KR20050110872A - Process for the preparation of weinreb amide derivatives - Google Patents
Process for the preparation of weinreb amide derivatives Download PDFInfo
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Abstract
본 발명은 의, 농약 등의 정밀화학 물질의 중간체 또는 천연물질의 전합성 과정에서 중간체로 유용한 Weinreb amide 유도체를 제조할 수 있는 새로운 제조방법에 관한 것이다. 카르복실산(carboxylic acid)유도체를 diphosgene과 triphenylphosphine 존재 하에서 N,O-dimethylhydroxylamine과 반응시키는 방법을 이용하여 카르복실산 유도체로부터 직접 Weinreb amide 유도체를 제조하는 새로운 방법이다.The present invention relates to a novel method for producing Weinreb amide derivatives useful as intermediates in the preparation of intermediates of fine chemicals, such as pesticides or natural substances. A new method for preparing Weinreb amide derivatives directly from carboxylic acid derivatives by the reaction of carboxylic acid derivatives with N, O-dimethylhydroxylamine in the presence of diphosgene and triphenylphosphine.
Description
본 발명은 의, 농약등의 정밀화학 물질의 중간체 또는 천연물질의 전합성 과정에서 중간체로 유용한 일반식 ( I )으로 표시되는 Weinreb amide 유도체의 새로운 제조방법으로, 일반식 (II)의 카르복실산(carboxylic acid)유도체를 diphosgene 과 triphenylphosphine 존재 하에서 N,O-dimethylhydroxylamine과 반응시키는 방법으로 카르복실산 유도체로부터 Weinreb amide유도체를 직접 제조하는 새로운 방법이다. The present invention is a novel method for preparing a Weinreb amide derivative represented by Formula (I) useful as an intermediate in the intermediate of fine chemicals such as agrochemicals or in the presynthesis of natural substances, carboxylic acid of Formula (II) It is a new method to prepare Weinreb amide derivatives directly from carboxylic acid derivatives by reacting (carboxylic acid) derivatives with N, O-dimethylhydroxylamine 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 일반적으로 반응성이 현저하게 떨어지는 것으로 지금까지 알려진 카르복실산으로부터 직접 Weinreb amide유도체를 얻는 방법으로, 전체 합성공정이 간단하고 상압, 실온 근처의 온화한 조건에서 반응시키고 또한 지금까지의 합성방법들에서 사용한 카르복실기를 활성화시키기 위한 새로운 중간체의 합성이 필요 없을 뿐만 아니라 부산물도 거의 생성되지 않는 Weinreb amide 유도체의 새로운 합성 방법을 제공하는데 그 목적이 있다. The present invention is generally a method of obtaining Weinreb amide derivatives directly from carboxylic acids known to be remarkably inferior in reactivity, and the overall synthesis process is simple and reacts at atmospheric pressure and mild conditions near room temperature. It is an object of the present invention to provide a novel method for synthesizing Weinreb amide derivatives, which does not require the synthesis of new intermediates to activate the carboxyl groups and generates little byproducts.
