WO2019240671A1 - Manufacturing method for benznidazole production and the industrial scaling thereof - Google Patents

Abstract

The present invention relates to a chemical synthesis method for obtaining benznidazole, or N-benzyl-2-(2-nitro-1H-imidazole-1-yl)acetamide, and to the industrial scaling thereof. It is a simple method that can be easily and safely manipulated and provides a high-yield high-purity product. The method can be carried out in the absence of a solvent and can also be carried out using water as a solvent, with the possibility of reusing the mother liquor in another synthesis method, when the process is carried out in an aqueous medium.

Description

 Manufacturing Method for the Production of Benznidazole and its Scaling

 Industrial

Technology Sector

The present invention relates to an organic synthesis method, under the green chemistry approach, for obtaining an imidazole derived molecule, with antiparasitic activity against trypanosome cruzi.

State of the art

Related to the subject of the present invention, are the documents that we comment below: GB 1138529, presents the synthesis of imidazole derivatives among which N-benzyl-2- (2-nitro-1 H-imidazol-1-yl appears) ) Acetamide (Benznidazole), for this compound describe the synthesis procedure from sodium methoxide / methanol, adding 2-nitroimidazole dissolved in N, N-dimethylformamide, the mixture is heated to 153 ° C to remove methanol. Subsequently, the 2-chloro-methyl acetate ester is added, the temperature of the reaction mixture drops to 122 ° C and then the formation of a precipitate occurs, the formed mixture is heated between 105 ° C and 1 15 ° C. The solvent is discarded in a bath at 50 ° C and reduced pressure 0.2 mm Hg and the solid formed is recrystallized from ethanol, the methyl 2- [2-nitroimidazol- (1) -yl] acetate ester is obtained. The methyl 2- [2-nitroimidazol- (1) -yl] acetate ester is treated with benzylamine dissolved in absolute methanol, left at room temperature overnight. The mixture was refrigerated for several hours and the crystals formed are collected by filtration, these crystals have a melting point 187.5 ° C at 189.5 ° C. The filtrate was concentrated under reduced pressure and the solid obtained was recrystallized from ethyl acetate, giving an additional melting point material 187.5 ° C at 189 ° C. Recrystallization from ethanol gives A / -benzyl-2- (2-nitro-1 H-imidazol-1-yl) acetamide, as melting point crystals 188.5 ° C at 190 ° C.

GB 1138529 describes a series of procedures for obtaining benznidazole, which include synthetic steps in the presence of heating and solvents such as methanol, N, N-dimethylformamide, which leads to procedures for removing solvents. In our invention no organic solvents are used and it does not require applying heat for any synthesis step. Pérez Eduardo, et al. An Easy and Efficient Microwave Assisted Method to Obtain 1- (4-Bromophenacyl) azoles in “Dry Media”. Heterocycles, Vol. 43, N ⁹ 3, 1996. Describe an easy and efficient method to obtain five compounds 1- (4-Bromofenacil) azoles obtained under solvent-free conditions, in the absence of base and in 1: 1 molar ratio of bromide of 4-bromophenylacil with the following compounds: pyrazole (1 a), 3,5-dimethylpyrazole (1 b), 1, 2,4-triazole (1c), indazole (2d), or benzotriazole (2e), under microwave irradiation .

The equations for reactions between 4-bromophenylacetyl bromide and (1a), (1 b), and (1 c), are presented in fig. 1.

 The equations for the reactions between 4-bromofenacil bromide and (2d), or (2e), are presented in fig. two.

( ^2e >

 Figure 2 Scheme of reactions between 4-bromophenacyl bromide and (2d), (2e), described by

Pérez Eduardo, et al. In all the cases raised, the A / -alkylated product in position 1, with respect to the heterocycle ring, is obtained as the main product of the synthesis, as a consequence of the absence of solvent, which could allow a tautomeric equilibrium and the molar ratio 1: 1 of the reactants that minimizes the phenomenon of quaternization. In Pérez Eduardo, et al., The reactions are carried out in the absence of solvent and used as a microwave heating source, while the present invention is carried out in the absence of organic solvent and without applying microwave irradiation or some other type of heating. Pérez Eduardo; et al, refer to the use of a halide which is an a-bromo ketone (4-bromophenacyl bromide), presenting a carbon a, which is more easily reversed due to its polarity, because the carbon that supports bromine has Adjacent position a ketone group that influences polarity inversion and may favor / V-alkylation. While the present invention works with the / V-benzyl-2-chlorbacetamide, which contains a chlorine instead of bromine, the chlorine has less ease as a leaving group and the carbon that supports it has an adjacent amide functional group which does not favor the reversal of polarity as does the ketone group.

