CN104292164A - Dihydropyrazole compounds, and preparation method and application thereof - Google Patents

Dihydropyrazole compounds, and preparation method and application thereof Download PDF

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CN104292164A
CN104292164A CN201410486267.6A CN201410486267A CN104292164A CN 104292164 A CN104292164 A CN 104292164A CN 201410486267 A CN201410486267 A CN 201410486267A CN 104292164 A CN104292164 A CN 104292164A
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compound
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phenyl
cdcl3
room temperature
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CN104292164B (en
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陈加荣
胡小强
肖文精
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Huazhong Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Agronomy & Crop Science (AREA)
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Abstract

The invention provides dihydropyrazole compounds, and a preparation method and application thereof. The compounds are compounds disclosed as Formula I, or enantiomers, diastereoisomers, racemes, pharmaceutically acceptable salts, crystalline hydrates or solvates thereof, wherein R1 is optionally substituted phenyl group, optionally substituted benzyl group or optionally substituted alkyl group, R2 is tosyl, trichloro-acetyl or mesyl group, and R3 and R4 are respectively independently H or alkyl group.

Description

One class pyrazoline compounds and its production and use
Technical field
The present invention relates to chemical field, concrete, the present invention relates to compound and its preparation method and application, more specifically, the present invention relates to compound and derivative and its preparation method and application shown in formula Ι.
Background technology
4,5-pyrazoline oxazoline derivates is the very important five-membered heterocycles of a class, is extensively present in many natural products and has in the drug molecule of important biomolecule activity.
But 4,5-current pyrazoline oxazoline derivates still need to be developed further.
Summary of the invention
The present invention is intended to solve one of technical problem in correlation technique at least to a certain extent.For this reason, the object of the invention is to the compound that proposition one class has anti-microbial activity.
In a first aspect of the present invention, provide a kind of compound.According to embodiments of the invention, the enantiomer that this compound is compound shown in compound shown in formula I or formula I, diastereomer, racemic modification, pharmacy acceptable salt, crystalline hydrate or solvate,
Wherein, R 1for the phenyl optionally replaced, the optional benzyl replaced or the alkyl optionally replaced; R 2for tosyl group, tribromo-acetyl base, methylsulfonyl; R 3and R 4be separately H or the optional alkyl replaced.
Contriver is surprised to find, and has antibiotic bioactive effectively according to the compound of the embodiment of the present invention.
According to embodiments of the invention, above-claimed cpd can also have following additional technical feature:
According to one embodiment of present invention, R 1for phenyl, 4-aminomethyl phenyl, 3-p-methoxy-phenyl, 4-chloro-phenyl-, 2-chloro-phenyl-, 2,4 dichloro benzene base, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-fluorophenyl, 4-trifluoromethyl, 1-methyl-benzyl.
According to one embodiment of present invention, R 1, R 3and R 4it is independently the alkyl containing 1 ~ 10 carbon atom.
According to one embodiment of present invention, described compound is the enantiomer of one of following compounds or described following compounds, diastereomer, racemic modification, pharmacy acceptable salt, crystalline hydrate or solvate:
In a second aspect of the present invention, the invention provides a kind of method preparing compound noted earlier, according to embodiments of the invention, the method comprises:
Compound shown in formula II is contacted with iodobenzene diacetate, to obtain compound shown in formula I,
Wherein, R 1, R 2, R 3, R 4as previously described.
According to embodiments of the invention, described contact is by compound shown in described formula II and Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane being dissolved in tetrahydrofuran (THF), and stirs under nitrogen protection and carry out for 5 minutes.
According to embodiments of the invention, the mol ratio of compound shown in described formula II and described Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane is 1:2, and compound shown in described formula II and PhI (OAc) 2mol ratio be 1:1.5.
Thus, according to embodiments of the invention, the present invention proposes a synthetic route, may be used for compound shown in preparation formula I
According to inventive embodiments, it is characterized in that, at room temperature, Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane of raw material beta, gamma-unsaturated hydrazone II and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III of 1.5 equivalents subsequently, reaction mixture continues at room temperature reaction until TLC detection reaction is complete, directly obtains formula I target product with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography.
A third aspect of the present invention, the invention provides a kind of agricultural chemicals, and it comprises compound described above.Contriver finds that this agricultural chemicals can effectively for antibacterial.
In a fourth aspect of the present invention, the invention provides the method for foregoing compound or agricultural chemicals treatment or prevention plant disease, described plant disease is by the following Gibberella zeae one of at least caused, Thanatephorus cucumeris, Botrytis cinereapers, optionally, described plant is at least one in wheat, paddy rice and cucumber.
