A pyrazopurine herbicide safener and its preparation method and application

Abstract

The invention discloses a pyrazopurine herbicide safener and a preparation method and application thereof, and belongs to the technical field of pesticides. The pyrazopurine herbicide safener of the invention has a structure shown in formula (I). In the formula, R1, R2, and R3 correspond to the definitions given in the specification. The invention also discloses a preparation method of the herbicide safener and an application of the herbicide safener. The herbicide safener of the invention can effectively eliminate the damage of the herbicide mesosulfuron to crops, and expands a new direction for the development of herbicide safeners.

Description

Technical Field

[0001] The invention belongs to the technical field of pesticides, and in particular relates to a pyrazopurine herbicide safener and a preparation method and application thereof. Background Art

[0002] Herbicide safeners, also known as antidotes, can selectively protect crops without reducing the activity of herbicides on target weeds, reduce the sensitivity of crops to herbicides, increase crop safety and improve weed control effects. Since the discovery of the first herbicide safener in the middle of the last century, this type of substance has brought huge economic benefits and potential research value.

[0003] Safeners play a very important role in improving the selectivity of herbicides. Their use can expand the application range of crops of herbicides with low or even no selectivity, improve the selectivity and broad spectrum of existing herbicide varieties, avoid the problem of herbicide damage caused by excessive use of herbicides, and use them together with herbicides to extend the service life of herbicides. Therefore, it is necessary to develop new herbicide safeners. Summary of the invention

[0004] Based on the above reasons, in view of the problems or defects in the prior art, the purpose of the present invention is to provide a pyrazopurine herbicide safener and a preparation method and application thereof, so as to solve or at least partially solve the above technical defects in the prior art.

[0005] In order to achieve the above first object of the present invention, the technical solution adopted by the present invention is as follows:

[0006] A pyrazopurine herbicide safener, wherein the pyrazopurine herbicide safener has the general structural formula (I) as follows:

[0007]

[0008] in:

[0009] R1 is selected from any one of C1-C10 alkyl, C1-C5 alkoxy, phenyl, halogenated phenyl, and thienyl;

[0010] R2 is selected from any one of C1-C5 alkyl groups;

[0011] R3 is selected from any one of hydrogen, C1-C6 alkyl, phenyl, halogenated phenyl, and C1-C3 alkyl-substituted phenyl.

[0012] Furthermore, in the above technical solution, R1 is selected from any one of C1-C5 alkyl, C2 alkoxy, phenyl, chlorophenyl or thienyl; R2 is selected from any one of C1-C2 alkyl; R3 is selected from any one of hydrogen, C2-C4 alkyl, and benzyl.

[0013] The second aspect of the present invention is to provide a method for preparing the above-mentioned pyrazopurine herbicide safener, comprising the following steps:

[0014] Step 1, dissolving 6-chloropurine and an acid-binding agent in an organic solvent 1, then adding a halogenated hydrocarbon (R3-X) dropwise, reacting the resulting mixed reaction solution 1 at room temperature for 24-48 hours, and then extracting, drying, filtering, concentrating, and purifying to obtain a 6-chloro-9-substituted purine compound;

[0015] Step 2: dissolving the 6-chloro-9-substituted purine compound and hydrazine hydrate described in step 1 in an organic solvent 2, and subjecting the obtained mixed reaction solution 2 to a reflux reaction; after the reaction is completed, precipitating, filtering, and washing to obtain a 9-substituted 6-hydrazine purine compound; the reaction temperature is 60-110° C., and the reaction time is 5-12 hours;

[0016] Step 3: dissolving the 9-substituted 6-hydrazinopurine compound described in step 2 in an organic solvent 3, and subjecting it to a reflux reaction with a 1,3-diketone compound; after the reaction is completed, recrystallizing the obtained product to obtain the pyrazopurine herbicide safener (structural formula as shown in formula (I)); the reaction temperature is 60-110° C., and the reaction time is 5-12 h.

[0017] Further, in the above technical solution, the organic solvent 1 in step 1 is one or any combination of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dimethyl sulfoxide, dichloromethane, tetrahydrofuran, and N-methylpyrrolidone. Preferably, it is one or any combination of N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0018] Furthermore, in the above technical solution, the acid binding agent in step 1 is any one of N,N-diisopropylethylamine, triethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, and sodium hydroxide. Any one of triethylamine, potassium carbonate, and sodium carbonate is preferred.

[0019] Furthermore, in the above technical solution, in R3-X in step 1, R3 is selected from one of hydrogen, C1-C6 alkyl, phenyl, halogenated phenyl or C1-C3 alkyl substituted phenyl.

[0020] Furthermore, in the above technical solution, the molar ratio of 6-chloropurine to R3-X in step 1 is 1:1.2-1.7.

[0021] Preferably, in the above technical solution, the molar ratio of 6-chloropurine to R3-X is 1:1.2-1.3.

[0022] Furthermore, in the above technical solution, the normal temperature in step 1 refers to the natural room temperature conditions in all seasons, without additional cooling or heating treatment, and the normal temperature is generally controlled at 10-30°C.

[0023] Furthermore, in the above technical solution, the room temperature is preferably 27-30°C.

[0024] Furthermore, in the above technical solution, the molar ratio of 6-chloro-9-substituted purine to hydrazine hydrate in step 2 is 1:5-8.

[0025] Preferably, in the above technical solution, the molar ratio of the 6-chloro-9-substituted purine to hydrazine hydrate is 1:6-7.

[0026] Furthermore, in the above technical solution, the reaction temperature in step 2 is 70-80°C.

[0027] Furthermore, in the above technical solution, the reaction time in step 2 is 5-7h.

[0028] Further, in the above technical solution, the organic solvent 2 in step 2 and the organic solvent 3 in step 3 may be the same or different, and both may be one or any combination of dichloromethane, anhydrous methanol, anhydrous ethanol, isopropanol, 1,4-dioxane, acetone, and ether. Preferably, one or a combination of anhydrous ethanol or anhydrous methanol.

[0029] Furthermore, in the above technical solution, the molar ratio of the 9-substituted 6-hydrazinopurine compound to the 1,3-diketone compound in step three is 1:1-2.

[0030] Preferably, in the above technical solution, the molar ratio of the 9-substituted 6-hydrazinopurine compound to the 1,3-diketone compound is 1:1.2-1.5.

[0031] Furthermore, in the above technical solution, the structural formula of the 1,3-diketone compound in step 3 is as follows:

[0032]

[0033] Wherein: R1 is selected from one of C1-C10 alkyl, C1-C5 alkoxy, phenyl, halogenated phenyl or thienyl, and R2 is selected from one of C1-C5 alkyl.

[0034] Furthermore, in the above technical solution, the temperature of the reflux reaction in step 3 is 70-80° C., and the reaction time is 7-9 h.

[0035] The third object of the present invention is to provide the use of the above-mentioned pyrazopurine herbicide safener for eliminating the toxicity of herbicides to crops.

