KR930002964B1 - Process for producing salicylic acid derivatives - Google Patents
Process for producing salicylic acid derivatives Download PDFInfo
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- KR930002964B1 KR930002964B1 KR1019900016769A KR900016769A KR930002964B1 KR 930002964 B1 KR930002964 B1 KR 930002964B1 KR 1019900016769 A KR1019900016769 A KR 1019900016769A KR 900016769 A KR900016769 A KR 900016769A KR 930002964 B1 KR930002964 B1 KR 930002964B1
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- aminophenol
- salicylic acid
- organic solvent
- monomethyl ether
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
- C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
- C07C65/10—Salicylic acid
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
본 발명은 살리실산 유도체의 제조방법에 관한 것으로서, 보다 상세하게는 다음 구조식(Ⅰ)로 표시되는 살리실산 유도체를 고수율로 제조하는 방법에 관한 것이다.The present invention relates to a method for producing salicylic acid derivatives, and more particularly, to a method for producing salicylic acid derivatives represented by the following structural formula (I) in high yield.
상기식에서, R1은 3-NH2, 4-NH2, 5-NH2이고, R2는 수소원자, 탄소수가 1 내지 6인 알킬기, 페닐기를 나타낸다.In the above formula, R 1 is 3-NH 2 , 4-NH 2 , 5-NH 2 , and R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a phenyl group.
살리실산 유도체는 궤양성 대장염치료제 및 의약품의 중간체로는 물론 염료 중간체 및 화장품의 첨가제로 널리 사용되고 있는 바, 이에 대한 종래 기술을 보면 일본 특공 소 45-10933호에는 수용액에 아미노페놀 알칼리염을 용해시키고 CO2압력을 50기압이상, 반응온도는 180℃이상에서 합성하는 방법이 기재되어 있으나, 상기 방법은 수율이 50%이하로 낮고 반응압력이 높아 위험한 문제점이 있었고, 체코슬로바키아 특허 제 178, 674/1979호에서는 수용액중에 알칼리염, 히드라진, 디아조벤젠유도체를 50 내지 150℃의 온도와 10기압이하에서 환원시켜서 합성(Raney 니켈촉매사용)시키는 방법이 소개되어 있으나, 상기 방법은 공정이 복잡하고, 고가의 촉매가 필요하게 되므로 비경제적이었다.Salicylic acid derivatives are widely used as an intermediate for ulcerative colitis and pharmaceuticals, as well as additives for dye intermediates and cosmetics. According to the prior art, Japanese Patent Office No. 45-10933 dissolves an aminophenol alkali salt in an aqueous solution and CO 2 The method of synthesizing the pressure above 50 atm and the reaction temperature above 180 ° C. has been described. However, the method has a low yield of less than 50% and a high reaction pressure, which has a dangerous problem. Czech Patent No. 178, 674/1979 No. 2 discloses a method of reducing alkali salts, hydrazines and diazobenzene derivatives in an aqueous solution at a temperature of 50 to 150 ° C. and below 10 atm, to synthesize them (using Raney nickel catalysts), but the method is complicated and expensive. It was uneconomical because a catalyst was needed.
또한, 독일 공개특허 제 3, 323, 702/1985호에는 살리실산을 황산, 질산혼합용매에 반응시켜서 니트로살리실산을 만든후 환원시켜서 합성하는 방법이 소개되어 있으나, 상기방법은 반응용매로서 황산, 질산을 사용하므로 위험성이 크고 공정이 다단계이므로 비경제적인 결점이 있었다.In addition, German Patent Application Publication No. 3, 323, 702/1985 discloses a method of synthesizing by reacting salicylic acid with a mixture of sulfuric acid and nitric acid to form nitrosalicylic acid, and then reducing the sulfuric acid and nitric acid as reaction solvents. The use is risky and the process is multi-stage, which results in an uneconomical drawback.
이에 본 발명은 상술한 바와같은 결점을 해소시켜 경제적이면서 고수율로 살리실산 유도체를 제조하는 방법을 제공하는데 그 목적이 있다.Accordingly, an object of the present invention is to provide a method for producing a salicylic acid derivative in economical and high yield by eliminating the above-described drawbacks.
이하 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.
