JP4521856B2 - Method for producing acetamidine derivative - Google Patents
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- JP4521856B2 JP4521856B2 JP2003286296A JP2003286296A JP4521856B2 JP 4521856 B2 JP4521856 B2 JP 4521856B2 JP 2003286296 A JP2003286296 A JP 2003286296A JP 2003286296 A JP2003286296 A JP 2003286296A JP 4521856 B2 JP4521856 B2 JP 4521856B2
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- 0 C*c(cc1)cnc1Cl Chemical compound C*c(cc1)cnc1Cl 0.000 description 1
- SKCNYHLTRZIINA-UHFFFAOYSA-N ClCc(cc1)cnc1Cl Chemical compound ClCc(cc1)cnc1Cl SKCNYHLTRZIINA-UHFFFAOYSA-N 0.000 description 1
Description
本発明は、式（III） The present invention provides a compound of formula (III)
アセトアミジン誘導体は、農業用殺虫剤としてきわめて有用な化合物であり、多用されている。その一般的製造方法として、クロロメチルピリジン類と、Ｎ−シアノ−Ｎ−メチルアセトアミジンとを、不活性有機溶媒中で反応させる方法が知られており、この反応を脱酸剤の存在下で行うことが提案されている。 Acetamidine derivatives are extremely useful compounds as agricultural insecticides and are frequently used. As a general production method, a method of reacting chloromethylpyridines with N-cyano-N-methylacetamidine in an inert organic solvent is known, and this reaction is carried out in the presence of a deoxidizer. It has been proposed to do.
例えば、脱酸剤として炭酸カリウム（Ｋ2ＣＯ3）を用いる方法として、下記式（化２）に示すように、６−クロロ−３−クロロメチルピリジン（８３ｍｇ，０．４５ｍｍｏｌ）又は５−クロロ−２−クロロメチルチアゾール（７４ｍｇ，０．４４ｍｍｏｌ）と、同量のＮ−シアノ−Ｎ’−メチルアセトアミジンとを、乾燥アセトニトリル中、同量の無水Ｋ2ＣＯ3存在下で６時間加熱環流下で反応させ、アセタミプリド及びその類似化合物を合成する方法（非特許文献１参照。）や、下記式（化３）に示すように、６−クロロニコチン酸クロリドをＮａＢＨ４を用いてメタノール中で分解させ、クロロホルム中でチオニルクロリドと反応させ、２−クロロ−５−クロロメチルピリジンを得、これと、Ｎ−シアノ−Ｎ’−メチルアセトアミジンとを、環流アセトニトリル中、Ｋ2ＣＯ3存在下で反応させ、アセタミプリドを製造する方法（非特許文献２参照。）が知られている。 For example, as a method using potassium carbonate (K 2 CO 3 ) as a deoxidizer, as shown in the following formula (Chemical Formula 2), 6-chloro-3-chloromethylpyridine (83 mg, 0.45 mmol) or 5-chloro 2-chloromethylthiazole (74 mg, 0.44 mmol) and the same amount of N-cyano-N′-methylacetamidine in dry acetonitrile for 6 hours in the presence of the same amount of anhydrous K 2 CO 3 And a method of synthesizing acetamiprid and its analogs (see Non-Patent Document 1), and, as shown in the following formula (Chemical Formula 3), 6-chloronicotinic acid chloride is dissolved in methanol using NaBH 4. Decomposition and reaction with thionyl chloride in chloroform to give 2-chloro-5-chloromethylpyridine, with N-cyano-N′-methylacetamidine And reflux in acetonitrile, is reacted with K 2 CO 3 presence, a method of manufacturing acetamiprid (Non-Patent Document 2 reference.) Is known.
また、本出願人によって、脱酸剤として水素化ナトリウム（ＮａＨ）を用いることが報告されている（特許文献１参照。）。これは、下記式（化４）に示すように、Ｎ−シアノ−Ｎ’シアノ−（２−クロロ−５−ピリジルメチル）アセトアミド３．０ｇをＤＭＦ２０ｍｌ中に溶解させた溶液に氷冷下ＮａＨ（純度６０％）０．７ｇを加え、同温度で一時間撹拌後沃化エチル２．７ｇ加え、室温で５時間撹拌し、反応終了後、氷冷中に反応液を注加し、この水溶液を酢酸エチルで抽出後、硫酸マグネシウム乾燥後、溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィーにより分離精製することにより、Ｎ−シアノ−Ｎ’−（２−クロロ−５−ピリジルメチル）−Ｎ’−エチルアセトアミジンを製造するものである。 Further, it has been reported by the present applicant that sodium hydride (NaH) is used as a deoxidizer (see Patent Document 1). As shown in the following formula (Formula 4), NH-cyano-N′cyano- (2-chloro-5-pyridylmethyl) acetamide (3.0 g) was dissolved in 20 ml of DMF in 20 ml of DMF under cooling with NaH ( (Purity 60%) 0.7 g was added, stirred at the same temperature for 1 hour, then added with 2.7 g of ethyl iodide and stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was poured into ice-cooled solution, After extraction with ethyl acetate and drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography to give N-cyano-N ′-(2-chloro-5-pyridylmethyl). ) -N'-ethylacetamidine.