[0036] Furthermore, the herbicide safener can alleviate the damage of sulfonylurea herbicides to crops.

[0037] Furthermore, the herbicide safener can alleviate the damage of the herbicide mesosulfuron to wheat.

[0038] The present invention also provides a safener for alleviating sulfonylurea herbicides, comprising the above-mentioned pyrazopurine herbicide safener of the present invention.

[0039] The present invention also provides a safener for alleviating the effects of mesosulfuron herbicide, comprising the pyrazopurine herbicide safener described above.

[0040] The chemical reaction formula involved in preparing the pyrazopurine herbicide safener of the present invention is as follows: 1.

[0042] 2.

[0044] 3.

[0046]

[0047] The present invention relates to a pyrazopurine herbicide safener and a preparation method and application thereof, which has the following characteristics:

[0048] Beneficial effects:

[0049] The present invention provides a pyrazopurine herbicide safener of formula (I) through the above technical scheme. The herbicide safener is easy to prepare, has excellent safety activity, can well improve the phytotoxicity problem caused by herbicides, has good detoxification effect, and is beneficial to the growth of crops. The safener can alleviate the phytotoxicity caused by sulfonylurea herbicides to crops, especially the phytotoxicity of mesosulfuron to wheat, and expands a new direction for the development of herbicide safeners. DETAILED DESCRIPTION

[0050] The present invention is further described in detail below through implementation cases. This implementation case is implemented based on the technology of the present invention, and a detailed implementation method and specific operation process are now given to illustrate that the present invention is creative, but the protection scope of the present invention is not limited to the following implementation cases.

[0051] The equipment and raw materials used in the present invention can be purchased from the market or are commonly used in the art. The methods in the following embodiments are all conventional methods in the art unless otherwise specified.

[0052] Example 1

[0053] The preparation method of 6-chloro-9-ethylpurine involved in this embodiment comprises the following steps:

[0054]

[0055] 6-Chloropurine (1 eq) and acid-binding agent K2CO3 (1.2 eq) were added to a three-necked flask containing 30 mL N,N-dimethylformamide, stirred at room temperature for 30 min, and then ethyl bromide (1.2 eq) was added dropwise. Then the mixture was reacted at 27-30°C for 24 h, and the reaction was complete when detected by TLC. The mixture was poured into distilled water, the aqueous phase was extracted with ethyl acetate, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain a crude product. The liquid silica gel column method was used, and the eluent was ethyl acetate: petroleum ether in a volume ratio of 5:1 to obtain 6-chloro-9-ethylpurine with a yield of 65.2% and mp 78.2-79.1°C.

[0056] Example 2 Preparation of 6-chloro-9-propylpurine

[0057]

[0058] 6-Chloropurine (1 eq) and acid-binding agent triethylamine (1.2 eq) were added to a three-necked flask containing 30 mL of N,N-dimethylacetamide, and 1-bromopropane (1.2 eq) was added dropwise after stirring at room temperature for 30 min. Then the mixture was reacted at 27-30 ° C for 24 h, and the reaction was complete after TLC detection. After the mixture was spin-dried, it was dissolved in ethyl acetate and washed three times with water, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain a crude product. The liquid silica gel column method was used, and the eluent was ethyl acetate: petroleum ether in a volume ratio of 6:1 to obtain 6-chloro-9-propylpurine with a yield of 63.3% and mp 71.3-72.8 ° C.

[0059] Example 3 Preparation of 6-chloro-9-butylpurine

[0060]

[0061] 6-Chloropurine (1 eq) and acid-binding agent Na2CO3 (1.2 eq) were added to a three-necked flask containing 30 mL of N,N-dimethylformamide, stirred at room temperature for 30 min, and then n-butyl bromide (1.2 eq) was added dropwise. Then the mixture was reacted at 27-30°C for 26 h, and the reaction was complete when detected by TLC. The mixture was poured into distilled water, the aqueous phase was extracted with ethyl acetate, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain a crude product. The liquid silica gel column method was used, and the eluent was ethyl acetate: petroleum ether in a volume ratio of 5:1 to obtain 6-chloro-9-butylpurine with a yield of 52.1% and mp 67.1-68.9°C.

[0062] Example 4 Preparation of 6-chloro-9-isopropylpurine

[0063]

[0064] 6-Chloropurine (1 eq) and acid-binding agent triethylamine (1.2 eq) were added to a three-necked flask containing 30 mL of dimethyl sulfoxide, stirred at room temperature for 30 min, and then bromoisopropyl (1.3 eq) was added dropwise. Then the mixture was reacted at 27-30°C for 25 h, and the reaction was complete when detected by TLC. The mixture was poured into distilled water, the aqueous phase was extracted with ethyl acetate, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain a crude product. The liquid silica gel column method was used, and the eluent was ethyl acetate: petroleum ether in a volume ratio of 6:1 to obtain 6-chloro-9-isopropylpurine with a yield of 49.0% and mp 107.6-108.5°C.

[0065] Example 5 Preparation of 6-chloro-9-benzylpurine

[0066]

[0067] 6-Chloropurine (1 eq) and acid-binding agent K2CO3 (1.2 eq) were added to a three-necked flask containing 30 mL of dimethyl sulfoxide, stirred at room temperature for 30 min, and then benzyl chloride (1.3 eq) was added dropwise. Then the mixture was reacted at 27-30°C for 24 h, and the reaction was complete when detected by TLC. The mixture was poured into distilled water, the aqueous phase was extracted with ethyl acetate, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain a crude product. The liquid silica gel column method was used, and the eluent was ethyl acetate: petroleum ether in a volume ratio of 8:1 to obtain 6-chloro-9-benzylpurine with a yield of 76.4% and mp 86.2-87.0°C.

[0068] Example 6 Preparation of 5-methyl-1-(9H-purine)-1H-pyrazole-3-carboxylic acid ethyl ester (I-1)

[0069] 1. Add 6-chloropurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, then add hydrazine hydrate (6 eq). Then reflux at 75°C for 6 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with anhydrous ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine purine.

[0070] 2. Add 6-hydrazinopurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with ethyl 2,4-dioxovalerate (1.2 eq) at 70°C for 8 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain ethyl 5-methyl-1-(9H-purine)-1H-pyrazole-3-carboxylate (I-1), with a yield of 65.2% and mp215.0-215.4°C; 1 H NMR (500MHz, TFA-d) δ (ppm) 12.35 (s, 1H), 8.35-8.28 (m, 2H), 4.17-4.11 (m, 2H), 2.18 (s, 3H), 1.10-1.06 (t, J = 2.0 Hz, 3H). The structural formula is as follows:

[0071]

[0072] Example 7 Preparation of 5-ethyl-1-(9H-purine)-1H-pyrazole-3-carboxylic acid ethyl ester (I-2)

[0073] 1. Add 6-chloropurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, then add hydrazine hydrate (6 eq). Then reflux at 75°C for 6 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with anhydrous ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine purine.

