CA1152981A - Process and intermediates for penicillanic acid 1,1-dioxide and esters thereof - Google Patents

Process and intermediates for penicillanic acid 1,1-dioxide and esters thereof

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Publication number
CA1152981A
CA1152981A CA000346954A CA346954A CA1152981A CA 1152981 A CA1152981 A CA 1152981A CA 000346954 A CA000346954 A CA 000346954A CA 346954 A CA346954 A CA 346954A CA 1152981 A CA1152981 A CA 1152981A
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acid
dioxide
added
ethyl acetate
sodium
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French (fr)
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Robert A. Volkmann
Ronnie D. Carroll
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Pfizer Inc
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Pfizer Inc
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D499/00Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE

A process for the preparation of penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo.
Said process involves oxidation of a 6,6-dihalo derivative of penicillanic acid, or an ester thereof readily hydrolyzable in vivo, to the corresponding 6,6-dihalo derivative of penicillanic acid 1,1-dioxide of ester thereof, followed by dehalogenation (e.g. by hydrogenolysis). The 6,6-dihalo derivatives of penicillanic acid 1,1-dioxides, and esters thereof readily hydrolyzable in vivo, are novel intermediates.
Penicillanic acid 1,1-dioxide, and esters thereof readily hydrolyzable in vivo, are known compounds which are useful as beta-lactamase inhibitors and for enhancing the effectiveness of certain beta-lactam antibiotics (e.g. the penicillins) in the treatment of bacterial infections in mammals, particularly humans.

Description

~ ~ 5;Z~B~

This invention relates to a new chemical process, and to new chemical compounds useful as intermediates in said process. More particularlyJ
it relates to a new chemical process for the preparation of penicillanic acid l,l-dioxide and esters thereof readily hydrolyzable in vivo. Said new chemical process comprises oxidation of a 6,6-dihalo derivative of penicillanic acid, or ester thereof readily hydrolyzable in vivo, to the corresponding l,l-dioxide, followed by dehalogenation. Said new chemical compounds useful as intermediates are 6,6-dihalo derivatives of penicillanic acid l,l-dioxides and esters thereof readily hydrolyzable in vivo.
Penicillanic acid l,l-dioxide and esters thereof readily hydrolyzable _ vivo are useful as beta-lactamase inhibitors and as agents which enhance the effectiveness of certain beta-lactam antibiotics when the latter are used to treat bacterial infections in mammals, particularly humans. Previously, penicillanic acid l,l-dioxide and esters thereof readily hydrolyzable in vivo have been prepared from 6-bromopenicillanic acid, or ester thereof readily hydrolyzable _ vivo, by debromination to give penicillanic acid, or ester thereof readily hydrolyzable in vivo, followed by oxidation to the l,l-dioxide.
Although the process of the present invention starts with a 6-halopenicillanic acid, or ester thereof readily hydrolyzable in vivo, and involves the steps of dehalogenation and oxidation, surprisingly it is found that, if the oxidation step is performed before the dehalogenation step, a better yield of product is obtained. See Belgian Patent No. 867,859, granted December 6, 1978; and West German Offenlegungsschrift No. 2,824,535 for details of methods of preparing penicillanic acid l,l-dioxide and esters thereof readily hydrolyzable in vivo.

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6-Halopenicillanic acids h~ye been disclosed ~y Cignarella et al~, ~ournal of Ox~ani~c Chemistry/ 27, 2668 (1~621 and in United State$; Ratent No. 3,206~6~;
~ydrogenolysis of 6-halopenIcillanIc acids to penicillanic acid is disclosed in British Patent Specification No.
1,Q72,1Q8.
Harrison et al., ournal of the Chemical Society (London), Perkin I~ 1772 ~9762- disclose; ~a2 the oxidation of 6,6-di~romopenicillanic acid with 3-chloroperbenzoic acid, to gi~ve a mixture of the corres-ponding alp~a- and ~eta-sulfoxides; (~2 oxidation of methyl 6,6-di~romopenicillanate ~ith 3 chloroper~enzoic acid to give a methyl 6,6-dibromopen;cillanate 1,1-dioxide; (c2 oxidation of methyl ~-alpha-chloropenicil-lanate with 3-chloroperbenzo~c acid, to give a mixture of the corresponding alpha- and beta-sulfox;des; and (d) oxidation of methyl 6-bromopenicillanate with 3-chloroperbenzoic acid, to give a mixture of the corres-ponding alpha- and beta-sulfoxides.
Clayton, Journal of the Chemical Society (London~, (C), 2123, (1969~, discloses: (al the preparation of 6,6-dibromo- and 6,6-diiodopenicillanic acid; n~l oxida-tion of 6,6-dibromopenicillanic acid with sodium periodate, to give a mixture of the corresponding sulfoxides; ~c2 25 hydrogenolysis of methyl 6,6-dibromopenicillanate to give methyl 6-alp~a-bromopenicillanate; (d2 hydrogenolysis of 6,6-dibromopenicillan;c acid, and its methyl ester, to giVe penicillanic acid and its methyl ester, respectively; and (e2 hydxogenolysis of a mixture of 30 methyl 6,6-diiodopen~cillanate and methyl 6-alpha~
- ~odopenic~llanate to giv~ pure methyl 6-alp~a-iodopen-~cillanate.
Th~s ;~nvention relates to a process ~or the preparation of a compound of tne formula H "S~ ~CH3 35 ~ ,Co3Rl - - -(I) 1~ S29~31 or a pharmaceutically-acceptable base salt thereof, wherein Rl is selected from the group consisting of hydrogen and ester-forming residues readily hydrolyzable _ vivo, which comprises the steps of:
(a) contacting a compound of the formula X", ~ S ~ H3 --- (II) ~ '~ 1 O CQOR

or a base salt thereof with a reagent selected from the group consisting of alkali metal permanganates, alkaline earth metal permanganates and organic peroxycarboxylic acids, to give a compound of the formula X" ~ ~lHCH3 --- (III) N -~
O COOR

or a base salt thereof, wherein X and Y are each selected from the group consisting of chloro, bromo and iodol with the proviso that when X and Y are both the same, they must both be bromo; and (b) dehalogenating the compound of formula III.
A preferred way of carrying out step (b) comprises contacting the product of step (a) with hydrogenl in an inert solvent, at a pressure in the range from about 1 to about 100 kg/cm2, at a temperature in the range from about O to about 60C., and at a pH in the range from about 4 to about 9, and in the presence of a hydrogenolysis catalyst. The hydrogenolysis catalyst is usually present in an amount from about 0.01 to about 2.5 weight-percent, and preferably from about 0.1 to about 1.0 weight-percent, based on the compound of formula III.

The preferred va.lue for X and Y is bromo, and the preferred reagents fQx carry~ing ~ut step (aI
are potassium pe~manganate and 3-chlorQper~enzoic acid.
In the case w~erein X and ~ are ~oth chloro, the compound of formula II is difficult to obtaIn. In the case wherein X and Y are ~oth iodo, step ~ of the process of this ~nvention proceeds inconveniently slowly.
Also embraced w~thin t~e am~it o~ this invention are the intermediates of formula III, wherein Xt Y and Rl are as defined a~ove. A pre-ferre.d intermediate ;~s 6,6-di~romopenicillanic acid l,l-dioxide, the compound of t~e formula III, wherein X and Y are ~romo and Rl i5 hydrogen.
This invention relates to the preparation of compounds of the formula I, and to several inter-mediates therefor. Throughout this specification, these compounds are named as deri~atives of peni-cillanic acid, which is represented by the folla~ing structural formula: -~ ~ C~3 - ~ -(IV) In derivatives of penic~:llanic acid, broken line attachment of a substituent to the ~icyclic nucleus indicate.s that the ~u~stituent IS` ~elo~ the plane of : . 25 th~ nucleus. $ucR a $ubstituent is s:a~d to ~e in the : :alpha-configuratlon. Conye~sely~, solid line attac~-~ ment of a substi.tuent to the ~.~cycl~c nucleus indicates .
: that the. su~stituent is a~o~e the plane of the nucleus.
: This latter configuration is referred to as the ~eta-~configuration. Thus, the group X has the alpha-configuration and the group Y~has the beta-configuration , in formula II.

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In this specification, w~en ~ is. an ester forming residue readil~ ~ydrolyza~le in ~y~, it is a grouping whi:ch.is notionally der;~ved ~rom an alcoh~l of the formula Rl-O~, such.that the moiety CQORl in such.a compound of ~ormula I represents an es.ter grouping. ~oreover, Rl is of such.a nature that the grouping COORl IS readily cleaved in vivo to li~erate a free carboxy group (cQoHl. That is to say, Rl is a group of the type that when a compound of formula I, wherein Rl is an ester-forming residue readily hydrolyzed in Vi70 ~ i` S exposed to mammali~n blood or tissue, the compound of formula I, wherein Rl is hydrogen, is readily produced. The.groups Rl are well known in the penicillin art. In most instances, they improve the absorption ch~racteristics of the penicillin compound. Additionally, Rl should ~e of such a nature that it imparts pharmaceutically-acceptable properties to a compound of formula I, and it liberates pharmaceutically-acceptable fragments when cleaved in vivo. The groups Rl are we~l known and are readily identified ~y those skilled in the penicillin art. See, for example, ~est German Offenlegungsschrift No. 2,517,316. Specific examples of groups for Rl are 3-phthal~dyl, 4-crotonolactonyl, gamoa-butyrolacton-4-yl and groups of the formula ~C-O-C-R and ~C-O~C~O-R

V VI
~, :
: wherein R2~an~d R3 are. each.selected fFom tn~ group consist~ng of ~ydrogen and a}kyl having from 1 to 2 carbon atoms, and R4 ~s alkyl having from 1 to 5 carbon atoms. However, preferred groups for R are .
, ' ~6-alkanoyloxymethyl having fro.m 3 tq 7 c~rbon atoms, l-(alkanoyloxyLeth~l hay~ng from 4 to 8 carb.on atoms, l~methyl-l-(alkanoyloxy~e.t~yl h~ving from 5 to 2 carbon atoms, alkoxycar~onyloxymethyl having from 3 to 6' car~on atoms, l-~alXo~ycarbonyloxy~et~yl having from 4 to 7 carbon atoms, l-methyl-l-alkoxy-carbonyloxy)ethyl having .from 5 to 8 car~on atoms, 3-phthalidyl, 4-crotonolactonyl and gamma-~uty-rolacton-4-yl.
lQ 3-Phthalidyl, 4-crotonolactonyl and gamma-butyrolacton-4-yl refer to structures VII~ V~II and IX. The wavy l;nes are ir.tended to denote either of the two epimers or a m~xture thereof.

o'~3 ,3 0~
O O o VII VIII IX

Step (a) of the process of this invention involves oxidation of the sulfide grouping in a compound of the formula II to a sulfone grouping, thereby producing a compound of the formula III. A
: wide variety of oxidants known in the art for the :20 oxidation of sulfides to sulfones can be used for this process~. However,.particularly convenient reagents are alkali metal permanganates such as sadium and potassium permanganate; alkaline earth.
~ meta~l permanganates, such as calcium and barium permanganates; and organic peroxycar~ox~lic acids, ~such.as peracetic acid a,nd 3-chlo,xoperb,enzo~c acid.

