KR0159511B1 - New quinoline derivatives and their process - Google Patents
New quinoline derivatives and their process Download PDFInfo
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- KR0159511B1 KR0159511B1 KR1019900022971A KR900022971A KR0159511B1 KR 0159511 B1 KR0159511 B1 KR 0159511B1 KR 1019900022971 A KR1019900022971 A KR 1019900022971A KR 900022971 A KR900022971 A KR 900022971A KR 0159511 B1 KR0159511 B1 KR 0159511B1
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—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
- 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
기존의 퀴놀론 유도체들은 3번 위치에 카르복실산기를 갖고 있으나 본 발명에 의한 화합물은 술폰산기를 지니고 있는 독창적인 화합물로 본 발명은 이들과 그 제조법에 관한 것이다.Existing quinolone derivatives have a carboxylic acid group at position 3, but the compound according to the present invention is an original compound having a sulfonic acid group, and the present invention relates to these and a preparation method thereof.
본 발명에 의한 화합물의 구조는 다음과 같다.The structure of the compound according to the present invention is as follows.
Description
본 발명은 신규한 하기 일반식(1)의 7-아미노-1-사이클로프로필-6-플루오로-4-옥소-1,4-디하이드로-퀴놀린-3-설핀산과 약제학적으로 사용가능한 이의 산 부가염 또는 알카리 금속염 및 그의 제조방법에 관한 것이다.The present invention provides a novel 7-amino-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-sulfinic acid of formula (1) It relates to an addition salt or an alkali metal salt and a method for producing the same.
상기식에서, R은 수소이며, R1및 R2는 이들이 부착되어 있는 질소원자, 및 필요시 추가의 헤테로원자(예컨대 산소, 황, 또는 NR3)와 함께 3원 내지 7환원을 형성하며, 상기 환은 탄소수 1 내지 6의 알킬 또는 알케닐, 하이드록실, 탄소수 1 내지 3의 알콕시 또는 알킬-머캡토, 알콜부위의 탄소수가 1 내지 4인 알콕시카보닐, 니트릴 및 아릴 중에서 선택된 라디칼(들)에 의해 일치환, 또는 다치환될 수 있고, 또한, 이중 결합을 함유할 수 있으며, R3은 수소; 탄소수 1 내지 6의 직쇄 또는 측쇄알킬, 알케닐, 또는 알키닐; 아르알킬; 임의 치환된 페닐 또는 나프틸 또는 헤테로사이클릭 라디칼; 알콕시카보닐; 탄소수 1 내지 6의 알카노일; 아릴; 알킬-또는 아릴-(티오)카바모일; 알킬-또는 아릴-설포닐; 또는 아미노 설포닐이다. 선행기술에는 7-아미노-1-사이클로프로필-4-옥소-1,4-디하이드로-퀴놀린-3-카복실산이 항균 특성을 갖는 것으로 기술되어 있다(USP 4,670,444).Wherein R is hydrogen, and R 1 and R 2 form a 3-7 membered ring together with the nitrogen atom to which they are attached and additional heteroatoms (eg oxygen, sulfur, or NR 3 ), if necessary The ring is selected by radical (s) selected from alkyl or alkenyl having 1 to 6 carbon atoms, hydroxyl, alkoxy or alkyl-mercapto having 1 to 3 carbon atoms, alkoxycarbonyl having 1 to 4 carbon atoms at the alcohol site, nitrile and aryl. Mono- or polysubstituted, and may also contain double bonds, R 3 is hydrogen; Straight or branched chain alkyl, alkenyl, or alkynyl having 1 to 6 carbon atoms; Aralkyl; Optionally substituted phenyl or naphthyl or heterocyclic radicals; Alkoxycarbonyl; Alkanoyl of 1 to 6 carbon atoms; Aryl; Alkyl- or aryl- (thio) carbamoyl; Alkyl- or aryl-sulfonyl; Or amino sulfonyl. The prior art describes that 7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid has antibacterial properties (USP 4,670,444).
본 발명의 화합물은 다음과 같이 제조한다.Compounds of the present invention are prepared as follows.
