JPH1149757A - Production of 5-perfluroalkyldihydrouracil derivative - Google Patents
Production of 5-perfluroalkyldihydrouracil derivativeInfo
- Publication number
- JPH1149757A JPH1149757A JP9212833A JP21283397A JPH1149757A JP H1149757 A JPH1149757 A JP H1149757A JP 9212833 A JP9212833 A JP 9212833A JP 21283397 A JP21283397 A JP 21283397A JP H1149757 A JPH1149757 A JP H1149757A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- derivative
- reaction
- perfluoroalkyldihydrouracil
- urea
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、５−パーフルオロ
アルキルジヒドロウラシル誘導体を製造する方法に関す
る。更に詳しくは、無水酢酸の存在下にα−パーフルオ
ロアルキルアクリル酸と尿素誘導体を反応させ、５−パ
ーフルオロアルキルジヒドロウラシル誘導体を製造する
方法における、改良された方法を提供するものである。TECHNICAL FIELD The present invention relates to a method for producing a 5-perfluoroalkyldihydrouracil derivative. More specifically, the present invention provides an improved method for producing a 5-perfluoroalkyldihydrouracil derivative by reacting an α-perfluoroalkylacrylic acid with a urea derivative in the presence of acetic anhydride.
【０００２】[0002]
【従来の技術】本発明により得られる５−パーフルオロ
アルキルジヒドロウラシル誘導体は、５，６位の水素基
の脱離反応により５−パーフルオロアルキルウラシル誘
導体へ誘導することが出来る。これら５−パーフルオロ
アルキルウラシル誘導体は、それ自身生理活性を有する
化合物であるばかりでなく、制癌剤、抗ウイルス剤とし
て知られる５−パーフルオロアルキルウリジン類または
５−パーフルオロアルキルデオキシウリジン類等の医薬
品の中間体として重要な物質である。2. Description of the Related Art A 5-perfluoroalkyldihydrouracil derivative obtained according to the present invention can be derived into a 5-perfluoroalkyluracil derivative by an elimination reaction of the hydrogen group at the 5,6-position. These 5-perfluoroalkyluracil derivatives are not only compounds having physiological activity themselves, but also pharmaceuticals such as 5-perfluoroalkyluridines or 5-perfluoroalkyldeoxyuridines known as anticancer agents and antiviral agents. It is an important substance as an intermediate of.
【０００３】従来、５−パーフルオロアルキルジヒドロ
ウラシル誘導体の製造方法として、パーフルオロアルキ
ルメチルケトンをシアノヒドリンとし、アセチル化した
後熱分解することによって得られるα−パーフルオロア
ルキルアクリルニトリルをメタノール中、臭化水素と反
応させβ−ブロモ−α−パーフルオロアルキルプロピオ
ンアミドとした後、尿素またはアセチル尿素と反応させ
て得られる化合物を塩酸中で環化させる方法が公知であ
る〔C.Heidelberger,D.G.Parsons and D.C.Remy,J.Med.
Chem.,7,1(1964)〕。しかし、この方法は工程が長く、
しかも総合収率は７〜１６％と極めて低いため、工業的
な製法としては満足できるものではない。Heretofore, as a method for producing a 5-perfluoroalkyldihydrouracil derivative, α-perfluoroalkylacrylonitrile obtained by converting perfluoroalkylmethylketone to cyanohydrin, acetylating the resultant, and then thermally decomposing the same in methanol, A method is known in which β-bromo-α-perfluoroalkylpropionamide is reacted with hydrogen chloride, and then the compound obtained by reacting with urea or acetylurea is cyclized in hydrochloric acid (C. Heidelberger, DG Parsons and DCRemy, J.Med.
Chem., 7, 1 (1964)]. However, this method requires a long process,
In addition, the overall yield is extremely low at 7 to 16%, which is not satisfactory as an industrial production method.
【０００４】また、特開昭５８−１７４３７１号公報に
は、触媒の存在下に２−ハロ−３，３，３−トリフルオ
ロプロペン、尿素誘導体および一酸化炭素を反応させ、
５−トリフルオロメチルジヒドロウラシル誘導体を製造
する方法が開示されている。しかしながら、この方法で
は５−トリフルオロメチルジヒドロウラシル誘導体の収
率は必ずしも高いとは言えず、工業的な製法としては満
足できるものではない。In Japanese Patent Application Laid-Open No. 58-174371, 2-halo-3,3,3-trifluoropropene, a urea derivative and carbon monoxide are reacted in the presence of a catalyst.
A method for producing a 5-trifluoromethyldihydrouracil derivative is disclosed. However, in this method, the yield of the 5-trifluoromethyldihydrouracil derivative is not always high, and is not satisfactory as an industrial production method.
【０００５】さらに、特公昭６１−４８８３０号公報に
は、α−パーフルオロアルキルアクリル酸と尿素誘導体
とから５−パーフルオロアルキルジヒドロウラシル誘導
体を製造する方法が開示されている。しかしながら、こ
の方法ではα−パーフルオロアルキルアクリル酸と尿素
誘導体の縮合反応に、ジシクロヘキシルカルボジイミド
などの高価な縮合剤が必要である。しかも反応後ジシク
ロヘキシルカルボジイミドに由来する副生物を分離する
操作が必要であり、工業的には不十分な方法と言わざる
をえない。Further, Japanese Patent Publication No. 61-48830 discloses a method for producing a 5-perfluoroalkyldihydrouracil derivative from α-perfluoroalkylacrylic acid and a urea derivative. However, in this method, an expensive condensing agent such as dicyclohexylcarbodiimide is required for the condensation reaction between the α-perfluoroalkylacrylic acid and the urea derivative. Moreover, after the reaction, an operation of separating by-products derived from dicyclohexylcarbodiimide is required, and it must be said that this method is industrially insufficient.
【０００６】さらに、特開昭６０−１９７７１号公報や
特開平８−２６９０２０号公報には、無水酢酸またはカ
ルボン酸無水物の存在下、α−パーフルオロアルキルア
クリル酸と尿素誘導体を反応させ、５−パーフルオロア
ルキルジヒドロウラシル誘導体を得る方法が開示されて
いる。この方法では所望の５−パーフルオロアルキルジ
ヒドロウラシル誘導体が６５〜７０％の比較的高い収率
で得られることが記載されている。Further, JP-A-60-19771 and JP-A-8-269020 disclose the reaction of α-perfluoroalkylacrylic acid with a urea derivative in the presence of acetic anhydride or carboxylic anhydride. A method for obtaining a perfluoroalkyldihydrouracil derivative is disclosed. This method describes that the desired 5-perfluoroalkyldihydrouracil derivative is obtained in a relatively high yield of 65 to 70%.
【０００７】本発明者らが上記公報に基づき、注意深く
追試を行なった結果、確かに５−トリフルオロメチルジ
ヒドロウラシルとされた固形物が理論量に対し約７５％
で得られた。しかしながら、本発明者らが精密に分析し
たところ、５−トリフルオロメチルジヒドロウラシルと
された固形物には不純物である大量のアセチル尿素が含
まれており、実際には理論量に対する５−トリフルオロ
メチルジヒドロウラシルの収率は５６％に留まることが
判明した。[0007] The inventors of the present invention have carried out a careful additional test based on the above-mentioned publication, and as a result, it has been confirmed that 5-trifluoromethyldihydrouracil solids are about 75% of the theoretical amount.
Was obtained. However, the present inventors have conducted a close analysis and found that the solid, which is regarded as 5-trifluoromethyldihydrouracil, contains a large amount of acetylurea as an impurity. The yield of methyldihydrouracil was found to be only 56%.
