KR100472048B1 - Novel method for producing Aztreonam - Google Patents

Abstract

The present invention relates to a novel manufacturing method of Aztreonam. According to the present invention, it is possible to effectively remove impurities that may be included in the production of aztreonam, it is possible to manufacture aztreonam in high yield, high purity.

Description

Novel method for producing Aztreonam

The present invention relates to a novel manufacturing method of Aztreonam.

Aztreonam of Formula 1a has excellent antibacterial ability and has been used in patients with weak immune mechanisms such as children and the elderly because of less side effects. Aztreonam is attracting attention as an alternative to aminoglycoside antibiotics because it has strong activity against gram-negative bacteria possessed by aminoglycoside antibiotics and is stable to beta-lactamase.

Manufacturing methods for Aztreonam are well known (US Pat. No. 4,775,670; Korean Patent Application No. 81-379, Publication No. 86-1289; Synthesis 494, 1977, Chem. Soc. Special Publication No. 28, 288, 1977), a representative one of the known manufacturing methods can be represented by the following scheme 1. That is, Aztreonam was synthesized by activating the compound of Formula 4 to make the compound of Formula 5, and then performing a coupling reaction with the compound of Formula 3.

Wherein R ¹ represents hydrogen or an amino protecting group; R ² represents hydrogen or a carboxylic acid protecting group; M represents hydrogen, a quaternary amine salt or a cation. General formula used in the reaction scheme The following compounds may be used as the activation reagent represented by.

However, the conventional manufacturing method has many problems in obtaining pure Aztreonam by separating. First, in order to activate the compound of Formula 4 to the compound of Formula 5, an activation reagent such as HOBT (1-Hydroxybenzotriazole) and a coupling reagent (DCC: carbodiimide such as dicyclocarbodiimide) should be used. Reaction by-products such as dicyclocarbodiaurea (DCU) are formed from the activating reagent and the coupling reagent used in this way, and these reaction by-products are present in the form of salts with sulfonic acid groups and salts of the compound of Formula 1, making it difficult to obtain pure aztreonam. do. After all, in order to effectively remove impurities from the form of these salts to obtain the compound of Formula 1 in the form of high purity, a potassium acid or sodium salt of strong acid or strong base must be added to substitute the form of the compound of Formula 6, followed by acid treatment. The desired compound must be obtained. In addition, in order to purify the compound of Formula 6 in the form of a pure salt, there is a problem that the column chromatography process using a resin such as HP 20, which is difficult to industrially mass production.

As described above, in the conventional manufacturing method, there is a problem that a separate process must be added to obtain pure aztreonam, and there are problems such as difficulty in handling salts of strong acids or strong bases, problems of environmental pollution, and troublesome processes, There was a difficulty in applying to enemy mass production.

The present inventors conducted a study to solve the problems of the prior art, and thus, to develop a novel manufacturing method and purification method of Aztreonam to complete the present invention. That is, it is an object of the present invention to provide a method for obtaining aztreonam with high purity and high yield and a method for purifying the same.

The present invention relates to a process for preparing the compound of formula 1, characterized in that the compound of formula 2 is reacted with a compound of formula 3:

Wherein R ¹ represents hydrogen or an amino protecting group; R ² represents hydrogen or a carboxylic acid protecting group; M represents hydrogen, quaternary amine salt or cation; X represents the following structure.

The amino protecting group may be a known one, for example phthaloyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methoxycarbonyl, ethoxycarbonyl, tertiary butoxycarbonyl, trichloro Oxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, diphenylmethyloxycarbonyl, ethoxymethyloxycarbonyl, trityl, trimethylsilyl, benzoyl, 2-thienylacetyl, phenylacetyl, formyl Or an acetyl group can be used. Preferably, trityl, formyl or acetyl group can be used .

In addition, the carboxylic acid protecting group may be a known one, for example, a substituted or unsubstituted alkyl group such as ethyl, propyl, butyl, tertiary butyl, trichloroethyl; Benzyl groups such as benzyl, diphenylmethyl, p-nitrobenzyl, methoxybenzyl; Acyloxyalkyl groups such as pivaloyloxyethyl, pivaloyloxypropyl, benzyloxymethyl, benzyloxyethyl, benzylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl; Alkoxyalkyl groups such as methoxymethyl and ethoxymethyl; Or silyl groups such as dimethylchlorosilyl, trichlorosilyl group, and the like. Preferably, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl or tertiary butyl groups can be used.

