FREY, Patrick (c/o Patent Department Wurmisweg 576, 4303 Kaiseraugst, CH)
LOTHSCHUETZ, Christian (c/o Patent Department Wurmisweg 576, 4303 Kaiseraugst, CH)
RIEBEL, Peter Hans (c/o Patent Department Wurmisweg 576, 4303 Kaiseraugst, CH)
WUESTENBERG, Bettina (c/o Patent Department Wurmisweg 576, 4303 Kaiseraugst, CH)
| by reacting the compound of formula (IV) with the compound of formula (III) 3. Process according to claim 2, wherein the compound of formula (IV) is used in a molar ratio of at least 2:1 (in regard to the compound of formula (III)). 4. Process according to claim 2 or 3, wherein the process is carried out at a temperature of between 0 - 150°C. 5. Process according to any of claims 2 to 4, wherein the process is carried out in the presence of at least one base. 6. Process according to claim 5, wherein the base is chosen from the group consisting of alkali hydroxide, earth alkali hydroxide, alkali carbonate, earth alkali carbonate, KF/AI2O3, NaOCH3 and KOCH3. 7. Process according to any of claims 2 to 6, wherein the process is carried out in at least one solvent. 8. Process according to claim 7, wherein the at least one solvent is chosen from the group consisting of CH2CI2, CHCI3, linear or branched C1-C4 alcohols, toluene, mixtures of alcohols/Cs-C? alkanes /water. 9. Process according to claim 7, wherein the solvent is at least one compound of formula (VI I) R-OH (VII), wherein R is a linear or branched C3-Cw-alkyl moiety. 10. Process according to claim 9, wherein the alcohol is chosen from the group consisting of 1 -pentanol, 2-pentanol, 2-methyl-butan-1-ol, 2-methyl-2-butanol and 3- methyl-1 -butanol. 11. Process according to claim 7, wherein the at least one solvent is an organic carbonate. 12. Process according to claim 11 , wherein the at least one solvent is an organic carbonate of compound of formula (VIII) wherein Ri is a Ci-C4alkyl moiety, and R2 is a Ci-C4alkyl moiety. 13. Process according to claim 11 or claim 12, wherein the organic carbonates are chosen from the group consisting of dimethylcarbonate and diethylcarbonate. 14. Process according to claim 11 or claim 12, wherein the organic carbonate is diethylcarbonate. |
The present invention relates to a new intermediate, which can be used in the process for producing p-carotene.
P-Carotene is an organic, strongly coloured red-orange pigment abundant in fungi, plants, and fruits. p-Carotene is an important product with many different ways of applications.
P-Carotene is the compound of the following formula (I)
P-Carotene is a member of the carotenes, which are terpenoids (isoprenoids), synthesized biochemically from eight isoprene units and thus having 40 carbons. Among the carotenes, p-carotene is distinguished by having beta-rings at both ends of the molecule.
P-Carotene is the most common form of carotene found in plants.
When used as a food colouring, it has the E number E160a (ii).
Furthermore, in nature, p-carotene is a precursor (inactive form) to vitamin A via the action of beta-carotene 15,15'-monooxygenase.
P-Carotene is a compound that gives vivid yellow, orange, and red colouring to vegetables. The human body converts p-carotene into vitamin A (retinol).
Next to its dyeing properties p-carotene has also some health benefits, such as effects on eye health, on improved cognitive function, on skin protection and on cancer prevention. A common way to produce p-carotene is shown in the following scheme wherein
X is halogen (such as Cl, Br, I)
Due to its importance, there is always a need for an improved way to obtain p-carotene. Surprisingly, we found that the use of a new intermediate, which has no halogen ion, leads to an excellent yield and excellent purity of the resulting p-carotene.
The following formate salt of formula (IV) is a new compound, which can be used in the synthesis of p-carotene.
Therefore, the present invention relates to the compound of formula (IV)
In the context of the present invention, all disclosed compounds (represented by the chemical formulae) can be in any possible stereochemical configuration. The new compound of formula (IV) can be produced according to the following process:
(V) (VI) (IV)
Therefore, the present invention relates to the process (P) of production of the compound of formula (IV) by reacting the compound of formula (V) with the compound of formula in the presence of formic acid (HCOOH).
