Improved process for the production of an astaxanthin intermediate

Abstract

The present invention relates to a process for the production of an intermediate, which is useful in organic synthesis, especially in the production of astaxanthin.

Description

[0001] Improved process for the production of an astaxanthin intermediate

[0002] The present invention relates to a process for the production of an intermediate, which is useful in organic synthesis, especially in the production of astaxanthin.

[0003] Astaxanthin, which is the compound of formula (I) is often used as a dietary supplement for human, animal, and aquaculture consumption.

[0004] Astaxanthin can be sourced from natural sources as well and it can be produced chemically as well as biochemically.

[0005] There are various processes known for the chemical synthesis of astaxanthin.

[0006] Most of the chemical reaction for the production of astaxanthin (or intermediate for the production of astaxanthin) uses an alkyllithium (alkyl-Li) such i.e. butyllithium or methyllithium.

[0007] For example, the following process for the production of such an intermediate is known from the prior art (R. Zell et al., Hel. Chim. Acta, Vol 64(7), 1981 , p.2447ff) An alkyllithium compound is used to produce one of the coupling partners.

[0008] Another process that can be used to manufacture astaxanthin is described in Widmer et al. in Hel. Chim. Acta, Vol 64(7), 1981 , p.2436ff. The authors describe a synthesis using alkyllithium compounds but mention the possibility of using ethyl magnesium bromide for a Grignard coupling to obtain compound (II). The authors do not consider the Grignard coupling as the best option for the synthesis of compound (II) as the yields are much lower than with alkyllithium.

[0009] Alkyllithium compounds are problematic compounds. They are very toxic to aquatic life with long lasting effects.

[0010] Due to the importance of such an intermediate, there is always a need for an improved way to obtain such a compound, and there is a particular need to replace alkyllithium compounds by less toxic reagents and thereby to avoid the toxic alkyllithium compounds, and yet achieve the same or even better yields.

[0011] We found a new and improved way to produce the important intermediate of formula (II) which can then be used in organic synthesis (especially for producing astaxanthin).

[0012] The new process according to the present invention consists of 3 process steps (step (i), step (ii) and step (iii)).

[0013] The new process is shown in the following scheme:

[0014] The definition of the substituents and the reaction conditions are disclosed in more detail in the following.

[0015] In the context of the present invention, the wavy bond means that the double bond geometry can be in E- or Z- configuration. This means that it can be in one configuration only or in a mixture of both configurations.

[0016] The new process avoids the use of any alkyllithium compound.

[0017] The new process allows higher yields of compound (II), even higher than with the use alkyllithium compounds as described in the prior art cited above. Some preferred embodiments further allow better separation from solvents used in the process.

[0018] All reaction steps of the process according to the present invention are discussed in more detail.

[0019] Step (i) solvent wherein

[0020] R is linear or branched C1- C14alkyl or cyclic C4- C8alkyl, and

[0021] R1is H, -C(R4)(R5)OR6, -Si(R7R8R9), tetrahydropyrane, -CH2OCH3or -COC(CH3)3, wherein

[0022] R4and R5are independently from each other linear or branched CrC4alkyl (preferably CH3or CH2CH3), and

[0023] R6is linear or branched CrC4alkyl (preferably CH3or CH2CH3), and

[0024] R7is linear or branched CrC4alkyl, unsubstituted phenyl or substituted phenyl, and

[0025] R8is linear or branched CrC4alkyl, unsubstituted phenyl or substituted phenyl, and

[0026] Rg is linear or branched CrC4alkyl, unsubstituted phenyl or substituted phenyl, and

[0027] X is Cl, Br, or I, preferably X is Cl, and with proviso that when R-| in the compound of formula (IV) is H then R-| in compound of formula (V) is MgX.

[0028] Preferably, in step (i) one of the following compounds (compounds of formulae (IVa) to (IVd)) is used.

[0029] More preferably, in step (i) the compound of formula (IVa) is used.

[0030] Furthermore, in step (i) it is preferred that the compound of formula (III) is chosen from the group consisting of CH3MgCI, CH3MgBr, CH3Mgl, CH3CH2MgCI, CH3CH2MgBr, CH3CH2Mgl, iPrMgCI, iPrMgBr, iPrMgl, CH3(CH2)7MgCI, CH3(CH2)7MgBr or CH3(CH2)7Mgl; more preferred in step (I) is that the compound of formula (III) is chosen from the group consisting of CH3MgCI, CH3CH2MgCI, iPrMgCI, CH3(CH2)7MgCI, CH3(CH2)7MgBr or CH3(CH2)7Mgl.

