KR820001236B1 - Process for preparing 5-acyl-1-hydrocarbylpyrrole-2-acetic acid - Google Patents
Process for preparing 5-acyl-1-hydrocarbylpyrrole-2-acetic acid Download PDFInfo
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/337—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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/323—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atoms
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Abstract
Description
본 발명은 5-시아노-1-하이드로카빌피롤-2-아세틱산을 출발물질로 하여 5-아실 -1-하이드로카빌피롤-2-아세틱산을 제조하는 방법에 관한 것이다.The present invention relates to a method for producing 5-acyl-1-hydrocarbylpyrrole-2-acetic acid using 5-cyano-1-hydrocarbylpyrrole-2-acetic acid as a starting material.
5-아실-1-하이드로카빌피롤-2-아세틱산은 유용한 약물학적 특성을 가지고 있다고 알려져 있다. 그예로 1-메틸-5-P-톨루오일피롤-2-아세틱산은 현저한 항염증효과를 가지고 있다.5-acyl-1-hydrocarbylpyrrole-2-acetic acid is known to have useful pharmacological properties. For example, 1-methyl-5-P-toluoylpyrrole-2-acetic acid has a significant anti-inflammatory effect.
〔J. Pharmacologgy and Experimental Therapeutics, 185, 127(1973)〕[J. Pharmacologgy and Experimental Therapeutics, 185, 127 (1973)]
보편적으로 1-메틸-5-아로일피롤-2-아세틱산과 같은 5-아실피롤-2-아세틱산은 상응하는 피롤-2-아세틱산, 피롤-2-아세틱산에스테르, 혹은 피롤-2-아세토니트릴을 아실화함으로써 만들었다. 이러한 아실화 반응에 사용되는 출발 피롤-2-아세틱산 유도체를 제조하는 알려진 방법은 아래와 같다.Typically 5-acylpyrrole-2-acetic acid, such as 1-methyl-5-aroylpyrrole-2-acetic acid, corresponds to the corresponding pyrrole-2-acetic acid, pyrrole-2-acetic acid ester, or pyrrole-2- Made by acylating acetonitrile. Known methods for preparing the starting pyrrole-2-acetic acid derivatives used in this acylation reaction are as follows.
(1) 1-메틸피롤과 촉매로서 구리분말 존재하에서 디아조아세테이트를 반응시켜 1-메틸피롤-2-아세틱산 에스테르를 얻는 방법. 〔J. Org. Chem., 14,664(1946)〕(1) A method of obtaining 1-methylpyrrole-2-acetic acid ester by reacting diazoacetate with 1-methylpyrrole in the presence of copper powder as a catalyst. [J. Org. Chem., 14,664 (1946)]
(2) 1-메틸피롤과 옥살일클로라이드의 프리델-크로프트반응에 의한 생성물과 알콜을 합성시켜 (1-메틸피롤일)글리옥살릭산 에스테르로 하고 하이드라진과 반응시킨 후 수산화칼륨으로 처리하여 얻은 생성물로부터 1-메틸피롤-2-아세틱산을 얻는 방법. (볼프-키슈너 반응)[Liebigs Ann. Chem., 721, 105(1969)].(2) From the product obtained by the synthesis of 1-methylpyrrole and oxalyl chloride by the Friedel-Croft reaction to alcohol (1-methylpyrroyl) glyoxalic acid ester, reaction with hydrazine and treatment with potassium hydroxide Method for obtaining 1-methylpyrrole-2-acetic acid. (Wolf-Kishner Reaction) [Liebigs Ann. Chem., 721, 105 (1969).
(3) 소위 만니히염기(만니히반응)에 의해 1-메틸피롤과 디메틸아민, 포름알데히드로부터 1-메틸피롤-2-아세토니트릴을 만들고 이를 가수분해하여 1-메틸피롤-2-아세틱산을 만든 후 메틸아이오다이드에 의해 메티오 아이오다이드로 변화시키고 시안화나트륨과 반응시키는 법. [J. Amer. Chem. Soc., 73, 4921 (1951)].(3) 1-methylpyrrole-2-acetonitrile was prepared from 1-methylpyrrole, dimethylamine and formaldehyde by the so-called Mannich base (Mannich reaction) and hydrolyzed to obtain 1-methylpyrrole-2-acetic acid. After making, change to methio iodide by methyl iodide and react with sodium cyanide. [J. Amer. Chem. Soc., 73, 4921 (1951).
이러한 방법들은 수득율이 낮고 반응출발물질이나 시약으로서 사용에 산업상 이용할 만한 양을 얻는데 어렵다는 결점들이 있다. 바람직한 피롤-2-아세틱산유도체의 아실화 방법은 아래와 같다.These methods have the disadvantages of low yield and difficulty in obtaining industrially available amounts for use as reaction starting materials or reagents. Preferred acylation method of the pyrrole-2-acetic acid derivative is as follows.
