CN104496901A

CN104496901A - Process for production of anthranilamide compound

Info

Publication number: CN104496901A
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: 2015-04-08
Anticipated expiration: 2027-12-14
Also published as: CN104496901B

Abstract

Disclosed is a process for producing a specific anthranilamide compound or a salt thereof. Specifically disclosed is a process for producing an anthranilamide compound represented by the formula (I): wherein R1a and R3 represent halogen or halogenate alkyl independently, R2 is cyclopropyl alkyl or cyclobutyl alkyl, Hal is helium atom or bromine atom. The method includes a working process of halogenating a compound provided by a formula (II) selectively. In formula (II), R1a, R2 and R3 are indicated as above.

Description

The manufacture method of anthranilamide compound

The divisional application that the manufacture method that the present application is application number is 201310116942.1 (its parent application number is 200780046280.8), denomination of invention is anthranilamide compound, the applying date are the application on December 14th, 2007.

Technical field

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

Background technology

About anthranilamide compound, such as, Patent Document 1 discloses the effect that the display of its noxious organism control agent as agriculture horticultural field is excellent.On the other hand, in patent documentation 2 and 3, describe the manufacture method of certain anthranilamide compound.

Patent documentation 1: International Publication publication WO 2005/077934

Patent documentation 2: International Publication publication WO 2003/016283

Patent documentation 3: International Publication publication WO 2004/011453

Summary of the invention

All the time, about the manufacture method of anthranilamide compound, propose various method, but require efficiently and manufacture the specific anthranilamide compound of substituting group mode or the method for its salt of aftermentioned formula (I) at an easy rate.

The present inventors are in order to solve above-mentioned problem, conduct in-depth research, found that, the optionally halogenation of the compound shown in through type (II), the anthranilamide compound shown in formula (I) or its salt can be manufactured with high yield, and the compound of the formula (II-1) as one of its raw material can be manufactured efficiently, thus complete the present invention.That is, the present invention relates to the manufacture method of anthranilamide (Anthranilamide) based compound shown in a kind of formula (I) or its salt, it is characterized in that, the compound shown in formula (II) and halogenating agent are reacted,

(in formula, R ^1aand R ³be separately halogen or haloalkyl, R ²for cyclopropyl alkyl or cyclobutylalkyl),

(in formula, Hal is chlorine atom or bromine atoms, R ^1a, R ²and R ³as mentioned above).In addition, the present invention relates to the manufacture method of a kind of anthranilamide compound or its salt, is the R of above-mentioned formula (I) ³for the manufacture method of the compound of the formula (I-1) of bromine atoms, it is characterized in that, the compound shown in above-mentioned formula (II-1) and halogenating agent reacted,

(in formula, R ^1a, R ²described above with Hal)

(in formula, R ^1aand R ²as mentioned above).

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

(in formula, R ^1aand R ²as mentioned above)

(in formula, R ⁴c ₅-C ₁₀the benzyl sulfenyl that alkyl oxy, the phenoxy group that can be substituted, the benzyl oxygen base that can be substituted, alkyl sulfenyl, the phenylsulfartyl that can be substituted maybe can be substituted),

(in formula, R ^1aand R ²as mentioned above).In addition, the present invention relates to the manufacture method of the compound shown in formula (II-1) of the raw material as above-mentioned reaction, compound shown in compound shown in formula (VI-1) and formula (VII) is reacted, manufacture the compound shown in formula (VIII-1), make compound and the SULPHURYL CHLORIDE of obtained formula (VIII-1), chlorizating agent or chloride of acid reaction, compound shown in manufacture formula (IX-1), then, the compound of obtained formula (IX-1) and bromizating agent are reacted, manufacture the compound shown in formula (III-1), and then make compound and the oxidant reaction of obtained formula (III-1), manufacture the compound of formula (II-1),

(in formula, R ^1aand R ²as mentioned above),

(in formula, R ^1aand R ²as mentioned above)

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

(in formula, R ^1aand R ²as mentioned above),

(in formula, L is alkylsulfonyloxy, alkoxy-carbonyl oxy, alkyl-carbonyl oxygen base, phenylsulfonyloxy group, tolysulfonyl oxygen base or chlorine atom, R ^1aand R ²as mentioned above)

(in formula, R ^1aand R ²as mentioned above).In addition, the present invention relates to the compound or its salt shown in formula (II-1); Compound or its salt shown in formula (V-1); Compound or its salt shown in formula (VI-1), the compound or its salt shown in formula (VIII-1); The compound or its salt of formula (IX-1); Compound or its salt shown in formula (III-1); Compound or its salt shown in formula (X-1); And the compound or its salt shown in formula (XI-1);

(in formula, R ^1aand R ²as mentioned above)

(in formula, R ^1a, R ²described above with L)

(in formula, R ^1aand R ²as mentioned above)

(in formula, R ⁵for alkyl, R ^1aand R ²as mentioned above),

(in formula, R ^1aand R ⁵as mentioned above).

As R ^1a, R ², R ³, R ⁴or R ⁵in alkyl or moieties, the alkyl of the such straight chain of methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl or branched C1-C6 can be listed.In addition, R ⁴" C5-C10 alkyl oxy " in moieties can be straight chain, also can be branched.

R ^1aor R ³in halogen or the halogen of alternatively base, each atom of fluorine, chlorine, bromine, iodine can be listed.Alternatively the number of the halogen of base can be more than 1 or 2, when for more than 2, each halogen can be the same or different.In addition, the position of substitution of halogen can be arbitrary position.

As R ⁴phenoxy group, benzyl oxygen base, phenylsulfartyl and benzyl sulfenyl substituting group, chlorine atom, bromine atoms, methyl, methoxyl group or nitro can be listed.

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

As the salt of above-claimed cpd, as long as allow on agricultural chemicals, any form can be comprised.An alkali metal salt that such as sodium salt, sylvite are such can be listed; The alkali earth metal salt that magnesium salts, calcium salt are such; The ammonium salt that dimethyl ammonium, triethyl ammonium salt are such; The inorganic salt that hydrochloride, perchlorate, vitriol, nitrate are such; The organic acid salt etc. that acetate, mesylate are such.

According to method of the present invention, the specific position that can be manufactured on phenyl ring and pyrazole ring efficiently has anthranilamide compound or its salt of halogen atom.

Embodiment

Below the manufacture method of anthranilamide compound of the present invention or its salt is described in detail.

The anthranilamide compound of formula (I) or its salt can manufacture according to the manufacture method of following reaction (A) and common salt.

In formula, R ^1a, R ², R ³described above with Hal.

Reaction (A) can by carrying out the compound of formula (II) with halogenating agent process usually under the existence of alkali and solvent.

As the compound of formula (II), the bromo-N-of 3-[the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl]-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-methane amide can be listed, the bromo-N-of 3-[the chloro-2-of 4-(Cyclopropyl-methyl-amino formyl) phenyl]-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-methane amide, N-[the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl]-3-Trifluoromethyl-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-methane amide etc.

As halogenating agent, chlorine or bromine can be selected.

As alkali, suitably can select one kind or two or more from the such alkali metal alcoholates of the such alkalimetal hydride of the such metal hydroxides of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, potassium hydride KH, sodium methylate, sodium ethylate, potassium tert.-butoxide etc.Alkali, relative 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, then can be used any one, can from such as ether, butyl methyl ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; The ester class that methyl acetate, ethyl acetate, propyl acetate are such; The ketone that acetone, methyl ethyl ketone, pimelinketone are such; Suitably select one kind or two or more in the polar aprotic solvent that acetonitrile, propionitrile, DMF, methyl-sulphoxide, HMPA, tetramethylene sulfone, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone are such etc.

Reaction (A) can be carried out at-20 ~ 120 DEG C, preferably 0 ~ 80 DEG C usually, and its reaction times can be 0.5 ~ 48 hours, preferably 1 ~ 24 hours usually.

In above-mentioned reaction, R ³for the compound of the formula (I-1) of bromine atoms can by the compound manufacture of formula (II-1).

In formula, R ^1a, R ²described above with Hal.

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

In formula, R ¹for alkyl, alkenyl, halogenated alkenyl, alkynyl group, haloalkynyl group, alkoxyl group, halogenated alkoxy, alkyl-carbonyl, halogenated alkyl carbonyl, alkoxy carbonyl, halo alkoxy carbonyl, nitro, formyl radical or cyano group, the alkyl that A be instead of by Y; Y is the C3-4 cycloalkyl that at least one substituting group that can be selected from halogen, alkyl and haloalkyl replaces, and m is 0 ~ 4.

R ¹, alkyl in A or Y or moieties can be straight chain or branched any one.As its concrete example, the C1-6 group etc. that methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, amyl group, hexyl are such can be listed.

R ¹in alkenyl or said alkenyl moiety can be straight chain or branched any one.As its concrete example, the group etc. of the such C2-6 of vinyl, 1-propenyl, allyl group, pseudoallyl, 1-butylene base, 1,3-butadiene base, 1-hexenyl can be listed.

R ¹in alkynyl group or alkynyl moieties can be straight chain or branched any one.As its concrete example, the group etc. of C2-6 of ethynyl, 2-butyne base, valerylene base, 3-hexin Kina sample can be listed.

R ¹or the halogen of halogen in Y or alternatively base, each atom of fluorine, chlorine, bromine, iodine can be listed.Alternatively the number of the halogen of base can be more than 1 or 2, when for more than 2, each halogen can be the same or different.In addition, the position of substitution of halogen can be arbitrary position.

Reaction (B) can be undertaken by the compound of process formula (III) and oxygenant usually in the presence of the solvent, manufactures the anthranilamide compound shown in formula (II-A).

As the compound of formula (III), the bromo-N-of 3-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-4 can be listed, 5-dihydro-1 h-pyrazole-5-methane amide, the bromo-N-of 3-(the chloro-6-of the bromo-4-of 2-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-4, 5-dihydro-1 h-pyrazole-5-methane amide, the bromo-N-of 3-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl)-6-aminomethyl phenyl)-1-(3-chloropyridine-2-base)-4, 5-dihydro-1 h-pyrazole-5-methane amide, the bromo-N-of 3-(the chloro-6-of the bromo-4-of 2-(Cyclopropyl-methyl-amino formyl) phenyl)-1-(3-chloropyridine-2-base)-4, 5-dihydro-1 h-pyrazole-5-methane amide, the bromo-N-of 3-(the chloro-2-of 4-(Cyclopropyl-methyl-amino formyl) phenyl)-1-(3-chloropyridine-2-base)-4, 5-dihydro-1 h-pyrazole-5-methane amide etc.

As oxygenant, can 2 be listed, 3-bis-chloro-5,6-dicyano-Isosorbide-5-Nitrae-benzoquinones, chloranil, adjacent tetrachlorobenzoquinone, hydrogen peroxide, peroxidation two ammonium sulfate, sodium peroxodisulfate, potassium persulphate, potassium permanganate, OXONE (trade(brand)name), clorox, Textone, benzoyl peroxide, tertbutyl peroxide, oxygen etc.Oxygenant, relative to the compound of formula (III), can use 1 ~ 10 times mole, preferably 1 ~ 4.5 times mole.

As solvent, as long as the solvent to reactionlessness, can from such as tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The ketone that acetone, methyl ethyl ketone are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; The ester class that methyl acetate, ethyl acetate, propyl acetate are such; Suitably select one kind or two or more in polar aprotic solvent, acetic acid or water etc. that acetonitrile, propionitrile, DMF, methyl-sulphoxide, HMPA, tetramethylene sulfone, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone are such.

Reaction (B) can be carried out at usual 0 ~ 150 DEG C, preferably 15 ~ 120 DEG C, and its reaction times can be 0.5 ~ 50 hours usually.

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

In formula, R ^1aand R ²as mentioned above.

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

In formula, R ¹, A, L and m be described above.

Reaction (C) usually can process in the presence of the solvent formula (IX) compound and wait mole more than bromizating agent carry out.

As the compound of formula (IX), 5-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenylcarbamoyl)-1-(3-chloropyridine-2-base)-4 can be listed, 5-dihydro-1 h-pyrazole-3-base 4-toluene sulfonic acide ester, 5-(the chloro-6-of the bromo-4-of 2-(1-cyclopropylethyl carbamyl) phenylcarbamoyl)-1-(3-chloropyridine-2-base)-4, 5-dihydro-1 h-pyrazole-3-base 4-toluene sulfonic acide ester, 5-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl)-6-MethYlphenylamino formyl)-1-(3-chloropyridine-2-base)-4, 5-dihydro-1 h-pyrazole-3-base 4-toluene sulfonic acide ester, 5-(the chloro-6-of the bromo-4-of 2-(Cyclopropyl-methyl-amino formyl) phenylcarbamoyl)-1-(3-chloropyridine-2-base)-4, 5-dihydro-1 h-pyrazole-3-base 4-toluene sulfonic acide ester, 5-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenylcarbamoyl)-1-(3-chloropyridine-2-base)-4, 5-dihydro-1 h-pyrazole-3-methylmethane sulphonate, 5-(the chloro-6-of the bromo-4-of 2-(1-cyclopropylethyl carbamyl) phenylcarbamoyl)-1-(3-chloropyridine-2-base)-4, 5-dihydro-1 h-pyrazole-3-methylmethane sulphonate, 5-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl)-6-MethYlphenylamino formyl)-1-(3-chloropyridine-2-base)-4, 5-dihydro-1 h-pyrazole-3-methylmethane sulphonate, 5-(the chloro-6-of the bromo-4-of 2-(Cyclopropyl-methyl-amino formyl) phenylcarbamoyl)-1-(3-chloropyridine-2-base)-4, 5-dihydro-1 h-pyrazole-3-methylmethane sulphonate, 5-(the chloro-2-of 4-(Cyclopropyl-methyl-amino formyl) phenylcarbamoyl)-1-(3-chloropyridine-2-base)-4, 5-dihydro-1 h-pyrazole-3-methylmethane sulphonate etc.

