CN113816932B - Synthesis of keto pantolactone - Google Patents
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- CN113816932B CN113816932B CN202111198100.6A CN202111198100A CN113816932B CN 113816932 B CN113816932 B CN 113816932B CN 202111198100 A CN202111198100 A CN 202111198100A CN 113816932 B CN113816932 B CN 113816932B
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Abstract
The invention provides a synthesis method of keto pantolactone, which comprises the following steps: step 1, performing aldol condensation reaction on isobutyraldehyde and oxalic acid chlorine monoethyl ester under the action of sodium alkoxide to generate 3, 3-dimethyl-2, 4-dioxo ethyl butyrate; and 2, selectively reducing aldehyde groups in the 3, 3-dimethyl-2, 4-dioxo ethyl butyrate by using borohydride, and then acidifying to generate the keto-pantolactone.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of keto-pantolactone.
Background
The calcium D-pantothenate, commonly known as vitamin B5, has the chemical name of D- (+) -N- (2, 4-dihydroxy-3, 3-dimethylbutyryl) -beta-aminopropionate, is white powder with slight bitter taste, and is an important food and feed additive. The main route for preparing D-calcium pantothenate is to obtain D-pantolactone by biological or chemical resolution of D, L-pantolactone, then react with beta-aminopropionic acid to obtain D-pantoic acid, and calcify to prepare D-calcium pantothenate, or prepare D, L-calcium pantothenate and then split to obtain D-calcium pantothenate. At present, the following four methods are mainly used for the synthesis process of D, L-pantolactone:
the isobutyraldehyde-formaldehyde-hydrogen cyanide synthesis route reported in U.S. Pat. No. 4,4200582 has many reaction steps, is easy to generate other side reactions, and has poor reproducibility.
U.S. Pat. No. 4,000,82 reports a synthesis route of isobutyraldehyde-aldehyde acetic acid, which avoids the use of highly toxic hydrocyanic acid, but the aldehyde acetic acid is expensive and the production cost is high.
The isobutyraldehyde-chloroform synthesis route reported in (III) U.S. Pat. No. 4200582 has the advantages of no use of hydrocyanic acid, easily available and cheap raw materials, but the disproportionation reaction of aldehyde group under strong alkaline condition easily occurs, and the yield is low.
The isobutyraldehyde-oxalyl chloride monoethyl ester synthesis route reported in (four) us patent 4200582, which departs from the highly toxic hydrocyanic acid and is attractive, but the hydrogenation process requires noble metals.
The four synthetic routes all generate half of the inactive L-pantolactone, so that the research and development of the green and environment-friendly low-cost D-pantolactone synthetic method has important significance for green industrial production of the D-calcium pantothenate. The key point of D-pantolactone lies in the synthesis of ketopantolactone raw material, so that the research and development of a method for synthesizing ketopantolactone, which is green and environment-friendly, simple and convenient to operate and low in cost, has important significance for green industrial production of D-calcium pantothenate.
Disclosure of Invention
The present invention has been made to solve the above problems, and an object of the present invention is to provide a method for synthesizing ketopantolactone, which is environmentally friendly, safe and simple to operate, and low in cost.
The invention provides a synthesis method of keto pantolactone, which is characterized by comprising the following steps: step 1, performing aldol condensation reaction on isobutyraldehyde and oxalic acid chlorine monoethyl ester under the action of sodium alkoxide to generate 3, 3-dimethyl-2, 4-dioxo ethyl butyrate;
and 2, selectively reducing aldehyde groups in the 3, 3-dimethyl-2, 4-dioxo ethyl butyrate by using borohydride, and then acidifying to generate the ketopantolactone.
