JP3819560B2 - Method for producing halogenated phenylpropionic acid compound - Google Patents
Method for producing halogenated phenylpropionic acid compound Download PDFInfo
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- JP3819560B2 JP3819560B2 JP26220497A JP26220497A JP3819560B2 JP 3819560 B2 JP3819560 B2 JP 3819560B2 JP 26220497 A JP26220497 A JP 26220497A JP 26220497 A JP26220497 A JP 26220497A JP 3819560 B2 JP3819560 B2 JP 3819560B2
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- 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
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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Description
【０００１】
【発明の属する技術分野】
本発明は、ハロゲン化フェニルプロピオン酸化合物の製造方法に関する。さらに詳しくは、副甲状腺機能亢進症に対して非常に有効な治療薬の重要中間体であるハロゲン化フェニルプロピオン酸化合物の製造方法に関する。
【０００２】
【従来の技術】
従来、ハロゲン化桂皮酸化合物の接触還元には、パラジウムまたは白金を成分とする触媒が用いられている。しかし、それらの触媒を用いてハロゲン化桂皮酸化合物の接触還元を行なうと、脱ハロゲン体が２．５〜１５％の生成率で生成してしまい、効率よくハロゲン化フェニルプロピオン酸化合物を得ることができない。
【０００３】
【発明が解決しようとする課題】
本発明は、前記従来技術に鑑みてなされたものであり、効率よく、簡便かつ工業的に有利にハロゲン化フェニルプロピオン酸化合物を製造する方法を提供することを目的とする。
【０００４】
【課題を解決するための手段】
本発明の要旨は、
（１） 一般式（Ｉ）：
【０００５】
【化３】
（式中、Ｘはハロゲン原子、Ｒは水素原子、メチル基、エチル基またはイソプロピル基を示す）で表されるハロゲン化桂皮酸化合物を、触媒としてルテニウムの存在下で接触還元させることを特徴とする一般式（II）：
【０００７】
【化４】
（式中、ＸおよびＲは前記と同じ）で表されるハロゲン化フェニルプロピオン酸化合物の製造方法、
（２） 一般式（Ｉ）で表されるハロゲン化桂皮酸化合物を低級アルコール中または低級アルコールと水との混合溶媒中で接触還元させる前記（１）記載のハロゲン化フェニルプロピオン酸化合物の製造方法、ならびに
（３） 一般式（Ｉ）で表されるハロゲン化桂皮酸化合物を反応温度２０〜３０℃の範囲で接触還元させる前記（１）または（２）記載のハロゲン化フェニルプロピオン酸化合物の製造方法、に関する。
【０００９】
【発明の実施の形態】
本発明のハロゲン化フェニルプロピオン酸化合物の製造方法によれば、前記したように、一般式（Ｉ）：
【００１０】
【化５】
（式中、Ｘはハロゲン原子、Ｒは水素原子、メチル基、エチル基またはイソプロピル基を示す）で表されるハロゲン化桂皮酸化合物を、触媒としてルテニウムの存在下で接触還元させることにより、一般式（II）：
【００１２】
【化６】
（式中、ＸおよびＲは前記と同じ）で表されるハロゲン化フェニルプロピオン酸化合物が得られる。
【００１４】
一般式（Ｉ）で表されるハロゲン化桂皮酸化合物において、Ｘはハロゲン原子、Ｒは水素原子、メチル基、エチル基またはイソプロピル基を示す。
【００１５】
前記ハロゲン原子としては、フッ素原子、塩素原子、臭素原子およびヨウ素原子が挙げられる。
【００１６】
前記一般式（Ｉ）で表されるハロゲン化桂皮酸化合物の具体例としては、例えば、ｏ−クロロ桂皮酸、ｏ−クロロ桂皮酸メチル等が挙げられる。
【００１７】
前記一般式（Ｉ）で表されるハロゲン化桂皮酸化合物の接触還元は、前記したように、触媒としてルテニウムの存在下で行なわれるが、溶媒中で行なわれることが好ましく、例えば、以下の方法にしたがって行なうことができる。
【００１８】
すなわち、前記一般式（Ｉ）で表されるハロゲン化桂皮酸化合物に溶媒を添加し、触媒としてルテニウムの存在下で、水素雰囲気下でかかる溶液を振とうもしくは攪拌することにより、または、水素ガスを溶液に吹き込むことにより、溶液中に水素を溶解させることができる。
