FR2521558A1 - Plant protection agent intermediate 1,2,4-triazole prodn. - by reaction of hydrazine with formic acid and/or ammonia; also used in pharmaceuticals - Google Patents

Abstract

In the prodn. of 1,2,4-triazole by reaction of hydrazine with formic acid and formamide and/or ammonia, (A) hydrazine and formic acid (opt. in the form of their aq. solns.) in a molar ratio of 1:0 to 1:3 are reacted with 1-2 molar proportions formamide and/or ammonia at 140-220 deg.C; (B) 1,2,4-triazole is sepd. from the reaction mixt. in a conventional manner; and (C) excess reagents are opt. recycled. 1,2,4-Triazole is chiefly used in the plant protection and pharmaceutical industries. Side reactions leading to the formation of 4-amino-1,2,4-triazole and 1,3,4-oxadiazole impurities do not occur.

Description

 "Process for the preparation of 1,2,4-triazole".

 The present invention relates to a new process for the preparation of 1,2,4-triazole by reaction of hydrazine, formic acid as well as formamide and / or ammonia.

 1,2,4-Triazole is mainly used for the production of agents for the protection of plants and for the pharmaceutical industry.

 For the preparation of 1,2,4-triazole, many. processes are known. Among these methods, those which are closest to the present invention are described below.

According to Luxembourg Patent No. 61,617, 1,2,4-trioleole can be prepared by reacting 1 mole of hydrazine and 3 moles of formamide at a temperature of 90 to 260 ° C in accordance with the chemical equations (1) and (2). ) below.

 The main disadvantage of this process is the high demand for formamide. At the same time, a large part of the ammonia contained in the formamide is lost as waste and, therefore, the industrial implementation of this process is not economical.

 German Patent No. 2,802,491 also describes a process starting from these two reagents and, in addition, ammonia.

According to this method, the reaction is carried out at a temperature of 100 to 2500C, preferably at a temperature of 110 to 2200C, in an apparatus comprising 3 or 4 reactors in series while the gases and vapors are condensed at different temperatures, and the condensates as well as the gases and vapors are recycled in one or the other of the reactors. According to this method ,. instead of 3 moles of formamide (3-n) moles of formamide or 0.34 n 4 i, in other words, formamide is partially replaced by ammonia [see chemical equation (3) below). ].

H2N-NH2 + (3-n) H-CO-NH2 + n NH3-e- (II) +
2 H 2 O + 2 NH 3 + (ln) CO (3) 0.3 4 n fg 1
This process is very complicated because of the need
to ensure the balance of the cascading system, in addition to the
cooling of gaseous products or in the form of vapors
up to different temperatures and the distribution of condensates as well as gases, and at the same time the decrease of the consumption of fomamide is not significant.

the triazole ring can also be formed via diformylhydrazine (C. Ainsworth and RB Jones
J. Am, Chem. Soc. 1955, 77, p. 621-24). We prepare the di
formylhydrazine from formic acid and hydrazine
according. the chemical equation (4) by heating for 12 hours at a temperature of 100 C; the overall yield is
equal to 60%.

H / NH 2 + 2H-COOH + (I) + 2H 2 O (4)
It is also possible to obtain diformylhydrazine from hydrazine and formamide at a temperature of 1000.degree.
2 hours ; the yield is, however, only 80%
(see equation 1). Cyclization of diformylhydrazine
1,2,4-triazole is achievable with ammonia according to the chemical equation (5), namely with ammonia conden
by heating the reaction mixture under pressure to a
2000C temperature for 24 hours.

(I) + NH 3 -> (II) + 2H 2 O (5)
1,2,4-Triazole is formed in 70% to 80% yield. the total yield, based on hydrazine, is in both cases less than 60%. These processes are different
ficiles to implement and are not economical.

Therefore, for the cyclization of diformylhydrazine, formamide, ammonia, or formamide and ammonia are respectively used (see equations 2 and 3). In addition to the main reaction, however, many side reactions may occur, for example
ple the reactions represented by the chemical equations
(6), (7) and (8) below (next page). [AT. Etienne
Treaty of Organic Chemistry (V. Grignard et al., Publishers), 21, 898, Masson, Paris, 1953; A. Hetzheim and K. Nickel
Advan. Heterocyclic Chem. 1, 183-224 (1966); GH Schwab
Z. anorg. allg. Chem. 262, 41-8 (1950) 1.

