1, 2, 3-thiadiazole amide derivative containing oxime ether unit as well as preparation method and application of 1, 2, 3-thiadiazole amide derivative

Abstract

The invention discloses a 1, 2, 3-thiadiazole amide derivative containing an oxime ether unit and a preparation method and application thereof.The structural formula of the derivative is shown in the formula I. The preparation method of the derivative comprises the steps that ethyl acetoacetate reacts with ethyl carbazate, thionyl chloride and a sodium hydroxide solution in sequence; the obtained product is subjected to a reaction with thionyl chloride again, and 4-methyl-1, 2, 3-thiadiazole-5-formyl chloride is obtained; then, the o-nitroacetophenone sequentially reacts with hydroxylamine hydrochloride, halogenated alkane, stannous chloride and 4-methyl-1, 2, 3-thiadiazole-5-formyl chloride, and the target compound is obtained. The 1, 2, 3-thiadiazole amide derivative containing the oxime ether unit has an inhibition effect on botrytis cinerea, rhizoctonia solani and fusarium graminearum, and can be used for preventing and treating plant diseases caused by fungi. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a compound, and particularly to a 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit, and a preparation method and application thereof. Background Art

[0002] Plant pathogenic fungi are a key factor restricting the development of agriculture in China. Diseases caused by them account for about 70% - 80% of the total agricultural diseases. After fungi infect crops, they will affect the normal biological and physiological functions of host plants, leading to crop lesions, yellowing, withering and death, resulting in a decrease in crop yield. At the same time, the parasitic pathogenic fungi can also secrete certain mycotoxins in the agricultural crops they infect, posing a great threat to human food safety and personal health. In the past half century, fungicides have played an extremely important role in controlling plant fungal diseases. However, the widespread use of fungicides in agricultural production has led to the rapid generation of fungal resistance, which not only greatly reduces the use effect of existing fungicides, but also indirectly causes problems such as pesticide residues and the recurrence of fungal diseases, seriously threatening the health of humans, livestock and the agricultural ecosystem. Therefore, the development of fungicides with novel structures, environmental friendliness and high economic benefits has far-reaching significance for the sustainable development of agriculture in China. Summary of the Invention

[0003] Object of the Invention: The first object of the present invention is to provide a 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit; the second object of the present invention is to provide a preparation method of the 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit; the third object of the present invention is to provide an application of the 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit in controlling plant fungal diseases.

[0004] Technical Solution: The 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit of the present invention has a structural formula as shown in Formula I:

[0005]

[0006] Wherein, R is selected from any substituted or unsubstituted alkyl group, any substituted or unsubstituted allyl group, any substituted or unsubstituted propargyl group, any substituted or unsubstituted cycloalkyl group, any substituted or unsubstituted cycloalkylmethyl group, any substituted or unsubstituted arylmethyl group.

[0007] Preferably, the R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,

[0008] Preferably, the structural formula of the compound is as follows:

[0009]

[0010] The preparation method of the 1,2,3-thiadiazole amide derivative containing an oxime ether unit according to the present invention comprises the following steps: After ethyl acetoacetate reacts with ethyl carbazate, thionyl chloride, and sodium hydroxide solution in sequence, the resulting product reacts with thionyl chloride again to obtain 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride; Subsequently, o-nitroacetophenone reacts with hydroxylamine hydrochloride, haloalkane, stannous chloride, and 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride in sequence to obtain the 1,2,3-thiadiazole amide derivative I containing an oxime ether unit. The synthesis route is as follows:

[0011]

[0012] Application of the 1,2,3-thiadiazole amide derivative containing an oxime ether unit according to the present invention in preventing and controlling plant fungal diseases.

[0013] The plant pathogenic fungi are Botrytis cinerea of tomato, Gibberella zeae of wheat, or Rhizoctonia solani of rice.

[0014] Beneficial effects: Compared with the prior art, the present invention has the following remarkable advantages: (1) The 1,2,3-thiadiazole amide derivative containing an oxime ether unit is a novel compound and has an inhibitory effect on Botrytis cinerea of tomato, Gibberella zeae of wheat, or Rhizoctonia solani of rice; (2) The 1,2,3-thiadiazole amide derivative containing an oxime ether unit according to the present invention can significantly inhibit Botrytis cinerea of tomato, Gibberella zeae of wheat, and Rhizoctonia solani of rice, and its optimal inhibition rates at a dose of 50 μg / mL are 98.4%, 52.2%, and 73.4% respectively; (3) The inhibition rates of the compound on Botrytis cinerea of tomato at a dose of 50 μg / mL (98.0%, 98.4%, and 89.8%) are superior to those of the control agent boscalid (83.0%); (4) The preparation method is simple and the raw materials are easily available. Description of the Drawings

[0015] Figure 1 is the synthesis route diagram of the present invention;

[0016] Figure 2 is the nuclear magnetic resonance hydrogen spectrum diagram of the 1,2,3-thiadiazole amide derivative containing an oxime ether unit prepared in Example 13;

[0017] Figure 3 is the nuclear magnetic resonance carbon spectrum diagram of the 1,2,3-thiadiazole amide derivative containing an oxime ether unit prepared in Example 13;

[0018] Figure 4 is the high-resolution mass spectrum diagram of the 1,2,3-thiadiazole amide derivative containing an oxime ether unit prepared in Example 13;

[0019] Figure 5 Single crystal diffraction pattern of the 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit prepared in Example 13. Detailed implementation mode

[0020] The technical solution of the present invention will be further described below in conjunction with embodiments.

[0021] Example 1

[0022] The 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit of the present invention, R = i-Bu, chemical name is (E)-N-(2-(1-(isobutoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide, English name is (E)-N-(2-(1-(isobutoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide, and the structural formula is as follows:

[0023]

[0024] First step: Synthesis of ethyl 2-(4-ethoxy-4-oxo-2-butylidene)hydrazine-1-carboxylate (Intermediate 1)

[0025]

[0026] A solution of ethyl acetoacetate (100 mmol) and ethyl hydrazinecarboxylate (100 mmol) in ethanol (50 mL) was stirred at room temperature for 10 h, and the excess ethanol was removed by distillation under reduced pressure. The resulting white solid was ethyl 2-(4-ethoxy-4-oxo-2-butylidene)hydrazine-1-carboxylate.

[0027] Second step: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (Intermediate 2)

[0028]

[0029] Dissolve ethyl 2-(4-ethoxy-4-oxobut-2-en-1-ylidene)hydrazine-1-carboxylate (50 mmol) obtained in the first step in 40 mL of dichloromethane, and then add 150 mmol of thionyl chloride to the above mixture under an ice bath condition. Stir the mixture at room temperature for 24 h and then perform vacuum distillation to obtain a yellow oil containing ethyl 4-methyl-1,2,3-thiadiazole-5-carboxylate. Add the above yellow oil (50 mmol) and 5% NaOH solution (10 mL) to 50 mL of ethanol, stir at room temperature for 5 h and then perform vacuum distillation to remove the excess ethanol. Add 50 mL of water to the obtained residue, adjust the pH of the solution to 1 - 2 with concentrated hydrochloric acid, and a large amount of yellow solid will be produced. Filter, and dry the filter cake to obtain the intermediate 4-methyl-1,2,3-thiadiazole-5-carboxylic acid.

