Novel astaxanthin synthesis

Abstract

This invention relates to a novel process for producing astaxanthin.

Description

Detailed Description of the Invention

[0001] The present invention relates to a novel process for producing astaxanthin.

[0002] The following formula (I)

Chemical formula

[0003] Astaxanthin is a natural pigment used to color foods, salmon, and trout.

[0004] Astaxanthin can be supplied from natural sources (by extraction / isolation). Alternatively, astaxanthin can be synthesized (bio)chemically.

[0005] Thus, many methods for the isolation or synthesis of astaxanthin are known. Thus, for example, the isolation of astaxanthin by extraction from the shells of crustaceans is known from the prior art (i.e., WO 8606082 A1 pamphlet).

[0006] Alternatively, astaxanthin can be obtained from fermentation processes or from microalgae.

[0007] Furthermore, it is possible to produce astaxanthin by chemical synthesis.

[0008] A very general and widely described method for producing astaxanthin is shown in the following reaction scheme.

Chemical formula

[0009] A drawback of conventional processes (for example, in Widmer et al. Helvetica Chimica Acta, Vol 64, no. 7, 1981; 2436-2446) is that one or more of the process steps (steps (i), (ii), and / or (iii)) are carried out in a halogenated solvent.

[0010] Most halogenated solvents remain in the air and / or in deposits, are ozone-depleting chemicals, and / or contribute to the generation of greenhouse gases. These concerns have led to stricter regulations and many users of halogenated solvents are exploring possible alternatives.

[0011] In chemical synthesis, halogenated solvents have several advantages over non-halogenated solvents, such as having relatively low boiling points and being inert, and therefore being usable in highly reactive reactions. However, there is an urgent need to avoid such halogenated solvents.

[0012] However, particularly in the optimized reaction described above, as described by Widmer et al., it is difficult to replace the halogenated solvent with a non-halogenated solvent due to the stringent conditions. The object of the present invention is to achieve a process in which all steps are carried out in a non-halogenated solvent and the yield of astaxanthin is as good as that reported in the prior art using halogenated solvents.

[0013] Surprisingly, contrary to Widmer et al.'s recommendation, it was found that when HBr-HCl is used in the first step (i), all steps can be carried out in a non-halogenated solvent (see the reaction scheme below). [ka]

[0014] Furthermore, another advantage of the present invention is that the compound of formula (III) is stable and can be isolated, in contrast to the corresponding compound having a bromine substituent. The ability to isolate the compound of formula (III) alone allows for the change of solvent required after step (i), which is necessary if a non-inert solvent must be used in at least one of the steps. This would not have been the case if HBr had been used instead of HCl in step (i). To optimize the conditions of this reaction, a change of solvent is necessary because there is no non-halogenated solvent that has the same properties as the halogenated solvent and can be used in both steps (i) and (ii) of the reaction scheme described above. The boiling point of the non-halogenated solvent should be as low as possible, preferably below 100°C, more preferably below 80°C.

[0015] Therefore, the present invention relates to formula (I) [ka] Regarding the process (P) for producing the compound, in the first step (i), formula (II) [ka] The compound is reacted with HCl in at least one solvent selected from the group consisting of hydrocarbons and carbonates, and then in step (ii), formula (III) [ka] The reaction product of step (i), which is a compound of formula (IV), is reacted with triphenylphosphine in acetonitrile and at least one solvent selected from the group consisting of C1-C8 alcohols, preferably methanol, ethanol, n-propanol, and isopropanol, and then in step (iii), formula (IV) [ka] The reaction product of step (ii), which is a compound of, is reacted with a compound of formula (V) in at least one solvent selected from toluene and C1-C8-alcohols, preferably at least one of methanol, ethanol, n-propanol and isopropanol, in the presence of at least one base.

Chemical formula

[0016] As described above, the present invention is carried out in a non-halogenated solvent.

[0017] Hereinafter, various steps of the present invention will be described in more detail.

[0018] [Step (i)] The reaction process of step (i) is as follows.

Chemical formula

[0019] As described above, this process step is carried out in at least one solvent selected from the group consisting of hydrocarbons and carbonates.

[0020] The hydrocarbon can be aliphatic and aromatic. The hydrocarbon can be straight-chain, branched or cyclic.

