CN114315703A - Preparation method of high-purity vitamin B6 - Google Patents
Preparation method of high-purity vitamin B6 Download PDFInfo
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- CN114315703A CN114315703A CN202111567993.7A CN202111567993A CN114315703A CN 114315703 A CN114315703 A CN 114315703A CN 202111567993 A CN202111567993 A CN 202111567993A CN 114315703 A CN114315703 A CN 114315703A
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- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 title claims abstract description 115
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 title claims abstract description 94
- 239000011726 vitamin B6 Substances 0.000 title claims abstract description 94
- 235000019158 vitamin B6 Nutrition 0.000 title claims abstract description 94
- 229940011671 vitamin b6 Drugs 0.000 title claims abstract description 94
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 109
- 238000005899 aromatization reaction Methods 0.000 claims abstract description 89
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 79
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- 238000000034 method Methods 0.000 claims abstract description 38
- 238000007670 refining Methods 0.000 claims abstract description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 231
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 141
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 132
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 96
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- 238000001914 filtration Methods 0.000 claims description 26
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 239000007864 aqueous solution Substances 0.000 claims description 23
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- 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 claims description 6
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- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
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- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 75
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 44
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- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 4
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
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- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
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- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
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- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
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- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical group CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
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- HRQDCDQDOPSGBR-UHFFFAOYSA-M sodium;octane-1-sulfonate Chemical compound [Na+].CCCCCCCCS([O-])(=O)=O HRQDCDQDOPSGBR-UHFFFAOYSA-M 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of high-purity vitamin B6. The method of the invention obtains the refined vitamin B6 through aromatization reaction, hydrolysis reaction and refining steps. The method of the invention improves the aromatization reaction, hydrolysis reaction and refining steps, and especially adds an organic solvent into the reaction system in the hydrolysis reaction step, thereby having outstanding effect on the improvement of the preparation process of the vitamin B6. The method has the advantages of high product purity, high content, less impurities, light color, high yield, simple and convenient operation, energy conservation, low cost and reduction of three-waste discharge.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis of vitamins, and particularly relates to a preparation method of high-purity vitamin B6.
Background
The main commercial form of vitamin B6, pyridoxine hydrochloride, is widely used in the fields of feed additives, food additives, health products, medicines, etc.
Currently, the oxazole method is widely used in industry to synthesize vitamin B6. The method comprises Diels-Alder (Diels-Alder) reaction, aromatization reaction, hydrolysis reaction, and refining to obtain refined vitamin B6.
The prior report of synthesizing vitamin B6 by using oxazole method is as follows:
patent document CN101402600A discloses a preparation method of vitamin B6, which is characterized in that an alkaline reagent (triethylamine) is added in a Diels-Alder reaction, an aromatization reaction system is a Diels-Alder reaction product, ethanol, water, hydrochloric acid and a metal ion chelating agent (ethylene diamine tetraacetic acid), after the aromatization reaction is completed, the solvent is recovered by reduced pressure distillation, hydrochloric acid is added for hydrolysis reaction, butyraldehyde and water are distilled out by reduced pressure distillation, and after the reaction is completed, the reaction product is treated by ethanol to obtain vitamin B6 with the content of 98.5%.
Patent document CN102584692A discloses a preparation method of pyridoxine hydrochloride, the aromatization reaction system of the patent comprises Diels-Alder reaction products, water, acid, and water-insoluble solvents (petroleum ether, cyclohexane, toluene, etc.), after aromatization reaction, hydrochloric acid is added for hydrolysis reaction, oil layer is removed, n-butyl aldehyde is distilled from water layer, water is distilled out, the reaction product is treated with ethanol to obtain crude product, and water is recrystallized to obtain final product. The quality of the product meets the standard of Chinese pharmacopoeia 2005 edition.
Patent document CN104710351A discloses a continuous preparation method of vitamin B6, in which a series continuous reaction device is adopted in the Diels-Alder reaction, an aromatization reaction system is a Diels-Alder reaction product, ethanol, water and hydrochloric acid, after the reaction is finished, ethanol and water are distilled off, hydrochloric acid is added for hydrolysis reaction, water is distilled off, and the reaction product is treated by ethanol. The purity of the product is 99.53 percent, and the product is earthy yellow in color.
Patent document CN110256335A discloses a synthesis process of vitamin B6, which uses cation exchange resin to prepare n-propyl-dioxoheptacyclo, and then the n-propyldioxoheptacyclo is subjected to Diels-Alder reaction, and the aromatization reaction system comprises Diels-Alder reaction product, ethanol, water and hydrochloric acid, after the reaction is finished, the ethanol is recovered under reduced pressure, hydrochloric acid is added to perform hydrolysis reaction, the mixture is concentrated under reduced pressure, and the reaction product is treated with ethanol. The content of the external standard method is 98.3 percent, and the product is brownish yellow.
Journal literature "vitamin B6 oxazole method synthesis new technology, Zhou Yuan, China journal of medical industry, 1994", the aromatization reaction system is Diels-Alder reaction product, ethanol, water, hydrochloric acid, after the reaction, evaporating ethanol and water, adding hydrochloric acid to carry out hydrolysis reaction, decompressing and concentrating, treating the reaction product with ethanol to obtain crude product, and recrystallizing water to obtain fine product.
Journal literature "improvement of synthesis process of vitamin B6, Chentianhao, journal of Chinese pharmaceutical industry, 2004", aromatization reaction system is Diels-Alder reaction product, ethanol, water, hydrochloric acid, after reaction, recovering ethanol under reduced pressure, adding hydrochloric acid to carry out hydrolysis reaction, concentrating under reduced pressure, treating reaction product with ethanol to obtain crude product with content of 98.5%; refining step active carbon decolorization three times at 80 ℃ and crystallization two times. The product quality is in accordance with BP98, USP 24.