 The essential object of the present invention is the development of a process for preparing 1,2,4-triazole more easily and economically than by carrying out previously known processes.

When studying the reaction of hydrazine, formic acid, formamide and / or ammonia, it is surprising to find that, under certain conditions, the formic acid salt formed with hydrazine, ie ie hydrazine formate, or the hydrazine itself is capable of cyclizing with formamide or with a mixture of formic acid and / or ammonia without prior preparation of diformylhydrazine. This surprising fact was not known until now and was unexpected. The reaction of hydrazine, formic acid as well as formamide and / or ammonia leads to the formation of 1,2,4-triazole a high speed and with a very good yield without formation, respectively, of 1,3,4-oxadiazole 4-amino-1,2,4-triazolevet as impu restraints according to the equations (6) and (7) representing the reactions - secondary interventions that intervene then.

The process according to the invention is represented by the global chemical equation (9) below
H2N-NH2 + m HCOOH + (3-min) HCONH2 +
+ (n + m-2) NH3 (II) + (2 + m) H20 + (1-n) CO (9) om3
Gold; nt; 1
1 # (min) # 4
The rapid and complete reaction of hydrazine, formic acid as well as formamide and / or ammonia is feasible in such a way that hydrazine or hydrate and formic acid are allowed to react. at a temperature of about 1800C with formamide or a mixture of ammonia and formic acid. During this reaction stage, it is advantageous for the reaction mixture to be saturated with ammonia. This can be achieved by introducing gaseous ammonia into the reaction mixture or by saturation of the hydrazine or formate solution. hydrazine in water, formamide or a mixture of water and formamide with ammonia gas, or by mixing it with an ammonia solution. the amount of formamide converted during the reaction can be partially or completely replaced by ammonia. Under such conditions, the formation of 1,2,4-triazole is so rapid that the feed rate is determined by the speed heat transfer. it is important that the temperature of the reaction mixture does not fall below 1400C and does not rise above 210bu because in the first case the reaction slows down while in the second case the distillation becomes significant. After the addition of hydrazine formate or hydrazine in formamide or a mixture of formic acid and ammonia, the reaction mixture is maintained at 1800 ° C. for 10 minutes and then cooled. Depending on the composition and the ratio of the reagents, the mass of the 1,2,4-triazole formed crystallizes or the reaction mixture cures. In both cases, the yield is equal to about 95%.

 the mole ratio of hydrazine to formic acid is about 1: 1 to 3, while the amount of formamide and / or ammonia, based on 1 mole of hydrazine, is 1 to 2 mol.

 During the reaction, it must be ensured that, after condensation, the water vapor which has escaped does not return to the system.

 The reaction product is a pure, colorless, homogeneous liquid and, when it is cooled, the 1,2,4-triazole formed separates in the form of a white crystalline substance, or the whole hardens into a crystalline mass. white.

 The reaction time for the formation of 1,2,4-triazole is about 5 to 60 minutes, depending on the reaction temperature and, in addition, the molar ratio and the composition of the reactants. The reaction temperature is between 140 and 2200C, and is preferably about 1800C.

 One possible mode of implementation of the method according to the invention is the use of excess formamide. Its role is twofold: firstly, it serves as a solvent and, possibly, it increases the solubility of ammonia, and, secondly, it ensures that, during the supply of reagents, a small amount of hydrazine or hydrazine formate is always in contact with formamide since it is present in large excess. In this case, about 6% by weight 1,2,4-triazole remains dissolved in the excess formamide after filtration of the crystalline product. The filtrate can be reused by recycling.

 During the process according to the invention, the recovery of the formamide remaining in the distilled water can be carried out at the same time as the reaction or, after having collected from time to time the mixture of formamide and water, can recycle the formamide thus recovered.

 Another possibility of carrying out the process according to the invention is to use hydrazine, formic acid and ammonia for the reaction and, when this is done, a mixture of hydrazine formate and ammonia is preferably added to a solution of ammonium formate at a temperature of 1800C. The proper rate of 1,2,4-triazole formation is provided by the presence of an excess of ammonia in the reaction mixture.

