CN107628963B - Vitamin B5Method for preparing crude product - Google Patents
Vitamin B5Method for preparing crude product Download PDFInfo
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Abstract
The invention relates to vitamin B5The preparation method of the crude product comprises the following process steps of absorbing D L-pantoyl lactonase hydrolysate by macroporous adsorption resinThe invention provides a method for separating and extracting D-pantoic acid and L-pantoic acid lactone by using macroporous adsorption resin, which overcomes the defects of quality and yield reduction caused by easy emulsification of an extraction process, simultaneously separates out VB5 by using a solvent method crystallization technology, shortens crystallization time, improves extraction yield and product quality, is favorable for improving economic benefits, is simple and convenient, has less solvent loss, can reduce environmental pollution, has strong operability and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to vitamin B5A preparation method of a crude product.
Background
Vitamin B5(VB 5), also known as calcium D-pantothenate, chemical name D-N- (2, 4-dihydroxy-3, 3-dimethylbutyryl) - β -aminopropionate), relative molecular weight 476.54 calcium pantothenate can be divided into three types, D L-type (mixed isomer), D-type (dextroisomer) and L-type (levoisomer), wherein only D-type (dextroisomer) has biological activity.
VB5 is an odorless, slightly bitter white powder. Its specific optical rotation + 250～＋280(ii) a The melting point is 159-160 ℃; dissolving in water and glycerol, and slightly dissolving in ethanol, chloroform and diethyl ether; is unstable under acidic and alkaline conditions and is stable under neutral conditions (pH5.0-7.0); is stable to light and heat.
VB5 enters human body to release calcium element and pantothenic acid, and the pantothenic acid is coenzyme A precursor, and then is converted into coenzyme A to produce physiological action, participate in the metabolism of carbohydrate, fat and protein, and is a trace substance indispensable for maintaining normal physiological function of human body and animal. Is mainly used for medicine, food and feed additive.
VB5 is clinically used for treating vitamin B deficiency, peripheral neuritis and postoperative intestinal colic. It can also be used as auxiliary nutritional product for improving body constitution and enhancing immunity. VB5 can also be used as a feed additive to effectively accelerate the growth of animals and improve the disease resistance of livestock and poultry.
According to the chiral characteristic of the calcium D-pantothenate, the research hotspot of the VB5 production process is inclined to the microbial enzyme method, namely the microbial fermentation production by using fusarium oxysporum (fusarium oxysporm) and other microorganismsThe D-pantoic acid lactone hydrolase (existing in mycelium) is added into D L-pantoic acid lactone liquid as a catalyst, the D-pantoic acid lactone in the asymmetric hydrolysis D L-pantoic acid lactone is selectively split, the D L-pantoic acid lactone is split into D-pantoic acid and L-pantoic acid lactone, the separated D-pantoic acid is lactonized to obtain the D-pantoic acid lactone, and then the D-pantoic acid lactone reacts with 3-calcium aminopropionate to synthesize the D-calcium pantothenate5(VB 5) manufacturers select firstly, however, in the process for splitting D L-pantoic acid lactone by enzymatic hydrolysis, D-pantoic acid and L-pantoic acid lactone are generally required to be extracted and separated, and an emulsification reaction is easy to occur in the extraction process, when slight emulsification is carried out, a proper amount of activated carbon, sodium chloride saturated saline and the like are required to be added for standing for a long time, effective separation can be realized, when the emulsification is serious, the effect is poor, and in addition, the D-pantoic acid is easy to be adsorbed by the added activated carbon, so that the extraction yield is influenced.
In the process of D-pantoic calcium synthesis, D-pantoic acid lactone (C) is generally used6H10O3，M130) with calcium 3-aminopropionate (C)6H6O4Ca, M218) to produce calcium D-pantothenate (C)18H32N2O10Ca, M476), the crystallization process needs low temperature, seed crystal is added, and precipitation is induced for a long time.
Disclosure of Invention
The present invention aims to overcome the defects of the prior art and provide a method for effectively improving vitamin B5The vitamin B has the advantages of simple extraction and product quality, simple process, less solvent loss, short preparation time and capability of reducing environmental pollution5A preparation method of a crude product.
