6-AMINOALKYLPENICILLANIC ACID 1,1-DIOXIDES AND DERIVATIVES AS BETA-LACTAMASE INHIBITORS

Abstract: beta-Lactamase inhibitors which are 6-alpha- and 6-beta-­ (aminomethyl) and (1-aminoethyl)pencillanic acid 1,1-dioxides, said aminomethyl compounds optionally substituted on amino nitrogen with benzyl, hydroxybenzyl, picolyl or phenethyl; phar­ maceutically-acceptable salts thereof; conventional esters thereof hydrolyzable in vivo; bis-methanediol esters thereof; or mixed methanediol esters with said beta-lactamase inhibitors and sulbactam. Pharmaceutical compositions thereof in combi­ nation with a conventional beta-lactam antibiotic, used in the treatment of bacterial infections; compounds useful as intermedi­ ates in the synthesis of said beta-lactamase inhibitors. Antibacte­ rial bis-methanediol esters of said beta-lactamase inhibitors and ampicillin or amoxicillin, also used in the treatment of bacterial infections; and intermediates therefor.

Description: 6-AMINOAbKYLPENICILL,ANIC ACID 1,1-DIOXIDES AND DERIVATIVES AS BETA-LACTAMASE INHIBITORS The present invention relates to 6-alpha- and 6 beta-(aminomethyl and l-aminoethyl)penicillanic acid l,l-dioxides, said aminomethyl compounds optionally substituted on amino nitrogen with benzyl, hydroxybenzyl, picolyl or phenethyl, pharmaceutically-accept- able salts thereof and conventional esters thereof which are hydrolyzable in vivo; bis-methanediol esters thereof; or mixed methanediol esters with said betalactamase inhibitors and sulbactam (penicillanic acid l,l-dioxide), said methanediol esters also hydrolyzable in vivo. While some of these compounds possess antibacterial activity per se, their principal value is as beta-lactamase inhibitors. Thus they are useful in combination with conventional beta-lactam antibiotics (penicillins and cephalosporins) against microorganisms resistant or partially resistant to beta-lactam antibiotics through production of beta-lactamase enzymes. Also encompassed by the present invention are pharmaceutical compositions comprising a present beta-lactamase inhibiting compound and a known betalactam antibiotic; bis-methanediol esters of the present beta-lactamase inhibiting compounds with either ampicillin or amoxicillin; pharmaceutical compositions of said bis-esters; methods of treating bacterial infections with either of the above pharmaceutical compositions; and compounds useful as intermediates in the preparation of these compounds. Related compounds, viz, penicillanic acid 1,1dioxide and esters thereof readily hydrolyzable in vivo (Barth, U.S. Patent 4,234,579); the bis-methanediol ester of sulbactam (Bigham, U.S. Patent 4,309,347); various 6-beta- (hydroxymethyl ) penicillanic acid 1,1dioxides and esters thereof (Kellogg, U.S. Patent 4,287,181); and 6-beta-(aminomethyl)penicillanic acid (McCombie, U.S Patent 4,237,051) have been previously described as beta-lactamase inhibitors useful in combination with beta-lactam antibiotics for the treatment of bacterial infections. Antibacterial bisesters of methanediol with penicillins and penicillanic acid l,l-dioxide (Bigham, U.S. Patent 4,244,951; Godtfredsen et al., U.S. Patent 4,342,772) have also been described. U.K. Patent Application 2,053,220, published February 4, 1981, broadly discloses beta-lactamase inhibiting compounds of the formula EMI2.1 The definitions of R , Rb and Rc define literally an infinite number of compounds. These definitions, by appropriate selection of Ra, Rb and Rc, may possibly define the simple 6-alpha and 6-beta-(aminoalkyl)penicillanic acid l,l-dioxides of the present invention. No specific method for preparation of these compounds is present in the disclosure of this U.K. application, and there is no hint or suggestion that from among the infinity of compounds proposed, the present aminomethyl and l-aminoethyl compounds are preferred compounds, possessing the particularly highly potent beta-lactamase inhibitory activity which we have determined for them. The present invention relates to compounds of the formulae EMI3.1 and EMI3.2 wherein in a first alternative: R is hydrogen; n is 1; Q is benzyl, o-, m- or -p-hydroxybenzyl, phenethyl, or 2-, 3- or 4-picolyl; and R1 is hydrogen, or a radical group forming an ester which is hydrolyzable under physiological conditions; in a second alternative: Q is hydrogen R is hydrogen or methyl; and n is 1 and R1 is hydrogen, a a radical group forming an ester hydrolyzable under physiological conditions, or 1,l-dioxopenicillanoyloxymethyl; or n is 2 and R1 is -CU2-; the pharmaceutically-acceptable acid addition salts thereof; and the pharmaceutically-acceptable cationic salts thereof when R1 is hydrogen. It will be understood by those skilled in the art that when R is methyl, each of the formulae (I) and (II) represent two different diastereoisomers (epimers). Depending on absolute stereochemistry, the side chains of these epimeric pairs are designated lR-aminoethyl and lS-aminoethyl. In each case one epimer has side chain configuration R and the other S. The same is true with respect to the formulae (III) and (IV), (V) and (VI), and (VII) and (VIII) below. These isomer pairs are generally separable by column chromatography at a variety of stages in the overall processes which are detailed below. Pharmaceutically-acceptable acid addition salts include, but are not limited to, those with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, citric acid, maleic acid, succinic acid, benzenesulfonic acid, p-toluenesulfonic acid,. 2-naphthalenesulfonic acid and methanesulfonic acid. Pharmaceuticallyacceptable cationic salts include, but are not limited to, those of sodium, potassium, calcium, N,N'-dibenzylethylenediamine, N-methylglucamine (meglumine) and diethanolamine. The reference to esters which are hydrolyzable under physiological conditions refers to those esters frequently referred to as "pro-drugs". Such esters are now as well-known and common in the penicillin art as pharmaceutically-acceptable salts. Such esters are generally used to enhance oral absorption, but in any event are readily hydrolyzed in vivo to the parent acid. Preferred esters show no tendency to hydrogenolyze under the conditions preferably employed for their preparation (see below). The more preferred ester forming radicals are: gamma-butyrolacton-4-yl, -CHR2OCOR3, and -CHR2OCOOR3, wherein R2 is hydrogen or methyl and R3 is (Cl-C6)alkyl. The most preferred radicals are pivaloyloxymethyl and I-ethoxycarbonyloxyethyl. When n is 1 and R1 is l,l-dioxopenicillanoyloxymethyl, EMI5.1 the compounds of the formulae (I) and (II) are diesters of methanediol. Such esters are also hydrolyzable under physiological conditions, yielding the parent acid of the formula (I) or (II), wherein n is 1 and R1 is H, and penicillanic acid l,l-dioxide. The latter compound also possesses beta-lactamase inhibitory activity. When n is 2 and R1 is -CH2-, the bis-ester is likewise hydrolyzed under physiological conditions, now producing two molecules of the parent acid from each molecule of the bis-ester. Both the 6-beta-compounds (I) and the 6-alphacompounds (II), regardless of side chain stereochemistry when R is methyl, are potent beta-lactamase inhibitors. For oral use, it is preferred that R1 is other than hydrogen. When R1 is a radical group forming an ester hydrolyzed in vivo, the preferred radicals are defined above. Because it is readily prepared in a highly pure, crystalline state (directly useful in mammals as a pharmaceutically-acceptable salt) pivaloyloxymethyl 6-alpha- (aminomethyl )penicillanate l,l-dioxide toluenesulfonate salt is a particularly valuable compound in this series. Also readily prepared and of special value for oral use are the 6-alpha(aminomethyl) derivatives (II) wherein n is 1 and R1 is l,l-dioxopenicillanoyloxymethyl or n is 2 and R1 is -CH2-. Both the 6-beta-compounds (I) and the 6-alphacompounds (II), regardless of side chain stereochemistry when R is methyl, are potent beta-lactamase inhibitors. The compounds of the formulae (I) and (II) are useful as inhibitors of beta-lactamase enzymes. By this mechanism, these compounds enhance the activity of beta-lactam antibiotics (penicillins and cephalosporins), particularly against those microorganisms which are resistant or partially resistant to the beta-lactam antibiotic through the production of enzymes (beta-lactamases) which would otherwise destroy or partially destroy the beta-lactam antibiotic. In this manner, the spectrum of activity of the beta-lactam antibiotic is increased. The beta-lactam antibiotics are one of the most well-known and widely-used class of antibacterial agents. These compounds are characterized by a nucleus consisting of a 2-azetidinone (beta-lactam) ring fused to either a thiazolidine or a dihydro-1,3thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are usually referred to generically as penicillins, whereas when the nucleus contains a dihydrothiazine ring, the compounds are referred to as cephalosporins. While the present compounds are effective in enhancing the activity of beta-lactam antibiotics in general, their preferred use is found in their combination with a penicillin or cephalosporin of established clinical utility, viz., amoxicillin, ampicillin, azlocillin, bacampicillin, carbenicillin, carbenicillin indanyl, carbenicillin phenyl, cefaclor, cefadroxil, cefaloram, cefamandole, cefamandole nafate, cefaparole, cefatrizine, cefazolin, cefonicid, cefmenoxime, cefodizime, cefoperazone, ceforanide, cefotaxime, cefoxitin, cefsulodin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, cephacetrile, cephalexin, cephaloglycin, cephaloridine, cephalothin, cephapirin, cephradine, cyclacillin, penicillin, hetacillin, levopropylcillin, mecillinam, mezlocillin, penicillin G, penicillin V, phenethicillin, piperacillin, pirbenicillin, pivampicillin, sarmoxicillin, sarpicillin, suncillin, talampicillin and ticarcillin, including the pharmaceutically-acceptable salts thereof. The names employed for these beta-lactams are generally USAN, i.e., United States Adopted Names. Preferred combinations are with ampicillin or an ampicillin derivative, with amoxicillin or an amoxicillin derivative or, most particularly, with cefoperazone. Although the compounds of the present invention can be administered separately from the beta-lactam antibiotic, combination dosage forms are preferred. The pharmaceutical composition, whether for oral or parenteral use, comprises in a ratio of 1:3 to 3:1 by weight a beta-lactamase inhibitor of the formula (I) or (II) and a beta-lactam antibiotic, in total amounts sufficient to successfully treat a bacterial infection in a mammal in a single or, more usually, multiple doses. Also encompassed by the present invention are antibacterial compounds having the stereochemical formulae EMI8.1 and EMI8.2 wherein R is hydrogen or methyl, and R4 is EMI8.3 wherein Y is hydrogen, hydroxy, (C2-C7) -alkanoyloxy, (C2-C7)-alkoxyearbonyloxy, benzoyloxy, or benzoyloxy monosubstituted with (Cl-C4)-alkyl, (C1-C4)alkoxy or halo; and the pharmaceutically-acceptable mono- and diacid addition salts thereof, the acids being as described above. These bis-methanediol esters (III) and (IV) are effective as antibacterials through their in vivo hydrolysis to the corresponding beta-lactamase inhibitors of the formulae (I) and (II) and to the corresponding ampicillin, amoxicillin or amoxicillin substituted