CN114315703B - Preparation method of high-purity vitamin B6 - Google Patents
Preparation method of high-purity vitamin B6 Download PDFInfo
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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 126
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 title claims abstract description 100
- 239000011726 vitamin B6 Substances 0.000 title claims abstract description 100
- 235000019158 vitamin B6 Nutrition 0.000 title claims abstract description 100
- 229940011671 vitamin b6 Drugs 0.000 title claims abstract description 100
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 106
- 238000005899 aromatization reaction Methods 0.000 claims abstract description 89
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 81
- 239000003960 organic solvent Substances 0.000 claims abstract description 51
- 238000000034 method Methods 0.000 claims abstract description 40
- 238000007670 refining Methods 0.000 claims abstract description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 222
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 146
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 126
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 92
- 239000000047 product Substances 0.000 claims description 61
- 150000001875 compounds Chemical class 0.000 claims description 54
- 238000010992 reflux Methods 0.000 claims description 43
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
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- 229940125898 compound 5 Drugs 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- -1 compound 5 Chemical compound 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
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- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 42
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
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- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 4
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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 description 4
- 238000012360 testing method Methods 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
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- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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- 235000019171 pyridoxine hydrochloride Nutrition 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
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
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- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 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 refined vitamin B6 through aromatization reaction, hydrolysis reaction and refining steps. The method of the invention improves the aromatization reaction, the hydrolysis reaction and the refining step, and particularly, the organic solvent is added into the reaction system in the hydrolysis reaction step, thereby having outstanding effect on improving the preparation process of 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 three-waste emission reduction.
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
Pyridoxine hydrochloride, a main commercial form of vitamin B6, is widely used in the fields of feed additives, food additives, health products, medicines and the like.
At present, an oxazole method is widely used in industry for synthesizing vitamin B6. The method comprises the steps of Diels-Alder reaction, aromatization reaction, hydrolysis reaction and refining to obtain refined vitamin B6.
The prior report of synthesizing vitamin B6 by adopting an oxazole method is as follows:
patent document CN101402600a discloses a method for preparing vitamin B6, which comprises adding alkaline reagent (triethylamine) into Diels-Alder reaction, wherein an aromatization reaction system comprises Diels-Alder reaction product, ethanol, water, hydrochloric acid and metal ion chelating agent (ethylenediamine tetraacetic acid), after the aromatization reaction is finished, distilling under reduced pressure to recover solvent, adding hydrochloric acid for hydrolysis reaction, distilling under reduced pressure to distill butyraldehyde and water, and treating the reaction product with ethanol after the reaction is finished to obtain vitamin B6 with the content of 98.5%.
Patent document CN102584692a discloses a preparation method of pyridoxine hydrochloride, the patent aromatization reaction system is composed of Diels-Alder reaction products, water, acid and water-insoluble solvents (petroleum ether, cyclohexane, toluene, etc.), hydrochloric acid is added to carry out hydrolysis reaction after aromatization reaction is completed, an oil layer is separated, a water layer is distilled to remove n-butyraldehyde, water is distilled, a reaction product is treated by ethanol, a crude product is obtained, and water is recrystallized to obtain a final product. The quality meets the 2005 edition standard of Chinese pharmacopoeia.
Patent document CN104710351a discloses a continuous preparation method of vitamin B6, the Diels-Alder reaction of the patent adopts a serial continuous reaction device, the aromatization reaction system is 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 color of the product is earthy yellow.
The patent document CN110256335A discloses a synthesis process of vitamin B6, wherein cation exchange resin is used for preparing n-propyl dioxygen heptaring, diels-Alder reaction is carried out, an aromatization reaction system comprises Diels-Alder reaction products, ethanol, water and hydrochloric acid, after the reaction is finished, the ethanol is recovered under reduced pressure, hydrochloric acid is added for hydrolysis reaction, and the reaction products are treated by ethanol under reduced pressure and concentrated. The content of the external standard method is 98.3 percent, and the product is brown yellow.
The new process for synthesizing vitamin B6 oxazole in journal literature, zhou Houyuan, journal of Chinese medicine industry, 1994, aromatization reaction system is Diels-Alder reaction product, alcohol, water and hydrochloric acid, after the reaction is finished, alcohol and water are distilled off, hydrochloric acid is added for hydrolysis reaction, decompression concentration is carried out, the reaction product is treated by alcohol to obtain crude product, and water is recrystallized to obtain fine product.
The journal literature is "improvement of synthesis process of vitamin B6, chen Tianhao, journal of Chinese medicine industry, 2004", the aromatization reaction system is Diels-Alder reaction product, ethanol, water and hydrochloric acid, after the reaction is finished, recovering ethanol under reduced pressure, adding hydrochloric acid for hydrolysis reaction, concentrating under reduced pressure, and treating the reaction product with ethanol to obtain crude product with the content of 98.5%; the refining step is that the activated carbon is decolorized at 80 ℃ for three times and crystallized for two times. The product quality accords with BP98 and USP24.
