Novel intermediates for beta-carotene synthesis
By reacting with formic acid using a new intermediate compound formula (IV) without halogen ions, the problem of insufficient yield and purity of the β-carotene production route in the prior art was solved, and the efficient synthesis of β-carotene was achieved.
Patent Information
- Application Number
- CN202380086669.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2022-12-21
- Filing Date
- 2023-12-19
- Publication Date
- 2025-07-25
AI Technical Summary
In the prior art, the production route of β-carotene has problems with insufficient yield and purity.
A new intermediate compound formula (IV) containing no halide ions is used to react with formic acid to synthesize β-carotene. The reaction is carried out in formic acid, with a temperature range of 30 to 120°C, and alkali metal hydroxides and the like can be used as catalysts.
The yield and purity of β-carotene is improved, providing an efficient synthesis method.
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Abstract
Description
[0001] The present invention relates to a new intermediate that can be used in a process for producing β-carotene.
[0002] β-carotene is an organic, strongly colored red-orange pigment that is widely present in fungi, plants, and fruits. β-carotene is an important product with various different application methods.
[0003] β-carotene is a compound of formula (I).
[0004]
[0005] β-carotene is a member of the carotene family and belongs to the terpene compounds (isoprenoid compounds). It is synthesized from eight isoprene units by biochemical methods and thus contains 40 carbon atoms. Among the carotene family, β-carotene is characterized by having β-rings at both ends of the molecule.
[0006] β-carotene is the most common form of carotene in plants.
[0007] When used as a food colorant, its E number is E160a(ii).
[0008] In addition, in nature, β-carotene becomes a precursor (inactive form) of vitamin A through the action of β-carotene 15,15'-monooxygenase.
[0009] β-carotene is a compound that gives vegetables their bright yellow, orange, and red colors. The human body converts β-carotene into vitamin A (retinol).
[0010] In addition to its coloring properties, β-carotene also has certain health benefits, such as effects on eye health, improvement of cognitive function, skin protection, and prevention of cancer.
[0011] The following reaction equation shows a common route for producing β-carotene.
[0012]
[0013] Due to its importance, there is always a need to find an improved route to obtain β-carotene.
[0014] Surprisingly, we have found that by using a new intermediate free of halogen ions, the final yield of β-carotene can be extremely high and the purity is also very excellent.
[0015] The following is the formate of formula (IV):
[0016]
[0017] As a new compound, it can be used for the synthesis of β-carotene.
[0018] Accordingly, the present invention relates to a compound of formula (IV):
[0019]
[0020] In the context of the present invention, all disclosed compounds (represented by chemical formulas) can be in any possible stereochemical configuration.
[0021] The new compound of formula (IV) can be produced according to the following method:
[0022]
[0023] Accordingly, the present invention relates to a method (P) for producing a compound of formula (IV)
[0024]
[0025] by reacting a compound of formula (V)
[0026]
[0027] with a compound of formula (VI)
[0028]
[0029] in the presence of formic acid (HCOOH).
[0030] The compounds of formula (V) and (VI) can be commercially purchased from various suppliers. Alternatively, they can also be synthesized using suitable starting materials.
[0031] The method for producing the compound of formula (IV) is carried out in formic acid. No additional inert solvent is required.
[0032] Optionally, an inert solvent can also be used.
[0033] Generally and preferably, formic acid (HCOOH) is used in a molar excess relative to the compound of formula (V).
[0034] Accordingly, the present invention relates to method (P1), which is method (P) wherein formic acid is in a molar excess relative to the compound of formula (V).
[0035] Generally, the compound of formula (VI) is used in a molar ratio of 1 to 1.5 (relative to the compound of formula (V)).
[0036] This means that the compound of formula (VI) can be used in an equimolar amount or in a slightly excessive amount relative to the compound of formula (V).
[0037] Therefore, the present invention also relates to method (P2), which is method (P) or (P1), wherein the compound of formula (VI) is used in a molar ratio of 1 to 1.5 (relative to the compound of formula (V)).
[0038] The method according to the present invention is generally carried out at an elevated temperature.
[0039] Generally, the method according to the present invention is carried out in the temperature range of 30 to 120 °C.
[0040] Therefore, the present invention also relates to method (P3), which is method (P), (P1) or (P2), wherein the method is carried out in the temperature range of 30 to 120 °C.
[0041] The novel compound of formula (IV) is used in the method for producing β-carotene.
[0042] The following reaction equation shows how to use the compound of formula (IV) as a starting material to obtain β-carotene:
[0043]
[0044] Therefore, the present invention also relates to the use of the compound of formula (IV) to produce β-carotene.
[0045] Therefore, the present invention also relates to the reaction method (RP) for producing β-carotene (the compound of formula (I))
[0046]
[0047] by reacting the compound of formula (IV)
[0048]
[0049] with the compound of formula (III)
[0050]
[0051] This reaction can be carried out using the known reaction conditions disclosed with the compound of formula (II) as the starting material.
