KR100501993B1 - Method for preparing phenylpropionic acid derivatives or salts thereof - Google Patents
Method for preparing phenylpropionic acid derivatives or salts thereof Download PDFInfo
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- KR100501993B1 KR100501993B1 KR10-1998-0049927A KR19980049927A KR100501993B1 KR 100501993 B1 KR100501993 B1 KR 100501993B1 KR 19980049927 A KR19980049927 A KR 19980049927A KR 100501993 B1 KR100501993 B1 KR 100501993B1
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Abstract
본 발명은 소염 진통제로서 유용한 페닐프로피온산 유도체 또는 그의 염의제조방법에 관한 것으로, 더욱 상세하게는 화학식 2의 2-(4-할로메틸)페닐프로피온산과 화학식 3의 사이클로펜타논을 반응시키는 공정을 포함하는 것을 특징으로 하는 화학식 1의 2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산 또는 그의 약제학적으로 허용가능한 염의 제조방법에 관한 것이다. The present invention relates to a method for preparing a phenylpropionic acid derivative or a salt thereof useful as an anti-inflammatory analgesic agent, and more particularly, comprising reacting 2- (4-halomethyl) phenylpropionic acid of Formula 2 with cyclopentanone of Formula 3. It relates to a process for preparing 2- (4- (2-oxocyclopentan-1-ylmethyl) phenyl) propionic acid or a pharmaceutically acceptable salt thereof of the formula (I).
(상기 구조식에서 X는 염소, 브롬 또는 요오드이다.)(Wherein X is chlorine, bromine or iodine).
Description
본 발명은 화학식 1의 2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산또는 그의 약제학적으로 허용가능한 염의 제조방법에 관한 것이다.The present invention relates to a process for the preparation of 2- (4- (2-oxocyclopentan-1-ylmethyl) phenyl) propionic acid or a pharmaceutically acceptable salt thereof.
2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산은 록소프로펜(Loxoprofen)으로 알려진 프로피온산계 소염진통제로서 통상 록소프로펜 나트륨염(Loxoprofen Sodium)의 형태로 사용되고 있다. 종래의 제조방법으로는 일본특허공보 제584699호에 기술된 바와 같이 2-(4-할로메틸페닐)프로피온산 에틸에스테르로부터 합성된 2-(4-(1-에틸카르보닐-2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산 에틸에스테르를 브롬산에서 가수분해 및 탈탄산화 반응을 통하여 2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산을 제조하는 것이다. 또한 다른 제조방법으로서, 미국특허공보 제4,161,538호에서 개시한 바와 같이, 1-피롤리디닐-1-사이클로펜텐과 2-(4-할로메틸페닐)프로피온산 에틸에스테르로부터 합성된 중간체를 수산화나트륨 용액하에서 가수분해하여 2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산을 제조하는 방법이 알려져 있다.2- (4- (2-oxocyclopentan-1-ylmethyl) phenyl) propionic acid is a propionic acid anti-inflammatory analgesic known as loxoprofen and is usually used in the form of loxoprofen sodium. have. Conventional production methods include 2- (4- (1-ethylcarbonyl-2-oxocyclopentane-1) synthesized from 2- (4-halomethylphenyl) propionic acid ethyl ester as described in Japanese Patent Publication No. 584699. It is to prepare 2- (4- (2-oxocyclopentan-1-ylmethyl) phenyl) propionic acid through hydrolysis and decarbonation reaction of -ylmethyl) phenyl) propionic acid ethyl ester in bromic acid. As another preparation method, an intermediate synthesized from 1-pyrrolidinyl-1-cyclopentene and 2- (4-halomethylphenyl) propionic acid ethyl ester, as disclosed in US Pat. It is known to decompose to produce 2- (4- (2-oxocyclopentan-1-ylmethyl) phenyl) propionic acid.
