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Abstract

The affordable and efficient methods for the syntheses of acyclic derivatives of 2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-oxopyridazin-1(6H)-yl)acetohydrazine as well as compounds with a combination of pyrazolyl-pyridazine fragment with various azoles in the molecules have been developed. The synthesized compounds showed a stimulating action on plant growth.

Keywords

4-chlorophenylacetamide heterocyclization N′-{2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-oxopyridazin-1(6H)-yl))acetyl}benzhydrazide N-arylhydrazine-1-carboxamide N-ethylhydrazine-1-carbothioamid plant growth stimulant activity pyrazolyloxoethyl derivative

Introduction

Pyridazine derivatives are one of the most active classes of organic compounds with a wide spectrum of physiological activity. Pyridazin-3-ones also exhibit diverse biological properties. A number of drugs synthesized on the basis of these heterocycles are widely used in medical practice.¹ In agriculture, the arsenal of pesticides based on pyridazine and pyridazinone includes mainly herbicides.² Due to the significant interest in these heterocyclic systems, in recent decades, studies were devoted toward pyridazine derivatives in terms of the search for new compounds with fungicidal,^3–6 herbicidal,^7,8 and insecticidal⁹ activities.

Pyrazolylpyridazines, obtained by cyclization of 3-hydrazino-pyridazines, have hypotensive, anti-inflammatory, antibacterial, and antioxidant activity.^10–13 However, it is surprising that in the literature there are practically no data on pesticides or plant growth stimulants based on non-fused heterocyclic system derivatives with a combination of pyrazolylpyridazine fragment and azoles in the structure. At the same time, the increasing awareness of environmental requirements, as well as the fact that harmful organisms can acquire resistance to chemical means of plant protection, make it necessary to replenish the pesticide arsenal with new and more environmentally friendly chemicals that have different mechanisms of action. In this regard, the targeted synthesis of new compounds with a combination of the above-mentioned pharmacophoric heterocycles in the same molecule can lead to new biologically active derivatives, against which plant pests and pathogens have not yet acquired resistance.

Results and discussion

2-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-oxopyridazin-1(6H)-yl)acetohydrazide (A) was used as the starting compound. Heterocyclization of A with pentane-2,4-dione gave the corresponding pyrazolyloxoethyl derivative 1. The reaction of the same hydrazide A with potassium rhodanide in hydrochloric acid led to the formation of salt 2, while reaction with various aryl aldehydes afforded arylidene derivatives 3a–c (Scheme 1). In the ¹Н NMR (nuclear magnetic resonance) spectra of the latter, two groups of signals were observed with an integral ratio of 85:15, corresponding to the E and Z isomers. In the ¹³C NMR spectra, only the signals of the predominant E-isomer were apparent.

Scheme 1.

Transformations based on 2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-oxopyridazin-1(6H)-yl)acetohydrazide.

As a result of the reaction of the starting acetohydrazide A with formic acid, acetic acid, acetic anhydride, or benzoyl chloride, the corresponding N′-formyl (4a), N′-acetyl (4b), and N′-benzoyl (5) derivatives were formed (Scheme 1).

The reaction of acetohydrazide A with sodium nitrite in an acetic acid medium yielded the corresponding azide 6, which under the action of 4-chloroaniline was converted into 4-chlorophenylacetamide 7 (Scheme 2).

Scheme 2.

Transformations based on acetohydrazide A.

The reaction of compound A with ethyl isothiocyanate and aryl isocyanates in absolute benzene led to the corresponding N-ethylhydrazine-1-carbothioamide 8 and N-arylhydrazine-1-carboxamides 10. At the same time, when the reaction with ethyl isothiocyanate was carried out in an alcoholic solution of NaOH, the heterocyclization proceeded with formation of a 5-thioxo-triazole ring (9) (Scheme 2).

The compound with a 5-thioxo-1,2,4-triazole moiety in the molecule was synthesized by treatment of acetohydrazide A with potassium rhodanide in an alcohol medium and subsequent boiling of intermediate salt 11 in a KOH solution (Scheme 3).