As bromizating agent, suitably can select one kind or two or more from the metal bromide of bromine, Sodium Bromide, Potassium Bromide, lithiumbromide, brometo de amonio, magnesium bromide, Calcium Bromide, barium bromide, aluminum bromide, phosphorus tribromide, phosphorus pentabromide, iron bromide, cupric bromide, zinc bromide etc. etc.

As solvent, as long as the solvent to reactionlessness, can from such as ether, butyl methyl ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; The ester class that methyl acetate, ethyl acetate, propyl acetate are such; The polar aprotic solvent that acetone, methyl ethyl ketone, pimelinketone, acetonitrile, propionitrile, DMF, methyl-sulphoxide, HMPA, tetramethylene sulfone, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone are such; Suitably select one kind or two or more in the protic solvent that acetic acid is such etc.

Reaction (C) can be carried out at-10 ~ 150 DEG C, preferably 0 ~ 120 DEG C usually, and its reaction times can be 0.1 ~ 24 hours usually.

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

In formula, R ^1a, R ²described above with L.

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

In formula, R ¹, A, L and m be described above.

Reaction (D) usually can process under the existence of alkali and solvent formula (VIII) compound and etc. mole more than SULPHURYL CHLORIDE, chlorizating agent or chloride of acid carry out.

As the compound of formula (VIII), N-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-3-hydroxyl-4 can be listed, 5-dihydro-1 h-pyrazole-5-methane amide, N-(the chloro-6-of the bromo-4-of 2-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-3-hydroxyl-4, 5-dihydro-1 h-pyrazole-5-methane amide, N-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl)-6-aminomethyl phenyl)-1-(3-chloropyridine-2-base)-3-hydroxyl-4, 5-dihydro-1 h-pyrazole-5-methane amide, N-(the chloro-6-of the bromo-4-of 2-(Cyclopropyl-methyl-amino formyl) phenyl)-1-(3-chloropyridine-2-base)-3-hydroxyl-4, 5-dihydro-1 h-pyrazole-5-methane amide, N-(the chloro-2-of 4-(Cyclopropyl-methyl-amino formyl) phenyl)-1-(3-chloropyridine-2-base)-3-hydroxyl-4, 5-dihydro-1 h-pyrazole-5-methane amide etc.

As SULPHURYL CHLORIDE, Tosyl chloride, methane sulfonyl chloride etc. can be listed.As chlorizating agent, Tosyl chloride, methane sulfonyl chloride, thionyl chloride, oxalic acid diacid chloride, phosphorus trichloride, phosphorus pentachloride etc. can be listed.As chloride of acid, Acetyl Chloride 98Min., methyl-chlorocarbonate, chlorine ethyl-carbonate etc. can be listed.

As alkali, can from the such mineral alkali of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, salt of wormwood; The alkali metal alcoholates that sodium tert-butoxide, potassium tert.-butoxide are such; The alkalimetal hydride that sodium hydride, potassium hydride KH are such; Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, 4-pyrollidinopyridine, N-methylmorpholine, N, accelerine, N, N-Diethyl Aniline, N-ethyl-N-methylaniline, 1, suitably select one kind or two or more in the tertiary amines that 8-diazabicyclo (5.4.0)-7-undecylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc.Alkali, relative 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 from such as ether, butyl methyl ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; The ester class that methyl acetate, ethyl acetate, propyl acetate are such; Suitably select one kind or two or more in the polar aprotic solvent that acetonitrile, propionitrile, DMF, methyl-sulphoxide are such etc.

Reaction (D) can be carried out-20 ~ 140 DEG C, preferably-10 ~ 120 DEG C usually, and its reaction times can be 0.1 ~ 10 hours usually.

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

In formula, R ^1a, R ²described above with L.

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

In formula, R ¹, A, X and m be described above.

Reaction (E) can by making the compound of formula (VI) usually under the atmospheric condition of rare gas element, and the compound processing formula (VII) under the existence of alkali and solvent carries out.

As the compound of formula (VI), such as N-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-5-pyrazolidone (oxopyrazolidine)-3-methane amide can be listed, N-(the chloro-6-of the bromo-4-of 2-(1-cyclopropylethyl carbamyl) phenyl)-5-pyrazolidone-3-methane amide, N-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl)-6-aminomethyl phenyl)-5-pyrazolidone-3-methane amide, N-(the chloro-6-of the bromo-4-of 2-(Cyclopropyl-methyl-amino formyl) phenyl)-5-pyrazolidone-3-methane amide, N-(the chloro-2-of 4-(Cyclopropyl-methyl-amino formyl) phenyl)-5-pyrazolidone-3-methane amide etc.

As rare gas element, nitrogen or the such gas of argon can be listed.

As alkali, can from the such mineral alkali of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, salt of wormwood, cesium carbonate, sodium hydride, potassium hydride KH, Tripotassium phosphate water and thing; Sodium tert-butoxide, potassium tert.-butoxide, sodium ethylate, sodium methylate, Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, 4-pyrollidinopyridine, N-methylmorpholine, N, accelerine, N, N-Diethyl Aniline, N-ethyl-N-methylaniline, 1, suitably select one kind or two or more in the organic bases that 8-diazabicyclo (5.4.0)-7-undecylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc.Alkali, relative to the compound of formula (VI), can use 1 ~ 5 times mole, preferably 1 ~ 3.5 times mole.

As solvent, as long as the solvent to reactionlessness, can from the such alcohols of such as methyl alcohol, ethanol, propyl alcohol, butanols, isopropyl alcohol, 2-methyl-2-propanol; Tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; Suitably select one kind or two or more in the polar aprotic solvent that acetonitrile, propionitrile, DMF, methyl-sulphoxide, HMPA, tetramethylene sulfone, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone are such etc.

In order to promote this reaction, metal catalyst can be added.As metal catalyst, suitably can select one kind or two or more from the such palladium catalyst of palladium-carbon, Palladous chloride, acid chloride, tetra-triphenylphosphine palladium, bis-triphenylphosphipalladium palladium dichloride.Metal catalyst, relative to the compound of formula (VI), can use 0.005 ~ 2.5 times mole, preferably 0.01 ~ 1 times mole.

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

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

In formula, R ^1a, R ²described above with X.

The compound of above-mentioned formula (VI) is manufactured by the compound of process formula (X) and hydrazine usually in the presence of the solvent.

In formula, R ¹, R ⁵, A and m be described above.

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

As the compound of formula (X), 4-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl amino)-4-oxygen methyl crotonate can be listed, 4-(the chloro-6-of the bromo-4-of 2-(1-cyclopropylethyl carbamyl) phenyl amino)-4-oxygen methyl crotonate, 4-(the chloro-6-of the bromo-4-of 2-(1-cyclopropylethyl carbamyl) phenyl amino)-4-oxygen ethyl crotonate, 4-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl)-6-MethYlphenylamino)-4-oxygen methyl crotonate, 4-(the chloro-6-of the bromo-4-of 2-(Cyclopropyl-methyl-amino formyl) phenyl amino)-4-oxygen methyl crotonate, 4-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl amino)-4-oxygen iso-crotonic acid methyl esters, 4-(the chloro-6-of the bromo-4-of 2-(1-cyclopropylethyl carbamyl) phenyl amino)-4-oxygen iso-crotonic acid methyl esters, 4-(the chloro-6-of the bromo-4-of 2-(1-cyclopropylethyl carbamyl) phenyl amino)-4-oxygen iso-crotonic acid ethyl ester, 4-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl)-6-MethYlphenylamino)-4-oxygen iso-crotonic acid methyl esters, 4-(the chloro-6-of the bromo-4-of 2-(Cyclopropyl-methyl-amino formyl) phenyl amino)-4-oxygen iso-crotonic acid methyl esters, 4-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl amino)-4-oxygen ethyl crotonate, 4-(the chloro-2-of 4-(Cyclopropyl-methyl-amino formyl) phenyl amino)-4-oxygen ethyl crotonate, 4-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl amino)-4-oxygen iso-crotonic acid methyl esters etc.

Hydrazine, relative 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 from the such protic solvent of such as methyl alcohol, ethanol, propyl alcohol, butanols, isopropyl alcohol, 2-methyl-2-propanol, water; Ether, butyl methyl ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; Suitably select one kind or two or more in the polar aprotic solvent that DMF, methyl-sulphoxide, HMPA, tetramethylene sulfone, N,N-dimethylacetamide, N-Methyl pyrrolidone are such etc.

This reaction can be carried out at-10 ~ 150 DEG C, preferably 0 ~ 120 DEG C usually, and its reaction times can be 0.2 ~ 20 hours usually.

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

In formula, R ^1a, R ²and R ⁵as mentioned above.

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

In formula, R ¹, R ⁵, A and m be described above.

There is the isomer of cis body and trans body in compound (X) and (XI), can be either party, also can be its mixture.

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

As the compound of formula (XI), (E)-3-(chloro-4-oxygen of 6--4H-benzo [d] [1,3] can be listed piperazine-2-base) methyl acrylate, (E)-3-(chloro-4-oxygen of the bromo-6-of 8--4H-benzo [d] [1,3] piperazine-2-base) methyl acrylate, (E)-3-(chloro-4-oxygen of the bromo-6-of 8--4H-benzo [d] [1,3] piperazine-2-base) ethyl propenoate, (E)-3-(chloro-8-methyl of 6--4-oxygen-4H-benzo [d] [1,3] piperazine-2-base) methyl acrylate, (Z)-3-(chloro-4-oxygen of 6--4H-benzo [d] [1,3] piperazine-2-base) methyl acrylate, (Z)-3-(chloro-4-oxygen of the bromo-6-of 8--4H-benzo [d] [1,3] piperazine-2-base) methyl acrylate, (Z)-3-(chloro-4-oxygen of the bromo-6-of 8--4H-benzo [d] [1,3] piperazine-2-base) ethyl propenoate, (Z)-3-(chloro-8-methyl of 6--4-oxygen-4H-benzo [d] [1,3] piperazine-2-base) methyl acrylate, (E)-3-(chloro-4-oxygen of 6--4H-benzo [d] [1,3] piperazine-2-base) ethyl propenoate etc.

In addition, as the compound of formula (XII), Alpha-Methyl-cyclopropylmethylamine, Alpha-Methyl-cyclobutylmethyl amine, cyclopropylmethylamine etc. can be used.As the salt of the compound of formula (XII), the salt of the mineral acid of hydrochloride, vitriol etc. can be used; The organic acid salt etc. of acetate, mesylate etc.The compound or its salt of formula (XII) relative to the compound of formula (XI), more than can using etc. mole, preferably 1 ~ 5 times mole.

When the salt of the compound of the formula of use (XII), preferably use alkali.As alkali, can from the such mineral alkali of such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride KH, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus; The alkali metal alcoholates that sodium tert-butoxide, potassium tert.-butoxide are such; Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, 4-pyrollidinopyridine, N-methylmorpholine, N, accelerine, N, N-Diethyl Aniline, N-ethyl-N-methylaniline, 1, suitably select one kind or two or more in the organic bases that 8-diazabicyclo (5.4.0)-7-undecylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc.Alkali, relative 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 from such as ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that methylene dichloride, chloroform, tetracol phenixin, chlorobenzene are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; Suitably select one kind or two or more in the polar aprotic solvent that acetonitrile, DMF, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, methyl-sulphoxide are such etc.

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

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

In formula, R ^1a, R ²and R ⁵as mentioned above.

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

In formula, R ¹, R ⁵, A and m be described above.There is the isomer of cis body and trans body in compound (X) and (XIII), can be either party, also can be its mixture.

As the compound of formula (V) operable in above-mentioned reaction, the chloro-N-of 2-amino-5-(1-cyclopropylethyl) benzamide, the chloro-N-of the bromo-5-of 2-amino-3-(1-cyclopropylethyl) benzamide, 2-amino-5-chloro-3-methyl-N-(1-cyclopropylethyl) benzamide, the chloro-N-of the bromo-5-of 2-amino-3-(Cvclopropvlmethvl) benzamide etc. can be listed.

The reaction of the first stage of reaction (H) is undertaken by the compound of process formula (V) and maleic anhydride usually in the presence of the solvent.

Maleic anhydride, relative 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 from such as tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; The ester class that methyl acetate, ethyl acetate, propyl acetate are such; Suitably select one kind or two or more in polar aprotic solvent, acetic acid etc. that acetone, methyl ethyl ketone, acetonitrile, propionitrile, DMF, methyl-sulphoxide, HMPA, tetramethylene sulfone, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone are such.

This reaction can desirably, be carried out in the presence of base.As alkali, can from the such mineral alkali of such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride KH, sodium carbonate, salt of wormwood; Alkali metal alcoholates, Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2 that sodium tert-butoxide, potassium tert.-butoxide are such, 6-lutidine, 4-pyrollidinopyridine, N-methylmorpholine, N, accelerine, N, N-Diethyl Aniline, N-ethyl-N-methylaniline, 1, suitably select one kind or two or more in the organic bases that 8-diazabicyclo (5.4.0)-7-undecylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc.Alkali, relative to the compound of formula (V), can use 0.7 ~ 5 times mole, preferably 1 ~ 2.5 times mole.

