KR20000033231A - Improved manufacturing method of 2-hydroxythiocoumarin derivatives, anti-coagulant type rodenticide - Google Patents

Improved manufacturing method of 2-hydroxythiocoumarin derivatives, anti-coagulant type rodenticide Download PDF

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KR20000033231A
KR20000033231A KR1019980050002A KR19980050002A KR20000033231A KR 20000033231 A KR20000033231 A KR 20000033231A KR 1019980050002 A KR1019980050002 A KR 1019980050002A KR 19980050002 A KR19980050002 A KR 19980050002A KR 20000033231 A KR20000033231 A KR 20000033231A
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thiocoumarin
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hydroxy
tetrahydro
hydroxythiocoumarin
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KR100327554B1 (en
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박외숙
정재철
김주천
장봉석
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안민동
국보제약 주식회사
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • 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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Abstract

PURPOSE: New manufacturing method of 4-hydroxy-£1,2,3,4-tetrahydro-3-{4-(4-trifluoromethyl-benzyloxy)phenyl}-1-naphtyl|thiocoumarin is provided which is carried out under mild condition and obtains the highly pure target compound in high yields. CONSTITUTION: Tetraol derivative is reacted with 4-hydroxythiocoumarin at about 100-110°C for 1-5 hrs concurrently with reflux. Thiocoumarin is prepared by the conventional methods of extracting, drying, filtering or removing the solvent after the reaction. The alkoxy group of the thiocoumarin is hydrolyzed by having a reflux with hydrogen halide for 5-10 hours to produce 4-hydroxy-£1,2,3,4-tetrahydro-3-S(4-hydroxyphenyl)-1-naphtyl|thiocoumarin under the conventional hydrolyzing condition of ester. The thiocoumarin compound reacts with trifluoromethylbenzen halide in the presence of alkoxide to produce 4-hydroxy-£1,2,3,4-tetrahydro-3-{4-(4-trifluoromethyl-benzyloxy)phenyl}-1-naphtyl|thiocoumarin(1)

Description

항혈액응고성 살서제인 4-하이드록시티오쿠마린 유도체의 개량된 제조방법Improved Preparation of 4-Hydroxythiocoumarin Derivative, an Anticoagulant Killer

본 발명은 다음 구조식(1)으로 표시되는 항혈액응고성 살서제인 4-하이드록시-3-[1,2,3,4-테트라하이드로-3-{4-(4-트리플루오로메틸-벤질옥시)페닐}-1-나프틸]티오쿠마린의 신규 개량된 제조방법에 관한 것이다.The present invention provides 4-hydroxy-3- [1,2,3,4-tetrahydro-3- {4- (4-trifluoromethyl-benzyl), which is an anticoagulant killing agent represented by the following structural formula (1): Oxy) phenyl} -1-naphthyl] thiocoumarin.

( 1 )( One )

상기 화학식(1)의 화합물은 공지화합물로서 대한민국 특허공고 제 92-10394호에 그 제조방법이 기재되어 있다.The compound of formula (1) is a known compound and a method for preparing the same is described in Korean Patent Publication No. 92-10394.

이 방법에 의하면, 4-히드록시티오쿠마린을 다음 화학식 (A)의 화합물과 열축합시키거나,According to this method, 4-hydroxythiocoumarin is thermally condensed with a compound of formula (A),

( A ) (A)

다음 화학식(B)의 1-하이드록시-3-(p-할로디페닐)테트라린을 CuCN과 반응시켜서 상응하는 올레핀을 생성한 다음 이 생성된 올레핀을 4-히드록시티오쿠마린과 커플링시키거나,And then reacting 1-hydroxy-3- (p-halodiphenyl) tetrarin of formula (B) with CuCN to produce the corresponding olefins and then coupling the resulting olefins with 4-hydroxythiocoumarin or ,

( B ) (B)

또는 1-케토-3-(p-할로디페닐)-테트라린(C)을 CuCN과 반응시킨 다음 생성된 시아노테트랄론을 상응하는 1-하이드록시화합물로 환원시키고, 상기 하이드록시화합물을 4-하이드록시티오쿠마린과 축합시켜서 제조하였다.Or reacting 1-keto-3- (p-halodiphenyl) -tetrarin (C) with CuCN and then reducing the resulting cyanotetralone to the corresponding 1-hydroxy compound, wherein the hydroxy compound is 4 Prepared by condensation with hydroxythiocoumarin.

