JPH054387B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel pyrimidine derivatives and methods for their production. More specifically, the present invention relates to a novel pyrimidine derivative derived from octafluoroisobutene and a method for producing the same. Recently, it has been reported that certain fluorine-containing organic compounds exhibit unique physiological activities that are thought to be due to the inherent properties of the fluorine atom, that is, its highest electronegativity and the second smallest atomic radius after hydrogen. It is receiving particular attention. By the way, octafluoroisobutene, which is a by-product during the production of hexafluoropropene, which is an important raw material for fluorine-containing copolymers, is not only highly toxic, but also because no effective method for its use has been found. Currently, there is a problem in how to dispose of it. As a result of intensive research aimed at effectively utilizing such octafluoroisobutene, the present inventors found that this compound cannot be stored in its original form due to its toxicity, and is generally used in lower alcohols such as methanol.
By actively utilizing the fact that alcohol adducts such as ethanol, n-propanol, isopropanol, and n-butanol are preserved, the alcohol adduct itself can be used as a starting material, or preferably, the alcohol adduct can be used as a base. Using the dehydrofluorinated product of pyrimidine, which can be easily obtained by contacting it, as a starting material, we succeeded in leading to a useful new pyrimidine derivative as shown by the general formula below (Preliminary lecture of the 47th Spring Annual Meeting of the Chemical Society of Japan) Collection number
726 pages). These new pyrimidine derivatives can be used in medicines such as anti-tumor agents and agricultural chemicals such as herbicides due to the unique physiological activity of fluorine-containing organic compounds; It is desirable to convert the 6-lower alkoxy group into a hydroxyl group in order to introduce additional substituents therein. However, no hydrolysis of lower alkoxy groups using acidic catalysts was successful. Therefore, the inventors of the present invention
As a result of investigating a new reaction process for the purpose of synthesizing a new pyrimidine derivative having a -hydroxyl group, we were able to obtain the desired product in good yield for the first time. Accordingly, the present invention relates to novel pyrimidine derivatives, which have the general formula (Here, R is a hydrocarbon group.) The present invention also relates to a method for producing such novel pyrimidine derivatives, wherein the pyrimidine derivatives are produced by the general formula (Here, R is a hydrocarbon group) This is carried out by subjecting an isothiourea derivative represented by R to a ring-closing reaction in the presence of a tertiary amine catalyst. The novel pyrimidine derivative represented by the above general formula [] is synthesized by the following reaction steps. Octafluoroisobutyl lower alkyl ether, which is the original starting material, is obtained as a lower alcohol adduct of octafluoroisobutene as described above, and is mixed with alkali metal or alkaline earth metal water in the presence of a phase transfer catalyst. 1 by stirring with an oxide or carbonate or a base such as a trialkylamine, followed by flash distillation and conventional distillation.
- It can be converted into lower alkoxy perfluoroisobutene. The 1-lower alkoxy perfluoroisobutene is reacted with a tertiary amine to form its tertiary amine addition salt. The tertiary amine used in this reaction is also a basic catalyst used when converting octafluoroisobutyl lower alkyl ether to 1-lower alkoxy perfluoroisobutene as described above. It is preferable to directly form the above-mentioned tertiary amine addition salt by using a tertiary amine in a molar ratio of 2 or more to octafluoroisobutyl lower alkyl ether without using perfluoroisobutene as a starting material. This reaction is generally carried out in the presence of an aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, sulfolane, hexamethylphosphoramide, etc. at a temperature of about 0-50°C. On the other hand, S-hydrocarbon-substituted isothiourea or its acid salt is prepared by mixing thiourea and a halogenated hydrocarbon, preferably an iodinated hydrocarbon, in the presence of an aprotic polar solvent such as the one described above at room temperature to about 100°C. It is synthesized by reacting at a temperature of . Examples of halogenated hydrocarbons include alkyl iodides such as methyl iodide, ethyl iodide, propyl iodide, butyl iodide, lauryl iodide, and corresponding alkyl bromides, benzyl iodide, benzyl bromide, and benzyl chloride. , allyl iodide, allyl bromide,
Allyl chloride etc. are used. The reaction of the tertiary amine addition salt with the S-hydrocarbon-substituted isothiourea or its acid salt is preferably carried out using an excess of the tertiary amine used in the formation of the addition salt, such as triethylamine, trimethylamine, pyridine, or the like, or a freshly added tertiary amine. In the presence of a catalyst such as a tertiary amine or a trisubstituted phosphine such as triphenylphosphine, tributylphosphine, or tricyclohexylphosphine, or a trisubstituted arsenic such as triphenylarsenic, in an aprotic polar solvent from room temperature to about 100% It is carried out at a temperature of °C. As a result of this reaction, an isothiourea derivative represented by the above formula [] is obtained, and this compound is heated to a temperature from room temperature to about 100°C in an aprotic polar solvent in the presence of the above tertiary amine catalyst. A ring-closing reaction occurs, and the new pyrimidine derivative represented by the above formula [] is converted to about 60% based on the starting material octafluoroisobutyl lower alkyl ether.
