KR100503267B1 - Method for the preparation of 2-acetyloxy-4-trifluoromethyl benzoic acid - Google Patents
Method for the preparation of 2-acetyloxy-4-trifluoromethyl benzoic acid Download PDFInfo
- Publication number
- KR100503267B1 KR100503267B1 KR10-2002-0056457A KR20020056457A KR100503267B1 KR 100503267 B1 KR100503267 B1 KR 100503267B1 KR 20020056457 A KR20020056457 A KR 20020056457A KR 100503267 B1 KR100503267 B1 KR 100503267B1
- Authority
- KR
- South Korea
- Prior art keywords
- formula
- compound
- derivative
- benzoic acid
- prepare
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/39—Preparation of carboxylic acid esters by oxidation of groups which are precursors for the acid moiety of the ester
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/18—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group
- C07C67/22—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group from nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
Abstract
본 발명에 따르면, 하기 반응식에 의해, 항혈전 작용이 우수한 하기 화학식 1의 2-아세틸옥시-4-트리플루오로메틸 벤조산을 용이하게 대량 생산할 수 있는 경제적인 제조 방법이 제공된다.According to the present invention, an economical production method capable of easily mass-producing 2-acetyloxy-4-trifluoromethyl benzoic acid of the general formula (1) excellent in antithrombotic action is provided by the following reaction scheme.
Description
본 발명은 항혈전 작용이 우수한 하기 화학식 1의 2-아세틸옥시-4-트리플루오로메틸 벤조산의 새로운 제조 방법에 관한 것이다.The present invention relates to a novel process for preparing 2-acetyloxy-4-trifluoromethyl benzoic acid of formula (1) with excellent antithrombotic action.
화학식 1의 화합물은 특히 혈소판 응집, 혈액의 응고 체계, 섬유소 융해 등에 효과가 있다는 것이 발견되어, 혈전에 관련된 질병을 치료에 유효한 화합물로 알려져 있다.Compounds of formula (1) have been found to be particularly effective for platelet aggregation, blood coagulation system, fibrin fusion, and the like, and are known as effective compounds for treating diseases related to thrombus.
상기 화학식 1의 화합물은 1978년 스페인 J.Uriach & Cia S.A.사가 개발한 화합물로서, 화학 물질 및 제조방법에 관한 특허는 전 세계에 항혈전제로서의 4-플루오로메틸 벤조산 유도체란 발명의 명칭으로 특허가 출원되었으며 (USP 4,096,252), 아세틸-4-트리플루오로메틸 살리실산이라는 발명의 명칭으로 그 제조 방법에 관한 특허가 허여되었다 (USP 2,894,984, USP 3,019,253). 상기의 특허들에 기술된 제조방법을 도식화하면 다음과 같다.The compound of Chemical Formula 1 was developed by J. Uriach & Cia SA, Spain, in 1978, and a patent on a chemical substance and a manufacturing method is patented under the name of a 4-fluoromethyl benzoic acid derivative as an antithrombotic agent worldwide. Has been filed (USP 4,096,252) and a patent has been issued for its preparation under the name acetyl-4-trifluoromethyl salicylic acid (USP 2,894,984, USP 3,019,253). Scheme of the manufacturing method described in the above patents is as follows.
그러나, 반응식 1에 기재된 단위 첫 번째 반응은 높은 반응 온도 (반응온도 190℃ 또는 220℃), 및 긴 반응시간 (보통 7일 내지 10일)을 요구하기 때문에 대량생산 및 공업화가 어렵고 경제적으로 불리하다. However, the unit first reaction described in Scheme 1 requires high reaction temperature (reaction temperature 190 ° C or 220 ° C), and long reaction time (usually 7 to 10 days), making mass production and industrialization difficult and economically disadvantageous. .
상기 특허출원에 기재된 제조방법을 더욱 구체적으로 살펴보면 다음과 같다.Looking at the manufacturing method described in the patent application in more detail as follows.
