JP2005272417A - Method for producing 2-chloro-4-aminomethylpyridine - Google Patents
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本発明は２−クロロ−４−アミノメチルピリジン類の製造方法に関する。本発明により得られる２−クロロ−４−アミノメチルピリジン類は、医薬、農薬の中間体として、例えばヒスタミン−Ｈ２ レセプター拮抗剤である２−（フルフリルスルフィニル）−Ｎ−（４−[４−(ピペリジノメチル)−２−ピリジル]オキシ−（Ｚ）−２−ブテニル）アセタミド（ＦＲＧ−８８１３）の合成中間体として有用である［ヨーロピアン ジャーナル オブ ファーマコロジー（Ｅｕｒｏｐｅａｎ Ｊｏｕｒｎａｌ ｏｆ Ｐｈａｒｍａｃｏｌｏｇｙ）、第２９７巻、第８７頁（１９９６年）参照］。 The present invention relates to a process for producing 2-chloro-4-aminomethylpyridines. 2-Chloro-4-aminomethylpyridines obtained by the present invention are, for example, histamine-H 2 receptor antagonist 2- (furfurylsulfinyl) -N- (4- [4 -(Piperidinomethyl) -2-pyridyl] oxy- (Z) -2-butenyl) acetamide (FRG-8813) useful as an intermediate [European Journal of Pharmacology, Vol. 297, 87 (1996)].
従来、２−クロロ−４−アミノメチルピリジン類の製造方法として、（１）２−クロロ−４−トリクロロメチルピリジンとアミン類および水素とを水素化触媒の存在下で反応させて２−クロロ−４−アミノメチルピリジンを製造する際に、反応進行とともに副生する塩化水素を過剰に用いたアミンで中和するか、反応系内に共存させた３級アミンで中和する方法（特許文献１参照）、（２）２−クロロ−４−トリクロロメチルピリジンとアミン類および水素とを水素化触媒の存在下で反応させて２−クロロ−４−アミノメチルピリジンを製造する際に、反応進行とともに副生する塩化水素を過剰に用いたアミン類で中和する方法（特許文献２参照）、（３）２−クロロ−４−クロロメチルピリジンをアミノ化する方法（特許文献３参照）などが知られている。 Conventionally, as a method for producing 2-chloro-4-aminomethylpyridines, (1) 2-chloro-4-trichloromethylpyridine is reacted with amines and hydrogen in the presence of a hydrogenation catalyst. When producing 4-aminomethylpyridine, a method of neutralizing hydrogen chloride produced as a by-product with the progress of the reaction with an excess of amine or a tertiary amine coexisting in the reaction system (Patent Document 1) (2) When 2-chloro-4-aminomethylpyridine is produced by reacting 2-chloro-4-trichloromethylpyridine with amines and hydrogen in the presence of a hydrogenation catalyst, A method of neutralizing with an excessive amount of hydrogen chloride produced as a by-product (see Patent Document 2), (3) a method of amination of 2-chloro-4-chloromethylpyridine (see Patent Document 3), etc. It is known.
上記の方法（１）では、過剰のアミン（反応剤）で中和するか、３級アミン（中和剤）を使用して中和しており、製造コストが高い。また、生成物である２−クロロ−４−アミノメチルピリジンはアミン類であり、反応後の３級アミンとの分離操作が煩雑となる。この方法（１）において、反応剤としてピペリジンを用い、中和剤としてトリエチルアミンを用いた系で反応を行ったところ、反応後の分液状態が悪く、抽出操作が煩雑となり、また収率も６２％と低く、工業的に適用できる方法ではないことが判明した（後述の比較例１を参照）。 In said method (1), it neutralizes with an excess amine (reactant), or neutralizes using a tertiary amine (neutralizer), and its manufacturing cost is high. Moreover, 2-chloro-4-aminomethylpyridine which is a product is an amine, and the separation operation from the tertiary amine after the reaction becomes complicated. In this method (1), when the reaction was carried out in a system using piperidine as a reactive agent and triethylamine as a neutralizing agent, the separation state after the reaction was poor, the extraction operation was complicated, and the yield was also 62. %, It was found that the method was not industrially applicable (see Comparative Example 1 described later).