このように、アセトアミジン誘導体の製造方法は種々知られているものの、いずれも収率が５０％程度と低く、収率を上げるために苛性アルカリの濃度を上げる等、反応条件を厳しくしても、副反応の進行により、目的とする化合物の収率が上げられないという問題があった。本発明の課題は、アセトアミジン誘導体を高収率で製造する方法を提供することにある。 Thus, although various methods for producing an acetamidine derivative are known, the yield is as low as about 50%, and even if the reaction conditions are severe, such as increasing the concentration of caustic alkali to increase the yield. There is a problem that the yield of the target compound cannot be increased due to the progress of the side reaction. An object of the present invention is to provide a method for producing an acetamidine derivative in a high yield.
本発明者らは、上記課題を解決するため鋭意研究した結果、２−クロロ−５−クロロメチルピリジンと、Ｎ−シアノ−Ｎ−メチルアセトアミジンとを反応させる工程において、脱酸剤とともに触媒として４級アンモニウム塩を用いると、高収率かつ容易にアセトアミジン誘導体を製造できることを見い出した。さらに、４級アンモニウムが沃素化合物である場合、又は、４級アンモニウム塩に加えて沃素化合物を共存させることにより、反応速度が増大することを見い出し、本発明を完成するに至った。 As a result of diligent research to solve the above-mentioned problems, the present inventors have used as a catalyst together with a deoxidizer in the step of reacting 2-chloro-5-chloromethylpyridine and N-cyano-N-methylacetamidine. It has been found that when a quaternary ammonium salt is used, an acetamidine derivative can be easily produced in a high yield. Furthermore, when the quaternary ammonium is an iodine compound, or when an iodine compound is allowed to coexist in addition to the quaternary ammonium salt, it has been found that the reaction rate is increased, and the present invention has been completed.
すなわち本発明は、式（Ｉ） That is, the present invention relates to the formula (I)
で表される２−クロロ−５−クロロメチルピリジンと、式（II） 2-chloro-5-chloromethylpyridine represented by formula (II)
で表されるＮ−シアノ−Ｎ−メチルアセトアミジンとを脱酸剤及び４級アンモニウム塩の存在下に反応させることを特徴とする式（III） Wherein N-cyano-N-methylacetamidine represented by the formula (III) is reacted in the presence of a deoxidizer and a quaternary ammonium salt.
で表されるＮ−［（６−クロロ−３−ピリジル）メチル］−Ｎ−シアノ−メチルアセトアミジンの製造方法に関する。
In represented by N - [(6- chloro-3-pyridyl) methyl] -N- cyano - relates to the manufacture how methyl acetamidine.
また本発明は、上記方法において、脱酸剤が、炭酸カリウムであることを特徴とするＮ−［（６−クロロ−３−ピリジル）メチル］−Ｎ−シアノ−メチルアセトアミジンの製造方法や、沃素イオンの存在下で反応させることを特徴とするＮ−［（６−クロロ−３−ピリジル）メチル］−Ｎ−シアノ−メチルアセトアミジンの製造方法に関する。 The present invention, in the above-mentioned method, a deoxidizing agent, N it is a potassium carbonate - [(6-chloro-3-pyridyl) methyl] -N- cyano - producing how methyl acetamidine and, N you comprises reacting in the presence of iodide ions - [(6-chloro-3-pyridyl) methyl] -N- cyano - relates to the manufacture how methyl acetamidine.
本発明の製造方法によると、容易に高効率、高純度なＮ−［（６−クロロ−３−ピリジル）メチル］−Ｎ−シアノ−メチルアセトアミジンを得ることができる。 According to the production method of the present invention, highly efficient and highly pure N-[(6-chloro-3-pyridyl) methyl] -N-cyano-methylacetamidine can be obtained.