In the prior art, after an aromatizing reaction is carried out on an addition product obtained by a Diels-Alder reaction to obtain an aromatized product, the aromatized product is directly hydrolyzed without separation of the aromatized product, so that the obtained aromatized product has low content and low purity, and the crude product of vitamin B6 has low content, low purity and deep color; so that the subsequent refining times are more, the three wastes are large, and the energy is not saved. In the prior art, hydrolysis reaction is carried out in a large amount of water, water is distilled out after the reaction is finished, the temperature is very high when the water is distilled out, a large amount of energy is consumed, and a large amount of wastewater is generated; when the water is distilled, the temperature is high, new impurities are generated after the product is heated, and the impurities are difficult to remove. Due to good water solubility of VB6, in order to improve the primary crystallization rate, water needs to be distilled thoroughly, but a large amount of VB6 is separated out in the later stage of distillation, the viscosity is high, and the water is not distilled thoroughly; in the prior art, ethanol is generally added, and the hydrous ethanol is distilled after dissolution, so that the effect is poor and the energy consumption is high; and a large amount of solids are separated out in the distillation process, so that the heat transfer effect is poor, the distillation time is long, and even the materials are decomposed due to local overheating. The hydrolysis product is treated by ethanol, and the method needs multiple operations, consumes energy and increases cost. After the hydrolysis reaction is finished, a byproduct of butyraldehyde needs to be distilled out, the boiling point of the butyraldehyde is about 75 ℃, and the hydrolysis product in the reaction system is damaged by high temperature. In the refining step in the prior art, the crude vitamin B6 product needs to be decolorized by activated carbon and recrystallized by water for multiple times, and the final product can approach the standards of food grade and pharmaceutical grade; the process consumes a large amount of pure water, the temperature of the hot water is about 80 ℃, a large amount of energy is consumed for heating the water, a large amount of waste water is generated, a large amount of activated carbon solid waste is generated, the environment is polluted, the operation steps are increased, and the cost is integrally increased.
Therefore, a preparation method of vitamin B6, which can greatly improve the purity content of the product, reduce impurities and light color, has high yield, simple and convenient operation, energy conservation, cost reduction and three-waste emission reduction, is needed, and still remains the technical problem to be solved in the field.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide the preparation method of the vitamin B6, which has the advantages of high product purity, high content, less impurities, light color, high yield, simple and convenient operation, energy conservation, low cost and reduction of three-waste emission.
The technical scheme of the invention is as follows:
a method for preparing vitamin B6 comprises aromatization reaction, hydrolysis reaction and refining, wherein the reaction formula A is as follows:
wherein R is1Is C1-C4 alkyl, R2Is hydrogen or C1-C4 alkyl;
characterized in that the hydrolysis reaction comprises the steps of: the aromatization product of the compound shown as the formula II is subjected to hydrolysis reaction in the presence of water, acid and an organic solvent 1; the organic solvent 1 is selected from one or a combination of dichloromethane, chloroform, acetone, methanol, ethanol or ethyl acetate.
Preferred according to the invention are the substituents R1Is ethyl, R2Is n-propyl or isopropyl.
Preferably, after the aromatization reaction is finished, the aromatization product compound of formula II is purified and added into the hydrolysis reaction system in the form of solid.
Preferably according to the invention, the water and acid are provided by an aqueous hydrochloric acid solution; the aqueous hydrochloric acid solution is preferably concentrated hydrochloric acid; the concentrated hydrochloric acid is preferably concentrated hydrochloric acid with the mass concentration of 30-38%.
According to a preferred embodiment of the invention, the organic solvent 1 is dichloromethane.
According to the invention, the ratio of the mass of the aromatization product compound of formula II to the volume of the organic solvent 1 is preferably 3-5: 5-15 g/ml, wherein the volume ratio of the mass of the aromatization product compound shown as the formula II to the mixed solution of acid and water is 1-5: 1 g/ml.
According to the invention, the hydrolysis reaction temperature is preferably from 30 to 70 ℃ and preferably from 40 to 65 ℃. The hydrolysis reaction time is 2 to 5 hours, preferably 3 hours.
According to the invention, the hydrolysis reaction is preferably carried out under heating reflux conditions; preferably, the heating reflux is carried out while water is distributed, the water is discharged out of the reaction system, and the water is distributed by reflux until the reaction is finished; further preferably, the reflux condition is atmospheric reflux. The reflux water diversion is realized according to the existing method, and preferably realized by a reflux device and a water diversion device.
The water separator comprises various common water separators in a chemical reaction device (including chemical experiments and chemical industry), and when the water separator is heated and refluxed, condensate flows into the water separator to be layered, one part returns to a reaction system, and the other part is discharged out of the reaction system. The structure and the installation mode of the water separator are shown in various chemical industry textbooks, tool books and experimental instruction books. When the organic solvent is dichloromethane, which is heavier than water, it is common in the art to modify the water distributor, for example, by providing a conduit at the lower layer, connecting the reaction feed ports to return the dichloromethane to the reaction system, and providing a conduit at the upper layer to drain the water.
In the invention, organic solvent and water flow into the water separator during condensation, the organic solvent is layered in the water separator, the organic solvent returns to the reaction system, and the water is discharged. The organic solvent is returned to the reaction system for saving, and if the organic solvent is also discharged from the reaction system, a new organic solvent may be added to the reaction system without affecting the reaction effect, and the present invention also includes the organic solvent.
According to a preferred embodiment of the present invention, the post-treatment of the reaction mixture obtained after completion of the hydrolysis reaction is as follows: cooling the reaction liquid, separating out a crude product, filtering and drying to obtain a crude product vitamin B6; preferably, the filtration is followed by washing the filter cake with 90 to 100 wt% ethanol, and more preferably with 95 wt% ethanol.
Preferably, according to the present invention, the hydrolysis reaction comprises the steps of: mixing dichloromethane and a compound of a formula II, adding concentrated hydrochloric acid with the mass concentration of 30-38%, performing normal-pressure reflux reaction at 40 ℃, performing water diversion at the same time of the reflux reaction, draining water out of a reaction system, performing reflux water diversion until the reaction is finished, cooling to 0-5 ℃, growing crystals for 1-2 hours, filtering, washing a filter cake with 95 wt% of ethanol, and performing vacuum drying at 40-70 ℃ to obtain a crude vitamin B6 product, namely the compound 5.
Preferably, according to the present invention, the aromatization reaction comprises the steps of: the compound of formula I is subjected to aromatization reaction in the presence of ethanol, water and acid; the method is characterized in that after the aromatization reaction is finished, an organic solvent 2 is added into the obtained reaction liquid, and the mixture is uniformly mixed, cooled, crystallized and filtered to obtain the solid of the aromatization product compound of formula II; the organic solvent 2 is selected from one or a combination of dichloromethane, chloroform, acetone, ethyl acetate, n-heptane, methanol or ethanol-water; preferably, in the ethanol-water, the mass ratio of ethanol to water is 1:1 to 2.
The compounds of formula I according to the invention can be prepared according to the prior art, for example by means of the Diels-Alder reaction described in the literature. Preferably, the compound of formula I is obtained by a Diels-Alder addition reaction, which is represented by the following reaction scheme B:
preferably, after the addition reaction is finished, the compound shown in the formula I is purified and put into the next aromatization reaction; or after the addition reaction is finished, directly carrying out the next aromatization reaction on the compound shown in the formula I without purification; further preferably, after the addition reaction is finished, the compound of formula I is directly subjected to the next aromatization reaction without purification.
Preferably, the organic solvent 2 is dichloromethane.
