WO1996019470A1 - Process for the preparation of pyrazole derivative - Google Patents

Abstract

An industrially advantageous process for the preparation of a pyrazole derivative useful as a herbicide capable of dispensing with isomer separation suffering from low yield and preparation of carboxylic acid necessitating complicated steps, which is represented by reaction formula (IV), (V), (VI), wherein R?1, R2 and X1¿ are each independently C¿1?-C4 alkyl; R?3¿ is H or C¿1?-C4 alkyl; X?2¿ is halogen; X3 is diazonium salt or halogen; and n is 0, 1 or 2.

Description

 Akira Itoda Manufacturing method for virazole derivatives

Technical field

 The present invention relates to a novel method for producing a virazole derivative useful as a herbicide, and an intermediate thereof. Background branch art

 Conventionally, when cultivating corn and the like, triazine herbicides atrazine and acid anilide herbicides arachlor and metolachlor have been used, but atrazine has a low activity against grass weeds. On the other hand, arlacrol and metrachlor have low activity on broad fibers. Therefore, it is currently difficult to control grass and broadleaf weeds at once with a single agent. In addition, these herbicides require high doses and are not preferred on environmental issues.

 On the other hand, as a virazol derivative having a herbicidal activity, WO 94/01431 does not cause harm to useful crops such as corn, wheat, barley, etc .; Novel virazole derivatives with excellent selectivity that can control both at low doses have been reported.

 The ピ ラ ^ method of a novel pyrazole derivative described in the IHJ publication requires the synthesis of a carboxylic acid by a Grignard reaction as a [i] -isomer, and the condensation reaction using dicyclohexylcarpo- imide (DCC). However, many steps such as a transfer reaction using a base were required.

Further, according to the publication, a thiochroman-41-one derivative, which is a raw material of an intermediate carboxylic acid, was prepared by the method described in Japanese Patent Application Laid-Open No. 58-198483, International Publication W088 / 06155 and Can. J. Chem. , 51, 839 (1973). However, some R-type thiochroman-4-one derivatives require an isomer separation step, resulting in low yield. Will be. Problems to be solved by the present invention

 Therefore, the present invention does not require an isomer separation step that results in a low yield as described above and a complicated step of synthesizing carboxylic acid to produce a virazole derivative useful as a herbicide. It is an object of the present invention to provide a method for producing a virazole derivative which is advantageous to the above.

 In other words, the purpose of the Kimi II sword is to provide a new method of producing a wild virulence attractant as a herbicide.

 Further, a second object of the present invention is to provide a process for producing a novel diazole or a hapogen compound, which is a production intermediate for producing a novel virazole derivative and is a novel compound.

 A third object of the present invention is to provide a method for producing an amino compound, which is a production intermediate for producing the above-mentioned diazonium or halogen compound and is a novel compound.

 A fourth object of the present invention is to provide a process for producing a nuclear halogenated amino compound, which is an intermediate for producing the amino compound and is a novel compound. A fifth object of the present invention is to provide a nitro compound which is an intermediate for producing the above-mentioned nucleated halogenated amino compound or amino compound and which is a novel compound.

The present inventors have conducted intensive studies to achieve the above objectives, and the results are shown below. ”: It is industrially possible, which does not include the isomer separation process and the synthetic soil of carboxylic acid. The inventors have found an advantageous method for producing a virazole derivative and an intermediate thereof, and have completed the present invention.

That is, the first object of the present invention is to provide a compound represented by the general formula (IV)

(Wherein, R ¹ and X ′ each independently represent a Ci-C ₄ alkyl group, X ³ represents a diazodium salt or a halogen atom, and n represents an integer of 0, 1 or 2.) A diazonium or halogen compound represented by the following formula (hereinafter referred to as “diazonium or halogen compound (IV)”);

(Wherein, R ² represents (,-. An alkyl group, R ³ represents a hydrogen atom or a C, -C ₄ alkyl group.)) A virazole compound (hereinafter, referred to as a “birazol compound (V ) ”). The general (VI) which is characterized by the reaction of

(Wherein R ′, R ² , X ¹ and n are as defined above.) (Hereinafter referred to as “Vila ′ nol derivative (VI)”) Is achieved by A second object of the present invention is to provide a compound of the general formula (III)

(Wherein, R ¹ and X ^{1 each} independently represent a C, to C ₄ alkyl group, and n represents an integer of 0, 1 or 2). II I) "). The general formula (IV) characterized in that diazotization is carried out and reacted with tetrafluoroboronic acid or cuprous halide.

(Shiki屮, R ', X' are as defined and n chopsticks ΰ constant, X ³ represents a Jiazo two © beam salts or halogen atom.) In - Jiazoniumu or halogen compound is (to the rear d , "Diazonium compound (IVa)" and "Halogen compound (IVb)."

 A third object of the present invention is to provide a compound of the general formula (式)

(Wherein R ¹ and X ^{1 each} independently represent a ~ C alkyl group, and X ² represents And n represents an integer of 0, 1 or 2. ) (Hereinafter referred to as “nuclear halogenated amino compound (II)”), characterized by the general formula (III)

(Wherein R ′, X ¹ and n are as defined above). According to the method for producing an amino compound represented by the formula:

(Formula width, R ¹ and) ('independently represents an alkyl group, X ² represents a halogen atom, and n represents an integer of 0, 1 or 2.) (Hereinafter, referred to as “nitro compound (I)”).

