KR101110331B1 - Isothiazole derivatives and process for the preparation thereof - Google Patents

Abstract

The present invention relates to a 3-hydroxy-5-mercapto-4-isothiazole alkyl ester or a salt thereof, a method for preparing the same, and a 4-carboxy-3-hydroxy-5-mer which is essential for preparing cetetane using the same. Provided are methods for preparing compounds of capto-4-isothiazole tri-salts.
By using the compound, the compound of 4-carboxy-3-hydroxy-5-mercapto-4-isothiazole tri-salt, which is essential for the preparation of cetetane, can be prepared for a short time at a significantly lower temperature than the conventional method. It is efficient and has the advantage that no harmful gas is generated as a by-product.

Description

Isothiazole derivatives and process for preparing the same

The present invention relates to a novel isothiazole derivative and a method for preparing the same, and more particularly to 4-carboxy-3-hydroxy-5-mercapto-isothiazole tri-salt, which is an intermediate useful for preparing cetetane. It relates to an intermediate for production and a method for producing the intermediate.

Celltetane is a semisynthetic injectable cephalosporin-based antibiotic having a structure of Formula 4, and is described in US Pat. Nos. 4,263,432 and Chem. Pharm. Bull. 28, 2629-2636 (1980).

[Formula 4]

U.S. Patent 4,263,432 and Chem. Pharm. Bull. 28, 2629-2636 (1980), the cetetane compound of formula 4 is 7α- (4-carboxy-3-hydroxyisothiazol-5-yl) thioacetamido-7 α-meth It is prepared from oxy-3- (1-methyltetrazol-5-yl) thiomethyl-Δ ³ -cepem-4-carboxylic acid.

[Chemical Formula 5]

The compound of Formula 5 is 7α- bromoacetaldehyde amide -7α--methoxy-3- (1-methyl-tetrazol-5-yl) thiomethyl -Δ ³ - cephem-4-carboxylic acid to the 4 of the formula (3) It is prepared by reacting with -carboxy-3-hydroxy-5-mercapto-isothiazole trisodium or tripotassium salt.

[Chemical Formula 3]

In Chemical Formula 3a,

R ^{2 '} , R ^3' , and R ⁴ are all potassium or sodium.

The 4-carboxy-3-hydroxy-5-mercapto-isothiazole trisodium or tripotassium is an essential intermediate in the preparation of cethetane.

The method for preparing 4-carboxy-3-hydroxy-5-mercapto-isothiazole trisodium salt or tripotassium salt of Chemical Formula 3a may be obtained by dicyano-1,1-ethylene-dithiol as shown in Scheme 1 below. Disodium salt or disodium salt (6) is reacted with 30% hydrogen peroxide to give disodium or disodium salt (7) of 3-hydroxy-5-mercapto-4-isothiazole carbonitrile, It is prepared by refluxing for 15 hours or more in an aqueous solution of sodium hydroxide (EP 1258482A).

Scheme 1

In Scheme 1, R ^{2 ′} , R ^{3 ′} , and R ⁴ are all Na or K.

The same method as in Scheme 1 is performed by dissolving the disodium or dipotassium salt of 3-hydroxy-5-mercapto-4-isothiazole carbonitrile in an aqueous solution of sodium hydroxide to prepare trisodium or tripotassium salt of Formula 3a. The reaction takes a long time because it has to be refluxed for more than 15 hours, the reaction temperature also has to draw up to 100 ℃ or more for reflux reaction, there is a drawback of excessive energy consumption. In addition, there is a problem that a large amount of ammonia gas, a strong alkaline substance harmful to the human body is generated as a by-product during the hydrolysis of the carbonitrile group during the reaction to cause environmental pollution.

