TWI402260B

TWI402260B - Method for producing phenyl triazolinone

Info

Publication number: TWI402260B
Application number: TW98100577A
Authority: TW
Inventors: Tsunehiro Kido; Hiroyuki Okita
Original assignee: Hokko Chem Ind Co
Priority date: 2008-01-10
Filing date: 2009-01-09
Publication date: 2013-07-21
Also published as: CN101910139A; JPWO2009088025A1; CN101910139B; JP5167283B2; WO2009088025A1; TW200934764A

Description

苯基***啉酮類之製造方法Method for producing phenyl triazolinones

本發明有關於苯基-1,2,4-***啉-5-酮類之製造方法，更詳之，有關於作為醫藥及農藥之合成用原料或中間體有用化合物之苯基-1,2,4-***啉-5-酮類之製造方法。The present invention relates to a method for producing phenyl-1,2,4-triazolin-5-ones, and more particularly to a phenyl-1 which is a useful compound for the synthesis of raw materials or intermediates for medicines and agricultural chemicals, A method for producing 2,4-triazolin-5-ones.

苯基-1,2,4-***啉-5-酮類(下文中，簡稱為苯基***啉酮類)乃作為醫藥及農藥之合成原料或中間體有用化合物，一向有各種製造方法。Phenyl-1,2,4-triazolin-5-ones (hereinafter, abbreviated as phenyltriazolinones) are useful as synthetic raw materials or intermediates for medicines and pesticides, and various manufacturing methods have been used. .

例如PCT國際公告WO98/38176號公報(參照專利文獻1)中記載藉由下列反應製造苯基***啉酮類。For example, PCT International Publication No. WO 98/38176 (see Patent Document 1) discloses the production of phenyltriazolinones by the following reaction.

(式中，n表示0或1至5之整數，X可為相同或不同，分別表示鹵素原子、低級烷基、低級鹵烷基等。)(wherein, n represents 0 or an integer of 1 to 5, and X may be the same or different and each represents a halogen atom, a lower alkyl group, a lower haloalkyl group, etc.)

然而，依照該專利文獻1所記載方法，反應步驟中需要分離苯腙(A-3)，另外，製造時使用昂價之環偶氮化二苯基磷醯(A-4)，製造苯基***啉酮(A-5)之成本很高。However, according to the method described in Patent Document 1, it is necessary to separate phenylhydrazine (A-3) in the reaction step, and to produce a phenyl group by using an inexpensive cyclophosphazene diphenylphosphonium (A-4). The cost of triazolinone (A-5) is high.

因此，專利文獻1中所記載上述方法難言為工業上有益之製造方法。Therefore, the above-described method described in Patent Document 1 is hardly an industrially advantageous manufacturing method.

另外，PCT國際公告WO02/12203號公報(專利文獻2)中記載具有於製造一般式(B-1)所示芳基***啉酮類之際，先將芳基腙(B-3)和氰酸鹼金屬鹽及酸反應，形成芳基***烷酮(B-2)，繼之，跟氧化劑反應之步驟之製造方法。In addition, in the case of producing an aryl triazolinone of the general formula (B-1), PCT International Publication No. WO02/12203 (Patent Document 2) discloses an aryl ruthenium (B-3) and A method of producing an aryl triazolidinone (B-2) by reacting an alkali metal cyanate with an acid, followed by a step of reacting with an oxidizing agent.

(式(B-1)中，X表示鹵素原子，碳數1至6之低級烷基，n表示0至5之整數。N表示2以上之整數時，複數個之X可為相同或不同。)(In the formula (B-1), X represents a halogen atom, a lower alkyl group having 1 to 6 carbon atoms, and n represents an integer of 0 to 5. When N represents an integer of 2 or more, a plurality of X's may be the same or different. )

然而，一般式(B-3)所示之甲醛-芳基腙會藉由酸而造成腙相互間偶合而變成四衍生物(參照Liebigs Ann. Chem.,635卷(1960),82-91頁)(非專利文獻1)。However, the formaldehyde-aryl oxime represented by the general formula (B-3) causes the oximes to be coupled to each other by the acid to become four. Derivative (refer to Liebigs Ann. Chem., vol. 635 (1960), pp. 82-91) (Non-Patent Document 1).

易言之，一般式(B-3)所示之甲醛-芳基腙在酸存在下不穩定。In other words, the formaldehyde-aryl hydrazine represented by the general formula (B-3) is unstable in the presence of an acid.

據此，依照專利文獻2所記載之將芳基腙(B-3)及氰酸鹼金屬鹽在酸存在下反應之方法，增大副反應，可能影響及目的物之收率及純度，也難言為適佳方法。Accordingly, according to the method described in Patent Document 2, the method of reacting aryl hydrazine (B-3) and an alkali metal cyanate in the presence of an acid increases the side reaction, which may affect the yield and purity of the target substance. It is hard to say that it is a good method.

又，PCT國際公告WO91/3470號公報相對應之日本特公平6-78322號公報(參照專利文獻3)中記載由一般式(C-1)所示芳基***烷酮In the PCT International Publication No. 6-78322 (refer to Patent Document 3), the aryl triazolidinone represented by the general formula (C-1) is described in the Japanese Patent Publication No. 6-78322 (see Patent Document 3).

(式(C-1)中，n表示1至3之整數，R表示鹵素原子、烷基、鹵烷基等，X各自獨立地表示氫、鹵素原子(Cl、Br、I)、低級烷基)，以次鹵酸或次鹵酸鹽處理而得一般式(C)所示芳基***啉酮之製造方法。(In the formula (C-1), n represents an integer of 1 to 3, R represents a halogen atom, an alkyl group, a haloalkyl group or the like, and X each independently represents hydrogen, a halogen atom (Cl, Br, I), a lower alkyl group The method for producing an aryltriazolinone of the general formula (C) is obtained by treating with a hypohalous acid or a hypohalite.

(式(C)中，n表示1至3之整數，R表示鹵素原子、烷基、鹵烷基等，X各自獨立地表示氫、鹵素原子、低級烷基等。)(In the formula (C), n represents an integer of 1 to 3, R represents a halogen atom, an alkyl group, a haloalkyl group or the like, and X each independently represents hydrogen, a halogen atom, a lower alkyl group or the like.)

又，PCT國際公開WO93/23382號公報相對應之日本特表平7-503253號公報(參照專利文獻4)中記載製造一般式(D)所示芳基***啉酮之方法中，In the method of producing the aryltriazolinone of the general formula (D), the method of producing the aryltriazolinone of the general formula (D) is described in the Japanese Patent Publication No. Hei 7-503253 (see Patent Document 4).

(式(D)中，R表示低級烷基，X獨立地表示鹵素、低級烷基、硝基、羥基、NHSO₂ R’、-N(SO₂ R’)₂ 、-N(R’)SO₂ R’(但是R’表示低級烷基)，n為0至3之整數。)(In the formula (D), R represents a lower alkyl group, and X independently represents a halogen, a lower alkyl group, a nitro group, a hydroxyl group, a NHSO ₂ R', -N(SO ₂ R') ₂ , or -N(R')SO. ₂ R' (but R' represents a lower alkyl group), and n is an integer from 0 to 3.)

在第三級丁醇溶劑中，將式為X_n -Ph-NH‧NH₂ (Ph表示苯基，n和專利文獻3相同)之芳基肼，依序使用(i)C1至C3醛，(ii)氰酸鹽及弱有機酸，及(iii)次氯酸或其鹽或鹵素處理而得芳基***啉酮。In the third-stage butanol solvent, an aryl hydrazine of the formula X _n -Ph-NH‧NH ₂ (Ph represents a phenyl group, n is the same as in Patent Document 3), and (i) a C1 to C3 aldehyde are used in that order. (ii) cyanate and a weak organic acid, and (iii) hypochlorous acid or a salt thereof or a halogen thereof to give an aryltriazolinone.

然而，上述專利文獻3及4中，式(C)或式(D)中，就R表示氫(H)之苯基***啉酮類及其製法並無任何記載或暗示。However, in the above-mentioned Patent Documents 3 and 4, in the formula (C) or the formula (D), the phenyl triazolinones in which R represents hydrogen (H) and the method for producing the same are not described or suggested.

專利文獻1：WO98/38176號公報Patent Document 1: WO98/38176

專利文獻2：WO02/12203號公報Patent Document 2: WO02/12203

專利文獻3：特公平6-78322號公報Patent Document 3: Special Fair 6-78322

專利文獻4：特表平7-503253號公報Patent Document 4: Japanese Patent Publication No. 7-503253

非專利文獻1：Liebigs Ann. Chem. 635卷(1960),82-91頁。Non-Patent Document 1: Liebigs Ann. Chem. 635 (1960), pp. 82-91.

本發明擬解決上述已往技術上所伴生之問題，使用更廉價之原料，以更簡單而安全且低成本之下，提供以高收率製造高純度之苯基***啉酮類之新穎之方法為其目的。The present invention is intended to solve the above-mentioned problems associated with the prior art, and to provide a novel method for producing high-purity phenyl triazolinones in high yield, using simpler, safer and lower cost, using cheaper raw materials. For its purpose.

本發明研究者為達成上述目的，經努力研究結果，在特定pH範圍下，形成甲醛-苯腙類(下文中，簡稱為苯腙類。)，再以所得甲醛-苯腙類和氰酸反應而形成苯基***烷酮類，在不伴生上述副反應下，以高收率且高純度製成苯基***啉酮類，終於完成了本發明。In order to achieve the above object, the inventors of the present invention have diligently studied the results to form formaldehyde-benzoquinones (hereinafter, simply referred to as benzoquinones) at a specific pH range, and then react with the obtained formaldehyde-benzoquinones and cyanic acid. Further, the phenyltriazolidinones were formed, and phenyltriazolinones were produced in high yield and high purity without the above-mentioned side reactions, and finally completed the present invention.

換言之，本發明研究者發現藉由下列途徑可以高收率且高純度製造目的化合物之苯基***啉酮類之方法。In other words, the inventors of the present invention found a method for producing a phenyltriazolinone of the object compound in high yield and high purity by the following route.

(1)由苯胺類經由甲醛-苯腙類形成苯基***烷酮類之反應階段中，在特定pH範圍下處理甲醛-苯腙類，緩和、減低共存之酸對於甲醛-苯腙類之不良影響(四衍生物的副產生)，(1) In the reaction stage in which phenylamines form phenyl triazolidinones via formaldehyde-benzoquinones, formaldehyde-benzoquinones are treated at specific pH ranges to alleviate and reduce coexisting acids for formaldehyde-benzoquinones. Adverse effects (four Sub-production of derivatives),

(2)環化加成氰酸於甲醛-苯腙類而製成。(2) Cyclization is carried out by adding cyanic acid to formaldehyde-benzoquinone.

又，本發明研究者在製造苯基***啉酮類之際，發現可選擇廉價而泛用性高之苯胺類為原料，可避免必要時需貯藏具有火災、***等危險性或對健康有害性之掛慮之苯肼方式之化學物質。Further, in the production of phenyltriazolinones, the present inventors have found that anilines which are inexpensive and highly versatile can be selected as raw materials, and can avoid the risk of fire, explosion, or the like if necessary. Chemical substances in the benzoquinone mode of concern.

更加之，本發明研究者也發現可將全部步驟以連續性處理進行。據此，不必經由伴生危險之精製步驟，可要安全地製造目的化合物之苯基***啉酮類，同時，也可為大規模工業生產之適佳方法。Furthermore, the inventors of the present invention have also found that all steps can be carried out in a continuous process. According to this, it is not necessary to carry out the purification step of the associated danger, and it is possible to safely produce the phenyltriazolinone of the objective compound, and at the same time, it is also a suitable method for large-scale industrial production.

如同以上所詳述，本發明研究者可以安全而有效率，且廉價而高收率地製造高純度之苯基***啉酮類(5)，終於完成了本發明。As described in detail above, the inventors of the present invention have finally completed the present invention by producing high-purity phenyltriazolinones (5) in a safe and efficient manner and at low cost and in high yield.

本發明有關苯基***啉酮類之製造方法中，適佳者為以下所記載之第1種製造方法、第2種製造方法、第3種製造方法、第4種製造方法及第5種製造方法。In the method for producing a phenyltriazolinone according to the present invention, the first production method, the second production method, the third production method, the fourth production method, and the fifth type described below are preferable. Production method.

本發明有關第1種製造方法，其特徵為將一般式(1)所示苯胺類The first aspect of the invention relates to a method for producing an aniline represented by the general formula (1)

(式(1)中，X表示鹵素原子、碳數1至6之低級烷基，n表示0至5之整數。n為2以上之整數時，複數個X可互為相同或不同。)和亞硝酸鹽類反應作成為重氮鹽之後，再以亞硫酸鹽類或亞硫酸氫鹽類還原，繼之，水解而得一般式(2)所示苯肼類，(In the formula (1), X represents a halogen atom, a lower alkyl group having 1 to 6 carbon atoms, and n represents an integer of 0 to 5. When n is an integer of 2 or more, plural X's may be the same or different from each other.) After the nitrite reaction is carried out as a diazonium salt, it is reduced by a sulfite or a bisulfite, and then hydrolyzed to obtain a benzoquinone represented by the general formula (2).

(式(2)中，X、n所示和式(1)中相同意義。)(In the formula (2), X and n have the same meanings as in the formula (1).)

然後，在觸媒存在下，將所得苯肼類(2)和甲醛在pH5至10中反應，形成一般式(3)所示甲醛-苯腙類，Then, in the presence of a catalyst, the obtained benzoquinone (2) and formaldehyde are reacted at pH 5 to 10 to form a formaldehyde-benzoquinone represented by the general formula (3).

(式(3)中，X、n所示和式(1)中相同意義。)(In the formula (3), X and n have the same meanings as in the formula (1).)

繼之，使該甲醛-苯腙類(3)和氰酸反應，形成一般式(4)所示苯基***烷酮類，Subsequently, the formaldehyde-benzoquinone (3) is reacted with cyanic acid to form a phenyl triazolidinone of the general formula (4).

(式(4)中，X、n所示和式(1)中相同意義。)(In the formula (4), X and n have the same meanings as in the formula (1).)

繼之，將該苯基***烷酮類(4)和選擇自次鹵酸鹽及氧中之氧化劑，在無觸媒下或氧化觸媒存在下反應而製成一般式Then, the phenyl triazolidinone (4) and the oxidizing agent selected from the hypohalite and oxygen are reacted in the absence of a catalyst or in the presence of an oxidation catalyst to form a general formula.

(5)所示苯基***啉酮類之製造方法。(5) A method for producing a phenyltriazolinone.

(式(5)中，X、n所示和式(1)中相同意義。)(In the formula (5), X and n have the same meanings as in the formula (1).)

本發明有關第2種製造方法，乃由含有上述一般式(2)所示苯肼類之反應混合物，According to a second aspect of the present invention, there is provided a reaction mixture comprising the benzoquinone represented by the above general formula (2),

(式(2)，X、n所示和式(1)中相同意義。)(Formula (2), X, n are the same as in equation (1).)

藉由過濾、傾析法等，必要時去除水層而分離得苯肼類(2)之粗生成物。The crude product of the benzoquinone (2) is separated by filtration, decantation, or the like, and if necessary, removing the water layer.

本發明有關第3種製造方法，乃由含有上述一般式(3)所示甲醛-苯腙類之反應混合物，The third production method of the present invention is a reaction mixture containing the formaldehyde-benzoquinone represented by the above general formula (3).

藉由過濾、傾析法等，必要時去除水層而分離得甲醛-苯腙類(3)之粗製物。The crude product of formaldehyde-benzoquinone (3) is isolated by filtration, decantation, etc., if necessary, by removing the water layer.

本發明有關第4種製造方法，乃將上述一般式(1)所示苯胺類，According to a fourth aspect of the present invention, the aniline represented by the above general formula (1),

(式(1)中，X表示鹵素原子、碳數1至6之低級烷基，n表示0至5之整數。n表示2以上之整數時，複數個X可互為相同或不同。)(In the formula (1), X represents a halogen atom, a lower alkyl group having 1 to 6 carbon atoms, and n represents an integer of 0 to 5. When n represents an integer of 2 or more, plural X's may be the same or different from each other.)