Dariusz Bogdal, et al. Remarkable Fast N-Alquilation of Azaheterocycles under Microwave Irradiation in Dry Media. Heterocycles, Vol. 45, No. 4, 1997. It shows a general method of / V-alkylation of heterocycles that have an acidic hydrogen. Maintaining the convenience of phase transfer catalysis (PTC) methods, but applying microwave heating under solvent-free conditions.

They present a rapid method of synthesis of / V-alkylaryl heterocycles in "dry" media under microwave irradiation according to Fig. 3.

Irradiation

 X = Cl, Br, I, TBAB: tetrabutylammonium bromide

Figure 3 .. Scheme of the reactions of the five-membered ring azaheterocyclics with the corresponding alkyl halides under microwave irradiation. Described by Dariusz

Bogdal, et al. Dariusz Bogdal, et al. they also present results for the reactions of the azaromatic compounds with fused rings shown in Fig. 3.

 I Microwave Irradiation

R 1 -10 in; 58-95%

K ₂ C0 ₃ / OH / TBAB

 Z = C: indole; Z = N: benzimidazole; TBAB: tetr butylammonium bromide.

 Figure 4. Reactions between alkyl halide and five-membered azaheterocyclic compounds fused to benzene rings and under microhyde irradiation. Described by Dariusz

 Bogdal, et ai.

The reaction is verified by a mixture of the azheterocyclic compound (5 mmol), with the corresponding alkyl halide (7.5 mmol), tetrabutylammonium bromide-TBAB (0.17 g, 0.50 mmol), and potassium carbonate (2.8 g, 20 mmol) , or mixture of potassium carbonate (2.8 g, 20 mmol) and potassium hydroxide (1.1 g, 20mmol), the mixture is heated in a domestic microwave oven. After cooling the reaction mixture is extracted with methylene chloride or tetrahydrofuran. The extract is dried with magnesium sulfate, filtered and the solvent is evaporated. Our invention, unlike Dariusz Bogdal, et al., Is carried out without applying any type of heating, it develops under mild conditions, it does not require the use of microwaves, it does not require the presence of a base such as KOH.

Gandolfi Donadío, L et al. Development of new technologies for the production of benznidazole. In: TecnoINTI edition 2013; 11 Open Days of Development, Innovation and Technology Transfer. 2-4 July 2013, Buenos Aires. Edited by the National Institute of Industrial Technology. Buenos Aires, October, 2013, 1st edition, page 218, ISBN 978-950-532-202-2. It describes reactions for the synthesis of Benznidazole following three alternative routes: Azo Route (Fig. ¼: T); - Imidazolone Route (Fig. 4.2) and Route 2-methyl-thi-Orimidazole (Fig. 4.3).

4 .1 Ru

Figure 4.1. Azo Route 2. Imidazolone Route

Figure 4.2. Imidazolone Route

4. 3. Route 2-methyl-thio-imidazole

 OI MVe

M _e + _KSCN HCI

 HN 1 N. Mel

H ₂ N ^ ₀ H ^ NH ·. NH _? OH.HCI G

Hi m reflux W Acetone K ₂ C0 ₃

 21 22

 23 75% (2 steps) 24 EtOH w

 twenty

 Figure 4.3. 2-methyl-thio-imidazole route

The Azo Route figure 4.1. It was used as the starting compound imidazole 9, the strategy presented by Gandolfi Donadío, L et al., Consists of introducing the nitrogen functionality by coupling between 9 and 8 to give the azoderivative 10. Then it presents the reduction of 10, to form an aminoimidazole derivative 15 in the presence of Pd (black) and formic acid. Oxidation via diazonium salt of 15 forms a mixture containing 2-chloroimidazole. According to the publication, derivatives 19 and 24 were synthesized in good yields and various reaction conditions were tested to obtain compound 20 without satisfactory results.

