CN105037346B - Pyrazoles bisamide class compound and its synthetic method and application of the one kind containing 1,2,3 thiadiazoles - Google Patents
Pyrazoles bisamide class compound and its synthetic method and application of the one kind containing 1,2,3 thiadiazoles Download PDFInfo
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
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Abstract
The invention discloses belong to pyrazoles bisamide class compound and its synthetic method and application, the compound of the one kind of technical field of organic synthesis containing 1,2,3 thiadiazoles to have the structure described in formula I.When preparing the compound, 4 amino-pyrazol intermediates and 1 are synthesized first, 2,3 thiadiazole formoxyl chloromethylated intermediates, then according to the condensation reaction condition of routine, both are condensed, you can synthesis compound of Formula I.Such compound is respectively provided with excellent mosquito-larvicidal activity and certain mythimna separate, and part of compounds has activity of resisting tobacco mosaic virus and bactericidal activity；Such compound structure is novel, modification transformation leeway is big, preparation method is rationally easy, can be furtherd investigate as pesticide activity guide, and can be applied as mosquitocide, has potential production application value.
Description
Technical field
The invention belongs to technical field of organic synthesis, more particularly to a kind of pyrazoles bisamide class for containing 1,2,3- thiadiazoles
Compound and its synthetic method and application.
Background technology
Fungal disease is that disease the most serious is endangered in plant disease, jeopardizes grain, water fruits and vegetables and horticultural production,
Harm is serious.Ring rot of apple is also known as the rotten disease of scurf, black rot, water, decayed fruit disease, wheel line brown rot or excipuliform scurf, sternly
Endanger again, in northern China orchard, large area occurs.Shandong, Henan, Beijing harm are most heavy.The disease increases with the age of tree, morbidity
Seriously, the age of tree in the fruit tree incidence of disease of 11~17 years 78.7%, disease index 53.8；And often with dry rot, anthracnose etc.
Mixing occur, be Fruits production significant threat, have in recent years sprawling exacerbation trend, current means of prevention using chemical prevention as
It is main.
Insect pest is the significant threat in agricultural production, and the generation of all kinds of insect pests can all cause huge economic loss every year.
The research field of insecticide is to seek safe efficient, environment-friendly green pesticide as target at present, representational saddlebag
Include ryanodine receptor class inhibitor and the research and development of anabasine insecticide to non-target beneficial insect safety etc..Health evil
Worm is the intermediate host of many great communicable diseases, human health is threatened greatly, and have a strong impact on quality of life and product
Matter.For a long time, hygienic insecticide is to borrow agricultural insecticide mostly, although can be control effectively to insect pest, sometimes
Important environmental hazard can be caused.The method and successful experience of reference for modern Pesticide Science research, study and find that new health is killed
Worm agent, it is an effective solution route, there is certain theory significance and actual application value.
Pyrazole compound has critical role in pesticide research field, is the heterocycle knot that pesticides discovery field is widely paid close attention to
Structure.Some contain the commercialization of pyrazoles agricultural chemicals, such as：Complex III inhibitor pyrazoles Fluoxastrobin, ryanodine receptor inhibitor
Chlorantraniliprole and cyanogen insect amide, Complex II inhibitor Tolfenpyrad and tebufenpyrad, pyrazole-4-carboxamide succinic acid dehydrogenase
Inhibitor etc..In field of medicaments, pyrazole compound also can be used for antiviral, antitumor etc. research.
L, 2,3- thiadiazole compounds have extensive bioactivity, and the current research about such compound, which concentrates on, plants
Thing induction of resistance, sterilization and weeding etc..The 1,2,3- thiadiazoles derivatives of commercialization have activating plants agent-Acibenzolar
(acibenzolar, BTH, benzo [l, 2,3]-thiadiazoles -7- thiocarboxylic acids methyl esters), rice field bactericide-tiadinil
(chloro- 4, the 4'- dimethyl -1,2 of tiadinil, TDL, 3'-, 3- thiadiazoles -5- formailides), and the plant found recently swash
Agent first thiophene living lures amine.But the research in terms of desinsection is few.
In pesticide screening test principle, the normal interval of pesticide molecule hydrophobic constant (logP, ester water partition coefficient) for [0,
5], but at present multiple N atoms and two amido link structures are contained in double heterocyclic skeletons of bis-heterocyclic compounds, therefore lipophilic is weak,
Hydrophily is strong.If making compound that there is normal hydrophobic constant, close ester group should be introduced in the structure.Double jeterocyclic chemistries in the application
Compound, long alkyl chain is introduced in its structure to adjust the hydrophobic constant of compound (logP), so as to reach improve its physicochemical property,
Increase its active purpose.
The content of the invention
In view of the shortcomings of the prior art, the invention provides a kind of pyrazoles bisamide class compound for containing 1,2,3- thiadiazoles,
The also synthetic method including such compound and application.
One kind contains the pyrazoles bisamide class compound of 1,2,3- thiadiazoles, and the compound has the structure as described in formula I：
Wherein, R1For C1~C4Alkyl or cycloalkyl；R2For H or C1~C4Alkyl；R3For C1~C12Alkyl, phenyl ring, substitution
Phenyl ring, heterocycle or substituted heterocycle；R4For C1~C4Alkyl or cycloalkyl；
Wherein described heterocycle is selected from the pyridine containing N, S or O atom, piperidines, pyrazoles, pyrazolidine, thiazole, furans or tetrahydrochysene
Furans.
Preferably, in formula I, R1For H, methyl or ethyl；R2For H or methyl；R3For methyl, ethyl, n-propyl, positive fourth
Base, n-pentyl, n-hexyl, n-octyl, positive decyl or dodecyl；R4For methyl.
It is further preferred that generalformulaⅰcompound is：N- (3- ethyls -5- (methylcarbamoyl) -1H- pyrazoles -4- bases) -
4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides, N- (3- ethyls -5- (ethyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl -
1,2,3- thiadiazoles -5- formamides, N- (3- ethyls -5- (n-propyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,
3- thiadiazoles -5- formamides, N- (3- ethyls -5- (normal-butyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiophenes
Diazole -5- formamides, N- (3- ethyls -5- (n-pentyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -
5- formamides, N- (3- ethyls -5- (n-hexyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- first
Acid amides, N- (3- ethyls -5- (n-octyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides,
N- (3- ethyls -5- (positive decyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides, N- (3-
Ethyl -5- (dodecyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides, N- (1-
Methyl -3- ethyls -5- (methylcarbamoyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides, N- (1-
Methyl -3- ethyls -5- (ethyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides, N- (1-
Methyl -3- ethyls -5- (n-propyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides, N-
(1- methyl -3- ethyls -5- (normal-butyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides,
N- (1- methyl -3- ethyls -5- (n-pentyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formyls
Amine, N- (1- methyl -3- ethyls -5- (n-hexyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- first
Acid amides, N- (1- methyl -3- ethyls -5- (n-octyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5-
Formamide, N- (1- methyl -3- ethyls -5- (positive decyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -
5- formamides, N- (1- methyl -3- ethyls -5- (dodecyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3-
Thiadiazoles -5- formamides.
