Synthesis method and application of a dianhydrosugar

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a synthesis method and application of a dianhydro sugar. The technical scheme takes methyl-alpha-D-glucopyranoside as raw material, and synthesizes 1,4:3,6-dianhydro-D-glucopyranose through six-step reactions. The raw material is cheap and easy to obtain, the reaction process is simple, large-scale production can be carried out, and the method has a wide application prospect. The raw material can be added to cigarettes to increase the sweet and moist feeling in the oral cavity, enrich the tobacco aroma, increase the smoke transmittance and delicacy, improve the aftertaste comfort, and has potential application value.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing dehydrated sugars and their application as a sweet flavoring ingredient in cigarettes. Background Technology

[0002] 1,4:3,6-D-d-pyranose (hereinafter referred to as disaccharide sugar) is widely found in cigarette smoke and sugar pyrolysis products. It belongs to the pyran compounds generated from sugar degradation and is characterized by volatility, fat solubility, and water solubility. However, there are few reports on the synthesis of disaccharide sugar compounds to date, and the existing synthetic processes are immature and the products are expensive. In 1987, Batelaan et al. used isomannitol nitrate (price > 50,000 RMB / g) or isosorbide nitrate (price > 5,000 RMB / g) for pyrolysis under high temperature and high vacuum. This synthetic method uses expensive raw materials, requires extremely harsh and difficult-to-control reaction conditions, and is therefore difficult to widely adopt. In 2007, Fabbri et al. obtained 3% disaccharide sugar product by direct thermal pyrolysis of cellulose at 350℃ without a catalyst. In 2016, Casoni et al. synthesized biomass oil using microcrystalline cellulose as a substrate and MCM-41 and Cu1-MCM-41 as catalysts. The highest yield of the dehydrated sugar component was about 6%. However, the catalyst synthesis process was cumbersome, and the yield decreased significantly when the catalyst was reused.

[0003] Currently, the synthesis method for commercially available disohydrated glucose standards involves collecting cellulose combustion flue gas and then purifying it using column chromatography. This method is extremely costly, with prices reaching as high as 50,000 yuan / g. Therefore, research into a novel synthesis method for 1,4:3,6-disohydrated-D-pyranose is of great significance. Summary of the Invention

[0004] The purpose of this invention is to provide a simple, high-yield, and easily scalable method for synthesizing 1,4:3,6-disodehydrated-D-pyranose glucose and its application as a specialty sweet flavoring ingredient in cigarettes.

[0005] To achieve the above objectives, this application employs the following technical solution:

[0006] A method for synthesizing a disaccharide, comprising the following steps:

[0007]

[0008] Step 1: Synthesis of intermediate compound I. In a reaction flask, the starting material methyl-α-D-glucopyranoside, benzaldehyde dimethyl acetal, catalyst and solvent were added sequentially. The mixture was stirred at 60-100℃ for 2-5 hours. After the reaction was completed, the mixture was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was extracted and dried with anhydrous Na2SO4. The solvent was removed by vacuum distillation. The crude product was purified by column chromatography to obtain intermediate compound I.

[0009] Step 2: Synthesis of intermediate compound II. In a reaction flask, intermediate compound I, base and solvent were added sequentially and stirred at 0-20°C for 0.5 h. Then, benzyl bromide was slowly added dropwise to the reaction system. After the addition was complete, the reaction was continued at 20°C for 10-15 h. Then, saturated sodium chloride solution and dichloromethane were added to the reaction system. The organic phase was extracted and separated and dried with anhydrous Na2SO4. The solvent was removed by vacuum distillation. The crude product was purified by column chromatography to obtain intermediate compound II.

[0010] Step 3: Synthesis of intermediate compound III. In a reaction flask, intermediate compound II, saturated hydrochloric acid solution and solvent are added sequentially. The reaction is carried out at 60-80℃ for 4-8 hours. After the reaction is completed, saturated sodium bicarbonate and dichloromethane are added. The organic phase is extracted and separated and dried with anhydrous Na2SO4. The solvent is removed by vacuum evaporation. The crude product is recrystallized with ethanol to obtain intermediate compound III.