必要時，在有機溶劑之存在下，和亞硝酸鹽類反應而形成重氮鹽。If necessary, it reacts with a nitrite to form a diazonium salt in the presence of an organic solvent.

又，本發明有關第5種製造方法，乃將上述一般式(4)所示苯基***烷酮類，Further, in the fifth production method of the present invention, the phenyl triazolidinone represented by the above general formula (4) is used.

和選擇自次鹵酸鹽及氧中之氧化劑，在無觸媒下或氧化觸媒存在下反應之後，必要時使用鹼處理而亦可精製得下述一般式(5)所示苯基***啉酮類。And selecting an oxidizing agent from the hypohalite and oxygen, and reacting in the absence of a catalyst or in the presence of an oxidation catalyst, if necessary, using an alkali treatment, or purifying the phenyltriazole represented by the following general formula (5) Bolinones.

本發明有關苯基***啉酮類(5)之製造方法中，可在較低溫於短時間完成反應，並以高收率獲得高純度之苯基***啉酮類(5)。In the production method of the phenyltriazolinone (5) of the present invention, the reaction can be completed at a relatively low temperature for a short period of time, and a high-purity phenyl triazolinone (5) can be obtained in a high yield.

又，本發明有關苯基***啉酮類(5)之製造方法中，由於在各步驟中不必分離或精製中間體而可連續地進行，所以可用少量熱能而有效率，安全且廉價地提供苯基***啉酮類(5)。因此，本發明之苯基***啉酮類(5)之製造方法，為適佳於大規模工業實施之方法。Further, in the method for producing a phenyltriazolinone (5) according to the present invention, since it is possible to continuously carry out the separation or purification of the intermediate in each step, it can be efficiently and safely and inexpensively provided with a small amount of heat energy. Phenyl triazolinones (5). Therefore, the production method of the phenyltriazolinones (5) of the present invention is a method suitable for large-scale industrial implementation.

(實施發明之最佳途徑)(Best way to implement the invention)

本發明有關苯基***啉酮類之製造方法，具體說明如下。The method for producing a phenyltriazolinone according to the present invention is specifically described below.

本發明有關苯基***啉酮類之製造方法中，下式(5)所示苯基***啉酮類可藉下列＜式A＞所示一連串之反應步驟而製成。In the method for producing a phenyltriazolinone according to the present invention, the phenyltriazolinones represented by the following formula (5) can be produced by a series of reaction steps shown by the following <Formula A>.

該製造方法中，以苯胺類(1)為原料，經由下列第1階段至第4階段，製造下式(5)所示苯基***啉酮類。In the production method, the phenyltriazolinones represented by the following formula (5) are produced from the aniline (1) as a raw material through the following first to fourth stages.

即，該苯基***啉酮類(5)之製造方法中，在第1階段，將苯胺類(1)與亞硝酸鹽類反應作成重氮鹽之後，使用亞硫酸鹽類或亞硫酸氫鹽類還原，繼之，水解而形成苯肼類(2)。That is, in the production method of the phenyltriazolinones (5), in the first stage, after the aniline (1) is reacted with a nitrite to form a diazonium salt, a sulfite or hydrogen sulfite is used. The salt is reduced, followed by hydrolysis to form the benzoquinone (2).

該苯肼類(2)從收率純度提升等觀點而言，不須單離，祇要從反應混合物經過濾、傾析法等除去水層製得苯肼類(2)之粗生成物或其水性懸濁液，就可直接提供後續反應步驟。The benzoquinone (2) does not need to be separated from the viewpoint of improving the purity of the yield, and the crude product of the benzoquinone (2) or the crude product thereof can be obtained by removing the aqueous layer from the reaction mixture by filtration, decantation or the like. The aqueous suspension provides a direct reaction step.

又，就收率提升及純度提升之觀點，亦可將苯胺類(1)在有機溶劑之存在下，和亞硝酸鹽類反應作成重氮鹽之後，再用亞硫酸鹽類或亞硫酸氫鹽類還原，繼之，水解而形成苯肼類(2)。Further, in view of improvement in yield and improvement in purity, aniline (1) may be reacted with nitrite in the presence of an organic solvent to form a diazonium salt, and then sulfite or bisulfite may be used. Reduction, followed by hydrolysis to form benzoquinones (2).

繼之，在第2階段中，將所得苯肼類(2)和甲醛在觸媒存在下，較佳在特定之pH下(pH5至10)反應，形成甲醛-苯腙類(3)。Subsequently, in the second stage, the obtained benzoquinone (2) and formaldehyde are preferably reacted at a specific pH (pH 5 to 10) in the presence of a catalyst to form a formaldehyde-benzoquinone (3).

該甲醛-苯腙類(3)，從收率純度提升之觀點，不須單離，祗要從反應混合物經過濾、傾析法等去除水層製得甲醛-苯腙類(3)之粗生成物或其水性懸濁液，就可以直接提供後續反應。The formaldehyde-benzoquinone (3), from the viewpoint of improving the purity of the yield, does not need to be separated, and the aqueous layer is removed from the reaction mixture by filtration, decantation, etc. to obtain a crude formaldehyde-benzoquinone (3). The product or its aqueous suspension can directly provide a subsequent reaction.

繼之，第3階段中，使該甲醛-苯腙類(3)和氰酸反應，形成苯基***烷酮類(4)。Next, in the third stage, the formaldehyde-benzoquinone (3) is reacted with cyanic acid to form a phenyl triazolidinone (4).

該苯基***烷酮類(4)多半不須經單離‧精製直接提供後續步驟(第4階段)中使用。Most of the phenyl triazolidinones (4) are used in the subsequent step (stage 4) without isolation or purification.

繼之，第4階段中，該苯基***烷酮類(4)和選擇自次鹵酸鹽及氧中之氧化劑，在無觸媒下或氧化觸媒存在下反應，製造苯基***啉酮類(5)。Subsequently, in the fourth stage, the phenyl triazolidinone (4) and the oxidizing agent selected from the hypohalite and oxygen are reacted in the absence of a catalyst or in the presence of an oxidation catalyst to produce a phenyltriazole. Bolinones (5).

該苯基***啉酮類(5)從純度提升之觀點，可在反應終了後，用鹼處理而精製之。The phenyltriazolinones (5) can be purified by alkali treatment from the viewpoint of improving the purity after completion of the reaction.

上述本發明有關製法中，必要時，苯肼類(2)可經單離，另外，必要時，甲醛-苯腙類(3)(下文中，或簡稱為苯腙類。)也可經單離。In the above-mentioned production method of the present invention, the benzoquinone (2) may be isolated if necessary, and, if necessary, the formaldehyde-benzoquinone (3) (hereinafter, or simply referred to as a benzoquinone) may also be subjected to a single from.

又，本發明有關製造方法中，在上述第1階段及第2階段之中，可於任一階段進行水層的去除。Further, in the manufacturing method of the present invention, in the first stage and the second stage, the water layer can be removed at any stage.

一般式(1)至(5)中，X表示鹵素原子、碳數1至6之低級烷基，n表示0至5之整數。n為2以上之整數時，複數個X可互為相同或不同。In the general formulae (1) to (5), X represents a halogen atom, a lower alkyl group having 1 to 6 carbon atoms, and n represents an integer of 0 to 5. When n is an integer of 2 or more, the plurality of Xs may be the same or different from each other.

又，「鹵素原子」可列舉氯、溴、氟、碘等原子。Further, examples of the "halogen atom" include atoms such as chlorine, bromine, fluorine, and iodine.

上述一般式(1)至(5)中，X為「低級烷基」時，該低級烷基可列舉碳數1至6之烷基，可為直鏈狀或歧鏈狀，具體而言，可列舉甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、正戊基、異戊基、2-甲基丁基、新戊基、正己基、4-甲基戊基、2,3-二甲丁基、1-乙基丁基、1-乙基-2-甲基-丙基、1-甲基-1-乙基丙基、1-甲基-2-乙基丙基、2-甲基-1-乙基丙基、2-甲基-1-乙基丙基或2-甲基-2-乙基丙基等。In the above general formulas (1) to (5), when X is a "lower alkyl group", the lower alkyl group may be an alkyl group having 1 to 6 carbon atoms, and may be linear or branched. Specifically, Mention may be made of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, new Pentyl, n-hexyl, 4-methylpentyl, 2,3-dimethylbutyl, 1-ethylbutyl, 1-ethyl-2-methyl-propyl, 1-methyl-1-B Propyl, 1-methyl-2-ethylpropyl, 2-methyl-1-ethylpropyl, 2-methyl-1-ethylpropyl or 2-methyl-2-ethylpropane Base.

又，苯肼類(2)可為鹽。Further, the benzoquinone (2) may be a salt.

<苯肼類(2)之合成(第1階段)><Synthesis of benzoquinones (2) (Phase 1)>

首先，「第1階段」中，將上述一般式(1)所示苯胺類藉由亞硝酸鹽類形成重氮鹽之後，所得重氮鹽用亞硫酸鹽類或亞硫酸氫鹽類還原，繼之，水解而製得相對應於上述一般式(2)所示苯肼類為適佳。First, in the "first stage", after the aniline represented by the above general formula (1) is formed into a diazonium salt by a nitrite, the obtained diazonium salt is reduced with a sulfite or a bisulfite. The hydrolysis is carried out to obtain a benzoquinone corresponding to the above general formula (2).

具體而言，例如將原料之苯胺類(1)和鹽酸反應而製成鹽。Specifically, for example, the aniline (1) of the raw material is reacted with hydrochloric acid to prepare a salt.

繼之，加入亞硝酸鈉於該鹽酸鹽行重氮化，繼之，將該重氮化物加入至經調整pH為5.5至8.0之亞硫酸鈉溶液中，加以還原，再水解而生成苯肼類(2)。Then, sodium nitrite is added to the hydrochloride to diazotize, and then the diazotide is added to a sodium sulfite solution having a pH adjusted to 5.5 to 8.0, which is reduced and then hydrolyzed to form a benzoquinone ( 2).

又，也可將原料之苯胺類(1)在有機溶劑之存在下和鹽酸反應形成鹽，繼之，加入亞硝酸鈉至該鹽酸鹽進行重氮化，繼之，將該重氮化物加入至經調整pH為5.5至8.0之亞硫酸鈉溶液中，加以還原，再水解而生成苯肼類(2)。Alternatively, the aniline (1) of the starting material may be reacted with hydrochloric acid in the presence of an organic solvent to form a salt, and then sodium nitrite is added to the hydrochloride for diazotization, and then the diazotide is added. The solution is reduced to a sodium sulfite solution having a pH adjusted to 5.5 to 8.0, and then hydrolyzed to form a benzoquinone (2).

第1階段中之重氮化，還原及水解可依照周知方法進行，但以更詳細說明第1階段中之反應步驟為目的，將本發明有關製造方法之適佳例舉示如下。The diazotization, reduction and hydrolysis in the first stage can be carried out according to a known method. However, for the purpose of explaining the reaction steps in the first stage in more detail, the preferred examples of the production method of the present invention are as follows.

第1階段之重氮化中，首先將苯胺類(1)，例如和鹽酸反應而製成鹽，或在有機溶劑之存在下，將苯胺類(1)和鹽酸反應而製成鹽。此時，本例中使用過剩量之鹽酸。In the first stage of diazotization, the aniline (1) is first reacted with hydrochloric acid to form a salt, or the aniline (1) and hydrochloric acid are reacted in the presence of an organic solvent to prepare a salt. At this time, an excess amount of hydrochloric acid was used in this example.

其次，例如加入亞硝酸鈉而重氮化。Second, for example, sodium nitrite is added to diazotize.

其次，將上述重氮化物例如加入至經以硫酸調整pH之亞硫酸鈉溶液而還原之。Next, the above diazotide is added, for example, to a sodium sulfite solution adjusted to pH with sulfuric acid to reduce it.

其次，水解所產生之苯肼硫酸鹽類可得苯肼類之鹽。Secondly, the benzoquinone sulfate produced by the hydrolysis can be obtained as a salt of a benzoquinone.

又，必要時，可中和所得苯肼類之鹽。Further, if necessary, the salt of the obtained benzoquinone can be neutralized.

此方式之使生成的重氮鹽之重氮化反應，一般，可在-25℃至25℃的溫度範圍，較佳在-5℃至20℃的溫度，常壓下進行15分鐘至2小時，以30分鐘至1小時為較佳。作為重氮化劑所使用之亞硝酸鹽類，具體列舉亞硝酸鈉、亞硝酸鉀等，以亞硝酸鈉為較佳。In this way, the diazotization reaction of the produced diazonium salt can be carried out in a temperature range of -25 ° C to 25 ° C, preferably at a temperature of -5 ° C to 20 ° C, at a normal pressure for 15 minutes to 2 hours. It is preferably from 30 minutes to 1 hour. Specific examples of the nitrites used in the diazotizing agent include sodium nitrite and potassium nitrite, and sodium nitrite is preferred.

其使用量，一般，對於苯胺類(1)1莫耳計，使用1.0至1.5莫耳之亞硝酸鹽類，以1.0至1.2莫耳量使用為較佳，亞硝酸鹽類可以固體狀使用，然而，一般以水溶液使用之。The amount thereof to be used is generally 1.0 to 1.5 moles of nitrite for the aniline (1) 1 mole meter, preferably 1.0 to 1.2 moles, and the nitrite can be used in a solid form. However, it is generally used as an aqueous solution.

又，該重氮化反應，一般，使用礦酸，可列舉鹽酸、硫酸、磷酸、硝酸等，以鹽酸、硫酸為較佳。該礦酸之使用量，對於苯胺類(1)1莫耳計，一般，使用1.0至10.0莫耳，以2.0至6.0莫耳量使用為較佳，一般，以水溶液使用之。Further, in the diazotization reaction, generally, mineral acid is used, and hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid or the like is used, and hydrochloric acid or sulfuric acid is preferred. The amount of the mineral acid used is generally 1.0 to 10.0 mol for the aniline (1) 1 mol, and preferably 2.0 to 6.0 mol, and is generally used as an aqueous solution.

又，該重氮化反應在有機溶劑之存在下使用礦酸進行時，一般，使用不會和水混合之有機溶劑。該有機溶劑例如可列舉戊烷、己烷、庚烷、石油醚等脂肪族烴類；苯、甲苯、二甲苯等芳香族烴類；二氯甲烷、氯仿、1,2-二氯乙烷、氯苯、二氯苯等鹵化烴類。Further, when the diazotization reaction is carried out using mineral acid in the presence of an organic solvent, generally, an organic solvent which does not mix with water is used. Examples of the organic solvent include aliphatic hydrocarbons such as pentane, hexane, heptane, and petroleum ether; aromatic hydrocarbons such as benzene, toluene, and xylene; dichloromethane, chloroform, and 1,2-dichloroethane. Halogenated hydrocarbons such as chlorobenzene and dichlorobenzene.

有機溶劑之使用量，一般，對於苯胺類計，為0.1重量倍以上，以約0.5至約5重量倍的範圍為較佳。又，此時所使用礦酸之種類及使用量如同上述。The amount of the organic solvent to be used is generally 0.1 part by weight or more, and preferably about 0.5 to about 5 times by weight, based on the aniline. Further, the type and amount of mineral acid used at this time are as described above.

上述條件中，在有機溶劑之存在下使用礦酸進行重氮化反應時，苯股類能均一分散在礦酸水溶液中，所以能以高轉換率進行重氮化反應，可生成高純度之苯肼類。其結果，可以高收率獲得高純度之苯基***啉酮類。Among the above conditions, when the diazotization reaction is carried out using mineral acid in the presence of an organic solvent, the benzene strands can be uniformly dispersed in the mineral acid aqueous solution, so that the diazotization reaction can be carried out at a high conversion rate, and a high purity benzene can be produced.肼 class. As a result, high-purity phenyl triazolinones can be obtained in high yield.

