Improved process for generating astaxanthin intermediates

Abstract

The present invention relates to a process for producing intermediates useful in organic synthesis, particularly in the production of astaxanthin.

Description

Detailed Description of the Invention

[0001] The present invention relates to a process for producing intermediates useful in organic synthesis, particularly in the production of astaxanthin.

[0002] Astaxanthin, a compound of formula (I)

Chemical formula

[0003] Astaxanthin can be supplied from natural sources, and can be produced not only chemically but also biochemically.

[0004] Regarding the chemical synthesis of astaxanthin, various processes are known.

[0005] Most of the chemical reactions for producing astaxanthin (or intermediates for producing astaxanthin) use alkyllithium (alkyl-Li), such as butyllithium or methyllithium.

[0006] For example, in order to produce such intermediates, the following process is known from the prior art (R. Zell et al., Hel. Chim. Acta, Vol 64(7), 1981, p. 2447ff).

Chemical formula

[0007] The alkyllithium compound is used to generate one of the coupling partners.

[0008] Another process that can be used to produce astaxanthin is described in Widmer et al. in Hel. Chim. Acta, Vol 64(7), 1981, p. 2436ff. While these authors describe a synthesis using alkyllithium compounds, they mention that ethylmagnesium bromide can be used in the Grignard coupling to obtain compound (II). The authors do not consider Grignard coupling to be the best option for synthesizing compound (II) because the yield is much lower than that obtained with alkyllithium.

[0009] Alkyllithium compounds are problematic compounds. They are highly toxic to aquatic organisms, and their effects are long-lasting.

[0010] Because such intermediates are important, there is always a need for improved methods to obtain such compounds, particularly to replace alkyllithium compounds with less toxic reagents, thereby avoiding toxic alkyllithium compounds while still achieving the same or better yields.

[0011] The inventors have identified an important intermediate of formula (II) [ka] We have discovered a novel and improved method for generating [a substance], which can then be used in organic synthesis (particularly for generating astaxanthin).

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

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

[0014] The definitions of the substituents and the reaction conditions will be disclosed in more detail below.

[0015] In connection with the present invention, a wavy bond means that the shape of the double bond can be in the E configuration or the Z configuration. This means that only one of the configurations or both configurations can be mixed.

[0016] This novel process avoids the use of any alkyl lithium compound.

[0017] This novel process enables a higher-yield compound (II) than that using an alkyl lithium compound as described in the prior art cited above. In some preferred embodiments, it is further possible to separate better from the solvent used in the process.

[0018] All the reaction steps of the process according to the present invention will be described in more detail.

[0019] [Step (i)] [Chemical formula] In the formula, R is a linear or branched C1-C 14 alkyl or cyclic C4-C8 alkyl, and R1 is H, -C(R4)(R5)OR6, -Si(R7R8R9), tetrahydropyran, -CH2OCH3 or -COC(CH3)3, In the formula, R4 and R5 are each independently a linear or branched C1-C4 alkyl (preferably CH3 or CH2CH3), and R6 is a linear or branched C1-C4 alkyl (preferably CH3 or CH2CH3), and R7 is a linear or branched C1-C4 alkyl, unsubstituted phenyl or substituted phenyl, and R8 is a linear or branched C1-C4 alkyl, unsubstituted phenyl or substituted phenyl, and R9 is a linear or branched C1-C4 alkyl, unsubstituted phenyl or substituted phenyl, and X is Cl, Br, or I, preferably, X is Cl, and However, when R1 in the compound of formula (IV) is H, it is a condition that R1 in the compound of formula (V) is MgX.

