RU2821795C1 - Method of producing benzodifurazan - Google Patents

Abstract

FIELD: organic chemistry; pharmaceutics.

SUBSTANCE: invention relates to a method of producing benzodifurazan of formula 1. Method involves cyclisation of 2,5,6-tris(hydroxyimino)cyclohex-3-en-1-one hydrate or benzo[c][1,2,5]oxadiazole-4,7-dione dioxime by boiling for 20–30 hours in an aqueous solution of hydroxylamine to obtain benzodifurazan.

EFFECT: obtaining benzodifurazan using an efficient method.

1 cl, 3 ex, 4 dwg

Description

The invention relates to organic chemistry and pharmaceuticals, namely to a method for producing benzodifurazan 1,

1

which is used directly or as a precursor in various areas of organic synthesis, is a bioactive compound and is of practical interest in the production of new drugs.

Globalization has caused an increase in the incidence of the world's population in almost all nosological groups: from cardiovascular diseases and cancer to mental disorders and large-scale epidemics. Against this background, the need for new effective, selectively acting and low-toxic drugs of natural and synthetic origin for pharmacotherapy and chemical laboratory diagnostics of various diseases is sharply increasing, as well as for the development of original and improvement of known approaches for their production.

There are a large number of antibacterial, antifungal, and antiparasitic drugs in the arsenal of pharmaceuticals. Despite this, modern medicine often faces the problem of microbial resistance to drugs. Therefore, the creation of new medicinal substances with long-term effects against a large number of bacteria and fungi is an important and urgent task in organic and medicinal chemistry.

In the last 10-15 years, using high-throughput screening (HTS) and combinatorial chemistry methods, various research groups and pharmaceutical companies have selected leading structures, on the basis of which a number of new drugs have been introduced into medical practice.

One of the possible leading structures could be benzodifurazan 1 or its derivatives.

It has been established: benzodifurazan 1 and its derivatives have pronounced antimicrobial, antimycotic and acaricidal properties. Thus, hydroxybenzodifurazan and methoxybenzodifurazan are more than 30 times more active than chlorophos. Nitro derivatives of benzodifurazan exhibit high bacteriostatic activity, superior in activity to the drugs Vasin and formalin. Hydroxynitrobenzodifurazan is two orders of magnitude superior in bacteriostatic activity to the well-known drug Sulgin. Benzodifurazan 1 has a pronounced antimicrobial effect. Its MBC (Minimum Bacteriostatic Concentration) against Staphylococcus aureus was 0.1%. [4,6]

There is a known patent for the use of benzodifurazan (WO 9854183 A2) [1]. Benzodifurazan 1 is present in the derivative ergoline 2, which is used as an effective drug in the treatment of depression, anxiety and bipolar disorders. The compound is indicated for the treatment of schizophrenia and dementia, in particular senile dementia of the Alzheimer's type.

2

Thus, both benzodifurazan 1 itself and its derivatives are bioactive compounds and are of practical interest as medicines.

However, methods for obtaining benzodifurazan 1 and its derivatives are multi-stage and complex [2-4]. This explains the high commercial cost of both benzodifurazan itself and its derivatives.

The work of W. Borsche [5] describes the synthesis of cyclohex-5-ene-1,2,3,4-tetraone-tetraoxime and the preparation of benzodifurazan by the action of acetic anhydride on this tetraoxime. When testing the method, we obtained benzo[c][1,2,5]oxadiazole-4,7-dione dioxime as the main and only product instead of tetraoxime. The product is, according to PMR data, a mixture of isomeric oximes in the ratio A:B:C = 1:4:1.7. All isomers were isolated by chromatography and characterized based on analytical and spectral data (example 1).

In known syntheses of benzodifurazan, they start from available benzofuroxans, in which the second furoxan ring is completed and N-oxides are removed [5-7].

The prototype of the present invention is a method for producing benzodifurazan 1, described in [6-7]. The method involves the nitration of chlorobenzofuroxan 3 with nitric acid in sulfuric acid to form 6-chloro-7-nitrobenzofuroxan 4, upon interaction of which with sodium azide the chlorine atom is replaced by an azido group. When azidonitrobenzofuroxan 5 is heated, cyclization occurs to form benzodifuroxan 6. Treatment of the latter with triethylphosphite leads to benzodifurazan 1 (Fig. 1. Method for obtaining benzodifurazan from chlorobenzofuroxan).