on phenolic oxygen. It will be further noted that such phenolic esters are also generally hydrolyzed in vivo to produce amoxicillin. The bis-methanediol ester compounds are formulated into pharmaceutical compositions, suitable for either parenteral or oral administration in single or (more usually) multiple dosage for the treatment of bacterial infections in mammals. Preferred compounds of the formulae (III) and (IV) have Y as hydrogen or hydroxy; most preferred compounds have Y as hydrogen. Further encompassed by the present invention are intermediates of the stereochemical formulae EMI9.1 wherein A EMI9.2 or S; and R is hydrogen or methyl; EMI10.1 wherein Y' is benzyloxycarbonyl amino amino azido or trifluoromethanesul fonyloxy; and R is hydrogen or methyl. Those compounds of the present invention of the formulae (I) and (II) are generally prepared from benzyl 6,6-dibromopenicillanate or from benzyl 6 alpha-iodopenicil lanate. A preferred route, particularly for the 6-beta (aminomethyl) series, involves as a first stage conversion of the dibromo compound to an epimeric mixture of mono-Grignard reagents. This is conveniently done by an exchange reaction using essentially one molar equivalent of methyl magnesium bromide in an ether solvent (ether, tetrahydrofuran, dimethoxyethane) at low temperature (-500 to -100 C), conveniently at -780C, the temperature of an acetone-dry ice bath. After a brief reaction time (5-30 minutes) at such reduced temperature, the mono-Grignard reagents are contacted with essentially 0.5 molar equivalents of benzyloxycarboxamidomethyl acetate (usually diluted with the same ether solvent and added to the cold Grignard reagent at such a rate that the low temperature of the reaction is maintained). Reaction time is not critical; 0.5 to 2 hours at -50 to -1000C is usually sufficient to achieve complete reaction. Mixed epimers of the above formulae (VII) and (VIII) wherein Y' is benzyloxycarbonylamino are readily recovered by acetic acid quench, concentration and chromatography. The mixture of epimers can be used directly in the next step, or if desired, separated-by further column chromatography on silica gel. The next step of the sequence is reductive removal of the bromine atom, conveniently accomplished by the action of excess tri-n-butyltin hydride, optionally in the presence of small amounts (less than 0.1 molar equivalents) of a free radical initiator such as 2,21-azobisisobutyronitrile (AIBN). Here and hereinafter, "reaction-inert solvent" is defined as a solvent which does not react with starting materials, reagents, intermediates or products in a manner which significantly reduces the yield of the desired product. Well-suited in the present case are hydrocarbon solvents such as benzene or toluene. Temperature should be elevated (60-1000C), such that reaction occurs in a reasonable time, but not so high as to cause undue thermal degradation. When this step is carried out on the mixed epimer precursors, the 6beta-epimer (V), wherein A is S, is generally recovered by crystallization; if desired the 6-alpha-epiner (VI, A = S) is recovered from the mother liquors by evaporation and chromatography. A second preferred route, particularly for the 6alpha(aminomethyl) series, is to react a cold ether solution of the Grignard reagent from benzyl 6-alpha iodopenicil lanate with a benzyloxycarboxamidomethyl acetate under conditions described above. The resulting mixture of compounds (V) and (VI), wherein A is S, can be separated by column chromatography, but preferably are oxidized to l,l-dioxides and then subjected to C-6 epimerization conditions to yield the clean alpha-epimer (VI, A = SO2) as detailed below. To form the 1-alpha and l-beta oxides of the formulae (V) and (VI), wherein A is S"'O or SO, the above sulfides of the formulae (V) and (VI), wherein A is S, are oxidized with substantially 1 molar equivalent of a peracid, conveniently m-chloroperbenzoic acid, in a reaction-inert solvent such as ethyl acetate at 0 -50 C. When benzyl 6-beta- (benzyloxycarbonylamino- methyl)penicillanate (V, R = H, A = S) is oxidized, the resulting alpha-oxide (V, R = H, A = S-O) is isolated by crystallization, while the beta-oxide (V, R = H, A = S O) is isolated from mother liquors by evaporation. If desired, other standard sulfoxide forming reagents can be used. If desired, benzyl 6-beta-(benzyloxycarbonylaminomethyl)penicillanate l-beta-oxide (V, A = S-O) is rearranged to the corresponding 6-alpha epimer (VI, A = S- O) by contacting the former with an equivalent of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) at 0-500C, conveniently at 250 where reaction is complete in a very short time {3-15 minutes). In like manner a 6beta dioxide (V, A = SO2) is converted to its 6-alpha epimer (VI, A = SO2). Oxidation of the sulfides (V) and (VI), wherein A is S, or further oxidation of the above sulfoxides, with excess peracid (but otherwise under conditions as generally described above for mono-oxide formation) yields the corresponding sulfones (l,l-dioxides) of the formulae (V) and (VI), wherein A is SO2. If desired, other sulfone forming reagents such as KMnO4 can be used. Hydrogenolyis of the resulting benzyl 6-(alpha or beta) (benzyloxycarbonylaminoalkyl )penicillanate 1,1dioxides, (V and VI, A = SO2) produces the corresponding 6-(alpha or beta)(aminomethyl or l-aminoethyl)penicillanic acids (I and II, Q = R1 = H). Hydrogenolysis is carried out by methods well-known in the penicillin art. The substrate, in a reactioninert solvent, is contacted with hydrogen in the presence of a noble metal catalyst, such as palladium, platinum or rhodium, optionally in the form of its oxide or a salt, or on a carrier such as carbon, an alkaline earth carbonate or alumina. Temperature is not critical (e.g. 0-500C), but is preferably 250C or lower in order to minimize thermal degradation. Pressure can be varied over a wide range (subatmospheric to 100 atmospheres), but as a matter of convenience will generally be in the range of 1 to 7 atmospheres. The reaction inert solvent is preferably relatively low boiling so as to be readily removed by concentration in vacuo. Aqueous tetrahydrofuran is a solvent particularly well-suited for the present purpose. The preferred catalyst is palladium, supported on carbon. To prepare an in vivo hydrolyzable ester [i.e., a compound of the formulae (I) or (II), wherein Q is hydrogen and R1 is a radical group forming an ester which is hydrolyzable under physiological conditions], the amino group of the 6-(aminoalkyl)penicillanic acid l,l-dioxide is first protected with a benzyloxycarbonyl group, using methods well-known in the art. For example, benzyl chloroformate is added slowly to the amine in a reaction-inert solvent such as aqueous acetone or aqueous tetrahydrofuran while maintaining pH 8.0 at a temperature of 0-350C, preferably 0-20 C. In this manner, compounds of the formulae (IX) and (X), wherein R1 is H, are formed. Alternatively, such compounds are formed by the partial hydrogenolysis of compounds of the formula (V) and (VI) wherein A is S02. Except to limit hydrogen uptake, conditions as described above are used. EMI14.1 The latter intermediates are then converted to the desired esters of the formulae (IX) and (X), wherein R1 now represents an in vivo hydrolyzable ester, according to known methods, readily identified by those skilled in the penicillin art (see for example U.S, Patents 4,234,579 and 4,287,181; and European patent publication No. 40,494). Preferred ester values of R1 have been defined above; preferred methods for the preparation of such esters are detailed in specific examples below and in European patent publication No. 40,494. The protected esters (IX) and (X) are converted to the desired esters of the formula (I) or (II) wherein Q is hydrogen, retaining R1 as the ester functionality, by hydrogenolysis, preferably in the presence of a weakly acidic buffer comprising equimolar quantities of a weakly basic amine, such as pyridin, and'a strong acid such as a mineral acid (e.g. HCl, UNTO3, H2S04) or preferably a sulfonic acid (such as methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid), otherwise according to methods described above, taking care to minimize exposure to conditions (e.g. water, lower alcohols, high acidity or basicity) which will cause hydrolysis of the sensitive ester or beta-lactam groups. It is preferred to isolate the ester directly from the reaction mixture in the form of the acid addition salt where the acid is the one used in the buffer. A particularly preferred buffer is pyridinium irtoluenesulfonate in which case the product is usually isolated as its ir toluenesulfonate salt. The compounds of the formulae (I) and (II) in the first alternative (i.e., wherein n is 1, R is hydrogen and Q is other than hydrogen) are readily prepared by reductive alkylation of the simple 6-(aminomethyl) compounds of the above formulae (I) and (II) wherein R and Q are both hydrogen, in the presence of an equimolar amount of the corresponding aldehyde, using sodium cyanoborohydride as the reducing agent. One molar equivalent of the aldehyde is fully satisfactory; an excess of sodium cyanoborohydride is generally used, e.g., about two thirds of a mole per mole of substrate. Temperature is not critical and can be in the range 0-500C; conveniently ambient temperature is employed. The above-defined pharmaceutically-acceptabe acid addition salts of the present invention are readily prepared by standard methods. For example, an equivalent of the acid is combined with the free amine form of the compound in an organic or aqueous organic solvent. The salt is isolated by concentration and!or the addition of a non-solvent. In some cases, the salt is isolated directly from a reaction mixture, without isolation of the free amine. The above-defined pharmaceutically-acceptable cationic salts of those compounds of the present invention having a free carboxylic acid group are also readily prepared by standard methods. For example, an equivalent of the corresponding cationic hydroxide, carbonate or bicarbonate or of an amine is combined with the carboxylic acid in an organic or aqueous solvent, preferably at reduced temperature (e.g. 0-50C), with vigorous agitation and slow addition of the base. The salt is isolated by concentration and/or the addition of a non-solvent. In some cases, the salt is isolated directly from a reaction mixture, without isolation of the free acid form. The bis-methanediol esters (III) and (IV), as well as those of the formulae (I) and (II) wherein n is 1 and R1 is 1,l-dioxopenicillanoyloxymethyl or n is 2 and R1 is -CU2-, are also prepared from the amino protected penicillanic acids acids (IX) and (X), wherein R1 is H. In one alternative, the latter compounds are first converted to the corresponding chloromethyl esters. The preferred method is to convert the acid to its tetrabutylammonium salt, which is then reacted with excess chloromethyl iodide at 0-500C, preferably at 250 or less. Although a chloromethyl ester can be used directly in the next step, it is preferred to first convert the chloromethyl ester to the corresponding iodomethyl ester. Contact of the chloromethyl ester with sodium iodide in acetone at 0-50 until reaction is substantially complete represents conditions particularly well-suited to this purpose. The iodomethylester is then reacted, in a reaction