KR100593643B1 - Method for preparing acid chloride using diphosgene - Google Patents
Method for preparing acid chloride using diphosgene Download PDFInfo
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- KR100593643B1 KR100593643B1 KR1020040085563A KR20040085563A KR100593643B1 KR 100593643 B1 KR100593643 B1 KR 100593643B1 KR 1020040085563 A KR1020040085563 A KR 1020040085563A KR 20040085563 A KR20040085563 A KR 20040085563A KR 100593643 B1 KR100593643 B1 KR 100593643B1
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Abstract
본 발명은 의약품 및 농약에서 이용되는 정밀화학 물질의 중간체 또는 천연물질의 전합성 과정에서 중간체로 유용한 acid chloride 유도체의 새로운 제조방법으로, 카르복실산(carboxylic acid) 유도체를 diphosgene과 triphenylphosphine 존재 하에서 반응시키는 방법을 이용하여 카르복실산 유도체로부터 acid chloride 유도체를 제조하는 새로운 방법이다.The present invention is a novel method for preparing acid chloride derivatives useful as intermediates in the intermediates of fine chemicals used in medicines and pesticides or in the presynthesis of natural substances. It is a new method for preparing acid chloride derivatives from carboxylic acid derivatives using the method.
carboxylic acid, acid chloride, diphosgene, triphenylphosphine carboxylic acid, acid chloride, diphosgene, triphenylphosphine
Description
본 발명은 의약품 및 농약에서 이용되는 정밀화학 물질의 중간체 또는 천연물질의 전합성 과정에서 중간체로 유용한 일반식 ( I )으로 표시되는 acid chloride 유도체의 새로운 제조방법으로, 일반식 (II)의 카르복실산(carboxylic acid) 유도체를 diphosgene과 triphenylphosphine 존재 하에서 반응시키는 방법으로 카르복실산 유도체로부터 acid chloride 유도체를 제조하는 새로운 방법이다.The present invention is a novel method for preparing an acid chloride derivative represented by the general formula (I), which is useful as an intermediate in the intermediate of the fine chemicals used in medicines and pesticides or in the presynthesis of natural substances, and the carboxyl of the general formula (II) A new method for preparing acid chloride derivatives from carboxylic acid derivatives is by reacting carboxylic acid derivatives in the presence of diphosgene and triphenylphosphine.
상기식에서 R은 수소, 탄소수 1 내지 20의 알킬 및 치환 알킬기, 또는 아릴 및 치환 아릴기를 나타낸다.In the formula, R represents hydrogen, alkyl and substituted alkyl group having 1 to 20 carbon atoms, or aryl and substituted aryl group.
본 발명은 지금까지 일반적으로 반응성이 현저하게 떨어지는 것으로 알려진 카르복실산으로부터 acid chloride 유도체를 얻는 새로운 방법에 관한 것이다. 이 방법은 전체 합성공정이 간단하고 상압, 실온 근처의 온화한 조건에서 반응시킬 수 있고 또한 지금까지의 다른 합성방법들에서 사용한 카르복실기를 활성화시키기 위해 반드시 필요했던 새로운 중간체의 합성, 분리가 필요 없다는 장점이 있을 뿐만 아니라 부산물도 거의 생성되지 않아 산업적으로 가치가 큰 acid chloride 유도체의 새로운 합성 방법을 제공하는데 그 목적이 있다. The present invention relates to a new process for obtaining acid chloride derivatives from carboxylic acids which are known to be generally significantly less reactive so far. This method has the advantage that the whole synthesis process is simple and can be reacted at atmospheric pressure and mild conditions near room temperature, and also does not require the synthesis and separation of new intermediates, which are necessary for activating the carboxyl groups used in other synthesis methods. In addition, it aims to provide a new method for the synthesis of acid chloride derivatives of high industrial value because little by-products are produced.
