JPH04221345A - Production of benzoyl acetic acid esters - Google Patents

Abstract

PURPOSE:To efficiently obtain a compound useful as a synthetic intermediate of a quinolone based antimicrobial agent at a low cost while suppressing formation of a by-product by reacting acetophenones with magnesium methyl carbonate and then reacting the reaction product with chloroformic acid esters. CONSTITUTION:Acetophenones expressed by formula I (R<1> to R<5> are H, F, C, 1, Br, I, lower alkyl, alkoxyl, amino, etc.) are reacted with magnesium methyl carbonate in a solvent (e.g. DMF) at 80-150 deg.C for 0.1-10hr and then reacted with chloroformic acid esters in the same reactor at -20 to 50 deg.C for 0.1-10hr and then a dilute acid is added thereto and after-treatment is carried out to provide benzoylacetic acid esters expressed by formula II (R<6> is alkyl, cycloalkyl, aryl, etc.). A magnesium methylcarbonate is used at an amount of 1-10 times by mol based on acetophenones.

Description

[Detailed description of the invention]

0001

FIELD OF INDUSTRIAL APPLICATION The present invention is a method for producing benzoyl acetates useful as intermediate raw materials for quinolone carboxylic acid-based synthetic antibacterial agents.

0002

[Prior Art] Currently, the most common method for producing benzoyl acetates is to react benzoyl chloride with diethyl malonate, followed by decarboxylation, as shown below. (Tokuhei 2-4
(See Publication No. 4827, etc.).

0003

[Chemical formula 3]

[0004] Furthermore, as shown below, a method is known in which acetophenone is reacted with a base and then reacted with diethyl carbonate (see Japanese Patent Publication No. 1-46512).
. However, in the following formula, X represents a chlorine atom or a fluorine atom, and R7 represents an alkyl group.

[0005]

[C4]

[0006]

[Problems to be Solved by the Invention] The most commonly used method of decarboxylation after reacting benzoyl chloride with diethyl malonate often produces acetophenone as a by-product during decarboxylation. The disadvantage is that the rate decreases. Furthermore, a method in which acetophenone is reacted with a base and then reacted with diethyl carbonate requires a strong base such as sodium hydride or lithium diisopropylamide, which is not practical in industrial production.

On the other hand, the method of Stiles et al. [J.
Am. Chem. Soc. , 81, 2598
(1959)], it is not possible to obtain benzoylacetic esters.

[0008]

[Means for Solving the Problems] The present invention has been made to solve the above-mentioned problems that the prior art had,
By reacting acetophenones represented by the following chemical formula (1) with magnesium methyl carbonate and then reacting with chloroformates, the following chemical formula (2) can be obtained.
) is a method for producing benzoyl acetates, characterized by producing benzoyl acetates represented by:

[0009]

[C5]

0010

[C6]

[0011] However, R1, R2, R3, R4
, R5 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a lower alkyl group, an alkoxyl group, an amino group, an alkylamino group, a dialkylamino group, or an alkylthio group, and R6 represents an alkyl group, Indicates a cycloalkyl group, aryl group, or aralkyl group.

[0012] Conventional methods had problems such as the generation of by-products and the use of strong bases that were difficult to use industrially, but the present method eliminates these problems and yields benzoyl acetate esters. be able to.

Acetophenones used as raw materials in this method can be easily obtained by Friedel-Crafts reaction or the like. In addition, magnesium methyl carbonate was prepared by the method of Finkbeiner et al. [
J. Org. Chem. , 28, 215 (1
963)] by reacting magnesium methylate with carbon dioxide in a suitable solvent.

As a solvent, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-
2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, etc. can be used, but preferably N,N
-dimethylformamide, N,N-dimethylacetamide. The amount of solvent used is 0.1 to 1 liter, preferably 0.1 to 1 liter per mole of magnesium methylate.
It is 0.5 liter.