The technological disadvantages of the prototype method are its multi-stage nature and labor intensity. The use of additional equipment (rotary evaporator, vacuum pump) significantly complicates the production technology. The use of chlorobenzofuroxan 3 as a starting compound, the synthesis of which occurs in several stages, requires additional time and material resources. The use of concentrated sulfuric and nitric acids, as well as highly toxic sodium azide and triethylphosphite, significantly reduces the environmental friendliness of the process.

The objective of the present invention is to develop a new effective method for producing benzodifurazan 1, the advantage of which is to simplify the technology and reduce material, time and energy costs.

The problem is solved by the proposed method for obtaining benzodifurazan 1 starting from benzoquinone oximes - 2,5,6-tris(hydroxyamino)cyclohex-3-en-1-one hydrate 9 or from benzo[c][1,2,5]oxadiazol-4, 7-dione dioxime 10 (Figure 2. Method for obtaining benzodifurazan from benzoquinone oximes).

The synthesis of benzoquinone oximes 9-10 is given in [8-9] and can be carried out starting from commercially available resorcinol, in accordance with Fig. 3 (Fig. 3. Synthesis of benzoquinoximes).

Nitrosation of resorcinol 7 in an aqueous solution of sodium nitrite in the presence of sulfuric acid leads with 98% yield to dinitrosoresorcinol 8. Oximation of dinitrosoresorcinol 8 with hydroxylamine hydrochloride in 50% alcohol by boiling for two hours leads with 90% yield to 2,5,6-tris( hydroxymino)cyclohex-3-en-1-one hydrate 9, and boiling for 20 hours with hydroxylamine hydrochloride in an acidic methanol solution gives benzo[c][1,2,5]oxadiazole-4,7-dione dioxime 10 s yield about 70%.

Heating of benzoquinone oximes - 2,5,6-tris(hydroxymino)-cyclohex-3-en-1-one hydrate 9 or benzo[c][1,2,5]oxadiazol-4,7-dione dioxime 10 in an aqueous solution of hydroxylamine leads to the formation of benzodifurazan 1. The installation for obtaining benzodifurazan 1 is shown in Fig. 4 (Fig. 4. Installation for obtaining benzodifurazan: 1-Heating mantle, 2-Three-neck flask with a volume of 500 ml, 3-Nozzle, 4-Dimroth or Othmer refrigerator, 5-Separating funnel for chloroform, 6-Nozzle, 7-Hydraulic seal, 8- Connection with the atmosphere). The resulting benzodifurazan 1 flies with water vapor and enters refrigerator 4, where it crystallizes on the cold surfaces of the refrigerator (melting point of benzodifurazan 61 ^o C). After a sufficient amount of benzodifurazan 1 has formed, it is washed off from separating funnel 5 with chloroform. The chloroform-containing extract is dried over MgSO _4, the desiccant is filtered off, the solvent is evaporated, the residue is suspended in hexane, the benzodifurazan 1 precipitate is filtered off and dried. Boiling time varies between 20-30 hours. The end of the process is determined visually when the target product, in the form of a white powder, stops accumulating on the cold parts of the refrigerator. Product yield 50 -54%.

The proposed method makes it possible to achieve ease of implementation of the technological process, without the use of expensive equipment and reagents, with minimal time and in compliance with environmental standards of the production process, while obtaining a promising bioactive product that can be used in the development of new drugs containing benzodifurazan.

Spectral studies were carried out at the Chemical Service Center for Collective Use of the SB RAS.

The invention is illustrated by the following examples:

Example 1. Preparation of benzo[c][1,2,5]oxadiazole-4,7-dione dioxime according to the Borsche method [5]

Add 37.2 g of dinitrosoresorcinol, 800 ml of methanol, 300 ml of conc. to a 2-liter round-bottom flask. hydrochloric acid and 42 g of hydroxylamine hydrochloric acid. The mixture is refluxed for 24 hours. Filter while hot. Evaporate to a volume of 50 ml, add about 10 ml of water, filter off the precipitate, wash with water, and dry. About 37 g of dioxime are obtained in the form of a brown powder. The product is highly soluble in ethyl acetate. According to thin layer chromatography on silfol plates in the system: ethyl acetate: hexane = 1:3, three spots were observed. All three substances were isolated by column chromatography. Isomers differ from each other in the configuration of their oxime groups.

The mixture of isomers was separated by chromatography on silica gel; first, a mixture of ethyl acetate: hexane = 1:3 was used as an eluent, then 1:1, and finally pure ethyl acetate.