[0031] The compound of formula (III) is usually added to the reaction mixture in a dissolved form. This solvent can be any solvent used as solvent for step (i), which is defined below.

[0032] The concentration of the compound of formula (III) in the solvent is from 0.5 to 5M. More preferred are the compounds of formulae (Va) to (Ve’) which are obtained as reaction product at the end of step (i) and can be isolated and analysed.

[0033] Most preferred are the compounds of formulae (Va) to (Ve) which are obtained as reaction product at the end of step (i) and can be isolated and analysed.

[0034] In the first step (step (i)) of the present invention the Grignard reagent (compound of formula (V)) is produced. Usually, the reaction of step (i) is carried out in at least one inert solvent.

[0035] Suitable solvents are inert organic solvents or ionic liquids.

[0036] Preferably polar aprotic solvent such as ethers or aromatic solvents (such as toluene, benzene) are used.

[0037] Most preferred polar aprotic solvents are ethers (such as i.e. tetra hydrofuran (THF), 2- methyl-THF, cyclopentyl methyl ether (CPME), dimethoxyethane (DME), dimethylether (DEM), tert-amyl methyl ether (TAME), tert-Butyl methyl ether (TBME), diethyl ether, diisopropyl ether and (poly)glycol ethers.

[0038] It is also possible to use mixtures of these polar aprotic solvents with alkanes. Preferred are branched, cyclic or unbranched alkanes such as pentane, hexane, heptane, cyclopentane, cyclohexane, methylcyclohexane, or mixtures thereof. More preferred alkanes can be selected from the group consisting of pentane, hexane, heptane, cyclohexane, or mixtures thereof.

[0039] Preferred mixtures of solvents as described hereinabove are mixtures of at least one solvent selected from the group consisting of tetrahydrofuran (THF), 2-methyl-THF, cyclopentyl methyl ether (CPME), dimethoxyethane (DME), dimethylether (DEM), tertamyl methyl ether (TAME), tert-butyl methyl ether (TBME), diethyl ether, diisopropyl ether and (poly)glycol ethers, and at least one solvent selected from the group consisting of pentane, hexane, heptane cyclopentane, cyclohexane, methylcyclohexane, or mixtures thereof . These solvents can be a mixture of one or more solvents of one of the two groups, and they are used in a ratio of ether : alkane of between 1 :100 to 100:1 , preferably in a ratio of between 20:80 and 80:20, more preferably in a ratio of between 30:70 and 70:30.

[0040] More preferred are mixtures of at least one ether selected from the group consisting of CPME, THF, DME and DEM, or mixtures thereof, and at least one alkane selected from the group consisting of pentane, hexane, heptane, cyclohexane, or mixtures thereof, preferably used in a ratio of ether : alkane between 1 : 100 and 100: 1 , more preferably used in a ratio between 20:80 and 80:20. Usually, the reaction of step (i) is carried out at a temperature of -10 to 60 °C. Preferably, at 0°C to 60 °C, more preferably at 0°C to 60 °C.

[0041] Usually and preferably, the reaction of step (i) is carried out at ambient pressure.

[0042] The compound of formula (IV) and the compound of formula (III) are used in about equimolar amounts. It is also possible to use the compound of formula (III) in a slight excess. When in the compound of formula (IV) R1is H then it is preferred to use at least 2 mol-eq of the compound of formula (III).

[0043] The reaction time of the reaction of step (i) is at least 10 minutes (to several hours). Usually, the reaction time of the reaction of step (i) is between 30 and 300 minutes.

[0044] Step (ii)

[0045] In the second step (step (ii)), the reaction product of step (i), which is the compound of formula (V) is coupled with a compound of formula (VI) wherein

[0046] R1is H, -C(R4)(R5)OR6, -Si(R7R8R9), tetrahydropyran (THP), methoxymethyl (MOM) CH2OCH3, pivalate -COC(CH3)3or MgX, wherein

[0047] R4and R5are independently from each other linear or branched CrC4alkyl (preferably CH3or CH2CH3), and

[0048] R6is linear or branched CrC4alkyl (preferably CH3or CH2CH3), and R7is linear or branched CrC4alkyl, unsubstituted phenyl or substituted phenyl, and

[0049] R8is linear or branched CrC4alkyl, unsubstituted phenyl or substituted phenyl, and

[0050] Rg is linear or branched CrC4alkyl, unsubstituted phenyl or substituted phenyl, and

[0051] R2is H, unsubstituted phenyl, substituted phenyl or a linear or branched CrC4alkyl group, and

[0052] R3is H, unsubstituted phenyl, substituted phenyl or a linear or branched CrC4alkyl group, and

[0053] X is Cl, Br, or I, preferably X is Cl, and.

