JP2974451B2 - Method for producing 2- (p-formylphenyl) propionic acid - Google Patents
Method for producing 2- (p-formylphenyl) propionic acidInfo
- Publication number
- JP2974451B2 JP2974451B2 JP3141933A JP14193391A JP2974451B2 JP 2974451 B2 JP2974451 B2 JP 2974451B2 JP 3141933 A JP3141933 A JP 3141933A JP 14193391 A JP14193391 A JP 14193391A JP 2974451 B2 JP2974451 B2 JP 2974451B2
- Authority
- JP
- Japan
- Prior art keywords
- propionic acid
- acid
- formylphenyl
- producing
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【０００１】[0001]
【産業上の利用分野】本発明は、抗炎症、鎮痛および解
熱作用のある医薬品（特開昭５４−３２４６０号）とし
て有用な原体の製造中間体の製法に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for preparing an intermediate for producing a drug substance useful as a drug having an anti-inflammatory, analgesic and antipyretic action (Japanese Patent Application Laid-Open No. 54-32460).
【０００２】[0002]
【従来の技術】本発明の目的化合物である２−（ｐ−ホ
ルミルフェニル）プロピオン酸を製造する従来の技術と
しては、２−（ｐ−ヒドロキシメチルフェニル）プロピ
オン酸を活性二酸化マンガンで酸化して得る方法〔特開
平２−３０６９３３号、参考例１（収率７１．０％）〕
がある。2. Description of the Related Art As a conventional technique for producing 2- (p-formylphenyl) propionic acid, which is an object compound of the present invention, 2- (p-hydroxymethylphenyl) propionic acid is oxidized with activated manganese dioxide. Method for obtaining [JP-A-2-306933, Reference Example 1 (71.0% yield)]
There is.
【０００３】[0003]
【発明が解決しようとする課題】しかし、この方法は、
活性二酸化マンガンを多量に用いるために、反応後のマ
ンガン化合物の廃棄処理上の問題があり、また収率の向
上が望まれていた。However, this method is
Since a large amount of activated manganese dioxide is used, there is a problem in disposal of the manganese compound after the reaction, and improvement in yield has been desired.
【０００４】[0004]
【課題を解決するための手段】本発明者等は前記の問題
点を解決するため、２−（ｐ−ヒドロキシメチルフェニ
ル）プロピオン酸を種々の酸化剤を用いて収率良く２−
（ｐ−ホルミルフェニル）プロピオン酸を得る方法につ
き鋭意研究を重ねた結果、酸化剤として次亜ハロゲン酸
化合物が有効であることを見出した。更に詳細に検討し
た結果、 エステル系有機溶媒を用い、酸性下で前記酸
化剤で酸化することにより高収率で目的化合物を得るこ
とができることを見出し、本発明を完成した。Means for Solving the Problems The present inventors have solved the above problems by using 2- (p-hydroxymethylphenyl) propionic acid with various oxidizing agents in a good yield.
As a result of intensive studies on a method for obtaining (p-formylphenyl) propionic acid, it has been found that a hypohalous acid compound is effective as an oxidizing agent. As a result of further detailed investigation, they have found that the target compound can be obtained in high yield by oxidizing with the oxidizing agent under acidic conditions using an ester organic solvent, and completed the present invention.
【０００５】[0005]
【発明の構成】２−（ｐ−ヒドロキシメチルフェニル）
プロピオン酸をエステル系有機溶媒中、酸性下で次亜ハ
ロゲン酸および／または次亜ハロゲン酸塩で酸化するこ
とを特徴とする２−（ｐ−ホルミルフェニル）プロピオ
ン酸の製法。DETAILED DESCRIPTION OF THE INVENTION 2- (p-Hydroxymethylphenyl)
A process for producing 2- (p-formylphenyl) propionic acid, comprising oxidizing propionic acid with a hypohalous acid and / or a hypohalite under acidic conditions in an ester organic solvent.