They also show two other routes of obtaining via imidazolone (Figure 4.2) and via 2-methyl thioimidazole (Figure 4.3). These routes pose as the last stage of synthesis, the reaction between / V-benzyl-2-chloroacetamide and 2-nitro-1 H-midazole in the presence of a strong NaH base and using DMF as solvent to obtain the benznidazole molecule.

The routes described by Gandolfi Donadío, L et al., Both in the imidazolone route and in the 2-methyl-thio-imidazole route, the three final steps of synthesis are steps that are being studied, according to the publication. In general, the routes proposed in Gandolfi Donadío, L et al present a series of steps that involve various reagents and heating conditions and the formation of several intermediary products. The present invention is carried out by reacting N-beñyl-2-chloroacetamide with 2-nitroimidazole, using tetrabutylammonium bromide (TBAB) and potassium carbonate (K2CO3) as catalyst. The reaction is carried out both in the absence of solvent as in the presence of water and in both cases without applying any type of heating.

Hernandez-Nuñez, Emanuel et al. Synthesis and in vitro trichomonicidal, giardicidal and amebicidal activity of A / -acetamide (sulfonamide) -2-methyl-4-nitro- 1 H-imidazoles. European Journal of Medicinal Chemistry, 44 (2009) 2975-2984. It presents a series of substituted a-chloroacetamides 16a and 16b-h, synthesized by condensation of 2-chloroacetyl chloride (18) with benzylamine (a) and substituted 4- anilines (bh), respectively, through two methodologies, according to the Figure 5. In the first, they use methylene chloride as solvent and triethylamine as the base. In the second, they use acetone and sodium bicarbonate as the base as solvent.

Hernandez-Nuñez, Emanuel et al. They describe that by means of the bimolecular nucleophilic substitution reaction they obtain a series of íniidazolic derivatives, / V-acetamide (sulfonamide) -2-methyl-4-nitroimidazoles, of general structure (i) and (i) according to figure 6.

Figura 6. Derivados imidazolicos obtenidos en Hernandez-Ñúñez, Emanuel et al.

Figure 6. Imidazolic derivatives obtained in Hernandez-Ñúñez, Emanuel et al.

Imidazole derivatives of the general formula (i) were prepared from anion 4 (5) -nitro-2-methyl-1 / - / - imidazole by a bimolecular nucleophilic substitution, using potassium carbonate and acetonitrile. The general method of synthesis is carried out with dissolution of 4 (5) -nitro-2-methyl-1 / - / - imidazole and potassium hydroxide, to generate anion 4 (5) -nitro-2-methyl-1 H-imidazole in the presence of acetonitrile. This solution is stirred for 30 minutes and to this mixture is added substituted a-chloroacetamide, dissolved in acetonitrile. It is stirred and heated at reflux for 8 hours. The solvent is removed in vacuo and the residue obtained is washed with water and subsequently recrystallized with an appropriate solvent. Imidazole derivatives of the general formula (i) were prepared via coupling reaction from anion 4 (5) -nitro-2-methyl-1 / - / - imidazole with arylsulfonyl chlorides, in the presence of potassium hydroxide, 4 -dimethylaminopyridine (catalyst) and triethylamine. Hernandez-Nunez, Emanuel et to the, has substituted derivatives -NO2 group 3 or 4 carbon substituent and methyl (-CH ₃₎ carbon 2. Reaction with chloroacetamide substituted a- is carried out in the presence ^'of potassium hydroxide , potassium carbonate and acetonitrile as solvent, and with reflux heating. The molecules obtained are derivatives homologous to metronidazpl, which have a nitro group (-NO2) in position 4 and a methyl group substituted on carbon 2.