그러나, 상기 종래의 제조방법에 따라 2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산을 제조하는 경우, 2-(4-할로메틸페닐)프로피온산 에틸에스테르로부터 여러 단계의 공정을 거쳐 합성하여야 하므로 반응이 매우 복잡할 뿐 아니라, 강산 혹은 강염기를 사용하여 높은 온도에서 반응시킴으로써 부산물이 동시에 생성되기 때문에 그 수율 및 순도가 매우 낮다는 문제점이 있다.However, in the case of preparing 2- (4- (2-oxocyclopentan-1-ylmethyl) phenyl) propionic acid according to the conventional production method, a multi-step process from 2- (4-halomethylphenyl) propionic acid ethyl ester Since the reaction is not only complicated, but also by-products are simultaneously generated by reacting at a high temperature using a strong acid or strong base, the yield and purity thereof are very low.
이에, 본 발명자들은 반응 공정이 간단할 뿐만 아니라 수율 및 순도가 우수한 2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산 또는 그의 약제학적으로 허용가능한 염의 제조방법을 개발하여 본 발명을 완성하게 되었다.Accordingly, the present inventors have developed a method for preparing 2- (4- (2-oxocyclopentan-1-ylmethyl) phenyl) propionic acid or a pharmaceutically acceptable salt thereof having a simple reaction process and excellent yield and purity. The present invention has been completed.
따라서, 본 발명은 신규의 2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산 또는 그의 약제학적으로 허용가능한 염의 제조방법을 제공하는 것을 목적으로 한다.It is therefore an object of the present invention to provide a process for the preparation of the novel 2- (4- (2-oxocyclopentan-1-ylmethyl) phenyl) propionic acid or a pharmaceutically acceptable salt thereof.
본 발명은 화학식 2의 2-(4-할로메틸페닐)프로피온산과 화학식 3의 사이클로펜타논을 반응시키는 것을 포함하는 것을 특징으로 하는 화학식 1의 2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산 또는 그의 약제학적으로 허용가능한 염을 제조하는 방법에 관한 것이다.The present invention comprises reacting 2- (4-halomethylphenyl) propionic acid of formula 2 with cyclopentanone of formula 3, wherein 2- (4- (2-oxocyclopentan-1-yl) of formula 1 is prepared. Methyl) phenyl) propionic acid or a pharmaceutically acceptable salt thereof.
상기 구조식에서 X는 염소, 브롬 또는 요오드이다.Wherein X is chlorine, bromine or iodine.
본 발명에 따른 제조방법은 화학식 2의 2-(4-할로메틸)페닐프로피온산과 화학식 3의 사이클로펜타논을 반응시키는 공정을 포함한다.The preparation method according to the present invention includes a step of reacting 2- (4-halomethyl) phenylpropionic acid of Formula 2 with cyclopentanone of Formula 3.
상기 화학식 2의 2-(4-할로메틸)페닐프로피온산과 화학식 3의 사이클로펜타논은 상업적으로 구입(ISOCHEM사 프랑스 또는 CHALFONT사 프랑스)할 수 있다.2- (4-halomethyl) phenylpropionic acid of Formula 2 and cyclopentanone of Formula 3 may be purchased commercially (ISOCHEM France or CHALFONT France).
본 발명에 따른 제조방법은 염기존재하에서 반응시키는 것이 바람직하다. 본 발명에서 사용가능한 염기로는 소디움하이드라이드, 포타슘 t-부톡사이드, 소디움메톡사이드 및 소디움에톡사이드로 이루어진 군으로부터 선택된 것이 바람직하고, 사용량은 출발물질인 화학식 2의 2-(4-할로메틸)페닐프로피온산에 대해 1당량 내지 10당량이 바람직하며, 1당량 내지 3당량을 반응시키는 것이 더욱 바람직하다. The preparation method according to the invention is preferably reacted in the presence of a base. The base usable in the present invention is preferably selected from the group consisting of sodium hydride, potassium t-butoxide, sodium methoxide and sodium ethoxide, the amount of which is used as a starting material 2- (4-halomethyl) 1 equivalent to 10 equivalents are preferred relative to) phenylpropionic acid, and more preferably 1 to 3 equivalents are reacted.
