CN113024491A - Preparation method of DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone - Google Patents
Preparation method of DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone Download PDFInfo
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Abstract
The invention discloses a preparation method of DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone, which comprises the following steps: s1, mixing formaldehyde and an organic base catalyst, and dropwise adding isobutyraldehyde to perform a condensation reaction to generate hydroxyl pivalaldehyde; s2, adding hydrocyanic acid, carrying out a cyanohydrin reaction, adjusting the pH value after hydrolysis and lactonization under an acidic condition, standing, removing a water phase to obtain a crude product, and concentrating the water phase to obtain ammonium salt; s3, rectifying and purifying the crude product to obtain DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone. The preparation method is simple and feasible, the yield and the chemical purity of the product are high, the whole process is green and environment-friendly, the atom economy is high, and the byproduct ammonium salt can create a certain economic value and is beneficial to large-scale industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone.
Background
DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone is also called DL-pantoic acid lactone, has wide application, simple production process and sufficient raw material supply, is an important intermediate for producing D-calcium pantothenate, D-panthenol, D-pantetheine and other pantothenic acid series products, and has a structural formula shown as a formula I:
pantothenic acid is a B-group vitamin substance, is a component of coenzyme A and is involved in sugar, fat and protein metabolism. It is also known that pantothenic acid is a coenzyme of coenzyme A, which is a complex molecule of pantothenic acid combined with adenosine-3-phosphate, pyrophosphate and beta-mercaptoethylamine, and thus functions as both a physiological function of pantothenic acid: participate in metabolism such as fatty acid degradation, fatty acid synthesis, citric acid circulation, choline acetylation, antibody synthesis and the like in vivo. The pantothenic acid products have wide application, and are researched from 40 years in China, industrial production devices are built in 60 years, and the pantothenic acid products can be widely applied to the fields of medicines, foods, feed industry and the like. With the growing market for the use of calcium pantothenate and panthenol, DL- α -hydroxy- β, β -dimethyl- γ -butyrolactone, which is a key precursor in the synthesis of calcium pantothenate, panthenol, and the like, occupies an important position in the whole production process. The technology for synthesizing DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone in China is old, has the characteristics of high cost, poor yield condition, poor quality stability and the like, and forms a bottleneck for the production and application of downstream products. Therefore, the continuous optimization of the preparation process of the DL-alpha-hydroxyl-beta, beta-dimethyl-gamma-butyrolactone has important practical significance.
The synthesis processes of DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone reported in the literature include isobutyraldehyde-glyoxylic acid route (Wuxibia, LvShiguo, Zhangwei. alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone green synthesis process research [ J ] proceedings of Qingdao university of science and technology, 2011(32):446 + 450), isobutyraldehyde-hydroxyacetonitrile method (application and synthesis of calcium pantothenate D2 in Li Ming [ J ]. Sichuan chemical industry and corrosion control, 1999 (2): 56258), isobutyraldehyde-formaldehyde-sodium cyanide route, and isobutyraldehyde-formaldehyde-hydrocyanic acid route (Li stand. D-calcium pantothenate synthesis technology and application [ J ]. Hubei chemical industry, 2002(2): 30-31). At present, two production processes adopted in China mainly comprise two routes of isobutyraldehyde-formaldehyde-sodium cyanide and isobutyraldehyde-formaldehyde-hydrocyanic acid, which are obtained by steps of hydroxymethylation, cyanohydrin, hydrolysis, lactonization and the like, and each route has advantages and disadvantages. The two processes are mature, wherein the isobutyraldehyde-formaldehyde-sodium cyanide method uses sodium cyanide solution as a raw material in the step of cyanohydrin reaction, the reaction effect is poor, the yield is low, and a large amount of cyanide-containing waste salt and wastewater are generated after the reaction, so that the post-treatment is difficult and the environmental protection pressure is high. The isobutyraldehyde-formaldehyde-hydrocyanic acid method is simple in reaction and low in cost, but is limited by the fact that the specificity (high toxicity and incapability of transportation and storage) of the raw material hydrocyanic acid has high requirements on process technology and safety measures, and further research and optimization are needed.