方法（２）では、反応により発生する塩化水素を反応剤であるアミンで中和しており、アミンを過剰に使用する必要があり、方法（１）と同様に製造コストが高い。方法（３）では、原料である２−クロロ−４−クロロメチルピリジンの製造方法として、２−クロロ−４−メチルピリジンの側鎖を塩素により塩素化する方法（特開平５−２３００２４号公報参照）が知られているが、この方法では４位のメチル基の塩素化が逐次的に起こるため、２−クロロ−４−クロロメチルピリジンの選択性は低く、工業的に有利な製法とは言い難い。 In the method (2), hydrogen chloride generated by the reaction is neutralized with an amine as a reactant, and it is necessary to use an excessive amount of amine, and the production cost is high as in the method (1). In the method (3), as a method for producing 2-chloro-4-chloromethylpyridine as a raw material, a method of chlorinating the side chain of 2-chloro-4-methylpyridine with chlorine (see JP-A-5-230024) However, since the chlorination of the 4-position methyl group occurs sequentially in this method, the selectivity of 2-chloro-4-chloromethylpyridine is low, and it is said to be an industrially advantageous production method. hard.
本発明の目的は、２−クロロ−４−アミノメチルピリジンの工業的に有利な製造方法を提供することにある。 An object of the present invention is to provide an industrially advantageous process for producing 2-chloro-4-aminomethylpyridine.
本発明は、２−クロロ−４−トリクロロメチルピリジン、２−クロロ−４−ジクロロメチルピリジン、２−クロロ−４−クロロメチルピリジンまたはこれらの混合物（以下、これらを原料化合物と総称する場合がある）と一般式（Ｉ） In the present invention, 2-chloro-4-trichloromethylpyridine, 2-chloro-4-dichloromethylpyridine, 2-chloro-4-chloromethylpyridine or a mixture thereof (hereinafter, these may be collectively referred to as raw material compounds). ) And general formula (I)
（式中、Ｒ１ およびＲ２ はそれぞれ水素原子、アルキル基もしくはアリール基を表すか、またはそれらが結合している窒素原子と一緒になって置換基を有してもよい４〜８員環を形成する。）
で示されるアミン類［以下、これをアミン類（Ｉ）と称する］および水素とを水素化触媒の存在下で反応させて一般式（ＩＩ）
Wherein R 1 and R 2 each represent a hydrogen atom, an alkyl group or an aryl group, or a 4- to 8-membered ring which may have a substituent together with the nitrogen atom to which they are bonded To form.)
A compound represented by the general formula (II) is reacted with hydrogen (hereinafter referred to as amines (I)) and hydrogen in the presence of a hydrogenation catalyst.
（式中、Ｒ１ およびＲ２ は上記定義のとおりである。）
で示される２−クロロ−４−アミノメチルピリジン類［以下、これを２−クロロ−４−アミノメチルピリジン類（ＩＩ）と称する］を製造するに際し、反応系内に塩化水素の中和剤として無機塩基を添加することを特徴とする２−クロロ−４−アミノメチルピリジン類（ＩＩ）の製造方法である。
(Wherein R 1 and R 2 are as defined above.)
As a neutralizing agent for hydrogen chloride in the reaction system, the 2-chloro-4-aminomethylpyridine represented by the formula [hereinafter referred to as 2-chloro-4-aminomethylpyridine (II)] is produced. An inorganic base is added to the process for producing 2-chloro-4-aminomethylpyridines (II).
本発明によれば、反応後の２−クロロ−４−アミノメチルピリジン類（ＩＩ）の分離操作が容易となり、工業的に有利に２−クロロ−４−アミノメチルピリジン類（ＩＩ）を製造することができる。 According to the present invention, the separation operation of 2-chloro-4-aminomethylpyridines (II) after the reaction is facilitated, and 2-chloro-4-aminomethylpyridines (II) are advantageously produced industrially. be able to.
