JP2005126389A - Method for producing 2,4-dichloro-5-fluoropyrimidine - Google Patents
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本発明は、２，４−ジクロロ−５−フルオロピリミジンの製造方法に関する。 The present invention relates to a method for producing 2,4-dichloro-5-fluoropyrimidine.
４−アミノ−２−クロロ−５−フルオロピリミジンは、例えば抗精神薬、たんぱくチロシンキナーゼ抑制剤、抗ウイルス剤等の医薬品の合成原料として有用であり（例えば特許文献１、特許文献２参照。）、その製造方法として、２，４−ジクロロ−５−フルオロピリミジンをアミノ化する方法が知られている（例えば特許文献３参照。）。かかる製造方法の原料である２，４−ジクロロ−５−フルオロピリミジンは、５−フルオロウラシルと塩素化剤とを、塩基の存在下に反応させることにより製造される（例えば特許文献３参照。）が、５−フルオロウラシルは、２−アルコキシ−５−フルオロ−４（３Ｈ）−ピリミジノン類を加水分解することにより製造しなければならず（例えば特許文献４参照。）、工業的な観点からは、より短工程で２，４−ジクロロ−５−フルオロピリミジンを製造する方法の開発が望まれていた。 4-Amino-2-chloro-5-fluoropyrimidine is useful as a raw material for synthesizing pharmaceuticals such as antipsychotics, protein tyrosine kinase inhibitors, antiviral agents, etc. (see, for example, Patent Document 1 and Patent Document 2). As a production method thereof, a method of amination of 2,4-dichloro-5-fluoropyrimidine is known (for example, see Patent Document 3). 2,4-Dichloro-5-fluoropyrimidine, which is a raw material for such a production method, is produced by reacting 5-fluorouracil and a chlorinating agent in the presence of a base (see, for example, Patent Document 3). , 5-fluorouracil must be produced by hydrolyzing 2-alkoxy-5-fluoro-4 (3H) -pyrimidinones (see, for example, Patent Document 4). From an industrial point of view, more Development of a method for producing 2,4-dichloro-5-fluoropyrimidine in a short process has been desired.
このような状況のもと、本発明者らは、より短工程で、収率よく２，４−ジクロロ−５−フルオロピリミジンを製造する方法について、検討したところ、２−アルコキシ−５−フルオロ−４（３Ｈ）−ピリミジノン類と塩素化剤とを、塩基の存在下に反応させることにより、２，４−ジクロロ−５−フルオロピリミジンが収率よく得られること、さらに、得られた２，４−ジクロロ−５−フルオロピリミジンをアミノ化することにより、４−アミノ−２−クロロ−５−フルオロピリミジンを製造することができることを見出し、本発明に至った。 Under such circumstances, the present inventors examined a method for producing 2,4-dichloro-5-fluoropyrimidine in a shorter process and with a higher yield. As a result, 2-alkoxy-5-fluoro- By reacting 4 (3H) -pyrimidinones with a chlorinating agent in the presence of a base, 2,4-dichloro-5-fluoropyrimidine can be obtained in good yield, and the obtained 2,4 It has been found that 4-amino-2-chloro-5-fluoropyrimidine can be produced by amination of -dichloro-5-fluoropyrimidine, and has led to the present invention.
すなわち本発明は、２−アルコキシ−５−フルオロ−４（３Ｈ）−ピリミジノン類と塩素化剤を、塩基の存在下に反応させることを特徴とする２，４−ジクロロ−５−フルオロピリミジンの製造方法および得られた２，４−ジクロロ−５−フルオロピリミジンにアンモニアを作用せしめることを特徴とする４−アミノ−２−クロロ−５−フルオロピリミジンの製造方法を提供するものである。 That is, the present invention relates to the production of 2,4-dichloro-5-fluoropyrimidine characterized by reacting 2-alkoxy-5-fluoro-4 (3H) -pyrimidinone with a chlorinating agent in the presence of a base. The present invention provides a process and a process for producing 4-amino-2-chloro-5-fluoropyrimidine, characterized by reacting ammonia with the obtained 2,4-dichloro-5-fluoropyrimidine.
本発明によれば、２−アルコキシ−５−フルオロ−４（３Ｈ）−ピリミジノン類から一工程で、収率よく２，４−ジクロロ−５−フルオロピリミジンを製造することができ、さらに、工業的により有利に、４−アミノ−２−クロロ−５−フルオロピリミジンを製造することができる。 According to the present invention, 2,4-dichloro-5-fluoropyrimidine can be produced from 2-alkoxy-5-fluoro-4 (3H) -pyrimidinones in a single step with a high yield. More advantageously, 4-amino-2-chloro-5-fluoropyrimidine can be produced.