本発明のＮ−［（６−クロロ−３−ピリジル）メチル］−Ｎ−シアノ−メチルアセトアミジンの製造方法としては、溶媒中に、式（Ｉ） The method for producing N-[(6-chloro-3-pyridyl) methyl] -N-cyano-methylacetamidine of the present invention includes a compound represented by the formula (I) in a solvent.
で表される２−クロロ−５−クロロメチルピリジンと、式（II） 2-chloro-5-chloromethylpyridine represented by formula (II)
で表されるＮ−シアノ−Ｎ−メチルアセトアミジンと、脱酸剤と、４級アンモニウム塩とを加えて反応させることにより、式（III） N-cyano-N-methylacetamidine represented by formula (III), a deoxidizing agent and a quaternary ammonium salt are added and reacted,
で表されるＮ−［（６−クロロ−３−ピリジル）メチル］−Ｎ−シアノ−メチルアセトアミジンを製造する方法であれば特に制限されるものではなく、本発明によるとＮ−［（６−クロロ−３−ピリジル）メチル］−Ｎ−シアノ−メチルアセトアミジンを高収率で得ることができる。 Is not particularly limited as long as it is a method for producing N-[(6-chloro-3-pyridyl) methyl] -N-cyano-methylacetamidine represented by the formula N-[(6 -Chloro-3-pyridyl) methyl] -N-cyano-methylacetamidine can be obtained in high yield.
本発明において、原料となる２−クロロ−５−クロロメチルピリジンやＮ−シアノ−Ｎ−メチルアセトアミジンは公知の方法により製造することができる（例えば、特開平６−３２７７９号公報、特開平５−３２０１３２号公報、特開平５−１７８８３３号公報参照）。これら２−クロロ−５−クロロメチルピリジンやＮ−シアノ−Ｎ−メチルアセトアミジンは、２−クロロ−５−クロロメチルピリジン１モルに対し、Ｎ−シアノ−Ｎ−メチルアセトアミジン１〜２モル、特に１．１〜１．３モルのモル比で反応させることが好ましい。 In the present invention, 2-chloro-5-chloromethylpyridine and N-cyano-N-methylacetamidine as raw materials can be produced by a known method (for example, JP-A-6-32779 and JP-A-5). -320132 and JP-A-5-178833). These 2-chloro-5-chloromethylpyridine and N-cyano-N-methylacetamidine are 1 to 2 mol of N-cyano-N-methylacetamidine with respect to 1 mol of 2-chloro-5-chloromethylpyridine, In particular, the reaction is preferably carried out at a molar ratio of 1.1 to 1.3 mol.
本発明における脱酸剤としては、従来公知の脱酸剤であれば特に制限されるものではなく、具体的には炭酸カリウム、炭酸ナトリウム、水素化ナトリウム、トリエチルアミン、ＤＢＵ（1,8-diazabicyelo[5,4,0]undec-7-ene）等を用いることができるが、取り扱いが容易で安価であることから、炭酸カリウムを用いることが好ましい。例えば、炭酸カリウムを用いる場合、２−クロロ−５−クロロメチルピリジン１モルに対し、炭酸カリウムを０．５〜２モルの範囲で添加することが好ましく、特に０．７５〜１．２５モルの範囲で添加することが好ましい。脱酸剤を添加するタイミングは特に制限されず、原料となる２−クロロ−５−クロロメチルピリジン及びＮ−シアノ−Ｎ−メチルアセトアミジンと同時に混合したり、所定量を２回又は複数回に分けて添加することもできる。 The deoxidizer in the present invention is not particularly limited as long as it is a conventionally known deoxidizer. Specifically, potassium carbonate, sodium carbonate, sodium hydride, triethylamine, DBU (1,8-diazabicyelo [ 5,4,0] undec-7-ene) can be used, but potassium carbonate is preferably used because it is easy to handle and inexpensive. For example, when potassium carbonate is used, it is preferable to add potassium carbonate in a range of 0.5 to 2 mol, particularly 0.75 to 1.25 mol, relative to 1 mol of 2-chloro-5-chloromethylpyridine. It is preferable to add in a range. The timing for adding the deoxidizer is not particularly limited, and it is mixed simultaneously with 2-chloro-5-chloromethylpyridine and N-cyano-N-methylacetamidine as raw materials, or a predetermined amount is added twice or a plurality of times. It can also be added separately.
本発明は、４級アンモニウム塩を触媒として添加することによって、反応がスムーズに進行し、収率を高めることができることを特徴とするものである。本発明における４級アンモニウム塩としては、例えば一般式（IV）で表される化合物を例示することができる。 The present invention is characterized in that the reaction proceeds smoothly and the yield can be increased by adding a quaternary ammonium salt as a catalyst. As a quaternary ammonium salt in this invention, the compound represented, for example by general formula (IV) can be illustrated.
