JPWO2004007420A1 - Process for producing α-methyl-β-ketoester - Google Patents
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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
- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
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- 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
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Abstract
β−ケトエステルを原料に、毒性を有する試薬や特別に苛烈な条件を使わず、効率よくα−メチル−β−ケトエステルが製造できる方法が開示されている。この方法は、β−ケトエステルと無水酢酸との混合液にペレット状のパラホルムアルデヒドを溶解させ、含水低級アルコールを加え、水素雰囲気下、パラジウム−炭素触媒で加水素分解して効率よくα−メチル−β−ケトエステルを製造する。A method is disclosed in which α-methyl-β-ketoester can be efficiently produced from β-ketoester as a raw material without using toxic reagents or specially harsh conditions. In this method, pellet-form paraformaldehyde is dissolved in a mixed solution of β-ketoester and acetic anhydride, a hydrous lower alcohol is added, and hydrogenolysis is performed with a palladium-carbon catalyst in a hydrogen atmosphere to efficiently produce α-methyl- A β-keto ester is produced.
Description
［発明の背景］
発明の分野
本発明は、医薬、農薬などの製造原料として有用な、α−メチル−β−ケトエステルの製造法に関する。
背景の技術
アセト酢酸エチルに代表されるβ−ケトエステルは、ピリン系解熱剤やスルホンアミド系の農薬などを製造する原料として有用な化合物であり、広く使用されている。
これらの中でα位にメチル基を導入したα−メチル−β−ケトエステルを製造する方法は数多く知られている。例えばアセト酢酸エチルを塩基存在下、臭化メチルまたはヨウ化メチルと反応させることにより製造する方法、あるいは２−ブロモプロピオン酸エチルと亜鉛存在下、無水酢酸と反応させる方法が知られている。しかし、前者の方法は臭化物またはヨウ化物の毒性およびコストの点で利用が限定され、また、後者の方法は金属亜鉛を化学量論的に使用するため、その産業廃棄物としての処理に配慮が必要となる。
また、特公昭４９−３４６６１号公報には、アセト酢酸エチルなどのβ−ケトエステルをホルムアルデヒドと縮合させ、生成するアルキリデン化合物をパラジウム触媒存在下、水素添加して目的のα−メチル−β−ケトエステルとする製造法が開示されている。しかしながら、この製造法では、目的化合物の収率は通常４０％程度であり、しかも触媒として塩化亜鉛を使用するため産業廃棄物の問題があり、工業的製造法としては改良の余地がある。また、スイス特許ＣＨ５６０１７６にはアセト酢酸エチルを無水酢酸存在下にホルムアルデヒドと縮合させ、生成する２−アセトキシメチル−アセト酢酸エチルをパラジウム触媒存在下、加水素分解して目的の２−メチル−アセト酢酸エチルとする製造法が開示されている。この方法では５０気圧の圧力を加える上、固形のパラホルムアルデヒドを一旦８０℃以上に加熱して熱分解し、ガス状のホルムアルデヒドとし、反応液中にガス状態で導入する方法が採用されている。このように、発ガン性が強く刺激性を有する化合物を気体状態で扱うことは、工業的スケールの製造法としては避けるべきである。
従って、α−メチル−β−ケトエステルを収率良くかつ安全に得ることができる製造法が依然として希求されている。
［発明の概要］