본 발명은 3-아미노페놀, 4-아미노페놀 또는 5-아미노페놀을 유기용매에 대해 15 내지 35중량%를 용해시킨 후 알칼리염을 아미노페놀 몰수의 1.1 내지 2.0몰배가 되도록 첨가시키고 CO2가스압력을 1 내지 8 기압으로 유지하면서 50 내지 150℃의 온도에서 4 내지 7시간 반응시켜서 다음구조식(Ⅰ)로 표시되는 살리실산 유도체를 고수율로 제조하는 방법임을 그 특징으로 한다.The present invention dissolves 15 to 35% by weight of 3-aminophenol, 4-aminophenol or 5-aminophenol in an organic solvent, and then adds an alkali salt so as to be 1.1 to 2.0 mole times the number of moles of aminophenol and CO 2 gas pressure. It is characterized in that the method of producing a salicylic acid derivative represented by the following structural formula (I) in a high yield by reacting for 4 to 7 hours at a temperature of 50 to 150 ℃ while maintaining at 1 to 8 atm.
상기식에서, R1은 3-NH2, 4-NH2, 5-NH2이고, R2는 수소원자, 탄소수가 1 내지 6인 알킬기, 페닐기를 나타낸다.In the above formula, R 1 is 3-NH 2 , 4-NH 2 , 5-NH 2 , and R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a phenyl group.
이하, 본 발명은 더욱 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in more detail as follows.
본 발명은 유기용매(예를들면, 에틸렌글리콜모노메틸에테르, 3-메톡시-1-부탄올, 프로필렌글리콜모노메틸에테르)에 아미노페놀 유도체(예를들면, 2-아미노페놀, 3-아미노페놀, 4-아미노페놀등)을 상기 유기용매에 대해 15 내지 35중량%를 넣어 용해시킨 다음 알칼리염(예를들면, KOH, K2CO3, Na2CO3등)을 아미노페놀 특히, 3-아미노페놀, 4-아미노페놀 또는 5-아미노페놀의 몰수의 1, 1 내지 2.0몰배가 되도록 넣고 CO2가스압력을 1 내지 8기압으로 유지하면서 50 내지 150℃의 온도에서 4 내지 7시간 촉매를 사용하지 않고 반응시키고 상온으로 냉각하여 여과시킨 고체를 수세하거나 또는 물에 용해시킨 다음 진한 염산을 적가하여 중화시킨후 여과.건조시켜서 상기 구조식(Ⅰ)로 표시되는 살리실산 유도체를 제조하는 방법인 것이다.The present invention relates to an aminophenol derivative (eg, 2-aminophenol, 3-aminophenol) in an organic solvent (eg, ethylene glycol monomethyl ether, 3-methoxy-1-butanol, propylene glycol monomethyl ether). 4-aminophenol, etc.) are dissolved in an amount of 15 to 35% by weight based on the organic solvent, and then an alkali salt (for example, KOH, K 2 CO 3 , Na 2 CO 3, etc.) Add 1, 1 to 2.0 mole times the number of moles of phenol, 4-aminophenol or 5-aminophenol, and do not use the catalyst for 4 to 7 hours at a temperature of 50 to 150 ° C while maintaining the CO 2 gas pressure at 1 to 8 atmospheres. It is a method of preparing the salicylic acid derivative represented by the above structural formula (I) by reacting with water, cooling to room temperature, and filtering the solid to be washed with water or dissolving in water, and then neutralizing by adding dropwise concentrated hydrochloric acid.
본 발명에서 유기용매의 사용량은 아미노페놀 무게의 3 내지 7배가 바람직한 바, 즉 용매중의 아미노페놀 농도는 15 내지 35중량%가 바람직하고 알칼리염의 사용량은 아미노페놀 몰수의 1.1 내지 2.0몰배가 바람직하다.In the present invention, the amount of the organic solvent is preferably 3 to 7 times the weight of the aminophenol, that is, the concentration of the aminophenol in the solvent is preferably 15 to 35% by weight and the amount of the alkali salt is preferably 1.1 to 2.0 mole times the number of moles of aminophenol. .
본 발명의 주요한 특징은 유기용매를 사용하여 살리실산 유도체의 수율을 크게 하는 것인바, 이는 다음 반응식(Ⅳ)과 같은 메카니즘으로 설명될 수 있다.The main feature of the present invention is to increase the yield of the salicylic acid derivative using an organic solvent, which can be explained by the mechanism shown in the following scheme (IV).