(1) 피롤-D-아세틱산유도체를 알킬 알미늄클로라이드 존재하에서 아로일클로라이드와 반응시키는 법.〔Ger. Offen 2, 524, 299〕(1) A method of reacting a pyrrole-D-acetic acid derivative with an aroyl chloride in the presence of an alkyl aluminum chloride. [Ger. Offen 2, 524, 299]
(2) 아릴카복실산과 무수트리플루오로아세틱산으로 부터 얻어진 무수혼합산을 이용하여 아실화하는 법. 일본공개 46-418(2) Acylation using anhydrous mixed acid obtained from arylcarboxylic acid and trifluoroacetic anhydride. Japanese Publication 46-418
(3) N, N-디메칠 아로일 아마이드와 포스포릴클로라이드로 부터 얻은 반응 생성물을 이용하여 아실화하는 법. 일본공개 46-418(3) Acylation using a reaction product obtained from N, N-dimethyl aroyl amide and phosphoryl chloride. Japanese Publication 46-418
(4) 무수 아릴카복실산과 메탄 설폰산과 그 유사한 것들로부터 얻어진 무수 혼합체를 이용하여 아실화하는 법. 일본공개 50-126660(4) Acylation using anhydrous mixtures obtained from arylcarboxylic anhydride, methane sulfonic acid and the like. Japan Publication 50-126660
(5) 피롤-2-아세틱산 유도체를 포스겐과 반응시켜 5-클로로카브닐 유도체를 만들고 금속아릴화합물과 반응시키는 방법. 〔U S 3,846,447〕.(5) A method of reacting a pyrrole-2-acetic acid derivative with phosgene to form a 5-chlorocarbyl derivative and reacting with a metal aryl compound. U S 3,846,447.
(6) 아로일클로라이드를 적당한 용매를 이용하여 1-알킬피롤-2-아세틱산유도체와 무촉매하에 아로일화 시키는 방법. 〔U. S〕3,998,844〕.(6) Aroyl chloride is aroylated in a catalyst-free manner with 1-alkylpyrrole-2-acetic acid derivative using a suitable solvent. [U. S] 3,998,844].
(7) 적당한 피롤-2- 아세틱산유도체를 연화알루미늄 같은 루이스산 존재하에서 여러 가지 아실화제로 아실화 하는 법. 〔U. S 3,752,826 : 3,755,307 : 3,803,169 : 3,803,171〕.(7) Acylation of suitable pyrrole-2-acetic acid derivatives with various acylating agents in the presence of Lewis acids such as aluminum softened. [U. S 3,752,826: 3,755,307: 3,803,169: 3,803,171].
이러한 방법들은 수득률이 낮거나 4-위치에 아실기를 가지는 부산물인 이성체를 분리해야 하는 결점이 있다.These methods have the drawback of separating isomers which are low yields or by-products having acyl groups in the 4-position.
본 발명자들은 산업상 규모로 쉽게 얻을 수 있는 출발물질로서 5-시아노-1-하이드로카빌피롤-2-아세틱산, 특히 5-시아노-1-메틸피롤-2-아세틱산을 이용하여 높은 수율로 5-아실 -1-하이드로카빌피롤-2-아세틱산을 제조하는 방법을 발명했다. 이 반응에서 5-시아노-1-하이드로카빌피롤-2-아세틱산은 그리그나드 하이드로카빌피롤과 반응하고, 반응생성물을 가수분해 시킨다.The inventors have found high yields using 5-cyano-1-hydrocarbylpyrrole-2-acetic acid, in particular 5-cyano-1-methylpyrrole-2-acetic acid, as readily available starting materials on an industrial scale. Invented a method for preparing 5-acyl-1-hydrocarbylpyrrole-2-acetic acid. In this reaction, 5-cyano-1-hydrocarbylpyrrole-2-acetic acid reacts with Grignard hydrocarbyl pyrrole and hydrolyzes the reaction product.
바람직한 출발물질인 5-시아노-1-메틸피롤-2-아세틱산은 1-메틸피롤과 트리할로 아세트 알데히드로부터 생성되는 1-메틸-2-(2',2',2'-트리할로-1'-하이드록시에틸)피롤과, 염기성 상태하에서 시안화제와 반응시킴으로 얻어진다.Preferred starting material, 5-cyano-1-methylpyrrole-2-acetic acid, is 1-methyl-2- (2 ', 2', 2'-trihal) produced from 1-methylpyrrole and trihalo acetaldehyde. It is obtained by reacting rho-1'-hydroxyethyl) pyrrole with a cyanating agent in a basic state.
이 반응식에서 1-에틸피롤, 1-프로필피롤, 1-아밀피롤, 1-페닐피롤, 1-사이클로헥실피롤, 1-벤질피롤과 1,3-디메틸피롤과 같은 1-하이드로카빌피롤의 다른 치환체들은 본 발명에서 다른 5-시아노-1-하이드로 카빌피롤-2-아세틱산을 만든다.In this scheme, 1-hydrocarbyl pyrrole such as 1-ethylpyrrole, 1-propylpyrrole, 1-amylpyrrole, 1-phenylpyrrole, 1-cyclohexylpyrrole, 1-benzylpyrrole and 1,3-dimethylpyrrole Other substituents make another 5-cyano-1-hydro carbyl pyrrole-2-acetic acid.