Embodiment
Embodiments of the invention are described below in detail.Embodiment is exemplary below, is intended to for explaining the present invention, and can not be interpreted as limitation of the present invention.
Embodiment 1
Compound I-1
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-1 (R 1=4-aminomethyl phenyl, R 2=p-toluenesulfonyl, R 3=hydrogen) the organic bases DABCO (67mg, 0.60mmol) of (99mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant of 1.5 equivalents subsequently, use the reaction yield of different oxygenant in table one, reaction mixture continues at room temperature reaction until TLC detection reaction is complete, and directly obtain formula I-1 target product 60mg with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 61%.
Table one oxygenant screens
Oxidant Yield(％)
mCPBA trace
TBHP trace
MnO 2 trace
PhI(O 2CCF 3) 2 35
PhI(OAc) 2 61
By the screening to oxygenant, we find traditional oxygenant such as: metachloroperbenzoic acid (mCPBA), peroxy tert-butyl alcohol (TBHP), Manganse Dioxide (MnO 2) good result can not be provided, only have and just can obtain target compound when oxygenant is high iodine compound, and when providing best result with iodobenzene diacetate as during oxygenant, yield is 61%.
1H?NMR(400MHz,CDCl3)δ(ppm)δ＝7.78(d,J＝8.0Hz,2H),7.53(d,J＝7.9Hz,2H),7.25(d,J＝8.0Hz,2H),7.17(d,J＝8.0Hz,2H),3.88–3.81(m,1H),3.14(dd,J＝16.9Hz,10.4Hz,1H),2.74(dd,J＝16.9Hz,9.8Hz,1H),2.36(s,3H),2.35(s,3H),1.62(d,J＝6.2,3H).
13C?NMR(100MHz,CDCl3)δ(ppm)δ＝157.32,143.98,140.77,131.96,129.36,129.21,128.58,128.10,126.73,58.06,41.50,21.81,21.53,21.42.
M.P.:143.9–144.7℃.
IR(in?KBr):2977,1490,1353,1164,1090,593cm-1.
High resolution: calculated value: [M+H]+: 329.1318, measured value: 329.1324.
Embodiment 2
Compound I-2
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-2 (R 1=phenyl, R 2=p-toluenesulfonyl, R 3=hydrogen) the organic bases DABCO (67mg, 0.60mmol) of (94mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III (145mg of 1.5 equivalents subsequently, 0.45mmol), reaction mixture continues at room temperature reaction until TLC detection reaction is complete, directly obtain formula I-2 target product 61mg with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 65%.
1H?NMR(600MHz,CDCl3)δ(ppm)δ＝7.84(d,J＝8.0Hz,2H),7.68(d,J＝6.8Hz,2H),7.44–7.39(m,3H),7.31(d,J＝8.0Hz,2H),3.96–3.89(m,1H),3.21(dd,J＝16.9Hz,10.6Hz,1H),2.81(dd,J＝16.9Hz,9.8Hz,1H),2.41(s,3H),1.67(d,J＝6.2Hz,3H).
13C?NMR(100MHz,CDCl3)δ(ppm)δ＝157.24,144.01,132.00,130.79,130.33,129.34,128.47,128.44,126.69,58.13,41.39,21.71,21.44.
IR(in?KBr):2973,1445,1351,1166,1091,588cm-1.
High resolution: calculated value: [M+H]+: 315.1162, measured value: 315.1173.
Embodiment 3
Compound I-3
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-3 (R 1=3-p-methoxy-phenyl, R 2=p-toluenesulfonyl, R 3=hydrogen) the organic bases DABCO (67mg, 0.60mmol) of (103mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III (145mg of 1.5 equivalents subsequently, 0.45mmol), reaction mixture continues at room temperature reaction until TLC detection reaction is complete, directly obtain formula I-3 target product 61mg with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 59%.
1H?NMR(600MHz,CDCl3)(600MHz,CDCl3)δ(ppm)δ＝7.83(d,J＝8.1Hz,2H),7.32(t,J＝3.8Hz,2H),7.30(s,2H),7.19(d,J＝7.6Hz,1H),6.98(d,J＝8.2Hz,1H),3.94–3.90(m,1H),3.87(s,3H),3.20(dd,J＝16.9Hz,10.6Hz,1H),2.79(dd,J＝16.9Hz,9.8Hz,1H),2.42(s,3H),1.67(d,J＝6.2Hz,3H).
