CN101337959A

CN101337959A - 2-amino-N-oxybenzamidecompounds with insecticidal activity

Info

Publication number: CN101337959A
Application number: CNA2008100320593A
Authority: CN
Inventors: 柳爱平; 胡志彬; 王永江; 王晓光; 黄明智; 欧晓明; 毛春晖; 庞怀林; 黄路
Original assignee: CHINA PESTICIDE DISCOVERY ENGINEERING TECHNICAL RESEARCH CENTRE
Current assignee: Hunan Research Institute of Chemical Industry
Priority date: 2008-08-12
Filing date: 2008-08-12
Publication date: 2009-01-07
Anticipated expiration: 2028-08-12
Also published as: CN101337959B

Abstract

The invention discloses an o-anisidine N-oxyl benzamide compound which is shown in a formula (1) and has insecticidal activity, N-oxide, salts, all geometrical isomers and a preparation method thereof, wherein, R<1>, R<2>, R<3>, R<4>, R<5> and R<6> are limited as shown in an instruction book.

Description

Adjacent amino N-oxybenzamide compounds with insecticidal activity

Technical field

The present invention relates to have the bioactive adjacent amino N of desinsection-oxybenzamide compounds.

Background technology

The control of insect is extremely important in the process that realizes high-efficiency agriculture.The control of insect simultaneously woods, herd, also very important in secondary, fishing and the public health.Though existing a lot of pest control agents on the market, but since the continuous expansion in market and the resistance of insect, the work-ing life of medicine etc. problem and people to the environment pay attention to day by day, need scientists constantly to study, and then exploitation efficient, the safety, the economy and the insecticide variety with different modes of action that make new advances.

E.I.Du Pont Company discloses the anthranilamides of the formula i of Arthropodicidal, R among the formula i in CN 1678192A ^4aBe C ₁-C ₄Alkyl; R ^4bBe H or methyl; E.I.Du Pont Company also discloses the anthranilamides of the formula ii of Arthropodicidal, R among the formula ii in CN 1972915A ⁴Be H or C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl or C ₂-C ₄Alkynyl, each is optional by CN or SMe replacement; And therefrom found chlorine insect amide (chlorantraniliprole) new pesticides shown in the formula iii.

Have the bioactive new compound of desinsection for designing and synthesizing, we are with R ²On the nitrogen-atoms in the-O-introducing acid amides, design and synthesize the adjacent amino N-oxybenzamide compounds shown in the formula (I) that has of not seeing bibliographical information with insecticidal activity.

Summary of the invention

The invention provides adjacent amino N-oxybenzamide compound, N-oxide compound or salt and all geometrical isomers thereof shown in the formula (I):

Wherein:

R ¹Be H or CH ₃

R ²Be H, C ₁-C ₃Alkyl, C ₃-C ₆Alkenyl, C ₃-C ₆Alkynyl, C ₁-C ₃Haloalkyl, C ₃-C ₆Halogenated alkenyl, C ₃-C ₆Halo alkynyl, C ₃-C ₆Methyl cycloalkyl, C ₃-C ₆Halogenated cycloalkyl methyl, substituted-phenyl methyl or C ₅-C ₁₀The heteroaryl methyl;

R ³Be H or halogen;

R ⁴Be halogen, trifluoromethyl, OCH ₂CF ₃Or OCF ₂H;

R ⁵Be H, halogen or methyl;

R ⁶Be H, halogen or cyano group;

Or its agricultural goes up the salt that is suitable for.

In the definition of the compound that provides above (I), no matter following substituting group is represented in the separately use or be used in the compound word of used term:

Halogen: refer to fluorine, chlorine, bromine, iodine;

Alkyl: refer to the straight or branched alkyl;

Haloalkyl: refer to the straight or branched alkyl, the hydrogen atom on these alkyl can partly or entirely be replaced by halogen atom." haloalkenyl group ", the definition and the term " haloalkyl " of " halo alkynyl " and " halogenated cycloalkyl " are identical;

Alkenyl; Refer to have the straight or branched of 3-6 carbon atom and can on any position, have two keys;

Alkynyl; Referring to has the straight or branched of 3-6 carbon atom and can have triple bond on any position.

Compound of the present invention can one or more steric isomers form exist.Various isomer comprise enantiomorph, diastereomer, geometrical isomer.Compound shown in formula of the present invention (I) is because R ²Middle carbon-to-carbon double bond connects different substituting groups and can form geometrical isomer (representing different configurations with Z and E respectively), the present invention includes the mixture of Z type isomer and E-isomer and their any ratios.

The invention still further relates to a kind of formula that contains biologic effective dose (I) compound and at least a other composition that is selected from tensio-active agent, solid diluent and liquid diluent of pest control.

The invention still further relates to a kind of formula that contains biologic effective dose (I) compound and at least a other bioactive compounds of significant quantity or the composition of preparation of pest control.

The invention still further relates to a kind of method of pest control, comprise formula (I) compound contact insect or its environment biologic effective dose.Also relate to simultaneously a kind of like this insect pest control method, insect or its environment are with formula (I) compound of biologic effective dose or contain at least a additional compounds of formula (I) compound and biologic effective dose or the mixture of preparation contacts pest control.

Formula of the present invention (I) compound has broad spectrum of activity: the compound that has can be used for preventing and treating on the various crops the various harmful insects such as mythimna separata, small cabbage moth, prodenia litura, beet armyworm, leafhopper, aphid; The compound that has can be used for preventing and treating on the various crops the various mite classes such as cotton spider mites, tangerine Panonychus citri, and the compound that has has very high biological activity and makes just can obtain good effect under very low dosage.

Those skilled in the art understand that not every nitrogen heterocyclic ring can form the N-oxide compound, because nitrogen need be oxidized to the lone-pair electron of oxide compound; Those skilled in the art knows that also which nitrogen heterocyclic ring can form the N-oxide compound.Those skilled in the art knows that also tertiary amine can form the N-oxide compound.The synthetic method of the N-oxide compound of preparation heterocycle and tertiary amine is well known to those skilled in the art, comprises that heterocycle and tertiary amine carry out oxidation with Peracetic Acid and metachloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxide such as tert-butyl hydroperoxide, Sodium peroxoborate and bisoxirane such as dimethyldioxirane.

The salt of The compounds of this invention comprises mineral acid or organic acid acid salt, as Hydrogen bromide, spirit of salt, nitric acid, phosphoric acid, sulfuric acid, acetate, propanedioic acid, oxalic acid, Whitfield's ointment.

In view of the economy and the biological activity of compound, preferred compound is:

Preferred 1 formula (I) compound, wherein R ¹Be H or CH ₃R ²Be H, C ₁-C ₃Alkyl, allyl group, propargyl, halogenated allyl, acetylenic halide propyl group, C ₃-C ₆Methyl cycloalkyl; R ³It is halogen; R ⁴It is halogen; R ⁵It is methyl; R ⁶Be H, halogen or cyano group; Or its agricultural goes up the salt that is suitable for.

Preferred 2 formulas (I) compound, wherein R ¹Be H; R ²Be methyl, allyl group, propargyl, halogenated allyl, acetylenic halide propyl group; R ³Be chlorine; R ⁴Be chlorine, bromine; R ⁵It is methyl; R ⁶Be H, chlorine, bromine or cyano group; Or its agricultural goes up the salt that is suitable for.

Particularly preferred formula (I) compound is selected from:

The compound of formula (I), wherein R ¹Be H; R ²It is methyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be H;

The compound of formula (I), wherein R ¹Be H; R ²It is methyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be chlorine;

The compound of formula (I), wherein R ¹Be H; R ²It is methyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶It is bromine;

The compound of formula (I), wherein R ¹Be H; R ²It is methyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be iodine;

The compound of formula (I), wherein R ¹Be H; R ²It is methyl; R ³Be chlorine; R ⁴Be chlorine; R ⁵It is methyl; R ⁶Be H;

The compound of formula (I), wherein R ¹Be H; R ²It is methyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be cyano group;

The compound of formula (I), wherein R ¹Be H; R ²It is methyl; R ³Be chlorine; R ⁴Be chlorine; R ⁵It is methyl; R ⁶Be chlorine;

The compound of formula (I), wherein R ¹Be H; R ²It is methyl; R ³Be chlorine; R ⁴Be chlorine; R ⁵It is methyl; R ⁶It is bromine;

The compound of formula (I), wherein R ¹Be H; R ²It is ethyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be H;

The compound of formula (I), wherein R ¹Be H; R ²It is ethyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be chlorine;

The compound of formula (I), wherein R ¹Be H; R ²It is sec.-propyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be chlorine;

The compound of formula (I), wherein R ¹Be H; R ²It is allyl group; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be chlorine;

The compound of formula (I), wherein R ¹Be H; R ²It is allyl group; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be hydrogen;

The compound of formula (I), wherein R ¹Be H; R ²Be 3,3-two chlorallyls; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be chlorine;

The compound of formula (I), wherein R ¹Be H; R ²It is the 2-chlorallyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be H;

The compound of formula (I), wherein R ¹Be H; R ²It is the 2-chlorallyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be chlorine;

The compound of formula (I), wherein R ¹Be H; R ²It is the 2-chlorallyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be cyano group;

The compound of formula (I), wherein R ¹Be H; R ²It is the 2-chlorallyl; R ³Be chlorine; R ⁴Be chlorine; R ⁵It is methyl; R ⁶Be cyano group;

The compound of formula (I), wherein R ¹Be H; R ²It is the 2-Chlorophenylmethyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be H;

The compound of formula (I), wherein R ¹It is methyl; R ²It is methyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be H;

The compound of formula (I), wherein R ¹It is methyl; R ²It is methyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be chlorine;

The compound of formula (I), wherein R ¹It is methyl; R ²It is methyl; R ³Be chlorine; R ⁴Be chlorine; R ⁵It is methyl; R ⁶Be H;

The compound of formula (I), wherein R ¹It is methyl; R ²It is methyl; R ³Be chlorine; R ⁴Be chlorine; R ⁵It is methyl; R ⁶Be chlorine;

The compound of formula (I), wherein R ¹It is methyl; R ²It is methyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶It is bromine;

The compound of formula (I), wherein R ¹Be H; R ²It is the cyclopropyl methyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be chlorine;

The compound of formula (I), wherein R ¹Be H; R ²It is (E) 3-chlorallyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be chlorine;

The compound of formula (I), wherein R ¹Be H; R ²It is the 2-methacrylic; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be chlorine;

The compound of formula (I), wherein R ¹Be H; R ²It is 2-propynyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be chlorine;

The compound of formula (I), wherein R ¹Be H; R ²It is 2-propynyl; R ³Be chlorine; R ⁴It is bromine; R ⁵It is methyl; R ⁶Be hydrogen.

Preferred compositions of the present invention is the composition that contains above-mentioned preferred compound.Preferable methods is to use the method for above-mentioned preferred compound.

Can the present invention be described with the compound of listing in the following table 1.But do not limit the present invention.Among the present invention the fusing point of giving all not calibrated, (APCI Pos) all can be observed its molecular ion peak in (Agilent 1100 Series LC/MSD) to all compounds at LC-MS in the table 1.Compound in the table 1 ¹H NMR (Varian INOVA-300 spectrometer usingtetramethylsilane (TMS) marks in doing) data see Table 2.