Scheme 3.

Synthesis of 6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-((5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl(1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl))pyridazin-3(2H)-ones.

For the introduction of other azoles into the molecule structure, initially the reaction of acetohydrazide A with a mixture of KOH and CS₂ (1:1.5:1.5) gave the salt 13. The alkaline and acidic hydrolysis of the latter led to the compounds with 5-thioxo-1,3,4-oxadiazole (14) and 5-thioxo-1,3,4-thiadiazole (15) rings (Scheme 3).

Biological properties of the synthesized compounds

Laboratory vegetative studies were carried out to determine the herbicidal, fungicidal, and growth-regulating properties of the synthesized compounds. All the products demonstrated a stimulating effect on plant growth. The activity of the compounds varied in the range of 50%–94% compared to a known test substance heteroauxin. The products having the greatest activity in the experiment (more than 80%) were selected for additional investigations and further field trials.

Conclusion

In summary, a simple and accessible method for the targeted synthesis of new 3-(pyrazol-1-yl)-6-oxopyridazine derivatives and compounds with a combination of different pharmacophoric heterocycles in the same molecule have been developed. The obtained compounds demonstrated a stimulating action on plant growth and are also of interest as precursors for the synthesis of new bioactive substances.

Experimental

General

The ¹H and ¹³C NMR spectra were recorded at 30°C using a Varian Mercury-300 NMR spectrometer (300 and 75 MHz, respectively) in a mixture of DMSO-d₆ + CCl₄ (3:1) using the standard pulse sequence, and TMS as an internal standard. For singlet, broad singlet, doublet, triplet, quadruplet, and multiplet NMR signals, the following abbreviations were used: s, brs, d, t, q, and m. The reactions were monitored by thin-layer chromatography (TLC) on “Silufol UV-254” plates (eluent: acetone/hexane 2:1). Elemental analysis was performed on a Eurovector EA3000 CHNS analyzer. Melting points were determined by the capillary method and are uncorrected.

6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-(2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-oxoethyl) pyridazin-3(2H)-one ( 1 )

To a mixture of 10 mmol of starting hydrazide A in 10 mL of acetic acid, at 0°C was added 10 mmol of pentane-2,4-dione and 3 drops of dimethylformamide (DMF). The reaction mixture was stirred at room temperature for 24 h. The next day, ice-cold water (20–30 mL) was added and the resulting precipitate was filtered off, washed with water, and dried. Yield 2.8 g (88%), white crystals, m.p. = 173–175°C. ¹H NMR δ (ppm), J (Hz): 2.22 and 2.26 (s, 6H, 3-CH₃, and 3′-CH₃), 2.47 and 2.53 (d, J = 0.8 Hz, 6H, 5-CH₃, and 5′-CH₃), 5.49 (s, 2H, CH₂), 5.96 and 6.09 (q, J = 0.8 Hz, 2H, 4-CH, and 4′-CH), 7.08 (d, J = 10.0 Hz, CH-pyrid.), 8.04 (d, J = 10.0 Hz, 1H, CH-pyrid.). ¹³C NMR δ (ppm): 13.0, 13.2, 13.29, 13.32, 53.8, 108.7, 110.9, 128.5, 131.0, 140.1, 141.6, 143.4, 148.9, 152.0, 157.7, 165.5. Anal. calcd for C₁₆H₁₈N₆O₂: C, 58.88; H, 5.56; N, 25.75; found: C, 58.71; H, 5.44; N, 25.49.

Thiocyanic acid salt of 2-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)-6-oxopyridazin-1(6H)-yl)acetohydrazide ( 2 )

