CN112457181A - Synthesis method of D-calcium pantothenate - Google Patents
Synthesis method of D-calcium pantothenate Download PDFInfo
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- CN112457181A CN112457181A CN202011436288.9A CN202011436288A CN112457181A CN 112457181 A CN112457181 A CN 112457181A CN 202011436288 A CN202011436288 A CN 202011436288A CN 112457181 A CN112457181 A CN 112457181A
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Abstract
The invention discloses a method for synthesizing D-calcium pantothenate, belonging to the technical field of organic synthesis. The method comprises the following steps: hydrolyzing DL-pantolactone under alkaline condition, and adding acid after hydrolysis; reacting with organic amine salt in a mixed solvent A, cooling and crystallizing after the reaction is finished, carrying out solid-liquid separation, extracting filter residue by adopting an extracting agent and water under an alkaline condition, carrying out organic phase separation on the extracting agent to obtain organic amine, concentrating a water phase, acidifying, and carrying out reduced pressure distillation to obtain L-pantothenic acid lactone; racemizing L-pantothenic acid lactone and phosphate to obtain DL-pantothenic acid lactone; extracting the filtrate under alkaline condition, concentrating the water phase, adding acid and alkali, evaporating the reaction product to dryness, purifying to obtain D-pantolactone, and separating the purified mother liquor to obtain DL-pantolactone; reusing the obtained DL-pantothenic acid lactone; reacting beta-amino calcium propionate and D-pantothenic acid lactone in methanol, and crystallizing in methanol to obtain D-calcium pantothenate.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing D-calcium pantothenate.
Background
Calcium D-pantothenate (D- (+) -N- (2, 4-dihydroxy-3, 3-dimethylbutyryl) - β -aminopropionate) is the calcium salt of the D-isomer of pantothenic acid, is a white powder, odorless, bitter, slightly hygroscopic, most stable at pH 5.0-7.0, soluble in glycerol, insoluble in ethanol, chloroform and diethyl ether. One of the B vitamins is an important raw material for medicines, foods, health products and the like.
The existing method for preparing the D-calcium pantothenate comprises the steps of obtaining D-pantothenic acid from a fermentation culture solution, obtaining the D-pantothenic acid by a resin extraction method, and preparing the calcium pantothenate from the pantothenic acid.
Disclosure of Invention
The invention aims to provide a method for synthesizing D-calcium pantothenate, which adopts a specific resolving agent for resolution, has good resolution effect, can recycle the resolving agent and L-pantothenic acid lactone, does not need resin extraction, improves the yield, and obtains a product with the purity of more than 99 percent, and the method has the following steps of a specific technical scheme:
the embodiment of the invention provides a method for synthesizing D-calcium pantothenate, which comprises the following steps:
(1) hydrolyzing DL-pantolactone (intermediate I) under alkaline condition (specifically adding sodium hydroxide) to pH12-13, and adjusting to 8-9 with acid (specifically hydrochloric acid).
(2) And (2) reacting the product obtained in the step (1) with organic amine salt in a mixed solvent A at the reaction temperature of 75-85 ℃, cooling and crystallizing after the reaction is finished (1.5-3.0 hours), and carrying out solid-liquid separation. Wherein the molar ratio of the organic amine salt to the DL-pantothenic acid lactone is 1: 1.5-2.0; the mixed solvent A is prepared by mixing water and an extracting agent according to the mol ratio of 7-9:1, and the dosage is added according to the requirement.
(3) Extracting the filter residue obtained in the step (2) by using an extracting agent and water under the condition of pH12-13 (specifically, adding sodium hydroxide), separating the organic phase from the extracting agent to obtain organic amine, using the separated organic amine to prepare organic amine salt, sending the organic amine salt to the step (2) for reuse, concentrating the water phase, adding acid to adjust the pH value to 1-2 for acidification, wherein the acidification temperature is 80-85 ℃, adding alkali to adjust the pH value to 6-7 after the acidification is finished, and then carrying out reduced pressure distillation to obtain the L-pantolactone. Wherein the organic amine is rosin amine, and correspondingly, the organic amine salt is rosin amine salt (specifically rosin amine hydrochloride).
(4) Performing racemization reaction on the L-pantolactone obtained in the step (3) and phosphate (specifically sodium phosphate) at the temperature of 190 ℃ at 170 ℃ to obtain DL-pantolactone, and sending the obtained DL-pantolactone to the step (1) for reuse. Wherein the molar ratio of L-pantolactone to phosphate is 15-25: 1.
(5) Extracting the filtrate obtained in the step (2) by using an extracting agent under the condition that the pH value is 12-13 (specifically, sodium hydroxide is added), concentrating a water phase, adding acid to adjust the pH value to 1-2 for acidification, wherein the acidification temperature is 80-85 ℃, adding alkali to adjust the pH value to 6-7 after the acidification is finished, evaporating a reaction product to dryness, purifying to obtain D-pantothenic acid lactone (an intermediate IV), and separating a purified mother liquor to obtain DL-pantothenic acid lactone, and then sending the DL-pantothenic acid lactone to the step (1) for reuse.
