Novel intermediates for beta-carotene synthesis

Abstract

The invention relates to a novel intermediate which can be used in a method for producing beta-carotene.

Description

[0001] The present invention relates to a novel intermediate which can be used in a method for producing beta-carotene.

[0002] Beta-carotene is an organic, intense red-orange pigment found in a wide range of fungi, plants and fruits. Beta-carotene is an important product with many different applications.

[0003] β-Carotene is a compound of the following formula (I).

[0004]

[0005] β-carotene is a member of the carotene family and belongs to the terpenoid class (isoprene compounds). It is synthesized biochemically from eight isoprene units and therefore contains 40 carbon atoms. In the carotene family, β-carotene is characterized by having β-rings at both ends of the molecule.

[0006] Beta-carotene is the most common form of carotene found in plants.

[0007] When used as a food colorant, its E number is E160a(ii).

[0008] In addition, in nature, β-carotene is converted into a precursor (inactive form) of vitamin A through the action of β-carotene 15,15'-monooxygenase.

[0009] Beta-carotene is a compound that gives vegetables their vibrant yellow, orange, and red colors. The body converts beta-carotene into vitamin A (retinol).

[0010] In addition to its coloring properties, beta-carotene has been linked to certain health benefits, such as effects on eye health, improved cognitive function, skin protection, and cancer prevention.

[0011] The reaction equation below shows a common route for producing β-carotene.

[0012]

[0013] Due to its importance, there is a constant need to find an improved route to obtain β-carotene.

[0014] Surprisingly, we found that using a new intermediate that does not contain halide ions can result in extremely high yields and excellent purity of the final β-carotene.

[0015] The following are vinyl salts of formula (IV):

[0016]

[0017] As a new compound, it can be used to synthesize β-carotene.

[0018] Therefore, the present invention relates to compounds of formula (IV):

[0019]

[0020] In the context of the present invention, all disclosed compounds (represented by chemical formulae) may be in any possible stereochemical configuration.

[0021] The novel compound of formula (IV) can be produced according to the following method:

[0022]

[0023] Therefore, the present invention relates to a process (P) for producing a compound of formula (IV)

[0024]

[0025] By making the compound of formula (V)

[0026]

[0027] and a compound of formula (VI)

[0028]

[0029] The reaction is carried out in the presence of acetic acid.

[0030] Compounds of formula (V) and (VI) are commercially available from various suppliers. Alternatively, they may be synthesized using appropriate starting materials.

[0031] The process for producing the compound of formula (IV) is carried out in acetic acid. No additional inert solvent is required.

[0032] Alternatively, inert solvents may also be used.

[0033] Typically and preferably, acetic acid (CH3COOH) is used in a molar excess relative to the compound of formula (V).

[0034] Therefore, the present invention relates to process (P1 ) which is process (P) wherein acetic acid is in molar excess relative to the compound of formula (V).

[0035] Typically, 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 slight excess to the compound of formula (V).

[0037] The present invention therefore relates to process (P2) which is process (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 process according to the invention is generally carried out at elevated temperature.

[0039] Typically, the process according to the invention is carried out at a temperature in the range of 30 to 120°C.

[0040] Therefore, the present invention relates to process (P3) which is process (P), (P1 ) or (P2), wherein the process is carried out in a temperature range of 30 to 120 °C.

[0041] The novel compounds of formula (IV) are used in a process for producing beta-carotene.

[0042] The following reaction equation shows how to obtain β-carotene using the compound of formula (IV) as a starting material:

[0043]

[0044] Therefore, the present invention relates to the use of compounds of formula (IV) for the production of β-carotene.

[0045] Therefore, the present invention relates to a reaction process (RP) for producing β-carotene (compound of formula (I))

[0046]

[0047] By making the compound of formula (IV)

[0048]

[0049] Reaction with a compound of formula (III) to achieve

[0050]

[0051] This reaction can be carried out using known reaction conditions which have been published using the compound of formula (II) as a starting material.