Preferably, the mass ratio of the compound of the formula I to the organic solvent 2 is 1-2: 1-2 g/ml; preferably 1:1 g/ml.
Preferably, the aromatization reaction also comprises a step of distilling under reduced pressure until the system is viscous, and then adding the organic solvent 2.
Preferably, the water and acid are provided by an aqueous hydrochloric acid solution; the concentration of the hydrochloric acid aqueous solution is 0.1-0.5 mol/L; further preferably, the concentration of the aqueous hydrochloric acid solution is 0.2 to 0.3 mol/L.
Preferably, the ethanol is used at a mass concentration of 95% ethanol.
Preferably, the mass of the compound of the formula I and the volume ratio of the mixed solution of acid and water are 1-2 g/mL; the mass ratio of the compound of the formula I to the volume of the ethanol is 1-2 g/mL.
Preferably, the aromatization reaction temperature is 20-60 ℃, and preferably 25-35 ℃. The reaction time is 8-14 h.
Preferably, the water and the acid are added dropwise to the system containing ethanol and the compound of formula i in the form of a mixture.
Preferably, the aromatization reaction is carried out under the protection of inert gas.
Preferably, the aromatization reaction comprises the steps of: adding ethanol into the compound shown in the formula I, dropwise adding a mixed solution of water and acid, reacting, distilling under reduced pressure until the system is viscous, adding the organic solvent 2, uniformly mixing, cooling, crystallizing, filtering, and leaching the organic solvent 2 to obtain an aromatization product, namely a solid of the compound shown in the formula II.
Further preferably, the aromatization reaction comprises the steps of: adding 95 wt% of ethanol into the compound shown in the formula I, controlling the temperature to be 20-60 ℃, dropwise adding 0.2-0.3mol/L hydrochloric acid aqueous solution, controlling the temperature to be 20-60 ℃ after dropwise adding, and reacting for 8-14 h; and distilling the ethanol under reduced pressure until the system is viscous, adding dichloromethane, uniformly mixing, cooling to 0-5 ℃, crystallizing, filtering, and leaching with dichloromethane to obtain a solid of the aromatization product compound of formula II. The reaction temperature is preferably 25-35 ℃.
Further preferably, the organic solvent 1 used in the hydrolysis reaction is the same as the organic solvent 2 used in the aromatization reaction.
Preferably according to the invention, the refining step comprises: decolorizing with activated carbon, and recrystallizing with water. Preferably, the activated carbon is decolorized once and the water is recrystallized once.
Preferably, the refining step comprises: mixing purified water and crude vitamin B6, i.e. compound 5, heating to dissolve, adding activated carbon, stirring and decolorizing; hot filtering, washing the activated carbon filter cake with hot water; and (3) distilling the filtrate under reduced pressure, cooling to room temperature, growing crystals in an ice bath, performing suction filtration, washing a filter cake with ethanol, and performing vacuum drying to obtain a finished product of vitamin B6, namely the compound shown in the formula 6.
Further preferably, the mass ratio of the crude vitamin B6 to the purified water is 1: 1.5-3, preferably 1: 2.
further preferably, the mass ratio of the crude vitamin B6 to the activated carbon is 150: 5-10, preferably 150: 7.5.
further preferably, the stirring decoloring temperature is 60-90 ℃, and preferably 70 ℃; stirring for decolorizing for 30-120min, preferably 60 min.
Further preferably, the temperature of the hot water is 60 to 90 ℃, preferably 80 ℃.
Further preferably, growing the crystal in ice bath for 1-2 h; the ice bath temperature is 0-10 deg.C, preferably 5 deg.C.
Further preferably, the refining step comprises: mixing purified water and crude vitamin B6, heating to dissolve, adding activated carbon, and stirring at 70 deg.C for decolorizing for 60 min; hot filtering, washing the activated carbon filter cake with hot water at 80 ℃; and (3) distilling the filtrate under reduced pressure, cooling to room temperature, growing crystals in ice bath for 1-2 h, performing suction filtration, washing a filter cake with 95 wt% ethanol, and performing vacuum drying to obtain a finished vitamin B6 product.
In the present invention, when R is1Is ethyl, R2In the case of the n-propyl group, the preferred reaction formula C is:
in reaction formula C:
when vitamin B6 is used as a food additive, a health product, and a pharmaceutical product, it is desirable that the product be high in purity, content, and impurities be low to provide better safety to consumers.
It is generally recognized by those skilled in the art that when the purpose of the process is to improve the purity and content of the product, the process usually causes problems of yield reduction, cost increase, operation complexity, more energy consumption, more three wastes generation, and the like.
The invention overcomes the prejudice existing in the prior art, provides the preparation method of the vitamin B6 with high purity content, has high product content, less impurities and light color, and simultaneously has the advantages of high yield, low cost, simple and convenient operation, energy conservation, three-waste discharge reduction and the like.
The present invention has been completed through a great deal of research in order to achieve the above object.
The invention has the following technical characteristics and beneficial effects:
1. in the prior art, the arylation product is not treated, and the next hydrolysis reaction is directly carried out. Impurities in the whole reaction system are brought into the next stage of hydrolysis reaction, so that the impurity content of the final product is high.
Research shows that after the aromatization reaction is finished, the organic solvent is added into the reaction system, stirred and stood to crystallize and separate out the aromatization product, and the solid aromatization product is filtered and separated out, so that the purity content of the aromatization product is increased, and a large amount of impurities are carried away by the organic solvent.
The organic solvent is preferably selected from dichloromethane, ethyl acetate and acetone, most preferably dichloromethane. The dichloromethane has high solubility to the impurities in the aromatization reaction system and low solubility to the aromatization products of the invention. The dichloromethane is easy to be removed from the reaction system, and is convenient for post-treatment and quality control.
2. In the prior art, hydrolysis reaction steps are carried out in a large amount of water, water is distilled after the reaction is finished, the temperature is very high when the water is distilled, a large amount of energy is consumed, a large amount of waste water is generated, the temperature is about 80-90 ℃ when the water is distilled, and new impurities are generated after products are heated.
Since VB6 has good water solubility, in order to improve the primary crystallization rate, it is necessary to evaporate water thoroughly. However, a large amount of VB6 is separated out in the later stage of distillation, the viscosity is high, and the water evaporation is incomplete. At present, ethanol is generally added in the prior art, and the hydrous ethanol is distilled after dissolution, so that the effect is poor and the energy consumption is high; and a large amount of solids are separated out in the distillation process, so that the heat transfer effect is poor, the distillation time is long, and even the materials are decomposed due to local overheating.
In the prior art, the hydrolysate is subsequently treated by ethanol (water in a system is taken away by adding ethanol in the prior art through multiple times of distillation or ethanol in the prior art is recrystallized), multiple operations are needed, energy is consumed, and the cost is increased.