유용한 화합물을 합성할 수 있는 중간체로서의 acid chloride 유도체 합성법은 여러 방법이 보고되어 있다. Ghosez등은 1979년 Journal of Chemical Society, Chemical Communications 1180쪽에 발표한 논문에서 카르복실산을 tetramethyl- α-halogenoenamines과 반응시켜서 acid chloride 유도체를 얻었다. 이 반응에서는 출발물질인 tetramethyl- α-halogenoenamines을 합성하여 다시 카르복실산과의 반응으로부터 acid chloride를 얻어야 하는 2단계 반응일 뿐만 아니라 순수하게 생성물을 얻기 위해서는 부산물인 amide를 효율적으로 제거해야 한다. Pellegata등은 1985년 Synthesis 517쪽에서 카르복실산을 고분자가 결합된 PCl5과 반응시켜 acid chloride 유도체를 얻었다. 그러나 이 반응은 매우 발열적으로 일어나기 때문에 주의가 요구되고 또한 반응 후 부산물로서 제거하기 힘든 고분자 물질이 생성된다는 문제점이 있다. Miginiac등은 1987년 Journal of organometallic Chemistry 322권 131쪽에 발표한 논문에서 카르복실산과 thionyl chloride를 반응시켜 acid chloride 유도체를 얻었다. 그러나 이 반응으로부터 생성물을 얻기 위해서는 비교적 높은 온도인 80 oC에서 가열을 하여야 하기 때문에 생성물의 수율이 낮다. Villeneuve등은 1997년 Tetrahedron Letters 38권 37호 6489쪽에 발표한 논문에서 카르복실산을 hexachloroacetone과 triphenylphosphine 존재 하에서 - 78 oC에서 반응시켜 acid chloride 유도체를 얻었다. 그러나 이 반응은 아주 낮은 온도에서 반응을 시켜야 하는 문제가 있을 뿐만 아니라 생성물의 수율이 매우 낮다. Akamanchi등은 1999년 Synlett 11호 1763쪽에서 카르복실산을 thionyl chloride와 benzotriazole의 존재 하에서 반응시켜 acid chloride 유도체를 얻었다. 그러나 이 반응에서는 진한 농도의 thionyl chloride와 benzotriazole의 stock solution을 만들어서 사용해야 하는 번거로움이 있을 뿐만 아니라 work-up 과정에서 과량의 NaOH를 사용할 경우 생성물 대신에 반응물인 카르복실산이 얻어진다는 문제점을 가지고 있다. Parang등은 2001년 Organic Letters 3권 2호 307쪽에서 고분자가 결합된 카르복실산 유도체를 oxalyl chloride를 toluene 용매에서 아주 높은 온도인 120 oC로 가열하여 acid chloride 유도체를 합성하였지만 또한 이 반응에서도 낮은 수율로 생성물이 얻어지는 단점이 있다. Zeller등은 2003년 Angewandte Chemi International Edition 42권 3호 303쪽에 발표한 논문에서 카르복실산을 oxalyl chloride와 반응시켜 acid chloride 유도체를 합성하였다. 그러나 이 반응에서는 과량의 oxalyl chloride가 사용되었고 또한 높은 반응온도에서 반응을 시켜야 하는 문제점이 있다.Several methods have been reported for the synthesis of acid chloride derivatives as intermediates for the synthesis of useful compounds. Ghosez et al., In a paper published in the 1979 Journal of Chemical Society, Chemical Communications, page 1180, reacted carboxylic acids with tetramethyl-α-halogenoenamines to obtain acid chloride derivatives. In this reaction, tetramethyl-α-halogenoenamines, which are starting materials, are synthesized and acid chloride is obtained from the reaction with carboxylic acid. In addition, by-product amide must be efficiently removed to obtain pure product. Pellegata et al. (1985) synthesized acid chloride derivatives by reacting carboxylic acid with polymer-bound PCl 5 on Synthesis 517. However, since this reaction is very exothermic, attention is required, and there is a problem in that a polymer material is generated that is difficult to remove as a by-product after the reaction. Miginiac et al., In a paper published in 1987 in Journal of organometallic Chemistry, Vol. 131, page 131, obtained acid chloride derivatives by reacting carboxylic acid with thionyl chloride. However, in order to obtain a product from this reaction, the yield of the product is low because it must be heated at a relatively high temperature of 80 ° C. Villeneuve et al., 1997, published in Tetrahedron Letters 38, 37, 6489, obtained acid chloride derivatives by reacting carboxylic acids at -78 o C in the presence of hexachloroacetone and triphenylphosphine. However, this reaction not only has a problem of reacting at a very low temperature but also a very low yield of the product. Akamanchi et al. (1999), Synlett 11, page 1763, reacted carboxylic acids in the presence of thionyl chloride and benzotriazole to obtain acid chloride derivatives. However, in this reaction, it is not only troublesome to make a concentrated stock solution of thionyl chloride and benzotriazole, but also has a problem that a reactant carboxylic acid is obtained instead of the product when excess NaOH is used during work-up. Parang et al. Synthesized acid chloride derivatives by heating oxalyl chloride to 120 o C in a toluene solvent in a toluene solvent. The disadvantage is that the product is obtained. Zeller et al. Synthesized acid chloride derivatives by reacting carboxylic acid with oxalyl chloride in a 2003 paper published in Angewandte Chemi International Edition, Vol. 42, No. 3, page 303. In this reaction, however, an excess of oxalyl chloride is used, and there is a problem that the reaction must be performed at a high reaction temperature.