Therefore, in order to solve the problems of high cost, low yield, unstable quality and the like in the existing production process of DL- α -hydroxy- β, β -dimethyl- γ -butyrolactone by combining the above problems, the research of an efficient preparation method is a problem that needs to be solved by those skilled in the art.
Disclosure of Invention
In view of the above, the invention provides a preparation method of DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone, which is green, environment-friendly, low in cost, high in yield, simple in process and suitable for industrial production.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a preparation method of DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone comprises the following steps:
s1, mixing formaldehyde and an organic base catalyst, and dropwise adding isobutyraldehyde to perform a condensation reaction to generate hydroxyl pivalaldehyde;
s2, adding hydrocyanic acid, simultaneously dropwise adding hydroxyl pivalic aldehyde and hydrocyanic acid by using a peristaltic pump, controlling the temperature and the pH value, carrying out a cyanohydrin reaction, adjusting the pH value of a reaction solution by using ammonia water after hydrolysis and lactonization under an acidic condition, standing, removing a water phase to obtain a crude product, and concentrating the water phase to obtain an ammonium salt;
s3, rectifying and purifying the crude product to obtain DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone.
Preferably, the chemical reaction formula of the preparation method of the DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone is shown as formula II:
preferably, the organic base catalyst in step S1 is one of ethylenediamine, diethylamine, triethylamine, propylamine, isopropylamine, dipropylamine, and n-butylamine.
Preferably, the organic base catalyst in step S1 is one of ethylenediamine, diethylamine and triethylamine.
Preferably, the mass ratio of the organic base catalyst to isobutyraldehyde in step S1 is 6-8:100, and the molar ratio of formaldehyde to isobutyraldehyde is 1.05-1.2: 1.0.
preferably, in the condensation reaction in the step S1, the temperature for dropwise adding isobutyraldehyde is controlled to be 10-30 ℃; the temperature is kept at 50-80 ℃ for 1-4h after dripping.
Preferably, the temperature in the cyanohydrin reaction in the step S2 is controlled to be 0-20 ℃, the pH value is 8-9, the temperature is kept at-10 ℃ to 10 ℃ after the completion of the dropwise addition, and the temperature is kept for 0.5-5 h.
Preferably, the acid solution used in the acidic condition in step S2 is one or more of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.
Preferably, the concentration of the acid solution under the acidic condition is 30-60%, the reaction temperature is 60-100 ℃, and the reaction time is 0.5-6 h.
Preferably, after the hydrolysis and lactonization in step S2, the pH of the reaction solution is adjusted to 4 to 7 with ammonia water.
Preferably, the rectification and purification in the step S3 adopt a high vacuum rectification mode, the system pressure is controlled to be 20-100Pa, and the temperature is controlled to be 80-120 ℃.
Through the technical scheme, compared with the prior art, the invention has the following beneficial effects:
the method optimizes the technological parameters, changes the material adding mode and improves the overall reaction efficiency on the basis of the original isobutyraldehyde-formaldehyde-hydrocyanic acid method route. The preparation method is simple and feasible, the yield and the chemical purity of the product are high, the whole process is environment-friendly, the atom economy is high, and the byproduct ammonium salt can create a certain economic value and is beneficial to large-scale industrial production.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described 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:
the embodiment 1 of the invention discloses a preparation method of DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone, which adopts the following technical scheme:
118.2g of a 37% formaldehyde solution and 8g of diethylamine were put into a 500mL three-necked flask, and cooled to 0 to 5 ℃ with stirring. And then slowly dripping 100g of isobutyraldehyde into the flask, controlling the temperature to be 10-15 ℃ in the process, slowly heating the reaction liquid to 55-60 ℃ after dripping, and keeping the temperature for reaction for 4 hours to obtain a hydroxyl pivalic aldehyde solution.
