Method for preparing high-purity xanthoxylin through catalysis

Abstract

The invention discloses a method for preparing high-purity xanthoxylin through catalysis, and belongs to the technical field of chemical synthesis. The method comprises the following steps: reacting a cinnamic acid derivative and homoveratramine in an organic solvent in the presence of a boron catalyst; after the reaction is finished, the xanthoxylin with the purity of more than 99.5% is obtained through simple treatment. The invention provides an economical and efficient amplification preparation method of xanthoxylin, the product purity is high, and wide application of xanthoxylin in the aspects of aging resistance, virus resistance, inflammation resistance and the like is expected to be promoted.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for catalytically preparing high-purity xanthocyanin. Background Technology

[0002] Zanthoxylum is a natural product with good neurological safety, and its core pharmacological characteristic is a significant anti-aging effect. Recent research further reveals that zanthoxylum also possesses anti-Alzheimer's disease (AD) activity, demonstrating extremely high potential for drug development. However, the content of this compound in natural zanthoxylum is low, making large-scale production through plant extraction difficult. Therefore, developing a chemical synthesis method for zanthoxylum is of great significance.

[0003] The core structure of xanthocyanin is a β-phenyl-α,β-unsaturated amide, and there are currently four main synthetic routes:

[0004] Route 1: Reaction of high resveratrol with cinnamic acid under stoichiometric conditions of classic condensing agents such as dicyclohexylcarbodiimide (DCC) or 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (CN102552229A, Molecules 2018, 23, 2663).

[0005] Route 2: Replace the condensing agent with tris(2,2,2-trifluoroethoxy)borane. Its dosage can be reduced to 50 mol% (J. Org. Chem. 2019, 84, 15294).

[0006] Route 3: First, cinnamic acid is converted to cinnamoyl chloride, and then reacted with resveratrol under alkaline conditions (CN103130647 A, Org. Lett. 2001, 3, 2411).

[0007] Route 4: First, synthesize a Horner-Wadsworth-Emmons (HWE) reagent containing a high resveratrol structure through multiple steps, and then react it with vanillin via an HWE reaction to obtain the product (WO2014 / 129874 A1, ACS Comb. Sci. 2013, 15, 208).

[0008] While all four routes can yield xanthocyanin, they all have significant drawbacks: Route 1 requires the use of a stoichiometric condensing agent, generating a large amount of waste; Route 2 uses... The compound is expensive and still requires relatively high quantities. Routes 3 and 4 are both multi-step syntheses, which suffer from complex post-processing, poor stereoselectivity, and numerous byproducts. In addition, biosynthesis (CN119432890 A) and flow chemistry (CN 117534586 A) have also been explored for the preparation of xanthocyanin, which further highlights the importance of this compound and the urgent need to develop novel and efficient synthetic processes.

[0009] Given that the target application areas of xanthoside (such as health products and medicines) have extremely high requirements for compound purity, developing a simple, efficient, convenient, low-cost and environmentally friendly method for synthesizing high-purity xanthoside has significant practical and economic value. Summary of the Invention

[0010] In view of this, the present invention provides a method for catalytic preparation of high-purity xanthocyanin, which has higher product purity than previous methods, and the reaction process is more environmentally friendly, making it suitable for industrial production of xanthocyanin.

[0011] The method for catalytically preparing high-purity xanthocyanin according to the present invention includes the following steps: using cinnamic acid derivative and high-reflexamine as raw materials, reacting in organic solvent A in the presence of boron catalyst; after the reaction is completed, adding organic solvent B and controlling the temperature to slowly crystallize and precipitate high-purity xanthocyanin.

[0012] Furthermore, in the above technical solution, the cinnamic acid derivative is selected from cinnamic acid or cinnamic esters. Preferably, the cinnamic ester is methyl cinnamate or ethyl cinnamate.

[0013] Furthermore, in the above technical solution, the molar ratio of high resveratrol to cinnamic acid derivative is 1:1-1.5, preferably 1:1; the molar ratio of high resveratrol to boron catalyst is 1:0.01-0.1, preferably 1:0.02.

[0014] Furthermore, in the above technical solution, the boron catalyst is a Lewis base-borane adduct.

[0015] Furthermore, in the above technical solution, the Lewis base-borane adduct has the structural formula R. 1 R 2 R 3 N . BH3 or R 1 R 2 R 3 P . BH3; where: R 1-3 Each is independently selected from hydrogen, alkyl, alkenyl, or aryl.

