CN114409618A - Process for producing D, L-pantolactone - Google Patents
Process for producing D, L-pantolactone Download PDFInfo
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- CN114409618A CN114409618A CN202210101781.8A CN202210101781A CN114409618A CN 114409618 A CN114409618 A CN 114409618A CN 202210101781 A CN202210101781 A CN 202210101781A CN 114409618 A CN114409618 A CN 114409618A
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- pantolactone
- acid
- triethylamine
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- SERHXTVXHNVDKA-SCSAIBSYSA-N (3s)-3-hydroxy-4,4-dimethyloxolan-2-one Chemical compound CC1(C)COC(=O)[C@H]1O SERHXTVXHNVDKA-SCSAIBSYSA-N 0.000 title claims abstract description 48
- 238000000034 method Methods 0.000 title claims abstract description 36
- 230000008569 process Effects 0.000 title claims abstract description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 99
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 77
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 claims abstract description 58
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims abstract description 54
- 238000004821 distillation Methods 0.000 claims abstract description 29
- 238000002360 preparation method Methods 0.000 claims abstract description 28
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 25
- OTOIIPJYVQJATP-BYPYZUCNSA-M (R)-pantoate Chemical compound OCC(C)(C)[C@@H](O)C([O-])=O OTOIIPJYVQJATP-BYPYZUCNSA-M 0.000 claims abstract description 22
- HVMPYIKTQSOMHA-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-4-oxobutanoic acid Chemical compound O=CC(C)(C)C(O)C(O)=O HVMPYIKTQSOMHA-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000007323 disproportionation reaction Methods 0.000 claims abstract description 18
- 239000003513 alkali Substances 0.000 claims abstract description 16
- 239000002253 acid Substances 0.000 claims abstract description 14
- 238000005882 aldol condensation reaction Methods 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims description 55
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 239000007864 aqueous solution Substances 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 239000012295 chemical reaction liquid Substances 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- 239000011541 reaction mixture Substances 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 12
- 239000008098 formaldehyde solution Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 5
- 239000000284 extract Substances 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- 230000009471 action Effects 0.000 abstract description 7
- 230000007547 defect Effects 0.000 abstract description 7
- 230000007613 environmental effect Effects 0.000 abstract description 5
- 230000003197 catalytic effect Effects 0.000 abstract description 4
- 150000003839 salts Chemical class 0.000 abstract description 4
- 239000002351 wastewater Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 239000004280 Sodium formate Substances 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 abstract description 2
- 235000019254 sodium formate Nutrition 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000001276 controlling effect Effects 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 150000002596 lactones Chemical class 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 4
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 description 2
- 229960002079 calcium pantothenate Drugs 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- SNPLKNRPJHDVJA-UHFFFAOYSA-N dl-panthenol Chemical compound OCC(C)(C)C(O)C(=O)NCCCO SNPLKNRPJHDVJA-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- 229940101267 panthenol Drugs 0.000 description 2
- 235000020957 pantothenol Nutrition 0.000 description 2
- 239000011619 pantothenol Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- -1 and D Chemical compound 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000007031 hydroxymethylation reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000007273 lactonization reaction Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- OTOIIPJYVQJATP-UHFFFAOYSA-N pantoic acid Chemical compound OCC(C)(C)C(O)C(O)=O OTOIIPJYVQJATP-UHFFFAOYSA-N 0.000 description 1
- SERHXTVXHNVDKA-UHFFFAOYSA-N pantolactone Chemical compound CC1(C)COC(=O)C1O SERHXTVXHNVDKA-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention belongs to the technical field of drug synthesis, and relates to a preparation method of D, L-pantolactone. The method comprises the following steps: performing aldol condensation reaction on glyoxylic acid and isobutyraldehyde under the action of triethylamine to generate 2-hydroxy-3-methyl-3-formylbutyric acid; carrying out disproportionation reaction on the 2-hydroxy-3-methyl-3-formyl butyric acid under the action of pH 11-13.5 and formaldehyde to generate a pantoate; then, the D, L-pantolactone is generated through strong acid catalytic cyclization reaction. The method has reasonable process design, and the prepared D, L-pantolactone has high quality, high yield, simple operation, low energy consumption, easy industrial popularization, safety and environmental protection; in the disproportionation reaction process, the dosage of formaldehyde is reduced, and the defect that a large amount of sodium formate is generated due to the self-disproportionation reaction of the formaldehyde is overcome; after the disproportionation reaction is finished, the organic alkali is recovered through low-temperature reduced pressure distillation for reuse, and the defect that the salt content in the wastewater in the later period is increased due to the organic alkali is avoided.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of D, L-pantoyl lactone.
