TW201141842A - Method for making a derivative of 1-substituted-4-carbamoyl-1,2,4-triazol-5-one - Google Patents

Abstract

This invention provides a method capable of making a high purity derivative of 1-substituted-4-carbamoyl-1,2,4-triazol-5-one with a high yield at low cost easily. It is a method for making a derivative of 1-substituted-4-carbamoyl-1,2,4-triazol-5-one by reacting a derivative of 1-substituted- 1,2,4-triazol-5-one with an alkali metal hydroxide under the presence of a quaternary ammonium salt or a phosphonium salt and in an aromatic hydrocarbon solution while the by-product of water is being removed by azeotropic distillation, and subsequently reacting the reactant mixture with a compound of a carbamoyl-chloride group, to obtain the derivative of 1-substituted 4-carbamoyl-1,2,4-triazol-5-one represented by the following formula (I) wherein X represents a halogen atom or a lower alkyl group, Y represents a halogen atom, R represents a lower alkyl group, n and m represents an integer of 0 to 5.

Description

201141842 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a process for producing a 1-substituted-4-aminoindenyl-1,2,4-triwax-5 ketone derivative. [Prior Art] The following formula (I)

[wherein, X represents a halogen atom or a lower alkyl group, Y represents a halogen atom, R represents a lower leuko group, and η and m represent an integer of 〇 to 5], and a 4-substituted amine-aryl-1, A compound in which a 2,4-tris-ol-5-one derivative is used as an active ingredient of a herbicide is known in the production method of the following formula (II) in an organic solvent.

In the formula (wherein X and η are synonymous with the above), the 1-substituted-1' 2,4-triazol-5-one derivative represented by the formula (η!)

[wherein, Y, R and m are synonymous with the above. A method of reacting an amine-based helium gas in the presence of a dehydrochlorinating agent (Example 4 322217 201141842 T, referred to the patent document 《, ", a method of reacting a phase transfer catalyst with a dehydrochlorinating agent (for example, Refer to Patent Document 2). However, the manufacturing method described in the above-mentioned Patent Document i is the present invention. However, in consideration of reactivity, etc., it is necessary to use an organic bath ▲ acetonitrile, a combination of salt and potassium, or Solvent and desalting _ both tasks (four), the combination of expensive organic solvent and dehydrochloric acid agent. In addition, the reaction speed of the combination of organic solvent and dehydrochlorination agent is "slow", U 卩 makes the reaction sometimes When the object to be obtained is purified, the extraction solvent may be re-added after the reaction solvent is removed. Therefore, there is a case where the operation is complicated and the cost becomes high. It is difficult to say that it is advantageous in the industry. ° = The manufacturing method described in the above Patent Document 2 is disclosed by the applicant of the present application, but in this method, in the presence of a phase transfer catalyst, for example, Organic solution The industrially relatively inexpensive organic solvent and dehydrochlorinating agent of benzene and/or water and dehydrochloric acid sodium hydroxide, and the above 1-substituted-1,2,4-triazole-5-one is derived. The object (11) is reacted with an amine group and a chlorine group to obtain a desired derivative (I). [Prior Art Document] (Patent Document) (Patent Document 1) International Publication No. 98/38176 (Part 1) [Patent Document 2] Japanese Laid-Open Patent Publication No. 2004-175756 [Claim of the Invention] [Problems to be Solved by the Invention] 322217 5 201141842 However, by the method described in Patent Document 2, the object is manufactured in a production scale in particular. When substituting +aminomethylmercapto], 2, 4, 3, and 3 ketones (1), 'receiving _ (4) is dissolved water, or reaction by-product water, the raw material of the raw material of the reaction The decomposing spoon will increase the side reaction, and the yield and purity of the target will decrease. In the next step, the reaction temperature will not rise due to the presence of water, and the reaction rate will become slower. Therefore, it is expected to develop a product that can be manufactured in a simpler, lower-cost, high-yield product. The present invention relates to an industrial production method of the above-mentioned prior art. The object of the present invention is to provide a simple, low-cost, high-yield product. The method of the high-purity 1 -substituted 4-amino hydrazin g | s-tris- _ 5- ketone derivative. [The means for solving the problem] The inventors of the present invention have found that the above-mentioned problems have been concentrated on the results of the above-mentioned research. Bu-substituted-1,2,4-three wow-5_Saki biological (9) reacts with an alkali metal hydroxide, and further reacts with an amine ruthenium chloride απ) to produce a 1-substituted-4-aminoindenyl group— In the case of hydrazine, 2,4_triazole-5-one derivative, firstly, in the presence of a phase transfer catalyst, the above 1-substituted-1,2'4-triazole-5 is present in a specific organic solvent. a ketone derivative (oxime) is reacted with an alkali metal hydroxide, and at the same time, water formed as a by-product is removed from the reaction system by azeotropic distillation together with a solvent, and then, an amine group is added to the reaction mixture. Formazan chloride (ΠΙ;) The specific method, if the amine methotrexate (III) reaction, can make the following formula 322217 6 20114184 2 (I) is substituted with a 4-amino-fluorenyl group. The present invention has been achieved in a high yield and high purity in a 4 cis' 々4 + ketone derivative. (Lianyang, Shangshang, etc.), also produced by the following formula (1) of the present invention, the base-1,2,4-tris-5, and the derivative=4 And the group formed by the squamous salt is characterized by: in the presence of the aromatic smog solvent, squirting to a > phase transfer catalyst, (a) the substance represented by the following formula (11), and generation i,2,4-diazolone-derived (b) alkali metal hydroxide, after a side-by-side reaction by azeotropic distillation, in the obtained reaction mixture, after the chloroformyl group And let the reaction. 4 into the lower speed ((1)) amine

(D

[In the formula (I), 'X represents a halogen atom or a lower alkyl group, γ represents a tooth atom, R represents a lower alkyl group, and η and in are each independently, and represents an integer of 〇 to 5] 〇d [in the formula (II) , X and η are synonymous with the above formula (I)] 322217 7 (III) 201141842

[In the formula (III), Y, R and m are synonymous with the above formula (I)]. In the present invention, the aromatic hydrocarbon solvent is preferably toluene and/or xylene. [Effects of the Invention] According to the production method of the present invention, high-purity 1-substituted-4-aminomethylmercapto-indole, 2,4-triazole-5-one derivative can be produced in a high yield, easily and inexpensively. Things. [Embodiment] [Formation for Carrying Out the Invention] Hereinafter, a method for producing the substituted 4-aminobutyryl-1,2,4-tris-succin-5-one derivative of the present invention will be specifically described. The present invention produces a 1-substituted-4-aminoindenyl-1,2,4-trian-5-one derivative (1) by the following reaction mechanism, that is, steps 1 and 2 (hereinafter) It is called compound (I), etc.). <step 1>

