A kind of synthesis process of 6-hydroxytropinone

Abstract

The invention discloses a synthesis process of 6-hydroxytropinone, and relates to the technical field of chemical synthesis. When preparing 6-hydroxytropinone, the present invention reacts diatomite, aluminum chloride, zirconium sulfate tetrahydrate and octyltriethoxysilane to obtain hydrophobic solid acid; furan and ammonium bromide are electrolyzed to obtain 2,5-dimethoxydihydrofuran, and then 2,5-dimethoxydihydrofuran and hydrophobic solid acid are reacted to obtain 2-hydroxy-1,4-succinaldehyde; acetone dicarboxylic acid, methylamine hydrochloride, and sodium acetate are formulated into a buffer, and 2-hydroxy-1,4-succinaldehyde and buffer are reacted and purified and dried to obtain 6-hydroxytropinone. The synthesis process of 6-hydroxytropinone of the present invention not only shortens the production time, improves the yield, but is also more economical and environmentally friendly.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, in particular to a synthesis process of 6-hydroxytropinone. Background Art

[0002] 6-Hydroxytropinone is a product of fine chemicals. It is an important intermediate for the synthesis of anisodamine, an anticholinergic nerve blocker, and the market demand is very huge. In the current synthesis method, a large amount of hydrochloric acid is needed, which not only corrodes the equipment and increases the maintenance cost, but also requires a large amount of alkali neutralization. A hydrophobic solid acid is now prepared to replace hydrochloric acid, which has high catalytic activity, less corrosion, is easy to separate, and can be reused to reduce costs. It often takes 3 to 4 days to prepare 6-Hydroxytropinone in industry, and it is necessary to optimize the synthesis process to shorten the time and increase the production capacity to improve the competitiveness of the product.

[0003] The industrial production and purification of 6-hydroxytropinone requires the continuous consumption of acetone. Acetone is highly toxic and its large-scale use will burden the environment. It is necessary to find a more environmentally friendly alternative solvent that does not affect the yield. Summary of the invention

[0004] The object of the present invention is to provide a synthesis process of 6-hydroxytropinone to solve the problems existing in the prior art.

[0005] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0006] A synthesis process of 6-hydroxytropinone. The 6-hydroxytropinone is prepared by electrolyzing furan and ammonium bromide to obtain 2,5-dimethoxydihydrofuran, reacting 2,5-dimethoxydihydrofuran with a hydrophobic solid acid to obtain 2-hydroxy-1,4-butanedialdehyde, reacting with a buffer solution, and then purifying and drying.

[0007] As an optimization, the hydrophobic solid acid is prepared by reacting diatomaceous earth, aluminum trichloride, zirconium sulfate tetrahydrate and octyltriethoxysilane.

[0008] As an optimization, the buffer solution is prepared by reacting acetone dicarboxylic acid, methylamine hydrochloride and sodium acetate.

[0009] A synthesis process of 6-hydroxytropinone comprises the following preparation steps:

[0010] (1) Mix 0.2 mol / L aluminum chloride and 0.3 mol / L sodium hydroxide in a mass ratio of 1:(2-2.5), stir at 60-80°C, 300-500 r / min, and prepare a pillaring agent; mix diatomaceous earth and deionized water in a mass ratio of 1:(40-50), ultrasonically disperse for 10 min, add 0.1-0.2 times the amount of diatomaceous earth as a pillaring agent, stir at 50-60°C, 300-500 r / min for 2-4 h, cool, centrifuge, wash with deionized water 3-5 times, and place in a vacuum. Drying at 70-80°C in a drying oven for 4-6 hours, and then keeping at 450-460°C in a muffle furnace for 2-3 hours to obtain aluminum-pillared diatomite; mixing aluminum-pillared diatomite, zirconium sulfate tetrahydrate, octyltriethoxysilane and deionized water in a mass ratio of (20-25):1:(0.1-0.3):(100-200) uniformly, stirring at 50-70°C, 300-500r / min for 1-2 hours, filtering, washing with deionized water 1-3 times, and drying at 90-100°C in a vacuum drying oven for 4-6 hours to obtain a hydrophobic solid acid;

[0011] (2) Mix ammonium bromide, furan and methanol in a mass ratio of 1: (10-20): (50-100) in a closed electrolytic cell and stir evenly, stir for 5-10 min at -5-0°C, pass current, electrolyze and stir for 1-2 h, and perform vacuum distillation at 1.6-1.8 kPa, collect the fraction at 50-55°C, and obtain 2,5-dimethoxydihydrofuran;

