WO2003057659A1 - Process for producing 6,6,6-trifluoro-3,5-dioxohexanoic acid ester and tautomer thereof - Google Patents

Process for producing 6,6,6-trifluoro-3,5-dioxohexanoic acid ester and tautomer thereof Download PDF

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WO2003057659A1
WO2003057659A1 PCT/JP2003/000012 JP0300012W WO03057659A1 WO 2003057659 A1 WO2003057659 A1 WO 2003057659A1 JP 0300012 W JP0300012 W JP 0300012W WO 03057659 A1 WO03057659 A1 WO 03057659A1
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acid ester
reacting
group
methyl
trifluoro
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PCT/JP2003/000012
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French (fr)
Japanese (ja)
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Kazuya Okano
Takako Takahashi
Hodaka Itou
Naoko Sumitani
Ken Tanaka
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Nihon Nohyaku Co., Ltd.
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Priority to AU2003202470A priority patent/AU2003202470A1/en
Publication of WO2003057659A1 publication Critical patent/WO2003057659A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms

Definitions

  • the present invention relates to a method for producing 6,6,6-trifluoro-3,5-dioxohexanoic acid ester useful as an agricultural chemical intermediate and a tautomer thereof.
  • 6,6,6-Trifluoro-3,5-dioxohexanoic acid ester and its tautomers are capable of forming pyrazole rings such as 1-methyl-13-trifluoromethylpyrazole-15-ylacetic acid ester compounds. It is a useful intermediate compound.
  • Pyrazole compounds having a trifluoromethyl group at the 3-position are useful as pesticides, and in particular, 1-methyl-3-trifluoromethylpyrazole-5-yl acetate compounds are useful as fungicides and insecticides. It is known to be useful (JP-A-6-32781 and WO01Z20993).
  • JP-A-6-32781 discloses that a methyl group at the 5-position of a 3-trifluoromethyl-5-methylvirazole compound is lithiated, then reacted with carbon dioxide, and then esterified to convert the methyl group to an alkoxy group.
  • a method for producing 1-methyl-13-trifluoromethylpyrazole-5-ylacetic acid ester which is converted into a carboxymethyl group is described.
  • WO01 / 20993 discloses that a 5-methyl group of a pyrazole compound is oxidized and then converted to an alkoxycarbonylmethyl group through several steps. A method for producing trifluoro-3-pyrromethylpyrazole-15-ylacetic acid ester is described. However, this method has a problem that the manufacturing process is long.
  • Example 1 of Japanese Patent Application Laid-Open No. 6-49039 discloses that trifluoroacetylacetoacetate ethyl ester, which is another name for 6,6,6-trifunoleo 3,5-dioxohexanoate (083 No. 1 55994) — 08— 4) is written.
  • this trifluoroacetate ethyl acetate is a typographical error of trifluoroacetoacetate. Therefore, 6,6,6_trifluoro-3,5-dioxohexanoic acid ester and its tautomer are not yet known. Disclosure of the invention
  • An object of the present invention is to provide 6,6-, 3-trifluoro-3,5-dioxohexanoic acid ester which can be used for producing 1-methyl-3-trifluoromethylpyrazole-5-ylacetic acid ester.
  • An object of the present invention is to provide tautomers and methods for producing them.
  • the present invention provides a method for reacting a 3-oxobutanoic acid ester with a base capable of reacting with a methylene group at the 2-position, reacting the resulting reactant with a base capable of reacting with a methyl group at the 4-position, and treating the resulting reactant.
  • FIG. 1 is an IR chart of the compound of the present invention obtained in the examples. BEST MODE FOR CARRYING OUT THE INVENTION
  • the present inventors have made a reaction between 3-oxobutanoic acid ester and a base to produce di-one and then react it with trifluoroacetic acid ester to give 6,6,6-trifluoro-3,5-dioxo. He knew that hexanoic acid esters and tautomers thereof could be produced, and completed the present invention.
  • the lower alkyl group in the lower alkyl group and the lower alkyl ester preferably means an alkyl group having 1 to 4 carbon atoms.
  • the 2-position methylene group of the 3-oxobutanoate which is the raw material, reacts with the salt group to form an anion, and then the 4-position methyl group reacts with a base to form a dianion. It is thought that trifluoroacetate (CF 3 C0 2 R,) reacts with this to form 6,6,6-trifluoro-3,5-dioxohexanoate and its tautomer.
  • any ester can be used.
  • alkyl esters particularly preferably lower alkyl esters, are used. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl esters of 3-oxobutanoic acid. Of these, methyl and ethyl esters are preferred.
  • Bases capable of reacting with the 2-position methylene group of 3-oxobutanoate include alkali metals such as sodium metal and lithium metal; alkali metal hydrides such as sodium hydride and potassium hydride; methyl lithium, butyl lithium, Organic lithiums such as xyllithium and phenyllithium; alkali metal amides such as sodium amide and dimethylisopropyl amide; alkali metal alkoxides such as potassium t-butoxide.
  • alkali metal hydride, organolithium, and alkali metal amide are preferred, and sodium hydride is particularly preferred.
  • the base is preferably used in an amount of at least equimolar to 3-oxobutanoic acid ester, particularly preferably in the range of from equimolar to 1.5-fold molar.
  • Examples of the base capable of reacting with the methyl group at the 4-position of 3-oxobutanoic acid ester include organic lithium and alkali metal amide. Of these, butyllithium and lithium diisopropylamide are preferred.
  • This base is also preferably used in an equimolar amount or more, particularly preferably in an equimolar to triple molar amount, with respect to the 3-oxobutanoic acid ester.
  • trifluoroacetate examples include an alkyl trifluoroacetate.
  • lower alkyl esters such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl are preferred, and methyl or ethyl esters are particularly preferred.
  • the trifluoroacetate is used in an amount of preferably 0.8 to 2 times, particularly preferably 1 to 1.2 times, the moles of the 3-oxobutanoate.
  • 3-oxobutanoic acid ester is dissolved in a solvent that is stable against a base, and then the base is reacted to produce anion.Then, the base is further reacted to produce diuyon. It is preferable to react by adding an ester.
  • the reaction temperature at this time is preferably lower at a temperature of 50 ° C or lower, more preferably 30 ° C or lower, particularly preferably 10 ° C or lower in terms of suppression of by-product formation and the like. C is performed in the following range. However, if the temperature is too low, it is not preferable in terms of equipment cost and reaction rate. Will be
  • the two-step reaction between the 3-oxobutanoate and the base is usually carried out for 0.1 to 10 hours, preferably for 0.2 to 1 hour. It is not preferable to spend too much time on the stability of the generated anion.
  • the reaction between the produced dione and the trifluoroacetate is generally carried out for 1 to 24 hours, preferably for 1 to 5 hours.
  • ethers such as tetrahydrofuran (THF), getyl ether, diisopropyl ether, dioxane, and methyl tert-butyl ether, and THF is particularly preferable.
  • the reaction when the reaction is carried out in a mixed solvent system in which an aliphatic hydrocarbon solvent such as hexane or heptane is used in addition to the above ether solvent, the yield is high even at a relatively high reaction temperature of 120 ° C or higher. This is industrially preferable because a product can be obtained.
  • the mixing ratio with the aliphatic hydrocarbon solvent is preferably at least 10 Vo 1% or more based on the total amount of the solvent, and more preferably not more than 50 Vo 1%. .