8 322217 201141842 [In the foregoing steps 1, 2, X represents a halogen atom or a lower alkyl group, γ represents a halogen atom, R represents a lower alkyl group, and η and m are each independently, and represent 〇 to 5 integers. η X &amp; m γ can be mutually identical or different. Also, when χ = is a halogen atom, 'may be mutually different or different. Also, χ and R are low-grade base days ^, which may be mutually identical or different. In the present invention, in step i, at least one phase transfer catalyst is selected from the group consisting of a quaternary ammonium salt and a scale salt (in the presence of a phantom, in an aromatic hydrocarbon solvent (C) (below) , also known as solvent (c), etc., (a) a sub-substituted-nf-triazole-5-one derivative represented by the above formula (Π) (hereinafter, also referred to as 丨_substitution 4, 2, 4-triazole _5-ketone derivative (Η), compound (II), etc., reacted with (b) alkali metal hydroxide (A), and substituted the obtained reaction intermediate _丨, 2, 4_ The test metal salt (IIa) of the triazolone bio-organism (II) and the by-produced water are removed together with the solvent (6) by azeotropic distillation to the outside of the system. Further, the reaction of this step 1 is in the formation of an alkali metal salt. After (Ila), although a reverse reaction is carried out in the case of forming an acidic condition (acid acid or more), in the present invention, since it does not contain a step which becomes an acidic condition, it is an irreversible reaction. Metal salt (I Ia) The reaction intermediate system can be confirmed by the generation of water. The reaction of step i as described above is performed right, and then the above steps are carried out. When the reaction of 2 is described, the reaction between the product (1) &amp; (1) &amp;) and the amine-based ruthenium chloride (1) I) can be substituted for the purpose of substituting _4_aminomercapto-1,2,4-triazole 322217 9 201141842 -5_ketone derivative (I). The aspect of the present invention is described later, but as shown in the foregoing mechanism, the above-mentioned derivative (1)) and phase transfer catalyst (8) money-measuring oxide (A) are added to the aromatic hydrocarbon (C) of the solvent. Under normal pressure, the mixture of the mixture of abundance (azeotropic) starts above the temperature below the hysteresis point of the aromatic hydrocarbon solvent (eg water/toluene: 8〇 to 11〇t), while Bu-substituted-1,2,4-tri-4-5' derivative (1)) reacts with metal hydroxide (4), and the water formed by the sub-formation and the solvent (6) at the time are borrowed from the reaction system. The intermediate metal salt (Ila) of the ketone derivative is removed. Then, in the present invention, the amine ruthenium chloride represented by the above formula (III) is added to the reaction mixture containing the phase transfer catalyst (B), the solvent (C) and the alkali metal salt (113). a class (hereinafter, also referred to as an aminoguanidine group (III), a compound (ΠΙ), etc.), and the alkali metal salt (IIa) and the aminoguanidinium chloride (III) are under normal pressure. The reaction is carried out at room temperature (15 to 25. hydrazine or heating (for example, 50 to 110 ° C), and the purpose of the preparation is to replace a 4-aminomethylmercapto-1,2,4-triazole-5-one. Derivative (丨). When the reaction of steps 1 and 2 is carried out in such a manner, it is preferable from the viewpoints of work efficiency, step management, reaction rate, yield, purity, etc. Further, in the above mechanism, each symbol X The meanings of the meanings of Y and R are as follows. In the present invention, the "lower alkyl group" in the definition of X and R may, for example, be a straight or branched alkyl group having 1 to 6 carbon atoms. Specifically, for example, anthracenyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 322217 10 201141842 first butyl, tert-butyl, n-pentyl Isoamyl, 2-methylbutyl, neopentyl, n-hexyl, 4-fylpentyl, 3-fylpentyl, 2-indenylpentyl, 3' 3-dimethylbutyl, j , bis dimethyl butyl,], 3-dimethyl butyl, 2, 3 - methyl butyl, 1-ethyl butyl, 1-ethyl 2-methylpropyl, methyl y - Ethylpropyl ' 1-indolyl-2-ethylpropyl, 2-methyl-i-ethylidyl, 2-methyl-2-ethylpropyl, etc. In the present invention, in the definition of X and γ The "dental atom" is specifically an atom of fluorine, gas, bromine or iodine. X is a linear or sub-group of carbon atoms 1 to 3 among chlorine atoms, fluorine atoms, and lower alkyl groups among the tooth atoms. a branched alkyl group, wherein a methyl group is preferred, and either or both of the halogen atom and the lower alkyl group may be present in the compound (II), the alkali metal salt (iIa), and the objective compound (1). a triazole group directly bonded to a stupid group, and these substituents X are bonded to the 2, 4, 2, 3 or 2 positions of the phenyl group, but from the viewpoint of the yield of the product (丨) It is preferable that 'R is from the viewpoint of the yield of the product (I). It is preferably an isopropyl group. The fluorine atom and the chlorine atom are preferably bonded to the 2, 4 or 4 of the phenyl group directly bonded to the amino group of the aminoguanidinium chloride (ΠΙ) and the aminocarboyl group of the objective compound (I). It is preferable to combine these halogen atoms, but it is preferable from the viewpoint of the yield of the product (I). Next, the preparation of the substituted 1,-, 2, 4-triazole 5 worm 彳 4 organism used in the step 1 will be described. (11), metal hydroxide (a), phase transfer catalyst (b), and aromatic hydrocarbon solvent (C) 'then, followed by the description of the amine helium (III) used in step 2 And the target product is substituted for the _4_aminomethionyl-1,2,4-triazol-5-one derivative (I). 322217 11 201141842 <1-Substituted-1,2,4-triazol-5-one derivative (π)> The specific compound (II) may specifically be, for example, a phenyl group, a 2,4-triazole -5-keto, 1-(2-indolyl)-1,2,4-triazol-5-one, 1-(3-chlorophenyl)-1,2,4-triazol-5-one, 1-(2-Fluorophenyltriazole-5-one, Bu (2-bromophenyl)-1,2,4-triazol-5-one, 1-(2-iodophenylhydrazine, 2, 4 - triazol-5-one, b (di)-, phenyl) hydrazine, 2,4-triazole _5-ketone, dichlorophenyl)-1'2,4-oxadiazol-5-one, 1 -(2,4-difluorophenyl)_;[,2,4-triazol-5-one, 1-(2,4-dibromophenyl)-1,2,4-triazole_5_ Ketone, Bu (2,4_dimothylphenyl)-1,2,4-tris-7, 1-(2,4-:methylphenylh'u-tris-5-one, Bu (2'3-dimethylphenyl h, 2, 4_3. sit a 5-ketone, wear 4-chlorophenyl)-ι, 2,4-triterpene+ketone, ι-(2-gas +Methylphenyl)], 2' 4-triazole-5-one, Bu (2-Don + Methylphenyl M, 2, 4-triazole I ketone, Bu (2 Yiqin-4-methyl) Phenyl H, 2, 4_tris- _5, 'methylphenyl H, 2,4-tris-s--5-one, b (2_mercapto + phenyl) -1' 2, 4 - 3 Oxazol-5-ketone, b. monomethyl + gas phenyl η 2, *-triazole I ketone, Bu (2-methyl-4-Molybdenum h, 2 士三唾_5,, and Bu (kib-4-iodophenyl)-1,2, 4-three Oxazol-5-ketone, etc. These compounds (in (1), as (2,4-dichlorophenyl)], 2 4_disindol-5-one, (2-chlorophenyl h, 2, 4 - three saliva _5__, dimethyl phenyl)-1,2,4-triazol-5-one, etc. The compound (II) is present by the phase transfer catalyst (8), the aromatic smoke solvent (6) Solubility. In addition, under heating conditions (4), the process is carried out: the step is carried out, and the stagnation point of the solvent is below (2). () The solvent is dissolved in the aromatic hydrocarbon solvent 322217 12 201141842 (C) ° 'may cause the formation of a reaction to replace the metal salt (IIa) of 4,23-triazole_5_g with the derivative (II), or to promote the reaction. The synthesis method of the starting material compound (Π) is not particularly limited. However, it is preferably synthesized according to the method described in paragraphs [〇〇39] to [〇〇82] of JP-A-2002-179655. <Alkali Metal Hydroxide (A)> In the present invention, it is used as Metal hydroxide for the reaction of the above 1-substituted d,2,4-triazole-5-one derivative (Π) The (A) may, for example, be sodium hydroxide, lithium hydroxide or potassium hydroxide, and it is preferable to use &amp; The amount of the metal hydroxide to be used is equal to or slightly excess relative to the 1-substituted-1,2,4-diin-5-one derivative (11) 1 equivalent' (for example: to equivalent) In terms of cost, reaction rate, yield, and purity, it is preferred. <Phase Transfer Catalyst (B)> In the present invention, the reaction of the above 1-substituted-1,2,4-trisucci-5-one derivative (π) with an alkali metal hydroxide (A) (Step 1 When the reaction of the alkali metal salt (I la) obtained by the reaction with the aminoguanidinium chloride (Ιπ) (step 2) is used, the phase transfer catalyst (β) which can be used as a catalyst is used. It forms an ion pair with the reaction raw material compound to exhibit a catalytic action of phase transfer, and reacts with the raw material compound to be reacted for the purpose of movement, and then returns to the original phase transfer catalyst to further react to the next reaction. The regeneration of the starting compound allows the catalyst to be used for phase transfer. Thus, the phase transfer catalyst is reversely phase-shifted and acts as a catalyst. 322217 13 201141842 For example, an emulsifier such as a fatty acid soap is classified as dispersing an oil phase in an aqueous phase or dispersing a water phase in an oil phase. The person. Further, the reaction raw material compound which acts as a phase transfer catalyst (B), in step 1, is a substituted-1,2,4-tris-5-one derivative (11) or a metal hydroxide (A) In addition, in step 2, an alkali metal salt (iIa) of the 4_triazolone derivative (π) or an aminoguanidine group (ΙΠ) is substituted. As the phase transfer catalyst used in the reaction (steps 1, 2), for example, a quaternary ammonium salt and a phosphonium salt are mentioned. In the present invention, since an aromatic hydrocarbon is used as the organic solvent, the phase transfer catalyst is preferably a quaternary ammonium salt and/or a scaly salt from the viewpoints of cost, reaction rate, yield and purity. The quaternary ammonium salt may specifically be, for example, desertified tetra-n-t-taki, sulphuric acid tetra-n-butylammonium, vaporized trioctylmethylammonium, and benzyltriethylammonium chloride. Specific examples of the scale salt include desertified tetra-n-butyl scale, desertified tetraphenyl scale, and tetraoctyl bromide scale. &amp; these quaternary ammonium salts, scalar salt Φ, + wide - run Li IT, in terms of cost, reaction speed, and purity, *3- A Oj /L ―, -Γ u scale and Ma Guanghua four N-butylammonium or tetra-n-butyl bromide may be used in combination with the above phase transfer catalyst. If the amount of the servant m catalyst (8) is considered, the metal hydrogen in the first step can be used for the test. "The reaction efficiency is equal to the molar ratio of the !-substituting-U shi Sanwa derivative (9). 322217 14 201141842 is preferably 1.0 to 10 mol%. Further, the amount of phase transfer catalyst (Β) is used as a raw material compound in step 2, and the amine methyl oxime (1) (10) molar number is used. Mol%), generally 1.0 to 20 mol%, preferably 丨〇 to 10 mol%. In the present invention, 'II is added to the reaction system by adding a phase transfer catalyst (8), especially in the aforementioned amount 'in step 1 The middle system can make the metal hydroxide (4) and the like dissolve well in the aromatic hydrocarbon (6) in the organic solvent, causing the formation of the substituted-1,2,4-tris-salt-5, derivative ((1) metal salt (1(4)). The reaction promotes the reaction. The phase transfer catalyst (8) is in the crucible of the step 1 of forming the core of the metal salt (1), and the water and the dissolved water generated by the azeotrope are continuously continuous from the anti-... Removal, can also make the secret metal salt of (1) (6) (1-): 1, 2, derivative (1)) metal salt (1) a) can be induced or promoted IIa) reaction with step 2 of the amine-based chlorinated chlorine compound), raising the reaction of the derivative of the target substance (1) to a half of the reaction of the person in the step 2, characterized in that only The organic solvent (6) is soluble by the phase transfer catalyst (8), and the "aromatic hydrocarbon solvent (c) &gt; the aromatic fumes used in the raw material is relative to the (^π) 1_1'2 used. '4H5, derivative (Π), amine 曱醯 类 成 取代 ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ As a task of (4), there is no particular limitation to 0 as such an aromatic hydrocarbon solvent (c), and specifically, for example, stupid

