Technical Field

The present invention relates to the synthesis of 4-aryl-1 ,2,4-triazolidine-

3,5-diones, particularly of 4-phenyl-1 , 2, 4-triazolidine-3,5-dione (= 4-phenylurazol), and 4-aryl-1 ,2,4-triazoline-3,5-dione, particularly of 4-phenyl-1 ^^-triazoline-S.S- dione (PTAD). Background of the invention

4-phenyl-1 ,2,4-triazoline-3,5-dione (PTAD) is one of the strongest dieno- philes and reacts rapidly with dienes in Diels-Alder reactions. Diels-Alder reaction is one of the most prominent chemical addition reaction. Hence, this substance is of great industrial importance. Any improvement of the process of its

manufacturing is of great importance.

Beside 4-phenyl-1 ,2,4-triazoline-3,5-dione, also some variants of this substance, particularly 4-aryl-1 ,2,4-triazoline-3,5-dione, are known to represent also suitable dienophiles.

As 4-phenyl-1 ,2,4-triazolidine-3,5-dione (= 4-phenylurazol) or 4-aryl-1 ,2,4- triazolidine-3,5-diones, respectively, are key intermediates for the synthesis of 4- phenyl-1 ,2,4-triazoline-3,5-dione or 4-aryl-1 ,2,4-triazoline-3,5-dione, respectively, any improvement of the process of its manufacturing is of great importance.

CN 1351990 A1 discloses the synthesis of 4-phenylurazole comprising the steps of reaction of hydrazine carboxylate with phenyl isocyanate in benzene derivatives as solvent, isolating the 4-phenyl-1-carboethoxy-semicarbazide and adding KOH solution to obtain 4-phenylurazole.

R.C. Cookson et al. in Organic Syntheses, Coll. Vol. 6, 936 (1988), Vol.

51, 121 (1971) discloses the synthesis of 4-phenyl-1 ,2,4-triazoline-3,5-dione and 4-phenylurazole. 4-phenylurazole is prepared from ethyl hydrazine carboxylate and phenyl isocyanate in dry benzene. The 4-phenyl-1-carbethoxysemicarbazide formed is described to be isolated and then treated with aqueous KOH, heated and then acidified with HCI to yield 4-phenylurazole.

CN 1351990 A1 discloses that a replacement of dry benzene by some benzene derivatives for the step of reaction between ethyl hydrazine carboxylate and phenyl isocyanate, would be an improvement over Cookson in view of benzene's high volatility, low recovery and high environmental pollution.

These pathways of synthesis of syntheses of 4-phenyl-1 ,2,4-triazolidine- 3,5-dione or 4-phenyl-1 ,2,4-triazoline-3,5-dione, respectively, use different solvents for the steps of a) reaction of the phenyl isocyanate and b) the cyclization reaction, and the necessity of isolation of the intermediate 4-phenyl-1 -carbethoxy- semicarbazide.

Such multistep reactions involving isolations intermediates and/or change of solvents and/or reaction vessels are very complex, labor intensive and costly Hence, there is great interest in a simpler, but nevertheless very efficient, reaction pathways for the synthesis of 4-aryl-1 ,2,4-triazolidine-3,5-diones and 4- aryl-1 ,2,4-triazoline-3,5-dione, in general, and 4-phenyl-1 ,2,4-triazolidine-3,5-dione (= 4-phenylurazol) and 4-phenyl-1 ,2,4-triazoline-3,5-dione (PTAD), in particular. Summary of the invention

Therefore, the problem to be solved by the present invention is to provide a one-pot reaction pathway for the manufacturing 4-aryl-1 ,2,4-triazolidine-3,5- diones or 4-phenyl-1 ,2,4-triazolidine-3,5-dione (= 4-phenylurazol), respectively a process of manufacturing 4-aryl-1 ,2,4-triazoline-3,5-dione, which is based on a one-pot reaction pathway for the manufacturing 4-aryl-1 ,2,4-triazolidine-3,5-diones or 4-phenyl-1 ,2,4-triazolidine-3,5-dione (= 4-phenylurazol).

