CN110105235B - Preparation method of high-purity sodium pantothenate - Google Patents
Preparation method of high-purity sodium pantothenate Download PDFInfo
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- CN110105235B CN110105235B CN201910466251.1A CN201910466251A CN110105235B CN 110105235 B CN110105235 B CN 110105235B CN 201910466251 A CN201910466251 A CN 201910466251A CN 110105235 B CN110105235 B CN 110105235B
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- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
Abstract
The invention discloses a preparation method of high-purity sodium pantothenate, which comprises the steps of taking beta-alanine and alkali as raw materials, reacting in a lower alkanol solvent to prepare beta-sodium alanine, reacting the beta-sodium alanine with D-pantoic acid lactone in the lower alkanol solvent to prepare a crude product of the sodium pantothenate, refining the crude product of the sodium pantothenate in 95% ethanol, and crystallizing to obtain the sodium pantothenate. The sodium pantothenate prepared by the method has the advantages of uniform granularity, good fluidity, small hygroscopicity, simple operation, environmental protection, high yield, high purity and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of high-purity sodium pantothenate.
Background
Pantothenic acid is a B-group vitamin substance, is one of water-soluble vitamins, widely exists in the biological world, is commonly called vitamin B, can be divided into DL-type (mixed isomer), D-type (dextroisomer) and L-type (levoisomer), only the D-type (dextroisomer) has bioactivity, is usually calcium salt or sodium salt, is widely applied to the industries of medicines, feeds, foods and the like, is sodium salt of D-type enantiomer of pantothenic acid, can form calcium phosphate to reduce the potency of the medicine to generate incompatibility due to the fact that the pantothenic acid is often required to be used together with other B-group vitamins such as riboflavin sodium phosphate, and can be avoided by adopting the sodium pantothenate so as to achieve the purpose of safe and effective medicine use. Therefore, the sodium pantothenate is better than calcium pantothenate in medicinal value and meets the use requirements of safe and effective medicines.
Sodium pantothenate, english name: D-Pantothenic Acid Sodium Salt, (chemical name (R) -N- (2, 4-dihydroxy-3, 3-dimethyl-1-oxobutyl) - β -alanine monosodium Salt) CAS registry number: 867-81-2, the chemical formula is:
it is a white crystal or crystalline powder, the crystal has hygroscopicity, and is suitable for long-term substitution treatment of congenital hypothyroidism (cretinism) and hypothyroidism caused by various reasons of children and adults.
At present, the process of calcium pantothenate is mature, and a large number of preparation schemes are published or reported at home and abroad, but the preparation reports of sodium pantothenate are few, and particularly, the synthetic documents of medicinal sodium pantothenate and sodium pantothenate have chemical methods and biological methods. The biological method is difficult to realize large-scale production due to strict requirements on conditions, expensive equipment, long production period and the like, and the chemical method comprises the following methods:
chinese patent CN 103145579a mentions a preparation method of sodium pantothenate: the method is a practical refining method of the sodium pantothenate, and the sodium pantothenate is crystallized and crystallized in an ultrasonic field, so that the conditions are harsh, the crystallization time is long, the working hours are consumed, and the ether solvent is used, so that the method is high in danger and not suitable for industrial production.
In US4258210, sodium hydroxide solution is used to saponify beta-amino propionitrile to obtain beta-sodium alanine, and the beta-sodium alanine reacts with D-pantolactone to obtain D-sodium pantothenate, which has harsh reaction conditions and is not suitable for industrial production.
Chinese patent CN109280015A adopts beta-aminopropionic acid methanol or ethanol, and adds sodium methoxide, and then the solution is cooled and DL-pantoic acid lactone is added for induced resolution to obtain D-sodium pantothenate, the final yield is about 45%, and the method is not suitable for industrial production.
The Chinese patent CN104592053B uses calcium pantothenate and sodium carbonate to react, and the calcium pantothenate is crystallized through a system of water, ethanol and acetone, the preparation method is complex to operate, and the used refined solvent is a system of water, ethanol and acetone.
The availability of vitamins in pure form is cumbersome and difficult due to their highly lyophilized nature, and in these products, the purity cannot be determined, which also has the following disadvantages: they are highly hygroscopic and, when exposed to normal humidity for a short period of time, they absorb water and thicken, which makes handling of pantothenic acid preparations a considerable problem.