The reaction equation for the synthetic route is as follows:
further, the method for synthesizing ketopantolactone of the present invention may have the following characteristics: the molar ratio of the sodium alkoxide to the isobutyraldehyde is (1-2): 1; the mol ratio of isobutyraldehyde to oxalic acid chloro-monoethyl ester is (1-2): 1; the mass ratio of the solvent used in the reaction in the step 1 to isobutyraldehyde is (3-5): 1.
further, the method for synthesizing ketopantolactone of the present invention may have the following characteristics: in the step 1, the reaction temperature is-20 ℃ to 60 ℃, and the reaction time is 6 hours to 12 hours. Optimally, the reaction temperature is-20 ℃ to 20 ℃, and the reaction time is 8 hours to 10 hours.
Further, the method for synthesizing ketopantolactone of the present invention may have the following characteristics: the molar ratio of the borohydride to the ethyl 3, 3-dimethyl-2, 4-dioxobutyrate prepared in the step 1 is (1.0-5.0): 1;
the mass ratio of the solvent used in the reaction in the step 2 to the 3, 3-dimethyl-2, 4-dioxoethyl butyrate prepared in the step 1 is (2-4): 1;
in the acidification step in the step 2, the PH of the reaction solution is adjusted to 1-3.
Most preferably, the molar ratio of borohydride to ethyl 3, 3-dimethyl-2, 4-dioxobutyrate prepared in step 1 is (1.5-3.0): 1
Further, the method for synthesizing ketopantolactone provided by the present invention may further have the following characteristics: when borohydride is selected to selectively reduce aldehyde group in 3, 3-dimethyl-2, 4-dioxo ethyl butyrate, the reaction temperature is-20 ℃ to 20 ℃, the reaction time is 4 hours to 6 hours,
during acidification, the PH of the reaction solution is adjusted to 1-3, then the temperature is raised to 35-45 ℃, and the reaction is stirred for 1 hour.
Optimally, when borohydride is selected to selectively reduce aldehyde groups in the 3, 3-dimethyl-2, 4-dioxo ethyl butyrate, the reaction temperature is-10 ℃ to 0 ℃.
Further, the method for synthesizing ketopantolactone provided by the present invention may further have the following characteristics: the sodium alkoxide is one or more of sodium methoxide, sodium ethoxide and sodium isopropoxide;
the solvent used in the reaction in the step 1 is one or more of tetrahydrofuran, dioxane and methyl tetrahydrofuran;
the solvent used in the reaction in the step 2 is one or more of polyethylene glycol 400, polyethylene glycol 600 and polyethylene glycol 800;
the reagent used in the acidification step in the step 2 is one or more of hydrochloric acid, sulfuric acid and acetic acid;
the borohydride is one or two of sodium borohydride and potassium borohydride.
Further, the method for synthesizing ketopantolactone provided by the present invention may further have the following characteristics: in step 1, after the reaction is completed, the step of separating the product ethyl 3, 3-dimethyl-2, 4-dioxobutyrate in the reaction solution is as follows: recovering the solvent used in the step 1 under reduced pressure, extracting and washing with ethyl acetate and water, washing the separated organic phase with saturated saline solution, drying the separated organic phase with anhydrous sodium sulfate, and then recovering ethyl acetate under reduced pressure to obtain colorless oily 3, 3-dimethyl-2, 4-dioxobutyric acid ethyl ester;
in step 2, after the reaction is completed, the step of separating the keto pantolactone from the reaction solution is as follows: cooling the reaction liquid, extracting and washing with ethyl acetate and water, washing the separated organic phase with saturated salt solution, drying the separated organic phase with anhydrous sodium sulfate, then recovering ethyl acetate under reduced pressure, and finally recrystallizing with carbon tetrachloride to obtain white solid ketopantolactone.
The present invention provides the following advantages:
the synthesis method of the ketopantolactone is environment-friendly, safe and simple to operate and low in cost. As a raw material for synthesizing D-pantolactone, keto-pantolactone can be directly synthesized into D-pantolactone by chiral catalysis, compared with the existing D, L-pantolactone process, the method can obviously reduce energy consumption, production time, cost and three wastes, successfully solves the problems of strong raw material toxicity and the like existing in the existing D, L-pantolactone synthesis process for a long time, and has good industrial practicability.
