KR100382715B1 - Process for the preparation of 4-hydroxythiocoumarin and nitrogen analogues thereof - Google Patents
Process for the preparation of 4-hydroxythiocoumarin and nitrogen analogues thereof Download PDFInfo
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- KR100382715B1 KR100382715B1 KR10-1999-0048102A KR19990048102A KR100382715B1 KR 100382715 B1 KR100382715 B1 KR 100382715B1 KR 19990048102 A KR19990048102 A KR 19990048102A KR 100382715 B1 KR100382715 B1 KR 100382715B1
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- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
본 발명은 일반식 (1)로 표시되는 쿠마린 유사체의 제조방법에 관한 것으로 일반식 (2)의 화합물과 일반식 (3)의 화합물을 염기조건 하에서 반응시킨 다음, 산 처리하여 일반식 (1)의 화합물을 제조한다.The present invention relates to a method for preparing a coumarin analogue represented by the general formula (1), wherein the compound of the general formula (2) and the compound of the general formula (3) are reacted under basic conditions, followed by acid treatment, to give a general formula (1) To prepare a compound.
상기식에서 X는 S 또는 -NH를 표시하고, R 및 R'은 같거나 다를 수 있으며, 각각 할로겐원자 또는 C1-4저급알콕시기이다.Wherein X represents S or —NH, and R and R ′ may be the same or different and are each a halogen atom or a C 1-4 lower alkoxy group.
본 발명은 상대적으로 저렴한 반응물질을 사용하여 용이한 반응공정으로, 순도가 높은 목적화합물을 높은 수율로 얻을 수 있으므로 산업상 이용가능성에서 뛰어난 효과를 기대할 수 있다.The present invention is an easy reaction process using a relatively inexpensive reactant, it is possible to obtain an excellent effect in the industrial applicability because the high purity of the target compound can be obtained in a high yield.
Description
본 발명은 뇌혈관 질환, 살서제 등 다양한 약리학적 활성을 갖는 쿠마린계 화합물의 원료물질인 4-히드록시티오쿠마린 및 그의 질소 유사체의 제조 방법에 관한 것이다.The present invention relates to a method for producing 4-hydroxythiocoumarin and its nitrogen analogs, which are raw materials of coumarin-based compounds having various pharmacological activities such as cerebrovascular disease and acaricide.
기존의 4-히드록시티오쿠마린 또는 4-히드록시퀴놀론의 제조방법은 티오페놀 또는 아닐린을 말론산 또는 말론산에스테르와 반응시키고 POCl3와 염화아연을 첨가하여 4-히드록시티오쿠마린 또는 4-히드록시퀴놀론을 제조하였다. 이러한 종래의 제조방법은 반응조건이 격렬하고, 수율이 저조할 뿐 만아니라 제조공정이 복잡하여, 4-히드록시티오쿠마린 또는 그의 질소 유사체를 제조하는데 많은 문제점이 있었다. 본 발명에서 이러한 문제점을 해결하고, 나아가 고순도의 쿠마린 유사체의 제조연구를 수행한 결과 본 발명을 완성하게 되었다.Conventional methods for preparing 4-hydroxythiocoumarin or 4-hydroxyquinolone are reactions of thiophenol or aniline with malonic acid or malonic acid ester and addition of POCl 3 and zinc chloride to 4-hydroxythiocoumarin or 4-hydride. Roxyquinolone was prepared. This conventional manufacturing method has a lot of problems in producing 4-hydroxythiocoumarin or its nitrogen analogues because of the violent reaction conditions, low yields, and complicated manufacturing processes. In order to solve these problems in the present invention, and to further study the preparation of high purity coumarin analogues, the present invention has been completed.
따라서, 본 발명의 목적은 저렴하고, 손쉽게 구할 수 있는 원료를 사용하여 용이한 제조 공정으로 4-히드록시티오쿠마린 또는 그의 질소유사체를 높은 수율로제조하는 방법을 제공하는 것이다.Accordingly, it is an object of the present invention to provide a method for producing 4-hydroxythiocoumarin or its nitrogen analogs in high yield in an easy manufacturing process using inexpensive and readily available raw materials.
