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    • 专利摘要:
    Pollen formation in cereal grain plants can be inhibited by application of novel 4-carboxy(or derivative)-1-aryl-5-pyrazolecarboxamide. Production of hybrid seed is facilitated by use of the compounds.
    公开号:SU1440343A3
    申请号:SU853954000
    申请日:1985-09-23
    公开日:1988-11-23
    发明作者:Ричард Бек Джеймс；Венделлинн Прайс Гароль
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

     s
    The invention relates to a process for the preparation of novel pyrazole derivatives of the general formula
    sonng
    COR
    where, RI and Rj are halogen, coxy, C-C-alkyl or hydrogen, R4 hydroxy, C, -C-alkoxy, C-4-a-alkenyloxy or phytologically acceptable residual. The intermediate product is dissolved in 13 l of chloroform and treated by bubbling nitrosyl chloride through the solution at ambient temperature. Nitrosyl chloride is obtained by slowly adding 1.23 kg of sodium nitrite in an aqueous solution to 7.2 g of concentrated hydrochloric acid. Addition of nitrite
           4c is controlled so that its addition, which forms the salt of carboxylic acid,
    lots that have the ability to inhibit the formation of pollen and can be used in agriculture for the production of hybrid cereal seeds.
    20
    The reaction took 2 hours and the maximum temperature of the reaction mixture was 35 ° C. The mixture is stirred at ambient temperature for 1 hour after the completion of the separation of nitrosyl chloride gas, and then the mixture is heated to boiling point and stirred for 1 hour at this temperature. The mixture is cooled
    The purpose of the invention is to obtain novel pyrazole derivatives that have the ability to inhibit pollen formation, and thereby contribute to obtaining hybrid seeds of cereals, which are of higher quality than when used to inhibit the formation of pollen from a known compound.
    Example 1. Preparation of 4-carboxy-1- (3-chlorophenyl) -5-pyrazolecarboxamide.
    In a 22 liter flask equipped with a heated jacket and a cooler, add 2 liters of deionized water, 7.55 liters of acetic acid, 1.37 kg of sodium acetate, 1.923 kg of 3-chlorophenylhydrazine hydrochloride and 1.884 kg of ethyl (ethoxymethylene) -cyanoacetic acid ethyl ester . The mixture is slowly heated to reflux and stirred at reflux for 4 hours. The mixture is cooled until a little water is added to keep the mixture at a density sufficient for stirring. The mixture is stirred at 10 ° C. for 1 h and filtered. The solid product is rinsed with water and dried. The solid product is then dissolved in 13 liters of denatured ethanol and the solution is heated to reflux temperature. The reaction mixture is filtered at elevated temperature, cooled with stirring, and filtered. 2.195 kg of product are obtained. The filtrate is concentrated and 170 g of product are obtained by successive crystallisations. Overall you
    a course of 2.3–5 kg of 5-amino-1- (3-chlorophenyl) -4-pyrazolecarboxylic acid ethyl ester.
    This intermediate was dissolved in 13 L of chloroform and treated by bubbling nitrosyl chloride through the solution at ambient temperature. Nitrosyl chloride is obtained by slowly adding 1.23 kg of sodium nitrite in an aqueous solution to 7.2 g of concentrated hydrochloric acid. Addition of nitrite
    control so that its added
    The reaction took 2 hours and the maximum temperature of the reaction mixture was 35 ° C. The mixture is stirred at ambient temperature for 1 hour after the completion of the separation of nitrosyl chloride gas, and then the mixture is heated to boiling point and stirred for 1 hour at this temperature. The mixture is cooled
    stirred overnight, dried with sodium sulfate and filtered. The solvent was removed in vacuo and the solid residue was crystallized from denatured ethanol to give 2.002 kg of 5-chloro-1- (3-chlorophenyl) -4-pyrazolecarboxylic acid ethyl ester.
    50
    intermediate product
    f
    anhydrous dime5
    0
    Specified
    is dissolved in 13 l of tilformamide and 686 g of anhydrous sodium cyanide is added to the solution. The mixture was stirred at 100 ° C; for 4 hours, left to stand overnight at ambient temperature with stirring. The mixture is then added in portions with stirring to 40 liters of ice water. The aqueous mixture is stirred for 45 minutes and filtered, the solid residue is washed several times with water. The solid residue is recrystallized from anhydrous ethanol to obtain 1.591 kg of 1- (3-chlorophenyl) -5-cyano-4-pyrazolecarboxylic acid ethyl ester.
    A portion of this intermediate product weighing 1.445 kg is added to 14 liters of denatured ethanol and heated to 0 ° C. To the mixture are added 5 liters of ethanol, 1 liter of water and 1.035 kg of 85% potassium hydroxide. The mixture is stirred at reflux temperature (76-77 ° C)
    2 h. The mixture is left to stand overnight at room temperature. The mixture is then reheated to about to dissolve all solids, and then 25-30 liters of ice-water is added, and the pH is lowered to 1-2 by addition of concentrated hydrochloric acid. The mixture is stirred for 1 hour and filtered. The solid residue is washed with water and dried at get 1.024 kg of the desired product, so pl. 223-225 C.
    Calculated,%: C 49.73; H 3.04; N 15.82.
    C HgClNjO,
    Found,%: C 49.81; H 2.82; N 15.61.
    Example 2. Preparation of 4-Carboxy-1 - (3-fluorofesh) -5-pyrazolecarboxamide.