And (2) simultaneously dripping the hydroxyl pivalaldehyde solution and 37.5g of hydrocyanic acid into a 500mL three-neck flask by using a peristaltic pump to react, controlling the dripping temperature to be 15-20 ℃, controlling the pH value to be 8-9 by adjusting the dripping speed of the hydroxyl pivalaldehyde solution and the hydrocyanic acid, and reducing the reaction temperature to 0-5 ℃ after dripping is finished, and keeping the temperature for reaction for 2 hours to obtain a cyanohydrin solution.
The cyanohydrin solution was added to 340g of 30% H2SO4And slowly heating the solution to 80-85 ℃ for reflux reaction for 3 hours, cooling the solution to 25 ℃ after the reaction is finished, dropwise adding ammonia water, adjusting the pH value of the reaction solution to 6.5-7.0, standing the solution, and removing a water phase to obtain a reddish brown transparent solution, namely a DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone crude product.
And (3) carrying out high vacuum rectification on the crude product, controlling the system pressure at 20-100Pa and the temperature at 80-120 ℃, wherein a small amount of front fraction and bottom fraction can be combined in the amplification production process, so that the overall yield is improved, and finally 150.42g of a finished product is obtained, wherein the content is 98.50% by gas chromatography detection, and the yield is 83.34%.
Example 2:
the embodiment 2 of the invention discloses a preparation method of DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone, which adopts the following technical scheme:
123.8g of a 37% formaldehyde solution and 6g of diethylamine were put into a 500mL three-necked flask, and the temperature was lowered to 0 to 5 ℃ with stirring. And then slowly dripping 100g of isobutyraldehyde into the flask, controlling the temperature of the process to be 15-20 ℃, slowly heating the reaction solution to 60-65 ℃ after dripping, preserving the temperature and reacting for 2 hours to obtain a hydroxyl pivalic aldehyde solution.
And (2) simultaneously dripping the hydroxyl pivalaldehyde solution and 37.5g of hydrocyanic acid into a 500mL three-neck flask by using a peristaltic pump to react, controlling the dripping temperature to be 15-20 ℃, controlling the pH value to be 8-9 by adjusting the dripping speed of the hydroxyl pivalaldehyde solution and the hydrocyanic acid, and reducing the reaction temperature to-5-0 ℃ after dripping is finished, and carrying out heat preservation reaction for 2 hours to obtain a cyanohydrin solution.
The cyanohydrin solution was added to 204g of 50% H2SO4And slowly heating the solution to 85-90 ℃ for reflux reaction for 3 hours, cooling the solution to 25 ℃ after the reaction is finished, dropwise adding ammonia water, adjusting the pH value of the reaction solution to 6.5-7.0, standing the solution, and removing a water phase to obtain a reddish brown transparent solution, namely a DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone crude product.
And (3) carrying out high vacuum rectification on the crude product, controlling the system pressure at 20-100Pa and the temperature at 80-120 ℃, and obtaining 154.20g of finished product, wherein the content is 98.88% by gas chromatography detection, and the yield is 85.43%.
Example 3:
the embodiment 3 of the invention discloses a preparation method of DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone, which adopts the following technical scheme:
134.0g of a 37% formaldehyde solution and 6g of diethylamine were put into a 500mL three-necked flask, and cooled to 0 to 5 ℃ with stirring. And then slowly dripping 100g of isobutyraldehyde into the flask, controlling the temperature of the process to be 15-20 ℃, slowly heating the reaction solution to 60-65 ℃ after dripping, preserving the temperature and reacting for 2 hours to obtain a hydroxyl pivalic aldehyde solution.
And (2) simultaneously dripping 39.4g of hydrocyanic acid and 39.4g of hydroxytetravaleraldehyde solution into a 500mL three-neck flask by using a peristaltic pump to react, controlling the dripping temperature to be 10-15 ℃, controlling the pH value to be 8-9 by adjusting the dripping speed of the hydroxytetravaleraldehyde solution and the hydrocyanic acid, and after dripping is finished, reducing the reaction temperature to-10- (-5) DEG C, and carrying out heat preservation reaction for 4 hours to obtain a cyanohydrin solution.