[0074] 2. Add 6-hydrazinopurine (1 eq) to a three-necked flask containing 30 mL of anhydrous methanol, and reflux with ethyl 2,4-diketohexanoate (1.3 eq) at 75°C for 7 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain ethyl 5-ethyl-1-(9H-purine)-1H-pyrazole-3-carboxylate (I-2), with a yield of 62.9% and mp 274.8-275.4°C; 1 H NMR (500MHz, TFA) δ (ppm): 9.33-9.31 (m, 2H), 7.01 (s, 1H), 4.65-4.60 (q, J = 2.5Hz, 2H), 3.51-3.46 (m, 2H), 1.52-1.45 (m, 6H). The structural formula is as follows:

[0075] Example 8 Preparation of ethyl 5-propyl-1-(9H-purine)-1H-pyrazole-3-carboxylate (I-3)

[0076] 1. Add 6-chloropurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, then add hydrazine hydrate (6 eq). Then reflux at 75°C for 6 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with anhydrous ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine purine.

[0077] 2. Add 6-hydrazinopurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with ethyl 2,4-diketoheptanoate (1.2 eq) at 78°C for 9 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain ethyl 5-propyl-1-(9H-purine)-1H-pyrazole-3-carboxylate (I-3), with a yield of 49.1% and mp 194.6-195.7°C; 1 H NMR (500MHz, TFA) δ (ppm): 9.46-9.43 (m, 2H), 7.11 (s, 1H), 4.74-4.60 (m, 2H), 3.95-3.19 (m, 2H), 2.30-1.83 (m, 2H), 1.82-1.38 (m, 3H), 1.37-0.86 (m, 3H). The structural formula is as follows:

[0078]

[0079] Example 9 Preparation of ethyl 5-isopropyl-1-(9H-purine)-1H-pyrazole-3-carboxylate (I-4)

[0080] 1. Add 6-chloropurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, then add hydrazine hydrate (6 eq). Then reflux at 75°C for 6 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with anhydrous ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine purine.

[0081] 2. Add 6-hydrazinopurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with 5-methyl-2,4-diketohexanoic acid ethyl ester (1.2 eq) at 70°C for 8 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 5-isopropyl-1-(9H-purine)-1H-pyrazole-3-carboxylic acid ethyl ester (I-4), with a yield of 38.0%, mp 225.9-226.7°C; 1HNMR (500MHz, TFA) δ (ppm): 9.32-9.28 (m, 1H), 8.95-8.76 (m, 1H), 7.01 (s, 1H), 4.62-4.31 (m, 2H), 3.65-3.42 (m, 1H), 1.42-0.94 (m, 9H). The structural formula is as follows:

[0082]

[0083] Example 10 Preparation of 5-tert-butyl-1-(9H-purine)-1H-pyrazole-3-carboxylic acid ethyl ester (I-5)

[0084] 1. Add 6-chloropurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, then add hydrazine hydrate (6 eq). Then reflux at 75°C for 6 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with anhydrous ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine purine.

[0085] 2. Add 6-hydrazinopurine (1 eq) to a three-necked flask containing 30 mL of anhydrous methanol, and reflux with 5,5-dimethyl-2,4-diketohexanoic acid ethyl ester (1.2 eq) at 78°C for 9 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 5-tert-butyl-1-(9H-purine)-1H-pyrazole-3-carboxylic acid ethyl ester (I-5), with a yield of 24.3%; 1 H NMR (500MHz,CDCl3)δ(ppm):12.71(s,1H),8.70-8.61(m,1H),8.52-8.26(m,1H),6.85(s,1H),4.47-4.31(m,2H),1.61-1.09(m,12H). The structural formula is as follows:

[0086]

[0087] Example 11 Preparation of ethyl 5-cyclopropyl-1-(9H-purine)-1H-pyrazole-3-carboxylate (I-6)

[0088] 1. Add 6-chloropurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, then add hydrazine hydrate (6 eq). Then reflux at 75°C for 6 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with anhydrous ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine purine.

[0089] 2. Add 6-hydrazinopurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with 4-cyclopropyl-2,4-diketobutyric acid ethyl ester (1.3 eq) at 78°C for 8 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 5-cyclopropyl-1-(9H-purine)-1H-pyrazole-3-carboxylic acid ethyl ester (I-6), with a yield of 47.6%, mp 228.1-229.1°C; 1 H NMR (500MHz, TFA) δ (ppm): 9.40-9.38 (m, 2H), 6.82 (s, 1H), 4.70-4.65 (q, J = 2.5 Hz, 2H), 3.16-3.11 (m, 1H), 1.57-1.54 (t, J = 1.5 Hz, 3H), 1.40-1.38 (d, J = 1.0 Hz, 2H), 1.00-0.99 (d, J = 0.5 Hz, 2H). The structural formula is as follows:

[0090]

[0091] Example 12 Preparation of ethyl 5-(4-chlorophenyl)-1-(9H-purine)-1H-pyrazole-3-carboxylate (I-7)

[0092] 1. Add 6-chloropurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, then add hydrazine hydrate (6 eq). Then reflux at 75°C for 6 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with anhydrous ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine purine.

[0093] 2. Add 6-hydrazinopurine (1 eq) to a three-necked flask containing 30 mL of anhydrous methanol, and reflux with ethyl 4-(4-chlorophenyl)-2,4-diketobutyrate (1.2 eq) at 78°C for 7 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain ethyl 5-(4-chlorophenyl)-1-(9H-purine)-1H-pyrazole-3-carboxylate (I-7), with a yield of 44.1% and mp 240.2-243.0°C; 1H NMR (500MHz, TFA) δ (ppm): 9.24 (s, 1H), 8.19-8.16 (m, 1H), 7.83-7.80 (m, 2H), 7.48-7.45 (m, 2H), 7.42 (s, 1H), 4.40-4.35 (q, J = 2.5 Hz, 2H), 1.39-1.36 (t, J = 1.5 Hz, 3H). The structural formula is as follows:

[0094]

[0095] Example 13 Preparation of ethyl 5-(2,4-dichlorophenyl)-1-(9H-purine)-1H-pyrazole-3-carboxylate (I-8)

[0096] 1. Add 6-chloropurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, then add hydrazine hydrate (6 eq). Then reflux at 75°C for 6 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with anhydrous ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine purine.

[0097] 2. Add 6-hydrazinopurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with ethyl 4-(2,4-dichlorophenyl)-2,4-diketobutyrate (1.2 eq) at 78°C for 8 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain ethyl 5-(2,4-dichlorophenyl)-1-(9H-purine)-1H-pyrazole-3-carboxylate (I-8), with a yield of 41.3%, mp 234.5-235.1°C; 1 HNMR (500MHz, DMSO) δ (ppm): 11.95 (s, 1H), 8.42-8.34 (m, 1H), 8.14-8.10 (m, 2H), 7.82 (s, 1H), 7.56-7.49 (m, 2H), 4.40-4.32 (m, 2H), 1.37-1.31 (m, 3H). The structural formula is as follows:

[0098]

[0099] Example 14 Preparation of 5-methyl-1-(9H-purine)-1H-pyrazole-3-carboxylic acid methyl ester (I-9)

[0100] 1. Add 6-chloropurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, then add hydrazine hydrate (6 eq). Then reflux at 75°C for 6 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with anhydrous ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine purine.