The preparation method of generalformulaⅰcompound, carry out in accordance with the following steps：
(1) the use of the compound of formula II is raw material：
Wherein R1For C1~C4Alkyl or cycloalkyl；R2For H or C1~C4Alkyl；
Make the compound nitration of formula II, obtain general formula III compound：
(2) according to the condensation reaction condition of the acyl chloride reaction in organic synthesis and acyl chlorides and amine, first with thionyl chloride pair
Compound of formula III carries out chloride, is then condensed under acid binding agent effect with amine, obtains general formulae IV compound：
Wherein R3For C1~C12Alkyl, phenyl ring, substituted benzene ring, heterocycle or substituted heterocycle；R4For C1~C4Alkyl or cycloalkanes
Base；
(3) reaction condition reduced according to nitro in organic synthesis, passes through catalytic hydrogenation by nitro in general formulae IV compound
Amino is reduced to, obtains compounds of formula V：
(4) according to the acyl chlorides preparation method in organic synthesis, -1,2,3- thiadiazoles -5- formic acid are substituted to use compound 4-
Thionyl chloride carries out chloride, obtains the compound of formula VI：
Wherein R4For C1~C4Alkyl or cycloalkyl；
(5) according to acyl chlorides in organic synthesis and the condensation condition of amine, compounds of formula V and the compound of formula VI are contracted
Close, obtain compound of Formula I.
In step (3), the temperature of the catalytic hydrogenating reduction is 75 DEG C, pressure 1.0MPa, reaction time 2h.
Application of the compound of Formula I in terms of agricultural pest is prevented and treated.
Compound of Formula I is used to prevent and treat mosquito larvae, mythimna separata, Botryosphaeria berengeriana f. sp and tobacco mosaic virus (TMV).
Beneficial effects of the present invention are：
1st, the present invention provides the pyrazoles bisamide class compound that one kind contains 1,2,3- thiadiazoles, passes through MOE2013 softwares
It is [- 0.55,4.84] to calculate its hydrophobic value section, basic with the normal interval of pesticide molecule hydrophobic constant (logP) [0,5]
Overlap, show that the introducing of long alkyl chain effectively improves the ester water partition coefficient of heterocyclic skeleton this physicochemical property.
2nd, the pyrazoles bisamide class compound for containing 1,2,3- thiadiazoles of the designed synthesis of the present invention is brand-new in structure,
With the excellent active and preferable mythimna separate of mosquitocidal worm, majority of compounds is under 10 μ g/mL concentration, to mosquito larvae
Fatal rate is 100%, and activity of the individual compound under 0.25 μ g/mL concentration still reaches 70%；Majority of compounds is in 600 μ
Under g/mL to the fatal rate of mythimna separata more than 50%, minority reaches 100%.It also has certain bactericidal activity and anti-phytopathy
Cytotoxic activity, under 50 μ g/mL concentration, part of compounds to the inhibitory activity of ring rot of apple between 38~40%, it is individualized
Compound is 62.5% to the inhibitory activity of wheat scab；Under 500 μ g/mL concentration, the resisting tobacco mosaic virus of part of compounds
Activity is suitable with virazole.Biologically active data shows the pyrazoles bisamide class containing 1,2,3- thiadiazoles structures in the application
Compound has definite bioactivity.
3rd, in the present invention, pyrazoles bisamide class compound structure novelty, the modification transformation leeway of 1,2,3- thiadiazoles are contained
Greatly, and synthetic method is rationally easy, the excellent bioactivity of binding compounds, can deeply be ground as agricultural chemicals guide structure
Study carefully, and can be developed and applied as agricultural and hygienic insecticide, there is potential production application value and social benefit.
Embodiment
The present invention provides pyrazoles bisamide class compound and its synthetic method and the application that one kind contains 1,2,3- thiadiazoles,
With reference to specific embodiment, the present invention will be further described, but it should not be taken to be limiting the present invention.
The N- of embodiment 1 (3- ethyls -5- (methylcarbamoyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -
5- formamides
(1) 3- ethyls -4- nitros -1H- pyrazoles -5- formic acid
7.5mL (183.78mmol) fuming nitric aicd is added into 50mL there-necked flasks, oleum is slowly added dropwise under ice bath
8.4mL (170.57mmol), control system temperature is less than 5 DEG C during dropwise addition, and 3- ethyl -1H- pyrazoles -5- formic acid is added portionwise
7.0g (50mmol), 18h is reacted at 60 DEG C, room temperature is cooled to, reaction solution is poured into 100g ice, white precipitate occur, filter,
Dry white solid 6.64g, yield：71.78%, m.p.150~152 DEG C；
(2) N- methyl -3- ethyls -4- nitros -1H- pyrazoles -5- formamides
3- ethyl -4- nitro -1H- pyrazoles -5- formic acid 10g (54mmol), thionyl chloride are added into 100mL there-necked flasks
51mL (702mmol), is heated to reflux 4h, and reaction is finished, and unreacted thionyl chloride is removed under reduced pressure, obtain 3- ethyl -4- nitros -
