WO2002085858A1 - Process for producing purified piperidine derivative - Google Patents

Process for producing purified piperidine derivative Download PDF

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Publication number
WO2002085858A1
WO2002085858A1 PCT/JP2002/003955 JP0203955W WO02085858A1 WO 2002085858 A1 WO2002085858 A1 WO 2002085858A1 JP 0203955 W JP0203955 W JP 0203955W WO 02085858 A1 WO02085858 A1 WO 02085858A1
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Prior art keywords
piperidine derivative
solution
derivative
acid
piperidine
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PCT/JP2002/003955
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French (fr)
Japanese (ja)
Inventor
Tomoko Taniguchi
Kazuhiko Hayashi
Kazuya Oharu
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Asahi Glass Company, Limited
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Priority to JP2002583385A priority Critical patent/JPWO2002085858A1/en
Publication of WO2002085858A1 publication Critical patent/WO2002085858A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • 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.
  • the method of recrystallizing a water-insoluble piperidine derivative from water is inefficient because the amount of recrystallizable crystals is small.
  • the time until crystallization is generally long, and there is a problem when the method is industrially performed.
  • the organic solvent remains in the crystal.
  • Methods for solving this problem include a distillation method and a silica gel column chromatography method.
  • the distillation method cannot be used.
  • the desired piperidine There is a problem that the body is decomposed and the recovery rate decreases.
  • the distillation method has a problem that coloring components cannot always be effectively removed.
  • the present invention has been made for the purpose of solving the drawbacks of the conventional technology, and is a purified piperidine derivative that can be industrially easily and efficiently implemented, and that can be implemented at low cost without environmental problems. And a method for producing the same.
  • the present invention provides a piperidine derivative by dissolving a piperidine derivative that is insoluble or hardly soluble in water in a medium under an acidic condition to form a solution, and then subjecting the solution to a basic condition.
  • a method for producing a purified piberidine derivative which is characterized in that the derivative is precipitated.
  • the piperidine derivative in the present invention refers to a compound having a ring structure based on a piperidine ring as a basic skeleton.
  • the ring structure based on a piperidine ring include a piberidine ring and a ring structure in which at least one carbon-carbon bond of the piperidine ring is an unsaturated bond (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.
  • the condensed ring include a quinoline ring and a naphthyridine ring. Further form these rings It is preferable that a hydrogen atom or a substituent is bonded to the carbon atom.
  • the halogen atom is one or more selected from a fluorine atom, a chlorine atom, a bromine atom, and a iodine atom.
  • Examples of the piperidine derivative in the present invention include a piperidine compound, a pyridine compound, a pyridone compound, and a naphthyridine compound.
  • Preferable examples include 3- (phenylethynyl) pyridine-1-N-oxide, 1-methyl-3,4-difluoro-2-quinolone, and 5-methyl-111
  • Preferably it is phenyl-1 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.
  • an uncolored piperidine derivative containing substantially no coloring component can be obtained.
  • the piperidine derivative in the present invention is insoluble or hardly soluble in water.
  • the term "insoluble or poorly soluble in water” means that the amount of water required to dissolve 1 g of a target piperidine derivative is 3 OmL or more when measured at 20 ° C.
  • the amount of the water is preferably at least 7 O mL, particularly preferably at least 10 O mL.
  • 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.
  • one or more acids selected from organic acids and inorganic acids are contained in the medium to make the medium acidic.
  • 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.
  • the acid selected from acetic acid, benzoic acid, oxalic acid, malic acid, hydrochloric acid, sulfuric acid, and phosphoric acid among the acids specified as food additives is used. It is preferred to use.
  • the acid may be used as it is or may be used as a solution.
  • a solution is prepared, it 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.
  • the concentration of the acid is preferably 1 to 50% by mass, particularly preferably 3 to 30% by mass.
  • the acid when the acid itself is in a liquid state, the acid may be used as a medium, but a medium other than the acid is usually and preferably used.
  • a medium other than the acid water and Z or an organic solvent are preferable.
