KR100245772B1 - Monobromination process of 6-aminopenicillanic acid - Google Patents

Abstract

The present invention is monobrominated by reacting 6-β-aminophenic silane acid with sodium bromide and sodium nitrite in a mixed solution of an inorganic acid and a water-soluble organic solvent, and the product is extracted with a halogen organic solvent and 6-bromophenic silane. The present invention relates to a method of preparing 6-bromophenic silane acid 1,1-dioxide by obtaining an acid and oxidizing the obtained 6-bromophenic silane acid without undergoing purification or drying. Inorganic acids that can be used in the present invention include sulfuric acid, bromic acid (HBr), hydrochloric acid and the like, sulfuric acid is preferable, alcohol is used as the water-soluble organic solvent, methanol, ethanol, iso-propanol and the like can be preferably used Halogen organic solvents that can be used for 6-bromophenic silane acid extraction include methylene chloride, dichloroethane, chlorobenzene and the like, with dichloroethane being most preferred. It is preferable to perform said monobromination reaction in the range of -20-20 degreeC, and it is more preferable to make it react at 10 degrees C or less.

Description

Method for preparing 6-bromophenic silane acid 1,1-dioxide

The present invention is monobromination of 6-β-aminophenicylanic acid (monobromination) to extract 6-bromophenic silane acid, the 6-bromophenic silane acid is oxidized 6-bromophenic silane 1 It relates to a method for producing, 1-dioxide. More specifically, the present invention mono-brominated the reaction of 6-β-aminophenic silane acid with sodium bromide and sodium nitrite in a mixed solution of an inorganic acid and a water-soluble organic solvent, the product is extracted with a halogen organic solvent 6-bro The present invention relates to a method of obtaining 6-bromophenic carboxylic acid 1,1-dioxide by obtaining morphenic acid and oxidizing the obtained 6-bromophenic silane acid without undergoing purification or drying. Peniclanic acid 1,1-dioxide is prepared from the 6-bromophenic silane 1,1-dioxide obtained in the present invention.

Methods are known for producing peniclanic acid 1,1-dioxide starting from 6-β-aminophenicylic acid produced by hydrolysis of penicillin G by enzymes. Penicilanic acid 1,1-dioxide has an effective inhibitory effect on β-lactamase, an enzyme that helps produce bacteria resistant to β-lactam antibiotics. As a known method for preparing 1,1-dioxide, diazotization-bromination of 6-β-aminophenic silane acid using bromine produces 6,6-dibromophenic silane acid. There is a method of oxidizing with 6,6-dibromophenic silane acid-1,1-dioxide followed by debromination.

European patent application 83200541 discloses 6,6-dibromophenic silane acid 1,1-dioxide and 6-α-bromophenicsilane by diazotizing-brominated 6-aminophenic silane acid 1,1-dioxide. A process for preparing a mixture of acid 1,1-dioxides is disclosed. The content ratio of the dibromo compound in the mixture is generally 80 to 90%, and the content ratio of the monobromo compound is 10 to 20%.

Dutch Patent Application Nos. 7806126 and 8001285 disclose methods for preparing peniclanic acid 1,1-dioxide, but these also include a mixture of an organic solvent and water containing at least equimolar amounts of hydrogen bromide and bromine that are harmful to the environment. Sodium nitrite is used to prepare 6,6-dibromophenicylanic acid derivatives. This dibromo compound is debrominated through a reduction reaction to produce peniclanic acid 1,1-dioxide.

In order to prepare peniclanic acid 1,1-dioxide from 6-β-aminophenicylanic acid, the reaction of removing 6-amino group of 6-β-aminophenicylanic acid is the most important step. The parent compound is made and subjected to hydrogenation under a transition metal catalyst or debromination with a metal reducing agent to remove the 6-amino group.

The preparation of 6-monobromophenic acid described by Cignarella in Journal of Organic Chemistry, 27, 2668 (1962), does not exceed 70% in yield and is not applicable to large scale production. have.

The present inventors have found that the use of a water-soluble organic solvent in the diazotization-bromination reaction of 6-β-aminophenicsilane acid significantly increases the yield of 6-β-aminophenicsilane acid. It was to develop a method for preparing 6-bromophenic silane acid characterized by producing 6-bromophenic silane acid by reacting with sodium nitrite in the presence of sodium bromide in the mixed solution.

