Environment-friendly preparation method of high-purity pantothenyl lactones

Abstract

The application relates to the technical field of fine chemical industry, in particular to a green and environment-friendly preparation method of high-purity pantoic acid lactone. The preparation method of the pantoic acid lactone comprises the following steps: providing (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt or (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt, and under the condition that the reaction temperature is not lower than 90 DEG C and the vacuum degree is-0.06 MPa to-0.1 MPa, a ring-closing reaction occurs to generate ammonia gas or ammonia water, and D-pantoic acid lactone or L-pantoic acid lactone is collected. The above method can generate high-purity D-pantoic acid lactone or L-pantoic acid lactone, the by-product ammonia water can be recycled, no salt is generated in the whole process, no waste water is generated, the method is green and environment-friendly, the loss of D-pantoic acid lactone or L-pantoic acid lactone is small, and the yield is high.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of fine chemical industry, in particular to a green and environmentally friendly preparation method of high-purity pantoic acid. BACKGROUND

[0002] Pantoic acid includes D-pantoic acid and L-pantoic acid. D-pantoic acid has biological activity and is an important pharmaceutical intermediate, which has wide application in the fields of biomedicine, food, feed and the like. D-pantoic acid is mainly used for synthesizing vitamin B5 or its derivative, i.e. D-calcium pantothenate and D-pantotheine. D-calcium pantothenate, as a water-soluble vitamin, is an essential nutrient for animals or human bodies, participates in various metabolic processes and promotes the absorption and utilization of various nutrients by animals or human bodies. L-pantoic acid has no biological activity. L-pantoic acid can be converted into DL-pantoic acid through a racemization reaction.

[0003] At present, through microbial enzyme resolution of DL-pantoic acid, (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt or (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt is obtained at the same time as L-pantoic acid or D-pantoic acid, and then the ammonium salt is converted into D-pantoic acid or L-pantoic acid by adding an acid agent and a base agent. Taking the preparation of D-pantoic acid as an example, (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt is added with an acid agent, a cyclization reaction is carried out under acidic conditions, and then a base agent is added to adjust the pH value to neutral, so as to obtain D-pantoic acid. However, this method generates a large amount of salt, produces a large amount of high-concentration waste brine, and causes great burden to environmental protection. Moreover, D-pantoic acid and L-pantoic acid are both soluble in water, and it is difficult to completely separate D-pantoic acid or L-pantoic acid from the high-concentration waste brine in the process of treating the high-concentration waste brine, resulting in the loss of D-pantoic acid or L-pantoic acid with the discharge of the high-concentration waste brine. SUMMARY

[0004] Based on this, the present application provides a green and environmentally friendly preparation method of high-purity pantoic acid, and the technical scheme is as follows:

[0005] A green and environmentally friendly preparation method of high-purity pantoic acid, comprising the following steps:

[0006] (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt or (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt is provided, and a cyclization reaction occurs under the condition that the reaction temperature is not lower than 90℃ and the vacuum degree is-0.06MPa~ -0.1MPa, ammonia gas or ammonia water is generated, and the obtained D-pantoic acid or L-pantoic acid is collected.

[0007] In some embodiments, the reaction temperature is 90°C to 145°C, and in some embodiments, the reaction temperature is 100°C to 130°C. In some embodiments, the reaction temperature is 100°C to 120°C.

[0008] In some embodiments, the vacuum degree is -0.09 MPa to -0.1 MPa.

[0009] In some embodiments, the ring-closing reaction time is 3 h to 5 h.

[0010] In some embodiments, the method for preparing the (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt or (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt comprises the following steps:

[0011] resolving DL-pantoic acid to obtain an aqueous solution of (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt or (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt;

[0012] concentrating the aqueous solution of (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt or (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt to precipitate solids.

[0013] In some embodiments, the concentration temperature is 30°C to 75°C, and the vacuum degree is -0.06 MPa to -0.10 MPa.

[0014] In some embodiments, ammonia gas or aqueous ammonia is introduced during the resolution of the DL-pantoic acid to obtain an aqueous solution of (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt or (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt.

[0015] In some embodiments, the method for collecting the D-pantoic acid or L-pantoic acid comprises the following steps:

[0016] adding an organic solvent to the reaction product after the ring-closing reaction of the (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt or (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt to dissolve, and crystallizing the obtained solution to obtain D-pantoic acid or L-pantoic acid.