[0101] 2. Add 6-hydrazinopurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with methyl 2,4-dioxovalerate (1.2 eq) at 78°C for 8 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain methyl 5-methyl-1-(9H-purine)-1H-pyrazole-3-carboxylate (I-9), with a yield of 67.8% and mp211.4-212.4°C; 1 H NMR (500MHz, DMSO) δ (ppm): 12.53-12.18 (m, 1H), 8.39-8.19 (m, 2H), 7.03 (s, 1H), 3.66 (s, 3H), 2.18 (s, 3H). The structural formula is as follows:

[0102]

[0103] Example 15 Preparation of 5-butyl-1-(9H-purine)-1H-pyrazole-3-carboxylic acid methyl ester (I-10)

[0104] 1. Add 6-chloropurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, then add hydrazine hydrate (6 eq). Then reflux at 75°C for 6 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with anhydrous ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine purine.

[0105] 2. Add 6-hydrazinopurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with 2,4-diketooctanoic acid methyl ester (1.2 eq) at 70°C for 9 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 5-butyl-1-(9H-purine)-1H-pyrazole-3-carboxylic acid methyl ester (I-10), with a yield of 47.0%, mp 154.9-155.5°C; 1HNMR (500MHz, TFA) δ (ppm): 9.32-9.27 (m, 1H), 9.00-8.68 (m, 1H), 6.96 (s, 1H), 4.26-3.80 (m, 3H), 3.65-3.25 (m, 2H), 1.88-1.62 (m, 2H), 1.61-1.41 (m, 2H), 0.99-0.93 (m, 3H). The structural formula is as follows:

[0106]

[0107] Example 16 Preparation of 5-isopropyl-1-(9H-purine)-1H-pyrazole-3-carboxylic acid methyl ester (I-11)

[0108] 1. Add 6-chloropurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, then add hydrazine hydrate (6 eq). Then reflux at 75°C for 6 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with anhydrous ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine purine.

[0109] 2. Add 6-hydrazinopurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with 5-methyl-2,4-diketohexanoic acid methyl ester (1.3 eq) at 78°C for 8 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 5-isopropyl-1-(9H-purine)-1H-pyrazole-3-carboxylic acid methyl ester (I-11), with a yield of 42.4%, mp 109.7-110.4°C; 1 HNMR (500MHz, TFA) δ (ppm): 9.35-9.31 (m, 1H), 8.98-8.88 (m, 1H), 7.03 (s, 1H), 4.14-4.11 (m, 3H), 3.46-3.42 (m, 1H), 1.54-0.78 (m, 6H). The structural formula is as follows:

[0110]

[0111] Example 17 Preparation of 5-isobutyl-1-(9H-purine)-1H-pyrazole-3-carboxylic acid methyl ester (I-12)

[0112] 1. Add 6-chloropurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, then add hydrazine hydrate (6 eq). Then reflux at 75°C for 6 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with anhydrous ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine purine.

[0113] 2. Add 6-hydrazinopurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with 6-methyl-2,4-diketoheptanoic acid methyl ester (1.3 eq) at 78°C for 8 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 5-isobutyl-1-(9H-purine)-1H-pyrazole-3-carboxylic acid methyl ester (I-12), with a yield of 28.3%, mp 201.2-203.7°C; 1 HNMR (500MHz, TFA) δ (ppm): 9.44-9.38 (m, 1H), 9.08-8.88 (m, 1H), 7.05 (s, 1H), 4.23 (s, 3H), 3.54-3.41 (m, 2H), 2.26-2.15 (m, 1H), 1.15-1.07 (m, 6H). The structural formula is as follows:

[0114]

[0115] Example 18 Preparation of 5-(thiophen-2-yl)-1-(9H-purine)-1H-pyrazole-3-carboxylic acid methyl ester (I-13)

[0116] 1. Add 6-chloropurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, then add hydrazine hydrate (6 eq). Then reflux at 75°C for 6 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with anhydrous ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine purine.

[0117] 2. Add 6-hydrazinopurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with 2,4-diketo-4-(thiophen-2-yl)butyric acid methyl ester (1.2 eq) at 80°C for 8 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 5-(thiophen-2-yl)-1-(9H-purine)-1H-pyrazole-3-carboxylic acid methyl ester (I-13), with a yield of 32.6%, mp 123.6-124.5°C; 1H NMR (500MHz, TFA) δ (ppm): 9.39-8.82 (m, 3H), 8.08-8.01 (m, 1H), 7.91 (s, 1H), 7.28-7.23 (m, 1H), 4.07-3.94 (m, 3H). The structural formula is as follows:

[0118] Example 19 Preparation of 1-(9-ethyl-purine)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-14)

[0119] 1. Add 6-chloro-9-ethylpurine (1 eq) prepared in Example 1 into a three-necked flask containing 30 mL of anhydrous methanol, stir and dissolve at room temperature, and then add hydrazine hydrate (6.5 eq). Then reflux at 78°C for 7 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine-9-ethylpurine.

[0120] 2. Add 6-hydrazino-9-ethylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with ethyl 2,4-dioxovalerate (1.3 eq) at 70°C for 9 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-ethyl-purine)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-14), with a yield of 73.0%, mp 207.6-208.4°C; 1 H NMR (500MHz, TFA) δ (ppm): 9.68-9.29 (m, 2H), 7.00 (s, 1H), 4.90-4.85 (m, 2H), 4.72-4.66 (m, 2H), 3.07 (s, 3H), 1.88-1.84 (m, 3H), 1.59-1.56 (m, 3H). The structural formula is as follows:

[0121]

[0122] Example 20 Preparation of 1-(9-ethyl-purine)-5-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-15)

[0123] 1. Add 6-chloro-9-ethylpurine (1 eq) prepared in Example 1 into a three-necked flask containing 30 mL of anhydrous methanol, stir and dissolve at room temperature, and then add hydrazine hydrate (6.5 eq). Then reflux at 78°C for 7 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine-9-ethylpurine.

[0124] 2. Add 6-hydrazino-9-ethylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with ethyl 2,4-diketohexanoate (1.2 eq) at 75°C for 8 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-ethyl-purine)-5-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-15), with a yield of 67.4%, mp 87.3-88.2°C; 1 H NMR (500MHz, TFA) δ (ppm): 9.71-9.24 (m, 2H), 7.09-7.02 (m, 1H), 5.16-4.46 (m, 4H), 3.61-3.52 (m, 2H), 1.95-1.74 (m, 3H), 1.67-1.28 (m, 6H). The structural formula is as follows:

[0125]

[0126] Example 21 Preparation of 1-(9-ethyl-purine)-5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-16)

[0127] 1. Add 6-chloro-9-ethylpurine (1 eq) prepared in Example 1 into a three-necked flask containing 30 mL of anhydrous methanol, stir and dissolve at room temperature, and then add hydrazine hydrate (6.5 eq). Then reflux at 78°C for 7 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine-9-ethylpurine.