２−アルコキシ−５−フルオロ−４（３Ｈ）−ピリミジノン類の２位のアルコキシ基としては、例えばメトキシ基、エトキシ基、ｎ−プロポキシ基、イソプロポキシ基、ｎ−ブトキシ基、イソブトキシ基、ｓｅｃ−ブトキシ基、ｔｅｒｔ−ブトキシ基、ｎ−ペンチルオキシ基、ｎ−ヘキシルオキシ基等の炭素数１〜６の直鎖状もしくは分枝鎖状の低級アルコキシ基が挙げられる。 As the alkoxy group at the 2-position of 2-alkoxy-5-fluoro-4 (3H) -pyrimidinones, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec- Examples thereof include linear or branched lower alkoxy groups having 1 to 6 carbon atoms such as butoxy group, tert-butoxy group, n-pentyloxy group and n-hexyloxy group.
かかる２−アルコキシ−５−フルオロ−４（３Ｈ）−ピリミジノン類としては、例えば５−フルオロ−２−メトキシ−４（３Ｈ）−ピリミジノン、５−フルオロ−２−エトキシ−４（３Ｈ）−ピリミジノン、５−フルオロ−２−ｎ−プロポキシ−４（３Ｈ）−ピリミジノン、５−フルオロ−２−イソプロポキシ−４（３Ｈ）−ピリミジノン、５−フルオロ−２−ｎ−ブトキシ−４（３Ｈ）−ピリミジノン、５−フルオロ−２−イソブトキシ−４（３Ｈ）−ピリミジノン、５−フルオロ−２−ｓｅｃ−ブトキシ−４（３Ｈ）−ピリミジノン、５−フルオロ−２−ｔｅｒｔ−ブトキシ−４（３Ｈ）−ピリミジノン、５−フルオロ−２−ｎ−ペンチルオキシ−４（３Ｈ）−ピリミジノン、５−フルオロ−２−ｎ−ヘキシルオキシ−４（３Ｈ）−ピリミジノン等が挙げられる。 Examples of such 2-alkoxy-5-fluoro-4 (3H) -pyrimidinones include 5-fluoro-2-methoxy-4 (3H) -pyrimidinone, 5-fluoro-2-ethoxy-4 (3H) -pyrimidinone, 5-fluoro-2-n-propoxy-4 (3H) -pyrimidinone, 5-fluoro-2-isopropoxy-4 (3H) -pyrimidinone, 5-fluoro-2-n-butoxy-4 (3H) -pyrimidinone, 5-fluoro-2-isobutoxy-4 (3H) -pyrimidinone, 5-fluoro-2-sec-butoxy-4 (3H) -pyrimidinone, 5-fluoro-2-tert-butoxy-4 (3H) -pyrimidinone, 5 -Fluoro-2-n-pentyloxy-4 (3H) -pyrimidinone, 5-fluoro-2-n-hexyloxy-4 (3H) -pyri Jin Won, and the like.
かかる２−アルコキシ−５−フルオロ−４（３Ｈ）−ピリミジノン類は、市販されているものを用いてもよいし、公知の方法（例えばＪ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，７９，４５５９（１９５７）等）に準じて製造したものを用いてもよい。 As such 2-alkoxy-5-fluoro-4 (3H) -pyrimidinones, commercially available ones may be used, or known methods (for example, J. Am. Chem. Soc., 79 , 4559 (1957)). Etc.) may be used.
塩素化剤としては、例えばオキシ塩化リン等が挙げられ、その使用量は、２−アルコキシ−５−フルオロ−４（３Ｈ）−ピリミジノン類に対して、通常２〜５モル倍、好ましくは２〜３モル倍である。 Examples of the chlorinating agent include phosphorus oxychloride, and the amount used is usually 2 to 5 mol times, preferably 2 to 2 times the amount of 2-alkoxy-5-fluoro-4 (3H) -pyrimidinones. 3 mole times.
塩基としては、例えばＮ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン等のＮ，Ｎ−ジ（低級アルキル）アニリン等が挙げられる。かかる塩基はそれぞれ単独で用いてもよいし、混合して用いてもよい。 Examples of the base include N, N-di (lower alkyl) aniline such as N, N-dimethylaniline and N, N-diethylaniline. Such bases may be used alone or in combination.