[0017] In some embodiments, the crystallization of the obtained solution comprises the following steps: cooling the obtained solution to 10°C to 20°C, adding D-pantoic acid crystal seeds or L-pantoic acid crystal seeds to the solution, and incubating for 1 h to 3 h; continuing to cool to -15°C to -5°C, and incubating for 2 h to 4 h.

[0018] In some embodiments, the organic solvent is selected from ethyl acetate, and the mass of the organic solvent is 25% to 40% of the mass of the reactants.

[0019] The present inventors surprisingly found that the ring-closing reaction of (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt or (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt can be carried out by appropriately increasing the temperature and negative pressure conditions without adding acid or base. This can be due to the ammonia or aqueous ammonia generated by the initial ring-closing reaction playing a catalytic role in the cyclization, so that the ring-closing reaction can continuously occur until completion.

[0020] Compared with the traditional scheme, the present application has the following beneficial effects:

[0021] The present application provides a method for cyclization to generate pantothenic acid lactone under traditional acid / base conditions. By high temperature and reduced pressure, the cyclization of (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt or (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt can be completed without adding acid and base agents, generating high-purity D-pantothenic acid lactone or L-pantothenic acid lactone. The by-product ammonia or aqueous ammonia can be recycled and used in the initial process of resolving DL-pantothenic acid lactone to obtain (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt or (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt. The entire process does not generate salt and produces no wastewater, and the method is green and environmentally friendly, with less loss of D-pantothenic acid lactone or L-pantothenic acid lactone, high purity, and high yield. BRIEF DESCRIPTION OF DRAWINGS

[0022] In order to more clearly illustrate the technical solutions in the embodiments of the present application, more completely understand the present application and its beneficial effects, the following will briefly introduce the drawings needed to be used in the embodiment description. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creating laborious work.

[0023] Figure 1 The flowchart of the preparation method of D-pantothenic acid lactone of an embodiment is shown in the figure.

[0024] Figure 2 The flowchart of the preparation method of L-pantothenic acid lactone of an embodiment is shown in the figure.

[0025] Figure 3 The chromatogram of the ee value of D-pantothenic acid lactone of Example 1 is shown in the figure. DETAILED DESCRIPTION

[0026] The application will be described in further detail below with reference to the drawings. The application can be implemented in numerous different forms, and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and fully convey the scope of the application to those skilled in the art.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description of the application herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0028] The term

[0029] Unless otherwise indicated or contradictory in context, the terms or phrases used herein have the following meanings:

[0030] In the present application, the term "optionally", "optional" or "alternatively" means either of the two parallel schemes, i.e. "yes" or "no". If there are multiple "optionally" in a technical solution, each "optionally" is independent of each other unless otherwise specified, and there is no contradictory or mutual restrictive relationship.

[0031] In the present application, the numerical interval (i.e. numerical range) is not specified, and the optional numerical distribution within the numerical interval is considered to be continuous, and includes the two numerical endpoints (i.e. the minimum value and the maximum value) of the numerical range, as well as each numerical value between the two numerical endpoints. If the numerical interval is only directed to the integers within the numerical interval, including the two endpoint integers of the numerical range and each integer between the two endpoints, in this document, it is equivalent to directly listing each integer, such as t is an integer selected from 1 to 10, which means that t is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In addition, when multiple ranges are provided to describe a feature or characteristic, these ranges can be combined. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0032] The temperature parameter in the present application is not particularly limited, and both constant temperature treatment and variation within a certain temperature range are allowed. It should be understood that the constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuation within a range such as ±5℃, ±4℃, ±3℃, ±2℃, ±1℃ is allowed.

[0033] In the present application, the percentage content is not particularly specified, and for solid-liquid mixing and solid-solid mixing, it refers to mass percentage, and for liquid-liquid mixing, it refers to volume percentage.

[0034] In the present application, the percentage concentration refers to the final concentration, unless otherwise specified. The final concentration refers to the proportion of the added component in the system after the component is added.

[0035] In the present application, %(w / w) and wt% both represent weight percentage, %(v / v) refers to volume percentage, and %(w / v) refers to mass volume percentage.

