KR102800868B1 - Novel method for preparing substituted 1-hydroxy-2-pyridone compound - Google Patents

Abstract

The present invention relates to a novel method for producing a substituted 1-hydroxy-2-pyridone compound, and more specifically, to a method for economically producing a substituted 1-hydroxy-2-pyridone compound useful for producing functional compounds in various fields.

Description

{Novel method for preparing substituted 1-hydroxy-2-pyridone compound}

The present invention relates to a novel method for producing a substituted 1-hydroxy-2-pyridone compound, and more specifically, to a method for economically producing a substituted 1-hydroxy-2-pyridone compound useful for producing functional compounds in various fields without using a transition metal catalyst.

Substituted 1-hydroxy-2-pyridone compounds are useful in the manufacture of functional compounds in various fields, and representative examples of such functional compounds include piroctone olamine, which significantly increases anti-inflammatory and antibacterial effects and can be effectively applied to skin diseases such as acne and seborrheic dermatitis, and ciclopirox, which is effective in the treatment of fungal infections of the skin.

Piroctone olamine, which is used for anti-dandruff purposes, exhibits excellent anti-dandruff bacteria effects and, especially in shampoo formulations containing an excessive amount of surfactant, has excellent solubility, making it suitable for the production of transparent shampoos.

In order to treat skin and scalp diseases such as dandruff, seborrheic dermatitis, psoriasis, and acne, agents that can 1) inhibit the growth of microorganisms on the skin surface, 2) reduce inflammation on the skin surface, or 3) reduce sebum production on the skin surface are generally used. In addition, by using ingredients such as ketoconazole, selenium sulfide, zinc pyrithione, coal tar, and piroctone olamine, and ciclopirox that can inhibit the growth of fungi, especially Malassezia furfur and Pityrosporum ovale, the growth of microorganisms is inhibited, helping to prevent and improve skin and scalp diseases.

Among the above ingredients, piroctone olamine is an ethanolamine salt of 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-(1H)-pyridone, which is the most widely used active ingredient in anti-dandruff compositions. Piroctone olamine has antifungal, skin hyperkeratosis suppression, and inflammation suppression effects, helping maintain a healthy and clean scalp and hair, and is used in products for skin with a lot of blemishes.

Also, ciclopirox is a drug that treats fungal infections of the skin. Depending on the formulation, nail lacquer is used to treat toenail fungus, liquid is used to treat seborrheic dermatitis of the scalp, and gel and cream are used to treat ringworm and candidiasis.

In order to synthesize substituted 1-hydroxy-2-pyridones, a method has been mainly used in the past, in which pyrone is reacted with a hydroxyl ammonium salt in the presence of a basic compound, a solvent, and an organic acid or a salt thereof. However, this method has the disadvantage of using a considerable amount of a relatively expensive compound, and this compound must be recovered not only for its price but also for environmental protection reasons. In addition, this method is time-consuming and the yield of the product is low, so there are many problems in applying it to commercial production.

In particular, since zinc pyrithione has recently been designated as a prohibited substance and cannot be used in cosmetics, it is known that companies that have been using zinc pyrithione are considering replacing it with compounds such as piroctone olamine. Accordingly, since the announcement of these regulations, the demand for piroctone olamine has increased, and the current supply is insufficient. The price is also rising, and the market growth and overall production of piroctone olamine are expected to increase in the future.

The purpose of the present invention is to provide a method for economically producing a substituted 1-hydroxy-2-pyridone compound without using a transition metal catalyst.

In order to solve the above problems, the present invention provides a method for preparing a substituted 1-hydroxy-2-pyridone compound of chemical formula I, comprising: (1) a step of reacting a compound of chemical formula II with an acidic compound to obtain a compound of chemical formula III; (2) a step of reacting a compound of chemical formula III with a basic compound and then reacting the resultant with an acid anhydride, an acid chloride or a carboxylic acid compound to obtain a compound of chemical formula IV; (3) a step of reacting a compound of chemical formula IV with an acid chloride or a carboxylic acid compound in the presence of a basic compound to obtain a compound of chemical formula V; and (4) a step of reacting a compound of chemical formula V with a hydroxyl ammonium salt in the presence of a basic compound to obtain a compound of chemical formula I.

