KR20190107926A - Method for preparing highly enantio-enriched gingerols - Google Patents

Abstract

Disclosed is a method for preparing a chiral Gingerol compound. To prepare the chiral Gingerol compound, a racemic Gingerol compound is treated with kinetic resolution in the presence of a chiral catalyst compound and an alkali metal fluoride so a chiral Gingerol compound with high optical purity can be prepared. An oligo ethylene glycol-derived compound including an oligo ethylene glycol functional group, a basic part, and a hydroxy functional group of a binol derivative, an acidic part, can be used as a chiral catalyst compound.

Description

Method for producing chiral gingeral compound of high optical purity {METHOD FOR PREPARING HIGHLY ENANTIO-ENRICHED GINGEROLS}

The present invention relates to a method for producing chiral gingeral compound having various physiologically active functions from racemic gingeral compound with high optical purity.

Gingerols (Gingerols) is a substance extracted from ginger is a useful substance having a variety of biological activity, such as anti-cancer, anti-inflammatory, antioxidant, antibacterial, anti-diabetic, anti-allergic, anti-aging. Therefore, studying the physiological activity according to the structure and optical purity of various gingerol compounds is an important study that can increase the pharmacological application of gingerol compound. However, since asymmetric syntheses for selectively synthesizing both optical isomers of gingerol compounds are rarely known, biological researches on gingerol compounds have been difficult.

Representative methods for synthesizing conventional chiral gingeral rolls include preparing a beta-hydroxy backbone through an aldol reaction using a proline catalyst and the like, and protecting the beta-hydroxy backbone using an alcohol protecting group such as a silyl group, followed by aldol. The reaction was carried out with vanillin using a reaction and reduced with a transition metal catalyst. However, this method requires many improvements, such as the long synthesis process and low optical purity.

It is an object of the present invention to provide a method for preparing a high optical purity gingerbread compound through kinetic resolution using optical selective water removal from racemic gingerroll compound.

The method for preparing a chiral gingeral compound according to an embodiment of the present invention includes the step of kinetic resolution of the racemic gingeral compound in the presence of a chiral catalyst compound and an alkali metal fluoride, wherein the chiral catalyst compound is a base moiety. Oligo ethylene glycols are derivatized compounds having an ether functional group of oligo ethylene glycol and a hydroxy functional group of a binol derivative which is an acidic moiety.

In one embodiment, the chiral catalyst compound may include a compound of Formula 1 or a compound of Formula 2.

[Formula 1]

[Formula 2]

In Chemical Formulas 1 and 2, R may be a halogen element or a fluoroalkyl group. In one embodiment, R may include one selected from the group consisting of iodine (I), trifluoromethyl (CF ₃ ), and pentafluoroethyl (C ₂ F ₅ ). For example, R may comprise trifluoromethyl (CF ₃ ).

In one embodiment, the chiral catalyst compound may be used in an amount of about 0.1 to 100 mol% based on the racemic gingerol compound.

In one embodiment, the alkali metal of the alkali metal fluoride may include one selected from the group consisting of sodium, potassium, rubidium and cesium. For example, the alkali metal may include potassium.

In one embodiment, the alkali metal fluoride may be used in an amount of about 0.1 to 10 equivalents based on the racemic gingerol compound. For example, the alkali metal fluoride may be used in an amount of 0.6 to 2 equivalents based on the racemic gingerol compound.

In one embodiment, the racemic gingerol compound may include a compound of formula (3).

[Formula 3]

In Formula 3, R ¹ includes a protecting group of hydrogen or alcohol, R ² includes an alkyl group having 1 to 24 carbon atoms. For example, R ² may include one selected from the group consisting of n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group and n-decanyl group. In this case, R ¹ may be hydrogen.

In one embodiment, the rate of dehydration for one of the R- and S-isomers of the racemic gingerol compound during the kinetic resolution may be greater than the rate of the other dehydration. In this case, the compound of Formula 4 may be formed through the dehydration reaction.

[Formula 4]

In one embodiment, the step of kinetic resolution of the racemic gingerbread compound may be carried out in an aprotic organic solvent. In this case, the aprotic organic solvent may include one or more selected from the group consisting of dichloromethane, benzene, toluene, o-xylene, m-xylene, p-xylene and mesitylene.