1H- pyrazoles -5- formyl chlorides, dissolved with 100mL dichloromethane standby；Methylamine hydrochloride 7.3g is added in 250mL there-necked flasks
(108mmol), triethylamine 30mL (216mmol), the 3- ethyl -4- nitro -1H- pyrazoles -5- first of above-mentioned preparation is added dropwise under ice bath
Acyl chlorides, 10 DEG C of temperature control, is added dropwise, normal-temperature reaction 24h.2 × 100mL dichloromethane extracts, and depressurizes precipitation, solid is with methanol weight
Crystallization, dry product 7.82g, yield：73%, m.p.196~198 DEG C；1H NMR (DMSO, ppm):1.21~1.26 (t, J
=7.5Hz, 3H), 2.74,2.76 (d, J=4.7Hz, 3H), 2.89~2.96 (q, J=7.5Hz, 2H), 8.49 (s, 1H),
13.84(s,1H)；MS 196.9[M-H]-；
(3) N- methyl -3- ethyls -4- amino -1H- pyrazoles -5- formamides
0.11g Pd/C are added into autoclave, add N- methyl -3- ethyl -4- nitro -1H- pyrazoles -5- formamides
2.00g (101mmol), 150mL absolute methanols, air in kettle is replaced, is warming up to 75 DEG C, the hydrogenating reduction under 1.0MPa, to pressure
Power no longer changes, and continues to react 2h, depressurizes precipitation, without further purification, is directly used in the next step；
(4) 4- methyl isophthalic acids, 2,3- thiadiazoles -5- formic acid
4- methyl isophthalic acids, 2,3- thiadiazoles -5- methyl formates 28.9g (183mmol), 50mL are added in 250mL there-necked flask
Methanol, add 50mL 16.80g containing sodium hydroxide (420mmol) aqueous solution, be heated to reflux 2.5h, decompression precipitation, residue with
10% watery hydrochloric acid is acidified to pH=2, filters, and dries, obtains khaki solid 16.05g, yield：60.84%, m.p.182~
183℃；
(5) 4- methyl isophthalic acids, 2,3- thiadiazoles -5- formyl chlorides
4- methyl isophthalic acids are added in 25mL single port bottles, 2,3- thiadiazoles -5- formic acid 0.865g (6mmol), add 5mL
(66mmol) thionyl chloride, 6h is heated to reflux, depressurizes precipitation, solid is standby with 25mL dichloromethane dissolving；
(6) N- (3- ethyls -5- (methylcarbamoyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- first
Acid amides
It is in 50mL single port bottles, N- methyl -3- ethyl -4- amino -1H- pyrazoles -5- formamides 0.50g (3mmol) is molten
In 10mL dichloromethane, triethylamine 2.1mL (15mmol) is added, 4- methyl isophthalic acids, 2,3- thiadiazoles -5- formyls are added dropwise under ice bath
The dichloromethane solution of chlorine, is added dropwise, normal-temperature reaction 12h, depressurizes precipitation, crude product column chromatography (VDichloromethane:VMethanol=80:1),
Obtain white solid 0.61g, yield：69.08%, m.p.210~211 DEG C；1H NMR(CH3OH-d4, ppm):1.25~1.30
(t, J=7.6Hz, 3H), 2.71~2.79 (q, J=7.6Hz, 2H), 2.88 (s, 3H), 2.95 (s, 3H)；HRMS Calcd
for[C11H14N6O2S+H]+295.0972,Found 295.0969。
The N- of embodiment 2 (3- ethyls -5- (ethyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -
5- formamides
(1) preparation of 3- ethyls -4- nitros -1H- pyrazoles -5- formic acid is with reference to embodiment 1；
(2) N, 3- diethyl -4- nitro -1H- pyrazoles -5- formamides are prepared with reference to embodiment 1：White solid, yield：
41.01%, m.p.150~152 DEG C.1H NMR(CDCl3,ppm):1.28~1.35 (m, 6H), 2.99~3.07 (q, J=
7.4Hz, 2H), 3.52~3.61 (m, 2H), 9.04 (s, 1H), 12.20 (s, 1H)；MS:210.8[M-H]-；
(3) preparation of N, 3- diethyl -4- amino -1H- pyrazoles -5- formamides is with reference to embodiment 1；
(4) 4- methyl isophthalic acids, the preparation of 2,3- thiadiazoles -5- formyl chlorides is with reference to embodiment 1；
(5) N- (3- ethyls -5- (ethyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- first
The preparation of acid amides is with reference to embodiment 1：White solid, yield:73.78%, m.p.196~197 DEG C；1H NMR(CH3OH-d4,
ppm):1.18~1.23 (t, J=7.2Hz, 3H), 1.24~1.29 (t, J=7.6Hz, 3H), 2.71~2.78 (q, J=
7.6Hz, 2H), 2.94 (s, 3H), 3.39~3.42 (q, J=7.2Hz, 2H)；HRMS Calcd for[C12H16N6O2S+H]+
309.1128,Found 309.2032。
The N- of embodiment 3 (3- ethyls -5- (n-propyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiophenes two
Azoles -5- formamides
(1) preparation of 3- ethyls -4- nitros -1H- pyrazoles -5- formic acid is with reference to embodiment 1；
(2) preparation of 3- ethyls-N- n-propyls -4- nitros -1H- pyrazoles -5- formamides is with reference to embodiment 1:White solid,
Yield:73.00%, m.p.132~134 DEG C；1H NMR(DMSO,ppm)：0.87~0.92 (t, J=7.4Hz, 3H), 1.20~
1.25 (t, J=7.5Hz, 3H), 1.47~1.54 (m, 2H), 2.86~2.94 (q, J=7.5Hz, 2H), 3.19 (m, 2H),
8.50(s,1H)；MS:227.1[M+H]+；
(3) preparation of 3- ethyls-N- n-propyls -4- amino -1H- pyrazoles -5- formamides is with reference to embodiment 1；
(4) 4- methyl isophthalic acids, the preparation of 2,3- thiadiazoles -5- formyl chlorides is with reference to embodiment 1；
(5) N- (3- ethyls -5- (n-propyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5-
The preparation of formamide is with reference to embodiment 1：White solid, yield:93.83%, m.p.186~187 DEG C；1H NMR(CH3OH-d4,
ppm):0.93~0.98 (t, J=7.4Hz, 3H), 1.23~1.28 (t, J=7.6Hz, 3H), 1.54~1.66 (m, 2H),
2.70~2.77 (q, J=7.6Hz, 2H), 2.93 (s, 3H), 3.25~3.30 (m, 2H)；HRMS Calcd for
[C13H18N6O2S+H]+323.1285,Found 323.1282。
The N- of embodiment 4 (3- ethyls -5- (normal-butyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiophenes two