Table 1

Continuous table 1

Table 2

No.	¹HNMRδ(ppm)
No.	¹HNMRδ(ppm)	01	(DMSO)2.188(s，3H，-Ph-CH ₃)，3.543(s，3H，-OCH ₃)，7.296(d，J＝2.4HZ，1H，-Ph4-H)，7.387(s， 1H，-Pyrazole4-H)，7.524(d，J＝2.4HZ，1H，-Ph6-H)，7.600(dd，J＝7.8HZ，4.5HZ，1H，-Py5-H)，8.155 (dd，J＝7.8HZ，1.5Hz，1H，-Py4-H)，8.479(dd，J＝4.5HZ，1.5Hz，-Py6-H)
02	(DMSO)2.186(s，3H，-PhCH ₃)，3.547(s，3H，-OCH ₃)，7.244-7.385(m，3H，-PhH)，7.405(s，1H， -Pyrazole4-H)，7.595(dd，J＝7.8HZ，4.5HZ，1H，-Py5-H)，8.149(dd，J＝7.8HZ，1.5Hz，1H，-Py4-H)， 8.478(dd，J＝4.5HZ，1.5Hz，-Py6-H)	01
02		03	(DMSO)3.724(s，3H，-NHOCH ₃)，7.188-8.060(m，4H，-PhH)，7.255(s，1H，-Pyrazole4-H)，7.642 (dd，J＝8.1HZ，4.5HZ，1H，-Py5-H)，8.194(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.517(dd，J＝4.5HZ， 1.5Hz，-Py6-H)
04	(DMSO)2.179(s，3H，-PhCH ₃)，3.568(s，3H，-NHOCH ₃)，7.414(d，J＝2.4HZ，1H，-Ph4-H)，7.366(s， 1H，-Pyrazole4-H)，7.580(dd，J＝8.1HZ，4.8HZ，1H，-Py5-H)，7.621(d，J＝2.4HZ，1H，-Ph6-H)，8.121 (dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.463(dd，J＝4.8HZ，1.5Hz，-Py6-H)	03
04		05	(DMSO)2.148(s，3H，-PhCH ₃)，3.563(s，3H，-NHOCH ₃)，7.363(s，1H，-Pyrazole4-H)，7.557(d，J＝ 1.5HZ，1H，-Ph4-H)，7.576(dd，J＝8.1HZ，4.8HZ，1H，-Py5-H)，7.778(d，J＝1.5HZ，1H，-Ph6-H)，8.116 (dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.462(dd，J＝4.8HZ，1.5Hz，-Py6-H)
07	(DMSO)3.175(s，3H，-NHOCH ₃)，7.235(s，1H，-Pyrazole4-H)，7.551(dd，J＝9HZ，J＝2.4HZ，1H， -Ph4-H)，7.640(dd，J＝8.1HZ，4.5HZ，1H，-Py5-H)，7.674(d，J＝2.4HZ，1H，-Ph6-H)，8.026(d，J＝9HZ， 1H，-Ph3-H)，8.191(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.513(dd，J＝4.5HZ，1.5Hz，-Py6-H)	05
07		08	(DMSO)2.185(s，3H，-PhCH ₃)，3.566(s，3H，-NHOCH ₃)，7.228-7.396(m，3H，-PhH)，7.336(s，1H， -Pyrazole4-H)，7.582(dd，J＝8.1HZ，4.5HZ，1H，-Py5-H)，8.130(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)， 8.468(dd，J＝4.5HZ，1.5Hz，-Py6-H)
09	(DMSO)2.243(s，3H，-Ph-CH ₃)，3.531(s，3H，-OCH ₃)，7.417(s，1H，-Pyrazole4-H)，7.605(dd， J＝7.8HZ，4.5HZ，1H，-Py5-H)，7.735(s，1H，-Ph4-H)，7.934(d，J＝1.2HZ，1H，-Ph6-H)，8.165(dd， J＝7.8HZ，1.5Hz，1H，-Py4-H)，8.479(dd，J＝4.5HZ，1.5Hz，-Py6-H)	08

10	(DMSO)2.245(s，3H，-Ph-CH ₃)，3.818(s，3H，-OCH ₃)，7.196(s，1H，-Pyrazole4-H)，7.363(dd， J＝8.1HZ，4.5HZ，1H，-Py5-H)，7.532(s，1H，-Ph4-H)，7.581(s，1H，-Ph6-H)，7.845(dd，J＝8.1HZ， 1.5Hz，1H，-Py4-H)，8.439(dd，J＝4.5HZ，1.5Hz，-Py6-H)
10		11	(DMSO)2.184(s，3H，-Ph-CH ₃)，3.540(s，3H，-OCH ₃)，7.298(d，J＝2.1HZ，1H，-Ph4-H)，7.339(s， 1H，-Pyrazole4-H)，7.524(d，J＝2.1HZ，1H，-Ph6-H)，7.600(dd，J＝5.1HZ，8.1HZ，1H，-Py5-H)，8.161 (d，J＝8.1HZ，1H，-Ph4-H)，8.476(d，J＝5.1HZ，1H，-Py6-H)
12	(DMSO)2.143(s，3H，-Ph-CH ₃)，3.538(s，3H，-OCH ₃)，7.337(s，1H，-Pyrazole4-H)，7.414(d， J＝2.1HZ，1H，-Ph4-H)，7.600(dd，J＝4.8HZ，8.1HZ，1H，-Py5-H)，7.657(d，J＝2.1HZ，1H，-Ph6-H)， 8.161(d，J＝8.1HZ，1H，-Ph4-H)，8.476(d，J＝4.8HZ，1H，-Py6-H)	11
12		13	(DMSO)2.177(s，3H，-PhCH ₃)，3.058(b r，3H，-NOCH ₃ CH ₃)，3.397(br，3H，-NO CH ₃CH ₃)， 7.209-7.342(m，3H，-PhH)，7.369(s，1H，-Pyrazole4-H)，7.615(dd，J＝7.8HZ，4.8HZ，1H，-Py5-H)， 8.135(dd，J＝7.8HZ，1.5Hz，1H，-Py4-H)，8.470(dd，J＝4.8HZ，1.5Hz，-Py6-H)
14	(DMSO)2.168(s，3H，-PhCH ₃)，3.133(br，3H，-NOCH ₃ CH ₃)，3.496(br，3H，-NO CH ₃CH ₃)，7.338(d， J＝1.8HZ，1H，-Ph4-H)，7.354(s，1H，-Pyrazole4-H)，7.478(d，J＝1.8HZ，1H，-Ph6-H)，7.613(dd， J＝8.1HZ，4.5HZ，1H，-Py5-H)，8.135(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.470(dd，J＝4.5HZ，1.5Hz， -Py6-H)	13
14		15	(DMSO)1.130(t，J＝6.9HZ，3H，-CH ₂C H ₃)，2.178(s，3H，-PhCH ₃)，3.800(q，J＝6.9HZ，2H， - CH ₂CH ₃)，7.245-7.372(m，3H，-PhH)，7.384(s，1H，-Pyrazole4H)，7.579(dd，J＝8.1HZ，4.5HZ，1H， -Py5-H)，8.116(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.469(dd，J＝4.5HZ，1.5Hz，-Py6-H)
16	(DMSO)1.126(t，J＝6.9HZ，3H，-CH ₂C H ₃)，2.179(s，3H，-PhCH ₃)，3.794(q，J＝6.9HZ，2H， - CH ₂CH ₃)，7.293(d，J＝2.4HZ，1H，-Ph4-H)，7.463(s，1H，-Pyrazole4-H)，7.476(d，J＝2.4HZ，1H， -Ph6-H)，7.588(dd，J＝8.1HZ，4.8HZ，1H，-Py5-H)，8.124(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.470 (dd，J＝4.8HZ，1.5Hz，-Py6-H)	15
16		17	(DMSO)1.120(d，J＝6.3HZ，6H，-CH(C H ₃) ₂)，2.164(s，3H，-PhCH ₃)，4.033(m，1H，-C H(CH ₃) ₂)， 7.222-7.372(m，3H，-PhH)，7.482(s，1H，-Pyrazole4-H)，7.585(dd，J＝8.1HZ，4.8HZ，1H，-Py5-H)， 8.119(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.472(dd，J＝4.8HZ，1.5Hz，-Py6-H)
18	(DMSO)1.12(d，J＝6HZ，6H，-CH(C H ₃) ₂)，2.175(s，3H，-PhCH ₃)，4.013(m，1H，-C H(CH ₃) ₂)，7.297 (d，J＝2.4HZ，-Ph4-H)，7.382(s，1H，-Pyrazole4-H)，7.485(d，J＝2.4HZ，-Ph6-H)，7.583(dd，J＝8.1HZ， 4.8HZ，1H，-Py5-H)，8.121(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.472(dd，J＝4.8HZ，1.5Hz，-Py6-H)	17
18		19	(DMSO)2.114(s，3H，-PhCH ₃)，6.478-7.249(m，1H，-PhH)，7.270(s，1H，-Pyrazole 4-H)， 7.620-8.514(m，3H，-PyH)
20	(DMSO)2.187(s，3H，-PhCH ₃)，4.410(d，J＝6.3HZ，2H，-NHOC H ₂CHCCl ₂)，6.295(t，J＝6.3HZ，1H， -NHOCH ₂C HCCl ₂)，7.257-7.388(m，3H，-PhH)，7.358(s，1H，-Pyrazole 4-H)，7.578(dd，J＝7.5HZ， J＝3.9HZ，1H，-Py5-H)，8.110(d，J＝7.5HZ，1H，-Py4-H)，8.462(d，J＝3.9HZ，7.5HZ，1H，-Py6-H)	19
20		21	(DMSO)2.190(s，3H，-PhCH ₃)，4.408(d，J＝6.6HZ，2H，-NHOC H ₂CHCCl ₂)，6.295(t，J＝6.6HZ，1H， -NHOCH ₂C HCCl ₂)，7.310(d，J＝2.1HZ，1H，-Ph4-H)，7.352(s，1H，-Pyrazole4-H)，7.499(d，J＝2.1HZ， 1H，-Ph6-H)，7.581(dd，J＝8.1HZ，4.5HZ，1H，-Py5-H)，7.581(dd，J＝8.1HZ，4.5HZ，1H，-Py5-H)， 8.115(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.464(dd，J＝4.5HZ，1.5Hz，-Py6-H)
22	(DMSO)2.180(s，3H，-PhCH ₃)，4.268(d，J＝6.0HZ，2H，-CONHOCH ₂CHC H ₂)，5.229(dd，2H， -CONHOCH ₂-)，5.920(m，H，-CONHOCH ₂C HCH ₂)，7.258(d，J＝2.1HZ，1H，-Ph4-H)，7.384(s，1H， -Pyrazole4-H)，7.484(d，J＝2.1HZ，1H，-Ph6-H)，7.579(dd，J＝8.1HZ，4.5HZ，1H，-Py5-H)，8.116(dd， J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.462(dd，J＝4.8HZ，1.5Hz，-Py6-H)	21
22		23	(DMSO)2.177(s，3H，-PhCH ₃)，4.275(d，J＝6.0HZ，2H，-CONHOCH ₂CHC H ₂)，5.240(dd，2H， -CONHOCH ₂-)，5.925(m，1H，-CONHOCH ₂C HCH ₂)，7.241-7.373(m，3H，-PhH)，7.388(s，1H， -Pyrazole4-H)，7.573(d d，J＝8.1HZ，4.8HZ，1H，-Py5-H)，8.112(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)， 8.462(dd，J＝4.8HZ，1.5Hz，-Py6-H)
24	(DMSO)2.176(s，3H，-PhCH ₃)，4.492(d，J＝8.0HZ，2H，-NO CH ₂-)，6.091(d，J＝6.9HZ，1H， -NOCH ₂ CH-)，6.460(d，J＝6.9HZ，1H，-NOCH ₂CH CHCl)，7.243-7.396(m，3H，-PhH)，7.367(s，1H， -Pyrazole4-H)，7.582(dd，J＝8.1HZ，4.8HZ，1H，-Py5-H)，8.122(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)， 8.465(dd，J＝4.8HZ，1.5Hz，-Py6-H)	23
24		25	(DMSO)2.179(s，3H，-PhCH ₃)，4.488(d，J＝8.0HZ，2H，-NO CH ₂-)，6.091(d，J＝7.2HZ，1H， -NOCH ₂ CH-)，6.491(d，J＝7.2HZ，1H，-NOCH ₂ CHCHCl)，7.305(d，J＝2.1HZ，1H，-Ph4-H)，7.375(s， 1H，-Pyrazole4-H)，7.516(d，J＝2.1HZ，1H，-Ph6-H)，7.588(dd，J＝8.1HZ，4.8HZ，1H，-Py5-H)，8.138 (d d，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.471(dd，J＝4.8HZ，1.5Hz，-Py6-H)