In one embodiment, the step of kinetic resolution of the racemic gingerol compound may be carried out at a temperature of about −50 ° C. to 30 ° C., and the racemic during the kinetic resolution of the racemic ginger roll compound. Stereoselective dehydration of the gingerol compound may occur. For example, the step of kinetic resolution of the racemic gingerbread compound may be performed at a temperature of 20 ° C to 30 ° C.

According to the present invention described above, the chiral gingerol compound having high optical purity through kinetic resolution from racemic gingerol compound through stereoselective water removal reaction using a small amount of organic catalyst and alkali metal fluoride is more efficient and It can be manufactured economically.

Hereinafter, embodiments of the present invention will be described in detail. As the inventive concept allows for various changes and numerous modifications, particular embodiments will be described in detail. However, this is not intended to limit the present invention to a specific disclosure form, it should be understood to include all modifications, equivalents, and substitutes included in the spirit and scope of the present invention.

Terms such as first and second may be used to describe various components, but the components should not be limited by the terms. The terms are used only for the purpose of distinguishing one component from another. For example, without departing from the scope of the present invention, the first component may be referred to as the second component, and similarly, the second component may also be referred to as the first component.

The terminology used herein is for the purpose of describing particular example embodiments only and is not intended to be limiting of the invention. Singular expressions include plural expressions unless the context clearly indicates otherwise. In this application, the terms "comprise" or "have" are intended to indicate that a feature, component, or the like described in the specification exists, and one or more other features or components may not be present or added thereto. It does not mean nothing.

Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art. Terms such as those defined in the commonly used dictionaries should be construed as having meanings consistent with the meanings in the context of the related art and shall not be construed in ideal or excessively formal meanings unless expressly defined in this application. Do not.

The method for preparing a chiral gingeral compound according to an embodiment of the present invention may include the step of kinetic resolution of the racemic gingeral compound in the presence of a chiral catalyst compound and an alkali metal fluoride, such a kinetic resolution The stereoselective dehydration reaction with respect to the optical isomers of the racemic gingeral compound is carried out) to produce a chiral gingeral compound.

The chiral catalyst compound may be an organic compound exhibiting bifunctionality capable of simultaneously activating a racemic gingerol compound and an alkali metal fluoride. In one embodiment, the chiral catalyst compound is a compound in which oligo ethylene glycol is derivatized, and includes an ether functional group of oligo ethylene glycol, which is a Lewis base moiety, and a hydroxyl functional group of a binol derivative, which is a Bronsted acidic moiety. can do.

For example, the chiral catalyst compound may be a compound of Formula 1 or Formula 2.

[Formula 1]

[Formula 2]

In Chemical Formulas 1 and 2, R may include a halogen element or an alkyl halide. For example, R can be I, CF ₃ or C ₂ F ₅ . Preferably, R may be CF ₃ .

The alkali metal fluoride may include one or more selected from sodium fluoride (NaF), potassium fluoride (KF), rubidium fluoride (RbF), cesium fluoride (CsF), and the like.

The alkali metal fluoride may act as a base in the presence of the chiral catalyst compound to remove the proton at the alpha position of the racemic gingeral compound so that stereoselective dehydration may proceed.

As the racemic gingerol compound, a compound of Formula 3 may be used.

[Formula 3]

In Chemical Formula 3, R ¹ may be a protecting group of hydrogen or an alcohol, and R ² may be an alkyl group having about 1 to 24 carbon atoms. The 'alcohol protecting group' represents a functional group capable of protecting the oxygen atom of the alcohol during the reaction, and is not particularly limited as long as it can protect the oxygen atom of the alcohol during the reaction. For example, the alcohol protecting group may be t-butyldimethylsilyl, trimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, tetrahydropyranyl and the like.

In one embodiment of the present invention, the method for preparing a chiral gingeral compound may be carried out in a solvent according to the following Scheme 1.

Scheme 1

In the reaction of Scheme 1, an aprotic organic solvent may be used as the solvent. For example, dichloromethane, benzene, toluene, o-xylene, m-xylene, p-xylene, mesitylene, or the like may be used as the solvent, or a mixture of two or more thereof.

