JPH08198851A - Synthesis of methylaminopyridine derivative - Google Patents
Synthesis of methylaminopyridine derivativeInfo
- Publication number
- JPH08198851A JPH08198851A JP7008231A JP823195A JPH08198851A JP H08198851 A JPH08198851 A JP H08198851A JP 7008231 A JP7008231 A JP 7008231A JP 823195 A JP823195 A JP 823195A JP H08198851 A JPH08198851 A JP H08198851A
- Authority
- JP
- Japan
- Prior art keywords
- formamide
- amino
- pyridyl
- methylamino
- derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pyridine Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、メチルアミノピリジン
誘導体の製造方法に関する。TECHNICAL FIELD The present invention relates to a method for producing a methylaminopyridine derivative.
【０００２】[0002]
【従来の技術】メチルアミノピリジン誘導体は、医薬、
農薬などの中間体、例えば循環器疾患治療剤、除草剤の
中間体として有用である。メチルアミノピリジン誘導体
の製造方法には、対応するハロピリジン誘導体とメチル
アミンとを反応させる方法（特公昭63−2555）や、対応
するアミノピリジン誘導体と１−ヒドロキシメチルベン
ゾトリアゾールとを縮合させた後に還元する方法（J. C
hem. Soc. Perkin Trans., 1987, 805）などが知られて
いる。しかしながらこれらの方法は、(１)オートクレー
ブ中、高温、長時間を要する、(２)原料あるいは試薬が
高価、(３)目的物以外の有機化合物が副生するなどの問
題があり、工業的な製造法としては満足のいくものでは
なかった。2. Description of the Related Art Methylaminopyridine derivatives are drugs
It is useful as an intermediate for pesticides, for example, a therapeutic agent for cardiovascular diseases and an intermediate for herbicides. The methylaminopyridine derivative can be produced by reacting the corresponding halopyridine derivative with methylamine (Japanese Patent Publication No. 63-2555) or by condensing the corresponding aminopyridine derivative with 1-hydroxymethylbenzotriazole and then reducing. How to do (J. C
hem. Soc. Perkin Trans., 1987, 805) and the like are known. However, these methods have the problems that (1) high temperature and long time are required in the autoclave, (2) raw materials or reagents are expensive, and (3) organic compounds other than the target product are by-produced, which are industrial The manufacturing method was not satisfactory.
【０００３】[0003]
【発明が解決しようとする課題】本発明は、上記の従来
技術の有する欠点を解決するものであり、メチルアミノ
ピリジン誘導体を経済的にかつ高収率で製造する方法を
提供することにある。SUMMARY OF THE INVENTION The present invention solves the above-mentioned drawbacks of the prior art and provides a method for economically producing a methylaminopyridine derivative in a high yield.
【０００４】[0004]
【課題を解決するための手段】本発明者らは、上記目的
を達成すべく鋭意研究した結果、メチルアミノピリジン
誘導体を温和な条件下で高収率に製造することができる
方法を見出し本発明を完成した。Means for Solving the Problems As a result of intensive studies aimed at achieving the above object, the present inventors have found a method capable of producing a methylaminopyridine derivative in a high yield under mild conditions. Was completed.
【０００５】すなわち、本発明は一般式(Ｉ)That is, the present invention has the general formula (I)
【化４】 （式中、ＲはＣ1〜Ｃ4アルキル基、ｎは１または２を表
す）で表されるアミノピリジン誘導体を、酢酸−ギ酸混
合酸無水物と反応させるか、又は無水酢酸の存在下にギ
酸と反応させて、一般式(II)[Chemical 4] (Wherein R represents a C 1 -C 4 alkyl group, n represents 1 or 2), an aminopyridine derivative is reacted with acetic acid-formic acid mixed acid anhydride, or in the presence of acetic anhydride. General formula (II)
【化５】 （式中、Ｒおよびｎは上記と同じ意味を有する）で表さ
れるホルムアミド誘導体とし、次いで還元することを特
徴とする、一般式(III)Embedded image (Wherein R and n have the same meanings as described above), and a formamide derivative represented by the following formula (III)
【化６】 （式中、Ｒおよびｎは上記と同じ意味を有する）で表さ
れるメチルアミノピリジン誘導体の製造方法である。[Chemical 6] (In the formula, R and n have the same meanings as described above).
【０００６】上記した一般式(Ｉ)〜(III)に於けるＲで
表されるC1〜C4アルキル基の具体例としては、メチル、
エチル、プロピル、イソプロピル、ブチル等が挙げられ
る。 上記した一般式(Ｉ)〜(III)に於けるアルキル基Ｒにつ
いてのｎが１である場合のピリジン環上のアルキル基の
置換位置としては３−位、４−位、５−位及び６−位が
挙げられ、又ｎが２である場合のピリジン環上の二つの
アルキル基の置換位置としては３,４−位、３,５−位、
３,６−位、４,５−位、４,６−位及び５,６−位が挙げ
られる。Specific examples of the C 1 -C 4 alkyl group represented by R in the above general formulas (I) to (III) include methyl and
Ethyl, propyl, isopropyl, butyl and the like can be mentioned. When n is 1 for the alkyl group R in the general formulas (I) to (III), the substitution position of the alkyl group on the pyridine ring is 3-position, 4-position, 5-position and 6-position. -Position, and when n is 2, the substitution positions of the two alkyl groups on the pyridine ring are 3,4-position, 3,5-position,
Examples include 3,6-position, 4,5-position, 4,6-position and 5,6-position.