The quaternary amine salt is not particularly limited, but tetrabutylammonium salt is preferably used. The cation is not particularly limited, but potassium or sodium ions are preferably used.

In the preparation method of the present invention, the compound of Formula 2 may be used in the amount of 1 to 2 equivalents, preferably 1 to 1.5 equivalents, based on the compound of Formula 3.

The solvent usable in the preparation method of the present invention is not particularly limited as long as it generally does not adversely affect the reaction, but preferably one or more solvents selected from dichloromethane, chloroform, acetonitrile and acetone can be used. have. More preferably, dichloromethane can be used.

The base usable in the production method of the present invention is not particularly limited, but preferably organic bases such as potassium salts, calcium salts, sodium salts and bases of acceptable inorganic bases or amines can be used. More preferably triethylamine can be used. The amount of triethyl amine may be used in the amount of 1 to 3 equivalents, preferably 1.5 to 2.5 equivalents, based on the compound of Formula 3 .

In the manufacturing method of this invention, reaction temperature is -15 degreeC-100 degreeC, Preferably it is -10 degreeC-20 degreeC. In the manufacturing method of this invention, reaction time is 30 minutes-24 hours, Preferably it is 2 hours-5 hours .

In addition, the present invention provides a purification method that can effectively remove impurities that may be included in the preparation of the compound of formula 1 to obtain the target compound in high yield, high purity.

That is, a mixed solvent of an organic solvent and water is added to the reaction product obtained after the acylation reaction, and diluted with an organic or inorganic acid diluted to adjust pH to 0.5 to 5 and then stirred. As the usable organic solvent, a halogen solvent such as dichloromethane, chloroform or a non-halogen solvent such as ethyl acetate, ether, hexane, tetrahydrofuran can be used. As the organic solvent used in the mixed solvent, a non-halogen solvent such as ethyl acetate or ether is preferable, and ethyl acetate is more preferably used .

The pH of the solution at recrystallization is 0.5 to 5, preferably pH 0.5 to 3 . Hydrochloric acid or sulfuric acid may be used to adjust the pH, and preferably a dilute hydrochloric acid solution may be used. The recrystallization temperature can be selected within the range from the freezing temperature of the mixed solvent to the distillation temperature, preferably -5 ° C to 20 ° C. The crystallization time is 30 minutes to 24 hours, more preferably within 12 hours.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the scope of the present invention is not limited by the following examples.

Example 1

[3S (Z)]-3-[[(2-amino-4-cyazolyl) [[1- (tertiarybutylcarbonyl-1-methylethoxy) imino] acetyl] amino] -4-methyl 2-oxo-1-azetidinesulfonic acid

Suspend 60 g (333 mmol) of (3S) -trans-3-amino-4-methyl-2-oxoazetidine-1-sulfonic acid in 2400 ml of dichloromethane and 115 ml (89.08) of triethylamine at 0 ° C. g, 832 mmol), then 2-[(2-amino-thiazol-4-yl)-(benzocyazol-2-yl-sulfanylcarbonyl) -methyleneaminooxy-2-methyl-propy 175 g (366 mmol) of onic acid tertiarybutyl ester were added. The mixture was stirred at 0 ° C. for 14 h and then the solvent was concentrated under reduced pressure. 500 ml of water and 500 ml of ethyl acetate were added to the residue, and the mixture was cooled to 0 ° C., and the pH was adjusted to 1.45 with 3N HCl aqueous solution. The reaction was stirred at the same temperature for 2 hours to dissolve the impurities in the ethyl acetate layer, and in the water layer [3S (Z)]-3-[[(2-amino-4-cyazolyl) [[1- (tary) Butylcarbonyl-1-methylethoxy) imino] acetyl] amino] -4-methyl-2-oxo-1-azetidinesulfonic acid was crystallized. The precipitated compound was filtered and dried under reduced pressure to obtain 154 g (yield 94%) of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 1.3 (m, 12H), 1.46 (s, 6H), 3.72 (d, J = 4.8 Hz, 1H), 4.07 (brs, 2H), 4.49 (dd, J = 4.8 , 8.0 Hz), 6.94 (s, 1H), 9.32 (d, J = 8.0 Hz, 1H)

