WO2015137216A1 - 2-アシルイミノピリジン誘導体の製造法 - Google Patents
2-アシルイミノピリジン誘導体の製造法 Download PDFInfo
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- WO2015137216A1 WO2015137216A1 PCT/JP2015/056409 JP2015056409W WO2015137216A1 WO 2015137216 A1 WO2015137216 A1 WO 2015137216A1 JP 2015056409 W JP2015056409 W JP 2015056409W WO 2015137216 A1 WO2015137216 A1 WO 2015137216A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
Definitions
- the present invention relates to a method for producing a derivative having a 2-acyliminopyridine structure.
- the 2-acyliminopyridine derivative represented by the following formula (I) is a useful compound as a pest control agent as shown in Patent Document 5.
- Patent Documents 1 to 5 and Non-Patent Document 2 are known.
- Patent Document 1, Patent Document 2, Patent Document 3, and Non-Patent Document 2 do not describe a production method using a compound represented by the following formula (B) as an intermediate.
- a specific production method is not described.
- Non-Patent Document 3 discloses N- (pyridine-2 (1H) -ylidene] -acetamide as a tautomer of 2-acetamidopyridine, a specific production method thereof, A method for producing a haloacyl derivative is not described.
- Patent Documents 4 and 5 disclose specific methods for producing the compound represented by the formula (I).
- an acid anhydride such as trifluoroacetic anhydride
- a high yield is often obtained due to its high reactivity, but 1 equivalent of a carboxylic acid compound is by-produced. It is disadvantageous industrially and economically and has a great impact on the environment.
- carboxylic acid compounds have low reactivity and are difficult to be subjected to acylation as they are, so a condensing agent is often used together, but when a condensing agent is used in combination, another waste is generated. .
- an acid chloride of a carboxylic acid compound is often produced and used for acylation.
- trifluoroacetic acid as described in Non-Patent Document 4, is acid chloride unless an auxiliary catalyst is added. Is usually difficult to synthesize.
- trifluoroacetic acid chloride is a gas having a boiling point of ⁇ 27 ° C., and special equipment is required for industrial use as acid chloride by derivatization from trifluoroacetic acid.
- an acylated product can also be obtained by dehydrating and refluxing trifluoroacetic acid with a solvent having a high boiling point such as toluene or xylene, but a reaction at a high temperature for a long time is required. It is industrially disadvantageous.
- the object of the present invention is to provide N- [1-((6-chloropyridin-3-yl) methyl) pyridine-2 (1H) -ylidene] -2,2,2-trifluoro represented by the following formula (I):
- An object of the present invention is to provide a production method in which the amount required of loacetamide as a pest control agent is stabilized, and the burden on the environment is reduced and provided at low cost.
- the inventors obtain a compound represented by the following formula (I) using the compound represented by the formula (A) as a starting material and the compound represented by the formula (B) as an intermediate.
- the production method by using trifluoroacetic acid and the reaction reagent (X), the amount of the reagent used is small, the waste generated in the reaction is small, and the target compound is produced industrially and economically efficiently.
- the present invention was completed.
- this invention provides the manufacturing method of the compound represented by the following formula (I) shown below.
- ⁇ 1> A method for producing a compound represented by the following formula (I),
- the present invention provides a production method comprising a step of alkylating a 1-position nitrogen atom of a compound represented by B) with a compound represented by formula (C).
- the reagent (X) used together with the acylating agent is thionyl chloride.
- the base used for the reaction of the compound represented by the formula (B) is pyridine or N-methylimidazole.
- ⁇ 4> The production method according to any one of ⁇ 1> to ⁇ 3>, wherein the solvent used in the reaction of the compound represented by formula (B) is an ether-based or ester-based solvent.
- the acylating agent trifluoroacetic acid is used in an amount of 1.0 to 2.0 equivalents relative to the compound represented by the formula (A), and simultaneously 0.5 to 1.5 equivalents of thionyl chloride and pyridine Alternatively, the production method according to any one of ⁇ 1> to ⁇ 4>, wherein 1.5 to 3.0 equivalents of N-methylimidazole are used.
- the base used in the production of the compound of formula (B) can be recovered and reused, and the generation of waste and the burden on the environment can be reduced.