본 발명을 다음에서 상세히 설명한다.The invention is explained in detail in the following.
본 발명은 일반식 (1)로 표시한 쿠마린 유사체의 합성방법을 제시하는 것으로, 구체적으로 설명하면, 일반식 (2)로 표시되는 화합물을 일반적인 유기용매에 혼합하고 염기 조건 하에서 일반식 (3)으로 표시되는 화합물과 실온교반 또는 환류한다. 이를 실온으로 냉각한 다음 산 처리하고 결정을 여과, 건조하여 일반식 (1)로 표시한 쿠마린 유사체를 얻는다.The present invention provides a method for synthesizing a coumarin analogue represented by the general formula (1). Specifically, the compound represented by the general formula (2) is mixed with a general organic solvent, and the general formula (3) The mixture is stirred at room temperature or refluxed. It is cooled to room temperature and then acid treated and the crystals are filtered and dried to obtain a coumarin analogue represented by the general formula (1).
이를 반응식 1에 나타내었다.This is shown in Scheme 1.
반응식 1Scheme 1
(2) (3) (1)(2) (3) (1)
상기식에서 X는 S 또는 -NH를 표시하고, R 및 R'은 같거나 다를 수 있으며, 각각 할로겐원자 또는 C1-4저급알콕시기이다.Wherein X represents S or —NH, and R and R ′ may be the same or different and are each a halogen atom or a C 1-4 lower alkoxy group.
할로겐원자로서는 클로라인, C1-4저급알콕시기로서는 에톡시기가 바람직하다.As a halogen atom, a chlorine is preferable and as a C 1-4 lower alkoxy group, an ethoxy group is preferable.
본 발명에 사용될 수 있는 유기용매는 통상적으로 널리 사용되는 유기용매로서, 예를 들면, 톨루엔, 벤젠, 메탄올, 에탄올, 부탄올, 디클로로메탄, 클로로포름 등을 들 수 있다.Organic solvents that can be used in the present invention are commonly used organic solvents, for example, toluene, benzene, methanol, ethanol, butanol, dichloromethane, chloroform and the like.
염기로서는, 소디움하이드라이드, 포타시움-티-부톡사이드, 소디움하이드록사이드를 사용할 수 있다.As the base, sodium hydride, potassium-t-butoxide, sodium hydroxide can be used.
다음의 실시예에서 본 발명을 상세하게 설명하지만 본 발명이 다음의 실시예로 한정되는 것은 아니다.The present invention is described in detail in the following examples, but the present invention is not limited to the following examples.
A) 4-히드록시티오쿠마린의 제조방법에 대한 실시예A) Example for the preparation of 4-hydroxythiocoumarin
4-히드록시-1-티오쿠마린의 합성Synthesis of 4-hydroxy-1-thiocoumarin
실시예 1Example 1
2-머캅토아세토페논(7.6 g, 50 mmol), 디에틸카르보네이트(14.8 g, 125 mmol)을 톨루엔(50 mL)에 혼합하고 여기에 NaH(3.0 g, 75 mmol, 60% dispersion mineral oil)를 톨루엔(16 mL)에 현탁한 용액을 질소분위기하에서 30분동안 적가한다. 반응혼합물을 1시간동안 환류교반한 다음 에탄올을 제거한 후 반응액을 실온으로 냉각한다. 반응혼합물에 물(36 mL)과 5%-염산(8 mL)을 넣어서, 생성된 고체를 여과, 물로 세척 후, 건조하여 미황색의 결정을 얻었다(86%, 7.7 g).2-mercaptoacetophenone (7.6 g, 50 mmol) and diethylcarbonate (14.8 g, 125 mmol) were mixed in toluene (50 mL) and added to NaH (3.0 g, 75 mmol, 60% dispersion mineral oil). ) Is added dropwise to toluene (16 mL) for 30 minutes under nitrogen atmosphere. After the reaction mixture was stirred under reflux for 1 hour, ethanol was removed and the reaction mixture was cooled to room temperature. Water (36 mL) and 5% hydrochloric acid (8 mL) were added to the reaction mixture, and the resulting solid was filtered, washed with water and dried to give a pale yellow crystal (86%, 7.7 g).
mp: 209-210℃mp: 209-210 ° C.