Surprisingly, it has been found the process according to claims 1 and 13 are able to solve this problem. This solution is very advantageous in that the alcohol used as solvent for both steps (isocyanate reaction and cyclization) can be used allowing a one-pot reaction. Furthermore, alcohols are very cheap and low risk solvents, very much in contrast to benzene. Hence, not only the presented solution offers advantages in view of economy but also in ecology. The yields in the proposed solution are still remarkably high.

Further aspects of the invention are subject of further independent claims.

Particularly preferred embodiments are subject of dependent claims. Detailed description of the invention

In a first aspect, the present invention relates to a process of

manufacturing a 4-aryl-1 ,2,4-triazolidine-3,5-dione of the formula (I) in a one-pot reaction comprising the step a)

a) reacting an aryl isocyanate of the formula (II) with a compound of the

formula (III) to form compound of the formula (IV) in an alcohol of the formula R ^1' -OH as solvent

followed by step b)

b) cyclisation of the compound of the formula (IV) by adding an aqueous base and upon heating and followed by acidification to yield the compound of the formula (I)

wherein R ¹ represents a Ci _-4 -alkyl group, preferably a Ci-3-alkyl group, particularly a methyl or ethyl group, more preferably an ethyl group;

R ^1' represents a Ci _-4 -alkyl group, preferably a Ci-3-alkyl group, particularly a methyl or ethyl group, more preferably an ethyl group

R ² and R ³ represent independently from each other hydrogen or methyl group R ⁴ represents either hydrogen or a methyl group or a nitro group. For sake of clarity in the following some terms as been used in the present document are defined as followed:

In the present document, a“C _x-y -alkyl” group is an alkyl group comprising x to y carbon atoms, i.e., for example, a Ci-3-alkyl group is an alkyl group comprising 1 to 3 carbon atoms. The alkyl group can be linear or branched. For example -CFI(CFl3)-CFl2-CFl3 is considered as a C ₄ -alkyl group.

In case identical labels for symbols or groups are present in several formulae, in the present document, the definition of said group or symbol made in the context of one specific formula applies also to other formulae which comprises said same label.

The two groups R ² and R ³ in any formula of this document are directly linked to the aromatic ring. The position of said group is in the ortho or the meta position. This is represented by the bond pointing into the aromatic ring.

Therefore, 4-phenyl-1 ,2,4-triazolidine-3,5-dione, 4-(o-tolyl)-1 ,2,4-triazoli- dine-3,5-dione, 4-(m-tolyl)-1 ,2,4-triazolidine-3,5-dione, 4-(p-tolyl)-1 ,2,4-triazolidine-

3.5-dione, 4-(2,3-dimethylphenyl)-1 ,2,4-triazolidine-3,5-dione, 4-(2,4-dimethyl- phenyl)-1 ,2,4-triazolidine-3,5-dione, 4-(2,5-dimethylphenyl)-1 ,2,4-triazolidine-3,5- dione, 4-(2,6-dimethylphenyl)-1 ,2,4-triazolidine-3,5-dione, 4-(3,4-dimethylphenyl)- 1 ,2,4-triazolidine-3,5-dione, 4-(3,5-dimethylphenyl)-1 ,2,4-triazolidine-3,5-dione, 4- mesityl-1 ,2,4-triazolidine-3,5-dione, 4-(2,4,5-trimethylphenyl)-1 ,2,4-triazolidine-3,5- dione, 4-(3,4,5-trimethylphenyl)-1 ,2,4-triazolidine-3,5-dione, 4-(3,5-dimethyl-4- nitrophenyl)-1 ,2,4-triazolidine-3,5-dione, 4-(2,5-dimethyl-4-nitrophenyl)-1 ,2,4-tria- zolidine-3,5-dione, 4-(2,6-dimethyl-4-nitrophenyl)-1 ,2,4-triazolidine-3,5-dione, 4- (2,3-dimethyl-4-nitrophenyl)-1 ,2,4-triazolidine-3,5-dione, 4-(2-methyl-4-nitro- phenyl)-1 ,2,4-triazolidine-3,5-dione, 4-(3-methyl-4-nitrophenyl)-1 ,2,4-triazolidine-

3.5-dione and 4-(4-nitrophenyl)-1 ,2,4-triazolidine-3,5-dione all are example of a compound of the formula (I).