하기 일반식(2)의 퀴놀린-3-설폰 유도체를 하기 일반식(5)의 아민과 반응시킨 후 수득되는 일반식(4)의 7-아미노-퀴놀린-3-설폰 유도체를 공지의 방법 예를들면 테트라부틸암모늄 플루오라이드 등으로 처리시켜 수득한다.(반응 Ⅰ)A 7-amino-quinoline-3-sulfone derivative of the general formula (4) obtained after reacting a quinoline-3-sulfone derivative of the general formula (2) with an amine of the following general formula (5) is a known method example. For example, by treatment with tetrabutylammonium fluoride or the like (Reaction I).
(상기식에서 R, R1, R2는 전술한 바와 같으며 X는 할로겐이다.)(Wherein R, R 1 and R 2 are as defined above and X is halogen.)
하기 일반식(3)의 퀴놀론-3-설핀산을, 필요시 산결합제 존재하에 상기한 바와 같은 일반식(5)의 아민과 반응시켜 수득한다.(반응 Ⅱ)Quinolone-3-sulfinic acid of the following general formula (3) is obtained by reacting with an amine of the general formula (5) as described above in the presence of an acid binder if necessary (reaction II).
(상기식에서 R, X는 전술한 바와 같다)(Wherein R and X are as described above)
예를들어 7-클로로-1-사이클로프로필-6-플루오로-4-옥소-3-(2-트리메틸실릴에틸설포닐)-1,4-디하이드로-퀴놀린 및 피페라진을 반응물로 사용할 경우, 본 발명의 반응(Ⅰ)은 다음과 같은 반응식으로 나타낼 수 있다.For example, when 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-3- (2-trimethylsilylethylsulfonyl) -1,4-dihydro-quinoline and piperazine are used as reactants, Reaction (I) of the present invention can be represented by the following reaction formula.
일반식(2) 또는 일반식(3)의 출발 화합물은 하기의 방법으로 제조할 수 있다.(관련 화합물의 일반식은 다음 반응식에 표시되어 있다.)Starting compounds of the general formula (2) or (3) can be prepared by the following method. (The general formula of the related compounds is shown in the following scheme.)
티올아세트산과 트리메틸비닐실란을 빛 또는 열 존재하에 티오에스테르(A)를 제조한 후, 이를 수산화나트륨으로 가수분해하면 티올(B)을 얻을 수 있다.Thiol acetic acid and trimethylvinylsilane may be prepared by preparing thioester (A) in the presence of light or heat, and then hydrolyzing it with sodium hydroxide to obtain thiol (B).
또한, 구조식(7)의 화합물은 구조식(6)의 화합물과 클로로아세틸클로라이드를 알루미늄클로라이드 촉매하에 프리델-크라프트 아실화반응을 통하여 제조하며, 이를 구조식(B)의 화합물과 염기 존재하에 S-알킬화반응을 하여 구조식(8)의 화합물로 전환시킨다.In addition, the compound of formula (7) is prepared by the Friedel-Craft acylation reaction of the compound of formula (6) and chloroacetyl chloride under an aluminum chloride catalyst, S-alkylation reaction in the presence of the compound of formula (B) and base To convert to the compound of formula (8).
구조식(8)의 화합물에 과산화수소 2당량을 빙초산을 용매로하여 작용시키면 설폰으로 산화된 구조식(9)의 화합물을 얻을 수 있다.When 2 equivalents of hydrogen peroxide is added to the compound of formula (8) with glacial acetic acid as a solvent, the compound of formula (9) oxidized with sulfone can be obtained.
엔아민(10)은 구조식(9)의 화합물에 1.5당량의 트리에틸 오르도포메이트와 2.5당량의 무수 초산을 가한 후 120℃에서 증류장치를 통하여 부생성물인 초산 에틸을 연속적으로 제거하면서 2시간 동안 교반하여 얻어지는 에놀에테르에 0℃에서 시클로프로필 아민을 천천히 적가하면 백색 고체로서 얻어진다.Enamine (10) was added with 1.5 equivalents of triethyl orthoformate and 2.5 equivalents of anhydrous acetic acid to the compound of formula (9), followed by continuously removing ethyl acetate as a byproduct through distillation at 120 ° C. for 2 hours. When cyclopropyl amine is slowly added dropwise at 0 ° C. to enol ether obtained by stirring, a white solid is obtained.