13C?NMR(100MHz,CDCl3)δ(ppm)δ＝159.46,157.18,144.03,132.10,131.93,129.45,129.34,128.45,119.36,116.36,111.47,58.14,55.28,41.47,21.72,21.45.
IR(in?KBr):2927,1432,1358,1168,1014,597cm-1.
High resolution: calculated value: [M+Na]+: 367.1087, measured value: 367.1093.
Embodiment 4
Compound I-4
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-4 (R 1=4-chloro-phenyl-, R 2=p-toluenesulfonyl, R 3=hydrogen) the organic bases DABCO (67mg, 0.60mmol) of (105mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III (145mg of 1.5 equivalents subsequently, 0.45mmol), reaction mixture continues at room temperature reaction until TLC detection reaction is complete, directly obtain formula I-4 target product 57mg with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 54%.
1H?NMR(600MHz,CDCl3)δ(ppm)δ＝7.83(d,J＝8.0Hz,2H),7.62(d,J＝8.2Hz,2H),7.38(d,J＝8.2Hz,2H),7.32(d,J＝7.9Hz,2H),3.96–3.93(m,1H),3.20(dd,J＝16.8Hz,10.6Hz,1H),2.79(dd,J＝16.8Hz,9.9Hz,1H),2.43(s,3H),1.68(d,J＝6.1Hz,3H).
13C?NMR(100MHz,CDCl3)δ(ppm)δ＝156.13,144.14,136.28,131.97,129.39,129.31,128.71,128.43,127.93,58.32,41.27,21.66,21.46.
M.P.:163.7–164.5℃.
IR(in?KBr):2933,1601,1356,1167,1033,592cm-1.
High resolution: calculated value: [M+H]+: 349.0772, measured value: 349.0775.
Embodiment 5
Compound I-5
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-5 (R 1=2-chloro-phenyl-, R 2=p-toluenesulfonyl, R 3=hydrogen) the organic bases DABCO (67mg, 0.60mmol) of (105mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III (145mg of 1.5 equivalents subsequently, 0.45mmol), reaction mixture continues at room temperature reaction until TLC detection reaction is complete, directly obtain formula I-5 target product 63mg with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 60%.
1H?NMR(600MHz,CDCl3)δ＝7.80(d,J＝8.2Hz,2H),7.63(s,1H),7.52(d,J＝7.8Hz,1H),7.37(d,J＝8.7Hz,1H),7.32–7.29(m,3H),3.95–3.90(m,1H),3.17(dd,J＝16.9Hz,10.7Hz,1H),2.75(dd,J＝16.9Hz,9.8Hz,1H),2.40(s,3H),1.64(d,J＝6.2Hz,3H).
13C?NMR(100MHz,CDCl3)δ(ppm)δ＝155.88,144.21,134.54,132.60,132.03,130.25,129.79,129.45,128.44,126.59,124.82,58.33,41.27,21.69,21.50.
M.P.:135.1–136.2℃
IR(in?KBr):2978,1595,1353,1164,1009,593cm-1.
High resolution: calculated value: [M+Na]+: 349.0772, measured value: 349.0780.
Embodiment 6
Compound I-6
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-6 (R 1=2,4 dichloro benzene base, R 2=p-toluenesulfonyl, R 3=hydrogen) the organic bases DABCO (67mg, 0.60mmol) of (115mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III (145mg of 1.5 equivalents subsequently, 0.45mmol), reaction mixture continues at room temperature reaction until TLC detection reaction is complete, directly obtain formula I-6 target product 63mg with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 55%.
1H?NMR(600MHz,CDCl3)δ(ppm)δ＝7.85(d,J＝8.1Hz,2H),7.62(d,J＝8.4Hz,1H),7.41(s,1H),7.36(d,J＝8.0Hz,2H),7.30(s,1H),3.97–3.93(m,1H),3.34(dd,J＝16.9Hz,10.4Hz,1H),3.02(dd,J＝17.3Hz,9.8Hz,1H),2.47(s,3H),1.68(d,J＝6.1Hz,3H).
13C?NMR(100MHz,CDCl3)(ppm)δ＝150.99,139.20,131.15,128.22,126.99,126.09,125.14,124.32,123.74,123.47,122.12,53.87,39.20,16.43,16.14.
M.P.:175.1–176.4℃
IR(in?KBr):2970,1588,1355,1167,1006,595cm-1.
High resolution: calculated value: [M+H]+: 383.0382, measured value: 383.0393.
Embodiment 7
Compound I-7
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-7 (R 1=3-bromophenyl, R 2=p-toluenesulfonyl, R 3=hydrogen) the organic bases DABCO (67mg, 0.60mmol) of (118mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III (145mg of 1.5 equivalents subsequently, 0.45mmol), reaction mixture continues at room temperature reaction until TLC detection reaction is complete, directly obtain formula I-7 target product 64mg with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 54%.