塩基の使用量は、２−アルコキシ−５−フルオロ−４（３Ｈ）−ピリミジノン類に対して、通常０．１〜０．９５モル倍である。 The usage-amount of a base is 0.1-0.95 mol times normally with respect to 2-alkoxy-5-fluoro-4 (3H) -pyrimidinones.
反応は、無溶媒で実施してもよいし、溶媒中で実施してもよい。溶媒としては、例えばトルエン、キシレン等の芳香族炭化水素系溶媒、例えばクロロベンゼン、ｏ−ジクロロベンゼン等のハロゲン化芳香族炭化水素系溶媒、例えばヘキサン、ヘプタン等の脂肪族炭化水素系溶媒、例えばジクロロメタン、クロロホルム等のハロゲン化脂肪族炭化水素系溶媒等の単独または混合溶媒が挙げられ、その使用量は特に制限されない。 The reaction may be carried out without a solvent or in a solvent. Examples of the solvent include aromatic hydrocarbon solvents such as toluene and xylene, halogenated aromatic hydrocarbon solvents such as chlorobenzene and o-dichlorobenzene, aliphatic hydrocarbon solvents such as hexane and heptane, such as dichloromethane, and the like. In addition, a single or mixed solvent such as a halogenated aliphatic hydrocarbon solvent such as chloroform may be used, and the amount used is not particularly limited.
反応温度は、通常２０〜１５０℃、好ましくは５０〜１５０℃である。反応は、通常常圧条件下で実施されるが、加圧条件下で実施してもよい。 The reaction temperature is usually 20 to 150 ° C, preferably 50 to 150 ° C. The reaction is usually carried out under normal pressure conditions, but may be carried out under pressurized conditions.
反応終了後、例えば反応液と水を混合し、必要に応じて水に不溶の有機溶媒を加えて抽出処理することにより、２，４−ジクロロ−５−フルオロピリミジンを含む有機層が得られ、該有機層を濃縮処理することにより、２，４−ジクロロ−５−フルオロピリミジンを取り出すことができる。また、反応液をそのまま濃縮処理することにより、２，４−ジクロロ−５−フルオロピリミジンを取り出すこともできる。取り出した２，４−ジクロロ−５−フルオロピリミジンは、例えば蒸留、再結晶等の通常の精製手段によりさらに精製してもよい。 After completion of the reaction, for example, the reaction solution and water are mixed, and an organic layer containing 2,4-dichloro-5-fluoropyrimidine is obtained by adding an organic solvent insoluble in water and extracting as necessary. By concentrating the organic layer, 2,4-dichloro-5-fluoropyrimidine can be taken out. Moreover, 2,4-dichloro-5-fluoropyrimidine can also be taken out by concentrating the reaction solution as it is. The taken out 2,4-dichloro-5-fluoropyrimidine may be further purified by ordinary purification means such as distillation and recrystallization.
得られた２，４−ジクロロ−５−フルオロピリミジンに、アンモニアを作用せしめることにより、４−アミノ−２−クロロ−５−フルオロピリミジンを製造することができる。前記で得られた２，４−ジクロロ−５−フルオロピリミジンを含む有機層にそのままアンモニアを作用せしめてもよいし、該有機層から２，４−ジクロロ−５−フルオロピリミジンを取り出し、アンモニアを作用せしめてもよい。２，４−ジクロロ−５−フルオロピリミジンとアンモニアの反応は、例えば特公昭３８−２６１８１号公報、特開平８−１２７５６９号公報等に記載の２，４−ジクロロ−５−フルオロピリミジンとアンモニアを、そのままもしくは溶媒中で混合する方法により実施される。 4-amino-2-chloro-5-fluoropyrimidine can be produced by allowing ammonia to act on the obtained 2,4-dichloro-5-fluoropyrimidine. Ammonia may be allowed to act on the organic layer containing 2,4-dichloro-5-fluoropyrimidine obtained above, or 2,4-dichloro-5-fluoropyrimidine is taken out of the organic layer and activated with ammonia. You may squeeze it. The reaction of 2,4-dichloro-5-fluoropyrimidine and ammonia is carried out by, for example, converting 2,4-dichloro-5-fluoropyrimidine and ammonia described in Japanese Patent Publication No. 38-26181, Japanese Patent Application Laid-Open No. 8-12769, etc. The reaction is carried out as it is or in a solvent.