Drawings
FIG. 1 is a NMR spectrum of a product of example one of the present invention;
FIG. 2 is the NMR spectrum of the product of example one of the present invention.
Detailed Description
In order to make the technical means, the creation features, the achievement purposes and the effects of the invention easy to understand, the following embodiments are specifically described in the synthesis method of the ketopantolactone of the invention with reference to the attached drawings.
< example one >
The synthesis method of keto pantolactone comprises the following steps:
step 1: preparation of ethyl 3, 3-dimethyl-2, 4-dioxobutyrate
Under the nitrogen atmosphere, 54 g of sodium methoxide and 300 g of tetrahydrofuran are added into a 1L four-mouth bottle, the mixture is stirred and cooled to 0 ℃, 72 g of isobutyraldehyde is added, then 136 g of oxalyl chloride monoethyl ester is added dropwise, the temperature of the reaction solution is controlled at 0 ℃, and the stirring is continued for 6 hours after the dropwise addition. After the reaction was completed, tetrahydrofuran was recovered under reduced pressure, extracted and washed with ethyl acetate and water, the separated organic phase was washed with saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, and ethyl acetate was recovered under reduced pressure to give 150 g of ethyl 3, 3-dimethyl-2, 4-dioxobutyrate as a colorless oily substance, which was used in the next reaction without purification.
Step 2: preparation of ketopantolactone
Dissolving the 3, 3-dimethyl-2, 4-dioxo-ethyl butyrate prepared in the step 1 in 450 g of polyethylene glycol 400, reducing the temperature of the reaction solution to 0 ℃, then adding 50 g of sodium borohydride in batches, continuously stirring for 4h after the reaction is finished, adjusting the pH value to about 2 (the error is +/-1, namely the pH value can be 1-3) by using concentrated hydrochloric acid, and stirring for 1h after the temperature is increased to 40 ℃. After the reaction, the temperature is reduced, ethyl acetate and water are used for extraction washing, the separated organic phase is washed by saturated saline, the separated organic phase is dried by anhydrous sodium sulfate, ethyl acetate is recovered under reduced pressure, and then carbon tetrachloride is used for recrystallization to obtain 92 g of white solid ketopantolactone.
The overall reaction yield was 71.8%.
< example two >
The synthesis method of the keto pantolactone comprises the following steps:
step 1: preparation of ethyl 3, 3-dimethyl-2, 4-dioxobutyrate
Under the nitrogen atmosphere, 136 g of sodium ethoxide and 216 g of tetrahydrofuran are added into a 1L four-mouth bottle, the stirring is carried out, the temperature is adjusted to 20 ℃, 72 g of isobutyraldehyde is added, then 68 g of oxalyl chloride monoethyl ester is added dropwise, the temperature of the reaction solution is controlled to be 20 ℃, and the stirring is continued for 8 hours after the dropwise addition. After the reaction was completed, tetrahydrofuran was recovered under reduced pressure, extracted and washed with ethyl acetate and water, the separated organic phase was washed with saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, and ethyl acetate was recovered under reduced pressure to give 71 g of ethyl 3, 3-dimethyl-2, 4-dioxobutyrate as a colorless oily substance, which was used in the next reaction without purification.
Step 2: preparation of ketopantolactone
Dissolving the 3, 3-dimethyl-2, 4-dioxoethyl butyrate prepared in the step 1 in 284 g of polyethylene glycol 400, cooling the temperature of the reaction solution to-10 ℃, then adding 30 g of sodium borohydride in batches, continuously stirring for 5h after the reaction is finished, adjusting the pH to about 2 (the error is +/-1, namely the pH can be 1-3) by using sulfuric acid, and heating to 35 ℃ and stirring for 1h. After the reaction is finished, cooling, extracting and washing by using ethyl acetate and water, washing the separated organic phase by using saturated saline, drying the separated organic phase by using anhydrous sodium sulfate, recovering ethyl acetate under reduced pressure, and recrystallizing by using carbon tetrachloride to obtain 40 g of white solid ketopantolactone.