To 10 mmol of compound A, 15 mL of water, 15 mL of 36% hydrochloric acid, and 12 mmol of potassium rhodanide were added. The reaction mixture was stirred at room temperature for 24 h, and then the water was evaporated. The precipitate was rinsed with benzene, filtered off, and dried. Yield 3.0 g (95%), pink crystals, m.p. > 300°C. ¹H NMR δ (ppm), J (Hz): 2.21 (s, 3H, 3-CH₃), 2.49 (d, J = 0.8 Hz, 3H, 5-CH₃), 4.80 (s, 2H, CH₂), 5.98 (brs, 1H, 4-CH), 7.07 (d, J = 10.0 Hz, 1H, CH-pyrid.), 7.99 (d, J = 10.0 Hz, 1H, CH-pyrid.), 10.8–12.7 (brs, 4H, NHNH₂, and HSCN). ¹³C NMR δ (ppm): 13.0, 13.4, 52.2, 108.8, 128.7, 131.0, 140.4, 141.7, 149.0, 157.9, 165.5. Anal. calcd for C₁₂H₁₅N₇O₂S: C, 44.85; H, 4.71; N, 30.51; found: C, 45.01; H, 4.65; N, 30.77.

Synthesis of compounds 3а–с

General

To 10 mmol of compound A were added 15 mL of water, 15 mL of 36% hydrochloric acid, and 12 mmol of the corresponding aldehyde. The mixture was stirred at room temperature for 24 h. Next day water (10–15 mL) was added and the resulting precipitate was filtered off and dried.

2-(3-(3,5-Dimethyl-1H-pyrazole-1-yl)-6-oxopyridazine-1(6H)-yl)-N′-(4-methoxybenzylidene)acetohydrazide ( 3а )

Yield 3.1 g (81%), white crystals, m.p. = 204–205 °С. ¹H NMR δ (ppm), J (Hz): (E/Z = 85:15%) 2.21 (s, 3H, 3-CH₃), 2.49 (d, J = 0.7 Hz, 3H, 5-CH₃), 3.82 (s, 3H, OCH₃), 4.74 (Z) (s, 0.15H, CH₂), 5.15 (E) (s, 0.85H, CH₂), 5.96 (brs, 1Н, CH-pyraz.), 6.89 and 7.60 (m, 4Н, C₆H₄), 7.05 (E) and 7.98 (E) (d, J = 9.9 Hz, 1.7H, CH-pyrid.), 7.06 (Z) and 7.99 (Z) (d, J = 9.9 Hz, 0.3H, CH-pyrid.), 7.93 (E) (s, 0.85H, CH = N), 7.93 (Z) (s, 0.15H, CH = N), 11.36 (Z) (s, 0.15H, NH), 11.51 (E) (s, 0.85H, NH). ¹³C NMR δ (ppm): (E)-isomer 13.0, 13.3, 52.3, 54.7, 108.6, 113.6, 126.5, 128.0, 128.2, 130.9, 140.2, 141.3, 143.7, 148.7, 157.9, 160.4, 166.6. Anal. calcd for C₁₉H₂₀N₆O₃: C, 59.99; H, 5.30; N, 22.09; found: C, 60.13; H, 5.46; N, 22.38.

2-(3-(3,5-Dimethyl-1H-pyrazole-1-yl)-6-oxopyridazine-1(6H)-yl)-N′-(4-hydroxy-3-methoxybenzylidene)acetohydrazide ( 3b )

Yield 3.0 g (77%), white crystals, m.p. = 144–146 °С. ¹H NMR δ (ppm), J (Hz): (E/Z = 85:15%) 2.22 (s, 3H, 3-CH₃); 2.50 (d, J = 0.7 Hz, 3H, 5-CH₃); 3.88 (s, 3H, OCH₃); 4.73 (Z) (s, 0.3H, CH₂); 5.16 (E) (s, 1.7H, CH₂); 5.96 (brs, 1Н, CH-pyraz.); 6.76, 7.02, and 7.23 (m, 3H, C₆H₃); 7.05 (E) and 7.98 (E) (d, J = 9.9 Hz, 1.7H, CH-pyrid.); 7.07 (Z) and 7.99 (Z) (d, J = 9.9 Hz, 0.3H, CH-pyrid.); 7.86 (E) (s, 0.85H, CH = N); 7.98 (Z) (s, 0.15H, CH = N); 8.94 (brs, 1Н, ОН); 11.28 (Z) (s, 0.15H, NH); 11.44 (E) (s, 0.85H, NH). ¹³C NMR δ (ppm): (E)-isomer 13.0, 13.3, 52.3, 55.3, 108.5, 109.0, 115.0, 121.4, 125.1, 128.2, 130.8, 140.1, 141.2, 144.3, 147.6, 148.7, 148.8, 157.8, 166.5. Anal. calcd for C₁₉H₂₀N₆O₄: C, 57.57; H, 5.09; N, 21.20; found: C, 57.43; H, 4.91; N, 21.41.