The synthesis of our invention, unlike that presented by HERNANDÉZ-NÚÑEZ, EMANUEL et al., Is carried out with 2-nitroimidazole, reacting it with / \ / - benzyl-2-chloroacetamide in the presence of only potassium carbonate and bromide of tetrabutylammonium as catalyst, in the absence of organic solvent and without heating. While Hernandéz-Núñez, Emanuel et al, presents derivatives substituted with nitro group (-N0 ₂ ) in carbon 3 or 4 and methyl substituent (-CH ₃ ) in carbon 2. The reaction with substituted a-chloroacetamides is carried out in presence of potassium hydroxide, potassium carbonate and acetonitrile as solvent, and with heating under reflux.

US Patent 9,765,036 B2 presents a method of preparing / V-benzyl-2- (2-nitro-1 H-imidazol-1-yl) acetamide using as materials ^; initials N-benzyl-1-hydroxyacetamide and 2-nitroimidazole in the solid state and in the absence of solvent. The procedure occurs by mixing the two initial materials and activating by microwave irradiation to form the N-benzyl-2- (2-nitro-tH-imidazol-1-yl) acetamide. The reaction mixture is purified on a chromatography column, using alumina as the stationary phase and ethyl acetate as the mobile phase: The method does not require acid catalysts or bases in the synthesis process.

The invention presented in US 9,765,036 B2 is carried out with 2-nitroimidazole, reacting N-benzyl-2-chloroacetamide in the presence of microwave irradiation, while the present does not require any type of heating and the procedure is carried out in Smooth reaction conditions and does not require the use of sophisticated equipment for its development.

Patent application WO 2017/205622 A1 presents a method for preparing benznidazole by reacting 2-nitroimidazole (1.5 g) of formula 1 in figure 7, potassium carbonate (6.72 g) and bromine ethyl acetate (8 , 12 g, 5; 39 mL) of formula 2 in Figure 7, heated at 70 ° C for 110 minutes, this reaction mixture is cooled to 50 ° C and benzylamine is added, the suspension is stirred for 16 hours. Water (50 mL) is added, the reaction mass is cooled from 0 to 5 ° C and stirred for 2 hours, filtered and wash with 25 mL of cold water. Benznidazole of formula 3 in Figure 7 is obtained as a solid paste. The solid paste is dried under vacuum and at 50 ° C for 16 hours and the benznidazole of formula 3 in figure 7 is obtained as a pale yellow solid, 10.01 g (87%). The benznidazole formula 3 in figure 7 is recrystallized with a mixture of acetone: methanol: water (49.9 mL, 49.9 mL, 5.3 mL).

two

In patent application WO 2017/205622 A1 benznidazole is prepared from 2- nitroimidazole and acetate halide ester, where the halide can be bromine, iodine and chlorine where R (of the alkoxide group) can be methyl, ethyl, isopropyl , neobutyl, butyl and terbutyl, preferably use ethyl bromoacetate as the ester, carrying out the reaction in the presence of potassium carbonate, by means of a series of steps that require heating and cooling. Obtaining benznidazole in the form of a solid paste that requires subsequent recrystallization process. While this invention is made from 2-nitroimidazole and / V-benzyl-2-chloroacetamide, does not require heating or cooling, benznidazole is obtained in the form of a solid that facilitates the washing process to obtain the product with high purity.

 Description of the invention

The present invention deals with a method of synthesis for the production of Benznidazole or / V-benzyl-2- (2-nitro-1 H-imidazol-1-yl) acephalamide of formula (I), of high purity,

by reacting 2-nitroimidazole of formula (II) with / V-bericyl-2-chloroacetamide of formula (III), at room temperature in a range of 20 to 35 ° C, carried out in a time of up to 72 hours , in the presence of a base and catalyst. Two synthetic routes were developed: one in the absence of solvent, and another in the presence of solvent.

It is a synthesis method carried out by using a base such as potassium carbonate (K ₂ CO ₃ ), and as a tetrabutylammonium bromide (TBAB) catalyst. The molar ratio of the molecule of formula (II) and carbonate of. Potassium (K ₂ GQ ₃ ) is from one to one to one to six, respectively. It is a synthesis method, it is carried out by mixing the compounds of formulas (II) and (III), using: molar ratios from one to one to one to one point five for the organic molecules, adding potassium carbonate, and then bromide of tetrabutylammonium, the route is performed in the absence of solvent. Several addition orders were tested to perform the synthesis: mixing the compounds of formulas (II) and (III), adding tetrabutylammonium bromide and then potassium carbonate, carried out _, in the absence of solvent. It was also tested by mixing the compounds of formulas (II) and (III), adding potassium carbonate, and then tetrabutylammonium bromide, carried out in the absence of solvent. Also the reaction is carried out mixing .e! compound of formula (II) with potassium carbonate, adding to this mixture the compound of formula (III), and then tetrabutylammonium bromide, carried out in the absence of solvent.

