JP3830206B2 - Method for producing α-benzyl acrylate - Google Patents

Description

（式中、Ｘ₁ 〜Ｘ₅ はそれぞれ水素原子、炭素数１〜１２の直鎖もしくは分枝アルキル基またはアルコキシ基を示す。）
【０００９】
【化５】

（式中、Ｙはハロゲン原子を示す。Ｒは炭素数１〜１８の直鎖または分枝アルキル基を示す。）
【００１０】
【化６】

【００１１】
本発明の反応が高収率で進行するのは、ルイス酸が一般式（３）で示される化合物のエステル部と式中のＹで示される原子または基に親和できることでアルカリカチオン的になりやすく、その結果ベンゼン環に対する求電子置換が容易になるためであると考えられる。これは今までこの種の反応では知られていない新しい反応である。
以下、本発明を具体的に説明する。
【００１２】
【発明の実施の形態】
本発明において一般式（３）で示されるα−ベンジルアクリル酸エステル類を得るための原料である一般式（１）で示される化合物としては、式中Ｘ₁ 〜Ｘ₅ はそれぞれ水素原子以上の電子供与性基であるものが好ましいが、水素原子でも十分な反応速度が得られる。反応性は電子供与性である方が高くなり、直鎖または分岐アルキル基、アルコキシ基が好ましいが、電子供与性が高すぎるとベンゼン環の反応位置が単一にならない場合があり、アルキル基、アルコキシ基が好ましい。
【００１４】
一般式（２）で示される化合物としては、Ｙはハロゲン原子であることが好ましく、特に塩素原子あるいは臭素原子であることが最も好ましい。しかしながら一般に易脱離基であれば十分である。
【００１５】
本発明を実施するに当り上記一般式（１）で示される化合物と一般式（２）で示される化合物の混合モル比は、一般式（１）で示される化合物が一般式（２）で示される化合物の１倍から２００倍であることが好ましい。一般に一般式（１）で示される化合物を大過剰用いた方が反応選択率が上がる傾向があり、混合モル比は、一般式（１）で示される化合物が一般式（２）で示される化合物の５倍から５０倍が最も好ましいが、一般式（１）で示される化合物の沸点が高く、除去が困難な場合は、一般式（１）で示される化合物が一般式（２）で示される化合物の１倍以上であれば十分使用可能である。
【００１６】
反応の際の混合順序は、一般式（１）で示される化合物と一般式（２）で示される化合物を混合してからルイス酸を添加する方法、一般式（１）で示される化合物とルイス酸を混合したものに、一般式（２）で示される化合物を添加する方法、一般式（２）で示される化合物とルイス酸を混合したものに、一般式（１）で示される化合物を添加する方法の何れを用いてもよい。好ましいのは、一般式（１）で示される化合物と一般式（２）で示される化合物を混合してからルイス酸を添加する方法、一般式（１）で示される化合物とルイス酸を混合したものに、一般式（２）で示される化合物を添加する方法である。
【００１７】
本発明で使用するルイス酸としては、一般にルイス酸と呼ばれるものならば使用することができる。一般にハロゲン化金属が好適に用いられ、例えば、ハロゲン化アルミニウム、ハロゲン化亜鉛、ハロゲン化チタン、ハロゲン化すず、ハロゲン化鉄、ハロゲン化ほう素、ハロゲン化マグネシウム、ハロゲン化アンチモン、ハロゲン化ケイ素、ランタニド金属のハロゲン化物などがあげられる。なお、置換ハロゲンの１つ以上は、トリフルオロメタンスルホニルオキシ基、炭素数１から２０までのアルキル基、炭素数１から２０までのアルコキシル基、フェノキシ基、１−ナフトキシ基、２−ナフトキシ基、１，１′−バイ−２−ナフトキシ基等で置換されていてもよい。一般には上述のハロゲン化金属で十分好適に反応し、最も一般的な塩化アルミニウムで十分に反応する場合が多く、コスト等を考えると好ましい。なお場合によっては硫酸、塩酸、りん酸、フッ化水素酸、硝酸などの鉱酸や酸性イオン交換樹脂なども使用できる。
【００１８】
ルイス酸は１つの化合物を用いることで十分であるが、場合によってはルイス酸同士の併用、ブレンステッド酸の併用も可能である。またルイス酸にいくつかの化合物を混入させた方が活性があがることがあり、このような添加物を加えても良い。
【００１９】
ルイス酸の使用量は一般に一般式（２）で示される化合物に対して０．０１〜１０当量で、好ましくは１〜５当量である。
【００２０】
