CH688149A5 - A method of synthesis of 1-alkyl-3-hydroxy-5-halo-1,2,4-triazoles and novel hydrazine. - Google Patents

Description

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CH 688 149 A5

Description

The present invention relates to a new process for the synthesis of 1-alkyl-3-hydroxy-5-halogenated-no-1,2,4-triazoles of general formula (I):

R

\

N N

I II

CC

/ \ / \

X N OH

in which R represents an alkyl group and X a halogen atom.

These compounds are important intermediates in the synthesis of pesticides, especially insecticides. The derivative for which R represents the isopropyl group and X chlorine is for example an intermediate in the synthesis of Isazofos, a pesticidal active material well known to those skilled in the art.

US Patent 3,992,398 describes the synthesis of 1-alkyl-3-hydroxy-5-chloro-1,2,4-triazoles by reaction of phosgene with a 1-alkyl-1-cyano-hydrazine obtained by reaction of a alkylhydrazine with cyanogen chloride. This route is currently widely used at the industrial stage.

US patent 4,006,157 describes the synthesis of 1-alkyl-3-hydroxy-5-halo-1,2,4-triazoles by reaction of an alkylhydrazine with dichloro-isocyano-N-carbonyl chloride, itself obtained by reaction of phosgene with cyanogen chloride.

The use in these processes of cyanogen chloride, a very toxic reagent, formerly used as combat gas, however has a very significant drawback and the person skilled in the art is constantly looking for a process which does not use this compound and is competitive with an economic point of view.

B. BÖHNER, D. DAWES and W. MEYER, in Kemia-Kemi, 1 (9), 585-9 (1974) describe the synthesis of 1-alkyl-3-hydroxy-5-chloro-1,2,4- triazoles by reaction of chlorine with a 1-alkyl-3-hydroxy-1,2,4-tria-zole, itself obtained by reaction of a 1-alkyl-2-carboxamide hydrazine with formic acid. This process however requires numerous unit operations making it very complicated. The yields are moreover not satisfactory and this process is economically unattractive for development at the industrial stage.

It has been discovered, unexpectedly, that 1-afkyl-3-hydroxy-5-halo-1,2,4-triazoles can be obtained, thanks in particular to the use of a particular catalyst, by reaction d 'a 1-alkyl-3,5-dioxo-1,2,4-triazole (also called 1-alkylurazole) with an ionic halogenating agent and that this ionic halogenation reaction is selective, it is to to say that it is carried out very preferentially-on the carbonyl function located in alpha of the nitrogen atom substituted by the alkyl group.

The 1-alkylurazoles, which are known compounds, can be obtained from alkylhydrazines by methods which disregard cyanogen halides. US Patent 3,663,564 describes for example the synthesis of 1-isopropylurazole by reaction of isopropylhydrazine with diethylimidodi-carboxylate.

In addition, it has been discovered that 1-isopropylurazole can be obtained from isopropylhydrazine by two preparation methods which are much more economical than known methods, thanks to the synthesis of new intermediate compounds, namely 1-isopropyl-1. -carboxamide hydrazine and the alkyl 2-isopropyl-2-carboxamide carbazates.

Much more economical methods of synthesizing 1-isopropyl-3-hydroxy-5-halo-1,2,4-triazoles are thus obtained from isopropylhydrazine, using no cyanogen halides as reagent.

The present invention therefore relates to a new process for the synthesis of 1-alkyl-3-hydroxy-5-halo-1,2,4-triazoles. This process is characterized in that a 1-alkyl-3,5-dioxo-1,2,4-triazole is reacted with a halogenating agent of ionic type, in the presence of a nitrogen catalyst chosen from the group consisting of tertiary amines, the halohydrates of these tertiary amines, in particular the hydrochlorides and hydrobromides, heterocyclic amines, the halohydrates of these heterocyclic amines, in particular the hydrochlorides and hydrobromides, and the N, N-disubstituted amides.