[0054] Preferably, in step (ii) a compound of formula (Va’) or of formula (Va”) more preferably, in step (ii) compound of formula (Va”), is reacted with the compound of formula (Via)

[0055] The reaction of step (II) is carried out in the same solvent as in step (i). Usually and preferably, the process of step (ii) is carried out at a temperature of 20°C to 100°C.

[0056] Usually and preferably, the process of step (ii) is carried out at ambient pressure.

[0057] The compound of formulae (V) and the compound of formulae (VI) are used in about equimolar amounts. But it is also possible to use either the compound of formulae (V) or the compound of formulae (VI) in a slight excess.

[0058] Preferably compound of formulae (V) is used in slight excess of compound of formulae (VI), this excess being between 1.05 and 1.6 molar equivalents of compound of formulae (V) in relation to compound of formulae (VI), more preferably compound of formulae (V) is used in molar equivalents of between 1 .2 and 1 .6 in relation to compound of formulae (VI), most preferably compound of formulae (V) is used in molar equivalents of between 1 .2 and 1.55 in relation to compound of formulae (VI).

[0059] The reaction time of the reaction of step (ii) is at least 10 minutes (to several hours). Usually, the reaction time of the reaction of step (ii) between 30 and 300 minutes.

[0060] The reaction product of step (ii), which is the compound of formula (VII)

[0061] Furthermore, the reaction product of step (ii), which is the compound of formula (VII), is a new compound, wherein R2and R3have the same meanings as defined above. Therefore, a further embodiment of the present invention is the compound of formula (VII) wherein

[0062] R1is -C(R4)(R5)OR6, -Si(R7R8R9), tetrahydropyran (THP), methoxymethyl (MOM)

[0063] CH2OCH3, pivalate -COC(CH3)3or MgX, wherein

[0064] R4and R5are independently from each other linear or branched CrC4alkyl (preferably CH3or CH2CH3), and

[0065] R6is linear or branched CrC4alkyl (preferably CH3or CH2CH3), and

[0066] R7is linear or branched CrC4alkyl, unsubstituted phenyl or substituted phenyl, and

[0067] R8is linear or branched CrC4alkyl, unsubstituted phenyl or substituted phenyl, and

[0068] Rg is linear or branched CrC4alkyl, unsubstituted phenyl or substituted phenyl, and

[0069] R2is H, unsubstituted phenyl, substituted phenyl or a linear or branched CrC4alkyl group, and

[0070] R3is H, unsubstituted phenyl, substituted phenyl or a linear or branched CrC4alkyl group, and

[0071] X is Cl, Br, or I, preferably X is Cl.

[0072] Especially preferred is a compound of formula (Vila) wherein

[0073] X is Br or Cl, preferably X is Cl.

[0074] Step (iii)

[0075] In step (iii), which is carried out in the same at least one inert solvent as step (i) and step (ii), which means as stated above that the process according to the present invention is carried out as a “one pot reaction”.

[0076] Usually and preferably, the process of step (iii) is carried out at a temperature of -10°C to 30°C.

[0077] At least one Bronsted acid is added to reaction mixture. The at least one Bransted acid can be any commonly known one.

[0078] Suitable Bronsted acids are e.g. HCI, HBr, H2SO4, H3PO4and pTsOH.

[0079] It is also possible to use acid ion exchange resins, such as polystyrene based ion exchange resin with strongly acidic sulfonic group. Such ion exchange resins are available commercially (e.g. Amberlyst®15). Usually and preferably, the process of step (iii) is carried out at ambient pressure.

[0080] The reaction time of the reaction of step (iii) is at least 10 minutes (to several hours).

[0081] Usually, the reaction time of the reaction of step (iii) between 30 and 300 minutes.

[0082] The removal of the protection groups in the compound of formula (VII) can be at once or in a sequence wherein first one of the two protecting group is removed and then the second one.

[0083] The compound of formula (VII’) and of formula (VII”) wherein the definitions of the substituents are the same as defined above, are the compounds, wherein one of the protecting groups has been removed.

[0084] As stated above the compound of formula (II) of the present invention is an intermediate for the synthesis of specific xanthophylls (such as astaxanthin).

