• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    METHOD FOR OBTAINING DERIVATIVES OF CEFALOSPORIN formula. “With S-cfe / -. f I -cgssoo Ne cephem-4-carboxylate-8-oxnd is reacted with an acid of the formula lJ-yC COOH TrHlf s T O-o-coo-c / Nd-ter as syn-isomer, where R and R have The indicated values of j Tf- - trityl, in an inert organic solvent such as methylene chloride, in the presence of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole at room temperature or with an acid halide of formula (O) in an inert organic solvent in the presence of an organic base with cooling or at room temperature product temperature under
    公开号:SU1194280A3
    申请号:SU833622788
    申请日:1983-07-12
    公开日:1985-11-23
    发明作者:Лабев Бернар；Сали Али
    申请人:Санофи (Фирма)；
    IPC主号:
    专利说明:

    Overthrow the interaction with the thiourea formula
    /But
    ct
    R4
    . "
    Nb
    where V., R.jKj and R; have the indicated meanings
    in an inert organic solvent such as dimethylacetamide, with cooling, the resulting product is treated with trifluoroacetic acid and the desired product is extracted.
     I
    This invention relates to a method for producing new cephalosporin antibiotics, which possess antibacterial activity and can be used for the treatment of animals and animals.
    It is known that cephalosporin antibiotics possess antimicrobial activity in both animals and humans against gram-positive and gram-negative bacteria t °
    However, in connection with the appearance of new strains of microbes and bacteria resistant to the known cephalosporin antibiotics, the discovery of new cephalosprin derivatives active with respect to the microorganism jp C-VjUlNJl, -1Т1: -srn-t 1 Ki strains is relevant. o iiy-CH s} 1 S iso-soon soy
    the form of syn-isomers,
    e Rj is a hydrogen atom, and the other is methyl, or Hg methyl, or R-together with the carbon atom to which they are attached, form cyclobutyl RjH independently of one another or hydrogen or C -C alkyl)
    mov resistant to known cephalosporins.
    The aim of the invention is to obtain new cephalosporins, which have enhanced antibacterial activity, have low toxicity and are well absorbed when administered orally or parenterally.
    This goal is achieved based on the reactions of acylation of the 7-amino group based on the cephalosporins known in chemistry, the interaction of the 3-halomethyl derivative with the N-thiourea derivative and the preparation of the Quaternary salts 4 by a three-step method for the preparation of cephalosporin derivatives of the formula
    R IR - one independently of the other is a hydrogen atom or C —C2-alkyl; 1, or
    Hj is a hydrogen atom, and the other is Ca-alkenyl, or H together form C -C-alkylene,
    the conclusion is that it is heated butyl7 - amino - 3 - bromomethyl - 3 - cephem - 4 - carboxylate - 5 - oxide "tf at / c SGSOO. subjected to interaction with acid dKJpMynbi N-jpC-COOH tsr s h 0-0-COO-TSYd-Tr R2. in the form of the syn-isomer, where H and Rj have the indicated Tf values. - trityl, in an inert organic solvent such as methylene chloride, in the presence of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole at room temperature or with an acid halide of the formula (C in the environment of an inert organic solvent in the presence of an organic base during cooling or at room temperature, the resulting product reacts with thiourea derivatives of the formula: K / -RS where Bj R., Rj. and Rj have the indicated values, in an inert organic solvent such as dimethyl form During cooling, the product is treated with trifluoroacetic acid and the desired product is