[0011] Step 4: Synthesis of intermediate compound IV. In a reaction flask, intermediate compound III, catalyst and solvent are added sequentially and reacted at 50-80℃ for 4-8 hours. After the reaction is completed, the solvent is removed by vacuum distillation, and the crude product is separated by silica gel column chromatography to obtain intermediate compound IV.

[0012] Step 5, Synthesis of intermediate compound V: In a reaction flask, intermediate compound IV, catalyst and solvent are added sequentially, and the reaction is carried out at 20-50℃ for 2-8 hours. After the reaction is completed, the solvent is removed by vacuum distillation, and the crude product is separated by silica gel column chromatography to obtain intermediate compound V.

[0013] Step 6, Synthesis of target product VI: In a reaction flask, compound V, Raney nickel and ethanol are added sequentially, and the reaction is carried out at 30-60℃ for 5-10 hours. After the reaction is completed, the mixture is filtered, the solvent is removed by vacuum distillation, and the crude product is recrystallized with ethanol to obtain target product VI.

[0014] Preferably, in step 1, the catalyst is one of p-toluenesulfonic acid, benzenesulfonic acid, or trifluoromethanesulfonic acid; the solvent is one of N,N-dimethylformamide, dichloromethane, or tetrahydrofuran; and the molar ratio of methyl-α-D-glucopyranoside, benzaldehyde dimethyl acetal, and the catalyst is 1:(1.0-2.0):(0.2-1.0).

[0015] Preferably, in step 2, the base is one of potassium hydroxide, sodium carbonate, or sodium hydroxide; the solvent is one of chloroform, dichloromethane, or tetrahydrofuran; and the molar ratio of intermediate compound I, benzyl bromide, and base is 1:(1-1.2):(1.5-3).

[0016] Preferably, in step 3, the solvent is one of ethanol, methanol, or isopropanol.

[0017] Preferably, in step 4, the catalyst is one of methanesulfonic anhydride, trifluoromethanesulfonic anhydride, or p-tolylsulfonic anhydride; the solvent is one of acetonitrile, methanol, or tetrahydrofuran; and the molar ratio of intermediate compound III to the catalyst is 1:(0.1-1).

[0018] Preferably, in step 5, the catalyst is one of p-toluenesulfonic acid, camphorsulfonic acid, or benzenesulfonic acid; and the solvent is one of acetonitrile, methanol, or tetrahydrofuran.

[0019] Preferably, in step 6, the mass ratio of intermediate compound V to Raney nickel is 1:(0.2 to 1.0).

[0020] In one application, the 1,4:3,6-disodehydrated-D-pyranose prepared according to any of the above methods is used as a sweet flavoring ingredient in cigarettes.

[0021] Preferably, the amount of 1,4:3,6-disodehydrated-D-pyranose added is 0.5-100 ppm of the weight of cigarette tobacco.

[0022] The beneficial effects of this invention are:

[0023] This technical solution synthesizes 1,4:3,6-disodehydrated-D-glucopyranoside as a starting material through a six-step reaction. Compared with existing synthetic methods, the raw materials of this invention are inexpensive and readily available, the reaction process is simple, and it can be produced on a large scale, showing broad application prospects. Adding it to cigarettes as a flavoring ingredient can increase the sweetness in the mouth, enrich the aroma, improve the transparency and smoothness of the smoke, and enhance the comfort of the aftertaste, demonstrating potential application value. Detailed Implementation

[0024] The technical solutions of the present invention will be described in detail below through embodiments. The following embodiments are merely exemplary and can only be used to explain and illustrate the technical solutions of the present invention, and should not be construed as limiting the technical solutions of the present invention.