[0052] The compound (IV) is used in a molar ratio of at least 2:1 (relative to the compound of formula (III)).
[0053] The present invention also relates to the reaction method (RP1), which is method (RP), wherein the compound of formula (IV) is used in a molar ratio of at least 2:1 (relative to the compound of formula (III)).
[0054] The method for producing β-carotene is generally carried out at a temperature of 0 - 150 °C. Preferably, the method is carried out in the temperature range of 5 °C to 130 °C.
[0055] Accordingly, the present invention relates to a method (RP2), which is the method (RP) or (RP1), wherein the method is carried out at a temperature of 0 - 150 °C.
[0056] Accordingly, the present invention relates to a method (RP2’), which is the method (RP) or (RP1), wherein the method is carried out at a temperature of 5 °C to 130 °C.
[0057] An alkali can also be added to the reaction mixture.
[0058] The alkali is generally an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkaline earth metal carbonate, KF / Al2O3, NaOCH3, and KOCH3.
[0059] Preferably, the alkali is CsOH, KOH, NaOH, Na2CO3, or K2CO3.
[0060] Relative to the compound of formula (III), the alkali is generally used in a molar excess. Usually, it is 2 - 20 molar equivalents of the compound of formula (III).
[0061] Accordingly, the present invention relates to a method (RP3), which is the method (RP), (RP1), (RP2), or (RP2’), wherein the method is carried out in the presence of at least one alkali.
[0062] Accordingly, the present invention relates to a method (RP3’), which is the method (RP3), wherein the alkali is selected from the group consisting of an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkaline earth metal carbonate, KF / Al2O3, NaOCH3, and KOCH3.
[0063] Accordingly, the present invention relates to a method (RP3”), which is the method (RP3), wherein the alkali is selected from the group consisting of CsOH, KOH, NaOH, Na2CO3, and K2CO3.
[0064] The method for producing β-carotene is generally and preferably carried out in a solvent.
[0065] Accordingly, the present invention relates to a method (RP4), which is the method (RP), (RP1), (RP2), (RP2’), (RP3), (RP3’), or (RP3”), wherein the method is carried out in at least one solvent.
[0066] Such a solvent can be any known solvent commonly used in the methods disclosed and described in the prior art.
[0067] Suitable solvents are CH2Cl2, CHCl3, straight-chain or branched C1-C4 alcohols, toluene, mixtures of alcohols / C5-C7 alkanes / water.
[0068] Preferred solvents are CH2Cl2 or CH3CH2OH.
[0069] Accordingly, the present invention relates to method (RP5), which is method (RP4) wherein the solvent is selected from the group consisting of CH2Cl2, CHCl3, straight-chain or branched C1-C4 alcohols, toluene, mixtures of alcohols / C5-C7 alkanes / water.
[0070] A very preferred solvent is the alcohol represented by formula (VII)
[0071] R-OH(VII),
[0072] wherein
[0073] R represents a straight-chain or branched C3-C 10 alkyl group (preferably a C4-C8 alkyl group, more preferably a C4-C7 alkyl group, most preferably a C5 alkyl group).
[0074] The most preferred solvents are 1-pentanol, 2-pentanol, 2-methyl-1-butanol, 2-methyl-2-butanol and / or 3-methyl-1-butanol.
[0075] Accordingly, the present invention relates to method (RP6), which is method (RP4) wherein the solvent is at least one compound of formula (VII)
[0076] R-OH(VII),
[0077] wherein
[0078] R represents a straight-chain or branched C3-C 10 alkyl group (preferably a C4-C8 alkyl group, more preferably a C4-C7 alkyl group, most preferably a C5 alkyl group).
[0079] Accordingly, the present invention relates to method (RP6’), which is method (RP6) wherein the alcohol of the compound of formula (VII) is selected from the group consisting of 1-pentanol, 2-pentanol, 2-methyl-1-butanol, 2-methyl-2-butanol and 3-methyl-1-butanol.
[0080] Another group of suitable solvents are organic carbonates.
[0081] Such organic carbonates have the following chemical formula (VIII)
[0082]
[0083] wherein
[0084] R1 is a C1-C4 alkyl group, and
[0085] R2 is a C1-C4 alkyl group.
[0086] Preferably, the organic carbonate as the solvent is a compound of formula (VIII), wherein
[0087] R1 is a C1-C2 alkyl group, and
[0088] R2 is a C1-C2 alkyl group.
[0089] More preferably, the organic carbonate of the compound of formula (VIII) as the solvent is selected from the group consisting of dimethyl carbonate and diethyl carbonate.
[0090] Most preferably, the organic carbonate of formula (VIII) is diethyl carbonate.