isolated. The products proposed do not have a clearly defined melting point, but only decomposition points that do not allow them to be characterized. Therefore, the products are characterized by their NMR spectra taken at 60 and 250 MHz, the internal standard is hexamethyldisiloxane. The spectra are taken in deuterated dimethyl sulfoxide. Example I. Trifluoroacetate 7-C2- (2-aminothiazole1-4) -2- (2-carboxy-2-propyloxyimino) -acetamidoJ 3- (N, N, N, N-tetramethyluronium thiome thyl) -3-cephem-4-carboxylic acid l-S-oxide, syn-isomer. SM 41089. 804 a) treg. Butyl-7-C2- (2-tritylam; Inothiazolyl-4) -2- (2-tert. Butoxycarbonyl-2-propyloxyimino) -acetamido-3-; bromomethyl-3-cephem-4-carboxylate -1-8-oxide, syn-isomer. 830 mg of tert-butyl-7-amino-3-bromomethyl-Zeceph-4-carboxylate-1-S-oxide hydrochloride is dissolved in 15 ml of methylene chloride, 209 mg of 2- (2-tritylaminothiazolyl-4) 2- (2 tert-butoxycarbon-1-2-propyloxyimino) acetic acid, 422 mg of dicyclohexylcarbodiimide and 10 mg of 1-hydroxybenzotriazole. After 4 hours of stirring at room temperature, filtering off the dicyclohexyl urea, methylene chloride is evaporated, the precipitate is dissolved in vacuo, and the solution is washed with 1N. hydrochloric acid, then with water, with saturated sodium bicarbonate solution and again with water. The ether phase is dried over magnesium sulfate and concentrated in vacuo. Chromatographic on 80 g of silica gel and elute with a mixture of hexane-ethyl acetate 60/40 (by volume). The precipitates are evaporated to give 650 mg of the compound. " Another method for obtaining the compound and. A suspension of 20 g of 2- (2-tritylaminothiazolyl-4) -2- (2-tert.carbonyl-2-propyloxyimino) acetic acid in 100 ml of methylene chloride, cooled to, is prepared. 7.3 g of PCtj is slowly added and stirred for 30 minutes at this temperature. Pour 1 liter of hexane to precipitate, then filter and dry under vacuum, p ”: yield 21.2 g of 2- (2trityl aminothiazolyl-4) acid chloride 2- (2-butoxycarbonyl 1 -2-proxy 1 hydroxyimo) acetic acid, m.p. . NMR spectrum in deuterium chloroform, ppm: 15 N at 7.40 (H trityl, s); 1H at. 6.42 (H thiazopa, s) -, 6H at 1.67 tCCCH), c) 9H at 1.45 Cc (cN3) s, s}. To suspension 1.5 g of hydrochloride tert. Booth1-7-amino-3-bromomethyl-3-cephem-4carboxylate-5-oxide in 30 ml of anhydrous methylene chloride is added at 2.2 g of the previously obtained iuiopanhydride and 1 ml of M, N-dimethylaniline. Allow to warm to room temperature; after 2.5 hours of stirring at room temperature, they are drunk in 100 ml of isopropyl ether to precipitate, filtered, washed with isopropyl ether, hexane and dried in vacuo, to obtain 3 g of product a. 6. Bromide tert. Butsh-7- 2- (2-tritylaminothiazolyl-4) -2- (2-tert. Butoxycarbonyl-2-propyloxyimino) acetamido-3- (K „K, N, N-tetramethyluronium thiomethyl) -3- cephem-4-carboxylate-S-oxide, syn-isomer. Leave for a day at a solution of 1 g of the product h and 0.21 g, of N, N, N, N of tetramethylthiourea in 5 ml of N, N-dimethylacetamide. The resulting solution is added dropwise to 100 ml of isopropyl ether with stirring. The resulting solid is dissolved in 5 ml of methylene chloride, then chromatographed on 25 g of silica gel, eluting with methylene chloride-methanol 90/10 (v / v). 0.7 g of product is obtained. 5. c. CM 41089. A solution of 0.62 g of product 6 in 4 MP of trifluoroacetic acid is left at room temperature for 45 minutes. Concentrated in vacuo, then precipitated by the addition of ether, filtered, washed with ether and dried over phosphoric anhydride, 0.43 g CM 41089 are obtained. NMR spectrum, ppm: 1H at 8.5 (CONH, D, Hz); 1H at 6.85 (H thiazole, s); 1H at 5.95 (N, dd, and 4 Hz); 1H at 5.02 (N, d, Hz); 1H at 4.10 (CHjrSAB, 1yy 13 Hz); 1H at 3.90 (CHiA. J / 8 13 Hz) -, 1H at 3.80 (, AB, G / (Hz); 1H at 3.70 (AB, Hz), 12H at 3.20. FtU, i C, with j, u... G2. 