JPS6287576A - Production of uracil-5-carboxylic acid higher alkyl ester - Google Patents

Abstract

PURPOSE:To obtain the titled substance useful as an intermediate for pharmaceuticals, in high yield from an inexpensive raw material, by carrying out the ester exchange reaction of a uracil-5-carboxylic acid lower alkyl ester with an alcohol having larger number of C atoms in the presence of an acid catalyst. CONSTITUTION:The titled substance is produced by the ester exchange reaction of a uracil-5-carboxylic acid lower alkyl ester of formula (R is CH3 or C2H5) with a >=3C alcohol in the presence of an acid catalyst (preferably sulfuric acid). The amount of the catalyst is 0.1-0.2mol per 1mol of the lower alkyl ester used as a raw material. The reaction is carried out at a temperature below the boiling point of the alcohol used as a raw material, e.g. at 100-105 deg.C for isobutyl alcohol for 4-10hr. The homogeneous solution or slurry produced by the reaction is cooled, crystallized, filtered and washed with water to obtain the objective substance. The filtrate can be recycled to the reaction system.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to higher alkyl esters of uracil-5-carboxylic acid useful as intermediates for pharmaceuticals, particularly preferably propyl esters and butyl esters of uracil-5-carboxylic acid. The present invention relates to a method for manufacturing.

[Prior Art] As a method for producing uracil-5-carboxylic acid ester, particularly methyl ester and ethyl ester, there has been a conventional method of using ureidomethylene malonic acid ester as a raw material and cyclizing it in the presence of an alkali in an aqueous medium. It is publicly known. (Refer to JP-A-55-104271) [Problem to be Solved by the Invention 1] However, although the above method is useful as a means for producing methyl esters and ethyl esters, malonic acid esters are It is obtained by reacting flufukidimethylene malonic acid ester, which is a reaction product of artificial chill and malonic acid ester, with urea, and since the use of alcohol is essential for these reactions, industrial production of methyl alcohol, ethyl alcohol, etc. There is no problem when using inexpensive raw materials that are easily available, but propyl alcohol and butyl alcohol are quite expensive, and on top of that, all of the above series of reactions involve dealcoholization reactions, so it is difficult to obtain the final target compound. Although an extremely large amount of alcohol is required to produce a certain uracil-5-carboxylic acid alkyl ester, in the end most of the alcohol is not needed. Although the alcohol can be recovered and used, it requires some kind of post-treatment such as distillation or extraction.
It is extremely impractical to produce butyl carboxylate and results in high costs.

[Means for solving the problem] Uracil-5-carboxylic acid lower alkyl ester (in the formula, R is a methyl group or an ethyl group) represented by the following is transesterified with an alcohol having two carbon atoms: −
In producing a 5-carboxylic acid higher alkyl ester, it was discovered that the objective can be achieved very easily and in high yield when the reaction is carried out in the presence of an acid catalyst, and the present invention has been completed.

That is, in the present invention, as mentioned above, industrial
The most distinctive feature of this method is that it utilizes the easy methyl ester and ethyl ester of uracil-5-carboxylic acid and transesterifies them in the presence of an acid catalyst.

Conventionally, transesterification has generally been carried out using an alkaline catalyst such as sodium ethylate or caustic soda. Examples of such acid catalysts include inorganic acids such as sulfuric acid, hydrochloric acid, phosphoric acid, and perchloric acid, p-toluenesulfonic acid, and methanesulfone. Examples include sulfonic acids such as acids, carboxylic acids such as trihalodenoacetic acid, Lewis acids such as aluminum chloride, zinc chloride, and boron fluoride, and sulfuric acid is particularly preferred. The amount of catalyst used is uracil-5-carboxylic acid lower alkyl ester 1
The range is approximately 0.05 to 1.0 mol, more preferably 0.1 to 0.2 mol.