    5.5 g of 5-cyano-1- (3-fluorophenyl) -4-pyrazolecarboxylic acid ethyl ester and 4.7 g of potassium hydroxide are dissolved in 100 ml of ethanol at the reflux temperature and the mixture is stirred at this temperature for 2 hours. The mixture is diluted to 350 ml with chlorine water and heated to dissolve, the solution is acidified with concentrated hydrochloric acid. The reaction product precipitates by the addition of small amounts of ice, the precipitate is filtered off and crystallized from the water-ethanol mixture, to obtain 3.6 g of the desired product, so pl. 215-216 C.
    . Calculated,%: C 53.01; H 3.21; N 16.87.
    C HsFNjOj.
    Found,%: C 53.16; H 3.27; N 16.91.
    PRI me R 3. Getting 4-carboxy-1-phenyl-5-pyrazole carboxamide ..
    4 g of 5-cyano-1-phenyl-4-pyrazolecarboxylic acid ethyl ester are treated with 2 g of potassium hydroxide in 60 ml of denatured ethanol. As described in Example 2, 2.7 g of the expected product are obtained, mp. 234- 235 ° C.
    Calculated,%: C 57.14; H 3.92; N 18.17.
    C, iH9NjO,
    Found,%: C 57.38; H 3.93; N 18.37.
    Example 4: 4-Carboxy-1- (4-xpriphenyl) -5-pyrazolecarboxameamide delivery.
    As described in Example 2, starting from 3.7 g of 1- (4-chlorophenyl) -5-cyano-4-11-irazolecarboxylic acid ethyl ester and 2 g of sodium hydroxide in 60 ml of denatured ethanol and 60 ml of water, crawl 2 , 3 g of the desired product, so pl. 249-250 C.
    Calculated,%: C 49.73; H 3.04; N 15.82.
    С, Н „С1Н, 0,
    Found,%: C 49.94; H 3.32; N 15.78.
    PRI me R 5. Preparation of 4-carboxy-1- (2,4-dichlorophenyl) -5-pyrazole-carboxamide.
    2.5 g of 1- (2,4-d1H-chlorophenyl) -5-cyano-4-pyrazolecarboxylic acid ethyl ester are treated with 1 g of hydrochloride potassium oxide in 60 ml of 50% aqueous ethanol, to obtain 1.2 g purified product, so pl. 239-240 S.
    Calculated,%: C 44.03; H 2.35; N 14.01.
    C ,, H-,
    Found,%: C 44.05; H 2.64; N 13.83.
    Example 6: Preparation of 1- (4-bromophenyl) -4-carboxy-5-pyrazolecarboxamide.
    3.5 g of 1- (4-bromophenyl) -5-cyano-4-pyrazolecarboxylic acid ethyl ester are treated with 2.15 g of potassium hydroxide in 50 ml of ethanol at reflux temperature for 2 hours. Obtained is 2.45 g of the target product, so pl. 251-252.5 C
    Calculated,%: C 42.61; H 2.60; N 13.55.
    C.HjBrNjOj
    Found,%: C 42.84; H 2.72; N, 13.29.
    PRI me R 7. Preparation of 4-carboxy-1 - (3,4-dichlorophenyl) -5-Shfazol-carboxamide.
    15 g of 1- (3,4-dichlorfensh1) -5-cyano-4-pyrazolecarboxylic acid ethyl ester is dissolved in 200 ml of ethanol and 5.6 g of potassium hydroxide is added. The reaction mixture is stirred at reflux temperature for 1 h, poured into ice and acidified with concentrated hydrochloric acid. The mixture is filtered, the solid residue, as determined by NMR,
    Consists of partially hydrolyzed A-carboxy-5-cyanopyrazole. 2 g of this intermediate product are taken for further investigation, and the remaining amount of solid residue is redissolved in 200 ml of ethanol and stirred at reflux temperature for 18 hours with 5.6 g of potassium hydroxide. The mixture was poured onto ice, acidified and filtered. The solid residue is recrystallized from ethanol and the mother liquor is chromatographed on a silica gel column with methanol as eluant. The fractions containing the product are evaporated to dryness and the residues are redrawed from methanol to give the desired product, so pl. 249-250 ° C.
    Calculated,%: C 44.03; H 2.35; N 14.00,
    C., H 7 Cl., N Os Found,%: C 43.93; H 2.37; N 13.9 Ü
    Froze Preparation of 4-Carboxy-1- (4-methylphenyl) -5-pyrazole-carboxamide.
    5.6 g of potassium hydroxide and 200 ml of water are added to 10 g of 5-cyano-1 (4-methylphenyl) -4-pyrazolecarboxylic acid ethyl ester and 200 ml of water, followed by an additional amount of water to dissolve the mixture. The mixture was stirred at reflux for 8 hours and left to stand for 3 days. The mixture is then poured onto ice, acidified and filtered. Filtered
    on ice, acidified and filtered, the solid residue is crystallized from the ethanol mixture, dried at 168 ° C and 10 g of the expected product are obtained, mp 215-217 ° C with decomposition. The reaction product is identified by NMR analysis in CDClg (DMSO-d. (F: 7.6b (s, 1), carboxamide; 7.30-7.64 (m, 4), aromatic; 8.08 (s, 1), pyrazole; 9,10 (s, 1), carboxamide.
    Example 10. Preparation of 4-carboxy-1- (3-methylphenyl) -5-pyrazolecarboxamiside.
