JP2965182B2 - Preparation of 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 an industrially useful process for producing .beta.-ketoesters which are important as raw materials for synthesizing heterocycles such as pyridine, pyrazole and isoxazole which are intermediate materials for pharmaceuticals and agricultural chemicals. It is.

[0002]

2. Description of the Prior Art Conventionally, a method for producing a β-ketoester has been described in J. Org.
3260, 1989 ".
J. The method of Roskamp et al. Is known. This method is a method for producing a β-ketoester by reacting a diazoacetic ester (a commercially available purified product) with an alkyl aldehyde in the presence of a catalytic amount of a Lewis acid.

In order to industrially produce β-ketoester, a process of synthesizing diazoacetate (first step) and a process of producing β-ketoester from diazoacetate and alkyl aldehyde (second step) are required. It needs to be done efficiently. Eric J. In order to use a purified product as in Roskamp et al., The diazoacetate must be isolated and purified after the first step. It is said that diazoacetic acid ester is stable among diazo compounds and can be distilled, but it is a well-known fact that the risk is still high. The necessity of isolating and purifying the ester poses a problem as a method for industrially producing β-ketoester.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide an industrially useful and novel process for producing a β-ketoester which is important as a raw material when synthesizing a heterocycle as an intermediate raw material for pharmaceuticals and agricultural chemicals. is there.

[0005]

Means for Solving the Problems The inventors of the present invention have made intensive studies to solve the above-mentioned problems, and as a result, after synthesizing diazoacetate, without isolating and purifying it, an expensive catalyst was used. Reduce the use of certain anhydrous stannous chloride,
By a dehydration treatment, a novel method for producing a β-ketoester in high yield and at a lower cost from this and an alkyl aldehyde has been found, and the present invention has been completed.

That is, the present invention provides the following formula (I): (Wherein R ¹ represents an alkyl group) in a two-layer system under acidic conditions comprising an organic solvent and an aqueous solution in the presence of a nitrosyl compound;
The separated organic solvent layer is dehydrated by a Karl Fischer method so that the water content becomes 1,000 ppm or less, and the product in the organic solvent layer is represented by the following formula (II):

[0007]

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Wherein R ¹ is as defined above, and a diazoacetic acid ester [compound (II)] represented by the following formula (II):
I): (Wherein R ² represents an alkyl group) with an alkyl aldehyde [compound (III)] using a catalytic amount of anhydrous stannous chloride. : (Wherein, R ¹ and R ² have the same meanings as described above.) The present invention relates to a process for producing a β-ketoester [compound (IV)].

Hereinafter, the present invention will be described in detail. Β-ketoester [compound (I
V)], alkyl aldehyde [compound (III)], diazoacetic acid ester [compound (I
I)], and glycine ester or a mineral acid salt thereof (compound (I)) as a raw material for producing diazoacetic acid ester are as follows.

As R ¹ , a linear or branched alkyl group can be exemplified; preferably, a linear or branched alkyl group having 1 to 10 carbon atoms is preferred; A chain alkyl group having 1 to 6 carbon atoms is preferred; a methyl group and an ethyl group are more preferred.
R ² is a linear or branched linear alkene,
Examples thereof include alkyne and an alkyl group which may have an aromatic group; preferably a linear or branched alkyl group having 1 to 10 carbon atoms; and more preferably a linear alkyl group. Alkyl groups having 1 to 6 carbon atoms are preferred;
More preferably, a methyl group and an ethyl group are preferable.

(Regarding the first step) Diazoacetic acid ester [compound (II)] is a reaction of a mineral salt of glycine ester in a two-layer system under an acidic condition comprising an organic solvent and an aqueous solution in the presence of a nitrosyl compound. Can be synthesized by As mineral salts, hydrochloric acid,
Salts such as hydrofluoric acid, hydriodic acid, sulfuric acid and phosphoric acid can be mentioned; preferably, hydrochloride and sulfate are used. Nitrosyl compounds are formed by the reaction of nitrites such as sodium nitrite and potassium nitrite with the mineral acids described above. The amount of the nitrite used is 1.0 to 2.0 times mol with respect to the glycine ester; preferably, it is 1.1 to 1.4 times mol.

The organic solvent is not particularly limited as long as it does not directly participate in the present reaction. Preferably, the organic solvent has good separation from water. Such solvents include, for example, chlorinated or non-chlorinated aromatics,
Aliphatic and alicyclic hydrocarbons (benzene, toluene, xylene, cyclohexane, methylene chloride, chloroform, dichloroethane, trichloroethylene, etc.), ethers (diethyl ether, diisopropyl ether, etc.), mixtures of the above solvents, etc. Can be
It is preferable to use methylene chloride, which can increase the reaction rate and is economically advantageous.

The pH of the solution is between 0.5 and 7; preferably between 2 and 6. To adjust the pH, the mineral acids mentioned above can be used; preferred mineral acids are hydrochloric acid, sulfuric acid, phosphoric acid. The reaction temperature is -50
-10 ° C; preferably -20 ° C to 5 ° C;
More preferably, it is -10 to 0C.

The reaction time varies depending on the dropping rate of the starting compound, the reaction temperature, and the like. After completion of the dropping of the starting material, the reaction can be terminated by further stirring for 10 to 30 minutes. 2 hours.