[0020] Preferably, in step (i), the following compounds (compounds of formula (IVa)-(IVd))

Chemical formula

[0021] More preferably, in step (i), the compound of formula (IVa)

Chemical formula

[0022] Furthermore, in step (i), preferably, the compound of formula (III) is selected from the group consisting of CH3MgCl, CH3MgBr, CH3MgI, CH3CH2MgCl, CH3CH2MgBr, CH3CH2MgI, iPrMgCl, iPrMgBr, iPrMgI, CH3(CH2)7MgCl, CH3(CH2)7MgBr or CH3(CH2)7Mgl; more preferably, in step (I), the compound of formula (III) is selected from the group consisting of CH3MgCl, CH3CH2MgCl, iPrMgCl, CH3(CH2)7MgCl, CH3(CH2)7MgBr or CH3(CH2)7Mgl.

[0023] The compound of formula (III) is usually added to the reaction mixture in a dissolved form. This solvent can be any solvent used as the solvent in step (i) defined below.

[0024] The concentration of the compound of formula (III) in the solvent is 0.5 to 5 M.

[0025] More preferable are compounds of formula (Va)~(Ve'). [ka] These are obtained as reaction products at the end of step (i) and can be isolated and analyzed.

[0026] The most preferred compounds are those of formula (Va) to (Ve), which are obtained as reaction products at the end of step (i) and can be isolated and analyzed.

[0027] In the first step (step (i)) of the present invention, a Grignard reagent (compound of formula (V)) is produced.

[0028] Typically, the reaction in step (i) is carried out in at least one inert solvent.

[0029] Suitable solvents are inert organic solvents or ionic liquids.

[0030] Preferably, a polar aprotic solvent, such as an ether, or an aromatic solvent (e.g., toluene, benzene) is used.

[0031] The most preferred polar aprotic solvents are ethers (e.g., tetrahydrofuran (THF), 2-methyl-THF, cyclopentyl methyl ether (CPME), dimethoxyethane (DME), dimethyl ether (DEM), tert-amyl methyl ether (TAME), tert-butyl methyl ether (TBME), diethyl ether, diisopropyl ether, and (poly)glycol ethers).

[0032] It is also possible to use mixtures of these polar aprotic solvents and alkanes. Branched, cyclic, or unbranched alkanes, such as pentane, hexane, heptane, cyclopentane, cyclohexane, methylcyclohexane, or mixtures thereof, are preferred. More preferred alkanes can be selected from the group consisting of pentane, hexane, heptane, cyclohexane, or mixtures thereof.

[0033] The preferred solvent mixtures described herein above are mixtures of at least one solvent selected from the group consisting of tetrahydrofuran (THF), 2-methyl-THF, cyclopentyl methyl ether (CPME), dimethoxyethane (DME), dimethyl ether (DEM), tert-amyl methyl ether (TAME), tert-butyl methyl ether (TBME), diethyl ether, diisopropyl ether, and (poly)glycol ether, and at least one solvent selected from the group consisting of pentane, hexane, heptanecyclopentane, cyclohexane, methylcyclohexane, or mixtures thereof. These solvents may be mixtures of one or more solvents from one of the two groups, and they are used in an ether:alkane ratio of 1:100 to 100:1, preferably 20:80 to 80:20, and more preferably 30:70 to 70:30.

[0034] More preferably, the mixture is 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, wherein the ether:alkane ratio is preferably 1:100 to 100:1, and more preferably 20:80 to 80:20.

[0035] Typically, the reaction in step (i) is carried out at a temperature of -10 to 60°C.

[0036] Preferably, the temperature is 0°C to 60°C, more preferably 0°C to 60°C.

[0037] Typically and preferably, the reaction in step (i) is carried out at ambient pressure.

[0038] The compound of formula (IV) and the compound of formula (III) are used in approximately equimolar amounts. It is also possible to use a slight excess of the compound of formula (III). In the compound of formula (IV), if R1 is H, it is preferable to use at least 2 molar equivalents of the compound of formula (III).

[0039] The reaction time for step (i) is at least 10 minutes (up to several hours). Typically, the reaction time for step (i) is between 30 minutes and 300 minutes.