Weinreb amide는 Weinreb등이 1981년 Tetrahedron Letters 22권 3815쪽에 발표한 논문에서 acyl기 도입 시약으로 유용함을 발표한 이후 Grignard시약, 또는 organolithium 시약과 반응하여 부산물 생성 없이 ketone유도체를 합성할 수 있는 유용한 중간체로 많은 관심의 대상이 되어왔다. 그 예로서, Woller등은 1997년 J. Am. Chem. Soc. 119권 3824쪽에 발표한 논문에서 천연물질의 전합성 과정에서 Weinreb amide를 acylation 반응에 의해 새로운 기능기들을 도입하고 적절한 후속 반응을 거쳐 목표화합물의 구조에 접근해가는 합성 중간체로 사용하였으며, Chrisman등은 1999년 Tetrahedron Letters 40권 7889쪽에 발표한 논문에서 Weinreb amide유도체를 직접 formylation 시약으로 사용하였고, George등은 2000년 J. Am. Chem. Soc. 122권 11995에 발표한 논문에서 Weinreb amide의 환원제에 대한 반응 선택성을 이용해서 aldehyde를 도입하는 시약으로도 사용하였다. 이렇게 여러 유용한 화합물을 합성할 수 있는 중간체로서의 Weinreb amide유도체는 여러 가지 합성 방법들이 보고 되어 있다. Weinreb등은 1977년 Tetrahedron Letters 18권 4171쪽에 발표한 논문에 transamination 반응에 의해서 Weinreb amide를 합성 하였지만 그 후, Weinreb amide에 대한 유용성이 인식 되면서 새로운 여러 가지 합성 방법들이 발표되었다. 반응성이 떨어지는 카르복실산 유도체로부터 amide유도체를 합성하는 방법으로 Weinreb amide의 유용성이 인식되기 이전인 1971년에 Barstow등은 J. Org. Chem. 36권 1305쪽에 발표한 논문에서 트리페닐포스핀과 CBr4를 THF 용매 내에서 reflux 반응시켜 phosphonium salt를 생성시킨 후 카르복실산과 아민유도체를 반응시켜 amide유도체를 얻었다. 이 경우 2단계 반응으로 첫 단계가 비교적 격렬한 반응조건이고 부산물로서 할로포름과 triphenylphosphite가 함께 생성되는 문제점이 있다. Weinreb amide의 유용성이 인식되면서 더 효율적인 합성법을 찾는 노력이 기울여 졌는데, Einhorn등은 앞의 Barstow등이 사용한 방법을 개선하여 1990년 Synthetic Communications 20권 8호의 1105쪽에 발표한 논문에서 트리페닐포스핀을 나중에 투입하는 방법으로 phosphonium salt를 생성시켜 카르복실산과 아민유도체를 반응시켜 Weinreb amide유도체를 얻었지만 역시 부산물이 생성되고 수율도 낮았다. Konrad Sandhoff등은 1992년 Tetrahedron 48권 28호 5855쪽에 발표한 논문에서 천연물 유사체 합성과정 중, 카르복실산 유도체를 hydroxybenzotrizole과 dicyclohexylcarbodiimide 및 ethyldiisopropylamine 존재 하에 N,O-dimethylhydroxylamine와 반응시켜 Weinreb amide유도체를 얻었다. Sibi등은 1995년 Synthetic Communications 25권 8호 1255쪽에서 Mukayama등이 베타락탐 합성시 사용했던 2-chloro-1-methylpyridinium iodide를 사용하여 methylene chloride용매 하에서 카르복실산 유도체와 N,O-dimethylhydroxylamine를 7시간 정도 reflux시켜 Weinreb amide유도체를 얻었는데 이 경우는 부산물로서 pyridone이 당량 비만큼 생성되는 문제점이 있다. Kessler등은 1998년 Tetrahedron Letters 39권 253쪽에서 polyphosphoric acid anhydride와 N-methylmorpholine존재 하에서 카르복실산 유도체와 N,O-dimethylhydroxylamine을 반응시켜 Weinreb amide유도체를 합성하였다. Singh등은 1999년 Synthetic Communications 29권 8호 3215쪽에 발표한 논문에서 카르복실산을 pivaloyl chloride와 반응시켜 입체 방해효과를 줄 수 있는 무수물을 제조한 후에 N,O-dimethylhydroxylamine과 반응시킴으로써 Weinreb amide유도체를 합성하였다. Georg등은 2000년 Organic Letters 2권 25호 4091쪽에서 카르복실산 유도체를 acid fluoride로 전환한 후에 다시 N,O-dimethylhydroxylamine과 반응시켜 Weinreb amide유도체를 얻었다. Taddle등은 2001년 J. Org. Chem. 66권 2534쪽에서 2-chloro-4,6-dimethoxy-[1,3,5]triazine을 사용하여 카르복실산 유도체를 활성화시킨 중간체를 얻은 후, 이것을 N,O-dimethylhydroxylamine과 반응시켜 Weinreb amide유도체를 얻는 2단계 반응으로 목적화합물을 얻었다.Weinreb amide is a useful intermediate for synthesizing ketone derivatives without generating by-products by reacting with Grignard reagent or organolithium reagent after Weinreb et al. It has been the subject of much interest. For example, Woller et al., 1997, J. Am. Chem. Soc. In the paper published in 119 vol. 3824, Weinreb amide was used as a synthetic intermediate to approach the structure of the target compound by introducing new functional groups through acylation reactions and appropriate subsequent reactions in the presynthesis of natural materials. In a paper published in Tetrahedron Letters 40, 7889, 1999, Weinreb amide derivatives were