JPS59190974A - Production of 5-carbamoyl-6-methyl-4-substituted-1,2,3,4- tetrahydro-2-thioxopyrimidine - Google Patents

Abstract

PURPOSE:To obtain the titled compound having the carcinostatic action in high yield in a short reaction time, by reacting an acetoacetamide with an aldehyde and thiourea as raw materials in an alcohol, e.g., isopropanol, in the presence of a catalyst. CONSTITUTION:Acetoaceamide, an aldehyde and thiourea as raw materials are dissolved in an alcohol, e.g. isopropanol, and the resultant solution is allowed to stand at room temperature in the presence of concentrated hydrochloric acid as a catalyst or heated under refluxing to give the titled compound of the formula (R is alkyl, aryl or aralkyl group). As an example, 1g acetacetamide, 1.06g benzaldehyde and 1.52g thiourea are dissolved in a mixture solution of 15ml isopropanol with 2ml concentrated hydrochloric acid, and the resultant solution is allowed to stand at room temperature. After 8hr, the resultant deposited crystals are filtered. The mother liquor is concentrated to give crystals which are then combined with the above-mentioned crystals, and the mixed crystals are recrystallized from methanol to afford the aimed compound.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 5-carbamoyl-6-methyl-4-substituted-
1゜2,3.4-tetrahydro-2-thioxopyrimidine (general formula ■).

where R stands for an alkyl, aryl, or aralkyl group. But what is the intention?

5-Carbamoyl-6-methyl-4-phenyl-1,2,3,4-, which is expected to be a compound with anticancer activity
The object of the present invention is to economically advantageously produce tetrahydro-2-thioxopyrimidine (in general formula 19, R means a phenyl group) and its homologues.

4-Phenyl-2-thioxopyrimidine (R in the general formula 19 means a phenyl group) is a compound that reacts with benzaldehyde and thiourea, which are prominent against lymphoid tumors in mice, in dilute methanol (75%) with block acid. reported a method of obtaining 69% yield by leaving it at room temperature in the presence of (Kato et al., Pharmaceutical Journal,
101. 182 (1981)). This method uses 5-ethoxycarbonyl-6-methyl-4-substituted-1,2,3,
4-tetrahydro-2-oxopyrimidine (general formula 1
In formula 9, C○2Et is substituted for CONH2, and O is substituted for S.
), the so-called Biginelli reaction (P-Biginell
i, Ber,.

24, 1317 (1891)), and the reaction conditions were exactly the same.

In contrast, the present invention can be said to be advantageous in terms of improved yield, shortened reaction time, and generality of the reaction.

x ;h t:, -RicetMeRmide 1σ (1 nmol), penzaldehyde 1.06 g (10 mmol), and thiourea 1.52 g (20 mmol) in isopropanol (15 ml) 4-phenyl-tetrahydrothioxopyrimidine (general formula 1.
R is a phenyl group) is obtained in 85%. Even if the reaction solution is heated under reflux on a water bath, substantially the same yield can be obtained. but,
If methanol or ethanol is used, the yield will decrease. The results of the solvent 2 reaction temperature, etc. are shown in Table 1.

1) *2) Kamai (lI, spoken language, 101. 182)
(+981).

The present invention is also applicable to the production of corresponding thioxopyrimidine derivatives (general formula I) using other aldehydes. In particular, as an example in which the yield is improved when isopropanol is used, for example, p-nitrobenzaldehyde is dissolved in 75% methanol-hydrochloric acid under previously reported conditions.
When left at room temperature, the desired 5-carbamoyl-4-
(p-nitrophenyl)-6-methyl-1,2°3.4
-tetrahydro-2-thioxopyrimidine (general formula I,
In the formula, R means p-nitrophenyl group) is 33%
However, it can be produced quantitatively under the conditions of isopropanol and concentrated hydrochloric acid.

The method of the present invention will be explained below with reference to nine examples.

Example 1. 5-hruhamoyl-6-methyl-4-
Phenyl-1,2,3,4-tetrahydro-2-thioxopyrimidine (general formula ■).

In the formula, R means a phenyl group) 1) Method of leaving at room temperature 1 g of acetoacetamide, 1.06 g of benzaldehyde,
and 152 g of thiourea were dissolved in a mixture of 15 ml of isopropanol and 2 ml of concentrated hydrochloric acid, and the solution was left at room temperature. After 8 hours, the precipitated crystals are counted. The crystals obtained by concentrating the mother liquor were combined and recrystallized from methanol to give 21 g (85
%) colorless prism, mp236°(dec,)
(Literature value mp236° (dec,)) is obtained.

Elemental analysis (C, 2H, 3N, O3) Calculated value: C, 58,06; H, 5,26; N, 16
．． 88° Actual value: C, 58, 37; H, 548; N,
16.642) Method of heating to reflux "1. Heat the reaction solution in a water bath" to reflux for 2 hours. After cooling, the precipitated crystals are washed with a small amount of methanol to obtain 1.8 g of almost pure colorless prisms. Concentrate the mother liquor and recrystallize the precipitated crystals from methanol to give 0.27 g.
Obtain a colorless prism. Total yield 2.07g (84%),
mp236° (dec, ) Example 2. 5-carbamoyl-6-methyl-4-(p-nitrophenyl)-
1,2,3,4-tetrahydro-2-thioxopyrimidine (general formula I9, in which R means p-nitrophenyl group) 1) Isopropanol-reaction in concentrated hydrochloric acid Aminoacetoacetate +-゛1 ．． Og (10 mmol), p-nitrobenzaldehyde], 51 g (1069 mol), and thiourea+52 g (20 mmol) were dissolved in a mixture of 15 ml of isopropanol and 2 ml of concentrated hydrochloric acid.

Heat to reflux for 2 hours. After cooling, the precipitated crystals are collected and washed with a small amount of methanol to obtain almost pure pale yellow prisms. Yield 2.89 g (quantitative), mp25
8° (dec,).

Infrared absorption spectrum (KBr): 3430.3360
．． 1650cm' elemental analysis (C,,H,2N,O,S
) Calculated value C, 49, 30; H, 4,] 3; N, 1
9.16゜Actual measurement C, 48,97; H, 4,07; N
, 18.922) Reaction in methanol-10% hydrochloric acid 303 g (30 mmol) of acetoacetamide, p-nitropenzurimol) are dissolved in a mixture of 45 ml of methanol and 15 ml of 1096 hydrochloric acid.

Leave at room temperature for 6 days. Collect the precipitated crystals, wash them with a small amount of methanol, and make two almost pure pale yellow prisms.
．． Obtain 78 g (33%). mp258° (dec,
) In the same manner, a novel thioxopyrimidine (I) was produced using five types of aldehydes. (Table 2) Table 2

Claims (1)

[Claims] 11 5-Carbamoyl-6-methyl-4-substitution characterized by dissolving acetoacetic acid a]', aldehyde and thiourea in an alcohol such as isopropanol, and leaving the solution at room temperature or heating under reflux in the presence of a concentrated hydrochloric acid catalyst. −],
2.3. Method for producing 4-tetrahydro-2-thioxopyrimidine (in the following general formula ■9, R means an alkyl, aryl, or aralkyl group)