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When a compound o~ the formula II, wh.e~ein X, Y
and Rl are as defined pre~iou~l~, is oxidIz.ed to the correspond~ng compound of the formula III ! usIng a metal permanganate, the reaction is usually carried out by treating the compound of the. ~ormula II ~it~
from about 0.5 to about ten molar equivalents, and preferably from a~out one to a~out four molar equivalents, of the permanganate in an appropriate, reaction-inert solvent system. An appropriate, reaction-inert solvent system is one that does not adversely interact with either the starting materials or the product, and water is commonly used. If des~red, a co-solvent which is misc.ible with water hut will not interact with the permanganate, such as tetxahydro-furan, can be added. Th reaction can ~e carriedout at a temperature in t~e range from about -30 to about 50C., and it is preferably carried out from about -10 to about 10C. At about 0C. the reaction is normally substantially complete within a short period, e.g.
within one hour. Although the reaction can be carried out under neutral, basic or acid conditions, it is preferable to operate at a pH in the range from about 4 to about 9, perferably 6-8. However, it is essen-tial to choose conditions which.avoid decomposition of the beta-lactam ring system of the compound of the formulae II or III. Indeed, it is often advantageous to buffer the pH of the reaction medium in the vicinity of neutral;~ty. T~e.product is recovered by con~entional techniques. An~ excess permanganate is ~ 30 usually decomposed using sodium bisul~ite, and then : ~ if the product is out of solution, it ig ~ecovered by filtrat~on. It is separated.~om manganese d}ox;de by extracting it into an OrganLc solvent and ~: :
. ~, :

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removing the solvent by evapo~ation. Alternati~ely, if the product is not out of solution at t~ end of the reaction, it is isolated ~y~ th~ usual proce ure of solvent extract;on.
~hen a compound o~ the for~ula II w~erein X, Y
and Rl are as previously defined, is oxidized to the corresponding compound of t~e formula III using a peroxycarboxylic acid, the react;~on is usually carried out by treating the compound of the formula II with from aBout l to about ~ molar equivalents, and prefera~ly a~out 2.2 molar e~uivalents of the oxidant in a reaction-inert organic solvent. Typical solvents are chlorinated hydrocarbons, such as d~chloromethane, chloroform and 1,2-dichloroethane; and ethers, such as diethyl ether, tetrahydrouran and 1,2-dimethoxyethane.
The reaction is normally carried out at a temperature of from about -30 to about 50C., and preferably from about 15 to about 3QC. At about 25C., reaction times of about 2 to about 16 hours are commonly used. The product is normally isolated by removal of the solvent by evaporation in vacuo. The reaction product can be purified by conventio~al methods, well known in the art. Alternatively, ~t can be used directly in step (b) without further purification.
Step (bl of the present process is a dehalogena-tion reaction. One convenient method of carrying out this trans~ormation is to stir or shake a solution of a compound o the formula II~ under an atmosphere o hydrogen, or hydrogen mixed w''th an inert diluent ~ such as nitrogen or axgon, i~n the presence o a hydx~genolysis ca*aly~t. $uita~le sol~ents fox t~s hydrogenolys~s react20~ are t~Qse which s~uB~tant;~all~

, . . . , , ~ :

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.. ,. : . , li~i~81 dissolve the starting compQund Qf the ~Q~mula III ~ut which do not themselves su~fer hydro~ena~tiQn ~x hydrogenolys~s. Examples Qf such sol~ents include ethers suc~ as dLethyl ether, tetrahydro~uran, s dioxan and 1,2-dimethDxyethane; lo~ ~olecular weight esters such as ethyl acetate and ~utyl acetate;
tertiary amLdes such as N~N~dimethylformamide, ~/N^
dimethylacetamide and N-methy~lpyrrolidone; water; and mixtures thereof. Addition~lly, it IS usual to buffer the reaction mixture so as to operate at a pH in the range from about 4 to 9, and preferably from about 6 to 8.
Borate and phosphate ~uf~exs are commonly used. ~ntro-duction of the hydrogen gas into the reaction medium is usually accomplished by carrying out the reaction in a sealed vessel, contain;ng the compound o~ ~ormula III, the solvent, the catalyst and the hydrogen. The pressure inside the reaction vessel can vary from about 1 to about 100 kg/cm2, The preferred pressure range, when the atmosphere inside the reaction vessel is substantially pure hydrogen, is rom about
2 to about 5 kg/cm2. The hydrogenolysis is generally run at a temperature of ~rom about Q to a~out 60C., and prefera~ly from about 25Q to a~out 50C.
Utilizing the preferred temperature and pressure values, hydrogenolysis generally takes place in a few hours, e.g., from about 2 hDurs to about 2n hours.
The catalysts used in this hydrogenolysis reaction are the type of agents known in the art ~or this kind of transformatlon, and typical exa~ples are the 3Q noble metals, such`as nickel, pallad~um, platinum and rhodium. The catalyst ~s usually present ~n ~n ~amount from afiout ~.~1 to a~ut 2.5 ~e~g~t-percent, `` :

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and preferably from about 0.1 to about 1.0 weight-percent, based on the compound of formula III. It is often convenient to suspend the catalyst on an inert support; a particularly convenient catalyst is palladium suspended on an inert support such as carbon.
Other methods can be used for reductive removal of the halogen from a compound of formula III, i.e. step (b). For example, X and Y can be removed using a dissolving metal reducing system, such as zinc dust in acetic acid, formic acid or a phosphate buffer, according to well-known procedures.
Alternatively, step (b) can be carried out using a tin hydride, for example a trialkyltin hydride such as tri-n-butyltin hydride.
As will be appreciated by one skilled in the art, when it is desired to prepare a compound of the formula I, wherein Rl is hydrogen, a compound of the formula II, wherein Rl is hydrogen, can be subjected to steps (a) and (b) of the process disclosed herein. In other words, the process comprises oxidation, followed by dehalogenation, of a 6,6-dihalo derivative of penicillanic acid with a free carboxy group at the 3-position. However, in a further aspect of this invention, it is possible to begin either of steps (a) and (b) with the carboxy group at the 3-position blocked by a conventional penicillin carboxy protecting group. The protecting group can be removed during or after step (a) or step (b), with regeneration of the free carboxy group. In this regard, a variety of protecting groups conventionally used in the penicillin art to protect the 3-carboxy group can be `'~

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~11--employed. The major re~uLxe~ents ~or the prQtecting group are that it must ~e attac~able to the part~cular compound of ~o~mula II or I~ nd xemQYable ~rom th~
part;`cular c~mpound of ~or~ula I~or I~ us~in~ condit~ons under w~ich the ~eta-lactam r;~ng s~ste~ remains substan-tially intact. For each of steps (~al and o~), typical examples are t~e tetr~ydropyranyl group, trialkylsilyl groups, the benzyl group, su~stituted ~enzyl groups (e.g, 4-nitrobenzyll~ the benzhydryl group, the 2,2,2-tri-chloroethyl group, the t~ut~l group and t~e phenacyl group. Although all protecting groups are not opera~le in all situations a particular group wh~ch can Be used in a particular situat~on ~ill Be readily selected by one skilled in the art. See ~urther: United States Patents 3,632,850 and 3,197,466; Br~tish Patent No. 1,041,985, Woodward et at, Journal of the American C~emical Society r 88j 852 (1966); Chau~ette, 3Ournal of Organic C~emistry~
36, 1259 (1371): Sheehan et al Journal of Organic _hemistry, 29, 2006 Cl964li and "Cephalosporin and -Penicillins, Chemistry and Biology", edite*-by H. E. Flynn, Academic Press, Inc., 1972. The penicillin carboxy protecting group is removed in conventional manner, having due regard ~or the lability of t~e beta-lactam ring system.
The compounds of formula I, II and III, wherein Rl is hydrogen, are acidic and ~11 f~rm salts w~th basic agents.
T~ese salts can be prepared by standard techniques, such as contacting the ac~dic and fiasic companents, usually in a stoichiometr~c ratio, in an a~ueous, non-a~ueous or Q partially~ a~ueous mediu~, as ~ppr~p~i~te. T~e~ are th~n recovered ~ filtrat2Qn, by prec~p2tation w~th a ~: non-solvent followed by ~iltratiQn, ~y evaporat~on of ::

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the solvent, or in the case Q~ a~ueous solutians, by lyophilization, as appropriate. Basic a~ent~ w~ic~ are suitably employed In salt forma~tion b.elQn~ to ~oth the organ-c and inorganic .ypes, and they include a~monia, organic amines, alk.ali metal hydroxides, car~onates, bicarbonates, hydrides and alkoxides, as well as alkaline earth metal hydroxides, car~onates, h~drides and alkoxides.
Representative examples of such.bases are primary amines, such as n-propylamine, n-~utylamine, an~line, cyclohexylamine, benzylamine and octylamine; secondary amines, such as diethy~lamine, moxp~sline, pyrrolidine and piperidine; tert;~ary am~nes, such a~ triethylamine, N-ethylpiperidine, N.~methylmorphol;ne and 1,5-dia-zabicyclor4.3.0]non-5-ene; hydroxides, such as sodium 15 hydroxide, potassium hydroxide, ammon;~um hydroxide and .
barium hydroxide; alkoxides, such as sodium ethoxide and potassium ethoxide; hydrides, such as calcium hydride and sodium hydride; carbonates, such as potas-sium carbonate and sodium carbonate; bicarbonates, such as sodium bicarbonate and potassium bicarbonate; and - alkali metal salts of long-chain fatty acids, such as sodium 2-ethylhexanoate. Preferred salts of the com-pound of the formula I are the sodium, pota.ssium and triethylamine salts.
The compound of formula ~, wherein Rl is hydrogen, and the salts thereof is active a an antibacterial agent of medium potency both in vitro and in vivo ! and the compounds of formula I, where~n ~ is an ester-forming residue readily~ hydr~l~za~le in v~vO~; are active as~ anti~acter~al agents.. of medium potency~ ~n vi~o~
: ~inimum inhi~i.tory concentrat~ons G~2C~s~L of penicillanic acid I,l-dioxide against several.micra~rgani~ms-are ShDWIl in Ta~le ~.
.

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TABLE I
In V tro Anti,~,a,ctexIal Activity o~ Pen~cilla,nic Acid l,l,-D~Qx~dè.

Microorganism ~IC ~mcg 5 Staphylococcus aureus lQQ
Streptococcus faecalIs 2QQ
Streptococcus pyogenes lQQ
Escherichia coli 5Q
Pseudomonas aeruginosa 2QQ
lQ Klebsiella pneumoniae 5Q
Proteus mirabilis 100 Proteus morgani lOQ
Salmonella typhimurium .5Q
Pasteurella multocida 50 15 Serratia marcescens lOQ
Enterobacter aerogenes 25 Enterobacter clocae lQQ
Citroba,cter ~reundii 5Q
; Providencia ~ lQQ
20:~ Staphylococcua eptdermi~s ~ 2QQ
Pseudomonas putiaa 2QQ
HemophLlus in~luenzae 5 Neisser~a gonorrh~eae Q.312 -; .. : . : :

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~ ~;2981 ~14~

The ln ~itro ant~actexial actiy~ty of the compound of t~e formula ~ he~ein Rl ~sA hydrQgen, and its salts, makes them useful as~ indus~trial an-timicro~ials~, for example in w~ter treatment, sl;me control, paint preservation and wood preservation, as well as for topical application as disinfectants. In the case of use of these compound~ for top~cal appli- `
cation, it is often convenient to adm~x the active ingredient ~ith a non-toxic carr~~er, such as vegetable or mineral oil or an emollient cream. S~milarly, it can be dissolved or d;~spexsed in liquid diluents or solvents such as water, alk~nols, glycols or mixtures thereof. In most instances it IS appropriate to employ concentrations of t~e actIve ingredient of from about 0.1 percent to a~out 10 percent by weight, based on total composition.
The in vivo activity o~ the compounds of formula I wherein Rl is hydro~en or an ester-forming residue readily hydrolyzable in vivo~ and the salts thereof, makes them suitable for the control of bacterial infections in mammals, including man, by both the oral and parenteral modes of administrat~on. The compounds will ~ind use in the control of infections caused by susceptible bacteria in human subjects, e.g. infections caused by strains of Neisseria qonorrhoeae.
When cons~dering therapeutic use o~ a compound of the formula I, or a salt thereof, in a mammal, particularly man, the compound can ~e adm~nistered alone, or it can be mixed w~t~ pharmaceut;~cally 3a acceptable carx;~ers or diluents. ~t can ~e administered orall~ or parenterally, ~.e~ ~ntxamuscularly, sub-cutaneausl~ or intraper~toneally~ T~e caxrier or diluent lS chssen on the ~asis of the Intend d .,, -~
~y , .