Example 2

[3S (Z)]-3-[[(2-amino-4-cyazolyl) [[1- (tertiarybutylcarbonyl-1-methylethoxy) imino] acetyl] amino] -4-methyl 2-oxo-1-azetidinesulfonic acid

6.57 g (15.5 mmol) of (3S) -trans-3-amino-4-methyl-2-oxoazetidine-1-sulfonic acid tetrabutyl ammonium salt and 2-[(2-amino-thiazol-4-yl)- (Benzosazol-2-yl-sulfanylcarbonyl) -methyleneaminooxy-2-methyl-propionic acid tertiarybutyl ester using 8.13 g (17.0 mmol) according to the method described in Example 1 [3S ( Z)]-3-[[(2-amino-4-cyazolyl) [[1- (tertiarybutylcarbonyl-1-methylethoxy) imino] acetyl] amino] -4-methyl-2- After synthesizing oxo-1-azetidinesulfonic acid, crystallization was carried out by the crystallization method used in Example 1 to obtain 6.42 g (yield 84%) of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 1.3 (m, 12H), 1.46 (s, 6H), 3.72 (d, J = 4.8 Hz, 1H), 4.07 (brs, 2H), 4.49 (dd, J = 4.8 , 8.0 Hz), 6.94 (s, 1H), 9.32 (d, J = 8.0 Hz, 1H)

Example 3

[3S (Z)]-3-[[(2-amino-4-cyazolyl) [[1- (tertiarybutylcarbonyl-1-methylethoxy) imino] acetyl] amino] -4-methyl 2-oxo-1-azetidinesulfonic acid

11.3 g (63 mmol) of (3S) -trans-3-amino-4-methyl-2-oxoazetidine-1-sulfonic acid and 2-[(2-amino-thiazol-4-yl)-(die [3S (Z)]-3 by the method described in Example 1 using 40 g (69 mmol) of oxy-thiophosphorylcarbonyl) -methyleneaminooxy-2-methyl-propionic acid tertiarybutyl ester -[[(2-amino-4-cyazolyl) [[1- (tertiarybutylcarbonyl-1-methylethoxy) imino] acetyl] amino] -4-methyl-2-oxo-1-ase After synthesis of thidinesulfonic acid, crystallization was carried out by the crystallization method used in Example 1 to obtain 25.4 g (yield 82%) of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 1.3 (m, 12H), 1.46 (s, 6H), 3.72 (d, J = 4.8 Hz, 1H), 4.07 (brs, 2H), 4.49 (dd, J = 4.8 , 8.0 Hz), 6.94 (s, 1H), 9.32 (d, J = 8.0 Hz, 1H)

Example 4

[3S (Z)]-3-[[(2-amino-4-cyazolyl) [[1- (tertiarybutylcarbonyl-1-methylethoxy) imino] acetyl] amino] -4-methyl 2-oxo-1-azetidinesulfonic acid

11.3 g (63 mmol) of (3S) -trans-3-amino-4-methyl-2-oxoazetidine-1-sulfonic acid and 2-[(2-amino-thiazol-4-yl)-(die [3S (Z)]-3- [by the method described in Example 1 using 35 g (80 mmol) of oxy-phosphorylcarbonyl) -methyleneaminooxy-2-methyl-propionic acid tertiarybutyl ester [(2-amino-4-cyazolyl) [[1- (tertiarybutylcarbonyl-1-methylethoxy) imino] acetyl] amino] -4-methyl-2-oxo-1-azetidinesulfonic acid Was synthesized and crystallized by the crystallization method used in Example 1 to obtain 32.1 g (yield 81%) of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 1.3 (m, 12H), 1.46 (s, 6H), 3.72 (d, J = 4.8 Hz, 1H), 4.07 (brs, 2H), 4.49 (dd, J = 4.8 , 8.0 Hz), 6.94 (s, 1H), 9.32 (d, J = 8.0 Hz, 1H)

Example 5

[3S (Z)]-3-[[(2-amino-4-cyazolyl) [[1- (diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl] amino] -4- Methyl-2-oxo-1-azetidinesulfonic acid