【０００７】上記した一般式(Ｉ)で表される化合物の具
体例としては、２−アミノ−４,６−ジメチルピリジ
ン、２−アミノ−３,４−ジメチルピリジン、２−アミ
ノ−３,５−ジメチルピリジン、２−アミノ−３,６−ジ
メチルピリジン、２−アミノ−４,５−ジメチルピリジ
ン、２−アミノ−５,６−ジメチルピリジン、２−アミ
ノ−３−メチルピリジン、２−アミノ−４−メチルピリ
ジン、２−アミノ−５−メチルピリジン、２−アミノ−
６−メチルピリジン、 ２−アミノ−４,６−ジエチル
ピリジン、２−アミノ−３−エチルピリジン、２−アミ
ノ−４−エチルピリジン、２−アミノ−５−エチルピリ
ジン、２−アミノ−６−エチルピリジン、２−アミノ−
４，６−ジプロピルピリジン、２−アミノ−３−プロピ
ルピリジン、２−アミノ−４−プロピルピリジン、２−
アミノ−５−プロピルピリジン、２−アミノ−６−プロ
ピルピリジン、２−アミノ−４,６−ジブチルピリジ
ン、２−アミノ−３−ブチルピリジン、２−アミノ−４
−ブチルピリジン、２−アミノ−５−ブチルピリジン、
２−アミノ−６−ブチルピリジン等が挙げられる。Specific examples of the compound represented by the above general formula (I) include 2-amino-4,6-dimethylpyridine, 2-amino-3,4-dimethylpyridine and 2-amino-3,5. -Dimethylpyridine, 2-amino-3,6-dimethylpyridine, 2-amino-4,5-dimethylpyridine, 2-amino-5,6-dimethylpyridine, 2-amino-3-methylpyridine, 2-amino- 4-methylpyridine, 2-amino-5-methylpyridine, 2-amino-
6-methylpyridine, 2-amino-4,6-diethylpyridine, 2-amino-3-ethylpyridine, 2-amino-4-ethylpyridine, 2-amino-5-ethylpyridine, 2-amino-6-ethyl Pyridine, 2-amino-
4,6-dipropylpyridine, 2-amino-3-propylpyridine, 2-amino-4-propylpyridine, 2-
Amino-5-propylpyridine, 2-amino-6-propylpyridine, 2-amino-4,6-dibutylpyridine, 2-amino-3-butylpyridine, 2-amino-4
-Butyl pyridine, 2-amino-5-butyl pyridine,
2-amino-6-butyl pyridine etc. are mentioned.
【０００８】一般式(II)で表される化合物の具体例とし
ては、Ｎ−〔２−（４,６−ジメチル）ピリジル〕ホル
ムアミド、Ｎ−〔２−（３，４−ジメチル）ピリジル〕
ホルムアミド、Ｎ−〔２−（３,５−ジメチル）ピリジ
ル〕ホルムアミド、Ｎ−〔２−（３，６−ジメチル）ピ
リジル〕ホルムアミド、Ｎ−〔２−（４,５−ジメチ
ル）ピリジル〕ホルムアミド、Ｎ−〔２−（５,６−ジ
メチル）ピリジル〕ホルムアミド、Ｎ−〔２−（３−メ
チル）ピリジル〕ホルムアミド、Ｎ−〔２−（４−メチ
ル）ピリジル〕ホルムアミド、Ｎ−〔２−（５−メチ
ル）ピリジル〕ホルムアミド、Ｎ−〔２−（６−メチ
ル）ピリジル〕ホルムアミド、Ｎ−〔２−（４,６−ジ
エチル）ピリジル〕ホルムアミド、Ｎ−〔２−（３−エ
チル）ピリジル〕ホルムアミド、Ｎ−〔２−（４−エチ
ル）ピリジル〕ホルムアミド、Ｎ−〔２−（５−エチ
ル）ピリジル〕ホルムアミド、Ｎ−〔２−（６−エチ
ル）ピリジル〕ホルムアミド，Ｎ−〔２−（４,６−ジ
プロピル）ピリジル〕ホルムアミド、Ｎ−〔２−（３−
プロピル）ピリジル〕ホルムアミド、Ｎ−〔２−（４−
メチル）ピリジル〕ホルムアミド、Ｎ−〔２−（５−メ
チル）ピリジル〕ホルムアミド、Ｎ−〔２−（６−プロ
ピル）ピリジル〕ホルムアミド、Ｎ−〔２−（４,６−
ジブチル）ピリジル〕ホルムアミド、Ｎ−〔２−（３−
ブチル）ピリジル〕ホルムアミド、Ｎ−〔２−（４−ブ
チル）ピリジル〕ホルムアミド、Ｎ−〔２−（５−ブチ
ル）ピリジル〕ホルムアミド、Ｎ−〔２−（６−ブチ
ル）ピリジル〕ホルムアミド等が挙げられる。Specific examples of the compound represented by the general formula (II) include N- [2- (4,6-dimethyl) pyridyl] formamide and N- [2- (3,4-dimethyl) pyridyl].
