JPWO2002085858A1 - Method for producing purified piperidine derivative - Google Patents
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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Abstract
本発明は、特殊な試薬や装置を必要とせず、短工程かつ簡便な操作で、医農薬中間体または原体として有用な精製されたピペリジン誘導体、ピリジン誘導体、キノリン誘導体を製造する。すなわち、本発明では、水に不溶性または難溶性である上記誘導体を酸性条件で媒体に溶解させて塩を形成させ、つぎに該溶液を塩基性条件にすることによって目的物を析出させる。The present invention produces a purified piperidine derivative, a pyridine derivative, and a quinoline derivative useful as a pharmaceutical or agricultural chemical intermediate or a drug substance by a short process and simple operation without requiring special reagents or equipment. That is, in the present invention, the above-mentioned derivative, which is insoluble or hardly soluble in water, is dissolved in a medium under acidic conditions to form a salt, and then the solution is made basic to precipitate the desired product.
Description
＜技術分野＞
本発明は、医農薬中間体または原体として有用な精製されたピペリジン誘導体の製造方法に関する。
＜背景技術＞
ピペリジン誘導体の一般的な単離精製法としては、再結晶法がある。また、他の方法として、蒸留法やシリカゲルカラムクロマトグラフ法等がある。
水に難溶性のピペリジン誘導体を水から再結晶する方法は、再結晶できる結晶の量が少なく効率的でない。また、有機溶媒の溶液から再結晶をする方法では、結晶化するまでの時間が一般には長く、工業的に実施する場合には問題がある。また、有機溶媒が結晶中に残留する問題もある。
さらに有機溶媒や水への溶解性を向上させるために、酸性条件で高濃度のピペリジン誘導体溶液を形成させ、該溶液から再結晶する方法もありうるが、該方法では、結晶化前のピペリジン誘導体溶液に含まれる可溶性の不純物を取り込んで結晶化する問題がある。さらに不純物が、ごく微量で結晶を着色させる可溶性成分である場合には、得られた結晶の純度が高くても結晶に着色が認められる問題がある。ピペリジン誘導体は、種々の医薬高次中間体や医薬原体としても利用されるため、人体に投与する最終製剤に、不純物に基づく着色成分が残留することは、問題になる。
この問題を解決する方法としては、蒸留法またはシリカゲルカラムクロマトグラフ法等がある。しかし、ピペリジン誘導体が高沸点である場合には、蒸留法を採用できない。また蒸留法を採用できても、蒸留中に目的とするピペリジン誘導体が分解して、回収率が低下する問題がある。また、蒸留法では、着色成分を必ずしも有効に除去できない問題がある。
また、シリカゲルカラムクロマトグラフ法で大量の精製を実施する場合には、膨大な量のシリカゲルと展開用の有機溶媒が必要である。使用したシリカゲルは再生が困難であり、大量の産業廃棄物が発生する、コスト高になる等の問題がある。また、シリカゲルクロマトグラフ法による単位時間あたりの精製量は、再結晶や蒸留と比較した場合に少ない問題もあり、工業的スケールでの採用は効率的ではない。
＜発明の開示＞
本発明は、従来の技術の欠点を解決する目的でなされたものであり、工業的に容易かつ効率的に実施でき、かつ、環境上の問題なく低コストで実施できる、精製されたピペリジン誘導体の製造方法を提供する。