The cyanohydrin solution was added to 204g of 50% H2SO4And slowly heating the solution to 85-90 ℃ for reflux reaction for 3 hours, cooling the solution to 25 ℃ after the reaction is finished, dropwise adding ammonia water, adjusting the pH value of the reaction solution to 6.5-7.0, standing the solution, and removing a water phase to obtain a reddish brown transparent solution, namely a DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone crude product.
And (3) carrying out high vacuum rectification on the crude product, controlling the system pressure at 20-100Pa and the temperature at 80-120 ℃, and obtaining 162.50g of finished product, wherein the content is 99.05% by gas chromatography detection, and the yield is 90.03%.
Example 4:
118.2g of a 37% formaldehyde solution and 8g of diethylamine were put into a 500mL three-necked flask, and cooled to 0 to 5 ℃ with stirring. And then slowly dripping 100g of isobutyraldehyde into the flask, controlling the temperature to be 25-30 ℃ in the process, slowly heating the reaction liquid to 75-80 ℃ after dripping, preserving the temperature and reacting for 2 hours to obtain a hydroxyl pivalic aldehyde solution.
And (2) simultaneously dripping 39.4g of hydrocyanic acid and 39.4g of hydroxyl pivalic aldehyde solution into a 500mL three-neck flask for reaction by using a peristaltic pump, controlling the dripping temperature to be 15-20 ℃, controlling the pH value to be 8-9 by adjusting the dripping speed of the hydroxyl pivalic aldehyde solution and the hydrocyanic acid, and reducing the reaction temperature to 5-10 ℃ after dripping is finished, and keeping the temperature for reaction for 2 hours to obtain a cyanohydrin solution.
The cyanohydrin solution was added to 204g of 50% H2SO4And slowly heating the solution to 80-85 ℃ for reflux reaction for 3 hours, cooling the solution to 25 ℃ after the reaction is finished, dropwise adding ammonia water, adjusting the pH value of the reaction solution to 6.5-7.0, standing the solution, and removing a water phase to obtain a reddish brown transparent solution, namely a DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone crude product.
And (3) carrying out high vacuum rectification on the crude product, controlling the system pressure at 20-100Pa and the temperature at 80-120 ℃, and obtaining 148.44g of finished product, wherein the content is 98.65% by gas chromatography detection, and the yield is 82.24%.
Comparative example 1:
118.2g of a 37% formaldehyde solution and 8g of diethylamine were put into a 500mL three-necked flask, and cooled to 0 to 5 ℃ with stirring. And then slowly dripping 100g of isobutyraldehyde into the flask, controlling the temperature to be 20-25 ℃ in the process, slowly heating the reaction liquid to 60-65 ℃ after dripping, preserving the temperature and reacting for 2 hours to obtain a hydroxyl pivalic aldehyde solution.
And (2) simultaneously dripping 39.4g of hydrocyanic acid and 39.4g of hydroxyl pivalic aldehyde solution into a 500mL three-neck flask by using a peristaltic pump to react, controlling the dripping temperature to be 20-25 ℃, controlling the pH value to be 8-9 by adjusting the dripping speed of the hydroxyl pivalic aldehyde solution and the hydrocyanic acid, and after dripping is finished, raising the reaction temperature to 30-35 ℃ and keeping the temperature for reaction for 2 hours to obtain a cyanohydrin solution.
The cyanohydrin solution was added to 340g of 30% H2SO4And slowly heating the solution to 90-95 ℃ for reflux reaction for 3 hours, cooling the solution to 25 ℃ after the reaction is finished, dropwise adding ammonia water, adjusting the pH value of the reaction solution to 6.5-7.0, standing the solution, and removing a water phase to obtain a reddish brown transparent solution, namely a DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone crude product.
And (3) carrying out high vacuum rectification on the crude product, controlling the system pressure at 20-100Pa and the temperature at 80-120 ℃, and obtaining 135.08g of finished product, wherein the content is 98.33% by gas chromatography detection, and the yield is 74.84%.