上記の一般式中、Ｒ１ およびＲ２ がそれぞれ表すアルキル基としては、直鎖状
、分岐状または環状のいずれでもよく、その炭素数は１〜６であるものが好ましい。アルキル基としては、例えばメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｔｅｒｔ−ブチル基、ヘキシル基、シクロヘキシル基などが挙げられる。これらのアルキル基は置換基を有していてもよく、かかる置換基としては、例えばメトキシ基、エトキシ基、プロポキシ基、ブトキシ基などのアルコキシ基；水酸基；ｔｅｒｔ−ブチルジメチルシリルオキシ基、ｔｅｒｔ−ブチルジフェニルシリルオキシ基などの三置換シリルオキシ基；アミノ基；フェニル基などのアリール基；ベンジル基、トリフェニルメチル基などのアラルキル基などが挙げられる。Ｒ１ およびＲ２ がそれぞれ表すアリール基としては、炭素数が６〜１０のものが好ましく、例えばフェニル基、トリル基、ナフチル基などが挙げられる。また、Ｒ１ およびＲ２ が、それらが結合している窒素原子と一緒になって形成する４〜８員環としては、例えばアゼチジノ基、ピロリジノ基、ピペリジノ基、ヘキサメチレンイミノ基、ヘプタメチレンイミノ基などが挙げられる。
In the above general formula, the alkyl groups represented by R 1 and R 2 may be linear, branched or cyclic, and preferably have 1 to 6 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a hexyl group, and a cyclohexyl group. These alkyl groups may have a substituent. Examples of the substituent include alkoxy groups such as methoxy group, ethoxy group, propoxy group, and butoxy group; hydroxyl group; tert-butyldimethylsilyloxy group, tert- Examples thereof include trisubstituted silyloxy groups such as butyldiphenylsilyloxy group; amino groups; aryl groups such as phenyl groups; aralkyl groups such as benzyl groups and triphenylmethyl groups. The aryl group represented by each of R 1 and R 2 preferably has 6 to 10 carbon atoms, and examples thereof include a phenyl group, a tolyl group, and a naphthyl group. Examples of the 4- to 8-membered ring formed by R 1 and R 2 together with the nitrogen atom to which they are bonded include, for example, azetidino group, pyrrolidino group, piperidino group, hexamethyleneimino group, heptamethyleneimino group. Groups and the like.
原料として用いられる２−クロロ−４−トリクロロメチルピリジン、２−クロロ−４−ジクロロメチルピリジンまたは２−クロロ−４−クロロメチルピリジンは、ラジカル開始剤の存在下に２−クロロ−４−メチルピリジンまたは２−ベンゼンスルホニル−４−メチルピリジンに塩素を作用させることにより合成される（国際公開公報ＷＯ９６／２６１８８参照）。 2-Chloro-4-trichloromethylpyridine, 2-chloro-4-dichloromethylpyridine or 2-chloro-4-chloromethylpyridine used as a raw material is obtained in the presence of a radical initiator in the presence of 2-chloro-4-methylpyridine. Alternatively, it is synthesized by allowing chlorine to act on 2-benzenesulfonyl-4-methylpyridine (see International Publication WO96 / 26188).
アミン類としては、例えば、アンモニア；メチルアミン、エチルアミンなどのモノアルキルアミン；エチレンジアミン、１，２−ジアミノプロパンなどのジアミン；ジメチルアミン、ジエチルアミン、ジイソプロピルアミン、ピロリジン、ピペリジンなどの２級アミンなどが使用される。これらの中でも、生成物の２−クロロ−４−アミノメチルピリジン類（ＩＩ）がさらに逐次反応により２量化体
、３量化体に変化するおそれが少ない点で２級アミンを使用するのが好ましい。アミン類の使用量は、原料化合物に対して２〜６倍モルの範囲であるのが好ましい。
Examples of amines include ammonia; monoalkylamines such as methylamine and ethylamine; diamines such as ethylenediamine and 1,2-diaminopropane; secondary amines such as dimethylamine, diethylamine, diisopropylamine, pyrrolidine, and piperidine. Is done. Among these, it is preferable to use a secondary amine in that the product 2-chloro-4-aminomethylpyridines (II) is further less likely to be converted into a dimer or a trimer by a sequential reaction. The amount of amine used is preferably in the range of 2 to 6 moles relative to the starting compound.