Compound A is isolated. (4Z,7Z) Benzo[c][1,2,5]oxodiazolo-4,7-dione dioxime is a yellow crystalline powder. m.p. 215-216 °C (alcohol). UV spectrum, λ max., nm, (log έ): 306 (4.07), 1H NMR spectrum, δ, ppm (Deuteroacetone): 7.50 s (2H, 2CH), 12.28 br. c.(4H, 4 OH) 13C NMR spectrum, δ, ppm (Deuteroacetone): 127.31 (all CH), 140.41, 143.38 (all C). Mass spectrum, m/z (Irel., %): 180 [M]+, (100), 163 (22) 120 (23), 103 (45), 80 (19), 76 (15). Found, %: From 40.12; H 2.25; N 31.09. M+ 180.0276. C6H4N4O3. Calculated, %: From 40.01; H 2.24; N 31.11. M 180.0278.

The second compound isolated was B. (4Z,7E) Benzo[c][1,2,5]oxodiazolo-4,7-dione dioxime - yellow crystalline powder. m.p. 226-227 °C (alcohol). UV spectrum, λ max., nm, (log έ): 298 (4.07). 1H NMR spectrum, δ, ppm (Deuteroacetone): 6.96 d (1H, CH) J =10.5 Hz), 7.42 d (1H, CH J =10.5 Hz), 12.30 br. With. (4H, 4OH) 13C NMR spectrum, δ, ppm (Deuteroacetone): 140.75, 141.29, 143.31, 148.361 (all C), 118.02, 129.93 (all CH). Mass spectrum, m/z (Irel., %): 180 [M]+, (100), 163 (24), 152 (30), 120 (27), 103 (47). 80 (12), 76 (16). Found, %: Since 40.08; H 2.28; N 30.90. M+ 180.0276. C6H4N4O3. Calculated, %: From 40.01; H 2.24; N 31.11. M 180.0278.

And the last compound isolated was B. (4E,7E) Benzo[c][1,2,5]oxodiazolo-4,7-dione dioxime - yellow crystalline powder. T. pl. 218-219 °C (alcohol). UV spectrum, λ max., nm, (log έ): 297 (4.07), 1H NMR spectrum, δ, ppm (Deuteroacetone): 7.50 (2H, 2CH). 12.28 us.s. (4H, 4 NOH) 13C NMR spectrum, δ, ppm (Deuteroacetone): 141.25, 148.40 (all C), 119.79 (CH). Mass spectrum, m/z (Irel., %): 180 [M]+, (100), 163 (24), 162 (77), 150 (12), 133(12), 120 (29), 103 (56). 93 (13), 80 (22), 76 (34). Found, %: From 40.00; H 2.47; N 31.24. M+ 180.0276 C6H4N4O3. Calculated, %: From 40.01; H 2.24; N 31.11. M 180.0278.

The configuration of oxime groups was determined according to literature data E. Breitmaier, W. Voelter "Carbon-13 NMR Spectroscopy...", 1987, p.173

Examples 2-3. Preparation of benzodifurazan 1.

Example 2. Prepare a solution of 24 g (0.6 mol) sodium hydroxide in 50 ml of water. Approximately 5 ml of the resulting sodium hydroxide solution is added to a mixture of 20.1 g (0.10 mol) of 2,5,6-tris(hydroxyamino)cyclohex-3-en-1-one hydrate, 9,250 ml of water and 41.7 g (0.6 mol) of hydroxylamine hydrochloride. The mixture is carefully heated until the exothermic reaction begins. The heat is removed and the remainder of the sodium hydroxide solution is added drop by drop at such a rate that the mixture boils gently. Addition time is approximately 1 hour. After adding the entire amount of sodium hydroxide solution, the mixture is heated to a boil and boiled with a Dimroth reflux condenser or an Othmer condenser. The product sublimes with water vapor and settles on the walls of the refrigerator. It is periodically washed off with chloroform. Boiling time is 20-30 hours until the product stops releasing. Chloroform is separated from water in a separating funnel and dried over calcined MgSO ₄ . The desiccant is filtered. Chloroform is evaporated. The residue is suspended in hexane, and the precipitate is filtered off. About 8.25 g (50.9%) of benzodifurazan 1 is obtained in the form of a white powder. T. pl. 59 – 60 °C

IR spectrum, ν/cm ^-1 : 676.92, 815.78, 873.64, 995.13, 1132.06, 1417.49, 1587.20, 3072.19. (Peaks with intensities greater than 30% are indicated). ). UV spectrum, λ max., nm, (log έ): 230 (4.07), 234 (4.07). ^1H NMR (400 MHz, CDCl ₃ , δ, ppm): 7.88 s (2H, 2CH). ¹³ C NMR (100 MHz, CDC1 ₃ , δ, ppm): 121.08 (CH), 139.59, 149.60 (C

Mass spectrum, m/z (Irel., %): (Peaks with intensity greater than 10% are indicated). 162 [M]+ (100), 104 (18), 84 (11), 75 (13), 64 (18), 51 (19), 50 (27). Found, %: C 44.43; H 1.25; N 34.59. M ⁺ 162.0176. _{C6H2N4O2 . ​ ​} Calculated, %: C 44.44; H 1.23; N 34.57. M 162.0172.

