Beta-carotene synthesis (I)
By using specific alkalis and organic carbonates as solvents in the production of β-carotene, the problems of phosphonium instability and product separation difficulties are solved, and the production of β-carotene with high yield and high purity is achieved, which is environmentally friendly.
Patent Information
- Application Number
- CN202380068839.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2022-09-29
- Filing Date
- 2023-09-25
- Publication Date
- 2025-05-06
AI Technical Summary
In the existing β-carotene production methods, phosphonium salt is unstable and unstable to strong bases, resulting in limited reaction conditions and difficult separation of products. Especially when using alcohol as a solvent, it is difficult to separate miscible products of lower alcohol and water.
Using specific bases and organic carbonates as solvents, the yield and purity of beta-carotene are improved by adding the phosphonium salt solution to the mixture of aldehyde components and performing a Wittig reaction.
Excellent yield and purity of β-carotene are achieved, the separation process of the product is simplified, and the use of carbonate as a solvent has the advantages of environmentally friendly and green solvents.
Smart Images
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Abstract
Description
[0001] The present invention relates to a method for producing beta-carotene in a specific solvent.
[0002] Beta-carotene is an organic, intense red-orange pigment found in abundance in fungi, plants and fruits. Beta-carotene is an important product that has many different applications.
[0003] β-carotene is a compound of formula (I)
[0004]
[0005] β-Carotene is a member of the carotenes, which are terpenoids (isoprenoids) biochemically synthesized from eight isoprene units and thus have 40 carbons. Among the carotenes, β-carotene is distinguished 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 coloring, its E number is E160a(ii).
[0008] Furthermore, in nature, β-carotene is a precursor (inactive form) of vitamin A formed through the action of β-carotene 15,15'-monooxygenase.
[0009] Beta-carotene is the 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 several health benefits, such as effects on eye health, improved cognitive function, skin protection, and cancer prevention.
[0011] The common method of producing beta-carotene is shown in the scheme below:
[0012]
[0013] Because of its importance, there is always a need for improved methods of obtaining beta-carotene.
[0014] The phosphonium salt (compound of formula (II)) and the aldehyde component (compound of formula (III)) are charged into a reactor, and at least one strong base is added to carry out a Wittig reaction.
[0015] It is particularly often observed that under these conditions the phosphonium salt is unstable and therefore higher amounts of phosphonium salt are required.
[0016] On the other hand, the aldehyde component is unstable to strong bases, which makes it generally impossible to load the aldehyde and base and add the phosphonium salt component.
[0017] Furthermore, by using alcohol as solvent (which is very common), there are problems when isolating the product (compound of formula (I)) since lower alcohols (C1-C3-alcohols) are miscible with water and are therefore difficult to separate.
[0018] Surprisingly, we have found that adding the phosphonium salt solution to the mixture of the aldehyde components and employing a specific base and a specific solvent leads to excellent yields and excellent purity of the resulting β-carotene.
[0019] The base (or mixture of bases) used in the context of the present invention is a compound of formula (IV) and / or a compound of formula (IV')
[0020] (X n+ ) 3-n -CO3 (IV)
[0021] (YH)-CO3 (IV'),
[0022] in
[0023] X is selected from the group of alkali metals or alkaline earth metals, and
[0024] n is 1 or 2 (which is the charge number of the alkali metal or alkaline earth metal), and
[0025] Y is an alkali metal.
[0026] The process according to the invention is generally carried out in at least one solvent.
[0027] The solvent of choice according to the method of the present invention is an organic carbonate.
[0028] Such organic carbonate has the following formula (V)
[0029]
[0030] in
[0031] R1 is a C1-C4 alkyl fragment, and
[0032] R2 is a C1-C4 alkyl moiety.
[0033] Therefore, the present invention relates to a process (P) for producing a compound of formula (I)
[0034]
[0035] wherein the compound of formula (II) is reacted with the compound of formula (III) in the presence of at least one compound of formula (IV) and / or a compound of formula (IV')
[0036]
[0037] (X n+ ) 3-n -CO3 (IV)
[0038] (YH)-CO3 (IV'),
[0039] in
[0040] X is selected from the group of alkali metals or alkaline earth metals, and
[0041] n is 1 or 2 (which is the charge number of the alkali metal or alkaline earth metal), and
[0042] Y is an alkali metal,
[0043] characterised in that at least one compound of formula (V) is used as solvent,
[0044]
[0045] in
[0046] R1 is a C1-C4 alkyl fragment, and
[0047] R2 is a C1-C4 alkyl moiety.