본 발명에서 다른 출발물질인 그리그 나드 화합물은 일반 그리그나드 합성법에 의해서 상응하는 유기할라이 부터 쉽게 만들어 진다. 그리그나드 화합물의 광범위한 제법은 문헌상에 잘 나타나 있는데 그 예로는 다음과 같다. Kharasch and Reinmuth, Grignard Reaction of Nonmetallic Substnces, Prentice Hall, New York, 1954:ana Metal-Organic Compounds, (Advances in Chemistry Series의 23권). 미국화학회, Washington, D. C., 1959, 73-81 pape.The Grignard compound, which is another starting material in the present invention, is easily prepared from the corresponding organic halide by general Grignard synthesis. Extensive preparations of the Grignard compound are well documented in the literature, for example: Kharasch and Reinmuth, Grignard Reaction of Nonmetallic Substnces, Prentice Hall, New York, 1954: ana Metal-Organic Compounds, (vol. 23 of Advances in Chemistry Series). American Chemical Society, Washington, D. C., 1959, 73-81 pape.
[아살화 단계][Assassination Stage]
본 발명의 아실화 단계를 수행하는데 용매를 사용하는것이 좋으며 용매의 예로는 에테르, 다이옥산, THF, 디메톡시에탄 같은 것이나, 탄화수소를 함유한 유기 4급 아민이 있다. 이러한 용매에 그리그다드 시약이 더해지고 5-시아노-1-하이드로카빌피롤-2-아세틱산이 가해진다. 반응 온도는 실온이나 사용되는 용매의 환류온도가 좋다. 본 발명에서 그리그나드 시약은 2몰 당량이상 가해지는 것이 좋다. 그리그나드 시약의 1몰 당량은 카복실산염을 형성하는데 소비되며 평형은 아실기의 도입에 이용된다.It is preferable to use a solvent to carry out the acylation step of the present invention. Examples of the solvent include organic quaternary amines containing hydrocarbons such as ether, dioxane, THF, dimethoxyethane. To this solvent Grigdad reagent is added and 5-cyano-1-hydrocarbylpyrrole-2-acetic acid is added. The reaction temperature is good at room temperature or the reflux temperature of the solvent used. In the present invention, the Grignard reagent is preferably added at 2 molar equivalents. One molar equivalent of Grignard reagent is consumed to form carboxylates and the equilibrium is used to introduce acyl groups.
이 단계에서 반응혼합물이 만들어지고 가수분해된다. 가수분해는 염산, 황산, 인상, 옥살린상, 염화암모늄 같은 산물지은 직접 가함으로 이루어 진다. 반응 메카니즘의 관점으로부터 반응은 아래와 같은 중간체로서 캐티민 염의 형성을 지나 이루어 진다.At this stage the reaction mixture is made and hydrolyzed. Hydrolysis is achieved by direct application of products such as hydrochloric acid, sulfuric acid, impressions, oxalin phase and ammonium chloride. From the point of view of the reaction mechanism, the reaction takes place after the formation of the catamine salt as an intermediate as follows.
(R과 R'는 알킬, 아릴과 같은 유기기를 나타내고 X는 할로겐 원자이다.)(R and R 'represent organic groups such as alkyl and aryl, and X is a halogen atom.)
본 발명에서 출발물질인 구조식(I)화합물은 아래와 같이 만들어 진다.Structural formula (I) compound as a starting material in the present invention is made as follows.
(X는 할로겐원자를 나타내고 R은 가능하면 저급 알킬기인 탄화수소이고 가장 바람직한 것은 메틸기이다.)(X represents a halogen atom and R is a hydrocarbon, preferably a lower alkyl group, most preferably a methyl group.)
환의 3-과/혹은 4-위치에 무해한 치환제(알킬, 등)가 존재할 수 있다.Harmless substituents (alkyl, etc.) may be present at the 3- and / or 4-positions of the ring.
[1차 반응-부가물형성][First Reaction-Adduct Formation]
상기에서 1단계 반응은, 피롤 반응체가 트리할로 아세트알데히드와 반응하여 부가물(II)를 생성하는 것이 골자이다.In the one-step reaction, it is preferred that the pyrrole reactant reacts with trihalo acetaldehyde to generate adduct (II).