繼之，所進行之將苯胺類(1)重氮化製得重氮鹽之還原反應，一般，在0℃至80℃的溫度範圍，較佳在10℃至70℃的溫度，常壓下進行1至24小時，以2至12小時為較佳。Subsequently, the reduction reaction of the diazonium salt by diazotizing the aniline (1) is carried out, generally, at a temperature ranging from 0 ° C to 80 ° C, preferably at a temperature of from 10 ° C to 70 ° C under normal pressure. It is preferably from 1 to 24 hours, preferably from 2 to 12 hours.

該還原反應所用還原劑之亞硫酸鹽類，例如可列舉亞硫酸銨、亞硫酸鈉、亞硫酸鉀等，其中以亞硫酸鈉之泛用性高等方面而言為較佳。Examples of the sulfites of the reducing agent used in the reduction reaction include ammonium sulfite, sodium sulfite, and potassium sulfite. Among them, sodium sulfite is preferred because of its high versatility.

又，該還原反應所用還原劑之亞硫酸氫鹽類，例如可列舉亞硫酸氫銨、亞硫酸氫鈉、亞硫酸氫鉀等，其中以亞硫酸氫鈉之泛用性高等方面為較佳。Further, examples of the bisulfite of the reducing agent used in the reduction reaction include ammonium hydrogen sulfite, sodium hydrogen sulfite, potassium hydrogen sulfite, and the like, and among them, high versatility of sodium hydrogen sulfite is preferred.

該還原劑可直接以原來形狀使用，但一般以水溶液而使用，該亞硫酸鹽類或亞硫酸氫鹽類之使用量，對於苯胺類(1)1莫耳計，通常為2.0莫耳以上，以2.5至4.0莫耳量為較佳。The reducing agent can be used directly in its original shape, but it is generally used in the form of an aqueous solution. The amount of the sulfite or bisulfite used is usually 2.0 mol or more for the aniline (1) 1 Torr. It is preferably from 2.5 to 4.0 moles.

該反應通常係將苯胺類(1)重氮化製得之重氮鹽加入至一般經調整pH在5.5至8.0之亞硫酸鹽類或亞硫氫酸鹽類之水溶液的溶液中反應之。反應系內之pH一般在5.5至8.0範圍，以調整為6.0至7.5範圍為較佳。該pH之調整可使用鹽酸、硫酸等酸類，或氫氧化鈉、氫氧化鉀、氨等鹼性水溶液而調整。The reaction is usually carried out by adding a diazonium salt obtained by diazotizing the aniline (1) to a solution of an aqueous solution of a sulfite or a sulfite having a pH adjusted to 5.5 to 8.0. The pH in the reaction system is generally in the range of 5.5 to 8.0, preferably adjusted to a range of 6.0 to 7.5. The pH can be adjusted by using an acid such as hydrochloric acid or sulfuric acid or an alkaline aqueous solution such as sodium hydroxide, potassium hydroxide or ammonia.

繼續該還原反應而進行之水解反應，通常在-5℃至90℃的溫度範圍，以0℃至80℃的溫度為較佳，常壓下進行1至24小時，以3至10小時為較佳。The hydrolysis reaction carried out by continuing the reduction reaction is usually carried out at a temperature of from -5 ° C to 90 ° C, preferably from 0 ° C to 80 ° C, at normal pressure for from 1 to 24 hours, and from 3 to 10 hours. good.

該水解反應通常使用礦酸，例如可列舉鹽酸、硫酸、磷酸、硝酸等，其中以鹽酸、硫酸為較佳。該礦酸之使用量，對於苯胺類(1)1莫耳計，通常為2.0莫耳以上，以5.0至30.0莫耳量為較佳(鹽酸時，以氯化氫之莫耳數計算。)The hydrolysis reaction generally uses a mineral acid, and examples thereof include hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid. Among them, hydrochloric acid and sulfuric acid are preferred. The amount of the mineral acid used is usually 2.0 mol or more for the aniline (1) 1 mol, and preferably 5.0 to 30.0 mol (the hydrochloric acid is calculated by the molar number of hydrogen chloride).

苯肼類(2)以該水解所得反應混合物之狀態，可直接使用於第2階段之反應，但以經鹼中和後使用為較佳。The benzoquinone (2) can be used as it is in the second stage in the state of the reaction mixture obtained by the hydrolysis, but it is preferably used after being neutralized with a base.

前述鹼可列舉氫氧化鈉、氫氧化鉀、碳酸鈉、碳酸鉀等。其中，以氫氧化鈉之泛用性高等方面而言為較佳。Examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. Among them, it is preferable in terms of high versatility of sodium hydroxide.

又，所得苯肼類(2)在該階段中可以混合物直接提供後續步驟，亦可在該階段中進行精製、單離以及去除水層而分離之任意處理後，提供後續步驟。Further, the obtained benzoquinone (2) may directly provide a subsequent step in the mixture in this stage, or may be subjected to any treatment after purification, isolation, and separation of the aqueous layer in this stage, to provide a subsequent step.

<甲醛-苯腙類(3)之合成(第2階段)><Formaldehyde-benzoquinone (3) synthesis (stage 2)>

其次，本發明之苯基***啉酮類(5)之第1種及第2種製造方法中所使用之「第2階段」中，將苯肼類(2)和甲醛在觸媒存在下，通常在pH5至10，較佳在pH6至8下，在溶劑中反應而生成相對應之甲醛-苯腙類(3)。Next, in the "second stage" used in the first and second production methods of the phenyltriazolinones (5) of the present invention, the benzoquinones (2) and formaldehyde are present in the presence of a catalyst. It is usually reacted in a solvent at a pH of 5 to 10, preferably at a pH of 6 to 8, to form a corresponding formaldehyde-benzoquinone (3).

該反應，可在上述第1階段中所得苯肼類(2)不進行精製、單離及去除水層而分離之任意處理的反應混合物中，直接將甲醛添加混合使其反應也能有效率地達成反應。In the reaction, the benzoquinone (2) obtained in the first step can be directly mixed with formaldehyde in a reaction mixture which is not subjected to purification, separation and removal of the aqueous layer, and the reaction can be efficiently carried out. Reach a reaction.

該第2階段之反應，通常在-10℃到「所使用溶劑之沸點」為止之溫度範圍，較佳在0℃至+40℃的溫度，常壓下一般進行10分鐘至24小時，以30分鐘至5小時為較佳。The second-stage reaction is usually carried out at a temperature ranging from -10 ° C to the "boiling point of the solvent used", preferably at a temperature of from 0 ° C to +40 ° C, and usually at a normal pressure for 10 minutes to 24 hours, to 30 Minutes to 5 hours are preferred.

反應之際，理論上苯肼類(2)及甲醛使用等莫耳量就可行，一般，對於苯肼類(2)1莫耳，使用1.0至2.0莫耳之甲醛，以1.0至1.2莫耳量使用為較佳，通常使用含有該量之甲醛的甲醛水溶液。In the reaction, theoretically, the amount of benzoquinone (2) and formaldehyde can be used. Generally, for benzoquinone (2) 1 mole, 1.0 to 2.0 moles of formaldehyde is used, and 1.0 to 1.2 moles are used. The amount is preferably used, and an aqueous formaldehyde solution containing the amount of formaldehyde is usually used.

又，上述苯肼類(2)和甲醛反應之際，所使用觸媒，具體而言，例如可列舉甲酸銨、甲酸鈉、甲酸鉀、乙酸銨、乙酸鈉、乙酸鉀等有機酸鹽類；甲酸、乙酸等有機酸；對-甲苯磺酸等磺酸類；氫氧化鈉、氫氧化鉀、碳酸鈉等無機鹼；三乙胺、吡啶、1,8-二氮雙環[5.4.0]十一碳-7-烯等胺類等。Further, when the benzoquinone (2) and formaldehyde are reacted, specific examples of the catalyst to be used include organic acid salts such as ammonium formate, sodium formate, potassium formate, ammonium acetate, sodium acetate, and potassium acetate; formic acid; , organic acids such as acetic acid; sulfonic acids such as p-toluenesulfonic acid; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate; triethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec carbon An amine such as -7-ene.

該觸媒之使用量，對於苯肼類(2)而言，一般為0.01至20.0莫耳%，以0.1至10.0莫耳%的量使用為較佳。The amount of the catalyst used is generally from 0.01 to 20.0 mol% for the benzoquinone (2), and is preferably from 0.1 to 10.0 mol%.

又，第2階段之反應中，使用含有第1階段所得苯肼類(2)之混合物進行反應時，上述混合物中所含苯肼類(2)之量可使用高速液體層析等分析而決定之。Further, in the second-stage reaction, when a mixture containing the benzoquinone (2) obtained in the first stage is used for the reaction, the amount of the benzoquinone (2) contained in the mixture can be determined by analysis such as high-speed liquid chromatography. It.

反應系內之pH值一般調整在5至10範圍，以調整在pH6至8範圍為較佳。pH值的調整可使用例如甲酸、乙酸、鹽酸、硫酸等酸類，或氫氧化鈉、氫氧化鉀等鹼性水溶液而進行。The pH in the reaction system is generally adjusted in the range of 5 to 10, preferably adjusted in the range of pH 6 to 8. The pH can be adjusted by using an acid such as formic acid, acetic acid, hydrochloric acid or sulfuric acid, or an aqueous alkaline solution such as sodium hydroxide or potassium hydroxide.

在上述pH範圍內使苯肼類(2)和甲醛反應時，由可抑制副反應方面而言為較佳。When the benzoquinone (2) and formaldehyde are reacted in the above pH range, it is preferred from the viewpoint of suppressing side reactions.

又，上述溶劑，例如可列舉水；甲醇、乙醇、正丙醇、異丙醇、甲氧基乙醇、正丁醇、第二丁醇、異丁醇、第三丁醇等醇類；四氫呋喃、二烷等醚類；乙腈、丙腈等腈類等，上述有機溶劑和水之混合溶劑也可使用，以使用第三丁醇及水之混合溶劑為較佳。Further, examples of the solvent include water; alcohols such as methanol, ethanol, n-propanol, isopropanol, methoxyethanol, n-butanol, second butanol, isobutanol, and third butanol; and tetrahydrofuran. two An ether such as an alkyl group; a nitrile such as acetonitrile or propionitrile; and a mixed solvent of the above organic solvent and water may be used, and a mixed solvent of a third butanol and water is preferably used.

混合溶劑可使用2種或2種以上之混合系。使用有機溶劑和水之混合溶劑時，對於100重量份之有機溶劑計，一般使用1至500重量份之水，以10至200重量份之量使用為較佳。Two or a mixture of two or more types may be used as the mixed solvent. When a mixed solvent of an organic solvent and water is used, it is generally used in an amount of from 10 to 200 parts by weight, based on 100 parts by weight of the organic solvent, and preferably from 10 to 200 parts by weight.

該溶劑用量，對於苯肼類(2)1莫耳計，例如以100g至4000g之量使用。The amount of the solvent used is, for example, benzoquinone (2) 1 Torr, in an amount of from 100 g to 4000 g.

又，溶劑用量，可根據下述甲醛-苯腙類(3)和氰酸之反應階段之第3階段，或下述苯基***烷酮類(4)和氧化劑之反應階段之第4階段等，隨各階段中之反應物及反應條件等而適度改變，不能一概而定。Further, the amount of the solvent may be based on the following third stage of the reaction stage of the formaldehyde-benzoquinone (3) and cyanic acid, or the fourth stage of the reaction stage of the following phenyl triazolidinone (4) and an oxidizing agent. Etc., with the reactants and reaction conditions in each stage, etc., may vary moderately and cannot be determined.

又，所得甲醛-苯腙類(3)可藉混合物狀直接提供後續步驟，或亦可在該步驟中進行精製、單離及去除水層而分離等任意處理後，提供後續步驟。Further, the obtained formaldehyde-benzoquinone (3) may be directly supplied to the subsequent step by a mixture, or may be subjected to any treatment such as purification, separation, and removal of the aqueous layer in this step, and then provides a subsequent step.

<苯基***烷酮類(4)之合成(第3階段)><Synthesis of Phenyltriazolidinones (4) (Phase 3)>

其次，本發明之苯基***啉酮類(5)之製造方法中較佳使用之「第3階段」中，將上述甲醛-苯腙類(3)和氰酸在溶劑中反應，形成苯基***烷酮類(4)。Next, in the "third stage" which is preferably used in the method for producing a phenyltriazolinone (5) of the present invention, the above-formaldehyde-benzoquinone (3) and cyanic acid are reacted in a solvent to form a benzene. Triazolone ketones (4).

該第3階段之反應係將上述第2階段中所得甲醛-苯腙類(3)可不進行精製、單離及去除水層而分離等任意處理，直接和氰酸反應而有效達成。又，亦可從上述第2階段中所得含有甲醛-苯腙類(3)之反應混合物將甲醛-苯腙類(3)進行精製、單離或水層的去除之後，再進行第3階段以後之反應。In the third-stage reaction, the formaldehyde-benzoquinone (3) obtained in the second step can be arbitrarily treated without any purification, separation, and separation of the aqueous layer, and can be directly reacted with cyanic acid to be effectively achieved. Further, the formaldehyde-benzoquinone (3) may be purified, separated, or removed from the reaction mixture containing the formaldehyde-benzoquinone (3) obtained in the second step, and then after the third stage. The reaction.

又，第3階段之反應係使用含有第2步驟所得甲醛-苯腙類(3)之混合物進行時，前述混合物中所含甲醛-苯腙類(3)之量可使用高速液體層析等分析而決定之。Further, when the third-stage reaction is carried out using a mixture containing the formaldehyde-benzoquinone (3) obtained in the second step, the amount of the formaldehyde-benzoquinone (3) contained in the mixture can be analyzed by high-speed liquid chromatography or the like. And decided.

該第3階段之反應，一般在-10℃至+60℃，較佳在0℃至+30℃的溫度，常壓下，一般進行1至24小時，較佳為1至5小時。The reaction of the third stage is generally carried out at a temperature of from -10 ° C to +60 ° C, preferably from 0 ° C to + 30 ° C, at normal pressure for from 1 to 24 hours, preferably from 1 to 5 hours.

理論上，上述甲醛-苯腙類(3)和氰酸可使用相等莫耳量，一般，對於甲醛-苯腙類(3)1莫耳計，氰酸為1.0至3.0莫耳，以1.0至2.0莫耳量使用為較佳。Theoretically, the above-formaldehyde-benzoquinone (3) and cyanic acid can be used in an equivalent molar amount. Generally, for formaldehyde-benzoquinone (3) 1 molar, cyanic acid is 1.0 to 3.0 m, from 1.0 to 2.0 Moir usage is preferred.

從操作處理效率性等方面而言，溶劑與上述第2階段中所用者相同。The solvent is the same as that used in the second stage described above in terms of handling efficiency and the like.

使用有機溶劑及水之混合溶劑時，對於有機溶劑100重量份而言，水一般為1至500重量份之量，以10至200重量份之量使用為較佳。When a mixed solvent of an organic solvent and water is used, water is usually used in an amount of from 1 to 500 parts by weight, based on 100 parts by weight of the organic solvent, and is preferably used in an amount of from 10 to 200 parts by weight.

又，該溶劑量，對於甲醛-苯腙類(3)1莫耳計，以100g至5000g之量使用。Further, the amount of the solvent is used in an amount of from 100 g to 5000 g for the formaldehyde-benzoquinone (3) 1 Torr.

又，第3階段所得苯基***烷酮類(4)，必要時，可精製、單離之，一般，以混合物狀直接提供第4階段。Further, the phenyltriazolidinone (4) obtained in the third stage can be purified and isolated if necessary, and generally, the fourth stage is directly provided in the form of a mixture.

<苯基***啉酮類(5)之合成(第4階段)><Synthesis of Phenyltriazolinones (5) (Phase 4)>

其次，本發明之苯基***啉酮類(5)之製造方法中，該「第4階段」中，選擇自次鹵酸鹽及氧中之氧化劑，和上述苯基***烷酮類(4)，在無觸媒下或氧化觸媒存在下，在溶劑中反應，形成目的物之苯基***啉酮類(5)。Next, in the method for producing a phenyltriazolinone (5) of the present invention, in the "fourth stage", an oxidizing agent from a hypohalite and oxygen, and the above phenyl triazolidinone are selected ( 4), in the absence of a catalyst or in the presence of an oxidation catalyst, reacting in a solvent to form a phenyltriazolinone (5) of the desired product.