1H?NMR(400MHz,CDCl3)δ(ppm)δ＝7.83(s,1H),7.81(s,2H),7.59(d,J＝7.8Hz,1H),7.54(d,J＝8.9Hz,1H),7.32(d,J＝8.1Hz,2H),7.28(d,J＝8.1Hz,1H),4.00–3.90(m,1H),3.19(dd,J＝16.9Hz,10.6Hz,1H),2.77(dd,J＝16.9Hz,9.8Hz,1H),2.42(s,3H),1.66(d,J＝6.2Hz,3H).
13C?NMR(100MHz,CDCl3)δ(ppm)δ＝155.69,144.16,133.13,132.80,131.95,129.99,129.48,129.42,128.41,125.20,122.60,58.28,41.21,21.67,21.47.
IR(in?KBr):2925,1593,1358,1168,1014,595cm-1.
High resolution: calculated value: [M+Na]+: 415.0086, measured value: 415.0084.
Embodiment 8
Compound I-8
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-8 (R 1=4-bromophenyl, R 2=p-toluenesulfonyl, R 3=hydrogen) the organic bases DABCO (67mg, 0.60mmol) of (118mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III (145mg of 1.5 equivalents subsequently, 0.45mmol), reaction mixture continues at room temperature reaction until TLC detection reaction is complete, directly obtain formula I-8 target product 68mg with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 58%.
1H?NMR(600MHz,CDCl3)δ(ppm)δ＝7.79(d,J＝8.1Hz,2H),7.51(s,4H),7.28(d,J＝8.0Hz,2H),3.93–3.89(m,1H),3.16(dd,J＝16.8Hz,10.6Hz,1H),2.75(dd,J＝?16.9Hz,9.9Hz,1H),2.39(s,3H),1.64(d,J＝6.2Hz,3H).
13C?NMR(100MHz,CDCl3)δ(ppm)δ＝156.18,144.16,131.98,131.69,129.75,129.40,128.45,128.13,124.72,58.33,41.23,21.68,21.49.
M.P.:178.3–179.0℃
IR(in?KBr):2979,1655,1353,1164,1007,594cm-1.
High resolution: calculated value: [M+Na]+: 415.0086, measured value: 415.0087.
Embodiment 9
Compound I-9
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-9 (R 1=4-fluorophenyl, R 2=p-toluenesulfonyl, R 3=hydrogen) the organic bases DABCO (67mg, 0.60mmol) of (100mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III (145mg of 1.5 equivalents subsequently, 0.45mmol), reaction mixture continues at room temperature reaction until TLC detection reaction is complete, directly obtain formula I-9 target product 56mg with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 56%.
1H?NMR(600MHz,CDCl3)δ(ppm)δ＝7.83(d,J＝8.0Hz,2H),7.68–7.66(m,2H),7.32(d,J＝8.0Hz,2H),7.09(t,J＝8.5Hz,2H),3.96–3.91(m,1H),3.20(dd,J＝16.8Hz,10.6Hz,1H),2.79(dd,J＝16.8Hz,9.9Hz,1H),2.42(s,3H),1.67(d,J＝6.2Hz,3H).
13C?NMR(100MHz,CDCl3)δ(ppm)δ＝165.12,162.62,156.24,144.11,131.98,129.38,128.76,128.68,128.47,127.13,115.71,115.49,58.23,41.45,21.67,21.46.
M.P.:142.1–142.9℃
IR(in?KBr):2975,1599,1358,1169,1010,593cm-1.
High resolution: calculated value: [M+Na]+: 355.0887, measured value: 355.0890.
Embodiment 10
Compound I-10
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-10 (R 1=3-fluorophenyl, R 2=p-toluenesulfonyl, R 3=hydrogen) the organic bases DABCO (67mg, 0.60mmol) of (100mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III (145mg of 1.5 equivalents subsequently, 0.45mmol), reaction mixture continues at room temperature reaction until TLC detection reaction is complete, directly obtain formula I-10 target product 54mg with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 54%.
1H?NMR(600MHz,CDCl3)δ(ppm)δ＝7.80(d,J＝8.0Hz,2H),7.39–7.37(m,2H),7.36–7.32(m,1H),7.29(d,J＝8.0Hz,2H),7.09(t,J＝7.9Hz,1H),3.95–3.91(m,1H),3.17(dd,J＝16.9Hz,10.6Hz,1H),2.76(dd,J＝16.9Hz,9.9Hz,1H),2.39(s,3H),1.64(d,J＝6.2Hz,3H).
