JP2018131390A - Method for producing optically active astaxanthin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an optically active 3(S),3'(S)-astaxanthin (I), with a 3(RS)-acetoxy-4-oxo-β-ionone derivative (IIab) of a racemate as the starting material.SOLUTION: The present invention provides a method for producing an optically active 3(S),3'(S)-astaxanthin, represented by formula (I), with a 3(RS)-acetoxy-4-oxo-β-ionone derivative (IIab) of a racemate as the starting material, the method including 8-9 separation and reaction steps.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing optically active astaxanthin and an intermediate used in the production method.

Conventionally, vinyl obtained by reacting 3 (RS) -acetoxy-4-oxo-β-ionone or 3 (RS)-(4-chlorobenzoyloxy) -4-oxo-β-ionone with vinylmagnesium chloride. Hydrolysis of the alcohol derivative, bromination of the resulting dialcohol derivative (with allyl transfer), reaction of the resulting allyl bromide derivative with triphenylphosphine, and conversion of the phosphonium bromide derivative (3 (S) derivative) And the racemic phosphonium bromide derivative is reacted with 2,7-dimethylocta-2,4,6-triene-1,8-dialdehyde in the presence of a base (Wittig reaction), 3 Methods for producing (RS), 3 ′ (RS) -astaxatin are known (for example, Patent Document 1 and Non-Patent Document 1).
Further, 3 (RS) -acetoxy-4-oxo-β-ionone is reacted with a microorganism belonging to the genus Bacillus, and the resulting mixture is subjected to fractional extraction to obtain 3 (S) -acetoxy-4-oxo-β-ionone. And 3 (RS)-(−)-camphanoyloxy-4-oxo-β-ionone is optically resolved using ion chromatography or fractional crystallization to give 3 (S)-(−) — A method for obtaining campanoyloxy-4-oxo-β-ionone is known (for example, Non-Patent Document 1).

  However, in order to produce optically active 3 (S), 3 ′ (S) -astaxatin, the above production method uses expensive (−)-camphanic acid, ion chromatography, fractionation, etc. Because it has problems such as requiring complicated purification / separation operations such as crystallization methods and many steps, it uses raw materials and reaction reagents that are easily obtained at low cost, and is based on simple purification / separation operations. Development of an industrial production method of optically active 3 (S), 3 ′ (S) -astaxatin, which is aimed at high yield and high purity through a small number of steps, is desired.

WO2007 / 072529

Helvetica Chimica Acta, Vol. 64, 2419-2435 (1981)

  As described above, in the conventional production method, expensive (-)-camphanic acid or the like is used, complicated purification and separation operations such as ion chromatography and fractional crystallization are required, and the number of steps is large. This has been a problem as an industrial production method of optically active astaxanthin.

  Under such circumstances, the present invention uses a raw material and a reaction reagent that are inexpensive and easily obtained, and uses a smaller number of steps under a simple operation, in a three-dimensional (position) specific, high yield. The main object of the present invention is to provide an industrial production method of optically active 3 (S), 3 ′ (S) -astaxatin, which is aimed at high purity. Furthermore, this invention also aims at providing the intermediate body used for the said manufacturing method.

上記式中、Ａｃは、アセチル基を示し、Ｑは、それが結合している炭素原子と一緒になって、保護されていてもよいカルボニル基を形成する。 The present inventors have intensively studied to solve the above problems. as a result,
Starting from the racemic 3 (RS) -acetoxy-4-oxo-β-ionone derivative (IIab), the desired optically active 3 (S), 3 in 8 to 9 separation / reaction steps. The present invention has been completed by finding a method for producing '(S) -astaxatin (I).

In the above formula, Ac represents an acetyl group, and Q, together with the carbon atom to which it is attached, forms an optionally protected carbonyl group.

を製造する方法であって、
式：

（式中、Ａｃは、アセチル基を示し、Ｑは、それが結合している炭素原子と一緒になって、保護されていてもよいカルボニル基を形成する。）
を有する、ラセミ体の３（ＲＳ）−アセトキシ−４−オキソ−β−イオノン誘導体（ＩＩａｂ）をリパーゼと反応させ、式：

（式中、Ａｃ及びＱは、前述したものと同意義を示す。）
を有する、３（Ｓ）−アセトキシ−４−オキソ−β−イオノン誘導体（ＩＩａ）と３（Ｒ）−ヒドロキシ−４−オキソ−β−イオノン誘導体（ＩＩＩｂ）の混合物を製造し、この混合物を、塩基の存在下、無水コハク酸と反応させ、得られた反応混合物と塩基性水溶液の懸濁液を水不混和性有機溶媒で抽出し、化合物（ＩＩＩｂ）のモノコハク酸エステル誘導体を除去し、得られた化合物（ＩＩａ）のカルボニル基の保護基を、所望により除去して、式：

（式中、Ａｃは、前述したものと同意義を示す。）
を有する、３（Ｓ）−アセトキシ−４−オキソ−β−イオノンを製造し、得られた化合物（ＩＶａ）を加水分解して、式：

を有する３（Ｓ）−ヒドロキシ−４−オキソ−β−イオノンを製造し、得られた化合物（Ｖａ）を、酸の存在下、式：

（式中、Ｒ^１及びＲ^２は、同一又は異なって、Ｃ_１−Ｃ_６アルキル基を示す。）
を有するビニル アルキル エーテル誘導体と反応させ、式：

（式中、Ｒ^１及びＲ^２は、前述したものと同意義を示す。）
を有する３（Ｓ）−アルコキシ−アルコキシ−４−オキソ−β−イオノン誘導体を製造し、得られた化合物（ＶＩＩａ）を、式：

（式中、Ｘは、ハロゲン原子を示す。）
を有するグリニヤール試薬と反応させ、式：

（式中、Ｒ^１及びＲ^２は、前述したものと同意義を示す。）
を有するアリルアルコール誘導体を製造し、得られた化合物（ＩＸａ）を、ハロゲン化水素と反応させ、式：

（式中、Ｙは、ハロゲン原子を示す。）
を有するアリルハライド誘導体を製造し、得られた化合物（Ｘａ）を、トリフェニルホスフィンと反応させ、式：

（式中、Ｐｈは、フェニル基を示し、Ｙは前述したものと同意義を示す。）
を有するホスホニウム塩誘導体を製造し、得られた化合物（ＸＩａ）を、塩基の存在下、式：

を有するジアルデヒド誘導体と反応させる工程を含む製造方法。
項２．化合物（ＩＩａｂ）との反応において、使用されるリパーゼが、カンディダ属（Ｃａｎｄｉｄａ ｓｐ．）由来のリパーゼである、項１に記載の製造方法。
項３．化合物（ＩＶａ）の加水分解を、ブタ肝臓由来のエステラーゼ及び大腸菌由来のエステラーゼから選択されるエステラーゼの存在下に行う、項１又は２項に記載の製造方法。
項４．化合物（Ｖａ）と化合物（ＶＩ）との反応において、使用される酸が、ピリジニウム ｐ−トルエンスルホン酸である、項１乃至３に記載の製造方法。
項５．化合物（ＸＩａ）と化合物（ＸＩＩ）との反応において、使用される塩基が、１，２−エポキシブタンである、項１乃至４に記載の製造方法。
項６．３（Ｓ），３’（Ｓ）−アスタキサチン（Ｉ）：