- a compound represented by the formula (I) useful as a pesticidal agent can be produced in one pot in an industrially and economically advantageous manner and with little burden on the environment, if necessary.
- the “equivalent” of the base is, for example, 2 equivalents when 1 mol of potassium carbonate is used per 1 mol of the compound represented by the formula (A), and sodium hydroxide or sodium bicarbonate. When 1 mol is used, it is 1 equivalent, and when 1 mol of organic base is used, it is 1 equivalent.
- salt refers to inorganic acid salts such as hydrochloride, sulfate and nitrate, and organic acid salts such as trifluoroacetate, difluoroacetate and dichloroacetate.
- the compound represented by the formula (B) shown in the above scheme in the present invention may be used in the next step without post-treatment or isolation.
- a method for producing a compound represented by formula (B) from a compound represented by formula (A) using trifluoroacetic acid is represented by formula (A) in a solvent-free or solvent that does not affect the reaction. It can be carried out using the reagent (X) in the presence or absence of a base in the compound.
- the number of equivalents of the reagent referred to here is the number of equivalents of the compound represented by the formula (A).
- Usable solvents include aromatic hydrocarbon solvents such as toluene, xylene and ethylbenzene, ester solvents such as methyl acetate, ethyl acetate and butyl acetate, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, tert- Ether solvents such as butyl methyl ether, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, acetonitrile, etc.
- aromatic hydrocarbon solvents such as toluene, xylene and ethylbenzene
- ester solvents such as methyl acetate, ethyl acetate and butyl acetate, diethyl ether, diisopropyl ether
- protic polar organic solvents examples include protic polar organic solvents, halogen solvents such as dichloromethane and chloroform, hydrocarbon solvents such as cyclohexane, ketone solvents such as acetone and methyl ethyl ketone, water, and mixed solvents thereof.
- halogen solvents such as dichloromethane and chloroform
- hydrocarbon solvents such as cyclohexane
- ketone solvents such as acetone and methyl ethyl ketone
- water and mixed solvents thereof.
- Preferred solvents include toluene, ester solvents, ether solvents, or mixed solvents thereof.
- Usable bases include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, magnesium hydroxide, calcium hydroxide, lithium hydroxide, barium hydroxide and other inorganic bases, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, triethylamine, diisopropylethylamine, pyridine, picoline, dimethylaminopyridine, N-methylimidazole, etc.
- examples thereof include alcoholates such as organic bases, sodium ethoxide, sodium methoxide, and tert-butoxypotassium.
- a base may not be used, but preferred bases for carrying out the reaction in the presence of a base include pyridine and N-methylimidazole.
- the amount of the base used is 0.01 to 20.0 equivalents, preferably 1.0 to 5.0 equivalents.
- the acylating agent trifluoroacetic acid can be used alone, but in some cases it can be mixed with one or more other acylating agents such as trifluoroacetic anhydride, trifluoroacetic acid chloride, ethyl trifluoroacetate and the like. May be used. Among these, it is preferable to use trifluoroacetic acid alone.
- the amount of the acylating agent used is preferably 0.5 to 10.0 equivalents, more preferably 1.0 to 5.0 equivalents.
- the reagent (X) used at the same time includes at least one reagent selected from thionyl chloride, phosphorus oxychloride, oxalic acid dichloride and the like, and these can be used alone or in combination.
- the amount of reagent (X) used is preferably 0.2 to 5.0 equivalents.
- the reaction temperature is preferably in the range of ⁇ 80 ° C. to 200 ° C.
- the reaction time is preferably in the range of 0.1 hour to 7 days.
- More preferable conditions include toluene, ether solvent, ester solvent, or a mixed solvent thereof, and 1.0 to 2.0 equivalents of trifluoroacetic acid, thionyl chloride, phosphorus oxychloride, or oxalic acid dichloride.
- the reaction temperature is ⁇ 10 ° C. to 80 ° C.
- the reaction time is 0.1 Time to 1 day.