[0128] 2. Add 6-hydrazino-9-ethylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous methanol, and reflux with ethyl 2,4-diketoheptanoate (1.2 eq) at 78°C for 9 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-ethyl-purine)-5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-16), with a yield of 60.9%, mp 183.6-184.4°C; 1H NMR (500 MHz, TFA) δ (ppm): 9.53-9.26 (m, 2H), 6.94 (s, 1H), 4.80-4.75 (q, J = 2.5 Hz, 2H), 4.61-4.57 (q, J = 2.0 Hz, 2H), 3.43-3.40 (t, J = 1.5 Hz, 2H), 1.90-1.82 (m, 2H), 1.77-1.74 (t, J = 1.5 Hz, 3H), 1.49-1.46 (t, J = 1.5 Hz, 3H), 1.11-1.08 (t, J = 1.5 Hz, 3H). The structural formula is as follows:

[0129]

[0130] Example 22 Preparation of 1-(9-ethyl-purine)-5-butyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-17)

[0131] 1. Add 6-chloro-9-ethylpurine (1 eq) prepared in Example 1 into a three-necked flask containing 30 mL of anhydrous methanol, stir and dissolve at room temperature, and then add hydrazine hydrate (6.5 eq). Then reflux at 78°C for 7 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine-9-ethylpurine.

[0132] 2. Add 6-hydrazino-9-ethylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with ethyl 2,4-diketooctanoate (1.3 eq) at 77°C for 7 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-ethyl-purine)-5-butyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-17), with a yield of 58.2%, mp 121.1-121.9°C; 1 H NMR (500 MHz, TFA) δ (ppm): 9.61-9.22 (m, 2H), 6.95 (s, 1H), 4.81-4.76 (q, J = 2.5 Hz, 2H), 4.64-4.58 (q, J = 3.0 Hz, 2H), 3.48-3.45 (t, J = 1.5 Hz, 3H), 1.85-1.79 (m, 2H), 1.78-1.70 (m, 3H), 1.56-1.48 (m, 3H), 1.02-0.99 (t, J = 1.5 Hz, 3H). The structural formula is as follows:

[0133]

[0134] Example 23 Preparation of 1-(9-ethyl-purine)-5-ethoxy-1H-pyrazole-3-carboxylic acid ethyl ester (I-18)

[0135] 1. Add 6-chloro-9-ethylpurine (1 eq) prepared in Example 1 into a three-necked flask containing 30 mL of anhydrous methanol, stir and dissolve at room temperature, and then add hydrazine hydrate (6.5 eq). Then reflux at 78°C for 7 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine-9-ethylpurine.

[0136] 2. Add 6-hydrazino-9-ethylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous methanol, and reflux with diethyl 2-oxosuccinate (1.3 eq) at 73°C for 9 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-ethyl-purine)-5-ethoxy-1H-pyrazole-3-carboxylic acid ethyl ester (I-18), with a yield of 42.0%, mp 175.4-176.2°C; 1 H NMR (500MHz, TFA) δ (ppm): 9.55 (s, 1H), 8.90 (s, 1H), 6.74 (s, 1H), 4.90-4.79 (m, 4H), 4.72-4.46 (m, 2H), 1.93-1.45 (m, 9H). The structural formula is as follows:

[0137] Example 24 Preparation of 1-(9-ethyl-purine)-5-cyclopropyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-19)

[0138] 1. Add 6-chloro-9-ethylpurine (1 eq) prepared in Example 1 into a three-necked flask containing 30 mL of anhydrous methanol, stir and dissolve at room temperature, and then add hydrazine hydrate (6.5 eq). Then reflux at 78°C for 7 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine-9-ethylpurine.

[0139] 2. Add 6-hydrazino-9-ethylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous methanol, and reflux with 4-cyclopropyl-2,4-diketobutyric acid ethyl ester (1.3 eq) at 78°C for 8 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-ethyl-purine)-5-cyclopropyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-19), with a yield of 59.8%, mp 192.5-193.6°C; 1 H NMR (500MHz, TFA) δ (ppm): 9.53-9.28 (m, 2H), 6.70 (s, 1H), 4.79 (s, 2H), 4.60-4.56 (q, J = 2.0 Hz, 2H), 3.11 (m, 1H), 1.79-1.76 (t, J = 1.5 Hz, 3H), 1.48-1.46 (t, J = 1.0 Hz, 3H), 1.28 (s, 2H), 0.89 (s, 2H). The structural formula is as follows:

[0140] Example 25 Preparation of 1-(9-ethyl-purine)-5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-20)

[0141] 1. Add 6-chloro-9-ethylpurine (1 eq) prepared in Example 1 into a three-necked flask containing 30 mL of anhydrous methanol, stir and dissolve at room temperature, and then add hydrazine hydrate (6.5 eq). Then reflux at 78°C for 7 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine-9-ethylpurine.

[0142] 2. Add 6-hydrazino-9-ethylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with 4-phenyl-2,4-diketobutyric acid ethyl ester (1.2 eq) at 80°C for 8 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-ethyl-purine)-5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-20), with a yield of 62.1%, mp 155.7-156.8°C; 1 H NMR (500MHz, TFA) δ (ppm): 9.75-9.03 (m, 2H), 8.12-7.58 (m, 5H), 7.25 (s, 1H), 4.94-4.76 (m, 4H), 1.94-1.46 (m, 6H). The structural formula is as follows:

[0143] Example 26 Preparation of 1-(9-ethyl-purine)-5-(3,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid methyl ester (I-21)

[0144] 1. Add 6-chloro-9-ethylpurine (1 eq) prepared in Example 1 into a three-necked flask containing 30 mL of anhydrous methanol, stir and dissolve at room temperature, and then add hydrazine hydrate (6.5 eq). Then reflux at 78°C for 7 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine-9-ethylpurine.

[0145] 2. Add 6-hydrazino-9-ethylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with 4-(3,4-dichlorophenyl)-2,4-diketobutyric acid methyl ester (1.3 eq) at 78°C for 9 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-ethyl-purine)-5-(3,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid methyl ester (I-21), with a yield of 51.0%, mp 227.1-227.9°C; 1 H NMR (500MHz, TFA) δ (ppm): 8.14 (s, 1H), 7.91-7.84 (m, 1H), 7.77-7.47 (m, 4H), 4.71-4.40 (m, 2H), 4.22-4.10 (m, 3H), 1.52-1.48 (m, 3H). The structural formula is as follows:

[0146]

[0147] Example 27 Preparation of 1-(9-ethyl-purine)-5-(thiophen-2-yl)-1H-pyrazole-3-carboxylic acid methyl ester (I-22)

[0148] 1. Add 6-chloro-9-ethylpurine (1 eq) prepared in Example 1 into a three-necked flask containing 30 mL of anhydrous methanol, stir and dissolve at room temperature, and then add hydrazine hydrate (6.5 eq). Then reflux at 78°C for 7 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine-9-ethylpurine.

