CN110759941B - Preparation method of D-gluconic acid-gamma-lactone and intermediate thereof - Google Patents

Abstract

The invention discloses a preparation method of D-gluconic acid-gamma-lactone and an intermediate thereof, belonging to the technical field of pharmaceutical chemicals, wherein the method takes gluconolactone as a starting material to react with a silane reagent under the condition of an alkaline reagent to obtain a high-purity solid D-gluconic acid-gamma-lactone intermediate; then under the condition of acidity or fluoride, removing the silane protecting group to obtain the D-gluconic acid-gamma-lactone. The preparation method provided by the invention has the advantages of cheap raw materials and reagents, low cost, simple and safe operation, high yield, stable yield, small environmental pollution and good economic effect, and is suitable for industrial production.

Description

A kind of preparation method of D-glucono-γ-lactone and intermediate thereof

technical field

The invention belongs to the technical field of medicine and chemical industry, and more particularly relates to a preparation method of D-glucono-γ-lactone and an intermediate thereof.

Background technique

D-glucono-γ-lactone [CAS: 1198-69-2] is a gluconolactone compound, which has been widely used in food additives as egg lactone protein coagulant, preservative, color preservative and sour agent field. In recent years, with the development of the research field of anti-diabetic drugs, as the main component of diabetes drugs, its application value has gradually increased. Therefore, it is necessary to develop a new process route of D-glucono-γ-lactone.

The traditional synthesis method of D-glucono-γ-lactone is based on the literature Journal of Carbohydrate Chemistry, 26(5&6), 329-338; 2007, with D-(+)-glucose as the starting material, in calcium chloride and carbonic acid D-gluconic acid was prepared under calcium and water conditions, then dissolved in dioxane and water solvent to prepare D-glucono-1,5-lactone, D-glucono-1,5-lactone in acetic acid and hydrochloric acid Converted to D-glucono-γ-lactone under conditions. The total yield of the above operation is only 48.8%, the reaction operation steps are many, and the yield is low, which is unfavorable for large-scale production.

In addition, it is reported in the patent WO2006005070 that D-gluconic acid is used as a starting material, and is converted into a mixture of D-glucono-γ-lactone and D-glucono-1,5-lactone by high temperature in an aqueous solvent. However, the above operation is not conducive to the purification and separation of the product, so the purity of the D-glucono-γ-lactone obtained by the above method is relatively low.

SUMMARY OF THE INVENTION

In view of the deficiencies in the prior art, the object of the present invention is to provide a preparation method of a D-glucono-γ-lactone intermediate, the required raw materials and reagents are cheap, the cost is low, the operation is simple and safe, the yield is high, and the yield is high. The rate is stable, the environmental pollution is small, and the economic effect is very good, which is suitable for industrial production.

In order to achieve the above purpose, the present invention provides the following technical scheme: a preparation method of a D-glucono-γ-lactone intermediate, comprising using D-glucolactone as a starting material, under the conditions of an alkaline reagent and DMAP It reacts with silane-based reagent RX, and obtains high-purity solid D-gluconic acid-γ-lactone intermediate after crystallization and purification.

By adopting the above technical scheme, under the condition of alkaline reagent and DMAP, D-glucolactone can be reacted with silyl reagent RX to obtain D-glucono-γ-lactone intermediate. The above operation not only requires raw materials and reagents Inexpensive, low cost, simple and safe operation, high yield, stable yield; at the same time, the environmental pollution is small, has good economic effect, and is suitable for industrial production.

Further, the silane-based reagent RX is selected from C ₁ -C ₁₂ silane reagents, and the C ₁ -C ₁₂ silane reagent is trimethylchlorosilane, triethylchlorosilane, trimethylbromosilane, triethylsilane One or more of bromosilane and tert-butyldimethylsilyl trifluoromethanesulfonate.