本発明の反応温度は−１００〜２００℃であるが、好ましくは−８０〜８０℃である。反応温度が低いと反応速度が遅くなり、温度が高いと副反応が増大するとともに、ベンゼン環の置換位置も制御できなくなる傾向にある。
【００２１】
反応圧力は、絶対圧で０．０１〜５０ｋｇ／ｃｍ² であり、好ましくは０．１〜１０ｋｇ／ｃｍ² である。さらに好ましくは０．８〜１．２ｋｇ／ｃｍ² である。
【００２２】
本発明の反応を行うに当り溶媒は必ずしも必要でないが、必要ならば溶媒を用いることができる。溶媒としては、例えば、塩化メチレンシ、クロロホルム、ジクロロエタン、テトラクロロエタン、１，１，２−トリクロロエタン、１，１，１−トリクロロエタン、四塩化炭素等のハロゲン系溶媒、ｎ−ヘキサン、シクロヘキサン等の脂肪族炭化水素、ニトロベンゼン、ベンゼン等の芳香族炭化水素、二硫化炭素、ニトロメタンなどを挙げることができる。
【００２３】
反応時間は、通常０．０１〜１００時間、好ましくは０．１〜２４時間である。
【００２４】
【実施例】
（実施例１）
Ｖｉｌｌｉｅｒａｓらの方法（Ｓｙｎｔｈｅｓｉｓ９２４（１９８２））に従って合成したα−ブロモメチルアクリル酸エチル５．０ｇの無水ベンゼン溶液３０ｍｌを、無水塩化アルミニウム７．５ｇを分散させた無水ベンゼン４０ｍｌ溶液に温度０〜５℃で滴下した後０〜５℃で２時間撹拌した。反応液を２規定塩酸１００ｍｌにあけ、有機相を分離した。有機相を２規定塩酸５０ｍｌ、水５０ｍｌ、食塩水５０ｍｌでそれぞれ洗浄した後、溶媒を留去し、４．９ｇのα−メチレンベンゼンプロパン酸エチルを得た。
【００２５】
得られたα−メチレンベンゼンプロパン酸エチルのＧＣ純度は９７％、収率は９７％であった。また、核磁気共鳴スペクトル（ＮＭＲ）による分析結果は次の通りであった。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃ ）１．２６（３Ｈ，ｔ，Ｊ＝７Ｈｚ），３．６３（２Ｈ，ｓ），４．１８（２Ｈ，ｑ，Ｊ＝７Ｈｚ），５．４４−５．４６（１Ｈ，ｍ），６．２３（１Ｈ，ｓ），７．１９−７．３２（５Ｈ，ｍ）．
【００２６】
（実施例２）
実施例１と同様にして合成した。α−ブロモメチルアクリル酸エチル６．０ｇの無水トルエン溶液４０ｍｌを、無水塩化アルミニウム９．４ｇを分散させた無水トルエン６０ｍｌ溶液に温度０〜５℃で滴下した後、０〜５℃で２時間撹拌した。反応液を２規定塩酸１００ｍｌにあけ、有機相を分離した。有機相を、２規定塩酸６０ｍｌ、水６０ｍｌ、食塩水６０ｍｌでそれぞれ洗浄した後、溶媒を留去し６．４ｇの４−メチル−α−メチレンベンゼンプロパン酸エチルと２−メチル−α−メチレンベンゼンプロパン酸エチルの混合物をそれぞれ５３％と４７％の存在比で得た。
【００２７】
かくして得られた両化合物を合わせたもののＧＣ純度は９６％、収率は９６％であった。また、ＮＭＲによる分析結果は次の通りであった。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃ ）１．２８，１．２９（３Ｈ，［ｔ，Ｊ＝７Ｈｚ］，［ｔ，Ｊ＝７Ｈｚ］），２．３２，２．５５（３Ｈ，ｓ，ｓ），３．５９，３．６２（２Ｈ，ｓ，ｓ），４．１８，４．２３（２Ｈ，［ｔ，Ｊ＝７Ｈｚ］，［ｔ，Ｊ＝７Ｈｚ］），５．１６−５．１７，５．４４−５．４５（１Ｈ，ｍ，ｍ），６．２１，６．２１（１Ｈ，ｓ，ｓ），６．９８−７．２３（４Ｈ，ｍ）．
【００２８】
【発明の効果】
本発明によればα−ベンジル−β−メルカプトプロピオン酸、α−ベンジル−β−ハロプロピオン酸、α−ベンジル−β−アミノプロピオン酸、α−ベンジル−β−ヒドロキシプロピオン酸など医薬中間体として有用な化合物の前駆体であるα−ベンジルアクリル酸誘導体を簡便な方法で効率的に合成できる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for synthesizing an α-benzylacrylic acid derivative which is a precursor of a compound useful as a pharmaceutical intermediate.
[0002]
[Prior art]