  • the solvent is preferably used in an amount of 1 to 100 times by volume, especially 5 to 30 times by volume of 3-oxobutanoic acid ester.
  • the ester portion of the 6,6,6-trifluoro-3,5_dioxohexanoic acid ester and its tautomer produced according to the present invention inherits the ester portion of 3_oxobutanoic acid ester in principle, When the ester part of 3-oxobutanoate and trifluoroacetate are different, 6,6,6_trifluoro-3,5-dioxohexanoate having an ester part derived from the ester part of trifluoroacetate and its Tautomers may also form.
  • a 1 L four-necked flask was charged with 8.80 g (22 Ommo 1) of 60% by weight sodium hydride washed twice with 5 OmL of hexane and 50 OmL of THF. At 4 ° C, 23.29 g (20 Ommo 1) of methyl 3-oxobutanoate was added, and the mixture was stirred at the same temperature for 15 minutes. Then, 1.32 mol (21 Ommo 1) of 1.59 mo 1 ZL of n-butyllithium-hexane solution was added dropwise at ⁇ 50 ° C. over 15 minutes, and the mixture was stirred at the same temperature for 15 minutes.
  • the obtained organic layer was concentrated under reduced pressure to obtain 48.Og of an oily substance.
  • Internal standard method The obtained oil contained 36.20 g of the desired product (yield 85%).
  • the oily product was purified by distillation under reduced pressure to obtain 32.84 g of the desired product as a fraction having a boiling point of 52 ° C at a pressure of 1.05 mmHg (isolation yield: 68%).
  • 6,6,6-Trifluoro-3,5_dioxohexanoic acid ester and its tautomers have four variable structures as described above. 6,6,6-Trifluoro-5-hydroxy oxyhexenoic acid ester, and in addition, at least in the solution, 6,6,6-Trifluoro-5-hydrogen It was found to be droxy-13-oxohexenoate.
  • 6,6,6-trifluoro-3,5-dioxohexanoate and its tautomers useful as pharmaceutical and agricultural chemical intermediates can be obtained easily and in good yield.

Abstract

A process for producing a 6,6,6-trifluoro-3,5-dioxohexanoic acid ester and a tautomer thereof which comprises reacting a 3-oxobutanoic acid ester with a base reactive with the 2-position methylene group, reacting the reaction product with a base reactive with the 4-position methyl group, and reacting the resultant reaction product with a trifluoroacetic acid ester.

Description

明 細 書  Specification
6， 6， 6—トリフルオロー 3， 5—ジォキソへキサン酸エステル 6,6,6-trifluoro-3,5-dioxohexanoic acid ester
及びその互変異性体の製造方法 技術分野  And method for producing tautomers thereof
本発明は、 農薬中間体として有用な 6, 6， 6—トリフルオロー 3, 5—ジ ォキソへキサン酸エステル及びその互変異性体の製造方法に関する。 6， 6, 6 _トリフルオロー 3， 5—ジォキソへキサン酸エステル及びその互変異性体 は、 1—メチル一 3 _トリフルォロメチルピラゾール一 5—ィル酢酸エステル 化合物等のピラゾール環形成に有用な中間体化合物である。 背景技術  The present invention relates to a method for producing 6,6,6-trifluoro-3,5-dioxohexanoic acid ester useful as an agricultural chemical intermediate and a tautomer thereof. 6,6,6-Trifluoro-3,5-dioxohexanoic acid ester and its tautomers are capable of forming pyrazole rings such as 1-methyl-13-trifluoromethylpyrazole-15-ylacetic acid ester compounds. It is a useful intermediate compound. Background art
トリフルォロメチル基を 3位に有するピラゾール化合物は、 農薬として有用 であり、 特に、 1—メチル— 3 _トリフルォロメチルピラゾール— 5—ィル酢 酸エステル化合物は、 殺菌剤や殺虫剤として有用であることが知られている (特開平 6 - 32781号公報、 WO01Z20993号明細書） 。  Pyrazole compounds having a trifluoromethyl group at the 3-position are useful as pesticides, and in particular, 1-methyl-3-trifluoromethylpyrazole-5-yl acetate compounds are useful as fungicides and insecticides. It is known to be useful (JP-A-6-32781 and WO01Z20993).
特開平 6 _ 32781号公報には、 3—トリフルォロメチルー 5—メチルビ ラゾール化合物の 5位のメチル基をリチォ化した後、 二酸化炭素と反応させ、 次いでエステル化することにより、 メチル基をアルコキシカルボ-ルメチル基 に変換する 1—メチル一 3—トリフルォロメチルピラゾールー 5—ィル酢酸ェ ステルの製造方法が記載されている。 しかしながら、 ピラゾール化合物の有す る置換基によっては、 この方法では 5位のメチル基を選択的にリチォ化するこ とが困難なことがある。  JP-A-6-32781 discloses that a methyl group at the 5-position of a 3-trifluoromethyl-5-methylvirazole compound is lithiated, then reacted with carbon dioxide, and then esterified to convert the methyl group to an alkoxy group. A method for producing 1-methyl-13-trifluoromethylpyrazole-5-ylacetic acid ester which is converted into a carboxymethyl group is described. However, depending on the substituents of the pyrazole compound, it may be difficult to selectively lithiate the 5-position methyl group by this method.
WO01/20993号明細書には、 ピラゾール化合物の 5位のメチル基を 酸化した後、 数工程を経てアルコキシカルボニルメチル基に変換する 1—メチ ル一 3—トリフルォロメチルピラゾール一 5—ィル酢酸エステルの製造方法が 記載されている。 しかしながら、 この方法は製造工程が長いという問題を有し ている。 WO01 / 20993 discloses that a 5-methyl group of a pyrazole compound is oxidized and then converted to an alkoxycarbonylmethyl group through several steps. A method for producing trifluoro-3-pyrromethylpyrazole-15-ylacetic acid ester is described. However, this method has a problem that the manufacturing process is long.
また、 同明細書には、 1一メチル一 3—トリフルォロメチルピラゾール一 5 fル酢酸エステルの製造方法として、 種々の 3, 5 _ジォキソへキサン酸 エステルをヒ ドラジン化合物と反応させるルートが記載されている。 しかしな がら、 その原料となる 3, 5—ジォキソへキサン酸エステル類の具体的な製造 例としては、 参考例 1として高価なメルドラム酸から 3, 5—ジォキソへキサ ン酸イソプロピルエステルを使用した例が記載されているのみであり、 6, 6, 6—トリフルオロー 3 , 5—ジォキソへキサン酸エステル及びそれを用いた 1—メチル一 3 _トリフノレオロメチノレビラゾーノレ一 5—ィノレ酢酸エステルの製 造方法は具体的には記載されていない。  In addition, in the specification, as a method for producing 1-methyl-13-trifluoromethylpyrazole-15f acetate, a route for reacting various 3,5-dioxohexanoates with a hydrazine compound is described. Has been described. However, as a specific example of the production of the 3,5-dioxohexanoic acid ester used as a raw material, isopropyl 3,5-dioxohexanoate from expensive Meldrum's acid was used as Reference Example 1. Examples are only described, and 6,6,6-trifluoro-3,5-dioxohexanoic acid ester and 1-methyl-13-trifnorolelomethinolevirazonole-5-inole using it are used. The method for producing acetate is not specifically described.