- ' 1152~Bl ~15-mode of administration. Por example, w~hen cons.ider-ing the oral mode o$ adm~ni~tration, the compound can be. used in the. ~orm o~ ta~lets.~, capsules, lozenges, troches, po~ders, sy~rups, eli~irs~, aqueous solutions and suspensions, and the like, in accordance with standard pharmaceutical practice. The proportional ratio of acti~Ve ingredient to carrier will depend on the chemical nature, solu~.ility and sta~ility of the active ingredient, as well as the d~sage contem-plated. However, pharmaceutical composit;ons con-taining an antifiacterial agent o~ the formula I ~ill likely conta;n from a~out 20% to aDout ~5% o~ active ingredient. In the case o~ ta~lets for oral use, carriers which are commonl~ used include lactose, lS sodium citrate and salts of phosphoric acid. Various disintegrants such as starch., and lu~ricating agents, such as magnesium stearate, sodium lauryl sulfate and talc, are commonly used in tablets. For oral admin-istration in capsule form, useful diluents are lactose and high molecular weight polyethylene glycols. When aqueous suspensions are required ~or oral use, the active ingredient can ~e combined with emulsifying and suspending agents. If desired, certain sweeten-ing and/or ~lavoring agents can ~e added. For parenteral administration, w~hich includes intramus-cular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the actiVe ingred;~ent are usually prepared, and the p~ of the solutions are suita.~ly adjusted and fiuffexe.d, For intravenous use, 30. th~ total concentration of salute~s sh~uld.be con-trolled to render th~ prepaXati.~n ~sotonic.
The. pres:cr~:fiing ph~s~cian w~ll ult.i~atel~ deter-: min~ th~ appropr~ate dose o~ a compound o~ ~ormula I
~or a given human su~ject,~ and t~is can fie expected to vary according to the age, weig~t, and response of the. individual patient, as well as the nature and the ;, ..
, , ~ , .

ii~2981 severity of the. patientls s~mptQms~ Th~ com,po~nd will norm,ally be used orally at dos,ages In th~ ra,nge from a~out 10 to aBout 2QQ mg. per k;~.logram ~ ~.ody weight per day, and parenterally at dosages from about lQ to a~out 4QQ mg. per ~lo~ram of ~ody weight per day. These figures are illustrative only, however, and in some cases it may be neces,sary to use dosages outside these l~mits.
The. compounds of the ~ormula I~ w.herein Rl is hydrogen,or an ester-forming re.sidue readily hydro-lyæa,ble in vivo, or a salt thereaf, enhance the anti-bacterial effectiveness of beta-lactam antibiotics in vivo. They lower the amount ~ t~e anti~iotic which is needed to protect mice against an otherwise lethal inoculum of certain ~eta-lactamase producing bacteria. This ability makes them valuable for co-administration with beta-lactam antibiotics in the treatment of bacterial infections in mammals, parti-cularly man. In the treatment of a bacterial in-fection, said compound of the formula I can be com-ingled with the beta-lactam antibiotic, and the two agents thereby administered simultaneously. Alterna-tively, said compound of the formula I can be admin-istered as a separate agent during a course of treatment with a beta-lactam antibiotic. In some instances it is advantageous to pre-dose the su~ject ~ith.the compound of the formula ~ before initiating treatment w~th a ~eta-lactam antib;.otic~
hen using pen~c~llanic acid l,l-diox~de, a salt ~: : 3Q or an ester thereof read~ly h~dxol~zable ~n vivo to : enhance the e~ect;~veneSs of ~eta~lacta,~ anti~iotic, it is admin~stered pre~erabI~ in formulati.on w~th standard p~armaceutica,l car~i,ers Qx di.luents7 T~e methods of fonmulat;~on di~3cussed earlier for use of 35 :~ penicillanic acid l,l-d~oxide,or an es.ter t~ereof : readily ~ydroly~able in vivo as a s~ngle-ent~ty ~, ~
.

' ' ~- ' .

~17~

antibacterial agent can be usced when co-administration with anoth~r ~eta-lactam anti~Qti:c ~ intended. A
pharmaceutical composition co~risin~ a pharmaceutically~
acceptable carrier, a beta-lactam antib~ot~c and penicillanic acid l~l-dioxLde or a readil~ hydrolyzable ester thereof ~ill normally contain from a~out 5 to about 80 percent of the pha~maceutically acceptable carrier by weight.
When using penicillanic acid l,l-dioxide or an ester thereof read~ly hydrolyza~le in vlVO in combina-tion ~ith another beta-lactam antibiotic, the sul~one can be administered orally or parenterally, i.e.
intramuscularly, subcutaneously ox intraper~toneally.
Although the prescribing physician will ultimately decide the dosage to be used in a human su~ject, the ratio of t~e.daily dosages of the penicillanic acid l,l-dioxide or salt or ester thereo~ and the beta-lactam antibiotic will normally be in the range from about 1:3 to 3:1. Additionally, when using penicil-lanic acid l,l-dioxide or salt or ester théreof readily hydrolyzable in vivo ~n com~ination with another beta-lactam antibiotic, the daily oral dosage of each component will normally be in the range from about la to about 200 mg. per kilogram o~ ~ody weight and the daily parenteral dosage of each component will normally ~e a~out lQ to a~out 400 mg. per kilogram of body weight. These $~gures are illus-trative. only, howe~er, and in some cases ~t may ~e necessary to use dosages outs~de the.se l~m~ts.
Typical ~eta-lactam anti.~iotics wIth~hic~
penicillanic acid l,l-d~oxide and ItS` es*ers read~ly hydrolyzaBle in VIvo can ~e co-adm~nistered are;
6-C2-phenylacet~midQlpenicillanic acid, 6-(P-2-amIno-2-phenylacetam;~do~penicillanic acid, ' ~15Z9E~3 -18~

6-(2~carboxy-2-phenylacetam~dQlpenicillanic acid, and 7-(2-~l-tetrazolyl]acetamidol~3-C2~I5~meth~1-1,3,4-thiadiazolyl]thiomethylL-3-des~cetoxymethyl-cephalosporanic acid.
Typical microorganisms against which the anti-~actexial activity o~ the abo~e beta-lactam anti~iotics is enhanced are:
StaphylocoCcuS aureus t Haemophilus influenzae~
Klebsiella pneumoniae and Bacteroides ~ragilis~
As w~ll be appreciated ~y Qne sk;~lled in the art, some beta-lactam compounds are e~ective when administered orally or parenterally, w~ile others are ef~ective only when administered by the parenteral route. When penicillanic acid l,l-dioxide, a salt or an ester thereof readily hydro}yzable in vivo, is to be used simultaneously ti.e. co-mingled) with a beta-lactam antibiotic which is effective only on~parenteraladministration, a combination $ormulation suitable for parenteral use will ~e required. When the penicil-lanic acid l,l-diox;de or ester thereof is to ~e used simultaneously Cco-mingled~ with a beta-lactam antibiotic which is ef~cttve orally or parenterally, combinations suitable ~ox either oral or parenteral administration can be prepared. Additionall~, it is possible to adm~nister preparations o~ th~ pen~cillanic acid~ dioxide or salt or estex t~exeo~ axally, 3a ~hile at th~ same time admInls~tex~n~ a ~urth~r ~eta-lacta~ anti~otic parenterally~; and ~t is also possi~le to admini~ter preparatI~ns of t~ penicillanic acid l,l-dIox~de or~salt or ester thereo~ parenterally, :
:
. ~

:' .

~1~Z98~

while at the same time ~dministerin.r the further beta-lactam antibiotic orally.
Further details concerning the use and synthesis of compounds of the formula I are disclosed in West German Offenlegungsschrift No. 2,824,535.
6-alpha-Chloropenicillanic acid and 6-alpha-bromoperlicillanic acid are prepared by diazotization of 6-aminopenicillanic acid in the presence of hydrochloric acid and hydrobromic acid, respectively (Journal of Organic Chemistry, 27, 2668 Ll962]). 6-alpha-Iodopenicillanic acid is prepared by diazotization of 6-aminopenicillanic acid in the presence of iodine, followed by hydrogenolysis ~Clavton, Journal of the C mical Society(C~, 2123 [1969]).
6-beta-Chloropenicillanic acid, 6-beta-bromopenicillanic acid and 6-iodo-penicillanic acid are prepared by reduction of 6-chloro-6-iodopenicillanic acid, 6,6-dibromopenicillanic acid and 6,6-diiodopenicillanic acid, respective-ly, with tri-n-butyltin hydride. 6-Chloro-6-iodopenicillanic acid is prepared by diazotization of 6-aminopenicillanic acid in the presence of iodine chloride; 6,6-dibromopenicillanic acid is prepared by the method of Clayton, Journal of the Chemical Society (London) (C) 2123 (1969); and 6,6-diiodo-pencillanic acid is prepared by diazotization of 6-aminopenicillanic acid in the presence of iodine.
The following examples and preparations are provided solely for the purpose of further illustration. Infrared ~IR) spectra were measured as potassium bromide discs (KBr discs)~ and diagnostic absorption bands are reported in wave numbers (cm ). Nuclear magnetic resonance spectra (NMR) were measured at 60 MHz for solutions in deuterochloroform (CDCl3), perdeutero acetone (CD3COCD3), perdeutero dimethyl sulfoxide (DMSO-d6) or deuterium oxide (D20), and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate. The following abbreviations for peak shapes are used: s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet.

ilS~38~

EXAM~LE 1 6-alpha-BromQpeni:cillan~c ACid l,l~ oxide To a s~t~~rred ml~xture o~ 5~0 ml o~ water, 3Qa ml o~
dichloromethane and 56.0 ~ o~ ~-alph~-bromopenicillanic acid w~s added 4N sod~um hydxoxide solut;~on until a sta.ble pH of 7.2 was achieved. Thi~ re~uired 55 ml of sodium hydroxide. The mixture .~as ~tirred at pH 7.2 for 10 m~nutes and then it was filtexed The layers were separated and the organic phase wa5 discarded. The aqueous phase ~as then poured ra~idly, wit~ stirring, into an oxidiztng mixture which had ~een pxepared as followS.
In a 3 l~ter flask was mixed 63.2 g o~ potassium permangana.te, 1,000 ml of watex and 48.Q g of acetic acid. This mixture was stixred for 15 minutes at 20 C.
and then it was cooled to 0 C.
After the 6-alpha-bromopenicillanic ac~d solution had been added to the oxidizing mixture, a cooling bath at -15 C. was maintained around the reaction mixture.
The internal temperature rose to 15 C. and then fell to 5 C. over a 20 minute period. At this point, 30.0 g of sodium metabisulfite ~as added w~ith stirring o~er a 10 minute period at about 1~ C. After a ~urther 15 minutes, the mixture was filtered, and the pH of the ~filtrate was lowered to 1.2 by the addition of 170 ml of 6N hydrochloric:acid.: The aqueous phase was extracted ~ ~ with chloro~orm, and then ~it~ ethyl acetate. Both the -~ : chloroform extracts and the eth~l acetate extracts ~ere : dried using anhydrous ma~nesiu~ sulfate and t~en they a were~:evaporated In y~ t T~e chloro~oxm ~olut~on.a~orded , :
~ :

i~S2~81 10.0 gt (16% y~eldl of th~ title compound, The ethyl acetate solution af$orded 57 g. Q~ an oil, w~c~ was triturated under hexane. A white s~lid appeared. It was f~ltered off, g~v~ng~ 41.5 ~ 66% ~eld~ of the title compound, mp 134~ C, (~eC.l~
Analysis:-calcd- ~or C8XlQErNQ5S: Cr 3~-78; H,
3.23; Br, 25.60; Nr 4.42; S~ lQ.27~, Found; C, 31.05;
H, 3.24; Br, 25.54; N~ 4.66; S~ 10.21%~
EXA~PLE 2 Oxidation of 6-alpha-c~loropenicillanic acid and 6-alpha-iodopenic;llanlc acid ~ith potass;~um permanganate, according to the procedure o~ Example 1, a~ords 6-alpha-chloropenicillan~c acid l,l-dIoxide and 6-alpha-iodopenicillantc acid l,l-dtoxide, respecti~ely.

6-beta-Chloropenicillanic Acid l,l-Dioxide An oxidizing solution was prepared from 185 mg. of potassium permanganate, ~.063 ml. of 85% phosphoric acid and 5 ml. of water. This oxidizing solution was added dropwise to a solution of 150 mg. o~ sodium 6-beta-chloropenicillanate in 5 ml. of ~ater at 0-5 C., until the purple color o~ the potassium permanganate persisted.
Approximatel~ half of the oxidizing solution was required.
At this point, the potassium permanganate color was discharged by the addition of solid sodium bisulfite, and then the reaction mixture ~as filtered. Ethyl acetate was added to the ~iltrate and the pH was adjust-; ed to 1.8. T~e layers were se~ated and the aqueous layer was ~urt~er ext~acted w~th ethyl acetate. The com~ined ethyl acetate laye~s wexe ~as-hed ~t~ water, dried and e~aporated In ~acuo to gi~e 118 m~. of t~e title compound. Th~ NMR spect~o= (~n CD3cqcD3E s~owed ~::
:
.

, - . ~

.. ;.: .... .
.,: .
:, -:

1~5Z98~

absorption at S.82 (d, lH~ ! 5 24 (~, lH~ ~ 4,53 C~, lH)~
1 . 6 2 ( S, 3H~ and 1.5Q (~, 3H~ p~
Th~ aboye product was di,ssol~ed ~n tetra~dro~uran and an equal volume o~ water w,as added. Tfi~ p~ was 5 adjusted to 6.8 using dilute sodium hydroxlde, the tetrahydrofuran was remo~ed ~ evaporat~on in acuo, and the residual aqu~ous solut~on ,w,as freeze dried. This afforded the sodium salt Q~ t~e title campound.
EXZ~P~: 4 6-beta-Bromopenicillan~,c Acid l,l-D~oxide To a solution of 255 mg~ o~ sodium 6-~eta-~romo-penicillanate in 5 ml. of ~ater, at Q to 5a C. ~ was added a solution prepared from 14Q mg~ of potassium permanganate, 0.11 ml. of 85% phosphoric a,cid and 5 ml. o water, at 0 to 5 C. The pH was maintained hetween 6.0 and 6.4 during the addition. The reaction mixture was stirred at pH 6.3 for 15 minutes, and then the purple solution was covered with ethyl acetate. T~e pH was adjusted to 1.7 and 330 mg. of sod~um bisul~ite was added. After 5 minutes, the layers were separated and the aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate soluti:ons were ~ashed w~th brine, dried (MgS~41 and evaporated in vacuo. This afforded 216 mg. of the title compound as white crystals. The NMR
spectrum (in D2O~ showed absorptions at 5.78 Cd, lH, J = 4Hz~, 5.25 ~d, lH, 3 = 4HZ~! 4. 20 ~S, lH), 1.65 ~s, 3H) and 1.46 (~, 3H~ ppm, 6-beta-Iodopen~c'~,llan~c ACi~a l,l-D~oxide Oxidation of 6'-~eta-iod~penic~llan~c ac~d ~tH
pot~ssium permanganate, ~ccoxd~n~ tQ tHe procedure o~
Example 4, a~ords 6-~eta-~dope~i,cIllan~c acid, 1,1-dio~de~

,.