[0040] [Step (ii)] In the second step (step (ii)), the reaction product of step (i), which is the compound of formula (V), becomes the compound of formula (VI). [ka] (In the formula, R1 is H, -C(R4)(R5)OR6, -Si(R7R8R9), tetrahydropyran (THP), methoxymethyl (MOM)CH2OCH3, pivalate-COC(CH3)3, or MgX. During the ceremony, R4 and R5 are independently linear or branched C1-C4 alkyl groups (preferably CH3 or CH2CH3), and R6 is a linear or branched C1-C4 alkyl group (preferably CH3 or CH2CH3), and R7 is a linear or branched C1-C4 alkyl, unsubstituted phenyl, or substituted phenyl, and R8 is a linear or branched C1-C4 alkyl, unsubstituted phenyl, or substituted phenyl, and R9 is a linear or branched C1-C4 alkyl, unsubstituted phenyl, or substituted phenyl, and R2 is H, unsubstituted phenyl, substituted phenyl, or a linear or branched C1-C4 alkyl group, and R3 is H, unsubstituted phenyl, substituted phenyl, or a linear or branched C1-C4 alkyl group, and X is Cl, Br, or I, preferably X is Cl. It is coupled with [this].

[0041] Preferably, the compound of formula (Va') or formula (Va'') in step (ii), More preferably, the compound of formula (Va'') in step (ii) [ka] The compound of formula (VIa) [ka] This elicits a reaction.

[0042] The reaction in step (ii) is carried out in the same solvent as in step (i).

[0043] Typically and preferably, the process of step (ii) is carried out at a temperature of 20°C to 100°C.

[0044] Typically and preferably, the process of step (ii) is carried out at ambient pressure.

[0045] Compound (V) and compound (VI) are used in approximately equimolar amounts. However, it is also possible to use either compound (V) or compound (VI) in a slightly excessive amount.

[0046] Preferably, a slightly excess of compound (VI) is used with respect to compound (V), where the excess is 1.05 to 1.6 molar equivalents of compound (V) relative to compound (VI), more preferably 1.2 to 1.6 molar equivalents of compound (V) relative to compound (VI), and most preferably 1.2 to 1.55 molar equivalents of compound (V) relative to compound (VI).

[0047] The reaction time for step (ii) is at least 10 minutes (up to several hours). Typically, the reaction time for step (ii) is between 30 minutes and 300 minutes.

[0048] The reaction product of step (ii) is the compound of formula (VII). [ka] That is the case.

[0049] Furthermore, the reaction product of step (ii), which is the compound of formula (VII), is a novel compound, and R1, R2, and R3 have the same meanings as defined above.

[0050] Therefore, a further embodiment of the present invention is a compound of formula (VII). [ka] (In the formula, R1 is -C(R4)(R5)OR6, -Si(R7R8R9), tetrahydropyran (THP), methoxymethyl (MOM)CH2OCH3, pivalate-COC(CH3)3, or MgX. During the ceremony, R4 and R5 are independently linear or branched C1-C4 alkyl groups (preferably CH3 or CH2CH3), and R6 is a linear or branched C1-C4 alkyl group (preferably CH3 or CH2CH3), and R7 is a linear or branched C1-C4 alkyl, unsubstituted phenyl, or substituted phenyl, and R8 is a linear or branched C1-C4 alkyl, unsubstituted phenyl, or substituted phenyl, and R9 is a linear or branched C1-C4 alkyl, unsubstituted phenyl, or substituted phenyl, and R2 is H, unsubstituted phenyl, substituted phenyl, or a linear or branched C1-C4 alkyl group, and R3 is H, unsubstituted phenyl, substituted phenyl, or a linear or branched C1-C4 alkyl group, and X is Cl, Br, or I, preferably X is Cl. That is the case.

[0051] Of particular preference are compounds of formula (VIIa). [ka] (In the formula, X is either Br or Cl, preferably X is Cl. That is the case.

[0052] [Step (iii)] [ka] Step (iii) is carried out in the same at least one inert solvent as in steps (i) and (ii), which means that the process according to the present invention is carried out as a "one-pot reaction" as described above.

