• 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:
    A high yielding process for converting 3,2',6'-tri-N-acetyl sisomicin to netilmicin comprising the step of silylating the starting material at the 5,2" positions, and optionally at the 4" position, converting the 1-amino substituents to a 1-N-imino substituent, converting the imino to an ethylamino, deprotecting the compound and recovering netilmicin. Also disclosed are novel intermediate compounds.
    公开号:SU1630614A3
    申请号:SU874202675
    申请日:1987-06-12
    公开日:1991-02-23
    发明作者:Танн Шу-Хонг；Каннаппан Триувенгадам Тируветтипурам；Ше-Хунг Шиц Джон；Колон Цезар
    申请人:Шеринг Корпорейшн (Фирма)；
    IPC主号:
    专利说明:

    The aim of the invention is to increase the yield of the target product, the antibiotic netilmicin, which is achieved by reacting siz.omitsin with protected amino groups with acetaldehyde in an aprotic organic solvent medium, destroying the resulting unreacted acetaldehyde. and subsequent deprotection and isolation of the desired product in free form or as an acid addition salt, Amino acid-protected acetaldehyde with amino groups is silylated in an anhydrous medium at the boiling point of the reaction mixture, and the silylated sisomycin is reacted with acetaldehyde in anhydrous medium.
    Example 1.A.V round-bottom three-neck flask with a capacity of 500 ml,
     equipped with a stirrer, a reflux cooler, equipped with a drying tube, and a thermometer, are fed 15.0 g (26.2 mmol) 3.2, 6 - three-M-acetyl sisomycin, 0.750 g (1.12 mmol) 3, 2, 6 -tru-1-acetylsisomycin as a sulfate salt, 150 ml of 1,2-dimethoxyethane and 25 ml (118.5 mmol) of hexamethyldisilazane. The reaction mixture is heated to boiling in an oil bath | b with a temperature of 105 ° CJ for 5 hours. The course of the silylation reaction is monitored by H-NMR. After removal of the solvent, one obtains
     18 g 3,2, b-tri-M-acetyl-5,2, trimethylsilylsizomycin.
    B. 150 ml of 1,2-dimethoxyethane and 1 50 ml of methylene chloride are added to the product of stage A at room temperature. After cooling the reaction mixture to 15 ° C, 3.0 ml (53.6 mmol) of cold acetaldehyde was added. Continue stirring for 30 minutes, after which 1.9 g (50.2 mmol) of powdered sodium boron are added. The reaction mixture is heated to room temperature and stirred for 15 minutes in order to completely destroy the excess acetaldehyde. Then 30 ml of 0.5 M aqueous borate buffer (pH 9.75) is quickly added to the reaction mixture, then stirred at room temperature for 2 hours in order to restore the imino group to
    from 5 o
    5 0 s
    0
    5 Q
    five
    corresponding ethylamino group. To the reaction mixture is added 30 ml of 10% aqueous sodium hydroxide, which serves to deactivate sodium borane. The solvents, 1,2, -dimethoxyethane and methylene chloride, are removed under reduced pressure. Then 200 ml of a 10% aqueous hydroxide solution are added. sodium and the reaction mixture are heated under reflux on an oil bath (103 ° C) under a nitrogen atmosphere for 20 hours. The progress of the reaction is monitored by thin layer chromatography using a mixture of chloroform, methanol and concentrated ammonium hydroxide as a solvent in a ratio of 1 : 1: 1. The hydrolysis product is cooled with ice.
    The baths are acidified to pH 6 by the addition of 25% aqueous sulfuric acid and the precipitate is filtered. After purification by chromatography on silica gel using a mixture of chloroform, methanol and ammonium hydroxide as eluent, 9.66 g (88% of theory) of netilmicin are obtained. CST + 164 ° (0.3%, H40).
    NQR (DU0) (G, (ppm) 1.05 (GH, t, Hz,); 1.19 (GH, s, -C-Scroll); 2.5 (GH, s, N-CKj ); 4.85 (1H, m, CH-); 4.95 (W, d, Hz, NG1); 5.33 OH, D, 5 Hz, H f).
    H-NQR spectra of the intermediate products of example 1.
    Trisylated tri-K-acetyl-RIZOMYCIN.
     H-NMR (CDgCla) (P, ppm: 0.118 G, 9H, 81- (0.124 s, 9H,
    si- (tc 9H) s1;
    1.38 tc, 3K, “C at 1.93 s, 3N, CHy-C-Nl; 1.96 s, 3N, CH, - {j-Nj;
    O °
    1J98 (s, 3H, CH3-C-N); 2.45 (s, ZN,
    ABOUT
     with C-3-); 4.69 (dd, 1H, J 3.29 and 4.02 Hz, CK at C-4); 5.01 (d, 1H, 19 Hz, CH at C-1); 5.08 (d, 1H, 82 Hz, CH at C-1); 6.03 (d, 1H, 99 Hz, NH-C-); 6.47.
    O (dd, 1H,, ll and 6.96 Hz, CH2-NH - (-);
    (7.1 (d, 1H,, 13 Hz, Shch-S-).
    ABOUT
    CH
    about
    NH,
    ABOUT
    Sh.