The compound of formula (V) and (VI) are available commercially from a variety of suppliers. Alternatively, they could also be synthesised using suitable starting materials.
The process to produce the compound of formula (IV) is carried out in formic acid. No additional inert solvent is needed.
Optionally, an inert solvent could be used as well.
Usually and preferably formic acid (HCOOH) is used in molar excess in regard to the compound of formula (V).
Therefore, the present invention relates to the process (P1), which process (P), wherein formic acid is used in molar excess in view of the compound of formula (V).
Usually the compound of formula (VI) is used in a molar ratio of 1 to 1.5. (in view of the compound of formula (V).
This means that the compound of formula (VI) can be used in an equimolar amount or in a slight excess in view of the compound of formula (V). Therefore, the present invention also relates to the process (P2), which process (P) or (P 1 ) , wherein the compound of formula (VI) is used in a molar ratio of 1 to 1 .5. (in view of the compound of formula (V).
The process according to the present invention is usually carried out at elevated temperatures.
Usually, the process according to the present invention is carried out at a temperature range of from 30 to 120°C.
Therefore, the present invention also relates to the process (P3), which process (P), (P1) or (P2), wherein the process is carried out at a temperature range of from 30 to 120°C.
The new compound of formula (IV) is used in a process to produce p-carotene.
The following reaction scheme shows how to obtain p-carotene when using the compound of formula (IV) as starting material:
Therefore, the present invention also relates to the use of the compound of formula (IV) to produce p-carotene. Therefore, the present invention also relates to a reaction process (RP) to produce p- carotene (compound of formula (I)) by reacting the compound of formula (IV) with the compound of formula (III)
This reaction can be carried using the known reaction conditions as disclosed for the compound of formula (II) as starting material.
The compound of formula (IV) is used in a molar ratio of at least 2:1 (in regard to the compound of formula (III)).
Therefore, the present invention also relates to the reaction process (RP1), which is the process (RP), wherein the compound of formula (IV) is used in a molar ratio of at least 2:1 (in regard to the compound of formula (III)).
The process to produce p-carotene is usually carried out at a temperature of between 0 - 150°C. Preferably, the process is carried out at a range of 5°C to 130°C. Therefore, the present invention relates to the process (RP2), which is the process (RP) or (RP1), wherein the process is carried out at a temperature of between 0 - 150°C.
Therefore, the present invention relates to the process (RP2’), which is the process (RP) or (RP1), wherein the process is carried out at a temperature of between 5°C to 130°C.
A base can be added as well to the reaction mixture.
The base is usually an alkali hydroxide, earth alkali hydroxide, alkali carbonate, earth alkali carbonate, KF/AI2O3, NaOCH 3 and KOCH 3 .
Preferably, the base is CsOH, KOH, NaOH, Na 2 CO 3 or K 2 CO 3 .
The base is usually used in molar excess in view of the compound of formula (III). Usually 2 - 20 mol-equivalent in view of the compound of formula (III).
Therefore, the present invention relates to a process (RP3), which is process (RP), (RP1), (RP2) or (RP2’), wherein the process is carried out in the presence of at least one base.
Therefore, the present invention relates to a process (RP3’), which is process (RP3), wherein the base is chosen from the group consisting of alkali hydroxide, earth alkali hydroxide, alkali carbonate, earth alkali carbonate, KF/AI 2 O 3 , NaOCH 3 and KOCH 3 .
Therefore, the present invention relates to a process (RP3”), which is process (RP3), wherein the base is chosen from the group consisting of CsOH, KOH, NaOH, Na 2 CO 3 and K 2 CO 3 .
The process to produce p-carotene is usually and preferably carried out in a solvent.
Therefore, the present invention relates to a process (RP4), which is process (RP), (RP1), (RP2), (RP2’), (RP3), (RP3’) or (RP3”), wherein the process is carried out in the in at least one solvent. Such a solvent can be any commonly known solvents used in the processes disclosed and described in the prior art.
Suitable solvents are CH 2 CI 2 , CHCI 3 , linear or branched Ci-C 4 alcohols, toluene, mixtures of alcohols/Cs-C? alkanes /water.