(6) Reacting beta-calcium aminopropionate (intermediate III) with the D-pantolactone obtained in the step (5) in methanol at the temperature of 60-65 ℃, and crystallizing in methanol after the reaction is finished (0.5-2.0 hours) to obtain the D-calcium pantothenate. Wherein the molar ratio of the beta-aminopropionic acid calcium to the D-pantothenic acid lactone is 1.0-1.2: 1.
Wherein the synthetic process of the DL-pantothenic acid lactone in the embodiment of the invention is as follows: dropping isobutyraldehyde into formaldehyde at 20-30 ℃ and alkalinity (specifically sodium carbonate) to carry out condensation reaction, wherein the pH is 9-10, the reaction temperature is 40-50 ℃, after the reaction is finished (2-5 hours), adding water and cyanide (specifically sodium cyanide) to carry out cyanidation reaction, the reaction temperature is 5-15 ℃, after the reaction is finished (1-4 hours), adding acid (specifically sulfuric acid) to adjust the pH to 0.5-2.0, carrying out acidification reaction at 140 ℃ of 100 ℃., (1-4 hours), cooling to 35-45 ℃, adding alkali (specifically ammonium bicarbonate) to adjust the pH to 5.5-6.5, standing for layering, carrying out reduced pressure distillation on the water phase, collecting fractions at 117 ℃ of 110-. Wherein the molar ratio of isobutyraldehyde to formaldehyde to cyanide is 1:0.8-1.2: 0.8-1.2.
The synthesis process of the beta-calcium aminopropionate in the embodiment of the invention comprises the following steps:
(61) acrylic acid and ammonia water carry out ammonolysis reaction under the action of inhibitor ammonium bicarbonate, the reaction temperature is 160-170 ℃, and the temperature is reduced after the reaction is finished (2-6 hours). Wherein the mol ratio of the acrylic acid to the ammonia water to the ammonium bicarbonate is 1:4.5-5.0:1.5-1.8, and the concentration of the ammonia water is more than 20 wt%.
(62) And (3) recovering ammonia gas at the temperature of 40-50 ℃ and the vacuum degree of less than or equal to-0.085 MPa, returning the ammonia gas to the step (61) for reuse, adding activated carbon for decolorization reaction at the decolorizing temperature of 60-70 ℃, filtering the activated carbon after the decolorization is finished (for 20-60 minutes), and concentrating and dehydrating the filtrate.
(63) And (3) dissolving the material obtained in the step (62) by adopting 90-98wt% of methanol at the dissolving temperature of 52-58 ℃, cooling (12-16 ℃) for crystallization after complete dissolution, and carrying out solid-liquid separation to obtain beta-aminopropionic acid (an intermediate II).
(64) And (4) sequentially adding calcium oxide and the beta-aminopropionic acid obtained in the step (63) into water, reacting under a micro-boiling condition, and after the reaction is finished (1-4 hours), decompressing and evaporating to dryness to obtain the beta-aminopropionic acid calcium. Wherein the mol ratio of the beta-aminopropionic acid to the calcium oxide to the water is 1:1.1-1.4:30-70, preferably 1:1.01-1.05: 30-50. Methanol is not required to be added as a solvent in this step as in the conventional technique, and purification is not required.
The synthesis process of the organic amine salt in the embodiment of the invention comprises the following steps: and (2) reacting organic amine (specifically dehydroabietylamine) with hydrochloric acid in a mixed solvent B at 75-85 ℃ to obtain an organic amine hydrochloride solution. Wherein the molar ratio of the organic amine to the hydrochloric acid is 1:1.0-1.2, and the mixed solvent B is prepared by mixing water and an extracting agent according to the molar ratio of 7-30: 1; accordingly, in step (3), the organic phase is distilled to obtain the extractant and the organic amine.
Specifically, the extractant in the embodiment of the present invention is methyl tert-butyl ether.
Further, step (6) in the embodiment of the present invention includes: reacting beta-calcium aminopropionate with the D-pantothenic acid lactone obtained in the step (5) in anhydrous methanol A at the temperature of 60-65 ℃, wherein the using amount of the anhydrous methanol A is 2-3 times of the total weight of the beta-calcium aminopropionate and the D-pantothenic acid lactone, filtering while the reaction is hot after the reaction is finished, transferring the mixture to an anhydrous methanol kettle which is cooled to the temperature below 20 ℃ and is filled with anhydrous methanol B, wherein the using amount of the anhydrous methanol B is 3-6 times of the weight of a reaction product, adding pure water after the materials are completely dissolved, wherein the using amount of the pure water is 1-3% of the weight of the anhydrous methanol B, carrying out heat preservation and crystallization for 4-8 hours at the temperature of 10-20 ℃, and carrying out solid-liquid separation at the temperature below 10 ℃ after the crystallization is finished to obtain the D-calcium pantothenate.
Preferably, in step (5), the purification process is: evaporating the reaction product to dryness, adding toluene to dissolve, distilling at 50-60 ℃ to obtain a crude product and a toluene fraction, adding the crude product into toluene to recrystallize at 75-85 ℃, wherein the mass ratio of the crude product to the toluene during recrystallization is 1:1-3, performing solid-liquid separation to obtain a refined product and a crystallized mother liquor, combining the crystallized mother liquor and the toluene fraction, rectifying to obtain toluene and DL-pantolactone, recycling the obtained toluene, and sending the obtained DL-pantolactone to the step (1) for recycling.