-.

1~5Z~98~

~23-EXA~RLE 6 PiYaloyloxy~ethyl 6.-alp~a-~romQpenicillanate l,l-D;~oxide Ta a soluti~n o~ 3~4 mg. o~ piyal~yloxymeth~l 6-alp~a-bxomopen~cillanate ~n lO. ~l. o~ d~chloromethane is .5 added 4Q0 mg. of 3-chloroper~enz~i:c acid a~ 0. to 5~ C.
The reaction mixture is stirred at 0 to Sa C. ~or 1 hour and then at 25 C~ ~or 24 houx~. Th~ filtered reaction mixture is evaporated to dr~ness in vacuo to gi~e the title compound.

The procedure of Example 6 ~s repeated, except that the pivaloyloxymethyl 6-beta-bromopenicillanate acid is replaced ~y:
3-phthalidyl 6-alpha-chloropen~cillanate,
4-crotonolactonyl 6-beta-chloropenicillanate, gamma-butyrolacton-4-yl 6-alpha-bromopen;c~llanate, acetoxymethyl 6-beta-bromopenicillanate, pivaloyloxymethyl 6-beta-bromopenicillanate, hexanoyloxymethyl 6-alpha-iodopenicillanate, l-(acetoxy)ethyl 6-beta-iodopenicillanate,-l-(isobutyryloxy~ethyl 6-alpha-chloropenicillanate, l-methyl-l-(acetoxylethyl 6-beta-~hloropenicillanate, l-methyl-l-(hexanoyloxylethyl 6-alpha-bromopenicillanate, :methoxycarbonyloxymethyl 6-alpha.-bromopenici~llanate~
25 propoxycarbonyloxymet~yl 6-beta-bromopenicillanate, ~:~ l-(ethoxycarbonyloxy~et~l 6~alpha-~romopenicillanate, l-(putoxycarbonyloxylet~yl 6-alpna-iodopenlcillanate, l-methyl-l-(methoxycax~on~loxy~eth~l 6-beta-iodopen~cil-lanate and 3Q l-meth~1-1-(~sop~opoxyca~bony~lQx~Leth~I 6-alpha-cnlorQ-:~ . pen1c~llanate~
:~ re~pect~el~, Tfi~s af~d~:

:

, .

1~5Z~
~24-3-phthalidyl 6-alpha~chloropenicill~n~te l~l-dioxide, 4-crotonolactonyl 6-beta-chIo~pen~c~llanate l,l-d~ox~de, gamma~hutyrolacton-4-yl 6-alpha-bxo~openIc~llanate 1,1-dioxide., acetoxymethyl 6-beta-bromopenicIllanate l,l-d~oxide, pi~aloyloxymethyl 6-~eta-hromopenicIllanate l,l-dioxide, hexanoyloxymethyl 6-alpha-iodopenicillanate l,l-d~oxide, l-(acetoxy~ethyl 6-~eta-iodopen~cillanate l,l-dioxide, l-(Iso~utyryloxyle*h~l ~-alpha-chloropenic;llanate 1,1-dioxide,l-methyl-l-Cacetoxy)ethyl 6-beta-chloropenicillanate l,l-dioxide, l-methyl-l-(hexanoyloxyIethyl 6~alpha-bxomopenicillanate 1, l-dioxide., methoxycarbonyloxymethyl 6-alpha-bromopenicillanate 1,1-dioxide, propoxycarbonyloxymethyl 6-beta-bromopen;cillanate 1,1-dioxide, l-(ethoxycarbonyloxy)ethyl 6-alpha-bromopenicillanate l,l-dioxide, -l-(butoxyca.rbonyloxylethyl 6-alpha-iodopenicillanate l,l-dioxide, l-methyl-l-(me.thoxycar~onyloxy~ethyl 6-beta-iodopenicil-lanate l,l-dioxide and l-methyl-l-(isopropoxycarbonyloxy~ethyl 6-alpha-chloropen-icillanate l,l-dioxide, respect;~ely.
` E$AMPLE 8 :~ Pen~cillan~c ~cid l.,l-Di~ox~de ; ~ 3~To lQQ ml. o~ ~ater ~a~ ~dded g~4 g, Q~ 6-alpha-~romopenic~llanic acid, l,l~d~ox;~de, at 22q C,, ~ollowed : ~y suff~c~ent 4N sod~um ~dxax~de ~qlut~on to achieve a : stabl:e p~ of 7.3. To th~ re~ulting solut on was added 2,25 g. of 5% pallad~um-~n-carbon ~ollowed By 6~g g. of dipotsss~um phosphatl trihydrlte. This mixture was then ~, ~i5~1 25~

shaken under an atmosphere of h~dr~gen ~t ~ pressure ~arying from 3,5 to 1.8 kg~cm2. ~en ~ydxo~en uptake ceased, t~e solids were xe~ove: ~y filtratIon, and t~e aqueous soluti~n was co~ered wit~ laQ ml. o~ ethyl acetate.
The pH was slo~ly lowered ~xom S.Q to 1.5 ~xt~ 6N ~ydro-chloric acid. T~e layer~ were separated, and the aqueous phase was extracted ~ith further eth~l acetate.
The combined eth~l acetate layers were washed ~it~
brine, dried using anh~dxous magnesium sulfate and evaporated in vacuo. T~e residue was triturated under ether and then the solid materi~l ~a~ collected by filtration. This afforded 4.5 g. (^65% yIeldl of t~e title compound.
Analysis:-Calcd. ~or C8HllNQ5S: C, 41.2Q; ~, 4.75;
lS N, 6.00; S, 13.75%. ~ound: C, 41.16, H, 4.81; N, 6.11;
S, 13.51%.
EXAMPLE ~
Penicillanic Acid 1,1-Dioxide H~drogenolysis of each of:
6-alpha-chloropenicillanic acid l,l-dioxidë, 6-alpha-iodopenicillanic acid l,l-dioxide, 6-beta-chloropenicillanic acid l,l-dioxide, 6-beta-bromopenicillan;c acid l,l-dioxide and 6-beta-iodopenicillanic acid 1,1-dioxide, according to the procedure of Example 8, a~ords pen-icillanic acid l,l-d;~oxide.

~: Pi:val,oyloxymet~lsrl Penici~llana,te l,l~ qxide To a solut~on o~ 1.0 ~. o~ p~valQyl~xymet~yl 6-alpha--bromopenicIllanate ~n lQ ml. a~ met~anol i~ added 3 ml. of lM sod~u~ bicar~anat~ and 2Q0 mg. of lQ% palladium on car~on. Tn~ reactl'~on m~xture~ shaken ~Igorously under an atmcsp~ere af ~ydr~ge~, ~t a p~es~u~e o~ abcut ' - - : -.
- , - . -. :.... , , ~ - . :

llS2~
~26~
5 kg/cm2, until hydrogen u~take ceas.es~ The m~xture is then filtered and t~ bulk of th~ m~thanol ~s remo~ed ~y evaporation ;n vacuo, Water and ~t~l acetate ~re added to the.res~due and the p~ lS; adjusted to 8.5. T~e layers are separated and the organic layer Is was~ed ~ith water, dried tNa2504~ and e~aporated ~n vacuo.
This af~ords the ti.tle comp~und.

Hydrogenolysi~ of the appropriate 6-halopenicil-lanic acid ester l,l-dioxtde ~rom Example 7, according to the procedure o~ Example 10, a~ords the ~ollowing compounds:
. 3-phthalidyl penicillanate l,l-dioxide, 4-crotonolactonyl penicillanate l,l-dtox;~de~
gamma-butyrolacton-4-yl penicillanate lll-dtoxide acetoxymethyl penicillanate l,l-dioxide., pivaloyloxymethyl penicillanate l,l-dioxide, hexanoyloxymethyl penicillanate l,l-dioxide, l-(acetoxy)ethyl penicillanate l,l-dioxide, l-(isobutyryloxy)ethyl penicillanate l,l-dioxide, l-methyl-l-(acetoxy~ethyl penicillanate l,l-dioxide, l-methyl-l-thexanoyloxy~ethyl penicillanates l,l-dioxide, methoxycarbonyloxymethyl penicillanate l,l-dioxide, propoxycarbonyloxymet~yl penicillanate l,l-dioxide, l-(ethoxycarbonyloxy~ethyl penicillanate l,l-dioxide l (butoxycarbon~l)ethyl penicillanate l,l-dioxide, l-methyl-l-tmethoxycarbonyloxy~ethyl penicillanate 1,1-dioxide and l-methyl-l-t~sopropox~ca~bonyl~x~et~yl pen~cillanate 3 a ltl-dioxidel ~ raspecti~eIy.

:
' ~ ' .
:
~:

~sz~
~27-Pivalovloxy~ethyl 6-Alp~a-~om~pen~cillanate l!l-Di~oxide An oxidi:zing soiut~on ~as: prepa~ed ~y com~nin~
4.26 ~, o~ potass;um perma,nganate,,2.65 g~ Q~ 85% phos~
phoric acid and 40 ml. of w~ter, T~ mixtuxe was stirred ~or one houx~ and then it wa,s a,dded slo~ly, durIng 20 minutes, at 5 to 10~ C~, to a, st;~rxed solution o~
5.32 g. o~ p~valoyloxymethyl 6~alpha-~romopenicillanate in 7Q ml. o~ acetone and lQ ml. o~ water. TRe mixture was stirred at 5~ C. ~or 3Q m~nutes-, and lOQ ml. o~
ethyl acetate was added. A~tex a ~urther 3a minutes~
a solution of 3.12 ~. of sodium ~isul~ite in 3Q ml. o~
water was added during 15 minute~ at a~out 1~ C.
Stirring was continued ~or another 30 m~nutes at 5 C.
and then the mixture was ~iltered. The organ~c phase was separated and washed with saturated sodium chloride solution. The dried organic layer was evaporated to give 5.4 g. o~ the title compound as an oil, which slowly crystallized. The NMR spectrum (:in CDC1 20 showed absorptions at 5.80 (:q, 2H~, 5.15 Cd, lH), 4.75 (d, lH), 4.50 ~s, lH), 1.60 Cs, 3HI, 1.40 Cs, 3H) and 1.20 (s, 9HI ppm.

., :, .

- . - -: ., -:
:

~lSZ9~33 -28~

EXA~LE 13 Pivaloyloxymethy~l Penic~ ,nate l,1~ Qx~de A solut~on o~ 4..4 ~ i~aloy~lox~meth~l 6~alp~a~
bromopenicIllanate 1,1-dioxide i,n 6Q ml. of tetra~
hydrofuran was added to 0~84 ~. of sod~um ~icar~onate in 12 ml. o~ water~ The soluti:on was shaken under an atmosphere of hydrogen ln the presence o~ 2. a g. of 5% palladium on car~on at 47 to.51 psig. ThQ reaction mixture was then ~;ltered and the ~esidue was ~as~ed ~ith.100 ml. of eth~l acetate and 25 ml. o~ water.
The combined filtrate and washes were separated, T~e organic layer w~s was~ed .with ~saturated sodium c~loride, and dried (~gSO4~ and e~aporated a~ording t~e title compound as an oil. Thi`S o~l was di~ssolved in ethyl acetate (:20 ml.l, To the solution was added hexane (,100 ml.) slo~ly, and the precipitate ~as filtered off.
Yield: 2.4 g. The NM~ spectrum ~n DMSO-d6~ showed absorptions at 5.75 (,q, 2H), 5.05 ~mr lH~, 4.40 Cs, lH~, 3.95 - 2.95 (m, 2H), 1.40 (S, 3H3, 1.25 (s, 3~1 and 1.10 (,s, 9H), ppm. ,, 2,2,2-Trichloroethyl 6-alpha-Bromopen c;~llanate l,l-Dioxide ~ 2,2,2-Trichloroethyl 6-alpha-bromopen~.cillanate : was oxidized.with potassium permanganate su~stantially according to the proceduxe of Example 12 to give the - title compound in 79~ yield. The ~MR spectrum o~ the product (:in CDC131 showed ~.so~ptions at 5,3Q to 4.70 (:m, 4H~, 4.60 (~ , 1.7Q ~, 3Hl and 1.5Q
Cs, 3Hl ppm.