Disclosure of Invention
The invention discloses a preparation method of high-purity sodium pantothenate, which comprises the steps of taking beta-alanine and alkali as raw materials, stirring and heating the raw materials in a low-grade alkanol solvent for reaction, cooling and crystallizing after the reaction is finished, filtering to obtain a wet product of the beta-sodium alanine, controlling the temperature and drying to obtain the beta-sodium alanine, heating the prepared beta-sodium alanine and D-pantoic acid lactone in a low-grade alkanol solvent for reaction, cooling and crystallizing after the reaction is finished, filtering to obtain a wet product of a crude product of the sodium pantothenate, controlling the temperature and drying to obtain a crude product of the sodium pantothenate, heating and dissolving the prepared crude product of the sodium pantothenate in a 95% ethanol solution, adding medicinal carbon for reflux and decoloring, cooling, stirring and crystallizing the filtrate to obtain a wet product of the sodium pantothenate, and controlling the temperature and drying to obtain the sodium pantothenate.
The reaction formula of the invention is as follows:
compared with the prior art, the method has the advantages of mild reaction conditions, simple operation and environmental protection, uses a refined solvent, has the advantage of being suitable for industrial production, and finds that the yield of the obtained sodium pantothenate reaches 90% and the purity reaches 99.99% by heating and dissolving the sodium pantothenate in the step (c) through continuous tests.
The invention achieves the purpose by the following technical scheme.
A preparation method of high-purity sodium pantothenate comprises the following steps:
(a) taking beta-alanine and alkali as raw materials, stirring and heating in a lower alkanol solvent for reaction, cooling and crystallizing after the reaction is finished, filtering to obtain a wet product of beta-sodium alanine, and controlling the temperature and drying to obtain the beta-sodium alanine.
(b) Heating the beta-sodium alanine prepared in the step (a) and D-pantoic acid lactone in a lower alkanol solvent for reaction, cooling and crystallizing after the reaction is finished, filtering to obtain a wet product of a sodium pantothenate crude product, and controlling the temperature and drying to obtain the sodium pantothenate crude product.
(c) Heating and dissolving the crude sodium pantothenate prepared in the step (b) by using a 95% ethanol solution, adding medicinal carbon, refluxing and decoloring, cooling, stirring and crystallizing the filtrate to obtain a wet sodium pantothenate product, and controlling the temperature and drying to obtain the sodium pantothenate.
Preferably, the base in step (a) is any one of sodium hydroxide, sodium methoxide and sodium ethoxide, and the lower alkanol solvent is isopropanol.
Preferably, in the step (a), the molar ratio of the beta-alanine to the alkali is 1:1, the reaction temperature is 60 +/-5 ℃, the reaction time is 1-3h, the crystallization temperature is 10 +/-5 ℃, the crystallization time is 2-4h, the drying temperature of a wet beta-alanine sodium product is 85 +/-5 ℃, and the drying time is 10-15 h.
Preferably, the ratio of sodium β -alaninate in step (b): d-pantoic acid lactone: the weight ratio of the lower alkanol solvent is as follows: 1:1.17:7-1:1.17:15.
Preferably, in the step (b), the reaction temperature is 65 +/-5 ℃, the reaction time is 4-6h, the crystallization temperature is 20 +/-5 ℃, the crystallization time is 3-6h, the drying temperature of the wet product of the crude sodium pantothenate product is 80 +/-5 ℃, and the drying time is 10-15 h.
Preferably, in step (c), crude sodium pantothenate: the weight ratio of the 95% ethanol is 1:3-1: 5.
Preferably, in the step (c), the temperature for raising the temperature is 75 +/-5 ℃, the temperature for lowering the temperature and crystallizing is 5 +/-5 ℃, the crystallizing time is more than 15 hours, the drying temperature for the wet product of the sodium pantothenate is 75 +/-5 ℃, and the drying time is 15-24 hours.
Preferably, in the step (c), the crude sodium pantothenate is dissolved by 95% ethanol solution at a high temperature, hydrochloric acid is added to adjust the pH value of the solution to 6.5-7.5, and medicinal carbon is added for reflux decoloration.
