JP4342940B2 - Process for producing 5-methyl-1-phenyl-2 (1H) pyridinone - Google Patents
Process for producing 5-methyl-1-phenyl-2 (1H) pyridinone Download PDFInfo
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- JP4342940B2 JP4342940B2 JP2003519037A JP2003519037A JP4342940B2 JP 4342940 B2 JP4342940 B2 JP 4342940B2 JP 2003519037 A JP2003519037 A JP 2003519037A JP 2003519037 A JP2003519037 A JP 2003519037A JP 4342940 B2 JP4342940 B2 JP 4342940B2
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- ISWRGOKTTBVCFA-UHFFFAOYSA-N CC(C=C1)=CN(c2ccccc2)C1=O Chemical compound CC(C=C1)=CN(c2ccccc2)C1=O ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 description 1
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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
- C07D213/04—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 having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—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 having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
Description
＜技術分野＞
本発明は、医薬原体や医薬中間体として有用な５−メチル−１−フェニル−２（１Ｈ）ピリジノンの製造方法に関する。
＜背景技術＞
５−メチル−１−フェニル−２（１Ｈ）ピリジノンの合成法としては、５−メチル−２（１Ｈ）ピリジノンとヨードベンゼンを、亜鉛−銅（０価）触媒を用いて、炭酸カリウム共存下で加熱還流させ、５−メチル−１−フェニル−２（１Ｈ）ピリジノンを合成する方法が知られている（ＵＳ３８３９３４６）。
しかし、ヨードベンゼンを用いる方法は、経済的に不利である問題があった。また加熱還流条件にするには、反応器内温をヨードベンゼンの沸点（約１９０℃）付近になるまで加熱する必要があり、エネルギーを多量に消費する点や、また、環境上不利である点で問題があった。
該方法の欠点を解決する目的で、より低沸点のブロモベンゼン（沸点１５６℃）を用いて、亜鉛−銅（０価）触媒、および、炭酸カリウム共存下で加熱還流を行う試みをしたが、きわめて反応収率が低く、工業的製造方法としては採用できない方法であった。また、亜鉛−銅触媒（０価）は用時にその都度調製しなければならないため、製造工程が煩雑になる問題があった。また触媒活性が一定である触媒を調製することが困難であり、製造工程の条件設定が定まらない問題もあった。
本発明は上記の問題を解決するためになされたものであり、安価なブロモベンゼンを用いて、従来よりも低い温度で、調製しやすい触媒を用い、かつ、安定な製造条件で、５−メチル−１−フェニル−２（１Ｈ）ピリジノンを高収率で製造する方法を提供する。
＜発明の開示＞
すなわち本発明は、下式１で表される５−メチル−２（１Ｈ）ピリジノンと、ブロモベンゼンまたはクロロベンゼンとを、１価銅触媒および２価銅触媒から選ばれる少なくとも１種の銅触媒、および、塩基の存在下で反応させることを特徴とする下式２で表される５−メチル−１−フェニル−２（１Ｈ）ピリジノンの製造方法を提供する。
式１で表される５−メチル−２（１Ｈ）ピリジノン、およびブロモベンゼン、とクロロベンゼンは公知の化合物であり、公知の方法で合成できる。
本発明においては、５−メチル−２（１Ｈ）ピリジノンをブロモベンゼンまたはクロロベンゼンと反応させる。ブロモベンゼンまたはクロロベンゼンの量は５−メチル−２（１Ｈ）ピリジノンに対して１〜５０倍モルが好ましく、操作性および容積効率の面から１．０〜１５倍モルが特に好ましく、１．０〜１０倍モルがさらに好ましい。さらに、ブロモベンゼンまたはクロロベンゼンを４〜１０倍モル使用した場合には、反応条件が調節しやすくなる等の反応の操作性が向上し、かつ、反応後の塩基および銅触媒の除去がしやすくなる利点があり、とりわけ好ましい。ブロモベンゼンおよびクロロベンゼンを、それぞれ過剰量使用した場合には、反応生成物からこれらを回収して、次の反応または他の反応にリサイクルすることができる。