Background
D, L-panthenoyl lactone, namely D, L-2-hydroxy-3, 3-dimethyl-4-butyrolactone, is an important intermediate for preparing calcium pantothenate, panthenol and the like, calcium pantothenate is one of nutrient substances necessary for biological growth, is widely applied to industries such as medicines, feed additives and food industry, and the application of panthenol in daily chemicals is continuously increased along with the improvement of living standard of people.
In the prior art, for example, the following processes are reported in U.S. Pat. No. 4,020,103(1977) and others: taking isobutyraldehyde and formaldehyde as raw materials, performing hydroxymethylation, performing cyanogen addition reaction with cyanohydric acid or sodium cyanide, and finally completing cyclization reaction after cyano group hydrolysis under the catalysis of strong acid to form the product D, L-pantolactone. The method is a main method for industrial production at present, but due to the use of highly toxic sodium cyanide or hydrocyanic acid, the method has the disadvantages of higher safety risk, high management difficulty, high requirement on industrial equipment, large amount of cyanide-containing wastewater and waste residue which are difficult to treat, and other methods are developed by production enterprises gradually.
Chinese patent document CN111440133A discloses a method for preparing D, L-panthenol by atmospheric reduction, which comprises the steps of using glyoxylic acid and isobutyraldehyde as main initial raw materials, carrying out condensation reaction under the action of organic base, carrying out catalytic reduction by using potassium borohydride or sodium borohydride, and carrying out catalytic cyclization by using strong acid to obtain D, L-panthenol. The method has the main defects that the used reducing agents of potassium borohydride and sodium borohydride are too high in price, industrial production cannot be realized, hydrogen can be generated through decomposition in the process, and safety risks exist.
Chinese patent document CN106008413B discloses a method for synthesizing D, L-pantoyl lactone, which comprises using glyoxylic acid and isobutyraldehyde as main raw materials, carrying out condensation reaction under the action of organic base, carrying out hydrogenation catalytic reduction by using hydrogen, and carrying out catalytic cyclization by using strong acid to obtain the D, L-pantoyl lactone. The method has the main defects that the high-pressure hydrogenation reaction belongs to one of 18 high-risk reactions specified by the state, the safety risk level is higher, the production cost is higher, and the industrial popularization is not facilitated.
Meanwhile, chinese patent document CN106008413B discloses a method for preparing D, L-pantolactone in its background art as follows: isobutyraldehyde and glyoxylic acid are used as raw materials, aldol condensation is carried out firstly, then disproportionation reaction and acidification are carried out under the action of strong acid and formaldehyde to obtain 2, 4-dihydroxy-3, 3-dimethyl butyric acid, and D, L-pantolactone is obtained through lactonization. The method has the main defects of large using amount of formaldehyde and sodium hydroxide, more salt-containing wastewater generated by reaction and no contribution to environmental protection.
Therefore, it is necessary to improve and optimize the preparation method of D, L-pantolactone, so as to find a preparation method with reasonable process design, high product quality, high yield, simple operation, low energy consumption, easy industrial popularization, safety and environmental protection.
Disclosure of Invention
Therefore, the invention aims to provide the preparation method of the D, L-pantoyl lactone, which has reasonable process design, high quality of the prepared D, L-pantoyl lactone, high yield, simple operation, low energy consumption, easy industrial popularization, safety and environmental protection.