【０００８】また、特開平８−２６９０２０号公報に
は、生成した５−トリフルオロメチルジヒドロウラシル
の精製方法が開示されており、α−パーフルオロアルキ
ルアクリル酸と尿素誘導体のモル比が１．０〜ｌ．５の
時に５−トリフルオロメチルジヒドロウラシルの収率は
７０％まで向上することが記載されている。Japanese Patent Application Laid-Open No. Hei 8-269020 discloses a method for purifying the produced 5-trifluoromethyldihydrouracil, wherein the molar ratio of α-perfluoroalkylacrylic acid to urea derivative is 1.0. ~ L. It is described that the yield of 5-trifluoromethyldihydrouracil at 5 is improved to 70%.
【０００９】また、特開昭６１−２５４５３８号公報に
は、無水酢酸存在下に２−ヒドロキシメチルー３，３，
３−トリフルオロプロピオン酸と尿素を反応させる方法
が開示されている。特開昭６１−２５４５３８号公報で
は目的の５−トリフルオロメチルジヒドロウラシルが８
９％の高収率で得られている。しかしながら、この方法
ではα−トリフルオロメチルアクリル酸から２−ヒドロ
キシメチル−３，３，３−トリフルオロプロピオン酸を
合成するため反応工程が一段長くなり、経済性と総合収
率を考慮すると必ずしも有利な方法とは言い難い。Japanese Patent Application Laid-Open No. 61-254538 discloses that 2-hydroxymethyl-3,3,3 is used in the presence of acetic anhydride.
A method for reacting 3-trifluoropropionic acid with urea is disclosed. JP-A-61-254538 discloses that the target 5-trifluoromethyldihydrouracil is 8
It is obtained in a high yield of 9%. However, in this method, since 2-hydroxymethyl-3,3,3-trifluoropropionic acid is synthesized from α-trifluoromethylacrylic acid, the reaction step becomes longer, and it is not necessarily advantageous in view of economy and overall yield. It's hard to say.
【００１０】[0010]
【発明が解決しようとする課題】そこで本発明が解決し
ようとする課題は、５−パーフルオロアルキルジヒドロ
ウラシル誘導体の製造法において、高収率で目的とする
生成物を得るのみならず、発熱量をコントロールするこ
とにより工業的に実施可能な安全な方法を提供すること
である。The problem to be solved by the present invention is to provide a method for producing a 5-perfluoroalkyldihydrouracil derivative, which not only obtains a desired product in a high yield, but also generates a calorific value. Is to provide a safe method that can be implemented industrially by controlling
【００１１】[0011]
【課題を解決するための手段】本発明者らは、無水酢酸
の存在下にα−パーフルオロアルキルアクリル酸と尿素
誘導体を反応させ、５−パーフルオロアルキルジヒドロ
ウラシル誘導体を製造する方法について検討したとこ
ろ、特開昭６０−１９７７１号公報および特開平８−２
６９０２０号公報に記載されているような原料を一括し
て仕込む反応方法では反応生成熱が極めて大きく、工業
的規模では反応温度の制御が不可能となるばかりでな
く、目的とする生成物の収率が著しく低下するという致
命的な欠点を有することを見いだした。因みに、本発明
者らが本反応の生成熱をＭＯＰＡＣ（Ｖｅｒ．６）ＰＭ
３および化学便覧〔基礎編ＩＩ〕に記載された燃焼熱を
用いて計算すると、本反応の生成熱は３０ｋｃａ１／ｍ
ｏｌの発熱であると推定された。Means for Solving the Problems The present inventors have studied a method for producing a 5-perfluoroalkyldihydrouracil derivative by reacting an α-perfluoroalkylacrylic acid with a urea derivative in the presence of acetic anhydride. However, Japanese Patent Application Laid-Open Nos. 60-19977 and 8-2
In the reaction method described in Japanese Patent No. 69020, in which the raw materials are charged all at once, the heat of reaction production is extremely large, so that not only is it impossible to control the reaction temperature on an industrial scale, but also the yield of the target product is reduced. It has been found that it has the fatal disadvantage that the rate drops significantly. Incidentally, the inventors of the present invention determined the heat of formation of this reaction by MOPAC (Ver. 6) PM
3 and the heat of combustion described in the Chemical Handbook [Basic Edition II], the heat of formation of this reaction was 30 kcal / m
It was presumed to be exothermic.
【００１２】本発明者らは、こうした現状に鑑み、無水
酢酸の存在下にα−パーフルオロアルキルアクリル酸と
尿素誘導体を反応させ、５−パーフルオロアルキルジヒ
ドロウラシル誘導体を製造する方法について鋭意検討
し、本発明を完成するに至った。すなわち、本発明は
（１）無水酢酸の存在下に、一般式（１）In view of these circumstances, the present inventors have intensively studied a method for producing a 5-perfluoroalkyldihydrouracil derivative by reacting α-perfluoroalkylacrylic acid with a urea derivative in the presence of acetic anhydride. Thus, the present invention has been completed. That is, the present invention provides (1) a compound represented by the general formula (1) in the presence of acetic anhydride:
【００１３】[0013]
【化５】 Embedded image
【００１４】（式中、Ｒｆは炭素数１ないし１０のα−
パーフルオロアルキル基を表す）で示されるα−パーフ
ルオロアルキルアクリル酸と、一般式（２） Ｒ1ＮＨＣＯＮＨＲ2 （２） （式中、Ｒ1およびＲ2はそれぞれ独立して水素、メチル
基またはエチル基を表す）で示される尿素誘導体を反応
させ、生成する酢酸を系外に除去しながら反応させるこ
とを特徴とする、一般式（３）(Wherein Rf is α-C 1 -C 10)
An α-perfluoroalkylacrylic acid represented by a perfluoroalkyl group) and R 1 NHCONHR 2 (2) (wherein R 1 and R 2 are each independently hydrogen, a methyl group or A urea derivative represented by the following general formula (3):
【００１５】[0015]
【化６】 Embedded image
【００１６】（式中、Ｒｆ、Ｒ1およびＲ2は前記定義に
同じ）で示される５−パーフルオロアルキルジヒドロウ
ラシル誘導体の製造方法、（２） 無水酢酸と一般式
（２） Ｒ1 無水酢酸の存在下に、一般式（２） Ｒ1ＮＨＣＯＮＨＲ2 （２） （式中、Ｒ1およびＲ2はそれぞれ独立して水素、メチル
基またはエチル基を表す）で示される尿素誘導体に、前
記一般式（１）で示されるα−パーフルオロアルキルア
クリル酸を逐次的に添加して反応させることを特徴とす
る、前記一般式（３）で示される５−パーフルオロアル
キルジヒドロウラシル誘導体の製造方法、（４） 生成
する酢酸を系外に除去しながら反応させることを特徴と
する前記（２）項に記載の５−パーフルオロアルキルジ
ヒドロウラシル誘導体の製造方法、（５） α−パーフ
ルオロアルキルアクリル酸に対する尿素誘導体の総量の
モル比が１．１以上３．０以下である前記（２）項また
は前記（３）項に記載の５−パーフルオロアルキルジヒ
ドロウラシル誘導体の製造方法、（６） α−パーフル
オロアルキルアクリル酸と尿素誘導体の反応温度が７０
から１２０℃である前記（１）項ないし前記（５）項の
いずれか１項に記載の５−パーフルオロアルキルジヒド
ロウラシル誘導体の製造方法、（７） 無水酢酸の量が
α−パーフルオロアルキルアクリル酸の総添加量の３な
いし１０倍量である請求項１ないし請求項６のいずれか
に記載の５−パーフルオロアルキルジヒドロウラシル誘
導体の製造方法、に関するものである。(Wherein Rf, R 1 and R 2 are as defined above), (2) acetic anhydride and the general formula (2) R 1 acetic anhydride In the presence of a urea derivative represented by the general formula (2) R 1 NHCONHR 2 (2) (wherein R 1 and R 2 each independently represent hydrogen, a methyl group or an ethyl group), A method for producing a 5-perfluoroalkyldihydrouracil derivative represented by the general formula (3), wherein α-perfluoroalkylacrylic acid represented by the formula (1) is sequentially added and reacted. (4) The method for producing a 5-perfluoroalkyldihydrouracil derivative according to the above (2), wherein the reaction is carried out while removing generated acetic acid out of the system, (5) α-perfur (5) The method for producing a 5-perfluoroalkyldihydrouracil derivative according to the above (2) or (3), wherein the molar ratio of the total amount of the urea derivative to the loalkylacrylic acid is 1.1 or more and 3.0 or less, 6) The reaction temperature of α-perfluoroalkylacrylic acid and urea derivative is 70
The method for producing a 5-perfluoroalkyldihydrouracil derivative according to any one of the above items (1) to (5), wherein (a) the amount of acetic anhydride is α-perfluoroalkylacrylic. The method for producing a 5-perfluoroalkyldihydrouracil derivative according to any one of claims 1 to 6, which is 3 to 10 times the total amount of the acid added.