式（IV）で表される化合物中、Ｒ1，Ｒ2，Ｒ3，Ｒ4はそれぞれ独立に、水素原子又は、直鎖又は分枝鎖を有するＣ１〜Ｃ２０アルキル基、Ｃ２〜Ｃ６アルケニル基、Ｃ２〜Ｃ６アルキニル基、アラルキル基を表し、Ｘはハロゲン化物イオン、硫酸イオン、硫酸水素イオン、硝酸イオン、酢酸イオン等の有機酸イオンを表し、ｎは１又は２の整数を表す。Ｒ1、Ｒ2、Ｒ3、Ｒ4として具体的には、水素原子、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、ｔ−ブチル基、ｎ−ペンチル基、イソアミル基、ｎ−ヘキシル基、ｎ−ヘプチル基、ｎ−オクチル基、ｎ−デシル基、ｎ−ドデカノイル基、ｎ−テトラデシル基、ｎ−オクタデシル基、ビニル基、プロパルギル基、アリル基、ベンジル基等を例示することができる。Ｘとして具体的には、フッ化物イオン、塩化物イオン、臭化物イオン、ヨウ化物イオン等のハロゲン化物イオン、硫酸イオン、硫酸水素イオン、硝酸イオン、酢酸イオン、水酸化物イオン等を例示することができる。ｎはＸすなわち対をなす陰イオンの価数に応じて１又は２の整数を表す。 In the compound represented by the formula (IV), R 1 , R 2 , R 3 , and R 4 are each independently a hydrogen atom, a C1-C20 alkyl group having a straight chain or a branched chain, or a C2-C6 alkenyl group. , A C2-C6 alkynyl group and an aralkyl group, X represents an organic acid ion such as a halide ion, sulfate ion, hydrogen sulfate ion, nitrate ion or acetate ion, and n represents an integer of 1 or 2. Specific examples of R 1 , R 2 , R 3 and R 4 include a hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, and n-pentyl. Group, isoamyl group, n-hexyl group, n-heptyl group, n-octyl group, n-decyl group, n-dodecanoyl group, n-tetradecyl group, n-octadecyl group, vinyl group, propargyl group, allyl group, benzyl Examples include groups. Specific examples of X include halide ions such as fluoride ions, chloride ions, bromide ions, iodide ions, sulfate ions, hydrogen sulfate ions, nitrate ions, acetate ions, hydroxide ions, and the like. it can. n represents an integer of 1 or 2 depending on X, that is, the valence of the anion forming a pair.
４級アンモニウム塩として、具体的には、水酸化テトラメチルアンモニウム、水酸化テトラエチルアンモニウム、水酸化テトラブチルアンモニウム、水酸化トリメチルベンジルアンモニウム、臭化テトラメチルアンモニウム、臭化テトラエチルアンモニウム、臭化テトラブチルアンモニウム、臭化トリエチルベンジルアンモニウム、臭化トリメチルフェニルアンモニウム、塩化テトラメチルアンモニウム、塩化テトラエチルアンモニウム、塩化テトラブチルアンモニウム、塩化トリエチルベンジルアンモニウム、塩化トリメチルフェニルアンモニウム、塩化トリオクチルメチルアンモニウム、塩化トリブチルベンジルアンモニウム、塩化トリメチルベンジルアンモニウム、塩化Ｎ−ラウリルピリジニウム、塩化Ｎ−ベンジルピコリニウム、塩化トリカプリルメチルアンモニウム、沃化テトラメチルアンモニウム、沃化テトラブチルアンモニウム、テトラブチルアンモニウムサルフェート等を例示することができる。 Specific examples of the quaternary ammonium salt include tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, trimethylbenzylammonium hydroxide, tetramethylammonium bromide, tetraethylammonium bromide, and tetrabutylammonium bromide. , Triethylbenzylammonium bromide, trimethylphenylammonium bromide, tetramethylammonium chloride, tetraethylammonium chloride, tetrabutylammonium chloride, triethylbenzylammonium chloride, trimethylphenylammonium chloride, trioctylmethylammonium chloride, tributylbenzylammonium chloride, trimethyl chloride Benzylammonium, N-laurylpyridinium chloride, N-benzylpicolinium chloride, salt Tricaprylylmethylammonium, iodide tetramethylammonium iodide tetrabutylammonium, may be exemplified tetrabutylammonium sulfate and the like.