本発明の反応は溶媒の存在下で行ってもよいが、溶媒の不存在下に行うのが好ましい。溶媒の不存在下に反応を実施した場合には、後処理で溶媒を除去する工程が不要になり、生成する５−メチル−１−フェニル−２（１Ｈ）ピリジノンへの溶媒の残留を防止でき、かつ、溶媒分の製造コストを抑えられること、等の利点がある。
溶媒を用いる場合には、反応条件下で不活性な溶媒から選ぶのが好ましい。該溶媒としては、トルエン、キシレン等の芳香族炭化水素系溶媒や、ヘプタンなどの脂肪族炭化水素系溶媒、ジメチルホルムアミド、ジメチルアセトアミド、Ｎ−メチルピロリジノンなどのアミド系溶媒、ジエチレングリコールジメチルエーテルなどのグライム系溶媒、ジメチルスルホキシド等が挙げられる。溶媒は、５−メチル−２（１Ｈ）ピリジノン１ｇに対して０．５〜２０ｍｌを使用するのが好ましい。
本発明の反応は、１価銅触媒および２価銅触媒から選ばれる少なくとも１種の銅触媒の存在下に行い、これらは触媒として作用する。１価銅触媒としては、酸化第一銅、酸化第二銅、ヨウ化第一銅、硫酸第一銅等が挙げられる。２価銅触媒としては、ヨウ化第二銅、臭化第一銅、臭化第二銅、塩化第一銅、塩化第二銅、硫酸第二銅等が挙げられる。なかでも反応性が良好なことから酸化第一銅が好ましい。本発明の方法で用いる銅触媒は、安価に市販されており、入手容易な触媒である。また、本発明の反応に用いる銅触媒は、精製することなしにそのまま使用でき、またその都度調製する必要のない点で、従来の方法で採用されていた触媒よりも使用しやすい触媒である。
５−メチル−２（１Ｈ）ピリジノン（式１）に対する銅触媒の量は、銅１原子あたりの量に換算した場合、５−メチル−２（１Ｈ）ピリジノン（式１）に対する銅触媒の量が０．００５倍モル〜１倍モルであるのが好ましく、０．０２倍モル〜０．５倍モルであるのがより好ましく、特に０．０５倍モル〜０．２倍モルであるのが好ましい。
また本発明の反応には塩基を存在させる。塩基としては、副生する臭化水素または塩化水素を捕捉できるものであれば特に限定されず、無機塩基であっても、有機塩基であってもよい。塩基としては、炭酸カリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸水素ナトリウム、水酸化カリウム、水酸化ナトリウム、トリエチルアミン、ジイロプロピルアミン、ジイソプロピルエチルアミンなどが挙げられ、後処理の容易さから無機塩基が好ましく、炭酸カリウム、炭酸ナトリウムが特に好ましい。
このような塩基の量は、５−メチル−２（１Ｈ）ピリジノン（式１）に対して、０．５倍モル〜１０倍モルが好ましく、０．８倍モル〜３倍モルが特に好ましい。
本発明の反応において使用される、ブロモベンゼン、クロロベンゼン、銅触媒、塩基の入手経路は特に限定されず、通常は市販品を用いるのが好ましい。市販品は必要に応じて精製してもよいが、通常の場合には精製せずに用いることができる。
本発明の反応は、５−メチル−２（１Ｈ）ピリジノン（式１）、銅触媒、塩基、および、ブロモベンゼンまたはクロロベンゼンを反応容器に入れて、通常は加熱することにより容易に実施できる。本発明の反応の温度は、８０℃〜１８０℃が好ましく、特に１００℃〜１６０℃が好ましい。反応の圧力は通常は常圧であるのが好ましいが、場合によっては加圧であってもよい。反応時間は１〜３０時間が好ましく、特に２〜２４時間が好ましい。
本発明の反応で生成する反応生成物は、通常の後処理方法や、目的に応じた精製を行うのが好ましい。具体的には、下記方法１〜４によるのが好ましい。
（方法１）；反応生成物を水で希釈し、つぎにジクロロメタン、トルエン、酢酸エチル等の非水溶性有機溶媒を加えて分液し、必要に応じて有機層に活性炭等の吸着剤を加えて吸着処理した後に、該有機層を濃縮し単離する方法。
（方法２）；反応生成物を水で希釈し、つぎにジクロロメタン、トルエン、酢酸エチル等の非水溶性有機溶媒を加えて分液し、必要に応じて有機層に活性炭等の吸着剤を加えて吸着処理した後に、該有機層から晶出させる方法。
（方法３）；反応生成物にジクロロメタン、トルエン、酢酸エチル等の非水溶性有機溶媒を加えて目的物を抽出したのち、該有機層を水や食塩水で洗浄する。さらに必要に応じて活性炭などの吸着剤を添加した後に、該有機層から晶出させる方法。
（方法４）；反応生成物にアルカリ水溶液などを加え、無機塩や銅触媒を溶解させ、つぎにジクロロメタン、トルエン、酢酸エチル等の非水溶性有機溶媒を加えて目的物を抽出したのち、該有機層を水や食塩水で洗浄する。さらに必要に応じて活性炭などの吸着剤、またはキレート剤を添加した後に、該有機層から晶出させる方法。
上記方法における、吸着剤（たとえば、活性炭など）の添加は、反応生成物中に含まれる、タール状物質などの不純物を除去できる。キレート剤（たとえば、エチレンジアミンテトラ酢酸（ＥＤＴＡ）など）の添加は、触媒に由来する重金属を除去できる。本発明の方法においては、反応生成物を吸着剤またはキレート剤で処理するのが好ましく、特に活性炭で処理するのが好ましい。
本発明の製造方法により得られる５−メチル−１−フェニル−２（１Ｈ）ピリジノン（式１）は医薬原体または医薬の中間体として有用な公知の化合物である。本発明によれば、特別な装置や試薬を使用することなく、安定にかつ温和な反応条件で該化合物を製造できる。
（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。