In order to achieve the above purpose of the present invention, the technical scheme adopted by the present invention is as follows: taking glyoxylic acid and isobutyraldehyde as main initial raw materials, and firstly carrying out aldol condensation reaction under the action of triethylamine to generate 2-hydroxy-3-methyl-3-formylbutyric acid; carrying out disproportionation reaction on 2-hydroxy-3-methyl-3-formylbutyric acid under the action of pH 11-13.5 and formaldehyde to generate a pantoate, namely 2, 4-dihydroxy-3, 3-dimethylbutyrate, and carrying out reduced pressure distillation on the reaction liquid to remove low-boiling-point substances and triethylamine; and then carrying out strong acid catalytic cyclization reaction to generate D, L-pantoyl lactone, and extracting the reaction solution by using an organic solvent and carrying out reduced pressure distillation on an organic extraction layer to obtain the high-purity D, L-pantoyl lactone.
According to the present invention, there is provided a process for producing D, L-pantolactone, comprising the steps of:
(1) preparation of 2-hydroxy-3-methyl-3-formylbutyric acid
Adding a glyoxylic acid aqueous solution into a first reaction container, dropwise adding triethylamine, and then dropwise adding isobutyraldehyde at the temperature of 35-50 ℃; after the isobutyraldehyde is dripped, carrying out aldol condensation reaction at 50-80 ℃ for 4-24 h to generate 2-hydroxy-3-methyl-3-formylbutyric acid;
(2) preparation of 2, 4-dihydroxy-3, 3-dimethylbutyrate
Adding a formaldehyde solution into a second reaction container, dropwise adding the reaction solution obtained in the step (1) at the temperature of 0-30 ℃, simultaneously maintaining the pH value of the reaction mixture to be 11-13.5 by using an alkali liquor, and carrying out a disproportionation reaction for 10-24 h after the dropwise adding is finished to convert the reaction mixture into 2, 4-dihydroxy-3, 3-dimethylbutyrate; after the reaction is finished, carrying out reduced pressure distillation on the reaction liquid at the temperature of 20-30 ℃ to remove low-boiling-point substances and triethylamine; wherein the alkali liquor is sodium hydroxide solution, potassium hydroxide solution or a mixture thereof;
(3) preparation of D, L-pantolactone
Adjusting the pH of the reaction solution obtained after the reduced pressure distillation in the step (2) to 1-1.5 by using acid, and performing cyclization reaction at the temperature of 80-100 ℃ to generate D, L-pantolactone; and (3) adjusting the pH value of the cyclization reaction solution to be 5-8 by using alkali liquor at room temperature, extracting by using an organic solvent, and distilling an extract liquor under reduced pressure to obtain the D, L-pantolactone.
Advantageous effects
Compared with the prior art, the invention has the technical advantages that:
(1) in the step (1), by controlling the addition mode of triethylamine, heat generated in the process can be removed in time, the temperature is prevented from rising rapidly, and side reactions are avoided to a certain extent; in addition, isobutyraldehyde can perform condensation reaction under the alkaline condition, so that the phenomenon of side reaction can be greatly reduced by dripping isobutyraldehyde into the reaction liquid in a dropwise manner;
(2) in the disproportionation reaction process in the step (2), the reaction conditions are controlled, so that the using amount of formaldehyde is reduced, and the defect that a large amount of sodium formate is generated due to the self-disproportionation reaction of the formaldehyde is overcome;
(3) after the disproportionation reaction is finished, because the pH value of the reaction system is between 11 and 13.5, the organic base triethylamine is in a free state at the moment, and the organic base can be recovered through low-temperature reduced pressure distillation for reuse, so that the production cost is greatly reduced, and the defect of salt increase caused by the organic base in later-stage wastewater is avoided;
(4) the process completely avoids the problems of safety, environmental protection, management and equipment caused by the use of highly toxic sodium cyanide or hydrocyanic acid, also avoids the process safety risk caused by high-pressure hydrogenation, and has low production cost and strong industrial value.
Drawings
FIGS. 1 to 5 are HPLC chromatogram and data of D, L-pantolactone prepared in examples 1 to 5.
Detailed Description
The process for producing D, L-pantolactone of the present invention is described more specifically below.
According to the invention, in the step (1) of preparing 2-hydroxy-3-methyl-3-formylbutyric acid, glyoxylic acid aqueous solution is added into a first reaction vessel, triethylamine is added dropwise, and then isobutyraldehyde is added dropwise at the temperature of 35-50 ℃; after the isobutyraldehyde is dripped, carrying out aldol condensation reaction for 4-24 h at 50-80 ℃ to generate the 2-hydroxy-3-methyl-3-formylbutyric acid.