The tertiary amines can be aliphatic, for example triethylamine, or aromatic, for example N, N-dimethylaniline. They can also include one or more non-aromatic rings, such as a cyclohexyl or cyclopentyl ring, directly or not linked to the nitrogen atom of the amine.

The term “heterocyclic” amine is conventionally understood to mean an amine in which the nitrogen atom is one of the vertices constituting the cycle, at least one other vertex of the cycle not being another nitrogen atom. This cycle can be aromatic, for example pyridine, or non-aromatic, for example N-methylmorpholine. The other vertices of the cycle may include at least one carbon atom and / or other heteroatoms, as is the case for N-methylmorpholine.

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CH 688 149 A5

Examples of heterocyclic amines that may be mentioned include pyridines, for example pyridine and 4-dimethylaminopyridine, picolines, in particular 5-ethyl-a-picoline, quinolines, N-substituted imidazoles, N-substituted pyrroles , N-substituted morpholines.

As examples of N, N-disubstituted amides, mention may be made of N, N-dialkylamides, in particular N, N-dialkylformamides such as N, N-dimethylformamide (DMF) and N, N-dialkylacetamides. In general, the substituents can be aliphatic, cycloaliphatic, aromatic or even form a ring. The reaction scheme of the process according to the invention is as follows:

RH R

\ / \

N - N halogenating agent N - N

| | ionic type | [[

C C> C C

Jf \ / \ nitrogen catalyst / \ / \

ONO X N OH

I

H

R and X having the above meaning.

In the context of the present invention, the term “halogenating agent of the ionic type” is intended to mean an agent capable of creating a carbon-halogen bond in an organic molecule according to an ionic reaction. These halogenating agents of the ionic type are opposed to the halogenating agents of the radical type, such as for example N-chloro (or bromo) succinimide, which also make it possible to create a carbon-halogen bond, but according to a reaction involving free radicals and not ions. Halogenating agents of the ionic type are well known to those skilled in the art. Examples of such agents include POCb, POBr3, SOCI2, PCI5, SOBr2, PBrs.

Preferably, the molar ratio between the nitrogen catalyst and the 1-alkylurazole is between 0.001 and 0.5.

Also preferably, the halogenating agent of the ionic type is a chlorinating agent, preferably POCI3, which makes it possible to obtain 1-alkyl-3-hydroxy-5-chloro-1,2,4-triazoles, or else another brominating agent, which makes it possible to obtain 1-alkyl-3-hydroxy-5-bromo-1,2,4-triazoles.

A strong excess of halogenating agent of the ionic type is preferably used when this makes it possible to avoid the use of an organic solvent. When necessary, especially when the medium is very viscous and therefore difficult to stir, an inert solvent can be used, preferably with a high boiling point chosen from aromatic solvents such as toluene, chlorobenzene, xylenes , ethylbenzene, orthodichlorobenzene, 1,2,3-trichlorobenzene.

When operating in the presence of an organic solvent, the molar ratio between the halogenating agent of the ionic type and the 1-alkylurazole is preferably between 1 and 3.

The reaction temperature is generally between 90 ° C and 250 ° C, preferably between 140 ° C and 200 ° C.

According to another preferred variant of the invention, the 1-alkyl chain of 1-alkyl-3,5-dioxo-1,2,4-triazole, and therefore the 1-alkyl chain of 1-alkyl-3-hydroxy- 5-halo-1,2,4-triazole obtained is a linear, cyclic or branched chain, comprising 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

In a particularly preferred manner, this chain is the isopropyl group.

According to a particularly preferred variant of the invention, 1-isopropyl-3-hydroxy-5-chloro-1,2,4-triazole is synthesized by reaction of 1-isopropyl-3,5-dioxo-1,2,4 -triazole with a chlorinating agent of ionic type, preferably POCI3. In the context of this particularly preferred variant, it is possible to synthesize 1-isopropylurazole according to known methods, which do not use cyanogen chloride. These methods are however relatively expensive. Two particularly economical new ways of synthesizing 1-isopropyl-3,5-dioxo-1,2,4-triazole from isopropylhydrazine have been discovered, which ultimately makes it possible to obtain 1-isopropyl-3-hydroxy. -5-chloro-1,2,4-triazole from isopropylhydrazine according to economically very advantageous processes, which can be industrialized and which avoid the use of cyanogen chloride.