［実施例１］
撹拌器、内温計を備えた１Ｌのフラスコに、５−メチル−２（１Ｈ）ピリジノン（１００．０６ｇ）、酸化第一銅（６．５６６ｇ）、炭酸カリウム（１３９．５ｇ）、ブロモベンゼン（２５９．４ｇ）をはかりとり、大気圧下、１７５℃に調整した油浴中、内温を１５６℃にして加熱還流を３．５時間行った。反応終了後、生成物に酢酸エチルを加えて抽出し、酢酸エチル層における不溶物をろ別した。ろ過後の酢酸エチル層を１０％食塩水で洗浄し、活性炭で処理したのち、晶析を行った。析出した結晶を濾別し、９０℃で５％酢酸に溶解させ、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、５℃まで冷却し、４時間保持した。析出した結晶をろ別し、充分に水洗した後に乾燥し、５−メチル−１−フェニル−２（１Ｈ）ピリジノン（１１０．０５ｇ）を得た。５−メチル−２（１Ｈ）ピリジノンからの収率は６４．８％であった。
［実施例２］
撹拌器、内温計、コンデンサを備えた５０ｍＬのフラスコに、５−メチル−２（１Ｈ）ピリジノン（５．００ｇ）、酸化第一銅（０．３３ｇ）、炭酸カリウム（６．９７ｇ）、ブロモベンゼン（１２．９５ｇ）をはかりとり、大気圧下、内温を１２０℃にして２２時間加熱した。反応終了後、生成物に酢酸エチルを加えて抽出し、酢酸エチル層における不溶物をろ別した。ろ過後の酢酸エチル層を１０％食塩水で洗浄し、活性炭で処理したのち、晶析を行った。析出した結晶を濾別し、９０℃で５％酢酸に溶解させ、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、５℃まで冷却し、５時間保持した。析出した結晶をろ別し、充分に水洗した後に乾燥し、５−メチル−１−フェニル−２（１Ｈ）ピリジノン（５．７０ｇ）を得た。５−メチル−２（１Ｈ）ピリジノンからの収率は６７．２％であった。
［実施例３］
撹拌器、内温計、コンデンサを備えた５０ｍＬのフラスコに、５−メチル−２（１Ｈ）ピリジノン（５．００ｇ）、酸化第一銅（０．６６ｇ）、炭酸カリウム（６．９７ｇ）、ブロモベンゼン（１２．９５ｇ）をはかりとり、大気圧下、内温を１２０℃にして９時間加熱した。反応終了後、生成物に酢酸エチルを加えて抽出し、酢酸エチル層における不溶物をろ別した。ろ過後の酢酸エチル層を１０％食塩水で洗浄し、活性炭で処理したのち、晶析を行った。析出した結晶を濾別し、９０℃で５％酢酸に溶解させ、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、５℃まで冷却し、５時間保持した。析出した結晶をろ別し、充分に水洗した後に乾燥し、５−メチル−１−フェニル−２（１Ｈ）ピリジノン（５．４１ｇ）を得た。５−メチル−２（１Ｈ）ピリジノンからの収率は６３．７％であった。
［実施例４］
撹拌器、内温計、コンデンサを備えた５００ｍＬのフラスコに、５−メチル−２（１Ｈ）ピリジノン（４０．００ｇ）、酸化第一銅（２．６２ｇ）、炭酸カリウム（５５．７３ｇ）、ブロモベンゼン（３４７．３９ｇ）をはかりとり、大気圧下、１７５℃に調整した油浴中、内温を１５６℃にして加熱還流を４時間行った。反応終了後、生成物に酢酸エチルを加えて抽出し、酢酸エチル層における不溶物をろ別した。ろ過後の酢酸エチル層を１０％食塩水で洗浄し、活性炭で処理したのち、晶析を行った。析出した結晶を濾別し、９０℃で５％酢酸に溶解させ、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、５℃まで冷却し、４．５時間保持した。析出した結晶をろ別し、充分に水洗した後に乾燥し、５−メチル−１−フェニル−２（１Ｈ）ピリジノン（４６．２４ｇ）を得た。５−メチル−２（１Ｈ）ピリジノンからの収率は６８．１％であった。
［参考例］
撹拌器、内温計、コンデンサを備えた５０ｍＬのフラスコに、５−メチル−２（１Ｈ）ピリジノン（５．４６ｇ）、亜鉛−銅（０価）触媒（６３．８ｍｇ）、炭酸カリウム（７．６２ｇ）、ブロモベンゼン（１４．１６ｇ）をはかりとり、１８０℃の油浴中で、４０時間、加熱還流させた。生成物をメタノールで抽出し、高速液体クロマトグラフィーで定量した結果、５−メチル−１−フェニル−２（１Ｈ）ピリジノンの収率は９．８５％であった。
＜産業上の利用可能性＞
本発明の方法によれば、５−メチル−２（１Ｈ）ピリジノン（式１）から短工程で、医薬原体または中間体として有用な５−メチル−１−フェニル−２（１Ｈ）ピリジノンを得ることができる。本発明の方法は、より安価で使用しやすい試薬を用いて、低い反応温度で実施できることから、経済性に優れた方法である。また、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、反応の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。<Technical field>
The present invention relates to a method for producing 5-methyl-1-phenyl-2 (1H) pyridinone useful as a drug substance or a pharmaceutical intermediate.
<Background technology>