반응식 2에서 화합물 2와 탄산칼륨을 섞은 후 40 기압의 이산화 탄소를 도입한 후에 일주일에 걸쳐서 서서히 온도를 190℃ 로 올린다. 이와 같이, 높은 반응 온도 및 긴 반응시간을 요구하기 때문에 대량생산 및 공업화가 어렵고 경제적으로 불리하다.After mixing Compound 2 with potassium carbonate in Scheme 2 and introducing 40 atmospheres of carbon dioxide, the temperature is gradually raised to 190 ° C. over a week. As such, since high reaction temperature and long reaction time are required, mass production and industrialization are difficult and economically disadvantageous.
따라서, 선행기술, 특히 상술한 특허 USP 2,894,984, USP 3,019,253의 문제점을 보완하고 동시에 반응조건을 간결하게 함으로써, 산업적 이용가능성을 극대화할 수 있는 새로운 제조방법에 대한 필요성이 요구되어 왔다.Therefore, there has been a need for a new production method that can maximize the industrial applicability, by complementing the problems of the prior art, in particular the patents US Pat. No. 2,894,984, USP 3,019,253 and at the same time condensing the reaction conditions.
본 발명자들은 항혈전 작용이 우수한 화학식 1의 2-아세틸옥시-4-트리플루오로메틸 벤조산을 용이하고 경제성 있게 합성할 수 있는 새로운 제조방법을 개발하기 위해 연구하였으며, 그 결과, 기존의 방법과는 다른 새로운 반응 경로 및 적절한 반응 조건을 찾아내어 고순도의 화학식 1의 화합물을 제조함으로써 본 발명을 완성하였다. The inventors of the present invention have studied to develop a new manufacturing method capable of easily and economically synthesizing 2-acetyloxy-4-trifluoromethyl benzoic acid of Chemical Formula 1 having excellent antithrombotic action, and as a result, The present invention has been accomplished by finding other new reaction pathways and appropriate reaction conditions to produce compounds of formula 1 of high purity.
본 발명의 목적은 항혈전 작용이 우수한 화학식 1의 2-아세틸옥시-4-트리플루오로메틸 벤조산의 제조 방법을 제공하는 것이다. It is an object of the present invention to provide a method for preparing 2-acetyloxy-4-trifluoromethyl benzoic acid of formula (1), which has excellent antithrombotic action.
[화학식 1][Formula 1]
구체적으로, 본 발명의 방법은 하기 단계를 포함한다: Specifically, the method of the present invention comprises the following steps:
(1) 화학식 2의 화합물을 요오드와 반응시켜 화학식 3의 요오드화된 유도체를 제조하고; (1) reacting a compound of Formula 2 with iodine to produce an iodinated derivative of Formula 3;
(2) 화학식 3의 요오드화된 유도체에 시안기를 도입하여 화학식 4의 시안 유도체를 제조하고; (2) introducing a cyan group to an iodide derivative of formula 3 to prepare a cyan derivative of formula 4;
(3) 화학식 4의 시안 유도체를 가수분해하여 화학식 5의 살리실산 유도체를 제조하고; (3) hydrolyzing the cyan derivative of Formula 4 to prepare a salicylic acid derivative of Formula 5;
(4) 화학식 5의 살리실산 유도체를 아세틸화하여 화학식 1의 아세틸 유도체를 제조하며;(4) acetylating the salicylic acid derivative of Formula 5 to prepare an acetyl derivative of Formula 1;
(5) 필요에 따라 이를 정제함:(5) Purify it as needed:
[화학식 1][Formula 1]
본 발명에 따른 제조방법, 즉 화학식 1의 화합물의 제조방법은 다음 반응식 3과 같이 도식화될 수 있다:The preparation method according to the present invention, i.e., the preparation method of the compound of Formula 1, can be represented as in Scheme 3:
본 발명의 2-아세틸옥시-4-트리플루오로메틸 벤조산을 합성하는 제조공정은 선행 기술의 제조방법과는 다르며, 그 반응 과정이 상이하고, 상대적으로 저온 저압의 반응 조건에서 반응을 실시함으로써, 산업적으로 이용가능성을 증가시켰다는 점에서 장점을 보유하고 있다.The production process of synthesizing 2-acetyloxy-4-trifluoromethyl benzoic acid of the present invention is different from the production method of the prior art, the reaction process is different, and by carrying out the reaction at the reaction conditions of the low temperature low pressure, It has the advantage of increasing industrial availability.