(Wherein R ′, X ′ and n are as defined above). The method is also achieved by a process for producing an amino compound represented by the formula: A fourth object of the present invention is to provide a compound represented by the general formula (I)

(Wherein, R ¹ and X ′ each independently represent a C ₄ alkyl group, X ² represents a halogen atom, and n represents an integer of 0, 1 or 2.) A compound characterized by the general formula (II)

(Wherein the formulas, R ¹ , X ′, X ² and n are as defined above). BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 is a diagram showing a process for producing the virazole derivative (VI) of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION

 In order to make the 解 solution of lljj '' ', the reaction reduced to 1 is referred to ff: rl while referring to virazole (VI), diazonium or a halogen compound (IV), an amino compound (III) ), The method for producing the nuclear halogenated amino compound (II) and the nitro compound (I) will be described sequentially.

Specific examples of the ^ -alkyl group in R ′, R ² , R ³ and X ¹ in the above compound include propyl groups such as methyl group, ethyl group, n-propyl group and i-propyl group. And butyl groups such as n-butyl group, i-butyl group and the like.

Specific examples of the halogen atom in X ² and X ^3, bromine, Ru include chlorine.

Specific examples of the diazonium salt of X ³ include 1 N ₂ ⁺ BF 3. The method for producing the birazol derivative (VI), which is the first object of the present invention, comprises a reaction scheme

(Wherein, R ′, RR ³ , X ¹ , X ³ and n are as defined above.) Wherein diazonium or a halogen compound (IV) and a birazol compound (V) are reacted with a metal catalyst and It is reacted with--oxidized ^ 尜 in the presence of a salt to give the bisazolyl form (VI) and is shown by step D in FIG.

 Examples of the metal catalyst that can be used in this reaction include transition metal catalysts such as palladium, rhodium, ruthenium, and platinum, and a palladium catalyst is preferable. The amount of the catalyst is generally from 0.01 to 1.0 equivalent relative to the diazonium or the halogen compound (IV), but preferably from 0.05 to 0.5 equivalent. The ligand used for the catalyst metal is not particularly limited, but an organophosphine compound of triphenylphosphine or tri-n-butylphosphine is preferred. The ^ of the ligand is 2.0 to 10.0 equivalents, preferably 2.0 to 4.0 equivalents to the metal catalyst.

Examples of the base coexisting in the reaction system include organic bases such as pyridine, triethylamine, N, N-dimethylaniline, and inorganic bases such as sodium carbonate, potassium carbonate, and sodium hydroxide, and preferably potassium carbonate. The amount of base is diazo It is 1.0 to 20.0 equivalents, preferably 1.0 to 10.0, relative to the nickel or halogen compound (IV). In addition, it is effective to use a phase transfer catalyst such as a tetra-n-butylamine in combination with these salts from the viewpoint of improving the reactivity.

This reaction is carried out in a carbon monoxide atmosphere. The pressure of carbon monoxide is generally from normal pressure to 200 kg / cm ² , but is preferably about 50 to 150 kg / cm ² . The reaction temperature is generally room temperature to 200 ° C, preferably 50 to 180 ° C. The reaction time is generally 30 minutes to 200 hours, but is usually completed in 1 to 100 hours. The reaction medium is not particularly limited as long as it does not hinder the reaction, but it is usually preferable to use 1,4-dioxane, acetonitrile and the like.

 The amount of the bisazole compound (V) used in the reaction is generally 1.0 to: I 0.0 equivalent, preferably 1.0 to 5.0 equivalent, relative to diazonium or halide (IV). -Go.

 After completion of the reaction, the virazole derivative (VI), which is the target product obtained in this reaction, is filtered off insolubles according to a conventional method, the solvent is distilled off, and the resulting residue is subjected to a suitable solvent such as ethyl acetate. It can be isolated by separating the liquid with a suitable '' I aqueous medium '' of the aqueous medium and the aqueous medium of W acidified lime, and drying the precipitate from the water. The crude crystal of the birazol derivative (VI) obtained here can be further purified by means such as column chromatography to obtain a sample for identification data.

In the method for producing a diazonium or a halogen compound (IV) which is the second object of the present invention, the method for producing a diazonium compound (IVa) wherein X ³ is a diazonium salt comprises a reaction formula

トラフルォ。木ゥ SS

Trafluo. Ki SS

(IVa) (Wherein R ′, X ¹ , X ³ and n are as defined above). The diamino compound (III) is diazotized and then reacted with tetrafluoroboronic acid to form a diazonium salt. This is a reaction to obtain the diazonium compound (IVa), which is shown by the step Ca in FIG.

 Solvents that can be used in this reaction include acetic acid and aqueous hydrochloric acid, and acetic acid is preferred.

 The diazotization reaction in the first stage can be carried out by a usual method. Preferably, an aqueous solution of sodium nitrite is added dropwise to a solution of the amino compound (III) and hydrohalic acid in a solvent such as acetic acid. Do by doing.

