JP2012067033A - Method for producing aminomethylpyridine derivative - Google Patents
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Abstract
Description
本発明は、高収率で、かつ安価にアミノメチルピリジン誘導体を製造する方法に関する。 The present invention relates to a method for producing an aminomethylpyridine derivative with high yield and low cost.
２−アルキルチオ−３−アミノメチルピリジン等のアミノメチルピリジン誘導体は、医薬、農薬等の中間体として有用である。
アミノメチルピリジン誘導体の製造方法として、特許文献１の段落〔０１２３〕の製造例２６１には、２−メチルチオニコチノニトリルのメタノール溶液に塩化コバルト（II）６水和物を加え、水素化ホウ素ナトリウムを加えて反応させ、１−（２−メチルチオピリジン−３−イル）メチルアミンを得る反応が示されている。
しかしながら、特許文献１の方法では、高価な塩化コバルトを大量に使用し、しかも収率は６０％程度である（下記反応式（Ａ）参照）。
Aminomethylpyridine derivatives such as 2-alkylthio-3-aminomethylpyridine are useful as intermediates for pharmaceuticals, agricultural chemicals and the like.
As a method for producing an aminomethylpyridine derivative, in Production Example 261 of paragraph [0123] of Patent Document 1, cobalt chloride (II) hexahydrate is added to a methanol solution of 2-methylthionicotinonitrile, and sodium borohydride is added. Is added to react to give 1- (2-methylthiopyridin-3-yl) methylamine.
However, in the method of Patent Document 1, a large amount of expensive cobalt chloride is used, and the yield is about 60% (see the following reaction formula (A)).
一方、非特許文献１には、ヒドリド試薬として水素化リチウムアルミニウムを用いて、２−メチルチオ−６−シアノピリミジン化合物を還元する方法が示されているが、ヘテロ環を有する化合物の場合、ヒドリド還元を行うと、側鎖よりもヘテロ環部分の還元が起き易いことが知られている（下記反応式（Ｂ）参照）。 On the other hand, Non-Patent Document 1 discloses a method of reducing a 2-methylthio-6-cyanopyrimidine compound using lithium aluminum hydride as a hydride reagent. In the case of a compound having a heterocycle, hydride reduction is performed. It is known that the reduction of the heterocyclic moiety occurs more easily than the side chain (see the following reaction formula (B)).
本発明は、上記の実情に鑑み、高収率で、かつ安価にアミノメチルピリジン誘導体を製造する方法を提供することを課題とする。 In view of the above circumstances, an object of the present invention is to provide a method for producing an aminomethylpyridine derivative with high yield and low cost.
本発明者らは、前記課題を解決するために鋭意研究した結果、水素化ホウ素アルミニウムを用いることにより、前記課題を解決し得ることを見出し、本発明を完成した。 As a result of intensive studies to solve the above problems, the present inventors have found that the above problems can be solved by using aluminum borohydride, and have completed the present invention.
すなわち、本発明は、次の〔１〕及び〔２〕を提供するものである。
〔１〕下記一般式（１）で表されるシアノピリジン(以下、「シアノピリジン（１）」ともいう。）と水素化ホウ素アルミニウムとを反応させることを特徴とする、下記一般式（２）で表されるアミノメチルピリジン誘導体（以下、「アミノメチルピリジン誘導体（２）」ともいう。）の製造方法。
That is, the present invention provides the following [1] and [2].
[1] A cyanopyridine represented by the following general formula (1) (hereinafter also referred to as “cyanopyridine (1)”) and aluminum borohydride are reacted, and the following general formula (2) A method for producing an aminomethylpyridine derivative represented by formula (hereinafter also referred to as “aminomethylpyridine derivative (2)”).