26	(DMSO)2.196(s，3H，-PhCH ₃)，4.325(s，2H，-CONHC H ₂-)，4.426(d，J＝1.5HZ，1H，-CClC H ₂)， 5.528(S，1H，-CClC H ₂)，7.310(d，J＝2.1HZ，1H，-Ph4-H)，7.420(s，1H，-Pyrazole4-H)，7.545(d， J＝2.1HZ，1H，-Ph6-H)，7.605(dd，J＝8.1HZ，4.5HZ，1H，-Py5-H)，8.165(dd，J＝8.1HZ，1.5Hz，1H， -Py4-H)，8.485(dd，J＝4.5HZ，1.5Hz，-Py6-H)
26		27	(DMSO)2.170(s，3H，-PhCH ₃)，4.366(s，2H，-CONHC H ₂-)，4.404(d，J＝1.5HZ，1H，-CClC H ₂)， 5.570(S，1H，-CClC H ₂)，7.199-7.362(m，3H，-PhH)，7.406(s，1H，-Pyrazole4-H)，7.582(dd，J＝8.1HZ， 4.5HZ，1H，-Py5-H)，8.127(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.475(dd，J＝4.5HZ，1.5Hz，-Py6-H)
28	(DMSO)0.207(d，J＝4.2HZ，2H，-NOCH ₂CHC ₂ H ₄)，0.491(d，J＝4.2HZ，2H，-NOCH ₂CHC ₂ H ₄)， 1.003(t，J＝6.9HZ，1H，-NOCH ₂ CHC ₂H ₄)，2.166(s，3H，-PhCH ₃)，3.579(d，J＝6.9HZ，2H， -NO CH ₂CHC ₂H ₄)，7.237-7.366(m，3H，-PhH)，7.386(s，1H，-Pyrazole4-H)，7.585(dd，J＝8.1HZ， 4.8HZ，1H，-Py5-H)，8.130(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.472(dd，J＝4.8HZ，1.5Hz，-Py6-H)	27
28		29	(DMSO)0.207(d，J＝4.8HZ，2H，-NOCH ₂CHC ₂ H ₄)，0.511(d，J＝4.8HZ，2H，-NOCH ₂CHC ₂ H ₄)， 1.034(t，J＝6.9HZ，1H，-NOCH ₂ CHC ₂H ₄)，2.168(s，3H，-PhCH ₃)，3.570(d，J＝6.9HZ，2H， -NO CH ₂CHC ₂H ₄)，7.289(d，J＝2.1HZ，1H，-Ph4-H)，7.365(s，1H，-Pyrazole4-H)，7.486(d，J＝2.1HZ， 1H，-Ph6-H)，7.590(dd，J＝8.1HZ，4.8HZ，1H，-Py5-H)，8.135(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.470 (dd，J＝4.8HZ，1.5Hz，-Py6-H)
30	(DMSO)1.740(s，3H，-CH ₂C CH ₃CH ₂)，2.173(s，3H，-PhCH ₃)，4.178(s，2H，- CH ₂CCH ₃CH ₂)，4.910 (d，J＝5.7HZ，2H，-CH ₂CCH ₃ CH ₂)，7.278(d，J＝2.4HZ，1H，-Ph4-H)，7.374(s，1H，-Pyrazole4-H)，7.492 (d，J＝2.4HZ，1H，-Ph6-H)，7.585(dd，J＝8.1HZ，4.8HZ，1H，-Py5-H)，8.130(dd，J＝8.1HZ，1.5Hz，1H， -Py4-H)，8.465(dd，J＝4.8HZ，1.5Hz，-Py6-H)	29
30		31	(DMSO)1.782(s，3H，-CH ₂C CH ₃CH ₂)，2.172(s，3H，-PhCH ₃)，4.181(s，2H，- CH ₂CCH ₃CH ₂)，4.910 (d，J＝8.1HZ，2H，-CH ₂CCH ₃ CH ₂)，7.218-7.69(m，3H，-PhH)，7.379(s，1H，-Pyrazole4-H)，7.582(dd， J＝8.1HZ，4.8HZ，1H，-Py5-H)，8.127(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.465(dd，J＝4.8HZ，1.5Hz， -Py6-H)
32	(DMSO)2.191(s，3H，-PhCH ₃)，3.601(t，J＝2.1HZ，1H，-CCH)，3.385(d，J＝2.4HZ，2H， -O CH ₂CCH)，7.307(d，J＝2.4HZ，1H，-Ph4-H)，7.398(s，1H，-Pyrazole4-H)，7.544(d，J＝2.4HZ，1H， -Ph6-H)，7.607(dd，J＝8.1HZ，4.8HZ，1H，-Py5-H)，8.160(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.481 (dd，J＝4.8HZ，1.5Hz，-Py6-H)	31
32		33	(DMSO)2.187(s，3H，-PhCH ₃)，3.494(t，J＝2.4HZ，1H，-CCH)，3.403(d，J＝2.4HZ，2H， -O CH ₂CCH)，7.248-7.405(m，3H，-PhH)，7.392(s，1H，-Pyrazole4-H)，7.586(dd，J＝8.1HZ，4.8HZ，1H， -Py5-H)，8.129(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.471(dd，J＝4.8HZ，1.5Hz，-Py6-H)
34	(CDCl ₃)2.253(s，3H，-PhCH ₃)，4.537(s，2H，-CONHC H ₂-)，5.514(s，2H，-CClC H ₂)，7.031(s，1H， -Pyrazole4-H)，7.385(dd，J＝8.1HZ，4.8HZ，1H，-Py5-H)，7.540(s，1H，-Ph4-H)，7.6.3(s，1H，-Ph6-H)， 7.863(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.447(dd，J＝4.8HZ，1.5Hz，-Py6-H)	33
34		35	(CDCl ₃)2.236(s，3H，-PhCH ₃)，4.507(s，2H，-CONHC H ₂-)，5.496(d，J＝3.6HZ，2H，-CClC H ₂)，6.940 (s，1H，-Pyrazole4-H)，7.375(dd，J＝8.1HZ，5.1HZ，1H，-Py5-H)，7.513(s，1H，-Ph4-H)，7.566(d， J＝1.2HZ，1H，-Ph6-H)，7.854(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.431(dd，J＝5.1HZ，1.5Hz，-Py6-H)
36	(DMSO)0.185-0.529(m，5H，-NHOCH ₂C ₃ H ₅)，2.231(s，3H，-PhCH ₃)，3.547(d，J＝7.5HZ，2H， -NHOC H ₂C ₃H ₅)，7.404(s，1H，-Pyrazole4-H)，7.610(dd，J＝8.1HZ，4.8HZ，1H，-Py5-H)，7.728(d， J＝1.2HZ，1H，-Ph4-H)，7.923(d，J＝1.2HZ，1H，-Ph6-H)，8.164(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)， 8.485(dd，J＝4.8HZ，1.5Hz，-Py6-H)	35
36		37	(DMSO)2.191(s，3H，-PhCH ₃)，4.883(s，2H，- CH ₂PH)，7.206-7.495(m，7H，-PhH)，7.397(s，1H， -Pyrazole4-H)，7.563(dd，J＝8.1HZ，4.8HZ，1H，-Py5-H)，8.115(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)， 8.425(dd，J＝4.8HZ，1.5Hz，-Py6-H)
38	(DMSO)2.174(s，3H，-PhCH ₃)，3.055(b r，3H，-NOCH ₃ CH ₃)，3.394(br，3H，-NO CH ₃CH ₃)， 7.205-7.368(m，3H，-PhH)，7.310(s，1H，-Pyrazole4-H)，7.610(dd，J＝8.1HZ，4.5HZ，1H，-Py5-H)， 8.135(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.470(dd，J＝4.5HZ，1.5Hz，-Py6-H)	37
38		39	(DMSO)2.170(s，3H，-PhCH3)，3.135(br，3H，-NOCH3CH3)，3.326(br，3H，-NOCH3CH3)，7.302 (s，1H，-Pyrazole4-H)，7.340(d，J＝2.1HZ，1H，-Ph4-H)，7.479(d，J＝2.1HZ，1H，-Ph6-H)，7.615(dd， J＝8.1HZ，4.5HZ，1H，-Py5-H)，8.186(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.498(dd，J＝4.5HZ，1.5Hz， -Py6-H)
40	(DMSO)2.166(s，3H，-PhCH3)，3.126(br，3H，-NOCH3CH3)，3.342(br，3H，-NOCH3CH3)，7.354 (s，1H，-Pyrazole4-H)，7.455(d，J＝2.1HZ，1H，-Ph4-H)，7.612(d，J＝2.1HZ，1H，-Ph6-H)，7.612(dd， J＝8.1HZ，4.5HZ，1H，-Py5-H)，8.183(dd，J＝8.1HZ，1.5Hz，1H，-Py4-H)，8.496(dd，J＝4.5HZ，1.5Hz， -Py6-H)	39

Compound shown in the formula of the present invention (I) can obtain by reaction formula 1-1 or the reaction formula 1-2 shown in following, (II) in the reaction formula 1, (III) and (IV) can obtain respectively by reaction formula 2, reaction formula 3 and the reaction formula 4 shown in following.Substituting group wherein except that specializing all as preceding qualification.

Reaction formula 1-1:

Reaction formula 1-2:

Reaction formula 2:

Reaction formula 3:

Reaction formula 4:

The compound of formula (I) can prepare (reaction formula 1-1) like this: in solvent-free or suitable solvent such as tetrahydrofuran (THF), ether, methylene dichloride, in 10 ℃ of reflux temperatures, with suitable alkali such as sodium bicarbonate, yellow soda ash, sodium-hydroxide treatment general formula (II) and compound (III) to solvent.