４級アンモニウム塩は、２−クロロ−５−クロロメチルピリジン１モルに対し、０．５〜１０モル％の範囲で添加することが好ましく、特に１〜５モル％の範囲で添加することが好ましい。 The quaternary ammonium salt is preferably added in a range of 0.5 to 10 mol%, particularly preferably in a range of 1 to 5 mol%, with respect to 1 mol of 2-chloro-5-chloromethylpyridine. .
本発明における２−クロロ−５−クロロメチルピリジンとＮ−シアノ−Ｎ−メチルアセトアミジンとの反応は、通常有機溶媒の存在下に行われる。用いる有機溶媒としては、非プロトン性の極性溶媒を好適に例示でき、例えば、アセトニトリル、酢酸エチル、アセトン、メチルエチルケトン（ＭＥＫ）、イソブチルメチルケトン（ＭＩＢＫ）等を、１種単独又は２種以上を混合して用いることができる。用いる溶媒の量は特に制限されないが、反応の安全性を考慮して、２−クロロ−５−クロロメチルピリジン１０ｇに対し、５０ｍｌ以上用いるのが好ましい。なお、本発明の製造方法において、少量の水を添加すると、反応速度が増大することがある。これは、溶解しにくい炭酸カリウム等の脱酸剤が少量の水によって溶けやすくなり、効率的に反応に関与するためと考えられる。 The reaction of 2-chloro-5-chloromethylpyridine and N-cyano-N-methylacetamidine in the present invention is usually carried out in the presence of an organic solvent. As the organic solvent to be used, an aprotic polar solvent can be suitably exemplified, for example, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone (MEK), isobutyl methyl ketone (MIBK), etc., alone or in combination of two or more. Can be used. The amount of the solvent to be used is not particularly limited, but it is preferable to use 50 ml or more with respect to 10 g of 2-chloro-5-chloromethylpyridine in consideration of the safety of the reaction. In the production method of the present invention, when a small amount of water is added, the reaction rate may increase. This is presumably because a deoxidizing agent such as potassium carbonate that is difficult to dissolve is easily dissolved by a small amount of water and efficiently participates in the reaction.
反応温度は、４０℃から用いる溶媒の沸点までの範囲であるが、高温では原料や生成物の分解あるいは副反応を伴う場合があることから、４０〜１００℃、特に５０〜８０℃の範囲で反応を行うのが好ましく、さらに、環流下での反応が好ましい。また、反応時間としては、１時間から数十時間を挙げることができる。 The reaction temperature is in the range from 40 ° C. to the boiling point of the solvent to be used, but it may be accompanied by decomposition of the raw materials and products or side reactions at high temperatures. The reaction is preferably carried out, and further the reaction under reflux is preferred. The reaction time can be 1 hour to several tens of hours.
また、２−クロロ−５−クロロメチルピリジンとＮ−シアノ−Ｎ−メチルアセトアミジンとの反応は、沃素イオンの存在下で反応させると、反応速度を増大させることができ、Ｎ−［（６−クロロ−３−ピリジル）メチル］−Ｎ−シアノ−メチルアセトアミジンの収率を向上させることができる。添加する沃素イオンとしては、沃化カリウム、沃化リチウム、沃化アンモニウム等、沃素化合物であれば、特に限定されるものではなく、２−クロロ−５−クロロメチルピリジン１モルに対し、沃素イオン濃度として０．１〜１０モル％、特に、１〜５モル％の範囲となるように添加することが好ましい。なお、４級アンモニウム塩として、沃化テトラメチルアンモニウム、沃化テトラブチルアンモニウム等の沃化アンモニウムを用いる場合には、反応系内に沃素イオンが存在することから、特に添加する必要はない。 Further, the reaction between 2-chloro-5-chloromethylpyridine and N-cyano-N-methylacetamidine can increase the reaction rate when reacted in the presence of iodine ions, and N-[(6 The yield of -chloro-3-pyridyl) methyl] -N-cyano-methylacetamidine can be improved. The iodine ion to be added is not particularly limited as long as it is an iodine compound such as potassium iodide, lithium iodide, and ammonium iodide. The iodine ion is added to 1 mol of 2-chloro-5-chloromethylpyridine. The concentration is preferably 0.1 to 10 mol%, particularly preferably 1 to 5 mol%. When ammonium iodide such as tetramethylammonium iodide or tetrabutylammonium iodide is used as the quaternary ammonium salt, there is no need to add it because iodine ions exist in the reaction system.