【００１９】
触媒として用いられるルテニウムは、例えば、一般に、炭素、アルミナ等の触媒化学で一般に知られている担体にルテニウムを担持させた担持体、酸化ルテニウム等として用いることができる。
【００２０】
前記ルテニウムの使用量は、一般式（Ｉ）で表されるハロゲン化桂皮酸化合物１００重量部に対して、０．１２５〜０．５重量部程度であることが好ましい。
【００２１】
前記溶媒としては、例えば、メタノール、エタノール、２−プロパノール等の炭素数１〜５の低級アルコールの１種または２種以上、それと水との混合溶媒等が挙げられる。これらのなかでは、２−プロパノールと水との混合溶媒およびメタノールが好ましい。なお、低級アルコールと水との混合比は、低級アルコール１００重量部に対して、水が０〜５０重量部程度であることが好ましい。
【００２２】
前記溶媒の使用量は、特に限定されないが、例えば、低級アルコールを使用する場合、その使用量は、一般式（Ｉ）で表されるハロゲン化桂皮酸化合物１００重量部に対して６００〜８００重量部程度であることが好ましく、低級アルコールと水との混合溶媒を使用する場合、その使用量は、一般式（Ｉ）で表されるハロゲン化桂皮酸化合物１００重量部に対して８００〜１０００重量部程度であることが好ましい。
【００２３】
また、接触還元の際には、例えば、触媒の被毒を抑えるために、活性炭等を適宜使用してもよい。
【００２４】
接触還元の際の反応温度は、反応速度の観点から、１０℃以上、好ましくは２０℃以上であることが望ましく、脱ハロゲン体の生成を抑制するという観点から、６０℃以下、好ましくは３０℃以下であることが望ましい。
【００２５】
反応時間は、触媒の使用量等の条件によって異なるので一慨には決定することができないが、接触還元が終了する程度の時間であればよく、通常、８〜２０時間程度であればよい。また、水素雰囲気下でハロゲン化桂皮酸化合物を溶媒に溶解させた溶液を振とうもしくは攪拌する場合には、水素ガスの圧力が３〜１８ｋｇｆ／ｃｍ2 程度であればよい。
【００２６】
接触還元の終了は、例えば、原料および生成物をエステル化した後に、ガスクロマトグラフィーを用いて転化率を調べることによって確認することができる。
【００２７】
反応終了後は、例えば、晶析、濾過、濃縮、洗浄、抽出などの通常の分離操作により、得られた一般式（II）で表されるハロゲン化フェニルプロピオン酸化合物を単離することができる。
【００２８】
以上説明した本発明の製造方法によれば、副生するフェニルプロピオン酸、その誘導体等の脱ハロゲン体の生成率が、通常、約０．５％以下と非常に微量となるため、効率よく一般式（II）で表されるハロゲン化フェニルプロピオン酸化合物を得ることができる。なお、脱ハロゲン体の生成率は、高速液体クロマトグラフィー（ＨＰＬＣ）を用いて測定することができる。
【００２９】
【実施例】
以下、実施例により本発明をさらに詳しく説明するが、本発明はかかる実施例によりなんら限定されるものではない。
【００３０】
実施例１
１リットル容のテフロンビーカーに、メタノール２４０ｇ、ｏ−クロロ桂皮酸３０ｇ、５％ルテニウム炭素（５０％含水）６ｇおよび粉末活性炭１．２ｇを仕込み、攪拌しながら約２５℃で接触還元を行なった。接触還元は、水素ガスを３〜５ｋｇｆ／ｃｍ2 で圧入しながら８時間行なった。接触還元終了後、触媒を濾過し、洗浄して、濾液と洗液をあわせた後、８％水酸化ナトリウム水溶液１２０ｇを加えて５５℃で３０分間攪拌した。メタノール２２５ｇを常圧留去した後、１０％塩酸１２０ｇを２０〜３０℃で滴下した。０〜５℃で１時間攪拌した後、結晶を濾過し、１０％メタノール水溶液１０ｇで洗浄して、乾燥させることにより、ｏ−クロロフェニルプロピオン酸２８ｇを得た（収率９３％、ＨＰＬＣ純度９９．８％、脱クロロ体０．２％、転化率９９．８％）。
【００３１】
実施例２
１リットル容のテフロンビーカーに、メタノール２４０ｇ、ｏ−クロロ桂皮酸３０ｇ、５％ルテニウム炭素（５０％含水）１．５ｇおよび粉末活性炭２．４ｇを仕込み、攪拌しながら約２５〜２９℃で接触還元を行なった。接触還元は、水素ガスを１７〜１８ｋｇｆ／ｃｍ2 で圧入しながら８時間行なった。接触還元終了後、触媒を濾過し、洗浄して、濾液と洗液をあわせた後、８％水酸化ナトリウム水溶液１２０ｇを加えて５５℃で３０分間攪拌した。メタノール２２５ｇを常圧留去した後、１０％塩酸１２０ｇを２０〜３０℃で滴下した。０〜５℃で１時間攪拌した後、結晶を濾過し、１０％メタノール水溶液１０ｇで洗浄して、乾燥させることにより、ｏ−クロロフェニルプロピオン酸２７ｇを得た（収率９０％、ＨＰＬＣ純度９９．８％、脱クロロ体０．１％、転化率９８．７％）。
【００３２】