[0052] 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 process (RP1) which is process (RC) 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 process for producing beta-carotene is generally carried out at a temperature of 0-150° C. Preferably, the process is carried out at a temperature in the range of 5° C. to 130° C.

[0055] Therefore, the present invention relates to process (RP2) which is process (RC) or (RP1), wherein the process is carried out at a temperature of from 0 to 150°C.

[0056] Therefore, the present invention relates to process (RP2') which is process (RC) or (RP1), wherein the process is carried out at a temperature of from 5°C to 130°C.

[0057] A base may also be added to the reaction mixture.

[0058] The base is typically 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 base is CsOH, KOH, NaOH, Na2CO3 or K2CO3.

[0060] The base is usually used in a molar excess relative to the compound of formula (III), usually 2 to 20 molar equivalents of the compound of formula (III).

[0061] The present invention therefore relates to process (RP3) which is process (RP), (RP1), (RP2) or (RP2′), wherein the process is carried out in the presence of at least one base.

[0062] Therefore, the present invention relates to process (RP3') which is process (RP3) 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.

[0063] Therefore, the present invention relates to process (RP3"), which is process (RP3), wherein the base is selected from the group consisting of CsOH, KOH, NaOH, Na2CO3 and K2CO3.

[0064] The process for producing beta-carotene is usually and preferably carried out in a solvent.

[0065] Therefore, the present invention relates to process (RP4) which is process (RP), (RP1), (RP2), (RP2′), (RP3), (RP3′) or (RP3″), wherein the process is carried out in at least one solvent.

[0066] Such solvent may be any known solvent commonly used in the processes disclosed and described in the prior art.

[0067] Suitable solvents are CH2Cl2, CHCl3, linear or branched C1-C4 alcohols, toluene, and mixtures of alcohols / C5-C7 alkanes / water.

[0068] Preferred solvents are CH2Cl2 or CH3CH2OH.

[0069] Therefore, the present invention relates to process (RP5) which is process (RP4) wherein the solvent is selected from the group consisting of.

[0070] A very preferred solvent is an alcohol represented by formula (VII)

[0071] R-OH(VII),

[0072] in

[0073] R represents a straight or branched C3-C 10 Alkyl group (preferably C4-C8 alkyl, more preferably C4-C7 alkyl, most preferably C5 alkyl).

[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] Therefore, the present invention relates to process (RP6) which is process (RP4), wherein the solvent is at least one compound of formula (VII)

[0076] R-OH(VII),

[0077] in

[0078] R represents a straight or branched C3-C 10 Alkyl group (preferably C4-C8 alkyl, more preferably C4-C7 alkyl, most preferably C5 alkyl).

[0079] Therefore, the present invention relates to process (RP6') which is process (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 the organic carbonates.

[0081] Such organic carbonate has the following chemical formula (VIII)

[0082]

[0083] in

[0084] R1 is a C1-C4 alkyl group, and

[0085] R2 is a C1-C4 alkyl group.

[0086] Preferably, the organic carbonate as 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 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] The present invention therefore relates to process (RP7) which is process (RP4) wherein the solvent is at least an organic carbonate.

[0092] Therefore, the present invention relates to process (RP7'), which is process (RP7), wherein the organic carbonate is a compound of formula (VIII)

[0093]

[0094] in

[0095] R1 is a C1-C4 alkyl group, and

[0096] R2 is a C1-C4 alkyl group.

[0097] Therefore, the present invention relates to process (RP7') which is process (RP7), wherein the organic carbonate is selected from the group consisting of dimethyl carbonate and diethyl carbonate.

[0098] Therefore, the present invention relates to process (RP7') which is process (RP7), wherein the organic carbonate is diethyl carbonate.

