JPH0798786B2 - Process for producing 2-hydroxyimino-3-ketobutyric acid esters - Google Patents

Description

TECHNICAL FIELD OF THE INVENTION The present invention relates to an improved process for preparing 2-hydroxyimino-3-ketobutyric acid esters.

Prior art JP-A-57-53474 discloses a formula 2- (2-aminothiazol-4-yl) -2- (syn) -hydroxyiminoacetic acid ester represented by the formula (wherein R is an alkyl group) is disclosed. This compound (I)
The modified hydroxyimino group is useful as a modifier for cephalosporins and penicillins.

In this document, the methylated compound of the above compound (I) is obtained by the following method.

That is, the formula (Wherein R is an alkyl group), 4-chloroacetoacetic acid ester is reacted with an aqueous solution of alkali nitrite in the presence of glacial acetic acid. To obtain 4-chloro-2-hydroxyimino-3-ketobutyric acid ester, which is reacted with thiourea without isolation to obtain the above compound (I), and finally phase conversion using dimethyl sulfate. It is methylated by a catalytic reaction.

Similarly, JP-B-59-19101 discloses the above compound (I).
Is disclosed. In this document, compound (I)
Is the expression (Wherein, X is a halogen and R is an alkyl group) 2
-Hydroxyimino-3-ketobutyric acid esters are described as obtained by reacting with thiourea. However, there is no disclosure about a method for producing the compound (IIb) as a raw material.

Problems to be Solved by the Invention As described above, according to JP-A-57-53474, the compound (IIa) has the formula It can be obtained by reacting 4-chloroacetoacetic acid ester represented by the formula (wherein R is an alkyl group) with an aqueous solution of alkali nitrite in the presence of glacial acetic acid. However, the yield is not always high, foaming, etc. Since abnormal reactions are likely to occur, it is not easy to control the reaction in industrial scale production, and the use of acetic acid is essential, and the burden of wastewater treatment is large. Industrially it was necessary to make further improvements.

In view of such circumstances, the present invention has been made to find an industrially advantageous method that does not have such problems.

Means for Solving the Problems The present invention provides a “general formula (Wherein, X is hydrogen or halogen, R ¹ is hydrogen, an alkyl group or an acyl group, and R ² is an alkyl group) and an enol-type acetoacetic acid ester is reacted with nitrosyl sulfuric acid. (X and R ² are the same as above), a process for producing 2-hydroxyimino 3-ketobutyric acid esters. Is the gist.

The present invention will be described in detail below.

Raw material <Enol type acetoacetic acid ester> In the present invention, as a raw material, The enol type acetoacetic acid ester represented by is used.

Here, X is hydrogen or halogen (Cl, Br, I, F), and Cl and Br are particularly important for practical use.

R ¹ is hydrogen, an alkyl group or an acyl group, examples of the alkyl group include a methyl group, ethyl group, propyl group and butyl group, and examples of the acyl group include an acetyl group and a propionyl group. .

R ² is an alkyl group, and examples thereof include a methyl group, an ethyl group, a propyl group, and a butyl group.

When R ¹ is hydrogen, the acetoacetic acid esters are tautomers of keto type and enol type, so the equilibrium shifts toward the enol type by the amount of the consumed enol type, and the enol type is generated sequentially. To do. Therefore, an acetoacetic acid ester having or not having a halogen at the 4-position can be used as a raw material.

On the other hand, when R ¹ is an alkyl group or an acyl group,
Since there is no keto type, the enol type will be used. The enol type acetoacetic acid esters in this case are derivatives of crotonic acid esters. The etherified product in which R ¹ is an alkyl group is obtained by reacting an acetoacetic acid ester having or not having a halogen at the 4-position with an alcohol in the presence of an acidic catalyst, and the acylated product in which R ¹ is an acyl group is: It can be obtained by reacting an acetoacetic acid ester having or not having a halogen at the 4-position with an acyl halide in the presence of a catalyst such as pyridine.

<Nitrosylsulfuric acid> Nitrosylsulfuric acid to be reacted with the enol type acetoacetic acid ethitels is represented by the formula NOHSO ₄ , and is usually used as a solution having a concentration of about 40 to 45% by weight in sulfuric acid.

Reaction conditions and reaction procedure The enol-type acetoacetic acid esters and nitrosylsulfuric acid are used in a ratio of 1.0 to 1.4 moles per 1 mole of the former in consideration of reaction rate and economic efficiency. .