( C ) (C)

그러나, 이들 방법은 실제로 그 중간단계의 반응물질들 및 최종생성물질을 제조하는 공정이 대단히 복잡하고, 그 제조수율이 저조할 뿐만 아니라 최종생성물질의 순도가 낮아서 상업적 생산에는 문제가 있었다.However, these methods have problems in commercial production due to the fact that the process of preparing the intermediates and the final product in the intermediate stage is extremely complicated, the production yield is low, and the purity of the final product is low.

본 발명자들은 이러한 기존의 제조방법의 문제점을 해결하기 위하여 오랜 연구를 행한 결과, 온화한 조건하에서 높은 수율 및 높은 순도로 목적화합물인 상기 화학식(1)의 화합물을 제조할 수 있는 새로운 제조방법을 발명하였다.The present inventors have conducted a long study to solve the problems of the existing production method, and invented a new production method that can produce the compound of formula (1) as a target compound in high yield and high purity under mild conditions. .

본 발명을 다음에서 상세히 설명한다.The invention is explained in detail in the following.

테트라올 유도체(4)를 4-하이드록시티오쿠마린과 반응시켜서 4-하이드록시-3-[1,2,3,4,-테트라하이드로-3-(4-알콕시페닐)-1-나프틸]-티오쿠마린(3)을 제조한다. 반응은 약 100-110℃에서 1-5시간 환류시켜서 행한다. 반응후에는 통상의 방법으로 추출, 건조 여과 또는 용매를 제거하여 티오쿠마린화합물(3)을 제조한다.Tetraol derivative (4) is reacted with 4-hydroxythiocoumarin to give 4-hydroxy-3- [1,2,3,4, -tetrahydro-3- (4-alkoxyphenyl) -1-naphthyl] Prepare thiocoumarin (3). The reaction is performed by refluxing at about 100-110 ° C. for 1-5 hours. After the reaction, the thiocoumarin compound (3) is prepared by extraction, dry filtration or removing the solvent by a conventional method.

앞에서 얻어진 티오쿠마린화합물(3)을 아세트산 및/또는 취화수소산등과 같은 할로겐화수소산과 5-10시간 환류시켜 알콕시기를 가수분해시켜서 4-하이드록시-3-[1,2,3,4-테트라하이드로-3-(4-하이드록시페닐)-1-나프틸]티오쿠마린(2)을 제조한다. 가수분해 조건은 통상의 에스테르 가수분해 조건하에서 행한다. 앞에서 얻어진 티오쿠마린화합물(3)을 트리플루오로메틸벤젠할라이드와 반응시켜서 4-하이드록시-3-[1,2,3,4-테트라하이드로-3-[4-(4-트리플루오로메틸벤젠옥시)페닐]-1-나프틸]-티오쿠마린(1)을 제조한다.The thiocoumarin compound (3) obtained above was refluxed with a halogenated acid such as acetic acid and / or hydrobromic acid for 5-10 hours to hydrolyze the alkoxy group to yield 4-hydroxy-3- [1,2,3,4-tetrahydro -3- (4-hydroxyphenyl) -1-naphthyl] thiocoumarin (2) was prepared. Hydrolysis conditions are performed under normal ester hydrolysis conditions. The thiocoumarin compound (3) obtained above was reacted with trifluoromethylbenzene halide to produce 4-hydroxy-3- [1,2,3,4-tetrahydro-3- [4- (4-trifluoromethylbenzene Oxy) phenyl] -1-naphthyl] -thiocoumarin (1) was prepared.

반응은 알콜류 바람직하게는 t-부틸알콜의 알카리금속의 알콕사이드 존재하에 알콜류 용매중에서 트리플루오로메틸벤젠할라이드를 반응시킨다. 반응후에는 통상의 방법으로 추출, 건조, 세척 및 용매를 제거하여 목적화합물을 제조한다.The reaction is reacted with trifluoromethylbenzene halide in an alcohol solvent in the presence of an alcohol, preferably an alkoxide of an alkali metal of t-butyl alcohol. After the reaction, extraction, drying, washing and removing the solvent in a conventional manner to prepare the target compound.

