JP2023077018A - METHOD FOR PRODUCING α-OXO 2-FURANACETIC ACID - Google Patents

Abstract

To provide a method for efficiently producing an α-oxo 2-furanacetic acid, as a pharmaceutical intermediate, without using sodium nitrite.SOLUTION: The present invention provides a method for producing an α-oxo 2-furanacetic acid from furfural through oxidation, chlorination, cyanation, and hydrolysis with a manganese- or chlorine-based oxidizer.SELECTED DRAWING: None

Description

The present invention relates to a method for producing α-oxo-2-furanacetic acid.

The demand for cefuroxime sodium and cefuroxime ester, which are cephalosporin antibiotics, has been increasing in recent years due to their good therapeutic effects.

Z-α-methoxyimino-2-furanacetate ammonium salt, which is a compound useful as an intermediate for this cephalosporin antibiotic, is industrially produced mainly from 2-acetylfuran to α-oxo-2-furanacetate. (Patent Documents 1 and 5).

However, in the production methods of Patent Documents 1 and 5, slight differences in reaction conditions such as pH, temperature, and reaction time have a great effect on the yield. Not suitable for production.

Techniques intended to improve such problems include (1) a method of adding a phase transfer catalyst (Patent Document 2), (2) a method of adding a metal salt such as a copper salt or zinc salt or a palladium catalyst ( Patent Documents 3 and 4) and (3) a method of adding an alkanoic acid having 1 to 10 carbon atoms (Patent Document 5) are known.

However, in the case of (1) above, the use of an expensive phase transfer catalyst is disadvantageous in terms of cost for mass production. Further, phase transfer catalysis is not sufficient as an industrial production method because it is easily affected by stirring efficiency. The method (2) above is not sufficient as an industrial production method for pharmaceutical intermediates, since it is necessary to pay attention to trace amounts of harmful metal residues. The method (3) uses an excess amount of alkanoic acid having 1 to 10 carbon atoms relative to 2-acetylfuran, which is disadvantageous in terms of cost for mass production.

Furthermore, in the above production method using sodium nitrite, there is a possibility that nitrosamines, which are carcinogenic substances, may be generated and remain. Regarding nitrosamines, in September 2019, the European Medicines Agency (EMA) announced that marketing authorization holders of all medicines (including generics and OTC products) will be assessed for the risk of nitrosamine contamination and appropriate risk mitigation measures should be taken. (See EMA/189634/2019 Notification).

Therefore, there is a demand for a method capable of stably producing α-oxo-2-furanacetic acid without using a method of oxidizing 2-acetylfuran with sodium nitrite. For example, a method for producing α-oxo-2-furanacetic acid using 2-furancarboxylic acid as a starting material is known (Patent Document 6), but since 2-furancarboxylic acid as a starting material is not cheap, it is cheaper. A desirable starting material is furfural, which is a complex compound.

In this regard, the oxidation reaction of furfural to 2-furancarboxylic acid includes (4) air oxidation using a metal catalyst (Non-Patent Document 1) and (5) enzymatic reaction (Non-Patent Document 2). The method (4) is not sufficient as an industrial production method for pharmaceutical intermediates because it is necessary to pay attention to trace amounts of harmful metal residues, and in the case of (5) above, it is not easy to optimize the enzymatic reaction. , Non-Patent Document 1, the reaction time is as long as 96 hours, which is not sufficient for mass production.

As described above, the actual situation is that there is a demand for means for industrially obtaining α-oxo-2-furanacetic acid from furfural in a large amount and by a simple operation.

Chinese Patent Publication No. 105254603 Chinese Patent Publication No. 110590719 Chinese Patent Publication No. 102863407 Chinese Patent Publication No. 110003151 Indian Patent Publication No. 2015MU02097 Chinese Patent Publication No. 102010390

Catalysts (2020), 10(1), 73 Green Chemistry (2019), 21(21), 5914－5923

As described above, in order to industrially produce α-oxo-2-furanacetic acid, in the method of oxidizing acetylfuran as a raw material with sodium nitrite, there are slight differences in reaction conditions such as pH, temperature and reaction time. It has a great influence on the yield and may form/residue carcinogenic nitrosamines. SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide means capable of stably mass-producing α-oxo-2-furanacetic acid without generating nitrosamines.

The present inventors have made intensive studies to solve such problems, and as a result, have found a method for producing α-oxo-2-furanacetic acid from furfural without using sodium nitrite, and have completed the present invention. rice field.