It is preferred that at least one of the groups R ² and R ³ and R ⁴ , preferable at least two one of the groups R ² and R ³ and R ⁴ , stand for FI. Particularly preferred compounds of the formula (I) are the ones selected from the group consisting of 4- phenyl-1 ,2,4-triazolidine-3,5-dione, 4-(o-tolyl)-1 ,2,4-triazolidine-3,5-dione, 4-(m- tolyl)-1 ,2,4-triazolidine-3,5-dione, 4-(p-tolyl)-1 ,2,4-triazolidine-3,5-dione and 4-(4- nitrophenyl)-1 ,2,4-triazolidine-3,5-dione, preferably selected from the group consisting of 4-phenyl-1 ,2,4-triazolidine-3,5-dione, 4-(o-tolyl)-1 ,2,4-triazolidine-3,5- dione, 4-(m-tolyl)-1 ,2,4-triazolidine-3,5-dione and 4-(p-tolyl)-1 ,2,4-triazolidine-3,5- dione.

More preferred is that both groups R ² and R ³ stand for H. Most preferred that all three groups R ² and R ⁴ stand for H. In other words, more preferably, compound of the formula (I) is 4-phenyl-1 ,2,4-triazolidine-3,5-dione or 4-(4-nitro- phenyl)-1 ,2,4-triazolidine-3,5-dione, most preferably compound of the formula (I) is 4-phenyl-1 ,2,4-triazolidine-3,5-dione. Said process of manufacturing a 4-aryl-1 ,2,4-triazolidine-3,5-dione of the formula (I) comprises in a first step a) the reaction of an aryl isocyanate of the formula (II) with a compound of the formula (III) to form a compound of the formula (IV) in an alcohol of the formula R ^1' -OH as solvent. This reaction comprising the step a) has been surprisingly found to take place very efficiently in an alcohol of the formula R ^1' -OH as solvent which allows that the whole process can be realized as a one-pot reaction, i.e. without the necessity to isolate the intermediate product of the formula (IV), respectively to have a change of solvents necessary for steps a) and b).

Respective alcohols of the formula R ^1' -OH are methanol, ethanol, n- propanol, iso- propanol, n-butanol, sec-butanol and tert- butanol. The alcohol of the formula R ^1' -OH are preferably selected from the group consisting of methanol, ethanol, n-propanol and iso- propanol. Ethanol is the most preferred alcohol of the formula R ^1' -OH.

It is preferred that the alcohol of the formula R ^1' -OH is dried, i.e. that the content of water is reduced to a large extent. More preferred said alcohols have a water content of less than 1 % by weight. Most preferred said alcohols are free of water.

Of course, principally, also mixtures of two or more alcohols of formula

R ^1' -OH can be used, such as e.g. mixtures of methanol and ethanol or mixtures of ethanol and n-butanol or mixtures of methanol and ethanol and iso- propanol. It is also possible that alcohol(s) of formula R ^1' -OH can be used in mixtures with other solvents, particularly with alcohols having alkyl chains with more than 4 carbon atoms, such as hexanol or dodecanol.

However, it is preferred that the solvent used in the reaction mentioned above consists only of one alcohol of the formula R ^1' -OH.

The fact, that an alcohol of the formula R ^1' -OH can be used as a solvent is particularly surprising for a reaction where isocyanates are used as reactants, as it is known that isocyanates are reactive with hydroxyl groups. Surprisingly, no significant amounts of such respective side product of the formula

have been found to be formed.

The reaction of step a) typically is performed by adding the compound of the formula (III) and the alcohol of the formula R ^1' -OH in a reaction vessel.

The aryl isocyan ate of the formula (II) is selected from the group consisting of phenyl isocyanate, o-tolyl isocyanate, m-tolyl isocyanate, p-tolyl isocyanate, 1- isocyanato-2,3-dimethylbenzene, 1 -isocyanato-2,4-dimethylbenzene, 1 -isocya- nato-2,5-dimethylbenzene, 1 -isocyanato-2,6-dimethylbenzene, 1 -isocyanato-3,4- dimethylbenzene, 1-isocyanato-3,5-dimethylbenzene and 1 -lsocyanato-4-nitro- benzene.