또한 상기 반응은 유기용매에서 반응시키는 것이 바람직하며, 이 때, 사용가능한 유기용매로는 메틸렌클로라이드, 클로로포름, 사염화탄소, 1,2-디클로로에탄, 벤젠, 톨루엔, 크실렌, 아세토니트릴, 1,4-디옥산, 테트라하이드로푸란 및 N,N-디메틸포름아미드로 이루어진 군으로부터 선택된 것이 바람직하고, 사용하는 용매의 양은 출발물질인 화학식 2의 2-(4-할로메틸)페닐프로피온산에 대해 당량비로서 0당량 내지 50당량을 사용하는 것이 바람직하며, 10당량 내지 20당량 사용하는 것이 더욱 바람직하다. 반응온도는 -50℃내지 100℃의 범위가 바람직하며, -20℃ 내지 0℃에서 반응시키는 것이 더욱 바람직하다. In addition, the reaction is preferably carried out in an organic solvent, wherein the usable organic solvent may be methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, xylene, acetonitrile, 1,4-di It is preferably selected from the group consisting of oxane, tetrahydrofuran and N, N-dimethylformamide, and the amount of the solvent to be used is from 0 equivalents to equivalent ratio of 2- (4-halomethyl) phenylpropionic acid of formula (2) as starting material. It is preferable to use 50 equivalents, more preferably 10 to 20 equivalents. The reaction temperature is preferably in the range of -50 ° C to 100 ° C, more preferably at -20 ° C to 0 ° C.
반응이 완결되면, 반응용액을 추출 및 농축시킨 후에 통상의 방법으로 용매를 가하여 결정화시키거나 실리카겔 컬럼크로마토그라피의 방법 등에 의해 순수한 목적화합물을 수득할 수 있다.After completion of the reaction, the reaction solution can be extracted and concentrated, and then crystallized by adding a solvent in a conventional manner, or a pure target compound can be obtained by silica gel column chromatography or the like.
상기와 같이 제조된 화학식 1의 2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산은 프로피온산계 소염진통제 분야에서 통상으로 사용되는 방법에 따라 염 형태(바람직하게는 나트륨염의 형태)로 제조할 수 있다. 예를들어, 2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산 나트륨으로 제조할 경우, 2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산을 에틸아세테이트, 에테르, 아세톤, 벤젠, 톨루엔, 1,4-디옥산, 테트라하이드로푸란, 또는 N,N-디메틸포름아미드 등의 용매에 용해하여 가성소다를 가하여 제조할 수 있다. 2- (4- (2-oxocyclopentan-1-ylmethyl) phenyl) propionic acid of Formula 1 prepared as described above is in the salt form (preferably sodium salt) according to a method commonly used in the field of propionic acid Form). For example, when prepared with sodium 2- (4- (2-oxocyclopentan-1-ylmethyl) phenyl) propionate, 2- (4- (2-oxocyclopentan-1-ylmethyl) phenyl) propionic acid Can be prepared by dissolving in a solvent such as ethyl acetate, ether, acetone, benzene, toluene, 1,4-dioxane, tetrahydrofuran, or N, N-dimethylformamide and adding caustic soda.
이하, 본 발명을 실시예를 통하여 더욱 상세하게 설명한다. 그러나 이들 실시예가 본 발명의 범위를 제한하는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples do not limit the scope of the present invention.
실시예 1. Example 1.
2-(4-브로모메틸페닐)프로피온산 20g과 사이클로펜타논 15g을 클로르포름 200g에 가하고 -10℃로 냉각하였다. 반응용액에 포타슘 t-부톡사이드 22g을 가하고 동온도에서 2시간 동안 반응시켰다. 반응이 완결된 것을 확인한 후, 물 170g과 염산 10ml를 가하였다. 유기층을 추출한 후 농축하고, 여기에 헥산/에테르(1/1) 용액 150g을 가하여 결정화시키고, 생성된 결정을 여과한 후 건조하여 2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산 17.2g을 얻었다.20 g of 2- (4-bromomethylphenyl) propionic acid and 15 g of cyclopentanone were added to 200 g of chloroform and cooled to -10 ° C. 22 g of potassium t-butoxide was added to the reaction solution and reacted at the same temperature for 2 hours. After confirming that the reaction was completed, 170 g of water and 10 ml of hydrochloric acid were added thereto. The organic layer was extracted, concentrated, and crystallized by adding 150 g of hexane / ether (1/1) solution. The resulting crystals were filtered and dried to obtain 2- (4- (2-oxocyclopentan-1-ylmethyl). 17.2 g of phenyl) propionic acid was obtained.
