Method for reducing farnesol content in (-)-alpha-bisabolol based on oxidation process

Abstract

The invention provides a method for reducing the content of farnesol in (-)-alpha-bisabolol based on an oxidation process, and belongs to the technical field of medicinal chemistry and biosynthesis. The method comprises the following steps: (1) impurity removal: mixing a (-)-alpha-bisabolol or (-)-alpha-bisabolol solution, an organic solvent and metal salt for reaction; (2) post-treatment; after the reaction is finished, an alkaline aqueous solution is added into a reaction solution obtained in the step (1), phase splitting is conducted, an organic phase is taken to be distilled and concentrated, a purified (-)-alpha-bisabolol product is obtained, and the content of farnesol is smaller than or equal to 0.05%. Compared with an existing method, the method has the advantages of being easy to operate, free of by-products, low in cost, easy to amplify production and the like, a brand new solution is provided for improving the quality and use safety of the bisabolol, and an efficient, green and safe industrialization scheme is provided for application of the bisabolol in the field of cosmetics.

Description

Technical Field

[0001] This invention belongs to the fields of medicinal chemistry and biosynthesis technology, and specifically relates to a method for reducing the content of farnesol in (-)-α-bisabolol based on an oxidation process. Background Technology

[0002] (-)-α-Bisabolol (or simply bisabolol) is a naturally occurring sesquiterpene alcohol with broad biological activity, primarily found in the essential oils of plants such as German chamomile (Matricaria recutita). Due to its excellent anti-inflammatory, antibacterial, wound-healing, and skin-repairing effects, bisabolol is widely used in cosmetics, pharmaceuticals, and skincare products, especially in sensitive skin care, anti-aging, and soothing repair products. However, naturally derived bisabolol is often accompanied by various structurally similar sesquiterpene impurities, with farnesol being one of the most prominent coexisting components. Because their biosynthetic pathways in plants are closely related (both originating from farnesyl pyrophosphate), traditional extraction methods struggle to effectively separate them, resulting in high levels of farnesol residue in commercially available bisabolol products, severely impacting its safety and market value.

[0003] Farnesol is a known contact allergen and has been listed as a restricted ingredient by EU cosmetic regulations (EC No 1223 / 2009), with its content in leave-on cosmetics strictly limited. Excessive farnesol residue in bisabolol may increase the risk of sensitization and affect consumer safety; its use is strictly restricted in high-risk products for infants, young children, and those with sensitive skin.

[0004] Bisabolol and farnesol have highly similar chemical properties (they have the same molecular weight, both C10). 15 H 26 The separation of bisabolol (an isomer of O) faces significant challenges from traditional methods. Since both have similar boiling points, conventional distillation is insufficient for efficient separation, and high temperatures lead to the degradation of heat-sensitive components. Currently, industrial methods for reducing the farnesol content in bisabolol mainly include precision molecular distillation, silver ion chromatography, enzymatic selective conversion, and supercritical CO2 extraction. These methods generally suffer from low separation efficiency, complex processes, high costs, or the introduction of new impurities, making it difficult to meet the demands of industrial production of high-purity bisabolol.

[0005] Patent application CN101400650A discloses a method for preparing pure bisabolol or enriching bisabolol by separating a mixture containing bisabolol and farnesol. This method uses a selective esterification-distillation process to separate and purify bisabolol. However, this method has the following drawbacks: cumbersome steps, high raw material requirements, equipment requiring high vacuum resistance, high energy consumption, the need for an evaporation tower for continuous production, high industrial production costs, potential residual harmful solvents, and difficulty in separating byproducts after esterification; it also poses a potential risk to the safety of the bisabolol product. Patent application CN118084616A discloses a method for separating and purifying (-)-α-bisabolol from fermentation broth using a solvent extraction-activated carbon decolorization-double-stage molecular distillation process. However, this method requires expensive molecular distillation equipment, has a small processing capacity, and requires multiple units in parallel for scale-up, resulting in high costs.