The technical scheme adopted for realizing the purpose is as follows:
vitamin B5The preparation method of the crude product is characterized by comprising the following process steps of sequentially adopting macroporous adsorption resin to adsorb and separate D L-pantoic acid lactonase hydrolysate and performing purification and filtration treatment, and adding salt into the obtained D-pantoic acid filtratePerforming esterification reaction on acid, extracting with a composite organic solvent, standing for separation, vacuum drying to obtain D-pantoic acid lactone, adding 3-aminopropionic acid calcium methanol solution into the D-pantoic acid lactone for synthetic reaction, crystallizing by adopting a solvent crystallization mode, performing suction filtration, and vacuum drying to obtain vitamin B5And (5) crude product.
When the macroporous adsorption resin is used for adsorption separation, the feeding speed is controlled to be 2-5 BV/h, the used macroporous adsorption resin is weak-polarity macroporous resin, and the model of the macroporous adsorption resin is L X1180, but not limited to L X1180.
The purification and filtration treatment refers to that D-pantoic acid solution obtained by adsorption and separation of macroporous adsorption resin is sequentially subjected to plate-frame filtration, carbon column filtration and titanium rod filtration.
Pre-laying perlite with the thickness of 2-3 cm on the filter cloth during plate-and-frame filtration; when carbon column, titanium stick filter, carbon column aperture 8 ~ 10um, titanium stick filter aperture 3.5 ~ 5.5 um.
The esterification reaction is to add hydrochloric acid to adjust the pH of the D-pantoic acid filtrate to 1.0-1.5 at the temperature of 65-70 ℃, and stir for 0.5-1.0 h.
The compound organic solvent extraction is to add a compound organic solvent into a D-pantoic acid lactone solution obtained by esterification, stir for 20-30 min, stand for 15-20 min, separate, and dry in vacuum, wherein the compound organic solvent is prepared by mixing the following components in a volume ratio of 3: 1, the dosage of the petroleum ether-amyl propionate composite solvent is 1/3-1/4 of the volume of the D-pantoic acid filtrate.
The synthesis reaction conditions are as follows: the reaction temperature is 55-60 ℃, the stirring speed is 110-140 rpm, and the reaction time is 10-12 h.
In the synthesis reaction process, the feeding ratio is as follows: 3-aminopropionic acid calcium (w) =1: 1.76-1.81, adding 30-32% (w/v) of 3-calcium aminopropionate methanol solution in mass volume concentration to react D-pantolactone with 3-calcium aminopropionate to synthesize vitamin B5。
The solvent crystallization is to slowly add ethanol with the volume of 1.5-3.0 times of that of the reaction liquid into the reaction liquid obtained in the synthesis reaction, then cool the reaction liquid to 2-5 ℃, add D-calcium pantothenate seed crystals with the volume of 0.1-0.3 per mill (w/v) of the reaction liquid, stir the crystals for 16-18 hours, and calculate the crystals according to the mass volume.
In the solvent crystallization process, the stirring speed is controlled to be 60-80 rpm.
The technical advantages of the invention are embodied in that:
the invention provides a method for separating and extracting D-pantoic acid and L-pantoic acid lactone by utilizing macroporous adsorption resin, which overcomes the disadvantages of quality and yield reduction caused by easy emulsification in the existing extraction process, and can improve the extraction yield by more than 4%.
2 the invention adopts a solvent crystallization method, the crystallization time is shortened by more than 10hr compared with the prior art, and the crystallization yield is improved by more than 6%.
3 the invention has simple operation flow, less solvent loss, reduced environmental pollution and strong operability.
Detailed description of the invention
The invention is illustrated below by way of examples, which are to be understood as being illustrative and not limiting. The scope and core content of the invention are to be determined by the claims.
The cured D-pantolactone hydrolase in the following examples is obtained by the following process flow:
freezing pipe
Bevel spore
Seed liquid
Fermentation liquor
Membrane filtration
Solidification of hypha
Granulating and drying
The D-pantolactone hydrolase is produced in a secondary fermentation mode, is stored in fusarium oxysporum (fusarium oxysporm) fermentation broth mycelium, is subjected to conventional embedding and solidification, and is used for enzymolysis of D L-pantolactone liquid.