13C?NMR(100MHz,CDCl3)δ(ppm)δ＝163.85,161.40,156.06,144.22,133.09,133.01,132.12,130.19,130.11,129.46,128.50,122.55,117.41,117.19,113.51,113.27,58.40,41.37,21.71,21.52.
IR(in?KBr):2976,1595,1358,1167,1015,586cm-1.
High resolution: calculated value: [M+H]+: 333.1068, measured value: 333.1072.
Embodiment 11
Compound I-11
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-11 (R 1=4-trifluoromethyl, R 2=p-toluenesulfonyl, R 3=hydrogen) the organic bases DABCO (67mg, 0.60mmol) of (115mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III (145mg of 1.5 equivalents subsequently, 0.45mmol), reaction mixture continues at room temperature reaction until TLC detection reaction is complete, directly obtain formula I-11 target product 64mg with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 56%.
1H?NMR(400MHz,CDCl3)δ(ppm)δ＝7.77(d,J＝8.1Hz,2H),7.72(d,J＝8.2Hz,2H),7.59(d,J＝8.3Hz,2H),7.26(d,J＝8.1Hz,2H),3.98–3.88(m,1H),3.18(dd,J＝?16.9Hz,10.7Hz,1H),2.75(dd,J＝16.9Hz,9.9Hz,1H),2.36(s,3H),1.62(d,J＝6.2Hz,3H).
13C?NMR(100MHz,CDCl3)δ(ppm)δ＝155.71,144.32,134.25,132.31,132.15,131.98,131.66,131.31,129.50,128.48,126.97,125.45,125.06,122.36,58.58,41.26,21.69,21.50.
M.P.:151.1–152.1℃
IR(in?KBr):2978,1595,1357,1168,1009,593cm-1.
High resolution: calculated value: [M+H]+: 383.1036, measured value: 383.1033.
Embodiment 12
Compound I-12
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-12 (R 1=cyclohexyl, R 2=p-toluenesulfonyl, R 3=hydrogen) the organic bases DABCO (67mg, 0.60mmol) of (96mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III (145mg of 1.5 equivalents subsequently, 0.45mmol), reaction mixture continues at room temperature reaction until TLC detection reaction is complete, directly obtain formula I-12 target product 52mg with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 53%.
1H?NMR(600MHz,CDCl3)δ(ppm)δ＝7.72(d,J＝8.0Hz,2H),7.27(d,J＝7.9Hz,2H),3.62–3.61(m,1H),2.63(dd,J＝17.6Hz,10.3Hz,1H),2.40(s,3H),2.30(dd,J＝16.9Hz,9.8Hz,1H),2.23(s,1H),1.69–1.68(m,3H),1.64(s,2H),1.49(d,J＝6.2Hz,3H),1.22–1.14(m,5H).
13C?NMR(100MHz,CDCl3)δ(ppm)δ＝166.52,143.75,131.60,129.04,128.61,57.09,41.84,39.08,30.13,29.74,25.63,25.50,25.42,21.61,21.46.
IR(in?KBr):2929,1597,1356,1167,987,595cm-1.
High resolution: calculated value: [M+Na]+: 343.1451, measured value: 343.1449.
Embodiment 13
Compound I-13
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-13 (R 1=sec.-propyl, R 2=p-toluenesulfonyl, R 3=hydrogen) the organic bases DABCO (67mg, 0.60mmol) of (84mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III (145mg of 1.5 equivalents subsequently, 0.45mmol), reaction mixture continues at room temperature reaction until TLC detection reaction is complete, directly obtain formula I-13 target product 54mg with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 64%.
1H?NMR(400MHz,CDCl3)δ(ppm)δ＝7.76(d,J＝8.2Hz,2H),7.31(d,J＝8.1Hz,2H),3.73–3.63(m,1H),2.68(dd,J＝17.2Hz,10.3Hz,1H),2.61–2.55(m,1H),2.44(s,3H),2.36(dd,J＝17.2Hz,9.6Hz,1H),1.53(d,J＝6.2Hz,3H),1.05(t,J＝7.2Hz,6H).
13C?NMR(100MHz,CDCl3)δ(ppm)δ＝167.36,143.86,131.78,129.13,128.77,57.45,41.55,29.77,21.74,21.56,19.97,19.64.
IR(in?KBr):2969,1493,1354,1167,1088,594cm-1.
High resolution: calculated value: [M+Na]+: 281.1318, measured value: 281.1318.