アンモニアとしては、アンモニア水を用いてもよいし、アンモニアガスや液体アンモニアを用いてもよい。また、例えばアンモニア／メタノール溶液等のアンモニアを溶媒に溶解させたアンモニア溶液を用いてもよい。アンモニアの使用量は、２，４−ジクロロ−５−フルオロピリミジンに対して、通常１〜１０モル倍である。 As ammonia, ammonia water may be used, or ammonia gas or liquid ammonia may be used. Further, for example, an ammonia solution in which ammonia is dissolved in a solvent such as an ammonia / methanol solution may be used. The amount of ammonia used is usually 1 to 10 moles relative to 2,4-dichloro-5-fluoropyrimidine.
２，４−ジクロロ−５−フルオロピリミジンとアンモニアの反応は、常圧条件下で実施してもよいし、加圧条件下で実施してもよい。反応温度は、通常２０〜８０℃である。 The reaction between 2,4-dichloro-5-fluoropyrimidine and ammonia may be carried out under normal pressure conditions or under pressurized conditions. The reaction temperature is usually 20-80 ° C.
溶媒としては、例えばメタノール、エタノール等のアルコール系溶媒、例えばジエチルエーテル、ジイソプロピルエーテル等のエーテル系溶媒、例えばトルエン、キシレン等の芳香族炭化水素系溶媒、例えばクロロベンゼン、ｏ−ジクロロベンゼン等のハロゲン化芳香族炭化水素系溶媒、例えばジクロロメタン、クロロホルム等のハロゲン化脂肪族炭化水素系溶媒、水等の単独もしくは混合溶媒が挙げられ、その使用量は特に制限されない。また、前記で得られた２，４−ジクロロ−５−フルオロピリミジンを含む有機層をそのまま用いる場合には、かかる溶媒を新たに用いなくてもよい。 Examples of the solvent include alcohol solvents such as methanol and ethanol, ether solvents such as diethyl ether and diisopropyl ether, aromatic hydrocarbon solvents such as toluene and xylene, and halogenated solvents such as chlorobenzene and o-dichlorobenzene. Aromatic hydrocarbon solvents, for example, halogenated aliphatic hydrocarbon solvents such as dichloromethane and chloroform, and single or mixed solvents such as water are used, and the amount used is not particularly limited. In addition, when the organic layer containing 2,4-dichloro-5-fluoropyrimidine obtained above is used as it is, such a solvent may not be newly used.
反応終了後、通常目的とする４−アミノ−２−クロロ−５−フルオロピリミジンの結晶が反応液中に析出しており、そのまま濾過処理して、４−アミノ−２−クロロ−５−フルオロピリミジンを取り出してもよいし、反応液を冷却した後、濾過処理して、４−アミノ−２−クロロ−５−フルオロピリミジンの結晶を取り出してもよい。取り出した４−アミノ−２−クロロ−５−フルオロピリミジンは、例えば再結晶等の通常の精製手段によりさらに精製してもよい。 After the completion of the reaction, the usual 4-amino-2-chloro-5-fluoropyrimidine crystals are precipitated in the reaction solution and filtered as it is to give 4-amino-2-chloro-5-fluoropyrimidine. Alternatively, after cooling the reaction solution, it may be filtered to take out crystals of 4-amino-2-chloro-5-fluoropyrimidine. The taken-out 4-amino-2-chloro-5-fluoropyrimidine may be further purified by ordinary purification means such as recrystallization.
実施例１
反応容器に、５−フルオロ−２−メトキシ−４（３Ｈ）−ピリミジノン１０ｇ、Ｎ，Ｎ−ジメチルアニリン４．５ｇおよびｏ−ジクロロベンゼン１５ｍＬを加え、内温１１０℃に加熱した。これに、オキシ塩化リン２４．５ｇを滴下した後、内温１２０〜１２５℃で、４時間攪拌、反応させた。反応終了後、内温６０℃に冷却し、反応液を水１３５ｍＬに滴下し、分液処理し、有機層と水層に分離した。水層をｏ−ジクロロベンゼン１５ｍＬで２回抽出処理し、得られた油層を先に得た有機層に合一し、２，４−ジクロロ−５−フルオロピリミジンを含む有機層を得た。２，４−ジクロロ−５−フルオロピリミジン含量：１１．８重量％、収率：８１％（５−フルオロ−２−メトキシ−４（３Ｈ）−ピリミジノン基準）。
Example 1
To the reaction vessel, 10 g of 5-fluoro-2-methoxy-4 (3H) -pyrimidinone, 4.5 g of N, N-dimethylaniline and 15 mL of o-dichlorobenzene were added and heated to an internal temperature of 110 ° C. To this was added dropwise 24.5 g of phosphorus oxychloride, and the mixture was stirred and reacted at an internal temperature of 120 to 125 ° C. for 4 hours. After completion of the reaction, the reaction solution was cooled to an internal temperature of 60 ° C., and the reaction solution was dropped into 135 mL of water and subjected to liquid separation treatment to separate an organic layer and an aqueous layer. The aqueous layer was extracted twice with 15 mL of o-dichlorobenzene, and the obtained oil layer was combined with the previously obtained organic layer to obtain an organic layer containing 2,4-dichloro-5-fluoropyrimidine. 2,4-Dichloro-5-fluoropyrimidine content: 11.8% by weight, yield: 81% (based on 5-fluoro-2-methoxy-4 (3H) -pyrimidinone).