이와 같이 종래의 알려진 카르복실산 유도체로부터 acid chloride 유도체를 합성하는 방법은 거의 대부분 격렬한 조건에서 카르복실산과 chlorinating reagent와 반응시키거나 또 반응성이 떨어지는 카르복실기를 활성화시키기 위해 다른 중간체를 합설하여 카르복실산 유도체와 반응시켜 acid chloride 유도체를 합성하였다. 그러나 이러한 종래의 합성방법들에서는 목적하는 생성물과 함께 생성되는 부산물을 효과적으로 분리해야 하는 문제가 발생되며, 높은 반응온도와 다단계 반응을 거쳐야 하기 때문에 제조공정 시간이 길어지고 전체수율도 낮아지는 등 산업적인 이용에는 한계가 있는 바람직하지 못한 방법들이다. 본 발명자들은 상기와 같은 문제점들을 예의 주시하면서 바람직한 제조법 확립을 위해 노력을 경주해온 결과, 간결한 1단계 반응이면서 상압, 실온근처의 온화한 조건에서 짧은 시간 내에 카르복실산 유도체로부터 부산물 생성 없이 acid chloride 유도체를 합성할 수 있는 새로운 방법을 개발함으로써 본 발명을 완성하게 되었다.
As described above, a method of synthesizing an acid chloride derivative from a known carboxylic acid derivative is almost always a carboxylic acid derivative by combining other intermediates to react with carboxylic acid and chlorinating reagent or to activate a less reactive carboxyl group under vigorous conditions. The acid chloride derivatives were synthesized by reaction with. However, these conventional synthesis methods have a problem of effectively separating the by-products generated with the desired product, and because the high reaction temperature and the multi-step reaction have to go through, the production time is long and the overall yield is low. There are undesirable ways of using them. The present inventors have made an effort to establish a desirable method while paying close attention to the above problems, and as a result, a simple one-step reaction and an acid chloride derivative are produced without generating by-products from the carboxylic acid derivative in a short time under normal conditions at room pressure and at room temperature. The present invention has been completed by developing new methods that can be synthesized.
본 발명은 의약품 및 농약에서 이용되는 정밀화학 물질의 중간체 또는 천연물질의 전합성 과정에서 중간체로 유용한 일반식 ( I )으로 표시되는 acid chloride 유도체의 새로운 제조방법으로, 일반식 (II)의 카르복실산(carboxylic acid) 유도체를 diphosgene과 triphenylphosphine 존재 하에서 반응시키는 방법으로 카르복실산 유도체로 부터 acid chloride 유도체를 제조하는 새로운 방법이다.The present invention is a novel method for preparing an acid chloride derivative represented by the general formula (I), which is useful as an intermediate in the intermediate of the fine chemicals used in medicines and pesticides or in the presynthesis of natural substances, and the carboxyl of the general formula (II) It is a new method to prepare acid chloride derivatives from carboxylic acid derivatives by reacting carboxylic acid derivatives in the presence of diphosgene and triphenylphosphine.