Further, the basic reagent is dimethylamine, diisopropylamine, imidazole, dicarbonyl imidazole, morpholine, N-methylmorpholine, N-methylcyclohexylamine, N-ethylcyclylamine , one or more of triethylamine, N,N'-diisopropylethylamine and dicyclohexylamine.

By adopting the above technical solutions, dimethylamine, diisopropylamine, imidazole, dicarbonyl imidazole, morpholine, N-methylmorpholine, N-methylcyclohexylamine, N-ethylcyclylamine, triethylamine Amine, N,N'-diisopropylethylamine, dicyclohexylamine are all common C ₁ -C ₁₂ silane reagents, while dimethylamine, diisopropylamine, imidazole, dicarbonyl imidazole, morpholine, N-methylcyclohexylamine, N-ethylcyclohexylamine, and dicyclohexylamine are all common alkaline reagents. By adding any one of the above C ₁ -C ₁₂ silane reagents and alkaline reagents, the D-gluconolactone reacts with the corresponding silane-based reagent RX to give D-glucono-γ-lactone intermediate.

Further, the ratio of the feeding amount of the alkaline reagent to the glucolactone is more than 4.0 times the equivalent.

Further, the ratio of the feeding amount of the above-mentioned alkaline reagent to the glucolactone is preferably 4.5 times.

By adopting the above technical scheme, by controlling the amount of the added alkaline reagent, the purity of the obtained D-glucono-γ-lactone intermediate can be effectively controlled.

Further, the reaction temperature is -20 to 80°C.

Further, the reaction temperature is preferably -5 to 25°C.

By adopting the above technical scheme and controlling the specific reaction temperature, the yield of the obtained D-glucono-γ-lactone intermediate can be effectively controlled.

Further, the specific operation of crystallization and purification is: after the reaction is detected by GC, it is filtered through a Buchner funnel, the filtrate is washed 1-3 times with water, extracted with n-heptane, concentrated under reduced pressure, and added with 10 equivalents of n-heptane. The D-glucono-γ-lactone intermediate can be obtained by crystallizing at a temperature of 25～-40°C.

The purity of the obtained D-glucono-γ-lactone intermediate can be effectively controlled by adopting the above technical scheme and crystallizing through n-heptane.

In view of the deficiencies in the prior art, another object of the present invention is to provide a preparation method of D-glucono-γ-lactone, which is not only simple in operation, but also has little environmental pollution and high yield, and is suitable for industrial production.

In order to achieve the above-mentioned another purpose, the present invention provides the following technical scheme: a preparation method of D-gluconic acid-γ-lactone, using the D-gluconic acid-γ-lactone intermediate, in the protection of dehydroxylation Under the action of the reagent, D-glucono-γ-lactone is obtained.

By adopting the above technical scheme, the synthesis of D-glucono-γ-lactone can be realized in one step, and the above-mentioned reagent has little pollution to the environment, and the obtained yield is high, which is suitable for industrial production.

Further, the dehydroxylation protection reagent is an acid, and the selected acid is sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, One or more of citric acid, tartaric acid, maleic acid, and fumaric acid.

Further, the dehydroxylation protection reagent is fluoride, and the selected fluoride is tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, cesium fluoride, sodium fluoride or potassium fluoride one of the.

Further, after the action of the dehydroxylation protective reagent, there is also a purification and crystallization operation: concentration under reduced pressure, adding 150-300ml of ethanol for heating and dissolving, cooling to room temperature, adding a small amount of seed crystals, precipitating a solid, and filtering to obtain D. -Glucono-gamma-lactone.

The purity of the obtained D-glucono-γ-lactone can be effectively improved by adopting the above technical scheme, dissolving by heating with ethanol, and adding a small amount of seed crystals after cooling for crystallization.

To sum up, the present invention has the following beneficial effects: the preparation method provided by the present invention requires cheap raw materials and reagents, low cost, simple and safe operation, high yield, stable yield, little environmental pollution, and good economy. effect, suitable for industrial production.