D L-pantoic acid lactone enzymolysis liquid (the process is carried out according to the conventional technology):
adding 20% (w/v) D L-pantolactone solution 2000m L prepared from methanol into a reactor with a stirring and heat-preserving device, controlling the stirring speed to be 150rpm and the temperature to be 30 ℃, adding 114g of D-pantolactone hydrolase hypha embedded cured product according to the enzymolysis concentration of 0.3U/g, reacting for 5 hours at 30 ℃, dropwise adding 2.0 mol/L NaOH to control the pH to be 7.0-7.5 in the reaction process, finishing the reaction, filtering to obtain filtrate, namely D L-pantolactone enzymolysis solution, drying filter residue (D-pantolactone hydrolase embedded cured product), and continuing to perform enzymatic hydrolysis reaction on the filtrate, wherein the filtrate is subjected to the following experiments.
500ml of 30% (w/v) 3-aminopropionic acid calcium methanol solution was prepared and used.
Preparing macroporous adsorption resin (model L X1180), soaking in ethanol for 24h → washing with ethanol until the effluent is not turbid with water 1: 5 → washing with water until no alcohol smell → 5% HCl passes through the resin column, soaking for 2-4h → washing with water until the effluent is neutral → 2% NaOH passes through the resin column, soaking for 2-4h → washing with water until the effluent is neutral, and reserving for later use.
Example 1
Taking 300ml of D L-pantoic acid lactonase hydrolysate (containing 6.6% (g/ml) of D-pantoic acid), feeding D L-pantoic acid lactonase hydrolysate into a macroporous adsorption resin, separating D-pantoic acid by a L-pantoic acid lactone adsorption column at a feeding speed of 2BV/h, performing top washing with 30% (g/g) of methanol until no D-pantoic acid flows out, obtaining 360ml of solution containing 5.4% (g/ml) of D-pantoic acid, wherein the solution is used for the following experiment, resolving L-pantoic acid lactone adsorbed by the macroporous adsorption resin by a petroleum ether-pentyl propionate composite solvent (volume ratio of 3: 1), resolving at a resolving speed of 0.5BV/h, collecting resolving solution, concentrating and recovering the solvent under reduced pressure to obtain L-pantoic acid lactone, and processing, wherein the D-pantoic acid yield is 98.2%.
Filtering the D-pantoic acid solution obtained by separating the macroporous adsorption resin by a plate-frame filter (perlite with the thickness of 2cm is pre-paved on filter cloth), a carbon column filter (aperture is 8um) and a titanium rod filter (aperture is 3.5um) to obtain D-pantoic acid filtrate, heating the D-pantoic acid filtrate to 65-66 ℃, adding hydrochloric acid to adjust the pH value to 1.0, stirring for 0.5hr, converting the D-pantoic acid into D-pantoic acid lactone by esterification reaction, adding a petroleum ether-pentyl propionate composite solvent (volume ratio is 3: 1) to extract, adding 90ml of the petroleum ether-pentyl propionate composite solvent (volume of D-pantoic acid solution (V) = the petroleum ether-pentyl propionate composite solvent (V) =1: 0.25), stirring for 20min, standing for 15min, separating a petroleum ether-pentyl propionate composite solvent layer, removing the petroleum ether and pentyl propionate solvents by reduced pressure distillation, 15.7g of D-pantolactone is obtained. The yield thereof was found to be 92.2%.
Weighing 15.7g of D-pantolactone, adding 92ml of 30% (g/ml) 3-aminopropionic acid methanol calcium solution (the feeding ratio of D-pantolactone (W) = 3-aminopropionic acid calcium (W) =1: 1.76), controlling the reaction temperature to be 55-56 ℃, stirring at the rotation speed of 110rpm, stirring for 10hr, and finishing the reaction.
And slowly adding ethanol with the concentration of more than 95% (v/v) into the reaction solution, cooling to 2 ℃, adding D-calcium pantothenate seed crystals with the addition of 0.1 per mill (w/v) of the volume of the reaction solution according to the addition of 1.5 times of the volume of the reaction solution, stirring at the rotating speed of 60rpm for 16 hours, after crystallization is finished, performing suction filtration and vacuum drying to obtain 26.6g of a VB5 crude product, wherein the yield is 92.4%. The total yield was 83.5%.
