• 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:

    公开号:SU852175A3
    申请号:SU802891755
    申请日:1980-03-12
    公开日:1981-07-30
    发明作者:Амиар Гастон；Борманн Дитер；Дюркхеймер Вальтер；Жолли Жан
    申请人:Руссель-Юклаф (Фирма)；
    IPC主号:
    专利说明:

    salt of an organic acid in methanol; crystallized sodium salt of formula Tb is isolated in the form of a methanol solvate, which if necessary is converted into a product of formula I that does not contain methanol, and then the hydrated product or its methanol solvate is hydrated.
    Preferably, a salt selected in the group consisting of sodium acetate, sodium salt of 2-ethylhexanoic acid and sodium salt of diethylacetic acid, preferably sodium acetate, is used.
    The methanol solvate obtained in the first stage is converted into a product that does not contain methanol by drying, for example at 30-50 ° C in vacuum. Thus, the resulting crystals are hygroscopic. The resulting product in the form of a methanol solvate or a product that does not contain methanol is converted into its stable form by hydration. Hydration is carried out either by holding the product in air or in another medium, such as nitrogen, with a high moisture content of these media, or the Methanol solvate or a product that does not contain methanol is suspended in an organic solvent, mixed with water and containing 1-10% of water. The solvent may be a ketone, such as acetone, or an alcohol, such as, for example, ethanol, n-propanol, isopropanol, or tert-butanol.
    In a preferred embodiment, the sodium salt is suspended in ethanol containing about 1-10% water, and the suspension is stirred at room temperature for 10-30. h
    Thus, the methanol solvate, as well as the compound no longer containing methanol, is converted into a crystalline stable phase, called form O. The moisture content of crystalline form D depends on the humidity of the medium and reaches 15% without changing the crystalline structure. By drying in vacuum at room temperature, the moisture content can be reduced to a preferred range from 3 to 6%.
    A preferred variant of the proposed method is that the acid of general formula T in unsolvated form, in the form of a hydrate, in the form of a solvate with ethanol or formic acid, or in the form of a mixture of hydrate and ethanol or formic acid solvate is subjected to the action of an organic acid sodium salt in methanol, then the resulting crystalline methanolic solvate of the sodium salt, is suspended in water mixed with a solvent, containing a small amount of water, left in suspension, and then the target is isolated th crystalline form 0. According to this variant sodium salt
    the organic acid is selected from the group consisting of sodium acetate, sodium salt of diethyl acetic acid and sodium salt of ethylhexanoic acid, and ethanol containing 1-10% is used as a solvent containing a small amount of water in which the methanol solvate is suspended. water.
    The conditions for performing the methods allow sterile operations.
    Like other forms of sodium salt 3-acetoxymethyl-7-C2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido cef-3-em-4-carboxylic acid, the form, called form D, has very good activity with one hand on gram-positive microbes, such as staphylococci, streptococci and, in particular, on penicillin-resistant phylococci and on the other hand on gram-negative microbes, in particular on Klebsiella, Proteus and Salmonella bacilli-shaped microbes. Hydrated Crystalline Sodium Salt
    C 3-acetoxymethyl-7- 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido3 cef-3-em-4-carboxylic acid, syn-isomer, is characterized by a powder X-ray diffraction shown below. The X-ray diffraction spectrum was taken using a copper radiation source at a wavelength of 1.54 A.
    The results are presented in the table.
    Distance of the plane
    Relative grid (d) line intensity (I / 1)
    Table continuation
    Example 1. Sodium salt of form 3-acetoxymethyl-7- crystallized in form D | 2- (2-amino-4-triaolol) -2-methoxyiminoacetamido cef-3-em-4-carboxylic acid, syn-isomer.
    Otadi A is a crystallized methanol solvate of sodium salt of 3-aCetoxymethyl-7-C2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido cef-3-em-4-carboxylic acid, syn-isomer.
    432 g of anhydrous sodium acetate are introduced into 12 liters of pure anhydrous methanol. After dissolving, 3000 g of 3-acetoxymethyl-7-C2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido3 and, eff-3-e-4 -carboxylic acid, syn-isomer, containing 5% are added at one time ethanol and 0.9% water. The mixture is stirred under nitrogen at 18–20 ° C and after 5 minutes, an almost complete solution is obtained. This solution is sent to the reactor under a nitrogen pressure of 1.5-2 bar.