이 반응에서 1-메틸피롤을 이용하여 얻어지는 1-메틸-2-(2',2',2'-트리할로-1'-하이드록시에틸)피롤(구조식(II) : R=메틸)은 알려진 화합물이며 그의 합성법은 1-메틸피롤이 루이스산인 염화아연의 몰당량이 존재하에서 새로 증류된 클로랄과 반응한다는 것은 보고되어 있다. 〔R.C. Blinn et al., J. Amer. Chem. Soc. 76, 37(1954)〕. 그렇지만 이 반응을 산업상 이용하는 것은 수율이 단지 26.5%밖에 되지 않으므로 어렵다. 이 반응을 더욱 연구하여 본 발명자는 반응체를 -10℃와 실온사이의 온도에서 처리함으로써 루이스산이나 그밖의 촉매를 가하지 않고 구조식(II)의 화합물을 거의 당량적으로 얻을 수 있는 방법을 발견했다. 이 반응의 비율은, 디에틸에테르, 다이옥산, THF와 같은 에테르류, 또 벤젠, 톨루엔, 헥산과 같은 탄화수소등의 반응에 직접적으로 작용하지 않는 용매의 존재에 의해 어느정도 유도되는데, 주로 사용된 클로랄의 본질(또는 순도)에 의해 결정된다는 것이 알려져 있다. 새로 개봉한 멸의 클로랄은 실온에서 N-메틸피롤과 반응하지 않으며 시간이 흐른뒤(어떤 때는 수일간)부가물을 형성한다. 그에 비해 오래된 병의 클로랄은 실온에서 즉시 반응한다. 클로랄이 분해됨으로 인해서 쉽게 생성되는 트리클로로 아세틱산이 이 반응에서 촉매역할을 한다는 가정하에서 본 발명자들은, 트리클로로 아세틱산, 아세틱산, P-톨루엔설포닉산 같은 유기산을 이 반응의 촉진제로서 반응 혼합물에 가하는 것을 발견했다. 이 세가지 산 중에서 P-톨루엔설포닉산이 다른것보다 더욱 효과적인 것으로 나타났다. 유기산이나, 양 이온교환수지(예, 엠버라이스트)의 형태로 가한 푸로펜상의 존재로 반응을 촉진시킴에 의해 부가물은 쉽게 형성되고 거의 당량비로 형성됐다.In this reaction, 1-methyl-2- (2 ', 2', 2'-trihalo-1'-hydroxyethyl) pyrrole obtained using 1-methylpyrrole is represented by Structural Formula (II): R = methyl) It is a known compound and its synthesis has reported that 1-methylpyrrole reacts with freshly distilled chloral in the presence of a molar equivalent of zinc chloride, Lewis acid. [R.C. Blinn et al., J. Amer. Chem. Soc. 76, 37 (1954). However, industrial use of this reaction is difficult because the yield is only 26.5%. By further studying this reaction, the inventors have found a way to obtain a compound of formula (II) almost equivalently without adding Lewis acid or other catalysts by treating the reactants at temperatures between -10 ° C and room temperature. . The proportion of this reaction is induced to some extent by the presence of a solvent that does not directly affect the reactions of diethyl ether, dioxane, ethers such as THF, and hydrocarbons such as benzene, toluene, hexane, etc. It is known that it is determined by the nature (or purity) of. Freshly opened chloral do not react with N-methylpyrrole at room temperature and form adducts over time (sometimes several days). In contrast, old bottles of chloral react immediately at room temperature. Assuming that trichloro acetic acid, which is readily produced due to the degradation of chloral, catalyzes the reaction, the present inventors have used organic acids such as trichloro acetic acid, acetic acid and P-toluenesulphonic acid as a reaction mixture for the reaction. Found to add to. Of these three acids, P-toluenesulphonic acid was found to be more effective than the others. By promoting the reaction in the presence of an organic acid or furophene phase added in the form of a positive ion exchange resin (e.g., amberlife), the adduct was easily formed and formed in approximately equivalence ratio.
[2단계 반응-시안화/초기 가수분해][2-Step Reaction-Cyanation / Initial Hydrolysis]
이 반응 구조식(II)의 화합물이 기초상태하에서 시안화제와 반응하는 것이 골자이다. 시안화제의 예로서는 시안화칼륨, 시안화나트륨, 시안화동 같은 종류와 아세톤시아노히드린과 같은 종류가 있다. 기초상태는 그것이 염기인 경우 대량의 시안화제를 사용함으로서 얻어질 수 있다. 더욱 바람직한 것은 탄산나트륨, 탄산칼륨 같은 알카리금속염이나 소디움메톡사이드, 소디움에톡사이드, 포타슘메톡사이드 같은 알카기금속 알콜사이드 존재하에서 시안화가 이루어지는 것이다(이러한 경우 물의 존재는 필수적이다)수산화나트륨이나 수산화칼륨을 사용하는 것이 바람직하다. 이 반응을 수행하는데 있어 용매를 사용하는 것이 바람직하며 용매의 예로는 메탄올, 에탄올과 같은 알콜, 에테르 다이옥산, THF 같은 에테르, 디메틸포르아마이드, 디메틸설폭사이드, 설포란 같은 극성용매 그리고 이상의 용매와 물의 혼합등이다.It is a gist of the compound of this reaction structure (II) to react with a cyanating agent under a basic state. Examples of cyanide include potassium cyanide, sodium cyanide, copper cyanide, and acetone cyanohydrin. The basic state can be obtained by using a large amount of cyanating agent if it is a base. More preferred is cyanation in the presence of alkali metal salts such as sodium carbonate, potassium carbonate or alkali metal alcohol side such as sodium methoxide, sodium ethoxide, potassium methoxide (in which case the presence of water is essential). It is preferable to use. It is preferable to use a solvent in carrying out the reaction. Examples of the solvent include methanol, alcohols such as ethanol, ether dioxane, ethers such as THF, polar solvents such as dimethylformamide, dimethylsulfoxide and sulfolane and a mixture of the above solvents and water. And so on.
그래서 반응 용매로서 메탄올과 물과의 혼합이 가장 좋은 결과가 얻어졌다. 반응은 실온근처에서 이루어지며, 필요하면 가열될 수 있다.Thus, the best result was obtained by mixing methanol and water as the reaction solvent. The reaction takes place near room temperature and can be heated if necessary.
위에서 언급한 조건과 알카리 추출과 산성화등의 방법에 의해 산성부분을 분리함을 원하는 5-시아노-1-하이드로카빌피롤-2-아세틱산을 선택적으로 얻을 수 있다.The 5-cyano-1-hydrocarbylpyrrole-2-acetic acid which is desired to separate the acidic portion by the above-mentioned conditions and alkali extraction and acidification can be selectively obtained.