[0048] In the context of the present invention, all disclosed compounds (represented by chemical formulae) may be in any possible stereochemical configuration.
[0049] When carbonate esters are used as solvents, distillation is not a problem. In addition, carbonate esters are considered green solvents.
[0050] A preferred process according to the present invention is a process wherein X of the compound of formula (IV) is selected from the group consisting of Ca, Mg, Cs, Li, Na and K.
[0051] A preferred process is one wherein Y of the compound of formula (IV') is selected from Li, Na and K.
[0052] Most preferably, the compound of formula (IV) and the compound of formula (IV′) are selected from the group consisting of CaCO 3 , MgCO 3 , Cs 2 CO 3 , Li 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , LiHCO 3 , NaHCO 3 and KHCO 3 .
[0053] Therefore, the present invention relates to process (P1) which is process (P), wherein at least one compound of formula (IV) is used, wherein X is selected from the group consisting of Ca, Mg, Cs, Li, Na and K.
[0054] Therefore, the present invention relates to process (P1′) which is process (P), wherein at least one compound of formula (IV′) is used, wherein Y is selected from the group consisting of Li, Na and K.
[0055] Therefore, the present invention relates to process (P1"), which is process (P), wherein the compound of formula (IV) and the compound of formula (IV') are selected from the group consisting of CaCO3, MgCO3, Cs2CO3, Li2CO3, Na2CO3, K2CO3, LiHCO3, NaHCO3 and KHCO3.
[0056] The process according to the invention is carried out in the presence of at least one solvent (compound of formula (V)).
[0057] Preferably, the process according to the invention is carried out in the presence of at least one compound of formula (V) as solvent, wherein
[0058] R1 is a C1-C2 alkyl fragment, and
[0059] R2 is a C1-C2 alkyl moiety.
[0060] More preferably, the process according to the present invention is carried out in the presence of at least one compound of formula (V) selected from the group consisting of dimethyl carbonate and diethyl carbonate as solvent.
[0061] Most preferably, the process according to the invention is carried out in diethyl carbonate as solvent.
[0062] Therefore, the present invention relates to process (P2) which is process (P), (P1), (P1′) or (P1″), wherein the process is carried out in the presence of at least one compound of formula (V) as solvent, wherein
[0063] R1 is a C1-C2 alkyl fragment, and
[0064] R2 is a C1-C2 alkyl moiety.
[0065] The present invention therefore relates to process (P2′) which is process (P), (P1), (P1′) or (P1″), wherein the process is carried out in the presence of at least one compound of formula (V) selected from the group consisting of dimethyl carbonate and diethyl carbonate as solvent.
[0066] The present invention therefore relates to process (P2′) which is process (P), (P1 ), (P1′) or (P1″), wherein the process is carried out in dimethyl carbonate.
[0067] In another embodiment of the present invention, at least one co-solvent (other than the organic carbonate) is used, the at least one co-solvent being methanol, ethanol and / or isopropanol.
[0068] Preferably, the at least one co-solvent is methanol and / or ethanol.
[0069] When these co-solvents are used, they are used in an amount of up to 50% by volume, typically 2-50% by volume, based on the total volume of the solvent.
[0070] Therefore, the present invention relates to process (P3) which is process (P), (P1), (P1'), (P1"), (P2) or (P2'), wherein at least one cosolvent selected from the group of methanol, ethanol and isopropanol is used.
[0071] Therefore, the present invention relates to process (P3') which is process (P), (P1), (P1'), (P1"), (P2) or (P2'), wherein at least one cosolvent selected from the group of methanol and ethanol is used.
[0072] Therefore, the present invention relates to process (P4) which is process (P3) or (P3'), wherein the at least one co-solvent is used in an amount of up to 50% by volume, based on the total volume of the solvent.