Embodiment 14
Compound I-14
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-14 (R 1=the tertiary butyl, R 2=p-toluenesulfonyl, R 3=hydrogen) the organic bases DABCO (67mg, 0.60mmol) of (88mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III (145mg of 1.5 equivalents subsequently, 0.45mmol), reaction mixture continues at room temperature reaction until TLC detection reaction is complete, directly obtain formula I-14 target product 67mg with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 76%.
1H?NMR(400MHz,CDCl3)δ(ppm)δ＝7.74(d,J＝8.2Hz,2H),7.29(d,J＝8.1Hz,2H),3.68–3.61(m,1H),2.70(dd,J＝17.1Hz,10.2Hz,1H),2.42(s,3H),2.34(dd,J＝17.1Hz,9.7Hz,1H),1.51(d,J＝6.2Hz,3H),1.06(s,9H).
13C?NMR(100MHz,CDCl3)δ(ppm)δ＝169.79,143.78,131.40,128.92,128.65,57.84,?40.43,33.99,27.67,21.59,21.42.IR(in?KBr):2931,1598,1355,1170,1089,595cm-1.
IR(in?KBr):2931,1598,1355,1170,1089,595cm-1.
High resolution: calculated value: [M+Na]+: 317.1294, measured value: 317.1300.
Embodiment 15
Compound I-15
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-15 (R 1=phenylethyl, R 2=p-toluenesulfonyl, R 3=hydrogen) the organic bases DABCO (67mg, 0.60mmol) of (103mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III (145mg of 1.5 equivalents subsequently, 0.45mmol), reaction mixture continues at room temperature reaction until TLC detection reaction is complete, directly obtain formula I-15 target product 33mg with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 32%.
1H?NMR(600MHz,CDCl3)δ＝7.75(d,J＝8.1Hz,2H),7.30(d,J＝8.1Hz,2H),7.25(t,J＝7.3Hz,2H),7.20(t,J＝7.1Hz,1H),7.06(d,J＝7.2Hz,2H),3.70–3.65(m,1H),2.88–2.83(m,1H),2.79–2.76(m,1H),2.59–2.51(m,3H),2.45(s,3H),2.30(dd,J＝17.5Hz,9.6Hz,1H),1.51(d,J＝6.2Hz,3H).
13C?NMR(100MHz,CDCl3)δ＝162.07,143.90,140.25,131.72,129.25,128.57,128.36,128.03,126.13,57.33,44.23,32.48,31.57,21.57,21.50.
IR(in?KBr):2929,1598,1349,1165,1089,594cm-1.
High resolution: calculated value: [M+H]+: 365.1294, measured value: 365.1301.
Embodiment 16
Compound I-16
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-16 (R 1=1-methyl-benzyl, R 2=p-toluenesulfonyl, R 3=hydrogen) the organic bases DABCO (67mg, 0.60mmol) of (103mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III (145mg of 1.5 equivalents subsequently, 0.45mmol), reaction mixture continues at room temperature reaction until TLC detection reaction is complete, formula I-16 target product 63mg is directly obtained with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 61%, dr=1:1 (dr is diastereomer ratio).
1H?NMR(600MHz,CDCl3)δ＝7.85(d,J＝8.2Hz,2H),7.82(d,J＝8.1Hz,2H),7.40(d,J＝7.9Hz,2H),7.35(d,J＝8.1Hz,2H),7.28–7.24(m,3H),7.22–7.17(m,3H),7.08(d,J＝6.7Hz,2H),6.82(d,J＝6.9Hz,2H),3.77–3.74(m,1H),3.70–3.63(m,3H),2.53(s,3H),2.52–2.45(m,5H),2.27–2.18(m,2H),1.53–1.49(m,9H),1.46(d,J＝7.0Hz,3H).
13C?NMR(100MHz,CDCl3)δ＝165.24,165.15,143.96,143.93,141.52,140.85,131.55,131.50,129.24,129.23,128.85,128.72,128.53,127.02,126.98,126.90,126.88,58.10,57.90,42.42,41.66,41.14,40.70,21.74,21.58,21.53,21.52,18.95,17.80.
M.P.:126.8–127.6℃
IR(in?KBr):2975,1596,1354,1167,1089,592cm-1.
High resolution: calculated value: [M+Na]+: 365.1294, measured value: 365.1304.
Embodiment 17
Compound I-17
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-17 (R 1=phenyl, R 2=p-toluenesulfonyl, R 3=methyl) the organic bases DABCO (67mg, 0.60mmol) of (103mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III (145mg of 1.5 equivalents subsequently, 0.45mmol), reaction mixture continues at room temperature reaction until TLC detection reaction is complete, directly obtain formula I-17 target product 40mg with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 39%.