This reaction can be carried out usual 0 ~ 150 DEG C, preferably 20 ~ 110 DEG C, and its reaction times can be 0.5 ~ 24 hours usually.

The reaction of subordinate phase of reaction (H) can process the compound of formula (XIII) and the R more than waiting mole usually in the presence of acid ⁵alcohol shown in-OH carries out.

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

As acid, can from the such hydrogen halide of hydrogenchloride, hydrogen bromide, hydrogen iodide; The mineral acid that sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, boric acid, chloric acid, chlorous acid, hypochlorous acid are such; The Lewis acid that halogenated titanium, aluminum halide, iron halide, tin halides, zinc halide, magnesium halide, silicon halide, copper halide, trifluoroboranes-ether complexes are such; Formic acid, C ₁-C ₆alkyl carboxylic acid, aromatic carboxylic acid, C ₁-C ₆suitably select one kind or two or more in the organic acid that alkylsulphonic acid, aromatic sulphonic acid are such etc.Acid, relative to compound (XIII), can use 0.05 ~ 10 times mole, preferably 0.1 ~ 5 times mole.

This reaction can desirably be carried out in the presence of the solvent.As solvent, as long as the solvent to reactionlessness, can from such as tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; Suitably select one kind or two or more in the polar aprotic solvent that acetonitrile, propionitrile, DMF, methyl-sulphoxide, HMPA, tetramethylene sulfone, N,N-dimethylacetamide, N-Methyl pyrrolidone are such etc.

This reaction can be carried out usually at 0 ~ 100 DEG C, preferably 10 ~ 50 DEG C, and its reaction times can be 1 ~ 50 hours usually.

In formula, R ⁶for chlorine atom or bromine atoms, R ¹, R ⁵, A and m be described above.There is the isomer of cis body and trans body in the compound of formula (X), (XIV) and (XV), can be either party, also can be its mixture.

The reaction of the first stage of reaction (I) can be undertaken by the compound of process formula (V) and the compound of formula (XIV) usually in the presence of the solvent.The Compound Phase of formula (XIV), for 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 from such as tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; Suitably select one kind or two or more in the polar aprotic solvent that acetonitrile, propionitrile, DMF, methyl-sulphoxide, HMPA, tetramethylene sulfone, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone are such etc.

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

The reaction of the subordinate phase of reaction (I) can by the compound of process formula (XV) and the R more than waiting mole under the existence of usual solvents ⁵alcohol shown in-OH carries out.

This reaction can desirably, be carried out in the presence of base.As alkali, can from the such mineral alkali of such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride KH, sodium carbonate, salt of wormwood; Alkali metal alcoholates, Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2 that sodium tert-butoxide, potassium tert.-butoxide are such, 6-lutidine, 4-pyrollidinopyridine, N-methylmorpholine, N, accelerine, N, N-Diethyl Aniline, N-ethyl-N-methylaniline, 1, suitably select one kind or two or more in the organic bases that 8-diazabicyclo (5.4.0)-7-undecylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc.Alkali, relative to alcohol, can use 0.7 ~ 5 times mole, preferably 1 ~ 2.5 times mole.

This reaction can be carried out at-10 ~ 150 DEG C usually, preferably 0 ~ 50 DEG C, and its reaction times can be 0.5 ~ 24 hours usually.

In addition, the compound of the formula (XI) used in above-mentioned reaction (G) can manufacture according to the reaction of (J), (K).

In formula, R ¹, R ⁵described above with m.There is the isomer of cis body and trans body in the compound of formula (XVI) and (XVII), can be either party, also can be its mixture.

Reaction (J) usually can by by the compound of formula (XVII) under the existence of alkali and solvent with the Viability derivative of acyl chlorides compound response transform, then react with the compound of formula (XVI) in the presence of base, so add activator reaction carry out.

As the compound of formula (XVI) operable in above-mentioned reaction, 5-chloro-o-amino benzoic acid, 3-bromo-5-chloro-o-amino benzoic acid, the chloro-3-methyl anthranilic acid of 5-etc. can be listed, as the compound of formula (XVII), toxilic acid monomethyl ester, maleic acid monoethyl ester, monopropyl maleate etc. can be used.

Above-mentioned reaction can be carried out in the presence of the solvent, also can carry out a series of reaction in identical solvent.As solvent, as long as the solvent to reactionlessness, can from the such halogenated hydrocarbons of such as chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; Ether, butyl methyl ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The ester class that methyl acetate, ethyl acetate, propyl acetate are such; The ketone that acetone, 2-butanone, 4-methyl-2 pentanone are such; Suitably select one kind or two or more in the polar aprotic solvent that acetonitrile, propionitrile, DMF are such etc.

As acyl chlorides compound, chlorine carbonates, SULPHURYL CHLORIDE or carboxyl acyl chloride etc. can be used.As chlorine carbonic ether, methyl-chlorocarbonate, chlorine ethyl-carbonate, chlorine isobutyl carbonate propyl diester etc. can be listed, as SULPHURYL CHLORIDE, methane sulfonyl chloride, propanesulfonic acid chloride, benzene sulfonyl chloride, Tosyl chloride etc. can be listed, as carboxyl acyl chloride, Acetyl Chloride 98Min., propionyl chloride etc. can be listed, wherein optimization methane SULPHURYL CHLORIDE.This reagent, relative to the compound of formula (XVII), is 1.0 ~ 3.0 times moles, preferably 1.1 ~ 2.0 times moles.

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

Reaction can be carried out usually at-30 ~ 60 DEG C, preferably-10 ~ 40 DEG C, and the reaction times is generally 5 minutes ~ 1 hours.

After the compound of formula (XVII) is transformed to reactive derivative, the Compound Phase of the formula (XVI) of reaction, for the compound of above-mentioned formula (XVII), is 0.9 ~ 1.2 times mole, preferably 1.0 ~ 1.05 times moles.

Alkali can use the alkali used during above-mentioned reactive derivative, relative to the compound of above-mentioned formula (XVI), is 2 ~ 4 times moles, preferably 2.9 ~ 3.5 times moles.The compound of formula (XVI) and alkali can add after forming the mixing solutions with solvent.

Reaction is carried out usually at-30 ~ 60 DEG C, preferably-10 ~ 40 DEG C, and the reaction times is generally 5 minutes ~ 1 hours.

As activator, chlorine carbonic ether, SULPHURYL CHLORIDE etc. can be used.As chlorine carbonic ether, methyl-chlorocarbonate, chlorine ethyl-carbonate, chlorine propylene carbonate can be listed, as SULPHURYL CHLORIDE, methane sulfonyl chloride, propanesulfonic acid chloride, benzene sulfonyl chloride, Tosyl chloride etc. can be listed, wherein optimization methane SULPHURYL CHLORIDE.Activator is 1.0 ~ 1.5 times moles of the compound of above-mentioned formula (XVI), preferably 1.1 ~ 1.3 times moles further.Activator preferably uses the activator identical with aforesaid acyl chlorides compound, adds after also can forming mixture with solvent.

Reaction can be carried out at-30 ~ 60 DEG C usually, preferably-10 ~ 40 DEG C, and the reaction times is generally 1 ~ 24 hours.

In formula, R ¹, R ⁵described above with m.

The compound of formula (XI) can carry out cyclization to manufacture by the compound of formula (XVIII) is transformed to reactive derivative in the presence of the solvent.

As the reagent making it be transformed to reactive derivative, chlorine carbonates, SULPHURYL CHLORIDE, thionyl chloride, carboxyl acyl chloride, carboxylic acid anhydride, phosphorus chloride etc. can be used.As chlorine carbonic ether, methyl-chlorocarbonate, chlorine ethyl-carbonate, chlorine isobutyl carbonate propyl diester etc. can be listed, as SULPHURYL CHLORIDE, methane sulfonyl chloride, propanesulfonic acid chloride, benzene sulfonyl chloride, Tosyl chloride etc. can be listed, as carboxylic acid anhydride, diacetyl oxide, propionic anhydride etc. can be listed, wherein optimization methane SULPHURYL CHLORIDE, diacetyl oxide.

Above-mentioned sensitization reagent is 1.0 ~ 1.5 times moles of the compound of above-mentioned formula (XVIII), preferably 1.1 ~ 1.3 times moles further, when using carboxylic acid anhydride as solvent, 3 ~ 20 times of weight of the compound of above-mentioned formula (XVIII) can be used.Activator adds after can forming mixture with solvent.In addition, also can be reacted by the acid adding sulfuric acid, hydrochloric acid etc.

As solvent, as long as the solvent to reactionlessness, can from the such halogenated hydrocarbons of such as chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; Ether, butyl methyl ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The ester class that methyl acetate, ethyl acetate, propyl acetate are such; The ketone that acetone, 2-butanone, 4-methyl-2 pentanone are such; The polar aprotic solvent that acetonitrile, propionitrile, DMF are such; Suitably select one kind or two or more in the carboxylic acid anhydride of diacetyl oxide, propionic anhydride etc. etc.

Reaction can be carried out usually at-30 ~ 100 DEG C, preferably-10 ~ 60 DEG C, and the reaction times is generally 1 ~ 24 hours.

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

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

In formula, R ¹, R ⁵described above with m.There is the isomer of cis body and trans body in compound (XVIII) and (XIX), can be a side respectively, also can be its mixture.

The reaction of the first stage of reaction (L) can be undertaken by the compound of process formula (XVI) and maleic anhydride usually in the presence of the solvent.Maleic anhydride, relative to the compound of formula (XVI), can use 0.9 ~ 3 times mole, preferably 1 ~ 1.5 times mole.

This reaction can desirably, be carried out in the presence of base.As alkali, can from the such mineral alkali of such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride KH, sodium carbonate, salt of wormwood; Alkali metal alcoholates, Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2 that sodium tert-butoxide, potassium tert.-butoxide are such, 6-lutidine, 4-pyrollidinopyridine, N-methylmorpholine, N, accelerine, N, N-Diethyl Aniline, N-ethyl-N-methylaniline, 1, suitably select one kind or two or more in the organic bases that 8-diazabicyclo (5.4.0)-7-undecylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc.Alkali, relative to the compound of formula (XVI), can use 0.7 ~ 5 times mole, preferably 1 ~ 2.5 times mole.

This reaction can be carried out usually at 0 ~ 150 DEG C, preferably 20 ~ 110 DEG C, and its reaction times can be 0.5 ~ 24 hours usually.

The reaction of the subordinate phase of reaction (L) usually can in the presence of acid by the compound of process formula (XIX) and the R more than waiting mole ⁵alcohol shown in-OH carries out.

As acid, can from the such hydrogen halide of hydrogenchloride, hydrogen bromide, hydrogen iodide; The mineral acid that sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, boric acid, chloric acid, chlorous acid, hypochlorous acid are such; The Lewis acid that halogenated titanium, aluminum halide, iron halide, tin halides, zinc halide, magnesium halide, silicon halide, copper halide, trifluoroboranes-ether complexes are such; Formic acid, C ₁-C ₆alkyl carboxylic acid, aromatic carboxylic acid, C ₁-C ₆suitably select one kind or two or more in the organic acid that alkylsulphonic acid, aromatic sulphonic acid are such etc.Acid, relative to the compound of formula (XIX), can use 0.05 ~ 10 times mole, preferably 0.1 ~ 5 times mole.

In formula, R ⁶for chlorine atom or bromine atoms, R ¹, R ⁵described above with m.There is the isomer of cis body and trans body in compound (XIV), (XVIII) and (XX), can be the isomer of a side respectively, also can be its mixture.

The reaction of the first stage of reaction (M) can be undertaken by the compound of process formula (XVI) and the compound of formula (XIV) usually in the presence of the solvent.The Compound Phase of formula (XIV), for the compound of formula (XVI), can use 0.9 ~ 3 times mole, preferably 1 ~ 1.5 times mole.

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

The reaction of the subordinate phase of reaction (M) usually can in the presence of the solvent by the compound of process formula (XX) and the R more than waiting mole ⁵alcohol shown in-OH carries out.In formula, R ⁵as mentioned above.

This reaction can desirably, be carried out in the presence of base.As alkali, can from the such mineral alkali of such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride KH, sodium carbonate, salt of wormwood; Alkali metal alcoholates, Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2 that sodium tert-butoxide, potassium tert.-butoxide are such, 6-lutidine, 4-pyrollidinopyridine, N-methylmorpholine, N, accelerine, N, N-Diethyl Aniline, N-ethyl-N-methylaniline, 1, suitably select one kind or two or more in the organic bases that 8-diazabicyclo (5.4.0)-7-undecylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc.Alkali, relative to the compound of formula (XX), can use 0.7 ~ 5 times mole, preferably 1 ~ 2.5 times mole.

This reaction can be carried out usually at-10 ~ 150 DEG C, preferably 0 ~ 50 DEG C, and its reaction times can be 0.5 ~ 24 hours usually.

Formula (II) compound comprising the compound of above-mentioned formula (II-1) can manufacture according to following reaction (N) ~ (Q).

In formula, R ^1a, R ², R ³and R ⁴as mentioned above.

As the compound of formula (IV) operable in above-mentioned reaction, the bromo-1-of amyl group 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylicesters, the chloro-1-of amyl group 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylicesters, the bromo-1-of phenyl 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylicesters, the bromo-1-of S-benzyl 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-thiocarboxylic (carbothioate) etc. can be listed.

As the compound of formula (V-1), the chloro-N-of 2-amino-5-(1-cyclopropylethyl) benzamide, the chloro-N-of 2-amino-5-(Cvclopropvlmethvl) benzamide, the chloro-3-trifluoromethyl of 2-amino-5--N-(1-cyclopropylethyl) benzamide etc. can be listed.