Description of drawings

Fig. 1 is a kind of D-gluconic acid-γ-lactone intermediate obtained in the preparation method Example 1 of a kind of D-gluconic acid-γ-lactone intermediate H NMR spectrogram;

Fig. 2 is the carbon nuclear magnetic resonance spectrogram of the D-gluconic acid-γ-lactone intermediate obtained in Example 1 of the preparation method of D-gluconic acid-γ-lactone intermediate;

Fig. 3 is a kind of D-gluconic acid-γ-lactone obtained in the preparation method Example 1 of D-gluconic acid-γ-lactone H NMR spectrogram;

4 is a carbon nuclear magnetic resonance spectrum of D-glucono-γ-lactone obtained in Example 1 of a preparation method of D-glucono-γ-lactone.

Detailed ways

The present invention will be further described in detail below with reference to the accompanying drawings.

1. Example

<1>, D-glucono-γ-lactone intermediate

Embodiment 1: A preparation method of D-glucono-γ-lactone intermediate, as shown in Figure 1, includes the following operation steps: under nitrogen protection, adding glucolactone (10.0g, 56.2mmol) to 100ml of tetrahydrofuran (THF), then N-methylcyclohexylamine (5.0eq) was added and stirred to dissolve, 0.5 g of 4-dimethylaminopyridine (DMAP) was added, the reaction system was cooled to -5°C, and trimethylamine was added dropwise. Chlorosilane (60 ml, 4.5 equiv.) was added dropwise, stirred at room temperature for 30 min, and the reaction was complete as detected by GC, and then filtered through a Buchner funnel under reduced pressure. Concentrate under pressure for 5 minutes, then add 10 equivalents of n-heptane to give a white solid after crystallization at 0°C.

Wherein, the chemical equation of above-mentioned synthetic D-gluconic acid-γ-lactone intermediate is:

Gluconolactone D-glucono-γ-lactone intermediate

As shown in Figure 1 and Figure 2, according to the nuclear magnetic resonance spectrum of the above-mentioned D-glucono-γ-lactone intermediate, combined with the data of the hydrogen nuclear magnetic resonance spectrum:

¹ H-NMR (CDCl3, 400MHz)δ: 0.05-0.18(m, 36H), 3.69-3.72(m, 2H), 4.03(d, 1H), 4.35-4.39(m, 2H), 4.54(d, 1H) ).

From this, it was found that the white solid obtained above was a D-glucono-γ-lactone intermediate.

Embodiment 2: a preparation method of a D-glucono-γ-lactone intermediate, which is different from Embodiment 1 in that the reaction system is cooled to 0°C.

Embodiment 3: a preparation method of a D-glucono-γ-lactone intermediate, the difference from Embodiment 1 is that the reaction system is cooled to 25°C.

Embodiment 4: a preparation method of a D-glucono-γ-lactone intermediate, the difference from Embodiment 1 is that the reaction system is cooled to -20°C.

Embodiment 5: a preparation method of a D-glucono-γ-lactone intermediate, the difference from Embodiment 1 is that the reaction system is cooled to 80°C.

Embodiment 6: a kind of preparation method of D-gluconic acid-γ-lactone intermediate, the difference from Example 1 is: the reaction is complete through GC detection, then vacuum filtration is carried out by Buchner funnel, and the filtrate is washed with water for 2 After three times, extract with 150 ml of n-heptane, concentrate under reduced pressure for 8 minutes, and then add 10 equivalents of n-heptane to crystallize at -40°C.

Embodiment 7: a kind of preparation method of D-gluconic acid-γ-lactone intermediate, the difference from Example 1 is: the reaction is completely detected by GC, then vacuum filtration is carried out by Buchner funnel, and the filtrate is washed with water for 2 After three times, extract with 80 ml of n-heptane, concentrate under reduced pressure for 3 minutes, then add 10 equivalents of n-heptane to crystallize at 25°C.