[0025] In the technical solution of this application, all reagents, instruments, etc. involved, unless otherwise explicitly stated, are commercially available.

[0026] The synthesis method of 1,4:3,6-disodehydrated-D-pyranose of this technical solution is shown in the following synthesis steps. The synthesis of all embodiments is carried out according to the following steps. The only difference is that the amount of each component in each embodiment is different, which leads to different yields, but does not affect the product in each synthesis step.

[0027]

[0028] Example 1

[0029] (1) Synthesis of intermediate compound (I): In a reaction flask, 1.94 g (10 mmol) of methyl-α-D-glucopyranoside, 2.25 g (15 mmol) of benzaldehyde dimethyl acetal, 1.72 g (10 mmol) of p-toluenesulfonic acid and tetrahydrofuran were added sequentially. The mixture was stirred at 60 °C for 5 h. After the reaction was completed, the mixture was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was extracted and dried with anhydrous Na2SO4. The solvent was removed by vacuum distillation. The crude product was purified by column chromatography to obtain 2.59 g (9.2 mmol) of intermediate compound (I).

[0030] (2) Synthesis of intermediate compound (II): In a reaction flask, 2.59 g (9.2 mmol) of intermediate compound (I), 1.03 g (18.4 mmol) of potassium hydroxide, and 25 ml of tetrahydrofuran were added sequentially. The mixture was stirred at 0–20 °C for 0.5 h. Then, 1.88 g (11 mmol) of benzyl bromide was slowly added dropwise to the reaction system. After the addition was complete, the reaction was continued at 20 °C for 10 h. Then, saturated sodium chloride solution and dichloromethane were added to the reaction system. The organic phase was extracted and separated, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain 3.20 g (8.6 mmol) of intermediate compound (II).

[0031] (3) Synthesis of intermediate compound (III): In a reaction flask, 3.20 g (8.6 mmol) of intermediate compound (II), saturated hydrochloric acid solution and ethanol were added in sequence. The reaction was carried out at 80 °C for 4 h. After the reaction was completed, saturated sodium bicarbonate and dichloromethane were added. The organic phase was extracted and separated and dried with anhydrous Na2SO4. The solvent was removed by vacuum evaporation. The crude product was recrystallized with ethanol to obtain 2.04 g (7.2 mmol) of intermediate compound (III).

[0032] (4) Synthesis of intermediate compound (IV): In a reaction flask, 2.04 g (7.2 mmol) of intermediate compound (III), 2.03 g (7.2 mmol) of trifluoromethanesulfonic anhydride and 25 ml of acetonitrile were added sequentially. The reaction was carried out at 70 °C for 8 h. After the reaction was completed, the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography to obtain 1.49 g (5.6 mmol) of intermediate compound (IV).

[0033] (5) Synthesis of intermediate compound (V): In a reaction flask, 1.49 g (5.6 mmol) of intermediate compound (IV), 0.26 g (1.1 mmol) of camphor sulfonic acid and 20 ml of acetonitrile were added sequentially. The reaction was carried out at 50 °C for 8 h. After the reaction was completed, the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography to obtain 0.96 g (4.1 mmol) of intermediate compound (V).

[0034] (6) Synthesis of target product (VI): In a reaction flask, 0.96 g (4.1 mmol) of intermediate compound (V), 0.5 g of Raney nickel and 10 ml of ethanol were added sequentially. The reaction was carried out at 60 °C for 10 h. After the reaction was completed, the mixture was filtered, the solvent was removed by vacuum distillation, and the crude product was recrystallized with ethanol to obtain 0.57 g (4.0 mmol) of target product (VI).

[0035] Example 2

[0036] (1) Synthesis of intermediate compound (I): In a reaction flask, 1.94 g (10 mmol) of methyl-α-D-glucopyranoside, 1.5 g (10 mmol) of benzaldehyde dimethyl acetal, 0.86 g (5 mmol) of p-toluenesulfonic acid and tetrahydrofuran were added sequentially. The mixture was stirred at 60 °C for 5 h. After the reaction was completed, the mixture was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was extracted and dried with anhydrous Na2SO4. The solvent was removed by vacuum distillation. The crude product was purified by column chromatography to obtain 2.37 g (8.4 mmol) of intermediate compound (I).

