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    • 专利摘要:
    The method of obtaining 6B-hydroxyalkylpenicillanic acid derivatives of the formula n (o) w, 5 o .P g COOH canoyl, benzoyl or aminobenzoyl; Rj is a hydrogen atom, C-C-alkyl, phenyl or benzyl, or their pharmaceutically acceptable basic salts, characterized in that in the compound of the formula h "n,. where Y has the indicated values, the benzyl group is removed by hydrogenation in the presence of a palladium catalyst in a reaction-inert solvent and the desired product is isolated as a free acid or ito of its pharmaceutically acceptable base salt N3. 1yu ;YU
    公开号:SU1122227A3
    申请号:SU802999190
    申请日:1980-10-21
    公开日:1984-10-30
    发明作者:Стефен Келлог Майкл
    申请人:Пфайзер Инк.(Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new analogs of penicillin, namely new oxyalkyl penicillanic acid derivatives or their pharmaceutically acceptable base salts, which have the properties of b-lactamase inhibitors. A known method for producing biologically active 7-acylaninopenicyl-lanoic acids is that the benzyl ester of the corresponding 7-acylaminopenicillanic acid is subjected to catalytic hydrogenolysis by hydrogenating them on a palladium catalyst in an inert solvent ij under reaction conditions. A known method for producing biologically active sulfur-containing analogs of penicillin is a photochemical reaction of 6-diazopenicillan acid esters with a thiol compound, followed by deesterification of the resulting 6-th derivative 2j. The purpose of the invention is to obtain new penicillin analogues, containing bV-oxyalkyl substituents, expanding the arsenal of 8-lactamase inhibitors. The goal is achieved based on the known de-esterification of penicillic acid complex benzyl esters by catalytic hydrogolysis by the method of obtaining b-oxyalkyl penicillanic acid derivatives of the formula / soon where Y is 1-hydroxy-3-phenylpropyl, tolyl sulfonyloxymethyl, or cal- fory of formula 0-R / CH- . where R. is a hydrogen atom, C-C dalkanoyl, benzoyl or aminobenzoyl; Rj is a hydrogen atom, C-C4 alkyl phenyl or benzyl; or their pharmaceutically acceptable basic salts, which consists in the fact that in the compound of the formula 1 7 S. CH, FjfJl CHa (II), -N / COOCHjCeHs where y has the indicated values, the benzyl group is removed by hydrogenation in the presence of a palladium catalyst in the reaction inert the solvent and the desired product is isolated in the form of the free acid or its pharmaceutically acceptable base salt. The starting compounds of formula II are usually prepared from benzyl 6,; 6-dibromopenicillat by condensation of the corresponding aldehyde with an enolate formed in the reaction of benzyl 6,6-dibromopenicillanate with an organometallic reagent, to form benzyl 6-bromo-6-hydroxyalkyl penenicane shanate intermediate. resulting in products of formula II. Experimentally, benzyl 6,6-dibromopenicillanate in an inert solvent at (-20) - (-78) C is treated with approximately one equivalent of tert-butyl lithium or tert-butyl magnesium chloride. The resulting enolt is treated with an appropriate aldehyde and, after a short time, the reaction is stopped and the product is isolated. Adding zinc chloride to ra-. An enolt solution before adding aldehyde affects the control of the condensation product stoichiometry. Accordingly, under these conditions, a significant (S) configuration prevails in the side chain. When dystilzinc is used as the initial organometallic reagent, the configuration (R) predominates in the side chain of the reaction product. The reaction is carried out in an anhydrous inert solvent that substantially dissolves the reagents, which is not accompanied by a noticeable reaction with the reagents or reaction products under the conditions used. Such solvents or mixtures thereof include aromatic solvents, for example toluene, and ether solvents, for example tetrahydrofuran and diethyl ether. The molar ratio of the original penicillanate derivative to the organometallic reagent does not play a decisive role in this process. The use of a small excess of an organometallic reagent, for example, 10% higher than an equimolar amount, leads to an early completion of the reaction. Moisture should be carefully removed from the reaction system using a nitrogen or argon atmosphere. The reaction time depends on the concentration of the reagents, the process temperature and the reactivity of the initial reagents. When the reaction is carried out at a preferred temperature in the range of (-60) - (-78) ° C, the reaction time for the formation of an enolta is 30-45 minutes. The reaction time to form an intermediate product from the indicated enolate and aldehyde is 30-60 minutes. After the reaction, the product is isolated and the diastereomeric mixture can be separated by column chromatography. To remove the 6-bromo substituent, OO and B epimers must be separated at the 6th carbon atom. Treatment of benzyl 6-bromo-6-c5 oxyalkyl penicillanate obtained in the first reaction with tri-n-butylolose hydride results in the formation of benzyl 6-hydroxyalkyl penicillanate, in a coiTopoM the 6-oxyalkyl fragment is in B-configuration. This result does not depend on the conformation of the substituents in position 6 of the initial reagents. Thus, Bs-bromo-bB-oxy alkyl ethers and 6B-bromo-6v4-hydroxyalkyl ethers give the same bB-hydroxyalkyl ether as the main product when treated with tri-n-butyltin hydride. The reaction is carried out in an inert solvent that visibly reacts the reagents without reacting to a significant degree with reagents or products under the conditions of the process. In addition, it is preferred that said solvent be aprotic, not miscible with water, and have a boiling point and metering compatible with reaction temperatures. Such solvents or mixtures thereof include benzene and tauol as preferred solvents. The reaction time depends on the concentration, reaction temperature and reactivity of the reactants. When the reaction is carried out at the preferred temperature, the refluxing temperature of the solvent, the reaction is usually completed within 4-5 hours. The molar ratio of the reactants is not critical to the process. An excess of tin hydride is usually used, which can be up to 100% compared with an equimolar amount. After completion of the reaction, the solvent is removed, the residue is treated with hexano to remove the organotin by-product. The intermediate product can be purified, and the isomers can be separated by column chromatography; The oxidation of the resulting 6B- (S) and (R) hydroxyalkylpenicillanate to the corresponding sulfones of formula II is usually carried out using an organic peroxy acid, such as, for example, W-chloroperbenzene acid. The reaction is carried out by treating the corresponding benzyl 6B- (S or (S) oxalkylpenicillanate 2-4. Equivalents, preferably 2.2, of an oxidizing agent in an inert solvent. Chlorine hydrocarbons, such as methylene chloride, chloroform and 1 , 2-dichloroethane. The oxidizing agent and the substrate are first mixed in a solvent at 0-5 C. The temperature is raised to room temperature. H-b h. During the separation of the sulfones, the solvent is removed, and the residue is separated between water and a water-immiscible solvent, So m as ethyl acetate. The pH of the water-organic solvent mixture is maintained at 7.0 and the excess peroxide is decomposed with sodium bisulfate. Debenzylation of the corresponding benzyl esters of the formula II is usually carried out as follows: benzyl ether is added to a suspension, a pre-hydrogenated catalyst consisting of 6% palladium on calcium carbonate in 50% aqueous methanol solution. The hydrogenolysis is carried out at room temperature, usually at a pressure of 45-50 psi. Under these conditions, the reaction is usually completed in 30-60 minutes. Filtration of the spent catalyst, followed by removal of the solvent by drying in the cold, results in calcium salt. Acidification of the filtrate after removal of the catalyst, followed by extraction with a water-immiscible solvent, such as ethyl acetate, results in the liberation of the free acid. The compounds of formula I are acidic and form salts with basic agents. Such salts are also within the scope of the present invention and can be obtained by standard methods, for example, by contacting acidic and basic components, usually at their ratio (molar) of 1: 1, in an aqueous, non-aqueous or partially aqueous medium. They are then isolated by filtration, precipitation with a non-solvent, followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization. The main agents that are commonly used in salt formation belong to both organic and inorganic compounds and may include ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, as well as alkaline earth metal hydroxides, carbonates, hydrides and alkoxides. Primary amines, such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine, can be basic. secondary amines, such as diethylamine, morpholine, pyrrolidine and piperidine; tertiary amines, such as triethylamine, N-ethylpiperidine, N-methylmorpholine and 1,5-diazabicyclo (4,3,0) non-5-ene; hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide; alkoxides such as sodium ethoxide and potassium ethoxide; hydrides such as calcium hydride. sodium hydride; carbonates such as sodium carbonate and potassium carbonate; bicarbonates such as sodium bicarbonate and potassium bicarbonate; as well as alkali metal salts of long chain fatty acids, for example 2-ethylhexanoate. Preferred salts of the compounds of formulas I are the sodium, potassium, and triethylamine salts. The compounds of formula I are inhibitors of microbial B-lactamase and increase the antibacterial efficacy of B-lactam antibiotics (penicillin and cephalosporin) in relation to many microorganisms, especially those that produce B-lactamase. The ability of these compounds of formula I to increase the efficacy of a B-lactam antibiotic can be assessed in experiments that measure the MIC of one given antibiotic and the compounds of formula I. The resulting MIC values are then compared with the MIC values obtained with the combination of this antibiotic and compound I. In this case, when the antibacterial power of the combination is significantly Bbmie, than the value that could be predicted, based on the powers of the individual components, the result obtained can be considered Leave as evidence of increased activity. The MIC values of the combination are measured using the Barry and Sabat method. The compounds of formula I increase the antibacterial efficacy of B-lactam antibiotics in vivo. In other words, they lower the amount of antibiotic that is needed to protect mice against the lethal amount of inoculum in other circumstances, from some B-lactam-producing bacteria. The ability of compounds of formula I to increase the efficacy of B-lactam antibiotic against B-lactam-producing bacteria makes them especially valuable for combined use with B-lactam antibiotics in the treatment of bacterial infections in mammals, especially in humans. In the treatment of a bacterial infection, a compound of formula I can be combined with a B-lactam antibiotic, and these two agents can be used simultaneously. Alternatively, a compound of formula I may be used as a separate agent during treatment with a B-lactam antibiotic. In some cases, it may be useful to pre-administer oooeline formula I before starting treatment with a lactam antibiotic. When using the compound of Lormula 1 in order to increase the efficacy of B-lactam antibiotics, mixture I with a (J-lactam antibiotic is used preferably in a formulation with standard pharmaceutical carriers or diluents. Pharmaceutical composition comprising a pharmaceutically acceptable carrier, Y-lactym antibiotic and a compound of formula I typically contains 5-80% by weight of a pharmaceutically acceptable carrier. When using compounds of formula I in combination with another B-pactam antibiotic, these compounds can be administered orally or parenterally, for example, intramuscularly, subcutaneously or intraperitoneally. The ratio of daily dosages of the compounds of formula I to the amount of 6-lactam antibiotic is usually 1: 3-3: 1. In addition, when using compounds of formula I in combination with another B-lactam With the antibiotic, the daily oral dosage of each component is usually 10–200 mg / kg of live weight, and the daily parenteral dosage of each component is usually 10–400 mg / kg of live weight. in some cases it is necessary to use dosages that go beyond the specified limits. Some of these B-lactam compounds are effective when administered orally or parenterally, while others are only effective when used parenterally. When compounds of Formula I are used simultaneously with B-lactam anti biotic, which is effective only for parenteral use, a combined formulation suitable for parenteral use is required. When compounds of formula I are used simultaneously with a B-lactam antibiotic that is effective for oral and parenteral use, combinations can be made that are suitable for oral and parenteral administration. In addition, preparations of compounds of the formula I can be administered orally, while an additional amount of B-lactam antibiotic is used by parenteral route; It is also possible to use preparations of compounds of the formula I parenterally, while simultaneously applying an additional amount of B-lactam antibiotic by the oral route. The test results of compounds of formula I are presented in table. 1-3. In the examples, NMR spectra were measured at 60 MHz for solutions in deuterochloroform (CDClI), perduterodimethylsulfoxide (daCO - d) or deuterium oxide (), unless otherwise indicated, and peak positions are expressed in parts per million (ppm) in descending order from peak given by tetramethylsilane or sodium 2,2-dimethyl-2-silapentane 5-sulfonate. Example 1. BV-hydroxymethylpenicillanic acid sulfone. A. Benzyl 6-bromo-6-hydroxymethyl penicillanate. A solution of 44.9 g of benzyl 6,6-dibromopenicillanate in 600 ml of dry tetrahydrofuran is added and 56.4 ml of tert-butyl magnesium chloride is added dropwise with vigorous stirring in an inert atmosphere, maintaining at the same time -60 ° C. After stirring for 30 min at -78 ° C, the solution is treated with formaldehyde gas in a stream of nitrogen before adding 5 mol. equiv. of this substance. The reaction is stopped by adding 5.7 ml of acetic acid over 45 minutes. The reaction solution is warmed to room temperature and concentrated in vacuo. 200 ml of water and 200 ml of ethyl acetate are added to the residue. The organic layer is separated and the aqueous layer is extracted again with ethyl acetate. The organic phases are combined, washed successively with water (200 ml), 5% aqueous sodium bicarbonate solution (200 ml) and brine (200 ml) and dried over magnesium sulfate. Removal of the solvent under reduced pressure gives 38.2 g of product,. epimer at C-6. B. Benzyl 6 (3-hydroxymethyl penicillanate. A solution containing 10 g of benzyl 6-bromo-6-hydroxymethyl penicillanate, 6.9 g of tri-n-butyl tin hydride and traces of azo-bis-isobutyronitrile in 200 ml of benzene are heated under reflux in a The reaction mixture is cooled and concentrated in vacuo 1 The residue is treated with hexane and chromatographed on silica gel using toluene / ethyl acetate (2: 1) as an eluant to give 7.5 g of product.