The chiral catalyst compound may be used in an amount of about 0.1 mol% to 100 mol% based on the racemic gingerol compound in consideration of optical purity and reaction rate. When the amount of the chiral catalyst compound is less than 0.1 mol% based on the racemic gingeral compound, a problem may occur that the reaction rate and stereoselectivity are significantly reduced. When the amount is greater than 100 mol%, the effect of the catalytic reaction is greatly affected. Economic problems may arise from the use of excessive amounts of expensive catalysts.

The alkali metal fluoride may be used in an amount of about 0.1 to 10 equivalents based on the racemic gingerbread compound. Preferably, the alkali metal fluoride may be used in an amount of about 0.6 to 2 equivalents based on the racemic gingerbread compound.

The reaction of Scheme 1 may be performed at a temperature of about -50 ° C to 30 ° C in consideration of reaction rate and optical selectivity. For example, the reaction of Scheme 1 is preferably performed at about 10 ° C to 30 ° C, more preferably at about 25 ° C. That is, the present invention can produce a chiral gingeral compound having high optical selectivity even if carried out at room temperature of about 25 ℃, it can be said that it is very useful for industrialization for mass production.

Hereinafter, various embodiments of the present invention will be described. However, the present invention is not limited to the following embodiments and may be variously changed.

In Examples 1 to 10 below, toluene was used as a solvent, the reaction was carried out at a reaction temperature of 25 ° C. for about 192 hours, and potassium fluoride (KF) was used as the alkali metal fluoride.

In Example 11 below, toluene was used as a solvent, and the reaction was performed at a reaction temperature of 25 ° C. for about 62 hours, and potassium fluoride (KF) was used as the alkali metal fluoride.

Example 1

After dissolving 1 mmol of racemic gingerol compound (1a) in 10 mL of toluene, 10 mol% of the chiral catalyst compound of Formula 2 (wherein R is CF ₃ ) and 2 equivalents of potassium fluoride were added sequentially and at 25 ° C. Stir for 8 days.

After the reaction, the mixture was filtered to recover potassium fluoride and then concentrated. The residue was purified by flash chromatography (ethyl acetate: hexane = 1: 4) to give a chiral gingeral compound (2a, 48% yield; 99.9% ee, (S) -form).

Enantioselectivity was measured using high performance liquid chromatography. (CHIRALCEL OJ-H, 90:10, hexanes: isopropyl alcohol, 1.0 mL / min, t (main product) = 48 minutes, t (by-product) = 54 minutes)

¹ H NMR (500 MHz, CDCl ₃ ): δ 6.82 (d, J = 8.0 Hz, 1H), 6.69-6.63 (m, 2H), 5.48 (s, 1H), 4.02 (qd, J = 7.8, 3.3 Hz , 1H), 3.87 (s, 3H), 2.91 (d, J = 3.5 Hz, 1H), 2.84 (t, J = 7.5 Hz, 2H), 2.73 (t, J = 7.3 Hz, 2H), 2.59-2.45 (m, 2H), 1.51-1.22 (m, 8H), 0.88 (t, J = 6.9 Hz, 3H).

¹³ C NMR (125 MHz, CDCl ₃ ): δ 211.44, 146.44, 143.99, 132.66, 120.75, 114.38, 110.98, 67.67, 55.89, 49.37, 45.45, 36.44, 31.74, 29.30, 25.13, 22.60, 14.02.

Example 2

After dissolving 1 mmol of racemic gingerol compound (1a) in 10 mL of toluene, 10 mol% of the chiral catalyst compound of formula 1 (wherein R is CF ₃ ) and 2 equivalents of potassium fluoride were added sequentially and at 25 ° C. Stir for 8 days.

After the reaction, the mixture was filtered to recover potassium fluoride and then concentrated. The residue was purified by flash chromatography (ethyl acetate: hexane = 1: 4) to give a chiral gingeral compound (2a, 48% yield; 99.9% ee, (R) -form).