The first route, which is preferred because the simplest and most economical, consists in obtaining 1-isopropyl-3,5-dioxo-1,2,4-triazole by phosgenation of 1-isopropyl-1-carboxamide hydrazine of for-

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CH 688 149 A5

CH3 O

\ //

mule ^ ^ 2 * This compound is a new compound, capable of ch3 nh2

example be obtained by reaction of sodium or potassium cyanate with isopropylhydrazine.

It should be remembered that cyanates, unlike cyanides and cyanogen halides, are not toxic.

The second route consists in obtaining 1-isopropyl-3,5-dioxo-1,2,4-triazole by cyclization, in basic medium, of an alkyl 2-isopropyl-2-carboxamide carbazate, for example methyl or ethyl. The alkyl 2-isopropyl-2-carboxamide carbazates, of general formula

CH3

\

ch o

/ \

CH3 N - NH - C

/ \ C = O O - alkyl

I

nh2

are new compounds which can, for example, be obtained by reaction of sodium cyanate with an alkyl 2-isopropylcarbazate, a known derivative easily accessible from isopropylhydrazine.

It is therefore only through the synthesis of new hydrazine derivatives, namely 1-isopropyl-1-carboxamide hydrazine and 2-isopropyl-2-carboxamide alkyl carbazates, that it has been possible to obtaining 1-isopropyl-3-hydroxy-5-chloro-1,2,4-triazole from isopropylhydrazine according to economically very advantageous processes, which can be industrialized and which do not use cyanogen chloride.

The present invention therefore also relates to 1-isopropyl-1-carboxamide hydrazine and the 2-isopropyl-2-carboxamide carbazates of alkyl, in particular that of methyl and that of ethyl.

The following nonlimiting examples illustrate the invention and the advantages which it provides.

Example 1

Synthesis of methyl 2-isopropyl-2-carboxamide carbazate.

To 10 g (76 mmol) of methyl 2-isopropylcarbazate, 8.5 g of water and 21.2 g of methanol are added. 2.2 ml of concentrated sulfuric acid are then poured in at 7 ° C. and the reaction medium is left under stirring at approximately 20 ° C. for 1 h. 5.1 g (79 mmol) of sodium cyanate are then added slowly, then the medium is left to stir at 20 ° C. for approximately 10 h. After removing the salts formed by filtration, the reaction medium is concentrated by evaporation under reduced pressure, then the product obtained is recrystallized from methanol.

11.3 g of methyl 2-isopropyl-2-carboxamide carbazate are thus collected (yield 85%), solid product identified by IR, 1 H NMR and mass spectrometries, the melting point of which is 161 ° C.

Example 2

Synthesis of ethyl 2-isopropyl-2-carboxamide carbazate.

To 50 g (343 mmol) of ethyl 2-isopropyl carbazate, 39 g of water and 80 g of ethanol are added. Then poured, at 5 ° C, 10.5 ml of concentrated sulfuric acid and then the reaction medium is allowed to stir at approximately 20 ° C for 1 h. 25.7 g (395 mmol) of sodium cyanate are then added slowly, then the medium is left to stir between 20 ° C and 75 ° C for about 10 h. After filtration of the salts formed, the reaction medium is concentrated by evaporation under reduced pressure, then the product obtained is recrystallized from ethanol.

36.3 g are thus collected (yield 73%) of ethyl 2-isopropyl-2-carboxamide carbazate, solid product identified by IR spectrometry, 1 H NMR and of 2 mass, the melting point of which is 185-187 ° C. .

Example 3

Synthesis of 1-isopropyl-3,5-dioxo-1,2,4-triazole (or 1-isopropylurazole) from methyl 2-isopropyl-2-car-boxamide carbazate.

