Preparation method of cotton yellow
Through the four-step synthesis process, the purity and yield problems of efficient preparation of cottonseed pigment were solved, and the preparation of high-purity and high-yield cottonseed pigment was achieved, promoting its application in health foods, medicines and cosmetics.
Patent Information
- Application Number
- CN202280048223.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Priority Date
- 2021-07-16
- Filing Date
- 2022-07-15
- Publication Date
- 2025-09-23
- Estimated Expiration
- 2042-07-15
AI Technical Summary
Existing technologies make it difficult to efficiently prepare gossypol in high purity and high yield, which limits its application.
A four-step synthesis process is adopted, including methylation of the compound, Friedel-Crafts reaction, condensation reaction and demethylation. Specific catalysts and solvents are used to optimize the reaction to improve purity and yield.
The preparation of high-purity and high-yield cotton yellow pigment is achieved, the production process is simplified, and the feasibility of industrial production is improved.
Smart Images
Figure BDA0004652047360000011 
Figure BDA0004652047360000021 
Figure BDA0004652047360000031
Abstract
Description
Technical Field
[0001] The present invention relates to a method for preparing gossypol, and more particularly to an efficient method for preparing gossypol with high purity and high yield. Background Art
[0002] Gossypetin is a type of flavonoid and is a compound represented by the following formula (1).
[0003]
[0004] Gossypium is isolated from the flowers and sepals of Hibiscus sabdariffa and is known to have strong antibacterial activity. In recent years, gossypium has been reported to be effective in improving osteoporosis and preventing or treating neurodegenerative diseases, and has garnered increasing attention as an ingredient in health functional foods and pharmaceuticals (see Korean Patent Publication No. 2017-0124242 and Patent Registration No. 210288). Furthermore, as an antioxidant, gossypium is used as an ingredient in pharmaceuticals, healthcare, cosmetics, and health foods.
[0005] However, gossypol is mainly extracted from natural products or synthesized through complex processes, making it difficult to produce on a large scale. Therefore, there is an urgent need to develop a method for industrial production of gossypol. Summary of the Invention
[0006] Technical issues
[0007] An object of the present invention is to provide an efficient method for preparing gossypol in high purity and high yield.
[0008] Technical Solution
[0009] One embodiment of the present invention relates to a method for preparing gossypolamine of the following formula (1), comprising the following steps:
[0010] (i) subjecting a compound of the following formula (2) to methylation to obtain a compound of the following formula (3);
[0011] (ii) subjecting the compound of the following formula (3) to a Friedel-Crafts reaction to obtain a compound of the following formula (4);
[0012] (iii) reacting a compound of the following formula (4) with a compound of the following formula (5) in the presence of a base to obtain a compound of the following formula (6); and
[0013] (iv) subjecting the compound of the following formula (6) to demethylation:
[0014]
[0015] Hereinafter, the preparation method of the present invention is described in more detail with reference to the following Reaction Scheme 1. The method described in the following Reaction Scheme 1 merely represents a typical example, and various changes can be made to the reagents and reaction conditions without limitation.
[0016] [Reaction Scheme 1]
[0017]
[0018] Step 1: Synthesis of compound of formula (3)
[0019] The compound of formula (3) can be prepared by subjecting the compound of formula (2) to methylation.
[0020] The methylation can be carried out by reacting the compound of formula (2) with a methyl halide, for example, methyl iodide, in the presence of a base.
[0021] As the base, potassium carbonate, cesium carbonate, etc. can be used. In particular, potassium carbonate is preferable.
[0022] The reaction temperature is preferably about 50°C to 70°C.
[0023] As the reaction solvent, acetone, N,N-dimethylformamide, etc. can be used. In particular, acetone is preferred.
[0024] Step 2: Synthesis of the compound of formula (4)
[0025] The compound of formula (4) can be prepared by subjecting the compound of formula (3) to a Friedel-Crafts reaction.
[0026] The Friedel-Crafts reaction can be carried out by reacting the compound of formula (3) with an acetyl halide in the presence of a Lewis acid.
[0027] As the Lewis acid, aluminum chloride, aluminum bromide, etc. can be used. In particular, aluminum chloride is preferable.
[0028] As the acetyl halide, acetyl chloride, acetyl bromide, etc. can be used. In particular, acetyl chloride is preferable.
[0029] The reaction temperature is preferably room temperature. As the reaction solvent, dichloromethane, diethyl ether, etc. can be used.
[0030] Step 3: Synthesis of the compound of formula (6)
[0031] The compound of formula (6) can be produced by reacting the compound of formula (4) with the compound of formula (5) in the presence of a base.
[0032] As the base, cyclic secondary amines such as pyrrolidine and piperidine can be used. In particular, pyrrolidine is preferred.
[0033] The amount of the base used may be 5 to 15 equivalents, preferably 8 to 12 equivalents, relative to 1 equivalent of the compound of formula (4).
[0034] The reaction temperature is preferably about 20°C to 80°C, more preferably 40°C to 60°C.
[0035] The reaction solvent is preferably a protic solvent, such as water, methanol, ethanol, especially water.
[0036] The reaction can be carried out in air or under an oxygen atmosphere.
[0037] According to one embodiment of the present invention, the compound of formula (4) and the compound of formula (5) are simultaneously subjected to aldol condensation followed by cyclization and oxidation, as shown in the following Reaction Scheme 2, so that the compound of formula (6) can be prepared in a one-step reaction.
[0038] [Reaction Scheme 2]
[0039]
[0040] This increases chemoselectivity and prevents the formation of isomers, resulting in higher yields and easier purification.