を製造する方法であって、
式：

（式中、Ｒ^１及びＲ^２は、同一又は異なって、Ｃ_１−Ｃ_６アルキル基を示す。）
を有するアリルアルコール誘導体（ＩＸａ）を、ハロゲン化水素と反応させ、式：

（式中、Ｙは、ハロゲン原子を示す。）
を有するアリルハライド誘導体を製造し、得られた化合物（Ｘａ）を、トリフェニルホスフィンと反応させ、式：

（式中、Ｐｈは、フェニル基を示し、Ｙは前述したものと同意義を示す。）
を有するホスホニウム塩誘導体を製造し、得られた化合物（ＸＩａ）を、塩基の存在下、式：

を有するジアルデヒド誘導体（ＸＩＩ）と反応させる工程を含む製造方法。
項７．式：

（式中、Ｒ^１及びＲ^２は、同一又は異なって、Ｃ_１−Ｃ_６アルキル基を示す。）
を有する３（Ｓ）−アルコキシ−アルコキシ−４−オキソ−β−イオノン誘導体。
項８．式：

（式中、Ｒ^１及びＲ^２は、同一又は異なって、Ｃ_１−Ｃ_６アルキル基を示す。）
を有するアリルアルコール誘導体。 That is, this invention provides the invention of the aspect hung up below.
Item 1.3 (S), 3 ′ (S) -astaxatin (I):

A method of manufacturing
formula:

(In the formula, Ac represents an acetyl group, and Q, together with the carbon atom to which it is bonded, forms an optionally protected carbonyl group.)
A racemic 3 (RS) -acetoxy-4-oxo-β-ionone derivative (IIab) having the formula:

(In the formula, Ac and Q are as defined above.)
A mixture of 3 (S) -acetoxy-4-oxo-β-ionone derivative (IIa) and 3 (R) -hydroxy-4-oxo-β-ionone derivative (IIIb) having the following structure: Reaction with succinic anhydride in the presence of a base, and a suspension of the resulting reaction mixture and a basic aqueous solution is extracted with a water-immiscible organic solvent to remove the monosuccinic acid ester derivative of compound (IIIb), The protecting group of the carbonyl group of the resulting compound (IIa) is optionally removed to give a compound of formula:

(In the formula, Ac is as defined above.)
3 (S) -acetoxy-4-oxo-β-ionone having the following structure is obtained and the resulting compound (IVa) is hydrolyzed to give the formula:

3 (S) -Hydroxy-4-oxo-β-ionone having the following formula (Va) in the presence of acid:

(In the formula, R ¹ and R ² are the same or different and represent a C ₁ -C ₆ alkyl group.)
Is reacted with a vinyl alkyl ether derivative having the formula:

(In the formula, R ¹ and R ² are as defined above.)
A 3 (S) -alkoxy-alkoxy-4-oxo-β-ionone derivative having the following structure is obtained, and the resulting compound (VIIa) is represented by the formula:

(In the formula, X represents a halogen atom.)
Is reacted with a Grignard reagent having the formula:

(In the formula, R ¹ and R ² are as defined above.)
And the resulting compound (IXa) is reacted with a hydrogen halide to produce a compound having the formula:

(In the formula, Y represents a halogen atom.)
And the resulting compound (Xa) is reacted with triphenylphosphine to give the formula:

(In the formula, Ph represents a phenyl group, and Y has the same meaning as described above.)
A phosphonium salt derivative having the following formula (XIa) is prepared in the presence of a base:

The manufacturing method including the process made to react with the dialdehyde derivative which has this.
Item 2. Item 2. The method according to Item 1, wherein the lipase used in the reaction with the compound (IIab) is a lipase derived from Candida sp.
Item 3. Item 3. The method according to Item 1 or 2, wherein the hydrolysis of the compound (IVa) is carried out in the presence of an esterase selected from an esterase derived from pig liver and an esterase derived from Escherichia coli.
Item 4. Claim | item 1 thru | or 3 manufacturing method whose acid used in reaction of compound (Va) and compound (VI) is pyridinium p-toluenesulfonic acid.
Item 5. Item 5. The production method according to Item 1 to 4, wherein the base used in the reaction of compound (XIa) and compound (XII) is 1,2-epoxybutane.
Item 6.3 (S), 3 ′ (S) -astaxatin (I):

A method of manufacturing
formula:

(In the formula, R ¹ and R ² are the same or different and represent a C ₁ -C ₆ alkyl group.)
An allyl alcohol derivative (IXa) having the formula:

(In the formula, Y represents a halogen atom.)
And the resulting compound (Xa) is reacted with triphenylphosphine to give the formula:

(In the formula, Ph represents a phenyl group, and Y has the same meaning as described above.)
A phosphonium salt derivative having the following formula (XIa) is prepared in the presence of a base:

The manufacturing method including the process made to react with the dialdehyde derivative (XII) which has this.
Item 7. formula:

(In the formula, R ¹ and R ² are the same or different and represent a C ₁ -C ₆ alkyl group.)
(S) -alkoxy-alkoxy-4-oxo-β-ionone derivatives having
Item 8. formula:

(In the formula, R ¹ and R ² are the same or different and represent a C ₁ -C ₆ alkyl group.)
An allyl alcohol derivative having

  The present invention uses a racemic 3 (RS) -acetoxy-4-oxo-β-ionone derivative (IIab) as a starting material and uses an inexpensive and easily obtainable reagent. In order to provide a method for producing the target optically active 3 (S), 3 ′ (S) -astaxatin (I) in a high yield and high purity in the reaction step, the optically active 3 (S) , 3 ′ (S) -astaxatin (I) can be significantly reduced in production cost. The present invention also provides a method for producing optically active 3 (S), 3 ′ (S) -astaxanthin (I) starting from an allyl alcohol derivative (IXa), which is a novel production intermediate, and a novel The production intermediates 3 (S) -alkoxy-alkoxy-4-oxo-β-ionone derivative (VIIa) and allyl alcohol derivative (IXa) can also be provided.

上記式中、Ａｃは、アセチル基を示し、Ｑは、それが結合している炭素原子と一緒になって、保護されていてもよいカルボニル基を形成し、Ｒ^１及びＲ^２は、同一又は異なって、Ｃ_１−Ｃ_６アルキル基を示し、Ｘは、ハロゲン原子を示し、Ｙは、ハロゲン原子を示し、Ｐｈは、フェニル基を示す。
Ｑのカルボニル基の保護基は、有機合成化学において、カルボニル基の保護基として、用いられるものなら、特に限定されないが、例えば、ジ−Ｃ_１−Ｃ_６アルキルオキシ基（例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ペントキシ、ヘキシルオキシ等）又はＣ_２−Ｃ_４アルキレンジオキシ基等であり得、好適には、ジ−Ｃ_１−Ｃ_４アルキルオキシ基又はＣ_２−Ｃ_３アルキレンジオキシ基であり、更に好適には、ジ−メトキシ基、ジ−エトキシ基又はエチレンジオキシ基であり、最も好適には、エチレンジオキシ基である。
Ｒ^１及びＲ^２のＣ_１−Ｃ_６アルキル基は、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ペンチル、ヘキシル等であり得、好適には、Ｃ_１−Ｃ_４アルキル基であり、更に好適には、メチル基又はエチル基であり、最も好適には、メチル基である。
Ｘ及びＹのハロゲン原子は、例えば、塩素原子、臭素原子、沃素原子等であり得、好適には、Ｘは、塩素原子又は臭素原子であり、Ｙは、臭素原子である。 The production method of the present invention is described in the following reaction scheme.