1H NMR (300 MHz, CDCl3) δ 11.64 (s, 1 H), 7.98-7.81 (m, 1 H),7.43-7.30 (m, 3 H), 5.93 (br s, 1 H) 1 H NMR (300 MHz, CDCl 3 ) δ 11.64 (s, 1 H), 7.98-7.81 (m, 1 H), 7.43-7.30 (m, 3 H), 5.93 (br s, 1 H)
13C NMR (75.47 MHz, CDCl3) δ 189.56, 171.28, 135.29, 132.89, 131.17, 129.51, 128.94, 126.81, 109.91 13 C NMR (75.47 MHz, CDCl 3 ) δ 189.56, 171.28, 135.29, 132.89, 131.17, 129.51, 128.94, 126.81, 109.91
IR (νmax, KBr) 3061-2550, 1519, 1265IR (ν max , KBr) 3061-2550, 1519, 1265
실시예 2Example 2
2-머캅토아세토페논(7.6 g, 50 mmol), 디에틸카르보네이트(14.8g, 125 mmol)을 디클로로메탄(60 mL)에 혼합하고 여기에 t-BuOK(10.1 g, 75 mmol)를 디클로로메탄(20 mL)에 현탁한 용액을 질소분위기하에서 30분동안 적가한다. 반응혼합물을 1시간동안 환류교반한 다음 증류하여 용매를 제거한 후 잔사에 물(32 mL)과 5%-염산(8 mL)을 넣어서, 생성된 고체를 여과, 물로 세척 후, 건조하여 미황색의 결정을 얻었다(76%, 6.8 g).2-mercaptoacetophenone (7.6 g, 50 mmol) and diethylcarbonate (14.8 g, 125 mmol) were mixed in dichloromethane (60 mL) and t-BuOK (10.1 g, 75 mmol) was added to dichloromethane. The solution suspended in methane (20 mL) is added dropwise under nitrogen atmosphere for 30 minutes. The reaction mixture was stirred under reflux for 1 hour, distilled to remove the solvent, and then water (32 mL) and 5% hydrochloric acid (8 mL) were added to the residue. The resulting solid was filtered, washed with water, and dried to light yellow crystals. Was obtained (76%, 6.8 g).
실시예 3Example 3
2-머캅토아세토페논(7.6 g, 50 mmol), 디에틸카르보네이트(14.8 g, 125 mmol)을 에탄올(44 mL)에 혼합하고 여기에 NaH(3.0 g, 75 mmol, 60% dispersion mineral oil)를 에탄올(10 mL)에 현탁한 용액을 질소분위기하에서 30분동안 적가한다. 반응혼합물을 1시간동안 환류교반한 다음 에탄올을 제거한 후 반응액을 실온으로 냉각한다. 잔사에 물(36 mL)과 5%-염산(8 mL)을 넣어서, 생성된 고체를 여과, 물로 세척 후, 건조하여 미황색의 결정을 얻었다(80%, 7.1 g).2-mercaptoacetophenone (7.6 g, 50 mmol) and diethylcarbonate (14.8 g, 125 mmol) were mixed in ethanol (44 mL) and NaH (3.0 g, 75 mmol, 60% dispersion mineral oil) ) Is added dropwise to the solution suspended in ethanol (10 mL) for 30 minutes under nitrogen atmosphere. After the reaction mixture was stirred under reflux for 1 hour, ethanol was removed and the reaction mixture was cooled to room temperature. Water (36 mL) and 5% hydrochloric acid (8 mL) were added to the residue. The resulting solid was filtered, washed with water, and dried to give a pale yellow crystal (80%, 7.1 g).