Reaction (N) can be undertaken by the compound of process formula (IV) and the compound of formula (V-1) usually under the existence of alkali and solvent.

As alkali, can from the such alkalimetal hydride of sodium hydride, potassium hydride KH; The alkali metal alcoholates that the such alkaline carbonate of sodium carbonate, salt of wormwood, sodium methylate, sodium ethylate, potassium tert.-butoxide are such; Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, 4-pyrollidinopyridine, N-methylmorpholine, N, accelerine, N, N-Diethyl Aniline, N-ethyl-N-methylaniline, 1, suitably select one kind or two or more in the tertiary amines that 8-diazabicyclo (5.4.0)-7-undecylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc.Alkali, relative to compound (V-1), can use 0.5 ~ 5 times mole, preferably 1 ~ 3 times mole.

As solvent, as long as the solvent to reactionlessness, can from such as ether, butyl methyl ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; Suitably select one kind or two or more in the polar aprotic solvent that acetonitrile, propionitrile, DMF, methyl-sulphoxide, HMPA, tetramethylene sulfone, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone are such etc.

In order to prevent the hydrolysis in reaction, dewatering agent can be added in reaction system.As dewatering agent, can anhydrous sodium sulphate, anhydrous magnesium sulfate etc. be listed, relative to compound (V-1), 1 times ~ 100 times moles can be added.

Reaction (N) can be carried out usually at 0 ~ 120 DEG C, preferably 5 ~ 80 DEG C, and its reaction times can be 0.25 ~ 24 hours, preferably 0.5 ~ 12 hours usually.

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

In formula, R ^1a, R ²and R ⁴as mentioned above.

As the compound of formula (IV-1) operable in above-mentioned reaction, the bromo-1-of amyl group 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylicesters, the bromo-1-of phenyl 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylicesters, the bromo-1-of S-benzyl 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-thiocarboxylic etc. can be listed.

In the compound (IV) used in reaction (N), R ⁴for C ₅-C ₁₀the compound (IV-2) of the benzyl oxygen base that alkyl oxy, the phenoxy group that can be substituted maybe can be substituted, can manufacture according to following reaction (O).

In formula, R ^4afor the benzyl oxygen base that C5-C10 alkyl oxy, the phenoxy group that can be substituted maybe can be substituted, R ³as mentioned above.

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

As oxygenant, hydrogen peroxide, Potassium Persulphate, Sodium Persulfate, Potassium peroxysulfate, potassium permanganate etc. can be listed, can suitably select one kind or two or more.Oxygenant, relative to compound (XXI), can use 1 ~ 5 times mole, preferably 1 ~ 2.5 times mole.

As acid, sulfuric acid, phosphoric acid, acetic acid etc. can be listed.Acid, relative to compound (XXI), can use 0.5 ~ 5 times mole.

As solvent, as long as the solvent to reactionlessness, can from such as tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The ketone that acetone, methyl ethyl ketone are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; Suitably select one kind or two or more in the polar aprotic solvent that acetonitrile, propionitrile, DMF, methyl-sulphoxide, HMPA, tetramethylene sulfone, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone are such or water etc.

Reaction (O) can be carried out at usual 0 ~ 150 DEG C, preferably 15 ~ 120 DEG C, and its reaction times can be 0.5 ~ 24 hours, preferably 1 ~ 4 hours usually.

In the compound (XXI) used in reaction (O), R ³for the compound of the formula (XXI-1) of chlorine atom or bromine atoms can manufacture according to following reaction (P).

In formula, R ^3afor chlorine atom or bromine atoms, R ^4aas mentioned above.

Reaction (P) usually can by carrying out the compound of formula (XXII) with halogenating agent process in the presence of the solvent.

As halogenating agent, the oxyhalogenation phosphorus that phosphorus oxybromide, Phosphorus Oxychloride are such can be used.Halogenating agent, relative to the compound of formula (XXII), can use 0.33 ~ 3 times mole, preferably 0.5 ~ 2 times mole.

Reaction (P) can be carried out usually at 0 ~ 120 DEG C, preferably 5 ~ 100 DEG C, can be 0.2 ~ 8 hours, preferably 0.5 ~ 4 hours usually as its reaction times.

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

In formula, R ^4aas mentioned above.

Reaction (Q) usually can by carrying out with chloro-2-diazanyl (Hydrazinyl) pyridine of 3-and fumarate or maleic acid ester or their mixture process under the existence of alkali and solvent.

As alkali, the alkali metal alcoholates that amylalcohol sodium, amylalcohol potassium are such can be used.These alkali metal alcoholates can by the such alkalimetal hydride of sodium hydride, potassium hydride KH; The basic metal of the alkali metal hydroxide that sodium hydroxide, potassium hydroxide are such and sodium, potassium etc. and alcohol are modulated.Alkali, relative to 3-chloride-2-hydrazinopyridine, can use 0.7 ~ 3 times mole, preferably 1 ~ 1.5 times mole.

As solvent, as long as the solvent to reactionlessness, can from such as tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; The polar aprotic solvent that acetonitrile, propionitrile, DMF, methyl-sulphoxide, HMPA, tetramethylene sulfone, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone are such; Suitably select one kind or two or more in the alcohols that 1-amylalcohol, 2-amylalcohol, 1-hexanol are such etc.Alcohol particularly preferably with form fumarate or the maleic acid ester alcohol identical with the alcohol of alkoxide group.

Reaction (Q) can be carried out usually at 0 ~ 150 DEG C, preferably 20 ~ 130 DEG C, and its reaction times can be 0.5 ~ 24 hours, preferably 1 ~ 4 hours usually.

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

In formula, R ^1a, R ², R ³, R ⁴described above with Hal.

Reaction (R) can be undertaken by the compound of process formula (IV) and the compound of formula (XXIV) usually under the existence of alkali and solvent.

As alkali, can from the such alkalimetal hydride of sodium hydride, potassium hydride KH; The alkali metal alcoholates that the such alkaline carbonate of sodium carbonate, salt of wormwood, sodium methylate, sodium ethylate, potassium tert.-butoxide are such; Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, 4-pyrollidinopyridine, N-methylmorpholine, N, accelerine, N, N-Diethyl Aniline, N-ethyl-N-methylaniline, 1, suitably select one kind or two or more in the tertiary amines that 8-diazabicyclo (5.4.0)-7-undecylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc.Alkali, relative to compound (IV), can use 0.5 ~ 5 times mole, preferably 1 ~ 3 times mole.

In order to prevent the hydrolysis in reaction, dewatering agent can be added in reaction system.As dewatering agent, can anhydrous sodium sulphate, anhydrous magnesium sulfate etc. be listed, relative to the compound of formula (XXIV), 1 times ~ 100 times moles can be added.

Reaction (R) can be carried out usually at 0 ~ 120 DEG C, preferably 5 ~ 80 DEG C, and its reaction times can be 0.5 ~ 24 hours, preferably 1 ~ 12 hours usually.

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

In formula, R ⁷for hydrogen atom, halogen, alkyl or haloalkyl, R ^1a, R ², R ³and R ⁴as mentioned above.

Reaction (S) usually can under the existence of alkali and solvent, be undertaken by the compound of process formula (IV) and the compound of formula (XXV).

In order to prevent the hydrolysis in reaction, dewatering agent can be added in reaction system.As dewatering agent, can anhydrous sodium sulphate, anhydrous magnesium sulfate etc. be listed, relative to compound (XXV), 1 times ~ 100 times moles can be added.

Reaction (S) can be carried out usually at 0 ~ 120 DEG C, preferably 5 ~ 80 DEG C, and its reaction times can be 0.5 ~ 24 hours, preferably 1 ~ 12 hours usually.

Compound (IV) can manufacture according to following reaction (T).

In formula, Z is chlorine atom, methoxycarbonyl oxygen base, ethoxy carbonyl oxygen base, sulfonyloxy methyl oxygen base, phenylsulfonyloxy group or tolysulfonyl oxygen base, R ³and R ⁴as mentioned above.

Reaction (T) the first operation can by by the compound of formula (XXVI) with wait mole more than chlorizating agent, acyl chlorides compound etc. process to carry out.

As chlorizating agent, such as thionyl chloride, oxalic acid diacid chloride, phosphorus trichloride, phosphorus pentachloride etc. can be listed.As acyl chlorides compound, methyl-chlorocarbonate, chlorine ethyl-carbonate, Methanesulfonyl chloride, phenylsulfonylchloride, Tosyl chloride etc. can be listed.

Can solvent be used in the reaction, as solvent, as long as the solvent to reactionlessness, can from such as ether, butyl methyl ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; The ester class that methyl acetate, ethyl acetate, propyl acetate are such; Suitably select one kind or two or more in the polar aprotic solvent that acetonitrile, propionitrile, DMF are such etc.

First operation of reaction (T) can be carried out usually at-20 ~ 140 DEG C, preferably-10 ~ 120 DEG C, and its reaction times can be 0.1 ~ 10 hours, preferably 0.5 ~ 5 hours usually.

When in the compound of formula (XXVII), Z is alkoxy-carbonyl oxy, sulfonyloxy methyl oxygen base, phenylsulfonyloxy group or tolysulfonyl oxygen base, the first operation also can be carried out in the presence of base.

As alkali, can from the such alkaline carbonate of such as sodium carbonate, salt of wormwood; The alkalimetal hydride that sodium hydride, potassium hydride KH are such; Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, 4-pyrollidinopyridine, N-methylmorpholine, N, accelerine, N, N-Diethyl Aniline, N-ethyl-N-methylaniline, 1, suitably select one kind or two or more in the tertiary amines that 8-diazabicyclo (5.4.0)-7-undecylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc.Alkali, relative to the compound of formula (XXVI), can use 1 ~ 5 times mole, preferably 1 ~ 2.5 times mole.

Second operation of reaction (T) can be undertaken by the compound of the compound and formula (XXVIII) that process formula (XXVII) under the existence of alkali and solvent usually.

As alkali, can from the such alkalimetal hydride of sodium hydride, potassium hydride KH; The alkali metal alcoholates that the such alkaline carbonate of sodium carbonate, salt of wormwood, sodium methylate, sodium ethylate, potassium tert.-butoxide are such; Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, 4-pyrollidinopyridine, N-methylmorpholine, N, accelerine, N, N-Diethyl Aniline, N-ethyl-N-methylaniline, 1, suitably select one kind or two or more in the tertiary amines that 8-diazabicyclo (5.4.0)-7-undecylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc.Alkali, relative to the 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 from such as ether, butyl methyl ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; The polar aprotic solvent that acetonitrile, propionitrile, DMF, methyl-sulphoxide, HMPA, tetramethylene sulfone, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone are such; Suitably select one kind or two or more in alcohols, water etc. that amylalcohol, hexanol, isoamyl alcohol are such.The such alcohols of amylalcohol, hexanol, isoamyl alcohol is an example of compound (XXVIII), and reaction reagent also can be used as solvent.

Second operation of reaction (T) can be carried out usually at-20 ~ 120 DEG C, preferably 0 ~ 40 DEG C, and its reaction times can be 0.25 ~ 24 hours, preferably 0.5 ~ 12 hours usually.

Compound (XXVI) is the known compound that the WO03/016283 etc. of the hydrolysis acquisition of the compound of through type (IV) records, and those skilled in the art can be obtained by known method.The compound of formula (XXVIII) is also the commercially available known compound that can easily obtain.

The compound of above-mentioned reaction (H) and (N) middle formula (V-1) used and the compound of the middle formula (XXIV) used of above-mentioned reaction (R) 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, R ²described above with Hal.

Reaction (U) the first operation can by make compound (XXIX) with wait mole more than chlorizating agent, chloride of acid etc. be used for carrying out.

As chlorizating agent, such as thionyl chloride, oxalic acid diacid chloride, phosphorus trichloride, phosphorus pentachloride etc. can be listed.As chloride of acid, methyl-chlorocarbonate, chlorine ethyl-carbonate etc. can be listed.

Can solvent be used in this reaction, as solvent, as long as the solvent to reactionlessness, can from such as ether, butyl methyl ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; The ester class that methyl acetate, ethyl acetate, propyl acetate are such; Suitably select one kind or two or more in the polar aprotic solvent that acetonitrile, propionitrile, DMF are such etc.

First operation of reaction (U) can be carried out usually at-20 ~ 140 DEG C, preferably-10 ~ 120 DEG C, and its reaction times can be 0.1 ~ 10 hours, preferably 0.5 ~ 5 hours usually.

Z in compound (XXX) ^awhen for methoxycarbonyl oxygen base or ethoxy carbonyl oxygen base, the first operation can be carried out in the presence of base.

As alkali, can from the such alkaline carbonate of such as sodium carbonate, salt of wormwood; The alkalimetal hydride that sodium hydride, potassium hydride KH are such; Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, 4-pyrollidinopyridine, N-methylmorpholine, N, accelerine, N, N-Diethyl Aniline, N-ethyl-N-methylaniline, 1, suitably select one kind or two or more in the tertiary amines that 8-diazabicyclo (5.4.0)-7-undecylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc.Alkali, relative to the compound of formula (XXIX), can use 1 ~ 5 times mole, preferably 1 ~ 2.5 times mole.

Reaction (U) the second operation usually can make in the presence of the solvent the compound of formula (XXX) with wait mole more than replacement amine (XII-1) be used for carrying out.

As solvent, as long as the solvent to reactionlessness, can from such as ether, butyl ethyl ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; The ester class that methyl acetate, ethyl acetate, propyl acetate are such; Suitably select one kind or two or more in the polar aprotic solvent that acetonitrile, propionitrile, DMF are such etc.