In the prior art, after an aromatic compound is obtained by carrying out an aromatization reaction on an addition product obtained by Diels-Alder reaction, the aromatic compound is directly hydrolyzed and is not separated, so that the obtained aromatic compound has low content and low purity, and the crude vitamin B6 product has low content, low purity and deep color; 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 after the reaction is finished, the temperature is very high when the water is distilled, a large amount of energy is consumed, and a large amount of wastewater is generated; the temperature of the distilled water is higher, and new impurities are generated after the product is heated, so that the impurities are difficult to remove. Because VB6 has good water solubility, the water is required to be thoroughly distilled in order to improve the primary crystallization rate, but a large amount of VB6 is separated out in the later stage of distillation, so that the viscosity is high, and the water is not thoroughly distilled; in the prior art, ethanol is generally added, and then the aqueous ethanol is distilled after dissolution, so that the effect is poor and the energy consumption is high; in addition, 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 material is decomposed due to local overheating. The hydrolysis product is treated by ethanol, which needs multiple operations, consumes energy and increases cost. After the hydrolysis reaction is finished, the byproduct butyraldehyde needs to be distilled off, the boiling point of butyraldehyde is about 75 ℃, and the hydrolysis product in the reaction system is damaged at high temperature. In the refining step in the prior art, crude vitamin B6 is decolorized by activated carbon for a plurality of times and recrystallized by water for a plurality of times, and the final product can be close to food grade and medicine grade standards; 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 solid waste of activated carbon is generated, the environment is polluted, the operation steps are increased, and the cost is increased as a whole.
Therefore, a vitamin B6 preparation method capable of greatly improving the purity content of the product, reducing impurities and lightening the color, and simultaneously having high yield, simple and convenient operation, energy conservation, cost reduction and three-waste emission reduction is needed, and the technical problem to be solved in the field is still needed.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide the vitamin B6 preparation method 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 discharge.
The technical scheme of the invention is as follows:
the preparation method of vitamin B6 comprises the steps of aromatization reaction, hydrolysis reaction and refining, wherein the reaction formula A is as follows:
wherein R is 1 Is C1-C4 alkyl, R 2 Is hydrogen or C1-C4 alkyl;
the hydrolysis reaction is characterized by comprising the following steps: aromatization products the compounds of formula II undergo hydrolysis in the presence of water, an 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.
According to a preferred embodiment of the invention, the substituents R 1 Is ethyl, R 2 Is n-propyl or isopropyl.
According to the invention, preferably, after the aromatization reaction is completed, the aromatization product, the compound of formula II, is purified and added to the hydrolysis reaction system as a solid.
Preferably, according to the present invention, the water and acid are provided by aqueous hydrochloric acid; the hydrochloric acid aqueous 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 present invention, the organic solvent 1 is methylene chloride.
According to the preferred invention, the mass ratio of the aromatization product of the compound of formula II to the organic solvent 1 is 3 to 5: 5-15 g/ml, the volume ratio of the mass of the aromatization product of the compound of the formula II to the mixed solution consisting of acid and water is 1-5: 1g/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 present invention, preferably, the hydrolysis reaction is carried out under heating reflux conditions; preferably, water diversion is carried out while heating and refluxing, water is discharged out of the reaction system, and water diversion is carried out until the reaction is completed; further preferably, the reflux condition is normal pressure reflux. The reflux water diversion is realized according to the prior method, preferably the reflux water diversion is realized by adding a water diversion device into a reflux device.
The water separator comprises various common water separators in chemical reaction devices (including chemical experiments and chemical industries), condensate flows into the water separator during heating reflux, and is 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 textbooks, tool books and experimental instruction books of chemical engineering. When the organic solvent is dichloromethane, the dichloromethane is heavier than water, and the modification of the water separator in this case is a common technology in the field, for example, a conduit is arranged at the lower layer, a reaction feed port is connected, the dichloromethane is returned to the reaction system, and a conduit is arranged at the upper layer, so that water is discharged.
In the invention, the organic solvent and water flow into the water separator during condensation, the organic solvent returns to the reaction system after layering in the water separator, 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 is also included.
According to the present invention, the post-treatment method of the reaction liquid obtained after the completion of the hydrolysis reaction is preferably as follows: cooling the reaction solution, precipitating a crude product, filtering and drying to obtain a crude vitamin B6; preferably, the filter cake is washed with 90-100wt% ethanol after filtration, more preferably with 95wt% ethanol.
According to a preferred embodiment of the present invention, the hydrolysis reaction comprises the steps of: mixing dichloromethane and a compound in a formula II, adding concentrated hydrochloric acid with the mass concentration of 30-38%, carrying out normal pressure reflux reaction at 40 ℃, separating water during the reflux reaction, discharging water out of a reaction system, refluxing and separating water until the reaction is finished, cooling to 0-5 ℃ for crystal growth for 1-2 h, filtering, washing a filter cake with 95wt% ethanol, and carrying out vacuum drying at 40-70 ℃ to obtain crude vitamin B6, namely the compound 5.
According to a preferred embodiment of the present invention, the aromatization reaction comprises the steps of: the aromatization reaction of the compound of formula I in the presence of ethanol, water and an 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 an aromatization product of the compound shown in the 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 the formula I according to the invention can be prepared in accordance with the prior art, for example by the Diels-Alder reaction described in the prior art. Preferably, the compound of formula I is obtained by Diels-Alder addition reaction of the formula B:
preferably, after the addition reaction is finished, the compound of 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 of the formula I without purification; further preferably, after the completion of the addition reaction, 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 formula I to the organic solvent 2 is 1-2: 1-2g/ml; preferably 1:1g/ml.
Preferably, the aromatization reaction further 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 aqueous hydrochloric acid; the concentration of the hydrochloric acid aqueous solution is 0.1-0.5mol/L; further preferably, the concentration of the aqueous hydrochloric acid solution is 0.2 to 0.3mol/L.
Preferably, the ethanol is 95% ethanol.
Preferably, the volume ratio of the mass of the compound of the formula I to the volume ratio of the mixed solution consisting of acid and water is 1-2g/mL; the mass-to-volume ratio of the compound of the formula I to the ethanol is 1-2g/mL.
