KR810001173B1 - Process for preparing 5-substituted-1,2-dihydro-3h-pyrrolo(1,2-alpha)-pyrrole-1-carboxylic acid from their corresponding novel nitriles - Google Patents

Abstract

Title compds. [I; Y = III (R = H, Me, cl), IV( R1 = H, C1-4 lower alkyl, alkoxy, Cl, F, Br, V(R2 = H, C1-4 lower alkyl) useful as analgesics and antiinflammatory agents, were prepd. by hydrolysis of II. Thus, 0.3 g II [ Y = III ( R = H) was hydrolyzed with 3.5 g conc. HCl at 100oC under N2 followed by extraction and filteration to give 0.17 g I(85%).

Description

신규의 대응 니트릴로부터 5-치환-1,2-디하이드로-3H-피롤로[1,2-a]-피롤-1-카르복실 산을 제조하는 방법Process for preparing 5-substituted-1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylic acid from novel corresponding nitriles

본 발명은 하기 구조식(I)의 5-치환-1,2-디하이드로- 3H- 피롤로〔1,2-a〕-피롤-1-카르복실산을 제조하는 신규 공정에 관한 것이다.The present invention relates to a novel process for preparing 5-substituted-1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylic acid of formula (I).

상기 식에서 Y는 R이 수소, 메틸, 클로로 혹은 보로모, R치환은 티오펜환의 3,4혹은 5 위치에 일어나고, R′은 수소, 1-4개의 탄소원자를 갖는 저급 알킬기, 1-4개의 탄소원자를 갖는 저급 알코옥시, 클로로, 플루오로, 혹은 브로모, R′치환은 아르일기의 오르토, 메타 혹은 파라 위치에서 일어나며, R²는 수소 혹은 1-4개의 탄소원자를 갖는 저급 알킬기인 하기 구조식의 기이다.Wherein Y is hydrogen, methyl, chloro or boromo, R is substituted at 3, 4 or 5 position of thiophene ring, R 'is hydrogen, lower alkyl group having 1-4 carbon atoms, 1-4 carbon source Lower alkooxy, chloro, fluoro, or bromo, R'substituted with the group occurs at the ortho, meta or para position of the aryl group, R ² is hydrogen or lower alkyl group having 1-4 carbon atoms to be.

본 발명의 신규 공정에 따라, Y가 상기 정의대로인 구조식(II)의 대응 5-치환 -1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-니트릴을 가수분해상에서 전환하여 구조식(I)의 화합물을 제조한다.According to the novel process of the present invention, a corresponding 5-substituted -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-nitrile of the formula (II) wherein Y is as defined above Conversion in the decomposition phase affords compounds of formula (I).

구조식(II)의 화합물을 구조식(I)의 화합물로 전환하는 방법은 하기에 도시되어 있다.The method for converting a compound of formula (II) to a compound of formula (I) is shown below.

구조식(I)의 화합물은 특히 벨기에 왕국 특허 제856681호 및 856682호에 이미 기술되어 있다.The compounds of the formula (I) are already described, in particular, in the patents of the Kingdom of Belgium, 85.851 and 856682.

구조식(II)의 화합물은 항염제, 진통제 및, 평활근 이완제로서 유용하다. 상기 물질은 또한 예방 및 치료상 유용하게 사용된다.Compounds of formula (II) are useful as anti-inflammatory agents, analgesics and smooth muscle relaxants. The materials are also useful for prophylactic and therapeutic purposes.

구조식(II)의 출발 화합물은 하기 설명된 제조 방법으로 제조한다.Starting compounds of formula (II) are prepared by the preparation process described below.

구조식(II) 화합물을 구조식(I) 화합물로 가수분해 전화하는 본 발명의 신규 공정은 일반적으로, 니트릴을 카르복실 산으로 전화할때 사용하는 조건과 마찬가지로 산성 혹은 염기성 상태하에서 진행한다.The novel process of the present invention, which hydrolyzes the compound of formula (II) to the compound of formula (I), generally proceeds under acidic or basic conditions as well as the conditions used to convert nitriles to carboxylic acids.

가수분해 전화 공정을 산성 상태에서 진행할 경우, 예를 들어, 초산, 포름산, 프로피온산과 같은 유기산이 존재하는 혹은 존재하지 않는 물의 존재하에서, 인산, 황산, 염산, 취화수소산 등의 강 무기산과 함께 진행시키는 것이 바람직하다. 필요에 따라, 무기산〔및 물 및 유기산〕과 혼합할 수 있는 유기용매를 사용할 수 있다.When the hydrolysis conversion process is carried out in an acidic state, for example, with a strong inorganic acid such as phosphoric acid, sulfuric acid, hydrochloric acid, and hydrochloric acid, in the presence or absence of water, with or without organic acids such as acetic acid, formic acid, propionic acid, etc. It is preferable. If necessary, an organic solvent which can be mixed with an inorganic acid [and water and an organic acid] can be used.

적당한 유기 용매로는 메탄올, 에탄올, 에틸렌 글리콜, 디메틸설폭사이드, 디옥산, 테트라하이드로퓨란, 에틸렌 글리콜 디메틸 에테르(glyme), 디에틸렌 글리콜 디메틸 에테르(diglyme) 등이 있다. 상기 반응은 예를 들어, 질소, 아르곤 등의 불활성 대기하에서 실시하는 것이 바람직하며 질소 대기하에서 진행하는 것이 가장 바람직하다. 반응 시간 및 온도는 임계적이 아니며, 사용되는 반응물질(및 반응혼합물의기타성분)에 따라 달라진다. 그러므로, 반응 시간은 1분에서 10시간 정도로 크게 다르며 5분 내지 3시간정도가 바람직하고, 반응 온도는 60℃내지 200℃, 바람직하게는 80℃ 내지 120℃ 정도이다.Suitable organic solvents include methanol, ethanol, ethylene glycol, dimethylsulfoxide, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and the like. The reaction is preferably carried out, for example, under an inert atmosphere such as nitrogen and argon, and most preferably under a nitrogen atmosphere. The reaction time and temperature are not critical and depend on the reactants (and other components of the reaction mixture) used. Therefore, the reaction time varies greatly from about 1 minute to 10 hours, preferably about 5 minutes to 3 hours, and the reaction temperature is about 60 ° C to 200 ° C, preferably about 80 ° C to 120 ° C.

