CN104496901B

CN104496901B - The manufacture method of anthranilamide compound

Info

Publication number: CN104496901B
Application number: CN201410822432.0A
Authority: CN
Inventors: 小柳彻; 山元一浩; 米田哲夫; 上林繁久; 谷村丰史; 田口阳平; 吉田辰德
Original assignee: Ishihara Sangyo Kaisha Ltd
Current assignee: Ishihara Sangyo Kaisha Ltd
Priority date: 2006-12-15
Filing date: 2007-12-14
Publication date: 2016-05-25
Anticipated expiration: 2027-12-14
Also published as: CN104496901A

Abstract

The invention provides the manufacture method of a kind of specific anthranilamide compound or its salt. Anthranilamide compound shown in formula (I) or the manufacture method of its salt are provided, comprise the operation of the compound selective ground halogenation making shown in formula (II),In formula, R^1aAnd R³Be halogen or haloalkyl independently respectively; R²For cyclopropyl alkyl or cyclobutyl alkyl; Hal is chlorine atom or bromine atoms,In formula, R^1a、R²And R³As mentioned above.

Description

The manufacture method of anthranilamide compound

The present application is that application number is 201310116942.1 (its female case application number is 200780046280.8), inventionManufacture method, the applying date that name is called anthranilamide compound are the division Shen of the application on December 14th, 2007Please.

Technical field

The present invention relates to the manufacture method of anthranilamide compound.

Background technology

About anthranilamide compound, for example, it is disclosed in patent documentation 1 as agriculture gardening fieldNoxious organism control agent shows excellent effect. On the other hand, in patent documentation 2 and 3, recorded certain o-amino benzoylThe manufacture method of acid amides based compound.

Patent documentation 1: International Publication communique WO2005/077934

Patent documentation 2: International Publication communique WO2003/016283

Patent documentation 3: International Publication communique WO2004/011453

Summary of the invention

All the time, about the manufacture method of anthranilamide compound, the whole bag of tricks is proposed, but requirementManufacture more efficiently and at an easy rate aftermentioned formula (I) specific substituting group mode anthranilamide compound orThe method of its salt.

The present inventors, in order to solve above-mentioned problem, conduct in-depth research, and found that the change shown in through type (II)The optionally halogenation of compound, can manufacture anthranilamide compound or its salt shown in formula (I) with high yield, andAnd can manufacture efficiently the compound of the formula (II-1) as one of its raw material, thereby complete the present invention. , the present inventionRelate to anthranilamide (Anthranilamide) based compound shown in a kind of formula (I) or the manufacture method of its salt, itsBe characterised in that, the compound shown in formula (II) reacted with halogenating agent,

(in formula, R^1aAnd R³Be halogen or haloalkyl independently respectively, R²For cyclopropyl alkyl or cyclobutyl alkyl),

(in formula, Hal is chlorine atom or bromine atoms, R^1a、R²And R³As mentioned above). In addition, the present invention relates to a kind of adjacent ammoniaThe manufacture method of yl-benzamide based compound or its salt is the R of above-mentioned formula (I)³For the compound of the formula (I-1) of bromine atomsManufacture method, is characterized in that, the compound shown in above-mentioned formula (II-1) is reacted with halogenating agent,

(in formula, R^1a、R²Described above with Hal)

(in formula, R^1aAnd R²As mentioned above).

In addition, the present invention relates to the manufacture method of the compound of above-mentioned formula (I-1), make compound and the halogen of formula (II-1)Agent reaction, wherein, the compound of described formula (II-1) is that the compound shown in formula (III-1) and oxidant reaction are obtained, or make the compound shown in formula (IV-1) react with the compound shown in formula (V-1) obtain,

(in formula, R^1aAnd R²As mentioned above)

(in formula, R⁴C₅-C₁₀Alkyl oxy, can substituted phenoxy group, can substituted benzyl oxygen base, alkyl sulfenyl,Can substituted phenyl sulfenyl or can substituted benzyl sulfenyl),

(in formula, R^1aAnd R²As mentioned above). In addition, the present invention relates to as shown in the formula (II-1) of the raw material of above-mentioned reactionThe manufacture method of compound, the compound shown in formula (VI-1) is reacted with the compound shown in formula (VII), carry out manufacture formula(VIII-1) compound shown in, makes the compound of obtained formula (VIII-1) react with sulfonic acid chloride, chlorinating agent or acid chloride,Compound shown in manufacture formula (IX-1), then, makes the compound of obtained formula (IX-1) react with bromating agent, carrys out manufacture formula(III-1) compound shown in, and then make compound and the oxidant reaction of obtained formula (III-1), carry out manufacture formula (II-1) compound,

(in formula, R^1aAnd R²As mentioned above),

(in formula, R^1aAnd R²As mentioned above)

(in formula, X be chlorine atom or bromine atoms)

(in formula, R^1aAnd R²As mentioned above),

(in formula, L is alkylsulfonyloxy, alkoxy-carbonyl oxy, alkyl-carbonyl oxygen base, phenyl sulfonyloxy, to tolueneSulfonyloxy or chlorine atom, R^1aAnd R²As mentioned above)

(in formula, R^1aAnd R²As mentioned above). In addition, the present invention relates to the compound or its salt shown in formula (II-1); Formula(V-1) compound or its salt shown in; Compound shown in compound or its salt shown in formula (VI-1), formula (VIII-1) or itsSalt; The compound or its salt of formula (IX-1); Compound or its salt shown in formula (III-1); Compound shown in formula (X-1) or itsSalt; And the compound or its salt shown in formula (XI-1);

(in formula, R^1aAnd R²As mentioned above)

(in formula, R^1a、R²Described above with L)

(in formula, R^1aAnd R²As mentioned above)

(in formula, R⁵For alkyl, R^1aAnd R²As mentioned above),

(in formula, R^1aAnd R⁵As mentioned above).

As R^1a、R²、R³、R⁴Or R⁵In alkyl or moieties, can list methyl, ethyl, propyl group, isopropyl,The alkyl of the straight chain that butyl, isobutyl group, the tert-butyl group, amyl group, hexyl are such or branched C1-C6. In addition, R⁴" C5-C10Alkyl oxy " in moieties can be straight chain, can be also branched.

R^1aOr R³In halogen or as substituent halogen, can list each atom of fluorine, chlorine, bromine, iodine. As gettingThe number of the halogen of Dai Ji can be more than 1 or 2, is being 2 above in the situation that, and each halogen can be the same or different. In addition,The position of substitution of halogen can be position arbitrarily.

As R⁴The substituting group of phenoxy group, benzyl oxygen base, phenyl sulfenyl and benzyl sulfenyl, can list chlorine atom,Bromine atoms, methyl, methoxyl group or nitro.

There is the isomers of cis body and trans body in formula (X-1) and compound (XI-1), can be either party, also canThink its mixture.

As the salt of above-claimed cpd, as long as allow, can comprise any form on agricultural chemicals. Can list exampleAlkali metal salt as sodium salt, sylvite; Magnesium salts, the such alkali earth metal salt of calcium salt; Dimethyl ammonium, triethyl ammonium salt thatThe ammonium salt of sample; Hydrochloride, perchlorate, sulfate, the such inorganic salts of nitrate; Such organic of acetate, mesylateHydrochlorate etc.

The method according to this invention, it is former that the specific position that can be manufactured on efficiently phenyl ring and pyrazole ring has halogenAnthranilamide compound or its salt of son.

Detailed description of the invention

Below the manufacture method of anthranilamide compound of the present invention or its salt is elaborated.

The anthranilamide compound of formula (I) or its salt can be according to following reaction (A) and common saltManufacture method is manufactured.

In formula, R^1a、R²、R³Described above with Hal.

Reaction (A) can be by entering the compound of formula (II) conventionally under the existence of alkali and solvent with halogenating agent processingOK.

As the compound of formula (II), can list the chloro-2-of the bromo-N-[4-of 3-(1-cyclopropyl ethylaminoFormyl) phenyl]-1-(3-chloropyridine-2-yl)-1H-pyrazoles-5-formamide, the chloro-2-of the bromo-N-[4-of 3-(cyclopropyl methylamino formyl) phenyl]-1-(3-chloropyridine-2-yl)-1H-pyrazoles-5-formamide, N-[4-Chloro-2-(1-cyclopropyl ethylamino formyl) phenyl]-3-Trifluoromethyl-1-(3-chloropyridine-2-yl)-1H-Pyrazoles-5-formamide etc.

As halogenating agent, can select chlorine or bromine.

As alkali, can be from NaOH, lithium hydroxide, potassium hydroxide, such metal hydroxides, the hydrogen of calcium hydroxideChange in the such alkali metal alcoholates of sodium, hydrofining such alkali metal hydride, sodium methoxide, caustic alcohol, potassium tert-butoxide etc. suitablySelect one kind or two or more. Alkali, with respect to compound (II), can use 0.8～5 times mole, preferably 1～3.5 times mole.

As solvent, as long as the solvent to reactionlessness, can use any, can be from for example ether, butylMethyl ether, oxolane, twoAlkane, the such ethers of dimethoxy-ethane; Chlorobenzene, dichloro-benzenes, carrene, chloroform, tetrachloroChange carbon, dichloroethanes, trichloroethanes, the such halogenated hydrocarbons of dichloroethylene; Such aromatic hydrocarbon based of benzene,toluene,xylene;Pentane, hexane, heptane, octane, the such aliphatic hydrocarbon of cyclohexane; Methyl acetate, ethyl acetate, the such ester of propyl acetateClass; Acetone, methyl ethyl ketone, the such ketone of cyclohexanone; Acetonitrile, propionitrile, DMF, methyl-sulfoxide, pregnancyIn the polar aprotic solvent that base phosphoric triamide, sulfolane, dimethylacetylamide, 1-METHYLPYRROLIDONE are such etc. suitablySelect one kind or two or more.

Reaction (A) conventionally can-20～120 DEG C, preferably 0～80 DEG C carry out, its reaction time can be 0.5 conventionally～About 48 hours, preferably about 1～24 hour.

In above-mentioned reaction, R³For the compound of the formula (I-1) of bromine atoms can be by the compound manufacture of formula (II-1).

In formula, R^1a、R²Described above with Hal.

The compound of the formula (II-A) of the compound of contained (II-1) using in reaction (A) can be used (B)～(M)Or, the method manufacture of (N)～(Q).

In formula, R¹For alkyl, alkenyl, halogenated alkenyl, alkynyl group, halo alkynyl group, alkoxyl, halogenated alkoxy,Alkyl-carbonyl, halogenated alkyl carbonyl, alkoxy carbonyl, halo alkoxy carbonyl, nitro, formoxyl or cyano group, A is replaced by YAlkyl; Y can be selected from the C3-4 cycloalkyl that at least one substituting group in halogen, alkyl and haloalkyl replaces, mBe 0～4.

R¹, alkyl in A or Y or moieties can be straight chain or branched any one. As its concrete example, canList such C1-6 group of methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, amyl group, hexyl etc.

R¹In alkenyl or alkenyl part can be straight chain or branched any one. As its concrete example, canList vinyl, 1-acrylic, pi-allyl, isopropenyl, 1-cyclobutenyl, 1,3-butadiene base, the such C2-of 1-hexenyl6 group etc.

R¹In alkynyl group or alkynyl group part can be straight chain or branched any one. As its concrete example, canList the group of the C2-6 of acetenyl, 2-butynyl, valerylene base, 3-hexin Kina sample etc.

R¹Or halogen in Y or as substituent halogen, can list each atom of fluorine, chlorine, bromine, iodine. As gettingThe number of the halogen of Dai Ji can be more than 1 or 2, is being 2 above in the situation that, and each halogen can be the same or different. In addition,The position of substitution of halogen can be position arbitrarily.

Reaction (B) can be undertaken by compound and the oxidant of processing formula (III) conventionally under the existence of solvent, comesAnthranilamide compound shown in manufacture formula (II-A).

As the compound of formula (III), can list the bromo-N-of 3-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) benzeneBase)-1-(3-chloropyridine-2-yl)-4,5-dihydro-1 h-pyrazole-5-formamide, the bromo-N-of 3-(the chloro-6-of the bromo-4-of 2-(1-cyclopropylEthylamino formyl) phenyl)-1-(3-chloropyridine-2-yl)-4,5-dihydro-1 h-pyrazole-5-formamide, (4-is chloro-for the bromo-N-of 3-2-(1-cyclopropyl ethylamino formyl)-6-aminomethyl phenyl)-1-(3-chloropyridine-2-yl)-4,5-dihydro-1 h-pyrazole-5-firstAcid amides, the bromo-N-of 3-(the chloro-6-of the bromo-4-of 2-(cyclopropyl methylamino formyl) phenyl)-1-(3-chloropyridine-2-yl)-4,5-bis-Hydrogen-1H-pyrazoles-5-formamide, the bromo-N-of 3-(the chloro-2-of 4-(cyclopropyl methylamino formyl) phenyl)-1-(3-chloropyridine-2-Base)-4,5-dihydro-1 h-pyrazole-5-formamide etc.

As oxidant, can list 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone, chloranil, adjacent tetrachlorobenzeneQuinone, hydrogen peroxide, peroxidating two ammonium sulfate, peroxidating two sodium sulphate, potassium persulphate, potassium permanganate, OXONE (commodityName), clorox, sodium chlorite, benzoyl peroxide, TBHP, oxygen etc. Oxidant is with respect to formula (III)Compound, can use 1～10 times mole, preferably 1～4.5 times mole.

As solvent, as long as the solvent to reactionlessness, can be from for example oxolane, twoAlkane, dimethoxyThe ethers that base ethane is such; Acetone, the such ketone of methyl ethyl ketone; Chlorobenzene, dichloro-benzenes, carrene, chloroform, tetrachloroCarbon, dichloroethanes, trichloroethanes, the such halogenated hydrocarbons of dichloroethylene; Such aromatic hydrocarbon based of benzene,toluene,xylene; PentaAlkane, hexane, heptane, octane, the such aliphatic hydrocarbon of cyclohexane; Methyl acetate, ethyl acetate, the such ester of propyl acetateClass; Acetonitrile, propionitrile, DMF, methyl-sulfoxide, HMPA, sulfolane, dimethylacetylamide, N-In such polar aprotic solvent, acetic acid or the water etc. of methyl pyrrolidone, suitably select one kind or two or more.

Reaction (B) can common 0～150 DEG C, preferably carry out at 15～120 DEG C, its reaction time can be 0.5 conventionallyAbout～50 hours.

In above-mentioned reaction, the compound of formula (II-1) can be by the compound manufacture of formula (III-1).

In formula, R^1aAnd R²As mentioned above.

The compound of above-mentioned formula (III) can be manufactured according to reaction (C).

In formula, R¹, A, L and m described above.

Reaction (C) conventionally can be under the existence of solvent processing formula (IX) compound and wait a mole above bromating agentCarry out.

As the compound of formula (IX), can list 5-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl aminoFormyl)-1-(3-chloropyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-base 4-toluene sulfonic acide ester, 5-(the chloro-6-of the bromo-4-of 2-(1-cyclopropyl ethylamino formyl) phenyl amino formyl)-1-(3-chloropyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-base 4-Toluene sulfonic acide ester, 5-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl)-6-aminomethyl phenyl carbamyl)-1-(3-chlorine pyrrolePyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-base 4-toluene sulfonic acide ester, 5-(the chloro-6-of the bromo-4-of 2-(cyclopropyl methylamino firstAcyl) phenyl amino formyl)-1-(3-chloropyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-base 4-toluene sulfonic acide ester, 5-(4-Chloro-2-(1-cyclopropyl ethylamino formyl) phenyl amino formyl)-1-(3-chloropyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-methylmethane sulphonic acid ester, 5-(the chloro-6-of the bromo-4-of 2-(1-cyclopropyl ethylamino formyl) phenyl amino formyl)-1-(3-chlorine pyrrolePyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-methylmethane sulphonic acid ester, 5-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl)-6-Aminomethyl phenyl carbamyl)-1-(3-chloropyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-methylmethane sulphonic acid ester, (2-is bromo-for 5-The chloro-6-of 4-(cyclopropyl methylamino formyl) phenyl amino formyl)-1-(3-chloropyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-methylmethane sulphonic acid ester, 5-(the chloro-2-of 4-(cyclopropyl methylamino formyl) phenyl amino formyl)-1-(3-chloropyridine-2-yl)-4,5-dihydro-1 h-pyrazole-3-methylmethane sulphonic acid ester etc.

As bromating agent, can from bromine, sodium bromide, KBr, lithium bromide, ammonium bromide, magnesium bromide, calcium bromide, barium bromide,In the metal bromide of aluminium bromide, phosphorus tribromide, phosphorus pentabromide, ferric bromide, copper bromide, zinc bromide etc. etc., suitably select a kind or 2More than kind.