이를 반응식으로 나타내면 다음과 같다.This is represented by the following scheme.

다음의 실시예로 본 발명을 더욱 상세히 설명하지만 본 발명이 다음의 실시예로 한정되는 것은 아니다.The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the following examples.

실시예 1:Example 1:

4-히드록시-3-[1,2,3,4-테드라히드로-3-(4-메톡시페닐)-1-나프틸]티오쿠마린 (3a)의 제조Preparation of 4-hydroxy-3- [1,2,3,4-tetrahydro-3- (4-methoxyphenyl) -1-naphthyl] thiocoumarin (3a)

100mL 둥근바닥플라스크에 테드라올 유도체(4), 1.96g, 히드록시 티오쿠마린 1.65g을 넣고, 1,2-디클로로메탄 40mL를 가하여 용액을 만든 다음, 파라톨루엔술폰산 1.47g을 가하고, 3시간동안 환류시킨다, 반응혼합물을 실온으로 냉각한 다음, 포화 중탄산소다수로 세척하고, 다시 물로 3회 세척한다. 무수 황산마그네슘으로 건조시키고 여과한 후 진공 회전 증발기로 완전히 농축시킨다. 관크로마토그래피로 분리하여 시스화합물 1.34 g와 트란스 화합물 1.08 g을 얻는다. 수율 (75.8%)Into a 100 mL round bottom flask, Tedraol derivative (4), 1.96 g, and 1.65 g of hydroxy thiocoumarin were added, 40 mL of 1,2-dichloromethane was added to make a solution, and then 1.47 g of paratoluene sulfonic acid was added and refluxed for 3 hours. The reaction mixture is cooled to room temperature, washed with saturated sodium bicarbonate water, and then washed three times with water. Dry over anhydrous magnesium sulfate, filter, and concentrate completely on a vacuum rotary evaporator. Separation by column chromatography yields 1.34 g of the cis compound and 1.08 g of the trans compound. Yield (75.8%)

시스화합물 (mp. 103 ∼ 106 ℃)Sheath compound (mp. 103-106 ℃)

1H NMR (300 MHz, CDCl3) δ 8.02 (d, J=8.02 Hz, 1 H), 7.49-7.18 (m, 9 H), 6.89 (d, J=8.44Hz, 2 H), 5.88 (br s, 1 H), 5.28-5.18 (m, 1 H), 3.78 (s, 3 H), 3.09 (br s, 3 H), 2.35 (t, J=6.27 Hz, 1 H), 1.95 (t, J=6.07 Hz, 1 H), 1 H NMR (300 MHz, CDCl 3 ) δ 8.02 (d, J = 8.02 Hz, 1 H), 7.49-7.18 (m, 9 H), 6.89 (d, J = 8.44 Hz, 2H), 5.88 (br s, 1 H), 5.28-5.18 (m, 1 H), 3.78 (s, 3 H), 3.09 (br s, 3 H), 2.35 (t, J = 6.27 Hz, 1 H), 1.95 (t, J = 6.07 Hz, 1 H),

13C NMR (300 MHz, CDCl3) δ 185.11, 161.38, 158.61, 138.61, 137.74, 136.09, 134.42, 130.81, 130.62, 128.93, 128.40, 128.12, 128.05, 126.62, 126.52, 125.51, 124.25, 121.34, 114.39, 55.70, 40.16, 38.81, 36.54, 36.38 13 C NMR (300 MHz, CDCl 3 ) δ 185.11, 161.38, 158.61, 138.61, 137.74, 136.09, 134.42, 130.81, 130.62, 128.93, 128.40, 128.12, 128.05, 126.62, 126.52, 125.51, 124.25, 121.34, 114. , 40.16, 38.81, 36.54, 36.38

IR (νmax, KBr) 3403, 2924, 1589, 1540, 1512, 1246IR (ν max , KBr) 3403, 2924, 1589, 1540, 1512, 1246