상기식에서 R은 수소, 탄소수 1 내지 20의 알킬 및 치환 알킬기, 또는 아릴 및 치환 아릴기를 나타낸다. In the formula, R represents hydrogen, alkyl and substituted alkyl group having 1 to 20 carbon atoms, or aryl and substituted aryl group.
본 발명에서 사용하는 diphosgene과 triphenylphosphine은 반응성이 떨어지는 카르복실기를 활성화 시키는 역할을 하며, diphosgene은 일반식 ( II )의 카르복실산 유도체 대비 0.50몰배 내지 1.00몰배를 사용하고 tripenylphosphine은 일반식 ( II )의 카르복실산 유도체 대비 1.0 몰배 내지 1.2몰배를 사용한다. 추정 메카니즘상 발생되는 HCl을 중화하기 위해 트리에틸아민과 같은 3차 아민을 사용하고, 반응 온도범위는 0 내지 45 oC이고, 바람직하게는 0 내지 25 oC에서 반응시킨다. 반응용매로는 클로로포름, 디클로로메탄, 톨루엔등과 같은 일반적인 유기용매들이 모두 사용 가능하다. 본 발명을 구성하는 반응순서를 언급하면 다음과 같다.Diphosgene and triphenylphosphine used in the present invention serves to activate a less reactive carboxyl group, diphosgene is used from 0.50 to 1.00 mole times compared to the carboxylic acid derivative of the general formula (II) and tripenylphosphine is a carbine of general formula (II) 1.0 mole to 1.2 mole times relative to the acid derivative is used. A tertiary amine, such as triethylamine, is used to neutralize HCl generated on the presumed mechanism, and the reaction temperature range is from 0 to 45 ° C., preferably from 0 to 25 ° C. As the reaction solvent, all common organic solvents such as chloroform, dichloromethane and toluene can be used. Referring to the reaction sequence constituting the present invention is as follows.
0 내지 5 oC에서 디클로로메탄에 diphosgene과 triphenylphosphine을 첨가하여 5분정도 교반하여 PPh3Cl2를 생성한 후에 일반식 ( II )의 카르복실산 유도체와 triethylamine을 투입하고 실온으로 자연 승온하면서 반응 혼합물을 교반해주면 결합전자들의 이동 및 재구성을 거쳐 목적하는 일반식 ( I )의 acid chloride 유도체를 얻을 수 있다.Diphosgene and triphenylphosphine were added to dichloromethane at 0-5 ° C., and stirred for about 5 minutes to produce PPh 3 Cl 2 , followed by adding carboxylic acid derivative of formula (II) and triethylamine, and then naturally warming to room temperature. Stirring to obtain the acid chloride derivative of the general formula (I) through the transfer and reconstitution of the bonding electrons.
본 발명에서 카르복실산의 활성화 시약으로 사용한 diphosgene은 Mai등이 1986년 Tetrahedron Letters 27권 20호의 2203쪽에 발표한 바와 같이 amide유도체로부터 nitrile 유도체를 합성할 수 있는 흡습제로 사용되거나, Seeger등이 1996년 J. Org. Chem. 61권 3883쪽에 발표한 바와 같이 아민으로부터 isocyanate유도체를 합성하는데 주로 사용되던 시약으로, 카르복실산을 활성화시켜 amide유도체를 합성하는 시약으로는 본 발명자들에 의해 최초로 확인이 되어 직접합성방법이 개발되었다. 이하 본 발명을 실시예에 의거 더욱 자세히 설명한다. 그러나 본 발명이 실시예에 제시된 방법들에만 국한 되는 것은 아니다.In the present invention, diphosgene used as an activator of carboxylic acid is used as an absorbent for synthesizing nitrile derivatives from amide derivatives, as Mai et al., Published on page 2203 of Tetrahedron Letters 27, 20, 1986, or Seeger et al. In 1996. J. Org. Chem. As published on 61,3883, the reagents used mainly for the synthesis of isocyanate derivatives from amines, the first synthetic reagents were synthesized by the inventors to activate the amide derivatives by activating carboxylic acids. . Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited to the methods presented in the Examples.
실시예 1.Example 1.