Formamide, N- [2- (3,5-dimethyl) pyridyl] formamide, N- [2- (3,6-dimethyl) pyridyl] formamide, N- [2- (4,5-dimethyl) pyridyl] formamide, N- [2- (5,6-dimethyl) pyridyl] formamide, N- [2- (3-methyl) pyridyl] formamide, N- [2- (4-methyl) pyridyl] formamide, N- [2- ( 5-methyl) pyridyl] formamide, N- [2- (6-methyl) pyridyl] formamide, N- [2- (4,6-diethyl) pyridyl] formamide, N- [2- (3-ethyl) pyridyl] Formamide, N- [2- (4-ethyl) pyridyl] formamide, N- [2- (5-ethyl) pyridyl] formamide, N- [2- (6-ethyl) pyridyl] formamide, N- [2- (4,6-dipropyl) pyridyl] formamide, N- [2- (3-
Propyl) pyridyl] formamide, N- [2- (4-
Methyl) pyridyl] formamide, N- [2- (5-methyl) pyridyl] formamide, N- [2- (6-propyl) pyridyl] formamide, N- [2- (4,6-
Dibutyl) pyridyl] formamide, N- [2- (3-
Butyl) pyridyl] formamide, N- [2- (4-butyl) pyridyl] formamide, N- [2- (5-butyl) pyridyl] formamide, N- [2- (6-butyl) pyridyl] formamide and the like. To be
【０００９】そして一般式(III)で表される化合物の具
体例としては、２−メチルアミノ−４,６−ジメチルピ
リジン、２−メチルアミノ−３,４−ジメチルピリジ
ン、２−メチルアミノ−３,５−ジメチルピリジン、２
−メチルアミノ−３,６−ジメチルピリジン、２−メチ
ルアミノ−４,５−ジメチルピリジン、２−メチルアミ
ノ−５,６−ジメチルピリジン、２−アミノ−３−メチ
ルピリジン、２−アミノ−４−メチルピリジン、２−メ
チルアミノ−５−メチルピリジン、２−メチルアミノ−
６−メチルピリジン、２−メチルアミノ−４,６−ジエ
チルピリジン、２−アミノ−３−エチルピリジン、２−
アミノ−４−エチルピリジン、２−メチルアミノ−５−
エチルピリジン、２−メチルアミノ−６−エチルピリジ
ン、２−メチルアミノ−４,６−ジプロピルピリジン、
２−メチルアミノ−３−プロピルピリジン、２−メチル
アミノ−４−プロピルピリジン、２−メチルアミノ−５
−プロピルピリジン、２−メチルアミノ−６−プロピル
ピリジン、２−メチルアミノ−４,６−ジブチルピリジ
ン、２−メチルアミノ−３−ブチルピリジン、２−メチ
ルアミノ−４−ブチルピリジン、２−メチルアミノ−５
−ブチルピリジン、２−メチルアミノ−６−ブチルピリ
ジン等が挙げられる。Specific examples of the compound represented by the general formula (III) include 2-methylamino-4,6-dimethylpyridine, 2-methylamino-3,4-dimethylpyridine and 2-methylamino-3. , 5-dimethylpyridine, 2
-Methylamino-3,6-dimethylpyridine, 2-methylamino-4,5-dimethylpyridine, 2-methylamino-5,6-dimethylpyridine, 2-amino-3-methylpyridine, 2-amino-4- Methylpyridine, 2-methylamino-5-methylpyridine, 2-methylamino-
6-methylpyridine, 2-methylamino-4,6-diethylpyridine, 2-amino-3-ethylpyridine, 2-
Amino-4-ethylpyridine, 2-methylamino-5-
Ethylpyridine, 2-methylamino-6-ethylpyridine, 2-methylamino-4,6-dipropylpyridine,
2-methylamino-3-propylpyridine, 2-methylamino-4-propylpyridine, 2-methylamino-5
-Propylpyridine, 2-methylamino-6-propylpyridine, 2-methylamino-4,6-dibutylpyridine, 2-methylamino-3-butylpyridine, 2-methylamino-4-butylpyridine, 2-methylamino -5
-Butylpyridine, 2-methylamino-6-butylpyridine and the like can be mentioned.