[0021] Preferably, the hydrocarbon is selected from the group consisting of n-hexane, n-heptane and toluene.

[0022] Carbonates such as dialkyl carbonate, preferably diethyl carbonate, are also preferred.

[0023] Therefore, the present invention also relates to a process in which at least one solvent is selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons and dialkyl carbonates.

[0024] Accordingly, the present invention also relates to a process in which at least one solvent is selected from the group consisting of n-hexane, n-heptane, toluene, and diethyl carbonate.

[0025] The reaction process in step (i) is carried out by reacting the compound of formula (II) with HCl.

[0026] HCl can be added as a gas and / or as an aqueous solution. Preferably, HCl is added as an aqueous solution.

[0027] HCl is added in at least equimolar amounts (relative to the compound of formula (II)). Typically and preferably, HCl is added in molar excess relative to the compound of formula (II).

[0028] Typically and preferably, the molar ratio of HCl to the compound of formula (II) is at least 1.2:1.

[0029] Typically and preferably, the molar ratio of HCl to the compound of formula (II) is at most 15:1.

[0030] The preferred molar ratio of HCl to the compound of formula (II) is 1.2:1 to 15:1, more preferably 1.2:1 to 10:1.

[0031] Accordingly, the present invention also relates to a process in which HCl is added in gaseous form to the reaction mixture in step (i).

[0032] Accordingly, the present invention also relates to a process in which HCl is added as an aqueous solution to the reaction mixture in step (i).

[0033] Accordingly, the present invention also relates to a process in which HCl is added to the reaction mixture of step (i) in equimolar ratios (relative to the compound of formula (II)).

[0034] Accordingly, the present invention also relates to a process in which, in step (i), the molar ratio of HCl to the compound of formula (II) is at least 1.2:1.

[0035] Accordingly, the present invention also relates to a process in which the molar ratio of HCl to the compound of formula (II) is at most 15:1 in step (i).

[0036] Accordingly, the present invention also relates to a process in which, in step (i), the molar ratio of HCl to the compound of formula (II) is 1.2:1 to 15:1.

[0037] Accordingly, the present invention also relates to a process in which, in step (i), the molar ratio of HCl to the compound of formula (II) is 1.2:1 to 10:1.

[0038] The reaction process in step (i) is typically carried out at a lower temperature.

[0039] Typically, the reaction process in step (i) is carried out at a temperature of -20°C to 10°C.

[0040] Typically, the reaction process in step (i) is carried out at a temperature of -10°C to 5°C.

[0041] Accordingly, the present invention also relates to a process in which the reaction process of step (i) is carried out at a temperature of -20°C to 10°C, preferably -10°C to 5°C.

[0042] The reaction time for step (i) is typically at least 30 minutes and up to several hours.

[0043] After the reaction process in step (i), the reaction product, which is the compound of formula (III), can be isolated from the reaction mixture.

[0044] This can be done by using a generally known process.

[0045] The compound of formula (III) can be further purified. As mentioned above, the compound of formula (III) is a stable compound and can be easily isolated. This is not possible with the conventional compounds of the following formulas. [ka]

[0046] Conventional methods for this compound are not stable, and therefore it is impossible to isolate it in an adequate manner. Without isolating this compound, achieving the required solvent exchange is not easy.

[0047] Furthermore, the compound of formula (III) is a novel compound.

[0048] Therefore, a further embodiment of the present invention is a compound of formula (III). [ka]

[0049] If step (ii) is carried out in the same solvent (or mixture of solvents) as step (i), the isolation step may be skipped.

[0050] [Step (ii)] [ka] The reaction process in step (ii) is carried out in acetonitrile and at least one solvent selected from the group consisting of C1-C8 alcohols, preferably methanol, ethanol, n-propanol, and isopropanol.

[0051] The reaction process in step (ii) is carried out by reacting the compound of formula (III) with triphenylphosphine.

[0052] Typically, triphenylphosphine is added in approximately equimolar amounts (relative to the compound of formula (III)). Typically, triphenylphosphine is added in a slightly molar excess relative to the compound of formula (III).

[0053] Typically and preferably, the molar ratio of triphenylphosphine to the compound of formula (III) is 1:1 to 2:1.

[0054] Accordingly, the present invention also relates to a process in which triphenylphosphine is added to the reaction mixture of step (ii) in equimolar ratio (relative to the compound of formula (III)).