第3階段中所得苯基***烷酮類(4)，一般不經單離，精製，以含有苯基***烷酮類(4)之混合物狀直接提供第4階段。因此，該反應可在含有第3階段所得苯基***烷酮類(4)之反應混合物中，添加氧化劑而有效率地進行。The phenyltriazolidinone (4) obtained in the third stage is generally unpurified and purified, and the fourth stage is directly provided in the form of a mixture containing the phenyltriazolidinone (4). Therefore, this reaction can be efficiently carried out by adding an oxidizing agent to the reaction mixture containing the phenyl triazolidinone (4) obtained in the third stage.

該第4階段之反應，一般在-20至60℃，較佳在0℃至30℃的溫度，常壓下，進行1至24小時，以2至8小時為較佳。The reaction of the fourth stage is carried out usually at from -20 to 60 ° C, preferably at a temperature of from 0 ° C to 30 ° C, at normal pressure for from 1 to 24 hours, preferably from 2 to 8 hours.

上述氧化劑之次鹵酸鹽之例如次氯酸鈉、次氯酸鉀、次氯酸鈣、次溴酸鈉、次溴酸鉀等，其中以次氯酸鈉就泛用性高等方面而言較佳。The hypohalite of the above oxidizing agent is, for example, sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, sodium hypobromite or potassium hypobromite, and among them, sodium hypochlorite is preferred in terms of high versatility.

上述次鹵酸鹽，必要時可在氧化觸媒之存在下使用。The above hypohalite may be used in the presence of an oxidation catalyst if necessary.

又，所使用氧化觸媒，例如可列舉氯化亞鐵、氯化鐵、溴化亞鐵、溴化鐵、硫酸亞鐵、硫酸鐵、氯化鈷、溴化鈷、硫酸鈷、硝酸鈷、乙酸鈷、氯化鎳等鐵族鹽；乙醯基丙酮鐵(III)、乙醯基丙酮鈷(II)、雙(亞柳基)乙二胺鈷(II)、六胺鎳(II)氯化物等鐵族錯合物；鉑、鈀等鉑族；氯化鈀、乙酸鈀、氧化鉑等鉑族鹽；氯(三苯膦)銠、二氯雙(三苯膦)釘等鉑族錯合物；氯化亞銅(I)、溴化亞銅(I)、氯化銅(II)、溴化銅(II)、硫酸銅、乙酸銅等銅鹽；乙醯基丙酮銅(II)、雙乙二胺銅等銅錯合物；氯化鋅等鋅鹽；三(乙二胺)鋅等鋅錯合物；五氧化二釩等釩鹽；氧化釩乙醯基丙酮等釩錯合物；氯化鈰、碘化釤等稀土類鹽等。Further, examples of the oxidation catalyst to be used include ferrous chloride, ferric chloride, ferrous bromide, iron bromide, ferrous sulfate, iron sulfate, cobalt chloride, cobalt bromide, cobalt sulfate, and cobalt nitrate. Iron group salts such as cobalt acetate and nickel chloride; iron (III) acetonitrile, cobalt (II) acetylate, bis(arylene) ethylenediamine cobalt (II), hexamine nickel (II) chloride Iron group complexes such as compounds; platinum groups such as platinum and palladium; platinum group salts such as palladium chloride, palladium acetate and platinum oxide; platinum group errors such as chloro (triphenylphosphine) ruthenium and dichlorobis (triphenylphosphine) nails Copper salt of copper (I) chloride, copper (I) bromide, copper (II) chloride, copper (II) bromide, copper sulfate, copper acetate, etc.; copper (II) , copper complexes such as bisethylenediamine copper; zinc salts such as zinc chloride; zinc complexes such as tris(ethylenediamine)zinc; vanadium salts such as vanadium pentoxide; vanadium complexes such as vanadylacetate a rare earth salt such as barium chloride or barium iodide.

該觸媒可單獨或2種以上混合使用。These catalysts may be used singly or in combination of two or more kinds.

理論上，該反應之際，上述苯基***烷酮類(4)和氧化劑可使用相等莫耳量，一般，對於苯基***烷酮類(4)1莫耳計，氧化劑一般為1.0至1.4莫耳量，以1.0至1.1莫耳量使用為較佳。Theoretically, at the time of the reaction, the above phenyl triazolidinone (4) and the oxidizing agent may be used in an equivalent molar amount. Generally, for the phenyl triazolidinone (4) 1 molar meter, the oxidizing agent is generally 1.0. To 1.4 moles, it is preferred to use from 1.0 to 1.1 moles.

具體言之，例如可使用5至25%(重量/重量)，較佳為5至15%濃度之次氯酸鈉之水溶液。又，必要時，所用上述氧化觸媒量，對於苯基***烷酮類(4)計，一般為0.01至10.0莫耳%，以0.1至1.0莫耳%之量使用為較佳。Specifically, for example, an aqueous solution of sodium hypochlorite at a concentration of 5 to 25% (w/w), preferably 5 to 15%, can be used. Further, the amount of the above-mentioned oxidizing catalyst to be used is usually 0.01 to 10.0 mol% based on the phenyl triazolidinone (4), and it is preferably used in an amount of 0.1 to 1.0 mol%.

又，第4階段之反應，使用含有第3步驟所得苯基***烷酮類(4)之混合物進行時，混合物中之前述苯基***烷酮類(4)量可使用高速液體層析分析而決定之。Further, when the fourth-stage reaction is carried out using a mixture containing the phenyltriazolidinone (4) obtained in the third step, the amount of the phenyltriazolidinone (4) in the mixture can be used in high-speed liquid chromatography. Analyze and decide.

溶劑可使用和上述第2階段、第3階段中所用者相同，使用有機溶劑及水之混合溶劑時，也可按照相同混合比率使用。又，該溶劑，對於苯基***烷酮類(4)1莫耳計，以100g至6000g之量使用。The solvent can be used in the same manner as in the second and third stages described above, and when a mixed solvent of an organic solvent and water is used, it can be used in the same mixing ratio. Further, the solvent is used in an amount of from 100 g to 6000 g for the phenyl triazolidinone (4) 1 Torr.

本發明之苯基***啉酮類(5)之製造方法中，於上述第1至第4階段之各階段中，上述反應液至少加以溫和地攪拌為較佳。In the method for producing a phenyltriazolinone (5) of the present invention, it is preferred that the reaction liquid is at least gently stirred in each of the first to fourth stages.

反應結束後，所用上述混合溶劑(有機溶劑及水之混合溶劑)中之有機溶劑，使用蒸餾設備等從反應混合物中蒸餾並回收以供再利用。After the completion of the reaction, the organic solvent in the above mixed solvent (mixed solvent of an organic solvent and water) is distilled from the reaction mixture using a distillation apparatus or the like and recovered for reuse.

目的物之苯基***啉酮類(5)經一般之萃取分液操作將其單離，或蒸餾去除有機溶劑之後，使目的物(5)沈澱水中，藉過濾而分取之。The phenyltriazolinone of the target substance (5) is isolated by a general extraction and liquid separation operation, or after the organic solvent is distilled off, the object (5) is precipitated in water and separated by filtration.

另外，單離精製目的物之苯基***啉酮類(5)之方法如下。Further, the method of separating the phenyltriazolinones (5) of the object of interest is as follows.

即，蒸餾去除反應混合物中之有機溶劑後，溶解目的物之苯基***啉酮類(5)於氫氧化鈉等鹼水溶液形成鹽後，用有機溶劑洗淨之。That is, after the organic solvent in the reaction mixture is distilled off, the phenyltriazolinone (5) which dissolves the target substance is formed into a salt in an aqueous alkali solution such as sodium hydroxide, and then washed with an organic solvent.

繼之，含有經洗淨處理之苯基***啉酮類(5)鹽之液中，加入鹽酸等礦酸，中和該含有苯基***啉酮類(5)鹽之液，使目的物之苯基***啉酮類(5)析出。Then, a mineral acid such as hydrochloric acid is added to the liquid containing the washed phenyltriazolinone (5) salt, and the liquid containing the phenyltriazolinone (5) salt is neutralized for the purpose. The phenyl triazolinones (5) precipitated.

過濾及水洗所析出結晶而得高純度之苯基***啉酮類(5)。The crystals precipitated by filtration and washing to obtain a highly pure phenyltriazolinone (5).

另一種單離精製目的物之苯基***啉酮類(5)之方法如下。Another method of separating the phenyl triazolinones (5) of the object of interest is as follows.

即，反應結束後，首先於反應混合物中加入鹼，形成目的物之苯基***啉酮類(5)之鹼鹽，同時進行分解反應副產物之鹼處理。其次，使用有機溶劑及水之混合溶劑為反應溶劑時，蒸餾去除有機溶劑後，含有目的物之苯基***啉酮類(5)之鹼鹽及不純物之水性混合物，以有機溶劑洗淨而可從該水性混合物中不伴隨目的物之損失而除去不純物。Namely, after completion of the reaction, a base is first added to the reaction mixture to form an alkali salt of the phenyltriazolinone (5) of the target, and a base treatment of a by-product of the decomposition reaction is carried out. Next, when a mixed solvent of an organic solvent and water is used as a reaction solvent, an organic solvent is distilled off, and an aqueous mixture containing an alkali salt of a phenyltriazolinone (5) and an impurity of the target substance is washed with an organic solvent. The impurities can be removed from the aqueous mixture without loss of the target.

繼之，含有經有機溶劑洗淨處理之苯基***啉酮類(5)之鹼鹽水溶液中，加入鹽酸等礦酸，中和該含有苯基***啉酮類(5)之鹼鹽水溶液，而使目的物之苯基***啉酮類(5)析出。Then, a mineral acid such as hydrochloric acid is added to the aqueous solution of the alkali salt of the phenyltriazolinone (5) which is washed with an organic solvent, and the alkali salt containing the phenyltriazolinone (5) is neutralized. The aqueous solution is used to precipitate the phenyltriazolinones (5) of the object.

所析出結晶經由過濾水洗而可得高純度之苯基***啉酮類(5)。The precipitated crystals are washed with filtered water to obtain a highly pure phenyltriazolinone (5).

該鹼處理一般在0℃至100℃，較佳在20℃至90℃的溫度，常壓下進行1至24小時，以1至12為較佳。The alkali treatment is usually carried out at a temperature of from 0 ° C to 100 ° C, preferably from 20 ° C to 90 ° C, at normal pressure for from 1 to 24 hours, preferably from 1 to 12.

所使用之鹼，可列舉氫氧化鈉、氫氧化鉀、碳酸鈉、碳酸鉀等。其中就泛用性高等方面而言，以氫氧化鈉為較佳。該鹼之用量，一般，對於苯基***啉酮類(5)1莫耳，為1.2至4.0莫耳，以2.0至2.5莫耳量使用為較佳。Examples of the base to be used include sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. Among them, sodium hydroxide is preferred in terms of high versatility. The amount of the base is generally from 1.2 to 4.0 moles for the phenyltriazolinone (5) 1 mole, and preferably from 2.0 to 2.5 moles.

上述洗淨用有機溶劑之例如戊烷、己烷、庚烷、石油醚等脂肪族烴類；苯、甲苯、二甲苯等芳香族烴類；***、異丙醚、第三丁基甲基醚等醚類；二氯甲烷、氯仿、1,2-二氯乙烷、氯苯、二氯苯等鹵化烴類等。The above-mentioned organic solvent for washing is an aliphatic hydrocarbon such as pentane, hexane, heptane or petroleum ether; an aromatic hydrocarbon such as benzene, toluene or xylene; and an ether such as diethyl ether, diisopropyl ether or tert-butyl methyl ether. Class; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, and the like.

在上述條件下，單離精製苯基***啉酮類(5)時，反應副產物會被鹼分解，所以使用有機溶劑洗淨鹼處理後之水性混合物，可不伴隨目的物之損失而去除不純物，以高收率取得高純度之苯基***啉酮類(5)。Under the above conditions, when the purified phenyltriazolinones (5) are separated, the by-products of the reaction are decomposed by alkali, so that the aqueous mixture after the alkali treatment is washed with an organic solvent, and the impurities can be removed without loss of the target. High purity phenyl triazolinones (5) are obtained in high yield.

所得目的物，必要時再用有機溶劑洗淨，亦可利用管柱層析或再結晶等方法精製。The object to be obtained may be washed with an organic solvent if necessary, or may be purified by column chromatography or recrystallization.

據此所得苯基***啉酮類(5)可提供作為農藥、醫藥之製造用原料等適佳用途。According to the phenyltriazolinones (5), the phenyltriazolinones (5) can be used as a raw material for the production of agricultural chemicals and pharmaceuticals.

又，本發明中，中間體生成物之上述一般式(2)所示苯肼類、或中間體生成物之上述一般式(3)所示甲醛-苯腙類以及中間體生成物之上述一般式(4)所示苯基***烷酮類，可不經精製、單離及去除水層之分離等任意方法處理，實施全步驟。Further, in the present invention, the above-mentioned general formula (2) represented by the general formula (2), or the intermediate product, the above-mentioned general formula (3) of the formaldehyde-benzoquinone and the intermediate product are generally The phenyl triazolidinone represented by the formula (4) can be subjected to any method such as purification, separation, and separation of the aqueous layer, and the entire step can be carried out.

又，上述各階段中，中間體生成物之上述一般式(2)所示苯肼類、中間體生成物之上述一般式(3)所示甲醛-苯腙類、或中間體生成物之上述一般式(4)所示苯基***烷酮類，必要時亦可經精製、單離及去除水層而分離之任意方法處理後，實施各步驟。Further, in the above-mentioned intermediates, the above-mentioned general formula (2) of the benzoquinone or intermediate product of the intermediate product is the above-mentioned formaldehyde-benzoquinone or the intermediate product represented by the general formula (3). The phenyl triazolidinone represented by the general formula (4) may be subjected to any step of purification, isolation, and removal of the aqueous layer, if necessary, and then subjected to each step.

該情況中，上述苯肼類、上述甲醛-苯腙類及上述苯基***烷酮類中，可為僅其1種使用上述任意方法處理，可為其2種以上使用上述任意方法處理，亦可為其3種皆用上述任意方法處理。In this case, one of the above-mentioned benzoquinones, the above-mentioned formaldehyde-benzoquinones, and the above-mentioned phenyltriazolidinones may be treated by any of the above methods, and two or more of them may be treated by any of the above methods. It is also possible to treat all three of them by any of the above methods.

上述各步驟中，溶媒以不影響反應，並且對於苯胺類(1)、苯肼類(2)、甲醛-苯腙類(3)及苯基***烷酮類(4)之任何種類皆具有良好溶解性之溶劑，在反應操作上為較佳，但可使用對於上述任何種類具有至少部分溶解或可混合之前述溶劑。In the above steps, the solvent does not affect the reaction, and has any type of aniline (1), benzoquinone (2), formaldehyde-benzoquinone (3), and phenyl triazolidinone (4). A solvent having good solubility is preferred in the reaction operation, but the aforementioned solvent having at least partially dissolved or miscible with any of the above kinds may be used.

依據本發明之製造方法，經由上述第1階段至第4階段所構成一連串之反應，可在上述較低溫之反應條件，且短時間內以高收率而得高純度之目的物之苯基***啉酮類(5)。According to the production method of the present invention, a series of reactions comprising the first stage to the fourth stage can be used to obtain a high-purity target phenyl group in a high yield in a short period of time under the above-mentioned reaction conditions of a relatively low temperature. Oxazolinones (5).

實施例Example

本發明藉實施例具體說明如下，唯本發明不侷限於該實施例範圍。The present invention is specifically described below by way of embodiments, but the invention is not limited to the scope of the embodiments.