:

' ,:
' .:
.

11529~
~29-. EXAMPLE 14A
Renicillanic Acid l,l-~ioxI~de To a stirred slur,r~ o~ 6.5 g. o~ zInc powder ~n lOQ ml. of a 70:3q glacial a,cet~c a,cid - tetra,h~dx~furan mixture, was added, portionw~Ise durin~ 5 m~nutes, 4.Q g.
of 2,2,2-trichloroeth~l 6~alp~a~romo~enic;~11anate 1,1-dioxide. The mixture ~as stirred at ambient temperature for 3 hours, and t~en It w,as filtered. T~e filtrate was concentrated to a, ~olume of lQ ml. and the tan solution was mixed ~ith 50 ml, af water and lQ0 ml. o~
ethyl acetate. T~e pH was adjusted tQ 1~3 and the layers were separated. The organic phase was ~ashed wttk satura,ted sod;~um c~Ior;~,de solution, drIed using magnesium sul~ate, and t~en concentrated to dryness in vacuo. The residue was triturated under et~er for 20 minutes. This afforded 553 mg. of the title compound as a solid. The NNR spectrum Cin CDC13~DMSO-d61 showed absorptions at 11.2 (~road,s, lH2, 4.65 ~n, lHl, 4.30 (,s, IH), 3.40 (m, 2H), 1.65 ~s, 3~1 and 1.50 Cs, 3H2 ppm.

Benzyl 6-alpha-Bromopenicillanate l,l-Dioxide Benzyl 6-alpha-bromopenicillanate was oxidized with potassium permanganate substantially according to t~e procedure o~ Example 12, to giYe the title compound in ~4% yield. The NMR spectrum C~n CDC131 sho~ed absorptions at 7.35 Cs, 5H~, 5.10 ~m, 3H1~ 4,85 ~m, lHl, 4.40 (~, lX~, 1.5Q (~, 3Hl and 1.25 rs, 3~1 ppm.

: ~

~ . . ' , . ' -~152~
~30-Peni~cillani~c Ac~d l,l-D~ox;~de A solution o~ 4~ a g . 0~ ~enz~l 6~alp~a-~x~o~
penic~llanate l,l-dioxl~de ;~n 5~ ml. o~ tetrahydro~uran was com~ined w~th a sclution o~ 6 g. of sQdIum ~car~onate in 50 ml. of water. To th mixture was added 2.Q g. o~ a 5~ su$pensIon of 5% pallad~um-on- -carbon in water, then t~is mixture was sha~en under an atmosphere of hydrogen, at a pressure of 46.5 to 50 psig.
for 20 minutes. The catalyst was removed ~ filtration, and then 30 ml. o~ tetrahydrofuran and 3.Q g. of a 50% suspensIon of 5% pallad~um-on-car~on were added.
The result~ng m~xture was shaken under an atmosphere of hydrogen, at pressure of fro~ 42 to 45 psig., for 65 minutes. The reaction m~xture was then filtered and the tetrahydrofuran was removed ~y evaporation. Ethyl acetate was added to the aqueous residue and the pH
was adjusted to 7.1. The ethyl acetate layer was remo~ed, and fresh ethyl acetate was added to the remaining aqueous phase. The pH was lowered to 1.5, and the layers were separated. The aqueous phase was further extracted with ethyl acetate, and the ~ombined ethyl acetate solutions were washed with saturated sodium chloride solution and dried (MgSO4I~ Evaporation in ~acuo ga~e a gum which was tr~turat~d under ether. Th~s af~orded 31 mg. o~ penicillanic acid l,l-dioxIde as a yello~
sol;d. T~e NMR spectrum Cin CDC13~DMSO~d61 showed absorptton at ~.45 ~ro~d s, lHl, 4.~Q ~t, lH~ 4.25 Cs, lH~, 3.4Q (d, 2~I~ 5 (~, 3~ and 1.3Q C~, 3Hl ppm.

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11 5Z9~31 -31~

EXA~P'LE 17
6,6-Dibromopen~c~llan,ic Aci~d l,l-~oxide Ta the d2chIoromet~a'ne solutiQn o~ 6,6:~
dibromopen-cillanic aci,d ~rom ~reparat~on K was added 300 ml of water, ~ollowed b~ the dropwis:e add~tion over a period of 30 minutes of 1~5 ml o$ 3N sodium ~ydrox~de. The p~ ~ta~ zed at 7.Q. The a~ueous layer was removed and the organic layer was extracted with water ~'2 x 10~ mll, To the com~ined aqueous solutions was added, at -5~C, a prem;~xed -qolution prepared from Sg.25g of potassIum pexmanganate, 18 ml of concentrated phosphDric acid and 6QQ ml of water, until the p~nk color of the permanganate pers~sted.
The addition took 5Q minutes and 550 ml of oxidant were required. At this point 500 ml of ethyl acetate was added and then the pH was lowered to 1.23 ~y the addition of 105 ml o~ 6N ~ydrochloric acid. Then 250 ml of lM sodium bisulfite was added during 10-15 minutes at ca, 10C. During the addition of the sodium bisulfite so}ution the pH was mainta-ined at 1.25-1.35 using 6N hydrochloric acid. The aqueous phase was saturated with sodium chloride and the two phases were separa,ted. The aqueous solution was extracted with additional ethyl acetate C2 x 150 ml~
and the combined ethyl acetate solutions were ~ashed with brine and dried Q~gS04~. This a~forded an ethyl acetate ~olution o~ 6,6-d;~romopenic211anic acid 1,1-~; ~ dioxide.
, Tne 6,6-di~ro~o~enc211an~c aci~d l,l-dioxide 3Q ~ can~e isolated' ~remo~al ~ tne sQlYent ~n ~acuo.
A: sa~ple so isol~ted ~r~ a,n ~nalogous, preparation ; had a melt~n~ po~nt o~ 2~1~C ~dec.~ T~e NMR

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spectrum tÇDC13~ D~S~-d~) s~o~ed a~so~ptian~s ~t ~.35 CS,1H1, 5.30 (~,lH~, 4.42 (~,lH~p 1.~3 ~,3H~ and 1.5Q (~,3H;~ppme The ~R spect~u~ (~BE d~scl s~wed a~sorptions at 3846-250Q, 1818, 1754, 1342 and 125Q~
1110 cm;l, 6-Chloro-6-~odopenicillanic Acid l,l-Dioxide To a solut~on of 4.~g of 6-c~loro-6-;odopencillanic ac~d ~n 50 ml o~ dic~loromethane was added 50 ml of water and then the pH was raised to
7.2 ustng 3N sodium hydrox~de. The layers were separated and the aqueous layer was cooled to 5C. To this solution was then added, dxop~i:se, over a 20 minute period, a prem~xed solut~on prepared ~rom 2.61g of potassium permanganate, 1.75 ml o~ con-centrated phosphoric acid and 50 ml of water. The pH
was maintained at 6, and the temperature was maintained below 10C, during the addition. At this point, 100 ml of ethyl acetate was added and the pE was adjusted to 1.5. To the mixture was then added 50 ml of 10%
sodium bisulfite, keeping the temperature bel~ 10C
and the pH at ca l.S by the addition o~ 6N hydro-chloric acid. The pH was lowered to 1.25 and the layers were separated. The aqueous layer was saturated with sodium chlortde and extracted ~it~ ethyl acetate.
The combined organic solut;ons were was~ed w~th ` brine, drted (~gS04~ and evapo~ated in ~acuo to give 4.2g of the title compound, ~p 143-145~C~ The NMR
~pectrum CDC13~ sAo~ed ~sorptions at 4~86 ~,1~l 4,38 (S,lHJ, :le 6Q (~s`~ 3~ and le 43 ~ 3Elpp~ TfiQ IR
spectxum G~B~- d~scl sAowed a~so~pt~ons-at 18~0~ 1740 a~d 125Q~lllQ cm , : ~
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~33-EXAM~LE 1~
6~Bxomo~6-iodo~enic~llan~c ACi`;d 1,l~D~oxide To a solut~on ~ 6,Q ~ 6~o~a~6-iadopenicillanic acLd ~n 5Q ~1 ~ dichlor~methane was added 5Q ml o~ watex, Ths pH wa~ ~ai:$ed to 7.3 using 3N sodium hydroxide and the aque~us la~er wa5 removed~ The or~anic layer was extracted with lQ ml o~ water. The com~;ned ~queou~ phases wexe cooled to 5C, and a prem~xed solution o~ 284g of potassium 10 permanganate in 2 ml of concentrated pnosp~ori~ -acid and 5Q ml of water was added dxop~;se, bet~een 5 and lOQC. The add~tion took 2Q m~nutes. At this point, 5Q ml of ethyl acetate wasi added and the pH
of the mixture was lo~ered to 1.5 using 6N hydrochIoric acid, To this two-phase system was added, drop~ise, 50 ml of 10% sodium ~isulfite, m~intaining the pH
at about 1.5 by the addition of 6N ~ydrochloric acid. An additional 50 ml of ethyl acetate was added, and then the pH was lowered to 1.23. The 2~ layers were separated and the aqueous layer. was saturated with ~odium chloride. The saturated solution was extracted with ethyl acetate C3 x 5a ml) and the combined ethyl acetate layers were wasXed with-brine, dried (MgSO41 and evaporated in ~vacuo. The resi~ue was dried under high vacuum, leaving 4.~2~ of the title compound, mp 145-14~.
The NMR spectru~ CCDC131 showed absorpt~ons at 4.qQ
~s,lH~ 4,30 ~s,lH~ 60 CS~3H1 and 1.42 ~,3H~ppm.
` T~e IR~spectr4m~(X3r d~sc~ s ~ ed ~sorptions at 18QQ, 174~, 133Q and 125Q lll~ c~l~

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115Z9~31 -34~

6-Chlo~o-6^~.omopen~ci11an~c Ac~d l!l~D~Qx~de Oxida,t~n o~ 6.~chlc~x~-6~o~pen~cillanlc acid with potass~um pex-manganate, accoxding to the procedure o~ Exampl~ 1~, af~ords 6~chloro~6~romopent-cillanic acid l,l-d~oxide.
EX~MPLE 21 Penic~llanic Ac~d l,l-D~oxtde .
The ethyl aceta.te solutlon of 6,6~di~romo-lQ penicillanTc acid l,l-dio~ide ~rom Example 17 ~as com~ined with 7~5 ~1 o~ satuxated sodium ~T.car~onate solut~on and 8.88g o~ 5% pall~dium-on-car~on cat-alyst. The m;xture was shaken under an atmosphere of hydrogen, at a pressure of a~out.5 kg~cm2~or a~out 1 hour. The catalyst was removed by ~iltratlon, and the pH of t~e aqueous phase of the filtrate was adjusted to 1.2 with 6N hydrochloric acid. The aqueous phase was saturated with.sodium chloride.
The layers were separated and the aqueous phase was 2~ extracted with further ethyl acetate ~3 x 20Q ml~.
The combined ethyl acetate solutions were dried tMgSO4) and evaporated in vacuo to afford 33.5g C58%
yield from 6-aminopenic;llanic acid~ o~ penicillanic acid l,l~dioxide. Tbis product was dissolved in ~00 ; 2:5 ml of ethyl acetate, the solution was decolorized using acti.vated car~on and the solvent was.~ removed by evaporàtion~ _ acuo. The product wa~ was~ed ~ith hexane. T~s af~oxded 31.Qg o~ pu~e pxoduct.
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~5Z39Bl H~drogenolys~ o~ e,a,ch.o~ ~chloxo~
iodopenicillanic acid l,l-di~oxLde, 6~xoma~6 ~odopenicillan~c ac~d and 6~chlQxo~firomopen~
cillanic acid, respect~:~el'y,,acc,ord~n~ to the proce-dure of Example 21, a~foxds, ~n ea,ch case, pen~cIllan~c acid l,l~dioxi,de.
EXAM~LE 23 Penicillan~c Acid l,l-D~ox~de To a stLrred suspension of 786 m~ of 6~
chloro-6~odopen;cillanic ac~d l,l~diox~de in lQ ml of ~enzene was added 0.3 ml of triet~ylam~ne foll~ed by Q.25 ml of trimethyls~lyl c~loride, at ca UC~
Stirring was continued for 5 m;nutes at ca Q~C and then at the reflux temperature o~ the solvent for 30 minutes. The react~on mixture Was cooled to 25C and the precipitated material was removed by filtration.
The filtrate was cooled to ca 0C and 1.16g of tri-n-butyltin hydride and a few milligrams of azobisiso-butyronitrile were added. The reaction mixture was ' stirred and irradiated with ultra~iolet light for 1 - hour at ca 0C and then for 3.5 hours at the reflux ~' temperature of the sol~ent. A further quantity of -, tri-n-butyltin hydr~de ~1.1 mll and a catalytic '~ ~25 ~amount of azobis~sobutyronitrile were added and stirring and irradiation at t~e xeflux temperature were continued for an add,t;onal 1 hour. The re~
action mlxture was then poured ~nto 5Q ml ~f cold 5%
;sodium bicaxbonate and the two-phase s~stem ~as stirred fox 3~. minutes~. Eth~l ~cetate ~a ml~ was add~d and the~p~ ~s adjusted to 1.5 w~th~6N ~yd~o-chlor~c ac;~d.~ T~ layers~ere~separa,ted and t~e , : ' .
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aqueous layer was extr,a,cted ~I~th ~th~l ~cetate, Th combined ethyl acetate ,soluti~ns wexe ~shed ~th, ~rine, drted (~g$~4~ and e~poxa,ted in V~CUO. Th~
res~due ~as triturated under hex~ne and then recovered by filtxat~on. Th~s afforded Q~Q75 mg o~ the t~tle EXA~,P,LE 24 Penictllanic ~cid l,l~Dioxide To a stirred suspens~on of Q~874g o~ 6~
bromo-6-iodopentcillanic ac;~d l,l-d~oxide in lQ ml lQ of benzene at ca S~C~ wa,s a,dded Q.3 ~1 of triethyl-amine followed by ~.25 ml of tr~methyls~lyl chlor;de.
Stirring was continued at ca 5~C ~or 5 minutes and then for 3Q m;nutes at the re~lux temperature o~ the solvent~ The reaction m;xture was cooled to room temperature and the solids were removed by filtration.
The filtrate was cooled to ca 5C, and 1.05 ml of tri-n-butyltin hydride a,nd a catalytic amount of azobisisobutyronitrile were added. The mixture was irradiated with ultraviolet light for 1 hour at ca 5C, and then it was poured into 30 ml of cold 5%
sodium bicarbonate. The mixture was stirred for 30 minutes and then 50 ml of ethyl acetate were added.
The mixture was acidif~ed to pH 1.5 and the layers were separated. The aqueous layer ~as extracted with ethyl acetate (2 x 25 mll and the comh~ned ethyl acetate layers we~e washed with ~rine, dried ~gS041 and e~aporated in vacuo~ The res~due w~s dr;~ed under high ~acuum and the 3Q ml o~ h~xane was~added, The nsoluble mater~al ~as~reco~e~ed ~ ltxat~Qn, affording Q.Q35~ of thb title compound.