Azoles -5- formamides
(1) preparation of 3- ethyls -4- nitros -1H- pyrazoles -5- formic acid is with reference to embodiment 1；
(2) preparation of 3- ethyls-N- normal-butyls -4- nitros -1H- pyrazoles -5- formamides is with reference to embodiment 1：Khaki is consolidated
Body, yield:49.00%, m.p.160~162 DEG C；1H NMR (DMSO, ppm)：0.88~0.92 (t, J=7.2Hz, 3H),
1.21~1.26 (t, J=7.5Hz, 3H), 1.27~1.32 (m, 2H), 1.47~1.51 (m, 2H), 2.89~2.96 (q, J=
7.5Hz, 2H), 3.17~3.24 (m, 2H), 8.53 (s, 1H)；MS：252.9[M-H]-；
(3) preparation of 3- ethyls-N- normal-butyls -4- amino -1H- pyrazoles -5- formamides is with reference to embodiment 1；
(4) 4- methyl isophthalic acids, the preparation of 2,3- thiadiazoles -5- formyl chlorides is with reference to embodiment 1；
(5) N- (3- ethyls -5- (normal-butyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5-
The preparation of formamide is with reference to embodiment 1：White solid, yield:75.06%, m.p.177~178 DEG C；1H NMR(CH3OH-d6,
ppm)：0.92~0.97 (t, J=7.6Hz, 3H), 1.23~1.28 (t, J=7.6Hz, 3H), 1.33~1.43 (m, 2H),
1.52~1.62 (m, 2H), 2.70~2.77 (q, J=7.6Hz, 2H), 2.93 (s, 3H), 3.27~3.34 (m, 2H)；HRMS
Calcd for[C14H20N6O2S+H]+337.1441,Found 337.1437。
The N- of embodiment 5 (3- ethyls -5- (n-pentyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiophenes two
Azoles -5- formamides
(1) preparation of 3- ethyls -4- nitros -1H- pyrazoles -5- formic acid is with reference to embodiment 1；
(2) preparation of 3- ethyls-N- n-pentyls -4- nitros -1H- pyrazoles -5- formamides is with reference to embodiment 1：Brown solid,
Yield:40.00%, m.p.152~156 DEG C；1H NMR(DMSO,ppm)：0.85~0.90 (t, J=7.5Hz, 3H), 1.20~
1.26 (t, J=7.5Hz, 3H), 1.27~1.32 (m, 4H), 1.45~1.51 (m, 2H), 2.89~2.96 (q, J=7.5Hz,
2H), 3.17~3.24 (q, J=6.5Hz, 2H), 8.52 (s, 1H)；MS 241.1[M+H]+；
(3) preparation of 3- ethyls-N- n-pentyls -4- amino -1H- pyrazoles -5- formamides is with reference to embodiment 1；
(4) 4- methyl isophthalic acids, the preparation of 2,3- thiadiazoles -5- formyl chlorides is with reference to embodiment 1；
(5) N- (3- ethyls -5- (n-pentyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5-
The preparation of formamide is with reference to embodiment 1：White solid, yield:75.62%, m.p：166~167 DEG C；1H NMR(CDCl3,
ppm):0.88~0.92 (t, J=7.2Hz, 3H), 1.26~1.31 (t, J=7.5Hz, 3H), 1.26~1.42 (m, 4H),
1.58~1.62 (m, 2H), 2.98~3.02 (q, J=7.5Hz, 2H), 3.03 (s, 3H), 3.36~3.42 (q, J=7.0Hz,
2H),6.85(s,1H),9.81,9.90(d,1H)；HRMS Calcd for[C15H22N6O2S+H]+351.1598,Found
351.2505。
The N- of embodiment 6 (3- ethyls -5- (n-hexyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiophenes two
Azoles -5- formamides
(1) preparation of 3- ethyls -4- nitros -1H- pyrazoles -5- formic acid is with reference to embodiment 1；
(2) preparation of 3- ethyls-N- n-hexyls -4- nitros -1H- pyrazoles -5- formamides is with reference to embodiment 1：White solid,
Yield：36.00%, m.p.150~152 DEG C；1H NMR(DMSO,ppm):0.85~0.89 (t, J=6.6Hz, 3H), 1.21~
1.26 (t, J=7.5Hz, 3H), 1.26~1.34 (m, 6H), 1.45~1.50 (m, 2H), 2.88~2.96 (q, J=7.5Hz,
2H), 3.17~3.24 (m, 2H), 8.52 (s, 1H)；MS 267.0[M-H]-；
(3) preparation of 3- ethyls-N- n-hexyls -4- amino -1H- pyrazoles -5- formamides is with reference to embodiment 1；
(4) 4- methyl isophthalic acids, the preparation of 2,3- thiadiazoles -5- formyl chlorides is with reference to embodiment 1；
(5) N- (3- ethyls -5- (n-hexyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5-
The preparation of formamide is with reference to embodiment 1：White solid, yield:72.71%, m.p.142~143 DEG C；1H NMR(CDCl3,
ppm):0.86~0.92 (t, J=6.6Hz, 3H), 1.26~1.34 (t, J=7.4Hz, 3H), 1.26~1.45 (m, 6H),
1.56~1.61 (m, 2H), 2.96~3.04 (q, J=7.4Hz, 2H), 3.04 (s, 3H), 3.36~3.42 (q, J=6.0Hz,
2H),6.86(s,1H),9.88(s,1H)；HRMS Calcd for[C16H24N6O2S+H]+365.1754,Found
365.1752。
The N- of embodiment 7 (3- ethyls -5- (n-octyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiophenes two
Azoles -5- formamides
(1) preparation of 3- ethyls -4- nitros -1H- pyrazoles -5- formic acid is with reference to embodiment 1；
(2) preparation of 3- ethyls-N- n-octyls -4- nitros -1H- pyrazoles -5- formamides is with reference to embodiment 1:Color solid, production
Rate:40.00%, m.p.148~150 DEG C；1H NMR(CDCl3,ppm)：0.86~0.90 (t, J=7.0Hz, 3H), 1.27~
1.40 (m, 10H), 1.30~1.38 (t, J=7.5Hz, 3H), 1.61~1.70 (m, 2H), 2.99~3.07 (q, J=7.5Hz,
2H), 3.48~3.56 (m, 2H), 9.03 (s, 1H)；MS 295.0[M-H]-；
(3) preparation of 3- ethyls-N- n-octyls -4- amino -1H- pyrazoles -5- formamides is with reference to embodiment 1；
(4) 4- methyl isophthalic acids, the preparation of 2,3- thiadiazoles -5- formyl chlorides is with reference to embodiment 1；
(5) N- (3- ethyls -5- (n-octyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5-
The preparation of formamide is with reference to embodiment 1：White solid, yield:71.33%, m.p.133~134 DEG C；1H NMR(CDCl3,
ppm):0.84~0.89 (t, J=6.6Hz, 3H), 1.26~1.31 (t, J=7.5Hz, 3H), 1.26~1.45 (m, 10H),
1.57~1.62 (m, 2H), 2.97~3.03 (q, J=7.5Hz, 2H), 3.04 (s, 3H), 3.35~3.42 (q, J=6.6Hz,
2H),6.87(s,1H),9.89(s,1H)；HRMS Calcd for[C18H28N6O2S+H]+393.2067,Found
393.2069。
The N- of embodiment 8 (3- ethyls -5- (positive decyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiophenes two
Azoles -5- formamides