To obtain benzoyl acetate using this method, first, acetophenones are added to a solution of magnesium methyl carbonate dissolved in the above-mentioned solvent and reacted. At this time, magnesium methyl carbonate is used 1 to 10 times the mole, preferably 1 to 5 times the mole of acetophenones, and the reaction temperature is 80°C to 150°C, preferably 10 to 10 times the molar amount.
The temperature is 0°C to 140°C. The reaction time is 0.1 to 10 hours, preferably 1 to 5 hours.

Next, the reaction mixture thus obtained is kept in the same container at -20°C to 50°C, preferably at -10°C.
Cool to ~25°C and add chloroformates. At this time, the chloroformic acid ester is used in a mole of 1 to 20 times, preferably 1 to 5 times the mole of the acetophenone, and 0.1
Allow to react for ~10 hours, preferably 1-5 hours. After that, a dilute acid is added for post-treatment to obtain benzoyl acetates.

In the present invention, R1, R2, R3
, R4 and R5 is preferably a halogen atom in terms of use. In particular, R4 is preferably a fluorine atom. Furthermore, at least one of R1 and R3 is preferably a halogen atom, and the halogen atom is preferably a fluorine atom, a chlorine atom, or a bromine atom. In particular, it is preferable that both R1 and R3 are chlorine atoms, and then one is a chlorine atom and the other is a fluorine atom, or both are preferably fluorine atoms.

R2 and R5 are both preferably other than a halogen atom, ie, a hydrogen atom, a lower alkyl group, an alkoxyl group, an amino group, an alkylamino group, a dialkylamino group, or an alkylthio group,
In particular, it is preferred that one or both of them be hydrogen atoms. When it is other than a hydrogen atom, a lower alkyl group or an alkoxyl group is preferred. R6 is an alkyl group, a cycloalkyl group, an aryl group, or an aralkyl group, and an alkyl group or an aralkyl group is particularly preferred. Specifically, a methyl group, an ethyl group, or a benzyl group is most preferred.

Among the above organic groups, ie, lower alkyl groups, alkyl groups, alkoxyl groups, alkylamino groups, dialkylamino groups, cycloalkyl groups, aryl groups, and aralkyl groups, the lower alkyl groups have 1 to 1 carbon atoms. 4, but the number of carbon atoms in other alkyl groups and the alkyl group portion of other organic groups is not necessarily limited to this. However, other alkyl groups and alkyl group moieties are also preferably lower alkyl groups. Further, the cycloalkyl group is preferably a cyclohexyl group or its lower alkyl group substituted product, the aryl group is preferably a phenyl group or its lower alkyl group, or its substituted product with a halogen atom, and the aralkyl group is preferably a benzyl group or its lower alkyl group. Alternatively, a halogen atom substituted product is preferable.

[0020] The present invention will be explained below with reference to Examples.
The present invention is not limited to these examples.

[0021]

[Example] [Reference example] Preparation of magnesium methyl carbonate Methanol 60
ml was added with 0.1 g of magnesium in the form of cut pieces, and heated until reflux started. After the reaction started on the magnesium surface, 2.4 g (100 mmol) of magnesium in the form of cut pieces was added over 1 hour at a rate that continued reflux. After stirring at room temperature for 1 hour, excess methanol was distilled off under reduced pressure to precipitate a white salt. 50 ml of N,N-dimethylformamide was added to form a suspension, and 17.6 g (400 mmol) of gaseous carbon dioxide was blown into the suspension over 1 hour to obtain a colorless and transparent solution. This solution
The mixture was heated to 130°C to completely distill off some remaining methanol.

[Example 1] 10.3 g (50 mmol) of 2',4'-dichloro-5'fluoroacetophenone was added to 50 ml of the N,N-dimethylformamide solution of magnesium methyl carbonate obtained in Reference Example.
The mixture was stirred at 130°C for 1 hour. After cooling to 0° C., 5.7 g (60 mmol) of methyl chloroformate was added and stirred for 2 hours. Add 50g of ice and 150ml of 1N hydrochloric acid to this solution.
When 1 was added, carbon dioxide was generated. Separate the organic layer;
Methyl 2,4-dichloro-5-fluorobenzoylacetate was extracted by extracting the aqueous layer twice with 40 ml of dichloromethane each time and concentrating the combined organic layers to dryness.12.
2g (yield 92%) was obtained. Although it is of good purity in this state, it can be further purified by vacuum distillation if necessary (boiling point 120-125 °C/1
mmHg).