ところで、 特開平 6— 49039号公報の実施例 1には、 6, 6, 6—トリ フノレオ口一 3, 5—ジォキソへキサン酸エステルの別名であるトリフルォロア セチルァセト酢酸ェチルエステル （0八3番号1 55994— 08— 4) が記 載されている。 しかしながら、 このトリフルォロアセチルァセト酢酸ェチルェ ステルは、 トリフルォロアセト酢酸ェチルの誤記であることが明らかである。 従って、 6， 6， 6_トリフルオロー 3, 5—ジォキソへキサン酸エステル 及びその互変異性体は未だ知られていない。 発明の開示  By the way, Example 1 of Japanese Patent Application Laid-Open No. 6-49039 discloses that trifluoroacetylacetoacetate ethyl ester, which is another name for 6,6,6-trifunoleo 3,5-dioxohexanoate (083 No. 1 55994) — 08— 4) is written. However, it is clear that this trifluoroacetate ethyl acetate is a typographical error of trifluoroacetoacetate. Therefore, 6,6,6_trifluoro-3,5-dioxohexanoic acid ester and its tautomer are not yet known. Disclosure of the invention
本発明の目的は、 1 _メチル_3_トリフロォロメチルピラゾール一5—ィ ル酢酸エステルの製造に用いることができる 6, 6, 6—トリフルオロー 3, 5—ジォキソへキサン酸エステル及ぴその互変異性体、 並びにそれらの製造方 法を提供することである。 本発明は、 3 _ォキソブタン酸エステルに、 2位のメチレン基と反応し得る 塩基を反応させ、 得られる反応物に 4位のメチル基と反応し得る塩基を反応さ せ、 得られる反応物にトリフルォロ酢酸エステルを反応させることを含む 6， 6 , 6—トリフルオロー 3， 5—ジォキソへキサン酸エステル及びその互変異 性体の製造方法及ぴ 6， 6 , 6—トリフルオロー 3 , 5—ジォキソへキサン酸 エステル及びその互変異性体に関する。 図面の簡単な説明 An object of the present invention is to provide 6,6-, 3-trifluoro-3,5-dioxohexanoic acid ester which can be used for producing 1-methyl-3-trifluoromethylpyrazole-5-ylacetic acid ester. An object of the present invention is to provide tautomers and methods for producing them. The present invention provides a method for reacting a 3-oxobutanoic acid ester with a base capable of reacting with a methylene group at the 2-position, reacting the resulting reactant with a base capable of reacting with a methyl group at the 4-position, and treating the resulting reactant. Method for producing 6,6,6-trifluoro-3,5-dioxohexanoic acid ester and its tautomer, which comprises reacting trifluoroacetate; and 6,6,6-trifluoro-3,5-dioxo The present invention relates to hexanoic acid esters and tautomers thereof. BRIEF DESCRIPTION OF THE FIGURES
第 1図は、 実施例で得られた本発明の化合物の I Rチヤ一ト図である。 発明の実施するための最良の形態  FIG. 1 is an IR chart of the compound of the present invention obtained in the examples. BEST MODE FOR CARRYING OUT THE INVENTION
本発明者らは、 3—ォキソブタン酸エステルに塩基を反応させてジァ-オン を生成させ、 これと トリフルォロ酢酸エステルとを反応させることにより、 6 , 6 , 6 _トリフルオロー 3 , 5 _ジォキソへキサン酸エステル及びその互変異 性体を製造できることを知り、 本発明を完成させた。  The present inventors have made a reaction between 3-oxobutanoic acid ester and a base to produce di-one and then react it with trifluoroacetic acid ester to give 6,6,6-trifluoro-3,5-dioxo. He knew that hexanoic acid esters and tautomers thereof could be produced, and completed the present invention.
以下、 本発明を詳細に説明する。 なお、 本明細書において低級アルキル基及 び低級アルキルエステル中の低級アルキル部分は、 好ましくは炭素数 1〜4の アルキル基を意味する。  Hereinafter, the present invention will be described in detail. In the present specification, the lower alkyl group in the lower alkyl group and the lower alkyl ester preferably means an alkyl group having 1 to 4 carbon atoms.
本発明に係る 6 , 6 , 6—トリフルオロー 3 , 5 _ジォキソへキサン酸エス テル及びその互変異性体の製造方法では、 反応は次式のように進行すると考え られる。 In the method for producing 6,6,6-trifluoro-3,5-dioxohexanoic acid ester and its tautomer according to the present invention, the reaction is considered to proceed as shown in the following formula.
O O σ o O" O" O O σ o O "O"
Figure imgf000006_0001
すなわち、 原料である 3—ォキソブタン酸エステルの 2位のメチレン基が塩 基と反応してァニオンとなり、 次に 4位のメチル基が塩基と反応してジァニォ ンとなる。 これにトリフルォロ酢酸エステル （CF3C02R，） が反応して、 6， 6 , 6—トリフルオロー 3 , 5一ジォキソへキサン酸エステル及びその互変異性体 が生成するものと考えられる。
Figure imgf000006_0001
In other words, the 2-position methylene group of the 3-oxobutanoate, which is the raw material, reacts with the salt group to form an anion, and then the 4-position methyl group reacts with a base to form a dianion. It is thought that trifluoroacetate (CF 3 C0 2 R,) reacts with this to form 6,6,6-trifluoro-3,5-dioxohexanoate and its tautomer.
原料の 3—ォキソブタン酸エステルとしては、 任意のエステルを用いること ができる。 好ましくはアルキルエステル、 特に好ましくは低級アルキルエステ ルを用いる。 例として、 3—ォキソブタン酸のメチル、 ェチル、 n—プロピル、 イソプロピル、 n—ブチル、 又はイソブチルエステル等が挙げられる。 このう ちメチル又はェチルエステルが好ましい。  As the 3-oxobutanoic acid ester as a raw material, any ester can be used. Preferably, alkyl esters, particularly preferably lower alkyl esters, are used. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl esters of 3-oxobutanoic acid. Of these, methyl and ethyl esters are preferred.
3—ォキソブタン酸エステルの 2位のメチレン基と反応し得る塩基としては、 金属ナトリウム、 金属リチウム等のアルカリ金属；水素化ナトリウム、 水素化 カリウム等のアルカリ金属水素化物；メチルリチウム、 ブチルリチウム、 へキ シルリチウム、 フエ-ルリチウム等の有機リチウム ；ナトリウムアミ ド、 リチ ゥムジィソプロピルアミ ド等のアルカリ金属ァミ ド；カリウム t—ブトキシド 等のアルカリ金属アルコキシド等が挙げられる。 これらのうちアルカリ金属水 素化物、 有機リチウム、 アルカリ金属アミ ドが好ましく、 水素化ナトリウムが 特に好ましい。 塩基は、 3—ォキソブタン酸エステルに対して好ましくは等モ ル以上用いられ、 特に好ましくは等モル〜 1 . 5倍モルの範囲で用いられる。 3—ォキソブタン酸ェステルの 4位のメチル基と反応し得る塩基としては、 有機リチウム、 アルカリ金属アミ ド等が挙げられる。 これらのうち、 プチルリ チウム、 リチウムジイソプロピルアミ ドが好ましい。 この塩基も、 3—ォキソ ブタン酸エステルに対して好ましくは等モル以上、 特に好ましくは等モル〜 3 倍モル用いる。 Bases capable of reacting with the 2-position methylene group of 3-oxobutanoate include alkali metals such as sodium metal and lithium metal; alkali metal hydrides such as sodium hydride and potassium hydride; methyl lithium, butyl lithium, Organic lithiums such as xyllithium and phenyllithium; alkali metal amides such as sodium amide and dimethylisopropyl amide; alkali metal alkoxides such as potassium t-butoxide. Of these, alkali metal hydride, organolithium, and alkali metal amide are preferred, and sodium hydride is particularly preferred. The base is preferably used in an amount of at least equimolar to 3-oxobutanoic acid ester, particularly preferably in the range of from equimolar to 1.5-fold molar. Examples of the base capable of reacting with the methyl group at the 4-position of 3-oxobutanoic acid ester include organic lithium and alkali metal amide. Of these, butyllithium and lithium diisopropylamide are preferred. This base is also preferably used in an equimolar amount or more, particularly preferably in an equimolar to triple molar amount, with respect to the 3-oxobutanoic acid ester.