    C. Sulfon benzyl by-hydroxymethyl penicillanate. M-chloroperbenzoic acid (11.8 g) is added to a solution of 7.5 g of benzyl bB-hydroxymethylphenicillanate in 600 ml of methylene chloride cooled to 05 ° C. The solution is then allowed to warm to room temperature and stirred for 5 hours. under vacuum, and the residue is partitioned between 200 ml of water and 200 ml of ethyl acetate. The pH of the mixture is adjusted to 7 by adding saturated sodium bicarbonate solution, then a sufficient amount is added.
    sodium bisulfite in order to get a negative peroxide test (starch - iodide). The layers are separated and the aqueous layer is washed with ethyl acetate. The organic layer, and the washing, is combined, washed successively with water, 5% sodium bicarbonate solution, brine, and dried over magnesium sulfate. Removal of the solvent under reduced pressure. The scientific research institute gives a foam which, after chromatography on silica gel (chloroform-ethyl acetate 20: 3), gives 3.5 g of intermediate
    D, Sulfon bV-hydroxymethyl penicillanate calcium. To 30 ml of a water-methanol solution (1: 1) was added 3.5 g of a catalyst consisting of 5% palladium on calcium carbonate, and the catalyst was first hydrogenated at a pressure of 47 psi In the apparatus for hydrogenation. To the resulting catalyst was added 3.5 g of benzyl sulfone. bV-hydroxymethyl penicillanate in 10 ml of methanol and 20 ml of tetrahydrofuran; the mixture is shaken in a hydrogen atmosphere under pressure
    48 psi (3.3 kg / cm) for 30 min. The catalyst is filtered through a filter and the filtrate is concentrated in vacuo. The aqueous residue is extracted with ethyl acetate (2 x 100 ml) and dried in the cold to form 3.0 g of the product as a calcium salt. In the NMR spectrum (CDCl1 - free acid), absorption bands are observed at 1.49 (S, 3N); 1.6 (S, 3N); 4.1 (t, 3N 4.32 (5, 1H); 4.9 (d, 1H, Hz) ppm
    PRI mme R 2. Sulfone (S) hydroxyett} penicillanic acid.
    A. Venzyl 6th-bromo-6oC-1 (S) hydroxyethyl-Jenicellanate. To a stirred solution of 9 g of benzyl 6,6-dibromopenicillanate in 200 ml of dry toluene
    when in the argon atmosphere, 15 ml of tert-butyl-lithium in pentane is added dropwise. The greenish-yellow solution is stirred for 15 minutes at -78 ° C, followed by the addition of 10 ml.
    0 1M solution of anhydrous zinc chloride in tetrahydrofuran. The mixture was stirred for 45 minutes at -78 ° C and 5 ml of acetaldehyde was added. After further stirring for 1 h, the reaction
    5 was stopped by adding 5 ml of acetic acid in 50 ml of ether at -78 ° C and the mixture was allowed to warm to room temperature. The toluene is removed in
    0 I vacuum, and the residue is partitioned between water and ethyl acetate. The organic phase is separated and the aqueous is extracted (2 x 100 ml) with ethyl acetate. The combined organic salts are washed with a 5% aqueous solution of sodium carbonate bi-5 and then with a saturated brine solution. They are then dried over magnesium sulphate and concentrated to an oil, which, by chromatography on silica gel using toluene-ethyl acetate (10: 2) as eluent, gives 3.5 g of benzyl 6o; -bromopenicillanate and 3.9 g of the desired product . The analytical sample is purified by recrystallization from ether, so pl. 124-125 C.
    In the NMR spectrum (CDCl,) absorption peaks at 1.42 (S, ZN); 1.45 (d, 3N, Hz); 1.67 (S, NN); 2.55 (s, 1H); 4.3 (q, 1H, Hz); 4.6 (s, 1H);
    0 5.3 (s, 2H); 5.5 (S, 1H) and 7.4 (S, 5H) ppm.
    B. Benzyl (S) Hydroxyethyl Phenicillanate. 1.1 g of 5% palladium-on calcium carbonate was added to 20 ml of a mixture of methanol 5 water (1: 1) and the resulting mixture was hydrogenated at a pressure of 47 psi (3.3 kg / cm) for 20 minutes . To black
    0 1.1 g of benzyl bB-bromo-C-l (3) hydroxyethyl penicillanate are added to the sludge
    and hydrogenation is continued at a pressure of 47 psi (3.3 kg / cm) for 30 minutes. The spent catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The pH of the remaining aqueous solution was adjusted to 8 and it was extracted with methylene chloride. The organic phase is separated, dried over magnesium sulphate and evaporated to an oil. The remaining oil is then chromatographed on 150 g of silica gel using chloroform ethyl acetate (10: 1) as eluent. Fractions 23-33 are combined and evaporated to give 148 mg of product. An NMR spectrum (CDCl1) gives the following absorption maxima at 1.35 (d, 3N); 1.4 (S, 3N); 1.58 (S, 3N); 2.5 (t, 1H); 3.45 (dd, 1H, I 10., 4 Hz); 4.2 (t, W); 4.33 (s, 1H); 5.13 (s, 2H); 5.38 (d, 1H, I 4 Hz) and 7.33 (S, 5H) ppm. C. Benzyl sulfone (S) hydroxyethyl depenicillanate. To a solution of 148 ml of benzyl (5) hydroxyethyl penicillanate in 20 ml of methylene chloride at 0-5 sec, 223 mg of m-chloropenbenzoic acid are added in portions. The resulting reaction mixture was stirred at commanding temperature overnight. The undissolved solids are filtered off and the filtrate is evaporated under reduced pressure to dryness. The residue is partitioned between 5% aqueous sodium bicarbonate and ethyl acetate. Sodium bisulfate is added to the well-stirred mixture to a negative peroxide (starch-iodide) sample. The organic layer is separated and the aqueous layer is extracted with additional ethyl acetate. The combined organic layers are successively washed with saturated aqueous sodium bicarbonate and brine, then dried over magnesium sulfate. Removal of the solvent in vacuo gives 160 g of product in the form of an oil. An NMR spectrum (CDCl1) gives the following absorption maxima at 1.27 (S, 3N); 1.35 (d, 3N, Hz) 1.5 (S, 3N); 3.2 (t, 1H); 3.85 (dd 1H, 1 11.5 Hz); 4.53 (s, 1H); 4.77 (t, W); 4.77 (d, 1H, Hz) 5.28 (ABq, 2H,. Hz) and 7.43 (S, 5H) ppm, .. D.Sulfone (S) hydroxy-ethyl penicidal. A suspension of 160 mg of 5% palladium-on calcium carbonate in 20 ml of a mixture of methanol and water (1: 1) is preliminarily hydrogenated to 2712 at a pressure of 47 psi (3.3 kg / cm) for 20 minutes. 160 mg of benzyl (5) -hydroxyethyl penicillanate are added to the resulting suspension and the hydrogenation is continued at 51 psi (3.3 kg / cm) for 1 hour. The spent catalyst is filtered and the pH of the filtrate is set to 8. After extraction of the aqueous solution the pH is adjusted to 1.8 with ethyl acetate and fresh ethyl acetate is added. The ethyl acetate layer was separated, dried over magnesium sulfate, and concentrated to an oil. J90 mg. Next, the oil is recrystallized with the formation of a white solid, so pl. 160-161.5 C. The NMR spectrum (CDCl1-DMSO-D) gives absorption peaks at 1.2 (d, 3N, Hz); 1.42 (S, 3N); 1.52 (S, 3N); 3.80 (dd, W, 5 Hz); 4.28 (s, 1H); 4.5 (t, 1H) and 5; 20 (d, 1H, Hz) ppm. Example 3. Sulfone (R) hydroxyethyl penicillanic acid. , A. Benzyl 6B-6poM-6eC-l (Yugidro-xyethyl penicillanate. To 50 ml of toluene, cooled to -78 ° C, 70 ml of diethylzinc, also cooled to -78 ° C, are added slowly. Then 45 g of benzyl 6.6 -dibromopenicillanate in 250 ml of toluene was added to the reaction mixture for 45 minutes, after one hour of stirring in the cold, 17 ml of acetaldehyde was added to the reaction (Noah the mixture and stirring was continued for 1 hour. The reaction was stopped by adding 11.5 ml of acetic acid). acids in 100 ml of diethyl ether. The cooling bath is removed and the reaction mixture is allowed to warm to room temperature. An equal volume of water and ethyl acetate is added to the reaction mixture and the mixture is stirred for 5 minutes, the organic phase is separated and washed successively with water (3x75 ml), saturated sodium bicarbonate solution (3x75 ml) and brine (1x100 ml). The organic layer is dried over magnesium sulfate and evaporated in vacuo to an oil, which is chromatographed on 500 g of silica gel using chloroform-ethyl acetate (lOtI) as eluant. Fractions 13-29 are combined and evaporated to dryness to form 20 g of a crude intermediate, which is recrystallized from diethyl ether / hexane to form 12.7, m.p. . The isolated compound also contains benzyl bB-bromo-6o, (yugide hydroxyethyl penicillanate.