    (I)
    by reacting the derivative of sisomycin with acetaldehyde in an aprotic organic solvent medium, destroying the unreacted acetaldehyde contained in the reaction mixture by the action of an excess of metal hydride, adjusting the pH of the medium to an alkaline value to restore the reaction product, followed by removal of the acetyl groups by hydrolysis and isolation of the target product by chromatographic measures grapes, characterized in that, in order to increase the yield of the target product, as a derivative of sisomycin use the compound of General formula OX
    N HY
    AND
    (one)
    0 NHY
    here X - organosilyl group
    one . / CV
    Si-CH,

    CH3
    X is hydrogen or the indicated organosilyl group; CID is an acetyl group obtained by reacting a compound of formula
    NHV
    (YY)
    M, TJ
    -NHY
    CH2-NHY
    where Y and Y have the indicated meanings, with hexamethyldisilazane in anhydrous
    an aprotic solvent at the boiling point of the reaction mixture in the presence of a sulfate salt of a compound of formula III as a catalyst, and the reaction of a derivative of formula II with acetaldehyde and the destruction of unreacted acetaldehyde contained in the reaction medium is carried out in an anhydrous medium, sodium borohydride is used as a metal hydride, and sodium borohydride is used as the metal hydride. The pH of the medium is carried out to a pH of 9.75.
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining netilmicin formula 1
    ch 5
    "
    /
    ch 3
    -ABOUT
    ch 3 ch 2 no
    by reacting a derivative of sisomycin with acetaldehyde in an aprotic organic solvent, destroying unreacted acetaldehyde contained in the reaction mixture by an excess of metal hydride, adjusting the pH to an alkaline value to restore the reaction product and then removing the acetyl groups by alkaline hydrolysis and isolating the target product by chromatographic methods, different the fact that, e the purpose of increasing the yield of the target <
    ΝΗ,
    • ΝΗ,
    product, as a derivative of sizomycin, a compound of the general formula
    tde X - organosilyl group / CH .
    51-CH 3
    h sn 3
    7
    1630614
    eight
    x 'is hydrogen or the indicated organosilyl group;
    Y and γ ’is an acetyl group,
    obtained by the interaction of the compounds of the formula
    HE
    where Υ and Ύ 1 have the indicated meanings, with hexamethyldisilazane in anhydrous
    an aprotic solvent at the boiling point of the reaction mixture in the presence of a sulfate salt of a compound of formula III as a catalyst and the reaction of a derivative of formula II with acetaldehyde and the destruction of unreacted acetaldehyde contained in the reaction medium is carried out in an anhydrous medium, sodium borohydride is used as a metal hydride, and the pH is adjusted carried out to a pH of 9.75.
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    同族专利:
    公开号 | 公开日
    ZA867785B|1988-05-25|
    PT83533A|1986-11-01|
    WO1987002365A2|1987-04-23|
    FI84486C|1991-12-10|
    DK169343B1|1994-10-10|
    ES2030395T3|1992-11-01|
    EP0242385B1|1991-06-12|
    WO1987002365A3|1987-08-27|
    DK299587A|1987-06-12|
    GR3002670T3|1993-01-25|
    IE59481B1|1994-03-09|
    IE862706L|1987-04-15|
    AU6474486A|1987-05-05|
    EP0219093A2|1987-04-22|
    FI872621A0|1987-06-12|
    KR870700632A|1987-12-30|
    PL149511B1|1990-02-28|
    KR930003493B1|1993-05-01|
    JPH06316589A|1994-11-15|
    HU199498B|1990-02-28|
    EP0219093A3|1987-11-25|
    JPS63501079A|1988-04-21|
    DK299587D0|1987-06-12|
    CA1290751C|1991-10-15|
    HUT43613A|1987-11-30|
    IL80299A|1991-06-10|
    AR242396A1|1994-08-31|
    PL261846A1|1988-06-23|
    IL80299D0|1987-01-30|
    BG51252A3|1993-03-15|
    EP0242385A1|1987-10-28|
    PT83533B|1989-05-31|
    JPH0649716B2|1994-06-29|
    FI872621A|1987-06-12|
    AU597285B2|1990-05-31|
    FI84486B|1991-08-30|
    PH24737A|1990-10-01|
    NZ217918A|1990-11-27|
    JPH0735394B2|1995-04-19|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    CA1034573A|1974-08-01|1978-07-11|Peter J.L. Daniels|Preparation of 1-n-substituted 4,6-di--1,3-diaminocyclitols|
    US4230847A|1976-06-17|1980-10-28|Schering Corporation|Aminoglycoside antibiotic compounds|
    DE2712160A1|1977-03-19|1978-09-28|Bayer Ag|PSEUDOTRISACCHARIDE, THE PROCESS FOR THEIR MANUFACTURING AND THEIR USE AS A MEDICINAL PRODUCT|
    DE2924659A1|1979-06-19|1981-01-22|Bayer Ag|PSEUDOTRISACCHARIDE, THEIR PRODUCTION AND USE AS A MEDICINAL PRODUCT|KR0139021B1|1995-02-09|1998-04-30|김은영|1-n-ethylsisomycin preparation process|
    GB2478990A|2010-03-26|2011-09-28|E2V Tech|Magnetron with high gfrequency cathode heater power supply|
    CN102796150A|2012-08-31|2012-11-28|无锡福祈制药有限公司|Method for separating and purifying high-purity sisomicin|
    CN105503972B|2015-12-09|2018-05-29|无锡济民可信山禾药业股份有限公司|One kind synthesizes 1-N- ethyl gentamicinCs by catalyst of heteropoly acid1aMethod|
    CN106866756A|2017-01-10|2017-06-20|苏利制药科技江阴有限公司|A kind of method for synthesizing 1 N Netilmicins|
    CN110885350A|2019-08-28|2020-03-17|山东安信制药有限公司|Preparation method of prazolmitrin|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US78719385A| true| 1985-10-15|1985-10-15|
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