 Examples of hydrohalic acid that can be used in the diazotization reaction include hydrobromic acid and hydrochloric acid. The hydrohalic acid is generally used in an amount of 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, relative to the amino compound (III). Sodium nitrite is generally used in an amount of 1.0 to 1.5 equivalents, preferably 1.0 to 1.2 equivalents, relative to the amino compound (III).

 The reaction temperature of the diazotization reaction is generally in the range of 20 ° C to 20 ° C, but is preferably 0 ° C or lower.

 The latter reaction for obtaining the diazonium salt is carried out by gradually dropping the solution after the first diazotization reaction (hereinafter referred to as “diazonium solution j”) into a tetrafluoroboronic acid solution. The diazonium compound (IVa) can be obtained The tetrafluoroboric acid used in the present reaction is a concept including a salt of tetrafluoroboric acid, and a specific example thereof is tetrafluoroborough. Acids, sodium borofluoride, ammonium fluoride, and the like, with tetrafluoroboric acid being preferred.

The use of tetrafluoroboronic acid is generally from 2.0 to 5.0, ¹ , A (preferably from 2.0 to 3.0) for the amino compound (III).

 The reaction temperature of the reaction for obtaining the diazodium salt is generally in the range of 20 to 100 ° C, preferably 0 ° C to room temperature. The reaction time is generally 30 minutes to 2 hours. The diazonium compound (IVa) thus obtained is a novel compound and is useful as an intermediate for producing the virazole derivative (VI).

In addition, the second object of the present invention, that is, diazonium or halogen compound (IV) The method for producing the halogen compound (IVb) wherein X ³ is a halogen atom comprises the reaction scheme

Wherein R ′, X ′, X ^{: i} and n are as defined above. The amino compound (III) is diazotized and then reacted with a cuprous halide to give a halogen This is a reaction for obtaining the compound (IVb), which is shown by the step Cb in FIG. The diazotization reaction in the first stage of the present method is as described in the method for producing the diazonium compound (IVa).

 In the latter reaction to obtain the halogen compound (IVb), the diazonium solution obtained by the first diazotization reaction is converted into a halogenated aqueous solution containing a cuprous halide, such as hydrobromic acid or hydrochloric acid. It is carried out by gradually shaking to obtain the desired halide (IVb). At this time, it is also effective to add a small amount of ethyl acetate to suppress foaming of the reaction solution.

 Cuprous halide which can be used in this reaction includes cuprous chloride, cuprous bromide and the like. The cuprous halide is generally used in an amount of 1.0 to 3.0 equivalents, preferably 1.0 to 2.0 equivalents, based on the amino compound (III).

 Hydrohalic acid is generally 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents to the amino compound (III).

 The reaction temperature is generally 0 ° (: up to 80, preferably 35 ° (: up to 45 ° C.) The reaction time is usually 10 minutes to 1 hour.

In order to prepare a cuprous halide solution having a higher activity, a solution prepared in advance by reacting copper sulfate with sodium halide may be used. To obtain a more active cuprous halide solution, dissolve copper sulfate in warm water at 50 ° C to 60 ° C, add 1.0 to: L.2 equivalent of sodium hacogenide, 0.5 to 1.0 By reacting 0.5% to 2.0 equivalents of sodium hydroxide to give a white precipitate of cuprous halide, which is added with hydrohalic acid to give the desired product. A solution can be obtained. The target halogen compound (IVb) can also be obtained by dropping a diazonium solution into this solution. It is also effective to add a small amount of ethyl acetate in order to suppress foaming of the reaction solution. After extraction, washing and drying of the organic layer, the solvent can be distilled off and isolated.

 The thus-obtained halogen compound (IVb) is a novel compound and is useful as an intermediate for producing the virazole derivative (VI).

The step C-a for obtaining the compound (IVa) and the step C-b for obtaining the compound (IVb) are defined as (i) using the same starting compound (III), and (ii) diazotization reaction. including, (iii) the obtained compound (IVa) and (IVb), except that the kind of X ¹ is different from the same structure, when reacted with the compound (V) in a subsequent step D, have In each case, the group X ³ is eliminated to give the same compound (VI). Therefore, these steps C-a and C-b are positioned as equivalent steps to each other.

 Among the methods for producing the amino compound (III), which is the third object of the present invention, the method for producing the amino compound (III) starting from the nucleated halogenated amino compound (II) is represented by the following reaction scheme.

Wherein R ", X ', X ² and n are as defined above. The nucleated halogenated amino compound (II) is reductively dehalogenated to give the amino compound (II I) This is the reaction obtained and is shown by step B1 in FIG.

In the wood reaction, ^^ Preferable examples of the hydrogenation catalyst that can be used include palladium and platinum, but palladium is preferable. The amount of the catalyst is generally 0.01 to 1.0 times, preferably 0.05 to 0.5 times, the weight of the nuclear halogenated amino compound (II).