    9 g of 5-cyano 1- (3-methylphenyl) -4-pyrazolecarboxylic acid ethyl ester is dissolved in 200 ml of ethanol and 5.8 g of potassium hydroxide is added. The mixture is stirred at reflux temperature.
    for 4 hours, cooled, diluted
    0
    water and acidified. The mixture is filtered and the solid is washed with ethyl acetate, as shown in Example 8, 3.8 g of the desired product are obtained, mp. 209-211 ° С with decomposition.
    Calculated,%: C 58.77; H 4.52; N -17.13.
    .NiOj.
    Found,%: C 58.58; H 4.63; N 16.85. .
    Example 11. Preparation of 4-carboxy-1- (4-fluorophenyl) -5-pyrazolecarboxamiside.
    2.5 g of 5-cyano-1- (4-fluorophenyl) -4-pyrazolecarboxylic acid ethyl ester and 2.6 g of potassium hydroxide are stirred under reflux in 100 ml of denatured5
    The remaining residue is heated in 100 ml of ethyl ethanol for 4 hours. The mixture of ohacetate, the undissolved solid residue is separated, dried, and creeping 4.25 g of the desired product, mp.260 ° C with decomposition. The product is identified by the NMR spectrum, the solvent is deuterated dimethyl sulfoxide, DMSO-dg. d; 2.36 (s, 3), methyl; 7.32 (d, 2), aromatic; 7.45 (s, 1), carboxamide; 8.33 (s, 1), carboxamide.
    PRI me R 9. Preparation of 1- (3-bromophenyl) -4-carboxy-5-pyrazolecarboxamide.
    14 g of 1- (3-bromo-ethyl ester, acidified, diluted with water and concentrated under vacuum, obtain 2.8 g of the title compound, mp 232 ° C with decomposition after recrystallization from acetone.
    Calculated,%: C 53.02; H 3.24; N 16.86.
    Ci HeFNjGj
    Found,%: C 53.27;
    50
    H 3.02; N 16.69.
    Example 12. Preparation of 4-carboxy-1- (2, 3-dichlorophenyl) -5-pyrazolecarboxamide.
    15 g of 1- (2,3-dinyl) -5-cyano-4-pyrazolecarboxylic acid-chlorophenyl) -5-cyano-4-pyrazolecarbonol ethyl ester are hydrolyzed while stirring; the acid is stirred at a temperature that is boiling under reflux. A reflux boil in 200 ml of ethanol with 6 g of hydroxide overnight in 200 ml of potassium ethanol for 2 hours. The mixture is extracted from 6 g of potassium hydroxide. Reactionary
    liquefied, acidified, diluted with water and concentrated in vacuo to give 2.8 g of the title compound, m.p. 232 ° C with decomposition after recrystallization from acetone.
    Calculated,%: C 53.02; H 3.24; N 16.86.
    Ci HeFNjGj
    Found,%: C 53.27;
    0
    H 3.02; N 16.69.
    Example 12. Preparation of 4-carboxy-1- (2, 3-dichlorophenyl) -5-pyrazolecarboxamide.
    71
    the mixture is chromatographed on silica gel, the fractions containing the product are combined and evaporated to dryness. The residue is recrystallized from water-ethanol mixture, to obtain 1.31 g of the target product, so pl. 228-230 C.
    Calculated,%: C 44.03; H 2.35; N 14.00,
    C.H CljNjO
    Found,%: C 44.04; H 2.39; N 13.88.
    PRI me R 13. Preparation of 4-carboxy-1- (3-chloro-4-methylphenyl) -5-pyrazole-carboxamide.
    9.5 g of 1- (3-chloro-4-methylphenyl) -5-cyano-4-pyrazolecarboxylic acid ethyl ester is dissolved in 250 ml of ethanol and 2 g of potassium hydroxide is added. The mixture is stirred at reflux for 30 minutes. 100 ml of water are added and stirred at the boiling point with refluxing with NIKOM for another 4 hours. While trying to isolate the reaction product, it has been found that it is difficult to separate. Therefore, the entire reaction mixture is returned to the flask, redissolved in aqueous ethanol and heated under reflux for 1 hour on a steam bath with 6 g of additional potassium hydroxide. The mixture is then diluted with aqueous acetic acid and filtered, the solid residue is dried, 5.2 g of the expected product are obtained, m.p. 228-232 With decomposition.
    Calculated,%: C 51.53; H 3.60; N 15.02.
    С „Н, оС1НзОз
    Found,%: C, 51.80; H 3.36; N 14.92.
    Examples are p14. Preparation of 5-aminocarbonyl-1- (3-chloro-phenyl) -4-pyrazolecarboxylic acid methyl ester.
    2.2 g of 4-carboxy-1- (3-chlorophenyl) -5-pyrazolecarboxamide is suspended in 40 ml of methanol and hydrogen chloride is bubbled through the mixture for 1 minute. The mixture was stirred at reflux temperature for 2 hours, poured onto ice and basified with dilute sodium hydroxide solution. The mixture is filtered and the solid is dried and crystallized from toluene, 1.7 g of the expected product are obtained, mp. 191-192 ° C.





    eight
    Calculated,%: C 51.53; H 3.60; N 15.02.
    C, jH, CC1K, Oz
    Found,%: C, 51.23; H 3.71; N 14.83.
    Example 15. Preparation of 5-aminocarbonyl-1- (3-chlorophenyl) -4-pyrazolecarboxylic allyl ester.