In the above formula, Ac represents an acetyl group, Q is taken together with the carbon atom to which it is bonded to form an optionally protected carbonyl group, and R ¹ and R ² are the same or Differently, it represents a C ₁ -C ₆ alkyl group, X represents a halogen atom, Y represents a halogen atom, and Ph represents a phenyl group.
The protecting group for the carbonyl group of Q is not particularly limited as long as it is used as a protecting group for the carbonyl group in organic synthetic chemistry. For example, a di-C ₁ -C ₆ alkyloxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, hexyloxy, etc.), or _C 2 -C ₄ alkylenedioxy group obtained, preferably, di _-C 1 -C ₄ alkyl group or _C 2 -C ₃ An alkylenedioxy group, more preferably a di-methoxy group, a di-ethoxy group or an ethylenedioxy group, and most preferably an ethylenedioxy group.
The C ₁ -C ₆ alkyl group of R ¹ and R ² can be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc., preferably a C ₁ -C ₄ alkyl group More preferred is a methyl group or an ethyl group, and most preferred is a methyl group.
The halogen atoms of X and Y can be, for example, a chlorine atom, a bromine atom, an iodine atom, etc., preferably X is a chlorine atom or a bromine atom, and Y is a bromine atom.

Step 1a is a step of producing a mixture of 3 (S) -acetoxy derivative (IIa) and 3 (R) -hydroxy derivative (IIIb), and 3 (RS) -acetoxy derivative (IIab) in an inert solvent. Is achieved by reacting with lipase.
The starting 3 (RS) -acetoxy derivative (IIab) is a known compound in the literature (for example, Helvetica Chimica Acta, Vol. 64, 2419-2435 (1981)) or a known compound in the literature. It is easily manufactured by the method.
Examples of the lipase used include lipase derived from porcine pancreas, Burkholderia sp., Pseudomonas sp., Candida sp., Rhizopus sp., Aspergillus It may be a lipase derived from microorganisms such as Aspergillus sp., Cryptococcus sp., Pichia sp., Bacillus sp., Etc., preferably Candida sp. .) Or a lipase derived from a microorganism of the genus Aspergillus sp., More preferably a lipase derived from a microorganism of the genus Candida sp.
The inert solvent used is not particularly limited as long as it dissolves the raw materials and reagents to some extent and is inert to the reaction. For example, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran, dioxane , Ethers such as dimethoxyethane, alcohols such as methanol, ethanol and isopropyl alcohol, ketones such as acetone and methyl ethyl ketone, water, a mixed solvent of water and these organic solvents, etc. A mixed solvent of water or a mixed solvent of aromatic hydrocarbons and water, more preferably a mixed solvent of aromatic hydrocarbons and water, and most preferably a mixed solvent of toluene and water.
In addition, this reaction is suitably performed in a buffer solution (for example, a phosphate buffer).
The reaction temperature varies depending on the type of lipase, solvent, etc., but is usually 0 ° C. to 60 ° C., preferably 20 ° C. to 40 ° C.
While the reaction time varies depending on the kind of lipase, solvent, etc., reaction temperature, etc., it is generally 1 hour to 72 hours, preferably 5 hours to 48 hours.

Step 1b is a step of separating 3 (S) -acetoxy derivative (IIa) from a mixture of 3 (S) -acetoxy derivative (IIa) and 3 (R) -hydroxy derivative (IIIb), which is an inert solvent. This is accomplished by reacting the mixture with succinic anhydride in the presence of a base and extracting the resulting reaction mixture in a basic aqueous solution with a water-immiscible organic solvent.
The reaction of the mixture with succinic anhydride is carried out in an inert solvent in the presence of a base.
The base used is not particularly limited as long as it is a base used for producing an ester derivative by reacting an alcohol derivative with a carboxylic acid anhydride. For example, pyridine, lutidine, N, N-dimethylamino is used. It may be an aromatic amine such as pyridine, or an aliphatic tertiary amine such as triethylamine or diisopropylmethylamine, preferably pyridine, lutidine, triethylamine or diisopropylmethylamine, and more preferably triethylamine.
The inert solvent used is not particularly limited as long as it dissolves the raw materials and reagents to some extent and is inert to the reaction. For example, aliphatic hydrocarbons such as hexane, heptane, cyclohexane, benzene, toluene, xylene, etc. Aromatic hydrocarbons, halogenated hydrocarbons such as carbon tetrachloride, chloroform, methylene chloride, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and esters such as ethyl acetate, propyl acetate, Preferred are aromatic hydrocarbons or ethers, more preferred are aromatic hydrocarbons, and most preferred is toluene.
While the reaction temperature varies depending on the type of base, solvent and the like, it is generally 0 ° C. to 100 ° C., preferably 20 ° C. to 60 ° C.
While the reaction time varies depending on the type of base, solvent, etc., reaction temperature, etc., it is generally 30 minutes to 10 hours, preferably 1 hour to 5 hours.
In the step of separating the 3 (S) -acetoxy derivative (IIa) from the reaction mixture of the mixture and succinic anhydride, the reaction mixture is poured into a basic aqueous solution (for example, an aqueous sodium bicarbonate solution) and immiscible with water. It is carried out by extraction with an organic solvent (for example, aromatic hydrocarbons, ethers, esters, etc.).
When the solvent used for the reaction of the mixture with succinic anhydride is a water-immiscible organic solvent (for example, aromatic hydrocarbons, ethers, esters, etc.), the reaction mixture is made basic. The 3 (S) -acetoxy derivative (IIa) is also separated by washing with an aqueous solution (for example, an aqueous sodium hydrogencarbonate solution).
That is, the reaction mixture is washed with an aqueous sodium hydrogen carbonate solution, dried if necessary, concentrated, added with an organic solvent as appropriate, cooled, and the precipitated crystals are collected by filtration to obtain a high (optical) purity of 3 The (S) -acetoxy derivative (IIa) is obtained.