In the prior art, after the reaction is finished, a byproduct of butyraldehyde needs to be distilled out, the boiling point of the butyraldehyde is about 75 ℃, and the hydrolysis product in the reaction system is damaged by high temperature.
In addition, in a reaction system with a large amount of water in the prior art, the phenolic hydroxyl and the alkyl hydroxyl adjacent to the phenolic hydroxyl in the structure of the crude vitamin B6 can form a six-membered ring together with butyraldehyde generated by hydrolysis reaction, so that an impurity A is generated, and the impurity A is difficult to remove in subsequent reactions.
Impurity A has the structural formula:
the method comprises the steps of adding an organic solvent into a hydrolysis reaction system, carrying out hydrolysis reaction in a water/organic solvent double-phase system, heating and refluxing at low temperature, cooling after refluxing is finished, separating out a crude product, filtering, and drying to obtain a crude product of vitamin B6.
The invention has low reaction temperature, does not destroy reactants and products, and does not generate new impurities.
The invention further prefers to carry out water diversion at the same time of reflux, evaporate the organic solvent and water, flow the organic solvent and water into the water segregator when condensing, stratify in the water segregator, the organic solvent returns to the reaction system, discharge water, the solid form of the hydrolysate is dispersed in the organic solvent after the reaction is finished, and the solid form of the hydrolysate can be separated by filtering.
The method does not need to add ethanol in the prior art for multiple times of distillation to take away water in the system or ethanol recrystallization in the prior art. The introduction of new impurities is avoided, the energy is saved, the cost is reduced, and the generation of waste water is reduced.
The organic solvent used in the hydrolysis step of the present invention is preferably dichloromethane. Advantages of dichloromethane: 1) methylene chloride may form an azeotrope with water and distill off together. 2) The hydrolysis by-product butyraldehyde is dissolved in dichloromethane, the butyraldehyde in the system can be taken away by the dichloromethane, the boiling point difference between the dichloromethane and the hydrolysis by-product butyraldehyde is large, the boiling point of the dichloromethane is about 40 ℃, the boiling point of the butyraldehyde is about 75 ℃, the butyraldehyde is convenient to separate during recovery, and the respective recovery rates are high. 3) The dichloromethane has high solubility to impurities in the hydrolysis reaction system of the invention and low solubility to the hydrolysate of the invention. 4) The dichloromethane is easy to be removed from the reaction system, and is convenient for post-treatment and quality control.
Compared with the prior art, after the hydrolysis reaction, the method omits the step of repeatedly treating the crude product with ethanol (such as heating recrystallization and the like in the prior art), simplifies the steps, saves energy, reduces the cost and shortens the production period.
Because the hydrolysis reaction system is a water/organic solvent two-phase system, a small amount of water exists in the system, crude vitamin B6 generated by the reaction is dissolved in the water, butyraldehyde generated by the hydrolysis reaction is dissolved in an organic phase (preferably dichloromethane), and the two are not in the same phase and can not react to form impurity A; as the reaction proceeds, water is distilled off, vitamin B6 crystallizes out, and vitamin B6 in solid form does not react with butyraldehyde dissolved in the organic phase, preferably dichloromethane.
The hydrolysis reaction temperature is low, the boiling point of the butyraldehyde is about 75 ℃, the butyraldehyde is remained in the reaction system in the reaction process and dissolved in an organic phase (preferably dichloromethane) without being distilled, and after the reaction is finished, the butyraldehyde is remained in a mother solution and can be separately distilled and recycled. Avoiding the evaporation of butyraldehyde and further avoiding the damage of hydrolysate.
The invention adds the organic solvent into the reaction system in the hydrolysis reaction step, and has outstanding effect on the improvement of the preparation process of the vitamin B6.
3. Preferably, in the steps of aromatization reaction and hydrolysis reaction, the same organic solvent is used, preferably dichloromethane is used, the solvents are unified, after the aromatization reaction is finished, the aromatization product does not need to be dried, and the wet material can be put into the next step of hydrolysis reaction. The operation steps are simplified, and the quality control is facilitated.
4. In the refining step in the prior art, the crude vitamin B6 product needs to be decolorized by active carbon and recrystallized by water for multiple times, and the final product can be close to the standards of food grade and medicine grade. The process consumes a large amount of pure water, the temperature of the hot water is about 80 ℃, a large amount of energy is consumed for heating the water, a large amount of waste water is generated, a large amount of activated carbon solid waste is generated, the environment is polluted, operation steps are increased, and the cost is increased integrally.
In the refining step, the crude vitamin B6 is decolorized by active carbon for one time and recrystallized for one time to obtain the final product. The method saves pure water, saves energy, generates less waste water and less active carbon solid waste, and protects the environment.
5. The product obtained by the invention has high quality, can reach the pharmaceutical grade standard, and the quality standard accords with 2020 edition of Chinese pharmacopoeia, XV of Japanese pharmacopoeia, 40 of United states pharmacopoeia, 10.0 of European pharmacopoeia and 2018 of British pharmacopoeia.
6. Although the invention adds the step of crystallizing the product after the aromatization reaction is finished, the step is simple to operate and does not need heating.
The invention saves the step of evaporating water in the hydrolysis reaction, the step of evaporating byproduct butyraldehyde, the step of processing ethanol for multiple times after the hydrolysis reaction, and the invention saves the times of decolorization and water recrystallization in the refining step.
The specific post-treatment method of the product after aromatization reaction is combined with hydrolysis reaction in the presence of an organic solvent, so that the invention can realize high purity of the target product by simpler refining steps; the excellent effects of the present invention are achieved by the process of the present invention as a whole. Generally speaking, the invention improves the quality of the final product, simplifies the operation, saves the energy, saves the pure water, reduces the solid waste of the active carbon, reduces the waste water discharge, and accords with the advanced concepts of green chemistry and carbon neutralization at present. Meanwhile, the cost is saved.
Drawings
FIG. 1: the purity and content of the crude vitamin B6 product obtained in the embodiment 2 of the invention, the content of impurity A, and an HPLC chart;
FIG. 2: the purity and content of the final vitamin B6 product obtained in example 3 of the invention, the content of impurity A and an HPLC chart.
FIG. 3: comparative example 1 (improved synthesis process of vitamin B6, Chentianhao, journal of Chinese medical industry, 2004) in prior art, purity, content, impurity A content of crude vitamin B6, HPLC chart;
FIG. 4: comparative example 1 (improved synthesis process of vitamin B6, Chentianhao, journal of Chinese medical industry, 2004) in prior art final product of vitamin B6 has purity, content, impurity A content, and HPLC chart.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.