で表されるフルフラールを、マンガン系酸化剤、又は亜塩素酸塩と次亜塩素酸の補足材としてスルファミン酸、２－メチル－２－ブテン及びジメチルスルホキシドのいずれか又はそれらの混合物とで、酸化し、下記一般式（２）：

で表される２－フランカルボン酸を得るステップと、
（２）前記ステップ（１）で得られた２－フランカルボン酸を塩素化剤と反応させて、下記一般式（３）：

で表される２－フランカルボン酸クロライドを得るステップと、
（３）前記ステップ（２）で得られた２－フランカルボン酸クロライドをシアノ化剤と反応させて下記一般式（４）：

で表されるα－オキソ２－フランアセトニトリルを得るステップと、
（４）前記ステップ（３）で得られたα－オキソ２－フランアセトニトリルを加水分解して下記一般式（５）：

で表されるα－オキソ２－フラン酢酸を得るステップと、
を含むことを特徴とするα－オキソ２－フラン酢酸の製造方法、を提供する。 That is, the present invention
(1) the following general formula (1):

Furfural represented by a manganese-based oxidizing agent, or sulfamic acid, 2-methyl-2-butene and dimethyl sulfoxide as supplements of chlorite and hypochlorous acid, or a mixture thereof. and the following general formula (2):

obtaining a 2-furancarboxylic acid represented by
(2) reacting the 2-furancarboxylic acid obtained in the step (1) with a chlorinating agent to give the following general formula (3):

obtaining a 2-furancarboxylic acid chloride represented by
(3) The 2-furancarboxylic acid chloride obtained in step (2) is reacted with a cyanating agent to give the following general formula (4):

obtaining α-oxo-2-furanacetonitrile represented by
(4) The α-oxo-2-furanacetonitrile obtained in step (3) is hydrolyzed to give the following general formula (5):

obtaining α-oxo-2-furanacetic acid represented by
A method for producing α-oxo-2-furanacetic acid, comprising:

In the method for producing α-oxo-2-furanacetic acid of the present invention, the manganese-based oxidizing agent in step (1) is preferably potassium permanganate, sodium permanganate or manganese dioxide.

According to the method for producing α-oxo-2-furanacetic acid according to the present invention, α-oxo-2-furanacetic acid can be industrially obtained from furfural in a large amount by a simple operation.

Hereinafter, representative embodiments of the method for producing α-oxo-2-furanacetic acid according to the present invention will be described in detail, but the present invention is not limited to these. Duplicate description may be omitted.

In the method for producing α-oxo-2-furanacetic acid according to the present embodiment, α-oxo-2-furanacetic acid is produced by the production route shown below, and (1) the process of oxidation reaction; (step), (2) chlorination reaction step (step), (3) cyanation reaction step (step) and (4) hydrolysis reaction step (step).

In the following, each of the above processes (steps) will also be described in detail.

(1) Oxidation reaction step First, as an oxidation reaction step, furfural represented by the general formula 1 is treated with a manganese-based oxidizing agent (1 to 6 equivalents), or a chlorite (1 to 6 equivalents) and hypochlorous acid. It is subjected to an oxidation reaction with an acid scavenger (1 to 6 equivalents) to obtain 2-furancarboxylic acid represented by the general formula (2).

The manganese-based oxidizing agent that can be used in the oxidation reaction step can be appropriately selected within a range that does not impair the effects of the present invention. Examples include potassium permanganate, sodium permanganate and manganese dioxide. is preferred, and potassium permanganate or manganese dioxide is more preferred.

Moreover, the chlorite that can be used in the oxidation reaction step can be appropriately selected within a range that does not impair the effects of the present invention, and sodium chlorite, for example, is preferable.

As a hypochlorous acid supplement that can be used in the oxidation reaction step, it can be appropriately selected within a range that does not impair the effects of the present invention. Acid amide sulfuric acid, preferably 2-methyl-2-butene or sulfamic acid. When chlorite is used, the reaction may be carried out under neutral to acidic conditions.

Any solvent can be used in this oxidation reaction step as long as it dissolves the raw material, oxidizing agent, and target substance to be treated. Specifically, for example, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, ethers such as tetrahydrofuran, ethylene glycol dimethyl ether, and dioxane, nitriles such as acetonitrile and propionitrile, dichloromethane, chloroform, 1,2-dichloroethane, and the like. halogenated hydrocarbons, organic acid esters such as ethyl acetate and butyl acetate, dimethyl sulfoxide, and water. These solvents can be used in combination of two or more, preferably a mixed solvent of ketones and water.

The reaction temperature in this oxidation reaction step is 0 to 60°C, preferably 5 to 40°C. Moreover, the reaction time may be adjusted as long as the raw material is substantially lost, and may be adjusted within that range, preferably 1 to 24 hours.