[0085] Therefore, the present invention also relates to the use of the compound of formula (II) as obtained from the process according to the present invention for the production of astaxanthin. The following scheme shows how astaxanthin can be obtained starting from the compound of formula (II)

[0086] 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.

[0087] EXAMPLES

[0088] Example 1 (synthesis of the compound of formula (II))

[0089] 1.2 mol-eq of the compound of formula (IVa) was dissolved in 0.4 mol-eq. CPME and the reaction solution was cooled to 5°C. Afterwards 1.5 mol-eq of CH3CH2MgBr (compound (III)) (1 M in THF) was added, and the temperature was increased to room temperature. After 1 h 15 min the mixture was heated to 60°C.

[0090] After 1 .5 h at 60°C 1 .5 mol-eq of the compound of formula (Via) (dissolved in 0.2 mol-eq CPME) was added to the freshly prepared Grignard reagent (compound of formula (Va’)) and stirred for an additional 3.5 h at 60 °C.

[0091] Then, the reaction mixture was cooled to 0°C and 2.2 eq. of aq. HCI (1 M) were added. After stirring for an additional 1 h at room temperature, the mixture was transferred to a separating funnel and the phases were separated. The organic layer was washed with saturated sodium bicarbonate solution. The aqueous phases were extracted twice with diethyl ether. The combined organic phases were dried over sodium sulphate, filtered and the solvent was evaporated to obtain the crude ketolyl pentol (compound of formula (II)) in a yield of 68 %.

[0092] In the following Table 1 , the reaction was carried out using the same conditions as in Example 1 but using a different solvent.

[0093] Table 1 In the following Table 2, the compound of formula (III) and its concentration in the dissolved form in THF has been varied. All the other reaction conditions (particularly molar equivalents) are the same as in Example 1

[0094] Table 2

[0095] In Table 3 different compounds of formula (IV) are used. All other conditions are the same as in Example 1

[0096] Table 3: Example 16 (synthesis of the compound of formula (II))

[0097] 1.30 eq. of the compound of formula (IVa) was dissolved in CPME (5 mL) and the solution was cooled to 5°C. Octylmagnesium chloride (compound of formulae (III)) (2.0 M in THF, 6.10 mmol, 1.30 eq.) was added at 5 - 10 °C and then the temperature was increased to room temperature. After 30 min a solution of isodiol acetonide (compound of formula (Via)) (4.69 mmol, 1.0 eq.) in CPME (2.5 mL) was added and the reaction mixture was heated to 60 °C for 3.5 h. Then, it was cooled to 0°C and aq. HCI (1 M, 2.2 eq., 10.3 mL) was added.

[0098] The organic layer was washed with saturated sodium bicarbonate solution (20 mL). The aqueous phases were extracted twice with CPME (20 mL). The combined organic phases were dried over sodium sulfate, filtered and the solvent was evaporated to obtain the crude ketolyl pentol (85% yield).

[0099] Example 17 (synthesis of the compound of formula (II))

[0100] 1.30 eq. of the compound of formula (IVa) was dissolved in CPME (5 mL) and the solution was cooled to 5°C. Tetradecylmagnesium chloride (compound of formulae (III)) (1.0 M in THF, 6.10 mmol, 1.30 eq.) was added at 5 - 10 °C and then the temperature was increased to room temperature. After 30 min a solution of isodiol acetonide (compound of formula (Via)) (4.69 mmol, 1.0 eq.) in CPME (2.5 mL) was added and the reaction mixture was heated to 60 °C for 3.5 h. Then, it was cooled to 0°C and aq. HCI (1 M, 2.2 eq., 10.3 mL) was added.

[0101] The organic layer was washed with saturated sodium bicarbonate solution (20 mL). The aqueous phases were extracted twice with CPME (20 mL). The combined organic phases were dried over sodium sulfate, filtered and the CPME was evaporated to obtain the crude ketolyl pentol (58% yield).