Specifically, in steps (3) and (5), the acid is concentrated sulfuric acid, the base is ammonium bicarbonate, and the concentration process is as follows: concentrating to 1/4-1/2.
Specifically, a method for synthesizing calcium D-pantothenate in an embodiment of the present invention includes:
preparation of S101 DL-pantolactone: dropwise adding isobutyraldehyde into formaldehyde at 20-30 ℃ under alkalinity (specifically adding sodium carbonate) to perform condensation reaction, wherein the pH is 9-10, the reaction temperature is 40-50 ℃, after the reaction is finished (2-5 hours), adding water and cyanide (specifically sodium cyanide) to perform cyanidation reaction, the reaction temperature is 5-15 ℃, after the reaction is finished (1-4 hours), adding sulfuric acid to adjust the pH to 0.5-2.0, performing acidification reaction at the temperature of 140 ℃, after the reaction is finished (1-4 hours), cooling to 35-45 ℃, adding ammonium bicarbonate to adjust the pH to 5.5-6.5, standing for layering, performing reduced pressure distillation on a water phase, collecting 110-117 ℃ fractions, and cooling and crystallizing to obtain the DL-pantothenic acid lactone. Wherein the molar ratio of isobutyraldehyde to formaldehyde to cyanide is 1:0.8-1.2: 0.8-1.2.
Hydrolysis of S102 DL-pantolactone: hydrolyzing DL-pantolactone under alkaline condition (specifically adding sodium hydroxide) to pH12-13, and adjusting to 8-9 with acid (specifically hydrochloric acid) after hydrolysis (hydrolysis temperature of 70-90 deg.C).
S103, synthesis of organic amine salt: reacting rosin amine and hydrochloric acid in a mixed solvent B at 75-85 ℃ to obtain a rosin amine hydrochloride solution. Wherein, the molar ratio of the rosin amine to the hydrochloric acid is 1:1.0-1.2, and the mixed solvent B is prepared by water and methyl tert-butyl ether according to the molar ratio of 7-30: 1; accordingly, in step (3), the organic phase is distilled to obtain methyl t-butyl ether and rosin amine.
Resolution of S104 DL-pantolactone: and (3) reacting the product obtained in the step (S103) with the rosin amine hydrochloride solution in the mixed solvent A at the reaction temperature of 75-85 ℃, cooling and crystallizing after the reaction is finished (1.5-3.0 hours), and carrying out solid-liquid separation. Wherein, the molar ratio of the rosin amine hydrochloride to the DL-pantothenic acid lactone is 1:1.5-2.0, and the mixed solvent A is prepared by water and methyl tert-butyl ether according to the molar ratio of 7-9: 1.
S105, recovery of organic amine salt: extracting the filter residue obtained in the step S104 by adopting methyl tert-butyl ether and water under the condition of pH12-13 (specifically adding sodium hydroxide), separating the organic phase from the methyl tert-butyl ether to obtain abietylamine, sending the abietylamine obtained by separation to the step S103 for reuse, concentrating the water phase, adding concentrated sulfuric acid to adjust the pH value to 1-2 for acidification, adjusting the acidification temperature to 80-85 ℃, adding ammonium bicarbonate to adjust the pH value to 6-7 after the acidification is finished, and then carrying out reduced pressure distillation to obtain the L-pantothenic acid lactone.
Racemization of S106L-pantolactone: the L-pantolactone obtained in step S105 and a phosphate (specifically sodium phosphate) are subjected to racemization reaction at 190 ℃ and 170 ℃ to obtain DL-pantolactone, and the obtained DL-pantolactone is sent to step S104 for reuse. Wherein the molar ratio of L-pantolactone to phosphate is 15-25: 1.
S107D isolation of pantothenic acid lactone: extracting the filtrate obtained in the step S102 by adopting methyl tert-butyl ether under the condition that the pH value is 12-13 (specifically, sodium hydroxide is added), concentrating the water phase, adding concentrated sulfuric acid to adjust the pH value to 1-2 for acidification, wherein the acidification temperature is 80-85 ℃, adding ammonium bicarbonate to adjust the pH value to 6-7 after the acidification is finished, evaporating the reaction product to dryness, recrystallizing by adopting toluene to obtain D-pantothenic acid lactone, and separating the purified mother liquor to obtain DL-pantothenic acid lactone, and sending the DL-pantothenic acid lactone to the step S104 for reuse.
Synthesis of S108 β -calcium aminopropionate: acrylic acid and ammonia water carry out ammonolysis reaction under the action of inhibitor ammonium bicarbonate, the reaction temperature is 160-170 ℃, and the temperature is reduced after the reaction is finished (2-6 hours); wherein the mol ratio of the acrylic acid to the ammonia water to the ammonium bicarbonate is 1:4.5-5.0:1.5-1.8, and the concentration of the ammonia water is more than 20 wt%. Recovering ammonia gas at 40-50 deg.C and vacuum degree of-0.085 MPa or lower, adding active carbon for decolorizing at 60-70 deg.C for 20-60 min, filtering to remove active carbon, and concentrating and dewatering the filtrate. And dissolving with 90-98wt% methanol at 52-58 deg.C, cooling to 12-16 deg.C for crystallization, and performing solid-liquid separation to obtain beta-alanine. Sequentially adding calcium oxide and beta-aminopropionic acid into water, reacting under the condition of slight boiling, and after the reaction is finished (1-4 hours), decompressing and evaporating to dryness to obtain the beta-aminopropionic acid calcium. Wherein the mol ratio of the beta-aminopropionic acid to the calcium oxide to the water is 1:1.1-1.4: 30-70.