    B. Benzyl (Ugid.roksietilT penicillanate. A solution of 1.0 g of benzyl 6B-6poM-6jk-l (Ugidroxyethyl penicyl lanata and 1.4 ml of hydride, three-n-butyltin in 35 ml of benzene is heated under reflux for 40 min
    in nitrogen atmosphere. The reaction mixture is then cooled to room temperature and the solvent is removed under reduced pressure. The residue is again treated with hexane. The residue is chromatographed on 100 g of silica gel using chloroform: ethyl acetate (20: 1) as eluent. Fractions 82-109 are combined and evaporated to give 750 ml of product. An NMR spectrum (CDCl1) gives the following absorption maxima at 1.18 (d, 3N, Hz); 1.38 (S, 3N); 1.62 (S, 3N); 2.6 (p, 1H); 3.45 (dd, 1H, 4 Hz); 4.2 (ha, 1H); 4.43 (s, 1H) 5.16 (s, 2H); 5.33 (d, 1H ,. Hz) and 7.33 (S, 5H) ppm.
    C. Benzyl 6B-p sulfone (Uhydroxyethyl penicillanate. A mixture of 335 mg of benzyl (K) hydroxyistile penicill: nata and 507 mg of m-chlorobenzoic acid in 50 ml of methylene chloride is stirred overnight at room temperature. The solids are filtered and the solvent is distilled off from of the filtrate. The residue is partitioned between 50 ml of water and 50 ml of ethyl acetate. Sodium bisulfite is added in portions to the stirred mixture
    until complete decomposition of the peroxide, as evidenced by the negative starch-iodide test. The organic phase is separated, dried over magnesium sulphate and the solvent is removed in a vacuum. The residue is used in the next step without further purification. t
    D.Sulfone 6B- And JuhydroxyethylPenicillanic acid. A suspension of 1.78 g of 5% palladium-calcium carbonate in 40 ml of a mixture of methanol and water (1: 1) is hydrogenated for 20 minutes at a pressure of 50 pounds / inch (3.5 kg / cm) Sulfobenzyl 6B-1 (R) hydroxyethyl penicillanate (1.67 g) is added to the resulting suspension
    and the hydrogenation is continued at a pressure of 50 psi (3.5 kg / cm) for 1 hour. Methanol is removed under reduced pressure and the aqueous residue is extracted with ethyl acetate. The aqueous layer is acidified to pH 2 and extracted with ethyl acetate. The organic phase is washed with a brine solution, dried over magnesium sulfate and concentrated to a white solid, 1.0 g, m.p. 182183 ° C, decomp.
    An NMR spectrum (DMSO-dg) shows the following absorption maxima at 1.15 (d, 3N, Hz); 1.37 (S, 3N); 1.47 (S, 3N); 3.87 (dd,; W, 5 Hz); 4.28 (s, 1H); 4.5 (t, 1H); 5.11 (d, 1H, Hz) and 5.5 (t, 4H) ppm.
    Example 4. Sulfone (S) hydroxyethyl-D-penicillanic acid.
    A. Benzyl sulfone bB-bromo-Cl (S) hydroxyethyl penicillanate. 14.7 g of benzyl 6B-bromo-bob-l (8) hydroxyethylZ penicillanate (Example 2A) and 17.8 g of m-chloroperbenzoic acid, obtained reaction the mixture is stirred overnight. A further 200 mg of the peracid is added and stirring is continued for 2.5 hours. The reaction mixture is filtered and the filtrate is concentrated to a white solid. An equal volume of a water-ethyl acetate mixture is added to the residue and the pH is adjusted to 7.4 with a saturated sodium bicarbonate solution. The organic phase is separated, added to fresh water and the pH is adjusted to 8.2 with a saturated sodium bicarbonate solution. The ethyl acetate layer was washed with a saturated solution of sodium bicarbonate (3x400 ml) and then with brine. The organic phase is separated, dissolved over magnesium sulphate and evaporated to an oil, 18.2 g.
    The NMR spectrum (CDCl1) shows the following absorption maxima at 1.28 (S, 3N); 1.43 (d, 3N, Hz); 1.55 (S, 3N); 4.2 (q, 1H, 1 6 Hz); 4.57 (s, 1H); 4.85 (s, 1H); 5.23 (ABq, 2H, Hz) and 7.38 (S, 5H) ppm.

    B. Sulfon benzyl (S) hydroxyethyl depenicillanate. To a solution of 151,740 mg of benzyl 6fi-6poM-6oi 1 (S) hydroxyethyl penicillanate sulfone in 10 ml of benzene under a nitrogen atmosphere, 0.52 ml of tri-n-butyltin hydride is added and the mixture is heated under reflux for 3 hours. Benzene removed in vacuo and the residue is treated with hexane. The hexane is decanted and the residue is used in the next step without further purification. C. Sulfone (5) hydroxyethyl penicillanic acid, 1 g of 5% palladium-on calcium carbonate in 20 ml of water is pre-reduced with hydrogen at a pressure of 50 psi (3.5 kg / cm). To the resulting slurry, crude benzyl (S) hydroxyethyl penicillanate sulfone in 20 ml of methanol from Example AB is added and hydrogenation is continued for 1 hour at 50 psi (3.5 kg / s). Another 500 mg of catalyst is added and the reaction is continued for 45 min. The spent catalyst is filtered and the filtrate is extracted (2 x 5 ml) with ethyl acetate. The aqueous layer is treated with ethyl acetate and the pH is set to 1.5. The organic phase is separated and the aqueous phase is extracted with ethyl acetate (7 x 100 ml). The ethyl acetate acidic extracts are combined, washed races thief of brine, dried over magnesium sulfate and concentrated in vacuo to dryness, 230 mg. The NMR spectrum is identical to the product obtained in Example 2D. Example 5. Sulfone (Yu hydroxyethyl penicillanic acid A. Sulfone benzyl 6B-bromo-6c (. (hydroxyethyl penicillanate. K a solution of 2.9 g of benzyl 6 (X-bromo-6o-l (R) hydroxyethyl penicillanate (example ZA) in 100 ml of methylene chloride cooled to 0-5, add 3.6 m-chloroperbenzoic acid and the resulting reaction mixture stirred overnight at room temperature. The solvent is removed under reduced pressure and the residue is dissolved in an equal volume of a mixture of water and ethyl acetate. The pH of the mixture is adjusted to 7.4 with the above sodium bicarbonate solution and the organic layer is separated. The organic phase is washed with whole (brine solution, dried over magnesium sulphate and concentrated to an oil, which crystallizes, 4.0 g. The NMR spectrum (CDClj) gives the following absorption maxima at 1.25 (S, ZN); 1.28 (d, 3N, Hz); 1.5 (S, 3N); 2.9 (t, 1H); 3.7 (dd, 1H, 5 Hz); 4.43 (S, 1H); 4, 6 (t, 1H); 4.57 (d, 1H, I 5 Hz); 5.17 (ABq, 2H, Hz) and 7.32 (S, 5H) ppm. Benzyl sulfone (R) -hydride - roxyethyl penicillanate. A mixture of 3.0 g of benzyl sulfone 6B-bromo-6, -1 (K) -hydroxyethyl penitsishanate and 2.9 ml of tri-n-butyltin hydride in 100 ml of benzene is heated under reflux under nitrogen atmosphere for 30 minutes, the Solvent is removed in vacuo and the residue is extracted several times with hexane. The remaining material is chromatographed on 250 g of silica gel to give 1.67 g of product, which is used in the next step. C. Sulfone (Uhydroxyethyl penicillanic acid. 1.7 g 5% palladium-on calcium carbonate in 40 ml of a 50% aqueous methanol solution is pre-reduced at 50 psi (3.5 kg / cm) for 20 minutes. To the resulting suspension was added 1.67 g of sulloxy benzyl (R) hydroxyethyl J penecylate, and the hydrogenation was continued for one hour. The catalyst is filtered and the methanol is removed from the filtrate in vacuo. The aqueous residue is extracted with water {1, after which the pH of the aqueous layer is set to 2.0. The acidified aqueous layer is extracted several times with ethyl acetate and the combined extracts are washed with a saturated brine solution and dried over magnesium sulfate. Removal of the solvent gives 1.0 g of product which is identical to that obtained in Example 3D. Example 6. Sulfone (S) hydroxybenzyl penicillanic acid and sulfone (K) hydroxybenzyl penicillanic acid. A. Benzyl-6o (, - bromo-bV-l (R) and (S) oxybenzyl penicillanate. To a solution of 9.0 g of benzyl 6,6-dibromopenicillanate in 200 ml of dry toluene, cooled to -78 ° C and located in an argon atmosphere, 14 ml of tert-butyl lithium cooled to -67 ° C are added. After stirring in cold for 2 minutes, 2 ml of benzaldehyde is added and the reaction mixture is left to stand with stirring for 1 h; Then, after 10 minutes, the solution is added 1.2 ml of acetic acid in 50 ml of diethyl ether, the mixture was stirred at -78 ° C for 30 minutes, then water (100 ml) was added and the diet Lovy ether (100 ml), the mixture was stirred at room temperature for 30 minutes, the organic layer was separated and the aqueous layer was washed with ether. The organic layer and ether washes were combined and washed successively with water (1x50 ml), saturated bicarbonate water sodium (2 x 50 ml) and brine. The organic phase is dried over magnesium sulphate and concentrated to give 10.3 g of an oil. The residue is chromatographed on 450 g of silica gel using chloroform-ethyl acetate (20: 1) as an eluent. Fractions 71-101 are combined and concentrated to give 1.97 g of product a, which has the form of a semi-solid. B. Benzyl (K) hydroxybenzyl} peni cillanate and benzyl (3) oxybenzyl penicillanate. A solution of 1.9 g of benzyl 6oi-6poM-6B-1 (R) and (8) oxybenzyl penicillanate and 1.1 ml of tri-n-butyltin hydride in 30 ml of dry benzene under nitrogen atmosphere is heated under reflux for 3, 5 hours. Then an additional 1, Q ml of hydride is added and refluxing is continued overnight. Ben-ZOL is removed in vacuo, and the residue is stirred with hexane. Hexane is decanted, 850 mg of the residue in the form of an oil is chromatographed on 100 g of silica gel, using chloroform-ethyl acetate (20: 3) as an eluent. Fractions 20-34 are combined and the solvent is removed to give 495 mg of benzyl (K) oxybenzyl penicillanate. In the NMR spectrum (CDCl), an absorption of 1.42 (s, 3N) is observed; 1.67 (with ST); 3.2 (cf. 1H); 3.9 (dv.d., 1H, 10 Hz); A, 42. (s., 1H); 5.2 (s., 2I); 5.2 (cf. 1H); 5.4 (d., 1H, Hz) and 7.35 (cf. YUN) ppm. Fractions 35-58 are combined and concentrated in vacuo, and as a result of 11,718, 380 mg of benzyl 6-p (8) hydroxybenzylT penicillanate are obtained. In the NMR