실시예 4Example 4
2-머캅토아세토페논(7.6 g, 50 mmol), 에틸클로로퍼메이트(13.6 g, 125 mmol)을 톨루엔(50 mL)에 혼합하고 여기에 NaH(3.0 g, 75 mmol, 60% dispersion mineral oil)를 톨루엔(16 mL)에 현탁한 용액을 질소분위기하에서 30분동안 적가한다. 반응혼합물을 1시간동안 환류교반한 다음 에탄올을 제거한 후 반응액을 실온으로 냉각한다. 잔사에 물(36 mL)과 5%-염산(8 mL)을 넣어서, 생성된 고체를 여과, 물로 세척 후, 건조하여 미황색의 결정을 얻었다(80%, 7.1 g).2-mercaptoacetophenone (7.6 g, 50 mmol) and ethylchloropermate (13.6 g, 125 mmol) were mixed in toluene (50 mL) and NaH (3.0 g, 75 mmol, 60% dispersion mineral oil) The solution suspended in toluene (16 mL) was added dropwise for 30 minutes under nitrogen atmosphere. After the reaction mixture was stirred under reflux for 1 hour, ethanol was removed and the reaction mixture was cooled to room temperature. Water (36 mL) and 5% hydrochloric acid (8 mL) were added to the residue. The resulting solid was filtered, washed with water, and dried to give a pale yellow crystal (80%, 7.1 g).
B) 4-히드록시퀴놀론의 제조방법에 대한 실시예B) Example for the preparation of 4-hydroxyquinolone
4-히드록시퀴놀린-2(14-hydroxyquinoline-2 (1 HH )-온의 합성Synthesis of -one
실시예 5Example 5
2-아미노아세토페논(8.1 g, 60 mmol), 디에틸카르보네이트(17.7 g, 150 mmol)을 톨루엔(55 mL)에 혼합하고 여기에 NaH(3.6 g, 90 mmol, 60% dispersion mineral oil)를 톨루엔(16 mL)에 현탁한 용액을 질소분위기하에서 30분동안 적가한다. 반응혼합물을 1시간동안 환류교반한 다음 에탄올을 제거한 후 반응액을 실온으로 냉각한다. 반응혼합물에 물(36 mL)과 5%-염산(8 mL)을 넣어서, 생성된 고체를 여과, 물로 세척 후, 건조하여 미황색의 결정을 얻었다(83%, 7.9 g).2-aminoacetophenone (8.1 g, 60 mmol) and diethylcarbonate (17.7 g, 150 mmol) were mixed in toluene (55 mL) and NaH (3.6 g, 90 mmol, 60% dispersion mineral oil) The solution suspended in toluene (16 mL) was added dropwise for 30 minutes under nitrogen atmosphere. After the reaction mixture was stirred under reflux for 1 hour, ethanol was removed and the reaction mixture was cooled to room temperature. Water (36 mL) and 5% hydrochloric acid (8 mL) were added to the reaction mixture. The resulting solid was filtered, washed with water, and dried to give a pale yellow crystal (83%, 7.9 g).
mp: 300℃ (dec)mp: 300 ° C. (dec)
1H NMR (300 MHz, DMSO) δ 13.42 (s, 1 H), 10.27 (s, 1 H), 8.73 (d,J=8.44, 1 H), 7.76-7.32 (m, 3 H), 6.33 (s, 1 H) 1 H NMR (300 MHz, DMSO) δ 13.42 (s, 1 H), 10.27 (s, 1 H), 8.73 (d, J = 8.44, 1 H), 7.76-7.32 (m, 3H), 6.33 ( s, 1 H)
13C NMR (75.47 MHz, DMSO) δ 162.46, 160.80, 155.52, 138.09, 130.47, 125.70, 119.03, 115.41, 87.67 13 C NMR (75.47 MHz, DMSO) δ 162.46, 160.80, 155.52, 138.09, 130.47, 125.70, 119.03, 115.41, 87.67
IR (νmax, KBr) 3276, 2867, 1647, 1466, 1267IR (ν max , KBr) 3276, 2867, 1647, 1466, 1267
실시예 6Example 6
2-아미노아세토페논(8.1 g, 60 mmol), 디에틸카르보네이트(17.7 g, 150 mmol)을 디클로로메탄(60 mL)에 혼합하고 여기에 t-BuOK(10.1 g, 90 mmol)를 디클로로메탄(20 mL)에 현탁한 용액을 질소분위기하에서 30분동안 적가한다. 반응혼합물을 1시간동안 환류교반한 다음 증류하여 용매를 제거한 후 반응액을 실온으로 냉각한다. 반응혼합물에 물(30 mL)과 5%-염산(8 mL)을 넣어서, 생성된 고체를 여과, 물로 세척 후, 건조하여 미황색의 결정을 얻었다(73%, 7.1 g).2-aminoacetophenone (8.1 g, 60 mmol) and diethylcarbonate (17.7 g, 150 mmol) were mixed in dichloromethane (60 mL) and t-BuOK (10.1 g, 90 mmol) was added to dichloromethane. The solution suspended in (20 mL) is added dropwise under nitrogen atmosphere for 30 minutes. The reaction mixture was stirred at reflux for 1 hour and then distilled to remove the solvent, and then the reaction mixture was cooled to room temperature. Water (30 mL) and 5% hydrochloric acid (8 mL) were added to the reaction mixture. The resulting solid was filtered, washed with water, and dried to give a pale yellow crystal (73%, 7.1 g).