The product is a white crystal substance having a melting point of 98 ° to 10 ° C. when the reaction temperature is 18 ° C.

 it is advantageous to transfer the mixture leaving the reaction vessel, and containing water vapor, ammonia, a little of the substance that has been used as raw material, intermediate reaction products and 1,2,4 -triazole formed in a condenser at a temperature of 110 to 1400C from which still usable components will be returned in the form of condensates in the reaction mixture. The steam and ammonia leaving the condenser are then cooled to 20 ° C to 800 ° C, and the ammonia is partially or fully recycled to the reaction mixture; thus, it is ensured that the reaction mixture is always saturated with ammonia. Ammonia added in excess can be absorbed in formic acid and recirculated back into the reaction mixture.

 If, after carrying out the reaction, substantial quantities of water and formamide in the product obtained are to be removed, this can be achieved by carrying out a distillation carried out under vacuum at a temperature of 1600 ° C., or alternatively, by maintaining the product at a temperature of 210 to 250 ° C. The vapors formed during these elementary operations are usable again during the preparation operation after condensation.

 The process according to the invention can be carried out either in discontinuous operation or in continuous operation.

 Hereinafter are given various examples, of course non-limiting, of implementation of said method.

 EXAMPLE 1 92 g (2.0 moles) of formic acid are introduced into a round-bottomed 250 ml flask and, over a period of 10 minutes, 69.5 g (1.0 mole) of a solution are added. 72% hydrazine hydrate. During this time, the cooling is adjusted so that, at the end of the solution supply, the temperature of the reaction mixture is equal to 800C; Meanwhile, another 250 ml round bottom flask was charged with 76.5 g (1.7 moles) of formamide and heated to 1800 ° C. To this formamide, the hydrazine formate solution is added at 1800 ° C. at a rate such that the temperature of the reaction mixture is maintained between 175 ° C. and 18 ° C. During the supply of the solution, the water supplied with the hydrate is maintained. hydrazine and that formed during the reaction are removed using a distillation apparatus mounted on the round bottom flask. After the completion of the supply of hydrazine formate, the mixture is maintained at a temperature of 1800 ° C. for a further 10 minutes, then allowed to cool and finally refrigerated to -1 to -2 ° C. Separated 2,4-triazole is collected by filtration. The mass of the dry product is 60.5 g, and its melting point is 120 to 121 ° C. The mass of the filtrate is 26.5 g and contains 19.5% 1,2,4-triazole dissolved; therefore, the total yield, based on hydrazine, is 95.8%.

 EXAMPLE 2 135 g (2.5 moles) of 85% formic acid are introduced into a 250 ml round-bottomed flask and 69.5 g (1.0 mole) of water are added with cooling. hydrazine hydrate at 72. At the same time, ammonia is introduced into the system at a rate of 6 liters / hour. The temperature of the reaction mixture is kept below 200C. After the end of the supply of hydrazine hydrate, the introduction of ammonia is continued until saturation. In another 250 ml round bottom flask, 45 g (1.0 mol) of formamide are introduced and heated to 1700C. To this formamide is added the solution of hydrazine formate saturated with ammonia. The temperature of the formamide is partially regulated by heating, partly by the feed rate so that it is stabilized above 1600C. The water introduced with the reactants and formed during the reaction is removed using a distillation apparatus. The total duration of the feeding operation is 50 to 55 minutes, after which the reaction mixture is maintained at the aforesaid temperature for a further 15 minutes, after which it is allowed to cool and finally refrigerated to -1 to C. It separates 1,2,4-triazole which is filtered off with suction to remove the filtrate. The mass of the dry product is 58.9 g, while the filtrate weighs 35.2 g. This filtrate contains 19.1% of 1,2,4-triazole dissolved. The total yield, based on hydrazine, is therefore equal to 95.1%.

EXAMPLE 3 In a round-bottomed 250 ml flask, one
weighs 92 g (2 moles) of formic acid and 45 g (1 mole) of
formamide. In 10 minutes, 32 gas moles of hydra are added.
Zine. The temperature of the reaction mixture is maintained at
40oC. In another flask, 22.5 g of formamide are weighed and
we heat up to 1800C .. While stirring energetically, we
add in one hour the hydrazine formate solution
in formamide contained in the first balloon, while
also bringing ammonia at a rate of 10 liters / hour.