30 mL 플라스크에 질소 분위기 하에서 디클로로메탄 15mL을 넣고 ice-bath에서 0내지 5 oC로 냉각시키고 triphenylphosphine 524 mg(2.0 mmole), diphosgene 198 mg(1.0 mmole)을 투입하고 5분간 교반한다. benzoic acid 244 mg(2.0 mmole)과 triethylamine 607 mg(6.0 mmole)을 투입하고 20분간 교반한 후 ice-bath를 제거하여 실온으로 자연 승온시키면서 교반, 반응시키면 약 1시간 후 TLC로 acid가 완벽하게 acid chloride로 전환된 것을 확인할 수 있다. 고체로 생성된 트리에틸아민 하이드로클로라이드를 short path 실리카겔 filter로 여과하여 제거하고 여액의 용매를 감압, 증류 제거하여 목적 화합물인 acid chloride 유도체를 278 mg 얻었다(수율 98.5%).15 mL of dichloromethane was added to a 30 mL flask under nitrogen atmosphere, cooled to 0-5 ° C in an ice bath, 524 mg (2.0 mmole) of triphenylphosphine and 198 mg (1.0 mmole) of diphosgene were added and stirred for 5 minutes. Add 244 mg (2.0 mmole) of benzoic acid and 607 mg (6.0 mmole) of triethylamine and stir for 20 minutes, remove the ice-bath and stir while warming to room temperature naturally. You can see the conversion to chloride. Triethylamine hydrochloride formed as a solid was filtered off using a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 278 mg of an acid chloride derivative as a target compound (yield 98.5%).
실시예 2Example 2
30 mL 플라스크에 질소 분위기 하에서 디클로로메탄 15mL을 넣고 ice-bath에서 0내지 5 oC로 냉각시키고 triphenylphosphine 524 mg(2.0 mmole), diphosgene 198 mg(1.0 mmole)을 투입하고 5분간 교반한다. 4-nitrobenzoic acid 334 mg(2.0 mmole)과 triethylamine 607 mg(6.0 mmole)을 투입하고 20분간 교반한 후 ice-bath를 제거하여 실온으로 자연 승온시키면서 교반, 반응시키면 약 1시간 후 TLC로 acid가 완벽하게 acid chloride로 전환된 것을 확인할 수 있다. 고체로 생성된 트리에틸아민 하이드로클로라이드를 short path 실리카겔 filter로 여과하여 제거하고 여액의 용매를 감압, 증류 제거하여 목적 화합물인 acid chloride 유도체를 362 mg 얻었다(수율 97.3%).15 mL of dichloromethane was added to a 30 mL flask under nitrogen atmosphere, cooled to 0-5 ° C in an ice bath, 524 mg (2.0 mmole) of triphenylphosphine and 198 mg (1.0 mmole) of diphosgene were added and stirred for 5 minutes. 4-nitrobenzoic acid 334 mg (2.0 mmole) and triethylamine 607 mg (6.0 mmole) were added and stirred for 20 minutes, then the ice-bath was removed and stirred while raising the temperature to room temperature. It can be seen that the conversion to acid chloride. Triethylamine hydrochloride formed as a solid was filtered off using a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 362 mg of an acid chloride derivative as a target compound (yield 97.3%).
실시예3Example 3
30 mL 플라스크에 질소 분위기 하에서 디클로로메탄 15mL을 넣고 ice-bath에서 0내지 5 oC로 냉각시키고 triphenylphosphine 524 mg(2.0 mmole), diphosgene 198 mg(1.0 mmole)을 투입하고 5분간 교반한다. nicotinic acid 246 mg(2.0 mmole)과 triethylamine 607 mg(6.0 mmole)을 투입하고 20분간 교반한 후 ice-bath를 제거하여 실온으로 자연 승온시키면서 교반, 반응시키면 약 1시간 후 TLC로 acid가 완벽하게 acid chloride로 전환된 것을 확인할 수 있다. 고체로 생성된 트리에틸아민 하이드로클로라이드를 short path 실리카겔 filter로 여과하여 제거하고 여액의 용매를 감압, 증류 제거하여 목적 화합물인 acid chloride 유도체를 272 mg 얻었다(수율 95.9%).15 mL of dichloromethane was added to a 30 mL flask under nitrogen atmosphere, cooled to 0-5 ° C in an ice bath, 524 mg (2.0 mmole) of triphenylphosphine and 198 mg (1.0 mmole) of diphosgene were added and stirred for 5 minutes. 246 mg (2.0 mmole) of nicotinic acid and 607 mg (6.0 mmole) of triethylamine were added thereto, stirred for 20 minutes, the ice-bath was removed, stirred and heated to room temperature naturally. You can see the conversion to chloride. Triethylamine hydrochloride produced as a solid was removed by filtration using a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 272 mg of an acid chloride derivative as a target compound (yield 95.9%).