By adopting the scheme, the sodium pantothenate prepared by the preparation method of the sodium pantothenate has the advantages of uniform granularity, good fluidity, small hygroscopicity, simple operation, environmental protection, high yield, high purity and suitability for industrial production.
Drawings
For a clearer explanation of the exemplary embodiments or technical solutions in the prior art, the drawings used in the description of the exemplary embodiments or prior art will be briefly described below.
FIG. 1 is a liquid chromatogram of a finished sodium pantothenate product of example 1 according to the present invention.
FIG. 2 is a liquid chromatogram of a finished sodium pantothenate product of example 4 according to the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention are described clearly and completely below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1:
(1) preparation of sodium beta-alaninate
90kg of isopropanol, 20kg of beta-alanine and 9kg of sodium hydroxide are added into a 200L reaction tank, heated to 60 +/-5 ℃, and stirred for reaction for 1-3 h. Stopping heating, cooling to 5-15 deg.C, stirring, and crystallizing for 3 hr. And (3) centrifuging the materials in the tank in a centrifuge in several times, collecting filter cakes to obtain beta-sodium alanine (wet product), controlling the temperature of the wet product to be 85 +/-5 ℃, drying for 12 hours, cooling to room temperature, collecting materials, sampling, weighing to obtain the beta-sodium alanine with the yield of 95%.
(2) Preparation of sodium pantothenate (crude)
Adding isopropanol (11.2 times of the weight of the beta-sodium alanine) into a 500L reaction tank, starting stirring, adding D-pantolactone (1.17 times of the weight of the beta-sodium alanine) and the beta-sodium alanine (the total amount of the previous working procedure), heating, controlling the temperature to be 65 +/-5 ℃, and reacting for 5 hours. Stopping heating, cooling to 20 +/-5 ℃, and crystallizing for 4 hours. And (2) centrifuging the materials in the tank in a centrifuge in several times, washing filter cakes (10 kg/time) twice by using isopropanol, starting high speed, centrifuging until no liquid is thrown out, collecting the filter cakes to obtain crude sodium pantothenate (wet), putting the crude sodium pantothenate (wet) into a double-cone dryer, heating, controlling the temperature to be 80 +/-5 ℃, drying for 12 hours, stopping drying, cooling to room temperature, collecting materials, sampling, weighing to obtain crude sodium pantothenate with the yield of 92%.
(3) Purification of sodium pantothenate
Adding 95% ethanol with the mass being 3 times that of the crude product into a 500L reaction tank, starting stirring, adding the crude product of sodium pantothenate, heating to raise the temperature, controlling the temperature to be 75 +/-5 ℃, stirring to dissolve, adding hydrochloric acid to adjust the pH value of the solution to be 6.5-7.5, adding 0.5kg of medicinal carbon after the adjustment, refluxing and decoloring for 0.5h, filtering to a 200L reaction tank, slowly cooling to be 5 +/-5 ℃, stirring and crystallizing for 15h, centrifuging, spin-drying, receiving material to obtain a wet product of sodium pantothenate, controlling the temperature of the wet product to be 75 +/-5 ℃, drying for 24h, cooling to room temperature, receiving material to obtain sodium pantothenate, wherein the yield is 90%, the purity is 99.99%, and the melting point is 166-171 ℃ determined by a melting point apparatus.
Example 2:
(1) preparation of sodium beta-alaninate
Adding 90g of anhydrous methanol, 20g of beta-alanine and 9g of sodium hydroxide into a 250ml flask, heating to 62 ℃, stirring for reaction for 3 hours, stopping heating, cooling to 10 ℃, stirring for crystallization for 3 hours, and separating out no crystal.
Example 3:
(1) preparation of sodium beta-alaninate
Adding 90g of absolute ethyl alcohol, 20g of beta-alanine and 9g of sodium hydroxide into a 250ml flask, heating to 62 ℃, stirring for reaction for 3 hours, stopping heating, cooling to 10 ℃, stirring for crystallization for 3 hours, and separating out crystals.
