Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
  • C07C403/24—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by six-membered non-aromatic rings, e.g. beta-carotene

Definitions

• the invention relates to an improved process for the preparation of the carotenoid astaxanthin by a double Wittig reaction of a 3-methyl-5-(2,6,6-trimethyl-3-oxo-4-hydroxy- l-cyclohexen-l-yl)-2,4-pentadienyltriphenylphosphonium salt(asta-Ci 5 - triphenylphosphonium salt) with 2,7-dimethyl-2,4,6-octatriene-l , 8-dial (Ci O -dial).
• Astaxanthin is a natural colour which is very much in demand for colouring foods, salmon and trout. Accordingly, numerous methods for isolating or synthesising astaxanthin are known. Thus, for example, WO A 86/6082 discloses the isolation of astaxanthin by extraction of crustacean shells. Furthermore, astaxanthin can be obtained by fermentation processes, as described, for example, in EP A 329 754. However, these methods have significant disadvantages. Firstly astaxanthin is present in nature only in very low concentration and therefore has to be isolated by complicated processes. Secondly, only unsatisfactory yields are obtained which means that these known processes are of no interest from the economic point of view.
• EP A 05 749 discloses a process for the preparation of astaxanthin by a Wittig reaction of a building block acylated on the hydroxyl group in the 4- position of the asta- Ci 5 -triarylphosphonium salt with Cio-dial and subsequent hydrolysis.
• isopropanol is mentioned as a solvent for this Wittig reaction.
• the process according to the invention starts from a known Wittig process in which, in a preliminary stage, ketolylpentol is converted by partial hydrogenation into ketolyldienol, from which the asta-Cis-triphenylphosphonium salt also referred to below as astenyl salt subsequently forms as a result of bromination and phosphination with triphenylphosphine.
• the astaxanthin is finally formed by a double Wittig reaction with the use of butenyl oxide as a base.
• a mixture consisting of astenyl salt and Cio-dialdehyde in ethanol and 1 ,2-butylene oxide is reacted.
• the reaction solution is filtered.
• the still moist crude product is purified by solvent exchange (ethanol for methylene chloride).
• the astaxanthin yield is 90.7%, based on Cio-dialdehyde, and 81%, based on astenyl salt.
• butylene oxide as a weak base has the advantage that the anion of the astenyl salt (for example bromide) is trapped and chemically bound. Thus, virtually no inorganic salts form.
• a disadvantage of the process is that butylene oxide is a relatively expensive and carcinogenic substance.
• astaxanthin can be prepared in a technically simple manner and in very good yields if the butylene oxide is replaced by a more economical but stronger base during the Wittig reaction while maintaining specific process conditions.
• an alcohol mixed with a nonpolar solvent is additionally used as a solvent for the Wittig reaction.
• EP A 0 733 619 has already disclosed an astaxanthin synthesis via a Wittig reaction in alcohol using a base
• the process disclosed therein differs substantially from the parameters chosen according to the invention, such as, for example, from the profile for metering the base into the reaction solution and from the choice of the reaction temperature.
• the invention therefore relates to a process for the preparation of astaxanthin of the formula I
• X represents chlorine, bromine or the (HSO 4 ) " radical, preferably bromine, in a Wittig reaction with one mol of the Cio-dialdehyde of the formula III
• the starting compounds of the formulae II and III are taken up in a solvent, the mixture is cooled to a temperature of not more than 10°C, preferably -18 0 C to +5°C,
• the base is metered and mixed in over a predetermined reaction time T so that at least a
• Vi base equivalent is added to the reaction mixture continuously or quasicontinuously within a timespan T' ⁇ %T and the remainder of the base within the remaining reaction time.
• alcohol and nonpolar solvents are used in an amount such that the concentration of the triphosphonium halides in the solvent mixture is 0.1 to 3 mol, preferably 0.8 to 1.5 mol, per litre of solvent mixture.
• the solvent used is, for example, an alcohol, a mixture of different alcohols or a mixture consisting of an alcohol and a nonpolar solvent miscible with the alcohol.
• a particularly preferred solvent mixture consists of methanol and dichloromethane in a mass ratio of 1 : 1.2 to 1 :8, for example 1 : 1.48.