2-(3-(3,5-Dimethyl-1H-pyrazole-1-yl)-6-oxopyridazine-1(6H)-yl)-N′-(3-nitro-benzylidene)acetohydrazide ( 3c )

Yield 2.6 g (67%), white crystals, m.p. = 285–287 °С. ¹H NMR δ (ppm), J (Hz): (E/Z = 85:15%) 2.22 (s, 3H, 3-CH₃); 2.48 (d, J = 0.7 Hz, 3H, 5-CH₃); 4.80 (Z) (s, 0.3H, CH₂); 5.22 (E) (s, 1.7H, CH₂); 6.01 (brs, 1Н, CH-pyraz.); 7.10 (E) and 7.99 (E) (d, J = 9.9 Hz, 1.7H, CH-pyrid.); 7.11 (Z) and 8.00 (Z) (d, J = 9.9 Hz, 0.3H, CH-pyrid.); 7.69, 8.13, 8.22, and 8.49 (m, 4H, C₆H₄); 8.14 (s, 0.85H, CH = N); 8.38 (s, 0.15H, CH = N); 11.84 (Z) (s, 0.15H, NH); 11.93 (E) (s, 0.85H, NH). ¹³C NMR δ (ppm): 13.0, 13.2, 52.3, 108.7, 120.8, 123.6, 128.5, 129.7, 131.0, 132.4, 135.7, 140.2, 141.3, 141.5, 148.0, 148.9, 158.0, 167.2. Anal. calcd. for C₁₈H₁₇N₇O₄: C, 54.68; H, 4.33; N, 24.80; found: C, 54.47; H, 4.44; N, 24.55.

2-(3-(3,5-Dimethyl-1H-pyrazole-1-yl)-6-oxopyridazine-1(6H)-yl)-N′-formylacetohydrazide ( 4а )

To 10 mmol of compound A was added 10 mL of formic acid. The mixture was refluxed for 1 h. The solvent was evaporated, 15 mL of water was added, and the resulting precipitate was filtered off, washed with water, and dried. Yield 2.6 g (91%), white crystals, m.p. = 243–245 °С. ¹H NMR δ (ppm), J (Hz): 2.20 (s, 3H, 3-CH₃), 2.48 (d, J = 0.7 Hz, 5-CH₃), 4.75 (s, 2H, CH₂), 5.96 (brs, 1Н, CH-pyraz.), 7.03 (d, J = 10.0 Hz, 1H, CH-pyrid.), 7.94 (s, 1H, CHO), 7.96 (d, J = 10.0 Hz, 1H, CH-pyrid.), 10.15 (s, 1H, NH), 10.45 (s, 1H, NH). ¹³C NMR δ (ppm): 12.9, 13.3, 51.8, 108.6, 128.2, 130.9, 140.4, 141.3, 148.7, 157.4, 163.6, 165.8. Anal. calcd for C₁₂H₁₄N₆O₃: C, 49.65; H, 4.86; N, 28.95; found: C, 49.73; H, 4.73; N, 28.77.