Claims

CLAIMS1. Process for the production of the compound of formula (II)wherein in a first step (step (i)) a compound of formulawhereinR-l is H, -C(R4)(R5)OR6, -Si(R7R8R9), tetrahydropyrane, -CH2OCH3or - COC(CH3)3, whereinR4and R5are independently from each other linear or branched CrC4alkyl (preferably CH3or CH2CH3), andR6is linear or branched CrC4alkyl (preferably CH3or CH2CH3), andR7is linear or branched CrC4alkyl, unsubstituted phenyl or substituted phenyl, andR8is linear or branched CrC4alkyl, unsubstituted phenyl or substituted phenyl, andRg is linear or branched CrC4alkyl, unsubstituted phenyl or substituted phenyl, and is reacted with a compound RMgX (III), whereinR is linear or branched C1- C14alkyl or cyclic C4- C8alkyl and,X is Cl, Br, or I, preferably wherein X is Cl, and the compound of formula (V)is obtained, with proviso that when R1in the compound of formula (IV) is H thenR1in compound of formula (V) is MgX, followed by step (ii), wherein the reaction product of step (i), which is the compound of formula (V) is reacted with a compound of formula (VI)whereinR2is H, unsubstituted phenyl, substituted phenyl or a linear or branched CrC4alkyl group, andR3is H, unsubstituted phenyl, substituted phenyl or a linear or branched C1-C4alkyl group, and, followed by step (iii), wherein the reaction product of step (ii), which is the compound of formulawherein all substituents have the same meanings as defined above, is reacted with at least one Bronsted acid.

2. Process according to claim 1 , wherein R1is -C(R4)(R5)OR6, whereinR4and R5are independently from each other linear or branched CrC4alkyl (preferably CH3or CH2CH3), andR6is linear or branched CrC4alkyl (preferably CH3or CH2CH3), andR7is linear or branched CrC4alkyl, unsubstituted phenyl or substituted phenyl, andR8is linear or branched CrC4alkyl, unsubstituted phenyl or substituted phenyl, andRg is linear or branched CrC4alkyl, unsubstituted phenyl or substituted phenyl.

3. Process according to claim 1 or claim 2, wherein the compound of formula (III) is chosen from the group consisting of CH3MgCI, CH3CH2MgCI, CH3CH2Mgl, iPrMgCI, CH3(CH2)7MgCI, CH3(CH2)7MgBr and CH3(CH2)7Mgl.

4. Process according to any of the preceding claims, wherein the reactions of step (i), step (ii) and step (iii) are carried out in at least one inert solvent, or in mixtures thereof, preferably in ethers, alkanes, or mixtures thereof.

5. Process according to claim 4, wherein the inert solvent is chosen from the group consisting of tetra hydrofuran (THF), 2-methyl-THF, cyclopentyl methyl ether (CPME), dimethoxyethane (DME), dimethylether (DEM), tert-amyl methyl ether (TAME), tert-Butyl methyl ether (TBME), diethyl ether, diisopropyl ether and (poly)glycol ethers.

6. Process according to any of the preceding claims, wherein the reaction of step (i) is carried out at a temperature of -10 to 60 °C.

7. Process according to any of the preceding claims, wherein the compound of formula (IV) and the compound of formula (III) in the reaction of step (i) are used in equimolar amounts.

8. Process according to any of the preceding claims, wherein the process of step (ii) is carried out at a temperature of 20°C to 100°C.

9. Process according to any of the preceding claims, wherein the compound of formula (V) is used in slight excess of the compound of formula (VI).

10. Process according to any of the preceding claims, wherein the process of step (iii) is carried out at a temperature of -10°C to 30°C.

11. Process according to any of the preceding claims, wherein the at least Bronsted acids is chosen from the group consisting of HCI, HBr, H2SO4, H3PO4and pTsOH.

12. A compound of formula (VII)whereinR1is -C(R4)(R5)OR6, -Si(R7R8R9), tetrahydropyran (THP), methoxymethyl (MOM) CH2OCH3, pivalate -COC(CH3)3or MgX, whereinR4and R5are independently from each other linear or branched CrC4alkyl (preferably CH3or CH2CH3), andRg is linear or branched CrC4alkyl (preferably CH3or CH2CH3), andR7is linear or branched C1-C4alkyl, unsubstituted phenyl or substituted phenyl, andR8is linear or branched CrC4alkyl, unsubstituted phenyl or substituted phenyl, andR9is linear or branched CrC4alkyl, unsubstituted phenyl or substituted phenyl, andR2is H, unsubstituted phenyl, substituted phenyl or a linear or branched CrC4alkyl group, andR3is H, unsubstituted phenyl, substituted phenyl or a linear or branched CrC4alkyl group, andX is Cl, Br, or I, preferably wherein X is Cl.

13. A compound of formula (Vila)whereinX is Br or Cl, preferably wherein X is Cl.

14. Use of the compound of formula (II)as obtained in the process of claims 1 - 11 for the production of astaxanthin.

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