[0149] 2. Add 6-hydrazino-9-ethylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with 2,4-diketo-4-(thiophene-2-yl)butyric acid methyl ester (1.3 eq) at 73°C for 7 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-ethyl-purine)-5-(thiophene-2-yl)-1H-pyrazole-3-carboxylic acid methyl ester (I-22), with a yield of 37.2%, mp 100.9-102.1°C; 1 H NMR (500MHz, TFA) δ (ppm): 9.89-9.78 (m, 1H), 9.36-9.27 (m, 1H), 7.84-7.62 (m, 2H), 7.49-7.35 (m, 2H), 5.11-4.91 (m, 3H), 4.90-4.82 (m, 2H), 1.79-1.69 (m, 3H). The structural formula is as follows:

[0150]

[0151] Example 28 Preparation of 1-(9-propyl-purine)-5-isopentyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-23)

[0152] 1. Add 6-chloro-9-propylpurine (1 eq) prepared in Example 2 into a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, and then add hydrazine hydrate (7 eq). Then reflux at 75°C for 5 h, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake three times with ethanol and distilled water, and dry to obtain a crude product of 6-hydrazine-9-propylpurine.

[0153] 2. Add 6-hydrazino-9-propylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous methanol, and reflux with 7-methyl-2,4-diketooctanoic acid ethyl ester (1.2 eq) at 70°C for 8 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-ethyl-purine)-5-isopentyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-23), with a yield of 35.1%, mp 92.9-93.4°C; 1HNMR (500MHz, TFA) δ (ppm): 9.49-9.31 (m, 2H), 7.00 (s, 1H), 4.74-4.62 (m, 4H), 3.62-3.40 (m, 2H), 2.23-2.17 (m, 2H), 1.84-1.73 (m, 3H), 1.55-1.51 (m, 3H), 1.20-0.96 (m, 9H). The structural formula is as follows:

[0154]

[0155] Example 29 Preparation of 1-(9-butyl-purine)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-24)

[0156] 1. Add 6-chloro-9-butylpurine (1 eq) prepared in Example 3 into a three-necked flask containing 30 mL of anhydrous methanol, stir and dissolve at room temperature, and then add hydrazine hydrate (6 eq). Then reflux at 80°C for 6 h, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine-9-butylpurine.

[0157] 2. Add 6-hydrazino-9-butylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with ethyl 2,4-dioxovalerate (1.3 eq) at 78°C for 8 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-butyl-purine)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-24), with a yield of 65.7%, mp 91.5-92.3°C; 1 HNMR (500MHz, TFA) δ (ppm): 9.54 (s, 1H), 9.38 (s, 1H), 7.02 (s, 1H), 4.84-4.81 (t, J = 1.5 Hz, 2H), 4.73-4.69 (q, J = 2.0 Hz, 2H), 3.08 (s, 3H), 2.23-2.17 (m, 2H), 1.65-1.58 (m, 5H), 1.15-1.12 (t, J = 1.5 Hz, 3H). The structural formula is as follows:

[0158] Example 30 Preparation of 1-(9-butyl-purine)-5-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-25)

[0159] 1. Add 6-chloro-9-butylpurine (1 eq) prepared in Example 3 into a three-necked flask containing 30 mL of anhydrous methanol, stir and dissolve at room temperature, and then add hydrazine hydrate (6 eq). Then reflux at 80°C for 6 h, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine-9-butylpurine.

[0160] 2. Add 6-hydrazino-9-butylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous methanol, and reflux with ethyl 2,4-diketohexanoate (1.3 eq) at 75°C for 8 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-butyl-purine)-5-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-25), with a yield of 63.2%, mp 74.3-76.1°C; 1 HNMR (500MHz, TFA) δ (ppm): 9.56 (s, 1H), 9.40 (s, 1H), 7.10 (s, 1H), 4.85-4.83 (t, J = 1.5Hz, 2H), 4.76-4.69 (m, 2H), 3.63-3.59 (q, J = 2.0Hz, 2H), 2.25-2.19 (m, 2H), 1.67-1.40 (m, 8H), 1.17-1.12 (m, 3H). The structural formula is as follows:

[0161]

[0162] Example 31 Preparation of 1-(9-isopropyl-purine)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-26)

[0163] 1. Add 6-chloro-9-isopropylpurine (1 eq) prepared in Example 4 into a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, and then add hydrazine hydrate (6 eq). Then reflux at 80°C for 7 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine-9-isopropylpurine.

[0164] 2. Add 6-hydrazino-9-isopropylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with ethyl 2,4-dioxovalerate (1.2 eq) at 73°C for 9 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-isopropyl-purine)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-26), with a yield of 61.0%, mp 232.8-234.2°C; 1 H NMR (500MHz, TFA) δ (ppm): 9.57 (s, 1H), 9.40 (s, 1H), 7.05 (s, 1H), 5.53-5.47 (m, 1H), 4.76-4.72 (q, J = 2.0 Hz, 2H), 3.11 (s, 3H), 2.01-2.00 (d, J = 0.5 Hz, 6H), 1.65-1.62 (t, J = 1.5 Hz, 3H). The structural formula is as follows:

[0165]

[0166] Example 32 Preparation of 1-(9-benzyl-purine)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-27)

[0167] 1. Add 6-chloro-9-benzylpurine (1 eq) prepared in Example 5 into a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, and then add hydrazine hydrate (7 eq). Then reflux at 70°C for 7 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine-9-benzylpurine.

[0168] 2. Add 6-hydrazino-9-benzylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with ethyl 2,4-dioxovalerate (1.3 eq) at 75°C for 9 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-benzyl-purine)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-27), with a yield of 78.2%, mp 166.7-167.6°C; 1 HNMR (500MHz, TFA) δ (ppm): 9.25-9.12 (m, 2H), 7.65-7.14 (m, 5H), 6.86 (s, 1H), 5.77 (s, 2H), 4.56-4.51 (m, 2H), 2.92 (s, 3H), 1.45-1.41 (m, 3H). The structural formula is as follows:

[0169]

[0170] Example 33 Preparation of 1-(9-benzyl-purine)-5-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-28)

[0171] 1. Add 6-chloro-9-benzylpurine (1 eq) prepared in Example 5 into a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, and then add hydrazine hydrate (7 eq). Then reflux at 70°C for 7 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine-9-benzylpurine.