Meanwhile, the experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
Preparation example 1: Diels-Alder reaction
The Diels-Alder reaction products of the present invention can be prepared according to the prior art. For example, it can be prepared as follows: adding 800g of the compound 2 into a reaction bottle, heating to 150 ℃, then adding 75g of the compound 1, preserving the temperature for 10-15 hours at the temperature of 140-160 ℃, and then carrying out reduced pressure distillation until no distillate exists basically to obtain a compound 3.
Example 1: aromatization reaction
Adding 180mL of 95 wt% ethanol aqueous solution into 300g of the compound 3 of the reaction formula D, replacing with nitrogen, controlling the temperature to be 25-30 ℃, dropwise adding 200mL of 0.2mol/L hydrochloric acid aqueous solution under the stirring condition, controlling the temperature to be 25-30 ℃ after dropwise adding, and stirring for reaction for 12 hours; distilling ethanol at 50 deg.C under reduced pressure until the system is viscous, adding 300ml of dichloromethane, stirring, mixing, cooling to 5 deg.C, and growing crystal for 1 h. Carrying out suction filtration and leaching with dichloromethane; compound 4 was obtained as crystals, 229 g. The aromatization reaction molar yield is 92 percent.
Example 2: preparation of crude vitamin B6 (hydrolysis reaction)
Adding 800ml of dichloromethane and 229g of the compound 4 prepared in the example 1 into a reaction bottle, adding 130ml of 32 wt% concentrated hydrochloric acid, refluxing for 3 hours at about 40 ℃ under normal pressure under the condition of stirring, adding a water separator into a reflux device, draining the reaction system, returning an organic phase into the reaction bottle, and refluxing and separating water until the reaction is finished; cooling to 5 ℃, growing the crystal for 1h, filtering, washing a filter cake by 95 wt% of ethanol water solution, and drying in vacuum at 40-70 ℃ to obtain 6g of crude vitamin B, 207 g. The hydrolysis reaction molar yield was 98%.
FIG. 1 shows the purity, content, impurity A content and HPLC chart of crude vitamin B6 obtained in this example; the purity of the vitamin B6 crude product (H029-S) is 99.88 percent, the content of impurity A (H029-S-I-06) is 0.06 percent, and the content of vitamin B6 is 99.56 percent.
Example 3: preparation (refining) of vitamin B6 finished product
Adding 300g of purified water and 150g of crude product B6 into a reaction bottle, heating to dissolve, adding 7.5g of activated carbon, stirring and decoloring for 60min at 70 ℃, filtering while hot, washing an activated carbon filter cake with 75g of hot water at 80 ℃, distilling the filtrate under reduced pressure until the residual weight of the system is 285-300 g, slowly cooling to room temperature, cooling to 5 ℃, growing crystals for 1h, performing suction filtration, washing the filter cake with 150ml of 95 wt% ethanol aqueous solution, and performing vacuum drying at 40-70 ℃ to obtain refined products of vitamin B6 and 135 g. The purification step gave a molar yield of 90%.
FIG. 2 is the purity, content, impurity A content and HPLC chart of the final vitamin B6 product obtained in this example; the purity of vitamin B6(H029-S) is 99.99%, the content of impurity A (H029-S-I-06) is 0.01%, and the content of vitamin B6 is 99.67%.
Example 1-3 Total molar yield of 81% and recovery yield of 95% (i.e., the yield of vitamin B6, combined with VB6 obtained at the first time, further recovered from the filtrate obtained by suction filtration after completion of crystal growth)
The purity of the final product is more than 99.5%, the content is more than 99.5%, and the color grade is less than Y0.5 (the color grade of Chinese pharmacopoeia is less than Y1); the quality of the product meets the requirements of China pharmacopoeia 2020 edition, Japanese pharmacopoeia XV, United states pharmacopoeia 40, European pharmacopoeia 10.0 and British pharmacopoeia 2018.
Example 4: aromatization reaction
Adding 180mL of 95 wt% ethanol aqueous solution into 300g of the compound 3 of the reaction formula D, replacing with nitrogen, controlling the temperature to be 25-30 ℃, dropwise adding 200mL of 0.2mol/L hydrochloric acid aqueous solution under the stirring condition, controlling the temperature to be 25-30 ℃ after dropwise adding, and stirring for reaction for 12 hours; distilling ethanol at 50 deg.C under reduced pressure until the system is viscous, adding 300ml of acetone, stirring, mixing, cooling to 5 deg.C, and growing crystal for 1 h. Carrying out suction filtration and leaching with acetone; compound 4 was obtained as crystals, 211 g. The aromatization reaction molar yield is 85 percent.
Example 5 aromatization reaction
Adding 180mL of 95 wt% ethanol aqueous solution into 300g of the compound 3 of the reaction formula D, replacing with nitrogen, controlling the temperature to be 25-30 ℃, dropwise adding 200mL of 0.2mol/L hydrochloric acid aqueous solution under the stirring condition, controlling the temperature to be 25-30 ℃ after dropwise adding, and stirring for reaction for 12 hours; distilling ethanol at 50 deg.C under reduced pressure until the system is viscous, adding 300ml ethyl acetate, stirring, mixing, cooling to 5 deg.C, and growing crystal for 1 h. Carrying out suction filtration and leaching with ethyl acetate; compound 4 was obtained as crystals, 216 g. The aromatization reaction molar yield is 87%.
Example 6 aromatization reaction
Adding 180mL of 95 wt% ethanol aqueous solution into 300g of the compound 3 of the reaction formula D, replacing with nitrogen, controlling the temperature to be 25-30 ℃, dropwise adding 200mL of 0.2mol/L hydrochloric acid aqueous solution under the stirring condition, controlling the temperature to be 25-30 ℃ after dropwise adding, and stirring for reaction for 12 hours; distilling ethanol at 50 deg.C under reduced pressure until the system is viscous, adding 300ml chloroform, stirring, mixing, cooling to 5 deg.C, and growing crystal for 1 h. Carrying out suction filtration and chloroform leaching; compound 4 was obtained as crystals, 220 g. The aromatization reaction molar yield is 88.6 percent.
Example 7 aromatization reaction
Adding 180mL of 95 wt% ethanol aqueous solution into 300g of the compound 3 of the reaction formula D, replacing with nitrogen, controlling the temperature to be 25-30 ℃, dropwise adding 200mL of 0.2mol/L hydrochloric acid aqueous solution under the stirring condition, controlling the temperature to be 25-30 ℃ after dropwise adding, and stirring for reaction for 12 hours; distilling ethanol at 50 deg.C under reduced pressure until the system is viscous, adding 300ml n-heptane, stirring, mixing, cooling to 5 deg.C, and growing crystal for 1 h. Carrying out suction filtration and leaching with n-heptane; compound 4 was obtained as crystals for use, 200 g. The aromatization reaction molar yield is 80.5 percent.