Enantioselectivity was measured using high performance liquid chromatography. (CHIRALCEL OJ-H, 90:10, hexanes: isopropyl alcohol, 1.0 mL / min, t (main product) = 54 minutes, t (by-product) = 48 minutes)

¹ H NMR (500 MHz, CDCl ₃ ): δ 6.82 (d, J = 8.0 Hz, 1H), 6.69-6.63 (m, 2H), 5.48 (s, 1H), 4.02 (qd, J = 7.8, 3.3 Hz , 1H), 3.87 (s, 3H), 2.91 (d, J = 3.5 Hz, 1H), 2.84 (t, J = 7.5 Hz, 2H), 2.73 (t, J = 7.3 Hz, 2H), 2.59-2.45 (m, 2H), 1.51-1.22 (m, 8H), 0.88 (t, J = 6.9 Hz, 3H).

¹³ C NMR (125 MHz, CDCl ₃ ): δ 211.44, 146.44, 143.99, 132.66, 120.75, 114.38, 110.98, 67.67, 55.89, 49.37, 45.45, 36.44, 31.74, 29.30, 25.13, 22.60, 14.02.

Example 3

After dissolving 1 mmol of racemic gingerol compound (1b) in 10 mL of toluene, 10 mol% of the chiral catalyst compound of Formula 2 (wherein R is CF ₃ ) and 2 equivalents of potassium fluoride were added in sequence and at 25 ° C. Stir for 8 days. The mixture was filtered to recover potassium fluoride and then concentrated. The residue was purified by flash chromatography (ethyl acetate: hexane = 1: 4) to give chiral gingeral compound (2b, 48% yield; 99.9% ee, (S) -form).

Enantioselectivity was measured using high performance liquid chromatography. (CHIRALCEL OJ-H, 90:10, hexane: isopropyl alcohol, 1.0 mL / min, t (main product) = 45 minutes, t (by-product) = 54 minutes)

¹ H NMR (500 MHz, CDCl ₃ ): δ 6.82 (d, J = 8.0 Hz, 1H), 6.69-6.64 (m, 2H), 5.47 (s, 1H), 4.02 (qd, J = 7.8, 3.3 Hz , 1H), 3.87 (s, 3H), 2.90 (d, J = 3.5 Hz, 1H), 2.84 (t, J = 7.5 Hz, 2H), 2.73 (t, J = 7.3 Hz, 2H), 2.59-2.45 (m, 2H), 1.51-1.22 (m, 10H), 0.88 (t, J = 6.9 Hz, 3H).

¹³ C NMR (125 MHz, CDCl ₃ ): δ 211.44, 146.47, 144.00, 132.65, 120.74, 114.11, 111.00, 67.68, 55.88, 49.37, 45.44, 36.49, 31.78, 29.29, 29.21, 25.42, 22.59, 14.07.

Example 4

After dissolving 1 mmol of racemic gingerol compound (1b) in 10 mL of toluene, 10 mol% of the chiral catalyst compound of Formula 1 (wherein R is CF ₃ ) and 2 equivalents of potassium fluoride were added sequentially and at 25 ° C. Stir for 8 days.

After the reaction, the mixture was filtered to recover potassium fluoride and then concentrated. The residue was purified by flash chromatography (ethyl acetate: hexane = 1: 4) to give chiral gingeral compound (2b, 48% yield; 99.9% ee, (R) -form).

Enantioselectivity was measured using high performance liquid chromatography. (CHIRALCEL OJ-H, 90:10, hexanes: isopropyl alcohol, 1.0 mL / min, t (main product) = 54 minutes, t (by-product) = 45 minutes)

¹ H NMR (500 MHz, CDCl ₃ ): δ 6.82 (d, J = 8.0 Hz, 1H), 6.69-6.64 (m, 2H), 5.47 (s, 1H), 4.02 (qd, J = 7.8, 3.3 Hz , 1H), 3.87 (s, 3H), 2.90 (d, J = 3.5 Hz, 1H), 2.84 (t, J = 7.5 Hz, 2H), 2.73 (t, J = 7.3 Hz, 2H), 2.59-2.45 (m, 2H), 1.51-1.22 (m, 10H), 0.88 (t, J = 6.9 Hz, 3H).

¹³ C NMR (125 MHz, CDCl ₃ ): δ 211.44, 146.47, 144.00, 132.65, 120.74, 114.11, 111.00, 67.68, 55.88, 49.37, 45.44, 36.49, 31.78, 29.29, 29.21, 25.42, 22.59, 14.07.

