• 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:
    7-[(D)-2-Amino-2-(4-hydroxyphenyl)acetamido]-3-[(Z)-1-propenyl]ceph-3- em-4-carboxylic acid in the form of its crystalline dimethylformamide solvate (1/1.5) has been provided.
    公开号:SU1414317A3
    申请号:SU864027831
    申请日:1986-07-25
    公开日:1988-07-30
    发明作者:Б.Краст Леонард (Младший)
    申请人:Бристоль-Мейерз Компани (Фирма)；
    IPC主号:
    专利说明:

    iu
    :R

    s
    This invention relates to the chemistry of antibiotics, in particular, to a method for producing 7- (D) -2-amine 0-2- (4-hydroxy-phenyl) acetamido-3- (Z) -1 propenyl which is stable when stored for long time and can be used in the manufacture of drugs.
    The aim of the invention is to create a new stable crystalline I form 7-C (0) -2-amino 2 (4 hydroxyphenyl)
    acetamido-3- (Z) -1-propei-1-mi-3-I-4-carboxylic acid cefem.
    7- (B) -2-Amino-2- (4-hydroxyphenyl) g; acetamido -3- (Z) -1 nponeH - 1 - Hri
    -Z-tsefem-4-carboxylic acid ow n
    Q-CH CON-T-fS .. 0
    ,
    CH-P1Rb)
    , M. 758-8СООаФМ
     A stirred solution of 18 liters of CCl with 1.8 liters of methanol and 12 g of p-benzoyl benzoic acid is cooled to 8 ° C while 970 ml of acetalde hydrochloride are added. The temperature of the resulting growth; the thief is raised to. After 5 minutes, 588 g (0.7749 mol) of diphenylmethyl-7-fenchacet tamvdo 3- (trifenesphosphorane-shdenmethyl) 3-c-fem-4-carboxylate are added. The cooling bath is removed and the mixture is thoroughly mixed for 4 hours at 35 ° C, closed from light, under an atmosphere of nitrogen until complete dissolution of the phosphorane proceeds.
    The resulting solution is concentrated under vacuum and the residue is dissolved in 2 liters of ethanol, after which the solution is concentrated under vacuum to obtain a semi-crystalline residue. Which slurry 3 liters of ethanol
    The mixture is stirred for 2 hours at 3 sec and left overnight, then dried under vacuum at three room temperatures, mp.


    -1 WIJ-3-cepheme-4-carboxylic acid in the form of a crystalline solvate of dimethylformamide () of formula
    AND
    C C-CH5-1.5 NSK (CH3) 2
    soon but
    It is an effective antibiotic j, but it is a liquid substance that is not subject to long storage, especially in the process of its accumulation in the manufacture of drugs
    The drawing shows the data of IR-spectrometry
    EXAMPLE 1, Diphenylnethyl- - .flnl-acetamido-3- f (Z) -nponeH-1-Hn3- -3-cephem-4-carboxylTe
    SNCO
    CU / CHjOH /
    about
    II
    CHoC ™ M. M. 524.6
    0
     C, it contains 7.5% trans ™ isomer, determined by liquid chromatography under high pressure on a Lichosorb Si 60 column (5 μm Merck, eluted with 85% toluene and 15% ethyl acetate).
    Example 2. Diphenylmethyl-7-amino-3 (E) hydrochloride propen-1 n-J-3-cepheme-4-carboxoxylate,
    To a stirred solution of 159.9 g of 5 (0.76 mol) PCly in 2.8 l. 56.7 ml (0.700 mol) of pyridine in 280 ml are added over 20 SRI. Under a nitrogen atmosphere, the suspension is cooled to 5 while 256 g (0.488 mol) of the product obtained in Example 1 are added. The mixture is stirred for 40 The resulting suspension was quickly poured into a thoroughly stirred solution of 1.4 liters and 209 ml (2.33 mol) t, 3-butenediol at -20 ° C so that the temperature did not rise above -5 C. Then the cooling bath was removed, o after 45 minutes the temperature rises
    five
    shake up to 10 ° C and maintain at this value for 35 minutes. Water (1.0 L) is added and stirring is continued for 5 minutes, after which conditions are provided for the separation of the layers. The organic layer is washed with 600 ml of 2N. hydrochloric acid and then 400 ml of saturated saline solution. The combined aqueous extracts are backwashed with 2x600 ml and combined with the initial extract of CH, C1.