[0012] (3) Mix acetone dicarboxylic acid, methylamine hydrochloride, sodium acetate and deionized water in a mass ratio of (2-2.3): (0.1-0.15): 1: (5-10) and stir evenly. Stir for 10-20 min at 0-10°C to prepare a buffer solution. At this time, the pH is controlled at 4.1-4.6. Mix hydrophobic solid acid, 2,5-dimethoxydihydrofuran and deionized water in a mass ratio of (0.08-0.1): 1: (30-40) and stir evenly. 20-30°C, rotation speed of 200-300r / min, stirring for 3-4h, filtering and collecting the filtrate, adding 0.01-0.02 times of 6mol / L sodium hydroxide of 2,5-dimethoxydihydrofuran, maintaining the temperature at 20-30°C, adjusting the pH to 6.8-7.3, preparing 2-hydroxy-1,4-butanedialdehyde, adding 1-2 times of 2,5-dimethoxydihydrofuran buffer to 2-hydroxy-1,4-butanedialdehyde, and stirring at 25-30°C. ℃, 300~500r / min stirring for 10~12h, then at 50~60℃, 300~500r / min stirring for 1~1.5h, cool to room temperature, add 15~20 times of sodium chloride and 5~8 times of potassium carbonate of 2,5-dimethoxydihydrofuran, adjust pH to 8~9, extract with chloroform 4~6 times, combine organic phases, distill off chloroform, and obtain a yellow-brown colloidal crystalline mixture, use petroleum ether and Ethyl acetate is prepared as an eluent in a volume ratio of 10:1, a yellow-brown colloidal crystalline mixture is placed in the eluent for slurrying, filtered, the filter cake is collected, ethanol and activated carbon are added, heated to 80-85°C, stirred for 30-40 minutes, the activated carbon is filtered while hot, then cooled to 5-10°C for crystallization, filtered, washed with anhydrous ethanol for 1-3 times, placed in a freeze dryer, and dried at -80--70°C, 30-50 Pa, for 3-5 hours to obtain 6-hydroxytropinone.

[0013] As an optimization, the electrolytic cell setting parameters in step (2) are as follows: the upper and lower electrode plates are graphite, the bottom of the electrode is 0.5~1cm away from the electrolytic cell, the voltage is 10~15V, the current is 1~3A, and the current density is 200~600A / m 2 .

[0014] As an optimization, the reaction process of 2,5-dimethoxydihydrofuran in step (2) is:

[0015] .

[0016] As an optimization, the reaction process of 6-hydroxytropinone described in step (3) is as follows:

[0017] .

[0018] As an optimization, the specification of the diatomaceous earth is 200 mesh.

[0019] Compared with the prior art, the beneficial effects achieved by the present invention are:

[0020] When preparing 6-hydroxytropinone, the present invention comprises the following steps: diatomaceous earth, aluminum trichloride, zirconium sulfate tetrahydrate and octyltriethoxysilane are reacted to obtain hydrophobic solid acid; furan and ammonium bromide are electrolyzed to obtain 2,5-dimethoxydihydrofuran, and 2,5-dimethoxydihydrofuran is reacted with the hydrophobic solid acid to obtain 2-hydroxy-1,4-butanedial; acetone dicarboxylic acid, methylamine hydrochloride and sodium acetate are prepared into a buffer solution, 2-hydroxy-1,4-butanedial is reacted with the buffer solution, and then purified and dried to obtain the 6-hydroxytropinone.

[0021] First, aluminum trichloride and sodium hydroxide are used to prepare aluminum pillaring agents, and diatomaceous earth is added to prepare aluminum pillared diatomaceous earth. By inserting aluminum pillars between diatomaceous earth layers, not only the interlayer spacing and specific surface area of ​​diatomaceous earth are increased, so that the hydrophobic solid acid can contact the raw materials more fully, but also the acidity can be enhanced by increasing Lewis acid sites, while the surface energy of diatomaceous earth is reduced, increasing its hydrophobicity; aluminum pillared diatomaceous earth is loaded with zirconium sulfate tetrahydrate and then modified with octyltriethoxysilane to prepare hydrophobic solid acid. Octyltriethoxysilane reacts with hydroxyl groups on the surface of diatomaceous earth, making aluminum pillared diatomaceous earth hydrophobic and oleophilic, making it easier to separate, recycle and reuse from water, reducing costs. Hydrochloric acid is highly corrosive, which will affect the life of the equipment, increase maintenance costs, and require a large amount of alkali for neutralization. The intense heat release during neutralization requires temperature control to reduce the impact on the reaction. Hydrophobic solid acid can reduce corrosion to the equipment. After filtration, only a small amount of alkali is needed to neutralize the system, which not only increases the reaction rate and shortens the reaction time, but also maintains a high yield.