spectrum (CDCl1), an absorption is observed at 1.33 (s., 3N); 1.67 (s., NN); 3.4 (cf., 1H); 3.85 (dv.d., 1H, 10 Hz); 4.42 (s, 1H); 5.10 (d, 1H, Hz); 5.10 (s, 2H); 5.10 (cf. 1H) and 7.35 (cf. YUN) pp. C. Sulfon benzyl (K) hydroxybenzylT penicilla: Nata. To a solution of 490 mg of benzyl 6B-LI (K) oxybenzyl2 penicillanate in 50 ml of methylene chloride, cooled to, was added 1.35 g of meta-chloroperbenzoic acid, and the resulting reaction mixture was stirred overnight. The solvent is distilled off in vacuo, and the residue is treated with an equal volume of ethyl acetate and water. The pH of the mixture is adjusted to 7.2 with a saturated solution of bi (sodium carbonate, a sufficient amount of sodium bisulfite is added to decompose excess acid (negative starch iodide test). The organic phase is separated and washed successively with water at pH 8.2 and saturated sodium bicarbonate , - refluxed for 3.5 hours. An additional 1.0 ml of the hydride is then added and the refluxing is continued overnight. The benzene is distilled off in vacuo, and the residue is mixed with hexane. Hexane is decanted, the remaining 850 mg of oil is chromatographed on 100 g of silica gel using chloroform-ethyl acetate (20: 3) as eluant. Fractions 20-34 are combined and the solvent is removed, yielding 495 mgbenzyl (Penoxillanate in the spectrum NMR (CDCl1) observed absorption at 1.42 (s., 3N); 1.67 (s., 3N); 3.2 (cf., 1H); 3.9 (dv.d., 1H, 10 Hz; 4.42 (s., 1H); 5.2 (s. 2H); 5.2 (cf. 1H); 5.4 (d., 1H, Hz) and 7.35 (cf. ., 10H) ppm. Fractions 35-58 are combined and concentrated in vacuo to obtain 380 mg of benzyl (5) oxybenzyl penicillanate. .In the NMR spectrum (CDClI), absorption was observed at 1.33 (s., 3N); 1.67 (s., NN); 3.4 (cf., 1H); 3.85 (dv.d., 1H, 10 Hz); 4.42 (s ..
    1I); 5.10 (d, 1H, Hz); 5.10 (s, 2H); 5.20 (cf. 1H) and 7.35 (cf. YUN) ppp1.
    C. Benzyl sulfone (UoxibenzylT penicillanate. To a solution of 490 mg of benzyl (K) oxybeneyl penicillanate in 50 ml of methylene chloride, cooled to -5 ° C, 1.35 g of meta-chloroperbenzoic acid was added and the resulting mixture was allowed to stand overnight with stirring The solvent is distilled off in vacuo and the residue is treated with an equal volume of ethyl acetate and water. The pH of the mixture is adjusted to 7.2 with a saturated solution of sodium bicarbonate, a sufficient amount of sodium bisulfite is added to decompose the excess peracid (negative concentration). t starch iodide.) The organic phase is isolated and washed successively with water at pH 8.2, saturated sodium bicarbonate solution and brine. The organic layer is separated, dried over magnesium sulfate and concentrated to 395 mg of white solid. The resulting product is chromatographed on 100 g of silica gel using toluene-ethyl acetate (10:12) as eluent. Fractions 18-27 are combined and concentrated to give 148 mg of an oily product.
     g
    In the NMR spectrum there is an absorption of 1.22 (s., 3N); 1.5 (s., NN);
    2.6 (cf. 2H); , 2.6 (cf., 1H);
    4.07 (ds, 1H, 5 Hz); 4.47 (with 1H); 4.67 (d, 1H, 5 Hz); 5.2 (ABq, 2H); 5.63 (d, 1H, .0 Hz) and
    7.37 (cf. UN) and 7.37 (cf. YUN) pp.
    WITH . Sulfone benzene (8) hydroxybenzyl penicillanate. Repeat; Example 6C starting from benzyl (S) hydroxybenzyl penicillanate. .
    In the NMR spectrum, there is an absorption of 1.19 (s., 3N); 1.5 (s., NN);
    2.8 (cf. 1H); 4.20 (dv.d., 1H, 5 Hz); 4.38 (d, 1H, Hz); 4.43 (s, 1H); 5.20 (ABq, 2H); 5.77 (up to 1H, Hz) and 7.37 (cf. YUN)
    RRI.
    D, Sulfone (R) oxybenzyljepenic acid; To a suspension of 148 mg of 5% palladium-calcium carbonate in 20 ml of aqueous methanol (1: 1), which has been previously hydrated, rutted at 47.5 psi (3.34 kg / cm) over a period of 20 minutes, is added mg of benzyl (R) oksibenzylKpenitsilanata sulfophenol, hydrogenation is continued at an initial pressure of 47 psi (3.3 kg / cm) for 40 minutes. An additional 140 mg of catalyst is added and the reaction is continued for 30 minutes. Then the remaining 140 mg of catalyst is added and the reaction is continued for another 30 minutes. The spent catalyst is filtered and the resulting filtrate is extracted with ethyl acetate. The aqueous layer was separated, the pH was adjusted to 1.5 by adding fresh ethyl acetate. The ethyl acetate extract was back-washed with brine and dried over magnesium sulfate. After removal of the solvent in vacuo, 90 mg of product is obtained in the form of an oil.
    .In the NMR spectrum (CDCl1), they have an absorption of 1.50 (s., 3N); 1.67 (s., NN); 4.1 (dv.d., 1H, 5 Hz); 4.45 (s, 1H); 4.78 (d, 1H, Hz) 5.7 (d, 1H, Hz) and 7.4 (cf. 5H) D. Sulfone (5) hydroxybenzyl penicillanic acid. To a suspension of 170 mg of pre-reduced 5% palladium-on calcium carbonate in 20 ml of aqueous methanol - (1: 1) 170 mg of benzyl sulfone (5) oxybenzyl penicillantag are added, and hydrogenation is carried out at 47 psi (3.3 kg / cm) within 40 min. Then an additional 340 mg of catalyst is added and the reduction is continued for 3 hours. The catalyst is filtered off, washed with tetrahydrofuran-water (1: 1) and the combined filtrate and washes are concentrated. The residual water is extracted with ethyl acetate, followed by acidification of the aqueous layer to a pH of 1.5 and extraction with smelt of ethyl acetate. The organic phase is backwashed with brine and dried over magnesium sulfate. After removing the solvent in vacuo, 100 mg of product is obtained with a mp. 164-165 With decomposition.
    In the NMR spectrum (CDCl,), an absorption is observed at 1.40 (s., 3N); 1.55 (s., ZN); 4.0 (dkv.d, 1H, 10 Hz 4.4 (d, 1H, Hz); 4.4 (s, 1H); 5.7 (d, 1H, Hz) and 7, 4 (cf. 5H) ppm.
    Example 7. Sulfone (S) hydroxy-2-phenethyl 3 of penicillanic acid and sulfone (Yoxy-2-phenethyl penicillan acid. A. Benzyl 60 (r-6poM-6ft-tl (K) oxy-2 phenethyl penicillanate and b-benzyl bV- bromine 6fi-fl (8Toxy-2-phenethyl 1 penicillanate. solution of ED) g of benzyl 6,6-dibromopenicillanate in 200 ml of toluene, cooled to -78 ° C and held in an argon atmosphere, added 9.2 ml of a 2.5 M solution tert-butyllies, the resulting reaction mixture is allowed to stand with stirring for 40 minutes, 2.34 ml of phenylacetaldehyde is then added. After stirring for 1 1.2 ml of acetic acid in 25 ml of diethyl ether is added, stirring is continued at -78 ° C for 30 minutes, the reaction mixture is allowed to warm to room temperature, then an equal volume of water is added. The organic layer is separated and collected and The iodine was extracted with ethyl acetate. The organic layer and the extracts were combined, washed successively with water, a saturated sodium bicarbonate solution and brine, and dried over magnesium sulfate. The oily residue (11.0 g), which remains after the solvent is removed in vacuo, is chromatographed on 500 g of silica gel using chloroform-ethyl acetate (1: 1) as an eluent. Fractions 150-154 are combined and concentrated to give benzyl 6 (Cs-bromo-68- | 1 (U-hydroxy-2phenethyl penicillanate 670 mg. Absorption (in CDClI) at 1.35 is observed in the NMR spectrum (s., 1H); 2.53 (s., 1H); 2.85 (cf., ZN); 4.23 (cf. 1H); 4.41 (s., 1H); 5.13 (s., 2H); 5.57 (s., 1H) and 7.33 (cf. CHON) rrga. Fractions 155-195 are combined and concentrated to give 4.84 g of benzyl bV-bromo-6-6-6 (1 oxy2-phenethyl | penicillanate. In the NMR spectrum (CDCl), an absorption of 1.35 (s., 3N), 1.60 (s, 3N), 2.85 (cf., 3N), 4.23 is observed. (cf. 1H); 4.41 (s., 1H); 5.08 (s., 2H); 5.42 (s., 1H) and 7.33 (cf., 10 Hz) pp B. Benzyl (K) hydroxy-2-phenethyl penicillanate and benzyl (5) xi2-phenethyl penicillanate. A benzene solution (80 ml) containing 5.51 g of benzyl 6cC-bromo-bB-1 (K) oxy-2-phenetIl3-penicillanate and benzyl bB-bromo-6ot 1 (5) oxy-2- penicillanate phenateshl, as they were, electrons, in Example 7A, are treated with 3.2 ml of tri-n-butyltin hydride, the reaction mixture is heated under reflux in nitrogen atmosphere for 4 hours. The solvent is removed under reduced pressure and the residue is washed several times hexane. 4.2 g of the residue is chromatographed on 500 g of silica gel using chloroform ethyl acetate (20: 3) as eluent. Fractions 50-61 are combined and concentrated to give 596 mg of benzyl) oxy2-phenethyl penicillanate. In the NMR spectrum (CDCl1), an absorption is observed at 1.35 (s., 3N); 1.69 (s., NN); 2.8 (cf., 2H); 3.1 (cf. 1H); 3.55 (dv.d., 1H, 10 Hz); 4.23 (cf. 1H); 4.40 (s, 1H); 5.15 (s, 1H); 5.35 (d, 1H, Hz); 7.22 (s. 5H) and 7.3 (s. 5H) ppm. Fractions 65-75 are combined and concentrated to give 1.5 g of benzyl (Yoxy-2-phenethyl penicillanate. In the NMR spectrum (CDCl), absorption is observed at 1.35 (s., 3N)); 1.6 (s. , ZN); 2.78 (cf., 2H); 2.9 (cf., 1H); 3.43 (dv.d, 1H, 9 Hz); 4.30 (cf., 1H); 4.40 (s, 1H); 5.12 (s, 1H); 5.22 (d, 1H, Hz); 7.19 (s, 5H) and 7.3 (s, 5H ppm. C. Benzyl (S) oxo-2f8HEThyl penicillanate sulfone. To a cooled (0-5 ° C) solution of 300 mg of benzyl (5) oxy-2-phenethyl1-penicillanate in 50 ml of methylene chloride was added 630 mg of meta-chloroperbenzoic acid, obtained the reaction mixture is left under stirring overnight. The solvent is removed in The residue is treated with an equal volume of water and ethyl acetate. The pH of the mixture is adjusted to 7.2 with saturated sodium bicarbonate solution and a sufficient amount of sodium bisulfite is added to obtain a negative starch-iodide test.The organic phase is separated, treated with an equal volume of water and the pH is adjusted 8.2 as before. The organic phase is taken up, washed with brine and dried over magnesium sulphate. After removal of the solvent, the desired product is obtained in the form of an oil, 320 mg.