【００１７】[0017]
【発明の実施の形態】以下、本発明について更に詳しく
説明する。BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail.
【００１８】本発明において使用される原料は、α−パ
ーフルオロアルキルアクリル酸、尿素誘導体および無水
酢酸である。The starting materials used in the present invention are α-perfluoroalkylacrylic acid, urea derivatives and acetic anhydride.
【００１９】本発明におけるα−パーフルオロアルキル
アクリル酸とは、前記一般式（１）で示されるようにα
位にパーフルオロアルキル基を有するα置換アクリル酸
である。パーフルオロアルキル基は炭素数が１〜１０の
弗素化されたアルキル基である。一般式（１）で表され
るα−パーフルオロアルキルアクリル酸の具体例として
は、例えばα−トリフルオロメチルアクリル酸、α−ペ
ンタフルオロエチルアクリル酸、α−ヘプタフルオロプ
ロピルアクリル酸、α−ノナフルオロブチルアクリル
酸、α−ヘプタフルオロ−ｉｓｏ−プロピルアクリル
酸、α−ノナフルオロ−ｉｓｏ−プチルアクリル酸、α
−ノナフルオロ−ｓｅｃ−ブチルアクリル酸、α−ノナ
フルオロ−ｔｅｒｔ−ブチルアクリル酸、α−ノナフル
オロペンチルアクリル酸、α−パーフルオロヘプチルア
クリル酸、α−パーフルオロオクチルアクリル酸等が挙
げられる。これらのうち、より好ましくはα−トリフル
オロメチルアクリル酸、α−ペンタフルオロエチルアク
リル酸が挙げられる。α−パーフルオロアルキルアクリ
ル酸の純度に特に制限はないが、望ましくは９５％以上
のものを用いるのが好ましい。これらα−パーフルオロ
アルキルアクリル酸は通常固体である。そのため固体を
粉体として反応に供しても差し支えないが、望ましくは
無水酢酸に溶解して液体として反応に供することがが好
ましい。In the present invention, α-perfluoroalkylacrylic acid refers to α-perfluoroalkylacrylic acid as represented by the above general formula (1).
Α-substituted acrylic acid having a perfluoroalkyl group at the 1-position. The perfluoroalkyl group is a fluorinated alkyl group having 1 to 10 carbon atoms. Specific examples of the α-perfluoroalkyl acrylic acid represented by the general formula (1) include, for example, α-trifluoromethyl acrylic acid, α-pentafluoroethyl acrylic acid, α-heptafluoropropyl acrylic acid, α-nona Fluorobutylacrylic acid, α-heptafluoro-iso-propylacrylic acid, α-nonafluoro-iso-butylacrylic acid, α
-Nonafluoro-sec-butylacrylic acid, α-nonafluoro-tert-butylacrylic acid, α-nonafluoropentylacrylic acid, α-perfluoroheptylacrylic acid, α-perfluorooctylacrylic acid, and the like. Among these, α-trifluoromethylacrylic acid and α-pentafluoroethylacrylic acid are more preferable. The purity of the α-perfluoroalkylacrylic acid is not particularly limited, but it is preferable to use a purity of 95% or more. These α-perfluoroalkylacrylic acids are usually solids. Therefore, the solid may be subjected to the reaction as a powder, but it is preferable that the solid is dissolved in acetic anhydride and then subjected to the reaction as a liquid.
【００２０】本発明における尿素誘導体とは、前記一般
式（２）で示される化合物であり、具体例として例えば
尿素、メチル尿素、エチル尿素、ジメチル尿素、ジエチ
ル尿素等が挙げられる。これらのうち、好ましくは尿素
またはメチル尿素である。これらの純度は特に制限はな
いが望ましくは９５％以上のものが好ましい。これら尿
素誘導体は通常固体である。そのため固体を粉体として
反応に供しても差し支えないが、望ましくは無水酢酸に
溶解し液体またはスラリーとして反応に供することが好
ましい。The urea derivative in the present invention is a compound represented by the general formula (2), and specific examples include urea, methyl urea, ethyl urea, dimethyl urea, diethyl urea and the like. Of these, urea or methyl urea is preferred. Their purity is not particularly limited, but is preferably 95% or more. These urea derivatives are usually solid. Therefore, the solid may be subjected to the reaction as a powder. However, it is preferable that the solid be dissolved in acetic anhydride and then subjected to the reaction as a liquid or a slurry.
【００２１】本発明における目的物である５−パーフル
オロアルキルジヒドロウラシル誘導体は、前記一般式
（３）で示される化合物であるが、具体的には、例えば
５−トリフルオロメチルジヒドロウラシル（式３−
１）、１−メチル−５−トリフルオロメチルジヒドロウ
ラシル（式３−２）、３−メチル−５−トリフルオロメ
チルジヒドロウラシル（式３−３）The 5-perfluoroalkyldihydrouracil derivative, which is the object of the present invention, is a compound represented by the above general formula (3). Specifically, for example, 5-trifluoromethyldihydrouracil (formula 3) −
1), 1-methyl-5-trifluoromethyldihydrouracil (Formula 3-2), 3-methyl-5-trifluoromethyldihydrouracil (Formula 3-3)
【００２２】[0022]
【化７】 Embedded image
【００２３】等を挙げることができる。And the like.
【００２４】本発明において脱水剤および溶媒として使
用される無水酢酸は、通常の市販品が使用できる。As the acetic anhydride used as the dehydrating agent and the solvent in the present invention, ordinary commercial products can be used.