[0022] Secondly, when 6-hydroxytropinone is prepared from 2,5-dimethoxydihydrofuran and buffer in a one-pot method, the reaction temperature, time and pH value will affect the reaction yield. By adjusting the reaction temperature and time, the reaction time can be shortened to the greatest extent and the production capacity can be increased while ensuring that the yield is not affected. Due to the mild conditions, the reaction will be in an intermediate state of incomplete decarboxylation. Increasing the temperature appropriately can shorten the reaction time. 2-Hydroxy-1,4-butanedialdehyde is easy to deteriorate at high temperatures for a long time, so it is very important to find the best temperature and time range to balance the two. Adding an appropriate amount of sodium chloride during post-treatment can better stratify and facilitate extraction. Adding sodium chloride to a saturated state can make it easier to extract 6-hydroxytropinone with good water solubility, reduce the number of extractions and the use of chloroform, and increase the yield of 6-hydroxytropinone. Petroleum ether and ethyl acetate are used instead of acetone during purification, which is more environmentally friendly and more economical. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 is the NMR image of 6-hydroxytropinone prepared in Example 2;

[0024] Figure 2 The liquid chromatogram of 6-hydroxytropinone prepared in Example 2, the ordinate is the response value, the peak width is 0.55min, the peak height is 18914689.5, and the peak area is 118855033.5;

[0025] Figure 3 The mass spectrum of 6-hydroxytropinone prepared in Example 2 is shown in FIG. DETAILED DESCRIPTION

[0026] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention. Embodiment 1:

[0027] A synthesis process of 6-hydroxytropinone, the synthesis process of 6-hydroxytropinone comprising the following steps:

[0028] (1) 0.2 mol / L aluminum chloride and 0.3 mol / L sodium hydroxide were mixed in a mass ratio of 1:2, stirred at 60°C, 300 r / min for 1 hour to obtain a pillaring agent; diatomaceous earth and deionized water were mixed in a mass ratio of 1:40, ultrasonically dispersed for 10 minutes, 0.1 times the pillaring agent of diatomaceous earth was added, stirred at 50°C, 300 r / min for 4 hours, cooled, centrifuged, washed with deionized water 3 times, placed in a vacuum drying oven at 70°C for 6 hours, and then kept warm at 450°C in a muffle furnace for 3 hours to obtain aluminum pillared diatomaceous earth; aluminum pillared diatomaceous earth, zirconium sulfate tetrahydrate, octyltriethoxysilane and deionized water were mixed in a mass ratio of 20:1:0.1:100, stirred at 50°C, 300 r / min for 2 hours, filtered, washed with deionized water once, placed in a vacuum drying oven at 90°C for 6 hours to obtain a hydrophobic solid acid;

[0029] (2) Ammonium bromide, furan and methanol were mixed and stirred evenly in a closed electrolytic cell at a mass ratio of 1:10:50. The mixture was stirred for 5 min at -5°C. The upper and lower electrode plates of the electrolytic cell were graphite, and the bottom of the electrode was 0.5 cm away from the electrolytic cell. The voltage was set to 10 V, the current was 1 A, and the current density was 200 A / m 2 , pass current, electrolyze and stir for 1 hour, distill under reduced pressure, collect the fraction at 50°C at 1.6 kPa, and obtain 2,5-dimethoxydihydrofuran;

[0030] (3) Acetone dicarboxylic acid, methylamine hydrochloride, sodium acetate and deionized water were mixed and stirred at a mass ratio of 2:0.1:1:5, stirred at 0°C for 10 minutes to prepare a buffer solution, at which the pH was controlled at 4.1. Hydrophobic solid acid, 2,5-dimethoxydihydrofuran and deionized water were mixed and stirred at a mass ratio of 0.08:1:30, stirred at 20°C at a speed of 200 r / min for 3 hours, filtered and collected the filtrate, 0.01 times of 6 mol / L sodium hydroxide in 2,5-dimethoxydihydrofuran was added to the filtrate, the temperature was maintained at 20°C, the pH was adjusted to 6.8, and 2-hydroxy-1,4-butanedialdehyde was prepared. 2,5-dimethoxydihydrofuran was added to the 2-hydroxy-1,4-butanedialdehyde in a buffer solution of 1 to 2 times, stirred at 25°C for 300 r / min. / min and stirred for 10 hours, then stirred at 50°C and 300r / min for 1 hour, cooled to room temperature, added 15 times of sodium chloride in 2,5-dimethoxydihydrofuran and 5 times of potassium carbonate in 2,5-dimethoxydihydrofuran, adjusted to pH 8, extracted with chloroform for 4 times, combined the organic phases, distilled off the chloroform to obtain a yellow-brown colloidal crystalline mixture, prepared eluent with petroleum ether and ethyl acetate in a volume ratio of 10:1, placed the yellow-brown colloidal crystalline mixture in the eluent for slurrying, filtered, collected the filter cake, added ethanol and activated carbon, heated to 80°C, stirred for 30 minutes, filtered the activated carbon while hot, then cooled to 5°C for crystallization, filtered, washed once with anhydrous ethanol, placed in a freeze dryer, at -80°C, 30Pa, dried for 3 hours to obtain 6-hydroxytropinone. Embodiment 2:

[0031] A synthesis process of 6-hydroxytropinone, the synthesis process of 6-hydroxytropinone comprising the following steps:

[0032] (1) 0.2 mol / L aluminum chloride and 0.3 mol / L sodium hydroxide were mixed in a mass ratio of 1:2.3, stirred at 70°C and 400 r / min for 1.5 h to prepare a pillaring agent; diatomaceous earth and deionized water were mixed in a mass ratio of 1:45, ultrasonically dispersed for 10 min, 0.15 times the amount of diatomaceous earth as a pillaring agent was added, stirred at 55°C and 400 r / min for 3 h, cooled, centrifuged and filtered, and washed with deionized water for 4 h. The mixture was placed in a vacuum drying oven at 75°C for 5 hours, and then kept at 455°C for 2.5 hours in a muffle furnace to obtain aluminum-pillared diatomite; aluminum-pillared diatomite, zirconium sulfate tetrahydrate, octyltriethoxysilane and deionized water were mixed uniformly in a mass ratio of 22:1:0.2:150, stirred at 60°C and 400r / min for 1.5 hours, filtered, washed twice with deionized water, and placed in a vacuum drying oven at 95°C for 5 hours to obtain a hydrophobic solid acid;

[0033] (2) Ammonium bromide, furan and methanol were mixed and stirred evenly in a closed electrolytic cell at a mass ratio of 1:15:70. The mixture was stirred at -2°C for 8 min. The upper and lower electrode plates of the electrolytic cell were graphite, and the bottom of the electrode was 0.8 cm away from the electrolytic cell. The voltage was set to 12 V, the current was 2 A, and the current density was 500 A / m 2 , pass current, electrolyze and stir for 1.5h, distill under reduced pressure, collect the fraction at 52℃ at 1.7kPa, and obtain 2,5-dimethoxydihydrofuran;

[0034] (3) Acetone dicarboxylic acid, methylamine hydrochloride, sodium acetate and deionized water were mixed and stirred at a mass ratio of 2.2:0.13:1:7, stirred at 5°C for 15 minutes to prepare a buffer solution, at which the pH was controlled at 4.4. Hydrophobic solid acid, 2,5-dimethoxydihydrofuran and deionized water were mixed and stirred at a mass ratio of 0.09:1:35, stirred at 25°C at a speed of 250 r / min for 3.5 hours, filtered and collected the filtrate, 0.015 times of 6 mol / L sodium hydroxide in 2,5-dimethoxydihydrofuran was added to the filtrate, the temperature was maintained at 25°C, the pH was adjusted to 7, and 2-hydroxy-1,4-butanedialdehyde was prepared. 2,5-dimethoxydihydrofuran was added to the 2-hydroxy-1,4-butanedialdehyde. The buffer solution was 1.5 times of 2,5-dimethoxydihydrofuran. The mixture was stirred at 28°C at 400 r / min. / min and stirred for 11 hours, then stirred at 55°C and 400r / min for 1.2 hours, cooled to room temperature, added 18 times of sodium chloride and 7 times of potassium carbonate in 2,5-dimethoxydihydrofuran, adjusted the pH to 8.5, extracted with chloroform 5 times, combined the organic phases, distilled off the chloroform to obtain a yellow-brown colloidal crystalline mixture, prepared eluent with petroleum ether and ethyl acetate in a volume ratio of 10:1, placed the yellow-brown colloidal crystalline mixture in the eluent for slurrying, filtered, collected the filter cake, added ethanol and activated carbon, heated to 82°C, stirred for 35 minutes, filtered the activated carbon while hot, then cooled to 7°C for crystallization, filtered, washed twice with anhydrous ethanol, placed in a freeze dryer, at -75°C, 40Pa, dried for 4 hours, to obtain 6-hydroxytropinone. Embodiment 3:

[0035] A synthesis process of 6-hydroxytropinone, the synthesis process of 6-hydroxytropinone comprising the following steps:

[0036] (1) 0.2 mol / L aluminum chloride and 0.3 mol / L sodium hydroxide were mixed in a mass ratio of 1:2.5, stirred at 80°C and 500 r / min for 2 hours to obtain a pillaring agent; diatomaceous earth and deionized water were mixed in a mass ratio of 1:50, ultrasonically dispersed for 10 minutes, 0.2 times the pillaring agent of diatomaceous earth was added, stirred at 60°C and 500 r / min for 4 hours, cooled, centrifuged and filtered, washed with deionized water 5 times, placed in a vacuum drying oven at 80°C for 6 hours, and then kept warm at 460°C in a muffle furnace for 3 hours to obtain aluminum pillared diatomaceous earth; aluminum pillared diatomaceous earth, zirconium sulfate tetrahydrate, octyltriethoxysilane and deionized water were mixed in a mass ratio of 25:1:0.3:200, stirred at 70°C and 500 r / min for 2 hours, filtered, washed with deionized water 3 times, placed in a vacuum drying oven at 100°C for 6 hours to obtain a hydrophobic solid acid;

