JP3176426B2 - Method for producing γ-chloroacetoacetic ester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing .gamma.-chloroacetoacetic acid ester which is useful as a synthetic intermediate for pigments and pharmaceuticals.

[0002]

2. Description of the Related Art
Chloroacetoacetate is produced, for example, by an esterification reaction between alcohol and γ-chloroacetoacetate chloride obtained by reacting diketene with chlorine.
In this esterification reaction, a large amount of by-products of an acetal compound or an enol derivative of γ-chloroacetoacetate ester is produced by a catalytic action of hydrogen chloride produced as a by-product. Therefore, some improved production methods have been proposed.

For example, JP-A-51-113824, JP-A-58-23373, and
No. 25951 discloses a method in which an alcohol such as methanol is added to a reaction mixture containing γ-chloroacetoacetic chloride obtained by chlorinating diketene in dichloroethane to cause a reaction. However, according to this method, the purity of the obtained γ-chloroacetoacetate ester is as low as about 90% or less, and when used as a synthetic intermediate such as a drug, a high-purity target compound cannot be obtained in good yield.

Japanese Patent Application Laid-Open No. 58-157747 discloses, contrary to the above method, a reaction mixture containing γ-chloroacetoacetic chloride obtained by chlorinating diketene in carbon tetrachloride. There is disclosed a method of esterification by gradually adding the mixture therein. But,
The purity of the γ-chloroacetoacetic ester obtained by this method is as low as about 85% or less, and the yield is as low as 90% or less.

Further, JP-A-60-25955 discloses a reaction mixture containing γ-chloroacetoacetic chloride obtained by chlorinating diketene in dichloroethane.
There is disclosed a method in which an alcohol such as methanol is dropped and reacted at a temperature of about −20 to 0 ° C. while removing by-product hydrogen chloride from the system by introducing an inert gas or reducing the pressure in the system. However, even by this method, the side reaction cannot be sufficiently suppressed. Further, since the reaction is carried out at a low temperature of 0 ° C. or lower, it cannot be said that the method is industrially preferable in terms of reaction control and production cost.

As described above, the conventional method cannot sufficiently suppress the side reaction caused by the by-produced hydrogen chloride, and cannot obtain high-purity γ-chloroacetoacetic ester in high yield.

Further, all of the above methods use a halogenated hydrocarbon such as dichloroethane or carbon tetrachloride as a solvent, which is not preferable from the viewpoint of protecting the global environment.

Accordingly, an object of the present invention is to provide an industrial method for obtaining high-purity γ-chloroacetoacetate in a high yield by a simple operation.

[0009]

The present inventors have conducted intensive studies in order to achieve the above object, and as a result, have found that as a reaction solvent for the esterification reaction between γ-chloroacetoacetic chloride and an alcohol,
It has been found that when hydrocarbons are used, side reactions are remarkably suppressed, and as a result, high-purity γ-chloroacetoacetic ester can be obtained in a high yield, and the present invention has been completed.

That is, the present invention provides a method for producing γ-chloroacetoacetate by reacting an alcohol with γ-chloroacetoacetate chloride, and provides a method for producing γ-chloroacetoacetate using a hydrocarbon as a solvent. .

The γ-chloroacetoacetic chloride used as a raw material in the present invention can be produced, for example, by chlorination of diketene or acetoacetic chloride, preferably chlorination of diketene. When producing γ-chloroacetoacetic chloride by chlorination of diketene,
The amount of chlorine used is usually 0.95 to 1 mol of diketene.
The reaction temperature is about -20 to 20C.

The γ-chloroacetoacetic chloride may be an isolated one, and the reaction mixture obtained by the chlorination reaction may be used as it is or may be concentrated if necessary.
Those subjected to an operation such as dilution can also be used.

The solvent for obtaining the γ-chloroacetoacetate chloride is not particularly limited, but is preferably a hydrocarbon used in the method of the present invention. In this case, a reaction product obtained by allowing chlorine to act on diketene can be directly used for the esterification reaction.

In general, hydrocarbons such as benzene have been
It was not used as a reaction solvent in the chlorination reaction of diketene. However, the solvent is extremely excellent as a reaction solvent for the reaction if appropriate reaction conditions are selected, and γ-
Chloroacetoacetic chloride can be obtained in high yield. Moreover, when the solvent is used for the chlorination reaction, the chlorination reaction mixture can be directly used for the esterification reaction without performing any operation such as solvent removal, which is industrially extremely advantageous.

The alcohol can be selected according to the desired ester. For example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methylpropanol, 2-methylpropanol
Methyl-2-propanol, 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol, 2
Monohydric alcohols such as ethylhexanol and cyclohexanol; dihydric alcohols such as ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol and propylene glycol; and polyhydric alcohols such as glycerin. Of these alcohols, monohydric alcohols such as methanol, ethanol and the like are frequently used.

The amount of the alcohol is not particularly limited, but is usually 0.5 to 5.0 mol, preferably 0.8 to 2.0 mol per 1 mol of γ-chloroacetoacetic chloride.
0 mol, more preferably 0.95 to 1.5 mol.