Embodiment 8: a preparation method of a D-gluconic acid-γ-lactone intermediate, which is different from Embodiment 1 in that dimethylamine is used as the alkaline reagent.

Embodiment 9: a preparation method of a D-gluconic acid-γ-lactone intermediate, which is different from Embodiment 1 in that the basic reagent is diisopropylamine.

Embodiment 10: a kind of preparation method of D-gluconic acid-γ-lactone intermediate, the difference with embodiment 1 is: basic reagent selects dicarbonyl imidazole and imidazole, and the weight percent of dicarbonyl imidazole and imidazole is 1:1.

Embodiment 11: a preparation method of a D-gluconic acid-γ-lactone intermediate, the difference from Embodiment 1 is that the silyl reagent RX is triethylchlorosilane, and the amount is 4.5 equivalents.

Embodiment 12: a preparation method of a D-gluconic acid-γ-lactone intermediate, which is different from Embodiment 1 in that the silyl reagent RX is trimethylbromosilane, and the amount is 4.5 equivalents.

Embodiment 13: a preparation method of a D-gluconic acid-γ-lactone intermediate, the difference from Embodiment 1 is that the silyl reagent RX is tert-butyldimethylsilyl trifluoromethanesulfonate, The amount used was 4.5 equivalents.

Embodiment 14: a preparation method of a D-gluconic acid-γ-lactone intermediate, which is different from Embodiment 1 in that the silyl reagent RX is triethylchlorosilane, and the amount is 5 equivalents.

Embodiment 15: a preparation method of a D-gluconic acid-γ-lactone intermediate, the difference from Embodiment 1 is that the silyl reagent RX is triethylchlorosilane, and the amount is 4.1 equivalents.

<2>, D-glucono-γ-lactone

Embodiment 16: a preparation method of D-gluconic acid-γ-lactone, comprising the following operation steps: under nitrogen protection, the D-gluconic acid-γ-lactone intermediate (50.0 g, 0.136 mmol) was added to 500 ml of methanol, stirred and dissolved at 100 rpm at room temperature (20°C), 0.5 g of potassium fluoride (KF) was added after 15 minutes, stirred at room temperature for 5 hours, then concentrated under reduced pressure, added After heating and dissolving 200 ml of ethanol, it was cooled to room temperature, a small amount of seed crystal was added, and a solid was precipitated. A solid was obtained after filtration through a Buchner funnel.

Wherein, the chemical equation of above-mentioned synthetic D-gluconic acid-γ-lactone is:

As shown in Figure 3 and Figure 4, according to the above-mentioned NMR spectrum of D-glucono-γ-lactone, combined with the data of 1H NMR spectrum:

¹ H-NMR (d6-DMSO, 400MHz)δ: 3.4-3.5(m, 1H), 3.55-3.60(m, 1H), 3.75-3.79(m, 1H), 4.04-4.10(m, 1H), 4.13 -4.16(m,1H),4.39-4.43(m,1H),4.65(t,J=5.5Hz,1H),4.95(d,J=6.0Hz,1H),5.59(d,J=4.5Hz, 1H), 6.22 (m, d, J=5.5Hz, 1H).

From this, it was found that the obtained solid was D-glucono-γ-lactone.

Embodiment 17: a preparation method of D-gluconic acid-γ-lactone, the difference from embodiment 16 is: the dehydroxylation protection reagent is tetramethylammonium fluoride, and the amount of tetramethylammonium fluoride is 0.5 grams.

Embodiment 18: a preparation method of D-gluconic acid-γ-lactone, the difference from embodiment 16 is: the dehydroxylation protection reagent is tetraethylammonium fluoride, and the amount of tetraethylammonium fluoride is 0.5 grams.