가수분해 전화 공정을 염기성 상태에서 실시할 경우, 물의 존재하에서 예를 들어, 수산화칼륨, 수산화나트륨, 수산화 리튬 등의 강 무기염물과 함께 진행하는 것이 바람직하다. 반응 물질을 보다 쉽게 용해하기 위하여, 물과 혼합할 수 있는 유기 용매, 즉, 2-메토옥시 에탄올, 메탄올, 에탄올, 에틸렌글리콜, 디메틸설폭사이드 등을 사용하는 것이 좋다. 상기 반응은 질소, 아르곤 등의 불활성 대기하에서 실시하는 것이 바람직하며 질소 대기하에서 실시하는 것이 바람직하며 질소 대기하에서 진행하는 것이 가장 바람직하다. 반응 시간 및 온도는 임계적이 아니며 사용하는 반응물질(및 반응 혼합물의 기타성분)에 따라 달라진다. 따라서, 반응 시간은 5분 내지 2시간, 바람직하게는 30분 내지 1시간 정도이며, 반응 온도는 60℃내지 환류온도, 바람직하게는 70℃ 내지 환류온도 정도이다.When the hydrolysis conversion step is carried out in a basic state, it is preferable to proceed with strong inorganic salts such as potassium hydroxide, sodium hydroxide and lithium hydroxide in the presence of water. In order to dissolve the reaction material more easily, it is preferable to use an organic solvent which can be mixed with water, that is, 2-methooxy ethanol, methanol, ethanol, ethylene glycol, dimethyl sulfoxide and the like. The reaction is preferably carried out under an inert atmosphere such as nitrogen and argon, preferably under a nitrogen atmosphere, and most preferably under a nitrogen atmosphere. The reaction time and temperature are not critical and depend on the reactants used (and other components of the reaction mixture). Therefore, the reaction time is about 5 minutes to 2 hours, preferably about 30 minutes to 1 hour, and the reaction temperature is about 60 ° C to reflux temperature, preferably about 70 ° C to reflux temperature.

구조식(I) 화합물을 함유하는 반응 혼합물에서 구조식(I) 화합물을 분리, 석출 및 정제하는 공정은 예를 들어, 추출, 여과, 증발, 증류, 결정, 엷은 층 크로마토그래피 혹은 컬럼 크로마토그래피 고압 액상 크로마토그래피 혹은 상기 공정의 혼합 방법과 같은 적당한 석출, 정제 공정으로 실시한다. 분리, 석출 및 정제 공정에 대한 설명은 하기실시예(및 제조방법)을 참조한다. 상기 공정 외에도 다른 분리, 석출 및 정제 공정을 사용할 수 있다.Separation, precipitation, and purification of the compounds of formula (I) in the reaction mixture containing the compounds of formula (I) may be carried out, for example, by extraction, filtration, evaporation, distillation, crystals, thin layer chromatography or column chromatography. It carries out by a suitable precipitation and purification process like the imaging method or the mixing method of the said process. See the following examples (and preparation methods) for a description of the separation, precipitation and purification processes. In addition to the above process, other separation, precipitation and purification processes may be used.

필요하다면, 제조방법 및 실시예를 되풀이하여 부수적인 제조 방법 및 실시예의 부가적인 물질을 제조한다.If necessary, the manufacturing methods and examples are repeated to prepare additional materials of the additional manufacturing methods and examples.

하기 실시예(및 제조방법)는 본 발명을 상술한 것으로 그 범위에 국한되는 것은 아니다. 물론 설명이 없는 한, 온도는 실온 혹은 주위 온도를 의미한다(약 20℃ 내지 30℃)The following examples (and preparation methods) are not limited to the scope of the present invention described above. Unless stated otherwise, of course, temperature means room temperature or ambient temperature (about 20 ° C to 30 ° C)

제조 방법 1Manufacturing method 1

A. 포름알데하이드 용액 8.21g 및 디메틸아민 하이드로클로라이드 8.84g의 혼합물에 11.5g의 N-하이드로옥시에틸피롤(Shun-Ichi Mulahashiesal, J.S.C. Chem comm, 1974, 931-932 참조)을 8분에 걸쳐 교반 첨가하고 온도를 60℃ 이하로 유지하며 필요에 따라 냉각하기도 한다. 온도를 실온으로 하강시키고, 반응 혼합물을 실온에서 15시간 교반한 다음, 25% 수성 수산화 나트륨 용액 16ml를 첨가하여 5분간 교반하고 염화 메틸렌 19ml 및 몰 20ml를 첨가한다. 유기층을 분리하고, 수성층은 염화메틸렌 19ml로 추출한다. 유기부분을 혼합하고, 포화 수성 염화 나트륨 용액 11ml 및 몰 8ml의 혼합물로 세척한다. 수성 유기층을 무수황산나트륨 상에서 건조하고, 진공하에서 용매를 제거하여 오렌지-황색의 유상인 화합물 17.2g을 얻으며, 실리카겔 크로마토그래피 컬럼(염화 메틸렌에서 10% 메탄올을 용매로 사용한다)상에서 정제하여 12.9g의 1-하이드로옥시에틸-2-〔(N,N-디메틸아미노)-메틸〕피롤을 얻는다.A. 11.5 g of N-hydrooxyethylpyrrole (see Shun-Ichi Mulahashiesal, JSC Chem comm, 1974, 931-932) was added to the mixture of 8.21 g of formaldehyde solution and 8.84 g of dimethylamine hydrochloride over 8 minutes. The temperature is kept below 60 ° C and cooled as needed. The temperature is lowered to room temperature, the reaction mixture is stirred at room temperature for 15 hours, then 16 ml of 25% aqueous sodium hydroxide solution is added for 5 minutes and 19 ml of methylene chloride and 20 ml of mole are added. The organic layer is separated and the aqueous layer is extracted with 19 ml of methylene chloride. The organic portions are mixed and washed with a mixture of 11 ml saturated aqueous sodium chloride solution and 8 ml molar. The aqueous organic layer was dried over anhydrous sodium sulfate, the solvent was removed under vacuum to afford 17.2 g of an orange-yellow oily compound, which was purified on a silica gel chromatography column (using 10% methanol in methylene chloride as solvent) to give 12.9 g of 1-hydrooxyethyl-2-[(N, N-dimethylamino) -methyl] pyrrole is obtained.