すなわち本発明は、水に不溶性または水に難溶性であるピペリジン誘導体を酸性条件で媒体に溶解させて溶液を形成させ、つぎに該溶液を塩基性条件にすることによってピペリジン誘導体を析出させることを特徴とする精製されたピペリジン誘導体の製造方法を提供する。
＜発明を実施するための最良の形態＞
本発明におけるピペリジン誘導体は、ピペリジン環を基本とする環構造を基本骨格とする化合物をいう。ピペリジン環を基本とする環構造としては、ピペリジン環、ピペリジン環の炭素−炭素結合の１以上が不飽和結合になった環構造（例えば、ピリジン環等）が挙げられる。またピペリジン環を基本骨格とする環構造は、縮合環を形成する環の１つであってもよい。該縮合環としては、たとえば、キノリン環、またはナフチリジン環などが挙げられる。さらにこれらの環を形成する炭素原子には、水素原子または置換基が結合しているのが好ましい。
置換基としては、酸や塩基に不活性な置換基から選択され、ハロゲン原子、水酸基、アミノ基、アルキル基、シクロアルキル基、アルケニル基、アリール基、チオアルキル基、ニトロ基、およびシアノ基から選ばれる１種以上の置換基が例示できる。また、環を形成する炭素原子は、オキソ基（Ｃ＝Ｏ）となっていてもよい。ここでハロゲン原子としては、フッ素原子、塩素原子、臭素原子、またはヨウ素原子から選ばれる１種以上である。
本発明におけるピペリジン誘導体としては、ピペリジン系化合物、ピリジン系化合物、ピリドン系化合物、またはナフチリジン系化合物等が挙げられる。好適な例として、３−（フェニルエチニル）ピリジン−Ｎ−オキシド、１−メチル−３，４−ジフルオロ−２−キノロンなどの他、特に着色しやすい問題を有することから、５−メチル−１−フェニル−２（１Ｈ）ピリドンであるのが好ましい。
このようなピペリジン誘導体の入手経路は特に限定されず、市販品であってもよく製造後の粗生成物等でもよい。また、精製前のピペリジン誘導体は純度が９０質量％以上であるのが好ましい。また、該ピペリジン誘導体は着色成分を含んでいてもよい。着色成分による着色の程度は、実施例中に記載する黄色度の測定方法で測定した場合に、２０超６０以下であるのが好ましい。たとえば本発明の方法を、着色成分を含むピペリジン誘導体に適用した場合には、該着色成分を実質的に含まない無着色のピペリジン誘導体を得ることができる。
本発明におけるピペリジン誘導体は、水に不溶性または水に難溶性である。本発明において水に不溶性または難溶性とは、２０℃において測定した場合に、対象となるピペリジン誘導体１ｇを溶解させるのに必要な水の量が３０ｍＬ以上であることをいい、該水の量が７０ｍＬ以上であるのが好ましく、特に１００ｍＬ以上であるのが好ましい。
本発明においては、水に不溶性または水に難溶性のピペリジン誘導体を酸性条件で媒体に溶解させて溶液にする。酸性条件とはｐＨが６以下であることをいい、本発明においてはｐＨが４以下であるのが好ましい。
本発明においては、有機酸および無機酸から選ばれる１種以上の酸を媒体中に含ませて酸性条件にするのが好ましい。酸としては、酢酸、ギ酸、トリフルオロ酢酸、トリクロロ酢酸、安息香酸、酒石酸、リンゴ酸、シュウ酸、塩酸、硫酸、硝酸、およびリン酸から選ばれる１種以上の酸が好ましく、酢酸、塩酸、または硫酸が特に好ましい。また、ピペリジン誘導体が医薬用途である場合には、食品添加物に指定される酸のうち、酢酸、安息香酸、シュウ酸、リンゴ酸、塩酸、硫酸、およびリン酸から選ばれる酸を使用するのが好ましい。該酸はそのままを用いてもよく、溶液にして用いてもよい。溶液にする場合には、酸以外の媒体、の溶液にするのが好ましく、エタノール、トルエン、酢酸エチル、または水の溶液にするのが特に好ましく、水溶液にするのがとりわけ好ましい。酸の溶液とする場合の酸の濃度は、１〜５０質量％が好ましく、特に３〜３０質量％が好ましい。
本発明における媒体としては、酸自体が液状である場合には、該酸を媒体としてもよいが、酸以外の媒体を用いるのが通常であり好ましい。酸以外の媒体としては、水および／または有機溶媒が好ましい。