 In this reaction, it is preferable to use a base together with the hydrogenation catalyst. There are no particular restrictions on the base that can be used, but inorganic bases such as carbonated sodium, sodium carbonate and sodium hydroxide, and organic bases such as triethylamine and pyridine can be used, with pyridine being particularly preferred. The amount of the base to be used is generally 1.0 to 5.0 equivalents, preferably 1.0 to 3.0 equivalents to 3b-s o with respect to the nuclear halogenated amino compound (II).

 The solvent used in this reaction is not particularly limited as long as it does not hinder the reaction, but methanol, ethanol and the like are preferable.

The reaction pressure of the hydrogen is not particularly restricted to normal pressure ~ 100 kg / cm ^2, preferably 3~30 kg / cm ^2.

 The reaction temperature is usually from room temperature to 60 ° (: particularly preferably room temperature. The reaction time is generally from 30 minutes to 60 hours, preferably from 2 to 30 hours.

 After completion of the reaction, the amino compound (III) obtained in this reaction is removed from the reaction mixture by a conventional method after removing the catalyst, the solvent is distilled off, and the obtained residue is dissolved in an appropriate organic solvent such as ethyl acetate. After dissolving, washing and drying the organic layer, the solvent can be distilled off and isolated. The amino compound (III) thus obtained is a novel compound and is useful as a compound during the production of the diazodimide compound (IVa) and the halogenated r compound (IVb). The production method of the compound (III) is a method in which a nuclear halogenated amino compound (II) is subjected to a reduction treatment, and a raw material nuclear halogenated amino compound (II) is produced by a reduction reaction of a nitro compound (I) described later. It can be obtained separately, but the nitro compound (I) is used as a raw material, and the nucleated halogenated amino compound (Π) generated by reduction of the nitro compound (Π) is continuously separated from the nitro compound (I) without isolation. It is also possible to obtain compound (III).

In other words, of the third method of producing the HI-like amino compound (II), The method for producing the amino compound (III) in one pot from the toro compound (I) is as follows:

(Wherein R ′, X ¹ , X ² and n are as defined above), by performing the two reduction treatment steps successively,

This is a reaction to obtain the target amino compound (III) by omitting the ^ treatment of (II) and the like.

 The one-step reaction of this reaction is a reaction for obtaining a nucleated halogenated amino compound (II) based on a nitrate (I). A fourth object of the present invention to be described later is a nucleated halogenated amino compound. This reaction corresponds to the production method of compound (II), and this reaction is also shown by step A in FIG.

 The first-stage reduction reaction is achieved by hydrogenating the nitro compound (I) in the presence of a hydrogenation catalyst. The catalyst that can be used here is not particularly limited, but palladium, platinum and the like can be used, and palladium is preferable.

う ί の^媒としては、 ' を しないものであれば に 制限はないが、 メタノール、 エタノール等が好ましい。

There is no particular limitation on the solvent used in the present invention as long as it does not perform ', but methanol and ethanol are preferred.

The reaction pressure of the hydrogen is not particularly limited to atmospheric pressure ~ 1 00 kg / cm ^2, the child preferable 3~30 kg / cm ^2.

 The reaction temperature is usually room temperature to 100 ° C, preferably room temperature to 60 ° C. The reaction time is from 1 hour to 24 hours, but usually about 8 hours.

Then, the subsequent primary reaction is carried out without releasing the nucleated halogenated amino compound (II) obtained in the previous reduction reaction. The latter il elementary reaction is a reaction in which the above-mentioned nucleated halogenated amino compound (II) is converted to an amino compound (III). This is also the reaction indicated by Bl. The details of the reaction and the method for post-treatment of the target amino compound (III) are as described above.

 The method for producing a nucleated halogenated amino compound (II), which is the fourth object of the present invention, comprises a reaction scheme

(Wherein II ¹ , X ¹ , X ² and n are as defined above), and the reaction of the nitro compound (I) with iS to give a nuclear halogenated amino compound (II) This is represented by l¾A in Fig. 1.

 The details of this reaction are not particularly limited in the method of reduction in the previous reduction reaction, but a method using a reducing agent such as iron or tin is simple. As an example of the reduction method, there is a method such as reduction with iron in the presence of a mineral acid. Examples of the mineral acid used here include hydrochloric acid, sulfuric acid and the like. The amount of the reducing agent, for example, in the case of iron, is generally 2 to 5 equivalents, preferably 2.5 to 4 equivalents to the nitro compound (I).

 The solvent that can be used in the H-stage reaction (の 'stage) is not particularly limited as long as it does not hinder the reaction.Ethanol and water are preferred, and ethanol is particularly preferred in consideration of the ill-stage reaction in the latter stage. .

 The reaction temperature of the first-stage reduction reaction is not particularly limited from room temperature to the reflux temperature of the solvent, but the reflux temperature of the solvent is preferred. The reaction time is usually 30 minutes to 24 hours, but preferably about 4 hours.

 After completion of the reaction, the nucleated halogenated amino compound (II) obtained by this reaction is washed with a suitable organic solvent such as ethyl acetate according to a conventional method to remove impurities. The water W is made alkaline with sodium hydroxide and extracted with ethyl acetate or the like.

After washing and drying, it can be isolated by distilling off the solvent. The nucleated halogenated amino compound (II) thus obtained is a novel compound and is useful as an intermediate for producing the amino compound (III).