[0053] Typically and preferably, the process of step (iii) is carried out at a temperature of -10°C to 30°C.

[0054] At least one Brønsted acid is added to the reaction mixture. The at least one Brønsted acid can be any of the generally known ones.

[0055] Suitable Brønsted acids include, for example, HCl, HBr, H2SO4, H3PO4, and pTsOH.

[0056] It is also possible to use acidic ion exchange resins, such as polystyrene-based ion exchange resins containing strongly acidic sulfonic acid groups. Such ion exchange resins are commercially available (e.g., Amberlyst® 15).

[0057] Typically and preferably, the process of step (iii) is carried out at ambient pressure.

[0058] The reaction time for step (iii) is at least 10 minutes (up to several hours). Typically, the reaction time for step (iii) is between 30 minutes and 300 minutes.

[0059] The removal of protecting groups in the compound of formula (VII) may be carried out all at once or sequentially, in which case the first protecting group of the two protecting groups is removed, followed by the removal of the second protecting group.

[0060] Compounds of formula (VII') and formula (VII'') [ka] (In the formula, the definition of substituents is the same as that defined above.) This is a compound in which one of the protecting groups has been removed.

[0061] As described above, the compound of formula (II) of the present invention is an intermediate for the synthesis of specific xanthophylls (such as astaxanthin).

[0062] Accordingly, the present invention also relates to the use of a compound of formula (II), such as one obtained from a process according to the present invention, for producing astaxanthin.

[0063] The following scheme shows how astaxanthin can be obtained starting from the compound of formula (II). [ka]

[0064] This reaction is publicly known from (B. Wuestenberg, et al. CHIMIA 2011, 65, 420-428).

[0065] The present invention will be illustrated without further limitation by the following examples. All percentages and parts shown are in terms of weight, and unless otherwise specified, temperatures are given in °C and pressures are in absolute pressure.

[0066] [Examples] [Example 1 (Synthesis of compound (II))] 1.2 molar equivalents of the compound of formula (IVa) were dissolved in 0.4 molar equivalents of CPME, and the reaction solution was cooled to 5°C. Then, 1.5 molar equivalents of CH3CH2MgBr (compound (III)) (1 M in THF) were added, and the temperature was raised to room temperature. After 1 hour and 15 minutes, the mixture was heated to 60°C.

[0067] After 1.5 hours at 60°C, 1.5 molar equivalents of the compound of formula (VIa) (dissolved in 0.2 molar equivalents of CPME) were added to the freshly prepared Grignard reagent (compound of formula (Va')), and the mixture was stirred for a further 3.5 hours at 60°C.

[0068] Next, the reaction mixture was cooled to 0°C, and 2.2 equivalents of HCl aqueous solution (1M) were added. After stirring for a further 1 hour at room temperature, the mixture was transferred to a separatory funnel and the phases were separated. The organic layer was washed with saturated sodium bicarbonate solution. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were dried over sodium sulfate and filtered, and the solvent was evaporated to obtain crude ketrylpentol (compound of formula (II)) in 68% yield.

[0069] Table 1 below shows that the reaction was carried out under the same conditions as in Example 1, but with a different solvent.

[0070] [Table 1]

[0071] Table 2 below shows the compound of formula (III) in its dissolved form in THF and its varying concentration. All other reaction conditions (especially molar equivalents) are the same as in Example 1.

[0072] [Table 2]

[0073] Table 3 shows that various compounds of formula (IV) are used. All other conditions are the same as in Example 1.

[0074] [Table 3]

[0075] [Example 16 (Synthesis of Compound (II))] 1.30 molar equivalents of the compound of formula (IVa) were dissolved in CPME (5 mL), and the solution was cooled to 5°C. Octyl magnesium chloride (compound of formula (III)) (2.0 M, 6.10 mmol, 1.30 equivalents in THF) was added at 5-10°C, and then the temperature was raised to room temperature. After 30 minutes, a solution of isodiol acetonide (compound of formula (VIa)) (4.69 mmol, 1.0 equivalent) in CPME (2.5 mL) was added, and the reaction mixture was heated to 60°C for 3.5 hours. Then, it was cooled to 0°C, and aqueous HCl (1 M, 2.2 equivalents, 10.3 mL) was added.