[Example 2] Magnesium methylate 8
．． Gaseous carbon dioxide 17 was added to a suspension of 6 g (100 mmol) and 50 ml of N,N-dimethylformamide.
．． 6 g (400 mmol) was blown into the solution over 1 hour. 2',4'-dichloro-5'-
Fluoroacetophenone 10.3g (50mmol)
was added and stirred at 130°C for 1 hour. After cooling to 0° C., 5.7 g (60 mmol) of methyl chloroformate was added and stirred for 2 hours. Add 50g of ice and 1N hydrochloric acid to this solution.
Carbon dioxide was generated when 150 ml was added. The organic layer was separated, the aqueous layer was extracted twice with 40 ml of dichloromethane, and the combined organic layers were concentrated to dryness.
, 12.5 g (yield 94%) of methyl 4-dichloro-5-fluorobenzoylacetate was obtained.

[Example 3] 0.46 g (3.1 mmol) of 2',4'-dichloro-5'-fluoroacetophenone was added to 3.1 ml of the N,N-dimethylformamide solution of magnesium methyl carbonate obtained in Reference Example. was added and stirred at 130°C for 1 hour. After cooling to 0°C,
0.41 g (3.7 mmol) of ethyl chloroformate was added and stirred for 2 hours. To this solution, add 3 g of ice and 9 g of 1N hydrochloric acid.
ml was added and carbon dioxide was evolved. The organic layer was separated, and the aqueous layer was extracted twice with 5 ml of dichloromethane each.
The combined organic layers were concentrated and then distilled under reduced pressure to give 0.7 ethyl 2,4-dichloro-5-fluorobenzoylacetate.
1 g (yield 82%) was obtained.

[Example 4] 0.37 g (1.8 mmol) of 2',4'-dichloro-5'-fluoroacetophenone was added to 3.5 ml of the N,N-dimethylformamide solution of magnesium methyl carbonate obtained in Reference Example. was added and stirred at 130°C for 1 hour. After cooling to 0°C,
0.48 g (2.8 mmol) of benzyl chloroformate was added and stirred for 2 hours. Add 2 g of ice and 1N hydrochloric acid to this solution.
ml was added and carbon dioxide was evolved. The organic layer was separated, and the aqueous layer was extracted twice with 5 ml of dichloromethane each.
The combined organic layers were concentrated and purified by silica gel chromatography to give 0.37 g of benzyl 2,4-dichloro-5-fluorobenzoylacetate (yield 62%).
I got it.

[0026]

Effects of the Invention The present invention is a method for producing benzoyl acetate, which produces fewer by-products in the reaction than conventional methods and, as a result, has a high yield. Moreover, this method does not require the strong base required in the conventional method, and is easy to implement industrially.

Claims (4)

[Claims] Claim 1: Manufacture benzoyl acetates represented by the following chemical formula (2) by reacting acetophenones represented by the following chemical formula (1) with magnesium methyl carbonate and then reacting with chloroformates. A method for producing benzoyl acetates, characterized by: [Chemical 1] [Chemical 2] However, R1, R2, R3, R4, and R5 are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a lower alkyl group, an alkoxyl group, an amino group, an alkylamino group. R6 represents an alkyl group, a cycloalkyl group, an aryl group, or an aralkyl group. 2. The method according to claim 1, wherein R1 and R3 are each independently a fluorine atom, a chlorine atom, or a bromine atom, R4 is a fluorine atom, and R2 and R5 are both hydrogen atoms. 3. The method according to claim 1, wherein R6 is a methyl group, an ethyl group or a benzyl group. Claim 4: The compound represented by the chemical formula (1) is 2',4
'-dichloro-5'-fluoroacetophenone,
The compound represented by chemical formula (2) is 2,4-dichloro -
2. The method of claim 1, wherein the ester is a 5-fluorobenzoyl acetate.