(2) Chlorination reaction step Next, in the chlorination reaction step, the 2-furancarboxylic acid obtained in the oxidation reaction step (1) is subjected to chlorination with chlorine, thionyl chloride, phosphorus trichloride, phosphorus oxychloride, or the like. 2-furancarboxylic acid chloride represented by the above general formula (3) is obtained by reacting with an agent.

The amount of the chlorinating agent used in this chlorination reaction step is 1 to 5 equivalents, preferably 1 to 3 equivalents.

The solvent used in this chlorination reaction step is not particularly limited as long as it does not interfere with the reaction. Examples include halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, and organic acids such as ethyl acetate and butyl acetate Esters, hydrocarbons such as toluene and xylene, ethers such as tetrahydrofuran, ethylene glycol dimethyl ether and dioxane, amides such as dimethylformamide and dimethylacetamide, and mixed solvents or no solvents thereof.

The reaction temperature in this chlorination reaction step is 0 to 100°C, preferably 20 to 90°C. The reaction time may be adjusted as long as the raw material is substantially lost, and may be adjusted within that range, preferably 1 to 10 hours.

(3) Cyanation reaction step Next, in the cyanation reaction step, the 2-furancarboxylic acid chloride obtained in the chlorination reaction step (2) is reacted with a cyanating agent to give the general formula (4). α-oxo-2-furanacetonitrile of the formula is obtained.

The cyanating agent that can be used in this cyanation reaction step can be appropriately selected within a range that does not impair the effects of the present invention. Examples include potassium cyanide, sodium cyanide and copper (I) cyanide, Sodium cyanide or potassium cyanide is preferred. Moreover, reaction efficiency can be improved by adding a quaternary ammonium salt as a catalyst.

The amount of the cyanating agent used in the cyanation reaction step may be 1 to 10 equivalents, preferably 1 to 3 equivalents.

The solvent used in this cyanation reaction step is not particularly limited as long as it does not interfere with the reaction. amides, organic acid esters such as ethyl acetate and butyl acetate, hydrocarbons such as toluene and xylene, dimethyl sulfoxide, and mixed solvents thereof, preferably acetonitrile and a mixture containing acetonitrile as a main component is a solvent.

The reaction temperature in this cyanation reaction step is -15 to 100°C, preferably 0 to 90°C. The reaction time may be adjusted as long as the raw materials are substantially lost, and may be adjusted within that range, preferably 0.5 to 10 hours.

(4) Hydrolysis reaction step Next, the α-oxo-2-furanacetonitrile obtained in the cyanation reaction step is hydrolyzed in the presence of an acid to obtain α-oxo-2- Furanacetic acid is obtained.

The acid that can be used in this hydrolysis reaction step can be appropriately selected within a range that does not impair the effects of the present invention, and may be an inorganic acid, preferably hydrochloric acid or sulfuric acid. The amount of acid to be used may be equal to or greater than the neutralization amount of by-produced ammonia, and is 1.1 to 50 equivalents, preferably 2 to 10 equivalents.

The reaction temperature in this hydrolysis reaction step is 0 to 100°C, preferably 20 to 100°C. The reaction time may be adjusted as long as the raw material is substantially lost, and may be adjusted within that range, preferably 0.5 to 24 hours.

Solvents other than water used in this hydrolysis reaction step are not particularly limited as long as they do not interfere with the reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, hydrocarbons such as toluene and xylene, ethers such as ethylene glycol dimethyl ether and dioxane, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, and It is a mixed solvent thereof or no solvent.

The representative embodiments of the method for producing α-oxo-2-furanacetic acid according to the present invention have been described above, and the present invention will be described in more detail below with reference to examples. However, the present invention is not limited by these examples.

<Experimental Example 1: Oxidation reaction step>
300 mg (3.1 mmol) of furfural represented by the general formula (1) was added to a mixed solvent of 12 ml of acetone and 3 ml of water at room temperature. Add and stir until complete dissolution. To this mixture was then slowly added 72% sodium chlorite (431 mg, 3.4 mmol) and stirred at room temperature for 5 hours. After completion of the reaction, acetone was distilled off and extraction was performed with dichloromethane (4×15 ml). The organic layer was dried with sodium sulfate and concentrated to obtain 317 mg of 2-furancarboxylic acid represented by the general formula (2) (yield 90%).

<Experimental Example 2: Oxidation reaction step>
100 mg (1.04 mmol) of furfural represented by the above general formula (1) was added to 5 ml of acetone at room temperature, and 329 mg (2.08 mmol) of potassium permanganate was previously suspended in 5 ml of water. The liquid was added and stirred at room temperature for 12 hours. After completion of the reaction, acetone was distilled off, and the aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid, extracted with ether (5 x 15 ml), washed with saturated brine, dried over magnesium sulfate, and concentrated to give a solution of the above general formula ( 50.7 mg (43% yield) of 2-furancarboxylic acid represented by 2) was obtained.