  • organic solvent examples 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; Examples include halogenated hydrocarbon solvents such as dichloromethane, chloroform, benzene, etc., ether solvents such as getyl ether, diisopropyl ether, methyl-tert-butyl ether, tetrahydrofuran, and dioxane, and nitrile solvents such as acetonitrile.
  • 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
  • the piperidine derivative is dissolved in a medium under acidic conditions to form a solution.
  • substantially all of the piperidine derivative is dissolved in the medium, but some piperidine derivatives may be phase-separated from the medium.
  • 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.
  • the temperature is preferably from 120 ° C to 150 ° C, particularly preferably from room temperature to + 120 ° C.
  • the pressure is not particularly limited, and is usually preferably atmospheric pressure. Heating and stirring may be performed as necessary.
  • solid impurities it is preferable to filter the acidic solution of the piperidine derivative.
  • the acidic solution of the piperidine derivative is made basic.
  • the basic condition means that pH is 8 or more, and in the present invention, pH is preferably 11 or more.
  • the basic conditions it is preferable to include one or more bases selected from organic bases and inorganic bases or a solution of the selected bases in an acidic solution.
  • bases selected from organic bases and inorganic bases or a solution of the selected bases in an acidic solution.
  • Potassium, sodium carbonate, potassium carbonate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, pyridine, triethylamine, diisopropylethylamine, 1,8-diazabidicro [5,4,0] Or 1,5-diazabidiclo [4,3,0] non-5-ene is preferred, and sodium hydroxide and sodium carbonate are particularly preferred.
  • sodium hydroxide, hydroxide hydroxide, sodium carbonate, or potassium carbonate is particularly preferable.
  • the base may be contained as it is in the acidic solution. Is preferably included as a solution.
  • the solution is preferably formed using water or a medium other than the aforementioned acids, 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.
  • the temperature is preferably from ⁇ 20 ° C. to 120 ° C., particularly from room temperature to + 100 ° C. in terms of operability. Is preferred.
  • the pressure is not particularly limited, and it is usually preferable to be atmospheric pressure.
  • the amount of the base is such that the basicity falls within the above range, and can be appropriately changed.
  • the piperidine derivative is precipitated by making the acidic solution of the piperidine derivative basic.
  • the piperidine derivative itself is basic, and its solubility is reduced under basic conditions to precipitate.However, if precipitation is difficult, increase the pH or lower the temperature of the solution. May be performed. In the case where crystals are precipitated as crystals, seed crystals may be added.
  • the method of precipitating under basic conditions in the present invention not only significantly reduces the time required for crystallization, but also incorporates the coloring component even if the crystal before purification contains the coloring component. And a non-colored piperidine derivative crystal.
  • 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 generally has a high purity of about 99.0 to 100%, and a yellowness of 20 or less, preferably 1% or less. It becomes 0 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 pyrididine derivative is usefully used as various higher intermediates of drugs and drug substances.
  • a base is added to a vessel containing a piperidine derivative solution under acidic conditions. Is preferably obtained. According to this method, only one container needs to be used, and it is efficient from the viewpoint of operation.
  • the yellowness in the examples is a value measured by the following method, and the closer to 0, the more uncolored. Normally, crystals are observed as white as they approach zero due to 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 the surface of a 55 mm diameter quartz container to a height of 10 mm, and color measurement was performed using a color difference meter (CR310, manufactured by Minolta Co., Ltd.) with the standard light C using the Yxy color system.
  • a color difference meter CR310, manufactured by Minolta Co., Ltd.
  • a purified piberidine derivative can be obtained from a piperidine derivative in a short step.
  • 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.
  • a colored 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.

Abstract

A process for producing a purified piperidine derivative, pyridine derivative, or quinoline derivative useful as an intermediate or starting material for medicines and agricultural chemicals through short steps and easy operations without necessitating a special reagent or apparatus. Any of those derivatives, which is insoluble or sparingly soluble in water, is dissolved in a medium under acidic conditions to form a salt, and the resultant solution is made basic to thereby precipitate the target compound.