Example 8 aromatization reaction
Adding 180mL of 95 wt% ethanol aqueous solution into 300g of the compound 3 of the reaction formula D, replacing with nitrogen, controlling the temperature to be 25-30 ℃, dropwise adding 200mL of 0.2mol/L hydrochloric acid aqueous solution under the stirring condition, controlling the temperature to be 25-30 ℃ after dropwise adding, and stirring for reaction for 12 hours; distilling ethanol at 50 deg.C under reduced pressure until the system is viscous, adding 300ml methanol, stirring, mixing, cooling to 5 deg.C, and growing crystal for 1 h. Carrying out suction filtration and methanol leaching; compound 4 was obtained as crystals, 161 g. The aromatization reaction molar yield was 65%.
Example 9 aromatization reaction
Adding 180mL of 95 wt% ethanol aqueous solution into 300g of the compound 3 of the reaction formula D, replacing with nitrogen, controlling the temperature to be 25-30 ℃, dropwise adding 200mL of 0.2mol/L hydrochloric acid aqueous solution under the stirring condition, controlling the temperature to be 25-30 ℃ after dropwise adding, and stirring for reaction for 12 hours; distilling ethanol at 50 deg.C under reduced pressure until the system is viscous, adding 300ml ethanol-water (mass ratio 1:1), stirring, mixing, cooling to 5 deg.C, and growing crystal for 1 h. Carrying out suction filtration, and leaching with ethanol-water (mass ratio of 1: 1); compound 4 was obtained as crystals for use, 180 g.
The aromatization reaction molar yield is 72.5 percent.
Example 10 aromatization reaction
Adding 180mL of 95 wt% ethanol aqueous solution into 300g of the compound 3 of the reaction formula D, replacing with nitrogen, controlling the temperature to be 25-30 ℃, dropwise adding 200mL of 0.2mol/L hydrochloric acid aqueous solution under the stirring condition, controlling the temperature to be 25-30 ℃ after dropwise adding, and stirring for reaction for 12 hours; distilling ethanol at 50 deg.C under reduced pressure until the system is viscous, adding 300ml ethanol-water (mass ratio of 1:2), stirring, mixing, cooling to 5 deg.C, and growing crystal for 1 h. Carrying out suction filtration, and leaching with ethanol-water (mass ratio of 1: 2); compound 4 was obtained as crystals, 185 g. The aromatization reaction molar yield is 74.5 percent.
Example 11 hydrolysis reaction
Adding 800ml of acetone and 229g of the compound 4 prepared in the example 1 into a reaction bottle, adding 130ml of 32% concentrated hydrochloric acid, refluxing for 3 hours at about 40 ℃ under normal pressure under the condition of stirring, adding a water separator into a reflux device, draining the reaction system, returning an organic phase into the reaction bottle, and refluxing and separating water until the reaction is finished; cooling to 5 ℃, growing the crystal for 1h, filtering, washing a filter cake by 95 wt% of ethanol water solution, and drying in vacuum at 40-70 ℃ to obtain crude vitamin B6, 198 g. The hydrolysis reaction molar yield was 94%.
EXAMPLE 12 hydrolysis reaction
Adding 800ml of methanol and 229g of the compound 4 prepared in the example 1 into a reaction bottle, adding 130ml of 32% concentrated hydrochloric acid, refluxing for 3 hours at about 40 ℃ under normal pressure under the condition of stirring, adding a water separator into a reflux device, draining the reaction system, returning an organic phase into the reaction bottle, and refluxing and separating water until the reaction is finished; cooling to 5 ℃, growing the crystal for 1h, filtering, washing a filter cake by 95 wt% of ethanol water solution, and drying in vacuum at 40-70 ℃ to obtain crude vitamin B6, 164 g. The hydrolysis reaction molar yield was 78%.
Example 13 hydrolysis reaction
Adding 800ml of chloroform and 229g of the compound 4 prepared in the example 1 into a reaction bottle, adding 130ml of 32% concentrated hydrochloric acid, refluxing for 3 hours at about 40 ℃ under normal pressure under the condition of stirring, adding a water separator into a reflux device, draining the reaction system, returning an organic phase into the reaction bottle, and refluxing and separating water until the reaction is finished; cooling to 5 ℃, growing the crystal for 1h, filtering, washing a filter cake by 95 wt% of ethanol water solution, and drying in vacuum at 40-70 ℃ to obtain crude vitamin B6, 180 g. The hydrolysis reaction molar yield is 85.6%.
EXAMPLE 14 hydrolysis reaction
Adding 800ml of ethanol and 229g of the compound 4 prepared in the example 1 into a reaction bottle, adding 130ml of 32% concentrated hydrochloric acid, refluxing for 3 hours at about 40 ℃ under normal pressure under the condition of stirring, adding a water separator into a reflux device, discharging water out of a reaction system, returning an organic phase into the reaction bottle, and refluxing and separating water until the reaction is finished; cooling to 5 ℃, growing the crystal for 1h, filtering, washing a filter cake by 95 wt% of ethanol water solution, and drying in vacuum at 40-70 ℃ to obtain crude vitamin B6, 153.5 g. The hydrolysis reaction molar yield was 73%.
Example 15 hydrolysis reaction
Adding 800ml of ethyl acetate and 229g of the compound 4 prepared in the example 1 into a reaction bottle, adding 130ml of 32% concentrated hydrochloric acid, refluxing for 3 hours at about 40 ℃ under normal pressure under the condition of stirring, adding a water separator into a reflux device, draining the reaction system, returning an organic phase into the reaction bottle, and refluxing and separating water until the reaction is finished; cooling to 5 ℃, growing the crystal for 1h, filtering, washing a filter cake by 95 wt% of ethanol water solution, and drying in vacuum at 40-70 ℃ to obtain crude vitamin B6, 143 g. The hydrolysis reaction molar yield was 68%.
Example 16 aromatization reaction
180mL of 95 wt% aqueous ethanol solution were added to 300g of the compound of formula I (substituent R) in reaction formula B1Is ethyl, R2Isopropyl), replacing nitrogen, controlling the temperature to be 25-30 ℃, dropwise adding 200ml of 0.2mol/L hydrochloric acid aqueous solution under the stirring condition, controlling the temperature to be 25-30 ℃ after dropwise adding, and stirring and reacting for 12 hours; distilling ethanol at 50 ℃ under reduced pressure until the system is viscous, adding 300ml of dichloromethane, stirring and mixing uniformly, cooling to 5 ℃, crystallizing, filtering, and leaching the dichloromethane; to give the compound of the formula II (R)2Isopropyl) was crystallized and 214g was used. The aromatization reaction molar yield was 86%.