実施例３
１リットル容のテフロンビーカーに、２−プロパノール２１６ｇ、水２４ｇ、ｏ−クロロ桂皮酸３０ｇ、５％ルテニウム炭素（５０％含水）１．５ｇおよび粉末活性炭２．４ｇを仕込み、攪拌しながら約２５〜２９℃で接触還元を行なった。接触還元は、水素ガスを１６〜１８ｋｇｆ／ｃｍ2 で圧入しながら１５時間行なった。接触還元終了後、触媒を濾過し、洗浄して、濾液と洗液をあわせた後、８％水酸化ナトリウム水溶液１２０ｇを加えて５５℃で３０分間攪拌した。２−プロパノール２００ｇを常圧留去した後、１０％塩酸１２０ｇを２０〜３０℃で滴下した。０〜５℃で１時間攪拌した後、結晶を濾過し、１０％メタノール水溶液１０ｇで洗浄して、乾燥させることにより、ｏ−クロロフェニルプロピオン酸２８ｇを得た（収率９３％、ＨＰＬＣ純度９９．８％、脱クロロ体０．２％、転化率９９．８％）。
【００３３】
実施例４
２００ｍｌ容のテフロンビーカーに、メタノール６０ｇ、ｏ−クロロ桂皮酸メチル１０ｇ、５％ルテニウム炭素（５０％含水）０．５ｇおよび粉末活性炭０．２ｇを仕込み、攪拌しながら約２０℃で接触還元を行なった。接触還元は、水素ガスを３〜５ｋｇｆ／ｃｍ2 で圧入しながら８時間行なった。接触還元終了後、触媒を濾過し、洗浄して、濾液と洗液をあわせた後、１４％水酸化ナトリウム水溶液２０ｇを加えて８０℃で加水分解し、メタノールを減圧留去した。１０％塩酸２９ｇおよびトルエン５４ｇを加えて抽出した後、溶媒を減圧濃縮で留去し、ｏ−クロロフェニルプロピオン酸８．５ｇを得た（収率８５％、ＨＰＬＣ純度９９．８％、脱クロロ体０．２％、転化率９８．０％）。
【００３４】
比較例１
１リットル容のテフロンビーカーに、メタノール２４０ｇ、ｏ−クロロ桂皮酸３０ｇ、５％Ｍ型パラジウム炭素（５０％含水）１．５ｇおよび粉末活性炭１．２ｇを仕込み、攪拌しながら約２７〜３２℃で接触還元を行なった。接触還元は、水素ガスを３〜４ｋｇｆ／ｃｍ2 で圧入しながら１５分間行なった。接触還元終了後、触媒を濾過し、洗浄して、濾液と洗液をあわせた後、８％水酸化ナトリウム水溶液１２０ｇを加えて５５℃で３０分間攪拌した。メタノール２２５ｇを常圧留去した後、１０％塩酸１２０ｇを２０〜３０℃で滴下した。０〜５℃で１時間攪拌した後、結晶を濾過し、１０％メタノール水溶液１０ｇで洗浄して、乾燥させることにより、ｏ−クロロフェニルプロピオン酸２８ｇを得た（収率９３％、ＨＰＬＣ純度９２．０％、脱クロロ体８．０％、転化率１００％）。
【００３５】
比較例２
３００ｍｌ容の四つ口フラスコに、２−プロパノール９０ｇ、水１０ｇ、ｏ−クロロ桂皮酸１０ｇ、５％白金炭素（５０％含水）０．５ｇおよび粉末活性炭０．５ｇを仕込み、攪拌しながら約４０℃で接触還元を行なった。接触還元は、水素ガスを常圧で圧入しながら６時間行なった。接触還元終了後、触媒を濾過し、洗浄して、濾液と洗液をあわせた後、８％水酸化ナトリウム水溶液４０ｇを加えて５５℃で３０分間攪拌した。２−プロパノール８５ｇを常圧留去した後、１０％塩酸４０ｇを２０〜３０℃で滴下した。０〜５℃で１時間攪拌した後、結晶を濾過し、１０％メタノール水溶液１０ｇで洗浄して、乾燥させることにより、ｏ−クロロフェニルプロピオン酸２７ｇを得た（収率９０％、ＨＰＬＣ純度８７．９％、脱クロロ体１２．１％、転化率９９．５％）。
【００３６】
比較例３
１リットル容のテフロンビーカーに、メタノール２４０ｇ、ｏ−クロロ桂皮酸３０ｇ、５％Ｍ型パラジウム炭素（５０％含水）６ｇおよび粉末活性炭１．２ｇを仕込み、攪拌しながら約３０℃で接触還元を行なった。接触還元は、水素ガスを３〜５ｋｇｆ／ｃｍ2 で圧入しながら８時間行なった。接触還元終了後、触媒を濾過し、洗浄して、濾液と洗液をあわせた後、８％水酸化ナトリウム水溶液１２０ｇを加えて５５℃で３０分間攪拌した。メタノール２２５ｇを常圧留去した後、１０％塩酸１２０ｇを２０〜３０℃で滴下した。０〜５℃で１時間攪拌した後、結晶を濾過し、１０％メタノール水溶液１０ｇで洗浄して、乾燥させることにより、ｏ−クロロフェニルプロピオン酸の脱クロロ体であるフェニルプロピオン酸２２ｇを得た（収率９１％、ＨＰＬＣ純度９９％）。
【００３７】
以上の結果より、触媒として、パラジウム炭素および白金炭素を使用した比較例１〜３と対比して、実施例１〜４では、ルテニウム炭素を使用しているため、副生成物である脱ハロゲン体の生成率が非常に低く、効率よく、簡便かつ工業的に有利にハロゲン化フェニルプロピオン酸化合物を得ることができることがわかる。
【００３８】
【発明の効果】