Second operation of reaction (U) can be carried out usually at-10 ~ 100 DEG C, preferably 0 ~ 50 DEG C, and its reaction times can be 0.1 ~ 24 hours, preferably 0.5 ~ 12 hours usually.

Second operation of reaction (U) also can be carried out in the presence of base.

As alkali, can from the such alkaline carbonate of such as sodium carbonate, salt of wormwood; The alkalimetal hydride that sodium hydride, potassium hydride KH are such; Trimethylamine, triethylamine, triisopropylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, 4-pyrollidinopyridine, N-methylmorpholine, N, accelerine, N, N-Diethyl Aniline, N-ethyl-N-methylaniline, 1, suitably select one kind or two or more in the tertiary amines that 8-diazabicyclo (5.4.0)-7-undecylene, Isosorbide-5-Nitrae-diazabicyclo (2.2.2) octane are such etc.Alkali, relative to the compound of formula (XXX), can use 1 ~ 5 times mole, preferably 1 ~ 2.5 times mole.

3rd operation of reaction (U), usually can in the presence of the solvent, make the compound of formula (XXXI) under normal pressure ~ several atmospheric nitrogen atmosphere, utilize metal catalyst to carry out catalytic hydrogenation, or also originally to carry out with metal catalyst effect in acid solvent.As above-mentioned metal catalyst, can, from such as, suitably select one kind or two or more in palladium carbon, platinum oxide, Raney nickel, iron, tin chloride etc.

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

As solvent, as long as the solvent to reactionlessness, can from such as water, acetic acid, ethyl acetate; The alcohols that methyl alcohol, ethanol, propyl alcohol, propyl carbinol, the trimethyl carbinol are such; Ether, butyl methyl ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; Suitably select one kind or two or more in the aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such etc.

3rd operation of reaction (U) can be carried out usually at-10 ~ 100 DEG C, preferably 0 ~ 80 DEG C, and its reaction times can be 0.5 ~ 24 hours, preferably 1 ~ 12 hours usually.

4th operation of reaction (U) can make the compound of formula (V-1) usually in the presence of the solvent, utilize halogenating agent process to carry out.In addition, as halogenating agent, when using chlorine or bromine, can carry out under the existence of alkali and solvent.

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

As alkali, suitably can select one kind or two or more from the such alkali metal alcoholates of the such alkalimetal hydride of the such metal hydroxides of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, potassium hydride KH, sodium methylate, sodium ethylate, potassium tert.-butoxide etc.Alkali, relative 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 from such as ether, butyl methyl ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such; The polar aprotic solvent that acetonitrile, propionitrile, DMF, methyl-sulphoxide, HMPA, tetramethylene sulfone, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone are such; Suitably select one kind or two or more in the alcohols that methyl alcohol, ethanol, propyl alcohol, propyl carbinol, the trimethyl carbinol are such etc.

4th operation of reaction (U) can be carried out usually at-20 ~ 120 DEG C, preferably 0 ~ 80 DEG C, and its reaction times can be 0.5 ~ 24 hours, preferably 1 ~ 12 hours usually.

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

In formula, R ^1bfor chlorine atom or bromine atoms, R ²as mentioned above.

First operation of formula (V) can be carried out equally with the second operation of above-mentioned reaction (U).Namely, compound (XXXIII) usually can in the presence of the solvent by make compound (XXXII) with etc. mole more than replacement amine (XII-1) be used for carrying out.

Second operation of formula (V) can be carried out equally with the 3rd operation of above-mentioned reaction (U).Namely, compound (XXXIV) usually can make compound (XXXIII) in the presence of the solvent under normal pressure ~ several atmospheric nitrogen atmosphere, utilize metal catalyst to carry out catalytic hydrogenation, or in acid solvent, make metal catalyst effect carry out also original synthesis.

3rd operation of reaction (V) can be used for halogenating agent synthesizing by making compound (XXXIV) usually in the presence of the solvent.

As halogenating agent, can from the such halogen of such as chlorine, bromine; The active halogen agent that TCCA (Trichloroisocyanuric acid), N-chloro-succinimide, N-bromine succinimide are such; Suitably select in the mixed aqueous solution of hydrogen peroxide and hydrogenchloride or hydrogen bromide etc.

As solvent, as long as the solvent to reactionlessness, can from such as ether, butyl methyl ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The ester class that methyl acetate, ethyl acetate, propyl acetate are such; Suitably select one kind or two or more in the polar aprotic solvent that acetonitrile, propionitrile, DMF are such etc.

3rd operation of reaction (V) can be carried out usually at-10 ~+100 DEG C, preferably 0 ~ 50 DEG C, and its reaction times can be 0.1 ~ 12 hours, preferably 0.5 ~ 6 hours usually.

The cycloalkylalkyl amine of compound (XII-1) used in above-mentioned reaction (U) and (V) etc. is known compound, can according to such as J.Am.Chem.Soc., 1966,88 volumes, 2267 pages of methods recorded, J.Med.Chem., 1997,40 volumes, the known data such as 3215 pages manufacture.In addition, the compound of formula (XXXVII) or can utilize following reaction (W) to carry out according to the method according to the method (Leuckart method) of Eur.J.Med.Chem, calendar year 2001, the record of 265-286 page.

In formula, R ⁸be cyclopropyl, cyclopropyl alkyl, cyclobutyl or cyclobutylalkyl, J is hydrogen or alkyl.

First operation of reaction (W) can make the compound of formula (XXXV) and methane amide be used for carrying out in presence of an acid.

As solvent, use methane amide to carry out, but as long as solvent to reactionlessness, can merge with methane amide and use, can from such as ether, butyl ethyl ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The polar aprotic solvent that acetonitrile, propionitrile, DMF, methyl-sulphoxide, HMPA, tetramethylene sulfone, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone are such; Suitably select one kind or two or more in alcohols, water etc. that methyl alcohol, ethanol, propyl alcohol, propyl carbinol, the trimethyl carbinol are such.

As acid, can from formic acid, C ₁-C ₆alkyl carboxylic acid, aromatic carboxylic acid, C ₁-C ₆the organic acid that alkylsulphonic acid, aromatic sulphonic acid are such; Ammonium chloride, trimethyl amine hydrochloride, triethylamine hydrochloride, pyridine hydrochloride, 4-dimethylaminopyridine hydrochloride, 2, the amine hydrochlorate class that 6-dimethyl pyrazole thiamine hydrochloride, 4-pyrollidinopyridine hydrochloride, N-methylmorpholine hydrochloride, DMA hydrochloride are such; Suitably select one kind or two or more in the Lewis acid that halogenated titanium, aluminum halide, iron halide, tin halides, zinc halide, magnesium halide, silicon halide, copper halide, trifluoroboranes-ether complexes are such etc.Acid, relative to compound (XXXV), can use 0.05 ~ 10 times mole, preferably 0.1 ~ 5 times mole.

First operation of reaction (W) can be carried out usually at 0 ~ 200 DEG C, preferably 30 ~ 180 DEG C, and its reaction times can be 1 ~ 24 hours, preferably 2 ~ 12 hours usually.

Second operation of reaction (W) is usually by using acid or alkali to make the compound hydrolysis of formula (XXXVI) to carry out in the presence of the solvent.As above-mentioned acid, can from the such hydrogen halide of hydrogenchloride, hydrogen bromide, hydrogen iodide, hydrogen fluoride; The mineral acid that sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, boric acid, chloric acid, chlorous acid, hypochlorous acid are such; The Lewis acid that halogenated titanium, aluminum halide, iron halide, tin halides, zinc halide, magnesium halide, silicon halide, copper halide, trifluoroboranes-ether complexes are such; Formic acid, C ₁-C ₆alkyl carboxylic acid, aromatic carboxylic acid, C ₁-C ₆suitably select one kind or two or more in the organic acid that alkylsulphonic acid, aromatic sulphonic acid are such etc.

As alkali, can from the such alkali metal hydroxide of sodium hydroxide, potassium hydroxide; The alkalimetal hydride that sodium hydride, potassium hydride KH are such; Suitably select one kind or two or more in the alkali metal alcoholates that the such alkaline carbonate of sodium carbonate, salt of wormwood, sodium methylate, sodium ethylate, potassium tert.-butoxide are such etc.Acid or alkali, relative to compound (XXXVI), can use 0.1 ~ 5 times mole, preferably 1 ~ 2.5 times mole.As the solvent in this situation, as long as the solvent to reactionlessness, can from such as ether, butyl methyl ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The polar solvent that acetonitrile, propionitrile, DMF, N-METHYLFORMAMIDE, methane amide, methyl-sulphoxide, HMPA, tetramethylene sulfone, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, formic acid, acetic acid, propionic acid, butyric acid are such; Suitably select one kind or two or more in alcohols, water etc. that methyl alcohol, ethanol, propyl alcohol, propyl carbinol, the trimethyl carbinol are such.

Second operation of reaction (W) can be carried out usually at-10 ~ 150 DEG C, preferably 0 ~ 100 DEG C, and its reaction times can be 0.1 ~ 10 hours, preferably 0.5 ~ 2 hours usually.

The compound of above-mentioned formula (XXXVII) also by adding the acid of hydrogenchloride, hydrochloric acid, sulfuric acid etc. in manufacturing process in reaction solution, can take out as salt.

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

In formula, R ⁸with J as previously mentioned, M is-OH or-OG (G is ether residue), as G, is the such C1-C6 alkyl of such as methyl, ethyl, the phenyl etc. that can be replaced by C1-C6 alkyl.

First operation of reaction (X) can make compound (XXXV) and compound (XXXVIII) be used for carrying out usually in the presence of the solvent.

As solvent, as long as the solvent to reactionlessness, can from such as ether, butyl methyl ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; The halogenated hydrocarbons that chlorobenzene, dichlorobenzene, methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, Ethylene Dichloride are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; The polar aprotic solvent that acetonitrile, propionitrile, DMF, methyl-sulphoxide, HMPA, tetramethylene sulfone, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone are such; Suitably select one kind or two or more in alcohols, water etc. that methyl alcohol, ethanol, propyl alcohol, propyl carbinol, the trimethyl carbinol are such.

1st operation of reaction (X) can be carried out usually at 0 ~ 150 DEG C, preferably 30 ~ 110 DEG C, and its reaction times can be 0.5 ~ 24 hours, preferably 1 ~ 12 hours usually.

Second operation of reaction (X) can make the compound of formula (XXXIX) also originally carry out by using in the presence of the solvent reductive agent usually.

As reductive agent, suitably can select one kind or two or more from such as lithium aluminum hydride, sodium borohydride etc.As reductive agent, when using sodium borohydride, adding the Lewis acid of molybdic oxide, titanium tetrachloride, cobalt chloride, nickelous chloride etc., can reactivity be improved.

As the solvent in this situation, as long as the solvent to reactionlessness, can from such as ether, butyl methyl ether, tetrahydrofuran (THF), two suitably select one kind or two or more in the ethers that alkane, glycol dimethyl ether are such etc.

In addition, second operation of reacting (X) can make the compound of formula (XXXIX) under normal pressure ~ several atmospheric nitrogen atmosphere usually in the presence of the solvent by reducing with the catalytic hydrogenation of metal catalyst.As metal catalyst, can, from such as, suitably select one kind or two or more in palladium carbon, platinum oxide, Raney nickel etc.

As the solvent in this situation, as long as the solvent to reactionlessness, can from such as water, acetic acid, ethyl acetate; The alcohols that methyl alcohol, ethanol, propyl alcohol, propyl carbinol, the trimethyl carbinol are such; Ether, butyl methyl ether, tetrahydrofuran (THF), two the ethers that alkane, glycol dimethyl ether are such; Such aromatic hydrocarbon based of benzene,toluene,xylene; Suitably select one kind or two or more in the aliphatic hydrocarbon that pentane, hexane, heptane, octane, hexanaphthene are such etc.

Second operation of reaction (X) can be carried out usually at-10 ~ 100 DEG C, preferably 0 ~ 80 DEG C, and its reaction times can be 0.5 ~ 24 hours, preferably 2 ~ 12 hours usually.

, sometimes there is the isomer that optical isomer, geometrical isomer are such, but in the present invention, comprise the both sides of Isomers and isomer mixture in the compound obtained in aforesaid reaction (A) ~ (X).In addition, in the present invention, in the scope of technology general knowledge in the art, also comprise above-mentioned outside various isomer.In addition, according to the kind of isomer, sometimes forming the chemical structure different from the structure recorded in above-mentioned reaction formula, because known this of those skilled in the art is relation due to isomer, is therefore known within the scope of the invention.

In addition, the present invention includes following method.

(1) according to above-mentioned reaction (B-1), the method for the compound of formula (II-1) is manufactured.

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

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

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

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

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

(7) according to above-mentioned reaction (B-1) and (A-1), manufacture the compound of formula (II-1), manufacture the method for the compound of formula (I-1).

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

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

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

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

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

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

Embodiment

In order in further detail the present invention is described, record embodiment below, but the present invention is not limited thereto.