[實施例1][Example 1] <1-(2,4-二氯苯基)-1,2,4-***-5-酮之製造>Production of <1-(2,4-dichlorophenyl)-1,2,4-triazol-5-one>

以備有攪拌機、溫度計、迪姆羅回流冷凝器之1L容量4頸燒瓶做為反應容器，加入330g之10%鹽酸及48.6g之2,4-二氯苯胺(純度>99%)，在30℃攪拌15分鐘。A 1 L capacity 4-necked flask equipped with a stirrer, a thermometer, and a Dimro reflux condenser was used as a reaction vessel, and 330 g of 10% hydrochloric acid and 48.6 g of 2,4-dichloroaniline (purity >99%) were added at 30 Stir at °C for 15 minutes.

冷卻所得混合物至-5℃，用30分鐘滴加63g之35%亞硝酸鈉水溶液之後，在-3℃至0℃攪拌1小時，而得重氮鹽溶液。The resulting mixture was cooled to -5 ° C, and 63 g of a 35% aqueous solution of sodium nitrite was added dropwise thereto over 30 minutes, followed by stirring at -3 ° C to 0 ° C for 1 hour to obtain a diazonium salt solution.

不同於上述容器，另以備有攪拌機、溫度計、迪姆羅回流冷凝器之2L容量之4頸燒瓶做為反應容器。在該反應容器內，97.4g之亞硫酸鈉(純度為97%)溶解於350g之水中，加入95%之硫酸調整為pH7.2。Unlike the above-mentioned container, a 2-neck flask having a 2 L capacity equipped with a stirrer, a thermometer, and a Dimro reflux condenser was used as a reaction vessel. In the reaction vessel, 97.4 g of sodium sulfite (purity of 97%) was dissolved in 350 g of water, and 95% of sulfuric acid was added to adjust to pH 7.2.

冷卻該溶液至10℃，迅速添加事先調製好之重氮鹽溶液。The solution was cooled to 10 ° C, and the previously prepared diazonium salt solution was quickly added.

所得該混合物用30分鐘升溫至20℃之後，加熱至65℃，在同溫度攪拌2小時還原重氮鹽，獲得含有2,4-二氯苯肼磺酸鹽之混合物。The obtained mixture was heated to 20 ° C over 30 minutes, heated to 65 ° C, and stirred at the same temperature for 2 hours to reduce the diazonium salt to obtain a mixture containing 2,4-dichlorophenyl sulfonate.

於所得混合物中加入200g之甲苯，在65℃攪拌15分鐘後洗淨水層，去除未反應原料及反應副產物之後，靜置而分液。200 g of toluene was added to the obtained mixture, and the mixture was stirred at 65 ° C for 15 minutes, and then the aqueous layer was washed to remove unreacted raw materials and reaction by-products, and then left to stand for liquid separation.

於備有攪拌機、溫度計、迪姆羅回流冷凝器之3L容量之4頸燒瓶之反應容器中，放入經分液之水層，繼之，在20℃用20分鐘滴加313g之35%鹽酸之後，在75℃攪拌3小時，水解2,4-二氯苯肼磺酸鹽，獲得含有2,4-二氯苯肼之鹽酸鹽之混合物。In a reaction vessel equipped with a 3 L flask of a 3 L capacity equipped with a stirrer, a thermometer, and a Dimro reflux condenser, a water-separated aqueous layer was placed, followed by dropwise addition of 313 g of 35% hydrochloric acid at 20 ° C for 20 minutes. Thereafter, the mixture was stirred at 75 ° C for 3 hours to hydrolyze 2,4-dichlorophenyl sulfonate to obtain a mixture containing hydrochloride of 2,4-dichlorophenylhydrazine.

冷卻該混合物至10℃，慢慢加入300g之50%之氫氧化鈉水溶液，使2,4-二氯苯肼析出，繼之，過濾去除水層獲得2,4-二氯苯肼之粗生成物。The mixture was cooled to 10 ° C, and 300 g of a 50% aqueous sodium hydroxide solution was slowly added to precipitate 2,4-dichlorophenylhydrazine, followed by filtration to remove the aqueous layer to obtain a crude product of 2,4-dichlorophenylhydrazine. Things.

所得2,4-二氯苯肼之粗生成物(純度為90%)為55g。The crude product of the obtained 2,4-dichlorophenylhydrazine (purity: 90%) was 55 g.

以備有攪拌機、溫度計、迪姆羅回流冷凝器之1L容量之4頸燒瓶做為反應容器，放入所得2,4-二氯苯肼之粗生成物，繼之，加入300g之第三丁醇、50g之水、2.5g之乙酸鈉，一邊在20℃維持混合物之pH值在6至8，一邊用10分鐘滴加27.5g之36%甲醛水溶液之後，在同溫度，同pH範圍攪拌2小時，而得含有甲醛-2,4-二氯苯腙之混合物。A 4-neck flask equipped with a 1 L capacity of a stirrer, a thermometer, and a Dimro reflux condenser was used as a reaction vessel, and the obtained crude product of 2,4-dichlorophenylhydrazine was placed, followed by the addition of 300 g of the third. Alcohol, 50 g of water, 2.5 g of sodium acetate, while maintaining the pH of the mixture at 6 to 8 at 20 ° C, while adding 27.5 g of a 36% aqueous formaldehyde solution over 10 minutes, stirring at the same temperature and the same pH range 2 In an hour, a mixture of formaldehyde-2,4-dichlorophenylhydrazine is obtained.

冷卻該反應混合物至10℃，加入19.4g之氰酸，在同溫度攪拌4小時，獲得含有2,4-二氯苯基***烷酮之混合物。The reaction mixture was cooled to 10 ° C, and 19.4 g of cyanic acid was added thereto, and stirred at the same temperature for 4 hours to obtain a mixture containing 2,4-dichlorophenyltriazolidinone.

分離之兩層(有機層及水層)中，去除水層而去除未反應之甲醛及鹽類之後，用30分鐘在10℃於所得有機層(即，第三丁醇層)中滴加162.5g之11%次氯酸鈉水溶液。In the separated two layers (organic layer and aqueous layer), after removing the aqueous layer to remove unreacted formaldehyde and salts, 162.5 was added dropwise to the obtained organic layer (ie, the third butanol layer) at 10 ° C for 30 minutes. 11% aqueous solution of sodium hypochlorite.

滴加後，在10℃攪拌1小時，再於25℃攪拌5小時，獲得含有標題之目的物質之混合物。After the dropwise addition, the mixture was stirred at 10 ° C for 1 hour and then at 25 ° C for 5 hours to obtain a mixture containing the title material.

蒸餾去除第三丁醇後之水層中，加入24g之氫氧化鈉，使形成標題之目的物質之鹽並溶解於水層中，繼之，加入100g之甲苯，攪拌而洗淨水層，從水層除去反應副產物之後，靜置而分液之。After distilling off the third butanol, add 24 g of sodium hydroxide to form a salt of the title substance and dissolve it in the water layer, then add 100 g of toluene, and then wash and wash the water layer. After removing the by-products of the reaction, the aqueous layer was allowed to stand for liquid separation.

經分液所得水層冷卻至15℃，使用15分鐘滴加94g之35%鹽酸，中和上述水層，使標題目的物質游離，過濾而收集所析出之結晶，以200g之水洗淨之。The aqueous layer obtained by liquid separation was cooled to 15 ° C, and 94 g of 35% hydrochloric acid was added dropwise thereto over 15 minutes to neutralize the aqueous layer, and the title material was freed, and the precipitated crystals were collected by filtration and washed with 200 g of water.

在真空乾燥機中充分乾燥上述結晶，而得63.5g之標題之目的化合物(收率為92%，純度為97%)。其融點為190至191℃。EI-MS：M⁺ 229。The crystals were sufficiently dried in a vacuum dryer to obtain 63.5 g of the title compound (yield: 92%, purity: 97%). Its melting point is 190 to 191 °C. EI-MS: M ⁺ 229.

[實施例2][Embodiment 2] <1-(2,4-二氯苯基)-1,2,4-***-5-酮之製造>Production of <1-(2,4-dichlorophenyl)-1,2,4-triazol-5-one>

以備有攪拌機、溫度計、迪姆羅回流冷凝器之1L容量之4頸燒瓶做為反應容器，加入330g之10%鹽酸及48.6g之2,4-二氯苯胺(純度>99%)，在30℃攪拌15分鐘。A 4-neck flask of 1 L capacity equipped with a stirrer, a thermometer, and a Dimro reflux condenser was used as a reaction vessel, and 330 g of 10% hydrochloric acid and 48.6 g of 2,4-dichloroaniline (purity >99%) were added. Stir at 30 ° C for 15 minutes.

冷卻所得混合物至-5℃，用30分鐘滴加63g之35%亞硝酸鈉水溶液之後，在-3℃至0℃攪拌1小時，獲得重氮鹽溶液。The resulting mixture was cooled to -5 ° C, and 63 g of a 35% aqueous solution of sodium nitrite was added dropwise thereto over 30 minutes, followed by stirring at -3 ° C to 0 ° C for 1 hour to obtain a diazonium salt solution.

上述容器之外，另以備有攪拌機、溫度計、迪姆羅回流冷凝器之4L容量之4頸燒瓶做為反應容器。在該反應容器內，於350g之水中溶解97.4g之亞硫酸鈉(純度為97%)，加入95%之硫酸調整為pH7.2。In addition to the above-mentioned container, a 4-neck flask having a 4 L capacity equipped with a stirrer, a thermometer, and a Dimro reflux condenser was used as a reaction vessel. In the reaction vessel, 97.4 g of sodium sulfite (purity: 97%) was dissolved in 350 g of water, and 95% of sulfuric acid was added to adjust to pH 7.2.

冷卻該溶液至10℃，迅速添加先前調製之重氮鹽溶液。The solution was cooled to 10 ° C and the previously prepared diazonium salt solution was quickly added.

用30分鐘將所得混合物提升至20℃之後，加熱至65℃，在同溫度攪拌2小時而還原重氮鹽，獲得含有2,4-二氯苯肼磺酸鹽之混合物。After the resulting mixture was elevated to 20 ° C over 30 minutes, it was heated to 65 ° C, and stirred at the same temperature for 2 hours to reduce the diazonium salt to obtain a mixture containing 2,4-dichlorophenyl sulfonate.

於所得混合物中加入200g之甲苯，在65℃攪拌15分鐘，洗淨水層，從水層去除未反應原料及反應副產物之後，分液之。200 g of toluene was added to the obtained mixture, and the mixture was stirred at 65 ° C for 15 minutes to wash the aqueous layer, and the unreacted raw materials and reaction by-products were removed from the aqueous layer, and then separated.

從分液所回收水層放入備有攪拌機、溫度計、迪姆羅回流冷凝器之3L容量之4頸燒瓶的反應容器中，使用20分鐘滴加313g之35%鹽酸後，在75℃攪拌3小時，水解2,4-二氯苯肼磺酸鹽，獲得含有2,4-二氯苯肼鹽酸鹽之混合物。The water layer recovered from the liquid separation was placed in a reaction vessel of a 3-liter flask equipped with a stirrer, a thermometer, and a Dimro reflux condenser, and 313 g of 35% hydrochloric acid was added dropwise thereto over 20 minutes, followed by stirring at 75 ° C. The 2,4-dichlorophenylhydrazine sulfonate was hydrolyzed to obtain a mixture containing 2,4-dichlorophenylhydrazine hydrochloride.

冷卻該混合物至10℃，慢慢加入300g之50%氫氧化鈉水溶液，使2,4-二氯苯肼析出，繼之，過濾而去除水層，獲得2,4-二氯苯肼之粗製物。The mixture was cooled to 10 ° C, and 300 g of a 50% aqueous sodium hydroxide solution was slowly added to precipitate 2,4-dichlorophenyl hydrazine, followed by filtration to remove the aqueous layer to obtain a crude 2,4-dichlorophenylhydrazine. Things.

所得2,4-二氯苯肼之粗生成物為55g(純度為90%)。The crude product of the obtained 2,4-dichlorophenylhydrazine was 55 g (purity: 90%).

以備有攪拌機、溫度計、迪姆羅回流冷凝器之1L容量之4頸燒瓶做為反應容器，加入該2,4-二氯苯肼粗生成物，繼之，加入300g之第三丁醇、50g之水、2.5g之乙酸鈉，一邊在20℃維持pH6至8，一邊使用10分鐘滴加27.5g之36%甲醛-2,4-二氯苯腙之混合物。A 4-neck flask having a 1 L capacity equipped with a stirrer, a thermometer, and a Dimro reflux condenser was used as a reaction vessel, and the crude product of 2,4-dichlorophenylhydrazine was added, followed by the addition of 300 g of tert-butanol. 50 g of water and 2.5 g of sodium acetate were added dropwise to a mixture of 27.5 g of 36% formaldehyde-2,4-dichlorophenylhydrazine over 10 minutes while maintaining a pH of 6 to 8 at 20 °C.

冷卻所得反應混合物至10℃，加入19.4g之氰酸，在同溫度攪拌4小時，分離而成之2層(即有機層、水層)之中，藉去除水層而去除未反應之甲醛及鹽類。The obtained reaction mixture was cooled to 10 ° C, and 19.4 g of cyanic acid was added thereto, and stirred at the same temperature for 4 hours, and separated into two layers (ie, an organic layer and an aqueous layer), and the unreacted formaldehyde was removed by removing the aqueous layer and Salt.

繼之，於所得有機層(即第三丁醇層)中加入180mg之乙酸酮(II)‧1水合物，一邊利用氧氣鋼瓶在反應混合物中以10ml/分鐘之流速導入氧氣，一邊在10℃攪拌8小時，再在25℃攪拌5小時，獲得含有標題之目的物質之混合物。Then, 180 mg of ketone (II) acetate hydrate was added to the obtained organic layer (ie, the third butanol layer), and oxygen was introduced into the reaction mixture at a flow rate of 10 ml/min using an oxygen cylinder while the temperature was 10 ° C. The mixture was stirred for 8 hours and further stirred at 25 ° C for 5 hours to obtain a mixture containing the title material.

蒸餾去除第三丁醇之後之水層中，加入24g之氫氧化鈉、100g之甲苯，攪拌而洗淨水層，去除反應副產物之後，靜置而分液之。After the third layer of butanol was distilled off, 24 g of sodium hydroxide and 100 g of toluene were added, and the aqueous layer was washed with stirring to remove reaction by-products, and then left to stand for liquid separation.

冷卻經分液之水層至15℃，用15分鐘滴加94g之35%鹽酸中和前述水層，使標題之目的物質游離，過濾而收集所析出之結晶，以200g之水洗淨之。The water layer which was separated was cooled to 15 ° C, and the aqueous layer was neutralized by dropwise addition of 94 g of 35% hydrochloric acid over 15 minutes, and the title material was separated, filtered, and the crystals precipitated were collected and washed with 200 g of water.

所得結晶在真空乾燥機中充分乾燥，獲得64.2g之標題之目的物質(收率為93%，純度為96%)。融點為190至191℃。EI-MS：M⁺ 229。The obtained crystals were sufficiently dried in a vacuum dryer to obtain 64.2 g of the title compound (yield: 93%, purity: 96%). The melting point is 190 to 191 °C. EI-MS: M ⁺ 229.

[實施例3][Example 3] <1-(2,4-二氯苯基)-1,2,4-***基-5-酮之製造>Production of <1-(2,4-dichlorophenyl)-1,2,4-triazolyl-5-one>

冷卻所得混合物至-5℃，用30分鐘滴加63g之35%亞硝酸鈉水溶液後，在-3℃至0℃攪拌1小時，獲得重氮鹽溶液。The resulting mixture was cooled to -5 ° C, and 63 g of a 35% aqueous solution of sodium nitrite was added dropwise thereto over 30 minutes, followed by stirring at -3 ° C to 0 ° C for 1 hour to obtain a diazonium salt solution.