After the completion of the application of formate, one
continue to agitate everything by bringing ammonia, then
interrupts agitation and ammonia supply and refrigerates
re the reaction mixture until -2 C and separate the
1,2,4-triazole by filtration. The mass of the dry product is
of 61.1 g, while that of the filtrate is equal to 20.5
g. During the supply of hydrazine formate, one collects
the 75 g of distillate in the distillation apparatus.

Example 4. The reaction is carried out by operating from
described in Example 3. After the interruption of
the supply of ammonia, the formamide is distilled off
under vacuum at a temperature of 160oC. 1,2,4-triazole
obtained in the form of a melt is then solidified.

 The mass of 1,2,4-triazole thus obtained is equal to 64.8 g.

Example 5 - Formic acid is mixed together with
85% and 73% hydrazine hydrate according to a mo
2: 1 all while cooling. In a balloon bottom
round equipped with an overflow pipe,
distillation, a mixer and a thermometer (the volume
of this flask being 100 ml), 180 g of the formate are introduced.
of hydrazine prepared in the manner described above and, in beam, 69 g of formamide per hour. We keep the story
of the balloon at a temperature value stabilized at
1800C. Each hour, 75 g of a solution
1,2,4-triazole; from this solution, we can
collect 62.1 g of dry 1,2,4-triazole.

Example 6. A cascade system with a tubing of
too-pléin comprising a liquid closure is built to
using three balloons of 100 ml each. Each balloon is
equipped with a mixer and a thermometer; on the first is mounted a reflux condenser-condenser; the second and the third each comprise a distillation apparatus. In the first flask, 85% formic acid was fed at a rate of 108 g / hr and 72% hydrazine hydrate at a rate of 70 g / hr. In this flask, the temperature of the reaction mixture is maintained at 80 ° C. The reaction mixture is discharged through said overflow tubing into the second flask kept at a temperature of 1800 ° C. and in which formamide is introduced at a flow rate of 77 g / hour. The distillate collected in the distillation apparatus also contains a little formamide, and therefore the collected aqueous solution is distilled again and the water-free formamide thus collected is recycled to the second flask. The reaction mixture is introduced into the third flask where, the temperature being maintained at 1900C, the last traces of water are distilled off. The 1,2,4-triazole solution in formamide exits the flask at a rate of 95 to 98 g / hr. 1,2,4-Triazole was collected from the reaction mixture by refrigeration and filtration, and the mother liquor was recycled to the second flask. In the system, 1,2,4-triazole is formed at 67.5 g / hour and this product has a melting point of 120 to 1210C.

 EXAMPLE 7 54.2 g (1.0 mol) of 85% formic acid are introduced into a 250 ml round bottom flask and 69.4 g (100 mol) of 24.5% ammonium hydroxide solution. The ammonium formate solution thus formed is heated to 1800 ° C. while gaseous ammonia is added thereto, regularly and with stirring, so that the water supplied with the solutions and formed during The reaction is removed using a distillation apparatus mounted on the round bottom flask. When the temperature of 1800C is reached, the addition of ammonia gas is discontinued. Meanwhile, hydrazine formate is prepared from 70.5 g (1.0 mole) of a 71% strength solution. hydrazine hydrate and from 54.2 g (1.0 mole) of 85% formic acid, then 34.7 g (0.5 mole) of a solution are added to these reagents. 24.5% ammonium hydroxide. The reaction mixture thus obtained is fed into the round bottom flask while continuously removing water and stirring such that the temperature is maintained between 175 and 185oC. After bringing the hydrazine formate and the ammonium hydroxide solution, the reaction mixture is maintained at a temperature of 1800 ° C. for a further 10 minutes. The weight of the cooled white crystalline 1,2,4-triazole is 65.8 g and the yield on the hydrazine hydrate basis is 95.3%. The purity of the product is 93%.

 Example 8 1,2,4-triazole is prepared by operating as described in Example 7, but after the hydrazine formate and the ammonium hydroxide solution are added, the temperature of the product is increased. reaction mixture up to 2000C and maintained at this value for 15 minutes. The mass of 1,2,4-triazole thus obtained is equal to 62 g, and the degree of purity is equal to 97%. The condensate is used during the next preparation operation.

