Method for efficiently synthesizing apoate

Abstract

The invention relates to the technical field of small molecule synthesis, in particular to a method for efficiently synthesizing apoate, which comprises the following steps: S1, condensation reaction: mixing C5 phosphate and C10 dialdehyde in a molar ratio of (0.8-1.2): 1 under the protection of inert gas, and carrying out catalytic reaction for 0.5-2 hours in a solvent at-10-10 DEG C through a base catalyst to generate a C15 aldehyde intermediate; and S2, condensation reaction: mixing C15 aldehyde and C15 phosphate ester in a solvent according to a molar ratio of (0.8-1.2): 1, dropwise adding an alkali catalyst at 0 DEG C, and reacting for 1-2 hours to obtain the apoester. High-activity condensation and coupling are achieved through the catalyst, the reaction time is shortened to be within 4 hours, and the yield is larger than or equal to 85%; compared with the traditional process, the discharge amount of three wastes is reduced by 40-60%, and toxic by-products are avoided; the problems of low yield and heavy pollution in the prior art are solved, and an efficient and economical solution is provided for large-scale clean production of the apoate.

Description

Technical Field

[0001] The present invention relates to the technical field of small molecule synthesis, and particularly to a method for efficiently synthesizing apo-ester. Background Art

[0002] Apo-ester (β-apo-8'-carotene acetate) is a yellow carotenoid that widely exists in nature, especially as a metabolite of apo-carotenal in plants. As a kind of carotenoid, the biological function of apo-ester is very similar to that of most natural carotenoids. It has significant antioxidant effects and good coloring ability, and can effectively improve the color of multiple parts in poultry, such as egg yolks, skin, shanks, and fat. One of its main applications is to add apo-ester to the feed of laying hens to supplement the deficiency of yellow pigments in the feed. By different addition schemes, the desired color of the egg yolk can be precisely controlled, thus meeting the market demand for the appearance of egg yolks and enhancing the market value of poultry products. In addition, apo-ester can also be used as an antioxidant to help improve the health of poultry, delay the aging process, and increase production efficiency.

[0003] The molecular structure of ethyl β-apo-8'-carotenoate contains multiple conjugated double bond systems. Its chemical synthesis route can theoretically be formed by combining different synthetic fragments through connection, and these fragments may gradually construct the final molecular structure through different chemical reactions. US2827481 reported the C25+C2+C3 process. This synthesis route requires the use of vinyl ethyl ether (C2), which has a low boiling point (35 - 36 °C) and a wide explosion limit (1.7 - 28% by volume). Therefore, there are significant safety risks during storage, especially more dangerous during large-scale production. In addition, in the reaction, ethyl 2-chloropropionate and triethyl phosphite are used to synthesize C3 phosphonate ester, but the yield of this process is low, and a large amount of high-COD phosphorus-containing wastewater will be generated, bringing significant environmental pollution problems. US 3989758 reported the C20+C10 route. Although the C20 phosphonium salt can be conveniently separated from the vitamin A synthesis system, the C10 synthesis process is relatively complex and involves a variety of raw materials and auxiliary materials. This process not only has a long route, large consumption of raw materials, but also a high discharge of three wastes, causing environmental pressure. In addition, due to multiple-step reactions and the use of expensive reagents, the cost of the whole process is high and the economy is poor. US 5773635 reported the C25+C5 route. Although the preparation of the C25+C5 route has been reported both at home and abroad and has been industrialized, it has some disadvantages. First, β-carotene will be generated during the preparation of C25. Due to its poor solubility, it is difficult to purify the C25 intermediate. Second, the preparation of C25 involves C15 phosphonium salt, and the by-product triphenylphosphine oxide generated after the reaction is difficult to remove, and the raw material cost is high.

[0004] Therefore, there is an urgent need to develop a synthesis process for apocynin, which should have a high yield, low cost, a simple preparation process, and meet environmental protection requirements to address the urgent needs in the current technical field. Summary of the Invention

[0005] (1) Technical Problems to be Solved

[0006] In view of the deficiencies of the prior art, the present invention provides a method for efficiently synthesizing apocynin.

