JP3201062B2 - Process for producing aliphatic β-ketoester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for producing an aliphatic .beta.-ketoester, in particular, an aliphatic .beta.-ketoester having steric hindrance. The aliphatic β-ketoester obtained according to the present invention is a very useful chemical as a synthetic intermediate for pharmaceuticals, agricultural chemicals and photographic materials.

[0002]

2. Description of the Related Art Conventionally, aliphatic β-ketoesters have been produced by the methods described in J. Amer. Chem. Soc., 66, 862 (1944) and J. A.
mer. Chem. Soc., 72, 1352 (1950), JP-A-50-12
The method by Claisen condensation disclosed in, for example, US Pat. No. 6,618,985 is well known. In this method, generally, a carboxylic acid ester is converted into an at least equimolar condensing agent such as sodium hydride, sodium amide, alkali metal alcoholate. Reaction in an inert solvent in the presence of a basic compound such as to obtain an aliphatic β-ketoester, and the yield is low and not practical for synthesizing an aliphatic β-ketoester having steric hindrance. .

On the other hand, JP-A-51-364200 discloses a method for synthesizing an aliphatic β-ketoester having a steric hindrance such as pivaloyl acetate with an improved yield by using sodium hydride and sodium amide. In the presence of such strongly basic compounds, as a solvent basic, bipolar,
A method is disclosed in which the reaction is carried out using an aprotic compound such as pyridine or an acid amide, preferably a carboxylic acid amide, specifically dimethylformamide. However, in this method, the sodium hydride and sodium amide used are expensive because they are synthesized from metallic sodium, and the handling operation is not easy, which is unsuitable for industrial use. Was. In addition, in this dimethylformamide solvent system, when an inexpensive metal alcoholate was used, the yield of the target product was even lower.

[0004]

As described above, the yields of sterically hindered aliphatic β-ketoesters are not satisfactory in the conventionally known methods for producing aliphatic β-ketoesters, and the process is further used. However, there is a problem that the condensing agent used is expensive and its handling operation is not easy. An object of the present invention is to provide an industrially suitable process for producing an aliphatic β-ketoester which is capable of producing a sterically hindered aliphatic β-ketoester in high yield using an inexpensive condensing agent. It is in.

[0005]

DISCLOSURE OF THE INVENTION In order to solve the above-mentioned problems in the process for producing an aliphatic β-ketoester known in the art, the present inventors have proposed an alcohol and sodium hydroxide or potassium hydroxide as condensing agents. As a result of intensive studies on a system using an inexpensive metal alcoholate easily synthesized from 1,3,3-dimethyl-2-imidazolidone (DMI) as a solvent, the desired aliphatic β -It has been found that the yield of ketoester is remarkably improved, and the present invention has been completed. That is, the present invention is characterized in that a dialkyl ketone and a dialkyl carbonate are reacted in 1,3-dimethyl-2-imidazolidone (DMI) in the presence of a metal alcoholate in an amount at least equimolar to the dialkyl ketone. Aliphatic β-
The present invention relates to a method for producing a ketoester.

Hereinafter, the method of the present invention will be described in detail.
The metal alcoholate used in the present invention is represented by the following general formula (I), and is preferably used in an amount at least equimolar to the dialkyl ketone, preferably at least twice the molar amount.

[0007]

Embedded image (Where R represents a lower alkyl group having 1 to 4 carbon atoms such as methyl and ethyl, and M represents an alkali metal such as sodium and potassium).

The dialkyl carbonate used in the present invention is represented by the following general formula (II), and dimethyl carbonate and diethyl carbonate are particularly preferred. The amount used is desirably at least equimolar to the dialkyl ketone, preferably in the range of 2 to 10 moles.

[0009]

Embedded image

(Wherein R ₁ and R ₂ are methyl, ethyl, n-propyl, iso-propyl, n-butyl, i
A lower alkyl group having 1 to 4 carbon atoms, such as so-butyl and tert-butyl, may be the same or different. The dialkyl ketone used in the present invention is represented by the following general formula (III).

[0011]

Embedded image

(Wherein, when R ₃ and R ₄ are not bonded, R ₃ is methyl, ethyl, n-propyl, i
so-propyl, n-butyl, iso-butyl, sec
-Butyl, an alkyl group having 1 to 15 carbon atoms such as tert-butyl, a cycloalkyl group having 5 to 15 carbon atoms such as a cyclohexyl group, and R ₄ is hydrogen or methyl, ethyl, n-propyl, iso-propyl, n-butyl, i
represents an alkyl group having 1 to 4 carbon atoms such as so-butyl, sec-butyl, tert-butyl, etc., and when R ₃ and R ₄ are combined to form a ring, R ₃ and R ₄ are pentamethylene The following shows the atomic groups required to complete a linear methylene group having 5 to 15 carbon atoms such as a group, a hexamethylene group, and a dodecamethylene group. )

In the present invention, the above-mentioned dialkyl ketone includes R ₃ and R ₄ in the general formula (III).
Is an aliphatic group having steric hindrance, and the remainder is an ethyl or methyl group, such as methyl isopropyl ketone, pinacolin (methyl tert-
Butyl ketone), methylcyclohexyl ketone, etc.
Methyl ketones having a tertiary alkyl group, a tertiary alkyl group or an alicyclic alkyl group as R ₃ or R _{4 in} the general formula (III), or alicyclic ketones such as cyclopentanone, cyclohexanone, cyclododecanone Is preferred.