〔２〕下記一般式（３）で表される３−シアノピリジン（以下、「３−シアノピリジン（３）」ともいう。）と水素化ホウ素アルミニウムとを反応させることを特徴とする、下記一般式（４）で表される３−アミノメチルピリジン誘導体（以下、「３−アミノメチルピリジン誘導体（４）」」ともいう。）の製造方法。 [2] 3-cyanopyridine represented by the following general formula (3) (hereinafter also referred to as “3-cyanopyridine (3)”) and aluminum borohydride are reacted, A method for producing a 3-aminomethylpyridine derivative represented by the formula (4) (hereinafter also referred to as “3-aminomethylpyridine derivative (4)”).
本発明によれば、高収率で、かつ安価にアミノメチルピリジン誘導体を製造する方法を提供できる。 According to the present invention, it is possible to provide a method for producing an aminomethylpyridine derivative with high yield and low cost.
本発明の、アミノメチルピリジン誘導体（２）の製造方法は、下記の反応式（Ｃ）に示すように、シアノピリジン（１）と水素化ホウ素アルミニウムとを反応させることを特徴とする。なお、式中、Ｒは前記定義のとおりである。 The method for producing an aminomethylpyridine derivative (2) of the present invention is characterized by reacting cyanopyridine (1) with aluminum borohydride as shown in the following reaction formula (C). In the formula, R is as defined above.
また、３−アミノメチルピリジン誘導体（４）の製造方法は、下記の反応式（Ｄ）に示すように、３−シアノピリジン（３）と水素化ホウ素アルミニウムとを反応させることを特徴とする。なお、式中、Ｒ'は前記定義のとおりである。 The method for producing the 3-aminomethylpyridine derivative (4) is characterized by reacting 3-cyanopyridine (3) with aluminum borohydride as shown in the following reaction formula (D). In the formula, R ′ is as defined above.
Ｒ又はＲ'が表す、炭素数１〜８のアルキル基としては、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、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基、２−エチル−１−ブチル基、各種ペンチル基、各種ヘキシル基、各種へプチル基、各種オクチル基等が挙げられる。ここで、「各種」とは、直鎖又は分岐を意味する。中でも、炭素数１〜６のアルキル基が好ましく、炭素数１〜４のアルキル基がより好ましく、メチル基、エチル基、ｎ−プロピル基、イソプロピル基が更に好ましく、メチル基が特に好ましい。
Ｒ又はＲ'が表す、炭素数３〜６のシクロアルキル基としては、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基が挙げられ、シクロヘキシル基が好ましい。
Examples of the alkyl group having 1 to 8 carbon atoms represented by R or R ′ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, and 2-ethyl. Examples include -1-butyl group, various pentyl groups, various hexyl groups, various heptyl groups, various octyl groups, and the like. Here, “various” means linear or branched. Among these, an alkyl group having 1 to 6 carbon atoms is preferable, an alkyl group having 1 to 4 carbon atoms is more preferable, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group are further preferable, and a methyl group is particularly preferable.
Examples of the cycloalkyl group having 3 to 6 carbon atoms represented by R or R ′ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, and a cyclohexyl group is preferable.
Ｒ又はＲ'が表す、炭素数４〜１４のシクロアルキルアルキル基とは、３〜６員環のシクロアルキル基で置換されている炭素数１〜６のアルキル基が好ましく、具体的には、シクロプロピルメチル基、シクロプロピルエチル基、シクロプロピルプロピル基、シクロプロピルブチル基、シクロブチルメチル基、シクロペンチルメチル基、シクロペンチルエチル基、シクロペンチルプロピル基、シクロヘキシルメチル基、シクロヘキシルエチル基、シクロヘキシルプロピル基等が挙げられる。中でも、３員環又は６員環のシクロアルキル基で置換されている炭素数１〜３のアルキル基がより好ましく、シクロプロピルメチル基、シクロプロピルエチル基、シクロヘキシルメチル基、シクロヘキシルエチル基が更に好ましい。 The C4-C14 cycloalkylalkyl group represented by R or R 'is preferably a C1-C6 alkyl group substituted with a 3- to 6-membered cycloalkyl group, specifically, Cyclopropylmethyl group, cyclopropylethyl group, cyclopropylpropyl group, cyclopropylbutyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclopentylethyl group, cyclopentylpropyl group, cyclohexylmethyl group, cyclohexylethyl group, cyclohexylpropyl group, etc. Can be mentioned. Among these, a C1-C3 alkyl group substituted with a 3-membered or 6-membered cycloalkyl group is more preferable, and a cyclopropylmethyl group, a cyclopropylethyl group, a cyclohexylmethyl group, and a cyclohexylethyl group are more preferable. .