本発明者らは、今般、安価なβ−ケトエステルを出発原料とし、パラホルムアルデヒドを熱分解することなく、固体のパラホルムアルデヒドをβ−ケトエステルと無水酢酸に溶解させ、低級アルコールの存在下反応させ、続いて加水素分解することでα−メチル−β−ケトエステルを良好な収率で得ることが出来るとの知見を得た。
従って、本発明は、α−メチル−β−ケトエステルを収率よくかつ安全に得ることができる製造方法の提供をその目的としている。
そして、本発明による製造法は、下記一般式（Ｉ）α−メチル−β−ケトエステルの製造法であって：
Ｒ１は、置換基を有していてもよい、直鎖または分岐鎖Ｃ１−６アルキル基、またはシクロアルキル基を表し、
Ｒ２は、直鎖または分岐鎖Ｃ１−４アルキル基を表す。］、
下記の一般式（ＩＩ）：
で表されるβ−ケトエステルと無水酢酸の混合物にパラホルムアルデヒドを溶解させた後、含水低級アルコールの存在下反応させて、下記の一般式（ＩＩＩ）：
で表されるα−アセトキシメチル−β−ケトエステルを生成させ、これを加水素分解することを少なくとも含んでなるものである。
［発明の具体的説明］
式（Ｉ）の化合物
本発明による製造方法の目的物は、上記式（Ｉ）で表されるα−メチル−β−ケトエステルである。この式（Ｉ）において、Ｒ１は、Ｃ１−６アルキル基またはシクロアルキル基を表し、このアルキル基は直鎖であっても分岐鎖であってもよい。また、このアルキル基は一または二以上の置換基で置換されていてもよく、置換基としてはハロゲン原子（例えば、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、水酸基、および直鎖または分岐鎖状のＣ１−４アルキル基が挙げられる。また、Ｒ１が表すシクロアルキル基は好ましくはＣ− シクロアルキル基である。また、式（Ｉ）において、Ｒ２は、直鎖または分岐鎖状のＣ１−４アルキル基を表す。
式（Ｉ）で表される化合物は、種々の有用化合物の合成中間体として有用である。例えば、ＷＯ０１／９２２３１公報に開示される６−ｔ−ブチル−８−フルオロキノリン誘導体は農園芸用病害に対して優れた防除活性を有する化合物であり、この化合物の合成に式（Ｉ）の化合物は用いられる。すなわち、４−ｔ−ブチル−２−フルオロアニリンまたはその塩を、ＷＯ０１／９２２３１公報、Ｊ．Ｃｈｅｍ．Ｓｏｃ．，（Ｃ）．２４２６（１９７０）またはＴｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ．，４９４５（１９６８）に記載の方法に準じて、α−メチル−β−ケトエステルと脱水縮合反応させ、ついでフェニルエーテル中２５０℃に加熱して６−ｔ−ブチル−３，４−ジメチル−８−フルオロキノロンを得て、これをアセチル体に変換して、４−アセトキシ−６−ｔ−ブチル−３，４−ジメチル−８−フルオロキノリンを得ることができる。
式（Ｉ）の化合物の製造法
本発明による方法にあっては、まず、式（ＩＩ）：
で表されるβ−ケトエステルと無水酢酸との混合物を用意する。式（ＩＩ）の化合物と無水酢酸の比は、次に添加されるパラホルムアルデヒドを溶解できる限り限定されないが、１：１０〜１０：１程度（重量比）が好ましく、より好ましくは１：５〜５：１程度（重量比）である。
次に、この式（ＩＩ）の化合物と無水酢酸の混合液にパラホルムアルデヒドを加え、溶解させる。前述の通り、ホルムアルデヒドを気体として反応に利用することは工業的製造法においては不利または避けることが望まれる。本発明にあっては、パラホルムアルデヒドを式（ＩＩ）の化合物と無水酢酸の混合液に溶解させるため、その取扱いが極めて容易となる点で有利である。本発明の好ましい態様によれば、パラホルムアルデヒドは式（ＩＩ）に対して１〜１０当量が好ましく、より好ましくは１〜３当量程度である。また、その取扱いの容易さから、パラホルムアルデヒドは、ペレット状のものの利用が好ましい。
本発明による方法にあっては、式（ＩＩ）の化合物と、無水酢酸と、パラホルムアルデヒドとの反応を、含水低級アルコールの存在下において行う。
本発明において、低級アルコールは好ましくはＣ１−６一価アルコールであり、より好ましくはエチルアルコールである。本発明にあっては、この低級アルコールは水を含む。その量は、アルコールに対して０．１〜１．５重量％程度でよく、好ましくは０．３〜０．８重量％であり、最も好ましくは０．５重量％である。このような微量の水を含む低級アルコールの存在により、副生成物が極めて抑制され、かつ大幅な収率の改善を図ることができる。本発明者らは、脱水低級アルコールによってはこのような利点が得られないことを、実験的に確認している。この含水低級アルコールの存在下に反応を進めることによって得られるこれら利点は、従来知られたα−メチル−β−ケトエステルの製造方法に比較して、極めて有利な点であるといえる。含水低級アルコールの反応系における存在量は適宜決定されてよいが、式（ＩＩ）の化合物と、無水酢酸と、パラホルムアルデヒドの合計量に対して、２〜５０重量％程度が好ましく、より好ましくは３〜３０重量％程度である。