Many methods for producing α-benzyl acrylate are known, but they are roughly divided into three methods. One is a method in which benzyl chloride and formalin are reacted with an active ester such as diethyl malonate or ethyl diethylphosphonoacetate, followed by dehydration. In this case, dimethylamine or the like may be reacted together. This reaction is described in J. Org. Issa et al, Synth. Commun. 1489 (1995), R.A. Queignec et al. Synth. Commun. , 1213 (1988), B.R. Kirschleger et al. , Synthesis 926 (1986), R .; B. Miller et al. Synth. Commun. 359 (1973).
[0003]
Another, alpha-like halomethyl acrylate ester such as phenyl magnesium halide, S _N 2 'which is a nucleophilic reaction (C.Najera et al., Tetrahedron Letters , 3837 (1989), H.Amri et al J. Organomet. Chem., C27 (1986)).
[0004]
Further, α-halomethylacrylic acid ester or the like is converted into an anion with zinc, and then reacted with phenyl halide in the presence of a palladium catalyst (N. El Alami et al., J. Organomet. Chem., 157 (1988)), etc. There is.
[0005]
[Problems to be solved by the invention]
However, even if it is going to use the method described in these literature as an industrial manufacturing method, it cannot necessarily be said to be practical, and the appearance of the simple and efficient synthesis method was desired.
[0006]
[Means for Solving the Problems]
In view of such a current situation, the present inventors rapidly reacted α-halomethyl acrylate and the like with substituted benzene by using a Lewis acid catalyst, and α-benzyl acrylate derivative is extremely highly selective. The present invention has been completed by finding that it can be obtained in a high yield.
[0007]
That is, the present invention provides an α represented by the general formula (3), which comprises reacting a compound represented by the following general formula (1) with a compound represented by the general formula (2) in the presence of a Lewis acid. -It exists in the manufacturing method of benzyl acrylate ester.
[0008]
[Formula 4]

