JP2024503655A - Method for producing high yield and high purity flomoxef - Google Patents

Abstract

The present invention relates to a method for producing flomoxef with high yield and high purity, and more particularly, the present invention relates to a method for producing flomoxef with high yield and high purity. -(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4 .2.0] The present invention relates to a method for producing oct-2-ene-2-carboxylic acid (also known as Flomoxef-FA) in high yield and purity.

Description

The present invention relates to a method for producing flomoxef with high yield and high purity.
More specifically, (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1- (2-Hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (also known as It concerns a method for producing flomoxef) in high yield and purity.

Cephem antibiotics include cephalosporins, cephamycin, oralcephem, penem, carbapenem, monobactam, beta-lactamase inhibitors and It can be divided into cephems, etc. They are also divided into injections and oral drugs depending on the route of administration.

Flomoxef sodium is an injectable antibiotic belonging to the oxacephem family developed by the Shionogi Research Institute of Japan. Chemically, it has a 1-oxacephem skeleton, similar to Latamoxef (see Chemical Formulas 1 and 2 below).

[Chemical formula 1]

[Chemical formula 2]

Furthermore, flomoxef sodium differs from conventional cephem antibiotics in that its basic structure is an oxacephem, which has an oxygen atom substituted for the sulfur atom at one position of the cephalosporin skeleton to increase its antibacterial activity. It is a formulation with enhanced antibacterial range, pharmacodynamic properties, side effects, and safety of β-lactamase.

In other words, flomoxef sodium compensates for the common weaknesses of third-generation cephems while maintaining antibacterial activity against Gram-negative bacteria, and is also effective against Gram-positive bacteria, especially methicillin-resistant staphylococci (MRSA), compared to conventional cephems. It is the latest antibiotic that exhibits stronger antibacterial power than other antibiotics.

Flomoxef is a new generation broad-spectrum antibiotic that takes full advantage of the excellent properties of latamoxef, an existing representative third-generation cephem-based injectable antibiotic, while improving its unsatisfactory properties.

In order to achieve the above two goals, we chemically modified the 7- and 3-positions of the 1-oxacephem nucleus and synthesized several compounds to produce flomoxef.

Among them, those with an alkylthioacetyl group at the 7th position and a tetrazol-thiomethyl group at the 3rd position exhibit excellent antibacterial activity against both Gram-positive and Gram-negative bacteria. I understand.

Furthermore, we will compare the antibacterial activity and pharmacokinetics of R1 in front of the 7th position and R2 in the tetrazole at the 3rd position, while in terms of safety, we will compare disulfiram's dual action and lack of nephrotoxicity. We conducted various studies using this as an indicator.

As a result, a difluoromethyl group was selected as R1, and a hydroxyethyl group was selected as R2.

Furthermore, it was confirmed that the antibacterial activity of flomoxef against Gram-positive and Gram-negative bacteria was 2 to 16 times stronger than that of the corresponding 1-thia cephalosporin derivative.

Among these antibiotics, the oxacephem antibiotics flomoxef (Shionogi, 1988) and latamoxef (Lilly, 1981) are currently commercially available, but their synthesis requires fermentation of intermediates or total synthesis. The reality is that there are no suppliers of intermediate or finished materials in the world other than Shionogi and Lilly. The company is currently arranging raw materials for generic development in Japan, but there are no suppliers other than in-house production.

In the case of oxacephem antibiotics, there are only a few types of products, and efficient bacterial strains have not been developed in the development of intermediates through fermentation. , antibiotic drug substances and intermediates should proceed with total synthesis. This is a very difficult item to easily access as it has to be produced through a total of 24 synthetic steps, so new synthetic methods need to be developed.

On the other hand, looking at the known literature regarding the production method of fluoromethylthioxacephalosporin, it is found that in carrying out the following reaction scheme 1 (synthesis of flomoxef), anisole ( Anisol) and deprotection using Titanium tetrachloride or Aluminum chloride or using trifluoroacetic acid instead of aluminum chloride.

[Reaction formula 1]

Therefore, the process of extracting the reaction mixture is not only not easy, but there is also the generation of side reactions during the reaction, and therefore the purity of the compound is also reduced.