17.5 g (0.1 mol) of 2-iso are introduced into 20 ml of a 4N aqueous solution of potassium hydroxide at 20 ° C.

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CH 688 149 A5

methyl propyl-2-carboxamide carbazate obtained according to Example 1. The reaction medium is brought to 95 ° C. and then this temperature is maintained for 40 min.

The medium is then neutralized, at 20 ° C., with a 12N aqueous hydrochloric acid solution. After concentration of the medium by evaporation under reduced pressure and heating to approximately 50 ° C., the desired product is extracted with methanol.

Cooling the methanolic phase to 0 ° C. makes it possible to collect, by precipitation, 11.2 g (78% yield) of 1-isopropylurazole, solid product identified by IR, 1 H NMR and mass spectrometries, the melting point of which is 186 ° C.

Example 4

Synthesis of 1-tsopropyl-3-hydroxy-5-chloro-1,2,4-triazole in an organic solvent medium and in the presence of 5-ethyl-a-picoline as catalyst.

1.05 g (7.1 mmol) of 1-isopropylurazole obtained according to Example 3 are mixed at approximately 20 ° C., 21.3 g (0.14 mol) of POCb, 0.2 g (1, 6 mmol) of 5-ethyl-a-picoline and 80 g of orthodichlorobenzene. The reaction medium is heated for 24 h between 160 and 170 ° C., then the desired product is isolated by chromatography on a silica column with elution with dichloromethane.

0.30 g is thus collected (26% yield) of 1-isopropyl-3-hydroxy-5-chloro-1,2,4-triazole, solid compound identified by 1 H NMR, 13 C NMR and mass spectrometries, the point of which melting point is 105.5 ° C.

Furthermore, a search for 1-isopropyl-3-chloro-5-hydroxy-1,2,4-triazole in the reaction medium was found to be negative.

In parallel with this example 4 according to the invention, a comparative example was carried out without 5-ethyl-a-picoline, all other conditions strictly identical elsewhere. It is found that the reaction medium does not contain 1-isopropyl-3-hydroxy-5-chloro-1,2,4-triazole. This comparative example, which is not part of the invention, clearly highlights the need for the presence of the nitrogen catalyst.

Example 5

Synthesis of 1-isopropyl-1-carboxamide hydrazine.

To 251 g of an aqueous solution of isopropylhydrazine at 15.1% (i.e. 51.2 mmol of isopropylhydrazine) cooled to 0 ° C., is added dropwise, while maintaining the temperature at 0 ° C., 2.87 g (28.2 mmol) of concentrated sulfuric acid then 3.56 g (54.7 mmol) of sodium cyanate.

The reaction medium is kept under stirring at approximately 20 ° C for 14 h, then filtered. The liquid phase resulting from filtration by evaporation under reduced pressure is then concentrated, then the product obtained is recrystallized from ethanol.

4.1 g (yield 69%) of 1-isopropyl-1-carboxamide hydrazine, a white solid compound identified by IR, 1 H NMR, 13 C NMR and mass spectrometry, are thus obtained.

Example 6

Synthesis of 1-isopropylurazole from 1-isopropyl-1-carboxamide hydrazine.

1.1 g (27.5 mmol) of magnesium oxide and 3 g (25.6 mmol) of 1-isopropyl-1-carboxamide hydrazine obtained according to Example 5 are suspended in 50 ml of toluene. Cool to 0 ° C and then add, at 0 ° C, 5.15 g (52 mmol) of phosgene gas. The mixture is heated to 35 ° C., then after removal of the excess phosgene, the medium is concentrated by evaporation under reduced pressure. The desired product is then isolated by chromatography on a silica column with elution with a methanol-chloroform mixture, respectively 1/9 by volume.

1.8 g (50% yield) of 1-isopropylurazole are thus obtained, a solid product identified by IR, 1 H NMR and mass spectrometries, the melting point of which is 184 ° C.