실시예 7Example 7
2-아미노아세토페논(8.1 g, 60 mmol), 디에틸카르보네이트(17.7 g, 150 mmol)을 에탄올(44 mL)에 혼합하고 여기에 NaH(3.6 g, 90 mmol, 60% dispersion mineral oil)를 에탄올(12 mL)에 현탁한 용액을 질소분위기하에서 30분동안 적가한다. 반응혼합물을 1시간동안 환류교반한 다음 에탄올을 제거한 후 반응액을 실온으로 냉각한다. 반응혼합물에 물(36 mL)과 5%-염산(8 mL)을 넣어서, 생성된 고체를 여과, 물로 세척 후, 건조하여 미황색의 결정을 얻었다(82%, 7.8 g).2-aminoacetophenone (8.1 g, 60 mmol) and diethylcarbonate (17.7 g, 150 mmol) were mixed in ethanol (44 mL) and NaH (3.6 g, 90 mmol, 60% dispersion mineral oil) The solution suspended in ethanol (12 mL) was added dropwise under nitrogen atmosphere for 30 minutes. After the reaction mixture was stirred under reflux for 1 hour, ethanol was removed and the reaction mixture was cooled to room temperature. Water (36 mL) and 5% hydrochloric acid (8 mL) were added to the reaction mixture. The resulting solid was filtered, washed with water, and dried to give a pale yellow crystal (82%, 7.8 g).
실시예 8Example 8
2-아미노아세토페논(8.1 g, 60 mmol), 에틸클로로퍼메이트(13.6 g, 125 mmol)을 톨루엔(50 mL)에 혼합하고 여기에 NaH(3.0 g, 75 mmol, 60% dispersion mineral oil)를 톨루엔(16 mL)에 현탁한 용액을 질소분위기하에서 30분동안 적가한다. 반응혼합물을 1시간동안 환류교반한 다음 에탄올을 제거한 후 반응액을 실온으로 냉각한다. 반응혼합물에 물(36 mL)과 5%-염산(8 mL)을 넣어서, 생성된 고체를 여과, 물로 세척 후, 건조하여 미황색의 결정을 얻었다(76%, 7.3 g).2-aminoacetophenone (8.1 g, 60 mmol) and ethylchloropermate (13.6 g, 125 mmol) were mixed in toluene (50 mL), followed by NaH (3.0 g, 75 mmol, 60% dispersion mineral oil). The solution suspended in toluene (16 mL) is added dropwise under nitrogen atmosphere for 30 minutes. After the reaction mixture was stirred under reflux for 1 hour, ethanol was removed and the reaction mixture was cooled to room temperature. Water (36 mL) and 5% hydrochloric acid (8 mL) were added to the reaction mixture, and the resulting solid was filtered, washed with water and dried to give a pale yellow crystal (76%, 7.3 g).
본 발명은 용이한 반응공정으로, 순도가 높은 4-히드록시티오쿠마린 및 그의 질소 유사체를 높은 수율로 얻을수 있으므로 산업상 이용가능성에서 뛰어난 효과를 기대할 수 있다.The present invention can be expected to have an excellent effect in industrial applicability since it is possible to obtain a high-purity 4-hydroxythiocoumarin and its nitrogen analogs in high yield in an easy reaction process.
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