[0099] The following examples further illustrate the invention without limiting it. All percentages and parts given are by weight, temperatures are given in ° C., and pressures are absolute unless otherwise specified. Example

[0100] Example 1: Synthesis of the compound of formula (IV)

[0101] At room temperature and in an argon atmosphere, triphenylphosphine (103.9 g, 1.1 eq., 392.2 mmol) was suspended in acetic acid (183.7 mL, 9 eq., 3.209 mol) and heated to 60 ° C in an oil bath. At this temperature, vinyl alcohol (83 mL, 1.00 eq., 356.5 mmol) was added dropwise via a syringe pump over 1 hour. After complete addition, stirring was continued for 2 hours. Then, the orange solution was cooled to room temperature within 30 minutes, transferred to a separatory funnel, and diluted with methanol (300 mL). Hexane (300 mL) was added. The mixture was shaken and the layers were separated. The methanol layer was extracted with hexane (300 mL) and the hexane layer was washed with methanol (100 mL). The methanol layers were combined and evaporated to dryness under reduced pressure. The product was obtained as an orange oil (278.0 g, 56.2%) with a yield of 83.5%. E / Z=9:1.

[0102] Example 2: Synthesis of β-carotene

[0103] At room temperature and in an argon atmosphere, a solution of the vinyl acetate salt (8.71 g, 2.1 eq., 10.7 mmol) obtained in Example 1 in 1-pentanol (20 mL) was adjusted to pH 7 by adding 5% NaOH (3 mL) and 10% NaOH (10.6 mL). C10-dialdehyde (841 mg, 1 eq., 5.10 mmol), i.e., a compound of formula (III), and 1-pentanol (5 mL) were added to the solution. The yellow suspension was cooled to 0° C. (ice bath) and NaOH (4.5 g, 4.1 mL, 10 wt%) was added. The cooling bath was then removed and replaced with an oil bath. The reaction mixture was heated to 40° C. and stirred for 1 hour, and then stirred for another 1 hour under reflux (100° C.). The oil bath was removed and the reaction mixture was cooled to 40° C. within 30 minutes. Distilled water (8 ml) was added within 10 minutes and stirring was continued for 16 hours. Afterwards, the red suspension was cooled to 0°C, stirred for 30 minutes and filtered. The filter cake was washed with 1-pentanol (8 mL) and distilled water (8 mL). The red crystals were dried under vacuum at 50°C. Dark purple crystals (2.45 g, 91.2 wt%) were obtained with a yield of 81.6%.

[0104] Example 3: Synthesis of β-carotene

[0105] At room temperature and in an argon environment, the vinyl acetate salt (5.00 g, 2.1 eq., 5.88 mmol) and C10-dialdehyde (462 mg, 1 eq., 2.80 mmol) obtained in Example 1, i.e., a compound of formula (III), were dissolved in isoamyl alcohol (20 mL). The yellow suspension was cooled to 0 ° C (ice bath), and 15% NaOH (9.0 g, 7.7 mL, 12 eq., 33.6 mmol) was added dropwise over 4 hours. The cooling bath was then removed and replaced with an oil bath. The reaction mixture was heated to 40 ° C and stirred for 1 hour, and then stirred for another 20 hours under reflux (99 ° C). The oil bath was removed, and the reaction mixture was cooled to 40 ° C in 30 minutes. Distilled water (10 ml) was added in 10 minutes. Afterwards, the red suspension was cooled to 0 ° C and filtered after stirring for 30 minutes. The filter cake was washed with distilled water (3x10 mL). The red crystals were dried in vacuo at 50 ° C. Red crystals (1.20 g, 90.6 wt %) were obtained with a yield of 72.3%.