有機溶媒としては、メタノール、エタノール、イソプロピルアルコール等のアルコール系溶媒、酢酸エチル、酢酸ｎ−ブチル等のエステル系溶媒、トルエン、キシレン、シクロヘキサン、ｎ−ヘキサン等の炭化水素系溶媒、ジクロロメタン、クロロホルム、クロロベンゼン等のハロゲン化炭化水素系溶媒、ジエチルエーテル、ジイソプロピルエーテル、メチル−ｔｅｒｔ−ブチルエーテル、テトラヒドロフラン、ジオキサン等のエーテル系溶媒、アセトニトリル等のニトリル系溶媒等が挙げられる。媒体としては、残留時の問題が少ないことから水が好ましい。
本発明においては、ピペリジン誘導体を酸性条件で媒体に溶解させて溶液にする。ピペリジン誘導体は、実質的に全てが媒体に溶解するのが好ましいが、一部のピペリジン誘導体が媒体と相分離していてもよい。ピペリジン誘導体の実質的に全てを媒体に溶解させるためには、媒体が酸のみである場合には、ピペリジン誘導体に対して酸を０．５〜５０倍質量使用するが好ましく、特に１〜１０倍質量使用するのが好ましい。また、媒体が酸の溶液である場合には、該溶液をピペリジン誘導体に対して２〜２０倍質量使用するのが好ましく、特に２〜１２倍質量が好ましい。
ピペリジン誘導体を酸性条件で媒体に溶解させる際には、−２０℃〜＋１５０℃にするのが好ましく、特に室温〜＋１２０℃にするのが好ましい。圧力は特に限定されず、通常は大気圧とするのが好ましい。また必要に応じて加熱や撹拌等をしてもよい。また、固体状の不純物が存在する場合には、ピペリジン誘導体の酸性溶液をろ過しておくのが好ましい。
つぎに本発明においては、ピペリジン誘導体の酸性溶液を塩基性条件にする。塩基性条件とは、ｐＨが８以上であることをいい、本発明においてはｐＨが１１以上であるのが好ましい。
塩基性条件にする方法としては、酸性溶液中に有機塩基および無機塩基から選ばれる１種以上の塩基、または該選ばれる塩基の溶液を含ませるのが好ましい
塩基としては、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、リン酸２水素カリウム、リン酸２水素ナトリウム、ピリジン、トリエチルアミン、ジイソプロピルエチルアミン、１，８−ジアザビジクロ［５，４，０］ウンデカ−７−エン、または１，５−ジアザビジクロ［４，３，０］ノナ−５−エンが好ましく、水酸化ナトリウム、炭酸ナトリウムが特に好ましい。また、ピペリジン誘導体が医薬用途である場合には、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、または炭酸カリウムが特に好ましい。
本発明においては、塩基は、そのままを酸性溶液中に含ませてもよいが、塩基の溶液として含ませるのが好ましい。塩基を溶液とする場合には、水または前述の酸以外の媒体を用いて溶液にするのが好ましく、特に水溶液にするのが好ましい。塩基の溶液にする場合の濃度は、１〜５０質量％が好ましく、特に３〜３０質量％が好ましい。
ピペリジン誘導体の酸性溶液を塩基性にする際には、−２０℃〜＋１２０℃にするのが好ましく、特に操作性の面で室温〜＋１００℃にするのが好ましい。また、圧力は特に限定されず、通常は大気圧とするのが好ましい。塩基の量は、塩基性が上記の範囲になるような量であり、適宜変更されうる。
本発明においては、ピペリジン誘導体の酸性溶液を塩基性にすることにより、該誘導体を析出させる。ピペリジン誘導体は、それ自体が塩基性であるため、塩基性条件にすると溶解性が低下して析出するが、析出しにくい場合には、ｐＨを高くする、溶液を低温にする等の操作を行ってもよい。また、結晶として析出させる場合には、種となる結晶を添加してもよい。さらに本発明における塩基性条件で析出させる方法は、結晶化に必要な時間を顕著に短縮させるだけではなく、仮に精製前の結晶が着色成分を含んでいたとしても、該着色成分をとりこむことなく、着色がないピペリジン誘導体の結晶として得ることができる。着色成分は、通常の場合には、結晶を分離した母液中に残留する。
析出したピペリジン誘導体は、通常の濾過、洗浄処理、および乾燥等の後処理を行うのが好ましい。さらに必要に応じて、析出したピペリジン誘導体を粉砕してもよい。本発明方法により得られる精製されたピペリジン誘導体は、通常は純度が９９．０〜１００．０％程度の高純度であり、かつ、黄色度は２０以下、好ましくは１０以下となる。着色成分を含むピペリジン誘導体と、精製されたピペリジン誘導体との黄色度の差は、５以上であるのが好ましい。該精製されたピペリジン誘導体は、種々の医薬高次中間体や医薬原体として有用に用いられる。