[0055] Accordingly, the present invention also relates to a process in which, in step (ii), the molar ratio of triphenylphosphine to the compound of formula (III) is 1:1 to 2:1.

[0056] The reaction process in step (ii) is typically carried out at a temperature of 10°C to 80°C.

[0057] Typically, the reaction process in step (ii) is carried out at a temperature of 20 to 60°C.

[0058] Preferably, the reaction process in step (ii) is carried out at a temperature of 30°C to 60°C.

[0059] Accordingly, the present invention also relates to a process in which the reaction process of step (ii) is carried out at a temperature of 10°C to 80°C.

[0060] Accordingly, the present invention also relates to a process in which the reaction process of step (ii) is carried out at a temperature of 20°C to 60°C.

[0061] Accordingly, the present invention also relates to a process in which the reaction process of step (ii) is carried out at a temperature of 30°C to 60°C.

[0062] The reaction time for step (ii) is typically 60 minutes to several hours.

[0063] Typically, after this reaction has taken place (60 minutes to several hours), a solvent exchange is performed, and the resulting reaction mixture is then subjected to high temperatures (50°C to 100°C).

[0064] Subsequently, the reaction product, which is the compound of formula (IV), can be isolated from the reaction mixture.

[0065] This can be done by using a generally known process.

[0066] The compound of formula (IV) can be further purified.

[0067] If step (iii) is carried out in the same solvent (or mixture of solvents) as step (ii), the isolation step may be skipped.

[0068] [Step (iii)] [ka] The reaction process of step (iii) is carried out in toluene and at least one solvent selected from the group consisting of C1-C8 alcohols, preferably methanol, ethanol, n-propanol, and isopropanol.

[0069] The reaction process in step (iii) is carried out by reacting the compound of formula (IV) with the compound of formula (V) to obtain astaxanthin (the compound of formula (I)).

[0070] Typically, the compound of formula (IV) is added in molar excess to the compound of formula (V).

[0071] Typically and preferably, the molar ratio of triphenylphosphine to the compound of formula (III) is 2:1 to 4:1.

[0072] Accordingly, the present invention also relates to a process in which, in step (iii), the molar ratio of the compound of formula (IV) to the compound of formula (V) is 1:1 to 4:1.

[0073] Step (iii) is carried out in the presence of at least one base.

[0074] Suitable bases include solutions of alkali metal or alkaline earth metal alkoxides or alkali metal or alkaline earth metal hydroxides in methanol or ethanol, alkali metal or alkaline earth metal hydroxides, ammonia, triethylamine, and alkali metal or alkaline earth metal carbonates.

[0075] More preferred bases are aqueous solutions of NaOH or KOH, methanolic sodium methoxide solution, or ethanolic sodium ethoxide solution.

[0076] Accordingly, the present invention also relates to a process in which at least one base is selected from the group consisting of an alkali metal solution in methanol or ethanol, an alkaline earth metal alkoxide solution, an alkali meta solution, an alkaline earth metal hydroxide solution, an alkali metal hydroxide, an alkaline earth metal hydroxide, ammonia, triethylamine, an alkali metal carbonate, and an alkaline earth metal carbonate.

[0077] Accordingly, the present invention also relates to a process in which at least one base is selected from the group consisting of an aqueous solution of NaOH, an aqueous solution of KOH, a methanolic sodium methoxide solution, and an ethanolic sodium ethoxide solution.

[0078] The molar ratio of at least one base to the compound of formula (IV) is 1 to 1.5, preferably 1 to 1.2.

[0079] Accordingly, the present invention also relates to a process in which the molar ratio of at least one base to the compound of formula (IV) is 1 to 1.5.

[0080] Accordingly, the present invention also relates to a process in which the molar ratio of at least one base to the compound of formula (IV) is 1 to 1.2.

[0081] The reaction process of step (iii) is usually carried out at a temperature of -10°C to 20°C, preferably -10°C to 10°C, and more preferably -5°C to 10°C, when at least one base is added to the reaction mixture.

[0082] Stir the reaction mixture within this temperature range for approximately 30 minutes to several hours.

[0083] Afterward (after reacting at a temperature of -10°C to 20°C), the reaction mixture is heated to a high temperature over several hours.