The second step is a step of producing 3 (S) -acetoxy-4-oxo-β-ionone (IVa), which is carried out as desired, and the carbonyl protecting group of 3 (S) -acetoxy derivative (IIa) ( This is achieved by removing Q).
The reaction for removing the carbonyl protecting group (Q) is performed in an inert solvent in the presence of an acid.
The acid used is not particularly limited as long as it is an acid used for producing a ketone derivative by removing the carbonyl protecting group. For example, mineral acids such as nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc. Phosphoric acids, acetic acid, trifluoroacetic acid, propionic acid, benzoic acid, organic carboxylic acids such as p-methylbenzoic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Organic sulfonic acids, preferably weak acids, more preferably dilute nitric acid, dilute hydrochloric acid, dilute sulfuric acid, acetic acid, benzoic acid or p-methylbenzoic acid, and even more preferably dilute hydrochloric acid. is there.
The inert solvent used is not particularly limited as long as it dissolves the raw materials and reagents to some extent and is inert to the reaction. For example, aliphatic hydrocarbons such as hexane, heptane, cyclohexane, benzene, toluene, xylene, etc. Aromatic hydrocarbons, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, alcohols such as methanol, ethanol, isopropyl alcohol, water, mixed solvents of water and these organic solvents, etc. Is a mixed solvent of alcohols and water or a mixed solvent of alcohols, aromatic hydrocarbons and water, more preferably a mixed solvent of toluene, methanol and water.
The reaction temperature varies depending on the type of acid, solvent, etc., but is usually 0 ° C. to 100 ° C., preferably 10 ° C. to 40 ° C.
While the reaction time varies depending on the type of acid, solvent, etc., reaction temperature, etc., it is usually 30 minutes to 10 hours, preferably 1 hour to 4 hours.

Water is added to the reaction mixture, and the separated organic layer is washed with a basic aqueous solution (for example, aqueous sodium hydrogen carbonate solution), dried if desired, concentrated, and the solvent is distilled off to obtain a high (optical ) Purified 3 (S) -acetoxy-4-oxo-β-ionone (IVa) is obtained.
If desired, 3 (S) -acetoxy-4-oxo-β-ionone (IVa) having a high (optical) purity can also be obtained by adding an organic solvent as appropriate, cooling, and collecting the precipitated crystals by filtration. can get.

The third step is a step of producing 3 (S) -hydroxy-4-oxo-β-ionone (Va) and hydrolyzing 3 (S) -acetoxy-4-oxo-β-ionone (IVa). Is achieved.
The hydrolysis reaction is carried out in an inert solvent, in the presence of water, in the presence of a base or esterase (particularly esterase).
The esterase used can be, for example, an esterase derived from porcine liver or an esterase derived from E. coli, and preferably an esterase derived from E. coli.
The base used is not particularly limited as long as it is a base used when hydrolyzing a carboxylic acid derivative to produce an alcohol derivative. For example, an alkali such as lithium hydroxide, sodium hydroxide, or potassium hydroxide is used. It can be an alkali metal carbonate such as a metal hydroxide, sodium carbonate or potassium carbonate, an alkali metal bicarbonate such as sodium bicarbonate or potassium bicarbonate, preferably an alkali metal hydroxide, and more preferably Is sodium hydroxide.
The inert solvent used is not particularly limited as long as it dissolves the raw materials and reagents to some extent and is inert to the reaction. For example, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol, ethanol, and isopropyl alcohol, Water, a mixed solvent of water and these organic solvents, etc., preferably a mixed solvent of ketones and water or water, and more preferably a mixed solvent of acetone and water.
In addition, this reaction is suitably performed in a buffer solution (for example, a phosphate buffer) when esterase is used.
While the reaction temperature varies depending on the type of base, esterase, solvent and the like, it is generally 0 ° C. to 100 ° C., preferably 10 ° C. to 40 ° C.
While the reaction time varies depending on the type of base, esterase, solvent, etc., reaction temperature, etc., it is generally 10 minutes to 10 hours, preferably 30 minutes to 5 hours.
If desired, esterase is filtered off from the reaction mixture, extracted with a water-immiscible organic solvent, the extract is washed with a basic aqueous solution (for example, aqueous sodium hydrogen carbonate solution), dried, and the solvent is removed. By distilling off, 3 (S) -hydroxy-4-oxo-β-ionone (Va) with high (optical) purity is obtained.

The fourth step is a step of producing a 3 (S) -alkoxy-alkoxy-4-oxo-β-ionone derivative (VIIa), and 3 (S) -hydroxy-4 in the presence of an acid in an inert solvent. This is achieved by reacting -oxo-β-ionone (Va) with a vinyl alkyl ether derivative (VI).
The acid used is not particularly limited as long as it is an acid used to protect an alcohol derivative and produce an ether derivative. For example, mineral acids such as nitric acid, hydrochloric acid and sulfuric acid, and phosphoric acids such as phosphoric acid , Organic carboxylic acids such as trifluoroacetic acid, acetic acid, propionic acid, benzoic acid and p-methylbenzoic acid, organic sulfones such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid Acids or salts of these acids with pyridines such as pyridine and lutidine, preferably weak acids, and more preferably dilute nitric acid, dilute hydrochloric acid, dilute sulfuric acid, acetic acid, benzoic acid, p-methylbenzoate Salts of acid or organic sulfonic acids and pyridines such as pyridine and lutidine, and more preferably methanesulfonic acid, trifluoromethanes An acid, benzenesulfonic acid or p- toluenesulfonic acid and pyridine, most preferably a salt with pyridine and p- toluenesulfonic acid.
The inert solvent used is not particularly limited as long as it dissolves the raw materials and reagents to some extent and is inert to the reaction. For example, halogenated hydrocarbons such as carbon tetrachloride, chloroform, methylene chloride, hexane, heptane, etc. , Aliphatic hydrocarbons such as cyclohexane, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, and esters such as ethyl acetate and propyl acetate, Preferred are halogenated hydrocarbons, ethers or aromatic hydrocarbons, more preferred are aromatic hydrocarbons, and most preferred is toluene.
The reaction temperature varies depending on the type of acid, solvent and the like, but is usually −30 ° C. to 30 ° C., and preferably −15 ° C. to 15 ° C.
The reaction time varies depending on the type of acid, solvent, etc., the reaction temperature, etc., but is usually 5 minutes to 5 hours, and preferably 10 minutes to 2 hours.
The reaction mixture is washed with a basic aqueous solution (for example, aqueous sodium hydrogen carbonate solution), the separated organic layer is dried, and the solvent is distilled off to obtain a high (optical) purity 3 (S) -alkoxy-alkoxy. A 4-oxo-β-ionone derivative (VIIa) is obtained.

The fifth step is a step of producing an allyl alcohol derivative (IXa). In an inert solvent, 3 (S) -alkoxy-alkoxy-4-oxo-β-ionone derivative (VIIa) and Grignard reagent (VIII) are used. This is achieved by reacting.
The inert solvent used is not particularly limited as long as it dissolves the raw materials and reagents to some extent and is inert to the reaction. For example, halogenated hydrocarbons such as carbon tetrachloride, chloroform, methylene chloride, diethyl ether, Ethers such as tetrahydrofuran, dioxane, dimethoxyethane and the like, preferably ethers, and more preferably tetrahydrofuran.
The reaction temperature varies depending on the kind of Grignard reagent, solvent and the like, but is usually −100 ° C. to 0 ° C., and preferably −80 ° C. to −50 ° C.
The reaction time varies depending on the kind of Grignard reagent, solvent and the like, reaction temperature, etc., but is usually 10 minutes to 10 hours, preferably 30 minutes to 4 hours.
Water and an aqueous ammonium chloride solution are added to the reaction mixture, and the mixture is extracted with a water-immiscible organic solvent (for example, ethyl acetate), dried, and the solvent is distilled off to obtain an allyl alcohol derivative (IXa) of good purity. Is obtained. Further, the obtained allyl alcohol derivative (IXa) is directly used in the next step without further purification.