[0006] Therefore, it is of great significance to develop a green, environmentally friendly, easy-to-operate, safe, and low-cost method to reduce the farnesol content in bisabolol. Summary of the Invention

[0007] To address the shortcomings of existing technologies, the present invention aims to provide a method for reducing the farnesol content in (-)-α-bisabolol that is simple to operate, produces no byproducts, is low in cost, and is easy to scale up for production.

[0008] This invention provides a method for reducing the farnesol content in (-)-α-bisabolol, the method comprising the following steps: (1) Impurity removal: Mix (-)-α-bisabolol or (-)-α-bisabolol solution, organic solvent and metal salt and react; (2) Post-processing: After the reaction is completed, an alkaline aqueous solution is added to the reaction solution obtained in step (1), the phases are separated, and the organic phase is concentrated by distillation to obtain the purified (-)-α-bisabolol product.

[0009] Further, in step (1), the content of (-)-α-bisabolol or (-)-α-bisabolol solution is ≥10%, and the content of farnesol is ≤1.5%; the solvent in the (-)-α-bisabolol solution is not an alcohol solvent.

[0010] Furthermore, in step (1), the content of (-)-α-bisabolol is ≥95%, and the content of farnesol is 0.15%~1.1%.

[0011] Further, the (-)-α-bisabolol mentioned in step (1) is a product prepared by solvent extraction, decolorization, concentration and molecular distillation of (-)-α-bisabolol fermentation broth; the (-)-α-bisabolol solution is an extract obtained by solvent extraction of (-)-α-bisabolol fermentation broth or a concentrate obtained by decolorization and concentration of the extract.

[0012] Furthermore, in the reaction described in step (1), no base is added or a base is added.

[0013] When the metal salt produces acidic byproducts during the reaction, an alkali must be added to the reaction system.

[0014] Further, the metal salt mentioned in step (1) is selected from any one of ferric chloride, ferric chloride hexahydrate, ferric sulfate, ferric nitrate, copper chloride, copper sulfate, aluminum sulfate, and aluminum isopropoxide, or any two or more of these reagents; The base is selected from any one of calcium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, and diethylamine, or any mixture of two or more of them. The alkaline aqueous solution mentioned in step (2) is selected from any one of sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, disodium hydrogen phosphate, and dipotassium hydrogen phosphate, or any two or more of these reagents in an aqueous solution.

[0015] Further, the metal salt mentioned in step (1) is selected from any one of ferric chloride, ferric chloride hexahydrate, ferric sulfate, ferric nitrate, copper chloride, copper sulfate, and aluminum sulfate, or any two or more of these reagents.

[0016] Furthermore, the metal salt mentioned in step (1) is selected from ferric chloride or ferric chloride hexahydrate, preferably ferric chloride hexahydrate.

[0017] Further, the organic solvent mentioned in step (1) is selected from C 5-12 Alkane solvents, C 3-6 Any one, or any two or more, of the ketone solvents.

[0018] Further, the organic solvent mentioned in step (1) is selected from any one of n-hexane, n-heptane, isododecane, n-dodecane, methyl ketone, ethyl ketone, acetone, or any mixture of two or more of them.

[0019] Further, the organic solvent mentioned in step (1) is selected from n-heptane or acetone.

[0020] Further, the alkaline aqueous solution in step (2) is selected from any one of sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, disodium hydrogen phosphate, and dipotassium hydrogen phosphate, or any two or more of these reagents in an aqueous solution.

[0021] Furthermore, step (2) includes decolorization before distillation and concentration.

[0022] Furthermore, the decolorization is carried out using activated carbon.

[0023] Furthermore, the distillation concentration method described in step (2) is atmospheric distillation or vacuum distillation, preferably vacuum distillation.