[0030] Step 3: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride (Intermediate 3)

[0031]

[0032] Add 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (0.50 g, 3.34 mmol) to 15 mL of thionyl chloride, reflux for 4 hours, and then perform vacuum distillation to remove the excess thionyl chloride to obtain the intermediate 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride.

[0033] Step 4: Synthesis of o-nitroacetophenone oxime (Intermediate 4)

[0034]

[0035] Add o-nitroacetophenone (18.17 mmol), hydroxylamine hydrochloride (54.50 mmol) and pyridine (20 mL) to 40 mL of ethanol, stir at room temperature for about 5 h, and then perform vacuum distillation to remove ethanol and pyridine. Add 50 mL of pure water to the obtained colorless ointment, shake vigorously, and white solid will be produced. Perform vacuum filtration, and dry the filter cake to obtain the intermediate o-nitroacetophenone oxime.

[0036] Step 5: Synthesis of (E)-1-(2-nitrophenyl)ethanone O-isobutyl oxime (Intermediate 5a)

[0037]

[0038] o-Nitroacetophenone oxime (16.65 mmol), isobutyl bromide (24.98 mmol) and potassium carbonate (49.45 mmol) were added to 50 mL of acetonitrile. The mixture was heated to reflux for 5 h and then filtered by suction. After removing acetonitrile from the filtrate by vacuum distillation, column chromatography was carried out using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 5:1. The colorless transparent liquid obtained was the intermediate (E)-1-(2-nitrophenyl)ethanone O-isobutyl oxime.

[0039] Step 6: Synthesis of (E)-1-(2-aminophenyl)ethanone O-isobutyl oxime (Intermediate 6a)

[0040]

[0041] (E)-1-(2-Nitrophenyl)ethanone O-isobutyl oxime (6.35 mmol) and stannous chloride (19.05 mmol) were added to 50 mL of ethanol. The mixture was heated to reflux for 5 h and then excess ethanol was removed by vacuum distillation. The residue obtained was dissolved in 50 mL of distilled water, and the pH value of the system was adjusted to 9 - 10 with sodium hydroxide solution. Then, it was extracted three times with 50 mL of dichloromethane. Subsequently, dichloromethane was removed by vacuum distillation, and column chromatography was carried out using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 15:1. The colorless transparent liquid obtained was the intermediate (E)-1-(2-aminophenyl)ethanone O-isobutyl oxime.

[0042] Step 7: Synthesis of (E)-N-(2-(1-(isobutoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (Target molecule I1)

[0043]

[0044] 4-Methyl-1,2,3-thiadiazole-5-carbonyl chloride (3.50 mmol) was dissolved in 25 mL of dichloromethane and stirred evenly for standby. Subsequently, (E)-1-(2-aminophenyl)ethanone O-isobutyl oxime (3.50 mmol) and triethylamine (10.50 mmol) were added to 25 mL of dichloromethane, and the dichloromethane solution containing 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride was slowly added under ice bath conditions. After 30 min, the ice bath was removed, and the mixture was stirred at room temperature for 5 h. After removing excess dichloromethane by vacuum distillation, column chromatography was carried out using a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 30:1. The white solid obtained was the target molecule I1.

[0045] The target compound I1 was a white solid with a yield of 52%; 11H NMR (400 MHz, CDCl3) δ 11.72 (s, 1H), 8.56 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.22 (t, J = 7.3 Hz, 1H), 3.90 (d, J = 6.4 Hz, 2H), 2.98 (s, 3H), 2.36 (s, 3H), 1.87 (dt, J = 12.3, 6.0 Hz, 1H), 0.90 (d, J = 5.4 Hz, 1H); 13 13C NMR (101 MHz, CDCl3) δ 160.42, 157.46, 157.06, 143.94, 135.96, 129.84, 128.64, 124.51, 123.20, 121.51, 81.23, 28.04, 18.99, 13.80, 13.74; HRMS (ESI) m / z [[M+H]] + calcd for C 16 H 21 N4O2S: 333.1380, found: 333.1383.

[0046] Example 2

[0047] The 1,2,3-thiadiazole carboxamide derivative containing an oxime ether unit of the present invention, R = n-Bu, with the chemical name of (E)-N-(2-(1-(butoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide and the English name of (E)-N-(2-(1-(butoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide, has the following structural formula:

[0048]

[0049] First step: Synthesis of ethyl 2-(4-ethoxy-4-oxo-2-butylidene)hydrazine-1-carboxylate (Intermediate 1)

[0050] As in the first step of Example 1.

[0051] Second step: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (Intermediate 2)

[0052] As in the second step of Example 1.

[0053] Third step: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride (Intermediate 3)

[0054] As in the third step of Example 1.

[0055] Step 4: Synthesis of o-nitroacetophenone oxime (Intermediate 4)

[0056] As in Step 4 of Example 1.

[0057] Step 5: Synthesis of (E)-1-(2-nitrophenyl)ethanone O-butyl oxime (Intermediate 5b)

[0058]

[0059] As in Step 5 of Example 1, except that bromobutane is used as the reactant.

[0060] Step 6: Synthesis of (E)-1-(2-aminophenyl)ethanone O-butyl oxime (Intermediate 6b)

[0061]

[0062] As in Step 6 of Example 1, except that (E)-1-(2-nitrophenyl)ethanone O-butyl oxime (Intermediate 5b) is used as the reactant.

[0063] Step 7: Synthesis of (E)-N-(2-(1-(butoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (Target molecule I2)

[0064]

[0065] As in Step 7 of Example 1, except that (E)-1-(2-aminophenyl)ethanone O-butyl oxime (Intermediate 6b) is used as the reactant.

[0066] The target compound I2 is a white solid with a yield of 56%; 1 H NMR (400 MHz, CDCl3) δ 11.75 (s, 1H), 8.57 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 4.14 (t, J = 6.1 Hz, 2H), 2.98 (s, 3H), 2.34 (s, 3H), 1.57 (dd, J = 13.6, 6.7 Hz, 2H), 1.36 (dt, J = 14.6, 7.2 Hz, 2H), 0.91 (t, J = 7.1 Hz, 3H); 1313C NMR (101 MHz, CDCl3) δ 160.48, 157.44, 157.04, 143.94, 135.98, 129.84, 128.64, 124.50, 123.20, 121.48, 74.73, 31.04, 19.12, 13.87, 13.81, 13.75; HRMS (ESI) m / z [M+H] + calcd for C 16 H 21 N4O2S: 333.1580, found: 333.1383.