The present invention is characterized in that a hydrocarbon is used as a solvent for the esterification reaction.

According to JP-A-58-157747, since γ-chloroacetoacetic chloride is unstable and highly reactive and must be stored at low temperature, alcohol is added to γ-chloroacetoacetic chloride. The method of reacting is not considered to be a satisfactory method as an industrial production method. Actually, in the method in which alcohol is added to γ-chloroacetoacetate chloride and reacted (see the examples described in JP-A-60-25955 and the like), the decomposition reaction of γ-chloroacetoacetate chloride and the by-product In order to suppress side reactions and the like caused by hydrogen chloride, all reactions are performed at a low temperature of -10 to 0C.

However, in the hydrocarbon solvent, γ
-Chloroacetoacetic chloride shows high stability. For example, a reaction mixture containing γ-chloroacetoacetate chloride obtained by reacting diketene and chlorine in the solvent may be left at a temperature of about 30 to 35 ° C. for several hours.
Almost no change is observed due to decomposition of chloroacetoacetic chloride. Therefore, it is not necessary to immediately use γ-chloroacetoacetic chloride obtained by the chlorination reaction, and the above-described alcohol addition method advantageous for suppressing side reactions can be adopted as an industrial method.

In the above-mentioned solvent, γ-chloroacetoacetic chloride has a high stability.
Since the reaction can be suitably performed even in a temperature range of about 100 ° C., the reaction control is easy and economically advantageous.

Further, when the above-mentioned solvent is used as a solvent for the esterification reaction, there is no change due to the decomposition of γ-chloroacetoacetate chloride and the side reaction by-produced hydrogen chloride is suppressed. It can be obtained in high yield.

The hydrocarbons include aromatic hydrocarbons, aliphatic hydrocarbons and alicyclic hydrocarbons. Benzene etc. are mentioned as said aromatic hydrocarbon. Preferred aromatic hydrocarbons are benzene and the like.

As the aliphatic hydrocarbon, pentane, isopentane, neopentane, hexane, isohexane,
Examples thereof include linear or branched aliphatic hydrocarbons such as heptane, 2-methylhexane, octane, 2-methylheptane, nonane, and decane. Among them, preferred are aliphatic hydrocarbons having 5 to 8 carbon atoms, especially hexane. As the alicyclic hydrocarbon, cyclohexane,
Methyl cyclohexane is exemplified.

The above hydrocarbons can be used alone or as a mixture of two or more.

The solvent in the method of the present invention is preferably (1) benzene or (2) a mixed solvent of benzene and an aliphatic or alicyclic hydrocarbon, particularly preferably (1) benzene or (2a) benzene. And a mixed solvent of hexane.

When a mixed solution of benzene and an aliphatic or alicyclic hydrocarbon is used as the solvent, the content of the aliphatic or alicyclic hydrocarbon is usually 1000 parts by weight based on 100 parts by weight of benzene. Parts or less, preferably 1 to
100 parts by weight, more preferably 3 to 30 parts by weight.

The amount of the solvent to be used can be arbitrarily selected within a range in which the reaction operation can be carried out smoothly.
000 parts by weight, preferably 50 to 1000 parts by weight.

The reaction of γ-chloroacetoacetic chloride with an alcohol can be carried out by any of a batch system, a semi-batch system and a continuous system, and the order of adding the raw material components is not particularly limited. A system in which an alcohol is sequentially added to acetic chloride and reacted is preferable. By adopting a method of sequentially adding alcohol, side reactions such as acetalization of γ-chloroacetoacetic ester are further suppressed. Incidentally, the sequential addition of alcohol may be continuous or intermittent.

In the production method of the present invention, a method of reacting γ-chloroacetoacetic chloride with an alcohol while distilling off the solvent is particularly recommended. Hereinafter, this method will be described.

Hydrocarbon such as benzene used as a solvent in the present invention has a property that hydrogen chloride is very easily entrained when boiling. Therefore, when the reaction temperature is set to a temperature at which the solvent boils and the reaction is performed while distilling off the solvent, the solvent functions as a carrier of hydrogen chloride, and hydrogen chloride as a by-product is efficiently discharged out of the system together with the solvent. And as a result,
Side reactions caused by hydrogen chloride are significantly suppressed.

In this case, the distillation rate of the solvent is appropriately determined according to the reaction rate and the like.
/ Hr, preferably 200 to 1000 ml / hr.

The reaction temperature is a temperature at which the solvent boils as described above, and varies depending on the type of the solvent used and the reaction pressure, but is usually from 10 to 100 ° C., preferably from 20 to 90 ° C.
It is about ° C.

The reaction may be carried out at normal pressure, but is usually carried out under reduced pressure, preferably at 100 to 755 Torr, more preferably at 200 to 750 Torr.

As described above, by employing a method of reacting γ-chloroacetoacetic acid chloride with an alcohol while distilling off the solvent, the side reaction caused by the by-produced hydrogen chloride can be almost completely suppressed.