[0037] (2) Synthesis of intermediate compound (II): In a reaction flask, 2.37 g (8.4 mmol) of intermediate compound (I), 0.71 g (12.6 mmol) of potassium hydroxide, and 25 ml of tetrahydrofuran were added sequentially. The mixture was stirred at 0–20 °C for 0.5 h. Then, 1.71 g (8.4 mmol) of benzyl bromide was slowly added dropwise to the reaction system. After the addition was complete, the reaction was continued at 20 °C for 10 h. Then, saturated sodium chloride solution and dichloromethane were added to the reaction system. The organic phase was extracted and separated, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain 3.01 g (8.1 mmol) of intermediate compound (II).

[0038] (3) Synthesis of intermediate compound (III): In a reaction flask, 3.01 g (8.1 mmol) of intermediate compound (II), saturated hydrochloric acid solution and methanol were added sequentially. The reaction was carried out at 80 °C for 4 h. After the reaction was completed, saturated sodium bicarbonate and dichloromethane were added. The organic phase was extracted and separated and dried with anhydrous Na2SO4. The solvent was removed by vacuum evaporation. The crude product was recrystallized with ethanol to obtain 1.88 g (6.7 mmol) of intermediate compound (III).

[0039] (4) Synthesis of intermediate compound (IV): In a reaction flask, 1.88 g (6.7 mmol) of intermediate compound (III), 1.52 g (5.4 mmol) of trifluoromethanesulfonic anhydride and 25 ml of acetonitrile were added sequentially. The reaction was carried out at 70 °C for 8 h. After the reaction was completed, the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography to obtain 1.32 g (5.0 mmol) of intermediate compound (IV).

[0040] (5) Synthesis of intermediate compound (V): In a reaction flask, 1.32 g (5.0 mmol) of intermediate compound (IV), 0.24 g (1 mmol) of camphor sulfonic acid and 20 ml of acetonitrile were added sequentially. The reaction was carried out at 50 °C for 8 h. After the reaction was completed, the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography to obtain 0.79 g (3.4 mmol) of intermediate compound (V).

[0041] (6) Synthesis of target product (VI): In a reaction flask, 0.79 g (3.4 mmol) of intermediate compound (V), 0.3 g of Raney nickel and 10 ml of ethanol were added sequentially. The reaction was carried out at 60 °C for 10 h. After the reaction was completed, the mixture was filtered, the solvent was removed by vacuum distillation, and the crude product was recrystallized with ethanol to obtain 0.43 g (3.0 mmol) of target product (VI).

[0042] Example 3

[0043] (1) Synthesis of intermediate compound (I): In a reaction flask, 1.94 g (10 mmol) of methyl-α-D-glucopyranoside, 3.0 g (20 mmol) of benzaldehyde dimethyl acetal, 1.72 g (10 mmol) of p-toluenesulfonic acid and tetrahydrofuran were added sequentially. The mixture was stirred at 60 °C for 5 h. After the reaction was completed, the mixture was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was extracted and dried with anhydrous Na2SO4. The solvent was removed by vacuum distillation. The crude product was purified by column chromatography to obtain 2.72 g (9.6 mmol) of intermediate compound (I).

[0044] (2) Synthesis of intermediate compound (II): In a reaction flask, 2.72 g (9.6 mmol) of intermediate compound (I), 1.08 g (19.2 mmol) of potassium hydroxide, and 30 ml of tetrahydrofuran were added sequentially. The mixture was stirred at 0–20 °C for 0.5 h. Then, 1.71 g (10 mmol) of benzyl bromide was slowly added dropwise to the reaction system. After the addition was complete, the reaction was continued at 20 °C for 10 h. Then, saturated sodium chloride solution and dichloromethane were added to the reaction system. The organic phase was extracted and separated, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain 3.43 g (9.2 mmol) of intermediate compound (II).

