RO107654B1 - Preparation process for an amide derivate - Google Patents

Description

The invention relates to a process for the preparation of an amide derivative of general formula I:

wherein one of X and Y represents a sulfur atom, and the other represents a carbon atom, each of R, and R ₂ represents a hydrogen atom, a halogen atom, an alkyl group having from 1 to 6 carbon atoms. carbon, a halomethyl group or a phenyl group, and R represents an alkoxy group having from 1 to 4 carbon atoms, an alkylthio group having from 1 to 4 carbon atoms, an alkynyloxy group having from 3 to 5 atoms. of carbon, an alkynylthio group having from 3 to 5 carbon atoms, or a pyrazolyl group.

Processes for the preparation of some amido derivatives of the general formula are known:

R, C - N CH - XRo

Hi ii ³

OR ₂ E wherein R, is phenyl, optionally substituted by halogen, alkyl. alkoxy, haloalkoxy, methylenedioxy, alkylthio. or cyano, R, is hydrogen. alkyl. alkenyl, X is oxygen or sulfur, R. is alkyl. haloalkyl or alkenyl and E is CN (US Patent No. 4447446).

The object of the invention is to extend the range of the amide derivatives of formula I above.

The problem to be solved by the invention is to determine the optimum reaction conditions for the above compounds.

The process according to the invention. It removes the disadvantages above. by halogenating the N-cyanomethylcarboxylic acid amide represented by general formula II:

^R VSZ ^R2 _Y pitch - CONHCH ₂ where X, Y, R, and R ₂ are those defined above to form an intermediate represented by formula III:

^r \ AZ ^R2 yC> | --- conhch.cn ^<nl) V ^Let X, Y, and R, and R, be those defined above, and Hal represents a halogen atom, and then the reaction of of the compound of general formula III, with a compound represented by general formula IV:

HR, (IV) wherein R, is the one defined above. in an inert solvent selected from aliphatic halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,4-dichloroethane; aliphatic carboxylic acid esters, such as methyl acetate, ethyl acetate, isopropylacetate and ethylpropionate, in the presence of a base selected from the group containing an organic base, such as triethylamine and dimethylaniline, at a temperature between 10 and 50 ° C.

The following are examples of embodiments of the invention.

Example 1. Synthesis of N [alpha-cyano-alpha (1-pyrazolyl) -methyl / -3-methylisothiazole-5-like rboxylic acid amide.

0.7 g of N-cyanomethyl) -3-methylisothiazole-5-carboxylic acid amide were dissolved in 30 ml of ethyl acetate. Bromine 0.8 g was added and the mixture was stirred for .30 min and then cooled in an ice bath. A mixture of 0.3 g pyrazole was added. 1.0 g of triethylamine and 5 ml of ethyl acetate in the reaction mixture with stirring. The mixture was stirred for 30 min. The ethyl acetate layer was washed with water and distilled under low pressure to remove the solvent. The residue was removed by silica gel column chromatography. Elution with ethyl acetate / benzene gave 0.75 g (78% yield) of the N - [tz // a-cyano-a // a- (1-pyrazolyl) -methyl] -3-methylisothiazole-5- acid amide. desired carboxylic acid.

Example 2. Synthesis of N [alpha-cyano-α-((-pyrazolyl) -methyl] -2,4-dimethylthiazole-5-carboxylic acid amide)

Synthesis of N-cyanomethyl 2,4-dimethylthiazole-5-carboxylic acid amide.

A mixture of 10 g of 2,4-dimethylthiazole-5-carboxylic acid, 13.6 g of thionyl chloride and 70 ml of toluene was cooled with ice and 8.4 g of N, N-dimethylformamide was added with stirring. The mixture was stirred for 3 h, at 5 ° C and for one hour at 20 C and 200 ml of toluene and 37 g of triethylamine were added. A solution of aminoacetonitrile ethyl acetate, prepared from aminoacetonitrile sulfate, using ethyl acetate and NaOH was gradually added to the reaction mixture being cooled with water. The mixture was stirred at room temperature for lh. The reaction mixture was poured with water and extracted with ethyl acetate. The ethyl acetate treatment was washed with water, dried and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography. Elution with ethyl acetate / hexane gave 6.6 g (53% yield) of amide N-cyanoethyl acid I-2,4-dimethyl and 1 thiazole-5-carboxylic acid.