[0067] Example 3

[0068] The 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit of the present invention with the chemical name of (E)-4-methyl-N-(2-(1-(((2-methylallyl)oxy)imino)ethyl)phenyl)-1,2,3-thiadiazole-5-carboxamide and the English name of (E)-4-methyl-N-(2-(1-(((2-methylallyl)oxy)imino)ethyl)phenyl)-1,2,3-thiadiazole-5-carboxamide, and the structural formula is as follows:

[0069]

[0070] Step 1: Synthesis of ethyl 2-(4-ethoxy-4-oxo-2-butylidene)hydrazine-1-carboxylate (Intermediate 1)

[0071] As in the first step of Example 1.

[0072] Step 2: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (Intermediate 2)

[0073] As in the second step of Example 1.

[0074] Step 3: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride (Intermediate 3)

[0075] As in the third step of Example 1.

[0076] Step 4: Synthesis of o-nitroacetophenone oxime (Intermediate 4)

[0077] As in the fourth step of Example 1.

[0078] Step 5: Synthesis of (E)-1-(2-nitrophenyl)ethanone O-(2-methylallyl)oxime (Intermediate 5c)

[0079]

[0080] In the fifth step of Example 1, the difference lies in using 1-bromo-3-chloro-2-methylpropane as the reactant.

[0081] Step 6: Synthesis of (E)-1-(2-aminophenyl)ethanone-O-(2-methylallyl)oxime (Intermediate 6c)

[0082]

[0083] In the sixth step of Example 1, the difference lies in using (E)-1-(2-nitrophenyl)ethanone-O-(2-methylallyl)oxime (Intermediate 5c) as the reactant.

[0084] Step 7: Synthesis of (E)-4-methyl-N-(2-(1-(((2-methylallyl)oxy)imino)ethyl)phenyl)-1,2,3-thiadiazole-5-carboxamide (Target Molecule I3)

[0085]

[0086] In the seventh step of Example 1, the difference lies in using (E)-1-(2-aminophenyl)ethanone-O-(2-methylallyl)oxime (Intermediate 6c) as the reactant.

[0087] The target compound I3 is a white solid with a yield of 61%; 1 H NMR (400 MHz, CDCl3) δ 11.52 (s, 1H), 8.53 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.23 (t, J = 7.3 HZ, 1H), 4.70 (s, 2H), 4.54 (s, 2H), 2.95 (s, 3H), 2.39 (s, 3H), 1.67 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 160.12, 157.64, 157.50, 144.17, 141.21, 135.82, 129.96, 128.71, 124.58, 123.28, 121.68, 112.21, 77.93, 19.29, 14.02, 13.65; HRMS (ESI) m / z [M+H] + calcd for C 16 H 19 N4O2S: 331.1223, found: 331.1224.

[0088] Example 4

[0089] The 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit of the present invention The chemical name is (E)-N-(2-(1-((allyloxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide, and the English name is (E)-N-(2-(1-((allyloxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide. The structural formula is as follows:

[0090]

[0091] Step 1: Synthesis of ethyl 2-(4-ethoxy-4-oxo-2-butylidene)hydrazine-1-carboxylate (Intermediate 1)

[0092] As in the first step of Example 1.

[0093] Step 2: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (Intermediate 2)

[0094] As in the second step of Example 1.

[0095] Step 3: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride (Intermediate 3)

[0096] As in the third step of Example 1.

[0097] Step 4: Synthesis of o-nitroacetophenone oxime (Intermediate 4)

[0098] As in the fourth step of Example 1.

[0099] Step 5: Synthesis of (E)-1-(2-nitrophenyl)ethanone O-allyl oxime (Intermediate 5d)

[0100]

[0101] As in the fifth step of Example 1, except that 3-bromopropene is used as the reactant.

[0102] Step 6: Synthesis of (E)-1-(2-aminophenyl)ethanone O-allyl oxime (Intermediate 6d)

[0103]

[0104] As in the sixth step of Example 1, except that (E)-1-(2-nitrophenyl)ethanone O-allyl oxime (Intermediate 5d) is used as the reactant.

[0105] Step 7: Synthesis of (E)-N-(2-(1-((allyloxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (Target Molecule I4)

[0106]

[0107] Same as Step 7 of Example 1, except that (E)-1-(2-aminophenyl)ethanone O-allyloxime (Intermediate 6d) was used as the reactant.

[0108] The target compound I4 was a white solid with a yield of 54%; 1 H NMR (400 MHz, CDCl3) δ 11.55 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.23 (t, J = 7.3 Hz, 1H), 5.93 - 5.77 (m, 1H), 5.09 (dd, J = 20.1, 14.6 Hz, 1H), 4.65 (s, 2H), 2.96 (s, 3H), 2.37 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 160.28, 157.64, 157.55, 144.06, 135.86, 133.34, 130.00, 128.72, 124.57, 123.23, 121.61, 117.56, 75.21, 14.07, 13.71; HRMS (ESI) m / z [M + H] + calcd for C 15 H 17 N4O2S: 317.1067, found: 317.1070.

[0109] Example 5

[0110] The 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit of the present invention with the chemical name of (E)-N-(2-(1-((cyclopentyloxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide and the English name of (E)-N-(2-(1-((cyclopentyloxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide has the following structural formula:

[0111]

[0112] Step 1: Synthesis of Ethyl 2-(4-ethoxy-4-oxo-2-butylidene)hydrazine-1-carboxylate (Intermediate 1)

[0113] As in the first step of Example 1

[0114] Step 2: Synthesis of 4-Methyl-1,2,3-thiadiazole-5-carboxylic acid (Intermediate 2)

[0115] As in the second step of Example 1

[0116] Step 3: Synthesis of 4-Methyl-1,2,3-thiadiazole-5-carbonyl chloride (Intermediate 3)

[0117] As in the third step of Example 1

[0118] Step 4: Synthesis of o-Nitroacetophenone oxime (Intermediate 4)

[0119] As in the fourth step of Example 1

[0120] Step 5: Synthesis of (E)-1-(2-Nitrophenyl)ethanone O-Cyclopentyl oxime (Intermediate 5e)

[0121]

[0122] As in the fifth step of Example 1, except that bromocyclopentane is used as the reactant

[0123] Step 6: Synthesis of (E)-1-(2-Nitrophenyl)ethanone O-Cyclopentyl oxime (Intermediate 6e)

[0124]

[0125] As in the sixth step of Example 1, except that (E)-1-(2-Nitrophenyl)ethanone O-Cyclopentyl oxime (Intermediate 5e) is used as the reactant

[0126] Step 7: Synthesis of (E)-N-(2-(1-((Cyclopentyloxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (Target molecule I5)

[0127]

[0128] As in the seventh step of Example 1, except that (E)-1-(2-Nitrophenyl)ethanone O-Cyclopentyl oxime (Intermediate 6e) is used as the reactant

[0129] The target compound I5 is a white solid with a yield of 32%; 11H NMR (400 MHz, CDCl3) δ 11.89 (s, 1H), 8.56 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.4 Hz, 1H), 4.69 (s, 1H), 2.97 (s, 3H), 2.31 (s, 3H), 1.78 - 1.51 (m, 8H); 13 13C NMR (101 MHz, CDCl3) δ 160.25, 157.58, 157.02, 144.10, 136.06, 129.75, 128.62, 124.47, 123.25, 121.50, 86.12, 32.07, 23.70, 13.73, 13.70; HRMS (ESI) m / z [M + H] + calcd for C 17 H 21 N4O2S: 345.1380, found: 345.1382.