used directly as formylation reagents. George et al., 2000, J. Am. Chem. Soc. In the paper published in Vol. 122, 11995, Weinreb amide was also used as a reagent to introduce aldehyde using the reaction selectivity of the reducing agent. Weinreb amide derivatives have been reported to synthesize various useful compounds. Weinreb et al. Synthesized Weinreb amide by transamination reaction in a paper published in Tetrahedron Letters 18, page 4171 in 1977. Since then, we have recognized a number of new synthetic methods. Barstow et al. In 1971, before the usefulness of Weinreb amide was recognized as a method of synthesizing an amide derivative from a less reactive carboxylic acid derivative. Chem. In a paper published on 36, 1305 pages, triphenylphosphine and CBr 4 were reflux reacted in THF solvent to form phosphonium salt, followed by reaction of carboxylic acid with amine derivative to obtain amide derivative. In this case, there is a problem that the first step is a relatively vigorous reaction condition in a two-step reaction, and haloform and triphenylphosphite are generated together as a by-product. Recognizing the usefulness of Weinreb amide, efforts were made to find a more efficient synthesis method. Einhorn et al. Improved the method used by Barstow et al. In a paper published on page 1105 of Synthetic Communications 20, no.8 in 1990. In the method of phosphonium salt was produced by the reaction of carboxylic acid and amine derivative to obtain Weinreb amide derivative, but also by-products were produced and yield was low. Konrad Sandhoff et al., 1992, published in Tetrahedron 48, 28, 5855, obtained Weinreb amide derivatives by reacting carboxylic acid derivatives with N, O-dimethylhydroxylamine in the presence of hydroxybenzotrizole, dicyclohexylcarbodiimide and ethyldiisopropylamine during the synthesis of natural analogues. Sibi et al. Used the 2-chloro-1-methylpyridinium iodide, which Mukayama et al. Used in the synthesis of beta-lactam in 1995, Synthetic Communications, Vol. Werereb amide derivatives were obtained by refluxing in this case. In this case, there is a problem in that pyridone is produced as an equivalent ratio as a by-product. Kessler et al. Synthesized Weinreb amide derivatives by reacting carboxylic acid derivatives with N, O-dimethylhydroxylamine in the presence of polyphosphoric acid anhydride and N-methylmorpholine in Tetrahedron Letters, vol. 39, 1998. Singh et al., 1999, published in Synthetic Communications, Vol. 29, No. 8, 3215, prepared an anhydride that reacted with carboxylic acid with pivaloyl chloride to produce steric hindrance, and then reacted with N, O-dimethylhydroxylamine to form Weinreb amide derivatives. Synthesized. Georg et al. Converted organic acid fluoride from acidic fluoride and then reacted with N, O-dimethylhydroxylamine to obtain Weinreb amide derivative in 2000. Taddle et al., 2001, J. Org. Chem. On page 66, page 2534, 2-chloro-4,6-dimethoxy- [1,3,5] triazine was used to obtain an intermediate that activated a carboxylic acid derivative, and then reacted with N, O-dimethylhydroxylamine to form a Weinreb amide derivative. The target compound was obtained by two-step reaction.