Further, in the present invention, diterpenic benzene or the like may be used. In a preferred aspect of the present invention, in the solvent (c), the task of forming a mixture of water with water to exhibit both a reaction solvent and an extraction solvent is inexpensive and the step of purifying the target (I) From the viewpoint of ease of washing and liquid separation, it is particularly preferable to use benzene and/or dimethyl benzene. The organic solvent (c) used in this reaction (step 2) can dissolve the starting compound during the reaction (Bu substituted - U2, 4_ triterpenoid (II), amine helium (111) And the like, and the purification step must be an amount of the hydrazine-substituted-4-aminoindenyl-hydrazine, 2,4-triazolone derivative (I) which is soluble in the target, for example, relative to the raw material _ The substituted hydrazine, 2,4-triazole-5-one derivative (11) is preferably used in an amount of 10 to 20 parts by weight, more preferably 5 to 15 parts by weight, even more preferably 8 to 12 parts by weight, based on 1 part by weight of the (11) (for example). The amount of the raw material in the reaction system (reaction pin) is lowered when a necessary amount or more of the solvent is used, and the amount of the target obtained by the first reaction (batch) is Therefore, in order to obtain a certain amount of the object, there must be more batches, and there are cases of time and cost. &lt;Aminomethyl hydrazine (ΙΠ)&gt; In 2, the amine group f 醯 chloro (III) is added to the reaction mixture obtained in the step , to obtain (the alkali metal salt (Ila) contained in the reaction mixture and A derivative of the desired target (1). J6 322217 201141842 As the compound (III), specifically, for example, N-methyl-N-2,4-difluorophenyl Aminomethylhydrazine chloride, N_ethyl_N_2,4-difluorophenylaminocarbazide, N-n-propyl-N-2, 4-difluorophenylaminomethylhydrazine chloride, N-iso propyl-N-2'4-difluorophenylaminocarbamidine chloride, N-methyl_N-4 fluorophenylaminocarbazide, N-ethyl-N-4-fluorophenylamine Base helium, N_n-propyl _n_4_ fluorophenylaminoformamidine E 'N-isopropyl-N_4_fluorophenylaminoformamidine chloride and N-isopropyl-N-phenylamino group Methyl hydrazine, etc. Among these, N-isopropyl u,4-difluorophenylaminocarbazide, N-isopropyl-N-4-fluorophenylamino ruthenium chloride, etc. The method for synthesizing the aminoguanidinium chloride (ΠΙ) is not particularly limited, and it is preferably, for example, a method according to paragraphs [0020] to [0033] described in JP-A-2002-145833. And synthesized by the method described in Chemiche Berichte, Vol. 88, No. 301 (1955). The amine helium (III) also replaces the triazole-5-one derivative according to the raw material (丨1) The reaction efficiency with respect to the alkali metal hydroxide (A), etc., for example, is equivalent to 1 equivalent of the derivative (U), and is theoretically used in an equivalent enthalpy (1 equivalent), but is generally 1.0. The amount of the user to 1.1 equivalent is preferred in terms of cost, reaction rate, yield, and purity. &lt;Substituted 4-aminomethylmercapto-1,2,4-triazole-5- Ketone Derivative (1)&gt; The object compound (I) which can be produced by the reaction of the above-mentioned step 2, for example, corresponds to the starting material compound {derivative (π), aminomethanthene (shown by the above mechanism). The combination of III)}. Specific examples of such a compound include, for example, phenyl-4-(indole-isopropyl N 4-fluoro or 2,4-difluorophenylaminoindenyl)-1,2,4-triolole -5-g, 322217 17 201141842 1-(2-Phenylphenyl)-4-(N-isopropyl-N-4-fluoro or 2,4-difluorophenylaminocarbamimidyl)-1 , 2,4-triazol-5-one, 1-(3-phenylphenyl)-4-(N-isopropyl-N-4-fluoro or 2,4-difluorophenylaminocarbamyl _1,2,4-triazol-5-one, 1-(2,4-dioxaphenyl)-4-(N-isopropyl-N-4-fluoro or 2,4-difluorophenyl) Aminoguanidino)_1,2,4-triazol-5-one, 1-(2-fluorophenyl)-4-(N-isopropyl-N-4-fluoro or 2,4-difluoro Phenylamino indenyl)-1,2,4-triazol-5-one, 1-(2,4-difluorophenyl)-4-(N-isopropyl-N-4-fluoro or 2,4-difluorophenylaminocarbamimidyl-1,2,4-triazol-5-one, 1-(2-fluoro-4-chlorophenyl)-4-(N-isopropyl -N-4-fluoro or 2,4-difluorophenylaminoindenyl)-1,2,4-triazol-5-one, 1-(2-methylphenyl)-4-(b Isopropyl 4-4-fluoro or 2,4~·monofluoro-based amide base)-1,2,4-tri. Sodium-5-oxime, 1_(2,3-dimercaptophenyl)-4-(N-isopropyl-N-4-fluoro or 2,4-difluorophenylaminomethyl)-1 , 2, 4-triazol-5-one, and 1-(2-chloro-4-mercaptophenyl)-4-(N-isopropyl-N-4-fluoro or 2,4-difluorobenzene Aminoguanidino)-1,2,4-triazol-5-one and the like. In the compound (I), the compound (II) corresponding to the above-mentioned appropriate aspect, the amine ruthenium chloride (II 〇 ^ ^ 一 一 dichlorophenyl) - 4 isopropyl (. isopropyl) -N-2,4-difluorophenylaminocarbamimid; ^, ^triazole _5-ketone, Bu (2-chlorophenyl)-4-(N-isopropyl-N-2, 4-difluorophenylaminocarbamido)-1'2,4-triazol-5-one, 1-(2,3-dimethylphenyl)-4-(i-isopropyl-N- 2,4-Difluorophenylaminocarbazinyl 2,4-triazole-5-ketone, Bu^,4-dichlorophenyl)-4-(N-isopropyl-N-4-fluorophenyl Aminomethylmercapto) 2, 4-tris-quinone-5-oxime or the like is preferred. &lt;Production Method of Compound (I)&gt; 322217 18 201141842 ^ In the present month, as described above, in order to obtain a target compound 1-Substituted-4-yl-methylmercapto-1,2,4-tris-salt-5, derivative (1), in the step 〖, then, the reaction of step 2 is carried out to obtain the target of substitution _4_amino group A醯基生物(1)' But first, Langqin the above step 1 ° &lt;Step 1&gt; In the present invention, in step 1, a group consisting of a quaternary salt and a quaternary salt is selected, and is selected to &gt; Aromatic hydrocarbons in the presence of phase transfer catalyst (8) In the agent (C), (4) is substituted with -1,2,4-tris-s--5-anthracene represented by the above formula (1)), and reacted with (b) an alkali metal hydroxide (A) to obtain a reaction intermediate. Substituting for the body], 2, 4 s of the metal salt of the _5-ketone derivative (II) (1) a) 'At the same time, the water formed by the by-product and the solvent (6) are removed to the outside by azeotropic distillation. (Conditions of temperature and pressure and time) The reaction of the step 1 may be carried out at normal temperature (15 to 25 &lt;&gt;c) or heating (depending on the type of the solvent (C), etc., but in the case of toluene, temperature: It is carried out in 3〇 to ii〇°c}, and when heated, the water and the solvent (the azeotropic distillation efficiency of hydrazine is good, and the formation of the intermediate product (IIa) is promoted. Further, the reaction of the step 1 is generally at normal pressure. It can be carried out under (standard atmospheric pressure, 1013.25 hPa), or under pressure. The reaction under normal pressure is also excellent in the handling and operation of the step management. The reaction of this step 1 is also dependent on temperature and pressure. The blending component and the amount thereof are determined according to 322217 19 201141842, but in the above range (temperature, pressure), for example, when 〇ι to 5, it is preferably carried out for about 0.2 to 3 hours, but in combination with step 2 described later. The time is from 0.5 to 6 hours, preferably from about 5 to about 4 hours. If the reaction of the step i is carried out under the above-mentioned desired force and temperature conditions, and then the reaction of the step 2 is carried out, the product between the preceding orders ( Na) Substituting for the reaction of the blood secrets (m) The yield of the +aminomethoxine 2 -1,2,4-triazol-5-one derivative (I) is increased. (Addition order and addition amount) Further, each of the reactions used in the above-mentioned step 1 is carried out. The components, that is, the order of addition of the phase transfer catalyst (B), the aromatic hydrocarbon solvent (c), the substitution of the Hi triazole-5 ketone derivative (II), and the metal hydroxide (4), are not particularly limited. In the present invention, for example, in the aromatic hydrocarbon ((:) of the solvent, the above-mentioned substitution is added to the normal temperature and the normal pressure, and the derivative (1) / alkali metal is added. The hydroxide (A) and the phase transfer catalyst (B) are then heated to the above temperature under normal pressure and stirred to dissolve or disperse the components, preferably in the reaction. The raw material used 取代-substituted-triazole-5-ketone derivative (II), alkali metal hydroxide (A), phase transfer catalyst (B), and volume