즉, 종래 기술의 합성방법은 긴 반응 시간을 필요로 하고, 반응 조건에서 고압 및 고온으로 유지해야 되는 등 많은 번거로움을 내포하고 있었으나, 본 발명은 일반적인 실시가 가능한 보다 온화한 반응 조건을 이용하여 목표화합물을 제조하는 방법을 제공한다. That is, the synthesis method of the prior art requires a long reaction time, and has a lot of trouble, such as maintaining at high pressure and high temperature in the reaction conditions, the present invention is aimed at using a milder reaction conditions that can be practiced in general Provided are methods for preparing the compounds.
하기 실시예에 의하여 본 발명을 구체적으로 설명한다.The present invention is explained in detail by the following examples.
실시예 1: 2-요오드-5-트리플루오로메틸페놀의 합성 (화합물 3)Example 1: Synthesis of 2-iodine-5-trifluoromethylphenol (Compound 3)
화합물 2(180.0 g, 1.11 mol)를 초산(675 mL)에 묽힌 용액에, 물 (540 mL)에 녹인 요오드산칼륨 (47.5 g, 0.22 mol, 0.2 당량) 용액을 넣은 다음 실온(~25℃)에서 10분간 교반한다. 초산 (2025 mL)에 녹인 요오드 (112.7 g, 0.22 mol, 0.4 당량) 용액을 본 반응용액에 30분 동안 실온에서 적가하였다. 실온(~25℃)에서 48시간 동안 교반한 후 소듐 싸이오술페이트 수용액 (2.7 L)으로 투입한 다음 에틸 아세테이트 (1.35 L)로 2회 추출하였다. 유기 용액층을 물과 탄산수소나트륨 포화용액으로 연속적으로 충분히 씻어 준 다음 무수 황산마그네슘으로 건조,여과 그리고 농축하여 연한 노랑색의 표제화합물을 오일 상 물질 (300.4 g)로 얻었다.To a solution of Compound 2 (180.0 g, 1.11 mol) in acetic acid (675 mL), add a solution of potassium iodide (47.5 g, 0.22 mol, 0.2 equiv) dissolved in water (540 mL), and then at room temperature (~ 25 ° C). Stir for 10 minutes. A solution of iodine (112.7 g, 0.22 mol, 0.4 equiv) dissolved in acetic acid (2025 mL) was added dropwise to the reaction solution at room temperature for 30 minutes. After 48 hours of stirring at room temperature (˜25 ° C.), the solution was added with aqueous sodium thiosulphate solution (2.7 L), and then extracted twice with ethyl acetate (1.35 L). The organic solution layer was washed successively with water and saturated sodium bicarbonate solution, and then dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound as a pale yellow oil (300.4 g).
실시예 1에서 제조한 화합물 3은 추가의 정제공정이 없이 실시예 2와 실시예 4에서 사용하였다. Compound 3 prepared in Example 1 was used in Examples 2 and 4 without further purification.