Preferably, the aromatization reaction temperature is 20 to 60 ℃, preferably 25 to 35 ℃. The reaction time is 8-14 h.
Preferably, the water and acid are added dropwise to the system containing ethanol and the compound of formula I as a mixture.
Preferably, the aromatization reaction is carried out under inert gas protection.
Preferably, 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 with the organic solvent 2 to obtain a solid of an aromatization product shown in a formula II.
Further preferably, the aromatization reaction comprises the steps of: adding 95wt% ethanol into a compound shown in a 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 the dropwise adding, and reacting for 8-14 h; and (3) 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 an aromatization product of the compound of the formula II. The reaction temperature is preferably 25 to 35 ℃.
Further preferably, the organic solvent 1 used in the hydrolysis reaction and the organic solvent 2 used in the aromatization reaction are the same.
According to a preferred embodiment of the present invention, the refining step comprises: decolorizing with active carbon, and recrystallizing with water. Preferably activated carbon is decolorized once and water is recrystallized once.
Preferably, the refining step comprises: mixing purified water and crude vitamin B6, namely compound 5, heating to dissolve, adding active carbon, stirring and decoloring; hot filtering, and washing an activated carbon filter cake with hot water; distilling the filtrate under reduced pressure, cooling to room temperature, growing crystals in ice bath, suction filtering, washing the filter cake with ethanol, and vacuum drying to obtain vitamin B6 product, i.e. the compound of formula 6.
Further preferably, the mass ratio of crude vitamin B6 to 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 decolorization temperature is 60-90 ℃, preferably 70 ℃; the stirring decolorization time is 30-120min, preferably 60min.
Further preferably, the temperature of the hot water is 60-90 ℃, preferably 80 ℃.
Further preferably, the crystal is grown in an ice bath for 1-2 hours; the ice bath temperature is 0-10deg.C, preferably 5deg.C.
Further preferably, the refining step comprises: mixing purified water and crude vitamin B6, heating to dissolve, adding active carbon, and decolorizing at 70deg.C for 60min; hot filtering, and washing an activated carbon filter cake by hot water at 80 ℃; distilling the filtrate under reduced pressure, cooling to room temperature, growing crystals in an ice bath for 1-2 h, carrying out suction filtration, washing a filter cake with 95wt% ethanol, and carrying out vacuum drying to obtain a vitamin B6 finished product.
In the present invention, when R 1 Is ethyl, R 2 In the case of n-propyl, the preferred formula C is:
in reaction formula C:
compound 3 is a Diels-Alder reaction product;
compound 4 is the aromatization reaction product;
compound 5 is a hydrolysis reaction product, namely a crude vitamin B6 product;
compound 6 is vitamin B6 finished product, i.e. vitamin B6 refined product.
Compound 3 is preferably obtained from a Diels-Alder addition reaction of the following formula D:
when vitamin B6 is used as a food additive, a health product and a pharmaceutical product, it is required that the purity of the product is high, the content is high, and impurities are less, so that it has better safety to consumers.
Those skilled in the art generally consider that when the purpose of the process is to increase the purity and content of the product, the process generally brings problems of reduced yield, increased cost, complex operation, more energy consumption, more three wastes and the like.
The invention overcomes the prejudice existing in the prior art, and provides the preparation method of the vitamin B6 with high purity content, which has the advantages of high product content, less impurities, light color, high yield, low cost, simple and convenient operation, energy conservation, three-waste emission reduction and the like.
The present invention has been accomplished in view of the above-mentioned problems.
The invention has the technical characteristics and beneficial effects that:
1. in the prior art, the aromatization product is not treated and is directly subjected to the next hydrolysis reaction. The impurities in the whole reaction system are brought into the next hydrolysis reaction, so that the impurity content of the final product is high.
After the aromatic reaction is finished, an organic solvent is added into a reaction system, stirred and stood, so that an aromatization product is crystallized and separated out, filtered, and a solid aromatization product is separated, the purity content of the aromatization product can be increased, and a large amount of impurities are taken away by the organic solvent.
After screening, the organic solvent is preferably dichloromethane, ethyl acetate and acetone, most preferably dichloromethane. The methylene dichloride has high solubility for impurities in the aromatization reaction system and low solubility for aromatization products. The dichloromethane is easy to remove from the reaction system, so that the post-treatment is convenient, and the quality control is convenient.
2. The hydrolysis reaction steps in the prior art are all carried out in a large amount of water, the 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 wastewater is generated, the temperature is about 80-90 ℃ when the water is distilled, and new impurities are generated after the product is heated.
Because VB6 has good water solubility, the water needs to be thoroughly distilled in order to improve the primary crystallization rate. However, a large amount of VB6 is precipitated in the later stage of distillation, the viscosity is high, and the distilled water is not thorough. At present, the prior art generally adds ethanol, and then distills out aqueous ethanol after dissolution, so that the effect is poor and the energy consumption is high; in addition, 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 material is decomposed due to local overheating.
The subsequent treatment of the hydrolysate with ethanol (in the prior art, ethanol is added for multiple times to distill away water in the system or ethanol in the prior art is recrystallized) requires multiple operations, consumes energy and increases cost.
In the prior art, the byproduct butyraldehyde needs to be distilled out after the reaction is finished, the boiling point of butyraldehyde is about 75 ℃, and the hydrolysis product in the reaction system is damaged at high temperature.
In addition, in the reaction system in which a large amount of water exists in the prior art, phenolic hydroxyl groups and adjacent alkyl hydroxyl groups in the crude vitamin B6 structure can form a six-membered ring together with butyraldehyde generated by hydrolysis reaction, so that impurity A is generated, and the impurity A is difficult to remove in subsequent reactions.