1H?NMR(400MHz,CDCl3)δ＝7.84(d,J＝8.2Hz,2H),7.65(dd,J＝7.8Hz,1.6Hz,2H),7.39(t,J＝6.4Hz,3H),7.34(d,J＝8.1Hz,2H),3.09(m,1H),2.44(s,3H),1.53(d,J＝6.5Hz,3H),1.25(s,3H),1.12(s,3H).
13C?NMR(100MHz,CDCl3)δ＝164.31,144.15,131.26,130.77,129.78,129.29,128.79,128.33,127.36,68.46,50.75,24.23,21.54,19.15,13.19.
High resolution: calculated value: [M+H]+: 343.1475, measured value: 343.1477.
Embodiment 18
Compound I-18
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-18 (R 1=phenyl, R 2=tribromo-acetyl base, R 3=methyl) the organic bases DABCO (67mg, 0.60mmol) of (100mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III (145mg of 1.5 equivalents subsequently, 0.45mmol), reaction mixture continues at room temperature reaction until TLC detection reaction is complete, directly obtain formula I-18 target product 29mg with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 29%.
1H?NMR(600MHz,CDCl3)δ＝7.81(d,J＝6.9Hz,2H),7.49–7.42(m,3H),4.31(q,J＝6.6Hz,1H),1.46(s,3H),1.42(s,3H),1.33(d,J＝6.7Hz,3H).
13C?NMR(100MHz,CDCl3)δ＝163.12,157.80,130.66,130.28,128.65,127.85,92.78,67.53,49.27,27.30,19.37,12.92.
High resolution: calculated value: [M+H]+: 333.0324, measured value: 333.0323.
Embodiment 19
Compound I-19
preparation
At room temperature, raw material beta, gamma-unsaturated hydrazone II-19 (R 1=phenyl, R 2=methylsulfonyl, R 3=methyl) the organic bases DABCO (67mg, 0.60mmol) of (80mg, 0.30mmol) and 2.0 equivalents is dissolved in tetrahydrofuran (THF), stirs 5 minutes under nitrogen protection.Add the oxygenant iodobenzene diacetate III (145mg of 1.5 equivalents subsequently, 0.45mmol), reaction mixture continues at room temperature reaction until TLC detection reaction is complete, directly obtain formula I-19 target product 26mg with V sherwood oil/V ethyl acetate=20:1-10:1 column chromatography, productive rate is 32%.
1H?NMR(400MHz,CDCl3)δ＝7.75–7.70(m,2H),7.43–7.39(m,3H),3.70–3.66(m,1H),3.10(s,3H),1.48(d,J＝6.5Hz,3H),1.39(s,3H),1.24(s,3H).
13C?NMR(100MHz,CDCl3)δ＝164.66,130.60,129.98,128.44,127.52,67.57,51.38,35.95,24.30,19.10,13.27.
High resolution: calculated value: [M+H]+: 267.1162, measured value: 267.1166.
Pharmacological Activity Screening is tested
4,5-pyrazoline analog derivative common manifestation goes out certain anti-microbial activity, and we have carried out following anti-microbial activity test to synthesized compound.
(1) target is tested
Fusarium graminearum (Gibberella zeae), the mould germ of rice banded sclerotial blight (Thanatephorus cucumeris), botrytis cinerea (Botrytis cinereapers).
(2) test material
Electronic balance, pocket knife, 50mL beaker, electric furnace, transfer pipet (10mL), dropper, rubber suction bulb, culture dish (diameter 9cm), circular filter paper, sterilization tank, thermostat container, spirit lamp, graduated scale, distilled water, water 1000g, tween-80, DMF, potato 200g, agar 15g, glucose 15g, testing sample.
(3) testing method
In vitro plate assay method: by 200g peeling potatoes, chopping, then boils, cold filtration in 700mL distilled water, and gained filtrate mixes with agar, glucose, then adds water to 900mL, reheats to boiling, namely obtains substratum after cooling.By substratum, distilled water and culture dish together high-temperature sterilization.With electronic balance weighing about 3mg testing sample, add a small amount of DMF and dissolve, drip 1 tween-80, adding distil water is mixed with 1000ppm.
Substratum high-temperature pressure-reduction sterilizing 15 minutes, after sterilizing, the substratum after 10mL sterilizing is measured while hot with transfer pipet, by itself and 1mL, concentration is the 10mL sample mixing that 1000ppm solution distilled water diluting 10 doubly obtains, can obtain the sample that concentration is 100ppm, build culture dish lid, horizontal positioned cools.