[0007] (2) Technical Solutions

[0008] A method for efficiently synthesizing apocynin, characterized by comprising the following steps:

[0009] S1, Condensation reaction of C5 phosphate and C10 dialdehyde: Under the protection of an inert gas, C5 phosphate and C10 dialdehyde are mixed in a molar ratio of 0.8 - 1.2:1, an alkali catalyst is added, and the molar ratio of the catalyst to C5 phosphate is 1 - 2:1. The reaction is carried out in a solvent at -10 - 10 °C for 0.5 - 2 h to form a C15 aldehyde intermediate;

[0010] S2, Condensation reaction of C15 aldehyde and C15 phosphate: The C15 aldehyde obtained in S1 and C15 phosphate are mixed in a molar ratio of 0.8 - 1.2:1. A sodium hydride catalyst solution is added dropwise to the system at 0 °C, and the molar ratio of the catalyst to C15 aldehyde is 1 - 2:1. At the same time, a solvent is added to the reaction system, and the reaction is carried out under the protection of an inert gas for 1 - 2 hours to finally obtain the apocynin product. The synthesis of C5 + C10 → C15 aldehyde → C30 apocynin can be completed only through two-step reactions, avoiding the complexity of traditional multi-step reactions. The whole process is protected by an inert gas to reduce oxidation by-products, and there are no high-temperature and high-pressure conditions, reducing energy consumption and the emission of three wastes.

[0011] Preferably, the structural formula of the C5 phosphate is:

[0012]

[0013] The structural formula of the C10 dialdehyde is:

[0014]

[0015] The structural formula of the C15 phosphate is:

[0016]

[0017] The synthesis route of the apocynin is as follows:

[0018]

[0019] Preferably, the base catalysts in S1 and S2 are independently selected from at least one of sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, and sodium tert-butoxide, and both are preferably sodium hydride. The reaction is carried out under the protection of nitrogen or argon. After the reaction is terminated, the solvent is removed by vacuum distillation, and the C15 aldehyde intermediate is purified by ethanol recrystallization. The sodium hydride catalyst still maintains high activity at low temperatures, avoiding the high-temperature requirements of traditional catalysts and reducing side reactions. The protection of nitrogen or argon prevents sodium hydride from exploding when encountering water and improves the operation safety.

[0020] Preferably, the specific operation of S2 includes: slowly adding the sodium hydride catalyst dropwise to the solution of C15 phosphate in 3 - 5 times, with an interval of 10 - 20 minutes each time, and the total dropping time is 0.5 - 1.5 hours; then adding the solution containing C15 aldehyde dropwise to the reaction system with a constant-pressure dropping funnel, controlling the dropping rate to keep the temperature of the reaction solution at 0 ± 2 °C, and continuing to stir and react after the dropping is completed until TLC detection shows that the raw materials are completely converted.

[0021] Preferably, the solvents of S1 and S2 are independently selected from at least one of methanol, ethanol, tetrahydrofuran, ether, toluene, n-hexane, dimethyl sulfoxide, dichloromethane, and 1,2-dichloroethane methanol. The mass ratio of the solvent of S1 to C5 phosphate is 8:1 - 15:1, and the mass ratio of the solvent of S2 to C15 aldehyde is 6:1 - 10:1.

[0022] Preferably, the purification of the final product apolactone adopts the ethanol recrystallization method. The specific steps are as follows: dissolving the crude product in 3 - 5 times the volume of hot ethanol at a temperature of 60 - 80 °C, stirring until completely dissolved; slowly cooling to 0 - 5 °C, standing for crystal precipitation for 2 - 4 hours; filtering to collect the crystals, washing with pre-cooled ethanol at a temperature of 0 °C, and the amount of ethanol used is 1 - 2 times the mass of the crystals; drying under vacuum at a drying temperature of 40 - 50 °C for 6 - 8 hours to obtain orange-red crystalline apolactone with a purity of ≥ 99.0%.

[0023] Preferably, the overall reaction yield is ≥ 85%, and the method is applicable to industrial production on a scale from grams to tons. There are no highly toxic by-products generated during the reaction process, and the three-waste emissions are reduced by more than 60% compared with the traditional process.

[0024] (III) Beneficial technical effects

[0025] Compared with the existing technology, the beneficial effects of the present invention are as follows:

[0026] 1. By precisely controlling the molar ratio of C5 phosphate to C10 dialdehyde and the condensation conditions of C15 phosphate, combined with the efficient catalytic effect of sodium hydride catalyst, side reactions are significantly reduced, and the overall reaction yield is ≥ 85%; the crude product of apocynin is purified by ethanol recrystallization method to effectively remove impurities and unreacted raw materials, and the purity of the final product apocynin is ≥ 99.0%, meeting the high standards in the fields of medicine and fine chemicals.

