JPH0717953A - Production of 5-isopropyluracil - Google Patents

Abstract

PURPOSE:To provide a production method capable of readily obtaining high- quality 5-isopropyluracil free from sulfur odor or isovaleric acid odor in a high yield. CONSTITUTION:This method for production of 5-isopropyluracil is characteristically carried out by conducting a reductive ring closure reaction of 2- cyanaoisovaleric acid ureido especially according to the catalytic reduction method in the presence of palladium black as a catalyst.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 5-isopropyluracil useful as a physiologically active substance.

[0002]

BACKGROUND OF THE INVENTION As a method for producing 5-isopropyluracil, isovaleric acid ester is formylated with ethyl formate and alcoholate, then condensed with thiourea to undergo ring closure, and then sulfur is replaced with oxygen. Method has been reported (Rocz. Chem. 1969,43,499-505,
Bull.Acad. Pol. Sci., Ser. Sci. Biol., 15, 527-530
(1967)). However, this method is not good because the sulfur compound derived from thiourea and the by-product isovaleric acid have a very bad odor and the yield is about 10%. Further, if thiourea is replaced with urea to try to solve the problem of odor and the replacement of sulfur with oxygen at the same time, the reactivity of urea is low and the yield is further lowered, which is not practical.

[0003]

Therefore, the present inventor has conducted earnest studies to develop a method for producing a high yield of 5-isopropyluracil free from the odor of sulfur compounds and isovaleric acid. As a result, they have found that high-yield and high-quality 5-isopropyluracil can be produced by reductively ring-closing 2-cyanoisovaleric acid ureide, and completed the present invention. That is, the gist of the present invention relates to a process for producing 5-isopropyluracil, which comprises reductively ring-closing 2-cyanoisovalerate ureide.

[0004]

[Chemical 1]

The 2-cyanoisovaleric acid ureide used in the present invention is obtained by condensing 2-cyanoisovaleric acid and urea in acetic anhydride, and specifically, it is a known method (J. Am. Pha
rm. Assoc., 44, 545-547 (1955)). That is, 2-cyanoisovaleric acid, urea and acetic anhydride are mixed and heated to about 50 ° C. Then, after keeping the temperature at about 80 ° C. for 1 hour, water is added, the mixture is stirred and cooled, and the precipitated crystals are collected by filtration to obtain 2-cyanoisovaleric acid ureide in a yield of about 80%.

The reduction method of the present invention is carried out as follows. First, 2-cyanoisovalerate ureido with water,
Concentrated hydrochloric acid, concentrated sulfuric acid, etc. are added. The amount of concentrated hydrochloric acid added is usually 0.5 to 2 ml with respect to 2-cyanoisovaleric acid ureide.
/ G. A catalytic amount of palladium black in the resulting acidic liquid,
Noble metal supported catalyst such as platinum black, or Raney nickel,
Add a Raney catalyst such as Raney cobalt and stir vigorously while passing a hydrogen stream. Here, the catalyst amount is usually 2
-0.05-0.1% by weight with respect to cyanoisovaleric acid ureide. The hydrogen pressure may be normal pressure, or 1 to 5 kg /
You may pressurize to cm ² . The reduction reaction is usually 20 to 6
Performed at 0 ° C.

After confirming that the theoretical amount of hydrogen has been absorbed, the reaction product is filtered to separate the catalyst, and the filtrate is heated to complete the ring-closing reaction. This heating temperature is usually about 8
It is 0 to 100 ° C., and the heating time is usually 1 to 4 hours, although it depends on the heating temperature. If the heating temperature is lower than 80 ° C, the reaction does not proceed sufficiently.

In order to isolate 5-isopropyluracil obtained by the production method of the present invention from the reaction solution, the reaction solution may be cooled and then the precipitated crystals may be filtered and dried. -When it is desired to obtain isopropyluracil, it is further dissolved in an aqueous sodium hydroxide solution, neutralized with hydrochloric acid, and the precipitated crystals are filtered and dried.

[0009]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. Example 1 A 1-liter four-necked flask was charged with 50 g of 2-cyanoisovaleric acid ureide, 500 ml of water, 60 ml of concentrated hydrochloric acid, and 10% palladium black having a catalytic amount (5 g) and vigorously stirred at room temperature while passing a hydrogen stream. After uptake of about 7 liters of hydrogen was confirmed, the reaction was filtered to remove the catalyst and the filtrate was heated at about 90 ° C. for 2 hours. Upon cooling, crystals began to precipitate, so the crystals were collected by filtration and dried to give 36.4 g (mp: 28) of 5-isopropyluracil.
7 ° C.) was obtained. The yield was 80%. Elemental analysis value: Experimental value: C54.7%, H6.8%, N1
8.4% Theoretical value: C54.5%, H6.5%, N18.2%

Example 2 A 1-liter four-necked flask was charged with 100 g of 2-cyanoisovaleric acid ureide, 500 ml of water, 100 ml of concentrated hydrochloric acid and 10% palladium black having a catalytic amount (5 g), and the mixture was vigorously stirred at room temperature while passing a hydrogen stream. It was stirred. After confirming the absorption of about 14 liters of hydrogen, heat it to about 90 ℃ 2
Reacted for hours. After cooling, the crystals were dissolved with an aqueous sodium hydroxide solution, the catalyst was removed, and the mixture was neutralized with hydrochloric acid. The precipitated crystals were collected by filtration and dried to obtain 70 g of 5-isopropyluracil. The yield was 77%.

[0011]

According to the production method of the present invention, high-quality 5-isopropyluracil free of sulfur odor can be easily obtained in high yield.

Claims (2)

[Claims] 1. A method for producing 5-isopropyluracil, which comprises reductively ring-closing 2-cyanoisovaleric acid ureide. 2. The production method according to claim 1, wherein the reductive ring closure is by a catalytic reduction method using palladium black as a catalyst.