As solvent, as long as the solvent to reactionlessness, can be from for example ether, butyl methyl ether, tetrahydrochysene furanMutter, twoAlkane, the such ethers of dimethoxy-ethane; Chlorobenzene, dichloro-benzenes, carrene, chloroform, carbon tetrachloride, two chloroethenesAlkane, trichloroethanes, the such halogenated hydrocarbons of dichloroethylene; Such aromatic hydrocarbon based of benzene,toluene,xylene; Pentane, hexane,Heptane, octane, the such aliphatic hydrocarbon of cyclohexane; Methyl acetate, ethyl acetate, the such ester class of propyl acetate; Acetone, firstBase ethyl ketone, cyclohexanone, acetonitrile, propionitrile, DMF, methyl-sulfoxide, HMPA, sulfolane, twoMethylacetamide, the such polar aprotic solvent of 1-METHYLPYRROLIDONE; Suitable in the protonic solvent that acetic acid is such etc.Select one kind or two or more.

Reaction (C) conventionally can-10～150 DEG C, preferably 0～120 DEG C carry out, its reaction time can be 0.1 conventionallyAbout～24 hours.

In above-mentioned reaction, the compound of formula (III-1) can be manufactured by the compound of formula (IX-1).

In formula, R^1a、R²Described above with L.

The compound of above-mentioned formula (IX) can be manufactured according to reaction (D).

In formula, R¹, A, L and m described above.

Reaction (D) conventionally can be under the existence of alkali and solvent processing formula (VIII) compound and etc. mole more than sulphurAcyl chlorides, chlorinating agent or acid chloride carry out.

As the compound of formula (VIII), can list N-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-yl)-3-hydroxyl-4,5-dihydro-1 h-pyrazole-5-formamide, N-(the chloro-6-of the bromo-4-of 2-(1-cyclopropyl secondBase carbamyl) phenyl)-1-(3-chloropyridine-2-yl)-3-hydroxyl-4,5-dihydro-1 h-pyrazole-5-formamide, (4-is chloro-for N-2-(1-cyclopropyl ethylamino formyl)-6-aminomethyl phenyl)-1-(3-chloropyridine-2-yl)-3-hydroxyl-4,5-dihydro-1H-pyrroleAzoles-5-formamide, N-(the chloro-6-of the bromo-4-of 2-(cyclopropyl methylamino formyl) phenyl)-1-(3-chloropyridine-2-yl)-3-hydroxylBase-4,5-dihydro-1 h-pyrazole-5-formamide, N-(the chloro-2-of 4-(cyclopropyl methylamino formyl) phenyl)-1-(3-chloropyridine-2-yl)-3-hydroxyl-4,5-dihydro-1 h-pyrazole-5-formamide etc.

As sulfonic acid chloride, can list paratoluensulfonyl chloride, methane sulfonyl chloride etc. As chlorinating agent, can listParatoluensulfonyl chloride, methane sulfonyl chloride, thionyl chloride, oxalic acid diacid chloride, phosphorus trichloride, phosphorus pentachloride etc. As acid chloride, canTo list chloroacetic chloride, methyl-chlorocarbonate, chlorine ethyl carbonate etc.

As alkali, can be such from NaOH, lithium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potashInorganic base; Sodium tert-butoxide, the such alkali metal alcoholates of potassium tert-butoxide; Sodium hydride, the such alkali metal hydride of hydrofining; Front threeBase amine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2,6-lutidines,4-pyrrolidinyl pyridine, N-methylmorpholine, DMA, N, N-diethylaniline, N-ethyl-methylphenylamine, 1,In the tertiary amines that 8-diazabicyclo (5.4.0)-7-endecatylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc. suitablySelect one kind or two or more. Alkali, with respect to the compound of formula (VIII), can use 1～5 times mole, preferably 1～3 times mole.

As solvent, as long as the solvent to reactionlessness, can be from for example ether, butyl methyl ether, tetrahydrochysene furanMutter, twoAlkane, the such ethers of dimethoxy-ethane; Chlorobenzene, dichloro-benzenes, carrene, chloroform, carbon tetrachloride, two chloroethenesAlkane, trichloroethanes, the such halogenated hydrocarbons of dichloroethylene; Such aromatic hydrocarbon based of benzene,toluene,xylene; Pentane, hexane,Heptane, octane, the such aliphatic hydrocarbon of cyclohexane; Methyl acetate, ethyl acetate, the such ester class of propyl acetate; Acetonitrile, thirdIn the polar aprotic solvent that nitrile, DMF, methyl-sulfoxide are such etc., suitably select one kind or two or more.

Reaction (D) can be carried out at-20～140 DEG C, preferred-10～120 DEG C conventionally, and its reaction time can be conventionallyAbout 0.1～10 hour.

In above-mentioned reaction, the compound of formula (IX-1) can be by the compound manufacture of formula (VIII-1).

In formula, R^1a、R²Described above with L.

The compound of above-mentioned formula (VIII) can be manufactured according to reaction (E).

In formula, R¹, A, X and m described above.

Reaction (E) can be by making the compound of formula (VI) conventionally under the atmospheric condition of inert gas, at alkali and solventExistence under the compound of processing formula (VII) carry out.

As the compound of formula (VI), can list for example N-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) benzeneBase)-5-pyrazolidone (oxopyrazolidine)-3-formamide, N-(the chloro-6-of the bromo-4-of 2-(1-cyclopropyl ethylamino firstAcyl) phenyl)-5-pyrazolidone-3-formamide, N-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl)-6-aminomethyl phenyl)-5-Pyrazolidone-3-formamide, N-(the chloro-6-of the bromo-4-of 2-(cyclopropyl methylamino formyl) phenyl)-5-pyrazolidone-3-formylAmine, N-(the chloro-2-of 4-(cyclopropyl methylamino formyl) phenyl)-5-pyrazolidone-3-formamide etc.

As inert gas, can list the such gas of nitrogen or argon.

As alkali, can be from NaOH, lithium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potash, carbonic acidCaesium, sodium hydride, hydrofining, tripotassium phosphate water and the such inorganic base of thing; Sodium tert-butoxide, potassium tert-butoxide, caustic alcohol, methyl alcoholSodium, Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2,6-diformazanYl pyridines, 4-pyrrolidinyl pyridine, N-methylmorpholine, DMA, N, N-diethylaniline, N-ethyl-N-methylAniline, 1, organic base that 8-diazabicyclo (5.4.0)-7-endecatylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc.In suitably select one kind or two or more. Alkali, with respect to the compound of formula (VI), can use 1～5 times mole, preferably 1～3.5 timesMole.

As solvent, as long as the solvent to reactionlessness, can be from for example methyl alcohol, ethanol, propyl alcohol, butanols, differentPropyl group alcohol, the such alcohols of 2-methyl-2-propanol; Oxolane, twoAlkane, the such ethers of dimethoxy-ethane; Chlorobenzene,Dichloro-benzenes, carrene, chloroform, carbon tetrachloride, dichloroethanes, trichloroethanes, the such halogenated hydrocarbons of dichloroethylene; Benzene, firstSuch aromatic hydrocarbon based of benzene, dimethylbenzene; Pentane, hexane, heptane, octane, the such aliphatic hydrocarbon of cyclohexane; Acetonitrile, thirdNitrile, DMF, methyl-sulfoxide, HMPA, sulfolane, dimethylacetylamide, N-crassitudeIn the polar aprotic solvent that ketone is such etc., suitably select one kind or two or more.

In order to promote this reaction, can add metallic catalyst. As metallic catalyst, can from palladium-carbon, palladium bichloride,In the such palladium catalyst of acid chloride, tetra-triphenylphosphine palladium, bi triphenyl phosphine dichloride palladium, suitably select one kind or two or more. GoldMetal catalyst, with respect to the compound of formula (VI), can use 0.005～2.5 times mole, preferably 0.01～1 times mole.

Reaction (E) can be conventionally 0～150 DEG C, preferably carry out at 25～120 DEG C, its reaction time can be 0.5 conventionallyAbout～50 hours.

In above-mentioned reaction, the compound of formula (VIII-1) can be by the compound manufacture of formula (VI-1).

In formula, R^1a、R²Described above with X.

The compound of above-mentioned formula (VI) is manufactured by compound and the hydrazine of processing formula (X) conventionally under the existence of solvent.

In formula, R¹、R⁵, A and m described above.

There is the isomers of cis body and trans body in the compound of formula (X), can be either party, can be also its mixingThing.

As the compound of formula (X), can list 4-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenylaminoBase)-4-oxygen ethyl crotonate, 4-(the chloro-6-of the bromo-4-of 2-(1-cyclopropyl ethylamino formyl) phenyl amino)-4-oxygen crotonic acidMethyl esters, 4-(the chloro-6-of the bromo-4-of 2-(1-cyclopropyl ethylamino formyl) phenyl amino)-4-oxygen ethyl crotonate, 4-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl)-6-aminomethyl phenyl amino)-4-oxygen ethyl crotonate, the 4-(chloro-6-(cyclopropyl of the bromo-4-of 2-Methylamino formyl) phenyl amino)-4-oxygen ethyl crotonate, 4-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenylaminoBase)-4-oxygen iso-crotonic acid methyl esters, 4-(the chloro-6-of the bromo-4-of 2-(1-cyclopropyl ethylamino formyl) the phenyl amino)-different bar of 4-oxygenBeans acid methyl esters, 4-(the chloro-6-of the bromo-4-of 2-(1-cyclopropyl ethylamino formyl) phenyl amino)-4-oxygen iso-crotonic acid ethyl ester, 4-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl)-6-aminomethyl phenyl amino)-4-oxygen iso-crotonic acid methyl esters, (the bromo-4-of 2-is chloro-for 4-6-(cyclopropyl methylamino formyl) phenyl amino)-4-oxygen iso-crotonic acid methyl esters, 4-(the chloro-2-of 4-(1-cyclopropyl ethylaminoFormyl) phenyl amino)-4-oxygen ethyl crotonate, 4-(the chloro-2-of 4-(cyclopropyl methylamino formyl) phenyl amino)-4-oxygen barBeans acetoacetic ester, 4-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl amino)-4-oxygen iso-crotonic acid methyl esters etc.

Hydrazine, with respect to the compound of formula (X), can use 0.9～1.5 times mole, preferably 1～1.2 times mole.

As solvent, as long as the solvent to reactionlessness, can be from for example methyl alcohol, ethanol, propyl alcohol, butanols, differentPropyl group alcohol, 2-methyl-2-propanol, the such protonic solvent of water; Ether, butyl methyl ether, oxolane, twoAlkane, diformazanThe ethers that oxygen base ethane is such; Chlorobenzene, dichloro-benzenes, carrene, chloroform, carbon tetrachloride, dichloroethanes, trichloroethanes, dichloroThe halogenated hydrocarbons that ethene is such; Such aromatic hydrocarbon based of benzene,toluene,xylene; Pentane, hexane, heptane, octane, cyclohexaneSuch aliphatic hydrocarbon; DMF, methyl-sulfoxide, HMPA, sulfolane, N, N-dimethyl secondIn the polar aprotic solvent that acid amides, 1-METHYLPYRROLIDONE are such etc., suitably select one kind or two or more.

This reaction can be conventionally-10～150 DEG C, preferably 0～120 DEG C carry out, its reaction time can be 0.2 conventionally～About 20 hours.

In above-mentioned reaction, the compound of formula (VI-1) can be by the compound manufacture of formula (X-1).

In formula, R^1a、R²And R⁵As mentioned above.

The compound of above-mentioned formula (X) can be manufactured according to (G).

In formula, R¹、R⁵, A and m described above.

Compound (X) and (XI) have the isomers of cis body and trans body, can be either party, can be also its mixingThing.

Reaction (G) can be passed through the compound of processing formula (XI) and the compound of formula (XII) under the existence of usual solvents,Or the salt of the compound of the compound of processing formula (XI) and formula (XII) carries out under the existence of solvent and alkali.

As the compound of formula (XI), can list (E)-3-(6-chloro-4-oxygen-4H-benzo [d] [1,3]Piperazine-2-Base) methyl acrylate, (E)-3-(the bromo-6-of 8-chloro-4-oxygen-4H-benzo [d] [1,3]Piperazine-2-yl) methyl acrylate,(E)-3-(the bromo-6-of 8-chloro-4-oxygen-4H-benzo [d] [1,3]Piperazine-2-yl) ethyl acrylate, (E)-3-(chloro-8-first of 6-Base-4-oxygen-4H-benzo [d] [1,3]Piperazine-2-yl) methyl acrylate, (Z)-3-(6-chloro-4-oxygen-4H-benzo [d] [1,3]Piperazine-2-yl) methyl acrylate, (Z)-3-(the bromo-6-of 8-chloro-4-oxygen-4H-benzo [d] [1,3]Piperazine-2-yl) propyleneAcid methyl esters, (Z)-3-(the bromo-6-of 8-chloro-4-oxygen-4H-benzo [d] [1,3]Piperazine-2-yl) ethyl acrylate, (Z)-3-(6-Chloro-8-methyl-4-oxygen-4H-benzo [d] [1,3]Piperazine-2-yl) methyl acrylate, (E)-3-(the chloro-4-oxygen-4H-of 6-benzo[d][1，3]Piperazine-2-yl) ethyl acrylate etc.

In addition, as the compound of formula (XII), can use Alpha-Methyl-cyclopropyl methyl amine, Alpha-Methyl-cyclobutylmethylBase amine, cyclopropyl methyl amine etc. As the salt of the compound of formula (XII), can use the inorganic acid of hydrochloride, sulfate etc.Salt; The organic acid salt of acetate, mesylate etc. etc. The compound or its salt of formula (XII) is with respect to the compound of formula (XI),Can use etc. mole above, preferably 1～5 times mole.

In the case of the salt of the compound of use formula (XII), preferably use alkali. As alkali, can be from for example hydroxideSodium, potassium hydroxide, sodium hydride, hydrofining, sodium carbonate, potash, sodium acid carbonate, the such inorganic base of saleratus; The tert-butyl alcoholSodium, the such alkali metal alcoholates of potassium tert-butoxide; Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine,4-dimethylaminopyridine, 2,6-lutidines, 4-pyrrolidinyl pyridine, N-methylmorpholine, DMA, N, N-Diethylaniline, N-ethyl-methylphenylamine, 1,8-diazabicyclo (5.4.0)-7-endecatylene, Isosorbide-5-Nitrae-diazabicycloIn the organic base that (2.2.2) octane is such etc., suitably select one kind or two or more. Alkali is with respect to the salt of the compound of formula (XII),Can use 0.7～5 times mole, preferably 1～1.5 times mole.

As solvent, as long as the solvent to reactionlessness, can be from for example ether, oxolane, twoAlkane,The ethers that dimethoxy-ethane is such; Carrene, chloroform, carbon tetrachloride, the such halogenated hydrocarbons of chlorobenzene; Benzene, toluene, diformazanSuch aromatic hydrocarbon based of benzene; Acetonitrile, DMF, dimethylacetylamide, 1-METHYLPYRROLIDONE, methyl-sulfoxideIn such polar aprotic solvent etc., suitably select one kind or two or more.

This reaction can-20～120 DEG C conventionally, preferably carry out at 0～80 DEG C, its reaction time can be 0.5 conventionallyAbout～24 hours.

In above-mentioned reaction, the compound of formula (X-1) can be by the compound manufacture of formula (XI-1).

In formula, R^1a、R²And R⁵As mentioned above.

The compound of above-mentioned formula (X) can be manufactured by the method for reaction (H) or (I).

In formula, R¹、R⁵, A and m described above. Compound (X) and (XIII) have the isomers of cis body and trans body, canThinking either party, can be also its mixture.

As the compound of operable formula (V) in above-mentioned reaction, can list the chloro-N-of 2-amino-5-(1-ring thirdBase ethyl) benzamide, the chloro-N-of the bromo-5-of 2-amino-3-(1-cyclopropyl ethyl) benzamide, the chloro-3-methyl of 2-amino-5--N-(1-cyclopropyl ethyl) benzamide, the chloro-N-of the bromo-5-of 2-amino-3-(cyclopropyl methyl) benzamide etc.

Reaction (H) first stage reaction conventionally under the existence of solvent by compound and the Malaysia of processing formula (V)Acid anhydrides carries out.

Maleic anhydride, with respect to the compound of formula (V), can use 0.9～3 times mole, preferably 1～1.5 times mole.

As solvent, as long as the solvent to reactionlessness, can be from for example oxolane, twoAlkane, dimethoxyThe ethers that base ethane is such; Chlorobenzene, dichloro-benzenes, carrene, chloroform, carbon tetrachloride, dichloroethanes, trichloroethanes, two chloroethenesThe halogenated hydrocarbons that alkene is such; Such aromatic hydrocarbon based of benzene,toluene,xylene; Pentane, hexane, heptane, octane, cyclohexane thatThe aliphatic hydrocarbon of sample; Methyl acetate, ethyl acetate, the such ester class of propyl acetate; Acetone, methyl ethyl ketone, acetonitrile, thirdNitrile, DMF, methyl-sulfoxide, HMPA, sulfolane, dimethylacetylamide, N-crassitudeIn such polar aprotic solvent, the acetic acid etc. of ketone, suitably select one kind or two or more.