[Chemical Formula I]

[Chemical Formula II]

[Chemical Formula III]

[Chemical Formula IV]

[Chemical formula V]

In the above, R ¹ to R ³ are each independently a C ₁ -C ₁₂ aliphatic hydrocarbon group unsubstituted or substituted with one or more halogen atoms; a C ₁ -C ₁₂ straight-chain alkyl group or a C ₃ -C ₁₂ branched alkyl group substituted or unsubstituted with one or more halogen atoms or alicyclic hydrocarbon groups; a C ₃ -C ₁₂ alicyclic hydrocarbon group substituted or unsubstituted with one or more halogen atoms; a C ₆ -C ₂₀ aryl group substituted or unsubstituted with one or more halogen atoms; a C ₇ -C ₂₀ arylalkyl group substituted or unsubstituted with one or more halogen atoms or a C ₁ -C ₁₂ alkylthio group; or a C ₇ -C ₂₀ alkylaryl group substituted or unsubstituted with one or more halogen atoms or a C ₁ -C ₁₂ alkylthio group.

According to another aspect of the present invention, a method is provided for using a substituted 1-hydroxy-2-pyridone compound of formula I prepared by the above method as an intermediate for preparing piroctone olamine or ciclopirox.

The manufacturing method according to the present invention has the advantage of excellent economic efficiency as it can manufacture a substituted 1-hydroxy-2-pyridone compound of the chemical formula I, which is useful for the manufacture of functional compounds in various fields, particularly, for the manufacture of piroctone olamine or ciclopirox, using inexpensive raw materials and under mild synthesis conditions without an expensive metal catalyst, and also has the advantage of excellent productivity with a high yield.

Hereinafter, the present invention will be described in more detail.

A method for preparing a substituted 1-hydroxy-2-pyridone compound of formula I of the present invention comprises the steps of: (1) reacting a compound of formula II with an acidic compound to obtain a compound of formula III; (2) reacting a compound of formula III with a basic compound and then reacting the resultant with an acid anhydride, an acid chloride or a carboxylic acid compound to obtain a compound of formula IV; (3) reacting a compound of formula IV with an acid chloride or a carboxylic acid compound in the presence of a basic compound to obtain a compound of formula V; and (4) reacting a compound of formula V with a hydroxyl ammonium salt in the presence of a basic compound to obtain a compound of formula I.

[Chemical Formula I]

[Chemical Formula II]

[Chemical Formula III]

[Chemical Formula IV]

[Chemical formula V]

In the above, R ¹ to R ³ are each independently a C ₁ -C ₁₂ aliphatic hydrocarbon group unsubstituted or substituted with one or more halogen atoms; a C ₁ -C ₁₂ straight-chain alkyl group or a C ₃ -C ₁₂ branched alkyl group substituted or unsubstituted with one or more halogen atoms or alicyclic hydrocarbon groups; a C ₃ -C ₁₂ alicyclic hydrocarbon group substituted or unsubstituted with one or more halogen atoms; a C ₆ -C ₂₀ aryl group substituted or unsubstituted with one or more halogen atoms; a C ₇ -C ₂₀ arylalkyl group substituted or unsubstituted with one or more halogen atoms or a C ₁ -C ₁₂ alkylthio group; or a C ₇ -C ₂₀ alkylaryl group substituted or unsubstituted with one or more halogen atoms or a C ₁ -C ₁₂ alkylthio group.

In the present invention, a substituent containing an “alkyl” moiety includes both straight-chain and branched forms, and “cycloalkyl” includes not only a single-ring system but also a multi-ring system hydrocarbon. In the present invention, “aryl” is an organic radical derived from an aromatic hydrocarbon by the removal of one hydrogen, and includes a single or fused ring system suitably containing 4 to 7, preferably 5 or 6 ring atoms in each ring, and includes even a form in which a plurality of aryls are connected by single bonds. In the present invention, C ₁ -C ₁₂ alkyl is more specifically C ₁ -C ₁₀ alkyl, and even more specifically C ₁ -C ₆ alkyl. In the present invention, C ₆ -C ₂₀ aryl is more specifically C ₆ -C ₁₈ aryl, and C ₃ -C ₁₂ cycloalkyl is more specifically C ₃ -C ₁₀ cycloalkyl.

In a preferred embodiment, R ¹ can be methyl and R ² can be 2,4,4-trimethylpentyl, cyclohexyl, 4-(4-chlorophenoxy)-phenoxymethyl or phenyl.

In a preferred specific embodiment, the substituted 1-hydroxy-2-pyridone derivative compound of formula I prepared according to the present invention may be selected from, but is not limited to, the following.