本発明においては、酸性条件のピペリジン誘導体溶液が入った容器に塩基を加えるのが好ましい。該方法によれば、一つの容器を使用するだけでよく、操作の点からも効率的である。
実施例
以下に実施例を示して、本発明をさらに詳しく説明するが、本発明はこれらに限定されない。なお、実施例における黄色度は以下の方法で測定した値であり、該値が０に近づくほど、無着色であることを示す。通常の場合、結晶は光散乱があるため、０に近づくほど白色として観察される。
本発明の黄色度の測定は、ＪＩＳ Ｋ７１０３に規定される黄色度試験法に準じて行った。試料を直径５５ｍｍの石英容器に高さ１０ｍｍになるように一面に敷き詰め、色差計（ミノルタ社製ＣＲ３１０）を用い、標準光ＣによりＹｘｙ表色系による色彩測定を行った。測定結果を三刺激値ＸＹＺに換算した後、ＪＩＳ Ｋ７１０３，６．１黄色度に規定される式［黄色度＝１００（１．２８Ｘ−１．０６Ｚ）／Ｙ］により黄色度を算出した。
［実施例１］
撹拌器、内温計、ジムロート、滴下ロートを備えた１Ｌのフラスコに、淡茶色（黄色度２１．３５）の５−メチル−１−フェニル−２（１Ｈ）ピリドン（５２．６２ｇ）を入れ、つぎに５％酢酸（４８７．９２ｇ）を加えて、９０℃で加熱溶解させた。この酸性溶液に２５％水酸化ナトリウム水溶液を、該溶液のｐＨが１３になるまで滴下した後に５℃まで冷却し、４時間保持した後、濾別した。充分に水洗した後に乾燥し、白色粉末状（黄色度８．２７）の５−メチル−１−フェニル−２（１Ｈ）ピリドンを８４％の回収率で得た。
［実施例２］
撹拌器、内温計、ジムロート、滴下ロートを備えた１０Ｌのセパラブルフラスコに、淡茶色（黄色度２３）の５−メチル−１−フェニル−２（１Ｈ）ピリドン（５８３．１ｇ）を入れ、つぎに５％酢酸（５４６１ｇ）を加えて、９０℃で加熱溶解させた。この酸性溶液に２５％水酸化ナトリウム水溶液を、該溶液のｐＨが１３になるまで滴下した後に５℃まで冷却し、４．５時間保持した後、濾別した。充分に水洗した後に乾燥し、淡黄白色粉末状（黄色度１５．６８）の５−メチル−１−フェニル−２（１Ｈ）ピリドンを８３％の回収率で得た。
［実施例３］
撹拌器、内温計、ジムロート、滴下ロートを備えた５００ｍＬのフラスコに、茶色（黄色度５９．７３）の３−（フェニルエチニル）ピリジン−Ｎ−オキシド（３０．８５ｇ）を入れ、つぎに１０％酢酸（１５７．６４ｇ）を加えて、１００℃で加熱溶解させた。この酸性溶液に２５％水酸化ナトリウム水溶液を溶液のｐＨが１３になるまで滴下した後に０℃まで冷却し、６時間保持した。白色粉末状（黄色度９．２１）の３−（フェニルエチニル）ピリジン−Ｎ−オキシドを８９％の回収率で得た。
［実施例４］
撹拌器、内温計、ジムロート、滴下ロートを備えた１Ｌのフラスコに、黄色（黄色度４１．０８）の１−メチル−３，４−ジフルオロ−２−キノロン（４８．９１ｇ）を入れ、５％酢酸（４５４．８３ｇ）を加え、９０℃にて加熱溶解させた。この酸性溶液に２５％水酸化ナトリウム水溶液を溶液のｐＨが１３になるまで滴下した後に５℃まで冷却し、６時間保持した後、濾別した。充分に水洗した後に乾燥し、白色粉末状（黄色度８．４１）の１−メチル−３，４−ジフルオロ−２−キノロンを７９％の回収率で得た。
＜産業上の利用可能性＞
本発明の方法によれば、ピペリジン誘導体から短工程で、精製されたピペリジン誘導体を得ることができる。本発明の製造方法は、特別な反応条件や反応装置を用いることなしに実施でき、精製工程の回収率も高いことから、工業的な大容量の製造方法として有用な方法である。また、本発明の方法によれば、短工程で着色成分を効果的に除去でき、高品質の医農薬中間体または原体として有用な精製されたピペリジン誘導体を提供できる。<Technical field>
The present invention relates to a method for producing a purified piperidine derivative useful as a pharmaceutical or agricultural chemical intermediate or a drug substance.