    To a solution kept at 15–20 ° C with very vigorous stirring and in a nitrogen atmosphere, 864 g of anhydrous sodium acetate in 4.5 liters of methanol are added at 18–20 ° C. A clear solution is obtained, which is kept under nitrogen at agitation and at 18–20 s. Then 10 ml of the reaction solution are taken, crystallization is seeded by scraping and the suspension thus obtained is re-introduced into the medium. Crystallization begins after 5 minutes. Incubated for 4 hours at 18–20 ° under nitrogen with rapid stirring. The crystallization gradually increases. The suspension is then cooled to, and then moved for 2 hours, poured and suction. Washed with a thickening 3 times with 1 l of pure anhydrous methanol with O-2®S and then 1 time with 1.5 l. Dry for about 48 hours at 20–22 ° C in vacuum and obtain 2630 g of the desired product,%:
     (Fisher) 1
    Methanol in vapor phase chromatography8
    The resulting product is sieved for homogenization.
    Stage B - sodium salt of 3-acetoxymethyl-7-2-(2-amino-4-thiazolyl) -2-methoxyiminoacetamido cef-3-em-4-carboxylic acid crystallized in the form of O, syn-isomer.
    100 g obtained in the previous
    Stage 0 of the sifted product is introduced into 800 ml of ethanol containing 5 water. Lured for 15-20 hours at 20 +. Sucked off, washed with 100 ml of ethanol containing 5% water, dried in
    5 vacuum in an oven at 20-25 C and get 99 g of the target product (weight without amendment,%):
    H „05.3
    ETON 0.2
    0
    MeOHVO, 2
    This product has the X-ray diffraction spectrum described in the description.
    Example 2. Sodium salt of -3-acetoxy5 methyl-7-2- (2-amino-4-thia; ylyl) -2-methoxyiminoacetamido cef-3-eM-4-carboxylic acid crystallized as form D, syn-isomer.
    While stirring, add 50 ml of 98% ethanol to a thief of 6 g of sodium acetate in 20 ml of water, and continuing the stirring, add 25 g of 3-acetoxymethyl-7-2 ethanol solvate (2-amino-4-thiazolyl) -2-methoxyiminoacetamido} 5-cef-3-em-4-carboxylic acid, synisomer. The acid goes into solution, which is cooled to. With stirring, 50 ml of 98% ethanol is added dropwise. After adding
    0 activated carbon solution is filtered and the filtrate is heated to. Crystallization begins spontaneously a little later. Suction filtration is carried out at room temperature after 16 hours. The pulsed product is first rinsed using a mixture of water and ethiol in the ratio of 1: 7, then with ethanol, and finally with ether.
    Colorless crystals obtained
    0 dried in high vacuum.
     (Fisher) 4.8%
    The diffraction spectrum confirms that Form D is obtained.
    Froze, Crystallized
    5 as a form O salt of sodium 3 of acetoxymethyl-7- 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido cef-3-em-4-carboxylic acid, syn-isomer. The same procedure is used as in Example 2, but with the difference that sodium salt of 2-ethylhexanoic acid is taken instead of sodium acetate. Operating under exactly the same conditions, crystals are obtained which are dried under high vacuum. IR spectrum in vaseline5
    OM oil confirms the receipt of the tabular form D.
    EXAMPLE 4 Crystalline ovine in the form of O salt of sodium 3-acetoxyethi-7-t-2-amino-4-thiazolyl) -2-methoxyimino-and-amido cef-3-em-4-carboxylic acid, syn-isomer.
    5.01 g of ethanol solataat 3-acetox methyl 7- (2- {2 amino-4-thiazolyl) -2-methoxy-amino-acetg1Mido cef-3-em-4-carboxylic acid, SYN-isomer, is added to diluent 2 # 2 Sodium sulfate diethate in a mixture of 4 m.wbda and 20 ml of 98% ethanol. Kissrta completely dissolved. 0.5 g of activated carbon is added to the reaction mixture, stirred for 5 minutes and then refluxed, the filtrate is stirred at room temperature, and crystallization begins spontaneously after an hour. After one night at room temperature, the precipitated crystals are precipitated, washed first with a mixture of ethanol and water in the ratio of 7: 1, then with ethanol and finally with ether and dried under high vacuum for 2 hours.
    Sodium salt is obtained in the form of D.