[0027] 2. Using inexpensive and readily available base catalysts such as sodium hydride to replace traditional noble metal catalysts, the raw material cost is significantly reduced; the usage of solvents such as methanol and tetrahydrofuran is optimized by the mass ratio of solvent to raw material to reduce reagent waste; the reaction steps are a simple two-step condensation, the operating conditions are mild, no complex equipment or high-pressure environment is required, and the total reaction time of the production cycle is ≤ 4 hours, suitable for rapid industrial production.

[0028] 3. The whole reaction process is carried out under the protection of inert gas to avoid the formation of oxidation by-products; there are no highly toxic intermediates or by-products such as halogen-containing wastes in the process, and the emissions of the three wastes are reduced compared with the traditional process; solvents such as methanol and tetrahydrofuran can be recycled, and low-toxic eluents such as petroleum ether and ethyl acetate are used in the purification process, meeting the requirements of green chemistry and sustainable development.

[0029] 4. The method is applicable to scale production from grams to tons. By adding the catalyst in batches at intervals of 10 - 20 min and precisely controlling the temperature, the stability and repeatability of the reaction system are ensured, meeting the flexible requirements of different scale production lines; the product can be directly used for the synthesis of high-value-added products such as vitamin A and carotenoids, providing efficient raw materials for the fields of medicine, food additives, etc., and having significant market competitiveness. Brief Description of the Drawings

[0030] Figure 1 It is a radar chart prepared by standardizing the product quality data of Example 1 with the pharmacopoeia standard;

[0031] Figure 2 It is a radar chart prepared by standardizing the product quality data of Example 2 with the pharmacopoeia standard;

[0032] Figure 3 It is a radar chart prepared by standardizing the product quality data of Example 3 with the pharmacopoeia standard;

[0033] Figure 4 It is the test result of the molar yield of the examples and the comparative examples;

[0034] Figure 5 It is the test result of the solvent recovery rate and raw material utilization rate of the examples and the comparative examples. Detailed Description of the Invention

[0035] Example 1

[0036] Raw materials and reagents: C5 phosphate: 10.0 g (0.05 mol); C10 dialdehyde: 7.2 g (0.05 mol); Sodium hydride (NaH), 60% dispersed in mineral oil: 2.4 g (0.1 mol); Methanol, analytical grade: 120 mL. The solvent dosage is 12 times the mass of C5 phosphate; Argon, purity ≥ 99.999%.

[0037] Operation steps: Condensation reaction S1: Purge the air in a 500 mL three-necked flask with argon, add C10 dialdehyde and 80 mL of methanol, and stir to dissolve. Dissolve C5 phosphate in 40 mL of methanol, and slowly add it dropwise to the reaction system through a constant pressure dropping funnel within 30 minutes, maintaining the system temperature at 0 °C. Add sodium hydride in batches, 3 times at intervals of 10 minutes, control the reaction temperature not to exceed 5 °C, and stir the reaction for 1.5 hours. The reaction solution is distilled under reduced pressure at 60 °C and 0.1 MPa to remove methanol. The residue is dissolved in 50 mL of dichloromethane and washed with water 3 times (30 mL each time) to remove inorganic salts. After the organic phase is dried over anhydrous sodium sulfate, it is recrystallized with ethanol to obtain 13.2 g of orange-red solid C15 aldehyde form III, with a yield of 89.5% and an HPLC purity of 98.5%.

[0038] Condensation reaction S2: In a 250 mL reaction flask, dissolve 15.0 g (0.034 mol) of C15 phosphate in 135 mL of methanol, and cool it to 0 °C in an ice bath. Add 1.8 g (0.075 mol) of sodium hydride in 4 portions at intervals of 15 minutes, maintaining the temperature ≤ 5 °C. Dissolve 13.7 g (0.034 mol) of C15 aldehyde in 15 mL of methanol, and add it dropwise through a constant pressure funnel within 1 hour. Continue to stir the reaction for 2 hours.

[0039] After monitoring by TLC and showing that the spots of the raw materials disappeared using a developing agent of petroleum ether - ethyl acetate (3:1), the reaction solution was extracted with ethyl acetate 3 times (50 mL each time). The organic phases were combined and concentrated to 1 / 3 of the original volume. The crude product was dissolved in ethanol at 60 °C, with a dosage 4 times the mass of the crude product. Stir until completely dissolved, slowly cool to 0 - 5 °C, stand for crystal precipitation for 3 h, filter and collect the crystals, wash them with pre-cooled ethanol (ethanol at 0 °C), with a dosage 1.5 times the mass of the crystals, and dry them under vacuum at 45 °C for 7 hours to obtain 18.5 g of orange-red crystalline apoplate, with a yield of 89.0% and a purity of 99.1%.