1 .i G9GGNL m about P. AN t, “and 1 Ah G {; .CHJ and, c 1; he with I ,;) Lv.in .; .o - -e 2 -3 Example 2 "7- 2- (2-aminothiazolyl-4) -2- (2-Karboxy-2-ethyloxyimino) acetamido 3- (N, N, N, N-tetramethyluronium thiomethyl) trifluoroacetate -Z-cephem-4-carboxylic acid l-S-oxide, syn-isomer. SR 41361 A. This product is obtained according to the same procedure and under the same operating conditions as CM 41089, starting from 2 (2-tritylaminothiazolyl-4) -2- (1-tert utoxycarbonyl-1-ethyloxyimino) xacetic acid. SR 41361, a mixture of 2 diastereoisoers, is identified by its spectrum. NMR spectrum, MNDD .-. 1H at 8.80 (CONH, 2d, J 9 Hz); 2H at 7.40 (NH2 thiazole, bs), 1H at 6.80 (H thiazole, 2c); 1H at 5.96 (H. ,, m); 1H at 5.00 (Nb, m), 1H at. 4.20 (SNg-SS d Hz); 1H at 4.55 (Cg-CHj, M) i IH at 3.85 (CHji-S-C. D, Hz); 2H at 3.75 (CHj-SO, M) i 12H at 3.15 С (СНз) гК, шс2, - ЗН at 1.40 (CHj-CH, д, Hz). Example 3. 7-C2- (2-aminothiazolyl-4) -2- (2-carboxy-2-propyloxyimino) acetamido 3- (N-methyl, N, N-pentamethylenuronium thiomethyl) -3-cephem-4-carboxylic trifluoroacetate acids - lS-oxide, syn-isomer. SR 41381 A. This product was prepared according to the described procedure, starting from compound o (example 1 and N-methyl, S, H-pentamethylene thiourea, obtained as follows. To 2.7 MP of piperidine, cooled to -30 ° C, slowly added 2 g of methyl isocyanate, diluted with 10 ml of methylene chloride, stirred for 1 h, then evaporated to dryness in vacuum. The residue is triturated with ether and filtered. After drying, 4 g of N-methyl, N, K-PentaGg are obtained. o methylenethiourea, m.p.,. „. SR 41381 is identified by its NMR spectrum, ppm: 1H at 9.50 (NHCrf, shs); 1H at 8.47 (CONH, d., Hz) ; 2H at 7.50 (W, ssh); 1H, 6.90 (H of thiazole, s); 1H at 5.96 (H, dd, J 9 and 4 Hz), 1H at 5.0 (Hj, d, J 4 Hz); 2H at 4.0 (CH, -8-C;: 1c, AB, 1hd 13 Hz) -, 2H at (CHi-SO, AB, Hz) 4H at 3.60 (, bs); 3N at 3.0 (CHjN, CHg h s); 6H at 1.35 (, ws)} 6H at 1.45 C (CH3) 2-C, s). Examples 4-13. vS I -N-JLc-C-TQH-T-f (/ -K CH-SO C-COOH COOH
    Designations of substituents are given in Table 1.
    NMR spectra for the compounds of Examples 4-13 are given in Table 2.

    The products offered can be used as antibiotics for human and veterinary medicine and can also be used for any bacterial infections with sensitive species.
    The proposed products were studied in relation to their pharmacological properties and, more specifically, their bacteriostatic action in vitro, which was determined in solid medium by the dilution method. The results are shown in Table. 3 and 11: AK are the minimum concentrations of inhibitions (MIC - mg / MP), they relate to the results obtained on different strains.
    4136 A
    sn
    3
    41363 A-C-02N n 3 CH3
    41380 A -00211 -% -СНз СНз
    Experiments on animals showed no toxicity of the proposed products.
    The pharmaceutical compositions are made from compounds (1) in the form of an acid or, when its solubility is insufficient, in the whole salt. The pharmaceutical compositions can be solid or liquid, for example, in the form of tablets, capsules, granules, lipsticks, creams | 7 gels or preparations for injection,
    Posology can vary in wide proportions, depending on the type and strength of the infection to be treated, and on the method of administration. Most often when injected into adults, it is found in me 0,250 and 4 days per day.