Therefore, the inventors of the present invention, 4-carboxy-3-hydroxy-5-mercapto-isothiazole tri-salts, which are essential intermediates for the preparation of cetetane, have been described in terms of reaction time and reaction conditions without generating gases harmful to the human body. As a result of studying a more efficient method, alkyl esters were introduced instead of carbonitrile of disodium salt or dipotassium salt of 3-hydroxy-5-mercapto-4-isothiazole carbonitrile, which is the intermediate for preparing the intermediate. When the reaction can be made more efficiently and no harmful gas to the human body was found to complete the present invention.

Accordingly, an object of the present invention is to provide a manufacturing intermediate for more efficiently preparing 4-carboxy-3-hydroxy-5-mercapto-isothiazole tri-salt, which is an intermediate of cetetane.

Another object of the present invention is to provide a method for preparing the intermediate.

Another object of the present invention is to provide a method for preparing 4-carboxy-3-hydroxy-5-mercapto-isothiazole tri-salt using the intermediate.

According to one aspect of the invention, there is provided a compound of formula (2).

[Formula 2]

In Chemical Formula 2,

R ¹ is C ₁ -C ₈ alkyl; benzyl; Or a benzyl substituted with C _{1 -6} alkyl, C _{1 -6} alkoxy, or halogen,

R ² and R ³ are each independently hydrogen, Li, Na, or K.

The compound of Formula 2 may exist as tautomers of the structure as shown in Formula 2c, and it is to be understood that the compound of Formula 2 encompasses the following tautomers.

[Formula 2c]

In Chemical Formula 2c,

R ¹ is C ₁ -C ₈ alkyl; benzyl; Or a benzyl substituted with C _{1 -6} alkyl, C _{1 -6} alkoxy, or halogen,

R ² and R ³ are each independently hydrogen, Li, Na, or K.

Among the compounds of Formula 2, compounds corresponding to Formula 2a may be prepared by a method comprising the step of reacting a compound of Formula 1 with hydrogen peroxide:

(2a)

In Chemical Formula 2a,

R ¹ is C ₁ -C ₈ alkyl; benzyl; Or a benzyl substituted with C _{1 -6} alkyl, C _{1 -6} alkoxy, or halogen,

R ^{2 '} and R ^3' are each independently Li, Na, or K;

[Formula 1]

In Chemical Formula 1,

R ¹ is C ₁ -C ₈ alkyl; benzyl; Or a benzyl substituted with C _{1 -6} alkyl, C _{1 -6} alkoxy, or halogen,

R ^{2 '} and R ^3' are each independently Li, Na, or K.

Among the compounds of Formula 2, compounds corresponding to Formula 2b may be prepared by a method comprising adjusting the pH to 4-6 by adding an acid to a solution of the compound of Formula 2a:

[Formula 2b]

In Formula 2b, R ¹ is C ₁ -C ₈ alkyl; benzyl; Or a C _{1 -6} alkyl substituted benzyl, C _{1 -6} alkoxy, or halogen.

In addition, the compound of Formula 2 may be used to prepare a compound of Formula 3, 4 to 8 equivalent bases selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof in a solution of the compound of Formula 2 The compound of formula 3 may be prepared by a method comprising adding and reacting at 70 ° C. to 80 ° C. for 30 minutes to 1 hour.

(3)

In Chemical Formula 3,

R ^{2 '} , R ^3' , and R ⁴ are each independently Li, Na, or K.

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

The compound of formula (2) provided by the present invention as a novel compound may be used as a preparation intermediate of the compound of formula (3), which is an intermediate necessary for the preparation of cetetane.

[Formula 2]

In Chemical Formula 2,

R ¹ is C ₁ -C ₈ alkyl; benzyl; Or a benzyl substituted with C _{1 -6} alkyl, C _{1 -6} alkoxy, or halogen,

R ² and R ³ are each independently hydrogen, Li, Na, or K;

(3)

In Chemical Formula 3,

R ^{2 '} , R ^3' , and R ⁴ are each independently Li, Na, or K.

The compound of Formula 3 is added 4 to 8 equivalents of a base selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof in a solution of the compound of formula 2 and the reaction temperature is 70 ℃ to 80 ℃, 30 It can be made by a method comprising the step of reacting for 1 minute to 1 hour.