실시예4Example 4
30 mL 플라스크에 질소 분위기 하에서 디클로로메탄 15mL을 넣고 ice-bath에서 0내지 5 oC로 냉각시키고 triphenylphosphine 524 mg(2.0 mmole), diphosgene 198 mg(1.0 mmole)을 투입하고 5분간 교반한다. trans-cinnamic acid 296 mg(2.0 mmole)과 triethylamine 607 mg(6.0 mmole)을 투입하고 20분간 교반한 후ice-bath를 제거하여 실온으로 자연 승온시키면서 교반, 반응시키면 약 1시간 후 TLC로 acid가 완벽하게 acid chloride로 전환된 것을 확인할 수 있다. 고체로 생성된 트리에틸아민 하이드로클로라이드를 short path 실리카겔 filter로 여과하여 제거하고 여액의 용매를 감압, 증류 제거하여 목적 화합물인 acid chloride 유도체를 315 mg 얻었다(수율 94.3%).15 mL of dichloromethane was added to a 30 mL flask under nitrogen atmosphere, cooled to 0-5 ° C in an ice bath, 524 mg (2.0 mmole) of triphenylphosphine and 198 mg (1.0 mmole) of diphosgene were added and stirred for 5 minutes. 296 mg (2.0 mmole) of trans- cinnamic acid and 607 mg (6.0 mmole) of triethylamine were added thereto and stirred for 20 minutes. After removing the ice-bath, the mixture was stirred while warming to room temperature. It can be seen that the conversion to acid chloride. Triethylamine hydrochloride produced as a solid was removed by filtration using a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 315 mg of an acid chloride derivative as a target compound (yield 94.3%).
실시예5Example 5
30 mL 플라스크에 질소 분위기 하에서 디클로로메탄 15mL을 넣고 ice-bath에서 0내지 5 oC로 냉각시키고 triphenylphosphine 524 mg(2.0 mmole), diphosgene 198 mg(1.0 mmole)을 투입하고 5분간 교반한다. 4-cyanobenzoic acid 294 mg(2.0 mmole)과 triethylamine 607 mg(6.0 mmole)을 투입하고 20분간 교반한 후ice-bath를 제거하여 실온으로 자연 승온시키면서 교반, 반응시키면 약 1시간 후 TLC로 acid가 완벽하게 acid chloride로 전환된 것을 확인할 수 있다. 고체로 생성된 트리에틸아민 하이드로클로라이드를 short path 실리카겔 filter로 여과하여 제거하고 여액의 용매를 감압, 증류 제거하여 목적 화합물인 acid chloride 유도체를 286 mg 얻었다(수율 97.3%).15 mL of dichloromethane was added to a 30 mL flask under nitrogen atmosphere, cooled to 0-5 ° C in an ice bath, 524 mg (2.0 mmole) of triphenylphosphine and 198 mg (1.0 mmole) of diphosgene were added and stirred for 5 minutes. 294 mg (2.0 mmole) of 4-cyanobenzoic acid and 607 mg (6.0 mmole) of triethylamine were added and stirred for 20 minutes, then the ice-bath was removed and stirred while raising the temperature to room temperature. It can be seen that the conversion to acid chloride. Triethylamine hydrochloride produced as a solid was removed by filtration using a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 286 mg of an acid chloride derivative as a target compound (yield 97.3%).