[0130] Example 6

[0131] The 1,2,3 - thiadiazolecarboxamide derivative containing an oxime ether unit of the present invention, with the chemical name of (E)-N-(2-(1-((2-chloroethoxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide and the English name of (E)-N-(2-(1-((2-chloroethoxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide, and the structural formula is as follows:

[0132]

[0133] The first step: Synthesis of ethyl 2-(4-ethoxy-4-oxo-2-butylidene)hydrazine-1-carboxylate (Intermediate 1)

[0134] As in the first step of Example 1.

[0135] The second step: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (Intermediate 2)

[0136] As in the second step of Example 1.

[0137] The third step: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride (Intermediate 3)

[0138] As in the third step of Example 1.

[0139] Step 4: Synthesis of o-nitroacetophenone oxime (Intermediate 4)

[0140] As in Step 4 of Example 1

[0141] Step 5: Synthesis of (E)-1-(2-nitrophenyl)ethanone-O-(2-chloroethyl)oxime (Intermediate 5f)

[0142]

[0143] As in Step 5 of Example 1, except that 1-bromo-2-chloroethane is used as the reactant

[0144] Step 6: Synthesis of (E)-1-(2-aminophenyl)ethanone-O-(2-chloroethyl)oxime (Intermediate 6f)

[0145]

[0146] As in Step 6 of Example 1, except that (E)-1-(2-nitrophenyl)ethanone-O-(2-chloroethyl)oxime (Intermediate 5f) is used as the reactant

[0147] Step 7: Synthesis of (E)-N-(2-(1-((2-chloroethoxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (Target Molecule I6)

[0148]

[0149] As in Step 7 of Example 1, except that (E)-1-(2-aminophenyl)ethanone-O-(2-chloroethyl)oxime (Intermediate 6f) is used as the reactant

[0150] The target compound I6 is a white solid with a yield of 54%; 1 H NMR (400 MHz, CDCl3) δ 11.39 (s, 1H), 8.56 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H), 4.40 (s, 2H), 3.66 (s, 2H), 2.99 (s, 3H), 2.39 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 160.72, 158.87, 157.33, 143.64, 135.80, 130.27, 128.88, 124.67, 123.05, 121.63, 74.18, 41.86, 14.32, 13.79; HRMS (ESI) m / z [M+H] + calcd for C 14H 16 ClN4O2S: 329.0677, found: 329.0678.

[0151] Example 7

[0152] The 1,2,3 - thiadiazolecarboxamide derivative containing an oxime ether unit of the present invention, where R = Bn, with the chemical name (E)-N-(2-(1-((benzyloxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide and the English name (E)-N-(2-(1-((benzyloxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide, has the following structural formula:

[0153]

[0154] First step: Synthesis of ethyl 2-(4-ethoxy-4-oxo-2-butylidene)hydrazine-1-carboxylate (Intermediate 1)

[0155] As in the first step of Example 1.

[0156] Second step: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (Intermediate 2)

[0157] As in the second step of Example 1.

[0158] Third step: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride (Intermediate 3)

[0159] As in the third step of Example 1.

[0160] Fourth step: Synthesis of o-nitroacetophenone oxime (Intermediate 4)

[0161] As in the fourth step of Example 1.

[0162] Fifth step: Synthesis of (E)-1-(2-nitrophenyl)ethanone O-benzyl oxime (Intermediate 5g)

[0163]

[0164] As in the fifth step of Example 1, except that benzyl chloride is used as the reactant.

[0165] Sixth step: Synthesis of (E)-1-(2-aminophenyl)ethanone O-benzyl oxime (Intermediate 6g)

[0166]

[0167] In the sixth step of Example 1, the difference lies in using (E)-1-(2-nitrophenyl)ethanone-O-benzyl oxime (Intermediate 5g) as the reactant.

[0168] Step 7: Synthesis of (E)-N-(2-(1-((benzyloxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (Target Molecule I7)

[0169]

[0170] In the seventh step of Example 1, the difference lies in using (E)-1-(2-aminophenyl)ethanone-O-benzyl oxime (Intermediate 6g) as the reactant.

[0171] The target compound I7 is a white solid with a yield of 62%; 1 H NMR (400 MHz, CDCl3) δ 11.48 (s, 1H), 8.52 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.34 - 7.21 (m, 4H), 7.18 (d, J = 6.3 Hz, 2H), 5.21 (s, 2H), 2.91 (s, 3H), 2.43 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 160.29, 158.10, 157.52, 143.93, 136.83, 135.91, 130.06, 128.79, 128.55, 128.01, 127.02, 124.57, 123.15, 121.66, 76.28, 14.25, 13.68; HRMS (ESI) m / z [M + H] + calcd for C 19 H 19 N4O2S: 367.1223, found: 367.1227.

[0172] Example 8

[0173] The 1,2,3-thiadiazole amide derivative containing an oxime ether unit of the present invention, with the chemical name of (E)-N-(2-(1-((prop-2-yn-1-yloxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide and the English name of (E)-N-(2-(1-((prop-2-yn-1-yloxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide, has the following structural formula:

[0174]

[0175] Step 1: Synthesis of ethyl 2-(4-ethoxy-4-oxo-2-butylidene)hydrazine-1-carboxylate (Intermediate 1)

[0176] As in Step 1 of Example 1.

[0177] Step 2: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (Intermediate 2)

[0178] As in Step 2 of Example 1.

[0179] Step 3: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride (Intermediate 3)

[0180] As in Step 3 of Example 1.

[0181] Step 4: Synthesis of o-nitroacetophenone oxime (Intermediate 4)

[0182] As in Step 4 of Example 1.

[0183] Step 5: Synthesis of (E)-1-(2-nitrophenyl)ethanone O-prop-2-yn-1-yl oxime (Intermediate 5h)

[0184]

[0185] As in Step 5 of Example 1, except that 3-bromopropyne is used as the reactant.

[0186] Step 6: Synthesis of (E)-1-(2-aminophenyl)ethanone O-prop-2-yn-1-yl oxime (Intermediate 6h)

[0187]

[0188] As in Step 6 of Example 1, except that (E)-1-(2-nitrophenyl)ethanone O-prop-2-yn-1-yl oxime (Intermediate 5h) is used as the reactant.

[0189] Step 7: Synthesis of (E)-N-(2-(1-((prop-2-yn-1-yloxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (Target molecule I8)

[0190]

[0191] As in Step 7 of Example 1, except that (E)-1-(2-aminophenyl)ethanone O-prop-2-yn-1-yl oxime (Intermediate 6h) is used as the reactant.