- Particularly preferable conditions are the following conditions. Trifluoroacetic acid is used as the acylating agent, an ether solvent, an ester solvent, or a mixed solvent thereof is used as the solvent, and the amount of the acylating agent used is 1.0 to 2.0 equivalents. Further, thionyl chloride is used at the same time, and the amount used is 0.5 to 1.5 equivalents. Further, 1.5 to 3.0 equivalents of pyridine or N-methylimidazole is used as a base, the reaction temperature is ⁇ 10 ° C. to 60 ° C., and the reaction time is 0.1 hour to 12 hours.
- Usable solvents include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, tert-butyl methyl ether, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide, acetonitrile, N-methyl -2-Pyrrolidinone, N-methyl-2-piperazinone, N, N-dimethyl-2-imidazolidinone, aprotic polar organic solvents such as acetonitrile, ester solvents such as methyl acetate, ethyl acetate, butyl acetate, dichloromethane Halogenated solvents such as chloroform, aromatic hydrocarbon solvents such as toluene, xylene, and ethylbenzene, and mixed solvents thereof, preferably aprotic polar organic solvents.
- ether solvents such as diethyl ether, di
- N is selected from the group consisting of N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, N, N-dimethyl-2-imidazolidinone, acetonitrile.
- a mixed solvent of one or more selected solvents and an aromatic hydrocarbon solvent particularly preferably dimethyl sulfoxide only, N, N-dimethylformamide only, or a mixed solvent of dimethyl sulfoxide and toluene, or N , N-dimethylformamide and toluene It is a solvent.
- Usable bases for the reaction in the presence of a base include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, magnesium hydroxide, calcium hydroxide, lithium hydroxide, barium hydroxide, etc. 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, triethylamine, diisopropylethylamine, pyridine, lutidine, collidine
- Organic bases such as N, N-dimethylaniline and N, N-diethylaniline, preferably potassium carbonate, potassium hydrogen carbonate, pyridine, triethylamine and the like, more preferably potassium carbonate.
- the amount of the compound represented by the formula (C) is preferably 0.7 to 2.0 equivalents, more preferably 0.7 to 1.2 equivalents relative to the compound represented by the formula (B). is there.
- the amount of the base used is preferably 1.0 to 10.0 equivalents, more preferably 1.0 to 6.0 equivalents, relative to the compound represented by the formula (B). Particularly preferred is 1.0 to 2.4 equivalents.
- the reaction temperature is preferably in the range of 20 ° C. to 100 ° C., more preferably in the range of 40 ° C. to 80 ° C.
- the reaction time is preferably in the range of 0.1 hour to 3 days, and more preferably in the range of 1 hour to 1 day.
- Particularly preferred conditions are represented by the formula (C) using only N, N-dimethylformamide, only dimethyl sulfoxide, a mixed solvent of N, N-dimethylformamide and toluene, or a mixed solvent of dimethyl sulfoxide and toluene as a solvent.
- the amount of the compound used is 0.7 to 1.2 equivalents relative to the compound represented by formula (B), the reaction temperature is 40 ° C. to 80 ° C., and the reaction time is 1 hour to 2 days. Yes, the base is 1.0 to 2.4 equivalents of potassium carbonate.
- reaction product represented by the formula (B) is left as it is, or after excess reagent is removed under reduced pressure, or the salt of a by-product organic base is removed by filtration, liquid separation operation, or the like.
- a compound represented by the formula (I) is obtained by adding a compound represented by the formula (C) and a base and reacting them under the above conditions.
- the compound represented by the formula (A) A salt of an organic base produced as a by-product after reacting with trifluoroacetic acid as an acylating agent using an ether solvent, an ester solvent, or a mixed solvent thereof to obtain a compound represented by formula (B) Is removed by filtration, liquid separation operation, etc., and an aromatic hydrocarbon solvent, an aprotic polar organic solvent, or a mixed solvent thereof, and a compound represented by formula (C) and a base are added as they are, or
- the reaction is carried out while distilling off the aromatic hydrocarbon solvent under reduced pressure to obtain the compound represented by the formula (I).
- acylating agent When trifluoroacetic acid is used as the acylating agent, particularly preferred conditions are as follows.
- Trifluoroacetic acid is used as the acylating agent, an ether solvent, an ester solvent, or a mixed solvent thereof is used as the solvent, and the amount of the acylating agent used is 1.0 to 2.0 equivalents. Further, thionyl chloride is used at the same time, and the amount used is 0.5 to 1.5 equivalents. Further, 1.5 to 3.0 equivalents of pyridine or N-methylimidazole is used as a base, the reaction temperature is ⁇ 10 ° C. to 60 ° C., and the reaction time is 0.1 hour to 12 hours.