The amount of the agent (C) or the type of the amine helium (ΙΠ) used in the step 2 is as described above. , S (sub-formed water) In this step 1, it is necessary to make the substitution of -1,2,4-three, and the derivative (II) reacts with the alkali metal hydroxide (A). The water produced by the sub-generation 322217 20 201141842 is removed from the reaction system by azeotropic distillation together with the aforementioned solvent (c). In the first step, in the reaction of the compound (II) with the metal hydroxide (A), the water formed by the reaction is continuously removed from the reaction system by azeotropic distillation, and can be efficiently produced. Alkali metal salt (Ila). The alkali metal salt (Ila) which produces such a reaction intermediate in the step 1 is as described above, and can be confirmed by the formation of water. Further, in the reaction of the compound (II) with the alkali metal hydroxide (A), the organic solvent (C) is not removed when the by-product water is removed from the reaction system together with the organic solvent (C) by azeotropic distillation. Since the aromatic hydroxyl group forms an azeotropic mixture with water, the boiling point is lower than that of the single phase system of only the organic solvent (C), and as a result, the reaction temperature is lowered. Therefore, the reaction speed is slow. The end point of the reaction in the step 1 can be judged from the decrease or the stop of the amount of the by-produced water. In the present invention, the alkali metal salt (11a) obtained in the above step 1 is further contained, and further contains a phase transfer catalyst (B), a solvent (C), an excess amount or an unreacted raw material compound (compound (II) The reaction mixture (reaction liquid) such as metal hydroxide (A)), if the convenience of the management of the steps and the rapid and efficient reaction, etc., are generally used directly in the second step 2, but The metal salt (Ila) of the 1-substituted-1,2,4-tris-s--5-one derivative (II) is purified and fractionated, and is used in the next step 2. In such a step 1, it is preferable to use a Dean Stark type device. The apparatus is a method for separating the azeotropically distilled mixture into an organic solvent and water, and only returning the organic solvent to the apparatus of the reaction pot almost completely, and returning the amount of the organic solvent not returned to the reaction pot, which is required for the reaction. The amount of organic solvent 21 322217 201141842 agent is a small amount of negligible. &lt;Step 2&gt; Next, the present invention is a 1-substituted-triazole-5-ketone living organism in the aromatic hydrocarbon solvent (C) in the presence of the aforementioned phase transfer catalyst (8). The test metal salt (1) a) is reacted with the amine-based chlorinated chlorine represented by the above formula (1) n, and the purpose of the preparation is to replace the _4-aminomethylmethyl hydrazine-, 2, triazole-5-one derivative ( I). The reaction of the second step is generally carried out by adding the aminoguanidine gas (1) (3) moxibustion to the reaction mixture (reaction liquid) obtained in the above step i. In the present invention, 'the reaction mixture containing the metal salt (1) a) used as the raw material in the step 2 is substantially water containing only a small amount (for example, weight/below 'preferably 5% by weight or less). , or completely absent (= 〇 weight%) is better. The amine-based helium (III) is previously dissolved in a small amount (about 1/2Q to (four) of the amount of the solvent in the step 1) of the solvent (C), and may be added to the reaction obtained in the first step. In the mixture (reaction liquid), such a method is preferable from the viewpoint of work efficiency (rapidity). Further, if necessary, the solvent (C) and the phase transfer catalyst (B) may be added, and then the reaction of the step 2 may be carried out. Further, it is also possible to reduce the raw material (derivative (11), metal hydrogenation by a small amount of by-product water remaining from the reaction mixture (reaction liquid) obtained in the above step 1 or by using an excess amount or the like. Oxide (1), etc., the real temporary temple knife to replace the ~1,2,4-three sputum sitting -5- 酉 same derivative of the test metal 趟f T丨\ ^ a 'then' to make this alkali metal salt (Ila) The presence of the derivative (I) which is reacted in the solvent (6) in the presence of the phase transfer catalyst (B) is produced in the same manner as the amine ruthenium chloride (III) 22 322217 201141842. "In this case, the phase transfer catalyst (β,) and the solvent (c,) used in the above-mentioned step 1 may be the same or different, but if they are the same, then this is the management of the amount, etc. It is preferable in terms of management convenience, etc. (conditions of temperature, pressure, time) In the appropriate aspect of the present invention, as in the foregoing, in the reaction mixture obtained in the step i and containing the metal salt (1) a), an amine group is added. Brewing chlorine GII) to / (15 to 25C) to solvent (boiling point of boiling point, preferably "5〇C" to the boiling point of bath (C)", more preferably "ribs" to "solvent" The reaction at the boiling point of the temperature can be used to produce the above-mentioned substituted 4-4-amino T-mercapto-1,2,4-triazol-5-one derivative (I). Further, the reaction of the step 2 is generally as usual. It can be carried out under pressure (standard atmospheric pressure, 1013. 25hPa), but it can also be carried out under pressure. The reaction under normal pressure is handled in the process of step management, etc., and the workability is also good. Depending on the temperature and pressure, it can be carried out in the above range (temperature, pressure), for example, from 1.0 to 4.0 hours. The end point can also be judged according to the above reaction time, but by HPLC (for example, HPLC system manufactured by Shimadzu Corporation), inspection / JSPD 1 〇AVP, pump LC-10 ATVP, column oven Q〇 It is preferable to judge by the analysis of _i〇ASVP). Specifically, the reduction of the HPLC area% value of the aminoguanidine gas (ΠΙ) which is one of the reaction raw materials is stopped, and the target substance is substituted with -4- The increase in the HPLC area % value of the aminomercapto-1,2,4-tris-s--5-one derivative (I) was stopped and it was judged that the reaction was terminated. 322217 23 201141842 Further, as described in the aforementioned Patent Document 2 In the production method, the by-produced water is not removed from the reaction system, and even if the reaction is continued, the target product of the 1-substituted 4-aminocarbamoyl group can be produced by the effect of the phase transfer catalyst (B). 1,2,4-triazol-5-one derivative (ί). However, in the aforementioned reaction (step 2), if water is present in the reaction system (in step 1, 'the step 2 is not removed without removing water) In addition to the alkali metal salt (na) of the 1-substituted-1,2,4-triazol-5-one derivative (π) which produces the main reaction, and the aminomethyl sulfonium (III) The reaction, but also competing (hostile;) the decomposition reaction of the compound (ΙΠ) which reacts with the amine-based helium (ΠΙ) by side reaction, and the replacement of the water and the target substance _ Decomposition reaction of the compound (ί) of the reaction of 4_aminomethionyl-1,2,4-dioxa-5-one derivative (I). The experimental scale of the general degree of progress (example: reaction pot area: 〇 丨 丨 10 10 10 10 10 10 10 丨 丨 10 10 10 10 10 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因It can be seen that the yield is greatly reduced. Therefore, in the case of the reaction solvent (C), water is not used in the present invention, and water formed by the reaction by the reaction is removed from the reaction system by azeotropic distillation with the reaction solvent (c). When the decomposition of the target substance (1) is suppressed in 2, and the decomposition of the aminoguanidinium chloride (ΠΙ) of the reaction raw material is prevented, the decrease of the reaction (4) can be prevented from proceeding, and the decomposition of the red by-product is reduced. The purity of the object (I) can be further improved. In addition, when the reaction of the field J exceeds the above range and the alkali (alkali metal oxychloride (A)) is excessively used, the influence is particularly large. 