inert solvent at 0-500C, with a salt of penicillanic acid 1,l-dioxide; a salt of the same amino protected penicillanic acid (IX) or (X) wherein R1 is H; a salt of azidocillin 16-(D-2-phenyl-2-azidoacetamido)peni- cillanic acid]; or a salt of an ampicillin or amoxicillin derivative of the formula EMI17.1 wherein Y" is H, benzyloxycarbonyloxy, (C2-C7)alkoxycarbonyloxy, benzoyloxy, or benzoyloxy mono-substituted with (C1-C4)alkyl, (Cl-C4)alkoxy or halo (F, C1 or Br). The preferred salt is the tetrabutylammonium salt, since it reacts very rapidly with the iodomethyl ester, minimizing degradation. In a second alternative, the bis-methanediol esters (III} and (IV), as well as the esters of the formula (I) or (II) where n is 1 and R1 is l,l-dioxo- penicillanoyloxymethyl are prepared by reacting the above salt of an amino-protected penicillanic acid (IX) or (X), wherein R1 is H, with a halomethyl ester (preferably and iodomethyl ester) of penicillanic acid l,l-dioxide, of azidocillin, or of an ampicillin or amoxicillin derivative of the formula (XI) above. In either alternative, the resulting protected methanediol diester is then converted to the desired end product of the formula (I), (II) (where n is 1 and R1 is l,l-dioxopenicillanoyloxymethyl or n is 2 and R1 is -CR2-), (III) or (IV) by hydrogenolysis, using methods detailed above; again minimizing exposure to conditions which cleave the sensitive methanediol ester bonds. The pharmaceutically-acceptable mono- or diacid addition salts of these methanediol diesters are prepared using one or two equivalents of the acid, as appropriate, according to methods described above. Another preferred route to the intermediates of the formulae (VII) and (VIII) wherein Y' is benzyloxycarbonylamino, particularly when R is methyl, is to prepare them from the corresponding known benzyl 6alpha-(hydroxymethyl or l-hydroxyethyl)-6-beta-bromo- penicillanate and benzyl 6-beta-(hydroxymethyl or 1 hydroxyethyl )-6-alpha-bromopenicillanate (also prepared from benzyl 6,6-dibromopenicillanate). In the first stage, the above hydroxymethyl or 1hydroxyethyl compounds are converted to the corresponding trifluoromethanesulfonate esters (VII and VIII, Y' = trifluoromethanesulfonyloxy). This reaction is conveniently carried out at room temperature using trifluoromethanesulfonic anhydride as reagent, in a reaction inert solvent such as methylene chloride in the presence of at least one equivalent of a tertamine such as pyridine or diisopropylethylamine. In the second stage the sulfonate group is displaced by azide, forming the azidomethyl compounds of the formulae (VII) and (VIII), wherein Y' is azido. An excellent reagent for this purpose is tetramethyl guanidinium azide in moderate excess. The reaction is carried out at 0-250C, preferably about lO0C, in a reaction-inert solvent such as chloroform or methylene chloride. In the third stage the azido group is reduced to an amino group, yielding compounds of the formulae (VII) and (VIII) wherein Y' is amino. A convenient reagent for this purpose is hydrogen sulfide, in the presence of a tertiary amine such as triethylamine in a reaction-inert solvent such as chloroform. Gaseous hydrogen sulfide is bubbled through the reaction mixture at 0-5O0C until reduction is substantially complete (usually about 3-4 hours at 250). Finally, the amino group is protected with a benzyloxycarbonyl group, using conditions standard in the art. For example benzyl chloroformate as reagent in the presence of a tertiary amine such as pyridine or N,N-diisopropylethyl amine, in a reaction-inert solvent such as methylene chloride at 0-500C, preferably at reduced temperature (O-lO0C). The resulting compounds of the formulae (VII) and (VIII) wherein yg is benzyloxycarbonylamino are then further processed according to methods detailed above. As indicated above, some of the compounds of the formulae (I) and (II), generally those wherein R1 is hydrogen, have in vitro antibacterial activity. Such activity is demonstrated by measuring the minimum inhibitory concentrations (MIC's) in mcg/ml against a variety of microorganisms. The procedure which is followed is the one recommended by the International Collaborative Study on Antibiotic Sensitivity Testing (Ericcson and Sherris, Acta. Pathologica et Microbiologia Scandinav, Supp. 217, Section B: 64-6,8 j19711), and employs brain heart infusion (BHI) agar and the inocula replicating device. Overnight growth tubes are diluted 100 fold for use as the standard inoculum (20,000-10,000 cells in approximately 0.002 ml are placed on the agar surface; 20 ml of BRI agar/dish). Twelve 2 fold dilutions of the test compound are employed, with initial concentration of the test drug being 200 mcg/ml. Single colonies are disregarded when reading plates after 18 hours at 370C. The susceptibility (MIC) of the test organism is accepted as the lowest concentration of compound capable of producing complete inhibition of growth as judged by the naked eye. Those compounds of the formulae (I) and (II) having said in vitro antibacterial activity are thus useful as industrial antimicrobials, for example in water treatment, slime control, paint preservation and wood preservation, as well as for topical application as a disinfectant. In the case of use of these compounds for topical application, it is often convenient to admix the active ingredient with a nontoxic carrier, such as vegetable or mineral oil or an emollient cream. Similarly, it can be dissolved or dispersed in liquid diluents or solvents such as water, alkanols, glycols or mixtures thereof. In most instances it is appropriate to employ concentrations of the active ingredient of from about 0.1 percent to about 10 percent by weight, based on total composition. As also indicated above, the compounds of the formulae (I) and (II) are of more particular value as potent inhibitors of microbial beta-lactamases. By this mechanism they increase the antibacterial effectiveness of beta-lactam antibiotics (penicillins and cephalosporins) against many microorganisms, particularly those which produce a beta-lactamase. The ability of the said compounds of the formula (I) or (II) to increase the effectiveness of a beta-lactam antibiotic can be appreciated by reference to experiments in which the MIC values of the antibiotic alone, and a compound of the formula (I) or (II) (having R1 as hydrogen) alone, are determined. These MIC1s are then compared with the MIC values obtained with a combination of the given antibiotic and the compound of the formula (I) or (II), wherein R1 is hydrogen. When the antibacterial potency of the combination is significantly greater than would have been predicted from the potencies of the individual compounds, this is considered to constitute enhancement of activity. The MIC values of combinations are measured using the method described by Barry and Sabath in "Manual of Clinical Microbiology", edited by tenette, Spaulding and Truant, 2nd Edition, 1974, American Society for Microbiology. The compounds of the formulae (I) and (II) enhance the antibacterial effectiveness of beta-lactam antibiotics in vivo. That is, they lower the amount of the antibiotic which is needed to protect mice against an otherwise lethal inoculum of certain betalactamase producing bacteria. In determining such activity, acute experimental infections are produced in mice by the intraperitoneal inoculation of the mice with a standardized culture of the test organism suspended in 5 percent hog gastric mucin. Infection severity is standardized so that the mice receive a lethal dose of the organism (the lethal dose is the minimum inoculum of organism required to consistently kill 100 percent of the infected, non-treated control mice). The test compound in combination with the antibiotic is administered at various dosage levels, or or i.p i.±., to groups of infected mice. At the end of the test, the activity of the mixture is assessed by counting the number of survivors among treated animals at a given dose. Activity is expressed as the percentage of animals which survive at a given dose, or calculated as a PD50 (dose which protects 50% of the animals from infection). Compounds of the formulae (III) and (IV) are tested for in vivo activity in like manner, except that they are generally dosed alone, not in combination with other beta-lactam antibiotics. In determining whether a particular strain of bacteria is sensitive to a particular compound of the formula (III) or (IV) it is not necessary to carry out an in vivo test. Instead, the MIC of a 1:1 mixture of a compound of the formula (I) or (II), wherein R1 is hydrogen, and ampicillin or amoxicillin, as appropriate, are measured according to methods described above. The ability of the compounds of formulae (I) and (11) to enhance the effectiveness of a beta-lactam antibiotic against beta-lactamase producing bacteria makes them valuable for coadministration with betalactam antibiotics in the treatment of bacterial infections in mammals, particularly man. In the treatment of a bacterial infection, the compound of the formula (I) or (II) can be comingled with the beta-lactam antibiotic, and the two agents thereby administered simultaneously. Alternatively, the compound of the formula (I) or (II) can be administered as a separate agent during a course of treatment with a beta-ladtam antibiotic. In some instances it will be advantageous to pre-dose the subject with the compound of the formula (I) or (II) before initiating treatment with a beta-lactam antibiotic. When using a compound of formula (I) or (11) to enhance the effectiveness of beta-lactam antibiotic, a mixture of (I) or (II) with the beta-lactam antibiotic is administered preferably in formulation with standard pharmaceutical carriers or diluents. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, a beta-lactam antibiotic and a compound of formula (I) or (II) will normally contain from about 5 to about 80 percent of the pharmaceutically acceptable carrier by weight. When using the compounds of formula (I) or (II) in combination with another beta-lactam antibiotic, said compounds can be administered orally or parenterally, i.e. intramuscularly, subcutaneously or intraperitoneally. Although the prescribing physician will ultimately decide the dosage to be used in a human subject, the ratio of the daily dosages of the compounds of formula (I) or (II) and the beta-lactam antibiotic will normally be in the range from about 1:3 to 3:1 by weight. Additionally, when using the compounds of formula (I) or (II) in combination with another beta-lactam antibiotic, the daily oral dosage of each component will normally be in the range from about 10 to about 200 mg per kilogram of body weight and the daily parenteral dosage of each component will normally be about 10 to about 40 mg per kilogram of body weight. These daily doses will usually be divided. In some instances, the prescribing physician will determine that dosages outside these limits are necessary. As will be appreciated by one skilled in the art, some beta-lactam compounds are effective when administered orally or parenterally, while others are effective only when administered by the parenteral route. When a compound of formula (I) or (II) is to be used simultaneously (i.e. comingled) with a betalactam antibiotic which is effective only on parenteral administration, a combination formulation suitable for parenteral use will be required. When a compound of formula (I) or (II) is to be used simultaneously (comingled) with a beta-lactam antibiotic which is effective orally or parenterally, combinations suitable for either oral or parenteral administration can be prepared. Additionally, it is possible to administer preparations of the compounds of formula (I) orally, while at the same time administering a further betalactam antibiotic parenterally; and it is also possible to administer preparations of the compounds of formula (I) parenterally, while at the same time administering the further beta-lactam antibiotic orally. It is the capacity of compounds of the formula (III) or (IV) to hydrolyze and provide both the compounds of the formula (I) or (II), wherein R1 is hydrogen, and ampicillin or amoxicillin, which enhances the activity and broadens the antibacterial spectrum of these compounds relative to the use of an equivalent amount of ampicillin or amoxicillin alone, particularly by the oral route. When using the present antibacterial compounds of the formula (III) or (IV) for control of bacterial infections in a mammal, particularly man, the compound is administered alone, or mixed with pharmaceutically acceptable carriers or diluents. Said carrier or diluent is chosen on the basis of the intended mode of administration. For oral administration, tablets, capsules, lozenges, troches, powders, syrups, elixirs, aqueous solutions and suspensions, and the like are used, in accordance with standard pharmaceutical practice. The proportional ratio of active ingredient to carrier will naturally depend on the chemical nature, solubility and stability of the active ingredient, as well as the dosage contemplated. In the case of tablets for oral use, carriers which are commonly used include lactose, sodium citrate and salts of phosphoric acid. Various disintegrants such as starch, and lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc, are commonly used in tablets. For oral administration in capsule form, useful diluents are lactose and high molecular weight polyethylene glycols, e.g polyethylene glycols having molecular weights of from 2000 to 4000. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying or suspending agents. If desired, certain sweetening and/or flavoring agents can be added. For parenteral administration, which includes intramuscular, intraperitoneal, subcutaneous, and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. When using compounds of the formula (III) or (IV) to control bacterial infections, the daily dosage will be similar to that of other clinically used betalactam antibiotics. Although the prescribing physician will ultimately decide the dosage to be used in a human subject, the compounds of formula (III) or IV) will normally be used orally at dosages in the range from about 20 to about 100 mg per kilogram of body weight per day, and parenterally at dosages from about 10 to about 100 mg per kilogram of body weight per day, usually in divided doses. in some instances, the prescribing physician will determine that dosages outside these limits are needed. The present invention is illustrated by the following examples. However, it should be understood that the invention is not limited to the specific details of these examples. Unless otherwise specified, proton nuclear magnetic resonance spectra are 60 MHz. EXAMPLE 1 Benzyl 6-alpha-bromo-6-beta-(benzyloxy carbonylaminomethyl ) penicillanate and 6-beta-bromo-6-alpha-(benzyloxycarbonyl aminomethyl) penicillanate To a solution of benzyl 6,6-dibromopenicillanate (108.73 g, 0.242 mole) in 600 ml dry tetrahydrofuran (THF), cooled to -780C, was added an ether solution of methyl magnesium bromide (83.5 ml of 2.9N). After stirring for 15 minutes at -780 a solution of benzyloxycarboxamidomethyl acetate (27 g, 0.121 mole) in 200 ml dry THF was added over 10 minutes. After stirring for an hour at -780 the reaction was quenched by the addition of 14.52 ml of acetic acid. The mixture was warmed to room temperature and volatiles removed in vacuo at less than 350C. Ethyl acetate was added to dissolve the residue, and the solution washed with water (100 ml), aqueous NaHCO3 (100 ml), and 2 x 100 ml water, then dried over Na2SO4 and concentrated in vacuo to 113 g of oily product. The oil was column chromatographed on 1.2 kg silica gel, eluting first with 6 liters of 1:1 hexane:chloroform and then with chloroform. The first 6 liters of eluate was discarded. Further eluate was collected in 25 ml fractions Fraction numbers 181-190 were concentrated. The pnmr spectrum of the residue in CDCl3 revealed benzyl 6-alpha-bromo-6-beta- (benzyloxy- carbonylaminomethyl)penicillanate: delta/TMS 1.37 (3H, s), 1.57 (3H, s), 3.86 (2H, d, J = 6Hz), 4.42 (lH, s), 5.06 (2H, s), 5.12 (2H, s), 5.52 (lH, s), 7.25 (lOH, s). Fraction numbers 201-249 were concentrated and the pnmr spectrum of this residue in CDCl3 revealed benzyl 6 -beta-bromo-6-alpha- (benzyloxy- carbonylaminomethyl)penicillanate: delta/TMS 1.36 (3H, s), 1.60 (3H, s), 3.90 (2H, d, J = 6.2Hz), 4.47 (1H, s), 5.07 (2H, s), 5.14 (2H, s), 5.40 (1H, t, J = 6.2), 5.47 (1H, s), 7.28 (5H, s), 7.30 (5H, s). The product from fraction numbers 171-240 was combined and concentrated to 22 g of foam and used in the experiment of Example 2. EXAMPLE 2 Benzyl 6-beta- (Benzyl oxycarbonyl - 'aminomethyl ) penicil 1 anate To a solution of title products (epimeric mixture) of the preceding Example (22 g, 0.0413 mole) in 100 ml benzene was added tri-n-butyltin hydride (32.7 ml, 0.124 mole). The mixture was refluxed under N2 for 2 hours, concentrated in vacuo to an oil and the oil triturated 4 x 100 ml hexane. The residual viscous oil was taken up in 70 ml of ether, from which title product crystallized over 1 hour [8.1 g in two crops] pnmr/CDCl3/delta/TMS: 1.37 (3H, s), 1.57 (3H, s), 3.58 (3H, m), 4.34 (1H, s), 5.04 (2H, s), 5.12 (2H, s), 5.33 (1H, d, J = 4Hz), 7.32 (10H, s). EXAMPLE 3 Benzyl 6-beta-(Benzyloxycarbonylaminomethyl) penicillanate l-alpha-Oxide and Benzyl 6-beta-(Benzyloxycarbonylaminomethyl) penicil lanate l-beta-Oxide To a solution of title product of the preceding Example (4.54 g, 0.01 mole) in 70 ml of ethyl acetate was added m-chloroperbenzoic acid (2.02 g, 0.01 mole) in 30 ml ethyl acetate. The mixture was stirred 30 minutes at room temperature, washed 1 x 50 ml saturated NaHCO3 and 2 x 50 ml H20, dried over Na2SO4 and concentrated in vacuo to a viscous oil. The oil was dissolved in 50 ml of ether and 10 ml.CHCl3 and crystallization of title alpha-oxide induced by scratching [2.2 g, mp 123-1240C, pnmr/CDC13Zdelta/TMS 1.22 (3H, s), 1.51 (3H, s), 3.7 (3H, m), 4.34 (lH, s), 4.63 (1H, d, J = 4Hz), 5.13 (2H, s), 5.22 (2H, s), 5.50 (1H, m), 7.34 (5H, s), 7.40 (5H, s)]. Concentration of mother liquor to dryness in vacuo gave the title beta-oxide as a viscous oil [2.5 g; pnmr/CDC13/delta/TMS 1.05 (3H, s), 1.60 (3H, s), 3.8 (3H, m), 4.63 (1H, s), 4.73 (1H, d, J = 4Hz), 5.13 (2H, s), 5.23 (2H, q), 5.70 (1H, m), 7.35 (5H, s), 7.39 (5H,s)]. EXAMPLE 4 Benzyl 6-alpha-(Benzyloxycarbonylamino methyl) penicillanate l-beta-Oxide To title beta-oxide of the preceding Example (2.3 g, 4.9 mmoles) in 100 ml CHCl3 was added 1,5diazabicyclo[4.3.0]non-5-ene (DBN, 0.607 g, 4.9 mmoles). The mixture was stirred at room temperature for 15 minutes, diluted with 50 ml 1N HC1, and the layers separated. The organic layer was washed 2 x 50 ml H20, dried over Na2SO4 and concentrated in vacuo to an oil (2.3 g). The oil was column chromatographed on 100 g silica gel, eluting with 4:1 CHC13:ethyl acetate in 20 ml fractions. Fractions 41-70 were combined and concentrated in vacuo to yield title product as a viscous oil [0.9 g; pnmr/ CDCl3/TMS 1.03 (3H, s), 1.60 (3H, s), 3.67 (3H, m), 4.46 (1H, s), 4.88 (1H, m) 5.08 (2H, s), 5.17 (2H, q), 5.39 (1H, m), 7.32 (5H, s), 7.37 (5H, s)]. EXAMPLE 5 Benzyl 6-beta-(Benzyloxycarbonylamino methyl)penicillanate l,l-Dioxide To a solution of title product of Example 2 (8.0 g, 0.0176 mole) in 200 ml ethyl acetate cooled to 0-50C was added m-chloroperbenzoic acid (10.68 g, 0.0528 mole). The mixture was warmed to room temperature, stirred for 6 hours, recooled to 0-50C and diluted with 50 ml of saturated NaHS03. The organic layer was separated, washed 2 x 50 ml saturated NaHC03 and 2 x 50 ml H20, dried over Na2SO4 and 3 concentrated in vacuo to a viscous oil (8.6 g). The oil was chromatographed on 250 g silica gel, eluting with 19:1 CHC13:ethyl acetate in 25 ml fractions. Fractions 44-150 were combined and concentrated in vacuo to yield title product as a white gummy foam ±7.6 g; pnmr/CDCl3/delta/TMS 1.25 (3H, s), 1.49 (3H, s), 3.98 (3H, m), 4.45 (lH, s), 4.59 (lH, d, J = 4Hz), 5.09 (2H, s), 5.19 (2H, q), 5.36 (lR, br), 7.36 (1OH, s)]. EXAMPLE 6 Benzyl 6-alpha- (Benzyl oxycarbonyl- aminomethyl)penicillanate 1,1-Dioxide By the procedure of Example 4, the title 1,1dioxide of the preceding Example (3.3 g, 6.79 mmoles) was converted to present title product (3.1 g crude), and purified by column chromatography on 150 g silica gel, eluting with 1:9 ethyl acetate:CHCl3 in 20 ml fractions. Fractions 26-37 were combined and concentrated in vacuo to yield purified title product, as a viscous oil which crystallized on standing [1.9 g; mp 112-1130C; pnmr/CDC13/delta/TMS 1.20 (3H, s), 1.49 (3H, s), 3.65 (3H, m), 4.32 (1H, s), 4.59 (1H, m), 5.07 (2H, s), 5.14 (2H, q), 5.30 (1H, br), 7.32 (10H, s)]. Present title product was also obtained by the further oxidation of the title product of Example 4 with excess m-chloroperbenzoic acid according to the method of Example 5. EXAMPLE 7 6-beta- (Aminomethyl ) - penicillanic Acid l,l-Dioxide Title product of Example 5 (1.9 g), THF (40 ml), H20 (40 ml) and 10% Pd/C (1.9 g) were combined and hydrogenated at 50 psig for 1 hour. Catalyst was recovered by filtration and THP removed from the filtrate in vacuo. The aqueous layer was washed with 30 ml ethyl acetate, freeze dried to a white powder and a first crystalline crop (0.26 g) obtained by trituration of the powder with 5 ml water. A second crop (0.14 g) crystallized on addition of 10 ml of acetone to the mother liquor and a third crop (0.35 g) by evaporating the second mother liquor to 2 ml and adding 50 ml of acetone. Total yield of title product was 0.75 g (pnmr/250 MHz/D20/delta/DSS 1.47 (3H, s), 1.59 (3H, s), 3.74 (2H, m), 4.36 (lH, td, J = 4, 5.5Hz), 4.45 (1H, s), 5.17 (1H, d, J = 4Hz)]. EXAMPLE 8 6-alpha-(Aminomethyl) penicillanic Acid l,l-Dioxide By the method of the preceding Example, title product of Example 6 (1.7 g) was converted to present title product, except that crystalline product was obtained directly by concentration in vacuo following the ethyl acetate extraction [0.7 g; pnmr/250 MHz/D20/ DSS 1.44 (3H, s), 1.59 (3H, s), 3.63 (2H, d, J = 5.5Hz) 4.07 (1H, td, J = 2, 5.5Hz) 4.31 (1H, s), 5.06 (1H, d, J = 2)]. EXAMPLE 9 Benzyl 6-beta-Bromo-6-alpha-trifluoro methanesulfonyloxymethylpenicillanate To a solution of trifluoromethanesulfonic anhydride (3.15 ml) in methylene chloride (20 ml) at room temperature was added a solution of benzyl 6 beta-bromo-6-alpha- (hydroxymethyl ) penicillanate (6.232 g, 15.6 mmoles) and pyridine (1.89 ml) in methylene chloride (20 ml) and the mixture stirred and cooled in an ice bath for 45 minutes. The methylene chloride was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The ethyl acetate phase was separated and the