(1) preparation of 3- ethyls -4- nitros -1H- pyrazoles -5- formic acid is with reference to embodiment 1；
(2) preparation of 3- ethyls-N- positive decyls -4- nitros -1H- pyrazoles -5- formamides is with reference to embodiment 1:White solid,
Yield:52.00%, m.p.148~150 DEG C；1H NMR(CDCl3,ppm):0.86~0.90 (t, J=6.4Hz, 3H), 1.22~
1.42 (m, 14H), 1.30~1.35 (t, J=7.5Hz, 3H), 1.60~1.69 (m, 2H), 2.99~3.07 (q, J=7.5Hz,
2H), 3.46~3.53 (q, J=7.0Hz, 2H), 9.01 (s, 1H)；MS 325.1[M+H]+；
(3) preparation of 3- ethyls-N- positive decyls -4- amino -1H- pyrazoles -5- formamides is with reference to embodiment 1；
(4) 4- methyl isophthalic acids, the preparation of 2,3- thiadiazoles -5- formyl chlorides is with reference to embodiment 1；
(5) N- (3- ethyls -5- (positive decyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5-
The preparation of formamide is with reference to embodiment 1:White solid, yield:87.38%, m.p.134~136 DEG C；1H NMR(CDCl3,
ppm):0.85~0.89 (t, J=6.9Hz, 3H), 1.26~1.31 (t, J=7.5Hz, 3H), 1.26~1.40 (m, 14H),
1.50~1.65 (m, 2H), 2.97~3.03 (q, J=7.5Hz, 2H), 3.04 (s, 3H), 3.35~3.42 (q, J=6.9Hz,
2H),6.85(s,1H),9.89(s,1H)；HRMS Calcd for[C20H32N6O2S+H]+421.2380,Found
421.2374。
The N- of embodiment 9 (3- ethyls -5- (dodecyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3-
Thiadiazoles -5- formamides
(1) preparation of 3- ethyls -4- nitros -1H- pyrazoles -5- formic acid is with reference to embodiment 1；
(2) preparation of 3- ethyls-N- dodecyls -4- nitros -1H- pyrazoles -5- formamides is with reference to embodiment 1：White is solid
Body, yield:30.00%, m.p.146~148 DEG C；1H NMR(CDCl3,ppm):0.87~0.92 (t, J=6.9Hz, 3H),
1.28~1.37 (m, 16H), 1.32~1.36 (t, J=7.5Hz, 3H), 1.65~1.70 (m, 4H), 3.00~3.08 (q, J=
7.5Hz, 2H), 3.45~3.55 (q, J=6.9Hz, 2H), 9.05 (s, 1H), 11.77 (s, 1H)；MS 351.2[M-H]-；
(3) preparation of 3- ethyls-N- dodecyls -4- amino -1H- pyrazoles -5- formamides is with reference to embodiment 1；
(4) 4- methyl isophthalic acids, the preparation of 2,3- thiadiazoles -5- formyl chlorides is with reference to embodiment 1；
(5) N- (3- ethyls -5- (dodecyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiophenes two
The preparation of azoles -5- formamides is with reference to embodiment 1：White solid, yield 75.79%, m.p.121~123 DEG C；1H NMR(CDCl3,
ppm):0.86~0.91 (t, J=6.9Hz, 3H), 1.26~1.32 (t, J=7.5Hz, 3H), 1.26~1.40 (m, 18H),
1.55~1.62 (m, 2H), 2.98~3.05 (q, J=7.5Hz, 2H), 3.05 (s, 3H), 3.36~3.43 (m, 2H), 6.88
(s,1H),9.90(s,1H)；HRMS Calcd for[C22H36N6O2S+H]+449.2693,Found 449.2691。
The N- of embodiment 10 (1- methyl -3- ethyls -5- (methylcarbamoyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,
3- thiadiazoles -5- formamides
(1) preparation of 1- methyl -3- ethyls -4- nitros -1H- pyrazoles -5- formic acid is with reference to embodiment 1；
(2) preparation of N, 1- dimethyl -3- ethyl -4- nitro -1H- pyrazoles -5- formamides is with reference to embodiment 1:White is solid
Body, yield:30.00%, m.p.164~166 DEG C；1H NMR(DMSO-d6,ppm):1.18~1.23 (t, J=7.5Hz, 3H),
2.80~2.90 (q, J=7.5Hz, 2H), 2.82 (s, 3H), 3.77 (s, 3H), 8.92,8.94 (d, 1H)；MS 213[M+H]+；
(3) preparation of N, 1- dimethyl -3- ethyl -4- amino -1H- pyrazoles -5- formamides is with reference to embodiment 1；
(4) 4- methyl isophthalic acids, 2,3- thiadiazoles -5- formyl chlorides are with reference to embodiment 1；
(5) N- (1- methyl -3- ethyls -5- (methylcarbamoyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiophenes two
The preparation of azoles -5- formamides is with reference to embodiment 1：White solid, yield:89.72%, m.p.192~193 DEG C；1H NMR
(CH3OH-d4,ppm):1.20~1.25 (t, J=7.6Hz, 3H), 2.57~2.64 (q, J=7.6Hz, 2H), 2.90 (s, 3H),
2.91(s,3H),3.97(s,3H)；HRMS Calcd for[C12H16N6O2S+H]+309.1128,Found 309.2032。
The N- of embodiment 11 (1- methyl -3- ethyls -5- (ethyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,
3- thiadiazoles -5- formamides
(1) preparation of 3- ethyls -1- methyl -4- nitros -1H- pyrazoles -5- formic acid is with reference to embodiment 1；
(2) preparation of 1- methyl-N, 3- diethyl -4- nitro -1H- pyrazoles -5- formamides is with reference to embodiment 1:White is solid
Body, yield:87.78%, m.p.110~112 DEG C；1H NMR(CDCl3,ppm):1.26~1.32 (m, 6H), 2.90~2.97
(q, J=7.5Hz, 2H), 3.49~3.58 (m, 2H), 4.03 (s, 3H), 7.33 (s, 1H)；MS227.1[M+H]+；
(3) preparation of 1- methyl-N, 3- diethyl -4- amino -1H- pyrazoles -5- formamides is with reference to embodiment 1；
(4) 4- methyl isophthalic acids, 2,3- thiadiazoles -5- formyl chlorides are with reference to embodiment 1；
(5) N- (1- methyl -3- ethyls -5- (ethyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiophenes two
The preparation of azoles -5- formamides is with reference to embodiment 1：White solid, yield:70.57%, m.p.187~188 DEG C；1H NMR
(CH3OH-d4, ppm):1.15~1.26 (m, 6H), 2.57~2.64 (q, J=7.6Hz, 2H), 2.92 (s, 3H), 3.30~
3.40 (q, J=7.6Hz, 2H), 3.96 (s, 3H)；HRMS Calcd for[C13H18N6O2S+H]+323.1285,Found
323.1280。
The N- of embodiment 12 (1- methyl -3- ethyls -5- (n-propyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids,
2,3- thiadiazoles -5- formamides
(1) preparation of 1- methyl -3- ethyls -4- nitros -1H- pyrazoles -5- formic acid is with reference to embodiment 1；
(2) preparation of 1- methyl -3- ethyls-N- n-propyls -4- nitros -1H- pyrazoles -5- formamides is with reference to embodiment 1：In vain