(Regarding the Second Step) The β-ketoester as the target compound is obtained by fractionating an organic solvent layer containing the diazoacetate [compound (II)] produced in the first step, and subjecting the fraction to a dehydration treatment. Then, an alkyl aldehyde [compound (III)] and a catalytic amount of anhydrous stannous chloride described below are added to the organic solvent and allowed to react with each other. As a dehydration method, a dehydrating agent (for example, sodium sulfate, sodium sulfate, calcium chloride, or the like), molecular sieves (for example, 3A, 4A, or the like) is used, and the amount of water after the dehydration treatment is reduced to 1 by the Karl Fischer method. 000 ppm or less; preferably 500 ppm or less.

The amount of the alkyl aldehyde [compound (III)] to be used can usually be used in excess with respect to the diazoacetic acid ester [compound (II)]; The molar amount is 0 times; more preferably, the molar amount is 1.1 to 1.8 times. The amount of anhydrous stannous chloride used as the catalyst is 0.1 to 30 with respect to compound (I).
%, Preferably 0.5 to 10% by weight; more preferably 1 to 7% by weight. The reaction temperature is from -50 to 100 ° C; preferably, from -20 to 100 ° C.
80 ° C; more preferably -10 to 40 ° C. The reaction time varies depending on the above-mentioned concentration and temperature, but after no more nitrogen is generated, the reaction can be terminated by stirring for another 20 minutes.
0.5 to 4 hours.

The method of mixing the raw material and the catalyst is as follows:
(I) Compound (II) is added dropwise to a solution comprising a catalytic amount of anhydrous stannous chloride, or a catalytic amount of anhydrous stannous chloride is added to a solution comprising compound (II) and compound (III) Alternatively, it can be carried out by adding compound (III) to a solution comprising compound (II) and a catalytic amount of anhydrous stannous chloride.

As the compound (II), for example, methyl diazoacetate, ethyl diazoacetate, propyl diazoacetate,
Examples thereof include isopropyl diazoacetate, butyl diazoacetate, isobutyl diazoacetate, amyl diazoacetate, and isoamyl diazoacetate.

As the compound (III), for example, propionaldehyde, n-butyraldehyde, isobutyraldehyde, n-valeraldehyde, isovaleraldehyde, pivalaldehyde, n-caprolaldehyde, isocaproaldehyde, n-heptylaldehyde, etc. Can be mentioned.

As described above, after synthesizing diazoacetate, the amount of anhydrous stannous chloride, which is an expensive catalyst, is reduced and the dehydration treatment is performed without isolation and purification. Β-ketoesters can be produced at a high yield and at a lower cost from and alkyl aldehydes. After completion of the reaction, the target β-ketoester thus produced can be obtained by removing the catalyst by filtration and concentrating the same. And, if necessary, it can be made highly purified by known means such as distillation purification and various types of chromatography.

As the target compound (IV), for example, corresponding to the above-mentioned compound (II) and compound (III),
For example, methyl propionyl acetate, ethyl propionyl acetate, propyl propionyl acetate, isopropyl propionyl acetate, butyl propionyl acetate, isobutyl propionyl acetate, amyl propionyl acetate, isoamyl propionyl acetate, ethyl butyryl acetate, ethyl isobutyryl acetate, ethyl valeryl acetate, ethyl isovaleryl acetate, Examples thereof include ethyl pivaloyl acetate, ethyl caproyl acetate, ethyl isocaproyl acetate, and ethyl heptanoyl acetate.

[0022]

The present invention will be described below in detail with reference to examples and comparative examples. Note that these examples do not limit the scope of the present invention. Example 1 Glycine ethyl ester hydrochloride (4.19 g, 30 mm
ol) in water and methylene chloride (18 ml)
After cooling to −5 ° C., a solution of sodium nitrite (2.5 g, 36.6 mmol) dissolved in water (6 ml) was added dropwise, and a 5% by weight phosphoric acid aqueous solution (3%) was added.
g) was slowly added dropwise so as not to exceed 1 ° C. After completion of the dropwise addition, the mixture was further stirred for 15 minutes to separate the organic solvent layer, and the aqueous layer was further extracted with methylene chloride (12 ml).

The obtained organic solvent layer was washed with water (10 ml), and dehydrated by adding magnesium sulfate (1 g) (water content was 470 ppm by Karl Fischer method). After filtering off magnesium sulfate, anhydrous stannous chloride (50 mg, 0.26 mmol) was added, and propionaldehyde (2.4 g, 41.7 mmol) was added dropwise with stirring, followed by stirring at room temperature for 2 hours. Ethyl propionyl acetate obtained by gas chromatography gave 3.
The amount was 5 g (yield: 82%).

The procedure of Example 1 was repeated except that no dehydration treatment was carried out (the water content was 2,400 ppm by the Karl Fischer method), and 3.11 g of ethyl propionyl acetate was used. (Yield 72%).

[0025]

According to the novel production method of the present invention, a .beta.-ketoester useful as a raw material for producing pharmaceuticals and agricultural chemicals can be produced at a high yield and at a lower cost.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) C07C 69/716 C07C 67/313 C07C 67/343 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. The following formula (I): (Wherein R ¹ represents an alkyl group) in a two-layer system under acidic conditions comprising an organic solvent and an aqueous solution in the presence of a nitrosyl compound;
The water content of the separated organic solvent layer is determined by the Karl Fischer method.
The organic solvent layer is dehydrated to 1,000 ppm or less, and the product in the organic solvent layer is the following formula (II): (Wherein R ¹ is as defined above) and the following formula (III): (Wherein R ² represents an alkyl group) with an alkyl aldehyde represented by the following formula (IV): (Wherein, R ¹ and R ² have the same meanings as described above).