Impurity A has the structural formula:
the hydrolysis reaction system is added with an organic solvent, so that the hydrolysis reaction is carried out in a water/organic solvent biphasic system, the low-temperature heating reflux is carried out, the temperature is reduced after the reflux is finished, the crude product is separated out, and the crude product is filtered and dried to obtain the vitamin B6 crude product.
The invention has low reaction temperature, does not destroy reactants and products and does not generate new impurities.
In the invention, water diversion is carried out at the same time of reflux, organic solvent and water are distilled out, the organic solvent and water flow into a water diversion device during condensation, the organic solvent is layered in the water diversion device, the organic solvent returns to a reaction system, water is discharged, hydrolysate solid forms are dispersed in the organic solvent after the reaction is finished, and the hydrolysate in the solid forms can be separated through filtration.
The invention does not need adding ethanol for multiple distillation to carry away water in the system or recrystallizing ethanol in the prior art. The novel impurity is avoided being introduced, the energy is saved, the cost is reduced, and the generation of wastewater is reduced.
The organic solvent is preferably methylene dichloride in the hydrolysis reaction step. Advantages of dichloromethane: 1) Dichloromethane and water can form an azeotropic mixture and can be distilled off together. 2) The butyraldehyde which is a hydrolysis byproduct is dissolved in methylene dichloride, butyraldehyde in the system can be taken away through the methylene dichloride, the boiling point difference between the methylene dichloride and the butyraldehyde which is a hydrolysis byproduct is large, the boiling point of the methylene dichloride is about 40 ℃, the boiling point of the butyraldehyde is about 75 ℃, the butyraldehyde is convenient to separate during recycling, and the recovery rate is high. 3) The methylene dichloride has high solubility to impurities in the hydrolysis reaction system and low solubility to the hydrolysis product. 4) The dichloromethane is easy to remove from the reaction system, so that the post-treatment is convenient, and the quality control is convenient.
Compared with the prior art, the method omits the steps of treating the crude product with ethanol for multiple times (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 is arranged in the system, crude vitamin B6 generated by the reaction is dissolved in the water, the byproduct butyraldehyde generated by the hydrolysis reaction is dissolved in an organic phase (preferably dichloromethane), and the two are not in the same phase, so that impurity A can not be formed by the reaction; as the reaction proceeds, water evaporates and vitamin B6 crystallizes out, nor does the solid form of vitamin B6 react with butyraldehyde dissolved in the organic phase (preferably methylene chloride).
The hydrolysis reaction temperature is carried out at a low temperature, the boiling point of butyraldehyde is about 75 ℃, butyraldehyde is remained in the reaction system and dissolved in an organic phase (preferably methylene dichloride) in the reaction process, distillation is not needed, and butyraldehyde is remained in mother liquor after the reaction is finished and can be separately distilled for recycling. The evaporation of butyraldehyde is avoided, and thus the destruction of the hydrolysis product is avoided.
The invention adds organic solvent into the reaction system in the hydrolysis reaction step, which has outstanding effect on improving the preparation process of vitamin B6.
3. Preferably, in the steps of the aromatization reaction and the hydrolysis reaction, the same organic solvent is used, preferably dichloromethane is used, the solvents are unified, and after the aromatization reaction is finished, the aromatization product can be put into the next hydrolysis reaction without drying the wet material. Simplifying the operation steps and facilitating the quality control.
4. In the refining step in the prior art, crude vitamin B6 is decolorized by activated carbon for a plurality of times and recrystallized by water for a plurality of times, and the final product can be close to food grade and medicine grade standards. 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 active carbon solid waste is generated, the environment is polluted, the operation steps are increased, and the cost is increased as a whole.
In the refining step, the crude vitamin B6 is decolorized by active carbon for one time and recrystallized for one time, thus obtaining the final product. The pure water is saved, the energy is saved, the waste water is rarely generated, the solid waste of the activated carbon is rarely generated, and the environment is protected.
5. The quality of the product obtained by the method is high, can reach the pharmaceutical grade standard, and the quality standard accords with the Chinese pharmacopoeia 2020 edition, japanese pharmacopoeia XV, united states pharmacopoeia 40, european pharmacopoeia 10.0 and British pharmacopoeia 2018.
6. The invention adds the crystallization step of the product after the aromatization reaction is finished, but the step is simple to operate and does not need heating.
The invention saves the step of steaming out water in the hydrolysis reaction, the step of steaming out byproduct butyraldehyde, the step of treating ethanol for many times after the hydrolysis reaction, and the times of decoloring and water recrystallization in the refining step.
The specific post-treatment method of the product after the aromatization reaction is combined with the hydrolysis reaction in the presence of an organic solvent, so that the high purity of the target product can be realized by a simpler refining step; the method of the invention as a whole achieves the excellent effect of the invention. In general, the invention simplifies the operation, saves energy, pure water, reduces solid waste of active carbon, reduces wastewater discharge and accords with the advanced concepts of green chemistry and carbon neutralization at present while improving the quality of the final product. Meanwhile, the cost is saved.
Drawings
Fig. 1: the purity, content and impurity A content of the vitamin B6 crude product obtained in the embodiment 2 are shown in an HPLC chart;
fig. 2: the purity, content, impurity A content and HPLC chart of the vitamin B6 final product obtained in the embodiment 3 of the invention.
Fig. 3: comparative example 1 (improvement of synthesis process of vitamin B6, chen Tianhao, journal of Chinese medicine industry, 2004) vitamin B6 crude product purity, content, impurity A content, HPLC diagram;
fig. 4: the prior art is a comparison of vitamin B6 final product purity, content, impurity A content, HPLC diagram of example 1 (improvement of vitamin B6 synthesis process, chen Tianhao, journal of Chinese medicine industry, 2004).