Color solid, yield:68.00%, m.p.110~112 DEG C；1H NMR(CDCl3,ppm):1.00~1.05 (t, J=7.4Hz,
3H), 1.26~1.31 (t, J=7.4Hz, 3H), 1.62~1.75 (m, 2H), 2.90~2.98 (q, J=7.5Hz, 2H), 3.42
~3.49 (q, J=6.0Hz, 2H), 4.04 (s, 3H), 7.40 (s, 1H)；MS 263[M+Na]+；
(3) preparation of 1- methyl -3- ethyls-N- n-propyls -4- amino -1H- pyrazoles -5- formamides is with reference to embodiment 1；
(4) 4- methyl isophthalic acids, 2,3- thiadiazoles -5- formyl chlorides are with reference to embodiment 1；
(5) N- (1- methyl -3- ethyls -5- (n-propyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiophenes
The preparation of diazole -5- formamides is with reference to embodiment 1：White solid, yield:75.06%, m.p.182~183 DEG C；1H NMR
(CH3OH-d4,ppm)：0.90~0.95 (t, J=7.5Hz, 3H), 1.21~1.26 (t, J=7.6Hz, 3H), 1.52~1.61
(m, 2H), 2.57~2.65 (q, J=7.6Hz, 2H), 2.92 (s, 3H), 3.96 (s, 3H)；HRMS Calcd for
[C14H20N6O2S+H]+337.1441,Found 337.2346。
The N- of embodiment 13 (1- methyl -3- ethyls -5- (normal-butyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids,
2,3- thiadiazoles -5- formamides
(1) preparation of 1- methyl -3- ethyls -4- nitros -1H- pyrazoles -5- formic acid is with reference to embodiment 1；
(2) preparation of 1- methyl -3- ethyls-N- normal-butyls -4- nitros -1H- pyrazoles -5- formamides is with reference to embodiment 1：In vain
Color solid, yield:63.00%, m.p.98~99 DEG C；1H NMR(CDCl3,ppm):0.96~1.01 (t, J=7.3Hz, 3H),
1.27~1.32 (t, J=7.5Hz, 3H), 1.41~1.51 (m, 2H), 1.62~1.67 (m, 2H), 2.90~2.98 (q, J=
7.5Hz, 2H), 3.46~3.52 (q, J=7.1Hz, 2H), 4.04 (s, 3H), 7.39 (s, 1H)；MS 255.1[M+H]+；
(3) preparation of 1- methyl -3- ethyls-N- normal-butyls -4- amino -1H- pyrazoles -5- formamides is with reference to embodiment 1；
(4) 4- methyl isophthalic acids, the preparation of 2,3- thiadiazoles -5- formyl chlorides is with reference to embodiment 1；
(5) N- (1- methyl -3- ethyls -5- (normal-butyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiophenes
The preparation of diazole -5- formamides is with reference to embodiment 1：White solid, yield:84.66%, m.p.160~162 DEG C；1H NMR
(CDCl3,ppm):0.86~0.90 (t, J=7.2Hz, 3H), 1.20~1.25 (t, J=7.6Hz, 3H), 1.30~1.37 (m,
2H), 1.48~1.55 (m, 2H), 2.53~2.64 (q, J=7.6Hz, 2H), 2.92 (s, 3H), 3.30~3.40 (q, J=
7.2Hz,2H),3.96(s,3H)；HRMS Calcd for[C15H22N6O2S+H]+351.1598,Found 351.1595。
The N- of embodiment 14 (1- methyl -3- ethyls -5- (n-pentyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids,
2,3- thiadiazoles -5- formamides
(1) preparation of 1- methyl -3- ethyls -4- nitros -1H- pyrazoles -5- formic acid is with reference to embodiment 1；
(2) preparation of 1- methyl -3- ethyls-N- n-pentyls -4- nitros -1H- pyrazoles -5- formamides is with reference to embodiment 1：In vain
Color solid, yield:67.00%, m.p.82~84 DEG C；1H NMR(CDCl3,ppm):0.91~0.96 (t, J=7.0Hz, 3H),
1.26~1.32 (t, J=7.5Hz, 3H), 1.37~1.42 (m, 4H), 1.61~1.68 (m, 2H), 2.90~2.98 (q, J=
7.5Hz, 2H), 3.44~3.51 (q, J=7.0Hz, 2H), 4.04 (s, 1H), 7.27 (s, 1H), 7.39 (s, 1H)；MS 267.1
[M-H]-；
(3) preparation of 1- methyl -3- ethyls-N- n-pentyls -4- amino -1H- pyrazoles -5- formamides is with reference to embodiment 1；
(4) 4- methyl isophthalic acids, 2,3- thiadiazoles -5- formyl chlorides are with reference to embodiment 1；
(5) N- (1- methyl -3- ethyls -5- (n-pentyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiophenes
The preparation of diazole -5- formamides is with reference to embodiment 1：White solid, yield:89.63%, m.p.121~123 DEG C；1H NMR
(CDCl3,ppm):0.85~0.90 (t, J=6.9Hz, 3H), 1.15~1.20 (t, J=7.5Hz, 3H), 1.20~1.30 (m,
4H), 1.55~1.75 (m, 2H), 2.46~2.53 (q, J=7.5Hz, 2H), 2.96 (s, 3H), 3.85 (m, 5H)；HRMS
Calcd for[C16H24N6O2S+H]+365.1754,Found 365.1749。
The N- of embodiment 15 (1- methyl -3- ethyls -5- (n-hexyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids,
2,3- thiadiazoles -5- formamides
(1) preparation of 1- methyl -3- ethyls -4- nitros -1H- pyrazoles -5- formic acid is with reference to embodiment 1；
(2) preparation of 1- methyl -3- ethyls-N- n-hexyls -4- nitros -1H- pyrazoles -5- formamides is with reference to embodiment 1：In vain
Color solid, yield:74.00%, m.p.88~89 DEG C；1H NMR(CDCl3,ppm):0.89~0.93 (t, J=6.9Hz, 3H),
1.26~1.31 (t, J=7.5Hz, 3H), 1.27~1.45 (m, 6H), 1.61~1.70 (m, 2H), 2.90~2.98 (q, J=
7.5Hz, 2H), 3.44~3.51 (q, J=6.9Hz, 2H), 4.04 (s, 3H), 7.39 (s, 1H)；MS 281.1[M-H]-；
(3) preparation of 1- methyl -3- ethyls-N- n-hexyls -4- amino -1H- pyrazoles -5- formamides is with reference to embodiment 1；
(4) 4- methyl isophthalic acids, the preparation of 2,3- thiadiazoles -5- formyl chlorides is with reference to embodiment 1；
(5) N- (1- methyl -3- ethyls -5- (n-hexyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiophenes
The preparation of diazole -5- formamides is with reference to embodiment 1：White solid, yield:69.35%, m.p.172~173 DEG C；1H NMR
(CDCl3,ppm):0.82~0.82 (t, J=6.9Hz, 3H), 1.20~1.24 (t, J=7.5Hz, 3H), 1.15~1.30 (m,
6H), 1.42~1.45 (m, 2H), 2.54~2.61 (q, J=7.5Hz, 2H), 3.00 (s, 3H), 3.21~3.31 (m, 2H),
3.89(s,3H),7.20(s,1H),8.04(s,1H)；HRMS Calcd for[C17H26N6O2S+H]+379.1911,
Found379.1907。
The N- of embodiment 16 (1- methyl -3- ethyls -5- (n-octyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids,
2,3- thiadiazoles -5- formamides
