A method for preparing 4-oxo-beta-apo-12'-carotenal and products and uses thereof

Abstract

The application discloses a preparation method of 4-oxo-beta-apo-12'-carotenal and products and applications thereof. The preparation method comprises the following steps: S1, under the protection of inert gas, 4-oxo-vinyl-beta-ionol is dissolved in a first organic solvent to prepare 4-oxo-C15 halide with a halogenating agent; S2, triphenylphosphine is added to the system in S1 to prepare 4-oxo-C15 phosphonium salt; S3, under the protection of inert gas, 8,8-dimethoxy-2,7-dimethyl-2,4,6-octatriene aldehyde, lye and a second organic solvent are added to the system in S2 to generate Wittig reaction; the system is adjusted to be acidic, and a hydrolysis reaction is performed to obtain 4-oxo-beta-apo-12'-carotenal. The method has the advantages of easy raw material, simple reaction and more than 95% of all-trans content of the product.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and in particular to a method for preparing 4-oxo-β-apo-12'-carotene, its products, and applications. Background Technology

[0002] 4-Oxo-β-apo-12'-carotene is a key intermediate in the synthesis of oxocarotenoids, mainly used in the synthesis of canthaxanthin, astaxanthin, ursulphone, calendula erythrin, and other carotenoids. Canthaxanthin belongs to the oxygen-containing carotenoid class; its activity in quenching reactive oxygen species and its ability to scavenge free radicals are twice that of β-carotene, and it is mainly used in the feed industry. Astaxanthin is the highest-yielding product of oxygen-containing carotenoids. In addition to its excellent coloring properties, astaxanthin can also protect cells, preventing oxidative damage to lipids and membrane lipoproteins, and is mainly used in pharmaceuticals, cosmetics, and aquaculture.

[0003] 4-O-β-Apo-12'-Carotene is a key intermediate in the synthesis of oxocarotene. Currently, there are few chemical synthesis methods for 4-oxo-β-Apo-12'-Carotene, and the synthesis reactions are complex, difficult to control, and yields are low. In 1978, patent US4209450A disclosed a reaction using β-Apo-12'-Carotene as a starting material and oxidizing it with sodium chlorate to prepare 4-oxo-β-Apo-12'-Carotene. The reaction time was approximately thirty hours, and the final yield was 66.35%.

[0004] In 1997, a method was disclosed for synthesizing 4-oxo-C15 bromophosphonium salt and C10 dialdehyde in 1,2-epoxybutane, followed by isomerization in an ethanol-water system and cryo-crystallization to obtain 4-oxo-β-apor-12'-carotene crystals. The yield of 4-oxo-β-apor-12'-carotene crystals was 50.48% for 4-oxo-C15 bromophosphonium salt and 60.09% for C10 dialdehyde. This synthetic method is time-consuming, cumbersome, requires isomerization, and has low yields, thus its industrial value is limited.

[0005] In view of this, a technical solution is provided to solve the above-mentioned technical problems. Summary of the Invention

[0006] To overcome the shortcomings of the prior art, the first objective of this invention is to provide a method for preparing 4-oxo-β-apo-12'-carotene, which has a convenient reaction route, simple and readily available raw materials, pure products, no isomerization required, and is suitable for large-scale industrial production.

[0007] A second objective of this invention is to provide a 4-oxo-β-apo-12'-carotene aldehyde in the trans configuration.

[0008] The third objective of this invention is to provide a method for preparing 4-oxo-β-apo-12'-carotene and its application in organic synthesis.

[0009] The first objective of this invention is achieved by the following technical solution:

[0010] A method for preparing 4-oxo-β-apo-12'-carotene includes the following steps:

[0011] S1, 4-oxovinyl-β-ionol reacted with a halogenating agent to prepare a 4-oxo-C15 halide;

[0012] S2. The 4-oxo-C15 halide obtained in step S1 is reacted with triphenylphosphine to prepare a 4-oxo-C15 phosphonium salt.

[0013] S3 and S2: The 4-oxo-C15 phosphonium salt obtained in step S2 undergoes an addition reaction with 8,8-dimethoxy-2,7-dimethyl-2,4,6-octtrienal, followed by hydrolysis to obtain 4-oxo-β-apori-12'-carotene aldehyde.

[0014] Further, step S1 involves reacting in a first organic solvent; step S3 involves reacting in a second organic solvent; the first organic solvent and the second organic solvent are each independently one or a combination of two or more of dichloromethane, ethanol, and methanol.

[0015] Further, in step S1, the halogenated agent is one or a combination of two or more of hydrochloric acid, hydrobromic acid, or thionyl chloride.