[0084] The temperature range is 30°C to 120°C.

[0085] Accordingly, the present invention also relates to a process in which the reaction process of step (iii) is initially carried out at a temperature of -10°C to 20°C.

[0086] Accordingly, the present invention also relates to a process in which the reaction process of step (iii) is initially carried out at a temperature of -10°C to 10°C.

[0087] Accordingly, the present invention also relates to a process in which the reaction process of step (iii) is initially carried out at a temperature of -5°C to 10°C.

[0088] Accordingly, the present invention also relates to a process in which the reaction of step (iii) is carried out at -10°C to 20°C, and then the reaction mixture of step (iii) is heated to a maximum of 30°C to 120°C.

[0089] After the reaction process of step (iii), the reaction product, which is the compound of formula (I), can be isolated from the reaction mixture.

[0090] This can be done by using a generally known process.

[0091] The compound of formula (I) can be further purified.

[0092] The following examples further illustrate the present invention without limiting it. All percentages and parts shown are in terms of weight, and unless otherwise specified, temperatures are given in °C and pressures are given in absolute pressure.

[0093] Details, examples, and preferred preferences provided herein with respect to any particular one or more of the embodiments of the Invention described herein apply equally to all embodiments of the Invention. Unless otherwise specified herein or unless the context clearly contradicts it, any combination of embodiments, examples, and preferred preferences described herein is incorporated into the Invention in all possible variations thereof.

[0094] [Examples] [Example 1] [Process (i)] Under an inert gas atmosphere, ketolyldienol (KDL, compound of formula (II)) (289.2 mmol) was suspended in toluene (188 mL) and cooled to 1°C. Within 60 minutes, 37% aqueous HCl solution (4.32 equivalents, 1249 mmol) was added, ensuring the temperature did not exceed 2°C. The brown solution was stirred at 0°C for a further 30 minutes, after which water (200 mL) was added.

[0095] The organic layers were separated and washed with water to a neutral pH. The aqueous layer was re-extracted using toluene (100 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure (rotary evaporator at a water bath temperature of 25°C) and high vacuum (15 minutes). KDL chloride was obtained in 94.4% yield as a dark brown oil.

[0096] The reaction in step (i) was carried out in methanol, tert-butyl methyl ether, cyclohexane, and acetic acid, and the yield of KDL chloride was very low.

[0097] [Step (ii)] Under an argon atmosphere, the freshly prepared KDL chloride (compound of formula (III)) from step (i) was dissolved in 1-propanol (378 mL), and triphenylphosphine (84.95 g, 1.11 equivalents, 320.64 mmol) was added. The mixture was stirred at 40°C for 20 hours. The dark orange solution (503.77 g) was concentrated to 243.7 g in a rotary evaporator at 35°C. Then, ethyl acetate (150 mL) was added to dissolve the viscous oil. Another portion of ethyl acetate (350 mL) was added to crystallize the product (fine yellow crystals). The slurry was heated under reflux and stirred for 1 hour. The suspension was then cooled to room temperature, and then to 0°C. The suspension was filtered, and the filter cake was rinsed with ethyl acetate (2 × 50 mL). The crystalline material was dried overnight in vacuum at 50°C. The phosphonium salt (compound of formula (IV)) was obtained as pale yellow crystals (121.48 g) in a yield of 75.5%. Another 10.9% yield was detected in the mother liquor, which corresponds to a total yield of 86.4% (based on KDL).

[0098] The table below shows the yield of step (ii) when the reaction in step (ii) was carried out in the same manner as described above, but in a different solvent.

[0099] [Table 1]

[0100] As can be seen, the reaction in step (ii) does not work in toluene, diethyl carbonate, THF, tert-butyl methyl ether, n-heptane, and ethyl acetate as solvents.