<Background technology>
As a general isolation and purification method of a piperidine derivative, there is a recrystallization method. Other methods include a distillation method and a silica gel column chromatography method.
The method of recrystallizing a water-insoluble piperidine derivative from water is inefficient because the amount of recrystallizable crystals is small. Further, in the method of recrystallization from a solution of an organic solvent, the time until crystallization is generally long, and there is a problem when the method is carried out industrially. There is also a problem that the organic solvent remains in the crystal.
In order to further improve the solubility in an organic solvent or water, there may be a method of forming a piperidine derivative solution at a high concentration under acidic conditions and recrystallizing the solution.In this method, the piperidine derivative before crystallization may be used. There is a problem that crystallization is caused by taking in soluble impurities contained in the solution. Further, when the impurities are soluble components that color the crystals in a very small amount, there is a problem that the crystals are colored even if the obtained crystals have high purity. Since piperidine derivatives are also used as various higher pharmaceutical intermediates and drug substances, it is a problem that coloring components based on impurities remain in the final preparation to be administered to the human body.
Methods for solving this problem include a distillation method and a silica gel column chromatography method. However, when the piperidine derivative has a high boiling point, the distillation method cannot be adopted. Further, even if the distillation method can be adopted, there is a problem that the target piperidine derivative is decomposed during the distillation and the recovery rate is reduced. Further, the distillation method has a problem that the coloring components cannot always be effectively removed.
In addition, when a large amount of purification is performed by silica gel column chromatography, an enormous amount of silica gel and an organic solvent for development are required. The used silica gel is difficult to regenerate, and has a problem that a large amount of industrial waste is generated and the cost is increased. Further, the purification amount per unit time by the silica gel chromatography method has a problem that it is smaller than that of recrystallization or distillation, and its adoption on an industrial scale is not efficient.
<Disclosure of the Invention>
The present invention has been made for the purpose of solving the drawbacks of the prior art, and can be carried out industrially easily and efficiently, and can be carried out at low cost without environmental problems. A manufacturing method is provided.
That is, the present invention provides that a piperidine derivative that is insoluble or hardly soluble in water is dissolved in a medium under acidic conditions to form a solution, and then the solution is made basic to precipitate the piperidine derivative. A method for producing a purified piperidine derivative is provided.
<Best mode for carrying out the invention>
The piperidine derivative in the present invention refers to a compound having a ring structure based on a piperidine ring as a basic skeleton. Examples of the ring structure based on a piperidine ring include a piperidine ring, and a ring structure in which one or more carbon-carbon bonds of the piperidine ring are unsaturated bonds (for example, a pyridine ring and the like). The ring structure having a piperidine ring as a basic skeleton may be one of the rings forming a condensed ring. Examples of the fused ring include a quinoline ring and a naphthyridine ring. Further, it is preferable that a hydrogen atom or a substituent is bonded to carbon atoms forming these rings.
The substituent is selected from a substituent inert to an acid or a base, and is selected from a halogen atom, a hydroxyl group, an amino group, an alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a thioalkyl group, a nitro group, and a cyano group. One or more substituents can be exemplified. Further, the carbon atom forming the ring may be an oxo group (C = O). Here, the halogen atom is at least one selected from a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
Examples of the piperidine derivative in the present invention include piperidine compounds, pyridine compounds, pyridone compounds, naphthyridine compounds, and the like. Preferable examples include 3- (phenylethynyl) pyridine-N-oxide and 1-methyl-3,4-difluoro-2-quinolone. Preferably it is phenyl-2 (1H) pyridone.