As a synthesis method of 5-methyl-1-phenyl-2 (1H) pyridinone, 5-methyl-2 (1H) pyridinone and iodobenzene are used in the presence of potassium carbonate using a zinc-copper (zero-valent) catalyst. A method of synthesizing 5-methyl-1-phenyl-2 (1H) pyridinone by heating under reflux is known (US3839346).
However, the method using iodobenzene has a problem that it is economically disadvantageous. In addition, in order to achieve heating and reflux conditions, it is necessary to heat the reactor internal temperature until it reaches the boiling point of iodobenzene (about 190 ° C.), which consumes a large amount of energy and is disadvantageous for the environment. There was a problem.
In order to solve the disadvantages of the method, an attempt was made to heat and reflux in the presence of a zinc-copper (zero valent) catalyst and potassium carbonate using bromobenzene (boiling point 156 ° C.) having a lower boiling point. The reaction yield was extremely low, and this method could not be adopted as an industrial production method. Further, since the zinc-copper catalyst (zero valence) must be prepared each time it is used, there is a problem that the manufacturing process becomes complicated. In addition, it is difficult to prepare a catalyst having a constant catalytic activity, and there is a problem that the conditions of the manufacturing process cannot be set.
The present invention has been made in order to solve the above-mentioned problems, and uses 5-bromomethyl, which is easy to prepare at a lower temperature than conventional ones, using inexpensive bromobenzene, and under stable production conditions. A method for producing -1-phenyl-2 (1H) pyridinone in high yield is provided.
<Disclosure of invention>
That is, the present invention provides 5-methyl-2 (1H) pyridinone represented by the following formula 1, bromobenzene or chlorobenzene, at least one copper catalyst selected from a monovalent copper catalyst and a divalent copper catalyst, and The present invention provides a method for producing 5-methyl-1-phenyl-2 (1H) pyridinone represented by the following formula 2, characterized by reacting in the presence of a base.
5-Methyl-2 (1H) pyridinone represented by Formula 1 and bromobenzene and chlorobenzene are known compounds and can be synthesized by a known method.