aqueous phase extracted with additional ethyl acetate. The combined ethyl acetate solutions were washed first with sodium bicarbonate solution at pH 8.3 and then with brine'. After drying over anhydrous sodium sulfate, the solution was evaporated under reduced pressure to give title product as an orange solid [8.296 g; pnmr/CDC13/ delta/TMS, 1.41 (s, 3H), 1.63 (s, 3H), 4.51 (s, iR), 4.87 (s, 2H), 5.14 (s, 2H), 5.44 (s, lH), 7.30 (s, SR)]. EXAMPLE 10 Benzyl 6-alpha-Azidomethyl-6 beta-bromopenicillanate Tetramethylguanidinium azide (2.96 g, 18.7 mmoles) was added to a solution of benzyl 6-betabromo-6-alpha-trifluoromethylsulfonyloxymethylpenicillanate (8.296 g, 15.6 mmoles) in chloroform (50 ml) at 100C. The reaction mixture was stirred for one hour and then reduced to one third volume and filtered through a pad of silica gel. The pad was eluted with 10% ethyl acetate/chloroform (100 ml) and the eluate evaporated to give an amber oil [6.744 g; pnmr/CDCl3/delta/TMS 1.38 (s, 3H), 1.61 (s, 3H), 3.96 (s, 2H), 4.53 (s, 1H), 5.17 (s, 2H), 5.40 (s, 1H), 7.34 (s, 5H)1. EXAMPLE 11 Benzyl 6-alpha-Bromo-6-beta-trifluoro- methanesulfonyloxymethylpenicillanate Following the procedure of Example 9, benzyl 6alpha-bromo-6-beta-hydroxymethylpenicillanate (0.548 g, 1.4 mmoles) in methylene chloride (4 ml) containing pyridine (0.17 ml) was reacted with a solution of trifluoromethanesulfonic anhdyride (0.42 ml) in methylene chloride (3 ml) to give title product as an amber oil [641 mg; pnmr/CDC13/delta/TMS 1.43 (s, 3H), 1.62 (s, 3H), 4.52 (s, 1H), 4.88 (q, 2H), 5.19 (s, 2H), 5.62 (s, 1H), 7.35 (s, 5H)]. EXAMPLE 12 Benzyl 6-alpha-Bromo-6-beta azidomethylpenicillanate To a solution of benzyl 6-alpha-bromo-6-beta- trifluoromethanesul fonyloxymethylpenicil lanate (641 mg, 1.2 mmoles) in chloroform (10 ml) was added tetramethylguanadinium azide (229 mg, 1.2 mmoles) at 100C. The reaction mixture was stirred for one hour and then evaporated under reduced pressure. The oily residue was filtered through a pad of silica gel and eluted therefrom with 10% ethyl acetate/chloroform. Evaporation of the eluate gave title product as an amber oil [420 mg; pnmr/CDC13/delta/TMS 1.43 (s, 3H), 1.61 (s, 3H), 3.91 (s, 2H), 4.48 (s, 1H), 5.15 (s, 2H), 5.57 (s, 1H), 7.37 (s, 5H)]. EXAMPLE 13 Benzyl 6-alpha-(Aminomethyl) 6-beta-bromopenicillanate Hydrogen sulfide was bubbled into a rapidly stirred solution of benzyl 6-alpha-azidomethyl-6beta-bromopenicillanate (541 mg, 1.3 mmoles) and triethylamine (0.71 ml, 4 equivalents) in chloroform (10 ml) for one hour. The reaction mixture was then evaporated in vacuo to a red oil. NMR data showed the residue to comprise the desired product contaminated with triethylamine [pnmr/CDC13/delta/TMS 1.39 (s, 3H), 1.64 (s, 3H), 3.35 (s, 2H), 4.51 (s, 1H), 5.16 (s, 2H), 5.35 (s, 1H), 7.33 (s, 5H)]. EXAMPLE 14 Benzyl 6-beta-Bromo-6-alpha- benzyloxycarbonylaminomethyl) penicil lanate A solution of pyridine (0.14 ml) and benzyl 6alpha-aminomethyl-6-beta-bromopenicillanate (239 mg, 0.6 mmoles) in methylene chloride (5 ml) was added via a syringe over a 5 minute period to a solution of benzylchloroformate in methylene chloride (5 ml) and the reaction mixture stirred in an ice bath under a nitrogen atmosphere for 75 minutes. The reaction mixture was evaporated in vacuo and the residue taken up in ethyl acetate/water. The pH was adjusted to 2.9 with dilute hydrochloric acid, the ethyl acetate phase separated and extracted with dilute sodium bicarbonate solution (pH 8.1), washed with brine and dried over anhydrous sodium sulfate, Evaporation under reduced pressure gave 312 mg which was taken up in chloroform and chromatographed on silica gel (15 g, 14 x 20 cm column) and eluted therefrom with 5% ethyl acetatelchloroform. Fractions of 4 ml each were collected. Fractions 14-27 were combined and evaporated under reduced pressure to give title product (168 mg, pnmr/CDC13/delta/TMS consistent with title product and identical with that of the same compound prepared in Example 1. EXAMPLE 15 Benzyl 6-beta-(Benzyloxy carbonylaminomethyl)penicillanate A solution of tri(n-butyl)tin hydride (0.25 ml) and benzyl 6-beta-bromo-6-alpha-(benzyloxycarbonyl- aminomethyl)penicillanate (168 mg, 0.31 mmoles) in benzene (4 ml) was refluxed for 2 hours. The benzene was then evaporated in vacuo and the residue triturated with hexane (3 x 2 ml). The remaining residue was then taken up in ethyl acetate/water, the ethyl acetate phase separated, washed with brine and dried over anhydrous sodium sulfate. Evaporation in vacuo gave 101 mg of an oil which was chromatographed on' silica gel (4 g, 1 x 11 cm column), set up with chloroform and eluted with 5% ethyl acetate/chloroform. Fractions of 4 ml volume were collected. Fractions 3-5 were combined and evaporated to give title product (66 mg; identified by-pnmr as identical with the product of Example 2). EXAMPLE 16 6-beta-(Benzylaminomethyl) penicillanic Acid l,l-Dioxide To a hazy solution of the beta-aminomethyl title product of Example 7 (0.3 g, 1.145 mmoles) in 30 ml methanol was added benzaldehyde (0.117 ml, 1.145 mmoles) followed by sodium cyanoborohydride (47.6 mg, 0.758 mmole). The mixture was stirred under N2 for 30 minutes at room temperature. The reaction mixture was clarified by filtration and concentrated to a foam in vacuo. The foam was dissolved in 30 ml H20, extracted 2 x 20 ml ethyl acetate and freeze dried to title product as a white glass (130 mg; pnmr/D20/ delta/DSS 1.57 (3H, s), 1.69 (3H, s), 3.7-4.4 (5H, m), 4.38 (lH, s), 5.21 (lH, d, J = 4), 7.56 (5H, s). EXAMPLE 17 6-beta-(2-Phenylethylamino methyl)penicillanic Acid 1,1-Dioxide Title beta-aminomethyl product of Example 7 (0.1 g) was reacted with phenylacetaldehyde (0.098 ml) by the method of the preceding Example. The reaction mixture was concentrated in vacuo and solids recovered by trituration with 20 ml ethyl acetate. The solids were dissolved in water, the solution combined with a water extract of the ethyl acetate phase and freeze dried to yield title product ±40 mg, pnmr/D20/delta/DSS 1.56 (3H, s), 1.70 (3H, s), 3.0-4.0 (6H, m), 4.28 (1H, m), 4.41 (1H, s), 5.24 (1H, d, J = 4), 7.48 (5H, s)l. EXAMPLE 18 6-beta-(4-Picolylaminomethyl)- penicillanic Acid l,l-Dioxide Title beta-aminomethyl product of Example 7 (0.1 g, 0.38 mmole) was slurried in 4 ml of water. 4-Pyridinecarbaldehyde (0.040 ml, 0.42 mmole) and then sodium cyanoborohydride (15.8 mg, 0.25 mmole) were added and the mixture stirred under nitrogen for 30 minutes at room temperature. The hazy solution was clarified, concentrated in vaduo, the residue taken up in 5 ml H20, extracted 10 ml ethyl acetate, and freeze dried to yield title product as a white glass [0.1 g; pnmr/D20/delta/DSS 1.53 (3H, s), 1.64 (3H, s), 3.3-4.1 (5H, m), 4.35 (1H, s), 5.14 (1H, d, J = 4Hz), 8.1 (4H, mole EXAMPLE 19 6-beta- ( 3-Picolylamino- methyl)penicillanic Acid 1,l-Dioxide The procedure of the preceding Example, substituting 3-pyridinecarbaldehyde (0.039 ml) for 4pyridinecarbaldehyde, gave present title product [70 mg, pnmr/D2O/delta/DSS 1.59 (3H, s), 1.71 (3H, s), 3.7-4.5 (5H, m), 4.45 (1H, s), 5.23 (1H, d, J = 4 Hz), 8.1 (4H, m)]. EXAMPLE 20 6-alpha-(Benzylaminomethyl) penicillanic Acid l,l-Dioxide The title alpha-aminomethyl compound of Example 8 (0.5 g, 1.91 mmoles) was reacted with benzaldehyde (0.194 ml, 1.91 mmole) and sodium cyanoborohydride (79.4 mg, 1.259 g) in a total of 26 ml of methanol according to the method of Example 16. Following the 30 minutes stir period the reaction mixture was clarified by filtration and concentrated in vacuo to a foamy residue. The residue was dissolved in 50 ml of ethyl acetate and crude product (0.45 g) precipitated by adding hexane. Crude product (0.35 g) was dissolved in 30 ml of water, extracted 2 x 30 ml ethyl acetate, and concentrated in vacuo to yield title product as a glass ±0.28 g; pnmr/D20/delta/DSS 1.54 (3H, s), 1.67 (3H, s), 3.47 (2H, m), 4.03 (3H, m), 4.33 (lH, s), 4.98 (1R, d, J = 2), 7.53 (5H, s)]. EXAMPLE 21 6-alpha-(2-Phenylethylamino methyl)penicillanic Acid 1,1-Dioxide ,The procedure of the preceding Example, substituting phenylacetaldehyde (0.446 ml) for benzaldehyde provided title product. Isolation was modified in that the crude product initially precipitated as a gum when the hexane was added to the ethyl acetate. The gum was isolated by decantation and partitioned between 20 ml ethyl acetate and 20 ml H2O and insoluble material (100 mg) removed by filtration. The aqueous layer was freeze dried to yield purified title product as a yellow solid ±0.18 g, pnmr/D20/delta/DSS 1.55 (3H, s), 1.70 (3H, s), 2.9-4.0 (7H, m), 4.34 (1H, s), 5.10 (1H, d), 7.43 (SR, salt EXAMPLE 22 6-alpha-(4-Picolylamino methyl ) penicil lanic Acid l,l-Dioxide The procedure of Example 20, substituting 4pyridinecarbaldehyde (0.182 ml) for benzaldehyde gave title product. Isolation was modified in that, following filtration of the reaction mixture, the filtrate was concentrated in vacuo to a yellow foam, which was triturated with ethyl acetate, taken up in 10 ml H20 and washed with 20 ml fresh ethyl acetate. The aqueous layer was reconcentrated in vacuo to yield title product as a second yellow foam (0.38 g; pnmr/D20/delta/DSS 1.57 (3H, s), 1.70 (3H, s), 3.39 (2H, m), 4.0 (3H, m), 4.32 (1H, s), 5.01 (1H, d, J = 2), 8.1 (4H, mole EXAMPLE 23 6-alpha-(3-Picolylamino methyl)penicillanic Acid 1,1-Dioxide The procedure of the preceding Example substituting 3-pyridinecarbaldehyde (0.182 ml) for 4-pyridinecarbaldehyde gave title product. Isolation was modified in that the initially isolated yellow foam was taken up in 10 ml H2O, extracted 2 x 10 ml ethyl acetate, and the aqueous layer freeze dried to yield title product as a second yellow foam [0.39 g, pnmr/ D20/delta/DSS 1.57 (3H, s), 1.70 (3H, s), 3.43 (2H, m), 4.1 (3U, m), 4.30 (lH, s), 5.00 (1H, d, J = 2), 8.1 (4H, m). EXAMPLE 24 6-alpha-(4-Hydroxybenzylamino- methyl)penicillanic Acid l,l-Dioxide By the procedure of the preceding Example, title product of Example 8 (0.1 g, 0.38 mmole) was reacted with 4-hydroxybenzaldehyde (46.6 mg, 0.38 ml) and sodium cyanoborohydride (15.8 mg, 0.25 mmole) in 5 ml methanol to produce freeze dried title product as a white solid (0.1 g, pnmr/D20/delta/DDS 1.53 (3H, s), 1.68 (3H, s), 3.52 (2H, m), 4.1 (3H, m), 4.33 (1H, s), 5.00 (1H, d, J = 2), 7.1 (4H, m). EXAMPLE 25 Benzyl 6-alpha-(Benzyloxycarbonylamino methyl)penicillanate and Benzyl 6-beta (Benzyloxycarbonylaminomethyl ) penicil lanate The required Grignard agent was prepared essentially according to the method of DiNinno et al., J. Org. Chem. 42, pp. 2960-2965 (1977). Thus benzyl 6alpha-iodopenicillanate was dissolved in 75 ml of dry tetrahydrofuran and cooled to -780C under dry N2. Methylmagnesium bromide (5.6 ml of 3M in ether) was added dropwise. After stirring an additional 15 minutes, a solution of benzyloxycarbonylaminomethyl acetate (1.87 g) in 25 ml of dry tetrahydrofuran was added in one portion. After a second 15 minutes of stirring at -780C, acetic acid (2 ml) was added', the mixture warmed to OOC and evaporated in vacuo. The residue was distributed between 250 ml ethyl acetate and 50 ml of water. The organic layer was separated, washed 1 x 100 ml saturated NaHCO3 and 2 x 100 ml brine, dried over Na2SO4, and evaporated in vacuo to an oil (7.3 g). The oil was chromatographed on 250 g silica gel, eluting with 1:10 ethyl acetate:chloroform in 20 ml