Example 4:
(1) preparation of sodium beta-alaninate
Adding 90g of isopropanol, 20g of beta-alanine and 9g of sodium hydroxide into a 250ml flask, heating to 62 ℃, stirring for reaction for 3h, stopping heating, cooling to 10 ℃, stirring for crystallization for 3h, filtering, collecting a filter cake to obtain beta-alanine sodium (wet product), controlling the temperature of the wet product to 85 ℃, drying for 12h, cooling to room temperature, collecting the material, sampling, weighing to obtain the beta-alanine sodium, wherein the yield is 95%.
(2) Preparation of sodium pantothenate (crude)
Adding isopropanol (11 times of the weight of beta-sodium alanine) into a 500ml flask, starting stirring, adding D-pantoic acid lactone (1.17 times of the weight of the beta-sodium alanine), adding the beta-sodium alanine (the whole amount of the previous process), heating, controlling the temperature to be 65 ℃, reacting for 5 hours, stopping heating, cooling to 20 ℃, crystallizing for 4 hours, filtering, washing a filter cake twice by using the isopropanol, filtering, collecting the filter cake to obtain a sodium pantothenate crude product (wet), controlling the temperature of the sodium pantothenate crude product (wet) to be 80 +/-5 ℃, drying for 12 hours, stopping drying, cooling to room temperature, collecting materials, sampling, weighing, obtaining the sodium pantothenate crude product, wherein the yield is 90%.
(3) Purification of sodium pantothenate
Adding absolute ethyl alcohol with the mass 3 times that of a crude product into a 500ml flask, starting stirring, adding the crude product of sodium pantothenate, heating to raise the temperature, controlling the temperature to be 75 ℃, stirring to dissolve, adding hydrochloric acid to adjust the pH value of the solution to be 6.5-7.5, adding 0.5g of medicinal carbon after the solution is adjusted, refluxing and decoloring for 0.5h, filtering to a 200ml flask, slowly cooling to 5 ℃, stirring and crystallizing for 15h, filtering to obtain a wet product of sodium pantothenate, controlling the temperature of the wet product to be 75 ℃, drying for 24h, cooling to room temperature, collecting materials to obtain sodium pantothenate, wherein the yield is 75%, the purity is 99.39%, and the melting point is 158-163 ℃ determined by a melting point instrument.
Example 5:
(1) preparation of sodium beta-alaninate
Adding 90g of isopropanol, 20g of beta-alanine and 9g of sodium hydroxide into a 250ml flask, heating to 63 ℃, stirring for reaction for 3 hours, stopping heating, cooling to 10 ℃, and stirring for crystallization for 3 hours. Filtering, collecting filter cakes to obtain beta-sodium alanine (wet product), controlling the temperature of the wet product to be 85 ℃, drying for 12 hours, cooling to room temperature, collecting materials, sampling and weighing to obtain the beta-sodium alanine with the yield of 95%.
(2) Preparation of sodium pantothenate (crude)
Adding isopropanol (11 times of the weight of beta-sodium alanine) into a 500ml flask, starting stirring, adding D-pantoic acid lactone (1.17 times of the weight of the beta-sodium alanine), adding the beta-sodium alanine (the whole amount of the previous process), heating, controlling the temperature to be 65 ℃, reacting for 5 hours, stopping heating, cooling to 20 ℃, crystallizing for 4 hours, filtering, washing a filter cake twice by using the isopropanol, filtering, collecting the filter cake to obtain a sodium pantothenate crude product (wet), controlling the temperature of the sodium pantothenate crude product (wet) to be 80 +/-5 ℃, drying for 12 hours, stopping drying, cooling to room temperature, collecting materials, sampling, weighing, obtaining the sodium pantothenate crude product, wherein the yield is 90%.
(3) Purification of sodium pantothenate
Adding 90% ethanol with the mass being 3 times that of the crude product into a 500ml flask, starting stirring, adding the crude product of sodium pantothenate, heating to raise the temperature, controlling the temperature to be 75 ℃, stirring until the solution is dissolved, adding hydrochloric acid to adjust the pH value of the solution to be 6.5-7.5, adding 0.5g of medicinal carbon after the solution is adjusted, refluxing and decoloring for 0.5h, filtering to a 200ml flask, slowly cooling to 5 ℃, stirring and crystallizing for 15h, filtering to obtain a wet product of sodium pantothenate, controlling the temperature of the wet product to be 75 ℃, drying for 24h, cooling to room temperature, collecting the material to obtain sodium pantothenate, wherein the yield is 60%.