[0037] (2) Ammonium bromide, furan and methanol were mixed and stirred in a closed electrolytic cell at a mass ratio of 1:20:100. The mixture was stirred at 0°C for 10 min. The upper and lower electrode plates of the electrolytic cell were graphite, and the bottom of the electrode was 1 cm away from the electrolytic cell. The voltage was set to 15 V, the current was 3 A, and the current density was 600 A / m 2 , pass current, electrolyze and stir for 2h, distill under reduced pressure, collect the fraction at 55℃ at 1.8kPa, and obtain 2,5-dimethoxydihydrofuran;

[0038] (3) Acetone dicarboxylic acid, methylamine hydrochloride, sodium acetate and deionized water were mixed and stirred at a mass ratio of 2.3:0.15:1:10, stirred at 10°C for 20 minutes to prepare a buffer solution, at which the pH was controlled at 4.6. Hydrophobic solid acid, 2,5-dimethoxydihydrofuran and deionized water were mixed and stirred at a mass ratio of 0.1:1:40, stirred at 30°C at a speed of 300 r / min for 4 hours, and the filtrate was collected by filtration. 0.02 times of 6 mol / L sodium hydroxide in 2,5-dimethoxydihydrofuran was added to the filtrate. The temperature was maintained at 30°C and the pH was adjusted to 7.3 to obtain 2-hydroxy-1,4-butanedialdehyde. 2 times of 2,5-dimethoxydihydrofuran in buffer solution was added to 2-hydroxy-1,4-butanedialdehyde. The mixture was stirred at 30°C for 500 r / min. / min and stirred for 12h, then stirred at 60℃ and 500r / min for 1.5h, cooled to room temperature, added 20 times of sodium chloride and 8 times of potassium carbonate in 2,5-dimethoxydihydrofuran, adjusted the pH to 9, extracted with chloroform for 6 times, combined the organic phases, distilled off the chloroform to obtain a yellow-brown colloidal crystalline mixture, prepared eluent with petroleum ether and ethyl acetate in a volume ratio of 10:1, placed the yellow-brown colloidal crystalline mixture in the eluent for slurrying, filtered, collected the filter cake, added ethanol and activated carbon, heated to 85℃, stirred for 40min, filtered the activated carbon while hot, then cooled to 10℃ for crystallization, filtered, washed with anhydrous ethanol 3 times, placed in a freeze dryer, at -70℃, 50Pa, dried for 5h, to obtain 6-hydroxytropinone.

[0039] Comparative Example 1:

[0040] The synthesis of 6-hydroxytropinone in Comparative Example 1 differs from that in Example 2 only in step (1), where step (1) is modified as follows: diatomaceous earth, zirconium sulfate tetrahydrate, octyltriethoxysilane and deionized water are mixed uniformly in a mass ratio of 22:1:0.2:150, stirred at 60°C and 400 r / min for 1.5 h, filtered, washed twice with deionized water, and dried in a vacuum drying oven at 95°C for 5 h to obtain a hydrophobic solid acid. The remaining steps are the same as in Example 2.

[0041] Comparative Example 2:

[0042] The synthesis of 6-hydroxytropinone in Comparative Example 2 differs from that in Example 2 only in step (1), where step (1) is modified as follows: 0.2 mol / L aluminum chloride and 0.3 mol / L sodium hydroxide are uniformly mixed in a mass ratio of 1:2.3, stirred at 70°C, 400 r / min, for 1.5 h to obtain a pillaring agent; diatomaceous earth and deionized water are mixed in a mass ratio of 1:45, ultrasonically dispersed for 10 min, 0.15 times the amount of diatomaceous earth as a pillaring agent is added, and stirred at 55°C, 400 r / m in stirring for 3 hours, cooling, centrifugal filtration, washing with deionized water 4 times, placing in a vacuum drying oven at 75°C for 5 hours, and then keeping in a muffle furnace at 455°C for 2.5 hours to obtain aluminum pillared diatomite; aluminum pillared diatomite, octyl triethoxysilane and deionized water were mixed uniformly in a mass ratio of 1:0.09:6.8, stirred at 60°C, 400r / min for 1.5 hours, filtered, washed with deionized water twice, placed in a vacuum drying oven at 95°C for 5 hours to obtain a hydrophobic solid acid. The remaining steps are the same as in Example 2.