fractions. Fractions 20-24 contained 1.3 g of a side product (oil); fractions 25-34 contained 0.62 g of a 3:2 beta:alpha mixture of title products by pnmr assay. Fractions 35-60 contained 2.2 g of a 3:1 alpha:beta mixture of title products. EXAMPLE 26 Benzyl 6-alpha-Bromo-6-beta- (lR-tri- fluoromethanesulfonyloxyethyl)penicillanate Benzyl 6-alpha-bromo-6-beta-(1R-hydroxyethyl)penicillanate (DiNinno et al., J. Org. Chem. 42, pp. 2960-2965, 1977; 20.28 g, 0.0489 mole) was dissolved in 400 ml CH2C12 and chilled with an acetone-ice bath. Pyridine (7.91 ml, 2 equivalents) was added and then, dropwise, trifluoromethanesulfonic anhydride (11.58 mi, 1.4 equivalents) maintaining temperature +5 . The mixture was stirred at 0 for 30 minutes, diluted with CH2Cl2, washed sequentially with saturated NaHCO3, H20 and saturated NaCl, evaporated in vacuo, and diluted with 1:1 hexane, thereby crystallizing title product, 18.71 g; pnmr/CDCl3/delta/TMS: 1.42 (3H, s), 1.55 (3H, d, J = 6Hz), 1.66 (3H, s), 4.58 (1H, s), 5.20 (2H, s), 5.34 (1H, q, J = 6Hz), 5.56 (1H, s), 7.38 (5H, s). EXAMPLE 27 Benzyl 6-alpha-Bromo-6-beta (1S-azidoethyl)penicillanate Title product of the preceding Example (34.4 g, 0.0628 mole) was dissolved in 400 ml of CH2C12. Tetrabutylammonium azide (25.0 g, 1.4 equivalents} in 100 ml CH2C12 was added dropwise and the mixture stirred for one hour at 25 C. The CH2C12 was stripped in vacuo and the residual oil filtered through 500 g of silica gel on a sintered glass funnel, eluting with 2 liters CH2Cl2. Evaporation gave title product as a pale yellow oil, 27 g; pnmr/CDCl3/delta/TMS: 1.40 (3H, s), 1.53 (3H, d, J = 6.3Hz), 1.57 (3H, s), 4.10 (1H, q, J = 6.3Hz), 4.47 (1H, s), 5.19 (2H, s), 5.61 (1H, s), 7.34 (5H, s). EXAMPLE 28 Benzyl 6-beta-(1S-Aminoethy1)- 6-alpha-bromopenicil lanate Title product of the preceding Example (27.0 g, 0.0613 mole) was dissolved in 300 ml CHCl3. Tri- ethylamine (35 ml, 4 equivalents) was added and then H2 S was bubbled through the reaction mixture for 3.5 hours. The reaction mixture was then flushed with N2 for 0.5 hour and stripped of CHCl3 in vacud. The resulting oil was distributed between ether and 1N HC1 (200 ml). The ether layer was extracted 3 x 200 ml fresh 1N HC1. The combined' aqueous layers were diluted with ethyl acetate and the pH of the two phase system adjusted to 8.5. The organic layer was separated and evaporated to yield title product as an oil (6.34 g). The original ether layer was diluted with water and the pH adjusted to 8.5. The ether layer was separated and evaporated to yield additional title product, 6.0 g, pnmr/CDC13/delta/TMS: 1.28 (3H, d, J = 6.3Hz), 1.40 (3H, s), 1.58 (3H, s), 3.34 (1H, g, J = 6.3Hz), 4.45 (1H, s), 5.16 (2H, s), 5.54 (1H, s), 7.33 (5H, s). EXAMPLE 29 Benzyl 6-beta-(1S-Benzyloxycarbonyl aminoethyl) -6-alpha-bromo-penicil lanate Benzyl chloroformate (5.10 ml, 1.2 equivalents) was dissolved in 20 ml of CH2Cl2, chilled in an acetone-ice bath. A solution of title product of the preceding Example (12.34 g, 0.02980 mole) in 50 ml of CH2Cl containing diisopropylethylamine (7.78 ml, 1.5 equivalents) was added dropwise, maintaining the temperature 0-50C with an ice water bath. The reaction mixture was stirred for 20 minutes, stripped of CH2C12 in vacuo, diluted with ethyl acetate and water (pH was noted to be 8.2), and adjusted to pR 2.0 with dilute HCl. The organic layer was separated, washed with H2O and then saturated NaCl and evaporated to yield title product as a pale yellow oil, 17 g; pnmr/CDCl3/delta/TMS: 1.35 (3H, s), 1.38 (3H, d), 1.55 (3H, s), 4.26 (1H, m), 4.45 (1H, s), 4.97 (1H, d), 5.08 (2H, S), 5.14 (2H, s), 5.53 (1H, s), 7.33 (10H, s). EXAMPLE 30 Benzyl 6-beta-(1S-Benzyloxy carbonylaminoethyl)penicillanate Title product of the preceding Example (16.33 g, 0.0298 mole) was dissolved in 200 ml benzene. Tri-nbutyltin hydride (23.5 ml, 3 equivalents) was added and the mixture refluxed 3 hours. Benzene was removed in vacuo and title product crystallized from the residue by addition of hexane, 9.26 g; pnmr/CDCl3/ delta/TMS: 1.39 (3H, d, J = 6Hz), 1.40 (3H, s), 1.63 (3H, s), 3.62 (1H, dd, J = 4, llEz), 4.12 (1H, m), 4.39 (1H, s), 4.81 (1H, d, J = 8Hz), 5.08 (2H, s), 5.17 (2H, s), 5.32 (1H, d, J = 4Hz), 7.32 (5H, s), 7.36 (5H, s). EXAMPLE 31 Benzyl 6-beta-(1S-Benzyloxycarbonyl aminoethyl)penicillanate 1,1-Dioxide By the procedure of Example 5, title product of the preceding Example (4.0 g, 0.0085 mole) was converted to present title product, isolated as a white foam, 4.25 g; pnmr/CDCl3/delta/TMS: 1.21 (3H, s), 1.33 (3H, d, J = 6Hz), 1.48 (3H, s), 4.20 (1H, m), 4.35 (1H, m), 4.40 (1H, s), 4.53 (1H, d, J = 4.5Hz), 5.08 (2H, s), 5.17 (2H, q), 5.45 (1H, d, J = 7Hz), 7.30 (5H, s), 7.35 (5H, s). EXAMPLE 32 6-beta-(1S-Aminoethyl) penicillanic Acid l,l-Dioxide Using 180 mg of 5% Pd/C as catalyst, title product of the preceding Example (175 mg) was converted to present title product by the procedure of Example 7. After recovery of the catalyst, the combined mother liquor and tetrahydrofuran/H2O washes were stripped of the former in vacuo and title product recovered by freeze drying the aqueous residue overnight, ir (KBr): 1765 cm 1; pnmr/D20/delta/DDS: 1.47 (3H, s), 1.53 (3H, d), 1.60 (3H, s), 4.35 (2H, m), 4.37 (1H, s), 5.12 (1H, d, J = 4Hz). EXAMPLE 33 Benzyl 6-alpha- ( lS-Benzyloxycarbonyl aminoethyl)penicillanate 1,1-Dioxide Title product of Example 31-(4.25 g, 0.0085 mole) was dissolved in 100 ml CH2C12. DBN (0.96 ml, 1 equivalent) was added dropwise and the mixture stirred three minutes at 250, then quenched by adding to 1 ml (2 equivalents) of glacial CH3C02H. The quenched mixture was diluted with CH2C12, washed in sequence with dilute HCl (pH 2.5), water and saturated NaCl, and evaporated in vacuo to yield crude title product as a white foam, 4.5 g. Column chromatography on silica gel, using 9:1 CH2C12:ethyl acetate as eluant, gave purified title product, white foam, 2.83 g, pnmr/CDCl3/delta/TMS: 1.21 (3H, s), 1.35 (3H, d, J = 7Hz), 1.51 (3H, s), 3.78 (1H, dd, J = 2, 4Hz), 4.27 (1H, m), 4.36 (1H, s), 4.56 (1H, d, J = 2Hz), 5.09 (2H, s), 5.16 (2H, q), 7.3 (1OH, s). EXAMPLE 34 6-alpha-(1S-Aminoethyl) penicillanic Acid l,l-Dioxide 5% Pd/C (4.5 g) was slurried in 50 ml H20 and prehydrogenated for 1.5 hours at 25*/50 psig. Title product of the previous Example (2.83 g) was dissolved in 50 ml ethyl acetate, added to the prehydrogenated aqueous catalyst slurry, and hydrogenated at 250/50 psig for 0.5 hour. Catalyst was recovered by filtration. The aqueous layer was separated. Title product crystallized in three crops (1.1 g total weight) as the aqueous layer was concentrated; pnmr/D2O/delta/DDS: 1.47 (3H, s), 1.52 (3H, d), 1.62 (3H, s), 4.05 (2H, m), 4.28 (1H, s), 5.10 (1H, d); ir (KBr) 1787 cm 1 EXAMPLE 35 Benzyl 6 -beta-Bromo- 6-alpha- (1 - trifluoromethylsulfonyloxyethyl)penicillanate By the procedure of Example 26, benzyl 6-betabromo-6-alpha-(1-hydroxymethyl)penicillanate (a mixture of side chain epimers; DiNinno et al., loc cit.; 8.90 g, 0.0214 mole) was converted to present title products. On addition of 1:1 hexane:ether a first crop of solids crystallized (4.70 g) which was primarily the 1R side chain epimer. (If desired, this epimer is carried through the procedures of Examples 25-30 to yield the title product of Example 32). The second crop of solids (2.40 g) and the third crop (an oil, 1.60 g) were mixed side chain epimers of title product, primarily the 1S side chain epimer; pnmr/CDCl3/delta/TMS: 1.41 (3H, s), 1.65 (3H, s), 1.78 (3H, d, J = 6.5Hz), 4.56 (1H, s), 5.22 (2H, s), 5.37 (1H, q, J = 6.5Hz), 5.48 (1H, s), 7.4 (5H, s). EXAMPLE 36 Benzyl 6-alpha-(1-Azidoethyl) 6-beta-bromopenicillanate Second and third crops (primarily 1S side-chain epimer) of title product of the preceding Example (4.0 g, 0.0073 mole) were converted to present title product (primarily 1R side chain epimer) by the procedure of Example 27. This product was isolated as a pale yellow oil, 2.91 g, pnmr/CDCl3/delta/TMS: 1.40 (3H, s), 1.56 (3H, d, J = 6.5Hz), 4.00 (1H, q, J = 6.5Hz), 4.48 (1H, s), 5.16 (2H, s), 5.34 (1H, s), 7.32 (5H, s). EXAMPLE 37 Benzyl 6-alpha- ( lR-Aminoethyl ) - 6-beta-bromopenicillanate and Benzyl 6-alpha-(1S-Aminoethyl) 6-beta-bromopenicillanate Title product of the previous Example (primarily the 1R side chain epimer; 2.91 g, 0.0066 mole) was converted to present title products according to the procedure of Example 28.. Following removal of CHC13 used as reaction solvent, the residue was distributed between ether and 1N HC1 (200 ml). The ether layer was separated and extracted 1 x 200 ml 1N HCl. The combined aqueous layers were layered with ethyl acetate and the pH adjusted to 8.5. The aqueous layer was separated and extracted with fresh ethyl acetate. The ethyl acetate layers were combined and evaporated to yield a mixture of title products (primarily the 1R isomer) as an oil, 1.53 g. The isomers were separated by column chromatography on 200 g silica gel, eluting with 1:1 CH2C12:ethyl acetate, monitoring by tlc (3:2 CH2Cl2: ethyl acetate). Clean, faster moving fractions (Rf 0.52) were combined and evaporated to yield title 1S isomer (0.172 g), which, if desired, is converted by the procedures of Examples 29-32 to title product of Example 34 Middle cuts gave a mixture of title products (.0.45 g), which, if desired, is rechromatographed to yield additional pure products. Clean, slower moving fractions (Rf 0.47) were combined to yield title 1R side-chain epimer, 0.674 g, pnmr/CDC13/delta/TMS: 1.29 (3H, d, J = 6Hz), 1.38 (3H, s), 1.64 (3H, s), 3.29 (1H, q, J = 6Hz), 4.51 (lR, s), 5.17 (2H, s), 5.38 (1H, s), 7.33 (5H, s). EXAMPLE 38 Benzyl 6-beta-Bromo-6-alpha-(lR- benzyloxycarbonylaminoethyl)penicillanate By the procedure of Example 29, 1R side chain title product of the preceding Example (0.674 g, 0.0016 mole) was converted to present title product, 0.877 g, Rf 0.85 (1:1 Cz2C12:ethyl acetate). EXAMPLE 39 Benzyl 6-beta- ( lR-Benzyloxy- carbonylaminoethyl)penicillanate By the procedure of Example 30, title product of the preceding Example (0.877 g, 0.0016 mole) was converted to present title product. After stripping, the benzene used as solvent, the residue was triturated 4 x 50 ml with hexane to yield crude product as an oil (627 mg). The oil was chromatographed on silica gel eluting with 19:1 chloroform:ethyl acetate to yield purified title product, 569 mg, pnmr/CDCl3/ delta/TMS: 1.10 (3H, d, J = 6.5Hz), 1.36 (3H, s), 1.60 (3H, s), 3.41 (1H, dd, J = 4, 11Hz), 4.16 (lH, m), 4.43 (1H, s), 5.08 (2H, s), 5.13 (2H, s), 5.32 (lH, d, J = 4Hz), 7.29 (5H, s), 7.33 (5H, s). EXAMPLE 40 Benzyl 6-beta-(1R-Benzyloxycarbonyl aminoethyl)penicillanate 1,1-Dioxide By the procedure of Example 5, title product of the preceding Example (0.569 g, 0.0012 mole) was converted to present title product, 0.681 g, pnmr/CDCl3/delta/TMS: 1.22 (3H, s), 1.27 (3H, d), 1.47 (3H, s), 3.94 (1H, dd, J = 4, 12Hz), 4.42 (1H, s), 4.48 (2H, m), 5.04 (2H, s), 5.13 (2H, q), 5.40 (1H, d, J = 8), 7.27 (5H, s), 7.32 (5H, s). EXAMPLE 41 6-beta-(1R-Aminoethyl) penicillanic Acid l,l-Dioxide Using 400 mg of 5% Pd/C, title product of the preceding Example (202 mg) was converted to present title product, 50 mg; ir (KBr) 1788 cm 1; pnmr/D2O/ delta/DDS: 1.45 (3H, s), 1.51 (3H, d), 1.57 (3H, s), 4.27 (1H, m), 4.33 (1H, s), 4.85 (1H, m), 5.15 (1H, d, J = 4Hz). EXAMPLE '42 Benzyl 6-alpha-tlR-Benzyloxycarbonyl- aminoethyl)penicillanate 1,1-Dioxide