[0016] Further, in step S1, the molar ratio of the halogenated agent to 4-oxovinyl-β-ionol is (1.0~1.05):1; in step S2, the molar amount of triphenylphosphine added is (1.0~1.1) times the molar amount of 4-oxovinyl-β-ionol in step S1; in step S3, the molar amount of 8,8-dimethoxy-2,7-dimethyl-2,4,6-octtrienal added is (0.85~0.95) times the molar amount of 4-oxovinyl-β-ionol in step S1.

[0017] Furthermore, the reaction temperature in step S1 is 0–10°C; the reaction temperature in step S2 is 20–30°C.

[0018] Further, in step S3, the addition reaction is carried out under alkaline conditions; the alkaline conditions are the addition of an inorganic base; the inorganic base is at least one of sodium hydroxide, potassium hydroxide, or lithium hydroxide; the molar amount of the inorganic base added is (1.0 to 1.1) times the molar amount of 4-oxovinyl-β-ionol in step S1.

[0019] Further, in step S3, after the 8,8-dimethoxy-2,7-dimethyl-2,4,6-octtrienal is dissolved in a second organic solvent, the reaction temperature is lowered to 0-5°C before an inorganic base is added; the inorganic base is added in the form of an alkaline solution with a mass concentration of 10%-15%.

[0020] Further, in step S3, the reaction system is first neutralized with 1,2-epoxybutane before 8,8-dimethoxy-2,7-dimethyl-2,4,6-octtrienal is added; during the addition reaction, the pH of the reaction system is kept ≤9.5 and the reaction temperature is 10-20℃; during the hydrolysis reaction, the pH of the reaction system is adjusted to 2.0-3.0 and the reaction temperature is 25-30℃.

[0021] The second objective of this invention is achieved by the following technical solution:

[0022] A 4-oxo-β-apo-12'-carotene was prepared by a method for preparing 4-oxo-β-apo-12'-carotene.

[0023] The third objective of this invention is achieved by the following technical solution:

[0024] A method for preparing 4-oxo-β-apo-12'-carotene aldehyde, or a 4-oxo-β-apo-12'-carotene aldehyde, is used to synthesize oxocarotene.

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

[0026] 1. The method for preparing 4-oxo-β-apor-12'-carotene aldehyde of the present invention involves reacting 4-oxovinyl-β-ionol with a halogenating agent to obtain a 4-oxo-C15 halide, followed by a Wittig condensation reaction with triphenylphosphine, a base, and 8,8-dimethoxy-2,7-dimethyl-2,4,6-octtrienal to obtain 4-oxo-β-apor-12'-carotene methyl acetal, and then hydrolyzing the acetal to obtain the target product. The addition reaction conditions are relatively mild, the product yield is good, and the double bond position of the alkene in the reaction product is the same as the carbonyl group in the carbonyl compound, resulting in virtually no other isomers in the product, a pure product, and a high all-trans structure content of up to 95%. The reaction route is convenient, the raw materials are simple and readily available, and the process requires little manpower, material resources, and financial resources, making it suitable for large-scale industrial production.

[0027] 2. The reaction raw materials used in this invention, such as halogenated agents, triphenylphosphine, 4-oxovinyl-β-ionol, and inorganic bases, are all bulk industrial products, readily available, and low in cost.

[0028] 3. In the preparation of 4-oxo-β-apo-12'-carotene, this invention does not use highly hazardous raw materials, and there are no other harmful byproducts remaining in the product. The production process is highly safe, and the product meets the usage standards. Detailed Implementation

[0029] The technical solution of the present invention will now be clearly and completely described with reference to specific embodiments. Obviously, the described embodiments are merely some embodiments of the present invention, and not all embodiments. 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.

[0030] Carotenoids are a collective term for a class of highly unsaturated compounds with conjugated double bonds and methyl branched chains as their basic structure. They are the main source of vitamin A in the human body and have antioxidant, immunomodulatory, anticancer, and anti-aging effects. Currently, the main ways to obtain carotenoids are through plant extraction, biosynthesis, and chemical synthesis. Direct extraction is widely available from plants, animals, and algae in nature, and most carotenoids can be obtained this way. However, in most cases, the purity is low or the raw material content is low, resulting in low efficiency and high cost. Biosynthesis is difficult to achieve due to the challenges of strain selection and domestication, and its successful application is limited, making it difficult to achieve industrial-scale production and meet market demand. Chemical synthesis is currently the main way to obtain most carotenoids in large quantities. It has relatively low cost and high purity. In particular, once a suitable synthetic route or method is found, its advantages of high efficiency and low cost are fully demonstrated.