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, materials, unless otherwise specified, are all commercially available.
Preparation example 1: diels-Alder reaction
The Diels-Alder reaction products of the present invention can be prepared as in the prior art. For example, it can be prepared as follows: 800g of compound 2 was added to a reaction flask and heated to 150℃followed by 75g of compound 1, which was kept at a temperature in the range of 140 to 160℃for 10 to 15 hours, and then distilled under reduced pressure until substantially no distillate was obtained to obtain compound 3.
Example 1: aromatization reaction
180mL of 95wt% ethanol aqueous solution is added into 300g of compound 3 in the reaction formula D, nitrogen replacement is performed, the temperature is controlled to be 25-30 ℃,200 mL of 0.2mol/L hydrochloric acid aqueous solution is dropwise added under the stirring condition, the temperature is controlled to be 25-30 ℃ after the dropwise addition, and the stirring reaction is performed for 12 hours; ethanol is distilled under reduced pressure at 50 ℃ until the system is viscous, 300ml of dichloromethane is added, the mixture is stirred and mixed uniformly, the temperature is reduced to 5 ℃, and the crystal is grown for 1h. Suction filtration and dichloromethane leaching; the compound 4 was crystallized for use, 229g. The molar yield of the aromatization reaction 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 32wt% concentrated hydrochloric acid, refluxing for 3 hours at about 40 ℃ under normal pressure under stirring, adding a water separator into a refluxing device, discharging water from 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 crystals for 1 hour, filtering, washing a filter cake by using 95wt% ethanol water solution, and vacuum drying at 40-70 ℃ to obtain crude vitamin B6, 207g. The molar yield of the hydrolysis reaction is 98%.
FIG. 1 is a HPLC chart showing the purity, content, and impurity A content of the crude vitamin B6 product obtained in this example; the purity of the vitamin B6 crude product (H029-S) is 99.88%, the content of the impurity A (H029-S-I-06) is 0.06%, and the content of the vitamin B6 is 99.56%.
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 active carbon, stirring and decoloring at 70 ℃ for 60min, filtering while the mixture is hot, washing an active carbon filter cake with 75g of hot water at 80 ℃, decompressing and distilling the filtrate until the residual weight of the system is 285-300 g, slowly cooling to room temperature, cooling to 5 ℃, crystallizing for 1h, filtering, washing the filter cake with 150ml of 95wt% ethanol aqueous solution, and drying in vacuum at 40-70 ℃ to obtain refined vitamin B6 and 135g. The molar yield of the refining step was 90%.
FIG. 2 is a HPLC chart showing the purity, content, and impurity A content of the final vitamin B6 product obtained in this example; vitamin B6 (H029-S) has a purity of 99.99%, impurity A (H029-S-I-06) content of 0.01%, and vitamin B6 content of 99.67%.
The total molar yield of each step of examples 1-3 was 81% and the recovery yield was 95% (means that the filtrate obtained by suction filtration after the end of crystal growth was further recovered in the total yield of vitamin B6 and VB6 obtained in the first time)
The purity of the final product is more than 99.5%, the content is more than 99.5%, the color grade is less than Y0.5 (the color grade of Chinese pharmacopoeia is less than Y1); the quality accords with the Chinese pharmacopoeia 2020 edition, japanese pharmacopoeia XV, united states pharmacopoeia 40, european pharmacopoeia 10.0 and British pharmacopoeia 2018.
Example 4: aromatization reaction
180mL of 95wt% ethanol aqueous solution is added into 300g of compound 3 in the reaction formula D, nitrogen replacement is performed, the temperature is controlled to be 25-30 ℃,200 mL of 0.2mol/L hydrochloric acid aqueous solution is dropwise added under the stirring condition, the temperature is controlled to be 25-30 ℃ after the dropwise addition, and the stirring reaction is performed for 12 hours; ethanol is distilled under reduced pressure at 50 ℃ until the system is viscous, 300ml of acetone is added, the mixture is stirred and mixed uniformly, the temperature is reduced to 5 ℃, and the crystal is grown for 1h. Suction filtration and acetone leaching; the compound 4 was crystallized for use, 211g. The molar yield of the aromatization reaction is 85 percent.
EXAMPLE 5 aromatization reaction
180mL of 95wt% ethanol aqueous solution is added into 300g of compound 3 in the reaction formula D, nitrogen replacement is performed, the temperature is controlled to be 25-30 ℃,200 mL of 0.2mol/L hydrochloric acid aqueous solution is dropwise added under the stirring condition, the temperature is controlled to be 25-30 ℃ after the dropwise addition, and the stirring reaction is performed for 12 hours; ethanol is distilled under reduced pressure at 50 ℃ until the system is viscous, 300ml of ethyl acetate is added, the mixture is stirred and mixed uniformly, the temperature is reduced to 5 ℃, and the crystal is grown for 1h. Suction filtration and ethyl acetate leaching; the compound 4 was crystallized for use, 216g. The molar yield of the aromatization reaction is 87 percent.
EXAMPLE 6 aromatization reaction
180mL of 95wt% ethanol aqueous solution is added into 300g of compound 3 in the reaction formula D, nitrogen replacement is performed, the temperature is controlled to be 25-30 ℃,200 mL of 0.2mol/L hydrochloric acid aqueous solution is dropwise added under the stirring condition, the temperature is controlled to be 25-30 ℃ after the dropwise addition, and the stirring reaction is performed for 12 hours; ethanol is distilled under reduced pressure at 50 ℃ until the system is viscous, 300ml of chloroform is added, the mixture is stirred and mixed uniformly, the temperature is reduced to 5 ℃, and the crystal is grown for 1h. Suction filtration and chloroform leaching; the compound 4 was crystallized for 220g. The molar yield of the aromatization reaction is 88.6 percent.