This reaction can, according to hope, be carried out under the existence of alkali. As alkali, can be from for example NaOH, hydroxidePotassium, sodium hydride, hydrofining, sodium carbonate, the such inorganic base of potash; The such alkali metal alcoholates of sodium tert-butoxide, potassium tert-butoxide,Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2,6-dimethylPyridine, 4-pyrrolidinyl pyridine, N-methylmorpholine, DMA, N, N-diethylaniline, N-ethyl-N-methylbenzeneAmine, 1, in organic base that 8-diazabicyclo (5.4.0)-7-endecatylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc.Suitably select one kind or two or more. Alkali, with respect to the compound of formula (V), can use 0.7～5 times mole, preferably 1～2.5 timesMole.

This reaction can common 0～150 DEG C, preferably 20～110 DEG C carry out, its reaction time can be 0.5 conventionally～About 24 hours.

The reaction of the second stage of reaction (H) can rub with waiting by the compound of processing formula (XIII) conventionally under sour existenceThe R that you are above⁵Alcohol shown in-OH carries out.

As alcohol, can from methyl alcohol, ethanol, propyl alcohol, butanols, isopropyl alcohol etc., suitably select.

As acid, can be from hydrogen chloride, hydrogen bromide, the such hydrogen halides of hydrogen iodide; Sulfuric acid, sulfurous acid, nitric acid, nitrousAcid, phosphoric acid, boric acid, chloric acid, chlorous acid, the such inorganic acid of hypochlorous acid; Halogenated titanium, aluminum halide, iron halide, tin halides, halogenationZinc, magnesium halide, silicon halide, copper halide, the such lewis acid of trifluoroboranes-ether complexes; Formic acid, C₁-C₆Alkyl carboxylic acid, virtueFragrant family carboxylic acid, C₁-C₆In the organic acid that alkyl sulfonic acid, aromatic sulphonic acid are such etc., suitably select one kind or two or more. Acid with respect toCompound (XIII), can use 0.05～10 times mole, preferably 0.1～5 times mole.

This reaction can be carried out according to hope under the existence of solvent. As solvent, as long as the solvent to reactionlessness, can be from for example oxolane, twoAlkane, the such ethers of dimethoxy-ethane; Chlorobenzene, dichloro-benzenes, carrene,Chloroform, carbon tetrachloride, dichloroethanes, trichloroethanes, the such halogenated hydrocarbons of dichloroethylene; The virtue that benzene,toluene,xylene is suchFragrant family hydro carbons; Pentane, hexane, heptane, octane, the such aliphatic hydrocarbon of cyclohexane; Acetonitrile, propionitrile, N, N-dimethyl formylThe such polarity of amine, methyl-sulfoxide, HMPA, sulfolane, DMA, 1-METHYLPYRROLIDONE is non-In protonic solvent etc., suitably select one kind or two or more.

This reaction conventionally can 0～100 DEG C, preferably carry out at 10～50 DEG C, its reaction time can be 1～50 conventionallyAbout hour.

In formula, R⁶For chlorine atom or bromine atoms, R¹、R⁵, A and m described above. Formula (X), (XIV) and compound (XV) are depositedAt the isomers of cis body and trans body, can be either party, can be also its mixture.

The reaction of the first stage of reaction (I) conventionally can be under the existence of solvent compound by processing formula (V) withThe compound of formula (XIV) carries out. The Compound Phase of formula (XIV), for the compound of formula (V), can use 0.9～3 times to rubYou, preferably 1～1.5 times mole.

As solvent, as long as the solvent to reactionlessness, can be from for example oxolane, twoAlkane, dimethoxyThe ethers that base ethane is such; Chlorobenzene, dichloro-benzenes, carrene, chloroform, carbon tetrachloride, dichloroethanes, trichloroethanes, two chloroethenesThe halogenated hydrocarbons that alkene is such; Such aromatic hydrocarbon based of benzene,toluene,xylene; Pentane, hexane, heptane, octane, cyclohexane thatThe aliphatic hydrocarbon of sample; Acetonitrile, propionitrile, DMF, methyl-sulfoxide, HMPA, sulfolane, diformazanIn the polar aprotic solvent that yl acetamide, 1-METHYLPYRROLIDONE are such etc., suitably select one kind or two or more.

This reaction can-10～150 DEG C conventionally, preferably at 0～50 DEG C, carry out, its reaction time can be conventionallyAbout 0.5～24 hour.

The reaction of the second stage of reaction (I) can be under the existence of usual solvents compound by processing formula (XV) withDeng a mole above R⁵Alcohol shown in-OH carries out.

This reaction can, according to hope, be carried out under the existence of alkali. As alkali, can be from for example NaOH, hydroxidePotassium, sodium hydride, hydrofining, sodium carbonate, the such inorganic base of potash; The such alkali metal alcoholates of sodium tert-butoxide, potassium tert-butoxide,Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2,6-dimethylPyridine, 4-pyrrolidinyl pyridine, N-methylmorpholine, DMA, N, N-diethylaniline, N-ethyl-N-methylbenzeneAmine, 1, in organic base that 8-diazabicyclo (5.4.0)-7-endecatylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc.Suitably select one kind or two or more. Alkali, with respect to alcohol, can use 0.7～5 times mole, preferably 1～2.5 times mole.

This reaction can-10～150 DEG C conventionally, preferably carry out at 0～50 DEG C, its reaction time can be 0.5 conventionallyAbout～24 hours.

The compound of the formula (XI) using in above-mentioned reaction (G) in addition, can be manufactured according to the reaction of (J), (K).

In formula, R¹、R⁵Described above with m. There is the isomery of cis body and trans body in formula (XVI) and compound (XVII)Body, can be either party, can be also its mixture.

Reaction (J) conventionally can be by reacting the compound of formula (XVII) under the existence of alkali and solvent with acyl chlorides compoundBe transformed into reactive derivative, then under the existence of alkali, react with the compound of formula (XVI), and then add activator reactionCarry out.

As the compound of operable formula (XVI) in above-mentioned reaction, can list 5-chloro-o-amino benzoic acid, 3-Bromo-5-chloro-o-amino benzoic acid, the chloro-3-methyl of 5-ortho-aminobenzoic acid etc., as the compound of formula (XVII), can use horseCome sour monomethyl ester, maleic acid list ethyl ester, maleic acid list propyl diester etc.

Above-mentioned reaction can be carried out under the existence of solvent, also can in identical solvent, carry out a series of reaction.As solvent, as long as the solvent to reactionlessness, can be from for example chlorobenzene, dichloro-benzenes, carrene, chloroform, tetrachloroChange carbon, dichloroethanes, trichloroethanes, the such halogenated hydrocarbons of dichloroethylene; Such aromatic hydrocarbon based of benzene,toluene,xylene;Pentane, hexane, heptane, octane, the such aliphatic hydrocarbon of cyclohexane; Ether, butyl methyl ether, oxolane, twoAlkane,The ethers that dimethoxy-ethane is such; Methyl acetate, ethyl acetate, the such ester class of propyl acetate; Acetone, 2-butanone, 4-firstThe ketone that base-2 pentanone is such; In the polar aprotic solvent that acetonitrile, propionitrile, DMF are such etc. suitablySelect one kind or two or more.

As acyl chlorides compound, can use chlorine carbonates, sulfonic acid chloride or carboxyl acyl chloride etc. As chlorine carbonic ester, Ke YilieEnumerate methyl-chlorocarbonate, chlorine ethyl carbonate, chlorine isobutyl carbonate propyl diester etc., as sulfonic acid chloride, can list methane sulfonyl chloride, thirdAlkanesulphonyl chlorides, benzene sulfonyl chloride, paratoluensulfonyl chloride etc., as carboxyl acyl chloride, can list chloroacetic chloride, propionyl chloride etc., Qi ZhongyouSelect methane sulfonyl chloride. This reagent is with respect to the compound of formula (XVII), be 1.0～3.0 times moles, preferably 1.1～2.0 times rubYou.

As alkali, can list pyridine, 2-picoline, 3-picoline, 2,6-lutidines, triethylamine,4-dimethylaminopyridine etc. Alkali is with respect to the compound of formula (XVI), be 1.0～2.0 times moles, preferably 1.2～1.7 times rubYou.

Reaction conventionally can-30～60 DEG C, preferably carry out at-10～40 DEG C, the reaction time is generally 5 minutes～1 littleTime about.

The compound of formula (XVII) is being transformed to after reactive derivative, and the Compound Phase of the formula (XVI) of reaction is for upperStating the compound of formula (XVII), is 0.9～1.2 times mole, preferably 1.0～1.05 times moles.

The alkali that alkali uses can use above-mentioned reactive derivative time, with respect to the compound of above-mentioned formula (XVI), is 2～4Doubly mole, preferably 2.9～3.5 times moles. The compound of formula (XVI) and alkali can add after the mixed solution of formation and solventAdd.

Reaction is carried out conventionally at-30～60 DEG C, preferred-10～40 DEG C, and the reaction time is generally 5 minutes～1 hour left sideRight.

As activator, can use chlorine carbonic ester, sulfonic acid chloride etc. As chlorine carbonic ester, can list chlorine carbonic acidMethyl esters, chlorine ethyl carbonate, chlorine isobutyl carbonate propyl ester, as sulfonic acid chloride, can list methane sulfonyl chloride, propane sulfonic acid chloride, benzene sulphurAcyl chlorides, paratoluensulfonyl chloride etc., wherein optimization methane sulfonic acid chloride. Activator be above-mentioned formula (XVI) compound 1.0～1.5 times moles, further preferably 1.1～1.3 times moles. Activator preferably uses the activity identical with aforesaid acyl chlorides compoundAgent, adds after also can forming mixture with solvent.

Reaction can be carried out at common-30～60 DEG C, preferred-10～40 DEG C, and the reaction time is generally 1～24 hour left sideRight.

In formula, R¹、R⁵Described above with m.

The compound of formula (XI) can be by being active derivative by the compound of formula (XVIII) at the down conversion that exists of solventThing carries out cyclization and manufactures.

As making its reagent that is transformed to reactive derivative, can use chlorine carbonates, sulfonic acid chloride, thionyl chloride, carboxylicAcyl chlorides, carboxylic acid anhydrides, phosphorus chloride etc. As chlorine carbonic ester, can list methyl-chlorocarbonate, chlorine ethyl carbonate, chlorine carbonic acid isopropylBase esters etc., as sulfonic acid chloride, can list methane sulfonyl chloride, propane sulfonic acid chloride, benzene sulfonyl chloride, paratoluensulfonyl chloride etc., doFor carboxylic acid anhydrides, can list acetic anhydride, propionic andydride etc., wherein optimization methane sulfonic acid chloride, acetic anhydride.

Above-mentioned activate reagent be 1.0～1.5 times moles of compound of above-mentioned formula (XVIII), further preferably 1.1～1.3 times moles, use in the situation of carboxylic acid anhydrides as solvent, can use 3～20 times of weights of the compound of above-mentioned formula (XVIII)Amount. Activator adds after can forming mixture with solvent. In addition, also can enter by the acid of adding sulfuric acid, hydrochloric acid etc.Row reaction.

As solvent, as long as the solvent to reactionlessness, can be from for example chlorobenzene, dichloro-benzenes, carrene, chlorineImitative, carbon tetrachloride, dichloroethanes, trichloroethanes, the such halogenated hydrocarbons of dichloroethylene; The fragrance that benzene,toluene,xylene is suchFamily's hydro carbons; Pentane, hexane, heptane, octane, the such aliphatic hydrocarbon of cyclohexane; Ether, butyl methyl ether, oxolane, twoAlkane, the such ethers of dimethoxy-ethane; Methyl acetate, ethyl acetate, the such ester class of propyl acetate; Acetone, 2-fourthKetone, the such ketone of 4-methyl-2 pentanone; Acetonitrile, propionitrile, the such polar aprotic solvent of DMF;In the carboxylic acid anhydrides of acetic anhydride, propionic andydride etc. etc., suitably select one kind or two or more.

Reaction can be carried out conventionally at-30～100 DEG C, preferred-10～60 DEG C, and the reaction time is generally 1～24 hourLeft and right.

The cis body of the compound of formula (XI) can be by processing with the acid of hydrochloric acid etc. and isomery turns to trans body.

The compound of above-mentioned formula (XVIII) can be manufactured according to the method for (L) or (M).

In formula, R¹、R⁵Described above with m. Compound (XVIII) and (XIX) have the isomers of cis body and trans body,Can be respectively a side, can be also its mixture.

The reaction of the first stage of reaction (L) conventionally can be by the compound of processing formula (XVI) under the existence of solventCarry out with maleic anhydride. Maleic anhydride is with respect to the compound of formula (XVI), can use 0.9～3 times mole, preferably 1～1.5 times moles.

This reaction can, according to hope, be carried out under the existence of alkali. As alkali, can be from for example NaOH, hydroxidePotassium, sodium hydride, hydrofining, sodium carbonate, the such inorganic base of potash; The such alkali metal alcoholates of sodium tert-butoxide, potassium tert-butoxide,Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2,6-dimethylPyridine, 4-pyrrolidinyl pyridine, N-methylmorpholine, DMA, N, N-diethylaniline, N-ethyl-N-methylbenzeneAmine, 1, in organic base that 8-diazabicyclo (5.4.0)-7-endecatylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc.Suitably select one kind or two or more. Alkali is with respect to the compound of formula (XVI), can use 0.7～5 times mole, preferably 1～2.5Doubly mole.

This reaction conventionally can 0～150 DEG C, preferably carry out at 20～110 DEG C, its reaction time can be 0.5 conventionallyAbout～24 hours.

The reaction of the second stage of reaction (L) conventionally can be under sour existence compound by processing formula (XIX) withDeng a mole above R⁵Alcohol shown in-OH carries out.

As acid, can be from hydrogen chloride, hydrogen bromide, the such hydrogen halides of hydrogen iodide; Sulfuric acid, sulfurous acid, nitric acid, nitrousAcid, phosphoric acid, boric acid, chloric acid, chlorous acid, the such inorganic acid of hypochlorous acid; Halogenated titanium, aluminum halide, iron halide, tin halides, halogenationZinc, magnesium halide, silicon halide, copper halide, the such lewis acid of trifluoroboranes-ether complexes; Formic acid, C₁-C₆Alkyl carboxylic acid, virtueFragrant family carboxylic acid, C₁-C₆In the organic acid that alkyl sulfonic acid, aromatic sulphonic acid are such etc., suitably select one kind or two or more. Acid with respect toThe compound of formula (XIX), can use 0.05～10 times mole, preferably 0.1～5 times mole.

In formula, R⁶For chlorine atom or bromine atoms, R¹、R⁵Described above with m. Compound (XIV), (XVIII) and (XX) existenceThe isomers of cis body and trans body, can be respectively a side isomers, can be also its mixture.

The reaction of the first stage of reaction (M) conventionally can be by the compound of processing formula (XVI) under the existence of solventAnd the compound of formula (XIV) carries out. The Compound Phase of formula (XIV), for the compound of formula (XVI), can use 0.9～3 timesMole, preferably 1～1.5 times mole.

This reaction conventionally can-10～150 DEG C, preferably at 0～50 DEG C, carry out, its reaction time can be conventionallyAbout 0.5～24 hour.

The reaction of the second stage of reaction (M) conventionally can be under the existence of solvent compound by processing formula (XX) withDeng a mole above R⁵Alcohol shown in-OH carries out. In formula, R⁵As mentioned above.

This reaction can, according to hope, be carried out under the existence of alkali. As alkali, can be from for example NaOH, hydroxidePotassium, sodium hydride, hydrofining, sodium carbonate, the such inorganic base of potash; The such alkali metal alcoholates of sodium tert-butoxide, potassium tert-butoxide,Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2,6-dimethylPyridine, 4-pyrrolidinyl pyridine, N-methylmorpholine, DMA, N, N-diethylaniline, N-ethyl-N-methylbenzeneAmine, 1, in organic base that 8-diazabicyclo (5.4.0)-7-endecatylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc.Suitably select one kind or two or more. Alkali, with respect to the compound of formula (XX), can use 0.7～5 times mole, preferably 1～2.5 timesMole.

This reaction conventionally can-10～150 DEG C, preferably carry out at 0～50 DEG C, its reaction time can be 0.5 conventionallyAbout～24 hours.

Formula (II) compound of the compound that comprises above-mentioned formula (II-1) can be made according to following reaction (N)～(Q)Make.

In formula, R^1a、R²、R³And R⁴As mentioned above.

As the compound of operable formula (IV) in above-mentioned reaction, can list the bromo-1-of amyl group 3-(3-chlorine pyrrolePyridine-2-yl)-1H-pyrazoles-5-carboxylate, the chloro-1-of amyl group 3-(3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxylate, phenyl 3-Bromo-1-(3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxylate, the bromo-1-of S-benzyl 3-(3-chloropyridine-2-yl)-1H-pyrazoles-5-Thiocarboxylic (carbothioate) etc.