 The fifth object of the present invention, a nitro compound (I), which is an intermediate for producing a nucleated halogenated amino compound (II) and is a novel compound, is represented by the following reaction scheme:

-1

 Five

(Wherein R ′, X ¹ , X ² and n are as defined above). This reaction is indicated above by X in. That is, the nitro compound (I) can be obtained by oximation of the thiochroman-4-one compound (VII) with an alkoxyamine (NH ₂ 0R ′), and in the thiochroman-4-one compound (VII), n is In the case of 0 or 1, that is, in the case of sulfide or sulfoxide, if necessary, this can be further oxidized to obtain a nitro compound (I) of general formula (I) where n = 1 or 2 in the formula (I), ie, sulfoxide or sulfone . It is also I that this oximation reaction and oxidation reaction can be performed continuously in one pot.

The nitrated platform (I) is prepared by adding a thiochroman 4-one compound (VII) and an alkoxyamine (NH ₂ 〇R ′) in water or an organic solvent (eg, ethanol, methanol, acetic acid, etc.) in an acid catalyst (eg, , Hydrochloric acid, etc.) or in the presence of a base catalyst (eg, pyridine, valine, sodium hydroxide, sodium carbonate, etc.). It is obtained by reacting at C to the reflux temperature of the solvent. Preferably, the reaction is carried out in ethanol in the presence of pyridine at the reflux temperature of the solvent.

The reaction can be 30 minutes to 8 IK'fl'J, but M '1 hour to 4 li ^. In degrees; 7U; S9.

 Next, when the thiochroman 14-one compound (VII), which is the starting material of the above reaction, is n = 0 (sulfide) or n = l (sulfoxide), the nitro compound obtained in the above oxidation reaction is obtained. A method for further oxidizing (I) to obtain a nitro compound (I) in which n = l (sulfoxide) or n = 2 (sulfone) will be described.

 By reacting the nitro compound (I) with n = 0 or 1 obtained in the above oximation reaction with an appropriate oxidizing agent, the nitro compound (I) with n = l or 2 can be deviated. it can.

 The oxidizing agent used in the present oxidation reaction is not particularly limited, and examples thereof include hydrogen peroxide, peracetic acid, and sodium metaperiodate. Hydrogen peroxide is preferable. The solvent to be used is not particularly limited as long as it does not interfere with the reaction. Examples thereof include acetic acid, water, and methanol, and acetic acid is preferable.

 After completion of the reaction, the obtained nitro compound (I) can be isolated by adding water to the reaction mixture, collecting the precipitated crystals, washing and drying according to a conventional method. m

 Next, examples of the present invention will be described, but the present invention is not limited to these examples.

 (Example 1)

6-nitro-8-chloro-5-methyl-4-methoxyiminothiochroman 1,1-dioxide (In the starting nitro compound (I), R '= CH ₃ , X' = CH ₃ , X ² = C1 , N = 2 compound)

 (1-a) Synthesis of 3,4-dichloro-6-nitrotoluene

1リッ トルフラスコ中の無水酢酸 205mlを撹拌しながら、 食塩水一氷浴中 にて 0^eC以下で発煙硝酸 （硝酸 94%含有） 22. 5mlを滴下した。 10分間 撹拌後、 濃硫酸 10滴を加え、 次いで 3， 4ージクロ口トルエン 29. 0 g (0. 18 mm o 1 ) を卜 で淌卜した。 さらに 30分 後、 0〜； 10。Cで 30分投 拌し、 二ト口化反応を完結させた。 反応混合物を 0°C以下に冷却後、 2リッ トル ビーカー中の氷 500 g上へ激しく撹拌しながら注き、 この混合物の液温が低い うちに、 そこへ水酸化ナトリウム 180 gと水 1. 2リットルとの水溶液 （予め 0^eCに冷却したもの） を徐々に注いだ。 さらに 30分撹拌し、 浮遊している淡黄 色固体を吸引濾過により集め、 風乾し、 目的物 35. 7 g (収率 96%) を得た。 N. M. R. (ppm、 内部標準：テトラメチルシラン、 溶媒： CDC 1₃) : 2 59 (3H, s) 、 7. 46 ( 1 H, s) 、 8. 12 (1H， s)

With stirring acetic anhydride 205ml in 1 liter Torufurasuko, fuming nitric acid below 0 ^e C with brine one ice bath (94% nitric acid containing) was added dropwise 22. 5 ml. After stirring for 10 minutes, 10 drops of concentrated sulfuric acid were added, and then 29.0 g (0.18 mmo 1) of 3,4-dichlorotoluene was filtered off with a filter. After an additional 30 minutes, 0-; The mixture was stirred with C for 30 minutes to complete the reaction. After the reaction mixture was cooled to 0 ° C or less, it was poured with vigorous stirring onto 500 g of ice in a 2-liter beaker, and while the liquid temperature of the mixture was low, 180 g of sodium hydroxide and water 1. An aqueous solution of 2 liters (pre-cooled to 0 ^e C) was slowly poured. The mixture was further stirred for 30 minutes, and the floating pale yellow solid was collected by suction filtration and air-dried to obtain 35.7 g of the desired product (96% yield). NMR (ppm, internal standard: tetramethylsilane, _{solvent: CDC 1 3): 2 59} (3H, s), 7. 46 (1 H, s), 8. 12 (1H, s)