- the compound represented by formula (I) is a crystallization method, solvent extraction method, column chromatography, etc., which are usually used alone, or , And can be purified and isolated by combining.
- the solvent used in the solvent extraction method is not particularly limited as long as it is not miscible with water, and specific examples include ethyl acetate, butyl acetate, toluene, ethylbenzene, diethyl ether, diisopropyl ether, dichloromethane, chloroform, and the like. .
- Solvents used in the crystallization method are water, hexane, toluene, acetone, N, N-dimethylformamide, dimethyl sulfoxide, methanol, 2-propanol, dichloromethane, chloroform, ethyl acetate, diethyl ether, xylene, N-methyl-2 -Pyrrolidinone, N, N-dimethylacetamide and the like, or a mixed solvent thereof.
- a preferred purification and isolation method of the compound represented by the formula (I) is a crystallization method, and as a crystallization solvent, acetone, toluene, water, N, N-dimethylformamide, dimethyl sulfoxide, methanol, xylene, N-methyl -2-Pyrrolidinone or N, N-dimethylacetamide is preferably used alone or in combination, more preferably a combination selected from water, methanol, N, N-dimethylformamide, or dimethylsulfoxide.
- the filtrate was concentrated under reduced pressure, and 33.4 g of 2-chloro-5-chloromethylpyridine, 55 g of dimethyl sulfoxide, 17.3 g of toluene, and 19.3 g of potassium carbonate (powder) were added. After stirring for 1 hour at 80 ° C. and 80 ° C., the reaction solution was poured into 120 g of water, and the solid remaining in the eggplant flask was washed with about 7.9 g of methanol. After stirring at room temperature for 1 hour, the precipitated solid was collected by filtration, washed twice with 40 g of water and twice with 34.7 g of toluene, and then dried overnight under reduced pressure to give 56.5 g of the desired compound.
- the tetrahydrofuran layer was separated and extracted from the lower layer twice using 35.6 g of tetrahydrofuran while warming to 45 ° C., and all the extracts were combined and concentrated under reduced pressure.
- 32.2 g of 2-chloro-5-chloromethylpyridine dissolved in 55 g of dimethyl sulfoxide, 17.3 g of toluene, and 19.3 g of potassium carbonate (powder) were added in this order, and 60 ° C., 130 hPa for 2 hours, 70 ° C., After stirring at 80 hPa for 1 hour, the reaction solution was poured into 120 g of water.
- the reaction solution was added dropwise to 670 g of water, and the reaction vessel was washed with 79 g of methanol. After stirring at room temperature for 1 hour, the precipitate was filtered. The filtrate was washed with 1000 g of water and 433 g of toluene and then dried under reduced pressure to obtain 275 g (yield 87.1%) of the target compound.
- the 2-acyliminopyridine derivative represented by the above formula (I), which is useful as a pesticidal agent, is industrially advantageous in one pot as needed, and can be used in an environment.
- the amount required as a pest control agent can be stably supplied at a low cost. Therefore, the present invention can greatly contribute to the field of pest control.