S109D-calcium pantothenate synthesis: reacting beta-calcium aminopropionate and D-pantothenic acid lactone in anhydrous methanol A at the temperature of 60-65 ℃, wherein the using amount of the anhydrous methanol A is 2-3 times of the total weight of the beta-calcium aminopropionate and the D-pantothenic acid lactone, filtering while hot after the reaction is finished, transferring the mixture to an anhydrous methanol kettle which is cooled to below 20 ℃ and contains the anhydrous methanol B, wherein the using amount of the anhydrous methanol B is 3-6 times of the weight of a reaction product, adding pure water after the materials are completely dissolved, wherein the using amount of the pure water is 1-3% of the weight of the anhydrous methanol B, carrying out heat preservation and crystallization at the temperature of 10-20 ℃ for 4-8 hours, and carrying out solid-liquid separation on the D-calcium pantothenate at the temperature of below 10 ℃ after the crystallization is finished.
The technical scheme provided by the invention has the following beneficial effects:
(1) specific organic amine salt is used as a resolving agent, the primary resolving rate exceeds 40-45%, D-pantothenic acid lactone is obtained as far as possible, and the organic amine and the L-pantothenic acid lactone can be recycled;
(2) DL-pantothenic acid lactone is hydrolyzed firstly and then split to obtain D-pantothenic acid lactone, and finally reacts with beta-calcium aminopropionate, and the DL-pantothenic acid lactone reacts with beta-calcium aminopropionate firstly and then is split under specific conditions, so that the yield is higher;
(3) the ammonium bicarbonate is used as an inhibitor, so that the generation of byproducts can be effectively inhibited, the ammonia water is effectively recovered and recycled, and the consumption of raw materials is reduced;
(4) toluene is used as a purification solvent, the bottom residue recovered from the mother solution is DL-pantothenic acid lactone which can be recycled, and the toluene can completely separate the DL-pantothenic acid lactone and the D-pantothenic acid lactone.
(5) In the crystallization process of the product, crystal seeds do not need to be added, the crystal form is good, the product quality is stable, and the problems of massive hardening, crystal holding and the like do not occur (in the prior art, if a conventional crystallization mode in a methanol solvent is directly adopted, the product quality is always unstable, the product appearance is powdery, the purity of a crystal-free product is suddenly high and low, impurities are difficult to control, and the problems of massive hardening, crystal holding and the like occur when the crystal seeds are added).
(6) The extractant, toluene, methanol, ammonia water and the like can be reused, and the production cost is reduced.
(7) The synthesis of the beta-calcium aminopropionate does not need to add an organic solvent or purify, thereby simplifying the process;
(8) is suitable for industrial production, the product content reaches more than 99 percent, and the specific optical rotation is plus 26.5° The above requirements of USP food and feed grade can be met.
Drawings
Fig. 1 is a flowchart of step S101;
FIG. 2 is a flowchart of steps S102-S107;
fig. 3 is a flowchart of step S108;
fig. 4 is a flowchart of step S109;
FIG. 5 is a photograph of a prior art wet pick;
FIG. 6 is a photograph of a wet good of the crystallization process provided by the present invention;
FIG. 7 is a photograph of a dried product of the crystallization method of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention are described in further detail below.
Example 1
Synthesis of Compound I (DL-pantolactone)
At room temperature (20-25 ℃), adjusting the pH value of 324kg (37 wt%) of formaldehyde solution to 9-10 (the using amount of sodium carbonate is about 36 kg) by using sodium carbonate, dropwise adding 95wt% of isobutyraldehyde into the formaldehyde solution, controlling the temperature to be 20-30 ℃, and after dropwise adding, heating to 40-50 ℃ and preserving heat for 3 hours;
adding 600kg of water into a cyanidation kettle, slowly adding 200kg of sodium cyanide under stirring to prepare a 30wt% aqueous solution, slowly dropwise adding the materials in the condensation kettle into the cyanidation kettle under stirring, controlling the dropwise adding temperature to be 10-15 ℃ and the dropwise adding time to be 2-3 hours;
adding 70wt% sulfuric acid solution into the cyanided product, adjusting the pH value to be 1-2, heating and controlling the temperature of 120 ℃, preserving the heat and refluxing for 2 hours, cooling to about 40 ℃, adding ammonium bicarbonate to adjust the pH value to be 6, standing for 30-60 minutes for layering, transferring the water phase to a distillation kettle for reduced pressure distillation, controlling the vacuum degree to be within 500Pa, controlling and receiving 113-117 ℃ positive fraction, applying the former fraction to the next batch of distillation, filling low slag as waste liquid, cooling and crystallizing the positive fraction to 10-15 ℃, and carrying out centrifugal separation.