    3.33 g of 4-carboxy-1- (3-chlorophenyl) -5-pyrazole-carboxamide is suspended in 35 ml of methanol and 0.68 g of sodium methoxide is added. The methanol is removed under vacuum to yield the sodium salt of the starting compound. This salt is mixed with 1.26 g of triethylamine and 1.51 g of allyl bromide in 35 ml of toluene and the mixture obtained is stirred at reflux temperature overnight. The mixture is taken up in 150 ml of an ice-water mixture, alkalinized with a saturated solution of sodium bicarbonate and extracted with 150 ml of ethyl acetate. The organic layer is washed with brine, dried and evaporated under vacuum to obtain a solid product, which is recrystallized from toluene, 1.48 g of purified product are obtained, mp. 132-133 ° C.
    Calculated,%: C 55.00; H 3.96; N 13.74.
    S „N., SSHZOZ
    Found,%: C 55.15; H 3.96; N 13.70.
    Example 16. Preparation of 5-aminocarbonyl-1- (3-chlorophenyl) -4-pyrazolecarboxylic acid ethyl ester.
    2.5 g of 4-carboxy-1- (3-chlorophenyl) -5-pyrazolecarboxamide are suspended in 50 ml of absolute ethanol, acidified, esterified and added as described in Example 14. 1.64 g of the expected product is obtained, m.p. ..
    Calculated,%: C 53.16; H 4.12; N 14.31.
    S, NN C1ZOZOZ
    Found,%: C 53.37; H 4.04; N 14.61.
    Example 17. Preparation of 5-aminocaronyl-1- (3-methylphenyl) -4-pyrazolecarboxylic acid methyl ester.
    Gaseous hydrogen chloride is bubbled for 1 minute into a suspension of 3 g of 4-carboxy-1- (3-methyl-phen1t) -5-pyrazolecarboxamide in 30 ml of methanol. The mixture was stirred at reflux temperature for 2 hours, cooled and left overnight. It is then poured into 150 ml of ice and water and alkalinized with dilute sodium hydroxide. The precipitated reaction product is filtered off, dried and recrystallized from toluene, and treated with charcoal to obtain 1.16 g of the desired product, mp.
    ley-ies c.
    Calculated,%: C 60.23; H 5.05; N 16.21.
    , EN -
    Found,%: C 60.18; H 4.99; N 16.08.
    PRI me R 18. Obtaining the sodium salt of 4-carboxy-1- (3-methylphenyl) 5-pyrazole carboxamide.
    3 g of 4-carboxy-1- (3-methylphenyl) -5-pyrazolecarboxamide is suspended in B 30 ml of methanol and 0.66 g of sodium methoxide is added. The mixture is stirred for a short time, filtered and evaporated to dryness. The residue is dissolved in methanol, treated with charcoal and recrystallized. The reaction product is very hygroscopic, it is dried for 8 hours at.
    Calculated,%: C 53.94; H 3.77; N 15.72.
    Ci4H ,, NjNaOjFound%: C 54.11; H 3.73; N 15.52 ..
    Take p19. Obtaining the sodium salt of 4-carboxy-1- (3-chlorophenyl) 5-pyrazolecarboxamide
    6.14 g of 4-carboxy-1- (3-chlorophenyl) 5-pyrazolecarboxamide is suspended in 60 ml of methanol and 1.25 g of sodium methoxide is added. The mixture is stirred for several weeks and filtered. The filtrate is evaporated to dryness under vacuum, the residue is dissolved in 50 ml of methanol and crystallized by the addition of diethyl ether. The solid residue is filtered, dried and receive 4.55 g of the target salt, so pl. 274С 45.93; H 2.45;
    276 ° C:
    Calculated N 14,61.
    C i H-jClNj-NaO.
    Found,%: C 46.10; H 2.26; N 14.58.
    PRI me R 20. Obtaining the potassium salt of 4-carboxy-1- (3-chlorophenyl) - 5-pyrazolecarboxamide.
    4.25 g of 4-carboxy-1- (3-chloro1) enyl) 5-pyrazolecarboxamide suspended
    in 40 ml of absolute ethanol together with 1.03 g of 85% potassium hydroxide and the mixture is heated to reflux temperature. A small amount of water is added to the boiling mixture to completely dissolve the entire mixture, then cooled to ambient temperature. Then the mixture is cooled in a refrigerator, filtered, and 3.32 g of the desired product is obtained, so pl. above 300 ° C with decomposition.
    Calculated,%: C 43.50; H 2.32;
    N 13.83.
    Ci H-ClKNgOj,
    Found,%: C 43.26; H 2.09; N 13.55.
    Example 21 Preparation of the 4-carboxy-1- (3-chlorophenyl) -5-pyrazolecarboxamide isopropylamine salt.
    4.25 g of 4-carboxy-1- (3-chlorophenyl) 5-pyrazolecarboxamide and 1.42 g of isopropylamine are added to 50 ml of absolute ethanol and stirred for several minutes. Then the mixtures were dried to dryness and recrystallized from methanol-diethyl ether mixture to obtain 4.4 g of the desired product, m.p. 157-164 C.
    Calculated,%: C 52.10; H 4.68; N 17.36.
    С „Н ,, С1Ы, Oz
    Found,%: C 5Z, 16; H 4.77;
    IN 17.19 P g. And im 22. Preparation of the tetrabutylammonium salt of 4-carboxy-1- (3-chlorophenyl) -5-pyrazolecarboxamide.
