RU2709732C1 - Substituted 4-nitropyrazolin-5-ones, a method for production thereof and use thereof as fungicidal agents - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry. Substituted 4-nitropyrazolin-5-ones of general formula:

where R=H, phenyl; R₁=lower alkyl, phenyl; R₂=alkyl C₁-C₆, benzyl, allyl, CH₂CH₂CN or R₁+R₂=(CH₂)₄, are obtained by a method in which the corresponding substituted pyrazolin-5-ones are reacted with sodium nitrite (NaNO₂) and iron nitrate (Fe(NO₃)₃) in an organic solvent medium, and the process is carried out in molar ratio pyrazolin-5-one : NaNO₂ : Fe(NO₃)₃ = 1:1–2:2–4. Compounds of formula I exhibit fungicidal activity.

EFFECT: disclosed substituted 4-nitropyrazolin-5-ones of general formula (I) are novel fungicidal agents exhibiting high fungicidal activity.

5 cl, 1 tbl, 12 ex

Description

The present invention relates to the field of organic chemistry, namely, substituted 4-nitropyrazolin-5-ones of the general formula:

where R = H, phenyl; R ₁ = lower alkyl, phenyl; R ₂ = C ₁ -C ₆ alkyl, benzyl, allyl, CH ₂ CH ₂ CN or R ₁ + R ₂ = (CH ₂ ) ₄ , to the method for their preparation and use of these compounds as fungicidal agents. The compounds of the general formula I can find application in agriculture as fungicidal agents in the composition of compositions for controlling fungal diseases of plants.

Derivatives of pyrazolones are widely known as anti-inflammatory drugs, analgesics and antipyretics, have long been used in medicine. It should be noted that fungicidal activity was previously described only for a few pyrazolones, usually characterized by a complex structure and containing additional carbocyclic and heterocyclic rings. So in the literature phenylhydrazones of pyrazolin-5-ones with a thiazole fragment of the general formula are described:

which have fungicidal activity against fungi Aspergillus niger and Candida albicans [M. RD Reddy, ARG Prasad, YN Spoorthy, LRKR Ravindranath, Synthesis, Characterization and Antimicrobial Activity of Certain Novel Aryl Hydrazone Pyrazoline-5-Ones Containing Thiazole Moiety, Advanced Pharmaceutical Bulletin ,, 2013, 3, 153. doi: 10.5681 / apb.2013.026 ].

Known N ¹ -nicotinoyl-3-methyl-4- (arylazo) -1,2-pyrazolin-5-ones of the general formula:

possessing fungicidal activity against Candida albicans, Candida neoformans, Sporothrix schenckii, Trichophyton mentagrophytes and Aspergillus fumigatus [S.S. Nayal, C.P. Singh, Synthesis and antifungal activity of N1-nicotinoyl-3-methyl-4- (substituted azo) -1,2-pyrazoline-5-one, Asian J. Chem. 1999, 11, 207-212].

Also known are 1 - [(2-benzoylamino) benzoyl] -3-methylpyrazolin-5-ones of the general formula:

где R=Н, Ph,

where R = H, Ph,

possessing fungicidal activity against Aspergillus niger and Aspergillus flavus, which is comparable with the activity of salicylic acid [M. Kidwai, R. Mohan, Ecofriendly Synthesis of Antifungal Azoles, J. Korean Chem. Soc. 2004, 48, 177-181. DOI: 10.5012 / jkcs.2004.48.2.177]. In the patent [US 5028717A, Herbicidal and fungicidal agents based on substituted pyrazolin-5-one derivatives] pyrazolones of the general formula are described:

as herbicides and fungicides.

In the patents [US 4666933A, (O-substituted oximino) -pyrazolin-5-one pesticides; EP 0166171 A1, Substituted pyrazolin-5-one] describes pyrazolones of the general formula:

as fungicides.

In the application [WO 9626191 A1, Fungicidal cyclic amides], devoted to cyclic amides with fungicidal activity, in the claims there are structures with a nitro group of the formula:

где R = алкил и др., R₁ = нитро и др., R₂ и R₃ = арил и др. [WO 9626191 А1, Fungicidal cyclic amides].

where R = alkyl and others, R ₁ = nitro and others, R ₂ and R ₃ = aryl and others [WO 9626191 A1, Fungicidal cyclic amides].

However, the patent does not provide data on the fungicidal activity of compounds of the general formula VII having, when R ₁ = a nitro group.

A number of publications report fungicidal activity of other polysubstituted pyrazolin-5-ones of complex structure [(1) WO 9636229 A1, WO 9636615 A1, Fungicidal cyclic amides; (2) WO 9931070 A1, Substituted phenylpyrazolones, method and intermediate products for the production thereof and their utilization for combating parasitic fungi and animal parasites; (3) EP 0967212 A1, Pyrazoline compounds and use as plant disease control agent].