[0036] For example, in the preparation of D-pantoic acid, a traditional reaction formula for preparing D-pantoic acid is as follows:

[0037]

[0038] The reaction equation of the side reaction is: 2NH3·H2O + H2SO4 = (NH4)2SO4 + H2O.

[0039] Sulfuric acid is added to (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt, a cyclization reaction occurs under acidic conditions, and then ammonia water is added to adjust the pH value to neutral to obtain D-pantoic acid. The sulfuric acid can be replaced by hydrochloric acid, nitric acid, phosphoric acid, or other inorganic or organic acids, and the ammonia water can be replaced by sodium hydroxide, sodium bicarbonate, potassium bicarbonate, or other inorganic bases or strong base salts.

[0040] The above reaction generates a large amount of ammonium sulfate (or other salts generated after replacing other acid agents and base agents), produces a large amount of high-concentration waste brine, and loses D-pantoic acid.

[0041] To solve the above problems, the present application provides a preparation method of pantoic acid. In one embodiment, please refer to Figure 1 The preparation of D-pantoic acid includes the following steps:

[0042] S10, resolving DL-pantoic acid to obtain an aqueous solution of (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt.

[0043] Optionally, the DL-pantoic acid is resolved by microbial enzymes. Optionally, ammonia gas or ammonia water is introduced during the resolution process to obtain an aqueous solution of (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt. The ammonia gas or ammonia water introduced in this process can be all or part of the ammonia gas or ammonia water generated in the subsequent cyclization reaction.

[0044] S20, concentrating the aqueous solution of (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt to precipitate solids to obtain (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt.

[0045] Optionally, the concentration temperature is 30°C to 75°C.

[0046] Optionally, the vacuum degree of concentration is -0.06 MPa to -0.10 MPa. Concentration under the above vacuum degree is beneficial to lowering the distillation temperature and preventing water from boiling during distillation.

[0047] In this embodiment, (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt is derived from an aqueous solution of (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt obtained after resolution of DL-pantoyl lactone. In other embodiments, (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt can also be commercially available.

[0048] S30. Allow (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt to undergo a cyclization reaction at a reaction temperature of not less than 90° C. and a vacuum degree of -0.06 MPa to -0.1 MPa to produce ammonia gas or ammonia water, and collect the obtained D-pantoyl lactone.

[0049] The reaction formula for the cyclization reaction of (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt is as follows:

[0050]

[0051] During the reaction, the ammonia can be removed promptly, shifting the reaction in the positive direction and accelerating the reaction. In this embodiment, (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt is placed in a confined space. The vacuum is then pumped out to maintain the vacuum level. During this process, the ammonia can be removed promptly, accelerating the reaction. The extracted ammonia can be recycled and reused.

[0052] If the reaction temperature is below 90°C, the cyclization reaction will be difficult, and the resulting product, D-pantoyl lactone, will not melt at this temperature. The heat transfer efficiency of the solid material is low, and the conversion will stop at about 5%. Optionally, the reaction temperature is 90°C to 145°C. Preferably, the reaction temperature is 100°C to 130°C. Below 100°C, the reaction is slow. After the reaction temperature exceeds 130°C, due to the negative pressure environment of the reaction system, the generated D-pantoyl lactone will be distilled out and lost, and the loss increases with increasing temperature. More preferably, the reaction temperature is 100°C to 120°C.

[0053] The higher the vacuum degree, the faster the reaction speed. Preferably, the vacuum degree is -0.09 MPa to -0.1 MPa, as the conversion effect is better within this range.

[0054] (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt gradually melts at the above reaction temperature and the above vacuum degree, a cyclization reaction occurs, ammonia water or ammonia gas is generated, and ammonia gas volatilized in the process can be detected. The cyclization reaction does not require the input of acid and base agents, does not produce a large amount of salt-containing wastewater, is more green and environmentally friendly, and the generated ammonia water or ammonia gas can be recycled to the resolution process.

[0055] In the present embodiment, the end point of the cyclization reaction can be determined by observing whether ammonia gas or ammonia water continues to be generated. Alternatively, the time of the cyclization reaction is 3h-24h. When the reaction temperature is 100℃-130℃, the cyclization product is in a molten state, and the entire reaction system is in a liquid state, which can greatly shorten the reaction time to 3h-5h, which is conducive to industrial production.