Embodiment 19: a preparation method of D-gluconic acid-γ-lactone, the difference from embodiment 16 is: the dehydroxylation protection reagent is tetraethylammonium fluoride, and the amount of tetraethylammonium fluoride is 0.5 grams.

Embodiment 20: a preparation method of D-glucono-γ-lactone, which is different from Embodiment 16 in that the dehydroxylation protection reagent is sodium fluoride, and the amount of sodium fluoride is 0.5 g.

Example 21: A preparation method of D-glucono-γ-lactone, the difference from Example 16 is that the dehydroxylation protection reagent is acetic acid, and the amount of acetic acid is 0.5 g.

Example 22: A preparation method of D-glucono-γ-lactone, the difference from Example 16 is that the dehydroxylation protection reagent is acetic acid, and the amount of acetic acid is 5 grams.

Embodiment 23: a preparation method of D-gluconic acid-γ-lactone, the difference from Example 16 is: the D-gluconic acid-γ-lactone intermediate used is selected from Example 14. D-glucono-γ-lactone intermediate.

Embodiment 24: a kind of preparation method of D-gluconic acid-γ-lactone, the difference from Example 16 is: the D-gluconic acid-γ-lactone intermediate used is the one prepared in Example 2. D-glucono-γ-lactone intermediate.

Embodiment 25: a kind of preparation method of D-gluconic acid-γ-lactone, the difference from Example 16 is: the D-gluconic acid-γ-lactone intermediate used is selected from the one prepared in Example 3. D-glucono-γ-lactone intermediate.

Embodiment 26: a kind of preparation method of D-glucono-γ-lactone, comprising the following operation steps: under nitrogen protection, TMS-glucolactone (50.0g, 0.136mmol) is added to 500ml of methanol, room temperature ( 20°C) after stirring and dissolving, add 5 grams of acetic acid, stir at room temperature (20°C) for 12 hours, then concentrate under reduced pressure, add 200ml of ethanol for heating and dissolving, cool to room temperature, add a small amount of seed crystals, and precipitate a large amount of solids. The solid was obtained by filtration through a Schenker funnel.

Wherein, the chemical equation of above-mentioned synthetic D-gluconic acid-γ-lactone is:

Embodiment 27: a preparation method of D-glucono-γ-lactone, which is different from Embodiment 26 in that the mixture is stirred at room temperature (20° C.) for 15 hours.

Example 28: A preparation method of D-glucono-γ-lactone, the difference from Example 26 is: stirring at room temperature (20° C.) for 18 hours.

Embodiment 29: a preparation method of D-glucono-γ-lactone, which is different from Embodiment 26 in that the mixture is stirred at room temperature (25° C.) for 12 hours.

Example 30: A preparation method of D-glucono-γ-lactone, the difference from Example 26 is: stirring at room temperature (15° C.) for 12 hours.

2. Comparative ratio

<1>, D-glucono-γ-lactone intermediate

Comparative Example 1: A preparation method of a D-glucono-γ-lactone intermediate, the difference from Example 1 is that the reaction system is cooled to -30°C.

Comparative Example 2: A preparation method of a D-glucono-γ-lactone intermediate, the difference from Example 1 is that the reaction system is cooled to 100°C.

Comparative Example 3: A preparation method of a D-gluconic acid-γ-lactone intermediate, which is different from Example 1 in that the silyl reagent RX is triethylchlorosilane, and the amount is 3 equivalents.

<2>, D-glucono-γ-lactone

Comparative example 4: a preparation method of D-glucono-γ-lactone, the difference from Example 1 is: with D-(+)-glucose as starting material, in calcium chloride and calcium carbonate D-gluconic acid was prepared under the condition of and water, then dissolved in dioxane and water solvent to prepare D-glucono-1,5-lactone, D-glucono-1,5-lactone was prepared in the condition of acetic acid and hydrochloric acid down-converted to D-glucono-γ-lactone.