Therefore, there continues to be a need for high-yield and high-purity methods of producing flomoxef.

The present invention relates to (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2- hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (herein referred to as The technical problem is to provide a method for producing flomoxef or flomoxef sodium (called Flomoxef-FA) in high yield and purity.

The present invention aims to solve the above technical problems, and the present invention aims to solve the above technical problems. -yl)sulfenyl)methyl)-7-methoxy-8oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate, cresol, toluene and their A method for producing flomoxef is provided, comprising a first step of reacting a solvent selected from the group consisting of a combination, and a second step of crystallizing the product of the first step to synthesize flomoxef.

According to the present invention, flomoxef-BH is used as a starting material and reacted with a solvent selected from the group consisting of cresol, toluene, and a combination thereof to produce flomoxef with high yield and high purity. Further, according to the present invention, both an SUS reactor and a G/L reactor can be used in producing flomoxef.

The present invention will be explained in more detail below.

In this specification,
Flomoxef-Cl is (6R,7R)-Benzhydryl3-(chloromethyl)-7-((1-(((Z)-2-chlorovinyl)oxy)-2-((difluoromethyl)thio)ethyl)amino)-7 -methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate.

Flomoxef-BH is (6S,7R)-benzhydryl-7-(difluoromethylthio)acetamide)-3-(((1-(2-hydroxyethyl)-1H-tetrazol-5-yl)sulfenyl)methyl)- 7-Methoxy-8oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate.

Flomoxef is (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo -5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

The method for producing flomoxef of the present invention includes:
(6R,7R)-benzhydryl-7-(difluoromethylthio)acetamide)-3-(((1-(2-hydroxyethyl)-1H-tetrazol-5-yl)sulfenyl)methyl)-7-methoxy-8 The first step of reacting oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (Flomoxef-BH) with cresol and the product of the first step are crystallized. The second step involves the synthesis of flomoxef.

For example, the method for producing flomoxef of the present invention includes reacting flomoxef-BH synthesized using flomoxef-Cl and a side chain with a cresol, such as m-cresol, and then crystallizing the reaction product. Flomoxef can be synthesized by (see reaction formula 2 below).

[Reaction formula 2]

Flomoxef-Cl((6R,7R)-Benzhydryl3-(chloromethyl)-7-((1-(((Z)-2-chlorovinyl)oxy)-2-((difluoromethyl)thio)ethyl)amino)-7- The side chain that reacts with methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate) is 1-(2-hydroxyethyl)-1H-tetrazole-5. -ylthiol sodium salt (1-(2-hydroxyethyl)-1H-tetrazol-5-ylthiol sodium salt), etc. can be used.

The method for producing flomoxef of the present invention includes (6R,7R)-benzhydryl-7-(difluoromethylthio)acetamide)-3-(((1-(2-hydroxyethyl)-1H-tetrazol-5-yl)sulfenyl ) methyl)-7-methoxy-8oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate (flomoxef-BH), cresol, toluene and their A first stage step of reacting a solvent selected from the group consisting of combinations is included.

In the prior art, in carrying out Scheme 2 (synthesis of flomoxef) as described above, carboxy deprotection was performed by adding Anisol and titanium tetrachloride or aluminum chloride to a liquid dissolved in dichloromethane (Dichloromethane). Aluminum chloride) or use trifluoroacetic acid instead of aluminum chloride. Therefore, not only is the process of extracting the reaction mixture not easy, but there is also the generation of some side reactions during the reaction. This caused a problem in that the purity of the compound also decreased.

In the method for producing flomoxef of the present invention, by reacting flomoxef-BH and cresol for carboxy deprotection, it not only solves the problems that occur in the conventional technology, but also has great advantages in terms of raw material cost and yield. Improvement is visible. In particular, when producing flomoxef, both an SUS reactor (a reactor whose interior is made of stainless steel) and a G/L reactor (a reactor whose interior is coated with glass) can be used. In the case of the conventional flomoxef production method, it could not be used in a SUS reactor due to acid corrosion, but the flomoxef production method of the present invention can also be used in a SUS reactor, so it can be applied at various production sites.

