• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Process for the preparation of compounds of general formula (I), and pharmaceutically acceptable salts thereof (wherein R stands for piperazinyl or 4-methyl-piperazinyl) which comprises reacting a compound of general formula (II), (wherein R<1> and R<2> stand for halogen; an aliphatic acyloxy group comprising 2-6 carbon atoms and optionally substituted by halogen; or an aromatic acyloxy group comprising 7-11 carbon atoms) with a piperazine of general formula (III), (wherein R<3> represents hydrogen or methyl) or a salt thereof, hydrolysing the compound of general Formula (IV), thus obtained (wherein R, R<1> and R<2> are as stated above) without or after hydrolysis and if desired converting the compound of general formula (I) thus obtained into a salt thereof or setting free the same from its salt. The compounds of general formula (I) are known antibacterial agents. The advantage of the process of the present invention is that it enables the preparation of the compounds of general formula (I) in a simple manner, with high yields and in a short reaction time.
    公开号:SU1579459A3
    申请号:SU874203110
    申请日:1987-08-07
    公开日:1990-07-15
    发明作者:Хермец Иштван；Керестури Геза；Вашвари Лелле；Хорват Агнеш；Балог Мария；Ковач Габор；Сютш Тамаш；Ритли Петер；Шипош Юдит；Пайор Анико
    申请人:Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра Рт (Инопредприятие)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of 1-methylamino-quinoline-carboxylic acid derivatives with physiological activity.
    The purpose of the invention is to increase the yield of the target product and reduce the time of the process.
    The goal is achieved by the interaction of compounds of General formula II

    cm
    VNONH
    where Rj, is a hydrogen atom or methyl with a compound of formula III:
    NH CH3
    where R.J and R are a halogen, aliphatic acyloxy group in an aprotic dipolar solvent at 70-120 ° C. predominantly in the presence of an acid binding agent.
    Example 1. A mixture of 6.87 g of 4-methyl-piperazine and 7.26 g of 6-fluoro-7-chloro-1-methyl-amino-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid anhydride and -difluoroboric acid, in 36 ml of dimethyl sulfoxide, stirred at 110 ° C for 3 hours. As the reaction proceeded, yellow crystals gradually precipitated from the reaction mixture. The thus formed anhydride of 6-fluoro-1- -methyl-amino-7- (4-methyl-piperazino) -4
    -oxo-1,4-dihydro-quinolin-3-carboxylic acid and difluoroboric acid undergo hydrolysis without isolation from the reaction mixture as follows.
    The reaction mixture is cooled to, after which 58 ml of a 6% w / v% aqueous solution of sodium hydroxide are added over 5 minutes. The reaction mixture is heated to boiling and stirred for 2 hours at low boiling. The solution is cooled to room temperature and the pH is adjusted to 7.2 by the addition of acetic acid. The crystalline mixture thus obtained is left to crystallize overnight in a refrigerator. The next morning, the precipitated crystals are filtered, washed twice each time with 10 ml of water and 5 ml of methanol. This gives 5.8 g of 6-fluoro-1-methylamino-7- (4-β-methyl piperazino) -4-oxo-1,4-dihydro-quinoline-3-carboxylic acid. Yield 76.1%, mp. 300-301 ° C (decomposition of dimethylformamide).
    Calculated, I: C 57.47; H 5.72; N 16.75.
    C, 6H ,, FN403
    Found,%: C 57.71; H 5.70; N 16.68.
    0
    five
    0
    0
    five
    five
    0 45 jO
    five
    Example 2. A mixture of 5.18 g of piperazine and 6.37 g of anhydride of 6-fluoro-7-chloro-1-methylamino-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and di - | fluoroboric acid, formed with
    32 ml of dimethyl sulfoxide was stirred at 110 ° C for 3 hours. The reaction mixture was filtered, the filtrate was evaporated in vacuo to 2/3 of the original volume and the pH of the solution was adjusted to 6.5-7 by addition of acetic acid. The reaction mixture is left to crystallize in the refrigerator overnight. The next morning, the precipitated crystals are filtered off, washed twice each time with 10 ml of water and 5 ml of methanol. This gives 5.3 g of 6-fluoro-1-ethylamino-7-piperazino-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid. Yield 82%, mp. 289-291 ° C (decomposition of dimethylformamide).