トリフルォロ酢酸エステルとしては、 トリフルォロ酢酸アルキルエステルが 挙げられる。 なかでも、 メチル、 ェチル、 n—プロピル、 イソプロピル、 n— ブチル、 及びィソブチル等の低級アルキルエステルが好ましく、 メチル又はェ チルエステルが特に好ましい。  Examples of the trifluoroacetate include an alkyl trifluoroacetate. Of these, lower alkyl esters such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl are preferred, and methyl or ethyl esters are particularly preferred.
トリフルォロ酢酸エステルは、 3 _ォキソブタン酸エステルに対して好まし くは 0 . 8〜2倍モル、 特に好ましくは 1〜1 . 2倍モル用いる。  The trifluoroacetate is used in an amount of preferably 0.8 to 2 times, particularly preferably 1 to 1.2 times, the moles of the 3-oxobutanoate.
反応は、 まず、 塩基に対して安定な溶媒に 3 _ォキソブタン酸エステルを溶 解した後に塩基を反応させァニオンを生成させた後、 更に塩基を反応させてジ ァユオンを生成させ、 これにトリフルォロ酢酸エステルを加えて反応させるの が好ましい。  In the reaction, first, 3-oxobutanoic acid ester is dissolved in a solvent that is stable against a base, and then the base is reacted to produce anion.Then, the base is further reacted to produce diuyon. It is preferable to react by adding an ester.
このときの反応温度としては、 副生物の生成抑制等の点でより低温の方がこ のましく、 通常、 5 0 °C以下、 より好ましくは 3 0 °C以下、 特に好ましくは 1 0 °C以下の範囲で行われる。 但し、 あまり低温すぎると設備コスト及び反応 速度等の点で好ましくないため、 通常、 _ 1 0 0 °C 以上、 好ましくは一 7 0 °C以上より好ましくは一 5 0 °C以上の温度で行われる。  The reaction temperature at this time is preferably lower at a temperature of 50 ° C or lower, more preferably 30 ° C or lower, particularly preferably 10 ° C or lower in terms of suppression of by-product formation and the like. C is performed in the following range. However, if the temperature is too low, it is not preferable in terms of equipment cost and reaction rate. Will be
3—ォキソブタン酸エステルと塩基との 2工程の反応は、 通常、 0 . 1〜1 0時間、 好ましくは 0 . 2〜1時間かけて行なわれる。 生成するァニオンの安 定性の点から、 時間をあまりかけすぎるのは好ましくない。  The two-step reaction between the 3-oxobutanoate and the base is usually carried out for 0.1 to 10 hours, preferably for 0.2 to 1 hour. It is not preferable to spend too much time on the stability of the generated anion.
また、 生成したジァ-オンと トリフルォロ酢酸エステルとの反応は、 通常、 1〜 2 4時間、 好ましくは 1〜 5時間かけて行われる。 溶媒としては、 テトラヒ ドロフラン （THF) 、 ジェチルエーテル、 ジイソ プロピルエーテル、 ジォキサン、 メチル t _ブチルエーテル等のエーテルを用 いるのが好ましく、 THFが特に好ましい。 The reaction between the produced dione and the trifluoroacetate is generally carried out for 1 to 24 hours, preferably for 1 to 5 hours. As the solvent, it is preferable to use ethers such as tetrahydrofuran (THF), getyl ether, diisopropyl ether, dioxane, and methyl tert-butyl ether, and THF is particularly preferable.
また、 上記エーテル系溶媒の他にへキサン、 ヘプタン等の脂肪族炭化水素系 溶媒を併用した混合溶媒系中で反応を行うと反応温度が一 20°C以上といった 比較的高温でも収率よく目的物が得られるため、 工業的には好ましい。 この場 合、 脂肪族炭化水素系溶媒との混合比率としては、 全溶媒量に対し少なくとも 10 V o 1 %以上用いるのが好ましく、 また、 50 V o 1 %を超えない範囲で 用いるのが好ましい。  In addition, when the reaction is carried out in a mixed solvent system in which an aliphatic hydrocarbon solvent such as hexane or heptane is used in addition to the above ether solvent, the yield is high even at a relatively high reaction temperature of 120 ° C or higher. This is industrially preferable because a product can be obtained. In this case, the mixing ratio with the aliphatic hydrocarbon solvent is preferably at least 10 Vo 1% or more based on the total amount of the solvent, and more preferably not more than 50 Vo 1%. .
溶媒は、 3—ォキソブタン酸エステルに対して 1〜 100体積倍、 特に 5〜 30体積倍用いることが好ましい。  The solvent is preferably used in an amount of 1 to 100 times by volume, especially 5 to 30 times by volume of 3-oxobutanoic acid ester.
本発明により製造される 6, 6， 6—トリフルオロー 3， 5 _ジォキソへキ サン酸エステル及びその互変異性体のエステル部分は、 原則として 3 _ォキソ ブタン酸エステルのエステル部分を引き継ぐが、 3—ォキソブタン酸エステル と トリフルォロ酢酸エステルのエステル部分が異なる場合には、 トリフルォロ 酢酸エステルのエステル部分に由来するエステル部分を有する 6, 6， 6_ト リフルオロー 3， 5 _ジォキソへキサン酸エステル及びその互変異性体が生成 することもある。  The ester portion of the 6,6,6-trifluoro-3,5_dioxohexanoic acid ester and its tautomer produced according to the present invention inherits the ester portion of 3_oxobutanoic acid ester in principle, When the ester part of 3-oxobutanoate and trifluoroacetate are different, 6,6,6_trifluoro-3,5-dioxohexanoate having an ester part derived from the ester part of trifluoroacetate and its Tautomers may also form.