[0056] After the cyclization reaction is completed, the obtained D-pantoic acid lactone is collected.

[0057] Alternatively, the method for collecting the D-pantoic acid lactone comprises the following steps:

[0058] An organic solvent is added to dissolve the reaction product after the cyclization reaction of the (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt, and the obtained solution is cooled to crystallize to obtain D-pantoic acid lactone.

[0059] In the present embodiment, after the cyclization reaction is completed, the temperature is lowered to 60℃-70℃, and an organic solvent is added for dissolution.

[0060] Alternatively, the organic solvent is ethyl acetate.

[0061] Alternatively, to obtain D-pantoic acid lactone with high ee value, cooling and crystallization of the obtained solution comprises the following steps: D-pantoic acid lactone seeds are added to the solution. Adding D-pantoic acid lactone seeds is conducive to rapid crystallization of D-pantoic acid lactone at low temperature.

[0062] Alternatively, cooling and crystallization of the obtained first solution comprises the following procedures: the obtained first solution is cooled to 10℃-20℃, the D-pantoic acid lactone seeds are added, and incubation is performed for 1h-3h, then the temperature is continuously lowered to -15℃--5℃, and incubation is performed for 2h-4h.

[0063] In the traditional method, cyclization is carried out under sulfuric acid conditions, and then ammonia water is added to adjust the pH value to neutral. The generated ammonium sulfate needs to be extracted twice with ethyl acetate. The solvent after extraction needs to be concentrated, and the water phase wastewater treatment also needs ethyl acetate recovery process, ammonium sulfate recovery process, etc. Compared with the above complex and cumbersome steps, the high-temperature and negative-pressure cyclization method of the present application is process-saving, economical and environmentally friendly, and can also reduce the loss of D-pantoic acid lactone product caused by waste salt water discharge.

[0064] The above embodiment provides a method different from the traditional acid ring-closing method for generating D-pantothenyl lactone. Through high temperature and reduced pressure, the ring-closing of (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt can be completed without adding acid and base agents, and high-purity D-pantothenyl lactone is generated. The by-product ammonia or ammonia water can be recycled to the DL-pantothenyl lactone resolution process. The entire process does not generate salt and wastewater, is green and environmentally friendly, has less loss of D-pantothenyl lactone, and has high yield.

[0065] In another embodiment, referring to Figure 2 , the method for preparing L-pantothenyl lactone comprises the following steps:

[0066] S10, resolving DL-pantothenyl lactone to obtain an aqueous solution of (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt.

[0067] Optionally, the DL-pantothenyl lactone is resolved by microbial enzymes. Optionally, ammonia gas or ammonia water is introduced during the resolution process to obtain an aqueous solution of (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt. The ammonia gas or ammonia water introduced in this process can be all or part of the ammonia gas or ammonia water generated in the subsequent ring-closing reaction.

[0068] S20, concentrating the aqueous solution of (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt to precipitate solids to obtain (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt.

[0069] Optionally, the concentration temperature is 30°C to 75°C.

[0070] Optionally, the vacuum degree for concentration is -0.06 MPa to -0.10 MPa. Concentration under the above vacuum degree is conducive to reducing the distillation temperature and preventing water from boiling during distillation.

[0071] In this embodiment, the (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt is derived from the aqueous solution of (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt after resolving DL-pantothenyl lactone. In other embodiments, the (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt can also be commercially available.

[0072] S30, making (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt undergo ring-closing reaction under the condition that the reaction temperature is not lower than 90°C and the vacuum degree is -0.06 MPa to -0.1 MPa to generate ammonia gas or ammonia water, and collecting the obtained L-pantothenyl lactone.

[0073] In the above reaction, the reaction formula of (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt undergoing ring-closing reaction is as follows:

[0074]

[0075] During the reaction, ammonia can be removed in time to make the reaction proceed in the positive direction, and the reaction speed is faster. In the embodiment, the (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt is placed in a closed space, vacuum is extracted, and the vacuum degree of the closed space is maintained. During the vacuum extraction process, ammonia can be extracted in time, and the reaction speed is fast. The extracted ammonia can be recycled and reused.