Example 5

After dissolving 1 mmol of racemic gingerol compound (1c) in 10 mL of toluene, 10 mol% of the chiral catalyst compound of Formula 2 (wherein R is CF ₃ ) and 2 equivalents of potassium fluoride were added sequentially and at 25 ° C. Stir for 8 days.

After the reaction, the mixture was filtered to recover potassium fluoride and then concentrated. The residue was purified by flash chromatography (ethyl acetate: hexane = 1: 4) to give chiral gingeral compound (2c, 48% yield; 99.9% ee, (S) -form).

Enantioselectivity was measured using high performance liquid chromatography. (CHIRALCEL OJ-H, 90:10, hexanes: isopropyl alcohol, 1.0 mL / min, t (main product) = 43 minutes, t (by-product) = 56 minutes)

¹ H NMR (500 MHz, CDCl ₃ ): δ 6.82 (d, J = 8.0 Hz, 1H), 6.69-6.63 (m, 2H), 5.47 (s, 1H), 4.02 (qd, J = 7.8, 3.3 Hz , 1H), 3.87 (s, 3H), 2.91 (d, J = 3.5 Hz, 1H), 2.84 (t, J = 7.5 Hz, 2H), 2.73 (t, J = 7.3 Hz, 2H), 2.59-2.45 (m, 2H), 1.51-1.22 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H).

¹³ C NMR (125 MHz, CDCl ₃ ): δ 211.44, 146.44, 143.99, 132.66, 120.75, 114.38, 110.98, 67.67, 55.89, 49.37, 45.45, 36.48, 31.80, 29.51, 29.30, 29.24, 25.46, 22.65, 14.09.

Example 6

After dissolving 1 mmol of racemic gingerol compound (1c) in 10 mL of toluene, 10 mol% of the chiral catalyst compound of formula (wherein R is CF ₃ ) and 2 equivalents of potassium fluoride were added sequentially and at 25 ° C. Stir for 8 days.

After the reaction, the mixture was filtered to recover potassium fluoride and then concentrated. The residue was purified by flash chromatography (ethyl acetate: hexane = 1: 4) to give a chiral gingeral compound (2c, 48% yield; 99.9% ee, (R) -form).

Enantioselectivity was measured using high performance liquid chromatography. (CHIRALCEL OJ-H, 90:10, hexanes: isopropyl alcohol, 1.0 mL / min, t (main product) = 56 minutes, t (by-product) = 43 minutes)

¹ H NMR (500 MHz, CDCl ₃ ): δ 6.82 (d, J = 8.0 Hz, 1H), 6.69-6.63 (m, 2H), 5.47 (s, 1H), 4.02 (qd, J = 7.8, 3.3 Hz , 1H), 3.87 (s, 3H), 2.91 (d, J = 3.5 Hz, 1H), 2.84 (t, J = 7.5 Hz, 2H), 2.73 (t, J = 7.3 Hz, 2H), 2.59-2.45 (m, 2H), 1.51-1.22 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H).

¹³ C NMR (125 MHz, CDCl ₃ ): δ 211.44, 146.44, 143.99, 132.66, 120.75, 114.38, 110.98, 67.67, 55.89, 49.37, 45.45, 36.48, 31.80, 29.51, 29.30, 29.24, 25.46, 22.65, 14.09.

Example 7

After dissolving 1 mmol of racemic gingerol compound (1d) in 10 mL of toluene, 10 mol% of the chiral catalyst compound of Formula 2 (wherein R is CF ₃ ) and 2 equivalents of potassium fluoride were added sequentially and at 25 ° C. Stir for 8 days.

After the reaction, the mixture was filtered to recover potassium fluoride and then concentrated. The residue was purified by flash chromatography (ethyl acetate: hexane = 1: 4) to give a chiral gingeral compound (2d, 47% yield; 99.9% ee, (S) -form).