The sixth step is a step of producing the allyl halide derivative (Xa), and is achieved by reacting the allyl alcohol derivative (IXa) with a hydrogen halide in an inert solvent.
The hydrogen halide used can be, for example, hydrogen iodide, hydrogen bromide, hydrogen chloride or the like, and is preferably hydrogen bromide.
The inert solvent used is not particularly limited as long as it dissolves the raw materials and reagents to some extent and is inert to the reaction. For example, halogenated hydrocarbons such as carbon tetrachloride, chloroform, methylene chloride, hexane, heptane, Aliphatic hydrocarbons such as cyclohexane, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, water, mixed solvents of these organic solvents and water, etc. Preferably, it is a mixed solvent of halogenated hydrocarbons and water, more preferably a mixed solvent of methylene chloride and water.
In addition, when using a hydrous hydrogen halide (for example, hydroiodic acid, hydrobromic acid, hydrochloric acid, etc.) as the hydrogen halide, the inert solvent used is preferably a carbon halide. More preferred is methylene chloride.
While the reaction temperature varies depending on the type of hydrogen halide, solvent, etc., it is generally −80 ° C. to 10 ° C., preferably −30 ° C. to 0 ° C.
While the reaction time varies depending on the type of hydrogen halide, solvent, etc., reaction temperature, etc., it is usually 5 minutes to 5 hours, preferably 10 minutes to 2 hours.
If desired, water-containing (or salt-containing) methylene chloride is added to the reaction mixture, the separated organic layer is dried, and the solvent is distilled off in the presence of a weak base (eg, 1,2-epoxybutane). Thus, a crude allyl halide derivative (Xa) is obtained. Further, the obtained allyl halide derivative (Xa) is used as it is in the next step without further purification.

Step 7a is a step of producing a phosphonium salt derivative (XIa), and is achieved by reacting the allyl halide derivative (Xa) with triphenylphosphine in an inert solvent.
The inert solvent used is not particularly limited as long as it dissolves the raw materials and reagents to some extent and is inert to the reaction. For example, halogenated hydrocarbons such as carbon tetrachloride, chloroform, methylene chloride, diethyl ether, tetrahydrofuran , Ethers such as dioxane and dimethoxyethane, and esters such as ethyl acetate and propyl acetate, preferably esters, and more preferably ethyl acetate.
The reaction temperature varies depending on the type of allyl halide derivative, solvent and the like, but is usually −20 ° C. to 100 ° C., and preferably −10 ° C. to 50 ° C.
While the reaction time varies depending on the type of allyl halide derivative, solvent, etc., reaction temperature, etc., it is generally 30 minutes to 48 hours, preferably 5 hours to 36 hours.
Moreover, this reaction is suitably performed in the presence of 1,2-epoxybutane.

  Crystals precipitated from the reaction mixture are collected by filtration and dried to obtain a phosphonium salt derivative (XIa) with high (optical) purity.

Step 7b is a step of producing 3 (S), 3 ′ (S) -astaxanthin (I), and is preferably carried out in an inert solvent in the presence of a base, preferably in a nitrogen atmosphere in the presence of a phosphonium salt derivative (XIa ) Is reacted with a dialdehyde derivative (XII).
The base used is not particularly limited as long as it generates a phosphonium ylide derivative and is used for the Wittig reaction. For example, sodium methoxide, sodium ethoxide, sodium proxy, potassium t-butoxide, Alkali metal alkoxides such as sodium t-pentoxide, 1,2-epoxybutane and the like can be used, and 1,2-epoxybutane is preferable.
Inert solvents used are aliphatic hydrocarbons such as hexane, heptane and cyclohexane, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, methanol, Alcohols such as ethanol and isopropyl alcohol, and ketones such as acetone and methyl ethyl ketone may be used, preferably alcohols, and more preferably isopropyl alcohol.
While the reaction temperature varies depending on the type of base, solvent and the like, it is generally 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
While the reaction time varies depending on the type of base, solvent, etc., reaction temperature, etc., it is generally 30 minutes to 72 hours, preferably 10 hours to 48 hours.
Moreover, this reaction is suitably performed in the presence of an antioxidant substance (for example, 2,6-di-t-butyl-p-cresol, tocopherol, etc.).

  The reaction mixture is cooled to about 0 ° C., and the precipitated crystals are collected by filtration to obtain high (optical) purity 3 (S), 3 ′ (S) -astaxanthin (I).

  After completion of each reaction, the target compound is collected from the reaction mixture by a conventional method. For example, the reaction mixture is poured into water, and if there is insoluble matter, it is filtered off as appropriate, and if it is acidic or alkaline, it is neutralized as appropriate, and a water-immiscible organic solvent (for example, The target compound is collected by extraction with ether, ethyl acetate, and the like, followed by drying and evaporation of the organic solvent. Furthermore, if necessary, the target compound is further purified by a conventional method (for example, distillation method, recrystallization method, column chromatography, preparative high-speed chromatography, etc.).

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these.