Specifically, at room temperature, adding a glyoxylic acid aqueous solution into a first reaction vessel, wherein the glyoxylic acid aqueous solution can be a glyoxylic acid aqueous solution with the concentration of 30-50 wt%, for example a glyoxylic acid aqueous solution with the concentration of 50 wt%; then, dropwise adding triethylamine, wherein the dropwise adding time of the triethylamine is controlled to be 30-60 min; after the triethylamine is added dropwise, slowly adding isobutyraldehyde dropwise into the reaction solution at the temperature of 35-50 ℃, wherein the dropwise adding time of the isobutyraldehyde is controlled to be 120-240 min; after the isobutyraldehyde is dripped, carrying out aldol condensation reaction for 4-24 h at 50-80 ℃, preferably 60-70 ℃, and cooling to room temperature after the reaction is finished. Wherein the molar ratio of the glyoxylic acid to the isobutyraldehyde to the triethylamine is 1: 1-1.2: 1.05-1.5, preferably 1: 1-1.1: 1.05 to 1.3.
Adding a formaldehyde solution into a second reaction container in the step (2) for preparing the 2, 4-dihydroxy-3, 3-dimethylbutyrate, dropwise adding the reaction solution obtained in the step (1) at 0-30 ℃, maintaining the pH of the reaction mixture at 11-13.5 by using an alkali liquor, and carrying out a disproportionation reaction for 10-24 hours after dropwise adding is finished to convert the mixture into the 2, 4-dihydroxy-3, 3-dimethylbutyrate; after the reaction is finished, carrying out reduced pressure distillation on the reaction liquid at the temperature of 20-30 ℃ to remove low-boiling-point substances and triethylamine; wherein the alkali liquor is sodium hydroxide solution, potassium hydroxide solution or a mixture thereof.
Specifically, adding a formaldehyde aqueous solution, for example, a 35 wt% -40 wt% formaldehyde aqueous solution, into the second reaction vessel, dropwise adding the reaction solution obtained in the step (1) at 0-30 ℃, preferably at 5-25 ℃, further 10-25 ℃, controlling the dropwise adding time to be 60-240 minutes, simultaneously maintaining the pH of the reaction mixture to be 11-13.5, preferably 11-12 with an alkali liquor, and carrying out a disproportionation reaction for 10-24 hours after the dropwise adding is finished; after the reaction is finished, carrying out reduced pressure distillation on the reaction liquid at the temperature of 20-30 ℃ and under the vacuum degree of less than or equal to-0.08 MPa to remove low-boiling-point substances and triethylamine, wherein the low-boiling-point substances such as formaldehyde and isobutyraldehyde can be repeatedly utilized in the process of preparing the 2-hydroxy-3-methyl-3-formylbutyric acid after rectification and purification of the triethylamine, the salt generation in the step (3) can be greatly reduced by separating the triethylamine out of the reaction system in advance, and the side reaction in the step (3) under the strong acid condition can be effectively prevented by distilling out the formaldehyde and the isobutyraldehyde. And in the step, the dosage of the formaldehyde is that the molar ratio of the formaldehyde to the glyoxylic acid is 1-1.5: 1, preferably 1.2 to 1.4: 1.
in the step (3) for preparing D, L-pantolactone, the reaction solution obtained after the reduced pressure distillation in the step (2) is adjusted to pH 1-1.5 by acid, and cyclization reaction is carried out at 80-100 ℃ to generate D, L-pantolactone; and (3) adjusting the pH value of the cyclization reaction solution to be 5-8 by using alkali liquor at room temperature, extracting by using an organic solvent, and distilling an extract liquor under reduced pressure to obtain the D, L-pantolactone.