By the procedure of Example 33, using 19:1 CHC13:ethyl acetate as eluant in the chromatography, title product of Example -40 (368 mg) was converted to present title product, 285 mg; pnmr/CDCl3/delta/TMS: 1.23 (3H, s), 1.33 (3H, d, J = 6.5Hz), 1.50 (3R, s), 3.61 (1H, dd, J = 2, 9Hz), 4.28, (1H, m), 4.34 (IH, s), 4.67 (1H, d, J = 2Hz), 4.98 (1H, d), 5.07 (2H, s), 5.18 (2H, q), 7.30 (5H, s), 7.35 (5H, s). EXAMPLE 43 6-alpha-(1R-Aminoethyl) penicillanic Acid 1,1-Dioxide By the procedure of Example 41, title product of the preceding Example (285 mg) was converted to present title product (132 mg; ir (KBr) 1768 cm 1; pnmr/D20/delta/DDS: 1.47 (3H, s), 1.54 (3H, d), 1.61 (3H, s), 4.03 (2H, m), 4.44 (1H, s), 5.10 (lH, d, J = 2). EXAMPLE 44 6-alpha- ( Benzyloxycarbonylamino- methyl)penicillanic Acid l,l-Dioxide Method A Title product of Example 6 (11.2 g) in THF (70 ml) and H2O (50 ml) in the presence of 6 g 10% Pd/C was partially hydrogenated at 50 psig for 30 minutes. Catalyst was removed by filtration over a pad of diatomaceous earth, THF was distilled from the filtrate in vacuo, and the aqueous residue was extracted with 100 ml ethyl acetate. The organic layer was separated, dried (Na2SO4) and evaporated to yield title product as a foam, 3.0 g; pnmr/CDCl3/TMS 1.40 (3H, s), 1.55 (3H, s), 3.70 (3H, m), 4.31 (lH, s), 4.58 (1H, m), 5.04 (2H, s), 7.24 (5it., s). The aqueous layer was concentrated to yield crystalline 6-alpha-(aminomethyl)penicillanic acid l,l-dioxide, 3.1 g, having pnmr fully identical with the same completely hydrogenated product of Example 8. Method B Title product of Example 8 (3.0 g, 11.45 moles) was dissolved in 100 ml 1:1 H20:methanol. The pH was adjusted and maintained at 8.3-8.7 as benzyl chloroformate (1.79 g, 12.59 mole) was added dropwise over several minutes. Following a brief period of stirring the pH was adjusted to 6.0 with 1N HCl and THF removed by distillation in vacuo. The aqueous residue was extracted with 30 ml of ethyl acetate and the extract discarded. Fresh ethyl acetate (50 ml) was added and the pH adjusted to 1.8 with 1N HCl. The aqueous layer was extracted with 50 ml fresh ethyl acetate. The combined organic layer and extract was washed 1 x 50 ml saturated NaCl, dried (Na2SO4) and evaporated in vacuo to yield title product as a foam, 3.7 g, having pnmr identical with that of title product obtained according to Method A immediately above. EXAMPLE 45 Pivaloyloxymethyl 6-alpha-(Benzyloxy carbonylaminomethyl)penicillanate 1,1-Dioxide The title product of the preceding Example 6.75 g, 17 mmoles) and N,N-diisopropylethylamine (3.34 ml, 18.7 mmoles) were dissolved in dimethylformamide (50 ml), chloromethyl pivalate (2.72 ml, 18.7 mmoles) were added, and the mixture allowed to stir at ambient temperature for 20 hours. The reaction mixture was diluted with ethyl ether (300 ml), washed with water (2 x 100 ml), dried (Na2SO4) and evaporated in vacuo to an oil. The oil was dissolved in 100 ml ether, washed 3 x 50 ml H2O, dried (Na2SO4) and concentrated in vacuo to yield purified title product as a viscous oil, 4.4 g, pnmr/CDCl3/TMS 1.20 (9H, s), 1.34 (3H, s), 1.51 (3H, s), 3.64 (3H, m), 4.31 (lH, s), 4.60 (lH, d), 5.04 (2H, s), 5.71 (2H, q), 7.24 (SH, s). EXAMPLE 46 p-Toluenesulfonate Salt of Pivaloyloxymethyl 6-alpha (Aminomethyl)penicillanate 1,1-Dioxide Title product of the preceding Example (1.8 g, 3.53 mmoles) was hydrogenated in a mixture of TMF (40 ml) and H20 (20 ml) over 1.8 g of 10* Pd/C in the presence of pyridinium p-toluenesulfonate (1.77 g, 7.06 mmoles) at 50 psig for 1.5 hours. The catalyst was recovered by filtration over diatmoaceous earth and the filtrate stripped of THF in vacuo, during which the title product crystallized, 1.2 g, mp 214-2150C (dec.); pnmr/DMSO-d6/TMS 1.16 (9H, s), 1.32 (3H, s), 1.48 (3H, s), 2.28 (3H, s), 3.34 (2H, m), 3.82 (1H, m), 4.60 (1H, s), 5.14 (1H, d, J = 2Hz), 5.75 (2H, ABq), 7.23 (4H, ABq). Anal. Calcd. for C15H24O7S.C6H7SO3H C, 48.16; H, 5.88; N, 5.11. Found: C, 48.31; H, 6.11; N, 5.08. EXAMPLE 47 Chloromethyl 6- (D- ( 2-azido-2- phenhylacetamido)]penicillanate A solution of 12.0 g (0.03 mole) 6-[D-(2-azido- 2-phenylacetamido)penicillanic acid sodium salt, 25 ml water was combined with 100 ml methylene chloride and 10.17 g (0.03 mole) tetrabutylammonium hydrogen sulfate. The mixture (pH 3.0) was adjusted to pR 7.5 with sodium bicarbonate, the organic layer is separated and the aqueous layer was extracted with 2 X 100 ml methylene chloride. The combined organic layers were dried (Na2SO4) and the solvent evaporated to yield a solid residue. The residue was triturated with ethyl acetate (300 ml), filtered, the cake washed with ethyl acetate followed by ethyl ether and dried under nitrogen to afford 16.5 g (89%) of tetrabutylammonium salt. A mixture of 12.32 g (0.02 mole) of the above salt was combined with 70 ml chloroiodomethane and the mixture stirred overnight at ambient temperature. The reaction mixture was concentrated to dryness and the residue purified by chromatography on 600 g silica gel, eluting with 1:1 ethyl acetate/hexane by volume to afford 8.1 g (95%) of the desired chloromethyl ester as a pale yellow viscous oil, pnmr/CDC13: 1.58 (s, 3H), 1.68 (s, 3H), 4.45 (s, 1H), 5.1 (s, 1H), 5.5-5.9 (dd m, 4H), 7.2 (d, 1H) and 7.4 (s, 5H) ppm. EXAMPLE 48 Iodomethyl 6-[D-(2-Azido-2 phenylacetamido)]penicillanate Title product of the preceding Example (1.45 g, 0.00342 mole) in 30 ml acetone was purged 3 minutes with N2. NaI (2.55 g, 0.01714 mole) was added and the resulting solution stirred 16 hours at ambient temperature. The reaction mixture was clarified by filtration, the filtrate concentrated in vacuo, and the residue taken into 75 ml CHCl3 and filtered. The CHCl3 filtrate was washed 2 x 30 ml saturated NaCl, dried (Na2SO4) and concentrated to yield title product as a foam, 1.23 g, pnmr/CDCl3/TMS/delta (ppm): 1.53 (3H, s), 1.64 (3H, s), 4.37 (1H, s), 5.05 (1H, s), 5.56 (2H, m, J = 4, 11 Hz), 5.87 (2H, ABq), 7.31 (5H, s). EXAMPLE 49 6-alpha-(benzyloxycarbonylaminomethyl) l,l-dioxopenicillanoyloxymethyl 6-[D-(2 Azido-2-phenylacetamido) ] penicillanate Title product of Example 16 (0.56 g, 1.43 mmoles) was dissolved in 50 ml CH2C12. H2O (20 ml) was added and the pH adjusted to 8.6 with 1N NaOH. NaHCO3 (0.121 g, 1.43 mmoles) was added followed by tetrabutylammonium hydrogen sulfate (0.488 g, 1.43 mmoles) in portions, while maintaining pH 8.0-8.3 with 1N NaOH, until near the end of the addition, when the pH was allowed to drop to 7.0. After stirring the mixture 15 minutes, the layers were separated. The aqueous layer was extracted 1 x 30 ml fresh CH2C12. The combined organic layer and extract was dried (Na2SO4) and concentrated in vacuo to yield tetrabutylammonium 6-alpha- (benzyloxycarbonylaminomethyl ) - penicillanate l,l-dioxide as a foam. The latter was dissolved in 20 ml acetone and added to a solution of title product of the preceding Example (0.714 g, 1.43 mmoles) in 15 ml acetone and the mixture stirred 1 hour at ambient temperature, concentrated in vacuo and the residue slurried in 30 ml of ethyl acetate to yield crystalline tetrabutylammonium iodide (0.42 g). The filtrate was evaporated to a foam (1.2 g) which was chromatographed on 100 g silica gel eluting with 208 ethyl acetate/CHC13 in 20 ml fractions. Clean product fractions (Rf 0.22 on tlc with the same eluant) were combined and concentrated in vacuo to yield purified title product as a foam, 0.61 g, pnmr/CDC13/delta (ppm): 1.33 (3H, s), 1.48 (3H, s), 1.52 (3H, s), 1.59 (3H, s), 3.65 (3H, m), 4.33 (1H, s), 4.42 (1H, s), 4.61 (1H, s tbr]), 5.05 (3H, s), 5.58 (5H, m), 7.24 (5H, s), 7.32 (5H, s). EXAMPLE 50 Di(p-toluenesulfonate) Salt of 6-alpha-(Aminomethyl)-l,l dioxopenicillanoyloxymethyl 6-[D-2- Amino-2-phenylacetamido)penicillanate Pd/C (10%, 2 g) was prehydrogenated in 20 ml of water. A solution of title product of the preceding Example (0.96 g, 1.226 mmoles) in 30 ml THF and then pyridinium p-toluenesulfonate (0.615 g, 2.452 mmoles) were added, and the mixture hydrogenated for 1.5 hours at 50 psig. Catalyst was recovered by filtration over diatomaceous earth with THF and H2O wash. THF was removed from the combined filtrate and washes by concentration in vacuo. The aqueous residue was extracted 3 x 30 ml ethyl acetate and freeze dried to yield title product, 0.66 g, contaminated with unreduced benzyloxycarbonyl compound. Fresh 10% Pd/C (1.0 g) was prehydrogenated in 20 ml of H2O. The contaminated title product (0.5 g) was dissolved in 30 ml THF and then added to the prereduced catalyst slurry. Finally, fresh pyridinium p-toluenesulfonate (0.315 g) was added and the mixture hydrogenated at 50 psig for 1.5 hours. Catalyst was recovered and purified title product recovered as above, 0.5 g, pnmr/DMSO-d6/TMS/delta (250 MHz): 1.35 (6H, br. s), 1.47 (6H, s), 2.30 (6H, s), 3.38 (2H, m), 3.94 (1H, m), 4.45 (1H, s), 4.72 (1H, s), 5.08 (lH, br. s), 5.31 (1H, br. s), 5.45 (1H, d, J = 4Hz), 5.60 (1u, m), 5.93 (2H, m), 7.32 (8H, ABq), 7.48 (5H, m). EXAMPLE 51 l,l-Dioxopenicillanoyloxymethyl 6 alpha-(Benzyloxycarbonylamino methyl)penicillanate l,l-Dioxide Title product of Example 16 (0.5 g, 1.26 mmoles) was dissolved in 50 ml CH2C12, H2O (10 ml) was added and the pH adjusted to 8.6 with 1N NaOH. NaHCO3 (0.106 g, 1.26 mmoles) and then tetrabutylammonium hydrogen sulfate (0.428 g, 1.26 mmoles) were added. The pH, which dropped to 5.0, was adjusted to 7.5 with 1N NaOH. After stirring 30 minutes at ambient temperature, the organic layer was separated, dried (Na2SO4) and concentrated in vacuo to yield tetrabutylammonium 6-alpha- (benzyloxycarbonylaminomethyl ) - penicillanate l,l-dioxide as a foam. The latter was dissolved in 20 ml of acetone. Iodomethyl penicillanate l,l-dioxide (prepared, for example, according to Godtfredsen et al., U.S. Patent 4,342,772; 0.47 g) in 15 ml acetone was added and the mixture stirred for 5 minutes, and then concentrated in vacuo. The residue was slurried in 30 ml of ethyl acetate and crystalline tetrabutylammonium iodide (0.33 g) recovered by filtration. The filtrate was concentrated in vacuo. The residue was slurried in 30 ml of ethyl acetate and crystalline tetrabutylammonium iodide (0.33 g) recovered by filtration. The filtrate was concentrated in vacuo to yield title product as a foam, 0.82 g, pnmr/CDC13/TMS/delta (ppm): 1.40 (3H, s), 1.42 (3H, s), 1.58 (6H, s), 3.41 (2H, m), 3.69 (3H, m), 4.40 (2H, s), 4.58 (2H, m), 5.08 (2H, s), 5.59 (1H, m), 5.86 (2H, s), 7.29 (5H, s). EXAMPLE 52 p-Toluenesulfonate Salt of l,l-Dioxo- penicillanoyloxymethyl 6-alpha- (Amino- methyl)penicillanate 1,1-Dioxide Pd/C (10%, 1.2 g) was prehydrogenated in 10 ml H2O. Pyridinium tosylate (0.482 g, 1.92 mmoles) and then a solution of title product of the preceding Example in 30 ml THF were added and the mixture hydrogenated at 50 psig for 1 hour. Catalyst was recovered by filtration over diatomaceous earth, with THF/H2O wash. THF was removed from the combined filtrate and wash by concentration in vacuo. The aqueous residue was extracted 1 x 30 ml ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to yield 60 mg of solids. The aqueous layer was concentrated to 10 ml. Crystalline title product was recovered by filtration, 100 mg; mp 228-229 C (dec); pnmr/DMSO-d6/delta (250 MHz): 1.35 (3H, s), 1.37 (3H, s), 1.49 (3H, s), 1.50 (3H, s), 2.29 (3H, s), 3.29 (1H, dd, J = 1.7, 16.6 Hz), 3.39 (2H, m), 3.72 (1H, dd, J = 