    In the NMR spectrum, absorption was observed at 1.22 (s, 1H); 1.5 (s, 1H); 2.8 (cf., 2H); 3.8 (dvd, 1H, 10 Hz); 4.42 (s, 1H); 4.6 (d, 1H, Hz); 4.75 (cf. 1H); 5.18 (ABq, 2H); 7.2 (s., 5H) and 7.3 (s., 511) rrga.
    C. Benzyl sulfone (Hooxy-phenethyl-2-penicillanate. In Example 7C, starting from 700 mg of benzyl (R) hydroxy-2-phenethyl) penicillanate and 850 m of meta-chloroperbenzoic acid, 610 mg of the expected product is obtained as an oil.
    In the NMR spectrum (CBCI 3), an absorption of 1.25 (s, 1H) is observed; 1.52 (s, 1H); 2.8 (cf., 2H)} 3.7 (dv.d. 1H, 10 Hz); 4.42 (s, 1H); 4.55 (d, 1H, Hz); 4.80 (cf. 1H); 5.18 (ABq, 2H); 7.22 (s. 5H) and 7.3 (s. 5H) ppm.
    D. Sodium salt of sulfone (K) hydroxy-2-phenethyl penicillanic acid. To a suspension of 600 mg of 5% palladium on calcium carbonate, previously hydrogenated at 3.3 kg / cm for 20 minutes, in 20 ml of a mixture of methanol and water (1: 1) was added 600 mg of benzyl sulfone (R) oK . C-2-fenetsh {| penicillanate. After continuing the hydrogenation for 35 minutes at 48 psi (3.37 kg / cmO), an additional 600 mg of catalyst was added and the hydrogenation at 48 psi (3.37 kg / cm) was continued for a further 10 minutes. The spent catalyst was filtered and washed with a mixture methanol-water (1: 1). The filtrate and washes are combined and the methanol is removed under reduced pressure. The remaining aqueous phase (pH 8.0) is extracted with ethyl acetate and the layers are separated. The aqueous layer is acidified to pH 1.8 and extracted ethyl acetate. The organic phase is separated, backwashed with saline and su After removal of the solvent in vacuo, 390 mg of the product is obtained as a solid. The free acid is dissolved in ethyl acetate containing a small amount of diethyl ether. To this solution is added 177 mg of sodium 2-ethnylhexanoate and the resulting solution with stirring for 1 hour. The sodium precipitated | the salt of the product is filtered off and
    dried, resulting in 250 mg of the product with so pl. 205-208 0, with decomposition.
    . In the NMR spectrum. (DjO), absorption is observed at 1.42 (s., 3N); 1.65 (s., NN); 2.9 (cf. 2H); 4.0 (dv.d., 1H, 10 Hz); 4.3 (s, 1H); 4.9 (cf., 1H); 5.0 (d, 1H, Hz) and 7.3 (s, 5H) ppm.
    D. Sulfone (8) hydroxy-2-phenethyl penicillanic acid. 320 mg of benzyl (8) hydroxy-2-phenethyl penicillanate sulfone are added to a suspension of 320 mg of pre-reduced palladium-calcium carbonate in 20 ml of methanol-water (1: 1) mixture, and the mixture is shaken in aTMOcdjepe of hydrogen at an initial pressure of about 47 psi (3.3 kg / cm) for 30 minutes. The catalyst is filtered off, washed with water: methanol, washed and the filtrate is combined. The aqueous residue, after the methanol is removed in vacuo, is extracted with ethyl acetate and then with fresh ethyl acetate. The extract is rinsed with a back-stream of brine, dried over magnesium sulphate and evaporated to give 80 mg of an oil, which solidifies, mp. 80-83 C with decomposition.
    In the NMR spectrum (CDCl,), an absorption is observed at 1.42 (s, 1H); 1.65 (s, 1H); 2.9 (cf. 2H); 4.0 (dv.d. 1H, 10 Hz); 4.3 (s, 1H); 4.8 (cf. 1H); 4.85 (d, 1H, Hz) and 7.3 (s., 3N) ppm.
    Example 8. Sulfone (R) hydroxy-3-phenylpropyl 3 of penicillanic acid and Sulfone (S) oxy-3-phenanpropyl-hypophosphate
    BUT.  Venzyl 6oL-6poM-6B-1 (R) and (S) ax-3-phenylpropyl penicillanate.  Benzyl 6,6-dibromopenicillanate (4.5 g) is dissolved in 100 ml of dry toluene and the resulting solution is cooled to -70 ° C.  7.3 mm of tert was added to the cooled solution. be quietly.  After stirring in the cold for 20 minutes, 1.3 ml of hydrochloric aldehyde are added and stirring is continued for 20 minutes.  0.57 ml of acetic acid is then added and the reaction mixture is allowed to warm to room temperature.  The toluene is removed in vacuo and an equal volume of chloroform and water is added.  The organic phase is isolated, backwashed, and dried over magnesium sulfate.  After removing the solvent, 5.3 g of product are obtained, which has the appearance of an oil.  This product is purified by chromatography on silica gel, is.  benefit in quality. f eluent mixture.  chloroform - ethyl acetate (20: 1).  Fractions 88-155 are combined and the solvent is removed in vacuo to give 3.2 g of product.  Calculated: C 57.2; H 5.2; N 2,8 Cj. . NSBr Found: C 56.5; H 5.2; N-2.9.  AT.  Benzyl (Hooxy-3-phenylpropyl | penicillanate and benzyl (hydroxy-3-phenylpropyl penicillanate.  A solution of 1.5 g benzyl boS-bromo-BJ-1 (and (S) oxy-3-phenylpropyl penicillan ta and 1.72 MP of tri-n-butyltin hydride in 100 ml of benzene is boiled under reflux under nitrogen atmosphere in for 2 h and 40 min. The solvent is removed in vacuo and the resulting residue (3.7 g) is chromatographed on 150 g of silica gel using chloroform ethyl acetate (20: 1) as the eluent.  Fractions 63-80 are combined and the solvent is removed, resulting in 244 mg of benzyl (5) hydroxy-3phenylpropylP penicillanate as an oil.  In the NMR spectrum (CDClj), an absorption is observed at 1.40 (c. , ZN)); 2.50 (s. , ZN)); 1.8 (cf. , 2H); 2.8, (cf. , ZN)); 3.59 (dv d. , 1H, 10 Hz); 4.1 (cf. , 1H); 4.43 (s. , 1H); 5.20 (s. , 2H); 5.43 (d ;, 1H, Hz); 7.25 (s. , 5НУ and 7,4 (с. , 5H) ppm.  Fractions 114-133 are combined and the solvent is evaporated, to give 369 mg of benzyl (R) hydroxy 3-phenylpropyl penicillanate as an oil.  In the NMR spectrum (CDCl1), an absorption is observed at 1.38 (c. , ZN)); 1.60 (s. , ZN)); 1.8 (cf. , 2H); 2.8 (cf. , ZN)); 3.55 (dv d. , 1H, 9 Hz); 4.1 (cf. , 1H); 4.43 (s. , 1H); 5.20 (s. , 2H); 5.35 (d. , 1H, Hz); 7.25 (s. , 5H) and 7.4 (s. , 5H) ppm.  WITH.  Benzyl sulfon (K) oxy3-phenylpropyl penicillanate.  To a razor of 585 mg of benzyl (R) hydroxyphenylpropyl penicillanate in 35 tylenchloride, cooled to 0–5 ° C, 700 ml of m-chloroperbenzoic acid 2726 is added and the reaction mixture is left under stirring overnight.  The solvent is removed under reduced pressure, the residue is treated equal. volume of water and ethyl acetate.  The pH is adjusted to 7.2 with a saturated sodium bicarbonate solution and the organic layer is separated.  An equal volume of water is added to the ethyl acetate layer and the pH is again adjusted, as before, to 8.4.  The ethyl acetate layer was separated, washed with a sodium bicarbonate solution (3 × 50 ml) and brine, and then dried over magnesium sulfate.  After removal of the solvent. - 678 mg of product is obtained in the form of an oil, which crystallizes on standing, t.  square  142-143 ° G.  In the NMR spectrum (CDC1,), an absorption is observed at 1.30 (c. , ZN)); 1.6 (s. , ZN)); 1.8 (cf. , 2H. ); 2.8 (cf. , 2H); 3.83 (dv d. , 1H, 9 Hz); 4.50 (s. , 1H); 4.55 (d. , 1H, Hz); 4.75 (cf. , 1H); 5.2 (ABq. , 2H); 7.2 (s. , 5H) and 7.38 (s. , 5H) ppm.  with.  Benzyl sulfone (5) hydroxy-3-phenylpropsh 1 penitsstlat.  According to the method of example 8C and proceeding from 300 mg of benzyl 6B-J (S) hydroxy-3-phenylpropyl penicillanate and 361 mg of meta-chloroperbenzoic acid in 35 ml of methylene chloride, 346 ml of product are obtained in the form of an oil.  In the NMR spectrum (CDCl), an absorption is observed at 1.28 (c. , ZN)); 1.52 (s. , 1H); 1.8 (cf. , 2H); 2.80 (cf. , 2H); 3.9 (dv d. , 1H, 10 Hz); 4.45 (s. , 1H); 4.62 (cf. , 1H); 4.67 (d. , 1H, Hz); 5.22 (ABq, 2H); 7.22 (s. , 5H) and 7.38 (s. , 5H) ppm.  D.  Sulfone (K) oxy-3-phenylpropyl penicillanic acid.  The benzyl (R) -oxy-3-phenyl-propyl-penicillanate sulfonic acid is added to a suspension of 700 mg of pre-hydrogenated 5% palladium-on calcium carbonate in 20 ml of a mixture of water and methanol (1: 1).  The resulting mixture is shaken under a hydrogen atmosphere at an initial pressure of 52 psi (3.66 kg / cmO for 1 h.  700 mg of catalyst are further added and the hydrogenation is continued for 1 hour.  Then the catalyst is filtered off and washed with a mixture of water - methanol.  The washing and the filtrate were combined and the methanol was distilled off in vacuo.  The aqueous residue is extracted with ethyl acetate, then the pH of the aqueous phase is adjusted to 1.5 and extracted with a fresh portion of ethyl acetate.  The organic phase is washed with a reverse jet of brine and dried over magnesium sulphate.  