JPH0684360B2 - Uracil manufacturing method - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing uracils. More specifically, it relates to a method for producing uracils from cytosines.

[Problems to be Solved by Prior Art and Present Invention]

Uracil is an important component of nucleic acids, and is also a useful compound as a raw material for medicines. Further, among 5-alkyluracils, 5-methyluracil is also called thymine and is also an important constituent component of nucleic acid, and thymine and other 5-alkyluracils are important compounds as medicinal raw materials. . For example, by fluorinating uracil, 5-fluorouracil (5-FU) having an antitumor action can be obtained, and further, various anticancer agents such as prominent futraful using this 5-FU as a raw material can be obtained. Is already known. In addition, the development of these anti-cancer agents is still in progress. It is also known that iodoxuridine, which is useful as an antiviral agent, is synthesized from uracil as a raw material.

As described above, since uracils are highly useful as raw materials for producing various pharmaceutical compounds, many studies have been conducted on the method for producing uracils.

As an example of a method for producing uracils that has been published to date, the production of uracil described in Tetorahedoron Letter, 1976 (2) 2321-2322, which comprises heating and reacting propiolic acid with urea in polyphosphoric acid, is performed. I can mention the law.

However, this method uses expensive carboxylic acid as a raw material and
Since the operation involves adding water to the reaction solution to precipitate uracil after the reaction, there are drawbacks such as difficulty in recovering and reusing a large amount of polyphosphoric acid used in the reaction, and what is satisfactory as a method for producing uracils I can't say.

In addition, as an example of a method for producing uracils, Trans.Scie
nce Soc.China, can be mentioned malic acid, as described in 8 83-4 (1934), a production method which comprises reacting urea with a large amount of fuming sulfuric acid. However, this method involves the use of a large amount of fuming sulfuric acid and the operation of precipitating uracils by diluting the reaction solution with a large amount of water after the reaction, so the urea used in the reaction and a large amount of fuming sulfuric acid are recovered. Since it is difficult to reuse, it cannot be said to be satisfactory as an industrial method for producing uracils.

Further, JP-A-58-38268 describes a method of obtaining uracil in two steps from 3,3-dialkoxypropionic acid ester and urea, and the starting material, 3,3-dialkoxypropionic acid ester. Can be synthesized by a palladium-catalyzed oxidation reaction of acryloate, and thus can be said to be an effective method for synthesizing uracils.

In addition, ACTA CHEMICA SCANDINAVICA 3 (1949) 422-432 describes that uracils were obtained by heating and refluxing cytosine in 0.4N sulfuric acid for 48 hours at 100 ° C, but the reaction time was too long. , Not an industrial method. However, according to JP-A-59-93059 and JP-A-59-93060, β, β-dialkoxyacrylonitrile or β-alkoxyacrylonitrile obtained by the oxidation of acrylonitrile to give cytosine is inexpensive and high. It can be obtained in yield. Therefore, the inventors of the present invention conducted extensive research into a method for producing uracil from cytosines having industrial value, and found the present invention.

That is, the present invention provides a method for producing uracils, which comprises producing uracil or 5-substituted uracil by heating cytosine or 5-substituted cytosine to 140 ° C. or higher in water in the presence of a strong acid. It is provided.

The cytosine or 5-substituted cytosine in the present invention can be represented by the following formula (I).

However, R in the formula is a hydrogen atom, a halogen atom, or a carbon number of 1.
~ 6 alkyl group, phenyl group and benzyl group are shown, and the phenyl group and benzyl group may be substituted with alkyl, alkoxy or halogen atom.

Specific examples of the 5-substituted cytosine include 5-methylcytosine, 5-ethylcytosine, 5-benzylcytosine, 5- (3,4,5) -trimethoxybenzylcytosine and 5-trifluoromethylcytosine. Can be mentioned.