[0045] (3) Synthesis of intermediate compound (III): In a reaction flask, 3.43 g (9.2 mmol) of intermediate compound (II), saturated hydrochloric acid solution and ethanol were added in sequence. The reaction was carried out at 80 °C for 4 h. After the reaction was completed, saturated sodium bicarbonate and dichloromethane were added. The organic phase was extracted and separated and dried with anhydrous Na2SO4. The solvent was removed by vacuum evaporation. The crude product was recrystallized with ethanol to obtain 2.23 g (7.9 mmol) of intermediate compound (III).

[0046] (4) Synthesis of intermediate compound (IV): 2.23 g (7.9 mmol) of intermediate compound (III), 2.58 g (7.9 mmol) of p-tolylsulfonic anhydride and 30 ml of acetonitrile were added to the reaction flask in sequence. The reaction was carried out at 70 °C for 8 h. After the reaction was completed, the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography to obtain 1.52 g (5.7 mmol) of intermediate compound (IV).

[0047] (5) Synthesis of intermediate compound (V): In a reaction flask, 1.52 g (5.7 mmol) of intermediate compound (IV), 0.34 g (2.0 mmol) of p-toluenesulfonic acid and acetonitrile (25 ml) were added sequentially. The reaction was carried out at 50 °C for 8 h. After the reaction was completed, the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography to obtain 0.94 g (4.0 mmol) of intermediate compound (V).

[0048] (6) Synthesis of target product (VI): In a reaction flask, 0.94 g (4.0 mmol) of intermediate compound (V), 0.6 g of Raney nickel and 15 ml of ethanol were added sequentially. The reaction was carried out at 60 °C for 10 h. After the reaction was completed, the mixture was filtered, the solvent was removed by vacuum distillation, and the crude product was recrystallized with ethanol to obtain 0.52 g (3.6 mmol) of target product (VI).

[0049] Fragrance performance testing:

[0050] A certain amount of 1,4:3,6-disodehydrated-D-pyranose was weighed and diluted with ethanol to prepare a 5% solution for later use. 100g of unflavored blank cigarette tobacco was weighed and evenly spread on a clean tray. The ethanol solution of the compound was evenly sprayed onto the tobacco to obtain cigarette tobacco with specific gravities of 0.5ppm, 1ppm, 10ppm, 50ppm, and 100ppm. The tobacco was sealed and left to stand for 4 hours, then dried in a 50℃ oven. It was then humidified with distilled water to the standard moisture content (12%), rolled into standard cigarettes, and equilibrated for 48 hours (humidity 60% ± 2%, temperature 22 ± 1℃) before evaluation. The control sample was a blank cigarette, equilibrated for 48 hours under the same temperature and humidity conditions.

[0051] Table 1 Sensory evaluation results

[0052]

[0053] As shown in Table 1, 1,4:3,6-disodehydrated-D-pyranose has a significant effect on improving and modifying the aroma of cigarettes, reducing irritation, improving the taste, and making the aftertaste clean and comfortable. Its prominent "sweetness" enhances the "sweetness" of cigarette smoke, highlighting the "sweet" and "smooth" flavor characteristics of cigarettes. Recommended dosage: 0.5-100 ppm.