以下、 実施例により、 本発明を更に具体的に説明するが、 本発明は、 これら 実施例に限定されるものではない。 なお、 いずれの実施例も、 十分に乾燥した 試薬及び溶媒を用い、 窒素雰囲気下で反応を行った。 実施例 1  Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples. In each of the examples, the reaction was performed under a nitrogen atmosphere using a sufficiently dried reagent and solvent. Example 1
60重量％水素化ナトリウム 0. 44 g (1 lmmo 1 ) をへキサン 5mL で 2回洗浄した後、 THF 25mLに懸濁し、 4 °Cで 3—ォキソブタン酸メチ ル 1. 16 g (1 Ommo 1 ) を加え、 同温度で 1 5分間攪拌した。 次いで、 これに 1. 59mM/mL n _ブチルリチウム一へキサン溶液 6. 6 m L (10. 5mmo 1 ) をー60°Cで 10分間かけて滴下し、 1 5分間攪拌した。 更に、 トリフルォロ酢酸メチノレ 0. 37 g (5mmo 1 ) を加え、 一 60°Cで 60分間攪拌した。 1. S SmMZmL n—ブチルリチウム一へキサン溶液 6. 6mL (10. 5mmo 1 ) を一 60 °Cで 10分間かけて滴下し、 1 5分 間攪拌した。 更に、 トリフルォロ酢酸メチル 0. 3 7 g (5mmo 1 ) を加 え、 — 60°Cで 180分間攪拌した。 反応液を室温とし、 濃塩酸 3. 5mLを 加えて 1 0分間攪拌した後、 水 1 OmL及びジェチルエーテル 3 OmLを加え た。 有機層をとり、 飽和食塩水 15 m Lで 3回洗浄した後、 無水硫酸マグネシ ゥムで乾燥した。 得られた有機層を減圧濃縮して油状物 4. 64 gを得た。 安 息香酸ェチルを内部標準物質として定量したところ、 得られた油状物には目的 生成物が 1. 7 O g含まれていた （収率 80%) 。 実施例 2 After washing 0.44 g (1 lmmo 1) of 60% by weight sodium hydride twice with 5 mL of hexane, the suspension was suspended in 25 mL of THF, and 4 g of methyl 3-oxobutanoate 1.16 g (1 Ommo 1 ) And stirred at the same temperature for 15 minutes. Then To this, 6.6 mL (10.5 mmol) of a 1.59 mM / mL n_butyllithium hexane solution was added dropwise at −60 ° C. over 10 minutes, followed by stirring for 15 minutes. Further, 0.37 g (5 mmo 1) of methyl trifluoroacetate was added, and the mixture was stirred at 160 ° C. for 60 minutes. 1. S SmMZmL 6.6 mL (10.5 mmo 1) of n-butyllithium-hexane solution was added dropwise at 160 ° C. over 10 minutes and stirred for 15 minutes. Further, 0.37 g (5 mmo 1) of methyl trifluoroacetate was added, and the mixture was stirred at —60 ° C. for 180 minutes. The reaction solution was brought to room temperature, 3.5 mL of concentrated hydrochloric acid was added, and the mixture was stirred for 10 minutes. The organic layer was taken, washed three times with 15 mL of a saturated saline solution, and dried over anhydrous magnesium sulfate. The obtained organic layer was concentrated under reduced pressure to obtain 4.64 g of an oil. When ethyl benzoate was quantified as an internal standard substance, the obtained oil contained 1.7 Og of the desired product (yield: 80%). Example 2
1 Lの四つ口フラスコに、 へキサン 5 OmLで 2回洗浄した 60重量％水素 化ナトリウム 8. 80 g (22 Ommo 1 ) 及び THF 50 OmLを仕込んだ。 4 °Cで 3—ォキソブタン酸メチル 23. 29 g (20 Ommo 1 ) を加え、 同 温度で 1 5分間攪拌した。 次いで、 1. 59 m o 1 ZLの n—ブチルリチウ ム—へキサン溶液 1 32m L (21 Ommo 1 ) を、 — 50°Cで 15分間かけ て滴下し、 同温度で 15分間攪拌した。 更に、 トリフルォロ酢酸ェチル 29. 50 g (208 mm o 1 ) を加え、 一 50 °Cで 120分間攪拌した。 反応液に 15 °C以下で濃塩酸 46mLを徐々に滴下し 10分間攪拌した後、 水 20 Om L及び酢酸ェチル 60 OmLを加えた。 有機層をとり、 水 20 OmLで 1回洗 浄した。 水層を合わせて、 酢酸ェチル 30 OmLで 2回抽出した。 有機層を合 わせた後、 飽和食塩水 30 OmLで 3回洗浄し、 無水硫酸マグネシウムで乾燥 した。 得られた有機層を減圧濃縮して油状物を 48. O l g得た。 内部標準法 により定量したところ、 得られた油状物には目的生成物がが 36. 20 g (収 率 85%) 含まれていた。 該油状物を減圧蒸留で精製し、 目的生成物を圧力 1. 05mmHgにおける沸点が 52°Cの留分として 32. 84 g得た （単離収率 68 %) 。 A 1 L four-necked flask was charged with 8.80 g (22 Ommo 1) of 60% by weight sodium hydride washed twice with 5 OmL of hexane and 50 OmL of THF. At 4 ° C, 23.29 g (20 Ommo 1) of methyl 3-oxobutanoate was added, and the mixture was stirred at the same temperature for 15 minutes. Then, 1.32 mol (21 Ommo 1) of 1.59 mo 1 ZL of n-butyllithium-hexane solution was added dropwise at −50 ° C. over 15 minutes, and the mixture was stirred at the same temperature for 15 minutes. Further, 29.50 g (208 mmo 1) of ethyl trifluoroacetate was added, and the mixture was stirred at 150 ° C. for 120 minutes. To the reaction solution, 46 mL of concentrated hydrochloric acid was gradually added dropwise at 15 ° C. or lower, and the mixture was stirred for 10 minutes. Then, 20 OmL of water and 60 OmL of ethyl acetate were added. The organic layer was taken and washed once with 20 OmL of water. The aqueous layers were combined and extracted twice with 30 OmL of ethyl acetate. After combining the organic layers, the mixture was washed three times with 30 OmL of saturated saline, and dried over anhydrous magnesium sulfate. The obtained organic layer was concentrated under reduced pressure to obtain 48.Og of an oily substance. Internal standard method The obtained oil contained 36.20 g of the desired product (yield 85%). The oily product was purified by distillation under reduced pressure to obtain 32.84 g of the desired product as a fraction having a boiling point of 52 ° C at a pressure of 1.05 mmHg (isolation yield: 68%).
上記で得られた生成物の同定データは以下に示される。  The product identification data obtained above is shown below.