The second reaction route consisted of carrying out the synthesis in the presence of solvent, reacting 2-nitroimidazole of formula (II) with / V-benCyl-2-chloroacetamide of formula (III), followed by the addition of potassium carbonate and tetrabutylammonium bromide, subsequently adding water to obtain a homogeneous reaction mixture.

Another procedure was to carry out the reaction by dissolving potassium carbonate in water, adding the compound of formula (II) and later. addition of the compound of formula (III) and tetrabutylammonium bromide. The synthesis methods described allow benznidazole of high purity to be obtained; It also allows the reuse of the mother liquor of the synthesis process, to obtain more benznidazole always of high purity. Our method has scaling check, we have worked on reactions using up to a mass of 2-nitroimidazole greater than 20 grams. The larger-scale syntheses have been carried out in the Fine Chemistry laboratory of the Pando Polo Scientific Institute (IPCP), Uruguay.

 The mother liquor obtained from the synthesis has been reused to carry out another process of the same synthesis, in some cases adding only 2-nitroimidazo and A / -benzyl-2-chloroacetamide. When the molar ratio of 2rhithroimidazole and potassium carbonate is from mole to mole, the second reaction state requires the addition of potassium carbonate. Obtaining high purity benznidazole.

Execution Example 1

This reaction is carried out as follows: 2-Nitroimidazole (1.0 g, 8.8 x 10 ³ moles) is mixed with 1 / V-benzyl-2-chloroacetamide (1,764 g, 9.7 x 10 ³ moles), in the absence of solvent. When the mixture is homogenized, tetrabutylammonium bromide (2.85 g 0, 8.8 x 10 ^ moles), is added and mixing is continued subsequently added carbonate- potassium (4.8892 g, 3.5 x 10 ^'2 moles). The reaction mixture is allowed to stand up to 72 hours. The synthesis product is isolated by performing water washes to neutral pH. To the The obtained benznidazole was performed by TLC analysis, high performance liquid chromatography with photodiode array detector (Figure 1 of annexes), corresponding to the retention time with reference standard, gas chromatography coupled to mass spectrometry corresponding time Withholding in the chromatogram and the mass spectrum with the reference standard, infrared spectroscopy was performed presenting signals of its spectrum that coincide with the signals of the reference standard.

Execution example 2.

This reaction is carried out as follows:

2-Nitroimidazole (1.0 g, 8.8 x 10 ³ moles) is mixed with / V-benzyl-2-chloroacetamide (1,764 g, 9.7 x 10 ³ moles) in the absence of solvent. Guando the mixture is homogenized, potassium carbonate, K2CO3 (4.8892 g, 3.5 x 10 is added ^'2 moles), mixing is continued subsequently tetrabutylammonium bromide (2.8510 g, 8.8 x 10 adds' ³ moles). The reaction mixture is allowed to stand up to 72 hours. The synthesis product is isolated by performing water washes to neutral pH. The benznidazole obtained was analyzed by TLC, high resolution liquid cryography with photodiode array detector (Figure 2 of years), corresponding to the retention time with reference standard, gas chromatography coupled to mass spectrometry corresponding the retention time in the chromatogram and the mass spectrum with the reference pattern, infrared spectroscopy was performed presenting signals of its spectrum that coincide with the signals of the reference pattern.

Execution example 3.