The aryl isocyanate of the formula (II) is preferably selected from the group consisting of phenyl isocyanate, o-tolyl isocyanate, m-tolyl isocyanate, p-tolyl isocyanate and 1 -lsocyanato-4-nitrobenzene, more preferably selected from the group consisting of phenyl isocyanate, o-tolyl isocyanate, m-tolyl isocyanate and p-tolyl isocyanate.

Most preferably, the aryl isocyanate of the formula (II) is phenyl

isocyanate. The compound of the formula (III) is selected from the group consisting of methyl hydrazinecarboxylate, ethyl hydrazinecarboxylate, propyl hydrazinecar- boxylate, iso- propyl hydrazinecarboxylate, butyl hydrazinecarboxylate, sec-butyl hydrazinecarboxylate and tert- butyl hydrazinecarboxylate.

Preferably, the compound of the formula (III) is selected from the group consisting of methyl hydrazinecarboxylate, ethyl hydrazinecarboxylate, propyl hydrazinecarboxylate and iso- propyl hydrazinecarboxylate.

The most preferred compound of the formula (III) is ethyl hydrazine- carboxylate.

The molar ratio of aryl isocyanate of the formula (II) to the compound of the formula (III) in step a) is preferably between 1.00 and 1.10, particularly between 1.0001 and 1.05. It is preferred that the aryl isocyanate of the formula (II) is subsequently added, preferably at slightly elevated temperatures, i.e. between 30°C and the boiling point of the solvent, particularly between 30°C and a temperature 5°C lower than the boiling point of the solvent, more particularly between 30°C and 60°C, preferably between 35°C and 57°C, most preferably between 45°C and 55°C.

The reaction of step a) is preferably performed at ambient pressure.

The reaction of the aryl isocyanate of the formula (II) with the compound of the formula (III) is exothermic during which the product of this reaction, i.e. the compound of the formula (IV) is precipitated.

With this mixture of reaction step b) is followed without the need of isolation of the compound of the formula (IV) or any change of solvents.

In step b) the compound of the formula (IV) is cyclised by heating the reaction mixture of step a) and adding an aqueous base and upon heating and acidification to yield the compound of the formula (I). As no change of solvents occurs, also reaction step b) is performed in in an alcohol of the formula R ^1' -OH as solvent. The heating in step b) is preferably an exposure to a temperature between between 30°C and the boiling point of the alcohol of the formula R ^1' -OH, particularly between 30°C and a temperature 5°C lower than the boiling point of the alcohol of the formula R ^1' -OH, more particularly between 37°C and 60°C, preferably between 37°C and 57°C, most preferably between 45°C and 55°C.

Step b) is preferably performed at ambient pressure.

The aqueous base is preferably an aqueous solution of a hydroxide of an alkali metal or an alkaline earth metal or NH3 or an alkali carbonate or

bicarbonate, preferably an aqueous solution of a hydroxide of an alkali metal or an alkaline earth metal, more preferably an aqueous solution of KOH or NaOH, most preferably an aqueous solution of NaOH.

The amount of base added is so that the pH of the reaction mixture is preferably in the basic region, more preferably a pH of 8 or higher.

The acidification is performed by adding an acid, being typically a carboxylic acid or an inorganic acid, preferably with an inorganic acid, particularly with an acid having a pK _a of less than 2, particularly less than 1. The preferred acids are HCI or H ₂ S0 ₄ or H2SO3. It has been surprisingly found that particularly H2S0 ₄ or H2SO3 other are very advantageous as these acids are much less corrosive for and do not introduced undesired chlorine atoms into the reaction mixture. It is most preferred that the acid is sulfuric acid. It is preferred that the acidification in step b) is performed by adding acid to the reaction mixture until the pH of said mixture is less than 3, particularly until the pH of the reaction mixture is between 1.5 and 2.5.

The compound of the formula (I) can be isolated by filtration and if neces- sary can be purified by standard methods such as extraction or re-crystallization.