【０００６】本発明で用いられる原料の２−（ｐ−ヒド
ロキシメチルフェニル）プロピオン酸（以下、「化合物
１」という）は、特開平２−３０６９３３号記載の方法
により得られる。The raw material 2- (p-hydroxymethylphenyl) propionic acid (hereinafter referred to as "compound 1") used in the present invention can be obtained by the method described in JP-A-2-306933.
【０００７】本発明で用いられるエステル系有機溶媒
は、脂肪酸エステル類が用いられ、中でも低級脂肪酸エ
ステルが好ましく、例えば、蟻酸メチル、蟻酸エチル、
酢酸メチル、酢酸エチル、プロピオン酸メチル、プロピ
オン酸エチル等が挙げられ、中でも酢酸エチルが好適で
ある。As the ester organic solvent used in the present invention, fatty acid esters are used, and among them, lower fatty acid esters are preferable, for example, methyl formate, ethyl formate, and the like.
Examples thereof include methyl acetate, ethyl acetate, methyl propionate, and ethyl propionate. Among them, ethyl acetate is preferable.
【０００８】エステル系有機溶媒の使用量は、特に限定
されないが、通常、化合物１の４〜３０倍量であり、好
ましくは５〜１５倍量である。The amount of the ester organic solvent is not particularly limited, but is usually 4 to 30 times, preferably 5 to 15 times the amount of the compound 1.
【０００９】本発明方法は酸性下で行われるが、その際
に使用される酸としては鉱酸が挙げられ、例としては、
塩酸、硫酸、硝酸および燐酸等が挙げられ、好ましくは
塩酸が挙げられる。The process of the present invention is carried out under acidic conditions, and the acid used in this case includes mineral acids.
Examples thereof include hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and preferably include hydrochloric acid.
【００１０】本発明で用いられる酸の使用量および濃度
は、反応系のpHが７未満、好ましくは４以下の範囲にな
るように調製される。反応系のpHが７以上になると化合
物２の収率が著しく低下する。The amount and concentration of the acid used in the present invention are adjusted so that the pH of the reaction system is less than 7, preferably 4 or less. When the pH of the reaction system becomes 7 or more, the yield of compound 2 is remarkably reduced.
【００１１】本発明で用いられる酸化剤の次亜ハロゲン
酸および次亜ハロゲン酸塩のハロゲンとしては、塩素、
臭素およびヨウ素が挙げられ、塩を構成する金属として
は、アルカリ金属が挙げられる。次亜ハロゲン酸および
次亜ハロゲン酸塩の例としては、次亜塩素酸、次亜臭素
酸、次亜ヨウ素酸、次亜塩素酸ナトリウム、次亜臭素酸
ナトリウム、次亜ヨウ素酸ナトリウム、次亜塩素酸カリ
ウム、次亜臭素酸カリウムおよび次亜ヨウ素酸カリウム
等が挙げられる。これらを添加する際、そのまま添加す
るよりも通常、水溶液として添加する方が好ましく、入
手のし易さから、工業的には市販の次亜塩素酸ナトリウ
ム水溶液が好適である。The halogens of hypohalous acid and hypohalous acid of the oxidizing agent used in the present invention include chlorine,
Bromine and iodine are mentioned, and as a metal constituting the salt, an alkali metal is mentioned. Examples of hypohalous acid and hypohalite include hypochlorous acid, hypobromite, hypoiodite, sodium hypochlorite, sodium hypobromite, sodium hypoiodite, Examples include potassium chlorate, potassium hypobromite, potassium hypoiodite and the like. When these are added, it is usually preferable to add them as an aqueous solution rather than adding them as they are, and commercially available aqueous sodium hypochlorite solution is industrially suitable from the viewpoint of availability.
