KR900006558B1 - Process for preparing derivatives of alpha-hydroxy 2-thiophene acetic acid - Google Patents
Process for preparing derivatives of alpha-hydroxy 2-thiophene acetic acid Download PDFInfo
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- KR900006558B1 KR900006558B1 KR1019830003476A KR830003476A KR900006558B1 KR 900006558 B1 KR900006558 B1 KR 900006558B1 KR 1019830003476 A KR1019830003476 A KR 1019830003476A KR 830003476 A KR830003476 A KR 830003476A KR 900006558 B1 KR900006558 B1 KR 900006558B1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
Description
본 발명은 다음 일단식(I)의 α-히드록시-2-티오펜 아세트산의 유도체의 제조방법에 관한 것이다 :The present invention relates to a process for preparing a derivative of α-hydroxy-2-thiophene acetic acid of the following formula (I):
상기식에서 R은 1 내지 4 탄소원자의 알킬기를 나타내고 Rl,R2및 R3의 각각은 같거나 다르며 수소원자 또는 1 내지 4 탄소원자의 알킬기를 나타낸다.Wherein R represents an alkyl group of 1 to 4 carbon atoms and each of R 1 , R 2 and R 3 is the same or different and represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms.
이러한 화합물들은 약리학적 화합물, 특히 항소염화합물의 제조에 사용할 수 있는 중간생성물들이다.These compounds are intermediates that can be used to prepare pharmacological compounds, in particular anti-inflammatory compounds.
일반식(I)의 화합물들로부터 출발하여 다음 일반식(A)의 화합물을 다음 문헌[F.Clemence 등, Eur.J.Med.Chem.1974(9) 390] 또는 프랑스특허 2,167,334호에 기재한 방법에 따라 제조할 수 있다.Starting from the compounds of formula (I), the compounds of formula (A) are described in F.Clemence et al., Eur. J. Med. Chem. 1974 (9) 390 or French Patent 2,167,334. It can manufacture according to a method.
상기식에서 R,Rl,R2및 R3는 상기에 기재된 바와 같다. 이 방법은 염산 매질중에서 염화 주석과 같은 약한 금속성 환원제가 사용됨을 특징으로 한다.Wherein R, R 1 , R 2 and R 3 are as described above. This method is characterized by the use of weak metallic reducing agents such as tin chloride in hydrochloric acid medium.
일반식(A)의 이들 화합물은 약물학적 성질을 나타내는 최종생성물들로 전환시킬 수 있다. 그런 전환에 대해서는 예를 들어 프랑스특허 2,068,42호 및 2,167,331호에 이미 기재되어 있다.These compounds of formula (A) can be converted into final products that exhibit pharmacological properties. Such conversions are already described, for example, in French Patents 2,068,42 and 2,167,331.
상기한 참고문헌[Eur.J.Med.Chem.1974(9) 390호]에는 일단식(I)의 제조방법이 기재되어 있다. 이 방법은 다음과 같다 :The above-mentioned reference [Eur. J. Med. Chem. 1974 (9) 390] describes a process for preparing formula (I). This method is as follows:
2-할로티오펜을 다음 일반식의 산과 반응시켜 연반식(I)의 유도체들을 제조하는 신규의 제조방법이 개발되었다.A novel process for the preparation of derivatives of general formula (I) has been developed by reacting 2-halothiophene with an acid of the general formula:
이들 두 화합물들은 손쉽게 구입할 수 있고, 이 반응은 중간 생성물의 분리없이 수행될 수 있다.These two compounds are readily available and this reaction can be carried out without separation of the intermediate product.
본 발명에 따른 방법은 다음 일반식(II)의 화합물을 다음 일반식(Ⅲ)의 화합물과 반응시키고 마그네슘 그룹의 가수분해 후에 얻고자 하는 일반식(I)의 화합물을 제조하는 것을 특징으로 한다 :The process according to the invention is characterized by reacting a compound of formula (II) with a compound of formula (III) and preparing a compound of formula (I) to be obtained after hydrolysis of the magnesium group:
상기식에서 R,Rl,R2및 R3는 상기 기재된 바와같고, X는 할로겐원자를 나타내고, A는 수소원자, 알칼리 금속원자 또는 마그네슘 또는 알칼리토금속의 등가물을 나타낸다.Wherein R, R 1 , R 2 and R 3 are as described above, X represents a halogen atom, A represents a hydrogen atom, an alkali metal atom or an equivalent of magnesium or alkaline earth metal.