Specifically, adjusting the pH of the reaction solution obtained after the reduced pressure distillation in the step (2) to 1-1.5 by using acid, wherein the acid is concentrated sulfuric acid, concentrated hydrochloric acid or a mixture thereof, performing a cyclization reaction at 80-100 ℃, preferably 80-90 ℃ for 2-24 hours, preferably 2-10 hours, and then cooling to room temperature; and (2) at room temperature, adjusting the pH of the cyclization reaction solution to 5-8, preferably 5.5-6.5, extracting with an organic solvent, distilling the extract under normal pressure or reduced pressure, recovering the organic solvent, distilling under reduced pressure, and collecting the D, L-panthenoyl lactone fraction, wherein the recovered organic solvent can be reused in the extraction process. Wherein the alkali liquor is sodium hydroxide solution, potassium hydroxide solution, ammonia water or a mixture thereof; the organic solvent is dichloromethane, ethyl acetate or a mixture thereof, and has the characteristics of water insolubility and normal-pressure boiling point lower than 100 ℃.
The preparation process of the present invention is further illustrated in detail by the following examples, and the scope of the present invention is not limited to the following examples, which are given for illustrative purposes only and do not limit the present invention in any way.
Example 1
(1) Preparation of 2-hydroxy-3-methyl-3-formylbutyric acid
Adding 148.0g (1mol) of 50 wt% glyoxylic acid aqueous solution into a first reaction container at room temperature, dropwise adding 121.4g (1.2mol) of triethylamine, and controlling the dropwise adding time to be 30-40 min; slowly dropwise adding 75.7g (1.05mol) of isobutyraldehyde at the temperature of 45-50 ℃, controlling the dropwise adding time to be 120-130 min, and controlling the temperature to be 50-55 ℃ to perform aldol condensation reaction for 20 h;
(2) preparation of 2, 4-dihydroxy-3, 3-dimethylbutyrate
Adding 89.3g of 37 wt% formaldehyde solution (the molar ratio of formaldehyde to glyoxylic acid is 1.1) into a second reaction vessel, dropwise adding the reaction solution obtained in the step (1) at 15-20 ℃, reacting for 90 minutes while maintaining the pH of the reaction mixture at 11.0-11.5 with 32% sodium hydroxide solution, and carrying out disproportionation reaction for 24 hours to convert the mixture into 2, 4-dihydroxy-3, 3-dimethylbutyrate; after the reaction is finished, carrying out reduced pressure distillation on the reaction liquid at the temperature of 20-30 ℃ and the vacuum degree of-0.085 MPa to remove low-boiling-point substances and triethylamine;
(3) preparation of D, L-pantolactone
Regulating the pH of the reaction liquid obtained after the reduced pressure distillation in the step (2) to 1.0-1.5 by using 60% concentrated sulfuric acid, and performing cyclization reaction for 3 hours at the temperature of 80-85 ℃ to generate D, L-pantolactone; adjusting the pH of the cyclization reaction solution to 5.5 by using 32% sodium hydroxide solution at room temperature, extracting by using ethyl acetate, separating an ethyl acetate extraction phase, carrying out reduced pressure distillation under the vacuum degree controlled below-0.09 MPa, recovering the ethyl acetate, and collecting a D, L-panthenolide fraction to obtain 120.1g of D, L-panthenolide. The HPLC purity was 99.43% (see FIG. 1) and the yield was 92.3% by HPLC chromatography.
Example 2
(1) Preparation of 2-hydroxy-3-methyl-3-formylbutyric acid
At room temperature, 246.7g (1mol) of 30 wt% glyoxylic acid aqueous solution is added into a first reaction container, 111.3g (1.1mol) of triethylamine is dropwise added, and the dropwise adding time is controlled to be 30-40 min; then, slowly dripping 86.5g (1.2mol) of isobutyraldehyde at the temperature of 40-45 ℃, controlling the dripping time to be 180-190 min, and controlling the temperature to be 60-65 ℃ to carry out aldol condensation reaction for 15 h;
(2) preparation of 2, 4-dihydroxy-3, 3-dimethylbutyrate
Adding 105.5g of 37 wt% formaldehyde solution (the molar ratio of formaldehyde to glyoxylic acid is 1.3) into a second reaction vessel, dropwise adding the reaction solution obtained in the step (1) at the temperature of between 20 and 25 ℃ for 120 minutes, maintaining the pH of the reaction mixture at 11.0 to 11.5 by using 32% sodium hydroxide solution, and carrying out disproportionation reaction for 15 hours to convert the mixture into 2, 4-dihydroxy-3, 3-dimethylbutyrate; after the reaction is finished, carrying out reduced pressure distillation on the reaction liquid at the temperature of 20-30 ℃ and the vacuum degree of-0.085 MPa to remove low-boiling-point substances and triethylamine;
(3) preparation of D, L-pantolactone
Regulating the pH of the reaction liquid obtained after the reduced pressure distillation in the step (2) to 1.3-1.5 by using 60% concentrated sulfuric acid, and performing cyclization reaction for 5 hours at the temperature of 80-85 ℃ to generate D, L-pantolactone; adjusting the pH of the cyclization reaction solution to 6.5 with 18% ammonia water at room temperature, extracting with ethyl acetate to separate an ethyl acetate extraction phase, carrying out reduced pressure distillation under the vacuum degree controlled below-0.09 MPa, recovering ethyl acetate, and collecting a D, L-panthenoyl lactone fraction to obtain 119.6g of D, L-panthenoyl lactone. HPLC purity was 99.36% (see fig. 2) and yield was 91.9% by HPLC chromatography.