[0016] Furthermore, in the above technical solution, organic solvent A is selected from one or more of ethyl acetate, tetrahydrofuran, acetonitrile, dichloromethane, toluene, o-xylene, p-xylene, m-xylene, ethanol, methanol, or water. It is preferably selected from toluene or xylene (including mixtures of o-, m-, and p-xylene).

[0017] Furthermore, in the above technical solution, the organic solvent B is selected from one or more of acetonitrile, dichloromethane, ethanol, methanol, or water. Ethanol and water are preferred.

[0018] Furthermore, in the above technical solution, as a further explanation of the present invention, the crystallization operation is as follows: (1) Concentrate the reaction system; (2) Add organic solvent B to the system; (3) Control the temperature to slowly crystallize and precipitate; (4) Wash the obtained solid n-hexane to obtain crystalline xanthocyanin, with a product purity of over 99.5%.

[0019] Typically, the present invention is represented by the following reaction equation: Wherein: R is selected from carboxyhydroxy, methoxy, ethoxy, etc.; X is selected from N and P. Beneficial effects of the invention

[0020] 1. This invention discloses a method for the green preparation of high-purity xanthocyanin, which has the advantages of simple and readily available raw materials, high solvent economy, suitable temperature control, and a single reaction product. Reaction byproducts can be promptly treated and removed from the reaction system, enabling the preparation of the target compound with high yield and high purity.

[0021] 2. The reagents and catalysts required in the reaction process of this invention are readily available, and most of them can be purchased directly; the reaction process generates little waste and causes little environmental pollution, and has the potential for large-scale synthesis. Attached Figure Description

[0022] Figure 1 The HPLC spectrum of the xanthocyanin product in Example 1 is shown below. Figure 2 The 1H NMR spectrum of the xanthocyanin product in Example 1; Figure 3 The carbon NMR spectrum of the xanthocyanin product in Example 1; Figure 4 The HPLC spectrum of the xanthocyanin product in Example 2 is shown below. Figure 5 The 1H NMR spectrum of the xanthocyanin product in Example 2; Figure 6 The carbon NMR spectrum of the xanthocyanin product in Example 2; Figure 7 Here is the HPLC spectrum of the xanthocyanin product from Example 3; Figure 8 The 1H NMR spectrum of the xanthocyanin product in Example 3; Figure 9 The carbon NMR spectrum of the xanthocyanin product in Example 3 is shown. Detailed Implementation

[0023] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0024] Example 1 Taking the synthesis of xanthocyanin using cinnamic acid and resveratrol as an example, the reaction conditions were optimized as follows: The chemical reaction formula is shown below:

[0025] After screening, the optimal conditions for synthesizing xanthocyanin were determined to be: using 2 mol% ammonia borane as a catalyst, cinnamic acid and resveratrol as raw materials, toluene as the reaction solvent, and refluxing for 5 hours. Typical operating steps are as follows: Cinnamic acid (1.482 g, 10 mmol), resveratrol (1.812 g, 10 mmol), ammonia borane (6.2 mg, 0.2 mmol), and 10 mL of toluene were added sequentially to a three-necked flask equipped with a reflux separator. After thorough mixing, the mixture was refluxed for 5 h. After the reaction was complete, the reaction mixture was concentrated to 2 mL, and then 2 mL of water was added to the mixture. The temperature was controlled to allow a white needle-like solid to precipitate slowly. The precipitate was filtered through a sintered glass funnel, washed with n-hexane, and the solid was collected to obtain 2.964 g of xanthocyanin, with a yield of 95.2% (HPLC 99.52%). 1 H NMR (CDCl3): δ 7.62 (d, J = 15.6 Hz, 1H), 7.52–7.42(m,2H), 7.38–7.31(m, 3H), 6.82(d, J = 8.0 Hz, 1H), 6.79– 6.72 (m, 2H), 6.33 (d, J =15.6 Hz, 1H), 5.72 (t, J = 6.0 Hz, 1H), 3.86 (s, 3H), 3.86 (s, 3H), 3.64 (q, J=6.6 Hz, 2H), 2.84 (t, J = 6.9 Hz, 2H). 13 C NMR(CDCl3): δ 166.00, 149.20, 147.86,141.19, 134.90, 131.4 8, 129.81, 128.94, 127.90, 120.79, 120.71, 112.08,111.52, 56.05, 56.00, 41.06, 35.34. Example 2 In a three-necked flask equipped with a reflux separator, 1.622 g (10 mol) of methyl cinnamate, 1.812 g (10 mmol) of resveratrol, 6.2 mg (0.2 mmol) of ammonia borane, and 10 mL of toluene were added sequentially. After stirring thoroughly, the mixture was heated to reflux for 5 h. After the reaction was complete, the reaction mixture was concentrated to 2 mL, and then 2 mL of water was added to the mixture. The temperature was controlled to allow a white needle-like solid to precipitate slowly. The precipitate was filtered through a sintered glass funnel, washed with n-hexane, and the solid was collected to obtain 2.802 g of xanthocyanin, with a yield of 90.0% (HPLC 99.56%). 1 H NMR (CDCl3): δ 7.62 (d, J = 15.6 Hz, 1H), 7.52–7.42 (m,2H), 7.38– 7.31 (m, 3H), 6.82 (d, J = 8.0 Hz, 1H), 6.79–6.72 (m, 2H), 6.33 (d, J = 15.6 Hz, 1H), 5.72 (t, J = 6.0 Hz, 1H), 3.86 (s, 3H), 3.86 (s, 3H), 3.64 (q, J = 6.6 Hz, 2H), 2.84 (t, J = 6.9 Hz, 2H). 13 C NMR(CDCl3): δ 166.00, 149.20,147.86, 141.19, 134.90, 131.4 8, 129.81, 128.94, 127.90, 120.79, 120.71,112.08, 111.52, 56.05, 56.00, 41.06, 35.34. Example 3 In a three-necked flask equipped with a reflux separator, 14.82 g (100 mmol) of cinnamic acid, 18.12 g (100 mmol) of resveratrol, 61.7 mg (2.0 mmol) of ammonia borane, and 100 mL of toluene were added sequentially. After stirring thoroughly, the mixture was heated to reflux for 8 h. After the reaction was complete, the reaction mixture was concentrated to 20 mL, and then 20 mL of water was added to the mixture. The temperature was controlled to allow a white needle-like solid to precipitate slowly. The precipitate was filtered through a sintered glass funnel, washed with n-hexane, and the solid was collected to obtain 28.91 g of xanthocyanin, with a yield of 92.8% (HPLC 99.86%). 1 H NMR (CDCl3): δ 7.62 (d, J = 15.6 Hz, 1H), 7.52–7.42 (m,2H), 7.38–7.31 (m, 3H), 6.82 (d, J = 8.0 Hz, 1H), 6.79– 6.72 (m, 2H), 6.33 (d, J = 15.6 Hz, 1H), 5.72 (t, J = 6.0 Hz, 1H), 3.86 (s, 3H), 3.86 (s, 3H), 3.64 (q, J = 6.6 Hz, 2H), 2.84 (t, J = 6.9 Hz, 2H). 13 C NMR(CDCl3): δ 166.00, 149.20,147.86, 141.19, 134.90, 131.48, 129.81, 128.94, 127.90, 120.79, 120.71,112.08, 111.52, 56.05, 56.00, 41.06, 35.34. The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for catalytically preparing high purity xanthohumol, characterized by, The method comprises the following steps: The high purity zanthoxylin is obtained by reacting the cinnamic acid derivative and the homopilosellamine in the presence of a boron catalyst in an organic solvent A, and then slowly crystallizing and separating the high purity zanthoxylin by adding an organic solvent B to control the temperature.

2. The method for catalytically preparing high-purity zanthoxylin according to claim 1, characterized in that: The cinnamic acid derivative is selected from cinnamic acid or cinnamic acid ester.

3. The method for catalytically preparing high-purity zanthoxylin according to claim 2, characterized in that: The cinnamic acid ester is selected from methyl cinnamate or ethyl cinnamate.

4. The method for catalytically preparing high-purity zanthoxylin according to claim 1, characterized in that: The molar ratio of the homopilosellamine to the cinnamic acid derivative is 1: 1-1.5, and the molar ratio of the homopilosellamine to the boron catalyst is 1: 0.01-0.

1.

5. The process for the catalytic preparation of high purity xanthin according to claim 1, characterized in that: The boron catalyst is a Lewis base-borane adduct.

6. The method for catalytically preparing high purity zanthoxylin according to claim 5, wherein: The Lewis base-borane adduct has the structural formula R 1 R 2 R 3 N . BH3or R 1 R 2 R 3 P . BH3; wherein: R 1-3 are each independently selected from hydrogen, alkyl, alkenyl, or aryl.

7. The method for catalytically preparing high purity zanthoxylin according to claim 1, wherein: The organic solvent A is selected from one or more of ethyl acetate, tetrahydrofuran, acetonitrile, dichloromethane, toluene, o-xylene, p-xylene, m-xylene, ethanol, methanol or water.

8. The method for catalytically preparing high purity zanthoxylin according to claim 1, wherein: The organic solvent B is selected from one or more of acetonitrile, dichloromethane, ethanol, methanol or water.

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