【００２５】次に、これらの原料を用いて反応を行な
う。反応は、例えば攪拌機、滴下装置、温度計および冷
却装置を備えた反応器を用いて行なう。本発明方法は、
反応系に生成する酢酸を系外の除去しながら反応を行な
うこと、および原料を特定の方法で逐次的に反応させ
て、反応生成熱を抑制しながら反応を行なうことに特徴
があり、反応形式としては、 無水酢酸の溶媒中に、α−パーフルオロアルキルアク
リル酸の無水酢酸溶液および尿素誘導体の無水酢酸溶液
を一括添加する方法、 無水酢酸の溶媒中に、α−パーフルオロアルキルアク
リル酸の無水酢酸溶液と尿素誘導体の無水酢酸溶液をそ
れぞれ逐次添加する方法、 α−パーフルオロアルキルアクリル酸の無水酢酸溶液
を尿素誘導体の無水酢酸溶液中に逐次添加する方法、 尿素誘導体の無水酢酸溶液をα−パーフルオロアルキ
ルアクリル酸の無水酢酸溶液に逐次添加する方法などが
考えられる。Next, a reaction is carried out using these raw materials. The reaction is performed using, for example, a reactor equipped with a stirrer, a dropping device, a thermometer, and a cooling device. The method of the present invention comprises:
It is characterized by performing the reaction while removing the acetic acid generated in the reaction system from the outside of the system, and performing the reaction while suppressing the heat of reaction formation by sequentially reacting the raw materials by a specific method. As a method of simultaneously adding an acetic anhydride solution of α-perfluoroalkylacrylic acid and an acetic anhydride solution of a urea derivative in a solvent of acetic anhydride, in a solvent of acetic anhydride, the anhydride of α-perfluoroalkylacrylic acid is added. A method of sequentially adding an acetic acid solution and an acetic anhydride solution of a urea derivative; a method of sequentially adding an acetic anhydride solution of α-perfluoroalkylacrylic acid to an acetic anhydride solution of a urea derivative; A method of sequentially adding perfluoroalkylacrylic acid to an acetic anhydride solution may be considered.
【００２６】本発明方法によれば、の方法は、反応熱
が極めて大きいため小規模の実験室的スケールで実施で
きるが、工業的なスケールには不向きである。の方法
は、原料のα−パーフルオロアルキルアクリル酸が重合
したり、尿素と多付加体を形成するため、収率が低下す
るので好ましくない。本発明の原料を特定の方法で逐次
的に反応させるとは、およびの方法であり、反応生
成熱を抑制しながら高収率に反応を行なうことができ
る。According to the method of the present invention, the method can be carried out on a small-scale laboratory scale due to an extremely large heat of reaction, but is not suitable for an industrial scale. The method of (1) is not preferable because the raw material α-perfluoroalkylacrylic acid is polymerized or forms a multi-adduct with urea, which lowers the yield. The method of sequentially reacting the raw materials of the present invention by a specific method is the method described in (1) and (2), and the reaction can be performed in high yield while suppressing the heat of reaction.
【００２７】これら２つの方法のうち、特に無水酢酸に
対する原料の溶解度、量および操作性を考慮しての方
法がより好ましい。Of these two methods, the method taking into account the solubility, amount and operability of the raw material in acetic anhydride is more preferable.
【００２８】本発明における、逐次添加による反応で
は、反応時間は反応による発熱と冷却速度を考慮しなが
ら通常１時間から３時間で行なう。このあと熟成を３０
分から１時間行なうことが好ましい。本反応中の攪拌速
度は特に制限はなく、反応器の形状や攪拌羽根の形状に
応じて適宜決められるが、通常２００〜１６００ｒｐｍ
である。In the reaction according to the present invention, the reaction is generally carried out for 1 to 3 hours in consideration of the heat generated by the reaction and the cooling rate. After this, aged 30
It is preferable to carry out for a minute to one hour. The stirring speed during this reaction is not particularly limited, and is appropriately determined according to the shape of the reactor and the shape of the stirring blade, and is usually 200 to 1600 rpm.
It is.
【００２９】本発明の方法は、反応温度は７０℃以上１
１０℃以下、好ましくは８０℃以上１００℃以下で実施
される。反応温度が７０℃未満では反応の進行が遅くな
り収率は低く、また、１１０℃を越えると５−パーフル
オロアルキルジヒドロウラシル誘導体の選択率が低くな
ったり、分解が生じるため実用的ではなくなる。In the method of the present invention, the reaction temperature is 70 ° C. or higher and 1
It is carried out at a temperature of 10 ° C or lower, preferably 80 ° C or higher and 100 ° C or lower. If the reaction temperature is lower than 70 ° C., the progress of the reaction is slowed and the yield is low, and if it exceeds 110 ° C., the selectivity of the 5-perfluoroalkyldihydrouracil derivative is lowered or decomposition occurs, which is not practical.
【００３０】本反応において、反応の進行とともに反応
系に酢酸が生成する。即ち、１モルの５−パーフルオロ
アルキルジヒドロウラシル誘導体（３）が生成すると１
モルの水が生成し、これが無水酢酸と直ちに反応して２
モルの酢酸が生成する。生成した酢酸は本反応系の酸性
度を低下させ、尿素誘導体と付加体を形成したり、α−
パーフルオロアルキルアクリル酸と競争反応するため尿
素誘導体との反応を疎外し、目的とする生成物の収率を
低下させる。In this reaction, acetic acid is generated in the reaction system as the reaction proceeds. That is, when one mole of the 5-perfluoroalkyldihydrouracil derivative (3) is formed, 1
Moles of water are formed which immediately react with acetic anhydride to form
Molar acetic acid is formed. The generated acetic acid lowers the acidity of the reaction system to form an adduct with the urea derivative,
Since it competes with perfluoroalkylacrylic acid, the reaction with urea derivatives is excluded, and the yield of the desired product is reduced.
【００３１】本発明によれば、反応により生成した酢酸
を逐次的に系外に除去することによって、例えば１００
〜３００ｍｍＨｇの減圧条件にすることによって、効率
的に反応を実施することができる。本操作により逐次添
加する尿素誘導体の過剰な添加量を節減し、かつ、目的
の５−パーフルオロアルキルジヒドロウラシル誘導体を
高収率で得ることが出来る。尿素誘導体のモル比は酢酸
の抜き出し量にも依るが、α−パーフルオロアルキルア
クリル酸に対して、１．１〜２．０、好ましくは１．１
〜１．５である。According to the present invention, the acetic acid generated by the reaction is sequentially removed from the system, for example, by removing 100% of the acetic acid.
The reaction can be efficiently performed by reducing the pressure to 300 mmHg. By this operation, an excessive amount of the urea derivative added sequentially can be reduced, and the desired 5-perfluoroalkyldihydrouracil derivative can be obtained in a high yield. Although the molar ratio of the urea derivative depends on the amount of acetic acid extracted, it is 1.1 to 2.0, preferably 1.1 to 2.0 with respect to the α-perfluoroalkylacrylic acid.
1.5.
【００３２】本発明によれば、本反応系より酢酸を抜き
出さない場合、目的生成物を高収率で得るために尿素誘
導体を大過剰量添加しなければならない。過剰量添加す
る尿素誘導体はα−パーフルオロアルキルアクリル酸に
対して、モル比で１．５以上４．０以下であり、好まし
くは１．７以上３．０以下である。１．５未満では必要
量以下となり収率が著しく低下する。一方４．０を越え
ると尿素誘導体が必要以上になるため経済性が失われ工
業的に好ましくない。According to the present invention, if acetic acid is not extracted from the reaction system, a large excess of a urea derivative must be added in order to obtain the desired product in a high yield. The urea derivative to be added in an excessive amount is 1.5 to 4.0, preferably 1.7 to 3.0 in molar ratio with respect to α-perfluoroalkylacrylic acid. If it is less than 1.5, it becomes less than the required amount, and the yield is remarkably reduced. On the other hand, if it exceeds 4.0, the urea derivative becomes unnecessarily necessary, and the economical efficiency is lost, which is not industrially preferable.
【００３３】本発明における反応雰囲気は特に限定され
ないが、窒素、アルゴンなどの不活性ガス雰囲気で実施
することが望ましい。The reaction atmosphere in the present invention is not particularly limited, but it is desirable to carry out the reaction in an atmosphere of an inert gas such as nitrogen or argon.