Ｒ又はＲ'が表す、炭素数６〜１２のアリール基としては、フェニル基、トリル基、キシリル基、エチルフェニル基、ナフチル基、メチルナフチル基、ジメチルナフチル基等が挙げられる。中でも、炭素数６〜１０のアリール基が好ましく、フェニル基がより好ましい。
Ｒ又はＲ'が表す、炭素数７〜１６のアラルキル基としては、炭素数６〜１０のアリール基で置換されている炭素数１〜６のアルキル基が好ましく、具体的には、ベンジル基、フェニルエチル基、フェニルプロピル基、ナフチルメチル基、ナフチルエチル基等が挙げられる。中でも、フェニル基で置換されている炭素数１〜３のアルキル基がより好ましく、ベンジル基が更に好ましい。
Ｒ又はＲ'としては、反応性等の観点から、炭素数１〜８の直鎖又は分岐鎖のアルキル基が好ましく、炭素数１〜８の直鎖のアルキル基がより好ましい。
Examples of the aryl group having 6 to 12 carbon atoms represented by R or R ′ include a phenyl group, a tolyl group, a xylyl group, an ethylphenyl group, a naphthyl group, a methylnaphthyl group, and a dimethylnaphthyl group. Among these, an aryl group having 6 to 10 carbon atoms is preferable, and a phenyl group is more preferable.
The aralkyl group having 7 to 16 carbon atoms represented by R or R ′ is preferably an alkyl group having 1 to 6 carbon atoms substituted with an aryl group having 6 to 10 carbon atoms, specifically, a benzyl group, A phenylethyl group, a phenylpropyl group, a naphthylmethyl group, a naphthylethyl group, etc. are mentioned. Among them, an alkyl group having 1 to 3 carbon atoms substituted with a phenyl group is more preferable, and a benzyl group is more preferable.
R or R ′ is preferably a linear or branched alkyl group having 1 to 8 carbon atoms, and more preferably a linear alkyl group having 1 to 8 carbon atoms from the viewpoint of reactivity or the like.
本発明の製造方法は、反応促進の観点から、有機溶媒の存在下で行うことが好ましい。使用できる有機溶媒は、反応に影響を与えないものであれば特に制限はなく、例えばトルエン、キシレン、メシチレン等の芳香族炭化水素；ヘキサン、ヘプタン、オクタン等の炭素数５〜１０の脂肪族炭化水素；ジエチルエーテル、ジイソプロピルエーテル、ジグライム、テトラヒドロフラン等のエーテル等が挙げられる。中でも、テトラヒドロフラン等のエーテルがより好ましい。
これらの有機溶媒は、１種単独で又は２種以上を混合して用いることができる。
有機溶媒の使用量は特に制限されないが、反応系の撹拌操作、反応時間、収率、製品品質等の観点から、シアノピリジン（１）又は３−シアノピリジン（３）に対して０．５〜１００質量倍が好ましく、０．５〜２０質量倍がより好ましい。
The production method of the present invention is preferably carried out in the presence of an organic solvent from the viewpoint of promoting the reaction. The organic solvent that can be used is not particularly limited as long as it does not affect the reaction. For example, aromatic hydrocarbons such as toluene, xylene, mesitylene, etc .; aliphatic carbons having 5 to 10 carbon atoms such as hexane, heptane, and octane. Hydrogen; ethers such as diethyl ether, diisopropyl ether, diglyme, and tetrahydrofuran are listed. Of these, ethers such as tetrahydrofuran are more preferable.