322217 24 201141842 Further, the amine ruthenium chloroformate (III) is slowly decomposed by an alkali metal hydroxide. Therefore, if the reaction rate is slow, only the amino group of the oxime group (III) is decomposed. When the amount is increased, the matter is related to the decrease in the yield of the reaction and the purity of the target. In this case, when the by-produced water is removed from the reaction system by azeotropic distillation, the reaction solvent is substantially as described above. In the single-phase system of the solvent, the boiling point is increased, and as a result, the reaction rate may increase while the reaction temperature rises. Therefore, the reaction time is shortened, the reaction efficiency (conversion rate) is increased, and the yield of the target product is also increased. Further, the purity of the object can be improved. Therefore, in the present invention, in the step 1, the reaction of the alkali metal salt (IIa) of the substituted triazol-5-one derivative (II) is formed in the phase. In the presence of the transfer catalyst (B), the water produced by the sub-generation is continuously reduced and removed from the reaction system by the distillation together with the dissolution (C), and is then known in step 2. In the reaction mixture, When the reaction is carried out as described above after the addition of the aminoguanidine group (I η ), the influence of the side reaction (hydrolysis reaction, etc.) as described above can be suppressed, and as a result, the target substance can be promoted to replace the 4-aminocarbamoyl group. Reaction yield and purity of the -1,2,4-triazol-5-one derivative (I). In the manufacture of the object compound (1), a series of reaction temperature-specific chambers of steps 丨 to 2 Warm to the temperature of the solvent (6) (four) point, preferably 2 (rc to the solvent (6) point. The reaction time is based on the reaction temperature or the compound (11) (1-substituted 4,2,4-triazolone derivative ( 11)), aminoguanidinium chloride group), solvent (C), metal hydroxide (4) catalyst 322217 25 201141842, etc., etc., but the total of steps 1 to 2 is generally 3Q minutes Up to 6 hours, most of the time is about 3 minutes to 4 hours. (Refining step) u, after the series of reactions in this step 1 to 2 are terminated, the excess used in the reaction; Substituting _!, 2, 4_3. Sitting __5_嗣 derivative (1)), metal hydride (A), phase transfer catalyst (B) sometimes remaining in the group containing a 4-amino group Acyl-1,2-trimethyl laugh -5 derivative ⑴ reactants. The residue which is contained in the reactants is substituted with 丨 三 三 三 =1 =1 = 1) when the amount of alkali metal hydroxide (A) is excessively used in the reaction, as 1 (1 substituted -1' 2, 4- 3 The alkali metal salt (Iia;) of the oxazol-5-one derivative (Π) exists in the form of a 4-aminomethylmercapto-purine, 2 4_three wow-5-saki creature (1) The refined step material is subjected to a water washing operation, which can be easily removed by an aqueous solution. The sentence is replaced by an aqueous solution, and the metal salt (IIa) of the 2, 4_three-shirt (1) is used as the aqueous solution. It is made acidic by hydrochloric acid and ^, and it is precipitated by substituting Sanwa phase = crystal, so it can be recovered by filtration and used. )of,,,. Further, the liquid separation in the purification step of the object (I) is generally carried out under normal urine temperature, but the metal hydroxide (4) can be water-soluble under heating (under the house) as desired. By the operation of the above-mentioned organism (II)_(IIa), it can be simultaneously changed, and 322217 26 201141842, a derivative of (1), can be simultaneously removed as an aqueous solution. The loss of the target (1) produced by the washing treatment of the mixed solid or the recrystallization is only a little 'can be high yield (example: (10) to 95%) and high purity (eg. 99.0 to 99.8 ( %)) The target compound is substituted for the +aminomercapto-1,2,4-triazol-5-one derivative (!), [Examples] Hereinafter, the present invention will be described in more detail by way of examples. The present invention is not limited by the following examples as long as the gist of the invention is not exceeded. Further, in the present invention, various compounds (II), compounds (III), and alkali metals as described above are arbitrarily selected. The hydroxide (phantom, aromatic hydrocarbon solvent (C) and phase transfer catalyst (B) can be produced by the method of the examples shown below The desired compound (I) was obtained in the same manner as in the examples. The analysis of the reaction and the purity was carried out using the high-speed liquid chromatography (hplc)* under the following conditions: [Synthesis Example 1] 1-(2, 4 The synthesis reaction and purity analysis of -dichlorophenyl)-1,2,4-tris-β-ketone-5-ketone were carried out under the following conditions using high-speed liquid chromatography. The device was manufactured by Shimadzu Corporation. HPLC system, UV detector; SPD-10 AVP, pump; LC-10 ATVP, column oven; CTO-10 ASVP, column; GL Science Inertsil ODS-3 (particle size of column packing; 5 // m, column inner diameter; 4. 6mm, column length; 250mm), UV detection wavelength; 254nm, mobile layer solvent capacity ratio and flow rate; acetonitrile: distilled water = 6〇: 4〇, 322217 27 201141842 1. Oml/min (in the case of the first intermediate product analysis), decyl alcohol: distilled water = 10:3, 0.5 ml/min' (in the case of the second intermediate product triazolidine, analysis of the objective compound) Yamat〇 Science (shares) melting point tester MP-21 'Quality 5 general use Japanese electronic (stock) mass spectrometer SUN-20 0 and In a reaction tank of 2000 liter capacity, add 2 丁 2 of butanol and 2,4-dichlorophenyl hydrazine hydrochloride 501^(234 2111〇1), nitrogen substitution. Then, at 25C Next, a solution of 9. 8 kg (245. 9 mol) of sodium hydroxide dissolved in 50 kg of water was added in one portion. After stirring at 25 ° C for 10 minutes, it was cooled to l〇t, and 36% aqueous solution of furfural was added dropwise over 30 minutes. 5kg (245. 9 mol). After the completion of the dropwise addition, after stirring at 10 ° C for 30 minutes, a small amount of the reaction mixture was sampled, and a solution dissolved in an appropriate amount of acetonitrile was analyzed by HpLC to confirm that the starting material of 2, 4-diphenylphenylamine was The area % composition of 0.2% (holding time 6.6 minutes) and the 2,4-diphenyl phenylamine aldehyde hydrazine oxime of the first intermediate product was 97% by weight (holding time of 15.1 minutes). Then, after adding sodium cyanate (s〇djum cyanate UQ. ikg (309. 2mol) in an aqueous solution of 8〇kg of water at 1〇c, immediately, 18.4kg (306.7mol) of acetic acid was simultaneously at the same temperature. Then, the temperature of the reaction mixture was raised to 25 = c. After stirring for 2 hours, the reaction mixture was sampled in small amounts, and the solution dissolved in an appropriate amount of sterol was analyzed by HPLC to confirm that The product of 2,4-dichlorophenyl hydrazine furfural oxime was 2.0% (retention time 20.8 minutes), and the second intermediate product of 2, 4-diphenyl phenyl oxazolidinone was 93. 〇% ( Hold time 7.4 minutes) 322217 28 201141842 area % composition. Then, the reaction mixture was further cooled to 1 Torr, and 5% (5%, 239. After the completion of the reaction, the mixture was stirred for 1 hour under ίοc, and further stirred at 25 ° C for 4 hours, and then the reaction mixture was sampled in a small amount, and the solution dissolved in an appropriate amount of methanol was analyzed by HPIX to confirm the second intermediate product. 2,4_digas base bis(tetra)ketone is 〇·5% (holding time 7.4 minutes), 1-C2, 4~1 of the target compound Phenyl) -1 2 4-- I Γ · 'saliva two 5-one derivative is 90.0% (retention time 8.6 minutes) of the area of disabilities. ,, and integrated into. Brown crystals were precipitated during stirring, and the precipitated crystals were filtered and washed with water. The singularity &amp; θ was air-dried to give the title compound 46. 8 kg (yield 87%). The purity, melting point and mass spectrometry data of this compound are described below. Purity: 97.2%, melting point: 188 to 189. (:, EI-MS: m/z229 M+ [Synthesis Example 2] Synthesis reaction and purity analysis of N-isopropyl-N-2,4-difluoro-p-benzylaminopyridinium chloride using gas chromatography And the following conditions are used for the 0 device. (Shares) Shimadzu Manufacturing Co., Ltd. Gc_14B, column: g_i〇〇(10)^