沸点： 52°C/1.0 mmHg Boiling point: 52 ° C / 1.0 mmHg
'H-NMR (CDC13, δ ppm)： 13.3 (1H, br), 6.05 (1H， s), 3.70 (3H， s), 3.50 (2H, s) 'H-NMR (CDC1 3, δ ppm): 13.3 (1H, br), 6.05 (1H, s), 3.70 (3H, s), 3.50 (2H, s)
13C-NMR (CDCI3, δ ppm)： 189.1, 174.1 (q， 2JC.F = 37.2 Hz), 166.6, 116.9 13 C-NMR (CDCI3, δ ppm): 189.1, 174.1 (. Q, 2 J C F = 37.2 Hz), 166.6, 116.9
(q, Mc— F = 281.6 Hz), 97.2 (q, 3JC_F = 2.4 Hz), 52.7, 44.5 (q, Mc-- F = 281.6 Hz), 97.2 (q, 3 J C _ F = 2.4 Hz), 52.7, 44.5
MS (3.0 kV) m/z: 212 (M+, 11), 181 (9)， 143 (95), 139 (100)， 111 (8)，MS (3.0 kV) m / z: 212 (M + , 11), 181 (9), 143 (95), 139 (100), 111 (8),
101 (29), 69 (58) 101 (29), 69 (58)
IR (neat, KBr) 第 1図参照  IR (neat, KBr) See Fig. 1
6, 6, 6—トリフルオロー 3, 5 _ジォキソへキサン酸エステル及ぴその 互変異性体は、 上述のように 4つの可変的な構造を有するものであるが、 以上 の結果から、 主としてェノール体、 特に 6， 6, 6—トリフルオロー 5—ヒ ド 口キシ一 3—ォキソへキセン酸エステルとして存在し、 加えて、 少なくとも溶 液中においては、 6, 6, 6_トリフルオロー 5—ヒ ドロキシ一3—ォキソへ キセン酸エステルであることが判明した。 実施例 3  6,6,6-Trifluoro-3,5_dioxohexanoic acid ester and its tautomers have four variable structures as described above. 6,6,6-Trifluoro-5-hydroxy oxyhexenoic acid ester, and in addition, at least in the solution, 6,6,6-Trifluoro-5-hydrogen It was found to be droxy-13-oxohexenoate. Example 3
5 OmLの三つ口フラスコに 60重量0 /0水素化ナトリウム 0. 44 g (1 1 mmo 1 ) をへキサン 5mLで 2回洗浄した後、 THF 25mLに懸濁し、 4 °Cで 3—ォキソブタン酸メチル 1. 16 g (1 Ommo 1 ) を加え、 同温度で 1 5分間攪拌した。 次いで、 これに 1. 58mMZmL n—ブチルリチウ ム一へキサン溶液 6. 8mL (10. 5 mmo 1 ) を _ 10 °Cで 10分間力、け て滴下した後、 トリフルォロ酢酸ェチル 1 · 4 2 g ( l Ommo l ) を加 え、 一 10°Cで 120分間攪拌した。 反応液を 0°Cとし、 氷浴中で濃塩酸 2. 3mLを加えて 1 0分間攪拌した後、 水 1 OmL及び酢酸ェチル 3 OmLを加 えた。 有機層をとり、 水層を酢酸ェチル 3 Om 1で 2回抽出し先に分液した有 機層と合わせ、 飽和食塩水 15 mLで 3回洗浄した後、 無水硫酸マグネシウム で乾燥した。 得られた有機層を減圧濃縮して油状物 2. 73 gを得た。 安息香 酸ェチルを内部標準物質として定量したところ、 得られた油状物には目的生成 物が 1. 48 g含まれていた （収率 70%) 。 実施例 4 5 60 wt necked flask OML 0/0 sodium hydride 0. 44 g (1 1 mmo 1 ) were washed twice with hexane 5mL f was suspended in THF 25 mL, at 4 ° C 3- Okisobutan 1.16 g (1 Ommo 1) of methyl acid was added, and the mixture was stirred at the same temperature for 15 minutes. Then, 6.8 mL (10.5 mmo 1) of 1.58 mM ZmL n-butyllithium-hexane solution was applied to this at _ 10 ° C for 10 minutes. Then, 1.42 g (10 mmol) of ethyl trifluoroacetate was added, and the mixture was stirred at 110 ° C for 120 minutes. The reaction solution was set to 0 ° C, 2.3 mL of concentrated hydrochloric acid was added in an ice bath, and the mixture was stirred for 10 minutes. Then, 1 OmL of water and 3 OmL of ethyl acetate were added. The organic layer was taken, and the aqueous layer was extracted twice with ethyl acetate 3 Om 1 and combined with the previously separated organic layer, washed three times with 15 mL of saturated saline, and dried over anhydrous magnesium sulfate. The obtained organic layer was concentrated under reduced pressure to obtain 2.73 g of an oil. When ethyl benzoate was quantified as an internal standard substance, the obtained oil contained 1.48 g of the desired product (yield 70%). Example 4
5 OmLの三つ口フラスコに 60重量0 /0水素化ナトリウム 0. 44 g (1 1 mmo 1 ) をへキサン 5mLで 2回洗浄した後、 THF 1 2. 5mLとへキサ ン 12. 5m 1の混合溶媒に懸濁し、 4。Cで 3 _ォキソブタン酸メチル 1. 1 6 g (l Ommo l) を加え、 同温度で 15分間攪拌した。 次いで、 これに 1. 58mM/mL n _ブチルリチウム一へキサン溶液 6. 8 m L (10. 5 m mo 1 ) を一 10°Cで 10分間かけて滴下した後、 トリフルォロ酢酸ェチル 1 · 42 g (l Ommo l ) を加え、 _ 10 °Cで 120分間攪拌した。 反応液を 0 °Cとし、 氷浴中で濃塩酸 3. 5111しを加ぇて10分間攪拌した後、 水 1 OmL 及び酢酸ェチル 3 OmLを加えた。 有機層をとり、 水層を酢酸ェチル 3 Om l で 2回抽出し先に分液した有機層と合わせ、 飽和食塩水 15 m Lで 3回洗浄し た後、 無水硫酸マグネシウムで乾燥した。 得られた有機層を減圧濃縮して油状 物 2. 56 gを得た。 安息香酸ェチルを内部標準物質として定量したところ、 得られた油状物には目的生成物が 1. 59 g含まれていた （収率 75%) 。 実施例 5 5 OML three-necked flask 60 weight 0/0 sodium hydride 0. 44 g (1 1 mmo 1 ) were washed twice with hexane 5mL f and hexa down 12. 5 m 1 to the THF 1 2. 5mL Suspended in a mixed solvent of 4. In C, 1.16 g (l Ommol) of methyl 3-oxobutanoate was added, and the mixture was stirred at the same temperature for 15 minutes. Then, 6.8 mL (10.5 mMol) of a 58 mM / mL n-butyllithium-hexane solution was added dropwise thereto at 10 ° C for 10 minutes, and ethyl trifluoroacetate was added. g (l Ommol) was added and stirred at -10 ° C for 120 minutes. The reaction solution was adjusted to 0 ° C., concentrated hydrochloric acid (3.5111) was added in an ice bath, and the mixture was stirred for 10 minutes. Then, 1 OmL of water and 3 OmL of ethyl acetate were added. The organic layer was separated, the aqueous layer was extracted twice with 3 Oml of ethyl acetate, combined with the organic layer separated above, washed three times with 15 mL of saturated saline, and dried over anhydrous magnesium sulfate. The obtained organic layer was concentrated under reduced pressure to obtain 2.56 g of an oily substance. When ethyl benzoate was quantified as an internal standard, the obtained oil contained 1.59 g of the desired product (yield 75%). Example 5
50 OmLの四つ口フラスコに 60重量0 /0水素化ナトリウム 4. 40 g ( 1 l Ommo l ) をへキサン 50 m Lで 2回洗浄した後、 THF 200mLとへ キサン 50m 1.の混合溶媒に懸濁し、 4。Cで 3—ォキソブタン酸メチル 1 1. 6 1 g (10 Ommo 1 ) を加え、 同温度で 1 5分間攪拌した。 次いで、 これ に 1. 56mMZmL n—ブチルリチウム一へキサン溶液 68 m L (105 mmo 1 ) を一 10°Cで 15分間かけて滴下した後、 トリフルォロ酢酸ェチル 14. 21 g (10 Ommo 1 ) を加え、 — 10°Cで 120分間攪拌した。 反 応液を 0°Cとし、 氷浴中で濃塩酸 23mLを加えて 10分間攪拌した後、 水 1 0 OmL及び酢酸ェチル 30 OmLを加えた。 有機層をとり、 水層を酢酸ェチ ル 300 m 1で 2回抽出し先に分液した有機層と合わせ、 飽和食塩水 1 50m Lで 3回洗浄した後、 無水硫酸マグネシウムで乾燥した。 得られた有機層を減 圧濃縮して油状物 27. 95 gを得た。 安息香酸ェチルを内部標準物質として 定量したところ、 得られた油状物には目的生成物が 1 7. 84 g含まれていた (収率 84 %) 。 実施例 6 After washing twice with hexane 50 f 50 60 weight 0/0 sodium hydride four-necked flask OmL 4. 