【００１０】一般式(II)で表される化合物は、一般式
(Ｉ)で表される化合物を、酢酸−ギ酸混合酸無水物でホ
ルミル化することにより得られる。一般式(Ｉ)で表され
る化合物１モルに対して、酢酸−ギ酸混合酸無水物は２
〜１０モル量、好ましくは２.５〜５モル量用いられ
る。反応は無溶媒で行うことも出来るが、反応操作をよ
り容易にしまた好ましい条件下に行うために反応溶媒を
用いることが好ましい。かかる反応溶媒としては、原
料、試薬と反応しないものならばよく、例えばジエチル
エーテル、テトラヒドロフラン等のエーテル系溶媒や、
ジクロロメタン等のハロゲン系溶媒等が用いられる。反
応温度は０〜６０℃、好ましくは０〜３０℃である。こ
こで、酢酸−ギ酸混合酸無水物は、無水酢酸１モルに対
し、ギ酸１〜５モル量、好ましくは１.５〜３モル量を
加え、反応温度１０〜６０℃で１〜４時間撹拌すること
で定量的に調製でき、精製することなく反応に使用する
ことができる。The compound represented by the general formula (II) has the general formula
It is obtained by formylating the compound represented by (I) with acetic acid-formic acid mixed acid anhydride. For 1 mol of the compound represented by the general formula (I), the acetic acid-formic acid mixed acid anhydride is 2
It is used in an amount of -10 mol, preferably 2.5-5 mol. The reaction can be carried out without a solvent, but it is preferable to use a reaction solvent in order to facilitate the reaction operation and carry out the reaction under preferable conditions. The reaction solvent may be any one that does not react with the raw materials and reagents, for example, an ether solvent such as diethyl ether or tetrahydrofuran,
A halogen-based solvent such as dichloromethane is used. The reaction temperature is 0 to 60 ° C, preferably 0 to 30 ° C. Here, the acetic acid-formic acid mixed acid anhydride is added with 1 to 5 mol of formic acid, preferably 1.5 to 3 mol per 1 mol of acetic anhydride, and stirred at a reaction temperature of 10 to 60 ° C. for 1 to 4 hours. By doing so, it can be quantitatively prepared and can be used in the reaction without purification.
【００１１】別法として、一般式(II)で表される化合物
は、一般式(Ｉ)で表される化合物を、無水酢酸の存在下
にギ酸を用いてホルミル化することによっても同様に得
られる。この場合、無水酢酸とギ酸とは、無水酢酸１モ
ルに対し、ギ酸１〜５モル量、好ましくは１.５〜３モ
ル量で用いることが出来る。 そして使用されるギ酸の量
は一般式(Ｉ)で表される化合物１モルに対して、２〜１
０モル、好ましくは２.５〜５モルの量である。Alternatively, the compound represented by the general formula (II) can be similarly obtained by formylating the compound represented by the general formula (I) with formic acid in the presence of acetic anhydride. To be In this case, acetic anhydride and formic acid can be used in an amount of 1 to 5 mol of formic acid, preferably 1.5 to 3 mol, per mol of acetic anhydride. The amount of formic acid used is 2 to 1 with respect to 1 mol of the compound represented by the general formula (I).
The amount is 0 mol, preferably 2.5 to 5 mol.
【００１２】一般式(III)で表される化合物は、一般式
(II)で表される化合物を、種々の還元剤で還元すること
で得られる。一般式(II)で表される化合物1モルに対し
て還元剤１〜５モル量、好ましくは１.５〜３モル量を
用いて行われる。還元剤としては、慣用の還元剤の例え
ば水素化アルミニウムリチウム、ジボラン、水素化ホウ
素ナトリウム−塩化コバルト、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等が用いられる。
反応溶媒は、原料、試薬と反応しないものならばよく、
例えばジエチルエーテル、テトラヒドロフラン等のエー
テル系溶媒や、ジクロロメタン等のハロゲン系溶媒等が
用いられる。反応は、０℃〜溶媒の沸点までの間の温度
で行われる。The compound represented by the general formula (III) has the general formula
It can be obtained by reducing the compound represented by (II) with various reducing agents. The reducing agent is used in an amount of 1 to 5 mols, preferably 1.5 to 3 mols, per mol of the compound represented by the general formula (II). As the reducing agent, a conventional reducing agent such as lithium aluminum hydride, diborane, sodium borohydride-cobalt chloride, sodium bis (2-methoxyethoxy) aluminum hydride or the like is used.
Any reaction solvent may be used as long as it does not react with the raw materials and reagents,
For example, an ether solvent such as diethyl ether or tetrahydrofuran, a halogen solvent such as dichloromethane, or the like is used. The reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent.
【００１３】[0013]
【発明の効果】上記に説明した本発明の方法によれば、
従来法における問題点を伴うことなく、目的とするメチ
ルアミノピリジン誘導体を効率よく製造することができ
る。以下に本発明を実施例によって具体的に説明する
が、これらは本発明を説明するためのものであり、これ
らによって本発明が限定されるものではない。According to the method of the present invention described above,
The target methylaminopyridine derivative can be efficiently produced without the problems in the conventional method. Hereinafter, the present invention will be specifically described with reference to Examples, but these are for explaining the present invention and the present invention is not limited thereto.