As the compound of formula (V-1), can list the chloro-N-of 2-amino-5-(1-cyclopropyl ethyl) benzamide, 2-The chloro-N-of amino-5-(cyclopropyl methyl) benzamide, the chloro-3-trifluoromethyl-N-of 2-amino-5-(1-cyclopropyl ethyl) benzene firstAcid amides etc.

Reaction (N) conventionally can be by the compound of processing formula (IV) and the change of formula (V-1) under the existence of alkali and solventCompound carries out.

As alkali, can be from sodium hydride, the such alkali metal hydride of hydrofining; Sodium carbonate, the such alkali gold of potashBelong to carbonate, sodium methoxide, caustic alcohol, the such alkali metal alcoholates of potassium tert-butoxide; Trimethylamine, triethylamine, triisopropylamine,Diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2,6-lutidines, 4-pyrrolidinyl pyridine, N-methylQuinoline, DMA, N, N-diethylaniline, N-ethyl-methylphenylamine, 1,8-diazabicyclo (5.4.0)-7-tenIn the tertiary amines that one carbene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc., suitably select one kind or two or more. Alkali with respect toCompound (V-1), can use 0.5～5 times mole, preferably 1～3 times mole.

As solvent, as long as the solvent to reactionlessness, can be from for example ether, butyl methyl ether, tetrahydrochysene furanMutter, twoAlkane, the such ethers of dimethoxy-ethane; Chlorobenzene, dichloro-benzenes, carrene, chloroform, carbon tetrachloride, two chloroethenesAlkane, trichloroethanes, the such halogenated hydrocarbons of dichloroethylene; Such aromatic hydrocarbon based of benzene,toluene,xylene; Pentane, hexane,Heptane, octane, the such aliphatic hydrocarbon of cyclohexane; Acetonitrile, propionitrile, DMF, methyl-sulfoxide, hempaIn the polar aprotic solvent that acyl triamine, sulfolane, dimethylacetylamide, 1-METHYLPYRROLIDONE are such etc., suitably select 1Plant or two or more.

In order to prevent the hydrolysis in reaction, can in reaction system, add dehydrating agent. As dehydrating agent, can listAnhydrous sodium sulfate, anhydrous magnesium sulfate etc., with respect to compound (V-1), can add 1 times～100 times moles.

Reaction (N) conventionally can 0～120 DEG C, preferably carry out at 5～80 DEG C, its reaction time can be 0.25 conventionallyAbout～24 hours, preferably about 0.5～12 hour.

In above-mentioned reaction, the compound of formula (II-1) can be by the compound manufacture of formula (IV-1).

In formula, R^1a、R²And R⁴As mentioned above.

As the compound of operable formula (IV-1) in above-mentioned reaction, can list the bromo-1-of amyl group 3-(3-chlorine pyrrolePyridine-2-yl)-1H-pyrazoles-5-carboxylate, the bromo-1-of phenyl 3-(3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxylate, S-benzylThe bromo-1-of 3-(3-chloropyridine-2-yl)-1H-pyrazoles-5-thiocarboxylic etc.

In the compound (IV) using in reaction (N), R⁴For C₅-C₁₀Alkyl oxy, can substituted phenoxy group or canThe compound (IV-2) of substituted benzyl oxygen base, can manufacture according to following reaction (O).

In formula, R^4aFor C5-C10 alkyl oxy, can substituted phenoxy group or can substituted benzyl oxygen base, R³As above instituteState.

Reaction (O) conventionally can by under acid and the existence of solvent, utilize the compound of oxidizer treatment formula (XXI)Carry out.

As oxidant, can list hydrogen peroxide, potassium peroxydisulfate, sodium peroxydisulfate, Potassium peroxysulfate, potassium permanganateDeng, can suitably select one kind or two or more. Oxidant, with respect to compound (XXI), can use 1～5 times mole, preferably 1～2.5 times moles.

As acid, can list sulfuric acid, phosphoric acid, acetic acid etc. Acid, with respect to compound (XXI), can be used 0.5～5Doubly mole.

As solvent, as long as the solvent to reactionlessness, can be from for example oxolane, twoAlkane, dimethoxyThe ethers that base ethane is such; Acetone, the such ketone of methyl ethyl ketone; Chlorobenzene, dichloro-benzenes, carrene, chloroform, tetrachloroCarbon, dichloroethanes, trichloroethanes, the such halogenated hydrocarbons of dichloroethylene; Such aromatic hydrocarbon based of benzene,toluene,xylene; PentaAlkane, hexane, heptane, octane, the such aliphatic hydrocarbon of cyclohexane; Acetonitrile, propionitrile, DMF, methyl-sulfoxide,HMPA, sulfolane, dimethylacetylamide, such polar aprotic solvent or the water etc. of 1-METHYLPYRROLIDONEIn suitably select one kind or two or more.

Reaction (O) can common 0～150 DEG C, preferably carry out at 15～120 DEG C, its reaction time can be 0.5 conventionallyAbout～24 hours, preferably about 1～4 hour.

In the compound (XXI) using in reaction (O), R³For the compound of the formula (XXI-1) of chlorine atom or bromine atoms canTo manufacture according to following reaction (P).

In formula, R^3aFor chlorine atom or bromine atoms, R^4aAs mentioned above.

Reaction (P) conventionally can be by entering the compound of formula (XXII) under the existence of solvent with halogenating agent processingOK.

As halogenating agent, can use phosphorus oxybromide, the such oxyhalogenation phosphorus of phosphorous oxychloride. Halogenating agent is with respect to formula(XXII) compound, can use 0.33～3 times mole, preferably 0.5～2 times mole.

Reaction (P) conventionally can 0～120 DEG C, preferably carry out at 5～100 DEG C, as its reaction time can be conventionallyAbout 0.2～8 hour, preferably about 0.5～4 hour.

Compound (XXII) can synthesize according to following reaction (Q).

In formula, R^4aAs mentioned above.

Reaction (Q) conventionally can be under the existence of alkali and solvent by with the chloro-2-diazanyl of 3-(Hydrazinyl) pyridine andFumarate or maleate or their mixture process are carried out.

As alkali, can use amylalcohol sodium, the such alkali metal alcoholates of amylalcohol potassium. These alkali metal alcoholates can be by hydrogenationSodium, the such alkali metal hydride of hydrofining; Such alkali metal hydroxide and sodium, the potassium etc. of NaOH, potassium hydroxideAlkali metal and alcohol are modulated. Alkali is with respect to 3-chloride-2-hydrazinopyridine, can use 0.7～3 times mole, preferably 1～1.5 times rubYou.

As solvent, as long as the solvent to reactionlessness, can be from for example oxolane, twoAlkane, dimethoxyThe ethers that base ethane is such; Chlorobenzene, dichloro-benzenes, carrene, chloroform, carbon tetrachloride, dichloroethanes, trichloroethanes, two chloroethenesThe halogenated hydrocarbons that alkene is such; Such aromatic hydrocarbon based of benzene,toluene,xylene; Pentane, hexane, heptane, octane, cyclohexane thatThe aliphatic hydrocarbon of sample; Acetonitrile, propionitrile, DMF, methyl-sulfoxide, HMPA, sulfolane, diformazanYl acetamide, the such polar aprotic solvent of 1-METHYLPYRROLIDONE; 1-amylalcohol, 2-amylalcohol, the such alcohols of 1-hexanolDeng in suitably select one kind or two or more. Alcohol is particularly preferably identical with the alcohol that forms fumarate or maleate and alkoxide groupAlcohol.

Reaction (Q) conventionally can 0～150 DEG C, preferably carry out at 20～130 DEG C, its reaction time can be 0.5 conventionallyAbout～24 hours, preferably about 1～4 hour.

In addition, the compound shown in above-mentioned formula (I) can come according to the manufacture method of following reaction (R) and common saltManufacture.

In formula, R^1a、R²、R³、R⁴Described above with Hal.

Reaction (R) conventionally can be by the compound of processing formula (IV) and the change of formula (XXIV) under the existence of alkali and solventCompound carries out.

As alkali, can be from sodium hydride, the such alkali metal hydride of hydrofining; Sodium carbonate, the such alkali gold of potashBelong to carbonate, sodium methoxide, caustic alcohol, the such alkali metal alcoholates of potassium tert-butoxide; Trimethylamine, triethylamine, triisopropylamine,Diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2,6-lutidines, 4-pyrrolidinyl pyridine, N-methylQuinoline, DMA, N, N-diethylaniline, N-ethyl-methylphenylamine, 1,8-diazabicyclo (5.4.0)-7-tenIn the tertiary amines that one carbene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc., suitably select one kind or two or more. Alkali with respect toCompound (IV), can use 0.5～5 times mole, preferably 1～3 times mole.

In order to prevent the hydrolysis in reaction, can in reaction system, add dehydrating agent. As dehydrating agent, can listAnhydrous sodium sulfate, anhydrous magnesium sulfate etc., with respect to the compound of formula (XXIV), can add 1 times～100 times moles.

Reaction (R) conventionally can 0～120 DEG C, preferably carry out at 5～80 DEG C, its reaction time can be 0.5 conventionally～About 24 hours, preferably about 1～12 hour.

And then, according to reaction (R), can make the compounds reaction (S) of formula (I-B) manufacture.

In formula, R⁷For hydrogen atom, halogen, alkyl or haloalkyl, R^1a、R²、R³And R⁴As mentioned above.

Reaction (S) conventionally can be under the existence of alkali and solvent, by the compound of processing formula (IV) and the change of formula (XXV)Compound carries out.

In order to prevent the hydrolysis in reaction, can in reaction system, add dehydrating agent. As dehydrating agent, can listAnhydrous sodium sulfate, anhydrous magnesium sulfate etc., with respect to compound (XXV), can add 1 times～100 times moles.

Reaction (S) conventionally can 0～120 DEG C, preferably carry out at 5～80 DEG C, its reaction time can be 0.5 conventionally～About 24 hours, preferably about 1～12 hour.

Compound (IV) can be manufactured according to following reaction (T).

In formula, Z is chlorine atom, methoxycarbonyl oxygen base, ethoxy carbonyl oxygen base, sulfonyloxy methyl oxygen base, phenyl sulphonyl oxygenBase or tolysulfonyl oxygen base, R³And R⁴As mentioned above.

The first operation of reaction (T) can be passed through the compound of formula (XXVI) and wait mole above chlorinating agent, an acyl chloridesThe processing such as compound are carried out.

As chlorinating agent, can list such as thionyl chloride, oxalic acid diacid chloride, phosphorus trichloride, phosphorus pentachloride etc. AsAcyl chlorides compound, can list methyl-chlorocarbonate, chlorine ethyl carbonate, methylsufonyl chloride, phenyl sulfonic acid chloride, paratoluensulfonyl chlorideDeng.

In this reaction, can use solvent, as solvent, as long as the solvent to reactionlessness, can be from for exampleEther, butyl methyl ether, oxolane, twoAlkane, the such ethers of dimethoxy-ethane; Chlorobenzene, dichloro-benzenes, carrene,Chloroform, carbon tetrachloride, dichloroethanes, trichloroethanes, the such halogenated hydrocarbons of dichloroethylene; The virtue that benzene,toluene,xylene is suchFragrant family hydro carbons; Pentane, hexane, heptane, octane, the such aliphatic hydrocarbon of cyclohexane; Methyl acetate, ethyl acetate, acetic acid thirdThe ester class that ester is such; In the polar aprotic solvent that acetonitrile, propionitrile, DMF are such etc., suitably select a kindOr two or more.

The first operation of reaction (T) can be carried out conventionally at-20～140 DEG C, preferred-10～120 DEG C, its reaction timeConventionally can be about 0.1～10 hour, preferably about 0.5～5 hour.

In the compound of formula (XXVII), Z is alkoxy-carbonyl oxy, sulfonyloxy methyl oxygen base, phenyl sulfonyloxy or to firstIn the situation of phenylsulfonyloxy, the first operation also can be carried out under the existence of alkali.

As alkali, can be from for example sodium carbonate, the such alkali carbonate of potash; Sodium hydride, hydrofining are suchAlkali metal hydride; Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylamino pyrrolePyridine, 2,6-lutidines, 4-pyrrolidinyl pyridine, N-methylmorpholine, DMA, N, N-diethylaniline, N-Ethyl-methylphenylamine, 1,8-diazabicyclo (5.4.0)-7-endecatylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane thatIn the tertiary amines of sample etc., suitably select one kind or two or more. Alkali, with respect to the compound of formula (XXVI), can use 1～5 times to rubYou, preferably 1～2.5 times mole.

The second operation of reaction (T) conventionally can be by the compound of processing formula (XXVII) under the existence of alkali and solventAnd the compound of formula (XXVIII) carries out.

As alkali, can be from sodium hydride, the such alkali metal hydride of hydrofining; Sodium carbonate, the such alkali gold of potashBelong to carbonate, sodium methoxide, caustic alcohol, the such alkali metal alcoholates of potassium tert-butoxide; Trimethylamine, triethylamine, triisopropylamine,Diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2,6-lutidines, 4-pyrrolidinyl pyridine, N-methylQuinoline, DMA, N, N-diethylaniline, N-ethyl-methylphenylamine, 1,8-diazabicyclo (5.4.0)-7-tenIn the tertiary amines that one carbene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc., suitably select one kind or two or more. Alkali with respect toThe compound of formula (XXVIII), can use 0.8～3 times mole, preferably 1～1.5 times mole.

As solvent, as long as the solvent to reactionlessness, can be from for example ether, butyl methyl ether, tetrahydrochysene furanMutter, twoAlkane, the such ethers of dimethoxy-ethane; Chlorobenzene, dichloro-benzenes, carrene, chloroform, carbon tetrachloride, two chloroethenesAlkane, trichloroethanes, the such halogenated hydrocarbons of dichloroethylene; Such aromatic hydrocarbon based of benzene,toluene,xylene; Pentane, hexane,Heptane, octane, the such aliphatic hydrocarbon of cyclohexane; Acetonitrile, propionitrile, DMF, methyl-sulfoxide, hempaAcyl triamine, sulfolane, dimethylacetylamide, the such polar aprotic solvent of 1-METHYLPYRROLIDONE; Amylalcohol, hexanol, differentIn such alcohols, the water etc. of amyl group alcohol, suitably select one kind or two or more. Amylalcohol, hexanol, such being of alcohols of isoamyl alcoholOne example of compound (XXVIII), also can be used reaction reagent as solvent.

The second operation of reaction (T) conventionally can-20～120 DEG C, preferably carry out at 0～40 DEG C, its reaction time is logicalCan be often about 0.25～24 hour, preferably about 0.5～12 hour.

Compound (XXVI) is the known of the records such as the WO03/016283 of the hydrolysis acquisition of the compound of through type (IV)Compound, those skilled in the art can obtain by known method. The compound of formula (XXVIII) is also commercially available energyEnough known compounds easily obtaining.

The formula (XXIV) using in the compound of the formula (V-1) using in above-mentioned reaction (H) and (N) and above-mentioned reaction (R)Compound can manufacture according to following reaction (U).

In formula, Z^aChlorine atom, methoxycarbonyl oxygen base, ethoxy carbonyl oxygen base or tolysulfonyl oxygen base, R^1a、R²WithHal is described above.

The first operation of reaction (U) can be by making compound (XXIX) and waiting mole above chlorinating agent, an acid chloride etc.Be used for carrying out.

As chlorinating agent, can list such as thionyl chloride, oxalic acid diacid chloride, phosphorus trichloride, phosphorus pentachloride etc. AsAcid chloride, can list methyl-chlorocarbonate, chlorine ethyl carbonate etc.

In this reaction, can use solvent, as solvent, as long as the solvent to reactionlessness, can be from for example secondEther, butyl methyl ether, oxolane, twoAlkane, the such ethers of dimethoxy-ethane; Chlorobenzene, dichloro-benzenes, carrene, chlorineImitative, carbon tetrachloride, dichloroethanes, trichloroethanes, the such halogenated hydrocarbons of dichloroethylene; The fragrance that benzene,toluene,xylene is suchFamily's hydro carbons; Pentane, hexane, heptane, octane, the such aliphatic hydrocarbon of cyclohexane; Methyl acetate, ethyl acetate, propyl acetateSuch ester class; In the polar aprotic solvent that acetonitrile, propionitrile, DMF are such etc., suitably select a kind or 2More than kind.

The first operation of reaction (U) can be carried out conventionally at-20～140 DEG C, preferred-10～120 DEG C, its reaction timeConventionally can be about 0.1～10 hour, preferably about 0.5～5 hour.

Z in compound (XXX)^aIn situation for methoxycarbonyl oxygen base or ethoxy carbonyl oxygen base, the first operation canUnder the existence of alkali, carry out.

As alkali, can be from for example sodium carbonate, the such alkali carbonate of potash; Sodium hydride, hydrofining are suchAlkali metal hydride; Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylamino pyrrolePyridine, 2,6-lutidines, 4-pyrrolidinyl pyridine, N-methylmorpholine, DMA, N, N-diethylaniline, N-Ethyl-methylphenylamine, 1,8-diazabicyclo (5.4.0)-7-endecatylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane thatIn the tertiary amines of sample etc., suitably select one kind or two or more. Alkali, with respect to the compound of formula (XXIX), can use 1～5 times to rubYou, preferably 1～2.5 times mole.