2- [2- (4 (S) -Acetoxy-3-oxo-2,6,6-trimethyl-1-cyclohexenyl) vinyl] -2-methyldioxolane (1) 2- [2- (4 (S) -Acetoxy-3-oxo-2,6,6-trimethyl-1-cyclohexenyl) vinyl] -2-methyldioxolane and 2- [2- (4 (R) -hydroxy-3-oxo-2,6,6) -Trimethyl-1-cyclohexenyl) vinyl] -2-methyldioxolane mixture 2- [2- (4 (RS) -acetoxy-3-oxo-2,6,6-trimethyl-1-cyclohexenyl) vinyl]- A solution of 2-methyldioxolane (racemate, 30.0 g, 97.3 mmol) in toluene (195 mL) was added to a lipase (LAY400-AF, Amano Enzyme, 3.0 g) sodium phosphate buffer. It was added to a solution (0.2M, pH 7.0,600mL), the reaction mixture was stirred for 24 hours at 37 ° C.. Ethyl acetate (210 mL) and ammonium sulfate (86 g) were added to the reaction mixture and stirred, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (150 mL), and the organic layer and the extract were combined. The obtained solution was concentrated under reduced pressure, methanol (300 mL) and a filter aid (Celpure S1000, 3 g) were added to the obtained concentrated residue, and the mixture was stirred and then filtered. The filtrate was concentrated under reduced pressure, and a mixed solution of ethyl acetate (90 mL) and hexane (10 mL) and aqueous sodium hydrogen carbonate solution (7%, 90 mL) were added to the concentrated residue, and the phases were separated, and the organic layer was separated. did. The obtained organic layer was washed with 10% brine and concentrated under reduced pressure to obtain the title mixture (28.0 g).
(2) 2- [2- (4 (S) -Acetoxy-3-oxo-2,6,6-trimethyl-1-cyclohexenyl) vinyl] -2-methyldioxolane Mixture (28) of Example 1 (1) 0.0 g) was added toluene (90 ml), triethylamine (7.88 g, 77.8 mmol) and succinic anhydride (7.79 g, 77.8 mmol) and the reaction mixture was stirred at 50 ° C. for 3 hours. The reaction mixture was washed twice with aqueous sodium bicarbonate (7%, 90 mL), then once with brine (10%, 90 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diisopropyl ether (7.5 mL) was added to the concentrated residue and dissolved. The resulting solution was cooled using a methanol / ice cooling bath, and after confirming the precipitation of crystals, diisopropyl ether (7.5 mL) and hexane (30 mL) were added, and the mixture was allowed to stand at room temperature for 1 hour. The precipitated crystals were collected by filtration to give the title compound (8.84 g, yield from the racemate 29.4%, purity 99.6%, optical purity 99.8% ee) as white crystals. The purity and optical purity of the product were determined using high performance liquid chromatography (column: CHIRAL-Pack IC manufactured by DAICEL and mobile phase: hexane / ethanol = 80/20).
Melting point: 48.3 ° C-49.1 ° C
IR spectrum (KBr, cm- ¹ ): 1742, 1693.
NMR spectrum (δ ppm, CDCl ₃ ): 6.33 (1H, d, J = 16.0 Hz), 5.60 (1H, d, J = 16.0 Hz), 5.51 (1H, dd, J = 6) .0Hz, 12.8Hz) 4.01-4.05 (2H, m), 3.90-3.93 (2H, m), 2.18 (3H, s), 1.99-2.09 (2H, m), 1.81 (3H, s), 1.53 (3H, s), 1.32 (3H, s), 1.16 (3H, s).
Mass spectrum (+ ESI, m / z): 309.17 (M + H) ⁺ .

4 (S) -Acetoxy-3-oxo-1- (3-oxo-1-butenyl) -2,6,6-trimethyl-1-cyclohexene- (3 (S) -acetoxy-4-oxo-β-ionone )
(1) 4 (S) -Acetoxy-3-oxo-1- (3-oxo-1-butenyl) -2,6,6-trimethyl-1-cyclohexene Compound of Example 1 (2) (50.0 g) To a toluene (250 mL) solution was added methanol (250 mL) and hydrochloric acid (1N, 101 g) and the reaction mixture was stirred at 20-30 ° C. for 2 h. To the reaction mixture, water (250 mL) was added and stirred, and the organic layer was separated. The aqueous layer was extracted with toluene (100 mL), and the organic layer and the extract were combined. The resulting solution was washed successively with aqueous sodium hydrogen carbonate solution (7%, 100 mL), water (100 mL) and 10% brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diisopropyl ether (50 mL) was added to the resulting concentrated residue to dissolve and stir. The precipitated crystals were collected by filtration to give the title compound (36.2 g, yield 84.5%, purity 97.8%, optical purity 99.0% ee) as pale yellowish white crystals. The purity and optical purity of the product were determined using high performance liquid chromatography (column: CHIRAL-Pack IC manufactured by DAICEL and mobile phase: hexane / ethanol = 75/25).
Melting point: 69.1 ° C-70.1 ° C
IR spectrum (KBr, cm ⁻¹ ): 1747, 1677.
NMR spectrum (δ ppm, CDCl ₃ ): 7.21 (1H, d, J = 16.8 Hz), 6.22 (1H, d, J = 16.8 Hz), 5.54 (1H, dd, J = 6) .0Hz, 13.6Hz), 2.36 (3H, s), 2.20 (3H, s), 2.11 (1H, dd, J = 12.6Hz, 13.6Hz), 2.05 (1H , Dd, J = 6.0 Hz, 12.4 Hz), 1.84 (3H, s), 1.37 (3H, s), 1.19 (3H, s).
Mass spectrum (+ ESI, m / z): 265.00 (M + H) ⁺ .
(2) 4 (S) -acetoxy-3-oxo-1- (3-oxo-1-butenyl) -2,6,6-trimethyl-1-cyclohexene Compound of Example 1 (2) (15.0 kg) Methanol (72 kg) and hydrochloric acid (1N, 30 kg) were added to a toluene (78 kg) solution, and the reaction mixture was stirred at 20-30 ° C. for 2 hours. Water (90 kg) was added to the reaction mixture and stirred, and the organic layer was separated. The aqueous layer was extracted with toluene (26 kg), and the organic layer and the extract were combined. The resulting solution was washed successively with aqueous sodium hydrogen carbonate solution (7%, 32.3 kg), water (30 kg) and 10% brine (33.3 kg), and concentrated under reduced pressure. Acetone solution was obtained by dissolving acetone (36 kg) in the obtained title compound (concentrated residue, 12.9 kg, purity 98.4%, optical purity 99.1% ee). This solution was used in the next step. The purity and optical purity of the product were determined using high performance liquid chromatography (column: CHIRAL-Pack IC manufactured by DAICEL and mobile phase: hexane / ethanol = 75/25).

4 (S) -Hydroxy-3-oxo-1- (3-oxo-1-butenyl) -2,6,6-trimethyl-1-cyclohexene- (3 (S) -hydroxy-4-oxo-β-ionone )
To a solution of the compound of Example 2 (2) (12.9 kg) in acetone (36 kg), an aqueous solution of sodium phosphate buffer (0.25 M, pH 7.0, 269 kg) and esterase (E-2, manufactured by Amano Enzyme, 0 .60 kg) was added and the reaction mixture was stirred at 20-30 ° C. for 1 hour. A filter aid (Celpure S1000, 1.3 kg) was added to the reaction mixture, and the mixture was stirred and then filtered. The filtrate was extracted three times with ethyl acetate (58 kg). The extracts were combined, washed successively with aqueous sodium bicarbonate (7%, 42 kg) and 15% brine (45.8 kg), and dried over anhydrous magnesium sulfate. And concentrated under reduced pressure. Toluene (47 kg) was added to the obtained title compound (concentrated residue, 4.01 kg, purity 96.3%, optical purity 99.7% ee) to obtain a toluene solution. This solution was used in the next step. The purity and optical purity of the product were determined using high performance liquid chromatography (column: CHIRAL-Pack IC manufactured by DAICEL and mobile phase: hexane / ethanol = 70/30).
Further, a very small amount of the title compound (concentrated residue) was taken, and the spectrum was measured as a sample without further purification, and the following IR spectrum, NMR spectrum and mass spectrum were obtained.
IR spectrum (liquid, cm ⁻¹ ): 3480, 1676.
NMR spectrum (δ ppm, CDCl ₃ ): 7.21 (1H, d, J = 16.4 Hz), 6.22 (1H, d, J = 16.4 Hz), 4.37 (1H, ddd, J = 1) .6 Hz, 6.0 Hz, 14.0 Hz), 3.61 (1 H, d, J = 2.0 Hz), 2.36 (3 H, s), 2.20 (1 H, dd, J = 6.0 Hz, 13.2 Hz) 1.87 (3H, s), 1.82-1.89 (1H, m), 1.35 (3H, s), 1.17 (3H, s).
Mass spectrum (+ ESI, m / z): 223.17 (M + H) ⁺ .

