KR100402049B1 - Method for preparing chiral ester - Google Patents

Abstract

The present invention selectively selects a ketone, a ruthenium complex of Formulas 1 to 3 which promotes a reaction of reducing the ketone to racemic alcohol and a racemization reaction of the racemic alcohol, and an enantiomer of one of the racemic alcohols. It provides a lipase to be acylated, a hydride donor for supplying a hydride to the ruthenium complex, and an acyl donor for supplying an acyl group to the lipase, and a method for producing a chiral ester. According to the present invention, chiral esters having excellent optical purity characteristics can be obtained in a high synthetic yield through a one-step reaction from ketones.

In the above formula, Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y ₅ , Y ₆ , Y ₇ , Y ₈ , Y ₉ , Y ₁₀ , Y ₁₁ , Y ₁₂ represent a single bond irrespective of each other, Hydrogen or an alkyl group having 1 to 5 carbon atoms, X is Br, Cl or I,

In the above formula, Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y ₅ , Y ₆ , Y ₇ , Y ₈ , Y ₉ , Y ₁₀ , Y ₁₁ , Y ₁₂ represent a single bond irrespective of each other, Hydrogen or an alkyl group having 1 to 5 carbon atoms, and X is Br, Cl or I.

Description

Method for preparing chiral ester

The present invention relates to a method for preparing chiral esters, and more particularly, to a method for preparing chiral esters from ketones using enzymes and metal catalysts.

The problem of stereoselectively synthesizing a compound having excellent optical purity is one of the most important fields in organic synthesis. In particular, research on asymmetric synthesis using metal catalysis and enzyme catalyst has been actively conducted.

Today, kinetic optical separation of racemic substrates using enzyme catalysts is fundamentally used in organic synthesis. In particular, various and efficient methods for hydrolysis of esters under lipase-catalysts and acylation reactions of alcohols are well known.

Kinetic optical splitting reactions are generally defined as reactions in which two enantiomers of a racemic mixture change into products at different rates. Thus, in this optical splitting process, one of the enantiomers of the racemic mixture is selectively converted to the product and the remaining enantiomers remain, as in Scheme 1 below.

On the other hand, as a method of obtaining a chiral ester from a ketone, a method of converting a ketone to an enol ester, and then reducing the ketone through an asymmetric hydrogenation reaction, and reducing the ketone through an asymmetric hydrogenation reaction to convert it into a chiral alcohol Next, there is a method of esterification. As described above, the conventional methods are all long and complex because the enol ester can be obtained from the ketone only through at least two reaction steps.

The technical problem to be achieved by the present invention is to solve the above problems and to provide a method for producing a chiral ester excellent in optical purity and synthesis yield while simplifying the manufacturing process.

In the present invention, to achieve the above technical problem,

A metal complex for promoting a reaction of reducing the ketone to racemic alcohol and a racemization reaction of the racemic alcohol, preferably a ruthenium complex, more preferably a ruthenium complex of Formulas 1 to 3,

Lipases for selectively acylating one enantiomer of the racemic alcohol,

A hydride donor for supplying a hydride to the ruthenium complex,

It provides a method for producing a chiral ester, characterized in that for mixing and reacting the acyl donor for supplying an acyl group to the lipase.

[Formula 1]

In the above formula, Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y ₅ , Y ₆ , Y ₇ , Y ₈ , Y ₉ , Y ₁₀ , Y ₁₁ , Y ₁₂ represent a single bond irrespective of each other, Hydrogen or an alkyl group having 1 to 5 carbon atoms

X is Br, Cl or I,

[Formula 2]

In the above formula, Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y ₅ , Y ₆ , Y ₇ , Y ₈ , Y ₉ , Y ₁₀ , Y ₁₁ , Y ₁₂ represent a single bond irrespective of each other, Hydrogen or an alkyl group having 1 to 5 carbon atoms

X is Br, Cl or I.

[Formula 3]

The ruthenium complex is more preferably selected from the compounds represented by the following formula (5-10). In particular, in the following Formula 5-10, X is Cl, Br or I, most preferably Cl.

Looking at the method for producing a chiral ester of Formula 100 from the ketone of Formula 4 through a one-step reaction of the present invention.