本発明の製造方法によれば、ハロゲン化桂皮酸化合物を接触還元させる際の触媒として、ルテニウムを触媒として用いることにより、効率よく、簡便かつ工業的に有利にハロゲン化フェニルプロピオン酸を製造することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing a halogenated phenylpropionic acid compound. More specifically, the present invention relates to a method for producing a halogenated phenylpropionic acid compound, which is an important intermediate of a therapeutic agent that is very effective for hyperparathyroidism.
[0002]
[Prior art]
Conventionally, a catalyst containing palladium or platinum as a component has been used for the catalytic reduction of a halogenated cinnamic acid compound. However, when catalytic reduction of halogenated cinnamic acid compounds is carried out using these catalysts, dehalogenated products are produced at a production rate of 2.5 to 15%, and a halogenated phenylpropionic acid compound can be obtained efficiently. I can't.
[0003]
[Problems to be solved by the invention]
This invention is made | formed in view of the said prior art, and it aims at providing the method of manufacturing a halogenated phenylpropionic acid compound efficiently, simply and industrially advantageously.
[0004]
[Means for Solving the Problems]
The gist of the present invention is as follows.
(1) General formula (I):
[0005]
[Chemical 3]
(Wherein X represents a halogen atom, R represents a hydrogen atom, a methyl group, an ethyl group, or an isopropyl group), and is characterized by catalytically reducing a halogenated cinnamic acid compound in the presence of ruthenium as a catalyst. General formula (II):
[0007]
[Formula 4]
(Wherein X and R are as defined above), a method for producing a halogenated phenylpropionic acid compound,
(2) The method for producing a halogenated phenylpropionic acid compound according to (1), wherein the halogenated cinnamic acid compound represented by the general formula (I) is catalytically reduced in a lower alcohol or a mixed solvent of a lower alcohol and water. And (3) producing the halogenated phenylpropionic acid compound according to (1) or (2) above, wherein the halogenated cinnamic acid compound represented by the general formula (I) is catalytically reduced at a reaction temperature in the range of 20 to 30 ° C. Method.