【００１４】[0014]
実施例 １ (１) Ｎ−〔２−（４,６−ジメチル）ピリジル〕ホル
ムアミドの製造 ８℃まで冷却した無水酢酸４５０ｇに、ギ酸２５０mLを
３５分間かけて滴下した。滴下終了後、室温で20分間撹
拌し、その後、さらに６０℃で２時間撹拌した。この酢
酸−ギ酸混合酸無水物溶液を８℃まで冷却した後、これ
に、２−アミノ−４,６−ジメチルピリジン２１０ｇを
テトラヒドロフラン６００mLに溶解した溶液を９０分間
かけて滴下した。滴下終了後、この反応液を室温で１５
時間撹拌した後、減圧下で濃縮した。得られた残留物に
酢酸エチル１Ｌを加えて溶解したものに、氷冷中、攪拌
しながら２５％水酸化ナトリウム水溶液１Ｌを加えて中
和した。これに酢酸エチル１.５Ｌを加えて抽出する操
作を３回繰り返した。抽出後の酢酸エチル層を合わせた
有機層を硫酸ナトリウムで乾燥した後、濃縮して粗結晶
２９６ｇを得た。この結晶に酢酸エチル１Ｌを加えて、
６０℃の湯浴中で溶解した後、徐々に冷却して結晶を析
出させ、濾過、洗浄、乾燥して、Ｎ−〔２−（４,６−
ジメチル）ピリジル〕ホルムアミド２２０ｇ（収率８５
％）を得た。 m.p. 107〜109℃1 H NMR (500MHz, CDCl3) d 2.30(s,3H), 2.33(s,3H),
2.42(s,3H), 2.43(s,3H), 6.47(s, 1H), 6.75(s, 1H),
6.77(s, 1H), 7.85(s,1H), 8.14(br,1H), 8.25(br, 1
H), 8.43(s,1H), 9.25(d,J=11Hz,1H)。 IR (KBr) 3204, 3128, 1696, 1623, 1573, 1339, 127
3, 841, 757cm-1。 MS (EI, 70eV) 150(M+)。Example 1 (1) Production of N- [2- (4,6-dimethyl) pyridyl] formamide To 450 g of acetic anhydride cooled to 8 ° C, 250 mL of formic acid was added dropwise over 35 minutes. After the completion of dropping, the mixture was stirred at room temperature for 20 minutes and then at 60 ° C. for 2 hours. This acetic acid-formic acid mixed acid anhydride solution was cooled to 8 ° C., and then a solution prepared by dissolving 210 g of 2-amino-4,6-dimethylpyridine in 600 mL of tetrahydrofuran was added dropwise over 90 minutes. After the completion of dropping, the reaction solution was allowed
After stirring for an hour, the mixture was concentrated under reduced pressure. 1 L of ethyl acetate was added to and dissolved in the obtained residue, and 1 L of a 25% aqueous sodium hydroxide solution was added to the residue for neutralization while cooling with ice. The operation of adding 1.5 L of ethyl acetate and extracting was repeated 3 times. The organic layers combined with the extracted ethyl acetate layer were dried over sodium sulfate and then concentrated to obtain 296 g of crude crystals. Add 1 L of ethyl acetate to the crystals,
After being dissolved in a water bath at 60 ° C., it was gradually cooled to precipitate crystals, which were filtered, washed and dried to obtain N- [2- (4,6-
220 g of dimethyl) pyridyl] formamide (yield 85
%) Was obtained. mp 107-109 ° C 1 H NMR (500MHz, CDCl 3 ) d 2.30 (s, 3H), 2.33 (s, 3H),
2.42 (s, 3H), 2.43 (s, 3H), 6.47 (s, 1H), 6.75 (s, 1H),
6.77 (s, 1H), 7.85 (s, 1H), 8.14 (br, 1H), 8.25 (br, 1
H), 8.43 (s, 1H), 9.25 (d, J = 11Hz, 1H). IR (KBr) 3204, 3128, 1696, 1623, 1573, 1339, 127
3, 841, 757 cm -1 . MS (EI, 70eV) 150 (M + ).
【００１５】(２) ２−メチルアミノ−４,６−ジメチ
ルピリジンの製造 テトラヒドロフラン２Ｌを氷冷し８℃にした後、アルゴ
ン気流下で、水素化アルミニウムリチウム８８.８ｇを
５分間かけて投入した。投入終了後、氷浴を外し、室温
下で撹拌しながら、Ｎ−〔２−（４,６−ジメチル）ピ
リジル〕ホルムアミド２２６ｇのテトラヒドロフラン溶
液１.７Ｌを７５分間かけて滴下した。滴下後、室温下
で４５分間撹拌した後、氷冷し、水８９mL、１５％水酸
化ナトリウム水溶液８９mL、水２６７mLを順次滴下し
た。滴下後、氷浴中で１０分間撹拌し、析出した不溶物
を濾別し、テトラヒドロフラン５００mLで３回洗浄し
た。濾液を濃縮すると黄色オイル２４３ｇが得られ、こ
のオイルをトルエン７００mLに溶解した後、飽和食塩水
１Ｌで洗浄した。有機層を硫酸ナトリウムで乾燥後、濃
縮して、２−メチルアミノ−４,６−ジメチルピリジン
１９８ｇ（収率９７％）を得た。 b.p. 112〜114℃（８mmHg)。 m.p. 30〜40℃1 H NMR（500MHz, CDCl3) d 2.21(s,3H), 2.33(s,3H),
2.87(d,J=5Hz,3H), 4.53(bs,1H), 6.02(s,1H), 6.31(s,