Using the method of the present invention, 6-bromophenic silane acid can be prepared in a yield of 90% or more. In addition, in the conventional method, 6,6-dibromophenic acid is mixed with about 15%, but according to the present invention, 6-bromophenic acid having a high purity of less than 1% of 6,6-dibromophenic acid can be obtained. have.

When using a water-soluble organic solvent it is difficult to extract the product of the aqueous layer, it is necessary to remove the alcohol by azeotropic distillation or vacuum evaporation. In particular, large-scale processes use vacuum distillation for a long time to evaporate alcohol, in which 6-bromophenic silane is decomposed, resulting in lower yield and lower purity. However, it has been found that the use of halogen organic solvents for extraction can easily extract only the product in the presence of alcohol. In addition, a portion of the extraction solution is vacuum distilled to remove a small amount of alcohol contained in the extraction solution without drying process can be used directly in the oxidation reaction.

It is an object of the present invention to provide a method which can increase the yield of 6-bromophenic silane acid to 90% or more when preparing 6-bromophenic silane acid from 6-β-aminophenic silane acid.

Another object of the present invention is to provide a method for producing high purity 6-bromophenic acid having less than 1% of 6,6-dibromosilane acid contained in 6-β-aminophenicylanic acid.

It is still another object of the present invention to provide a process for preparing 6-bromophenic silane acid 1,1-dioxide without removing the alcohol which is a water soluble organic solvent.

It is yet another object of the present invention to provide a process for the preparation of environmentally friendly 6-bromophenicylanic acid 1,1-dioxide, avoiding hazardous processes using highly toxic bromine.

It is still another object of the present invention to reduce the use of a reducing agent by more than equimolar amounts in comparison to the debromination of dibromo compounds when debromination of 6-bromophenic silane or its derivatives using a metal reducing agent. To provide a method for producing bromophenic silane acid 1,1-dioxide.

The above and other objects of the present invention can be achieved by the present invention described below.

The present invention is monobrominated by reacting 6-β-aminophenic silane acid with sodium bromide and sodium nitrite in a mixed solution of an inorganic acid and a water-soluble organic solvent, and the product is extracted with a halogen organic solvent and 6-bromophenic silane. The present invention relates to a reaction for obtaining 6-bromophenic carboxylic acid 1,1-dioxide by obtaining an acid and oxidizing the obtained 6-bromophenic silane acid without undergoing purification or drying.

The preparation method of 6-bromophenic silane acid 1,1-dioxide of the present invention is described in detail below.

The method for preparing 6-bromophenic silane acid 1,1-dioxide of the present invention comprises the steps of monobromizing 6-β-aminophenicylanic acid, extracting 6-bromophenic silane acid from the product. And oxidizing the 6-bromophenic silane.

In order to monobromize 6-β-aminophenic silane acid, 6-β-aminophenic silane acid is reacted with sodium bromide and sodium nitrite in a mixed solution of an inorganic acid and a water-soluble organic solvent. A 6-β-aminophenic silane acid, an inorganic acid, a water-soluble organic solvent, and sodium bromide are mixed, and an aqueous sodium nitrite solution is added dropwise to this mixed solution. Inorganic acids that can be used here include sulfuric acid, bromic acid (HBr), hydrochloric acid, and the like, with sulfuric acid being most preferred.

Alcohol is used as the water-soluble organic solvent, and methanol, ethanol, iso-propanol and the like are preferably used. The solution in which sodium nitrite is added dropwise is stirred for about 1 hour and then the extraction process is performed. It is preferable to perform said monobromination reaction in the range of -20-20 degreeC, and it is more preferable to make it react at 10 degrees C or less.

The product is extracted using a halogen organic solvent. Halogen organic solvents used herein include methylene chloride, dichloroethane, chlorobenzene and the like, with dichloroethane being most preferred. In this extraction step, since the halogen organic solvent is used, it is not necessary to remove the alcohol and the oxidation step can be performed without the need to dry the 6-bromophenic silane acid after extraction. 6-bromophenic silane acid is extracted from the monobrominated product and subjected to azeotropic evaporation to remove the small amount of alcohol contained in the extraction process.

The 6-bromophenic carboxylic acid extracted above may be oxidized without drying to obtain 6-bromophenic silane 1,1-dioxide.

Peniclanic acid 1,1-dioxide is prepared from the 6-bromophenic silane 1,1-dioxide obtained in the present invention.

The invention will be further illustrated by the following examples which are intended to illustrate the invention and are not intended to limit the scope of the appended claims.

