) cuprous bromide into, and amine part changes 0.24g (4mmol) 1，2-diaminoethane into, and other operate with embodiment 1, obtain yellow solid 1.90g.Liquid Detection pyridoxol transformation efficiency reaches 87%, and reaction preference is 95%.The total recovery of two-step reaction is 74%.
Embodiment 4
Catalyzer is changed to 0.17g (1mmol) 4-amino-2,2,6,6-tetramethyl piperidine-1-oxyradical, 30% hydrogen peroxide changes 0.55g (5mmol) into, and inorganic salt change 0.095g (0.5mmol) cupric iodide into, and amine part changes 0.24g (5mmol) 35% ammoniacal liquor into, other operate with embodiment 1, obtain yellow solid 2.07g.Liquid Detection pyridoxol transformation efficiency reaches 91%, and reaction preference is 95%.The total recovery of two-step reaction is 80%.
Embodiment 5
Catalyzer is changed to 0.09g (0.5mmol) 4-amino-2,2,6,6-tetramethyl piperidine-1-oxyradical, 30% hydrogen peroxide changes 2.8g (25mmol) into, and inorganic salt change 0.20g (2mmol) cupric chloride into, and amine part changes 1.4g (16mmol) morpholine into, other operate with embodiment 1, obtain yellow solid 2.29g.Liquid Detection pyridoxol transformation efficiency reaches 98%, and reaction preference is 96%.The total recovery of two-step reaction is 86%.
Embodiment 6
Catalyzer is changed to 0.086g (0.5mmol) 4-hydroxyl-2,2,6,6-tetramethyl piperidine-1-oxyradical, oxygen source changes an atmospheric air into, and inorganic salt change 1.0 (5mmol) neutralized verdigris into, amine part changes 1.3g (7mmol) tri-n-butylamine into, temperature of reaction changes 0～5 DEG C into, and other operate with embodiment 1, obtain yellow solid 1.93g.Liquid Detection pyridoxol transformation efficiency reaches 85%, and reaction preference is 95%.The total recovery of two-step reaction is 72%.
Embodiment 7
Catalyzer is changed to 0.86g (5mmol) 4-hydroxyl-2,2,6,6-tetramethyl piperidine-1-oxyradical, 30% hydrogen peroxide changes 1.4g (12mmol) into, 0.15g (1mmol) cupric bromide, amine part is changed to 0.095 (1mmol) 4-pyridone, temperature of reaction changes 30～35 DEG C into, and other operate with embodiment 1, obtain yellow solid 2.05g.Liquid Detection pyridoxol transformation efficiency reaches 92%, and reaction preference is 96%.The total recovery of two-step reaction is 81%.
Embodiment 8
Catalyzer changes 0.16g (0.8mmol) 4-acetylaminohydroxyphenylarsonic acid 2 into, 2,6,6-tetramethyl piperidine-1-nitroxyl free radical, oxygen source changes 1 atmospheric oxygen into, and inorganic salt change 0.29g (2mmol) cupric nitrate into, and amine part is changed to 1.2g (12mmol) triethylamine, other operate with embodiment 1, obtain yellow solid 2.10g.Liquid Detection pyridoxol transformation efficiency reaches 99%, and reaction preference is 92%.The total recovery of two-step reaction is 84%.
Embodiment 9
Catalyzer changes 3.0g (15mmol) 4-acetylaminohydroxyphenylarsonic acid 2 into, 2,6,6-tetramethyl piperidine-1-nitroxyl free radical, 30% hydrogen peroxide changes 1.4g (12mmol) into, and inorganic salt change 2.6g (18mmol) cuprous bromide into, and amine part is changed to 0.98 (8mmol) DMAP, other operate with embodiment 1, obtain yellow solid 1.95g.Liquid Detection pyridoxol transformation efficiency reaches 86%, and reaction preference is 97%.The total recovery of two-step reaction is 75%.
Embodiment 10
Catalyzer is changed to 4.3g (25mmol) 2,2,6,6-tetramethyl piperidine-nitrogen-oxyradical, 30% hydrogen peroxide changes 2.3g (20mmol) into, and inorganic salt change 0.38g (2mmol) cupric iodide into, and amine part changes 0.009g (0.1mmol) morpholine into, other operate with embodiment 1, obtain yellow solid 2.05g.Liquid Detection pyridoxol transformation efficiency reaches 93%, and reaction preference is 99%.The total recovery of two-step reaction is 85%.
Embodiment 11
Catalyzer is changed to 4.7g (30mmol) 2,2,6,6-tetramethyl piperidine-nitrogen-oxyradical, inorganic salt change 0.20g (2mmol) cupric chloride into, and amine part changes 1.9g (10mmol) tri-n-butylamine into, other operate with embodiment 1, obtain yellow solid 2.02g.Liquid Detection pyridoxol transformation efficiency reaches 90%, and reaction preference is 95%.The total recovery of two-step reaction is 76%.