含水低級アルコールの存在下における、式（ＩＩ）の化合物と、無水酢酸と、パラホルムアルデヒドとの反応は、加熱下行われる。その温度および反応時間は、副生成物の生成、収率等を勘業しながら適宜決定されていよいが、室温〜１００℃程度が一般的であり、好ましくは３５〜５０℃の範囲であり、最も好ましくは４０℃程度であり、反応時間は５〜１００時間程度が一般的であり、好ましくは７〜８０時間である。
上記反応により、式（ＩＩＩ）：
で表されるα−アセトキシメチル−β−ケトエステルが生成される。本発明にあっては、式（ＩＩＩ）の化合物を加水素分解に付し、式（Ｉ）で表されるα−メチル−β−ケトエステルを得る。この加水素分解は式（Ｉ）の化合物が得られる限り適宜決定されてよいが、本発明の好ましい態様によれば、パラジウム−炭素触媒下での水素との接触（例えば、水素を反応混合物に直接通すか、反応混合物を水素雰囲気に置く）が好ましい、反応条件も適宜決定されてよいが、水素圧力は１〜５０気圧程度が好ましく、より好ましくは１〜２０気圧程度であり、温度は室温〜１００℃程度が好ましく、より好ましくは３５〜５０℃程度であり、反応時間は５〜１００時間程度が好ましく、より好ましくは７〜８０時間程度である。パラジウム−炭素の存在量も適宜決定されていよいが、式（ＩＩＩ）の化合物に対して、０．０１〜０．２重量％程度が好ましく、より好ましくは０．０２〜０．１重量％程度である。
本発明の好ましい態様によれば、上記した式（ＩＩ）の化合物と無水酢酸とパラホルムアルデヒドとの反応による式（ＩＩＩ）の化合物を生成する工程と、式（ＩＩＩ）の化合物の加水素分解反応とを、一つの反応系で連続して行うことが出来る。この際の反応条件は、水素圧力１〜５０気圧程度が好ましく、より好ましくは１〜２０気圧程度であり、温度は室温〜１００℃程度が好ましく、より好ましくは３５〜５０℃程度であり、反応時間は５〜１００時間程度が好ましく、より好ましくは７〜８０時間程度である。
得られた式（Ｉ）の化合物は、その後反応系から単離され、例えばのような工程に付して、精製されるのが好ましい。[Background of the invention]
The present invention relates to a process for producing α-methyl-β-ketoesters useful as raw materials for producing pharmaceuticals, agricultural chemicals and the like.
Background Art β-ketoesters typified by ethyl acetoacetate are compounds that are useful as raw materials for producing pyrin-based antipyretic agents, sulfonamide-based agricultural chemicals, and the like, and are widely used.
Among these, many methods for producing an α-methyl-β-ketoester having a methyl group introduced at the α-position are known. For example, a method of producing ethyl acetoacetate by reacting with methyl bromide or methyl iodide in the presence of a base, or a method of reacting with acetic anhydride in the presence of ethyl 2-bromopropionate and zinc is known. However, the former method is limited in terms of the toxicity and cost of bromide or iodide, and the latter method uses metal zinc in a stoichiometric manner, so that it is considered to be treated as industrial waste. Necessary.