    Example 5 Sodium salt crystallized as form D 3-acetoxymethyl-7-2-C2-amino-4-thiaoolyl) -2-mec. Remove the amide OZ cef-3-em-4-carboxylic acid, syn-isomer.
    4.55 g of 3-acetoxymethyl-7-2- (, 2-clmino-4-thiazolyl) -2-methoxy minoacetamido cef-3-em-4-carboxylic acid, syn-, 13 isomers, are introduced into the solution 0.85 g of sodium bicarbonate in 5 ml of water. A viscous solution is obtained, to which is added. drop 10 ml of 98% ethanol, and filter. 20 ml of ethanol is added dropwise to the solution thus obtained at room temperature and with stirring. Then the daieth crystallizes out. When crystallization is complete, the colorless crystals are isolated, washed with a mixture of ethanol and water in a ratio of 7: 1 and C5 paat.
    The X-ray diffraction specimen reports the identity of the obtained sodium salt with the example of Example 1.
    Example b. Crystallized in EI. Form D salt, sodium 3-acetoxynmvtil-7- 2- (2-shlen-4-thiazolyl) -2-methoxyiminoacetamido cef-3-4-carboxylic acid, syn-isomer.
    15 g 3-acetoxymeth 11p-7-C2- (2-a, given-4-thiazols) -2-methoxyiminoacetamides |. cef-3-em-4-carbono-pyr1, synew a, is introduced and dissolved at 15 s in a solution of 5 g sodium acetate with 100 MP of methanol. 3 g of activated charcoal is added to the solution and then filtered and heated to.
    Crystals of the methanol solvate of a sodium copoly 3-acetoxymethyl-7-C2 - (. 2-amino-4-thiazolyl) -2-methoxyiminoacetamido cef-3-em-4-carboxylic acid, syn-isomer, are isolated. These crystals and the crystals obtained in Step A of Example 1 are identical with each other.
    Some of the crystals thus obtained are dried under high vacuum. The methanol is removed, and the methanol-free crystals are incubated for one night in an atmosphere saturated with water vapor. The resulting colorless crystals are dried at room temperature under vacuum.
    Thus, the obtained crystals contain 5.2% water (according to the Fisher method). ,
    The X-ray diffraction spectrum confirms identity with the prodrug obtained in Example 1.
    Another part of the crystals is incubated without any pretreatment for one night in an atmosphere saturated with water vapor. The crystals are isolated and dried for two hours in vacuo at room temperature.
    The Fisher method indicates the presence of 4.9% water. The X-ray diffraction spectrum proves identity with the product obtained in Example 1.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining the hydrated crystalline form of the sodium salt of 3-acetoxymethyl-7- | 2- (2-amino-4-thiazolyl) -2-methoxyimine-acetamidJ cef-3-em-4-carboxylic acid, syn-isomer, formula T
    g N
    - tJlfO- (en. COjHo
    characterized in that, in order to obtain a cephalosporin antibiotic in a new crystalline form, which has an increased stability and weak hydroacility, 3-acetoxy methyl 10- | 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamide C cef-3-em-4-carboxylic acid, syn-isomer, or its hydrate, fl. 1Nol., Solvate, formic acid sulfate, or a mixture of hydrate and ethanolic or formic acid solvate in a medium of methanol, interact with the sodium salt of an organic acid selected from the group consisting of sodium acetate, sodium ethyl hexanoate and sodium diethyl acetate; the crystalline sodium methanol solvate of the sodium salt is separated into formulas
    9 852175.10
    crystalline and sodium salt, not sources of information,
    ordering of methanol, and hydrated prine examination
    or crystalline sodium salt ,.
    not containing methanol, or directly. USSR patent application
    The crystalline methanol is 2439518 / 23-04, cl. C 07 O 501/60,
    sopivat sodium sopi. since 1976.