[0073] Therefore, the present invention relates to process (P4'), ie process (P3) or (P3'), wherein the at least one co-solvent is used in an amount of 2 to 50% by volume, based on the total amount of solvent.
[0074] The reaction according to the process of the present invention is usually carried out at a temperature of 0-150°C. Preferably, the process is carried out at 5°C to 130°C.
[0075] Therefore, the present invention relates to process (P5) which is process (P), (P1), (P1'), (P1"), (P2), (P2'), (P3), (P3'), (P4) or (P4'), wherein the process is carried out at a temperature of 0-150°C.
[0076] Therefore, the present invention relates to process (P5') which is process (P5), wherein the process is carried out at a temperature of from 5°C to 130°C.
[0077] The compound of formula (II) is added to the reaction mixture in an amount of at least 2 molar equivalents relative to the compound of formula (III). It can also be added in excess.
[0078] Therefore, the present invention relates to method (P6), which is method (P), (P1), (P1'), (P1"), (P2), (P2'), (P3), (P3'), (P4), (P4'), (P5) or (P5'), wherein the compound of formula (II) is added to the reaction mixture in an amount of at least 2 molar equivalents relative to the compound of formula (III).
[0079] The following examples illustrate the invention. The temperatures are given in ° C. and all percentages are by weight. Example
[0080] Example 1
[0081] In a 1-liter reactor, C 10 - dialdehyde (9.03 g) (which is a compound of formula (III)) and anhydrous K2CO3 (37.9 g), and dimethyl carbonate (324.3 g) are added. The mixture is heated to an internal temperature of 40°C.
[0082] After this time, the vinyl salt (60.1 g, 2.2 eq.), which is the compound of formula (II), dissolved in MeOH (15.0 g) was added.
[0083] After addition of the vinyl salt solution, the dark red suspension was stirred for 240 minutes at 40° C. At the end of this time, another 0.02 equivalents of the vinyl salt (as a solution in MeOH) were added.
[0084] The reaction mixture was heated to reflux and the azeotropic mixture of dimethyl carbonate and methanol was removed by distillation.
[0085] Finally the reaction mixture was cooled to 20°C and deionized water (150 g) was added. The solid was filtered off.
[0086] The solid product was washed with MeOH (90.0 g), water (200 g), and finally with MeOH (90.0 g) again.
[0087] The dark purple solid was dried under reduced pressure at 40°C for 8 hours.
[0088] Yield: 25.3 g (86.3%) of crude β-carotene, an isomeric mixture of all-trans β-carotene (85-92%) and β-carotene cis isomers (8-15%).
[0089] Example 2
[0090] In a 1-liter reactor, C 10 - dialdehyde (9.03 g) (which is a compound of formula (III)) and anhydrous K2CO3 (37.9 g), and a mixture of dimethyl carbonate and methanol (95 / 5 wt%, 324.3 g) were added. The mixture was heated to an internal temperature of 40°C.
[0091] After this time, the vinyl salt (60.1 g, 2.2 eq.), which is the compound of formula (II), dissolved in MeOH (15.0 g) was added.
[0092] After addition of the vinyl salt solution, the dark red suspension was stirred for 240 minutes at 40° C. At the end of this time, another 0.02 equivalents of the vinyl salt (as a solution in MeOH) were added.
[0093] The reaction mixture was heated to reflux and the azeotropic mixture of dimethyl carbonate and methanol was removed by distillation.
[0094] Finally, the reaction mixture was cooled to 20°C and deionized water (150 g) was added. The solid was filtered off.
[0095] The solid product was washed with MeOH (90.0 g), water (200 g), and finally washed again with MeOH (90.0 g).The dark purple solid was dried under reduced pressure at 40°C for 8 hours.
[0096] Yield: 25.5 g (87.0%) of crude β-carotene, an isomer mixture of all-trans β-carotene (88-92 wt %) and β-carotene cis isomer (8-12 wt %).
[0097] Example 3
[0098] In a 1-liter reactor, C 10 - dialdehyde (9.03 g) (which is a compound of formula (III)) and anhydrous K2CO3 (37.9 g), and a mixture of dimethyl carbonate and methanol (324.3 g) are added. The mixture is set to an internal temperature of 10°C.