The enol type acetoacetic acid ester is diluted with a suitable organic solvent or is not diluted and is used as it is. In some cases, acetic acid may be used instead of or together with the organic solvent.

Nitrosyl sulfuric acid is supplied as a solution dissolved in sulfuric acid as described above.

For the charging, a method in which one of the enol type acetoacetic acid ester and the nitrosylsulfate is added dropwise to the other is preferably adopted. It is difficult to charge both of them in a batch because the reaction is difficult to control.

The reaction typically goes through a first step in which one of the enol-type acetoacetic acid esters and nitrosylsulfate is added dropwise to react with the other, and a second step in which the temperature is gradually raised to complete aging after completion of the dropping. When the target 2-hydroxyimino-3-ketobutyric acid esters are not isolated from the reaction mixture and the next step, the thiazole formation step, is carried out, thiourea is added in the second step. It can also be done in the state.

The reaction temperature in the first step is around 0 ° C to -20 ° C,
In the second stage, the temperature is finally raised to about room temperature. However, depending on the raw material (for example, when the enol-type acetoacetic acid ester is a derivative of crotonic acid ester), it is possible to carry out the reaction in the first step at a temperature up to room temperature.

When an organic solvent is used, it is immiscible with water such as halogenated hydrocarbons such as ethylene dichloride, carbon tetrachloride, chloroform and methylene chloride, aromatic hydrocarbons such as benzene, toluene and xylene. Organic solvents can be used.

After the completion of the second step, the desired product, 2-hydroxyimino-3-ketobutyric acid ester, is isolated by adding water and performing known isolation and purification means such as solvent extraction, crystallization, recrystallization and chromatography. . For example, when an organic solvent is used, the organic solvent layer is separated, when the organic solvent is not used, extraction is performed with the organic solvent, and then the organic solvent is removed from the separated or extracted organic solvent layer to obtain the desired product. The means for obtaining

Also, without isolating this desired product from the reaction mixture,
It can also be subjected to the next step, the thiazole formation step.

Action The reaction in the present invention is performed as an intermediate product. It is presumed that the reaction proceeds via

The method of the present invention has the same object as the conventionally known method using alkali nitrite, but since the reaction mechanism and the intermediate product are different, there are differences in terms of yield, control of the reaction, etc. It seems to be.

After obtaining the target product, 2-hydroxyimino-3-ketobutyric acid ester, by reacting it with thiourea, the compound (I) described at the beginning of the section "Prior art",
That is, 2- (2-aminothiazol-4-yl)-
2- (Syn) -hydroxyiminoacetic acid ester can be synthesized.

EXAMPLES Next, the present invention will be further described with reference to examples.

Example 1 11.8 g (0.072 mol) of ethyl 4-chloroacetoacetate was dissolved in 20 ml of ethylene dichloride and cooled to 0 ° C. Add 43.8% nitrosyl sulfuric acid (NOHSO ₄ ) sulfuric acid solution 25.0 to this solution.
g (0.086 mol) was added dropwise at 0 ° C to -17 ° C over 50 minutes,
After that, the temperature was raised to room temperature over 2 hours. During the dropping, almost no foaming was observed, and there was no problem.

Then, 10 ml of water was added, and liquid separation was performed to obtain an organic layer. Ethylene dichloride in the organic layer was expelled by an evaporator to obtain 13.3 g of an oily substance.

This substance has the formula It is ethyl 4-chloro-2-hydroxyimino-3-ketobutyrate represented by and the yield was 95.5% based on ethyl 4-chloroacetoacetate.

Comparative Example 1 24.7 g (0.15 mol) of ethyl 4-chloroacetoacetate and 27.0 g of glacial acetic acid were placed in a flask and cooled to 0 ° C. Add 10.9 g (0.16 mol) of 99% sodium nitrite to this solution.
A solution dissolved in 8 g of water was added dropwise over 45 minutes, cooled during that time, the internal temperature was slowly decreased, and -15 ° C was reached at the end of the addition. The solution was cooled to this temperature for an additional 2 hours. Foaming was liable to occur during the dropping, and careful control was required to control the reaction.