• methanol it is also possible to use ethanol, 1-propanol, 2-propanol, n-butanol and acetone, tetrahydrofuran, dioxane or ethyl acetate as alcohols or polar solvents which can be used for the process according to the invention.
• the base is introduced into the reaction mixture in general at temperatures of -18°C to +8°C, preferably at -18°C to 0°C, for example at -10°C to -5°C, according to the abovementioned metering profile specified below.
• the reaction mixture may be a homogenous solution or a suspension.
• the reaction time T for the introduction of the bases and reaction are in general 0.5 to 30 hours, preferably 8 to 20 hours.
• a Vi to % base equivalent is added to the reaction mixture continuously or quasi continuously within a timespan T' ⁇ !4 T and the remainder of the base within the remaining reaction time.
• reaction mixture After complete addition of the base, it is advantageous to allow the reaction mixture to continue reacting for at least 15 min, preferably at least 30 min, in a subsequent reaction before the total mixture in the subsequent reaction is neutralized with an inorganic or organic acid, for example with acetic acid, glacial acetic acid or sulphuric acid.
• an inorganic or organic acid for example with acetic acid, glacial acetic acid or sulphuric acid.
• the astaxanthin obtained according to the invention is generally thermally isomerized for conversion into the particularly desirable all-(E)-isomers. It is known that the thermal isomerization or the isomerization and purification can be readily carried out by heating in an alcohol.
• the process according to the invention is firstly characterized by the choice of the base, the method of metering and the composition of the solvent mixture. This novel procedure has two substantial advantages. Firstly, the novel process permits in particular the use of economical raw materials, and does so with at least identical operational safety and increased yield, which leads to an extremely economical production of astaxanthin, and secondly fewer byproducts, such as, for example, astacin and semiastacin, form in the process according to the invention.
• a substantial obstacle which had to be overcome according to the invention in the choice of a stronger base than butylene oxide was the problem that the formation of astacin and semiastacin is promoted owing to the relatively strong base chosen, such as, for example, sodium methylate.
• Figure 4 in Table 1 shows five different base metering profiles over a reaction time T of 20 to 25 hours and at a preferred reaction temperature of -5°C. For the region of half an equivalent (10 ml) three different metering speeds were tested (profiles 2,4,5).
• profile 4 was chosen.
• Table 2 shows that, with a base excess of 1.5%, based on astenyl salt, the proportion of semiastacin can be reduced below the 1 % mark, and this can be achieved at a yield of at least 80%.
• the speed of the base addition automatically decreases from the first to the second phase.
• it is preferably 0.02 ml/min to 0.2 ml/min in the 1 st phase or 0.01 ml/min to 0.05 ml/min in the 2 nd phase and, on the production scale, 40 1/h to 500 1/h in the 1 st phase or 15 1/h to 25 1/h in the 2 nd phase.
• glacial acetic acid instead of aqueous acetic acid.
• concentrated acetic acid it is also possible to use concentrated acetic acid.
• the neutralized reaction mixture was then heated in a reactor having a jacket temperature of 6O 0 C. At the boiling point (internal temperature about 45°/jacket temperature about 60 0 C) continuous solvent exchange was then effected over a timespan of 5 h, the reflux ratio being adjusted so that the level in the reactor was maintained. During the solvent exchange, 426.6 g (540 ml) of methanol were metered in continuously in the course of said time span and about 540 ml of solvent mixture were distilled off until an internal temperature of 65°C was reached.
• the reaction mixture was cooled at 25°C/h to an internal temperature of 20 0 C and stirred for at least a further 15 min and the suspension was filtered over a glass suction filter.
• the reactor was then washed first with the mother liquor and then with 158 g (200 ml) of methanol, and the wash solutions were filtered in succession over the crystals. Thereafter, the crystals were washed again with 2 x 158 g (200 ml) of methanol and dried at 55°C and ⁇ 60 mbar in a vacuum drying oven.
• the astaxanthin production can be divided up as follows, starting from the process according to the invention:
• Astenyl salt in a mixture of methanol and methylene chloride is reacted with Ci 0 - dialdehyde ideally at -5°C throughout and under atmospheric pressure to give astaxanthin.
• the base used for the Wittig reaction is sodium methylate, the base being metered in in the course of 15 to 30 h, preferably 15 to 25 h, for example 20 h, on the production scale.
• Triphenylphosphine oxide (TPPO), sodium bromide and methanol are formed as byproducts.
• the postreaction takes place at -10°C to 5°C, preferably at -10° to -5°C, for example at -5°C, and takes from 30 min to 2 h, for example 1 h 40 min. Acidification with acetic acid is then effected.
• the distillate is then cooled to 20°C and the suspension is then centrifuged.
• the filter cake is washed with methanol.
• the amount of wash agent depends on the amount of TPPO present in the product.
• Moist astaxanthin is finally made into a slurry with methylene chloride in a dissolution vessel and refluxed at an internal temperature of, for example, 40°C for 2 to 5 h.
• the astaxanthin suspended in methylene chloride is heated to the reflux temperature, and the methylene chloride/methanol mixture is then distilled off. The distillation is stopped at an internal temperature of > 61°C, methanol being metered in up to this temperature. The suspension is then centrifuged. The filter cake is washed with methanol.
• Moist astaxanthin is finally dried in a dryer at an internal temperature of 50-70°C and a final vacuum of ⁇ 20 mbar.
• the operations "dissolution”, “solvent exchange 2", “crystallization” and “centrifuging” can alternatively also be omitted if, by a suitable choice of procedure, the residual content of byproducts already meets the requirements after the first centrifuging step.
• a reactor vessel was evacuated to -0.8 bar and flushed with N 2 gas.
• 1151 kg of astenyl salt, 161 kg of Cio-dialdehyde and 9 kg of astaxanthin were then introduced into the reactor, hi order to eliminate influences of oxygen after the introduction, the vessel was evacuated again and flushed with nitrogen gas.
• 2457 kg of methylene chloride and 1700 kg of regenerated methanol (97% of methanol and 2% of methylene chloride) were added. It was then possible to begin the metering of sodium methylate (30% in methanol) at -5°C.
• the metering was carried out as follows: 1 st phase metering: 44 1/h with a total time of 4 h 35 min (amount metered 194 kg) 2 nd phase metering: 11 1/h with a total time of 15 h 26 min (amount metered 165 kg) After the metering of sodium methylate, the reaction solution was stirred for a further 30 min before the neutralization of excess sodium methylate was begun. For this purpose, 60 kg of 100% glacial acetic acid were finally metered in.
• reaction solution thus formed was then transferred to a second reaction vessel and the subsequent solvent exchange was carried out so that the product formed was present in virtually pure methanol.
• the astaxanthin suspension was then cooled down to an internal temperature of 20°C in the crystallizer.
• the crystallization time was about 1 A h.
• the suspension was stirred again for 15 min at 20°C.
• the crystal slurry could now be separated on a centrifuge and then dried in a dryer. The drying process was carried out with a constant jacket temperature of 60°C.
• the following metering profile was chosen: During the 1 st phase, the metering was on average about 450 1/h with a total time of 45 min. Thereafter, the metering was reduced stepwise over about 25 min from 450 1/h to 50 1/h (amount metered about 394 kg). The subsequent second phase was operated at 17 1/h and for a total time of 15 h 30 min (amount metered about 260 kg).
• reaction solution formed was then transferred to a further vessel in which the reaction solution was washed with 500 ml of methylene chloride.
• the subsequent solvent exchange and the drying process were carried out in each case analogously to the above mentioned first experimental example.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Priority Applications (2)

Applications Claiming Priority (2)

Publications (1)

Family

ID=38328192

Family Applications (1)

Country Status (3)

Cited By (8)

Families Citing this family (1)

Citations (4)

Family Cites Families (4)

• 2007
  • 2007-05-08 WO PCT/EP2007/004071 patent/WO2007128574A1/en active Application Filing
  • 2007-05-08 CN CN2007800169821A patent/CN101454280B/zh active Active
  • 2007-05-08 DE DE112007001144T patent/DE112007001144T5/de not_active Withdrawn

Patent Citations (4)

Also Published As

Similar Documents

Legal Events