[0043] Comparative Example 3:

[0044] The synthesis of 6-hydroxytropinone in Comparative Example 3 differs from that in Example 2 only in step (1), where step (1) is modified as follows: 0.2 mol / L aluminum chloride and 0.3 mol / L sodium hydroxide are uniformly mixed in a mass ratio of 1:2.3, stirred at 70°C, 400 r / min, for 1.5 h to obtain a pillaring agent; diatomaceous earth and deionized water are mixed in a mass ratio of 1:45, ultrasonically dispersed for 10 min, 0.15 times the amount of diatomaceous earth as a pillaring agent is added, and stirred at 55°C, 400 r / min, for 1.5 h to obtain a pillaring agent; r / min for 3h, cooled, centrifugally filtered, washed with deionized water 4 times, placed in a vacuum drying oven at 75°C for 5h, and then kept at 455°C for 2.5h in a muffle furnace to obtain aluminum pillared diatomite; aluminum pillared diatomite, zirconium sulfate tetrahydrate and deionized water were mixed uniformly in a mass ratio of 22:1:150, stirred at 60°C and 400r / min for 1.5h, filtered, washed with deionized water twice, placed in a vacuum drying oven at 95°C for 5h, and a hydrophobic solid acid was obtained. The remaining steps are the same as in Example 2.

[0045] Comparative Example 4:

[0046] The synthesis of 6-hydroxytropinone in Comparative Example 4 is different from that in Example 2 in that step (1) is not performed, and step (3) is modified as follows: acetone dicarboxylic acid, methylamine hydrochloride, sodium acetate and deionized water are mixed and stirred at a mass ratio of 2.2:0.13:1:7, stirred at 5°C for 15 minutes to prepare a buffer solution, at which the pH is controlled at 4.4; 12 mol / L concentrated hydrochloric acid, 2,5-dimethoxydihydrofuran and deionized water are mixed at a mass ratio of 0.7:1:5, stirred at 25°C at a speed of 250 r / min for 3.5 hours, the filtrate is collected by filtration, 6 mol / L sodium hydroxide (1.4 times the amount of 2,5-dimethoxydihydrofuran) is added to the filtrate, the pH is adjusted to 7, and 2-hydroxy-1,4-butanedialdehyde is obtained; 2,5-dimethoxydihydrofuran is added to 2-hydroxy-1,4-butanedialdehyde. .5 times of buffer, stirred at 28°C, 400r / min for 11h, then stirred at 55°C, 400r / min for 1.2h, cooled to room temperature, added 18 times of sodium chloride and 7 times of potassium carbonate in 2,5-dimethoxydihydrofuran, adjusted pH to 8.5, extracted with chloroform 5 times, combined organic phases, distilled to remove chloroform, obtained a yellow-brown colloidal crystalline mixture, prepared eluent with petroleum ether and ethyl acetate in a volume ratio of 10:1, placed the yellow-brown colloidal crystalline mixture in the eluent for pulping, filtered, collected the filter cake, added ethanol and activated carbon, heated to 82°C, stirred for 35min, filtered the activated carbon while hot, then cooled to 7°C for crystallization, filtered, washed twice with anhydrous ethanol, placed in a freeze dryer, at -75°C, 40Pa, dried for 4h, to obtain 6-hydroxytropinone. The remaining steps are the same as in Example 2.

[0047] Comparative Example 5:

[0048] The synthesis of 6-hydroxytropinone in Comparative Example 5 differs from that in Example 2 only in step (3). Step (3) is modified as follows: acetone dicarboxylic acid, methylamine hydrochloride, sodium acetate and deionized water are mixed and stirred at a mass ratio of 2.2:0.13:1:7, stirred at 5°C for 15 minutes to prepare a buffer solution, at which the pH is controlled at 4.4; hydrophobic solid acid, 2,5-dimethoxydihydrofuran and deionized water are mixed and stirred at a mass ratio of 0.09:1:35, stirred at 25°C at a speed of 250 r / min for 3.5 hours, and the filtrate is collected by filtration; 0.015 times of 6 mol / L sodium hydroxide in 2,5-dimethoxydihydrofuran is added to the filtrate, the temperature is maintained at 25°C, and the pH is adjusted to 7 to obtain 2-hydroxy-1,4-butanedialdehyde; in 2-hydroxy-1,4-butanedialdehyde, Add 1.5 times of 2,5-dimethoxydihydrofuran buffer to 4-butanedialdehyde, stir at 28°C, 400r / min for 11h, then stir at 55°C, 400r / min for 1.2h, cool to room temperature, add 18 times of sodium chloride and 7 times of potassium carbonate, adjust pH to 8.5, extract with chloroform 5 times, combine organic phases, distill off chloroform, obtain yellow-brown colloidal crystalline mixture, beat with acetone, filter, collect filter cake, add ethanol and activated carbon, heat to 82°C, stir for 35min, filter activated carbon while hot, then cool to 7°C for crystallization, filter, wash twice with anhydrous ethanol, place in freeze dryer, dry at -75°C, 40Pa for 4h, and obtain 6-hydroxytropinone. The remaining steps are the same as in Example 2.

