JPH032146B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel isothiourea derivative and a method for producing the same. More specifically, the present invention relates to a novel isothiourea 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.
For example, actively utilize the fact that alcohol adducts such as methanol, ethanol, n-propanol, isopropanol, and n-butanol are preserved, and use the alcohol adduct itself as a starting material, or preferably use the alcohol adduct as a starting material. Using the dehydrofluorinated product of pyrimidine easily obtained by contacting it with a base as a starting material, we succeeded in leading to a useful new pyrimidine derivative as shown by the general formula below (Chemical Society of Japan 47th Spring Annual Meeting). Proceedings of the conference, page 726). (R: lower alkyl group) Such novel pyrimidine derivatives can be used in medicines such as anti-seed agents, agricultural chemicals such as herbicides, etc. due to the unique physiological activity of fluorine-containing organic compounds. , it is desired to convert the 6-lower alkoxy group into a hydroxyl group in order to further introduce substituents therein that increase the affinity with living organisms. 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. The present invention relates to novel isothiourea derivatives used as intermediates in the synthesis of such novel pyrimidine derivatives. That is, the novel isothiourea derivative according to the present invention has the general formula (Here, R is a lower alkyl group.) The present invention also relates to a method for producing such a novel isothiourea derivative, and the production of the isothiourea derivative comprises:
Tertiary amine addition salt of octafluoroisobutyl lower alkyl ether and s-[lower alkyl]
This is carried out by reacting a substituted isothiourea or its acid salt. Synthesis of a novel pyrimidine derivative using such a novel isothiourea derivative as an intermediate is carried out through the following reaction steps. Octafluoroisobutyl lower alkyl ether, which is the starting material, is obtained as a lower alcohol adduct of octafluoroisobutene as described above, and is converted into an alkali metal or alkaline earth metal hydroxide in the presence of a phase transfer catalyst. Alternatively, it can be easily converted to 1-lower alkoxyperfluoroisobutene by stirring with a carbonate or a base such as a trialkylamine, followed by flash distillation and conventional distillation. 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. Instead of using lower alkoxy perfluoroisobutene as a starting material, a third compound with a molar ratio of 2 or more is added to octafluoroisobutyl lower alkyl ether.
Preferably, the tertiary amine addition salt is formed directly using an amine. 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-lower alkyl-substituted isothiourea or its acid salt is a combination of thiourea and halogenated hydrocarbon,
Preferably, the iodinated hydrocarbon is heated from room temperature to about
It is synthesized by reacting at a temperature of °C. As the halogenated hydrocarbon, lower alkyl iodides such as methyl iodide, ethyl iodide, propyl iodide, butyl iodide, and corresponding lower alkyl bromides are used. The reaction between the tertiary amine addition salt and the S-lower alkyl-substituted isothiourea or its acid salt is preferably carried out using an excess of the tertiary amine addition salt used in the formation of the addition salt, such as triethylamine, trimethylamine, pyridine, etc.
In the presence of an amine or a newly added tertiary amine, or a catalyst such as a trisubstituted phosphine such as triphenylphosphine, tributylphosphine, tricyclohexylphosphine, trisubstituted arsenic such as triphenylarsenic, aprotic polar It is carried out in a solvent at a temperature of room temperature to about 100°C. As a result of this reaction, an isothiourea derivative represented by the above general formula is obtained. When heated to a temperature of about 100°C, a ring-closing reaction occurs, and the novel pyrimidine derivative represented by the above formula [] is produced with a good overall yield of about 60% or more based on the starting material octafluoroisobutyl lower alkyl ether. give. 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. 198.3 g (yield: 74%) of an isothiourea derivative believed to have the structural formula shown by the following formula was obtained. [Molecular weight 268] Melting point: 117.5-118.5℃ Mass spectrum: m/e = 268 (M ⁺ ) ¹ H-NMR: δ = 2.43 (CH ₃ ) 4.03 (sept.J = 7.9Hz) 3.15 9.48 (br) (NH) Examples 2 to 4 In Example 1, the reaction was carried out using another alkyl iodide instead of methyl iodide to obtain an isothiourea derivative having a corresponding alkylthio group. Its yield and characteristic values are shown in the following table.

[Table] Reference example 26.8g of isothiourea derivative obtained in Example 1
(0.1 mole) was dissolved in about 200 g of dimethylformamide, and 11.1 g (0.11 mole) of triethylamine was dissolved in about 200 g of dimethylformamide.
mol) was added and 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 ⁺ ) ¹ H-NMR: δ = 2.57 (CH ₃ ) 12.47 (br) (OH)

Claims (1)

[Claims] 1. General formula (wherein R is a lower alkyl group). 2 General formula characterized by reacting a tertiary amine addition salt of octafluoroisobutyl lower alkyl ether and an S-lower alkyl-substituted isothiourea or an acid salt thereof (Here, R is a lower alkyl group.) A method for producing an isothiourea derivative represented by: 3. The method for producing an isothiourea derivative according to claim 2, wherein the reaction is carried out in the presence of an aprotic polar solvent.