KR101974850B1 - Novel preparation method for acetaminophen - Google Patents

Abstract

The present invention relates to a novel process for the preparation of acetaminophen, and more particularly to a process for the preparation of acetaminophen which comprises reacting a benzene compound substituted with a specific functional group with acetamide in the presence of a metal catalyst. And reacting the product with an aqueous solution in the presence of a metal catalyst and a base to prepare acetaminophen. In particular, the present invention relates to a process for producing acetaminophen which is eco-friendly since no strong acid is used in the production process, and acetaminophen can be produced at a high reaction yield by omitting the step of isolating the position isomers.

Description

NOVEL PREPARATION METHOD FOR ACETAMINOPHEN [0002]

The present invention relates to a novel process for the preparation of acetaminophen. More specifically, the present invention relates to a method for producing acetaminophen which can realize a high yield and excellent isomer selectivity while simplifying the synthesis process, and is environmentally friendly and highly economical.

Acetaminophen is a nonsteroidal antiinflammatory drug that is known to have analgesic, antiinflammatory, and antipyretic actions as a mechanism to inhibit the synthesis of prostaglandins.

As a general method for producing such acetaminophen, there is a method using benzene chloride and phenol as starting materials. In the method using benzene chloride as a starting material, benzene chloride is reacted with a mixed acid of nitric acid and sulfuric acid, which are strong acids, to carry out the nitration reaction, and nitrobenzene chloride as an intermediate substance is produced. At this time, the benzene ring ortho of the reaction process in nitro - (ortho -), meta - (meta -), and para - (para -) A mixture of the regioisomeric functional group is introduced into the night position is generated. From the mixture thus obtained, benzene chloride is separated with para-nitrate, and para-nitro phenol is synthesized through a hydroxylation reaction. The nitro functional group of the resulting para-nitrophenol is reduced to obtain para-aminophenol, and the resulting amino functional group is subjected to an acetylation reaction to synthesize acetaminophen.

In the method using phenol in which hydroxy is already introduced into the benzene ring, the nitration reaction is carried out by reacting with a mixed acid of nitric acid and sulfuric acid to introduce an amide functional group at the para-position of the phenol. Nitrophenol containing positional isomers is synthesized through the nitration reaction, wherein only the para-isomer is separated and reduced to obtain para-aminophenol, which is subjected to acetylation reaction to synthesize acetaminophen.

However, the previously known methods for preparing acetaminophen have undergone several steps of reaction in order to introduce an amino group or a hydroxy group into the benzene ring. In particular, the use of strong acids in the process of introducing nitro functional groups to the benzene ring has involved manufacturing processes which are not harmful or environmentally friendly to the human body and require additional apparatus or process steps to recover or dispose of the strong acids used and discarded.

In the reaction the nitro in benzene ring functional groups nitro, ortho - (ortho -), meta - (meta -), and para - (para -) since the introduction of greater than or equal to 1 for the location of the various positional isomers are generated, these There is a limitation that a separation process for separating only desired para-isomers must be introduced. Even if the process of separating only the para-isomer is performed, there is a certain limit in increasing the synthesis yield and selectivity of the final product.

Accordingly, while it is possible to synthesize acetaminophen with high yield and excellent isomer selectivity while simplifying the synthesis process, an environmentally friendly manufacturing process design capable of satisfying both the increasing environmental regulation and the harmfulness problem of the human body manufacturing process There is a demand for development of a process for producing acetaminophen.

The present invention provides a method for producing acetaminophen which can realize a high yield and excellent isomer selectivity while simplifying the synthesis process, and is environmentally friendly and highly economical.

The present invention relates to a process for preparing a compound of formula (I), which comprises reacting a compound of formula (I) with acetamide in the presence of a first metal catalyst comprising at least one compound selected from the group consisting of a copper compound and a palladium compound, Reacting the compound of Formula 2 with water in the presence of a base and a second metal catalyst comprising a copper compound and a base.

[Chemical Formula 1]

(2)

X ¹ and X ² are each independently selected from the group consisting of halogen, an alkoxy group having 1 to 4 carbon atoms, nitro (NO ₂ ), a diazonium salt, a sulfonate, a phosphate, Tosylate, or Triflate. In Formula 2, X ³ represents X ¹ and X ² Is an unsubstituted functional group in the reaction with acetamide. X ¹ and X ² are each preferably halogen and more preferably iodine (I) in order to obtain acetaminophen with high isomer selectivity and excellent reaction yield.