Synthesis of N- [alpha-cyano-alpha- (1-pyrazol.olyl) -methyl] -2.4-dimethylthiazole-5-carboxyHc acid amide

1.0 g of N-cyanomethyl-2,4-dimethylthiazole 5-carboxylic acid amide was dissolved in 30 ml of ethyl acetate. Bromine (0.3 ml) was added and the mixture was refluxed until the dark brown color of the bromine disappeared. The reaction mixture was cooled on ice bath and 0.5 g of pyrazole, 2.0 g of triethylamine and 10 ml of ethyl acetate were added at the above temperature. The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate.

The ethyl acetate layer was washed with water, dried and distilled under low pressure to remove the solvent. The residue a was purified by silica gel column chromatography. Elution with ethyl acetate / hexane gave

0.74 g (54.0% yield) of N- (alpha-cyanoalpha-1-pyrazolyl) -ethyl 1J - 2,4-dimethylthiazole-5-carboxylic acid amide.

Example 3. Synthesis of N- (alpha-cyano15 alpha-ethoxymethyl) -2,4-dimethylthiazole-5-carboxylic acid amide

1.0 g of N-cyanomethyl-2,4-dimethylthiazole-5-carboxylic acid amide were dissolved in 30 ml of ethyl acetate. The 0.3 ml bromine was added and the mixture was heated under reflux until the bromine color was gone. The reaction mixture was cooled in an ice bath and 1.0 g ethanol, 2.0 g triethylamine and 10 ml 25 ethyl acetate were added at the above temperature.

The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with 30 water, dried and distilled at low pressure to remove the solvent. The residue was purified by silica gel column chromatography. Elution with hexane / ethyl acetate gave 0.53 g (43.1% yield) of the desired N- (α-cyano-cyano35 <z // d-ethoxymethyl) -2.4-dimethylthiazole-5-carboxylic acid amide.

As is apparent from the invention, treating N-cyanomethyl-carboxy II amide with a halogenating agent in a suitable solvent 40 gives an N-bromsuccinimide. Examples of solvents are aliphatic halogenated hydrocarbons. such as dichloromethane. chloroform, carbon tetrachloride and 1,4-dichloroethane and aliphatic carboxylic acid esters such as methyl acetate. ethyl acetate. isopropyl acetate and ethyl propionate. The reaction temperature is from 20 to 80 ° C, preferably from 30 to 50 ° C. This reaction can be carried out in an inert gas atmosphere. As the halogenation intermediate III is unstable, it reacts immediately with HR, 5

IV. This reaction is carried out in the presence of an acid acceptor. Examples of acid acceptors are tertiary amines, such as triethylamine and dimethylaniline, although they are not limiting. Desirably this reaction is carried out in a solvent or diluent. It is desirable to avoid the high temperatures when carrying out this reaction, because the thermal stability of the intermediate is low. Desirable is achieved with cooling, because it is exothermic. The desired amide derivative II can be purified in the usual way by recrystallization, column chromatography.

The invention has advantages in that it performs a process for the preparation of compounds having important herbicidal properties.

Claims (1)

Claim 25 Process for preparing an amide derivative of general formula I: X ^CN m ³⁰ XOj - CONHCH < _R3 wherein one of X and Y represents a sulfur atom, and the other represents a carbon atom, each of R, and R ₂ represents a hydrogen atom, a halogen atom. an alkyl group having from I to 6 carbon atoms, a halomethyl group or a phenyl group. and R _; represents a 40 alkoxy group having from 1 to 4 carbon atoms, an alkylthio group having from 1 to 4 carbon atoms, an alkynyl oxy group having from 3 to 5 carbon atoms, an alkynylthio group having from 5 to 8 carbon atoms, or a pyrazoyl group, characterized in that it comprises halogenation of the N-cyanomethyl-carboxylic acid amide represented by general formula II: wherein X, Y, R, and R are those defined above to form an intermediate represented by formula III. conhch.cn Hal (III) wherein XY R, and R ₂ are those defined above, and Hal represents a halogen atom and then reacting the compound of general formula III with a compound represented by general formula IV: HR, (IV) wherein R, is as defined above, in an inert solvent selected from aliphatic halogenated hydrocarbons, such as dichloromethane. chloroform, carbon tetrachloride and 1,4-dichloroethanol; esters of aliphatic carboxylic acids, such as methyl acetate, ethyl acetate. isopropylacetate and ethylpropionate. in the presence of a base selected from the group containing an organic base, such as trimethylamine and dimethylaniline. at a temperature between 10 and 50C.