The reaction steps of the method for preparing a substituted 1-hydroxy-2-pyridone derivative compound of chemical formula I according to the present invention are schematically represented as follows.

[In the above reaction formula, R ¹ to R ³ are as defined above.]

Hereinafter, the method for preparing a substituted 1-hydroxy-2-pyridone compound of chemical formula I of the present invention is described in detail step by step.

(1) Step

In step (1) of the method for producing a compound of chemical formula I of the present invention, a compound of chemical formula II is reacted with an acidic compound to obtain a compound of chemical formula III.

In one specific embodiment, the acidic compound can be selected from sulfuric acid, hydrochloric acid, nitric acid or a combination thereof, and more specifically, sulfuric acid.

In one specific embodiment, the acidic compound may be used in an amount of 0.5 to 3.0 equivalents, more specifically, 1.5 to 2.5 equivalents, per 1 equivalent of the compound of formula II.

In one specific example, the pH of the reaction mixture in step (1) may be 3 or lower, and the reaction temperature may be room temperature (e.g., 20 to 30° C.), but is not limited thereto.

(2) Step

In step (2) of the method for producing a compound of chemical formula I of the present invention, a compound of chemical formula III is reacted with a basic compound, and then the resultant is reacted with an acid anhydride, an acid chloride, or a carboxylic acid compound to obtain a compound of chemical formula IV.

In one specific embodiment, the basic compound can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide or a combination thereof, and more specifically can be sodium hydroxide.

In one specific example, the basic compound may be used in an amount of 3.0 to 6.0 equivalents, more specifically, 4.0 to 5.5 equivalents, per 1 equivalent of the compound of formula III.

In one specific embodiment, the acid anhydride, acid chloride or carboxylic acid compound can be selected from acetic acid, acetic anhydride, acetyl chloride or a combination thereof, and more specifically, acetic anhydride.

In one specific embodiment, the acid anhydride, acid chloride or carboxylic acid compound may be used in an amount of 1.0 to 5.0 equivalents, more specifically 2.0 to 4.0 equivalents, per 1 equivalent of the compound of formula III.

In one specific example, the reaction temperature in step (2) may be 50 to 120°C, more specifically 60 to 100°C, but is not limited thereto.

(3) Step

In step (3) of the method for producing a compound of chemical formula I of the present invention, a compound of chemical formula IV is reacted with an acid chloride or a carboxylic acid compound in the presence of a basic compound to obtain a compound of chemical formula V.

In one specific embodiment, the basic compound can be selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, 1,8-diazabicyclo(5.4.0)undec-7-ene, tetramethylguanidine, triethylamine or a combination thereof, and more specifically, potassium carbonate.

In one specific example, the basic compound may be used in an amount of 0.9 to 5.0 equivalents, more specifically 2.0 to 4.0 equivalents, per 1 equivalent of the compound of formula IV.

In one specific embodiment, the acid chloride or carboxylic acid compound can be selected from 3,5,5-trimethylhexanoyl chloride, cyclohexyl chloride, 4-(4-chlorophenoxy)-phenoxymethyl chloride or a combination thereof, more specifically 3,5,5-trimethylhexanoyl chloride.

In one specific embodiment, the acid chloride or carboxylic acid compound may be used in an amount of 0.9 to 1.5 equivalents, more specifically 1.0 to 1.2 equivalents, per 1 equivalent of the compound of formula IV.

In one specific example, the reaction temperature in step (3) may be 50 to 120°C, more specifically 60 to 100°C, but is not limited thereto.

(4) Step

In step (4) of the method for producing a compound of chemical formula I of the present invention, a compound of chemical formula V is reacted with a hydroxyl ammonium salt in the presence of a basic compound to obtain a compound of chemical formula I.

In one specific embodiment, the hydroxyl ammonium salt can be hydroxyl ammonium chloride.

In one specific embodiment, the hydroxyl ammonium salt may be used in an amount of 0.9 to 5.0 equivalents, more specifically 2.0 to 4.0 equivalents, per 1 equivalent of the compound of formula V.

In one specific embodiment, the basic compound can be selected from an alkali metal carbonate, an alkali metal bicarbonate or a combination thereof, more specifically, can be selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or a combination thereof, and even more specifically, can be sodium carbonate or potassium carbonate.

In one specific example, the basic compound may be used in an amount of 0.2 to 1.5 equivalents, more specifically 0.5 to 1.0 equivalents, relative to 1 equivalent of the hydroxyl ammonium salt.