본 발명을 아래의 실시예에 의해서 자세히 설명한다.The invention is illustrated in detail by the following examples.
[실시예 1] 부가물형성-촉매를 가하지 않음Example 1 Addition Formation—No Catalyst Added
벤젠(10ml)에 용해된 N-메틸피롤(810mg, 10mmol)용액을 빙냉상에서 40분간 처리된 벤젠(5ml)에 용해된 클로랄(1.47g, 10mmol)을 방울씩 가한다. 실온에서 1시간동안 혼합물을 교반한 후 물을 가하고 에테르로 혼합물을 추출한다.N-methylpyrrole (810 mg, 10 mmol) solution dissolved in benzene (10 ml) was added dropwise to chloral (1.47 g, 10 mmol) dissolved in benzene (5 ml) treated for 40 minutes on an ice-cold phase. After stirring the mixture at room temperature for 1 hour, water is added and the mixture is extracted with ether.
추출물을 소디움설페이트상에서 건조시킨 후 농축시켜 기름상태의 1-메틸-2-(2',2',2'-트리클로로-1'-하이드록시에틸)피롤(2.04g)을 얻는다.The extract is dried over sodium sulfate and then concentrated to give oily 1-methyl-2- (2 ', 2', 2'-trichloro-1'-hydroxyethyl) pyrrole (2.04 g).
수율 : 90%Yield: 90%
NMR(CCl4):83.61(3H, s), 5.03(1H,S), 5.95(1H,m), 6.32(1Hm), 6.47(1H,m).NMR (CCl 4 ): 83.61 (3H, s), 5.03 (1H, S), 5.95 (1H, m), 6.32 (1Hm), 6.47 (1H, m).
[실시예 2] 부가물형성-산촉매를 가함Example 2 Addition Formation—Adding Acid Catalyst
에테르(50ml)에 녹인 N-메틸피롤(8.10mg, 0.1mmol)용액 에테르(50ml)에 녹인 클로랄(16.21g, 0.1mol)용액을 가한다. 여기에 P-톨루엔설포닉산(200mg)과 하이드로퀴논(5mg)을 가한다. 그 다음 혼합체를 15시간동안 환류시킨다.N-methylpyrrole (8.10 mg, 0.1 mmol) solution in ether (50 ml) Chloral (16.21 g, 0.1 mol) solution in ether (50 ml) is added. To this was added P-toluenesulphonic acid (200 mg) and hydroquinone (5 mg). The mixture is then refluxed for 15 hours.
트리에틸아민(5ml)을 가한후 5분 동안 교반한다.Triethylamine (5 ml) is added and stirred for 5 minutes.
소금물(100ml)을 가한후 유기층을 분리한다.After adding brine (100ml), the organic layer is separated.
황산 마그네슘상에서 건조시킨후, 유기용액을 활성탄층을 통과시켜 여과하고, 통축시켜 연갈색결정의 1-메틸-2-(2',2',2'-트리클로로-1'-하이드록시에틸)-피롤 부가물을 얻는다.After drying over magnesium sulfate, the organic solution was filtered through an activated carbon layer and condensed to give light brown crystals 1-methyl-2- (2 ', 2', 2'-trichloro-1'-hydroxyethyl)- Obtain the pyrrole adduct.
[실시예 3] 부가물형성과 시안화/염기성가수분해Example 3 Adduct Formation and Cyanide / Base Hydrolysis
N-메틸피롤(2.43g, 30.0mmol)과 클로랄(4.50g, 30.5mmol)이 실온에서 4시간동안 다이옥산(10ml)중에서 반응하여 상기 부가물이 된다. 이 용액을 메탄올(100ml)중에 용해된 시안화칼륨(1.90g, 47.5mmol)용액에 방울씩 가한다. 탄산칼륨(8g.58mmol)을 가하고 실온에서 5일간 교반한다. 용매의 대부분이 제거된 후 물을 가하고 혼합물을 메틸렌 클로라이드로 세척한다.N-methylpyrrole (2.43 g, 30.0 mmol) and chloral (4.50 g, 30.5 mmol) react in dioxane (10 ml) at room temperature for 4 hours to form the adduct. This solution is added dropwise to a solution of potassium cyanide (1.90 g, 47.5 mmol) dissolved in methanol (100 ml). Potassium carbonate (8 g. 58 mmol) is added and stirred at room temperature for 5 days. After most of the solvent is removed, water is added and the mixture is washed with methylene chloride.
메틸렌클로라이드층을 건조시키고 농축시켜 출발부가물(7.2mmol)과 1-메틸피롤-2-알데히드(2.6mmol)을 얻는다.The methylene chloride layer is dried and concentrated to give starting adduct (7.2 mmol) and 1-methylpyrrole-2-aldehyde (2.6 mmol).
위에서 언급한 용액을 염산 산성으로 만들고 메틸렌 클로라이드로 추출한다. 추출물은 황산마그네슘상에서 건조시킨 후 농축된다. 잔사는 컬럼크로마토그라피에 의해 정제되어 5-시아노-1-메틸피롤-2-아세틱산(940mg)이 된다.The solution mentioned above is made hydrochloric acid and extracted with methylene chloride. The extract is dried over magnesium sulfate and concentrated. The residue is purified by column chromatography to give 5-cyano-1-methylpyrrole-2-acetic acid (940 mg).