실시예 2: 2-시아노-5-트리플루오로메틸페놀의 합성 (화합물 4)Example 2: Synthesis of 2-cyano-5-trifluoromethylphenol (Compound 4)
N,N-다이메틸포름아미드 (1.2 L)에 실시예 1에서 얻은 화합물 3 (300.0 g) 과 CuCN (99.4 g, 1.11 mol)을 넣고 120~130℃ 에서 8시간 동안 교반하였다. 반응혼합물을 소듐 싸이오술페이트 수용액 (2.4 L)로 중화시킨 후 에틸 아세테이트 (1.8 L)를 투입하고, 추출한 후 유기 용액층을 물 (2.4 L, 2회)로 세척하였다. 분리한 유기용 액층에 물 (1.2 L)을 넣은 다음 2.0N 수산화 나트륨 수용액을 사용하여 반응용액의 pH를 13이 되도록 조정한 후 유기 용액층을 제거하였다. 분리된 수용액층을 10% 염산 수용액을 사용하여 pH 2 까지 조정한 후 에틸 아세테이트 (1.2 L)로 추출하였다. 분리한 유기 용액층을 포화 소금물용액과 물로 연속하여 세척한 다음 무수 황산마그네슘으로 건조, 여과 그리고 농축하여 화합물 4를 연한 노랑색의 고상 물질 (170.3 g, 0.91 mol, 실시예 1로부터 실시예 2까지의 반응 전체 수율 82%)로 얻었다. Compound 3 (300.0 g) and CuCN (99.4 g, 1.11 mol) obtained in Example 1 were added to N, N-dimethylformamide (1.2 L), and the mixture was stirred at 120 to 130 ° C. for 8 hours. The reaction mixture was neutralized with aqueous sodium thiosulphate solution (2.4 L), ethyl acetate (1.8 L) was added thereto, followed by extraction. The organic solution layer was washed with water (2.4 L, twice). Water (1.2 L) was added to the separated organic solution layer, and then the pH of the reaction solution was adjusted to 13 using a 2.0N sodium hydroxide aqueous solution, and the organic solution layer was removed. The separated aqueous layer was adjusted to pH 2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1.2 L). The separated organic solution layer was washed successively with saturated brine solution and water, and then dried over anhydrous magnesium sulfate, filtered and concentrated to give Compound 4 as pale yellow solid (170.3 g, 0.91 mol, Example 1 to Example 2). Overall reaction yield 82%).
1H NMR(400MHz, CDCl3) 7.11(1H, m), 7.27(1H, m), 7.59(1H, d), 10.83(1H, s). 1 H NMR (400 MHz, CDCl 3 ) 7.11 (1 H, m), 7.27 (1 H, m), 7.59 (1 H, d), 10.83 (1 H, s).
실시예 3: 2-히드록시-4-트리플루오로메틸 벤조산의 합성 (화합물 5) Example 3: Synthesis of 2-hydroxy-4-trifluoromethyl benzoic acid (Compound 5)
수산화나트륨 (100.0 g)을 물 (1.0 L)에 녹인 용액에 화합물 4 (100.0 g, 534.4 mmol)을 투입한 다음 반응용액을 9시간 동안 환류시켰다. 반응 용액을 실온까지 냉각한 다음 물 (1.0 L)을 투입하여 희석하고, 10% 염산 수용액으로 반응용액의 pH를 조절하여 pH 2가 되도록 조정한다. 흰색 침전물이 형성된 반용액을 1시간 동안 실온에서 교반하고 여과한다. 얻어진 여과물을 물 (4.0 L)로 충분히 세척한 다음 헥산 (2.0 L)으로 세척 후 감압 건조하여 화합물 5의 표제화합물을 흰색 고상 물질 (101.6 g, 493 mmol, 수율 92.2%)로 얻었다 Compound 4 (100.0 g, 534.4 mmol) was added to a solution of sodium hydroxide (100.0 g) in water (1.0 L), and the reaction solution was refluxed for 9 hours. The reaction solution was cooled to room temperature, diluted with water (1.0 L), and adjusted to pH 2 by adjusting the pH of the reaction solution with an aqueous 10% hydrochloric acid solution. The half solution with white precipitate formed is stirred at room temperature for 1 hour and filtered. The obtained filtrate was sufficiently washed with water (4.0 L), washed with hexane (2.0 L) and dried under reduced pressure to obtain the title compound of compound 5 as a white solid (101.6 g, 493 mmol, 92.2% yield).