【００１２】本発明で用いられる次亜ハロゲン酸および
次亜ハロゲン酸塩の水溶液の濃度は適宜決められるが、
通常、２〜３０wt％の範囲で用いられ、好ましくは８〜
１３wt％である。The concentration of the aqueous solution of hypohalous acid and hypohalous acid used in the present invention is appropriately determined.
Usually, it is used in the range of 2 to 30% by weight, preferably 8 to 30% by weight.
13 wt%.
【００１３】次亜ハロゲン酸および／または次亜ハロゲ
ン酸塩の使用量は、特に限定されないが通常、化合物１
に対して１. ０〜５. ０当量であり、好ましくは１. ０
５〜１. ５当量である。The amount of hypohalous acid and / or hypohalous acid used is not particularly limited, but usually, compound 1
1.0 to 5.0 equivalents, preferably 1.0
It is 5 to 1.5 equivalents.
【００１４】次亜ハロゲン酸および次亜ハロゲン酸塩の
添加温度は、大体０〜８０℃の範囲であり、好ましくは
５〜４０℃である。The temperature at which the hypohalous acid and the hypohalite are added is generally in the range of 0 to 80 ° C., preferably 5 to 40 ° C.
【００１５】反応の熟成は上記温度で、反応液組成をガ
スクロマトグラフィーまたは高速液体クロマトグラフィ
ー等により分析し、化合物１がほとんど消失するまで行
うが、通常１時間前後で反応は終了する。The reaction is ripened at the above-mentioned temperature until the composition of the reaction solution is analyzed by gas chromatography or high performance liquid chromatography, etc., until almost all of the compound 1 disappears, but the reaction is usually completed in about one hour.
【００１６】反応終了後、水層を分液し、油層を亜硫酸
ナトリウム水溶液で洗浄し、油層を濃縮すると化合物２
の粗結晶が得られる。所望であれば、この粗結晶を有機
溶媒、例えば塩素系炭化水素溶媒あるいはエーテル系溶
媒、即ち塩化メチレン、ジクロロエタン、トリクロロエ
タン、クロロホルム、四塩化炭素、エチルエーテルおよ
びイソプロピルエーテル等で再結晶することにより、高
純度の化合物２が得られる。After completion of the reaction, the aqueous layer was separated, the oil layer was washed with an aqueous sodium sulfite solution, and the oil layer was concentrated.
Is obtained. If desired, the crude crystals are recrystallized with an organic solvent, for example, a chlorinated hydrocarbon solvent or an ethereal solvent, i.e., methylene chloride, dichloroethane, trichloroethane, chloroform, carbon tetrachloride, ethyl ether and isopropyl ether, etc. Compound 2 of high purity is obtained.
【００１７】[0017]
【実施例】以下に実施例および比較例を挙げ、本発明を
具体的に示す。The present invention will be specifically described below with reference to examples and comparative examples.
【００１８】［実施例１］２−（ｐ−ヒドロキシメチル
フェニル）プロピオン酸１０ｇに酢酸エチル（溶媒）１
００mlを加えて溶かし、１規定塩酸７０mlを加え、３０
℃で撹拌下、市販の１０wt％次亜塩素酸ナトリウム水溶
液４６．７ml（１．１３当量）を１時間で添加した（pH
＝１．０）。同温度で１０分間熟成後、水層を分液し、
油層を亜硫酸ナトリウム水溶液で洗浄後、溶媒を留去す
ると結晶が得られた。これを四塩化炭素４５mlを用いて
再結晶し、融点８３〜８５℃を示す２−（ｐ−ホルミル
フェニル）プロピオン酸８. ３ｇ（収率８３. ７％）が
得られた。Example 1 10 g of 2- (p-hydroxymethylphenyl) propionic acid was added to ethyl acetate (solvent) 1
After adding 00 ml, dissolve, add 1N hydrochloric acid 70 ml, and add 30 ml.