Hereinafter, a method for producing acetaminophen according to a specific embodiment of the present invention will be described in detail.

The present inventors have studied about an environmentally friendly, efficient and economical production method of acetaminophen which has widely used analgesic, antiinflammatory and antipyretic activities which are widely used in the world, and found that a benzene compound substituted with a specific functional group in the presence of the above- Amide and water in the presence of a base to produce acetaminophen.

According to this production method, acetaminophen can be provided with a high yield and excellent isomer selectivity while simplifying the synthesis process, and it is possible to design an environmentally friendly and harmless process by minimizing the use of an organic solvent such as strong acid, Because the introduction of hydroxy groups or amino groups into the benzene ring does not involve complex compounds and complex processes, the cost of process design and production cost of the final product can be reduced.

According to one embodiment of the invention, there is provided a process for the preparation of a compound of formula (I), which comprises reacting a compound of formula (I) with acetamide in the presence of a first metal catalyst comprising at least one compound selected from the group consisting of a copper compound and a palladium compound, ; And a step of reacting the compound of formula (2) with water in the presence of a base and a second metal catalyst comprising a copper compound, and a method for producing acetaminophen.

[Chemical Formula 1]

(2)

X ¹ and X ² are each independently selected from the group consisting of halogen, an alkoxy group having 1 to 4 carbon atoms, nitro (NO ₂ ), a diazonium salt, a sulfonate, a phosphate, Tosylate, and Triflate. In Formula 2, X ³ is an unsubstituted functional group in the reaction of X ¹ and X ² with the acetamide.

In the production method of the acetaminophen and the compound of formula (I) as starting material, p-in the existing production process - a has been performed in order to introduce a functional group at a position, generated by the reaction nitro ortho - (para) - (ortho - ), Meta - ( meta -), and para - ( para -) may be omitted. In addition, it is an economical, efficient and environmentally friendly production method without using a strong acid such as nitric acid and sulfuric acid added in the nitration reaction. In addition, the production method of the acetaminophen is para compound of the formula 1 - (para -) to the combined effect of X ^1, X ² leaving group metal catalyst of the present in position with high isomeric selectivity compared to the conventional method , And acetaminophen can be obtained with excellent reaction yield.

More specifically, when the compound of Formula 1 is reacted with acetamide in the presence of a first metal catalyst comprising at least one compound selected from the group consisting of the copper compound and the palladium compound, X ¹ and X ^One of the two can be acetamidated to form the para form of formula 2. [ In other words, so that, in the production method of the acetaminophen it can be acetaminophen that the final composite is substantially obtained most p (para) form only by forming as an intermediate a compound of formula 2 in the presence of a metal catalyst.

The cuprous compound contained in the metal catalyst or a bimetallic catalyst is a halogenated copper, copper acetate (Cu (OAc) _2), copper cyanide (CuCN), triflate copper (Cu (OTf) _2), triflate copper benzene Composition ((CuOTf) ₂ Benzene) may be a copper sulfate (CuSO _4), or a mixture thereof. In order to improve the yield of the acetaminophen production method, it is preferable to use copper halide as the copper compound, and specific examples of the copper halide include copper chloride, copper bromide, and copper iodide.

The palladium compound may be palladium acetate (Pd (OAc) ₂ ), trisdibenzylidacetone dipalladium (Pd ₂ (dba) ₃ ), or a mixture thereof.

The amount of the first metal catalyst used in the step of forming the compound of Formula 2 may be appropriately controlled according to the amount of the reactant to be introduced. For example, the metal catalyst may be used in an amount of 0.1 to 10 mol% May be used in an amount of 1 to 4 mol%.

The first metal catalyst may further include an organic ligand compound. The organic ligand compound may form a complex with the metal catalyst, and electrons may be donated to the metal catalyst to increase the selectivity of the isomer of acetaminophen produced together with the activity of the catalyst.

The free ligand can be appropriately controlled depending on the specific components or properties of the metal catalyst used. Specifically, as the organic ligand compound, an amine compound, an amino acid, an organic phosphorus compound, or a mixture of two or more thereof may be used.