上述容器之外，另以備有攪拌機、溫度計、迪姆羅回流冷凝器之2L容量之4頸燒瓶做為反應容器。在該反應容器中，於350g之水中溶解97.4g之亞硫鈉(純度為97%)，加入95%硫酸調整為pH7.2。In addition to the above-mentioned container, a 4-neck flask having a 2 L capacity equipped with a stirrer, a thermometer, and a Dimro reflux condenser was used as a reaction vessel. In the reaction vessel, 97.4 g of sodium sulfite (purity of 97%) was dissolved in 350 g of water, and adjusted to pH 7.2 by adding 95% sulfuric acid.

冷卻該溶液至10℃，迅速添加先前製備之重氮鹽溶液。The solution was cooled to 10 ° C and the previously prepared diazonium salt solution was quickly added.

使用30分鐘使所得混合物昇溫至20℃後，加熱至65℃，在同溫度攪拌2小時還原重氮鹽，獲得含有2,4-二氯苯肼磺酸鹽之混合物。於所得混合物中加入200g之甲苯，在65℃攪拌15分鐘而洗淨水層，從水層去除未反應原料及反應副產物之後，靜置而分液。After the resulting mixture was heated to 20 ° C over 30 minutes, it was heated to 65 ° C, and the diazonium salt was reduced by stirring at the same temperature for 2 hours to obtain a mixture containing 2,4-dichlorophenyl sulfonate. 200 g of toluene was added to the obtained mixture, and the aqueous layer was washed by stirring at 65 ° C for 15 minutes, and the unreacted raw materials and reaction by-products were removed from the aqueous layer, and then left to stand for liquid separation.

經分液之水層放入備有攪拌機、溫度計、迪姆羅回流冷凝器之3L容量之4頸燒瓶所成反應容器中，使用20分鐘在20℃，滴加313g之35%鹽酸後，在75℃攪拌3小時，水解先前所得2,4-二氯苯肼磺酸鹽，獲得含有2,4-二氯苯肼鹽酸鹽之混合物。The liquid layer was placed in a reaction vessel containing a 3 L flask of a 3 L capacity equipped with a stirrer, a thermometer, and a Dimro reflux condenser. After adding 313 g of 35% hydrochloric acid at 20 ° C for 20 minutes, After stirring at 75 ° C for 3 hours, the previously obtained 2,4-dichlorophenylhydrazine sulfonate was hydrolyzed to obtain a mixture containing 2,4-dichlorophenylhydrazine hydrochloride.

冷卻該混合物至10℃，慢慢加入300g之50%氫氧化鈉水溶液，使2,4-二氯苯肼析出，獲得2,4-二氯苯肼水性懸濁液。The mixture was cooled to 10 ° C, and 300 g of a 50% aqueous sodium hydroxide solution was slowly added to precipitate 2,4-dichlorophenylhydrazine to obtain an aqueous suspension of 2,4-dichlorophenylhydrazine.

繼之，於該懸濁液中加入2.5g之乙酸鈉，一邊在20℃維持混合物的pH為6至8一邊用10分鐘滴加27.5g之36%甲醛水溶液後，在同溫度，同pH範圍攪拌2小時。繼之，從反應混合物藉過濾去除水層獲得甲醛-2,4-二氯苯腙粗製物。所得該甲醛-2,4-二氯苯腙粗生成物為58g(純度為90%)。Then, 2.5 g of sodium acetate was added to the suspension, and while maintaining the pH of the mixture at 6 to 8 at 20 ° C, 27.5 g of a 36% aqueous formaldehyde solution was added dropwise over 10 minutes, at the same temperature and the same pH range. Stir for 2 hours. Subsequently, the aqueous layer was removed from the reaction mixture by filtration to obtain a crude formaldehyde-2,4-dichlorophenylhydrazine. The crude formaldehyde-2,4-dichlorophenylhydrazine obtained was 58 g (purity: 90%).

繼之，於備有攪拌機、溫度計、迪姆羅回流冷凝器之1L容量之4頸燒瓶的反應容器中，放入甲醛-2,4-二氯苯腙粗生成物，加入300g之第三丁醇，冷卻混合物至10℃，加入19.4g之氰酸，在同溫度攪拌4小時，獲得含有2,4-二氯苯基***烷酮之混合物。Then, in a reaction vessel of a 4-liter flask equipped with a stirrer, a thermometer, and a Dimro reflux condenser, a crude product of formaldehyde-2,4-dichlorophenylhydrazine was placed, and 300 g of the third was added. The alcohol was cooled to 10 ° C, 19.4 g of cyanic acid was added, and stirred at the same temperature for 4 hours to obtain a mixture containing 2,4-dichlorophenyl triazolidinone.

繼之，在同溫度，使用30分鐘於所得混合物中滴加162.5g之11%次氯酸鈉水溶液。滴加後，在10℃攪拌1小時，再在25℃攪拌5小時，獲得含有標題之目的物質之混合物。Subsequently, 162.5 g of an 11% aqueous sodium hypochlorite solution was added dropwise to the resulting mixture at the same temperature for 30 minutes. After the dropwise addition, the mixture was stirred at 10 ° C for 1 hour, and further stirred at 25 ° C for 5 hours to obtain a mixture containing the title compound.

蒸餾去除第三丁醇後之水層中，加入50g之水、24g之氫氧化鈉，形成標題之目的物質之鹽並溶解於水層中，繼之，加入100g之甲苯，攪拌而洗淨水層，從水層中去除反應副產物之後，靜置而分液。After distilling off the third butanol, adding 50 g of water and 24 g of sodium hydroxide to form a salt of the title substance and dissolving in the aqueous layer, followed by adding 100 g of toluene, stirring and washing the water. The layer, after removing the reaction by-product from the aqueous layer, is allowed to stand for liquid separation.

冷卻分液所回收之水層至15℃，用15分鐘滴加94g之35%鹽酸中和前述水層，使標題之目的物質游離、過濾而收集析出之結晶，用200g之水洗淨之。The aqueous layer recovered by liquid separation was cooled to 15 ° C, and the aqueous layer was neutralized by dropwise addition of 94 g of 35% hydrochloric acid over 15 minutes, and the title material was freed, filtered, and crystals were collected and washed with 200 g of water.

所得結晶用真空乾燥機充分乾燥，獲得62.1g之標題之目的物質(收率為90%，純度為96%)。融點為190至191℃。EI-MS：M⁺ 229。The obtained crystals were sufficiently dried with a vacuum dryer to obtain 62.1 g of the title compound (yield: 90%, purity: 96%). The melting point is 190 to 191 °C. EI-MS: M ⁺ 229.

[實施例4][Example 4] <1-苯基-1,2,4-***基-5-酮之製造><Manufacture of <1-phenyl-1,2,4-triazolyl-5-one>

以備有攪拌機、溫度計、迪姆羅回流冷凝器之1L容量之4頸燒瓶做為反應容器，加入330g之10%鹽酸及27.9g之苯胺(純度>99%)，在30℃攪拌15分鐘。A 4-neck flask of a 1 L capacity equipped with a stirrer, a thermometer, and a Dimro reflux condenser was used as a reaction vessel, and 330 g of 10% hydrochloric acid and 27.9 g of aniline (purity >99%) were added, and the mixture was stirred at 30 ° C for 15 minutes.

上述容器之外，另以備有攪拌機、溫度計、迪姆羅回流冷凝器之2L容量之4頸燒瓶做為反應容器。在該反應容器內，於350g之水中溶解97.4g之亞硝酸鈉(純度為97%)，加入95%硫酸調整為pH7.2。In addition to the above-mentioned container, a 4-neck flask having a 2 L capacity equipped with a stirrer, a thermometer, and a Dimro reflux condenser was used as a reaction vessel. In the reaction vessel, 97.4 g of sodium nitrite (purity of 97%) was dissolved in 350 g of water, and 95% sulfuric acid was added to adjust to pH 7.2.

冷卻該溶液至10℃，迅速添加先前調製成之重氮鹽溶液。The solution was cooled to 10 ° C and the previously prepared diazonium salt solution was quickly added.

用30分鐘使所得混合物昇溫至20℃後，加熱至65℃，在同溫度攪拌2小時還原重氮鹽，獲得含有苯肼磺酸鹽之混合物。After the resulting mixture was heated to 20 ° C over 30 minutes, it was heated to 65 ° C, and the diazonium salt was reduced by stirring at the same temperature for 2 hours to obtain a mixture containing phenylhydrazine sulfonate.

於所得混合物中加入200g之甲苯，在65℃攪拌15分鐘洗淨水層而從水層中去除未反應原料及反應副產物之後，靜置而分液。200 g of toluene was added to the obtained mixture, and the aqueous layer was washed with stirring at 65 ° C for 15 minutes to remove unreacted raw materials and reaction by-products from the aqueous layer, and then left to stand for liquid separation.

於備有攪拌機、溫度計、迪姆羅回流冷凝器之3L容量之4頸燒瓶反應容器中，放入經分液之水層，繼之，用20分鐘在20℃滴加313g之35%鹽酸之後，在75℃攪拌3小時，水解先前所得苯肼磺酸鹽，獲得含有苯肼鹽酸鹽之混合物。In a 4-neck flask reaction vessel equipped with a stirrer, a thermometer, and a Dimro reflux condenser, a water-separated aqueous layer was placed, followed by dropwise addition of 313 g of 35% hydrochloric acid at 20 ° C for 20 minutes. The mixture was stirred at 75 ° C for 3 hours to hydrolyze the previously obtained phenylhydrazine sulfonate to obtain a mixture containing phenylhydrazine hydrochloride.

冷卻該混合物至10℃，慢慢加入300g之50%氫氧化鈉水溶液，使苯肼析出，繼之，過濾而去除水層，回收得苯肼粗生成物。The mixture was cooled to 10 ° C, and 300 g of a 50% aqueous sodium hydroxide solution was gradually added to precipitate phenylhydrazine, followed by filtration to remove the aqueous layer, and a crude benzoquinone product was recovered.

所得苯肼粗生成物為34g(純度為90%)。The obtained crude phenylhydrazine product was 34 g (purity was 90%).

於備有攪拌機、溫度計、迪姆羅回流冷凝器之1L容量之4頸燒瓶反應容器中，放入所得苯肼粗生成物，繼之，加入300g之第三丁醇、50g之水、2.5g之乙酸鈉，一邊在20℃，維持混合物的pH為6至8，一邊用10分鐘滴加27.5g之36%甲醛水溶液後，在同溫度、同pH範圍攪拌2小時，獲得含有甲醛-苯腙之混合物。The resulting phenylhydrazine crude product was placed in a 1 L flask in a 4-neck flask equipped with a stirrer, a thermometer, and a Dimro reflux condenser, and then 300 g of a third butanol, 50 g of water, and 2.5 g were added. Sodium acetate, while maintaining the pH of the mixture at 6 to 8 at 20 ° C, 27.5 g of a 36% aqueous formaldehyde solution was added dropwise over 10 minutes, and then stirred at the same temperature and the same pH range for 2 hours to obtain formaldehyde-benzoquinone. a mixture.

冷卻所得反應混合物至10℃，加入19.4g之氰酸，在同溫度攪拌4小時，獲得含有苯基***烷酮之混合物。The resulting reaction mixture was cooled to 10 ° C, and 19.4 g of cyanic acid was added thereto, and stirred at the same temperature for 4 hours to obtain a mixture containing a phenyl triazolidinone.

繼之，在同溫度，於所得混合物中用30分鐘滴加162.5g之11%次氯酸鈉水溶液。滴加後，在10℃攪拌1小時，再在25℃攪拌5小時，獲得含有標題之目的物質之混合物。Then, at the same temperature, 162.5 g of an 11% aqueous sodium hypochlorite solution was added dropwise to the resulting mixture over 30 minutes. After the dropwise addition, the mixture was stirred at 10 ° C for 1 hour, and further stirred at 25 ° C for 5 hours to obtain a mixture containing the title compound.

蒸餾去除第三丁醇後之水層中，加入24g之氫氧化鈉形成標題之目的物質之鹽並溶解於水層中，繼之，加入100g之甲苯，攪拌而洗淨水層，而從水層去除反應副產物之後，靜置而分液。After distilling off the third butanol, the aqueous layer was added with 24 g of sodium hydroxide to form a salt of the title substance and dissolved in the aqueous layer. Then, 100 g of toluene was added, and the aqueous layer was washed and washed from the water. After the layer was removed from the reaction by-product, it was allowed to stand for liquid separation.

冷卻分液所得水層至15℃，用15分鐘滴加94g之3%鹽酸中和上述水層，使標題之目的物質游離，過濾而收集所析出之結晶，用150g之水洗淨之。The aqueous layer obtained by liquid separation was cooled to 15 ° C, and the aqueous layer was neutralized by dropwise addition of 94 g of 3% hydrochloric acid over 15 minutes to remove the title material, and the precipitated crystals were collected by filtration and washed with 150 g of water.

所得結晶用真空乾燥機充分乾燥，而得到42.5g之標題之目的物質(收率為88%，純度為96%)。融點為184至185℃。EI-MS：M⁺ 161。The obtained crystals were sufficiently dried with a vacuum dryer to obtain 42.5 g of the title compound (yield: 88%, purity: 96%). The melting point is 184 to 185 °C. EI-MS: M ⁺ 161.

[實施例5][Example 5] <1-(2,3-二甲基苯基)-1,2,4-***-5-酮之製造>Production of <1-(2,3-dimethylphenyl)-1,2,4-triazol-5-one>

使用備有攪拌機、溫度計、迪姆羅回流冷凝器之1L容量之4頸燒瓶做為反應容器，加入330g之10%鹽酸及36.3g之2,3-二甲基苯胺(純度>99%)，在30℃攪拌15分鐘。A 1N-capacity 4-neck flask equipped with a stirrer, a thermometer, and a Dimro reflux condenser was used as a reaction vessel, and 330 g of 10% hydrochloric acid and 36.3 g of 2,3-dimethylaniline (purity >99%) were added. Stir at 30 ° C for 15 minutes.

冷卻所得混合物至-5℃，使用30分鐘滴加63g之35%亞硝酸鈉水溶液後，在-3℃至0℃攪拌1小時，獲得重氮鹽溶液。The resulting mixture was cooled to -5 ° C, and 63 g of a 35% aqueous sodium nitrite solution was added dropwise thereto over 30 minutes, and then stirred at -3 ° C to 0 ° C for 1 hour to obtain a diazonium salt solution.

上述容器之外，另使用備有攪拌機、溫度計、迪姆羅回流冷凝器之5L容量之4頸燒瓶做為反應容器，於350g之水中溶解97.4g之亞硫酸鈉(純度為97%)，加入95%硫酸調整為pH7.2。In addition to the above-mentioned container, a 4-neck flask of 5 L capacity equipped with a stirrer, a thermometer, and a Dimro reflux condenser was used as a reaction vessel, and 97.4 g of sodium sulfite (purity of 97%) was dissolved in 350 g of water, and 95% was added. The sulfuric acid was adjusted to pH 7.2.

冷卻該溶液至10℃，迅速添加先前調製好之重氮鹽溶液。用30分鐘使該混合物昇溫至20℃之後，再加熱至65℃，在同溫度攪拌2小時還原重氮鹽，獲得含有2,3-二甲苯肼磺酸鹽之反應混合物。The solution was cooled to 10 ° C and the previously prepared diazonium salt solution was quickly added. After the mixture was heated to 20 ° C over 30 minutes, it was further heated to 65 ° C, and the diazonium salt was reduced by stirring at the same temperature for 2 hours to obtain a reaction mixture containing 2,3-xylene sulfonate.

冷卻所得反應混合物至20℃，用20分鐘滴加313g之35%鹽酸後，在75℃攪拌3小時，水解先前所得2,3-二甲苯肼磺酸鹽，獲得含有2,3-二甲基苯肼之鹽酸鹽之混合物。The obtained reaction mixture was cooled to 20 ° C, and 313 g of 35% hydrochloric acid was added dropwise thereto over 20 minutes, and then stirred at 75 ° C for 3 hours to hydrolyze the previously obtained 2,3-xylene sulfonate to obtain 2,3-dimethyl group. a mixture of phenylhydrazine hydrochloride.