    As an example of a pharmaceutical composition, ampoules can be prepared containing 1 g of CM 41089, 0.212 g of L-LYSIN and 4 ml of water to form an injection solution.
    Table 1
    xCH
    -N: SNZ
     Nki
    n
    .Shg-SN "SNg
    -to:
    n / nz .SR, COO-Rs
    SNS

    SR 41382 A -
    sns
    pHz-C-02H
    SR 41383 A
    CH3 fH3
    -s-yo n s z
    SR 41384 A
    SNS
    u
    -С-С02Н g
    10 SR 41385 A CHS
    SNS
    -s-soon
    11 SR 41605 A
    SNS
    SNS "
    12 SR 41609 A
    SNS
    13 SR 41912 A
    1H at 8.80 2H at 7.50 1H at 6.80 1H at 5.96 1H at 5.0

     -
    / CHj CH2 CH "2,
    CHj
    -N
    n
    .СНз
    -N
    n
    .KhSgN5
    n
    -NH-CjHs
    -Kq
    -CS-CHj
    -NH-CH3
    Table 2
     (CONH, d, Hz)
    (Nljji thiazole, bs)
    (H thiazole, s)
    (N, dd, Hz, 72. 4
    (Hf, d, Hz)
    Z: Z :: E: L: Z :: IZ
    1H at 4.10 (CHi-S-cC d, Hz)
    1H at 3.90 (D, Hz)
    2H at 3.80 (CHjSO, AB, -17 Hz)
    12H at 3.10С-С- (Н (СНз)), shs
    4H at 2,
    211 at
    41363 A 4H at 9.40
    R
    1H at 8.40 (CONH, d, Hz)
    2H at 7.40 (NY thiazole, bc)
    1H at 6.90 (thiazole, s)
    1H at 6.0 (1C, dd, j «9 Hz, Hz)
    1H at 5.0 (Hj, d, J 4 Hz)
    2H at 4.10 (СНгЗ-с АВ, Hz)
    2H at 3.80 (. AB, 17 Hz)
    6H at 1.45 cCCHj), cj
    41380 A 1H at 9.50 (NH, shs)
    R
    1H at 8.50 (NONH, d. Hz)
    2H at 7.50 (NH thiazole, bs)
    1H at 6.90 (H thiazole, s)
    1H at 5.96 1H at 5.80 (, m) 2H at 5.10 (-CHi-CH-CJlj, m).
    1H at 5
    ZN at 4,10 (CHj, -5 and CHj-N, m)
    119428012
    . Continuation of the table. 2
    N
    m in position to
    h cyclobutyl
     .V v v
    nn
    I

    1.85 m in a tie-position NII H 00211 cyclobutyl
    (SS
    shs)
    NHj
    l
    (HT, dd, Hz, Jj.4 Hz)
    (Hj, d, Hz)
    13
    1H at 3.95 2H at 3.90 6H at 3.20 6H at 1.45
    SR 41382 A 1H at 8.47 2H at 7.40 1H at 6.90 1H at 5.95 1H at 5.6 2H at 4.0 2H at 3.80 4H at 3.55 6H at 3.10 6H at 1.55 6H at 1j45
    SR 41383 A 1H at 9.50
    1H at 9.40
    1H at 8.47
    2H at 7.40
    1H at 6.90
    1H at 5.95
    1H at 5.0
    2H at 4.20
    2H at 3.80
    ZN at 2.95
    ZN at 2.80
    6H at 1.45
    SR 41384 A 1H at 9.40
    1I9428Q
    14 Continued table. 2
    (. D, 13 Hz) (CHj-SO, AB, 7 17 Hz)
    With (SNZ), with
    , with)
    (NHCO, d, Hz) (NH thiazole, bs) CH thiazole, s) (N, dd, Hz,) Hz) H, d, Hz) (CH-Sc: J AB, 7dv 13 Hz) (CH, SO , AB, 1d8 17 Hz) (, shs)
    CCClJa), with (, shs)
    SSSSNz), with
    (NHCHj, woo)
    (NHCHj, woo)
    (GONa, D, Hz)
    (NH 2 thiazole, bs)
    (H thiazole, s)
    (Fl, dd, J 4 Hz, Jj 9 Hz)
    (Hj, d, Hz)
    (CHj-S- | J AB, Hz)
    (CHjSO, - AB, Jdg 17 Hz)
    (SNM, s)
    (CHjN, s)
    C (CHj) -C, .c
    (NH, shs)
    15
    119428016
    Continuation of table 2
    17
    SR 41609 A 1H at 9.10 1H at 8.45 W at 6.75 1H at 6.0
    6H at 1.45
    SR 91912 A 1H at 6.90 1H at 5.95 1H at 5.0
    6Н at 3.15 ЗН at 3.05 4Н at 2.40
    2H at 1.90
    119428018
    Continued table. 2
    (NH-CHj, ws)
    (NH-CO, d, Hz;
    (H thiazole, s)
    (H, dd, J 9 Hz, J 4 Hz)
    k
    CHj
    (H thiazole, s) (H: ,, m) ("4 m)
    xCH (-N ws)
    Ctia.