Preferred solvents are CH 2 CI 2 or CH 3 CH 2 OH.
Therefore, the present invention relates to a process (RP5), which is process (RP4), wherein the solvent is chosen from the group consisting of CH 2 CI 2 , CHCI 3 , linear or branched Ci-C 4 alcohols, toluene, mixtures of alcohols/Cs-C? alkanes /water.
Very preferred solvents are alcohols represented by the compound of formula (VII)
R-OH (VII), wherein
R is a linear or branched C 3 -Ci 0 -alkyl moiety (preferably C 4 -C 8 -alkyl, more preferred C 4 - C 7 -alkyl, most preferred C 5 alkyl).
Most preferably, 1 -pentanol, 2-pentanol, 2-methyl-butan-1-ol, 2-methyl-2-butanol and/or 3-methyl-1 -butanol is used as solvent.
Therefore, the present invention relates to a process (RP6), which is process (RP4), wherein the solvent is at least one compound of formula (VII)
R-OH (VII), wherein
R is a linear or branched C 3 -Cio-alkyl moiety (preferably C 4 -C 8 -alkyl, more preferred C 4 - Cyalkyl, most preferred Csalkyl). Therefore, the present invention relates to a process (RP6’), which is process (RP6), wherein the alcohol of the compound of formula (VII) is chosen from the group consisting of 1 -pentanol, 2-pentanol, 2-methyl-butan-1-ol, 2-methyl-2-butanol and 3-methyl-1- butanol.
Another group of suitable solvents are organic carbonates.
Such organic carbonates have the following formula (VIII)
OR., o Z (VIII)
OR 2 wherein
Ri is a Ci-C 4 alkyl moiety, and
R 2 is a Ci-C 4 alkyl moiety.
Preferably, organic carbonates of compound of formula (VIII) are those, wherein
Ri is a Ci-C 2 alkyl moiety, and
R 2 is a Ci-C 2 alkyl moiety, as solvent.
More preferably, organic carbonates of compound of formula (VIII) are chosen from the group consisting of dimethylcarbonate and diethylcarbonate as solvent.
Most preferably, the organic carbonate of formula (VIII) is diethylcarbonate.
Therefore, the present invention relates to a process (RP7), which is process (RP4), wherein the solvent is at least one organic carbonate. Therefore, the present invention relates to a process (RP7’), which is process (RP7), wherein the organic carbonate is a compound of formula (VIII)
OR., o Z (VIII)
OR 2 wherein
Ri is a Ci-C 4 alkyl moiety, and R 2 is a Ci-C 4 alkyl moiety.
Therefore, the present invention relates to a process (RP7’), which is process (RP7), wherein the organic carbonates are chosen from the group consisting of dimethylcarbonate and diethylcarbonate.
Therefore, the present invention relates to a process (RP7’), which is process (RP7), wherein the organic carbonate is diethylcarbonate.
The following Examples illustrate the invention further without limiting it. All percentages and parts, which are given, are related to the weight and the temperatures are given in °C, and the pressures are absolute pressures when not otherwise stated.
EXAMPLES
Example 1 : Synthesis compound of formula (IV)
Under 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).
The suspension was warmed to 60 °C in an oil-bath and the triphenylphosphine dissolves. Vinylol (100.00 g, 10 mL, 1.00 eq. 44.56 mmol) was added within 1 hour. After addition was complete, stirring was continued for another 2 hours at the same temperature.
Then, the orange-coloured solution was cooled to room temperature over 30 min. After that, the solution was diluted with methanol (30 mL) and hexane (30 mL) and transferred into a separation 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-coloured oil (26.78 g, in 67.7% yield.
Example 2: Synthesis of p-carotene
Under 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 over 20 min. The reaction mixture was warmed to 65 °C in an oil-bath and stirred for 4 hours and then allowed to cool to 40 °C in 30 min. Distilled water (15 mL) was added over 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 (3x 10 mL). The dark red crystalline material was dried in vacuum at 50 °C overnight. The crude p- carotene was obtained as dark red crystals (2.62 g) in 87.2% yield.
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