Description

明 細 書  Specification
精製されたピペリジン誘導体の製造方法  Method for producing purified piperidine derivative
<技術分野 > <Technical field>
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ぺリジン誘導体 の製造方法に関する。 ぐ背景技術 >  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>
ピぺ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。  As a general isolation and purification method for piperidine derivatives, there is a recrystallization method. Other methods include distillation and silica gel column chromatography.
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。  The method of recrystallizing a water-insoluble piperidine derivative from water is inefficient because the amount of recrystallizable crystals is small. In addition, 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 industrially performed. There is also a problem that the organic solvent remains in the crystal.
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ぺ 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、 結晶化前のピぺ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。 ピぺリジン誘導体は、 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。  In order to further improve the solubility in an organic solvent or water, there may be a method of forming a high-concentration piperidine derivative solution under acidic conditions and recrystallization from the solution. There is a problem of taking in soluble impurities contained in the piperidine derivative solution and crystallization. Further, when the impurities are soluble components that cause coloring of the crystals in a very small amount, there is a problem that the coloring of the crystals is recognized even if the purity of the obtained crystals is high. Since the piperidine derivative is also used as a variety of higher-order intermediates or drug substances, it is a problem that the coloring components based on impurities remain in the final preparation to be administered to the human body.
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、 ピぺ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ぺリジン誘導 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。 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 used. Also, even if the distillation method can be adopted, the desired piperidine There is a problem that the body is decomposed and the recovery rate decreases. In addition, the distillation method has a problem that coloring components cannot always be effectively removed.
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、 膨大な量のシリ力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 晶ゃ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。 ぐ発明の開示〉  Also, when performing large-scale purification by silica gel column chromatography, an enormous amount of silica gel and an organic solvent for development are required. The silica gel used is difficult to regenerate, causing problems such as the generation of large amounts of industrial waste and the increase in cost. In addition, the purification amount per unit time by the silica gel chromatography method is smaller than that of recrystallization / distillation, and its use on an industrial scale is not efficient. Disclosure of the Invention>
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。  The present invention has been made for the purpose of solving the drawbacks of the conventional technology, and is a purified piperidine derivative that can be industrially easily and efficiently implemented, and that can be implemented at low cost without environmental problems. And a method for producing the same.
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 とによってピぺ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ベリジ ン誘導体の製造方法を提供する。 ぐ発明を実施するための最良の形態 >  That is, the present invention provides a piperidine derivative by dissolving a piperidine derivative that is insoluble or hardly soluble in water in a medium under an acidic condition to form a solution, and then subjecting the solution to a basic condition. Provided is a method for producing a purified piberidine derivative, which is characterized in that the derivative is precipitated. BEST MODE FOR CARRYING OUT THE INVENTION>
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。 ピぺリジン環を基本とする環構造としては、 ピベリジ ン環、 ピぺリジン環の炭素一炭素結合の 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。 またピぺ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。 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 piberidine ring and a ring structure in which at least one carbon-carbon bond of the piperidine ring is an unsaturated bond (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 condensed ring include a quinoline ring and a naphthyridine ring. Further form these rings It is preferable that a hydrogen atom or a substituent is bonded to the carbon atom.
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、 ァリール基、 チォアルキル基、 ニトロ基、 およびシァノ基から選ばれる 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、 ォキソ基 （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 ョゥ素原子から選ばれる 1種以上である。  Substituents are selected from those that are inert to acids and bases, and include halogen atoms, hydroxyl groups, amino groups, alkyl groups, cycloalkyl groups, alkenyl groups, aryl groups, thioalkyl groups, nitro groups, and cyano groups. And at least one substituent selected from the group consisting of: Further, the carbon atom forming the ring may be an oxo group (c = o). Here, the halogen atom is one or more selected from a fluorine atom, a chlorine atom, a bromine atom, and a iodine atom.