13.9 g (77 mmol) of (3S) -trans-3-amino-4-methyl-2-oxoazetidine-1-sulfonic acid and (2-amino-thiazol-4-yl) -diphenylmethoxyimino- [3S (Z)]-3-[[(2-amino-4-cytoxy) by the method described in Example 1 using 50 g (85 mmol) of thioacetic acid S-benzothiazol-2-yl ester Example 1 after synthesizing azolyl) [[1- (diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl] amino] -4-methyl-2-oxo-1-azetidinesulfonic acid Crystallization was carried out by the crystallization method used at, yielding 42.6 g (yield 92%) of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 1.29 (m, 3H), 1.46 (s, 6H), 3.72 (d, J = 4.8 Hz, 1H), 4.06 (brs, 2H), 4.5 (dd, J = 4.8 , 8.0 Hz), 6.05 (s, 1H), 6.94 (s, 1H), 7.31 (m, 10H), 9.32 (d, J = 8.0 Hz, 1H)

Example 6

[3S (Z)]-3-[[(2-amino-4-cyazolyl) [[1- (diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl] amino] -4- Methyl-2-oxo-1-azetidinesulfonic acid

6.57 g (15.5 mmol) of (3S) -trans-3-amino-4-methyl-2-oxoazetidine-1-sulfonic acid tetrabutyl ammonium and (2-amino-thiazol-4-yl) -diphenylme [3S (Z)]-3-[[(2-amino-) according to the method described in Example 1 using 10.1 g (17.1 mmol) of oxyimino-thioacetic acid S-benzothiazol-2-yl ester 4-Sazolyl) [[1- (diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl] amino] -4-methyl-2-oxo-1-azetidinesulfonic acid, after synthesis Crystallization was carried out by the crystallization method used in Example 1 to obtain 7.82 g (yield 84%) of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 1.29 (m, 3H), 1.46 (s, 6H), 3.72 (d, J = 4.8 Hz, 1H), 4.06 (brs, 2H), 4.5 (dd, J = 4.8 , 8.0 Hz), 6.05 (s, 1H), 6.94 (s, 1H), 7.31 (m, 10H), 9.32 (d, J = 8.0 Hz, 1H)

Example 7

[3S (Z)]-3-[[(2-amino-4-cyazolyl) [[1- (diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl] amino] -4- Methyl-2-oxo-1-azetidinesulfonic acid

30 g (166 mmol) of (3S) -trans-3-amino-4-methyl-2-oxoazetidine-1-sulfonic acid and 2-[(2-amino-thiazol-4-yl)-(die [3S (Z)]-3 by the method described in Example 1 using 105 g (183 mmol) of oxy-thiophosphorylcarbonyl) -methyleneaminooxy-2-methyl-propionic acid benzhydryl ester -[[(2-amino-4-cyazolyl) [[1- (diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl] amino] -4-methyl-2-oxo-1- After the synthesis of azetidinesulfonic acid, crystallization was carried out by the crystallization method used in Example 1 to obtain 81 g (yield 82%) of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 1.29 (m, 3H), 1.46 (s, 6H), 3.72 (d, J = 4.8 Hz, 1H), 4.06 (brs, 2H), 4.5 (dd, J = 4.8 , 8.0 Hz), 6.05 (s, 1H), 6.94 (s, 1H), 7.31 (m, 10H), 9.32 (d, J = 8.0 Hz, 1H)

Example 8

[3S (Z)]-3-[[(2-amino-4-cyazolyl) [[1- (diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl] amino] -4- Methyl-2-oxo-1-azetidinesulfonic acid

45 g (250 mmol) of (3S) -trans-3-amino-4-methyl-2-oxoazetidine-1-sulfonic acid and 2-[(2-amino-thiazol-4-yl)-(die [3S (Z)]-3- [by the method described in Example 1 using 153 g (275 mmol) of oxy-phosphorylcarbonyl) -methyleneaminooxy-2-methyl-propionic acid benzhydryl ester [(2-amino-4-cyazolyl) [[1- (diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl] amino] -4-methyl-2-oxo-1-azetidine After the synthesis of sulfonic acid, crystallization was carried out by the crystallization method used in Example 1 to obtain 127 g (yield 85%) of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 1.29 (m, 3H), 1.46 (s, 6H), 3.72 (d, J = 4.8 Hz, 1H), 4.06 (brs, 2H), 4.5 (dd, J = 4.8 , 8.0 Hz), 6.05 (s, 1H), 6.94 (s, 1H), 7.31 (m, 10H), 9.32 (d, J = 8.0 Hz, 1H)