1H)。 IR (KBr) 3256, 2920, 1614, 1577, 1472, 1415, 123
4, 809cm-1。 MS (EI, 70eV) 136(M+)。(2) Production of 2-methylamino-4,6-dimethylpyridine 2 L of tetrahydrofuran was ice-cooled to 8 ° C., and then 88.8 g of lithium aluminum hydride was added over 5 minutes under an argon stream. . After the addition was completed, the ice bath was removed, and 1.7 L of a tetrahydrofuran solution containing 226 g of N- [2- (4,6-dimethyl) pyridyl] formamide in tetrahydrofuran was added dropwise over 75 minutes while stirring at room temperature. After the dropping, the mixture was stirred at room temperature for 45 minutes, cooled with ice, and 89 mL of water, 89 mL of 15% sodium hydroxide aqueous solution, and 267 mL of water were sequentially added dropwise. After the dropping, the mixture was stirred for 10 minutes in an ice bath, the precipitated insoluble matter was filtered off, and washed with 500 mL of tetrahydrofuran three times. The filtrate was concentrated to obtain 243 g of a yellow oil, which was dissolved in 700 mL of toluene and then washed with 1 L of saturated saline. The organic layer was dried over sodium sulfate and then concentrated to obtain 198 g of 2-methylamino-4,6-dimethylpyridine (yield 97%). bp 112-114 ° C (8 mmHg). mp 30-40 ° C. 1 H NMR (500 MHz, CDCl 3 ) d 2.21 (s, 3H), 2.33 (s, 3H),
2.87 (d, J = 5Hz, 3H), 4.53 (bs, 1H), 6.02 (s, 1H), 6.31 (s,
1H). IR (KBr) 3256, 2920, 1614, 1577, 1472, 1415, 123
4, 809 cm -1 . MS (EI, 70eV) 136 (M + ).
【００１６】実施例 ２ (１) Ｎ−〔２−（３−メチル）ピリジル〕ホルムアミ
ドの製造 ２−アミノ−３−メチルピリジンを原料として用い、実
施例１(１)の方法に従って標題化合物を得た。 m.p. 140〜141℃。1 H NMR（500MHz, CDCl3) d 2.26(s,3H), 7.00(dd,J=4H
z,7Hz,1H), 7.48(d,J=7Hz,1H), 7.94(bs,1H), 8.15(d,J
=4Hz), 9.49(d,J=10Hz,1H)。 IR (KBr) 3232, 1691, 1588, 1461, 1404, 1288, 125
8, 792cm-1。 MS (EI, 70eV) 136(M+)。Example 2 (1) Preparation of N- [2- (3-methyl) pyridyl] formamide Using 2-amino-3-methylpyridine as a starting material, the title compound was obtained according to the method of Example 1 (1). It was mp 140-141 ° C. 1 H NMR (500MHz, CDCl3) d 2.26 (s, 3H), 7.00 (dd, J = 4H
z, 7Hz, 1H), 7.48 (d, J = 7Hz, 1H), 7.94 (bs, 1H), 8.15 (d, J
= 4Hz), 9.49 (d, J = 10Hz, 1H). IR (KBr) 3232, 1691, 1588, 1461, 1404, 1288, 125
8, 792 cm -1 . MS (EI, 70eV) 136 (M + ).
【００１７】(２) ２−メチルアミノ−３−メチルピリ
ジンの製造 Ｎ−〔２−（３−メチル）ピリジル〕ホルムアミドを原
料として用い、実施例１(２)の方法に従って標題化合物
を得た。 b.p. 82〜83℃（６mmHg)。1 H NMR（500MHz, CDCl3) d 2.07(s,3H), 3.04(d,J=5H
z,3H), 4.17(bs,1H), 6.50-6.53(m,1H), 7.19-7.21(m,1
H), 8.05(d,J=4Hz,1H)。 IR (neat) 3330, 2938, 1605, 1512, 1475, 1398, 118
7, 765cm-1。 MS (EI, 70eV) 122(M+)。(2) Preparation of 2-methylamino-3-methylpyridine Using N- [2- (3-methyl) pyridyl] formamide as a starting material, the title compound was obtained according to the method of Example 1 (2). bp 82-83 ° C (6 mmHg). 1 H NMR (500 MHz, CDCl 3 ) d 2.07 (s, 3H), 3.04 (d, J = 5H
z, 3H), 4.17 (bs, 1H), 6.50-6.53 (m, 1H), 7.19-7.21 (m, 1
H), 8.05 (d, J = 4Hz, 1H). IR (neat) 3330, 2938, 1605, 1512, 1475, 1398, 118
7, 765 cm -1 . MS (EI, 70eV) 122 (M + ).