In Japanese Patent Publication No. 49-34661, a β-ketoester such as ethyl acetoacetate is condensed with formaldehyde, and the resulting alkylidene compound is hydrogenated in the presence of a palladium catalyst to obtain the desired α-methyl-β-ketoester. A manufacturing method is disclosed. However, in this production method, the yield of the target compound is usually about 40%, and since zinc chloride is used as a catalyst, there is a problem of industrial waste, and there is room for improvement as an industrial production method. Further, Swiss patent CH560176 condenses ethyl acetoacetate with formaldehyde in the presence of acetic anhydride, and hydrogenates the resulting 2-acetoxymethyl-ethyl acetoacetate in the presence of a palladium catalyst to give the desired 2-methyl-acetoacetic acid. A process for producing ethyl is disclosed. In this method, in addition to applying a pressure of 50 atm, solid paraformaldehyde is once heated to 80 ° C. or higher and thermally decomposed to form gaseous formaldehyde and introduced into the reaction solution in a gas state. Thus, handling a compound having strong carcinogenicity and irritation in a gaseous state should be avoided as a manufacturing method on an industrial scale.
Therefore, there is still a need for a production method capable of obtaining the α-methyl-β-ketoester with good yield and safety.
[Summary of Invention]
The present inventors have recently used an inexpensive β-ketoester as a starting material, and without dissolving paraformaldehyde, solid paraformaldehyde is dissolved in β-ketoester and acetic anhydride and reacted in the presence of a lower alcohol. Subsequently, it was found that α-methyl-β-ketoester can be obtained in good yield by hydrogenolysis.
Accordingly, an object of the present invention is to provide a production method capable of obtaining α-methyl-β-ketoester with good yield and safety.
The production method according to the present invention is a production method of the following general formula (I) α-methyl-β-ketoester:
R 1 represents a linear or branched C 1-6 alkyl group or cycloalkyl group which may have a substituent,
R 2 represents a linear or branched C 1-4 alkyl group. ],
The following general formula (II):
Paraformaldehyde is dissolved in a mixture of β-ketoester and acetic anhydride represented by the following formula, and reacted in the presence of a hydrous lower alcohol to give the following general formula (III):
At least comprising hydrogenating the α-acetoxymethyl-β-ketoester represented by the following formula.
[Detailed Description of the Invention]
Compound of Formula (I) The object of the production method according to the present invention is α-methyl-β-ketoester represented by the above formula (I). In the formula (I), R 1 represents a C 1-6 alkyl group or a cycloalkyl group, and the alkyl group may be linear or branched. The alkyl group may be substituted with one or more substituents. Examples of the substituent include a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom), a hydroxyl group, and a linear or branched group. A chain C 1-4 alkyl group may be mentioned. The cycloalkyl group represented by R 1 is preferably a C - cycloalkyl group. In the formula (I), R 2 represents a linear or branched C 1-4 alkyl group.
The compound represented by the formula (I) is useful as an intermediate for the synthesis of various useful compounds. For example, a 6-t-butyl-8-fluoroquinoline derivative disclosed in WO01 / 92231 is a compound having excellent control activity against agricultural and horticultural diseases, and the compound of formula (I) is synthesized in the synthesis of this compound. Is used. That is, 4-t-butyl-2-fluoroaniline or a salt thereof is disclosed in WO 01/92231, J. Org. Chem. Soc. , (C). 2426 (1970) or Tetrahedron Lett. 4945 (1968), a dehydration condensation reaction with α-methyl-β-ketoester, followed by heating to 250 ° C. in phenyl ether to give 6-tert-butyl-3,4-dimethyl-8-. Fluoroquinolone can be obtained and converted to the acetyl form to give 4-acetoxy-6-tert-butyl-3,4-dimethyl-8-fluoroquinoline.
Process for the preparation of the compound of formula (I) In the process according to the invention, first of all the formula (II):
The mixture of (beta) -ketoester represented by these and acetic anhydride is prepared. The ratio of the compound of the formula (II) and acetic anhydride is not limited as long as the paraformaldehyde added next can be dissolved, but is preferably about 1:10 to 10: 1 (weight ratio), more preferably 1: 5 to 5. It is about 5: 1 (weight ratio).