In the present invention, 5-methyl-2 (1H) pyridinone is reacted with bromobenzene or chlorobenzene. The amount of bromobenzene or chlorobenzene is preferably 1 to 50-fold mol with respect to 5-methyl-2 (1H) pyridinone, particularly preferably 1.0 to 15-fold mol in terms of operability and volume efficiency, 10 times mole is more preferable. Furthermore, when bromobenzene or chlorobenzene is used in an amount of 4 to 10 times mol, the operability of the reaction such as easy adjustment of the reaction conditions is improved, and the base and copper catalyst after the reaction are easily removed. There are advantages, especially preferred. When an excess amount of bromobenzene and chlorobenzene is used, they can be recovered from the reaction product and recycled to the next reaction or another reaction.
The reaction of the present invention may be carried out in the presence of a solvent, but is preferably carried out in the absence of a solvent. When the reaction is carried out in the absence of a solvent, the step of removing the solvent in the post-treatment is not necessary, and it is possible to prevent the solvent from remaining in the resulting 5-methyl-1-phenyl-2 (1H) pyridinone. In addition, there are advantages such as that the production cost of the solvent can be suppressed.
If a solvent is used, it is preferably selected from solvents that are inert under the reaction conditions. Examples of the solvent include aromatic hydrocarbon solvents such as toluene and xylene, aliphatic hydrocarbon solvents such as heptane, amide solvents such as dimethylformamide, dimethylacetamide and N-methylpyrrolidinone, and glyme solvents such as diethylene glycol dimethyl ether. A solvent, dimethyl sulfoxide, etc. are mentioned. The solvent is preferably used in an amount of 0.5 to 20 ml with respect to 1 g of 5-methyl-2 (1H) pyridinone.
The reaction of the present invention is carried out in the presence of at least one copper catalyst selected from a monovalent copper catalyst and a divalent copper catalyst, and these act as a catalyst. Examples of the monovalent copper catalyst include cuprous oxide, cupric oxide, cuprous iodide, cuprous sulfate and the like. Examples of the divalent copper catalyst include cupric iodide, cuprous bromide, cupric bromide, cuprous chloride, cupric chloride, cupric sulfate and the like. Of these, cuprous oxide is preferred because of its good reactivity. The copper catalyst used in the method of the present invention is commercially available at a low cost and is an easily available catalyst. In addition, the copper catalyst used in the reaction of the present invention can be used as it is without being purified, and is easier to use than the catalyst employed in the conventional method because it does not need to be prepared each time.
The amount of copper catalyst relative to 5-methyl-2 (1H) pyridinone (formula 1), when converted to the amount per copper atom, is the amount of copper catalyst relative to 5-methyl-2 (1H) pyridinone (formula 1). It is preferably 0.005 mol to 1 mol, more preferably 0.02 mol to 0.5 mol, and particularly preferably 0.05 mol to 0.2 mol. .
A base is present in the reaction of the present invention. The base is not particularly limited as long as it can capture by-produced hydrogen bromide or hydrogen chloride, and may be an inorganic base or an organic base. Examples of the base include potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydroxide, sodium hydroxide, triethylamine, diilopropylamine, diisopropylethylamine, and an inorganic base is preferable because of easy post-treatment. Particularly preferred are potassium carbonate and sodium carbonate.
The amount of such a base is preferably 0.5 to 10-fold mol, particularly preferably 0.8 to 3-fold mol based on 5-methyl-2 (1H) pyridinone (Formula 1).
The route for obtaining bromobenzene, chlorobenzene, copper catalyst, and base used in the reaction of the present invention is not particularly limited, and it is usually preferable to use a commercially available product. Commercial products may be purified as necessary, but can be used without purification in normal cases.
The reaction of the present invention can be easily carried out by placing 5-methyl-2 (1H) pyridinone (formula 1), a copper catalyst, a base, and bromobenzene or chlorobenzene into a reaction vessel and usually heating. The reaction temperature of the present invention is preferably from 80 ° C to 180 ° C, particularly preferably from 100 ° C to 160 ° C. The pressure of the reaction is usually preferably normal pressure, but may be increased depending on circumstances. The reaction time is preferably 1 to 30 hours, particularly preferably 2 to 24 hours.