【００３４】本発明において、無水酢酸の量がα−パー
フルオロアルキルアクリル酸の３以上１０倍量以下、好
ましくは３以上６倍量以下である。６倍量を越えると反
応器が大きくなり経済性が失われ工業的に好ましくな
い。In the present invention, the amount of acetic anhydride is 3 to 10 times, preferably 3 to 6 times the amount of α-perfluoroalkylacrylic acid. If the amount exceeds 6 times, the reactor becomes large and economical efficiency is lost, which is not industrially preferable.
【００３５】かくして、反応を行なった後、５−パーフ
ルオロアルキルジヒドロウラシル誘導体は、例えば、次
のようにして反応液から回収することができる。Thus, after performing the reaction, the 5-perfluoroalkyldihydrouracil derivative can be recovered from the reaction solution, for example, as follows.
【００３６】すなわち、反応系を真空ポンプにより滅圧
し、無水酢酸と酢酸を留去し、濃縮された反応母液を得
る。分離した無水酢酸および酢酸の溶液は必要に応じて
精製し再利用することができる。濃縮された反応母液に
大量のエタノールを添加し加温した後、室温に冷却する
と所望の５−パーフルオロアルキルジヒドロウラシル誘
導体が晶析する。添加するエタノールの量は通常５−パ
ーフルオロアルキルジヒドロウラシル誘導体の濃度が、
１５重量％以上３５重量％以下、好ましくは２０重量％
以上３０重量％以下となるように調整するのがよい。１
５重量％未満では目的生成物の母液への溶解により収率
が低下してしまう。３５重量％を越えると結晶が完溶し
ないため品質を低下させる。That is, the pressure in the reaction system is reduced by a vacuum pump, and acetic anhydride and acetic acid are distilled off to obtain a concentrated reaction mother liquor. The separated solution of acetic anhydride and acetic acid can be purified and reused as necessary. A large amount of ethanol is added to the concentrated reaction mother liquor, heated, and then cooled to room temperature, whereby a desired 5-perfluoroalkyldihydrouracil derivative is crystallized. The amount of ethanol to be added is usually the concentration of the 5-perfluoroalkyldihydrouracil derivative,
15% by weight or more and 35% by weight or less, preferably 20% by weight
It is preferable to adjust the amount to be 30% by weight or less. 1
If the amount is less than 5% by weight, the yield is reduced due to the dissolution of the target product in the mother liquor. If it exceeds 35% by weight, the crystals will not be completely dissolved, thus deteriorating the quality.
【００３７】晶析された５−パーフルオロアルキルジヒ
ドロウラシル誘導体は、濾過し乾燥することにより所望
の５−パーフルオロアルキルジヒドロウラシル誘導体
（１次結晶）が得られる。The crystallized 5-perfluoroalkyldihydrouracil derivative is filtered and dried to obtain a desired 5-perfluoroalkyldihydrouracil derivative (primary crystal).
【００３８】さらに、母液を、例えば、ロータリーエバ
ポレーターで減圧して、濃縮し再結晶させると５−パー
フルオロアルキルジヒドロウラシル誘導体（２次結晶）
が得られる。このようにして１次結晶と２次結晶を合わ
せて、５−パーフルオロアルキルジヒドロウラシル誘導
体を高収率で得ることができる。Further, the mother liquor is reduced in pressure with, for example, a rotary evaporator, concentrated and recrystallized to give a 5-perfluoroalkyldihydrouracil derivative (secondary crystal)
Is obtained. Thus, the 5-perfluoroalkyldihydrouracil derivative can be obtained in high yield by combining the primary crystal and the secondary crystal.
【００３９】[0039]
【実施例】以下、本発明を具体的に実施例にて説明する
が、本発明はこれらの実施例のみに限定されるものでな
い。EXAMPLES Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples.
【００４０】実施例１ 攪拌機、滴下ロート、温度計および冷却装置を備えた３
００ｍｌ四口フラスコに、無水酢酸（日本合成化学社製
市販品）７２．０ｇ（０．７１モル）と尿素（三井東
圧化学社製 市販品）１７．４ｇ（０．２９モル）をと
り、窒素雰囲気下に、８００ｒｐｍで攪拌しながら溶液
の温度を９０℃まで昇温した。このとき溶液中の尿素は
スラリー状であつた。ここへ反応温度を９０〜９５℃に
保ちながら２０．０ｇ（０．１４モル）のα−トリフル
オロメチルアクリル酸（エフテック社製 純度９５．３
％）の無水酢酸２８．０ｇ（０．２７モル）溶液を２時
間で滴下した。反応開始直後に系内を１５０ｍｍＨｇに
減圧し、系内に生成した酢酸を１４．０ｇ（理論量に対
して８３．３％）回収した。滴下終了後４５分間反応液
を熟成させた。熟成終了後、反応液を真空ポンプにより
減圧し、無水酢酸と酢酸を蒸留分離し、濃縮された反応
母液を得た。ここヘエタノール１２５ｃｃを添加し加温
した後、室温に冷却し５−トリフルオロメチルジヒドロ
ウラシルを晶析した。次にこれを母液と結晶に濾過分離
した。５−トリフルオロメチルジヒドロウラシルの結晶
は乾燥し、１次結晶２０．５ｇ（高速液体クロマトグラ
フによる内部標準法により算出）を得た。さらに、母液
をロータリーエバポレーターで減圧濃縮し、晶析するこ
とにより５−トリフルオロメチルジヒドロウラシルの２
次結晶０．６ｇを得た。１次結晶と２次結晶を合わせた
５−トリフルオロメチルジヒドロウラシルの全収率は８
２．８％であった。このとき生成したアセチル尿素は
３．６ｇであった。得られた５−トリフルオロメチルジ
ヒドロウラシルの分析結果を以下に示す。Example 1 3 equipped with a stirrer, a dropping funnel, a thermometer and a cooling device
In a 00 ml four-necked flask, 72.0 g (0.71 mol) of acetic anhydride (commercially available from Nippon Synthetic Chemical Company) and 17.4 g (0.29 mol) of urea (commercially available from Mitsui Toatsu Chemicals) were added. Under a nitrogen atmosphere, the temperature of the solution was increased to 90 ° C. while stirring at 800 rpm. At this time, the urea in the solution was in a slurry state. While maintaining the reaction temperature at 90 to 95 ° C., 20.0 g (0.14 mol) of α-trifluoromethylacrylic acid (purity 95.3, manufactured by F-Tech) was added.
%) In 28.0 g (0.27 mol) of acetic anhydride was added dropwise over 2 hours. Immediately after the start of the reaction, the pressure in the system was reduced to 150 mmHg, and 14.0 g (83.3% of the theoretical amount) of acetic acid generated in the system was recovered. After completion of the dropwise addition, the reaction solution was aged for 45 minutes. After completion of the aging, the reaction solution was depressurized by a vacuum pump, and acetic anhydride and acetic acid were separated by distillation to obtain a concentrated reaction mother liquor. After 125 cc of ethanol was added thereto and the mixture was heated, the mixture was cooled to room temperature to crystallize 5-trifluoromethyldihydrouracil. Next, this was separated by filtration into a mother liquor and crystals. The crystals of 5-trifluoromethyldihydrouracil were dried to obtain 20.5 g of primary crystals (calculated by an internal standard method using high performance liquid chromatography). Further, the mother liquor was concentrated under reduced pressure with a rotary evaporator, and crystallized to obtain 2-trifluoromethyldihydrouracil.
0.6 g of the next crystal was obtained. The total yield of 5-trifluoromethyldihydrouracil obtained by combining the primary crystal and the secondary crystal is 8
2.8%. The acetyl urea generated at this time was 3.6 g. The analysis results of the obtained 5-trifluoromethyldihydrouracil are shown below.