[0192] The target compound I8 is a white solid with a yield of 47%; 11H NMR (400 MHz, CDCl3) δ 11.41 (s, 1H), 8.53 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 4.73 (s, 2H), 2.97 (s, 3H), 2.37 (s, 3H), 2.15 (s, 1H); 13 13C NMR (101 MHz, CDCl3) δ 160.08, 158.81, 157.73, 144.32, 135.79, 130.28, 128.88, 124.64, 123.08, 121.85, 78.87, 75.08, 14.25, 13.71; HRMS (ESI) m / z [M+H] + calcd for C 15 H 15 N4O2S: 315.0910, found: 315.0911.

[0193] Example 9

[0194] The 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit of the present invention, R = 4-ClBn, with the chemical name of (E)-N-(2-(1-((4-chlorobenzyloxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide, and the English name of (E)-N-(2-(1-(((4-chlorobenzyl)oxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide, has the following structural formula:

[0195]

[0196] First step: Synthesis of ethyl 2-(4-ethoxy-4-oxo-2-butylidene)hydrazine-1-carboxylate (Intermediate 1)

[0197] As in the first step of Example 1.

[0198] Second step: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (Intermediate 2)

[0199] As in the second step of Example 1.

[0200] Third step: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride (Intermediate 3)

[0201] As in the third step of Example 1.

[0202] Step 4: Synthesis of o-Nitroacetophenone Oxime (Intermediate 4)

[0203] As in Step 4 of Example 1

[0204] Step 5: Synthesis of (E)-1-(2-Nitrophenyl)ethanone O-(4-Chlorobenzyl) Oxime (Intermediate 5i)

[0205]

[0206] As in Step 5 of Example 1, except that 4-Chlorobenzyl Chloride is used as the reactant

[0207] Step 6: Synthesis of (E)-1-(2-Aminophenyl)ethanone O-(4-Chlorobenzyl) Oxime (Intermediate 6i)

[0208]

[0209] As in Step 6 of Example 1, except that (E)-1-(2-Nitrophenyl)ethanone O-(4-Chlorobenzyl) Oxime (Intermediate 5i) is used as the reactant

[0210] Step 7: Synthesis of (E)-N-(2-(1-((4-Chlorobenzyloxy)imino)ethyl)phenyl)-4-Methyl-1,2,3-Thiadiazole-5-Carboxamide (Target Molecule I9)

[0211]

[0212] As in Step 7 of Example 1, except that (E)-1-(2-Aminophenyl)ethanone O-(4-Chlorobenzyl) Oxime (Intermediate 6i) is used as the reactant

[0213] The target compound I9 is a white solid with a yield of 66%; 1 H NMR (400 MHz, CDCl3) δ 11.44 (s, 1H), 8.51 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.24 (t, J = 8.8 Hz, 3H), 7.09 (d, J = 7.3 Hz, 2H), 5.17 (s, 2H), 2.92 (s, 3H), 2.42 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 160.42, 158.44, 157.40, 143.82, 135.91, 135.29, 133.80, 130.19, 128.82, 128.75, 128.34, 124.60, 122.92, 121.65, 75.45, 14.25, 13.65; HRMS (ESI) m / z [M+H] + calcd forC19 H 18 ClN4O2S: 401.0834, found: 401.0833.

[0214] Example 10

[0215] The 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit of the present invention, R = Me, with the chemical name of (E)-N-(2-(1-(methoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide and the English name of (E)-N-(2-(1-(methoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide, has the following structural formula:

[0216]

[0217] First step: Synthesis of ethyl 2-(4-ethoxy-4-oxo-2-butylidene)hydrazine-1-carboxylate (Intermediate 1)

[0218] As in the first step of Example 1.

[0219] Second step: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (Intermediate 2)

[0220] As in the second step of Example 1.

[0221] Third step: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride (Intermediate 3)

[0222] As in the third step of Example 1.

[0223] Fourth step: Synthesis of o-nitroacetophenone oxime (Intermediate 4)

[0224] As in the fourth step of Example 1.

[0225] Fifth step: Synthesis of (E)-1-(2-nitrophenyl)ethanone O-methyl oxime (Intermediate 5j)

[0226]

[0227] As in the fifth step of Example 1, except that methyl iodide is used as the reactant.

[0228] Sixth step: Synthesis of (E)-1-(2-aminophenyl)ethanone O-methyl oxime (Intermediate 6j)

[0229]

[0230] As in the sixth step of Example 1, the difference is that (E)-1-(2-nitrophenyl)ethanone-O-methyl oxime (intermediate 5j) is used as the reactant.

[0231] Seventh step: Synthesis of (E)-N-(2-(1-(methoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (target molecule I 10 )

[0232]

[0233] As in the seventh step of Example 1, the difference is that (E)-1-(2-aminophenyl)ethanone-O-methyl oxime (intermediate 6j) is used as the reactant.

[0234] Target compound I 10 is a white solid with a yield of 80%; 1 H NMR (400 MHz, CDCl3) δ 11.66 (s, 1H), 8.60 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 3.98 (s, 3H), 3.01 (s, 3H), 2.34 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 160.74, 157.40, 157.36, 143.82, 135.95, 130.00, 128.68, 124.53, 123.06, 121.49, 62.56, 13.83; HRMS (ESI) m / z [M+H] + calcd for C 13 H 15 N4O2S: 291.0910, found: 291.0971.

[0235] Example 11

[0236] The 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit of the present invention, with R = Et, has the chemical name (E)-N-(2-(1-(ethoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide and the English name (E)-N-(2-(1-(ethoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide. The structural formula is as follows:

[0237]

[0238] Step 1: Synthesis of Ethyl 2-(4-ethoxy-4-oxo-2-butylidene)hydrazine-1-carboxylate (Intermediate 1)

[0239] As in the first step of Example 1.

[0240] Step 2: Synthesis of 4-Methyl-1,2,3-thiadiazole-5-carboxylic acid (Intermediate 2)

[0241] As in the second step of Example 1.

[0242] Step 3: Synthesis of 4-Methyl-1,2,3-thiadiazole-5-carbonyl chloride (Intermediate 3)

[0243] As in the third step of Example 1.

[0244] Step 4: Synthesis of o-Nitroacetophenone oxime (Intermediate 4)

[0245] As in the fourth step of Example 1.

[0246] Step 5: Synthesis of (E)-1-(2-Nitrophenyl)ethanone O-Ethyl oxime (Intermediate 5k)

[0247]

[0248] As in the fifth step of Example 1, except that bromoethane is used as the reactant.

[0249] Step 6: Synthesis of (E)-1-(2-Aminophenyl)ethanone O-Ethyl oxime (Intermediate 6k)

[0250]

[0251] As in the sixth step of Example 1, except that (E)-1-(2-Nitrophenyl)ethanone O-Ethyl oxime (Intermediate 5k) is used as the reactant.