[0049] Comparative Example 6:

[0050] The synthesis of 6-hydroxytropinone in Comparative Example 6 differs from that in Example 2 only in step (3), where step (3) is modified as follows: acetone dicarboxylic acid, methylamine hydrochloride, sodium acetate and deionized water are mixed and stirred at a mass ratio of 2.2:0.13:1:7, stirred at 5°C for 15 min to prepare a buffer solution, at which the pH is controlled at 4.4; a hydrophobic solid acid, 2,5-dimethoxydihydrofuran and deionized water are mixed and stirred at a mass ratio of 0.09:1:35, stirred at 25°C at a speed of 250 r / min for 3.5 h, the filtrate is collected by filtration, 0.015 times the amount of 6 mol / L sodium hydroxide in 2,5-dimethoxydihydrofuran is added to the filtrate, the temperature is maintained at 25°C, and the pH is adjusted to 7 to obtain 2-hydroxy-1, 4-butanedialdehyde, add 1.5 times of 2,5-dimethoxydihydrofuran buffer to 2-hydroxy-1,4-butanedialdehyde, stir at 28°C, 400r / min for 48h, add 18 times of sodium chloride and 7 times of potassium carbonate, adjust the pH to 8.5, extract with chloroform 5 times, combine the organic phases, distill off the chloroform, obtain a yellow-brown colloidal crystalline mixture, beat with acetone, filter, collect the filter cake, add ethanol and activated carbon, heat to 82°C, stir for 35min, filter the activated carbon while hot, then cool to 7°C for crystallization, filter, wash twice with anhydrous ethanol, place in a freeze dryer, dry at -75°C, 40Pa for 4h, and obtain 6-hydroxytropinone. The remaining steps are the same as in Example 2.

[0051] Test Example 1

[0052] Yield test

[0053] The yield was calculated based on the actual amount and purity of the target product obtained in the examples and comparative examples. Yield = (actual amount of target product produced / theoretical amount of target product produced) × purity. The results are shown in Table 1.

[0054] Table 1

[0055] Yield (%) purity(%) Yield (%) purity(%) Example 1 69.82 99.16 Comparative Example 1 51.04 98.26 Example 2 70.03 99.34 Comparative Example 2 42.56 97.37 Example 3 69.86 99.25 Comparative Example 3 67.21 98.69 Comparative Example 4 66.59 99.15 Comparative Example 5 71.43 99.02 Comparative Example 6 68.37 99.18

[0056] From the comparison of the experimental data of Examples 1 to 3 and Comparative Examples 1 to 6 in Table 1, it can be found that the synthesis process of the present invention improves the yield of 6-hydroxytropinone.

[0057] By comparison, the yields of Examples 1 to 3 are greater than that of Comparative Example 1. Aluminum-pillared diatomite can increase the acid sites of diatomite to enhance acidity, and can also increase interlayer spacing and specific surface area to increase the contact surface with reactants to improve yield.

[0058] By comparison, the yields of Examples 1 to 3 are greater than that of Comparative Example 2, and zirconium sulfate tetrahydrate is loaded as a solid acid to catalyze the reaction and improve the yield.

[0059] By comparison, the yields of Examples 1 to 3 are greater than that of Comparative Example 2, indicating that the hydrophobic solid acid not only shortens the reaction time but also improves the yield compared to hydrochloric acid.

[0060] The specific implementation methods described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific implementation method of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A synthesis process for 6-hydroxytropinone, characterized in that, The 6-hydroxytropinone is prepared by electrolyzing furan and ammonium bromide to obtain 2,5-dimethoxydihydrofuran, reacting 2,5-dimethoxydihydrofuran with a hydrophobic solid acid to obtain 2-hydroxy-1,4-butanedialdehyde, and reacting with a buffer solution, followed by purification and drying. The hydrophobic solid acid is prepared by reacting diatomaceous earth, aluminum trichloride, zirconium sulfate tetrahydrate and octyltriethoxysilane; The preparation method of the hydrophobic solid acid comprises: uniformly mixing 0.2 mol / L aluminum chloride and 0.3 mol / L sodium hydroxide in a mass ratio of 1:(2-2.5), stirring at 60-80°C and 300-500 r / min for 1-2 hours to obtain a pillaring agent; mixing diatomaceous earth and deionized water in a mass ratio of 1:(40-50), ultrasonically dispersing for 10 minutes, adding 0.1-0.2 times the pillaring agent of diatomaceous earth, stirring at 50-60°C and 300-500 r / min for 2-4 hours, cooling, centrifugally filtering, and washing with deionized water for 3-5 minutes. The method comprises the following steps: mixing the aluminum-pillared diatomite, zirconium sulfate tetrahydrate, octyltriethoxysilane and deionized water in a mass ratio of (20-25):1:(0.1-0.3):(100-200), stirring at 50-70°C and 300-500r / min for 1-2h, filtering, washing with deionized water for 1-3 times, and drying at 90-100°C in a vacuum drying oven for 4-6h to obtain a hydrophobic solid acid.