The difference of the structures proposed in the present invention from the known pyrazolin-5-ones exhibiting fungicidal activity is the presence of two substituents at C-4 of pyrazolin-5-one, one of which is a nitro group, and the second is a hydrocarbon substituent according to the general formula I.

The disadvantages of these known compounds are the complexity of the synthesis and the need for expensive reagents.

A known method for producing nitropyrazolones consists in treating the corresponding starting pyrazolin-5-ones with nitric acid, a mixture of nitric and sulfuric acid, or a mixture of nitric acid and trifluoroacetic anhydride [WO 9626191 A1, Fungicidal cyclic amides]. The disadvantage of this method is the severe strongly acidic synthesis conditions, as well as low selectivity. For example, if phenyl substituents are present in the molecule, they are also nitrated [(1) K.-A. Kovar, W. Rohlfes, N. Auterhoff, Nitrierungsprodukte des Propyphenazons und deren Farbreaktionen mit Aceton und Kalilauge, Arch. Pharm. 1981, 314, 532-541. DOI: 10.1002 / ardp.19813140611. (2) A. G. Burton, M. Dereli, A. R. Katritzky, H. O. Tarhan, The kinetics and mechanism of the electrophilic substitution of heteroaromatic compounds. Part XXXV. The Nitration of Phenylpyrazolones, J. Chem. Soc, Perkin Trans. 2, 1974, 382-388.], Therefore, the known method is unsuitable for obtaining the proposed compounds.

An object of the present invention is to expand the range of fungicidal agents based on substituted 4-nitropyrazolin-5-ones, as well as to develop a process for their preparation. The stated technical problem is achieved by substituted 4-nitropyrazolin-5-ones of the general formula:

where R = H, phenyl; R ₁ = lower alkyl, phenyl; R ₂ = alkyl C ₁ -C ₆ , benzyl, allyl, CH ₂ CH ₂ CN or R ₁ + R ₂ = (CH ₂ ) ₄ having fungicidal activity. The 4-nitropyrazolin-5-ones of the general formula I proposed in the present invention are fundamentally different from all the previously described fungicides containing the pyrazolone ring by the presence of two substituents at position 4 of the pyrazolone, one of which is necessarily a nitro group. The proposed fungicides are new undescribed in the literature. A compound of general formula I, where R = phenyl, a R ₁ and R ₂ = Me, (3,4-dimethyl-4-nitro-1-phenylpyrazolin-5-one (Ia) participated in a screening of biological activity (CAS 957359-02 -3) (data from the PubChem database, SID 22412834, https://pubchem.ncbi.nlm.nih.gov/bioassay/804#sid=22412834&section=Top), but no fungicidal activity was found. way to get it.

The proposed compounds are of interest as fungicidal agents for controlling plant pathogens.

Also proposed is a method not described in the literature for preparing substituted 4-nitropyrazolin-5-ones of the general formula:

where R = H, phenyl; R ₁ = lower alkyl, phenyl; R ₂ = alkyl C ₁ -C ₆ , benzyl, allyl, CH ₂ CH ₂ CN or R ₁ + R ₂ = (CH ₂ ) ₄ , namely that the corresponding substituted pyrazolin-5-ones of the general formula:

, где R, R₁ и R₂ имеют вышеуказанные значения, подвергают взаимодействию с нитритом натрия (NaNO₂) и нитратом железа (Fe(NO₃)₃) в среде органического растворителя, и процесс проводят при мольном соотношении пиразолин-5-он : NaNO₂ : Fe(NO₃)₃=1:1-2:2-4. Процесс протекает по следующей схеме:

where R, R ₁ and R ₂ have the above meanings, are reacted with sodium nitrite (NaNO ₂ ) and iron nitrate (Fe (NO ₃ ) ₃ ) in an organic solvent, and the process is carried out at a molar ratio of pyrazolin-5-one: NaNO ₂ : Fe (NO ₃ ) ₃ = 1: 1-2: 2-4. The process proceeds as follows:

In the above scheme, R, R ₁ , and R ₂ have the above meanings of the general formula I.

The process is carried out at room temperature, and, for example, acetonitrile (MeCN) is used as an organic solvent.

The process can be carried out by adding to the initial corresponding substituted pyrazolin-5-ones a mixture of NaNO ₂ and Fe (NO ₃ ) ₃ in an organic solvent, or by adding Fe (NO ₃ ) ₃ to a mixture of the corresponding starting substituted pyrazolin-5-one, NaNO ₂ and organic solvent.

The invention is illustrated by examples of the preparation of the proposed compounds of general formula I, and the results of their testing as fungicides against plant pathogens.