The route of obtaining such a piperidine derivative is not particularly limited, and may be a commercially available product or a crude product after production. Further, the purity of the piperidine derivative before purification is preferably 90% by mass or more. Further, the piperidine derivative may contain a coloring component. The degree of coloring by the coloring component is preferably more than 20 and 60 or less as measured by the method for measuring yellowness described in the examples. For example, when the method of the present invention is applied to a piperidine derivative containing a coloring component, an uncolored piperidine derivative substantially not containing the coloring component can be obtained.
The piperidine derivative in the present invention is insoluble or poorly soluble in water. In the present invention, insoluble or poorly soluble in water means that the amount of water required to dissolve 1 g of the target piperidine derivative is 30 mL or more when measured at 20 ° C. It is preferably at least 70 mL, particularly preferably at least 100 mL.
In the present invention, a piperidine derivative insoluble in water or hardly soluble in water is dissolved in a medium under acidic conditions to form a solution. The acidic condition means that the pH is 6 or less, and in the present invention, the pH is preferably 4 or less.
In the present invention, it is preferred that one or more acids selected from organic acids and inorganic acids are contained in the medium to make the medium acidic. As the acid, one or more acids selected from acetic acid, formic acid, trifluoroacetic acid, trichloroacetic acid, benzoic acid, tartaric acid, malic acid, oxalic acid, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid are preferable, and acetic acid, hydrochloric acid, Or sulfuric acid is particularly preferred. Further, when the piperidine derivative is used for medicine, among acids specified as food additives, an acid selected from acetic acid, benzoic acid, oxalic acid, malic acid, hydrochloric acid, sulfuric acid, and phosphoric acid is used. Is preferred. The acid may be used as it is or may be used as a solution. When a solution is used, the solution is preferably a solution of a medium other than an acid, particularly preferably a solution of ethanol, toluene, ethyl acetate, or water, and particularly preferably an aqueous solution. When the acid solution is used, the concentration of the acid is preferably 1 to 50% by mass, and particularly preferably 3 to 30% by mass.
As the medium in the present invention, when the acid itself is in a liquid state, the acid may be used as the medium. However, it is usual and preferable to use a medium other than the acid. As a medium other than an acid, water and / or an organic solvent are preferable.
Examples of the organic solvent include alcohol solvents such as methanol, ethanol, and isopropyl alcohol; ester solvents such as ethyl acetate and n-butyl acetate; hydrocarbon solvents such as toluene, xylene, cyclohexane, and n-hexane; dichloromethane, chloroform; Examples thereof include halogenated hydrocarbon solvents such as chlorobenzene, ether solvents such as diethyl ether, diisopropyl ether, methyl-tert-butyl ether, tetrahydrofuran, and dioxane; and nitrile solvents such as acetonitrile. As the medium, water is preferable because there is little problem at the time of residual.
In the present invention, the piperidine derivative is dissolved in a medium under acidic conditions to form a solution. Preferably, substantially all of the piperidine derivative is dissolved in the medium, but some piperidine derivatives may be phase-separated from the medium. In order to dissolve substantially all of the piperidine derivative in the medium, when the medium is an acid alone, it is preferable to use 0.5 to 50 times by mass of the acid with respect to the piperidine derivative, particularly 1 to 10 times. It is preferred to use mass. When the medium is an acid solution, the solution is preferably used in an amount of 2 to 20 times, more preferably 2 to 12 times the mass of the piperidine derivative.
When the piperidine derivative is dissolved in a medium under acidic conditions, the temperature is preferably from -20 ° C to + 150 ° C, particularly preferably from room temperature to + 120 ° C. The pressure is not particularly limited, and is usually preferably atmospheric pressure. Moreover, you may heat and stir etc. as needed. When solid impurities are present, it is preferable to filter the acidic solution of the piperidine derivative.
Next, in the present invention, the acidic solution of the piperidine derivative is made basic. The basic condition means that the pH is 8 or more, and in the present invention, the pH is preferably 11 or more.