Under stirring at 4 ° C., 46.7 ml (1.13 equivalents) of a commercially available 10 wt% aqueous sodium hypochlorite solution was added over 1 hour (pH
= 1.0). After aging for 10 minutes at the same temperature, the aqueous layer was separated,
After washing the oil layer with an aqueous solution of sodium sulfite, the solvent was distilled off to obtain crystals. This was recrystallized from 45 ml of carbon tetrachloride to obtain 8.3 g (yield: 83.7%) of 2- (p-formylphenyl) propionic acid having a melting point of 83 to 85 ° C.
【００１９】［実施例２］２−（ｐ−ヒドロキシメチル
フェニル）プロピオン酸１０ｇに酢酸エチル１００mlを
加えて溶かし、１規定塩酸３０mlを加え、３０℃で撹拌
下、１０wt％次亜塩素酸水溶液３２．２ｇ（１．１３当
量）を１時間で添加した（pH＝０．１）。同温度で１０
分間熟成後、実施例１と同様に処理したところ、２−
（ｐ−ホルミルフェニル）プロピオン酸７．９ｇ（収率
７９．８％）が得られた。Example 2 10 g of 2- (p-hydroxymethylphenyl) propionic acid was dissolved in 100 ml of ethyl acetate, 30 ml of 1N hydrochloric acid was added, and the mixture was stirred at 30.degree. 0.2 g (1.13 eq) were added in 1 hour (pH = 0.1). 10 at the same temperature
After aging for 1 minute, the same treatment as in Example 1 was carried out.
7.9 g (79.8% yield) of (p-formylphenyl) propionic acid were obtained.
【００２０】［比較例１］２−（ｐ−ヒドロキシメチル
フェニル）プロピオン酸１０ｇを塩化メチレン１００ml
に溶かし、１規定塩酸７０mlを加え、３０℃で撹拌下、
１０wt％次亜塩素酸ナトリウム水溶液４６．７ｇ（１．
１３当量）を１時間で添加した（pH＝１．０）。同温度
で３０分間熟成後、実施例１と同様に処理したが目的物
の収率は１０％であった。Comparative Example 1 10 g of 2- (p-hydroxymethylphenyl) propionic acid was added to 100 ml of methylene chloride.
, And 1N hydrochloric acid (70 ml) was added thereto.
46.7 g of a 10 wt% aqueous sodium hypochlorite solution (1.
13 equivalents) was added in one hour (pH = 1.0). After aging at the same temperature for 30 minutes, the same treatment as in Example 1 was performed, but the yield of the target product was 10%.
【００２１】［比較例２］２−（ｐ−ヒドロキシメチル
フェニル）プロピオン酸１０ｇを酢酸エチル１００mlに
溶かし、３０℃で撹拌下、１０wt％次亜塩素酸ナトリウ
ム水溶液４６．７ｇ（１．１３当量）を１時間で添加し
た（pH＝７．５）。同温度で１時間熟成後、実施例１と
同様に処理したが目的物の収率は５０％であった。Comparative Example 2 10 g of 2- (p-hydroxymethylphenyl) propionic acid was dissolved in 100 ml of ethyl acetate, and 46.7 g (1.13 equivalents) of a 10 wt% aqueous sodium hypochlorite solution was stirred at 30 ° C. Was added over 1 hour (pH = 7.5). After aging at the same temperature for 1 hour, the same treatment as in Example 1 was performed, but the yield of the target product was 50%.