N′-Acetyl-2-(3-(3,5-dimethyl-1H-pyrazole-1-yl)-6-oxopyridazine-1(6H)-yl) acetohydrazide ( 4b )

I. To 10 mmol of compound A, 10 mL of acetic acid was added and the mixture was refluxed for 5 h. Then the solvent was evaporated, 20 mL of water was added, the residue was filtered off, washed with water, and dried. Yield 2.1 g (71%), white crystals, m.p. = 238–240 °С. ¹H NMR δ (ppm), J (Hz): 1.90 (s, 3H, COCH₃), 2.21 (s, 3H, 3-CH₃), 2.49 (d, J = 0.7 Hz, 5-CH₃), 4.74 (s, 2H, CH₂), 5.97 (brs, 1Н, CH-pyraz.), 7.03 and 7.96 (d, J = 9.9 Hz, 2H, CH-pyrid.), 9.94 (s, 1H, NH), 10.17 (s, 1H, NH). ¹³C NMR δ (ppm): 13.0, 13.3, 20.0, 51.9, 108.5, 128.2, 130.9, 140.4, 141.3, 148.7, 157.7, 163.9, 166.6. Anal. calcd for C₁₃H₁₆N₆O₃: C, 51.31; H, 5.30; N, 27.62; found: C, 51.41; H, 5.40; N, 27.49.

II. To a mixture of 10 mmol of compound A in 15 mL of ethyl acetate, 10 mmol of acetic anhydride was added. The mixture was heated and stirred at 55–60°C for 5–6 h. The solvent was evaporated, the residue was rinsed with diluted solution of NaHCO₃, filtered off, washed with water, and dried. Yield 1.6 g (54%). The ¹H and ¹³С NMR spectra were identical to the spectra of the compound obtained by method I).

N′-(2-(3-(3,5-Dimethyl-1H-pyrazole-1-yl)-6-oxopyridazine-1(6H)-yl)acetyl)benzohydrazide ( 5 )

To 10 mmol of compound A in 10 mL of DMF was added the equimolar amount of benzoyl chloride. The mixture was refluxed for 1–2 h, cooled, rinsed with ice water, and the precipitate was filtered off and dried. Yield 2.6 g (70%), white crystals, m.p. = 196–198 °С. ¹H NMR δ (ppm), J (Hz): 2.21 (s, 3H, 3-CH₃), 2.52 (d, J = 0.7 Hz, 5-CH₃), 4.80 (s, 2H, CH₂), 5.98 (brs, 1Н, CH-pyraz.), 7.03 and 7.95 (d, J = 9.9 Hz, 2H, CH-pyrid.), 7.40–7.99 (m, 5H, C₆H₅), 10.40 (brs, 2H, NHNH). ¹³C NMR δ (ppm): 13.0, 13.4, 52.2, 108.6, 127.4, 127.6, 128.3, 130.86, 130.93, 132.3, 140.5, 141.4, 148.8, 157.9, 164.6, 164.9. Anal. calcd for C₁₈H₁₈N₆O₃: C, 59.01; H, 4.95; N, 22.94; found: C, 59.11; H, 4.82; N, 22.72.

2-(3-(3,5-Dimethyl-1H-pyrazole-1-yl)-6-oxopyridazine-1(6H)-yl)acetyl azide ( 6 )

To a mixture of 20 mmol of compound A and an aqueous solution of 56 mmol of NaNO₂, at 0–5°C was added 56 mmol of acetic acid dropwise. The reaction mixture was stirred at room temperature for 3–4 h, rinsed with 20–30 mL of water, and the precipitate filtered off and dried. Yield 2.5 g (93%), white crystals, m.p. = 99–100 °С. ¹H NMR δ (ppm), J (Hz): 2.21 (s, 3H, 3-CH₃), 2.48 (d, J = 0.8 Hz, 3H, 5-CH₃), 4.84 (s, 2H, CH₂), 5.98 (brs, 1Н, CH-pyraz.), 7.08 and 8.03 (d, J = 10.0 Hz, 2H, CH-pyrid.). ¹³C NMR δ (ppm): 13.0, 13.3, 54.1, 108.9, 128.8, 131.0, 140.2, 141.8, 149.0, 157.5, 173.5. Anal. calcd for C₁₁H₁₁N₇O₂: C, 48.35; H, 4.06; N, 35.88; found: C, 48.22; H, 4.16; N, 36.61.