The compound of formula (I) can also prepare (reaction formula 1-2) like this: in suitable solvent such as acetonitrile, tetrahydrofuran (THF), methylene dichloride, in-10 ℃ to 0 ℃, in the presence of suitable alkali such as tertiary amines triethylamine or pyridine, handle the compound of formula V (Y=OH) and the compound of formula (IV) with Methanesulfonyl chloride.

The compound of formula (I) also can prepare (reaction formula 1-2) like this: in suitable solvent such as methylene dichloride, toluene, benzene, tetrahydrofuran (THF), in-10 ℃ to the solvent refluxing temperature, add suitable alkali such as tertiary amines triethylamine or pyridine in case of necessity, react with the compound of formula (IV) and the compound of formula V (Y=Cl).

The compound of formula (II) can prepare according to several different methods, the method of reaction formula 2 is included in suitable solvent such as acetonitrile, tetrahydrofuran (THF), the methylene dichloride, in-10 ℃ to 0 ℃, in the presence of tertiary amine such as pyridine, Methanesulfonyl chloride is joined in the pyrazole carboxylic acid of formula V (Y=OH), then add formula (VI) or anthranilic acid (VII), and then add tertiary amine and Methanesulfonyl chloride.In embodiment 4,7,8 or 9, more detailed elaboration is arranged.

The compound of formula (III) can prepare according to several different methods, and the method for reaction formula 3 is included in suitable solvent such as N, in the dinethylformamide (DMF), and in the presence of acid binding agent such as triethylamine, R ²X and N-hydroxyphthalimide react, and obtain the compound of formula (IX), with the compound of sour example hydrochloric acid processing formula (IX), obtain the compound of formula (III).In embodiment below such as embodiment 8 and 9 more detailed elaboration is arranged.

The compound of formula (IV) can prepare according to the method for reaction formula 4, promptly in suitable solvent such as tetrahydrofuran (THF) or ethyl acetate, obtain the compound of formula (VIII) with light gas disposal formula (VI), the compound of handling formula (VIII) according to multiple currently known methods obtains the compound of formula (IX).And then in suitable solvent such as ethyl acetate or tetrahydrofuran (THF), with the compound of suitable alkali such as alkali metal hydroxide, alkaline carbonate processing formula (IX) and formula (III).Among embodiment below such as the embodiment 1 more detailed elaboration is arranged.

Formula provided by the invention (I) compound, biologically active and the compound that has have good biological activity. particularly aspect the preventing and treating of agricultural, gardening, flowers and sanitary insect pest, show high reactivity.Harmful organism described here include but not limited to this:

Harmful insect: Orthoptera such as blattaria, Thysanoptera such as cotton thrips, rice thrips, melon thrips, Homoptera such as leafhopper, plant hopper, aphid, lepidopteran such as oriental armyworm, prodenia litura, small cabbage moth, beet armyworm, cabbage looper, cabbage caterpillar, Hymenoptera such as sawfly larva, Diptera such as yellow-fever mosquito, culex, fly;

Pest mite class: acarina such as tangerine Panonychus citri, cotton spider mites, T.urticae Koch;

Formula provided by the invention (I) compound is effective for Pest Control and mite.Usually use formula (I) compound of 10-5000ppm, it is dispersed in water or other the aqueous carrier, impose in the soil of plant, crop or plant growth, can prevent effectively that crop from suffering the infringement of worm and/or mite.

When using formula of the present invention (I) compound separately, be that effectively they also can use with the other biological chemical substance to control worm and/or mite, these biochemicals comprise other sterilants, nematocides and miticide.Formula for example of the present invention (I) compound is sterilants such as organic phosphates, pyrethroid, amino formate, class nicotinoids, neural sodium channel blockers, parasiticidal macrolide, γ-An Jidingsuan (GABA) antagonist, desinsection ureas and neotonin analoglike thing effectively, and miticides such as aramite, propargite, methamidophos, azoles mite ester, hexythiazox and pyridaben cooperate or mix use together.

With (I) provided by the invention compound, Agrotechnical formulation as effective ingredient, can make desirable any formulation as the compressing grains done, easily flow mixture, granula, wettable powder, water dispersible granules, emulsifiable concentrate, pulvis, powdery enriched material, microemulsion, suspension agent, missible oil, aqueous emulsion, soluble liquid, aqua, dispersible agent, suitable auxiliary agent comprises carrier (thinner) and other auxiliary such as spreader-sticker, emulsifying agent, wetting agent, dispersion agent, tackiness agent and decomposition agent.Contain the compound of the present invention that same inert, the acceptable solid of pharmacology or liquid diluent have mixed in these preparations.

For example: wettable powder of the present invention, pulvis and powder enriched material, can be by with formula (I) compound of the about 5-30% of weight, mill together and prepare with the solid anion surfactant of the about 5-30% of weight.The dioctyl ester that a kind of suitable anion surfactant is a sodium sulfosuccinate.The also inert solid diluent of operating weight 40%-90% in these preparations is as talcum, kaolin, diatomite, Wingdale, silicate etc.

The preparation of compressing grains is that the gypsum as 5-30 part formula (I) compound and solid surfactant and about 40-90 part of about equivalent is milled together, and the mixture recompression is about 10-100 order (1.676-0.152mm) size or bigger particle then.

Employed solid surfactant not only has the dioctyl phenyl ester of anionic sodium sulfosuccinate in the present invention's prescription, also has the block polymer of non-ionic type oxyethane and propylene oxide.

Easily flowing agent can be used with the aqueous solution on the spot.

Formula (I) solid preparation can be used in combination with other sterilant, can be used as multicomponent mixture and uses, and perhaps sequentially uses.

In like manner, the liquid preparation of formula (I) also can be used in combination with other sterilant, can mix in container or use successively respectively in the liquid spray mode.Effective formula (I) compound that should contain the 50-5000ppm that has an appointment in the spray liquid agent prescription of the present invention.

The example of composition of the present invention also can be wettable powder, pulvis, granule and liquor, emulsible enriching agent, emulsion, suspension enriching agent, aerosol and smoke substance.Wettable powder contains 15,25,50 weight activeconstituentss usually, and usually except that solid inert carrier, also contains 3-10% weight fraction powder, can add 0-10% weight stablizer and/or other additive such as permeate agent and tackiness agent in case of necessity.Pulvis may be molded to the pulvis enriching agent that has the composition similar to wettable powder but do not have dispersion agent usually.Granula is made usually has 10-100 order (1.676-0.152mm) size, and available agglomerating or implantttion technique preparation.Usually, granula contains the activeconstituents of 0.5-50% weight and 0-10% weight additive such as stablizer, tensio-active agent, slowly-releasing modifying agent.Outside but emulsion concentrate desolventizes, can contain cosolvent in case of necessity, the 1-50%W/V activeconstituents, other additive of 2-20%W/V emulsifying agent and 0-20%W/V such as stablizer, permeate agent and corrosion inhibitor, suspension enriching agent contain the activeconstituents of 10-75% weight, the dispersion agent of 0.5-15% weight, other additive such as defoamer, corrosion inhibitor, stablizer, permeate agent and the tackiness agent of 0.1-10% weight usually.

Water dispersant and emulsion, for example by dilute with water according to the composition that wettable powder of the present invention or enriched material obtain, also list scope of the present invention in.Indication emulsion comprises two kinds of water-in-oil and oil-in-waters.

The invention will be further described below in conjunction with embodiment, and the yield among the embodiment is all without optimization.

Embodiment

Embodiment 1

The preparation method of compound 01 in this example instruction card 1.

Steps A: preparation 3-methyl isatoic anhydride

With trichloromethylchloroformate (9.5g, tetrahydrofuran (THF) 48mmol) (10mL) ice bath 10 minutes, drip 2 pyridines, follow under condition of ice bath 2-amino-3-tolyl acid (6.04g, tetrahydrofuran (THF) 40mmol) (60mL) solution dripped in 1 hour, after being added dropwise to complete reaction mixture slowly was warming up to room temperature.At room temperature keep stirring spending the night, reaction mixture forms white solid precipitates.Reactant is filtered, with tetrahydrofuran (THF) (2 * 5ml) washings, oven dry.Isolate desired title compound, get white solid (7.24g).

Step B: preparation N-methoxyl group-2-amino-3-methyl benzamide

With 3-methyl isatoic anhydride (2.64g, ethyl acetate 15mmol) (35ml) solution stirring at room is after 10 minutes, drip glacial acetic acid (0.4g), stir after 0.5 hour, then slowly drip methoxamine hydrochloride (2.76g, 33mmol) and sodium hydroxide (1.32g, water 33mmol) (5.00g) solution, be added dropwise to complete back stirring at room 24 hours, with reaction solution once with the 40g water washing, the organic phase anhydrous sodium sulfate drying obtains title compound, light yellow look solid (2.54g) except that after desolvating.

Step C: preparation N-methoxyl group-2-amino-3-methyl-5-chloro benzamide

With N-methoxyl group-2-amino-3-methyl benzamide (1.11g, 6.17mmol) N, dinethylformamide (7mL) ice bath 10 minutes, slowly drip concentrated hydrochloric acid (4.10g, 40.74mmol), be added dropwise to complete under the condition of ice bath of back and stirred 10 minutes, slowly be warming up to 30 ℃, slowly drip 30% hydrogen peroxide (1.06g then, 9.31mmol), be added dropwise to complete back 30 ℃ and stirred 4 hours, after HPLC detects no raw material, the reaction solution ice bath cooled off 10 minutes after, drip water (10mL), (0.44g 3.50mmol), stirs after 1 hour under the condition of ice bath to add S-WAT again, sodium hydroxide solution with 30% transfers to PH to 9, reactant is filtered water (2 * 3ml) washings, natural air drying.Isolate desired title compound, light gray solid (0.24g).

Step D: preparation 3-chloro-2-hydrazino pyridine

With 2, (88.8g, (80%, 370g) the solution back flow reaction is 4 hours, and cooling is filtered, and washes natural air drying with water for hydrazine hydrate 0.6mol) for the 3-dichloropyridine.Get light gray solid title compound 76.22g.

Step e: preparation 1-(3-chloro-2-pyridyl)-3-pyrazolidone-5-ethyl formate

With sodium (after 3.00g, ethanol 130.43mmol) (100mL) solution refluxed 0.5 hour, be chilled to room temperature, add 3-chloro-2-hydrazino pyridine (17.00g, 118mmol).After the back flow reaction 1 hour, and the dropping ethyl maleate (22mL, 136.00mmol).Drip and finish back continuation backflow 10 minutes.After being chilled to 60 ℃, add glacial acetic acid (5mL), then drip water (30mL).Reducing to-5 ℃ after being added dropwise to complete stirred 4 hours.Reactant is filtered the ethanolic soln with 40% (3 * 10mL) washings, natural air drying.Get white solid (6.20g).

Step F: preparation 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyridine alkane ketone-5-ethyl formate

With 1-(3-chloro-2-pyridyl)-3-pyrazolidone-5-ethyl formate (5.00g, 18.50mmol) acetonitrile (40mL) solution ice bath 30 minutes, add tribromo oxygen phosphorus (3.41g, 11.90mmol), reflux refluxed 1-2 hour to orange solution again, and decompression removes most of solvent.With in the enriched material impouring sodium bicarbonate aqueous solution and vigorous stirring 30 minutes, stop to produce until gas.Mixture dilutes with methylene dichloride, restir 30 minutes.Layer overlay cotton on the filter paper, with the mixture decompress filter, filtrate is told organic layer, uses dichloromethane extraction twice again, merges organic layer, and anhydrous sodium sulfate drying removes solvent.Isolate desired title compound, dark amber oil (5.15g).