【００４１】 ５−トリフルオロメチルジヒドロウラシル ｍ．ｐ．：２０３〜２０５℃（分解）（文献値２０３〜２０５℃（分解）） ＩＲ（ＫＢｒ）：３５００〜２７５０ｃｍ-1（νN-H） １７２５，１７５０ｃｍ-1（νC=O） 1Ｈ ＮＭＲ（ｄ6−ＤＭＳＯ，ＴＭＳ）：σ ３．４〜４．０（ｍ，３Ｈ） ７．８（ｂｓ，１Ｈ）１０．５（ｂｓ，１Ｈ） 19Ｆ ＮＭＲ（ｄ6−ＤＭＳＯ，ＣＦＣｌ3）：σ−６５．６（ｄ） 実施例２ 実施例１と同一の反応器に、無水酢酸４８．０ｇ（０．
４７モル）と尿素１７．１ｇ（０．２９モル）をとり、
実施例１と同一の反応条件下で、２０．０ｇ（０．１４
モル）のα−トリフルオロメチルアクリル酸の無水酢酸
２８．０ｇ（０．２７モル）溶液を２時間で滴下し、滴
下終了後４５分間熟成させた。熟成終了後、実施例１と
全く同様の操作を行ない、５−トリフルオロメチルジヒ
ドロウラシルの１次結晶と２次結晶を合わせて１９．４
ｇ得た。α−トリフルオロメチルアクリル酸ベースの全
収率は７６．１％であった。このとき生成したアセチル
尿素は９．６ｇであった。5-trifluoromethyldihydrouracil m. p. : 203 to 205 ° C (decomposition) (literature value: 203 to 205 ° C (decomposition)) IR (KBr): 3500 to 2750 cm -1 (ν NH ) 1725, 1750 cm -1 (ν C = O ) 1 H NMR (d 6) -DMSO, TMS): σ 3.4 to 4.0 (m, 3H) 7.8 (bs, 1H) 10.5 (bs, 1H) 19 F NMR (d 6 -DMSO, CFCl 3 ): σ- 65.6 (d) Example 2 In the same reactor as in Example 1, 48.0 g of acetic anhydride (0.
47 mol) and 17.1 g (0.29 mol) of urea,
Under the same reaction conditions as in Example 1, 20.0 g (0.14 g
28.0 g (0.27 mol) of α-trifluoromethylacrylic acid in 2 mol of acetic anhydride was added dropwise over 2 hours, and the mixture was aged for 45 minutes after completion of the dropwise addition. After completion of the aging, the same operation as in Example 1 was performed, and the total of the primary and secondary crystals of 5-trifluoromethyldihydrouracil was 19.4.
g was obtained. The overall yield based on α-trifluoromethylacrylic acid was 76.1%. The acetyl urea generated at this time was 9.6 g.
【００４２】実施例３ 実施例１と同一の反応器に、無水酢酸７２．０ｇ（０．
７１モル）と尿素１２．６ｇ（０．２１モル）をとり、
実施例１と同一の反応条件で、２０．０（０．１４モ
ル）のα−トリフルオロメチルアクリル酸の無水酢酸２
８．０ｇ（０．２７モル）溶液を２時間で滴下した。反
応開始直後に系内を１５０ｍｍＨｇに減圧し、系内に生
成した酢酸を１１．９ｇ（理論量に対して７０．８％）
回収した。滴下終了後４５分間反応液を熟成させた。熟
成終了後、実施例１と全く同様の操作を行ない、５−ト
リフルオロメチルジヒドロウラシルの１次結晶と２次結
晶を合わせて１７．５ｇ得た。α−トリフルオロメチル
アクリル酸ベースの全収率は６８．５％であった。この
とき生成したアセチル尿素は６．３ｇであった。Example 3 In the same reactor as in Example 1, 72.0 g of acetic anhydride (0.
71 mol) and 12.6 g (0.21 mol) of urea,
Under the same reaction conditions as in Example 1, 20.0 (0.14 mol) of α-trifluoromethyl acrylic acid in acetic anhydride 2
An 8.0 g (0.27 mol) solution was added dropwise over 2 hours. Immediately after the start of the reaction, the pressure in the system was reduced to 150 mmHg, and 11.9 g of acetic acid generated in the system (70.8% based on the theoretical amount).
Collected. After completion of the dropwise addition, the reaction solution was aged for 45 minutes. After completion of the aging, the same operation as in Example 1 was carried out to obtain a total of 17.5 g of primary and secondary crystals of 5-trifluoromethyldihydrouracil. The total yield based on α-trifluoromethylacrylic acid was 68.5%. The acetyl urea generated at this time was 6.3 g.
【００４３】比較例１ 実施例１と同一の反応器に、無水酢酸４８．０ｇ（０．
４７モル）と尿素９．２ｇ（０．１５モル）をとり、実
施例１と同一の反応条件下で、２０．０ｇ（０．１４モ
ル）のα−トリフルオロメチルアクリル酸の無水酢酸２
８．０ｇ（０．２７モル）溶液を２時間で滴下し、滴下
終了後４５分間熟成させた。熟成終了後、実施例１と全
く同様の操作を行ない、５−トリフルオロメチルジヒド
ロウラシルの１次結晶と２次結晶を合わせて６．４ｇ得
た。α−トリフルオロメチルアクリル酸ベースの全収率
は２５．１％であった。このとき生成したアセチル尿素
は１１．２ｇであった。Comparative Example 1 In the same reactor as in Example 1, 48.0 g of acetic anhydride (0.
47 mol) and 9.2 g (0.15 mol) of urea, and under the same reaction conditions as in Example 1, 20.0 g (0.14 mol) of α-trifluoromethylacrylic acid in acetic anhydride 2
8.0 g (0.27 mol) of the solution was added dropwise over 2 hours, and the mixture was aged for 45 minutes after completion of the addition. After the completion of the ripening, the same operation as in Example 1 was performed to obtain 6.4 g of primary crystals and secondary crystals of 5-trifluoromethyldihydrouracil in total. The total yield based on α-trifluoromethylacrylic acid was 25.1%. The acetyl urea produced at this time was 11.2 g.
【００４４】比較例２ 実施例１と同一の反応器に、無水酢酸４８．０ｇ（０．
４７モル）とα−トリフルオロメチルアクリル酸２０．
０ｇ（０．１４モル）をとり、実施例１と同一の反応条
件下で、尿素９．２ｇ（０．１５モル）の無水酢酸２
８．０ｇ（０．２７モル）溶液を２時間で滴下し、滴下
終了後４５分間熟成させた。熟成終了後、実施例１と全
く同様の操作を行ない、５−トリフルオロメチルジヒド
ロウラシルの１次結晶と２次結晶を合わせて４．５ｇ得
た。α−トリフルオロメチルアクリル酸ベースの全収率
は１７．６％であった。このとき生成したアセチル尿素
は５．４ｇであった。Comparative Example 2 In the same reactor as in Example 1, 48.0 g of acetic anhydride (0.
47 mol) and α-trifluoromethylacrylic acid.
Under the same reaction conditions as in Example 1, 9.2 g (0.15 mol) of urea and acetic anhydride 2
8.0 g (0.27 mol) of the solution was added dropwise over 2 hours, and the mixture was aged for 45 minutes after completion of the addition. After the completion of the ripening, the same operation as in Example 1 was performed to obtain a total of 4.5 g of primary crystals and secondary crystals of 5-trifluoromethyldihydrouracil. The overall yield based on α-trifluoromethylacrylic acid was 17.6%. The acetyl urea produced at this time was 5.4 g.