Example 7

Synthesis of 1-isopropyl-3-hydroxy-5-chloro-1,2,4-triazole in an organic solvent medium and in the presence of 5-ethyl-a-picoline as catalyst.

1.05 g (7.1 mmol) of 1-isopropylurazole obtained according to Example 6, 3.15 g (14 ml) of POCI3, 0.1 g (0.8 mmol) are mixed at approximately 20 ° C. ) of 5-ethyl-a-picoline and 50 g of orthodichlorobenzene. The reaction medium is heated for 36 h between 160 ° C. and 170 ° C., then the desired product is isolated by chromatography on a silica column with elution with dichloromethane.

0.25 g is thus collected (yield 21.5%) of 1-isopropyl-3-hydroxy-5-chloro-1,2,4-triazole, identified by IR spectrometry, 1 H NMR, 13 C NMR and mass, including the melting point is 105 ° C.

Claims (1)

Claims 1. Process for the synthesis of 1-alkyl-3-hydroxy-5-halo-1,2,4-triazoles characterized in that a 1-alkyl-3,5-dioxo-1,2,4- is reacted triazole with an ionic halogenating agent, in the presence of a 5 5 10 15 20 25 30 35 40 45 50 55 60 65 CH 688 149 A5 nitrogen catalyst chosen from the group consisting of tertiary amines and their halohydrates, heterocyclic amines and their halohydrates and by N, N-disubstituted amides. 2. Synthesis process according to claim 1, characterized in that the nitrogen catalyst is chosen from the group consisting of tertiary amines, heterocyclic amines and N, N-di-substituted amides. 3. Synthesis process according to any one of the preceding claims, characterized in that the heterocyclic amines are aromatic heterocyclic amines. 4. Synthesis process according to claim 3, characterized in that the aromatic heterocyclic amines are pyridines. 5. Synthesis process according to any one of the preceding claims, characterized in that the nitrogen catalyst is 5-ethyl-a-picoline. 6. Synthesis process according to any one of the preceding claims, characterized in that the ionic-type halogenating agent is a chlorinating agent or a brominating agent, preferably POCh. 7. Synthesis process according to any one of the preceding claims, characterized in that the 1-alkyl group contains 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. 8. Synthesis process according to any one of the preceding claims, characterized in that the reaction temperature is between 90 ° C and 250 ° C. 9. Synthesis process according to any one of the preceding claims, characterized in that an excess of halogenating agent of the ionic type is used. 10. Synthesis process according to any one of the preceding claims, characterized in that between 0.1% and 50 mol% of nitrogenous catalyst are used relative to 1-alkyl-3,5-dioxo-1,2, 4-tria-zole. 11. Synthesis process according to any one of the preceding claims, characterized in that 1-isopropyl-3-hydroxy-5-chloro-1,2,4-triazole is synthesized by reaction of 1-isopropyl-3, 5-dioxo-1,2,4-triazole with an ionic-type chlorinating agent. 12. Process for the synthesis of 1-isopropyl-3-hydroxy-5-chloro-1,2,4-triazole, characterized in that 1-isopropyl-3,5-dioxo-1,2,4- is prepared triazole by cyclization in basic medium of an alkyl 2-isopropyl-2-car-boxamide carbazate, then that the product thus prepared is transformed into 1-isopropyl-3-hydroxy-5-chloro-1,2,4 -triazole by the process as defined in claim 1. 13. Process for the synthesis of 1-isopropyl-3-hydroxy-5-chloro-1,2,4-triazole, characterized in that 1-isopropyl-3,5-dioxo-1,2,4- is prepared triazole by phosgenation of 1-isopropyl-1-carboxamide hydrazine, then the product thus prepared is transformed into 1-isopropyl-3-hydroxy-5-chloro-1,2,4-triazole by the process as defined in claim 1. 14. 1-isopropyl-1-carboxamide hydrazine for carrying out the process according to claim 13. 15. 2-isopropyl-2-carboxamide alkyl carbazates for carrying out the process according to claim 12. 6