4.6, 16.6 Hz), 3.92 (1H, m), 4.60 (1H, s), 4.77 (1z, s), 5.21 (2H, m), 5.96 (2z, s), 7.31 (4H, ABq). Anal. Calcd. for C18H25N3010S2. CH3C6H4SO3R: C, 44.17; H, 4.89; N, 6.18 Found: C, 45.53; H, 4.76; N, 6.10. The aqueous mother liquor was freeze dried to yield 160 mg solids. These were slurried in a small amount of water, filtered, washed with a small amount of ethyl acetate and dried to yield an additional 70 mg of purified title product, having identical mp and pnmr. EXAMPLE 53 Chloromethyl 6-alpha- (Benzyloxycarbonyl- aminomethyl ) penicillanate l,l-Dioxide By the method of Example 49, title product of Example 16 (0.396 g, 1.0 mmole) was converted to its tetrabutylammonium salt. The latter was dissolved in 30 ml bromochloromethane, stirred at ambient temperature for 18 hours, concentrated in vacuo to a foam, and chromatographed on 50 g silica gel with 208 ethyl acetate/CHC13 as eluant in 20 ml fractions. Fractions 6-10 were combined and concentrated in vacuo to a foam, 0.25 g, Rf 0.7 on tlc with same eluant; pnmr/ CDC13/TMS/delta (ppm): 1.37 (3H, s), 1.54 (3H, s), 3.70 (3H, m), 4.38 (1H, s), 4.67 (1H, br s), 5.07 (2H, s), 5.66 (1H, d, J = 9 Hz), 5.70 (2H, ABq), 7.33 (5H, s). EXAMPLE 54 Iodomethyl 6-alpha-(Benzyloxycarbonyl- aminomethyl )penicillanate 1,l-Dioxide Title product of the preceding Example (0.25 g, 0.563 mmole) was dissolved in 15 ml of acetone and purged with N2. NaI (0.42 g, 2.8 mmoles) was added and the resulting solution stirred 17 hours and then concentrated in vacuo. The solids were triturated with CHC13, insolubles removed by filtration and title product recovered from filtrate by concentration in vacuo to a foam, 0.23 g, pnmr/CDCl3/TMS/delta (ppm): 1.39 (3H, s), 1.55 (3H, s), 3.64 (3H, m), 4.28 (lH, s), 4.59 (lH, br. s), 5.04 (2H, s), 5.48 (lH, m), 5.83 (2H, ABq), 5.23 (5H, s). EXAMPLE 55 Methylene bis- [6-alpha-(Benzyloxycarbonyl- aminomethyl)-1,1-dioxopenicillanate] Title product of Example 16 (0.17 g, 0.429 mmole) was converted to its tetrabutylammonium salt (0.27 g) according to the procedure of Example 49. The latter was dissolved in 10 ml acetone and added to a solution of title product of the preceding Example (0.23 g, 0.429 mmole) in 10 ml acetone. The mixture was stirred 15 minutes, concentrated to a foam in vacuo and the foam slurried in 20 ml ethyl acetate. The slurry was filtered to yield tetrabutylammonium iodide (110 mg) and the filtrate concentrated in vacuo to yield title product as a foam, 0.28 g, pnmr/CDCl3/TMS/delta (ppm): 1.36 (6H, s), 1.52 (6H, s), 3.73 (6z, m), 4.40 (2H, s), 4.69 (2H, br. s), 5.08 (4H, s), 5.77 (4H, m), 7.28 (10H, s). EXAMPLE 56 bis-(p-Toluenesulfonate) Salt of Methylene bis- [6-alpha (Aminomethyl)-1,1-dioxopenicillanate] By the procedure of Example 52, title product of the preceding Example was hydrogenated. After recovery of catalyst and removal of THF, the aqueous residue was extracted 3 x 20 ml ethyl acetate and freeze dried to yield title product, 0.19 g, pnmr/ DMSO-d6/TMS/delta (250 MHz): 1.37 (6H, s), 1.50 (6H, s), 2.31 (6H, s), 3.40 (4H, m), 3.94 (2H, m), 4.77 (2H, s), 5.30 (2H, m), 5.98 (2H, m), 7.32 (8H, A8q)

Claims: CLAIMS 1. A compound having the stereochemical formula EMI66.1 wherein in a first alternative n is 1; R is hydrogen; Q is benzyl, o-, m- or -2-hydroxybenzyl, phenethyl, or 2-, 3- or 4-picolyl; and RÚ is hydrogen, or a radical group forming an ester which is h hydrolyzable under physiological conditions; and in a second alternative Q is hydrogen; R is hydrogen or methyl; and n is 2 'and R1 is -CR2-; or n is 1 and R1 is hydrogen, a radical group forming an ester hydrolyzable under physiological conditions; l,l-dioxopenicillanoyloxymethyl; or R4 wherein s EMI67.1 wherein Y is hydrogen, hydroxy, (C2-C7)-alkanoyloxy, (C2-C7)-alkoxycarbonyloxy, benzoyloxy, or benzoyloxy monosubstituted with (Cl-C4)-alkyl, (Cl-C4)-alkoxy or halo; a pharmaceutically-acceptable acid addition salt thereof; or a pharmaceutically-acceptable cationic salt thereof when R1 is hydrogen. 2. A compound of claim 1 in the second alternative, wherein n is 1, R1 is hydrogen and R is hydrogen or methyl. 3. A compound of claim 1 in the second alternative wherein n is 1 and ,R is pivaloyloxymethyl. 4. A compound of claim 3 which is in the form of its P-toluenesulfonate salt. 5. A compound of claim 1 in the second alternative wherein n is: í and R1 is l,l-dioxopenicillanoyloxymethyl. 6. A compound of claim 1 in the second alternative wherein n is 2 and R is -CH2-. 7. A compound of claim 1 in the first alternative. 8. A compound of the stereochemical formula EMI68.1 wherein R is hydrogen or methyl and X is chloro or iodo. 9 A compound of the stereochemical formula EMI68.2 wherein R is hydrogen or methyl, and A EMI68.3 or S. 10. A compound of the stereochemical formula EMI69.1 wherein R is hydrogen or methyl and Y' is benzyloxycarbonyl amino, amino, azido, or trifluoromethanesulfonyloxy. 11. A pharmaceutical composition for treating bacterial infections which comprises in a weight ratio of 1:3 to 3:1 a compound of claim 1 excluding compounds of the second alternative wherein Q is hydrogen, R is hydrogen or methyl, n is I and R1 is R , and a beta-lactam antibiotic. 12.- A pharmaceutical composition aordiAg to claim 11 wherein the beta-lactam antibiotic is: amoxicillin, ampicil lin, azlocil lin, bacampicillin, carbenicillin, carbenicillin indanyl, carbenicillin phenyl, cefaclor, cefadroxil, cefaloram, cefamandole, cefamandole nafate, cefaparole, cefatrizine, cefazolin, cefmenoxime cefonicid cefodizime cefoperazone, ceforanide, cefotaxime, cefoxitin, cefsulodin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, cephacetrile, cephal exin, cephaloglycin, cephal oridine, cephal othin, cephapirin, cephradine, cyclacillin, epicil lin, hetacil lin, levopropylcillin, mecillinam, mezlocillin, penicillin G, penicillin V, phenethicillin, piperacillin, pirbenicillin, pivampicil lin, sarmoxicil lin, sarpicillin, suncillin, talampicillin or ticarcillin; or a pharmaceutically acceptable salt thereof. 13. A pharmaceutical composition suitable for treating a bacterial infection in a mammal which comprises an antibacterially effective amount of a compound of claim 1 in the second alternative wherein Q is hydrogen, R is hydrogen or methyl, n is 1 and RÚ is R4, together with a pharmaceutically acceptable diluent or carrier. EMI72.1 1. A process for preparing a compound having the stereochemical formula EMI72.2 wherein R is hydrogen or methyl; and n is 2 and RÚ is -CH2-; or n is 1-- ana R is hydrogen, a radical group forming an ester hydrolyzable under physiological conditions; 1,1-dioxopenicillanoyloxymethyl; or R4 wherein R4 is EMI72.3 wherein Y is hydrogen, hydroxy, (C2-C7)-alkanoyloxy, (C2-C7)-alkkxycarbonyl, benzoyloxy, or benzoyloxy monosubstituted with (C1-C4)-alkyl, (C1-C4)-alkoxy or halo; which is characterized by hydrogenolysis, in a reaction inert solvent over a noble metal catalyst, of a compound of the formula EMI73.1 wherein R is hydrogen or methyl; and 5 n is 2 and R is -CR2-; or n is 1 and R5 is benzyl, a radical group forming an ester hydrolyzable under physiological conditions; 1,l-dioxopenicillanoyloxymethyl; or EMI73.2 wherein Y" is hydrogen, benzyloxycarbonyloxy, (C2-C7 )-alkanoyloxy, (C2-C7 ) -alkoxycarbonyloxy, benzoyloxy, or benzoyloxy monosubstituted with (C1-C4)-alkyl, (C1-C4)-alkoxy or halo; and Z is azido, or benzyloxycarbonylamino; and, if desired, converting said compound of the formula (I) or (II) to a pharmaceutically acceptable acid addition salt, or to a pharmaceutically acceptable cationic salt when R1 is hydrogen. 2. A process of claim 1 which is further characterized by the preparation of the compound of the formula (III) or (IV) wherein R is hydrogen or methyl, n is 2 and R5 is -CH2- by reacting a compound of the formula EMI74.1 wherein R is hydrogen or methyl and X is chloro or bromo, with a salt of an acid of the formula EMI75.1 3. A process of claim 1 which is further characterized by the preparation of the compound of the formula (III) or (IV) wherein R is hydrogen or methyl1 n is 1 and R5 is benzyl, by one step or stepwise oxidation of a sulfide of the formula EMI75.2 wherein R is hydrogen or methyl. 4. A process of claim 1 which is further characterized by the preparation of the compound of the formula (III) or (IV) wherein R is hydrogen or methyl, n is 1 and R5 is a radical group forming an ester hydrolyzable under physiological conditions selected from the group consisting of pivaloyloxymethyl and acetoxymethyl, by reacting chloromethyl pivalate or bromomethyl acetate with a salt of an acid of the formula (VII) or (VIII). 5. A process of claim 1 which is further characterized by preparation of the compound of the formula (III) or (IV) wherein R is hydrogen or methyl, n is 1 and g5 is l,l-dioxopenicillanoyloxymethyl by either reacting the halomethyl ester of the formula (V) or (VI) with a salt of penicillanic acid 1,1dioxide; or reacting the salt of an acid of the formula (VII) or (VIII) with a halomethyl ester of penicillanic acid. 6. A process of claim 1 which is further characterized by the preparation of the compound of the formula (III) or (IV) wherein R is hydrogen or methyl, n is 1 and R5 is the radical of the formula (B) by either reacting the iodomethyl ester of the formula (V) or (VI) with a salt of an acid of the formula EMI76.1 wherein Y" is H, benzyloxycarbonyloxy, (C2-C7)alkoxycarbonyloxy, benzoyloxy, or benzoyloxy mono-substituted with (C1-C4)alkyl, (Cl-C4)alkoxy or halo; or reacting the salt of the acid of the formula (VII) or (VIII) with a halomethyl ester of the acid of the formula (XI). 7. A process for preparing a compound of the formula EMI77.1 wherein Q is benzyl, o-, m- or -p-hydroxybenzyl, phenethyl, or 2-, 3- or 4-picolyl; and 7 is hydrogen, or a radical group forming an ester which is hydrolyzable under physiological conditions; which is characterized by reacting an aminomethyl compound of the formula EMI78.1 wherein R7 is as defined above, with an equivalent of benzaldehyde, o-, m- or ±-hydroxybenzaldehyde, phenyl acetaldehyde or 2-, 3- or 4-pyridinecarbaldehyde in the presence of excess sodium cyanoborohydride; and, if desired, converting said compound of the formula (,XII) or (XIII) to a pharmaceutically-acceptable acid addition salt; or converting a compound of the formula (XII) or (XII) wherein R1 is hydrogen to a pharmaceutically acceptable cationic salt. 8. A process for the preparation of a compound of the formula EMI78.2 which is characterized by one step or stepwise oxidation of a compound of the formula EMI79.1 9. A process for the preparation of a compound of the formula EMI79.2 which is characterized by the steps of (a) reacting an alcohol of the formula EMI80.1 with trifluoromethanesulfonyl chloride to form tri fluoromethanesulfonate ester of the formula EMI80.2 (b) reacting said trifluoromethanesulfonate ester with an azide salt to form an azido compound of the formula EMI81.1 (c) reducing said azido compound with hydrogen sulfide'to form an amino bromo compound of the formula EMI81.2 (d) reacting said amino bromo compound with benzyl chloroformate to. form an amido bromo compound of the formula EMI82.1 (e) debrominating said amido bromo compound with tri(n-butyl)tin hydride.

Inventors: BARTH, WAYNE ERNEST
Applicants: PFIZER INC.
Application year: 1983
Main classification: C07D499
IPC codes: A61K31, C07D499, A61P31, A61P43, C07D519