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  • 权利要求
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    • 专利摘要:
    2 beta -Acetoxymethyl-2 alpha -methyl-(5R)penam-3 alpha -carboxylic acid 1,1-dioxide, pharmaceutically-acceptable salts thereof and esters thereof readily hydrolyzable in vivo; pharmaceutical compositions containing 2 beta -acetoxymethyl-2 alpha -methyl-(5R)penam-3 alpha -carboxylic acid 1,1-dioxide or salt or ester thereof; and method of enhancing the effectiveness of a beta -lactam antibiotic using 2 beta -acetoxymethyl-2 alpha -methyl-(5R)penam-3 alpha -carboxylic acid 1,1-dioxide or salt or ester thereof.
    公开号:SU959628A3
    申请号:SU802983144
    申请日:1980-09-19
    公开日:1982-09-15
    发明作者:Эрнст Барт Вэйн
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    subjected to oxidation by treating with organic peracid in an inert solvent at temperatures from OC to room temperature, followed by the removal of the carboxy protecting group, such as bexyl, hydrophore, and the release of the desired product in the form of the free acid or by transferring it to the salt with alkali metal by treating the base. As the organic peracid it is preferable to use - 3-chloroperbenzoic acid ,. The reaction is usually carried out by treating a compound of formula I 1 approximately 2-5 mol-eq. preferably 2.2 equiv. of an oxidizing agent in an organic solvent inert with respect to the reaction. Typical solvents are chlorinated hydrocarbons, such as dichloromethane, chloro-stills or 1,2-dichloroethane, and ethers, such as diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane. The reaction is usually carried out at a temperature of preferably about. At a temperature of about 2. Usually, a reaction time of about 2 to 16 hours is used. The product is usually recovered by removing the solvent by evaporation in vacuo. When oxidizing a compound of formula O to a compound of formula T, it is sometimes convenient to add a catalyst, such a manganese salt, such as manganese acetylacetonate. To remove the protective group R, such as benzyl, using catalytic hydrogenolysis, a solution of the compound (1rmula 1, in which F is benzyl, mixed or mixed, is shaken in an atmosphere of hydrogen or hydrogen mixed with an inert diluent, such as nitrogen or argon, in the presence of a catalytic amount of a palladium catalyst on carbon. Convenient solvents for this hydrogenolysis are a lower alkanol, such as methanol, an ether, such as methanol, an ether, such as tetrahydrofuran or dioxap, p low molecular weight, such as ethyl acetate or bugnl "ietat water go mixtures of these solvents. The hydrogenolysis is usually carried out at room temperature and at a pressure of about 0.5 to 5 kg / cm. Kptalnoagor usually present in the co; icache-tpo from about 10% by weight in pacifi-t but starting material to an amount equal to the weight of the original material, but large quantities can be used. The reaction usually lasts 1 hour, after which the compound of formula 1, of which R is a hydrogen atom, is isolated by filtration, followed by solvent in vacuo. Compounds of formula t and their compounds with alkali metals enhance the antibacterial efficacy of β-lactam antibiotics (and Vivo, i.e., they reduce the amount of antibiotic that is needed to protect mice from lethal infection with certain bacteria producing p-lactamase. Ability compounds I and their salts to increase the effectiveness of l - lactam antibiotics against bacteria that produce β-lactamase, makes them valuable means for co-administration with | b, β-lactam antibiotics in the treatment of bacterial In the treatment of bacterial charging, the compound can be mixed with a β-lactam antibiotic, and two agents are administered simultaneously. Alternatively, the compound of the formula .1 can be administered as a separate agent during treatment with an ft-lactam antibiotic, In some cases some dose of a compound of formula 1, before starting treatment of a patient with a p-lactam antibiotic. When using a compound of formula 1 or its salt to increase the efficacy of a p) -lactam antibiotic in the body In a human, it may be administered alone or may be mixed with pharmaceutically acceptable carriers or diluents. It can be administered orally or parenterally, i.e. intramuscularly, subcutaneously, or intramuscularly. The carrier or diluent is selected depending on the intended mode of administration. The pharmaceutical composition typically should contain from about 2% to about 95% by weight of a compound of formula I. When using a compound of formula I in combination with another p) lactam antibiotic, the compound can be administered orally or parenterally, i.e. intramuscularly, subcutaneously or intraperitoneally. Typically, the ratio of daily doses of penam of formula 1 to f-lactam antibiotic is in the range of about 1: 3 to 3: 1; The daily dose of each component is approximately 10 to 200 mg