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    同族专利:
    公开号 | 公开日
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    IE781669L|1979-02-17|
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    PL209080A1|1979-06-04|
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    IT7850648D0|1978-08-08|
    DK163514C|1992-07-27|
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    DK159786D0|1986-04-09|
    IE47230B1|1984-01-25|
    EP0001024A1|1979-03-07|
    DE2860358D1|1981-03-12|
    SI7811917A8|1997-12-31|
    FR2400519B1|1980-05-16|
    YU42166B|1988-06-30|
    FI65433B|1984-01-31|
    JPS5441890A|1979-04-03|
    SU799666A3|1981-01-23|
    GR73661B|1984-03-28|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3970651A|1974-01-07|1976-07-20|Bristol-Myers Company|Crystalline cephalosporin derivative|
    US3985747A|1974-05-24|1976-10-12|Bristol-Myers Company|Crystalline sesquihydrate of 7-[D-α-amino-α-acetamido]-3--3-cephem-4-carboxylic acid|
    DK154939C|1974-12-19|1989-06-12|Takeda Chemical Industries Ltd|METHOD OF ANALOGUE FOR THE PREPARATION OF THIAZOLYLACETAMIDO-CEPHEM COMPOUNDS OR PHARMACEUTICAL ACCEPTABLE SALTS OR ESTERS THEREOF|
    US4006138A|1975-04-11|1977-02-01|Eli Lilly And Company|Crystalline form of sodium O-formylcefamandole|
    DE2760123C2|1976-01-23|1986-04-30|Roussel-Uclaf, Paris|7-Aminothiazolyl-syn-oxyiminoacetamidocephalosporanic acids, their preparation and pharmaceutical compositions containing them|
    SE440655B|1976-01-23|1985-08-12|Roussel Uclaf|SET TO MAKE NEW OXIME DERIVATIVES OF 7-AMINO-THIAZOLYL-ACETAMIDO-CEPHALOSPORANIC ACID|JPS60120886A|1983-12-02|1985-06-28|Takeda Chem Ind Ltd|Crystal of cephemcarboxylic acid sodium salt|
    JPH0516437B2|1983-12-29|1993-03-04|Mochida Pharm Co Ltd|
    DE150507T1|1983-12-29|1987-02-26|Mochida Pharmaceutical Co., Ltd., Tokio/Tokyo, Jp|CEPHALOSPORINE COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS.|
    US4840945A|1985-04-01|1989-06-20|Mochida Pharmaceutical Co., Ltd.|Cephalosporin derivatives|
    WO1987001117A2|1985-08-12|1987-02-26|The Upjohn Company|Conversion of cephalosporin hydrohalide salt to alkali metal salt|
    US4880798A|1986-11-25|1989-11-14|Mochida Pharmaceutical Co., Ltd.|Cephalosporin derivatives|
    JPS63132893A|1986-11-25|1988-06-04|Mochida Pharmaceut Co Ltd|Novel cephalosporin derivative, production thereof and antibacterial agent containing said derivative as active ingredient|
    RU2021274C1|1991-05-17|1994-10-15|Польска Акадэмия Наук Институт Хэмии Органичнэй|Process for preparing aminothiazolyl cephalosporin derivatives|
    US5318781A|1993-04-06|1994-06-07|Hoffmann-La Roche Inc.|Absorption enhancement of antibiotics|
    US5574154A|1994-09-29|1996-11-12|Alnejma Bulk Pharmaceutical Co. A.B.P.C.|Process for the preparation of cephalosporanic compounds|
    GB9423459D0|1994-11-21|1995-01-11|Biochemie Gmbh|Silylation process|
    AT402928B|1994-12-23|1997-09-25|Biochemie Gmbh|NEW METHOD FOR PRODUCING CEFOTAXIM|
    AU690482B2|1996-03-18|1998-04-23|Ranbaxy Laboratories Limited|Process for producing cephalosporin antibiotics|
    GB9717629D0|1997-08-21|1997-10-22|Johnson Matthey Plc|Removal of residual organic solvents|
    WO2001092254A1|2000-05-30|2001-12-06|Fujisawa Pharmaceutical Co., Ltd.|Method for replacing organic solvents contained in clathrate crystals|
    WO2004063203A1|2003-01-10|2004-07-29|Orchid Chemicals & Pharmaceuticals Ltd|Process for the preparation of cefotaxime sodium|
    CN100361995C|2004-10-27|2008-01-16|山东瑞阳制药有限公司|One-step preparation process of aseptic cefotaxime sodium for injection|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR7725142A|FR2400519B1|1977-08-17|1977-08-17|MD94-0267A| MD225C2|1977-08-17|1994-09-08|Method of hydrated crystalline form of natrium salt 3-acetoxymethyl-7o2--2-methoxyiminoacetamidou cef-3-em-4-carbonic acid, sin isomer preparation|
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