Examples 1-12: Preparation of 6-bromophenic silane acid

Example 1

To 50 ml of an aqueous 2.5N sulfuric acid solution cooled to 0 ° C., 40 ml of methanol, 4.32 g of 6-β-aminophenicylanic acid and 10.4 g of sodium bromide were added. While keeping the temperature below 5 ° C., 2.12 g of sodium nitrite was dissolved in 10 ml of water and added dropwise to the stirred mixture for 30 minutes. After further stirring at 0 ° C. for 1 hour, the temperature was slowly raised to room temperature and 50 ml of methylene chloride was added to extract the reaction. The layers were separated and the aqueous layer was extracted twice more with 50 ml of ethyl acetate. The extract was dried (MgSO ₄ ) and evaporated to dryness in vacuo. This gave 5.04 g (yield 90.0%) of the title compound. 300 MHz NMR spectral analysis showed 6,6-dibromophenic silane acid at a rate of 1%.

Example 2

The same procedure as in Example 1 was conducted except that 40 ml of ethanol was used instead of methanol. The yield of 6-bromophenic silane acid was 4.93 g and the yield was 88.1%.

Example 3

The same procedure as in Example 1 was conducted except that 40 ml of isopropyl alcohol was used instead of methanol. The yield of 6-bromophenic silane acid was 3.93 g and the yield was 70.2%.

Example 4

To 250 ml of 2.5N aqueous sulfuric acid solution cooled to 0 ° C., 250 ml of methanol, 21.6 g of 6-aminophenicylanic acid and 41.1 g of sodium bromide were added. While maintaining the temperature at 5 ° C. or lower, 10.4 g of sodium nitrite was dissolved in 30 ml of water and added dropwise to the stirred mixture for 1 hour. After stirring for 1 hour or less at 5 ° C, the temperature was slowly raised to room temperature and methanol was evaporated in a vacuum dryer. At this time, water and methanol were evaporated together. After 300-350 ml of water and methanol were recovered, 100 ml of methylene chloride was added to extract the reaction. The layers were separated and the aqueous layer was extracted twice more with 100 ml of methylene chloride. The extract was dried (MgSO ₄ ) and evaporated to dryness in vacuo. This gave 23.1 g (yield 82.5%) of the title compound.

Example 5

The same procedure as in Example 4 was carried out except that 250 ml of 2.5N sulfuric acid aqueous solution and 250 ml of methanol were used instead of 200 ml of 2.5N sulfuric acid aqueous solution and 200 ml of methanol. The yield of 6-bromophenic silane acid was 25.6 g and the yield was 91.5%.

Example 6

The same procedure as in Example 4 was carried out except that 150 ml of 2.5N sulfuric acid and 150 ml of methanol were used instead of 250 ml of 2.5N sulfuric acid and 250 ml of methanol. The yield of 6-bromophenic silane acid was 25.3 g and the yield was 90.3%.

Example 7

The same procedure as in Example 4 was carried out except that 250 ml of 2.5N sulfuric acid aqueous solution and 125 ml of 2.5N sulfuric acid aqueous solution were used instead of 250 ml of methanol. The yield of 6-bromophenic silane acid was 25.4 g and the yield was 90.7%.

Example 8

It was carried out in the same manner as in Example 4 except that 100 ml of 2.5N sulfuric acid aqueous solution and 100 ml of methanol were used instead of 250 ml of 2.5N sulfuric acid aqueous solution and 250 ml of methanol. The yield of 6-bromophenic silane acid was 25.5 g and the yield was 90.9%.

Example 9

It was carried out in the same manner as in Example 4 except that 10075 ml of 2.5N sulfuric acid aqueous solution and 75 ml of methanol were used instead of 250 ml of 2.5N sulfuric acid aqueous solution and 250 ml of methanol. The yield of 6-bromophenisilane acid was 23.9 g and the yield was 85.8%.

Example 10

The same procedure as in Example 4 was carried out except that 50 ml of 2.5N sulfuric acid aqueous solution and 150 ml of methanol were used instead of 250 ml of 2.5N sulfuric acid aqueous solution and 250 ml of methanol. The yield of 6-bromophenisilane acid was 23.5 g and the yield was 84.0%.

Example 11

The same procedure as in Example 4 was carried out except that 250 ml of 2.5N sulfuric acid aqueous solution and 200 ml of methanol were used. The yield of 6-bromophenic silane acid was 22.4 g and the yield was 80.1%.