[0041] Step 4: Preparation of cypermethrin of formula (1)
[0042] The compound of formula (1) can be prepared by subjecting the compound of formula (6) to demethylation.
[0043] The demethylation can be carried out in the presence of a catalyst such as boron tribromide and aluminum tribromide.
[0044] The reaction temperature is preferably room temperature, and dichloromethane, acetonitrile, or the like can be used as a reaction solvent.
[0045] Beneficial effects
[0046] According to the preparation method of the present invention, high-purity gossypolamine can be efficiently prepared with high yield through a four-step process. DETAILED DESCRIPTION
[0047] The present invention will be described in more detail by the following examples. It will be apparent to those skilled in the art that these examples are merely described to illustrate the present invention, and the scope of the present invention is not limited thereto.
[0048] Example 1: Synthesis of compound of formula (3)
[0049] The compound of formula (2) (500 g) was dissolved in acetone (3000 mL), and anhydrous potassium carbonate (375.18 g) was added. Then, CH3I (500.90 g) was added, and the reaction mixture was stirred at 60°C overnight. The reaction solution was concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound (470 g, 87% yield).
[0050] 1 H NMR (400MHz, CDCl3): 6.15(2H), 3.85(6H), 3.78(6H).
[0051] Example 2: Synthesis of compound of formula (4)
[0052] The compound of formula (3) (470 g) was dissolved in dichloromethane, and AlCl (474.21 g) and acetyl chloride (241.97 g) were added. The reaction mixture was stirred at room temperature overnight, and the crude product was subjected to silica gel column chromatography to obtain the title compound (440 g, yield 82%).
[0053] 1 H NMR (400MHz, CDCl3): 13.80(1H), 5.98(1H), 3.94(3H), 3.89(3H), 3.81(3H), 2.62(3H).
[0054] Example 3: Synthesis of compound of formula (6)
[0055] The compound of formula (4) (440 g) and the compound of formula (5) (356 g) were dissolved in water (1800 g), pyrrolidine (152.13 g) was added, and the reaction mixture was stirred in air at 50° C. overnight. The crude product was subjected to silica gel column chromatography to obtain the title compound (117 g, yield 30%).
[0056] 1 H NMR(400MHz, CDCl3):7.93(t,2H),7.41(s,b,1H),7.05(d,1H),6.44(1H),4.04-3.99(m,15H)
[0057] 13 C NMR (100MHz, CDCl3):172.26,156.67,156.16,150.92,150.36,148.87,142.18,137.30,130.5 4,124.02,124.02,120.90,111.08,110.15,106.07,91.75,61.50,56.52,56.47,56.02,55.89.
[0058] Example 4: Synthesis of the compound of formula (1)
[0059] The compound of formula (6) (117 g) was dissolved in dichloromethane and BBr3 (1132 g) was added at -78°C. The reaction mixture was stirred at room temperature overnight. The crude product was subjected to silica gel column chromatography to obtain the title compound (80 g, yield 83.4%).
[0060] Then, preparative HPLC (mobile phase: A: water (0.2% TFA), B: acetonitrile (0.2% TFA); gradient: 5%-45%, 25 minutes) was performed to obtain the title compound (32.5 g, single impurity less than 0.5%) with a purity of 99.45%.
[0061] 1 H NMR (400 MHz, DMSO-d 6 ):11.92(1H),10.41(1H),9.57(1H),9.28(2H),8.60(1H),7.79(1H),7.67(1H),6.90(1H),6.27(1H)
[0062] 13 C NMR (100 MHz, DMSO-d 6 ):176.56,153.11,152.67,148.14,147.11,145.46,145.35,136.92,125.18,122.75,120.66,115.94,115.75,103.21,98.42.
Claims
1. A method for preparing the cotton yellow pigment of the following formula (1), comprising the following steps: (i) subjecting a compound of the following formula (2) to methylation to obtain a compound of the following formula (3); (ii) subjecting the compound of the following formula (3) to a Friedel-Crafts reaction to obtain a compound of the following formula (4); (iii) reacting a compound of the following formula (4) with a compound of the following formula (5) in the presence of a base to obtain a compound of the following formula (6); and (iv) subjecting the compound of the following formula (6) to demethylation:
2. The method according to claim 1, wherein the methylation of step (i) is performed by reacting the compound of formula (2) with a methyl halide in the presence of a base.
3. The method according to claim 1, wherein the Friedel-Crafts reaction of step (ii) is performed by reacting the compound of formula (3) with an acetyl halide in the presence of a Lewis acid.
4. The process according to claim 1, wherein the base of step (iii) is a cyclic secondary amine. The method according to claim 1 , wherein the base in step (iii) is pyrrolidine.
6. The method according to claim 1, wherein the base of step (iii) is used in an amount of 8 to 12 equivalents relative to 1 equivalent of the compound of formula (4).
7. The method according to claim 1, wherein the reaction temperature of step (iii) is 40°C to 60°C.
8. The method according to claim 1, wherein the reaction solvent in step (iii) is a protic solvent.
9. The method according to claim 1, wherein the reaction solvent in step (iii) is water.
10. The method according to claim 1, wherein the reaction of step (iii) is carried out in air.
11. The process according to claim 1, wherein the demethylation of step (iv) is carried out in the presence of boron tribromide.
Citation Information
Patent Citations
Maniod ebish flower extract, extraction and analysis method and extract preparation and use thereof
CN101385748A
Cosmetic and / or dermopharmaceutical preparations containing leaf extracts of the plant argania spinosa
WO2002045728A1