水素圧力は、常圧〜１００ｋｇ／ｃｍ２ の範囲であるのが好ましい。 The hydrogen pressure is preferably in the range of normal pressure to 100 kg / cm 2 .
水素化触媒としては、例えば、ラネ−ニッケル、ラネ−コバルトなどのラネ−触媒；ルテニウム、パラジウム、ロジウム、白金などの貴金属をシリカ、アルミナ、カーボンなどに担持させた触媒などが挙げられる。これらの中でも、ラネ−ニッケルを使用するのが好ましい。水素化触媒の使用量は、原料化合物に対して１〜２０重量％の範囲であるのが好ましく、２〜１０重量％の範囲であるのがより好ましい。 Examples of the hydrogenation catalyst include a Raney catalyst such as Raney-nickel and Raney-Cobalt; a catalyst in which a noble metal such as ruthenium, palladium, rhodium, and platinum is supported on silica, alumina, carbon, and the like. Of these, Raney-nickel is preferably used. The amount of the hydrogenation catalyst used is preferably in the range of 1 to 20% by weight, more preferably in the range of 2 to 10% by weight with respect to the raw material compound.
本発明の特徴は、塩化水素の中和剤として無機塩基を使用することにある。無機塩基としては、例えば、水酸化リチウム、水酸化ナトリウム、水酸化カリウムなどの水酸化物；炭酸ナトリウム、炭酸カリウムなどの炭酸塩；炭酸水素ナトリウム、炭酸水素カリウムなどの重炭酸塩などが挙げられる。無機塩基の使用量は、原料化合物に対して２〜１０倍モルの範囲であるのが好ましい。塩化水素の中和剤として無機塩基を使用することにより、反応後の液をろ過するか、または水洗するだけで中和塩を容易に除去することができるため、反応後の２−クロロ−４−アミノメチルピリジン類（ＩＩ）の分離操作が容易となる。しかも、無機塩基は安価に入手できることから、２−クロロ−４−アミノメチルピリジン類（ＩＩ）の製造コストを低減させることができる。 A feature of the present invention is that an inorganic base is used as a neutralizing agent for hydrogen chloride. Examples of the inorganic base include hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; carbonates such as sodium carbonate and potassium carbonate; bicarbonates such as sodium bicarbonate and potassium bicarbonate. . It is preferable that the usage-amount of an inorganic base is the range of 2-10 times mole with respect to a raw material compound. By using an inorganic base as a hydrogen chloride neutralizing agent, the neutralized salt can be easily removed by simply filtering the solution after the reaction or washing with water. -Aminomethylpyridines (II) can be easily separated. And since an inorganic base can be obtained in low cost, the manufacturing cost of 2-chloro-4-aminomethylpyridines (II) can be reduced.
反応は溶媒の存在下または不存在下に実施される。溶媒としては、反応に悪影響を与えない限り特に制限されないが、例えば、メタノール、エタノール、イソプロパノールなどのアルコール；水、アセトニトリル、ジメチルホルムアミドなどの極性溶媒；ベンゼン、トルエン、キシレン、エチルベンゼン、メシチレンなどの芳香族炭化水素などが挙げられる。使用される溶媒は、水素化触媒との組合わせで適宜選択される。触媒としてラネーニッケルを使用する場合には、溶媒としてアルコールを使用するのが好ましい。溶媒は単独で使用しても、２種以上を組合わせて使用してもよい。溶媒の使用量は、原料化合物に対して１〜５０倍重量の範囲であるのが好ましく、４〜２０倍重量の範囲であるのがより好ましい。 The reaction is carried out in the presence or absence of a solvent. The solvent is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol and isopropanol; polar solvents such as water, acetonitrile and dimethylformamide; aromatics such as benzene, toluene, xylene, ethylbenzene and mesitylene Group hydrocarbons and the like. The solvent used is appropriately selected in combination with the hydrogenation catalyst. When Raney nickel is used as the catalyst, it is preferable to use alcohol as the solvent. A solvent may be used individually or may be used in combination of 2 or more type. The amount of the solvent used is preferably in the range of 1 to 50 times the weight of the raw material compound, and more preferably in the range of 4 to 20 times the weight.