Example 12

The same procedure as in Example 4 was performed except that 150 ml of 2.5N sulfuric acid aqueous solution and 50 ml of tetrahydrofuran were used instead of 250 ml of 2.5N sulfuric acid aqueous solution and 250 ml of methanol. 25.7 g of 6-bromophenic silane acid containing some sodium bromide was obtained. The yield was 92.0%. The 300 MHz NMR spectrum analysis showed that 6,6-dibromophenic silane acid contained 4%.

Examples 13-17 Preparation of 6-bromophenicylanic acid-1,1-dioxide

Example 13

100 ml of a 2.5 N aqueous sulfuric acid solution cooled to 0 ° C., 21.6 g of 6-β-aminophenic silane acid, and 41.1 g of sodium bromide were added thereto. After further stirring the temperature at 5 ° C. for 1 hour, the temperature was slowly raised to room temperature and evaporated in vacuo to remove the methanol in the solvent. 100 ml of methylene chloride was added to extract the reaction. The layers were separated and the aqueous layer was extracted twice more with 100 ml of methylene chloride. 150 ml of water was added to the extract solution, and 3N sodium hydroxide was added dropwise (about 35 ml) until pH = 7.0. The aqueous layer was separated and the organic layer was extracted with 100 ml of water. The extracted aqueous solutions were combined and slowly added dropwise to 33.1 g of potassium permanganate, 7 ml of concentrated phosphoric acid and 500 ml of water. The dropping time is about 1 hour and the internal temperature does not exceed 10 ℃. After dropping, 100 ml of ethyl acetate was added thereto, and the pH was adjusted to 1.3 using 6N hydrochloric acid. Then, 1M sodium bisulfite aqueous solution was slowly added dropwise until the color of the reaction solution disappeared. The pH was maintained between 1.25 and 1.35 using 6N hydrochloric acid during the addition of aqueous sodium bisulfite solution. The aqueous layer was saturated with sodium chloride and the layers separated. The aqueous solution was extracted twice more with 100 ml of ethyl acetate and dried (MgSO ₄ ). The solvent was evaporated in vacuo and 200 ml of n-hexane was slowly added dropwise with the remaining solution remaining about 50 ml. After stirring for 1 hour, the title compound precipitated as a solid. This gave 22.4 g (yield 71.8%) of the title compound.

Example 14

The same procedure as in Example 13 was carried out except that 200 ml of 2.5N sulfuric acid aqueous solution and 150 ml of methanol were used instead of 100 ml of 2.5N sulfuric acid aqueous solution and 100 ml of methanol. The yield of 6-bromophenisilane acid-1,1-dioxide was 21.77 g and the yield was 69.8%.

Example 15

The same procedure as in Example 13 was carried out except that 100 ml of 2.5N sulfuric acid aqueous solution and 100 ml of methanol were used instead of 200 ml of 2.5N sulfuric acid aqueous solution and 150 ml of methanol. The yield of 6-bromophenisilane acid-1,1-dioxide was 21.77 g and the yield was 69.8%.

Example 16

To 1000 ml of 2.5N sulfuric acid aqueous solution cooled to 0 ° C., 1000 ml of methanol, 216 g of 6-aminophenicylanic acid and 411 g of sodium bromide were added. While maintaining the temperature below 10 ℃ to the stirred mixture, 104g of sodium nitrite was dissolved in 300ml of water and added dropwise for 1.5 hours. After further stirring at 5 ° C. for 1 hour, the temperature was slowly raised to room temperature and evaporated in vacuo to remove the methanol in the solvent. 1000 ml of methylene chloride was added to extract the reaction. The layers are separated and the aqueous layer is extracted twice more with 500 ml of methylene chloride. 1000 ml of water was added to the extract solution, and 3N sodium hydroxide was added dropwise (about 350 m) until pH = 7.0. The aqueous layer was separated and the organic layer was extracted with 500 ml of water. The extracted aqueous solution was combined and slowly added dropwise to 331 g of potassium permanganese potassium salt, 70 ml of concentrated phosphoric acid, and 1500 ml of water. The dropping time is about 1 hour and the internal temperature should not exceed 10 ℃. 1000 ml of ethyl acetate was added after the addition, and the mixture was lowered to pH = 1.3 using 6N hydrochloric acid. Then, 1M sodium bisulfite aqueous solution was slowly added dropwise until the color of the reaction solution disappeared. The pH was maintained between 1.25 and 1.35 using 6N hydrochloric acid during the addition of aqueous sodium bisulfite solution. The aqueous layer was saturated with sodium chloride and the layers separated. The aqueous solution was extracted twice more with 100 ml of ethyl acetate and dried (MgSO ₄ ). The solvent was evaporated in vacuo and slowly added dropwise 2000 ml of n-hexane when the remaining solution remained about 500 ml. After stirring for 1 hour, the yellowish title compound precipitated out as a solid. This gave 192 g (yield 61.5%) of the title compound.