冷卻該混合物至10℃，慢慢加入300g之50%氫氧化鈉水溶液，使2,3-二甲基苯肼析出獲得2,3-二甲基苯肼水性懸濁液。The mixture was cooled to 10 ° C, and 300 g of a 50% aqueous sodium hydroxide solution was slowly added to precipitate 2,3-dimethylphenylhydrazine to obtain an aqueous suspension of 2,3-dimethylphenylhydrazine.

繼之，於所得2,3-二甲基苯肼水性懸濁液中加入1500g之第三丁醇及2.5g之乙酸鈉，一邊在20℃維持混合物的pH為6至8，一邊用10分鐘滴加27.5g之36%甲醛水溶液後，在同溫度、同pH範圍攪拌2小時，獲得含有甲醛-2,3-二甲基苯腙之混合物。Then, 1500 g of tert-butanol and 2.5 g of sodium acetate were added to the obtained aqueous suspension of 2,3-dimethylphenylhydrazine, while maintaining the pH of the mixture at 6 to 8 at 20 ° C for 10 minutes. After dropwise addition of 27.5 g of a 36% aqueous formaldehyde solution, the mixture was stirred at the same temperature and the same pH for 2 hours to obtain a mixture containing formaldehyde-2,3-dimethylphenylhydrazine.

冷卻反應混合物至10℃，加入19.4g之氰酸，在同溫度攪拌4小時，獲得含有2,3-二甲基苯基***烷酮之混合物。The reaction mixture was cooled to 10 ° C, and 19.4 g of cyanic acid was added thereto, and stirred at the same temperature for 4 hours to obtain a mixture containing 2,3-dimethylphenyltriazolidinone.

所分離2層(即有機層、水層)之中，去除水層而去除未反應之甲醛及鹽類後，所得有機層(即第三丁醇層)中，用30分鐘在10℃，滴加162.5g之11%次氯酸鈉水溶液。In the separated two layers (ie, the organic layer and the aqueous layer), the aqueous layer was removed to remove unreacted formaldehyde and salts, and the obtained organic layer (ie, the third butanol layer) was dropped at 10 ° C for 30 minutes. 162.5 g of an 11% aqueous solution of sodium hypochlorite was added.

滴加後，在10℃攪拌1小時，再在25℃攪拌5小時，獲得含有標題之目的物質之混合物。After the dropwise addition, the mixture was stirred at 10 ° C for 1 hour, and further stirred at 25 ° C for 5 hours to obtain a mixture containing the title compound.

蒸餾去除第三丁醇後之水層中，加入24g之氫氧化鈉形成標題之目的物質之鹽，並溶解於水層中，繼之，加入100g之甲苯，洗淨水層後，靜置而分液。After distilling off the third butanol aqueous layer, 24 g of sodium hydroxide was added to form a salt of the title substance, and dissolved in the aqueous layer, followed by adding 100 g of toluene, and after washing the aqueous layer, it was allowed to stand. Liquid separation.

冷卻分液所得水層至15℃，用15分鐘滴加94g之35%鹽酸中和前述水層，使標題之目的物質游離，過濾而收集所析出結晶，使用150g之水洗淨之。The aqueous layer obtained by liquid separation was cooled to 15 ° C, and the aqueous layer was neutralized by dropwise addition of 94 g of 35% hydrochloric acid over 15 minutes to remove the title material, and the precipitated crystals were collected by filtration and washed with 150 g of water.

所得結晶使用真空乾燥器充分乾燥，而得51.6g之標題之目的化合物(收率為91%，純度為95%)。融點為191至192℃。EI-MS：M⁺ 189。The obtained crystals were sufficiently dried using a vacuum dryer to obtain 51.6 g of the title compound (yield: 91%, purity: 95%). The melting point is 191 to 192 °C. EI-MS: M ⁺ 189.

[實施例6][Embodiment 6] <1-(2,4-二氯苯基)-1,2,4-***-5-酮之製造>Production of <1-(2,4-dichlorophenyl)-1,2,4-triazol-5-one>

以備有攪拌機、溫度計、迪姆羅回流冷凝器之5L容量之4頸燒瓶做為反應容器，加入350.0g之2,4-二氯苯胺(純度>99%)及350g之10%鹽酸，再於30℃攪拌15分鐘。A 4-neck flask equipped with a stirrer, a thermometer, and a Dimro reflux condenser was used as a reaction vessel, and 350.0 g of 2,4-dichloroaniline (purity >99%) and 350 g of 10% hydrochloric acid were added. Stir at 30 ° C for 15 minutes.

冷卻所得混合物至-5℃，用30分鐘滴加452g之35%亞硝酸鈉水溶液後，在-3℃至0℃攪拌1小時獲得重氮鹽溶液。The resulting mixture was cooled to -5 ° C, and 452 g of a 35% aqueous solution of sodium nitrite was added dropwise thereto over 30 minutes, followed by stirring at -3 ° C to 0 ° C for 1 hour to obtain a diazonium salt solution.

上述容器之外，以另一個備有攪拌機、溫度計、迪姆羅回流冷凝器之10L容量之4頸燒瓶做為反應容器。該反應容器內，於2796g之水中溶解698.9g之亞硫酸鈉(純度為97%)，再加入22.2g之95%硫酸調整為pH7.2。In addition to the above vessel, a 4-neck flask of 10 L capacity equipped with a stirrer, a thermometer, and a Dimro reflux condenser was used as a reaction vessel. In the reaction vessel, 698.9 g of sodium sulfite (purity of 97%) was dissolved in 2,796 g of water, and 22.2 g of 95% sulfuric acid was added thereto to adjust to pH 7.2.

冷卻該溶液至10℃，使用5分鐘添加先前調製好之重氮鹽溶液。The solution was cooled to 10 ° C and the previously prepared diazonium salt solution was added over 5 minutes.

用30分鐘所得混合物昇溫至20℃後，加熱至65℃，於同溫度攪拌2小時還原重氮鹽，獲得含有2,4-二氯苯肼磺酸鹽之混合物。After the mixture was heated to 20 ° C over 30 minutes, it was heated to 65 ° C, and the diazonium salt was reduced by stirring at the same temperature for 2 hours to obtain a mixture containing 2,4-dichlorophenyl sulfonate.

靜置所得混合物，使甲苯層及水層分液，去除甲苯層所含未反應原料及反應副產物。The resulting mixture was allowed to stand, and the toluene layer and the aqueous layer were separated to remove unreacted raw materials and reaction by-products contained in the toluene layer.

於備有攪拌機、溫度計、迪姆羅回流冷凝器之10L容量之4頸燒瓶反應容器，放入上述分液之層，繼之，在20℃使用30分鐘滴加2241g之35%鹽酸後，在75℃攪拌3小時，水解2,4-二氯苯肼磺酸鹽，獲得含有2,4-二氯苯肼鹽酸鹽之混合物。In a 4-neck flask reaction vessel equipped with a stirrer, a thermometer, and a Dimro reflux condenser, the above-mentioned liquid separation layer was placed, followed by dropwise addition of 2241 g of 35% hydrochloric acid at 20 ° C for 30 minutes. After stirring at 75 ° C for 3 hours, 2,4-dichlorophenyl sulfonate was hydrolyzed to obtain a mixture containing 2,4-dichlorophenylhydrazine hydrochloride.

冷卻該混合物至10℃，使用30分鐘滴加2241g之48%氫氧化鈉水溶液，使2,4-二氯苯肼析出，繼之，過濾而去除水層，獲得2,4-二氯苯肼之粗生成物。所得2,4-二氯苯肼之粗生成物為900g(純度為98%)。The mixture was cooled to 10 ° C, and 2241 g of a 48% aqueous sodium hydroxide solution was added dropwise over 30 minutes to precipitate 2,4-dichlorophenylhydrazine, followed by filtration to remove the aqueous layer to obtain 2,4-dichlorophenylhydrazine. The crude product. The crude product of the obtained 2,4-dichlorophenylhydrazine was 900 g (purity: 98%).

於備有攪拌機、溫度計、迪姆羅回流冷凝器之10L容量之4頸燒瓶的反應容器中，放入所得2,4-二氯苯肼粗生成物，繼之，加入1904g之第三丁醇、1500g之水，一邊在20℃維持混合物之pH為6至8，一邊用15分鐘滴加174.6g之37%甲醛水溶液。繼之，所得混合物中，在20℃用5分鐘滴加在44g之水中溶解有8.8g之乙酸鈉及2.6g之乙酸所成溶液後，一邊在20℃維持混合物之pH為5.5至6，一邊攪拌2小時，獲得含有甲醛-2,4-二氯苯腙之混合物。The resulting 2,4-dichlorophenylhydrazine crude product was placed in a reaction vessel of a 4-liter flask equipped with a stirrer, a thermometer, and a Dimro reflux condenser, followed by the addition of 1904 g of the third butanol. With 1500 g of water, while maintaining the pH of the mixture at 6 to 8 at 20 ° C, 174.6 g of a 37% aqueous formaldehyde solution was added dropwise over 15 minutes. Then, in the obtained mixture, a solution obtained by dissolving 8.8 g of sodium acetate and 2.6 g of acetic acid in 44 g of water was added dropwise at 20 ° C for 5 minutes, while maintaining the pH of the mixture at 5.5 to 6 at 20 ° C. After stirring for 2 hours, a mixture containing formaldehyde-2,4-dichlorophenylhydrazine was obtained.

繼之，冷卻反應混合物至10℃，加入130.1g之氰酸，在同溫度攪拌4小時，獲得含有2,4-二氯苯基***烷酮之混合物。Subsequently, the reaction mixture was cooled to 10 ° C, 130.1 g of cyanic acid was added, and stirred at the same temperature for 4 hours to obtain a mixture containing 2,4-dichlorophenyl triazolidinone.

所得混合物，一邊在混合物之溫度不超過10℃，一邊用45分鐘滴加1441g之10%次氯酸鈉水溶液。滴加後，在10℃攪拌1小時，再在25℃攪拌5小時，獲得含有標題之目的物質之混合物。The resulting mixture was dropwise added with 1441 g of a 10% aqueous sodium hypochlorite solution over 45 minutes while the temperature of the mixture did not exceed 10 °C. After the dropwise addition, the mixture was stirred at 10 ° C for 1 hour, and further stirred at 25 ° C for 5 hours to obtain a mixture containing the title compound.

繼之，於所得混合中加入359g之48%氫氧化鈉水溶液，在80℃攪拌2小時後，從該混合物中蒸餾去除第三丁醇。含有標題之目的化合物之鈉鹽及不純物之水性混合物中，加入990g之二氯乙烷，經攪拌洗淨而從水層中去除不純物之後，靜置而分液。經分液所得含有標題之目的化合物之鈉鹽之水層，冷卻至20℃，用60分鐘滴加1660g之18%鹽酸中和水層，使標題之目的化合物游離，過濾而收集析出之結晶，用2000g之水洗淨之。Then, 359 g of a 48% aqueous sodium hydroxide solution was added to the resulting mixture, and after stirring at 80 ° C for 2 hours, the third butanol was distilled off from the mixture. To the aqueous mixture containing the sodium salt of the title compound and the impurity, 990 g of dichloroethane was added, and after washing with stirring, the impurities were removed from the aqueous layer, and then left to stand for liquid separation. The aqueous layer containing the sodium salt of the title compound was obtained by liquid separation, and the mixture was cooled to 20 ° C, and 1660 g of 18% hydrochloric acid was added dropwise over 60 minutes to neutralize the title compound. Wash with 2000g of water.

所得結晶在真空乾燥機中充分乾燥，而得標題之目的化合物472g(收率為95%，純度為99%)。融點為190至191℃。EI-MS：M⁺ 229。The obtained crystals were sufficiently dried in a vacuum dryer to give the title compound 472 g (yield: 95%, purity: 99%). The melting point is 190 to 191 °C. EI-MS: M ⁺ 229.

[實施例7][Embodiment 7] <1-(2,4-二氯苯基)-1,2,4-***-5-酮之製造>Production of <1-(2,4-dichlorophenyl)-1,2,4-triazol-5-one>

以備有攪拌機、溫度計、迪姆羅回流冷凝器之5L容量之4頸燒瓶做為反應容器，加入350.0g之2,4-二氯苯胺(純度>99%)及350.0g之甲苯，在30℃攪拌15分鐘後，加入2353g之10%鹽酸，再於30℃攪拌15分鐘。A 4 N flask of 5 L capacity equipped with a stirrer, a thermometer, and a Dimro reflux condenser was used as a reaction vessel, and 350.0 g of 2,4-dichloroaniline (purity >99%) and 350.0 g of toluene were added at 30 After stirring at ° C for 15 minutes, 2353 g of 10% hydrochloric acid was added, followed by stirring at 30 ° C for 15 minutes.

所得混合物冷卻至-5℃，用30分鐘滴加452g之35%亞硝酸鈉水溶液後，在-3℃至0℃攪拌1小時，獲得重氮鹽溶液。The resulting mixture was cooled to -5 ° C, and 452 g of a 35% aqueous solution of sodium nitrite was added dropwise thereto over 30 minutes, and then stirred at -3 ° C to 0 ° C for 1 hour to obtain a diazonium salt solution.

上述容器之外，另備以備有攪拌機、溫度計、迪姆羅回流冷凝器之10L容量之4頸燒瓶做為反應容器。在該容器內，於2796g之水中溶解698.9g之亞硫酸鈉(純度為97%)，加入22.2g之95%硫酸調整為pH7.2。In addition to the above-mentioned container, a 4-neck flask having a 10 L capacity equipped with a stirrer, a thermometer, and a Dimro reflux condenser was used as a reaction vessel. In the vessel, 698.9 g of sodium sulfite (purity of 97%) was dissolved in 2,796 g of water, and 22.2 g of 95% sulfuric acid was added to adjust to pH 7.2.

用30分鐘使所得混合物昇溫至20℃之後，再加熱至65℃，在同溫度攪拌2小時還原重氮鹽，獲得含有2,4-二氯苯肼磺酸鹽之混合物。After the resulting mixture was heated to 20 ° C over 30 minutes, it was further heated to 65 ° C, and the diazonium salt was reduced by stirring at the same temperature for 2 hours to obtain a mixture containing 2,4-dichlorophenyl sulfonate.

靜置所得混合物分液成甲苯層及水層，去除甲苯層中所含未反應原料及反應副產物。The mixture obtained by standing was separated into a toluene layer and an aqueous layer to remove unreacted raw materials and reaction by-products contained in the toluene layer.

於備有攪拌機、溫度計、迪姆羅回流冷凝器之10L容量之4頸燒瓶的反應容器，放入經分液之水層，繼之，在20℃使用30分鐘滴加2241g之35%鹽酸後，在75℃攪拌3小時，水解2,4-二氯苯肼磺酸鹽，獲得含有2,4-二氯苯肼鹽酸鹽之混合物。The reaction vessel of a 4-neck flask equipped with a stirrer, a thermometer, and a Dimro reflux condenser was placed in a water-separated aqueous layer, followed by dropwise addition of 2241 g of 35% hydrochloric acid at 20 ° C for 30 minutes. The mixture was stirred at 75 ° C for 3 hours to hydrolyze 2,4-dichlorophenyl sulfonate to obtain a mixture containing 2,4-dichlorophenylhydrazine hydrochloride.

冷卻該混合物至10℃，用30分鐘滴加2241g之48%氫氧化鈉水溶液，使2,4-二氯苯肼析出，獲得含2,4-二氯苯肼水性懸濁液。The mixture was cooled to 10 ° C, and 2241 g of a 48% aqueous sodium hydroxide solution was added dropwise thereto over 30 minutes to precipitate 2,4-dichlorophenylhydrazine to obtain an aqueous suspension containing 2,4-dichlorophenylhydrazine.