즉 상기 반응식(Ⅳ)은 가역반응으로서 수용액상태에서는 상기 구조식(B)이 물에 많이 녹아서 분해되는 양이 많아 수율이 높지 않은 반면, 유기용매 사용시에는 상기 구조식(B)가 거의 녹지않고 고체로 석출되어 분해되는 양이 적으므로 르-샤틀 리에 원리에 의해서 생성물의 양이 점점 많아져 수율이 높게된다.That is, the reaction formula (IV) is a reversible reaction in the aqueous state, the structural formula (B) is dissolved in water and the amount of decomposition is large, the yield is not high, while using the organic solvent, the structural formula (B) is hardly dissolved and precipitated as a solid Since the amount of decomposition is small, the amount of the product is increased by the Le-Chatlier principle and the yield is high.
본 발명에 따른 제조방법으로 경제적이면서 안정성있게 고수율로 여러 용도의 중간체, 첨가제로 쓰이는 살리실산 유도체를 제조할 수 있다.The production method according to the present invention can produce a salicylic acid derivative used as an intermediate, an additive for various uses in a high yield economically and stably.
이하, 본 발명을 실시예에 의거 더욱 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in more detail with reference to Examples.
[실시예 1]Example 1
[아미노살리실산의 제조][Production of Aminosalicylic Acid]
500ml 용량의 가압반응기에 3-메톡시-1-부탄올 240g과 4-아미노페놀 43.7g(0.40몰)을 넣어 용해시킨 후 탄산칼륨 71.9g(0.52몰)을 넣고 CO2압력을 8기압으로 유지하면서 140℃에서 5시간 반응시켰다.After dissolving 240 g of 3-methoxy-1-butanol and 43.7 g (0.40 mole) of 4-aminophenol in a 500 ml pressurized reactor, 71.9 g (0.52 mole) of potassium carbonate was added and the CO 2 pressure was maintained at 8 atm. It was made to react at 140 degreeC for 5 hours.
상온으로 냉각하여 여과하고 여과된 고체를 물 150g에 용해시킨 다음 진한 염산 90g을 적가하여 중화시킨 후 생성된 고체를 여과하여 건조시킨 결과 상기 목적화합물 49.0g(0.32몰)을 얻을 수 있었다.After cooling to room temperature, the filtered solid was dissolved in 150 g of water, neutralized by dropwise addition of 90 g of concentrated hydrochloric acid, and the resultant solid was filtered and dried to obtain 49.0 g (0.32 mol) of the target compound.
융점 : 279~281℃(흰색고체)Melting Point: 279 ~ 281 ℃ (White Solid)
수율 : 80.0%Yield: 80.0%
[실시예 2]Example 2
[메틸 5-아미노살리실레이트의 제조][Preparation of methyl 5-aminosalicylate]
콘덴서, 온도계가 장치된 500ml 4구 플라스크에 실시예 1에서 얻은 5-아미노 살리실산 76.6g(0.5몰)과 메탄올 235g을 넣고 용해시킨 다음 4-톨루엔술폰산 4.3g(0.025몰)을 넣고 65℃에서 2시간동안 반응시켰다.In a 500 ml four-necked flask equipped with a condenser and a thermometer, 76.6 g (0.5 mol) of 5-amino salicylic acid and 235 g of methanol obtained in Example 1 were dissolved, followed by 4.3 g (0.025 mol) of 4-toluenesulfonic acid. The reaction was carried out for a time.
실온으로 냉각시켜 여과한 후 물 100g으로 씻어주고 건조시킨 결과 상기 목적화합물 108.9g(0.48몰)을 얻었다.After cooling to room temperature, the mixture was washed with 100 g of water and dried to obtain 108.9 g (0.48 mol) of the target compound.
수율 : 95%(흰색고체)Yield: 95% (white solid)
[실시예 3]Example 3
[4-아미노살리실산의 제조][Production of 4-aminosalicylic acid]
실시예 1과 같은 반응기에 프로필렌 글리콜 모노메틸 에테르 230g과 3-아미노페놀 43.7g(0.40몰)을 넣어 용해시킨 후 탄산칼륨(0.48몰)을 넣고 CO2압력을 2기압으로 유지하면서 120℃에서 4시간 반응시켰다.230 g of propylene glycol monomethyl ether and 43.7 g (0.40 mole) of 3-aminophenol were dissolved in the same reactor as in Example 1, followed by adding potassium carbonate (0.48 mole) and maintaining the CO 2 pressure at 2 atm. The reaction was time.
이하 실시예 1과 같은 방법으로 하여 상기 목적화합물 52.4g(0.34몰)을 얻었다.In the same manner as in Example 1 below, 52.4 g (0.34 mol) of the target compound was obtained.