(1) preparation of 1- methyl -3- ethyls -4- nitros -1H- pyrazoles -5- formic acid is with reference to embodiment 1；
(2) preparation of 1- methyl -3- ethyls-N- n-octyls -4- nitros -1H- pyrazoles -5- formamides is with reference to embodiment 1:In vain
Color solid, yield:74.00%, m.p.92~94 DEG C；1H NMR(CDCl3,ppm):0.88~0.92 (t, J=6.9Hz, 3H),
1.27~1.32 (t, J=7.5Hz, 3H), 1.27~1.51 (m, 10H), 1.60~1.68 (m, 2H), 2.90~2.98 (q, J=
7.5Hz, 2H), 3.45~3.51 (m, 2H), 4.04 (s, 3H), 7.39 (s, 1H)；MS309.2[M-H]-；
(3) preparation of 4- amino -3- ethyls -1- methyl-N- n-octylcyclams H- pyrazoles -5- formamides is with reference to embodiment 1；
(4) 4- methyl isophthalic acids, the preparation of 2,3- thiadiazoles -5- formyl chlorides is with reference to embodiment 1；
(5) N- (1- methyl -3- ethyls -5- (n-octyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiophenes
The preparation of diazole -5- formamides is with reference to embodiment 1：White solid, yield:92.85%, m.p.134~135 DEG C；1H NMR
(CDCl3,ppm):0.84~0.89 (t, J=6.9Hz, 3H), 1.20~1.25 (t, J=7.5Hz, 3H), 1.15~1.40 (m,
10H), 1.42~1.45 (m, 2H), 2.54~2.61 (q, J=7.5Hz, 2H), 3.00 (s, 3H), 3.25~3.31 (q, 6.9Hz
2H),3.90(s,3H),7.20(s,1H),7.95(s,1H)；HRMS Calcd for[C19H30N6O2S+H]+407.2224,
Found 407.2218。
The N- of embodiment 17 (1- methyl -3- ethyls -5- (positive decyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids,
2,3- thiadiazoles -5- formamides
(1) preparation of 1- methyl -3- ethyls -4- nitros -1H- pyrazoles -5- formic acid is with reference to embodiment 1；
(2) preparation of 1- methyl -3- ethyls-N- positive decyls -4- nitros -1H- pyrazoles -5- formamides is with reference to embodiment 1：In vain
Color solid, yield:79.00%, m.p.86~87 DEG C；1H NMR(CDCl3,ppm):0.87~0.92 (t, J=6.9Hz, 3H),
1.27~1.32 (t, J=7.5Hz, 3H), 1.27~1.51 (m, 10H), 1.61~1.68 (m, 2H), 2.91~2.98 (q, J=
7.5Hz, 2H), 3.45~3.51 (q, J=6.9Hz, 2H), 4.04 (s, 3H), 7.40 (s, 1H)；MS 337.1[M-H]-；
(3) preparation of 1- methyl -3- ethyls -4- amino-N- positive decyls -1H- pyrazoles -5- formamides is with reference to embodiment 1；
(4) 4- methyl isophthalic acids, the preparation of 2,3- thiadiazoles -5- formyl chlorides is with reference to embodiment 1；
(5) N- (1- methyl -3- ethyls -5- (positive decyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiophenes
The preparation of diazole -5- formamides is with reference to embodiment 1：White solid, yield:73.63%, m.p.117~118 DEG C；1HNMR
(CDCl3,ppm):0.86~0.90 (t, J=6.9Hz, 3H), 1.20~1.24 (t, J=7.5Hz, 3H), 1.15~1.36 (m,
14H), 1.43~1.45 (m, 2H), 2.55~2.62 (q, J=7.5Hz, 2H), 3.00 (s, 3H), 3.26~3.32 (q, J=
6.9Hz 2H),3.92(s,3H),7.18(s,1H),7.83(s,1H)；HRMS Calcd for[C21H34N6O2S+H]+
435.2537,Found 435.2532。
The N- of embodiment 18 (1- methyl -3- ethyls -5- (dodecyl carbamyl) -1H- pyrazoles -4- bases) -4- first
Base -1,2,3- thiadiazoles -5- formamides
(1) preparation of 1- methyl -3- ethyls -4- nitros -1H- pyrazoles -5- formic acid is with reference to embodiment 1；
(2) preparation of -1- methyl -3- ethyls-N- dodecyls -4- nitros -1H- pyrazoles -5- formamides is with reference to embodiment
1:White solid, yield:82.00%, m.p.76~79 DEG C；1H NMR(CDCl3,ppm):0.87~0.92 (t, J=6.9Hz,
3H), 1.28~1.32 (t, J=7.5Hz, 3H), 1.27~1.40 (m, 18H), 2.90~2.98 (q, J=7.5Hz, 2H),
3.45~3.51 (q, J=6.9Hz, 2H), 4.04 (s, 3H), 7.39 (s, 1H)；MS 367.3[M+H]+；
(3) preparation of 1- methyl -3- ethyls-N- dodecyls -4- amino -1H- pyrazoles -5- formamides is with reference to embodiment 1；
(4) 4- methyl isophthalic acids, the preparation of 2,3- thiadiazoles -5- formyl chlorides is with reference to embodiment 1；
(5) N- (1- methyl -3- ethyls -5- (dodecyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,
The preparation of 3- thiadiazoles -5- formamides is with reference to embodiment 1：White solid, yield:71.87%, m.p.115~117 DEG C；1H
NMR(CDCl3,ppm):0.87~0.92 (t, J=6.9Hz, 3H), 1.22~1.27 (q, J=7.5Hz, 3H), 1.10~1.45
(m, 18H), 1.45~1.48 (m, 2H), 2.56~2.63 (q, J=7.5Hz, 2H), 3.02 (s, 3H), 3.28~3.34 (q, J
=6.9Hz, 2H), 3.94 (s, 3H), 7.19 (s, 1H), 7.81 (s, 1H)；HRMS Calcd for[C23H38N6O2S+H]+
463.2850,Found 463.2845。
The insecticidal activity of the compound of embodiment 19
Test worm oriental armyworm (Mythimma separata Walker) is the normal population with maize leaves indoor feeding, is adopted
Activity of the compound to mythimna separata is determined with leaf dipping method.Compound is configured to 600 μ g/mL acetone soln, impregnates Maize Seedling
Leaf, it is put into after drying in diameter 7cm culture dishes, 4 instar larvae 10 is accessed, as treatment group；The maize leaves raising of acetone soak
Larva as a control group.The death condition of mythimna separata is observed behind 24 and 48h, the death rate is calculated, the results are shown in Table 1.
Test worm culex pipiens pallens (Culex pipiens pallens) larva is the normal population of indoor feeding,
Activity of the compound to mosquito larvae is determined using immersion method.Compound is first configured to 200 μ g/mL acetone soln, pipetted
Solution 2.5mL is stated, test concentrations are diluted to the running water of certain volume in beaker, of the right age mosquito larvae 10 is put into, after 24h
Its death condition is observed, the death rate is calculated, the results are shown in Table 1.