When the organic ligand compound is reacted in the presence of a metal catalyst containing a copper compound, it is preferable to add an amine compound or an amino acid as an organic ligand compound The yield is obtained, and it is more preferable to add diamine. When the reaction is carried out in the presence of a metal catalyst containing a palladium compound, an organic phosphorus compound is preferably added.

Specific examples of the amine compound is ethylenediamine (ethylenediamine), N, N ' - dimethyl-ethylenediamine (N, N' -dimethylethylenediamine, DMEDA ), N, N, N ', N' - tetramethyl ethylene diamine min (N, N, N ', N' -tetramethylethylenediamine), cyclohexane diamine (cyclohexanediamine), N, N ' - dimethyl-cyclohexane-diamine (N, N' -dimethylcyclohexanediamine), 1,10- phenanthroline (1,10-phenanthroline), or a mixture of two or more thereof.

Examples of the amino acids glycine (glycine), proline (proline), N, N - there may be mentioned dimethyl glycine (N, N -dimethylglycine), or combinations of two or more of the mixture,

The organophosphorous compound refers to a compound in which hydrogen or a hydrocarbon is substituted for a phosphorus atom. Specifically, the central phosphorus atom is substituted with hydrogen, an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an alkynyl group having 2 to 20 carbon atoms alkynyl), a cycloalkylene group having 4 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms, or an aliphatic heterocyclic group or aromatic heterocyclic group having 5 to 30 carbon atoms including nitrogen, oxygen or sulfur . Preferable examples of the organophosphorous compound include 2- (Dicylcohexylphosphino) biphenyl, 2- (di-tert-butylphosphino) biphenyl, BINAP, Xantphos or a mixture of two or more thereof.

The molar ratio of the first metal catalyst to the organic ligand compound may be 1: 1 to 1:20, preferably 1: 1 to 1:10, and more preferably 1: 1 to 1: 5. If the molar ratio of the catalyst to the organic ligand compound is less than 1: 1, the degree of catalytic activity may be insignificant, and if the molar ratio exceeds 1:20, the purification process may be difficult.

The step of forming the compound of formula (2) may be carried out in the presence of an organic solvent. Specific examples of the usable organic solvent include benzene, toluene, alkylbenzene, dimethylsulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran (THF), dioxane, ethyl acetate (EA) , Or a mixture thereof.

Meanwhile, the step of forming the compound of Formula 2 may further include adding a base. As the base is added in the step of reacting the compound of formula (1) with the acetamide in the presence of the metal catalyst, the compound of formula (2), which mediates effectively the reaction between the compound of formula (1), acetamide and the first metal catalyst, Thereby making it possible to improve the efficiency of the production process and the selectivity of the final reaction product while reducing the total reaction time.

The type of base that can be used in the step of forming the compound of Formula 2 is not particularly limited and specific examples thereof include powdery or granular tribasic potassium phosphate (K ₃ PO ₄ ), potassium carbonate (K ₂ CO ₃ ) include cesium carbonate (Cs ₂ CO _3), potassium fluoride (KF), sodium fluoride (NaF), a cesium fluoride (CsF), tetrabutyl ammonium fluoride (TBAF), or a mixture thereof .

The step of forming the compound of Formula 2 may be performed at 25 to 200 ° C, preferably 60 to 150 ° C, more preferably 70 to 130 ° C. If the reaction temperature is lower than 25 ° C, the reactants may not sufficiently react to lower the yield of the reaction, or the amount of acetaminophen may be insignificant. When the reaction temperature is higher than 200 ° C, unnecessary side reactions may occur excessively The stereoisomeric selectivity of the final compound may be greatly reduced.

On the other hand, the by water and in the presence of a bimetallic catalyst and a base comprising a compound of formula (2) obtained by reacting the compound and acetamide of the formula in the presence of the above-mentioned first metal catalyst is a copper compound X ¹ and X ² The unsubstituted functional group may be substituted with a hydroxy group.

The water reacting with the compound of formula (2) may be not only general water but also distilled water, supernatant water or deionized water.