Example 1. Obtaining 3,4-dimethyl-4-nitro-1-phenylpyrazolin-5-one (Ia). Fe (NO ₃ ) ₃ ⋅ 9H ₂ O (2 mmol, 808 mg) was added to the mixture of NaNO ₂ (1 mmol, 69 mg) and MeCN (5 ml) with stirring at room temperature over 5-10 seconds. After 5 minutes, 3,4-dimethyl-1-phenylpyrazolin-5-one (1 mmol, 188 mg) was added to the stirred reaction mixture for 5-15 seconds, stirring was continued for 20 minutes. The reaction mixture was diluted with CH ₂ Cl ₂ (10 ml) and 3% aqueous HCl (30 ml), shaken and the organic layer was separated. The aqueous layer was extracted with CH ₂ Cl ₂ (2 × 10 ml), after which all organic extracts were combined, washed with water (2 × 20 ml), dried with MgSO ₄ . The solvent was removed in a vacuum of a water-jet pump on a rotary evaporator. The product was isolated by silica gel column chromatography using CH ₂ Cl ₂ as eluent. Received 3,4-dimethyl-4-nitro-1-phenylpyrazolin-5-one in the form of a viscous mass, crystallizing upon standing with a yield of 58% (0.58 mmol, 135 mg). _Mp = 40-41 ° C; ¹ H NMR (300.13 MHz, CDCl ₃ ): δ = 7.94-7.84 (m, 2H), 7.51-7.39 (m, 2H), 7.32-7.22 (m, 1H), 2.22 (s, 3H), 1.95 (s , 3H); ¹³ C NMR (75.47 MHz, CDCl ₃ ): δ = 164.6, 154.7, 137.0, 129.2, 126.2, 119.0, 91.8, 17.8, 13.3; IR (thin layer): ν _max = 1731, 1597, 1558, 1501, 1383, 1368, 1294, 1147, 759, 691 cm ^-1 ; high resolution mass spectrum (Electrospray): m / z = 256.0697, calc. For C ₁₁ H ₁₁ N ₃ O ₃ + Na ⁺ : 256.0693.

Example 2. Obtaining 3a-nitro-2-phenyl-2,3a, 4,5,6,7-hexahydro-3H-indazol-3-one (Ib).

Fe (NO ₃ ) ₃ ⋅ 9H ₂ O (2 mmol, 808 mg) was added to the mixture of NaNO ₂ (1 mmol, 69 mg) and MeCN (5 ml) with stirring at room temperature over 5-10 seconds. After 5 minutes, 2-phenyl-1,2,4,5,6,7-hexahydro-3H-indazol-3-one (1 mmol, 214 mg) was added to the stirred reaction mixture for 5-15 seconds, stirring was continued. 20 minutes. The reaction mixture was diluted with CH ₂ Cl ₂ (10 ml) and 3% aqueous HCl (30 ml), shaken and the organic layer was separated. The aqueous layer was extracted with CH ₂ Cl ₂ (2 × 10 ml), after which all organic extracts were combined, washed with water (2 × 20 ml), dried with MgSO ₄ . The solvent was removed in a vacuum of a water-jet pump on a rotary evaporator. The product was isolated by silica gel column chromatography using CH ₂ Cl ₂ as eluent. 3a-Nitro-2-phenyl-2,3a, 4,5,6,7-hexahydro-3H-indazol-3-one was obtained as a brownish powder in 66% yield (171 mg, 0.66 mmol). _Mp = 86-87 ° C; ¹ H NMR (300.13 MHz, CDCl ₃ ): δ = 7.89 (d, J = 8.1 Hz, 2H), 7.50-7.38 (m, 2H), 7.31-7.21 (m, 1H), 3.26-3.12 (m, 1H ), 2.97-2.83 (m, 1H), 2.59-2.42 (m, 1H), 2.30-2.10 (m, 1H), 2.04-1.74 (m, 2H), 1.70-1.48 (m, 2H); ¹³ C NMR (75.47 MHz, CDCl ₃ ): δ = 164.0, 157.5, 137.1, 129.1, 126.1, 119.0, 91.3, 33.9, 27.54, 27.47, 21.0; IR (KBr): ν _max = 1726, 1557, 1500, 1385 cm ^-1 ; Elemental analysis, calculated (%) for C ₁₃ H ₁₃ N ₃ O ₃ : C 60.23, H 5.05, N 16.21; Found: C 60.27, H 5.18, N 16.08.

Example 3. Obtaining 4-benzyl-3-methyl-4-nitro-1H-pyrazolin-5-one (Ic)