Comparative example 5: a kind of preparation method of D-gluconic acid-γ-lactone, the difference with embodiment 1 is: take D-gluconic acid as starting material, in water solvent, be converted into D-glucose by high temperature A mixture of acid-gamma-lactone and D-glucono-1,5-lactone.

3. Performance testing and analysis Test 1: Performance testing of D-glucono-γ-lactone intermediates

Test object: The D-glucono-γ-lactone intermediate prepared in Example 1-15 was used as test sample 1-15, and the D-glucono-γ-lactone intermediate prepared in Comparative Example 1-3 As control samples 1-3.

Test results: As can be seen in Table 1, the yields of test samples 1-15 are higher than those of control samples 1-3. At the same time, compared with test sample 1, the purity of control sample 1 and control sample 2 is close to that of test sample 1, but the yield of control sample 1 and control sample 2 is much lower than that of test sample 1. Secondly, the yields of test samples 4 and 5 are also significantly lower than those of test samples 1-3; at the same time, the yield of test sample 2 is the highest. It can be seen that the yield of the reaction is higher when the temperature is between -5 and 25°C, and the optimum reaction temperature is at 0°C.

In addition, compared with the control sample 3, the purity of the test samples 1-15 is higher than that of the control sample 3. At the same time, by comparing the test sample 11, the sample sample 14 and the test sample 15, it can be seen that the purity of the test sample 11 is higher than that of the sample sample 14 and the test sample 15. It can be seen that the ratio of the feeding amount of the alkaline reagent to the glucolactone is preferably more than 4 times, and the best when the ratio of the feeding amount of the alkaline reagent to the glucolactone is 4.5 times.

Table 1 Test results of yield and purity of test samples 1-15 and control samples 1-3

test subject Yield(%) purity(%) test subject Yield(%) purity(%) Test sample 1 95.4 99.8 Test sample 10 95.5 99.3 Test sample 2 96.6 98.6 Test sample 11 95.6 99.5 Test sample 3 95.6 99.4 Test sample 12 95.8 98.6 Test sample 4 93.7 99.1 Test sample 13 94.7 99.4 Test sample 5 94.2 98.7 Test sample 14 95.2 99.4 Test sample 6 96.1 98.7 Test sample 15 96.1 99.2 Test sample 7 95.6 99.5 control sample 1 54.2 98.5 Test sample 8 95.5 99.6 control sample 2 55.4 98.3 Test sample 9 95.4 99.5 Control sample 3 85.6 86.4

Test 2: Performance testing of D-glucono-γ-lactone

Test object: D-glucono-γ-lactone prepared in Example 16-30 was taken as test sample 16-30, and D-glucono-γ-lactone prepared in Comparative Example 4-5 was taken as control sample 4 -5.

Test results: As shown in Table 2, the yield and purity of sample samples 16-30 are higher than those of control samples 4-5. At the same time, the yield of the control sample 4 is close to half of the yield of the sample sample 16, while comparing the sample samples 21, 22 and 26, it can be seen that when acetic acid is used as the dehydroxylation protection reagent instead of the fluoride, the It is only necessary to replace the acetic acid with fluoride, and the amount of acetic acid needs to be adjusted.

Table 2 The yield and purity test results of test samples 16-30 and control samples 4-5

The specific embodiment is only an explanation of the present invention, and it is not a limitation of the present invention. Those skilled in the art can make modifications to the present embodiment without creative contribution as needed after reading this specification, but only in the claims of the present invention are protected by patent law.