反応は、０℃〜１００℃の温度範囲で行うのが好ましい。 The reaction is preferably performed in a temperature range of 0 ° C to 100 ° C.
この方法で得られた２−クロロ−４−アミノメチルピリジン類（ＩＩ）の反応混合物からの単離・精製は、通常の有機化合物の単離・精製に用いられる方法により行われる。例えば、反応混合物を冷却した後、水素化触媒および無機塩をろ過し、中和、溶媒留去の操作を行った後に、酢酸エチルなどの有機溶媒を加えて抽出し、抽出液を濃縮し、得られる粗生成物を蒸留、再結晶、シリカゲルクロマトグラフィーなどにより精製する。 Isolation and purification from the reaction mixture of 2-chloro-4-aminomethylpyridines (II) obtained by this method is carried out by a method used for isolation and purification of ordinary organic compounds. For example, after cooling the reaction mixture, the hydrogenation catalyst and inorganic salts are filtered, neutralized, and the solvent is distilled off, followed by extraction with an organic solvent such as ethyl acetate, and the extract is concentrated, The resulting crude product is purified by distillation, recrystallization, silica gel chromatography and the like.
以下、実施例により本発明を具体的に説明するが、本発明はこれらの実施例により何ら制限されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not restrict | limited at all by these Examples.
参考例１
２−クロロ−４−トリクロロメチルピリジンの合成
温度計およびガス吹き込み口を備えた内容量５００ｍＬの反応器に、クロロベンゼン１３０ｇおよび２−ベンゼンスルホニル−４−メチルピリジン８０ｇ（３４３ｍｏｌ）を仕込んだ。この溶液を８０℃に加熱し、２，２’−アゾビス（イソブチロニトリル）０．６４ｇを添加した後、塩素を１００ｍＬ／分で１６時間吹き込んだ。この間、２時間毎に２，２’−アゾビス（イソブチロニトリル）を０．３２ｇずつ追加した。反応終了後、内温を３０℃に冷却して３０分間窒素を吹き込んだ後、５％水酸化ナトリウム水溶液を加えて反応液をアルカリ性とし、分液して有機層を抽出した。水層にクロロベンゼン６５ｇを加えて再度抽出し、有機層を合わせて水６５ｇで水洗した後に、減圧下で濃縮し、粗２−クロロ−４−トリクロロメチルピリジン１２９ｇ（ｎｅｔ：６８ｇ、収率８６％）を得た。
Reference example 1
Synthesis of 2-chloro-4-trichloromethylpyridine 130 g of chlorobenzene and 80 g (343 mol) of 2-benzenesulfonyl-4-methylpyridine were charged into a 500 mL reactor equipped with a thermometer and a gas inlet. This solution was heated to 80 ° C., 2,4′-azobis (isobutyronitrile) 0.64 g was added, and then chlorine was blown in at 100 mL / min for 16 hours. During this time, 0.32 g of 2,2′-azobis (isobutyronitrile) was added every 2 hours. After completion of the reaction, the internal temperature was cooled to 30 ° C. and nitrogen was blown for 30 minutes, and then a 5% aqueous sodium hydroxide solution was added to make the reaction solution alkaline, followed by liquid separation to extract an organic layer. Chlorobenzene (65 g) was added to the aqueous layer and extracted again. The organic layers were combined and washed with 65 g of water, and then concentrated under reduced pressure to give 129 g of crude 2-chloro-4-trichloromethylpyridine (net: 68 g, 86% yield). )
実施例１
１０００ｍＬのオートクレーブに参考例１で得られた２−クロロ−４−トリクロロメチルピリジン３８．０ｇ（ｎｅｔ：２０ｇ、０．０８７ｍｏｌ）、ピペリジン１４．７ｇ（０．１７ｍｏｌ）、炭酸ナトリウム１８．４ｇ（０．１７ｍｏｌ）、メタノール９０ｍＬおよびラネ−ニッケル（日興リカ株式会社製Ｒ−１００）０．５ｇを仕込み、水素でゲージ圧５ｋｇ／ｃｍ２ となるように加圧し、７５℃に昇温した。内温７５℃、ゲージ圧５ｋｇ／ｃｍ２ を保つように水素の導入を行いながら３時間反応を行った。反応終了後、反応液を３０℃まで冷却した後、触媒と無機塩をろ過し、反応液を減圧下に濃縮した。濃縮物に１０％塩酸４５ｇを加えて反応液を酸性化した後、トルエン４５ｍＬで２回抽出し、有機層を除去した。この際、目的物は水層に存在し、酸性、中性の不純物が有機層側に除去された。水層を４０％水酸化ナトリウム水溶液を用いてアルカリ性とし、トルエン４５ｍＬで２回抽出した。有機層を合わせて、減圧下で溶媒を留去して、下記の物性を有する粗２−クロロ−４−ピペリジノメチルピリジン１７．５ｇ（ｎｅｔ：１５．５ｇ、純度８８．６％、収率８５．０％）を得た。
