JP2973497B2 - Method for producing N-nitroisothiourea derivative - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel method for producing an N-nitroisothiourea derivative useful as an agricultural chemical or as an intermediate for medicines and agricultural chemicals.

[Prior art] Journal of Medicinal Chemisty 20 , 901 (1977) discloses that, as shown in formula [A], monomethyl sulfate of N, S-dimethylisothiourea is reacted with fuming nitric acid in concentrated sulfuric acid. A process for the production of N, S-dimethyl-N'-nitroisothiourea is described.

However, the above literature does not describe the yield, and when a supplementary test was conducted, it was found that the target product could be obtained only in an extremely low yield.

[Problems to be solved by the invention]

An object of the present invention is to produce an N-nitroisothiourea derivative more efficiently than the conventional method by using a novel production method comprising reacting N-nitroimidodithiocarbonates and amines. .

[Means for Solving the Problems] Structure of the Invention The production method of the present invention has the following structure.

General formula [I] (Wherein, R has the same meaning as described above).
Nitroimidodithiocarbonates and general formula (II) (Wherein, R ₁ and R ₂ have the same meanings as described above).
I] (Wherein, R, R ₁ and R ₂ have the same meanings as described above).

Detailed description a. Definition of terms A heterocycle is a 5- or 6-membered ring compound containing a nitrogen atom, and may be further substituted with a halogen group such as chloro or bromo or an alkyl group such as methyl or ethyl. is there.

B. Production raw material General formula [I] (In the formula, R represents an alkyl group.) Examples of the N-nitroimidodithiocarbonates represented by the formula (1) include dimethyl N-nitroimidodithiocarbonate and diethyl ester. 2-
It can be easily obtained according to the method of 186108.

General formula (II) (Wherein, R ₁ and R ₂ each represent a hydrogen atom, an alkyl group or an alkyl group substituted with a heterocyclic ring, except that both R ₁ and R ₂ are hydrogen atoms). Examples of amines include methylamine, ethylamine, isopropylamine, 2-chloro-5-pyridylmethylamine, 2-chloro-5-thiazoylmethylamine, 1- (2-chloro-5-pyridyl) ethylamine and the like. Primary amines or dimethylamine, diethylamine, N- (2-chloro-5-pyridylmethyl) -N
-Methylamine and secondary amines such as N- (2-chloro-5-thiazoylmethyl) -N-methylamine. These compounds may be used, if necessary, in the new experimental chemistry course, Vol. 14, [III] p. It can be synthesized by the method described in 1332-1399.

The amount of the amines used is 1 to 1.5 times, preferably 1 to 1.2 times the mol of the compound represented by the general formula [I]. Promotes undesirable.

C. Solvents are not particularly limited as long as they are inert to the reaction reagents. Examples thereof include halogen-based solvents such as chloroform and methylene chloride, alcohol-based solvents such as methanol and ethanol, and aromatic solvents such as toluene and chlorobenzene. Group solvents.

The amount of the solvent used is desirably such that the compound represented by the general formula [I] dissolves under the reaction conditions used.

D. The reaction temperature is in the range of −30 ° C. to the boiling point of the solvent used, and generally the reaction proceeds sufficiently at a temperature around room temperature, which does not require a heating and cooling device.

E. After completion of the post-treatment reaction, the precipitated target crystals are collected by filtration,
Alternatively, after removing the reaction solvent, the residue is subjected to a post-treatment using a general method such as recrystallization or column chromatography, whereby a high-purity target compound can be obtained.

F. Existence of isomer The target product represented by the general formula [III] includes a syn-anti isomer. When _one of R ₁ and R ₂ is a hydrogen atom, the following tautomers exist.

[Examples] Hereinafter, the present invention will be described with reference to Examples, but the present invention is not limited thereto.

Example 1 N, S-dimethyl-N'-nitroisothiourea N-nitroimidodithiocarbonic acid dimethyl ester 2.49 g
(15 mmol) was dissolved in 15 ml of chlorobenzene, and under stirring, 1.18 g (15.2 mmol) of a 40% methanol solution of methylamine was added dropwise at 21 to 24 ° C over 7 minutes.

The reaction solution was stirred at room temperature for 2 hours, and the precipitated crystals were collected by filtration, washed with 5 ml of chlorobenzene, and dried to obtain 1.94 g of the target crystals. As a result of analysis by high performance liquid chromatography, the purity was 98.1%. Net yield 85.1%.

Example 2 N, S-dimethyl-N'-nitroisothiourea 2.49 g of dimethyl N-nitroimidodithiocarbonate
(15 mmol) was dissolved in 10 ml of chloroform.
1.16 g of methanol solution of 15% methylamine (15 mmol)
Was added dropwise at 24 to 26 ° C over 10 minutes.

After stirring at room temperature for 2 hours, the precipitated crystals were collected by filtration, washed with 2 ml of chloroform, and dried to obtain 1.81 g of the desired crystals. As a result of analysis by high performance liquid chromatography,
Purity was 98.6%. 79.9% net yield. Melting point 149-15
1.5 ° C.

Example 3 N- (2-chloro-5-pyridylmethyl) -S-methyl-N'-nitroisothiourea 2.49 g (15 mmol) of N-nitroimide carbonic acid dimethyl ester was dissolved in 10 ml of chloroform, and a solution composed of 2.20 g (15.4 mmol) of 2-chloro-5-pyridylmethylamine and 2 ml of chloroform was stirred at 21 to 24 ° C. 1
It was added dropwise over 2 minutes.

On the way, 3 ml of chloroform was added, and after stirring at room temperature for 2.5 hours, 5 ml of chloroform was further added. The precipitated crystals were collected by filtration, washed with 5 ml of cold chloroform, and dried to obtain 3.49 g of crystals of the target compound. As a result of analysis by high performance liquid chromatography, the purity was 98.9%. Net yield 88.3%. 142.5-144 ° C.

Comparative Example 1 N, S-dimethyl-N'-nitroisothiourea N, S-dimethylisothiourea monomethyl sulfate 1
0.8 g (50 mmol) of 45 ml of concentrated sulfuric acid and fuming nitric acid (d = 1.5
2) In a mixed acid made from 15 ml at -20 ° C, with stirring
Over 5 minutes and stirred at the same temperature for 5 minutes.
Dried to 0ml.

The precipitated crystals were collected by filtration, washed with water, and dried to obtain 0.53 g of the target crystals. Yield 7.1%.

〔The invention's effect〕

As is apparent from a comparison between Example 1 or Example 2 based on the production method of the present invention and Comparative Example 1 based on the conventional production method, the target N-
The yield of the nitroisothiourea derivative was greatly improved.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁶ , DB name) C07C 335/00 C07D 213/00 REGISTRY (STN) CA (STN)

Claims (1)

(57) [Claims] 1. A compound of the formula [I] (Wherein R represents an alkyl group) and an N-nitroimidodithiocarbonate represented by the general formula [II]: (Wherein, R ₁ and R ₂ each represent a hydrogen atom, an alkyl group or an alkyl group substituted with a heterocyclic ring, except that both R ₁ and R ₂ are hydrogen atoms). General formula [III] characterized by reacting with an amine (Wherein, R, R ₁ and R ₂ have the same meanings as described above).