[0009]
DETAILED DESCRIPTION OF THE INVENTION
According to the method for producing a halogenated phenylpropionic acid compound of the present invention, as described above, the general formula (I):
[0010]
[Chemical formula 5]
(Wherein X represents a halogen atom, R represents a hydrogen atom, a methyl group, an ethyl group, or an isopropyl group), by catalytically reducing a halogenated cinnamic acid compound in the presence of ruthenium as a catalyst, Formula (II):
[0012]
[Chemical 6]
A halogenated phenylpropionic acid compound represented by the formula (wherein X and R are as defined above) is obtained.
[0014]
In the halogenated cinnamic acid compound represented by the general formula (I), X represents a halogen atom, and R represents a hydrogen atom, a methyl group, an ethyl group or an isopropyl group.
[0015]
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
[0016]
Specific examples of the halogenated cinnamic acid compound represented by the general formula (I) include o-chlorocinnamic acid and o-chlorocinnamic acid methyl.
[0017]
As described above, the catalytic reduction of the halogenated cinnamic acid compound represented by the general formula (I) is performed in the presence of ruthenium as a catalyst, but it is preferably performed in a solvent. Can be done according to
[0018]
That is, a solvent is added to the halogenated cinnamic acid compound represented by the general formula (I), and the solution is shaken or stirred in a hydrogen atmosphere in the presence of ruthenium as a catalyst, or hydrogen gas Can be dissolved in the solution.
[0019]
Ruthenium used as a catalyst can be used, for example, as a support in which ruthenium is supported on a carrier generally known in catalytic chemistry such as carbon and alumina, ruthenium oxide and the like.
[0020]
The amount of ruthenium used is preferably about 0.125 to 0.5 parts by weight with respect to 100 parts by weight of the halogenated cinnamic acid compound represented by the general formula (I).
[0021]
Examples of the solvent include one kind or two or more kinds of lower alcohols having 1 to 5 carbon atoms such as methanol, ethanol, 2-propanol, and a mixed solvent thereof with water. Among these, a mixed solvent of 2-propanol and water and methanol are preferable. In addition, it is preferable that the mixing ratio of a lower alcohol and water is about 0-50 weight part of water with respect to 100 weight part of lower alcohol.
[0022]
The amount of the solvent used is not particularly limited. For example, when a lower alcohol is used, the amount used is 600 to 800 weights with respect to 100 parts by weight of the halogenated cinnamic acid compound represented by the general formula (I). When a mixed solvent of lower alcohol and water is used, the amount used is 800 to 1000 weights with respect to 100 weight parts of the halogenated cinnamic acid compound represented by the general formula (I). It is preferable that it is about a part.
[0023]
In the catalytic reduction, for example, activated carbon or the like may be used as appropriate in order to suppress poisoning of the catalyst.
[0024]
The reaction temperature during the catalytic reduction is preferably 10 ° C. or higher, preferably 20 ° C. or higher from the viewpoint of reaction rate, and 60 ° C. or lower, preferably 30 ° C. from the viewpoint of suppressing the formation of dehalogenated products. The following is desirable.
[0025]
Since the reaction time varies depending on conditions such as the amount of catalyst used, it cannot be determined at a glance. However, it may be a time to the extent that the catalytic reduction is completed, and usually about 8 to 20 hours. In addition, when a solution obtained by dissolving a halogenated cinnamic acid compound in a solvent is shaken or stirred under a hydrogen atmosphere, the hydrogen gas pressure may be about 3 to 18 kgf / cm 2 .
[0026]
The completion of the catalytic reduction can be confirmed, for example, by examining the conversion using gas chromatography after esterifying the raw material and the product.
[0027]
After completion of the reaction, for example, the obtained halogenated phenylpropionic acid compound represented by the general formula (II) can be isolated by ordinary separation operations such as crystallization, filtration, concentration, washing, and extraction. .
[0028]
According to the production method of the present invention described above, the production rate of dehalogenated products such as by-produced phenylpropionic acid and its derivatives is usually very small, about 0.5% or less. A halogenated phenylpropionic acid compound represented by the formula (II) can be obtained. In addition, the production | generation rate of a dehalogenation body can be measured using a high performance liquid chromatography (HPLC).