수율 : 25%Yield: 25%
m.p 125-126℃m.p 125-126 ℃
NMR(CDCl3):83.64(5H, s), 6.05(1H,d,J=4H2), 6.68(1H,d,J=4H2).NMR (CDCl 3 ): 83.64 (5H, s), 6.05 (1H, d, J = 4H 2 ), 6.68 (1H, d, J = 4H 2 ).
IR(KBr) : 3200, 2215, 1740cm-1 IR (KBr): 3200, 2215, 1740cm -1
[실시예 4] 부가물형성과 시안화/염기성가수분해Example 4 Adduct Formation and Cyanide / Base Hydrolysis
N-메틸피롤(1.62g, 20.0mmol)과 클로랄(3.20g, 21.7mmol)을 다이옥산(5ml)중에서 반응시켜 부가물을 만든다. 여기에 메탄올(150ml)중에 용해시킨 시안화칼륨(5.70g, 88mmol)과 탄산칼륨(2.80g, 20mmol)을 가하고 4일 동안 교반한다. 수산화 나트륨(3.0g, 75mmol)을 혼합물과 등량가하고 3일동안 방치한다. 반응 혼합물을 실시예 3에서와 같은 방법으로 처리하여 우너하는 물질인 5-시아노-1-메틸피롤-2-아세틱산(1.50g)을 얻는다.N-methylpyrrole (1.62 g, 20.0 mmol) and chloral (3.20 g, 21.7 mmol) are reacted in dioxane (5 ml) to make an adduct. To this was added potassium cyanide (5.70 g, 88 mmol) and potassium carbonate (2.80 g, 20 mmol) dissolved in methanol (150 ml) and stirred for 4 days. Sodium hydroxide (3.0 g, 75 mmol) is added to the mixture in an equal amount and left for 3 days. The reaction mixture was treated in the same manner as in Example 3 to obtain 5-cyano-1-methylpyrrole-2-acetic acid (1.50 g), which was a well material.
수율 : 50%Yield: 50%
[실시예 5] 부가물형성과 시안화/염기성가수분해Example 5 Addition Formation and Cyanide / Base Hydrolysis
N-메틸피롤(1.62g, 20.0mmol)과 클로랄(3.20g, 21.7mmol)을 다이옥산(5ml)중에서 반응시켜 부가물을 만든다. 이 용액에 메탄올(100ml)중에 용해된 시안화칼륨(6.20g, 95mmol)과 탄산칼륨(2.80g)을 가한 후 이 용액을 21시간동안 환류시키면서 가열한다. 반응 혼합물은 실시예 3에서 기술한 방법으로 계속 처리하여 같은 생성물을 얻는다. (880mg).N-methylpyrrole (1.62 g, 20.0 mmol) and chloral (3.20 g, 21.7 mmol) are reacted in dioxane (5 ml) to make an adduct. Potassium cyanide (6.20 g, 95 mmol) and potassium carbonate (2.80 g) dissolved in methanol (100 ml) were added to the solution, and the solution was heated to reflux for 21 hours. The reaction mixture is continuously treated in the manner described in Example 3 to obtain the same product. (880 mg).
수율 : 27%Yield: 27%
[실시예 6] 부가물형성과 시안화/염기성가수분해Example 6 Addition Formation and Cyanide / Base Hydrolysis
N-메틸피롤(810g, 10mmol)과 클로랄(1.6g, 10.7mmol)의 에테프(10ml)용액을 24시간동안 환류시킨다. 용매를 진곤 상태 실온에서 제거시킨 후 잔사를 메탄올(30ml)에 용해시킨다. 이 용액을 물(30ml)중의 시안화나트륨(3.0g, 60mmol)에 가한다. 이 용액을 유욕(油浴)상에서 20시간동안 30-35℃로 가열하면서 물(15ml)에 녹인 수산화 칼륨(2.6g, 40mmol)용액을 가한다. 모두 가한 후 반응 혼합물을 가한 2배의 시간동안 같은 온도로 유지시킨다.A solution of N-methylpyrrole (810 g, 10 mmol) and chloral (1.6 g, 10.7 mmol) of eteph (10 ml) was refluxed for 24 hours. The solvent is removed at room temperature and the residue is dissolved in methanol (30 ml). This solution is added to sodium cyanide (3.0 g, 60 mmol) in water (30 ml). A solution of potassium hydroxide (2.6 g, 40 mmol) dissolved in water (15 ml) is added while heating this solution to 30-35 ° C. for 20 hours on an oil bath. After all additions, the reaction mixture is kept at the same temperature for twice the amount of time added.
혼합물을 물로 희석하고 메틸렌클로라이드로 세척한다. (이 유기층에는 출발물질이 거의 없다). 수층을 염산을 사용하여 조심하여 산성으로 한 후 메틸렌클로라이드로 수시간 동안 추출한다. 추출물을 합하고 소금물로 세척한다.The mixture is diluted with water and washed with methylene chloride. (There is very little starting material in this organic layer). The aqueous layer is carefully acidified with hydrochloric acid and then extracted with methylene chloride for several hours. Combine the extracts and wash with brine.