(10)에서 (2)로의 환화반응은 약 100℃에서 탄산칼륨 존재하에 진행되며 용매로는 DMF가 사용되었다. 구조식(2)의 화합물에 테트라부틸 암모늄 플루오라이드를 이용하여 탈보호화 반응을 수행하면 일반식(3)의 화합물을 얻을 수 있다.The cyclization reaction from (10) to (2) proceeded in the presence of potassium carbonate at about 100 ° C. and DMF was used as a solvent. When the deprotection reaction is carried out using tetrabutyl ammonium fluoride to the compound of formula (2), the compound of formula (3) can be obtained.
일반식(2) 또는 (3)의 화합물을 제조하기 위한 전술한 방법을 반응식으로 나타내면 다음과 간다.When the above-mentioned method for preparing the compound of the general formula (2) or (3) is represented by the reaction scheme, the following goes.
반응(Ⅰ), (Ⅱ)에 사용가능한 바람직한 불활성 유기용매는 에탄올, 디옥산, 톨루엔, 디메틸포름아미드, 디메틸설폭사이드, 피리딘 등이며 반응(Ⅱ)에 사용가능한 산결합제로는 알카리카보네이트, 알카리금속 수산화물 또는 3급 유기염기(예; 바람직하게는 트리에틸아민 및 DBU, DBN)가 바람직하다.Preferred inert organic solvents usable in reactions (I) and (II) are ethanol, dioxane, toluene, dimethylformamide, dimethylsulfoxide, pyridine, and the like. Preference is given to hydroxides or tertiary organic bases (e.g. triethylamine and DBU, DBN).
반응(Ⅰ), (Ⅱ)의 반응온도는 일반적으로 20℃ 내지 180℃이나 바람직하게는 60℃ 내지 140℃에서 반응시키는 것이 바람직하며 일반식(2) 또는 (3) 화합물에 반응되어지는 아민의 양은 1몰당 1 내지 5몰, 특히 바람직하게는 2 내지 4몰의 아민을 사용한다.The reaction temperature of reactions (I) and (II) is generally from 20 ° C to 180 ° C, but preferably from 60 ° C to 140 ° C. The amount uses 1 to 5 moles, particularly preferably 2 to 4 moles of amine per mole.
신규의 항균활성 화합물의 예를들면 다음과 같다.Examples of the novel antimicrobial active compounds are as follows.
7-피페라지노-1-사이클로프로필-4-옥소-1,4-디하이드로-퀴놀린-3-설핀산7-piperazino-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-sulfinic acid
7-(4-메틸피페라지노)-1-사이클로프로필-4-옥소-1,4-디하이드로-퀴놀린-3-설핀산7- (4-Methylpiperazino) -1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-sulfinic acid
7-(3-아미노피롤리디노)-1-사이클로프로필-4-옥소-1,4-디하이드로-퀴놀린-3-설핀산7- (3-aminopyrrolidino) -1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-sulfinic acid
7-몰포리-1-사이클로프로필-4-옥소-1,4-디하이드로-퀴놀린-3-설핀산 및 이의 약제학적으로 허용된 산부가염 또는 알카리금속염.7-morpholi-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-sulfinic acid and pharmaceutically acceptable acid addition salts or alkali metal salts thereof.
본 발명은 다음의 실시예들에 의해서 설명되는데, 본 발명이 이들 실시예에 제한되는 것은 아니다.The invention is illustrated by the following examples, which are not intended to limit the invention.