Example 3
(1) Preparation of 2-hydroxy-3-methyl-3-formylbutyric acid
Adding 185.0g (1mol) of 40 wt% glyoxylic acid aqueous solution into a first reaction container at room temperature, dropwise adding 121.4g (1.2mol) of triethylamine, and controlling the dropwise adding time to be 40-50 min; slowly dropwise adding 75.7g (1.05mol) of isobutyraldehyde at the temperature of 35-40 ℃, controlling the dropwise adding time to be 140-150 min, and controlling the temperature to be 65-70 ℃ to perform aldol condensation reaction for 17 h;
(2) preparation of 2, 4-dihydroxy-3, 3-dimethylbutyrate
Adding 105.5g of 37 wt% formaldehyde solution (the molar ratio of formaldehyde to glyoxylic acid is 1.3) into a second reaction vessel, dropwise adding the reaction solution obtained in the step (1) at 15-20 ℃, reacting for 240 minutes while maintaining the pH of the reaction mixture at 11.5-12.0 by using 32% sodium hydroxide solution, and carrying out disproportionation reaction for 24 hours to convert the mixture into 2, 4-dihydroxy-3, 3-dimethylbutyrate; after the reaction is finished, carrying out reduced pressure distillation on the reaction liquid at the temperature of 20-30 ℃ and the vacuum degree of-0.085 MPa to remove low-boiling-point substances and triethylamine;
(3) preparation of D, L-pantolactone
Regulating the pH of the reaction solution obtained after the reduced pressure distillation in the step (2) to 1.0-1.2 by using 36% concentrated hydrochloric acid, and performing cyclization reaction for 10 hours at the temperature of 80-85 ℃ to generate D, L-pantolactone; at room temperature, the pH of the cyclization reaction solution was adjusted to 6.0 with 32% sodium hydroxide solution, and then extracted with ethyl acetate to separate an ethyl acetate extract phase, vacuum distilled under-0.09 MPa, after recovering ethyl acetate, the D, L-pantoyl lactone fraction was collected to obtain 117.5g of D, L-pantoyl lactone. The HPLC purity was 99.44% (see fig. 3) and the yield was 90.3% by HPLC chromatography.