[0252] Step 7: Synthesis of (E)-N-(2-(1-(Ethoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (Target Molecule I 11 )

[0253]

[0254] As in the seventh step of Example 1, except that (E)-1-(2-Aminophenyl)ethanone O-Ethyl oxime (Intermediate 6k) is used as the reactant.

[0255] Target Compound I 11 is a white solid with a yield of 85%; 11H NMR (400 MHz, CDCl3) δ 11.75 (s, 1H), 8.58 (d, J = 9.0 Hz, 1H), 7.55 (dd, J = 8.0, 1.4 Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.24 (td, J = 8.0, 1.2 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 2.99 (s, 3H), 2.35 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ 160.58, 157.44, 157.08, 143.93, 135.95, 129.88, 128.66, 124.53, 123.25, 121.50, 70.45, 14.45, 13.89, 13.78; HRMS (ESI) m / z [M+H] + calcd for C 14 H 17 N4O2S: 305.1066, found: 305.0989.

[0256] Example 12

[0257] The 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit of the present invention, R = n-Pr, with the chemical name of (E)-N-(2-(1-(propoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide and the English name of (E)-N-(2-(1-(propoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide, has the following structural formula:

[0258]

[0259] The first step: Synthesis of ethyl 2-(4-ethoxy-4-oxo-2-butylidene)hydrazine-1-carboxylate (Intermediate 1)

[0260] As in the first step of Example 1.

[0261] The second step: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (Intermediate 2)

[0262] As in the second step of Example 1.

[0263] The third step: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride (Intermediate 3)

[0264] As in the third step of Example 1.

[0265] Step 4: Synthesis of o-nitroacetophenone oxime (Intermediate 4)

[0266] Same as step 4 of Example 1

[0267] Step 5: Synthesis of (E)-1-(2-nitrophenyl)ethanone O-propyl oxime (Intermediate 5l)

[0268]

[0269] Same as step 5 of Example 1, except that 1-bromopropane is used as the reactant

[0270] Step 6: Synthesis of (E)-1-(2-aminophenyl)ethanone O-propyl oxime (Intermediate 6l)

[0271]

[0272] Same as step 6 of Example 1, except that (E)-1-(2-nitrophenyl)ethanone O-propyl oxime (Intermediate 5l) is used as the reactant

[0273] Step 7: Synthesis of (E)-N-(2-(1-(propoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (Target molecule I 12 )

[0274]

[0275] Same as step 7 of Example 1, except that (E)-1-(2-aminophenyl)ethanone O-propyl oxime (Intermediate 6l) is used as the reactant

[0276] Target compound I 12 is a white solid with a yield of 67%; 1 H NMR (400 MHz, CDCl3) δ 11.77 (s, 1H), 8.58 (d, J = 8.3 Hz, 1H), 7.56 (dd, J = 8.0, 1.3 Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.24 (t, J = 7.1 Hz, 1H), 4.10 (t, J = 6.6 Hz, 2H), 2.99 (s, 3H), 2.36 (s, 3H), 1.68 - 1.58 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 160.53, 157.47, 157.10, 143.93, 135.97, 129.87, 128.65, 124.52, 123.23, 121.51, 76.40, 22.31, 13.82, 13.78, 10.33; HRMS (ESI) m / z [M + H]+ Calculated for C 15 H 19 N4O2S: 319.1223, found: 319.1263.

[0277] Example 13

[0278] The 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit of the present invention, R = i-Pr, with the chemical name of (E)-N-(2-(1-(isopropoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide and the English name of (E)-N-(2-(1(isopropoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide, has the following structural formula:

[0279]

[0280] The first step: Synthesis of ethyl 2-(4-ethoxy-4-oxo-2-butylidene)hydrazine-1-carboxylate (Intermediate 1)

[0281] As in the first step of Example 1.

[0282] The second step: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (Intermediate 2)

[0283] As in the second step of Example 1.

[0284] The third step: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride (Intermediate 3)

[0285] As in the third step of Example 1.

[0286] The fourth step: Synthesis of o-nitroacetophenone oxime (Intermediate 4)

[0287] As in the fourth step of Example 1.

[0288] The fifth step: Synthesis of (E)-1-(2-nitrophenyl)ethanone O-isopropyl oxime (Intermediate 5m)

[0289]

[0290] As in the fifth step of Example 1, except that isopropyl bromide is used as the reactant.

[0291] The sixth step: Synthesis of (E)-1-(2-aminophenyl)ethanone O-isopropyl oxime (Intermediate 6m)

[0292]

[0293] As in the sixth step of Example 1, the difference is that (E)-1-(2-nitrophenyl)ethanone O-isopropyl oxime (Intermediate 5m) is used as the reactant.

[0294] Seventh step: Synthesis of (E)-N-(2-(1-(isopropoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (Target molecule I 13 )

[0295]

[0296] As in the seventh step of Example 1, the difference is that (E)-1-(2-aminophenyl)ethanone O-isopropyl oxime (Intermediate 6m) is used as the reactant.

[0297] Target compound I 13 is a white solid with a yield of 69%; 1 H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.56 (dd, J = 8.3, 0.8 Hz, 1H), 7.56 (dd, J = 8.0, 1.4 Hz, 1H), 7.43 (t, J = 8.5 Hz, 1H), 7.24 (td, J = 8.0, 1.3 Hz, 1H), 4.36 (hept, J = 6.2 Hz, 1H), 2.98 (s, 3H), 2.34 (s, 3H), 1.19 (d, J = 6.2 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 160.33, 157.57, 156.71, 144.03, 135.95, 129.75, 128.64, 124.53, 123.43, 121.54, 76.57, 21.61, 13.88, 13.70; HRMS (ESI) m / z [M+H] + calcd for C 15 H 19 N4O2S: 319.1223, found: 319.1263.

[0298] Example 14

[0299] The 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit of the present invention, The chemical name is (E)-N-(2-(1-((cyclopropylmethoxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide, and the structural formula is as follows:

[0300]

[0301] Step 1: Synthesis of ethyl 2-(4-ethoxy-4-oxo-2-butylidene)hydrazine-1-carboxylate (Intermediate 1)

[0302] As in the first step of Example 1.

[0303] Step 2: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (Intermediate 2)

[0304] As in the second step of Example 1.

[0305] Step 3: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride (Intermediate 3)

[0306] As in the third step of Example 1.

[0307] Step 4: Synthesis of o-nitroacetophenone oxime (Intermediate 4)

[0308] As in the fourth step of Example 1.

[0309] Step 5: Synthesis of (E)-1-(2-nitrophenyl)ethanone O-cyclopropylmethyl oxime (Intermediate 5n)

[0310]

[0311] As in the fifth step of Example 1, except that bromomethylcyclopropane is used as the reactant.