[실시예 1]Example 1
[2,4-디클로로-5-플루로오-(2-클로로아세틸)벤젠의 합성][Synthesis of 2,4-dichloro-5-fluoro- (2-chloroacetyl) benzene]
25g의 1,3-디클로로-4-플루오로 벤젠 및 39.9g 무수 알루미늄 클로라이드 혼합물에 18.8g의 크로로아세틸 클로라이드를 실온에서 약 1.5시간 동안 교반하에 적가 한후, 75℃에서 약 1.5시간 더 교반시켰다. 이 반응 혼합물을 실온으로 냉각 후, 냉각된 6N-염산 수용액에 서서히 가하여 얻어진 고체를 여고, 건조하면 31.5g의 2,4-디클로로-5-플루오로-(2-클로로아세틸)벤젠이 얻어진다.(수율:60%)To 25 g of 1,3-dichloro-4-fluoro benzene and 39.9 g anhydrous aluminum chloride mixture was added dropwise 18.8 g of chloroacetyl chloride under stirring at room temperature for about 1.5 hours, followed by further stirring at 75 ° C. for about 1.5 hours. After cooling this reaction mixture to room temperature, the solid obtained by slowly adding to the cooled 6N hydrochloric acid aqueous solution was opened, and it dried, and 31.5g of 2, 4- dichloro-5-fluoro- (2-chloroacetyl) benzene was obtained. (Yield: 60%)
[실시예 2]Example 2
[2-트리메틸실릴에틸 티오아세테이트의 합성][Synthesis of 2-trimethylsilylethyl thioacetate]
22.8g의 티올아세트산을 시클로헥산과 트리메틸 비닐실란 혼합용액에 실온에서 약 90분간 적가하고, 45℃에서 교반한다. 용매를 감압하에서 제거 후, 잔류물을 감압 분별증류하면 6.7g의 무색 액체로서 2-트리메틸실릴에틸 티오아세테이트가 얻어진다.(수율:38%)22.8 g of thiol acetic acid is added dropwise to the mixed solution of cyclohexane and trimethyl vinylsilane at room temperature for about 90 minutes and stirred at 45 ° C. After the solvent was removed under reduced pressure, the residue was subjected to fractional distillation under reduced pressure to yield 2-trimethylsilylethyl thioacetate as a colorless liquid of 6.7 g. (Yield: 38%)
[실시예 3]Example 3
[2-트리메틸실릴에탄티올의 합성][Synthesis of 2-trimethylsilylethanethiol]
6.5g의 2-트리메틸실릴에틸 티오아세테이트를 에탄올 4ml에 녹이고, 1.5g의 수산화나트륨을 10ml의 물에 녹인 용액을 혼합 후, 2시간동안 환류교반한다.6.5 g of 2-trimethylsilylethyl thioacetate is dissolved in 4 ml of ethanol, and a solution of 1.5 g of sodium hydroxide in 10 ml of water is mixed and stirred under reflux for 2 hours.
반응 혼합물을 실온으로 냉각 후, 6N-염산으로 중화하고 n-헥산으로 추출하여 용매를 제거한 잔류물을 감압분별 증류하면 무색 액체로서 2.2g의 2-트리메틸실릴에탄티올가 얻어진다.(수율:40%)The reaction mixture was cooled to room temperature, neutralized with 6N hydrochloric acid, extracted with n-hexane, and the residue from which the solvent was removed was fractionated under reduced pressure to yield 2.2 g of 2-trimethylsilylethanethiol as a colorless liquid. (Yield: 40% )
[실시예 4]Example 4
[2,4-디클로로-5-플루오로-(2-트리메틸실릴에틸티오아세틸)벤젠의 합성][Synthesis of 2,4-dichloro-5-fluoro- (2-trimethylsilylethylthioacetyl) benzene]
2,4-디클로로-5-플루오로-(2-클로로아세틸)벤젠 7.68g과 4.6g의 2-트리메틸실릴에탄티올을 4.4g의 탄산칼륨 존재하에, THF를 용매로하여 약 20시간 환류 교반하였다. 반응 혼합물을 실온으로 냉각 후, 용매를 제거한 잔류물을 에틸 에세테이트에 녹이고 물로 세척한다. 감압하에서 용매를 제거하면 순수한 6.2g의 2,4-디클로로-5-플루오로-(2-트리메틸실릴에틸티오아세틸)벤젠이 얻어진다.(수율:57%)7.68 g of 2,4-dichloro-5-fluoro- (2-chloroacetyl) benzene and 4.6 g of 2-trimethylsilylethanethiol were stirred under reflux for about 20 hours using THF as a solvent in the presence of 4.4 g of potassium carbonate. . After cooling the reaction mixture to room temperature, the solvent-free residue is taken up in ethyl acetate and washed with water. Removal of the solvent under reduced pressure yields 6.2 g of pure 2,4-dichloro-5-fluoro- (2-trimethylsilylethylthioacetyl) benzene (yield: 57%).