Water, methanol, ethanol may be used as a solvent used to prepare a solution of the compound of Formula 2, and specifically water may be used.

Since the alkyl ester of the compound of Formula 2 is significantly more reactive than the conventional carbonnitrile, when 4 to 8 equivalents of the base is added to a solution of the compound of Formula 2 and reacted at 70 ° C. to 80 ° C. for 30 minutes to 1 hour. Compounds of formula 3 can be produced. Therefore, by using the compound of Formula 2, the compound of Formula 3 may be efficiently prepared by reacting for a short time at a significantly lower reaction temperature than the conventional method. In addition, the compound of formula (2) is a salt but less hygroscopic can be used for direct industrial use in commercial production. In addition, since the compound of Formula 2 has an alkylester structure, and thus produces alcohol as a by-product when preparing the compound of Formula 3, the conventional 3-hydroxy-5-mercapto-4-isothiazole carbonitrile di- Unlike salt-based methods that generate harmful ammonia gas, it does not cause environmental pollution.

The compound of formula 3 prepared by the above method may be purified according to a conventional method known in the field of organic chemistry, for example, the product is concentrated under reduced pressure at a temperature of 50 ℃ to 60 ℃ cooled to ambient temperature The organic solvent is added to the concentrate, the precipitate is filtered off, washed with a solvent, and dried under reduced pressure again at a temperature of 30 ° C. to 50 ° C. to obtain a pure compound of Chemical Formula 3. The organic solvent for producing the precipitate may be selected from the group consisting of methanol, ethanol, isopropanol, 1-butanol, acetone, methyl ethyl ketone, and mixtures thereof, but is not limited thereto. An organic solvent can be used.

Among the compounds of Formula 2, the compound of Formula 2a may be generated by reacting the compound of Formula 1 with hydrogen peroxide.

(2a)

In Chemical Formula 2a,

R ¹ is C ₁ -C ₈ alkyl; benzyl; Or a benzyl substituted with C _{1 -6} alkyl, C _{1 -6} alkoxy, or halogen,

R ^{2 '} and R ^3' are each independently Li, Na, or K;

[Formula 1]

In Chemical Formula 1,

R ¹ is C ₁ -C ₈ alkyl; benzyl; Or a benzyl substituted with C _{1 -6} alkyl, C _{1 -6} alkoxy, or halogen,

R ^{2 '} and R ^3' are each independently Li, Na, or K.

Specifically, the di-salt of α-cyano-α-carboalkoxy-1,1-ethylene-dithiol of the formula (1) is dissolved in an organic solvent and is -10 ° C to 30 ° C, preferably 5 ° C to After maintaining at a temperature of 15 ℃, by adding 5% to 35% of hydrogen peroxide and reacted for 2 hours to 3 hours to obtain the compound of Formula 2a in high yield.

The method for preparing the compound of Formula 1 may be prepared by conventional methods known in the art, for example, by reacting cyano alkyl ester and carbon disulfide under basic conditions in an organic solvent, in high purity, high yield. (GOMPPER UND Tmm PFL. 2861-2870, 1963; Acta. Chem. Scand. 17. 362-376, 1963; Acta. Chem. Scand. 22. 1107. 1968).

The organic solvent may be any compound as long as the compound of Formula 1 and a compound capable of dissolving hydrogen peroxide, for example, water, methanol, ethanol may be used.

The compound of Formula 2a prepared by the above method may be directly used to prepare the compound of Formula 3 without purification, but the process of purifying the compound of Formula 2a may be performed. The product was concentrated under reduced pressure, an organic solvent was added to form a precipitate, and the precipitate was filtered, washed with a solvent, and dried under reduced pressure at 30 ° C. to 40 ° C. again, 3-hydroxy-5-mercapto- of Formula 2a. 4-isothiazole alkylester di-salts can be obtained with high purity. As an organic solvent for producing the precipitate, a solvent of ethanol, isopropanol, 1-butanol, acetone may be used, and specifically, may be selected from the group consisting of isopropanol.