【００２２】[0022]
【発明の効果】本発明の方法によれば、従来法に比べて
化合物２の収率が一段と向上し、また金属を使用しない
ため、廃棄処理上の問題が無くなり、操作性も大幅に改
善され工業化が容易となった。According to the method of the present invention, the yield of compound 2 is further improved as compared with the conventional method, and since no metal is used, there is no problem in disposal and the operability is greatly improved. Industrialization became easy.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 高橋 修 神奈川県川崎市高津区久地788番地 三 共有機合成株式会社内 (56)参考文献 特開 平２−306933（ＪＰ，Ａ) 特開 昭63−145248（ＪＰ，Ａ) 特開 平１−151534（ＪＰ，Ａ) 特開 昭64−50836（ＪＰ，Ａ) 特開 昭52−3014（ＪＰ，Ａ) 特開 平２−200653（ＪＰ，Ａ) 化学工学論文集，11［４］（1985）, 424−431. Ｉｓｒ．Ｊ．Ｃｈｅｍ．，26［３ ］（1985），229−234 Ａｃｔａ Ｃｈｅｍ．Ｓｃａｎｄ．, Ｂ38［４］（1984），343−344. (58)調査した分野(Int.Cl.6，ＤＢ名) C07C 51/373 C07C 59/74 ＢＥＩＬＳＴＥＩＮ（ＳＴＮ) ＣＡＰＬＵＳ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)──────────────────────────────────────────────────続 き Continuation of front page (72) Inventor Osamu Takahashi 788-3 Kuchi, Takatsu-ku, Kawasaki-shi, Kanagawa Within Shared Machine Synthesis Co., Ltd. (56) References JP-A-2-306933 (JP, A) JP-A-63 JP-A-145248 (JP, A) JP-A-1-151534 (JP, A) JP-A-64-50836 (JP, A) JP-A-52-3014 (JP, A) JP-A-2-200653 (JP, A) ) Chemical Engineering, 11 [4] (1985), 424-431. J. Chem. , 26 [3] (1985), 229-234 Acta Chem. Scand. , B38 [4] (1984), 343-344. (58) Fields investigated (Int. Cl. 6 , DB name) C07C 51/373 C07C 59/74 BEILSTEIN (STN) CAPLUS (STN) REGISTRY (STN)
Claims (1)
ロピオン酸をエステル系有機溶媒中、酸性下で次亜ハロ
ゲン酸および／または次亜ハロゲン酸塩で酸化すること
を特徴とする２−（ｐ−ホルミルフェニル）プロピオン
酸の製法。1. A method of oxidizing 2- (p-hydroxymethylphenyl) propionic acid with a hypohalous acid and / or a hypohalite in an ester organic solvent under acidic conditions. -Formylphenyl) propionic acid production process.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3141933A JP2974451B2 (en) | 1991-06-13 | 1991-06-13 | Method for producing 2- (p-formylphenyl) propionic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3141933A JP2974451B2 (en) | 1991-06-13 | 1991-06-13 | Method for producing 2- (p-formylphenyl) propionic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04368353A JPH04368353A (en) | 1992-12-21 |
| JP2974451B2 true JP2974451B2 (en) | 1999-11-10 |
Family
ID=15303528
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3141933A Expired - Fee Related JP2974451B2 (en) | 1991-06-13 | 1991-06-13 | Method for producing 2- (p-formylphenyl) propionic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2974451B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101393010B1 (en) * | 2012-03-06 | 2014-05-12 | 주식회사 한서켐 | A process for preparing 2-(4-formylphenyl)propionic acid by using TEMPO catalyst |
| KR101393009B1 (en) * | 2012-03-06 | 2014-05-12 | 주식회사 한서켐 | A process for preparing 2-(4-formylphenyl)propionic acid by using carbon-based catalyst |
-
1991
- 1991-06-13 JP JP3141933A patent/JP2974451B2/en not_active Expired - Fee Related
Non-Patent Citations (3)
| Title |
|---|
| Ａｃｔａ Ｃｈｅｍ．Ｓｃａｎｄ．，Ｂ３８［４］（１９８４），３４３−３４４． |
| Ｉｓｒ．Ｊ．Ｃｈｅｍ．，２６［３］（１９８５），２２９−２３４ |
| 化学工学論文集，１１［４］（１９８５），４２４−４３１． |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH04368353A (en) | 1992-12-21 |
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| Date | Code | Title | Description |
|---|---|---|---|
| S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313532 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| LAPS | Cancellation because of no payment of annual fees |