(In the formula, X _{1 to} X ₅ each represent a hydrogen atom, a linear or branched alkyl group having 1 to 12 carbon atoms, or an alkoxy group .)
[0009]
[Chemical formula 5]

(Wherein, Y is .R showing a halogen atom is a straight-chain or branched alkyl group having 1 to 18 carbon atoms.)
[0010]
[Chemical 6]

[0011]
The reaction of the present invention proceeds at a high yield because the Lewis acid can easily become an alkali cation because it can have affinity with the ester moiety of the compound represented by the general formula (3) and the atom or group represented by Y in the formula. As a result, the electrophilic substitution on the benzene ring is facilitated. This is a new reaction that has not been known so far for this type of reaction.
The present invention will be specifically described below.
[0012]
DETAILED DESCRIPTION OF THE INVENTION
It is a raw material for obtaining the α- benzyl acrylate esters as the compounds represented by the general formula (1), wherein X ₁ to X ₅ are, respectively it hydrogen represented by the general formula (3) in the present invention Those having an electron donating group of atoms or more are preferred, but a sufficient reaction rate can be obtained even with a hydrogen atom. The reactivity is higher when it is electron-donating, and linear or branched alkyl groups and alkoxy groups are preferred. However, if the electron-donating property is too high, the reaction position of the benzene ring may not be single, and the alkyl group, Alkoxy groups are preferred.
[0014]
In the compound represented by the general formula (2), Y is preferably a halogen atom, and most preferably a chlorine atom or a bromine atom. However, generally an easily leaving group is sufficient.
[0015]
In carrying out the present invention, the mixing molar ratio of the compound represented by the general formula (1) and the compound represented by the general formula (2) is the same as the compound represented by the general formula (1). It is preferable that it is 1 to 200 times the compound to be obtained. In general, the reaction selectivity tends to increase when the compound represented by the general formula (1) is used in a large excess, and the mixing molar ratio of the compound represented by the general formula (1) is the compound represented by the general formula (2). The compound represented by the general formula (1) is represented by the general formula (2) when the boiling point of the compound represented by the general formula (1) is high and removal is difficult. If it is 1 time or more of a compound, it can fully be used.
[0016]
The mixing order during the reaction is the method of adding the Lewis acid after mixing the compound represented by the general formula (1) and the compound represented by the general formula (2), the compound represented by the general formula (1) and Lewis A method of adding a compound represented by general formula (2) to a mixture of acids, a compound represented by general formula (1) being added to a mixture of a compound represented by general formula (2) and a Lewis acid Any method may be used. Preferred is a method in which a compound represented by the general formula (1) and a compound represented by the general formula (2) are mixed and then a Lewis acid is added. A compound represented by the general formula (1) and a Lewis acid are mixed. In this method, the compound represented by the general formula (2) is added to the product.
[0017]
As the Lewis acid used in the present invention, those generally called Lewis acids can be used. Generally, metal halides are preferably used. For example, aluminum halide, zinc halide, titanium halide, tin halide, iron halide, boron halide, magnesium halide, antimony halide, silicon halide, lanthanide Examples thereof include metal halides. One or more of the substituted halogens are a trifluoromethanesulfonyloxy group, an alkyl group having 1 to 20 carbon atoms, an alkoxyl group having 1 to 20 carbon atoms, a phenoxy group, a 1-naphthoxy group, a 2-naphthoxy group, , 1′-bi-2-naphthoxy group or the like. In general, the above-mentioned metal halides react sufficiently well, and the most common aluminum chloride often reacts well, which is preferable in view of cost and the like. In some cases, mineral acids such as sulfuric acid, hydrochloric acid, phosphoric acid, hydrofluoric acid, and nitric acid, and acidic ion exchange resins can also be used.
[0018]
