KR810001744B1 - Process for preparing benzin.midazolinone derivatives - Google Patents
Process for preparing benzin.midazolinone derivatives Download PDFInfo
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- KR810001744B1 KR810001744B1 KR1019800004477A KR800004477A KR810001744B1 KR 810001744 B1 KR810001744 B1 KR 810001744B1 KR 1019800004477 A KR1019800004477 A KR 1019800004477A KR 800004477 A KR800004477 A KR 800004477A KR 810001744 B1 KR810001744 B1 KR 810001744B1
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Description
본 발명은 하기 구조식(1)로 표시되는 벤즈이미다졸리논 유도체 및 그 염의 신규제조방법에 관한 것이다.The present invention relates to a benzimidazolinone derivative represented by the following structural formula (1) and a novel production method thereof.
본 제품은 현저한 진토작용(Antiemetics)를 보이며 특히 소화불량이나 구토증에 효과가 있는 약물이라고 알려지고 있다. 종래의 이와 유사한 화합물등의 제조방법에 대해서는 다수의 특허가 존재하며 그중 몇가지를 소개하면 다음과 같다.This product has a pronounced antitiemetic effect and is known to be particularly effective for indigestion and vomiting. A number of patents exist for a conventional method for preparing similar compounds and the like, and some of them are as follows.
첫째) 벨지움 특허 제844087호에 의하면Firstly, according to Belgian patent no.
등의 제조방법이 알려지고 있다.Production methods such as these are known.
둘째) 미국특허 제3196157호에 의하면 하기의 제조방법이 기재되어 있다.Secondly, according to US Patent No. 3196157, the following manufacturing method is described.
(상기 구조식 중 n은 2-5, R1은 수소, 하이드록시, 시아노, 카바모일, 저급알킬카보닐로 구성된기, R2는 아릴, R3는 아릴 또는 아릴메틸렌, R4는 수소, 저급알킬, 저급알킬카보닐, 저급알콕시 저급알킬로 구성된 기로 선택된다.(Wherein n is 2-5, R 1 is hydrogen, hydroxy, cyano, carbamoyl, lower alkylcarbonyl, R 2 is aryl, R 3 is aryl or arylmethylene, R 4 is hydrogen, Lower alkyl, lower alkylcarbonyl, lower alkoxy lower alkyl.
셋째) 미국특허 제3989707호에 의하면 하기 제조방법이 기재되어 있다.Third) According to US Pat. No. 3,89,707, the following manufacturing method is described.
상기식에서 Ar1및 Ar2는 페닐, 할로페닐등이며, R1, R2는 수소, 할로, 저급알킬등이며, R3는 수소, 메틸 L은 수소, 저급알킬, 페닐저급알킬 등이다.In the above formula, Ar 1 and Ar 2 are phenyl, halophenyl, and the like, R 1 , R 2 are hydrogen, halo, lower alkyl and the like, R 3 is hydrogen, methyl L is hydrogen, lower alkyl, phenyl lower alkyl and the like.
넷째) 이들 외에도 본 발명의 목적물과 구조 및 효과가 유사한 제제에 대한 제조 방법이 한국 특허 제5010,7594호, 그리고 미국특허 제3141823,3161645호 및 영국특허 제989755,1542514호, 벨기에 특허 제830403호, 프랑스 특허 제3695M호, 독일공개 특허 제2632870호가 있으며 또한 일본 공개특허 소48-92378, 51-13780호 등 다수가 존재한다.Fourth) In addition to this, a preparation method for a preparation having a structure and effect similar to the object of the present invention is disclosed in Korean Patent No. 5010,7594, US Patent Nos. , French Patent No. 3695M, German Laid-Open Patent No. 2632870, and many others, including Japanese Patent Laid-Open Nos. 48-92378 and 51-13780.
특히 미국 특허 제3161645호 및 미국 특허 명세서 일련번호 제417702호에 의하면 하기 일반식(M)을 갖는 화합물의 제조방법이 공지되어 있다.In particular, according to US Pat. No. 3191645 and US Pat. No. 417702, methods for preparing compounds having the general formula (M) are known.