本発明におけるピぺリジン誘導体としては、 ピぺリジン系化合物、 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— （フエ二ルェチニル） ピリジン一 N—ォキシド、 1—メチルー 3， 4—ジフルオロー 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—メチル一 1一フエニル一 2 ( 1 H) ピリドンであるのが好ましい。 このようなピぺリジン誘導体の入手経路は特に限定されず、 市販品であつても よく製造後の粗生成物等でもよい。 また、 精製前のピぺリジン誘導体は純度が 9 0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、 2 0超 6 0以下であるのが好ましい。 たとえば本発明の 方法を、 着色成分を含むピぺ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。  Examples of the piperidine derivative in the present invention include a piperidine compound, a pyridine compound, a pyridone compound, and a naphthyridine compound. Preferable examples include 3- (phenylethynyl) pyridine-1-N-oxide, 1-methyl-3,4-difluoro-2-quinolone, and 5-methyl-111 Preferably it is phenyl-1 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 containing substantially no coloring component can be obtained.
本発明におけるピぺリジン誘導体は、 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、 2 0 °Cにおいて測定した場合に、 対 象となるピぺリジン誘導体 1 gを溶解させるのに必要な水の量が 3 O mL以上で あることをいい、 該水の量が 7 O mL以上であるのが好ましく、 特に 1 0 O mL 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 P Hが 6以下であることをいい、 本発明においては p Hが 4以下であるのが好ましい。 The piperidine derivative in the present invention is insoluble or hardly soluble in water. In the present invention, the term "insoluble or poorly soluble in water" means that the amount of water required to dissolve 1 g of a target piperidine derivative is 3 OmL or more when measured at 20 ° C. The amount of the water is preferably at least 7 O mL, particularly preferably at least 10 O 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.
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、 トリフルォロ 酢酸、 トリクロ口酢酸、 安息香酸、 酒石酸、 リンゴ酸、 シユウ酸、 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、 ピぺ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、 シユウ酸、 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、 酢酸ェチル、 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、 1〜5 0質量％が好ましく、 特に 3〜3 0質量％が好ましレ^ 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 Zまたは有機溶媒が好ましい。  In the present invention, it is preferable 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. In addition, when the piperidine derivative is used for medicine, the acid selected from acetic acid, benzoic acid, oxalic acid, malic acid, hydrochloric acid, sulfuric acid, and phosphoric acid among the acids specified as food additives is used. It is preferred to use. The acid may be used as it is or may be used as a solution. When a solution is prepared, it 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, 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 a medium, but a medium other than the acid is usually and preferably used. As a medium other than the acid, water and Z or an organic solvent are preferable.
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ァ ルコール系溶媒、 酢酸ェチル、 酢酸 n—ブチル等のエステル系溶媒、 トルエン、 キシレン、 シクロへキサン、 n—へキサン等の炭化水素系溶媒、 ジクロロメタン、 クロ口ホルム、 クロ口ベンゼン等のハロゲン化炭化水素系溶媒、 ジェチルエーテ ル、 ジイソプロピルエーテル、 メチルー t e r t —ブチルエーテル、 テトラヒド 口フラン、 ジォキサン等のエーテル系溶媒、 ァセトニトリル等の二トリル系溶媒 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。 ピぺリジン誘導体は、 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。 ピぺ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、 ピぺリジン 誘導体に対して酸を 0 . 5〜 5 0倍質量使用するが好ましく、 特に 1〜1 0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、 該溶液をピぺ リジン誘導体に対して 2〜2 0倍質量使用するのが好ましく、 特に 2〜1 2倍質 量が好ましい。 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; Examples include halogenated hydrocarbon solvents such as dichloromethane, chloroform, benzene, etc., ether solvents such as getyl ether, diisopropyl ether, methyl-tert-butyl ether, tetrahydrofuran, and dioxane, and nitrile solvents such as acetonitrile. Can be As a medium, water is preferable because there is little problem when remaining. In the present invention, the piperidine derivative is dissolved in a medium under acidic conditions to form a solution. You. 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 the mass of the acid relative to the piperidine derivative, It is particularly preferable to use 1 to 10 times the 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.
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、 一 2 0 °C〜十 1 5 0 °Cにするのが好ましく、 特に室温〜 + 1 2 0 °C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、 ピぺリジン誘導体 の酸性溶液をろ過しておくのが好ましい。  When the piperidine derivative is dissolved in a medium under acidic conditions, the temperature is preferably from 120 ° C to 150 ° C, particularly preferably from room temperature to + 120 ° C. The pressure is not particularly limited, and is usually preferably atmospheric pressure. Heating and stirring may be performed as necessary. When solid impurities are present, it is preferable to filter the acidic solution of the piperidine derivative.