IR(cm-1); 2953, 1698, 1468, 859IR (cm −1 ); 2953, 1698, 1468, 859
NMR(ppm); 0.03(s,9H), 0.9(m,2H), 2.5-3.0(m, 2H), 3.8(s,2H), 7.33(d,1H), 7.42(d,1H)NMR (ppm); 0.03 (s, 9H), 0.9 (m, 2H), 2.5-3.0 (m, 2H), 3.8 (s, 2H), 7.33 (d, 1H), 7.42 (d, 1H)
[실시예 5]Example 5
[2,4-디클로로-5-플루오로-(2-트리메틸실릴에틸설포닐아세틸)벤젠의 합성][Synthesis of 2,4-dichloro-5-fluoro- (2-trimethylsilylethylsulfonylacetyl) benzene]
2,4-디클로로-5-플루오로-(2-트리메틸실릴에틸티오아세틸)벤젠 4g을 빙초산 50ml에 녹인 후 30%-과산화수소수 3g을 가하여 실온에서 12시간 교반한다.4 g of 2,4-dichloro-5-fluoro- (2-trimethylsilylethylthioacetyl) benzene was dissolved in 50 ml of glacial acetic acid, and 3 g of 30% hydrogen peroxide solution was added thereto, followed by stirring at room temperature for 12 hours.
위 반응액에 물 200ml 가한 후, 에틸 아세테이트로 추출하고 물로 수회 세척한다. 용매를 제거한 후 얻어지는 잔류물에 n-헥산을 가하면 4g의 흰색 고체로서 2,4-디클로로-5-플루오로-(2-트리메틸실릴에틸설포닐아세틸)벤젠이 얻어진다.(수율:91%)200 ml of water was added to the reaction solution, which was then extracted with ethyl acetate and washed several times with water. After the solvent was removed, n-hexane was added to the obtained residue to give 2,4-dichloro-5-fluoro- (2-trimethylsilylethylsulfonylacetyl) benzene as a white solid of 4 g (yield: 91%).
IR(cm-1); 1701, 1317, 1250, 859IR (cm −1 ); 1701, 1317, 1250, 859
NMR(ppm); 0.1(s,9H), 0.96-1.19(m,2H), 3.08-3.30(m, 2H), 4.61(s,2H), 7.51(d,1H), 7.54(d,1H)NMR (ppm); 0.1 (s, 9H), 0.96-1.19 (m, 2H), 3.08-3.30 (m, 2H), 4.61 (s, 2H), 7.51 (d, 1H), 7.54 (d, 1H)
[실시예 6]Example 6
[2,4-디클로로-5-플루오로-[2-(2-트리메틸실릴에틸설포닐)-3-사이클로프로필아미노-2-프로페노닐] 벤젠의 합성][2,4-Dichloro-5-fluoro- [2- (2-trimethylsilylethylsulfonyl) -3-cyclopropylamino-2-propenyl] Synthesis of Benzene]
2,4-디클로로-5-플루오로-(2-트리메틸실릴에틸설포닐아세틸)벤젠 5.3g과 4.5g의 트리에틸오르도 포메이트 및 4.5g의 무소초산의 혼합물을 120℃에서 2시간 동안 교반한다. 감압 하에서 모든 휘발성 물질을 제거하여 얻어진 잔유물에 30ml의 에탄올을 가하여 녹인 용액을 0℃로 냉각하고 사이클로프로필아민을 5분동안 적가하고 30분간 교반하면 흰 고체가 석출된다.A mixture of 5.3 g of 2,4-dichloro-5-fluoro- (2-trimethylsilylethylsulfonylacetyl) benzene, 4.5 g of triethylordoformate and 4.5 g of anhydrous acetic acid is stirred at 120 ° C. for 2 hours. . 30 ml of ethanol was added to the residue obtained by removing all volatiles under reduced pressure, and the dissolved solution was cooled to 0 ° C., cyclopropylamine was added dropwise for 5 minutes, and stirred for 30 minutes to precipitate a white solid.