Examples of the base that can be used in this reaction step are not particularly limited, but specifically include powdery or granular tribasic potassium phosphate (K ₃ PO ₄ ), potassium carbonate (K ₂ CO ₃ ), cesium carbonate (Cs ₂ CO ₃ ), Potassium fluoride (KF), sodium fluoride (NaF), cesium fluoride (CsF), tetrabutylammonium fluoride (TBAF), or a mixture of two or more thereof.

The copper compound may be at least one selected from the group consisting of copper halide, copper acetate (Cu (OAc) ₂ ), copper cyanide (CuCN), triflate copper (Cu (OTf) ₂ ), triplet copper benzene complex (CuOTf ₂ Benzene) ₄ ), or a mixture thereof. Specific examples of the copper halide include copper chloride, copper bromide, and copper iodide. It is preferable to use copper halide for high yield.

The second metal catalyst may further include an organic ligand compound. The organic ligand compound may form a complex with the metal catalyst, and electrons may be donated to the metal catalyst to increase the selectivity of the isomer of acetaminophen produced together with the activity of the catalyst. .

The free ligand can be appropriately controlled depending on the specific components or properties of the metal catalyst used. In the case of the second metal catalyst containing the copper compound, it is preferable to use an amine compound or an amino acid as the organic ligand, more preferably a diamine compound.

The amount of the second metal catalyst used in the step of reacting the compound of Formula 2 with water may be appropriately controlled according to the amount of the reactant to be introduced. For example, the second metal catalyst may be used in an amount of 5 to 15 mol %, Preferably 8 to 13 mol%.

The molar ratio of the metal catalyst to the organic ligand compound may be 1: 1 to 1:20, preferably 1: 1 to 1:10, and more preferably 1: 1 to 1: 5. If the molar ratio of the catalyst to the organic ligand compound is less than 1: 1, the degree of catalytic activity may be insignificant, and if the molar ratio exceeds 1:20, the purification process may be somewhat difficult.

Specific examples of the organic ligand compound include amine compounds, amino acids, and mixtures thereof. The amine-based compound is particularly ethylenediamine (ethylenediamine), N, N ' - dimethyl-ethylenediamine (N, N' -dimethylethylenediamine, DMEDA ), N, N, N ', N' - tetramethyl ethylene diamine (N, N, N ', N' -tetramethylethylenediamine), cyclohexane diamine (cyclohexanediamine), N, N'- dimethyl-cyclohexane-diamine (N, N '-dimethylcyclohexanediamine), 1,10- phenanthroline ( 1,10-phenanthroline, or a mixture of two or more thereof.

In addition, specific examples of the amino acid is glycine (glycine), proline (proline), N, N - there may be mentioned dimethyl glycine (N, N -dimethylglycine), or combinations of two or more thereof.

In addition, the step of reacting the compound of Formula 2 with water may be carried out in the presence of a predetermined solvent. In the step of reacting the compound of Formula 2 with water, a mixture of a water-soluble solvent and an organic solvent or a water-soluble solvent alone may be used as a solvent. Preferable examples of the solvent include a mixture of an organic solvent of DMSO or DMF and a water-soluble solvent containing water, or water. However, in order to improve the reaction yield and isomer selectivity to acetaminophen finally synthesized and to omit the step of separating the organic solvent, the step of reacting the compound of Formula 2 with an aqueous solution is preferably carried out in a water-soluble solvent , And a preferable example of the water-soluble solvent is water.

The step of reacting the compound of Formula 2 with water may be performed at 25 to 200 ° C, preferably 100 to 200 ° C, more preferably 130 to 200 ° C. If the reaction temperature is lower than 25 ° C, the reactants may not sufficiently react to lower the yield of the reaction, or the amount of acetaminophen may be insignificant. When the reaction temperature is higher than 200 ° C, unnecessary side reactions may occur excessively The stereoisomeric selectivity of the final compound may be greatly reduced.

The reaction vessel can be used without any limitations as long as it can be commonly used for the synthesis of the compound and the like. The size, shape and kind of the reactor can be appropriately controlled in consideration of the reaction conditions, the amount of the reactant and the amount of the product. Preferably a glass round bottom flask, a reactor which is injected with inert gas or is easy to remove air, or a reactor capable of withstanding high pressure such as a pressure tube can be used.

According to the present invention, it is possible to provide an economical and efficient method for producing acetaminophen which can exhibit excellent isomer selectivity and omit the step of separating the regioisomers. More specifically, it is possible to provide a method for producing acetaminophen which is environmentally friendly A novel process for the preparation of acetaminophen which can give the final product in reaction yield can be provided.