 Example 9 In a 250 ml round-bottomed flask, 108.4 g (2.0 mol) of 85% formic acid and 138.8 g (2.0 mol) of a solution of ammonium hydroxide at 24.5%, and then the procedure is as in Example 7 except that, when the temperature of 1800C is reached, it is not hydrazine formate which is to the round bottom flask, but a mixture of 70.5 g (1.0 mole) of hydrazine hydrate 71% and 74.7 g (0.5 mole) of a solution of 24, 5% ammonium hydroxide. The mass of 1,2,4-triazole thus obtained is equal to 66.0 g.

EXAMPLE 10 In a 250 ml round-bottomed flask, 86 g (1.9 mol) of 100% formamide are weighed and heated.
To 1800C, then, with continuous stirring and continuous removal of water, 70.5 g (1.0 mole) of a 71% hydrazine hydrate solution and 5.4 g ( 0.1 mole) of 85% formic acid so that the temperature remains between 175 and 185oC. After the addition of hydrazine hydrate and formic acid, the reaction mixture is maintained at a temperature of 1800 ° C. for a further 10 minutes and is then allowed to cool. The mass of the solidified crystallized product is equal to 66.0 g and the yield is equal to 95.7%.

 Example 11 In a reactor having a volume of 1000 ml and which is equipped with a mixer, an overflow and a distillation apparatus, the 1,2,4-triazole solution is prepared by operating as described in Examples 7, 8, 9 or 10, then, in the melt at a temperature of 180 ° C, the aqueous hydrate solution, formic acid and ammonia are fed in molar ratios. of 1: 2 :: 1.3 and at a rate of 434 g / hour. the gases and vapors leaving the reactor are cooled to 12 ° C, and the condensate is reintroduced into the reaction vessel. the condensate, containing ammonia and water, formed during the subsequent cooling of the gases and vapors to 1250C is withdrawn, and the ammonia gas is reintroduced into the reaction vessel. Ammonia used in excess is absorbed and is used again for the operation. The mass of 1,2,4-triazole continuously leaving the overflow of the reactor at a temperature of 100 C is equal to 100.3 g; the yield, based on hydrazine, is 96.9%, and the degree of purity of the product is 92.0%.

 Example 12 The melt leaving the reactor described in the example is continuously fed into a container at a temperature of 22,000 and a volume of 250 ml, said container being equipped with an overflow, a mixer and a distillation apparatus. the vapors formed are cooled to 600C, and the condensate is returned to the reactor of Example 11. The amount of 1,2,4-triazole leaving the overflow is equal to 98.3 g / hour. the degree of purity of the product is equal to 98.0%.

The process according to the invention has the following main advantages:
- use as raw materials of cheap substances available in large quantities
cyclization, or cycle closure, is rapid and almost quantitative
- the reagents used in excess can be recy key
each reaction of the process is rapid and is carried out in homogeneous phase, and consequently the process can be carried out in a single elementary operation, simply, and in continuous operation too; and
the 1,2,4-triazole obtained in a crystallized state is very pure.

Claims (7)

 A process for the preparation of 1,2,4-triazole by reaction of hydrazine, formic acid as well as formamide and / or ammonia, which process is characterized in that said hydrazine and formic acid or their aqueous solutions are allowed to react in the presence of formamide and / or ammonia in a molar ratio of from 1: 0 to 3 with, on the hydrazine basis, from 1 to 2 moles of formamide and / or ammonia at a temperature of 140 to 2200C, the 1,1,4-triazole formed is recovered from the reaction mixture in a known manner, and, optionally, the excess reagents used are recycled.  2. Method according to claim 1, characterized in that hydrazine, an aqueous mixture or a mixture free of water and containing hydrazine and formic acid or hydrazine, formic acid and ammonia is added to a water-free or aqueous mixture of ammonia and formic acid.  3. Process according to claim 1, characterized in that hydrazine, or an aqueous or water-free mixture containing hydrazine and formic acid or hyrazine, formic acid and formamide, is added to formamide, optionally in the presence of hydrazine.  4. Method according to claim 1, characterized in that the reagents are added in a melt or a solution of 1,2,4-triazole.  5. Method according to claim 1, characterized in that the ammonia formed during the reaction is partially or completely recycled.  6. Method according to claim 1, characterized in that the mixture of water and formed formamide is separated, and the water-free formamide is optionally recycled.  7. Method according to claim 1, characterized in that the vapors formed are cooled to 110 to 1400C and the condensate is returned to the reaction mixture.