Next, paraformaldehyde is added to and dissolved in the mixture of the compound of formula (II) and acetic anhydride. As described above, the use of formaldehyde as a gas for the reaction is disadvantageous or desired to be avoided in industrial production methods. In the present invention, since paraformaldehyde is dissolved in a mixed solution of the compound of formula (II) and acetic anhydride, it is advantageous in that handling becomes extremely easy. According to a preferred embodiment of the present invention, paraformaldehyde is preferably 1 to 10 equivalents, more preferably about 1 to 3 equivalents, relative to formula (II). Also, in view of ease of handling, it is preferable to use paraformaldehyde in the form of pellets.
In the method according to the present invention, the reaction of the compound of formula (II), acetic anhydride and paraformaldehyde is carried out in the presence of a hydrous lower alcohol.
In the present invention, the lower alcohol is preferably a C 1-6 monohydric alcohol, and more preferably ethyl alcohol. In the present invention, the lower alcohol contains water. The amount may be about 0.1 to 1.5% by weight with respect to the alcohol, preferably 0.3 to 0.8% by weight, and most preferably 0.5% by weight. By the presence of such a lower alcohol containing a small amount of water, by-products are extremely suppressed, and a significant improvement in yield can be achieved. The present inventors have experimentally confirmed that such advantages cannot be obtained with dehydrated lower alcohol. These advantages obtained by proceeding the reaction in the presence of the water-containing lower alcohol can be said to be extremely advantageous as compared with the conventionally known methods for producing α-methyl-β-ketoesters. The abundance of the hydrous lower alcohol in the reaction system may be appropriately determined, but is preferably about 2 to 50% by weight, more preferably, based on the total amount of the compound of formula (II), acetic anhydride and paraformaldehyde. About 3 to 30% by weight.
The reaction of the compound of formula (II), acetic anhydride and paraformaldehyde in the presence of a hydrous lower alcohol is carried out under heating. The temperature and reaction time may be appropriately determined while taking into consideration the production of by-products, the yield, etc., but generally room temperature to about 100 ° C., preferably in the range of 35 to 50 ° C., Most preferably, it is about 40 ° C., and the reaction time is generally about 5 to 100 hours, preferably 7 to 80 hours.
By the above reaction, the formula (III):
The α-acetoxymethyl-β-ketoester represented by In the present invention, the compound of formula (III) is subjected to hydrogenolysis to obtain α-methyl-β-ketoester represented by formula (I). This hydrogenolysis may be appropriately determined as long as the compound of formula (I) is obtained, but according to a preferred embodiment of the present invention, contact with hydrogen under a palladium-carbon catalyst (for example, hydrogen into the reaction mixture). The reaction conditions may be appropriately determined. The hydrogen pressure is preferably about 1 to 50 atm, more preferably about 1 to 20 atm, and the temperature is room temperature. About 100-100 degreeC is preferable, More preferably, it is about 35-50 degreeC, Reaction time has preferable about 5-100 hours, More preferably, it is about 7-80 hours. Although the abundance of palladium-carbon may be appropriately determined, it is preferably about 0.01 to 0.2% by weight, more preferably about 0.02 to 0.1% by weight with respect to the compound of formula (III). It is.
According to a preferred embodiment of the present invention, a step of producing a compound of formula (III) by reaction of a compound of formula (II) with acetic anhydride and paraformaldehyde, and a hydrogenolysis reaction of the compound of formula (III) Can be carried out continuously in one reaction system. The reaction conditions in this case are preferably a hydrogen pressure of about 1 to 50 atmospheres, more preferably about 1 to 20 atmospheres, and the temperature is preferably room temperature to about 100 ° C., more preferably about 35 to 50 ° C. The time is preferably about 5 to 100 hours, more preferably about 7 to 80 hours.
The resulting compound of formula (I) is then preferably isolated from the reaction system and purified by subjecting it to the following steps, for example.