40 g (1 l Ommo l) m L, a mixed solvent of hexane 50 m 1. to a THF 200 mL Suspended in 4. C. To the mixture was added methyl 3-oxobutanoate 11.61 g (10 Ommo 1), and the mixture was stirred at the same temperature for 15 minutes. Then, 68 mL (105 mmo 1) of 1.56 mM ZmL n-butyllithium hexane solution was added dropwise thereto at 110 ° C for 15 minutes, and 14.21 g (10 Ommo 1) of ethyl trifluoroacetate was added thereto. In addition, — stirred at 10 ° C. for 120 minutes. The reaction solution was adjusted to 0 ° C, 23 mL of concentrated hydrochloric acid was added in an ice bath, and the mixture was stirred for 10 minutes. Then, 10 OmL of water and 30 OmL of ethyl acetate were added. The organic layer was separated, the aqueous layer was extracted twice with 300 ml of ethyl acetate, combined with the organic layer separated earlier, washed three times with 150 ml of saturated saline, and dried over anhydrous magnesium sulfate. The obtained organic layer was concentrated under reduced pressure to obtain 27.95 g of an oil. As a result of quantitative determination of ethyl benzoate as an internal standard, the obtained oil contained 17.84 g of the desired product (yield 84%). Example 6
5 OmLの三つ口フラスコに 60重量0 /0水素化ナトリウム 0. 44 g (1 1 mmo 1 ) をへキサン 5mLで 2回洗浄した後、 T H F 20 m Lとシクロへキ サン 5 m 1の混合溶媒に懸濁し、 4°Cで 3—ォキソブタン酸メチル 1. 16 g (1 Ommo 1 ) を加え、 同温度で 1 5分間攪拌した。 次いで、 これに 1. 5 8 mM/mL n—ブチルリチウム一へキサン溶液 6. 8mL (10. 5 mm o 1 ) を— 10°Cで 10分間かけて滴下した後、 トリフルォロ酢酸ェチル 1. 42 g (1 Ommo 1 ) を加え、 一 10°Cで 1 20分間攪拌した。 反応液を 0 °Cとし、 氷浴中で濃塩酸 3. 5mLを加えて 10分間攪拌した後、 水 1 OmL 及び酢酸ェチル 3 OmLを加えた。 有機層をとり、 水層を酢酸ェチル 3 Om l で 2回抽出し先に分液した有機層と合わせ、 飽和食塩水 1 5 mLで 3回洗浄し た後、 無水硫酸マグネシウムで乾燥した。 得られた有機層を減圧濃縮して油状 物 2. 46 gを得た。 安息香酸ェチルを内部標準物質として定量したところ、 得られた油状物には目的生成物が 1. 67 g含まれていた （収率 79%) 。 実施例 7 5 After washing twice with OmL f 60 wt necked flask 0/0 sodium hydride 0. 44 g (1 1 mmo 1 ) of hexane 5mL, THF 20 m L and the cyclo key San 5 m 1 The suspension was suspended in a mixed solvent, and thereto was added 1.16 g (1 Ommo 1) of methyl 3-oxobutanoate at 4 ° C., followed by stirring at the same temperature for 15 minutes. Then, 5.8 mL (10.5 mmo 1) of a 1.5 mM / mL n-butyllithium-hexane solution was added dropwise thereto at −10 ° C. over 10 minutes, and then ethyl trifluoroacetate 1.42 was added. g (1 Ommo 1) was added and the mixture was stirred at 110 ° C for 120 minutes. The reaction solution was brought to 0 ° C, 3.5 mL of concentrated hydrochloric acid was added in an ice bath, and the mixture was stirred for 10 minutes. Then, 1 OmL of water and 3 OmL of ethyl acetate were added. Take the organic layer and the aqueous layer with ethyl acetate 3 Oml Extracted twice, combined with the organic layer separated earlier, washed three times with 15 mL of saturated saline, and dried over anhydrous magnesium sulfate. The obtained organic layer was concentrated under reduced pressure to obtain 2.46 g of an oily substance. When ethyl benzoate was quantified as an internal standard, the obtained oil contained 1.67 g of the desired product (yield 79%). Example 7
100 OmLの四つ口フラスコに 60重量0 /0水素化ナトリウム 8. 80 g (220 mm o 1 ) をへキサン 100 m Lで 2回洗浄した後、 THF 400m Lとヘプタン 100m lの混合溶媒に懸濁し、 4°Cで 3 _ォキソブタン酸メチ ル 23. 22 g (20 Ommo 1 ) を加え、 同温度で 1 5分間攪拌した。 次い で、 これに 1. 58mMZmL n _ブチルリチウム一へキサン溶液 133 m L (21 Ommo 1 ) を一 10 °Cで 30分間かけて滴下した後、 トリフノレオ口 酢酸ェチル 28. 42 g (20 Ommo 1 ) を加え、 _ 10°Cで 120分間攪 拌した。 反応液を 0°Cとし、 氷浴中で濃塩酸 46mLを加えて 10分間攪拌し た後、 水 20 OmL及び酢酸ェチル 60 OmLを加えた。 有機層をとり、 水層 を酢酸ェチル 600m lで 2回抽出し先に分液した有機層と合わせ、 飽和食塩 水 30 OmLで 3回洗浄した後、 無水硫酸マグネシウムで乾燥した。 得られた 有機層を減圧濃縮して油状物 46. 47 gを得た。 安息香酸ェチルを内部標準 物質として定量したところ、 得られた油状物には目的生成物が 33. 09 g含 まれていた （収率 78%) 。 該油状物を減圧蒸留で精製し、 目的生成物を圧力 0. 9mmHgにおける沸点が 44°Cの留分として 27. 80 g得た （単離収 率 68 %) 。 本発明を詳細にまた特定の実施態様を参照して説明したが、 本発明の精神と 範囲を逸脱することなく様々な変更や修正を加えることができることは当業者 にとつて明らかである。 本出願は、 2002年 1月 8 日出願の日本特許出願番号 2002-1771及び 2002 年 9月 19 日出願の日本特許出願番号 2002-272479に基づくものであり、 その 内容はここに参照として取り込まれる。 産業上の利用可能性 After washing twice with 100 sodium 60 weight 0/0 hydride four-necked flask OmL 8. 80 g (220 mm o 1) f hexane 100 m L, in a mixed solvent of THF 400 meters L and heptane 100 m l The suspension was added, and 23.22 g (20 Ommo 1) of methyl 3-oxobutanoate was added at 4 ° C., followed by stirring at the same temperature for 15 minutes. Next, 133 mL (21 Ommo 1) of 1.58 mM ZmL n-butyllithium-hexane solution was added dropwise at 110 ° C. over 30 minutes, and then triethylenoethyl acetate 28.42 g (20 Ommo 1) was added and stirred at -10 ° C for 120 minutes. The reaction solution was adjusted to 0 ° C., 46 mL of concentrated hydrochloric acid was added in an ice bath, and the mixture was stirred for 10 minutes. Then, 20 OmL of water and 60 OmL of ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted twice with 600 ml of ethyl acetate, combined with the organic layer separated earlier, washed three times with 30 OmL of saturated saline, and dried over anhydrous magnesium sulfate. The obtained organic layer was concentrated under reduced pressure to obtain 46.47 g of an oily substance. When ethyl benzoate was quantified as an internal standard, the obtained oil contained 33.09 g of the desired product (78% yield). The oil was purified by distillation under reduced pressure to obtain 27.80 g of the desired product as a fraction having a boiling point of 44 ° C at a pressure of 0.9 mmHg (isolation yield: 68%). Although the present invention has been described in detail and with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention. This application is based on Japanese Patent Application No. 2002-1771 filed on Jan. 8, 2002 and Japanese Patent Application No. 2002-272479 filed on Sep. 19, 2002, the contents of which are incorporated herein by reference. . Industrial applicability
本発明によれば、 医農薬中間体として有用な 6 , 6 , 6—トリフルオロー 3 , 5—ジォキソへキサン酸エステル及ぴその互変異性体を簡便且つ収率よく得る とことができる。  According to the present invention, 6,6,6-trifluoro-3,5-dioxohexanoate and its tautomers useful as pharmaceutical and agricultural chemical intermediates can be obtained easily and in good yield.