Step G: preparation 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyridine-5-ethyl formate

(98%1.60mL 0.031mmol) slowly is added dropwise to 3-bromo-1-(3-chloro-2-pyridyl)-4 at ambient temperature, and (5.15g is in acetonitrile 15.56mmol) (37.5mL) solution for 5-dihydro-1H-pyridine alkane ketone-5-ethyl formate with the vitriol oil.Stirring at room 15 minutes, (6.00g 31.00mmol) handles mixture with Potassium Persulphate.Soup compound reflux 3 hours.The orange soup compound of gained remains on 60 ℃, filters and tells white precipitate of good quality.Filter cake washs with acetonitrile.Filtrate removes 2/3rds solvent.Spissated reactant joined in 10 minutes in the water (400mL) of vigorous stirring.Product separates after filtration, contains acetonitrile (3 * 3mL) washings, water (1 * 3mL) washing, the natural air drying of 25% water.Isolate desired title compound, orange powder (4.45g).

Step H: preparation 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyridine-5-formic acid

Under the room temperature condition, (0.54g 13.50mmol) adds 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyridine-5-ethyl formate (4.00g with sodium hydroxide, 12.16mmol) methyl alcohol (10mL) and water (6mL) solution in, heated and stirred refluxed 1 hour, added entry (15mL), and decompression removes methyl alcohol.(1 * 5mL) washs the aqueous solution with chloroform.Solution dropwise be acidified to PH=5 with concentrated hydrochloric acid, product separates after filtration, water (2 * 3mL) washing, natural air drying.Isolate desired title compound, filbert powder (3.38g).

Step I: amino preparation 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-chloro-2-methyl-6-[((methoxyl group))-carbonyl] phenyl]-1H-pyrazoles-5-methane amide (01 compound in the table 1)

To N-methoxyl group-2-amino-3-methyl-5-chloro benzamide (0.24g, 1.12mmol) and 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-formic acid (0.36g, 1.18mmol) acetonitrile (5mL) mixture in drip pyridine (0.24g, 3.04mmol), stir 10 minutes postcooling to-5 ℃, (0.17g 1.48mmol), slowly was warming up to room temperature reaction 12 hours with reactant after being added dropwise to complete slowly to drip Methanesulfonyl chloride.Then reactant is filtered, acetonitrile (3mL * 2) washing is used in the acetonitrile solution with moisture 25% (2mL * 3) washing again, infrared lamp oven dry down.Isolate desired title compound, a kind of compound of the present invention, pale powder (0.18g), m.p.180.5-182 ℃.

Embodiment 2

The preparation method of compound 02 in this example instruction card 1.

Preparation 3-bromo-1-(3-chloro-2-pyridyl)-N-[2-methyl-6-[((methoxyl group) amino)-and carbonyl] phenyl]-1H-pyrazoles-5-methane amide (02 compound in the table 1)

To N-methoxyl group-2-amino-3-methyl benzamide (0.20g, 1.12mmol) and 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-formic acid (0.36g, 1.18mmol) acetonitrile (5mL) mixture in drip pyridine (0.24g, 3.04mmol), stir 10 minutes postcooling to-5 ℃, (0.17g 1.48mmol), slowly was warming up to room temperature reaction 12 hours with reactant after being added dropwise to complete slowly to drip Methanesulfonyl chloride.Then reactant is filtered, acetonitrile (3mL * 2) washing is used in the acetonitrile solution with moisture 25% (2mL * 3) washing again, infrared lamp oven dry down.Isolate desired title compound, a kind of compound of the present invention, pale powder (0.16g), m.p.187.5-189.5 ℃.

Embodiment 3

The preparation method of compound 04 in this example instruction card 1.

Steps A: preparation 5-bromo-3-methyl isatoic anhydride

Under the room temperature, (1.00g, (1.00g 5.62mmol), is heated to 55 ℃ with reaction mixture after adding is finished, and reacts 10 hours, stops heating, room temperature reaction 12 hours to add NBS in DMF 5.65mmol) (3ml) solution to 3-methyl isatoic anhydride.To obtain the sorrel solid in the reaction mixture frozen water (13ml) that impouring is stirred lentamente.Stir after 1 hour mixture is filtered, water (4 * 3ml) washings, infrared lamp oven dry down.Isolate desired title compound, sorrel solid (1.09g).

Step B: preparation N-methoxyl group-2-amino-3-methyl-5-brombenzamide

With 5-bromo-3-methyl isatoic anhydride (0.44g, 1.71mmol) ethyl acetate (7ml) solution stirring at room after 10 minutes, drip glacial acetic acid (0.03g), stir after 0.5 hour, then slowly drip methoxamine hydrochloride (0.28g, 3.35mmol) and sodium hydroxide (0.14g, 3.5mmol) water (0.40g) solution, be added dropwise to complete back stirring at room 24 hours, after HPLC detects no raw material, with reaction solution once with the 4g water washing, the organic phase anhydrous sodium sulfate drying, obtain title compound, light yellow look solid (0.36g) except that after desolvating.

Step C: preparation 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyridine-5-ethyl formate

With 3-chloro-1-(3-chloro-2-pyridyl)-4, and 5-dihydro-1H-pyridine alkane ketone-5-ethyl formate (15.8,54.86mmol) be cooled to 0 ℃, to wherein feeding bromize hydrogen gas uniformly, HPLC detects no raw material, stirring at room 2 hours after 2 hours, logical nitrogen is driven excessive bromize hydrogen gas away, is cooled to 0 ℃, adds ammoniacal liquor to PH=7 to reactant, (3 * 40mL) washings of reaction solution water, anhydrous sodium sulfate drying, decompression removes solvent, gets garnet oily matter, placement is spent the night, and separates out red crystals.Isolate desired title compound, red solid (16.89g).Make 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyridine-5-formic acid with reference to correlation method among the embodiment 1.

Step D: amino preparation 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-bromo-2-methyl-6-[((methoxyl group))-carbonyl] phenyl]-1H-pyrazoles-5-methane amide (compound 04 in the table 1)

To N-methoxyl group-2-amino-3-methyl-5-brombenzamide (0.36g, 1.39mmol) and 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-formic acid (0.40g, 1.32mmol) acetonitrile (7ml) mixture in drip pyridine (0.32g, 4.05mmol), stir 10 minutes postcooling to-5 ℃, (0.22g 1.92mmol), slowly was warming up to room temperature reaction 12 hours with reactant after being added dropwise to complete slowly to drip Methanesulfonyl chloride.Then reactant is filtered, acetonitrile (3ml * 2) washing is used in the acetonitrile solution with 75% (2ml * 3) washing again, infrared lamp oven dry down.Isolate desired title compound, a kind of compound of the present invention, pale yellow powder (0.30g), m.p.191.0-192.0 ℃.

Embodiment 4

The preparation method of compound 05 in this example instruction card 1.

Steps A: preparation 2-amino-3-methyl-5-iodo-benzoic acid

Under the room temperature condition, (15.1g, (22.5g 100mmol), is heated to 70 ℃ of reactions with reaction mixture after adding is finished and spends the night to add NIS in DMF 100mmol) (80ml) solution to 2-amino-3-tolyl acid.To obtain light gray solid in the reaction mixture frozen water (300ml) that impouring is stirred lentamente.Stir after 1 hour mixture is filtered, water (4 * 20ml) washings, infrared lamp oven dry down.Isolate desired title compound, pale red brown solid (25.62g).

Step B: preparation 2-[3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazine-4-ketone

Under the room temperature condition, to pyridine (0.16g, 2.03mmol) acetonitrile (1.5ml) solution in add 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-carboxylic acid (0.45g, 1.49mmol), then reaction mixture is cooled to-5 ℃, stir after 10 minutes, to wherein dripping Methanesulfonyl chloride (0.22g, 1.92mmol) acetonitrile solution (1mL), stir after 5 minutes to wherein adding 2-amino-3-methyl-5-iodo-benzoic acid (0.44g, 1.59mmol), stir that (0.32g, acetonitrile 4.05mmol) (1mL) solution stir after 15 minutes again to wherein slowly dripping Methanesulfonyl chloride (0.22g to wherein slowly dripping pyridine after 2 minutes, 1.92mmol) acetonitrile solution (1mL), stir and slowly be warming up to room temperature reaction 12 hours after 15 minutes.In reactant, slowly drip water (3g), stirred 15 minutes.Product separates after filtration, with acetonitrile solution (2mL * 2) washing that contains 33% water, uses acetonitrile (1mL * 1) washing again, oven dry.Isolate desired title compound, pale solid (0.68g).

Step C:3-bromo-1-(3-chloro-2-pyridyl) N-[4-iodo-2-methyl-6-[((methoxyl group) carbonyl amino)] phenyl]-1H-pyrazoles-5-methane amide

To 2-[3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazine-4-ketone (0.68g, 1.25mmol) THF (4ml) solution in slowly drip methoxamine hydrochloride (0.63g, 7.50mmol) and sodium hydroxide (0.30g, 7.50mmol) mixture in water (0.30g), be added dropwise to complete back room temperature reaction 24 hours.Drip water (2g) then, stirring reduced pressure after 15 minutes removes THF, stirs 30 minutes after-filtration to wherein adding acetonitrile (4ml), with acetonitrile solution (2ml * 3) washing that contains 25% water, uses acetonitrile (2ml * 2) washing again, oven dry under the infrared lamp.Isolate desired title compound, a kind of compound of the present invention, off-white powder (0.55g), m.p.205.5-205.7 ℃.

Embodiment 5

The preparation method of compound 08 in this example instruction card 1.

Steps A: preparation 3-chloro-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyridine alkane ketone-5-ethyl formate

With 1-(3-chloro-2-the pyridyl)-3-pyrazolidone-5-ethyl formate (16.14g that makes among the embodiment 1, acetonitrile 60mmol) (125mL) solution ice bath 30 minutes, slowly drip phosphorus oxychloride (11.05g, 72mmol), being added dropwise to complete post-heating refluxes, refluxed after becoming orange solution 45 minutes, decompression removes most of solvent again.Enriched material was joined in the sodium bicarbonate aqueous solution in 10 minutes, added the back vigorous stirring 30 minutes, stop to produce until gas.Mixture dilutes with methylene dichloride, restir 30 minutes.Layer overlay cotton on the filter paper, with the mixture decompress filter, filtrate is told organic layer, uses dichloromethane extraction twice again, merges organic layer, and anhydrous sodium sulfate drying removes solvent.Isolate desired title compound, dark amber oil (16.30g).Make 3-chloro-1-(3-chloro-2-pyridyl)-1H-pyridine-5-formic acid with reference to correlation method among the embodiment 1.

Step B: carbonyl amino preparation 3-chloro-1-(3-chloro-2-pyridyl)-N-[2-methyl-6-[((methoxyl group))] phenyl]-1H-pyrazoles-5-methane amide (compound 08 in the table 1)

To N-methoxyl group-2-amino-3-methyl benzamide (0.19g, 1.06mmol) and 3-chloro-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-formic acid (0.26g, 1.01mmol) acetonitrile (5ml) mixture in drip pyridine (0.21g, 2.66mmol), stir 10 minutes postcooling to-5 ℃, (0.14g 1.22mmol), slowly was warming up to room temperature reaction 12 hours with reactant after being added dropwise to complete slowly to drip Methanesulfonyl chloride.Then reactant is filtered, acetonitrile (3ml * 2) washing is used in the acetonitrile solution with 75% (2ml * 3) washing again, infrared lamp oven dry down.Isolate desired title compound, a kind of compound of the present invention, off-white powder (0.28g), m.p.179.6-180.4 ℃.