Example 1
In a 1000 mL autoclave, 38.0 g (net: 20 g, 0.087 mol) of 2-chloro-4-trichloromethylpyridine obtained in Reference Example 1, 14.7 g (0.17 mol) of piperidine, 18.4 g of sodium carbonate (0 .17 mol), 90 mL of methanol and 0.5 g of Raney-nickel (R-100 manufactured by Nikko Rika Co., Ltd.) were charged, pressurized with hydrogen to a gauge pressure of 5 kg / cm 2, and heated to 75 ° C. The reaction was carried out for 3 hours while introducing hydrogen so as to maintain an internal temperature of 75 ° C. and a gauge pressure of 5 kg / cm 2 . After completion of the reaction, the reaction solution was cooled to 30 ° C., then the catalyst and inorganic salt were filtered, and the reaction solution was concentrated under reduced pressure. The concentrate was acidified by adding 45 g of 10% hydrochloric acid, and extracted twice with 45 mL of toluene to remove the organic layer. At this time, the target product was present in the aqueous layer, and acidic and neutral impurities were removed to the organic layer side. The aqueous layer was made alkaline with 40% aqueous sodium hydroxide and extracted twice with 45 mL of toluene. The organic layers were combined, the solvent was distilled off under reduced pressure, and 17.5 g of crude 2-chloro-4-piperidinomethylpyridine having the following physical properties (net: 15.5 g, purity 88.6%, yield). 85.0%).
１Ｈ−ＮＭＲスペクトル（ＣＤＣｌ３ ）δ：１．３０〜１．８０（ｍ，６Ｈ）、２．２０〜２．５０（ｂｒ，４Ｈ）、３．４４（ｓ，２Ｈ）、７．２０（ｄ，１Ｈ，Ｊ＝５．０Ｈｚ）、７．３３（ｓ，１Ｈ）、８．２８（ｄ，１Ｈ，Ｊ＝５．０Ｈｚ） 1 H-NMR spectrum (CDCl 3 ) δ: 1.30 to 1.80 (m, 6H), 2.20 to 2.50 (br, 4H), 3.44 (s, 2H), 7.20 ( d, 1H, J = 5.0 Hz), 7.33 (s, 1H), 8.28 (d, 1H, J = 5.0 Hz)
実施例２
１０００ｍＬのオートクレーブに参考例１で得られた２−クロロ−４−トリクロロメチルピリジン３８．０ｇ（ｎｅｔ：２０ｇ、０．０８７ｍｏｌ）、ピペリジン１４．７ｇ（０．１７ｍｏｌ）、炭酸ナトリウム１８．４ｇ（０．１７ｍｏｌ）、メタノール９０ｍＬおよびラネ−ニッケル（前記のとおり）０．５ｇを仕込み、温度が４５℃である以外は実施例１と同様な条件で１５時間反応を行った。反応後の後処理も実施例１と同様に行い、粗２−クロロ−４−ピペリジノメチルピリジン１８．８ｇ（ｎｅｔ：１４．７ｇ、純度７８．０％、収率８０．０％）を得た。
Example 2
In a 1000 mL autoclave, 38.0 g (net: 20 g, 0.087 mol) of 2-chloro-4-trichloromethylpyridine obtained in Reference Example 1, 14.7 g (0.17 mol) of piperidine, 18.4 g of sodium carbonate (0 .17 mol), 90 mL of methanol and 0.5 g of Raney-Nickel (as described above) were charged, and the reaction was performed for 15 hours under the same conditions as in Example 1 except that the temperature was 45 ° C. The post-treatment after the reaction was carried out in the same manner as in Example 1, and 18.8 g of crude 2-chloro-4-piperidinomethylpyridine (net: 14.7 g, purity 78.0%, yield 80.0%) was added. Obtained.