The compound that the second operation of reaction (U) can make formula (XXX) conventionally under the existence of solvent with wait mole more thanReplacement amine (XII-1) be used for carrying out.

As solvent, as long as the solvent to reactionlessness, can be from for example ether, butyl ethyl ether, tetrahydrochysene furanMutter, twoAlkane, the such ethers of dimethoxy-ethane; Chlorobenzene, dichloro-benzenes, carrene, chloroform, carbon tetrachloride, two chloroethenesAlkane, trichloroethanes, the such halogenated hydrocarbons of dichloroethylene; Such aromatic hydrocarbon based of benzene,toluene,xylene; Pentane, hexane,Heptane, octane, the such aliphatic hydrocarbon of cyclohexane; Methyl acetate, ethyl acetate, the such ester class of propyl acetate; Acetonitrile, thirdIn the polar aprotic solvent that nitrile, DMF are such etc., suitably select one kind or two or more.

The second operation of reaction (U) conventionally can-10～100 DEG C, preferably carry out at 0～50 DEG C, its reaction time is logicalCan be often about 0.1～24 hour, preferably about 0.5～12 hour.

The second operation of reaction (U) also can be carried out under the existence of alkali.

As alkali, can be from for example sodium carbonate, the such alkali carbonate of potash; Sodium hydride, hydrofining are suchAlkali metal hydride; Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylamino pyrrolePyridine, 2,6-lutidines, 4-pyrrolidinyl pyridine, N-methylmorpholine, DMA, N, N-diethylaniline, N-Ethyl-methylphenylamine, 1,8-diazabicyclo (5.4.0)-7-endecatylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane thatIn the tertiary amines of sample etc., suitably select one kind or two or more. Alkali, with respect to the compound of formula (XXX), can use 1～5 times to rubYou, preferably 1～2.5 times mole.

The 3rd operation of reaction (U), conventionally can be under the existence of solvent, make the compound of formula (XXXI) at normal pressure～numberUnder individual atmospheric nitrogen atmosphere, utilize metallic catalyst to carry out catalytic hydrogenation, or in acid flux material with metallic catalyst effectAlso originally carried out. As above-mentioned metallic catalyst, can be from for example, in palladium carbon, platinum oxide, Raney nickel, iron, stannic chloride etc.Suitably select one kind or two or more.

The hydrogen of reaction (U) the 3rd operation is with respect to the compound of formula (XXXI), can use 1～200 times mole, preferably 1～50 times moles.

As solvent, as long as the solvent to reactionlessness, can be from for example water, acetic acid, ethyl acetate; Methyl alcohol,Ethanol, propyl alcohol, n-butanol, the such alcohols of the tert-butyl alcohol; Ether, butyl methyl ether, oxolane, twoAlkane, dimethoxy secondThe ethers that alkane is such; Such aromatic hydrocarbon based of benzene,toluene,xylene; Pentane, hexane, heptane, octane, cyclohexane are suchIn aliphatic hydrocarbon etc., suitably select one kind or two or more.

The 3rd operation of reaction (U) conventionally can-10～100 DEG C, preferably carry out at 0～80 DEG C, its reaction time is logicalCan be often about 0.5～24 hour, preferably about 1～12 hour.

The compound that the 4th operation of reaction (U) can make formula (V-1) conventionally under the existence of solvent, utilize halogenating agent placeReason is carried out. In addition, as halogenating agent, in the situation that using chlorine or bromine, can under the existence of alkali and solvent, carry out.

As halogenating agent, can select chlorine, bromine, N-bromine succinimide or N-chloro-succinimide.

As alkali, can be from NaOH, lithium hydroxide, potassium hydroxide, such metal hydroxides, the hydrogen of calcium hydroxideChange in the such alkali metal alcoholates of sodium, hydrofining such alkali metal hydride, sodium methoxide, caustic alcohol, potassium tert-butoxide etc. suitablySelect one kind or two or more. Alkali, with respect to compound (V-1), can use 0.8～5 times mole, preferably 1～3 times mole.

As solvent, as long as the solvent to reactionlessness, can be from for example ether, butyl methyl ether, tetrahydrochysene furanMutter, twoAlkane, the such ethers of dimethoxy-ethane; Chlorobenzene, dichloro-benzenes, carrene, chloroform, carbon tetrachloride, two chloroethenesAlkane, trichloroethanes, the such halogenated hydrocarbons of dichloroethylene; Such aromatic hydrocarbon based of benzene,toluene,xylene; Pentane, hexane,Heptane, octane, the such aliphatic hydrocarbon of cyclohexane; Acetonitrile, propionitrile, DMF, methyl-sulfoxide, hempaAcyl triamine, sulfolane, dimethylacetylamide, the such polar aprotic solvent of 1-METHYLPYRROLIDONE; Methyl alcohol, ethanol, thirdIn the alcohols that alcohol, n-butanol, the tert-butyl alcohol are such etc., suitably select one kind or two or more.

The 4th operation of reaction (U) conventionally can-20～120 DEG C, preferably carry out at 0～80 DEG C, its reaction time is logicalCan be often about 0.5～24 hour, preferably about 1～12 hour.

In addition, R in the compound of compound (V-1)^1aFor the compound of chlorine atom or bromine atoms, can be according to following anti-Should (V) manufacture.

In formula, R^1bFor chlorine atom or bromine atoms, R²As mentioned above.

The first operation of formula (V) can be carried out equally with the second operation of above-mentioned reaction (U). , compound (XXXIII)Conventionally can be under the existence of solvent by the replacement amine (XII-1) more than making compound (XXXII) and waiting mole be used for intoOK.

The second operation of formula (V) can with same the carrying out of the 3rd operation of above-mentioned reaction (U). , compound (XXXIV)Conventionally can under the existence of solvent, make compound (XXXIII) under normal pressure～several atmospheric nitrogen atmosphere, utilize metal to urgeAgent is carried out catalytic hydrogenation, or it is original synthetic in acid flux material, to make metallic catalyst effect go back.

The 3rd operation of reaction (V) can be by making compound (XXXIV) conventionally under the existence of solvent with halogenating agentBe used for synthesizing.

As halogenating agent, can be from for example chlorine, the such halogen of bromine; TCCA, N-chloro-succinimide, N-The active halogen agent that bromine succinimide is such; Suitably choosing in the mixed aqueous solution of hydrogen peroxide and hydrogen chloride or hydrogen bromide etc.Select.

As solvent, as long as the solvent to reactionlessness, can be from for example ether, butyl methyl ether, tetrahydrochysene furanMutter, twoAlkane, the such ethers of dimethoxy-ethane; Methyl acetate, ethyl acetate, the such ester class of propyl acetate; Acetonitrile,In the polar aprotic solvent that propionitrile, DMF are such etc., suitably select one kind or two or more.

The 3rd operation of reaction (V) conventionally can-10～+ 100 DEG C, preferably carry out at 0～50 DEG C, its reaction time is logicalCan be often about 0.1～12 hour, preferably about 0.5～6 hour.

The cycloalkyl-alkyl amine of the compound (XII-1) using in above-mentioned reaction (U) and (V) etc. is known compound, canWith according to J.Am.Chem.Soc. for example,, the method for 88 volumes, 2267 pages of records, J.Med.Chem., 1997,40 in 1966Volume, the known data such as 3215 pages are manufactured. In addition, the compound of formula (XXXVII) can be according to Eur.J.Med.Chem, 2001Year, 265-286 page record method (Leuckart method) or carry out according to the reaction below the method utilization (W).

In formula, R⁸Be cyclopropyl, cyclopropyl alkyl, cyclobutyl or cyclobutyl alkyl, J is hydrogen or alkyl.

The first operation of reaction (W) can make the compound of formula (XXXV) and formamide be used for carrying out under acid exists.

As solvent, carry out with formamide, but as long as the solvent to reactionlessness, can with formamideMerge and use, can be from for example ether, butyl ethyl ether, oxolane, twoAlkane, the such ethers of dimethoxy-ethane; ChlorineBenzene, dichloro-benzenes, carrene, chloroform, carbon tetrachloride, dichloroethanes, trichloroethanes, the such halogenated hydrocarbons of dichloroethylene; Benzene,Such aromatic hydrocarbon based of toluene, dimethylbenzene; Acetonitrile, propionitrile, DMF, methyl-sulfoxide, hexamethyl phosphinylidyne threeAmine, sulfolane, dimethylacetylamide, the such polar aprotic solvent of 1-METHYLPYRROLIDONE; Methyl alcohol, ethanol, propyl alcohol, justIn such alcohols, the water etc. of butanols, the tert-butyl alcohol, suitably select one kind or two or more.

As acid, can be from formic acid, C₁-C₆Alkyl carboxylic acid, aromatic carboxylic acid, C₁-C₆Alkyl sulfonic acid, aromatic sulphonic acid thatThe organic acid of sample; Ammonium chloride, Trimethylamine hydrochloride, triethylamine hydrochloride, pyridine hydrochloride, 4-dimethylaminopyridine saltHydrochlorate, 2,6-dimethyl pyrazole thiamine hydrochloride, 4-pyrrolidinyl pyridine hydrochloride, N-methylmorpholine hydrochloride, N, N-dimethyl benzeneThe amine hydrochlorate class that amine hydrochlorate is such; Halogenated titanium, aluminum halide, iron halide, tin halides, zinc halide, magnesium halide, silicon halide, halogenChange in the such lewis acid of copper, trifluoroboranes-ether complexes etc., suitably select one kind or two or more. Acid is with respect to compound(XXXV), can use 0.05～10 times mole, preferably 0.1～5 times mole.

The first operation of reaction (W) conventionally can 0～200 DEG C, preferably carry out at 30～180 DEG C, its reaction time is logicalCan be often about 1～24 hour, preferably about 2～12 hours.

The second operation of reaction (W) conventionally by being used acid or alkali to make the compound of formula (XXXVI) under the existence of solventHydrolysis is carried out. As above-mentioned acid, can be from hydrogen chloride, hydrogen bromide, hydrogen iodide, the such hydrogen halides of hydrogen fluoride; Sulfuric acid, sulfurousAcid, nitric acid, nitrous acid, phosphoric acid, boric acid, chloric acid, chlorous acid, the such inorganic acid of hypochlorous acid; Halogenated titanium, aluminum halide, iron halide,Tin halides, zinc halide, magnesium halide, silicon halide, copper halide, the such lewis acid of trifluoroboranes-ether complexes; Formic acid, C₁-C₆Alkyl carboxylic acid, aromatic carboxylic acid, C₁-C₆In the organic acid that alkyl sulfonic acid, aromatic sulphonic acid are such etc., suitably select a kind or 2 kinds withOn.

As alkali, can be from NaOH, the such alkali metal hydroxide of potassium hydroxide; Sodium hydride, hydrofining are suchAlkali metal hydride; Sodium carbonate, the such such alkali of alkali carbonate, sodium methoxide, caustic alcohol, potassium tert-butoxide of potashIn metal alkoxide etc., suitably select one kind or two or more. Acid or alkali, with respect to compound (XXXVI), can use 0.1～5 times to rubYou, preferably 1～2.5 times mole. As the solvent in this situation, as long as the solvent to reactionlessness, can be from for exampleEther, butyl methyl ether, oxolane, twoAlkane, the such ethers of dimethoxy-ethane; Chlorobenzene, dichloro-benzenes, carrene,Chloroform, carbon tetrachloride, dichloroethanes, trichloroethanes, the such halogenated hydrocarbons of dichloroethylene; The virtue that benzene,toluene,xylene is suchFragrant family hydro carbons; Acetonitrile, propionitrile, DMF, N-METHYLFORMAMIDE, formamide, methyl-sulfoxide, hexamethyl phosphinylidyne threeAmine, sulfolane, dimethylacetylamide, 1-METHYLPYRROLIDONE, formic acid, acetic acid, propionic acid, the such polar solvent of butyric acid; Methyl alcohol,In such alcohols, the water etc. of ethanol, propyl alcohol, n-butanol, the tert-butyl alcohol, suitably select one kind or two or more.

The second operation of reaction (W) conventionally can-10～150 DEG C, preferably carry out at 0～100 DEG C, its reaction time is logicalCan be often about 0.1～10 hour, preferably about 0.5～2 hour.

The compound of above-mentioned formula (XXXVII) also can be by adding hydrogen chloride, salt in manufacturing process in reactant liquorThe acid of acid, sulfuric acid etc., takes out as salt.

And then compound (XXXVII) also can be manufactured according to following method.

In formula, R⁸With J as previously mentioned, M for-OH or-OG (G is ether residue), as G, be that for example methyl, ethyl are suchC1-C6 alkyl, the phenyl that can be replaced by C1-C6 alkyl etc.

The first operation of reaction (X) can make compound (XXXV) and compound conventionally under the existence of solvent(XXXVIII) be used for carrying out.

As solvent, as long as the solvent to reactionlessness, can be from for example ether, butyl methyl ether, tetrahydrochysene furanMutter, twoAlkane, the such ethers of dimethoxy-ethane; Chlorobenzene, dichloro-benzenes, carrene, chloroform, carbon tetrachloride, two chloroethenesAlkane, trichloroethanes, the such halogenated hydrocarbons of dichloroethylene; Such aromatic hydrocarbon based of benzene,toluene,xylene; Acetonitrile, propionitrile,DMF, methyl-sulfoxide, HMPA, sulfolane, dimethylacetylamide, 1-METHYLPYRROLIDONE thatThe polar aprotic solvent of sample; In such alcohols, the water etc. of methyl alcohol, ethanol, propyl alcohol, n-butanol, the tert-butyl alcohol, suitably select a kindOr two or more.

The 1st operation of reaction (X) conventionally can 0～150 DEG C, preferably carry out at 30～110 DEG C, its reaction time is commonCan be about 0.5～24 hour, preferably about 1～12 hour.

The second operation of reaction (X) conventionally can be by being used reducing agent to make the change of formula (XXXIX) under the existence of solventCompound also carried out originally.

As reducing agent, can from such as lithium aluminium hydride reduction, sodium borohydride etc., suitably select one kind or two or more. As going backFormer dose, in the situation that using sodium borohydride, add the lewis acid of molybdenum trioxide, titanium tetrachloride, cobalt chloride, nickel chloride etc.,Can improve reactivity.

As the solvent in this situation, as long as the solvent to reactionlessness, can be from for example ether, butyl methylEther, oxolane, twoIn the ethers that alkane, dimethoxy-ethane are such etc., suitably select one kind or two or more.

In addition, the second operation of reaction (X) can make the compound of formula (XXXIX) at normal pressure conventionally under the existence of solventUnder～several atmospheric nitrogen atmosphere by reducing with the catalytic hydrogenation of metallic catalyst. As metallic catalyst, canWith from for example, in palladium carbon, platinum oxide, Raney nickel etc., suitably select one kind or two or more.

As the solvent in this situation, as long as the solvent to reactionlessness, can be from for example water, acetic acid, acetic acidEthyl ester; Methyl alcohol, ethanol, propyl alcohol, n-butanol, the such alcohols of the tert-butyl alcohol; Ether, butyl methyl ether, oxolane, twoAlkane,The ethers that dimethoxy-ethane is such; Such aromatic hydrocarbon based of benzene,toluene,xylene; Pentane, hexane, heptane, octane, ringIn the aliphatic hydrocarbon that hexane is such etc., suitably select one kind or two or more.

The second operation of reaction (X) conventionally can-10～100 DEG C, preferably carry out at 0～80 DEG C, its reaction time is logicalCan be often about 0.5～24 hour, preferably about 2～12 hours.

The compound obtaining in aforesaid reaction (A)～(X), exists optical isomer, geometric isomer such sometimesIsomers, but in the present invention, the both sides that comprise each isomers and isomer mixture. In addition, in the present invention, lead in this technologyIn the scope of the technology general knowledge in territory, also comprise the various isomers outside above-mentioned. In addition, according to the kind of isomers, sometimesForm the chemical constitution different from the structure of recording in above-mentioned reaction equation, because known this of those skilled in the art is due to isomeryTherefore the relation of body is known within the scope of the invention.

In addition, the present invention includes following method.

(1), according to above-mentioned reaction (B-1), carry out the method for the compound of manufacture formula (II-1).

(2), according to above-mentioned reaction (C-1), carry out the method for the compound of manufacture formula (III-1).

(3), according to above-mentioned reaction (D-1), carry out the method for the compound of manufacture formula (IX-1).

(4), according to above-mentioned reaction (E-1), carry out the method for the compound of manufacture formula (VIII-1).

(5), according to above-mentioned reaction (F-1), carry out the method for the compound of manufacture formula (VI-1).

(6), according to above-mentioned reaction (G-1), carry out the method for the compound of manufacture formula (X-1).

(7), according to above-mentioned reaction (B-1) and (A-1), come the compound of manufacture formula (II-1), the chemical combination of manufacture formula (I-1)The method of thing.