(11-b) Synthesis of 3- (2-chloro-5-methyl-412-trofenerthio) propionic acid

300 ml of N, N-dimethylformamide was placed in a 500 ml flask, and 35.7 g (0.173 mmol) of 3,4-dichloro-6-nitrotoluene obtained in (1-a) above, 20.2 g (0.26 mmo 1) of mercaptopropionic acid and 36.0 g of potassium carbonate were sequentially added, and the mixture was stirred at room temperature for 20 hours and reacted at 70 to 80 ° C for 10 hours. After cooling the reaction mixture to room temperature, 1.5 liters of water was added, and the insoluble solid was removed by suction filtration. While cooling the solution, a 12N aqueous hydrochloric acid solution was added thereto to adjust the pH to 2-3. The precipitated pale yellow solid was collected by suction filtration, washed with water and dried under reduced pressure to obtain 43.5 g (yield 91%) of the desired product.

NMR (ppm. Internal standard: tetramethylsilane, solvent: heavy acetone): 2.63 (3H, s), 2.82 (2H, t), 3.42 (2H, t), 7.δ 2 (1 H, s), 8.07 (1 H, s)

(1-1c) Synthesis of 8-chloro-5-methyl-6-12-trothiochroman-1-one

To 300 g of polyphosphoric acid (containing 20% P ₂ O ₅ ) in a 1-liter beaker, 43.5 g of 2-chloro-5-methyl-41-2-trofenerylthiopropionic acid obtained in (1-1b) above was added. In addition, the reaction was homogenized by stirring at 50-7 CTC. Further, the temperature of the reaction solution was raised to 120 ° C., and the reaction was performed for 3 hours. After cooling, 500 g of ice was added, the contents were transferred to a 1-liter flask, and the beaker wall was washed with 100 ml of acetic acid and added to the flask together. After refluxing for 1 hour, the mixture was left to cool, and the precipitated black solid was collected by suction filtration, washed with water, and extracted with ethyl acetate using Soxhlet. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 34.2 g (yield 84%) of the desired product.

 NMR (ppm, internal standard: tetramethylsilane, solvent: ^ acetone): 2.50 (3H, s), 3.0-3.2 (2H, m), 3.3-3.6 (2H , M), 8.02 (1 H, s)

(1 -d) Synthesis of 6-nitro-8-chloro-5-methyl-4-methoxyiminothiochroman

0 ゥ

In a 500 ml eggplant flask, add 8-methyl-5-methyl obtained in (1-1c) above. 6-Nitrothiochroman 4-one 30.0 g (117 mmol), dimethylhydroxamine hydrochloride (alkoxyamine) 10.7 g (128 mmol, 1.1 equivalents), pyridine 23.0 g (291 mmol) , 2.5 equivalents), 300 ml of ethanol was added, and at 2.5 o'clock WJiS was allowed to flow. After cooling, 15 Oml of water was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with 10 Oml of a 1: 1 solution of ethanol: water, dried under reduced pressure, and dried under reduced pressure to obtain the desired compound (nitro compound (1, n = 0)) 31.9 g (95% yield).

NMR (ppm, internal standard: tetramethylsilane, _{solvent: CDC 1 3):. 2.} 60 (3H, t), 2. 8-3 4 (4H, m), 4. 01 (3H, s), 7 . 79 (1 H, s)

(1-e) 6-Nitro 8-Chloro-5-Methyl-4-methoxyiminothiochroman 1, 1-Dioxide ¾

Oku

In a 1-liter eggplant flask, 31.9 g of 8-chloro-5-methyl-6-twotro 4-methoxyiminothiochroman (two-nitro compound (1, n = 0)) obtained in (1-1d) above (ll lmmo l), 30% H ₂ O, (oxidizing agent) 29.0 g (255mm

01, 2.5 equivalents) and 12 Oml of acetic acid were added and reacted at 90 ° C for 2.5 hours. After allowing to cool, add 700 ml of water to the reaction mixture, collect the crystals, wash with 100 ml of water, and then kill / Ι: ½ ^ to obtain 11 targets (nitrated iVT (1, n = 2)) 34.3 g (97% yield) were obtained.

 N.M.R. (ρρπκ Internal standard: tetramethylsilane, solvent: heavy acetone):

2.55 (3H, t), 3.2-3.δ (4H, m), 4.00 (3H, s), 5.5-5.7 (2H, m), 7.76 (lH, s) (Example 2)

 Synthesis of 6-amino-8-chloro-5-methyl-4-methoximininothiochroman 1,1 dioxide (compound 1 in Table 1 below) (Step A in FIG. 1)

 In a 50 Oml eggplant-shaped flask, the 6-two-row 8-chloro-5-methyl-4-methoximininothiochroman-1,1-dioxide (nitro compound (1, n = 2)) obtained in Example 1 above was used. g (37.7 mmo 1), iron powder (reducing agent) 7.4 g (13 lmmo 1, 3.5 equivalents), ethanol 9 Oml and water 6 Oml. Mineral acid) 2. Oml was added. After refluxing for 3.5 hours, the reaction mixture was allowed to cool, 20 Oml of ethyl acetate was added thereto, and the insoluble solid was removed by filtration. The insoluble solid was further washed twice with 10 mL of ethyl acetate, and the washing was combined with the filtrate (organic layer). The organic layer is washed three times with water and once with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain the desired product (nuclear halogenated amino compound (II)). g (96% yield). Table 1 shows the structural formula and N.M.R. data of the obtained target compound (Compound 1).