In the method of the present invention, an inert gas such as nitrogen may be introduced into the reaction system. However, when the reaction is carried out while distilling off the solvent, the solvent functions as an excellent carrier for hydrogen chloride. In order to do so, it is not necessary to particularly introduce them.

After completion of the reaction, the desired compound, γ-chloroacetoacetate, can be easily obtained by conventional separation means such as concentration, solvent extraction, column chromatography and the like.

According to the method of the present invention, since side reactions are remarkably suppressed, high-purity γ-chloroacetoacetate can be obtained in high yield only by concentrating the reaction mixture.
The γ-chloroacetoacetate thus obtained can be suitably used as a synthetic intermediate for pigments and pharmaceuticals.

Preferred embodiments of the present invention include the following embodiments.

(1) An alcohol was added to a mixed solution containing γ-chloroacetoacetic chloride obtained by reacting diketene and chlorine in a hydrocarbon solvent under reduced pressure while distilling off the solvent together with by-produced hydrogen chloride. Γ to be added sequentially and reacted
-A method for producing chloroacetoacetic ester.

(2) The method for producing γ-chloroacetoacetic ester according to (1), wherein the reaction is carried out at a reduced pressure of 200 to 750 Torr.

(3) The method for producing γ-chloroacetoacetate according to the above (2), wherein the reaction is carried out in a temperature range of 20 to 90 ° C.

[0042]

According to the method of the present invention, high-purity γ-chloroacetoacetate can be produced from γ-chloroacetoacetate chloride and alcohol by a simple operation in a high yield.

[0043]

EXAMPLES The present invention will be described below in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 420.5 g (5 mol) of diketene was dissolved in a mixed solution of 3364 g of benzene and 420.5 g of hexane, and -5
At a temperature of ° C., 355 g (5 mol) of chlorine was charged over 7.5 hours to produce γ-chloroacetoacetic chloride. The conversion of diketene was 99.0%, and the selectivity for γ-chloroacetoacetic chloride was 98.05%.

Next, the obtained reaction mixture was added to a temperature of 50
At a temperature of 400 ° C. and a pressure of 400 Torr, 208 g (6.5 mol) of methanol was successively added over 2 hours while distilling off the solvent. Concentrate the reaction mixture to 97.64% purity
730.8 g of methyl γ-chloroacetoacetate was obtained. The yield was 94.8% based on diketene.

Comparative Example 1 To 3784.5 g of dichloroethane, 420.5 of diketene were added.
g (5 moles) and at a temperature of −5 ° C., 355 g of chlorine
(5 mol) was charged over 7.5 hours to produce γ-chloroacetoacetic chloride.

Next, the obtained reaction mixture was added with a temperature of -5.
208 g of methanol at 400 ° C. under a pressure of 400 ° C.
(6.5 mol) were added sequentially over 2 hours. Under these conditions, no solvent was distilled off. The reaction mixture was concentrated and methyl γ-chloroacetoacetate 69 with a purity of 82.4% was added.
6.8 g were obtained. The yield was 76.3 based on diketene.
%Met.

Example 2 84.1 g (1 mol) of diketene was dissolved in 756.9 g of benzene, and 71 g (1 mol) of chlorine was charged over 2 hours at a temperature of 1 to 3 ° C. to give γ-chloroacetoacetic chloride. Was manufactured. The reaction yield was 97.23%.

Next, the obtained reaction mixture was added to a temperature of 78.
35.2 (1.1 mol) of methanol was successively added over 30 minutes while distilling off the solvent under the conditions of a temperature of 740 Torr and a temperature of 740 Torr. The reaction mixture was concentrated to obtain methyl γ-chloroacetoacetate having a purity of 96.7% in a yield of 88.5% (based on diketene).

Example 3 To 504.6 g of benzene, 126.2 (1.5
Mol), and at a temperature of 1 to 3 ° C., 106.5 g of chlorine
(1.5 mol) was charged over 4 hours to produce γ-chloroacetoacetic chloride.

The reaction mixture obtained is heated at about 30-35 ° C. for 2 hours.
After standing for a time, the solvent was distilled off under heating at a pressure of 300 Torr while distilling off the solvent (48 g, 1.5 g).
Mol) was added sequentially over 1 hour. The reaction mixture was concentrated to obtain methyl γ-chloroacetoacetate having a purity of 96.6% in a yield of 88.0% (based on diketene).

As described above, even when the chlorination reaction solution containing γ-chloroacetoacetic acid chloride is left at about 30 ° C. for 2 hours and then subjected to the esterification reaction, a high-purity target compound can be obtained in a high yield. Was.

Claims (3)

(57) [Claims] 1. A method for producing γ-chloroacetoacetate by reacting alcohol with γ-chloroacetoacetate chloride, wherein γ-chloroacetoacetate uses hydrocarbon as a solvent.
A method for producing chloroacetoacetic ester. 2. The reaction while distilling off the solvent.
A method for producing the γ-chloroacetoacetic ester according to the above. 3. The method for producing γ-chloroacetoacetate according to claim 1, wherein γ-chloroacetoacetate chloride obtained by reacting diketene with chlorine in a hydrocarbon solvent is used.