Example 2
Taking 300ml of D L-pantoic acid lactonase hydrolysate (containing 6.6% (g/ml) of D-pantoic acid), feeding D L-pantoic acid lactonase hydrolysate into macroporous adsorption resin at a feeding speed of 3BV/h, carrying out top washing with 30% (g/g) of methanol until no D-pantoic acid flows out, obtaining 355ml of solution containing 5.5% (g/ml) of D-pantoic acid, using the 355ml of solution in the following experiments, resolving L-pantoic acid lactone adsorbed by the macroporous adsorption resin with a petroleum ether-amyl propionate composite solvent (volume ratio of 3: 1) at a resolving speed of 1.0BV/h, collecting resolving solution, concentrating under reduced pressure and recovering the solvent, obtaining L-pantoic acid lactone, and carrying out additional treatment, wherein the yield of the D-pantoic acid is 98.5%.
Filtering 5.5% (g/ml) D-pantoic acid solution obtained by separating the macroporous adsorption resin by a plate frame (filter cloth is pre-paved with perlite with the thickness of 2.5 cm), a carbon column filter (the aperture is 9um) and a titanium rod filter (the aperture is 4.5um) to obtain D-pantoic acid filtrate, heating the D-pantoic acid filtrate to 66-67 ℃, adding hydrochloric acid to adjust the pH to 1.2, stirring for 40min, carrying out lactonization reaction to convert the D-pantoic acid into D-pantoic acid lactone, adding a petroleum ether-pentyl propionate composite solvent (the volume ratio is 3: 1) to extract, adding 96ml (the volume of the D-pantoic acid solution (V) = the petroleum ether-pentyl propionate composite solvent (V) =1: 0.27) of the petroleum ether-pentyl propionate composite solvent, stirring for 25min, standing for 17min, separating out a petroleum ether-pentyl propionate composite solvent layer, removing the petroleum ether by reduced pressure distillation, Propionic acid pentyl ester solvent, to obtain 16.2g of D-pantolactone. The yield thereof was found to be 94.6%.
Weighing 16.2g of D-pantolactone, adding 93ml of 31% (g/ml) 3-calcium aminopropionate methanol solution (the feeding ratio of D-pantolactone (W): 3-calcium aminopropionate (W) =1: 1.78), controlling the reaction temperature to be 56-57 ℃, stirring at the rotating speed of 120rpm, stirring for 11hr, and finishing the reaction.
And slowly adding ethanol with the concentration of more than 95% (v/v) into the reaction solution, cooling to 3 ℃, adding D-calcium pantothenate seed crystals with the addition of 0.2 per mill (w/v) of the volume of the reaction solution according to the addition of 2.0 times of the volume of the reaction solution, stirring at the rotating speed of 70rpm for 17 hours, after crystallization is finished, performing suction filtration and vacuum drying to obtain 27.3g of a VB5 crude product, wherein the yield is 92.0%. The total yield is 85.6%.
Example 3
Taking 300ml of D L-pantoic acid lactonase hydrolysate (containing 6.6% (g/ml) of D-pantoic acid), putting D L-pantoic acid lactonase hydrolysate into macroporous adsorption resin, feeding at a speed of 4BV/h, carrying out top washing with 30% (g/g) methanol until no D-pantoic acid flows out, obtaining 352ml of D-pantoic acid solution at a speed of 5.4% (g/ml), resolving L-pantoic acid lactone adsorbed by the macroporous adsorption resin with a petroleum ether-amyl propionate composite solvent (volume ratio of 3: 1) at a resolving speed of 1.5BV/h, collecting resolving solution, concentrating under reduced pressure and recovering the solvent, obtaining L-pantoic acid lactone, carrying out additional treatment, and obtaining the yield of the D-pantoic acid of 96.5%.
Filtering 5.4% (g/ml) D-pantoic acid solution obtained by separating the macroporous adsorption resin by a plate frame (filter cloth is pre-paved with perlite with the thickness of 3 cm), a carbon column filter (the aperture is 10 mu m) and a titanium rod filter (the aperture is 4.5 mu m) to obtain D-pantoic acid filtrate, heating the D-pantoic acid filtrate to 67-68 ℃, adding hydrochloric acid to adjust the pH to 1.3, stirring for 50min, carrying out lactonization reaction to convert the D-pantoic acid into D-pantoic acid lactone, adding a petroleum ether-pentyl propionate composite solvent (the volume ratio is 3: 1) to extract, adding 106ml (D-pantoic acid solution volume (V): petroleum ether-pentyl propionate composite solvent (V) =1: 0.30) of petroleum ether-pentyl propionate composite solvent, stirring for 20-30 min, standing for 20min, separating out a petroleum ether-pentyl propionate composite solvent layer, removing the petroleum ether by reduced pressure distillation, Propionic acid pentyl ester solvent, to obtain 15.1g of D-pantolactone. The yield thereof was found to be 90.0%.