It is given with a good overall yield as above. The resulting new pyrimidine derivatives can be used as intermediates for the synthesis of 2-methylthio-4-di-lower alkylamino-5-trifluoromethyl-6-hydroxypyrimidines by reacting the 4-fluoro group with di-lower alkylamines. It can be used as a body. Next, the present invention will be explained with reference to examples. Example 1 Octafluoroisobutyl methyl ether 23.2
g (0.1 mol) in about 100 g of dimethylformamide, and while cooling this solution in an ice bath,
20.2 g (0.2 mol) of triethylamine was added dropwise thereto, and the temperature of the solution was raised from 0° C. to room temperature within 1 hour after the completion of the dropwise addition. Separately, 9.12 g (0.12 mol) of thiourea is dissolved in about 100 g of dimethylformamide, 21.3 g (0.15 mol) of methyl iodide is added to this solution, and the mixture is reacted at 80° C. for 3 hours. This thiourea-methyl iodide reaction solution was added dropwise to the triethylamine addition salt reaction solution, and the mixture was left to stand at room temperature for 3 hours. The reaction mixture was poured into water and the precipitated reaction product was filtered off and dried. 198.3g (yield 74%) of an intermediate reaction product believed to have the structural formula shown by the following formula was obtained. Melting point: 117.5-118.5℃ Mass spectrum: m/e = 268 (M ⁺ ) 1H-NMR: δ = 2.43 (CH ₃ ) 4.03 (sept.J = 7.9Hz) 3.15 9.48 (br) (NH) Obtained Intermediate reaction product 26.8g (0.1 mol)
Dissolved in about 200 g of dimethylformamide,
11.1 g (0.11 mol) of triethylamine was added to this, and the mixture was reacted at 70°C for 3 hours. After the reaction was completed, the reaction mixture was poured into water, and the precipitated reaction product was filtered out and dried. From the following characteristic values, 19.7g (yield 86.4%, total process yield 64%) of a reaction product believed to be 2-methylthio-4-fluoro-5-trifluoromethyl-6-hydroxypyrimidine was obtained. Ta. Melting point: 189-190°C Mass spectrum: m/e = 228 (M ⁺ ) 1H-NMR: δ = 2.57 (CH ₃ ) 12.47 (br) (OH) Examples 2-4 In Example 1, methyl iodide Instead, equivalent molar amounts of ethyl iodide, propyl iodide or butyl iodide were used to obtain pyrimidine derivatives having the corresponding 2-ethylthio, 2-propylthio or 2-butylthio groups, respectively. 【table】

Claims (1)

[Claims] 1. General formula A novel pyrimidine derivative represented by (wherein R is a hydrocarbon group). 2 General formula A general formula characterized by subjecting an isothiourea derivative represented by (herein, R is a hydrocarbon group) to a ring-closing reaction in the presence of a tertiary amine catalyst. (Here, R is a hydrocarbon group) A method for producing a novel pyrimidine derivative.