치환체 R,Rl,R2및 R3는 저급 알킬기, 즉 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, 이급 부틸 또는 3급-부틸을 나타낼 수 있다.Substituents R, R 1 , R 2 and R 3 may represent lower alkyl groups, ie methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tert-butyl.
X는 염소, 요오드 또는 브롬원자를 나타낼 수 있고, 브롬이 바람직하다.X may represent chlorine, iodine or bromine atom, with bromine being preferred.
A는 수소원자 이외에드, 나트륨, 칼륨 또는 리튬원자를 나타낼 수 있다. 수소 및 리튬원자가 바람직하고 특히 리튬원자가 바람직하다. A는 또한 마그네슘의 등가물 또는 칼슘 또는 바륨과 같은 알칼리토금속의 등가물을 나타낼 수 있다.A can represent a hydrogen, potassium, or lithium atom other than a hydrogen atom. Hydrogen and lithium atoms are preferred, especially lithium atoms. A may also represent an equivalent of magnesium or an equivalent of an alkaline earth metal such as calcium or barium.
일반식(III)의 화합물과 반응하는 일반식(II)의 마그네슘화합물은 테트라히드로푸란 또는 에틸 에테르와같은 유기용매중에서 즉시 바람직하게 제조된다.Magnesium compounds of formula (II) which react with compounds of formula (III) are preferably prepared immediately in an organic solvent such as tetrahydrofuran or ethyl ether.
바람직하게 리튬염과 같은 알칼리 금속염이 일반식(III)의 화합물로서 사용될때, 이 염은 톨루엔 또는 테트라히드로푸란과 같은 유기용매중에서 즉시 제조될 수 있다. 벤젠 또는 에틸 에테르와 같은 에테르가 사용될 수 있다.Preferably, when an alkali metal salt such as lithium salt is used as the compound of formula (III), this salt can be prepared immediately in an organic solvent such as toluene or tetrahydrofuran. Ethers such as benzene or ethyl ether can be used.
이러한 반응은 마그네슘 화합물이 제조되는 용매중 또는 상기한 용매들의 혼합물중에서 수행된다.This reaction is carried out in the solvent in which the magnesium compound is prepared or in a mixture of the solvents described above.
마그네슘 화합물의 가수분해는 산수용액 매질중에서 수행되며, 사용되는 산은 염산, 황산 또는 아세트산이다. 이러한 반응은 염화암모늄의 존재하에서 수행될 수 있다.Hydrolysis of the magnesium compound is carried out in an acid aqueous medium, and the acid used is hydrochloric acid, sulfuric acid or acetic acid. This reaction can be carried out in the presence of ammonium chloride.
본 발명은 특히 상기한·조건하에서 2-티에닐마그네슘 할라이드로부터 출발하여 다음 일반식(I')의 화합물을 제조하는 방법에도 관한 것이다.The present invention also relates to a process for preparing the compound of the general formula (I ′) starting from 2-thienyl magnesium halide, especially under the above-described conditions.
상기식에서, R은 상기한 바와 같다.Wherein R is as defined above.