Among the compounds of Formula 2, the compound of Formula 2b may be produced by a method comprising adjusting the pH to 4-6 by adding an acid to a solution of the compound of Formula 2a.

[Formula 2b]

As a solvent used in the preparation of the solution of Formula 2a, any solvent capable of dissolving the compound of Formula 2a may be used, specifically, selected from the group consisting of water, isopropanol, 1-butanol, and mixtures thereof. It may be used, most preferably water may be used.

The acid that can be used to adjust the pH of the compound of Formula 2a to 4-6 is not particularly limited, and typically may be selected from the group consisting of hydrochloric acid, nitric acid, sulfuric acid, acetic acid and mixtures thereof.

The compound of Formula 2b produced by the above method may be used directly to prepare the compound of Formula 3 without purification, but the process of purifying the compound of Formula 2b may be performed. Since the compound of Chemical Formula 2b is water insoluble unlike the compound of Chemical Formula 2a, an organic solvent capable of selectively dissolving Chemical Formula 2b with respect to other reactants and solvents is added and mixed, and then the organic layer is separated and concentrated under reduced pressure. The compound of can be refine | purified. As such, the organic solvent that may be used to purify the compound of Formula 2b may be selected from the group consisting of dichloromethane, ethyl acetate, toluene, ether, and mixtures thereof. The compound of formula 2b is stable in such an organic solvent while being selectively dissolved in such an organic solvent, and the compound of formula 2b is particularly preferable among the compounds of formula 2 in that the purification is very easy due to this property.

When the compounds of Formulas 2a and 2b described above and the process for preparing the compounds of Formula 3 are continuously expressed, they may be represented by the following Scheme 2:

Scheme 2

In the above scheme, R ¹ , R ^{2 '} , R ^3' , and R ⁴ are the same as defined in Chemical Formulas 1, 2, 2a, 2b, and 3 above.

As described above, using 4-hydroxy-5-mercapto-4-isothiazole alkyl esters or salts thereof provided in the present invention, 4-carboxy-3-hydroxy-5- is essential for the preparation of cetetane. Mercapto-isothiazole tri-salts can be prepared for a short time at significantly lower temperatures than conventional methods and are not only efficient but also produce no harmful gases as a by-product, unlike conventional methods of generating ammonia gas. .

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrating the present invention, and the present invention is not limited by these examples.

Example  One

3-hydroxy-5- Mercapto -4- Isothiazole Ethyl ester Disodium salt  Produce

The disodium salt of α-cyano-α-carboethoxy-dithiolate (100 g, 0.429 mol) was dissolved in methanol (400 ml) and the temperature of the reactor was maintained at a temperature of 5 ° C. to 15 ° C. To this was added 35% hydrogen peroxide (42 g, 0.432 mol) dropwise over 3 hours.

After completion of the dropwise addition, the mixture was stirred for 30 minutes and concentrated under reduced pressure. Isopropanol (300 ml) was added to the mixture to give a precipitate. The precipitate was filtered off, washed with isopropanol and dried under reduced pressure at 40 ° C. for 4 hours to give 101 g (94%) of the title compound as a pale yellow powder.

HPLC (Purity): 97%, K.F .: 9.1%

¹ H NMR (D ₂ O) (300 MHz): 3.971 ppm (2H, q), 1.096 ppm (3H, t)

¹³ C NMR (D ₂ O, DMSO) (300 MHz): 218.48 ppm, 168.04 ppm, 125.80 ppm,

                               79.13ppm, 61.08ppm, 14.80ppm

FT-IR (SiO ₂ ): 3416,2988,2199,2181,1604 (cm ^-1 )

Example  2

3-hydroxy-5- Mercapto -4- Isothiazole Ethyl ester Dipotassium salt  Produce

The dipotassium salt of α-cyano-α-carboethoxy-dithiolate (100 g, 0.398 mol) was dissolved in water (400 ml) and the temperature of the reactor was maintained at a temperature of 5 ° C to 15 ° C. To this was added 35% hydrogen peroxide (39 g, 0.401 mol) dropwise over 3 hours.