[0031] Oxylated carotenoids are oxygen-containing derivatives of carotenoids. Among them, canthaxanthin and astaxanthin are oxylated carotenoids, composed of two ionone rings linked by a polyene chain. This polyene chain, along with the auxochrome, not only determines the light absorption characteristics of carotenoids but also endows them with antioxidant capabilities. Canthaxanthin's quenching activity of reactive oxygen species and its ability to scavenge free radicals are twice that of β-carotene. Astaxanthin possesses even more outstanding antioxidant capabilities, approximately 10 times stronger than zeaxanthin, lutein, and canthaxanthin, about 65 times stronger than vitamin C, and about 100 times stronger than α-tocopherol. It can be used in pharmaceuticals, cosmetics, and aquaculture.

[0032] 4-O-β-Apo-12'-Carotene is a key intermediate in the synthesis of oxocarotene. However, there are few reported methods for the synthesis of 4-oxo-β-Apo-12'-Carotene. The disclosed methods generally suffer from complex and difficult-to-control reaction conditions, long synthesis times, cumbersome operations, and low yields. Therefore, this invention provides a method for the preparation of 4-oxo-β-Apo-12'-Carotene.

[0033] A method for preparing 4-oxo-β-apo-12'-carotene includes the following steps:

[0034] S1, 4-oxovinyl-β-ionol (abbreviated as 4-oxo-C15 alcohol) reacts with a halogenating agent to prepare 4-oxo-C15 halogenated products;

[0035] S2. The 4-oxo-C15 halide obtained in step S1 reacts with triphenylphosphine to prepare a 4-oxo-C15 phosphonium salt; the reaction formula is shown in Formula I:

[0036]

[0037] S3 and S2: The 4-oxo-C15 phosphonium salt obtained in step S2 undergoes an addition reaction with 8,8-dimethoxy-2,7-dimethyl-2,4,6-octtrienal (abbreviated as C10 monoaldehyde methyl acetal), followed by hydrolysis to obtain 4-oxo-β-apori-12'-carotene aldehyde.

[0038] Furthermore, the S3 reaction formula is shown in Formula II:

[0039]

[0040] The addition reaction in step S3 is the Wittig reaction. The Wittig reaction is a nucleophilic addition reaction between an aldehyde or ketone and a phosphonium ylide (Wittig reagent) to form an alkene, and can be used to synthesize alkenes with a defined double bond position. The reactants in the Wittig reaction are generally an aldehyde / ketone and a monosubstituted phosphonium inner salt. Phosphonium ylides can be classified into ylides of different stabilities based on the nature of the substituent attached to the α-carbon. Ylides derived from triphenylphosphine, when the substituent attached to the α-carbon is a carbonyl, ester, nitrile, sulfone, or other such conjugated group, are called stable ylides. Furthermore, the selectivity of the final product for the E or Z configuration can be determined by the degree of anionic stabilization of the inner salt imparted by the substituent on the α-carbon.

[0041] In this invention, a 4-oxo-C15 halide is first prepared by reacting a 4-oxo-C15 alcohol with a halogenating agent, and then reacted with triphenylphosphine to generate a 4-oxo-C15 phosphonium salt. The 4-oxo-C15 phosphonium salt is a stable phosphine ylide. Stable ylides react only with aldehydes, not ketones, and the reaction usually yields an E-configuration product. In contrast, Wittig reagents do not undergo 1,4-addition with unsaturated aldehydes, and the double bond position is fixed. For the 4-oxo-β-apor-12'-carotene of this invention, the E-configuration and the trans-configuration are identical.

[0042] In the industrial-scale synthesis of β-apo-12'-carotene, the presence of a portion of cis isomers prevents the product from precipitating as a solid. Furthermore, the viscous paste extracted from the crystallization mother liquor, with a high proportion of cis isomers, is difficult to filter and purify, hindering its direct use in subsequent reactions and affecting the quality and yield of the final product. Additionally, since this method yields the E-configuration (trans-configuration) of 4-oxo-β-apo-12'-carotene, the subsequent product molecule exhibits a fully -E configuration where no branching groups of the double bonds compete for space, resulting in a stable oxocarotene. The organic synthesis routes for 4-oxo-β-apo-12'-carotene are similar to those for β-apo-12'-carotene. These include the Wittig-Horner route or the aldol condensation route for preparing ethyl 4-oxo-β-apo-8'-carotene via C25+C5.

[0043] Further, step S1 involves a reaction in a first organic solvent; step S3 involves a reaction in a second organic solvent; the first and second organic solvents are each independently one or a combination of two or more of dichloromethane, ethanol, and methanol. Dichloromethane is the least toxic of the methane chlorides.