수율 : 85%, HPLC에 의한 순도 : 99.2%Yield: 85%, purity by HPLC: 99.2%
NMR(CDCl3, ppm) : 1.49~1.56(4H, m), 1.75(1H, m), 1.95(1H, m), 2.12(2H, m), 2.34(2H, m), 2.51(1H, dd), 3.12(1H, dd), 3.70(1H, q), 7.22(4H, dd), 11.8(1H, bs)NMR (CDCl 3 , ppm): 1.49 ~ 1.56 (4H, m), 1.75 (1H, m), 1.95 (1H, m), 2.12 (2H, m), 2.34 (2H, m), 2.51 (1H, dd ), 3.12 (1H, dd), 3.70 (1H, q), 7.22 (4H, dd), 11.8 (1H, bs)
실시예 2. Example 2.
2-(4-브로모메틸페닐)프로피온산 20g과 사이클로펜타논 15g을 클로르포름 200g에 가하고 -10℃로 냉각하였다. 반응용액에 포타슘 t-부톡사이드 22g을 가하고 동온도에서 2시간 동안 반응시켰다. 반응이 완결된 것을 확인한 후, 용매를 감압하에서 제거하였다. 농축액에 농염산 200g을 가하고 80℃에서 15시간동안 가열 환류하였다. 반응이 완결된 것을 확인한 후 에틸아세테이트 200g을 가하여 추출 후 물층을 제거하였다. 유기층에 물 200g을 가한 후 10%-염산으로 pH를 5로 조절하고 유기층을 다시 분리하였다. 20% 가성소다 수용액을 가하면서 pH를 8로 조절하고, 온도를 10℃로 냉각하여 3시간 동안 결정화시켰다. 생성된 결정을 여과한 후 건조하여 2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산 나트륨염 16.4g을 얻었다.20 g of 2- (4-bromomethylphenyl) propionic acid and 15 g of cyclopentanone were added to 200 g of chloroform and cooled to -10 ° C. 22 g of potassium t-butoxide was added to the reaction solution and reacted at the same temperature for 2 hours. After confirming that the reaction was completed, the solvent was removed under reduced pressure. 200 g of concentrated hydrochloric acid was added to the concentrate, and the mixture was heated to reflux at 80 ° C. for 15 hours. After confirming that the reaction was completed, ethyl acetate 200g was added to remove the water layer after extraction. 200 g of water was added to the organic layer, the pH was adjusted to 5 with 10% hydrochloric acid, and the organic layer was separated again. The pH was adjusted to 8 with 20% aqueous solution of caustic soda and the temperature was cooled to 10 ° C. to crystallize for 3 hours. The resulting crystals were filtered and dried to give 16.4 g of 2- (4- (2-oxocyclopentan-1-ylmethyl) phenyl) sodium propionate.
수율 : 81%, HPLC에 의한 순도 : 99.0%Yield: 81%, purity by HPLC: 99.0%
NMR(D2O, ppm) : 1.25(3H, d), 1.48(1H, m), 1.64(1H, m), 1.83(1H, m), 1.93(1H, m), 2.10(1H, m), 2.25(1H, m), 2.46~2.52(2H, m), 2.89(1H, dd), 3.50(1H, q), 7.16(4H, dd)NMR (D 2 O, ppm): 1.25 (3H, d), 1.48 (1H, m), 1.64 (1H, m), 1.83 (1H, m), 1.93 (1H, m), 2.10 (1H, m) , 2.25 (1H, m), 2.46-2.52 (2H, m), 2.89 (1H, dd), 3.50 (1H, q), 7.16 (4H, dd)
실시예 3. Example 3.