[0024] Furthermore, the vacuum distillation mentioned in step (2) is one or a combination of two distillation methods, namely, distillation column and molecular distillation.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention provides a method for removing farnesol impurities from (-)-α-bisabolol. The method uses (-)-α-bisabolol containing farnesol impurities, obtained through bio-fermentation, as a raw material. It utilizes the steric hindrance difference of the hydroxyl groups in farnesol and bisabolol molecules, and selectively oxidizes the alcohol groups in farnesol by using a compound with mild oxidizing function as a metal salt. The resulting farnesic acid, excess metal salt, and byproducts generated by the oxidation can be removed by washing with an aqueous solution of inorganic alkali or organic acid, thereby effectively reducing the farnesol content in (-)-α-bisabolol.

[0026] Compared with the esterification method for reducing farnesol content, this process has advantages such as simple operation, low impurity removal cost, no by-products generated during impurity removal, and no metal salt residues in the product, thus ensuring product quality.

[0027] Specifically, the method of the present invention has the following significant advantages: (1) Green and environmentally friendly: It uses safe and reliable reagents and avoids the use of toxic and harmful reagents, which expands its potential application scenarios in the fields of health care products, cosmetics and biomaterials; at the same time, no toxic and harmful materials are generated during the production process, which meets the requirements of sustainable development.

[0028] (2) Simple process: It is carried out under normal pressure and suitable temperature conditions. The post-processing is simple, no complicated equipment is required, and the by-products are easy to handle, which improves the product quality.

[0029] (3) Great industrialization potential: The reaction conditions are mild, the equipment and operation are simple, the cost is low, it is easy to scale up production, and it is suitable for large-scale application.

[0030] (4) Low farnesol content: The farnesol content in the bisabolol obtained in this invention is less than 0.05%.

[0031] The process of this invention is extremely simple. Through innovative impurity removal methods and optimized reaction conditions, the content of farnesol is effectively reduced, solving the problems of complex processes, high costs, and the introduction of new impurities in existing technologies. Compared with existing methods, this invention has the advantages of simple operation, no by-products, low cost, and easy scale-up production. It provides a brand-new solution for improving the quality and safety of bisabolol, and also provides an efficient, green, and safe industrialization solution for the application of bisabolol in the cosmetics field.

[0032] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0033] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0034] Unless otherwise specified, the raw materials and equipment used in the specific embodiments of the present invention are all known products and were obtained by purchasing commercially available products.

[0035] The raw material bisabolol in this embodiment of the invention is obtained by solvent extraction, decolorization, concentration, and molecular distillation of (-)-α-bisabolol fermentation broth. The product contains ≥95% bisabolol and 0.1%~0.7% farnesol. The fermentation medium formula used to prepare the (-)-α-bisabolol fermentation broth is: 23 g / L dried slurry powder, 5.5 g / L magnesium sulfate heptahydrate, 6.5 g / L potassium dihydrogen phosphate, 0.2 g / L defoamer, and the remainder is water. The fermentation medium is prepared by dissolving all components except the defoamer in water, then adding the defoamer, and sterilizing at 121-123℃ for 30 minutes. The fermentation method is as follows: Saccharomyces cerevisiae is cultured in the aforementioned fermentation medium at pH 5.25 at 37℃ and 500 rpm for 51 hours to activate the inoculum. The activated seed culture is then inoculated into the aforementioned fermentation medium and fermented for 90 hours to obtain the fermentation broth.

[0036] Example 1: Method for reducing the content of farnesol in (-)-α-bisabolol Weigh 50g of bisabolol product, add 50ml of isododecane, stir well, then add 0.5g of copper chloride and 0.49g of ferric chloride hexahydrate, react for 5 hours. After the reaction is complete, add 100ml of 0.5% oxalic acid solution to the reaction solution and wash for 30min. Separate the phases, take the organic phase, add 5% sodium carbonate solution and wash for 30min, separate the phases, take the organic phase and perform molecular distillation, collect the fractions at 75℃ and 85℃ respectively, to obtain bisabolol products with purities of 95.6% and 97.9% respectively, and farnesol content of 0.05%.