Abstract
Description
<1> 下記の式(I)で表される化合物の製造方法であって、
式(B)で表される化合物の1位窒素原子を、さらに式(C)で表される化合物を用いてアルキル化する工程を含む、製造方法を提供するものである。
<2> アシル化剤と同時に用いる試薬(X)がチオニルクロリドである<1>に記載の製造方法。
<3> 式(B)で表される化合物の反応に用いる塩基がピリジンまたはN-メチルイミダゾールである<1>または<2>に記載の製造方法。
<4> 式(B)で表される化合物の反応に用いる溶媒がエーテル系またはエステル系の溶媒である<1>から<3>のいずれか一に記載の製造方法。
<5> アシル化剤のトリフルオロ酢酸を、式(A)で表される化合物に対して、1.0~2.0当量を用いて、同時にチオニルクロリド0.5~1.5当量およびピリジンまたはN-メチルイミダゾール1.5~3.0当量を用いる<1>から<4>のいずれか一に記載の製造方法。
本発明を以下のスキームに沿ってさらに詳細に説明する。
式(A)で表される化合物は、市販されている化合物を利用することもでき、または、例えば、文献(Journal of labeled compounds & radiopharmaceuticals(1987),24(2)119-123)に記載の方法で得ることもできる。
式(B)で表される化合物から式(I)で表される化合物を製造する方法としては、無溶媒あるいは溶媒中で、式(B)で表される化合物に塩基存在下、式(C)で表される化合物と反応させることで得ることができる。
式(A)で表される化合物から式(I)で表される化合物を合成する際、式(B)で表される化合物を単離することなく、次工程を行い、式(I)で表される化合物を得ることが可能である。
ここで言う試薬の当量数とは、全て式(A)で表される化合物に対する当量数である。
式(B)で表される化合物から式(I)で表される化合物を得るための特に好ましい条件は、溶媒としてN,N-ジメチルホルムアミドのみ、ジメチルスルホキシドのみ、N,N-ジメチルホルムアミドとトルエンとの混合溶媒、またはジメチルスルホキシドとトルエンとの混合溶媒を用い、式(C)で表される化合物の使用量は、式(B)で表わされる化合物に対して0.7~1.2当量であり、反応温度は40℃~80℃、反応時間は1時間~2日間であり、塩基は炭酸カリウムを1.0~2.4当量である。
式(I)で表わされる化合物は、通常用いられる結晶化法、溶媒抽出法、カラムクロマトグラフィーなどを単独、または、組み合わせることによって精製単離することができる。溶媒抽出法に用いられる溶媒は、水と混和しない溶媒であれば特に制限はないが、具体的には酢酸エチル、酢酸ブチル、トルエン、エチルベンゼン、ジエチルエーテル、ジイソプロピルエーテル、ジクロロメタン、クロロホルムなどが挙げられる。結晶化法に用いられる溶媒は、水、ヘキサン、トルエン、アセトン、N,N-ジメチルホルムアミド、ジメチルスルホキシド、メタノール、2-プロパノール、ジクロロメタン、クロロホルム、酢酸エチル、ジエチルエーテル、キシレン、N-メチル-2-ピロリジノン、N,N-ジメチルアセトアミドなど、またはそれらの混合溶媒が挙げられる。
2-アミノピリジン18.8gを1,2-ジメトキシエタン34.7g、ピリジン34.8gに溶かし、0℃でトリフルオロ酢酸25.1g、チオニルクロリド26.2gを順に滴下し、室温で1時間撹拌した。反応液を110hPa、50℃で25分減圧濃縮した後、1,2-ジメトキシエタン26gを加え、析出した固体をろ過して除き、固体を1,2-ジメトキシエタン計86.8gを使用して洗いこんだ。
1H-NMR(CDCl3,δ,ppm):5.57(2H,s),6.92(1H,td),7.31(1H,d),7.80(1H,td),7.87(1H,dd),
7.99(1H,dd),8.48(2H,m)
13C-NMR(CDCl3,δ,ppm):53.8,115.5,117.2(q),122.1,124.7,130.0,139.2,140.0,142.5,149.7,151.8,158.9,163.5(q)
MS:m/z=316(M+H)。