2-(4-클로로메틸페닐)프로피온산 16.5g과 사이클로펜타논 16g을 클로로포름 180g에 가하고 0℃로 냉각하였다. 반응용액에 포타슘 t-부톡사이드 20g을 가하고 동온도에서 2시간동안 반응시켰다. 반응이 완결된 것을 확인한 후, 물 150g과 염산 10ml를 가하였다. 유기층을 추출한 후 농축하고, 여기에 헥산/에테르(1/1)용액 150g을 가하여 결정화시키고, 생성된 결정을 여과한 후 건조하여 2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산 16.9g을 얻었다.16.5 g of 2- (4-chloromethylphenyl) propionic acid and 16 g of cyclopentanone were added to 180 g of chloroform and cooled to 0 ° C. 20 g of potassium t-butoxide was added to the reaction solution and reacted at the same temperature for 2 hours. After confirming that the reaction was completed, 150 g of water and 10 ml of hydrochloric acid were added thereto. The organic layer was extracted, concentrated, and crystallized by adding 150 g of hexane / ether (1/1) solution. The resulting crystals were filtered and dried to obtain 2- (4- (2-oxocyclopentan-1-ylmethyl). 16.9 g of phenyl) propionic acid were obtained.
수율 : 82%, HPLC에 의한 순도 : 99.1%Yield: 82%, purity by HPLC: 99.1%
실시예 4. Example 4.
2-(4-클로로메틸페닐)프로피온산 16.5g과 사이클로펜타논 16g을 클로로포름 180g에 가하고 0℃로 냉각하였다. 반응용액에 포타슘 t-부톡사이드 20g을 가하고 동온도에서 2시간동안 반응시켰다. 반응이 환결된 것을 확인한 후, 용매를 감압하에서 제거하였다. 농축액에 농염산 200g을 가하고 80℃에서 15시간동안 가열 환류하였다. 반응이 완결된 것을 확인한 후 에틸아세테이트 200g을 가하여 추출 후 물층을 제거하였다. 유기층에 물 200g을 가한 후 10%-염산으로 pH를 5로 조절하고 유기층을 다시 분리하였다. 20% 가성소다 수용액을 가하면서 pH를 8로 조절하고, 온도를 10℃로 냉각하여 3시간 동안 결정화시켰다. 생성된 결정을 여과한 후 건조하여 2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산 나트륨염 17.0g을 얻었다.16.5 g of 2- (4-chloromethylphenyl) propionic acid and 16 g of cyclopentanone were added to 180 g of chloroform and cooled to 0 ° C. 20 g of potassium t-butoxide was added to the reaction solution and reacted at the same temperature for 2 hours. After confirming that the reaction was round, the solvent was removed under reduced pressure. 200 g of concentrated hydrochloric acid was added to the concentrate, and the mixture was heated to reflux at 80 ° C. for 15 hours. After confirming that the reaction was completed, ethyl acetate 200g was added to remove the water layer after extraction. 200 g of water was added to the organic layer, the pH was adjusted to 5 with 10% hydrochloric acid, and the organic layer was separated again. The pH was adjusted to 8 with 20% aqueous solution of caustic soda and the temperature was cooled to 10 ° C. to crystallize for 3 hours. The resulting crystals were filtered off and dried to obtain 17.0 g of 2- (4- (2-oxocyclopentan-1-ylmethyl) phenyl) sodium propionate.
수율 : 83%, HPLC에 의한 순도 : 99.3% Yield: 83%, purity by HPLC: 99.3%
비교예. Comparative example.
비교예로서 종래기술(일본특허공보 제584699호)에 따라 2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산을 제조하였다. 즉, 디메틸포름아미드 200ml에 포타슘하이드록사이드 6g과 2-카르보에톡시사이클로펜타논 15.6g을 가하고 0℃로 냉각하에서 교반하였다. 반응용액에 2-(4-클로로메틸페닐)프로피온산 에틸에스테르 25g을 가한 후, 80℃로 가열하여 2시간동안 반응시켰다. 반응완결 후, 에테르로 추출하고 용매를 제거하여, 오일상의 화합물 20g을 수득하였다. 수득한 화합물에 디옥산 30ml와 47% 브롬산용액 100ml를 가하고 6시간 동안 가열환류시켰다. 반응이 완결되면 에테르를 가하여 추출하고 용매 제거 후, 진공증류하여 2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산 13.1g을 얻었다.As a comparative example, 2- (4- (2-oxocyclopentan-1-ylmethyl) phenyl) propionic acid was prepared according to the prior art (Japanese Patent Publication No. 584699). That is, 6 g of potassium hydroxide and 15.6 g of 2-carboethoxycyclopentanone were added to 200 ml of dimethylformamide, followed by stirring under cooling to 0 ° C. 25 g of 2- (4-chloromethylphenyl) propionic acid ethyl ester was added to the reaction solution, followed by heating at 80 ° C for 2 hours. After completion of the reaction, the mixture was extracted with ether and the solvent was removed to give 20 g of an oily compound. 30 ml of dioxane and 100 ml of 47% bromic acid solution were added to the obtained compound, and the mixture was heated to reflux for 6 hours. When the reaction was completed, ether was added to extract, the solvent was removed, and vacuum distilled to obtain 13.1 g of 2- (4- (2-oxocyclopentan-1-ylmethyl) phenyl) propionic acid.