계산치 : C 64.25% H 9.59% N 16.65%Calculated Value: C 64.25% H 9.59% N 16.65%

실험치 : C 63.39% H 10.14% N 16.46%Experimental Value: C 63.39% H 10.14% N 16.46%

B.아세톤 100ml에 1-하이드로옥시에틸-2-(N,N -디메틸아미노) -메틸 〕-피롤 21.5g을 첨가한 다음, 0℃의 상기 혼합물에 온도를 2℃이하로 유지하면서 16.4g의 디메틸 설페이트를 교반 첨가한다. 온도를 실온으로 가열하고 상기 반응 혼합물을 실온에서 1시간 교반한다. 상기 방법으로 얻은 반응 혼합물을 물 27ml에 용해한 나트륨 시아나이드 12.6g 용액(약 90℃)에 첨가하고, 이 때 첨가율은 동 시간 단위당 용매가 증발하는 율과 비슷하여 초기 반응 플래스크 온도가 90°-95℃로 유지될 수 있도록 조절한다. 첨가한 다음, 혼합물을 환류하고 환류하에서 15분간 가열한다. 혼합물을 25℃로 냉각한 다음, 물 40ml및 염화 메틸렌 60ml를 첨가한다. 유기층을 분리하고, 50:50 비율의 포화수성 염화나트륨 및 물의 혼합 물 30ml로 세척한 다음 수성층을 염화 메틸렌 30ml로 2번 추출하고 혼합 유기층을 무수 황산 나트륨 상에서 건조한다. 진공하에서 용매를 제거하여 얻은 갈색의 유상 화합물 21g을 실리카겔 크로마토그래피 컬럼(용매로서 50:50의 에틸 아세테이트:헥산을 사용)상에서 정제하여 13g의 1-하이드로옥시에틸피롤-2-아세토니트릴을 얻는다.21.5 g of 1-hydrooxyethyl-2- (N, N-dimethylamino) -methyl] -pyrrole was added to 100 ml of acetone, and then 16.4 g of the mixture was kept at 0 ° C. while maintaining the temperature below 2 ° C. Dimethyl sulfate is added by stirring. The temperature is heated to room temperature and the reaction mixture is stirred at room temperature for 1 hour. The reaction mixture obtained by the above method was added to a solution of 12.6 g of sodium cyanide (about 90 ° C.) dissolved in 27 ml of water, where the addition rate was similar to the rate at which the solvent evaporated per unit of time so that the initial reaction flask temperature was 90 °- Adjust to maintain at 95 ° C. After addition, the mixture is refluxed and heated at reflux for 15 minutes. The mixture is cooled to 25 ° C., then 40 ml of water and 60 ml of methylene chloride are added. The organic layer is separated, washed with 30 ml of a 50:50 mixture of saturated aqueous sodium chloride and water, the aqueous layer is extracted twice with 30 ml of methylene chloride and the mixed organic layer is dried over anhydrous sodium sulfate. 21 g of a brown oily compound obtained by removing the solvent in vacuo was purified on a silica gel chromatography column (using 50:50 ethyl acetate: hexane as a solvent) to obtain 13 g of 1-hydrooxyethylpyrrole-2-acetonitrile.

계산치 : C 63.98% H 6.71% N 18.66%Calculated Value: C 63.98% H 6.71% N 18.66%

실험치 : C 63.91% H 6.76% N 18.91%Experimental Value: C 63.91% H 6.76% N 18.91%

C. 1.6의 1-하이드로옥시에틸-2-피롤아세토니트릴을 염화 메틸렌 12ml 및 트리에틸아민 1.3g 의 혼합물에 넣고, 상기 물질이 들어 있는 플라스크를 질소로 정화한 다음, 내용물을 -10℃로 냉각한다. 온도를 0℃로 유지하면서 1.34g의 염화 메탄설포닐을 첨가하고, 상기 반응 혼합물을 0℃로 15분간 교반한다. 상기 혼합물에 50:50 비율의 포화 수성 염화 나트륨 용액 및 물을 혼합물 10ml를 첨가하고 염화메틸렌 15ml로 4번 추출한 다음 희석된 수성 염화나트륨 용액으로 세척하여 무수 황산 나트륨상에서 건조하고 진공하에서 용매를 제거하여 얻은 조 1-(2′-메탄설포닐에탄)-피롤-2-아세토니트릴 2.52g을 아세토니트릴 35ml 및 나트륨 요오다이드 3.76g의 혼합물에 첨가한다. 상기와 같이 얻은 혼합물을 77℃로 1시간 가열하고, 25℃로 냉각한 다음, 상기 혼합물에 15ml의 염화 메틸렌을 첨가한다. 유기염을 여과, 제거하고 염화 메틸렌으로 세척한다. 진공하에서, 여액으로 부터 용매를 제거하고, 남은 잔사를 회석된 수성 염화 나트륨 용액 30ml 혼합물에 모아 놓는다. 생성된 유기층을 무수 황산 나트륨 상에서 건조한 다음 진공하에서 용매를 제거하여 얻은 조 1-(2-요오도에탄)-피롤-2-아세토니트릴 2.85g 중 2.7g을 디메틸포름아미드 10ml에 용해하고, 상기 용액을 15℃ 이하의 온도로 유지하면서, 디메틸포름아미드 10ml에 용해한 나트륨 하이드라이드(50% 의 오일 현탁액 0.48g에서 얻음) 0.24g 현탁액에 서서히 첨가한다. 상기 반응 슬러리를 질소 대기하에서, 20℃로 1시간 교반하고 물 35ml를 첨가한 다음, 디에틸 에테르 20ml로 5번 추출한다. 유기 추출물을 혼합하고 황산 나트륨 상에서 건조한 다음, 대기압에서 용매를 제거하여 얻은 밤색의 유상 화합물 1.4g을 실시카겔 크로마토그래피컬럼(용매로서 3:1 비율의 헥산 및 에틸 아세테이트를 사용) 정제하여 44℃-45℃ 융점(에탄올로 결정됨)의 1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-니트릴 1g을 얻는다.C. 1.6 1-hydrooxyethyl-2-pyrroleacetonitrile was added to a mixture of 12 ml of methylene chloride and 1.3 g of triethylamine, the flask containing the material was purged with nitrogen and the contents cooled to -10 ° C. do. 1.34 g of methanesulfonyl chloride is added while maintaining the temperature at 0 ° C. and the reaction mixture is stirred at 0 ° C. for 15 minutes. The mixture was obtained by adding 10 ml of a 50:50 saturated aqueous sodium chloride solution and water to the mixture, extracting four times with 15 ml of methylene chloride, washing with diluted aqueous sodium chloride solution, drying over anhydrous sodium sulfate and removing the solvent under vacuum. 2.52 g of crude 1- (2'-methanesulfonylethane) -pyrrole-2-acetonitrile is added to a mixture of 35 ml of acetonitrile and 3.76 g of sodium iodide. The mixture so obtained is heated to 77 ° C. for 1 hour, cooled to 25 ° C. and 15 ml of methylene chloride is added to the mixture. The organic salts are filtered off and washed with methylene chloride. Under vacuum, the solvent is removed from the filtrate and the remaining residue is collected in a 30 ml mixture of dilute aqueous sodium chloride solution. The resulting organic layer was dried over anhydrous sodium sulfate and then the solvent was removed under vacuum to dissolve 2.7 g of 2.85 g of crude 1- (2-iodoethane) -pyrrole-2-acetonitrile in 10 ml of dimethylformamide, and the solution Is slowly added to a 0.24 g suspension of sodium hydride (obtained from 0.48 g of 50% oil suspension) dissolved in 10 ml of dimethylformamide, maintaining the temperature below 15 ° C. The reaction slurry is stirred under nitrogen atmosphere for 1 hour at 20 ° C., 35 ml of water is added, and then extracted 5 times with 20 ml of diethyl ether. The organic extract was mixed, dried over sodium sulfate, and then 1.4 g of a brown oily compound obtained by removing the solvent at atmospheric pressure was purified by a gel-gel chromatography column (using 3: 1 ratio of hexane and ethyl acetate as solvent) at 44 ° C. 1 g of 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-nitrile is obtained at a melting point of 45 ° C. (determined from ethanol).