[0312] Step 6: Synthesis of (E)-1-(2-aminophenyl)ethanone O-cyclopropylmethyl oxime (Intermediate 6n)

[0313]

[0314] As in the sixth step of Example 1, except that (E)-1-(2-nitrophenyl)ethanone O-cyclopropylmethyl oxime (Intermediate 5n) is used as the reactant.

[0315] Step 7: (E)-N-(2-(1-((cyclopropylmethoxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (Target molecule I)14 ) Synthesis

[0316]

[0317] In the seventh step of Example 1, the difference is that (E)-1-(2-aminophenyl)ethanone O-cyclopropylmethyl oxime (Intermediate 6n) is used as the reactant.

[0318] Target compound I 14 is a white solid with a yield of 74%; 1 H NMR (400 MHz, CDCl3) δ 11.72 (s, 1H), 8.58 (d, J = 8.3 Hz, 1H), 7.56 (dd, J = 8.0, 1.3 Hz, 1H), 7.43 (t, J = 8.5 Hz, 1H), 7.24 (td, J = 8.0, 1.2 Hz, 1H), 3.97 (d, J = 7.0 Hz, 2H), 2.99 (s, 3H), 2.38 (s, 3H), 1.10 - 0.99 (m, 1H), 0.58 - 0.52 (m, 2H), 0.26 (q, J = 4.8 Hz, 2H); 13 C NMR (101 MHz, CDCl3) δ 160.55, 157.45, 157.15, 143.91, 135.92, 129.87, 128.69, 124.55, 123.33, 121.50, 79.47, 14.02, 13.78, 10.07, 3.14; HRMS (ESI) m / z [M + H] + calcd for C 16 H 19 N4O2S: 331.1223, found: 331.1235.

[0319] Example 15

[0320] The oxime ether unit-containing 1,2,3-thiadiazole amide derivative of the present invention, R = s-Bu, with the chemical name of (E)-N-(2-(1-(sec-butoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide and the English name of (E)-N-(2-(1-(sec-butoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide, has the following structural formula:

[0321]

[0322] Step 1: Synthesis of ethyl 2-(4-ethoxy-4-oxo-2-butylidene)hydrazine-1-carboxylate (Intermediate 1)

[0323] As in the first step of Example 1.

[0324] Second step: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (Intermediate 2)

[0325] As in the second step of Example 1.

[0326] Third step: Synthesis of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride (Intermediate 3)

[0327] As in the third step of Example 1.

[0328] Fourth step: Synthesis of o-nitroacetophenone oxime (Intermediate 4)

[0329] As in the fourth step of Example 1.

[0330] Fifth step: Synthesis of (E)-1-(2-nitrophenyl)ethanone O-sec-butyl oxime (Intermediate 5o)

[0331]

[0332] As in the fifth step of Example 1, except that 2-bromobutane is used as the reactant.

[0333] Sixth step: Synthesis of (E)-1-(2-aminophenyl)ethanone O-sec-butyl oxime (Intermediate 6o)

[0334]

[0335] As in the sixth step of Example 1, except that (E)-1-(2-nitrophenyl)ethanone O-sec-butyl oxime (Intermediate 5o) is used as the reactant.

[0336] Seventh step: Synthesis of (E)-N-(2-(1-(sec-butoxyimino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (Target molecule I 15 )

[0337]

[0338] As in the seventh step of Example 1, except that (E)-1-(2-aminophenyl)ethanone O-sec-butyl oxime (Intermediate 6o) is used as the reactant.

[0339] Target compound I 15 is a white solid with a yield of 76%; 11H NMR (400 MHz, CDCl3) δ 11.80 (s, 1H), 8.56 (d, J = 7.6 Hz, 1H), 7.56 (dd, J = 8.0, 1.4 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.23 (td, J = 8.0, 1.2 Hz, 1H), 4.15 (h, J = 6.2 Hz, 1H), 2.97 (s, 3H), 2.35 (s, 3H), 1.66 - 1.43 (m, 2H), 1.14 (d, J = 6.3 Hz, 3H), 0.88 (t, J = 7.5 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ 160.25, 157.60, 156.71, 144.03, 135.94, 129.71, 128.61, 124.53, 123.45, 121.55, 81.45, 28.33, 19.14, 13.85, 13.69, 9.45; HRMS (ESI) m / z [M + H] + calcd for C 16 H 21 N4O2S: 333.1379, found: 333.1388.

[0340] Example 16

[0341] The 1,2,3 - thiadiazolecarboxamide derivative containing an oxime ether unit of the present invention with the chemical name of (E)-N-(2-(1-((2,2,2 - trifluoroethoxy)imino)ethyl)phenyl)-4 - methyl - 1,2,3 - thiadiazole - 5 - carboxamide and the English name of (E)-N-(2-(1-((2,2,2 - trifluoroethoxy)imino)ethyl)phenyl)-4 - methyl - 1,2,3 - thiadiazole - 5 - carboxamide has the following structural formula:

[0342]

[0343] The first step: Synthesis of ethyl 2-(4 - ethoxy - 4 - oxo - 2 - butylidene)hydrazine - 1 - carboxylate (Intermediate 1)

[0344] As in the first step of Example 1.

[0345] The second step: Synthesis of 4 - methyl - 1,2,3 - thiadiazole - 5 - carboxylic acid (Intermediate 2)

[0346] As in the second step of Example 1.

[0347] Step 3: Synthesis of 4-Methyl-1,2,3-thiadiazole-5-carbonyl Chloride (Intermediate 3)

[0348] As in Step 3 of Example 1

[0349] Step 4: Synthesis of o-Nitroacetophenone Oxime (Intermediate 4)

[0350] As in Step 4 of Example 1

[0351] Step 5: Synthesis of (E)-1-(2-Nitrophenyl)ethanone O-(2,2,2-Trifluoroethyl) Oxime (Intermediate 5p)

[0352]

[0353] As in Step 5 of Example 1, except that 1-Bromotrifluoroethane is used as the reactant

[0354] Step 6: Synthesis of (E)-1-(2-Aminophenyl)ethanone O-(2,2,2-Trifluoroethyl) Oxime (Intermediate 6p)

[0355]

[0356] As in Step 6 of Example 1, except that (E)-1-(2-Nitrophenyl)ethanone O-(2,2,2-Trifluoroethyl) Oxime (Intermediate 5p) is used as the reactant

[0357] Step 7: Synthesis of (E)-N-(2-(1-((2,2,2-Trifluoroethoxy)imino)ethyl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (Target Molecule I 16 )

[0358]

[0359] As in Step 7 of Example 1, except that (E)-1-(2-Aminophenyl)ethanone O-(2,2,2-Trifluoroethyl) Oxime (Intermediate 6p) is used as the reactant

[0360] Target Compound I 16 is a white solid with a yield of 55%; 1 H NMR (400 MHz, CDCl3) δ 7.68 - 7.58 (m, 2H), 7.50 (td, J = 7.7, 1.7 Hz, 1H), 7.22 (dd, J = 7.8, 0.8 Hz, 1H), 4.37 (q, J = 8.4 Hz, 2H), 2.89 (s, 6H); 1313C NMR (101 MHz, CDCl3) δ 162.89, 162.44, 156.11, 141.35, 136.37, 133.50, 131.62, 131.05, 130.88, 130.29, 123.22 (d, J = 280.0 Hz), 70.90 (q, J = 34.3 Hz), 15.08, 14.19; 19 19F NMR (376 MHz, CDCl3) δ -73.94; HRMS (ESI) m / z [M+H] + calcd for C 14 H 14 F3N4O2S: 359.0784, found: 359.0879.

