• 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:
    The novel compound alpha -bromodiethylcarbonate, its use in the preparation of 1-ethoxycarbonyloxyethyl esters of penicillins and cephalosporins, in particular bacampicillin, and improvements in the method for preparing such esters.
    公开号:SU1245262A3
    申请号:SU833611596
    申请日:1983-06-28
    公开日:1986-07-15
    发明作者:Ратти Луиджи；Регинальд Пальмер Дерек；Грахам Тысон Роберт
    申请人:Астра Лекемедель Аб (Фирма)；
    IPC主号:
    专利说明:

    // V-CH-HPMN. BUT/
    w H-pY YcHa
    NZS-cjjA i.
    one .
    at
    ABOUT
    CO, where R has the indicated meaning, is converted into the 1-ethoxycarbonyl-hydroxyethyl ester of (-) - 2-amino. The invention relates to a method for producing a penicillin antibiotic, i.e., 1-ethoxycarbonyl-hydroxyethyl ester of (-) - 2-amy- but-2-phenylacetamide-penicillanic acid in the form of its additive salt with hydrohalic acid and can be used as an antimicrobial agent.
    The aim of the invention is to increase the yield of the target product.
    This goal is achieved using ampicillin as a starting penicillin derivative, transferring it to the N- (1-alkoxycarbonyl propen-2-Sh1) derivative, which is then subjected to esterification followed by removal of the 1-alkoxycarbonyl-propen-2-yl protecting group.
    The invention is illustrated by the following examples.
    Example I. 25.08 g (0.181 mol of finely powdered anhydrous potassium carbonate are suspended in 200 ml of K, H-dimethylacetamide 1 and then 32.4 ml (0.3 mol) of acetoacetic acid methyl ester and 60.4 g (0; 15 mole) ampicillin trihydrate. I
    The mixture was stirred at 20-25 G for 5 hours, after which 46.1 g (0.234 mol) of bromodiethyl carbonate, 6 g (0.02 mol) of tetrabutylammonium bromide and 100 ml of N, N-dimethyl acetamide were added. After stirring, the mixture is heated at 40-42 ° C for 10 hours and then 1200 ml are poured into the mixture.
    COOCH-O-COOCgHs
    sh
    I
    -2-Phenylacetamido-penicillanic acid by hydrolysis in the presence of hydrohalic acid.
    water and 400 ml of n-butyl acetate. The aqueous phase is collected and extracted with 100 ml of n-butyl acetate.
    The combined organic phases are washed twice with 100 ml of water, after which .150 ml of 1N hydrochloric acid and 370 MJl of water are added with stirring. The reaction mixture is stirred for another 4 h at 22-23 0.
    The aqueous phase is collected and the organic phase is extracted with 100 ml of water. The combined aqueous phases are adjusted to pH 4 by addition of a 10% aqueous solution of sodium carbonate, then carbon is added and filtered. To, in addition, 300 ml of n-butyl acetate and 80 g of sodium chloride are added.
    The organic phase is separated and the aqueous phase is extracted with 200 ml of n-butyl acetate.
    The combined phase in n-butyl acetate is concentrated to a volume of 300 ml at 40 ° C and low pressure. The product is crystallized at 5 ° C for 15 hours. It is filtered, washed with 100 ml of n-butyl acetate and 100 ml of ethyl acetate and dried in vacuo for 24 hours.
    54.2 g (72%) of 1-ethoxycarbonyloxy-methyl ester, (-) - o (.-Amino-N-phenylacetamido - penicillanic acid in water and hydrochloride-wda with a melting point of 160-162 ° C.) are obtained (melt. ).
    PRI mme R 2. 36.4 (0.075 mol) of potassium salt of N- (1-methoxycarbonyl-propen-2-yl) -6-D- (-) -c-amino-o-phenylacetamido} Penicillanic acid, prepared as in Example 1, is added to a solution of 17.8 g (0.116 mol) (x-chloro-diethyl carbonate and 3 g (o, 0 mol) of tetra-butylammonium bromide) in 150 ml of H, K-dimethyl-formamide. While stirring, the temperature is raised to 45 ° C and maintained at 45-50 ° C for 5 hours. Then the reaction mixture is poured into a mixture of 300 ml of 14% aqueous solution of sodium chloride and 600 ml of n-butyl acetate. leremeshivat for 10 min, the body The organic phase is separated and the aqueous phase is extracted with 100 ml of n-butyl acetate.The combined organic phases are washed twice, 75 ml of 14% aqueous sodium chloride solution and concentrated under low pressure to obtain an oil, which is mixed with 200 ml of tetrahydrofuran and 100 water. The resulting solution, having a pH value of 4.8, is brought to pH 1.5 with stirring by adding 12 ml of 6N hydrochloric acid for 1 hour. The reaction solution is left to stand for an additional 1 hour at those with the environment, tetrahydrofuran removed t at 40 ° C and low pressure, and 150 ml of n-butyl acetate and 15 g of sodium chloride are successively added to the remaining aqueous phase (150 ml). The organic phase is separated and the aqueous phase is extracted with 100 ml of n-butyl acetate. .
    The combined organic phases are concentrated to a volume of 120 ml at 4 ° C. c. vacuum.
    . The product crystallizes at 5 ° C for 15 hours. It is filtered, washed with 50 ml of n-butyl acetate and 50 ml of ethyl acetate and dried under vacuum at 40 ° C.