N-(4-Chlorophenyl)-2-(3-(3,5-dimethyl-1H-pyrazole-1-yl)-6-oxopyridazine-1(6H)-yl)acetamide ( 7 )

To a mixture of 10 mmol of compound 6 and 10 mL of dry toluene, 2 drops of pyridine (catalytic amount) and 10 mmol of p-chloroaniline were added. The mixture was refluxed for 4 h at 120°C, then the solvent was evaporated. Hexane (15–20 mL) was added, and the formed precipitate was filtered off and dried. Yield 3.4 g (95%), brown crystals, m.p. = 240–240 °С. ¹H NMR δ (ppm), J (Hz): 2.21 (s, 3H, 3-CH₃), 2.48 (d, J = 0.7 Hz, 3H, 5-CH₃), 4.82 (s, 2H, CH₂), 5.95 (brs, 1Н, CH-pyraz.), 7.06 and 7.98 (d, J = 9.9, 2H, CH-pyrid.), 7.23 and 7.60 (m, 4H, C₆H₄), 10.22 (s, 1H, NH). ¹³C NMR δ (ppm): 13.0, 13.2, 54.1, 108.5, 120.3, 127.2, 128.0, 128.4, 130.9, 137.2, 140.2, 141.3, 148.8, 157.8, 164.1. Anal. calcd for C₁₇H₁₆ClN₅O₂: C, 57.07; H, 4.51; N, 19.57; found: C, 56.97; H, 4.42; N, 19.36.

2-(2-(3-(3,5-Dimethyl-1H-pyrazole-1-yl)-6-oxopyridazine-1(6H)-yl))acetyl)-N-ethylhydrazine-1-carbothioamide ( 8 )

To a mixture of 10 mmol of compound A and 10 mL of dry benzene, 10 mmol of C₂H₅NCS was added. The reaction mixture was refluxed with stirring for 6 h. After cooling, 10 mL of benzene was added, and the precipitate filtered off and dried. Yield 3.1 g (90%), white crystals, m.p. = 228–230 °С. ¹H NMR δ (ppm), J (Hz): 1.20 (t, J = 6.9 Hz, 3H, CH₃CH₂N), 2.22 (s, 3H, 3-CH₃), 2.50 (d, J = 0.7 Hz, 3H, 5-CH₃), 3.50 (m, 2H, CH₃CH₂N), 4.82 (s, 2H, CH₂), 5.99 (brs, 1Н, CH-pyraz.), 7.06 and 7.98 (d, J = 9.9, 2H, CH-pyrid.), 7.55 (t, J = 5.9, 1H, NH-Et), 9.16 (s, 1H, NH), 10.11 (s, 1H, NH). Anal. calcd for C₁₄H₁₉N₇O₂S: C, 58.12; H, 5.48; N, 28.06; found: C, 58.20; H, 5.55; N, 28.39.

6-(3,5-Dimethyl-1H-pyrazole-1-yl)-2-((4-ethyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)methyl)pyridazine-3(2H)-one ( 9 )

To a mixture of 10 mmol of compound A and 10 mL of ethanol, 10 mmol of C₂H₅NCS and 10 mmol of NaOH were added. The mixture was stirred at room temperature for 6 h and allowed to stand overnight. The next day, the solvent was evaporated, 15–20 mL of water was added and the solution acidified with hydrochloric acid until pH = 4. The obtained precipitate was filtered off, and recrystallized from ethanol/water. Yield 2.0 g (86%), white crystals, m.p. = 205–207 °С. ¹H NMR δ (ppm), J (Hz): 1.20 (t, J = 7.0 Hz, 3H, CH₃CH₂N), 2.19 (s, 3H, 3-CH₃), 2.34 (d, J = 0.7 Hz, 3H, 5-CH₃), 4.04 (q, J = 7.0 Hz, 2H, CH₃CH₂N), 5.32 (s, 2H, CH₂), 5.95 (brs, 1Н, CH-pyraz.), 7.09 and 8.02 (d, J = 9.9 Hz, 2H, CH-pyrid.), 13.59 (s, 1H, NH). ¹³C NMR δ (ppm): 13.0, 13.3, 38.2, 44.1, 109.1, 118.3, 131.2, 140.4, 142.0, 146.3, 149.1, 157.3, 167.0. Anal. calcd for C₁₄H₁₇N₇OS: C, 50.74; H, 5.17; N, 29.59; found: C, 50.63; H, 5.28; N, 29.27.