1H NMR(400MHz, CDCl3) 6.69(1H, bs), 7.10(1H, m), 7.19(1H, m), 7.99(1H, d), 11.45(1H, bs). 1 H NMR (400 MHz, CDCl 3 ) 6.69 (1H, bs), 7.10 (1H, m), 7.19 (1H, m), 7.99 (1H, d), 11.45 (1H, bs).
융점 179-180℃ Melting point 179-180 ℃
실시예 4: 2-히드록시-4-트리플루오로메틸 벤조산의 합성 (화합물 5) Example 4: Synthesis of 2-hydroxy-4-trifluoromethyl benzoic acid (Compound 5)
실시예 1에서 얻은 화합물 3 (100.0 g)과 CuCN (33.2 g, 0.37 mol)을 N,N-다이메틸포름아미드 (400 mL)에 넣어 현탁시킨 후 120~130°C 에서 8시간 동안 교반하였다. 반응혼합물을 소듐 싸이오술페이트 수용액 (800 mL)에 붓고 에틸 아세테이 트(600 mL)를 투입하고, 추출한 후 유기 용액층을 물 (600 mL, 2회)로 세척하였다. 분리한 유기 용액층에 물 (600 mL)을 넣은 다음 2.0N 수산화 나트륨 수용액을 사용하여 반응용액의 pH를 13이 되도록 조정한 후 유기 용액층을 제거하였다. 분리한 반응용액에 수산화나트륨 (45.0 g)을 투입한 다음 9시간 동안 환류시켰다. 반응 용액을 실온까지 냉각한 다음 물 (600 mL)을 투입하여 희석하고, 10% 염산 수용액으로 반응용액의 pH를 조절하여 pH 2가 되도록 조정한다. 흰색 침전물이 형성된 반용액을 1시간 동안 실온에서 교반하고 여과한다. 얻어진 여과물을 물 (1.5 L)로 충분히 세척한 다음 헥 산(800 mL)으로 세척 후 감압 건조하여 화합물 5의 표제화합물을 흰색 고상 물질 (53.2 g, 258.1 mmol, 화합물 2로부터 화합물 5까지의 3 단계 총 수율 69.7%)로 얻었다 Compound 3 (100.0 g) and CuCN (33.2 g, 0.37 mol) obtained in Example 1 were suspended in N, N-dimethylformamide (400 mL) and stirred at 120 ° C to 130 ° C for 8 hours. The reaction mixture was poured into aqueous sodium thiosulphate solution (800 mL), ethyl acetate (600 mL) was added, extracted, and the organic solution layer was washed with water (600 mL, twice). Water (600 mL) was added to the separated organic solution layer, and then the pH of the reaction solution was adjusted to 13 using a 2.0N sodium hydroxide aqueous solution, and the organic solution layer was removed. Sodium hydroxide (45.0 g) was added to the separated reaction solution, and the mixture was refluxed for 9 hours. The reaction solution was cooled to room temperature, diluted with water (600 mL), and adjusted to pH 2 by adjusting the pH of the reaction solution with an aqueous 10% hydrochloric acid solution. The half solution with white precipitate formed is stirred at room temperature for 1 hour and filtered. The resulting filtrate was washed sufficiently with water (1.5 L), then with hexane (800 mL) and dried under reduced pressure to give the title compound of compound 5 as a white solid (53.2 g, 258.1 mmol, 3 to 5). Step yield (69.7%)
1H NMR(400MHz, CDCl3) 6.69(1H, bs), 7.10(1H, m), 7.19(1H, m), 7.99(1H, d), 11.45(1H, bs). 1 H NMR (400 MHz, CDCl 3 ) 6.69 (1H, bs), 7.10 (1H, m), 7.19 (1H, m), 7.99 (1H, d), 11.45 (1H, bs).