    3.26g 4-carboxy-1- (3-chlorofensh1) -5-pyrazolecarboxamide suspended
    50 MP of methanol and 12 ml in 1 M tetrabut ammonium hydroxide solution are added. The mixture is stirred for 30 minutes and evaporated to dryness under vacuum to obtain 5.2 g of the target product, m.p. 120-121 C.
    Calculated,%: N 11.05.
    S.N4zS1K40e
    Found,%: N 11.07.
    PRI me R 23. Preparation of 4-carboxy-1- (3,4-dimethylphenyl) -5-pyrazolecarboxamide.
    2.5 g of 5-cyano-1- (3,4-dimethylphenyl) -4-pyrazolecarboxylic acid ethyl ester is hydrolyzed in 50 ml of ethanol and 12 MP of water with 1.3 g of potassium hydroxide at reflux temperature in for 2.25 hours. The mixture is cooled and howl
    watered in 300 ml of water. The aqueous mixture is filtered, acidified with concentrated hydrochloric acid and filtered. The solid residue is dried and recrystallized from ethanol-Won mixture. Obtain 1.62 g of the target product, so pl. 231-232.5 ° C.
    Calculated,%: C 60.23; H 5.05; N 16.21.


    C ,, H ,,
    Found,%: C 60.47; H 4.94; N 16.05.
    PRI me R 24. Preparation of 4-carboxy-1 - (3-Ethylphenyl) -5-pyrazolecarboxamide.
    A 60.6 g portion of 3-ethylaniline is added to 132 g of concentrated hydrochloric acid and 67 g of ice is added, another 67 g of ice is added and the mixture is again cooled to. 36.3 g of sodium nitrite dissolved in 75 ml of water for 1 h are added dropwise to the mixture, maintaining the temperature below 6 C. During this time, a solution of potassium sulfite is obtained by flowing sulfur dioxide through a solution of 163.8 g of potassium hydroxide 750m of water. Sulfur dioxide continues to pass through to a pH of 4.7. 67 g of ice are then added and the solution is cooled to 0 ° C.
    The two drugs are mixed together as quickly as possible, resulting in a temperature rise up to 8 ° C. The mixture is then heated on a steam bath to 70 ° C and stirred at this temperature for 1 hour. The mixture is then cooled to 0 ° C and the precipitated reaction product is separated by filtration and dried. The solids are recrystallized from a large amount of ethanol, 70.9 g of 3-ethylphenylhydrazine potassium sulfonate are obtained, decompose at a temperature higher than 195 ° C.
    15.0 g of the specified intermediate product is stirred in 150 ml of water and 75 ml of hydrochloric acid
    together with a small amount of wood- 50 Pa, the organic layer is dried and
    carbon and the mixture is filtered in a hot state. The filtrate is cooled to ambient temperature overnight, and after turbulence of the solution, a precipitate immediately begins to precipitate. The solids are separated by filtration, dried, and 3 g ethylphenyl hydrazine hydrochloride are obtained, m.p. 147-157 C.
    7.9 g of oily product are evaporated, which is purified by high performance liquid chromatography, eluting with 1,2-di-55 hporethan. Evaporation of the fractions containing the reaction product yields 6.1 g of 5-cyano 1- (3-ethyl-nsh1) -4-pyrazolecarboxylic acid ethyl ester as an oil.
    I 2
    10.7 g of this intermediate product are mixed with 10.5 g of ethoxy (ethoxymethylene) -cyanoacetic acid and 10.2 g of sodium acetate in 100 ml of ethanol, and the mixture is stirred at reflux temperature for 20 hours. Mixture The mixture is poured onto 400 ml of an ice-water mixture with stirring and the solid residue is filtered off and dried. The solid residue is recrystallized from aqueous ethanol to obtain 12.7 g of 5-amino 1- (3-ethylphenyl) -4-pyraol-carboxylic acid ethyl ester, mp. 79-79 ,. 10.2 g of this intermediate are dissolved in a minimum amount of chloroform and through solution
    Hydrogen chloride gas is bubbled at room temperature for 1 min. Then, gaseous nitrosyl chloride is bubbled through this mixture for 20 minutes;
    keeping the temperature in the range of 20-35 ° С with the help of an ice-bath. The mixture is then heated on a steam bath to remove excess nitrosyl chloride, dried using phase separating paper, and the organic portion is evaporated under vacuum. The residue is purified by high performance HPLC chromatography, eluted with 1,2-dichloroethane. the fractions containing the reaction product are collected and evaporated under vacuum, to obtain 2.9 g of 5-chloro-1- (3-ethylphenyl) -4-pyrazolecarboxylic acid ethyl ester as an oil.
    8.9 g of this intermediate product are mixed with 35 ml of dimethylformamide and 3.4 g of sodium cyanide and the mixture is heated for 6 hours at about 100 ° C. The mixture is cooled, an additional amount of sodium cyanide is added and the mixture is heated at 100 ° C for more than 2 hours. The mixture is cooled, poured into 300 ml of ice-water mixture, extracted with 300 ml of diethyl effluent to give 7.9 g of oily product, which purified by high performance liquid chromatography, eluted with 1,2-dichloroethane. Evaporation of the fractions containing the reaction product yields 6.1 g of 5-cyano 1- (3-ethyl phenyl 1) -4-pyrazolecarboxylic acid ethyl ester as an oil.
    2.5 g of this intermediate are added to 25 ml of ethanol containing 1.6 g of potassium hydroxide, and the mixture is heated at the boiling point for 20 minutes. 5 ml of water are added, the mixture is heated under reflux for 1.5 hours and then poured into 100 ml of water. The mixture is acidified with concentrated hydrochloric acid, cooled under refrigeration and filtered, to obtain 2.0 g of the desired product, mp1-177,.