고체를 여과하고 찬 에탄올로 세척하여 건조하면 4.7g의 2,4-디클로로-5-플루오로-[2-(2-트리메틸실릴에틸설포닐)-3-사이클로프로필아미노-2-프로페노닐] 벤젠이 얻어진다.(수율:75%)The solid was filtered off, washed with cold ethanol and dried to afford 4.7 g of 2,4-dichloro-5-fluoro- [2- (2-trimethylsilylethylsulfonyl) -3-cyclopropylamino-2-propenyl] Benzene is obtained (yield: 75%).
IR(cm-1); 2954, 1614, 1475, 1182, 860IR (cm −1 ); 2954, 1614, 1475, 1182, 860
NMR(ppm); 0.06(s,9H), 0.86(m,2H), 0.94(m, 4H), 2.63(m.2H), 2.85(m,1H), 7.15(d,1H), 7.43(d,1H), 8.13(d,1H)NMR (ppm); 0.06 (s, 9H), 0.86 (m, 2H), 0.94 (m, 4H), 2.63 (m.2H), 2.85 (m, 1H), 7.15 (d, 1H), 7.43 (d, 1H), 8.13 (d, 1H)
[실시예 7]Example 7
[7-클로로-1-사이클로프로필-6-플루오로-4-옥소-3-(2-트리메틸실릴에틸설포닐)-1,4-디하이드로-퀴놀린의 합성][Synthesis of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-3- (2-trimethylsilylethylsulfonyl) -1,4-dihydro-quinoline]
2,4-디클로로-5-플루오로-[2-(2-트리메틸실릴에틸설포닐)-3-사이클로프로필아미노-2-프로페노일]벤젠을 과량의 탄산 칼륨 존재하에 30ml DMF에서 100℃에서 3시간 동안 교반한다. DMF를 완전히 제거한 후 클로로포름을 넣고 무기물들을 여과, 제거한다.2,4-dichloro-5-fluoro- [2- (2-trimethylsilylethylsulfonyl) -3-cyclopropylamino-2-propenyl] benzene was added at 100 ° C. in 30 ml DMF in the presence of excess potassium carbonate. Stir for 3 hours. After completely removing DMF, chloroform is added and the inorganics are filtered and removed.
여액속의 용매를 제거한 후 벤젠과 n-헥산으로 하면 2.0g의 7-클로로-1-사이클로프로필-6-플루오로-4-옥소-3-(2-트리메틸실릴에틸설포닐)-1,4-디하이드로-퀴놀린 얻어진다.(수율:67%, 융점:184-185℃)After removing the solvent in the filtrate and using benzene and n-hexane, 2.0 g of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-3- (2-trimethylsilylethylsulfonyl) -1,4- Dihydro-quinoline is obtained. (Yield: 67%, Melting point: 184-185 ° C.)