[0076] When the reaction temperature is lower than 90℃, the cyclization reaction is difficult, and the generated product L-pantothenyl lactone cannot melt at this temperature, and the heat transfer efficiency of the solid material is low, and the conversion stops at about 5%. Alternatively, the reaction temperature is 90℃-145℃. Preferably, the reaction temperature is 100℃-130℃. When the reaction temperature is lower than 100℃, the reaction is slow. When the reaction temperature exceeds 130℃, the generated L-pantothenyl lactone is lost due to the negative pressure environment of the reaction system, and the loss increases with the increase of temperature. More preferably, the reaction temperature is 100℃-120℃.

[0077] The higher the vacuum degree, the faster the reaction speed. Preferably, the vacuum degree is -0.09MPa--0.1MPa, and the conversion effect is better in this range.

[0078] The (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt gradually melts at the above reaction temperature and the above vacuum degree, and a cyclization reaction occurs to generate ammonia water or ammonia gas, and ammonia gas can be detected during the volatilization of ammonia water. The above cyclization reaction does not need to invest acid and alkali agents, and a large amount of salt-containing wastewater is not generated, which is more green and environmentally friendly. And the generated ammonia water or ammonia gas can be recycled to the separation process.

[0079] In the embodiment, the end point of the cyclization reaction can be judged by observing whether ammonia gas or ammonia water continues to be generated. Alternatively, the time of the cyclization reaction is 3h-24h. When the reaction temperature is 100℃-130℃, the cyclization product is in a molten state, and the entire reaction system is in a liquid state, which can greatly shorten the reaction time to 3h-5h, which is beneficial to industrial production.

[0080] After the cyclization reaction is completed, the obtained L-pantothenyl lactone is collected.

[0081] Alternatively, the method for collecting the L-pantothenyl lactone comprises the following steps:

[0082] An organic solvent is added to the reaction product after the cyclization reaction of the (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt to dissolve, and the obtained solution is cooled and crystallized to obtain L-pantothenyl lactone.

[0083] In this embodiment, after the cyclization reaction is completed, the temperature is lowered to 60-70°C, and an organic solvent is added for dissolution.

[0084] Optionally, the organic solvent is ethyl acetate.

[0085] Optionally, to obtain L-pantothenyl lactate with high ee value, the obtained solution is cooled and crystallized, including the following steps: adding L-pantothenyl lactate crystal seeds to the solution.

[0086] Optionally, the obtained solution is cooled and crystallized, including the following procedures: cooling the obtained solution to 10-20°C, adding the L-pantothenyl lactate crystal seeds, incubating for 1-3 hours, continuing to cool to -15 to -5°C, and incubating for 2-4 hours.

[0087] The above embodiment provides a method for cyclization to generate L-pantothenyl lactate under traditional acidic conditions. Through high temperature and reduced pressure, the cyclization of (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt can be completed without adding acid and base agents, high-purity L-pantothenyl lactate is generated, the byproduct ammonia or ammonia water can be recycled, no salt is generated, no wastewater is generated, the method is green and environmentally friendly, the loss of L-pantothenyl lactate is small, and the yield is high.

[0088] The following is further illustrated by specific examples and comparative examples. The raw materials involved in the following specific examples and comparative examples, if not specifically stated, can be sourced from the market. The instruments used, if not specifically stated, can be sourced from the market. The processes involved, if not specifically stated, are commonly selected by those skilled in the art.

[0089] Chromatographic conditions for detecting D-pantothenyl lactate crude product and L-pantothenyl lactate crude product:

[0090] Chromatographic column: Phenomenex Luna C18, 250mm*4.6mm*5um, or equivalent chromatographic column

[0091] Mobile phase A: 0.1% formic acid aqueous solution

[0092] Mobile phase B: methanol

[0093] Flow rate: 1.0 ml / min

[0094] Detection wavelength: 214 nm

[0095] Column temperature: 40°C

[0096] Injection volume: 10uL

[0097] Run time: 20 min

[0098] Chiralpak IC column, 4.6 mm x 250 mm x 5 μm

[0099] Chiralpak IC column, 4.6 mm x 250 mm x 5 μm

[0100] Mobile phase A: 0.1% formic acid in water

[0101] Mobile phase B: methanol

[0102] Flow rate: 0.5 ml / min

[0103] Detection wavelength: 214 nm

[0104] Column temperature: 30 °C

[0105] Injection volume: 10 uL

[0106] Run time: 20 min

[0107] Elution gradient: A:B = 60:40, isocratic elution.