(8) according to above-mentioned reaction (E-1), (D-1), (C-1) and (B-1), come compound, the manufacture of manufacture formula (VIII-1)The method of the compound of the compound of formula (IX-1), the compound of manufacture formula (III-1), manufacture formula (II-1).

(9), according to above-mentioned reaction (E-1), (D-1), (C-1), (B-1) and (A-1), carry out the chemical combination of manufacture formula (VIII-1)The compound of thing, manufacture formula (IX-1), the compound of manufacture formula (III-1), the compound of manufacture formula (II-1), manufacture formula (I-1) method of compound.

(10), according to above-mentioned reaction (F-1), (E-1), (D-1), (C-1) and (B-1), carry out the chemical combination of manufacture formula (VI-1)The compound of thing, manufacture formula (VIII-1), the compound of manufacture formula (IX-1), the compound of manufacture formula (III-1), manufacture formula(II-1) method of compound.

(11) according to above-mentioned reaction (G-1), (F-1), (E-1), (D-1), (C-1) and (B-1), carry out manufacture formula (X-1)Compound, the manufacture of the compound of compound, manufacture formula (VI-1), the compound of manufacture formula (VIII-1), manufacture formula (IX-1)The method of the compound of formula (III-1), the compound of manufacture formula (II-1).

(12) according to according to above-mentioned reaction (N-1), carry out the method for the compound of manufacture formula (II-1).

(13), according to according to above-mentioned reaction (N-1) and (A-1), come compound, the manufacture formula (I-1) of manufacture formula (II-1)The method of compound.

Embodiment

For the present invention is described in further detail, record embodiment below, but the invention is not restricted to this.

Embodiment 1 (E)-3-(6-chloro-4-oxygen-4H-benzo [d] [1,3]Piperazine-2-yl) methyl acrylate synthetic(1)

The mixed solution of methane sulfonyl chloride 1.49g and acetonitrile 10ml is carried out ice-cooled, by maleic acid monomethyl ester 1.3gWith the acetonitrile 10ml solution of pyridine 1.34g after ice-cooled lower use drips for 5 minutes, synthermal stirring 5 minutes. Under ice-cooled,With the acetonitrile solution 10ml that drips 5-chloro-o-amino benzoic acid 1.72g, pyridine 2.77g for 2 minutes, then use acetonitrile 5ml drip washing,Synthermal stirring 20 minutes. Under ice-cooled, with 2 minutes interpolation methane sulfonyl chloride 1.49g, then use acetonitrile 2ml drip washing, stir30 minutes, then return to room temperature, react 4 hours. Reactant liquor is put in water 20ml, then stirred 30 minutes. Filter knotCrystalline substance, water, acetonitrile: after the washing of water (2:1) mixed liquor, the dry object 1.82g (fusing point: 162～164 DEG C) that obtains brown.

¹H-NMR(400MHz，CDCl₃)δ:8.20(dd，1H)，7.77(dd，1H)，7.61(dd，1H)，7.23(d，1H)，7.01(d，1H)，3.84(s，3H)

Embodiment 2 (E)-3-(6-chloro-4-oxygen-4H-benzo [d] [1,3]Piperazine-2-yl) methyl acrylate synthetic(2)

(1) the chloro-2-of (Z)-5-(4-methoxyl group-4-oxygen-2-crotonamide) is benzoic synthetic

At room temperature, in the methyl alcohol of 120ml, absorb the hydrogen chloride gas of 3.7g, then add (Z)-2-(3-carboxyl thirdAlkene acid amides)-5-chlorobenzoic acid 30.2g, stirs 2 hours at 30～35 DEG C. In reactant liquor, add the water of 150ml, by what separate outCrystallization suction filtration. Filtrate is washed with water, dry, obtain object 25.4g.

(2) (E)-3-(6-chloro-4-oxygen-4H-benzo [d] [1,3]Piperazine-2-yl) methyl acrylate synthetic

Mixing of the chloro-2-of (Z)-5-(4-methoxyl group-4-oxygen-2-crotonamide) benzoic acid 15.2g and ethyl acetate 61mlClose in solution and add acetic anhydride 15.2mL and concentrated sulfuric acid 0.15mL, at room temperature stir 45 minutes. Add after concentrated hydrochloric acid 0.3ml,Synthermal stirring 1 hour. Filtering for crystallizing, with after ethyl acetate washing, dry, obtain white object 13.3g.

Closing of embodiment 34-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl amino)-4-oxygen ethyl crotonateBecome

The mixed solution of the acetonitrile 12ml of Alpha-Methyl-cyclopropyl methylamine hydrochloride 0.73g, triethylamine 0.91g is existedAfter stirring at room temperature 1 hour, (E)-3-(the 6-chloro-4-oxygen-4H-benzo [d] [1,3] obtaining in operation before room temperature addsPiperazine-2-yl) the coarse crystallization 0.53g of methyl acrylate, room temperature reaction 3 hours. In reactant liquor, add after water, use ethyl acetateExtraction. With saturated common salt water washing organic layer, add anhydrous sodium sulfate to be dried. Solvent is under reduced pressure heated up in a steamer, by residueRefining with silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1～8/2), obtain flaxen object 0.22g (moltenPoint: 154.4 DEG C).

¹H-NMR(400MHz，CDCl₃)δ:11.62(br，1H)，8.69-8.66(m，1H)，7.46-7.43(m，2H)，7.05(d，1H)，6.88(d，2H)，6.21(brd，1H)，3.80(s，3H)，3.53-3.48(m，1H)，1.32(d，3H)，0.96-0.90(m，1H)，0.62-0.48(m，2H)，0.42-0.36(m，1H)，0.34-0.29(m，1H)

Embodiment 4N-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-5-pyrazolidone-3-formamideSynthetic (1)

At 4-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl amino)-4-oxygen ethyl crotonate 0.56g and ethanolIn the mixed liquor of 3ml, add the mixed liquor of hydrazine one water and thing 90mg and ethanol 3ml, with after ethanol 2ml drip washing, add hot reflux 6 littleTime. After reactant liquor is let cool, by the crystallization suction filtration of separating out, crystallization is washed with ethanol, air-dry acquisition object 0.16g (fusing point:248℃)。

¹H-NMR(300MHz，DMSO-d₆)δ:11.83(s，1H)，9.14(d，1H)，8.53(d，1H)，8.36(dd，1H)，7.57(t，1H)，7.38(dd，1H)，5.99(dd，1H)，3.99(t，1H)，3.30(m，1H)，2.56(dd，1H)，2.27-2.32(m，1H)，1.04(q，3H)，0.81(m，1H)，0.00-0.40(m，4H)

Embodiment 5N-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-yl)-3-hydroxylBase-4, synthetic (1) of 5-dihydro-1 h-pyrazole-5-formamide

At N-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-5-pyrazolidone-3-formamide 0.10g and 2,In the 2-methyl-2-propanol 3ml mixed liquor of 3-dichloropyridine 0.09g, add palladium-carbon (ア Le De リッチ society system, DeGussaTypeE105CA/W) 15 % by weight, then add sodium tert-butoxide 0.045g. Mixed liquor is reacted 9 hours under refluxing. Let coolAfter, reactant liquor is injected in the 1MHCl aqueous solution, be extracted with ethyl acetate. With saturated common salt water washing organic layer, add anhydrousSodium sulphate is dried. With diatomite filtration, filtrate is under reduced pressure concentrated, and by silica gel column chromatography for residue, (eluent: n-is ownAlkane/ethyl acetate=1/0～1/1) refining, obtain object 0.11g (fusing point: 165～167 DEG C).

¹H-NMR(300MHz，CDCl₃)δ:12.17(s，1H)，8.58(d，1H)，8.25(dd，1H)，7.82(br，1H)，7.72(d，1H)，7.42(ds，2H)，7.10(dd，1H)，6.26(d，1H)，4.93(m，1H)，3.45(m，1H)，2.93(ds，2H)，1.24(d，3H)，0.89(m，1H)，0.12-0.64(m，4H)

Embodiment 6N-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-yl)-3-hydroxylBase-4, synthetic (2) of 5-dihydro-1 h-pyrazole-5-formamide

N-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-5-pyrazolidone-3-formamide 1.0g is dissolved inIn the DMF of 10mL, add 2,3-dichloropyridine 460mg, then add sodium hydride 350mg, under blanket of nitrogen, after 7 hours, let cool at approximately 70 DEG C of stir abouts. After adding water to stir, acquisition will be extracted with ethyl acetate in reactant liquorSlightly for product, silica gel column chromatography (eluent: ethyl acetate/methanol=9/1) is refining, obtains object 1.15g.

Embodiment 75-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl amino formyl)-1-(3-chloropyridine-2-Base)-4,5-dihydro-1 h-pyrazole-3-base 4-toluene sulfonic acide ester synthetic

By N-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-yl)-3-hydroxyl-4,5-The mixed liquor of dihydro-1 h-pyrazole-5-formamide 2.0g and DMF 41ml 0 DEG C cooling, add sodium hydride(60% oil suspension) 0.2g. Stir after 1 hour, add paratoluensulfonyl chloride 1.2g at 0 DEG C. Stir after 1.5 hours, will reactLiquid is injected in 1MHCl aqueous solution 120ml, is extracted with ethyl acetate. With saturated common salt water washing organic layer, add anhydrous sulphurAcid sodium is dried. Solvent is under reduced pressure heated up in a steamer, by (the eluent: n-hexane/ethyl acetate=1/ of silica gel column chromatography for residue0～1/1) refining, the object 2.45g of acquisition cream pasty state.

¹H-NMR(300MHz，CDCl₃)δ:11.16(d，1H)，8.48(m，1H)，8.25(dd，1H)，8.08(dd，1H)，8.00(d，2H)，7.61(d，1H)，7.36(m，4H)，6.83(m，1H)，6.04(t，1H)，5.49(ddd，1H)，3.28-3.46(m，3H)，2.45(s，3H)，1.23(dd，3H)，0.86(m，1H)，0.23-0.63(m，4H)

The bromo-N-of embodiment 83-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-Base)-4, synthetic (1) of 5-dihydro-1 h-pyrazole-5-formamide

At 5-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl amino formyl)-1-(3-chloropyridine-2-yl)-4,In the mixed liquor of 5-dihydro-1 h-pyrazole-3-base 4-toluene sulfonic acide ester 1.0g and DMF 25ml, add brominationAmmonium 0.54g, is heated to 93 DEG C. After 1 hour, reactant liquor is injected in water 50ml, uses extracted with diethyl ether. Use saturated common salt water washingOrganic layer, adds anhydrous sodium sulfate to be dried. Solvent is under reduced pressure heated up in a steamer, by (the eluent: n-of silica gel column chromatography for residueHexane/ethyl acetate=1/0～1/1) refining, the object 0.11g of acquisition cream pasty state.

¹H-NMR(300MHz，CDCl₃)δ:11.48(d，1H)，8.50(dd，1H)，8.13(t，1H)，7.67(d，1H)，7.4(ds，2H)，6.9(m，1H)，6.03(t，1H)，5.50(ddd，1H)，3.35-3.58(m，3H)，1.17(d，3H)，0.85(m，1H)，0.23-0.6(m，4H)

The bromo-N-of embodiment 93-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-Base)-4, synthetic (2) of 5-dihydro-1 h-pyrazole-5-formamide

Under ice-cooled, at 5-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl amino formyl)-1-(3-chlorine pyrrolePyridine-2-yl)-4, in the mixed liquor of 5-dihydro-1 h-pyrazole-3-base 4-toluene sulfonic acide ester 1.0g and oxolane 9ml, drip threeOxolane (1ml) solution of phosphonium bromide 0.16g. Stir after 5 minutes, be heated to 45 DEG C. After 5 hours, reactant liquor is injected intoIn water 50ml, be extracted with ethyl acetate. With saturated common salt water washing organic layer, add anhydrous sodium sulfate to be dried. By solventUnder reduced pressure heat up in a steamer, silica gel column chromatography for residue (eluent: n-hexane/ethyl acetate=1/0～1/1) is refining, obtain creamThe object 0.73g of pasty state.

The bromo-N-of embodiment 103-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-Base)-4, synthetic (3) of 5-dihydro-1 h-pyrazole-5-formamide

At 5-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl amino formyl)-1-(3-chloropyridine-2-yl)-4,In the mixed liquor of 5-dihydro-1 h-pyrazole-3-base 4-toluene sulfonic acide ester 1.0g and toluene 10ml, add calcium bromide 2 water and thing0.25g, approximately 90 DEG C of heating 6.5 hours. After letting cool, in reactant liquor, add sodium acid carbonate 0.41g, water 10ml, stir. SeparatoryAfter, with saturated common salt water washing organic layer, add anhydrous sodium sulfate to be dried. Solvent is under reduced pressure heated up in a steamer, obtain refiningObject 0.96g.

The bromo-N-of embodiment 113-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-Base) synthetic (1) of-1H-pyrazoles-5-formamide

Chloro-5 at 2,3-bis-, Isosorbide-5-Nitrae-bis-of 6-dicyano-p-benzoquinones 0.14gIn alkane 6ml solution, add the bromo-N-of 3-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-yl)-4,5-dihydro-1 h-pyrazole-5-formylAmine 0.13g, adds hot reflux 18 hours. After letting cool, reactant liquor is put in water, be extracted with ethyl acetate, organic layer is used fullWith saline solution washing, use dried over sodium sulfate. By filtrate under reduced pressure heat up in a steamer, by silica gel column chromatography for residue (eluent: n-oneselfAlkane/ethyl acetate=8/2～7/3) refining, obtain object 33mg (fusing point: 231-233 DEG C).

¹H-NMR(400MHz，CDCl₃)δ:12.25(br，1H)，8.48(dd，1H)，8.44(d，1H)，7.89(dd，1H)，7.45-7.33(m，3H)，7.01(s，1H)，6.23(d，1H)，3.57-3.54(m，1H)，1.34(d，3H)，0.95-0.90(m，1H)，0.63-0.51(m，2H)，0.43-0.32(m，2H)

The bromo-N-of embodiment 123-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-Base) synthetic (2) of-1H-pyrazoles-5-formamide

At the bromo-N-of 3-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-yl)-4,5-bis-In the DMF 3ml solution of hydrogen-1H-pyrazoles-5-formamide 0.10g, add potassium persulphate 0.24g andSulfuric acid 0.02g, adds hot reflux. After 1.5 hours, let cool, reactant liquor is injected in water 10ml, be extracted with ethyl acetate. With fullWith saline solution washing organic layer, add anhydrous sodium sulfate to be dried. Solvent is under reduced pressure heated up in a steamer, by residue silicagel column lookSpectrum (eluent: n-hexane/ethyl acetate=1/0～1/2) is refining, obtains object 0.09g.

The bromo-N-of embodiment 133-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-Base) synthetic (3) of-1H-pyrazoles-5-formamide

At the bromo-N-of 3-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-yl)-4,5-bis-In the ethyl acetate 12ml solution of hydrogen-1H-pyrazoles-5-formamide 0.53g, add 30% aquae hydrogenii dioxidi 1.13g, add hot reflux.After 30 hours, let cool, reactant liquor is injected in water, be extracted with ethyl acetate. With saturated common salt water washing organic layer, add nothingAqueous sodium persulfate is dried. Solvent is under reduced pressure heated up in a steamer, by (the eluent: n-hexane/ethyl acetate of silica gel column chromatography for residue=4/1) refining, obtain object 0.32g.

The chloro-6-[[(1-cyclopropyl of the bromo-4-of the bromo-N-[2-of embodiment 143-ethyl] amino] carbonyl] phenyl]-1-(3-chlorinePyridine-2-yl) synthetic (1) of-1H-pyrazoles-5-formamide

By bromo-3-N-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-yl)-1H-pyrroleThe mixed solution of azoles-5-formamide 6.0g and ethyl acetate 75ml carries out ice-cooled, adds after NaOH (laminar) 1.4g,With within 2 hours, adding bromine 2.8g. After 18 hours, in reactant liquor, add water 60ml in stirring at room temperature, be extracted with ethyl acetate. To haveMachine layer washs with saline solution, adds anhydrous sodium sulfate, dry. By solvent under reduced pressure heat up in a steamer, by the crystallization of separating out acetic acid secondAfter mixed solution (1:5) the 20ml washing of ester and hexane, filter, obtain the object 6.2g of white crystals.

Embodiment 15N-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-5-pyrazolidone-3-formamideSynthetic (2)

(1) synthesizing of (Z)-2-(3-carboxyl acrylamide)-5-chlorobenzoic acid

In 5-chloro-o-amino benzoic acid 15g and maleic anhydride 10.3g, add twoAlkane 150ml, adds hot reflux. Stir 5After hour, reactant liquor is let cool, by the crystallization suction filtration of separating out. By filtrate hexane: after the washing of ethyl acetate (3:1) mixed liquorAir-dry, obtain flaxen object 15g (fusing point: 194.4 DEG C).