[0044] Furthermore, the reactions in steps S1 and S3 are carried out under the protection of an inert gas, namely nitrogen. Since phosphine ylides are sensitive to water and oxygen, the organic solvent and nitrogen work together to protect the phosphine ylides formed in the reaction.

[0045] Further, in step S1, the halogenating agent is one or a combination of two or more of hydrochloric acid, hydrobromic acid, or thionyl chloride. The hydrochloric acid and hydrobromic acid, after reacting as halogenating agents, require extraction and drying.

[0046] Further, in step S1, the molar ratio of the halogenated agent to 4-oxovinyl-β-ionol is (1.0~1.05):1; in step S2, the molar amount of triphenylphosphine added is (1.0~1.1) times the molar amount of 4-oxovinyl-β-ionol in step S1; in step S3, the molar amount of 8,8-dimethoxy-2,7-dimethyl-2,4,6-octtrienal added is (0.85~0.95) times the molar amount of 4-oxovinyl-β-ionol in step S1.

[0047] Furthermore, the reaction temperature in step S1 is 0–10°C; the reaction temperature in step S2 is 20–30°C.

[0048] Furthermore, in step S1, the halogenated agent is added dropwise over a period of 15-20 minutes. After the halogenated agent is added, the reaction continues for 30 minutes.

[0049] Furthermore, the reaction time in step S2 is 2 hours.

[0050] Since the present application prepares stable phosphine ylide, which can be further separated and purified, step S2 further includes the following steps:

[0051] S21. After the triphenylphosphine reacts completely with the 4-oxo-C15 alcohol, 50 mL of water is added and stirred to disperse evenly to obtain a mixture of 4-oxo-C15 phosphine salt and water.

[0052] S22. Transfer the mixture of 4-oxo-C15 phosphonium salt and water to a separatory funnel to separate the organic phase;

[0053] S23. The aqueous phase was extracted twice with dichloromethane, and the extracts were combined and washed once with water.

[0054] S24. The organic phase washed with water is dried with sodium sulfate and concentrated under reduced pressure to obtain a 4-oxo-C15 phosphonium salt concentrate, which is then directly used for the next reaction.

[0055] Furthermore, the S2 reaction system is adjusted to neutral using 1,2-epoxybutane.

[0056] Further, in step S3, the addition reaction is carried out under alkaline conditions; the alkaline conditions are the addition of an inorganic base; the inorganic base is at least one of sodium hydroxide, potassium hydroxide, or lithium hydroxide; the molar amount of the inorganic base added is (1.0 to 1.1) times the molar amount of 4-oxovinyl-β-ionol in step S1.

[0057] Further, in step S3, after the 8,8-dimethoxy-2,7-dimethyl-2,4,6-octtrienal is dissolved in a second organic solvent, the reaction temperature is lowered to 0-5°C before an inorganic base is added; the inorganic base is added in the form of an alkaline solution with a mass concentration of 10%-15%.

[0058] Furthermore, the alkali solution is added to the system dropwise to initiate the Wittig reaction; the pH of the system fluctuates significantly in the early stage of the dropwise addition, and when the pH value of the system stabilizes, the addition of alkali solution is stopped, and the reaction continues at 10-20°C for 2.0 h to complete the addition reaction.

[0059] Further, in step S3, the second organic solvent is ethanol or methanol. This is because the stable phosphonium ylide (4-oxo-C15 phosphonium salt) and the conjugated carbonyl compound (8,8-dimethoxy-2,7-dimethyl-2,4,6-octtrienal) formed in step S2 of this invention react better in an alcohol solvent to give the trans-configured 4-oxo-β-apori-12'-carotene aldehyde.

[0060] Further, in step S3, the system is first neutralized with 1,2-epoxybutane before 8,8-dimethoxy-2,7-dimethyl-2,4,6-octtrienal is added; during the Wittig reaction with the addition of alkaline solution, the pH of the reaction system is kept ≤9.5 in the early stage of addition; the temperature of the addition reaction is 10-20℃; during the hydrolysis reaction, the pH of the system is adjusted to be acidic in the range of 2.0-3.0; the temperature of the hydrolysis reaction is 25-30℃.

[0061] Furthermore, in step S3, when adjusting the reaction system to acidity, the pH of the system is adjusted using a 20% sulfuric acid aqueous solution; the hydrolysis reaction time is 15-20 min.

[0062] Furthermore, step S3 also includes the following steps:

[0063] S31. After the hydrolysis reaction is completed, the temperature is lowered to 0-10℃, crystallization is carried out for 30 minutes, and then the product filter cake is obtained by vacuum filtration.