These organic solvents can be used individually by 1 type or in mixture of 2 or more types.
The amount of the organic solvent used is not particularly limited, but from the viewpoints of stirring operation of the reaction system, reaction time, yield, product quality, etc., 0.5 to 0.5 with respect to cyanopyridine (1) or 3-cyanopyridine (3). 100 mass times is preferable and 0.5-20 mass times is more preferable.
本発明の製造方法は、水素化ホウ素アルミニウムを用いることが最大の特徴である。
水素化ホウ素アルミニウムは還元剤として使用されるが、市販品をそのまま使用しても、公知の方法で調製してもよい。例えば、下記反応式に示すように、エーテル等の溶媒中で、水素化ホウ素ナトリウム３モルに対して塩化アルミニウム１モルで塩交換反応させることにより、容易に調製することができる。
３ＮａＢＨ4 ＋ ＡｌＣｌ3 → Ａｌ（ＢＨ4）3 ＋ ３ＮａＣｌ
水素化ホウ素アルミニウムの使用量は、反応促進の観点から、シアノピリジン（１）又は３−シアノピリジン（３）に対して、化学量論比で１〜１０倍モルが好ましく、１〜５倍モルがより好ましく、１〜３倍モルが更に好ましい。
The production method of the present invention is most characterized by using aluminum borohydride.
Aluminum borohydride is used as a reducing agent, but a commercially available product may be used as it is or may be prepared by a known method. For example, as shown in the following reaction formula, it can be easily prepared by carrying out a salt exchange reaction with 1 mol of aluminum chloride per 3 mol of sodium borohydride in a solvent such as ether.
3NaBH 4 + AlCl 3 → Al (BH 4 ) 3 + 3NaCl
The amount of aluminum borohydride used is preferably 1 to 10 moles in terms of the stoichiometric ratio with respect to cyanopyridine (1) or 3-cyanopyridine (3) from the viewpoint of promoting the reaction, and 1 to 5 moles. Is more preferable, and a molar ratio of 1 to 3 is more preferable.
本発明の製造方法では、反応促進の観点から、反応温度は−３０〜１００℃が好ましく、−２０〜８０℃がより好ましく、−１０〜６０℃が更に好ましく、５〜４０℃が特に好ましい。反応圧力は常圧でも加圧でもよい。反応時間は、反応温度等にもよるが、０．４〜５０時間が好ましく、０．６〜３０時間がより好ましく、０．８〜１０時間が更に好ましい。
本発明の製造方法は、窒素等の不活性ガス雰囲気下、前記有機溶媒中で水素化ホウ素ナトリウムと塩化アルミニウムから水素化ホウ素アルミニウムを調製した後、続いてシアノピリジン（１）又は３−シアノピリジン（３）、又は前記有機溶媒溶液を添加し、所定温度で所定時間反応させることにより行うことができる。
または、不活性ガス雰囲気下、水素化ホウ素ナトリウムとシアノピリジン（１）又は３−シアノピリジン（３）を有機溶媒中で混合し、そこに塩化アルミニウムを添加し、かかる混合液に所定温度で所定時間反応させることにより行うことができる。
In the production method of the present invention, from the viewpoint of promoting the reaction, the reaction temperature is preferably -30 to 100 ° C, more preferably -20 to 80 ° C, still more preferably -10 to 60 ° C, and particularly preferably 5 to 40 ° C. The reaction pressure may be normal pressure or increased pressure. Although reaction time is based also on reaction temperature etc., 0.4-50 hours are preferable, 0.6-30 hours are more preferable, 0.8-10 hours are still more preferable.
In the production method of the present invention, aluminum borohydride is prepared from sodium borohydride and aluminum chloride in the organic solvent under an inert gas atmosphere such as nitrogen, and then cyanopyridine (1) or 3-cyanopyridine. (3) Alternatively, the organic solvent solution can be added and reacted at a predetermined temperature for a predetermined time.