Example 2
Synthesis of Compound II (. beta. -calcium aminopropionate)
At room temperature (20-25 ℃), adding 400L of water and 150kg of ammonium bicarbonate into a reaction kettle, slowly dropwise adding 80kg of raw material acrylic acid into the reaction kettle for 1.5-2 hours, wherein flushing is prevented in the dropwise adding process, the reaction lasts for 30 minutes after the dropwise adding is finished, and the time is prolonged if more reaction bubbles exist.
Pumping the materials in the batching kettle into a high-pressure reaction kettle by a pump, controlling the temperature of the reaction kettle to be 130-.
Pressing the materials into a decoloring kettle for decoloring, adding 1kg of active carbon and 2kg of filter aid, controlling the temperature to be 60-70 ℃, decoloring for 30 minutes, then carrying out filter pressing, concentrating the filter-pressed materials into a concentration kettle, controlling the internal temperature to be 40-55 ℃, concentrating for 8 hours under the vacuum degree of less than or equal to-0.085 MPa, transferring the materials into a dry dissolving kettle, adding 1200L of prepared 95wt% methanol solution into the dissolving kettle, controlling the internal temperature to be 52-58 ℃ for heat preservation and reflux for 1 hour, then discharging the materials into a crystallization kettle for cooling and crystallization, controlling the temperature (12-16 ℃) for crystallization for 8 hours, and carrying out centrifugal separation to obtain the beta-aminopropionic acid.
Adding 1000L of water into a beta-calcium aminopropionate synthesis kettle, sequentially adding 80kg of calcium oxide and about 90kg of the obtained beta-aminopropionic acid, reacting under the condition of slight boiling, controlling the internal temperature to be 40-55 ℃ after the reaction is finished for 2 hours, and evaporating under reduced pressure until the vacuum degree is less than or equal to-0.085 MPa to obtain the beta-calcium aminopropionate.
Example 3
Synthesis of Compound III (D-pantolactone)
In the amine salt preparation kettle: at room temperature (20-25 deg.C), 215kg of dehydroabietylamine is dissolved in 400L of methyl tert-butyl ether, the methyl tert-butyl ether is recovered by heating and distilling until no liquid flows out at 95 deg.C, 600L of water is added, about 27kg of 37wt% hydrochloric acid is used for adjusting pH value to 3-4, 300L of water is added and the mixture is transferred to a resolution kettle for standby.
Pan ester hydrolysis kettle: adding 500L of water into a kettle, adding 200kg of pantolactone, adjusting the pH value of the system to be 13-14 by using about 65kg of sodium hydroxide under the stirring state, then stirring and heating to 80 ℃, preserving the temperature for reaction for 30-60 minutes, and then adding dilute hydrochloric acid to adjust the pH value of the system to be 8-9.
And discharging the materials in the hydrolysis kettle into a splitting kettle, mixing the materials with the prepared amine salt, controlling the mixing temperature to be about 60 ℃, then heating to 80 ℃, preserving heat for 1.5-2 hours, cooling to 40-45 ℃ by using circulating water, then cooling to 20 ℃ by using ice brine, preserving heat for 30-60 minutes, and carrying out centrifugal separation to obtain a filter cake and a mother liquor.
Putting the obtained filter cake into a stainless steel extraction kettle, adding 400L of water and 400L of methyl tert-butyl ether, adjusting the pH value of a system to be 13-14 by using sodium hydroxide under the stirring state, stirring for 30-60 minutes, standing for 30-60 minutes for layering, allowing a water phase to enter an L-shaped concentration kettle, controlling the temperature of the water phase in the concentration kettle to be 40-60 ℃, carrying out reduced pressure concentration for about 8 hours, adding 110-120kg of concentrated sulfuric acid to adjust the pH value to be 1.5, heating to 80 ℃, carrying out heat preservation for 1 hour, adding 30-50kg of ammonium bicarbonate to adjust the pH value to be 6-7, adding 10kg of sodium phosphate, heating to control the temperature to be 180 ℃, and racemizing for 1.5-2 hours for later use; and transferring the oil phase into a recovery kettle, controlling the temperature of the recovery kettle to be 60-95 ℃, distilling for 2 hours until no liquid flows out, wherein the recovered liquid is methyl tert-butyl ether, and the bottom material is resolving agent rosin amine which can be recycled.
Transferring the mother liquor centrifugally separated in the splitting kettle into a layering kettle, adding 150L of methyl tert-butyl ether as a solvent, regulating the pH value of a system to be 13-14 by using about 4kg of sodium hydroxide under the stirring state, stirring for 30-60 minutes, standing for 30-60 minutes for layering, allowing a water phase to enter a D-configuration concentration kettle, concentrating the water phase in the concentration kettle to the residual amount of 1/3, transferring the water phase into an acidification kettle by using a pump, adding about 60kg of concentrated sulfuric acid to regulate the pH value to be 1.5, adding ammonium bicarbonate to regulate the pH value to be 6-7, transferring the water phase into a distillation dissolution kettle, controlling the temperature to be 100 ℃ and 110 ℃ for drying by distillation, cooling to 80 ℃, controlling the water content to be below 0.5%, adding 200L of toluene (the water content is below 0.5%) for stirring for 30 minutes, controlling the temperature to be 40-50 ℃ for heat filtration and salt removal, allowing a filtrate to enter a crystallization kettle for concentrating and recovering about 50L of, cooling to 0 deg.C, maintaining the temperature for 30-60 min, and centrifuging to obtain D-pantolactone crude product; the oil phase is transferred into a recovery kettle to be recovered together with the oil phase.