Claims (3)

1. a preparation method of D-gluconic acid-γ-lactone intermediate, is characterized in that, under nitrogen protection, 10.0g, 56.2mmol glucolactone are added to the tetrahydrofuran of 100ml, then add 5.0eq N-methyl After the cyclohexylamine was stirred and dissolved, 0.5 g of 4-dimethylaminopyridine was added, the reaction system was cooled to -5°C, 60 ml, 4.5 equivalents of trimethylchlorosilane were added dropwise, the addition was completed, and the stirring was performed at room temperature for 30 min. After the reaction was completed, the Buchner funnel was used for vacuum filtration. After the filtrate was washed twice with water, extracted with 100 ml of n-heptane, concentrated under reduced pressure for 5 minutes, and then added 10 equivalents of n-heptane to obtain D after crystallization at 0 °C. - Glucono-γ-lactone intermediate; Or the reaction system is cooled to 0°C; Or the reaction system is cooled to 25°C; Or the reaction system is cooled to -20°C; Or the reaction system is cooled to 80°C; Or after GC detects that the reaction is complete, then carry out suction filtration under reduced pressure with a Buchner funnel, wash the filtrate twice, extract with 150 ml of n-heptane, concentrate under reduced pressure for 8 minutes, then add 10 equivalents of n-heptane at -40 ℃ crystallize; Or after GC detection, the reaction is complete, and then the Buchner funnel is used for vacuum filtration. After the filtrate is washed twice, extracted with 80 ml of n-heptane, concentrated under reduced pressure for 3 minutes, and then added 10 equivalents of n-heptane at 25 ° C. crystallization; Or use dimethylamine to replace N-methylcyclohexylamine; Or use diisopropylamine to replace N-methylcyclohexylamine; Or select dicarbonyl imidazole and imidazole to replace N-methylhexylamine, and the weight percent of dicarbonyl imidazole and imidazole is 1:1; Or select triethyl chlorosilane to replace trimethyl chlorosilane, and the consumption is 4.5 equivalents; Or select trimethyl bromide silane to replace trimethyl chlorosilane, and the consumption is 4.5 equivalents; Or select tert-butyldimethylsilyl trifluoromethanesulfonate to replace trimethylchlorosilane, and the consumption is 4.5 equivalents; Or select triethyl chlorosilane to replace trimethyl chlorosilane, and the consumption is 5 equivalents; Or use triethylchlorosilane instead of trimethylchlorosilane, and the amount is 4.1 equivalents. 2. a preparation method of D-gluconic acid-γ-lactone, is characterized in that, under nitrogen protection, by 50.0g, 0.136mmol D-gluconic acid-γ-lactone intermediate described in claim 1 is added In 500ml of methanol, stir and dissolve at 20°C at 100 r/min, add 0.5g of potassium fluoride after 15 minutes, stir at room temperature for 5 hours, then concentrate under reduced pressure, add 200ml of ethanol, heat and dissolve, cool to room temperature, add A small amount of seed crystals precipitated solids, which were filtered through a Buchner funnel to obtain D-glucono-γ-lactone; Or select tetramethylammonium fluoride to replace potassium fluoride, and the tetramethylammonium fluoride consumption is 0.5 grams; Or select tetraethylammonium fluoride to replace potassium fluoride, and the tetraethylammonium fluoride consumption is 0.5 grams; Or select sodium fluoride to replace potassium fluoride, and the consumption of sodium fluoride is 0.5 grams; Or select acetic acid to replace potassium fluoride, and the consumption of acetic acid is 0.5 grams; Or choose acetic acid to replace potassium fluoride, and the consumption of acetic acid is 5 grams. 3. a preparation method of D-gluconic acid-γ-lactone, is characterized in that, under nitrogen protection, 50.0g, 0.136mmol D-gluconic acid-γ-lactone intermediate described in claim 1 is added To 500ml of methanol, after stirring and dissolving at 20°C, add 5g of acetic acid, stir at 20°C for 12 hours, then concentrate under reduced pressure, add 200ml of ethanol to dissolve by heating, cool to room temperature, add a small amount of seed crystals, and precipitate a large amount of solids. Buchner funnel filtration to obtain D-glucono-γ-lactone; or stirring at 20°C for 15 hours; or stirring at 20°C for 18 hours; or stirring at 25°C for 12 hours; Or stir at 15°C for 12 hours.

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