Embodiment 6

The preparation method of compound 11 in this example instruction card 1.

Steps A: amino preparation 3-chloro-1-(3-chloro-2-pyridyl)-N-[4-chloro-2-methyl-6-[((methoxyl group))-carbonyl] phenyl]-1H-pyrazoles-5-methane amide (compound in the table 1)

To N-methoxyl group-2-amino-3-methyl-5-chloro benzamide (0.23g, 1.07mmol) and 3-chloro-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-formic acid (0.26g, 1.01mmol) acetonitrile (5ml) mixture in drip pyridine (0.21g, 2.66mmol), stir 10 minutes postcooling to-5 ℃, (0.14g 1.22mmol), slowly was warming up to room temperature reaction 12 hours with reactant after being added dropwise to complete slowly to drip Methanesulfonyl chloride.Then reactant is filtered, acetonitrile (3ml * 2) washing is used in the acetonitrile solution with 75% (2ml * 3) washing again, infrared lamp oven dry down.Isolate desired title compound, a kind of compound of the present invention, off-white powder (0.18g), m.p.157.1-159 ℃.

Embodiment 7

The preparation method of compound 14 in this example instruction card 1.

Steps A: alkylsulfonyl preparation 3-[[(4-tolyl)] the oxygen base]-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyridine-5-ethyl formate

Under the room temperature condition, with Tosyl chloride (4.43g, 23.25mmol) be added drop-wise to 1-(3-chloro-2-the pyridyl)-3-pyrazolidone-5-ethyl formate (6.20g among the real embodiment 1, methylene dichloride 23mmol) (60mL) solution, be cooled to-5 ℃, slowly drip triethylamine (2.32g, 22.97mmol), (0.22g 1.15mmol), drips triethylamine (0.12g at last to drip Tosyl chloride then, 1.19mmol), drip back and slowly be warmed up to 35 ℃ after finishing, react after 12 hours HPLC detect no raw material, to reactant adding sodium bicarbonate to PH=7, (3 * 20mL) washings of reaction solution water, anhydrous sodium sulfate drying, decompression removes most of solvent, and enriched material is poured in the mixed solution of sherwood oil (16mL) and ethyl acetate (34mL) slowly,-5 ℃ were stirred 5 hours, product separates after filtration, sherwood oil (2 * 5mL) washings, natural air drying.Isolate desired title compound, light yellow solid (8.51g).

Step B: preparation 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyridine-5-ethyl formate

With the 3-[[(4-tolyl) alkylsulfonyl] the oxygen base]-1-(3-chloro-2-pyridyl)-4; 5-dihydro-1H-pyridine-5-ethyl formate (8.51; 20.07mmol) be cooled to 0 ℃; to wherein feeding bromize hydrogen gas uniformly; HPLC detects no raw material after 2 hours; stirring at room 2 hours; logical nitrogen is driven excessive bromize hydrogen gas away, is cooled to 0 ℃, adds ammoniacal liquor to PH=7 to reactant; (3 * 40mL) washings of reaction solution water; anhydrous sodium sulfate drying, decompression removes solvent, gets garnet oily matter; placement is spent the night, and separates out red crystals.Isolate desired title compound, red solid (5.91g).Make 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyridine-5-formic acid with reference to correlation method among the embodiment 1.

Step C: preparation N-methyl-N-methoxyl group-2-amino-3-methyl-5-chloro benzamide

With 3-methyl-5-chloro isatoic anhydride (0.42g, 1.98mmol) ethyl acetate (8ml) solution stirring at room after 10 minutes, drip glacial acetic acid (0.04g), stir after 0.5 hour, then slowly drip dimethyl azanol hydrochloride (0.23g, 2.38mmol) and sodium bicarbonate (0.20g, 2.38mmol) water (0.30g) solution, be added dropwise to complete back stirring at room 24 hours, after HPLC detects no raw material, with reaction solution once with the 3g water washing, the organic phase anhydrous sodium sulfate drying, obtain title compound, light yellow look solid (0.34g) except that after desolvating.

Step D: carbonyl amino preparation 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-chloro-2-methyl-6-[((N-methyl-N-methoxyl group))] phenyl]-1H-pyrazoles-5-methane amide (compound 14 in the table 1)

(0.50g, (0.50g, 4.20mmol), reflux 12 hours removes solvent to drip thionyl chloride in toluene 1.65mmol) (5ml) solution to 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-formic acid.Add methylene dichloride (7ml), (0.35g 1.65mmol) handles reactant with N-methyl-N-methoxyl group-2-amino-3-methyl-5-chloro benzamide, stir drip after 5 minutes triethylamine (0.40g, 3.96mmol), stirring at room 5 hours, HPLC removes solvent after detecting no raw material.Resistates is carried out purifying with silica gel column chromatography (chloroform wash-out).Isolate desired title compound, a kind of compound of the present invention, yellow powder (0.22g), m.p.167.2-168.5 ℃.

Embodiment 8

The preparation method of compound 15 in this example instruction card 1.

Steps A: preparation 2-[3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-yl]-8-methyl-4H-3,1-benzoxazine-4-ketone

Under the room temperature condition, to pyridine (2.61g, 33.04mmol) acetonitrile (9ml) solution in add 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-carboxylic acid (3.60g, 11.9mmol), then reaction mixture is cooled to-5 ℃, stir after 10 minutes, to wherein dripping Methanesulfonyl chloride (1.78g, 15.5mmol) acetonitrile solution (12mL), stir after 5 minutes to wherein adding 2-amino-3-tolyl acid (1.80g, 11.9mmol), stir that (2.61g, acetonitrile 33mmol) (9mL) solution stir after 15 minutes again to wherein slowly dripping Methanesulfonyl chloride (1.78g to wherein slowly dripping pyridine after 2 minutes, 15.5mmol) acetonitrile (6ml) solution, stir and slowly be warming up to room temperature reaction 12 hours after 15 minutes.In reactant, slowly drip water (17g), stirred 15 minutes.Product separates after filtration, with acetonitrile solution (3mL * 3) washing that contains 33% water, uses acetonitrile (2mL * 2) washing again, infrared lamp oven dry down.Isolate desired title compound, pale solid (3.65g).

Step B: preparation N-hydroxyphthalimide

Under the room temperature condition, with yellow soda ash (56.73g, 0.535mol) (74.38g is in water 1.07mol) (245mL) solution for the oxammonium hydrochloride that add to stir, stirred 10 minutes, in 1 hour, in reactant, add in batches Tetra hydro Phthalic anhydride (160g, 1.08mol), add finish after, be warming up to 80 ℃, reacted 6.5 hours, HPLC detects no raw material, reduces to room temperature.Reactant is filtered water (3 * 20ml) washings, natural air drying.Isolate desired title compound, milk yellow solid (143.02g).

Step C: preparation N-oxyethyl group phthalic imidine

Under the room temperature condition, with monobromethane (2.77g, 25.41mmol) adding N-hydroxyphthalimide (3.18g, N 19.5mmol) is in dinethylformamide (8mL) solution, stirred 5 minutes, (3.12g 30.89mmol), is warming up to 80 ℃ after being added dropwise to complete slowly to drip triethylamine in reactant, reacted 13 hours, and be chilled to room temperature.White precipitate of good quality is told in filtration.Filter cake N, the dinethylformamide washing.Filtrate is slowly poured in the frozen water (40mL) of stirring, stirs 2 hours, mixture is filtered water (3 * 10ml) washings, natural air drying.Isolate desired title compound, white solid (3.02g).

Step D: preparation ethoxy amine hydrochloride

With N-oxyethyl group phthalic imidine (3.02g, hydrochloric acid 15.81mmol) (20mL) solution is heated to 80 ℃, reacts 3.5 hours, HPLC detects no raw material, reduces to room temperature.White precipitate of good quality is told in filtration.(2 * 5mL) washings, decompression removes solvent to filtrate with ethyl acetate.Isolate desired title compound, white solid (0.92g).

Step e: amino preparation 3-bromo-1-(3-chloro-2-pyridyl)-N-[2-methyl-6-[((1-oxyethyl group))-carbonyl] phenyl]-1H-pyrazoles-5-methane amide (compound 15 in the table 1)

To 2-[3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-yl]-8-methyl-4H-3,1-benzoxazine-4-ketone (0.25g, 0.60mmol) THF (4ml) solution in slowly drip ethoxy amine hydrochloride (0.24g, 2.46mmol) and sodium hydroxide (0.10g, 2.50mmol) mixture in water (0.30g), be added dropwise to complete back room temperature reaction 24 hours.Drip water (2g) then, stirring reduced pressure after 15 minutes removes THF, stirs 30 minutes after-filtration to wherein adding acetonitrile (4ml), with acetonitrile solution (2ml * 3) washing that contains 25% water, uses acetonitrile (2ml * 2) washing again, oven dry under the infrared lamp.Isolate desired title compound, a kind of compound of the present invention, white powder (0.20g), m.p.198.5-199.5 ℃.

Embodiment 9

The preparation method of compound 26 in this example instruction card 1.

Preparation 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-chloro-2-methyl-6-[((2-chloroallyloxyamino) carbonyl amino)] phenyl]-1H-pyrazoles-5-methane amide (compound 26 in the table 1)

To 2-[3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-ketone (0.45g, 1.00mmol) THF (4ml) solution in slowly drip 2-propenyl chloride oxygen amine hydrochlorate (0.58g, 4.00mmol) and sodium hydroxide (0.16g, 4.00mmol) mixture in water (0.30g), be added dropwise to complete back room temperature reaction 24 hours.Drip water (2g) then, stirring reduced pressure after 15 minutes removes THF, stirs 30 minutes after-filtration to wherein adding acetonitrile (4ml), with acetonitrile solution (2ml * 2) washing that contains 25% water, uses acetonitrile (2ml * 2) washing again, oven dry under the infrared lamp.Isolate desired title compound, a kind of compound of the present invention, white powder (0.21g), m.p.182.2-182.4 ℃.

Embodiment 10

The preparation method of compound 29 in this example instruction card 1.

Steps A: preparation 2-amino-3-methyl-5-chloro phenylformic acid

Under the room temperature condition, (3.02g, (2.66g 20mmol), is heated to 100 ℃ with reaction mixture after adding is finished, and reacts 30 minutes, stops heating, and room temperature reaction spends the night to add NCS in DMF 20mmol) (10ml) solution to 2-amino-3-tolyl acid.To obtain pale red brown solid in the reaction mixture frozen water (50ml) that impouring is stirred lentamente.Stir after 1 hour mixture is filtered, water (4 * 10ml) washings, infrared lamp oven dry down.Isolate desired title compound, pale red brown solid (2.90g).