[0037] Example 2: Method for reducing the content of farnesol in (-)-α-bisabolol Weigh 50g of bisabolol product, add 50ml of n-heptane, stir well, then add 0.2g of ferric chloride and triethylamine and react for 6 hours. After the reaction is complete, add 100ml of 0.1% sodium hydroxide solution to the reaction solution and wash for 30min. Separate the phases, take the organic phase, add 5% citric acid solution and wash for 30min, separate the phases, take the organic phase and perform molecular distillation, collect the fractions at 75℃ and 85℃ respectively, to obtain bisabolol products with purities of 98.7% and 98.5% respectively, and farnesol content of 0.05%.

[0038] Example 3: Method for reducing the content of farnesol in (-)-α-bisabolol Weigh 100g of bisabolol product, add 100ml of n-dodecane, stir well, then add 0.7g of ferric chloride hexahydrate and react for 6 hours. After the reaction is complete, add 200ml of 5% sodium bicarbonate solution to the reaction solution and wash for 30min. Separate the phases, take 200ml of the organic phase, add 0.5% citric acid solution and wash for 30min. Separate the phases, take the organic phase and perform molecular distillation, collecting the fractions at 75℃ and 85℃ respectively, to obtain bisabolol products with purities of 98.1% and 98% respectively, and farnesol content of 0.04%.

[0039] Example 4: Method for reducing the content of farnesol in (-)-α-bisabolol Weigh 100g of bisabolol product, add 100ml of n-hexane, stir well, then add 1g of ferric sulfate and 0.47g of ferric chloride. React for 8 hours. After the reaction is complete, add 200ml of 5% citric acid solution to the reaction solution and wash for 30min. Separate the phases. Take 200ml of the organic phase, add 0.5% sodium hydroxide solution and wash for 30min. Separate the phases. Take the organic phase for molecular distillation and collect the fractions at 75℃ and 85℃ respectively to obtain bisabolol products with purities of 95.5% and 97% respectively, and farnesol content of 0.05%.

[0040] Example 5: Method for reducing the content of farnesol in (-)-α-bisabolol Weigh 50g of bisabolol product, add 50ml of acetone, stir well, then add 0.2g of ferric chloride hexahydrate and react for 4 hours. After the reaction is complete, add 200ml of 0.5% oxalic acid solution to the reaction solution and wash for 30min. Separate the phases, take 200ml of the organic phase, add saturated calcium hydroxide solution and wash for 30min. Separate the phases, take the organic phase and perform molecular distillation, collecting the fractions at 75℃ and 85℃ respectively, to obtain bisabolol products with purities of 98.5% and 99% respectively, and farnesol content of 0.01%.

[0041] Example 6: Method for reducing the content of farnesol in (-)-α-bisabolol Weigh 50g of bisabolol product, add 50ml of acetone, stir well, then add 0.5g of ferric chloride hexahydrate and react for 4 hours. After the reaction is complete, add 200ml of 5% disodium hydrogen phosphate solution to the reaction solution and wash for 30min. Separate the phases, take 200ml of the organic phase, add saturated calcium hydroxide solution and wash for 30min. Separate the phases, take the organic phase and perform molecular distillation, collect the fractions at 75℃ and 85℃ respectively, to obtain bisabolol products with purities of 97.5% and 98% respectively, and farnesol content of 0.01%.

[0042] Example 7: Method for reducing the content of farnesol in (-)-α-bisabolol Weigh 50g of bisabolol product, add 50ml of isododecane, stir well, then add 0.8g of aluminum sulfate and 0.74g of ferric chloride hexahydrate, react for 4 hours. After the reaction is complete, add 200ml of 5% disodium hydrogen phosphate solution to the reaction solution and wash for 30min. Separate the phases, take 200ml of the organic phase, add saturated calcium hydroxide solution and wash for 30min, separate the phases, take the organic phase and perform molecular distillation, collect the fractions at 75℃ and 85℃ respectively, to obtain bisabolol products with purities of 97.5% and 98% respectively, and farnesol content of 0.05%.