Length 2〇m, FilmThickness〇· 5_, iDi2mm), analysis conditions; 80°C (Initial), 20°/male, 曰. , υ / knife clock, (heat up to 280 C (Final)), detector: TCD (300 〇 C), carrier gas. 翕r9n, / \ also, autumn milk '虱 (20ml / min), and, compound The mass spectrum was measured using a Japanese Electronics Co., Ltd., τ, and a machine 贳I analyzer SUN-200. [Synthesis Example 2-1] Synthesis of N-isopropyl-N-2,4-difluoroaniline In a reaction volume of 200 liters, 2,4-dimeramide 4 〇kg was added 322217 29 201141842 (310. Lmol)^ 2~^ ^ ^ (isopropyibr〇niide) 18kg (146 3 m〇1) 'Start heating. The temperature rises slowly, and at the time of it KOt: - 28 kg (227·) of 2-bromopropene is kept at i赃, and a small amount is dropped in a small amount. The whole amount was dripped in 4 hours, and the temperature was further increased by heating at (10) °C for 3 G minutes to generate a gas desert suspension of N_iso-diyl-N_2,4-dianiline. Take a small amount of the reaction suspension as a sample, and add an appropriate amount of 25% of the oil to be separated from the gas. The oil was analyzed by gas chromatography to confirm that the raw material of 2,4-difluoroaniline was 5.2%. The reaction time was terminated by maintaining the time of 3.5 minutes), the isopropyl group of the objective compound, and the area % composition of 91% by weight (holding time of 5.1 minutes). After the end of the reaction, the reaction mixture was cooled to IGOt, and 4 kg of water was added to dissolve the hydrogen salt of N-isopropyl 12' 4-di-amine. Then, after the reaction mixture was cooled to 25 ° C, 54.6 kg (341.3 m Torr) of a 25% aqueous sodium hydroxide solution was added, and the mixture was stirred at 25 C for 20 minutes to obtain an organic layer and an aqueous layer. The obtained aqueous layer was extracted with 8.5 kg of toluene 2: owed. The obtained organic layer and the benzene layer of the extracted aqueous layer were washed twice with saturated brine 丨〇kg twice, and when the toluene was removed under reduced pressure (pressure θ: 40 kPa), a reddish oil was obtained. The target product was isopropylidene-indole-2, 4-difluoroaniline 50.6 kg. When the residue was purified by distillation under reduced pressure, N-isopropyl_N-2,4-difluoroaniline 47. lkg (yield 88.7%, boiling point 86 to 87ΐ/2. 4kPa). The purity and mass spectrometry data of this compound are described below. Purity: 99.9%, EI-MS: m/zl71 M+ [Synthesis Example 2-2] Synthesis of N-isopropyl-N-2, 4-difluorophenylamine helium 322217 30 201141842 at 250 To the reaction volume of the reaction steel, 45 kg (263.2 mol) of N-isopropyl-N-2,4-difluoroaniline and 90 kg of toluene were added. Then, while the solution of 27.30 kg (92. lmol) of triphogen dissolved in 55 kg was kept at 20 to 30 ° C, it was added dropwise over 1 hour. After the completion of the dropwise addition, the temperature was raised to 110 ° C and reacted for 2 hours. 2%(保持时间5. 0分钟), The N-isopropyl-N-2,4-difluoroaniline was 2. 2% (holding time 5. 0 minutes), The target N-isopropyl-N-2,4-difluorophenylaminocarbazide chloride was composed of an area % of 92.6% (holding time 6.2 minutes) to terminate the reaction. After the completion of the reaction, the hydrazine was removed under reduced pressure (pressure: 40 kPa) to obtain the object of the brown oil. N-isopropyl-N-2,4_di-phenylamino ruthenium chloride 62.0 Kg. The product is purified by steaming with a reduced pressure to obtain the object N-isopropyl-N-2, 4-diphenylbenzene as a colorless oil.