KG of body weight, and the daily parenteral is approximately 10 to 40 of MF per kilogram of body weight. If necessary, you can use dosages that go beyond these limits. You can prescribe drugs that are formulated with formula 1 or if they are orally and orally, and one replacement, additional p-lactam antibiotic is parenteral, and you can also prescribe compound forms. Mules I or its salts are parenteral and, in this case, a single additional lactam antibiotic, orally. IR spectra were measured on disks from 6poiv KCToro potassium (KBr disks). NMR spectra were measured at 60 MHz for long solutions in deuterium chloroform (CD CE), or DMSO-d, and peak-to-peak peaks are expressed in ppm in the lower region of tetramethylsilane. Example 1. 1,1-dioxide benzyl ester of 2 p. Acetoxymethyl-2o {.-Methyl- / 5P / -penam-1-carboxylic acid. A stirred solution of 3.49 g of benzl-2-acetoxymethyl-2 o.-methyl- (51) -penam-ZvS-carboxylate in 35 ml of chloroform is cooled to 0 ° C and 5 g are added with a 15-minute break -chloroperbenzoic acid of 85% purity. The cooling bath is removed and the mixture is stirred overnight without cooling. The reaction mixture is then cooled again until OO is added with 7 O ml of water and 70 ml of ethyl acetate. The organic layer is removed and then washed successively with an aqueous solution of sodium sulfite, with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride. The dried organic layer (N02.504) was evaporated in vacuo to give 4.8 g of a brown oil, which slowly crystallized. The above product was dissolved in 35 Ml of chloroform and then oxidized using 5 g of 85% 3-chloroperbenzoic acid for 19 hours. The reaction mixture was worked up as previously, to obtain the crude desired Product. This product is dissolved in dichlesmetry and the solution is washed with a saturated aqueous solution of sodium bicarbonate and sodium. Magnesium sulphate and decolorizing carbon are added to the dichloromethane solution, and then the filtered dichloromethane solution is evaporated in vacuo. Poluchmt 3, O g (79% yield) of a ridiculous compound. An NMR spectrum (CD ce 7,) the product shows the absorption at 1.25 (s, 3N), 2, OO (s, 3N), 3.4O (d, 2H), 4.55 (m, 4H, 5.15 (fc, 2H) to 7, ZO (s, 5H), Example 2. 1,1-Dioxide 2 L of acetoxymethyl-2 oC-methyl- (5K) -penac-3 "carboxylic acid. To a solution of 84.5 g 1 The benzyl ester 1-dioxide of 2 p-acetoxymethyl-2cC-methyl (5p) -3O1-phenamic acid in 1.1 l of ethyl acetate is added 44 g of 5% palladium on carbon. The mixture is shaken with hydrogen 3.515 kg / cm for 2 hours and then K (the analyzer is removed by filtration. The above filtrate is combined with the corresponding eltrom from the repeated experiment and the volume is reduced to 1.5 L. To this solution slowly yes.; 1.7 liters of hexane is added. The volume is reduced to approximately 2 liters and the solid that precipitates is separated by filtration and suspended with hexane to give 98 g (76% yield) of the desired product. The NMR spectrum (CDCe + DMSO-L) shows the absorption at It6 (s, 3N), 2.15 (s, 3N), 3.55 (d , 2H) and 4.65 (m, 4H). The infrared spectrum of the product (KBG disk) absorbs absorption at 1785, 133O, 1225, and 1190 cm -. Calculated,%; C 41.2; H 4.49; N 4.80; S 11.00 Found: C 41.34; H 4.55; Ы4,81; S 11.08. Example 3. Benzyl ester of 2p) -acetoxymethyl-2oi-methyl- (5R) -penes-3ot-carboxylic acid. A mixture of 68 ml of acetic anhydride and 10 ml of toluene is heated to II2 C in a {carbon-carbon flask equipped with a nozzle for distillation and a set of distillation nozzle and a set of distillate and a set of distillate and a set of distillate and a set of distillate; distillation. When the temperature reaches .112 ° C and the liquid begins to be distilled, prewarmed toluene is added to the round bottom flask (approximately at the same rate as the distillate is collected. Slow distillation and the addition of preheated toluene continue for 2 minutes.) 2.2-dime benzyl ester 2,2-dimeTHui- (5R) -3 ot-carboxylic acid benzyl ester added to the liquid in the South-Yak-oKHCH twist-flask. A solution is formed immediately. Slow distillation of the solution in the round-column
    flask and the addition of heated toluene to ghadwarthela continue for another 15 min. Throughout this procedure, the temperature in the round flask is maintained at 112 ° C. The liquid in the round bottom flask is then cooled to room temperature and evaporated in vacuo. A brown oil is obtained, which dissolves between 100 ml of ethyl acetate and 10 ml of water, the pH of the aqueous phase is adjusted to 7.9 and the organic layer is removed. The organic layer is washed successively with water and saturated aqueous sodium chloride, and then dried and decolorized using sodium sulfate and charcoal decolorizing. Evaporation in vacuo gives 10.1 g crude: desired product.
    Example 4. Benzyl ester 2p-acetoximbenyl-2 CZ-methyl- (51) -Zo6-carboxylic acid.