[0054] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing a disaccharide, characterized in that, The steps are as follows: ; Step 1: Synthesis of intermediate compound (I): In a reaction flask, the starting material methyl-α-D-glucopyranoside, benzaldehyde dimethyl acetal, catalyst, and solvent were added sequentially. The mixture was stirred at 60–100 °C for 2–5 h. After the reaction was completed, the mixture was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was extracted and dried with anhydrous Na2SO4. The solvent was removed by vacuum distillation. The crude product was purified by column chromatography to obtain intermediate compound (I). Step 2: Synthesis of intermediate compound (II). In a reaction flask, intermediate compound (I), base, and solvent were added sequentially and stirred at 0–20 °C for 0.5 h. Then, benzyl bromide was slowly added dropwise to the reaction system. After the addition was complete, the reaction was continued at 20 °C for 10–15 h. Then, saturated sodium chloride solution and dichloromethane were added to the reaction system. The organic phase was extracted and separated and dried with anhydrous Na2SO4. The solvent was removed by vacuum distillation. The crude product was purified by column chromatography to obtain intermediate compound (II). Step 3: Synthesis of intermediate compound (III) In a reaction flask, intermediate compound (II), saturated hydrochloric acid solution and solvent are added in sequence and reacted at 60-80 °C for 4-8 h. After the reaction is completed, saturated sodium bicarbonate and dichloromethane are added, the organic phase is extracted and separated and dried with anhydrous Na2SO4, the solvent is removed by vacuum evaporation, and the crude product is recrystallized with ethanol to obtain intermediate compound (III). Step 4: Synthesis of intermediate compound (IV) In a reaction flask, intermediate compound (III), catalyst and solvent are added sequentially and reacted at 50-80 °C for 4-8 h. After the reaction is completed, the solvent is removed by vacuum distillation, and the crude product is separated by silica gel column chromatography to obtain intermediate compound (IV). Step 5, Synthesis of intermediate compound (V): In a reaction flask, intermediate compound (IV), catalyst and solvent are added sequentially, and the reaction is carried out at 20-50 °C for 2-8 h. After the reaction is completed, the solvent is removed by vacuum distillation, and the crude product is separated by silica gel column chromatography to obtain intermediate compound (V). Step 6, Synthesis of target product (VI): In a reaction flask, compound (V), Raney nickel and ethanol are added sequentially and reacted at 30-60℃ for 5-10 h. After the reaction is completed, the mixture is filtered, the solvent is removed by vacuum distillation, and the crude product is recrystallized with ethanol to obtain target product (VI).

2. The method for synthesizing disohydrated sugar according to claim 1, characterized in that, In step 1, the catalyst is one of p-toluenesulfonic acid, benzenesulfonic acid, or trifluoromethanesulfonic acid; the solvent is one of N,N-dimethylformamide, dichloromethane, or tetrahydrofuran; and the molar ratio of methyl-α-D-glucopyranoside, benzaldehyde dimethyl acetal, and catalyst is 1:(1.0-2.0):(0.2-1.0).

3. The method for synthesizing disaccharides according to claim 1, characterized in that, In step 2, the base is one of potassium hydroxide, sodium carbonate, or sodium hydroxide; the solvent is one of chloroform, dichloromethane, or tetrahydrofuran; and the molar ratio of intermediate compound (I), benzyl bromide, and base is 1:(1-1.2):(1.5-3).

4. The method for synthesizing disohydrated sugar according to claim 1, characterized in that, In step 3, the solvent is one of ethanol, methanol, or isopropanol.

5. The method for synthesizing disohydrated sugar according to claim 1, characterized in that, In step 4, the catalyst is one of methanesulfonic anhydride, trifluoromethanesulfonic anhydride or p-tolylsulfonic anhydride; the solvent is one of acetonitrile, methanol or tetrahydrofuran; and the molar ratio of intermediate compound (III) to catalyst is 1:(0.1~1).

6. The method for synthesizing disohydrated sugar according to claim 1, characterized in that, In step 5, the catalyst is one of p-toluenesulfonic acid, camphorsulfonic acid, or benzenesulfonic acid; the solvent is one of acetonitrile, methanol, or tetrahydrofuran.

7. The method for synthesizing disohydrated sugar according to claim 1, characterized in that, In step 6, the mass ratio of intermediate compound (V) to Raney nickel is 1:(0.2 to 1.0).

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