Dissolving the obtained D-pantolactone crude product in toluene according to the weight ratio of 1:1, heating to 80 ℃ to dissolve for 30-60 minutes, then cooling to 0 ℃ and preserving the temperature for 30-60 minutes, and carrying out centrifugal separation to obtain a refined product of D-pantolactone; the crude toluene mother liquor and the fine toluene mother liquor both contain DL pantoic acid lactone, the crude toluene mother liquor and the fine toluene mother liquor are mixed for several batches and then enter a toluene recovery kettle together for recovery and distillation, the temperature is controlled at 135 ℃, the toluene is recovered after distillation for 0.5-1.5 hours, and the DL pantoic acid lactone is obtained after the residual materials are subjected to reduced pressure distillation.
Example 4
Synthesis of Compound IV (calcium D-pantothenate)
At room temperature (20-25 ℃), adding 140kg of D-pantothenic acid lactone into a synthesis reaction kettle containing 120kg of beta-calcium aminopropionate in 600kg of anhydrous methanol, heating to control the reaction temperature to 60-65 ℃ for micro-boiling reaction for 1 hour, filtering while the reaction is hot after the reaction is finished, transferring the material into a crystallization kettle which is cooled to below 20 ℃ and has 1500L of anhydrous methanol, stirring until the material is completely dissolved, adding 20kg of pure water, cooling the system to 10-20 ℃, carrying out heat preservation crystallization for 4-8 hours, and carrying out solid-liquid separation at below 10 ℃ after the crystallization is finished to obtain the D-calcium pantothenate.
The obtained D-calcium pantothenate is white needle crystal, the melting point of the product is 195 deg.C, the content is 99.5%, the content of calcium in the dried product is 8.5%, the content of nitrogen is 5.8%, and the specific optical rotation is + 26.5%°Can meet the USP food and feed grade requirements.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (9)
1. A method for synthesizing calcium D-pantothenate, comprising:
(1) hydrolyzing DL-pantolactone under alkaline condition to pH12-13, and adjusting to 8-9 with acid;
(2) reacting the product obtained in the step (1) with organic amine salt in a mixed solvent A at the reaction temperature of 75-85 ℃, cooling and crystallizing after the reaction is finished, and carrying out solid-liquid separation, wherein the molar ratio of the organic amine salt to the DL-pantothenic acid lactone is 1:1.5-2.0, and the mixed solvent A is prepared by water and an extracting agent according to the molar ratio of 7-9: 1;
(3) extracting the filter residue obtained in the step (2) by using an extracting agent and water under the condition of pH12-13, separating the extracting agent by using an organic phase to obtain organic amine, using the organic amine obtained by separation to prepare organic amine salt, sending the organic amine salt to the step (2) for reuse, adding acid to adjust the pH value to 1-2 for acidification after water phase concentration, wherein the acidification temperature is 80-85 ℃, adding alkali to adjust the pH value to 6-7 after acidification is finished, and carrying out reduced pressure distillation to obtain L-pantothenic acid lactone, wherein the organic amine is abietylamine, and correspondingly, the organic amine salt is abietylamine salt;
(4) performing racemization reaction on the L-pantolactone obtained in the step (3) and phosphate at the temperature of 190 ℃ at 170 ℃ to obtain DL-pantolactone, and delivering the obtained DL-pantolactone to the step (1) for reuse, wherein the molar ratio of the L-pantolactone to the phosphate is 15-25: 1;
(5) extracting the filtrate obtained in the step (2) by using an extracting agent under the condition that the pH value is 12-13, concentrating a water phase, adding acid to adjust the pH value to 1-2 for acidification, adjusting the acidification temperature to 80-85 ℃, adding alkali to adjust the pH value to 6-7 after the acidification is finished, evaporating a reaction product to dryness, purifying to obtain D-pantolactone, and separating a purified mother solution to obtain DL-pantolactone, and sending the DL-pantolactone to the step (1) for reuse;
(6) reacting beta-calcium aminopropionate with the D-pantothenic acid lactone obtained in the step (5) in methanol at the temperature of 60-65 ℃, and crystallizing in the methanol after the reaction is finished to obtain the D-calcium pantothenate, wherein the molar ratio of the beta-calcium aminopropionate to the D-pantothenic acid lactone is 1.0-1.2: 1.