Fe (NO ₃ ) _{3 was} added to a mixture of 4-benzyl-3-methyl-pyrazolin-5-one (1 mmol, 188 mg), NaNO ₂ (1 mmol, 69 mg) and MeCN (5 ml) with stirring at room temperature ⋅9H ₂ O (2 mmol, 808 mg) for 5-10 seconds, stirring was continued for 20 minutes. The reaction mixture was diluted with CH ₂ Cl ₂ (10 ml) and 3% aqueous HCl (30 ml), shaken and the organic layer was separated. The aqueous layer was extracted with CH ₂ Cl ₂ (2 × 10 ml), after which all organic extracts were combined, washed with water (2 × 20 ml), dried with MgSO ₄ . The solvent was removed in a vacuum of a water-jet pump on a rotary evaporator. The product was isolated by silica gel column chromatography using EtOAc / CH ₂ Cl ₂ = 1/20 as eluent. 4-benzyl-3-methyl-4-nitro-1H-pyrazolin-5-one was obtained as a yellowish powder in 83% yield (0.83 mmol, 194 mg). _Mp = 84-85 ° C with decomp .; ¹ H NMR (300.13 MHz, CDCl ₃ ): δ = 8.53 (bs, 1H), 7.35-7.26 (m, 3H), 7.23-7.14 (m, 2H), 3.79 (d, J = 13.5 Hz, 1H), 3.62 (d, J = 13.5 Hz, 1H); 2.16 (s, 3H); ¹³ C NMR (75.47 MHz, CDCl ₃ ): δ = 167.8, 153.8, 129.9, 129.8, 129.2, 128.6, 93.2, 37.7, 14.4; IR (KBr): ν _max = 3238, 1733, 1564, 1352, 1312, 1271, 773, 757, 711, 699, 604 cm ^-1 ; high resolution mass spectrum (Electrospray): m / z = 256.0698, calc. For C ₁₁ H ₁₁ N ₃ O ₃ + Na ⁺ : 256.0693. Elemental analysis, calculated (%) for C ₁₁ H ₁₁ N ₃ O ₃ : C 56.65, H 4.75, N 18.02; Found: C 56.47, H 4.58, N 17.77.

Example 4. Obtaining 4-methyl-4-nitro-3-phenyl-1H-pyrazolin-5-one (Id).

Fe (NO ₃ ) ₃ ⋅ 9H ₂ O (2 mmol, 808 mg) was added to the mixture of NaNO ₂ (1 mmol, 69 mg) and MeCN (5 ml) with stirring at room temperature over 5-10 seconds. After 5 minutes, 4-methyl-3-phenylpyrazolin-5-one (1 mmol, 174 mg) was added to the stirred reaction mixture for 5-15 seconds, stirring was continued for 20 minutes. The reaction mixture was diluted with EtOAc (10 ml) and a solution prepared from water (14 ml), concentrated hydrochloric acid (2 ml) and saturated NaCl solution (20 ml). After agitating the resulting mixture, the organic layer was separated, and the aqueous layer was extracted with EtOAc (2 × 10 ml). All organic extracts were combined, washed with saturated aqueous NaCl (20 ml), dried over MgSO ₄ . The solvent was removed in a vacuum of a water-jet pump on a rotary evaporator. The product was isolated by silica gel column chromatography using EtOAc / CH ₂ Cl ₂ = 1/20 as eluent. 4-Methyl-4-nitro-3-phenyl-1H-pyrazolin-5-one (Id) was obtained as a white powder in 77% yield (169 mg, 0.77 mmol). _Mp = 138-140 ° C; ¹ H NMR (300.13 MHz, CDCl ₃ ): δ = 9.14 (bs, 1H), 7.70-7.55 (m, 2H), 7.54-7.37 (m, 3H), 2.07 (s, 3H); ¹³ C NMR (75.47 MHz, CDCl ₃ ): δ = 169.3, 154.7, 131.6, 129.5, 128.2, 126.0, 88.9, 19.3; IR (KBr): ν _max = 3242, 1727, 1550, 1385, 769, 758, 693, 651 cm ^-1 ; Elemental analysis, calculated (%) for C ₁₀ H ₉ N ₃ O ₃ : C 54.79, H 4.14, N 19.17; Found: C 54.78, H 4.12, N 19.16.

Example 5. Obtaining 4-allyl-3-methyl-4-nitro-1H-pyrazolin-5-one (Ie)

To a mixture of 4-allyl-5-methyl-1,2-dihydro-3H-pyrazol-3-one (1 mmol, 138 mg), NaNO ₂ (1 mmol, 69 mg) and MeCN (5 ml) with stirring at room temperature Fe (NO ₃ ) ₃ ⋅ 9H ₂ O (2 mmol, 808 mg) was added over 5–10 seconds, stirring was continued for 20 minutes. The reaction mixture was diluted with EtOAc (10 ml) and a solution prepared from water (14 ml), concentrated hydrochloric acid (2 ml) and saturated NaCl solution (20 ml). After agitating the resulting mixture, the organic layer was separated, and the aqueous layer was extracted with EtOAc (2 × 10 ml). All organic extracts were combined, washed with saturated aqueous NaCl (20 ml), dried over MgSO ₄ . The solvent was removed in a vacuum of a water-jet pump on a rotary evaporator. The product was isolated by silica gel column chromatography using EtOAc / CH ₂ Cl ₂ = 1/20 as eluent. 4-allyl-3-methyl-4-nitro-1H-pyrazolin-5-one was obtained in the form of a slightly brownish viscous mass with a yield of 84% (0.84 mmol, 154 mg). ¹ H NMR (300.13 MHz, CDCl ₃ ): δ = 8.92 (bs, 1H), 5.59-5.20 (m, 3H), 3.18 (dd, J = 13.7, 6.8 Hz, 1H), 3.04 (dd, J = 13.7 7.0 Hz, 1H); 2.10 (s, 3H); ¹³ C NMR (75.47 MHz, CDCl ₃ ): δ = 167.7, 154.0, 126.2, 123.4, 91.8, 36.1, 14.0; IR (KBr): ν _max = 3528, 1730, 1557, 1422, 1404, 1384, 1350, 1305, 1264, 942, 818, 761, 746, 694, 611, 548 cm ^-1 ; Elemental analysis, calculated (%) for C ₇ H ₉ N ₃ O _3: C 45.90, H 4.95, N 22.94; Found: C 45.98, H 4.90, N 22.98.