이와 같이 종래의 알려진 카르복실산유도체로 부터 직접 Weinreb amide유도체를 합성하는 방법들은 반응성이 떨어지는 카르복실기를 활성화시키기 위해 격렬한 조건에서 또 다른 중간체를 합성하여 N,O-dimethylhydroxylamine과 반응시키거나, 또는 카르복실기의 반응성을 높이기 위해 먼저 카르복실산을 활성화 시킨 중간체를 합성한 후 N,O-dimethylhydroxylamine과 반응시켜 Weinreb amide유도체를 합성하였다. 그러나 이러한 종래의 합성방법들에서는 목적하는 생성물외에 함께 생성되는 부산물과의 분리문제가 발생되며, 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 유도체를 직접 N,O-dimethylhydroxylamine과 반응시켜 부산물 생성 없이 Weinreb amide유도체를 합성할 수 있는 새로운 방법을 개발함으로써 본 발명을 완성하게 되었다. As described above, methods for synthesizing Weinreb amide derivatives directly from known carboxylic acid derivatives may be carried out by synthesizing another intermediate under violent conditions and reacting with N, O-dimethylhydroxylamine to activate the less reactive carboxyl groups, or To increase the reactivity, we first synthesized the intermediate that activated carboxylic acid and then reacted with N, O-dimethylhydroxylamine to synthesize Weinreb amide derivative. However, these conventional synthesis methods have a problem of separation from the by-products generated together with the desired product, and because of the multi-step reaction, there is a limit in industrial use such as a long manufacturing process and a low overall yield. That's how they didn't. The present inventors have made an effort to establish a desirable method while paying close attention to the above problems, and as a result, the carboxylic acid derivative is directly converted to N, O-dimethylhydroxylamine and carboxylic acid derivatives in a short time under mild conditions near normal pressure and room temperature. The present invention was completed by developing a new method for synthesizing Weinreb amide derivatives without reacting byproducts.
본 발명은 의,농약등의 정밀화학물질의 중간체 또는 천연물질의 전합성 과정에서 중간체로 유용한 일반식 ( I )으로 표시되는 Weinreb amide유도체의 새로운 제조방법으로, 일반식 (II)의 카르복실산(carboxylic acid)유도체를 diphosgene 과 triphenylphosphine 존재 하에서 N,O-dimethylhydroxylamine과 반응시키는 방법으로 불필요한 다른 카르복실산의 활성화 단계를 거치지 않고 카르복실산 유도체로부터 Weinreb amide유도체를 직접 제조하는 새로운 방법이다. The present invention is a novel process for the preparation of Weinreb amide derivatives represented by general formula (I) useful as intermediates in the preparation of intermediates of fine chemicals, such as agrochemicals or in the presynthesis of natural substances, and the carboxylic acid of general formula (II) The reaction of (carboxylic acid) derivatives with N, O-dimethylhydroxylamine in the presence of diphosgene and triphenylphosphine is a new method for the production of Weinreb amide derivatives directly from carboxylic acid derivatives without the need for unnecessary activation of other carboxylic acids.