Weighing 15.1g of D-pantolactone, adding 84ml of 32% (g/ml) of 3-calcium aminopropionate methanol solution (the feeding ratio of D-pantolactone (W) = 3-calcium aminopropionate (W) =1: 1.79), controlling the reaction temperature to be 57-58 ℃, stirring at the rotating speed of 130rpm, stirring for 12hr, and finishing the reaction.
And slowly adding ethanol with the concentration of more than 95% (v/v) into the reaction solution, cooling to 4 ℃ by the volume of 2.5 times of the reaction solution, adding D-calcium pantothenate seed crystals with the addition of 0.3 per mill (w/v) of the volume of the reaction solution, stirring at the rotating speed of 80rpm, crystallizing for 18 hours, after the crystallization is finished, performing suction filtration and vacuum drying to obtain 26.2g of a VB5 crude product, wherein the yield is 94.7%. The total yield is 82.2%.
Example 4
Taking 300ml of D L-pantoic acid lactonase hydrolysate (containing 6.6% (g/ml) of D-pantoic acid), putting D L-pantoic acid lactonase hydrolysate into macroporous adsorption resin, feeding at the speed of 5BV/h, carrying out top washing with 30% (g/g) methanol until no D-pantoic acid flows out, obtaining 5.5% (g/ml) of D-pantoic acid solution 355ml, resolving L-pantoic acid lactone adsorbed by the macroporous adsorption resin with a petroleum ether-amyl propionate composite solvent (volume ratio of 3: 1) at the resolving speed of 1.0BV/h, collecting resolving solution, decompressing, concentrating and recovering the solvent, obtaining L-pantoic acid lactone, carrying out additional treatment, and obtaining the yield of the D-pantoic acid of 99.0%.
Filtering 5.5% (g/ml) D-pantoic acid solution obtained by separating the macroporous adsorption resin with a plate frame (filter cloth is pre-paved with perlite with the thickness of 2.5 cm), a carbon column filter (with the aperture of 9um) and a titanium rod filter (with the aperture of 5.5um) to obtain D-pantoic acid filtrate, heating the D-pantoic acid filtrate to 68-69 ℃, adding hydrochloric acid to adjust the pH to 1.4, stirring for 1.0hr, performing lactonization reaction to convert D-pantoic acid into D-pantoic acid lactone, adding a petroleum ether-pentyl propionate composite solvent (volume ratio of 3: 1) to extract, adding 117ml of the petroleum ether-pentyl propionate composite solvent (volume of D-pantoic acid solution (V): petroleum ether-pentyl propionate composite solvent (V) =1: 0.33), stirring for 20-30 min, standing for 18min, separating out a petroleum ether-pentyl propionate composite solvent layer, and removing the petroleum ether, the oil, Propionic acid pentyl ester solvent, to obtain 15.9g of D-pantolactone. The yield thereof was found to be 92.4%.
Weighing 15.9g of D-pantolactone, adding 92ml of 31% (g/ml) 3-calcium aminopropionate methanol solution (the feeding ratio of D-pantolactone (W) = 3-calcium aminopropionate (W) =1: 1.80), controlling the reaction temperature to be 58-59 ℃, stirring at the rotating speed of 140rpm, stirring for 11hr, and finishing the reaction.
And slowly adding ethanol with the concentration of more than 95% (v/v) into the reaction solution, cooling to 5 ℃ by the volume of 3.0 times of the reaction solution, adding D-calcium pantothenate seed crystals with the addition of 0.2 thousandth (w/v) of the volume of the reaction solution, stirring at the rotating speed of 70rpm, crystallizing for 17 hours, after the crystallization is finished, performing suction filtration and vacuum drying to obtain 28.1g of a VB5 crude product, wherein the yield is 96.4%. The total yield is 88.2%.