[0172] 2. Add 6-hydrazino-9-benzylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with ethyl 2,4-diketohexanoate (1.3 eq) at 80°C for 9 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-benzyl-purine)-5-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-28), with a yield of 73.4%, mp 209.3-209.9°C; 1 H NMR (500MHz, TFA) δ (ppm): 9.26-9.14 (m, 2H), 7.44 (s, 5H), 6.94 (s, 1H), 5.79 (s, 2H), 4.59-4.54 (m, 2H), 3.47-3.43 (m, 2H), 1.47-1.40 (m, 6H). The structural formula is as follows:

[0173]

[0174] Example 34 Preparation of 1-(9-benzyl-purine)-5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-29)

[0175] 1. Add 6-chloro-9-benzylpurine (1 eq) prepared in Example 5 into a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, and then add hydrazine hydrate (7 eq). Then reflux at 70°C for 7 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine-9-benzylpurine.

[0176] 2. Add 6-hydrazino-9-benzylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with ethyl 2,4-diketoheptanoate (1.2 eq) at 70°C for 7 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-benzyl-purine)-5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-29), with a yield of 67.5%, mp 138.2-138.8°C; 1 H NMR (500MHz, TFA) δ (ppm): 9.26-9.15 (m, 2H), 7.44 (s, 5H), 6.92 (s, 1H), 5.80 (s, 2H), 4.59-4.54 (m, 2H), 3.42-3.39 (m, 2H), 1.88-1.82 (m, 2H), 1.47-1.44 (m, 3H), 1.10-1.06 (m, 3H). The structural formula is as follows:

[0177]

[0178] Example 35 Preparation of 1-(9-benzyl-purine)-5-isopentyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-30)

[0179] 1. Add 6-chloro-9-benzylpurine (1 eq) prepared in Example 5 into a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, and then add hydrazine hydrate (7 eq). Then reflux at 70°C for 7 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine-9-benzylpurine.

[0180] 2. Add 6-hydrazino-9-benzylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with ethyl 2,4-diketoheptanoate (1.3 eq) at 75°C for 9 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-benzyl-purine)-5-isopentyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-30), with a yield of 53.1%, mp 135.4-136.2°C; 1HNMR (500MHz, TFA) δ (ppm): 9.49-9.41 (m, 2H), 7.70-7.63 (m, 5H), 7.16 (s, 1H), 6.04 (s, 2H), 4.83-4.77 (m, 2H), 3.76-3.68 (m, 2H), 2.01-1.45 (m, 6H), 1.24-1.05 (m, 6H). The structural formula is as follows:

[0181]

[0182] Example 36 Preparation of 1-(9-benzyl-purine)-5-cyclopropyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-31)

[0183] 1. Add 6-chloro-9-benzylpurine (1 eq) prepared in Example 5 into a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, and then add hydrazine hydrate (7 eq). Then reflux at 70°C for 7 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine-9-benzylpurine.

[0184] 2. Add 6-hydrazino-9-benzylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous methanol, and reflux with 4-cyclopropyl-2,4-diketobutyric acid ethyl ester (1.2 eq) at 80°C for 8 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-benzyl-purine)-5-cyclopropyl-1H-pyrazole-3-carboxylic acid ethyl ester (I-31), with a yield of 62.4%, mp 160.2-161.1°C; 1 H NMR (500MHz, TFA) δ (ppm): 9.27-9.15 (m, 2H), 7.61-7.45 (m, 5H), 6.67 (s, 1H), 5.80 (s, 2H), 4.57-4.52 (m, 2H), 3.11-3.06 (m, H), 1.46-1.26 (m, 5H), 0.89-0.85 (m, 2H). The structural formula is as follows:

[0185]

[0186] Example 37 Preparation of 1-(9-benzyl-purine)-5-(thiophen-2-yl)-1H-pyrazole-3-carboxylic acid methyl ester (I-32)

[0187] 1. Add 6-chloro-9-benzylpurine (1 eq) prepared in Example 5 into a three-necked flask containing 30 mL of anhydrous ethanol, stir and dissolve at room temperature, and then add hydrazine hydrate (7 eq). Then reflux at 70°C for 7 hours, and the reaction is complete when detected by TLC. Cool to room temperature, and a precipitate is formed. Filter by suction, wash the filter cake with ethanol and distilled water three times each, and dry to obtain a crude product of 6-hydrazine-9-benzylpurine.

[0188] 2. Add 6-hydrazino-9-benzylpurine (1 eq) to a three-necked flask containing 30 mL of anhydrous ethanol, and reflux with 2,4-diketo-4-(thiophen-2-yl)butyric acid methyl ester (1.2 eq) at 80°C for 9 h. The reaction is complete when detected by TLC, and the solvent is removed under reduced pressure. The mixture is recrystallized from a solvent system with a volume ratio of dichloromethane: anhydrous methanol = 10:1 to obtain 1-(9-benzyl-purine)-5-(thiophen-2-yl)-1H-pyrazole-3-carboxylic acid methyl ester (I-32), with a yield of 49.2%, mp 230.7-231.5°C; 1 H NMR (500MHz, TFA) δ (ppm): 9.52-8.67 (m, 2H), 8.21-7.86 (m, 2H), 7.61-7.23 (m, 6H), 5.89-5.64 (m, 2H), 4.26-3.89 (m, 3H). The structural formula is as follows:

[0189]

[0190] Example 38: Screening of concentrations of experimental herbicides and compounds

[0191] The small cup method was used to treat the stems and leaves of wheat seedlings damaged by the herbicide mesosulfuron-methyl to conduct a preliminary safety activity test.

[0192] Greenhouse small cup method: take a certain amount of soil that has passed through a 5mm sieve into a paper cup, soak the selected crop seeds in warm water for 12 hours, and place them in a 25℃ incubator for germination for 24 hours. Select 5-8 uniform and well-germinated crop seeds, place them evenly on the soil surface with the navel facing down, cover them with 1cm thick dry soil, and culture them at a temperature of 26.5℃, a humidity of 75%, and a 12h light and dark cycle.

[0193] Herbicide concentration screening: Select different concentrations of herbicide methyl disulfone (0g ai / hm 2 、15ga.i. / hm 2 , 20g ai / hm 2 , 25g ai / hm 2 、30g ai / hm 2 、35g ai / hm 2、40g ai / hm 2 ), respectively, wheat (emergence to 2-3 leaves and 1 heart stage) was treated with herbicide spray, and after 5 days of treatment, the concentration of methyl disulfone that caused certain phytotoxicity to wheat was screened out by measuring the root length, root fresh weight, two-leaf plant height, plant fresh weight, and chlorophyll content of wheat. According to the analysis of wheat growth indicators shown in Table 1 below, it was found that the phytotoxicity of wheat crops at different concentrations was different, among which 30 g a.i. / hm 2 The damage of pesticide to the treated wheat was quite obvious.