융점 179-180℃ Melting point 179-180 ℃
실시예 5: 2-아세틸옥시-4-트리플루오로메틸 벤조산의 합성 (화합물 1) Example 5: Synthesis of 2-acetyloxy-4-trifluoromethyl benzoic acid (Compound 1)
실시예 3 또는 실시예 4 에서 수득한 2-히드록시-4-트리플루오로메틸 벤조산 (화합물 5) 103.0g (0.5 mmol)과 아세트산 무수물 (350 mL), 그리고 황산 (7 mL) 을 섞은 후에 50℃ 로 가열한 다음 이 온도에서 30분 동안 교반하였다. 반응물을 상온으로 식힌 후에 냉각수 (800 mL)를 가한 다음, 침전물을 거르고 냉각수로 씻어주었다. 저온에서 건조하여 얻은 흰색 고체를 페트롤륨 에테르와 에테르를 이용하여 재결정하여 순수한 화합물 1을 얻었다 (87.2 g, 351.4mmol, 수율 70.3%).Example 3 or Example 2 to give the 4-a-hydroxy-4-trifluoromethyl-benzoic acid (Compound 5) After mixing 103.0 g (0.5 mmol) with acetic anhydride (350 mL) and sulfuric acid (7 mL), the mixture was heated to 50 ° C. and stirred at this temperature for 30 minutes. After the reaction was cooled to room temperature, cooling water (800 mL) was added, and the precipitate was filtered off and washed with cooling water. The white solid obtained by drying at low temperature was recrystallized with petroleum ether and ether to give pure compound 1 (87.2 g, 351.4 mmol, 70.3% yield).
1H NMR(400MHz, CDCl3) 2.37(3H, s), 7.43(1H, d), 7.61(1H, m), 8.24(1H, d), 11.30(1H, bs). 1 H NMR (400 MHz, CDCl 3 ) 2.37 (3H, s), 7.43 (1H, d), 7.61 (1H, m), 8.24 (1H, d), 11.30 (1H, bs).
융점 120~122℃ Melting Point 120 ~ 122 ℃
본 발명의 방법은 2-아세틸옥시-4-트리플루오로메틸 벤조산 외에도, 이의 유도체의 제조에도 적용할 수 있음은 물론이며, 이러한 방법 또한 본 발명의 범주에 포함된다. In addition to 2-acetyloxy-4-trifluoromethyl benzoic acid, the method of the present invention can be applied to the preparation of derivatives thereof, and such a method is also included in the scope of the present invention.
본 발명에 따르면, 항혈전 작용이 우수한 화학식 1의 2-아세틸옥시-4-트리플루오로메틸 벤조산을 용이하고 경제성 있게 고순도 및 고수율로 제조할 수 있다. According to the present invention, 2-acetyloxy-4-trifluoromethyl benzoic acid of Chemical Formula 1 having excellent antithrombotic action can be easily and economically prepared in high purity and high yield.