Example 6. Obtaining 4-ethyl-3-methyl-4-nitro-1H-pyrazolin-5-one (If)

To a mixture of 4-ethyl-5-methyl-1,2-dihydro-3H-pyrazol-3-one (1 mmol, 126 mg), NaNO ₂ (1 mmol, 69 mg) and MeCN (5 ml) with stirring at room temperature Fe (NO ₃ ) ₃ ⋅ 9H ₂ O (2 mmol, 808 mg) was added over 5–10 seconds, stirring was continued for 20 minutes. The reaction mixture was diluted with EtOAc (10 ml) and a solution prepared from water (14 ml), concentrated hydrochloric acid (2 ml) and saturated NaCl solution (20 ml). After agitating the resulting mixture, the organic layer was separated, and the aqueous layer was extracted with EtOAc (2 × 10 ml). All organic extracts were combined, washed with saturated aqueous NaCl (20 ml), dried over MgSO ₄ . The solvent was removed in a vacuum of a water-jet pump on a rotary evaporator. The product was isolated by silica gel column chromatography using EtOAc / CH ₂ Cl ₂ = 1/20 as eluent. 4-ethyl-3-methyl-4-nitro-1H-pyrazolin-5-one was obtained as a yellowish powder in 74% yield (0.74 mmol, 93 mg). _Mp = 64-66 ° C; ¹ H NMR (300.13 MHz, CDCl ₃ ): δ = 9.01 (bs, 1H), 2.51 (dq, J = 14.9, 7.5 Hz, 1H), 2.28 (dq, J = 14.9, 7.5 Hz, 1H), 2.09 ( s, 3H), 0.90 (t, J = 7.5 Hz, 3H); ¹³ C NMR (75.47 MHz, CDCl ₃ ): δ = 168.0, 154.2, 93.5, 25.1, 13.7, 6.8; IR (KBr): ν _max = 3323, 3259, 1742, 1717, 1561, 1546, 1358, 821, 663, 582 cm ^-1 ; high resolution mass spectrum (electrospray): m / z = 194.0530, calcd. for C ₆ H ₉ N ₃ O ₃ + Na ⁺ : 194.0536.

Example 7. Obtaining 4-butyl-3-methyl-4-nitro-1H-pyrazolin-5-one (Ig)

To a mixture of 4-butyl-5-methyl-1,2-dihydro-3H-pyrazol-3-one (1 mmol, 154 mg), NaNO ₂ (1 mmol, 69 mg) and MeCN (5 ml) with stirring at room temperature Fe (NO ₃ ) ₃ ⋅ 9H ₂ O (2 mmol, 808 mg) was added over 5–10 seconds, stirring was continued for 20 minutes. The reaction mixture was diluted with CH ₂ Cl ₂ (10 ml) and 3% aqueous HCl (30 ml), shaken and the organic layer was separated. The aqueous layer was extracted with CH ₂ Cl ₂ (2 × 10 ml), after which all organic extracts were combined, washed with water (2 × 20 ml), dried with MgSO ₄ . The solvent was removed in a vacuum of a water-jet pump on a rotary evaporator. The product was isolated by silica gel column chromatography using EtOAc / CH ₂ Cl ₂ = 1/20 as eluent. Received 4-butyl-3-methyl-4-nitro-1H-pyrazolin-5-one in the form of a yellowish viscous mass with a yield of 80% (0.80 mmol, 123 mg). ¹ H NMR (300.13 MHz, CDCl ₃ ): δ = 8.70 (bs, 1H), 2.55-2.38 (m, 1H), 2.31-2.15 (m, 1H), 2.08 (s, 3H), 1.47-1.30 (m , 2H), 1.30-1.01 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); ¹³ C NMR (75.47 MHz, CDCl ₃ ): δ = 168.0, 154.4, 92.9, 31.3, 24.4, 22.5, 13.75, 13.71; IR (KBr): ν _max = 3279, 2963, 2935, 2875, 1739, 1556, 1432, 1383, 1352, 1251, 819, 760 cm ^-1 ; high resolution mass spectrum (electrospray): m / z = 222.0842, calcd. for C ₈ H ₁₃ N ₃ O ₃ + Na ⁺ : 222.0849.