    Calculated,%: C 56.24; H 5.34; N 12.49.
    C, H, 7FN40,
    Found,%: C 56.15,: H H 5.37; N 12.61.
    A mixture of 1 g of 6-fluoro-1-methylamino-7-piperazino-4 oxo-1,4-dihydro-quinoline-3-carboxylic acid and 1.5 ml of water is treated with 0.6 g of p-toluenesulfonic acid and the mixture is poured into 10 ml of methyl ethyl ketone. The reaction mixture was allowed to crystallize overnight. The next morning, the precipitated crystals are filtered and washed with methyl ethyl ketone. So get 1.3 g p-toluene-sulfonate salt of 6-fluoro-1-methylamino-7-piperazin-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, yield 84.5 g
    Calculated,%: C 53.65; H 5.11; N 11.37.
    C (5H, 7FN40, C-rHgO S.
    Found,%: C 53.89; H 4.96; N 11.25.
    IrimerZ. 5g ethyl-6-fluoro 1-M-formyl-N-methylamino-7-chloro-4-ox-with-1,4-dihydro-quinoline-3-carboxylate is stirred in 25 ml of 50 wt./vol.% an aqueous solution of hydrogen-fluoro-borate at 90-95 ° C for 4 hours. After 1.5 hours, precipitation of crystals begins. The reaction mixture is cooled to room temperature and left to crystallize overnight in a refrigerator. The next morning, the precipitated crystals are filtered and washed with some g of water. Thus, 4.55 g of 6-fluoro-7-chloro-1-methyl-amino-4-α-oxo-1,4-dihydro-quinoline-3-carboxylic acid anhydride and di-fluoroboric acid are obtained. Yield 93.4%. Mp. 277 ° C (decomposition).
    Calculated,%: C 41.48; K 2.22; N 8.79.
    C „H7B, C1NZ0,
    Found,%: C 41.59; H 2.34; N 8.58.
    II p. and me 4. 4. 0.797 g (6-fluoro-7-.-chloro-1,4-dihydro-1- (methyl-amino) 4- -oxo-3-quinoline-carboxylate-O -O / - -bis (acetate 0) of boron and 0.6 g of 1-methyl-piperazine are reacted in the presence of 5 ml of dimethyl sulfoxide at 110 ° C for 2 hours. Then an aqueous solution of 6% by weight per volume of sodium hydroxide is added (5 , 1 ml) and stirred for another 1 h at 110 ° C. After that, the mixture is cooled to 40 ° C and the pH is adjusted to 6.5 96% by weight per volume of acetic acid.
    Next, the mixture is cooled to room temperature, and the crystals precipitate. The mixture was left to stand overnight in a refrigerator, after which it was diluted with 15 ml of water and the precipitated crystals were filtered, washed with water and cold methanol. 0.56 g (84%) of 6-fluoro-1,4-dihydro-1- (methylamino) -7- (4-methyl-piperaeno) -4-oxo-3-quinoline-carboxylic acid is obtained. After recrystallization from dimethylformamide, decomposition at 293 ° C.
    Calculated,%: C 57.48; H 5.73; N 16.76.
    ; 6 Nh FN40 s
    Found,%: C 58.0; H 5.9; N 16.9%.
    Getting the source material.
    0.586 g of boric acid and 3.28 g of acetic anhydride are reacted in the presence of 1 mg of zinc chloride, and the temperature of the reaction mixture rises to 46 ° C. The whole suspension is gradually heated to 100 ° C and 2.0 g of ethyl 7-chloro-6-fluoro-1 4-dihydro-1- (formylmethyl-amino) -4-oxo-3-quinoline-carboxylate, which is previously was dissolved in 10 ml of 96% w / v acetic acid. The reaction mixture is additionally heated for 2 hours at 110 ° C. The solution is cooled to room temperature and diluted with 40 ml of cold
    water. The precipitated crystals are filtered off, washed with cold water and absolute alcohol, and dried. 1.75 g of white crystalline (6-fluoro-7-chloro-1,4-dihydro-1- (methyl-amino) -4-oxo-3-quinoline-carboxylate-03-0 / bis (acetate -0) boron. Decomposition of 272 ° C.