EXAMPLE 7 aromatization reaction
180mL of 95wt% ethanol aqueous solution is added into 300g of compound 3 in the reaction formula D, nitrogen replacement is performed, the temperature is controlled to be 25-30 ℃,200 mL of 0.2mol/L hydrochloric acid aqueous solution is dropwise added under the stirring condition, the temperature is controlled to be 25-30 ℃ after the dropwise addition, and the stirring reaction is performed for 12 hours; ethanol is distilled under reduced pressure at 50 ℃ until the system is viscous, 300ml of n-heptane is added, the mixture is stirred and mixed uniformly, the temperature is reduced to 5 ℃, and the crystal is grown for 1h. Suction filtration and n-heptane leaching; the compound 4 was crystallized for 200g. The molar yield of the aromatization reaction is 80.5 percent.
EXAMPLE 8 aromatization reaction
180mL of 95wt% ethanol aqueous solution is added into 300g of compound 3 in the reaction formula D, nitrogen replacement is performed, the temperature is controlled to be 25-30 ℃,200 mL of 0.2mol/L hydrochloric acid aqueous solution is dropwise added under the stirring condition, the temperature is controlled to be 25-30 ℃ after the dropwise addition, and the stirring reaction is performed for 12 hours; ethanol is distilled under reduced pressure at 50 ℃ until the system is viscous, 300ml of methanol is added, the mixture is stirred and mixed uniformly, the temperature is reduced to 5 ℃, and the crystal is grown for 1h. Suction filtration and methanol leaching; the compound 4 was crystallized to prepare 161g. The molar yield of the aromatization reaction is 65 percent.
EXAMPLE 9 aromatization reaction
180mL of 95wt% ethanol aqueous solution is added into 300g of compound 3 in the reaction formula D, nitrogen replacement is performed, the temperature is controlled to be 25-30 ℃,200 mL of 0.2mol/L hydrochloric acid aqueous solution is dropwise added under the stirring condition, the temperature is controlled to be 25-30 ℃ after the dropwise addition, and the stirring reaction is performed for 12 hours; distilling ethanol under reduced pressure at 50deg.C until the system is viscous, adding 300ml of ethanol-water (mass ratio of 1:1), stirring, mixing, cooling to 5deg.C, and crystallizing for 1 hr. Leaching, and leaching with ethanol-water (mass ratio is 1:1); the compound 4 was crystallized for 180g.
The molar yield of the aromatization reaction is 72.5 percent.
EXAMPLE 10 aromatization reaction
180mL of 95wt% ethanol aqueous solution is added into 300g of compound 3 in the reaction formula D, nitrogen replacement is performed, the temperature is controlled to be 25-30 ℃,200 mL of 0.2mol/L hydrochloric acid aqueous solution is dropwise added under the stirring condition, the temperature is controlled to be 25-30 ℃ after the dropwise addition, and the stirring reaction is performed for 12 hours; distilling ethanol under reduced pressure at 50deg.C until the system is viscous, adding 300ml of ethanol-water (mass ratio of 1:2), stirring, mixing, cooling to 5deg.C, and crystallizing for 1 hr. Leaching, and leaching with ethanol-water (mass ratio is 1:2); the compound 4 was crystallized for use, 185g. The molar yield of the aromatization reaction 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 stirring, adding a water separator into a refluxing device, discharging water from 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 crystals for 1h, filtering, washing a filter cake by using 95wt% ethanol water solution, and vacuum drying at 40-70 ℃ to obtain 198g of crude vitamin B6. The molar yield of the hydrolysis reaction 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 stirring, adding a water separator into a refluxing device, discharging water from 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 crystals for 1h, filtering, washing a filter cake by using 95wt% ethanol water solution, and vacuum drying at 40-70 ℃ to obtain 164g of crude vitamin B6. The molar yield of the hydrolysis reaction 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 stirring, adding a water separator into a refluxing device, discharging water from 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 crystals for 1 hour, filtering, washing a filter cake by using 95wt% ethanol water solution, and vacuum drying at 40-70 ℃ to obtain crude vitamin B6, 180g. The molar yield of the hydrolysis reaction 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 stirring, adding a water separator into a refluxing device, discharging water from 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 crystals for 1h, filtering, washing a filter cake by using 95wt% ethanol water solution, and vacuum drying at 40-70 ℃ to obtain 153.5g of crude vitamin B6. The molar yield of the hydrolysis reaction 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 stirring, adding a water separator into a refluxing device, discharging water from 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 crystals for 1 hour, filtering, washing a filter cake by using 95wt% ethanol water solution, and vacuum drying at 40-70 ℃ to obtain crude vitamin B6, 143g. The molar yield of the hydrolysis reaction was 68%.
EXAMPLE 16 aromatization reaction
180mL of 95wt% aqueous ethanol was added to 300g of a compound of formula I (substituent R 1 Is ethyl, R 2 Isopropyl), nitrogen substitution, 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 12h; distilling ethanol at 50deg.C under reduced pressure until the system is viscous, adding 300ml of dichloromethane, stirring, mixing, cooling to 5deg.C, crystallizing, vacuum filtering, and eluting with dichloromethane; to give a compound of formula II (R 2 Isopropyl) was crystallized for use, 214g. The molar yield of the aromatization reaction is 86 percent.