The invention will be described in more detail in the following examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

Example  : Acetaminophen Manufacturing

[ Example  One]

One. N- Acetyl -p- iodoaniline : ≪

To the reactor was added para-diiodobenzene (1 mmol), acetamide (1.5 mmol), CsF (1.5 mmol), CuI (0.02 mmol) and DMEDA (0.2 mmol) in THF (4 mL) And the reaction temperature was raised to 75 캜 and allowed to react for 24 hours. After the reaction mixture was cooled to room temperature, 20 mL of ethyl acetate was added, and the organic layer was washed with a saturated aqueous solution of NH ₄ Cl (20 mL) or distilled water (20 mL). Then, MgSO ₄ or NaSO ₄ was added thereto, All the organic solvent was removed from the remaining organic layer through a reduced pressure concentrator. The concentrated material was purified by column chromatography to give the desired product in 76% yield. At this time, the yield was calculated as (moles of the obtained compound / moles of the starting material) * 100.

Formula ^{2-1: 1 H NMR (DMSO)} δ 10.03 (s, 1H), 7.61 (d, 2H, J = 8.4), 7.42 (d, 2H, J = 8), 2.03 (s, 3H)

2. Acetaminophen  Produce:

Of formula 2-1 to the synthesis pressure tube N- acetyl-p-iodo-aniline (1 mmol) and, CsF (2 mmol), CuI (0.1 mmol), DMEDA (0.5 mmol) of distilled water (H ₂ O, 4 mL ), Inert gas was injected and stirred, and the reaction temperature was raised to 160 ° C or 180 ° C and allowed to react for 24 hours.

At the time when the reaction is completed, the lower the temperature of the pressure tube to room temperature, placed into 20 mL of ethyl acetate, after washed the organic layer with saturated NH ₄ Cl solution (20 mL) or distilled water (20 mL), MgSO ₄ or NaSO ₄ And the precipitate was removed by a filter, and the remaining organic layer was removed from the organic solvent through a vacuum concentrator. The concentrated material was purified by column chromatography to give the desired product in 63% yield. At this time, the yield was calculated as (moles of the obtained compound / moles of the starting material) * 100.

Formula ^{3: 1 H NMR (DMSO)} δ 9.65 (s, 1H), 9.14 (s, 1H), 7.33 (d, 2H, J = 9.6), 6.67 (d, 2H, J = 8.4), 2.00 (s, 3H)

¹³ C NMR (DMSO)? 167.4, 153.0, 130.9, 120.7, 114.9, 23.6

[ Example 2 ]

Acetyl-p-bromoaniline and Acetaminophen were obtained in the same manner as in Example 1 except that para-dibromobenzene (1 mmol, Formula 2-2) was used instead of para-diiodobenzene (1 mmol) .

2H, J = 9.2), 2.05 (s, 3H), 7.46 (d, 2H, J =

[ Example 3 ]

Acetyl-p-chroloaniline and Acetaminophen (1 mmol) were obtained in the same manner as in Example 1, except that para-dichlorobenzene (1 mmol, Formula 2-3) was used instead of para-diiodobenzene .

(D, 2H, J = 8.8), 7.34 (d, 2H, J = 8.8), 2.04 (s, 3H)

In the above examples, acetaminophen can be synthesized using para-dihalogenated benzene as a starting material and a specific metal catalyst using N-acetyl-para-halogenated aniline as an intermediate, with high isomer selectivity and high reaction yield .

Further, in the above example, the synthesis step can be simplified by omitting the step of introducing a nitro group at the para position of the benzene ring, the step of reducing the nitro group, and the like. In addition, The use of an organic solvent can be suppressed, and acetaminophen can be produced in an environmentally friendly and economical manner.

In addition, it has been confirmed that acetaminophen can be produced in a high yield (Example 1) of 60% or more through the above-described process for producing acetaminophen which is simpler, economical and environmentally friendly than the conventional process.