[0064] S32. The product filter cake was rinsed once with pure water and dried under vacuum at 50°C to obtain a red solid, thus completing the preparation of 4-oxo-β-apo-12'-carotene.

[0065] A 4-oxo-β-apo-12'-carotene aldehyde prepared by the above method has an all-trans content of 95%. The product obtained by the above method for preparing 4-oxo-β-apo-12'-carotene aldehyde can be used for the synthesis of oxocarotene.

[0066] The present invention will now be further described in conjunction with specific embodiments;

[0067] Example 1

[0068] A method for preparing 4-oxo-β-apo-12'-carotene includes the following steps:

[0069] Preparation of S1,4-oxo-C15 halogenated products:

[0070] Under nitrogen protection, 0.10 mol of 4-oxovinyl-β-ionol and 100 mL of dichloromethane were added to a 500 mL reaction flask. The mixture was mechanically stirred and cooled to 0 °C. 0.10 mol of thionyl chloride was added dropwise, with the internal temperature controlled at ≤10 °C during the dropwise addition. The addition was completed in 20 min. After the addition was completed, the reaction was continued at about 5 °C for 30 min. After the reaction was completed, the next step of the reaction was carried out directly.

[0071] Preparation of S2,4-oxo-C15 phosphonium salts:

[0072] 0.102 mol of triphenylphosphine was added to the reaction system of S1, and the mixture was stirred and reacted at about 25°C for 2.0 h.

[0073] After the reaction was complete, 50 mL of water was added and the mixture was evenly dispersed. The mixture was then transferred to a separatory funnel to separate the organic phase. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with water and dried with sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a 4-oxo-C15 phosphonium salt concentrate, which was then used for the next reaction.

[0074] Preparation of S3,4-oxo-β-apo-12'-carotene acetal:

[0075] First, the 4-oxo-C15 phosphonium salt concentrate obtained from S2 was adjusted to neutral with 1,2-epoxybutane. Then, 0.085 mol of C10 monoaldehyde methyl acetal and 100 mL of ethanol were added. After stirring to dissolve and disperse completely, the mixture was cooled to 0°C. 0.110 mol of sodium hydroxide was slowly added dropwise to prepare a 10% sodium hydroxide ethanol solution. During the dropwise addition, the internal temperature was controlled to be ≤15°C, and the pH value of the system was controlled to not exceed 9.5 in the early stage. The pH value of the system fluctuated greatly in the early stage of the dropwise addition, and tended to stabilize in the later stage. When the pH value of the system remained basically unchanged, the addition of alkali was stopped, and the reaction was continued at about 15°C for 2.0 h until the reaction was completed.

[0076] Preparation of S4, 4-oxo-β-apo-12'-carotene:

[0077] A 20% sulfuric acid aqueous solution was added dropwise to the S3 reaction system until the pH reached 3.0. Hydrolysis was carried out at approximately 25°C for 15 min, followed by cooling to 5°C for 30 min to allow crystallization. The mixture was filtered, and the filter cake was washed once with 75% ethanol and water, then dried under vacuum at 50°C to obtain 38.07 g of a red solid. HPLC analysis revealed that the red solid contained 80.65% 4-oxo-β-apo-12'-carotene, with a yield of 84.23% for 4-oxo-C15 alcohol and 99.09% for C10 monoaldehyde methyl acetal.

[0078] Example 2

[0079] A method for preparing 4-oxo-β-apo-12'-carotene includes the following steps:

[0080] Preparation of S1,4-oxo-C15 halogenated products:

[0081] Under nitrogen protection, 0.10 mol of 4-oxovinyl-β-ionol and 100 mL of dichloromethane were added to a 500 mL reaction flask. The mixture was mechanically stirred and cooled to 0 °C. 0.102 mol of thionyl chloride was added dropwise, with the internal temperature controlled at ≤10 °C during the dropwise addition. The addition was completed in 15 min. After the addition was completed, the reaction was continued at 0–10 °C for 30 min. After the reaction was completed, the next reaction was carried out directly.

[0082] Preparation of S2,4-oxo-C15 phosphonium salts:

[0083] Add 0.105 mol of triphenylphosphine to the reaction system of S1, stir, and react at about 25°C for 2.0 h.

[0084] After the reaction was complete, 50 mL of water was added and the mixture was dispersed evenly. The mixture was then transferred to a separatory funnel to separate the organic phase. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with water and dried with sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a 4-oxo-C15 phosphonium salt concentrate, which was then directly used for the next reaction.