2. The method for synthesizing calcium D-pantothenate according to claim 1, wherein the DL-pantolactone is synthesized by:
dropwise adding isobutyraldehyde into formaldehyde at 20-30 ℃ and under alkalinity for condensation reaction, wherein the pH value is 9-10, the reaction temperature is 40-50 ℃, adding water and cyanide for cyanidation reaction after the reaction is finished, the reaction temperature is 5-15 ℃, adding acid for adjusting the pH value to 0.5-2.0 after the reaction is finished, carrying out acidification reaction at 100-140 ℃, cooling to 35-45 ℃ after the reaction is finished, adding alkali for adjusting the pH value to 5.5-6.5, standing for layering, carrying out reduced pressure distillation on a water phase, collecting a fraction with the temperature of 110-117 ℃, cooling and crystallizing to obtain DL-pantothenic lactone, wherein the molar ratio of isobutyraldehyde, formaldehyde and cyanide is 1:0.8-1.2: 0.8-1.2.
3. The method of synthesizing calcium D-pantothenate according to claim 1, wherein the synthesizing process of the calcium β -aminopropionate is:
(61) acrylic acid and ammonia water carry out ammonolysis reaction under the action of inhibitor ammonium bicarbonate, the reaction temperature is 160-170 ℃, and the temperature is reduced after the reaction is finished; the molar ratio of the acrylic acid to the ammonia water to the ammonium bicarbonate is 1:4.5-5.0:1.5-1.8, and the concentration of the ammonia water is more than 20 wt%;
(62) recovering ammonia gas at 40-50 deg.C and vacuum degree of-0.085 MPa or lower, returning to step (61), adding activated carbon for decolorizing reaction at 60-70 deg.C, filtering off activated carbon, and concentrating and dehydrating the filtrate;
(63) dissolving the material obtained in the step (62) by adopting 90-98wt% of methanol, wherein the dissolving temperature is 52-58 ℃, cooling for crystallization after complete dissolution, and carrying out solid-liquid separation to obtain beta-aminopropionic acid;
(64) and (3) sequentially adding calcium oxide and the beta-aminopropionic acid obtained in the step (63) into water, reacting under a micro-boiling condition, and after the reaction is finished, decompressing and evaporating to obtain the beta-aminopropionic acid calcium, wherein the molar ratio of the beta-aminopropionic acid to the calcium oxide to the water is 1:1.1-1.4: 30-70.
4. The method for synthesizing calcium D-pantothenate according to claim 1, wherein the organic amine salt is synthesized by: reacting organic amine and hydrochloric acid in a mixed solvent B at the temperature of 75-85 ℃ to obtain an organic amine hydrochloride solution after the reaction is finished, wherein the molar ratio of the organic amine to the hydrochloric acid is 1:1.0-1.2, and the mixed solvent B is prepared by mixing water and an extracting agent according to the molar ratio of 7-30: 1; accordingly, in step (3), the organic phase is distilled to obtain the extractant and the organic amine.
5. The method of synthesizing calcium D-pantothenate according to claim 4, wherein the extractant is methyl t-butyl ether.
6. The method for synthesizing calcium D-pantothenate according to claim 1, wherein the step (6) comprises: reacting beta-calcium aminopropionate with the D-pantothenic acid lactone obtained in the step (5) in anhydrous methanol A at the temperature of 60-65 ℃, wherein the using amount of the anhydrous methanol A is 2-3 times of the total weight of the beta-calcium aminopropionate and the D-pantothenic acid lactone, filtering while the reaction is hot after the reaction is finished, transferring the mixture to an anhydrous methanol kettle which is cooled to the temperature below 20 ℃ and is filled with anhydrous methanol B, wherein the using amount of the anhydrous methanol B is 3-6 times of the weight of a reaction product, adding pure water after the materials are completely dissolved, wherein the using amount of the pure water is 1-3% of the weight of the anhydrous methanol B, carrying out heat preservation and crystallization for 4-8 hours at the temperature of 10-20 ℃, and carrying out solid-liquid separation at the temperature below 10 ℃ after the crystallization is finished to obtain the D-calcium pantothenate.
7. The method for synthesizing calcium D-pantothenate according to claim 1, wherein in step (5), the purification process is: evaporating the reaction product to dryness, adding toluene to dissolve, distilling at 50-60 ℃ to obtain a crude product and a toluene fraction, adding the crude product into toluene to recrystallize at 75-85 ℃, wherein the mass ratio of the crude product to the toluene during recrystallization is 1:1-3, performing solid-liquid separation to obtain a refined product and a crystallization mother liquor, combining the crystallization mother liquor and the toluene fraction, rectifying to obtain toluene and DL-pantolactone, recycling the obtained toluene, and sending the obtained DL-pantolactone to the step (1) for recycling.
8. The method for synthesizing calcium D-pantothenate according to claim 1, wherein in steps (3) and (5), the acid is concentrated sulfuric acid, the base is ammonium bicarbonate, and the concentration process is: concentrating to 1/4-1/2.