황산마그네슘상에서 건조시킨 후 유기용액을 농축시킨다. 잔사를 실리카겔 크로마토그라피(핵산 에틸아세테이트 : 용출제로 원하는 시아노산인 5-시아노-1-메틸피롤-2-아세틱산(945mg)을 얻는다.After drying over magnesium sulfate, the organic solution is concentrated. The residue is subjected to silica gel chromatography (nucleic acid ethyl acetate: 5-cyano-1-methylpyrrole-2-acetic acid (945 mg) which is a cyano acid desired as an eluent).
수율 : 58%Yield: 58%
[실시예 7] 시안화/염기성가수분해Example 7 Cyanide / Base Hydrolysis
실시예 6에서 준비된 클로랄/N-메틸피롤 부가물을 실시예 6에서의 일반적인 순서에 따라 시아노하시킨다. 반응 조건과 결과가 다음 표에 요약되어 있다.The chloral / N-methylpyrrole adduct prepared in Example 6 is cyanoha according to the general procedure in Example 6. Reaction conditions and results are summarized in the following table.
<5-시아노-1-메틸피롤-2-아세틱산의 생성><Production of 5-cyano-1-methylpyrrole-2-acetic acid>
[실시예 8] 아실화Example 8 Acylation
마그네슘(1.14g, 46.9matom)과 P-브롬화톨루엔(8.20g, 47.9mmol)을 THF에 녹여 그리그나드시약을 준비한다. THF(5ml)에 용해시킨 5-시아노-1-메틸피롤-2-아세틱산(1.61g, 9.8mmol)을 위의 용액에 가하고 이 혼액을 가열하면서 2시간 동안 환류시킨다. 염산으로 산성으로 환후 에테르로 추출한다. 에테르층을 건조시키고 농축시킨 후 실리카겔컬럼 크로마토그라프로 정제하여 500mg의 출발 니트릴을 얻는다.Prepare Grignard reagent by dissolving magnesium (1.14g, 46.9matom) and P-toluene bromide (8.20g, 47.9mmol) in THF. 5-Cyano-1-methylpyrrole-2-acetic acid (1.61 g, 9.8 mmol) dissolved in THF (5 ml) was added to the above solution and the mixture was refluxed for 2 hours while heating. Acidified with hydrochloric acid and extracted with ether. The ether layer is dried, concentrated and purified by silica gel column chromatography to yield 500 mg of starting nitrile.
수층을 실온에서 2주일간 정치시킨다. 이 반응 혼합물을 에테르로 추출하고 에테르 층을 건조, 농축시켜 1-메틴-5-P-톨루오일-피롤-2-아세틱산(1.60g)의 결정을 얻는다.The aqueous layer is allowed to stand for two weeks at room temperature. The reaction mixture is extracted with ether and the ether layer is dried and concentrated to give crystals of 1-methine-5-P-toluoyl-pyrrole-2-acetic acid (1.60 g).
수율 : 92%Yield: 92%
m.p 155-156℃m.p 155-156 ℃
NMR(CDCl3):82.37(3H, s), 3.69(2H,s), 3.89(3H,s), 6.60(1H,d,J=4H2), 6.62(1H,d,J=4Hz), 7.18(2H,d,JEQUALSHz), 7.66(2H,D,JEQUALS 8Hz) : 3425, 2940, 2900, 170, 1600-1.NMR (CDCl 3 ): 82.37 (3H, s), 3.69 (2H, s), 3.89 (3H, s), 6.60 (1H, d, J = 4H 2 ), 6.62 (1H, d, J = 4 Hz), 7.18 (2H, d, JEQUALS Hz), 7.66 (2H, D, JEQUALS 8 Hz): 3425, 2940, 2900, 170, 1600 -1 .
[실시예 9] 아실화Example 9 Acylation
실시예 8에서 기술한 방법대로 마그네슘(890mg, 36.6matom)과 P-브로모톨루엔(6.25g, 36.5mmol)로 부터 그리그나드 시약을 준비한다. 이 용액에 5-시아노-1-메틸피롤-2-아세틱산(1.50g, 9.14mmol)을 THF(15ml)에 녹인 용액을 가하고 이 혼액을 가열하면서 21시간 동안 환류시킨다.The Grignard reagent is prepared from magnesium (890 mg, 36.6 matom) and P-bromotoluene (6.25 g, 36.5 mmol) as described in Example 8. To this solution was added a solution of 5-cyano-1-methylpyrrole-2-acetic acid (1.50 g, 9.14 mmol) in THF (15 ml) and refluxed for 21 hours while heating the mixture.
이 혼액에 수포화된 에테르를 가한뒤 아세틱산(4ml)와 물을 순차로 가한다.To this mixture is added a saturated ether, and then acetic acid (4 ml) and water are added sequentially.