Alternatively, sodium borohydride and cyanopyridine (1) or 3-cyanopyridine (3) are mixed in an organic solvent under an inert gas atmosphere, and aluminum chloride is added thereto, and the mixture is mixed at a predetermined temperature at a predetermined temperature. It can be performed by reacting for a period of time.
上記反応後は、塩酸水溶液、硫酸水溶液、リン酸水溶液、酢酸水溶液、塩化アンモニウム水溶液等を添加して、未反応の水素化ホウ素アルミニウムを失活させることが好ましい。
得られたアミノメチルピリジン誘導体（２）又は３−アミノメチルピリジン誘導体（４）は、公知の方法で単離精製することができる。
例えば、上記のようにして未反応の水素化ホウ素アルミニウムを失活させた後の反応混合液に塩基性化合物の水溶液を添加してｐＨ７以上にした後、（ｉ）芳香族炭化水素
等の有機溶媒で抽出し、分離する方法、（ii）前記と同様の処理をした後、蒸留により単離する方法、（iii）前記と同様の処理をした後、溶媒を留去し、析出した塩をろ取する方法等が挙げられる。
このようにして得られたアミノメチルピリジン誘導体（２）又は３−アミノメチルピリジン誘導体（４）は、例えば、塩酸、硫酸、硝酸等の無機塩と塩を形成させることにより、保存安定性を高めることができ、保存中も高品質を保つことができる。また、必要に応じて、再結晶、蒸留、昇華等で純度を更に高めることができる。
After the reaction, it is preferable to deactivate the unreacted aluminum borohydride by adding an aqueous hydrochloric acid solution, an aqueous sulfuric acid solution, an aqueous phosphoric acid solution, an aqueous acetic acid solution, an aqueous ammonium chloride solution, or the like.
The obtained aminomethylpyridine derivative (2) or 3-aminomethylpyridine derivative (4) can be isolated and purified by a known method.
For example, after adding an aqueous solution of a basic compound to the reaction mixture after deactivating the unreacted aluminum borohydride as described above to pH 7 or higher, (i) organics such as aromatic hydrocarbons (Ii) A method of separating by distillation after performing the same treatment as above, (iii) A method similar to the above, and then distilling off the solvent and removing the precipitated salt. The method of filtering, etc. are mentioned.
The aminomethylpyridine derivative (2) or the 3-aminomethylpyridine derivative (4) thus obtained has improved storage stability by forming a salt with an inorganic salt such as hydrochloric acid, sulfuric acid or nitric acid. And can maintain high quality during storage. If necessary, the purity can be further increased by recrystallization, distillation, sublimation or the like.
以下、実施例及び比較例を挙げて、本発明を更に具体的に説明するが、本発明はこれらの実施例により、なんら限定されるものではない。
実施例１（２−メチルチオ−３−アミノメチルピリジンの製造）
温度計及び撹拌装置を備えた内容積１００ｍｌの三口フラスコに、窒素雰囲気下、テトラヒドロフラン１３．５ｇを仕込み、水素化ホウ素ナトリウム２．０８ｇ（５５ｍｍｏｌ）を加え、内温を１０℃以下に冷却した。次いで、内温を３０℃以下に保ちながら塩化アルミニウム２．４３ｇ（１８ｍｍｏｌ）を添加し、添加終了後１５分間撹拌して、水素化ホウ素アルミニウムを含む混合液を調製した。
続いて、得られた上記混合液に、２−メチルチオ−３−シアノピリジンのテトラヒドロフラン溶液１９．５ｇ（３０ｍｍｏｌ）を、内温を３０℃以下に保ちながら滴下し、滴下終了後２０〜２５℃で３時間撹拌した。
得られた反応混合液に、１０％塩酸水溶液２０ｇを内温を３０℃以下に保ちながら滴下し、滴下終了後１時間撹拌した。次いで、２０％水酸化ナトリウム水溶液１６．５ｇを３０℃で滴下し、反応混合液のｐＨを１０以上として３０分間撹拌した後、静置し、有機層と水層を分液した。