繼之，一邊在20℃維持該懸濁液的pH為6至8，一邊使用15分鐘滴加174.6g之37%甲醛水溶液。在20℃，使用5分鐘於所得混合物中滴加於44g之水中溶解有8.8g之乙酸鈉及2.6g之乙酸之溶液後，一邊在20℃維持混合物的pH為5.5至6，一邊攪拌2小時。繼之，從反應混合物過濾而去除水層，獲得甲醛2,4-二氯苯腙粗生成物。所得甲醛-2,4-二氯苯腙粗生成物為400g(純度為95%)。Subsequently, while maintaining the pH of the suspension at 6 ° C at 20 ° C, 174.6 g of a 37% aqueous formaldehyde solution was added dropwise over 15 minutes. After the solution was dissolved in 44 g of water and dissolved in a solution of 8.8 g of sodium acetate and 2.6 g of acetic acid at 20 ° C for 5 minutes, the mixture was stirred for 2 hours while maintaining the pH of the mixture at 5.5 to 6 at 20 ° C. . Subsequently, the aqueous layer was removed by filtration from the reaction mixture to obtain a crude product of formaldehyde 2,4-dichlorophenylhydrazine. The obtained crude formaldehyde-2,4-dichlorophenylhydrazine was 400 g (purity: 95%).

繼之，於備有攪拌機、溫度計、迪姆羅回流冷凝器之10L容量之4頸燒瓶的反應容器，放入所得甲醛-2,4-二氯苯腙粗生成物，再加入1900g之第三丁醇，冷卻混合物至10℃，加入130.1g之氰酸，在同溫度攪拌4小時，獲得含有2,4-二氯苯基***烷酮之混合物。Then, in a reaction vessel of a 4-neck flask equipped with a stirrer, a thermometer, and a Dimro reflux condenser, a crude product of formaldehyde-2,4-dichlorophenylhydrazine was added, and then a third of 1900 g was added. Butanol, the mixture was cooled to 10 ° C, 130.1 g of cyanic acid was added, and stirred at the same temperature for 4 hours to obtain a mixture containing 2,4-dichlorophenyl triazolidinone.

所得混合物中，一邊在混合物之溫度不超過10℃，一邊用45分鐘滴加1441g之10%次氯酸鈉水溶液。滴加後，在10℃攪拌1小時，再於25℃攪拌3小時，獲得含有標題之目的化合物之混合物。In the obtained mixture, 1441 g of a 10% aqueous sodium hypochlorite solution was added dropwise over 45 minutes while the temperature of the mixture did not exceed 10 °C. After the dropwise addition, the mixture was stirred at 10 ° C for 1 hour and then at 25 ° C for 3 hours to obtain a mixture containing the title compound.

繼之，於所得混合物中加入359g之48%氫氧化鈉水溶液，在80℃攪拌2小時之後，從該混合物中蒸餾去除第三丁醇。於含有標題之目的化合物之鈉鹽及不純物質之水性混合物中加入990g之二氯乙烷，經攪拌洗淨而由水層去除不純物後，靜置而分液。冷卻經分液所得含有標題之目的化合物之鈉鹽之水層至20℃，用60分鐘滴加1660g之18%鹽酸中和該水層，使標題之目的化合物游離，過濾而收集析出之結晶，用2000g之水洗淨之。Subsequently, 359 g of a 48% aqueous sodium hydroxide solution was added to the resulting mixture, and after stirring at 80 ° C for 2 hours, the third butanol was distilled off from the mixture. 990 g of dichloroethane was added to the aqueous mixture containing the sodium salt of the objective compound and the impurity, and the mixture was washed with stirring to remove impurities from the aqueous layer, and then left to stand for liquid separation. The aqueous layer containing the sodium salt of the title compound of the title compound was cooled to 20 ° C, and the aqueous layer was neutralized by dropwise addition of 1660 g of 18% hydrochloric acid over 60 minutes to allow the title compound to be freed, and the precipitated crystals were collected by filtration. Wash with 2000g of water.

所得結晶在真空乾燥機中充分乾燥，而得468g之標題之目的化合物(收率為94%，純度為99%)。融點為190至191℃。EI-MS：M⁺ 229。The obtained crystals were sufficiently dried in a vacuum dryer to give 468 g of the title compound (yield: 94%, purity: 99%). The melting point is 190 to 191 °C. EI-MS: M ⁺ 229.

[比較製造例][Comparative Manufacturing Example]

依據上述WO02/12203號公報(參照專利文獻2)所記載實施例製造1-(2,4-二氯苯基)-1,2,4-***-5-酮。1-(2,4-Dichlorophenyl)-1,2,4-triazol-5-one was produced according to the examples described in the above-mentioned WO02/12203 (refer to Patent Document 2).

<1-(2,4-二氯苯基)-1,2,4-***-5-酮之製造>Production of <1-(2,4-dichlorophenyl)-1,2,4-triazol-5-one>

10L容量之4頸燒瓶中，於250g之水中溶解51.5g之氫氧化鈉，再加入1300g之第三丁醇。In a 4 L flask of 4 L capacity, 51.5 g of sodium hydroxide was dissolved in 250 g of water, and 1300 g of third butanol was further added.

繼之，在20℃添加105g之37%甲醛水溶液後，使用30分鐘加入250g之2,4-二氯苯肼鹽酸鹽，在20℃攪拌2小時。Subsequently, after adding 105 g of a 37% aqueous formaldehyde solution at 20 ° C, 250 g of 2,4-dichlorophenylhydrazine hydrochloride was added over 30 minutes, and the mixture was stirred at 20 ° C for 2 hours.

繼之，在冰水浴中保持反應混合物於10℃，於500g之水中懸濁有127g之90%氰酸鈉，一次就加入反應混合物中，用80g之水洗淨附著於容器之氰酸鈉，同時將洗液注入燒瓶中。經添加氰酸鈉使反應混合物的溫度上升15℃。Then, the reaction mixture was kept at 10 ° C in an ice water bath, and 127 g of 90% sodium cyanate was suspended in 500 g of water, and the reaction mixture was added to the reaction mixture once, and 80 g of water was used to wash the sodium cyanate attached to the container. At the same time, the washing solution was poured into the flask. The temperature of the reaction mixture was raised by 15 ° C by the addition of sodium cyanate.

添加氰酸鈉後，冷卻反應混合物至10℃，繼之，用15分鐘添加119g之乙酸。After the addition of sodium cyanate, the reaction mixture was cooled to 10 ° C, and then, 119 g of acetic acid was added over 15 minutes.

從乙酸添加完後立即產生紅褐色飴狀難溶物，因多量之紅褐色飴狀難溶物而攪拌發生困難，所以從反應系中僅去除紅褐色飴狀難溶物，再在10℃攪拌2小時。Immediately after the addition of acetic acid, a reddish-brown smear-like insoluble matter is produced, and it is difficult to stir due to a large amount of reddish brown enamel-like insoluble matter. Therefore, only the reddish-brown scorpion-like insoluble matter is removed from the reaction system, and then stirred at 10 ° C. 2 hours.

然後，一邊保持溫度為10℃一邊用90分鐘添加730g之12%次氯酸鈉水溶液。Then, 730 g of a 12% aqueous sodium hypochlorite solution was added over 90 minutes while maintaining the temperature at 10 °C.

滴加後在冰水浴中攪拌1小時，再於室溫攪拌4小時。After the dropwise addition, the mixture was stirred in an ice water bath for 1 hour and then at room temperature for 4 hours.

反應結束後，減壓下從反應混合物中蒸餾去除第三丁醇而濃縮之。After completion of the reaction, the third butanol was distilled off from the reaction mixture under reduced pressure to concentrate.

其中，加入1000g之甲苯及320g之30%氫氧化鈉水溶液，激烈攪拌而萃取標題之目的化合物。分液後，所分離之水層用200g之甲苯洗淨、分液、冷卻該水層至15℃，用30分鐘滴加250g之35%鹽酸。Among them, 1000 g of toluene and 320 g of a 30% aqueous sodium hydroxide solution were added, and the title compound was extracted with vigorous stirring. After liquid separation, the separated aqueous layer was washed with 200 g of toluene, separated, and the aqueous layer was cooled to 15 ° C, and 250 g of 35% hydrochloric acid was added dropwise over 30 minutes.

過濾收集析出之固體，用500g之水洗淨。充分乾燥該固體，而得167g之標題之目的物質(收率為62%，純度為81%)。The precipitated solid was collected by filtration and washed with 500 g of water. The solid was sufficiently dried to give 167 g of title compound (yield: 62%, purity: 81%).

上述比較製造例中，所得1-(2,4-二氯苯基)-1,2,4-***-5-酮之收率及純度低之原因，擬主在對於酸不安定之甲醛-2,4-二氯苯腙之一部分，由於乙酸之存在而二聚化，產生難溶性之四所造成。In the above comparative production example, the yield and purity of the obtained 1-(2,4-dichlorophenyl)-1,2,4-triazol-5-one are low, and the main reason is that the formaldehyde is unstable to the acid. - a part of -2,4-dichlorophenylhydrazine, dimerized by the presence of acetic acid, resulting in a poorly soluble caused.

[產業上之利用可行性][Industry use feasibility]

依據本發明有關之苯基***啉酮類之製造方法，可使用更廉價之原料，更簡單而安全且依成本下以高收率而製成高純度之苯基***啉酮類。所以本發明之苯基***啉酮之製造方法乃大規模工業生產上適佳之實施方法。According to the method for producing phenyltriazolinones according to the present invention, it is possible to produce phenyltriazolinones of high purity in a simple and safe manner and at high cost in a high yield by using a cheaper raw material. Therefore, the method for producing phenyltriazolinone of the present invention is a suitable method for industrial production on a large scale.

Claims

一種下列一般式(5)所示苯基***啉酮之製造方法， (式(5)中，X表示鹵素原子、碳數1至6之低級烷基，n為0至5之整數，當n表示2以上之整數時，複數個X可為相同或不同)；其特徵為使下列一般式(1)所示苯胺類和亞硝酸鹽類反應製成重氮鹽後， (式(1)中，X及n所示意義和上述式(5)相同)；使用亞硫酸鹽類或亞硫酸氫鹽類還原，繼之，水解而形成下列一般式(2)所示苯肼類， (式(2)中，X及n所示意義如同上述式(5))；繼之，觸媒存在下，將所得苯肼類(2)和甲醛在pH5至10反應，形成下列一般式(3)所示甲醛-苯腙類， (式(3)中，X及n所示意義如同上述式(5))繼之，使該甲醛-苯腙類(3)和氰酸反應，形成下列一般式(4)所示苯基***烷酮， (式(4)中，X及n所示意義如同上述式(5))繼之，使該苯基***烷酮類(4)和選擇自次鹵酸鹽及氧中之氧化劑，在無觸媒下或氧化觸媒存在下反應而製成。a method for producing a phenyltriazolinone represented by the following general formula (5), (In the formula (5), X represents a halogen atom, a lower alkyl group having 1 to 6 carbon atoms, n is an integer of 0 to 5, and when n represents an integer of 2 or more, plural X's may be the same or different); It is characterized in that after the aniline and nitrite represented by the following general formula (1) are reacted to form a diazonium salt, (In the formula (1), X and n have the same meanings as in the above formula (5)); reduction using a sulfite or bisulfite, followed by hydrolysis to form a benzene represented by the following general formula (2) Ape, (In the formula (2), X and n have the same meanings as in the above formula (5)); then, in the presence of a catalyst, the obtained benzoquinone (2) and formaldehyde are reacted at pH 5 to 10 to form the following general formula ( 3) Formaldehyde-benzoquinones, (In the formula (3), X and n have the same meanings as in the above formula (5)), and the formaldehyde-benzoquinone (3) is reacted with cyanic acid to form the phenyl group represented by the following general formula (4). Oxazolidinone, (In the formula (4), X and n have the same meanings as in the above formula (5)), and the phenyl triazolidinone (4) and the oxidizing agent selected from the hypohalite and oxygen are It is prepared by reacting under a catalyst or in the presence of an oxidation catalyst.

如申請專利範圍第1項之苯基***啉酮類之製造方法，其係使用從含有上述一般式(2)所示苯肼類之反應混合物中去除水層而得苯肼類之粗生成物者， (式(2)中，X及n所示意義如同申請專利範圍第1項中之式(5))。The method for producing a phenyltriazolinone according to the first aspect of the invention, wherein the crude layer of the benzoquinone is obtained by removing the aqueous layer from the reaction mixture containing the benzoquinone represented by the above general formula (2). Object, (In the formula (2), the meanings of X and n are as in the formula (5) in the first item of the patent application.

如申請專利範圍第1項之苯基***啉酮類之製造方法，其係使用從含有上述一般式(3)所示甲醛-苯腙類之反應混合物中去除水層，而得甲醛-苯腙類之粗生成物者， (式(3)中，X及n所示意義如同申請專利範圍第1項中之式(5))。The method for producing a phenyltriazolinone according to the first aspect of the patent application, which comprises removing a water layer from a reaction mixture containing the formaldehyde-benzoquinone represented by the above general formula (3), thereby obtaining formaldehyde-benzene. The crude product of the cockroach, (In the formula (3), the meanings of X and n are as in the formula (5) in the first item of the patent application.

如申請專利範圍第1項之苯基***啉酮類之製造方法，其係上述一般式(1)所示苯胺類， (式(1)中，X表示鹵素原子、碳數1至6之低級烷基，n為0至5之整數，當n表示2以上之整數時，複數個X可為相同或不同)在有機溶劑之存在下，和亞硝酸鹽類反應成為重氮鹽者。A method for producing a phenyltriazolinone according to the first aspect of the invention, which is an aniline represented by the above general formula (1), (In the formula (1), X represents a halogen atom, a lower alkyl group having 1 to 6 carbon atoms, n is an integer of 0 to 5, and when n represents an integer of 2 or more, plural X may be the same or different) in organic In the presence of a solvent, it reacts with a nitrite to form a diazonium salt.

如申請專利範圍第2項之苯基***啉酮類之製造方法，其係上述一般式(1)所示苯胺類， (式(1)中，X表示鹵素原子、碳數1至6之低級烷基，n為0至5之整數，當n表示2以上之整數時，複數個X可為相同或不同)在有機溶劑之存在下，和亞硝酸鹽類反應成為重氮鹽者。A method for producing a phenyltriazolinone according to item 2 of the patent application, which is an aniline represented by the above general formula (1), (In the formula (1), X represents a halogen atom, a lower alkyl group having 1 to 6 carbon atoms, n is an integer of 0 to 5, and when n represents an integer of 2 or more, plural X may be the same or different) in organic In the presence of a solvent, it reacts with a nitrite to form a diazonium salt.

如申請專利範圍第3項之苯基***啉酮類之製造方法，其係上述一般式(1)所示苯胺類， (式(1)中，X表示鹵素原子、碳數1至6之低級烷基，n為0至5之整數，當n表示2以上之整數時，複數個 X可為相同或不同)在有機溶劑之存在下，和亞硝酸鹽類反應成為重氮鹽者。A method for producing a phenyltriazolinone according to item 3 of the patent application, which is an aniline represented by the above general formula (1), (In the formula (1), X represents a halogen atom, a lower alkyl group having 1 to 6 carbon atoms, n is an integer of 0 to 5, and when n represents an integer of 2 or more, plural X may be the same or different) in organic In the presence of a solvent, it reacts with a nitrite to form a diazonium salt.

如申請專利範圍第1項至第6項中任一項之苯基***啉酮類之製造方法，其係上述一般式(4)所示苯基***烷酮類， (式(4)中，X及n所示意義如同申請專利範圍第1項中之式(5))和選擇自次鹵酸鹽及氧中之氧化劑，在無觸媒下或氧化觸媒存在下反應後，使用鹼處理，而精製上述一般式(5)所示苯基***啉酮類者， (式(5)中，X及n所示意義如同申請專利範圍第1項中之式(5))。The method for producing a phenyltriazolinone according to any one of claims 1 to 6, which is a phenyltriazolidinone represented by the above general formula (4), (In the formula (4), the meanings of X and n are as in the formula (5) in the first paragraph of the patent application) and the oxidizing agent selected from the hypohalite and oxygen, in the absence of a catalyst or an oxidation catalyst. After the next reaction, the phenyl triazolinone represented by the above general formula (5) is purified by treatment with a base. (In the formula (5), the meanings of X and n are as in the formula (5) in the first item of the patent application.