Example 8. Obtaining 4-hexyl-3-methyl-4-nitro-1H-pyrazolin-5-one (Ih)

To a mixture of 4-hexyl-5-methyl-1,2-dihydro-3H-pyrazol-3-one (1 mmol, 182 mg), NaNO ₂ (1 mmol, 69 mg) and MeCN (5 ml) with stirring at room temperature Fe (NO ₃ ) ₃ ⋅ 9H ₂ O (2 mmol, 808 mg) was added over 5–10 seconds, stirring was continued for 20 minutes. The reaction mixture was diluted with CH ₂ Cl ₂ (10 ml) and 3% aqueous HCl (30 ml), shaken and the organic layer was separated. The aqueous layer was extracted with CH ₂ Cl ₂ (2 × 10 ml), after which all organic extracts were combined, washed with water (2 × 20 ml), dried with MgSO ₄ . The solvent was removed in a vacuum of a water-jet pump on a rotary evaporator. The product was isolated by silica gel column chromatography using EtOAc / CH ₂ Cl ₂ = 1/20 as eluent. 4-hexyl-3-methyl-4-nitro-1H-pyrazolin-5-one was obtained as a brownish viscous mass with a yield of 70% (0.70 mmol, 159 mg). ¹ H NMR (300.13 MHz, CDCl ₃ ): δ = 8.98 (bs, 1H), 2.45 (td, J = 12.8, 4.8 Hz, 1H), 2.21 (td, J = 12.8, 4.8 Hz, 1H), 2.08 ( s, 3H), 1.46-1.02 (m, 8H), 0.87 (t, J = 6.4 Hz, 3H); ¹³ C NMR (75.47 MHz, CDCl ₃ ): δ = 168.2, 154.5, 93.0, 31.5, 31.3, 29.0, 22.5, 22.2, 14.1, 13.7; IR (thin layer): ν _max = 3278, 2958, 2931, 2861, 1737, 1557, 1381, 1349, 819, 760 cm ^-1 ; Elemental analysis, calculated (%) for C ₁₀ H ₁₇ N ₃ O ₃ : C 52.85, H 7.54, N 18.49; Found: C 53.13, H 7.78, N 18.06.

Example 9. Obtaining 4-methyl-4-nitro-3-propyl-1H-pyrazolin-5-one (Ii)

To a mixture of 4-methyl-5-propyl-1,2-dihydro-3H-pyrazol-3-one (1 mmol, 140 mg), NaNO ₂ (1 mmol, 69 mg) and MeCN (5 ml) with stirring at room Fe (NO ₃ ) ₃ ⋅ 9H ₂ O (2 mmol, 808 mg) was added over 5–10 seconds, stirring was continued for 20 minutes. The reaction mixture was diluted with CH ₂ Cl ₂ (10 ml) and 3% aqueous HCl (30 ml), shaken and the organic layer was separated. The aqueous layer was extracted with CH ₂ Cl ₂ (2 × 10 ml), after which all organic extracts were combined, washed with water (2 × 20 ml), dried with MgSO ₄ . The solvent was removed in a vacuum of a water-jet pump on a rotary evaporator. The product was isolated by silica gel column chromatography using EtOAc / CH ₂ Cl ₂ = 1/20 as eluent. 4-methyl-4-nitro-3-propyl-1H-pyrazolin-5-one was obtained as a yellowish powder in 84% yield (0.84 mmol, 118 mg). _Mp = 67-69 ° C dec .; ¹ H NMR (300.13 MHz, CDCl ₃ ): δ = 9.05 (bs, 1H), 2.38-2.25 (m, 2H), 1.84 (s, 3H), 1.76-1.57 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H); ¹³ C NMR (75.47 MHz, CDCl ₃ ): δ = 169.1, 158.5, 89.6, 29.5, 18.4, 17.5, 13.7; IR (KBr): ν _max = 3300, 1736, 1711, 1568, 1560, 1384, 667 cm ^-1 ; high resolution mass spectrum (electrospray): m / z = 208.0696, calcd. for C ₇ H ₁₁ N ₃ O ₃ + Na ⁺ : 208.0693.

Example 10. Obtaining 3- (3-Methyl-4-nitro-5-oxo-4,5-dihydro-1H-pyrazol-4-yl) propiontrile (Ij)