This reaction is carried out as follows:

2-Nitroimidazole (5.0 g, 4.4 x 10 ^-2 moles) is mixed with. / y-benzyl-2-chloroacetamide (8.932 g, 4.8 x 10 ^'2 moles) in absence of solvent. When the mixture is homogenized, potassium carbonate (24,446 g, 1.7 x 10 ^'1 mol) is added continuously mixing it subsequently tetrabutylammonium bromide (14.225 g, 4.4.x 10 ^_1 moles) is added. The reaction mixture is allowed to stand up to 72 hours. É | Synthesis product is isolated by performing water washings until pH _< neutral. The benznidazole obtained was analyzed by TLC, high performance liquid chromatography with photodiode array detector, corresponding to the retention time with standard of reference, gas chromatography coupled to mass spectrometry corresponding retention time in the chromatogram was performed infrared spectroscopy spectrum showing signals matching ^'with the signal reference pattern. Execution example 4.

This reaction is carried out as follows:

In the presence of magnetic stirring, 2-nitroimidazole (5.0 g, 4.4 x 10 ² moles) is added to a container containing water, then potassium carbonate (24,446 g, 1.7 x 10 ¹ moles) is added, mixing is continued until it forms a Homogeneous mixture, then / / / - benzyl-2-chloroacetamide (8,932 g, 4.8 x 10 ² moles) is added. Finally, tetrabutylammonium bromide (4.225 g, 4.4 x 10 ¹ mol) is added. The reaction mixture is continued stirring up to 72 hours. The synthesis product is isolated by performing water washes to neutral pH. The benznidazole obtained was analyzed by TLC, high performance liquid chromatography with photodiode array detector (Figure 3 of annexes), corresponding to the retention time with reference standard, gas chromatography coupled to mass spectrometry corresponding to retention time in the chromatogram and the mass spectrum with the reference pattern, infrared spectroscopy was performed presenting signals of its spectrum that coincide with the signals of the reference pattern.

Execution example 5.

This reaction is carried out as follows:

8 x -10- ^1, 2-nitroimidazole (10.0 g, 8.8 × 10 ² moles), A / 2-chloroacetamide -benóil-(17.864 g, 9.7 × 10 ² mol), tetrabutylammonium bromide (28.45 g, 8 are mixed moles), potassium carbonate (48,892 g, 0.35 moles) and then water is added forming a homogeneous mixture. The reaction mixture is maintained with magnetic stirring for up to 72 hours. The synthesis product is isolated by performing water washes to neutral pH. To the obtained benznidazole, TLC analysis, high resolution liquid chromatography with photodiode array detector (Figure 4 of annexes) were performed, corresponding to the retention time with reference standard, gas chromatography coupled to mass spectrometry corresponding to retention time on the chromatogram and mass spectrum with the reference standard, was performed

13 Infrared spectroscopy presenting signals of its spectrum that coincide with the signals of the reference standard.

Execution example 6.

This reaction is carried out as follows: In the presence of agitation, potassium carbonate (12.2219 g, 8.8 x 10 ² moles) is dissolved in water, then 2-nitroimidazole (5.0 g, 4.4 x ID ² moles) is added until Complete solution is subsequently added A / -benzyl-2-doroacetamide (8,932 g, 4.8 x 10 ² moles), stirring is continued until homogeneous mixing. Finally, tetrabutylammonium bromide (14,225 g, 4.4 x 10 ¹ mol) is added. The reaction mixture is stirred for up to 72 hours. The synthesis product is isolated by performing water washes to neutral pH. To the obtained benznidazole, TLC analysis, high resolution liquid chromatography with photodiode array detector (Figure 5 of annexes) were performed, corresponding to the retention time with reference standard, gas chromatography coupled to mass spectrometry corresponding to Chromatography retention time was performed infrared spectroscopy presenting signals of its spectrum that coincide with the signals of the reference standard.

Execution example 7.

This reaction is carried out as follows: In the presence of agitation, it is dissolved in potassium carbonate water (6.1110 g, 4.4 x 10 ² moles), then 2-nitroimidazole (5.0 g, 4.4 x 10 ^:? Moles) is added until complete dissolution, N-bendl-2-chloroacetamide (8,932 g, 4.8 x 10 ² moles) is added until stirring is continued until homogeneous mixing. Finally, tetrabutylammonium bromide (14,225 g, 4.4 x 10: ¹ mol) is added. The reaction mixture is continued stirring up to 72 hours. The synthesis product ^' is. isolated by performing water washes to neutral pH. To the obtained benznidazole, TLC analysis, high resolution liquid chromatography with photodiode array detector (Figure 6 of annexes) were performed, corresponding to the retention time with reference standard, gas chromatography coupled to mass spectrometry corresponding to Chromatogram retention time was performed infrared spectroscopy presenting signals of its spectrum that match the signals of the reference standard. Execution example 8.