Example 5
Taking 300ml of D L-pantoic acid lactonase hydrolysate (containing 6.6% (g/ml) of D-pantoic acid), putting D L-pantoic acid lactonase hydrolysate into macroporous adsorption resin, feeding at a speed of 4BV/h, carrying out top washing with 30% (g/g) methanol until no D-pantoic acid flows out, obtaining 352ml of D-pantoic acid solution of 5.5% (g/ml), resolving L-pantoic acid lactone adsorbed by the macroporous adsorption resin with a petroleum ether-amyl propionate composite solvent (volume ratio of 3: 1) at a resolving speed of 1.0BV/h, collecting resolving solution, concentrating under reduced pressure and recovering the solvent, obtaining L-pantoic acid lactone, carrying out additional treatment, and obtaining the yield of the D-pantoic acid of 98.0%.
Filtering 5.5% (g/ml) D-pantoic acid solution obtained by separating the macroporous adsorption resin by a plate frame (filter cloth is pre-paved with perlite with the thickness of 2.5 cm), a carbon column filter (the aperture is 9um) and a titanium rod filter (the aperture is 4.5um) to obtain D-pantoic acid filtrate, heating the D-pantoic acid filtrate to 69-70 ℃, adding hydrochloric acid to adjust the pH value to 1.5, stirring for 45min, carrying out lactonization reaction to convert the D-pantoic acid into D-pantoic acid lactone, adding a petroleum ether-pentyl propionate composite solvent (the volume ratio is 3: 1) to extract, adding 106ml (D-pantoic acid solution volume (V): the petroleum ether-pentyl propionate composite solvent (V) =1: 0.30), stirring for 20-30 min, standing for 18min, separating out a petroleum ether-pentyl propionate composite solvent layer, removing the petroleum ether by reduced pressure distillation, Propionic acid pentyl ester solvent, to obtain 15.6g of D-pantolactone. The yield thereof was found to be 91.5%.
Weighing 15.6g of D-pantolactone, adding 91ml of 31% (g/ml) 3-calcium aminopropionate methanol solution (the feeding ratio of D-pantolactone (W) = 3-calcium aminopropionate (W) =1: 1.81), controlling the reaction temperature to be 59-60 ℃, stirring at the rotating speed of 130rpm, stirring for 11hr, and finishing the reaction.
And slowly adding ethanol with the concentration of more than 95% (v/v) into the reaction solution, cooling to 3 ℃, adding D-calcium pantothenate seed crystals with the addition amount of 0.2 thousandth (w/v) of the volume of the reaction solution, stirring at the rotating speed of 70rpm, crystallizing for 17 hours, after the crystallization is finished, performing suction filtration and vacuum drying to obtain 27.2g of a VB5 crude product, wherein the addition amount of the ethanol is 2.5 times of the volume of the reaction solution, and the yield is 95.1%. The total yield is 85.3%.
Comparative example 1
Taking 300ml of D L-pantoic acid lactonase hydrolysate (containing 6.6% (g/ml) of D-pantoic acid), adding 1% (w/v) of activated carbon into the reaction solution, uniformly stirring, heating for 30min, filtering by a PE microporous rod, heating the filtrate to 30 +/-2 ℃, adding ethyl acetate with the same volume while stirring, stirring for 20min, adding saturated NaC L solution, stirring for 40min according to 8 per mill (v/v) of the volume of the filtrate, standing, and performing extraction separation, wherein the water phase is D-pantoic acid, the organic phase is L-pantoic acid lactone, after one-time extraction, adding ethyl acetate into the water phase, performing three-time extraction until the optical rotation of the reaction solution is not changed any more (the water phase does not contain L-pantoic acid lactone), and collecting the water phase to obtain 292ml of the solution containing 6.4% (g/ml) of D-pantoic acid, wherein the extraction yield is 94.4%.
Adding hydrochloric acid into the aqueous phase liquid to adjust the pH value to 1, heating to 80 ℃, and keeping the temperature for about 30min to carry out lactonization on the hydrolyzed D-pantoic acid. Adding petroleum ether for extraction, adding 73ml (volume (V) of D-pantoic acid solution: petroleum ether (V) =1: 0.25), stirring for 20min, standing for 15min, separating out a petroleum ether layer, and removing the petroleum ether by reduced pressure distillation to obtain 15.1g of D-pantoic acid lactone. The yield thereof was found to be 91.9%.