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、 p Hが 8以上であることをいい、 本発明においては p Hが 1 1 以上であるのが好ましい。  Next, in the present invention, the acidic solution of the piperidine derivative is made basic. The basic condition means that pH is 8 or more, and in the present invention, pH is preferably 11 or more.
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、 炭酸力 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、 トリェチ ルァミン、 ジイソプロピルェチルァミン、 1， 8—ジァザビジクロ [ 5， 4 , 0 ] ゥンデ力一 7—ェン、 または 1 , 5—ジァザビジクロ [ 4 , 3 , 0 ] ノナ一 5—ェンが好ましく、 水酸化ナトリウム、 炭酸ナトリウムが特に好ましい。 また、 ピぺ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、 水酸化力リウ ム、 炭酸ナトリウム、 または炭酸カリウムが特に好ましい。  As a method for setting the basic conditions, it is preferable to include one or more bases selected from organic bases and inorganic bases or a solution of the selected bases in an acidic solution. Potassium, sodium carbonate, potassium carbonate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, pyridine, triethylamine, diisopropylethylamine, 1,8-diazabidicro [5,4,0] Or 1,5-diazabidiclo [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, hydroxide hydroxide, sodium carbonate, or potassium carbonate is particularly preferable.
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 レ 。 塩基の溶液にする場合の濃度は、 1〜5 0質量％が好ましく、 特に 3〜3 0 質量％が好ましい。 In the present invention, the base may be contained as it is in the acidic solution. Is preferably included as a solution. When the base is used as a solution, the solution is preferably formed using water or a medium other than the aforementioned acids, 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.
ピぺリジン誘導体の酸性溶液を塩基性にする際には、 —2 0 °C〜十 1 2 0 °Cに するのが好ましく、 特に操作性の面で室温〜 + 1 0 0 °C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。  When making the acidic solution of the piperidine derivative basic, the temperature is preferably from −20 ° C. to 120 ° C., particularly from room temperature to + 100 ° C. in terms of operability. Is preferred. In addition, the pressure is not particularly limited, and it is usually preferable to be atmospheric pressure. The amount of the base is such that the basicity falls within the above range, and can be appropriately changed.
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。 ピぺリジン誘導体は、 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、 p H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、 着色がないピぺ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。  In the present invention, the piperidine derivative is precipitated by making the acidic solution of the piperidine derivative basic. The piperidine derivative itself is basic, and its solubility is reduced under basic conditions to precipitate.However, if precipitation is difficult, increase the pH or lower the temperature of the solution. May be performed. 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 reduces the time required for crystallization, but also incorporates the coloring component even if the crystal before purification contains the coloring component. And a non-colored piperidine derivative crystal. The coloring component usually remains in the mother liquor from which the crystals have been separated.
析出したピぺリジン誘導体は、 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、 析出したピぺ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 9 9 . 0〜 1 0 0 . ひ％程度の高純度であり、 かつ、 黄色度は 2 0以下、 好 ましくは 1 0以下となる。 着色成分を含むピぺリジン誘導体と、 精製されたピぺ 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。 該精製されたピぺ 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 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 generally has a high purity of about 99.0 to 100%, and a yellowness of 20 or less, preferably 1% or less. It becomes 0 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 pyrididine derivative is usefully used as various higher intermediates of drugs and drug substances. In the present invention, a base is added to a vessel containing a piperidine derivative solution under acidic conditions. Is preferably obtained. According to this method, only one container needs to be used, and it is efficient from the viewpoint of operation. Example
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。  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 to 0, the more uncolored. Normally, crystals are observed as white as they approach zero due to light scattering.