트란스화합물 (mp. 136.5 ∼ 137.5 ℃)Trans compound (mp. 136.5 ~ 137.5 ℃)

1H NMR (300 MHz, CDCl3) δ 8.02 (d, J=8.15 Hz, 1 H), 7.48-7.22 (m, 7 H), 7.13 (d, J=8.63Hz, 2 H), 6.82 (d, J=8.66 Hz, 2 H), 6.41 (br s, 1 H), 4.95 (t, J=5.21Hz, 1 H), 3.77 (s, 3 H), 3.28 (dd, J=15.94 Hz, J=3.79 Hz, 1 H), 3.22-3.01 (m, 2 H), 2.39-2.29 (m, 1 H), 2.23-2.19 (m, 1 H) 1 H NMR (300 MHz, CDCl 3 ) δ 8.02 (d, J = 8.15 Hz, 1 H), 7.48-7.22 (m, 7 H), 7.13 (d, J = 8.63 Hz, 2H), 6.82 (d , J = 8.66 Hz, 2H), 6.41 (br s, 1H), 4.95 (t, J = 5.21Hz, 1H), 3.77 (s, 3H), 3.28 (dd, J = 15.94 Hz, J = 3.79 Hz, 1 H), 3.22-3.01 (m, 2H), 2.39-2.29 (m, 1H), 2.23-2.19 (m, 1H)

13C NMR (300 MHz, CDCl3) δ 185.04, 162.12, 158.48, 138.28, 137.16, 136.08, 134.77, 130.93, 130.45, 128.78, 128.22, 126.62, 126.49, 125.36, 124.38, 120.98, 114.29, 55.63, 37.61, 36.72, 36.38, 35.09 13 C NMR (300 MHz, CDCl 3 ) δ 185.04, 162.12, 158.48, 138.28, 137.16, 136.08, 134.77, 130.93, 130.45, 128.78, 128.22, 126.62, 126.49, 125.36, 124.38, 120.98, 114.29, 55.63, 37.61, 37.61 , 36.38, 35.09

IR (νmax, KBr) 3413, 2911, 1589, 1543, 1510, 1243IR (ν max , KBr) 3413, 2911, 1589, 1543, 1510, 1243

실시예 2:Example 2:

4-히드록시-3-[1,2,3,4-테드라히드로-3-(4-히드록시페닐)-1-나프틸]티오쿠마린 (2)의 제조Preparation of 4-hydroxy-3- [1,2,3,4-tetrahydro-3- (4-hydroxyphenyl) -1-naphthyl] thiocoumarin (2)

200 mL 이구플라스크에 실시예 1에서 얻어진 시스 티오쿠마린 유도체(3) 2.57 g을 질소가스하에서 메틸렌클로라이드 65 mL에 녹인 후 소금-얼음욕조를 사용하여 -15℃로 냉각후 BBr328.6 mL (메틸렌클로라이드 1 M 용액)을 적가한 후 실온이 될 때까지 교반한 다음 계속하여 12시간 동안 교반하였다. 반응혼합용액에 포화 NaHCO3수용액 28.6mL를 가한후 메틸렌클로라이드로 추출하였다. 유기층을 물로 씻고, 황산마그네슘으로 건조시킨 다음 여과하고 감압하에서 용매를 제거하여 2.15 g (수율: 89.9%)의 생성물을 얻는다.2.57 g of the cis thiocoumarin derivative (3) obtained in Example 1 was dissolved in a 200 mL two-neck flask in 65 mL of methylene chloride under nitrogen gas, cooled to -15 ° C using a salt-ice bath, and 28.6 mL of BBr 3 (methylene chloride). 1 M solution) was added dropwise and stirred until it became room temperature, followed by stirring for 12 hours. 28.6 mL of saturated NaHCO 3 aqueous solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer is washed with water, dried over magnesium sulfate, filtered and the solvent is removed under reduced pressure to yield 2.15 g (yield: 89.9%) of product.

트란스 티오쿠마린유도체도 같은 방법으로 반응시킨다.The trans thiocoumarin derivative is reacted in the same manner.