以下実施例を挙げて本発明を具体的に説明する。
実施例１ ２−メチルアセト酢酸エチルの合成（水素圧１気圧）
アセト酢酸エチル（１００ｇ，０．７６８ｍｏｌ）と無水酢酸（８６．０ｇ，０．８４５ｍｏｌ）との混合液にペレット状のパラホルムアルデヒド（４６．０ｇ，１．５４ｍｏｌ）を溶解させた。この溶液と９９．５％エタノール（含水率０．５重量％）４５０ｍＬを加え、基質重量に対し５％にあたる５．００ｇの１０％パラジウム−炭素触媒（川研ファインケミカル製ＡＤ１０％Ｐｄ／Ｃ）とを反応器に加え、脱気を行った。その後、水素を導入し、反応器内を１気圧の水素雰囲気に保ちながら、４０℃に加温し、反応液を激しく撹拌しながら２２時間反応を行った。反応液を冷却した後、固形物を濾過して除き、ろ液を減圧濃縮して残渣を得た。これをヘリパックカラムを用いて蒸留して、２−メチルアセト酢酸エチル１１１ｇを無色油状物として得た。収率７４．８％。
実施例２ ２−メチルアセト酢酸エチルの合成（水素圧１０気圧）
アセト酢酸エチル（１００ｇ，０．７６８ｍｏｌ）と無水酢酸（８６．０ｇ，０．８４５ｍｏｌ）との混合液にペレット状のパラホルムアルデヒド（４６．０ｇ，１．５４ｍｏｌ）を溶解させた。この溶液に９９．５％エタノール（含水率０．５重量％）４５０ｍＬを加え、基質重量に対し０．５％にあたる５００ｍｇの１０％パラジウム−炭素触媒（川研ファインケミカル製ＡＤ１０％Ｐｄ／Ｃ）とをオートクレーブに加えた。オートクレーブ中を水素雰囲気下に置換した後、水素圧力を１０気圧まで加圧し、４０℃に加温して撹拌した。時々水素を補充して１０気圧を保ちながら４８時間反応を行った。反応液を冷却した後、固形物を濾過して除き、ろ液を減圧濃縮して残渣を得た。これをヘリパックカラムを用いて蒸留して、２−メチルアセト酢酸エチル８４．６ｇを無色油状物として得た。収率５７．０％。
実施例３ ２−メチルアセト酢酸エチルの合成（水素圧１０気圧）
アセト酢酸エチル（１００ｇ，０．７６８ｍｏｌ）と無水酢酸（８６．０ｇ，０．８４５ｍｏｌ）との混合液にペレット状のパラホルムアルデヒド（４６．０ｇ，１．５４ｍｏｌ）を溶解させた。この溶液に９９．５％エタノール（含水量０．５重量％）４５０ｍＬを加え、基質重量に対し０．５％にあたる５００ｍｇの５％パラジウム−炭素触媒（川研ファインケミカル製ＡＤ５％Ｐｄ／Ｃ）とをオートクレーブに加えた。オートクレーブ中を水素雰囲気下に置換した後、水素圧力を１０気圧まで加圧し、４０℃に加温して撹拌した。時々水素を補充して１０気圧を保ちながら７２時間反応を行った。反応液を冷却した後、固形物を濾過して除き、ろ液を減圧濃縮して残渣を得た。これをヘリパックカラムを用いて蒸留して、２−メチルアセト酢酸エチル９２．０ｇを無色油状物として得た。収率６５．０％。
比較例１ ２−メチルアセト酢酸エチルの合成（水素圧１気圧）
アセト酢酸エチル（１００ｇ，０．７６８ｍｏｌ）と無水酢酸（８６．０ｇ，０．８４５ｍｏｌ）との混合液の中に、ペレット状のパラホルムアルデヒド（４６．０ｇ，１．５４ｍｏｌ）を溶解させた。この溶液と、塩基性触媒としての酢酸ナトリウム（６３．０ｇ，０．７６８ｍｏｌ）と、５．００ｇのパラジウム−炭素触媒（川研ファインケミカル製ＡＤ１０％Ｐｄ／Ｃ）とを反応器に加え、脱気を行った。その後、水素を導入し、反応器内を１気圧の水素雰囲気に保ちながら、４０℃に加温し、反応液を激しく撹拌しながら６時間反応を行った。反応液を冷却した後、固形物を濾過して除き、ろ液を減圧濃縮して残渣を得た。これを２０ｃｍのヘリパックカラムを用いて蒸留して、２−メチルアセト酢酸エチル２３．７ｇを無色油状物として得た。収率１６．０％
ＥＩ−ＭＳ；ｍ／ｚ１４５（Ｍ＋Ｈ）＋；１ＨＮＭＲ（ＣＤＣｌ３）δ１．２８（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），１．３５（３Ｈ，ｄ，Ｊ＝７．３Ｈｚ），２．２５（３Ｈ，ｓ），３．５１（１Ｈ，ｑ，Ｊ＝７．３Ｈｚ），４．２０（１Ｈ，ｑｄ，Ｊ＝７．３，１．０Ｈｚ）．Hereinafter, the present invention will be specifically described with reference to examples.