    After standing, an additional 0.45 g of product crystallizes out of the mother liquor.
    Calculated,%: C 45,55; H 3.31; N 3.54.
    с15н „BCIFN CT
    Found,%: C 45.2; H 3.2; N 3.6.
    0
    five
    five
    Example 5. 0.797 g (6-fluoro-7-0-chloro-1,4-dihydro-1- (methyl-amino) -4-oxo-3-quinolinecarboxylate-0.0 / -bis (acetate-0) -borage and 0.52 piperazine are subjected to reaction in the presence of 5 ml of dimethyl sulfoxide at 110 ° C for 2 hours. 5 Then a solution of 6% by weight per volume of sodium hydroxide (5 ml) is added to the reaction mixture, after which it is slightly boiled for 1 hour The first crystals are precipitated after 10 minutes. The reaction mixture is cooled to 40 ° C and the pH is adjusted to 6.5 by adding 96% by weight per volume of acetic acid and the suspension is diluted. The precipitated crystals are filtered, washed with water and abs o ethanol. Yellowish-beige crystals of 6-fluoro-1,4-dihydro-1- (methylamino) -7-piperazino-4-oxo-3-quinoline-carboxylic acid (0.42 g 65%) are obtained.
    0 Calculated; %: C, 56.24; H 5.35; N 17.49.
    C15K TFN403 Found: C N 17.8.
    II p and me 6.
    55.9; H 5.5;
    0.426 g (6-fluoro-7-chloro-1, 4-dihydro-1- (methylamino) -4-ox-with-3-quinoline-carboxylate-0, 0 (-bis- (propionate-0) boron and 0 3 g of 1-methyl-piperazino is reacted in the presence of 2.5 ml of dimethyl sulfoxide for 2 hours at 110 ° C. An aqueous solution of 6% by weight per volume of aqueous solution of sodium hydroxide (2.5 ml) is then added. ml) and the mixture is additionally heated for 1 hour at the above temperature, the reaction mixture is then cooled to 40 ° C and the pH is adjusted to 6.5 by adding 96% by weight per volume of acetic acid.
    five
    immediately precipitated. The reaction mixture is left to stand overnight in a refrigerator and the separated crystals are filtered, washed with some water and methanol. A total of 0.22 g (66%) of 6-fluoro-1,4-dihydro-1 - (methylamine) -7- (4-methyl) piperazine) 4-oxo-3 quinoline-carboxylic acid, decomposing with 294 C after recrystallization From dimethylformamide. When mixing the Product with the product of the previous example in any ratio, no decrease in the melting point is observed.
    Getting the source material. 1.5 g of ethyl 6-fluoro-fluoro-1- (M-form-mil-M-methyl-amino) -7-chloro-4-oxo-1, 4-dihydro-quinoline-3-carboxylate are mixed in 25 ml of 50% by weight per volume of aqueous solution of hydrogen fluoroboric acid at 90-95 ° C for 4 hours. After 4.5 hours, precipitation of crystals begins. The reaction mixture is cooled to room temperature, then placed in a refrigerator and allowed to crystallize overnight. The next morning, the precipitated crystals are filtered and washed with some water. Thus, 4.55 g of 6-fluoro-7-chloro-1- (methylamino) -4-oxo4-dihydro-quinoline-3-carboxylic acid anhydride and 4.55 g are obtained, yield is 93.4%. M.p. 277 ° C (decomposition).
    Calculated,%: C 41.48; H 2.21; N 8.79,
    C iH7BF3ClN2 (b
    Found,%: C 41.59; H 2.34;
    N 8.58.
    2.5 g of 6-fluoro-7-chloro-1-methylamino-A-oxo-1,4-dihydro-quinoline-3-carboxylic acid are stirred in 25 ml of 50% by weight per volume of aqueous solution hydrofluoroboric acid at 80-90 ° C for 2 hours. After 45 minutes, the crystals begin to precipitate. The reaction mixture is first cooled to room temperature, then left to crystallize for 2 hours at 0 ° C. The precipitated crystals are filtered and washed with some water. 4.95 g of 6-fluoro-7-chloro-1-methyl-amino-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and difluoroboric acid anhydride are obtained in this way. 84.5% % m.p. 277 ° C (decomposition). A mixture of yarn product
    about
    0
    five
    in this manner, any amount of product prepared according to Example 1 does not show any melting point depression.