¹H-NMR(400MHz，Acetone-d₆)δ:11.62(br，1H)，8.67(d，1H)，8.08(d，1H)，7.70(dd，1H)，6.67(d，1H)，6.39(d，1H)

(2) the chloro-2-of (Z)-5-(4-methoxyl group-4-oxygen-2-crotonamide) is benzoic synthetic

In the mixed liquor of the methyl alcohol 20ml of (Z)-2-(3-carboxyl acrylamide)-5-chlorobenzoic acid 1.0g, add sulfuric acid 10Drip, stirring at room temperature 4.5 hours. In reactant liquor, add water, be extracted with ethyl acetate, with saturated common salt water washing organic layer,Add anhydrous sodium sulfate to be dried. Solvent is under reduced pressure heated up in a steamer, obtain object 0.91g (fusing point: 136.9 DEG C).

¹H-NMR(400MHz，DMSO-d₆)δ:11.17(s，1H)，8.44(d，1H)，7.92(d，1H)，7.68(dd，1H)，6.65(d，1H)，6.43(d，1H)，3.64(s，3H)

(3) (Z)-3-(6-chloro-4-oxygen-4H-benzo [d] [1,3]Piperazine-2-yl) methyl acrylate synthetic

By the mixed liquor of chloro-(Z)-5-2-(4-methoxyl group-4-oxygen-2-crotonamide) benzoic acid 0.35g and acetic anhydride 2mlStirring at room temperature 30 minutes, and then add acetic anhydride 3ml, with 6.5 hours at room temperature reaction. Reactant liquor is put in water, usedEthyl acetate extraction, by organic layer saturated common salt water washing. Add anhydrous sodium sulfate, dry. Solvent is under reduced pressure heated up in a steamer,Silica gel column chromatography for residue (eluent: n-hexane/ethyl acetate=9/1～8/2) is refining, obtain object 0.24g (moltenPoint: 117-118 DEG C).

¹H-NMR(400MHz，DMSO-d₆)δ:8.09(d，1H)，7.97(d，1H)，7.65(dd，1H)，6.80(d，1H)，6.59(d，1H)，3.76(s，3H)

(4) N-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-5-pyrazolidone-3-formamide is synthetic

(Z)-methyl 3-(the 6-chloro-4-oxygen-4H-benzo [d] [1,3] obtaining in operation before usingPiperazine-2-yl) propyleneAcid esters, according to the method for above-mentioned synthesis example 3 and synthesis example 4, can manufacture N-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl)Phenyl)-5-pyrazolidone-3-formamide.

Embodiment 16N-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-5-pyrazolidone-3-formamideSynthetic (3)

(1) 4-(the chloro-2-cyclopropyl of 4-ethylamino formyl) phenyl amino)-4-oxygen iso-crotonic acid synthetic

By mixing of chloro-2-amino-5-N-(1-cyclopropyl ethyl) benzamide 100g and DMF 300mlClose liquid and be heated to 65 DEG C. Under agitation, add therein maleic anhydride 49.5g. After 1 hour, under stirring, in the water of 900ml, noteEnter reactant liquor. Stir after 10 minutes, by the crystallization suction filtration of separating out. By ethyl acetate 250ml washing for filtrate, air-dry, obtainObject 135g (fusing point: 173 DEG C).

¹H-NMR(300MHz，CDCl₃)δ:12.39(s，1H)，8.60(d，1H)，7.54(s，1H)，7.51(d，1H)，6.43(q，2H)，6.09(br，1H)，3.5(m，1H)，1.34(d，3H)，0.95(m，1H)，0.29-0.69(m，4H)

(2) 4-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl amino)-4-oxygen iso-crotonic acid methyl esters is synthetic

By 4-(the chloro-2-cyclopropyl of 4-ethylamino formyl) phenyl amino) the methyl alcohol 950ml of-4-oxygen iso-crotonic acid 97.7gMixed liquor be cooled to 0 DEG C. Under stirring, drip sulfuric acid. When slowly being returned to room temperature, stirs reactant liquor 20 hours. InsteadAnswer the saturated aqueous common salt that adds 1.4L in liquid, be extracted with ethyl acetate. By organic phase saturated common salt water washing, add anhydrous sulphurAcid sodium, dry. Solvent is under reduced pressure heated up in a steamer, obtain object 95.0g (fusing point: 131 DEG C).

¹H-NMR(300MHzCDCl₃)δ:11.19(s，1H)，8.57(d，1H)，7.44(d，1H)，7.4(dd，1H)，6.38(br，1H)，6.29(q，2H)，3.77(s，3H)，3.48(m，1H)，1.31(d，3H)，0.94(m，1H)，0.27-0.69(m，4H)

(3) N-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-5-pyrazolidone-3-formamide is synthetic

At 4-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl amino)-4-oxygen iso-crotonic acid methyl esters 25g and ethanolIn the mixed liquor of 250ml, drip hydrazine one water and thing 3.58g, add hot reflux. Stir after 5.5 hours, reactant liquor is let cool. To separate outCrystallization suction filtration. Filtrate is washed with ethyl acetate, then with hexane washing, air-dry, obtain object 13g.

The bromo-N-of embodiment 173-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-Base) synthetic (4) of-1H-pyrazoles-5-formamide

(1) amyl group 2-(3-chloropyridine-2-yl)-5-pyrazolidone-3-carboxylate is synthetic

In the mixed solution of 1-amylalcohol 15ml and toluene 30ml, add NaOH 0.75g, use azeotropic dehydration deviceWhen adding hot reflux, after dehydration, heat up in a steamer toluene. And then after toluene 20ml is joined in system, toluene is heated up in a steamer in heating again,Obtain the 1-amyl alcohol solution of amylalcohol sodium. In this reactant liquor at 70～80 DEG C with within 5 minutes, adding gradually 3-chloride-2-hydrazinopyridineAfter 2.5g, add 1-amylalcohol 5ml, 70～80 DEG C of heating after 25 minutes, with 15 minutes droppings maleic acid pentyl ester 5.1g and 1-pentaThe mixed solution of alcohol 5ml, and then 70～80 DEG C of reactions 2 hours. After letting cool, in reactant liquor, add acetic acid, after neutralization, subtractingDepress concentrated. In residue, add water, after being extracted with ethyl acetate, by watery hydrochloric acid and saline solution washing for organic layer, add nothingAqueous sodium persulfate, dry. Solvent is under reduced pressure heated up in a steamer, by silica gel column chromatography for residue (eluent: n-hexane/ethyl acetate=6/4～0/1) refining, object (fusing point: 66～68 DEG C) 1.29g of acquisition brown crystallization.

(2) the bromo-1-of amyl group 3-(3-chloropyridine-2-yl)-4,5-dihydro-1 h-pyrazole-5-carboxylate is synthetic

By amyl group 2-(3-chloropyridine-2-yl)-5-pyrazolidone-3-carboxylate 1.2g, phosphorus oxybromide 0.59g and acetonitrileThe mixed solution of 18ml slowly heats up, and after 25 minutes, makes it add hot reflux, refluxes 1 hour. After letting cool, at saturated sodium bicarbonateIn the aqueous solution, slowly add reactant liquor, stir 5 minutes. This mixed liquor is extracted with ethyl acetate, organic layer is washed with saltWash, add anhydrous sodium sulfate, dry. By solvent under reduced pressure heat up in a steamer, by (the eluent: n-hexane/second of silica gel column chromatography for residueAcetoacetic ester=9/1～8/2) refine, obtain object (fusing point: 39～42 DEG C) 1.06g of faint yellow crystallization.

(3) the bromo-1-of amyl group 3-(3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxylate is synthetic

At the bromo-1-of amyl group 3-(3-chloropyridine-2-yl)-4,5-dihydro-1 h-pyrazole-5-carboxylate 1.0g and acetonitrile 20mlMixed solution in add concentrated sulfuric acid 0.5ml and potassium persulphate 1.4g, add hot reflux 3 hours 20 minutes. After letting cool,In water, slowly add reactant liquor, stir 15 minutes. This mixed liquor is extracted with ethyl acetate, by organic layer saturated sodium bicarbonateThe aqueous solution and saline solution washing, add anhydrous sodium sulfate, dry. By solvent under reduced pressure heat up in a steamer, by residue silica gel column chromatography(eluent: n-hexane/ethyl acetate=8.5/1.5～8/2) is refining, obtains the object 0.47g of oily.

(4) the bromo-N-of 3-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-yl)-1H-pyrroleSynthesizing of azoles-5-formamide

At the chloro-N-of 2-amino-5-(1-cyclopropyl ethyl) benzamide 0.19g, the bromo-1-of amyl group 3-(3-chloropyridine-2-Base) add potassium tert-butoxide 0.11g in the mixed solution of-1H-pyrazoles-5-carboxylate 0.30g and methyl-sulfoxide 3ml, anti-in room temperatureAnswer 45 minutes. In watery hydrochloric acid 40ml, slowly add reactant liquor. This mixed liquor is extracted with ethyl acetate, by organic layer with saturatedSodium bicarbonate aqueous solution and saline solution washing, add anhydrous sodium sulfate, dry. By solvent under reduced pressure heat up in a steamer, by residue siliconGlue column chromatography (eluent: n-hexane/ethyl acetate=8/2～7.5/2.5) is refining, obtain white crystals object (fusing point:231～233℃)0.058g。

The chloro-6-[[(1-cyclopropyl of the bromo-4-of the bromo-N-[2-of embodiment 183-ethyl) amino] carbonyl] phenyl]-1-(3-chlorinePyridine-2-yl) synthetic (2) of-1H-pyrazoles-5-formamide

By bromo-3-N-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-yl)-1H-pyrroleThe mixed solution of azoles-5-formamide 0.24g and dimethyl formamide 5ml carries out ice-cooled, adds after 60% sodium hydride 46mg, extensiveArrive again room temperature, stir 25 minutes. Reactant liquor is again ice-cooled, with within 1 minute, dripping bromine 0.15g and dimethyl formamide 1mlAfter mixed solution, room temperature reaction 2 hours 45 minutes. After reaction finishes, in watery hydrochloric acid 60ml, slowly add reactant liquor. ShouldMixed liquor is extracted with ethyl acetate, and by saturated sodium bicarbonate aqueous solution and saline solution washing for organic layer, adds anhydrous sodium sulfate,Dry. By solvent under reduced pressure heat up in a steamer, by silica gel column chromatography for residue (eluent: n-hexane/ethyl acetate=8/2～0/1)Refining, object (fusing point: 244～247 DEG C) 0.20g of acquisition white crystals.

The bromo-N-of embodiment 193-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-Base) synthetic (5) of-1H-pyrazoles-5-formamide

(1) the bromo-1-of phenyl 3-(3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxylate is synthetic

In the mixed solution of the bromo-1-of 3-(3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxylic acid 3.0g and toluene 30ml, add5 of thionyl chloride 3ml and dimethyl formamides, added hot reflux after 1 hour, heats up in a steamer thionyl chloride and toluene, obtains the bromo-1-of 3-The rough thing of (3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxyl acyl chloride.

In the mixed solution of phenol 1.03g and oxolane 30ml, under ice-cooled, add 60% sodium hydride 0.48g,After room temperature reaction 20 minutes, again use ice bath cooling. In this mixed liquor at the above-mentioned rough thing of ice-cooled lower dropping and tolueneThe mixed solution of 20ml, use toluene 10ml drip washing reaction vessel. Ice-cooled lower reaction 15 minutes, at room temperature reaction after 1 hour,In water, slowly add reactant liquor. This mixed liquor is extracted with ethyl acetate, organic layer is washed with saline solution, add anhydrous sulphurAcid sodium, dry. Solvent is under reduced pressure heated up in a steamer, by (the eluent: n-hexane/ethyl acetate=9.5/ of silica gel column chromatography for residue0.5～7/3) refining, object (fusing point: 65～67 DEG C) 2.37g of acquisition white crystals.

(2) the bromo-N-of 3-(the chloro-2-of 4-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chloropyridine-2-yl)-1H-pyrroleSynthesizing of azoles-5-formamide

At the chloro-N-of 2-amino-5-(1-cyclopropyl ethyl) benzamide 0.23g, the bromo-1-of phenyl 3-(3-chloropyridine-2-Base) add potassium tert-butoxide 0.18g in the mixed solution of-1H-pyrazoles-5-carboxylate 0.30g and methyl-sulfoxide 5ml, anti-in room temperatureAnswer 1 hour. In watery hydrochloric acid, slowly add reactant liquor, this mixed liquor is extracted with ethyl acetate, by organic layer unsaturated carbonateHydrogen sodium water solution and saline solution washing, add anhydrous sodium sulfate, dry. By solvent under reduced pressure heat up in a steamer, by residue silicagel columnChromatogram (eluent: n-hexane/ethyl acetate=8/2～7.5/2.5) is refining, obtains object 0.16g.

The bromo-N-of embodiment 203-(the chloro-6-of the bromo-4-of 2-(1-cyclopropyl ethylamino formyl) phenyl)-1-(3-chlorine pyrrolePyridine-2-yl) synthetic (3) of-1H-pyrazoles-5-formamide

At the chloro-N-of the bromo-5-of 2-amino-3-(1-cyclopropyl ethyl) benzamide 0.23g, the bromo-1-of phenyl 3-(3-chlorine pyrrolePyridine-2-yl) in the mixed solution of-1H-pyrazoles-5-carboxylate 0.27g and methyl-sulfoxide 5ml, at room temperature add anhydrous slufuric acidAfter sodium 0.45g, add potassium tert-butoxide 0.16g, react 1 hour. Then, in water, slowly add reactant liquor. This mixed liquor is usedAfter ethyl acetate extraction, organic layer is washed with saline solution, add anhydrous sodium sulfate, dry. Solvent is under reduced pressure heated up in a steamer, willSilica gel column chromatography for residue (eluent: n-hexane/ethyl acetate=8/2～4/6) is refining, obtains object 0.24g.

Synthetic (1) ethyl 1-of the bromo-1-of embodiment 21 phenyl 3-(3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxylateSynthesizing of (3-chloropyridine-2-yl)-5-furyl-1H-pyrazole-3-carboxylic ester

In acetic acid (150ml) solution of ethyl 2-furoyl pyruvate 11.19g, at room temperature add the chloro-2-of 3-After hydrazino pyridine 7.64g, and then stirring at room temperature 1 hour. Then reaction solution is heated to 100 DEG C, reacts 3 hours. ReactionAfter end, acetic acid is under reduced pressure heated up in a steamer, add ethyl acetate and water to extract. Organic layer is used successively to (1) sodium acid carbonateAfter saturated aqueous solution, (2) water, (3) saturated common salt water washing, use anhydrous magnesium sulfate drying. Solvent is under reduced pressure heated up in a steamer, obtainedObject crystallization (116.7 DEG C of fusing points) 14.5g.

(2) 1-(3-chloropyridine-2-yl)-5-furyl-1H-pyrazoles-3-carboxylic acid is synthetic

By ethyl 1-(3-chloropyridine-2-yl)-5-furyl-4 that obtain in front operation (1), 5-dihydro-1 h-pyrazole-3-Carboxylate 14.5g adds NaOH 2.2g after being dissolved in the mixed solvent of methyl alcohol 90ml and water 45ml, reaction under refluxing3 hours. After reaction finishes, heat up in a steamer desolventizing, in residue, add after water, wash with ether. Water layer is adjusted to pH3 with concentrated hydrochloric acidAfter, be extracted with ethyl acetate. By after organic layer water and saturated common salt water washing, use anhydrous magnesium sulfate drying. Solvent is being subtractedDepress and heat up in a steamer, obtain object crystallization 11.9g (179.3 DEG C of fusing points).

(3) 3-N-benzyl oxygen base carbonylamino-1-(3-chloropyridine-2-yl)-5-furyl-1H-pyrazoles is synthetic

By 1-(3-the chloro-2-pyridyl)-5-furyl-1H-pyrazoles-3-carboxylic acid 11.9g, the benzyl that obtain in front operation (2)Base alcohol 4.89g, diphenylphosphine acyl azide compound 12.4g and triethylamine 5.0g join twoAfter in alkane 100ml, at 90 DEG CReact 3 hours. After reaction finishes, under reduced pressure heat up in a steamer, add ethyl acetate and water to extract solvent. By organic layer successivelyWith after (1) 5% hydrochloric acid, (2) saturated sodium bicarbonate aqueous solution, (3) water, (4) saturated common salt water washing, dry with anhydrous magnesium sulfateDry. Solvent is under reduced pressure heated up in a steamer, silica gel column chromatography for residue (eluent: hexane/ethyl acetate=1/1) is refined, obtainObject crystallization 11.0g (133.4 DEG C of fusing points).