Example 17 hydrolysis reaction
800ml of methylene chloride and 229g of the compound of the formula II prepared in example 16 (R)2Isopropyl) is added into a reaction bottle, 130ml of 32 percent concentrated hydrochloric acid is added, reflux is carried out for 3 hours under the condition of stirring and normal pressure at the temperature of about 40 ℃, a water separator is added into a reflux device, water is discharged out of the reaction system, an organic phase returns to the reaction bottle, and the reflux water separation is carried out until the reaction is finished; cooling to 5 ℃, growing the crystal for 1h, filtering, washing a filter cake by 95 wt% of ethanol water solution, and drying in vacuum at 40-70 ℃ to obtain crude vitamin B6, 189 g. The hydrolysis reaction molar yield was 96%.
EXAMPLE 18 hydrolysis reaction
Adding 800ml of dichloromethane and 229g of the compound 4 prepared in the example 1 into a reaction bottle, adding 130ml of 32% concentrated hydrochloric acid, refluxing for 3 hours at about 40 ℃ under normal pressure under the condition of stirring until the reaction is finished; cooling to 5 ℃, growing the crystal for 1h, filtering, washing a filter cake by 95 wt% of ethanol water solution, and drying in vacuum at 40-70 ℃ to obtain crude vitamin B6, 190 g. The hydrolysis reaction molar yield is 90%.
Example 19 method of HPLC (high Performance liquid chromatography) in the examples and figures of the present invention
Solvent: 10% methanol solution
Test solution: taking a proper amount of the product, precisely weighing, adding a solvent to dissolve and fix the volume, and diluting to prepare a solution containing about 1mg in each 1 ml.
Chromatographic conditions are as follows: the column was packed with octadecylsilane bonded silica gel (Agilent InfinityLab Poroshell 120EC-C18, 4.6 x 150mm, 4 μm); mobile phase A: 0.01mol/l sodium octane sulfonate solution (ph2.5) -acetonitrile (80-20), mobile phase B: acetonitrile; the flow rate is 1.0 ml/min; the detection wavelength is 285 nm; the column temperature is 30 ℃; the injection volume was 5. mu.l.
The determination method comprises the following steps: precisely measuring the test solution, injecting into a liquid chromatograph, and recording the chromatogram. Calculated by area normalization.
Comparative example 1
Experiments were conducted according to the improvement of the synthesis process of vitamin B6 in journal literature, the aromatization reaction, hydrolysis reaction and refining method in chentianhao, journal of chinese medical industry, 2004.
FIG. 3 is a HPLC chart showing the purity, content, impurity A content of crude vitamin B6 obtained in this comparative example; the purity of the crude vitamin B6(H029-S) is 98.88%, the content of impurity A (H029-S-I-06) is 0.94%, and the content of vitamin B6 is 96.76%.
FIG. 4 is a HPLC chart showing the purity, content, impurity A content of the final vitamin B6 product obtained in this comparative example; the purity of the final product of vitamin B6(H029-S) is 99.87%, the content of impurity A (H029-S-I-06) is 0.08%, and the content of vitamin B6 is 99.52%.
Comparative example 2
Experiments are carried out according to the new synthesis process of vitamin B6 oxazole in journal literature, aromatization reaction, hydrolysis reaction and refining method in Zhou Yuan, journal of Chinese medicine industry, 1994.
Comparative example 3
Crude vitamin B6 was prepared (hydrolysis) as described in example 2, except that: the solvent dichloromethane is replaced by petroleum ether; the other steps and conditions were identical to those of example 2.
Comparative example 4
Crude vitamin B6 was prepared (hydrolysis) as described in example 2, except that: the solvent used, dichloromethane, was replaced by cyclohexane; the other steps and conditions were identical to those of example 2.
Comparative example 5
Crude vitamin B6 was prepared (hydrolysis) as described in example 2, except that: the solvent dichloromethane was replaced by toluene; the other steps and conditions were identical to those of example 2.
Comparative example 6
Crude vitamin B6 was prepared (hydrolysis) as described in example 2, except that: the solvent dichloromethane is replaced by 1, 2-dichloroethane; the other steps and conditions were identical to those of example 2.
Test example 1: aromatization reaction organic solvent screening
Preferably, the lighter the color of the aromatization product, the better, the white-like color is preferred.
Preferably with low solubility for the aromatization products.
TABLE 1
Test example 2: hydrolysis reaction organic solvent screening
Preferably, the organic solvent has low solubility for the hydrolysate;
preferably, the boiling point of the butyraldehyde is not close to that of butyraldehyde, and the boiling point of the butyraldehyde is 77.6;
TABLE 2
Test example 3: comparison of the crude product obtained in the hydrolysis step:
TABLE 3
| Sample (I) | Characteristic impurity A content | Purity of crude product | Crude product content | Crude color |
| Example 2 | ＜0.1％ | ＞99％ | ＞99％ | Off-white color |
| Comparative examples 1 to 2 | 0.5％＜A＜1％ | ＜99％ | ＜97％ | Reddish brown |
Test example 4: and (3) refining step comparison:
TABLE 4
Claims (10)
1. A method for preparing vitamin B6 comprises aromatization reaction, hydrolysis reaction and refining, wherein the reaction formula A is as follows:
wherein R is1Is C1-C4 alkyl, R2Is hydrogen or C1-C4 alkyl;
characterized in that the hydrolysis reaction comprises the steps of: the aromatization product of the compound shown as the formula II is subjected to hydrolysis reaction in the presence of water, acid and an organic solvent 1; the organic solvent 1 is selected from one or a combination of dichloromethane, chloroform, acetone, methanol, ethanol or ethyl acetate.
2. The process for the preparation of vitamin B6 according to claim 1, wherein one or more of the following conditions are included:
a. substituent R1Is ethyl, R2Is n-propyl or isopropyl;
b. after the aromatization reaction is finished, purifying an aromatization product compound shown as a formula II, and adding the aromatization product compound into a hydrolysis reaction system in a solid form;
c. the water and acid are provided by aqueous hydrochloric acid; the aqueous hydrochloric acid solution is preferably concentrated hydrochloric acid; the concentrated hydrochloric acid is preferably concentrated hydrochloric acid with the mass concentration of 30-38%;
d. the organic solvent 1 is dichloromethane;
e. the mass of the aromatization product compound shown as the formula II is 3-5 volume ratio of the organic solvent 1: 5-15 g/ml, wherein the volume ratio of the mass of the aromatization product compound shown as the formula II to the mixed solution of acid and water is 1-5: 1 g/ml;
f. the hydrolysis reaction temperature is 30-70 ℃, and preferably 40-65 ℃;
g. the hydrolysis reaction is carried out under the condition of heating reflux; preferably, the heating reflux is carried out while water is distributed, the water is discharged out of the reaction system, and the water is distributed by reflux until the reaction is finished; further preferably, the reflux condition is normal pressure reflux;
h. the post-treatment method of the reaction liquid obtained after the hydrolysis reaction is finished comprises the following steps: cooling the reaction liquid, separating out a crude product, filtering and drying to obtain a crude product vitamin B6; preferably, the filtration is followed by washing the filter cake with 90 to 100 wt% ethanol, and more preferably with 95 wt% ethanol.