First, ruthenium complexes of Formulas 1 to 3, lipases, hydride donors, acyl group donors, and ketones are mixed and then reacted by adding an appropriate solvent and base thereto (Scheme 2). The reaction conditions depend on the structure of the ruthenium complex used. That is, when using a ruthenium complex (X = Cl) of the formula (5) is the reaction temperature is 40 to 50 ℃, when using a ruthenium complex (X = Cl) of the formula (8) is 40 to 50 ℃, When using the ruthenium complex of formula (3), the reaction temperature is 70 to 80 ℃. In particular, the ruthenium complexes of formula (5) are readily available commercially and are converted to the ruthenium complexes of formula (8) under alcohol / amine basic conditions, thus substantially the synthesis obtained when using the ruthenium complexes of formula (5) and when the ruthenium complexes of formula (8) are used. The result is almost the same. And the content of the ruthenium complex is preferably 0.1 to 5 mol% based on the ketone. If the content of the ruthenium complex is more than 5 mol%, the manufacturing cost rises and if the content is less than 0.1 mol%, the reaction is slow and not preferable.

Wherein R ₁ , R ₂ and R ₃ are each independently selected from the group consisting of an unsubstituted or substituted alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted cycloalkyl group, and Therefore, R ₁ and R ₂ , R ₁ and R ₃ , R ₂ and R ₃ may be connected to each other. Here, as the functional group substitutable for an alkyl group, an aryl group and a cycloalkyl group, a hetero atom such as a halogen element, a cyan (CN) group, or the like is possible.

In this reaction, the ruthenium complex serves as a catalyst for the hydrogen transfer reaction to promote the reaction of reducing the starting material ketone to racemic alcohol. In addition, the racemization reaction of the obtained racemic alcohol is promoted.

The lipase is a hydrolase of an ester, and selectively acylates one enantiomer of racemic alcohol to produce a chiral ester having excellent optical purity characteristics. Specific examples of such lipases are selected from candida antarctica lipase and Pseudomonas cepacias lipase, and preferably candida antarctica lipase candida antarctica component. B lipase supported on acrylic resin (trade name: Novozym 435) (Novo), Pseudomonas cepacias lipase supported on ceramic particle (trade name: Lipase PS-C) (Amano) Among them, Candida anthartica component B lipase supported on acrylic resin is most preferred in terms of properties such as heat resistance, reactivity and optical purity. And the content of lipase is 10 to 60mg, preferably 30mg per 1mmol ketone in the case of novozyme, 40 to 240mg, preferably 80mg per 1mmol ketone for lipase PS-C.

The ketone is generally represented by the general formula (4), and the structure thereof is not particularly limited, but in the present invention, a compound of the following general formula (4a-g) is used.

Wherein R ₁ , R ₂ , R ₃ are as defined in Scheme 2 above.

The acyl donor serves to supply an acyl group to the lipase to shift the equilibrium in the acyl transfer reaction under the lipase catalyst to the acylated product. As such acyl donors, aryl esters or alkenyl acetates are preferred, in particular aryl esters having an electron withdrawing group, for example p-chlorophenyl acetate. And an example of alkenyl acetate is isopropenyl acetate. Such compounds are preferred as acyl donors because they have adequate reactivity and do not interfere with the racemization reaction. And the content of acyl donor is preferably 2 to 4 equivalents based on 1 equivalent of ketone. Here, if the content of acyl donor exceeds 4 equivalents, there is a problem in separation after the reaction, and if less than 2 equivalents, the acylation reaction rate decreases, which is not preferable.

The hydride donor of the present invention serves to supply hydra groups to the lutetium complex. Specific examples of hydride donors include 2,6-dimethylheptan-4-ol, hydrogen, formic acid, and the like. The content of this hydride donor is preferably 1 to 2 equivalents based on ketone. Here, when the content of the hydride donor is outside the above range, it is not preferable because it interferes with the racemization reaction.

In the chiral ester production reaction, the base reacts with the acid generated during the reaction to remove the acid, and specific examples thereof include an amine base triethylamine, diisopropylethyl amine, and the like. At this time, the content of the base is preferably 1 to 2 equivalents based on the ketone.