本発明の方法は、上記反応終了後、溶媒を濃縮、再結晶等通常の精製処理をすることにより、高効率で、高純度なＮ−［（６−クロロ−３−ピリジル）メチル］−Ｎ−シアノ−メチルアセトアミジンを得ることができる。 After completion of the above reaction, the method of the present invention performs high-efficiency and high-purity N-[(6-chloro-3-pyridyl) methyl] -N by subjecting the solvent to normal purification treatment such as concentration and recrystallization. -Cyano-methylacetamidine can be obtained.
以下、実施例により本発明をより具体的に説明するが、本発明の技術的範囲はこれらの例示に限定されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, the technical scope of this invention is not limited to these illustrations.
アセトニトリル２０ｍｌ中に、２−クロロ−５−クロロメチルピリジン３．２４ｇ、Ｎ−シアノ−Ｎ−メチルアセトアミジン２．１４ｇ、及び表１に示す４級アンモニウム塩を触媒として加えた。次いで、炭酸カリウム２．０７ｇを加え、環流下で所定時間反応させた。反応終了後、反応混合物を室温まで冷却し、結晶を濾別し、アセトニトリル２０ｍｌで洗浄した。濾液と洗浄液とを合わせて、ＨＰＬＣ（島津製作所社製）にて定量分析し、収率を求めた。結果を表１に示す。（収率は、Ｎ−シアノ−Ｎ−メチルアセトアミジンに対する。以下、同様。） In 20 ml of acetonitrile, 3.24 g of 2-chloro-5-chloromethylpyridine, 2.14 g of N-cyano-N-methylacetamidine and a quaternary ammonium salt shown in Table 1 were added as a catalyst. Next, 2.07 g of potassium carbonate was added and allowed to react for a predetermined time under reflux. After completion of the reaction, the reaction mixture was cooled to room temperature, and the crystals were filtered off and washed with 20 ml of acetonitrile. The filtrate and the washing solution were combined and quantitatively analyzed by HPLC (manufactured by Shimadzu Corporation) to determine the yield. The results are shown in Table 1. (The yield is based on N-cyano-N-methylacetamidine. The same applies hereinafter.)
アセトニトリル１００ｍｌ中に、Ｎ−シアノ−Ｎ−メチルアセトアミジン１０．６８ｇ（１１０ｍｍｏｌ）、沃化テトラエチルアンモニウム１．２９ｇ（５ｍｍｏｌ）、炭酸カリウム１０．３７ｇ（７５ｍｍｏｌ）、２−クロロ−５−クロロメチルピリジン１６．２０ｇ（１００ｍｍｏｌ）を加え、次いで環流下に４時間Ｎ−［（６−クロロ−３−ピリジル）メチル］−Ｎ−シアノ−メチルアセトアミジン１８．４２ｇを含有していた。（収率：８２．７％） In 100 ml of acetonitrile, 10.68 g (110 mmol) of N-cyano-N-methylacetamidine, 1.29 g (5 mmol) of tetraethylammonium iodide, 10.37 g (75 mmol) of potassium carbonate, 2-chloro-5-chloromethylpyridine 16.20 g (100 mmol) was added and then contained 18.42 g of N-[(6-chloro-3-pyridyl) methyl] -N-cyano-methylacetamidine under reflux for 4 hours. (Yield: 82.7%)
アセトニトリル１００ｍｌ中に、Ｎ−シアノ−Ｎ−メチルアセトアミジン１０．６８ｇ（１１０ｍｍｏｌ）、塩化ベンジルトリ−ｎ−ブチルアンモニウム１．５６ｇ（５ｍｍｏｌ）、沃化カリウム１．６６ｇ（７５ｍｍｏｌ）、炭酸カリウム１０．３７ｇ（７５ｍｍｏｌ）、２−クロロ−５−クロロメチルピリジン１６．２０ｇ（１００ｍｍｏｌ）を加え、次いで環流下に５時間Ｎ−［（６−クロロ−３−ピリジル）メチル］−Ｎ−シアノ−メチルアセトアミジン１３．６１ｇを含有していた。（収率：６１．１％） In 100 ml of acetonitrile, 10.68 g (110 mmol) of N-cyano-N-methylacetamidine, 1.56 g (5 mmol) of benzyltri-n-butylammonium chloride, 1.66 g (75 mmol) of potassium iodide, 10.37 g of potassium carbonate. (75 mmol), 16.20 g (100 mmol) of 2-chloro-5-chloromethylpyridine, and then N-[(6-chloro-3-pyridyl) methyl] -N-cyano-methylacetamidine under reflux for 5 hours. 13.61 g was contained. (Yield: 61.1%)