[0099] After this time, the vinyl salt (60.1 g, 2.2 eq.), which is the compound of formula (II), dissolved in MeOH (35.0 g) was added.
[0100] After addition of the vinyl salt solution, the dark red suspension was stirred for 240 minutes at 10° C. At the end of this time, another 0.02 equivalents of the vinyl salt (as a solution in MeOH) were added.
[0101] The reaction mixture was heated to 40°C and kept for another 60 minutes at this temperature. Subsequently, the suspension was heated to reflux and the azeotropic mixture of dimethyl carbonate and methanol was removed by distillation. Dimethyl carbonate (100-150mL) was added to the reaction mixture. The reaction mixture was stirred for another 2 hours at 80°C.
[0102] Finally the reaction mixture was cooled to 20°C and deionized water (150 g) was added. The solid was filtered off.
[0103] Yield: 27.7 g (94.5%) of crude β-carotene as an isomer mixture of all-trans β-carotene (90-94% by weight) and cis-isomer of β-carotene (6-10% by weight).
[0104] Crude β-carotene (100 g) consisting of 85-94 wt% of all-trans β-carotene and 6-15 wt% of an isomeric mixture of β-carotene cis isomers was suspended in a mixture of MeOH / DMC (330 g, 90 / 10 in wt%). The suspension was heated to 120° C. in an autoclave for 8-16 hours.
[0105] Thereafter, the suspension was cooled to 20° C. and the solid product was filtered off.
[0106] Yield: 97.0 g (97%) pure β-carotene as an isomer mixture of all-trans β-carotene (95-98% by weight) and β-carotene cis-isomer (2-5% by weight).
Claims
1. A method for producing a compound of formula (I), wherein the compound of formula (II) is reacted with the compound of formula (III) in the presence of at least one compound of formula (IV) and / or compound of formula (IV'), wherein X is a halogen (preferably Cl, Br or I), wherein X is selected from the group of alkali metals or alkaline earth metals, and n is 1 or 2 (which is the charge number of the alkali metal or alkaline earth metal), and Y is an alkali metal, Features At least one compound of formula (V) is used as solvent, wherein R1 is a C1-C4 alkyl fragment, and R2 is a C1-C4 alkyl moiety.
2. The method according to claim 1, wherein X of the compound of formula (IV) is selected from the group consisting of Ca, Mg, Cs, Li, Na and K.
3. The method according to claim 1 or claim 2, wherein Y of the compound of formula (IV') is selected from the group consisting of Li, Na and K.
4. The process according to any one of the preceding claims, wherein at least one compound of formula (IV) is used, wherein X is selected from the group consisting of Ca, Mg, Cs, Li, Na and K.
5. The process according to any one of the preceding claims, wherein at least one compound of formula (IV') is used, wherein Y is selected from the group consisting of Li, Na and K.
6. The method according to any one of the preceding claims, wherein the compound of formula (IV) and the compound of formula (IV') are selected from the group consisting of CaCO3, MgCO3, Cs2CO3, Li2CO3, Na2CO3, K2CO3, LiHCO3, NaHCO3 and KHCO3.
7. The process according to any one of the preceding claims, wherein the process is carried out in at least one compound of formula (V), wherein R1 is a C1-C2 alkyl fragment, and R2 is a C1-C2 alkyl moiety.
8. The process according to any one of the preceding claims, wherein the process is carried out in at least one compound of formula (V) selected from the group consisting of dimethyl carbonate and diethyl carbonate as solvent.
9. A process according to any one of the preceding claims, wherein the compound of formula (V) is dimethyl carbonate.
10. The process according to any one of the preceding claims, wherein at least one co-solvent selected from the group of methanol, ethanol and isopropanol is used.
11. The method according to claim 10, wherein the at least one co-solvent is used in an amount of 2-50% by volume based on the total volume of the solvent.
12. A process according to any one of the preceding claims, wherein the process is carried out at an elevated temperature.
13. The method according to claim 12, wherein the method is carried out at a temperature of 0°C to 150°C.
14. A process according to any one of the preceding claims, wherein the compound of formula (II) is added to the reaction mixture in an amount of at least 2 molar equivalents of the compound of formula (III).