수율 : 42%, HPLC에 의한 순도 : 93.0%Yield: 42%, purity by HPLC: 93.0%
상기와 같은 본 발명에 따른 제조방법은 2-(4-할로메틸)페닐프로피온산을 직접 출발물질로 사용하여 중간 생성물을 분리하지 않고 2-(4-(2-옥소사이클로펜탄-1-일메틸)페닐)프로피온산 또는 그의 약제학적으로 허용가능한 염을 제조함으로써 반응공정이 간단할 뿐 아니라, 상기 실시예에서 확인할 수 있는 바와 같이 수율 및 순도가 종래의 제조방법에 비하여 월등히 높은 장점이 있다.The preparation method according to the present invention as described above is a 2- (4- (2-oxocyclopentan-1-ylmethyl) without separating intermediate products using 2- (4-halomethyl) phenylpropionic acid as a direct starting material. By preparing phenyl) propionic acid or a pharmaceutically acceptable salt thereof, not only is the reaction process simple, but as can be seen in the above examples, the yield and purity are much higher than those of the conventional manufacturing method.
Claims (4)
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS53127444A (en) * | 1977-04-05 | 1978-11-07 | Sankyo Co Ltd | Oxime substd. phenylacetic acid derivtives and their preparation |
| JPS53135958A (en) * | 1977-04-05 | 1978-11-28 | Sankyo Co Ltd | Substituted phenylacetic acid derivatives and their preparation |
| US4254274A (en) * | 1977-08-16 | 1981-03-03 | Sankyo Company Limited | Cycloalkylidenemethylphenylacetic acid derivatives and process for the preparation thereof |
| JPS62161740A (en) * | 1986-01-09 | 1987-07-17 | Sankyo Yuki Gosei Kk | Production of phenylpropionic acid derivative |
| WO1997047581A1 (en) * | 1996-06-13 | 1997-12-18 | Kyowa Hakko Kogyo Co., Ltd. | Process for the preparation of halomethylated 2-phenylpropionic acid derivatives |
| JPH10265433A (en) * | 1997-03-21 | 1998-10-06 | Kyowa Hakko Kogyo Co Ltd | Production of phenylpropionic acid derivative |
-
1998
- 1998-11-20 KR KR10-1998-0049927A patent/KR100501993B1/en not_active IP Right Cessation
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS53127444A (en) * | 1977-04-05 | 1978-11-07 | Sankyo Co Ltd | Oxime substd. phenylacetic acid derivtives and their preparation |
| JPS53135958A (en) * | 1977-04-05 | 1978-11-28 | Sankyo Co Ltd | Substituted phenylacetic acid derivatives and their preparation |
| US4254274A (en) * | 1977-08-16 | 1981-03-03 | Sankyo Company Limited | Cycloalkylidenemethylphenylacetic acid derivatives and process for the preparation thereof |
| JPS62161740A (en) * | 1986-01-09 | 1987-07-17 | Sankyo Yuki Gosei Kk | Production of phenylpropionic acid derivative |
| WO1997047581A1 (en) * | 1996-06-13 | 1997-12-18 | Kyowa Hakko Kogyo Co., Ltd. | Process for the preparation of halomethylated 2-phenylpropionic acid derivatives |
| JPH10265433A (en) * | 1997-03-21 | 1998-10-06 | Kyowa Hakko Kogyo Co Ltd | Production of phenylpropionic acid derivative |
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