(Example 3)

 Synthesis of 6,1-amino-5-methyl-4-methoxyiminothiochroman 1,1 dioxide (compound 2 of 1-subs) (Step B1 in FIG. 1)

In a 300 ml autoclave, 6-amino-8-chloro-5-methyl-4-methoxyminothiochroman-1,1-dioxide (nuclear halogenated amino compound (II)) obtained in Example 2 above (compound 1) 1 g (3.5 mmo 1), 0.28 g of pyridine (3.5 mmol, 1 equivalent), 0.4 g of 5% palladium / activated carbon (hydrogenation catalyst), 15 ml of ethanol, and hydrogen pressure 30 kg / Reaction was performed for 15 hours at room temperature under cm ² . After the reaction, the catalyst was removed by filtration, and ethanol was distilled off. The obtained residue was dissolved in ethyl acetate, washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain the desired product (amino compound (ΙΠ)), 0.8 δg (96% yield). C The structural formula and NMR data of the obtained desired product (compound 2) are shown in Table 1. . (Example 4)

 Synthesis of 6-amino-5-methyl-4-methyximinothiochroman 1,1-dioxide (Compound 2 in Table 1) (1-pot method) (Step B2 in Figure 1)

 In a 300 ml autoclave, add 6-two-row 8-chloro-

5-methyl-4-methoxyiminothiochroman 1,1-dioxide (dimethoxy compound (I)) 3.2 g (1.0 mmo 1), pyridine 0.8 g (1.0 mmo 1,

1 equivalent), 5% palladium on activated carbon (hydrogenation catalyst) 1.6 g, ethanol 15 ml, react under hydrogen pressure 30 kg / cm ² at room temperature for 30 hours, and perform reductive amination of nitro group at position 6 and The reductive elimination of the chlorine atom was performed. After the reaction, the catalyst was removed by filtration, and ethanol was distilled off. The obtained residue was dissolved in ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain the desired product (amino compound (III)) 2.1 (81% yield). Table 1 shows the structural formula and NMR data of the obtained target compound (Compound 2).

(Example 5)

 Synthesis of 6-promo 5-methyl-4-methoxyiminothiochroman 1,1-dioxide (compound 3 in Table 1) (Step C-b in Figure 1)

 (5-a) Diazotization

 1.12 g of the 6-amino-5-methyl-4-methoximininothiochroman 1,1-dioxide (amino compound (III)) (compound 2) obtained in Example 10 4 mmo 1), 9 ml of 16% HBr (hydrogen halide) (3 ml of 48% HBr + 6 ml of water) and 5 ml of acetic acid were added, and the mixture was ice-cooled to 5 ° C or lower. A solution of 0.33 g of NaNO ^ (4.8 mmol, 1.1 equivalent S) in 4 ml of water was added at 5 ° C or less, and the mixture was stirred for 15 minutes, and further stirred at room temperature for 30 minutes. A suspension of the desired diazonium compound was prepared.

(5-b) Preparation of CuB r chaos

In a 100 ml flask, put 1.25 g (5 Ommo 1) of CuSC ^ * 5H20 and 0.57 g (5.5 mmol, 1.1 equivalent) of NaBr, and add 50-60. It was dissolved in 5 ml of warm water at ° C. To this _{solution, NaHS0 3 0. 27 g (2.} 6 m mo 1, 0. 52 eq), NaOH 0. 18 g (4. 5mmo l, 0. 9 eq) which was dissolved in water 3ml added The mixture was allowed to cool with stirring. At this time, a white precipitate of CuBr was formed. To this, 2 ml of 48% HBr was added to obtain an aqueous solution of CuBr (5 mmo 1) HBr.

(5-c) Bromination

To the CuBr solution prepared in (5-b) above, 15 ml of ethyl acetate is added, and the solution of the diazonium compound prepared in (5-a) is gradually added while bubbling at 35-45 ° C. Was added. The diazonium compound attached to the vessel was dissolved in a small amount of acetic acid and added. The mixture was further stirred for 15 minutes, allowed to cool, and extracted with 100 ml of ethyl acetate. The organic layer diluted hydrochloric acid, water, saturated NaHCO ₃ water (several times), washed sequentially with saturated saline, dried over anhydrous sodium sulfate, purpose objects by distilling off the solvent 1. 32 g (95% yield) I got Table 1 shows the structural formula and NMR data of the obtained target compound (halogen compound (IVb)) (compound 3).