After the dropwise addition was stirred for 30 minutes, an aqueous solution of 3-hydroxy-5-mercapto-4-isothiazole ethylester dipotassium salt was obtained.

HPLC (Purity): 96%,

¹³ C NMR (D ₂ O, DMSO) (300 MHz): 218.80 ppm, 168.29 ppm, 125.93 ppm,

                               79.05ppm, 60.99ppm, 14.79ppm

Example  3

3-hydroxy-5- Mercapto -4- Isothiazole Methyl ester Disodium salt  Produce

After disodium salt of α-cyano-α-carbomethoxy-dithiolate (85 g, 0.388 mol) was added to methanol (300 ml), the temperature of the reactor was maintained at a temperature of 5 ° C to 10 ° C. To this was added 35% hydrogen peroxide (38 g, 0.391 mol) dropwise for 3 hours.

After completion of the dropwise addition, the mixture was stirred for 30 minutes, and then, isopropanol (100 ml) was added to the mixture to obtain a precipitate. The precipitate was filtered off, washed with isopropanol and then dried under reduced pressure at 40 ° C. for 4 hours to give 83 g (91%) of the title compound as a pale yellow powder.

HPLC (Purity): 96%, K.F .: 11.8%

¹ H NMR (D ₂ O) (300 MHz): 3.709 ppm (s)

¹³ C NMR (D ₂ O, DMSO) (300 MHz): 218.40 ppm, 168.21 ppm, 125.72 ppm,

                               78.60ppm, 51.78ppm

FT-IR (SiO ₂ ): 2183,1638,1440,1340 (cm ^-1 )

Example  4

3-hydroxy-5- Mercapto -4- Isothiazole Benzyl esters Disodium salt  Produce

The disodium salt of α-cyano-α-carbenzyloxy-dithiolate (68 g, 0.23 mol) was dissolved in methanol (700 ml) and the temperature of the reactor was maintained at a temperature of 5 ° C to 15 ° C. To this was added 35% hydrogen peroxide (22.5 g, 0.23 mol) dropwise over 3 hours.

After completion of the dropwise addition, the mixture was stirred for 30 minutes and concentrated under reduced pressure. Isopropanol (500 ml) was added to the mixture to give a precipitate. The precipitate was filtered off, washed with isopropanol and dried under reduced pressure at 40 ° C. for 4 hours to give 50 g (70%) of the title compound as a pale yellow powder.

HPLC (Purity): 94%, K.F .: 12%

¹ H NMR (D ₂ O) (300 MHz): 7.48-7.41 ppm (5H, m), 3.35 ppm (2H, s)

¹³ C NMR (D ₂ O, DMSO) (300 MHz): 170.31 ppm, 136.71 ppm, 129.61 ppm,

                              129.52ppm, 129.47ppm, 129.09ppm,

                              128.81ppm, 119.54ppm, 49.70ppm

FT-IR (SiO ₂ ): 2148,1646,1359 (cm ^-1 )

Example  5

5- Mercapto -4- Ethyl ester - Isothiazole Preparation of -3-one Formula 2 b)

The disodium salt of α-cyano-α-carboethoxy-dithiolate (100 g, 0.429 mol) was dissolved in water (400 ml) and the temperature of the reactor was maintained at a temperature of 5 ° C. to 15 ° C. To this was added 35% hydrogen peroxide (42 g, 0.432 mol) dropwise over 3 hours. After completion of the dropwise addition, the mixture was stirred for 30 minutes, and then concentrated hydrochloric acid was added to the mixture to adjust the pH of the mixture to 4. Dichloromethane (500 ml) was added twice at room temperature, and the organic layer was separated and concentrated under reduced pressure at a temperature of 30 ° C. to give 82 g (93%) of the title compound as a light yellow powder.