수층을 메칠렌클로라이드와 다이옥산(100ml)로 세척하고 농염산(4ml)를 가한다. 이 수혼합액을 실온에서 1일 정치시킨 후 메틸렌클로라이드로 추출한다. 유기층을 건조농축시켜 원하는 물질인 1-메틸-5-P-톨루오일피롤-2-아세틱산 1.57g을 얻는다. 수층에 다이옥산(50ml)를 더 가하고 이 혼액을 2일간 정치시킨후 상기한 방법대로 처리해서 부가를 400mg의 원하는 물질을 얻는다.The aqueous layer is washed with methylene chloride and dioxane (100 ml) and concentrated hydrochloric acid (4 ml) is added. This aqueous mixture is left to stand at room temperature for 1 day and then extracted with methylene chloride. The organic layer is concentrated to dryness to obtain 1.57 g of 1-methyl-5-P-toluoylpyrrole-2-acetic acid as a desired substance. Dioxane (50 ml) is further added to the aqueous layer, and the mixed solution is allowed to stand for 2 days and then treated according to the method described above to obtain 400 mg of the desired substance.
총수율 : 84%Total yield: 84%
[실시예 10] 부가물형성-양이온교환수지Example 10 Adduct Formation-Cation Exchange Resin
N-메틸피롤(1.62g, 20mmol), 1N-에테르(10ml)용액에 에테르(10ml)에 용해시킨 클로랄(3.24g, 22mmol)용액을 가한다. 여기에 엠버리스트(160mg)을 가하고 이 혼합물을 18시간동안 환류시키면서 교반한다. 실온으로 냉각하고 트리에틸아민(0.3ml)을 가한다. 혼합물을 5분간 교반하고 세라이트로 여과한다. 여과물을 저압하에서 농축하고 조약한 부가물 1-메틸-2-(2',2',2'-트리클로로-1'-하이드록시에틸)피롤(4.68g)의 연 갈색결정을 얻는다.To a solution of N-methylpyrrole (1.62 g, 20 mmol) and 1 N-ether (10 ml) was added chloral (3.24 g, 22 mmol) dissolved in ether (10 ml). Emberist (160 mg) is added thereto and the mixture is stirred at reflux for 18 hours. Cool to room temperature and add triethylamine (0.3 ml). The mixture is stirred for 5 minutes and filtered through celite. The filtrate is concentrated under low pressure to give light brown crystals of the crude adduct 1-methyl-2- (2 ', 2', 2'-trichloro-1'-hydroxyethyl) pyrrole (4.68 g).
[실시예 11] 시안화/염기성가수분해Example 11 Cyanide / Base Hydrolysis
실시예 2에서 만든 1-메틸-2-(2',2',2'-트리클로로-1-하이드록시에틸)피롤(1,14g,5mmol)을 아래표의 용매(15ml)에 녹인다. 이 용액에 물(15ml)와 알칼리금속시안화제(MCN : 그양은 아래 표에 있다)을 가하고 이용액에 강렬하게 교반(45℃) 교반하면서 6시간에 걸쳐 수산화칼륨수용액(10ml)를 가한다. 출발물질인 클로랄부가물(밤세워방치)이 없어질때까지 교반한 후 반응 혼합물은 물로(100ml) 희석하고 에틸아세테이트로 2번 추출한다.Dissolve 1-methyl-2- (2 ', 2', 2'-trichloro-1-hydroxyethyl) pyrrole (1,14 g, 5 mmol) prepared in Example 2 in a solvent (15 ml) in the table below. To this solution is added water (15 ml) and alkali metal cyanide (MCN: the amounts are in the table below), and an aqueous potassium hydroxide solution (10 ml) is added to the solution over 6 hours with vigorous stirring (45 ° C). After stirring until the starting material, chloral adduct, was removed, the reaction mixture was diluted with water (100 ml) and extracted twice with ethyl acetate.
유기추출물을 세척하고 무수황산마그네슘으로 건조한다. 저압으로 하여 용매를 제거하고 잔사를 에틸아세테이트 50ml에 다시 용해시킨다. 용액일정량을 취해서 1N-에테르에 용해시킨 디아조메탄으로 처리한다. 과잉의 디아조메탄을 저압에서 제거하고, 중간표준물로서 트란스스틸렌을 가하고 GC(2% EGA컬럼, 1M, 160℃)에 의해 메틸-5-시아노-1-메틸피롤-2-아세테이트(이론수율치, 5mmol)을 결정한다.The organic extract is washed and dried over anhydrous magnesium sulfate. The solvent is removed at low pressure and the residue is dissolved again in 50 ml of ethyl acetate. A certain amount of solution is taken and treated with diazomethane dissolved in 1N-ether. Excess diazomethane was removed at low pressure, transstyrene was added as an intermediate standard and methyl-5-cyano-1-methylpyrrole-2-acetate (Theory) by GC (2% EGA column, 1M, 160 ° C) Yield, 5 mmol).
<5-시아노-1-메틸피롤-2-아세틱산><5-cyano-1-methylpyrrole-2-acetic acid>
A) 출발 1-메틸-2-(2',2'2'-트리클로로-2'-하이드록시에틸)피롤과의 몰비A) molar ratio with starting 1-methyl-2- (2 ', 2'2'-trichloro-2'-hydroxyethyl) pyrrole
B) 1.5시간동안 KOH 수용액을 가함.B) Aqueous KOH solution was added for 1.5 hours.
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KR7803676A KR820001236B1 (en) | 1978-12-07 | 1978-12-07 | Process for preparing 5-acyl-1-hydrocarbylpyrrole-2-acetic acid |
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KR7803676A KR820001236B1 (en) | 1978-12-07 | 1978-12-07 | Process for preparing 5-acyl-1-hydrocarbylpyrrole-2-acetic acid |
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1978
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