After removal of the solvent, 304 mg of product are obtained with this. square  138-140 ° C with decomposition.  A sample of the free acid (190 mg is dissolved in ethyl acetate, and then treated with 99 mg of sodium-2-ethylhexanoate.  After stirring overnight, the sodium salt of the desired product (165 mg) is filtered off and dried.  In the NMR spectrum (DMSO-D) is free; acids observe absorption at 1.45 (c. TH); 1.53 (s. , 1H); 1.8 (cf. , 2H); 2.80 (cf. 2H), 3.85 da, d , 1H, 9 Hz); 4.35 (s. , 1H); 4.60 (d. , 1H, Hz); 4.75 (cf. , 1H) and 7.23 (s. , 5H) ppm.  .  D.  Sulfone (S) oxy-3-phenyl propyl-Jenicyclic acid.  Example 8D is repeated, starting with 346 mg of benzyl sulfone (8) hydroxy-3-pheny propyl penicillanate and 350 mg of 5% np palladium-on calcium carbonate in 20 water-methanol mixtures (1: 1), resulting in 196 mg of the desired product with t. square  146-148 With decomposition.  Sample 126 mg sulfone (S) oxy-3-phenylpropyl | penicillanic acid is dissolved in a small amount of ethyl acetate, then treated with 57 mg of sodium-2-ethylhexanoate. A certain amount of diethyl ether is added and the resulting precipitate is filtered off and dried, resulting in 57 mg of the sodium salt of the target product.  In the NMR spectrum (DMSO-D), free acids are observed to absorb at 1.47 (c. , 1H); 1.60 (s, 1H); 2.0 (s. , 2H); 2.8 (cf. , 2H); 3.9 (dv d 1H); (, 10 Hz); 4.40 (s. , 1H); 4.67 (cf.  1H); 4.70 (d. , 1H) and 7.2 (s. , 5H) ppm.  Example 9  Sulfone (R hydroxy-1- (2-pyridyl) methylZ penicillanic acid and sulfone (S) oKsi-1- (2-pyridyl) methyl penicillanic acid.  BUT.  Benzyl (K) and (8) hydroxy-1 (2-pyridyl) methyl propenicillanate.  To a cooled solution of (-78 ° C) 9.0 benzyl 6,6-dibromopenicillanate in 728 with 200 ml of toluene under argon atmosphere, 11.8 ml of tert-butyl lithium are added and the resulting green solution is left under stirring for 30 minutes.  2-Pyridylcarboxaldehyde (1.9 ml) is then added and the reaction mixture is stirred in the cold for 45 minutes.  Then 1.2 ml of acetic acid in 25 ml of diethyl ether are added over 20 minutes.  The resulting mixture is left under stirring in the cold for 30 minutes and then allowed to warm to.  The reaction mixture was chromatographed on a Florisil column using toluene: ethyl acetate (2: 1) as eluent.  Fractions (300 ml each) 3-5 are combined and evaporated to give 4.8 g of oil.  This oil is dissolved in 60 ml of dry benzene, to which 3.2 ml of tri-n-butyltin hydride is added.  The resulting reaction mixture was heated under reflux in a nitrogen atmosphere for 2.5 hours.  An additional 2.0 ml of hydride is then added, heating is continued overnight.  The benzene is removed in vacuo, and a residue is suspended several times in hexane.  The remaining oil is chromatographed on 500 g of silica gel using toluene-ethyl acetate (2: 1) as eluent.  Fractions 104-131 are combined and the solvent is removed under reduced pressure, to obtain 480 mg of benzyl (R) o KCH-1- (2-pyridyl) methyl penicillanate as an oil.  In the NMR spectrum (CDCl,), an absorption is observed at 1.45 (c. , ZN)); 1.73 (s. , ZN)); 3.87 (dv d. , 1H, 10 Hz); 4.53 (s. , 1H); 4.65 (cf. , 1H); 5.20 (cf. , 1H); 5.23 (s. , 2H); 5.48 (d. , 1H, Hz); 7.4 (s. , 5H); 7.5 (cf. , ZN) and 8.6 (cf. , 1H) ppm.  Fractions 136-190 were combined and the solvent was removed in vacuo to give 950 mg of benzyl (S) oxy-1- (2-pyridyl) methyl penicillanate as an oil.  In the NMR spectrum (CDClj), an absorption is observed at 1.40 (c. , ZN)); 1.68 (s. , ZN)); 4.0 (cf. , 1H); 4.05 (dv d. , 1H, 9 Hz); 4.55 (s. , 1H); 5.2 (s. , 2H), 5.22 (cf. , 1H); 5.46 (d. , 1H, Hz); 7.3 (s. , 5H); 7.4 (cf. , ZN) and 8.5 (cf. , 1H) ppm.  AT.  Benzyl (R) oxy-1 (2-pyridyl) methyl zpenicillanate sulfone.  29 500 mg of meta-chloroperbenzoic acid are added to a nitrogen atmosphere to a solution of 480 mg of benzyl (K) oxy-1 (2-pyrndyl) methyl penicillayate in 40 ml of methylene chloride, cooled to 0-5 C.  After stirring for 1 hour, the solvent is removed in vacuo, and the residue is treated with an equal volume of water and ethyl acetate.  The pH is adjusted to 7.2 with a saturated sodium bicarbonate solution, and then a sufficient amount of sodium bi-sulfite is added to obtain a negative starch-iodide test.  Thereafter, the aqueous layer was separated and added. fresh ethyl acetate, pH increased as before, to 8.2, the ethyl acetate layer was separated, backwashed with sodium bicarbonate solution and brine, and dried over magnesium sulfate.  After removing the solvent, 480 mg of oil is obtained, which is then chromatographed on 50 g of silica gel, using ethyl acetate as eluent.  Fractions 2.2-55 are combined and the solvent is removed in vacuo, yielding 125 mg of product.  In the spectrum (CDCl1), absorption is observed at 1.22 (c. , ZN)); 1.50 (s. , ZN)); 4.40 (s, 1H); 4.79 (cf. , 1H); 4.80 (d. , 1H, Hz); 5.18 (ABq, 2H; Hz); 5.6 (cf. , 1H); 7.2 (cf. , ZN)); 7.25 (s. , 5H) and 8.1 (cf. , 1H) ppm.  AT.  Benzyl sulfone (s) oKsi-1- (2-pyridyl) methyl penicillanate. Starting with 250 mg of benzyl (3) hydroxy-1- (2-pyridyl) methyl penicillanate and 320 mg of methachloroperbenzoic acid in 25 ml of methylene chloride according to Example 12B, 240 are obtained. mg of the desired product as a solid with m. square  140-145 0.  In the NMR spectrum (CDCl1), absorption was observed at 1.23 (s. , ZN)); 1.59 (s. , ZN)); 4.6 (s. , 1H); 4.8 (cf. , 2H); 5.3 (ABq, 2H, Hz 6.95 (cf. , 1H); 7.4 (s. , 5H); 7.5 (cf. , ZN) and 8.4 (cf. , 1H) ppm.   WITH.  Sulfone 6B- 1 (Euoxy-1- (2-pyridyl) methyl 1 -penicillanic acid.  To a suspension of 120 mg of pre-reduced 5% palladium-n calcium carbonate in 20 ml of a mixture of methanol and water (1: 1) was added 120 mg of benzyl sulphone benzyl-bB-1 (P) oxy-1- (2 pyridyl) - methyl penicillanate, the mixture is shaken in a hydrogen atmosphere at an initial pressure of 47 psi (3.3 kg / cm) for 30 minutes.  An additional 120 mg of catalyst is then added and hydration is continued for 45 minutes at 47 psi (3.3 kg / cm).  The catalyst is filtered off, washed with a mixture of methanol water and washing, and the filtrate is combined.  The methanol is removed in vacuo, the aqueous residue is extracted with ethyl acetate.  The aqueous layer is freeze dried, resulting in 90 mg of the desired product as a calcium salt.  In the NMR spectrum (DjO) of the calcium salt, absorption is observed at 1.50 (c. , ZN)); 1.65 (with ,, a); 4.35 (s. , 1H); 4.70 (cf. , 1H); 5.18 (d. , 1H, Hz); 5.65 (d. , 1H, Hz); 7.7 (cf. , ZN) and 8.6 (wide d. , 1H) ppm.  with.  Sulfone (3) hydroxy-1- (2 pyridyl) methyl penicillanic acid.  In Example 9C, starting from 240 mg of benzyl6B-1 (3) -oxy-1- (2-pyridyl) methyl penicillanate and 480 mg of palladium on calcium carbonate, 20. mp methanol water get 170 mg of the calcium salt of the target product.  Example 10 Sulfone bV-acetoxymethylpenicillanic acid.  BUT.  Benzyl sulfide bV-acetoxymethylpenicillanic acid.  To a solution of 500 mg of benzyl bV-hydroxymethyl penicillanate sulfone and 0.196 ml of triethylamine in 20 ml of methylene chloride cooled to 0.1 ml of acetyl chloride and 10 mg of 4-dimethylaminopyridine are added.  After stirring for 20 minutes, the solvent is removed. vacuum, ethyl acetate is added to the residue.  The resulting solid is filtered, the filtrate is washed successively with water, water at pH 1.0, all of sodium bicarbonate and brine.  The organic phase is dried over magnesium sulphate and the solvent is removed in vacuo to yield 600 mg of product, which is in the form of an oil.  In the NMR spectrum (CDCl1), an absorption is observed at 1.30 (c. , ZN)); 1.59 (s. , 3); 2.1 (s. , ZN)); 4.2 (cf, 1H); 4.5 (s. , 1H); 4.6 (cf. , 2H); 3.65 (d. , 1H); 5, 22 (ABq, 2H, Hz) and 7.4 (s. , 5H) ppm.  311 c.  BV-acetoxymethylphenicillanic acid sulfone.  To a suspension of 600 mg of 5% palladium-on calcium carbonate, previously reduced in 20 ml of a mixture of water and hydrogen to 50 psi (3.5 kg / cm) within 20 minutes, is added.  600 mg of benzyl bB-acetoxymethylpenicillanic acid sulfone.  The resulting mixture was shaken in a hydrogen atmosphere at initial davdentsi 50 psi (3.5 kg / cm) for 45 minutes.  At the same time, the catalyst is filtered off and washed with a methanol-water mixture.  The filtrate and the washings are combined and freeze dried, resulting in 360 mg of the desired product as a calcium salt.  