(4) 3-benzyl oxygen base carbonylamino-1-(3-chloropyridine-2-yl)-1H-5-pyrazole carboxylic acid is synthetic

By 3-benzyl oxygen base carbonylamino-1-(3-chloropyridine-2-yl)-5-furyl-1H-obtaining in front operation (3)Pyrazoles 8.9g adds ruthenic chloride 0.70g and sodium periodate after being dissolved in the mixed solvent of acetonitrile 70ml and carbon tetrachloride 70mlThe aqueous solution (150ml) of 21.5g, stirring at room temperature 12 hours. After reaction finishes, by diatomite filtration for reaction solution, will filterLiquid adds ethyl acetate and 1N hydrochloric acid after under reduced pressure concentrating in residue, extracts. After organic layer is washed with water, use carbonThe washing of acid aqueous saturated sodium hydrogen, is adjusted to water layer after pH3 with concentrated hydrochloric acid, is extracted with ethyl acetate. By organic layer water andAfter saturated common salt water washing, use anhydrous magnesium sulfate drying. By solvent under reduced pressure heat up in a steamer, object crystallization 4.4g (fusing point 79.1℃)。

(5) 3-benzyl oxygen base carbonylamino-1-(3-chloropyridine-2-yl)-1H-5-pyrazole carboxylic acid phenylester is synthetic

By 3-benzyl oxygen base carbonylamino-1-(3-chloropyridine-2-yl)-1H-5-pyrazole carboxylic acid obtaining in front operation (4)2.97g adds oxalyl chloride 0.8ml and dimethyl formamide after being dissolved in and removing in the carrene 30ml after methyl alcohol with aluminium oxideOne,, after 30 minutes, reflux 2 hours in stirring at room temperature. After reaction finishes, solvent is under reduced pressure heated up in a steamer, obtain 3-benzyl oxygenBase carbonylamino-1-(3-chloropyridine-2-yl)-1H-5-pyrazoles carboxyl acyl chloride. The oxolane of this acid chloride (10ml) solution is existedIce-cooled lower oxolane (30ml) suspendible that slowly joins phenol 0.75g and sodium hydride (60% oily suspended matter) 0.35g is moltenAfter in liquid, stirring at room temperature 8 hours. After reaction finishes, oxolane is under reduced pressure heated up in a steamer, in residue, add ethyl acetateAnd water, extraction, by after organic layer water and saturated common salt water washing, uses anhydrous magnesium sulfate drying. By solvent under reduced pressure heat up in a steamer,Silica gel column chromatography for residue (eluent: hexane/ethyl acetate=1/1) is refining, acquisition object crystallization 2.8g (fusing point:150.2℃)。

(6) 3-amino-1-(3-chloropyridine-2-yl)-1H-5-pyrazole carboxylic acid phenylester is synthetic

3-benzyl oxygen base carbonylamino-1-(3-chloropyridine-2-yl)-1H-5-that operation (5) obtains before passing through repeatedlyIn acetic acid (50ml) solution of pyrazole carboxylic acid phenylester 3.0g, add 10%Pd-C powder 0.6g, under nitrogen atmosphere, stir in room temperatureMix 12 hours. By reaction solution with after diatomite filtration, by filtrate and diatomite cleaning solution reduced pressure concentration. By residue silicagel columnChromatogram (eluent: ethyl acetate) is refining, obtains object crystallization 1.1g (fusing point: 140.4 DEG C).

(7) the bromo-1-of 3-(3-chloropyridine-2-yl)-1H-5-pyrazole carboxylic acid phenylester is synthetic

In acetonitrile (20ml) solution of copper bromide (II) 0.72g and nitrite tert-butyl (90%) 0.55g, drip at 0 DEG CAdd the acetonitrile of 3-amino-1-(3-chloropyridine-2-yl)-1H-5-pyrazole carboxylic acid phenylester 1.0g obtaining in front operation (6)(15ml) solution, stirs after 2 hours in synthermal and then continuation, slowly returns to room temperature. After reaction finishes, reaction solution is existedDecompression is lower concentrated, and silica gel column chromatography for residue (eluent: hexane/ethyl acetate=1/1) is refining, obtains object crystallization0.88g (fusing point: 64.3 DEG C).

Embodiment 22

(1) the bromo-1-of benzyl 3-(3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxylate is synthetic

In the mixed solution of the bromo-1-of 3-(3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxylic acid 1.0g and toluene 10ml, add2 of thionyl chloride 1.5ml and dimethyl formamides, added hot reflux after 1 hour, heats up in a steamer thionyl chloride and toluene, obtains the bromo-1-of 3-The rough thing of (3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxyl acyl chloride.

In the mixed solution of benzyl alcohol 0.43g, triethylamine 0.40g and toluene 10ml, above-mentioned in ice-cooled lower droppingThe mixed solution of rough thing and toluene 10ml. At room temperature react after 1 hour, in water, slowly add reactant liquor. By this mixingLiquid is extracted with ethyl acetate, and organic layer is washed with saline solution, adds anhydrous sodium sulfate, dry. Solvent is under reduced pressure heated up in a steamer,Silica gel column chromatography for residue (eluent: n-hexane/ethyl acetate=7/3) is refining, the object 1.13g of acquisition oily.

At the chloro-N-of 2-amino-5-(1-cyclopropyl ethyl) benzamide 0.12g, the bromo-1-of benzyl 3-(3-chloropyridine-2-Base) in the mixed solution of-1H-pyrazoles-5-carboxylate 0.20g and methyl-sulfoxide 5ml, at room temperature add anhydrous sodium sulfate0.42g, stirred after 5 minutes, added potassium tert-butoxide 0.072g, room temperature reaction 1 hour. Then in water, slowly add reactionLiquid. This mixed liquor is extracted with ethyl acetate, organic layer is washed with saline solution, add anhydrous sodium sulfate, dry. Solvent is existedUnder decompression, heat up in a steamer, silica gel column chromatography for residue (eluent: n-hexane/ethyl acetate=8/2～7/3) is refining, obtain targetThing 0.050g.

Synthesizing of the bromo-1-of embodiment 234-methoxy-benzyl 3-(3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxylate

Bromo-3-1-(3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxylic acid 1.52g is dissolved in the chloroform of 10ml, drips sub-Chlorosulfuric acid 0.55ml, adds DMF0.05ml, refluxes 30 minutes. After letting cool, solvent is under reduced pressure heated up in a steamer, obtain the bromo-1-of 3-The rough thing of (3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxyl acyl chloride. At 4-methoxy-benzyl alcohol 0.85g, triethylamine 1.11mlIn the mixed solution of chloroform 20ml, at the mixed solution of the above-mentioned rough thing of ice-cooled lower dropping and chloroform 5ml. Stir 5 minutesAfter, at room temperature react 1.5 hours. Dereaction solvent is heated up in a steamer in decompression, adds water 50ml, is extracted with ethyl acetate. Organic layer is usedSaturated common salt water washing, makes it dry with sodium sulphate. By solvent under reduced pressure heat up in a steamer, by silica gel column chromatography for residue (eluent:N-hexane/ethyl acetate=1/0～3/1) refining, obtain object 1.6g (fusing point: 83 DEG C).

Embodiment 24

(1) the bromo-1-of S-benzyl 3-(3-chloropyridine-2-yl)-1H-pyrazoles-5-thiocarboxylic is synthetic

In the mixed solution of the bromo-1-of 3-(3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxylic acid 1.5g and toluene 10ml, add2 of thionyl chloride 1.5ml and dimethyl formamides, added hot reflux after 1 hour, heats up in a steamer thionyl chloride and toluene, obtains the bromo-1-of 3-The rough thing of (3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxyl acyl chloride.

In the mixed solution of benzyl mercaptan 0.68g, triethylamine 0.61g and toluene 20ml, in ice-cooled lower droppingState the mixed solution of rough thing and toluene 5ml. After 1 hour, in water, slowly add reactant liquor, by this mixed liquor at room temperature reactionBe extracted with ethyl acetate, organic layer is washed with saline solution, add anhydrous sodium sulfate, dry. Solvent is under reduced pressure heated up in a steamer, incited somebody to actionSilica gel column chromatography for residue (eluent: n-hexane/ethyl acetate=9/1～7/3) is refining, obtains the object 1.65g of oily.

At the chloro-N-of 2-amino-5-(1-cyclopropyl ethyl) benzamide 0.24g, the bromo-1-of S-benzyl 3-(3-chloropyridine-2-Base) in the mixed solution of-1H-pyrazoles-5-thiocarboxylic 0.41g and methyl-sulfoxide 5ml, add anhydrous sodium sulfate in room temperature0.85g, stirred after 5 minutes, added potassium tert-butoxide 0.14g, room temperature reaction 1 hour. In water, slowly add reactant liquor, shouldMixed liquor is extracted with ethyl acetate, and organic layer is washed with saline solution, adds anhydrous sodium sulfate, dry. By solvent under reduced pressureHeat up in a steamer, silica gel column chromatography for residue (eluent: n-hexane/ethyl acetate=9/1～7.5/2.5) is refined, obtain object0.22g。

Embodiment 25

(1) the bromo-1-of S-ethyl 3-(3-chloropyridine-2-yl)-1H-pyrazoles-5-thiocarboxylic is synthetic

Bromo-3-1-(3-chloropyridine-2-yl)-1H-pyrazoles-5-carboxylic acid 1.52g is dissolved in the chloroform of 10ml, drips sub-Chlorosulfuric acid 0.55ml, adds DMF0.05ml, refluxes 30 minutes. After letting cool, solvent is under reduced pressure heated up in a steamer, obtain the bromo-1-of 3-The rough thing of (3-chloropyridine-2-yl)-1H-pyrazoles-5-formyl chloride. Then, at ethane mercaptan 0.5ml, triethylamine 1.11mlIn the mixed solution of chloroform 20ml, at the mixed solution of the above-mentioned rough thing of ice-cooled lower dropping and toluene 5ml. Stir 5 minutesAfter, room temperature reaction 14 hours. Dereaction solvent is heated up in a steamer in decompression, adds water 50ml, is extracted with ethyl acetate. By organic layer with saturatedSaline solution washing, adds sodium sulphate, dry. By solvent under reduced pressure heat up in a steamer, by silica gel column chromatography for residue (eluent: n-oneselfAlkane/ethyl acetate=1/0～3/1) refine, obtain the object 1.4g (fusing point: 94 DEG C) of orange red crystallization.

By the bromo-1-of S-ethyl 3-(3-chloropyridine-2-yl)-1H-pyrazoles-5-thiocarboxylic 0.35g and 2-amino-5-Chloro-N-(1-cyclopropyl ethyl) benzamide 0.24g is dissolved in methyl-sulfoxide 5ml, adds anhydrous sodium sulfate 0.85g, stirs 5Minute. At room temperature, add therein potassium tert-butoxide 0.14g, stir 1.5 hours. Reactant liquor is added to the water, uses acetic acid secondEster extraction. With saturated common salt water washing organic layer, add anhydrous sodium sulfate to be dried. Solvent is under reduced pressure heated up in a steamer, by residualSilica gel column chromatography for slag (eluent: n-hexane/ethyl acetate=1/0～1/1) is refining, obtains object 0.24g.

Synthetic (the using the method for Leuckart method) of embodiment 261-cyclopropylethylamin

(1) N-(1-cyclopropyl ethyl) formamide is synthetic

The mixed solution of 1-cyclopropyl methyl ketone 30g and formamide 66.2g is at room temperature stirred, add formic acid 7.5gAfter, add hot reflux at 180 DEG C, appended formic acid 7.5g every 1 hour simultaneously, react 8 hours. After reaction finishes, in water, addReactant mixture, is extracted with ethyl acetate. By organic layer saturated common salt water washing, with after dried over sodium sulfate, second is heated up in a steamer in decompressionAcetoacetic ester, obtains the grease of rough N-(1-cyclopropyl ethyl) formamide.

(2) 1-cyclopropylethylamin is synthetic

In the grease of rough N-(the 1-cyclopropyl ethyl) formamide obtaining, add concentrated hydrochloric acid 115ml in (1), addHot reflux 1 hour. After cooling in system, decompression heated up in a steamer to obtained hydrochloride and be dissolved in water. Ice will be carried out in systemCooling, make freeization of 1-cyclopropylethylamin by hydrochloride with NaOH, then carry out air-distillation, by boiling point be 80～The fraction of 100 DEG C obtains the cut 20g that comprises object.

The synthetic of embodiment 271-cyclopropylethylamin (used PtO₂Synthetic)

In the aqueous solution 200ml of cyclopropyl methyl ketone 50g, add hydroxylammonium chloride 54.7g, when high degree of agitation byGradually add sodium carbonate 33.6g, reflux 4 hours. After letting cool, use extracted with diethyl ether. By organic layer successively water and saturated common salt washingWash, add anhydrous sodium sulfate, dry. Solvent is under reduced pressure heated up in a steamer, obtain thick cyclopropyl methyl ketone oxime 50g.

Then, obtained thick cyclopropyl methyl ketone oxime 10g is dissolved in ethyl acetate 100ml, adds platinum oxide(IV) 1g, will carry out after hydrogen displacement high degree of agitation in reactor. Stir after 16 hours and stop stirring, by the platinum mistake of precipitationFilter. In supernatant, add concentrated hydrochloric acid 10ml, with the fierce vibration of separatory funnel, two solvents reduced pressure and heated up in a steamer under 70 DEG C of heating,Obtain thick 1-cyclopropylethylamin hydrochloride 10g (purity 50%).

Thick 1-cyclopropylethylamin hydrochloride 10g is dissolved in water 10ml, is cooled to 0 DEG C. Following slow at 5 DEG C thereinSlowly add NaOH, pH is adjusted to 14. Assembling is provided with the distilling apparatus of dry ice blender, obtains boiling point 92 under normal pressureThe 1-cyclopropylethylamin 5g of～94 DEG C.

Synthesizing of the chloro-N-of the bromo-5-of embodiment 282-amino-3-(1-cyclopropyl ethyl) benzamide

(1) the chloro-N-of 5-(1-cyclopropyl ethyl)-2-nitrobenzamide is synthetic

By the mixing of chloro-5-2-nitrobenzoic acid 25g, toluene 25ml, thionyl chloride 22.2g, dimethyl formamide 0.1mlLiquid adds hot reflux 1 hour, synthetic acyl chlorides compound. In the mixed solution of 1-cyclopropylethylamin 13.75g, oxolane 375mlAdd triethylamine 18.0g, carry out ice-cooled. Under ice-cooled, above-mentioned synthetic acyl chlorides compound is dissolved in toluene 30ml, dripsAdd. After dropping finishes, at room temperature react 15 hours. After reaction finishes, reactant mixture is put in water, used ethyl acetateExtraction. By organic layer saturated common salt water washing, with after dried over sodium sulfate, ethyl acetate is heated up in a steamer in decompression. By residue silicagel columnChromatographic refining, obtains flaxen object 25g (fusing point: 137-141 DEG C).

(2) the chloro-N-of 2-amino-5-(1-cyclopropyl ethyl) benzamide is synthetic

Chloro-5-N-(1-cyclopropyl ethyl)-2-nitrobenzamide 5.8g is dissolved in ethanol 88ml, ice-cooledUnder, drip concentrated hydrochloric acid 12.6ml. In synthermal lower stirring, after 0.5 hour, a point several adds reduced iron 4.0g. At room temperature stirAfter 3 hours, add water at reactant mixture, be extracted with ethyl acetate. By organic layer saturated common salt water washing, dry with sodium sulphateAfter dry, ethyl acetate decompression is heated up in a steamer. In residue, add hexane/ethyl acetate, after stirring, leaching, obtains flaxen orderMark thing 3.5g (fusing point: 135 DEG C).

(3) the chloro-N-of the bromo-5-of 2-amino-3-(1-cyclopropyl ethyl) benzamide is synthetic

Chloro-2-amino-5-N-(1-cyclopropyl ethyl) benzamide 0.1g is dissolved in to DMF 3mlIn, be cooled to 0 DEG C. Add therein sodium hydride 0.02g, stir after 1 hour, add bromine 0.09g, stir 2 hours. By reactant liquorJoin in the 1M-HCl aqueous solution, be extracted with ethyl acetate. With saturated common salt water washing organic layer, add anhydrous sodium sulfate to carry outDry. Solvent is under reduced pressure heated up in a steamer, by silica gel column chromatography for residue (eluent: n-hexane/ethyl acetate=1/0～1/1)Refining, obtain flaxen object 0.08g (fusing point: 177 DEG C).

Industry utilizability

The invention provides as the noxious organism control agent in agriculture and garden field show excellent effect at phenyl ring and pyrazolesThe specific position of ring has new anthranilamide compound or its salt and the efficient manufacture thereof of halogen atomMethod.

In addition, the Japan Patent that the present application is quoted on December 15th, 2006 application go out to be willing to No. 2006-339100 andThe Japan Patent of on June 8th, 2007 application goes out to be willing in description, claims, summary whole of No. 2007-152718Hold, as the content of description of the present invention.

Claims

1. the compound or its salt shown in formula (VI-1),

In formula, R^1aFor halogen or haloalkyl, R²For cyclopropyl alkyl or cyclobutyl alkyl.

2. the compound or its salt shown in formula (X-1),

In formula, R^1aFor halogen or haloalkyl, R²For cyclopropyl alkyl or cyclobutyl alkyl, R⁵For alkyl.