As a method for setting the basic conditions, one or more bases selected from an organic base and an inorganic base in an acidic solution, or a base preferably containing a solution of the selected base is preferably sodium hydroxide, hydroxide or the like. Potassium, sodium carbonate, potassium carbonate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, pyridine, triethylamine, diisopropylethylamine, 1,8-diazabidiclo [5,4,0] undec-7-ene, or 1,5- Diazabidicro [4,3,0] non-5-ene is preferred, and sodium hydroxide and sodium carbonate are particularly preferred. When the piperidine derivative is used for medicine, sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate is particularly preferable.
In the present invention, the base may be directly contained in the acidic solution, but is preferably contained as a solution of the base. When a base is used as a solution, the solution is preferably formed using water or a medium other than the above-described acid, and particularly preferably an aqueous solution. The concentration of the base solution is preferably from 1 to 50% by mass, more preferably from 3 to 30% by mass.
When making the acidic solution of the piperidine derivative basic, the temperature is preferably from -20 ° C to + 120 ° C, and particularly preferably from room temperature to + 100 ° C in terms of operability. Further, the pressure is not particularly limited, and it is usually preferable that the pressure is atmospheric pressure. The amount of the base is such that the basicity falls within the above range, and can be appropriately changed.
In the present invention, the acidic solution of the piperidine derivative is made basic to precipitate the derivative. Since the piperidine derivative itself is basic, the solubility is reduced under basic conditions and precipitates.However, when precipitation is difficult, operations such as increasing the pH and lowering the temperature of the solution are performed. You may. In the case where crystals are precipitated as crystals, seed crystals may be added. Furthermore, the method of precipitating under basic conditions in the present invention not only significantly shortens the time required for crystallization, but even if the crystal before purification contains a coloring component, without incorporating the coloring component. Can be obtained as crystals of the piperidine derivative without coloring. The coloring component usually remains in the mother liquor from which the crystals have been separated.
The precipitated piperidine derivative is preferably subjected to ordinary post-treatments such as filtration, washing, and drying. If necessary, the precipitated piperidine derivative may be pulverized. The purified piperidine derivative obtained by the method of the present invention usually has a high purity of about 99.0 to 100.0% and a yellowness of 20 or less, preferably 10 or less. The difference in yellowness between the piperidine derivative containing a coloring component and the purified piperidine derivative is preferably 5 or more. The purified piperidine derivative is usefully used as various high-order intermediates of pharmaceuticals and drug substances.
In the present invention, it is preferable to add a base to a container containing a piperidine derivative solution under acidic conditions. According to the method, only one container needs to be used, and the operation is efficient.
Examples Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. The yellowness in the examples is a value measured by the following method, and the closer the value is to 0, the more colorless. In a normal case, the crystal is observed as white as it approaches 0 because of light scattering.
The yellowness of the present invention was measured according to the yellowness test method specified in JIS K7103. The sample was laid all over a quartz container having a diameter of 55 mm so as to have a height of 10 mm, and color measurement was performed using a color difference meter (CR310, manufactured by Minolta Co., Ltd.) using a standard light C and a Yxy color system. After converting the measurement results into tristimulus values XYZ, the yellowness was calculated by the formula [yellowness = 100 (1.28X-1.06Z) / Y] defined in JIS K7103, 6.1 Yellowness.
[Example 1]
Into a 1 L flask equipped with a stirrer, an internal thermometer, a Dimroth funnel, and a dropping funnel, 5-methyl-1-phenyl-2 (1H) pyridone (52.62 g) of light brown (yellowness 21.35) was put, Next, 5% acetic acid (487.92 g) was added and dissolved by heating at 90 ° C. A 25% aqueous sodium hydroxide solution was added dropwise to the acidic solution until the pH of the solution reached 13, then cooled to 5 ° C., kept for 4 hours, and filtered. After sufficiently washing with water, the product was dried to obtain 5-methyl-1-phenyl-2 (1H) pyridone as a white powder (yellowness: 8.27) with a recovery of 84%.