Example 9

[3S (Z)]-3-[[(2-formylamino-4-cyazolyl) [[2- (nitrobenzyl) -1,1-dimethyl-2-oxoethoxy] imino] acetyl ] Amino] -2-oxo-1-azetidinesulfonic acid

10 g (55 mmol) of (3S) -trans-3-amino-4-methyl-2-oxoazetidine-1-sulfonic acid and 2-[(2-formylamino-thiazol-4-yl)-( [3S (Z) by the method described in Example 1 using 35.4 g (60 mmol) of benzocyazol-2-yl-sulfanylcarbonyl) -methyleneaminooxy-2-methyl-propionic acid nitrobenzyl ester ] -3-[[(2-formylamino-4-cyazolyl) [[2- (nitrobenzyl) -1,1-dimethyl-2-oxoethoxy] imino] acetyl] amino] -2 -Oxo-1-azetidinesulfonic acid was synthesized and crystallized by the crystallization method used in Example 1 to obtain 26.5 g (yield 80%) of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 1.28 (m, 3H), 1.45 (s, 6H), 3.72 (d, J = 4.8 Hz, 1H), 4.06 (brs, 2H), 4.49 (dd, J = 4.8 , 8.0 Hz), 5.45 (s, 2H), 6.94 (s, 1H), 7.45 (m, 4H), 8.7 (s, 1H), 9.32 (d, J = 8.0 Hz, 1H)

Example 10

[3S (Z)]-3-[[(2-tritylamino-4-cyazolyl) [[2- (paramethoxybenzyl) -1,1-dimethyl-2-oxoethoxy] imino ] Acetyl] amino] -2-oxo-1-azetidinesulfonic acid

10 g (55 mmol) of (3S) -trans-3-amino-4-methyl-2-oxoazetidine-1-sulfonic acid and 2-[(2-tritylamino-thiazol-4-yl)-( Benzothiazol-2-yl-sulfanylcarbonyl) -methyleneaminooxy-2-methyl-propionic acid paramethoxybenzyl ester 47.44 g (60 mmol) was used to obtain [3S ( Z)]-3-[[(2-tritylamino-4-cyazolyl) [[2- (paramethoxybenzyl) -1,1-dimethyl-2-oxoethoxy] imino] acetyl] Amino] -2-oxo-1-azetidinesulfonic acid was synthesized and crystallized by the crystallization method used in Example 1 to obtain 34.2 g (yield 78%) of the title compound.

¹ H NMR (DMSO-d ₆ ) δ 1.28 (m, 3H), 1.45 (s, 6H), 3.72 (d, J = 4.8 Hz, 1H), 3.75 (s, 3H), 4.06 (brs, 2H), 4.49 (dd, J = 4.8, 8.0 Hz), 5.45 (s, 2H), 6.94 (s, 1H), 6.9-7.4 (m, 19H), 9.30 (d, J = 8.0 Hz, 1H)

Example 11

[3S (Z)]-3-[[(2-amino-4-cyazolyl) [[(1,1-dimethyl) imino] acetyl] amino] -4-methyl-2-oxo-1- Azetidinesulfonic acid

[3S (Z)]-3-[[(2-amino-4-cyazolyl) [[1- (tertiarybutylcarb) synthesized in Examples 1 to 4 in 10 ml of aniazole and 40 ml of dichloromethane. 12 g (24.2 mmol) of carbonyl-1-methylethoxy) imino] acetyl] amino] -4-methyl-2-oxo-1-azetidinesulfonic acid were suspended, cooled to −10 ° C., and then to trifluoro. 24.2 ml of acetic acid was added slowly. After stirring for 5 hours between −10 ° C. and 0 ° C., 60.5 ml of a mixed solvent of 880 ml of ethanol, 72 ml of acetone, and 48 ml of water were added thereto, followed by stirring at room temperature for 30 minutes and then again at 0 ° C. for 30 minutes. Crystallized. The resulting solid target compound was filtered, washed twice with 50 ml of dichloromethane, and dried under reduced pressure to obtain 7.16 g (yield 68%) of the target compound as a white solid.