Weighing 15.1g of D-pantolactone, adding 84ml of 30% (g/ml) of 3-calcium aminopropionate methanol solution, controlling the reaction temperature to 55-56 ℃, stirring at the rotation speed of 110rpm, and stirring for 10hr to finish the reaction, wherein the addition ratio of D-pantolactone (W) = 3-calcium aminopropionate (W) =1: 1.68.
Cooling the reaction to-5 ℃, adding 4mg of D-calcium pantothenate seed crystal (the seed crystal addition amount is 0.1 per mill (g/ml)) to induce crystallization, controlling the stirring speed to be 60rpm, the crystallization time to be 26hr, after the crystallization is finished, carrying out suction filtration and vacuum drying to obtain 24.5g of VB5 crude product, wherein the yield is 88.5%. The total yield is 76.9%.
Comparative example 2
Taking 300ml of D L-pantoic acid lactonase hydrolysate (containing 6.6% (g/ml) of D-pantoic acid), adding 2% (w/v) of activated carbon into the reaction solution, stirring uniformly, heating for 30min, filtering by a PE microporous rod, heating the filtrate to 30 +/-2 ℃, adding ethyl acetate with the same volume while stirring, stirring for 30min, adding saturated NaC L solution, stirring for 50min according to 12 per mill (v/v) of the volume of the filtrate, standing, and performing extraction separation, wherein the water phase is D-pantoic acid, the organic phase is L-pantoic acid lactone, after one-time extraction, adding ethyl acetate into the water phase, performing three-time extraction until the optical rotation of the reaction solution is not changed any more (the water phase does not contain L-pantoic acid lactone), and collecting the water phase to obtain 296ml of the D-pantoic acid lactonase hydrolysate containing 6.2% (g/ml), and the extraction yield is 94.4%.
Adding hydrochloric acid into the aqueous phase liquid to adjust the pH value to 1, heating to 80 ℃, and keeping the temperature for about 30min to carry out lactonization on the hydrolyzed D-pantoic acid. Adding petroleum ether for extraction, adding 79ml (volume (V) of D-pantoic acid solution) =1: 0.27), stirring for 25min, standing for 15min, separating out a petroleum ether layer, and removing the petroleum ether by reduced pressure distillation to obtain 14.4g of D-pantoic acid lactone, wherein the yield is 89.1%.
Weighing 14.4g of D-pantolactone, adding 81ml of 30% (g/ml) of 3-calcium aminopropionate methanol solution, controlling the reaction temperature to be 56-57 ℃, stirring at the rotating speed of 120rpm, and stirring for 11hr, wherein the addition ratio of D-pantolactone (W) = 3-calcium aminopropionate (W) =1:1.68, and finishing the reaction.
Cooling the reaction to-5 ℃, adding 7mg of D-calcium pantothenate seed crystal (the seed crystal addition amount is 0.2 per mill (g/ml)) to induce crystallization, controlling the stirring speed to be 70rpm, the crystallization time to be 28hr, after the crystallization is finished, performing suction filtration and vacuum drying to obtain 23.7g of VB5 crude product, wherein the yield is 89.8%. The total yield was 74.4%.
Comparative example 3
Taking 300ml of D L-pantoic acid lactonase hydrolysate (containing 6.6% (g/ml) of D-pantoic acid), adding 3% (w/v) of activated carbon into the reaction solution, uniformly stirring, heating for 30min, filtering by a PE microporous rod, heating the filtrate to 30 +/-2 ℃, adding ethyl acetate with the same volume while stirring, stirring for 30min, adding a saturated NaC L solution, stirring for 50min according to 15 per thousand (v/v) of the volume of the filtrate, standing, and performing extraction separation, wherein the water phase is D-pantoic acid, the organic phase is L-pantoic acid lactone, after one-time extraction, adding ethyl acetate into the water phase, performing three-time extraction until the optical rotation of the reaction solution is not changed any more (the water phase does not contain L-pantoic acid lactone), and collecting the water phase to obtain 301ml of the solution containing 6.2% (g/ml) of D-pantoic acid, and the extraction yield is 94.9%.