The solvent of the present invention is not particularly limited. However, it is preferable to use methylene chloride, benzene, toluene, hexane and the like because an enzyme catalysis such as lipase is usually influenced by a solvent in terms of synthesis yield and stereoselectivity of the product. And the content of the solvent is adjusted to the solution of the substance to be dissolved in the concentration range of 0.2-0.3M.

When the reaction of the ruthenium complex, the lipase, the hydride donor, the acyl group donor, and the ketone described above is completed, a chiral ester may be obtained through a work-up process.

As described above, the chiral ester compound prepared according to the present invention is prepared in the following structure.

R ₁ , R ₂ and R ₃ in Formula 100 are each independently selected from the group consisting of an unsubstituted or substituted alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted cycloalkyl group, and Therefore, R ₁ and R ₂ , R ₁ and R ₃ , R ₂ and R ₃ may be connected to each other.

The chiral ester of Formula 100 according to the present invention can be used as a raw material for the synthesis of chiral drugs, chiral pesticides, and other chiral new substances. Specifically, for example, atorvastatin of Formula 101 used as a drug for treating hyperlipidemia ( Atorvastatin), L-Carnitine of Formula 102 used as a functional additive in foods or pharmaceuticals, and Agenerase of Formula 103 used as a drug for treating AIDS. Can be used.

Among the compounds for the above-mentioned use, for example, in the case of the compound of the general formula (101), which has recently attracted much attention as a high value-added product as a raw material of atorvastatin, a chiral compound represented by the following general formula (100a) among chiral esters according to the present invention is used as a raw material. For example, it may be prepared by a method known in US Pat. No. 5,908,953.

In the formula, R means a lower alkyl group.

In particular, the chiral ester of the formula (100) prepared according to the present invention is 100% less than the synthesis of by-products, such as unreacted alcohol, compared to the conventional production process, and preferably the maximum yield so as not to produce at all synthetic yield 100 The optical purity is up to 99% while maximizing up to 100%. Therefore, the production yield is greatly improved by minimizing the by-products above all. Since the purity of the final product can be greatly improved, it can be preferably used as a raw material for preparing a wide range of compounds for producing chiral derivatives in the field of fine chemicals where purity is very important, especially in the food and pharmaceutical manufacturing fields.

Hereinafter, the present invention will be described with reference to the following examples, but the present invention is not limited only to the following examples.

Example 1

Ketone of formula 4a (0.25 mmol), triethylamine (0.25 mmol), ruthenium complex of formula 5 (X = Cl) (0.0130 mmol), 2,6-dimethylheptan-4-ol (0.38 mmol) and lipase PS- 20 mg of C (Amano) was mixed in 1.2 ml of dichloromethane and stirred at room temperature for 5 minutes. Subsequently, p-chlorophenyl acetate (0.75 mmol) is added to the reaction mixture to give a dark purple suspension.

Oxygen was removed from the suspension under vacuum conditions and then the reaction vessel was purged with argon. Thereafter, the reaction mixture was heated at 50 ° C. for 78 hours.

Example 2-5

The same procedure as in Example 1 was carried out except that the ketones of formulas 4b to 4e were used instead of the ketones of formula 4a.

Example 6

The ruthenium complex (X = Cl) was used instead of the ruthenium complex (X = Cl), except that ruthenium complex (X = Cl) was used in the same manner as in Example 1.

Example 7-10

Except for using the ketone of the formula 4b-4e instead of the ketone of the formula (4a) was carried out in the same manner as in Example 6.

Example 11

Ketone of formula 4a (0.25 mmol), ruthenium complex of formula 3 (0.050 mmol), 2,6-dimethylheptan-4-ol (0.38 mmol), novozyme 435 (Novo) (7.5 mg), p-chlorophenyl Acetate (0.75 mmol) was mixed with 0.8 mL of toluene to prepare a yellowish suspension.

Oxygen was removed from the suspension under vacuum conditions and then argon was purged in the reaction vessel. The reaction mixture was then heated at 70 ° C. for 44 h.