The reaction product produced by the reaction of the present invention is preferably subjected to a usual post-treatment method or purification according to the purpose. Specifically, the following methods 1 to 4 are preferable.
(Method 1): Dilute the reaction product with water, add a water-insoluble organic solvent such as dichloromethane, toluene, ethyl acetate, etc. to separate the solution, and add an adsorbent such as activated carbon to the organic layer as necessary. The organic layer is concentrated and isolated after the adsorption treatment.
(Method 2): Dilute the reaction product with water, add a water-insoluble organic solvent such as dichloromethane, toluene, ethyl acetate, etc. to separate the solution, and add an adsorbent such as activated carbon to the organic layer as necessary. And crystallization from the organic layer after the adsorption treatment.
(Method 3): A non-water-soluble organic solvent such as dichloromethane, toluene, ethyl acetate or the like is added to the reaction product to extract the target product, and then the organic layer is washed with water or brine. Furthermore, after adding adsorbents, such as activated carbon, as needed, it is made to crystallize from this organic layer.
(Method 4): An aqueous alkali solution or the like is added to the reaction product to dissolve the inorganic salt or copper catalyst. Next, a water-insoluble organic solvent such as dichloromethane, toluene or ethyl acetate is added to extract the target product, Wash the organic layer with water or brine. Further, a method of crystallizing from the organic layer after adding an adsorbent such as activated carbon or a chelating agent as required.
Addition of an adsorbent (for example, activated carbon, etc.) in the above method can remove impurities such as tar-like substances contained in the reaction product. Addition of a chelating agent (eg, ethylenediaminetetraacetic acid (EDTA), etc.) can remove heavy metals originating from the catalyst. In the method of the present invention, the reaction product is preferably treated with an adsorbent or a chelating agent, particularly preferably with activated carbon.
5-Methyl-1-phenyl-2 (1H) pyridinone (Formula 1) obtained by the production method of the present invention is a known compound useful as a drug substance or a pharmaceutical intermediate. According to the present invention, the compound can be produced stably and under mild reaction conditions without using a special apparatus or reagent.
(Example)
The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
[Example 1]
To a 1 L flask equipped with a stirrer and an internal thermometer, 5-methyl-2 (1H) pyridinone (100.06 g), cuprous oxide (6.566 g), potassium carbonate (139.5 g), bromobenzene ( 259.4 g) was weighed out and heated to reflux for 3.5 hours at an internal temperature of 156 ° C. in an oil bath adjusted to 175 ° C. under atmospheric pressure. After completion of the reaction, the product was extracted by adding ethyl acetate, and insoluble matters in the ethyl acetate layer were filtered off. The ethyl acetate layer after filtration was washed with 10% brine, treated with activated carbon, and then crystallized. The precipitated crystals were separated by filtration, dissolved in 5% acetic acid at 90 ° C., and a 25% aqueous sodium hydroxide solution was added dropwise until the pH of the solution reached 13, then cooled to 5 ° C. and held for 4 hours. The precipitated crystals were collected by filtration, washed thoroughly with water and then dried to obtain 5-methyl-1-phenyl-2 (1H) pyridinone (110.05 g). The yield based on 5-methyl-2 (1H) pyridinone was 64.8%.
[Example 2]
In a 50 mL flask equipped with a stirrer, an internal thermometer and a condenser, 5-methyl-2 (1H) pyridinone (5.00 g), cuprous oxide (0.33 g), potassium carbonate (6.97 g), bromo Benzene (12.95 g) was weighed and heated at atmospheric pressure at an internal temperature of 120 ° C. for 22 hours. After completion of the reaction, the product was extracted by adding ethyl acetate, and insoluble matters in the ethyl acetate layer were filtered off. The ethyl acetate layer after filtration was washed with 10% brine, treated with activated carbon, and then crystallized. The precipitated crystals were separated by filtration, dissolved in 5% acetic acid at 90 ° C., and 25% aqueous sodium hydroxide solution was added dropwise until the pH of the solution reached 13, then cooled to 5 ° C. and held for 5 hours. The precipitated crystals were separated by filtration, sufficiently washed with water and then dried to obtain 5-methyl-1-phenyl-2 (1H) pyridinone (5.70 g). The yield based on 5-methyl-2 (1H) pyridinone was 67.2%.