本発明の黄色度の測定は、 J I S 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、 J I S K7103, 6. 1黄色度に規定される式 [黄色度 = 100 (1. 28X— 1. 06 Z) ZY] により黄色度を算出した。  The yellowness of the present invention was measured according to the yellowness test method specified in JIS K7103. The sample was laid all over the surface of a 55 mm diameter quartz container to a height of 10 mm, and color measurement was performed using a color difference meter (CR310, manufactured by Minolta Co., Ltd.) with the standard light C using the Yxy color system. After converting the measurement results into tristimulus values XYZ, the yellowness was calculated by the equation [yellowness = 100 (1.28X-1.06Z) ZY] defined in JIS K7103, 6.1 Yellowness.
[実施例 1 ] [Example 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—フエ二ルー 2 (1H) ピリドン （52. 62 g) を入れ、 つぎに 5%酢酸 （487. 92 g) を加えて、 90°Cで加熱溶 解させた。 この酸性溶液に 25 %水酸化ナトリゥム水溶液を、 該溶液の p Hが 1 3になるまで滴下した後に 5°C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—メチルー 1一フエ ニル一 2 (1 H) ピリドンを 84%の回収率で得た。  Into a 1 L flask equipped with a stirrer, internal thermometer, Dimroth, and dropping funnel, light brown (yellowness 21.35) 5-methyl_1-phenyl-2- (1H) pyridone (52.62 g) Then, 5% acetic acid (487.92 g) was added, and the mixture was heated and dissolved at 90 ° C. A 25% aqueous solution of sodium hydroxide was added dropwise to the acidic solution until the pH of the solution became 13, the solution was cooled to 5 ° C, kept for 4 hours, and filtered. After sufficiently washing with water, drying was performed to obtain a white powder (yellowness: 8.27) of 5-methyl-11-phenyl-12 (1H) pyridone with a recovery of 84%.
[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—メチル一 1一フエ二ルー 2 (1H) ピリドン[Example 2] 10-liter separable flask with stirrer, internal thermometer, gym funnel, and dropping funnel, pale brown (yellow 23) 5-methyl-1-phenyl-2- (1H) pyridone
(583. 1 g) を入れ、 つぎに 5%酢酸 （546 l g) を加えて、 90°C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°C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 チルー 1一フエ二ルー 2 (1H) ピリドンを 83 %の回収率で得た。 (583.1 g), 5% acetic acid (546 lg) was added, and the mixture was heated and dissolved at 90 ° C. A 25% aqueous sodium hydroxide solution was added dropwise to the acidic solution until the pH of the solution became 13, then cooled to 5 ° C, kept for 4.5 hours, and filtered. After sufficiently washing with water, the product was dried to obtain 5-methyl-1,1-phenyl-2- (1H) pyridone as a pale yellowish white powder (yellowness 15.68) with a recovery of 83%.
[実施例 3] [Example 3]
撹拌器、 内温計、 ジムロート、 滴下ロートを備えた 50 OmLのフラスコに、 茶色 （黄色度 59. 73) の 3— （フエ二ルェチニル） ピリジン一 N—ォキシド (30. 85 g) を入れ、 つぎに 10 %酢酸 （157. 64 g) を加えて、 10 0 °Cで加熱溶解させた。 この酸性溶液に 25 %水酸化ナトリゥム水溶液を溶液の pHが 13になるまで滴下した後に 0°Cまで冷却し、 6時間保持した。 白色粉末 状 （黄色度 9. 21) の 3— (フエ二ルェチニル） ピリジン一 N—才キシドを 8 9 %の回収率で得た。  In a 50 OmL flask equipped with a stirrer, internal thermometer, Dimroth, and dropping funnel, put brown (yellowness 59.73) 3-((phenylenetin)) pyridine-N-oxide (30.85 g) into a 50-mL flask. Next, 10% 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 became 13, then cooled to 0 ° C and maintained for 6 hours. A white powder (yellowness 9.21) of 3- (phenylenetin) pyridine-1-N-oxide was obtained with a recovery of 89%.