    A mixture of 1.42 g of boric acid and 10.6 g of propionic anhydride was stirred at 100 ° C for 15 minutes, after which the reaction mixture was heated to boiling point. After 30 minutes, the temperature of the reaction mixture was lowered to 110 ° C and 4.2 g of 6-fluoro-7-chloro--1-methylamino-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid was added.
    After a few minutes, the crystals begin to precipitate. The reaction mixture was stirred at 110 ° C for 2 hours, cooled to 10 ° C, after which 20 ml of water and 20 ml of ethanol were added to the crystalline suspension. The reaction mixture is left to crystallize in the refrigerator overnight. The precipitated crystals are filtered, washed with water and dried. A total of 6.12 g of (6-fluoro-7-chloro-1-methylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid-boron dipropionyloxy) anhydride are obtained. Yield 93.5%, m.p. 215 ° C (decomposition).
    Calculated,%: C, 47.86; H 4.01; N 6.56.
    CA7H 7BClN2Or
    Found,%: C 48.07; H 3.87; N 6.48.
    权利要求:
    Claims (4)
    [1]
    1. A method for preparing 1-methylaminoquinoline carboxylic acid derivatives of the general formula I
    soon
    where K is piperazinyl or 4-methylpiperazinyl,
    or their addition salts with pharmaceutically acceptable acids by reacting a 1,4-dihydroquinoline derivative with a piperazine of general formula II
    Rl is hydrogen or methyl,
    Where
    when heated in an organic solvent medium, characterized in that, in order to increase the yield of the target product and shorten the process time, a compound of general formula III is used as a 1,4-dihydroquinoline derivative
    157
    R
    Where
    R3 IR4
    halogen, aliphatic Cr-C acyloxy,
    e10
    579459. ten
    an aprotic dipolar solvent is used as an organic solvent, the process is carried out at 70-120 ° C, and the resulting compound is isolated or subjected to alkaline hydrolysis to isolate the desired product in free form or as a pharmaceutically acceptable salt.
    [2]
    2. A method according to claim 1, wherein the process of reacting a compound of formula II to form formula III is carried out in the presence of an acid binding agent.
    [3]
    3. Method pop. 1 and 2, characterized in that an excess of the compound of the general formula 11 is used as an acid binding agent.
    [4]
    4. A method according to claim 1, characterized in that an alkali metal hydroxide is used as a hydrating agent.
    15
    20
    类似技术:
    公开号 | 公开日 | 专利标题
    KR0149172B1|1998-10-15|An improved process for the preparation of substituted isoflavone derivatives
    US4499091A|1985-02-12|1-Amino |-1,4-dihydro-4-oxo-6-fluoro-7-heterylquinoline-3-carboxylic acids and their use as antibacterial agents
    RU1838302C|1993-08-30|Mixed anhydrides of quinolinecarboxylic acid and boric acid as intermediate products for synthesis of piperazinyl-3-quinolinecarboxylic acid derivatives showing antibacterial activity
    SU1722228A3|1992-03-23|Method for synthesis of quinoline carboxylic acid derivatives or its methane-sulphonate salt
    SU1579459A3|1990-07-15|Method of obtaining derivatives of 1-methylaminoquinolinecarboxylic acid or their salts connecting pharmaceutically acceptable acids
    SU1701110A3|1991-12-23|Method for preparation of quinoline carboxylic acid or theirs pharmaceutically acceptable salts
    ES2006994A6|1989-05-16|Process for the preparation of quinoline carboxylic acid derivatives.