[0361] Application performance test

[0362] Test method for inhibiting the activity of phytopathogenic fungi:

[0363] The inhibitory effects of the target molecule on Fusarium graminearum, Rhizoctonia solanis and Botrytis cinerea were determined by the mycelial growth rate method at a drug mass concentration of 50 μg / mL. Potato slices (200 g) were added to boiling distilled water (800 mL), and the mixture was boiled until the potato slices could be easily picked up with a glass rod. After filtering with gauze, the filtrate was collected. Agar powder (20 g) was added to 200 mL of distilled water, stirred evenly and then added to the filtrate obtained in the previous step. Distilled water was added to make up to 1 L, glucose (20 g) was added after boiling, and the mixture was stirred evenly and then dispensed into conical flasks to obtain PDA medium. After sterilizing the newly prepared PDA medium at 121 °C for 20 min, 100 μL of drug-containing DMSO was measured with a 200 μL pipette and added to 45 mL of sterilized and uncooled PDA medium. After shaking well, the drug-containing medium was evenly transferred to three disposable petri dishes and allowed to cool naturally under ultraviolet light. After cooling, a mycelial disc with a diameter of 5 mm was inoculated at the center of the disposable petri dish, and then transferred to an incubator at 25 °C and incubated upside down in the dark. When the colony diameter (C) of the blank control grew to 70 - 80 mm, the colony diameter (T) of each treatment group was measured by the cross method. Subsequently, the inhibition rate (I) of each treatment group against phytopathogenic fungi was calculated based on the colony diameters obtained from the blank group and the drug-treated group. The calculation formula is as follows:

[0364]

[0365] Using the agricultural fungicides hymexazol and boscalid as positive controls, the inhibitory activities of target molecules I1 - I against Gibberella zeae, Rhizoctonia solani, and Botrytis cinerea were determined by the mycelial growth rate method. 16 The test results at a drug mass concentration of 50 μg / mL are shown in Table 1.

[0366] Table 1 Inhibitory activities of compounds I1 - I 16 against phytopathogenic fungi at a concentration of 50 μg / mL

[0367] Compound Gibberella zeae Rhizoctonia solani Botrytis cinerea <![CDATA[I1]]> 45.8±0.8 53.0±0.3 55.3±0.6 <![CDATA[I2]]> 36.9±0.4 44.5±0.7 56.0±1.4 <![CDATA[I3]]> 39.1±0.4 54.8±0.1 70.4±0.9 I4 51.6±0.4 61.3±0.1 98.0±0.5 <![CDATA[I5]]> 44.9±0.4 68.2±1.1 55.5±0.3 <![CDATA[I6]]> 10.4±0.2 69.0±0.3 17.1±0.9 <![CDATA[I7]]> 13.8±0.4 59.2±0.7 13.6±1.3 <![CDATA[I8]]> 52.2±1.0 61.3±0.1 72.1±1.1 <![CDATA[I9]]> 6.9±0.4 39.0±1.0 7.5±0.3 <![CDATA[I 10 > 19.2±0.7 73.4±1.1 27.4±0.8 <![CDATA[I 11 > 29.1±0.8 39.5±0.7 98.4±0.2 <![CDATA[I 12 > 27.0±1.0 63.8±0.8 80.3±0.7 <![CDATA[I 13 > 40.8±0.9 60.9±1.9 89.8±0.9 <![CDATA[I 14 > 47.7±1.7 79.8±1.2 59.7±0.8 <![CDATA[I15]]> 37.9±0.7 47.3±1.2 68.9±1.1 <![CDATA[I 16 > 29.9±1.0 62.9±0.7 41.8±0.9 Hymexazol 46.7±2.2 41.6±3.2 63.6±2.5 Boscalid 29.8±1.4 87.3±1.7 83.0±1.6

[0368] As can be seen from Table 1, some target molecules showed obvious antibacterial effects against Gibberella zeae, Rhizoctonia solani, and Botrytis cinerea at 50 μg / mL. Among them, target molecules I4, I8, and I 14 could significantly inhibit the growth of the mycelia of Gibberella zeae at 50 μg / mL, with inhibition rates of 51.6%, 52.2%, and 47.7% respectively, and the antibacterial effects were better than those of hymexazol (46.7%) and boscalid (29.8%). At the same time, the inhibition rates of target molecules I4, I5, I6, I8, I 10 、I 12 、I 13 、I 14 and I 16 against Rhizoctonia solani at 50 μg / mL all exceeded 60%, and the antibacterial effects were better than those of hymexazol (41.6%). In addition, the inhibition rates of target molecules I3, I4, I8, I 11 、I 12 、I 13 and I 15 against Botrytis cinerea at 50 μg / mL were 70.4%, 98.0%, 72.1%, 98.4%, 80.3%, 89.8%, and 68.9% respectively, and the antibacterial effects were better than those of hymexazol (63.6%). It is worth noting that the inhibition rates of compounds I4, I 11 and I 13 against Botrytis cinerea at 50 μg / mL (98.0%, 98.4%, and 89.8%) were significantly better than those of the control drug boscalid (83.0%), showing the potential for in - depth exploration as potential agricultural fungicides.

Claims

1. A 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit, characterized in that, The structural formula is as shown in Formula I: Wherein: R is selected from optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted allyl, optionally substituted or unsubstituted propargyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted cycloalkylmethyl, optionally substituted or unsubstituted arylmethyl.

2. The 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit according to claim 1, wherein R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 3. The 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit according to claim 1, characterized in that Selected from the following specific compounds:

4. A method for preparing a 1,2,3-thiadiazolecarboxamide derivative containing an oxime ether unit according to any one of claims 1 to 3, characterized in that, Comprising the following steps: Ethyl acetoacetate is successively reacted with ethyl carbazate, thionyl chloride and sodium hydroxide solution, and the obtained product is reacted with thionyl chloride again to obtain 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride; subsequently, 2'-nitroacetophenone is successively reacted with hydroxylamine hydrochloride, haloalkane, stannous chloride and 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride to obtain the 1,2,3-thiadiazole amide derivative I containing an oxime ether unit. The synthetic route is as follows:

5. Use of the 1,2,3-thiadiazole amide derivative containing an oxime ether unit according to any one of claims 1 to 3 in controlling plant fungal diseases.

6. The application according to claim 5, characterized in that, The plant pathogenic fungi are Fusarium graminearum, Botrytis cinerea or Rhizoctonia solani.

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