¹ H NMR (DMSO-d ₆ ) δ 1.3 (d, J = 16.5 Hz, 3H), 1.47 (s, 6H), 3.72 (d, J = 4.8 Hz, 1H), 4.07 (brs, 2H), 4.49 ( dd, J = 4.8, 8.0 Hz), 6.94 (s, 1H), 9.34 (d, J = 8.0 Hz, 1H)

Example 12

[3S (Z)]-3-[[(2-amino-4-cyazolyl) [[(1,1-dimethyl) imino] acetyl] amino] -4-methyl-2-oxo-1- Azetidinesulfonic acid

[3S (Z)]-3-[[(2-amino-4-cyazolyl) [[1- (diphenylmethoxycarbonyl-1-methylethoxy) imino synthesized in Examples 5-8 ] Acetyl] amino] -4-methyl-2-oxo-1-azetidinesulfonic acid using 15 g (24 mmol) of the white solid [3S (Z)]-3- [ [(2-amino-4-cyazolyl) [[(1,1-dimethyl) imino] acetyl] amino] -4-methyl-2-oxo-1-azetidinesulfonic acid 7.81 g (72% yield) Got.

¹ H NMR (DMSO-d ₆ ) δ 1.3 (d, J = 16.5 Hz, 3H), 1.47 (s, 6H), 3.72 (d, J = 4.8 Hz, 1H), 4.07 (brs, 2H), 4.49 ( dd, J = 4.8, 8.0 Hz), 6.94 (s, 1H), 9.34 (d, J = 8.0 Hz, 1H)

In the preparation of aztreonam, in the prior art, an activation reagent such as HOBT and a coupling reagent such as DCC (dicyclocarbodiimide) had to be used for the acylation reaction. In this case, reaction byproducts such as DCU (dicyclocarbodiaurea) and the like are formed, and these reaction byproducts have a problem of being present in the form of a sulfonic acid and a salt of formula (1). However, in the present invention, since no additional coupling reagent is added for the acylation reaction, the problem of contamination by the reaction by-product does not occur, thereby obtaining quantitatively pure Aztreonam.

In addition, the prior art has a problem that after the acylation reaction to add a salt of a strong acid or a strong base such as potassium or sodium to remove the reaction by-products, using ion exchange column chromatography, followed by an additional step of acid treatment. However, in the present invention, the target compound can be obtained in high yield and high purity through the crystallization without the additional process as described above.

Claims (9)

A method for preparing a compound of Formula 1, comprising reacting a compound of Formula 2 with a compound of Formula 3: Wherein R ¹ is hydrogen or phthaloyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methoxycarbonyl, ethoxycarbonyl, tertiarybutoxycarbonyl, trichloroethoxycarbonyl, An amino protecting group selected from the group consisting of trityl, trimethylsilyl, benzoyl, 2-thienylacetyl, phenylacetyl, formyl or acetyl; R ² is hydrogen or ethyl, propyl, butyl, tertiarybutyl, trichloroethyl, benzyl, diphenylmethyl, p-nitrobenzyl, p-methoxybenzyl, pivaloyloxyethyl, benzyloxymethyl, benzyloxyethyl Carboxylic acid protecting group selected from the group consisting of benzylcarbonyloxymethyl, methoxymethyl, ethoxymethyl, dimethylchlorosilyl or trichlorosilyl; M represents hydrogen, quaternary amine salts or potassium or sodium ions; X represents the following structure. The method according to claim 1, wherein the amino protecting group is a trityl, formyl or acetyl group. The p-nitrobenzyl, p-methoxybenzyl of claim 1, wherein the carboxylic acid protecting group is used. A diphenylmethyl or tertiary butyl group. The method according to claim 1, wherein the quaternary amine salt is a tetrabutylammonium salt. delete The method of claim 1, wherein the reaction is carried out at -15 ℃ to 100 ℃. The method according to any one of claims 1 to 6, further comprising recrystallizing the obtained compound of Chemical Formula 1 in a mixed solvent of an organic solvent and water. The method according to claim 7, wherein the organic solvent is a halogen solvent such as dichloromethane or chloroform or a non-halogen solvent such as ethyl acetate, ether, hexane, tetrahydrofuran, and the like. 8. A process according to claim 7, wherein said recrystallization is carried out under the conditions of pH 0.5-5.