융점 : 152℃(흰색고체)Melting Point: 152 ℃ (White Solid)
수율 : 85.5%Yield: 85.5%
[실시예 4]Example 4
[4-아미노 살리실산의 제조][Production of 4-amino salicylic acid]
탄산칼륨 대신에 탄산나트륨을 사용하여 실시한 것을 제외하고는 실시예 3과 같이 실시한 결과 상기 목적화합물 48.1g(0.31몰)을 얻었다.48.1 g (0.31 mol) of the target compound was obtained as in Example 3, except that sodium carbonate was used instead of potassium carbonate.
융점 : 152℃(흰색고체)Melting Point: 152 ℃ (White Solid)
수율 : 78.5%Yield: 78.5%
[실시예 5]Example 5
[3-아미노 살리실산의 제조][Production of 3-Aminosalicylic Acid]
실시예 1과 같은 반응기에 에틸렌 글리콜 모노메틸 에테르 270g을 넣고 2-아미노 페놀 76.6g(0.50몰)을 용해시킨 후 수산화칼륨 30.9g(0.55몰)을 넣고 CO2압력을 6기압으로 유지하면서 145℃에서 7시간 반응시켰다.270 g of ethylene glycol monomethyl ether was added to the same reactor as in Example 1, 76.6 g (0.50 mole) of 2-amino phenol was dissolved, 30.9 g (0.55 mole) of potassium hydroxide was added thereto, and the CO 2 pressure was maintained at 6 atm. Reaction was carried out for 7 hours.
이하 실시예 1과 같은 방법으로하여 상기 목적화합물 60.7g(0.40몰)을 얻었다.Hereinafter, 60.7 g (0.40 mol) of the target compound was obtained in the same manner as in Example 1.
융점 : 240℃(흰색고체)Melting Point: 240 ℃ (White Solid)
수율 : 79.3%Yield: 79.3%
[실시예 6]Example 6
[페닐 4-아미노 살리실레이트의 제조][Production of Phenyl 4-amino Salicylate]
상기 실시예 2와 같은 반응기에 실시예 3에서 얻은 4-아미노살리실산 91.9g(0.60몰)과 페놀 56.5g(0.60몰)을 에틸아세테이트 270g에 녹이고 4-톨루엔술폰산 5.2g(0.030몰)을 넣고 77℃에서 1시간 반응시켰다.In the same reactor as in Example 2, 91.9 g (0.60 mole) of 4-aminosalicylic acid and 56.5 g (0.60 mole) of phenol were dissolved in 270 g of ethyl acetate, and 5.2 g (0.030 mole) of 4-toluenesulfonic acid was added thereto. It was made to react at 1 degreeC.
실온으로 냉각시켜 여과한 후 물 100g으로 씻어주고 건조시킨 결과 상기 목적화합물 135g(0.59몰)을 얻었다.After cooling to room temperature, the mixture was washed with 100 g of water and dried to obtain 135 g (0.59 mol) of the target compound.
융점 : 153℃(흰색고체)Melting Point: 153 ℃ (White Solid)
수율 : 98%Yield: 98%
Claims (2)
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| KR1019900016769A KR930002964B1 (en) | 1990-10-20 | 1990-10-20 | Process for producing salicylic acid derivatives |
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| KR1019900016769A KR930002964B1 (en) | 1990-10-20 | 1990-10-20 | Process for producing salicylic acid derivatives |
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| KR930002964B1 true KR930002964B1 (en) | 1993-04-16 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102311357A (en) * | 2011-10-17 | 2012-01-11 | 上海安诺芳胺化学品有限公司 | Preparation method of 2-hydroxy-4-aminobenzoic acid |
| CN102408329A (en) * | 2011-10-17 | 2012-04-11 | 上海安诺芳胺化学品有限公司 | Preparation method of 2,4-dihydroxy benzoic acid |
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1990
- 1990-10-20 KR KR1019900016769A patent/KR930002964B1/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102311357A (en) * | 2011-10-17 | 2012-01-11 | 上海安诺芳胺化学品有限公司 | Preparation method of 2-hydroxy-4-aminobenzoic acid |
| CN102408329A (en) * | 2011-10-17 | 2012-04-11 | 上海安诺芳胺化学品有限公司 | Preparation method of 2,4-dihydroxy benzoic acid |
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| Publication number | Publication date |
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| KR920007978A (en) | 1992-05-27 |
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