It is sufficient to use a Lewis acid as one compound, but in some cases, a combination of Lewis acids and a Bronsted acid can be used. Further, mixing some compounds with Lewis acid may increase the activity, and such additives may be added.
[0019]
Generally the usage-amount of a Lewis acid is 0.01-10 equivalent with respect to the compound shown by General formula (2), Preferably it is 1-5 equivalent.
[0020]
Although the reaction temperature of this invention is -100-200 degreeC, Preferably it is -80-80 degreeC. When the reaction temperature is low, the reaction rate is slow, and when the temperature is high, side reactions increase and the substitution position of the benzene ring tends to be uncontrollable.
[0021]
The reaction pressure is 0.01 to 50 kg / cm ² in absolute pressure, preferably 0.1 to 10 kg / cm ² . More preferably, it is 0.8-1.2 kg / cm < ² >.
[0022]
A solvent is not necessarily required for carrying out the reaction of the present invention, but a solvent can be used if necessary. Examples of the solvent include halogen solvents such as methylene chloride, chloroform, dichloroethane, tetrachloroethane, 1,1,2-trichloroethane, 1,1,1-trichloroethane, carbon tetrachloride, and aliphatic such as n-hexane and cyclohexane. Examples include hydrocarbons, aromatic hydrocarbons such as nitrobenzene and benzene, carbon disulfide, and nitromethane.
[0023]
The reaction time is usually 0.01 to 100 hours, preferably 0.1 to 24 hours.
[0024]
【Example】
Example 1
30 ml of an anhydrous benzene solution of 5.0 g of ethyl α-bromomethylacrylate synthesized according to the method of Villieras et al. After dropwise addition, the mixture was stirred at 0 to 5 ° C. for 2 hours. The reaction solution was poured into 100 ml of 2N hydrochloric acid, and the organic phase was separated. The organic phase was washed with 50 ml of 2N hydrochloric acid, 50 ml of water and 50 ml of brine, respectively, and then the solvent was distilled off to obtain 4.9 g of ethyl α-methylenebenzenepropanoate.
[0025]
GC purity of the obtained ethyl α-methylenebenzenepropanoate was 97%, and the yield was 97%. Moreover, the analysis result by a nuclear magnetic resonance spectrum (NMR) was as follows.
¹ H-NMR (CDCl ₃ ) 1.26 (3H, t, J = 7 Hz), 3.63 (2H, s), 4.18 (2H, q, J = 7 Hz), 5.44-5.46 (1H, m), 6.23 (1H, s), 7.19-7.32 (5H, m).
[0026]
(Example 2)
Synthesis was performed in the same manner as in Example 1. After dripping 40 ml of anhydrous toluene solution of 6.0 g of ethyl α-bromomethylacrylate into 60 ml of anhydrous toluene solution in which 9.4 g of anhydrous aluminum chloride is dispersed at a temperature of 0 to 5 ° C., the mixture is stirred at 0 to 5 ° C. for 2 hours. did. The reaction solution was poured into 100 ml of 2N hydrochloric acid, and the organic phase was separated. The organic phase was washed with 60 ml of 2N hydrochloric acid, 60 ml of water and 60 ml of brine, respectively, and the solvent was distilled off to obtain 6.4 g of ethyl 4-methyl-α-methylenebenzenepropanoate and 2-methyl-α-methylenebenzene. A mixture of ethyl propanoate was obtained with abundance ratios of 53% and 47%, respectively.
[0027]
The GC purity of the combination of both compounds thus obtained was 96% and the yield was 96%. Moreover, the analysis result by NMR was as follows.
¹ H-NMR (CDCl ₃ ) 1.28, 1.29 (3H, [t, J = 7 Hz], [t, J = 7 Hz]), 2.32, 2.55 (3H, s, s), 3.59, 3.62 (2H, s, s), 4.18, 4.23 (2H, [t, J = 7 Hz], [t, J = 7 Hz]), 5.16-5.17, 5.44-5.45 (1H, m, m), 6.21, 6.21 (1H, s, s), 6.98-7.23 (4H, m).
[0028]
【The invention's effect】
According to the present invention, α-benzyl-β-mercaptopropionic acid, α-benzyl-β-halopropionic acid, α-benzyl-β-aminopropionic acid, α-benzyl-β-hydroxypropionic acid and other useful pharmaceutical intermediates An α-benzylacrylic acid derivative which is a precursor of a simple compound can be efficiently synthesized by a simple method.

Claims (1)

A compound represented by the following general formula (1) and a compound represented by the general formula (2) are reacted in the presence of a Lewis acid; Production method.

(In the formula, X _{1 to} X ₅ each represent a hydrogen atom, a linear or branched alkyl group having 1 to 12 carbon atoms, or an alkoxy group .)

(Wherein, Y is .R showing a halogen atom is a straight-chain or branched alkyl group having 1 to 18 carbon atoms.)

(Wherein, X _{1 to} X ₅ are the compounds of the general formula (1), and R is the same definition as the compound of the general formula (2).)