The solvent used in the first step of the process for producing flomoxef of the present invention may be selected from the group consisting of o-cresol, m-cresol, p-cresol, toluene and combinations thereof, examples of combinations being , a mixture of 62% m-cresol + 38% p-cresol can be used.

In the first step of the method for producing flomoxef of the present invention, the weight of the solvent selected from the group consisting of cresol, toluene, and combinations thereof to be reacted per 100 parts by weight of flomoxef-BH is 400 parts by weight or more, 420 parts by weight or more, It may be more than 450 parts by weight or more than 500 parts by weight, it can be less than 800 parts by weight, less than 750 parts by weight, less than 700 parts by weight or less than 600 parts by weight, for example 400-800 parts by weight, 420-750 parts by weight. parts, 450 to 700 parts by weight, or 500 to 600 parts by weight. If the weight of the solvent is lower than the above range, side reactions may occur, resulting in a significant decrease in yield; if it exceeds the above range, no additional effects will occur, but the unit production cost will increase. occurs.

In the method for producing flomoxef-FA of the present invention, the first step is performed at ambient temperature. It can be carried out in a suitable solvent at a temperature in the reflux temperature range of the solvent, and can be carried out at a reaction temperature of 50°C to 70°C, such as 55°C to 65°C or 60°C to 70°C, 2 to 8 It can be carried out for a period of time, for example 2 to 6 hours or 3 to 5 hours. If the reaction temperature and reaction time are outside the above ranges, the yield of flomoxef may decrease.

The method for producing flomoxef of the present invention can additionally include the step of adding an acid to the product of the first step to remove impurities. The acid may be selected from the group consisting of acetic acid, trifluoroacetic acid, phosphoric acid, citric acid and combinations thereof.

The method for producing flomoxef of the present invention includes a second step of crystallizing the product of the first step and synthesizing flomoxef.

In the second stage, crystallization can be carried out by adding a solvent, which is a combination of acetone and dichloromethane, to the product of the first stage.

According to the present invention, flomoxef-BH is reacted as a starting material with a solvent selected from the group consisting of cresol, toluene, and a combination thereof to produce flomoxef in high yield and purity. Further, according to the present invention, both an SUS reactor and a G/L reactor can be used in producing flomoxef.

Hereinafter, the present invention will be explained in more detail through Examples and Comparative Examples. However, the scope of the present invention is not limited thereto.

Examples Synthesis example: Synthesis of flomoxef-BH
(6R,7R)-benzhydryl3-(chloromethyl)-7-((1-(((Z)-2-chlorovinyl)oxy)-2-((difluoromethyl)thio)ethyl)amino)-7-methoxy-8- 100 g of oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate was dissolved in 237 g of dimethylformamide and then cooled to 0±3° C. to prepare the reaction. 36.5 g of 1-(2-Hydroxyethyl)-1H-tetrazol-5-ylthiol sodium salt was slowly heated at 0±3°C. After addition, it was stirred for 1-2 hours.

After the reaction was completed, 335 g of ethanol + 326 g of purified water were charged into the reactor. Crystallization proceeded at 20°C to 30°C for 3 to 4 hours. An additional 500 g of purified water was added and stirred for 1 to 2 hours. The generated solid was filtered, and the filtered solid was washed with 103 g of ethanol and 100 g of purified water. Target compound obtained by filtration (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7- 120 g (yield 99.9%, purity 99.2%) of methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (flomoxef-BH) was obtained. .

Example 1: Synthesis of flomoxef (using m-Cresol)
(6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5- 120 g of oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (Flomoxef-BH) was added to 620 g of m-cresol heated to 60°C to 70°C. After melting, the temperature was maintained at 65°C to 70°C and stirred for 3 hours.