계산치 : C 72.70% H 6.10% N 21.20%Calculated Value: C 72.70% H 6.10% N 21.20%

실험치 : C 72.72% H 6.25% N 21.17%Experimental Value: C 72.72% H 6.25% N 21.17%

제조 방법 2Manufacturing method 2

250g의 2-테오닐 클로라이드〔L.D. Joneo 및 C.D. Hurd, J, Am, Chem. Soc.43. 2444(1921)의 방법으로 제조〕를 테트라하이드로퓨란 1500ml에 첨가한다. 상기 혼합물을 0℃로 냉각하고, 20℃이하로 유지하면서 40℃ 수성 디메틸아민 용액 1217ml 를 첨가한다. 반응 혼합물을 15분간 교반하고, 진공하에서 테트라하이드로퓨란을 제거한 다음, 염화메틸렌 1500ml로 2번에 걸쳐 수성 용액을 추출하고, 무수 황산나트륨상에서 건조한다. 진공하에서 용매를 제거하고, 잔사를 9mmHg 압력 및 146℃의 온도하에서 증류하여 40°-41.5℃ 융점의 N,N-디메틸-2-티에닐카르복시아미드 227.3g을 얻는다.250 g of 2-theonyl chloride [L.D. Joneo and C.D. Hurd, J, Am, Chem. Soc.43. 2444 (1921)] is added to 1500 ml of tetrahydrofuran. The mixture is cooled to 0 ° C. and 1217 ml of 40 ° C. aqueous dimethylamine solution are added while maintaining below 20 ° C. The reaction mixture is stirred for 15 minutes, the tetrahydrofuran is removed under vacuum, then the aqueous solution is extracted twice with 1500 ml of methylene chloride and dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the residue is distilled under 9 mmHg pressure and at a temperature of 146 ° C. to obtain 227.3 g of N, N-dimethyl-2-thienylcarboxyamide having a melting point of 40 ° -41.5 ° C.

상기 공정에 있어서, 2-테오닐 클로라이드 대신 화학량적으로 동량의 하기 화합물:벤조일 클로라이드In the above process, a stoichiometrically equivalent amount of the following compound in place of 2-theonyl chloride: benzoyl chloride

N-n-부틸-2-피롤 클로라이드를 사용하여 각각 하기의 화합물을 얻는다.The following compounds are each obtained using N-n-butyl-2-pyrrole chloride.

N,N-디메틸-2-벤조일 카르복사미드N, N-dimethyl-2-benzoyl carboxamide

N,N-디메틸-2-O-톨루오일 카르복사미드N, N-dimethyl-2-O-toluoyl carboxamide

N,N-디메틸-2-m-톨루오일 카르복사미드N, N-dimethyl-2-m-toluoyl carboxamide

N,N-디메틸-2-p-톨루오일 카르복사미드N, N-dimethyl-2-p-toluoyl carboxamide

N,N-디메틸-2-p-메토옥시벤조일 카르복사미드N, N-dimethyl-2-p-methooxybenzoyl carboxamide

N,N-디메틸-p-에토옥시벤조일 카르복사미드N, N-dimethyl-p-ethoxybenzoyl carboxamide

N,N-디메틸-2-O-클로로벤조일 카르복사미드N, N-dimethyl-2-O-chlorobenzoyl carboxamide

N,N-디메틸-2-m-클로로벤조일 카르복사미드N, N-dimethyl-2-m-chlorobenzoyl carboxamide

N,N-디메틸-2-p-클로로벤조일 카르복사미드N, N-dimethyl-2-p-chlorobenzoyl carboxamide

N,N-디메틸-2-O-플루오로벤조일 카르복사미드N, N-dimethyl-2-O-fluorobenzoyl carboxamide

N,N-디메틸-2-m-플루오로벤조일 카르복사미드N, N-dimethyl-2-m-fluorobenzoyl carboxamide

N,N-디메틸-2-p-플루오로벤조일 카르복사미드N, N-dimethyl-2-p-fluorobenzoyl carboxamide

N,N-디메틸-2-(3-클로로-2-티에닐) 카르복사미드N, N-dimethyl-2- (3-chloro-2-thienyl) carboxamide

N,N-디메틸-2-(4-클로로-2-티에닐) 카르복사미드N, N-dimethyl-2- (4-chloro-2-thienyl) carboxamide

N,N-디메틸-2-(5-클로로-2-티에닐) 카르복사미드N, N-dimethyl-2- (5-chloro-2-thienyl) carboxamide

N,N-디메틸-2-(3-브로모-2-티에닐) 카르복사미드N, N-dimethyl-2- (3-bromo-2-thienyl) carboxamide

N,N-디메틸-2-(4-브로모-2-티에닐) 카르복사미드N, N-dimethyl-2- (4-bromo-2-thienyl) carboxamide

N,N-디메틸-2-(5-브로모-2-티에닐) 카르복사미드N, N-dimethyl-2- (5-bromo-2-thienyl) carboxamide

N,N-디메틸-2-(3-메틸-2-티에닐) 카르복사미드N, N-dimethyl-2- (3-methyl-2-thienyl) carboxamide

N,N-디메틸-2-(4-메틸-2-티에닐) 카르복사미드N, N-dimethyl-2- (4-methyl-2-thienyl) carboxamide

N,N-디메틸-2-(4-메틸-2-티에닐) 카르복사미드N, N-dimethyl-2- (4-methyl-2-thienyl) carboxamide

N,N-디메틸-2-(2-피롤)카르복사미드N, N-dimethyl-2- (2-pyrrole) carboxamide

N,N-디메틸-2-(N-메틸-2-피로일) 카르복사미드 및N, N-dimethyl-2- (N-methyl-2-pyroyl) carboxamide and