The overall yield of the reaction was 62.5%.
< example three >
The synthesis method of keto pantolactone comprises the following steps:
step 1: preparation of ethyl 3, 3-dimethyl-2, 4-dioxobutyrate
Under the nitrogen atmosphere, 123 g of sodium isopropoxide and 360 g of methyl tetrahydrofuran are added into a 1L four-mouth bottle, the mixture is stirred, the temperature is heated to 60 ℃, 72 g of isobutyraldehyde is added, then 90 g of oxalyl chloride monoethyl ester is added dropwise, the temperature of the reaction solution is controlled to be 60 ℃, and the stirring is continued for 10 hours after the dropwise addition. After the reaction was completed, methyltetrahydrofuran was recovered under reduced pressure, extracted and washed with ethyl acetate and water, the separated organic phase was washed with saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, and ethyl acetate was recovered under reduced pressure to give 56 g of ethyl 3, 3-dimethyl-2, 4-dioxobutyrate as a colorless oily substance, which was used in the next reaction without purification.
Step 2: preparation of ketopantolactone
Dissolving the 3, 3-dimethyl-2, 4-dioxo-ethyl butyrate prepared in the step 1 in 112 g of polyethylene glycol 600, reducing the temperature of the reaction solution to-5 ℃, then adding 36 g of sodium borohydride in batches, continuously stirring for 4h after the reaction is finished, adjusting the pH value to about 2 (the error is +/-1, namely the pH value can be 1-3) by using acetic acid, and stirring for 1h after the temperature is increased to 45 ℃. After the reaction, the temperature is reduced, ethyl acetate and water are used for extraction washing, the separated organic phase is washed by saturated saline, the separated organic phase is dried by anhydrous sodium sulfate, ethyl acetate is recovered under reduced pressure, and then carbon tetrachloride is used for recrystallization to obtain 33 g of white solid ketopantolactone.
The overall reaction yield was 39.1%.
< example four >
The synthesis method of the keto pantolactone comprises the following steps:
step 1: preparation of ethyl 3, 3-dimethyl-2, 4-dioxobutyrate
Under the nitrogen atmosphere, 54 g of sodium methoxide and 300 g of tetrahydrofuran are added into a 1L four-mouth bottle, the stirring is carried out, the temperature is adjusted to-20 ℃, 72 g of isobutyraldehyde is added, then 136 g of oxalyl chloride monoethyl ester is added dropwise, the temperature of the reaction solution is controlled to-20 ℃, and the stirring is continued for 12 hours after the dropwise addition. After the reaction was completed, tetrahydrofuran was recovered under reduced pressure, extracted and washed with ethyl acetate and water, the separated organic phase was washed with saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, and ethyl acetate was recovered under reduced pressure to obtain 145 g of ethyl 3, 3-dimethyl-2, 4-dioxobutyrate as a colorless oily substance which was used in the next reaction without purification.
Step 2: preparation of ketopantolactone
Dissolving the 3, 3-dimethyl-2, 4-dioxo-ethyl butyrate prepared in the step 1 in 450 g of polyethylene glycol 400, reducing the temperature of the reaction solution to-20 ℃, then adding 45 g of potassium borohydride in batches, continuously stirring for 6h after the reaction is finished, adjusting the pH value to about 2 (the error is +/-1, namely the pH value can be 1-3) by using concentrated hydrochloric acid, and stirring for 1h after the temperature is increased to 40 ℃. After the reaction is finished, cooling, extracting and washing by using ethyl acetate and water, washing the separated organic phase by using saturated saline, drying the separated organic phase by using anhydrous sodium sulfate, recovering ethyl acetate under reduced pressure, and recrystallizing by using carbon tetrachloride to obtain 79 g of white solid ketopantolactone.