実施例２
実施例１で得た２，４−ジクロロ−５−フルオロピリミジンを含む有機層に、２８重量％アンモニア水３０．１ｇを加え、密閉条件下、内温６０℃で６時間攪拌、反応させた。反応終了後、内温０〜５℃に冷却し、同温度で２時間攪拌、保持した。析出結晶を濾取し、濾取した結晶を冷イソプロパノール水（イソプロパノール／水体積比＝１／３）３０ｍＬで洗浄した後、減圧条件下で乾燥させ、４−アミノ−２−クロロ−５−フルオロピリミジン７．４ｇを得た。収率：７２％（５−フルオロ−２−メトキシ−４（３Ｈ）−ピリミジノン基準）。
Example 2
To the organic layer containing 2,4-dichloro-5-fluoropyrimidine obtained in Example 1, 30.1 g of 28 wt% aqueous ammonia was added, and the mixture was stirred and reacted at an internal temperature of 60 ° C. for 6 hours under sealed conditions. After completion of the reaction, the internal temperature was cooled to 0 to 5 ° C., and the mixture was stirred and maintained at the same temperature for 2 hours. The precipitated crystals were collected by filtration, washed with 30 mL of cold isopropanol water (isopropanol / water volume ratio = 1/3), dried under reduced pressure, and 4-amino-2-chloro-5-fluoro. 7.4 g of pyrimidine was obtained. Yield: 72% (based on 5-fluoro-2-methoxy-4 (3H) -pyrimidinone).
Claims (4)
4. Production of 4-amino-2-chloro-5-fluoropyrimidine, characterized in that ammonia is allowed to act on 2,4-dichloro-5-fluoropyrimidine obtained by the method according to any one of claims 1 to 3. Method.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| EP2562166A1 (en) | 2008-01-22 | 2013-02-27 | Dow AgroSciences LLC | 5-fluoro pyrimidine derivatives as fungicides |
| CN109776426A (en) * | 2019-03-18 | 2019-05-21 | 河南中医药大学 | A method of the preparation chloro- 5-FU of 2,4- bis- is reacted using ultraviolet catalytic |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2562166A1 (en) | 2008-01-22 | 2013-02-27 | Dow AgroSciences LLC | 5-fluoro pyrimidine derivatives as fungicides |
| EP2562163A1 (en) | 2008-01-22 | 2013-02-27 | Dow AgroSciences LLC | 5-fluoro pyrimidine derivatives as fungicides |
| EP2562165A1 (en) | 2008-01-22 | 2013-02-27 | Dow AgroSciences LLC | 5-fluoro pyrimidine derivatives as fungicides |
| EP2562167A1 (en) | 2008-01-22 | 2013-02-27 | Dow AgroSciences LLC | 5-fluoro pyrimidine derivatives as fungicides |
| EP2562162A1 (en) | 2008-01-22 | 2013-02-27 | Dow AgroSciences LLC | 5-fluoro pyrimidine derivatives as fungicides |
| EP2562175A1 (en) | 2008-01-22 | 2013-02-27 | Dow AgroSciences LLC | 5-fluoro pyrimidine derivatives as fungicides |
| EP2562164A1 (en) | 2008-01-22 | 2013-02-27 | Dow AgroSciences LLC | 5-fluoro pyrimidine derivatives as fungicides |
| EP2562161A1 (en) | 2008-01-22 | 2013-02-27 | Dow AgroSciences LLC | 5-fluoro pyrimidine derivatives as fungicides |
| CN109776426A (en) * | 2019-03-18 | 2019-05-21 | 河南中医药大学 | A method of the preparation chloro- 5-FU of 2,4- bis- is reacted using ultraviolet catalytic |
| CN109776426B (en) * | 2019-03-18 | 2022-03-01 | 河南中医药大学 | Method for preparing 2, 4-dichloro-5-fluoropyrimidine by utilizing ultraviolet light catalytic reaction |
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