50 ml of water was added to this solution, and 50 ml of ethylene dichloride was added to the solution.
Extracted twice. Combine the two ethylene dichloride layers,
By removing the solvent with an evaporator, ethyl 2-chloro-2-hydroxyimino-3-ketobutyrate 21.7
got g. The yield is 74.based on ethyl 4-chloroacetoacetate.
It was 8%, and the yield was inferior to the case of Example 1.

Example 2 The same experiment as in Example 1 was performed except that 10.8 g (0.072 mol) of methyl 4-chloroacetoacetate was used in place of 11.8 g (0.072 mol) of ethyl 4-chloroacetoacetate, resulting in 4-chloro-2. -Hydroxyimino-3-methyl ketobutyrate 12.6
got g. The yield is 92 based on methyl 4-chloroacetoacetate.
It was 4%.

Example 3 The same experiment as in Example 1 was conducted except that ethyl acetoacetate 9.36 g (0.072 mol) was used in place of ethyl 4-chloroacetoacetate 11.8 g (0.072 mol), and as a result, 2-hydroxyimino-3- 10.4 g of ethyl ketobutyrate was obtained. The yield was 86.3% based on ethyl acetoacetate.

Example 4 50.0 g (0.177 mol) of 45% nitrosyl sulfuric acid (NOHSO ₄ ) sulfuric acid solution was added with methyl 2-chloro-3-acetocyclocyclotonate 2.
8.4 g (0.148 mol) was added dropwise at -10 ° C to -3 ° C over 30 minutes. Then, the temperature was gradually raised to room temperature over 2.5 hours for aging. Then, add 20 ml of water, extract with ethylene dichloride, dry with sodium sulfate, and then remove ethylene dichloride with an evaporator, and methyl 4-chloro-2-hydroxyimino-3-ketobutyrate having a melting point of 69.2 ° C represented by the following formula. Got Yield 24.8g, based on methyl 4-chloro-3-acetocyclocyclotonate
It was 93.4%.

Example 5 25.0 g (0.089 mol) of 45% nitrosyl sulfuric acid (NOHSO ₄ ) sulfuric acid solution was added with ethyl 4-chloro-3-acetocyclocyclotonate 1
5.2 g (0.074 mol) was added dropwise at -10 ° C to -3 ° C over 30 minutes. Then gradually warm to room temperature over 2.5 hours,
Aged. Then, 10 ml of water was added, and the mixture was extracted with ethylene dichloride, dried over sodium sulfate, and then the ethylene dichloride was removed by an evaporator to give 4-chloro-2.
-Ethyl hydroxyimino-3-ketobutyrate was obtained. The yield was 13.4 g, and the yield was 94.1% based on ethyl 4-chloro-3-acetocyclocyclotonate.

Example 6 Methyl 4-chloro-3-acetocyclocyclotonate 28.4 g
The same experiment as in Example 4 was carried out except that 24.3 g (0.148 mol) of methyl 4-chloro-3-methoxycrotonate was used instead of (0.148 mol).

As a result, methyl 4-chloro-2-hydroxyimino-3-ketobutyrate was obtained. The yield was 23.9 g, and the yield was 90.1% based on methyl 4-chloro-3-methoxycrotonate.

Example 7 Methyl 4-chloro-3-acetocyclocyclotonate 28.4 g
Ethyl 3-ethoxycrotonate 2 in place of (0.148 mol)
The same experiment as in Example 4 was conducted except that 8.5 g (0.148 mol) was used.

As a result, ethyl 2-hydroxyimino-3-ketobutyrate was obtained. The yield is 25.7g. The yield was 89.7% based on ethyl 3-ethoxycrotonate.

EFFECTS OF THE INVENTION The method of the present invention is improved in yield, foaming, etc., as compared with a conventional method, that is, a method of reacting 4-chloroacetoacetic acid ester with an aqueous alkaline nitrite solution in the presence of glacial acetic acid. Since an abnormal reaction hardly occurs, it is easy to control the reaction, and since it is possible to avoid using acetic acid, the wastewater treatment load is small, which is industrially advantageous.

Claims (1)

[Claims] 1. A general formula (Wherein, X is hydrogen or halogen, R ¹ is hydrogen, an alkyl group or an acyl group, and R ² is an alkyl group) and an enol-type acetoacetic acid ester is reacted with nitrosyl sulfuric acid. (X and R ² are the same as the above), a process for producing 2-hydroxyimino-3-ketobutyric acid esters.