N,N-디메틸-2-(N-n-부틸-2-피로일) 카르복사미드N, N-dimethyl-2- (N-n-butyl-2-pyroyl) carboxamide

제조 방법 3Manufacturing Method 3

1.77g의 N,N-디메틸-2-티에닐카르복사미드를 1,2-디클로로에탄 12.2ml 및 포스포스스 옥시클로라이드 1.74 g의 혼합물에 첨가한다. 상기 혼합물을 질소로 정화하고 1시간 30분간 환류온도로 가열한다. 25℃로 냉각하고, 1,2-디클로로에탄 4.4ml에 용해한 1,2-디하이드로-3H-피롤로-〔1,2-a〕-피롤 1-니트릴 0.95g 용액을 첨가하여 얻은 용액을 환류온도로 10시간 가열한 다음, 25℃로 냉각한다. 냉각된 상기 용액에 물 48ml에 용해한 나트륨 아세테이트 5.12g 용액을 첨가하고, 환류온도도 1시간 동안 격렬하게 교반 가열한 다음, 실온으로 냉각하여 유기층을 분리한다. 수성층을 염화 메틸렌 20ml로 2번 추출하고 각 유기층을 희석된 수성 탄산 나트륨 용액 20ml로 세척한 다음 희석된 수성 염화 나트륨 용액 20ml로 다시 세척한다. 혼합한 유기 용액을 모두 황산 나트륨 상에서 건조하고 진공하에서 용매를 제거하여 얻은 밤색의 유상 화합물 2.4g을 실리카겔 크로마토그래피 컬럼(용매로서 2.5:1 비율의 헥산 아세테이트를 사용) 상에서 정제하여 106°-107.5℃ 융점(에탄올로 결정됨)의 5-(2-테노일)-1,2-디하이드로-3H-피롤토〔1,2-a〕-피롤-1-니트릴 1.45g을 얻는다.1.77 g of N, N-dimethyl-2-thienylcarboxamide is added to a mixture of 12.2 ml of 1,2-dichloroethane and 1.74 g of phosphose oxychloride. The mixture is purged with nitrogen and heated to reflux for 1 hour 30 minutes. The solution obtained by cooling to 25 degreeC and adding the 0.95g solution of the 1, 2- dihydro-3H- pyrrolo- [1, 2-a]-pyrrole 1-nitrile dissolved in 4.4 ml of 1, 2- dichloroethanes was refluxed. Heat to temperature for 10 hours and then cool to 25 ° C. To the cooled solution, a solution of 5.12 g of sodium acetate dissolved in 48 ml of water was added, and the reflux temperature was also vigorously stirred and heated for 1 hour, and then cooled to room temperature to separate the organic layer. The aqueous layer is extracted twice with 20 ml of methylene chloride and each organic layer is washed with 20 ml of diluted aqueous sodium carbonate solution and then again with 20 ml of diluted aqueous sodium chloride solution. All the mixed organic solutions were dried over sodium sulfate and the solvent was removed under vacuum to remove 2.4 g of a brown oily compound which was purified on a silica gel chromatography column (using a 2.5: 1 ratio of hexane acetate as a solvent) to 106 ° -107.5 ° C. 1.45 g of 5- (2-tenoyl) -1,2-dihydro-3H-pyrroto [1,2-a] -pyrrole-1-nitrile having a melting point (determined by ethanol) is obtained.

계산치 : C 64.44% H 4.16% N 11.56% S 13.24%Calculated Value: C 64.44% H 4.16% N 11.56% S 13.24%

실험치 : C 64.54% H 4.10% N 11.48% S 13.46%Experimental Value: C 64.54% H 4.10% N 11.48% S 13.46%

상기 공정에 있어서, N,N-디메틸-2-티에닐카르복사미드 대신 화학량 적으로 동량의 화합물 :In the above process, stoichiometrically equivalent compounds instead of N, N-dimethyl-2-thienylcarboxamide:

N,N-디메틸-2-벤조일카르복사미드N, N-dimethyl-2-benzoylcarboxamide

N,N-디메틸-2.O-톨루오일카르복사미드N, N-dimethyl-2.O-toluoylcarboxamide

N,N-디메틸-2-m-톨루오일카르복사미드N, N-dimethyl-2-m-toluoylcarboxamide

N,N-디메틸-2-p-톨루오일카르복사미드N, N-dimethyl-2-p-toluoylcarboxamide

N,N-디메틸-2-p-메토옥시벤조일카르복사미드N, N-dimethyl-2-p-methooxybenzoylcarboxamide

N,N-디메틸-2-p-에토옥시벤조일카르복사미드N, N-dimethyl-2-p-ethoxybenzoylcarboxamide

N,N-디메틸-2-O-클로로벤조일카르복사미드N, N-dimethyl-2-O-chlorobenzoylcarboxamide

N,N-디메틸-2-m-클로로벤조일카르복사미드N, N-dimethyl-2-m-chlorobenzoylcarboxamide

N,N-디메틸-2-p-클로로벤조일카르복사미드N, N-dimethyl-2-p-chlorobenzoylcarboxamide

N,N-디메틸-2-O-플루오로벤조일카르복사미드N, N-dimethyl-2-O-fluorobenzoylcarboxamide

N,N-디메틸-2-m-플루오로벤조일카르복사미드N, N-dimethyl-2-m-fluorobenzoylcarboxamide

N,N-디메틸-2-p-플루오로벤조일카르복사미드N, N-dimethyl-2-p-fluorobenzoylcarboxamide

N,N-디메틸-2-(3-클로로-2-티에닐) 카르복사미드N, N-dimethyl-2- (3-chloro-2-thienyl) carboxamide

N,N-디메틸-2-(4-클로로-2-티에닐) 카르복사미드N, N-dimethyl-2- (4-chloro-2-thienyl) carboxamide

N,N-디메틸-2-(5-클로로-2-티에닐) 카르복사미드N, N-dimethyl-2- (5-chloro-2-thienyl) carboxamide

N,N-디메틸-2-(3-브로모-2-티에닐) 카르복사미드N, N-dimethyl-2- (3-bromo-2-thienyl) carboxamide

N,N-디메틸-2-(4-브로모-2-티에닐) 카르복사미드N, N-dimethyl-2- (4-bromo-2-thienyl) carboxamide

N,N-디메틸-2-(5-브로모-2-티에닐) 카르복사미드N, N-dimethyl-2- (5-bromo-2-thienyl) carboxamide

N,N-디메틸-2-(3-메틸-2-티에닐) 카르복사미드N, N-dimethyl-2- (3-methyl-2-thienyl) carboxamide

N,N-디메틸-2-(4-메틸-2-티에닐) 카르복사미드N, N-dimethyl-2- (4-methyl-2-thienyl) carboxamide

N,N-디메틸-2-(5-메틸-2-티에닐) 카르복사미드N, N-dimethyl-2- (5-methyl-2-thienyl) carboxamide

N,N-디메틸-2-(2-피로일) 카르복사미드N, N-dimethyl-2- (2-pyroyl) carboxamide

N,N-디메틸-2-(N-메틸-2-피로일)카르복사미드N, N-dimethyl-2- (N-methyl-2-pyroyl) carboxamide

N,N-디메틸-2-(N-n-부틸-2-피로일) 카르복사미드를 사용하여 각각 하기 화합물을 얻는다.The following compounds are each obtained using N, N-dimethyl-2- (N-n-butyl-2-pyroyl) carboxamide.