This reaction was carried out in the Fine Chemistry laboratory of the Pando Polo Scientific Institute (IPCP), Uruguay and is carried out as follows:

In the presence of mechanical stirring, potassium carbonate (431.21 g; 3.12 moles) is dissolved in water, then 2-nitroimidazole (88.23g; 0.78 moles) is added, until completely dissolved. Then / V-benzyl-2-chloroacetamide (157.50g; 0.86 mol) is added until homogeneous. Finally, tetrabutylammonium bromide (251, 47; 0.78 moles) is added. The reaction mixture is continued stirring up to 72 hours. The synthesis product is isolated by performing washings. with water to neutral pH. To the obtained benznidazole, TLC analysis, high resolution liquid chromatography with photodiode array detector> (Figure 7 of annexes) were performed, corresponding to the retention time with reference standard, gas chromatography coupled to mass spectrometry corresponding the retention time in the chromatogram and the mass spectrum with the reference pattern, infrared spectroscopy was performed presenting signals of its spectrum .. that coincide with the signals of the reference pattern.

Execution example 9.

This reaction was carried out in the Fine Chemistry laboratory of the Pando Polo Scientific Institute (IPCP), Uruguay and is carried out as follows:

In the presence of mechanical agitation, potassium carbonate (1186.3 g; 8.58 moles) is dissolved in water, then 2-nitroimidazole (242.6 g; .2, 14 moles) is added, until completely dissolved. Then A / -benzyl-2-chloroacetamide (431.80 g; 2.35 moles) is added until homogeneous. Finally, tetrabutylammonium bromide (691.4 g; 2.14 moles) is added. The reaction mixture is continued stirring up to 72 hours. The synthesis product is isolated by performing water washes to neutral pH. The benznidazole obtained was analyzed by TLC, high performance liquid chromatography with photodiode array detector V (Figure 8 of annexes), corresponding to the retention time with reference standard, gas chromatography coupled to corresponding mass spectrometry. ' the retention time in the chromatogram and the mass spectrum with the reference pattern, infrared spectroscopy was performed presenting signals of its spectrum that coincide with the signals of the reference pattern. Execution example 10.

Using 25 mL of example reaction mother liquors ^: from: run 8, 1 gram of 2-nitroimidazole is reacted with 1.78 grams of '/ V-benzyl-2-chloroacetamide the reaction mixture is stirred for 72 hours at room temperature . The solid formed is separated from the solution by vacuum distillation by doing several washings with water until neutral pH is reached in the washings. The product obtained was analyzed by high performance liquid chromatography with photodiod array detector (Figure 9 of annexes), corresponding to the retention time with benznidazole reference standard. The product obtained has high purity according to the HPLC analyzes performed.

Execution example 11.

Using 50 mL of sample reaction mother liquors! of execution 7, 2.5 grams of 2-nitroimidazole are reacted with 4,412 grams of / V-benzyl-2-chloroacetamide, the reaction mixture is stirred for 72; hours at room temperature. The solid formed is separated from the solution by vacuum distillation by doing several washings with water until neutral pH is reached in the washings. The product obtained was analyzed by high performance liquid chromatography with photodiode array detector (Figure 10 of annexes), corresponding to the retention time with benznidazole reference standard. The product obtained has high purity according to the HPLC analysis performed.

Claims

Claims 1) A synthesis method for obtaining Benznidazole or A / -benzyl-2- (2-nitro-1 H- midazol-1-yl) acetamide of formula (I), of high purity,

characterized by reacting 2-nitroimidazole of formula (II) with / V-benzyl-2-chloroacetamide of formula (III), in the absence of solvent, at room temperature in a range of 20 to 35 ° C, carried out in a time of up to 72 hours, in the presence of a base and catalyst.