In one specific example, the reaction temperature in step (4) may be 50 to 150°C, more specifically 80 to 120°C, but is not limited thereto.

According to one specific example, the amount of solvent used in the method for preparing the compound of formula I of the present invention may be 50 wt% or less of the total reaction mixture.

According to one specific example, the method for preparing a compound of formula I of the present invention may further include, after step (4), a step of washing the reaction result with a sodium carbonate or sodium hydroxide solution.

According to one specific example, the method for preparing a compound of chemical formula I of the present invention may further include, after step (4), a step of distilling and removing a solvent, an organic substance (e.g., an organic acid), or both present in the reaction result.

The substituted 1-hydroxy-2-pyridone compound of chemical formula I prepared as described above can be usefully used as an intermediate for preparing piroctone olamine or ciclopirox.

Therefore, according to another aspect of the present invention, a method is provided which uses a substituted 1-hydroxy-2-pyridone compound of formula I prepared by the method of the present invention as an intermediate for preparing piroctone olamine or ciclopirox.

There is no particular limitation on the production of piroctone olamine or ciclopirox, except for using the compound of formula I manufactured according to the present invention as an intermediate, and these final compounds can be manufactured according to known methods.

According to one specific example, a compound having the following structure as a substituted 1-hydroxy-2-pyridone compound of chemical formula I can be used as an intermediate for producing piroctone olamine:

The above compound can react with ethanolamine to form piroctone olamine.

According to another specific example, a compound having the following structure as a substituted 1-hydroxy-2-pyridone compound of formula I can be used as an intermediate for producing ciclopirox:

The above compound can react with ethanolamine to form ciclopirox.

Hereinafter, the present invention will be described in more detail through examples. However, the scope of the present invention is not limited to these examples.

[Example]

Example 1: Preparation of 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-pyridone (1)

(1) Preparation of ethyl isodihydracetate

To 10.00 g (77.0 mmol) of ethyl acetoacetate, 15.08 g (154.0 mmol) of a concentrated sulfuric acid solution was added after cooling to 0°C or below. The mixture was stirred for 24 hours while maintaining the reaction temperature at 25°C. The reaction product was poured onto ice (30 g) and extracted with isopropyl ether (3 x 50 mL). The separated organic layer was washed with 10% aqueous sodium carbonate (1 x 50 mL), and then the separated organic layer was washed twice with purified water. The recovered organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The concentrated residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: n -heptane = 1:4) to obtain 7.14 g (94.7%) of ethyl isodihydracetate.

¹ H NMR (δ _ppm ; CDCl ₃ ): δ = 6.01 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 2.22 (s, 2H), 1.37 (t, J = 7.1 Hz, 3H)

δ 8.65 - 8.62 (dd, 1H), 8.05 - 8.02 (d, 1H), 7.66 - 7.55 (dd, 1H), 7.41 - 7.35 (d, 1H), 7.31 - 7.29 (dd, 1H), 3.43 - 3.38 (m, 4H), 3.05 (t, 2H), 1.87 - 1.77 (m, 2H), 1.04 (t, 3H)

MS( m/z ): 196

(2) Preparation of 4-methyl-2H-pyran-2,6(3H)-dione

Ethyl isodihydracetate obtained above 7.14 g (36.4 mmol) was dissolved in water (40 mL), 7.28 g (182.0 mmol) of sodium hydroxide was added, and the mixture was stirred at 60°C. Then, after cooling to 25°C, the reaction solution was washed with ethyl acetate solution (50 mL), and concentrated hydrogen chloride solution was added until the aqueous layer became pH = 2. The mixture was extracted with ethyl acetate (3 x 50 mL), and the separated organic layer was washed twice with purified water, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. To the obtained concentrated residue, 9.37 g (91.8 mmol) of acetic anhydride was added, stirred, and heated to reflux at 80°C. Then, after cooling to room temperature, acetic anhydride was removed by distillation under reduced pressure. After diluting with isopropyl ether (50 ml), the solution was filtered under reduced pressure to obtain 3.71 g (80.9%) of 4-methyl-2H-pyran-2,6(3H)-dione.