[0101] [Step (iii)] Under an inert gas atmosphere, the astenyl salt (compound of formula (IV)) obtained in step (ii) (86.18 g, 2.04 equivalents, 155.0 mmol) was dissolved in 1-propanol (300 mL) and cooled to 0°C. Then, C 10- Dialdehyde (compound of formula (V)) (12.94 g, 1.00 equivalent, 75.98 mmol) was added. Sodium ethoxide (55.9 mL, 21.5% in ethanol, 2.04 equivalent, 155.0 mmol) was added dropwise to this yellow suspension over 5 hours. After the addition was complete, stirring was continued at 0°C for a further 2 hours. Formic acid (3.07 mL, 1.05 equivalent, 79.78 mmol) was added dropwise. The reaction mixture was heated and refluxed, and a portion of the solvent (80 mL) was removed by distillation. The solution was removed and replaced with 1-propanol (80 mL). The dark red suspension was heated to 97°C for 17 hours, then cooled to room temperature, stirred for a further 1 hour, and filtered. The filter cake was rinsed with 1-propanol (2 × 60 mL) and water (3 × 60 mL). The resulting crystalline material was dried at 60°C under vacuum for 16 hours. Crude astaxanthin (compound of formula (I)) (40.59 g, 93.19 wt%) was obtained as dark purple crystals in 83.4% yield.

[0102] After solvent extraction and removal, a further yield of 1.56% was detected in the mother liquor. This represents an overall yield of 85.0% (C 10 - Corresponds to dialdehyde-based materials.

[0103] Crude astaxanthin was recrystallized in an autoclave at 96°C for 5 hours, followed by a further 1 hour at room temperature, using an acetone / methanol / water 70:25:5 solution. After filtration and drying (60°C, 14 hours), the purified product was obtained with a crystallization yield of 98.4% (based on the crude material) and a high purity of 96.45% by weight.

[0104] The reaction in step (iii) was also carried out in methanol, ethanol, THF, and 1-butanol, and the yields were similar to those achieved in 1-propanol.

Claims

1. Equation (I) 【Chemistry 1】 A process for producing the compound of formula (II), in the first step (i), 【Chemistry 2】 The compound is reacted with HCl in at least one solvent selected from the group consisting of hydrocarbons and carbonates, and then in step (ii), formula (III) 【Transformation 3】 The reaction product of step (i), which is a compound of acetonitrile and C １ ~C ８ - Triphenylphosphine is reacted with an alcohol, preferably at least one solvent selected from the group consisting of methanol, ethanol, n-propanol, and isopropanol, and then in step (iii), formula (IV) 【Chemistry 4】 The reaction product of step (ii), which is a compound of toluene and C １ ~C ８ - In an alcohol, preferably at least one solvent selected from the group consisting of methanol, ethanol, n-propanol and isopropanol, in the presence of at least one base, formula (V) 【Transformation 5】 A process in which the compound is reacted with the compound.

2. The process according to claim 1, wherein HCl is added in gaseous form to the reaction mixture in step (i).

3. The process according to claim 1, wherein HCl is added as an aqueous solution to the reaction mixture in step (i).

4. The process according to any one of claims 1 to 3, wherein HCl is added in equimolar ratio (relative to the compound of formula (II)).

5. The process according to any one of claims 1 to 3, wherein in step (i), the molar ratio of HCl to the compound of formula (II) is 2:1 to 15:

1.

6. The reaction process of step (i) is carried out at a temperature of -20°C to 10°C, according to any one of claims 1 to 5.

7. The process according to any one of claims 1 to 6, wherein triphenylphosphine is added to the reaction mixture of step (ii) in equimolar ratio (relative to the compound of formula (III)).

8. The process according to any one of claims 1 to 6, wherein in step (ii), the molar ratio of triphenylphosphine to the compound of formula (III) is 1:1 to 2:

1.

9. The process according to any one of claims 1 to 8, wherein the reaction process of step (ii) is usually carried out at a temperature of 10°C to 80°C.

10. The process according to any one of claims 1 to 9, wherein the compound of formula (IV) is added to the reaction mixture of step (iii) in equimolar ratio (relative to the compound of formula (V)).

11. The process according to any one of claims 1 to 9, wherein in step (i), the molar ratio of the compound of formula (IV) to the compound of formula (V) is 1:1 to 4:

1.

12. The process according to any one of claims 1 to 11, wherein the at least one base in step (iii) is selected from the group consisting of an alkali metal solution in methanol or ethanol, an alkaline earth metal alkoxide solution, an alkali meta solution, an alkaline earth metal hydroxide solution, an alkali metal hydroxide, an alkaline earth metal hydroxide, ammonia, triethylamine, an alkali metal carbonate, and an alkaline earth metal carbonate.

13. Formula (III) 【Transformation 6】 A compound of [this].

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