【００１８】実施例 ３ (１) Ｎ−〔２−（４−メチル）ピリジル〕ホルムアミ
ドの製造 ２−アミノ−４−メチルピリジンを原料として用い、実
施例１(１)の方法に従って標題化合物を得た。 m.p. 88〜89℃。1 H NMR（500MHz, CDCl3) d 2.36(s,3H), 2.39(s,3H),
6.70(s,1H), 6.89-6.93(m,1H), 8.08(s,1H), 8.17(d,J=
5Hz,1H), 8.49(s,1H), 9.29(d,J=11Hz,1H), 9.05(bs,1
H;H). IR (KBr) 2816, 1699, 1616, 1583, 1426, 1299, 119
5, 819cm-1。 MS (EI, 70eV) 136(M+)。Example 3 (1) Preparation of N- [2- (4-methyl) pyridyl] formamide Using 2-amino-4-methylpyridine as a starting material, the title compound was obtained according to the method of Example 1 (1). It was mp 88-89 ° C. 1 H NMR (500 MHz, CDCl 3 ) d 2.36 (s, 3H), 2.39 (s, 3H),
6.70 (s, 1H), 6.89-6.93 (m, 1H), 8.08 (s, 1H), 8.17 (d, J =
5Hz, 1H), 8.49 (s, 1H), 9.29 (d, J = 11Hz, 1H), 9.05 (bs, 1
H; H) .IR (KBr) 2816, 1699, 1616, 1583, 1426, 1299, 119
5, 819 cm -1 . MS (EI, 70eV) 136 (M + ).
【００１９】(２) ２−メチルアミノ−４−メチルピリ
ジンの製造 Ｎ−〔２−（４−メチル）ピリジル〕ホルムアミドを原
料として用い、実施例１(２)の方法に従って標題化合物
を得た。 b.p. 92〜93℃（6 mmHg）.1 H NMR（500MHz, CDCl3) d 2.24(s,3H), 2.89(d,J=5H
z,3H), 4.57(bs,1H), 6.20(s,1H), 6.41(d,J=5Hz,1H),
7.95(d,J=5Hz,1H)。 IR (neat) 3262, 2898, 1617, 1522, 1413, 1292, 118
5, 798cm-1。 MS (EI, 70eV) 122(M+)。(2) Preparation of 2-methylamino-4-methylpyridine Using N- [2- (4-methyl) pyridyl] formamide as a starting material, the title compound was obtained according to the method of Example 1 (2). bp 92-93 ° C (6 mmHg). 1 H NMR (500 MHz, CDCl 3 ) d 2.24 (s, 3H), 2.89 (d, J = 5H
z, 3H), 4.57 (bs, 1H), 6.20 (s, 1H), 6.41 (d, J = 5Hz, 1H),
7.95 (d, J = 5Hz, 1H). IR (neat) 3262, 2898, 1617, 1522, 1413, 1292, 118
5, 798 cm -1 . MS (EI, 70eV) 122 (M + ).
【００２０】実施例 ４ (１) Ｎ−〔２−（５−メチル）ピリジル〕ホルムアミ
ドの製造 ２−アミノ−５−メチルピリジンを原料として用い、実
施例１(１)の方法に従って標題化合物を得た。 m.p. 121〜122℃。1 H NMR（500MHz, CDCl3) d 2.31(s.3H), 6.80(d,J=8H
z,1H), 7.49(dd,J=1Hz,8Hz,1H), 7.54(dd,J=2Hz,8Hz,1
H), 8.11(d,J=8Hz,1H), 8.12(s,1H), 8.14(s,1H), 8.64
(bs,1H), 8.47(d,J=1Hz,1H), 9.23(d,J=11Hz,1H)。 IR (KBr) 2970, 1695, 1680, 1603, 1542, 1422, 130
6, 831cm-1。 MS (EI, 70eV) 136(M+)。Example 4 (1) Preparation of N- [2- (5-methyl) pyridyl] formamide Using 2-amino-5-methylpyridine as a starting material, the title compound was obtained according to the method of Example 1 (1). It was mp 121-122 ° C. 1 H NMR (500MHz, CDCl 3 ) d 2.31 (s.3H), 6.80 (d, J = 8H
z, 1H), 7.49 (dd, J = 1Hz, 8Hz, 1H), 7.54 (dd, J = 2Hz, 8Hz, 1
H), 8.11 (d, J = 8Hz, 1H), 8.12 (s, 1H), 8.14 (s, 1H), 8.64
(bs, 1H), 8.47 (d, J = 1Hz, 1H), 9.23 (d, J = 11Hz, 1H). IR (KBr) 2970, 1695, 1680, 1603, 1542, 1422, 130
6, 831 cm -1 . MS (EI, 70eV) 136 (M + ).
【００２１】(２) ２−メチルアミノ−５−メチルピリ
ジンの製造 Ｎ−〔２−（５−メチル）ピリジル〕ホルムアミドを原
料として用い、実施例１(２)の方法に従って標題化合物
を得た。 b.p. 92〜93℃（６mmHg)。1 H NMR（500MHz, CDCl3) d 2.17(s,3H), 2.88(d,J=5H
z,3H), 4.47(bs,1H), 6.32(d,J=9Hz,1H), 7.25-7.27(m,
1H), 7.92(d,J=1Hz,1H)。 IR (neat) 3268, 2922, 1621, 1519, 1376, 1291, 816
cm-1。 MS (EI, 70eV) 122(M+)。(2) Preparation of 2-methylamino-5-methylpyridine Using N- [2- (5-methyl) pyridyl] formamide as a starting material, the title compound was obtained according to the method of Example 1 (2). bp 92-93 ° C (6 mmHg). 1 H NMR (500 MHz, CDCl 3 ) d 2.17 (s, 3H), 2.88 (d, J = 5H
z, 3H), 4.47 (bs, 1H), 6.32 (d, J = 9Hz, 1H), 7.25-7.27 (m,
1H), 7.92 (d, J = 1Hz, 1H). IR (neat) 3268, 2922, 1621, 1519, 1376, 1291, 816
cm -1 . MS (EI, 70eV) 122 (M + ).