The base amine helium gas is 50. 4 kg (yield 82.0%, boiling point 120 to 125. (: /〇. eY kPa).

The purity and mass spectrometry data of this compound are described below. Purity: 99.7%, EI-MS: m/z233 1T

[Examples] The analysis of the reaction and the purity was carried out under the following conditions using high-speed liquid chromatography (HPLC). Device: Shimadzu HPLC system, UV detector; SPD-10 AVP, Lipu; LC-10 ATVP, column oven; CTO-10 ASVP, column; GL Science

Inertsil 0DS-3 (particle size of column packing: 5/xm, inner diameter of tube 4.: 4. 6mm, length of column: 250mm), UV detection wavelength: 254nm, mobile layer solvent capacity ratio and flow rate; acetonitrile: distilled water =50: 50, 1.5 ml/min 曰 322217 31 201141842 Further, the melting point of the compound was measured using a Yamato Scientific melting point measuring instrument MP-21, and the mass spectrum was measured using a Nippon Electronics Co., Ltd. mass spectrometer SUN-200. [Example 1] 1-(2,4-diphenylphenyl)-4-(N-isopropyl-N-2,4-difluorophenylaminocarboxamyl)-1,2,4- Manufacture of 5-ketone ketone; in a 1000 liter capacity reaction vessel equipped with a Dean-Stark type azeotropic distillation apparatus, 500 kg of toluene is placed, and chlorophenyl)-1,2,4-tri Oxazol-5-one 501^(217.4111〇1), sodium hydroxide 8.71^ (217.4mol) and tetra-n-butylammonium bromide 7.0kg (21.7in〇1) at room temperature (20 C) Add in order and start heating while stirring vigorously. If the temperature of the reaction mixture begins to exceed 80t:, the azeotrope of A stupid and water begins to slowly relax in the dehydration unit. If the temperature of the mixture is increased to 110t after the addition of the mixture, there will be '3 9kg during this period. The water is distilled off. Then, in this reaction mixture 100 Torr, a solution dissolved in a sputum-isopropyl-hydrazino-phenylamine helium 5 〇.8 anvil (2) 74 mol) was added over 30 minutes, while stirring vigorously. Take 反应 it reacts for 2 hours. After the reaction temperature reached 11 (rc i hours, a small amount of the reaction mixture was taken as a sample, and the liquid transferred to the appropriate amount was compared by the results of the analysis of the ruthenium diisopropyldifluorophenylamino group. Hyperbarium gas is 0.5% (holding time 丨9.88, compound ««, 卜二气phenyl (4)~ 笨 基 冬 ^ ^ ^ ^ ^ ^ ^ ^ ^ -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 It is 97% (% (in the case of "6. 322217 32 201141842"), and the area is not changed, so it is confirmed that the reaction is finished. After the end of the water reaction, the temperature of the reaction mixture is cooled to 85. 〇, add 10 side The temperature was maintained at 50 to 6 (rc, and the mixing was stopped while stirring vigorously, and the reaction mixture was separated into the upper layer of the benzene layer and the water layer of the pot, and the water layer was taken out. The reaction product (the benzene layer) was added to the water while the temperature was maintained at 6 Torr. (~&gt;, p ^ i ' while stirring vigorously for 10 minutes, the enthalpy of removing the separated aqueous layer was repeated twice. Then, 'from the mixture remaining in the reaction pot (the benzene layer), distilled under pressure (pressure · · 4 kPa) After 400 kg of sputum, it is usually 75 to 8 Torr while stirring. (: After adding 370 kg of hexane, it is cooled to 5 to 1 Torr. (: The solids precipitated to 5 are taken out from the reaction vessel under normal pressure, Filtration, cooling 1 (Γ (: sterol 90kg washed, dried at 40 to 50 ° C, get

° The target compound (solid) 88.2 kg (yield 95%). The compound t purity, K 'tower' point and mass spectrum data are described below. "Going to" purity: &quot;· 8%, melting point: 129 to 13 (TC, EI-MS ·· m/z 426 M+ L Example 2]