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~37~

E~MP~E 25 Pivalo~loxymeth~l 6,6~D~omopen~cillan~:te 1,l~Dioxlde To a solution o~ 4~73g o~ p~alo~oxymet~l 6,6-dibromopen~cillanate ~n 15 ml o~ dichlo~o~ethane is added 3.8Qg of 3-chloroperbenzoic acid at a to 5C.
The reaction mixture ~s st;sred at Q to 5 QC for 1 hour and then at 253C ~or 24 n~urs. Th~ ~iltered reaction mixture. is e~apor~ted to dryness In vacuo and the residue is part~tioned between ethyl ace.tate and water. T~e pE of the a~ueous phase. ~s adjusted to 7.5, and t~e layers are separated. Th ethyl acetate p~ase is dried (Na2SO4l and e~apor~ted in ~acuo to give the title compound.

Oxidat;on of each.o~ the 6,6-dihalopeni-cillanic acid esters o~ Preparation P using 3-chloro-perbenzoic acid, according to the procedure of Example 25, affords the foll~wing compounds:
3-phthalidyl 6,6-dibromopenicillanate l,l-dioxide, 4-crotonolactonyl 6-chloro-6-iodopenicillanate, 1,1-dioxide, : y-butyrolactonyl 6-bromo-6-iodopencillanate 1,1-dioxide, : acetoxymethyl 6-chlora~6 ~romopen~c~llanate 1,1-dioxide, piyaloyloxy~etnyl ~chl~xo~6~dQpen~ci~ nate 1,1-d~oxide, .~ j :

~15Z~
~ 38-hex~noyloxymethyl 6,6-d~ro~penicillan~te 1,l~dioxide f l-(acetoxy)et~l 6~6~d~k~om.~pen~c~ nate l,l-d~ox~de, l-Cisobut~xyloxy~ethyl 6~bxomo~6~odopen~cill~nate l,l-diox~de, s l-methyl-l-(acetoxy~ethy~l 6,6-di~romo.penicillanate l,l-dioxide, l-methyl-l-(hexanoyloxy~et~l 6~c~1oxo-6~xo~o~
penicillanate, methoxy~arbonyloxymethyl 6,6-dibromopenictllanate l,l-dioxide, propoxycarbonyloxymethyl 6-c~loro-6~iodopenicIllanate l,l-dioxide, l-(ethoxycarbonyloxy)ethyl 6,6 dibromopenicillanate l,l-dioxide, l-(~utoxycar~onyloxylethyl 6~bromo-6-iodopenicillanate : l,l-dioxide, .~ .
l-methyl-l-(~ethoxycar~onylox~)e.thyl 6,6-d;bromo-penicillante l,l-d~ox~de and methyl-l-C~sop~opQx~cax~QnylQ~eth~l 6,6-dt~xomo~
2Q penicillanate l,l-d~oxide., res~ectiYel~.

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11~;Z~81 EXA~PLE 27 Pivalo~lox~methyl P;enIcilla;nat;e l,l~D~ de To a solut;~on o~ l~Qg. of p~yalo~lox~meth~l 6,6-di~omopenicillanate l,l-di~xide in lQ ~l o~ met~anol is added 3 ml Q~ 1~ sodiu~ hicax~.onate and 2Q~ mg o~ lQ%
palladium on car~on. The reaction mixtuxe is sha~en vigorously under an atmosp~exe o~ hydxo~en, at a pressure of a~out 5 kg~cm , until h~dxo~en upta~e ceases. T~.e mixture. is then f~ltered and t~e Bulk of the methanol is remo~ed ~y e~aporation In vacuo.
~ater and ethyl acetate axe added to the ~esidue and the pH is ad~usted to 8.5. The layexs axe sepaxated and the organ;c layer i$ wa.s:he.d ~ith watex, dr~ed (Na2SO4) and evaporated ~n vacuo. Th~s a~fords pivaloyloxymethyl penicillanate l,l-dioxide.

Hydrogenolysis of each of the 6,6-dihalo-penicillanic acid ester l,l-dioxides ~rom Example 26, according to the procedure of Example 27, affords the following compounds~
3-phthalidyl penicillanate l,l-dioxide, 4-crotonolactonyl penicillana.te l,l-dioxide, gamma-butyrolacton-4-yl penicillanate 1,l-dioxide, acetoxymethyl penicillanate l,l-diaxide, ~5 pivaloyloxymethyl penicillanate l,l-dioxide, hexanoyloxymethyl penicillanate l,l-dioxide, (acetox~lethyl penici.llanate l,l~d;oxide, l-(isobutyryloxylethyl pen~cillanate l,l~dio~ide, .:

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l-methyl-(acetoxyleth~l pen~cill~n~te l,l-d~ox~de~
l-methyl-l-(hexanoyloxy~eth~l penic~llan~te 1 t dioxide, methoxycar~onylox~et~l penic;llanate l,l~d~oxides, propoxycar~onyloxymet~yl penicillanate l,l-dioxIde, l-(~ethoxycax~onyloxylethyl pen~cillan te l,l-dLoxtde, l-(butoxycarbonyl~eth~l penIc~llanate l,l-d~ox~de, l-methyl-l-~methoxycarBonyloxyLethyl penic~llanate l,l-dioxide and l-methyl-l-(isopropoxycarbonylox~ethyl pen~cillanate l,l-dioxide, respectivel~.
EXAMPLE 2~
Pivalo~loxvmethyl 6,-D~bromopenicillanate l,l-Dloxide A stirred solutton of 3.~2g of 6,6~dibromo-penicillanic acid l,l-dioxide in 2Q ml of NrN~
dimethylformamide was cooled to QC and then 1.2~g of diisopropylethylamine was added. This was followed by 1.51g of chloromethyl pivalate. This reaction mixture was stirred at 0C for 3 hours, and then at room temperature for 16 hours. The reaction mixture was then diluted with 25 ml of ethyl acetate and 25 ~1 of water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed with cold 5% sodium bicarbonate solut-on, water and ~rine. The ethyl acetate solut~on was then treated with Darco (an activated charcoal~, dr~ed Q~S~4L and e~aporated in vacuo to a ~rown o;~l weig~ ng 2.lg. T~s oil was chromato~xaphed on 2aQ~ o~ sil~ca gel, us~ng dichloro-methane ~s eIuant. The ~a~t~onS conta-~ntng the desired :

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11529~i product were combined and xechxQ~to~raphed on sil~ca gel to giYe. Q. QZ5g o~ th title cQmpound. Tfie ~R
spectrum ~CDC13~ showed abso~pt~ons~ at 6.1Q C~, 2~1, 5.00 rs, lH~ 4.55 (-s,lH~ Q ~,3H1~ 1.5a ~s,3~1, and 1,15 (s,~lppm.
EXAMPLE 3 a Pivaloyloxymet~l Penic~llanate l,l-D~ox~de To a st~rred solut~on of 6Q mg. o~ pivaloyloxy-methyl 6,6-dibromopen~c~llanate l,l-di,ox~de in 5 ml of benzene ~as added 52 ~1 o~ tr~-n~butyltin hyaride followed by a catalytic amount o~ azobisisobutytroni-trile. Th~ reaction mixtu~e was cooled to ca 5C, and then ~t was irradiated ~ith ultrav~let light for 1 hour. The reaction mixture was poured into 2a ml Of cold 5% sodium bicarbonate and st~rred ~or 30 minutes. Ethyl acetate was added and the pH of the aqueous phase was adjusted to 7Ø The layers were separated, and the aqueous phase was further extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried Q~gSO41 and evaporated n vacuo. The residue was dried under high vacuum for 30 minutes. This a~forded 7Q mg of a yellaw oil which was shown by NMR spectroscopy to contain the title compound, together with some impurities contain-ing n-butyl groups.

-1~5Z9131 6,6-DIbromopent~c~llani~c Ac~d 1 r l-pl~x~de To a solution o~ 3S~ ~ o~ 6,~d~fixomopenicill~nic ac;d in 30 ml o~ d~chloro~eth~ne ~s added 38~ ~ o~ 3~
chloroperfienzoic ac~d at a-s~c, T~ reaction ml~xture is stirred at Q-5~C. ~or 30 m~nutes and t~en at 25C for 24 hours. Th~ ~Iltered reaction m~xture is evaporated in vacuo to give the title compound.

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l~SZ~l EXAM~LE 32 Benzyl 6!6-D~b:,romopen~cillanate l,l~D~Qx~de A ml~xture of la.a g. o~ 6~6:-d~romQpenicillanic acid l,l-di~xide, 2,15 g. o~ sod~um ~carbonate, 3.~6 ml.
of benzyl bromIde and lQQ ~1. of N~N~dimethylformami~de ~a,s stixred at amb~ent tem,perature o~ern~ght. Most af th~ solvent was removed by evaporation in vacuo and the residue ~as partitiQned between ethyl acetate and water. The organic layer was removed, washed ~ith lN
1o hydrochloric acid and w~th satuxated sodium chloride, and dried ~Na2S041, Evaporation 'n vacuo a~forded 11.55 g. o~ the title compound. Th~ NMR spectrum Cin CDC13) showed absorptions at 7.4Q ~s, 5Hl, 5.3Q C~, 2~, 4.95 (s, lH), 4.55 Cs, lH), 1.5Q (s, 3~1 and 1.2Q
(s, 3H) ppm.

Penicillanic Ac;d l,l-Dioxide To a solution of 2.3 g. of benzyl 6,6-dibromopeni-cillanate l,l-dioxide in 50 ml. of tetrahydrofuran was added a solution of 0.699 g. of sodium bicarbonate in 50 ml. of water, followed by 2.0 g. of 5% palladium-on-carbon. This mixture was then shaken under an atmosphere of hydrogen, at about 50 psig., for 7a m~nutes. The tetrahydrofuran was removed by eva,poration, and the residue was partitioned between eth~l acetate and water at pH 7.37. The aqueous layer was removed and fresh ~t~yl acetate was added. The p~ was lowered to 1,17 and the eth~l acetate ~as remo~ed and washed wIth saturated sod~um chlor~de sQlutxQn~ Eya,poratxQn in ~ ~ 30 vacuo ga~e 423 mg. o~ th~ t~tle product.

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. . . , . , li5;~:~81 ~44-EXA~LE 34 2,2,2-Tri:chloroeth~l 6,6-D~omo.peni~ci~ n~te l,l Dioxi~de Th~ t~.tle compound was prepared fxo~ 6',~.~d~.~xomQ-penic;~llanic acid l,l-~io.x~de. and 2,2~2-tx~chloroet~yl chloroformate, substantIall~ according to the procedure o~ Preparatton ~, The product was pur~.~ied ~y chroma-tography on silica gel. The NMR spectrum o~ the product (in CDC13~ showed absorptions at 4.85 ~m, 2~, 1.65 (s, 3H) and 1.45 (s, 3E~ pp~.