¹ H NMR (δ _ppm ; DMSO): δ = 6.09 (s, 1H), 3.64 (s, 2H), 1.97 (s, 3H)

MS( m/z ): 126

(3) Preparation of 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one

3.71 g (29.4 mmol) of the obtained 4-methyl-2H-pyran-2,6(3H)-dione and 12.19 g (88.2 mmol) of potassium carbonate were added to acetonitrile (30 mL), and 5.71 g (32.4 mmol) of 3,5,5-trimethylhexanoyl chloride was added and stirred at 80°C. Then, purified water was added and stirred, and the mixture was extracted with ethyl acetate (3x30 mL). The separated organic layer was washed twice with purified water, and the solvent was removed by distillation under reduced pressure. The product obtained by distillation of the organic layer under reduced pressure was added to ethyl acetate (7 mL), and 2.88 g (29.4 mmol) of a concentrated sulfuric acid solution was added and stirred at 60°C. The reaction mass was poured onto ice (30 g) and extracted with ethyl acetate (3x30 mL). After washing the separated organic layer with 10% aqueous sodium carbonate (1x50mL), the separated organic layer was washed twice with purified water, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The concentrated residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: n -heptane = 1:4) to obtain 5.94 g (90.9%) of 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one.

¹ H NMR (δ _ppm ; CDCl ₃ ): δ 6.22 (s, 1H), 6.18 (d, J = 1.0 Hz, 1H), 2.33 (ddd, J = 12.2, 7.0, 0.8 Hz, 1H), 2.14 (d, J = 0.9 Hz, 3H), 2.13 - 2.09 (m, 1H), 1.83 (ddd, J = 12.4, 7.0, 0.7 Hz, 1H), 1.59 (d, J = 4.9 Hz, 1H), 1.36 (d, J = 4.9 Hz, 1H), 1.08 (s, 9H), 1.06 (d, J = 6.4) Hz, 3H).

MS( m/z ): 222

(4) Preparation of 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-pyridone (1)

5.94 g (26.7 mmol) of the above-obtained 4-methyl-6-(2,4,4-trimethylpentyl)-2H-pyran-2-one, 5.57 g (80.1 mmol) of hydroxyl ammonium chloride, and 5.66 g (53.4 mmol) of sodium carbonate were added to n-heptane (6 mL) and water (0.3 mL) and stirred at 100°C. The mixture was filtered while hot and washed with ethyl acetate to obtain 5.73 g (90.4%) of compound (1) (1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-pyridone) having the following structure.

¹ H NMR (δ _ppm ; CDCl ₃ ): δ 5.87 (d, J = 1.0 Hz, 1H), 5.69 (s, 1H), 4.27 (s, 1H), 2.59 (ddd, J = 12.2, 7.0, 0.7 Hz, 1H), 2.37 (ddd, J = 12.2, 7.2, 0.7 Hz, 1H), 2.33 - 2.24 (m, 1H), 2.16 (d, J = 0.6 Hz, 3H), 1.61 (d, J = 4.5 Hz, 1H), 1.13 (d, J = 4.4 Hz, 1H), 1.11 (d, J = 6.4 Hz, 3H), 1.01 (s, 9H).

MS( m/z ): 237

Examples 2 and 3: Preparation of 1-hydroxy-4-methyl-6-cyclohexyl-2-pyridone (2) and 1-hydroxy-4-methyl-6-phenyl-2-pyridone (3)

The following compounds (2) and (3) were prepared in the same manner as in Example 1.

Examples 4 and 5: Preparation of piroctone olamine and ciclopirox using the compounds of Examples 1 and 2

(1) Production of piroctone olamine

5.73 g (24.1 mmol) of 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-pyridone(1) prepared in Example 1 and 1.77 g (29.0 mmol) of ethanolamine were added to ethyl acetate (8.60 mL) and stirred at 55°C. After stirring for 2 hours, the mixture was cooled to 0°C and filtered. The filtered solid was washed with cold ethyl acetate to obtain 6.85 g (95.1%) of piroctone olamine.

¹ H NMR (δ _ppm ; CDCl ₃ ): δ 6.93 (d, J = 55.4 Hz, 4H), 5.91 (d, J = 2.2 Hz, 1H), 5.87 (d, J = 2.8 Hz, 1H), 3.79 - 3.72 (m, 2H), 2.93 - 2.85 (m, 2H), 2.77 (dd, J = 13.4, 5.7 Hz, 1H), 2.38 (dd, J = 13.5, 8.9 Hz, 1H), 2.16 - 2.08 (m, 1H), 2.05 (s, 3H), 1.28 (dd, J = 14.0, 4.0 Hz, 1H), 1.16 (dd, J = 13.9, 6.0 Hz, 1H), 0.90 (d, J = 6.8 Hz, 3H), 0.89 (s, 9H).