Upon cyclization, an alcohol of the formula R ¹ -OH is formed. The reaction of step b) occurs in an alcohol of the formula R ^1' -OH as solvent. In case of R ^1' being different from R ¹ the reaction mixture after step b) comprises a mixture of alcohols of the formulae R ¹ -OH and R ^1' -OH. However, it is preferred that R ¹ = R ^1' . This has the big advantage that the alcohol of the formula R ¹ -OH being formed upon cyclization does not contaminate the alcohol of the formula R ^1' -OH which is used as solvent. Therefore, the alcohol R ^1' -OH used as solvent can be easily recycled after termination of the cyclization step. This economically and ecologically very interesting.

The compound of the formula (III) can be prepared by reacting a compound of the formula (V) with hydrazine to yield a compound of the formula (III).

Hence, in one preferred embodiment, in the above mentioned process, the compound of the formula (III) is prepared in step ao) prior to step a)

ao) reacting a compound of the formula (V) with hydrazine to yield a

compound of the formula (III)

Hydrazine is a liquid which is very toxic and dangerous to handle in its anhydrous form. Therefore, despite, principally, hydrazine as such, i.e. in its anhydrous form, could be used, it is preferred to use hydrazine in one preferred embodiment rather in the form of an aqueous solution of hydrazine. ln another preferred embodiment, hydrazine is used in the form of hydrazine hydrate of the formula (VI)

H ₂ N - NH ₂ H ₂ 0 (VI).

The reaction is performed as described in Cheng-Xia Tan et al., J.

Heterocyclic Chem., 51 , 690 (2014), particularly for the preparation for ethyl hydrazine carboxylate 1 on page 692, the entire content of which is hereby incorporated by reference.

The reaction of step ao) can be performed without a solvent or in a solvent. The selection of solvent, however, is limited to those solvents which are inert to hydrazine.

Surprisingly, it has been shown that for this reaction the alcohol of the formula R ^1' -OH.

This allows that all the reactions starting from hydrazine and the compound of formula (V) up to the targeted compound, i.e. 4-aryl-1 ,2,4-triazoli- dine-3,5-dione, are performed in a one-pot reaction, without the need of isolation of any intermediate, or change of solvent or reaction vessel. This of course is economically and ecologically very interesting. Also, the use of alcohols of the formula R ^1' -OH as solvent is very interesting as those solvents are cheap, easy to handle and ecologically advantageous.

Therefore, in a further aspect, the invention relates to the use of an alcohol of the formula R ^1' -OH as solvent for the reaction of an aryl isocyanate of the formula (II) with a compound of the formula (III) to form the compound of the formula (IV)

The compounds of formulae (II), (III), (IV) and R ^1' -OH as well as their preferred embodiments and syntheses have been discussed already above in great detail.

Respectively, it relates also to the use of alcohol of the formula R ^1' -OH as solvent for the reaction of a compound of the formula (V) with hydrazine to yield a compound of the formula (III)

followed by the reaction of an aryl isocyanate of the formula (II) with said compound of the formula (III) to form the compound of the formula (IV)

The compounds of formulae (II), (III), (IV), (V) and R ^1' -OH as well as their preferred embodiments and syntheses have been discussed already above in great detail.

Preferably, said above reaction

between aryl isocyanate of the formula (II) with said compound of the formula (III)

or the reactions between

a compound of the formula (V) with hydrazine to yield a compound of the formula (III) followed between aryl isocyan ate of the formula (II) with said compound of the formula (III)

are one-pot reactions.

In an even further aspect, the invention relates to a composition comprising

i) an aryl isocyanate of the formula (II);

ii) a compound of the formula (II); and

iii) an alcohol of the formula R ^1' -OH

The compounds of formulae (II), (III) and R ^1' -OH as well as their preferred embodiments and syntheses have been discussed already above in great detail. The 4-aryl-1 ,2,4-triazolidine-3,5-dione of the formula (I) can be used as starting material for a 4-aryl-1 ,2,4-triazole-3,5-dione of the formula (VII).