[0029]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited at all by this Example.
[0030]
Example 1
A 1-liter Teflon beaker was charged with 240 g of methanol, 30 g of o-chlorocinnamic acid, 6 g of 5% ruthenium carbon (containing 50% water) and 1.2 g of powdered activated carbon, and catalytic reduction was performed at about 25 ° C. with stirring. The catalytic reduction was carried out for 8 hours while injecting hydrogen gas at 3 to 5 kgf / cm 2 . After completion of the catalytic reduction, the catalyst was filtered and washed, and the filtrate and the washing solution were combined. Then, 120 g of 8% aqueous sodium hydroxide solution was added, and the mixture was stirred at 55 ° C. for 30 minutes. After 225 g of methanol was distilled off at normal pressure, 120 g of 10% hydrochloric acid was added dropwise at 20 to 30 ° C. After stirring at 0 to 5 ° C. for 1 hour, the crystals were filtered, washed with 10 g of a 10% aqueous methanol solution and dried to obtain 28 g of o-chlorophenylpropionic acid (yield 93%, HPLC purity 99. 8%, dechlorinated product 0.2%, conversion 99.8%).
[0031]
Example 2
A 1 liter Teflon beaker is charged with 240 g of methanol, 30 g of o-chlorocinnamic acid, 1.5 g of 5% ruthenium carbon (containing 50% water) and 2.4 g of powdered activated carbon, and catalytic reduction at about 25-29 ° C. with stirring. Was done. The catalytic reduction was performed for 8 hours while injecting hydrogen gas at 17 to 18 kgf / cm 2 . After completion of the catalytic reduction, the catalyst was filtered and washed, and the filtrate and the washing solution were combined. Then, 120 g of 8% aqueous sodium hydroxide solution was added, and the mixture was stirred at 55 ° C. for 30 minutes. After 225 g of methanol was distilled off at normal pressure, 120 g of 10% hydrochloric acid was added dropwise at 20 to 30 ° C. After stirring at 0 to 5 ° C. for 1 hour, the crystals were filtered, washed with 10 g of a 10% aqueous methanol solution and dried to obtain 27 g of o-chlorophenylpropionic acid (yield 90%, HPLC purity 99. 8%, dechlorinated product 0.1%, conversion 98.7%).
[0032]
Example 3
A 1-liter Teflon beaker is charged with 216 g of 2-propanol, 24 g of water, 30 g of o-chlorocinnamic acid, 1.5 g of 5% ruthenium carbon (containing 50% water) and 2.4 g of powdered activated carbon, and is stirred for about 25 to 25%. Catalytic reduction was performed at 29 ° C. The catalytic reduction was performed for 15 hours while injecting hydrogen gas at 16 to 18 kgf / cm 2 . After completion of the catalytic reduction, the catalyst was filtered and washed, and the filtrate and the washing solution were combined. Then, 120 g of 8% aqueous sodium hydroxide solution was added, and the mixture was stirred at 55 ° C. for 30 minutes. After 200 g of 2-propanol was distilled off at normal pressure, 120 g of 10% hydrochloric acid was added dropwise at 20 to 30 ° C. After stirring at 0 to 5 ° C. for 1 hour, the crystals were filtered, washed with 10 g of a 10% aqueous methanol solution and dried to obtain 28 g of o-chlorophenylpropionic acid (yield 93%, HPLC purity 99. 8%, dechlorinated product 0.2%, conversion 99.8%).
[0033]
Example 4
A 200 ml Teflon beaker is charged with 60 g of methanol, 10 g of methyl o-chlorocinnamate, 0.5 g of 5% ruthenium carbon (containing 50% water) and 0.2 g of powdered activated carbon, and catalytic reduction is performed at about 20 ° C. with stirring. It was. The catalytic reduction was carried out for 8 hours while injecting hydrogen gas at 3 to 5 kgf / cm 2 . After completion of the catalytic reduction, the catalyst was filtered and washed, and the filtrate and the washing solution were combined. Then, 20 g of a 14% aqueous sodium hydroxide solution was added and hydrolyzed at 80 ° C., and methanol was distilled off under reduced pressure. After extraction by adding 29 g of 10% hydrochloric acid and 54 g of toluene, the solvent was distilled off by concentration under reduced pressure to obtain 8.5 g of o-chlorophenylpropionic acid (yield 85%, HPLC purity 99.8%, dechloroform). 0.2%, conversion 98.0%).