分液した有機層にトルエン３０ｇ及び水３０ｇを加えて、抽出し、有機層を減圧下で濃縮して収率９０％（４．１６ｇ：２７ｍｍｏｌ）で２−メチルチオ−３−アミノメチルピリジンを得た。得られた２−メチルチオ−３−アミノメチルピリジンをイソプロパノール２０ｇに溶解させ、濃塩酸６．０２ｇ（５９．４ｍｍｏｌ）を加え、析出した塩をろ取、乾燥することにより、２−メチルチオ−３−アミノメチルピリジン二塩酸塩５．５２ｇ（２４．３ｍｍｏｌ）を得た。
得られた２−メチルチオ−３−アミノメチルピリジン二塩酸塩について、1Ｈ−ＮＭＲ分析を行い、その構造を確認した。結果を以下に示す。
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3，ＴＭＳ）δ（ｐｐｍ）：１．４９（２Ｈ，ｂｒ），２．５８（３Ｈ，ｓ），３．８４（２Ｈ，ｓ），６．９７−７．００（１Ｈ，ｄｄ，Ｊ＝７．２Ｈｚ，４．８Ｈｚ），７．５１−７．５３（１Ｈ，ｍ），８．３４−８．３６（１Ｈ，ｄｄ，Ｊ＝４．８Ｈｚ，２．０Ｈｚ）
EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated further more concretely, this invention is not limited at all by these Examples.
Example 1 (Production of 2-methylthio-3-aminomethylpyridine)
In a 100 ml three-necked flask equipped with a thermometer and a stirrer, 13.5 g of tetrahydrofuran was charged under a nitrogen atmosphere, 2.08 g (55 mmol) of sodium borohydride was added, and the internal temperature was cooled to 10 ° C. or lower. Next, 2.43 g (18 mmol) of aluminum chloride was added while maintaining the internal temperature at 30 ° C. or less, and the mixture was stirred for 15 minutes after the addition was completed to prepare a mixed solution containing aluminum borohydride.
Subsequently, 19.5 g (30 mmol) of a tetrahydrofuran solution of 2-methylthio-3-cyanopyridine was added dropwise to the obtained mixed solution while keeping the internal temperature at 30 ° C. or lower. Stir for 3 hours.
To the resulting reaction mixture, 20 g of a 10% aqueous hydrochloric acid solution was added dropwise while maintaining the internal temperature at 30 ° C. or lower, and the mixture was stirred for 1 hour after the completion of the addition. Next, 16.5 g of a 20% aqueous sodium hydroxide solution was added dropwise at 30 ° C., the reaction mixture was adjusted to pH 10 or higher and stirred for 30 minutes, and then allowed to stand to separate the organic layer and the aqueous layer.
To the separated organic layer, 30 g of toluene and 30 g of water were added for extraction, and the organic layer was concentrated under reduced pressure to obtain 2-methylthio-3-aminomethylpyridine in a yield of 90% (4.16 g: 27 mmol). It was. The obtained 2-methylthio-3-aminomethylpyridine was dissolved in 20 g of isopropanol, 6.02 g (59.4 mmol) of concentrated hydrochloric acid was added, and the precipitated salt was collected by filtration and dried to give 2-methylthio-3- 5.52 g (24.3 mmol) of aminomethylpyridine dihydrochloride was obtained.
The obtained 2-methylthio-3-aminomethylpyridine dihydrochloride was subjected to 1 H-NMR analysis, and its structure was confirmed. The results are shown below.
