• 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 stable trihydrate of (2S, 5R, 6R)-6-{(2R)-2-[(2R)-2-amino-3-(N-methylcarbamoyl)propionamido]-2-(p-hyd oxyphenyl)acetamido}-3,3-dimethyl-7-oxo-4-thia-1-azabic yclo[3.2.0]heptane-2-carboxylic acid and process for preparing the same are disclosed.
    公开号:SU1517764A3
    申请号:SU874203390
    申请日:1987-09-23
    公开日:1989-10-23
    发明作者:Охсиро Сусуму；Сенума Масару；Вагацума Мицуеси
    申请人:Танабе Сейяку Ко., Лтд (Фирма)；
    IPC主号:
    专利说明:

    This mixture is stirred for one hour and then cooled to 5 ° C. The precipitates obtained are collected by filtration, washed with water and dried, thereby obtaining N-methyl-B-asparaginylamoxycillin trihydrate (8 g) as a white crystalline solid.
    The water content (Karl Fischer method) is 10.05% (corresponds to .3 mol), the content of the product (HPLC) is 99.7%. Eve + 179.5 ° (with 1.0 water).
    X-ray powder diffraction patterns of crystalline K-methyl-B-asparaginylamoxycillin trihydrate and amorphous anhydrate N-methyl-P-asparaginyl-amoxicillin are shown in Table 1 (CurNi power source, 40 kV, 35 mA, ...).
    Example 2. The amorphous anhydrate of N-methyl-B-asparaginylamoxycillin (10 g) is dissolved in water (500 ml) (pH of the solution is 4.3). The solution is concentrated under reduced pressure to 250 g, after which ethanol (250 g) is added to it. The resulting precipitates are collected by filtration and dried, thereby obtaining N-methyl-D-acnapa-hydroxylamine oxydiline trihydrate (5 g) as a white crystalline solid.
    The water content of Karl Fischer) is 10.74% (corresponds to 3 mol), the content of the product (HPLC) is 99.3%.
     179.3 ° (c 1.0, water).
    Example H. To an amorphous N-methyl-D-asparaginyl-amoxicillin anhydrate (22.2 g), water (70 ml) is added and an aqueous 20% sodium hydroxide solution (5.4 ml) is added drops in order to dissolve the anhydrate. Activated carbon is added to the solution and the mixture is filtered. The filtrate was adjusted to pH 3.5 with 20% hydrochloric acid (about 5.5 ml). The resulting precipitates are collected by filtration and dried, thereby obtaining N-methyl-D-β-asparaginylamoxycillin trihydrate (17 g) as a white crystalline solid.
    The water content (Karl Fischer method) is 10.21% (corresponds to 3 mol, the content of the product (HPLC) is 99.7%.
    SP 179.9 ° (with 1.0, water). Example 4 Thiobenzamide (20.5 g) was dissolved in ethanol (290 ml) and trihydrate (2S, 5R, 6R) -6- (2R) -2- (2R) -2 was added to the mixture.


    five
    Q 5
    five
    - (o-nitrophenylsulfenyl) -amino-3- (N-methylcarbamoyl) propionamido - -2- (p-hydroxyphenyl) acetamido-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo Z. 2.0 heptane-2-carboxylic acid (32.21 g). The mixture is stirred at a temperature of from 15 to 20 ° C for 17 hours in order to remove the amino-protecting group (i.e., the o-nitrophenylsulfenyl group). Precipitates (i.e., H-methyl-O-asparaginylaminoxycillin) are collected by filtration, dried and then added; to a suspension of activated carbon (3 g) in water (50 ml). The suspension is adjusted to pH 5.5 with 1% hydrochloric acid (about 3 ml) and stirred at room temperature for one hour. The insoluble materials are filtered off and the filtrate is concentrated under reduced pressure to obtain an M-methyl-B-asparaginylaminoxycillin concentration of 40% by weight. The concentrated solution is stirred at 30 ° C for one hour and then cooled to 5 ° C. The resulting precipitates are collected by filtration and dried, thereby obtaining N-methyl-D- -asparaginylaminoxycillin trihydrate (12.5 g) as a white crystalline solid .
    The water content (Karl Fischer Netod) is 10.1% (corresponds to 3 mol), the content of the product (HPLC) is 99.7%, Ml + ,, 0 (s 1.0, water)
    Example 5. Stability test. The crystalline N-methyl-B-asparaginylaminoxycillin trihydrate (compound 1) and the amorphous anhydrate N-methyl-B-asparaginyl-amoxicillin (prepared in accordance with a known method, compound 2) are settled at 40 ° C in a sealed tube for 5, 10, 15, or 30 days, and the stability of each compound is assessed by measuring the content of N-methyl-B-asparaginylaminoxycillin.
    The results are shown in table 2.