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. N,O-dimethylhydroxylamine은 상업화 되어 있는 HCl salt 형태로 사용하며, 일반식 ( II )의 카르복실산 유도체 대비 1.0 내지 2.0 몰배, 바람직하게는 1.0 내지 1.2몰배를 사용한다. N,O-dimethylhydroxyl amine HCl salt 형태를 중화시키기 위해서, 그리고 메카니즘상 발생되는 HCl을 중화하기 위해 트리에틸아민과 같은 3차 아민을 사용하며, 반응온도는 0 내지 45 oC, 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. N, O-dimethylhydroxylamine is used in the form of a commercially available HCl salt, 1.0 to 2.0 mole times, preferably 1.0 to 1.2 mole times compared to the carboxylic acid derivative of the general formula (II). Tertiary amines such as triethylamine are used to neutralize the form of N, O-dimethylhydroxyl amine HCl salt and to neutralize the mechanism of HCl generated, with a reaction temperature of 0 to 45 ° C., preferably 0 to Reaction at 25 o 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 형성한 후에 일반식 ( II )의 카르복실산 유도체와 triethylamine을 투입하고 교반하면 카르복실기의 반응성이 증가된 acid chloride형태의 중간체가 형성되며, 여기에 HCl salt 형태의N,O-dimethylhydroxylamine 을 투입하고 실온으로 자연 승온하면서 교반해주면 결합전자들의 이동 및 재구성을 거쳐 목적하는 일반식 ( I )의 Weinreb amide유도체를 얻을 수 있다.Diphosgene and triphenylphosphine were added to dichloromethane at 0-5 ° C., stirred for 5 minutes to form PPh 3 Cl 2 , and then the carboxylic acid derivative and triethylamine of formula (II) were added and stirred to increase the reactivity of the carboxyl group. An acid chloride-type intermediate is formed, and HCl salt-type N, O-dimethylhydroxylamine is added thereto, and the mixture is stirred while naturally warming to room temperature. Can be obtained.
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 809 mg(8.0 mmole)을 투입하고 20분간 교반한 후, N,O-dimethylhydroxylamine hydrochloride 195 mg(2.0 mmole)을 투입한 후 ice-bath를 제거하여 실온으로 자연 승온시키면서 교반, 반응시키면 약 1시간 후 TLC로 benzoic acid가 완벽하게 Weinreb amide유도체로 전환된 것을 확인할 수 있다. 고체로 생성된 트리에틸아민 하이드로클로라이드를 short path 실리카겔 filter로 여과하여 제거하고 여액의 용매를 감압, 증류 제거하여 목적 화합물인 Weinreb amide를 310 mg 얻었다(수율 94.0%).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. Benzoic acid 244 mg (2.0 mmole) and triethylamine 809 mg (8.0 mmole) were added and stirred for 20 minutes. N, O-dimethylhydroxylamine hydrochloride 195 mg (2.0 mmole) was added and the ice-bath was removed. After stirring and raising the temperature while reacting, the benzoic acid was completely converted into Weinreb amide derivative by TLC after about 1 hour. Triethylamine hydrochloride produced 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 310 mg of Weinreb amide as a target compound (yield 94.0%).
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. 2,4-dinitrobenzoic acid 426 mg(2.0 mmole)과 triethylamine 809 mg(8.0 mmole)을 투입하고 5분간 교반한 후, N,O-dimethylhydroxylamine hydrochloride 195 mg(2.0 mmole)을 투입한 후 ice-bath를 제거하여 실온으로 자연 승온시키면서 교반, 반응시키면 약 1시간 후 TLC로 acid가 완벽하게 Weinreb amide유도체로 전환된 것을 확인할 수 있다. 고체로 생성된 트리에틸아민 하이드로클로라이드를 short path 실리카겔 filter로 여과하여 제거하고 여액의 용매를 감압, 증류 제거하여 목적 화합물인 Weinreb amide를 485 mg 얻었다(수율 95.0%).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. 426 mg (2.0 mmole) of 2,4-dinitrobenzoic acid and 809 mg (8.0 mmole) of triethylamine were added thereto, stirred for 5 minutes, 195 mg (2.0 mmole) of N, O-dimethylhydroxylamine hydrochloride was added and the ice-bath was removed. After stirring and reacting with the natural temperature at room temperature, it was confirmed that the acid was completely converted to Weinreb amide derivative by TLC after about 1 hour. 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 485 mg of Weinreb amide as a target compound (yield 95.0%).