[0076] The organic layer was washed with saturated sodium bicarbonate solution (20 mL). The aqueous phase was extracted twice with CPME (20 mL). The combined organic phases were dried over sodium sulfate, filtered, and the solvent was evaporated to obtain crude ketrilpentol (yield 85%).

[0077] [Example 17 (Synthesis of compound of formula (II)] 1.30 molar equivalents of the compound of formula (IVa) were dissolved in CPME (5 mL), and the solution was cooled to 5°C. Tetradecyl magnesium chloride (compound of formula (III)) (1.0 M, 6.10 mmol, 1.30 equivalents in THF) was added at 5-10°C, and then the temperature was raised to room temperature. After 30 minutes, a solution of isodiol acetonide (compound of formula (VIa)) (4.69 mmol, 1.0 equivalent) in CPME (2.5 mL) was added, and the reaction mixture was heated to 60°C for 3.5 hours. Then, it was cooled to 0°C, and aqueous HCl (1 M, 2.2 equivalents, 10.3 mL) was added.

[0078] The organic layer was washed with saturated sodium bicarbonate solution (20 mL). The aqueous phase was extracted twice with CPME (20 mL). The combined organic phases were dried over sodium sulfate and filtered, and the CPME was evaporated to obtain crude ketrilpentol (yield 58%).

Claims

1. Compound of formula (II) 【Chemistry 1】 A process for generating, In the first step (step (i)), Compound of formula (IV) 【Chemistry 2】 (In the formula, R １ is H, -C(R ４ )(R ５ )OR ６ , -Si(R ７ R ８ R ９ ), tetrahydropyran, -CH ２ OCH ３ or -COC(CH ３ ) ３ and During the ceremony, R ４ and R ５ This refers to linear or branched chains C, which are independent of each other. １ ~C ４ Alkyl (preferably CH ３ or CH ２ CH ３ ) and R ６ C is a straight or branched chain. １ ~C ４ Alkyl (preferably CH ３ or CH ２ CH ３ ) and R ７ C is a straight or branched chain. １ ~C ４ Alkyl, unsubstituted phenyl, or substituted phenyl, and R ８ C is a straight or branched chain. １ ~C ４ Alkyl, unsubstituted phenyl, or substituted phenyl, and R ９ C is a straight or branched chain. １ ~C ４ (It is an alkyl, unsubstituted phenyl, or substituted phenyl.) compound RMgX(III) (In the formula, R is a straight or branched chain C １ ~C １４ Alkyl or cyclic C ４ ~C ８ It is alkyl, and X is Cl, Br, or I, preferably X is Cl. And it will react, Compound of formula (V) 【Transformation 3】 This is obtained, however, R in the compound of formula (IV) above. １ When is H, R in the compound of formula (V) １ The condition is that it is MgX, Next, in step (ii), the reaction product of step (i), which is the compound of formula (V), is used to form the compound of formula (VI). 【Chemistry 4】 (In the formula, R ２ This is H, unsubstituted phenyl, substituted phenyl, or linear or branched C １ ~C ４ It is an alkyl group, and R ３ This is H, unsubstituted phenyl, substituted phenyl, or linear or branched C １ ~C ４ (It is an alkyl group.) The reaction is carried out, and then in step (iii), the reaction product of step (ii), which is the compound of formula (VII), is formed. 【Transformation 5】 (In the formula, all substituents have the same meaning as defined above.) A process of reacting with at least one Brønsted acid.