The solvent effectively used in the present invention is 1,3-
By using this solvent with dimethyl-2-imidazolidone (DMI), a sterically hindered aliphatic β-ketoester can be synthesized with a high yield. Its usage is
It is desirable that the amount is at least equimolar or more with respect to the dialkyl ketone.

As a form of the reaction of the present invention, a method in which a dialkyl ketone is slowly dropped at a predetermined temperature into a mixture of a metal alcoholate, a dialkyl carbonate and 1,3-dimethyl-2-imidazolidone (DMI) is intended. Is preferable for synthesizing an aliphatic β-ketoester of high yield. The dropping time is 1 to 6 hours, preferably 1 to 3 hours, and the reaction temperature is 20 to 80 ° C, preferably 40 to 6 hours.
It is desirable to be in the range of 0 ° C. The reaction is preferably completed in 1 to 3 hours after the completion of the dropwise addition of the dialkyl ketone.

After the reaction, the aliphatic β-keto ester as a target substance is present as a metal salt thereof. , Free aliphatic β-ketoesters. The aliphatic β-ketoester thus obtained is desirably extracted with an organic solvent such as ethyl acetate or toluene, and then separated and purified by distillation. Representative aliphatic β-ketoesters obtained in the present invention include, for example, pivaloyl acetate, which is an important intermediate of photographic materials, and isobutyryl acetate, which is an important intermediate of pharmaceuticals.

[0017]

EXAMPLES Next, the method of the present invention will be described specifically with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples.

Example 1 4.62 g (85.6 mmol) of sodium methoxide
With dimethyl carbonate (11 g, 122.2 mmol) and DM
After suspending I in 7.32 g (64 mmol), the temperature was slowly raised to 50 ° C. Then, pinacolin2.
14 g (21.4 mmol) was added dropwise over 1.5 hours, and the reaction was further continued with stirring for 1.5 hours. After completion of the reaction, the cooled reaction mixture was carefully neutralized with aqueous hydrochloric acid, and the product was extracted with ethyl acetate. When the reaction product was quantified by gas chromatography, it was found to be 92%
The desired pivaloyl acetic acid methyl ester was produced in a yield of. The product was ethyl acetate: hexane = 1:
Using 4 as a developing solvent, the product was isolated and purified by column chromatography, and was confirmed to be the desired product by NMR, IR, and mass spectrum.

Comparative Example 1 The reaction was carried out in the same manner as in Example 1 except that 4.69 g (64 mmol) of dimethylformamide was used instead of DMI in Example 1, and the amount of the product was quantified. At this time, the yield of pivaloyl acetic acid methyl ester was 75%.

Comparative Example 2 The reaction was carried out in the same manner as in Example 1 except that 7.32 g (100 mmol) of dimethylformamide was used instead of DMI in Example 1, and the amount of the product was quantified. At this time, the yield of pivaloyl acetic acid methyl ester was 64%.

Comparative Example 3 The procedure of Example 1 was repeated except that 4.69 g (64 mmol) of dimethylformamide was used instead of DMI and the amount of sodium methoxide was reduced to 2.77 g (51.3 mmol). The reaction was carried out in the same manner as in Example 1, and the product was quantified. At this time, the yield of pivaloyl acetic acid methyl ester was 47%.

Comparative Example 4 The reaction was carried out in the same manner as in Example 1 except that 7.45 g (64 mmol) of tetramethylurea was used in place of DMI in Example 1, and the product was quantified. At this time, the yield of pivaloyl acetic acid methyl ester was 72%.

Example 2 Instead of pinacolin in Example 1, 3-methyl-2
-The reaction was carried out in the same manner as in Example 1, except that 1.84 g (21.4 mmol) of butanone was used. When the reaction product was quantified by gas chromatography, methyl isobutyryl acetate was produced in a yield of 88%. The product was isolated and purified by column chromatography using ethyl acetate: hexane = 1: 4 as a developing solvent, and identified by NMR, IR, and mass spectrum.

[0024]

According to the method of the present invention for reacting a dialkyl ketone and a dialkyl carbonate in 1,3-dimethyl-2-imidazolidone, an aliphatic compound having steric hindrance can be prepared by using a metal alcoholate which is an inexpensive condensing agent. β-ketoesters can be produced in high yields.

Continued on the front page (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 69/716 C07C 67/327 C07C 67/343 CA (STN) CASREAT (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. An aliphatic β-functional compound comprising reacting a dialkyl ketone with a dialkyl carbonate in 1,3-dimethyl-2-imidazolidone in the presence of a metal alcoholate in an amount at least equimolar to the dialkyl ketone. Method for producing ketoester.