시스화합물 (mp. 202 ∼ 204 ℃)Cis compound (mp. 202 ~ 204 ℃)

1H NMR (300 MHz, CDCl3) δ 8.02 (d, J=8.08 Hz, 1 H), 7.51-7.40 (m, 2 H), 7.38-7.33 (m, 1 H), 7.24-7.19 (m, 4 H), 7.09 (d, J=8.43 Hz, 2 H), 6.79 (d, J=8.41 Hz, 2 H), 5.88 (br s, 1 H), 5.69 (br s, 1 H), 5.22 (t, J=5.68 Hz, 1 H), 3.06(br s, 3 H), 2.31 (t, J=6.52 Hz, 1 H), 1.91 (t, J=6.07 Hz, 1 H), 1 H NMR (300 MHz, CDCl 3 ) δ 8.02 (d, J = 8.08 Hz, 1 H), 7.51-7.40 (m, 2H), 7.38-7.33 (m, 1H), 7.24-7.19 (m, 4 H), 7.09 (d, J = 8.43 Hz, 2 H), 6.79 (d, J = 8.41 Hz, 2 H), 5.88 (br s, 1 H), 5.69 (br s, 1 H), 5.22 ( t, J = 5.68 Hz, 1 H), 3.06 (br s, 3 H), 2.31 (t, J = 6.52 Hz, 1 H), 1.91 (t, J = 6.07 Hz, 1 H),

13C NMR (300 MHz, CDCl3) δ 185.28, 161.27, 154.43, 138.26, 137.08, 135.60, 133.83, 130.44, 130.28, 128.48, 128.03, 127.76, 126.30, 126.15, 125.10, 123.78, 120.90, 115.40, 39.70, 38.32, 36.19, 36.05 13 C NMR (300 MHz, CDCl 3 ) δ 185.28, 161.27, 154.43, 138.26, 137.08, 135.60, 133.83, 130.44, 130.28, 128.48, 128.03, 127.76, 126.30, 126.15, 125.10, 123.78, 120.90, 115.40, 39.32 , 36.19, 36.05

IR (νmax, KBr) 3411, 2920, 1590, 1540, 1512, 1230IR (ν max , KBr) 3411, 2920, 1590, 1540, 1512, 1230

트란스화합물 (mp. 119∼122 ℃)Trans compound (mp. 119∼122 ℃)

1H NMR (300 MHz, CDCl3) δ 7.99 (dd, J=8.15 Hz, J=0.95 Hz, 1 H), 7.48-7.20 (m, 7 H), 7.03(d, J=8.54 Hz, 2 H), 6.75 (d, J=8.56 Hz, 2 H), 6.45 (br s, 1 H), 6.33(br s, 1 H), 4.95 (t, J=5.34 Hz, 1 H), 3.25 (dd, J=13.87 Hz, J=4.03 Hz, 1 H), 3.17-2.97 (m, 2H), 2.37-2.27 (m, 1 H), 2.21-2.14 (m, Hz, 1H), 1 H NMR (300 MHz, CDCl 3 ) δ 7.99 (dd, J = 8.15 Hz, J = 0.95 Hz, 1 H), 7.48-7.20 (m, 7H), 7.03 (d, J = 8.54 Hz, 2H ), 6.75 (d, J = 8.56 Hz, 2 H), 6.45 (br s, 1 H), 6.33 (br s, 1 H), 4.95 (t, J = 5.34 Hz, 1 H), 3.25 (dd, J = 13.87 Hz, J = 4.03 Hz, 1 H), 3.17-2.97 (m, 2H), 2.37-2.27 (m, 1H), 2.21-2.14 (m, Hz, 1H),

13C NMR (300 MHz, CDCl3) δ 185.47, 162.16, 154.54, 137.96, 136.26, 135.53, 134.16, 130.57, 130.16, 130.09, 128.42, 127.86, 127.77, 126.27, 126.22, 125.87, 124.98, 123.90, 120.62, 115.41, 37.20, 36.24, 36.00, 34.72 13 C NMR (300 MHz, CDCl 3 ) δ 185.47, 162.16, 154.54, 137.96, 136.26, 135.53, 134.16, 130.57, 130.16, 130.09, 128.42, 127.86, 127.77, 126.27, 126.22, 125.87, 124.98, 123.90. , 37.20, 36.24, 36.00, 34.72