Enantioselectivity was measured using high performance liquid chromatography. (CHIRALCEL OJ-H, 90:10, hexanes: isopropyl alcohol, 1.0 mL / min, t (main product) = 41 minutes, t (by-product) = 52 minutes)

¹ H NMR (500 MHz, CDCl ₃ ): δ 6.82 (d, J = 8.0 Hz, 1H), 6.69-6.63 (m, 2H), 5.53 (s, 1H), 4.02 (qd, J = 7.8, 3.3 Hz , 1H), 3.87 (s, 3H), 2.94 (s, 1H), 2.83 (t, J = 7.4 Hz, 2H), 2.73 (t, J = 7.6 Hz, 2H), 2.59-2.45 (m, 2H) , 1.51-1.22 (m, 14H), 0.88 (t, J = 6.9 Hz, 3H).

¹³ C NMR (125 MHz, CDCl ₃ ): δ 211.44, 146.46, 144.00, 132.65, 120.74, 114.41, 111.00, 67.68, 55.88, 49.37, 45.45, 36.49, 31.87, 29.55, 29.54, 29.29, 29.25, 25.46, 22.67, 14.11.

Example 8

After dissolving 1 mmol of racemic gingerol compound (1d) in 10 mL of toluene, 10 mol% of the chiral catalyst compound of Formula 1 (wherein R is CF ₃ ) and 2 equivalents of potassium fluoride were added sequentially and at 25 ° C. Stir for 8 days.

After the reaction, the mixture was filtered to recover potassium fluoride and then concentrated. The residue was purified by flash chromatography (ethyl acetate: hexane = 1: 4) to give chiral gingeral compound (2d, 47% yield; 99.9% ee, (R) -form).

Enantioselectivity was measured using high performance liquid chromatography. (CHIRALCEL OJ-H, 90:10, hexane: isopropyl alcohol, 1.0 mL / min, t (main product) = 52 minutes, t (by-product) = 41 minutes)

¹ H NMR (500 MHz, CDCl ₃ ): δ 6.82 (d, J = 8.0 Hz, 1H), 6.69-6.63 (m, 2H), 5.53 (s, 1H), 4.02 (qd, J = 7.8, 3.3 Hz , 1H), 3.87 (s, 3H), 2.94 (s, 1H), 2.83 (t, J = 7.4 Hz, 2H), 2.73 (t, J = 7.6 Hz, 2H), 2.59-2.45 (m, 2H) , 1.51-1.22 (m, 14H), 0.88 (t, J = 6.9 Hz, 3H).

¹³ C NMR (125 MHz, CDCl ₃ ): δ 211.44, 146.46, 144.00, 132.65, 120.74, 114.41, 111.00, 67.68, 55.88, 49.37, 45.45, 36.49, 31.87, 29.55, 29.54, 29.29, 29.25, 25.46, 22.67, 14.11.

Example 9

After dissolving 1 mmol of racemic gingerol compound (1e) in 10 mL of toluene, 10 mol% of the chiral catalyst compound of Formula 2 (wherein R is CF ₃ ) and 2 equivalents of potassium fluoride were added sequentially and at 25 ° C. Stir for 8 days.

After the reaction, the mixture was filtered to recover potassium fluoride and then concentrated. The residue was purified by flash chromatography (ethyl acetate: hexane = 1: 4) to give a chiral gingeral compound (2f, 47% yield; 99.9% ee, (S) -form).

Enantioselectivity was measured using high performance liquid chromatography. (CHIRALCEL OJ-H, 90:10, hexanes: isopropyl alcohol, 1.0 mL / min, t (main product) = 36 minutes, t (by-product) = 42 minutes)

¹ H NMR (500 MHz, CDCl ₃ ): δ 6.82 (d, J = 8.0 Hz, 1H), 6.69-6.63 (m, 2H), 5.50 (s, 1H), 4.02 (qd, J = 7.8, 3.3 Hz , 1H), 3.87 (s, 3H), 2.91 (d, J = 3.5 Hz, 1H), 2.84 (t, J = 7.5 Hz, 2H), 2.73 (t, J = 7.3 Hz, 2H), 2.59-2.45 (m, 2H), 1.51-1.22 (m, 16H), 0.88 (t, J = 6.9 Hz, 3H).

¹³ C NMR (125 MHz, CDCl ₃ ): δ 211.44, 146.45, 144.00, 132.66, 120.75, 114.39, 110.98, 67.67, 55.88, 49.37, 45.45, 36.49, 31.89, 29.58, 29.55, 29.31, 29.29, 25.46, 22.68, 14.11.