Embodiment 1 (E)-3-(the chloro-4-oxygen of 6--4H-benzo [d] [1,3] piperazine-2-base) synthesis (1) of methyl acrylate

The mixing solutions of methane sulfonyl chloride 1.49g and acetonitrile 10ml is carried out ice-cooled, after the acetonitrile 10ml solution of toxilic acid monomethyl ester 1.3g and pyridine 1.34g was dripped with 5 minutes under ice-cooling, synthermal stirring 5 minutes.Under ice-cooled, dripped the acetonitrile solution 10ml of 5-chloro-o-amino benzoic acid 1.72g, pyridine 2.77g with 2 minutes, then use acetonitrile 5ml drip washing, synthermal stirring 20 minutes.Under ice-cooling, added methane sulfonyl chloride 1.49g with 2 minutes, then use acetonitrile 2ml drip washing, stir 30 minutes, then return to room temperature, react 4 hours.Reaction solution is put in water 20ml, then stir 30 minutes.Filtering for crystallizing, with water, acetonitrile: after the washing of water (2:1) mixed solution, the dry target compound 1.82g (fusing point: 162 ~ 164 DEG C) obtaining brown.

¹H-NMR(400MHz，CDCl ₃)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-(the chloro-4-oxygen of 6--4H-benzo [d] [1,3] piperazine-2-base) synthesis (2) of methyl acrylate

(1) the chloro-2-of (Z)-5-(4-methoxyl group-4-oxygen-2-butylene acid amides) benzoic synthesis

At room temperature, in the methyl alcohol of 120ml, absorb the hydrogen chloride gas of 3.7g, then add (Z)-2-(3-carboxyl acrylamide)-5-chloro-benzoic acid 30.2g, stir 2 hours at 30 ~ 35 DEG C.The water of 150ml is added, by the crystallization suction filtration of separating out in reaction solution.Filtrate is washed with water, dry, obtain target compound 25.4g.

(2) (E)-3-(chloro-4-oxygen of 6--4H-benzo [d] [1,3] piperazine-2-base) synthesis of methyl acrylate

In the mixing solutions of the chloro-2-of (Z)-5-(4-methoxyl group-4-oxygen-2-butylene acid amides) phenylformic acid 15.2g and ethyl acetate 61ml, add diacetyl oxide 15.2mL and vitriol oil 0.15mL, at room temperature stir 45 minutes.After adding concentrated hydrochloric acid 0.3ml, synthermal stirring 1 hour.Filtering for crystallizing, after ethyl acetate washing, dry, obtain the target compound 13.3g of white.

The synthesis of embodiment 3 4-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl amino)-4-oxygen methyl crotonate

By the mixing solutions of the acetonitrile 12ml of Alpha-Methyl-Cvclopropvlmethvl amine hydrochlorate 0.73g, triethylamine 0.91g in stirring at room temperature after 1 hour, (E)-3-(the chloro-4-oxygen of 6--4H-benzo [d] [1,3] obtained in operation before room temperature adds piperazine-2-base) the coarse crystallization 0.53g of methyl acrylate, room temperature reaction 3 hours.Add water in reaction solution after, be extracted with ethyl acetate.With saturated common salt water washing organic layer, add anhydrous sodium sulphate and carry out drying.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=9/1 ~ 8/2) is refined, obtains flaxen target compound 0.22g (fusing point: 154.4 DEG C).

¹H-NMR(400MHz，CDCl ₃)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)

The synthesis (1) of embodiment 4 N-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-5-pyrazolidone-3-methane amide

The mixed solution of hydrazine one water and thing 90mg and ethanol 3ml is added in the mixed solution of 4-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl amino)-4-oxygen methyl crotonate 0.56g and ethanol 3ml, after ethanol 2ml drip washing, reflux 6 hours.After reaction solution is let cool, by the crystallization suction filtration of separating out, by crystallization washing with alcohol, air-dry acquisition target compound 0.16g (fusing point: 248 DEG C).

¹H-NMR(300MHz，DMSO-d ₆)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)

The synthesis (1) of embodiment 5 N-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-3-hydroxyl-4,5-dihydro-1 h-pyrazole-5-methane amide

At N-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-5-pyrazolidone-3-methane amide 0.10g and 2, palladium-carbon (ア Le De リッチ society system is added in the 2-methyl-2-propanol 3ml mixed solution of 3-dichloropyridine 0.09g, DeGussa typeE105CA/W) 15 % by weight, then add sodium tert-butoxide 0.045g.Mixed solution is reacted 9 hours under reflux.After letting cool, reaction solution is injected in the 1MHCl aqueous solution, is extracted with ethyl acetate.With saturated common salt water washing organic layer, add anhydrous sodium sulphate and carry out drying.With diatomite filtration, filtrate is under reduced pressure concentrated, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=1/0 ~ 1/1) is refined, obtains target compound 0.11g (fusing point: 165 ~ 167 DEG C).

¹H-NMR(300MHz，CDCl ₃)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)

The synthesis (2) of embodiment 6 N-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-3-hydroxyl-4,5-dihydro-1 h-pyrazole-5-methane amide

N-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-5-pyrazolidone-3-methane amide 1.0g is dissolved in the N of 10mL, in dinethylformamide, add 2,3-dichloropyridine 460mg, then add sodium hydride 350mg,, let cool after 7 hours at about 70 DEG C of stir abouts under nitrogen atmosphere.Add after water stirs in reaction solution, the thick resultant silica gel column chromatography (elutriant: ethyl acetate/methanol=9/1) being extracted with ethyl acetate acquisition is refined, obtains target compound 1.15g.

The synthesis of embodiment 7 5-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenylcarbamoyl)-1-(3-chloropyridine-2-base)-4,5-dihydro-1 h-pyrazole-3-base 4-toluene sulfonic acide ester

By N-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-3-hydroxyl-4,5-dihydro-1 h-pyrazole-5-methane amide 2.0g and N, the mixed solution of dinethylformamide 41ml, 0 DEG C of cooling, adds sodium hydride (60% oil suspension) 0.2g.Stir after 1 hour, add Tosyl chloride 1.2g at 0 DEG C.Stir after 1.5 hours, reaction solution is injected in 1MHCl aqueous solution 120ml, is extracted with ethyl acetate.With saturated common salt water washing organic layer, add anhydrous sodium sulphate and carry out drying.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=1/0 ~ 1/1) is refined, obtains the target compound 2.45g of cream pasty state.

¹H-NMR(300MHz，CDCl ₃)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 synthesis (1) of the bromo-N-of embodiment 8 3-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-4,5-dihydro-1 h-pyrazole-5-methane amides

At 5-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenylcarbamoyl)-1-(3-chloropyridine-2-base)-4,5-dihydro-1 h-pyrazole-3-base 4-toluene sulfonic acide ester 1.0g and N, add brometo de amonio 0.54g in the mixed solution of dinethylformamide 25ml, be heated to 93 DEG C.After 1 hour, reaction solution is injected in water 50ml, uses extracted with diethyl ether.With saturated common salt water washing organic layer, add anhydrous sodium sulphate and carry out drying.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=1/0 ~ 1/1) is refined, obtains the target compound 0.11g of cream pasty state.

¹H-NMR(300MHz，CDCl ₃)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 synthesis (2) of the bromo-N-of embodiment 9 3-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-4,5-dihydro-1 h-pyrazole-5-methane amides

Under ice-cooling, tetrahydrofuran (THF) (1ml) solution of phosphorus tribromide 0.16g is dripped in the mixed solution of 5-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenylcarbamoyl)-1-(3-chloropyridine-2-base)-4,5-dihydro-1 h-pyrazole-3-base 4-toluene sulfonic acide ester 1.0g and tetrahydrofuran (THF) 9ml.Stir after 5 minutes, be heated to 45 DEG C.After 5 hours, reaction solution is injected in water 50ml, is extracted with ethyl acetate.With saturated common salt water washing organic layer, add anhydrous sodium sulphate and carry out drying.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=1/0 ~ 1/1) is refined, obtains the target compound 0.73g of cream pasty state.

The synthesis (3) of the bromo-N-of embodiment 10 3-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-4,5-dihydro-1 h-pyrazole-5-methane amides

At 5-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenylcarbamoyl)-1-(3-chloropyridine-2-base)-4, Calcium Bromide 2 water and thing 0.25g is added, about 90 DEG C of heating 6.5 hours in the mixed solution of 5-dihydro-1 h-pyrazole-3-base 4-toluene sulfonic acide ester 1.0g and toluene 10ml.After letting cool, in reaction solution, add sodium bicarbonate 0.41g, water 10ml, stir.After separatory, with saturated common salt water washing organic layer, add anhydrous sodium sulphate and carry out drying.Solvent is under reduced pressure heated up in a steamer, obtains refining target compound 0.96g.

The synthesis (1) of the bromo-N-of embodiment 11 3-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-methane amide

At the Isosorbide-5-Nitrae-two of chloro-5, the 6-dicyano-p-benzoquinones 0.14g of 2,3-bis- in alkane 6ml solution, add the bromo-N-of 3-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-4,5-dihydro-1 h-pyrazole-5-methane amide 0.13g, reflux 18 hours.After letting cool, reaction solution is put in water, be extracted with ethyl acetate, organic layer is used saturated common salt water washing, use dried over sodium sulfate.Filtrate is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=8/2 ~ 7/3) is refined, obtain target compound 33mg (fusing point: 231-233 DEG C).

¹H-NMR(400MHz，CDCl ₃)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 synthesis (2) of the bromo-N-of embodiment 12 3-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-methane amide

At the bromo-N-of 3-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-4, the N of 5-dihydro-1 h-pyrazole-5-methane amide 0.10g, in dinethylformamide 3ml solution, add potassium persulphate 0.24g and sulfuric acid 0.02g, reflux.After 1.5 hours, let cool, reaction solution is injected in water 10ml, is extracted with ethyl acetate.With saturated common salt water washing organic layer, add anhydrous sodium sulphate and carry out drying.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=1/0 ~ 1/2) is refined, obtains target compound 0.09g.

The synthesis (3) of the bromo-N-of embodiment 13 3-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-methane amide

At the bromo-N-of 3-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-4,30% aquae hydrogenii dioxidi 1.13g is added, reflux in the ethyl acetate 12ml solution of 5-dihydro-1 h-pyrazole-5-methane amide 0.53g.After 30 hours, let cool, reaction solution is injected in water, is extracted with ethyl acetate.With saturated common salt water washing organic layer, add anhydrous sodium sulphate and carry out drying.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=4/1) is refined, obtains target compound 0.32g.

The bromo-N-of embodiment 14 3-[the chloro-6-of the bromo-4-of 2-[[(1-cyclopropylethyl] is amino] carbonyl] phenyl] synthesis (1) of-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-methane amide

The mixing solutions of bromo-for 3-N-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-methane amide 6.0g and ethyl acetate 75ml is carried out ice-cooled, after adding sodium hydroxide (flake) 1.4g, added bromine 2.8g with 2 hours.In stirring at room temperature after 18 hours, in reaction solution, add water 60ml, be extracted with ethyl acetate.By organic layer brine It, add anhydrous sodium sulphate, dry.After solvent under reduced pressure being heated up in a steamer, mixing solutions (1:5) 20ml of the crystallized from ethyl acetate of separating out and hexane being washed, filter, obtain the target compound 6.2g of white crystals.

The synthesis (2) of embodiment 15 N-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-5-pyrazolidone-3-methane amide

(1) synthesis of (Z)-2-(3-carboxyl acrylamide)-5-chloro-benzoic acid

Two are added in 5-chloro-o-amino benzoic acid 15g and maleic anhydride 10.3g alkane 150ml, reflux.Stir after 5 hours, reaction solution is let cool, by the crystallization suction filtration of separating out.By filtrate hexane: air-dry after the washing of ethyl acetate (3:1) mixed solution, obtain flaxen target compound 15g (fusing point: 194.4 DEG C).

¹H-NMR(400MHz，Acetone-d ₆)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-butylene acid amides) benzoic synthesis

10, sulfuric acid is added, stirring at room temperature 4.5 hours in the mixed solution of the methyl alcohol 20ml of (Z)-2-(3-carboxyl acrylamide)-5-chloro-benzoic acid 1.0g.In reaction solution, add water, be extracted with ethyl acetate, with saturated common salt water washing organic layer, add anhydrous sodium sulphate and carry out drying.Solvent is under reduced pressure heated up in a steamer, obtains target compound 0.91g (fusing point: 136.9 DEG C).

¹H-NMR(400MHz，DMSO-d ₆)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-(chloro-4-oxygen of 6--4H-benzo [d] [1,3] piperazine-2-base) synthesis of methyl acrylate

By the mixed solution of the chloro-2-of (Z)-5-(4-methoxyl group-4-oxygen-2-butylene acid amides) phenylformic acid 0.35g and diacetyl oxide 2ml stirring at room temperature 30 minutes, and then add diacetyl oxide 3ml, with 6.5 hours at room temperature reaction.Reaction solution is put in water, be extracted with ethyl acetate, organic layer is used saturated common salt water washing.Add anhydrous sodium sulphate, dry.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=9/1 ~ 8/2) is refined, obtains target compound 0.24g (fusing point: 117-118 DEG C).

¹H-NMR(400MHz，DMSO-d ₆)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) synthesis of N-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-5-pyrazolidone-3-methane amide

Use (Z)-methyl 3-(the chloro-4-oxygen of 6--4H-benzo [d] [1,3] obtained in front operation piperazine-2-base) acrylate, according to the method for above-mentioned synthesis example 3 and synthesis example 4, N-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-5-pyrazolidone-3-methane amide can be manufactured.

The synthesis (3) of embodiment 16 N-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-5-pyrazolidone-3-methane amide

(1) 4-(4-chloro-2-cyclopropylethyl carbamyl) phenyl amino) synthesis of-4-oxygen iso-crotonic acid

The mixed solution of the chloro-N-of 2-amino-5-(1-cyclopropylethyl) benzamide 100g and DMF 300ml is heated to 65 DEG C.Under agitation, maleic anhydride 49.5g is added wherein.After 1 hour, under stirring, in the water of 900ml, inject reaction solution.Stir after 10 minutes, by the crystallization suction filtration of separating out.By filtrate ethyl acetate 250ml washing, air-dry, obtain target compound 135g (fusing point: 173 DEG C).