IR (νmax, KBr) 3378, 1587, 1539, 1514, 1234IR (ν max , KBr) 3378, 1587, 1539, 1514, 1234

실시예 3:Example 3:

4-히드록시-3-[1,2,3,4-테드라히드로-3-{4-(4-트리플루오르메틸벤질옥시)페닐)-1-나프틸]티오쿠마린(1)의 제조Preparation of 4-hydroxy-3- [1,2,3,4-tetrahydro-3- {4- (4-trifluoromethylbenzyloxy) phenyl) -1-naphthyl] thiocoumarin (1)

(1)(One)

무수헥산으로 3회 세척한 수소화나트륨 (60%) 320mg을 무수테트라히드로푸란 5mL를 넣고 얼음욕을 사용하여 0℃로 냉각한다. 질소기류하에서 여기에 실시예 7에서 얻어진 시스 티오쿠마린 유도체(2) 2.68 g을 테트라히이드로푸란 20 mL에 녹인 용액을 천천히 가한후 15분간 교반한다. 이 혼합용액에 트리플루오르메틸 벤질브로마이드 570 mg을 더한다. 상온에서 12시간 교반한 후 테트라히이드로푸란을 제거한후 에테르를 가한다. 유기층을 물로 세척하고, 황산마그네슘으로 건조, 여과한 후 용매를 감압하에서 제거한다. 2.01 g (수율: 54.5%)의 생성물을 얻는다.320 mg of sodium hydride (60%) washed three times with anhydrous hexane was added with 5 mL of anhydrous tetrahydrofuran and cooled to 0 ° C. using an ice bath. Under nitrogen stream, a solution obtained by dissolving 2.68 g of the cis thiocoumarin derivative (2) obtained in Example 7 in 20 mL of tetrahydrofuran was slowly added thereto, followed by stirring for 15 minutes. 570 mg of trifluoromethyl benzyl bromide is added to this mixed solution. After stirring at room temperature for 12 hours, tetrahydrofuran was removed and ether was added thereto. The organic layer is washed with water, dried over magnesium sulfate, filtered and the solvent is removed under reduced pressure. 2.01 g (yield: 54.5%) of product are obtained.

트란스티오쿠마린 유도체도 같은 방법으로 반응시킨다.The transthiocoumarin derivatives are also reacted in the same manner.

트란스(mp. 79∼81 ℃)Trans (mp. 79-81 ℃)

1H NMR (300 MHz, CDCl3) δ 7.98 (d, J=8.20 Hz, 1 H), 7.63-7.20 (m, 11 H), 7.13 (d, J=8.58Hz, 2 H), 6.87 (d, J=8.56 Hz, 2 H), 6.36 (br s, 1 H), 5.07 (s, 2 H), 4.95 (t, J=5.39 Hz, 1 H), 3.30-3.14 (m, 2 H), 3.09 (m, 1 H), 2.39-2.27(m, 1 H), 2.23-2.18 (m, 1 H) 1 H NMR (300 MHz, CDCl 3 ) δ 7.98 (d, J = 8.20 Hz, 1 H), 7.63-7.20 (m, 11 H), 7.13 (d, J = 8.58 Hz, 2H), 6.87 (d , J = 8.56 Hz, 2H), 6.36 (br s, 1H), 5.07 (s, 2H), 4.95 (t, J = 5.39 Hz, 1H), 3.30-3.14 (m, 2H), 3.09 (m, 1H), 2.39-2.27 (m, 1H), 2.23-2.18 (m, 1H)

13C NMR (300 MHz, CDCl3) δ 184.69, 161.75, 156.95 141.27, 137.82, 137.45, 135.71, 134.32, 130.56, 130.13, 130.09, 128.45, 127.99, 127.84, 127.36, 126.24, 126.12, 125.54, 125.49, 124.99, 123.98, 120.56, 114.87, 69.15, 37.12, 36.36, 35.97, 34.65 13 C NMR (300 MHz, CDCl 3 ) δ 184.69, 161.75, 156.95 141.27, 137.82, 137.45, 135.71, 134.32, 130.56, 130.13, 130.09, 128.45, 127.99, 127.84, 127.36, 126.24, 126.12, 125.54, 125.54, 125.54 123.98, 120.56, 114.87, 69.15, 37.12, 36.36, 35.97, 34.65