¹ H NMR (CDCl ₃ ) (300 MHz): 4.37 ppm (q), 1.57 ppm (br s), 1.39 ppm (t)

¹³ C NMR (CDCl ₃ ) (300 MHz): 171.59 ppm, 163.64 ppm, 113.30 ppm,

                            91.83ppm, 63.63ppm, 14.11ppm

FT-IR (SiO ₂ ): 2983,2366,2212,1668,1656,1473 (cm ^-1 )

Example  6

4- Carboxy -3-hydroxy-5- Mercapto - Isothiazole Trisodium salt  Manufacture (1)

3-hydroxy-5-mercapto-4-isothiazole ethyl ester disodium salt (100 g, 0.40 mol) was dissolved in water (400 ml) and the reactor temperature was maintained at 5 ° C. To this was added sodium hydroxide (80 g, 2.00 mol).

After the mixture was stirred for 30 minutes, the temperature of the reactor was raised to 80 ° C. and stirred for 30 minutes. The reactor was cooled to 50 ° C. and then concentrated under reduced pressure. Ethanol (200 ml) was added to the mixture, followed by concentration under reduced pressure again. After cooling the temperature of the reactor to 40 ℃ isopropanol (300ml) was added to obtain a precipitate. The precipitate was filtered off, washed with isopropanol and then dried under reduced pressure at 40 ° C. for 4 hours to give 93 g (95%) of the title compound as a white powder.

HPLC (Purity): 99%, K.F .: 23%

¹³ C NMR (D ₂ O, DMSO) (300 MHz): 176.50 ppm, 175.85 ppm, 169.14 ppm,

                              126.62ppm

Example  7

4- Carboxy -3-hydroxy-5- Mercapto - Isothiazole Trisodium salt  Manufacture (2)

3-hydroxy-5-mercapto-4-isothiazole methylester disodium salt (60 g, 0.255 mol) was dissolved in water (250 ml) and the temperature of the reactor was maintained at 5 ° C. To this was added sodium hydroxide (52 g, 1.3 mol).

After the mixture was stirred for 30 minutes, the temperature of the reactor was raised to 70 ° C. and stirred for 30 minutes. The reactor was cooled to 50 ° C. and then concentrated under reduced pressure. Ethanol (150 ml) was added to the mixture, followed by concentration under reduced pressure again. After cooling the temperature of the reactor to 40 ℃ isopropanol (200ml) was added to obtain a precipitate. The precipitate was filtered off, washed with isopropanol and dried under reduced pressure at 40 ° C. for 4 hours to give 50 g (81%) of the title compound as a white powder.

Example  8

4- Carboxy -3-hydroxy-5- Mercapto - Isothiazole Disodium Monopotassium salt

Manufacture (3)

3-hydroxy-5-mercapto-4-isothiazole ethyl ester disodium salt (100 g, 0.40 mol) was dissolved in water (400 ml) and the reactor temperature was maintained at 5 ° C. To this was added 85% potassium hydroxide (132 g, 2.00 mol).

After the mixture was stirred for 30 minutes, the temperature of the reactor was raised to 80 ° C. and stirred for 30 minutes. After cooling the temperature of the reactor to 50 ℃ concentrated under reduced pressure. Ethanol (200 ml) was added to the mixture, followed by concentration under reduced pressure again. After cooling the temperature of the reactor to 40 ℃ isopropanol (400ml) was added to obtain a precipitate. The precipitate was filtered off, washed with isopropanol and then dried under reduced pressure at 40 ° C. for 4 hours to give 95 g (91%) of the title compound as a white powder.