[Example 3]
In a 50 mL flask equipped with a stirrer, an internal thermometer and a condenser, 5-methyl-2 (1H) pyridinone (5.00 g), cuprous oxide (0.66 g), potassium carbonate (6.97 g), bromo Benzene (12.95 g) was weighed and heated at atmospheric pressure with an internal temperature of 120 ° C. for 9 hours. After completion of the reaction, the product was extracted by adding ethyl acetate, and insoluble matters in the ethyl acetate layer were filtered off. The ethyl acetate layer after filtration was washed with 10% brine, treated with activated carbon, and then crystallized. The precipitated crystals were separated by filtration, dissolved in 5% acetic acid at 90 ° C., and 25% aqueous sodium hydroxide solution was added dropwise until the pH of the solution reached 13, then cooled to 5 ° C. and held for 5 hours. The precipitated crystals were collected by filtration, washed thoroughly with water and then dried to obtain 5-methyl-1-phenyl-2 (1H) pyridinone (5.41 g). The yield based on 5-methyl-2 (1H) pyridinone was 63.7%.
[Example 4]
To a 500 mL flask equipped with a stirrer, an internal thermometer and a condenser, 5-methyl-2 (1H) pyridinone (40.00 g), cuprous oxide (2.62 g), potassium carbonate (55.73 g), bromo Benzene (347.39 g) was weighed and heated under reflux for 4 hours at an internal temperature of 156 ° C. in an oil bath adjusted to 175 ° C. under atmospheric pressure. After completion of the reaction, the product was extracted by adding ethyl acetate, and insoluble matters in the ethyl acetate layer were separated by filtration. The ethyl acetate layer after filtration was washed with 10% brine, treated with activated carbon, and then crystallized. The precipitated crystals were separated by filtration, dissolved in 5% acetic acid at 90 ° C., 25% aqueous sodium hydroxide solution was added dropwise until the pH of the solution reached 13, and then cooled to 5 ° C. and held for 4.5 hours. The precipitated crystals were collected by filtration, washed thoroughly with water and then dried to obtain 5-methyl-1-phenyl-2 (1H) pyridinone (46.24 g). The yield based on 5-methyl-2 (1H) pyridinone was 68.1%.
[Reference example]
In a 50 mL flask equipped with a stirrer, an internal thermometer, and a condenser, 5-methyl-2 (1H) pyridinone (5.46 g), zinc-copper (zero valent) catalyst (63.8 mg), potassium carbonate (7. 62 g) and bromobenzene (14.16 g) were weighed and heated to reflux in an oil bath at 180 ° C. for 40 hours. The product was extracted with methanol and quantified by high performance liquid chromatography. As a result, the yield of 5-methyl-1-phenyl-2 (1H) pyridinone was 9.85%.
<Industrial applicability>
According to the method of the present invention, 5-methyl-1-phenyl-2 (1H) pyridinone useful as a drug substance or intermediate is obtained from 5-methyl-2 (1H) pyridinone (Formula 1) in a short step. be able to. Since the method of the present invention can be carried out at a low reaction temperature using a cheaper and easier-to-use reagent, it is an economical method. In addition, the production method of the present invention can be carried out without using special reaction conditions and reactors, and the reaction yield is high. Therefore, the production method is useful as an industrial large-capacity production method.