Adding hydrochloric acid into the aqueous phase liquid to adjust the pH value to 1, heating to 80 ℃, and keeping the temperature for about 30min to carry out lactonization on the hydrolyzed D-pantoic acid. Adding petroleum ether for extraction, adding 90ml (volume (V) of D-pantoic acid solution) =1: 0.30), stirring for 20-30 min, standing for 15min, and separating out a petroleum ether layer to obtain 14.9g of D-pantoic acid lactone.
Weighing 14.9g of D-pantolactone, adding 83ml of 30% (g/ml) 3-calcium aminopropionate methanol solution, controlling the reaction temperature to 59-60 ℃, stirring at the rotating speed of 140rpm, stirring for 12hr and finishing the reaction, wherein the addition ratio of D-pantolactone (W) = 3-calcium aminopropionate (W) =1: 1.68.
Cooling the reaction to-5 ℃, adding 5mg of D-calcium pantothenate seed crystal (the seed crystal addition amount is 0.3 per mill (g/ml)) to induce crystallization, controlling the stirring speed to be 80rpm, the crystallization time to be 30hr, after the crystallization is finished, performing suction filtration and vacuum drying to obtain 24.4g of VB5 crude product, wherein the yield is 89.4%. The total yield is 76.6%.
Claims (6)
1. Vitamin B5The preparation method of the crude product is characterized by comprising the following process steps of sequentially subjecting D L-pantoic acid lactonase hydrolysate to adsorption separation by macroporous adsorption resin, plate-frame filtration, carbon column filtration and titanium rod filtration, adding hydrochloric acid into the obtained D-pantoic acid filtrate for esterification reaction, extracting by using a composite organic solvent, standing for separation, vacuum drying to obtain D-pantoic acid lactone, adding a 3-aminopropionic acid calcium methanol solution into the D-pantoic acid lactone for synthesis reaction, crystallizing by using a solvent crystallization mode, performing suction filtration, and vacuum drying to obtain the vitamin B5A crude product;
the volume ratio of the composite organic solvent is 3: 1, using 1/3-1/4 of the volume of the D-pantoic acid filtrate as a petroleum ether-pentyl propionate composite solvent;
the solvent crystallization is to slowly add ethanol with the volume of 1.5-3.0 times of that of the reaction liquid into the reaction liquid obtained in the synthesis reaction, then cool the reaction liquid to 2-5 ℃, add D-calcium pantothenate crystal seeds with the volume of 0.1-0.3 per mill of that of the reaction liquid, stir the mixture for crystallization for 16-18 hours, and calculate the solution according to the mass volume;
when the macroporous adsorption resin is used for adsorption separation, the feeding speed is controlled to be 2-5 BV/h, and the used macroporous resin is weak-polarity macroporous adsorption resin;
pre-laying perlite with the thickness of 2-3 cm on the filter cloth during plate-and-frame filtration; when carbon column, titanium stick filter, carbon column aperture 8 ~ 10um, titanium stick filter aperture 3.5 ~ 5.5 um.
2. Vitamin B in accordance with claim 15The preparation method of the crude product is characterized in that the esterification reaction is carried out by adding hydrochloric acid to adjust the pH of D-pantoic acid filtrate to 1.0-1.5 at the temperature of 65-70 ℃, and stirring for reaction for 0.5-1.0 h.
3. Vitamin B in accordance with claim 15The preparation method of the crude product is characterized in that the compound organic solvent extraction is to add the compound organic solvent into a D-pantoic acid lactone solution obtained by esterification, stir for 20-30 min, stand for 15-20 min, separate and dry in vacuum.
4. Vitamin B in accordance with claim 15The preparation method of the crude product is characterized in that the synthesis reaction conditions are as follows: the reaction temperature is 55-60 ℃, the stirring speed is 110-140 rpm, and the reaction time is 10-12 h.
5. Vitamin B in accordance with claim 15The preparation method of the crude product is characterized in that in the synthesis reaction process, the charging ratio is as follows according to the mass ratio of D-pantoic acid lactone: 3-aminopropionic acid calcium =1: 1.76-1.81, and adding a 3-aminopropionic acid calcium methanol solution with the mass volume concentration of 30-32%.
6. Vitamin B in accordance with claim 15The preparation method of the crude product is characterized in that the stirring speed is controlled at 60-80 rpm in the solvent crystallization process.
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