[0194] Table 1 Effects of different concentrations of mesosulfuron on wheat growth indicators

[0195]

[0196] Compound concentration screening: The wheat cup method was used for compound concentration screening. Wheat seeds with full grains were selected and soaked in warm water at 30°C for 30 minutes. They were then soaked in 0.6% (w / v) carbendazim for 30 minutes. The soaked wheat seeds were then washed with water and soaked with 0 mg / kg, 5 mg / kg, 10 mg / kg, 20 mg / kg, 40 mg / kg, and 80 mg / kg of compounds, respectively. The seeds were placed in an incubator and soaked for 12 hours. The humidity in the incubator was then set to 75% and the temperature to 26.5°C, and the seeds were placed in it for germination for 24 hours. 5-8 uniform and well-germinated crop seeds were selected and wheat was cultured using the greenhouse cup method. When wheat seedlings grew to 2 to 3 leaves and 1 heart, the spray concentration was 30 g ai / hm. 2 The herbicide methyl disulfiram was used to test the effects of the compound on root length, root fresh weight, plant height, plant fresh weight and chlorophyll content in wheat. The detoxification effects of the herbicide on wheat crops were different at different concentrations, thus determining the optimal detoxification concentration of the compound.

[0197] Taking I-1 as an example, the compound concentrations were: 0 mg / kg, 5 mg / kg, 10 mg / kg, 20 mg / kg, 40 mg / kg, and 80 mg / kg, and the wheat cup method was used to screen the safener concentration. The effects of each concentration on wheat growth indicators are shown in Table 2. The protective effects of different concentrations of target compounds on wheat are significantly different. Comprehensively considering the five indicators of plant height, plant fresh weight, root length, root fresh weight and chlorophyll content, the compound concentration of 20 mg / kg achieves a better detoxification effect.

[0198] Table 2 Effects of different concentrations of I-1 on wheat growth indicators

[0199]

[0200] The pyrazopurine herbicide safeners prepared in Examples 6 to 37 of the present invention are effective for 30 g ai / hm 2 Study on the Protective Effect of Mesosulfuron-methyl on Wheat Injury

[0201] Evaluation method of protective effect: When wheat seedlings grow to the 2-leaf stage, the herbicide mesotrione is sprayed on the stems and leaves. Five days later, plant height, root length, plant fresh weight, root fresh weight, and chlorophyll content are measured. The same concentration of commercial safener pyraclostrobin is used as a positive control, and the same amount of distilled water is used as a blank control. Each treatment is repeated three times, and the recovery rate of the safener on each index is calculated. The recovery rate formula is as follows:

[0202]

[0203] Table 3 Compounds of Formula I and pyraclostrobin for 30 g ai / hm 2 The protective effect of mesosulfuron on wheat injury

[0204]

[0205]

[0206] The dosage of each compound in this table is 20 mg / kg.

[0207] As shown in Table 3, most of the target compounds have a certain recovery effect on the roots, stems and chlorophyll content of wheat damaged by the herbicide mesosulfuron-methyl. The detoxification effect of some compounds is comparable to that of the commercial safener pyraclostrobin, and some compounds are even higher than that of the commercial safener pyraclostrobin. For example, compounds I-7, I-8 and I-21 show excellent safener activity, among which compound I-21 shows the best safety activity. The root fresh weight recovery rate is 101.24%, the plant fresh weight recovery rate is 86.74%, the root length recovery rate is 87.68%, the plant height recovery rate is 87.27%, and the chlorophyll content recovery rate is 79.77%.

[0208] From the above data, it can be seen that the pyrazopurine herbicide safener prepared by the present invention has a high safener activity, can effectively alleviate the herbicide mesosulfuron-methyl-methyl-induced phytotoxicity to wheat, and the effect of some individual compounds is better than that of the commercial safener pyraclostrobin.

[0209] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the various technical features being combined in any other suitable manner. These simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A pyrazopurine herbicide safener, characterized in that: The general structural formula (I) of the pyrazopurine herbicide safener is: Wherein: R1 is selected from any one of C1-C10 alkyl, C1-C5 alkoxy, phenyl, halogenated phenyl, and thienyl; R2 is selected from any one of C1-C5 alkyl groups; R3 is selected from any one of hydrogen, C1-C6 alkyl, phenyl, halogenated phenyl, and C1-C3 alkyl-substituted phenyl.

2. The pyrazopurine herbicide safener according to claim 1, characterized in that: The R1 is selected from any one of C1-C5 alkyl, C2 alkoxy, phenyl, chlorophenyl or thienyl; R2 is selected from any one of C1-C2 alkyl; R3 is selected from any one of hydrogen and C2-C4 alkyl.

3. A method for preparing the pyrazopurine herbicide safener according to claim 1 or 2, characterized in that: The steps include: Step 1, dissolving 6-chloropurine and an acid-binding agent in an organic solvent 1, and then adding a halogenated hydrocarbon R3-X dropwise, wherein R3 is selected from any one of hydrogen, C1-C6 alkyl, phenyl, halogenated phenyl, and C1-C3 alkyl-substituted phenyl; reacting the obtained mixed reaction liquid 1 at room temperature for 24-48 hours, extracting, drying, filtering, concentrating, and purifying to obtain a 6-chloro-9-substituted purine compound; Step 2: dissolving the 6-chloro-9-substituted purine compound and hydrazine hydrate described in step 1 in an organic solvent 2, and subjecting the obtained mixed reaction solution 2 to a reflux reaction; after the reaction is completed, precipitating, filtering, and washing to obtain a 9-substituted 6-hydrazine purine compound; the reaction temperature is 60-110° C., and the reaction time is 5-12 hours; Step 3, dissolving the 9-substituted 6-hydrazinopurine compound described in step 2 in an organic solvent 3, and subjecting it to a reflux reaction with a 1,3-diketone compound; after the reaction is completed, recrystallizing the obtained product to obtain the pyrazopurine herbicide safener; the reaction temperature is 60-110° C., and the reaction time is 5-12 hours; wherein: the structural formula of the 1,3-diketone compound described in step 3 is as follows: Wherein: R1 is selected from one of C1-C10 alkyl, C1-C5 alkoxy, phenyl, halogenated phenyl or thienyl, and R2 is selected from one of C1-C5 alkyl.

4. The preparation method according to claim 3, characterized in that: The acid binding agent in step 1 is any one of N,N-diisopropylethylamine, triethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, and sodium hydroxide.

5. The preparation method according to claim 3, characterized in that: The molar ratio of 6-chloropurine to R3-X in step 1 is 1:1.2-1.

7.

6. The preparation method according to claim 3, characterized in that: The molar ratio of 6-chloro-9-substituted purine to hydrazine hydrate in step 2 is 1:5-8.

7. The preparation method according to claim 3, characterized in that: The reaction temperature in step 2 is 70-80°C and the reaction time is 5-7h.

8. The preparation method according to claim 3, characterized in that: The molar ratio of the 9-substituted 6-hydrazinopurine compound to the 1,3-diketone compound in step 3 is 1:1-2.

9. Use of the pyrazopurine herbicide safener according to claim 1 or 2 or the pyrazopurine herbicide safener prepared by the method according to any one of claims 3 to 8 in relieving the toxicity of herbicides on crops.

10. A safener for alleviating sulfonylurea herbicides, characterized in that: The invention comprises the pyrazopurine herbicide safener according to claim 1 or 2 or the pyrazopurine herbicide safener prepared by the method according to any one of claims 3 to 8.

Images