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2002-0056457A KR100503267B1 (en) | 2002-09-17 | 2002-09-17 | Method for the preparation of 2-acetyloxy-4-trifluoromethyl benzoic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2002-0056457A KR100503267B1 (en) | 2002-09-17 | 2002-09-17 | Method for the preparation of 2-acetyloxy-4-trifluoromethyl benzoic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20040025971A KR20040025971A (en) | 2004-03-27 |
| KR100503267B1 true KR100503267B1 (en) | 2005-07-22 |
Family
ID=37328560
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR10-2002-0056457A KR100503267B1 (en) | 2002-09-17 | 2002-09-17 | Method for the preparation of 2-acetyloxy-4-trifluoromethyl benzoic acid |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR100503267B1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1308282C (en) * | 2005-01-11 | 2007-04-04 | 山东师范大学 | Catalytic synthesis of 4-trifluoromethylvinyl salicylic acid |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4096252A (en) * | 1976-06-10 | 1978-06-20 | J. Uriach & Cia S.A. | 4-Trifluoromethylbenzoic acid derivatives as thromboembolic agents |
-
2002
- 2002-09-17 KR KR10-2002-0056457A patent/KR100503267B1/en not_active IP Right Cessation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4096252A (en) * | 1976-06-10 | 1978-06-20 | J. Uriach & Cia S.A. | 4-Trifluoromethylbenzoic acid derivatives as thromboembolic agents |
| US4110442A (en) * | 1976-06-10 | 1978-08-29 | J. Uriach & Cia S.A. | 2-phosphonoxy-4-trifluoromethylbenzoic acid derivatives and pharmaceutical compositions containing same |
Non-Patent Citations (1)
| Title |
|---|
| 초록 참조, J. Labelled Compd. Radiopharm., 19(3), 373-84, French, 1982 * |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20040025971A (en) | 2004-03-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0227787B1 (en) | Production of indole alpha-ketoacids from alpha-aminoacid, particularly of indolepyruvic acid | |
| JPH03109384A (en) | Production of (s)-4-hydroxymethyl-gamma-lactone | |
| KR100503267B1 (en) | Method for the preparation of 2-acetyloxy-4-trifluoromethyl benzoic acid | |
| JPS6024781B2 (en) | Method for producing cis-2-hydroxy-2-phenyl-r-1-cyclohexanecarboxylic acid | |
| JP3907787B2 (en) | Method for producing benzoic acid derivative | |
| JPH09268186A (en) | Production of 4-chromanones | |
| US4061668A (en) | Process for the preparation of 2-(4-isobutylphenyl)-propiohydroxamic acid | |
| KR900007370B1 (en) | Process for the preparation of 2,4-dibromo-5-fluorobenroicacid | |
| JP3573249B2 (en) | 2,3,4-trifluoro-5-iodobenzoic acid, esters thereof and process for producing the same | |
| JP3137430B2 (en) | Method for producing 5,5-disubstituted hydantoin | |
| JP2716243B2 (en) | N-benzyl-3-hydroxysuccinamic acid and method for producing the same | |
| JP4675234B2 (en) | Intermediate for producing optically active quinolonecarboxylic acid derivative and process for producing the same | |
| JPS61172846A (en) | Method of optical resolution of (+-)-2-chloroprorionic acid | |
| JP2003137835A (en) | Method for producing (r)-3-hydroxy-3-(2-phenyl)hexanoic acid | |
| KR100483317B1 (en) | METHOD FOR THE PREPARATION OF α-PHENYL-α-PROPOXYBENZENEACETIC ACID 1-METHYL-4-PIPERIDINYL ESTER HYDROCHLORIDE | |
| KR100311949B1 (en) | Process for the preparation of 1-[(cyclopent-3-en-1-yl)methyl]-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione | |
| JP2000198779A (en) | Purification of 3-alkylflavanol derivative | |
| SU904295A1 (en) | Process for producing 3-(amidazo(1,2,a)benzimidazolyl-3)acryl acids | |
| KR100516383B1 (en) | New manufacturing process of dihydrocarbostyril derivatives | |
| JPH08109152A (en) | Production of phenylpyruvic acid derivative | |
| JPH0124782B2 (en) | ||
| KR910002282B1 (en) | Process for the preparation of inden acetic acid | |
| JPH04288081A (en) | Method for synthesizing benzopyrano(2,3-b)pyridine derivative | |
| JPH07145162A (en) | Production of 4h-pyran-4-one | |
| JPH0769972A (en) | Preparation of hydroxyphenylacetic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant | ||
| FPAY | Annual fee payment |
Payment date: 20100614 Year of fee payment: 6 |
|
| LAPS | Lapse due to unpaid annual fee |