2-アミノピリジン4.7gをトルエン26g、ピリジン9.5gに溶かし、0℃でトリフルオロ酢酸6.27g、チオニルクロリド6.54gを順に滴下し、室温で1時間撹拌した。反応液を120hPa、60℃で10分減圧濃縮した後、トルエン17.3gを加え、110hPa、60℃で10分減圧濃縮した。析出した固体をろ過して除き、固体をトルエン計39gを使用して洗浄した。
2-アミノピリジン28.2gをジオキサン56.4gに溶解し、これにN-メチルイミダゾール54.2gを加えた。氷冷下、トリフルオロ酢酸35.9gおよびチオニルクロリド41.0gを加えた。室温で1.5時間撹拌後、ジオキサン層を分離し、下層をジオキサン56.4gで抽出した。抽出を3回繰り返し、回収したジオキサン層を濃縮した。これに2-クロロ-5-クロロメチルピリジン46.2g、N,N-ジメチルホルムアミド66.6g、トルエン24.4gおよび炭酸カリウム29.0gを加え、60℃で120~80hPaの減圧下4時間反応した。反応液を温水170gに滴下し、析出物をろ過した。ろ物を水84gおよびトルエン72.8gで洗浄後、減圧乾燥し、目的とする化合物82.6g(収率87.2%)を得た。
2-アミノピリジン18.8gをテトラヒドロフラン35.6g、ピリジン34.8gに溶かし、0℃でトリフルオロ酢酸25.1g、チオニルクロリド26.2gを順に滴下し、40℃で1時間撹拌した。テトラヒドロフラン層を分離し、45℃に温めながら、下層からテトラヒドロフラン35.6gを用いて2回抽出し、抽出液を全て合一して減圧濃縮した。これに、ジメチルスルホキシド55gに溶解した2-クロロ-5-クロロメチルピリジン32.2g、トルエン17.3g、炭酸カリウム(粉末)19.3gの順に加え、60℃、130hPaで2時間、70℃、80hPaで1時間撹拌した後、反応液を120gの水に注ぎ込んだ。これを室温で1時間撹拌した後、析出した固体をろ集し、水40gで2回、トルエン34.7gで2回かけ洗いした後、一晩減圧乾燥することで目的とする化合物55.3g(収率88%)を得た。
2-アミノピリジン18.8gをピリジン34.8gおよびtert-ブチルメチルエーテル37.6gの混合溶媒に溶解し、トリフルオロ酢酸23.9gおよびチオニルクロリド26.2gを氷冷下加えて、室温で1時間撹拌した。反応液をろ過し、tert-ブチルメチルエーテル18.7gで3回洗浄した。ろ液を全て合わせ、減圧下に溶媒を留去した。これにジメチルスルホキシド51.7gおよび2-クロロ-5-クロロメチルピリジン16.2gを加えて溶解し、さらに粉末炭酸カリウム19.3gを加えて60℃で2時間、70℃で30分間撹拌した。反応液を水120gに添加した後、室温まで放冷して30分間撹拌した。結晶をろ過し、水40gで4回、トルエン34.7gで2回洗浄した。得られた結晶を減圧下60℃で乾燥して、目的とする化合物を53.4g(収率84.8%)得た。
2-アミノピリジン18.8gをジオキサン37.6gに溶解し、これにピリジン34.8gを加えた。氷冷下、トリフルオロ酢酸23.9gおよびチオニルクロリド26.2gを加えた。室温で45分間撹拌後、ジオキサン層を分離し、下層をジオキサン37.6gで抽出した。抽出を3回繰り返し、回収したジオキサン層を減圧濃縮した。これに2-クロロ-5-クロロメチルピリジン32.4g、ジメチルスルホキシド73.7g、トルエン40.7gおよび炭酸カリウム19.3gを加え、60℃、100hPaの減圧下、2時間撹拌した。さらに炭酸カリウム2.76gを加えて同条件で1時間撹拌した。反応液を温水180gに滴下し、メタノール7.9gで洗い込んだ。室温で1時間撹拌した後、析出物をろ過した。ろ物を水およびトルエンで洗浄後、一旦減圧乾燥した。これを再度水で洗浄した後、再度減圧乾燥して、目的とする化合物58.6g(収率93.0%)を得た。
例えば合成例6に従って得られたピリジン塩酸塩からジオキサンを減圧留去し、185gの粗ピリジン塩酸塩を得た。氷冷下、7Nのアンモニアメタノール溶液を添加して中和した後、蒸留を行った。約110~114℃の留分を回収し、ピリジン93.3gを得た。
例えば合成例6に従って得られたピリジン塩酸塩からジオキサンを減圧留去し、282gの粗ピリジン塩酸塩を得た。メタノール100gを加えて溶解した後、氷冷下、ナトリウムメトキシド118.8gを加えて中和した後、流動パラフィン87gを加えた。蒸留を行い、約110~114℃の留分を回収し、ピリジン116.4gを得た。