Example 12-17

The same procedure as in Example 11 was carried out except that the ketones of formulas 4b to 4g were used instead of the ketones of formula 4a.

In preparing the chiral esters according to Examples 1-5 and 11-17, the synthetic yield of the by-product alcohol, the synthetic yield of the chiral acetate, and the optical purity were measured and shown in Table 1 below. Herein, the synthetic yields of alcohol and chiral acetate were analyzed using gas chromatography, and optical purity was analyzed using chiral high performance liquid chromatography (HPLC). The GC used for analysis is Hewlett Packard 5890 Series II and HPLC is SpectraSystem P2000.

As can be seen from Table 1, according to Examples 1-5 and 11-17, a ruthenium complex for simultaneously carrying out a hydrogen transfer reaction and a racemization reaction and a lipase for carrying out an esterification reaction of an alcohol from the ketone are appropriately combined. Chiral esters could be prepared in a one-step reaction, and the optical purity of the chiral esters thus obtained was excellent. In addition, the content of unreacted alcohol was 5% or less, it was confirmed that the excellent yield of the chiral ester.

According to the present invention, a chiral ester having excellent optical purity characteristics can be obtained in a high synthetic yield by a simple method through a one-step reaction from a ketone.

Claims (9)

The ketone of Formula 4, A ruthenium complex represented by Chemical Formulas 1 to 3 to promote the reaction of reducing the ketone to racemic alcohol and the racemization reaction of the racemic alcohol; Lipases for selectively acylating one enantiomer of the racemic alcohol, A hydride donor selected from the group consisting of 2,6-dimethylheptan-4-ol, hydrogen and formic acid, which supplies a hydride to the ruthenium complex, Mixing and reacting an acyl donor selected from an unsubstituted or substituted C ₆ -C ₁₀ aryl ester and an unsubstituted or substituted C ₂ -C ₁₀ alkenyl acetate, wherein the substituent is a halogen atom. To produce a chiral ester of the following formula (100). [Formula 1] In the above formula, Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y ₅ , Y ₆ , Y ₇ , Y ₈ , Y ₉ , Y ₁₀ , Y ₁₁ , Y ₁₂ represent a single bond irrespective of each other, Hydrogen or an alkyl group having 1 to 5 carbon atoms X is Br, Cl or I, [Formula 2] In the above formula, Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y ₅ , Y ₆ , Y ₇ , Y ₈ , Y ₉ , Y ₁₀ , Y ₁₁ , Y ₁₂ represent a single bond irrespective of each other, Hydrogen or an alkyl group having 1 to 5 carbon atoms X is Br, Cl or I. [Formula 3] [Formula 4] [Formula 100] In Formula 4 and Formula 100, R ¹ , R ² and R ³ are each independently an unsubstituted or substituted C ₁ -C ₁₀ alkyl group, an unsubstituted or substituted C ₆ -C ₁₀ aryl group, non- It may be selected from the group consisting of a substituted or substituted C ₃ -C ₁₀ cycloalkyl group, optionally R ¹ and R ² , R ¹ and R ³ , R ² and R ³ may be connected to each other, the alkyl group , An aryl group or a cycloalkyl group may be substituted with a substituent selected from a halogen atom, a C ₁ -C ₁₀ alkoxy group and a cyan group. The method of claim 1, wherein the ketone is selected from the formulas 4a-4g. [Formula 4a] [Formula 4b] [Formula 4c] [Formula 4d] [Formula 4e] [Formula 4f] [Formula 4g] The method according to claim 1, wherein the ruthenium complex is selected from compounds represented by the following Chemical Formulas 5-10. [Formula 5] [Formula 6] [Formula 7] [Formula 8] [Formula 9] [Formula 10] Wherein X is Br, Cl or I. The method of claim 1, wherein in the compounds of Formulas 1 to 3, X is Cl. The method of claim 1, wherein the lipase is selected from the group consisting of Pseudomonas cepacias lipase and candida antarctica component B lipase. delete The method of claim 1 wherein the aryl ester is p-chlorophenyl acetate. delete The method according to claim 1, wherein the ruthenium complex is present in an amount of 0.1 to 5 mol% based on ketones.