3. The process for preparing vitamin B6, according to claim 1, wherein the hydrolysis reaction comprises the steps of: mixing dichloromethane and a compound shown in a formula II, adding concentrated hydrochloric acid with the mass concentration of 30-38%, performing normal-pressure reflux reaction at 40 ℃, performing water diversion at the same time of the reflux reaction, draining water out of a reaction system, performing reflux water diversion until the reaction is finished, cooling to 0-5 ℃, growing crystals for 1-2 hours, filtering, washing a filter cake with 95 wt% of ethanol, and performing vacuum drying at 40-70 ℃ to obtain a crude vitamin B6 product, namely the compound 5.
4. The process for preparing vitamin B6 according to claim 1, wherein the compound of formula i is obtained by a Diels-Alder addition reaction represented by the following reaction scheme B:
preferably, after the addition reaction is finished, the compound shown in the formula I is purified and put into the next aromatization reaction; or after the addition reaction is finished, directly carrying out the next aromatization reaction on the compound shown in the formula I without purification; further preferably, after the addition reaction is finished, the compound of formula I is directly subjected to the next aromatization reaction without purification.
5. The process for preparing vitamin B6 according to claim 1, wherein the aromatization reaction comprises the steps of: the compound of formula I is subjected to aromatization reaction in the presence of ethanol, water and acid; the method is characterized in that after the aromatization reaction is finished, an organic solvent 2 is added into the obtained reaction liquid, and the mixture is uniformly mixed, cooled, crystallized and filtered to obtain the solid of the aromatization product compound of formula II; the organic solvent 2 is selected from one or a combination of dichloromethane, chloroform, acetone, ethyl acetate, n-heptane, methanol or ethanol-water; preferably, in the ethanol-water, the mass ratio of ethanol to water is 1:1 to 2.
6. The process for the preparation of vitamin B6, according to claim 5, wherein one or more of the following conditions are included:
a. the organic solvent 2 is dichloromethane;
b. the mass ratio of the compound of the formula I to the organic solvent 2 is 1-2: 1-2 g/ml; preferably 1:1 g/ml;
c. after the aromatization reaction is finished, the step of distilling under reduced pressure until the system is viscous is included, and then an organic solvent 2 is added;
d. the water and acid are provided by aqueous hydrochloric acid; the concentration of the hydrochloric acid aqueous solution is 0.1-0.5 mol/L; further preferably, the concentration of the hydrochloric acid aqueous solution is 0.2-0.3 mol/L;
e. the ethanol is ethanol with the mass concentration of 95 percent;
f. the mass of the compound of the formula I and the volume ratio of mixed liquid consisting of acid and water are 1-2 g/mL; the mass ratio of the compound of the formula I to the volume of the ethanol is 1-2 g/mL;
g. the aromatization reaction temperature is 20-60 ℃, and preferably 25-35 ℃;
h. the water and the acid are dripped into a system containing ethanol and the compound shown in the formula I in a form of mixed liquid;
i. the aromatization reaction is carried out under the protection of inert gas;
j. the organic solvent 1 used for the hydrolysis reaction is the same as the organic solvent 2 used for the aromatization reaction.
7. The process for preparing vitamin B6 according to claim 5, wherein the aromatization reaction comprises the steps of: adding ethanol into a compound shown in a formula I, dropwise adding a mixed solution of water and acid, reacting, distilling under reduced pressure until the system is viscous, adding an organic solvent 2, uniformly mixing, cooling, crystallizing, filtering, and leaching the organic solvent 2 to obtain an aromatization product, namely a solid of a compound shown in a formula II;
preferably, the aromatization reaction comprises the steps of: adding 95 wt% of ethanol into the compound shown in the formula I, controlling the temperature to be 20-60 ℃, dropwise adding 0.2-0.3mol/L hydrochloric acid aqueous solution, controlling the temperature to be 20-60 ℃ after dropwise adding, and reacting for 8-14 h; distilling ethanol under reduced pressure until the system is viscous, adding dichloromethane, mixing uniformly, cooling to 0-5 ℃, crystallizing, filtering, and leaching with dichloromethane to obtain an aromatization product, namely a solid of the compound of formula II; the reaction temperature is preferably 25-35 ℃.
8. The process for preparing vitamin B6, according to claim 1, wherein the refining step comprises: decolorizing with activated carbon, and recrystallizing with water; preferably, the activated carbon is decolorized once and the water is recrystallized once.
9. The process of claim 8, wherein the refining step comprises: mixing purified water and crude vitamin B6, i.e. compound 5, heating to dissolve, adding activated carbon, stirring and decolorizing; hot filtering, washing the activated carbon filter cake with hot water; and (3) distilling the filtrate under reduced pressure, cooling to room temperature, growing crystals in an ice bath, performing suction filtration, washing a filter cake with ethanol, and performing vacuum drying to obtain a finished product of vitamin B6, namely the compound shown in the formula 6.
10. The process for the preparation of vitamin B6, according to claim 9, comprising one or more of the following conditions:
a. the mass ratio of the crude vitamin B6 to the purified water is 1: 1.5-3, preferably 1: 2;
b. the mass ratio of the crude vitamin B6 to the active carbon is 150: 5-10, preferably 150: 7.5;
c. stirring and decolorizing at 60-90 deg.C, preferably 70 deg.C; stirring for decolorizing for 30-120min, preferably 60 min;
d. the temperature of the hot water is 60-90 ℃, and preferably 80 ℃;
e. growing crystal for 1-2 h in ice bath; the ice bath temperature is 0-10 ℃, preferably 5 ℃;
f. the refining step comprises: mixing purified water and crude vitamin B6, heating to dissolve, adding activated carbon, and stirring at 70 deg.C for decolorizing for 60 min; hot filtering, washing the activated carbon filter cake with hot water at 80 ℃; and (3) distilling the filtrate under reduced pressure, cooling to room temperature, growing crystals in ice bath for 1-2 h, performing suction filtration, washing a filter cake with 95 wt% ethanol, and performing vacuum drying to obtain a finished vitamin B6 product.
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| 周后元等: "维生素b6噁唑法合成新工艺", 中国医药工业杂志, vol. 25, no. 9, pages 388 * |
| 范卫东等: "维生素B6的合成工艺改进", 广州化工, vol. 40, no. 17, pages 47 * |
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