    The process is carried out analogously to example 3, using a U-fold amount of the starting materials. The internal temperature is maintained at 115 ° C. after the benzyl ester is added, heating is continued for 1 hour. The yield of the product is 122 g.
    The product of this example is combined with the product of example 3, chromatographed on 4 kg of silica gel, the column eluted with a mixture of ethyl acetate and chloroform 1: 9, while selecting 500 ml of fractions. Chromatography followed by thin layer chromatography. Three main fractions are collected: fraction 1 of 7.0 g of oil is discarded; Fraction 2 of 67.5 g of solid — practically pure desired product; A fraction of 3 of 21.7 g of solid is also practically pure product. Combining 4ractions 2 and 3, get a yield of 72%.
    Fraction 2 is dissolved in 45 O ml of isopropanol, the solution is slowly cooled and the product is filtered. The output of the village. After recrystallization 34.1 g
    NMR spectrum (C1) C € d,) gives the absorber at 1, 30 (s, s), 2.1 o (s, s), 3.05 (two doublets, 1H), 3.55 (two doublets, 1H) , 4.05 (q, 2H), 4.80 (s, 1H), 5.20 (s, 2H), 5, 30 (m, 1H) and 7, 30 (s, 5H).
    Stage 5. Benzyl ester 2ft-41io oxnmuN-2-2o4.-Methyl- (5P) -penam-: .oC-caroic acid.
    PacTiiop 31 g of 1 o-benzyl oxide l | nfl 2,2 dimethyl- (5H) -pena.m-3cA-car1n m1m: 1 kyogota in 210 ml of acetic acid
    anhydride and 32O ml of toluene are heated to the boiling point, liquids are allowed to slowly distil and toluene is added dropwise to maintain a constant volume in the reaction vessel. After 30 minutes, a sample was taken and checked by NMR spectroscopy. The analysis showed that the reaction mixture contained 1 o-oxide, b-1 methyl ester of 2,2-dimethyl- (5H) -penam-3 x 1 -carboxylic acid, 1 p-benzyl oxide 2,2-dimethyl- (5) -penam-3 ot-carboxylic acid ester and benzyl ester 2 f-acetoxymethyl-2 o6-m-thyl- (5R) -penam-3 o.-carboxylic acid in a ratio of approximately 1: 4: 4. Milled neperofacy and addition of fresh toluene are allowed to continue for another 25 minutes, and the reaction mixture is then cooled to room temperature. The solvents are removed by evaporation in vacuo. The residue is partitioned between water and ethyl acetate. The pH value of the aqueous layer was adjusted to 3, O, and the layers were moved for 15 minutes. The pH is raised to 8.0 and the layers are separated. lt are The organic layer is washed successively with water at pH 8.0 and sat. sodium hydroxide solution and then dried using sodium sulfate. Evaporation of the organic layer in vacuo gives an oil, which is purified by chromatography, on a column of silica gel using a mixture of ethyl acetate and chloroform 9: 1 as eluent. The column is developed by thin layer chromatography and fixation (which clearly contain a substantially pure product, collected and evaporated. 17 g of the title compound are obtained. A small sample of this material is suspended with ether and separated by filtration in a white water solid.
    Calculated,%: - C58., 4O; H5.48; W4, O1.
     H.o N055
    Found,%: C 58.38; H 5.55; N 3.99
    The earlier fractions from the column are re-recorded and the additional product obtained is combined with the substance obtained previously. The combined material is suspended with ether to obtain 18 g (5O% yield) of benzyl ester 2 | L-acetoxylmethyl-2o-methyl- (5K) -Penam-3-6 carbonic acid 1.
    Example 6: 1,1-Dioxide 2 L-acetooxime-2 o -methyl- (5R) -peyl m .-. Cho -KOJ.xylate: sodium.
    to a stirred suspension of 50 g of 1,1-aiooxyCi 2 fi-acetosoxymethyl-2o (.-metsch1 (5K) -Penam-Za-aprboxylic acid in 10OO ml of water is added 1N sodium hydroxide until it becomes more stable pH 5.0, the aqueous pactBop thus obtained, LIOFN1IE1FUYT, yields 5O g (92% yield) of the desired product.
     109.4 (, p. 1).
    An NMR spectrum (AMCO-dg) shows an absorption of 1.50 (s, ZN), 2.10 (s, ZN), 3.35 {k, 2H), 3.90 (s, 1H), 4.55, ( k, 2H) and 5, OO (m, 1H).
    IR spectrum (KBG disk) shows the absorption of the 1785, 1625, 1325 n 1240 CM-I
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    ". A method for the preparation of 1,1-dioxides of 2-acetoxymetl-2-methylpenam-3-carboxylic acid or its salts with alkali metals of the formula I
    1 f i
    .
    ,
    oCOOK
    where R is a hydrogen atom or an alkali metal,
    characterized in that the derivative of 2-acetoxymethyl-2-methylpenes is 3-carboxylic acid (II)
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    法律状态:
    优先权:
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