Hence, in an even further aspect, the invention relates to a process of manufacturing 4-aryl-1 ,2,4-triazole-3,5-dione of the formula (VII)

characterized comprising the steps

aa) manufacturing a 4-aryl-1 ,2,4-triazolidine-3,5-dione of the formula (I) in a one-pot reaction according to a process as described above in great detail;

bb) oxidizing the 4-aryl-1 ,2,4-triazolidine-3,5-dione of the formula (I) to the 4- aryl-1 ,2,4-triazole-3,5-dione of the formula (Vll)-by means of an oxidizing agent;

wherein R ² and R ³ represent independently from each other hydrogen or methyl group; and

R ⁴ represents either hydrogen or a methyl group or a nitro group.

In other words, this process comprises the steps a) and b) as described above in great detail as well as bb). The oxidizing step is known per se already since long, for example as disclosed in R.C. Cookson et al. in Organic Syntheses, Coll. Vol. 6, 936 (1988), Vol. 51, 121 (1971).

Suitable oxidizing agents are particularly tert- butyl hypochlorite and sodium hypochlorite.

The process of this invention is very advantageous in view of cost, labor, speed and ecology in that at least the majority of steps of synthesis between compound of aryl isocyanate of the formula (II) up to 4-aryl-1 ,2,4-triazole-3,5-dione of the formula (VII) are performed in one-pot process.

Figures

Figure 1 show schematically the different reactions within the present invention.

In a one-pot reaction ( OP-1) the aryl isocyanate of the formula (II) is reacted in an alcohol of the formula R ^1' -OH as solvent with the compound of the formula (III) to form in step a) the intermediate compound of the formula (IV) directly followed by a cyclisation reaction in step b) by adding an aqueous base (B) and upon heating (D) and followed by acidification (H ⁺ ) a to yield 4-aryl-1 ,2,4- triazolidine-3,5-dione of the formula (I).

In a preferred embodiment of the invention the one-reaction (OP-II) encompasses also the reaction of the compound of the formula (V) with hydrazine to yield a compound of the formula (III) in step ao). This allows to perform the whole sequence of all reactions starting from dialkylcarbonate (V) up to the 4-aryl- 1 ,2,4-triazolidine-3,5-dione (I) in a one-pot reaction, i.e. to take place in the same reaction vessel without the need of change of solvents or isolation or purification of an intermediate.

Figure 1 also represents the subsequent reaction to 4-aryl-1 ,2,4-triazole- 3,5-dione of the formula (VII). Flence, figure 1 , represents a reaction pathway of the synthesis which takes advantage of the manufacturing a 4-aryl-1 ,2,4-triazoli- dine-3,5-dione (aa) ) and its oxidation by means of an oxidizing agent (OA)) oxidizing (bb) ) and by doing so lead to a very easy and cost efficient pathway of synthesis of 4-aryl-1 ,2,4-triazole-3,5-dione (VII). Examples

The present invention is further illustrated by the following experiments.

Preparation of 4-phenyl-1.2.4-triazolidine-3,5-dione

Step a)

41.1 g (383 mmol) of ethyl hydrazine carboxylate and 94 g ethanol were added to a glass flask. After heating to 50°C, 47.2 g (388 mmol) of phenyl isocyanate was added over the course of 30 minutes, keeping the exothermal reaction below 55°C. The intermediate ethyl 2-(phenylcarbamoyl)hydrazine-1 -carboxylate precipitated and the reaction mixture was stirred for 60 minutes at a temperature of 50°C.

Step b)

Still at 50°C, to the above reaction mixture, 86.6g of a NaOH solution (20 % (weight by weight) in water) (433mmol) were added over the course of 30 minutes not exceeding a temperature of 55°C. Upon addition of the base the solid dissolved. Then 100.1 g of a mixture of water and ethanol were distilled off at a temperature between 100 and 115°C. After cooling to 25°C, sulfuric acid (10 % (weight by weight) in water)) was added dropwise in an amount to achieve a pH of 2. The so formed slurry was stirred overnight at 25°C, from which the product 4- phenyl-1 ,2,4-triazolidine-3,5-dione was isolated. After drying, 60.8 g (341 mmol) 4- phenyl-1 ,2,4-triazolidine-3,5-dione was obtained (yield: 87 %).