Example 10

After dissolving 1 mmol of racemic gingerol compound (1e) in 10 mL of toluene, 10 mol% of the chiral catalyst compound of Formula 1 (wherein R is CF ₃ ) and 2 equivalents of potassium fluoride were added sequentially and at 25 ° C. Stir for 8 days.

After the reaction, the mixture was filtered to recover potassium fluoride and then concentrated. The residue was purified by flash chromatography (ethyl acetate: hexane = 1: 4) to give chiral gingeral compound (2f, 47% yield; 99.9% ee, (R) -form).

Enantioselectivity was measured using high performance liquid chromatography. (CHIRALCEL OJ-H, 90:10, hexanes: isopropyl alcohol, 1.0 mL / min, t (main product) = 42 minutes, t (by-product) = 36 minutes)

¹ H NMR (500 MHz, CDCl ₃ ): δ 6.82 (d, J = 8.0 Hz, 1H), 6.69-6.63 (m, 2H), 5.50 (s, 1H), 4.02 (qd, J = 7.8, 3.3 Hz , 1H), 3.87 (s, 3H), 2.91 (d, J = 3.5 Hz, 1H), 2.84 (t, J = 7.5 Hz, 2H), 2.73 (t, J = 7.3 Hz, 2H), 2.59-2.45 (m, 2H), 1.51-1.22 (m, 16H), 0.88 (t, J = 6.9 Hz, 3H).

¹³ C NMR (125 MHz, CDCl ₃ ): δ 211.44, 146.45, 144.00, 132.66, 120.75, 114.39, 110.98, 67.67, 55.88, 49.37, 45.45, 36.49, 31.89, 29.58, 29.55, 29.31, 29.29, 25.46, 22.68, 14.11.

Example 11

0.1 mmol of racemic gingerol compound (1f) was dissolved in 1 mL of toluene, followed by the addition of 10 mol% of the chiral catalyst compound of Formula 2 (wherein R is CF ₃ ) and 1.2 equivalents of potassium fluoride, at 25 ° C. Stir for 62 hours.

After the reaction, the mixture was filtered to recover potassium fluoride and then concentrated. The residue was purified by flash chromatography (ethyl acetate: hexane = 1: 4) to give a chiral gingeral compound (2 g, 50% yield; 98.8% ee, (S) -form).

Enantioselectivity was measured using high performance liquid chromatography. (egis (R, R) Whelk-O1, 98: 2, hexanes: isopropyl alcohol, 0.7 mL / min, t (main product) = 37 minutes, t (product) = 39 minutes)

¹ H NMR (500 MHz, CDCl ₃ ): δ 6.75 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 1.9 Hz, 1H), 6.60 (dd, J = 8.0, 2.0 Hz, 1H), 4.05-3.98 (m, 1H), 3.78 (s, 3H), 2.92 (d, J = 3.4 Hz, 1H), 2.83 (t, J = 7.5 Hz, 2H), 2.76-2.70 (m, 2H), 2.59 2.44 (m, 2H), 1.51-1.21 (m, 9H), 0.99 (s, 9H), 0.88 (t, J = 6.9 Hz, 3H), 0.14 (s, 6H).

¹³ C NMR (125 MHz, CDCl ₃ ): δ 211.58, 150.83, 143.38, 134.16, 120.84, 120.26, 112.43, 67.66, 55.50, 49.40, 45.37, 36.44, 31.75, 29.37, 25.73, 25.14, 22.60, 18.44, 14.03, -4.64.

The results of Examples 1 to 11 are shown in Tables 1 and 2 below.

Example Reactant catalyst product yield(%) ee (%) One

Formula 2
(R = CF ₃ )

48 99 2 Formula 1
(R = CF ₃ )

48 99 3

Formula 2
(R = CF ₃ )

48 99 4 Formula 1
(R = CF ₃ )

48 99 5

Formula 2
(R = CF ₃ )

48 99 6 Formula 1
(R = CF ₃ )

48 99 7

Formula 2
(R = CF ₃ )

47 99 8 Formula 1
(R = CF ₃ )

47 99 9

Formula 2
(R = CF ₃ )

47 99 10 Formula 1
(R = CF ₃ )

47 99 11

Formula 2
(R = CF ₃ )

50 98.8

According to the present invention described above, the chiral gingerol compound having high optical purity from racemic gingerol compound is more efficient and economical through kinetic resolution using stereoselective dehydration using a small amount of organic catalyst and alkali metal fluoride. It can be prepared by.