The overall reaction yield was 61.7%.
< example five >
The synthesis method of the keto pantolactone comprises the following steps:
step 1: preparation of ethyl 3, 3-dimethyl-2, 4-dioxobutyrate
Under the nitrogen atmosphere, 54 g of sodium methoxide and 300 g of tetrahydrofuran are added into a 1L four-mouth bottle, the stirring is carried out, the temperature is adjusted to-10 ℃, 72 g of isobutyraldehyde is added, then 136 g of oxalyl chloride monoethyl ester is added dropwise, the temperature of the reaction solution is controlled to-10 ℃, and the stirring is continued for 9h after the dropwise addition. After the reaction was completed, tetrahydrofuran was recovered under reduced pressure, extracted and washed with ethyl acetate and water, the separated organic phase was washed with saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, and ethyl acetate was recovered under reduced pressure to obtain 147 g of ethyl 3, 3-dimethyl-2, 4-dioxobutyrate as a colorless oily substance, which was used in the next reaction without purification.
Step 2: preparation of ketopantolactone
Dissolving the 3, 3-dimethyl-2, 4-dioxo-ethyl butyrate prepared in the step 1 in 450 g of polyethylene glycol 400, adjusting the temperature of the reaction solution to 20 ℃, then adding 158 g of potassium borohydride in batches, continuously stirring for 4h after the completion, adjusting the pH value to about 2 (the error is +/-1, namely the pH value can be 1-3) by using concentrated hydrochloric acid, and stirring for 1h after the temperature is raised to 40 ℃. After the reaction is finished, cooling, extracting and washing by using ethyl acetate and water, washing the separated organic phase by using saturated saline, drying the separated organic phase by using anhydrous sodium sulfate, recovering ethyl acetate under reduced pressure, and recrystallizing by using carbon tetrachloride to obtain 75 g of white solid ketopantolactone.
The overall reaction yield was 58.5%.
< example six >
Step 1: preparation of ethyl 3, 3-dimethyl-2, 4-dioxobutyrate
Under the nitrogen atmosphere, 54 g of sodium methoxide and 300 g of dioxane are added into a 1L four-mouth bottle, the temperature is reduced to 0 ℃ by stirring, 72 g of isobutyraldehyde is added, then 136 g of oxalyl chloride monoethyl ester is added dropwise, the temperature of the reaction solution is controlled to be about 0 ℃, and stirring is continued for 6 hours after the dropwise addition. Tetrahydrofuran was recovered under reduced pressure, extracted and washed with ethyl acetate and water, the separated organic phase was washed with saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, and ethyl acetate was recovered under reduced pressure to give 120 g of ethyl 3, 3-dimethyl-2, 4-dioxobutyrate as a colorless oily substance, which was used in the next reaction without purification.
Step 2: preparation of ketopantolactone
Dissolving the 3, 3-dimethyl-2, 4-dioxo-ethyl butyrate prepared in the step 1 in 360 g of polyethylene glycol 400, reducing the temperature of the reaction solution to 0 ℃, then adding 40 g of sodium borohydride in batches, continuously stirring for 4h after the reaction is finished, adjusting the pH value to about 2 (the error is +/-1, namely the pH value can be 1-3) by using concentrated hydrochloric acid, and stirring for 1h after the temperature is increased to 40 ℃. After the reaction is finished, cooling, extracting and washing by using ethyl acetate and water, washing the separated organic phase by using saturated saline, drying the separated organic phase by using anhydrous sodium sulfate, recovering ethyl acetate under reduced pressure, and recrystallizing by using carbon tetrachloride to obtain 72 g of white solid ketopantolactone.
The total reaction yield was 56.2%.