Pen;ci.llanic Acid l,l-Dioxide 2,2,.2-Trichloroethyl 6,6-di~romopenicillanate 1,1-dioxide was reduced ~ith zinc dust ;n a mixture of glacial acetic acid and tetrahydrofuran, su~stantially according to Example 14A. The yield was 27%.

1-CEthoxycarbonyloxy)ethyl 6,6-Dibromopenicillanate l,l-Dioxide A mixture of 2.26 g. of 6,6-dibromopenicillanic acid l,l-dioxide, 1.02 ml. of l-~ethoxycarbonyloxy]-ethyl chloride, 1.32 ml. of diisopropylethylamine and 10 ml. of N,N-dimethylformamide was stirred at room temperature for 28 hours. The reaction mixture was diluted with 100 ml. of ethyl acetate, and then it was washed se~uent~ally with ~ater, dilute hydrochloric acid, saturated sodium bicar~onate and satuxated s~dium chloride. T~e dr~ed eth~l acetate solut~on was evaporated ln vacuo to gi~e 1.50 ~. o~ an oil which.was cHroma-tographed on s~l~ca ~el. This.~af~o~ded 353 m~. of t~e . 3Q title compound contam~nated w~th.$ome l-(Qthox~car~onyl-oxy~ethyl 6-bxo~openic llanate..

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l-(Ethoxycarbon~loxyleth~l Pen~cillan~te l!l-D~ox~de A port~on (:2~0 m~l o~ the product o~ Exa~ple 36 was dissolve~ ~n lQ ml. o~ toluene. To thi~ was added a. 4 ml. o~ tri-n-~ut~ltin h~dr~de, followed ~y ~.164 g.
of azo~isiso~utyronitrile, and t~e mIxture was heated to 70-80 C. for 3.5 hours. The solvent was removed ~y evaporation in ~acuo, and the residue was dissolved in 25 ml. of acetonitr~le. Th acetonitrile solution was washed with hexane se~eral times, and then ~t was evaporated _ vacu~. The residue was dxssolved in ether, and the~ ether solut;on was washed wit~ 5%
potassium fluoride and followed ~y saturated sod~um chloride. The dried (Na2S~41 et~er solution was evaporated in ~acuo, and t~e residue was chroma-tographed on silica gel, to g~ve O.Q43 g. of the title product. The NMR spectrum (in CDC131 showed a~sorptions at 6.75 tml, 4.60 (~I, 4.30 (~), 4.15 Csl, 4.00 Cs~, 3.30 (d) and 1.75-1.00 (~1 ppm.

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PREPARAT~QN A
6-C~loro-6~i~dopenlc~11ani~c ~cid To 3.38 g~ o~ ;~odine monochIo~de ~n 3~ ml, o~
dichloromethane wPs added, with ~t~xr~ng~ at a-s~ c. ~
11.1 ml. of 2.5N sul~urIc acid, ~ollowed ~ 1.92 g. of sodium nitrite. At this point, 3.QQ g. o~ ~-amino-penicIllan;~c acid was added all at once, and stirring was continued or 30 minutes at Q-5~ C. To the reaction mixture was then added 22.8 ml. of 1~ sodium sulfite solution in portions, and the la~ers were separated.
The aqueous layer was washed wiith ~urther dichloromet~ane, and then all the organic phases ~ere washed w~th saturated sodium chloride. The dichloromethane solution was dried (Na2SO4~ and evaporated ~n vacuo giv;ng 3,48 g. o~ the title compound.
The above product was dissolved in 30 ml. o~ tetra-hydrofuran, and then 30 ml. of water were added. The pH
was adjusted to 6.8 with dilute sodium hydroxide and the tetrahydrofuran was removed in vacuo. The remaining aqueous phase was freeze-dried and the residue was washed with diethyl ether. This a~forded 3.67 g. o~ the title compound as its sodium salt.
PREPARATION B
6-~eta-Chloropenicillanic Acid A 2.95-g. sample o~ sodium 6-chloro-6~iodopenicil-lanic acid was convexted to the free ac~d, and t~en it was disso:l~ed ~n 12S ml. of benzene unde_ n~trogen~ To the solut;~on was-added l.Q8 ml. o~ tr~et~ylamine, and the mixture was cooled to a-s~ c~ To the cooled mixture was then added Q.~77 ml. ~f trimet~ylsil~l cnloride, and ; the reaction mixture was st~xred at ~-5~ C, for 5 minutes, at 25 C. ~or 6Q minutes and at sa~ c. ~or 3Q minutes.
The~reaction mixture ~as cooled tQ 25 C~ and the ~, `
:
, triethylamine hydrochlaride ~s~ ~e~oyed h~ filt~at~on.
To the filtrate was added 15 ~ge Qf azofi~s;~obutyron~trile, followad ~ 2.~2 ml. o~ t~-n~utyltrn ~ydride. The mixture was tnen irrad~ated w~th ultxa~olet lIgnt ~r 15 minutes with cooling to maInta~n at temperature of ca. 20 C. The solvent was then rem~ved ~y evaporation in vacuo, and the res~due was dissolved In a 1~1 mixture of tetrah~dro~uran-water. The pH was adjusted to 7.0 and the tetrahydro~uran wa~ removed By e~aporat;~on in vacuo. The aqueous phase was washed w~tn ether, and then an equal volume of ethyl acetate was added. The p~
was adjusted to 1.8 and the ethyl acetate layer was removed~ T~e aqueous phase was extracted with further ethyl acetate, and then the com~ned ethyl acetate solutions were dried and evaporated in acuo. This afforded 980 mg. of 6-beta-chlorpenicillanic acid.
The above product was dissol~ed in tetrahydrofuran, and an equal volume of water was added. The p~ was adjusted to 6.8, and the tetrahydrofuran was removed ~y evaporation 1n vacuo. The aqueous phase remaining was freeze-dried to give 850 mg. of sodium 6-beta-chloro-penicillanate. The NMR spectrum (D201 showed absorption at 5.70 (d, lH, J = 4Hz~, 5.50 Cd, lH, J = 4~z), 4.36 (s, lHl, 1.6Q (:s, 3Hl and 1~53 Ls, 3Hl ppm.
PREPARAT}~N C
6-beta-Bromopen;cillanic Acid A m~xture o~ 5.~ g~ of 6,6~dibromopenicIllanic acid, 1.54 ml. of tr~ethylamine and lQQ ml. o~ ~enzene ~as st~rred under n~trogen until a ~Qluti~n was o~ta~ned.
~he solution was cooled to a-5q C~, and 1~78 ml. of tr~ethyls~lyl cnIo~ide ~as add~d. The ~eaction m;xture was stirred at ~-S~ C, ~Q~ 2--3 mi~nutes, and then at 50~ C.
for 35 m~nutes. The cooled react~on mixture was filtered and t~fi}trate was~ cooled to a-5~ c. A small quantity ,, -, .
: :

~lSZ~
-48~

of azobisisobutyronitxile was, ~dded ~ollo~ed ~y~ 3.68 ml.
of tri~ utylti:n ~yd~de. The reactr~n ~lask was irxadia,ted ~ith ultra,~iplet light ~or l5 m~nutes~ and t~en the react~on was sti~rred at ca,~ 25~ C. for 1.75 hours.
The reaction mi,xture was irrad~,ated a,ga~n f~r 15 minutes and t~en stirring was continued 2.5 hours. At t~is point a further s~all quantity~o~ azo~isiso~utyronitrile was added, followed by ~.6 ml. o~ tri-n-butyltin hydride (Q.6 ml,),, added and th~ m~xture wa~ again irradIated for 30 minutes. The solvent w~s then removed by evapora-tion in ~acuo, and to the residue wa,s added 5% sodium ~icarbonate solution and d~eth~l ether. The two-phase system was s~aken vigorously ~or lQ minutes and then the pH was adjusted to 2.0,. Th~ ether layer was removed, dried and evaporated in vacuo to gi~e 2.33 g. of an oil.
The oil was converted into a sodium salt by adding water containing 1 equivalent of sodium bicarbonate foll~ed by freeze drying the solution thus obtained. The afforded sodium 6-beta-bromopenicillanate, contaminated with a small amount o~ the alpha-isomer.
The sodium salt was purified by chromotography on Sephadex LH-20, com~ined with some further material of the same quality and re-chromatographed. The NMR spectrum (D2O~ of the product thus obtained showed absorptions at 5.56 (s, 2H1, 4.25 Cs, lH), 1.60 C5, 3Hl and 1.5Q ~, 3H) ppm.
REPARAT~QN D
6-~eta-~od~penic~llan~c ~c~d Th~ tl~tle compound is~prepared b~ reduct;~on of 6,6-diiodopen~c;illa,nic acid, ~it~ tri-n-~ut~ltin ~ydr~de, according t~ the procedure o~ P~eparat~on ~.

,: :

:~:

.
.. :
`

`` 1152981 -49~

PRE~ARAT~QN E
Pi,~aloylo~ymeth~l 6,~a,1~a,~Bx:omopen~c~llan~te To a solut~on o~ 28~ ~. o~ 6~a,1p~ romopenicil-lanic aci,d in 2 ml. o~ ~,N~di,met~ a~m~mi~de ~s added 260 mg. o~ di~sopropylethylamIne ~ollowed ~y 155 mg. o~
chloromethyl p~alate and 15 mg. o~ sodium iodide. The react~on mixture is s*~rred at room temperature ~or 24 hours, and then it ~s d;luted with eth~l acetate and water. The pH ~s ad~usted to 7.5,,and then the ethyl acetate layer IS separated and ,washed three times with water and once with satu~ated sodiu~ chlor~de solution.
The ethyl acetate solut~on ts then drt,ed using anhydrous sodium sulfate; and e~aporated in vacuo to gi~e t~e title compound.
PRE2ARAT~ON ~
Reaction o~ the appropriate 6-halopen~cillan;c acid with 3-phthalidyl chloride, 4-crotonolactonyl chloride, gamma-butyrolacton-4-yl chloride or t~e requisite alkanoyloxymethyl chloride, l-~alkanoyloxylethyl chloride, l-methyl-l-(alkanoyloxy~ethyl chloride, alXoxycarbonyl-oxymethyl chloride, l-ralkoxycarbonyloxy~ethyl chloride or l-methyl-l-(alkoxycarbonyloxylethyl chloride, according to the procedure of Preparation E, affords the ~ollowing compounds;
3-phthalidyl 6-alpha-chlQropenicillanate, 4-crotonolactonyl 6-beta~chlorope~icillanate, .
gam,ma-but~rolacton-4-yl 6-a,lpha-~r~openicillanate, acetoxymet~yl 6-~eta-~romopenicillana,te, pi~aloylo~ym,eth~l 6-~eta-~romQpen~c~llan~te, h~xanoyloxymet~y~l ~-alp~a'-~Qdo~en~c~llan~te, ace,toxy~thyl 6-~,eta-~odapen2cillanate,~
l-GIsoliutyryl y ~et~y;l ~-alpha,.-chl'QrQpen.ic.illanate~
l-met~ tacetoxylethyl 6-~eta-c~loropen cillanate, l-methyl~ xano~loxyleth~l ~-alp~a-~romopenicillanate, ~ 3S metho~ycar~onyloxy~meth~l 6-alpha-~romopen;~c~llanate, :, :

.

1152~8~

propoxycarbonyloxymethyl ~-het~;~rQ~openicill~n~te~
l-(ethoxyca,rban~loxy~eth~l 6~a,1pha,;~xomopen~c~11anat~, l-butoxyca,r~onyloxylethyl 6-alpha-~odopen~c~llanate, l-meth~l-l-('met~oxycar~on~loxyl,eth~l 6-~eta-iod~penicil~
lanate,,and l-methyl-l-(;sopropoxycar~onylox~eth~l 6ralpha-chloro-penicillanates, respectivel~.
PREP~RATI,ON G
lQ 6,6`~DiiodQpenic~llan~c Acid ~ m~xture of 15~23 g. of iodine, lQ ml. o~ 2.5N
sulfuric acid, 2.76 g. o~ sod~um nitr;te and 75 ml. o~
dichloromethane was stirred at 5 C,, and 4~32 g. of 6 aminopenicillan;c acid were added over a period of 15 minutes. Stirring was continued at 5-lQ C. for 45 minutes after the addition was complete, and then 100 ml. of 10~ sodium bisul~ite wa,s added dropwise. The layers were separated, and the aqueous layer was further extracted with dichloromethane. The combined dichloro-methane layers were washed with brine, dried ~MgS041 andevaporated in ~acuo. T~is afforded 1.4 g. of the title compound, contaminated with some 6-iodopenic;llanic acid. The product had a melting point of 58-64 C. The NNR spectrum CCDC131 showed a~sorptions at 5,77 Cs, lH~, 4.60 (s, 1~1, 1.71 C~, 3H), and 1.54 Cs, 3H~ ppm.