Examples of the strong acid of the present invention include sulfuric acid, hydrochloric acid, phosphoric acid, methanesulfonic acid aqueous solution, and the like, but sulfuric acid is preferable in consideration of price, corrosion when a metal pressure vessel is used, and the like.

The concentration of the aqueous solution of strong acid is 0.01-12N, preferably 0.1-6N.
Is.

The heating temperature of the present invention is 140 ° C. or higher.

At a temperature lower than 140 ° C, it takes a long reaction time to obtain the target product and the yield is low.

The temperature may be any number as long as it is 140 ° C. or higher, but it is preferably 300 ° C. or lower in consideration of decomposition of the product.

In the present invention, as described above, cytosine or 5-substituted cytosine is heated in water to 140 ° C. or higher in the presence of a strong acid to cause a reaction to obtain uracils represented by the following formula (II). .

However, in the above formula (II), R corresponds to R in the general formula of the cytosines. Specific examples of specific compounds of the above-mentioned uracils include 5-methyluracil, 5-ethyluracil, 5-benzyluracil, 5- (3,4,5) -trimethoxybenzyluracil, 5-trifluoromethyluracil and the like. Can be mentioned.

After completion of the reaction, uracils are precipitated as a precipitate. This precipitate can be taken out by filtration and then purified if necessary to obtain highly pure uracils.

Next, the present invention will be described in more detail with reference to Examples.

〔Example〕

Example 1. 4.00 g of cytosine and 40 ml of 1.6N (normal) sulfuric acid aqueous solution were charged into a stainless steel autoclave. After replacing the air in the autoclave with nitrogen gas, the mixture was reacted at 200 ° C. for 5 hours. After cooling, the autoclave was opened, the precipitated white crystals were filtered, and the crystals were washed with water and dried to give 3.83 g of white crystals. This IR and elemental analysis were in agreement with those of uracil. Melting point (mp) 333-3
At 35 ° C, the yield was 95%. In the thin layer chromatography (TLC) of the filtrate, there was only a spot corresponding to cytosine, and no uracil spot was found.

Example 2 Example 1 was repeated except that 4.00 g of cytosine was reacted in a 0.4N sulfuric acid aqueous solution. As a result, 3.22 g (80%) of uracil crystals were obtained. According to TLC analysis, no raw material cytosine remained.

Comparative Example 1. 0.50 g of cytosine was dissolved in a 0.8 N sulfuric acid aqueous solution, and the mixture was reacted in a 50 ml flask equipped with a reflux condenser at a reflux temperature (100 ° C.) for 48 hours. 0.20 g (40% yield) of uracil was obtained,
A large amount of unreacted cytosine remained in the filtrate.

Example 3 The same procedure as in Example 1 was carried out except that 4.00 g of cytosine was reacted in a 1.6N aqueous sulfuric acid solution in a stainless autoclave having an internal volume of 300 ml at 150 ° C. for 5 hours. As a result, 3.15 g (yield 7
8%) of uracil was obtained, but 0.61 g of unreacted cytosine was recovered by neutralizing the filtrate with aqueous ammonia.

Example 4 Example 4 was repeated except that the reaction temperature was 200 ° C and the reaction time was 2 hours. As a result, 3.61 g (91% yield)
Got uracil. There was a very small amount of unreacted cytosine in the filtrate.

Example 5 The procedure of Example 1 was repeated except that 4.00 g of 5-methylcytosine was used and a 100 ml stainless steel autoclave was used. 3.72 g of 5-methyluracil (thymine) crystals (yield 9
3%) was obtained. No unreacted 5-methyltocin remained.

〔The invention's effect〕

ADVANTAGE OF THE INVENTION According to this invention, the reaction time is short and the industrial manufacturing method which can manufacture with high yield is provided.

Claims (1)

[Claims] 1. A method for producing uracils, which comprises producing uracil or 5-substituted uracil by heating cytosine or 5-substituted cytosine in water in the presence of a strong acid to 140 ° C. or higher.