Product characteristics correspond to literature data [7].

Example 3. Prepare a solution of 12 g (0.3 mol) sodium hydroxide in 25 ml of water. Approximately 5 ml of the resulting solution is added to a mixture of 9.0 g (0.05 mol) benzo[c][1,2,5]oxadiazol-4,7-dione dioxime 10 in 100 ml of water and 20.85 g (0.3 mol) hydroxylamine hydrochloride. The mixture is carefully heated until the exothermic reaction begins. The heat is removed and the remainder of the sodium hydroxide solution is added drop by drop at such a rate that the mixture boils gently. Addition time is approximately 1 hour. After adding the entire amount of caustic soda solution, the mixture is heated to boiling and boiled with a Dimroth reflux condenser or an Othmer reflux condenser. The product sublimes and settles on the walls of the refrigerator. It is periodically washed off with chloroform. Boiling time is 20-30 hours until the product stops releasing. Chloroform is separated from water in a separating funnel and dried over calcined MgSO ₄ . The desiccant is filtered off and the chloroform is evaporated. The residue is suspended in hexane and filtered. About 4.5 g (54%) of benzodifurazan 1 is obtained in the form of a white powder. T.pl. 59-60 °C.

IR spectrum, ν/cm-1: 676.92, 815.78, 873.64, 995.13, 1132.06, 1417.49, 1587.20, 3072.19 (Peaks with an intensity of more than 30% are indicated). ^1H NMR (400 MHz, CDCl ₃ , δ, ppm): 7.88 (s, 2H). ¹³ C NMR (100 MHz, CDC1 ₃ , δ, ppm): 121.08 (CH), 139.59, 149.60 (C). Product characteristics correspond to literature data [7].

Literature:

1. Patent WO9854183A2

2. E. A. Ermolaeva Synthesis of the structure and properties of nitro-substituted benzofurazan and benzodifurazan // Dis. Kazan 2005.

3. S. I. Efimov Substituted benzofurazan and benzodifurazan: synthesis, structure, properties // Dis. Kazan 2001.

4. R. G. Karimova Pharmaco-toxicological assessment of substituted benzodifurazan // Dis. Kazan 2003.

5. W. Borsche; H. Weber Justus Liebigs Annalen der Chemie, 489 (1931), 270-291.

6. F. S. Levinson, M. I. Evgeniev, E. A. Ermolaeva, S. I. Efimov, I. F. Falyakhov, T. V. Garipov, R. G. Karimova Chemical-pharmaceutical journal. 37, (2003), 12-15.

7. C. M. Cillo,  T. D. Lash, Journal of Heterocyclic Chemistry, 41, (2004), 955–962.

8. A. J. Boulton, et al. Journal of the Chemical Society, (1965), 5958 – 5964.

9. V. A. Samsonov, G. E. Salґnikov, and A. M. Genayev Russian Chemical Bulletin, International Edition, 58, (2009), 2369–2375.

10. V. A. Samsonov, L. B Volodarsky. HGS, 10, (1991), 1408-1413.

11. J. J. Lewis, J. Heterocycl. Chem., 12, (1975), p. 601.

12. R. M. Paton, 1.2.5-Oxadiazoles / Science of Synthesis – 2009-vol, 13 – Ch.8 –p. 185-218.

13. L.I.Khmelnitsky, S.S.Novikov, T.I.Godovikova Chemistry of furoxans, reactions and applications. Science Moscow. 1983.page 309.

14. Database on the properties and reactions of chemical substances - Reaxys from Elsevier.

Claims (3)

Method for obtaining benzodifurazan of formula 1 1 , consisting in the cyclization of 2,5,6-tris(hydroxyamino)cyclohex-3-en-1-one hydrate or benzo[c][1,2,5]oxadiazole-4,7-dione dioxime by boiling for 20-30 hours at reflux in an aqueous solution of hydroxylamine.