특히 본 발명에 따른 방법은 R이 메틸 또는 에틸기를 나타내는 일반식(III)의 화합물을 상기의 방법에 사용하는 것을 특징으로 하는, R이 메틸 또는 에틸기를 나타내는 일반식(I')의 화합물의 제조방법이다. 더욱 본 발명에 따른 방법은 Rl,R2및 R3가 각각 수소원자를 나타내는 일반식(II)의 화합물과 R이 메틸기를 나타내는 일반식(Ⅲ)의 화합물을 상기의 방법에 사용하는 것을 특징으로 하는 α-에틸-α-히드록시-2-티오펜 아세트산의 제조에 관한 것이다. X가 브롬원자를 나타내는 일반식(II)의 화합물과 A가 수소원자 또는 리튬원자를 나타내는 일반식(III)의 화합물을 본 발명에 따른 방법에 출발물질로서 바람직하게 사용한다. 얻어진 마그네슘 그룹의 가수분해는 산 수용액 매질중에서 수행된다. 최종적으로 본 발명은 2-티에닐-마그네슘 브롬화물을 피루브산 리튬에 반응시키고 얻어진 생성물을 염산의 수용액으로 가수분해시키는 것을 특징으로 하는 α-메틸-α-히드록시-2-티오펜 아세트산의 제조방법에 관한 것이다.In particular, the process according to the invention uses a compound of formula (III) wherein R represents a methyl or ethyl group in the above process, wherein R represents a methyl or ethyl group. Way. Further, the method according to the present invention is characterized in that a compound of formula (II) wherein R 1 , R 2 and R 3 each represent a hydrogen atom and a compound of formula (III) wherein R represents a methyl group are used in the above method. The present invention relates to the production of α-ethyl-α-hydroxy-2-thiophene acetic acid. Compounds of the general formula (II) in which X represents a bromine atom and compounds of the general formula (III) in which A represents a hydrogen atom or a lithium atom are preferably used as starting materials in the process according to the present invention. Hydrolysis of the resulting magnesium groups is carried out in an acid aqueous solution medium. Finally, the present invention is a method for producing α-methyl-α-hydroxy-2-thiophene acetic acid, characterized in that 2-thienyl-magnesium bromide is reacted with lithium pyruvate and the resulting product is hydrolyzed with an aqueous solution of hydrochloric acid. It is about.
다음의 실시예들은 본 발명을 설명하지만 이것으로 본 발명을 제한하는 것은 아니다.The following examples illustrate the invention but do not limit it.
[실시예 1]Example 1
α-메틸-α-히드록시-2-티오펜 아세트산α-methyl-α-hydroxy-2-thiophene acetic acid
(a) 피루브산 리튬의 제조(a) Preparation of lithium pyruvate
7.96kg의 탄산리튬을 210리터의 톨루엔중에서 비등하도록 가열하고 2 내지 3시간 동안 교반시키는 반면, 105 내지 108℃로 내부 온도를 유지시키고 형성된 물을 경사지워 버리고, 24.6kg의 피루브산을 부가시킨다. 이 혼합물을 한시간 동안 환류시키는 반면에 형성된 물과 피루브산의 혼합물 4리터를 경사지워 버린다.7.96 kg of lithium carbonate is heated to boil in 210 liters of toluene and stirred for 2-3 hours, while maintaining the internal temperature at 105 to 108 ° C. and decanting the formed water and adding 24.6 kg of pyruvic acid. The mixture is refluxed for one hour while the 4 liter mixture of water and pyruvic acid formed is decanted.
이어서 혼합물을 약 30분간 대기압하에서 증류하여 나머지 미량의 물 및 산을 제거한다. 그 다음 35리터의 톨루엔-산-물 혼합물을 회수한다.The mixture is then distilled under atmospheric pressure for about 30 minutes to remove the remaining traces of water and acid. 35 liters of toluene-acid-water mixture is then recovered.
(b) 마그네슘티에닐 브롬화물의 제조(b) Preparation of Magnesium Thienyl Bromide
아르곤중에서, 5.74kg의 마그네슘 가루를 81.5리터의 테트라히드로푸란에 부가시키고 약 2.5g의 승화된 요오드를 첨가한다. 이것을 +20 및 +25℃ 사이에서 10분간 교반하고 60리터의 테트라히드로푸란에 35kg의 2-브로모티오펜을 용해시킨 용액을 약 5리터 부가시킨다. 반응 개시후 온도를 35℃로 높이고 그것이 안정화되었을 때 상기 단계에서 제조한 2-브로모 티오펜 용액의 잔여물을 같은 온도를 유지하면서 1시간 30분에 걸쳐 서서히 부가시킨다. 부가가 완결되었을 때 혼합물을 아르곤하에서 30 및 35℃ 사이의 온도를 유지하며 2시간동안 교반한다.In argon, 5.74 kg of magnesium powder is added to 81.5 liters of tetrahydrofuran and about 2.5 g of sublimated iodine is added. It is stirred for 10 minutes between +20 and + 25 ° C and about 5 liters of a solution of 35 kg of 2-bromothiophene dissolved in 60 liters of tetrahydrofuran is added. After the start of the reaction, the temperature is raised to 35 ° C. and when it is stabilized, the residue of the 2-bromo thiophene solution prepared in the above step is slowly added over 1 hour and 30 minutes while maintaining the same temperature. When the addition is complete the mixture is stirred under argon for 2 hours keeping the temperature between 30 and 35 ° C.