상기식에서 R1은 할로, 저급알킬 및 트리플루오로 메틸이며 R2는 수소, 할로, 저급알킬 및 트리플루오로 메틸이고 R3는 수소 및 메틸인데 R3가 메틸일때 R3는 피페리딘핵의 2-나 3-위치에 있으며 L는 수소, 저급알킬, 저급알킬옥시 카르보닐-저급알킬, 저급알킬카르보닐-저급알킬 및 페닐 저급알킬이다.Wherein R 1 is halo, lower alkyl and trifluoro methyl, R 2 is hydrogen, halo, lower alkyl and trifluoro methyl and R 3 is hydrogen and methyl when R 3 is methyl and R 3 is 2 of the piperidine nucleus. In the 3-position and L is hydrogen, lower alkyl, lower alkyloxy carbonyl-lower alkyl, lower alkylcarbonyl-lower alkyl and phenyl lower alkyl.
상기 방법중 특히 첫째) 방법에 의하여 제조되는 물질은 본 발명의 목적물과 동일한 화합물을 얻을 수 있으나 종래의 제조방법은 반응공정이 까다롭고 반응중 부산물의 생성으로 인하여 반복되는 세척 및 재결정을 하여야 비로서 순수한 목적들을 얻을 수 있어 원료의 손실이 많을 뿐만 아니라 수율은 통상 30%정도로 저조하여 본 제품을 대규모적으로 제조하기에는 공정상 또는 산업상 적당치 못하였다.Particularly, the material prepared by the first method of the above method can obtain the same compound as the object of the present invention. However, the conventional production method is difficult to perform the reaction process and requires repeated washing and recrystallization due to the generation of by-products during the reaction. Pure objectives can be attained, resulting in high loss of raw materials and low yields of around 30%, making them unsuitable for process or industrial production on a large scale.
또한 각 반응은 축합 반응으로서 고가의 4-메틸-2-펜타논등을 유기용매로 사용하였으며, 반응 속도가 완만하므로 이를 촉진키 위해 조촉매인 고가의 칼륨아이오다이드(K1)를 사용하고 있어 비록 소량을 사용한다 하여도 대량 생산시 원료가의 고가 상승을 배제할 수 없었던 것이다.In addition, each reaction used expensive 4-methyl-2-pentanone as an organic solvent as a condensation reaction, and since the reaction rate is slow, expensive potassium iodide (K1), which is a promoter, is used to promote this reaction. Even if a small amount was used, high prices of raw materials could not be excluded during mass production.
본 발명은 종래의 이와 같은 결점을 개선하여 반응 부산물의 생성을 방지하고 고가의 유기용매나 조촉매를 사용함이 없이 간단한 환원반응에 의하여 본 목적물을 제조할 수 있는 방법으로서 반응이 간편할 뿐만 아니라 대량으로 고수율의 목적물을 제조하기에 적당하며 종래의 것보다 개량된 방법으로서 그 의의가 크다.The present invention improves these drawbacks in the prior art to prevent the formation of reaction by-products and to produce the target product by a simple reduction reaction without the use of expensive organic solvents or promoters, the reaction is not only simple but also large quantities It is suitable for producing a high yield of the target object and the significance of the improved method than the conventional one.
즉 공지 화합물인 4-(5-클로로-2-옥소-1-벤즈 이미다졸리딜)-1-피페리딘 염산염(2)에 염가로 제공이 가능한 1-클로로-3-부로모-푸로판-2-온 (3)을 축합시켜 구조식(4) 화합물을 제조하고 여기에 다시 소이움아마이드 존재하에서 공지 화합물인 구조식(5) 화합물을 축합시켜 구조식(6) 화합물을 제조함을 특징으로 하여 구조식(6) 화합물을 환원시켜 비교적 간단하고 고수율로 목적물(1)을 얻는 방법인 것이다.That is, 1-chloro-3-bromo-furophane which can be provided inexpensively to the known compound 4- (5-chloro-2-oxo-1- benz imidazolidyl) -1-piperidine hydrochloride (2) 2-one (3) is condensed to produce the compound of formula (4), and condensation of the compound of formula (5), which is a known compound, in the presence of sodium amide, to produce the compound of formula (6) (6) It is a method of obtaining the target object (1) in a relatively simple and high yield by reducing the compound.
본 발명을 반응도표로 표시하면 다음과 같다.When the present invention is represented by the reaction diagram as follows.