MS( m/z ): 298

(2) Manufacturing of ciclopirox

5.00 g (24.1 mmol) of 1-hydroxy-4-methyl-6-cyclohexyl-2-pyridone (2) prepared in Example 2 and 1.77 g (29.0 mmol) of ethanolamine were added to ethyl acetate (7.50 mL) and stirred at 55°C. After stirring for 2 hours, the mixture was cooled to 0°C and filtered. The filtered solid was washed with cold ethyl acetate to obtain 6.13 g (94.7%) of ciclopirox.

¹ H NMR (δ _ppm ; CDCl ₃ ): δ 6.06 (s, 1H), 5.84 (s, 1H), 4.42 - 4.30 (m, 3H), 4.11 - 3.96 (m, 2H), 2.97 (t, J = 2.4 Hz, 3H), 2.32 - 2.21 (m, 2H), 2.17 - 2.16 (m, 3H), 2.16 - 2.12 (m, 2H), 1.75 - 1.65 (m, 6H).

MS( m/z ): 268

Claims (12)

A method for preparing a substituted 1-hydroxy-2-pyridone compound of chemical formula I,
(1) a step of reacting a compound of chemical formula II with an acidic compound to obtain a compound of chemical formula III;
(2) a step of reacting a compound of chemical formula III with a basic compound and then reacting the resultant with an acid anhydride, acid chloride or carboxylic acid compound to obtain a compound of chemical formula IV;
(3) a step of reacting a compound of chemical formula IV with an acid chloride or a carboxylic acid compound in the presence of a basic compound to obtain a compound of chemical formula V; and
(4) a method comprising the step of reacting a compound of formula V with a hydroxyl ammonium salt in the presence of a basic compound to obtain a compound of formula I;
[Chemical Formula I]

[Chemical Formula II]

[Chemical Formula III]

[Chemical Formula IV]

[Chemical formula V]

In the above,
R ¹ and R ³ are each independently a C ₁ -C ₁₀ alkyl group which is unsubstituted or substituted with one or more halogen atoms,
R ² is a C ₁ -C ₁₀ alkyl group which is unsubstituted or substituted with one or more halogen atoms; a C ₆ -C ₁₈ aryl group which is unsubstituted or substituted with one or more halogen atoms; or a C ₃ -C ₁₀ cycloalkyl group which is unsubstituted or substituted with one or more halogen atoms. A method in claim 1, wherein R ¹ is methyl and R ² is 2,4,4-trimethylpentyl, cyclohexyl, 4-(4-chlorophenoxy)-phenoxymethyl or phenyl. A method in which, in step (1), the acidic compound is selected from sulfuric acid, hydrochloric acid, nitric acid or a combination thereof, and is used in an amount of 0.5 to 3.0 equivalents per 1 equivalent of the compound of chemical formula II. A method in which, in step (2), the basic compound is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide or a combination thereof, and is used in an amount of 3.0 to 6.0 equivalents per 1 equivalent of the compound of chemical formula III. A method in which, in step (2), the acid anhydride, acid chloride or carboxylic acid compound is selected from acetic acid, acetic anhydride, acetyl chloride or a combination thereof, and is used in an amount of 1.0 to 5.0 equivalents per 1 equivalent of the compound of formula III. In the first paragraph, in the step (3), the basic compound is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, 1,8-diazabicyclo(5.4.0)undec-7-ene, tetramethylguanidine, triethylamine or a combination thereof, and is used in an amount of 0.9 to 5.0 equivalents per 1 equivalent of the compound of formula IV. A method in which, in step (3), the acid chloride or carboxylic acid compound is selected from 3,5,5-trimethylhexanoyl chloride, cyclohexyl chloride, 4-(4-chlorophenoxy)-phenoxymethyl chloride or a combination thereof, and is used in an amount of 0.9 to 1.5 equivalents per 1 equivalent of the compound of formula IV. A method in which, in the first paragraph, the hydroxyl ammonium salt in the step (4) is hydroxyl ammonium chloride, which is used in an amount of 0.9 to 5.0 equivalents per 1 equivalent of the compound of formula V. A method in which, in the step (4), the basic compound is selected from an alkali metal carbonate, an alkali metal bicarbonate or a combination thereof, and is used in an amount of 0.2 to 1.5 equivalents per 1 equivalent of the hydroxyl ammonium salt. delete delete delete