5-벤조일-1,2-디하이드로-3H-피롤토〔1,2-a〕피롤-1-니트릴5-benzoyl-1,2-dihydro-3H-pyrroto [1,2-a] pyrrole-1-nitrile

5-O-톨루오일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-O-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-m-톨루오일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-m-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-P-톨루오일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-P-Toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-P-메토옥시벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-P-methooxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-p-에토옥시벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-p-Ethooxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-O-클로로벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-O-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-m-클로로벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-p-클로로벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-O-플루오로벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-O-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-m-플루오로벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-m-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-p-플루오로벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-(3-클로로-2-테오닐)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5- (3-chloro-2-theonyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-(4-클로로-2-테오닐)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-니트릴5- (4-chloro-2-theonyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-nitrile

5-(5-클로로-2-테오닐)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-니트릴5- (5-chloro-2-theonyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-nitrile

5-(3-브로모-2-테오닐)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-니트릴5- (3-bromo-2-theonyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-nitrile

5-(4-브로모-2-테오닐)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-니트릴5- (4-bromo-2-theonyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-nitrile

5-(5-브로모-2-테오닐)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-니트릴5- (5-Bromo-2-theonyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-nitrile

5-(3-메틸-2-테오닐)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-니트릴5- (3-methyl-2-theonyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-nitrile

5-(4-메틸-2-테오닐)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-니트릴5- (4-methyl-2-theonyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-nitrile

5-(5-메틸-2-테오닐)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-니트릴5- (5-methyl-2-theonyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-nitrile

5-(2-피로일)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-니트릴5- (2-Pyroyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-nitrile

5-(N-메틸-2-피로일)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-니트릴5- (N-methyl-2-pyroyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-nitrile

5-(N-n-부틸-2-피로일)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-니트릴5- (N-n-butyl-2-pyroyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-nitrile

[실시예 1]Example 1

농축 염산(37% 수성) 3.5g에 실온의 5-(2-테오닐)-1,2-디하이드로-3H-피롤로〔1,2-a]-피롤-1-니트릴 0.3g을 첨가한다. 반응 혼합물을 질소로 정화하여 100℃로 가열한다. 상기 반응 혼합물을 질소 대기하에서 7분간 교반하고, 실온으로 냉각한 다음 냉각된 물(4℃) 10ml를 첨가한다. 반응 혼합물을 에틸 아세테이트 5ml로 2번 추출한다. 각 에틸 아세테이트 추출물을 혼합하여 무수 황산 나트륨상에서 건조하고 용매를 완전 증발시켜 5-(2-테오닐)-1,2- 디하이드로 -3H- 피롤로 〔1,2-a〕피롤-1-카복실산을 함유하는 조 생성물(고압의 액성 크로마토그래피로 측정한 결과 93% 순도) 0.32g(102%)을 얻는다.To 3.5 g concentrated hydrochloric acid (37% aqueous) add 0.3 g of 5- (2-theonyl) -1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1-nitrile at room temperature . The reaction mixture is purged with nitrogen and heated to 100 ° C. The reaction mixture is stirred for 7 minutes under a nitrogen atmosphere, cooled to room temperature and 10 ml of cooled water (4 ° C.) is added. The reaction mixture is extracted twice with 5 ml of ethyl acetate. Each ethyl acetate extract was mixed and dried over anhydrous sodium sulfate and the solvent was evaporated completely to afford 5- (2-theonyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid. 0.32 g (102%) of crude product (93% purity as measured by high pressure liquid chromatography) was obtained.

상기에서 얻은 조 생성물 0.3g을 뜨거운 에틸 아세테이트 3ml에 용해하고 0℃로 냉각한 다음, 여과 수집하여 154-155℃ 융점의 5-(2-테오닐)-1,2-디하이드로 -3H-피롤로〔1,2-a]-피롤-1-카르복실산 0.2g(66.6%)을 얻는다. 모액에서 부차적인 양의 생성물을 얻을 수 있다.0.3 g of the crude product obtained above was dissolved in 3 ml of hot ethyl acetate, cooled to 0 ° C., and then collected by filtration to collect 5- (2-theonyl) -1,2-dihydro-3H-P at 154-155 ° C. melting point. 0.2 g (66.6%) of [1,2-a] -pyrrole-1-carboxylic acid is obtained with a roll. A secondary amount of product can be obtained in the mother liquor.

상기에서 얻은 5-(2-테오닐)-1,2-디하이드로-3H-피롤로 〔1,2-a〕피롤 -1-카르복실산을 에틸 아세테이트 3ml 및 메탄올 1ml에 넣고 0.2g의 탈색화 탄을 첨가한다. 혼합물을 50℃로 가열하고 탈색화 탄을 여과 제거한 다음 메탄올은 증류, 제거한다. 남은 용액량의 2ml로 될 때까지 에틸 아세테이트를 첨가하고 0℃로 냉각한 다음, 여과 수집하여 154-155℃ 융점의 95% 순도(고압 액성 크로마토그래피토 결정)5-(2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕-피롤-1-카르복실 산을 0.179(85%)을 얻는다.5- (2-theonyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid obtained above was added to 3 ml of ethyl acetate and 1 ml of methanol, and 0.2 g of decolorization was added. Add coal. The mixture is heated to 50 ° C., the decolored carbon is filtered off and the methanol is distilled off. Ethyl acetate was added until it became 2 ml of the remaining solution, cooled to 0 ° C., and then collected by filtration to obtain 95% purity of 154-155 ° C. melting point (high pressure liquid chromatography) 5- (2-tenoyl)- This yields 0.179 (85%) of 1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylic acid.

표준 결정화 공정으로 모액으로부터 2차적인 양의 생성물을 얻을 수 있다.Standard crystallization processes yield secondary amounts of product from the mother liquor.

상기 방법으로 농축 염산(37% 수성)대신 동일 화학량의 황산(40% 수성)을 사용하여 5-(2-테노일)-1,2-디하이드로-3H-피로토-[1,2-a] 피롤-1-카르복실 산을 얻는다.This method uses 5- (2-tenoyl) -1,2-dihydro-3H-pyroto- [1,2-a using the same stoichiometric amount of sulfuric acid (40% aqueous) instead of concentrated hydrochloric acid (37% aqueous). ] Pyrrole-1-carboxylic acid is obtained.

[실시예 2]Example 2

60% 수성 황산 3.5g에 0.5g의 5-(2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴을 첨가한다. 반응 혼합물을 질소로 정화하여 100℃로 가열한다. 반응 혼합물을 질소 대기하에서 12분간 교반한 다음 냉각한 물(4℃) 10ml를 첨가한다. 반응 혼합물을 에틸 아세테이트 5ml로 2번 추출한다. 각 에틸 아세테이트 추출물을 혼합하고, 무수 황산 나트륨상에서 건조한 다음 건조 농축하여 5-(2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-카르복실산을 함유하는 조 생성물(고압 액성 크로마토그래피로 측정한 결과 56% 순도임) 0.5g(92.7%)을 얻는다.To 3.5 g of 60% aqueous sulfuric acid, 0.5 g of 5- (2-tenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile is added. The reaction mixture is purged with nitrogen and heated to 100 ° C. The reaction mixture is stirred for 12 minutes under a nitrogen atmosphere and then 10 ml of cooled water (4 ° C.) is added. The reaction mixture is extracted twice with 5 ml of ethyl acetate. Each ethyl acetate extract was mixed, dried over anhydrous sodium sulfate, and then concentrated to dryness to afford 5- (2-tenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxyl. 0.5 g (92.7%) of crude product containing acid (56% pure as determined by high pressure liquid chromatography) is obtained.