[0106] Example 4: Synthesis of β-carotene

[0107] At room temperature and in an argon atmosphere, C10-dialdehyde (457 mg, 1 eq., 2.77 mmol), i.e., a compound of formula (III), and potassium carbonate (4.64 g, 12 eq., 33.3 mmol) were suspended in isoamyl alcohol (7 mL). The yellow suspension was heated to 40 ° C in an oil bath, and a solution of freshly prepared vinyl acetate salt (5.00 g, 2.1 eq., 5.82 mmol) obtained in Example 1 in isoamyl alcohol (10 mL) was added dropwise over 20 minutes. The reaction mixture was then heated to 80 ° C and stirred for 4 hours. Distilled water (15 mL) was added through an addition funnel. Afterwards, the reaction mixture was heated to 100 ° C and stirred for 1 hour. The oil bath was removed, and the reaction mixture was cooled to 40 ° C within 30 minutes. Distilled water (10 ml) was added within 10 minutes. Afterwards, the red suspension was cooled to 0 ° C, stirred for 30 minutes, and filtered. The filter cake was washed with isoamyl alcohol (5 mL) and distilled water (3×10 mL). The dark red crystals were dried under vacuum at 50° C. Red crystals (1.05 g, 92.7 wt %) were obtained with a yield of 65.4%.

[0108] Example 5: Synthesis of β-carotene

[0109] At room temperature and in an argon environment, C10-dialdehyde (444mg, 1eq., 2.70mmol), i.e., a compound of formula (III), and potassium carbonate (4.52g, 12eq., 32.3mmol) were suspended in methanol (7mL). The yellow suspension was cooled to 0°C in an ice bath, and a solution of freshly prepared vinyl acetate salt (5.00g, 2.1eq., 5.66mmol) obtained from Example 1 in methanol (10mL) was added dropwise within 20 minutes. Then, the reaction mixture was heated to 65°C in an oil bath and stirred for 4 hours. The oil bath was removed, and the reaction mixture was cooled to 40°C within 30 minutes. Distilled water (25mL) was added by adding a funnel (20 minutes). Afterwards, the red suspension was cooled to 0°C and filtered after stirring for 30 minutes. The filter cake was washed with distilled water (3x10 mL). The dark red crystals were dried in vacuo at 50°C. Dark red crystals (3.70 g, 35.6 wt %) were obtained with a yield of 91.0%.

[0110] Example 6: Synthesis of β-carotene

[0111] At room temperature and in an argon environment, C10-dialdehyde (462 mg, 1 eq., 2.80 mmol), i.e., a compound of formula (III), and potassium carbonate (4.69 g, 12 eq., 33.6 mmol) were suspended in 1-propanol (7 mL). The yellow suspension was cooled to 0 ° C in an ice bath, and a solution of freshly prepared vinyl acetate salt (5.00 g, 2.1 eq., 5.88 mmol) obtained from Example 1 in methanol (10 mL) was added dropwise over 20 minutes. Then, the reaction mixture was heated to 60 ° C in an oil bath and stirred for 4 hours. Afterwards, the reaction mixture was heated to reflux (97 ° C) for another 1 hour. The oil bath was removed, and the reaction mixture was cooled to 40 ° C in 30 minutes. Distilled water (25 mL) was added by adding a funnel (20 minutes). Afterwards, the red suspension was cooled to 0 ° C, stirred for 30 minutes, and filtered. The filter cake was washed with distilled water (3x10 mL). The dark red crystals were dried in vacuo at 50° C. Dark red crystals (1.70 g, 71.1 wt %) were obtained with a yield of 80.3%.

Claims

1. A compound of formula (IV), 2. Method for producing the compound of formula (I) By making the compound of formula (IV) React with a compound of formula (III) to achieve 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 method of 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 method 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 method according to claim 7, wherein the solvent is at least one compound of formula (VII) R-OH(VII), in R represents a straight or branched C3-C 10 Alkyl group.

10. The method of 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 method of claim 7, wherein the at least one solvent is an organic carbonate.

12. The method according to claim 11, wherein the at least one solvent is an organic carbonate of a compound of formula (VIII) in R1 is a C1-C4 alkyl group, and R2 is a C1-C4 alkyl group.

13. A method according to claim 11 or claim 12, wherein the organic carbonate is selected from the group consisting of dimethyl carbonate and diethyl carbonate.

14. A method according to claim 11 or claim 12, wherein the organic carbonate is diethyl carbonate.

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