【００４５】実施例４ 実施例１と同一の反応器に、無水酢酸４０．０ｇ（０．
３９モル）をとり、実施例１と同一の反応条件で、２
０．０（０．１４モル）のα−トリフルオロメチルアク
リル酸の無水酢酸２８．０ｇ（０．２７モル）溶液と尿
素２５．２ｇ（０．４２モル）の無水酢酸３２．０ｇ
（０．３１モル）を同時に２時間で滴下した。反応開始
直後に系内を１５０ｍｍＨｇに減圧し、系内に生成した
酢酸を１０．５ｇ（理論量に対して６２．５％）回収し
た。滴下終了後４５分間反応液を熟成させた。熟成終了
後、実施例１と全く同様の操作を行ない、５−トリフル
オロメチルジヒドロウラシルの１次結晶と２次結晶を合
わせて１６．１ｇ得た。α−トリフルオロメチルアクリ
ル酸ベースの全収率は６３．１％であった。このとき生
成したアセチル尿素は８．１ｇであった。Example 4 In the same reactor as in Example 1, 40.0 g of acetic anhydride (0.
39 mol) under the same reaction conditions as in Example 1.
A solution of 0.0 (0.14 mol) of α-trifluoromethylacrylic acid in 28.0 g (0.27 mol) of acetic anhydride and 25.2 g (0.42 mol) of urea in 32.0 g of acetic anhydride
(0.31 mol) were simultaneously added dropwise over 2 hours. Immediately after the start of the reaction, the pressure in the system was reduced to 150 mmHg, and 10.5 g (62.5% of the theoretical amount) of acetic acid generated in the system was recovered. After completion of the dropwise addition, the reaction solution was aged for 45 minutes. After the completion of the aging, the same operation as in Example 1 was performed to obtain a total of 16.1 g of primary crystals and secondary crystals of 5-trifluoromethyldihydrouracil. The total yield based on α-trifluoromethylacrylic acid was 63.1%. The acetyl urea generated at this time was 8.1 g.
【００４６】実施例５ 実施例１と同一の反応器に、無水酢酸４０．０ｇ（０．
３９モル）をとり、実施例１と同一の反応条件で、２
０．０（０．１４モル）のα−トリフルオロメチルアク
リル酸の無水酢酸２８．０ｇ（０．２７モル）溶液と尿
素２５．２ｇ（０．４２モル）の無水酢酸３２．０ｇ
（０．３１モル）を同時に２時間で滴下し、滴下終了後
４５分間反応液を熟成させた。熟成終了後、実施例１と
全く同様の操作を行ない、５−トリフルオロメチルジヒ
ドロウラシルの１次結晶と２次結晶を合わせて１３．８
ｇ得た。α−トリフルオロメチルアクリル酸ベースの全
収率は５４．１％であった。このとき生成したアセチル
尿素は９．８ｇであった。Example 5 In the same reactor as in Example 1, 40.0 g of acetic anhydride (0.
39 mol) under the same reaction conditions as in Example 1.
A solution of 0.0 (0.14 mol) of α-trifluoromethylacrylic acid in 28.0 g (0.27 mol) of acetic anhydride and 25.2 g (0.42 mol) of urea in 32.0 g of acetic anhydride
(0.31 mol) was simultaneously added dropwise over 2 hours, and the reaction solution was aged for 45 minutes after completion of the addition. After aging, the same operation as in Example 1 was carried out, and the total of the primary and secondary crystals of 5-trifluoromethyldihydrouracil was 13.8.
g was obtained. The total yield based on α-trifluoromethylacrylic acid was 54.1%. The acetyl urea produced at this time was 9.8 g.
【００４７】比較例３ 実施例１と同一の反応器に、無水酢酸４０．０ｇ（０．
３９モル）をとり、実施例１と同一の反応条件で、２
０．０（０．１４モル）のα−トリフルオロメチルアク
リル酸の無水酢酸２８．０ｇ（０．２７モル）溶液と尿
素９．０ｇ（０．１５モル）の無水酢酸３２．０ｇ
（０．３１モル）を同時に２時間で滴下し、滴下終了後
４５分間反応液を熟成させた。熟成終了後、実施例１と
全く同様の操作を行ない、５−トリフルオロメチルジヒ
ドロウラシルの１次結晶と２次結晶を合わせて６．１ｇ
得た。α−トリフルオロメチルアクリル酸ベースの全収
率は２３．９％であった。このとき生成したアセチル尿
素は１０．５ｇであった。Comparative Example 3 Into the same reactor as in Example 1, 40.0 g of acetic anhydride (0.
39 mol) under the same reaction conditions as in Example 1.
A solution of 0.0 (0.14 mol) of α-trifluoromethylacrylic acid in 28.0 g (0.27 mol) of acetic anhydride and 9.0 g (0.15 mol) of urea in 32.0 g of acetic anhydride
(0.31 mol) was simultaneously added dropwise over 2 hours, and the reaction solution was aged for 45 minutes after completion of the addition. After completion of the aging, the same operation as in Example 1 was performed, and the total of the primary crystals and the secondary crystals of 5-trifluoromethyldihydrouracil was 6.1 g.
Obtained. The overall yield based on α-trifluoromethylacrylic acid was 23.9%. The acetyl urea generated at this time was 10.5 g.
【００４８】実施例６ 実施例１と同一の反応器に、無水酢酸６２．２ｇ（０．
６１モル）、尿素９．０ｇ（０．１５モル）およびα−
トリフルオロメチルアクリル酸２０．２ｇ（０．１４モ
ル）をとり、窒素雰囲気下に、８００ｒｐｍにて室温よ
り昇温を開始した。反応温度は１１８℃まで上昇した。
反応開始直後に系内を１５０ｍｍＨｇに減圧し、系内に
生成した酢酸を１１．６ｇ（理論量に対し６９．０％）
回収した。反応終了後４５分間反応液を熟成させた。熟
成終了後、実施例１と全く同様の操作を行ない、５−ト
リフルオロメチルジヒドロウラシルの１次結晶と２次結
晶を合わせて１２．３ｇ得た。α−トリフルオロメチル
アクリル酸ベースの全収率は４８．２％であった。この
とき生成したアセチル尿素は８．５ｇであった。Example 6 In the same reactor as in Example 1, 62.2 g of acetic anhydride (0.
61 mol), 9.0 g (0.15 mol) of urea and α-
20.2 g (0.14 mol) of trifluoromethylacrylic acid was taken, and the temperature was raised from room temperature at 800 rpm in a nitrogen atmosphere. The reaction temperature rose to 118 ° C.
Immediately after the start of the reaction, the pressure in the system was reduced to 150 mmHg, and 11.6 g of acetic acid generated in the system (69.0% of the theoretical amount).
Collected. After completion of the reaction, the reaction solution was aged for 45 minutes. After aging, the same operation as in Example 1 was carried out to obtain 12.3 g of a primary crystal and a secondary crystal of 5-trifluoromethyldihydrouracil in total. The overall yield based on α-trifluoromethylacrylic acid was 48.2%. The acetyl urea generated at this time was 8.5 g.
【００４９】比較例４ 実施例１と同一の反応器に、無水酢酸６２．２ｇ（０．
６１モル）、尿素９．０ｇ（０．１５モル）およびα−
トリフルオロメチルアクリル酸２０．２ｇ（０．１４モ
ル）をとり、窒素雰囲気下に、８００ｒｐｍにて室温よ
り昇温を開始した。反応温度は１２０℃まで上昇した。
反応は昇温開始から１時間行なった。反応終了後４５分
間反応液を熟成させた。熟成終了後、実施例１と全く同
様の操作を行ない、５−トリフルオロメチルジヒドロウ
ラシルの１次結晶と２次結晶を合わせて１０．９ｇ得
た。α−トリフルオロメチルアクリル酸ベースの全収率
は４２．７％であった。このとき生成したアセチル尿素
は９．９ｇであった。Comparative Example 4 In the same reactor as in Example 1, 62.2 g of acetic anhydride (0.