상기에서 얻은 조 생성물 0.4g을 메탄올 4ml에 용해하고 물 4ml를 첨가한다. 혼합물을 교반, 여과한다. 상기 공정으로 얻은 고체 물질을 에틸 아세테이트 5ml 및 메탄올 1ml에 용해하고 탈색화 탄 0.5g을 첨가하다. 상기 혼합물을 50℃로 가열하고, 탈색화 탄을 여과, 제거한 다음 메탄올을 제거한다. 상기 양에 에틸 아세테이트를 첨가하여 2ml로 만든 다음 0℃로 냉각하고 여과하여 147℃-148℃ 융점의 5-(2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-카르복실산 0.2g(50%)을 얻는다. 상기 융점은 상기 화합물을 에틸 아세테이트로 2번 결정하고 고압 액성 크로마토그래프로 79.8%의 순도를 얻은 후에도 동일하다.0.4 g of the crude product obtained above is dissolved in 4 ml of methanol and 4 ml of water is added. The mixture is stirred and filtered. The solid material obtained in the above process is dissolved in 5 ml of ethyl acetate and 1 ml of methanol and 0.5 g of decolorized carbon is added. The mixture is heated to 50 ° C., the decolored carbon is filtered off and the methanol is removed. To this amount was added ethyl acetate to make 2 ml, then cooled to 0 ° C. and filtered to give 5- (2-tenoyl) -1,2-dihydro-3H-pyrrolo [1,2 at 147 ° C.-148 ° C. melting point. -a] 0.2 g (50%) of pyrrole-1-carboxylic acid is obtained. The melting point is the same after determining the compound twice with ethyl acetate and obtaining a purity of 79.8% by high pressure liquid chromatography.

[실시예 3]Example 3

빙초산 8ml 및 85% 인산 8ml의 혼합물에 1.6g의 5-(2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴을 첨가한다. 반응 혼합물을 질소로 정화하고 질소 대기하에서 110°-115℃로 2시간 20분간 유지시킨다. 반응 혼합물을 냉각하고 70% 수성 포화 염화 나트륨 용액-30% 물의 혼합물을 첨가한다. 침전하는 물질을 에틸 아세테이트 10ml로 추출하고, 추출물을 무수 황산 나트륨상에서 건조한 다음 용매를 모두 제거, 농축하고 헥산 20ml를 첨가한다. 여과하고 45℃의 진공하에서 건조하여 5-(2-테노일)-1,2-디하이드로-3H-피롤로 -〔1,2-a〕피롤-1-카르복실 산을 함유하는 조 생성물(고압액성 크로마토크래피로 측정한 결과 79% 순도) 1.66g(96.3%)을 얻는다.To a mixture of 8 ml glacial acetic acid and 8 ml 85% phosphoric acid is added 1.6 g of 5- (2-tenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile. The reaction mixture is purged with nitrogen and held at 110 ° -115 ° C. for 2 hours and 20 minutes under nitrogen atmosphere. The reaction mixture is cooled and a mixture of 70% aqueous saturated sodium chloride solution-30% water is added. The precipitated material is extracted with 10 ml of ethyl acetate, the extract is dried over anhydrous sodium sulfate, all solvent is removed, concentrated and 20 ml of hexane is added. A crude product containing 5- (2-tenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid, filtered and dried under vacuum at 45 ° C. 1.66 g (96.3%) of 79% purity was obtained as a result of high pressure liquid chromatography.

상기에서 얻은 조 생성물 1.4g을 메탄올 15ml에 첨가하고 탈색화 탄 0.5g을 첨가한 다음 15분간 교반하여 탄을 여과, 제거하고 5ml로 농축한 양에 물 5ml를 첨가한다. 상기 수성 혼합물을 10분간 교반하고 여과하여 5-(2-테노일)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-카르복실 산을 함유하는 생성물 1.1g(78.6%)을 얻는다.1.4 g of the crude product obtained above was added to 15 ml of methanol, 0.5 g of decolorized carbon was added, followed by stirring for 15 minutes to filter, remove the coal, and add 5 ml of water to the concentrated concentration to 5 ml. The aqueous mixture was stirred for 10 minutes and filtered to give product 1.1 containing 5- (2-tenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid. g (78.6%) is obtained.

상기에서 얻는 생성물 1.0g을 뜨거운 에틸 아세테이트 6ml에 첨가하고 상기 혼합물을 0℃로 냉각하여 15분간 교반한 다음, 여과하고 냉각(0℃) 에틸 아세테이트 2ml로 세척하여 158°-159℃ 융점의 5-(2-테노일)-1,2-디하이드로-3H-피롤로 -〔1,2-a〕피롤-1-카르복실산 0.6g(60%)을 얻는다. 표준 결정화 공정으로 에틸 아세테이트로부터 2차적인 생성물을 얻는다.1.0 g of the product obtained above was added to 6 ml of hot ethyl acetate and the mixture was cooled to 0 ° C. and stirred for 15 minutes, then filtered and washed with 2 ml of cooled (0 ° C.) ethyl acetate to give a 5-158 ° C.-159 ° C. melting point. 0.6 g (60%) of (2-tenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid is obtained. Standard crystallization processes give a secondary product from ethyl acetate.

[실시예 4]Example 4

2-메토옥시에탄올 7.8ml에 5-(2-테노일)-1,2-디하이드로-3H-피롤로 〔1,2-a〕피롤-1-니트릴 0.8g을 첨가한다. 질소로 정화하고 1.6ml의 20% 수성 수산화 칼륨 용액을 첨가한 다음 질소 대기하에서 상기 혼합물을 48분간 환류한다. 반응 용액을 20℃로 냉각하고 10ml의 물을 첨가한 다음 염화 메틸렌 20ml로 세척한다. 상기 수성층을 추출하고 농축 염산을 첨가하여 pH 3으로 조절한 다음 침전한 물질을 에틸 아세테이트 20ml로 추출하여 무수 황산 나트륨상에서 건조하고 건조 농축하며 5-(2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-카르복실 산을 함유하는 조 생성물 0.776g(90%)을 얻는다.To 7.8 ml of 2-methooxyethanol is added 0.8 g of 5- (2-tenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile. Purify with nitrogen, add 1.6 ml of 20% aqueous potassium hydroxide solution and reflux the mixture for 48 minutes under nitrogen atmosphere. The reaction solution is cooled to 20 ° C., 10 ml of water is added and washed with 20 ml of methylene chloride. The aqueous layer was extracted, adjusted to pH 3 by addition of concentrated hydrochloric acid, and the precipitated material was extracted with 20 ml of ethyl acetate, dried over anhydrous sodium sulfate, concentrated to dryness and 5- (2-tenoyl) -1,2-dihydro 0.776 g (90%) of crude product containing -3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid is obtained.