[Example 2]
In a 10 L separable flask equipped with a stirrer, internal thermometer, Dimroth, and dropping funnel, 5-methyl-1-phenyl-2 (1H) pyridone (583.1 g) of light brown (yellowness: 23) was put, Next, 5% acetic acid (5461 g) was added and dissolved by heating at 90 ° C. A 25% aqueous sodium hydroxide solution was added dropwise to the acidic solution until the pH of the solution reached 13, then cooled to 5 ° C, kept for 4.5 hours, and filtered. After sufficiently washing with water, drying was performed to obtain 5-methyl-1-phenyl-2 (1H) pyridone as a pale yellowish white powder (yellowness 15.68) with a recovery of 83%.
[Example 3]
A 500 mL flask equipped with a stirrer, an internal thermometer, a Dimroth funnel, and a dropping funnel was charged with brown (yellowness 59.73) 3- (phenylethynyl) pyridine-N-oxide (30.85 g). % Acetic acid (157.64 g) was added and dissolved by heating at 100 ° C. A 25% aqueous solution of sodium hydroxide was added dropwise to the acidic solution until the pH of the solution reached 13, then cooled to 0 ° C. and maintained for 6 hours. 3- (Phenylethynyl) pyridine-N-oxide in the form of a white powder (yellowness: 9.21) was obtained with a recovery of 89%.
[Example 4]
Yellow (yellowity 41.08) 1-methyl-3,4-difluoro-2-quinolone (48.91 g) was placed in a 1 L flask equipped with a stirrer, an internal thermometer, a Dim funnel, and a dropping funnel. % Acetic acid (454.83 g) was added and dissolved by heating at 90 ° C. A 25% aqueous sodium hydroxide solution was added dropwise to the acidic solution until the pH of the solution became 13, cooled to 5 ° C., kept for 6 hours, and filtered. After sufficiently washing with water, drying was performed to obtain 1-methyl-3,4-difluoro-2-quinolone as a white powder (yellowness: 8.41) with a recovery of 79%.
<Industrial applicability>
According to the method of the present invention, a purified piperidine derivative can be obtained in a short step from a piperidine derivative. The production method of the present invention can be carried out without using any special reaction conditions or reaction equipment, and has a high recovery rate in the purification step, and is therefore a useful method as an industrial large-capacity production method. Further, according to the method of the present invention, a coloring component can be effectively removed in a short step, and a purified piperidine derivative useful as a high-quality pharmaceutical or agricultural chemical intermediate or a drug substance can be provided.
Claims (10)
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| JP2001122855 | 2001-04-20 | ||
| JP2001122855 | 2001-04-20 | ||
| PCT/JP2002/003955 WO2002085858A1 (en) | 2001-04-20 | 2002-04-19 | Process for producing purified piperidine derivative |
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| DK1928454T3 (en) | 2005-05-10 | 2014-11-03 | Intermune Inc | PYRIDONE DERIVATIVES FOR MODULATING STRESS-ACTIVATED PROTEINKINATION SYSTEM |
| JP5627574B2 (en) | 2008-06-03 | 2014-11-19 | インターミューン， インコーポレイテッド | Compounds and methods for treating inflammatory and fibrotic diseases |
| TWI434833B (en) * | 2009-06-03 | 2014-04-21 | Intermune Inc | Improved method for synthesizing pirfenidone |
| CN102382043A (en) * | 2011-09-23 | 2012-03-21 | 安徽工业大学 | Purification method for yellowed pyridine |
| AR092742A1 (en) | 2012-10-02 | 2015-04-29 | Intermune Inc | ANTIFIBROTIC PYRIDINONES |
| RU2692485C2 (en) | 2014-04-02 | 2019-06-25 | Интермьюн, Инк. | Antifibrous pyridinones |
| US11066368B2 (en) | 2016-01-14 | 2021-07-20 | Laurus Labs Limited | Process for the preparation and particle size reduction of pirfenidone |
| CN112409246B (en) * | 2019-08-21 | 2023-04-07 | 北京凯因科技股份有限公司 | Crystal form of pirfenidone and preparation method thereof |
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| JPS57171940A (en) * | 1981-04-14 | 1982-10-22 | Sumitomo Chem Co Ltd | Purification and concentration of quaternary ammonium compound |
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