While the foregoing has been described with reference to preferred embodiments of the present invention, those skilled in the art will be able to variously modify and change the present invention without departing from the spirit and scope of the invention as set forth in the claims below. It will be appreciated.

Claims (18)

Kinetic resolution of the racemic gingerol compound in the presence of a chiral catalyst compound and an alkali metal fluoride,
The chiral catalyst compound comprises a compound in which an oligo ethylene glycol having a ether functional group of oligo ethylene glycol as a base moiety and a hydroxy functional group of a binol derivative as an acidic moiety is derivatized. . The method of claim 1,
The chiral catalyst compound is characterized in that it comprises a compound of formula (1) or a compound of formula (2), a method for producing a chiral gingeral compound
[Formula 1]

[Formula 2]

In Chemical Formulas 1 and 2, R is a halogen element or a fluoroalkyl group. The method of claim 2,
The R is characterized in that it comprises one selected from the group consisting of iodine (I), trifluoromethyl (CF ₃ ) and pentafluoroethyl (C ₂ F ₅ ), a method for producing a chiral gingeral compound. The method of claim 3,
The R is characterized in that it comprises trifluoromethyl (CF ₃ ), the chiral gingeral compound manufacturing method. The method of claim 2,
The chiral catalyst compound is used in an amount of 0.1 to 100 mol% based on the racemic gingeral compound, a method for producing a chiral gingeral compound. The method of claim 1,
The alkali metal of the alkali metal fluoride is characterized in that it comprises one selected from the group consisting of sodium, potassium, rubidium and cesium, a method for producing a chiral gingerbread compound. The method of claim 6,
The alkali metal is characterized in that it comprises potassium, method of producing a chiral gingeral compound. The method of claim 6,
The alkali metal fluoride is used in an amount of 0.1 to 10 equivalents based on the racemic gingerbread compound, a method for producing a chiral gingerbread compound. The method of claim 6,
The alkali metal fluoride is used in an amount of 0.6 to 2 equivalents based on the racemic gingerbread compound, a method for producing a chiral gingerbread compound. The method of claim 1,
The racemic ginger roll compound is characterized in that it comprises a compound of the formula (3), a chiral ginger roll compound manufacturing method:
[Formula 3]

In Formula 3, R ¹ includes a protecting group of hydrogen or alcohol, R ² includes an alkyl group having 1 to 24 carbon atoms. The method of claim 10,
R ² is a chiral gingerbread compound, characterized in that it comprises one selected from the group consisting of n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group and n-decanyl group Manufacturing method. The method of claim 10,
R ¹ is hydrogen, a method for producing a chiral gingeral compound. The method of claim 10,
The dehydration reaction rate for one of the R- and S-isomers of the racemic gingerol compound during the kinetic resolution, characterized in that greater than the other dehydration reaction rate, the method for producing a chiral ginger roll compound. The method of claim 13,
Method for producing a chiral gingeral compound, characterized in that to form a compound of the formula (4) through the dehydration reaction:
[Formula 4]

The method of claim 1,
Kinetic resolution of the racemic gingeral compound is characterized in that it is carried out in an aprotic organic solvent, a method for producing a chiral gingeral compound. The method of claim 15,
The aprotic organic solvent may include at least one selected from the group consisting of dichloromethane, benzene, toluene, o-xylene, m-xylene, p-xylene and mesitylene. Manufacturing method. The method of claim 15,
Kinetic resolution of the racemic gingerol compound is carried out at a temperature of -50 ° C to 30 ° C,
Method for producing a chiral gingerbread compound, characterized in that the stereoselective dehydration reaction to the racemic gingerbread compound occurs during the kinetic resolution of the racemic gingerroll compound. The method of claim 15,
Kinetic resolution of the racemic ginger roll compound (Kinetic resolution), characterized in that carried out at a temperature of 20 ℃ to 30 ℃, a method for producing a chiral ginger roll compound.