< example seven >
Step 1: preparation of ethyl 3, 3-dimethyl-2, 4-dioxobutyrate
Under the nitrogen atmosphere, 54 g of sodium methoxide and 300 g of tetrahydrofuran are added into a 1L four-mouth bottle, the mixture is stirred and cooled to 0 ℃, 72 g of isobutyraldehyde is added, then 136 g of oxalyl chloride monoethyl ester is added dropwise, the temperature of the reaction solution is controlled at 0 ℃, and the stirring is continued for 6 hours after the dropwise addition. After the reaction, tetrahydrofuran was recovered under reduced pressure, extracted and washed with ethyl acetate and water, the separated organic phase was washed with saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, and ethyl acetate was recovered under reduced pressure to give 150 g of ethyl 3, 3-dimethyl-2, 4-dioxobutyrate as a colorless oily substance, which was used in the next reaction without purification.
And 2, step: preparation of ketopantolactone
Dissolving the 3, 3-dimethyl-2, 4-dioxo-ethyl butyrate prepared in the step 1 in 450 g of polyethylene glycol 800, reducing the temperature of the reaction solution to 0 ℃, then adding 50 g of sodium borohydride in batches, continuously stirring for 4h after the reaction is finished, adjusting the pH value to about 2 (the error is +/-1, namely the pH value can be 1-3) by using concentrated hydrochloric acid, and stirring for 1h after the temperature is increased to 40 ℃. After the reaction is finished, cooling, extracting and washing by ethyl acetate and water, washing the separated organic phase by saturated saline, drying the separated organic phase by anhydrous sodium sulfate, recovering ethyl acetate under reduced pressure, and recrystallizing by carbon tetrachloride to obtain 85 g of white solid ketopantolactone.
The overall reaction yield was 66.3%.
< example eight >
Step 1: preparation of ethyl 3, 3-dimethyl-2, 4-dioxobutyrate
Under the nitrogen atmosphere, 54 g of sodium methoxide and 300 g of tetrahydrofuran are added into a 1L four-mouth bottle, the mixture is stirred and heated to 40 ℃, 72 g of isobutyraldehyde is added, then 136 g of oxalyl chloride monoethyl ester is added in a dropwise manner, the temperature of the reaction solution is controlled to be 40 ℃ by a water bath, and the stirring is continued for 6h after the dropwise addition. After the reaction was completed, tetrahydrofuran was recovered under reduced pressure, extracted and washed with ethyl acetate and water, the separated organic phase was washed with saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, and ethyl acetate was recovered under reduced pressure to obtain 90 g of ethyl 3, 3-dimethyl-2, 4-dioxobutyrate as a colorless oily substance which was used in the next reaction without purification.
Step 2: preparation of ketopantolactone
Dissolving the 3, 3-dimethyl-2, 4-dioxo-ethyl butyrate prepared in the step 1 in 270 g of polyethylene glycol 400, reducing the temperature of the reaction solution to 0 ℃, then adding 30 g of sodium borohydride in batches, continuously stirring for 4h after the reaction is finished, adjusting the pH value to about 2 (the error is +/-1, namely the pH value can be 1-3) by using concentrated hydrochloric acid, and stirring for 1h after the temperature is increased to 40 ℃. After the reaction is finished, cooling, extracting and washing by ethyl acetate and water, washing the separated organic phase by saturated saline, drying the separated organic phase by anhydrous sodium sulfate, recovering ethyl acetate under reduced pressure, and recrystallizing by carbon tetrachloride to obtain 55 g of white solid ketopantolactone.
The total reaction yield was 42.9%.
< example nine >
Step 1: preparation of ethyl 3, 3-dimethyl-2, 4-dioxobutyrate
Adding 80 g of sodium methoxide and 300 g of tetrahydrofuran into a 1L four-mouth bottle under the nitrogen atmosphere, stirring and cooling to 0 ℃, adding 72 g of isobutyraldehyde, then dripping 136 g of oxalyl chloride monoethyl ester, controlling the temperature of the reaction solution at about 0 ℃, and continuously stirring for 6h after dripping. After the reaction was completed, tetrahydrofuran was recovered under reduced pressure, extracted and washed with ethyl acetate and water, the separated organic phase was washed with saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, and ethyl acetate was recovered under reduced pressure to obtain 140 g of ethyl 3, 3-dimethyl-2, 4-dioxobutyrate as a colorless oily substance, which was used in the next reaction without purification.