HPLC (Purity): 99%, K.F .: 13.8%

¹³ C NMR (D ₂ O, DMSO) (300 MHz): 176.50 ppm, 175.85 ppm, 169.14 ppm,

                              126.62ppm

FT-IR (SiO ₂ ): 2183,1638,1440,1340 (cm ^-1 )

Example  9

4- Carboxy -3-hydroxy-5- Mercapto - Isothiazole Trisodium salt  Manufacture (4)

Sodium hydroxide (120 g, 3 mol) was dissolved in water (400 ml) and the reactor temperature was maintained at 5 ° C. 5-mercapto-4-ethylester-isothiazol-3-one (80 g, 0.39 mol) was added thereto.

After the mixture was stirred for 30 minutes, the temperature of the reactor was raised to 70 ° C. and stirred for 1 hour. The reactor was cooled to 50 ° C. and then concentrated under reduced pressure. Ethanol (200 ml) was added to the mixture, followed by concentration under reduced pressure again. After cooling the temperature of the reactor to 40 ℃ isopropanol (300ml) was added to obtain a precipitate. The precipitate was filtered off, washed with isopropanol and dried under reduced pressure at 40 ° C. for 4 hours to give 70 g (73%) of the title compound as a white powder.

Claims (6)

A compound of formula
(2)

In Chemical Formula 2,
R ¹ is C ₁ -C ₈ alkyl; benzyl; Or a benzyl substituted with C _{1 -6} alkyl, C _{1 -6} alkoxy, or halogen,
R ² and R ³ are each independently hydrogen, Li, Na, or K. A process for preparing a compound of formula 2a comprising reacting a compound of formula 1 with hydrogen peroxide:
(2a)

In Chemical Formula 2a,
R ¹ is C ₁ -C ₈ alkyl; benzyl; Or a benzyl substituted with C _{1 -6} alkyl, C _{1 -6} alkoxy, or halogen,
R ^{2 '} and R ^3' are each independently Li, Na, or K.
[Formula 1]

In Chemical Formula 1,
R ¹ is C ₁ -C ₈ alkyl; benzyl; Or a benzyl substituted with C _{1 -6} alkyl, C _{1 -6} alkoxy, or halogen,
R ^{2 '} and R ^3' are each independently Li, Na, or K. The method of claim 2, wherein an organic solvent selected from the group consisting of ethanol, isopropanol, 1-butanol, acetone, and methyl ethyl ketone is added to precipitate the compound of Formula 2a, filtered, washed with the organic solvent, and dried under reduced pressure. Manufacturing method characterized in that it further comprises. To prepare a compound of formula 2b comprising the step of adjusting the pH to 4-6 by adding an acid to a solution of the compound of formula 2a:
(2a)

In Chemical Formula 2a,
R ¹ is C ₁ -C ₈ alkyl; benzyl; Or a benzyl substituted with C _{1 -6} alkyl, C _{1 -6} alkoxy, or halogen,
R ^{2 '} and R ^3' are each independently Li, Na, or K;
(2b)

In Formula 2b, R ¹ is C ₁ -C ₈ alkyl; benzyl; Or a C _{1 -6} alkyl substituted benzyl, C _{1 -6} alkoxy, or halogen. The method of claim 4, wherein the solution of the compound of Formula 2a is an aqueous solution, and a group consisting of dichloromethane, ethyl acetate, toluene, ether, and mixtures thereof is carried out after the step of adjusting the pH to 4-6 by adding an acid. The method of preparing a compound of Chemical Formula 2b, further comprising the step of purifying the compound of Chemical Formula 2 by adding and mixing the selected organic solvent and then separating the organic layer and concentrating under reduced pressure. Adding 4 to 8 equivalents of a base selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof in a solution of the compound of Formula 2 and reacting at 60 ° C. to 80 ° C. for 30 minutes to 1 hour. To prepare a compound of Formula 3
(2)

In Chemical Formula 2,
R ¹ is C ₁ -C ₈ alkyl; benzyl; Or a benzyl substituted with C _{1 -6} alkyl, C _{1 -6} alkoxy, or halogen,
R ² and R ³ are each independently hydrogen, Li, Na, or K;
(3)

In Chemical Formula 3,
R ^{2 '} , R ^3' , and R ⁴ are each independently Li, Na, or K.