[0085] Preparation of S3,4-oxo-β-apo-12'-carotene acetal:

[0086] First, the 4-oxo-C15 phosphonium salt concentrate obtained from S2 was adjusted to neutral with 1,2-epoxybutane. Then, 0.090 mol of C10 monoaldehyde methyl acetal and 100 mL of methanol were added. After stirring and dissolving, the mixture was cooled to 0°C. 0.10 mol of sodium hydroxide was slowly added dropwise to prepare a 12% sodium hydroxide methanol solution. During the dropwise addition, the internal temperature was controlled to be ≤10°C, and the pH value of the system was controlled to be no more than 9.5 in the early stage. The pH value of the system fluctuated greatly in the early stage of the dropwise addition, and tended to stabilize in the later stage. When the pH value of the system was basically unchanged, the addition of alkali was stopped, and the reaction was continued at about 10°C for 2.0 h until the reaction was completed.

[0087] Preparation of S4, 4-oxo-β-apo-12'-carotene:

[0088] Add 20% sulfuric acid aqueous solution dropwise to the S3 reaction system until the pH value of the system is 3.0. Hydrolyze at about 25℃ for 15 min, cool to 5℃, crystallize for 30 min, filter, wash the filter cake once with 70% methanol water, dry under vacuum at 50℃, and obtain 37.82 g of red solid. HPLC analysis of the red solid showed that the content of 4-oxo-β-apo-12'-carotene was 85.24%, the yield of 4-oxo-C15 alcohol was 88.44%, and the yield of C10 monoaldehyde methyl acetal was 98.27%.

[0089] Example 3

[0090] A method for preparing 4-oxo-β-apo-12'-carotene includes the following steps:

[0091] Preparation of S1,4-oxoC15 halogenated products:

[0092] Under nitrogen protection, 0.10 mol of 4-oxovinyl-β-ionol and 120 mL of dichloromethane were added to a 500 mL reaction flask. The mixture was mechanically stirred and cooled to 0 °C. 0.105 mol of thionyl chloride was added dropwise, with the internal temperature controlled at ≤10 °C during the dropwise addition. The addition was completed in 20 min. After the addition was completed, the reaction was continued at around 10 °C for 30 min. After the reaction was completed, the next step of the reaction was carried out directly.

[0093] Preparation of S2,4-oxoC15 phosphonium salts:

[0094] Add 0.11 mol of triphenylphosphine to the reaction system of S1, stir, and react at about 25°C for 2.0 h.

[0095] After the reaction was complete, 50 mL of water was added and the mixture was dispersed evenly. The mixture was then transferred to a separatory funnel to separate the organic phase. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with water and dried with sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a 4-oxo-C15 phosphonium salt concentrate, which was then directly used for the next reaction.

[0096] Preparation of S3,4-oxo-β-apo-12'-carotene acetal:

[0097] First, the 4-oxo-C15 phosphonium salt concentrate obtained from S2 was adjusted to neutral with 1,2-epoxybutane. Then, 0.095 mol of C10 monoaldehyde methyl acetal and 120 mL of ethanol were added. After stirring and dissolving, the mixture was cooled to 0°C. 0.105 mol of potassium hydroxide was slowly added dropwise to prepare a 15% potassium hydroxide ethanol solution. During the dropwise addition, the internal temperature was controlled to be ≤20°C, and the pH value of the system was controlled to be no more than 9.5 in the early stage. The pH value of the system fluctuated greatly in the early stage of the dropwise addition, and tended to stabilize in the later stage. When the pH value of the system was basically unchanged, the addition of alkali was stopped, and the reaction was continued at about 20°C for 2.0 h until the reaction was completed.

[0098] Preparation of S4, 4-oxo-β-apo-12'-carotene:

[0099] Add 20% sulfuric acid aqueous solution dropwise to the S3 reaction system until the pH value of the system is 3.0. Hydrolyze at about 30℃ for 15 min. After hydrolysis, cool to 5℃ and crystallize for 30 min. Filter, wash the filter cake once with 80% ethanol water, dry under vacuum at 50℃ to obtain 38.42 g of red solid. HPLC analysis of the red solid showed that the content of 4-oxo-β-apo-12'-carotene was 88.65%, the yield of 4-oxo-C15 alcohol was 93.44%, and the yield of C10 monoaldehyde methyl acetal was 98.35%.