    The content of N-methyl-B-asparaginylaminoxycillin is measured by high performance liquid chromatography (HPLC) under the following conditions: column: Octadecyl silane (4.6 mm X 150 MM) J mobile phase: phosphate buffer — acetonitrile (87:13) (pH 3.0) volumetric flow rate 1.0 ml / min; column temperature.
    Continuation of table 1
    Crystalline trihydrate Amorphous anhydrate of N -methyl-D-acnaN -methyl-B-asparaginyl-ragiiylammoksitsillina
    amoxicillin
    D Value Relative d Value Relative
    intensity intensity
    3.25m
    3.13VW
    3,01W
    2.86os
    2.81 sos
    2.60os
    2.40 s

    Relative intensities are estimated by comparing line intensities.
    against the system of rates: vs - very high, s - high, -m - average, W - low, VW - very low.
    table 2
    Test Residual concentration of N -methyl B-asparagin 1 -bench-sicillin compounds,%
    for the period of time during which the test compound is defended, days
    Starting 5 10
    1100.0 100.0 100.0 100.0 99.5
    2100.0 91.0 90.0 88.5 85.5
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of producing trihydrate (2S, 5R, 6R) -6- {(2R) -2- [(2R) -2-3mhho-3-
    - (N-Metiparcarbamoyl) propionamido] -2-
    - (p-hydroxyphenyl) -acetamido] -3,3-dime type-7-ok with o-4-thia-1-az ab acyclo o [3.2.0] heptane-2-carboxylic acid with the following diffraction pattern
    4.23 m 3.97 w 3.77 vw 3.64 vw 3.54 w 3.48 w 3.37 w 3.25 m 3.13 vw 3.01 w 2.86 vw 2.81 vw 2.65 vw 2.60 vw 2.40 w
    where vs is very high, s is high, radiographs:
    about.
    d (A) w - medium, w - low, vw ~ very low,
    15.77
    10.77
    9.21
    7.89
    5.98
    5.57
    5.34
    4.98
    4.62
    4.39
    Relative intensity
    W
    W
    Vw
    W
    S
    VS
    W
    Vw
    VS
    W characterized in that the pH of the solution is (2S, 5R, 6R) -6- [(2R) -2- [(2R) ~ -2-amino-Z-04-methylcarbamoyl) propionamido] -2- (p-hydroxyphenyl) -acetamido] -3,3, -dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid or its salt is adjusted to a value of · from 3.5 to 5.5 using hydrochloric acid with crystallization of the target product by cooling or condensing the solution or by adding ethanol.
    T a b l i c a 1 Crystalline trihydrate 4Amorphous Anhydrate N “methyl-D-acna- N-methyl-O-asparaginyl- raginylammoxicillin amoc sicillin D value Relative D value Relative intensity*intensity*
    15.77 W 5.94 vw 10.77 w 5.50 vw 9.21 vw 4,57 vw 7.89 V5.98 s5.57 vs5.34 w4.98 vw4.62 vs4.39 w4.23 m3.97 m3.77 vw3.64 vw3.54 w3.48 w3.37 w
    Continuation of table 1
    Crystalline trihydrate N ^ -MeTHn-D-acnaparinilamocyl sicillin Amorphous Anhydrate N 4 ~ MeTnn-D _ acnaragin Ilammoxicillin D value Relative intensity D value Relative intensity * 3.25 m3.13 vw3.01 w2.86 OS2.81 OS2.60 OS2.40 from
    The relative intensities are estimated by comparing the intensities of the lines against the system of standards: vs - very high, s - high, w - medium, w - low, vw - very low.
    table 2
    Test subject Residual concentration of N-methyl-D-asparaginyl amine sicillin compound,% over the period of time during which the test compound is defended, days
    Elementary 5 10 i 15thirty 1 100.0 100.0 100.0 100.0 99.5 2 100.0 91, 0 90.0 88.5 85.5
    类似技术:
    公开号 | 公开日 | 专利标题
    CA2121351C|2003-08-05|The resolution of 5-methyltetrahydrofolic acid
    AT392472B|1991-04-10|METHOD FOR PRODUCING A STABLE CRYSTALLINE DI- OR TRIHYDRATE OF 7BETA- | -2- | -4-CARBOXYBUT-2- ENOYLAMINO) -3-CEPHEM-4-CARBONIC ACID
    SU1272992A3|1986-11-23|Method of producing 9-|-guanine
    KR920005744B1|1992-07-18|A method for the resolution folinic acid
    SU1517764A3|1989-10-23|Method of producing trihydrate of |-6/|-2/|-2-amino-3|propyonamido/-3-3-dimethyl-7-oxo-4-thia-1-azabicyclo/3,2.0/ heptae carbolic acid
    CN1153176A|1997-07-02|Stable crystalline tetrahydrofolic acid salts