Examples of alcohols having 3 or more carbon atoms to be transesterified with uracil-5-carboxylic acid lower alkyl ester include low propyl alcohol, isopropyl alcohol, lobethyl alcohol, isobutyl alcohol, S-butyl alcohol, t-butyl alcohol, n-amyl alcohol, Examples include, but are not limited to, isoamyl alcohol, hexyl alcohol, \heptyl alcohol, and octyl alcohol. Practically speaking, the amount is 10 to 50 mol, more preferably 20 to 30 mol, per 1 mol of isobutyl-5'-carboxylic acid lower alkyl ester.The reaction solvent is usually the above-mentioned alcohol having 3 or more carbon atoms. Therefore, although not particularly necessary, it is advisable to use neutral solvents that do not participate in the reaction and have a higher boiling point and lower temperature than the alcohol, such as aliphatic hydrocarbons, aromatic hydrocarbons, and halogenated hydrocarbons. .

When carrying out the reaction, the uracil-5-carboxylic acid lower alkyl ester, the alcohol having 3 or more carbon atoms, and the acid catalyst are charged into a reactor all at once or either component or two components are divided or continuously. . Depending on the type of raw materials used, the amount charged, and the reaction temperature, the reaction system may be a homogeneous solution system or a slurry system, but the present invention can be applied to either system. The preferred reaction temperature is below the boiling point of the raw material alcohol, for example, in the case of isobutyl alcohol, 100
It is around ~105°C. Although it differs depending on the reaction time and other conditions, the reaction was followed over time and the reaction mixture was analyzed by high performance liquid chromatography (HLC) or thin layer chromatography (TLC). The opening is usually about 4 to 10 hours in advance.

After the reaction is completed, a homogeneous solution or slurry solution is obtained, which is cooled and crystallized, filtered, and washed with water until the washing liquid becomes neutral to remove sulfuric acid.

The liquid after removing the crystals can be recycled.

If necessary, the obtained crystals are subjected to activated carbon treatment, recrystallization, etc., and purification, followed by washing and drying to obtain the desired crystals of uracil-5-carboxylic acid higher alkyl ester.

[Effect 1] In the present invention, a higher ester of uracil-5-carboxylic acid can be obtained by a simple means using an industrially inexpensive raw material of uracil-5-carboxylic acid methyl ester or ethyl ester, and its practical use is improved. Its value is extremely high, and its yield is high at over 90%, and there is almost no loss of product due to the recycled use of r-liquid.
The reaction efficiency is also very high.

[Example 1] Next, the method of the present invention will be explained in more detail with reference to Examples.

Example I SOOmj Yotsuro 7 rasf with isobutyl furfur 29
6 g (4 mol) was added, 18.48 (0.1 mol) of uracil-5-carboxylic acid ethyl ester was suspended, and sulfuric acid o, sg (o, os mol) was added, and the reaction was carried out with stirring. The reaction was carried out at a temperature of 102 to 105[deg.] C. until by-produced ethyl alfur was distilled off and uracil-5-carboxylic acid ethyl ester could no longer be detected by HLC (reaction time 4 hours).

The resulting reaction solution was cooled to room temperature, and the crystallized crystals were collected in a furnace, washed with water to remove sulfuric acid, and dried under vacuum.
9.3 g (0,091 mol) of white crystals of uracil-5-carboxylic acid butyl ester were obtained. Yield 91% (reaction was carried out in the same manner as in the same example except for pairing (reaction time 8 hours)
Although the reaction system was in a slurry state from beginning to end, the reaction proceeded successfully and the final yield was 19.9 g (0,0
94 mol) of crystals were obtained. Yield 94%.

Examples 3 to 7 Reactions were carried out in the same manner as in Example 1 except that the raw materials and reaction conditions were changed as shown in the table. The results are also shown in the table. Note that all yields are based on the raw material uracil-5-carboxylic acid methyl ester or ethyl ester.

(Margin below)

Claims (1)

[Claims] Uracil-5-carboxylic acid lower alkyl ester (in the formula, R is a methyl group or an ethyl group) represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ Uracil-5 by transesterification
- In producing carboxylic acid higher alkyl ester,
A method for producing uracil-5-carboxylic acid higher alkyl ester, characterized in that the reaction is carried out in the presence of an acid catalyst.