<Experimental Example 3: Chlorination reaction step>
1 g of 2-furancarboxylic acid obtained in Experimental Example 1 was dissolved in 5.2 ml of thionyl chloride, a catalytic amount of dimethylformamide was added dropwise, and the mixture was stirred at 80° C. for 4 hours. After completion of the reaction, the reaction mixture was concentrated to obtain 2-furancarboxylic acid chloride represented by the general formula (3).

<Experimental Example 4: Cyanation reaction step>
891 mg of sodium cyanide was added to 3 ml of acetonitrile, and a solution of 2-furancarboxylic acid chloride obtained in Experimental Example 3 dissolved in 3 ml of acetonitrile was added dropwise while stirring at 0 to 4°C. The reaction solution was stirred at room temperature for 15 minutes and then at 90° C. for 1 hour. After completion of the reaction, the reaction solution was returned to room temperature, filtered and concentrated to obtain oily α-oxo-2-furanacetonitrile represented by the general formula (4).

<Experimental Example 5: Hydrolysis reaction step>
10 ml of water and 7 ml of concentrated hydrochloric acid were added to the α-oxo-2-furanacetonitrile obtained in Experimental Example 4, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, it was extracted with ethyl acetate (3×5 ml), washed with saturated brine, dried over sodium sulfate, and concentrated to give α-oxo-2-furanacetic acid (2-furan in the chlorination reaction step of Experimental Example 3 above). 48% yield from 1 g of carboxylic acid) was obtained.

<Experimental Example 6: Cyanation reaction step>
5.87 g of potassium cyanide was added to 67 ml of acetonitrile, and while stirring at 5° C. with ice cooling, 5.87 g of 2-furancarboxylic acid chloride (manufactured by Tokyo Kasei Kogyo Co., Ltd.) was added while maintaining the temperature at 8° C. or lower, and the mixture was stirred for 15 minutes. . After stirring, the mixture was heated under reflux for 30 minutes, cooled to room temperature, filtered and concentrated to obtain 5.7 g of α-oxo-2-furanacetonitrile represented by the general formula (4).

<Experimental Example 7: Hydrolysis reaction step>
13 ml of concentrated hydrochloric acid was added to 1.9 g of α-oxo-2-furanacetonitrile obtained in Experimental Example 6, and the mixture was stirred at room temperature for 24 hours. After adding 7 ml of water to the reaction solution and stirring for 5 minutes, the mixture was extracted with ethyl acetate (5×9 ml), and the organic layer was washed with saturated brine. After drying with sodium sulfate, it was concentrated to obtain 1.88 g of α-oxo-2-furanacetic acid (70% yield from 5.87 g of 2-furancarboxylic acid chloride in the cyanation reaction step of Experimental Example 6 above). rice field.

[evaluation]
As can be seen from Experimental Examples 1 to 7 above, according to the method for producing α-oxo-2-furanacetic acid according to the present invention, α-oxo-2-furanacetic acid, which is a pharmaceutical intermediate, is produced without using sodium nitrite. It was demonstrated that it can be efficiently manufactured in

The method for producing α-oxo-2-furanacetic acid according to the present invention can be used for the production of pharmaceutical intermediates, and cefuroxime derived from α-oxo-2-furanacetic acid can be used as an antibiotic drug.

Claims (2)

(1) the following general formula (1):

Furfural represented by a manganese-based oxidizing agent, or sulfamic acid, 2-methyl-2-butene and dimethyl sulfoxide as supplements of chlorite and hypochlorous acid, or a mixture thereof. and the following general formula (2):

obtaining a 2-furancarboxylic acid represented by
(2) reacting the 2-furancarboxylic acid obtained in the step (1) with a chlorinating agent to give the following general formula (3):

obtaining a 2-furancarboxylic acid chloride represented by
(3) The 2-furancarboxylic acid chloride obtained in step (2) is reacted with a cyanating agent to give the following general formula (4):

obtaining α-oxo-2-furanacetonitrile represented by
(4) The α-oxo-2-furanacetonitrile obtained in step (3) is hydrolyzed to give the following general formula (5):

obtaining α-oxo-2-furanacetic acid represented by
A method for producing α-oxo-2-furanacetic acid, comprising: The manganese-based oxidizing agent in step (1) is potassium permanganate, sodium permanganate or manganese dioxide;
The method for producing α-oxo-2-furanacetic acid according to claim 1, characterized in that