After the reaction was completed, 1080 g of ethyl acetate and 1200 g of brine were added to the reaction solution while maintaining the temperature at 5 to 10°C. Here, 16.7 g of sodium bicarbonate was added while maintaining the same temperature, the mixture was stirred to adjust to neutrality, and after being allowed to stand still, the mixture was separated to collect the aqueous layer. After extraction, 600 g of saturated brine was added to the organic layer again, and the layers were separated. After collecting all the aqueous layers, 540 g of ethyl acetate was added, the aqueous layers were washed, and the layers were separated. After collecting the aqueous layer, 360 g of salt and 1080 g of ethyl acetate were added, and 31.3 g of phosphoric acid was added to make the mixture acidic, followed by extraction and the organic layer was collected. The aqueous layer was extracted again using 540 g of ethyl acetate, and the organic layer was collected. The organic layer was dehydrated by adding 24 g of magnesium sulfate, decolorized using 12 g of activated carbon, filtered, and washed with 108 g of ethyl acetate. After concentrating the organic layer in vacuo, 235 g of acetone was added to the concentrated residue to dissolve it, and then 3192 g of dichloromethane was slowly added. After maintaining the temperature at 0° C. and stirring for 12 hours, the resulting solid was filtered and washed with 160 g of dichloromethane. The filtered solid was vacuum dried at 30±3℃ for 12 hours to obtain the target compound (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol- 79 g (yield 87.8%) , solvent correction value, purity 99.8%).

Example 2: Synthesis of flomoxef (using o-Cresol)
(6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5- Examples except for the case where 120 g of oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (Flomoxef-BH) was added to 620 g of o-cresol heated to 60°C to 70°C. Proceed as in 1 to obtain the target compound (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7- methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (Flomoxef-FA) 69.6 g (yield 77.4%, solvent correction value, purity 99 .8%) was obtained.

Example 3: Synthesis of flomoxef (using p-Cresol)
(6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5- Examples except for the case where 120 g of oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (Flomoxef-BH) was added to 620 g of p-cresol heated to 60°C to 70°C. Proceed as in step 1 to obtain the target compound (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy -8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (Flomoxef-FA) 58.3g (yield 64.8%, solvent correction value, purity 99. 4%).

Comparative Example 1: Synthesis of flomoxef (using m-Cresol)
(6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5- Except that 120 g of oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (Flomoxef-BH) was added to 370.8 g of m-cresol heated at 60°C to 70°C. , In the same manner as in Example 1, the target compound (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]- 7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (Flomoxef-FA) 69.6 g (yield 70.2%, solvent correction value, A purity of 99.3% was obtained.

The present invention aims to solve the above technical problems, and the present invention aims to solve the above - mentioned technical problems. 5-yl)sulfenyl)methyl)-7-methoxy-8oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate, cresol, toluene and the like Provided is a method for producing flomoxef, comprising a first step of reacting a solvent selected from the group consisting of a combination of: and a second step of crystallizing the product of the first step to synthesize flomoxef.

In this specification,
Flomoxef-Cl is (6R,7R)-benzhydryl(7-(2-difluoromethylthio)acetamido)-3-(chloromethyl)-7-methoxy-8-oxo-5-oxa-1-aza-bicyclo[4,2 ,0] means oct-2-ene-2-carboxylate .

Flomoxef-BH is: (6 R ,7R)-benzhydryl-7- ( (difluoromethylthio)acetamide)-3-(((1-(2-hydroxyethyl)-1H-tetrazol-5-yl)sulfenyl) methyl)-7-methoxy-8oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate.

The method for producing flomoxef of the present invention includes:
(6R,7R)-Benzhydryl-7- ( (difluoromethylthio)acetamide)-3-(((1-(2-hydroxyethyl)-1H-tetrazol-5-yl)sulfenyl)methyl)-7-methoxy- The first step of reacting 8oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (Flomoxef-BH) with cresol and the product of the first step are crystallized. The second step involves the synthesis of flomoxef.

The method for producing flomoxef of the present invention includes (6R,7R)-benzhydryl-7- ( (difluoromethylthio)acetamido)-3-(((1-(2-hydroxyethyl)-1H-tetrazol-5-yl)sulfur phenyl)methyl)-7-methoxy-8oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate (flomoxef-BH), cresol, toluene and the like A first stage step of reacting a solvent selected from the group consisting of a combination of.