Step B: preparation 2-[3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-ketone

Under the room temperature condition, to pyridine (2.61g, 33.04mmol) acetonitrile (12ml) solution in add 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-carboxylic acid (3.60g, 11.9mmol), then reaction mixture is cooled to-5 ℃, stir after 10 minutes, to wherein dripping Methanesulfonyl chloride (1.78g, 15.5mmol) acetonitrile solution (12mL), stir after 5 minutes to wherein adding 2-amino-3-tolyl acid (2.21g, 11.9mmol), stir that (2.61g, acetonitrile 33mmol) (9mL) solution stir after 15 minutes again to wherein slowly dripping Methanesulfonyl chloride (1.78g to wherein slowly dripping pyridine after 2 minutes, 15.5mmol) acetonitrile (6ml) solution, stir and slowly be warming up to room temperature reaction 12 hours after 15 minutes.In reactant, slowly drip water (17g), stirred 15 minutes.Product separates after filtration, with acetonitrile solution (3mL * 3) washing that contains 33% water, uses acetonitrile (2mL * 2) washing again, infrared lamp oven dry down.Isolate desired title compound, pale solid (3.72g).

Step C: preparation N-cyclo propyl methoxy phthalic imidine

Under the room temperature condition, (4.00g 29.60mmol) adds N-hydroxyphthalimide (4.39g, N 26.9mmol) with monobromethane, in dinethylformamide (6mL) solution, stirred 5 minutes, and slow dropping triethylamine in reactant (4.10g, 40.59mmol), be warming up to 60 ℃ after being added dropwise to complete, reacted 13 hours, HPLC detects no raw material, reduces to room temperature.White precipitate of good quality is told in filtration.Filter cake N, the dinethylformamide washing.Filtrate is slowly poured in the frozen water (35mL) of stirring, stirs 2 hours, mixture is filtered water (3 * 10ml) washings, natural air drying.Isolate desired title compound, white solid (4.78g).

Step D: preparation N-cyclopropyl methoxamine hydrochloride

Under the room temperature condition, with N-cyclo propyl methoxy phthalic imidine (4.78g, 22.03mmol) add concentrated hydrochloric acid (5.00g, water 50.00mmol) (20mL) solution, reflux 1 hour, HPLC detects no raw material, reduces to room temperature.White precipitate of good quality is told in filtration.(2 * 5mL) washings, decompression removes solvent to filtrate with ethyl acetate.Isolate desired title compound, white solid (1.95g).

Step e: amino preparation 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-chloro-2-methyl-6-[((1-cyclo propyl methoxy))-carbonyl] phenyl]-1H-pyrazoles-5-methane amide

To 2-[3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-ketone (0.45g, 1.00mmol) THF (4ml) solution in slow dripping hydrochloric acid N-cyclopropyl methoxamine hydrochloride (0.62g, 5.02mmol) and sodium hydroxide (0.20g, 5.00mmol) mixture in water (0.30g), be added dropwise to complete back room temperature reaction 24 hours.Drip water (3g) then, stirring reduced pressure after 15 minutes removes THF, stirs 30 minutes after-filtration to wherein adding acetonitrile (7ml), with acetonitrile solution (3ml * 3) washing that contains 25% water, uses acetonitrile (3ml * 2) washing again, oven dry under the infrared lamp.Isolate desired title compound, a kind of compound of the present invention, granular powder (0.36g), m.p.190.0-190.5 ℃.

Embodiment 11

The preparation method of compound 34 in this example instruction card 1.

Preparation 3-bromo-1-(3-chloro-2-pyridyl)-N-[4-iodo-2-methyl-6-[((1-methoxyl group) amino)-and carbonyl] phenyl]-1H-pyrazoles-5-methane amide

Steps A: preparation 2-amino-3-methyl-5-cyanobenzoic acid

Under the room temperature condition, (8.5g, (3.60g 40.00mmol), is heated to 140 ℃ with reaction mixture after adding is finished and reacted 24 hours to add cuprous cyanide in DMF 30.69mmol) (100ml) solution to 2-amino-3-methyl-5-iodo-benzoic acid.Then, remove most of solvent in decompression with the reaction mixture cooling.(50ml) joins in the residue with tetrahydrofuran (THF), the vigorous stirring mixture is to dissolve most of solid, filter and remove residual solid, in filtrate, add entry (50ml), decompression removes tetrahydrofuran (THF), adds quadrol (10ml) subsequently, and the vigorous stirring mixture is with the dissolved solids material then, in filtrate, add concentrated hydrochloric acid and regulate PH=5, when PH reduces, be settled out a large amount of solids.Mixture is filtered the water of PH=5 (3 * 5mL) washings, natural air drying.Isolate desired title compound, brown solid (4.00g).

Step B: preparation 2-[3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-yl]-6-cyano group-8-methyl-4H-3,1-benzoxazine-4-ketone

Under the room temperature condition, to pyridine (0.69g, 8.34mmol) acetonitrile (7ml) solution in add 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-carboxylic acid (1.95g, 6.45mmol), then reaction mixture is cooled to-5 ℃, stir after 10 minutes, to wherein dripping Methanesulfonyl chloride (0.99g, 8.65mmol) acetonitrile solution (6mL), stir after 5 minutes to wherein adding 2-amino-3-methyl-5-cyanobenzoic acid (1.17g, 6.64mmol), stir that (1.42g, acetonitrile 17.97mmol) (6mL) solution stir after 15 minutes again to wherein slowly dripping Methanesulfonyl chloride (0.99g to wherein slowly dripping pyridine after 2 minutes, 8.65mmol) acetonitrile solution (3mL), stir and slowly be warming up to room temperature reaction 12 hours after 15 minutes.In reactant, slowly drip water (3g), stirred 15 minutes.Product separates after filtration, with acetonitrile solution (3mL * 3) washing that contains 33% water, uses acetonitrile (2mL * 1) washing again, infrared lamp oven dry down.Isolate desired title compound, pale solid (2.23g).

Step C: amino preparation 3-bromo-1-(3-chloro-2-pyridyl) N-[4-cyano group-2-methyl-6-[((1-methoxyl group))-carbonyl] phenyl]-1H-pyrazoles-5-methane amide

To 2-[3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-yl]-6-cyano group-8-methyl-4H-3,1-benzoxazine-4-ketone (0.50g, 1.13mmol) THF (5ml) solution in slowly drip 2-propenyl chloride oxygen amine hydrochlorate (0.72g, 5.00mmol) and sodium hydroxide (0.20g, 5.00mmol) mixture in water (0.30g), be added dropwise to complete back room temperature reaction 24 hours.Drip water (2g) then, stirring reduced pressure after 15 minutes removes THF, stirs 30 minutes after-filtration to wherein adding acetonitrile (4ml), with acetonitrile solution (2ml * 3) washing that contains 25% water, uses acetonitrile (2ml * 2) washing again, oven dry under the infrared lamp.Isolate desired title compound, a kind of compound of the present invention, pale yellow powder (0.21g), m.p.108.0 ℃ (incipient melting).

Embodiment 12

The preparation method of compound 37 in this example instruction card 1.

The adjacent chlorine benzyloxy of preparation 3-bromo-1-(3-chloro-2-pyridyl)-N-[2-methyl-6-[((1-) amino)-and carbonyl] phenyl]-1H-pyrazoles-5-methane amide

Steps A: the adjacent chlorine benzyloxy of preparation N-phthalic imidine

Under the room temperature condition, (17.70g 109.94mmol) adds N-hydroxyphthalimide (16.30g, N 100.00mmol) with o-chloro benzyl chloride, in dinethylformamide (40mL) solution, stirred 10 minutes, and slow dropping triethylamine in reactant (15.15g, 150.00mmol), be warming up to 80 ℃ after being added dropwise to complete, reacted 13 hours, HPLC detects no raw material, reduces to room temperature.White precipitate of good quality is told in filtration.Filter cake N, the dinethylformamide washing.Filtrate is slowly poured in the frozen water (40mL) of stirring, stirs 2 hours, mixture is filtered water (3 * 25ml) washings, natural air drying.Isolate desired title compound, white solid (18.81g).

Step B: prepare adjacent benzyl chloride oxygen amine

Under the room temperature condition, with hydrazine hydrate (80%, 3.60g, 57.60mmol) (3.60g in dehydrated alcohol 12.50mmol) (50mL) solution, is heated to backflow to drip the adjacent chlorine benzyloxy of N-phthalic imidine, reacted 5 hours, HPLC detects no raw material, reduces to room temperature.White precipitate of good quality is told in filtration.The filtrate decompression precipitation gets yellow solid matter, and to wherein adding tetrahydrofuran (THF) (50mL), vigorous stirring 10 minutes is filtered, and filtrate removes solvent.Isolate desired title compound, light yellow liquid (1.47g).

Step C: the amino adjacent chlorine benzyloxy of preparation 3-bromo-1-(3-chloro-2-pyridyl)-N-[2-methyl-6-[((1-))-carbonyl] phenyl]-1H-pyrazoles-5-methane amide (compound 37 in the table 1)

To 2-[3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazoles-5-yl]-8-methyl-4H-3,1-benzoxazine-4-ketone (0.45g, 1.08mmol) THF (5ml) solution in slowly drip adjacent benzyl chloride oxygen amine (0.79g, 2.46mmol) tetrahydrofuran (THF) (2ml) solution, be added dropwise to complete back room temperature reaction 24 hours.HPLC detects no raw material, drips water (20g) then, removes tetrahydrofuran (THF), adds trichloromethane (20ml) in the resistates and stirs 15 minutes, then reactant is filtered, and trichloromethane (3ml * 2) washing is used in water (2ml * 3) washing again, infrared lamp oven dry down.Isolate desired title compound, a kind of compound of the present invention, white powder end (0.12g), m.p.203.0-204.0 ℃.

Embodiment 13

The preparation suspension agent: the wetting dispersing agent with 2-6% is diluted in the frostproofer of 4-10% earlier, and in this solution, slowly add a certain amount of water, then under the high speed shear cutter stirs, formula provided by the invention (I) active compound that adds 5-80% successively, the 0.01-0.05% sanitas, 0.01-0.05% defoamer and thickening material etc.Mill in the last impouring sand mill, add solvent again to volume.Be diluted with water to required any concentration during use.

Embodiment 14

3-bromo-1-(3-chloro-2-pyridyl)-N-[4-chloro-2-methyl-6-[((methoxyl group) amino)-and carbonyl] phenyl]-preparation of 1H-pyrazoles-5-methane amide (01) 10% suspension agent

Earlier with 5 parts of suitable tensio-active agents such as naphthalenesulfonic acid-formaldehyde condensate, the sodium dibutyl naphthalene sulfonate formaldehyde condensation products is diluted in 5 parts of suitable frostproofers such as ethylene glycol, in the glycerol, and in this solution, slowly add entry, under stirring fast, add 10 parts of active compound 3-bromo-1-provided by the invention (3-chloro-2-pyridyl)-N-[4-chloro-2-methyl-6-[((methoxyl group successively) amino)-carbonyl] phenyl]-1H-pyrazoles-5-methane amide (01) and other suitable auxiliary agent such as sanitas (phenylformic acid or formaldehyde etc.), defoamer (organic silicone) and thickening material (xanthan gum or carboxymethyl cellulose etc.), finish the back it is milled, add residual solvent at last to volume.

Embodiment 15

Preparation concentrates floating agent: water, tensio-active agent, antifreezing agent, defoamer, thickening material and the sanitas with certain proportioning mixes composition homogeneous water earlier, formula provided by the invention (I) compound, suitable solvent and emulsifying agent, co-emulsifier mixed making it become even oil phase then.At last under high-speed stirring with the even oil phase emulsifiable concentrates that promptly can be made into mixed with water.Be diluted with water to required any concentration during use.