To a mixture of 3- (5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl) propionitrile (1 mmol, 196 mg), NaNO ₂ (1 mmol, 69 mg) and MeCN (5 ml ) Fe (NO ₃ ) ₃ ⋅ 9H ₂ O (2 mmol, 808 mg) was added with stirring at room temperature over 5-10 seconds, stirring was continued for 20 minutes. The reaction mixture was diluted with EtOAc (10 ml) and a solution prepared from water (14 ml), concentrated hydrochloric acid (2 ml) and saturated NaCl solution (20 ml). After agitating the resulting mixture, the organic layer was separated, and the aqueous layer was extracted with EtOAc (2 × 10 ml). All organic extracts were combined, washed with saturated aqueous NaCl (20 ml), dried over MgSO ₄ . The solvent was removed in a vacuum of a water-jet pump on a rotary evaporator. The product was isolated by silica gel column chromatography using EtOAc / CH ₂ Cl ₂ = 1/20 as eluent. Received 3- (3-Methyl-4-nitro-5-oxo-4,5-dihydro-1H-pyrazol-4-yl) propiontrile in the form of a yellowish powder with a yield of 80% (0.80 mmol, 157 mg). _Mp = 105-107 ° C; ¹ H NMR (300.13 MHz, DMSO-d ₆ ): δ = 12.10 (bs, 1H), 2.78-2.65 (m, 2H), 2.65-54 (m, 2H), 2.07 (s, 3H); ¹³ C NMR (75.47 MHz, DMSO-d ₆ ): δ = 167.1, 153.0, 118.5, 91.5, 25.7, 13.4, 10.6; IR (KBr): ν _max = 3249, 2263, 1735, 1556, 1345, 1256, 826, 674, 604, 552 cm ^-1 ; Elemental analysis, calculated (%) for C ₇ H ₈ N ₄ O ₃ : C 42.86, H 4.11, N 28.56; Found: C 42.93, H 4.08, N 28.39.

Example 11. Obtaining 4-isopropyl-3-methyl-4-nitro-1H-pyrazolin-5-one (Ik)

Fe (NO ₃ ) _{3 was} added to a mixture of 4-isopropyl-3-methyl-pyrazolin-5-one (1 mmol, 140 mg), NaNO ₂ (2 mmol, 138 mg) and MeCN (5 ml) with stirring at room temperature ⋅9H ₂ O (4 mmol, 1616 mg) for 5-10 seconds, stirring was continued for 20 minutes. The reaction mixture was diluted with CH ₂ Cl ₂ (10 ml) and 3% aqueous HCl (30 ml), shaken and the organic layer was separated. The aqueous layer was extracted with CH ₂ Cl ₂ (2 × 10 ml), after which all organic extracts were combined, washed with water (2 × 20 ml), dried with MgSO ₄ . The solvent was removed in a vacuum of a water-jet pump on a rotary evaporator. The product was isolated by silica gel column chromatography using EtOAc / CH ₂ Cl ₂ = 1/20 as eluent. 4-Isopropyl-3-methyl-4-nitro-1H-pyrazolin-5-one was obtained as a yellowish powder in 74% yield (0.74 mmol, 137 mg). _Mp = 80-81 ° C with decomp .; ¹ H NMR (300.13 MHz, CDCl ₃ ): δ = 8.74 (bs, 1H), 3.01-2.85 (m, 1H), 2.13 (s, 3H), 1.14 (d, J = 6.8 Hz, 3H), 1.01 ( d, J = 7.1 Hz, 3H); ¹³ C NMR (75.47 MHz, CDCl ₃ ): δ = 167.3, 153.8, 95.9, 32.8, 16.2, 14.9, 14.5; IR (KBr): ν _{max =} 3285, 1726, 1555, 1471, 1436, 1397, 1377, 1356, 1342, 1265, 822, 757, 727, 680, 565 cm ^-1 . Elemental analysis, calculated (%) for C ₇ H ₁₁ N ₃ O ₃ : C 45.40, H 5.99, N 22.69; Found: C 45.64, H 6.16, N 22.60.

Example 12. Obtaining 3a-nitro-2,3a, 4,5,6,7-hexahydro-3H-indazol-3-one (Il)

To a mixture of 1,2,4,5,6,7-hexahydro-3H-indazol-3-one (1 mmol, 138 mg), NaNO ₂ (1 mmol, 69 mg) and MeCN (5 ml) with stirring at room Fe (NO ₃ ) ₃ ⋅ 9H ₂ O (2 mmol, 808 mg) was added over 5–10 seconds, stirring was continued for 20 minutes. The reaction mixture was diluted with CH ₂ Cl ₂ (10 ml) and 3% aqueous HCl (30 ml), shaken and the organic layer was separated. The aqueous layer was extracted with CH ₂ Cl ₂ (2 × 10 ml), after which all organic extracts were combined, washed with water (2 × 20 ml), dried with MgSO ₄ . The solvent was removed in a vacuum of a water-jet pump on a rotary evaporator. The product was isolated by silica gel column chromatography using EtOAc / CH ₂ Cl ₂ = 1/20 as eluent. 3a-nitro-2,3a, 4,5,6,7-hexahydro-3H-indazol-3-one was obtained as a white powder in 61% yield (0.61 mmol, 84 mg). T _pl = 127-128 ° C decomp .; ¹ H NMR (300.13 MHz, CDCl ₃ ): δ = 9.21 (bs, 1H), 3.18-3.01 (m, 1H), 2.85-2.68 (m, 1H), 2.50-2.29 (m, 1H), 2.21-2.06 (m, 1H), 1.97-1.82 (m, 1H), 1.81-1.64 (m, 1H), 1.62-1.38 (m, 2H); ¹³ C NMR (75.47 MHz, CDCl ₃ ): δ = 168.1, 158.1, 89.1, 33.6, 27.5, 21.0; IR (KBr): ν _max = 3336, 1721, 1557, 1351, 1339, 1325, 829 cm ^-1 ; Elemental analysis, calculated (%) for C ₇ H ₉ N ₃ O ₃ : C 45.90, H 4.95, N 22.94; Found: C 45.87, H 4.83, N 22.87.