(II) (III) 2) A synthesis method according to claim 1, characterized in that potassium carbonate (K ₂ CO 3) is used as the base. 3) A synthesis method according to claim 1, characterized in that tetrabutylammonium bromide (TBAB) is used as catalyst. 4) A method according to claim 1, characterized by using molar ratios from one to one to one to one point five for organic molecules of formulas (II) and (III) respectively. 5) A synthesis method according to claim 1, characterized by carrying out the reaction in molar ratio of compound of formula (II) and potassium carbonate (K2CO ₃ ) from one to one to one to six respectively. 6) A synthesis method according to claim 1, characterized by carrying out the reaction in molar ratio of compound of formula (II) and tetrabutylammonium bromide (TBAB). one to one each compound .; 7) A synthesis method according to claim 1, characterized by carrying out the reaction by mixing the compounds of formulas (II) and (III), adding tetrabutylammonium bromide and then potassium carbonate, carried out in the absence of solvent. 8) A synthesis method according to claim 1, characterized in that the reaction is carried out by mixing the compounds of formulas (II) and (lllj, adding potassium carbonate, and then tetrabutylammonium bromide, carried out in the absence of solvent. 9) A synthesis method according to claim 1, characterized in that the reaction is carried out by mixing the compound of formula (II) with potassium carbonate, adding to this mixture the compound of formula (III), and subsequently tetrabutylammonium bromide, carried out in the absence of solvent. 10) A synthesis method for obtaining Benznidazole or A / -benzyl-2- (2-nitro-1 H- imidazo! -1-yl) acetamide of formula (I), of high purity.

characterized by reacting 2-nitroimidazole of formula (II) with N-benzyl-2-chloroacetamide of formula (III), in the presence of solvent at room temperature in a range of 20 to 35 ° C, carried out with stirring, in a time of up to a maximum of 72 hours, in the presence of a base and catalyst.

11) A synthesis method according to claim 10, characterized in that potassium carbonate (K2CO3) is used as the base. 12) A synthesis method according to claim 10, characterized in that tetrabutylammonium bromide (TBAB) is used as catalyst. 13) A synthesis method according to claim 10, characterized in that water is used as solvent. 14) A method according to claim 10, characterized by using molar ratios from one to one to one to one point five for organic molecules of formulas (II) and (III) respectively. 15) A synthesis method according to claim 10, characterized by carrying out the reaction in molar ratio of molecule of formula (| i) and potassium carbonate (K2CO3) from one to one to one to six respectively. 16) A synthesis method according to claim 10, characterized by carrying out the reaction by stirring the aqueous mixture for a maximum of 72 hours. 17) A synthesis method according to claim 10, characterized in that the reaction is carried out by mixing the compounds of formulas (II), (III), potassium carbonate and tetrabutylammonium bromide, subsequently adding andp _; water to obtain homogeneous reaction mixture. 18) A synthesis method according to claim 10, characterized by carrying out the reaction by dissolving potassium carbonate in water, adding the compound of formula (II) and subsequent addition of the compound of formula (III) and tetrabutylammonium bromide. 19) A synthesis method according to claim 10, characterized by obtaining high purity benznidazole by washing with water until neutral pH. 20) A synthesis method according to claim 10, characterized by reusing the mother liquors of the synthesis process, in the presence of solvent by adding the compounds of formulas (II) and (III), to obtain benzmdezol of high purity. 21) A synthesis method for obtaining Benznidazbi or A / -benzyl-2- (2-nitro-1 H -imidazol-1-yl) acetamide of formula (I), of high purity,

characterized by reacting 2-nitroimidazole of formula (II) with A / -benzyl-2-chloroacetamide of formula (III), in the absence or presence of solvent, at room temperature in a range of 20 to 35 ° C, carried out in a time of up to 72 hours, in the presence of a base and catalyst,

the molar ratios being: from one to one to one to one point five for organic molecules of formulas (II) and (III) respectively, the compound of formula (II) and potassium carbonate (K2CO3) from one to one to one á six respectively and the compound of formula (II) with the tetrabutylaphionium bromide (TBAB) one by one, using different orders of addition of the reactants, / use of the mother liquors of the synthesis process when it is carried out in the presence of solvent , adding the compounds of formulas (II) and (III), to obtain high purity behznidazole.