(c) 축합(c) condensation
상기 a) 단게에서 얻어진 피루브산 리튬의 현탁액을 교반시키면서 -15℃로 냉각시키고 상기 b) 단계에서 얻어진 마그네슘 용액을 질소기류하에서 약 5분동안 서서히 부가시킴과 동시에 -15 내지 -20℃의 온도에서 염수의 외부 순환에 의해 현탁액을 냉각시킨다.The suspension of lithium pyruvate obtained in step a) is cooled to −15 ° C. while stirring, and the magnesium solution obtained in step b) is slowly added for about 5 minutes under a nitrogen stream, and at the temperature of −15 to −20 ° C. The suspension is cooled by external circulation.
온도를 약 45℃로 상승시킨다. 부가과정에 있어서 마그네슘 용액을 금속교반시켜 분산시킨다. 현탁액을 35리터의 테트라히드로푸란으로 헹구어 내고 그 다음 약 30분에 걸쳐 내부온도를 20-25℃로 서서히 낮추고 혼합물을 이 온도에서 질소기류하에 약 16시간동안 교반시킨다.The temperature is raised to about 45 ° C. In addition, the magnesium solution is dispersed by stirring the metal. Rinse the suspension with 35 liters of tetrahydrofuran and then slowly lower the internal temperature to 20-25 ° C. over about 30 minutes and stir the mixture at this temperature for about 16 hours under a stream of nitrogen.
약 15분에 걸쳐 현탁액을 140kg의 얼음조각과 47리터의 염산의 혼합물중에 쏟아붓는다. 내부온도를 필요한 만큼으로 얼음을 첨가시켜 25℃에 유지시킨다. 장치를 50리터의 물로서 헹구어내고 염산으로서 pH를 1로 조절한다. 용액이 완성될때까지 20 및 25℃ 사이에서 교반시킨 후 유기상을 분리하고 수용액상을 각기 20리터의 톨루엔으로 3회 추출하고, 유기상을 모은 다음 12리터의 물을 가하고 약 1.5리터의 암모니아를 pH 4가 될때까지 서서히 부가한 다음 경사지워 버리고 다시 12리터의 증류수로 세척한 다음 암모니아를 가하여 pH 4로 조정하고, 유기상을 분리시키고 그것을 감압하에서 122리터의 용적으로 농축시키는 한편 40℃이하로 내부온도를 유지시키고 테트라히드로푸란 및 물을 함유하는 약 175리터의 톨루엔을 수집한다. 3회연속 증류를 각각 70리터의 톨루엔과 함께 같은 조건하에서 수행한다. 0℃로 냉각시키고 이 온도에서 2시간동안 교반한 후 얻어진 생성물을 분리하고, 0℃에서 35리터의 톨루엔으로 두번 세척하고 오븐에서 건조시킨다. 27.35kg의 원하는 생성물을 얻는다.Over about 15 minutes, the suspension is poured into a mixture of 140 kg of ice cubes and 47 liters of hydrochloric acid. Keep the internal temperature at 25 ° C by adding ice as needed. The device is rinsed with 50 liters of water and the pH is adjusted to 1 as hydrochloric acid. After stirring between 20 and 25 ° C. until the solution is complete, the organic phase is separated and the aqueous phase is extracted three times with 20 liters of toluene each, the organic phases are collected, 12 liters of water is added and about 1.5 liters of ammonia is added to pH 4 Add slowly until it is inclined and wash again with 12 liters of distilled water, adjust to pH 4 by adding ammonia, separate the organic phase and concentrate it to 122 liters under reduced pressure, while keeping the internal temperature below 40 ℃. Maintain and collect about 175 liters of toluene containing tetrahydrofuran and water. Three successive distillations are performed under the same conditions with 70 liters of toluene each. After cooling to 0 ° C. and stirring at this temperature for 2 hours, the resulting product is separated, washed twice with 35 liters of toluene at 0 ° C. and dried in an oven. Obtain 27.35 kg of the desired product.