    CA2077562A1|1993-03-08|Diastereomers of 1-| ethyl 3-cephem-4-carboxylate and processes for their preparation
    CN1015263B|1992-01-01|Process for preparation of 3-propenyl cephalosporin solvates
    RU96121625A|1999-01-27|STABLE CRYSTALLINE TETRAHYDROPHOLIC ACID SALT
    RU95121158A|1998-01-10|THIENOPYRIDONES, METHOD FOR PRODUCING THEM, PHARMACEUTICAL COMPOSITION, METHOD FOR PRODUCING IT, METHOD FOR COMBATING DISEASES
    SU925251A3|1982-04-30|Process for producing d-configuration crystalline form of sesquisalt of sodium 7beta-[alpha-carboxy-alpha-| acetamido-7-alpha-methoxy-3-| thiomethyl-2-oxadethia-3-cefem-4-carboxyate
    KR100696422B1|2007-03-20|Cephalosporines having cyclic aminoguanidine substituents as antibiotics
    RU2000107822A|2002-01-10|OPTICALLY PURE ANALOGUES OF CAMPTOTECINE, OPTICALLY PURE INTERMEDIATE SYNTHESIS PRODUCT AND METHOD FOR PRODUCING IT
    US4168376A|1979-09-18|Process for crystalline sodium cefamandole
    SU860705A3|1981-08-30|Method of preparing crystalline form of d-configuration of diammonium salt of 7-beta-/-alpha-carboxy-alpha-p-oxyphenyl acetamido /-7-alpha-methoxy-3-|-thiomethyl-1-oxydethia-3-cephem-4-carboxalic acid
    FI89454C|1993-10-11|Process for preparing a lyophilized antibacterial preparation
    FI75169C|1988-05-09|Process for the preparation of crystalline sodium cefoperazone.
    DE2645144C2|1986-11-27|Cephalosporins, processes for their preparation and pharmaceutical compositions containing them
    US5391738A|1995-02-21|Process for the separation of folinic acids
    CA1181741A|1985-01-29|Water soluble derivatives of cephalexin and processfor their preparation
    KR950013570B1|1995-11-09|The preparation method of cefodizime bisodium salts
    DE3745094B4|2004-12-30|New stable hydrate of 7-butenoyl:amino- cephalosporin derivs. - esp. formulated in soft gelatin capsules sealed with gelatin layer
    JPH0665254A|1994-03-08|Ceforanide derivative
    同族专利:
    公开号 | 公开日
    KR920003902B1|1992-05-18|
    NO169717C|1992-07-29|
    SG15393G|1993-04-16|
    FI874152A0|1987-09-23|
    JPH0448795B2|1992-08-07|
    IL83786D0|1988-02-29|
    CN1021225C|1993-06-16|
    NO873969D0|1987-09-23|
    FI86853C|1992-10-26|
    DE3766921D1|1991-02-07|
    HUT45263A|1988-06-28|
    ES2026545T3|1992-05-01|
    CN87106308A|1988-04-13|
    IE872346L|1988-03-14|
    FI86853B|1992-07-15|
    IL83786A|1991-11-21|
    NO169717B|1992-04-21|
    PT85773A|1987-10-01|
    AU592467B2|1990-01-11|
    KR880003955A|1988-05-31|
    FI874152A|1988-03-25|
    PT85773B|1990-07-31|
    DK500887A|1988-03-25|
    DK500887D0|1987-09-23|
    HK42093A|1993-05-07|
    CA1286285C|1991-07-16|
    EP0261823A1|1988-03-30|
    IE60042B1|1994-05-18|
    ZA876739B|1988-03-14|
    HU196810B|1989-01-30|
    EP0261823B1|1991-01-02|
    AU7882787A|1988-03-31|
    MY102553A|1992-07-31|
    US4866170A|1989-09-12|
    JPS6379888A|1988-04-09|
    ATA273187A|1989-04-15|
    AT389311B|1989-11-27|
    DK167319B1|1993-10-11|
    PH23644A|1989-09-27|
    GR3001274T3|1992-08-25|
    AT59655T|1991-01-15|
    NO873969L|1988-03-25|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    NL6705789A|1967-03-08|1968-09-09|
    GB1241844A|1968-08-23|1971-08-04|Beecham Group Ltd|Penicillins|
    US4053609A|1975-09-12|1977-10-11|Tanabe Seiyaku Co., Ltd.|Penicillins and processes for preparing the same|
    JPS6210511B2|1979-09-11|1987-03-06|Tanabe Seiyaku Co|US5375123A|1993-02-05|1994-12-20|Telefonakitebolaget L. M. Ericsson|Allocation of channels using interference estimation|
    US6473602B1|1996-10-28|2002-10-29|Ericsson Inc.|Mobile assisted handoff in radiocommunication systems|
    PE20000879A1|1998-04-29|2000-09-23|Dsm Nv|METHOD TO CRYSTALLIZE A ß-LACTAMIC ANTIBIOTIC|
    KR101879756B1|2016-11-30|2018-08-17|주식회사 지앤지비|Heating apparatus for bathroom|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP61226423A|JPH0448795B2|1986-09-24|1986-09-24|
    [返回顶部]