[0100] Example 4

[0101] A method for preparing 4-oxo-β-apo-12'-carotene includes the following steps:

[0102] Preparation of S1,4-oxo-C15 halogenated products:

[0103] Under nitrogen protection, 0.10 mol of 4-oxovinyl-β-ionol and 120 mL of dichloromethane were added to a 500 mL reaction flask. The mixture was mechanically stirred and cooled to 0 °C. 0.105 mol of hydrobromic acid was added dropwise, with the internal temperature controlled at ≤10 °C during the addition process. The addition was completed in 20 min. After the addition was completed, the reaction was continued at around 10 °C for 30 min. After the reaction was completed, the mixture was transferred to a separatory funnel to separate the organic phase. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with water and dried with sodium sulfate. The dried organic phase was then directly used for the next reaction.

[0104] Preparation of S2,4-oxoC15 phosphonium salts:

[0105] 0.11 mol of triphenylphosphine was added to the dried organic phase of S1 and stirred. The mixture was reacted at about 25°C for 2.0 h. After the reaction was completed, the mixture was concentrated under reduced pressure and dried to obtain a 4-oxo-C15 phosphonium salt concentrate, which was then directly used for the next reaction.

[0106] Preparation of S3,4-oxo-β-apo-12'-carotene acetal:

[0107] First, the 4-oxo-C15 phosphonium salt concentrate obtained from S2 was adjusted to neutral with 1,2-epoxybutane. Then, 0.095 mol of C10 monoaldehyde methyl acetal and 120 mL of ethanol were added. After stirring and dissolving, the mixture was cooled to 5 °C. 0.1 mol of potassium hydroxide was slowly added dropwise to prepare a 15% potassium hydroxide ethanol solution. During the dropwise addition, the internal temperature was controlled to be ≤20 °C, and the pH value of the system was controlled to not exceed 9.5 in the early stage. The pH value of the system fluctuated greatly in the early stage of the dropwise addition, but tended to stabilize in the later stage. When the pH value of the system remained basically unchanged, the addition of alkali was stopped, and the reaction was continued at about 20 °C for 2.0 h until the reaction was completed.

[0108] Preparation of S4, 4-oxo-β-apo-12'-carotene:

[0109] Add 20% sulfuric acid aqueous solution dropwise to the S3 reaction system until the pH value of the system is 3.0. Hydrolyze at about 30℃ for 15 min. After hydrolysis, cool to 5℃ and crystallize for 30 min. Filter, wash the filter cake once with 80% ethanol water, dry under vacuum at 50℃ to obtain 38.24 g of red solid. HPLC analysis of the red solid showed that the content of 4-oxo-β-apo-12'-carotene was 86.45%, the yield of 4-oxo-C15 alcohol was 90.68%, and the yield of C10 monoaldehyde methyl acetal was 95.46%.

[0110] Example 5

[0111] A method for preparing 4-oxo-β-apo-12'-carotene includes the following steps:

[0112] Preparation of S1,4-oxo-C15 halogenated products:

[0113] Under nitrogen protection, 0.10 mol of 4-oxovinyl-β-ionol and 120 mL of dichloromethane were added to a 500 mL reaction flask. The mixture was mechanically stirred and cooled to 0 °C. 0.105 mol of hydrochloric acid was added dropwise, with the internal temperature controlled at ≤10 °C during the addition process. The addition was completed in 20 min. After the addition was completed, the reaction was continued at around 10 °C for 30 min. After the reaction was completed, the mixture was transferred to a separatory funnel to separate the organic phase. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with water and dried with sodium sulfate. The dried organic phase was then directly used for the next reaction.

[0114] Preparation of S2,4-oxoC15 phosphonium salts:

[0115] 0.11 mol of triphenylphosphine was added to the dried organic phase of S1 and stirred. The mixture was reacted at about 25°C for 2.0 h. After the reaction was completed, the mixture was concentrated under reduced pressure and dried to obtain a 4-oxo-C15 phosphonium salt concentrate, which was then directly used for the next reaction.

[0116] Preparation of S3,4-oxo-β-apo-12'-carotene acetal:

[0117] First, the 4-oxo-C15 phosphonium salt concentrate obtained from S2 was neutralized to neutral with 1,2-epoxybutane. Then, 0.095 mol of C10 monoaldehyde methyl acetal and 120 mL of methanol were added. After stirring and dissolving, the mixture was cooled to 5 °C. 0.105 mol of sodium hydroxide was slowly added dropwise to prepare a 12% sodium hydroxide methanol solution. During the dropwise addition, the internal temperature was controlled to be ≤10 °C, and the pH value of the system was controlled to not exceed 9.5 in the early stage. The pH value of the system fluctuated greatly in the early stage of the dropwise addition, but tended to stabilize in the later stage. When the pH value of the system was basically unchanged, the addition of alkali was stopped, and the reaction was continued at about 20 °C for 2.0 h until the reaction was completed.