¹H-NMR(300MHz，CDCl ₃)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) synthesis of 4-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl amino)-4-oxygen iso-crotonic acid methyl esters

By 4-(4-chloro-2-cyclopropylethyl carbamyl) phenyl amino) mixed solution of the methyl alcohol 950ml of-4-oxygen iso-crotonic acid 97.7g is cooled to 0 DEG C.Under stirring, drip sulfuric acid.20 hours are stirred while reaction solution is slowly returned to room temperature.In reaction solution, add the saturated aqueous common salt of 1.4L, be extracted with ethyl acetate.Organic phase is used saturated common salt water washing, add anhydrous sodium sulphate, dry.Solvent is under reduced pressure heated up in a steamer, obtains target compound 95.0g (fusing point: 131 DEG C).

¹H-NMR(300MHzCDCl ₃)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) synthesis of N-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-5-pyrazolidone-3-methane amide

Hydrazine one water and thing 3.58g is dripped, reflux in the mixed solution of 4-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl amino)-4-oxygen iso-crotonic acid methyl esters 25g and ethanol 250ml.Stir after 5.5 hours, reaction solution is let cool.By the crystallization suction filtration of separating out.Filtrate ethyl acetate is washed, then uses hexanes wash, air-dry, obtain target compound 13g.

The synthesis (4) of the bromo-N-of embodiment 17 3-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-methane amide

(1) synthesis of amyl group 2-(3-chloropyridine-2-base)-5-pyrazolidone-3-carboxylicesters

In the mixing solutions of 1-amylalcohol 15ml and toluene 30ml, add sodium hydroxide 0.75g, while using azeotropic dehydration device reflux after dehydration, heat up in a steamer toluene.And then joined after in system by toluene 20ml, toluene is heated up in a steamer in heating again, obtains the 1-amyl alcohol solution of amylalcohol sodium.Added 3-chloride-2-hydrazinopyridine 2.5g at 70 ~ 80 DEG C gradually with 5 minutes in this reaction solution after, add 1-amylalcohol 5ml, after 25 minutes, the mixing solutions of toxilic acid pentyl ester 5.1g and 1-amylalcohol 5ml was dripped with 15 minutes 70 ~ 80 DEG C of heating, and then 70 ~ 80 DEG C of reactions 2 hours.After letting cool, in reaction solution, add acetic acid, after neutralization, under reduced pressure concentrate.In residue, add water, after being extracted with ethyl acetate, by organic layer dilute hydrochloric acid and brine It, add anhydrous sodium sulphate, dry.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=6/4 ~ 0/1) is refined, obtains target compound (fusing point: 66 ~ 68 DEG C) 1.29g of tan crystals.

(2) synthesis of the bromo-1-of amyl group 3-(3-chloropyridine-2-base)-4,5-dihydro-1 h-pyrazole-5-carboxylicesters

The mixing solutions of amyl group 2-(3-chloropyridine-2-base)-5-pyrazolidone-3-carboxylicesters 1.2g, phosphorus oxybromide 0.59g and acetonitrile 18ml is slowly heated up, after 25 minutes, makes its reflux, reflux 1 hour.After letting cool, in saturated sodium bicarbonate aqueous solution, slowly add reaction solution, stir 5 minutes.This mixed solution is extracted with ethyl acetate, by organic layer brine It, adds anhydrous sodium sulphate, dry.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=9/1 ~ 8/2) is refined, obtain target compound (fusing point: 39 ~ 42 DEG C) 1.06g of pale yellow crystals.

(3) synthesis of the bromo-1-of amyl group 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylicesters

Vitriol oil 0.5ml and potassium persulphate 1.4g is added, reflux 3 hours 20 minutes in the mixing solutions of the bromo-1-of amyl group 3-(3-chloropyridine-2-base)-4,5-dihydro-1 h-pyrazole-5-carboxylicesters 1.0g and acetonitrile 20ml.After letting cool, in water, slowly add reaction solution, stir 15 minutes.This mixed solution is extracted with ethyl acetate, by organic layer saturated sodium bicarbonate aqueous solution and brine It, adds anhydrous sodium sulphate, dry.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=8.5/1.5 ~ 8/2) is refined, obtain the target compound 0.47g of oily.

(4) synthesis of the bromo-N-of 3-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-methane amide

Potassium tert.-butoxide 0.11g is added, room temperature reaction 45 minutes in the mixing solutions of the chloro-N-of 2-amino-5-(1-cyclopropylethyl) benzamide 0.19g, the bromo-1-of amyl group 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylicesters 0.30g and methyl-sulphoxide 3ml.Slowly reaction solution is added in dilute hydrochloric acid 40ml.This mixed solution is extracted with ethyl acetate, by organic layer saturated sodium bicarbonate aqueous solution and brine It, adds anhydrous sodium sulphate, dry.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=8/2 ~ 7.5/2.5) is refined, obtain target compound (fusing point: 231 ~ 233 DEG C) 0.058g of white crystals.

The synthesis (2) of the bromo-N-of embodiment 18 3-[the chloro-6-of the bromo-4-of 2-[[(1-cyclopropylethyl) is amino] carbonyl] phenyl]-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-methane amide

The mixing solutions of bromo-for 3-N-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-methane amide 0.24g and dimethyl formamide 5ml is carried out ice-cooled, after adding 60% sodium hydride 46mg, return to room temperature, stir 25 minutes.Reaction solution is again ice-cooled, after dripping the mixing solutions of bromine 0.15g and dimethyl formamide 1ml with 1 minute, room temperature reaction 2 hours 45 minutes.After reaction terminates, in dilute hydrochloric acid 60ml, slowly add reaction solution.This mixed solution is extracted with ethyl acetate, by organic layer saturated sodium bicarbonate aqueous solution and brine It, adds anhydrous sodium sulphate, dry.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=8/2 ~ 0/1) is refined, obtain target compound (fusing point: 244 ~ 247 DEG C) 0.20g of white crystals.

The synthesis (5) of the bromo-N-of embodiment 19 3-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-methane amide

(1) synthesis of the bromo-1-of phenyl 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylicesters

Thionyl chloride 3ml and dimethyl formamide 5 is added in the mixing solutions of the bromo-1-of 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylic acid 3.0g and toluene 30ml, reflux is after 1 hour, heat up in a steamer thionyl chloride and toluene, obtain the rough thing of 3-bromo-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxyl acyl chloride.

In the mixing solutions of phenol 1.03g and tetrahydrofuran (THF) 30ml, add 60% sodium hydride 0.48g under ice-cooling, after 20 minutes, be again cooled with an ice bath at room temperature reaction.In this mixed solution, drip the mixing solutions of above-mentioned rough thing and toluene 20ml under ice-cooling, use toluene 10ml drip washing reaction vessel.React 15 minutes under ice-cooling, after 1 hour, in water, slowly add reaction solution at room temperature reaction.This mixed solution is extracted with ethyl acetate, by organic layer brine It, adds anhydrous sodium sulphate, dry.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=9.5/0.5 ~ 7/3) is refined, obtains target compound (fusing point: 65 ~ 67 DEG C) 2.37g of white crystals.

(2) synthesis of the bromo-N-of 3-(the chloro-2-of 4-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-methane amide

Potassium tert.-butoxide 0.18g is added, room temperature reaction 1 hour in the mixing solutions of the chloro-N-of 2-amino-5-(1-cyclopropylethyl) benzamide 0.23g, the bromo-1-of phenyl 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylicesters 0.30g and methyl-sulphoxide 5ml.In dilute hydrochloric acid, slowly add reaction solution, this mixed solution is extracted with ethyl acetate, by organic layer saturated sodium bicarbonate aqueous solution and brine It, add anhydrous sodium sulphate, dry.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=8/2 ~ 7.5/2.5) is refined, obtain target compound 0.16g.

The synthesis (3) of the bromo-N-of embodiment 20 3-(the chloro-6-of the bromo-4-of 2-(1-cyclopropylethyl carbamyl) phenyl)-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-methane amide

In the mixing solutions of the chloro-N-of the bromo-5-of 2-amino-3-(1-cyclopropylethyl) benzamide 0.23g, the bromo-1-of phenyl 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylicesters 0.27g and methyl-sulphoxide 5ml, after at room temperature adding anhydrous sodium sulphate 0.45g, add potassium tert.-butoxide 0.16g, react 1 hour.Then, in water, slowly reaction solution is added.After being extracted with ethyl acetate by this mixed solution, by organic layer brine It, add anhydrous sodium sulphate, dry.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=8/2 ~ 4/6) is refined, obtains target compound 0.24g.

The synthesis of synthesis (1) ethyl 1-(3-chloropyridine-2-the base)-5-furyl-1H-pyrazole-3-carboxylic ester of the bromo-1-of embodiment 21 phenyl 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylicesters

At room temperature add 3-chloride-2-hydrazinopyridine 7.64g in acetic acid (150ml) solution of ethyl 2-furoyl pyruvate 11.19g after, and then stirring at room temperature 1 hour.Then reaction soln is heated to 100 DEG C, reacts 3 hours.After reaction terminates, acetic acid is under reduced pressure heated up in a steamer, add ethyl acetate and water extracts.After organic layer being used successively (1) saturated aqueous solution of sodium bicarbonate, (2) water, (3) saturated common salt water washing, use anhydrous magnesium sulfate drying.Solvent is under reduced pressure heated up in a steamer, obtains target compound crystallization (fusing point 116.7 DEG C) 14.5g.

(2) synthesis of 1-(3-chloropyridine-2-base)-5-furyl-1H-pyrazoles-3-carboxylic acid

By ethyl 1-(3-chloropyridine-2-the base)-5-furyl-4 obtained in front operation (1), 5-dihydro-1 h-pyrazole-3-carboxylicesters 14.5g is dissolved in after in the mixed solvent of methyl alcohol 90ml and water 45ml, add sodium hydroxide 2.2g, react 3 hours under reflux.After reaction terminates, heat up in a steamer desolventizing, add water in residue after, use washed with diethylether.After water layer concentrated hydrochloric acid is adjusted to pH3, be extracted with ethyl acetate.After organic layers with water and saturated common salt water washing, use anhydrous magnesium sulfate drying.Solvent is under reduced pressure heated up in a steamer, obtains target compound crystallization 11.9g (fusing point 179.3 DEG C).

(3) synthesis of 3-N-benzyloxycarbonyl amino-1-(3-chloropyridine-2-base)-5-furyl-1H-pyrazoles

1-(3-the chloro-2-pyridyl)-5-furyl-1H-pyrazoles-3-carboxylic acid 11.9g obtained in front operation (2), benzyl alcohol 4.89g, diphenylphosphoryl azide 12.4g and triethylamine 5.0g are joined two after in alkane 100ml, 90 DEG C of reactions 3 hours.After reaction terminates, solvent is under reduced pressure heated up in a steamer, adds ethyl acetate and water extracts.After organic layer being used successively (1) 5% hydrochloric acid, (2) saturated sodium bicarbonate aqueous solution, (3) water, (4) saturated common salt water washing, use anhydrous magnesium sulfate drying.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: hexane/ethyl acetate=1/1) is refined, obtain target compound crystallization 11.0g (fusing point 133.4 DEG C).

(4) synthesis of 3-benzyloxycarbonyl amino-1-(3-chloropyridine-2-base)-1H-5-pyrazole carboxylic acid

3-benzyloxycarbonyl amino-1-(3-chloropyridine-2-the base)-5-furyl-1H-pyrazoles 8.9g obtained in front operation (3) is dissolved in after in the mixed solvent of acetonitrile 70ml and tetracol phenixin 70ml, add the aqueous solution (150ml) of ruthenium chloride 0.70g and sodium periodate 21.5g, stirring at room temperature 12 hours.After reaction terminates, by reaction soln diatomite filtration, filtrate is under reduced pressure concentrated after, in residue, add ethyl acetate and 1N hydrochloric acid, extract.After organic layers with water is washed, with saturated aqueous solution of sodium bicarbonate washing, after water layer concentrated hydrochloric acid is adjusted to pH3, be extracted with ethyl acetate.After organic layers with water and saturated common salt water washing, use anhydrous magnesium sulfate drying.Solvent is under reduced pressure heated up in a steamer, target compound crystallization 4.4g (fusing point 79.1 DEG C).

(5) synthesis of 3-benzyloxycarbonyl amino-1-(3-chloropyridine-2-base)-1H-5-pyrazole carboxylic acid phenylester

3-benzyloxycarbonyl amino-1-(3-chloropyridine-2-the base)-1H-5-pyrazole carboxylic acid 2.97g obtained in front operation (4) is dissolved in after in the methylene dichloride 30ml after with aluminum oxide removing methyl alcohol, add oxalyl chloride 0.8ml and dimethyl formamide one, in stirring at room temperature after 30 minutes, reflux 2 hours.After reaction terminates, solvent is under reduced pressure heated up in a steamer, obtain 3-benzyloxycarbonyl amino-1-(3-chloropyridine-2-base)-1H-5-pyrazoles carboxyl acyl chloride.Tetrahydrofuran (THF) (10ml) solution of this chloride of acid is slowly joined under ice-cooling after in tetrahydrofuran (THF) (30ml) suspension solution of phenol 0.75g and sodium hydride (60% oily suspended matter) 0.35g, stirring at room temperature 8 hours.After reaction terminates, under reduced pressure heated up in a steamer by tetrahydrofuran (THF), add ethyl acetate and water in residue, extraction, after organic layers with water and saturated common salt water washing, uses anhydrous magnesium sulfate drying.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: hexane/ethyl acetate=1/1) is refined, obtain target compound crystallization 2.8g (fusing point: 150.2 DEG C).