N-(3,4-Dichlorophenyl)-2-(2-(3-(3,5-dimethyl-1H-pyrazole-1-yl)-6-oxopyridazine-1(6H)-yl)acetyl)hydrazine-1-carboxamide ( 10 )

To a mixture of 10 mmol of compound A and 15 mL of dry benzene, 10 mmol of 3,4-Cl₂C₆H₃NCO was added. The reaction mixture was refluxed with stirring for 6 h. After cooling, 15–20 mL of benzene was added, and the obtained precipitate was filtered off and dried. Yield 3.6 g (80%), white crystals, m.p. = 245–247 °С. ¹H NMR δ (ppm), J (Hz): 2.22 (s, 3H, 3-CH₃), 2.51 (d, J = 0.7 Hz, 3H, 5-CH₃), 4.78 (s, 2H, CH₂), 5.98 (brs, 1Н, CH-pyraz.), 7.07 and 8.00 (d, J = 9.9 Hz, 2H, CH-pyrid.), 7.30–8.02 (m, 3H, C₆H₃), 8.33 (s, 1H, NH), 8.72 (s, 1H, NH), 10.17 (s, 1H, NH). ¹³C NMR δ (ppm): 13.0, 13.4, 52.9, 108.7, 117.8, 119.5, 123.6, 128.5, 129.5, 130.9, 131.2, 139.4, 140.5, 141.7, 148.9, 154.4, 158.1, 165.6. Anal. calcd for C₁₈H₁₇Cl₂N₇O₃: C, 48.01; H, 3.81; N, 21.78; found: C, 47.91; H, 3.90; N, 21.57.

6-(3,5-Dimethyl-1H-pyrazole-1-yl)-2-((5-thioxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)methyl)pyridazine-3(2H)-one ( 12 )

To a mixture of 28 mmol of compound A and 15 mL of ethanol, 3 drops of conc. hydrochloric acid and 51 mmol of KSCN were added. The reaction mixture was refluxed with stirring for 3 h. The mixture was cooled, the residue filtered off, washed with ethanol, dried, and the precipitate of compound 11 was dissolved in 20 mL of water, then 13 mmol of KOH was added, and the resulting solution was refluxed for 3 h. After cooling, the solution was carefully acidified with hydrochloric acid until pH = 4. The precipitate was filtered off, washed with water and dried. Yield 1.8 g (60%), white crystals, m.p. > 300 °С. ¹H NMR δ (ppm), J (Hz): 2.20 (s, 3H, 3-CH₃), 2.36 (d, J = 0.7 Hz, 3H, 5-CH₃), 5.16 (s, 2H, CH₂), 5.95 (brs, 1Н, CH-pyraz.), 7.05 and 7.98 (d, J = 9.9 Hz, 2H, CH-pyrid.), 13.24 and 13.28 (brs, 2H, 2 × NH). ¹³C NMR δ (ppm): 13.0, 13.3, 45.0, 108.9, 128.2, 131.3, 140.5, 141.8, 146.8, 148.9, 157.5, 166.7. Anal. calcd for C₁₂H₁₃N₇OS: C, 47.51; H, 4.32; N, 32.32; found: C, 47.62; H, 4.29; N, 32.06.

Potassium 2-(2-(3-(3,5-Dimethyl-1H-pyrazole-1-yl)-6-oxopyridazine-1(6H)-yl)acetyl)hydrazine-1-carbodithioate ( 13 )