[0108] Example 1

[0109] This example provides a D-pantoic acid and a method for preparing the same, the steps of which are as follows:

[0110] In a 2000 ml three-necked flask, (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt aqueous solution 1430 g (content 34.48 wt%) was added in batches, the three-necked flask was sealed, and concentrated under reduced pressure, with a vacuum degree of -0.091 MPa and an internal temperature controlled at 55 °C. After the solid was precipitated, (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt was obtained in the three-necked flask. The temperature in the three-necked flask was gradually increased to an internal temperature of 130 °C, while the vacuum was maintained at -0.091 MPa. The (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt gradually melted and underwent cyclization reaction. After 4 h of reaction, the temperature was lowered to 65 °C, and the product D-pantoic acid crude product was obtained. The conversion rate of the raw material was 99.8%, as measured by the chromatographic conditions for D-pantoic acid crude product described above. Ethyl acetate 267 g was added to dissolve the D-pantoic acid crude product, and the solution was cooled to 15 °C. D-pantoic acid seed crystals were added and incubated for 2 h. The temperature was continuously lowered to -10 °C for crystallization for 3 h. The filtrate was a mixture containing D-pantoic acid and L-pantoic acid, which was recycled for use in the next separation. The filtered solid was D-pantoic acid, with a yield of 75%. The chiral purity ee value was 100%, as measured by the ee value chromatographic conditions for D-pantoic acid described above. The chromatogram is shown in Figure 1. Figure 3 .

[0111] Example 2

[0112] (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt solution 1430 g (content 34.48 wt%) was added in batches in a 2000 ml three-necked reaction flask. After sealing the three-necked reaction flask, it was concentrated under reduced pressure, the vacuum degree was -0.089 MPa, the internal temperature was controlled at 55°C, and (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt was obtained in the three-necked reaction flask after the solid was precipitated. The temperature in the three-necked flask was gradually increased to an internal temperature of 120°C while maintaining the vacuum at -0.092 MPa, and (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt gradually melted and underwent cyclization reaction. After 3 h of reaction, the temperature was lowered to 65°C, and the product D-pantoic acid lactone crude product was obtained. The conversion rate of the raw material was 99.6% as measured by the chromatographic conditions of the D-pantoic acid lactone crude product described above. Ethyl acetate 267 g was added to dissolve the D-pantoic acid lactone crude product, and the solution was cooled to 15°C. D-pantoic acid lactone seed crystals were added and incubated for 2 h. The temperature was continuously lowered to -10°C for crystallization for 3 h. Filtration was performed, and the filtrate was a mixture containing D-pantoic acid lactone and L-pantoic acid lactone. The cycle was repeated for use in the next separation. The filtered solid was D-pantoic acid lactone, and the yield was 78%. The chiral purity ee value was 100% as measured by the ee value chromatographic conditions of D-pantoic acid lactone described above.

[0113] Example 3

[0114] (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt solution 1430 g (content 34.48 wt%) was added in batches in a 2000 ml three-necked reaction flask. After sealing the three-necked reaction flask, it was concentrated under reduced pressure, the vacuum degree was -0.089 MPa, the internal temperature was controlled at 55°C, and (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt was obtained in the three-necked reaction flask after the solid was precipitated. The temperature in the three-necked flask was gradually increased to an internal temperature of 120°C while maintaining the vacuum at -0.092 MPa, and (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt gradually melted and underwent cyclization reaction. After 3 h of reaction, the temperature was lowered to 65°C, and the product D-pantoic acid lactone crude product was obtained. The conversion rate of the raw material was 99.6% as measured by the chromatographic conditions of the D-pantoic acid lactone crude product described above. Ethyl acetate 267 g was added to dissolve the D-pantoic acid lactone crude product, and the solution was cooled to 15°C. D-pantoic acid lactone seed crystals were added and incubated for 2 h. The temperature was continuously lowered to -10°C for crystallization for 3 h. Filtration was performed, and the filtrate was a mixture containing D-pantoic acid lactone and L-pantoic acid lactone. The cycle was repeated for use in the next separation. The filtered solid was D-pantoic acid lactone, and the yield was 78%. The chiral purity ee value was 100% as measured by the ee value chromatographic conditions of D-pantoic acid lactone described above.