    (NH-CHj, d, J
    x2
    one
    one
    2
    sixteen
    one
    one
    one
    eight
    one
    2
    0.5 0.5
    2,128
    权利要求:
    Claims (1)
    [1]
    METHOD OF OBTAINING ARRANGEMENT ·
    Cefalosporin formula z R 3
    SHI s D
    UN-C-UNC
    H 2 in the form of syn-isomers, a hydrogen atom, and the other methyl, methyl ·, or TCi R £ together with the carbon atom to which they are attached form cyclobutyl;
    one independently of the other, a hydrogen atom or C ^ -C ^ -alkyl; one independently of the other, a hydrogen atom or a C 4 -C 2 -alkyl, or R y or a hydrogen atom, and the other a C 3 -alkenyl, il .. Ry hRj together form a C4-C5 alkylene, characterized in that trvt. butyl-7-amino-3-bromomethyl-Zgde R 4 or Rj or 1Ci R 2 ~
    R a HR 4 K 5 And Cephem-D-carboxylate-B-oxide is reacted with an acid of the formula
    C — COOH
    H O-C-COO-C ^ Nd-Tert Ig syn-isomer, and R 2 have trityl in an inert medium such as in the presence of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole at room temperature or with acid halide of the formula (s) in medium inert organic solvent in the presence of an organic base under cooling or at room temperature, the resulting product as a podTrHN wherein R, (II) indicated meanings · ρ organic raskak methylene chloride, and
    are reacted with a thiourea derivative of the formula where R 3 , B *, K 5 and R 4 have the indicated meanings, in an inert organic solvent such as dimethylacetamide, upon cooling, the resulting product is treated with trifluoroacetic acid and the target product is isolated.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DK128611B|1961-05-16|1974-06-04|Glaxo Lab Ltd|Process for the preparation of derivatives of cephalosporin C or salts thereof.|
    GB1012943A|1961-05-16|1965-12-15|Glaxo Lab Ltd|Improvements in or relating to antibiotics|
    DE2716677C2|1977-04-15|1985-10-10|Hoechst Ag, 6230 Frankfurt|Cephem derivatives and processes for their preparation|
    FR2442240B1|1978-11-27|1982-04-23|Roussel Uclaf|GB8413152D0|1983-06-03|1984-06-27|Ici Pharma|Cephalosporin derivatives|
    US4855420A|1983-06-03|1989-08-08|Ici Pharma|Cephalosporin derivatives|
    US4868173A|1984-11-20|1989-09-19|Ici Pharma|Cephalosporin derivatives|
    EP0333082A3|1988-03-15|1991-05-02|Takeda Chemical Industries, Ltd.|Cephem compounds, their production and use|
    JPH0320265A|1989-02-10|1991-01-29|Meiji Seika Kaisha Ltd|Aminothiazoleacetic acid derivative and its production|
    EP2766735B1|2011-10-14|2017-02-01|Universite De Liege|Method for measuring beta-lactam antibiotics|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8212317A|FR2530248B1|1982-07-13|1982-07-13|
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