4 (S)-(2-methoxypropan-2-yloxy) -3-oxo-1- (3-oxo-1-butenyl) -2,6,6-trimethyl-1-cyclohexene- (3 (S)- (2-Methoxypropan-2-yloxy) -4-oxo-β-ionone)
A toluene (47 kg) solution of the compound of Example 3 (4.01 kg) was cooled to −5 to 5 ° C., pyridinium p-toluenesulfonic acid (2.30 g) was added, and 2-methoxypropene was stirred. (3.90 kg) was added dropwise at −5 to 5 ° C., and the reaction mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, an aqueous sodium hydrogen carbonate solution (7%, 12.9 kg) was added at −5 to 10 ° C., stirred, the organic layer was separated, and the obtained organic layer was dried over anhydrous sodium carbonate and reduced in pressure. Concentration gave the title compound (concentrated residue, 4.42 kg, purity 94.1%, optical purity 99.4% ee). This compound was used in the next step. The purity and optical purity of the product were determined using high performance liquid chromatography (column: CHIRAL-Pack IC manufactured by DAICEL and mobile phase: hexane / ethanol = 95/5).
Further, a very small amount of the title compound (concentrated residue) was taken, and the spectrum was measured as a sample without further purification, and the following IR spectrum, NMR spectrum and mass spectrum were obtained.
IR spectrum (liquid, cm ⁻¹ ): 1691.
NMR spectrum (δ ppm, CDCl ₃ ): 7.21 (1H, d, J = 16.4 Hz), 6.21 (1H, d, J = 16.4 Hz), 4.49 (1H, dd, J = 6) .0Hz, 12.8Hz), 3.32 (3H, s), 2.35 (3H, s), 1.95-2.06 (2H, m), 1.83 (3H, s), 1. 43 (3H, s) 1.41 (3H, s), 1.35 (3H, s), 1.17 (3H, s).
Mass spectrum (+ ESI, m / z): 295.00 (M + H) ⁺ .

1- (3-hydroxy-3-methyl-1,4-pentadienyl) -4 (S)-(2-methoxypropan-2-yloxy) -3-oxo-2,6,6-trimethyl-1-cyclohexene To a solution of the compound of Example 4 (4.42 kg) in tetrahydrofuran (118 kg) at −75 to −55 ° C. was added dropwise a solution of vinylmagnesium chloride in tetrahydrofuran (1.55 mol / kg, 19.4 kg), and the reaction mixture was The mixture was stirred at −75 to −60 ° C. for 2 hours. To the reaction mixture was added aqueous ammonium chloride solution (20%, 4.4 kg) at -75 to -65 ° C, the reaction mixture was stirred at the same temperature for 30 minutes, and then warmed to an internal temperature of 0 to 30 ° C. Water (124 kg) and aqueous ammonium chloride solution (20%, 4.4 kg) were sequentially added to the reaction mixture to dissolve inorganic substances, ethyl acetate (20 kg) was added, the reaction mixture was stirred, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate (20 kg), the organic layer and the extract were combined, and the solution was washed successively with aqueous ammonium chloride (20%, 22 kg) and 10% brine (22 kg), and anhydrous. The extract was dried over magnesium sulfate and concentrated under reduced pressure to obtain the title compound (concentrated residue, 4.84 kg, purity 69.3%). This compound was directly used in the next step. The purity of the product was determined using high performance liquid chromatography (column: YMC-PAC ODS-A manufactured by YMC and mobile phase: acetonitrile / water = 55/45).
Further, a very small amount of the title compound (concentrated residue) was taken, and the spectrum was measured as a sample without further purification, and the following IR spectrum, NMR spectrum and mass spectrum were obtained.
IR spectrum (liquid, cm ⁻¹ ): 3464, 1682.
NMR spectrum (δ ppm, CDCl ₃ ): 6.24 (1H, d, J = 15.6 Hz), 6.00 (1H, dd, J = 10.6 Hz, 17.2 Hz), 5.74 (1H, d , J = 17.2 Hz), 5.29 (1H, d, J = 17.2 Hz), 5.13 (1H, d, J = 10.4 Hz), 4.46 (1H, dd, J = 6. 0Hz, 12.8Hz), 3.33 (3H, s), 1.91-1.98 (2H, m), 1.81 (3H, s), 1.45 (3H, s) 1.43 ( 3H, s), 1.42 (3H, s), 1.29 (3H, s), 1.13 (3H, s).
Mass spectrum (+ ESI, m / z): 345.25 (M + Na) ⁺ .

1- (5-Bromo-3-methyl-1,4-pentadienyl) -4 (S) -hydroxy-3-oxo-2,6,6-trimethyl-1-cyclohexene Compound of Example 5 (4.84 kg) To a methylene chloride (90 kg) solution of hydrobromic acid (49%, 7.44 kg) was added dropwise at −21 to −11 ° C., and the reaction mixture was stirred at the same temperature for 30 minutes. Methylene chloride (90 kg) and 20% brine (95 kg) were added to the reaction mixture at −5 to 5 ° C., and the mixture was stirred and the organic layer was separated. The obtained organic layer was washed twice at -5 to 5 ° C with 20% brine (95 kg), and added to a suspension of anhydrous magnesium sulfate (1.5 kg) and ethyl acetate (27 kg). Added at ~ 5 ° C and dried. Solids were filtered off, 1,2-epoxybutane (130 kg) was added to the dried organic layer, and the solution was concentrated under reduced pressure until the internal volume was about 50 L. Further, ethyl acetate (44 kg) was added to the obtained concentrated solution, and the solution was concentrated under reduced pressure until the internal volume became about 50 L, to obtain a concentrated solution of the title compound. This concentrated solution was directly used in the next step.