Tests for the fungicidal activity of compounds of the general formula I were carried out in vitro [Methodological recommendations for testing chemicals for fungicidal activity. Cherkasy: NPO "Plant Protection", VNII KhSZR, 1990-68]. For this, solutions of substances in acetone with a concentration of 3 mg / ml were prepared. The resulting solutions were added to preheated to 50 ° C sucrose-potato agar in the amount of 0.9 ml per 90 ml of agar. Thus, the concentration of the test substance in the medium was 30 mg / L. The media prepared in this way were poured into 15 ml into Petri dishes with an internal diameter of 9 cm. Highly effective triadimefon fungicides of the formula were used as standards:

The surface of the medium cooled to room temperature was inoculated with slices of mycelium from a three-day culture of fungi and kept at 25 ° C for 72 hours. Then the diameter of the colonies of the microorganisms was measured and the inhibition of mycelial growth was calculated as a percentage of the untreated Abbot control.

Phytopathogenic fungi of various taxonomic classes were used for biological tests: Venturia inaequalis (V. i.) (Pathogen of apple scab, class of ascomycetes), Rhizoctonia solani (R. s.) (Pathogen of black potato scab, class of basidomycetes), Fusarium oxysporum (F o.) (pathogen of tracheomycotic wilting of various cultures, class of deuteromycetes), Fusarium moniliforme (F. m.) (causative agent of cereal fusarium, “disease of bad shoots” of rice, class of ascomycetes), Helminthosporium sativum (H. s.) (root pathogen rot, leaf spot, black germ and other grain diseases o, class of deuteromycetes), Sclerotinia sclerotiorum (S. s.) (causative agent of white rot of various cultures, class of ascomycetes). The results are shown in the table. Table. Test results of substituted 4-nitropyrazolin-5-ones for fungicidal activity at a concentration of 30 mg / L.

Test data on the fungicidal activity of compounds Ia-Id are presented. As can be seen from the table, the compounds of general formula I exhibit fungicidal activity against phytopathogenic fungi. Compound Ia at a concentration of 30 mg / L is superior in activity to both standards in relation to almost all used cultures of phytopathogenic fungi.

The technical result of the invention is the creation of new fungicidal agents based on substituted 4-nitropyrazolin-5-ones of the general formula I, which exhibit high fungicidal activity in comparison with the known triadimefon and kresoxim-methyl. According to the results of fungicidal tests in vitro, the most active is 3,4-dimethyl-4-nitro-1-phenylpyrazolin-5-one (Ia), superior to the reference triadimephone and kresoxim-methyl in relation to almost all of the tested types of fungus pathogens.

The use of compounds of the general formula I in the compositions will make it possible to more effectively fight against fungal diseases of agricultural crops in comparison with such widely used fungicides as triadimefon and kresoxim-methyl.

Claims (12)

1. Substituted 4-nitropyrazolin-5-ones of the general formula:

where R = H, phenyl; R ₁ = lower alkyl, phenyl; R ₂ = alkyl C ₁ -C ₆ , benzyl, allyl, CH ₂ CH ₂ CN or R ₁ + R ₂ = (CH ₂ ) ₄ having fungicidal activity. 2. Compounds according to claim 1 of the general formula:

where R = H, phenyl; R ₁ = methyl, phenyl; R ₂ = methyl, benzyl or R ₁ + R ₂ = (CH ₂ ) ₄ having fungicidal activity. 3. The method of producing substituted 4-nitropyrazolin-5-ones according to claim 1 of the general formula:

where R = H, phenyl; R ₁ = lower alkyl, phenyl; R ₂ = alkyl C ₁ -C ₆ , benzyl, allyl, CH ₂ CH ₂ CN or R ₁ + R ₂ = (CH ₂ ) ₄ , which consists in the fact that the corresponding substituted pyrazolin-5-ones of the general formula:

where R, R ₁ and R ₂ have the above meanings, are reacted with sodium nitrite (NaNO ₂ ) and iron nitrate (Fe (NO ₃ ) ₃ ) in an organic solvent, and the process is carried out at a molar ratio of pyrazolin-5-one: NaNO ₃ : Fe (NO ₃ ) ₃ = 1: 1-2: 2-4. 4. The method according to p. 3, characterized in that acetonitrile is used as an organic solvent. 5. The use of compounds according to claims. 1, 2 as fungicidal agents.