0.45g의 조 생성물을 뜨거운 에틸 아세테이트 5ml에 첨가하여 0℃로 냉각하고 5분간 교반한 다음 여과하여 2:1비율의 에틸 아세테이트-헥산 혼합물 2ml로 세척하고 45℃의 진공하에서 건조하여 157°-159℃ 융점의 5-(2-테노일)-1,2-디하이드로 -3H-피롤로-〔1,2-a〕피롤-1-카르복실산 0.32g(71% W/W)을 얻는다. 표준 결정화 공정으로 2차적인 생성물을 얻는다.0.45 g of crude product was added to 5 ml of hot ethyl acetate, cooled to 0 ° C., stirred for 5 minutes, filtered, washed with 2 ml of a 2: 1 ratio ethyl acetate-hexane mixture and dried under vacuum at 45 ° C. to 157 ° -159 0.32 g (71% W / W) of 5- (2-tenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid having a melting point of ° C is obtained. Standard crystallization processes yield secondary products.

상기 공정에서, 수산화 칼륨 대신 화학량적으로 동량의 수산화 나트륨 혹은 수산화 리튬을 사용하여 5-(2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-카르복실산을 얻는다.In this process, 5- (2-tenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 using stoichiometrically equal amounts of sodium or lithium hydroxide instead of potassium hydroxide Obtain carboxylic acid.

[실시예 5]Example 5

실시예 1,2,3 및 4 공정에 있어서, 5-(2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕-피롤-1-니트릴 대신 화학량적으로 동량의 하기 화합물 :Examples 1, 2, 3 and 4 in terms of stoichiometry for 5- (2-tenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1-nitrile Equivalent amounts of the following compounds:

5-벤조일-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-니트릴5-benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-nitrile

5- O-톨루오일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-O-Toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-m-톨루오일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-m-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-P-톨루오일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-P-Toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-P-메토옥시벤조일-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-니트릴5-P-methooxybenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-nitrile

5-P-에토옥시벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-P-Ethooxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-O-클로로벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-O-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-m-클로로벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-P-클로로벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-P-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-O-클로로벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-O-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5- m-클로로벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5- P-클로로벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5-P-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-(3-클로로-2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5- (3-chloro-2-tennoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-(4-클로로-2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5- (4-chloro-2-tenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-(5-클로로-2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5- (5-chloro-2-tenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-(3-클로로-2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5- (3-chloro-2-tennoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-(4-클로로-2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5- (4-chloro-2-tenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-(5-클로로-2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5- (5-chloro-2-tenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-(3-브로모-2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5- (3-bromo-2-tenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-(4-메틸-2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5- (4-methyl-2-tennoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-(5-메틸-2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5- (5-methyl-2-tennoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-(2-피로일)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-니트릴5- (2-Pyroyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-nitrile

5-(N-메틸-2-피로일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴5- (N-methyl-2-pyroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile

5-(N-n-부틸-2-피로일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-니트릴을 사용하여 각각 하기 화합물을 얻는다.5- (N-n-butyl-2-pyroyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-nitrile is used to obtain the following compounds, respectively.

160-161℃ 융점의 5-벤조일-1,2-디하이드로-3H-피톨로〔1,2-a〕피롤-1-카르복실산5-benzoyl-1,2-dihydro-3H-phytolo [1,2-a] pyrrole-1-carboxylic acid with a melting point of 160-161 ° C

유상의 5-O-톨루오일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-카르복실산Oily 5-O-Toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid

5-m-톨루오일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-카르복실산5-m-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid

182-183℃ 융점의 5-P-톨루오일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-카르복실산5-P-Toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid with a melting point of 182-183 ° C

187-187.5℃ 융점의 5-P-메토옥시벤조일-1,2-디하이드로로-3H-피롤로 〔1,2-a〕피롤-1-카르복실산5-P-methooxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid having a melting point of 187-187.5 ° C

169.5℃-170℃ 융점의 5-P-에토옥시벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-카르복실산5-P-Ethooxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid having a melting point of 169.5 ° C-170 ° C

5-0-클로로벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-카르복실산5-0-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid

180-181℃ 융점의 5-m-클로로벤조일-1,2-디하이드로-3H-피롤로 〔1,2 -a〕피롤-1-카르복실산5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid at 180-181 ° C. melting point

281.5-202.5℃ 융점의 5-P-클로로벤조일-1,2-디하이드로-3H-피롤로 〔1,2-a〕피롤-1-카르복실산5-P-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid at 281.5-202.5 ° C. melting point

5-0-플루오르벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-카르복실산5-0-Fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid

179.5-180.5℃ 융점의 5-P-플루오르벤조일-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-카르복실산5-P-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid having a melting point of 179.5-180.5 ° C

5-(3-클로로-2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-카르복실산5- (3-Chloro-2-tenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid

5-(4-클로로-2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-카르복실산5- (4-chloro-2-tenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid

5-(5-클로로-2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-카르복실산5- (5-chloro-2-tenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid

5-(3-브로모-2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-카르복실산5- (3-Bromo-2-tenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid

5-(4-브로모-2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-카르복실산5- (4-Bromo-2-tenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid

5-(5-브로모-2-테노일)-1,2-디하이드로-3H-피롤로〔1,2-a〕피롤-1-카르복실산5- (5-Bromo-2-tenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid

5-(3-메틸-2-테노일)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-카르복실산,5- (3-methyl-2-tenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid,

5-(4-메틸-2-테노일)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-카르복실산.5- (4-Methyl-2-tenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid.

5-(5-메틸-2-테노일)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-카르복실산,5- (5-methyl-2-tenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid,

217-218℃ 융점의 5-(2-피로일)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-카르복실산.5- (2-Pyroyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid having a melting point of 217-218 ° C.

161-161.5℃ 융점의 5-(N-메틸-2-피로일)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-카르복실산,5- (N-methyl-2-pyroyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid having a melting point of 161-161.5 ° C.,

5-(N-n-부틸-2-피로일)-1,2-디하이드로-3H-피롤로-〔1,2-a〕피롤-1-카르복실산,5- (N-n-butyl-2-pyroyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid,

Claims (1)

하기 구조식(II)의 화합물을 가수분해하여 하기 구조식(I)의 화합물을 제조하는 방법 :A method for preparing a compound of formula (I) by hydrolysis of a compound of formula (II):

상기 식에서 Y는Where Y is

(여기에서 R은 티오펜환의 3,4 혹은 5 위치에 존재하는 치환물로서 수소, 메틸, 클로로 혹은 브로모이고, R¹은 아토일기의 오르토, 메타 혹은 파라 위치에 존재하는 치환물로서 수소, 1에서 4탄소 원자의 저급 알킬기, 1에서 4탄소원자의 저급알콕시기, 클로로, 플루오로 혹은 브로모이고, R²는 수소, 또는 1에서 4탄소 원자의 저급 알킬기임)이다.Wherein R is hydrogen, methyl, chloro or bromo as a substituent in the 3,4 or 5 position of the thiophene ring, and R ¹ is hydrogen, 1 as the substituent in the ortho, meta or para position of the atoyl group. Is a lower alkyl group of 4 carbon atoms in, a lower alkoxy group of 1 to 4 carbon atoms, chloro, fluoro or bromo, and R ² is hydrogen or a lower alkyl group of 1 to 4 carbon atoms.