Example 1 Synthesis of ethyl 2-methylacetoacetate (hydrogen pressure 1 atm)
Pellet formaldehyde (46.0 g, 1.54 mol) was dissolved in a mixture of ethyl acetoacetate (100 g, 0.768 mol) and acetic anhydride (86.0 g, 0.845 mol). 450 mL of this solution and 99.5% ethanol (water content 0.5 wt%) were added, and 5.00 g of 10% palladium-carbon catalyst (AD10% Pd / C manufactured by Kawaken Fine Chemical Co., Ltd.) corresponding to 5% of the substrate weight was added. Was added to the reactor and degassed. Thereafter, hydrogen was introduced, and the reactor was heated to 40 ° C. while maintaining a 1 atmosphere of hydrogen atmosphere, and the reaction was carried out for 22 hours while vigorously stirring the reaction solution. After cooling the reaction solution, the solid matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a residue. This was distilled using a Helipak column to obtain 111 g of ethyl 2-methylacetoacetate as a colorless oil. Yield 74.8%.
Example 2 Synthesis of ethyl 2 -methylacetoacetate (hydrogen pressure 10 atm)
Pellet formaldehyde (46.0 g, 1.54 mol) was dissolved in a mixture of ethyl acetoacetate (100 g, 0.768 mol) and acetic anhydride (86.0 g, 0.845 mol). To this solution, 450 mL of 99.5% ethanol (water content: 0.5% by weight) was added, and 500 mg of 10% palladium-carbon catalyst (AD10% Pd / C manufactured by Kawaken Fine Chemical Co., Ltd.) corresponding to 0.5% of the substrate weight. Was added to the autoclave. After replacing the inside of the autoclave with a hydrogen atmosphere, the hydrogen pressure was increased to 10 atm, heated to 40 ° C. and stirred. The reaction was carried out for 48 hours while replenishing hydrogen from time to time and maintaining 10 atm. After cooling the reaction solution, the solid matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a residue. This was distilled using a Helipak column to obtain 84.6 g of ethyl 2-methylacetoacetate as a colorless oil. Yield 57.0%.
Example 3 Synthesis of ethyl 2-methylacetoacetate (hydrogen pressure 10 atm)
Pellet formaldehyde (46.0 g, 1.54 mol) was dissolved in a mixture of ethyl acetoacetate (100 g, 0.768 mol) and acetic anhydride (86.0 g, 0.845 mol). To this solution was added 450 mL of 99.5% ethanol (water content: 0.5% by weight), and 500 mg of 5% palladium-carbon catalyst (AD5% Pd / C manufactured by Kawaken Fine Chemical Co., Ltd.) corresponding to 0.5% of the substrate weight. Was added to the autoclave. After replacing the inside of the autoclave with a hydrogen atmosphere, the hydrogen pressure was increased to 10 atm, heated to 40 ° C. and stirred. The reaction was carried out for 72 hours while maintaining 10 atm. After cooling the reaction solution, the solid matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a residue. This was distilled using a Helipac column to obtain 92.0 g of ethyl 2-methylacetoacetate as a colorless oil. Yield 65.0%.