;, ~5Z~

PREPAR~TI~N H
Pivaloylo~ymet~yl 6-alpha-BxQmo~en~c~ n~te To a stirred mixture a~ 11.2 ~. of ~al~ha~
bromopenic~llan~c acid, 3.7 g. o~ ~od~u~ ~icar~onate and 44 ml. o~ N,N~d~meth~l~ormamide was added 6.16 g. of chloro~et~yl p;valate, dropwise, dux~ng 5 m~nutes ! at ambient temperature. St~rring ~as cQntinued ~or 66 hours and then t~e react~on mixture was diluted with lQQ ml.
of ethyl acetate and 100 ml. of w~ter. T~e layers were separated, and the ethyl acetate layer was washed sequentially w;th water, saturated sodium c~loride, saturated sodium ~;car~onate, water and saturated sod~um chloride. The decolorized ethyl acetate solution was dried ~MgSO4J and evaporated to dryness in vacuo. Th~s afforded 12.8 g. (:80% y~eld~ of the t;tle compound.
P~EPARATI~N I
Benzyl 6-alpha-Bromopenicillanate The title compound was prepared by esterification of 6-alpha-bromopenicillanic acid ~ith benzyl bromide, substantially according to the procedure of Preparation H
~ield 83%). The NMR spectrum ~in CDC13J showed absorp-tions at 7.35 (s, 5H), 5.35 (m, lH), 5.15 Cs, 2H], 4.70 (m, lH), 4.60 (s, lH), 1.55 ~s, 3H) and 1.35 Cs, 3H~ ppm.

'.

, . .
.:...... .

1~5~6~

PREpARAT~QN J
2,2,2-Tr~chlQ~oeth~l Penicillan~te To a s;tirred solution Qf 11~2 g~ ~f ~-alpha-~romopenicillanic ac~d in 5Q ml~ o~ tetrahydxo~uran, at QR C, ~ was added 3.48 ~. o~ p~xidine o~er a one-minute period. To th~ hazy solution so o~tained was added, oYer a lQ minute period, 8.47 g. o~ 2,2,2-~ri-chloroeth~l chloroformate, maintaining t~e temperature between 0 and 2~ C, Stirring was continued for lQ 30 minutes, and then the coolin~ bath was removed~
Stirring was continued at am~ient temperature overnight.
The reaction mixture was then waxmed to 35 C. for five minutes and then it was ~lltered. The filtrate was evaporated and the residue was dissol~ed In lOQ ml.
Of ethyl acetate. ~he ethyl acetate solution was washed sequentially w;th saturated sodium bicarbonate, water and saturated sodium chlorIde. The ethyl acetate solution was then decolorized, and dried, and then it was concentrated to small volume. To the resulting mixture was added lO0 ml. of hexane, and the solids were removed by filtration, giving 10.5 g. of the title compound, m.p. 105-llQ C. The NMR spectrum Cin CDC132 showed absorptions at 5.50 Cd, l~), 4.q5 Cd, lH~, 4.90 Cs, 2X), 4.65 Cs, lH~ 1.7Q Cs, 3H~ and l,55 Cs, 3X~ ppm.

' , :

; ., ~152~

~53~

PREP.ARATIQN K
6,6-Di:~romopenicill~nic Aci~d To 5QQ. ~1 of dic~lo~omet~ane coaled.tQ 5QC
was added 11~.9~ o~ ~rom;~ne, 2QQ. ml of 2.5N sulfurtc acid and 34.5g o~ sod~.um nitr.~.te. To this s~t~rred mixture was t~n added 54.Qg o~ 6-am~nopen~cillanic acid, portionwise o~er 3a m~nute.s, with the temperature maintained from 4 to lOQC~ ~t~rring was continued for 3Q minutes at 5~C, and then 410 ml of a l.QM
solution of sodium ~isulf~te was added dropw~se at 5 to lO~C during 2Q minutes. The layexs were separated and the aqueous layer was extracted tw~ce w;th 15Q
ml of dichloromethane. T~e original dichloromethane layer was combined wIth t~e two extracts to give a solution of 6,6-dibromopenicillanic acid. Thi.s solution was used directly in Example 17.
PREPARATION L
6-ChlGro-6-iodopenicillanic Acid To 100 ml of dichloromethane cooled to 3C
was added 4.87g of iodine chloride, 10 ml of 2.5N
sulfuric acid and 2.76g of sodium nitrite. To this stirred mixture was then added 4.32g o~ 6-amino-- penicillanic acid portionwise during a 15 m~nute : period. Stirring was continued for 2Q minutes at Q -25. 5C, and then lQQ ml of lQ% sodium bisul~ite solution was added drop~se at ca 4QC. ~tirring was continued ~or 5 m;~nutes and then the layers were separated.
:Thc aqueaus layer was extracted ~;~th.dicnloromethane '' ' :
' ~.

~lS2g~1 -54~
(2 x 50 ml) and the comblned dichlQromethane ~oluti~ns were washed with brIne, d~Led (~SQ4~ and eyapoxated in Vacuo to g~e the title compound a~ a tan solid, mp 148-152QC. The NMR spectX~m Q~ the product (:CDC13J showed absorptiQns at 5.4Q ~,lH~ 4.56 (s,lH), 1.67 Cs,3EI and 1,50 (~,3E)ppm. The IR
spectrum ~KBr d~scI s~owed a~sorptions at 178Q and 1715 cml.
PgEPARATION ~
6-Bromo-6-iodopenic;llanic Ac;~d To lQ0 ml o~ dichlQromethane, cooled to 5C, was added lQ ml of 2.5N sulfur~c acid, 6.21g o~
Iodine brom~de and 2.76g o~ sodium n~trite~ To this mixture was added, w:ith v;~gorous stirrIng, at Q -5C, over 15 minutes, 4.32g o~ 6-aminopenLcillanic acid. Stirring was continued for a $urther 20 minutes at 0 - 5C, and then lQ0 ml of 10% sodium bisulfite was added dropwise between Q and 10C. At this point, the layers were separated and the aqueous layer was extracted with dichloromethane C3 x 50 ml). The combined dichloromethane layers were washed with brine, dried (MgSO41 and evaporated in vacuo.
The residue was dried under high ~acuum ~or 30 minutes to give 6.Qg (72~ yield) o~ the title compound mp 144-147C. The NMR spectrum ~CDC13~ showed absorptions at 5.5Q (s,lHl! 4.53 (s,lH~, 1.7Q Cst3H~
and 1.53 (s,3Hlppm. The ~R spectrum ~Br d~scl showed absorptions at 1785 and 171Q cml. T~e mass s~ectrum s~owed a prom~nent ~on at m/e ~ 4Q6.

:
~:

.

~152~81 -55~

,pREPARAT~ON N
6-CWoro-6:~fix.QmQpen~cI,llanl':c Ac~d 6~Chloro-~-~romopeni~c~llanic a,cxd is prepaxed from 6-ami,nopen~c~llan~c ac~d ~ia diazat-zation followed ~ reaction with ~rom~ne chloride,according to the proc~duxe o~ Pr~Paxat~on M.
~REPARA,T~N O
Pivaloylo~ymethy~l 6,6-d.;~.~xo.mopenicillanate To a stirred solution o~ 3.5~g o~ 6~6-la di~romopenic~llanic acid in 2Q ml o~ N,N~dimeth~l-~ormamide is added 1.3Qg o~ di~sopxQp~lethylamin~
follo~ed ~y 1.50g o~ chlQromethyl p~valate at ca 0C. The reaction m~xture ~,s stirred at ca aoc for 30 minutes and then at room temperature for 24 hours. The reaction mixture ~s then dtluted wit~
ethyl acetate and water and the pH o~ t~e aqueous phase is adjusted to 7.5. The ethyl acetate layer is separated and washed three times with water and once with saturated sodium chloride solution. The ethyl acetate solution is then dried, using anhydrous sodium sul~ate, and evaporated in ~acuo to give the title compound.

. :~

' `

, .

.. . . .

., . . ~

~15298~

PREPARATION ~
Rea.ction o~ the app~oprI~te 6,6:-dihalQpeni-cillanic acid w~th.'3-pht~lidyl chloxide, 4.crotonlac-tonly chloride, gamma.~butyrolacti~on-4.yl c~Ioride. or the re~uisite alkanoyloxy~ethyl chloxide, l_Calkany-loxylethyl chIoride, l-methyl-l-(alkanoyloxyleth~l chloride, alkoxycarbony~loxy~ethyl chloxide, l-Cal~oxy-carbonyloxy~lethyl chlor;~de or l-methyl-l~C~lk.ony-carbonyloxy)ethyl chloride, according to the procedure of Preparation 0, afford~ the ~Qll~ing compounds;
3-phthalidyl 6,6-d~romopenicillanate, 4-crotonola.ctonyl 6,chloro-6~iodopenicillanate, y-butyrolactonyl 6-bromo-6_iodopenicillanate, acetoxymethyl 6-chloro-6-bromopenicillanate, pivaloyoxymethyl 6-chloro-6~iodopenicillana'te, hexanoyloxymethyl 6,6-di~romopenicillanate, : l-(acetoxylethy~ 6,6-di~romopenicillanate, isobutyryloxy~eth~l 6~brQmo-6-~odopenicillante, l-met~yl-l-(:ace.toxyJeth~l 6~6-dihromopenicillanate~

2Q l-methyl-l-n~xanoyloxy~eth~l ~.c~loro-6-bromopeni.
cillante, methoxycarbonyloxymet~yl 6',6-dibromopenicillanate, ~; propoxycar~onyloxymethyl 6'-chloro-6'-~odopenicillanate, ., .;
.
.
.. .

29E~31 -57~

l-(ethoxycarbonyloxy~ethy~l 6,6-di~omopen~c~ nate, 1- ~utoxycar~ony~loxy~ethyl 6.~rom~6:-20dopen~c~11anate, l-met~yl~ nethoxycar~Qny~loxyl~th~l 6,~d~romo-penicillanate and l-methyl-l-(~isopropoxy~car~onyloxyI~th~l 6,6 di~romo-penicillanate.

~ ~:

:~: : . , : :

:

.

Claims (5)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula ---(I) or a pharmaceutically-acceptable base salt thereof, wherein R1 is selected from the group consisting of hydrogen and ester-forming residues readily hydrolyzable in vivo, which comprises the steps of:
(a) contacting a compound of the formula ---(II) or a base salt thereof with a reagent selected from the group consisting of alkali metal permanganates, alkaline earth metal permanganates and organic peroxy-carboxylic acids, to give a compound of the formula ---(III) or a base salt thereof, wherein X and Y are each selected from the group consisting of chloro, bromo and iodo, with the proviso that when X and Y are both the same, they must both be, bromo; and (b) dehalogenating the product of step (a).
2. The process according to claim 1, characterized in that step (b) is carried out by catalytic hydro-genolysis.
3. The process according to claim 2, characterized in that said catalytic hydrogenolysis is carried out in an inert solvent, in the presence of 0.01 to 2.5 weight-percent of a hydrogenolysis catalyst, at a temperature in the range from 0 to 60° C., and at a pH in the range from 4 to 9.
4. The process according to claim 3, characterized in that R1 is hydrogen.
5. The process according to any of claims 2 to 4, characterized in that X and Y are both bromo.
CA000346954A 1979-03-05 1980-03-04 Process and intermediates for penicillanic acid 1,1-dioxide and esters thereof Expired CA1152981A (en)

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US17,808 1979-03-05

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Country Status (6)

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BE (1) BE882028A (en)
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GT (1) GT198062836A (en)
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ZA (1) ZA80646B (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN159362B (en) * 1981-03-23 1987-05-09 Pfizer
US4393001A (en) 1981-03-23 1983-07-12 Pfizer Inc. Intermediates for production of 1,1-dioxopenicillanoyloxymethyl 6-(2-amino-2-phenylacetamido)penicillanates
US4419284A (en) * 1981-03-23 1983-12-06 Pfizer Inc. Preparation of halomethyl esters (and related esters) of penicillanic acid 1,1-dioxide
JPS62249988A (en) * 1986-04-22 1987-10-30 Taiho Yakuhin Kogyo Kk Production of 2beta-halogenomethyl-2alpha-methylpenam-3alpha-carboxylic acid derivative
US4835674A (en) * 1986-07-28 1989-05-30 Bull Hn Information Systems Inc. Computer network system for multiple processing elements

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4203992A (en) * 1978-12-11 1980-05-20 E. R. Squibb & Sons, Inc. β-Bromopenicillanic acid sulfone
JPS5598186A (en) * 1979-01-10 1980-07-25 Beecham Group Ltd Manufacture of penicillin derivative

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