NMR(ppm); 0.04(s,9H), 1.16(m,2H), 1.31(m, 4H), 3.56(m,3H), 8.09(d,1H), 8.13(d,1H), 8.49(s,1H)NMR (ppm); 0.04 (s, 9H), 1.16 (m, 2H), 1.31 (m, 4H), 3.56 (m, 3H), 8.09 (d, 1H), 8.13 (d, 1H), 8.49 (s, 1H)
[실시예 8]Example 8
[1-시클로프로필-6-플루오로-4-옥소-3-(2-트리메틸실릴에틸설포닐)-7-피페라지닐-1,4-디하이드로-퀴놀린의 합성][Synthesis of 1-cyclopropyl-6-fluoro-4-oxo-3- (2-trimethylsilylethylsulfonyl) -7-piperazinyl-1,4-dihydro-quinoline]
14.2g의 7-클로로-1-시클로프로필-3-플루오로-4-옥소-3-(2-트리메닐실릴에틸설포닐)-1,4-디하이드로-퀴놀린과 과량의 피페라진을 DMSO을 용매로 하여 120℃에서 6시간 교반한다. 감압하에 DMSO를 제거한 후, 물과, 에틸 아세테이트, 각각 100ml씩 가하여 추출한다. 유기층을 분리하고 용매를 제거하면, 고체가 얻어지며 이를 클로로포름과 에틸 아세테이트로 재결정하면 무색 결정으로서 7.5g의 1-사이클로프로필-6-플루오로-4-옥소-3-(2-트리메틸실릴에틸설포닐)-7-피페라지닐-1,4-디하이드로-퀴놀린가 얻어진다.(수율:58%, 융점:270℃ 분해)14.2 g of 7-chloro-1-cyclopropyl-3-fluoro-4-oxo-3- (2-trimenylsilylethylsulfonyl) -1,4-dihydro-quinoline and excess piperazine was dissolved in DMSO It stirred at 120 degreeC for 6 hours as a solvent. DMSO was removed under reduced pressure, followed by extraction with 100 ml of water and ethyl acetate. When the organic layer is separated and the solvent is removed, a solid is obtained, which is recrystallized with chloroform and ethyl acetate to give 7.5 g of 1-cyclopropyl-6-fluoro-4-oxo-3- (2-trimethylsilylethylsulfur as colorless crystals. Phonyl) -7-piperazinyl-1,4-dihydro-quinoline is obtained (yield: 58%, melting point: 270 DEG C decomposition)
IR(cm-1); 3452, 2953, 1623, 1480, 1131IR (cm −1 ); 3452, 2953, 1623, 1480, 1131
NMR(ppm); 0.04(s,9H), 0.88(m,2H), 1.23(m, 4H), 3.31-4.3(m,11H), 7.49(d,1H), 7.93(d,1H), 8.43(s,1H)NMR (ppm); 0.04 (s, 9H), 0.88 (m, 2H), 1.23 (m, 4H), 3.31-4.3 (m, 11H), 7.49 (d, 1H), 7.93 (d, 1H), 8.43 (s, 1H)
[실시예 9]Example 9
[1-시클로프로필-6-플루오로-4-옥소-7-피페라지닐-1,4-디하이드로-퀴놀린-3-설핀산의 합성][Synthesis of 1-cyclopropyl-6-fluoro-4-oxo-7-piperazinyl-1,4-dihydro-quinoline-3-sulfinic acid]
7.0g의 1-시클로프로필-6-플루오로-4-옥소-3-(2-트리메틸실릴에틸설포닐)-7-피페라지닐-1,4-디하이드로-퀴놀린을 2.0당량의 1M-테트라부틸암모늄 플루오라이드에 가하고 5분동안 환류 교반한다. 이 반응혼합물을 실온으로 냉각한 후, 물을 소량씩 가하여 얻어지는 백색 고체를 여과, 건조하면 4.2g의 1-시클로프로필-6-플루오로-4-옥소-7-피페라지닐-1,4-디하이드로-퀴놀린-3-설핀산이 얻어진다.(수율:64%, 융점:216℃ 분해)7.0 grams of 1-cyclopropyl-6-fluoro-4-oxo-3- (2-trimethylsilylethylsulfonyl) -7-piperazinyl-1,4-dihydro-quinoline with 2.0 equivalents of 1M-tetra Add butylammonium fluoride and stir at reflux for 5 minutes. After cooling the reaction mixture to room temperature, the white solid obtained by adding a small amount of water was filtered and dried to obtain 4.2 g of 1-cyclopropyl-6-fluoro-4-oxo-7-piperazinyl-1,4- Dihydro-quinoline-3-sulfonic acid is obtained (yield: 64%, melting point: 216 DEG C decomposition).
IR(cm-1); 3429, 3041, 2503, 1609, 1535, 941IR (cm −1 ); 3429, 3041, 2503, 1609, 1535, 941
NMR(ppm); 1.43(m,4H), 3.4-3.90(m,9H), 7.58(d,1H), 7.69(d,1H), 8.46(s,1H)NMR (ppm); 1.43 (m, 4H), 3.4-3.90 (m, 9H), 7.58 (d, 1H), 7.69 (d, 1H), 8.46 (s, 1H)
Claims (5)
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