Comparative Example 1 Synthesis of ethyl 2-methylacetoacetate (hydrogen pressure 1 atm)
Pellet formaldehyde (46.0 g, 1.54 mol) was dissolved in a mixture of ethyl acetoacetate (100 g, 0.768 mol) and acetic anhydride (86.0 g, 0.845 mol). This solution, sodium acetate (63.0 g, 0.768 mol) as a basic catalyst, and 5.00 g of palladium-carbon catalyst (AD10% Pd / C manufactured by Kawaken Fine Chemical) were added to the reactor, and degassed. Went. Thereafter, hydrogen was introduced and the reactor was heated to 40 ° C. while maintaining a 1 atmosphere hydrogen atmosphere, and the reaction was carried out for 6 hours while vigorously stirring the reaction solution. After cooling the reaction solution, the solid matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a residue. This was distilled using a 20 cm Helipak column to obtain 23.7 g of ethyl 2-methylacetoacetate as a colorless oil. Yield 16.0%
EI-MS; m / z 145 (M + H) + ; 1 HNMR (CDCl 3 ) δ 1.28 (3H, t, J = 7.1 Hz), 1.35 (3H, d, J = 7.3 Hz), 2. 25 (3H, s), 3.51 (1H, q, J = 7.3 Hz), 4.20 (1H, qd, J = 7.3, 1.0 Hz).
Claims (5)
Ｒ１は、置換基を有していてもよい、直鎖または分岐鎖Ｃ１−６アルキル基、またはシクロアルキル基を表し、
Ｒ２は、直鎖または分岐鎖Ｃ１−４アルキル基を表す。］、
下記の一般式（ＩＩ）：
で表されるβ−ケトエステルと無水酢酸の混合物にパラホルムアルデヒドを溶解させた後、含水低級アルコールの存在下反応させて、下記の一般式（ＩＩＩ）：
で表されるα−アセトキシメチル−β−ケトエステルを生成させ、これを加水素分解することを少なくとも含んでなる、製造方法。A process for producing an α-methyl-β-ketoester represented by the following general formula (I):
R 1 represents a linear or branched C 1-6 alkyl group or cycloalkyl group which may have a substituent,
R 2 represents a linear or branched C 1-4 alkyl group. ],
The following general formula (II):
Paraformaldehyde is dissolved in a mixture of β-ketoester and acetic anhydride represented by the following formula, and reacted in the presence of a hydrous lower alcohol to give the following general formula (III):
A production method comprising at least the production of α-acetoxymethyl-β-ketoester represented by the formula (1) and hydrogenolysis thereof.
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| Application Number | Priority Date | Filing Date | Title |
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| JP2002202214 | 2002-07-11 | ||
| JP2002202214 | 2002-07-11 | ||
| PCT/JP2003/008847 WO2004007420A1 (en) | 2002-07-11 | 2003-07-11 | PROCESS FOR PRODUCING α-METHYL-ß-KETO ESTER |
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| JPWO2004007420A1 true JPWO2004007420A1 (en) | 2005-11-10 |
| JP4316499B2 JP4316499B2 (en) | 2009-08-19 |
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| CN (1) | CN1318379C (en) |
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| TW200925147A (en) * | 2007-08-08 | 2009-06-16 | Meiji Seika Kaisha | Novel method for producing ?-methyl-?-ketoester |
| CN107188807A (en) * | 2017-07-10 | 2017-09-22 | 济南大学 | The method that arabinose prepares ethyl levulinate |
| CN110483290B (en) * | 2019-08-09 | 2022-05-31 | 上海应用技术大学 | Method for synthesizing beta-keto ester by copper catalysis |
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| CH560176A5 (en) * | 1972-04-24 | 1975-03-27 | Lonza Ag | Ethyl alpha-methyl-aceto-acetate prodn. - from formaldehyde gas and acetoacetic ester contg. acetic anhydride and hydrogenation |
| DE3326635A1 (en) * | 1983-07-23 | 1985-01-31 | Bayer Ag, 5090 Leverkusen | METHOD FOR PRODUCING MONOMETHYL-SUBSTITUTED METHYLENE COMPOUNDS |
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| AU2003280975A1 (en) | 2004-02-02 |
| JP4316499B2 (en) | 2009-08-19 |
| TW200403221A (en) | 2004-03-01 |
| WO2004007420A1 (en) | 2004-01-22 |
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