[0091] Accordingly, the present invention relates to method (RP7), which is method (RP4), wherein the solvent is at least one organic carbonate.
[0092] Accordingly, the present invention relates to method (RP7'), which is method (RP7), wherein the organic carbonate is a compound of formula (VIII)
[0093]
[0094] wherein
[0095] R1 is a C1-C4 alkyl group, and
[0096] R2 is a C1-C4 alkyl group.
[0097] Accordingly, the present invention relates to method (RP7'), which is method (RP7), wherein the organic carbonate is selected from the group consisting of dimethyl carbonate and diethyl carbonate.
[0098] Accordingly, the present invention relates to method (RP7'), which is method (RP7), wherein the organic carbonate is diethyl carbonate.
[0099] The following examples further illustrate but do not limit the present invention. All percentages and parts are by weight, temperature is given in °C, and pressure is absolute pressure unless otherwise specified. Examples
[0100] Example 1: Synthesis of the compound of formula (IV)
[0101] Under an inert gas atmosphere, triphenylphosphine (12.99 g, 1.1 eq., 49.02 mmol) was suspended in formic acid (18.46 g, 15.13 mL, 9 eq., 401.1 mmol).
[0102] The suspension was heated to 60 °C in an oil bath and triphenylphosphine dissolved. Vinyl alcohol (100.00 g, 10 mL, 1.00 eq., 44.56 mmol) was added within 1 h. After the addition was complete, stirring was continued for 2 h at the same temperature. Then, the orange solution was cooled to room temperature within 30 min. Thereafter, the solution was diluted with methanol (30 mL) and hexane (30 mL) and transferred to a separatory funnel. After shaking, the layers were separated. The methanol layer was extracted with hexane (30 mL) and the hexane layer was washed with methanol (30 mL). The methanol layers were combined and the solvent was evaporated under reduced pressure (55 °C, 1 h). The crude vinyl salt was obtained as an orange oil (26.78 g, yield 67.7%).
[0103] Example 2: Synthesis of β-carotene
[0104] Under an inert gas atmosphere, C10-dialdehyde (442 mg, 1.0 eq., 2.68 mmol) and potassium carbonate (4.40 g, 12.0 eq., 32.2 mmol) were suspended in methanol (7 mL). The yellow suspension was cooled to 0 °C with an ice bath. Then, a solution of vinyl salt formate (IV) (5.00 g, 2.1 eq., 5.63 mmol) in methanol (15 mL) was added dropwise within 20 min. The reaction mixture was heated to 65 °C in an oil bath and stirred for 4 h, then cooled to 40 °C within 30 min. Distilled water (15 mL) was added within 20 min. The reaction mixture was cooled to 0 °C with an ice bath and stirred for 30 min. Then the red suspension was filtered and the filter cake was rinsed with deionized water (3 times, 10 mL each time). The dark red crystalline material was dried in vacuo at 50 °C overnight. The crude β-carotene was obtained as dark red crystals (2.62 g), with a yield of 87.2%.
Claims
1. A compound of formula (IV), 2. A process for producing a compound of formula (I) by reacting a compound of formula (IV) with a compound of formula (III).
3. The process according to claim 2, wherein the compound of formula (IV) is used in a molar ratio of at least 2:1 (relative to the compound of formula (III)).
4. The process according to claim 2 or 3, wherein the process is carried out at a temperature between 0 - 150 °C.
5. The process according to any one of claims 2 to 4, wherein the process is carried out in the presence of at least one base.
6. The process according to claim 5, wherein the base is selected from the group consisting of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, KF / Al2O3, NaOCH3, and KOCH3.
7. The process according to any one of claims 2 to 6, wherein the process is carried out in at least one solvent.
8. The process according to claim 7, wherein the at least one solvent is selected from the group consisting of CH2Cl2, CHCl3, linear or branched C1 - C4 alcohols, toluene, and mixtures of alcohols / C5 - C7 alkanes / water.
9. The process according to claim 7, wherein the solvent is at least one compound of formula (VII) R-OH(VII), wherein R represents a straight-chain or branched C3-C 10 alkyl group.
10. The process according to claim 9, wherein the alcohol is selected from the group consisting of 1 - pentanol, 2 - pentanol, 2 - methyl - 1 - butanol, 2 - methyl - 2 - butanol, and 3 - methyl - 1 - butanol.
11. The process according to claim 7, wherein the at least one solvent is an organic carbonate.
12. The process according to claim 11, wherein the at least one solvent is an organic carbonate of a compound of formula (VIII) wherein R1 is a C1 - C4 alkyl group, and R2 is a C1 - C4 alkyl group.
13. The process according to claim 11 or claim 12, wherein the organic carbonate is selected from the group consisting of dimethyl carbonate and diethyl carbonate.
14. The process according to claim 11 or claim 12, wherein the organic carbonate is diethyl carbonate.