(Example 6)

 Synthesis of 4-methoxyminnow 5-methyl-6- (1-ethyl-5-hydroxyvillazol 4-yl) thiochroman 1,1-dioxide (compound 4 in Table 1) (Step D in Figure 1)

In a 150 ml autoclave, 3.0 g (9.4 mmol) of 1-, 1-dioxide (halogen compound (IVb)), 6-promo 5-methyl-4-methoximinothiochroman obtained in Example 5 above, Echiru 5 hydroxycarboxylic pyrazole (Birazo - Le compound (V)) 4. 24 g ( 37. 9mmo 1, 4 eq), K ₂ C0 ₃ (inorganic salt group) 3. 9g (28mmo l, 3 eq), Triethylamine (organic base) 3.8 g (38 mmo 1, 4 equivalents), (n-Bu) NBr (phase transfer catalyst) 1.2 g (3.7 mmol, 0.4 equivalents), PdCl ₂ (PPh ₃ ) ₂ (Metal catalyst) 0.67 g (0.9 mmol, 0.1 equivalent), 100 ml of 1,4-dioxane, put at 150 ° C under carbon monoxide pressure 7 Okg / cm ² (initial pressure) The reaction was performed for 15 hours. Anti After completion of the reaction, the insoluble matter was removed by filtration, and dioxane in the filtrate was distilled off. The resulting acid Echiru and 5% K ₂ C0 ₃ aqueous solution was separated by adding to the residue. The aqueous layer was neutralized with 5% hydrochloric acid, and the precipitated crystals were collected by filtration and air-dried to obtain 2.5 g (yield 70%) of the desired product.

 Further, the obtained crystals were purified by column chromatography (elution solvent: black-mouthed form) to obtain 1.6 g (yield 46%) of the target compound (virazole derivative (VI)) as yellow crystals. Table 1 shows the structural formula and N.M.R. data of the obtained target compound (Compound 4).

2 (below)

Three

Industrial availability

 According to the present invention, an industrially advantageous virazole derivative which does not require a step of separating isomers which leads to a low yield and a complicated step of synthesizing a carboxylic acid is not required for producing a birazol derivative useful as a herbicide. A manufacturing method was provided.

 Further, the present invention provides a production intermediate useful for producing a virazole derivative and a production method thereof.

(Hereinafter the margin)

Two

 Five

Claims

Special Words 1 · — General formula (IV)

(Wherein, R ¹ and X ^{1 each} independently represent a C, -C ₄ alkyl group, X ³ represents a diazodium salt or a halogen atom, and n represents an integer of 0, 1 or 2.) ) And a diazonium or a halogen compound represented by the general formula (V)

(Wherein, R ² represents a C, to C ₄ alkyl group, and R ³ represents a hydrogen atom or a C, to C ₄ alkyl group.) A virazole compound represented by the following formula: Below, a general formula (VI) characterized by reacting with carbon monoxide.

(Wherein, R ′, R ² , R \ X ¹ and n are as described above; as defined). 2. General formula (III)

(Wherein, R ′ and X ¹ are each independently., ~ (^ Represents an alkyl group, and n represents an integer of 0, 1 or 2). General formula (IV) characterized by reacting with an acid or cuprous halide

(Wherein, I ¹ , X ¹ and n are as defined above, and X ³ represents a diazodium salt or a halogen atom.) A method for producing a diazonium or a halogen compound represented by the formula: 3. —General formula (II)

(The formulas B, R 'and X ^{1 each} independently represent C, ~. An alkyl group, X ² represents a halogen atom, and n represents an integer of 0, 1 or 2.) Halogenated A compound represented by the general formula (III):

(Wherein, R ′, X ¹ and n are as defined above). 4. General formula (I)

(Wherein, R ¹ and X ^{1 each} independently represent a C, to C ₄ alkyl group, X ² represents a halogen atom, and n represents an integer of 0, 1 or 2.) Nitro compounds, characterized by the general formula (-)

(Shiki屮, RX ^1, X ² and n Wahikijo! Is as ¾.) The preparation of nuclear halogenation Amino compounds ¾ in. 5. General formula (I)

(Wherein, R ¹ and X ^{1 each} independently represent a C, -C ₄ alkyl group, X ² represents a halogen atom, and n represents an integer of 0, 1 or 2). General formula (III) characterized in that a nitro compound is reduced

(Wherein R ′, X ′ and r are as defined above.) A process for producing an amino compound represented by the formula: 6. General formula (IV)

(Formula, R 'and X' each independently represent C alkyl ^, X ³ represents a diazo salt or a halogen atom, and m represents an integer of 1 or 2.) Halogen compounds. 7. General formula (III)

(Wherein, R ¹ and X ^{1 each} independently represent 0 ^ to ( ₄ alkyl groups, and n represents an integer of 0, 1 or 2)). 8. General formula (II)

(Wherein, R ¹ and X ^{1 each} independently represent a C, -C ₄ alkyl group, X ² represents a halogen atom, and n represents a number of 0, 1 or 2). Nuclear halogenated amino compounds. 9. General formula (I)

(Wherein, R ¹ and X ^{1 each} independently represent C,... Represents an alkyl group, X ² represents a halogen atom, and n represents an integer of 0, 1 or 2.) Compound.