(6) synthesis of 3-amino-1-(3-chloropyridine-2-base)-1H-5-pyrazole carboxylic acid phenylester

10%Pd-C powder 0.6g is added, under a hydrogen atmosphere, stirring at room temperature 12 hours in acetic acid (50ml) solution of 3-benzyloxycarbonyl amino-1-(3-chloropyridine-2-the base)-1H-5-pyrazole carboxylic acid phenylester 3.0g of acquisition by operation (5) before repeatedly.After reaction soln diatomite filtration, by filtrate and diatomite washings concentrating under reduced pressure.Residue silica gel column chromatography (elutriant: ethyl acetate) is refined, obtains target compound crystallization 1.1g (fusing point: 140.4 DEG C).

(7) synthesis of the bromo-1-of 3-(3-chloropyridine-2-base)-1H-5-pyrazole carboxylic acid phenylester

In acetonitrile (20ml) solution of cupric bromide (II) 0.72g and nitrite tert-butyl (90%) 0.55g, acetonitrile (15ml) solution of 3-amino-1-(3-chloropyridine-2-the base)-1H-5-pyrazole carboxylic acid phenylester 1.0g obtained in operation (6) before 0 DEG C drips, synthermal and then continue stirring after 2 hours, slowly return to room temperature.After reaction terminates, reaction soln is under reduced pressure concentrated, residue silica gel column chromatography (elutriant: hexane/ethyl acetate=1/1) is refined, obtains target compound crystallization 0.88g (fusing point: 64.3 DEG C).

Embodiment 22

(1) synthesis of the bromo-1-of benzyl 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylicesters

Thionyl chloride 1.5ml and dimethyl formamide 2 is added in the mixing solutions of the bromo-1-of 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylic acid 1.0g and toluene 10ml, reflux is after 1 hour, heat up in a steamer thionyl chloride and toluene, obtain the rough thing of 3-bromo-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxyl acyl chloride.

In the mixing solutions of benzyl alcohol 0.43g, triethylamine 0.40g and toluene 10ml, drip the mixing solutions of above-mentioned rough thing and toluene 10ml under ice-cooling.At room temperature react after 1 hour, in water, slowly add reaction solution.This mixed solution is extracted with ethyl acetate, by organic layer brine It, adds anhydrous sodium sulphate, dry.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=7/3) is refined, obtains the target compound 1.13g of oily.

In the mixing solutions of the chloro-N-of 2-amino-5-(1-cyclopropylethyl) benzamide 0.12g, the bromo-1-of benzyl 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylicesters 0.20g and methyl-sulphoxide 5ml, at room temperature add anhydrous sodium sulphate 0.42g, stir after 5 minutes, add potassium tert.-butoxide 0.072g, room temperature reaction 1 hour.Then in water, slowly reaction solution is added.This mixed solution is extracted with ethyl acetate, by organic layer brine It, adds anhydrous sodium sulphate, dry.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=8/2 ~ 7/3) is refined, obtains target compound 0.050g.

The synthesis of the bromo-1-of embodiment 23 4-methoxy-benzyl 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylicesters

Bromo-for 3-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylic acid 1.52g is dissolved in the chloroform of 10ml, drips thionyl chloride 0.55ml, add DMF0.05ml, reflux 30 minutes.After letting cool, solvent is under reduced pressure heated up in a steamer, obtain the rough thing of 3-bromo-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxyl acyl chloride.In the mixing solutions of 4-methoxy-benzyl alcohol 0.85g, triethylamine 1.11ml and chloroform 20ml, drip the mixing solutions of above-mentioned rough thing and chloroform 5ml under ice-cooling.Stir after 5 minutes, 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 used saturated common salt water washing, make it dry with sodium sulfate.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=1/0 ~ 3/1) is refined, obtain target compound 1.6g (fusing point: 83 DEG C).

Embodiment 24

(1) synthesis of the bromo-1-of S-benzyl 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-thiocarboxylic

Thionyl chloride 1.5ml and dimethyl formamide 2 is added in the mixing solutions of the bromo-1-of 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylic acid 1.5g and toluene 10ml, reflux is after 1 hour, heat up in a steamer thionyl chloride and toluene, obtain the rough thing of 3-bromo-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxyl acyl chloride.

In the mixing solutions of benzyl mercaptan 0.68g, triethylamine 0.61g and toluene 20ml, drip the mixing solutions of above-mentioned rough thing and toluene 5ml under ice-cooling.After 1 hour, in water, slowly add reaction solution at room temperature reaction, this mixed solution is extracted with ethyl acetate, by organic layer brine It, add anhydrous sodium sulphate, dry.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=9/1 ~ 7/3) is refined, obtain the target compound 1.65g of oily.

In the mixing solutions of the chloro-N-of 2-amino-5-(1-cyclopropylethyl) benzamide 0.24g, the bromo-1-of S-benzyl 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-thiocarboxylic 0.41g and methyl-sulphoxide 5ml, anhydrous sodium sulphate 0.85g is added in room temperature, stir after 5 minutes, add potassium tert.-butoxide 0.14g, room temperature reaction 1 hour.In water, slowly add reaction solution, this mixed solution is extracted with ethyl acetate, by organic layer brine It, add anhydrous sodium sulphate, dry.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=9/1 ~ 7.5/2.5) is refined, obtain target compound 0.22g.

Embodiment 25

(1) synthesis of the bromo-1-of S-ethyl 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-thiocarboxylic

Bromo-for 3-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-carboxylic acid 1.52g is dissolved in the chloroform of 10ml, drips thionyl chloride 0.55ml, add DMF0.05ml, reflux 30 minutes.After letting cool, solvent is under reduced pressure heated up in a steamer, obtain the rough thing of 3-bromo-1-(3-chloropyridine-2-base)-1H-pyrazoles-5-formyl chloride.Then, in the mixing solutions of ethane thiol 0.5ml, triethylamine 1.11ml and chloroform 20ml, drip the mixing solutions of above-mentioned rough thing and toluene 5ml under ice-cooling.Stir after 5 minutes, room temperature reaction 14 hours.Dereaction solvent is heated up in a steamer in decompression, adds water 50ml, is extracted with ethyl acetate.Organic layer is used saturated common salt water washing, add sodium sulfate, dry.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=1/0 ~ 3/1) is refined, obtain the target compound 1.4g (fusing point: 94 DEG C) of orange red crystallization.

The bromo-1-of S-ethyl 3-(3-chloropyridine-2-base)-1H-pyrazoles-5-thiocarboxylic 0.35g and the chloro-N-of 2-amino-5-(1-cyclopropylethyl) benzamide 0.24g is dissolved in methyl-sulphoxide 5ml, add anhydrous sodium sulphate 0.85g, stir 5 minutes.At room temperature, add potassium tert.-butoxide 0.14g wherein, stir 1.5 hours.Reaction solution is added to the water, is extracted with ethyl acetate.With saturated common salt water washing organic layer, add anhydrous sodium sulphate and carry out drying.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=1/0 ~ 1/1) is refined, obtains target compound 0.24g.

The synthesis (using the method for Leuckart method) of embodiment 26 1-cyclopropylethylamin

(1) synthesis of N-(1-cyclopropylethyl) methane amide

At room temperature stirred by the mixing solutions of 1-Cyclopropyl Methyl Ketone 30g and methane amide 66.2g, after adding formic acid 7.5g, 180 DEG C of reflux, the additional formic acid 7.5g every 1 hour, reacts 8 hours simultaneously.After reaction terminates, in water, add reaction mixture, be extracted with ethyl acetate.Organic layer is used saturated common salt water washing, after dried over sodium sulfate, ethyl acetate is heated up in a steamer in decompression, obtains the oily matter of rough N-(1-cyclopropylethyl) methane amide.

(2) synthesis of 1-cyclopropylethylamin

Concentrated hydrochloric acid 115ml is added, reflux 1 hour in the oily matter of rough N-(1-cyclopropylethyl) methane amide obtained in (1).After cooling in system, decompression is heated up in a steamer obtained hydrochloride salt in water.Ice-cooled by carrying out in system, make 1-cyclopropylethylamin freeization with sodium hydroxide by hydrochloride, then carry out air distillation, the fraction being 80 ~ 100 DEG C by boiling point obtains the cut 20g comprising target compound.

The synthesis of embodiment 27 1-cyclopropylethylamin (uses PtO ₂synthesis)

In the aqueous solution 200ml of Cyclopropyl Methyl Ketone 50g, add hydroxylammonium chloride 54.7g, while high degree of agitation, add sodium carbonate 33.6g gradually, reflux 4 hours.After letting cool, use extracted with diethyl ether.Organic layer is used successively water and saturated common salt water washing, add anhydrous sodium sulphate, dry.Solvent is under reduced pressure heated up in a steamer, obtains thick Cvclopropvlmethvl ketoxime 50g.

Then, obtained thick Cvclopropvlmethvl ketoxime 10g is dissolved in ethyl acetate 100ml, adds platinum oxide (IV) 1g, after carrying out hydrogen displacement in reactor, high degree of agitation.Stir after 16 hours and stop stirring, the platinum of precipitation is filtered.In supernatant liquor, add concentrated hydrochloric acid 10ml, with the vibration of separating funnel fierceness, two solvents are reduced pressure under 70 DEG C of heating and heats up in a steamer, obtain thick 1-cyclopropylethyl amine hydrochlorate 10g (purity 50%).

Thick 1-cyclopropylethyl amine hydrochlorate 10g is dissolved in water 10ml, is cooled to 0 DEG C.Below 5 DEG C, slowly adding sodium hydroxide wherein, is 14 by pH regulator.Assembling is provided with the water distilling apparatus of dry ice mixing tank, obtains the 1-cyclopropylethylamin 5g of boiling point 92 ~ 94 DEG C at ambient pressure.

The synthesis of the embodiment 28 2-bromo-5-of amino-3-chloro-N-(1-cyclopropylethyl) benzamide

(1) synthesis of the chloro-N-of 5-(1-cyclopropylethyl)-2-nitrobenzamide

By the mixed solution reflux 1 hour of chloro-for 5-2-nitrobenzoic acid 25g, toluene 25ml, thionyl chloride 22.2g, dimethyl formamide 0.1ml, synthesis acyl chlorides compound.In the mixing solutions of 1-cyclopropylethylamin 13.75g, tetrahydrofuran (THF) 375ml, add triethylamine 18.0g, carry out ice-cooled.Under ice-cooled, the acyl chlorides compound of above-mentioned synthesis is dissolved in toluene 30ml, drips.After dropping terminates, at room temperature react 15 hours.After reaction terminates, reaction mixture is put in water, be extracted with ethyl acetate.Organic layer is used saturated common salt water washing, after dried over sodium sulfate, ethyl acetate is heated up in a steamer in decompression.Residue silica gel column chromatography is refined, obtains flaxen target compound 25g (fusing point: 137-141 DEG C).

(2) synthesis of the chloro-N-of 2-amino-5-(1-cyclopropylethyl) benzamide

Chloro-for 5-N-(1-cyclopropylethyl)-2-nitrobenzamide 5.8g is dissolved in ethanol 88ml, under ice-cooling, drips concentrated hydrochloric acid 12.6ml.In synthermal lower stirring after 0.5 hour, a point several adds reduced iron 4.0g.At room temperature stir after 3 hours, add water at reaction mixture, be extracted with ethyl acetate.Organic layer is used saturated common salt water washing, after dried over sodium sulfate, ethyl acetate decompression is heated up in a steamer.In residue, add hexane/ethyl acetate, after stirring, leaching, obtains flaxen target compound 3.5g (fusing point: 135 DEG C).

(3) synthesis of the chloro-N-of the bromo-5-of 2-amino-3-(1-cyclopropylethyl) benzamide

The chloro-N-of 2-amino-5-(1-cyclopropylethyl) benzamide 0.1g is dissolved in DMF 3ml, is cooled to 0 DEG C.Add sodium hydride 0.02g wherein, stir after 1 hour, add bromine 0.09g, stir 2 hours.Reaction solution is joined in the 1M-HCl aqueous solution, be extracted with ethyl acetate.With saturated common salt water washing organic layer, add anhydrous sodium sulphate and carry out drying.Solvent is under reduced pressure heated up in a steamer, residue silica gel column chromatography (elutriant: n-hexane/ethyl acetate=1/0 ~ 1/1) is refined, obtains flaxen target compound 0.08g (fusing point: 177 DEG C).

Industrial Availability

The invention provides as the new anthranilamide compound in the specific position of phenyl ring and pyrazole ring with halogen atom of the noxious organism control agent display excellent effect in agriculture and garden field or its salt and efficient manufacture method thereof.

In addition, the Japanese Patent that the present application quotes application on December 15th, 2006 go out to be willing to the Japanese Patent applied in No. 2006-339100 and on June 8th, 2007 go out to be willing to No. 2007-152718 specification sheets, claims, summary full content, as the content of specification sheets of the present invention.

Claims

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

In formula, R ^1afor halogen or haloalkyl, R ²for cyclopropyl alkyl or cyclobutylalkyl.

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

In formula, R ^1afor halogen or haloalkyl, R ²for cyclopropyl alkyl or cyclobutylalkyl, R ⁵for alkyl.