Claims (5)
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| JP2001237937 | 2001-08-06 | ||
| JP2001237937 | 2001-08-06 | ||
| PCT/JP2002/008022 WO2003014087A1 (en) | 2001-08-06 | 2002-08-06 | Process for preparation of 5-methyl-1-phenyl-2(1h) -pyridinone |
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| WO2012107831A1 (en) * | 2011-02-11 | 2012-08-16 | Signa S.A. De C.V. | Method of making a pyridone compound, 5-ethyl-1-phenyl-2-(1h)-pyridone, and intermediates thereof |
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| JP2005272417A (en) * | 2004-03-26 | 2005-10-06 | Kuraray Co Ltd | Method for producing 2-chloro-4-aminomethylpyridine |
| ES2600460T3 (en) | 2005-05-10 | 2017-02-09 | Intermune, Inc. | Pyridone-2-one derivatives as modulators of the stress-activated protein kinase system |
| MX2007006349A (en) * | 2007-05-29 | 2009-02-18 | Cell Therapy And Technology S | New process of synthesis for obtaining 5-methyl-1-phenyl-2 (ih) -pyridone, composition and use of the same. |
| CA2726588C (en) | 2008-06-03 | 2019-04-16 | Karl Kossen | Compounds and methods for treating inflammatory and fibrotic disorders |
| US20110313004A1 (en) | 2008-12-04 | 2011-12-22 | Concert Pharmaceuticals, Inc. | Deuterated pyridinones |
| TWI434833B (en) * | 2009-06-03 | 2014-04-21 | Intermune Inc | Improved method for synthesizing pirfenidone |
| CN101891676A (en) * | 2010-08-03 | 2010-11-24 | 陕西合成药业有限公司 | Novel method for preparing 5-methyl-1-phenyl-2-(1H)-pyridone |
| US10105356B2 (en) | 2011-01-31 | 2018-10-23 | Avalyn Pharma Inc. | Aerosol pirfenidone and pyridone analog compounds and uses thereof |
| EP2670242B1 (en) | 2011-01-31 | 2022-03-16 | Avalyn Pharma Inc. | Aerosol pirfenidone and pyridone analog compounds and uses thereof |
| AR092742A1 (en) | 2012-10-02 | 2015-04-29 | Intermune Inc | ANTIFIBROTIC PYRIDINONES |
| NZ760541A (en) | 2014-01-10 | 2022-08-26 | Avalyn Pharma Inc | Aerosol pirfenidone and pyridone analog compounds and uses thereof |
| CN110452216B (en) | 2014-04-02 | 2022-08-26 | 英特穆恩公司 | Anti-fibrotic pyridinones |
| WO2016122420A1 (en) * | 2015-01-26 | 2016-08-04 | Ulkar Kimya Sanayii Ve Ticaret A. S. | An improved method for the synthesis and purification of pirfenidone |
| ITUB20154832A1 (en) * | 2015-10-29 | 2017-04-29 | Procos Spa | PROCESS FOR SYNTHESIS OF PYRPHENING |
| CN105315198A (en) * | 2015-11-02 | 2016-02-10 | 重庆康乐制药有限公司 | Crystal form of pirfenidone and preparation method of crystal form |
| CN105330598B (en) * | 2015-12-02 | 2017-11-14 | 新发药业有限公司 | A kind of preparation method of pirfenidone |
| US11066368B2 (en) | 2016-01-14 | 2021-07-20 | Laurus Labs Limited | Process for the preparation and particle size reduction of pirfenidone |
| IT201600108927A1 (en) * | 2016-10-27 | 2018-04-27 | Dipharma Francis Srl | METHOD FOR SYNTHESIZING AN ANTI-BIBROCT MEDICINE |
| US20180009753A1 (en) | 2016-07-08 | 2018-01-11 | Dipharma Francis S.R.L. | Method for preparing an antifibrotic agent |
| WO2018178996A1 (en) * | 2017-03-28 | 2018-10-04 | Natco Pharma Limited | Improved process for the preparation of pirfenidone |
| AU2019339536A1 (en) | 2018-09-14 | 2021-04-29 | Puretech Lyt 100, Inc. | Deuterium-enriched pirfenidone and methods of use thereof |
| WO2022051984A1 (en) * | 2020-09-10 | 2022-03-17 | 苏州富德兆丰生化科技有限公司 | Synthesis method for pirfenidone |
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| US3974271A (en) * | 1972-08-19 | 1976-08-10 | Beecham Group Limited | Lipstick containing 8-amino-2-(azo-benzene-4-sulphonic acid)-1-naphthol-3,6-disulphonic acid or an edible salt thereof |
| US3839346A (en) * | 1972-12-18 | 1974-10-01 | Affiliated Med Res | N-substituted pyridone and general method for preparing pyridones |
| CA1049411A (en) * | 1972-12-18 | 1979-02-27 | Affiliated Medical Research | N-substituted pyridone and general method for preparing pyridones |
| DE10024938A1 (en) * | 2000-05-19 | 2001-11-22 | Bayer Ag | New substituted iminoazine derivatives useful as herbicides, especially for weed control in crops |
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| WO2012107831A1 (en) * | 2011-02-11 | 2012-08-16 | Signa S.A. De C.V. | Method of making a pyridone compound, 5-ethyl-1-phenyl-2-(1h)-pyridone, and intermediates thereof |
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| KR100898888B1 (en) | 2009-05-21 |
| KR20040022232A (en) | 2004-03-11 |
| WO2003014087A1 (en) | 2003-02-20 |
| JPWO2003014087A1 (en) | 2004-11-25 |
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