Step 2: preparation of ketopantolactone
Dissolving the 3, 3-dimethyl-2, 4-dioxo-ethyl butyrate prepared in the step 1 in 420 g of polyethylene glycol 400, reducing the temperature of the reaction solution to 0 ℃, then adding 47 g of sodium borohydride in batches, continuously stirring for 4h after the reaction is finished, adjusting the pH value to about 2 (the error is +/-1, namely the pH value can be 1-3) by using concentrated hydrochloric acid, and stirring for 1h after the temperature is increased to 40 ℃. After the reaction is finished, cooling, extracting and washing by using ethyl acetate and water, washing the separated organic phase by using saturated saline, drying the separated organic phase by using anhydrous sodium sulfate, recovering ethyl acetate under reduced pressure, and recrystallizing by using carbon tetrachloride to obtain 90 g of white solid ketopantolactone.
The overall yield of the reaction was 70.2%.
Nuclear magnetic resonance was performed on the products of examples one through nine. NMR was measured by Bruker NMR. Through detection, the products in all the first to ninth examples are ketopantolactone.
The NMR data and spectra in example one are provided herein, with the NMR spectra in example one being shown in figures 1 and 2, and the NMR data in example one being shown below:
1 HNMR(400MHz,CDCl 3 ):δ＝1.32(s,6H),4.46(s,2H)； 13 CNMR(100MHz,CDCl 3 ):δ＝22.17,41.86,160.49,198.11。
the process for the synthesis of ketopantolactone according to the invention is not limited to the scope of the specific examples. The above description is only a basic description of the present invention, and any equivalent changes made according to the technical solution of the present invention should fall within the protection scope of the present invention.
Claims (10)
1. A method for synthesizing ketopantolactone, comprising the steps of:
step 1, performing aldol condensation reaction on isobutyraldehyde and oxalic acid chlorine monoethyl ester under the action of sodium alkoxide to generate 3, 3-dimethyl-2, 4-dioxo ethyl butyrate;
and 2, selectively reducing aldehyde groups in the 3, 3-dimethyl-2, 4-dioxo ethyl butyrate by using borohydride, then acidifying to generate ketopantolactone, wherein a solvent used for reaction is one or more of polyethylene glycol 400, polyethylene glycol 600 and polyethylene glycol 800, the reaction temperature is-20 ℃, the borohydride is one or two of sodium borohydride and potassium borohydride, and the molar ratio of the borohydride to the 3, 3-dimethyl-2, 4-dioxo ethyl butyrate prepared in the step 1 is (1.0-5.0): 1.
2. the process for the synthesis of ketopantolactone according to claim 1, characterized in that:
the molar ratio of the sodium alkoxide to the isobutyraldehyde is (1-2): 1; the mol ratio of isobutyraldehyde to oxalic acid chloro-monoethyl ester is (1-2): 1; the mass ratio of the solvent used in the reaction in the step 1 to isobutyraldehyde is (3-5): 1.
3. the process for the synthesis of ketopantolactone according to claim 1, characterized in that:
in the step 1, the reaction temperature is-20 ℃ to 60 ℃, and the reaction time is 6 hours to 12 hours.
4. A process for the synthesis of ketopantolactone according to claim 3, characterized in that:
in the step 1, the reaction temperature is-20 ℃ to 20 ℃, and the reaction time is 8 hours to 10 hours.
5. The process for the synthesis of ketopantolactone according to claim 1, characterized in that:
the mass ratio of the solvent used in the reaction in the step 2 to the 3, 3-dimethyl-2, 4-dioxoethyl butyrate prepared in the step 1 is (2-4): 1;
in the acidification step in the step 2, the pH of the reaction solution is adjusted to 1-3.