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. p-toluic acid 272 mg(2.0 mmole)과 triethylamine 809 mg(8.0 mmole)을 투입하고 5분간 교반한 후, N,O-dimethylhydroxylamine hydrochloride 195 mg(2.0 mmole)을 투입한 후 ice-bath를 제거하여 실온으로 자연 승온시키면서 교반, 반응시키면 약 1시간 후 TLC로 acid가 완벽하게 Weinreb amide유도체로 전환된 것을 확인할 수 있다. 고체로 생성된 트리에틸아민 하이드로클로라이드를 short path 실리카겔 filter로 여과하여 제거하고 여액의 용매를 감압, 증류 제거하여 목적 화합물인 Weinreb amide를 345 mg 얻었다(수율 96.2%).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 p-toluic acid and 809 mg (8.0 mmole) of triethylamine were added thereto and stirred for 5 minutes. After adding 195 mg (2.0 mmole) of N, O-dimethylhydroxylamine hydrochloride, the ice-bath was removed. After stirring and reacting with a natural temperature increase, the acid was completely converted to Weinreb amide derivative by TLC after about 1 hour. Triethylamine hydrochloride produced as a solid was removed by filtration through a short path silica gel filter, and the solvent of the filtrate was distilled off under reduced pressure to obtain 345 mg of the target compound, Weinreb amide (yield 96.2%).
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. 4-(dimethylamino) benzoic acid 330 mg(2.0 mmole)과 triethylamine 809 mg(8.0 mmole)을 투입하고 5분간 교반한 후, N,O-dimethylhydroxylamine hydrochloride 195 mg(2.0 mmole)을 투입한 후 ice-bath를 제거하여 실온으로 자연 승온시키면서 교반, 반응시키면 약 1시간 후 TLC로 acid가 완벽하게 Weinreb amide유도체로 전환된 것을 확인할 수 있다. 고체로 생성된 트리에틸아민 하이드로클로라이드를 short path 실리카겔 filter로 여과하여 제거하고 여액의 용매를 감압, 증류 제거하여 목적 화합물인 Weinreb amide를 400 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. 330 mg (2.0 mmole) of 4- (dimethylamino) benzoic acid and 809 mg (8.0 mmole) of triethylamine were added thereto, stirred for 5 minutes, and then 195 mg (2.0 mmole) of N, O-dimethylhydroxylamine hydrochloride was added. After removing, stirring and reacting with natural warming to room temperature, it was confirmed that the acid was completely converted to Weinreb amide derivative by TLC after about 1 hour. Triethylamine hydrochloride produced 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 400 mg of Weinreb amide as a target compound (yield 95.9%).
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. nicotinic acid 246 mg(2.0 mmole)과 triethylamine 809 mg(8.0 mmole)을 투입하고 5분간 교반한 후, N,O-dimethylhydroxylamine hydrochloride 195 mg(2.0 mmole)을 투입한 후 ice-bath를 제거하여 실온으로 자연 승온시키면서 교반, 반응시키면 약 1시간 후 TLC로acid가 완벽하게 Weinreb amide유도체로 전환된 것을 확인할 수 있다. 고체로 생성된 트리에틸아민 하이드로클로라이드를 short path 실리카겔 filter로 여과하여 제거하고 여액의 용매를 감압, 증류 제거하여 목적 화합물인 Weinreb amide를 305 mg 얻었다(수율 91.9%).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 809 mg (8.0 mmole) of triethylamine were added and stirred for 5 minutes. Then, 195 mg (2.0 mmole) of N, O-dimethylhydroxylamine hydrochloride was added and the ice-bath was removed. When the reaction was stirred while raising the temperature, the acid was completely converted to Weinreb amide derivative by TLC after about 1 hour. 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 305 mg of Weinreb amide as a target compound (yield 91.9%).