    Calculated,%: C 60.23; H 5.05; N 16.21.
    nHliNgO ..
    Found,%: C 60.03; H 4.83; N 15.93o
    EXAMPLE 25 Preparation of 4-carboxy-1- (3-methoxyphenyl) -5-pyrazole-boxamide.
    34.9 g of 3-methoxyphenyl hydrazine hydrochloride are added to 300 ml of acetic acid, 100 ml of water, 36 g of sodium acetate and 37.2 g of (ethoxymethylene) cyanoacetic acid ethyl ester. The mixture is heated overnight in a steam bath, then cooled and drunk in 1 liter of ice / water mixture with vigorous stirring. The mixture is filtered and the solid residue is air dried and recrystallized from aqueous ethanol with charcoal to obtain 27.4 g of 5-amino-1- (3-methoxyphenyl) -4-pyrazole-carboxylic acid ester, m.p. 66g67 S.
    13.3 g of this intermediate product is dissolved in 80 ml of bromoform and the mixture is cooled to 5 ° C. To the mixture is added dropwise 10.5 g of tert-butyl nitrite, left to reach ambient temperature and heated on a steam bath in for 15 minutes The mixture was evaporated under vacuum to give 21.1 g of a dark oil, which was dissolved in ethyl acetate. The solution was washed with 1 N hydrochloric acid, water, saturated sodium bicarbonate solution and brine, and then dried and evaporated under vacuum to obtain a dark oil, which was purified by high performance liquid chromatography, eluting 1: 3 with a mixture of ethyl acetate and hexane, to obtain 10.6 g of ethyl 5-bro-1- (3-methoxy-,
    phenyl) -4-pyrazolecarboxylic acid, so pl. 77-79 ° C.
    3.6 g of this intermediate product is mixed with 1.2 g of sodium cyanide in 20 ml of dimethylformamide and the mixture is heated for 10 hours at. An additional amount (0.3 g) of sodium cyanide is added and the mixture is heated overnight at, then drunk in 100 ml of ice-water mixture. The precipitate is separated by filtration and dried, then recrystallized from ethanol with charcoal, poluchigot 1.0 g of ethyl ester of 5-cyano-1- (3-methoxy-phenyl-1) -4-pyrazolecarboxylic acid, so pl. 84-85 ° C.
    0.95 g of this intermediate is added to 25 ml of ethanol and 0.6 g of potassium hydroxide and the mixture is heated to reflux. 10 ml of water are added and the mixture is heated under reflux for 1.5 hours. Then it is cooled and filtered, and the filtrate is poured into 100 ml of water. The aqueous mixture is acidified with concentrated hydrochloric acid and vigorously stirred, cooled in the refrigerator. The precipitate formed is separated by filtration, dried, and recrystallized from aqueous ethanol. 0.4 g of the expected product are obtained, m.p. 213-216 ° C.
    Calculated,%: C 55.17; H 4.24; N 16.08.
    C, .H ,, N, 0 ,.
    Found,%: C 55,12; H 3.99; N 15.83.
    The proposed compounds are thoroughly tested to demonstrate their activity in inhibiting the formation of pollen. The results of the ET1-1X tests are shown below.
    Test 1.
    The experiment recorded here was a field experiment conducted in central Indiana, USA. The experiment began with sowing of narrow strips of wheat of Aubin and Bow in the fall. Some narrow strips were cut by 4 oct. Br, and others by 14 oct. Br. During sowing, the field was fertilized with a combination of fertilizers suitable for growing sackcloth. Neighboring narrow strips of wheat Aubin and Bow were sown with pollen supply cases of mixed wheat varieties Caldvil, Aubin and Titan in a 1: 1: 2 ratio. Pollen-supplying plots were sown at 1 oct. Bb, with a rate of 113.6 kg of grain per hectare (100 pounds per acre).
    The compound in this experiment was the compound from Example 1. The compound was introduced into the composition for use in a 1: 1 volume ratio of a mixture of acetone and denatured alcohol. The organic solution is diluted with water containing 0.25% poly-sorbate 20 when applied. All applications (applications) were carried out with a volumetric rate of 4728 liters per hectare (500 gallons per acre) and were applied by spraying the foliage of the test pieces.
    The first use of the compound was carried out on April 26 after sowing wheat. If the compound was used repeatedly, the later applications were carried out at one week intervals.
    My case was 4 p yes g 396.5 cm (4 p yes x13 foot).
    During the appearance of the panicle, some laths in each of the treated plots were tucked into the sacks with the help of grain plastic cellophane insulating membranes. In the bags, five netelok were covered in each row of each test case.
    When grains were formed, it was envisaged to count the content of the number of grains in the panicle in plants,
    15 covered in sacks and in which the formation of pollen was inhibited, because these grains can be formed only by self-pollination. The number of grains in the panicle in unopened plants of the research institutes in each tested section counted the same as the number of grains in the panicle in the untreated control files.
    The two cases were treated with the cohs. The test cases were planned for each treatment mode and were measured by the Auben and Boy wheat zones, the results are presented in the average, which become the female divisions in the table. 1, which is given by the actives for the cultivation of hybrid wheat, the value of the compound of example 1 with regard to inhibiting the formation of dust from the dust-lining of the speck. The size of each test is 30, TSA wheat.