[0115] Example 4

[0116] In a 2000ml three-necked flask, (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt aqueous solution 1430g (content 34.48wt%) was added in batches, after sealing the three-necked flask, concentrated under reduced pressure, the vacuum degree was -0.089MPa, the internal temperature was controlled at 55℃, after concentrated to solid precipitated, (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt was obtained in the three-necked flask. Gradually the temperature in the three-necked flask was increased to 106℃, while keeping the vacuum at 0.093MPa, (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt gradually melted, cyclization reaction occurred, after 5h reaction, the temperature was decreased to 65℃, the product L-pantoic acid crude product was obtained, referring to the chromatographic conditions of D-pantoic acid crude product above, the conversion rate of raw material was 99.7%. To the L-pantoic acid crude product, ethyl acetate 267g was added to dissolve, the solution was cooled to 15℃, L-pantoic acid crystal seed was added and kept for 2h, continued to cool to -10℃ crystallization for 3h, filtered, the filtrate was a mixture containing D-pantoic acid and L-pantoic acid, which was recycled for next separation, the solid after filtration was L-pantoic acid, yield: 75%. Referring to the ee value chromatographic conditions of L-pantoic acid above, the chiral purity ee value was 100%.

[0117] Example 5

[0118] In a 2000ml three-necked flask, (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt aqueous solution 1430g (content 34.48wt%) was added in batches, after sealing the three-necked flask, concentrated under reduced pressure, the vacuum degree was -0.089MPa, the internal temperature was controlled at 55℃, after concentrated to solid precipitated, (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt was obtained in the three-necked flask. Gradually the temperature in the three-necked flask was increased to 106℃, while keeping the vacuum at 0.093MPa, (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt gradually melted, cyclization reaction occurred, after 5h reaction, the temperature was decreased to 65℃, the product L-pantoic acid crude product was obtained, referring to the chromatographic conditions of D-pantoic acid crude product above, the conversion rate of raw material was 99.7%. To the L-pantoic acid crude product, ethyl acetate 267g was added to dissolve, the solution was cooled to 15℃, L-pantoic acid crystal seed was added and kept for 2h, continued to cool to -10℃ crystallization for 3h, filtered, the filtrate was a mixture containing D-pantoic acid and L-pantoic acid, which was recycled for next separation, the solid after filtration was L-pantoic acid, yield: 75%. Referring to the ee value chromatographic conditions of L-pantoic acid above, the chiral purity ee value was 100%.

[0119] Comparative Example 1

[0120] In a 2000ml four-port reaction bottle, add (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt aqueous solution 1430g (content 34.48wt%), drop 230g concentrated sulfuric acid, adjust pH to 1.0~1.5, warm to 90℃, keep warm for 1h, cyclization reaction to generate D-pantothenic acid lactone crude product, refer to the chromatographic conditions of D-pantothenic acid lactone crude product in the above, the conversion rate of raw material is 99.6%. Cool to 40℃, drop 60g ammonia water to adjust pH to 6.0, stand and separate, the upper layer is D-pantothenic acid lactone, the lower layer is water layer, extract with ethyl acetate twice, each 900g. Combine the upper layer after extraction with the D-pantothenic acid lactone separated by standing, concentrate to a concentrate weight of 750g, cool to 15℃, add D-pantothenic acid lactone seed and keep warm for 2h, continue to cool to-10℃ for 3h, filter, get D-pantothenic acid lactone solid, yield: 73%. The chiral purity ee value is 97%.

[0121] The total amount of waste brine produced in this comparative example is 1088g, which mainly contains ammonium sulfate, ethyl acetate, D-pantothenic acid lactone, (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt, etc. The high COD and high ammonia nitrogen content in the waste water cause a great burden on sewage treatment.

[0122] Comparative example 2

[0123] In a 2000ml three-port reaction bottle, add (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt aqueous solution 1430g (content 34.48wt%) in batches, seal the three-port reaction bottle, reduce pressure and concentrate, the vacuum degree is-0.091MPa, the internal temperature is controlled at 55℃, concentrate to a large amount of solid precipitates, then get (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt in the three-port reaction bottle. Keep the temperature in the three-port bottle at 85℃, and keep the vacuum at-0.091MPa, after 6h of reaction, no raw material melting phenomenon is generated. The material in the reaction bottle solidifies and cannot be stirred. The D-pantothenic acid lactone content is 4.54%, after 12h of reaction, the D-pantothenic acid lactone content is 4.78%. The material in the reaction bottle solidifies and forms a lump, which cannot continue to react.