융점 : 115℃Melting Point: 115 ℃
적용 : α-메틸-2-티오펜 아세트산Application: α-methyl-2-thiophene acetic acid
75리터의 22°Be 염산과 75kg의 단 프로토클로라이드의 혼합물을 질소 기류하에서 40℃로 가열하고 이것에 125리터의 빙초산을 한번에 첨가한다. 용액이 완성되면 50kg의 α-메틸-α-히드록시-2-티오펜 아세트산을 질소기류하에서 교반하면서 서서히 부가시킨다. 온도를 1시간 30분간 40℃로 유지시키는 한편 질소기류하에서 교반시킨다.A mixture of 75 liters of 22 ° Be hydrochloric acid and 75 kg of sweet protochloride is heated to 40 ° C. under a stream of nitrogen and to it is added 125 liters of glacial acetic acid at once. When the solution is complete, 50 kg of α-methyl-α-hydroxy-2-thiophene acetic acid is slowly added while stirring under a nitrogen stream. The temperature is kept at 40 ° C. for 1 hour 30 minutes while stirring under nitrogen stream.
20 및 25℃ 사이의 온도로 냉각시키고, 15분에 걸쳐 150리터의 증류수와 100kg의 얼음조각의 혼합물에 쏟아부은 후 15분간 다시 교반하고 수용액상을 20℃±2℃에서 50리터의 디클로로-에탄으로 6회 추출한다. 디클로로-에단 추출물을 42.5리터의 물중의 8.5리터의 20℃ Be 염산으로 4회 세척하고 50리터의 물로 3회 세척한다. 디클로로-에탄 용액을 40℃ 이하에서 감압하에 농축시킨다. 약 225리터의 디클로로 에탄을 수집하고 45.3kg의 원하는 조악한 산을 얻는다.Cool to a temperature between 20 and 25 ° C, pour into a mixture of 150 liters of distilled water and 100 kg of ice cubes over 15 minutes, then stir again for 15 minutes and the aqueous phase is 50 liters of dichloro-ethane at 20 ° C ± 2 ° C. Extract 6 times. The dichloro-edane extract is washed four times with 8.5 liters of 20 ° C. Be hydrochloric acid in 42.5 liters of water and three times with 50 liters of water. The dichloro-ethane solution is concentrated under reduced pressure at 40 ° C. or lower. Approximately 225 liters of dichloroethane is collected and 45.3 kg of the desired crude acid is obtained.
이 생성물을 120℃ 이하에서 0.7torr의 압력하에서 증류한다. 39.45kg의 원하는 생성물을 얻는다.This product is distilled off at a pressure of 0.7 torr at 120 ° C. or lower. Obtain 39.45 kg of the desired product.
[실시예 2]Example 2
α-에 틸-α-히드록시 -2-티오펜 아세트산α-Ethyl-α-hydroxy-2-thiophene acetic acid
500cm3의 테트라히드로푸란중의 375g의 2-브로모티오펜의 용액 50㎤을 750㎤의 테트라히드로푸란중의 59.3g의 마그네슘가루의 혼합물에 부가시킨다. 요오드 결정을 c첨가하다. 반응의 개시 후 잔여분의 브로모티오펜 용액을 교반하면서 35℃에서 1시간동안 부가시킨다. 부가를 종결시킨 후 두시간동안 교단을 지속시 키면서 온도를 25℃로 강하시킨다.50 cm 3 of a solution of 375 g of 2-bromothiophene in 500 cm 3 of tetrahydrofuran is added to a mixture of 59.3 g of magnesium powder in 750 cm 3 of tetrahydrofuran. Add c iodine crystals After initiation of the reaction, the remaining bromothiophene solution is added at 35 ° C. for 1 hour with stirring. After the addition was terminated, the temperature was lowered to 25 ° C. with continuation for two hours.