9. The method for synthesizing calcium D-pantothenate according to claim 1, wherein the method comprises:
preparation of S101 DL-pantolactone: dropwise adding isobutyraldehyde into formaldehyde at 20-30 ℃ and alkalinity for condensation reaction, wherein the pH is 9-10, the reaction temperature is 40-50 ℃, adding water and cyanide for cyanidation reaction after the reaction is finished, the reaction temperature is 5-15 ℃, adding sulfuric acid for adjusting the pH to 0.5-2.0 after the reaction is finished, carrying out acidification reaction at 100-140 ℃, cooling to 35-45 ℃ after the reaction is finished, adding ammonium bicarbonate for adjusting the pH to 5.5-6.5, standing for layering, carrying out reduced pressure distillation on a water phase, collecting 110-117 ℃ fraction, cooling and crystallizing to obtain DL-pantolactone, wherein the molar ratio of isobutyraldehyde, formaldehyde and cyanide is 1:0.8-1.2: 0.8-1.2;
hydrolysis of S102 DL-pantolactone: hydrolyzing DL-pantolactone under alkaline condition to pH12-13, and adjusting to 8-9 with acid;
s103, synthesis of organic amine salt: reacting rosin amine and hydrochloric acid in a mixed solvent B at the temperature of 75-85 ℃ to obtain a rosin amine hydrochloride solution after the reaction is finished, wherein the molar ratio of the rosin amine to the hydrochloric acid is 1:1.0-1.2, and the mixed solvent B is prepared by mixing water and methyl tert-butyl ether according to the molar ratio of 7-30: 1; correspondingly, in the step (3), the organic phase is distilled to obtain methyl tert-butyl ether and rosin amine;
resolution of S104 DL-pantolactone: reacting the product obtained in the step S103 with a rosin amine hydrochloride solution in a mixed solvent A at the reaction temperature of 75-85 ℃, cooling and crystallizing after the reaction is finished, and performing solid-liquid separation, wherein the molar ratio of the rosin amine hydrochloride to DL-pantolactone is 1:1.5-2.0, and the mixed solvent A is prepared from water and methyl tert-butyl ether according to the molar ratio of 7-9: 1;
s105, recovery of organic amine salt: extracting the filter residue obtained in the step S104 by adopting methyl tert-butyl ether and water under the condition of pH12-13, separating the methyl tert-butyl ether from an organic phase to obtain abietylamine, sending the abietylamine obtained by separation to the step S103 for reuse, adding concentrated sulfuric acid to adjust the pH value to 1-2 for acidification after the water phase is concentrated, adjusting the pH value to 6-7 by adding ammonium bicarbonate after the acidification is finished, and then carrying out reduced pressure distillation to obtain L-pantothenic acid lactone;
racemization of S106L-pantolactone: performing racemization reaction on the L-pantolactone obtained in the step S105 and phosphate at the temperature of 190 ℃ at 170 ℃ to obtain DL-pantolactone, and sending the obtained DL-pantolactone to a step S104 for reuse, wherein the molar ratio of the L-pantolactone to the phosphate is 15-25: 1;
S107D isolation of pantothenic acid lactone: extracting the filtrate obtained in the step S102 by adopting methyl tert-butyl ether under the condition that the pH value is 12-13, concentrating a water phase, adding concentrated sulfuric acid to adjust the pH value to 1-2 for acidification, wherein the acidification temperature is 80-85 ℃, adding ammonium bicarbonate to adjust the pH value to 6-7 after the acidification is finished, evaporating a reaction product to dryness, recrystallizing by adopting toluene to obtain D-pantothenic acid lactone, and separating a purified mother solution to obtain DL-pantothenic acid lactone, and sending the DL-pantothenic acid lactone to the step S104 for reuse;
synthesis of S108 β -calcium aminopropionate: acrylic acid and ammonia water carry out ammonolysis reaction under the action of inhibitor ammonium bicarbonate, the reaction temperature is 160-170 ℃, and the temperature is reduced after the reaction is finished; the molar ratio of the acrylic acid to the ammonia water to the ammonium bicarbonate is 1:4.5-5.0:1.5-1.8, and the concentration of the ammonia water is more than 20 wt%; recovering ammonia gas at 40-50 deg.C and vacuum degree of-0.085 MPa or lower, adding active carbon for decolorizing at 60-70 deg.C, filtering off active carbon, and concentrating and dehydrating the filtrate; dissolving with 90-98wt% methanol at 52-58 deg.C, cooling for crystallization, and separating solid and liquid to obtain beta-alanine; sequentially adding calcium oxide and beta-aminopropionic acid into water, reacting under a micro-boiling condition, and after the reaction is finished, evaporating to dryness under reduced pressure to obtain beta-aminopropionic acid calcium, wherein the molar ratio of the beta-aminopropionic acid to the calcium oxide to the water is 1:1.1-1.4: 30-70;
S109D-calcium pantothenate synthesis: reacting beta-calcium aminopropionate and D-pantothenic acid lactone in anhydrous methanol A at the temperature of 60-65 ℃, wherein the using amount of the anhydrous methanol A is 2-3 times of the total weight of the beta-calcium aminopropionate and the D-pantothenic acid lactone, filtering while hot after the reaction is finished, transferring the mixture to an anhydrous methanol kettle which is cooled to below 20 ℃ and contains the anhydrous methanol B, wherein the using amount of the anhydrous methanol B is 3-6 times of the weight of a reaction product, adding pure water after the materials are completely dissolved, wherein the using amount of the pure water is 1-3% of the weight of the anhydrous methanol B, carrying out heat preservation and crystallization at the temperature of 10-20 ℃ for 4-8 hours, and carrying out solid-liquid separation on the D-calcium pantothenate at the temperature of below 10 ℃ after the crystallization is finished.
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