본 발명을 실시예에 따라 구체적으로 설명하면 하기와 같으며 실시예중 모든 부는 중량부를 뜻하는 것이다.Hereinafter, the present invention will be described in detail with reference to the following examples, and all parts in the examples refer to parts by weight.
[실시예 1]Example 1
1-4-(5-클로로-2-옥소-1-벤즈이미다졸리딜)-1-피페리딜-3-클로로 푸로판-2-온의 제조.Preparation of 1-4- (5-chloro-2-oxo-1-benzimidazolidyl) -1-piperidyl-3-chloro furophan-2-one.
4-(5-클로로-2-옥소-1-벤즈 이미다졸리딜)-1-피페리딘 염산염 4.2부를 가열하면서 140부의 테트라 히드로 푸란에 용해시킨 다음 여기에 메탄을 내 5부의 3-클로로-1-부로모-푸로판-2-온을 녹인 용액을 적가하고 4부의 트리에틸 아민을 연속적으로 첨가한다. 전체를 증발시키고 남은 고체 잔유물을 물과 염산용액으로 연속 세척하고 결정화시켜 8.2부의 1-4-(5-클로로-2-옥소-1-벤즈이미다졸리딜)-1-피페리딜-3-클로로푸로판-2-온의 백색 결정을 얻는다. (수율 84.5%)4.2 parts of 4- (5-chloro-2-oxo-1-benzimidazolidil) -1-piperidine hydrochloride were dissolved in 140 parts of tetrahydrofuran while heating, and then methane was added to 5 parts of 3-chloro- A solution of 1-Buromo-furopan-2-one is added dropwise and 4 parts of triethyl amine are added continuously. The whole was evaporated and the remaining solid residue was washed successively with water and hydrochloric acid solution and crystallized to give 8.2 parts of 1-4- (5-chloro-2-oxo-1-benzimidazolidyl) -1-piperidyl-3- Obtain white crystals of chlorofuropan-2-one. (Yield 84.5%)
융 점 : 123-126℃ C MW342.03Melting Point: 123-126 ℃ C MW342.03
C15H17N3Cl2O2 C 15 H 17 N 3 Cl 2 O 2
이론치 : C 49.45 ; H 4.67 ; N 15.38 ; Cl 22.71 ; O 8.79Theoretic value: C 49.45; H 4.67; N 15.38; C1 22.71; O 8.79
실험치 : C 49.51 ; H 4.65 ; N 15.33 ; Cl 22.68 ; O 8.83Found: C 49.51; H 4.65; N 15.33; C1 22.68; O 8.83
[실시예 2]Example 2
1-4-(5-클로로-2-옥소-1-벤즈이미다졸리딜)-1-피페리딜-3-(2-옥소-1-벤즈 이미다졸리딜)-푸로판-2-온의 제조.1-4- (5-chloro-2-oxo-1-benzimidazolidyl) -1-piperidyl-3- (2-oxo-1-benzimidazolidyl) -furopan-2-one Manufacturing.
1-4-(5-클로로-2-옥소-1-벤즈 이미다졸리딜)-1-피페리딜-3-클로로 푸로판-2-온 5.6부와 소디움아마이드 1.05부 및 4-(2-옥소-1-벤즈 이미다졸딜)-5-피페리딘 염산염 4.6부를 70℃로 가열하면서 132부의 벤젠 및 14부의 메탄올의 혼합 용액에 조금씩 적가하면서 교반하고 58℃에서 2시간 동안 교반 및 환류시킨다.5.6 parts of 1-4- (5-chloro-2-oxo-1-benzimidazolidil) -1-piperidyl-3-chloro furophan-2-one with 1.05 parts of sodium amide and 4- (2- 4.6 parts of oxo-1-benzimidazolyl) -5-piperidine hydrochloride are stirred dropwise into a mixed solution of 132 parts of benzene and 14 parts of methanol while heating to 70 ° C. and stirred and refluxed at 58 ° C. for 2 hours.