In the spectrum of NMR () calcium; salts see absorption at 1.5 (c. , ZN)); 1.61 (s. , ZN)); 2.18 (s. , ZN)); 4.25 (s. , 1H); 4.3 (cf. , 1H); 4.60 (cf. , 2H) and 5.07 (d. , 1H, Hz) pp.  Example 11  Sulfone bB-steroyloxymethylpenicillanic acid.  A. Sulfon benzyl bB-stearoylox methylpenicillanate.  Starting from 500 m of benzyl sulfate bV-hydroxymethyl penicyl lanate 430 mg of stearoyl chloride, 0.196 ml of triethyl mine and 10 mg of 4-dimethylaminopyridine, according to Example JA, 784 mg of the expected product are obtained in the form of an oil.  In the NMR spectrum (CDCl), absorption is observed at 1.4 (cf. , ZN)); 2.4 (cf. , 2H); 4.2 (cf. , 1H); 4.52 (s. , 1H); 4.60 (cf. , 2H); 4.63 (d. , 1H, Hz); 5.22 (ABq, 2H, Hz) and 7.4 (s. , 5H) ppm.  B. Sulphone bB-stearyloxymethylpenicillanic acid.  In Example 10B, starting from 776 mg of benzyl bB-stearoyloxymethylpenicillan sulfate and 880 mg of 5% palladium-on calcium carbonate in 25 ml of methanol-water (1: 1), 524 mg of the calcium salt of the desired product are obtained.  The calcium salt is sequentially suspended in 200 ml of ethyl acetate and 200 ml of water and treated with a sufficient amount of 6N.  hydrochloric acid to reach pH 2.0.  The ethyl acetate layer is separated, backwashed with brine, and dried over magnesium sulfate.  After removing the solvent, 732 260 mg of the desired product are obtained in the form of a white solid.  In the NMR spectrum (CDCl and DMSO-De), absorption is observed at 1.4 (cf. , ZN)); 2.35 (cf. , 2I); 4.2- (cf. , 1H); 4.39 (s. , 1H); 4.60 (cf. , 2H) and 4.63 (d. , 1H, Hz) pp.  Example 12  BV-benzoyloxymethylpenicillanic acid sulfone.  BUT.  Benzyl benzoyloxymethylpenicillanic acid sulfone.  To a solution of 300 mg of benzyl bB-hydroxymethyl-penicillanate sulfone and 0.11 ml of triethylamine in 25 ml of methylene chloride cooled to, 0.094 ml of benzoyl chloride and 10 mg of 4-dimethylaminopyridine are added.  After stirring in the cold for 30 minutes, the solution is washed successively with water, water at pH 1.0, with an sodium bicarbonate solution and brine.  The organic phase is dried over magnesium sulphate and the solvent is removed in vacuo.  The residue is chromatographed on 20 g of silica gel using toluene-ethyl acetate (8: 1) as eluent, fractions 15-30 are combined and concentrated in vacuo to give 280 mg of product as an oil; In the NMR spectrum (CDCl1), an absorption is observed at 1.26 (c. , ZN)); 1.53 (s. , ZN)); 4.2 (cf. , 1H); 4.57 (s. , 1H); 4.79 (d. , 1H, Hz); 4.9 (cf. , 2H); 5.2 (ABq, 2H, Hz); 7.4 (s. , 5H); 7.5 (cf. , ZN) and 8.2 (cf. , 2H) ppm.  AT.  Sulfone 6B-benzosh1OXimethylpenicillanic acid.  270 ml of benzyl-bB-benzoyloxymethyl-penicillanic acid sulfone are added to a suspension of 270 mg of pre-reduced 5% palladium-calcium carbonate in 15 ml of water-methanol (1: 1), and the mixture is shaken in a hydrogen atmosphere at an initial pressure of 50 Psi (3.5 kg / cm) for 40 minutes.  The catalyst is filtered off and the methanol is evaporated.  The remaining aqueous layer is extracted with ethyl acetate, then freeze-dried, to give the calcium salt of the product, 200 mg.  In the x; NMR spectrum (Dj O) of the calcium salt, absorption is observed at 1.5 (c. 3H) J 1.6 (s. , ZN)); 4.8 (cf. , ZN)); 5.1 (d , 1H, Hz); 7.6 (cf. , ЗН) Iи 8,0 (cf. , 2H) ppm.  For example 13.  Sulphone 6B-4 aminobenzoyloxymethylpenicillanic acid.  A. Sulfon benzyl-bB-4 -nitroben zoyloxymethylpenicillanate.  Under an argon atmosphere, 264 mg of 4-nitrobenzoyl chloride and 10 mg of 4-dimethylaminopyrid are added to 500 mg of benzyl bB-hydroxymethylpenylnenate sulfone and 0.196 ml of triethylamine in 20 ml of methylene chloride cooled to.  After stirring in the cold for 30 minutes, the reaction mixture was washed successively with water, water at pH 1.0, saturated sodium bicarbonate solution and brine.  The organic phase is dried over magnesium sulphate and the solvent is removed in vacuo, to give 657 mg of the product as a semi-solid blend.  In the NMR spectrum (CDClj), the attendance of 1.33 is observed (s. . , ZN)); 1.58 (s. , ZN)); 4.3 (cf. , 1H); 4.58 (s ,, 1H 4.8 (d , 1H, Hz); 4.9 (cf. , 2H) 5.23 (ABq, 2H, Hz); 7.39 (s. , 5H) and 8.2 (s. , 4I) rrga.  B. Sulphone bB-4-aminobenzoylog with methylpenicillanic acid.  To a suspension of 650 mg of pre-reduced 5% palladium on calcium carbonate in 20 ml of a mixture of water and methanol (1: 1) and 10 ml of tetrahydrofuran were added 650 mg of benzyl bV-4-nitrobenzoyl oxymethylpenicillanic acid, the mixture was shaken in an atmosphere hydrogen at an initial pressure of 50 psi (3.5 kg / cmO for 1 h.  The spent catalyst is filtered off and the residue is distributed between ethyl acetate and water.  The aqueous layer was isolated and freeze dried, resulting in 560 mg of product in the form of a calcium salt.  In the NMR spectrum (DjO) of the calcium salt, absorption is observed at 1.5 (c. , ZN)); 1.6 (s. , ZN)); 4.39 (s. , 1H); 4.70 (cp. , 3iO; 5.1 (d , 1H, Hz); 6.78 (d , 2H, Hz) and 7.8 (d. , 2H, Hz) ppm.  PREMIER 14.  Sulfone 6B-4 tolylsulfonyloxymethylpenicillan acid.  BUT.  Benzyl bV-4-tolylsulfonyl simetilpenitsillanat.  To 1.24 g of 4-tolylsulfonyl chloride in 3.5 ml of pyridine, cooled to 0 ° C under atmosphere 7, argon is added dropwise.  800 mg of benzyl bV-hydroxymethyl penicillanate in 1.5 ml of pyridine.  After stirring in the cold for 2 hours, 0.80 ul of water is added and stirring is continued for 30 minutes at 0 ° C.  The reaction mixture is added to 30 ml of water and the pH is adjusted to 1.0 with dilute hydrochloric acid.  The aqueous layer is extracted with diethyl ether, the organic phase is extracted and washed successively with 1.2N.  hydrochloric acid, water and brine.  The organic layer is dried over magnesium sulfate and evaporated to an oil (841 mg), which. e are chromatographed on 100 g of silica gel using chloroform-ethyl acetate (10: 1) as an eluant; fractions 10-25 are combined and the solvent is removed in vacuo to give 680 mg of product, B. bB-4-tolylsulfonyloxymethylpenicillanic acid.  To a suspension of 680 mg of pre-reduced 5% palladium-on calcium carbonate in 20 ml of methanol-water (1: 1) was added 680 mg of benzyl-6B-4tolylsulfonyloxymethylpenicillanate, the reduction was continued at 49 psi (3.45 kg / cm) within 30 min.  An additional 680 mg of catalyst is then added and the reaction is continued for another 30 minutes.  The catalyst is filtered off and the methanol is evaporated from the filtrate.  The aqueous residue is extracted with ethyl acetate, and the aqueous layer is acidified to pH 2.0.  Fresh ethyl acetate was used to extract the acidified aqueous phase.  The organic phase is separated, dried over magnesium sulphate and the solvent is removed in vacuo to give 463 mg of product as a semi-solid.  In the NMR spectrum (CDCl,), an absorption is observed at 1.57 (c. , ZN)); 1.6 (s. , ZN)); 2.37 (s. , ZN)); 4.1 (cf. , ZN)); 4.2 (s. , 1H); 5.4 (d. , 1H, Hz) and 7.6 (ABq, 4H, Hz) ppm.  C. Sulphone 6B-4-tolylsulfonyloxymethylpenicillanic acid.  20 ml of water are added to 460 mg of bB-4 tolylsulfonyloxymethylpenicillanic acid in 20 ml of methylene chloride and the pH of the resulting mixture is adjusted with sodium hydroxide solution 6.9.  The aqueous layer was separated, and the organic layer was further extracted with water (2x20 ml), 238 mg of potassium permanganate in 5 ml of water containing 0.16 ml of phosphoric acid was added dropwise to the combined aqueous layer and the washings.  During the reaction time (45 min), the pH of the reaction mixture is maintained at 6.0-6.4 by adding aqueous hydroxide.  The pH of the reaction mixture is then adjusted to 1.5 & n.  hydrochloric acid and 20 ml of ethyl acetate are added.  After cooling the mixture to OC, 460 mg of sodium bisulfite is immediately added.  pH is set to 1.5 to 6 n.  hydrochloric acid, the organic phase is filtered off, washed with a reverse jet of brine, and dried over magnesium sulfate.  After removal of the solvent, 300 mg of product is obtained as a foam.  In the NMR spectrum (CDCl), an absorption is observed at 1.45 (c. , ZN)); 1.65 (s. , ZN)); 2.45 (s. , ZN)); 4.4 (cf. , ZN)); 4.42 (C. , 1H); 4.8 (d. , 1H, Hz) and 7.6 (ABq, 4H,. Hz) rrt Example 15.  bB-methylsulfonyloxymethyl penicillanic acid.  A. Benzyl 6B-metshlsulfonyloxymethylpenicillanate.  