例えば合成例6に従って得られたピリジン塩酸塩からジオキサンを減圧留去し、136.1gの粗ピリジン塩酸塩を得た。水32gおよび48%苛性ソーダ100gを加えて中和し、これを酢酸エチル90gで抽出した。水相に水120gを加え、再度酢酸エチル45gで抽出し、酢酸エチル層を合わせた。これを蒸留し、約76℃の留分を除いた後、残渣にシクロヘキサン20gを加えて、dean-stark還流装置で水を脱水した。シクロヘキサンを蒸留で除いた後、残渣を蒸留して約114℃の留分を回収し、ピリジン57.8gを得た。
2-アミノピリジン18.8gをジオキサン35.5gに溶解し、これに合成例8で回収したピリジン30.1gおよび新しいピリジン7gを加えた。氷冷下、トリフルオロ酢酸23.9gおよびチオニルクロリド26.2gを加えた。室温で45分間撹拌後、ジオキサン層を分離し、下層をジオキサン37.6gで抽出した。抽出を2回繰り返し、回収したジオキサン層を濃縮した。これに2-クロロ-5-クロロメチルピリジン30.8g、ジメチルスルホキシド51.7gおよび炭酸カリウム19.3gを加え、60℃で3時間、70℃で1時間撹拌した。反応液を水110gに滴下し、反応容器をメタノール7.9gで洗い込んだ。室温で1時間撹拌した後、析出物をろ過した。ろ物を水およびトルエンで洗浄後、減圧乾燥し、目的とする化合物53.2g(収率84.3%)を得た。
2-アミノピリジン18.8gを酢酸エチル37.6gおよびピリジン34.8gに溶解した。氷冷下、トリフルオロ酢酸23.9gおよびチオニルクロリド26.2gを加えた。45℃で45分間撹拌後、酢酸エチル層を分離し、下層を酢酸エチル37.6gで45℃で抽出した。抽出を2回繰り返し、回収した酢酸エチル層を濃縮した。これに2-クロロ-5-クロロメチルピリジン32.4g、ジメチルスルホキシド62gおよび炭酸カリウム19.3gを加え、60℃で3時間撹拌した。反応液を水132gに滴下し、反応容器をメタノール9.5gで洗い込んだ。室温で1時間撹拌した後、析出物をろ過した。ろ物を水200gおよびトルエン100gで洗浄後、減圧乾燥し、目的とする化合物57.8g(収率91.7%)を得た。
2-アミノピリジン9.4gを酢酸ブチル18.8gおよびピリジン17.4gに溶解した。氷冷下、トリフルオロ酢酸11.97gおよびチオニルクロリド13.1gを加えた。45℃で30分間撹拌後、酢酸ブチル層を分離し、下層を酢酸ブチル18.8gで45℃で抽出した。抽出を2回繰り返し、回収した酢酸ブチル層を濃縮した。これに2-クロロ-5-クロロメチルピリジン16.0g、ジメチルスルホキシド31gおよび炭酸カリウム9.7gを加え、60℃、80hPaの減圧下で2時間撹拌した。反応液を水75gに滴下し、反応容器をメタノール6gで洗い込んだ。室温で1時間撹拌した後、析出物をろ過した。ろ物を水100gおよびトルエン52.2gで洗浄後、減圧乾燥し、目的とする化合物28.8g(収率91.4%)を得た。
2-アミノピリジン94gを酢酸エチル188gおよびピリジン174gに溶解した。6~30℃の温度下、トリフルオロ酢酸119.7gおよびチオニルクロリド131gを加えた。35~45℃で30分間撹拌後、酢酸エチル94gを加え、再度30℃で45分間撹拌した。これをろ過し、反応容器に酢酸エチル188gを加え、残った残渣を30℃で5分間撹拌して洗浄した。これを再度ろ過し、再び反応容器に酢酸エチル94gを加え、残った残渣を30℃で5分間撹拌して洗浄した。これを再度ろ過し、全てのろ液を合した後、溶媒を濃縮した。これに2-クロロ-5-クロロメチルピリジン156.3g、ジメチルスルホキシド310gおよび炭酸カリウム96.6gを加え、60℃、300hPaの減圧下で2.5時間撹拌した。反応液を水670gに滴下し、反応容器をメタノール79gで洗い込んだ。室温で1時間撹拌した後、析出物をろ過した。ろ物を水1000gおよびトルエン433gで洗浄後、減圧乾燥し、目的とする化合物275g(収率87.1%)を得た。