Example 4
(1) Preparation of 2-hydroxy-3-methyl-3-formylbutyric acid
Adding 148.0g (1mol) of 50 wt% glyoxylic acid aqueous solution into a first reaction container at room temperature, dropwise adding 151.7g (1.5mol) of triethylamine, and controlling the dropwise adding time to be 50-60 min; then, slowly dropwise adding 86.5g (1.2mol) of isobutyraldehyde at the temperature of 45-50 ℃, controlling the dropwise adding time to be 200-230 min, and controlling the temperature to be 50-55 ℃ to perform aldol condensation reaction for 20 h;
(2) preparation of 2, 4-dihydroxy-3, 3-dimethylbutyrate
Adding 121.8g of 37 wt% formaldehyde solution (the molar ratio of formaldehyde to glyoxylic acid is 1.5) into a second reaction vessel, dropwise adding the reaction solution obtained in the step (1) at the temperature of between 20 and 25 ℃ for 150 minutes, maintaining the pH of the reaction mixture at 11.0 to 11.5 by using 32% sodium hydroxide solution, and carrying out disproportionation reaction for 10 hours to convert the mixture into 2, 4-dihydroxy-3, 3-dimethylbutyrate; after the reaction is finished, carrying out reduced pressure distillation on the reaction liquid at the temperature of 20-30 ℃ and the vacuum degree of-0.08 MPa to remove low-boiling-point substances and triethylamine;
(3) preparation of D, L-pantolactone
Regulating the pH of the reaction liquid obtained after the reduced pressure distillation in the step (2) to 1.0-1.2 by using 60% concentrated sulfuric acid, and performing cyclization reaction for 2 hours at the temperature of 90-95 ℃ to generate D, L-pantolactone; adjusting the pH of the cyclization reaction solution to 7.0 by using 32% sodium hydroxide solution at room temperature, extracting by using dichloromethane, separating a dichloromethane extraction phase, distilling at normal pressure, recovering dichloromethane, carrying out reduced pressure distillation under the condition that the vacuum degree is controlled to be below-0.09 MPa, and collecting D, L-panthenoyl lactone fraction to obtain 120.5g of D, L-panthenoyl lactone. HPLC purity was 99.54% (see fig. 4) and yield was 92.6% by HPLC chromatography.
Example 5
(1) Preparation of 2-hydroxy-3-methyl-3-formylbutyric acid
Adding 148.0g (1mol) of 50 wt% glyoxylic acid aqueous solution into a first reaction container at room temperature, dropwise adding 121.4g (1.2mol) of triethylamine, and controlling the dropwise adding time to be 50-60 min; slowly dropwise adding 75.7g (1.05mol) of isobutyraldehyde at the temperature of 45-50 ℃, controlling the dropwise adding time to be 200-230 min, and controlling the temperature to be 70-80 ℃ to perform aldol condensation reaction for 5 h;
(2) preparation of 2, 4-dihydroxy-3, 3-dimethylbutyrate
Adding 121.8g of 37 wt% formaldehyde solution (the molar ratio of formaldehyde to glyoxylic acid is 1.5) into a second reaction vessel, dropwise adding the reaction solution obtained in the step (1) at 15-20 ℃, reacting for 60 minutes while maintaining the pH of the reaction mixture at 11.0-11.5 with 32% sodium hydroxide solution, and carrying out disproportionation reaction for 23 hours to convert the mixture into 2, 4-dihydroxy-3, 3-dimethylbutyrate; after the reaction is finished, carrying out reduced pressure distillation on the reaction liquid at the temperature of 20-30 ℃ and the vacuum degree of-0.08 MPa to remove low-boiling-point substances and triethylamine;
(3) preparation of D, L-pantolactone
Regulating the pH of the reaction liquid obtained after the reduced pressure distillation in the step (2) to 1.3-1.5 by using 60% concentrated sulfuric acid, and performing cyclization reaction for 3 hours at the temperature of 80-85 ℃ to generate D, L-pantolactone; adjusting the pH of the cyclization reaction solution to 5.5 with 32% sodium hydroxide solution at room temperature, extracting with ethyl acetate to separate an ethyl acetate extraction phase, carrying out reduced pressure distillation under the vacuum degree controlled below-0.09 MPa, recovering ethyl acetate, and collecting D, L-panthenoyl lactone fraction to obtain 122g of D, L-panthenoyl lactone. HPLC purity was 99.38% (see fig. 5) and yield was 93.8% by HPLC chromatography.