실시예 6 Example 6
30 mL 플라스크에 질소 분위기 하에서 디클로로메탄 15mL을 넣고 ice-bath에서 0내지 5 oC로 냉각시키고 triphenylphosphine 524 mg(2.0 mmole), diphosgene 198 mg(1.0 mmole)을 투입하고 5분간 교반한다. 4-chlorobenzoic acid 272 mg(2.0 mmole)과 triethylamine 607 mg(6.0 mmole)을 투입하고 20분간 교반한 후 ice-bath를 제거하여 실온으로 자연 승온시키면서 교반, 반응시키면 약 1시간 후 TLC로 acid가 완벽하게 acid chloride로 전환된 것을 확인할 수 있다. 고체로 생성된 트리에틸아민 하이드로클로라이드를 short path 실리카겔 filter로 여과하여 제거하고 여액의 용매를 감압, 증류 제거하여 목적 화합물인 acid chloride 유도체를 331 mg 얻었다(수율 94.7%).15 mL of dichloromethane was added to a 30 mL flask under nitrogen atmosphere, cooled to 0-5 ° C in an ice bath, 524 mg (2.0 mmole) of triphenylphosphine and 198 mg (1.0 mmole) of diphosgene were added and stirred for 5 minutes. 272 mg (2.0 mmole) of 4-chlorobenzoic acid and 607 mg (6.0 mmole) of triethylamine were added thereto, stirred for 20 minutes, and then the ice-bath was removed. It can be seen that the conversion to acid chloride. Triethylamine hydrochloride produced as a solid was removed by filtration using a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 331 mg of an acid chloride derivative as a target compound (yield 94.7%).
카르복실산 유도체로부터 acid chloride 유도체를 합성하는 방법은 거의 대부분 격렬한 조건에서 카르복실산과 chlorinating reagent와 반응시키거나 또 반응성이 떨어지는 카르복실기를 활성화시키기 위해 다른 중간체를 합성하여 카르복실산 유도체와 반응시켜 acid chloride 유도체를 합성하였다. 그러나 이러한 종래의 합성방법들에서는 목적하는 생성물과 함께 생성되는 부산물을 효과적으로 분리해야하는 문제가 발생되며, 높은 반응온도와 다단계 반응을 거쳐야 하기 때문에 제조공정 시간이 길어지고 전체수율도 낮아지는 등 산업적인 이용에는 한계가 있는 바람직하지 못한 방법들이다. 이에 비해 본 발명은 다단계 반응이 아닌 간결한 1단계 반응처럼 진행시킬 수 있으며 상압, 실온 근처의 온화한 조건에서 짧은 시간 내에 카르복실산 유도체로부터 부산물 생성 없이 acid chloride 유도체를 합성할 수 있는 새로운 방법이다. 따라서 전체 합성공정이 간단하고 짧은 시간에 반응을 완결 시킬 수 있을 뿐만 아니라, 부산물도 거의 생성되지 않는 새로운 acid chloride 유도체의 합성 방법으로, 반응의 신뢰성 및 재현성이 우수한 합성 Process 이므로 산업화시 기존의 방법들에 비해 환경문제를 일으키지 않으면서 목적화합물의 분리, 정제 과정도 수월하여 경제성 제고에 크게 기여할 것으로 판단된다.
Most of the methods for synthesizing acid chloride derivatives from carboxylic acid derivatives react with carboxylic acid derivatives by synthesizing other intermediates to react with carboxylic acid and chlorinating reagent or to activate less reactive carboxyl groups under vigorous conditions. Derivatives were synthesized. However, these conventional synthesis methods have a problem of effectively separating the by-products generated with the desired product, and the high production temperature and the multi-step reaction require a long process time and lower the overall yield. There are some undesirable ways to limit. In contrast, the present invention can proceed as a simple one-step reaction rather than a multi-step reaction, and is a new method for synthesizing an acid chloride derivative from a carboxylic acid derivative without generating by-products from a carboxylic acid derivative in a short time under normal pressure and mild conditions near room temperature. Therefore, the whole synthesis process is simple and can complete the reaction in a short time, and it is a synthesis method of the new acid chloride derivative which generates little by-products.It is a synthetic process with excellent reaction reliability and reproducibility. Compared to the above, it is easy to separate and purify the target compound without causing environmental problems, which will greatly contribute to economic efficiency.
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