Claims

請 求 の 範 囲 The scope of the claims
1 . 3—ォキソブタン酸エステルに、 2位のメチレン基と反応し得る塩基 を反応させ、 1.3-oxobutanoic acid ester is reacted with a base capable of reacting with the methylene group at the 2-position,
得られる反応物に 4位のメチル基と反応し得る塩基を反応させ、  The resulting reactant is reacted with a base capable of reacting with the methyl group at the 4-position,
得られる反応物にトリフルォロ酢酸エステルを反応させる、  Reacting the obtained reaction product with trifluoroacetic acid ester,
ことを含む、 6 , 6 , 6—トリフルオロー 3 , 5—ジォキソへキサン酸エステ ル及びその互変異性体の製造方法。 A process for producing 6,6,6-trifluoro-3,5-dioxohexanoic acid ester and its tautomer, comprising:
2 . 2位のメチレン基と反応し得る塩基が、 アルカリ金属、 アルカリ金属 水素化物及び金属アルコキシドよりなる群から選ばれる、 請求の範囲 1記載の 方法。 2. The method according to claim 1, wherein the base capable of reacting with the methylene group at the 2-position is selected from the group consisting of alkali metals, alkali metal hydrides and metal alkoxides.
3 . 2位のメチレン基と反応し得る塩基が、 水素化ナトリウムである、 請 求の範囲 1または 2記載の方法。 3. The method according to claim 1, wherein the base capable of reacting with the methylene group at the 2-position is sodium hydride.
4 . 2位のメチレン基と反応し得る塩基が、 3—ォキソブタン酸エステル に対して、 等モル以上用いられる、 請求の範囲 1〜3のいずれか 1項に記載の 方法。 4. The method according to any one of claims 1 to 3, wherein the base capable of reacting with the methylene group at the 2-position is used in an equimolar amount or more with respect to 3-oxobutanoate.
5 . 4位のメチル基と反応し得る塩基が、 有機リチウム及びアルカリ金属 アミ ドよりなる群から選ばれる、 請求の範囲 1〜4のいずれか 1項に記載の方 法。 5. The method according to any one of claims 1 to 4, wherein the base capable of reacting with the methyl group at the 4-position is selected from the group consisting of organolithium and alkali metal amides.
6 . 4位のメチル基と反応し得る塩基が、 ブチルリチウムである、 請求の 範囲 1〜 5のいずれか 1項に記載の方法。 6. The method according to any one of claims 1 to 5, wherein the base capable of reacting with the methyl group at the 4-position is butyllithium.
7. 4位のメチル基と反応し得る塩基が、 3—ォキソブタン酸エステルに 対して、 等モル以上用いられる、 請求の範囲 1〜6のいずれか 1項に記載の方 法。 7. The method according to any one of claims 1 to 6, wherein the base capable of reacting with the methyl group at the 4-position is used in an equimolar amount or more with respect to the 3-oxobutanoate.
8. 3—ォキソブタン酸エステノレが、 3—ォキソブタン酸メチルエステル 及び 3 _ォキソブタン酸ェチルエステルよりなる群から選ばれる、 請求の範囲 1〜 7のいずれか 1項に記載の方法。 8. The method according to any one of claims 1 to 7, wherein the 3-oxobutanoic acid ester is selected from the group consisting of methyl 3-oxobutanoate and ethyl ethyl 3-oxobutanoate.
9. トリフルォロ酢酸エステルが、 トリフルォロ酢酸メチルエステル及び トリフルォロ酢酸ェチルエステルよりなる群から選ばれる、 請求の範囲 1〜8 のいずれか 1項に記載の方法。 9. The method according to any one of claims 1 to 8, wherein the trifluoroacetic acid ester is selected from the group consisting of trifluoroacetic acid methyl ester and trifluoroacetic acid ethyl ester.
1 0. 反応をエーテル系溶媒及び脂肪族炭化水素系溶媒からなる混合溶媒 中で行い、 脂肪族炭化水素系溶媒の使用量が全溶媒量に対して 50 V o 1 %以 下である、 請求の範囲 1〜 9のいずれか 1項に記載の方法。 10. The reaction is performed in a mixed solvent composed of an ether solvent and an aliphatic hydrocarbon solvent, and the amount of the aliphatic hydrocarbon solvent used is 50 V o 1% or less based on the total solvent amount. The method according to any one of claims 1 to 9.
1 1. 6, 6, 6_トリフルオロー 3， 5 _ジォキソへキサン酸エステル 及びその互変異性体。 1 1. 6, 6, 6_trifluoro-3,5_dioxohexanoate and its tautomers.
1 2. 6， 6, 6_トリフルオロー 3， 5—ジォキソへキサン酸メチル及 びその互変異性体。 1 2. 6,6,6_Methyl trifluoro-3,5-dioxohexanoate and its tautomers.
PCT/JP2003/000012 2002-01-08 2003-01-06 Process for producing 6,6,6-trifluoro-3,5-dioxohexanoic acid ester and tautomer thereof WO2003057659A1 (en)

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US9145391B2 (en) 2011-05-10 2015-09-29 Merck Sharp & Dohme Corp. Bipyridylaminopyridines as Syk inhibitors
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US9487504B2 (en) 2012-06-20 2016-11-08 Merck Sharp & Dohme Corp. Imidazolyl analogs as syk inhibitors
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US9624210B2 (en) 2012-12-12 2017-04-18 Merck Sharp & Dohme Corp. Amino-pyrimidine-containing spleen tyrosine kinase (Syk) inhibitors
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US9783531B2 (en) 2013-12-20 2017-10-10 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
US9822107B2 (en) 2013-12-20 2017-11-21 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
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