[実施例 4 ] [Example 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—メチルー 3, 4—ジフルオロー 2—キノロン （48. 91 g) を入れ、 5%酢酸 （454. 83 g) を加え、 90°Cにて加熱溶解させ た。 この酸性溶液に 25 %水酸化ナトリゥム水溶液を溶液の p Hが 13になるま で滴下した後に 5°C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ーメチルー 3， 4ージフルォロ 一 2一キノロンを 79 %の回収率で得た。 <産業上の利用可能性 > In a 1-L flask equipped with a stirrer, internal thermometer, Dimroth, and dropping funnel, add yellow (yellowness 41.08) 1-methyl-3,4-difluoro-2-quinolone (48.91 g), and add 5% Acetic acid (454.83 g) was added and dissolved by heating at 90 ° C. A 25% aqueous solution of sodium hydroxide 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 carried out to obtain 1-methyl-3,4-difluoro-12-quinolone as a white powder (yellowness 8.41) with a recovery of 79%. <Industrial applicability>
本発明の方法によれば、 ピぺリジン誘導体から短工程で、 精製されたピベリジ 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 製されたピぺリジン誘導体を提供できる。  According to the method of the present invention, a purified piberidine derivative can be obtained from a piperidine derivative in a short step. 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 colored 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

請求の範囲 The scope of the claims
1 . 水に不溶性または水に難溶性であるピぺ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。 1. Dissolve the piperidine derivative, which is insoluble or poorly soluble in water, in a medium under acidic conditions to form a solution, and then precipitate the piperidine derivative by subjecting the solution to basic conditions. A method for producing a purified piperidine derivative, characterized in that:
2 . 酢酸を用いて酸性条件にする請求項 1に記載の製造方法。 2. The production method according to claim 1, wherein acidic conditions are used using acetic acid.
3 . 水酸化ナトリゥムを用いて塩基性条件にする請求項 1または 2に記載の製造 方法。 3. The production method according to claim 1, wherein the conditions are adjusted to basic conditions using sodium hydroxide.
4. 水に不溶性または水に難溶性であるピぺリジン誘導体が着色成分を含むピぺ リジン誘導体であり、 精製されたピペリジン誘導体が着色成分を実質的に含まな ぃピペリジン誘導体である請求項 1、 2、 または 3に記載の製造方法。 4. The piperidine derivative which is insoluble or hardly soluble in water is a piperidine derivative containing a coloring component, and the purified piperidine derivative is a piperidine derivative substantially containing no coloring component. , 2, or 3.
5 . 着色成分を含むピぺリジン誘導体の、 J I S K 7 1 0 7に準じる試験法に よる黄色度が 2 0超 6 0以下であり、 精製されたピペリジン誘導体の黄色度が 2 0以下である請求項 4に記載の製造方法。 5. The piperidine derivative containing a coloring component has a yellowness of more than 20 and 60 or less according to a test method according to JISK 7107, and the purified piperidine derivative has a yellowness of 20 or less. Item 4. The production method according to Item 4.
6 . ピペリジン誘導体の沸点が 2 5 0 °C以上である請求項 1〜 5のいずれかに記 載の製造方法。 6. The method according to any one of claims 1 to 5, wherein the piperidine derivative has a boiling point of 250 ° C or more.
7 . ピペリジン誘導体を結晶として析出させる請求項 1〜 6のいずれかに記載の 製造方法。 7. The method according to any one of claims 1 to 6, wherein the piperidine derivative is precipitated as crystals.
8. ピぺリジン誘導体が 5—メチルー 1一フエ二ルー 2 (1H) ピリドンである 請求項 1〜 7のいずれかに記載の製造方法。 8. The production method according to any one of claims 1 to 7, wherein the piperidine derivative is 5-methyl-11-phenyl-2 (1H) pyridone.
9. ピぺリジン誘導体が 3— （フエ二ルェチニル） ピリジン一 N—ォキシドであ る請求項 1〜 7のいずれかに記載の製造方法。 9. The production method according to claim 1, wherein the piperidine derivative is 3- (phenylethynyl) pyridine-1-N-oxide.
10. ピぺリジン誘導体が 1ーメチルー 3， 4ージフルオロー 2—キノロンであ る請求項 1〜 7のいずれかに記載の製造方法。 10. The method according to claim 1, wherein the piperidine derivative is 1-methyl-3,4-difluoro-2-quinolone.
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