이어서 500㎤의 테트라히드로푸란중의 102g의 피루브산 용액을 25℃에서 45분동안 부가한다. 이 혼합물을 25℃에서 18시간동안 교반하고 130㎤의 66°Be 황산을 함유하는 2.6리터의 물-얼음 혼합물중에 쏟아붓고 10분간 교반한다. 유기상을 경사지워 버리고 260㎤의 아세트산 에틸로서 4회 재추출한다. 유기상을260㎤의 증류수로 2회 세척한 다음 우선 520㎤의 2N의 수용액인 빙냉수산화나트륨으로 재추출한 다음 260㎤의 양으로 3회 추출한다. 나트륨 용액을 260㎤의 아세트산 에틸로서 4회 세척하고, 얼음의 존재하에 교반하며 120㎤의 22°Be 염산을 첨가하여 pH 1로 산성화 시킨다. 우선 520㎤의 아세트산 에틸로서 추출한 다음 260㎤의 아세트산 에틸로 4회 추출하고, 결과된 유기상을 260㎤의 증류수로 2회 세척하고 황산나트륨에서 건조시키고 약 10g의 활성탄을 부가시키고, 분리후 용매를 감압하에서 증발시켜 건고하게하고 145.5g의 기대하는 생성물을 얻는다.Then 102 g of pyruvic acid solution in 500 cm 3 of tetrahydrofuran are added at 25 ° C. for 45 minutes. The mixture is stirred at 25 ° C. for 18 hours and poured into 2.6 liters of water-ice mixture containing 130 cm 3 of 66 ° Be sulfuric acid and stirred for 10 minutes. The organic phase is decanted and reextracted four times with 260 cm 3 of ethyl acetate. The organic phase is washed twice with 260 cm 3 distilled water and then re-extracted with ice cold sodium hydroxide, 520 cm 3 2N aqueous solution, and then extracted three times in an amount of 260 cm 3. The sodium solution is washed four times with 260 cm 3 of ethyl acetate, stirred in the presence of ice and acidified to pH 1 by addition of 120 cm 3 of 22 ° Be hydrochloric acid. First extracted with 520 cm 3 of ethyl acetate and then extracted 4 times with 260 cm 3 of ethyl acetate, the resulting organic phase was washed twice with 260 cm 3 of distilled water, dried over sodium sulfate and added about 10 g of activated carbon, and the solvent was separated under reduced pressure. Evaporate off to dryness to afford 145.5 g of the expected product.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8307021 | 1983-04-28 | ||
| FR8307021A FR2545085B1 (en) | 1983-04-28 | 1983-04-28 | NOVEL PROCESS FOR THE PREPARATION OF A-HYDROXY 2-THIOPHENE ACETIC ACID DERIVATIVES |
| FR83-07021 | 1983-04-28 |
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| Publication Number | Publication Date |
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| KR840008351A KR840008351A (en) | 1984-12-14 |
| KR900006558B1 true KR900006558B1 (en) | 1990-09-13 |
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| FR1067828A (en) * | 1951-01-19 | 1954-06-18 | Sterling Drug Inc | Improvements relating to a process for preparing organic chemicals |
| GB806710A (en) * | 1955-07-05 | 1958-12-31 | Metal & Thermit Corp | Reactions of organomagnesium chloride complexes |
| GB820083A (en) * | 1955-07-05 | 1959-09-16 | Metal & Thermit Corp | Reactions of organomagnesium chloride reagents |
| FR2068425B1 (en) * | 1969-11-12 | 1973-01-12 | Roussel Uclaf | |
| FR2167334A1 (en) * | 1972-01-13 | 1973-08-24 | Roussel Uclaf | 4-aroyl-5-alkylthiophene-2-acetic acids - with analgesic and antiinflammatory activity |
| GB1584120A (en) * | 1977-07-21 | 1981-02-04 | Sagami Chem Res | Process for the preparation of thiophene derivatives and thiophene derivatives obtained therethrough |
| GB2030131B (en) * | 1978-09-12 | 1982-12-22 | Taiyo Pharma Ind | Process for producing 2-(4-(2-thienyl-carbonyl) phenyl) propionic acid |
| JPS5835145A (en) * | 1981-08-26 | 1983-03-01 | Taisho Pharmaceut Co Ltd | Preparation of alpha-arylalkanoic acid ester |
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