    SU1604156A3|1990-10-30|Method of producing anhydrides of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carbolic acid and boric acids
    US4439436A|1984-03-27|1,3-Dioxolo|quinoline compounds
    Ho et al.1969|Inhibitors of Monoamine Oxidase III: 9-Substituted-β-Carbolines
    EP0055068B1|1984-10-17|Quinolone derivatives and their use as pharmaceuticals
    SU1584751A3|1990-08-07|Method of producing anhydrides of 6-fluoro-7-chloro-1-methylamino-4-oxo-1,4-dihydroquinoline-3-carbolic acid and boric acids
    US5166354A|1992-11-24|Quinoline derivatives and processes for the preparation thereof
    US5395936A|1995-03-07|7-|sulphonyl]-1-piperazinyl fluorquinolonic derivatives and synthesis
    US4841092A|1989-06-20|Preparation of tris|amine
    SU1671660A1|1991-08-23|Method for preparation of 2-selenooxo-5- arylideneimidazolidine-4-ones
    EP0260102B1|1993-03-17|Chemical process
    SU1143745A1|1985-03-07|Method of obtaining derivatives of 3-| propionic acid
    US5294712A|1994-03-15|Process for the preparation of quinoline carboxylic acids
    US2807616A|1957-09-24|Oxazolopyrimidines and method of preparing same
    GB2245562A|1992-01-08|Process for the preparation of quinoline carboxylic acid derivatives
    JP3221151B2|2001-10-22|Method for producing pyrrole derivatives
    JPH05163272A|1993-06-29|Method of preparing 5,11-dihydro-6h-dipyrido- |-diazepine
    SU470111A3|1975-05-05|The method of obtaining 5- | -6-dialkylaminoalkoxy-4,7-dimethoxybenzofuran derivatives
    EP0195135B1|1992-06-17|A process for the preparation of quinoline carboxylic acid derivatives
    同族专利:
    公开号 | 公开日
    CA1294621C|1992-01-21|
    FI873097A|1987-07-13|
    EP0248876B1|1995-03-15|
    WO1987003586A1|1987-06-18|
    CS261250B2|1989-01-12|
    HU196782B|1989-01-30|
    YU210586A|1987-12-31|
    KR880700792A|1988-04-12|
    NO170153B|1992-06-09|
    FI86420C|1992-08-25|
    FI873097A0|1987-07-13|
    FI86420B|1992-05-15|
    KR940008304B1|1994-09-12|
    YU45392B|1992-05-28|
    NO873097D0|1987-07-23|
    AT119884T|1995-04-15|
    HUT43840A|1987-12-28|
    EP0248876A1|1987-12-16|
    DD252602A5|1987-12-23|
    NO873097L|1987-07-23|
    CS909086A2|1988-05-16|
    US4871849A|1989-10-03|
    NO170153C|1992-09-16|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    JPS6011913B2|1977-12-27|1985-03-28|Koei Chemical Co|
    EP0090424B1|1982-03-31|1986-05-28|Sterling Drug Inc.|New quinolone compounds and preparation thereof|
    JPS5980683A|1982-10-30|1984-05-10|Koei Chem Co Ltd|6-fluoro-1,8-naphthyridine derivative and its preparation|
    AU553415B2|1983-09-19|1986-07-17|Abbott Japan Co., Ltd.|6-fluoro-1-4-dihydro-4-oxo-7-substituted piperazinyl- quinoline-3-carboxylic acids|
    EP2332987A1|2009-12-10|2011-06-15|ModiQuest B.V.|Anti-inflammatory agents directed against citrullinated epitopes|HU198709B|1987-04-08|1989-11-28|Chinoin Gyogyszer Es Vegyeszet|Process for producing quinoline-carboxylic acid derivatives|
    SI8810667A8|1987-04-08|1996-04-30|Chinoin Gyogyszer Es Vegyeszet|Anhydride of quinoline carboxylic acid of boron acid and process for their production.|
    US5380845A|1987-06-24|1995-01-10|Chinoin Gyogyszer- Es Vegyeszeti Termekek Gyara Rt.|Process for the preparation of quinoline carboxylic acid derivatives|
    HU203746B|1988-12-22|1991-09-30|Chinoin Gyogyszer Es Vegyeszet|Process for producing quinoline-carboxylic acid derivatives|
    AU2003203088A1|2002-02-07|2003-09-02|Browne And Co. Ltd.|Non-symmetrical photo tooling and dual surface etching|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU854691A|HU196782B|1985-12-09|1985-12-09|Process for production of quinoline carbonic acid|
    [返回顶部]