    The extract is dried over anhydrous MgSO4 g, the MgS04 suspension is filtered and the MgSO4 is washed with 2 X 500 ml. The combined filtrates are concentrated under vacuum in a rotary evaporator to 2.4 liters and. diluted with 2.5 L of ethyl acetate. The solution is again concentrated to a volume of approximately 1.3 liters. The resulting crystal is filtered off with cusp and 3x300 ml of ethyladetate are lame. After drying in air and in vacuum, in order to obtain from 149.8 g of the desired compound, in the form of beige crystals,
    Yield 69.3%,
    Example 3. 7-Amino-3- (Z) -1-propanol-1-yl-3 cepam-4-carboxylic acid
    To a stirred solution of 260 ml of anisole and 1.38 l of trifluoroacetic acid, cooled to 0 ° C, 149.7 g (05338 mol) of diphenylmethyl-7-amino-3- (Z) -1-propane hydrochloride: En-l- IlZ-3-cepheme-4-carboxylic acid (0.33 V mol). The resulting suspension is stirred at room temperature for 1 hour. Most of the excess trifluoroacetic acid is distilled off in a vacuum on a rotary evaporator. The remaining supernatant solution is decanted and the remaining suspension is triturated with 1.5 dry ether for 1 hour. The crystalline product is filtered and dried over to give 87.24 g of trifluoroacetate of the desired compound, suspended and stirred in 900 ml of water (pH 2.5) ). The mixture is cooled to and then adjusted to pH 0.6 with 12 N hydrochloric acid. The yellow solution is treated with charcoal and the suspension is filtered on diatomaceous ft
    -
    land. The resulting solution is cooled to 5 Cj, after which the pH is adjusted to 2.0 with a 20% sodium hydroxide solution. The suspension is pulled out for 1 hour in a refrigerator in order to facilitate: the crystallization process. The crystals are collected, washed with 800 ml. . water, 800 ml of acetone and dried in vacuum at room temperature. Yield 69.4 g (85.5%), Compound containing 9.7% trans isomer, determined by the method of liquid chromatograph at high pressure using an RP 18 MERCK column; H (NH), PO 0.1 mol, 95 ml + CHjCN 5 ml (detected at a wavelength of 290 nm).
    Example 4, 1,5-Dimetsh1formamid solvate 7- (D) -2-amhIO-2- (4-oxyphenyl) -athetamido-3- (2) -sch open-1-yl} -3- cephem 4-carboxylic acid.
    H.N
    J5 20 25
    2Q
    55,
    soon
    M.m. 240.28
    ABOUT
    If
    n
    35
    50
    C-C-Isft-C
     Sh
    1.5 DMF solvate, M.mg 512 COOH To the mixed suspension 54 g i
    (0.225 mol) of the product obtained according to example 3, 59.9 ml (0.472 mol) of trimetnlchlorosilane, 28.9 ml (0.229 mol) of DO methylaniline and 62.64 ml (0.432 mol ) triethylamine, maintaining the temperature of the suspension at 20 ° C. Semi-suspension 1-1N is stirred for 2 hours at 2Q ° C and then cooled to -10 ° C. Dimethylaniline hydrochloride is added in an amount of 27.4 ml (33%) 5 and then, for 43 minutes, 64.3 g (0.229 mol) of p-hydroxyphenylglycine chloride hydrochloride, having a purity of 80%, was added in four portions. The suspension is stirred for 2 hours (-2 hours at -10 ° C, 23 ml of methanol are added and the mixture is stirred for 10 minutes. At the same time, 350 ml of water are added dropwise while thoroughly mixing) to avoid gum formation. The mixture is cooled to + 5 ° C and the pH is adjusted to 2.2 with triethnlamine.
    The aqueous phase (650 ml) is washed three times with 150 ml. The insoluble material is filtered off and the pH of the aqueous phase is adjusted to 4.5. by the addition of triethylamine, dimethylformamide (1,3-l) and isopropanol. (0.65 l). The mixture is stirred for 2 hours and
    ; leave overnight at 5 ° C. Crystals (in order to exclude the presence; collect, wash with a minimum amount of acetonitrile), the resulting solution; honest dimethylformamide and then three
    times 200 ml of acetone and dried; vacuum at room temperature. : Yield 74.4 g (64%) as a solvate
    dimethylformamide, with the composition
    the compound corresponds to 1.5 mol of i dimethylformamide (DMF) per 1 mol of i 7- (B) -2-amino- (4-hydroxyphenyl) acetam-; (d) -1-propene 1-sh1 3-cephem-: 4-carboxylic acid.
    Spectral characteristics of this
    solvates are presented in table. 1-3 Scan speed 2 per miutu
    in the range of angles from 5 to 40, with
    this data log is recorded
    with the help of a mechanical device; in order to mark the angles of maximal: diffraction. From this data; the distances (d) and relative intensities (1 / 1d) are determined.
    Example 5. 7- (0) -2-Amino2-. (4-hydroxyfensh1) acetamido -3 (Z) -1 I propen-1-nt-3-cephem 4 carboxylic acid I. : Dimethylformamts solvate (25 g),
    obtained according to example 4, dissolved: in 400 ml of water. After filtering the NIL of insoluble material, the solution is injected into the column with a diameter of
     (MODULPREP device, JOBINJVON), filled with Lichroprep, and chromatographed using a solvent system water:
    Gacetonitrile (92: 8) Availability of Products O
    i tt
    frozen and lyophilized. The lyophilized sample (14.2 g) was poured into 140 ml of water and stirred for 10 minutes in an ice bath. The resulting crystal is collected and dried under vacuum (without PgOy) overnight. This gives 13.34 g of the desired product, the yield after purification is 65%.