[0040] Example 2

[0041] Solvent replacement: Replace methanol with tetrahydrofuran (THF) to enhance the low-temperature reaction activity.

[0042] Gradient addition of the catalyst: Add sodium hydride in stages to control the heat release.

[0043] Operation process: In stage S1: 50.0 g (0.25 mol) of C5 phosphate and 36.0 g (0.25 mol) of C10 dialdehyde were dissolved in 500 mL of THF, and 12.0 g (0.5 mol) of sodium hydride was added dropwise at -5°C, followed by reacting for 1 hour; after purification, 67.3 g of C15 aldehyde was obtained with a yield of 92.3% and a purity of 99.0%.

[0044] In stage S2: 67.3 g (0.17 mol) of C15 aldehyde and 75.6 g (0.17 mol) of C15 phosphate were reacted in THF, and sodium hydride was added in 5 portions with a total amount of 8.5 g (0.35 mol).

[0045] The yield of the final product apolactone was 93.5%, the purity was 99.4%, and the solvent recovery rate was 85%.

[0046] Example 3

[0047] Equipment and process

[0048] Reactor: 10 m 3 Glass-lined reaction kettle with jacket temperature control system

[0049] Production process: In stage S1: 1 ton (5 kmol) of C5 phosphate, 720 kg (5 kmol) of C10 dialdehyde, and 10 tons of THF were fed, and the reaction was carried out at -5°C for 1 hour; continuous extraction and purification were carried out to obtain 1.32 tons of C15 aldehyde with a yield of 90.1%.

[0050] In stage S2: 1.32 tons of C15 aldehyde and 1.46 tons of C15 phosphate were reacted in THF, and 240 kg (10 kmol) of sodium hydride was added in 10 batches; the reaction solution was centrifuged and the solvent THF was recovered with a recovery rate of 94%, obtaining 2.05 t of apolactone with a yield of 89.8% and a purity of 99.0%.

[0051] Comparative example

[0052] Traditional C25 + C5 condensation process: C25 phosphonium salt and C5 aldehyde were condensed in DMF at 80°C for 8 hours with a yield of 65%. Isomerization required a Pd / C catalyst with a loading of 5%, pressurized with hydrogen to 5 atm, and reacted for 12 hours with a yield of 70%; after three column chromatographies + two recrystallizations, the total yield was ≤50%.

[0053] Reaction condition and efficiency comparison table:

[0054] Project Example 1 Example 2 Example 3 Comparative Example Catalyst type Sodium hydride Sodium hydride Sodium hydride Triethylamine Reaction temperature °C 0 -5 -5 80 Total reaction time h 3.5 2.5 2.0 20 Molar yield % 91.2 93.5 89.8 50 Solvent toxicity Low Low Low High DMF

[0055] Conclusion: The reaction temperature is reduced from 80 °C to -5 to 0 °C to avoid the decomposition of heat-sensitive raw materials, and the yield is increased by 39.8% from 50% to 89.8%; the total reaction time is compressed from 20 hours to 2 to 3.5 hours, and the production efficiency is increased by 5 to 10 times, which is suitable for continuous production; the low-toxicity solvents methanol or THF are used to replace the carcinogenic DMF, and the risk of worker exposure is reduced by 90%.

[0056] Comparison table of environmental protection and economic benefits:

[0057] Index Example 1 Example 2 Example 3 Comparative Example COD emission g / L 120 100 95 850 Hazardous waste amount kg / ton 0.8 0.7 0.6 5.2 Solvent recovery rate % 92 85 94 60 Unit energy consumption kWh / kg 0.8 0.7 0.6 2.8 Raw material utilization rate % 98 97 96 82

[0058] Conclusion: The COD emission is reduced by 88.2% from 850 to 95 g / L, and 425 tons of organic pollutants are reduced annually, meeting the discharge standard of HJ501-2019; the solvent recovery rate is increased to 94%; the product energy consumption is reduced from 28,000 kWh to 6,000 kWh, and 11 million kWh of electricity is saved annually;

[0059] Comparison table of product quality and market competitiveness:

[0060] Parameter Example 1 Example 2 Example 3 Pharmacopoeia standard Purity HPLC % 99.1 99.4 99.0 ≥98.0 Moisture content % 0.12 0.09 0.10 ≤0.5 Heavy metal ppm <1 <1 <1 ≤10 Crystal form stability 24 months 24 months 24 months 12 months Market unit price ¥ / kg 3200 3350 3100 2800

[0061] Conclusion: The HPLC purity is stably ≥99.0%, meeting the requirements of high-end pharmaceutical intermediates such as vitamin A API, with a 15-20% premium compared to similar products; the crystal form stability is extended to 24 months, reducing customer storage losses, the heavy metal residue <1 ppm, passing the FDA and EDQM certifications, entering the high-end markets in Europe and America, and the export unit price is increased by 30%.

[0062] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill 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 present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for efficiently synthesizing apoesters, characterized in that: The following steps are involved: S1, condensation reaction of C5 phosphate and C10 dialdehyde: under the protection of inert gas, C5 phosphate and C10 dialdehyde are mixed at a molar ratio of 0.8-1.2:1, a base catalyst is added, and the molar ratio of the catalyst to C5 phosphate is 1-2:1, and the reaction is carried out in a solvent at -10-10°C for 0.5-2h to generate a C15 aldehyde intermediate; S2, condensation reaction of C15 aldehyde and C15 phosphate: C15 aldehyde obtained in S1 is mixed with C15 phosphate in a molar ratio of 0.8-1.2:1, and a base catalyst is added dropwise to the system at 0°C, wherein the molar ratio of the catalyst to C15 aldehyde is 1-2:

1. Meanwhile, a solvent is added to the reaction system, and the reaction is carried out for 1-2 hours under the protection of an inert gas to finally obtain an apo ester product.

2. A method for efficiently synthesizing apoester according to claim 1, characterized in that: The structural formula of the C5 phosphate is: The structural formula of the C10 dialdehyde is: The structural formula of the C15 phosphate is: The synthetic route of the apoester is as follows:

3. A method for efficiently synthesizing apoester according to claim 1, characterized in that: The base catalysts in S1 and S2 are independently selected from at least one of sodium hydrogen, sodium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide and sodium tert-butoxide, preferably sodium hydrogen, and the reaction is carried out under the protection of nitrogen or argon. After the reaction is terminated, the solvent is removed by reduced pressure distillation, and the C15 aldehyde intermediate is purified by ethanol recrystallization.

4. A method for efficiently synthesizing apoester according to claim 1, characterized in that: The specific operation of S2 includes: slowly adding the base catalyst to the solution of C15 phosphate in 3-5 times, with an interval of 10-20 minutes between each addition and a total addition time of 0.5-1.5 hours; then, adding the solution containing C15 aldehyde dropwise into the reaction system with a constant pressure dropping funnel, controlling the dropping speed so that the temperature of the reaction liquid is maintained at 0±2°C, and continuing to stir the reaction after the addition is completed until TLC detection shows that the raw material is completely converted.

5. A method for efficiently synthesizing apoester according to claim 1, characterized in that: The solvents of S1 and S2 are independently selected from at least one of methanol, ethanol, tetrahydrofuran, ether, toluene, n-hexane, dimethyl sulfoxide, dichloromethane and 1,2-dichloroethanemethanol, and the mass ratio of the solvent of S1 to the C5 phosphate is 8:1-15:1, and the mass ratio of the solvent of S2 to the C15 aldehyde is 6:1-10:

1.

6. The method according to claim 1, characterized in that: The final product, apo-ester, is purified by an ethanol recrystallization method, and the specific steps are: dissolving the crude product in 3-5 times the volume of hot ethanol at a temperature of 60-80°C, and stirring until completely dissolved; slowly cooling to 0-5°C, standing for crystallization for 2-4 hours; filtering and collecting the crystals, and washing with pre-cooled ethanol at a temperature of 0°C and an amount of 1-2 times the mass of the crystals; vacuum drying at a drying temperature of 40-50°C and a drying time of 6-8 hours to obtain orange-red crystalline apo-ester with a purity of ≥99.0%.

7. A method for efficiently synthesizing apoester according to any one of claims 1 to 5, characterized in that: The overall reaction yield is ≥85%, and the method is suitable for industrial production on a gram-ton scale. No highly toxic by-products are generated during the reaction, and the discharge of three wastes is reduced by more than 60% compared with traditional processes.

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