Institute's synthetic compound is carried out desinsection and acaricidal activity test, now listed the experimental result of part of compounds.

The evaluated biological activity of 16 pairs of mythimna separatas of embodiment (Mythimna separata)

Will be by the wettable powder of the provided by the invention adjacent amino N-oxybenzamide compounds of above-mentioned Agrotechnical formulation embodiment method preparation or emulsifiable concentrate, dilute with water is made into the pesticidal solutions of predetermined concentration, choose 20 3 age mythimna separata and 10 one cun long maize leafs be put in the culture dish and quantitatively spray, dry the back and move into normal raising the in the greenhouse, statistics survival and death toll after 24-72 hour.Experiment repeats 3 times, results averaged.Activity in per-cent, is divided into A, B, C, D level Four with respect to blank, and mortality ratio 100%-90% is the A level, and mortality ratio 90%-70% is the B level, and mortality ratio 70%-50% is the C level, and mortality ratio 0%-50% is the D level.Partial test the results are shown in Table 3 and table 4.

Table 3 part of compounds when test concentrations is 1000mg/l to the activity of mythimna separata (Mythimna separata)

Compound	Active rank	Compound	Active rank	Compound	Active rank	Compound	Active rank
Compound	Active rank	Compound	Active rank	Compound	Active rank	Compound	Active rank	01	A	11	A	21	A	31	A
02	A	12	A	22	A	32	A	01	A	11	A	21	A	31	A
02	A	12	A	22	A	32	A	03	A	13	A	23	A	33	A
04	A	14	A	24	A	34	A	03	A	13	A	23	A	33	A
04	A	14	A	24	A	34	A	05	A	15	A	25	A	35	A
06	A	16	A	26	A	36	A	05	A	15	A	25	A	35	A
06	A	16	A	26	A	36	A	07	A	17	C	27	A	37	A
08	A	18	A	28	A	38	A	07	A	17	C	27	A	37	A
08	A	18	A	28	A	38	A	09	A	19	D	29	A	39	A
10	A	20	B	30	A	40	A	09	A	19	D	29	A	39	A

Table 4 part of compounds when test concentrations is 100mg/l to the activity of mythimna separata (Mythimna separata)

Compound	Active rank	Compound	Active rank	Compound	Active rank	Compound	Active rank
Compound	Active rank	Compound	Active rank	Compound	Active rank	Compound	Active rank	01	A	10	A	16	A	26	A
02	A	11	A	18	A	29	A	01	A	10	A	16	A	26	A
02	A	11	A	18	A	29	A	04	A	12	A	21	A	30	A
05	A	13	A	22	A	32	A	04	A	12	A	21	A	30	A
05	A	13	A	22	A	32	A	08	A	14	A	23	A	33	A
09	A	15	A	25	A			08	A	14	A	23	A	33	A

The acaricidal activity evaluation of 17 pairs of two-spotted spider mites of embodiment (Tetranychus urticae)

Method is as follows: the bean seedlings of selecting to grow fine are inoculated red spider, after treating that red spider grows surely, flooded 10 seconds being with the mite bean seedlings to cut in the provided by the invention adjacent amino N for preparing-oxybenzamide compounds soup, taking-up is inhaled with filter paper and is removed unnecessary soup, insert in the beaker that is filled with water, in observing indoor cultivation, checking after 24 hours survival and dead mite number has 100-200 mite on every strain bean seedlings.Experiment repeats 3 times.Results averaged.Activity in per-cent, is divided into A, B, C, D level Four with respect to blank, and grade scale is with embodiment 16.The partial test result shows that compound 01,04 is the A level to the acaricidal activity of two-spotted spider mite (Tetranychus urticae) when test concentrations is 500mg/l, compound 02,05 is the B level to the acaricidal activity of two-spotted spider mite (Tetranychus urticae) when test concentrations is 500mg/l.

The insecticidal activity evaluation of 18 pairs of rice green leafhoppers of embodiment (Nephotettix cincticeps)

Will be by the missible oil or the wettable powder of the provided by the invention adjacent amino N-oxybenzamide compounds of above-mentioned Agrotechnical formulation embodiment method preparation, dilute with water is made into the pesticidal solutions of predetermined concentration, choosing two core rice seedlings immerses in the soup, take out after 5 seconds and dry, place Boiling tube, 20 or above rice green leafhopper nymph in 5 age are introduced in every pipe 20 strains then, the mouth of pipe is placed under the greenhouse experiment with white gauze wrapping, checks survival and dead borer population after 24 hours.Experiment repeats 3 times.Results averaged.Activity in per-cent, is divided into A, B, C, D level Four with respect to blank, and grade scale is with embodiment 16.Partial test the results are shown in Table 5.

Table 5 part of compounds when test concentrations is 500mg/l to the activity of rice green leafhopper (Nephotettix cincticeps)

Compound	01	02	18
Compound	01	02	18	Active rank	A	B	B

The insecticidal activity evaluation of 19 pairs of bean aphids of embodiment (Aphis fabae)

Will be by the missible oil or the wettable powder of the provided by the invention adjacent amino N-oxybenzamide compounds of above-mentioned Agrotechnical formulation embodiment method preparation, dilute with water is made into the pesticidal solutions of predetermined concentration, bean aphid is connected on the bean seedlings that just have been unearthed, every strain connects more than 20, then bean seedlings is dipped in the soup together with the examination worm, takes out after 5 seconds, unnecessary soup is removed in suction, insert in the sponge of suction, cover, check survival and dead borer population after 24 hours with glass-tube.Repeat results averaged 3 times.Active blank relatively is divided into A, B, C, D level Four in per-cent, and grade scale is with embodiment 16.Partial test the results are shown in Table 6.

Table 6 part of compounds when test concentrations is 500mg/l to the activity of bean aphid (Aphis fabae)

Compound	01	02	04	05	08	27
Compound	01	02	04	05	08	27	Active rank	A	B	A	B	A	B

Claims

1. be selected from the adjacent amino N-oxybenzamide compounds with insecticidal activity of formula (I), its N-oxide compound or salt

Wherein:

R ¹Be H or CH ₃

R ²Be H, C ₁-C ₃Alkyl, C ₃-C ₆Alkenyl, C ₃-C ₆Alkynyl, C ₁-C ₃Haloalkyl, C ₃-C ₆Halogenated alkenyl, C ₃-C R ²Be H, C ₁-C ₃Alkyl, C ₃-C ₆Alkenyl, C ₃-C ₆Alkynyl, C ₁-C ₃Haloalkyl, C ₃-C ₆Halogenated alkenyl, C ₃-C ₆Halo alkynyl, C ₃-C ₆Methyl cycloalkyl, C ₃-C ₆Halogenated cycloalkyl methyl, substituted-phenyl methyl or C ₅-C ₁₀The heteroaryl methyl;

R ³Be H or halogen;

R ⁴Be halogen, trifluoromethyl, OCH ₂CF ₃Or OCF ₂H;

R ⁵Be H, halogen or methyl;

R ⁶Be H, halogen or cyano group;

Or its agricultural goes up the salt that is suitable for;

Halogen: refer to fluorine, chlorine, bromine, iodine;

Alkyl: refer to the straight or branched alkyl;

Haloalkyl: refer to the straight or branched alkyl, the hydrogen atom on these alkyl can partly or entirely be replaced by halogen atom; " haloalkenyl group ", the definition and the term " haloalkyl " of " halo alkynyl " and " halogenated cycloalkyl " are identical;

2. according to the adjacent amino N-oxybenzamide compounds shown in the claim 1, it is characterized in that preferred compound is with insecticidal activity:

The compound of formula (I), wherein R ¹Be H or CH ₃R ²Be H, C ₁-C ₃Alkyl, allyl group, propargyl, halogenated allyl, acetylenic halide propyl group, C ₃-C ₆Methyl cycloalkyl; R ³It is halogen; R ⁴It is halogen; R ⁵It is methyl; R ⁶Be H, halogen or cyano group; Or its agricultural goes up the salt that is suitable for;

The compound of formula (I), wherein R ¹Be H; R ²Be methyl, allyl group, propargyl, halogenated allyl, acetylenic halide propyl group; R ³Be chlorine; R ⁴Be chlorine, bromine; R ⁵It is methyl; R ⁶Be H, chlorine, bromine or cyano group; Or its agricultural goes up the salt that is suitable for.

3. according to the adjacent amino N-oxybenzamide compounds shown in claim 1 or 2, it is characterized in that particularly preferred compound is with insecticidal activity:

4, according to claim 1 or 2,3 described adjacent amino N-oxybenzamide compounds, it is characterized in that the compound shown in the formula (I) comprises geometrical isomer E formula and Z formula with insecticidal activity, and the mixture of E formula and Z formula.

5, according to claim 1 or 2,3 described preparation methods with adjacent amino N-oxybenzamide compounds of insecticidal activity, it is characterized in that in solvents tetrahydrofurane (THF), in 10-100 ℃, obtain the compound of formula (I) with the compound of any one processing formula (III) in salt of wormwood or potassium hydroxide, sodium bicarbonate, yellow soda ash, the sodium hydroxide and formula (II), reaction formula is as follows:

R in the formula ¹, R ², R ³, R ⁴, R ⁵, R ⁶Has the above-mentioned definition of giving.

6, according to claim 1 or 2,3 described preparation methods with adjacent amino N-oxybenzamide compounds of insecticidal activity, it is characterized in that in solvent acetonitrile, in-10～0 ℃, in the presence of pyridine, the compound of handling formula V (Y=OH) and formula (IV) with Methanesulfonyl chloride obtains the compound of formula (I); Or in methylene dichloride, in-10 ℃ to the solvent refluxing temperature, add triethylamine or pyridine in case of necessity, obtain the compound of formula (I) with the reaction of the compound of formula (IV) and formula V (Y=Cl), reaction formula is as follows:

7, the preparation method with adjacent amino N-oxybenzamide compounds of insecticidal activity according to claim 5, the preparation method who it is characterized in that the compound of formula (III) is at solvent N, in the dinethylformamide (DMF), in the presence of the acid binding agent triethylamine, R ²X and N-hydroxyphthalimide react, and obtain the compound of formula (IX), with the compound of salt acid treatment formula (IX), obtain the compound of formula (III), and reaction formula is as follows:

R in the formula ¹, R ²Has the above-mentioned definition of giving.

8, the preparation method with adjacent amino N-oxybenzamide compounds of insecticidal activity according to claim 6, the preparation method who it is characterized in that the compound of formula (IV) is in solvents tetrahydrofurane, obtain the compound of formula (VIII) with the compound of light gas disposal formula (VI), the compound of handling formula (VIII) according to well-known process obtains the compound of formula (X); And then in solvent ethyl acetate, the compound of handling formula (X) and formula (III) with sodium hydroxide or sodium bicarbonate obtains the compound of formula (IV), and reaction formula is as follows:

R in the formula ¹, R ², R ⁵, R ⁶Has the above-mentioned definition of giving.

9. according to claim 1 or 2,3 described purposes with adjacent amino N-oxybenzamide compounds of insecticidal activity, it is characterized in that the single use of formula (I) compound or be used in combination that insect and mite are had prevention effect with other bioactive compounds.