    T a b l n c a i
    1,136
    90
    12
    My case was 4 p yes g 396.5 cm (4 p yes x13 foot).
    During the appearance of the panicle, some laths in each of the treated plots were bagged with the help of grain plastic cellophane insulating membranes. In the pouches, five netelok were covered in each row of each test case.
    When grains were formed, it was envisaged to count the content of the number of grains in the panicle in plants,
    covered in sacks and in which pollen was inhibited, because these grains can only be formed by self-pollination. The number of grains in the panicle in unopened plants in each test case counted as the same as the number of grains in the pan for untreated control files.
    Two cases were processed sogT a b l n c a i
    73
    26
    100
    98
    Data is presented separately for each type of wheat and for each sowing date. The earlier sown seeds are labeled as period I, and later as period 2. The columns entitled fertility represent the number of grains in the panicle of the treated, covered in sacks, plants, as a percentage of the untreated control plants, and therefore represent Direct measure of pollen formation. The columns, entitled hybrid, represent the difference between the number of grains in the panicle, processed, unopened in the bags, plants and grains in the panicle, processed, covered in the bags, plants
    as a percentage of untreated container processing.
    Test 2.
    The compound of example 1 was applied to 61 varieties of wheat. Each test case consists of three 61 cm (2 feet) hand-seeded rows each, with a distance of 61 cm (2 feet) between groups of three rows. Affairs were seated in central Indiana on 5 Oct. br. In the next 5 years, two of the three rows were sprayed with plant control plants. Thus, this column represents the number of grown hybrid grains compared to grains grown from untreated control plants. The purity of the grown hybrid kernels can be determined by comparing the percentage of fertility and the percentage
    hybrid
    Additional cases in the same group of wheat plants of Aubin and Bou were processed once, or 4 ma, for 10 ma, after sowing the spea
    in October. The results of these experiments are presented below in Table. 2, where the activity of the compound of example 1 in relation to the inhibition of pollen formation at the table,
    The compound of Example 1 was at a rate of 5.68 kg per 1 ha (5 pounds per acre) and 11.36 kg per 1 ha (10 pounds per acre), and the third row was left as untreated control plants.
    The plants were covered in sacks and the formation of grains of the nestled in the sacs, unopened in the sacs and the untreated plants was calculated as
    nineteen
    this is described in test 1. Ptitsa for these experiments was provided with zones of the same mixture of wheat 1 supplying pollen, which was described in test 1.
    The data from this group of experiments are presented in Table. 3 in a summed form, in the form of a number of wheat varieties, which show the fertility of sheltered treated plants within different limits as compared to that of untreated control plants.
    Table 3
    Test 3.
    A standardized greenhouse test was used to evaluate the proposed compounds. The test was started by sowing Voddron's sackcloth in cases of 10 cm (4 inches), 4 grains per case in sterile, sandy-loamy soil. Wheats Preferred compounds of the present invention, which are also preferred compounds for the practical application of the present methods for inhibiting pollen formation, are 4-carboxy-1- (3-chlorophenyl) -5-pyrazolecarboxamide, 4-carboxy-1- (3-methylphenyl) -5-pyrazolecarboxamide, 4-carbo
    It was allowed to grow in good t to xi-1- (3-ethyl lenyl) -5-pyrazole carboxamide, 4-carboxy-1- (3,4-dichlorophenyl) -5-pyrazole carboxamide, and 4-carboxy-1- (3-methoxyphenyl) -5-pyrazole carboxamide. The alkali metal salts of ammonium salts and mono-, di-, and tri (C-C4-alkyl) -amine salts of the compounds just mentioned are also preferred compounds of the present invention.
    greenhouse environment, and the plants were treated three times with the tested composition. The first application (application was made about 22 days after sowing the seeds, and the second and third application was made about 3 and 10 days after the first application.
    Each compound was formulated for testing by dissolving the required amount for two identical rows in the subway and for three applications (applications) depending on the concentration to be tested in 5 ml of a 1: 1 volume mixture of acetone and denatured alcohol containing 10% by volume of polysorbate 20. Dissolving compounds were finely dispersed in a solvent.

    Then the organic mixture was diluted to 30 ml with deionized water at ambient temperature, and the aqueous dispersion was uniformly sprayed onto the foliage of two divisions of wheat.
    In each experiment, untreated control plants were provided.
    The results of the experiments are presented as the number of spikelets extracted from the treated plants, and as the number of grains per spikelet. The average number of spikelets per normal plant is about 15, and the number of grains per spike varies from about 1.5 to 2.5 m. .
    In tab. 4-14 averaged the results of the copied experiments. If the experimental results did not differ from the results that coincided in the time of the untreated control plants, then the inactivity is simply the letter N.
    Preferred compounds of the present invention, which are also preferred compounds for the practical application of the present methods for inhibiting pollen formation, are 4-carboxy-1- (3-chlorophenyl) -5-pyrazolecarboxamide, 4-carboxy -1- (3-methylphenyl) -5-pyrazolecarboxamide, 4-carboxy-1- (3-ethyl benyl) -5-pyrazolecarbo
    Xamide, 4-carboxy-1- (3,4-dichlorophenyl) -5-pyrazolecarboxamide and 4-carboxy-1- (3-methoxyphenyl) -5-pyrazolecarboxamide. Alkali metal salts, ammonium salts, and mono-, di-, and tri (C-C4-alkyl) -amine salts of the compounds just mentioned are also preferred compounds of the present invention.