比較例１
１０００ｍＬのオートクレーブに参考例１で得られた２−クロロ−４−トリクロロメチルピリジン３８．０ｇ（ｎｅｔ：２０ｇ、０．０８７ｍｏｌ）、ピペリジン２２．１ｇ（０．２６ｍｏｌ）、トリエチルアミン２６．３ｇ（０．２６ｍｏｌ）、メタノール９０ｍＬおよびラネ−ニッケル（前記のとおり）０．５ｇを仕込み、温度が４５℃である以外は実施例１と同様な条件で３時間反応を行った。反応終了後、反応液を３０℃まで冷却した後、触媒をろ過し、反応液を減圧下に濃縮した。濃縮物に１０％塩酸４５ｇを加えて反応液を酸性化した後、トルエン４５ｍＬで２回抽出し、有機層を除去した。この際、目的物は水層に存在し、酸性、中性の不純物が有機層側に除去された。水層を４０％水酸化ナトリウム水溶液を用いてアルカリ性とし、トルエン４５ｍＬで２回抽出した。この際、分液状態が悪く、界面に不溶成分が析出した。有機層を合わせて、水３０ｍＬで水洗を行った。この際も分液性が悪かった。減圧下で溶媒を留去して、粗２−クロロ−４−ピペリジノメチルピリジン１５．７ｇ（ｎｅｔ：１１．３ｇ、純度７１．９％、収率６２．０％）を得た。
Comparative Example 1
In a 1000 mL autoclave, 38.0 g (net: 20 g, 0.087 mol) of 2-chloro-4-trichloromethylpyridine obtained in Reference Example 1, 22.1 g (0.26 mol) of piperidine, 26.3 g (0.36 mol) of triethylamine. 26 mol), 90 mL of methanol and 0.5 g of Raney-Nickel (as described above) were charged, and the reaction was carried out for 3 hours under the same conditions as in Example 1 except that the temperature was 45 ° C. After completion of the reaction, the reaction solution was cooled to 30 ° C., then the catalyst was filtered, and the reaction solution was concentrated under reduced pressure. The concentrate was acidified by adding 45 g of 10% hydrochloric acid, and extracted twice with 45 mL of toluene to remove the organic layer. At this time, the target product was present in the aqueous layer, and acidic and neutral impurities were removed to the organic layer side. The aqueous layer was made alkaline with 40% aqueous sodium hydroxide and extracted twice with 45 mL of toluene. At this time, the liquid separation state was poor, and insoluble components were deposited at the interface. The organic layers were combined and washed with 30 mL of water. At this time, the liquid separation property was poor. The solvent was distilled off under reduced pressure to obtain 15.7 g of crude 2-chloro-4-piperidinomethylpyridine (net: 11.3 g, purity: 71.9%, yield: 62.0%).
本発明により得られる２−クロロ−４−アミノメチルピリジン類は、医薬、農薬の中間体として、例えばヒスタミン−Ｈ２ レセプター拮抗剤である２−（フルフリルスルフィニル）−Ｎ−（４−[４−(ピペリジノメチル)−２−ピリジル]オキシ−（Ｚ）−２−ブテニル）アセタミド（ＦＲＧ−８８１３）の合成中間体として有用である。
2-Chloro-4-aminomethylpyridines obtained by the present invention are, for example, histamine-H 2 receptor antagonist 2- (furfurylsulfinyl) -N- (4- [4 It is useful as an intermediate for the synthesis of-(piperidinomethyl) -2-pyridyl] oxy- (Z) -2-butenyl) acetamide (FRG-8813).