[0043] Example 8: Method for reducing the content of farnesol in (-)-α-bisabolol Weigh 50g of bisabolol product, add 50ml of isododecane, stir well, then add 0.5g of ferric nitrate and 0.86g of ferric chloride hexahydrate. React for 8 hours. After the reaction is complete, add 200ml of 5% disodium hydrogen phosphate solution to the reaction solution and wash for 30min. Separate the phases. Take 200ml of the organic phase, add saturated calcium hydroxide solution and wash for 30min. Separate the phases. Add 5% citric acid solution to the organic phase and wash for 30min. Separate the phases. Take the organic phase and perform molecular distillation. Collect the fractions at 75℃ and 85℃ respectively to obtain bisabolol products with purities of 96.4% and 97%, respectively. The farnesol content is 0.04%.

[0044] In summary, this invention provides a method for removing farnesol impurities from (-)-α-bisabolol. This process offers advantages such as simple operation, low impurity removal cost, no byproducts or metal salt residues generated during impurity removal, and ease of scale-up production. It provides a novel solution for improving the quality and safety of bisabolol, and also offers an efficient, green, and safe industrialization solution for the application of bisabolol in the cosmetics field.

Claims

1. A method for reducing the farnesol content in (-)-α-bisabolol, characterized in that: The method includes the following steps: (1) Impurity removal: Mix (-)-α-bisabolol or (-)-α-bisabolol solution, organic solvent and metal salt and react; (2) Post-processing: After the reaction is completed, an alkaline aqueous solution is added to the reaction solution obtained in step (1), the phases are separated, and the organic phase is concentrated by distillation to obtain the purified (-)-α-bisabolol product.

2. The method according to claim 1, characterized in that: In step (1), the content of (-)-α-bisabolol or (-)-α-bisabolol solution is ≥10%, and the content of farnesol is ≤1.5%; the solvent in the (-)-α-bisabolol solution is not an alcohol solvent.

3. The method according to claim 1, characterized in that: The (-)-α-bisabolol mentioned in step (1) is a product prepared by solvent extraction, decolorization, concentration and molecular distillation of (-)-α-bisabolol fermentation broth; the (-)-α-bisabolol solution is an extract obtained by solvent extraction of (-)-α-bisabolol fermentation broth or a concentrate obtained by decolorization and concentration of the extract.

4. The method according to claim 1, characterized in that: The metal salt mentioned in step (1) is selected from any one of ferric chloride, ferric chloride hexahydrate, ferric sulfate, ferric nitrate, copper chloride, copper sulfate, aluminum sulfate, and aluminum isopropoxide, or any two or more of these reagents; The base is selected from any one of calcium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, and diethylamine, or any mixture of two or more of them. The alkaline aqueous solution mentioned in step (2) is selected from any one of sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, disodium hydrogen phosphate, and dipotassium hydrogen phosphate, or any two or more of these reagents in an aqueous solution.

5. The method according to any one of claims 1 to 4, characterized in that: The organic solvent mentioned in step (1) is selected from C 5-12 Alkane solvents, C 3-6 Any one, or any two or more, of the ketone solvents.

6. The method according to claim 5, characterized in that: The organic solvent mentioned in step (1) is selected from any one of n-hexane, n-heptane, isododecane, n-dodecane, methyl ketone, ethyl ketone, acetone, or any mixture of two or more of them.

7. The method according to claim 1, characterized in that: Step (2) before distillation and concentration also includes decolorization; The distillation concentration method described in step (2) is atmospheric distillation or vacuum distillation, preferably vacuum distillation.

8. The method according to claim 7, characterized in that: The decolorization is performed using activated carbon.

9. The method according to claim 7, characterized in that: The vacuum distillation mentioned in step (2) is one or a combination of two distillation methods, namely distillation column and molecular distillation.

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