Claims (9)
1. the preparation method of a pyridoxal or pyridoxal hydrochloride, described preparation method comprises: taking the pyridoxol shown in formula III or pyridoxine hydrochloride as initial feed, taking water as reaction solvent, described pyridoxol or pyridoxine hydrochloride in water under the effect of catalytic oxidation system selective oxidation make the pyridoxal shown in formula I or pyridoxal hydrochloride; Described selective oxidation carries out under the temperature condition of 0～55 DEG C;
Described catalytic oxidation system comprises oxygen source, catalyzer, inorganic salt and amine part;
It is one of following that described oxygen source is selected from: air, oxygen, hydrogen peroxide;
Described catalyzer is selected from following a kind of or several combination arbitrarily: 2,2,6,6-tetramethyl piperidine-nitrogen-oxyradical, 4-hydroxyl-2,2,6,6-tetramethyl piperidine-1-oxyradical, 4-acetylaminohydroxyphenylarsonic acid 2,2,6,6-tetramethyl piperidine-1-nitroxyl free radical, 4-amino-2,2,6,6-tetramethyl piperidine-1-oxyradical;
Described inorganic salt are selected from following a kind of or several combination arbitrarily: cupric nitrate, copper sulfate, neutralized verdigris, cupric bromide, cuprous bromide, cupric iodide, cuprous iodide, cupric chloride, cuprous chloride;
Described amine part is selected from following a kind of or several combination arbitrarily: 1，2-diaminoethane, TERTIARY BUTYL AMINE, diethylamine, triethylamine, tri-tert amine, tri-n-butylamine, 1,4-diazabicylo [2.2.2] octane, morpholine, pyridine, PA, DMAP, 4,6-dimethyl-2-pyridine amine, ammoniacal liquor, 2,2'-dipyridyl, 4-isopropyl pyridine, 4-pyridone.
2. the preparation method of pyridoxal as claimed in claim 1 or pyridoxal hydrochloride, is characterized in that: described selective oxidation carries out under the temperature condition of 10～30 DEG C.
3. the preparation method of pyridoxal as claimed in claim 1 or pyridoxal hydrochloride, is characterized in that: described catalytic oxidation system is made up of oxygen source, catalyzer, inorganic salt and amine part.
4. the preparation method of the pyridoxal as described in one of claim 1～3 or pyridoxal hydrochloride, is characterized in that: the mol ratio of described pyridoxol or pyridoxine hydrochloride and catalyzer, inorganic salt, amine part is 1:0.01～5:0.01～3:0.01～5; And described oxygen source is air or oxygen, the pressure of described air or oxygen is 1～5 normal atmosphere, or described oxygen source is hydrogen peroxide, and the mol ratio of described pyridoxol or pyridoxine hydrochloride and H2O2 is 1:0.5～8.
5. the preparation method of pyridoxal as claimed in claim 4 or pyridoxal hydrochloride, is characterized in that: the mol ratio of described pyridoxol or pyridoxine hydrochloride and catalyzer, inorganic salt, amine part is 1:0.05～3:0.01～1:0.01～1; And described oxygen source is air or oxygen, the pressure of described air or oxygen is 1～2 normal atmosphere, or described oxygen source is hydrogen peroxide, and the mol ratio of described pyridoxol or pyridoxine hydrochloride and H2O2 is 1:1～2.
6. the preparation method of pyridoxal as claimed in claim 4 or pyridoxal hydrochloride, is characterized in that: described inorganic salt are selected from following one: cupric bromide, cupric iodide, cupric chloride, cupric nitrate.
7. the preparation method of pyridoxal as claimed in claim 5 or pyridoxal hydrochloride, is characterized in that: described inorganic salt are selected from following one: cupric bromide, cupric iodide, cupric chloride, cupric nitrate.
8. the preparation method of the pyridoxal as described in claim 6 or 7 or pyridoxal hydrochloride, is characterized in that: described amine part is selected from one of following: DMAP, 4-pyridone, ammoniacal liquor, triethylamine.
9. the preparation method of pyridoxal as claimed in claim 1 or pyridoxal hydrochloride, it is characterized in that: described preparation method also comprises the steps: after selective oxidation completes, gained reaction solution directly adds p-ethoxyaniline without separating, reaction obtains the Schiff alkali shown in formula (IX), described pyridoxal or pyridoxal hydrochloride are preserved with the form of Schiff alkali
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| CN108976259A (en) * | 2017-06-01 | 2018-12-11 | 上海凯赛生物技术研发中心有限公司 | A kind of synthetic method of phosphopyridoxal pyridoxal phosphate |
| CN107236770A (en) * | 2017-06-28 | 2017-10-10 | 武汉科技大学 | A kind of chemical and bio combined method for catalyzing and synthesizing phosphopyridoxal pyridoxal phosphate |
| CN107382838B (en) * | 2017-08-08 | 2019-11-19 | 东瑞（南通）医药科技有限公司 | A kind of preparation method of phosphopyridoxal pyridoxal phosphate intermediate |
| WO2020155595A1 (en) * | 2019-02-01 | 2020-08-06 | 清华大学 | Aerobic oxidation system containing sulfinic acid, sulfonic acid or derivatives thereof and photocatalytic oxidation method therefor |
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