【００２２】実施例 ５ (１) Ｎ−〔２−（６−メチル）ピリジル〕ホルムアミ
ドの製造 ２−アミノ−６−メチルピリジンを原料として用い、実
施例１(１)の方法に従って標題化合物を得た。 m.p. 79〜80℃。1 H NMR（500MHz, CDCl3) d 2.47(s,3H), 2.48(s,3H),
6.65(d,J=8Hz,1H), 6.92(d,J=8Hz,1H), 6.94(d,J=8Hz,1
H), 7.54(t,J=8Hz,1H), 7.62(t,J=8Hz,1H), 8.00(d,J=8
Hz,1H), 8.21(bs,1H), 8.46(s,1H), 9.29(d,J=11Hz,1
H)。 IR (KBr) 3100, 1691, 1577, 1443, 1304, 1269, 116
1, 785cm-1。 MS (EI, 70eV) 136(M+)。Example 5 (1) Preparation of N- [2- (6-methyl) pyridyl] formamide Using 2-amino-6-methylpyridine as a starting material, the title compound was obtained according to the method of Example 1 (1). It was mp 79-80 ° C. 1 H NMR (500 MHz, CDCl 3 ) d 2.47 (s, 3H), 2.48 (s, 3H),
6.65 (d, J = 8Hz, 1H), 6.92 (d, J = 8Hz, 1H), 6.94 (d, J = 8Hz, 1
H), 7.54 (t, J = 8Hz, 1H), 7.62 (t, J = 8Hz, 1H), 8.00 (d, J = 8
Hz, 1H), 8.21 (bs, 1H), 8.46 (s, 1H), 9.29 (d, J = 11Hz, 1
H). IR (KBr) 3100, 1691, 1577, 1443, 1304, 1269, 116
1, 785 cm -1 . MS (EI, 70eV) 136 (M + ).
【００２３】(２) ２−メチルアミノ−６−メチルピリ
ジンの製造 Ｎ−〔２−（６−メチル）ピリジル〕ホルムアミドを原
料として用い、実施例１(2）の方法に従って標題化合物
を得た。 b.p. 78〜79℃（６mmHg)。1 H NMR（500MHz, CDCl3) d 2.37(s,3H), 2.89(d,J=5H
z,3H), 4.54(bs,1H), 6.19(d,J=8Hz,1H), 6.45(d,J=7H
z,1H), 7.34-7.38(m,1H)。 IR (neat) 3264, 2908, 1601, 1472, 1428, 1334, 115
7, 779cm-1。 MS (EI, 70eV) 122(M+)。(2) Preparation of 2-methylamino-6-methylpyridine Using N- [2- (6-methyl) pyridyl] formamide as a starting material, the title compound was obtained according to the method of Example 1 (2). bp 78 to 79 ° C (6 mmHg). 1 H NMR (500 MHz, CDCl 3 ) d 2.37 (s, 3H), 2.89 (d, J = 5H
z, 3H), 4.54 (bs, 1H), 6.19 (d, J = 8Hz, 1H), 6.45 (d, J = 7H
z, 1H), 7.34-7.38 (m, 1H). IR (neat) 3264, 2908, 1601, 1472, 1428, 1334, 115
7,779 cm -1 . MS (EI, 70eV) 122 (M + ).
Claims (1)
す）で表されるアミノピリジン誘導体を、酢酸−ギ酸混
合酸無水物と反応させるか、又は無水酢酸の存在下にギ
酸と反応させて、一般式(II) 【化２】 （式中、Ｒおよびｎは上記と同じ意味を有する）で表さ
れるホルムアミド誘導体とし、次いで還元することを特
徴とする、一般式(III) 【化３】 （式中、Ｒおよびｎは上記と同じ意味を有する）で表さ
れるメチルアミノピリジン誘導体の製造方法。1. A compound represented by the general formula (I): (Wherein R represents a C 1 -C 4 alkyl group, n represents 1 or 2), an aminopyridine derivative is reacted with acetic acid-formic acid mixed acid anhydride, or in the presence of acetic anhydride. The compound of the general formula (II): Wherein a formamide derivative represented by the formula (wherein R and n have the same meanings as described above), and then the compound is reduced to a general formula (III): (In the formula, R and n have the same meanings as described above) A method for producing a methylaminopyridine derivative.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP00823195A JP3484248B2 (en) | 1995-01-23 | 1995-01-23 | Method for synthesizing methylaminopyridine derivative |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP00823195A JP3484248B2 (en) | 1995-01-23 | 1995-01-23 | Method for synthesizing methylaminopyridine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH08198851A true JPH08198851A (en) | 1996-08-06 |
| JP3484248B2 JP3484248B2 (en) | 2004-01-06 |
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ID=11687395
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP00823195A Expired - Fee Related JP3484248B2 (en) | 1995-01-23 | 1995-01-23 | Method for synthesizing methylaminopyridine derivative |
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| Country | Link |
|---|---|
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1995
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