61 mol), 9.0 g (0.15 mol) of urea and α-
20.2 g (0.14 mol) of trifluoromethylacrylic acid was taken, and the temperature was raised from room temperature at 800 rpm in a nitrogen atmosphere. The reaction temperature rose to 120 ° C.
The reaction was performed for 1 hour from the start of the temperature rise. After completion of the reaction, the reaction solution was aged for 45 minutes. After completion of the ripening, the same operation as in Example 1 was performed to obtain a total of 10.9 g of primary crystals and secondary crystals of 5-trifluoromethyldihydrouracil. The overall yield based on α-trifluoromethylacrylic acid was 42.7%. The acetyl urea generated at this time was 9.9 g.
【００５０】[0050]
【発明の効果】以上に記載したように、５−パーフルオ
ロアルキルジヒドロウラシル誘導体の製造方法におい
て、α−パーフルオロアルキルアクリル酸、尿素誘導体
を逐次添加しながら、α−パーフルオロアルキルアクリ
ル酸に対して尿素誘導体のモル比を１．５以上用いるこ
と、または反応系に生成する酢酸を蒸留により除去しな
がら反応すると、副生成物のアセチル尿素の生成を押さ
え、高収率で目的とする５−パーフルオロアルキルジヒ
ドロウラシル誘導体を得るのみならず、発熱量をコント
ロールすることにより工業的に実施可能な安全に製造す
ることが可能になる。As described above, in the method for producing a 5-perfluoroalkyldihydrouracil derivative, α-perfluoroalkylacrylic acid and urea derivative are added successively to α-perfluoroalkylacrylic acid. When the molar ratio of the urea derivative is 1.5 or more, or when the reaction is performed while removing acetic acid generated in the reaction system by distillation, the production of acetyl urea as a by-product is suppressed, and the desired 5- (5)-(3- (4- (4- (4- (4- (4- (4- (4-dimethoxy-)))-acetyl)) urea is produced in high yield. In addition to obtaining perfluoroalkyldihydrouracil derivatives, by controlling the amount of heat generated, industrially practicable and safe production becomes possible.
Claims (7)
アルキル基を表す）で示されるα−パーフルオロアルキ
ルアクリル酸と、一般式（２） Ｒ1ＮＨＣＯＮＨＲ2 （２） （式中、Ｒ1およびＲ2はそれぞれ独立して水素、メチル
基またはエチル基を表す）で示される尿素誘導体を反応
させ、生成する酢酸を系外に除去しながら反応させるこ
とを特徴とする、一般式（３） 【化２】 （式中、Ｒｆ、Ｒ1およびＲ2は前記定義に同じ）で示さ
れる５−パーフルオロアルキルジヒドロウラシル誘導体
の製造方法。1. A compound of the general formula (1) in the presence of acetic anhydride (Wherein, Rf represents an α-perfluoroalkyl group having 1 to 10 carbon atoms), and R 1 NHCONHR 2 (2) represented by the general formula (2) 1 and R 2 each independently represent hydrogen, a methyl group or an ethyl group), and reacting while removing acetic acid generated outside the system. ) (Wherein, Rf, R 1 and R 2 are the same as defined above), and a method for producing a 5-perfluoroalkyldihydrouracil derivative represented by the formula:
基またはエチル基を表す）で示される尿素誘導体に、一
般式（１） 【化３】 （式中、Ｒｆは炭素数１ないし１０のα−パーフルオロ
アルキル基を表す）で示されるα−パーフルオロアルキ
ルアクリル酸を逐次的に添加して反応させることを特徴
とする、一般式（３） 【化４】 （式中、Ｒｆ、Ｒ1およびＲ2は前記定義に同じ）で示さ
れる５−パーフルオロアルキルジヒドロウラシル誘導体
の製造方法。2. A compound represented by the general formula (2) R 1 NHCONHR 2 (2) (wherein R 1 and R 2 each independently represent hydrogen, a methyl group or an ethyl group) in the presence of acetic anhydride. The urea derivative to be used has the general formula (1) (Wherein, Rf represents an α-perfluoroalkyl group having 1 to 10 carbon atoms), and the reaction is carried out by sequentially adding α-perfluoroalkylacrylic acid represented by the general formula (3) ) (Wherein, Rf, R 1 and R 2 are the same as defined above), and a method for producing a 5-perfluoroalkyldihydrouracil derivative represented by the formula:
させることを特徴とする請求項２に記載の５−パーフル
オロアルキルジヒドロウラシル誘導体の製造方法。3. The method for producing a 5-perfluoroalkyldihydrouracil derivative according to claim 2, wherein the reaction is performed while removing generated acetic acid out of the system.
対する尿素誘導体の総量のモル比が１．５以上４．０以
下である請求項２に記載の５−パーフルオロアルキルジ
ヒドロウラシル誘導体の製造方法。4. The method for producing a 5-perfluoroalkyldihydrouracil derivative according to claim 2, wherein the molar ratio of the total amount of the urea derivative to α-perfluoroalkylacrylic acid is 1.5 or more and 4.0 or less.
対する尿素誘導体の総量のモル比が１．１以上３．０以
下である請求項２または請求項３に記載の５−パーフル
オロアルキルジヒドロウラシル誘導体の製造方法。5. The 5-perfluoroalkyldihydrouracil derivative according to claim 2 or 3, wherein the molar ratio of the total amount of the urea derivative to α-perfluoroalkylacrylic acid is 1.1 or more and 3.0 or less. Production method.
尿素誘導体の反応温度が７０から１２０℃である請求項
１ないし請求項５のいずれか１項に記載の５−パーフル
オロアルキルジヒドロウラシル誘導体の製造方法。6. The method for producing a 5-perfluoroalkyldihydrouracil derivative according to claim 1, wherein the reaction temperature between the α-perfluoroalkylacrylic acid and the urea derivative is 70 to 120 ° C. Method.
ルアクリル酸の総添加量の３ないし１０倍量である請求
項１ないし請求項６のいずれかに記載の５−パーフルオ
ロアルキルジヒドロウラシル誘導体の製造方法。7. The 5-perfluoroalkyldihydrouracil derivative according to claim 1, wherein the amount of acetic anhydride is 3 to 10 times the total amount of α-perfluoroalkylacrylic acid. Manufacturing method.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21283397A JP4268691B2 (en) | 1997-08-07 | 1997-08-07 | Process for producing 5-perfluoroalkyldihydrouracil derivative |
| FR9809708A FR2769911B1 (en) | 1997-08-07 | 1998-07-29 | PROCESS FOR PREPARING 5-PERFLUOROALKYLURACIL DERIVATIVES |
| US09/129,344 US6087499A (en) | 1997-08-07 | 1998-08-05 | Process for producing 5-perfluoroalkyluracil derivatives |
| DE19835866.0A DE19835866B4 (en) | 1997-08-07 | 1998-08-07 | Process for the preparation of 5-perfluoroalkyluracil derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21283397A JP4268691B2 (en) | 1997-08-07 | 1997-08-07 | Process for producing 5-perfluoroalkyldihydrouracil derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH1149757A true JPH1149757A (en) | 1999-02-23 |
| JP4268691B2 JP4268691B2 (en) | 2009-05-27 |
Family
ID=16629119
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP21283397A Expired - Fee Related JP4268691B2 (en) | 1997-08-07 | 1997-08-07 | Process for producing 5-perfluoroalkyldihydrouracil derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4268691B2 (en) |
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1997
- 1997-08-07 JP JP21283397A patent/JP4268691B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP4268691B2 (en) | 2009-05-27 |
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