Examples effect comparison results:
as shown by the comparative experiment, isopropanol is preferably used for preparing the beta-sodium alanine, and a solvent, preferably 95% ethanol, is used for refining the sodium pantothenate.
In conclusion, the sodium pantothenate prepared by the preparation method of the sodium pantothenate has the advantages of uniform granularity, good fluidity, small hygroscopicity, simple operation, environmental protection, high yield, high purity and suitability for industrial production, and a refined solvent is used.
It should be noted that the above-mentioned embodiments are only preferred embodiments of the present invention, and it is obvious to those skilled in the art that the present invention is not limited to the details of the above-mentioned exemplary embodiments, and that the present invention can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Claims (1)
1. A preparation method of sodium pantothenate is characterized by comprising the following steps:
(a) taking beta-alanine and sodium hydroxide as raw materials, stirring and heating in an isopropanol solvent for reaction, after the reaction is finished, cooling and crystallizing, filtering to obtain a wet beta-alanine sodium product, and drying at a controlled temperature to obtain the beta-alanine sodium, wherein the molar ratio of the beta-alanine to the sodium hydroxide is 1:1, the reaction temperature is 60 +/-5 ℃, the reaction time is 1-3 hours, the crystallization temperature is 10 +/-5 ℃, the crystallization time is 2-4 hours, the drying temperature of the wet beta-alanine sodium product is 85 +/-5 ℃, and the drying time is 10-15 hours;
(b) heating the beta-sodium alanine prepared in the step (a) and D-pantoic acid lactone in an isopropanol solvent for reaction, cooling and crystallizing after the reaction is finished, filtering to obtain a wet product of a sodium pantothenate crude product, and drying at controlled temperature to obtain the sodium pantothenate crude product, wherein the beta-sodium alanine: d-pantoic acid lactone: the weight ratio of the isopropanol solvent is as follows: 1:1.17:7-1:1.17:15, wherein the reaction temperature is 65 +/-5 ℃, the reaction time is 4-6h, the crystallization temperature is 20 +/-5 ℃, the crystallization time is 3-6h, the drying temperature of a wet product of a crude sodium pantothenate product is 80 +/-5 ℃, and the drying time is 10-15 h;
(c) heating and dissolving the sodium pantothenate crude product prepared in the step (b) by using a 95% ethanol solution, adding medicinal carbon for reflux decolorization, cooling the filtrate, stirring and crystallizing to obtain a sodium pantothenate wet product, and drying at controlled temperature to obtain sodium pantothenate, wherein the sodium pantothenate crude product is prepared by the following steps: the weight ratio of 95% ethanol is 1:3-1:5, the temperature of heating is 75 +/-5 ℃, the temperature of cooling and crystallization is 5 +/-5 ℃, the crystallization time is more than 15 hours, the drying temperature of a wet product of sodium pantothenate is 75 +/-5 ℃, the drying time is 15-24 hours, after the crude product of sodium pantothenate is heated and dissolved by 95% ethanol solution, hydrochloric acid is added to adjust the pH value of the solution to 6.5-7.5, and medicinal carbon is added for reflux and decoloration.
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| US4258210A (en) * | 1978-05-18 | 1981-03-24 | Hoffmann-La Roche Inc. | Process for manufacturing sodium pantothenate |
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| CN109280015A (en) * | 2018-08-17 | 2019-01-29 | 无锡凯夫制药有限公司 | A kind of synthesis of D-VB5 sodium and chiral separation method |
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| GB565976A (en) * | 1941-05-26 | 1944-12-07 | Parke Davis & Co | Process for the manufacture of crystalline sodium-d-pantothenate |
| US2367791A (en) * | 1941-05-26 | 1945-01-23 | Parke Davis & Co | Vitamin composition and method of obtaining same |
| US4258210A (en) * | 1978-05-18 | 1981-03-24 | Hoffmann-La Roche Inc. | Process for manufacturing sodium pantothenate |
| CN101801915A (en) * | 2007-07-31 | 2010-08-11 | 帝斯曼知识产权资产管理有限公司 | Process for the synthesis of na-beta-alaninate and calcium pantothenate |
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