Example 17

1000 ml of methanol, 216 g of 6-aminophenicylanic acid and 411 g of sodium bromide were added to 1000 ml of a 2.5 N aqueous sulfuric acid solution cooled to 0 ° C. While maintaining the temperature below 10 ℃ to the stirred mixture, 104g of sodium nitrite was dissolved in 300ml of water and added dropwise for 1.5 hours. After stirring for 1 hour at 5 ° C., the temperature was slowly raised to room temperature and extracted three more times with 1000 ml of dichloroethane. 500-1000 ml of solvent was removed under reduced pressure. 1000 ml of water was added to the remaining extract solution, and 3N sodium hydroxide was added dropwise (about 350 ml) until pH = 7.0. The aqueous layer was separated and the organic layer was extracted with 500 ml of water. The extracted aqueous solutions were combined and slowly added dropwise to 331 g of potassium permanganate, 70 ml of concentrated phosphoric acid, and 1500 ml of water. The dropping time is about 1 hour and the internal temperature does not exceed 10 ℃. 1000 ml of ethyl acetate was added after dropwise addition, and the mixture was diluted to pH = 1.3 using 6N hydrochloric acid. Then, 1M sodium bisulfite aqueous solution was slowly added dropwise until the color of the reaction solution disappeared. The pH was maintained at 1.25-1.35 with 6N hydrochloric acid while the aqueous sodium bisulfite solution was added. The aqueous layer was saturated with sodium chloride and the layers separated. The aqueous solution was extracted two more times with 1000 ml of ethyl acetate and dried (MgSO ₄ ). The solvent was evaporated in vacuo to precipitate the title compound as a colorless solid. This gave 211.6 g (67.8%) of the title compound.

The method for preparing 6-bromophenic silane acid of the present invention can increase the yield of 6-bromophenic silane acid to 90% or more when preparing 6-bromophenic silane acid from 6-β-aminophenic silane acid. 6,6-dibromosilane acid contained in 6-β-aminophenic silane acid can be prepared with less than 1% of high purity 6-bromophenic silane acid, without removing the alcohol which is a water-soluble organic solvent 6 It is possible to produce bromophenic silane 1,1-dioxide and avoid environmentally dangerous processes using toxic bromine to provide environmentally friendly 6-bromophenic silane 1,1-dioxide and reduce metals. In the case of debromination of 6-bromophenic silane acid or a derivative thereof, the use of a reducing agent can be reduced to an equimolar amount or more as compared to the debromination reaction of a dibromo compound.

Simple modifications or variations of the present invention can be readily used by those skilled in the art, and all such modifications or changes can be regarded as being included in the scope of the present invention.

Claims (7)

Monobromizing the 6-β-aminophenicsilane acid with sodium bromide and sodium nitrite in a mixed solution of an inorganic acid and a water-soluble organic solvent; And Extracting the monobrominated product with a halogen organic solvent; Method for producing 6-bromophenic silane acid, characterized in that consisting of. The method of claim 1, wherein the inorganic acid is selected from the group consisting of sulfuric acid, bromic acid and hydrochloric acid. The method for producing 6-bromophenic silane acid according to claim 1, wherein the water-soluble organic solvent is an alcohol. 4. The method of claim 3, wherein said alcohol is selected from the group consisting of methanol, ethanol and isopropanol. The method of claim 1, wherein the halogen organic solvent is selected from the group consisting of methylene chloride, dichloroethane, and chlorobenzene. The method of claim 1, further comprising removing the alcohol contained in the extract solution through azeotropic distillation. Monobromizing the 6-β-aminophenicsilane acid with sodium bromide and sodium nitrite in a mixed solution of an inorganic acid and a water-soluble organic solvent; Extracting the monobrominated product with a halogen organic solvent; And Oxidizing the extracted 6-bromophenic silane; Method for producing 6-bromophenic silane acid-1,1-dioxide, characterized in that consisting of.