To the cooled solution (-10 ° C). 800 mg of benzyl 6-oxymethyl penicillanate and 0.55 nl of triethylamine in 19 ml of methylene chloride were added 194 mg of methylene sulfyl chloride.  After stirring for 1 h, the reaction mixture was washed successively with water, water at pH 1.0, saturated sodium bicarbonate solution and brine.  The organic phases are dried over magnesium sulphate and evaporated to dryness, in the result 650 mg of the desired product are obtained.  B. bB-methylsulfonyloxymethyl penicillanic acid.  To a suspension of 300 kg of 5% palladium on calcium carbonate, previously reduced by hydrogen at a pressure of 47 p (3.3 kg / cmO for 15 minutes). , in 20 methanol-water mixtures (1: 1), 300 mg of benzyl bV-methylsulfonyloxy methylpenicillanate is added, the reduction is continued for 30 minutes at 47 psi (3.3 kg / cm).  An additional 300 mg of catalyst is then added and the reduction is continued for another 30 minutes.  The spent catalyst is filtered off and the methanol is removed from the filtrate in vacuo.  The aqueous residue 2736 current is extracted with ethyl acetate, the pH of the iodine layer is set to 2.0 with 6 n.  hydrochloric acid.  The acidified water layer is extracted with a fresh portion of ethyl acetate, the organic layer is separated and washed with a backwash of saturated brine.  The organic layer is dried over magnesium sulfate and evaporated, the result is 269 mg of the desired product as an oil.  In the NMR spectrum (CDCl,), an absorption is observed at 1.56 (c. , ZN)); 1.68 (s. , ZN)); 3.06 (s. , ZN); 4.1 (cf. , 1H); 4.41 (s. , 1H); 4.52 (cf. , 2H); 5.47 (d. , 1H,) and 8.3 (s. , 1H) ppm.  Example 16  (8) hydroxy-3phenylpropyl penicillanic acid.  To a suspension of 244 mg of 5% palladium calcium carbonate, previously reduced by hydrogen at 50 psi (3.5 kg / cm) for 20 minutes, 244 mg of benzyl (S o-3-phenyl-propyl-J penicillanate (Example 11B), the mixture is shaken in a hydrogen atmosphere at an initial pressure of 52 psi (3.66 kg / cm) for 1 hour.  at this time, an additional 244 mg of catalyst is added, and the hydrogenation is continued for 1 hour.  Then 244 mg of catalyst is added again and the reduction is continued for another 1 hour.  The catalyst is filtered off and methane is removed in vacuo.  The aqueous residue is extracted with ethyl acetate and then acidified to pH 1.8 with 6N.  hydrochloric acid.  The acidified aqueous layer is extracted with fresh ethyl acetate, the organic phase is separated, backwashed with saline and recharged over magnesium sulfate.  After removal of the solvent, it is reduced. 127 mg of the desired product is obtained under pressure. square  135-137.5 pp.  In the NMR spectrum (CDClI, DMSO-D), the absorption is observed at 1.57 (c. , ZN)); 1.59 (s. , ZN)); 1.8 (cf. , 2H); (cf. , 2H); 3.6 (d. d. , 4 Hz), 4.0 (cf. , 1H); 4.13 (s. , 1H); 5.4 (d. , 1H, Hz) and 7.2 (s. , 5H) ppm.  Example 17  (K) hydroxy-3phenylpropyl penicillanic acid.  To a suspension of 369 mg of 3% palladium calcium carbonate, previously reduced by hydrogen, pp
    52 psi (3.66 kg / cm) over 20 minutes, 369 mg of benzyl-6B-1 (R hydroxy-3-phenylpropyl peiicillanate (Example P) are added to 20 ml of methanol-water (1: 1); the mixture is shaken under a hydrogen atmosphere at a pressure of 52 psi (3.66 kg / cm) for 1 hour. A portion of the catalyst is added at 570 mg every hour, followed by the pressure of 52 psi (3.66 kg / cm). After an hour after the last addition of the catalyst, it is filtered off, the methanol is removed from the filtrate. The aqueous residue is extracted with ethyl acetate and then
    acidified to pH 1.5 6N. hydrochloric acid. Fresh ethyl acetate is added to the acidified aqueous phase, the organic layer is extracted, washed with brine and dried over magnesium sulfate. After removal of the solvent in vacuo, 110 mg of the expected product is obtained with a mp. 131-135p.
    In the NMR spectrum (CDCl ,, DMSO-Efe, absorption is observed at 1.53 (s., 3N); 1.65 (s., 3N); 1.8 (cf. 2H) j 2.8 (cf., 2H); 3.5 (dd.d., 4 Hz) 4.1 (cf., 1H), 4.3 (s., 1H); 5.3 (d., 1H, Hz) and 7, 3 (s., 5H) ppm
    Table
    HOCH, j-
    Penicillin G
    CgllyCOjCHj-
    Ampicillin
    4-HjNC H COjCH2 ti CH3 (CH2), COjCHjCHjCDjCHj0-CHi l
    .sn1)

    2 (E cloacae 67B009)
    11.4 52.0 77.0 28.2
    65.6
    2 2 51.3
    15.9
    100
    HO
    Ampicillin
    -
    Penicillin G Rep G (33 | cM)
    "" U)
    99.A
    BUT

    34.0 t
    (}
    SvN5- CH
    100
    but
    BH5-.CH2
    100
    but
    IR)
    CgH5 CH97 .8
    but
    but
    100
    v
    but

    97.6 but
    CeH. ,, s)
    h
     mypicillin
    SbNz-ČSN CgHg
    CgHgN .CH35 .2
    but
    BUT
    but
    14.1
    but
    (3)
    sn11 .2
    (to)
    68
    but
    |
    HOCHj-
    Ampicillin
    Penicillin G
    HOCHj-
    HOCHj-
    Ampicillin
    nineteen
    2 20
    2 (Kleb. Ph. 53A079)
    81.2 100 100
    2 (Pseud, aer. 52A104)
    21.7 93.4 98.8
    2 (E. coli 51A129)
    92.1 95.7 100 100
     Antibiotic concentration 33 µM
     Inhibitor Concentration 1.0j 16.5; 66 µM Inhibitor concentration hereafter 66 µM Inhibitor concentration 16.5 µM Inhibitor concentration 67; 1.0; 16.5; 66 μM
    Microorganism
    Staphylococcus aureus 01A400
    Citrobacter diverus 70C031
    Escherichia cell 51A129
    Pseudomonas aerupinosa 52A104
    Klebsiella pneuropniae
     MIC is the minimal inhibitory concentration
    H og
     CP-50,575 Z.
    NOSH, SOGN
    about
    table 2
    CP-50 activity in vitro, MIC
    CP-50,575
    CP-50,575 +
    Ampicillin Ampicillin
    200
    25
    3.12
    200
    200
    25
    200
    12.5
    50
    100
    200
    200
    GSNs
    Agent
    CP-50,575 activity in vivo Staph.
    aureus 01А400, PD,
    , 0
    MG / KG, with the introduction of
    peroralpsky but
    n
    wear
    100
    100
    CP-50,575
    Ampicillin
    CP-50,575 + ampicillin
    (1: 1)
     PDcQ - dose, protect and 50% of test animals
    100 96
    MOP 17.1
    权利要求:
    Claims (1)
    [1]
    The method of obtaining derivatives
    6B-hydroxyalkylpenicillanic acid of the formula 'C00H ’where Y is 1-hydroxy-3-phenylpropyl, tolylsulfonyloxymethyl or a radical of the formula'
    0-ri
    R 2 -CH where R t is a hydrogen atom, C 2 ~ C 18 a ^ "canoyl, benzoyl or aminobenzoyl;
    R 2 is a hydrogen atom, C ^ -C ^ -alkyl, phenyl or benzyl, or their pharmaceutically acceptable distinguishing compounds of the formula of basic salts, with the fact that in
    SNZ SNZ
    COOCH g C 6 H5 where Y has the indicated meanings, the benzyl group is removed by hydrogenation in the presence of a palladium catalyst in a reaction-inert solvent and the target product is isolated in the form of a free acid or its pharmaceutically acceptable base salt.
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    PL227420A1|1982-08-30|
    HU183236B|1984-04-28|
    RO81225B|1983-02-28|
    PT71946B|1981-08-31|
    DK389480A|1981-04-23|
    GB2129421A|1984-05-16|
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    YU42075B|1988-04-30|
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    PH16219A|1983-08-09|
    BG38639A3|1986-01-15|
    RO86176B|1985-03-31|
    IN154918B|1984-12-22|
    CS219291B2|1983-03-25|
    NO803136L|1981-04-23|
    PL129638B1|1984-05-31|
    MX6094E|1984-11-12|
    JPS6135197B2|1986-08-12|
    KR830004309A|1983-07-09|
    BG35189A3|1984-02-15|
    AR227164A1|1982-09-30|
    IL61307A|1984-03-30|
    NO159019B|1988-08-15|
    BE885812A|1981-04-21|
    CS219292B2|1983-03-25|
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    NO159019C|1988-11-23|
    GB8316830D0|1983-07-27|
    GR70714B|1983-01-18|
    PL235907A1|1982-09-13|
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    CA1144159A|1983-04-05|
    IT1149259B|1986-12-03|
    FR2467852A1|1981-04-30|
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    SU1026654A3|1983-06-30|
    RO86176A|1985-03-15|
    FI71156B|1986-08-14|
    GB2061930A|1981-05-20|
    NL183358C|1988-10-03|
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    DE3039504A1|1981-04-30|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/086,864|US4287181A|1979-10-22|1979-10-22|Derivatives of 6β-hydroxyalkylpenicillanic acids as β-lactamase inhibitors|
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