To a mixture of 10 mmol of compound A and 10 mL of ethanol, an alcoholic solution of 15 mmol of potassium hydroxide at 0–5°C and 15 mmol of CS₂ were added dropwise with continuous stirring. The reaction mixture was stirred at room temperature for 6 h. The next day Ethanol (10 mL) was added, and the obtained precipitate was filtered off and dried. Yield 3.6 g (95%), yellow crystals, m.p. = 242–244 °С (dec). ¹H NMR δ (ppm), J (Hz) (D₂O): 2.18 (s, 3H, 3-CH₃), 2.35 (d, J = 0.7 Hz, 3H, 5-CH₃), 4.82 (s, 2H, CH₂), 6.07 (brs, 1Н, CH-pyraz.), 7.18 and 7.82 (d, J = 9.9 Hz, 2H, CH-pyrid.). ¹³C NMR δ (ppm) (D₂O): 11.7, 11.8, 53.5, 108.5, 129.3, 131.0, 142.2, 142.6, 151.5, 160.4, 163.2. Anal. calcd for C₁₂H₁₃KN₆O₂S₂: C, 38.28; H, 3.48; N, 22.32; found: C, 38.42; H, 3.31; N, 22.04.

6-(3,5-Dimethyl-1H-pyrazole-1-yl)-2-((5-thioxo-4,5-dihydro-1H-1,3,4-oxadiazole-2-yl) methyl)pyridazine-3(2H)-one ( 14 )

A mixture of 10 mmol of compound A and 20 mL of ethanol was refluxed for 8 h with continuous stirring. The solution was evaporated, the residue was treated with 20–30 mL of water, neutralized with acetic acid, filtered off, and dried. Yield 2.8 g (93%), white crystals, m.p. = 198–200 °С. ¹H NMR δ (ppm), J (Hz): 2.20 (s, 3H, 3-CH₃-pyraz.), 2.43 (d, J = 0.8 Hz, 3H, 5-CH₃-pyraz.), 5.31 (s, 2H, NCH₂), 5.97 (q, J = 0.8 Hz, 1H, CH-pyraz.), 7.09 and 8.03 (d, J = 9.9 Hz, 2H, CH-pyrid.), 14.32 (s, 1H, NH). ¹³C NMR δ (ppm): 12.9, 13.4, 44.6, 109.1, 128.6, 131.3, 140.4, 141.94, 149.1, 157.1, 157.7, 177.9. Anal. calcd for C₁₂H₁₂N₆O₂S: C, 47.36; H, 3.97; N, 27.62; found: C, 47.46; H, 3.84; N, 27.46.

6-(3,5-Dimethyl-1H-pyrazole-1-yl)-2-((5-thioxo-4,5-dyhidro-1,3,4-thiadiazole-2-yl) methyl)pyridazine-3(2H)-one ( 15 )

A mixture of 10 mmol of compound A and 10–12 mL of H₂SO₄ was refluxed with continuous stirring for 6 h. After cooling, 10–15 mL of cold water was added and the solution was carefully neutralized with conc. NH₄OH solution until pH = 7. The precipitate was filtered off, washed with water, and dried. Yield 2.3 g (71%), yellow crystals, m.p. = 248–250 °С. ¹H NMR δ (ppm), J (Hz): 2.21 (s, 3H, 3-CH₃), 2.51 (d, J = 0.7 Hz, 3H, 5-CH₃), 5.31 (s, 2H, CH₂), 5.99 (brs, 1Н, CH-pyraz.), 7.10 and 8.04 (d, J = 9.9 Hz, 2H, CH-pyrid.), 14.34 (brs, 1H, NH). ¹³C NMR δ (ppm): 13.0, 13.5, 49.5, 109.1, 128.6, 131.2, 131.3, 140.3, 142.2, 149.1, 155.7, 157.3, 189.1. Anal. calcd for C₁₂H₁₂N₆OS₂: C, 44.99; H, 3.78; N, 26.23; found: C, 45.05; H, 3.66; N, 26.01.

Supplemental Material

Supplementary_Material – Supplemental material for Synthesis and biological properties of novel 3-(pyrazol-1-yl)-6-oxopyridazine derivatives

Supplemental material, Supplementary_Material for Synthesis and biological properties of novel 3-(pyrazol-1-yl)-6-oxopyridazine derivatives by Roza S Shainova, Tiruhi A Gomktsyan, Armen V Karapetyan and Aleksandr P Yengoyan in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Roza S Shainova

Supplemental material

The 1H and 13C NMR spectra and biological activites of compounds 1-15 are available online.

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