Claims (1)
で示されるアミン類および水素とを水素化触媒の存在下で反応させて一般式（ＩＩ）
で示される２−クロロ−４−アミノメチルピリジン類を製造するに際し、反応系内に塩化水素の中和剤として無機塩基を添加することを特徴とする上記の２−クロロ−４−アミノメチルピリジン類の製造方法。
2-chloro-4-trichloromethylpyridine, 2-chloro-4-dichloromethylpyridine, 2-chloro-4-chloromethylpyridine or mixtures thereof and the general formula (I)
Is reacted with an amine represented by the formula (II) and hydrogen in the presence of a hydrogenation catalyst.
The above-mentioned 2-chloro-4-aminomethylpyridine is characterized in that an inorganic base is added as a hydrogen chloride neutralizing agent to the reaction system when producing 2-chloro-4-aminomethylpyridine represented by Manufacturing method.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009214946A (en) * | 2008-03-06 | 2009-09-24 | Double Vision Inc | Goods delivery control device and its method |
| CN115010657A (en) * | 2022-07-18 | 2022-09-06 | 江苏瑞祥化工有限公司 | Method for preparing 2-chloro-5-methylpyridine by continuous flow |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59227879A (en) * | 1983-06-10 | 1984-12-21 | Kyowa Hakko Kogyo Co Ltd | Dibenzo(b,e)oxepin derivative and antiallergic containing it |
| EP0163855A1 (en) * | 1984-04-13 | 1985-12-11 | Nihon Tokushu Noyaku Seizo K.K. | Nitromethylene derivatives, intermediates, and process for their preparation as insecticides |
| JPH06128187A (en) * | 1992-10-15 | 1994-05-10 | Kuraray Co Ltd | New polyisoprenoid hydroquinone derivative |
| JPH09176121A (en) * | 1995-12-28 | 1997-07-08 | Koei Chem Co Ltd | Production of chloro-(aminomethyl)pyridines |
| JPH10231288A (en) * | 1997-02-21 | 1998-09-02 | Kuraray Co Ltd | Production of 2-chloro-4-aminomethylpyridine |
| WO2003014087A1 (en) * | 2001-08-06 | 2003-02-20 | Asahi Glass Company, Limited | Process for preparation of 5-methyl-1-phenyl-2(1h) -pyridinone |
-
2004
- 2004-03-26 JP JP2004092001A patent/JP2005272417A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59227879A (en) * | 1983-06-10 | 1984-12-21 | Kyowa Hakko Kogyo Co Ltd | Dibenzo(b,e)oxepin derivative and antiallergic containing it |
| EP0163855A1 (en) * | 1984-04-13 | 1985-12-11 | Nihon Tokushu Noyaku Seizo K.K. | Nitromethylene derivatives, intermediates, and process for their preparation as insecticides |
| JPH06128187A (en) * | 1992-10-15 | 1994-05-10 | Kuraray Co Ltd | New polyisoprenoid hydroquinone derivative |
| JPH09176121A (en) * | 1995-12-28 | 1997-07-08 | Koei Chem Co Ltd | Production of chloro-(aminomethyl)pyridines |
| JPH10231288A (en) * | 1997-02-21 | 1998-09-02 | Kuraray Co Ltd | Production of 2-chloro-4-aminomethylpyridine |
| WO2003014087A1 (en) * | 2001-08-06 | 2003-02-20 | Asahi Glass Company, Limited | Process for preparation of 5-methyl-1-phenyl-2(1h) -pyridinone |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009214946A (en) * | 2008-03-06 | 2009-09-24 | Double Vision Inc | Goods delivery control device and its method |
| CN115010657A (en) * | 2022-07-18 | 2022-09-06 | 江苏瑞祥化工有限公司 | Method for preparing 2-chloro-5-methylpyridine by continuous flow |
| CN115010657B (en) * | 2022-07-18 | 2024-01-23 | 江苏瑞祥化工有限公司 | Method for preparing 2-chloro-5-methylpyridine through continuous flow |
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