6. The process for the synthesis of ketopantolactone according to claim 5, characterized in that:
the molar ratio of the borohydride to the ethyl 3, 3-dimethyl-2, 4-dioxobutyrate prepared in the step 1 is (1.5-3.0): 1.
7. the process for the synthesis of ketopantolactone according to claim 1, characterized in that:
when borohydride is selected to selectively reduce aldehyde group in 3, 3-dimethyl-2, 4-dioxo ethyl butyrate, the reaction time is 4 hours to 6 hours,
during acidification, the PH of the reaction solution is adjusted to 1-3, then the temperature is raised to 35-45 ℃, and the reaction is stirred for 1 hour.
8. The process for the synthesis of ketopantolactone of claim 1, characterized in that:
when borohydride is selected to selectively reduce aldehyde group in 3, 3-dimethyl-2, 4-dioxo ethyl butyrate, the reaction temperature is-10 ℃ to 0 ℃.
9. The process for the synthesis of ketopantolactone according to claim 1, characterized in that:
the sodium alkoxide is one or more of sodium methoxide, sodium ethoxide and sodium isopropoxide;
the solvent used in the reaction in the step 1 is one or more of tetrahydrofuran, dioxane and methyl tetrahydrofuran;
the reagent used in the acidification step in the step 2 is one or more of hydrochloric acid, sulfuric acid and acetic acid.
10. The process for the synthesis of ketopantolactone according to claim 1, characterized in that:
in step 1, after the reaction is completed, the step of separating the product ethyl 3, 3-dimethyl-2, 4-dioxobutyrate in the reaction solution is as follows: recovering the solvent used in the step 1 under reduced pressure, extracting and washing with ethyl acetate and water, washing the separated organic phase with saturated saline solution, drying the separated organic phase with anhydrous sodium sulfate, and then recovering ethyl acetate under reduced pressure to obtain colorless oily 3, 3-dimethyl-2, 4-dioxobutyric acid ethyl ester;
in step 2, after the reaction is completed, the step of separating the keto pantolactone from the reaction solution is as follows: cooling the reaction liquid, extracting and washing with ethyl acetate and water, washing the separated organic phase with saturated salt solution, drying the separated organic phase with anhydrous sodium sulfate, then recovering ethyl acetate under reduced pressure, and finally recrystallizing with carbon tetrachloride to obtain white solid ketopantolactone.
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| JPH0495086A (en) * | 1990-08-10 | 1992-03-27 | Takeda Chem Ind Ltd | Production of ketopantolactone |
| JPH0495085A (en) * | 1990-08-10 | 1992-03-27 | Takeda Chem Ind Ltd | Production of ketopantolactone |
| US5821374A (en) * | 1995-11-21 | 1998-10-13 | Hoffmann-La Roche Inc. | Process for the oxidation of alcohols |
| WO2003091235A1 (en) * | 2002-04-25 | 2003-11-06 | Dsm Ip Assets B.V. | Manufacture of ketopantolactone |
| CN1319937C (en) * | 2005-10-24 | 2007-06-06 | 浙江大学宁波理工学院 | D-calcium pantothenate synthesis method |
| EP2230312A1 (en) * | 2009-03-19 | 2010-09-22 | Helmholtz-Zentrum für Infektionsforschung GmbH | Probe compound for detecting and isolating enzymes and means and methods using the same |
| CN110283067B (en) * | 2019-06-27 | 2022-02-11 | 湖北大学 | Synthetic method of 2, 4-dihydroxy-3, 3-dimethylbutyric acid |
| CN112979513A (en) * | 2021-02-07 | 2021-06-18 | 武汉工程大学 | Chiral sulfoxide containing styrene monomer and preparation method thereof |
| CN113004228A (en) * | 2021-03-12 | 2021-06-22 | 上海欣海健伟实业有限公司 | Synthesis process of D-calcium pantothenate intermediate D-pantolactone |
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