The compound of table 1 is to mythimna separata and the killing activity of mosquito larvae
The bactericidal activity of the part of compounds of embodiment 20
Bactericidal activity is determined using mycelial growth rate method.After first test-compound 50mg is dissolved with 10mL DMSO, with training
Foster base is diluted to 50 μ g/mL, then by cultured pathogen, under aseptic technique with diameter 7mm sterilization punchers, from
Colony edge cuts bacteria cake, with inoculator downwards, covers ware lid, is placed in 25 pure culture biscuits involvng inoculation in drug containing flat board center, mycelia
Cultivated in DEG C incubator.After the bacterium colony in blank control fully grows, calculate bacterium colony and increase diameter.According to blank control bacterium colony
The bacterium colony for increasing diameter and chemicals treatment increases mycelial growth inhibition rate of each chemicals treatment of diameter calculating to various pathogens, knot
Fruit is shown in Table 2.
Bactericidal activity of the part of compounds of table 2 under 50 μ g/mL concentration
The antiviral activity of the compound of embodiment 21
(1) the virus inactivation active testing of compound
Test-compound is weighed by required concentration, 80 μ L DMF dissolvings is added, adds a large amount of distilled water dilutings, be settled to
500 μ g/mL are standby.Six leaf age tobaccos (N.tabacum L.) plant healthy leaves is chosen, is 5.88 μ g/mL's by TMV concentration
Viral solution hatches 30min after being mixed in equal volume with testing compound solution, and mixture is inoculated into three, plant top blade
On, the viral solution of compound will not added to be inoculated into the blade of bottom three as blank control.Inoculation checks blade spot after 3 days
Count out, three times, virazole and Ningnanmycin with concentration make activity to each compound for parallel determination under 500 μ g/mL concentration
Control.The inhibiting rate of compound is calculated by the scab number of blade, the results are shown in Table 3.
(2) the live body protection activity test of part of compounds
Test-compound is weighed by required concentration, 80 μ L DMF dissolvings is added, adds a large amount of distilled water dilutings, be settled to
500 μ g/mL are standby.Six leaf age tobaccos (N.tabacum L.) plant healthy leaves is chosen, compound solution is uniformly applied to
On the blade of three, plant top, prior warp will be inoculated into respectively containing the viral solution that TMV concentration is 5.88 μ g/mL after 12h
On the blade of upper and lower portion three of abrasive three blades in plant top of diamond dust, it is inoculated with after 30min with water cleaning blade 2~3
It is secondary, check blade number of spots after 3 days, each compound under 500 μ g/mL concentration parallel determination three times, with the virus of concentration
Azoles and Ningnanmycin make active control.The inhibiting rate of compound is calculated by the scab number of blade, the results are shown in Table 3.
Activity of resisting tobacco mosaic virus of the part of compounds of table 3 under 500 μ g/mL concentration
By embodiment 19-21 it can be found that a series of pyrazoles containing 1,2,3- thiadiazoles structure provided by the invention are double
Amides compound has the active and preferable mythimna separate of excellent mosquitocidal worm, and majority of compounds is in 10 μ g/mL concentration
Under, the fatal rate to mosquito larvae is 100%, and activity of the individual compound under 0.25 μ g/mL concentration still reaches 70%；It is most of
Compound under 600 μ g/mL to the fatal rate of mythimna separata more than 50%, minority reaches 100%.Show that these compounds may have
There is preferable insecticidal activity, there is potential researching value, can be used as insecticide.Another part of compounds has certain kill
Bacterium activity and anti-phytoviral activity.Under 50 μ g/mL concentration, part of compounds to the inhibitory activity of ring rot of apple 38~
Between 47%, individual compound is 62.5% to the inhibitory activity of wheat scab；Under 500 μ g/mL concentration, some compounds
Activity of resisting tobacco mosaic virus is suitable with virazole.Biologically active data shows the above-mentioned pyrazoles containing 1,2,3- thiadiazoles structures
Bisamide class compound has definite bioactivity, and compound has the characteristics of structural modification space is larger, can conduct
Agricultural chemicals guide structure is furtherd investigate, and can be developed and applied as agricultural and hygienic insecticide, is had potential raw
Production value and social benefit.
Claims (4)
1. one kind contains the pyrazoles bisamide class compound of 1,2,3- thiadiazoles, it is characterised in that the compound has such as the institute of formula I
The structure stated：
Generalformulaⅰcompound is：N- (3- ethyls -5- (ethyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiophenes two
Azoles -5- formamides, N- (3- ethyls -5- (n-propyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5-
Formamide, N- (3- ethyls -5- (n-pentyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formyls
Amine, N- (3- ethyls -5- (n-hexyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides, N-
(3- ethyls -5- (n-octyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides, N- (3- second
Base -5- (positive decyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides, N- (3- ethyls -5-
(dodecyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides, N- (1- methyl -3-
Ethyl -5- (methylcarbamoyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides, N- (1- methyl -3-
Ethyl -5- (ethyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides, N- (1- methyl -3-
Ethyl -5- (n-propyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides, N- (1- methyl -
3- ethyls -5- (n-pentyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides, N- (1- first
Base -3- ethyls -5- (n-hexyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides, N- (1-
Methyl -3- ethyls -5- (n-octyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides, N-
(1- methyl -3- ethyls -5- (positive decyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5- formamides,
N- (1- methyl -3- ethyls -5- (dodecyl carbamyl) -1H- pyrazoles -4- bases) -4- methyl isophthalic acids, 2,3- thiadiazoles -5-
Formamide.
2. the preparation method of generalformulaⅰcompound as claimed in claim 1, it is characterised in that carry out in accordance with the following steps：
(1) the use of the compound of formula II is raw material：
Wherein R1、R2With R in claim 11、R2Unanimously；
Make the compound nitration of formula II, obtain general formula III compound：
(2) according to the condensation reaction condition of the acyl chloride reaction in organic synthesis and acyl chlorides and amine, first with thionyl chloride mutual-through type
III compounds carry out chloride, are then condensed under acid binding agent effect with amine, obtain general formulae IV compound：
Wherein R3With R in claim 13Unanimously；
(3) reaction condition reduced according to nitro in organic synthesis, passes through catalytic hydrogenating reduction by nitro in general formulae IV compound
For amino, compounds of formula V is obtained：
(4) according to the acyl chlorides preparation method in organic synthesis, compound 4- is substituted into -1,2,3- thiadiazoles -5- formic acid dichloros
Sulfoxide carries out chloride, obtains the compound of formula VI：
Wherein R4With R in claim 14Unanimously；
(5) according to acyl chlorides in organic synthesis and the condensation condition of amine, compounds of formula V and the compound of formula VI are condensed,
Obtain compound of Formula I.
3. application of the compound of Formula I as claimed in claim 1 in terms of preventing and treating agricultural pest medicine is prepared.
4. application of the compound of Formula I in terms of preventing and treating agricultural pest medicine is prepared, its feature exist according to claim 3
In compound of Formula I is used for the medicine for preparing preventing and treating mosquito larvae, mythimna separata, Botryosphaeria berengeriana f. sp and tobacco mosaic virus (TMV).
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