1 H-NMR (400 MHz, CDCl 3 , TMS) δ (ppm): 1.49 (2H, br), 2.58 (3H, s), 3.84 (2H, s), 6.97-7. 00 (1H, dd, J = 7.2 Hz, 4.8 Hz), 7.51-7.53 (1H, m), 8.34-8.36 (1H, dd, J = 4.8 Hz, 2. 0Hz)
比較例１
実施例１において、水素化ホウ素アルミニウムを調製して用いる代わりに、水素化ビス（２−メトキシエトキシ）アルミニウムナトリウムの７０％トルエン溶液１７．３３ｇ（６０ｍｍｏｌ）を用いた以外は、実施例１と同様の操作を行った。その結果、２−メチルチオ−３−アミノメチルピリジンの収率は７．５％であった。
比較例２
実施例１において、水素化ホウ素アルミニウムを調製して用いる代わりに、水素化リチウムアルミニウムを２．２８ｇ（６０ｍｍｏｌ）用いた以外は、実施例１と同様の操作を行った。その結果、２−メチルチオ−３−アミノメチルピリジンの収率は２９．１％であった。
比較例３
実施例１において、水素化ホウ素アルミニウムを調製して用いる代わりに、水素化ホウ素ナトリウム２．２７ｇ（６０ｍｍｏｌ）と酢酸３．６０ｇ（６０ｍｍｏｌ）から調製した還元剤を用いた以外は、実施例１と同様の操作を行った結果、２−メチルチオ−３−アミノメチルピリジンの収率は１７．７％であった。
Comparative Example 1
In Example 1, instead of preparing and using aluminum borohydride, the same as Example 1 except that 17.33 g (60 mmol) of a 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride was used. Was performed. As a result, the yield of 2-methylthio-3-aminomethylpyridine was 7.5%.
Comparative Example 2
In Example 1, instead of preparing and using aluminum borohydride, the same operation as in Example 1 was performed except that 2.28 g (60 mmol) of lithium aluminum hydride was used. As a result, the yield of 2-methylthio-3-aminomethylpyridine was 29.1%.
Comparative Example 3
In Example 1, instead of preparing and using aluminum borohydride, Example 1 was used except that a reducing agent prepared from 2.27 g (60 mmol) of sodium borohydride and 3.60 g (60 mmol) of acetic acid was used. As a result of the same operation, the yield of 2-methylthio-3-aminomethylpyridine was 17.7%.
本発明の製造方法によれば、高収率で、かつ安価にアミノメチルピリジン誘導体を製造することができるため、工業的に有利である。得られたアミノメチルピリジン誘導体は、医薬、農薬、その製品の中間体等として有用である。 According to the production method of the present invention, an aminomethylpyridine derivative can be produced at a high yield and at a low cost, which is industrially advantageous. The obtained aminomethylpyridine derivative is useful as a pharmaceutical, an agricultural chemical, an intermediate of the product, and the like.
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| WO2014097272A2 (en) | 2012-12-21 | 2014-06-26 | Mankind Research Centre | Method for production of (s,s)-6-benzyloctahydro-1h-pyrrolo[3,4-b]pyridine, an intermediate of azabicyclo pyridine derivatives |
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| JPS63239280A (en) * | 1985-12-24 | 1988-10-05 | Asahi Chem Ind Co Ltd | Production of thienylethylamine |
| JP2008001633A (en) * | 2006-06-22 | 2008-01-10 | Showa Denko Kk | Reduction reaction by borohydride compound in the presence of aluminum chloride using tetrahydropyran as solvent |
| WO2010024430A1 (en) * | 2008-09-01 | 2010-03-04 | アステラス製薬株式会社 | 2,4-diaminopyrimidine compound |
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| JPS63239280A (en) * | 1985-12-24 | 1988-10-05 | Asahi Chem Ind Co Ltd | Production of thienylethylamine |
| JP2008001633A (en) * | 2006-06-22 | 2008-01-10 | Showa Denko Kk | Reduction reaction by borohydride compound in the presence of aluminum chloride using tetrahydropyran as solvent |
| WO2010024430A1 (en) * | 2008-09-01 | 2010-03-04 | アステラス製薬株式会社 | 2,4-diaminopyrimidine compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2014097272A2 (en) | 2012-12-21 | 2014-06-26 | Mankind Research Centre | Method for production of (s,s)-6-benzyloctahydro-1h-pyrrolo[3,4-b]pyridine, an intermediate of azabicyclo pyridine derivatives |
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