Get blank agar block with the punch tool that diameter is 5mm, choose in culture dish with pincet, mycelia faces down, and 2 ~ 3 kinds of bacterium placed by each culture dish.Before getting bacterium, punch tool and the calcination of pincet palpus spirit lamp are sterilized.Same aforesaid method, does not add testing sample, and each bacterial classification does primary blank contrast.Then 48 ~ 72h " Invest, Then Investigate " in sterile constant-temperature case is placed in.Measure the diameter of bacterial plaque, according to blank photograph, suppress to represent drug effect with diameter.
Inhibiting rate %=[(CK-process)/CK] × 100%
(4) test result
Compound I-1, I-3, I-5, I-7 shows good activity to wheat scab, and the preventive effect that in vitro ware is surveyed is respectively: 41%, 41%, 40%, 30%.Compound I-4, I-8 shows good activity to rice banded sclerotial blight mildew, and the preventive effect that in vitro ware is surveyed is respectively: 59%, 42%.Compound I-10, I-11 shows good activity to rice banded sclerotial blight mildew: 32%, and 25%.
(5) measuring unit
Shanghai organic chemistry institute of the Chinese Academy of Sciences.
In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment or example.And the specific features of description, structure, material or feature can combine in one or more embodiment in office or example in an appropriate manner.In addition, when not conflicting, the feature of the different embodiment described in this specification sheets or example and different embodiment or example can carry out combining and combining by those skilled in the art.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, and those of ordinary skill in the art can change above-described embodiment within the scope of the invention, revises, replace and modification.

Claims (10)

1. a compound, is characterized in that, the enantiomer that described compound is compound shown in compound shown in formula I or formula I, diastereomer, racemic modification, pharmacy acceptable salt, crystalline hydrate or solvate,
Wherein,
R 1for the phenyl optionally replaced, the optional benzyl replaced or the alkyl optionally replaced;
R 2for tosyl group, tribromo-acetyl base, methylsulfonyl;
R 3and R 4be separately H or the optional alkyl replaced.
2. compound according to claim 1, is characterized in that, R 1for phenyl, 4-aminomethyl phenyl, 3-p-methoxy-phenyl, 4-chloro-phenyl-, 2-chloro-phenyl-, 2,4 dichloro benzene base, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 3-fluorophenyl, 4-trifluoromethyl or 1-methyl-benzyl.
3. compound according to claim 1, is characterized in that, R 1, R 3and R 4it is separately the alkyl containing 1 ~ 10 carbon atom.
4. compound according to claim 1, it is characterized in that, described compound is the enantiomer of one of following compounds or described following compounds, diastereomer, racemic modification, pharmacy acceptable salt, crystalline hydrate or solvate:
5. prepare a method for compound described in any one of Claims 1 to 4, it is characterized in that, comprising:
Compound shown in formula II is contacted with iodobenzene diacetate, to obtain compound shown in formula I,
Wherein R 1, R 2, R 3, R 4as in any one of Claims 1 to 4 define.
6. method according to claim 5, is characterized in that, described contact is by compound shown in described formula II and Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane being dissolved in tetrahydrofuran (THF), and stirs under nitrogen protection and carry out for 5 minutes.
7. method according to claim 5, is characterized in that, the mol ratio of compound shown in described formula II and described Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane is 1:2, and
The mol ratio of compound and iodobenzene diacetate shown in described formula II is 1:1.5.
8. method according to claim 5, is characterized in that, comprises further:
Silica gel column chromatography is purified, and is separated compound shown in described formula I, and wherein, described column chromatography adopts the mixture of sherwood oil and ethyl acetate as being separated phase, and the volume ratio of sherwood oil and ethyl acetate is 10:1 ~ 20:1.
9. an agricultural chemicals, is characterized in that, comprises the compound defined in any one of Claims 1 to 4.
10. a method for treatment or prevention plant disease, is characterized in that, for described plant applies the compound described in any one of Claims 1 to 4, or agricultural chemicals according to claim 9,
Optionally, described plant disease one of is at least caused by following:
Gibberella?zeae，Thanatephorus?cucumeris，Botrytis?cinereapers，
Optionally, described plant is at least one in wheat, paddy rice and cucumber.
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CN110627692B (en) * 2019-10-14 2021-09-24 河南科技大学 Paeonol benzenesulfonylhydrazone and derivative thereof, preparation method of paeonol benzenesulfonylhydrazone and derivative thereof, botanical insecticide and application of botanical insecticide

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