2. R １ が、-C(R ４ )(R ５ )OR ６ (In the formula, R ４ and R ５ This refers to linear or branched chains C, which are independent of each other. １ ~C ４ Alkyl (preferably CH ３ or CH ２ CH ３ ) and R ６ C is a straight or branched chain. １ ~C ４ Alkyl (preferably CH ３ or CH ２ CH ３ ) and R ７ C is a straight or branched chain. １ ~C ４ Alkyl, unsubstituted phenyl, or substituted phenyl, and R ８ C is a straight or branched chain. １ ~C ４ Alkyl, unsubstituted phenyl, or substituted phenyl, and R ９ C is a straight or branched chain. １ ~C ４ (It is an alkyl, unsubstituted phenyl, or substituted phenyl.) The process according to claim 1.

3. The compound of formula (III) is CH ３ MgCl, CH ３ CH ２ MgCl, CH ３ CH ２ MgI, iPrMgCl, CH ３ (CH ２ ) ７ MgCl, CH ３ (CH ２ ) ７ MgBr and CH ３ (CH ２ ) ７ The process according to claim 1 or 2, selected from the group consisting of Mgl.

4. The process according to any one of claims 1 to 3, wherein the reactions of step (i), step (ii), and step (iii) are carried out in at least one inert solvent, or in a mixture thereof, preferably in an ether, an alkane, or a mixture thereof.

5. The process according to claim 4, wherein the inert solvent is selected from the group consisting of tetrahydrofuran (THF), 2-methyl-THF, cyclopentyl methyl ether (CPME), dimethoxyethane (DME), dimethyl ether (DEM), tert-amyl methyl ether (TAME), tert-butyl methyl ether (TBME), diethyl ether, diisopropyl ether, and (poly)glycol ether.

6. The process according to any one of claims 1 to 5, wherein the reaction in step (i) is carried out at a temperature of -10 to 60°C.

7. The process according to any one of claims 1 to 6, wherein the compound of formula (IV) and the compound of formula (III) in the reaction of step (i) are used in equimolar amounts.

8. The process according to any one of claims 1 to 7, wherein the process of step (ii) is carried out at a temperature of 20°C to 100°C.

9. The process according to any one of claims 1 to 8, wherein a slightly excess of the compound of formula (VI) is used with respect to the compound of formula (V).

10. The process according to any one of claims 1 to 9, wherein the process of step (iii) is carried out at a temperature of -10°C to 30°C.

11. The aforementioned at least Brønsted acid is HCl, HBr, H ２ SO ４ H ３ PO ４ The process according to any one of claims 1 to 10, selected from the group consisting of and pTsOH.

12. Compound of formula (VII) 【Transformation 6】 (In the formula, R １ is -C(R ４ )(R ５ )OR ６ , -Si(R ７ R ８ R ９ ), tetrahydropyran (THP), methoxymethyl (MOM) CH ２ OCH ３ , pivalate -COC(CH ３ ) ３ or MgX, During the ceremony, R ４ and R ５ This refers to linear or branched chains C, which are independent of each other. １ ~C ４ Alkyl (preferably CH ３ or CH ２ CH ３ ) and R ６ C is a straight or branched chain. １ ~C ４ Alkyl (preferably CH ３ or CH ２ CH ３ ) and R ７ C is a straight or branched chain. １ ~C ４ Alkyl, unsubstituted phenyl, or substituted phenyl, and R ８ C is a straight or branched chain. １ ~C ４ Alkyl, unsubstituted phenyl, or substituted phenyl, and R ９ C is a straight or branched chain. １ ~C ４ Alkyl, unsubstituted phenyl, or substituted phenyl, and R ２ This is H, unsubstituted phenyl, substituted phenyl, or linear or branched C １ ~C ４ It is an alkyl group, and R ３ This is H, unsubstituted phenyl, substituted phenyl, or linear or branched C １ ~C ４ It is an alkyl group, and X is Cl, Br, or I, preferably X is Cl).

13. Compound of formula (VIIa) 【Transformation 7】 (In the formula, X is Br or Cl, preferably X is Cl).

14. A compound of formula (II) obtained by a process according to any one of claims 1 to 11 for producing astaxanthin. 【Transformation 8】 Use.

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