As can be seen from this comparative example, in the step of the cyanohydrin reaction, the yield of the product was significantly reduced by increasing the dropping temperature of hydrocyanic acid and the subsequent incubation reaction temperature, and the author speculates that the polymerization of hydrocyanic acid as a raw material was likely to occur due to the excessively high temperature in this step, thereby reducing the yield of the subsequent product.
The embodiments in the present description are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments are referred to each other.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (9)
1. A preparation method of DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone is characterized by comprising the following steps:
s1, mixing formaldehyde and an organic base catalyst, and dropwise adding isobutyraldehyde to perform a condensation reaction to generate hydroxyl pivalaldehyde;
s2, adding hydrocyanic acid, simultaneously dropwise adding hydroxyl pivalic aldehyde and hydrocyanic acid by using a peristaltic pump, controlling the temperature and the pH value, carrying out a cyanohydrin reaction, adjusting the pH value of a reaction solution by using ammonia water after hydrolysis and lactonization under an acidic condition, standing, removing a water phase to obtain a crude product, and concentrating the water phase to obtain an ammonium salt;
s3, rectifying and purifying the crude product to obtain DL-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone.
2. The method of claim 1, wherein the organic base catalyst in step S1 is one of ethylenediamine, diethylamine, triethylamine, propylamine, isopropylamine, dipropylamine, and n-butylamine.
3. The method of claim 1, wherein the mass ratio of the organic base catalyst to isobutyraldehyde in step S1 is 6-8:100, the molar ratio of formaldehyde to isobutyraldehyde is 1.05-1.2: 1.0.
4. the method for preparing DL- α -hydroxy- β, β -dimethyl- γ -butyrolactone according to claim 1, wherein in the condensation reaction in step S1, the temperature of dropwise adding isobutyraldehyde is controlled to 10-30 ℃; the temperature is kept at 50-80 ℃ for 1-4h after dripping.
5. The method for preparing DL- α -hydroxy- β, β -dimethyl- γ -butyrolactone according to claim 1, wherein the temperature in the cyanohydrin reaction in step S2 is controlled at 0-20 deg.C, pH is controlled at 8-9, after finishing the titration, the temperature is maintained at-10 deg.C to 10 deg.C, and the holding time is 0.5-5 h.
6. The method of claim 1, wherein the acid solution used in the acidic condition of step S2 is a mixture of one or more of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.
7. The method for preparing DL- α -hydroxy- β, β -dimethyl- γ -butyrolactone according to claim 6, wherein the concentration of the acid solution under acidic condition is 30% -60%, the reaction temperature is 60-100 ℃, and the reaction time is 0.5-6 h.
8. The process for preparing DL- α -hydroxy- β, β -dimethyl- γ -butyrolactone according to claim 1, wherein after the hydrolysis and lactonization in step S2, the pH of the reaction solution is adjusted to 4-7 with ammonia water.
9. The method for preparing DL- α -hydroxy- β, β -dimethyl- γ -butyrolactone according to claim 1, wherein the rectification and purification in step S3 employs high vacuum rectification mode, the system pressure is controlled at 20-100Pa, and the temperature is controlled at 80-120 ℃.
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| CN114409618A (en) * | 2022-01-27 | 2022-04-29 | 国药集团威奇达药业有限公司 | Process for producing D, L-pantolactone |
| CN114478192A (en) * | 2021-12-29 | 2022-05-13 | 安徽泰格生物科技有限公司 | Method for separating neopentyl glycol from DL-pantoic acid lactone synthetic material liquid |
| CN114773295A (en) * | 2022-05-26 | 2022-07-22 | 重庆医药高等专科学校 | Method for synthesizing pantolactone |
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Cited By (3)
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| CN114478192A (en) * | 2021-12-29 | 2022-05-13 | 安徽泰格生物科技有限公司 | Method for separating neopentyl glycol from DL-pantoic acid lactone synthetic material liquid |
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Application publication date: 20210625 |
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