EXAMPLE 17 hydrolysis reaction
800ml of methylene chloride, 229g of the compound of formula II (R) prepared in example 16 2 Isopropyl), 130ml of 32% concentrated hydrochloric acid is added into a reaction bottle, under the stirring condition, the mixture is refluxed for 3 hours at about 40 ℃ under normal pressure, a water separator is added into a reflux device, water is discharged from a reaction system, an organic phase is returned into the reaction bottle, and the reflux water is separated until the reaction is finished; cooling to 5 ℃, growing the crystals for 1 hour, filtering, washing a filter cake by using 95wt% ethanol water solution, and vacuum drying at 40-70 ℃ to obtain 189g of crude vitamin B6. The molar yield of the hydrolysis reaction is 96%.
EXAMPLE 18 hydrolysis reaction
800ml of dichloromethane and 229g of the compound 4 prepared in example 1 are added into a reaction bottle, 130ml of 32% concentrated hydrochloric acid is added, and under stirring, reflux is carried out for 3 hours at about 40 ℃ under normal pressure until the reaction is completed; cooling to 5 ℃, growing the crystals for 1 hour, filtering, washing a filter cake by using 95wt% ethanol water solution, and vacuum drying at 40-70 ℃ to obtain crude vitamin B6, 190g. The molar yield of the hydrolysis reaction is 90%.
EXAMPLE 19 HPLC (high Performance liquid chromatography) method in the examples and figures of the present invention
Solvent: 10% methanol solution
Test solution: the product is taken to be properly weighed, precisely weighed, dissolved by a solvent and diluted to prepare a solution containing about 1mg per 1 ml.
Chromatographic conditions: the column was packed with octadecylsilane chemically bonded silica (Agilent InfinityLab Poroshell EC-C18,4.6 x 150mm,4 μm); mobile phase a:0.01mol/l sodium octane sulfonate solution (pH 2.5) -acetonitrile (80-20), mobile phase B: acetonitrile; the flow rate is 1.0ml/min; the detection wavelength is 285nm; the column temperature is 30 ℃; the sample volume was 5. Mu.l.
Assay: precisely measuring the solution of the sample, injecting into a liquid chromatograph, and recording the chromatogram. Calculated according to an area normalization method.
Comparative example 1
Experiments were performed according to the journal literature "improvement of vitamin B6 synthesis process, chen Tianhao, journal of chinese medical industry, 2004", aromatization reaction, hydrolysis reaction, and refining method.
FIG. 3 is a HPLC chart showing the purity, content, impurity A content of the crude vitamin B6 product 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 were carried out according to the aromatization reaction, hydrolysis reaction and refining method in journal literature "vitamin B6 oxazol method synthesis new process, zhou Houyuan, journal of Chinese medical industry, 1994".
Comparative example 3
Preparation of crude vitamin B6 (hydrolysis reaction) as described in example 2, except that: the solvent methylene dichloride is replaced by petroleum ether; other steps and conditions were consistent with example 2.
Comparative example 4
Preparation of crude vitamin B6 (hydrolysis reaction) as described in example 2, except that: the solvent methylene chloride used is replaced by cyclohexane; other steps and conditions were consistent with example 2.
Comparative example 5
Preparation of crude vitamin B6 (hydrolysis reaction) as described in example 2, except that: the solvent methylene chloride used was replaced by toluene; other steps and conditions were consistent with example 2.
Comparative example 6
Preparation of crude vitamin B6 (hydrolysis reaction) as described in example 2, except that: the solvent dichloromethane used was replaced by 1, 2-dichloroethane; other steps and conditions were consistent with example 2.
Test example 1: organic solvent screening for aromatization reactions
The lighter the aromatization product, the better, preferably off-white.
Preferably, the solubility to the aromatization product is small.
TABLE 1
Test example 2: organic solvent screening for hydrolysis reactions
Preferably, the organic solvent has low solubility in the hydrolysate;
preferably, the boiling point is not close to that of butyraldehyde, and the boiling point of butyraldehyde is 77.6;
TABLE 2
Test example 3: crude product comparison obtained in the hydrolysis step:
TABLE 3 Table 3
| Sample of | Characteristic impurity A content | Purity of crude product | Crude product content | Crude color |
| Example 2 | ＜0.1％ | ＞99％ | ＞99％ | White-like color |
| Comparative examples 1 to 2 | 0.5％＜A＜1％ | ＜99％ | ＜97％ | Brownish red |
Test example 4: comparison of refining steps:
TABLE 4 Table 4
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Claims (15)
1. The preparation method of vitamin B6 comprises the steps of aromatization reaction, hydrolysis reaction and refining, wherein the reaction formula A is as follows:
wherein R is 1 Is C1-C4 alkyl, R 2 Is hydrogen or C1-C4 alkyl;
the hydrolysis reaction is characterized by comprising the following steps: aromatization products the compounds of formula II undergo hydrolysis in the presence of water, an 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; the water and acid are provided by aqueous hydrochloric acid; after the aromatization reaction is finished, the aromatization product of the compound of the formula II is purified and added into a hydrolysis reaction system in a solid form.