3 (S), 3 ′ (S) -Astaxanthin (1) 5- [4 (S) -Hydroxy-3-oxo-2,6,6-trimethyl-1-cyclohexenyl] -3-methyl-2,4 -Pentadienyl triphenyl phosphonium bromide The concentrated solution of Example 6 was added dropwise to a solution of triphenylphosphine (11.8 kg) and 1,2-epoxybutane (130 g) in ethyl acetate (44 kg) at 0 to 30 ° C. to react. The mixture was stirred at the same temperature for 24 hours. The precipitated solid was collected by filtration, and the wet crystals were dissolved in methylene chloride (39 kg). The obtained solution was added dropwise to ethyl acetate (305 kg) while stirring to confirm solid precipitation. The precipitated solid was collected by filtration and dried in vacuo to give the title compound (3.95 kg, purity 87.5% (trans isomer), 5.8% (cis isomer)) as a white solid. The purity of the product was determined by high performance liquid chromatography (column: YMC-PAC ODS-A manufactured by YMC and mobile phase: acetonitrile containing 0.1% trifluoroacetic acid / 0.1% trifluoroacetic acid water = 5-95 / 45-5).
Melting point: 165.7 ° C.-166.4 ° C.
IR spectrum (KBr, cm ⁻¹ ): 3295, 1686, 1665.
NMR spectrum (δ ppm, DMSO-d ₆ ): 7.93-7.78 (15H, m), 6.31 (1H, d, J = 16.8 Hz), 6.13 (1H, d, J = 14) .8 Hz), 5.64 (1H, dd, J = 7.6 Hz, 15.2 Hz), 5.08 (1H, d, J = 4.4 Hz), 4.68 (2H, dd, J = 8. 0 Hz, 16.8 Hz), 4.18 (1H, td, J = 4.8 Hz, 13.6 Hz), 1.94 (1H, dd, J = 5.2 Hz, 12.8 Hz) 1.70 (3H, s), 1.67 (1H, t, J = 12.8 Hz), 1.45 (3H, d, J = 3.6 Hz), 1.21 (3H, s), 1.05 (3H, s) .
Mass spectrum (+ ESI, m / z): 495.46 (M) ⁺ .
(2) 3 (S), 3 ′ (S) -Astaxanthin 2,7-dimethylocta-2,4,6-triene-1,8-dialdehyde (0.484 kg), compound of Example 7 (1) (3.90 kg), 2,6-di-t-butyl-p-cresol (32.5 g) and 1,2-epoxybutane (1.9 kg) were suspended in 2-propanol (15 kg) and suspended. The solution was heated to reflux for 30 hours under a nitrogen atmosphere. The reaction mixture was cooled to −5 to 5 ° C., stirred for 1 hour, and the precipitated solid was collected by filtration to give the title compound (1.53 kg, yield 86.9%, purity 98.8%, optical purity 97. 9% ee) was obtained as a dark purple solid. The purity of the product was determined by high performance liquid chromatography (column: Trial C18 ExRS Plus manufactured by YMC and mobile phase: acetonitrile containing 0.025% trifluoroacetic acid / 0.025% aqueous trifluoroacetic acid = 30 to 98/70 to 2).
The optical purity of the product was determined using high performance liquid chromatography (column: YMC CHIRAL Cellulose-SB manufactured by YMC and mobile phase: hexane / tetrahydrofuran = 85/15).
Melting point: 213.2 ° C.-217.4 ° C.
IR spectrum (KBr, cm ⁻¹ ): 3482, 2920, 1651.
NMR spectrum (δ ppm, CDCl ₃ ): 6.20-6.69 (14H, m), 4.33 (2H, ddd, J = 2.0 Hz, J = 5.6 Hz, J = 14.0 Hz), 3 .69 (2H, d, J = 2.0 Hz), 2.16 (2H, dd, J = 5.2 Hz, J = 12.8 Hz), 2.00 (6H, s), 1.99 (6H, s) 1.95 (6H, s), 1.81 (2H, t, J = 12.8 Hz), 1.32 (6H, s), 1.21 (6H, s).
Mass spectrum (+ ESI, m / z): 597.25 (M + H) ⁺ .

The production method of the present invention uses optically active 3 (S), 3 ′ (S) -astaxanthin, which is used as an active ingredient in supplements and pharmaceuticals, at low cost and easily from raw materials and reaction reagents. Since this method is (optical) pure and can be produced in large quantities, it can be used in the food and pharmaceutical industries.

Claims (8)

3 (S), 3 ′ (S) -astaxatin (I):

A method of manufacturing
formula:

(In the formula, Ac represents an acetyl group, and Q, together with the carbon atom to which it is bonded, forms an optionally protected carbonyl group.)
A racemic 3 (RS) -acetoxy-4-oxo-β-ionone derivative (IIab) having the formula:

(In the formula, Ac and Q are as defined above.)
A mixture of 3 (S) -acetoxy-4-oxo-β-ionone derivative (IIa) and 3 (R) -hydroxy-4-oxo-β-ionone derivative (IIIb) having the following structure: Reaction with succinic anhydride in the presence of a base, and a suspension of the resulting reaction mixture and a basic aqueous solution is extracted with a water-immiscible organic solvent to remove the monosuccinic acid ester derivative of compound (IIIb), The protecting group of the carbonyl group of the resulting compound (IIa) is optionally removed to give a compound of formula:

(In the formula, Ac is as defined above.)
3 (S) -acetoxy-4-oxo-β-ionone having the following structure is obtained and the resulting compound (IVa) is hydrolyzed to give the formula:

3 (S) -Hydroxy-4-oxo-β-ionone having the following formula (Va) in the presence of acid:

(In the formula, R ¹ and R ² are the same or different and represent a C ₁ -C ₆ alkyl group.)
Is reacted with a vinyl alkyl ether derivative having the formula:

(In the formula, R ¹ and R ² are as defined above.)
A 3 (S) -alkoxy-alkoxy-4-oxo-β-ionone derivative having the following structure is obtained, and the resulting compound (VIIa) is represented by the formula:

(In the formula, X represents a halogen atom.)
Is reacted with a Grignard reagent having the formula:

(In the formula, R ¹ and R ² are as defined above.)
And the resulting compound (IXa) is reacted with a hydrogen halide to produce a compound having the formula:

(In the formula, Y represents a halogen atom.)
And the resulting compound (Xa) is reacted with triphenylphosphine to give the formula:

(In the formula, Ph represents a phenyl group, and Y has the same meaning as described above.)
A phosphonium salt derivative having the following formula (XIa) is prepared in the presence of a base:

The manufacturing method including the process made to react with the dialdehyde derivative which has this.   The production method according to claim 1, wherein the lipase used in the reaction with the compound (IIab) is a lipase derived from Candida sp.   The production method according to claim 1 or 2, wherein the hydrolysis of compound (IVa) is carried out in the presence of an esterase selected from an esterase derived from pig liver and an esterase derived from E. coli.   The production method according to claim 1, wherein the acid used in the reaction of compound (Va) and compound (VI) is pyridinium p-toluenesulfonic acid.   The production method according to claim 1, wherein the base used in the reaction of compound (XIa) and compound (XII) is 1,2-epoxybutane. 3 (S), 3 ′ (S) -astaxatin (I):

A method of manufacturing
formula:

(In the formula, R ¹ and R ² are the same or different and represent a C ₁ -C ₆ alkyl group.)
An allyl alcohol derivative (IXa) having the formula:

(In the formula, Y represents a halogen atom.)
And the resulting compound (Xa) is reacted with triphenylphosphine to give the formula:

(In the formula, Ph represents a phenyl group, and Y has the same meaning as described above.)
A phosphonium salt derivative having the following formula (XIa) is prepared in the presence of a base:

The manufacturing method including the process made to react with the dialdehyde derivative which has this. formula:

(In the formula, R ¹ and R ² are the same or different and represent a C ₁ -C ₆ alkyl group.)
(S) -alkoxy-alkoxy-4-oxo-β-ionone derivatives having formula:

(In the formula, R ¹ and R ² are the same or different and represent a C ₁ -C ₆ alkyl group.)
An allyl alcohol derivative having