IR (νmax, KBr) 3393, 1590, 1548, 1511, 1326IR (ν max , KBr) 3393, 1590, 1548, 1511, 1326

시스화합물 (mp. 112∼115 ℃)Sheath compound (mp. 112 to 115 ° C)

1H NMR (300 MHz, CDCl3) δ 8.02 (d, J=8.05Hz, 1 H), 7.64-7.19 (m, 13 H), 6.89 (d, J=8.44Hz, 2 H), 5.88 (br s, 1 H), 5.28-5.18 (m, 1 H), 5.10 (s, 2 H), 3.09 (br s, 3 H), 2.35 (t, J=6.27 Hz, 1 H), 1.95 (t, J=6.07Hz, 1 H), 1 H NMR (300 MHz, CDCl 3 ) δ 8.02 (d, J = 8.05 Hz, 1 H), 7.64-7.19 (m, 13 H), 6.89 (d, J = 8.44 Hz, 2 H), 5.88 (br s, 1 H), 5.28-5.18 (m, 1 H), 5.10 (s, 2 H), 3.09 (br s, 3 H), 2.35 (t, J = 6.27 Hz, 1 H), 1.95 (t, J = 6.07 Hz, 1 H),

13C NMR (300 MHz, CDCl3) δ 184.25, 160.53, 156.57, 140.81, 137.66, 137.58, 135.22, 133.51, 129.95, 129.77, 128.07, 127.57, 127.34, 126.91, 125.76, 125.47, 125.08, 125.04, 124.65, 123.37, 120.42, 114.46, 68.71, 39.31, 37.87, 35.66, 35.51 13 C NMR (300 MHz, CDCl 3 ) δ 184.25, 160.53, 156.57, 140.81, 137.66, 137.58, 135.22, 133.51, 129.95, 129.77, 128.07, 127.57, 127.34, 126.91, 125.76, 125.47, 125.08, 125.04, 125.04, 125.04. , 120.42, 114.46, 68.71, 39.31, 37.87, 35.66, 35.51

IR (νmax, KBr) 3414, 2922, 1592, 1540, 1511, 1326IR (ν max , KBr) 3414, 2922, 1592, 1540, 1511, 1326

본 발명의 효과는 4-히드록시-3-[1,2,3,4,-테트라히드로-3-{4-(4-트리플루오로메틸-벤질옥시)페닐}-1-나프틸]티오쿠마린을 간단한 공정으로 만들 수 있어 조작이 용이하고 높은 수율 및 높은 순도의 목적 화합물을 얻을 수 있으므로 생산성이 뛰어나 경제적인 잇점이 탁월하다는 것이다.The effect of the present invention is 4-hydroxy-3- [1,2,3,4, -tetrahydro-3- {4- (4-trifluoromethyl-benzyloxy) phenyl} -1-naphthyl] thio Coumarin can be made in a simple process, which is easy to operate, and yields high yield and high purity of the target compound, which is excellent in productivity and economical advantages.

Claims (4)

다음 화학식(2)의 화합물을 화학식 (5)의 화합물과 반응시켜 목적화합물 (1)을 제조하는 방법.A method for preparing the target compound (1) by reacting the compound of formula (2) with the compound of formula (5). ( 1 )( One ) ( 2 ) ( 5 )(2) (5) 제 1항에 있어서, 화합물(2)은 화합물(3)을 가수분해시켜서 제조하는 것을 특징으로 하는 방법.A method according to claim 1, wherein compound (2) is prepared by hydrolyzing compound (3). ( 2 ) ( 3 )(2) (3) 식중 R은 탄소수 1-4의 저급알킬기이다.R is a lower alkyl group having 1-4 carbon atoms. 다음 화합물 (2)Next compound (2) ( 2 ) ( 2 ) 다음 화합물 (3)Next compound (3) ( 3 ) (3)
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