Gas-based)-4-(N-isopropyl-N-4-fluorophenylaminocarbazinyl) π-spin-5~ ketone manufacture; &amp;θ; with azeotrope with Dean-Stark type In a 1000-liter reaction vessel of the steaming unit, 500 kg of hydrazine was added, and 1-(2,4-dichlorophenyl)- 1 2 my~-flavor-5-ketone 50 kg (217. 4 mol), sodium hydroxide was placed. 8. 7kg of 6.4m〇1) and tetra-n-butylammonium bromide 7. 0kg (21. 7mol) were added sequentially under normal pressure (2 〇c), and heating was started while vigorously mixing. If 33 322217 201141842 reaction mixture temperature begins to exceed 8 〇 v, the accompaniment is dehydrated and shaken (10), and the surface temperature is increased to n〇t ' at the meeting: :,: Distillation of water. j mine has 3. 9kg then, the reaction mixture j〇〇tt &gt; g work w to toluene 25k§ isopropyl-N-4 fluorophenylaminocarbazide 46 8kg (2) 7. such as (4) solution After adding for 30 minutes, U (rc reaction was carried out for 2 hours while stirring vigorously. After the reaction temperature reached 11 hrs and 2 hours, a small amount of the reaction mixture was taken as a sample to dissolve the solution in an appropriate amount of acetonitrile. When compared by the results of HPLC analysis, the Ν_isopropyl_Ν_4-fluorophenylamino oxime was 0.3% (holding time; [7. 9 minutes), the target compound (2'4) -2,2,4,4-triazol-5-one is 97.4% (holding time 23.0 minutes) The 〇/〇 composition was not changed, so it was confirmed that the reaction was completed. After the reaction was completed, the temperature of the reaction mixture was cooled to 85 ° C, and 150 kg of water was added thereto while maintaining the temperature at 5 Torr to 6 (rc, while stirring vigorously for 10 minutes). The stirring was stopped, the reaction mixture was separated into the upper layer and the lower layer, and the aqueous layer was taken out. The same as before, the mixture was left in the reaction pot. The compound (toluene layer) was stirred for 150 minutes while maintaining the temperature at 50 to 60 Torr, and the operation of removing the separated aqueous layer was repeated twice. ' Then' from the mixture remaining in the reaction pot ( The benzene layer was distilled off under reduced pressure (pressure: 40 kPa), and then stirred at a pressure of 75 to 80 at normal pressure ((: after adding 350 kg of hexane, cooling to 5) l (rc. 34 322217 201141842 The solid precipitated from the reaction pot was taken out under normal pressure, filtered, washed with 80 kg of methanol cooled to 5 to 10 ° C, and dried at 40 to 50 ° C to obtain the purpose of marking. The compound (solid) 82.7 kg (yield 93 ° /.). The purity, melting point and mass spectrum data of the compound are described below. Purity: 99.7%, melting point: Π0 to 172 °C, EI-MS: m /z 408 M+ [Example 3] 1-(2-Chlorophenyl)-4-(N-isopropyl-N-2,4-difluorophenylaminocarbamido)-1,2, 4 -Production of triazole-5-one; In a reaction vessel having a 2-liter capacity equipped with an azeotropic distillation apparatus of the Dean-Stark type, 600 kg of toluene was placed, i-(2-phenylphenyl) -1,2,4-tris-5-one 601^(30 6.9〇1〇1), sodium hydroxide 12.31^ (306.9m〇l) and tetra-n-butylammonium bromide 9.9kg (3〇. 7 mol) in normal pressure at room temperature (20 ° C) Adding, heating is started while stirring vigorously. If the temperature of the reaction mixture starts to exceed 80 曱, the mixture of hydrazine and water starts to be slowly distilled off in the dehydration device, and if the heating is continued for 2 hours, the temperature of the reaction mixture rises to 1 HTC. 'There will be 5 5kg of water distilled during this period. Then, in the reaction mixture HKTC, a solution of 71.7 kg (3〇6.s mol) of N-isopropyl-Ν-2ϋphenylaminoglycol in toluene was added for 3 minutes, and then - While vigorously mixing, 11 〇t: reaction for 2 hours. After the reaction temperature reached 11 (rc! hours and 2 hours later, the amount of the anti-anchor compound was taken as a sample, and the solution was dissolved in an appropriate amount of the solution of the B guess by the HPLC analysis of the knot (four). Propyldifluorophenylaminocarbazide is 0.4% (holding time 19·7 minutes), and the target is 322217 35 201141842 1-(2-phenylene)-4-(N-isophenyl-N) -2, 4-di-Itylphenylaminoindenyl-1,2,4-triazol-5-one was 97.0% (holding time 15.8 minutes). The area % composition did not change, so the reaction was confirmed. After the completion of the reaction, the temperature of the reaction mixture was cooled to 85 ° C, 200 kg of water was added, and the temperature was maintained at 50 to 60 ° C while stirring vigorously for 10 minutes. The stirring was stopped to separate the reaction mixture into the upper layer of toluene. After the water layer of the layer and the lower layer, the water layer was taken out. In the same manner as before, 150 kg of water was added to the mixture (the benzene layer) remaining in the reaction vessel, and the temperature was maintained at 50 to 60 ° C while stirring vigorously for 10 minutes. The operation of removing the separated aqueous layer was repeated twice. Then, from the mixture remaining in the reaction vessel (the benzene layer), under reduced pressure (pressure Force: 40 kPa) 500 kg of toluene was distilled off, and while stirring, 400 kg of hexane was added at 75 to 80 ° C under normal pressure, and then cooled to 5 to 10 ° C. The precipitated solid was reacted under normal pressure. The product was taken out, filtered, and washed with 100 kg of methanol cooled to 5 to 10 ° C, and dried at 40 to 50 ° C to obtain the title compound (solid) 11.0 kg (yield 93%). Purity, melting point and mass spectrometry data are described below. Purity: 99.8%, melting point: 146 to 147 ° C, EI-MS: m/z 392 M+ [Example 4] 1-(2,3-dimethyl Manufacture of phenyl)-4-(N-isopropyl-N-2,4-difluorophenylaminocarbamimidyl)-1,2,4-triazol-5-one; - In a 2000 liter capacity reaction vessel of a Stark-type azeotrope unit, 550 kg of diphenylbenzene was placed, and 1-(2,3-dimercaptophenyl)-1,2,4-tris-sal-5 was placed. -ketone 55kg (291. Omol), sodium hydroxide 11.6kg 36 322217 201141842 (291.0mol) and tetra-n-butyl bromide 9 9kg (29.lm〇1) under normal pressure at room temperature (2GC) Under the order of adding people's - intense stirring - start heating. If the temperature of the reaction mixture begins to exceed 8 ° C, xylene The azeotrope with water begins to slowly relax in the dehydration unit. If the heating is continued for 2 hours, the temperature of the reaction mixture rises to 144 tons, during which time 5 water is distilled off. Then, the reaction mixture is 100°. In C, the solution of isopropyl 12,4-di-tert-phenylamino group: 6-branched chlorine 67.9_91 溶解 dissolved in xylene is added in 3 g minutes, and then stirred for 14 generations. 2 hours. After the reaction temperature reached 14 generations for 1 hour and 2 hours later, the amount of the reaction mixture was used as a sample to dissolve in the # — 、, Ν 异丙-isopropyl-Ν-2, 4- = 本 曱G.7% (holding time Μ minute), the purpose of stupid amino-methyl thiol "" Λ 异 异 苯基 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 The face lion (keeping time. Knife clock) was not changed, so it was confirmed that the reaction was over. After the water 2 (^ should be finished), the temperature of the reaction mixture is cooled to 85 ° C, and the temperature is maintained at 5 G to _... while stirring vigorously; the inside: if mixed 'to separate the reaction mixture into the upper layer of xylene Should be pot; mixed butterfly; ^) plus = before the same, in the remaining 15_, - while the edge of the temperature (four) layer of the fiber for 1Q minutes, remove the separated water and then from the remaining in the reaction pin (2 曱 曱 layer), after subtracting 322217 37 201141842 under pressure (pressure: 30kPa), distilling off 500kg of dimethyl benzene, and stirring, while adding 400kg of hexane at 75 to 80 ° C under normal pressure, cooling To 5 to ΙΟ. . . The precipitated solid is taken out from the reaction vessel under normal pressure and filtered, and washed with 90 kg of sterol cooled to 5 to 10 ° C, and dried at 40 to 50 t to obtain a labeled target compound (solid) 103. 3 kg (yield 92%). The purity, melting point and mass spectrometry data of this compound are described below. Purity: 99.6%, melting point: 109 to ll 〇〇 C, EI-MS: m/z 386 M+ [Comparative Example 1] 1-(2, 4-diphenyl)-4-(N-isopropyl Production of benzyl-N-2,4-difluorophenylaminoindenyl-1,2,4-triazol-5-one (method described in Patent Document 2); in a reaction vessel of 1000 liter capacity 'Into the benzene 5 〇〇 kg, 1- (2, 4-diphenyl)-1,2,4-triazol-5-one 50 kg (217. 4 mol), sodium hydroxide 8.7 kg (217.4 Mol) and tetra-n-butylammonium bromide 7. 0 kg (217 m 〇 1) were added sequentially at room temperature while vigorously stirring at 9 Torr. 〇 Heated for a few hours. The reaction mixture was left to cool to 6 (TC), and dissolved in a solution of 25 kg of N-isopropyl-N-2,4-difluorophenylaminocarbazide 5 〇. 8 kg (217. 4 mol) of the solution. After 30 minutes of addition, it was heated at 9 ° C for 6 hours while stirring vigorously. After the reaction temperature reached 9 ° C for 5 hours and 6 hours, a small amount of the reaction mixture was taken as a sample to dissolve in an appropriate amount of acetonitrile. 4%(保持时间1. 9分钟), 1 of the target compound, when the solution was compared by the result of the HPLC analysis, N-isopropyl N-2, 4-fluorobenzamide A formazan gas was 2. 4% (holding time 19.8 minutes) -(2, 4-dioxaphenyl)_4_(n-isophenyl_N-2,4-H-phenylaminoindenyl)-1,2,4-triazol-5-one is go.面积% (holding time 322217 38 201141842 between 29.6 minutes) The composition of the area % is not changed again, so the reaction is confirmed. After the reaction is completed, 150 kg of water is added while maintaining the temperature at 5 〇 to 60 ° C while stirring vigorously. After 10 minutes, the stirring was stopped, and the reaction mixture was separated into an upper layer of a benzene layer and an aqueous layer of the lower layer, and then the aqueous layer was taken out. The mixture remaining in the reaction vessel (toluene layer) was added in the same manner as before. 150 kg of water and vigorously stirred for 10 minutes, and the operation of removing the separated aqueous layer was repeated twice. Then, 400 kg of toluene was distilled off from the mixture remaining in the reaction vessel (peptone layer) under reduced pressure (pressure: 40 kPa). After adding 370 kg of hexane at 75 to 80 ° C while stirring in the mixture remaining in the reaction pot, it was cooled to 5 to 10 ° C. The precipitated solid was taken to cool to 5 to 1 〇 ° c After washing with 80 kg of methanol, it is dried at 40 to 50 ° C to obtain 69. 6 kg (yield: 75%) of the title compound solid. The purity, melting point and mass spectrometry data of the compound are described below. Purity: 99. 6 %, melting point: 129 to 13 (TC, EI-MS: m/z _ M+ Comparative Example 1 is an unsubstituted-1,2,4-triazole-5- which is only subjected to the step of removing water from Example 1. When the ketone derivative was compared with the comparative example i, it was found that the target compound was obtained in a high yield by removing the water formed by the reaction, and the reaction was not removed in Comparative Example 1. The water generated by the sub-generation cannot make the reaction temperature higher than 90 degrees, thus making the reaction time longer. Ming] No. [Main component symbol description] No 0 322217 39

Claims (1)

201141842 VII. Patent application scope: l - A method for producing a hydrazine-substituted _4_amino fluorenyl bis--5--derivative represented by the following formula (I), characterized in that it is selected from four In the presence of at least one phase transfer catalyst in the group of the ammonium salt and the scale salt, in the aromatic hydrocarbon solvent, (a) substituted with the formula (1) below, -1, 2, The 4-triazol-5-one derivative is reacted with (b) the alkali metal hydroxide-surface by a side of the water which is co-formed, and the following formula is added to the reaction mixture ( The amine group helium shown in 1 (1) and reacts; [In the formula (1), 'x represents a halogen atom or a lower leuko group, γ represents an i atom, and r represents a lower alkyl group, and n and m each independently represent an integer of 0 to 5,] [in the formula (II), X and η are Synonymous with the above formula (1)] cTs~Ovm [In the formula (III), 'Y'RAn^ is synonymous with the above formula (1)]. 322217 40 201141842 2. A method for producing a substituted 4-aminomethylmercapto-1,2,4-triazol-5-one derivative according to claim 1, wherein the aromatic hydrocarbon The solvent is toluene and/or xylene. 41 322217 201141842 IV. Designated representative map: There is no schema in this case. (1) The representative representative of the case is: ( ). (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 3 322217