［比較例１］
アセトニトリル１００ｍｌ中に、Ｎ−シアノ−Ｎ−メチルアセトアミジン１０．６８ｇ（１１０ｍｍｏｌ）、炭酸カリウム１０．３７ｇ（７５ｍｍｏｌ）、２−クロロ−５−クロロメチルピリジン１６．２０ｇ（１００ｍｍｏｌ）を加え、次いで環流下に６時間Ｎ−［（６−クロロ−３−ピリジル）メチル］−Ｎ−シアノ−メチルアセトアミジン１０．１６ｇを含有していた。（収率：４５．６％）
[Comparative Example 1]
To 100 ml of acetonitrile are added 10.68 g (110 mmol) of N-cyano-N-methylacetamidine, 10.37 g (75 mmol) of potassium carbonate, 16.20 g (100 mmol) of 2-chloro-5-chloromethylpyridine, and then refluxing. The bottom contained 10.16 g of N-[(6-chloro-3-pyridyl) methyl] -N-cyano-methylacetamidine for 6 hours. (Yield: 45.6%)
［比較例２］
アセトニトリル１００ｍｌ中に、Ｎ−シアノ−Ｎ−メチルアセトアミジン１０．６８ｇ（１１０ｍｍｏｌ）、沃化カリウム１．６６ｇ（１０ｍｍｏｌ）、炭酸カリウム１０．３７ｇ（７５ｍｍｏｌ）、２−クロロ−５−クロロメチルピリジン１６．２０ｇ（１００ｍｍｏｌ）を加え、次いで環流下に６時間Ｎ−［（６−クロロ−３−ピリジル）メチル］−Ｎ−シアノ−メチルアセトアミジン９．７８ｇを含有していた。（収率：４３．９％）
[Comparative Example 2]
In 100 ml of acetonitrile, 10.68 g (110 mmol) of N-cyano-N-methylacetamidine, 1.66 g (10 mmol) of potassium iodide, 10.37 g (75 mmol) of potassium carbonate, 2-chloro-5-chloromethylpyridine 16 .20 g (100 mmol) was added and then contained 9.78 g of N-[(6-chloro-3-pyridyl) methyl] -N-cyano-methylacetamidine under reflux for 6 hours. (Yield: 43.9%)
アセトニトリル１００ｍｌ中に、Ｎ−シアノ−Ｎ−メチルアセトアミジン１０．６８ｇ（１１０ｍｍｏｌ）、５０％臭化テトラ−ｎ−ブチルアンモニウム水溶液３．２２ｇ（５ｍｍｏｌ）、沃化カリウム１．６６ｇ（１０ｍｍｏｌ）、炭酸カリウム１０．３７ｇ（７５ｍｍｏｌ）、２−クロロ−５−クロロメチルピリジン１６．２０ｇ（１００ｍｍｏｌ）を加え、次いで環流下に６時間Ｎ−［（６−クロロ−３−ピリジル）メチル］−Ｎ−シアノ−メチルアセトアミジン１４．９２ｇを含有していた。（収率：６７．０％） In 100 ml of acetonitrile, 10.68 g (110 mmol) of N-cyano-N-methylacetamidine, 3.22 g (5 mmol) of 50% tetra-n-butylammonium bromide aqueous solution, 1.66 g (10 mmol) of potassium iodide, carbonic acid 10.37 g (75 mmol) of potassium and 16.20 g (100 mmol) of 2-chloro-5-chloromethylpyridine were added, and then N-[(6-chloro-3-pyridyl) methyl] -N-cyano at reflux for 6 hours. -It contained 14.92 g of methylacetamidine. (Yield: 67.0%)
溶媒をアセトニトリルから酢酸エチルに替えて、実施例４と同様に試験したところ、Ｎ−［（６−クロロ−３−ピリジル）メチル］−Ｎ−シアノ−メチルアセトアミジン１５．３０ｇを含有していた。（収率：６８．７％） When the solvent was changed from acetonitrile to ethyl acetate and the test was conducted in the same manner as in Example 4, it contained 15.30 g of N-[(6-chloro-3-pyridyl) methyl] -N-cyano-methylacetamidine. . (Yield: 68.7%)
溶媒をアセトニトリルからアセトンに替えて、実施例４と同様に試験したところ、Ｎ−［（６−クロロ−３−ピリジル）メチル］−Ｎ−シアノ−メチルアセトアミジン１５．４８ｇを含有していた。（収率：６９．５％） When the solvent was changed from acetonitrile to acetone and a test was conducted in the same manner as in Example 4, it contained 15.48 g of N-[(6-chloro-3-pyridyl) methyl] -N-cyano-methylacetamidine. (Yield: 69.5%)