현탁액을 실온에서 격렬하게 진탕하며 18시간 유지한 후 다시 30부의 물을 가하여 현탁하고 침전된 생성물을 여과하고 아세톤으로 세척하여 6.15부의 1-4-(5-클로로-2-옥소-1-벤즈아미다졸리딜)-1-피페리딜-3-(2-옥소-1-벤즈이미다졸리딜)-푸로판-2-온의 결정물을 얻는다.(수율 92.5%)The suspension was vigorously shaken at room temperature and held for 18 hours. The suspension was then suspended by addition of 30 parts of water and the precipitated product was filtered and washed with acetone to give 6.15 parts of 1-4- (5-chloro-2-oxo-1-benzami Obtained crystals of dazolidil) -1-piperidyl-3- (2-oxo-1-benzimidazoliyl) -furopan-2-one (yield 92.5%).
융 점 : 173-176℃ MW 439.5Melting Point: 173-176 ℃ MW 439.5
C22H22Cl N5O3 C 22 H 22 Cl N 5 O 3
이론치 : C 60.06 ; H 5.03 ; Cl 8.07 ; N 15.92 ; O 10.92Theoretic value: C 60.06; H 5.03; C1 8.07; N 15.92; O 10.92
실험치 : C 59.84 ; H 5.15 ; Cl 8.11 ; N 15.87 ; O 11.03Found: C 59.84; H 5.15; C1 8.11; N 15.87; O 11.03
[실시예 3]Example 3
1-4-(5-클로로-2-옥소-1-벤즈이미다졸리딜)-1-피페리딜-3-(2-옥소-1-벤즈 이미다졸리딜) 푸로판 및 염산염의 제조 70부의 테트라하이드로 푸란과 1.5부의 리튬알루미늄 하이드라이드의 교반 혼합물에 58부의 테트라하이드로 푸란내 5.1부의 1-4-(5-클로로-2-옥소-1-벤즈 이미다졸리딜)-1-피페리딜-3-(2-옥소-1-벤즈 이미다졸리딜) 푸로판-2-온을 녹인 용액을 소량씩 첨가한 후 전체를 실온에서 1.5시간동안 교반하고 환류온도에서 2시간 교반한다. 이와 같이 한 반응 혼합물을 10℃로 냉각하고 1.1부의 물 0.8부의 17% 수산화나트륨 용액, 그리고 3.7부의 물을 연속적으로 첨가하여 분해시킨다. 전 반응 혼합물을 여과한 후 에텔로 세척하고 증발, 건고시켜 4.6부의 1-4-(5-클로로-2-옥소-1-벤즈 이미다졸리딜)-1-피페리딜-3-(2-옥소-1-벤즈이미다졸리딜)푸로판을 얻는다. (수율 96.4%)Preparation of 1-4- (5-chloro-2-oxo-1-benzimidazolidyl) -1-piperidyl-3- (2-oxo-1-benz imidazolidyl) furophan and hydrochloride 70 5.1 parts 1-4- (5-chloro-2-oxo-1-benz imidazolidyl) -1-piperidyl in 58 parts tetrahydrofuran in a stirred mixture of parts tetrahydrofuran and 1.5 parts lithium aluminum hydride A small amount of -3- (2-oxo-1-benzimidazoliyl) furanpan-2-one was added in small portions, and the whole was stirred at room temperature for 1.5 hours and at reflux for 2 hours. The reaction mixture was cooled to 10 ° C. and decomposed by successively adding 1.1 parts of 0.8 parts of 17% sodium hydroxide solution, and 3.7 parts of water. The entire reaction mixture was filtered, washed with ether, evaporated and dried to give 4.6 parts of 1-4- (5-chloro-2-oxo-1-benz imidazolidyl) -1-piperidyl-3- (2- Obtain oxo-1-benzimidazoliyl) furopane. (Yield 96.4%)
융 점 : 252-245℃ MW 425.65Melting Point: 252-245 ℃ MW 425.65
C22H24N5O2ClC 22 H 24 N 5 O 2 Cl
이론치 : C 62.02 ; H 5.68 ; N 16.45 ; O 7.52 ; Cl 8.33Theoretic value: C 62.02; H 5.68; N 16.45; 0 7.52; Cl 8.33
실험치 : C 59.95 ; H 5.63 ; N 16.48 ; L 7.56 ; Cl 8.38Found: C 59.95; H 5.63; N 16.48; L 7.56; Cl 8.38
계속하여 상기 결정성 물질을 메탄올과 에텔내에서 염화수소 가스로 처리하여 염산염을 얻는다.The crystalline material is then treated with hydrogen chloride gas in methanol and ether to obtain hydrochloride.
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