Claims (9)
1. A method for preparing D, L-pantolactone, comprising the steps of:
(1) preparation of 2-hydroxy-3-methyl-3-formylbutyric acid
Adding a glyoxylic acid aqueous solution into a first reaction container, dropwise adding triethylamine, and then dropwise adding isobutyraldehyde at the temperature of 35-50 ℃; after the isobutyraldehyde is dripped, carrying out aldol condensation reaction at 50-80 ℃ for 4-24 h to generate 2-hydroxy-3-methyl-3-formylbutyric acid;
(2) preparation of 2, 4-dihydroxy-3, 3-dimethylbutyrate
Adding a formaldehyde solution into a second reaction container, dropwise adding the reaction solution obtained in the step (1) at the temperature of 0-30 ℃, simultaneously maintaining the pH value of the reaction mixture to be 11-13.5 by using an alkali liquor, and carrying out a disproportionation reaction for 10-24 h after the dropwise adding is finished to convert the reaction mixture into 2, 4-dihydroxy-3, 3-dimethylbutyrate; after the reaction is finished, carrying out reduced pressure distillation on the reaction liquid at the temperature of 20-30 ℃ to remove low-boiling-point substances and triethylamine; wherein the alkali liquor is sodium hydroxide solution, potassium hydroxide solution or a mixture thereof;
(3) preparation of D, L-pantolactone
Adjusting the pH of the reaction solution obtained after the reduced pressure distillation in the step (2) to 1-1.5 by using acid, and performing cyclization reaction at the temperature of 80-100 ℃ to generate D, L-pantolactone; and (3) adjusting the pH value of the cyclization reaction solution to be 5-8 by using alkali liquor at room temperature, extracting by using an organic solvent, and distilling an extract liquor under reduced pressure to obtain the D, L-pantolactone.
2. The process according to claim 1, wherein the step of preparing 2-hydroxy-3-methyl-3-formylbutyric acid in the step (1) comprises adding an aqueous solution of glyoxylic acid having a concentration of 30 to 50 wt.% to a first reaction vessel at room temperature; then, dropwise adding triethylamine, wherein the dropwise adding time of the triethylamine is controlled to be 30-60 min; after the triethylamine is added dropwise, slowly adding isobutyraldehyde dropwise into the reaction solution at the temperature of 35-50 ℃, wherein the dropwise adding time of the isobutyraldehyde is controlled to be 120-240 min.
3. The process for producing D, L-pantolactone according to claim 1, wherein in the production of 2-hydroxy-3-methyl-3-formylbutyric acid in the step (1), the molar ratio of glyoxylic acid, isobutyraldehyde and triethylamine is 1: 1-1.2: 1.05 to 1.5.
4. The method for preparing D, L-pantolactone according to claim 1, wherein in the preparation of 2-hydroxy-3-methyl-3-formylbutyric acid in the step (1), aldol condensation is performed at 60 to 70 ℃ for 4 to 24 hours after isobutyraldehyde is added dropwise, and the temperature is reduced to room temperature after the reaction.
5. The process according to claim 1, wherein the 2, 4-dihydroxy-3, 3-dimethylbutyrate is prepared by adding a 35-40 wt% aqueous solution of formaldehyde to a second reaction vessel, dropping the reaction mixture of step (1) at 5-25 ℃ for 60-240 minutes while maintaining the pH of the reaction mixture at 11-12 with an alkali solution.
6. The process for producing D, L-pantolactone according to claim 1, wherein in the production of 2, 4-dihydroxy-3, 3-dimethylbutyrate in the step (2), after completion of the reaction, the reaction mixture is distilled under reduced pressure at 20 ℃ to 30 ℃ under a vacuum degree of not more than-0.08 MPa to remove low boiling substances and triethylamine.
7. The process for producing D, L-pantolactone according to claim 1, wherein in the production of 2, 4-dihydroxy-3, 3-dimethylbutyrate in the step (2), formaldehyde is used in such an amount that the molar ratio of formaldehyde to glyoxylic acid is 1 to 1.5: 1.
8. the process according to claim 1, wherein in the production of D, L-pantolactone according to the step (3), the reaction solution obtained by the distillation under reduced pressure in the step (2) is subjected to a cyclization reaction at 80 to 90 ℃ for 2 to 10 hours with an acid such as concentrated sulfuric acid, concentrated hydrochloric acid or a mixture thereof to adjust the pH to 1 to 1.5, and then cooled to room temperature.
9. The process according to claim 1, wherein in the production of D, L-pantolactone according to the step (3), a pH of a cyclization reaction solution is adjusted to 5.5 to 6.5 with an alkali solution at room temperature, and then an organic solvent is used for extraction, and an extract is subjected to distillation under normal pressure or reduced pressure to recover the organic solvent, and then the organic solvent is subjected to distillation under reduced pressure to collect a D, L-pantolactone fraction; wherein the alkali liquor is sodium hydroxide solution, potassium hydroxide solution, ammonia water or a mixture thereof; the organic solvent is dichloromethane, ethyl acetate or a mixture thereof.
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