[0034]
Comparative Example 1
A 1 liter Teflon beaker is charged with 240 g of methanol, 30 g of o-chlorocinnamic acid, 1.5 g of 5% M-type palladium carbon (containing 50% water) and 1.2 g of powdered activated carbon at about 27 to 32 ° C. with stirring. Catalytic reduction was performed. The catalytic reduction was performed for 15 minutes while injecting hydrogen gas at 3 to 4 kgf / cm 2 . After completion of the catalytic reduction, the catalyst was filtered and washed, and the filtrate and the washing solution were combined. Then, 120 g of 8% aqueous sodium hydroxide solution was added, and the mixture was stirred at 55 ° C. for 30 minutes. After 225 g of methanol was distilled off at normal pressure, 120 g of 10% hydrochloric acid was added dropwise at 20 to 30 ° C. After stirring at 0-5 ° C. for 1 hour, the crystals were filtered, washed with 10 g of a 10% aqueous methanol solution and dried to obtain 28 g of o-chlorophenylpropionic acid (yield 93%, HPLC purity 92. 0%, dechlorinated product 8.0%, conversion rate 100%).
[0035]
Comparative Example 2
A 300 ml four-necked flask was charged with 90 g of 2-propanol, 10 g of water, 10 g of o-chlorocinnamic acid, 0.5 g of 5% platinum carbon (containing 50% water) and 0.5 g of powdered activated carbon, and stirred for about 40 Catalytic reduction was performed at ° C. The catalytic reduction was performed for 6 hours while injecting hydrogen gas at normal pressure. After completion of the catalytic reduction, the catalyst was filtered and washed, and the filtrate and the washing solution were combined. Then, 40 g of an 8% aqueous sodium hydroxide solution was added, and the mixture was stirred at 55 ° C. for 30 minutes. After 85 g of 2-propanol was distilled off at normal pressure, 40 g of 10% hydrochloric acid was added dropwise at 20 to 30 ° C. After stirring at 0 to 5 ° C. for 1 hour, the crystals were filtered, washed with 10 g of 10% aqueous methanol and dried to obtain 27 g of o-chlorophenylpropionic acid (yield 90%, HPLC purity 87. 9%, dechlorinated product 12.1%, conversion 99.5%).
[0036]
Comparative Example 3
A 1 liter Teflon beaker is charged with 240 g of methanol, 30 g of o-chlorocinnamic acid, 6 g of 5% M-type palladium carbon (containing 50% water) and 1.2 g of powdered activated carbon, and catalytic reduction is performed at about 30 ° C. with stirring. It was. The catalytic reduction was carried out for 8 hours while injecting hydrogen gas at 3 to 5 kgf / cm 2 . After completion of the catalytic reduction, the catalyst was filtered and washed, and the filtrate and the washing solution were combined. Then, 120 g of 8% aqueous sodium hydroxide solution was added, and the mixture was stirred at 55 ° C. for 30 minutes. After 225 g of methanol was distilled off at normal pressure, 120 g of 10% hydrochloric acid was added dropwise at 20 to 30 ° C. After stirring at 0 to 5 ° C. for 1 hour, the crystals were filtered, washed with 10 g of a 10% aqueous methanol solution and dried to obtain 22 g of phenylpropionic acid which is a dechloro form of o-chlorophenylpropionic acid ( (Yield 91%, HPLC purity 99%).
[0037]
From the above results, as compared with Comparative Examples 1 to 3 using palladium carbon and platinum carbon as catalysts, in Examples 1 to 4, ruthenium carbon is used, and therefore, a dehalogenated product that is a by-product. It can be seen that a halogenated phenylpropionic acid compound can be obtained efficiently, conveniently, and industrially advantageously.
[0038]
【The invention's effect】
According to the production method of the present invention, by using ruthenium as a catalyst for catalytic reduction of a halogenated cinnamic acid compound, a halogenated phenylpropionic acid can be produced efficiently, conveniently and industrially advantageously. Can do.
Claims (3)
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| JP26220497A JP3819560B2 (en) | 1997-09-26 | 1997-09-26 | Method for producing halogenated phenylpropionic acid compound |
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| JP26220497A JP3819560B2 (en) | 1997-09-26 | 1997-09-26 | Method for producing halogenated phenylpropionic acid compound |
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