    20 Thus, 7- (D) -2-Amix o-2- (4-oxyphenyl) acetamido j -3- (Z) -1-propen-1-yl-Z-cephem-4-carboxylic acid obtained by the proposed method crystalline acid acid
    25 vat of dimethylformamide (1: 1.5) is easily collected by filtration and can be washed on the filter with substances that are not its solvents, such as dimethyl forma30 MIT, acetone or methylene chloride, and is stable when stored in ordinary containers for a long period, even if the temperature or humidity limit values are placed on it.
    35
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining the 7- (D) -2-amino--2- (4-hydroxyphenyl) acetamido-3- {(Z) -l-propen-1-yl-3-cephem-4-carboxylic KISU1OTY in the form of a crystalline solvate of dimethylformamide (1: 1.5) formula
    n
    I C CCH3-t, 5HCNlCH5b, T I
    ABOUT
    soon n
    characterized by the following studies of diffraction; x-ray di-x-ray powder:
    (i) I / I, (b i / i
    100
    four,
    in
    25
    4.29
    33
    This is detected at a wavelength of 325 nm and monitored using high pressure liquid chromatography. The appropriate fractions (10-20) are collected, each fraction having a volume of approximately 250 ml, and concentrated to 1.5 liters.
    (in order to exclude the presence of acetonitrile), the resulting solution
    frozen and lyophilized. The lyophilized sample (14.2 g) was poured into 140 ml of water and stirred for 10 minutes in an ice bath. The resulting crystalline product is collected and dried under vacuum (without PgOy) overnight. At the same time, 13.34 g of the product is obtained, the yield after purification is 65%.
    Thus, the 7- (D) -2-Amsh o-2- (4-oxyphenyl) acetamido j-3- (Z) -1-propen-1-yl-Z-cephem-4-carboxylic acid obtained by the proposed method is The form of the crystalline solvate of dimethylformamide (1: 1.5) is easily collected by filtration and can be washed on the filter with substances that are not its solvents, such as dimethylformaID, acetone or methylene chloride, and is stable when stored in ordinary containers for a long period, even when exposed to extreme values of temperature or humidity.
    Invention Formula
    The method of obtaining the 7- (D) -2-amino--2- (4-hydroxyphenyl) acetamido-3- {(Z) -l-propen-1-yl-3-cephem-4-carboxylic KISU1OTY in the form of a crystalline solvate of dimethylformamide (1: 1.5) formula
    n
    C-C CCH3-t, 5HCNlCH5b, I
    un n
    7.82 7.42
    55
    6.76 7.14
    9 10
    15 12
    4.10 4.04
    3.62 3.69
    13 10
    6 5
    5.88
    3.58
    5.28
    ten
    3.56
    Note: Trimethylsilylpropanesulfonic acid is used as a reference.
    1414317
    distinguished by the fact that the aqueous solution is freshly prepared
    91414317 0
    Table 2 IR spectrum Dgranula KBG)
    Wave number, cm. Functional group 2600-3250OH, NH, NH
    17 0 -Lactam
    1700 Amide
    1665 Amide (DMF)
    1570c:
    tagging. Determination of gvovod t on a Rugaki porous diffractometer using an x-ray tube with a copper target, a nickel filter and a sample placed on a glass saucer.
    anHDi ofiuodu
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    引用文献:
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    DE3381408D1|1982-12-27|1990-05-10|Lilly Co Eli|INTERMEDIATE COMPOUNDS FOR THE PRODUCTION OF CEFTAZIDIN AND METHOD FOR THE PRODUCTION THEREOF.|
    US4520022A|1983-01-28|1985-05-28|Bristol-Myers Company|Substituted vinyl cephalosporins|US5128336A|1988-03-23|1992-07-07|Eli Lilly And Company|3--1-carba-3-cephems|
    AT399876B|1992-02-05|1995-08-25|Biochemie Gmbh|Purificn. of 7-amino-3--1-propen-1-yl)-3 -cephem-4-carboxylic acid - useful in prodn. of broadband antibiotics|
    AT205214T|1992-02-05|2001-09-15|Biochemie Gmbh|METHOD FOR PURIFYING A 3-CEPHEM-4-CARBOXYL ACID DERIVATE|
    PT102061B|1997-10-08|2000-06-30|J K Ind Ltd|PROCESS OF PREPARATION OF AN ECHALOSPORIN ANTIBIOTIC ACID GENERALLY ACTIVE-CEFIXIME|
    AT335747T|1999-09-30|2006-09-15|Otsuka Kagaku Kk|CRYSTALLINE 3-CEPHEM DERIVATIVE|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/759,805|US4694079A|1985-07-29|1985-07-29|3-propenyl cephalosporin solvates|
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