2. The method of preparing vitamin B6 according to claim 1, comprising one or more of the following conditions:
a. substituent R 1 Is ethyl, R 2 Is n-propyl or isopropyl;
b. the hydrochloric acid aqueous solution is concentrated hydrochloric acid with the mass concentration of 30-38%;
c. the organic solvent 1 is dichloromethane;
d. the mass ratio of the aromatization product of the compound of the formula II to the organic solvent 1 is 3-5: 5-15 g/ml, the volume ratio of the mass of the aromatization product of the compound of the formula II to the mixed solution consisting of acid and water is 1-5: 1g/ml;
e. the hydrolysis reaction temperature is 30-70 ℃;
f. the hydrolysis reaction is carried out under the condition of heating reflux;
g. the post-treatment method of the reaction liquid obtained after the hydrolysis reaction is finished is as follows: cooling the reaction liquid, precipitating a crude product, filtering and drying to obtain the crude vitamin B6.
3. The method of preparing vitamin B6 according to claim 2, comprising one or more of the following conditions:
i. the hydrolysis reaction temperature is 40-65 ℃;
ii. Heating and refluxing while water diversion is carried out, discharging water out of the reaction system, and refluxing and water diversion are carried out until the reaction is completed; the reflux condition is normal pressure reflux;
in the post-treatment method of the reaction solution, the filter cake is washed by 90-100wt% ethanol after filtration.
4. The method for producing vitamin B6 according to claim 1, wherein 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%, carrying out normal pressure reflux reaction at 40 ℃, separating water during the reflux reaction, discharging water out of a reaction system, refluxing and separating water until the reaction is finished, cooling to 0-5 ℃ for crystal growth for 1-2 h, filtering, washing a filter cake with 95wt% ethanol, and carrying out vacuum drying at 40-70 ℃ to obtain a crude vitamin B6, namely the compound 5.
5. The method for preparing vitamin B6 according to claim 1, wherein the compound of formula i is obtained by Diels-Alder addition reaction having the following reaction formula B:
6. the process for the preparation of vitamin B6 as claimed in claim 5, wherein after the addition reaction, the compound of formula i is purified and put into the next aromatization reaction; or after the addition reaction is finished, the compound of the formula I is directly subjected to the next aromatization reaction without purification.
7. The method for producing vitamin B6 according to claim 1, wherein the aromatization reaction comprises the steps of: the aromatization reaction of the compound of formula I in the presence of ethanol, water and an 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 an aromatization product of the compound shown in the 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; in the ethanol-water, the mass ratio of ethanol to water is 1:1 to 2.
8. The method of claim 7, comprising one or more of the following conditions:
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: 1-2g/ml;
c. the aromatization reaction further comprises the step of distilling under reduced pressure until the system is sticky, and then adding an organic solvent 2;
d. the water and acid are provided by aqueous hydrochloric acid; the concentration of the hydrochloric acid aqueous solution is 0.1-0.5mol/L;
e. the ethanol is ethanol with the mass concentration of 95%;
f. the volume ratio of the mass of the compound of the formula I to the mixed solution consisting of acid and water is 1-2g/mL; the mass-to-volume ratio of the compound of the formula I to the ethanol is 1-2g/mL;
g. the aromatization reaction temperature is 20-60 ℃;
h. the water and the acid are added dropwise to a system containing ethanol and the compound of formula I in the form of a mixed solution;
i. the aromatization reaction is carried out under the protection of inert gas;
j. the organic solvent 1 used in the hydrolysis reaction and the organic solvent 2 used in the aromatization reaction are the same in kind.
9. The method of preparing vitamin B6 of claim 8, comprising one or more of the following conditions:
i. the concentration of the aqueous solution of hydrochloric acid is 0.2-0.3mol/L;
ii. The aromatization reaction temperature is 25-35 ℃.
10. The method for producing vitamin B6 as claimed in claim 7, 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 with the organic solvent 2 to obtain a solid of an aromatization product shown in a formula II.
11. The method for producing vitamin B6 according to claim 10, wherein the aromatization reaction comprises the steps of: adding 95wt% ethanol into a compound shown in a 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 the dropwise adding, and reacting for 8-14 h; and (3) 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 an aromatization product of the compound of the formula II.
12. The method for producing vitamin B6 according to claim 1, wherein the refining step comprises: decolorizing with active carbon, and recrystallizing with water.
13. The method for preparing vitamin B6 of claim 12, wherein the activated carbon is decolorized once and the water is recrystallized once.
14. The method for producing vitamin B6 according to claim 12, wherein the refining step comprises: mixing purified water and crude vitamin B6, namely compound 5, heating to dissolve, adding active carbon, stirring and decoloring; hot filtering, and washing an activated carbon filter cake with hot water; distilling the filtrate under reduced pressure, cooling to room temperature, growing crystals in ice bath, filtering, washing the filter cake with ethanol, and vacuum drying to obtain vitamin B6 product, namely compound 6.
15. The method of preparing vitamin B6 according to claim 14, 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;
b. the mass ratio of the crude vitamin B6 to the active carbon is 150:5-10;
c. stirring and decoloring at 60-90 ℃; stirring for decolorizing for 30-120min;
d. the temperature of the hot water is 60-90 ℃;
e. ice bath crystal growing for 1-2 h; the ice bath temperature is 0-10 ℃;
f. the refining step comprises the following steps: mixing purified water and crude vitamin B6, heating to dissolve, adding active carbon, and decolorizing at 70deg.C for 60min; hot filtering, and washing an activated carbon filter cake by hot water at 80 ℃; distilling the filtrate under reduced pressure, cooling to room temperature, growing crystals in an ice bath for 1-2 h, carrying out suction filtration, washing a filter cake with 95wt% ethanol, and carrying out vacuum drying to obtain a vitamin B6 finished product.
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| 维生素b6噁唑法合成新工艺;周后元等;中国医药工业杂志;第25卷(第9期);388页左栏第5段 * |
| 维生素B6的合成工艺改进;范卫东等;广州化工;第40卷(第17期);第47页1.2 * |
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