[0124] As can be seen from the above, by controlling the temperature and vacuum degree, under a certain high temperature and negative pressure, (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt cyclization reaction can occur to prepare D-pantothenic acid lactone, which is economical and environmentally friendly, and can also reduce the loss of D-pantothenic acid lactone product caused by waste brine discharge. When the cyclization reaction temperature is lower, for example in example 3, the reaction temperature is 90℃, a longer reaction time is needed, when the cyclization reaction temperature is higher, for example in example 5, the generated product D-pantothenic acid lactone also evaporates a lot after cyclization reaction, the yield is lower. Preferably, the reaction temperature is 100℃~130℃, at this time, the D-pantothenic acid lactone yield is high and the time is short.

[0125] Each technical feature of the above-described embodiments can be combined with any other technical feature, and for the sake of brevity, not all possible combinations are described, but it is understood that the scope of the present disclosure encompasses all such possible combinations.

[0126] The above-described embodiments are merely illustrative of several embodiments of the present application, and the description is relatively specific and detailed, but should not be understood as limiting the scope of the patent. It should be noted that for those skilled in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are all within the scope of the present application. Therefore, the scope of the patent of the present application should be subject to the appended claims.

Claims

1. A green and environmentally friendly method for preparing high-purity pantothenolactone, characterized in that: The following steps are involved: (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt or (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt is provided, and a cyclization reaction is carried out under the conditions of a reaction temperature not lower than 90°C and a vacuum degree of -0.06 MPa to -0.1 MPa to produce ammonia gas or ammonia water, and the obtained D-pantoyl lactone or L-pantoyl lactone is collected.

2. The green and environmentally friendly preparation method of high-purity pantolactone according to claim 1, characterized in that: The reaction temperature is 100°C to 130°C.

3. The green and environmentally friendly preparation method of high-purity pantolactone according to claim 1, characterized in that: The vacuum degree is -0.09MPa~-0.10MPa.

4. The green and environmentally friendly preparation method of high-purity pantolactone according to claim 1, characterized in that: The cyclization reaction time is 3h~5h.

5. The green and environmentally friendly method for preparing high-purity pantothenolactone according to any one of claims 1 to 4, characterized in that: The preparation method of the (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt or the (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt comprises the following steps: Resolving DL-pantoyl lactone to obtain an aqueous solution of (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt or (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt; The aqueous solution of the (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt or the (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt is concentrated until a solid is precipitated.

6. The green and environmentally friendly preparation method of high-purity pantolactone according to claim 5, characterized in that: The concentration temperature is 30° C. to 75° C., and the vacuum degree is -0.06 MPa to -0.10 MPa.

7. The green and environmentally friendly preparation method of high-purity pantolactone according to claim 5, characterized in that: During the separation of the DL-pantoyl lactone, ammonia gas or aqueous ammonia is introduced to obtain an aqueous solution of (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt or (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt.

8. The green and environmentally friendly method for preparing high-purity pantothenolactone according to any one of claims 1 to 4, characterized in that: The method for collecting the D-pantolactone or L-pantolactone comprises the following steps: An organic solvent is added to the reactant after the cyclization reaction of the (R)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt or the (S)-2,4-dihydroxy-3,3-dimethylbutyric acid ammonium salt to dissolve the reactant, and the obtained solution is cooled and crystallized to obtain D-pantoyl lactone or L-pantoyl lactone.

9. The green and environmentally friendly preparation method of high-purity pantolactone according to claim 8, characterized in that: The cooling crystallization of the obtained solution comprises the following steps: cooling the obtained solution to 10°C to 20°C, adding D-pantolactone seed crystals or L-pantolactone seed crystals to the solution, and keeping the temperature for 1 hour to 3 hours; and continuing to cool the solution to -15°C to -5°C, and keeping the temperature for 2 hours to 4 hours.

10. The green and environmentally friendly preparation method of high-purity pantothenolactone according to claim 8, characterized in that: The organic solvent is selected from ethyl acetate, and the mass of the organic solvent accounts for 25% to 40% of the mass of the reactants.

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