酢酸エチル１００ｍｌ中に、Ｎ−シアノ−Ｎ−メチルアセトアミジン１１．２０ｇ（１１５ｍｍｏｌ）、臭化テトラ−ｎ−ブチルアンモニウム水溶液０．６４ｇ（２ｍｍｏｌ）、沃化カリウム０．３３ｇ（２ｍｍｏｌ）、炭酸カリウム６．９１ｇ（５０ｍｍｏｌ）、２−クロロ−５−クロロメチルピリジン１６．２０ｇ（１００ｍｍｏｌ）を加え、環流下に２時間炭酸カリウム６．９１ｇ（５０ｍｍｏｌ）を追加して環流下に２時間撹拌し、更に、炭酸カリウム１．３８ｇ（１０ｍｍｏｌ）を追加して環流下に３時間撹拌した。反応終了後、反応混合物を室温まで冷却し、結晶を濾別し、酢酸エチル２０ｍｌで洗浄した。濾液と洗浄液とを合わせて、ＨＰＬＣにて定量分析したところ、Ｎ−［（６−クロロ−３−ピリジル）メチル］−Ｎ−シアノ−メチルアセトアミジン１８．４２ｇを含有していた。（収率：８２．７％） In 100 ml of ethyl acetate, 11.20 g (115 mmol) of N-cyano-N-methylacetamidine, 0.64 g (2 mmol) of tetra-n-butylammonium bromide aqueous solution, 0.33 g (2 mmol) of potassium iodide, potassium carbonate 6.91 g (50 mmol) and 2-chloro-5-chloromethylpyridine 16.20 g (100 mmol) were added, and potassium carbonate 6.91 g (50 mmol) was added under reflux for 2 hours, followed by stirring under reflux for 2 hours. Further, 1.38 g (10 mmol) of potassium carbonate was added and stirred for 3 hours under reflux. After completion of the reaction, the reaction mixture was cooled to room temperature, and the crystals were separated by filtration and washed with 20 ml of ethyl acetate. The filtrate and the washing solution were combined and quantitatively analyzed by HPLC. As a result, 18.42 g of N-[(6-chloro-3-pyridyl) methyl] -N-cyano-methylacetamidine was contained. (Yield: 82.7%)
メチルエチルケトン１００ｍｌ中に、Ｎ−シアノ−Ｎ−メチルアセトアミジン１１．２０ｇ（１１５ｍｍｏｌ）、臭化テトラ−ｎ−ブチルアンモニウム水溶液０．６４ｇ（２ｍｍｏｌ）、沃化カリウム０．３３ｇ（２ｍｍｏｌ）、炭酸カリウム１０．３７ｇ（７５ｍｍｏｌ）、２−クロロ−５−クロロメチルピリジン１６．２０ｇ（１００ｍｍｏｌ）を加え、５０℃で２時間、次いで７０℃で２時間炭酸カリウム４．８４ｇ（３５ｍｍｏｌ）を追加して７０℃で２時間、環流下で１時間撹拌した。反応終了後、反応混合物を室温まで冷却し、結晶を濾別し、メチルエチルケトン２０ｍｌで洗浄した。濾液と洗浄液とを合わせて、ＨＰＬＣにて定量分析したところ、Ｎ−［（６−クロロ−３−ピリジル）メチル］−Ｎ−シアノ−メチルアセトアミジン１８．９７ｇを含有していた。（収率：８５．２％） In 100 ml of methyl ethyl ketone, 11.20 g (115 mmol) of N-cyano-N-methylacetamidine, 0.64 g (2 mmol) of tetra-n-butylammonium bromide aqueous solution, 0.33 g (2 mmol) of potassium iodide, 10 of potassium carbonate .37 g (75 mmol) and 2-chloro-5-chloromethylpyridine 16.20 g (100 mmol) were added, and potassium carbonate 4.84 g (35 mmol) was added at 50 ° C. for 2 hours and then at 70 ° C. for 2 hours, and then 70 ° C. For 2 hours and at reflux for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, the crystals were filtered off and washed with 20 ml of methyl ethyl ketone. The filtrate and the washing solution were combined and quantitatively analyzed by HPLC. As a result, N-[(6-chloro-3-pyridyl) methyl] -N-cyano-methylacetamidine was contained in an amount of 18.97 g. (Yield: 85.2%)
Claims (2)
The method for producing N-[(6-chloro-3-pyridyl) methyl] -N-cyano-methylacetamidine according to claim 1, wherein the deoxidizer is potassium carbonate.
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