[0118] Preparation of S4, 4-oxo-β-apo-12'-carotene:

[0119] Add 20% sulfuric acid aqueous solution dropwise to the S3 reaction system until the pH value of the system is 2.5. Hydrolyze at about 25℃ for 15 min. After hydrolysis, cool to 5℃ and crystallize for 30 min. Filter, wash the filter cake once with 80% methanol water, dry under vacuum at 50℃ to obtain 38.42 g of red solid. HPLC analysis of the red solid showed that the content of 4-oxo-β-apo-12'-carotene was 87.14%, the yield of 4-oxo-C15 alcohol was 91.85%, and the yield of C10 monoaldehyde methyl acetal was 96.68%.

[0120] The present invention provides a method for preparing 4-oxo-β-apo-12'-carotene, which has a simple synthetic route, readily available raw materials, mild reaction conditions, high product yield, and specific configuration, making it an ideal method for the industrial production of 4-oxo-β-apo-12'-carotene.

[0121] For those skilled in the art, various other corresponding changes and modifications can be made based on the technical solutions and concepts described above, and all such changes and modifications should fall within the protection scope of the claims of this invention.

Claims

1. A method for preparing 4-oxo-β-apo-12'-carotene, characterized in that, Includes the following steps: S1, 4-oxovinyl-β-ionol reacted with a halogenating agent to prepare a 4-oxo-C15 halide; S2. The 4-oxo-C15 halide obtained in step S1 is reacted with triphenylphosphine to prepare a 4-oxo-C15 phosphonium salt. S3 and S2: The 4-oxo-C15 phosphonium salt obtained in step S2 undergoes an addition reaction with 8,8-dimethoxy-2,7-dimethyl-2,4,6-octtrienal, followed by hydrolysis to obtain 4-oxo-β-apori-12'-carotene aldehyde. In step S3, after the 8,8-dimethoxy-2,7-dimethyl-2,4,6-octtrienal is dissolved in the second organic solvent, the reaction temperature is lowered to 0-5°C before an inorganic base is added. In step S3, the second organic solvent is ethanol or methanol; In step S3, the addition reaction is carried out under alkaline conditions; the alkaline conditions are the addition of an inorganic base; the inorganic base is at least one of sodium hydroxide, potassium hydroxide, or lithium hydroxide; the molar amount of the inorganic base added is (1.0 to 1.1) times the molar amount of 4-oxovinyl-β-ionol in step S1, and the inorganic base is added in the form of an alkaline solution with a mass concentration of 10% to 15%. In step S3, the reaction system is first neutralized with 1,2-epoxybutane before 8,8-dimethoxy-2,7-dimethyl-2,4,6-octtrienal is added; during the addition reaction, the pH of the reaction system is kept ≤9.5 and the reaction temperature is 10-20℃; during the hydrolysis reaction, the pH of the reaction system is adjusted to 2.0-3.0 and the reaction temperature is 25-30℃. S3 also includes the following steps: S31. After the hydrolysis reaction is completed, the temperature is lowered to 0-10℃, crystallization is carried out for 30 minutes, and then the product filter cake is obtained by vacuum filtration. S32. The product filter cake was rinsed once with pure water and dried under vacuum at 50°C to obtain a red solid, thus completing the preparation of 4-oxo-β-apo-12'-carotene.

2. The method for preparing 4-oxo-β-apo-12'-carotene according to claim 1, characterized in that, Step S1 involves reacting in a first organic solvent; step S3 involves reacting in a second organic solvent; the first and second organic solvents are each independently one or a combination of two or more of dichloromethane, ethanol, and methanol.

3. The method for preparing 4-oxo-β-apo-12'-carotene according to claim 1, characterized in that, In step S1, the halogenated reagent is one or a combination of two or more of hydrochloric acid, hydrobromic acid, or thionyl chloride.

4. The method for preparing 4-oxo-β-apo-12'-carotene according to claim 1, characterized in that, In step S1, the molar ratio of the halogenated reagent to 4-oxovinyl-β-ionol is (1.0–1.05):1; in step S2, the molar amount of triphenylphosphine added is (1.0–1.1) times the molar amount of 4-oxovinyl-β-ionol in step S1; in step S3, the molar amount of 8,8-dimethoxy-2,7-dimethyl-2,4,6-octtrienal added is (0.85–0.95) times the molar amount of 4-oxovinyl-β-ionol in step S1.

5. The method for preparing 4-oxo-β-apo-12'-carotene according to claim 1, characterized in that, The reaction temperature in step S1 is 0–10°C; the reaction temperature in step S2 is 20–30°C.

6. The application of the method for preparing 4-oxo-β-apor-12'-carotene according to any one of claims 1-5 in organic synthesis.

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