Examples Synthesis example: Synthesis of flomoxef-BH
(6R,7R)-benzhydryl(7-(2-difluoromethylthio)acetamido)-3-(chloromethyl)-7-methoxy-8-oxo-5-oxa-1-aza-bicyclo[4,2,0]oct- A reaction was prepared by dissolving 100 g of 2-ene-2-carboxylate in 237 g of dimethylformamide and cooling it to 0±3°C. 36.5 g of 1-(2-Hydroxyethyl)-1H-tetrazol-5-ylthiol sodium salt was slowly heated at 0±3°C. After addition, it was stirred for 1-2 hours.

After the reaction was completed, 335 g of ethanol + 326 g of purified water were charged into the reactor. Crystallization proceeded at 20°C to 30°C for 3 to 4 hours. An additional 500 g of purified water was added and stirred for 1 to 2 hours. The generated solid was filtered, and the filtered solid was washed with 103 g of ethanol and 100 g of purified water. The target compound obtained by filtration (6R,7R) -benzhydryl- 7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]- 120 g of 7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (Flomoxef-BH) (yield 99.9%, purity 99.2%) Obtained.

Example 1: Synthesis of flomoxef (using m-Cresol)
(6R,7R)- benzhydryl- 7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo- 120 g of 5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (furomoxef-BH) was added to 620 g of m-cresol heated at 60°C to 70°C. After melting, the temperature was maintained at 65°C to 70°C and stirred for 3 hours.

Example 2: Synthesis of flomoxef (using o-Cresol)
(6R,7R)- benzhydryl- 7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo- Except for the case where 120 g of 5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (Flomoxef-BH) was added to 620 g of o-cresol heated at 60°C to 70°C. The procedure was carried out in the same manner as in Example 1, and the target compound (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]- 7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (Flomoxef-FA) 69.6 g (yield 77.4%, solvent correction value, A purity of 99.8%) was obtained.

Example 3: Synthesis of flomoxef (using p-Cresol)
(6R,7R)- benzhydryl- 7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo- Except for the case where 120g of 5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (Flomoxef-BH) was added to 620g of p-cresol heated at 60°C to 70°C. The procedure was carried out in the same manner as in Example 1 to obtain the target compound (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7 -methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (Flomoxef-FA) 58.3g (yield 64.8%, solvent correction value, purity 99.4%).

Comparative Example 1: Synthesis of flomoxef (using m-Cresol)
(6R,7R)- benzhydryl- 7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo- 120 g of 5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (Flomoxef-BH) was added to 370.8 g of m-cresol heated at 60°C to 70°C. The target compound (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl ]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (Flomoxef-FA) 69.6 g (yield 70.2%, solvent correction (purity: 99.3%).

Claims (7)

(6R,7R)-benzhydryl-7-(difluoromethylthio)acetamide)-3-(((1-(2-hydroxyethyl)-1H-tetrazol-5-yl)sulfenyl)methyl)-7-methoxy-8 A first step of reacting oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate with a solvent selected from the group consisting of cresol, toluene and combinations thereof. and a second step of synthesizing flomoxef by crystallizing the product of the first step. A method for producing flomoxef in paragraph 1, wherein the solvent is selected from the group consisting of o-cresol, m-cresol, p-cresol, toluene, and combinations thereof. The method for producing flomoxef according to item 1, wherein in the first step, 400 to 800 parts by weight of a solvent selected from the group consisting of cresol, toluene, and a combination thereof is reacted per 100 parts by weight of flomoxef-BH. The method for producing flomoxef according to item 1, wherein the first step is carried out at a reaction temperature of 50°C to 70°C. The method for producing flomoxef according to claim 1, wherein the first step is carried out for 2 to 8 hours. In paragraph 1, further comprising adding an acid selected from the group consisting of acetic acid, trifluoroacetic acid, phosphoric acid, citric acid and combinations thereof to the product of the first step to remove impurities. A method for producing flomoxef, including. 1. The method for producing flomoxef according to item 1, wherein in the second step, crystallization is performed by adding a solvent that is a combination of acetone and dichloromethane to the product of the first step.