Claims (19)

Reacting a compound represented by the following formula (1) with acetamide in the presence of a first metal catalyst comprising at least one compound selected from the group consisting of a copper compound and a palladium compound to form a compound of the following formula (2); And
Reacting the compound of Formula 2 with water in the presence of a second metal catalyst comprising a copper compound and a base,
[Chemical Formula 1]

(2)

X ¹ and X ² are each independently selected from the group consisting of halogen, an alkoxy group having 1 to 4 carbon atoms, nitro (NO ₂ ), a diazonium salt, a sulfonate, a phosphate, , Tosylate, and Triflate, and is selected from the group consisting of:
In Formula 2, X ³ represents X ¹ and X ² Is an unsubstituted functional group in the reaction with acetamide. The method according to claim 1,
The cuprous compound contained in the metal catalyst or a bimetallic catalyst is a halogenated copper, copper acetate (Cu (OAc) _2), copper cyanide (CuCN), triflate copper (Cu (OTf) _2), triflate copper benzene A complex ((CuOTf) ₂ Benzene), and a copper sulfate (CuSO ₄ ). The method according to claim 1,
Wherein the palladium compound comprises at least one selected from the group consisting of palladium acetate (Pd (OAc) ₂ ) and trisdibenzylidetacetone dipalladium (Pd ₂ (dba) ₃ ). The method according to claim 1,
Wherein the first metal catalyst further comprises an organic ligand compound. 5. The method of claim 4,
Wherein the molar ratio of the first metal catalyst to the organic ligand compound is from 1: 1 to 1:20. 5. The method of claim 4,
Wherein the organic ligand compound comprises at least one compound selected from the group consisting of an amine compound, an amino acid, and an organic phosphorus compound. The method according to claim 6,
Wherein the amine compound is ethylenediamine (ethylenediamine), N, N ' - dimethyl-ethylenediamine (N, N' -dimethylethylenediamine, DMEDA ), N, N, N ', N' - tetramethyl ethylene diamine (N , N, N ', N' -tetramethylethylenediamine), cyclohexane diamine (cyclohexanediamine), N, N ' - dimethyl-cyclohexane-diamine (N, N' -dimethylcyclohexanediamine), and 1,10-phenanthroline (1 , 10-phenanthroline). ≪ / RTI > The method according to claim 6,
The amino acid glycine (glycine), proline (proline), and N, N - dimethyl glycine method of acetaminophen comprising at least one compound from the group consisting of (N, N -dimethylglycine). The method according to claim 6,
Wherein the organophosphorous compound comprises at least one compound selected from the group consisting of 2- (Dicylcohexylphosphino) biphenyl, 2- (di-tert-butylphosphino) biphenyl, BINAP and Xantphos. The method according to claim 1,
Wherein the step of forming the compound of Formula 2 is carried out in an organic solvent. 11. The method of claim 10,
The solvent is selected from the group consisting of benzene, toluene, alkylbenzene, dimethylsulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran (THF), dioxane, and ethyl acetate (EA) A method for producing acetaminophen comprising at least one compound. The method according to claim 1,
Wherein the step of forming the compound of Formula 2 further comprises the step of adding a base. 13. The method of claim 12,
The base is selected from the group consisting of potassium tribasic (K ₃ PO ₄ ), potassium carbonate (K ₂ CO ₃ ), cesium carbonate (Cs ₂ CO ₃ ), potassium fluoride (KF), sodium fluoride (NaF), cesium fluoride ), And tetrabutylammonium fluoride (TBAF). ≪ / RTI > The method according to claim 1,
Wherein the step of forming the compound of Formula 2 is carried out at 25 to 200 ° C. The method according to claim 1,
The base used in the step of reacting the compound of the formula (2) with water may be potassium _tertiary phosphate (K ₃ PO ₄ ), potassium carbonate (K ₂ CO ₃ ), cesium carbonate (Cs ₂ CO ₃ ), potassium fluoride ), Sodium fluoride (NaF), cesium fluoride (CsF), and tetrabutylammonium fluoride (TBAF). The method according to claim 1,
Wherein the second metal catalyst further comprises an organic ligand compound. 17. The method of claim 16,
Wherein the molar ratio of the second metal catalyst to the organic ligand compound is from 1: 1 to 1:20. The method according to claim 1,
The step of reacting the compound of formula (2) with water is carried out in a water-soluble solvent. The method according to claim 1,
Wherein the step of reacting the compound of Formula 2 with water is carried out at 25 to 200 ° C.