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. 2-thiopheneacetic acid 284 mg(2.0 mmole)과 triethylamine 809 mg(8.0 mmole)을 투입하고 5분간 교반한 후, N,O-dimethylhydroxylamine hydrochloride 195 mg(2.0 mmole)을 투입한 후 ice-bath를 제거하여 실온으로 자연 승온시키면서 교반, 반응시키면 약 1시간 후 TLC로 acid가 완벽하게 Weinreb amide유도체로 전환된 것을 확인할 수 있다. 고체로 생성된 트리에틸아민 하이드로클로라이드를 short path 실리카겔 filter로 여과하여 제거하고 여액의 용매를 감압, 증류 제거하여 목적 화합물인 Weinreb amide를 335 mg 얻었다(수율 90.5%).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. 284 mg (2.0 mmole) of 2-thiopheneacetic acid and 809 mg (8.0 mmole) of triethylamine were added thereto, stirred for 5 minutes, 195 mg (2.0 mmole) of N, O-dimethylhydroxylamine hydrochloride was added, and the ice-bath was removed. After stirring and reacting with a natural temperature increase, the acid was completely converted to Weinreb amide derivative by TLC after about 1 hour. 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 335 mg of Weinreb amide as a target compound (yield 90.5%).
카르복실산유도체로부터 직접 Weinreb amide유도체를 합성하는 종래의 알려진 방법들은 반응성이 떨어지는 카르복실기를 활성화시키기 위해 격렬한 조건에서 또 다른 중간체를 합성하여 N,O-dimethylhydroxylamine과 반응시키거나, 또는 카르복실기의 반응성을 높이기 위해 먼저 카르복실산과 결합된 중간체를 합성한 후, 이 중간체를 N,O-dimethylhydroxylamine과 반응시켜 Weinreb amide유도체를 합성하였다. 그러나 이러한 종래의 합성방법들에서는 목적하는 생성물과 함께 생성되는 부산물과의 분리문제가 발생되며, 다단계 반응을 거쳐야 하기 때문에 제조공정 시간이 길어지고 전체수율도 낮아지는 등 산업적인 이용에는 한계가 있는 바람직하지 못한 방법들이었다. 이에 비해 본 발명은 간결한 1단계 반응처럼 진행 시킬 수 있는 방법으로서 상압, 실온 근처의 온화한 조건에서 짧은 시간 내에 카르복실산 유도체를 직접 N,O-dimethylhydroxylamine과 반응시켜 부산물 생성 없이 Weinreb amide유도체를 합성할 수 있는 새로운 방법이다. 따라서 전체 합성공정이 간단하고 짧은 시간에 반응을 완결 시킬 수 있다는 장점이 있다. 뿐만 아니라, 이 새로운 Weinreb amide 유도체의 합성 방법은 부산물도 거의 생성되지 않고 반응의 신뢰성 및 재현성이 매우 우수하여 산업화시 이전의 방법들에 비해 환경문제를 일으키지 않으면서 목적화합물의 분리, 정제 비용도 크게 절감하여 경제성 제고에 크게 기여할 것으로 판단된다. Conventional known methods for synthesizing Weinreb amide derivatives directly from carboxylic acid derivatives can be achieved by synthesizing another intermediate under intense conditions to react with N, O-dimethylhydroxylamine or carboxyl group in order to activate a less reactive carboxyl group. In order to synthesize the intermediate combined with carboxylic acid first, the intermediate was reacted with N, O-dimethylhydroxylamine to synthesize Weinreb amide derivative. However, these conventional synthesis methods have a problem of separation from the by-products generated with the desired product, and because of the multi-step reaction, the production time is long and the overall yield is low. It was a way they did not. In contrast, the present invention can proceed as a simple one-step reaction to synthesize Weinreb amide derivatives without reacting by-products by directly reacting carboxylic acid derivatives with N, O-dimethylhydroxylamine in a short time under mild conditions near normal pressure and room temperature. It's a new way to do it. Therefore, there is an advantage that the whole synthesis process is simple and can complete the reaction in a short time. In addition, the synthesis method of this new Weinreb amide derivative generates little by-products and the reaction reliability and reproducibility are very good. Therefore, the cost of separation and purification of the target compound is greatly increased without causing environmental problems compared to the previous methods during industrialization. It is expected to contribute greatly to economic efficiency by reducing the cost.
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