    When known compounds are used for this purpose, namely 1-aryl-1,4-dihydro-4-oxo (sh1I thio) pyridazines, hybrid seeds of the deformed form are produced, while hybrid seeds obtained using the proposed compounds have normal appearance.
    In tab. 4 shows data on personal testing of compounds.

    Table 4
    In tab. 5-12 are given depending on the concentration of compounds. Concentration of ppm: in table. 5-1,200; in tab. 6 - 1000; in tab. 7 - 800; in tab. 8 - 600; in tab. 9 - 400; in tab. 10 - -300; in tab. 11 200; Ib table 12 - 100.
    22
    Table 5
    Spikelets
    Grain / spikelet
    1 1 2 5
    10.6 11.7 N 13.5
    T a b l
    About 0.22
    0.01 and c 6
    five
    0
    five
    0
    five
    0
    five
    9.0 9.4 12.0 11.2 N N N
    12.9 13.8 13.5 12.3 13.6 13.7 15.3 12.7 15.5 15.5 15 14.0 15.3 15.0
    Oh oh
    0.16 0.27
    ABOUT
    ABOUT
    0.50
    0.41
    0.68
    0.84
    1.28
    I
    0.89 0.81 0.69 0.05 0.08 0.98
    29 Continued table. eleven
    I
    Table 12
    9.5
    N
    11.7 10.9 13.5 14.5 14.0 14.5 14.3 14.3 N N N N N N N
    1.21
    1.79 1.79 1.78 1.97
    .1.77 0.66 1.60
    1.92
    14A0343
    30 Continued table. 12
    Test 4.
    This test was carried out according to the method described in test 3, except that the compounds were applied (inserted) only twice,
    with an interval of 4 days. In other respects, the test method and the method of obtaining the presented data were the same. In addition, only the compound of Example 1 was tested.
    35
    13
    40
    45
    IN
    5s
    .and
    11p1) D (.zhiemne liitbji.l 3
    Test 5.
    Again, the test method from test 4 was used, but the interval between the two applications of the compound was 6 days.
    Table 14
    1/4 /, (D) DZ
    15
    20
    33 Continued table. 1A
    600 600
    600
    U, 5 13.7
    ; 14,2
    0.09 0.18
    0.18
    1А403АЗ
    34
    37
    where R, RguR. - independently friend
    from a friend, halogen.
    C — C alkoxy,
    provided
    2
    C, -C.Appsch1 or hydrogen, that at least one of Ri ,, R Rg is hydrogen and provided that R can represent a group other than hydrogen, only when one of R and Rj, and not both, is group other than hydrogen; RCH oxyC. -C4 alkoxy, C2-C4 alkylene 1oxy or phytologically acceptable residue forming a carboxylic acid salt, characterized in that the nitrile of the general formula is hydrolyzed
    .
    , ten
    where k
    ; -f
    034338
    CN. COORs

    I r
    R i and R 5 have the indicated meanings; Rу is a lower C-C-alkyl, in the presence of a base at the boiling point of the solvent, with the separation of the target product, where R4 is a hydroxy group, or with the separation of the target product as an ether, where R is C1, -C-alkoxy or 5 C; 2-C4-alkenyloxy, or in the form of a phytologically acceptable salt.
    权利要求:
    Claims (1)
    [1]
    Claim
    A method of producing pyrazole derivatives of the general formula conh 2
    1440343 where R o Rj and Rj are independently from each other, halogen, C ^ -Cd alkoxy, C t -C 4 -alkyl or hydrogen, provided that at least one of R <,, R 2 , R 3 - hydrogen and provided that <Rj may represent a group other than hydrogen only when one of R ^ and R } , and not both, represents a group other than hydrogen; R 4 - hydroxy, 10 C, .- C 4 alkoxy, C 2 _ ~ C4 alkenyloxy or fitologicheski acceptable moiety forming a salt of the carboxylic sour + s, characterized in that the hydrolyzing the nitrile of general Formula 15
    CN. Cools
    I, R, where K 4 , R 2 h R j have the indicated meanings, R ζ is lower C ^ -Cd-alkyl, in the presence of a base at the boiling point of the solvent with the isolation of the target product, where R 4 is an oxy group, or with the isolation of the target the product in the form of an ether, where R 4 is C 4 -C 4 alkoxy or C ^ -C ^ alkenyloxy, or in the form of a phytologically acceptable salt.
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    同族专利:
    公开号 | 公开日
    RO92792A|1987-11-30|
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    PT81174B|1988-01-22|
    GR852318B|1986-01-24|
    PL148599B1|1989-11-30|
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    PL255491A1|1987-08-24|
    CS259532B2|1988-10-14|
    PH21852A|1988-03-25|
    DK432685D0|1985-09-24|
    FI853644L|1986-03-26|
    ES547260A0|1987-02-01|
    RO92792B|1987-12-01|
    EP0177242A2|1986-04-09|
    BG60351B2|1994-08-15|
    NZ213590A|1988-08-30|
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    KR860002472A|1986-04-26|
    PT81174A|1985-10-01|
    AU581927B2|1989-03-09|
    HU196291B|1988-11-28|
    ES8703141A1|1987-02-01|
    US4666504A|1987-05-19|
    JPS6187668A|1986-05-06|
    CS678385A2|1988-03-15|
    CN1016398B|1992-04-29|
    CA1262911A|1989-11-14|
    DOP1985004354A|1990-11-09|
    IL76463D0|1986-01-31|
    DD236870A5|1986-06-25|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US65406184A| true| 1984-09-25|1984-09-25|
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