2. A synthesis process for 6-hydroxytropinone according to claim 1, characterized in that, The buffer solution is prepared by reacting acetone dicarboxylic acid, methylamine hydrochloride and sodium acetate.

3. A synthesis process for 6-hydroxytropinone according to claim 1, characterized in that, The method comprises the following preparation steps: (1) Mix 0.2 mol / L aluminum chloride and 0.3 mol / L sodium hydroxide in a mass ratio of 1:(2-2.5), stir at 60-80°C, 300-500 r / min, and prepare a pillaring agent; mix diatomaceous earth and deionized water in a mass ratio of 1:(40-50), ultrasonically disperse for 10 min, add 0.1-0.2 times the amount of diatomaceous earth as a pillaring agent, stir at 50-60°C, 300-500 r / min for 2-4 h, cool, centrifuge, wash with deionized water 3-5 times, and place in a vacuum. Drying at 70-80°C in a drying oven for 4-6 hours, and then keeping at 450-460°C in a muffle furnace for 2-3 hours to obtain aluminum-pillared diatomite; mixing aluminum-pillared diatomite, zirconium sulfate tetrahydrate, octyltriethoxysilane and deionized water in a mass ratio of (20-25):1:(0.1-0.3):(100-200) uniformly, stirring at 50-70°C, 300-500r / min for 1-2 hours, filtering, washing with deionized water 1-3 times, and drying at 90-100°C in a vacuum drying oven for 4-6 hours to obtain a hydrophobic solid acid; (2) Mix ammonium bromide, furan and methanol in a mass ratio of 1: (10-20): (50-100) in a closed electrolytic cell and stir evenly, stir for 5-10 min at -5-0°C, pass current, electrolyze and stir for 1-2 h, and perform vacuum distillation at 1.6-1.8 kPa, collect the fraction at 50-55°C, and obtain 2,5-dimethoxydihydrofuran; (3) Mix acetone dicarboxylic acid, methylamine hydrochloride, sodium acetate and deionized water in a mass ratio of (2-2.3): (0.1-0.15): 1: (5-10) and stir evenly. Stir for 10-20 min at 0-10°C to prepare a buffer solution. At this time, the pH is controlled at 4.1-4.

6. Mix hydrophobic solid acid, 2,5-dimethoxydihydrofuran and deionized water in a mass ratio of (0.08-0.1): 1: (30-40) and stir evenly. 20-30°C, rotation speed of 200-300r / min, stirring for 3-4h, filtering and collecting the filtrate, adding 0.01-0.02 times of 6mol / L sodium hydroxide of 2,5-dimethoxydihydrofuran, maintaining the temperature at 20-30°C, adjusting the pH to 6.8-7.3, preparing 2-hydroxy-1,4-butanedialdehyde, adding 1-2 times of 2,5-dimethoxydihydrofuran buffer to 2-hydroxy-1,4-butanedialdehyde, and stirring at 25-30°C. ℃, 300~500r / min stirring for 10~12h, then at 50~60℃, 300~500r / min stirring for 1~1.5h, cool to room temperature, add 15~20 times of sodium chloride and 5~8 times of potassium carbonate of 2,5-dimethoxydihydrofuran, adjust pH to 8~9, extract with chloroform 4~6 times, combine organic phases, distill off chloroform, and obtain a yellow-brown colloidal crystalline mixture, use petroleum ether and Ethyl acetate is prepared as an eluent in a volume ratio of 10:1, a yellow-brown colloidal crystalline mixture is placed in the eluent for slurrying, filtered, the filter cake is collected, ethanol and activated carbon are added, heated to 80-85°C, stirred for 30-40 minutes, the activated carbon is filtered while hot, then cooled to 5-10°C for crystallization, filtered, washed with anhydrous ethanol for 1-3 times, placed in a freeze dryer, and dried at -80--70°C, 30-50 Pa, for 3-5 hours to obtain 6-hydroxytropinone.

4. A synthesis process for 6-hydroxytropinone according to claim 3, characterized in that, The electrolytic cell setting parameters in step (2) are as follows: the upper and lower electrode plates are graphite, the bottom of the electrode is 0.5-1 cm away from the electrolytic cell, the voltage is 10-15 V, the current is 1-3 A, and the current density is 200-600 A / m 2 .

5. A synthesis process for 6-hydroxytropinone according to claim 3, characterized in that, The reaction process of 2,5-dimethoxydihydrofuran in step (2) is as follows: 。 6. A synthesis process for 6-hydroxytropinone according to claim 3, characterized in that, The reaction process of 6-hydroxytropinone in step (3) is as follows: 。

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