    25.2 g (66.9%) of a gchdrochlid compound are obtained. 1-ethoxycarbonroxy-ethyl ester of b-CB - (-) - 1-amino-oh: -phenylacetamido-penicillanic acid with a melting point of 160-162 °.
    VNIIPI Zaka.z 3931/60
    Circulation 379
    Subscription
    Random polygons pr-tie, Uzhgorod, st. Project, 4
    PRI me R 3. 16.2 ml (o, .15
    mole

    acetoacetic acid methyl ester and 30.30 g (0.075 mol) of ampicillin trihydrate were added to a suspension of 12.54 g (0.0907 mol) of powdered anhydrous potassium carbonate in 100 ml of N N-dimethylformamide. The mixture is stirred at 22-23 ° C for 3 hours, after which 17.8 g (0.117 mol) of o-chloro-diethyl carbonate, 3 g (0.01 mol) of tetrabutylammonium bromide and 50 ml of N-N are added. - dimethylformamide. After stirring, the mixture is heated at 45-50 ° C for 5 hours and then left to stand at 5 ° C for 15 hours.
    The reaction mass is poured into a mixture of 600 ml of water and 200 ml of n-butyl acetate and stirred until a solution is obtained. The aqueous phase is collected and extracted with 50 ml of n-butyl acetate. The combined organic phases are washed twice with 50 ml of water, after which 75 ml of 1N are added with stirring. hydrochloric acid and 185 ml of water. Then continue to stir at 22-23 ° C for 4 hours.
    The aqueous phase is collected and the organic: phase is extracted with 50 ml of water. The combined aqueous phases are adjusted to pH 4 by adding a 10% aqueous solution of sodium carbonate, carbon is added and filtered. 150 ml of n-butyl acetate and 40 g of sodium chloride are added to the aqueous filtrate. The organic phase is separated and the aqueous phase is extracted with 100 ml of n-butyl acetate. The combined phases in n-butyl acetate are concentrated to a volume of 150 ml at 40 ° C and low pressure. The product crystallizes at 5 ° C for 15 hours. It is filtered, washed with 50 ml of n-butyl acetate and 50 ml of ethyl acetate and dried at 25 C. for 24 hours in a vacuum of 10 mm Hg. in the presence of moisture.
    20.8 g (55%) of 6-CG 1-ethoxycarbonyloxyethyl ester hydrochloride (.). Minoo (-β-phenylacetamidoJ-penicillanic acid, melting point 159-161 ° C.
    Circulation 379
    Subscription
    权利要求:
    Claims (2)
    [1]
    1 .
    R where R has the indicated meaning, is converted to 6- (D - (-) - 2-amino 1-ethoxycarbonyloxyethyl ester
    1-ethoxycarbonyloxyethyl ether
    6- [D - (-) - 2-C-derivative 2-phenylacetamido] penicillanic acid of the formula
    H 3 C- (jjA ^ o soo - sn-o-soos 2 n 5
    Η-ογο CH 3
    6- [D - (-) - 2-AMINO-2-PHENYLACETAMIDO) -PENYCYLANIC ACID 1-Ethoxycarbonyl-ethoxyethyl ester in the form of its ADDITIVE SALT with the HALOID 6) - 2-π-alkaline metal 2-phenylacetamido] -penicyl- 'lanoic acid with </ - halogenated diethyl carbonate of the formula I with hydrogen chloride, · characterized in that, in order to increase the yield of the target product in an aprotic solvent, ampicillin is reacted with-c. an excess of lower acetoacetic acid alkyl ester in the presence of an alkali metal carbonate at room temperature, the resulting compound! of formula I is reacted with d-halide diethyl carbonate of formula 1
    SU "„ 1245262 AZ where R is C4-C ,, is an alkoxy group;
    X is an alkali metal, in the presence of a quaternary ammonium salt, and the resulting complex
    [2]
    -2-phenylacetamido] -penicillanic acid by hydrolysis in the presence of hydrogen halide.
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    引用文献:
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    GB991586A|1963-02-28|1965-05-12|Beecham Res Lab|Process for the preparation of penicillins|
    FR4394M|1964-04-23|
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    GB1302917A|1970-07-14|1973-01-10|
    US3873521A|1970-09-17|1975-03-25|Astra Laekemedel Ab|Esters of {60 -amino penicillins|
    IE35648B1|1970-09-25|1976-04-14|Beecham Group Ltd|Penicillins|
    BE756806A|1970-09-29|1971-03-29|Vnii Antibiotikov|Process for 6--alpha-amino-phenylacet- - amido)-penicillanic acid|
    GB1347979A|1970-11-12|1974-02-27|Beecham Group Ltd|Penicillins|
    DE2161420A1|1970-12-30|1972-07-27|Toyama Chemical Co. Ltd., Tokio|Penicillin derivatives and processes for their preparation|
    GB1377817A|1971-06-09|1974-12-18|Beecham Group Ltd|Penicillins and cephalosporins|
    GB1390754A|1971-06-09|1975-04-16|Beecham Group Ltd|Penicillin and cephalosporin esters|
    GB1364672A|1971-06-09|1974-08-29|Beecham Group Ltd|Penicillins|
    BE784800A|1971-06-15|1972-10-02|Yamanouchi Pharma Co Ltd|PROCESS FOR PREPARING NEW OXYMETHYL ESTERS OF PENICILLIN AND CEPHALOSPORIN|
    GB1433131A|1972-03-13|1976-04-22|Astra Laekemedel Ab|Penicillins|
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