2-アミノピリジン94gを酢酸エチル282gおよびピリジン174gに溶解した。6~30℃の温度下、トリフルオロ酢酸119.7gおよびチオニルクロリド131gを加えた。35~45℃で30分間撹拌後、再度30℃で90分間撹拌した。これをろ過し、反応容器に酢酸エチル188gを加え、残った残渣を30℃で5分間撹拌して洗浄した。これを再度ろ過し、酢酸エチル188gを加え、残った残渣を30℃で5分間撹拌して洗浄した。これを再度ろ過し、再び反応容器に酢酸エチル94gを加え、残った残渣を30℃で5分間撹拌して洗浄した。これを再度ろ過し、全てのろ液を合した後、溶媒を濃縮した。これに2-クロロ-5-クロロメチルピリジン150.3g、ジメチルスルホキシド267gおよび炭酸カリウム96.6gを加え、60℃、150hPaの減圧下で2時間撹拌した。反応液を70℃に昇温した後、水564gに滴下し、反応容器を水94gおよびメタノール55mLで洗い込んだ。室温で2時間撹拌した後、析出物をろ過した。ろ物を水600mLおよび60%メタノール400mLで洗浄後、減圧乾燥し、目的とする化合物269.3g(収率85.5%)を得た。
2-アミノピリジン4.7gを酢酸エチル28.2gおよびピリジン11.9gに溶解した。0~40℃の温度下、トリフルオロ酢酸11.4gおよびチオニルクロリド8.9gを加えた。35~45℃で30分間撹拌後、酢酸エチル層を回収し、下層を酢酸エチル14.1gで抽出した。抽出を2回繰り返し、回収した酢酸エチル層を濃縮した。これに2-クロロ-5-クロロメチルピリジン8.76g、ジメチルスルホキシド17gおよび炭酸カリウム8.28gを加え、60℃で4時間撹拌した。反応液を70℃に昇温した後、水50gに滴下し、反応容器をメタノール5mLで洗い込んだ。室温で1時間撹拌した後、析出物をろ過した。ろ物を水20mLおよび60%メタノール20mLで洗浄後、減圧乾燥し、目的とする化合物14.7g(収率93.1%)を得た。
Claims (4)
- アシル化剤と同時に用いる試薬(X)がチオニルクロリドである請求項1に記載の製造方法。
- 式(B)で表される化合物の反応に用いる塩基がピリジンまたはN-メチルイミダゾールである請求項1または2に記載の製造方法。
- 式(B)で表される化合物の反応に用いる溶媒がエーテル系またはエステル系の溶媒である請求項1から3のいずれか一項に記載の製造方法。
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JP2018529703A (ja) * | 2015-09-28 | 2018-10-11 | バイエル・クロップサイエンス・アクチェンゲゼルシャフト | N−(1,3,4−オキサジアゾール−2−イル)アリールカルボキサミド類を合成する方法 |
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WO2018052115A1 (ja) | 2016-09-16 | 2018-03-22 | Meiji Seikaファルマ株式会社 | 有害生物防除剤の最適化製造法 |
CN109715606A (zh) * | 2016-09-16 | 2019-05-03 | 明治制果药业株式会社 | 有害生物防除剂的最佳制造方法 |
KR20190051952A (ko) | 2016-09-16 | 2019-05-15 | 메이지 세이카 파루마 가부시키가이샤 | 유해 생물 방제제의 최적화된 제조방법 |
JPWO2018052115A1 (ja) * | 2016-09-16 | 2019-06-27 | Meiji Seikaファルマ株式会社 | 有害生物防除剤の最適化製造法 |
US20190270709A1 (en) * | 2016-09-16 | 2019-09-05 | Meiji Seika Pharma Co., Ltd. | Optimized production method for pest control agent |
CN109715606B (zh) * | 2016-09-16 | 2022-05-10 | 株式会社Mmag | 有害生物防除剂的最佳制造方法 |
CN114716369A (zh) * | 2016-09-16 | 2022-07-08 | 株式会社Mmag | 有害生物防除剂的最佳制造方法 |
EP4089075A1 (en) | 2016-09-16 | 2022-11-16 | MMAG Co., Ltd. | Optimized production method for pest control agent |
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